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Photocatalytic Hydroaminoalkylation of Styrenes with Unprotected Primary Alkylamines
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Journal of the American Chemical Society

Cite this: J. Am. Chem. Soc. 2021, 143, 39, 15936–15945
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https://doi.org/10.1021/jacs.1c07401
Published September 20, 2021

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Abstract

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Catalytic, intermolecular hydroaminoalkylation (HAA) of styrenes provides a powerful disconnection for pharmacologically relevant γ-arylamines, but current methods cannot utilize unprotected primary alkylamines as feedstocks. Metal-catalyzed HAA protocols are also highly sensitive to α-substitution on the amine partner, and no catalytic solutions exist for α-tertiary γ-arylamine synthesis via this approach. We report a solution to these problems using organophotoredox catalysis, enabling a direct, modular, and sustainable preparation of α-(di)substituted γ-arylamines, including challenging electron-neutral and moderately electron-rich aryl groups. A broad range of functionalities are tolerated, and the reactions can be run on multigram scale in continuous flow. The method is applied to a concise, protecting-group-free synthesis of the blockbuster drug Fingolimod, as well as a phosphonate mimic of its in vivo active form (by iterative α-C–H functionalization of ethanolamine). The reaction can also be sequenced with an intramolecular N-arylation to provide a general and modular access to valuable (spirocyclic) 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydronaphthyridines. Mechanistic and kinetic studies support an irreversible hydrogen atom transfer activation of the alkylamine by the azidyl radical and some contribution from a radical chain. The reaction is photon-limited and exhibits a zero-order dependence on amine, azide, and photocatalyst, with a first-order dependence on styrene.

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Introduction

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Aliphatic amines and (semi)saturated azacycles are privileged motifs in pharmaceuticals, agrochemicals, biological probes, and other functional molecules, (1) and the development of more efficient methods for their synthesis is a research priority. (2) Perhaps the most attractive and atom-economical approach for the construction of α-alkylated amines is the net insertion of an alkene into an amine α-C–H bond, often termed a hydroaminoalkylation (HAA) reaction. (3) For secondary (4) and tertiary (5) amines, the catalytic HAA of non-electrophilic (6) alkenes has been dominated by early transition-metal-based catalysts. These reactions are typically sensitive to the substitution α to nitrogen, with the majority of reports focusing on N-methyl group functionalization, and linear selectivity being a particular challenge. (4e) Linear-selective alkene HAAs with non-electrophilic alkenes are more common for late transition metal catalysis, (7) but there is a need for specially tailored directing groups on the amine nitrogen. A different strategy altogether for alkene HAA deploys nucleophilic α-amino radicals generated via photoredox catalysis, (8) but this approach is typically limited to suitably electrophilic alkenes such as acrylates or vinylpyridines. (3b,8,9) For example, we recently reported a photoredox-catalyzed formation of γ-lactams 3 from primary alkylamines 1 and acrylates 2, (9d) and Rovis, Schoenebeck, and co-workers developed a similar process (9i) based on in situN-protection of the amine with CO2 (Figure 1A). Despite the above successes, the HAA of electronically unbiased styrenes with primary alkylamines lacks a general and practical solution, (10) although styrene HAA reactions have recently been developed with tertiary (11a,b) and (protected) secondary (11c) amines. With primary amines, the only reported intermolecular examples have utilized 2-pyridyl directing groups on the amine nitrogen (12) (with Ru or Ir catalysts) or N-silyl protecting groups at high temperature (>140 °C with Ti or Zr catalysts). (4d,13) The use of unprotected primary alkylamines in catalytic HAA with non-electrophilic alkenes is currently limited to simple, unfunctionalized examples in the intramolecular mode (110–145 °C, 5–20 mol% Ti catalyst). (14) Given the importance of γ-arylamines and their occurrence in several clinically approved drugs [e.g., Fingolimod 4, Elayta 5 (Figure 1B), Cinacalcet, Fendiline, Pheniramine], a generally applicable catalytic HAA of simple styrenes with unprotected primary alkylamines would constitute a significant advance. We report a solution to this problem using visible-light photoredox catalysis in combination with hydrogen atom transfer (HAT) catalysis. (15) This enables a direct and modular synthesis of pharmacologically relevant γ-arylamines 7, including Fingolimod 4 and analogues thereof. Further application to the expedient synthesis of (spirocyclic) 1,2,3,4-tetrahydroquinolines 8 and 1,2,3,4-tetrahydronaphthyridines 9 is also described (Figure 1C).

Figure 1

Figure 1. (A) Prior art for catalytic γ-lactam synthesis from primary alkylamines. (B) Importance of γ-arylamines. (C) This work.

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Results and Discussion

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Reaction Optimization

The generation of α-amino radicals directly from primary alkylamines 1 by single-electron oxidation followed by deprotonation is complicated by the high oxidation potential of the nitrogen lone pair (Ep/2red = +1.53 V vs SCE in MeCN for cyclohexylamine (9d)), (16) and the possibility for aminium radicals to form N-centered aminyl radicals by N–H cleavage. (17) We recently found that azide ion (N3–) can serve as an effective catalytic mediator in the photoredox-catalyzed formation of α-amino radicals from primary alkylamines. (9d) Chemoselective oxidation of azide ion (Ep/2red = +0.87 V vs SCE in MeCN (9d)) by the excited photocatalyst 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN) (18) serves to generate the highly electrophilic azidyl radical (N3•), that can participate in a polarity-matched (19) HAT process with the weak α-C–H bond of a primary alkylamine (BDE = 89–91 ± 2 kcal mol–1). (20) The resultant α-amino radicals are highly nucleophilic and they engage successfully with electrophilic alkenes such as acrylates (9d) and vinyl phosphonates. (9b) To determine if non-electrophilic alkenes could be accommodated as reaction partners, we irradiated p-methylstyrene 6a with cyclohexylamine 1a in MeCN at 425 nm, using 4CzIPN as the photocatalyst and tetrabutylammonium azide (Bu4N+N3–) 10 as the HAT catalyst (Figure 2). Only a very low level of reactivity was found, with the HAA product 7aa formed in 17% NMR yield (entry 1). We reasoned that photocatalyst turnover may be the issue, given that the reduction of a putative benzylic radical by the reduced photocatalyst (PC–•) should be far less facile than with an electrophilic alkene acceptor [i.e., E1/2red = −1.43 V vs SCE for •CH2Ph/–CH2Ph in MeCN, (21) compared to E1/2red = −0.63 V vs SCE for •CH2CO2Et/–CH2CO2Et in MeCN (22)]. On that basis, we assayed photocatalysts known to be more strongly reducing in their reduced form. 4DPAIPN gave enhanced reactivity (entry 2), but the most promising result was obtained with 3DPA2FBN [E1/2 (PC/PC–•) = −1.92 V vs SCE in CH2Cl2 (23)] (entry 3). Further experimentation showed that doubling the loading of azide ion to 20 mol% enhanced the yield (entry 4), which may be a consequence of the reduced excited state lifetime of 3DPA2FBN (kp–1 = 4.2 ns) relative to 4CzIPN (kp–1 = 12.7 ns) (i.e., competition of bimolecular quenching by N3– with unimolecular fluorescence from 1PC*). (23) After switching the alkene partner to styrene 6b for further optimization, giving a somewhat reduced yield (entry 5), we changed the reaction solvent to dimethylformamide (DMF) from acetonitrile (MeCN) (entry 6). Finally, we surveyed a series of other commonly used HAT catalysts (11–15), to gauge whether or not the use of azide ion 10 conferred unique reactivity. Although tri(isopropyl)silanethiolate 11 (entry 7) did give appreciable turnover (56% NMR yield), it significantly underperformed azide ion 10. Bromide ion 12, (24) thiobenzoate 13, (25) chloride ion 14, (26) and quinuclidine 15 (9f,i) all gave negligible reactivity (entries 8–11). Control experiments verified that 3DPA2FBN, visible light, and azide catalyst are all necessary components for successful HAA.

Figure 2

Figure 2. Yields measured by 1H NMR against 1,3,5-trimethoxybenzene as an internal standard. Reference for redox potentials of photocatalysts. (23) References for oxidation potentials of HAT catalysts: 10, ref (9d); 11, ref (27); 12, ref (16); 13, ref (25); 14, ref (16); and 15, ref (9i).

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Amine Scope

With optimized conditions in hand, we next sought to determine the generality of the HAA reaction with respect to the alkylamine component 1 (Figure 3). 2-Bromostyrene 6c was selected as the representative alkene partner, not because this confers the highest yields (i.e., electron-neutral styrenes 6a or 6b are superior), but because the bromine atom provides a useful synthetic handle for further elaboration (vide infra). The good performance of simple α,α-dialkylated amines such as cyclohexylamine 1a and isopropylamine 1b highlights a particular strength of this strategy relative to state-of-the-art metal-catalyzed HAAs: the insensitivity of the reaction to steric encumbrance at the α-position of the alkylamine. Indeed, this process is one of the few catalytic transformations on record that gives direct access to unprotected α-tertiary primary amines by C–C bond formation at the α-position. (9b,d,28) Pleasingly, the reaction also proved efficient with α-monosubstituted amine 1c, with only 6% of α,α-dialkylation (with respect to 1c). Some other α-monosubstituted amines gave more substantial α,α-dialkylation, but this issue was remedied by employing a 3-fold excess of the amine 1. No reactivity with benzylamine 1d was observed, and this suggests that the addition step to the C═C bond may be problematic, due to the higher thermodynamic stability of the α-amino radical. (29) However, as evidenced by products 7ec and 7fc, the presence of benzylic C–H bonds on the alkylamine partner does not in itself pose a chemoselectivity issue, despite the fact that such C–H bonds are weaker than those α to the NH2 group (e.g., BDE = 85.4 ± 1.5 kcal mol–1 for PhCH2Me). (20) Given that the N3• radical is capable of hydrogen abstraction even from unactivated alkanes, the high selectivity here may arise from polarity-matching (19) of the electrophilic azidyl radical with the more “hydridic” C–H bond α to the alkylamine. A diastereoselective reaction with exo-norbornylamine 1g also proved possible, delivering product 7gc as a single diastereomer, consistent with the proclivity of norbornyl radicals to be intercepted on the exo face. Steric encumbrance at the β-carbon of the alkylamine does not adversely affect the reaction, as evidenced by the successful HAA using Rimantadine 1h—a marketed antiviral drug. The functional group compatibility of the reaction was next explored, including alkylamines bearing ether (1i,q), thioether (1j), carbamate (1k,l,s), acetal (1m), hydroxyl (1n,r), ester (1o), cyano (1p), and silyl (1t) groups. In all cases, the functionality was well accommodated and the selectivity for HAT α to the primary amine was very high, (30) even in the presence of other weak and relatively “hydridic” C–H bonds, such as those α to free alcohols or acetals (i.e., 1m,n,r). One of the most challenging amine substrates examined was 3-amino-N-Boc-azetidine 1l, which gave the α-alkylated product 7lc in 42% yield, returning 44% of unreacted amine 1l. A strengthening of the α-C–H bond by virtue of the ring strain in 1l is likely to be responsible for its lower reactivity. (9d) A variety of heteroaromatic motifs were also tolerated, including thiophene (1u), imidazole (1v), and pyridine (1w) rings. Protected analogues of dopamine (1x), tryptamine (1y), and Baclofen (1z) were also successfully engaged in the HAA protocol. Even the complex antiviral drug Oseltamivir (1aa) could be α-C–H alkylated at the unprotected amino group, albeit in low yield.

Figure 3

Figure 3. All reactions were carried out on a scale of 0.45 mmol. Isolated yields are reported. Notes: [a] 6% of inseparable, dialkylated product (wrt 1c). [b] With 3.0 equiv of amine. [c] With 1.0 equiv of amine. [d] The mass balance comprised a mixture of unidentified byproducts but no detectable starting materials. [e] 44% of unreacted amine 1l. [f] 46% of dialkylated product (wrt 1n). [g] 41% of dialkylated product (wrt 1s). [h] 54% of unreacted amine 1t and 6% styrene 6c. [i] 9% of dialkylated product (wrt 1u). [j] 9% of dialkylated product (wrt 1u). [k] Incomplete conversion to a complex mixture of products, which may include dialkylated material. [l] Isolated yield of Boc-protected 7zc (61:39 dr) plus 11% of the lactam derived from thermal lactamization of 7zc during workup. [m] 18% of dialkylated product (wrt 6c). [n] Incomplete conversion to a complex mixture of products. Boc = tert-butoxycarbonyl.

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Scale Up in Continuous Flow

To demonstrate the scalability of the HAA process, we next performed a gram-scale reaction between 4-amino-N-Boc-piperidine 1k and 2-bromostyrene 6c in continuous flow. (31) Using a Vapourtec R-series flow system equipped with a Uniqsis cold coil tubing module (5 mL) and a PhotoSyn HP LED photoreactor with a water-cooled 420 nm LED array (∼260 W radiant output power), a steady-state space-time yield (STY) of 625 mg h–1 for γ-arylamine 7kc was obtained (Figure 3B). For a run time of 149 min, this delivered 1.55 g of isolated 7kc, though a productivity of 6.25 g h–1 would be possible using the 50 mL reactor coil.

Styrene Scope

The generality of the HAA protocol with respect to the styrene partner was next determined (Figure 4). Both styrene itself (6b) and α-methylstyrene (6d) returned γ-arylamines 7ab and 7ad, respectively, in yields exceeding 90%, although trans-β-methylstyrene (6e) gave incomplete conversion to 7ae (i.e., 24% remaining 6e), which was isolated in 28% yield. A similar issue was encountered with the cis-configured alkene indene (6f), which delivered 7af in 38% yield. Notably, methyl cinnamate (6g) gave a HAA product derived from radical attack at the α-position of the cinnamate, contrary to the behavior of simple acrylates but congruent with other literature reports. (11b,c,32) Remarkably, the electron-rich acceptor p-methoxystyrene (6h) afforded the HAA product 7ah in 59% yield, (33) despite the pronounced polarity-mismatch of this reaction. Other electronically diverse para-substituents surveyed on the styrene partner included methyl (6a), fluoro (6i), bromo (6j), (pinacolato)boryl [pinB] (6k), trifluoromethyl (6l), and methyl ester (6m), with acceptable to excellent yields obtained in all cases. An electronic trend is difficult to identify, but it is clear that inclusion of strong +M (e.g., −OMe) or −M groups (e.g., −CF3) on the styrene partner does diminish the isolated yield. It should also be noted that a degree of styrene polymerization was suspected in some cases (i.e., insoluble precipitates formed when running earlier reactions in MeCN), and this may be operative to different extent with various styrenes. Although borylated product 7ak was generated cleanly and quantitatively by 1H NMR, difficulties in purification led us to oxidize this compound with H2O2 and isolate the corresponding phenol (in >99% yield over two steps). Doubly halogenated styrenes 6n and 6o also participated, but the latter substrate also produced 22% of a debrominated HAA side-product, significantly compromising the yield of 7ao (13%). This may arise from competitive attack of the electron-rich α-amino radical intermediate on the C–Br bond (activated by the adjacent chloro substituent) in an X atom transfer (XAT) step. (34) Heteroaromatic styrene analogues were also assessed, bearing pyridyl (6p), thiazolyl (6q), and pyrazinyl (6r) motifs in lieu of a benzenoid ring. Although the pyridyl ring was well tolerated, and the thiazolyl ring to a lesser extent, the vinylpyrazine 6r performed poorly, giving 22% of the HAA product 7ar. Competitive telomerization (9% of a 1:2 adduct) and reductive homocoupling of 6r (43% with respect to 6r) were identified as side reactions in the latter case. Finally, the use of 2-bromovinylpyridine (6s) was attempted, to provide a functional handle for further elaboration (vide infra). However, competitive XAT at the C–Br bond was again problematic, and 7as was obtained in 27% yield, alongside its debrominated analogue (∼1.5:1 ratio). Thankfully, this problem could be resolved by utilizing the 2-fluoro analogue 6t, which delivered the γ-pyridylamine 7at in 97% yield.

Figure 4

Figure 4. All reactions were carried out on a scale of 0.45 mmol. Isolated yields are reported. Notes: [a] Gave 40% NMR yield of 7ae along with 24% unreacted 6e and 6% of allylbenzene, plus other unidentified products. [b] Isolated as the phenol by oxidation the Bpin group with H2O2. [c] 22% of inseparable, debrominated product was also produced. [d] Yield given is for the N-Boc-protected derivative of 7ar, which proved easier to isolate. [e] 9% of a 1:2 telomer and 43% (wrt 6r) of reductive homocoupling product 1,4-di(pyrazin-2-yl)butane was also isolated. [f] The crude product mixture contained a 60:40 ratio of 7as to its debrominated analogue.

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Synthesis of Fingolimod

To showcase the utility of our method, we next sought to apply our HAA protocol to the synthesis of a blockbuster drug. Fingolimod (4), developed by Novartis, is a S1P1 receptor agonist used to treat relapsing-remitting multiple sclerosis, with worldwide sales of $3 billion in 2020. (35) It has also been recently identified as a promising lead for troponin-directed heart failure therapeutics. (36) Several concise synthetic routes to Fingolimod 4 have been developed over the past two decades, (37) but we reasoned that a HAA approach could raise the bar in terms of atom- and step-economy. Gratifyingly, the application of our optimized conditions to serinol 16 and 4-octylstyrene 17 (derived in 1 step from the commercial aldehyde) gave Fingolimod 4 in 43% isolated yield (Figure 5A). This is the shortest synthesis of Fingolimod on record, exhibiting 100% atom economy in the key step and with no recourse to any protecting groups. We anticipate that this operationally simple HAA procedure will find use in the synthesis of a diverse range of γ-arylamines as potential S1P1 receptor agonists. (38)

Figure 5

Figure 5. (A) Application to a protecting group-free synthesis of Fingolimod (4). (B) One-pot synthesis of a phosphonate mimic (21) of Fingolimod phosphate by tandem sequential α-C–H alkylation of ethanolamine (1r). Note: [a] 23% of the dialkylation product of 1r with 17 was also isolated. TMS = trimethylsilyl.

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We were also drawn to the possibility of synthesizing α-tertiary amines by tandem sequential α-C–H dialkylation of an amine with two different radicophiles. (9c) An obvious target to showcase this strategy was the phosphonic acid analogue 21 of Fingolimod phosphate (the active form of 4in vivo), which has been utilized as a nonhydrolyzable phosphate mimic in mechanism of action studies. (39) Starting from ethanolamine 1r, a photocatalytic α-C–H alkylation with 4-octylstyrene 17 followed by injection of vinyl phosphonate 19 into the reaction mixture and resubjection to irradiation gave α-tertiary amine 20 in 22% yield (over two steps, with respect to 1r), in addition to 23% of the dialkylation product of 1r with 17 (Figure 5B). A known phosphonate ester hydrolysis step would deliver target molecule 21 in only two synthetic operations. The previous synthetic route to 21 comprised nine steps from diethyl 2-aminomalonate, (39) so the power of this new disconnection strategy for α-tertiary amines is clear.

Synthesis of 1,2,3,4-Tetrahydroquinolines

Our HAA protocol can also serve as a key C–C bond-forming step for the synthesis of 1,2,3,4-tetrahydroquinolines (THQs) 8. (40) As partially saturated, benzo-fused N-heterocycles, THQs occupy a privileged position as core scaffolds in a host of natural and unnatural bioactives. (41) Of the ∼43 000 known small-molecule THQs featuring alkylation α to nitrogen at C(2), only a third are α,α-dialkylated (almost exclusively α,α-dimethyl), and only ∼1% are spirocyclic at C(2). (42) Given the explosion of interest in spirocycles in medicinal chemistry over the past two decades, (43) the rarity of spirocyclic THQs is somewhat surprising. Thus, a modular strategy to access C(2)-(di)alkylated (including spirocyclic) THQs that is relatively insensitive to the electronics of the benzenoid component could greatly expand the accessible chemical space in this area. This is of particular relevance to fragment-based drug discovery, (44) given that THQs exhibit multiple synthetically accessible growth vectors in three dimensions, (45) and α-alkylated THQs have already been reported as fragment hits. (46) By harnessing our HAA procedure to synthesize 2-bromo-substituted γ-arylamines 7-c/m (see Figures 3 and 4), a palladium-catalyzed, intramolecular N-arylation allows for an expedient and modular assembly of (spirocyclic) THQs 8 (Figure 6A). Alternatively, in the case of 2-fluoropyridine substrate 7at, a simple SNAr reaction under basic conditions enabled access to a spirocyclic 1,2,3,4-tetrahydronaphthyridine (THN) scaffold 9at (Figure 6B). THNs feature prominently as arginine mimics in αv integrin inhibitors (e.g., 23), (47) and the THN scaffold has also been deployed as a semi-saturated bioisostere of a quinoline, to enhance compound solubility (e.g., 24). (48)

Figure 6

Figure 6. (A) Modular synthesis of 1,2,3,4-tetrahydroquinolines (THQs). In all cases except for 8an, the remaining mass balance comprised unreacted starting material. Note: [a] Obtained as an inseparable mixture with 8ac (14%), the proto-dechlorinated analogue of 8an. (B) Modular synthesis of 1,2,3,4-tetrahydronaphthyridines (THNs).

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Proposed Catalytic Cycle and Mechanistic Analysis

Our proposed catalytic cycle for the HAA process is outlined in Figure 7A. Initial oxidation of azide ion (Ep/2red = +0.87 V vs SCE in MeCN (9d)) by the photoexcited 3DPA2FBN [E1/2 (PC*/PC–•) = +0.92 V vs SCE (23)] generates the azidyl radical, N3•. This reductive quenching step is supported by Stern–Volmer luminescence quenching experiments (Figure 7B). Subsequent HAT from the relatively weak α-C–H bond of the primary alkylamine (BDE = 89–91 ± 2 kcal mol–1) (20) occurs to give α-amino radical 25, (49) which undergoes addition to the styrene acceptor 6 to give a benzylic radical 26 [E1/2red = −1.43 V vs SCE for •CH2Ph/–CH2Ph in MeCN (21)]. Reduction of this radical to the corresponding carbanion 27 by the [3DPA2FBN]−• radical anion [E1/2 (PC/PC–•) = −1.92 V vs SCE in MeCN] is presumably followed by proton transfer from HN3 (pKa = 7.9 in DMSO) (50) to give the γ-arylamine product 7 and regenerate the azide ion. Alternatively, a chain process involving HAT from HN3 (BDE = 93 kcal mol–1) to the benzylic radical 26 (BDE = 85.4 ± 1.5 kcal mol–1 for PhCH2Me) (20) can be envisaged. (51) To probe the latter possibility, the reaction quantum yield (Φprod) was measured for the reaction of cyclohexylamine 1a with styrene 6b and found to be 0.31 (at 66% conversion to 7ab by NMR). (52) Given that quantum efficiencies for dual catalytic photoredox processes in which a cocatalyst is the quencher are typically very low (Φprod < 0.1), (9d,53) a value of 0.31 is suggestive of at least some contribution from an innate chain (with a photonically inefficient initiation step). The operation of a photoredox process in parallel with an innate chain thus cannot be excluded. (52) The reversibility of the HAT step between the alkylamine and N3• was next investigated. Using enantiopure amine (S)-1e, the reaction with styrene 6b was run to incomplete conversion (i.e., 78% of 1e remaining) and the unreacted 1e was recovered (Figure 7C). The enantiopurity of 1e was found to have suffered no erosion during catalytic turnover (i.e., still >99:1 er), proving that formation of α-amino radical 25 is irreversible under the conditions. To gain further insight into the reaction mechanism, a variable time normalization analysis (VTNA) kinetic study was also conducted. (54) The reaction of isopropylamine 1b with styrene 6b in DMF was run in continuous flow (see Supporting Information), using automated variation of residence times to construct the necessary concentration–time profiles (Figure 7D). The reaction displayed first order kinetics, with a first order dependence on styrene 6b and a zero order dependence on amine 1b, azide ion and photocatalyst (3DPA2FBN). This suggests that α-amino radical 25 addition to styrene 6 or, potentially, the photocatalyst regeneration step (PC–• + 26 → PC + 27) is turnover-limiting. (55,56) A zero-order dependence on photocatalyst is consistent with the reaction operating in a “photon-limited” regime, where the rate is controlled by the light intensity and not by the photocatalyst concentration. (57)

Figure 7

Figure 7. (A) Proposed catalytic cycle. (B) Stern–Volmer luminescence quenching. (C) Irreversibility of the HAT step. (D) Variable time normalization (VTNA) kinetic analysis using automated flow chemistry.

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Conclusion

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We have developed a metal-free, photoredox-catalyzed HAA of styrenes with unprotected primary alkylamines that provides direct access to γ-arylamines, including valuable α-tertiary derivatives. The protocol is executed under mild conditions, tolerates a wide variety of functional groups, and can be readily scaled in flow. We further illustrate the utility of this method in the shortest ever synthesis of the blockbuster drug Fingolimod, requiring no protecting groups. An iterative double α-C–H functionalization of the simple feedstock chemical ethanolamine is also showcased, to provide direct, one-pot access to a complex α-tertiary β-hydroxy amine (20) that previously required an eight-step synthesis. The application of this chemistry to the expedient synthesis of functionalized (and spirocyclic) 1,2,3,4-tetrahydroquinolines (THQs) and 1,2,3,4-tetrahydronaphthyridines (THNs) is also demonstrated, affording access to underexplored chemical space for drug discovery. Detailed mechanistic studies, including luminescence quenching and kinetic analyses, support a catalytic mechanism featuring reductive quenching of the organic photocatalyst by azide ion, to generate a highly reactive azidyl radical. This engages with the primary alkylamine in an irreversible HAT step to generate the key α-amino radical intermediate. The turnover-limiting step of the cycle is either radical addition to the styrene or regeneration of the photocatalyst, and a quantum yield measurement suggests some contribution from a radical chain process. In summary, we believe that the unique disconnection enabled by this new HAA protocol, together with its operational simplicity and sustainability, will help streamline the synthesis of complex alkylamines in both academia and industry. (58)

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.1c07401.

  • All experimental procedures and compound characterization (PDF)

Accession Codes

CCDC 2093033 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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Author Information

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  • Corresponding Author
  • Authors
    • Hannah E. Askey - Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
    • James D. Grayson - Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
    • Joshua D. Tibbetts - Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.;  Orcidhttps://orcid.org/0000-0002-1269-6573
    • Jacob C. Turner-Dore - Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
    • Jake M. Holmes - Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
    • Gabriele Kociok-Kohn - Materials and Chemical Characterisation Facility (MC2), University of Bath, Claverton Down, Bath BA2 7AY, U.K.;  Orcidhttps://orcid.org/0000-0002-7186-1399
    • Gail L. Wrigley - Oncology R&D, Research & Early Development, AstraZeneca, Darwin Building, 310, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work was supported by the Engineering and Physical Sciences Research Council (EP/S028595/1 and EP/R020752/1). A.J.C. thanks the Royal Society for a University Research Fellowship (UF150533), the University of Bath for a Ph.D. studentship (H.E.A.), the EPSRC and Syngenta for an iCASE PhD studentship (J.C.T.-D.), and AstraZeneca for generous financial support. The authors gratefully acknowledge the technical staff within Chemistry at the University of Bath for technical support and assistance in this work, including the Material and Chemical Characterisation Facility (MC2) (https://doi.org/10.15125/mx6j-3r54). We also acknowledge valuable discussions with Dr. Darren Stead at AstraZeneca and thank Freddy Sweeten for assistance with starting material synthesis.

References

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This article references 58 other publications.

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    (i) Ye, J.; Kalvet, I.; Schoenebeck, F.; Rovis, T. Direct α-alkylation of primary aliphatic amines enabled by CO2 and electrostatics. Nat. Chem. 2018, 10, 1037– 1041,  DOI: 10.1038/s41557-018-0085-9
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    9i
    Direct α-alkylation of primary aliphatic amines enabled by CO2 and electrostatics
    Ye, Juntao; Kalvet, Indrek; Schoenebeck, Franziska; Rovis, Tomislav
    Nature Chemistry (2018), 10 (10), 1037-1041CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)
    Primary aliph. amines are important building blocks in org. synthesis due to the presence of a synthetically versatile NH2 group. N-functionalization of primary amines is well established, but selective C-functionalization of unprotected primary amines remains challenging. Here, we report the use of CO2 as an activator for the direct transformation of abundant primary aliph. amines into valuable γ-lactams under photoredox and hydrogen atom transfer (HAT) catalysis. Exptl. and computational studies suggest that CO2 not only inhibits undesired N-alkylation of primary amines, but also promotes selective intermol. HAT by an electrostatically accelerated interaction between the in situ-generated neg. charged carbamate and the pos. charged quinuclidinium radical. This electrostatic attraction overwhelms the inherent bond dissocn. energies which suggest that HAT should occur unselectively. We anticipate that our findings will open up new avenues for amine functionalizations as well as selectivity control in HAT reactions.
    (j) McManus, J. B.; Onuska, N. P. R.; Nicewicz, D. A. Generation and Alkylation of α-Carbamyl Radicals via Organic Photoredox Catalysis. J. Am. Chem. Soc. 2018, 140, 9056– 9060,  DOI: 10.1021/jacs.8b04890
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    9j
    Generation and Alkylation of α-Carbamyl Radicals via Organic Photoredox Catalysis
    McManus, Joshua B.; Onuska, Nicholas P. R.; Nicewicz, David A.
    Journal of the American Chemical Society (2018), 140 (29), 9056-9060CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Strategies for the direct C-H functionalization of amines are valuable as these compds. comprise a no. of pharmaceuticals, agrochems. and natural products. This work describes a novel method for the C-H functionalization of carbamate-protected secondary amines via α-carbamyl radicals generated using photoredox catalysis. The use of the highly oxidizing, org. acridinium photoredox catalyst allows for direct oxidn. of carbamate-protected amines with high redox potentials to give the corresponding carbamyl cation radical. Following deprotonation, the resultant open-shell species can be intercepted by a variety of Michael acceptors to give elaborate α-functionalized secondary amines. The reaction proceeds under mild conditions without the requirement of exogenous redox mediators or substrate prefunctionalization. Addnl., we were able to showcase the utility of this methodol. through the enantioselective synthesis of the indolizidine alkaloid, (+)-monomorine I.
    (k) Lee, K. N.; Lei, Z.; Ngai, M.-Y. β-Selective Reductive Coupling of Alkenylpyridines with Aldehydes and Imines via Synergistic Lewis Acid/Photoredox Catalysis. J. Am. Chem. Soc. 2017, 139, 5003– 5006,  DOI: 10.1021/jacs.7b01373
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    9k
    β-Selective Reductive Coupling of Alkenylpyridines with Aldehydes and Imines via Synergistic Lewis Acid/Photoredox Catalysis
    Lee, Katarzyna N.; Lei, Zhen; Ngai, Ming-Yu
    Journal of the American Chemical Society (2017), 139 (14), 5003-5006CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Umpolung (polarity reversal) strategies of aldehydes and imines have dramatically expanded the scope of carbonyl and iminyl chem. by facilitating reactions with non-nucleophilic reagents. Herein, we report the first visible light photoredox-catalyzed β-selective reductive coupling of alkenylpyridines with carbonyl or iminyl derivs. with the aid of a Lewis acid co-catalyst. Our process tolerates complex mol. scaffolds (e.g., sugar, natural product, and peptide derivs.) and is applicable to the prepn. of compds. contg. a broad range of heterocyclic moieties. Mechanistic investigations indicate that the key step involves single-electron-transfer redn. of aldehydes or imines followed by the addn. of resulting ketyl or α-aminoalkyl radicals to Lewis acid-activated alkenylpyridines.
    (l) Chu, L.; Ohta, C.; Zuo, Z.; MacMillan, D. W. C. Carboxylic Acids as A Traceless Activation Group for Conjugate Additions: A Three-Step Synthesis of (±)-Pregabalin. J. Am. Chem. Soc. 2014, 136, 10886– 10889,  DOI: 10.1021/ja505964r
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    9l
    Carboxylic Acids as A Traceless Activation Group for Conjugate Additions: A Three-Step Synthesis of (±)-Pregabalin
    Chu, Lingling; Ohta, Chisa; Zuo, Zhiwei; MacMillan, David W. C.
    Journal of the American Chemical Society (2014), 136 (31), 10886-10889CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The direct application of carboxylic acids as a traceless activation group for radical Michael addns. has been accomplished via visible light-mediated photoredox catalysis. Photon-induced oxidn. of a broad series of carboxylic acids, including hydrocarbon-substituted, α-oxy, and α-amino acids, provides a versatile CO2-extrusion platform to generate Michael donors without the requirement for organometallic activation or propagation. A diverse array of Michael acceptors is amenable to this new conjugate addn. strategy. An application of this technol. to a three-step synthesis of the medicinal agent pregabalin (commercialized by Pfizer under the trade name Lyrica) is also presented.
    (m) Miyake, Y.; Nakajima, K.; Nishibayashi, Y. Visible-Light-Mediated Utilization of α-Aminoalkyl Radicals: Addition to Electron-Deficient Alkenes Using Photoredox Catalysts. J. Am. Chem. Soc. 2012, 134, 3338– 3341,  DOI: 10.1021/ja211770y
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    9m
    Visible-Light-Mediated Utilization of α-Aminoalkyl Radicals: Addition to Electron-Deficient Alkenes Using Photoredox Catalysts
    Miyake, Yoshihiro; Nakajima, Kazunari; Nishibayashi, Yoshiaki
    Journal of the American Chemical Society (2012), 134 (7), 3338-3341CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Synthetic use of α-aminoalkyl radicals formed by single electron oxidn. of amines is quite limited. Here the authors demonstrate addn. of α-aminoalkyl radicals to electron-deficient alkenes by visible-light-mediated electron transfer using transition metal polypyridyl complexes as photocatalysts, via a sequential redox pathway.
  10. 10
    The non-catalytic HAA of unprotected primary amines with non-electrophilic alkenes necessitates a large excess of the amine partner (∼13–26 equiv) and forcing reaction conditions (>120 °C, ∼10 mol% peroxide) and gives extensive telomerization. See:Urry, W. H.; Juveland, O. O. Free Radical Additions of Amines to Olefins. J. Am. Chem. Soc. 1958, 80, 3322– 3328,  DOI: 10.1021/ja01546a033
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    10
    Free radical additions of amines to olefins
    Urry, W. H.; Juveland, O. O.
    Journal of the American Chemical Society (1958), 80 (), 3322-8CODEN: JACSAT; ISSN:0002-7863.
    The free radical chain addns. of amines to olefins in the presence of peroxides or light yield higher homologous amines which are products of α-C alkylation. BuNH2 (370 g.), b77 -8°, n20D 1.4013, 28 g. 1-octene (I), b. 120-1° n20D 1.4090, and 4.5 g. (Me3CO)2 (II) (half-life in Bu3N at 125° 11.3 hrs., and at 135° 4.6 hrs.) heated 48 hrs. in a sealed tube at 123-6° and fractionated yielded 2.5 g. Me3COH, 12.35 g. I and BuNH2, 7.35 g. PrCH(NH2)C8H17 (III), b1 70-1°, n20D 1.4407, 3.0 g. distillate, b1 110-60°, n20D 1.4728, and 7.1 g. residue. PrCOC8H17 treated with HCO2H and HCO2NH4 yielded 34% III, b1 69-71°, n20D 1.4408. III gave with PhNCS a phenylthiourea deriv., m. 58-8.5°. III gave with HCl the III.HCl, m. 88.5-90°. III (1.7 g.) was obtained when 490 g. BuNH2 and 30 g. I were illuminated internally 120 hrs. with a Hg vapor lamp at 30-5°; 6.35 g. higher boiling residue was also formed. I (26 g.) and 4.5 g. II in 458 g. C6H13NH2 heated 60 hrs. at 124-7° and distd. gave 4 g. Me3COH, unchanged C6H13NH2, 16.0 g. AmCH(NH2)C8H17 (IV), b1, 84-5°, n20D 1.4435 (phenylthiourea deriv., m. 69-9.5°), 5.7 g. distillate, b1 120-55°, n20D 1.4560, and 12 g. residue. IV, b1 84-6°, n20D 1.4432, was also obtained from AmCOC8H17 with HCO2H and HCO2NH4. Me2CHNH2 (118 g.), 18 g. I, and 3 g. II heated 55 hrs. at 188-22° yielded 12 g. Me2C(NH2)C8H17, b1, 47-8°, n20D 1.4333 (HCl salt, m. 116-17°), 3.5 g. distillate, b1 80-120°, and 5.5 g residue. Cyclohexylamine (V) (497 g.), 25 g. I, and 6.0 g. II heated 53 hrs. at 124-8° and distd. gave 5.5 g. Me3COH and unchanged V and the following fractions: (1) 1.85 g., b1 88-9°, n20D 1.4788; (2) 2.7 g., b1 89-92° n20D 1.4772; (3) 4.0 g., b1 92°, n20D 1.4759; (4) 23 g. 1-amino-1-octylcyclohexane (VI), b1 95-7°, n20D 1.4657 (HCl salt, m. 107.5-8.5°; phenylthiourea deriv., m. 91-1.5°); (5) 4.8 g., b1, 150-65°, n20D 1.4770 (apparently a mixt. of VI and the addn. product from 2 moles I and 1 mole V); (5) 9.4 g., residue. Fractions 1, 2, and 3 combined and an aliquot (3.2 g.) hydrogenated gave 1 g. VI, b1 94-6°, n20D 1.4680. CH2:CHCH2OH (VII) (23 g.) and 5.0 g. II in 380 g. pyrrolidine heated 48 hrs. at 120-2° in a sealed tube and distd. gave 27.8 g. 2-(3-hydroxypropyl)pyrrolidine (VIII), b1 80-1°, n20D 1.4870, and 10.2 g. residue. VIII (4.25 g.) and 95 cc. 48% HBr heated 12 hrs. in a sealed tube at 100° and evapd. and the residue recrystd. from Me2CO yielded 2.5 g. 2-(3-bromopropyl)pyrrolidine.HBr (IX), m. 102-3°. IX (2.5 g.) added during 2.5 hrs. with stirring to 200 cc. 0.1N NaOH at 50°, cooled, treated with 3 g. PhSO2Cl, allowed to stand 1 hr., and steam-distd., the distillate extd. with Et2O, and the ext. treated with 2 g. picric acid yielded 1.5 g. pyrrolizidine picrate, m. 256.6-8°. Piperidine (X) (81 g.) and 1.1 g. II pressured 24 hrs. at 125° with 30-40 lb. C2H4 while adding an addnl. 1.8 g. II after 8 hrs., and the mixt. distd. yielded 2.7 g. Me3COH, 72 g. X, and 2.6 g. 2-ethylpiperidine, b52 73-5°, n20D 1.4544 (HCl salt, m. 180-1°; picrate, m. 130-1°; chloro platinate, m. 202-4°), and left 1.1 g. residue. II (1.2 g.) and 87 g. X kept 12 hrs. at 125° under 30-40 lb. MeCH:CH2 while adding an addnl. 1.8 g. II after hrs. and distd. gave 4 g. dl-coniine, b70 93°, n23D 1.4513 (HCl salt, m. 211-12°; platinichloride, m. 155-7°), 1.40 g. forerun, and 2.6 g. residue. X (360 g.), 23 g. 1-hexene, and 5 g. II heated 50 hrs. in a sealed tube at 122-5° and fractionated gave 3.7 g. Me3COH, 8.5 g. 1-hexene, and piperidine as forerun followed by 15.6 g. 2-hexylpiperidine (XI), b4.5 77-8°, n20D 1.4580, 2.8 g. distillate, b3 80-140°, n20D 1.4740, and 4.4 g. residue. α-Picoline (55.5 g.) treated with 30.2 g. AmBr and 27 g. NaNH2 yielded 60% XI, b5 80°, n20D 1.4575 (HCl salt, m. 162-3°). X (382 g.), 40 g. I, and 3 g. II kept 50 hrs. at 120° under N while being treated after 6 hrs. and after 12 hrs. with addnl. 2-g. portions II and the mixt. distd. yielded 6.3 g. Me3COH, 359.5 g. unchanged X, 9.5 g. I, b. 118-20°, 31.7 g. 2-octylpiperidine (XII), b1 89°, n20D 1.4589, 5.8 g. distillate, b1 145-55°, n20D 1.4683 (apparently condensation product of 1 mole X with 2 moles I), and 4.5 g. residue. 2-Octylpyridine (obtained in 65% yield by the reaction of 111 g. α-picoline with 1.2 moles C7H15Br, and 54 g. NaNH2) hydrogenated over PtO2 in AcOH yielded 95% XII, b1 89°, n20D 1.4587; phenylthiourea deriv., m. 95°; HCl salt, m. 155-6°; picrate, m. 78-80°. I (20.5 g.) in 207 g. X illuminated 168 hrs. with a quartz-Hg discharge tube at 30-5° gave 1 g. XII. X (385 g.), 19 g. VII, and 4.5 g. II heated 48 hrs. at 122-30° in a sealed tube and distd. gave 21.8 g. 2-(3-hydroxypropyl)piperidine (XIII), b1 93-5°, n25D 1.4890; HCl salt, m. 129-30°. X (340 g.), 19 g. VII, and 4.5 g. (EtMe2CO)2 kept 48 hrs. at 100° gave 2.3 g. XIII, b1, 93-5°, n20D 1.4900, and 4.2 g. residue. X (180 g.), 9 g. VII, and 1.5 g. (Me3CO.OCHMe)2 kept 50 hrs. at 95° gave 1.1 g. XIII and 2.6 g. residue. XIII (3 g.) in 60 cc. 48% HBr heated 12 hrs. at 100° and evapd. in vacuo, the residue recrystd. from Me2CO, the resulting 3.7 g. 2-(3-bromopropyl)piperidine, m. 180-2°, added during 2 hrs. at 50° to 2000 cc. 0.1N NaOH, cooled, treated with 3 g. PhSO2Cl, and steam-distd., the distillate (50 cc.) extd. with Et2O, and the ext. worked up gave 0.7 g. 1-azabicyclo[4.3.0]nonane, b32 86°, n21D 1.4697. X (374 g.), 21 g. CH2:CHCH2CN, and 5 g. II kept 72 hrs. at 120-4° yielded 20.7 g. 2-(3-cyanopropyl)piperidine, b1 59-60°, n20D 1.4748 (HCl salt, m. 135-6°), and 7.1 g. distillate, b1 100-40°, n20D 1.5024. 4-Pipecoline (198 g.), 10 g. VII, and 3 g. II heated 48 hrs. at 123-5° in a sealed tube gave 9.1 g. 4-Me deriv. of XIII, b1 99-100°, n20D 1.4875, and 8.0 g. residue. N-Methylpiperidine (284 g.), 20 g. I, and 6 g. II heated 48 hrs. at 122-6° in a sealed tube and distd. gave 6 g. 1-methyl-2-octylpiperidine (XIV), b1 84-5°, n20D 1.4593, 6.8 g. distillate, b1, 110-70°, n20D 1.4692, and 8.6 g. residue. HCO2H (18.9 g.), 14 g. 35% aq. CH2O, and 29 g. XII yielded 23.3 g. XIV, b1 85°, n20D 1.4590; XIV.MeI, m. 165°; XIV.EtI, m. 138-9°.
  11. 11

    Non-electrophilic styrenes in photoredox-catalyzed, intermolecular HAA are scarce and limited to tertiary amines or N-Boc α-amino acids:

    (a) Wu, Z.; Gockel, S.; Hull, K. Anti-Markovnikov Hydro(amino)alkylation of Vinylarenes via Photoredox Catalysis. Research Square Preprint 2021,  DOI: 10.21203/rs.3.rs-366556/v1
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    There is no corresponding record for this reference.
    (b) Larionova, N.; Ondozabal, J. M.; Smith, E. G.; Cambeiro, X. A. A photocatalytic regioselective hydroaminoalkylation of aryl-substituted alkenes with simple amines. Org. Lett. 2021, 23, 5383– 5388,  DOI: 10.1021/acs.orglett.1c01715
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    11b
    A Photocatalytic Regioselective Direct Hydroaminoalkylation of Aryl-Substituted Alkenes with Amines
    Larionova, Natalia A.; Ondozabal, Jun Miyatake; Smith, Emily G.; Cambeiro, Xacobe C.
    Organic Letters (2021), 23 (14), 5383-5388CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    A photocatalytic method for the α-selective hydroaminoalkylation of cinnamate esters has been developed. The reaction involves the regioselective addn. of α-aminoalkyl radicals generated from aniline derivs. or aliph. amines to the α-position of unsatd. esters. The scope of arom. alkenes was extended to styrenes undergoing hydroaminoalkylation with anti-Markovnikov selectivity, which confirms the importance of the arom. group at the β-position. Simple scale-up is demonstrated under continuous flow conditions, highlighting the practicality of the method.
    (c) Lovett, G. H.; Sparling, B. A. Decarboxylative Anti-Michael Addition to Olefins Mediated by Photoredox Catalysis. Org. Lett. 2016, 18, 3494– 3497,  DOI: 10.1021/acs.orglett.6b01712
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    11c
    Decarboxylative Anti-Michael Addition to Olefins Mediated by Photoredox Catalysis
    Lovett, Gabrielle H.; Sparling, Brian A.
    Organic Letters (2016), 18 (14), 3494-3497CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    Decarboxylative coupling of carboxylic acids with activated olefins has been accomplished using visible light photoredox catalysis. The strategic placement of a radical-stabilizing arom. group at the β-position of the olefin component biases the regioselectivity of the addn., allowing reliable, facile access to anti-Michael-type products from readily available precursors. The scope of this methodol. was demonstrated with a range of carboxylic acids and appropriately substituted olefins and was applied toward a two-step synthesis of the antiarrhythmic agent encainide.
  12. 12
    (a) Nagai, M.; Nagamoto, M.; Nishimura, T.; Yorimitsu, H. Iridium-Catalyzed sp3 C–H Alkylation of 3-Carbonyl-2-(alkylamino)pyridines with Alkenes. Chem. Lett. 2017, 46, 1176– 1178,  DOI: 10.1246/cl.170373
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    12a
    Iridium-catalyzed sp3 C-H alkylation of 3-carbonyl-2-(alkylamino)pyridines with alkenes
    Nagai, Masaki; Nagamoto, Midori; Nishimura, Takahiro; Yorimitsu, Hideki
    Chemistry Letters (2017), 46 (8), 1176-1178CODEN: CMLTAG; ISSN:0366-7022. (Chemical Society of Japan)
    Iridium-catalyzed C-H alkylation of 3-carbonyl-2-(alkylamino)pyridines via secondary sp3 C-H activation adjacent to the nitrogen atom, with terminal alkenes proceeded to give the corresponding α-secondary amines such as I [R1 = Ph, NH2, pyrrolodin-1-yl, etc; R2 = CH2OH, 4-ClC6H4, Bn, etc.; R3 = Me, CH2CH3, Ph , etc.] in high yields. The reaction was efficiently catalyzed by a cationic iridium complex coordinated with 1,5-cyclooctadiene.
    (b) Pan, S.; Matsuo, Y.; Endo, K.; Shibata, T. Cationic iridium-catalyzed enantioselective activation of secondary sp3 C–H bond adjacent to nitrogen atom. Tetrahedron 2012, 68, 9009– 9015,  DOI: 10.1016/j.tet.2012.08.071
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    12b
    Cationic iridium-catalyzed enantioselective activation of secondary sp3 C-H bond adjacent to nitrogen atom
    Pan, Shiguang; Matsuo, Yusuke; Endo, Kohei; Shibata, Takanori
    Tetrahedron (2012), 68 (44), 9009-9015CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
    A cationic Ir(I)-tolBINAP complex catalyzed an enantioselective C-C bond formation, which was initiated by secondary sp3 C-H bond cleavage adjacent to nitrogen atom. A wide variety of 2-(alkylamino)pyridines and alkenes were selectively transformed into the corresponding chiral amines with moderate to almost perfect enantiomeric excesses. E.g., reaction of 2-(ethylamino)pyridine and styrene gave (-)-I. Alkynes were also investigated as coupling partners. The effect of alkyl structure in substrates and directing groups were studied. This transformation represents the first example of a highly enantioselective C-H bond activation of a methylene group, not at allylic or benzylic position.
    (c) Pan, S.; Endo, K.; Shibata, T. Ir(I)-Catalyzed Enantioselective Secondary sp3 C–H Bond Activation of 2-(Alkylamino)pyridines with Alkenes. Org. Lett. 2011, 13, 4692– 4695,  DOI: 10.1021/ol201907w
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    12c
    Ir(I)-Catalyzed Enantioselective Secondary sp3 C-H Bond Activation of 2-(Alkylamino)pyridines with Alkenes
    Pan, Shiguang; Endo, Kohei; Shibata, Takanori
    Organic Letters (2011), 13 (17), 4692-4695CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    A cationic Ir(I)-tolBINAP complex catalyzed an enantioselective C-C bond formation initiated by secondary sp3 C-H bond cleavage adjacent to a nitrogen atom. The reaction of 2-(alkylamino)pyridines with various alkenes gave chiral amines, e.g., I, in good yields with high enantiomeric excesses.
  13. 13
    Koperniku, A.; Foth, P. J.; Sammis, G. M.; Schafer, L. L. Zirconium Hydroaminoalkylation. An Alternative Disconnection for the Catalytic Synthesis of α-Arylated Primary Amines. J. Am. Chem. Soc. 2019, 141, 18944– 18948,  DOI: 10.1021/jacs.9b10465
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    13
    Zirconium Hydroaminoalkylation. An Alternative Disconnection for the Catalytic Synthesis of α-Arylated Primary Amines
    Koperniku, Ana; Foth, Paul J.; Sammis, Glenn M.; Schafer, Laurel L.
    Journal of the American Chemical Society (2019), 141 (48), 18944-18948CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Primary amine products have been prepd. using zirconium catalyzed hydroaminoalkylation of alkenes with N-silylated benzylamine substrates. Catalysis using com. available Zr(NMe2)4, affords an alternative disconnection to access α-arylated primary amines upon aq. work-up. Substrate dependent regio- and diastereoselectivity of the reaction is obsd. Bulky substituents on the terminal alkene exclusively generate the linear regioisomer. This atom-economic catalytic strategy for the synthesis of building blocks that can underwent further synthetic elaboration is highlighted in the prepn. of trifluoroethylated-α-arylated amines.
  14. 14
    (a) Bexrud, J. A.; Eisenberger, P.; Leitch, D. C.; Payne, P. R.; Schafer, L. L. Selective C–H Activation α to Primary Amines. Bridging Metallaaziridines for Catalytic, Intramolecular α-Alkylation. J. Am. Chem. Soc. 2009, 131, 2116– 2118,  DOI: 10.1021/ja808862w
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    14a
    Selective C-H activation α to primary amines. Bridging metallaaziridines for catalytic, intramolecular α-alkylation
    Bexrud, Jason A.; Eisenberger, Patrick; Leitch, David C.; Payne, Philippa R.; Schafer, Laurel L.
    Journal of the American Chemical Society (2009), 131 (6), 2116-2118CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Primary 5- and 6-unsatd. aliph. amines undergo α-C-H-activation rather than intramol. hydroamination in the presence of Ti and Zr amido-complexes, resulting in stereoselective formation of cyclic amines. Selective benzylic α-C-H activation of benzylamine results in the prepn. of the first bridging metallaaziridine complex [(PhCONHAr-κO,κN)Ti(μ-PhCH2N-κN:κN)(μ-PhCH2N-κC,N:κN)(μ-PhCONHAr-κO:κN)Ti(PhCONHAr-κO,κN)] (2) for the catalytic α-alkylation of primary amines. Crystal structure of 2 is reported. Zirconium tetramide gave 2-pyridonate complex [(PyO)2Zr(NMe2)2] [3; PyO = 6-tert-butyl-3-phenyl-2-pyridinonato(1-)], which was also characterized by x-ray structural anal. Cyclization of RCH2NH2 (R = 2-(3-butenylphenyl), 2,2-diphenyl-6-heptenyl, 1-(4-pentenyl)cyclopentenyl, 7-heptenyl, 6-hexenyl) and CH2:CH(CH2)4CHPhNH2 catalyzed by zirconium complex 3 gave the corresponding 2-Me-1-tetralinamine, cyclohexane- and cyclopentanamines as a result of α-C-H activation, followed by cyclization of the reactive zirconaaziridine with pendant double bond. No nitrogen protecting groups are required for this reaction, which is capable of assembling quaternary chiral centers α to nitrogen. Preliminary mechanistic investigations suggest bridging metallaaziridine species are the catalytically active intermediates for this α-functionalization reaction, while monomeric imido complexes furnish azepane hydroamination products.
    (b) Kubiak, R.; Prochnow, I.; Doye, S. Titanium-Catalyzed Hydroaminoalkylation of Alkenes by C–H Bond Activation at sp3 Centers in the α-Position to a Nitrogen Atom. Angew. Chem., Int. Ed. 2009, 48, 1153– 1156,  DOI: 10.1002/anie.200805169
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    14b
    Titanium-catalyzed hydroaminoalkylation of alkenes by C-H bond activation at sp3 centers in the α-position to a nitrogen atom
    Kubiak, Raphael; Prochnow, Insa; Doye, Sven
    Angewandte Chemie, International Edition (2009), 48 (6), 1153-1156CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Hydroaminoalkylations of alkenes, which take place by C-H bond activation in the α-position to nitrogen atoms, are catalyzed by various neutral titanium complexes. Primary as well as secondary amines can be used as substrates, and the reactions can be achieved intra- and intermolecularly.
  15. 15
    Chu, J. C. K.; Rovis, T. Complementary Strategies for Directed C(sp3)–H Functionalization: A Comparison of Transition-Metal-Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer. Angew. Chem., Int. Ed. 2018, 57, 62– 101,  DOI: 10.1002/anie.201703743
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    15
    Complementary Strategies for Directed C(sp3)-H Functionalization: A Comparison of Transition-Metal-Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer
    Chu, John C. K.; Rovis, Tomislav
    Angewandte Chemie, International Edition (2018), 57 (1), 62-101CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. The functionalization of C(sp3)-H bonds streamlines chem. synthesis by allowing the use of simple mols. and providing novel synthetic disconnections. Intensive recent efforts in the development of new reactions based on C-H functionalization have led to its wider adoption across a range of research areas. This Review discusses the strengths and weaknesses of three main approaches: transition-metal-catalyzed C-H activation, 1,n-hydrogen atom transfer, and transition-metal-catalyzed carbene/nitrene transfer, for the directed functionalization of unactivated C(sp3)-H bonds. For each strategy, the scope, the reactivity of different C-H bonds, the position of the reacting C-H bonds relative to the directing group, and stereochem. outcomes are illustrated with examples in the literature. The aim of this Review is to provide guidance for the use of C-H functionalization reactions and inspire future research in this area.
  16. 16
    For a comparison to the oxidation potential of other common amine classes, see:Roth, H. G.; Romero, N. A.; Nicewicz, D. A. Experimental and Calculated Electrochemical Potentials of Common Organic Molecules for Applications to Single-Electron Redox Chemistry. Synlett 2016, 27, 714– 723,  DOI: 10.1055/s-0035-1561297
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    Experimental and Calculated Electrochemical Potentials of Common Organic Molecules for Applications to Single-Electron Redox Chemistry
    Roth, Hudson G.; Romero, Nathan A.; Nicewicz, David A.
    Synlett (2016), 27 (5), 714-723CODEN: SYNLES; ISSN:0936-5214. (Georg Thieme Verlag)
    Herein, we report half-peak potentials for over 180 org. substrates obtained via cyclic voltammetry. These values are of great use in assessing the thermodn. of an electron-transfer process. In addn., we disclose a simple computational method to det. redox potentials of org. substrates.
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    Morozova, O. B.; Yurkovskaya, A. V. Aminium Cation Radical of Glycylglycine and its Deprotonation to Aminyl Radical in Aqueous Solution. J. Phys. Chem. B 2008, 112, 12859– 12862,  DOI: 10.1021/jp807149a
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    Aminium Cation Radical of Glycylglycine and its Deprotonation to Aminyl Radical in Aqueous Solution
    Morozova, Olga B.; Yurkovskaya, Alexandra V.
    Journal of Physical Chemistry B (2008), 112 (40), 12859-12862CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
    The photochem. reaction between glycylglycine and triplet 4-carboxybenzophenone has been investigated using time-resolved chem. induced dynamic nuclear polarization (CIDNP). It is shown that the mechanism of the peptide reaction with triplet excited carboxybenzophenone is electron transfer from the amino group of the peptide, leading to the formation of an aminium cation radical that deprotonates to a neutral aminyl radical. Simulation of the CIDNP kinetics leads to an estn. of the paramagnetic relaxation time for the α-protons at the N-terminus at 20 to 40 μs with the best-fit value of 25 μs.
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    Luo, J.; Zhang, J. Donor–Acceptor Fluorophores for Visible-Light-Promoted Organic Synthesis: Photoredox/Ni Dual Catalytic C(sp3)–C(sp2) Cross Coupling. ACS Catal. 2016, 6, 873– 877,  DOI: 10.1021/acscatal.5b02204
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    Donor-Acceptor Fluorophores for Visible-Light-Promoted Organic Synthesis: Photoredox/Ni Dual Catalytic C(sp3)-C(sp2) Cross-Coupling
    Luo, Jian; Zhang, Jian
    ACS Catalysis (2016), 6 (2), 873-877CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    We describe carbazolyl dicyanobenzene (CDCB)-based donor-acceptor (D-A) fluorophores as a class of cheap, easily accessible, and efficient metal-free photoredox catalysts for org. synthesis. By changing the no. and position of carbazolyl and cyano groups on the center benzene ring, CDCBs with a wide range of photoredox potentials are obtained to effectively drive the energetically demanding C(sp3)-C(sp2) cross-coupling of carboxylic acids and alkyltrifluoroborates with aryl halides via a photoredox/Ni dual catalysis mechanism. This work validates the utility of D-A fluorophores in guiding the rational design of metal-free photoredox catalysts for visible-light-promoted org. synthesis.
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    Le, C.; Liang, Y.; Evans, R. W.; Li, X.; MacMillan, D. W. C. Selective sp3 C–H alkylation via polarity-match-based cross-coupling. Nature 2017, 547, 79– 83,  DOI: 10.1038/nature22813
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    Selective sp3 C-H alkylation via polarity-match-based cross-coupling
    Le, Chip; Liang, Yufan; Evans, Ryan W.; Li, Ximing; MacMillan, David W. C.
    Nature (London, United Kingdom) (2017), 547 (7661), 79-83CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    The functionalization of carbon-hydrogen (C-H) bonds is one of the most attractive strategies for mol. construction in org. chem. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in org. mols. and its availability for functionalization at almost any stage in a synthetic sequence. Although many C-H functionalization reactions involve C(sp3)-C(sp2) coupling, there is a growing demand for C-H alkylation reactions, wherein sp3 C-H bonds are replaced with sp3 C-alkyl groups. Here, we describe a polarity-match-based selective sp3 C-H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodol. simultaneously uses three catalytic cycles to achieve hydridic C-H bond abstraction (enabled by polarity matching), alkyl halide oxidative addn., and reductive elimination to enable alkyl-alkyl fragment coupling. The sp3 C-H alkylation is highly selective for the α-C-H of amines, ethers and sulfides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chem.
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    Luo, Y.-R Comprehensive Handbook of Chemical Bond Energies; CRC Press: Boca Raton, FL, 2007.
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    (a) Sim, B. A.; Griller, D.; Wayner, D. D. M. Reduction Potentials for Substituted Benzyl Radicals: pKa Values for the Corresponding Toluenes. J. Am. Chem. Soc. 1989, 111, 754– 755,  DOI: 10.1021/ja00184a066
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    Reduction potentials for substituted benzyl radicals: pKa values for the corresponding toluenes
    Sim, B. A.; Griller, D.; Wayner, D. D. M.
    Journal of the American Chemical Society (1989), 111 (2), 754-5CODEN: JACSAT; ISSN:0002-7863.
    The electrochem. redn. potentials of nine 3- and 4-substituted benzyl radicals were detd. by photomodulation voltammetry (PMV) in MeCN/di-tert-butylperoxide (9:1) contg. 0.1 M Bu4NClO4. The measured half-wave potentials for the redns. are close to E° and lead to ests. of the abs. pKa's for the toluenes in MeCN.
    (b) Wayner, D. D. M.; McPhee, D. J.; Griller, D. Oxidation and reduction potentials of transient free radicals. J. Am. Chem. Soc. 1988, 110, 132– 137,  DOI: 10.1021/ja00209a021
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    Oxidation and reduction potentials of transient free radicals
    Wayner, D. D. M.; McPhee, D. J.; Griller, D.
    Journal of the American Chemical Society (1988), 110 (1), 132-7CODEN: JACSAT; ISSN:0002-7863.
    The oxidn. and redn. potentials of a variety of carbon-centered radicals have been measured by a technique that makes use of modulated photolysis for radical generation and phase-sensitive voltammetry for their detection. The measured half-wave potentials were close to the thermodynamically significant E° values for the arylmethyl radicals and led to ests. of pKa(R-H) and pKR(R-OH) as well as data for the solvation energies of these ions and radicals.
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    Bortolamei, N.; Isse, A. A.; Gennaro, A. Estimation of standard reduction potentials of alkyl radicals involved in atom-transfer radical polymerization. Electrochim. Acta 2010, 55, 8312– 8318,  DOI: 10.1016/j.electacta.2010.02.099
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    Estimation of standard reduction potentials of alkyl radicals involved in atom transfer radical polymerization
    Bortolamei, Nicola; Isse, Abdirisak A.; Gennaro, Armando
    Electrochimica Acta (2010), 55 (27), 8312-8318CODEN: ELCAAV; ISSN:0013-4686. (Elsevier B.V.)
    The redox properties of some alkyl radicals, which are important in atom transfer radical polymn. both as initiators and mimics of the propagating radical chains, have been investigated in CH3CN by an indirect electrochem. method based on homogeneous redox catalysis involving alkyl halides (RX) and electrogenerated arom. or heteroarom. radical anions (D·-). Dissociative electron transfer between RX and D·- yields an intermediate radical (R·), which further reacts with D·- either by radical coupling or by electron transfer. Examn. of the competition between these reactions, which depends on ED°D/D·-/D·-, allows detn. of the std. redn. potential of R· as well as the self-exchange reorganization energy λR·/R-·. The std. redn. potentials obtained for the radicals ·CH2CN, ·CH2CO2Et and ·CH(CH3)CO2Me are -0.72 ± 0.06, -0.63 ± 0.07 and -0.66 ± 0.07 V vs. SCE, resp. Quite high values of λR·/R- (from 122 to 164 kJ mol-1) were found for all radicals, indicating that a significant change of structure accompanies electron transfer to R·.
  23. 23
    Speckmeier, E.; Fischer, T. G.; Zeitler, K. A Toolbox Approach To Construct Broadly Applicable Metal-Free Catalysts for Photoredox Chemistry: Deliberate Tuning of Redox Potentials and Importance of Halogens in Donor–Acceptor Cyanoarenes. J. Am. Chem. Soc. 2018, 140, 15353– 15365,  DOI: 10.1021/jacs.8b08933
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    23
    A Toolbox Approach To Construct Broadly Applicable Metal-Free Catalysts for Photoredox Chemistry: Deliberate Tuning of Redox Potentials and Importance of Halogens in Donor-Acceptor Cyanoarenes
    Speckmeier, Elisabeth; Fischer, Tillmann G.; Zeitler, Kirsten
    Journal of the American Chemical Society (2018), 140 (45), 15353-15365CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The targeted choice of specific photocatalysts has been shown to play a crit. role for the successful realization of challenging photoredox catalytic transformations. Herein, we demonstrate the successful implementation of a rational design strategy for a series of deliberate structural manipulations of cyanoarene-based, purely org. donor-acceptor photocatalysts, using 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) as a starting point. Systematic modifications of both the donor substituents as well as the acceptors' mol. core allowed us to identify strongly oxidizing as well as strongly reducing catalysts (e.g., for an unprecedented detriflation of unactivated naphthol triflate), which addnl. offer remarkably balanced redox potentials with predictable trends. Esp. halogen arene core substitutions are instrumental for our targeted alterations of the catalysts' redox properties. Based on their preeminent electrochem. and photophys. characteristics, all novel, purely org. photoredox catalysts were evaluated in three challenging, mechanistically distinct classes of benchmark reactions (either requiring balanced, highly oxidizing or strongly reducing properties) to demonstrate their enormous potential as customizable photocatalysts, that outperform and complement prevailing typical best photocatalysts.
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    Ji, X.; Liu, Q.; Wang, Z.; Wang, P.; Deng, G.-J.; Huang, H. LiBr-promoted photoredox neutral Minisci hydroxyalkylations of quinolines with aldehydes. Green Chem. 2020, 22, 8233– 8237,  DOI: 10.1039/D0GC01872D
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    24
    LiBr-promoted photoredox neutral Minisci hydroxyalkylations of quinolines with aldehydes
    Ji, Xiaochen; Liu, Qiong; Wang, Zhongzhen; Wang, Pu; Deng, Guo-Jun; Huang, Huawen
    Green Chemistry (2020), 22 (23), 8233-8237CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
    Photoredox-neutral hydroxyalkylations of quinolines I [R = H; R1 = H; RR1 = -CH=CHCH=CH-, -CH=C(OCH3)C(OCH3)=CH-; R2 = H, n-Bu, Cl; R3 = H; R2R3 = -CH=C(Br)CH=CH-; R4 = H, 4-phenylphenyl, 3-chlorophenyl, thiophen-2-yl, etc.] with aldehydes R5CHO (R5 = 2-bromo-5-fluorophenyl, thiophen-2-yl, naphthalen-2-yl, etc.), induced by sustainable visible light under mild conditions, are described. Non-toxic and inexpensive LiBr is found to be the key for the success of the atom-economical Minisci method. Combined with a highly oxidative photocatalyst and visible light irradn., the bromide additive mediates the H abstraction/acyl radical formation directly from aldehydes. The present mild photoredox neutral protocol provides an important alternative, esp. for the challenging Minisci hydroalkylations, as well as a promising approach for atom-economical Minisci reactions with broader N-heterocycle spectra.
  25. 25
    Ide, T.; Barham, J. P.; Fujita, M.; Kawato, K.; Egami, H.; Hamashima, Y. Regio- and chemoselective Csp3–H arylation of benzylamines by single electron transfer/hydrogen atom transfer synergistic catalysis. Chem. Sci. 2018, 9, 8453– 8460,  DOI: 10.1039/C8SC02965B
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    25
    Regio- and chemoselective Csp3-H arylation of benzylamines by single electron transfer/hydrogen atom transfer synergistic catalysis
    Ide, Takafumi; Barham, Joshua P.; Fujita, Masashi; Kawato, Yuji; Egami, Hiromichi; Hamashima, Yoshitaka
    Chemical Science (2018), 9 (44), 8453-8460CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    A highly regio- and chemoselective Csp3-H arylation of benzylamines mediated by synergy of single electron transfer (SET) and hydrogen atom transfer (HAT) catalysis is reported. Under well precedented SET catalysis alone, the arylation reaction of N,N-dimethylbenzylamine proceeded via aminium radical cation formation and selectively targeted the N-Me group. In contrast, addn. of PhC(O)SH as a HAT catalyst precursor completely switched the regioselectivity to Csp3-H arylation at the N-benzylic position. Measurement of oxidn. potentials indicated that the conjugate base of PhC(O)SH is oxidized in preference to the substrate amine. The discovery of the thiocarboxylate as a novel HAT catalyst allowed for the selective generation of the sulfur-centered radical, so that the N-benzyl selectivity was achieved by overriding the inherent N-Me and/or N-methylene selectivity under SET catalysis conditions. While visible light-driven α-C-H functionalization of amines has mostly been demonstrated with aniline derivs. and tetrahydroisoquinolines (THIQs), our method is applicable to a variety of primary, secondary and tertiary benzylamines for efficient N-benzylic C-H arylation. Functional group tolerance was high, and various 1,1-diarylmethylamines, including an α,α,α-trisubstituted amine, were obtained in good to excellent yield (up to 98%). Importantly, the reaction is applicable to late-stage functionalization of pharmaceuticals.
  26. 26
    Rohe, S.; Morris, A. O.; McCallum, T.; Barriault, L. Hydrogen Atom Transfer Reactions via Photoredox Catalyzed Chlorine Atom Generation. Angew. Chem., Int. Ed. 2018, 57, 15664– 15669,  DOI: 10.1002/anie.201810187
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    Hydrogen Atom Transfer Reactions via Photoredox Catalyzed Chlorine Atom Generation
    Rohe, Samantha; Morris, Avery O.; McCallum, Terry; Barriault, Louis
    Angewandte Chemie, International Edition (2018), 57 (48), 15664-15669CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The selective functionalization of chem. inert C-H bonds remains to be fully realized in achieving org. transformations that are redox-neutral, waste-limiting, and atom-economical. The catalytic generation of chlorine atoms from chloride ions is one of the most challenging redox processes, where the requirement of harsh and oxidizing reaction conditions renders it seldom utilized in synthetic applications. We report the mild, controlled, and catalytic generation of chlorine atoms as a new opportunity for access to a wide variety of hydrogen atom transfer (HAT) reactions owing to the high stability of HCl.The discovery of the photoredox mediated generation of chlorine atoms with Ir-based polypyridyl complex, [Ir(dF(CF3)ppy)2(dtbbpy)]Cl, under blue LED irradn. is reported.
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    Zhou, R.; Goh, Y. Y.; Liu, H.; Tao, H.; Li, L.; Wu, J. Visible-Light-Mediated Metal-Free Hydrosilylation of Alkenes through Selective Hydrogen Atom Transfer for Si–H Activation. Angew. Chem., Int. Ed. 2017, 56, 16621– 16625,  DOI: 10.1002/anie.201711250
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    27
    Visible-Light-Mediated Metal-Free Hydrosilylation of Alkenes through Selective Hydrogen Atom Transfer for Si-H Activation
    Zhou, Rong; Goh, Yi Yiing; Liu, Haiwang; Tao, Hairong; Li, Lihua; Wu, Jie
    Angewandte Chemie, International Edition (2017), 56 (52), 16621-16625CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Although there has been significant progress in the development of transition-metal-catalyzed hydrosilylations of alkenes over the past several decades, metal-free hydrosilylation is still rare and highly desirable. Herein, authors report a convenient visible-light-driven metal-free hydrosilylation of both electron-deficient and electron-rich alkenes that proceeds through selective hydrogen atom transfer for Si-H activation. The synergistic combination of the organophotoredox catalyst 4CzIPN with quinuclidin-3-yl acetate enabled the hydrosilylation of electron-deficient alkenes by selective Si-H activation while the hydrosilylation of electron-rich alkenes was achieved by merging photoredox and polarity-reversal catalysis.
  28. 28
    (a) Morisaki, K.; Morimoto, H.; Ohshima, T. Recent Progress on Catalytic Addition Reactions to N-Unsubstituted Imines. ACS Catal. 2020, 10, 6924– 6951,  DOI: 10.1021/acscatal.0c01212
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    28a
    Recent Progress on Catalytic Addition Reactions to N-Unsubstituted Imines
    Morisaki, Kazuhiro; Morimoto, Hiroyuki; Ohshima, Takashi
    ACS Catalysis (2020), 10 (12), 6924-6951CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    A review. Catalytic addn. reactions to N-unsubstituted (N-unprotected) imines can provide a more straightforward synthesis of amines. This direct process eliminates the unnecessary protecting-group manipulations that are required with N-substituted (N-protected) imines and can contribute to the development of green chem. Although their use has been limited due to difficulties assocd. with the nature of N-unsubstituted imines, recently developed catalytic methods enable the use of N-unsubstituted imines as electrophiles in various catalytic addn. reactions. To facilitate an understanding of the state of the art development of synthetic methodologies, herein we review recent progress on catalytic addn. reactions to N-unsubstituted imines. An overview of the chem. of N-unsubstituted imines is given, followed by a summary of recent progress categorized according to the reaction type is . We hope this review will help to stimulate further development of greener syntheses of nitrogen-contg. compds.
    (b) Nicastri, M. C.; Lehnherr, D.; Lam, Y.-h.; DiRocco, D. A.; Rovis, T. Synthesis of Sterically Hindered Primary Amines by Concurrent Tandem Photoredox Catalysis. J. Am. Chem. Soc. 2020, 142, 987– 998,  DOI: 10.1021/jacs.9b10871
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    28b
    Synthesis of Sterically Hindered Primary Amines by Concurrent Tandem Photoredox Catalysis
    Nicastri, Michael C.; Lehnherr, Dan; Lam, Yu-hong; DiRocco, Daniel A.; Rovis, Tomislav
    Journal of the American Chemical Society (2020), 142 (2), 987-998CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Primary amines are an important structural motif in active pharmaceutical ingredients (APIs) and intermediates thereof, as well as members of ligand libraries for either biol. or catalytic applications. Many chem. methodologies exist for amine synthesis, but the direct synthesis of primary amines with a fully substituted α carbon center is an underdeveloped area. We report a method which utilizes photoredox catalysis to couple readily available O-benzoyl oximes with cyanoarenes to synthesize primary amines with fully substituted α-carbons. We also demonstrate that this method enables the synthesis of amines with α-trifluoromethyl functionality. Based on exptl. and computational results, we propose a mechanism where the photocatalyst engages in concurrent tandem catalysis by reacting with the oxime as a triplet sensitizer in the first catalytic cycle and a reductant toward the cyanoarene in the second catalytic cycle to achieve the synthesis of hindered primary amines via heterocoupling of radicals from readily available oximes.
    (c) Lehnherr, D.; Lam, Y.-h.; Nicastri, M. C.; Liu, J.; Newman, J. A.; Regalado, E. L.; DiRocco, D. A.; Rovis, T. Electrochemical Synthesis of Hindered Primary and Secondary Amines via Proton-Coupled Electron Transfer. J. Am. Chem. Soc. 2020, 142, 468– 478,  DOI: 10.1021/jacs.9b10870
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    28c
    Electrochemical Synthesis of Hindered Primary and Secondary Amines via Proton-Coupled Electron Transfer
    Lehnherr, Dan; Lam, Yu-hong; Nicastri, Michael C.; Liu, Jinchu; Newman, Justin A.; Regalado, Erik L.; DiRocco, Daniel A.; Rovis, Tomislav
    Journal of the American Chemical Society (2020), 142 (1), 468-478CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Accessing hindered amines, particularly primary amines α to a fully substituted carbon center, is synthetically challenging. We report an electrochem. method to access such hindered amines starting from benchtop-stable iminium salts and cyanoheteroarenes. A wide variety of substituted heterocycles (pyridine, pyrimidine, pyrazine, purine, azaindole) can be utilized in the cross-coupling reaction, including those substituted with a halide, trifluoromethyl, ester, amide, or ether group, a heterocycle, or an unprotected alc. or alkyne. Mechanistic insight based on DFT data, as well as cyclic voltammetry and NMR spectroscopy, suggests that a proton-coupled electron-transfer mechanism is operational as part of a hetero-biradical cross-coupling of α-amino radicals and radicals derived from cyanoheteroarenes. Safety: cyanide may be released as a byproduct leading to release of toxic HCN.
    (d) Ushakov, D. B.; Gilmore, K.; Kopetzki, D.; McQuade, D. T.; Seeberger, P. H. Continuous-Flow Oxidative Cyanation of Primary and Secondary Amines Using Singlet Oxygen. Angew. Chem., Int. Ed. 2014, 53, 557– 561,  DOI: 10.1002/anie.201307778
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    28d
    Continuous-Flow Oxidative Cyanation of Primary and Secondary Amines Using Singlet Oxygen
    Ushakov, Dmitry B.; Gilmore, Kerry; Kopetzki, Daniel; McQuade, D. Tyler; Seeberger, Peter H.
    Angewandte Chemie, International Edition (2014), 53 (2), 557-561CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Primary and secondary amines can be rapidly and quant. oxidized to the corresponding imines by singlet oxygen. This reactive form of oxygen was produced using a variable-temp. continuous-flow LED-photoreactor with a catalytic amt. of tetraphenylporphyrin as the sensitizer. α-Aminonitriles were obtained in good to excellent yields when trimethylsilyl cyanide served as an in situ imine trap. At 25°C, primary amines were found to undergo oxidative coupling prior to cyanide addn. and yielded secondary α-aminonitriles. Primary α-aminonitriles were synthesized from the corresponding primary amines for the first time, by an oxidative Strecker reaction at -50°C. This atom-economic and protecting-group-free pathway provides a route to racemic amino acids, which was exemplified by the synthesis of tert-leucine hydrochloride from neopentylamine.
  29. 29

    The addition step may be slower than potential side reactions (e.g., benzylic radical dimerization) or be reversible and endergonic, such that catalytic turnover is impeded. However, the photocatalytic α-C–H alkylation of tertiary benzylic amines with electrophilic alkenes has been achieved via an SET oxidation–deprotonation approach; see ref (9c).

    There is no corresponding record for this reference.
  30. 30

    In general, quantification of the HAT site selectivity was not possible, but minor unidentified byproducts were visible in the crude 1H NMR spectra for some compounds. We previously showed, both experimentally and theoretically, that the selectivity for α-C–H functionalization of cyclohexylamine versus cyclohexanol with photogenerated azidyl radical is >20:1, with cyclohexanol itself being α-C–H alkylated with methyl acrylate in only 12% yield in a standalone experiment; see ref (9d).

    There is no corresponding record for this reference.
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    Cambié, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noël, T. Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment. Chem. Rev. 2016, 116, 10276– 10341,  DOI: 10.1021/acs.chemrev.5b00707
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    Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment
    Cambie, Dario; Bottecchia, Cecilia; Straathof, Natan J. W.; Hessel, Volker; Noel, Timothy
    Chemical Reviews (Washington, DC, United States) (2016), 116 (17), 10276-10341CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. Continuous-flow photochem. in microreactors receives a lot of attention from researchers in academia and industry as this technol. provides reduced reaction times, higher selectivities, straightforward scalability, and the possibility to safely use hazardous intermediates and gaseous reactants. In this review, an up-to-date overview is given of photochem. transformations in continuous-flow reactors, including applications in org. synthesis, material science, and water treatment. In addn., the advantages of continuous-flow photochem. are pointed out and a thorough comparison with batch processing is presented.
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    Incidentally, compound 7ag was misassigned as the other regioisomer in our previous work; see ref (9d). We now have conclusive 2D NMR and single-crystal XRD support for the revised structure of 7ag.

    There is no corresponding record for this reference.
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    As the closest literature comparison, a recent α-amino radical addition to 6h (with a tertiary amine) proceeded in only 7% yield; see ref (11b).

    There is no corresponding record for this reference.
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    Constantin, T.; Zanini, M.; Regni, A.; Sheikh, N. S.; Juliá, F.; Leonori, D. Aminoalkyl radicals as halogen-atom transfer agents for activation of alkyl and aryl halides. Science 2020, 367, 1021– 1026,  DOI: 10.1126/science.aba2419
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    Aminoalkyl radicals as halogen-atom transfer agents for activation of alkyl and aryl halides
    Constantin, Timothee; Zanini, Margherita; Regni, Alessio; Sheikh, Nadeem S.; Julia, Fabio; Leonori, Daniele
    Science (Washington, DC, United States) (2020), 367 (6481), 1021-1026CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
    Org. halides are important building blocks in synthesis, but their use in (photo)redox chem. is limited by their low redn. potentials. Halogen-atom transfer remains the most reliable approach to exploit these substrates in radical processes despite its requirement for hazardous reagents and initiators such as tributyltin hydride. In this study, we demonstrate that α-aminoalkyl radicals, easily accessible from simple amines, promote the homolytic activation of carbon-halogen bonds with a reactivity profile mirroring that of classical tin radicals. This strategy conveniently engages alkyl and aryl halides in a wide range of redox transformations to construct sp3-sp3, sp3-sp2, and sp2-sp2 carbon-carbon bonds under mild conditions with high chemoselectivity.
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    Sanford, M. Fingolimod: A Review of Its Use in Relapsing-Remitting Multiple Sclerosis. Drugs 2014, 74, 1411– 1433,  DOI: 10.1007/s40265-014-0264-y
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    Fingolimod: A Review of Its Use in Relapsing-Remitting Multiple Sclerosis
    Sanford, Mark
    Drugs (2014), 74 (12), 1411-1433CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)
    A review. Fingolimod (Gilenya) is an orally administered disease modifying agent (DMA) for use in relapsing-remitting multiple sclerosis (RRMS). In placebo-controlled trials in patients with RRMS with active disease, fingolimod 0.5 mg/day significantly reduced the annualized relapse rate (ARR) by approx. one-half over 2-yr trial periods. It also significantly increased the proportion of patients with no disability progression, reduced deterioration from baseline in the Extended Disability Status Scale score and reduced MRI markers of disease progression (new/newly enlarging brain lesions and percentage change in brain vol.). In a 12-mo, comparison with i.m. interferon β-1a (IFNβ- 1a) 30 μg/wk, the ARR in fingolimod 0.5 mg/day recipients was significantly lower than in IFNβ-1a recipients by one-half; fingolimod recipients also had significantly lower MRI markers of disease progression. In extensions to the pivotal clin. trials, fingolimod exposure for up to 4 years was assocd. with low relapse rates and continuing benefits in terms of disability and disease progression. In clin. trials, adverse events in fingolimod recipients were generally mild to moderate in severity. In the pivotal placebo-controlled trial, serious adverse events occurred in similar proportions of fingolimod 0.5 mg/day and placebo recipients. First-dose bradycardia and atrioventricular block, which are generally asymptomatic, were clin. important adverse events assocd. with fingolimod in placebo-controlled trials. The risk for serious cardiovascular adverse events at the approved fingolimod dosage appears to be low in patients without pre-existing cardiac conditions. Fingolimod is an efficacious therapy for RRMS that reduces relapses, disability progression, new brain lesions and loss of brain vol. It has an acceptable tolerability profile and provides a useful alternative treatment in patients with RRMS who have responded poorly to other DMAs.
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    Parijat, P.; Kondacs, L.; Alexandrovich, A.; Gautel, M.; Cobb, A. J. A.; Kampourakis, T. High Throughput Screen Identifies Small Molecule Effectors That Modulate Thin Filament Activation in Cardiac Muscle. ACS Chem. Biol. 2021, 16, 225– 235,  DOI: 10.1021/acschembio.0c00908
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    High Throughput Screen Identifies Small Molecule Effectors That Modulate Thin Filament Activation in Cardiac Muscle
    Parijat, Priyanka; Kondacs, Laszlo; Alexandrovich, Alexander; Gautel, Mathias; Cobb, Alexander J. A.; Kampourakis, Thomas
    ACS Chemical Biology (2021), 16 (1), 225-235CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
    Current therapeutic interventions for both heart disease and heart failure are largely insufficient and assocd. with undesired side effects. Biomedical research has emphasized the role of sarcomeric protein function for the normal performance and energy efficiency of the heart, suggesting that directly targeting the contractile myofilaments themselves using small mol. effectors has therapeutic potential and will likely result in greater drug efficacy and selectivity. In this study, we developed a robust and highly reproducible fluorescence polarization-based high throughput screening (HTS) assay that directly targets the calcium-dependent interaction between cardiac troponin C (cTnC) and the switch region of cardiac troponin I (cTnISP), with the aim of identifying small mol. effectors of the cardiac thin filament activation pathway. We screened a com. available small mol. library and identified several hit compds. with both inhibitory and activating effects. We used a range of biophys. and biochem. methods to characterize hit compds. and identified fingolimod, a sphingosin-1-phosphate receptor modulator, as a new troponin-based small mol. effector. Fingolimod decreased the ATPase activity and calcium sensitivity of demembranated cardiac muscle fibers in a dose-dependent manner, suggesting that the compd. acts as a calcium desensitizer. We investigated fingolimod's mechanism of action using a combination of computational studies, biophys. methods, and synthetic chem., showing that fingolimod bound to cTnC repels cTnISP via mainly electrostatic repulsion of its pos. charged tail. These results suggest that fingolimod is a potential new lead compd./scaffold for the development of troponin-directed heart failure therapeutics.
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    Mulakayala, N. A Comprehensive Review on Synthetic Approach for Fingolimod. Indian J. Adv. Chem. Sci. 2016, 4, 362– 366
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    A comprehensive review on synthetic approach for fingolimod
    Mulakayala, Naveen
    Indian Journal of Advances in Chemical Science (2016), 4 (4), 362-366CODEN: IJACKX; ISSN:2320-0928. (KROS Publications)
    A review. Multiple sclerosis (MS) often consequences in chronic inflammatory and autoimmune disorders, and recent developments have lead to newer therapeutic options for the treatment of the disease. In this review, we have summarized the literature known synthetic strategies of fingolimod which is the key small mol., and the first oral drug candidate for MS which have been launched in the market.
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    Urbano, M.; Guerrero, M.; Rosen, H.; Roberts, E. Modulators of the Sphingosine 1-phosphate receptor 1. Bioorg. Med. Chem. Lett. 2013, 23, 6377– 6389,  DOI: 10.1016/j.bmcl.2013.09.058
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    Modulators of the Sphingosine 1-phosphate receptor 1
    Urbano, Mariangela; Guerrero, Miguel; Rosen, Hugh; Roberts, Edward
    Bioorganic & Medicinal Chemistry Letters (2013), 23 (23), 6377-6389CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    A review. The Sphingosine 1-phosphate receptor (S1P-R) signaling system has proven to be of biol. and medical importance in autoimmune settings. S1P1-R is a validated drug target for multiple sclerosis (MS) for which FTY720 (Fingolimod), a S1P1,3-5-R pan-agonist, was recently approved as the first orally active drug for the treatment of relapsing-remitting MS. Transient bradycardia and long half-life are the FTY720 crit. pitfalls. This review provides the latest advances on next-generation S1P1-R modulators from 2012 up to date, with an overview of the chem. structures, structure-activity relationships, and relevant biol. and clin. properties.
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    Mandala, S.; Hajdu, R.; Bergstrom, J.; Quackenbush, E.; Xie, J.; Milligan, J.; Thornton, R.; Shei, G. J.; Card, D.; Keohane, C. A. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002, 296, 346– 349,  DOI: 10.1126/science.1070238
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    Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists
    Mandala, Suzanne; Hajdu, Richard; Bergstrom, James; Quackenbush, Elizabeth; Xie, Jenny; Milligan, James; Thornton, Rosemary; Shei, Gan-Ju; Card, Deborah; Keohane, Carolann; Rosenbach, Mark; Hale, Jeffrey; Lynch, Christopher L.; Rupprecht, Kathleen; Parsons, William; Rosen, Hugh
    Science (Washington, DC, United States) (2002), 296 (5566), 346-349CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Blood lymphocyte nos., essential for the development of efficient immune responses, are maintained by recirculation through secondary Lymphoid organs. We show that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolite of the immunosuppressive agent FTY720. Both species were high-affinity agonists of at least four of the five S1P receptors. These agonists produce lymphopenia in blood and thoracic duct lymph by sequestration of lymphocytes in lymph nodes, but not spleen. S1P receptor agonists induced emptying of lymphoid sinuses by retention of lymphocytes on the abluminal side of sinus-lining endothelium and inhibition of egress into lymph. Inhibition of lymphocyte recirculation by activation of S1P receptors may result in therapeutically useful immunosuppression.
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    (a) Chen, S.; Yang, L.; Shang, Y.; Mao, J.; Walsh, P. J. Base-Promoted Tandem Synthesis of 2-Azaaryl Tetrahydroquinolines. Org. Lett. 2021, 23, 1594– 1599,  DOI: 10.1021/acs.orglett.0c04306
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    Base-Promoted Tandem Synthesis of 2-Azaaryl Tetrahydroquinolines
    Chen, Shuguang; Yang, Langxuan; Shang, Yongjia; Mao, Jianyou; Walsh, Patrick J.
    Organic Letters (2021), 23 (5), 1594-1599CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    A novel method to synthesize 2-azaaryl tetrahydroquinolines by the base-promoted tandem reaction of azaaryl Me amines and styrene derivs. was reported (over 30 examples, yields up to 95%). Mechanistic probe expts. demonstrate that the deprotonation of the benzylic C-H bond and the addn. to the styrene vinyl group proceeds via the SNAr mechanism.
    (b) Warsitz, M.; Doye, S. Two-Step Procedure for the Synthesis of 1,2,3,4-Tetrahydroquinolines. Eur. J. Org. Chem. 2020, 2020, 6997– 7014,  DOI: 10.1002/ejoc.202001337
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    Two-Step Procedure for the Synthesis of 1,2,3,4-Tetrahydro-quinolines
    Warsitz, Michael; Doye, Sven
    European Journal of Organic Chemistry (2020), 2020 (45), 6997-7014CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A new two-step procedure that includes an initial regioselective intermol. hydroaminoalkylation of ortho-chlorostyrenes with N-methylanilines and a subsequent intramol. Buchwald-Hartwig amination gives direct access to 1,2,3,4-tetrahydroquinolines. The hydroaminoalkylation reaction of the ortho-chlorostyrenes is catalyzed by a 2,6-bis(phenylamino)pyridinato titanium complex which delivers the linear regioisomers with high selectivities. In addn., the formation of unexpected dihydroaminoalkylation products from styrenes and N-methylanilines is reported.
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    Muthukrishnan, I.; Sridharan, V.; Menéndez, J. C. Progress in the Chemistry of Tetrahydroquinolines. Chem. Rev. 2019, 119, 5057– 5191,  DOI: 10.1021/acs.chemrev.8b00567
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    Progress in the Chemistry of Tetrahydroquinolines
    Muthukrishnan, Isravel; Sridharan, Vellaisamy; Menendez, J. Carlos
    Chemical Reviews (Washington, DC, United States) (2019), 119 (8), 5057-5191CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. This review summarizes the progress achieved in the chem. of tetrahydroquinolines, with emphasis on their synthesis, during the mid-2010 to early 2018 period.
  42. 42

    Based on a Scifinder search conducted in April 2021, with the following constraints applied: benzenoid-fused only, 800 MW max, no other ring fusions, only H/C/S attached to N, no isotopes/metals.

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    Hiesinger, K.; Dar’in, D.; Proschak, E.; Krasavin, M. Spirocyclic Scaffolds in Medicinal Chemistry. J. Med. Chem. 2021, 64, 150– 183,  DOI: 10.1021/acs.jmedchem.0c01473
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    Spirocyclic Scaffolds in Medicinal Chemistry
    Hiesinger, Kerstin; Dar'in, Dmitry; Proschak, Ewgenij; Krasavin, Mikhail
    Journal of Medicinal Chemistry (2021), 64 (1), 150-183CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A review. Spirocyclic scaffolds are incorporated in various approved drugs and drug candidates. The increasing interest in less planar bioactive compds. has given rise to the development of synthetic methodologies for the prepn. of spirocyclic scaffolds. In this Perspective, we summarize the diverse synthetic routes to obtain spirocyclic systems. The impact of spirocycles on potency and selectivity, including the aspect of stereochem., is discussed. Furthermore, we examine the changes in physicochem. properties as well as in in vitro and in vivo ADME using selected studies that compare spirocyclic compds. to their nonspirocyclic counterparts. In conclusion, the value of spirocyclic scaffolds in medicinal chem. is discussed.
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    St. Denis, J. D.; Hall, R. J.; Murray, C. W.; Heightman, T. D.; Rees, D. C. Fragment-based drug discovery: opportunities for organic synthesis. RSC Med. Chem. 2021, 12, 321– 329,  DOI: 10.1039/D0MD00375A
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    Fragment-based drug discovery: opportunities for organic synthesis
    St. Denis, Jeffrey D.; Hall, Richard J.; Murray, Christopher W.; Heightman, Tom D.; Rees, David C.
    RSC Medicinal Chemistry (2021), 12 (3), 321-329CODEN: RMCSEZ; ISSN:2632-8682. (Royal Society of Chemistry)
    A review. This Review describes the increasing demand for org. synthesis to facilitate fragment-based drug discovery (FBDD), focusing on polar, unprotected fragments. In FBDD, X-ray crystal structures are used to design target mols. for synthesis with new groups added onto a fragment via specific growth vectors. This requires challenging synthesis which slows down drug discovery, and some fragments are not progressed into optimization due to synthetic intractability. We have evaluated the output from Astex's fragment screenings for a no. of programs, including urokinase-type plasminogen activator, hematopoietic prostaglandin D2 synthase, and hepatitis C virus NS3 protease-helicase, and identified fragments that were not elaborated due, in part, to a lack of com. available analogs and/or suitable synthetic methodol. This represents an opportunity for the development of new synthetic research to enable rapid access to novel chem. space and fragment optimization.
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    Twigg, D. G.; Kondo, N.; Mitchell, S. L.; Galloway, W. R. D.; Sore, H. F.; Madin, A.; Spring, D. R. Partially Saturated Bicyclic Heteroaromatics as an sp3-Enriched Fragment Collection. Angew. Chem., Int. Ed. 2016, 55, 12479– 12483,  DOI: 10.1002/anie.201606496
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    Partially Saturated Bicyclic Heteroaromatics as an sp3-Enriched Fragment Collection
    Twigg, David G.; Kondo, Noriyasu; Mitchell, Sophie L.; Galloway, Warren R. J. D.; Sore, Hannah F.; Madin, Andrew; Spring, David R.
    Angewandte Chemie, International Edition (2016), 55 (40), 12479-12483CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Fragment-based lead generation has proven to be an effective means of identifying high-quality lead compds. for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp2-rich arom. compds., which limits the structural (and hence biol.) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially satd. bicyclic heteroarom. scaffolds with enhanced sp3 character. Subsequent derivatization led to a fragment collection featuring regio- and stereo-controlled introduction of substituents on the satd. ring system, often with formation of new stereocenters.
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    Law, R. P.; Atkinson, S. J.; Bamborough, P.; Chung, C.-w.; Demont, E. H.; Gordon, L. J.; Lindon, M.; Prinjha, R. K.; Watson, A. J. B.; Hirst, D. J. Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain. J. Med. Chem. 2018, 61, 4317– 4334,  DOI: 10.1021/acs.jmedchem.7b01666
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    Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain
    Law, Robert P.; Atkinson, Stephen J.; Bamborough, Paul; Chung, Chun-wa; Demont, Emmanuel H.; Gordon, Laurie J.; Lindon, Matthew; Prinjha, Rab K.; Watson, Allan J. B.; Hirst, David J.
    Journal of Medicinal Chemistry (2018), 61 (10), 4317-4334CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomains-BRD2, BRD3, BRD4, and BRDT-each contain two bromodomain modules. BET bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the BET family. Inhibitors with selectivity for the first or second bromodomain are desired to aid investigation of the biol. function of these domains. Focused library screening identified a series of tetrahydroquinoxalines with selectivity for the second bromodomains of the BET family (BD2). Structure-guided optimization of the template improved potency, selectivity, and physicochem. properties, culminating in potent BET inhibitors with BD2 selectivity.
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    Procopiou, P. A.; Anderson, N. A.; Barrett, J.; Barrett, T. N.; Crawford, M. H. J.; Fallon, B. J.; Hancock, A. P.; Le, J.; Lemma, S.; Marshall, R. P. Discovery of (S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-l)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αvβ6 Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary Fibrosis. J. Med. Chem. 2018, 61, 8417– 8443,  DOI: 10.1021/acs.jmedchem.8b00959
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    Discovery of (S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αvβ6 Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary Fibrosis
    Procopiou, Panayiotis A.; Anderson, Niall A.; Barrett, John; Barrett, Tim N.; Crawford, Matthew H. J.; Fallon, Brendan J.; Hancock, Ashley P.; Le, Joelle; Lemma, Seble; Marshall, Richard P.; Morrell, Josie; Pritchard, John M.; Rowedder, James E.; Saklatvala, Paula; Slack, Robert J.; Sollis, Steven L.; Suckling, Colin J.; Thorp, Lee R.; Vitulli, Giovanni; Macdonald, Simon J. F.
    Journal of Medicinal Chemistry (2018), 61 (18), 8417-8443CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A series of 3-aryl-(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, which involved rhodium catalyzed asym. 1,4-addn. of arylboronic acids in the presence of (R)-BINAP to a crotonate ester to provide the (S) abs. configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole and cyclic ether were screened in cell adhesion assays for affinity against αvβ1, αvβ3, αvβ5, αvβ6 and αvβ8 integrins. Several analogs with high affinity and selectivity for the αvβ6 integrin were identified. The analog I·HCl was found to have high affinity for αvβ6 integrin in a radioligand binding assay (pKi = 11), a long dissocn. half-life (7 h) , high soly. in saline at pH 7 (>71 mg/mL) and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It was selected for further investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.
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    Fairhurst, R. A.; Knoepfel, T.; Buschmann, N.; Leblanc, C.; Mah, R.; Todorov, M.; Nimsgern, P.; Ripoche, S.; Niklaus, M.; Warin, N. Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4. J. Med. Chem. 2020, 63, 12542– 12573,  DOI: 10.1021/acs.jmedchem.0c01019
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    Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4
    Fairhurst, Robin A.; Knoepfel, Thomas; Buschmann, Nicole; Leblanc, Catherine; Mah, Robert; Todorov, Milen; Nimsgern, Pierre; Ripoche, Sebastien; Niklaus, Michel; Warin, Nicolas; Luu, Van Huy; Madoerin, Mario; Wirth, Jasmin; Graus-Porta, Diana; Weiss, Andreas; Kiffe, Michael; Wartmann, Markus; Kinyamu-Akunda, Jacqueline; Sterker, Dario; Stamm, Christelle; Adler, Flavia; Buhles, Alexandra; Schadt, Heiko; Couttet, Philippe; Blank, Jutta; Galuba, Inga; Trappe, Jorg; Voshol, Johannes; Ostermann, Nils; Zou, Chao; Berghausen, Jorg; Del Rio Espinola, Alberto; Jahnke, Wolfgang; Furet, Pascal
    Journal of Medicinal Chemistry (2020), 63 (21), 12542-12573CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    FGF19 signaling through the FGFR4/β-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas, making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarized which made use of both rational and unbiased screening approaches. The optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimization are improving the FGFR4 potency, metabolic stability, and soly. leading ultimately to the highly selective first-in-class clin. candidate roblitinib.
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    We cannot exclude the possibility that azidyl radical may react initially with the DMF solvent to generate an α-carbamoyl radical by HAT with a C–H bond on one of the N-Me groups (BDE ≈ 105 kcal mol–1; see ref (20)) and that this radical may in turn be responsible for abstracting a hydrogen from the alkylamine. We thank a reviewer for this suggestion.

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    Prieto, A.; Taillefer, M. Visible-Light Decatungstate/Disulfide Dual Catalysis for the Hydro-Functionalization of Styrenes. Org. Lett. 2021, 23 (4), 1484– 1488,  DOI: 10.1021/acs.orglett.1c00189
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    Visible-Light Decatungstate/Disulfide Dual Catalysis for the Hydro-Functionalization of Styrenes
    Prieto, Alexis; Taillefer, Marc
    Organic Letters (2021), 23 (4), 1484-1488CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    An efficient photoredox system, relied on decatungstate/disulfide catalysts, for the hydrofunctionalization of styrenes was described. In this methodol. the use of disulfide as a cocatalyst was shown to be crucial for the reaction efficiency. This photoredox system was employed for the hydro-carbamoylation, -acylation, -alkylation, and -silylation of styrenes, gave access to a large variety of useful building blocks and high-value mols. such as amides and unsym. ketones from simple starting materials.
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    Cismesia, M. A.; Yoon, T. P. Characterizing chain processes in visible light photoredox catalysis. Chem. Sci. 2015, 6, 5426– 5434,  DOI: 10.1039/C5SC02185E
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    Characterizing chain processes in visible light photoredox catalysis
    Cismesia, Megan A.; Yoon, Tehshik P.
    Chemical Science (2015), 6 (10), 5426-5434CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    The recognition that Ru(bpy)32+ and similar visible light absorbing transition metal complexes can be photocatalysts for a variety of synthetically useful org. reactions has resulted in a recent resurgence of interest in photoredox catalysis. However, many of the crit. mechanistic aspects of this class of reactions remain poorly understood. In particular, the degree to which visible light photoredox reactions involve radical chain processes has been a point of some disagreement that has not been subjected to systematic anal. We have now performed quantum yield measurements to demonstrate that three representative, mechanistically distinct photoredox processes involve product-forming chain reactions. Moreover, we show that the combination of quantum yield and luminescence quenching expts. provides a rapid method to est. the length of these chains. Together, these measurements constitute a robust, operationally facile strategy for characterizing chain processes in a wide range of visible light photoredox reactions.
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    Tagami, T.; Arakawa, Y.; Minagawa, K.; Imada, Y. Efficient Use of Photons in Photoredox/Enamine Dual Catalysis with a Peptide-Bridged Flavin–Amine Hybrid. Org. Lett. 2019, 21, 6978– 6982,  DOI: 10.1021/acs.orglett.9b02567
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    Efficient Use of Photons in Photoredox/Enamine Dual Catalysis with a Peptide-Bridged Flavin-Amine Hybrid
    Tagami, Takuma; Arakawa, Yukihiro; Minagawa, Keiji; Imada, Yasushi
    Organic Letters (2019), 21 (17), 6978-6982CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    An isoalloxazine (flavin) ring system and a secondary amine have been integrated through a short peptide linker with the aim of using photons as efficiently as possible in photoredox/enamine dual catalysis. We herein report a peptide-bridged flavin-amine hybrid that can catalyze α-oxyamination of aldehydes with TEMPO under weak blue light irradn. to achieve an extremely high quantum yield of reaction (Φ = 0.80).
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    Burés, J. Variable Time Normalization Analysis: General Graphical Elucidation of Reaction Orders from Concentration Profiles. Angew. Chem., Int. Ed. 2016, 55, 16084– 16087,  DOI: 10.1002/anie.201609757
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    Variable Time Normalization Analysis: General Graphical Elucidation of Reaction Orders from Concentration Profiles
    Bures, Jordi
    Angewandte Chemie, International Edition (2016), 55 (52), 16084-16087CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The recent technol. evolution of reaction monitoring techniques has not been paralleled by the development of modern kinetic analyses. The analyses currently used disregard part of the data acquired, thus requiring an increased no. of expts. to obtain sufficient kinetic information for a given chem. reaction. Herein, we present a simple graphical anal. method that takes advantage of the data-rich results provided by modern reaction monitoring tools. This anal. uses a variable normalization of the time scale to enable the visual comparison of entire concn. reaction profiles. As a result, the order in each component of the reaction, as well as kobs , is detd. with just a few expts. using a simple and quick math. data treatment. This anal. facilitates the rapid extn. of relevant kinetic information and will be a valuable tool for the study of reaction mechanisms.
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    If the addition step of the α-amino radical 25 to the styrene 6 is reversible, then the concentration of benzylic radical 26 would exhibit a dependence on the concentration of styrene 6 (pre-equilibrium approximation). However, if the addition step is rapid and essentially irreversible, then saturation kinetics will occur and the concentration of benzylic radical 26 will become independent of styrene 6 concentration.

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    Bloh, J. Z. A Holistic Approach to Model the Kinetics of Photocatalytic Reactions. Front. Chem. 2019, 7, 128,  DOI: 10.3389/fchem.2019.00128
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    A holistic approach to model the kinetics of photocatalytic reactions
    Bloh, Jonathan Z.
    Frontiers in Chemistry (Lausanne, Switzerland) (2019), 7 (), 128CODEN: FCLSAA; ISSN:2296-2646. (Frontiers Media S.A.)
    Understanding and modeling kinetics is an essential part of the optimization and implementation of chem. reactions. In the case of photocatalytic reactions this is mostly done one-dimensionally, i.e., only considering the effect of one parameter at the same time. However, as discussed in this study, many of the relevant reaction parameters have mutual interdependencies that call for a holistic multi-dimensional approach to accurately model and understand their influence. Such an approach is described herein, and all the relevant equations given so that researchers can readily implement it to analyze and model their reactions.
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    (a) Ji, Y.; DiRocco, D. A.; Kind, J.; Thiele, C. M.; Gschwind, R. M.; Reibarkh, M. LED-Illuminated NMR Spectroscopy: A Practical Tool for Mechanistic Studies of Photochemical Reactions. ChemPhotoChem. 2019, 3, 984– 992,  DOI: 10.1002/cptc.201900109
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    LED-Illuminated NMR Spectroscopy: A Practical Tool for Mechanistic Studies of Photochemical Reactions
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    ChemPhotoChem (2019), 3 (10), 984-992CODEN: CHEMYH ISSN:. (Wiley-VCH Verlag GmbH & Co. KGaA)
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  • Abstract

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    Figure 1

    Figure 1. (A) Prior art for catalytic γ-lactam synthesis from primary alkylamines. (B) Importance of γ-arylamines. (C) This work.

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    Figure 2

    Figure 2. Yields measured by 1H NMR against 1,3,5-trimethoxybenzene as an internal standard. Reference for redox potentials of photocatalysts. (23) References for oxidation potentials of HAT catalysts: 10, ref (9d); 11, ref (27); 12, ref (16); 13, ref (25); 14, ref (16); and 15, ref (9i).

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    Figure 3

    Figure 3. All reactions were carried out on a scale of 0.45 mmol. Isolated yields are reported. Notes: [a] 6% of inseparable, dialkylated product (wrt 1c). [b] With 3.0 equiv of amine. [c] With 1.0 equiv of amine. [d] The mass balance comprised a mixture of unidentified byproducts but no detectable starting materials. [e] 44% of unreacted amine 1l. [f] 46% of dialkylated product (wrt 1n). [g] 41% of dialkylated product (wrt 1s). [h] 54% of unreacted amine 1t and 6% styrene 6c. [i] 9% of dialkylated product (wrt 1u). [j] 9% of dialkylated product (wrt 1u). [k] Incomplete conversion to a complex mixture of products, which may include dialkylated material. [l] Isolated yield of Boc-protected 7zc (61:39 dr) plus 11% of the lactam derived from thermal lactamization of 7zc during workup. [m] 18% of dialkylated product (wrt 6c). [n] Incomplete conversion to a complex mixture of products. Boc = tert-butoxycarbonyl.

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    Figure 4

    Figure 4. All reactions were carried out on a scale of 0.45 mmol. Isolated yields are reported. Notes: [a] Gave 40% NMR yield of 7ae along with 24% unreacted 6e and 6% of allylbenzene, plus other unidentified products. [b] Isolated as the phenol by oxidation the Bpin group with H2O2. [c] 22% of inseparable, debrominated product was also produced. [d] Yield given is for the N-Boc-protected derivative of 7ar, which proved easier to isolate. [e] 9% of a 1:2 telomer and 43% (wrt 6r) of reductive homocoupling product 1,4-di(pyrazin-2-yl)butane was also isolated. [f] The crude product mixture contained a 60:40 ratio of 7as to its debrominated analogue.

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    Figure 5

    Figure 5. (A) Application to a protecting group-free synthesis of Fingolimod (4). (B) One-pot synthesis of a phosphonate mimic (21) of Fingolimod phosphate by tandem sequential α-C–H alkylation of ethanolamine (1r). Note: [a] 23% of the dialkylation product of 1r with 17 was also isolated. TMS = trimethylsilyl.

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    Figure 6

    Figure 6. (A) Modular synthesis of 1,2,3,4-tetrahydroquinolines (THQs). In all cases except for 8an, the remaining mass balance comprised unreacted starting material. Note: [a] Obtained as an inseparable mixture with 8ac (14%), the proto-dechlorinated analogue of 8an. (B) Modular synthesis of 1,2,3,4-tetrahydronaphthyridines (THNs).

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    Figure 7

    Figure 7. (A) Proposed catalytic cycle. (B) Stern–Volmer luminescence quenching. (C) Irreversibility of the HAT step. (D) Variable time normalization (VTNA) kinetic analysis using automated flow chemistry.

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  • References

    This article references 58 other publications.

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      Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and Applications; Wiley-VCH, 2010.
      There is no corresponding record for this reference.
    2. 2
      Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.; Thomas, A. W.; Wilson, D. M.; Wood, A. Organic Synthesis Provides Opportunities to Transform Drug Discovery. Nat. Chem. 2018, 10, 383– 394,  DOI: 10.1038/s41557-018-0021-z
      2
      Organic synthesis provides opportunities to transform drug discovery
      Blakemore, David C.; Castro, Luis; Churcher, Ian; Rees, David C.; Thomas, Andrew W.; Wilson, David M.; Wood, Anthony
      Nature Chemistry (2018), 10 (4), 383-394CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)
      Despite decades of ground-breaking research in academia, org. synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic org. chem. from the perspective of the pharmaceutical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of transformational medicines. Significant synthesis challenges arise from the fact that drug mols. typically contain amines and N-heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non-traditional disconnections, more C-H bond activation and late-stage functionalization, as well as stereoselectively substituted aliph. heterocyclic ring synthesis, C-X or C-C bond formation. We also emphasize that syntheses compatible with biomacromols. will find increasing use, while new technologies such as machine-assisted approaches and artificial intelligence for synthesis planning have the potential to dramatically accelerate the drug-discovery process. We believe that increasing collaboration between academic and industrial chemists is crucial to address the challenges outlined here.
    3. 3
      (a) Manßen, M.; Schafer, L. L. Early Transition Metal-Catalyzed Hydroaminoalkylation. Trends Chem. 2021, 3, 428– 429,  DOI: 10.1016/j.trechm.2020.11.007
      3a
      Early Transition Metal-Catalyzed Hydroaminoalkylation
      Manssen, Manfred; Schafer, Laurel L.
      Trends in Chemistry (2021), 3 (5), 428-429CODEN: TCRHBQ; ISSN:2589-5974. (Cell Press)
      There is no expanded citation for this reference.
      (b) Trowbridge, A.; Walton, S. M.; Gaunt, M. J. New Strategies for the Transition-Metal Catalyzed Synthesis of Aliphatic Amines. Chem. Rev. 2020, 120, 2613– 2692,  DOI: 10.1021/acs.chemrev.9b00462
      3b
      New Strategies for the Transition-Metal Catalyzed Synthesis of Aliphatic Amines
      Trowbridge, Aaron; Walton, Scarlett M.; Gaunt, Matthew J.
      Chemical Reviews (Washington, DC, United States) (2020), 120 (5), 2613-2692CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. In light of the ever-increasing importance of aliph. amines across the range of chem. sciences, this review aims to provide a concise overview of modern transition-metal catalyzed approaches to alkylamine synthesis and their functionalization. Selected examples of amine bond forming reactions include, hydroamination and hydroaminoalkylation, transition-metal catalyzed C(sp3)-H functionalization and transition-metal catalyzed visible-light-mediated light photoredox catalysis.
      (c) Edwards, P. M.; Schafer, L. L. Early transition metal-catalyzed C–H alkylation: hydroaminoalkylation for Csp3–Csp3 bond-formation in the synthesis of selectively substituted amines. Chem. Commun. 2018, 54, 12543– 12560,  DOI: 10.1039/C8CC06445H
      3c
      Early transition metal-catalyzed C-H alkylation: hydroaminoalkylation for Csp3-Csp3 bond formation in the synthesis of selectively substituted amines
      Edwards, P. M.; Schafer, L. L.
      Chemical Communications (Cambridge, United Kingdom) (2018), 54 (89), 12543-12560CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      A review. In this feature article, various selectively substituted amines that can be accessed by hydroaminoalkylation, with a special focus on the development of early transition metal catalysts for their rapid, step and atom efficient assembly were discussed.
    4. 4
      (a) Manßen, M.; Deng, D.; Zheng, C. H. M.; DiPucchio, R. C.; Chen, D.; Schafer, L. L. Ureate Titanium Catalysts for Hydroaminoalkylation: Using Ligand Design to Increase Reactivity and Utility. ACS Catal. 2021, 11, 4550– 4560,  DOI: 10.1021/acscatal.1c00014
      4a
      Ureate Titanium Catalysts for Hydroaminoalkylation: Using Ligand Design to Increase Reactivity and Utility
      Manssen, Manfred; Deng, Danfeng; Zheng, Cameron H. M.; DiPucchio, Rebecca C.; Chen, Dafa; Schafer, Laurel L.
      ACS Catalysis (2021), 11 (8), 4550-4560CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      Herein, an earth-abundant and cost-efficient titanium catalyst generated in situ using com. available Ti(NMe2)4 and a simple to synthesize urea proligand was described. This system demonstrated high TOFs for hydroaminoalkylation with unactivated substrates and features easy to use com. available titanium amido precursors. Addnl., a high catalytic activity, scope of reactivity, and regioselectivity were all demonstrated in the transformation of unactivated terminal olefins with various alkyl and aryl secondary amines. Finally, syntheses of useful amine-contg. monomers suitable for the generation of amine-contg. materials, as well as amine-contg. building blocks for medicinal chem., were disclosed. These preparative methods avoid the necessity of glovebox techniques and were modified to be useful to all synthetic chemists.
      (b) Koperniku, A.; Schafer, L. L. Zirconium Catalyzed Hydroaminoalkylation for the Synthesis of α-Arylated Amines and N-Heterocycles. Chem. - Eur. J. 2021, 27, 6334– 6339,  DOI: 10.1002/chem.202100014
      4b
      Zirconium Catalyzed Hydroaminoalkylation for the Synthesis of α-Arylated Amines and N-Heterocycles
      Koperniku, Ana; Schafer, Laurel L.
      Chemistry - A European Journal (2021), 27 (20), 6334-6339CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The zirconium catalyzed hydroaminoalkylation of alkenes with N-aryl- and sterically demanding N-alkyl-α-arylated secondary amines by using com. available Zr(NMe2)4 is reported. N-phenyl- and N-isopropylbenzylamine are used as amine substrates to establish the alkene substrate scope. Exclusively linear products are obtained in the presence of bulky vinylsilanes. Challenging α-heteroarylated amines and functionalized alkene substrates are compatible with this easy to use catalyst, affording a new disconnection strategy for the atom- and step-economic prepn. of selectively substituted satd. α-arylated heterocycles.
      (c) Daneshmand, P.; Roşca, S.-C.; Dalhoff, R.; Yin, K.; DiPucchio, R. C.; Ivanovich, R. A.; Polat, D. E.; Beauchemin, A. M.; Schafer, L. L. Cyclic Ureate Tantalum Catalyst for Preferential Hydroaminoalkylation with Aliphatic Amines: Mechanistic Insights into Substrate Controlled Reactivity. J. Am. Chem. Soc. 2020, 142, 15740– 15750,  DOI: 10.1021/jacs.0c04579
      4c
      Cyclic Ureate Tantalum Catalyst for Preferential Hydroaminoalkylation with Aliphatic Amines: Mechanistic Insights into Substrate Controlled Reactivity
      Daneshmand, Pargol; Rosca, Sorin-Claudiu; Dalhoff, Rosalie; Yin, Kejun; DiPucchio, Rebecca C.; Ivanovich, Ryan A.; Polat, Dilan E.; Beauchemin, Andre M.; Schafer, Laurel L.
      Journal of the American Chemical Society (2020), 142 (37), 15740-15750CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The efficient and catalytic amination of unactivated alkenes with simple secondary alkyl amines is preferentially achieved. A sterically accessible, N,O-chelated cyclic ureate tantalum catalyst was prepd. and characterized by X-ray crystallog. This optimized catalyst can be used for the hydroaminoalkylation of 1-octene with a variety of aryl and alkyl amines, but notably enhanced catalytic activity can be realized with challenging N-alkyl secondary amine substrates. This catalyst offers turnover frequencies of up to 60 h-1, affording full conversion at 5 mol% catalyst loading in approx. 20 min with these nucleophilic amines. Mechanistic investigations, including kinetic isotope effect (KIE) studies, reveal that catalytic turnover is limited by protonolysis of the intermediate 5-membered azametallacycle. A Hammett kinetic anal. shows that catalytic turnover is promoted by electron rich amine substrates that enable catalytic turnover. This more active catalyst is shown to be effective for late stage drug modification.
      (d) Bielefeld, J.; Doye, S. Fast Titanium-Catalyzed Hydroaminomethylation of Alkenes and the Formal Conversion of Methylamine. Angew. Chem., Int. Ed. 2020, 59, 6138– 6143,  DOI: 10.1002/anie.202001111
      4d
      Fast Titanium-Catalyzed Hydroaminomethylation of Alkenes and the Formal Conversion of Methylamine
      Bielefeld, Jens; Doye, Sven
      Angewandte Chemie, International Edition (2020), 59 (15), 6138-6143CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The scientific interest in catalytic hydroaminoalkylation reactions of alkenes has vastly increased over the past decade, but these reactions have struggled to become a viable option for general lab. or industrial use because of reaction times of several days. The titanium-based catalytic system introduced in this work not only reduces the reaction time by several orders of magnitude, into the range of minutes, but the catalyst also is easily available from common starting materials, at a cost of ∼1 euro per mmol of catalyst. The authors were also able to formally perform C-H activation of methylamine and achieve coupling to a broad variety of alkenes, through silyl protection of the amine and simple deprotection by water.
      (e) Warsitz, M.; Doye, S. Linear Hydroaminoalkylation Products from Alkyl-Substituted Alkenes. Chem. - Eur. J. 2020, 26, 15121– 15125,  DOI: 10.1002/chem.202003223
      4e
      Linear Hydroaminoalkylation Products from Alkyl-Substituted Alkenes
      Warsitz, Michael; Doye, Sven
      Chemistry - A European Journal (2020), 26 (66), 15121-15125CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A new one-pot procedure that includes an initial alkene hydroaminoalkylation with an α-silylated amine substrate and a subsequent protodesilylation reaction that delivers linear hydroaminoalkylation products with high selectivity from simple alkyl-substituted alkenes was presented. For that purpose, new titanium catalysts were developed, which are able to activate the α-C-H bond of more challenging α-silylated amine substrates. In addn., a direct relationship between the ligand structure of the new catalysts and the obtained regioselectivity was described.
    5. 5
      Geik, D.; Rosien, M.; Bielefeld, J.; Schmidtmann, M.; Doye, S. Titanium-Catalyzed Intermolecular Hydroaminoalkylation of Alkenes with Tertiary Amines. Angew. Chem., Int. Ed. 2021, 60, 9936– 9940,  DOI: 10.1002/anie.202100431
      5
      Titanium-Catalyzed Intermolecular Hydroaminoalkylation of Alkenes with Tertiary Amines
      Geik, Dennis; Rosien, Michael; Bielefeld, Jens; Schmidtmann, Marc; Doye, Sven
      Angewandte Chemie, International Edition (2021), 60 (18), 9936-9940CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The first cationic titanium catalyst system for the intermol. hydroaminoalkylation of alkenes with various tertiary alkylamines is presented. Corresponding reactions which involve the addn. of the α-C-H bond of a tertiary amine across the C-C double bond of an alkene take place at temps. close to room temp. with excellent regioselectivity to deliver the branched products exclusively. Interestingly, for selected amines, α-C-H bond activation occurs not only at N-Me but also at N-methylene groups.
    6. 6

      We use this term to refer to alkenes that do not readily participate as Michael acceptors in polar reactions with two-electron nucleophiles (e.g., non-conjugated alkenes, styrenes lacking π-acceptor substituents).

      There is no corresponding record for this reference.
    7. 7
      (a) Verma, P.; Richter, J. M.; Chekshin, N.; Qiao, J. X.; Yu, J.-Q. Iridium(I)-Catalyzed α-C(sp3)–H Alkylation of Saturated Azacycles. J. Am. Chem. Soc. 2020, 142, 5117– 5125,  DOI: 10.1021/jacs.9b12320
      7a
      Iridium(I)-Catalyzed α-C(sp3)-H Alkylation of Saturated Azacycles
      Verma, Pritha; Richter, Jeremy M.; Chekshin, Nikita; Qiao, Jennifer X.; Yu, Jin-Quan
      Journal of the American Chemical Society (2020), 142 (11), 5117-5125CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Satd. azacycles are commonly encountered in bioactive compds. and approved therapeutic agents. The development of methods for functionalization of the α-methylene C-H bonds of these highly privileged building blocks is of great importance, esp. in drug discovery. While much effort has been dedicated towards this goal of using a directed C-H activation approach, the development of directing groups that are both general, as well as practical, remains a significant challenge. Herein, the design and development of novel amidoxime directing groups is described for Ir(I)-catalyzed α-C(sp3)-H alkylation of satd. azacycles using readily available olefins as coupling partners. This protocol extends the scope of satd. azacycles to piperidines, azepane, and tetrahydroisoquinoline that are incompatible with our previously reported directing group. A variety of olefin coupling partners, including previously unreactive di-substituted terminal olefins and internal olefins, are compatible with this transformation. The selectivity for a branched α-C(sp3)-alkylation product is also obsd. for the first time when acrylate is used as the reaction partner. The development of practical, one-step installation and removal protocols further add to the utility of amidoxime directing groups.
      (b) Tran, A. T.; Yu, J.-Q. Practical Alkoxythiocarbonyl Auxiliaries for Iridium(I)-Catalyzed C–H Alkylation of Azacycles. Angew. Chem., Int. Ed. 2017, 56, 10530– 10534,  DOI: 10.1002/anie.201704755
      7b
      Practical Alkoxythiocarbonyl Auxiliaries for Iridium(I)-Catalyzed C-H Alkylation of Azacycles
      Tran, Anh T.; Yu, Jin-Quan
      Angewandte Chemie, International Edition (2017), 56 (35), 10530-10534CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The development of new and practical alkylated 3-pentoxythiocarbonyl auxiliaries, e.g., I for Ir(I)-catalyzed C-H alkylation of azacycles was described. This method allowed for the α-C-H alkylation of a variety of substituted pyrrolidines, piperidines and tetrahydroisoquinolines through alkylation with alkenes. While the practicality of these simple carbamate-type auxiliaries was underscored by the ease of installation and removal, the method's utility was demonstrated in its ability to functionalize biol. relevant L-proline and L-trans-hydroxyproline, delivering unique 2,5-dialkylated amino acid analogs that were not accessible by other C-H functionalization methods.
      (c) Lahm, G.; Opatz, T. Unique Regioselectivity in the C(sp3)–H α-Alkylation of Amines: The Benzoxazole Moiety as a Removable Directing Group. Org. Lett. 2014, 16, 4201– 4203,  DOI: 10.1021/ol501935d
      7c
      Unique Regioselectivity in the C(sp3)-H α-Alkylation of Amines: The Benzoxazole Moiety as a Removable Directing Group
      Lahm, Guenther; Opatz, Till
      Organic Letters (2014), 16 (16), 4201-4203CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      The benzoxazol-2-yl- substituent was found to act as a removable activating and directing group in the Ir-catalyzed alkylation of C(sp3)-H bonds adjacent to nitrogen in secondary amines. It can be easily introduced by oxidative coupling or by an SNAr reaction, and it can be removed by hydroxide or by hydride redn. For 1,2,3,4-tetrahydroisoquinolines, activation exclusively takes place in the 3-position. A variety of activated as well as unactivated terminal olefins are suitable reaction partners.
      (d) Schinkel, M.; Wang, L.; Bielefeld, K.; Ackermann, L. Ruthenium(II)-Catalyzed C(sp3)–H α-Alkylation of Pyrrolidines. Org. Lett. 2014, 16, 1876– 1879,  DOI: 10.1021/ol500300w
      7d
      Ruthenium(II)-Catalyzed C(sp3)-H α-Alkylation of Pyrrolidines
      Schinkel, Marvin; Wang, Lianhui; Bielefeld, Kris; Ackermann, Lutz
      Organic Letters (2014), 16 (7), 1876-1879CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      A catalytic system comprising [RuCl2(PPh3)3], AgOTf, and BINAP enabled atom- and step-economical addns. of C(sp3)-H bonds onto unactivated alkenes under comparably mild reaction conditions. The pyridyl directing group was easily removed to furnish the corresponding (NH)-free amines with ample scope.
    8. 8
      Visible light photocatalysis in organic chemistry; Stephenson, C. R. J., Yoon, T., MacMillan, D. W. C., Eds.; Wiley-VCH: Berlin, 2018.
      There is no corresponding record for this reference.
    9. 9

      Selected examples:

      (a) Zhao, H.; Leonori, D. Minimization of Back-Electron Transfer Enables the Elusive sp3 C–H Functionalization of Secondary Anilines. Angew. Chem., Int. Ed. 2021, 60, 7669– 7674,  DOI: 10.1002/anie.202100051
      9a
      Minimization of Back-Electron Transfer Enables the Elusive sp3 C-H Functionalization of Secondary Anilines
      Zhao, Huaibo; Leonori, Daniele
      Angewandte Chemie, International Edition (2021), 60 (14), 7669-7674CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Anilines are some of the most used class of substrates for application in photoinduced electron transfer. N,N-Dialkyl-derivs. enable radical generation α to the N-atom by oxidn. followed by deprotonation. This approach is however elusive to monosubstituted anilines owing to fast back-electron transfer (BET). Here we demonstrate that BET can be minimised by using photoredox catalysis in the presence of an exogenous alkylamine. This approach synergistically aids aniline SET oxidn. and then accelerates the following deprotonation. In this way, the generation of α-anilinoalkyl radicals is now possible and these species can be used in a general sense to achieve divergent sp3 C-H functionalization.
      (b) Grayson, J. D.; Cresswell, A. J. γ-Amino Phosphonates via the Photocatalytic α-C–H Alkylation of Primary Amines. Tetrahedron 2021, 81, 131896,  DOI: 10.1016/j.tet.2020.131896
      9b
      γ-Amino phosphonates via the photocatalytic α-C-H alkylation of primary amines
      Grayson, James D.; Cresswell, Alexander J.
      Tetrahedron (2021), 81 (), 131896CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
      We report a simple photocatalytic protocol for the direct synthesis of γ-aminophosphonates via the α-C-H alkylation of unprotected, aliph. primary amines with di-Et vinylphosphonate. These motifs are valuable bioisosteres of γ-amino acids and O-phosphorylated amino alcs. Visible-light photoredox catalysis in combination with hydrogen atom transfer (HAT) catalysis is used to access the necessary α-amino radical intermediates for C-C bond formation. The procedure is also demonstrated on gram-scale in continuous flow for the synthesis of a racemic, protected deriv. of the mGlu agonist 2-amino-4-phosphonobutyric acid (AP4).
      (c) Leng, L.; Fu, Y.; Liu, P.; Ready, J. M. Regioselective, Photocatalytic α-Functionalization of Amines. J. Am. Chem. Soc. 2020, 142, 11972– 11977,  DOI: 10.1021/jacs.0c03758
      9c
      Regioselective, Photocatalytic α-Functionalization of Amines
      Leng, Lingying; Fu, Yue; Liu, Peng; Ready, Joseph M.
      Journal of the American Chemical Society (2020), 142 (28), 11972-11977CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Photocatalytic α-functionalization of amines provided a mild and atom-economical means to synthesized α-branched amines. Prior examples featured sym. or electronically biased substrates. A controllable α-functionalization of amines in which regioselectivity can be tuned with minor changes to the reaction conditions.
      (d) Ryder, A. S. H.; Cunningham, W. B.; Ballantyne, G.; Mules, T.; Kinsella, A. G.; Turner-Dore, J.; Alder, C. M.; Edwards, L. J.; McKay, B. S. J.; Grayson, M. N.; Cresswell, A. J. Photocatalytic α-Tertiary Amine Synthesis via C–H Alkylation of Unmasked Primary Amines. Angew. Chem., Int. Ed. 2020, 59, 14986– 14991,  DOI: 10.1002/anie.202005294
      9d
      Photocatalytic α-Tertiary Amine Synthesis via C-H Alkylation of Unmasked Primary Amines
      Ryder, Alison S. H.; Cunningham, William B.; Ballantyne, George; Mules, Tom; Kinsella, Anna G.; Turner-Dore, Jacob; Alder, Catherine M.; Edwards, Lee J.; McKay, Blandine S. J.; Grayson, Matthew N.; Cresswell, Alexander J.
      Angewandte Chemie, International Edition (2020), 59 (35), 14986-14991CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A practical, catalytic entry to α,α,α-trisubstituted (α-tertiary) primary amines by C-H functionalization has long been recognized as a crit. gap in the synthetic toolbox. The authors report a simple and scalable soln. to this problem that does not require any in situ protection of the amino group and proceeds with 100% atom-economy. The authors' strategy, which uses an org. photocatalyst in combination with azide ion as a hydrogen atom transfer (HAT) catalyst, provides a direct synthesis of α-tertiary amines, or their corresponding γ-lactams. The authors anticipate that this methodol. will inspire new retrosynthetic disconnections for substituted amine derivs. in org. synthesis, and particularly for challenging α-tertiary primary amines.
      (e) Cao, K.; Tan, S. M.; Lee, R.; Yang, S.; Jia, H.; Zhao, X.; Qiao, B.; Jiang, Z. Catalytic Enantioselective Addition of Prochiral Radicals to Vinylpyridines. J. Am. Chem. Soc. 2019, 141, 5437– 5443,  DOI: 10.1021/jacs.9b00286
      9e
      Catalytic Enantioselective Addition of Prochiral Radicals to Vinylpyridines
      Cao, Kangning; Tan, Siu Min; Lee, Richmond; Yang, Songwei; Jia, Hongshao; Zhao, Xiaowei; Qiao, Baokun; Jiang, Zhiyong
      Journal of the American Chemical Society (2019), 141 (13), 5437-5443CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Pyridine, one of the most important azaarenes, is ubiquitous in functional mols. The electronic properties of pyridine were exploited to trigger asym. transformations of prochiral species as a direct approach for accessing chiral pyridine derivs. However, the full potential of this synthetic strategy for the construction of enantioenriched γ-functionalized pyridines remains untapped. Here, the authors describe the first enantioselective addn. of prochiral radicals to vinylpyridines under cooperative photoredox and asym. catalysis mediated by visible light. The enantioselective reductive couplings of vinylpyridines with aldehydes, ketones, and imines were achieved by employing a chiral Bronsted acid to activate the reaction partners and provide stereocontrol via H-bonding interactions. Valuable chiral γ-secondary/tertiary hydroxyl- and amino-substituted pyridines were obtained in high yields with good to excellent enantioselectivities.
      (f) Ashley, M. A.; Yamauchi, C.; Chu, J. C. K.; Otsuka, S.; Yorimitsu, H.; Rovis, T. Photoredox-Catalyzed Site-Selective α-Csp3–H Alkylation of Primary Amine Derivatives. Angew. Chem., Int. Ed. 2019, 58, 4002– 4006,  DOI: 10.1002/anie.201812227
      9f
      Photoredox-Catalyzed Site-Selective α-C(sp3)-H Alkylation of Primary Amine Derivatives
      Ashley, Melissa A.; Yamauchi, Chiaki; Chu, John C. K.; Otsuka, Shinya; Yorimitsu, Hideki; Rovis, Tomislav
      Angewandte Chemie, International Edition (2019), 58 (12), 4002-4006CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The synthetic utility of tertiary amines to oxidatively generate α-amino radicals is well established, however, primary amines remain challenging because of competitive side reactions. This report describes the site-selective α-functionalization of primary amine derivs. through the generation of α-amino radical intermediates. Employing visible-light photoredox catalysis, primary sulfonamides are coupled with electron-deficient alkenes to efficiently and mildly construct C-C bonds. Interestingly, a divergence between intermol. hydrogen-atom transfer (HAT) catalysis and intramol. [1,5] HAT was obsd. through precise manipulation of the protecting group. This dichotomy was leveraged to achieve excellent α/δ site-selectivity.
      (g) Rossolini, T.; Leitch, J. A.; Grainger, R.; Dixon, D. J. Photocatalytic Three-Component Umpolung Synthesis of 1,3-Diamines. Org. Lett. 2018, 20, 6794– 6798,  DOI: 10.1021/acs.orglett.8b02923
      9g
      Photocatalytic Three-Component Umpolung Synthesis of 1,3-Diamines
      Rossolini, Thomas; Leitch, Jamie A.; Grainger, Rachel; Dixon, Darren J.
      Organic Letters (2018), 20 (21), 6794-6798CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      A visible-light-mediated photocatalytic umpolung synthesis of 1,3-diamines from in situ-generated imines and dehydroalanine derivs. is described. Pivoting on a key nucleophilic addn. of photocatalytically generated α-amino radicals to electron-deficient alkenes, this three-component coupling reaction affords 1,3-diamines efficiently and diastereoselectively. The mild protocol tolerates a wide variety of functionalities including heterocycles, pinacol boronates, and aliph. chains. Application to biol. relevant α-amino-γ-lactam synthesis and extension to 1,3-aminoalcs. is also demonstrated.
      (h) Trowbridge, A.; Reich, D.; Gaunt, M. J. Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylation. Nature 2018, 561, 522– 527,  DOI: 10.1038/s41586-018-0537-9
      9h
      Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylation
      Trowbridge, Aaron; Reich, Dominik; Gaunt, Matthew J.
      Nature (London, United Kingdom) (2018), 561 (7724), 522-527CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
      A multicomponent reductive photocatalytic technol. was reported that combines readily available dialkylamines, carbonyls and alkenes to build architecturally complex and functionally diverse tertiary alkylamines in a single step. This olefin-hydroaminoalkylation process involved a visible-light-mediated redn. of in-situ-generated iminium ions to selectively furnish previously inaccessible alkyl-substituted α-amino radicals, which subsequently reacted with alkenes to form C(sp3)-C(sp3) bonds. The operationally straightforward reaction exhibited broad functional-group tolerance, facilitated the synthesis of drug-like amines that were not readily accessible by other methods and was amenable to late-stage functionalization applications, making it of interest in areas such as pharmaceutical and agrochem. research.
      (i) Ye, J.; Kalvet, I.; Schoenebeck, F.; Rovis, T. Direct α-alkylation of primary aliphatic amines enabled by CO2 and electrostatics. Nat. Chem. 2018, 10, 1037– 1041,  DOI: 10.1038/s41557-018-0085-9
      9i
      Direct α-alkylation of primary aliphatic amines enabled by CO2 and electrostatics
      Ye, Juntao; Kalvet, Indrek; Schoenebeck, Franziska; Rovis, Tomislav
      Nature Chemistry (2018), 10 (10), 1037-1041CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)
      Primary aliph. amines are important building blocks in org. synthesis due to the presence of a synthetically versatile NH2 group. N-functionalization of primary amines is well established, but selective C-functionalization of unprotected primary amines remains challenging. Here, we report the use of CO2 as an activator for the direct transformation of abundant primary aliph. amines into valuable γ-lactams under photoredox and hydrogen atom transfer (HAT) catalysis. Exptl. and computational studies suggest that CO2 not only inhibits undesired N-alkylation of primary amines, but also promotes selective intermol. HAT by an electrostatically accelerated interaction between the in situ-generated neg. charged carbamate and the pos. charged quinuclidinium radical. This electrostatic attraction overwhelms the inherent bond dissocn. energies which suggest that HAT should occur unselectively. We anticipate that our findings will open up new avenues for amine functionalizations as well as selectivity control in HAT reactions.
      (j) McManus, J. B.; Onuska, N. P. R.; Nicewicz, D. A. Generation and Alkylation of α-Carbamyl Radicals via Organic Photoredox Catalysis. J. Am. Chem. Soc. 2018, 140, 9056– 9060,  DOI: 10.1021/jacs.8b04890
      9j
      Generation and Alkylation of α-Carbamyl Radicals via Organic Photoredox Catalysis
      McManus, Joshua B.; Onuska, Nicholas P. R.; Nicewicz, David A.
      Journal of the American Chemical Society (2018), 140 (29), 9056-9060CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Strategies for the direct C-H functionalization of amines are valuable as these compds. comprise a no. of pharmaceuticals, agrochems. and natural products. This work describes a novel method for the C-H functionalization of carbamate-protected secondary amines via α-carbamyl radicals generated using photoredox catalysis. The use of the highly oxidizing, org. acridinium photoredox catalyst allows for direct oxidn. of carbamate-protected amines with high redox potentials to give the corresponding carbamyl cation radical. Following deprotonation, the resultant open-shell species can be intercepted by a variety of Michael acceptors to give elaborate α-functionalized secondary amines. The reaction proceeds under mild conditions without the requirement of exogenous redox mediators or substrate prefunctionalization. Addnl., we were able to showcase the utility of this methodol. through the enantioselective synthesis of the indolizidine alkaloid, (+)-monomorine I.
      (k) Lee, K. N.; Lei, Z.; Ngai, M.-Y. β-Selective Reductive Coupling of Alkenylpyridines with Aldehydes and Imines via Synergistic Lewis Acid/Photoredox Catalysis. J. Am. Chem. Soc. 2017, 139, 5003– 5006,  DOI: 10.1021/jacs.7b01373
      9k
      β-Selective Reductive Coupling of Alkenylpyridines with Aldehydes and Imines via Synergistic Lewis Acid/Photoredox Catalysis
      Lee, Katarzyna N.; Lei, Zhen; Ngai, Ming-Yu
      Journal of the American Chemical Society (2017), 139 (14), 5003-5006CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Umpolung (polarity reversal) strategies of aldehydes and imines have dramatically expanded the scope of carbonyl and iminyl chem. by facilitating reactions with non-nucleophilic reagents. Herein, we report the first visible light photoredox-catalyzed β-selective reductive coupling of alkenylpyridines with carbonyl or iminyl derivs. with the aid of a Lewis acid co-catalyst. Our process tolerates complex mol. scaffolds (e.g., sugar, natural product, and peptide derivs.) and is applicable to the prepn. of compds. contg. a broad range of heterocyclic moieties. Mechanistic investigations indicate that the key step involves single-electron-transfer redn. of aldehydes or imines followed by the addn. of resulting ketyl or α-aminoalkyl radicals to Lewis acid-activated alkenylpyridines.
      (l) Chu, L.; Ohta, C.; Zuo, Z.; MacMillan, D. W. C. Carboxylic Acids as A Traceless Activation Group for Conjugate Additions: A Three-Step Synthesis of (±)-Pregabalin. J. Am. Chem. Soc. 2014, 136, 10886– 10889,  DOI: 10.1021/ja505964r
      9l
      Carboxylic Acids as A Traceless Activation Group for Conjugate Additions: A Three-Step Synthesis of (±)-Pregabalin
      Chu, Lingling; Ohta, Chisa; Zuo, Zhiwei; MacMillan, David W. C.
      Journal of the American Chemical Society (2014), 136 (31), 10886-10889CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The direct application of carboxylic acids as a traceless activation group for radical Michael addns. has been accomplished via visible light-mediated photoredox catalysis. Photon-induced oxidn. of a broad series of carboxylic acids, including hydrocarbon-substituted, α-oxy, and α-amino acids, provides a versatile CO2-extrusion platform to generate Michael donors without the requirement for organometallic activation or propagation. A diverse array of Michael acceptors is amenable to this new conjugate addn. strategy. An application of this technol. to a three-step synthesis of the medicinal agent pregabalin (commercialized by Pfizer under the trade name Lyrica) is also presented.
      (m) Miyake, Y.; Nakajima, K.; Nishibayashi, Y. Visible-Light-Mediated Utilization of α-Aminoalkyl Radicals: Addition to Electron-Deficient Alkenes Using Photoredox Catalysts. J. Am. Chem. Soc. 2012, 134, 3338– 3341,  DOI: 10.1021/ja211770y
      9m
      Visible-Light-Mediated Utilization of α-Aminoalkyl Radicals: Addition to Electron-Deficient Alkenes Using Photoredox Catalysts
      Miyake, Yoshihiro; Nakajima, Kazunari; Nishibayashi, Yoshiaki
      Journal of the American Chemical Society (2012), 134 (7), 3338-3341CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Synthetic use of α-aminoalkyl radicals formed by single electron oxidn. of amines is quite limited. Here the authors demonstrate addn. of α-aminoalkyl radicals to electron-deficient alkenes by visible-light-mediated electron transfer using transition metal polypyridyl complexes as photocatalysts, via a sequential redox pathway.
    10. 10
      The non-catalytic HAA of unprotected primary amines with non-electrophilic alkenes necessitates a large excess of the amine partner (∼13–26 equiv) and forcing reaction conditions (>120 °C, ∼10 mol% peroxide) and gives extensive telomerization. See:Urry, W. H.; Juveland, O. O. Free Radical Additions of Amines to Olefins. J. Am. Chem. Soc. 1958, 80, 3322– 3328,  DOI: 10.1021/ja01546a033
      10
      Free radical additions of amines to olefins
      Urry, W. H.; Juveland, O. O.
      Journal of the American Chemical Society (1958), 80 (), 3322-8CODEN: JACSAT; ISSN:0002-7863.
      The free radical chain addns. of amines to olefins in the presence of peroxides or light yield higher homologous amines which are products of α-C alkylation. BuNH2 (370 g.), b77 -8°, n20D 1.4013, 28 g. 1-octene (I), b. 120-1° n20D 1.4090, and 4.5 g. (Me3CO)2 (II) (half-life in Bu3N at 125° 11.3 hrs., and at 135° 4.6 hrs.) heated 48 hrs. in a sealed tube at 123-6° and fractionated yielded 2.5 g. Me3COH, 12.35 g. I and BuNH2, 7.35 g. PrCH(NH2)C8H17 (III), b1 70-1°, n20D 1.4407, 3.0 g. distillate, b1 110-60°, n20D 1.4728, and 7.1 g. residue. PrCOC8H17 treated with HCO2H and HCO2NH4 yielded 34% III, b1 69-71°, n20D 1.4408. III gave with PhNCS a phenylthiourea deriv., m. 58-8.5°. III gave with HCl the III.HCl, m. 88.5-90°. III (1.7 g.) was obtained when 490 g. BuNH2 and 30 g. I were illuminated internally 120 hrs. with a Hg vapor lamp at 30-5°; 6.35 g. higher boiling residue was also formed. I (26 g.) and 4.5 g. II in 458 g. C6H13NH2 heated 60 hrs. at 124-7° and distd. gave 4 g. Me3COH, unchanged C6H13NH2, 16.0 g. AmCH(NH2)C8H17 (IV), b1, 84-5°, n20D 1.4435 (phenylthiourea deriv., m. 69-9.5°), 5.7 g. distillate, b1 120-55°, n20D 1.4560, and 12 g. residue. IV, b1 84-6°, n20D 1.4432, was also obtained from AmCOC8H17 with HCO2H and HCO2NH4. Me2CHNH2 (118 g.), 18 g. I, and 3 g. II heated 55 hrs. at 188-22° yielded 12 g. Me2C(NH2)C8H17, b1, 47-8°, n20D 1.4333 (HCl salt, m. 116-17°), 3.5 g. distillate, b1 80-120°, and 5.5 g residue. Cyclohexylamine (V) (497 g.), 25 g. I, and 6.0 g. II heated 53 hrs. at 124-8° and distd. gave 5.5 g. Me3COH and unchanged V and the following fractions: (1) 1.85 g., b1 88-9°, n20D 1.4788; (2) 2.7 g., b1 89-92° n20D 1.4772; (3) 4.0 g., b1 92°, n20D 1.4759; (4) 23 g. 1-amino-1-octylcyclohexane (VI), b1 95-7°, n20D 1.4657 (HCl salt, m. 107.5-8.5°; phenylthiourea deriv., m. 91-1.5°); (5) 4.8 g., b1, 150-65°, n20D 1.4770 (apparently a mixt. of VI and the addn. product from 2 moles I and 1 mole V); (5) 9.4 g., residue. Fractions 1, 2, and 3 combined and an aliquot (3.2 g.) hydrogenated gave 1 g. VI, b1 94-6°, n20D 1.4680. CH2:CHCH2OH (VII) (23 g.) and 5.0 g. II in 380 g. pyrrolidine heated 48 hrs. at 120-2° in a sealed tube and distd. gave 27.8 g. 2-(3-hydroxypropyl)pyrrolidine (VIII), b1 80-1°, n20D 1.4870, and 10.2 g. residue. VIII (4.25 g.) and 95 cc. 48% HBr heated 12 hrs. in a sealed tube at 100° and evapd. and the residue recrystd. from Me2CO yielded 2.5 g. 2-(3-bromopropyl)pyrrolidine.HBr (IX), m. 102-3°. IX (2.5 g.) added during 2.5 hrs. with stirring to 200 cc. 0.1N NaOH at 50°, cooled, treated with 3 g. PhSO2Cl, allowed to stand 1 hr., and steam-distd., the distillate extd. with Et2O, and the ext. treated with 2 g. picric acid yielded 1.5 g. pyrrolizidine picrate, m. 256.6-8°. Piperidine (X) (81 g.) and 1.1 g. II pressured 24 hrs. at 125° with 30-40 lb. C2H4 while adding an addnl. 1.8 g. II after 8 hrs., and the mixt. distd. yielded 2.7 g. Me3COH, 72 g. X, and 2.6 g. 2-ethylpiperidine, b52 73-5°, n20D 1.4544 (HCl salt, m. 180-1°; picrate, m. 130-1°; chloro platinate, m. 202-4°), and left 1.1 g. residue. II (1.2 g.) and 87 g. X kept 12 hrs. at 125° under 30-40 lb. MeCH:CH2 while adding an addnl. 1.8 g. II after hrs. and distd. gave 4 g. dl-coniine, b70 93°, n23D 1.4513 (HCl salt, m. 211-12°; platinichloride, m. 155-7°), 1.40 g. forerun, and 2.6 g. residue. X (360 g.), 23 g. 1-hexene, and 5 g. II heated 50 hrs. in a sealed tube at 122-5° and fractionated gave 3.7 g. Me3COH, 8.5 g. 1-hexene, and piperidine as forerun followed by 15.6 g. 2-hexylpiperidine (XI), b4.5 77-8°, n20D 1.4580, 2.8 g. distillate, b3 80-140°, n20D 1.4740, and 4.4 g. residue. α-Picoline (55.5 g.) treated with 30.2 g. AmBr and 27 g. NaNH2 yielded 60% XI, b5 80°, n20D 1.4575 (HCl salt, m. 162-3°). X (382 g.), 40 g. I, and 3 g. II kept 50 hrs. at 120° under N while being treated after 6 hrs. and after 12 hrs. with addnl. 2-g. portions II and the mixt. distd. yielded 6.3 g. Me3COH, 359.5 g. unchanged X, 9.5 g. I, b. 118-20°, 31.7 g. 2-octylpiperidine (XII), b1 89°, n20D 1.4589, 5.8 g. distillate, b1 145-55°, n20D 1.4683 (apparently condensation product of 1 mole X with 2 moles I), and 4.5 g. residue. 2-Octylpyridine (obtained in 65% yield by the reaction of 111 g. α-picoline with 1.2 moles C7H15Br, and 54 g. NaNH2) hydrogenated over PtO2 in AcOH yielded 95% XII, b1 89°, n20D 1.4587; phenylthiourea deriv., m. 95°; HCl salt, m. 155-6°; picrate, m. 78-80°. I (20.5 g.) in 207 g. X illuminated 168 hrs. with a quartz-Hg discharge tube at 30-5° gave 1 g. XII. X (385 g.), 19 g. VII, and 4.5 g. II heated 48 hrs. at 122-30° in a sealed tube and distd. gave 21.8 g. 2-(3-hydroxypropyl)piperidine (XIII), b1 93-5°, n25D 1.4890; HCl salt, m. 129-30°. X (340 g.), 19 g. VII, and 4.5 g. (EtMe2CO)2 kept 48 hrs. at 100° gave 2.3 g. XIII, b1, 93-5°, n20D 1.4900, and 4.2 g. residue. X (180 g.), 9 g. VII, and 1.5 g. (Me3CO.OCHMe)2 kept 50 hrs. at 95° gave 1.1 g. XIII and 2.6 g. residue. XIII (3 g.) in 60 cc. 48% HBr heated 12 hrs. at 100° and evapd. in vacuo, the residue recrystd. from Me2CO, the resulting 3.7 g. 2-(3-bromopropyl)piperidine, m. 180-2°, added during 2 hrs. at 50° to 2000 cc. 0.1N NaOH, cooled, treated with 3 g. PhSO2Cl, and steam-distd., the distillate (50 cc.) extd. with Et2O, and the ext. worked up gave 0.7 g. 1-azabicyclo[4.3.0]nonane, b32 86°, n21D 1.4697. X (374 g.), 21 g. CH2:CHCH2CN, and 5 g. II kept 72 hrs. at 120-4° yielded 20.7 g. 2-(3-cyanopropyl)piperidine, b1 59-60°, n20D 1.4748 (HCl salt, m. 135-6°), and 7.1 g. distillate, b1 100-40°, n20D 1.5024. 4-Pipecoline (198 g.), 10 g. VII, and 3 g. II heated 48 hrs. at 123-5° in a sealed tube gave 9.1 g. 4-Me deriv. of XIII, b1 99-100°, n20D 1.4875, and 8.0 g. residue. N-Methylpiperidine (284 g.), 20 g. I, and 6 g. II heated 48 hrs. at 122-6° in a sealed tube and distd. gave 6 g. 1-methyl-2-octylpiperidine (XIV), b1 84-5°, n20D 1.4593, 6.8 g. distillate, b1, 110-70°, n20D 1.4692, and 8.6 g. residue. HCO2H (18.9 g.), 14 g. 35% aq. CH2O, and 29 g. XII yielded 23.3 g. XIV, b1 85°, n20D 1.4590; XIV.MeI, m. 165°; XIV.EtI, m. 138-9°.
    11. 11

      Non-electrophilic styrenes in photoredox-catalyzed, intermolecular HAA are scarce and limited to tertiary amines or N-Boc α-amino acids:

      (a) Wu, Z.; Gockel, S.; Hull, K. Anti-Markovnikov Hydro(amino)alkylation of Vinylarenes via Photoredox Catalysis. Research Square Preprint 2021,  DOI: 10.21203/rs.3.rs-366556/v1
      There is no corresponding record for this reference.
      (b) Larionova, N.; Ondozabal, J. M.; Smith, E. G.; Cambeiro, X. A. A photocatalytic regioselective hydroaminoalkylation of aryl-substituted alkenes with simple amines. Org. Lett. 2021, 23, 5383– 5388,  DOI: 10.1021/acs.orglett.1c01715
      11b
      A Photocatalytic Regioselective Direct Hydroaminoalkylation of Aryl-Substituted Alkenes with Amines
      Larionova, Natalia A.; Ondozabal, Jun Miyatake; Smith, Emily G.; Cambeiro, Xacobe C.
      Organic Letters (2021), 23 (14), 5383-5388CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      A photocatalytic method for the α-selective hydroaminoalkylation of cinnamate esters has been developed. The reaction involves the regioselective addn. of α-aminoalkyl radicals generated from aniline derivs. or aliph. amines to the α-position of unsatd. esters. The scope of arom. alkenes was extended to styrenes undergoing hydroaminoalkylation with anti-Markovnikov selectivity, which confirms the importance of the arom. group at the β-position. Simple scale-up is demonstrated under continuous flow conditions, highlighting the practicality of the method.
      (c) Lovett, G. H.; Sparling, B. A. Decarboxylative Anti-Michael Addition to Olefins Mediated by Photoredox Catalysis. Org. Lett. 2016, 18, 3494– 3497,  DOI: 10.1021/acs.orglett.6b01712
      11c
      Decarboxylative Anti-Michael Addition to Olefins Mediated by Photoredox Catalysis
      Lovett, Gabrielle H.; Sparling, Brian A.
      Organic Letters (2016), 18 (14), 3494-3497CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      Decarboxylative coupling of carboxylic acids with activated olefins has been accomplished using visible light photoredox catalysis. The strategic placement of a radical-stabilizing arom. group at the β-position of the olefin component biases the regioselectivity of the addn., allowing reliable, facile access to anti-Michael-type products from readily available precursors. The scope of this methodol. was demonstrated with a range of carboxylic acids and appropriately substituted olefins and was applied toward a two-step synthesis of the antiarrhythmic agent encainide.
    12. 12
      (a) Nagai, M.; Nagamoto, M.; Nishimura, T.; Yorimitsu, H. Iridium-Catalyzed sp3 C–H Alkylation of 3-Carbonyl-2-(alkylamino)pyridines with Alkenes. Chem. Lett. 2017, 46, 1176– 1178,  DOI: 10.1246/cl.170373
      12a
      Iridium-catalyzed sp3 C-H alkylation of 3-carbonyl-2-(alkylamino)pyridines with alkenes
      Nagai, Masaki; Nagamoto, Midori; Nishimura, Takahiro; Yorimitsu, Hideki
      Chemistry Letters (2017), 46 (8), 1176-1178CODEN: CMLTAG; ISSN:0366-7022. (Chemical Society of Japan)
      Iridium-catalyzed C-H alkylation of 3-carbonyl-2-(alkylamino)pyridines via secondary sp3 C-H activation adjacent to the nitrogen atom, with terminal alkenes proceeded to give the corresponding α-secondary amines such as I [R1 = Ph, NH2, pyrrolodin-1-yl, etc; R2 = CH2OH, 4-ClC6H4, Bn, etc.; R3 = Me, CH2CH3, Ph , etc.] in high yields. The reaction was efficiently catalyzed by a cationic iridium complex coordinated with 1,5-cyclooctadiene.
      (b) Pan, S.; Matsuo, Y.; Endo, K.; Shibata, T. Cationic iridium-catalyzed enantioselective activation of secondary sp3 C–H bond adjacent to nitrogen atom. Tetrahedron 2012, 68, 9009– 9015,  DOI: 10.1016/j.tet.2012.08.071
      12b
      Cationic iridium-catalyzed enantioselective activation of secondary sp3 C-H bond adjacent to nitrogen atom
      Pan, Shiguang; Matsuo, Yusuke; Endo, Kohei; Shibata, Takanori
      Tetrahedron (2012), 68 (44), 9009-9015CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
      A cationic Ir(I)-tolBINAP complex catalyzed an enantioselective C-C bond formation, which was initiated by secondary sp3 C-H bond cleavage adjacent to nitrogen atom. A wide variety of 2-(alkylamino)pyridines and alkenes were selectively transformed into the corresponding chiral amines with moderate to almost perfect enantiomeric excesses. E.g., reaction of 2-(ethylamino)pyridine and styrene gave (-)-I. Alkynes were also investigated as coupling partners. The effect of alkyl structure in substrates and directing groups were studied. This transformation represents the first example of a highly enantioselective C-H bond activation of a methylene group, not at allylic or benzylic position.
      (c) Pan, S.; Endo, K.; Shibata, T. Ir(I)-Catalyzed Enantioselective Secondary sp3 C–H Bond Activation of 2-(Alkylamino)pyridines with Alkenes. Org. Lett. 2011, 13, 4692– 4695,  DOI: 10.1021/ol201907w
      12c
      Ir(I)-Catalyzed Enantioselective Secondary sp3 C-H Bond Activation of 2-(Alkylamino)pyridines with Alkenes
      Pan, Shiguang; Endo, Kohei; Shibata, Takanori
      Organic Letters (2011), 13 (17), 4692-4695CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      A cationic Ir(I)-tolBINAP complex catalyzed an enantioselective C-C bond formation initiated by secondary sp3 C-H bond cleavage adjacent to a nitrogen atom. The reaction of 2-(alkylamino)pyridines with various alkenes gave chiral amines, e.g., I, in good yields with high enantiomeric excesses.
    13. 13
      Koperniku, A.; Foth, P. J.; Sammis, G. M.; Schafer, L. L. Zirconium Hydroaminoalkylation. An Alternative Disconnection for the Catalytic Synthesis of α-Arylated Primary Amines. J. Am. Chem. Soc. 2019, 141, 18944– 18948,  DOI: 10.1021/jacs.9b10465
      13
      Zirconium Hydroaminoalkylation. An Alternative Disconnection for the Catalytic Synthesis of α-Arylated Primary Amines
      Koperniku, Ana; Foth, Paul J.; Sammis, Glenn M.; Schafer, Laurel L.
      Journal of the American Chemical Society (2019), 141 (48), 18944-18948CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Primary amine products have been prepd. using zirconium catalyzed hydroaminoalkylation of alkenes with N-silylated benzylamine substrates. Catalysis using com. available Zr(NMe2)4, affords an alternative disconnection to access α-arylated primary amines upon aq. work-up. Substrate dependent regio- and diastereoselectivity of the reaction is obsd. Bulky substituents on the terminal alkene exclusively generate the linear regioisomer. This atom-economic catalytic strategy for the synthesis of building blocks that can underwent further synthetic elaboration is highlighted in the prepn. of trifluoroethylated-α-arylated amines.
    14. 14
      (a) Bexrud, J. A.; Eisenberger, P.; Leitch, D. C.; Payne, P. R.; Schafer, L. L. Selective C–H Activation α to Primary Amines. Bridging Metallaaziridines for Catalytic, Intramolecular α-Alkylation. J. Am. Chem. Soc. 2009, 131, 2116– 2118,  DOI: 10.1021/ja808862w
      14a
      Selective C-H activation α to primary amines. Bridging metallaaziridines for catalytic, intramolecular α-alkylation
      Bexrud, Jason A.; Eisenberger, Patrick; Leitch, David C.; Payne, Philippa R.; Schafer, Laurel L.
      Journal of the American Chemical Society (2009), 131 (6), 2116-2118CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Primary 5- and 6-unsatd. aliph. amines undergo α-C-H-activation rather than intramol. hydroamination in the presence of Ti and Zr amido-complexes, resulting in stereoselective formation of cyclic amines. Selective benzylic α-C-H activation of benzylamine results in the prepn. of the first bridging metallaaziridine complex [(PhCONHAr-κO,κN)Ti(μ-PhCH2N-κN:κN)(μ-PhCH2N-κC,N:κN)(μ-PhCONHAr-κO:κN)Ti(PhCONHAr-κO,κN)] (2) for the catalytic α-alkylation of primary amines. Crystal structure of 2 is reported. Zirconium tetramide gave 2-pyridonate complex [(PyO)2Zr(NMe2)2] [3; PyO = 6-tert-butyl-3-phenyl-2-pyridinonato(1-)], which was also characterized by x-ray structural anal. Cyclization of RCH2NH2 (R = 2-(3-butenylphenyl), 2,2-diphenyl-6-heptenyl, 1-(4-pentenyl)cyclopentenyl, 7-heptenyl, 6-hexenyl) and CH2:CH(CH2)4CHPhNH2 catalyzed by zirconium complex 3 gave the corresponding 2-Me-1-tetralinamine, cyclohexane- and cyclopentanamines as a result of α-C-H activation, followed by cyclization of the reactive zirconaaziridine with pendant double bond. No nitrogen protecting groups are required for this reaction, which is capable of assembling quaternary chiral centers α to nitrogen. Preliminary mechanistic investigations suggest bridging metallaaziridine species are the catalytically active intermediates for this α-functionalization reaction, while monomeric imido complexes furnish azepane hydroamination products.
      (b) Kubiak, R.; Prochnow, I.; Doye, S. Titanium-Catalyzed Hydroaminoalkylation of Alkenes by C–H Bond Activation at sp3 Centers in the α-Position to a Nitrogen Atom. Angew. Chem., Int. Ed. 2009, 48, 1153– 1156,  DOI: 10.1002/anie.200805169
      14b
      Titanium-catalyzed hydroaminoalkylation of alkenes by C-H bond activation at sp3 centers in the α-position to a nitrogen atom
      Kubiak, Raphael; Prochnow, Insa; Doye, Sven
      Angewandte Chemie, International Edition (2009), 48 (6), 1153-1156CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Hydroaminoalkylations of alkenes, which take place by C-H bond activation in the α-position to nitrogen atoms, are catalyzed by various neutral titanium complexes. Primary as well as secondary amines can be used as substrates, and the reactions can be achieved intra- and intermolecularly.
    15. 15
      Chu, J. C. K.; Rovis, T. Complementary Strategies for Directed C(sp3)–H Functionalization: A Comparison of Transition-Metal-Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer. Angew. Chem., Int. Ed. 2018, 57, 62– 101,  DOI: 10.1002/anie.201703743
      15
      Complementary Strategies for Directed C(sp3)-H Functionalization: A Comparison of Transition-Metal-Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer
      Chu, John C. K.; Rovis, Tomislav
      Angewandte Chemie, International Edition (2018), 57 (1), 62-101CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. The functionalization of C(sp3)-H bonds streamlines chem. synthesis by allowing the use of simple mols. and providing novel synthetic disconnections. Intensive recent efforts in the development of new reactions based on C-H functionalization have led to its wider adoption across a range of research areas. This Review discusses the strengths and weaknesses of three main approaches: transition-metal-catalyzed C-H activation, 1,n-hydrogen atom transfer, and transition-metal-catalyzed carbene/nitrene transfer, for the directed functionalization of unactivated C(sp3)-H bonds. For each strategy, the scope, the reactivity of different C-H bonds, the position of the reacting C-H bonds relative to the directing group, and stereochem. outcomes are illustrated with examples in the literature. The aim of this Review is to provide guidance for the use of C-H functionalization reactions and inspire future research in this area.
    16. 16
      For a comparison to the oxidation potential of other common amine classes, see:Roth, H. G.; Romero, N. A.; Nicewicz, D. A. Experimental and Calculated Electrochemical Potentials of Common Organic Molecules for Applications to Single-Electron Redox Chemistry. Synlett 2016, 27, 714– 723,  DOI: 10.1055/s-0035-1561297
      16
      Experimental and Calculated Electrochemical Potentials of Common Organic Molecules for Applications to Single-Electron Redox Chemistry
      Roth, Hudson G.; Romero, Nathan A.; Nicewicz, David A.
      Synlett (2016), 27 (5), 714-723CODEN: SYNLES; ISSN:0936-5214. (Georg Thieme Verlag)
      Herein, we report half-peak potentials for over 180 org. substrates obtained via cyclic voltammetry. These values are of great use in assessing the thermodn. of an electron-transfer process. In addn., we disclose a simple computational method to det. redox potentials of org. substrates.
    17. 17
      Morozova, O. B.; Yurkovskaya, A. V. Aminium Cation Radical of Glycylglycine and its Deprotonation to Aminyl Radical in Aqueous Solution. J. Phys. Chem. B 2008, 112, 12859– 12862,  DOI: 10.1021/jp807149a
      17
      Aminium Cation Radical of Glycylglycine and its Deprotonation to Aminyl Radical in Aqueous Solution
      Morozova, Olga B.; Yurkovskaya, Alexandra V.
      Journal of Physical Chemistry B (2008), 112 (40), 12859-12862CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
      The photochem. reaction between glycylglycine and triplet 4-carboxybenzophenone has been investigated using time-resolved chem. induced dynamic nuclear polarization (CIDNP). It is shown that the mechanism of the peptide reaction with triplet excited carboxybenzophenone is electron transfer from the amino group of the peptide, leading to the formation of an aminium cation radical that deprotonates to a neutral aminyl radical. Simulation of the CIDNP kinetics leads to an estn. of the paramagnetic relaxation time for the α-protons at the N-terminus at 20 to 40 μs with the best-fit value of 25 μs.
    18. 18
      Luo, J.; Zhang, J. Donor–Acceptor Fluorophores for Visible-Light-Promoted Organic Synthesis: Photoredox/Ni Dual Catalytic C(sp3)–C(sp2) Cross Coupling. ACS Catal. 2016, 6, 873– 877,  DOI: 10.1021/acscatal.5b02204
      18
      Donor-Acceptor Fluorophores for Visible-Light-Promoted Organic Synthesis: Photoredox/Ni Dual Catalytic C(sp3)-C(sp2) Cross-Coupling
      Luo, Jian; Zhang, Jian
      ACS Catalysis (2016), 6 (2), 873-877CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      We describe carbazolyl dicyanobenzene (CDCB)-based donor-acceptor (D-A) fluorophores as a class of cheap, easily accessible, and efficient metal-free photoredox catalysts for org. synthesis. By changing the no. and position of carbazolyl and cyano groups on the center benzene ring, CDCBs with a wide range of photoredox potentials are obtained to effectively drive the energetically demanding C(sp3)-C(sp2) cross-coupling of carboxylic acids and alkyltrifluoroborates with aryl halides via a photoredox/Ni dual catalysis mechanism. This work validates the utility of D-A fluorophores in guiding the rational design of metal-free photoredox catalysts for visible-light-promoted org. synthesis.
    19. 19
      Le, C.; Liang, Y.; Evans, R. W.; Li, X.; MacMillan, D. W. C. Selective sp3 C–H alkylation via polarity-match-based cross-coupling. Nature 2017, 547, 79– 83,  DOI: 10.1038/nature22813
      19
      Selective sp3 C-H alkylation via polarity-match-based cross-coupling
      Le, Chip; Liang, Yufan; Evans, Ryan W.; Li, Ximing; MacMillan, David W. C.
      Nature (London, United Kingdom) (2017), 547 (7661), 79-83CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      The functionalization of carbon-hydrogen (C-H) bonds is one of the most attractive strategies for mol. construction in org. chem. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in org. mols. and its availability for functionalization at almost any stage in a synthetic sequence. Although many C-H functionalization reactions involve C(sp3)-C(sp2) coupling, there is a growing demand for C-H alkylation reactions, wherein sp3 C-H bonds are replaced with sp3 C-alkyl groups. Here, we describe a polarity-match-based selective sp3 C-H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodol. simultaneously uses three catalytic cycles to achieve hydridic C-H bond abstraction (enabled by polarity matching), alkyl halide oxidative addn., and reductive elimination to enable alkyl-alkyl fragment coupling. The sp3 C-H alkylation is highly selective for the α-C-H of amines, ethers and sulfides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chem.
    20. 20
      Luo, Y.-R Comprehensive Handbook of Chemical Bond Energies; CRC Press: Boca Raton, FL, 2007.
      There is no corresponding record for this reference.
    21. 21
      (a) Sim, B. A.; Griller, D.; Wayner, D. D. M. Reduction Potentials for Substituted Benzyl Radicals: pKa Values for the Corresponding Toluenes. J. Am. Chem. Soc. 1989, 111, 754– 755,  DOI: 10.1021/ja00184a066
      21a
      Reduction potentials for substituted benzyl radicals: pKa values for the corresponding toluenes
      Sim, B. A.; Griller, D.; Wayner, D. D. M.
      Journal of the American Chemical Society (1989), 111 (2), 754-5CODEN: JACSAT; ISSN:0002-7863.
      The electrochem. redn. potentials of nine 3- and 4-substituted benzyl radicals were detd. by photomodulation voltammetry (PMV) in MeCN/di-tert-butylperoxide (9:1) contg. 0.1 M Bu4NClO4. The measured half-wave potentials for the redns. are close to E° and lead to ests. of the abs. pKa's for the toluenes in MeCN.
      (b) Wayner, D. D. M.; McPhee, D. J.; Griller, D. Oxidation and reduction potentials of transient free radicals. J. Am. Chem. Soc. 1988, 110, 132– 137,  DOI: 10.1021/ja00209a021
      21b
      Oxidation and reduction potentials of transient free radicals
      Wayner, D. D. M.; McPhee, D. J.; Griller, D.
      Journal of the American Chemical Society (1988), 110 (1), 132-7CODEN: JACSAT; ISSN:0002-7863.
      The oxidn. and redn. potentials of a variety of carbon-centered radicals have been measured by a technique that makes use of modulated photolysis for radical generation and phase-sensitive voltammetry for their detection. The measured half-wave potentials were close to the thermodynamically significant E° values for the arylmethyl radicals and led to ests. of pKa(R-H) and pKR(R-OH) as well as data for the solvation energies of these ions and radicals.
    22. 22
      Bortolamei, N.; Isse, A. A.; Gennaro, A. Estimation of standard reduction potentials of alkyl radicals involved in atom-transfer radical polymerization. Electrochim. Acta 2010, 55, 8312– 8318,  DOI: 10.1016/j.electacta.2010.02.099
      22
      Estimation of standard reduction potentials of alkyl radicals involved in atom transfer radical polymerization
      Bortolamei, Nicola; Isse, Abdirisak A.; Gennaro, Armando
      Electrochimica Acta (2010), 55 (27), 8312-8318CODEN: ELCAAV; ISSN:0013-4686. (Elsevier B.V.)
      The redox properties of some alkyl radicals, which are important in atom transfer radical polymn. both as initiators and mimics of the propagating radical chains, have been investigated in CH3CN by an indirect electrochem. method based on homogeneous redox catalysis involving alkyl halides (RX) and electrogenerated arom. or heteroarom. radical anions (D·-). Dissociative electron transfer between RX and D·- yields an intermediate radical (R·), which further reacts with D·- either by radical coupling or by electron transfer. Examn. of the competition between these reactions, which depends on ED°D/D·-/D·-, allows detn. of the std. redn. potential of R· as well as the self-exchange reorganization energy λR·/R-·. The std. redn. potentials obtained for the radicals ·CH2CN, ·CH2CO2Et and ·CH(CH3)CO2Me are -0.72 ± 0.06, -0.63 ± 0.07 and -0.66 ± 0.07 V vs. SCE, resp. Quite high values of λR·/R- (from 122 to 164 kJ mol-1) were found for all radicals, indicating that a significant change of structure accompanies electron transfer to R·.
    23. 23
      Speckmeier, E.; Fischer, T. G.; Zeitler, K. A Toolbox Approach To Construct Broadly Applicable Metal-Free Catalysts for Photoredox Chemistry: Deliberate Tuning of Redox Potentials and Importance of Halogens in Donor–Acceptor Cyanoarenes. J. Am. Chem. Soc. 2018, 140, 15353– 15365,  DOI: 10.1021/jacs.8b08933
      23
      A Toolbox Approach To Construct Broadly Applicable Metal-Free Catalysts for Photoredox Chemistry: Deliberate Tuning of Redox Potentials and Importance of Halogens in Donor-Acceptor Cyanoarenes
      Speckmeier, Elisabeth; Fischer, Tillmann G.; Zeitler, Kirsten
      Journal of the American Chemical Society (2018), 140 (45), 15353-15365CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The targeted choice of specific photocatalysts has been shown to play a crit. role for the successful realization of challenging photoredox catalytic transformations. Herein, we demonstrate the successful implementation of a rational design strategy for a series of deliberate structural manipulations of cyanoarene-based, purely org. donor-acceptor photocatalysts, using 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) as a starting point. Systematic modifications of both the donor substituents as well as the acceptors' mol. core allowed us to identify strongly oxidizing as well as strongly reducing catalysts (e.g., for an unprecedented detriflation of unactivated naphthol triflate), which addnl. offer remarkably balanced redox potentials with predictable trends. Esp. halogen arene core substitutions are instrumental for our targeted alterations of the catalysts' redox properties. Based on their preeminent electrochem. and photophys. characteristics, all novel, purely org. photoredox catalysts were evaluated in three challenging, mechanistically distinct classes of benchmark reactions (either requiring balanced, highly oxidizing or strongly reducing properties) to demonstrate their enormous potential as customizable photocatalysts, that outperform and complement prevailing typical best photocatalysts.
    24. 24
      Ji, X.; Liu, Q.; Wang, Z.; Wang, P.; Deng, G.-J.; Huang, H. LiBr-promoted photoredox neutral Minisci hydroxyalkylations of quinolines with aldehydes. Green Chem. 2020, 22, 8233– 8237,  DOI: 10.1039/D0GC01872D
      24
      LiBr-promoted photoredox neutral Minisci hydroxyalkylations of quinolines with aldehydes
      Ji, Xiaochen; Liu, Qiong; Wang, Zhongzhen; Wang, Pu; Deng, Guo-Jun; Huang, Huawen
      Green Chemistry (2020), 22 (23), 8233-8237CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
      Photoredox-neutral hydroxyalkylations of quinolines I [R = H; R1 = H; RR1 = -CH=CHCH=CH-, -CH=C(OCH3)C(OCH3)=CH-; R2 = H, n-Bu, Cl; R3 = H; R2R3 = -CH=C(Br)CH=CH-; R4 = H, 4-phenylphenyl, 3-chlorophenyl, thiophen-2-yl, etc.] with aldehydes R5CHO (R5 = 2-bromo-5-fluorophenyl, thiophen-2-yl, naphthalen-2-yl, etc.), induced by sustainable visible light under mild conditions, are described. Non-toxic and inexpensive LiBr is found to be the key for the success of the atom-economical Minisci method. Combined with a highly oxidative photocatalyst and visible light irradn., the bromide additive mediates the H abstraction/acyl radical formation directly from aldehydes. The present mild photoredox neutral protocol provides an important alternative, esp. for the challenging Minisci hydroalkylations, as well as a promising approach for atom-economical Minisci reactions with broader N-heterocycle spectra.
    25. 25
      Ide, T.; Barham, J. P.; Fujita, M.; Kawato, K.; Egami, H.; Hamashima, Y. Regio- and chemoselective Csp3–H arylation of benzylamines by single electron transfer/hydrogen atom transfer synergistic catalysis. Chem. Sci. 2018, 9, 8453– 8460,  DOI: 10.1039/C8SC02965B
      25
      Regio- and chemoselective Csp3-H arylation of benzylamines by single electron transfer/hydrogen atom transfer synergistic catalysis
      Ide, Takafumi; Barham, Joshua P.; Fujita, Masashi; Kawato, Yuji; Egami, Hiromichi; Hamashima, Yoshitaka
      Chemical Science (2018), 9 (44), 8453-8460CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      A highly regio- and chemoselective Csp3-H arylation of benzylamines mediated by synergy of single electron transfer (SET) and hydrogen atom transfer (HAT) catalysis is reported. Under well precedented SET catalysis alone, the arylation reaction of N,N-dimethylbenzylamine proceeded via aminium radical cation formation and selectively targeted the N-Me group. In contrast, addn. of PhC(O)SH as a HAT catalyst precursor completely switched the regioselectivity to Csp3-H arylation at the N-benzylic position. Measurement of oxidn. potentials indicated that the conjugate base of PhC(O)SH is oxidized in preference to the substrate amine. The discovery of the thiocarboxylate as a novel HAT catalyst allowed for the selective generation of the sulfur-centered radical, so that the N-benzyl selectivity was achieved by overriding the inherent N-Me and/or N-methylene selectivity under SET catalysis conditions. While visible light-driven α-C-H functionalization of amines has mostly been demonstrated with aniline derivs. and tetrahydroisoquinolines (THIQs), our method is applicable to a variety of primary, secondary and tertiary benzylamines for efficient N-benzylic C-H arylation. Functional group tolerance was high, and various 1,1-diarylmethylamines, including an α,α,α-trisubstituted amine, were obtained in good to excellent yield (up to 98%). Importantly, the reaction is applicable to late-stage functionalization of pharmaceuticals.
    26. 26
      Rohe, S.; Morris, A. O.; McCallum, T.; Barriault, L. Hydrogen Atom Transfer Reactions via Photoredox Catalyzed Chlorine Atom Generation. Angew. Chem., Int. Ed. 2018, 57, 15664– 15669,  DOI: 10.1002/anie.201810187
      26
      Hydrogen Atom Transfer Reactions via Photoredox Catalyzed Chlorine Atom Generation
      Rohe, Samantha; Morris, Avery O.; McCallum, Terry; Barriault, Louis
      Angewandte Chemie, International Edition (2018), 57 (48), 15664-15669CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The selective functionalization of chem. inert C-H bonds remains to be fully realized in achieving org. transformations that are redox-neutral, waste-limiting, and atom-economical. The catalytic generation of chlorine atoms from chloride ions is one of the most challenging redox processes, where the requirement of harsh and oxidizing reaction conditions renders it seldom utilized in synthetic applications. We report the mild, controlled, and catalytic generation of chlorine atoms as a new opportunity for access to a wide variety of hydrogen atom transfer (HAT) reactions owing to the high stability of HCl.The discovery of the photoredox mediated generation of chlorine atoms with Ir-based polypyridyl complex, [Ir(dF(CF3)ppy)2(dtbbpy)]Cl, under blue LED irradn. is reported.
    27. 27
      Zhou, R.; Goh, Y. Y.; Liu, H.; Tao, H.; Li, L.; Wu, J. Visible-Light-Mediated Metal-Free Hydrosilylation of Alkenes through Selective Hydrogen Atom Transfer for Si–H Activation. Angew. Chem., Int. Ed. 2017, 56, 16621– 16625,  DOI: 10.1002/anie.201711250
      27
      Visible-Light-Mediated Metal-Free Hydrosilylation of Alkenes through Selective Hydrogen Atom Transfer for Si-H Activation
      Zhou, Rong; Goh, Yi Yiing; Liu, Haiwang; Tao, Hairong; Li, Lihua; Wu, Jie
      Angewandte Chemie, International Edition (2017), 56 (52), 16621-16625CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Although there has been significant progress in the development of transition-metal-catalyzed hydrosilylations of alkenes over the past several decades, metal-free hydrosilylation is still rare and highly desirable. Herein, authors report a convenient visible-light-driven metal-free hydrosilylation of both electron-deficient and electron-rich alkenes that proceeds through selective hydrogen atom transfer for Si-H activation. The synergistic combination of the organophotoredox catalyst 4CzIPN with quinuclidin-3-yl acetate enabled the hydrosilylation of electron-deficient alkenes by selective Si-H activation while the hydrosilylation of electron-rich alkenes was achieved by merging photoredox and polarity-reversal catalysis.
    28. 28
      (a) Morisaki, K.; Morimoto, H.; Ohshima, T. Recent Progress on Catalytic Addition Reactions to N-Unsubstituted Imines. ACS Catal. 2020, 10, 6924– 6951,  DOI: 10.1021/acscatal.0c01212
      28a
      Recent Progress on Catalytic Addition Reactions to N-Unsubstituted Imines
      Morisaki, Kazuhiro; Morimoto, Hiroyuki; Ohshima, Takashi
      ACS Catalysis (2020), 10 (12), 6924-6951CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      A review. Catalytic addn. reactions to N-unsubstituted (N-unprotected) imines can provide a more straightforward synthesis of amines. This direct process eliminates the unnecessary protecting-group manipulations that are required with N-substituted (N-protected) imines and can contribute to the development of green chem. Although their use has been limited due to difficulties assocd. with the nature of N-unsubstituted imines, recently developed catalytic methods enable the use of N-unsubstituted imines as electrophiles in various catalytic addn. reactions. To facilitate an understanding of the state of the art development of synthetic methodologies, herein we review recent progress on catalytic addn. reactions to N-unsubstituted imines. An overview of the chem. of N-unsubstituted imines is given, followed by a summary of recent progress categorized according to the reaction type is . We hope this review will help to stimulate further development of greener syntheses of nitrogen-contg. compds.
      (b) Nicastri, M. C.; Lehnherr, D.; Lam, Y.-h.; DiRocco, D. A.; Rovis, T. Synthesis of Sterically Hindered Primary Amines by Concurrent Tandem Photoredox Catalysis. J. Am. Chem. Soc. 2020, 142, 987– 998,  DOI: 10.1021/jacs.9b10871
      28b
      Synthesis of Sterically Hindered Primary Amines by Concurrent Tandem Photoredox Catalysis
      Nicastri, Michael C.; Lehnherr, Dan; Lam, Yu-hong; DiRocco, Daniel A.; Rovis, Tomislav
      Journal of the American Chemical Society (2020), 142 (2), 987-998CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Primary amines are an important structural motif in active pharmaceutical ingredients (APIs) and intermediates thereof, as well as members of ligand libraries for either biol. or catalytic applications. Many chem. methodologies exist for amine synthesis, but the direct synthesis of primary amines with a fully substituted α carbon center is an underdeveloped area. We report a method which utilizes photoredox catalysis to couple readily available O-benzoyl oximes with cyanoarenes to synthesize primary amines with fully substituted α-carbons. We also demonstrate that this method enables the synthesis of amines with α-trifluoromethyl functionality. Based on exptl. and computational results, we propose a mechanism where the photocatalyst engages in concurrent tandem catalysis by reacting with the oxime as a triplet sensitizer in the first catalytic cycle and a reductant toward the cyanoarene in the second catalytic cycle to achieve the synthesis of hindered primary amines via heterocoupling of radicals from readily available oximes.
      (c) Lehnherr, D.; Lam, Y.-h.; Nicastri, M. C.; Liu, J.; Newman, J. A.; Regalado, E. L.; DiRocco, D. A.; Rovis, T. Electrochemical Synthesis of Hindered Primary and Secondary Amines via Proton-Coupled Electron Transfer. J. Am. Chem. Soc. 2020, 142, 468– 478,  DOI: 10.1021/jacs.9b10870
      28c
      Electrochemical Synthesis of Hindered Primary and Secondary Amines via Proton-Coupled Electron Transfer
      Lehnherr, Dan; Lam, Yu-hong; Nicastri, Michael C.; Liu, Jinchu; Newman, Justin A.; Regalado, Erik L.; DiRocco, Daniel A.; Rovis, Tomislav
      Journal of the American Chemical Society (2020), 142 (1), 468-478CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Accessing hindered amines, particularly primary amines α to a fully substituted carbon center, is synthetically challenging. We report an electrochem. method to access such hindered amines starting from benchtop-stable iminium salts and cyanoheteroarenes. A wide variety of substituted heterocycles (pyridine, pyrimidine, pyrazine, purine, azaindole) can be utilized in the cross-coupling reaction, including those substituted with a halide, trifluoromethyl, ester, amide, or ether group, a heterocycle, or an unprotected alc. or alkyne. Mechanistic insight based on DFT data, as well as cyclic voltammetry and NMR spectroscopy, suggests that a proton-coupled electron-transfer mechanism is operational as part of a hetero-biradical cross-coupling of α-amino radicals and radicals derived from cyanoheteroarenes. Safety: cyanide may be released as a byproduct leading to release of toxic HCN.
      (d) Ushakov, D. B.; Gilmore, K.; Kopetzki, D.; McQuade, D. T.; Seeberger, P. H. Continuous-Flow Oxidative Cyanation of Primary and Secondary Amines Using Singlet Oxygen. Angew. Chem., Int. Ed. 2014, 53, 557– 561,  DOI: 10.1002/anie.201307778
      28d
      Continuous-Flow Oxidative Cyanation of Primary and Secondary Amines Using Singlet Oxygen
      Ushakov, Dmitry B.; Gilmore, Kerry; Kopetzki, Daniel; McQuade, D. Tyler; Seeberger, Peter H.
      Angewandte Chemie, International Edition (2014), 53 (2), 557-561CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Primary and secondary amines can be rapidly and quant. oxidized to the corresponding imines by singlet oxygen. This reactive form of oxygen was produced using a variable-temp. continuous-flow LED-photoreactor with a catalytic amt. of tetraphenylporphyrin as the sensitizer. α-Aminonitriles were obtained in good to excellent yields when trimethylsilyl cyanide served as an in situ imine trap. At 25°C, primary amines were found to undergo oxidative coupling prior to cyanide addn. and yielded secondary α-aminonitriles. Primary α-aminonitriles were synthesized from the corresponding primary amines for the first time, by an oxidative Strecker reaction at -50°C. This atom-economic and protecting-group-free pathway provides a route to racemic amino acids, which was exemplified by the synthesis of tert-leucine hydrochloride from neopentylamine.
    29. 29

      The addition step may be slower than potential side reactions (e.g., benzylic radical dimerization) or be reversible and endergonic, such that catalytic turnover is impeded. However, the photocatalytic α-C–H alkylation of tertiary benzylic amines with electrophilic alkenes has been achieved via an SET oxidation–deprotonation approach; see ref (9c).

      There is no corresponding record for this reference.
    30. 30

      In general, quantification of the HAT site selectivity was not possible, but minor unidentified byproducts were visible in the crude 1H NMR spectra for some compounds. We previously showed, both experimentally and theoretically, that the selectivity for α-C–H functionalization of cyclohexylamine versus cyclohexanol with photogenerated azidyl radical is >20:1, with cyclohexanol itself being α-C–H alkylated with methyl acrylate in only 12% yield in a standalone experiment; see ref (9d).

      There is no corresponding record for this reference.
    31. 31
      Cambié, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noël, T. Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment. Chem. Rev. 2016, 116, 10276– 10341,  DOI: 10.1021/acs.chemrev.5b00707
      31
      Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment
      Cambie, Dario; Bottecchia, Cecilia; Straathof, Natan J. W.; Hessel, Volker; Noel, Timothy
      Chemical Reviews (Washington, DC, United States) (2016), 116 (17), 10276-10341CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. Continuous-flow photochem. in microreactors receives a lot of attention from researchers in academia and industry as this technol. provides reduced reaction times, higher selectivities, straightforward scalability, and the possibility to safely use hazardous intermediates and gaseous reactants. In this review, an up-to-date overview is given of photochem. transformations in continuous-flow reactors, including applications in org. synthesis, material science, and water treatment. In addn., the advantages of continuous-flow photochem. are pointed out and a thorough comparison with batch processing is presented.
    32. 32

      Incidentally, compound 7ag was misassigned as the other regioisomer in our previous work; see ref (9d). We now have conclusive 2D NMR and single-crystal XRD support for the revised structure of 7ag.

      There is no corresponding record for this reference.
    33. 33

      As the closest literature comparison, a recent α-amino radical addition to 6h (with a tertiary amine) proceeded in only 7% yield; see ref (11b).

      There is no corresponding record for this reference.
    34. 34
      Constantin, T.; Zanini, M.; Regni, A.; Sheikh, N. S.; Juliá, F.; Leonori, D. Aminoalkyl radicals as halogen-atom transfer agents for activation of alkyl and aryl halides. Science 2020, 367, 1021– 1026,  DOI: 10.1126/science.aba2419
      34
      Aminoalkyl radicals as halogen-atom transfer agents for activation of alkyl and aryl halides
      Constantin, Timothee; Zanini, Margherita; Regni, Alessio; Sheikh, Nadeem S.; Julia, Fabio; Leonori, Daniele
      Science (Washington, DC, United States) (2020), 367 (6481), 1021-1026CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
      Org. halides are important building blocks in synthesis, but their use in (photo)redox chem. is limited by their low redn. potentials. Halogen-atom transfer remains the most reliable approach to exploit these substrates in radical processes despite its requirement for hazardous reagents and initiators such as tributyltin hydride. In this study, we demonstrate that α-aminoalkyl radicals, easily accessible from simple amines, promote the homolytic activation of carbon-halogen bonds with a reactivity profile mirroring that of classical tin radicals. This strategy conveniently engages alkyl and aryl halides in a wide range of redox transformations to construct sp3-sp3, sp3-sp2, and sp2-sp2 carbon-carbon bonds under mild conditions with high chemoselectivity.
    35. 35
      Sanford, M. Fingolimod: A Review of Its Use in Relapsing-Remitting Multiple Sclerosis. Drugs 2014, 74, 1411– 1433,  DOI: 10.1007/s40265-014-0264-y
      35
      Fingolimod: A Review of Its Use in Relapsing-Remitting Multiple Sclerosis
      Sanford, Mark
      Drugs (2014), 74 (12), 1411-1433CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)
      A review. Fingolimod (Gilenya) is an orally administered disease modifying agent (DMA) for use in relapsing-remitting multiple sclerosis (RRMS). In placebo-controlled trials in patients with RRMS with active disease, fingolimod 0.5 mg/day significantly reduced the annualized relapse rate (ARR) by approx. one-half over 2-yr trial periods. It also significantly increased the proportion of patients with no disability progression, reduced deterioration from baseline in the Extended Disability Status Scale score and reduced MRI markers of disease progression (new/newly enlarging brain lesions and percentage change in brain vol.). In a 12-mo, comparison with i.m. interferon β-1a (IFNβ- 1a) 30 μg/wk, the ARR in fingolimod 0.5 mg/day recipients was significantly lower than in IFNβ-1a recipients by one-half; fingolimod recipients also had significantly lower MRI markers of disease progression. In extensions to the pivotal clin. trials, fingolimod exposure for up to 4 years was assocd. with low relapse rates and continuing benefits in terms of disability and disease progression. In clin. trials, adverse events in fingolimod recipients were generally mild to moderate in severity. In the pivotal placebo-controlled trial, serious adverse events occurred in similar proportions of fingolimod 0.5 mg/day and placebo recipients. First-dose bradycardia and atrioventricular block, which are generally asymptomatic, were clin. important adverse events assocd. with fingolimod in placebo-controlled trials. The risk for serious cardiovascular adverse events at the approved fingolimod dosage appears to be low in patients without pre-existing cardiac conditions. Fingolimod is an efficacious therapy for RRMS that reduces relapses, disability progression, new brain lesions and loss of brain vol. It has an acceptable tolerability profile and provides a useful alternative treatment in patients with RRMS who have responded poorly to other DMAs.
    36. 36
      Parijat, P.; Kondacs, L.; Alexandrovich, A.; Gautel, M.; Cobb, A. J. A.; Kampourakis, T. High Throughput Screen Identifies Small Molecule Effectors That Modulate Thin Filament Activation in Cardiac Muscle. ACS Chem. Biol. 2021, 16, 225– 235,  DOI: 10.1021/acschembio.0c00908
      36
      High Throughput Screen Identifies Small Molecule Effectors That Modulate Thin Filament Activation in Cardiac Muscle
      Parijat, Priyanka; Kondacs, Laszlo; Alexandrovich, Alexander; Gautel, Mathias; Cobb, Alexander J. A.; Kampourakis, Thomas
      ACS Chemical Biology (2021), 16 (1), 225-235CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
      Current therapeutic interventions for both heart disease and heart failure are largely insufficient and assocd. with undesired side effects. Biomedical research has emphasized the role of sarcomeric protein function for the normal performance and energy efficiency of the heart, suggesting that directly targeting the contractile myofilaments themselves using small mol. effectors has therapeutic potential and will likely result in greater drug efficacy and selectivity. In this study, we developed a robust and highly reproducible fluorescence polarization-based high throughput screening (HTS) assay that directly targets the calcium-dependent interaction between cardiac troponin C (cTnC) and the switch region of cardiac troponin I (cTnISP), with the aim of identifying small mol. effectors of the cardiac thin filament activation pathway. We screened a com. available small mol. library and identified several hit compds. with both inhibitory and activating effects. We used a range of biophys. and biochem. methods to characterize hit compds. and identified fingolimod, a sphingosin-1-phosphate receptor modulator, as a new troponin-based small mol. effector. Fingolimod decreased the ATPase activity and calcium sensitivity of demembranated cardiac muscle fibers in a dose-dependent manner, suggesting that the compd. acts as a calcium desensitizer. We investigated fingolimod's mechanism of action using a combination of computational studies, biophys. methods, and synthetic chem., showing that fingolimod bound to cTnC repels cTnISP via mainly electrostatic repulsion of its pos. charged tail. These results suggest that fingolimod is a potential new lead compd./scaffold for the development of troponin-directed heart failure therapeutics.
    37. 37
      Mulakayala, N. A Comprehensive Review on Synthetic Approach for Fingolimod. Indian J. Adv. Chem. Sci. 2016, 4, 362– 366
      37
      A comprehensive review on synthetic approach for fingolimod
      Mulakayala, Naveen
      Indian Journal of Advances in Chemical Science (2016), 4 (4), 362-366CODEN: IJACKX; ISSN:2320-0928. (KROS Publications)
      A review. Multiple sclerosis (MS) often consequences in chronic inflammatory and autoimmune disorders, and recent developments have lead to newer therapeutic options for the treatment of the disease. In this review, we have summarized the literature known synthetic strategies of fingolimod which is the key small mol., and the first oral drug candidate for MS which have been launched in the market.
    38. 38
      Urbano, M.; Guerrero, M.; Rosen, H.; Roberts, E. Modulators of the Sphingosine 1-phosphate receptor 1. Bioorg. Med. Chem. Lett. 2013, 23, 6377– 6389,  DOI: 10.1016/j.bmcl.2013.09.058
      38
      Modulators of the Sphingosine 1-phosphate receptor 1
      Urbano, Mariangela; Guerrero, Miguel; Rosen, Hugh; Roberts, Edward
      Bioorganic & Medicinal Chemistry Letters (2013), 23 (23), 6377-6389CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      A review. The Sphingosine 1-phosphate receptor (S1P-R) signaling system has proven to be of biol. and medical importance in autoimmune settings. S1P1-R is a validated drug target for multiple sclerosis (MS) for which FTY720 (Fingolimod), a S1P1,3-5-R pan-agonist, was recently approved as the first orally active drug for the treatment of relapsing-remitting MS. Transient bradycardia and long half-life are the FTY720 crit. pitfalls. This review provides the latest advances on next-generation S1P1-R modulators from 2012 up to date, with an overview of the chem. structures, structure-activity relationships, and relevant biol. and clin. properties.
    39. 39
      Mandala, S.; Hajdu, R.; Bergstrom, J.; Quackenbush, E.; Xie, J.; Milligan, J.; Thornton, R.; Shei, G. J.; Card, D.; Keohane, C. A. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002, 296, 346– 349,  DOI: 10.1126/science.1070238
      39
      Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists
      Mandala, Suzanne; Hajdu, Richard; Bergstrom, James; Quackenbush, Elizabeth; Xie, Jenny; Milligan, James; Thornton, Rosemary; Shei, Gan-Ju; Card, Deborah; Keohane, Carolann; Rosenbach, Mark; Hale, Jeffrey; Lynch, Christopher L.; Rupprecht, Kathleen; Parsons, William; Rosen, Hugh
      Science (Washington, DC, United States) (2002), 296 (5566), 346-349CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      Blood lymphocyte nos., essential for the development of efficient immune responses, are maintained by recirculation through secondary Lymphoid organs. We show that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolite of the immunosuppressive agent FTY720. Both species were high-affinity agonists of at least four of the five S1P receptors. These agonists produce lymphopenia in blood and thoracic duct lymph by sequestration of lymphocytes in lymph nodes, but not spleen. S1P receptor agonists induced emptying of lymphoid sinuses by retention of lymphocytes on the abluminal side of sinus-lining endothelium and inhibition of egress into lymph. Inhibition of lymphocyte recirculation by activation of S1P receptors may result in therapeutically useful immunosuppression.
    40. 40
      (a) Chen, S.; Yang, L.; Shang, Y.; Mao, J.; Walsh, P. J. Base-Promoted Tandem Synthesis of 2-Azaaryl Tetrahydroquinolines. Org. Lett. 2021, 23, 1594– 1599,  DOI: 10.1021/acs.orglett.0c04306
      40a
      Base-Promoted Tandem Synthesis of 2-Azaaryl Tetrahydroquinolines
      Chen, Shuguang; Yang, Langxuan; Shang, Yongjia; Mao, Jianyou; Walsh, Patrick J.
      Organic Letters (2021), 23 (5), 1594-1599CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      A novel method to synthesize 2-azaaryl tetrahydroquinolines by the base-promoted tandem reaction of azaaryl Me amines and styrene derivs. was reported (over 30 examples, yields up to 95%). Mechanistic probe expts. demonstrate that the deprotonation of the benzylic C-H bond and the addn. to the styrene vinyl group proceeds via the SNAr mechanism.
      (b) Warsitz, M.; Doye, S. Two-Step Procedure for the Synthesis of 1,2,3,4-Tetrahydroquinolines. Eur. J. Org. Chem. 2020, 2020, 6997– 7014,  DOI: 10.1002/ejoc.202001337
      40b
      Two-Step Procedure for the Synthesis of 1,2,3,4-Tetrahydro-quinolines
      Warsitz, Michael; Doye, Sven
      European Journal of Organic Chemistry (2020), 2020 (45), 6997-7014CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A new two-step procedure that includes an initial regioselective intermol. hydroaminoalkylation of ortho-chlorostyrenes with N-methylanilines and a subsequent intramol. Buchwald-Hartwig amination gives direct access to 1,2,3,4-tetrahydroquinolines. The hydroaminoalkylation reaction of the ortho-chlorostyrenes is catalyzed by a 2,6-bis(phenylamino)pyridinato titanium complex which delivers the linear regioisomers with high selectivities. In addn., the formation of unexpected dihydroaminoalkylation products from styrenes and N-methylanilines is reported.
    41. 41
      Muthukrishnan, I.; Sridharan, V.; Menéndez, J. C. Progress in the Chemistry of Tetrahydroquinolines. Chem. Rev. 2019, 119, 5057– 5191,  DOI: 10.1021/acs.chemrev.8b00567
      41
      Progress in the Chemistry of Tetrahydroquinolines
      Muthukrishnan, Isravel; Sridharan, Vellaisamy; Menendez, J. Carlos
      Chemical Reviews (Washington, DC, United States) (2019), 119 (8), 5057-5191CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. This review summarizes the progress achieved in the chem. of tetrahydroquinolines, with emphasis on their synthesis, during the mid-2010 to early 2018 period.
    42. 42

      Based on a Scifinder search conducted in April 2021, with the following constraints applied: benzenoid-fused only, 800 MW max, no other ring fusions, only H/C/S attached to N, no isotopes/metals.

      There is no corresponding record for this reference.
    43. 43
      Hiesinger, K.; Dar’in, D.; Proschak, E.; Krasavin, M. Spirocyclic Scaffolds in Medicinal Chemistry. J. Med. Chem. 2021, 64, 150– 183,  DOI: 10.1021/acs.jmedchem.0c01473
      43
      Spirocyclic Scaffolds in Medicinal Chemistry
      Hiesinger, Kerstin; Dar'in, Dmitry; Proschak, Ewgenij; Krasavin, Mikhail
      Journal of Medicinal Chemistry (2021), 64 (1), 150-183CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review. Spirocyclic scaffolds are incorporated in various approved drugs and drug candidates. The increasing interest in less planar bioactive compds. has given rise to the development of synthetic methodologies for the prepn. of spirocyclic scaffolds. In this Perspective, we summarize the diverse synthetic routes to obtain spirocyclic systems. The impact of spirocycles on potency and selectivity, including the aspect of stereochem., is discussed. Furthermore, we examine the changes in physicochem. properties as well as in in vitro and in vivo ADME using selected studies that compare spirocyclic compds. to their nonspirocyclic counterparts. In conclusion, the value of spirocyclic scaffolds in medicinal chem. is discussed.
    44. 44
      St. Denis, J. D.; Hall, R. J.; Murray, C. W.; Heightman, T. D.; Rees, D. C. Fragment-based drug discovery: opportunities for organic synthesis. RSC Med. Chem. 2021, 12, 321– 329,  DOI: 10.1039/D0MD00375A
      44
      Fragment-based drug discovery: opportunities for organic synthesis
      St. Denis, Jeffrey D.; Hall, Richard J.; Murray, Christopher W.; Heightman, Tom D.; Rees, David C.
      RSC Medicinal Chemistry (2021), 12 (3), 321-329CODEN: RMCSEZ; ISSN:2632-8682. (Royal Society of Chemistry)
      A review. This Review describes the increasing demand for org. synthesis to facilitate fragment-based drug discovery (FBDD), focusing on polar, unprotected fragments. In FBDD, X-ray crystal structures are used to design target mols. for synthesis with new groups added onto a fragment via specific growth vectors. This requires challenging synthesis which slows down drug discovery, and some fragments are not progressed into optimization due to synthetic intractability. We have evaluated the output from Astex's fragment screenings for a no. of programs, including urokinase-type plasminogen activator, hematopoietic prostaglandin D2 synthase, and hepatitis C virus NS3 protease-helicase, and identified fragments that were not elaborated due, in part, to a lack of com. available analogs and/or suitable synthetic methodol. This represents an opportunity for the development of new synthetic research to enable rapid access to novel chem. space and fragment optimization.
    45. 45
      Twigg, D. G.; Kondo, N.; Mitchell, S. L.; Galloway, W. R. D.; Sore, H. F.; Madin, A.; Spring, D. R. Partially Saturated Bicyclic Heteroaromatics as an sp3-Enriched Fragment Collection. Angew. Chem., Int. Ed. 2016, 55, 12479– 12483,  DOI: 10.1002/anie.201606496
      45
      Partially Saturated Bicyclic Heteroaromatics as an sp3-Enriched Fragment Collection
      Twigg, David G.; Kondo, Noriyasu; Mitchell, Sophie L.; Galloway, Warren R. J. D.; Sore, Hannah F.; Madin, Andrew; Spring, David R.
      Angewandte Chemie, International Edition (2016), 55 (40), 12479-12483CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Fragment-based lead generation has proven to be an effective means of identifying high-quality lead compds. for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp2-rich arom. compds., which limits the structural (and hence biol.) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially satd. bicyclic heteroarom. scaffolds with enhanced sp3 character. Subsequent derivatization led to a fragment collection featuring regio- and stereo-controlled introduction of substituents on the satd. ring system, often with formation of new stereocenters.
    46. 46
      Law, R. P.; Atkinson, S. J.; Bamborough, P.; Chung, C.-w.; Demont, E. H.; Gordon, L. J.; Lindon, M.; Prinjha, R. K.; Watson, A. J. B.; Hirst, D. J. Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain. J. Med. Chem. 2018, 61, 4317– 4334,  DOI: 10.1021/acs.jmedchem.7b01666
      46
      Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain
      Law, Robert P.; Atkinson, Stephen J.; Bamborough, Paul; Chung, Chun-wa; Demont, Emmanuel H.; Gordon, Laurie J.; Lindon, Matthew; Prinjha, Rab K.; Watson, Allan J. B.; Hirst, David J.
      Journal of Medicinal Chemistry (2018), 61 (10), 4317-4334CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomains-BRD2, BRD3, BRD4, and BRDT-each contain two bromodomain modules. BET bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the BET family. Inhibitors with selectivity for the first or second bromodomain are desired to aid investigation of the biol. function of these domains. Focused library screening identified a series of tetrahydroquinoxalines with selectivity for the second bromodomains of the BET family (BD2). Structure-guided optimization of the template improved potency, selectivity, and physicochem. properties, culminating in potent BET inhibitors with BD2 selectivity.
    47. 47
      Procopiou, P. A.; Anderson, N. A.; Barrett, J.; Barrett, T. N.; Crawford, M. H. J.; Fallon, B. J.; Hancock, A. P.; Le, J.; Lemma, S.; Marshall, R. P. Discovery of (S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-l)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αvβ6 Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary Fibrosis. J. Med. Chem. 2018, 61, 8417– 8443,  DOI: 10.1021/acs.jmedchem.8b00959
      47
      Discovery of (S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αvβ6 Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary Fibrosis
      Procopiou, Panayiotis A.; Anderson, Niall A.; Barrett, John; Barrett, Tim N.; Crawford, Matthew H. J.; Fallon, Brendan J.; Hancock, Ashley P.; Le, Joelle; Lemma, Seble; Marshall, Richard P.; Morrell, Josie; Pritchard, John M.; Rowedder, James E.; Saklatvala, Paula; Slack, Robert J.; Sollis, Steven L.; Suckling, Colin J.; Thorp, Lee R.; Vitulli, Giovanni; Macdonald, Simon J. F.
      Journal of Medicinal Chemistry (2018), 61 (18), 8417-8443CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A series of 3-aryl-(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, which involved rhodium catalyzed asym. 1,4-addn. of arylboronic acids in the presence of (R)-BINAP to a crotonate ester to provide the (S) abs. configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole and cyclic ether were screened in cell adhesion assays for affinity against αvβ1, αvβ3, αvβ5, αvβ6 and αvβ8 integrins. Several analogs with high affinity and selectivity for the αvβ6 integrin were identified. The analog I·HCl was found to have high affinity for αvβ6 integrin in a radioligand binding assay (pKi = 11), a long dissocn. half-life (7 h) , high soly. in saline at pH 7 (>71 mg/mL) and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It was selected for further investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.
    48. 48
      Fairhurst, R. A.; Knoepfel, T.; Buschmann, N.; Leblanc, C.; Mah, R.; Todorov, M.; Nimsgern, P.; Ripoche, S.; Niklaus, M.; Warin, N. Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4. J. Med. Chem. 2020, 63, 12542– 12573,  DOI: 10.1021/acs.jmedchem.0c01019
      48
      Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4
      Fairhurst, Robin A.; Knoepfel, Thomas; Buschmann, Nicole; Leblanc, Catherine; Mah, Robert; Todorov, Milen; Nimsgern, Pierre; Ripoche, Sebastien; Niklaus, Michel; Warin, Nicolas; Luu, Van Huy; Madoerin, Mario; Wirth, Jasmin; Graus-Porta, Diana; Weiss, Andreas; Kiffe, Michael; Wartmann, Markus; Kinyamu-Akunda, Jacqueline; Sterker, Dario; Stamm, Christelle; Adler, Flavia; Buhles, Alexandra; Schadt, Heiko; Couttet, Philippe; Blank, Jutta; Galuba, Inga; Trappe, Jorg; Voshol, Johannes; Ostermann, Nils; Zou, Chao; Berghausen, Jorg; Del Rio Espinola, Alberto; Jahnke, Wolfgang; Furet, Pascal
      Journal of Medicinal Chemistry (2020), 63 (21), 12542-12573CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      FGF19 signaling through the FGFR4/β-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas, making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarized which made use of both rational and unbiased screening approaches. The optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimization are improving the FGFR4 potency, metabolic stability, and soly. leading ultimately to the highly selective first-in-class clin. candidate roblitinib.
    49. 49

      We cannot exclude the possibility that azidyl radical may react initially with the DMF solvent to generate an α-carbamoyl radical by HAT with a C–H bond on one of the N-Me groups (BDE ≈ 105 kcal mol–1; see ref (20)) and that this radical may in turn be responsible for abstracting a hydrogen from the alkylamine. We thank a reviewer for this suggestion.

      There is no corresponding record for this reference.
    50. 50
      Bordwell, F. G. Equilibrium Acidities in Dimethyl Sulfoxide Solution. Acc. Chem. Res. 1988, 21, 456– 463,  DOI: 10.1021/ar00156a004
      50
      Equilibrium acidities in dimethyl sulfoxide solution
      Bordwell, Frederick G.
      Accounts of Chemical Research (1988), 21 (12), 456-63CODEN: ACHRE4; ISSN:0001-4842.
      A review with 62 refs.
    51. 51
      Prieto, A.; Taillefer, M. Visible-Light Decatungstate/Disulfide Dual Catalysis for the Hydro-Functionalization of Styrenes. Org. Lett. 2021, 23 (4), 1484– 1488,  DOI: 10.1021/acs.orglett.1c00189
      51
      Visible-Light Decatungstate/Disulfide Dual Catalysis for the Hydro-Functionalization of Styrenes
      Prieto, Alexis; Taillefer, Marc
      Organic Letters (2021), 23 (4), 1484-1488CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      An efficient photoredox system, relied on decatungstate/disulfide catalysts, for the hydrofunctionalization of styrenes was described. In this methodol. the use of disulfide as a cocatalyst was shown to be crucial for the reaction efficiency. This photoredox system was employed for the hydro-carbamoylation, -acylation, -alkylation, and -silylation of styrenes, gave access to a large variety of useful building blocks and high-value mols. such as amides and unsym. ketones from simple starting materials.
    52. 52
      Cismesia, M. A.; Yoon, T. P. Characterizing chain processes in visible light photoredox catalysis. Chem. Sci. 2015, 6, 5426– 5434,  DOI: 10.1039/C5SC02185E
      52
      Characterizing chain processes in visible light photoredox catalysis
      Cismesia, Megan A.; Yoon, Tehshik P.
      Chemical Science (2015), 6 (10), 5426-5434CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      The recognition that Ru(bpy)32+ and similar visible light absorbing transition metal complexes can be photocatalysts for a variety of synthetically useful org. reactions has resulted in a recent resurgence of interest in photoredox catalysis. However, many of the crit. mechanistic aspects of this class of reactions remain poorly understood. In particular, the degree to which visible light photoredox reactions involve radical chain processes has been a point of some disagreement that has not been subjected to systematic anal. We have now performed quantum yield measurements to demonstrate that three representative, mechanistically distinct photoredox processes involve product-forming chain reactions. Moreover, we show that the combination of quantum yield and luminescence quenching expts. provides a rapid method to est. the length of these chains. Together, these measurements constitute a robust, operationally facile strategy for characterizing chain processes in a wide range of visible light photoredox reactions.
    53. 53
      Tagami, T.; Arakawa, Y.; Minagawa, K.; Imada, Y. Efficient Use of Photons in Photoredox/Enamine Dual Catalysis with a Peptide-Bridged Flavin–Amine Hybrid. Org. Lett. 2019, 21, 6978– 6982,  DOI: 10.1021/acs.orglett.9b02567
      53
      Efficient Use of Photons in Photoredox/Enamine Dual Catalysis with a Peptide-Bridged Flavin-Amine Hybrid
      Tagami, Takuma; Arakawa, Yukihiro; Minagawa, Keiji; Imada, Yasushi
      Organic Letters (2019), 21 (17), 6978-6982CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
      An isoalloxazine (flavin) ring system and a secondary amine have been integrated through a short peptide linker with the aim of using photons as efficiently as possible in photoredox/enamine dual catalysis. We herein report a peptide-bridged flavin-amine hybrid that can catalyze α-oxyamination of aldehydes with TEMPO under weak blue light irradn. to achieve an extremely high quantum yield of reaction (Φ = 0.80).
    54. 54
      Burés, J. Variable Time Normalization Analysis: General Graphical Elucidation of Reaction Orders from Concentration Profiles. Angew. Chem., Int. Ed. 2016, 55, 16084– 16087,  DOI: 10.1002/anie.201609757
      54
      Variable Time Normalization Analysis: General Graphical Elucidation of Reaction Orders from Concentration Profiles
      Bures, Jordi
      Angewandte Chemie, International Edition (2016), 55 (52), 16084-16087CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The recent technol. evolution of reaction monitoring techniques has not been paralleled by the development of modern kinetic analyses. The analyses currently used disregard part of the data acquired, thus requiring an increased no. of expts. to obtain sufficient kinetic information for a given chem. reaction. Herein, we present a simple graphical anal. method that takes advantage of the data-rich results provided by modern reaction monitoring tools. This anal. uses a variable normalization of the time scale to enable the visual comparison of entire concn. reaction profiles. As a result, the order in each component of the reaction, as well as kobs , is detd. with just a few expts. using a simple and quick math. data treatment. This anal. facilitates the rapid extn. of relevant kinetic information and will be a valuable tool for the study of reaction mechanisms.
    55. 55

      If the addition step of the α-amino radical 25 to the styrene 6 is reversible, then the concentration of benzylic radical 26 would exhibit a dependence on the concentration of styrene 6 (pre-equilibrium approximation). However, if the addition step is rapid and essentially irreversible, then saturation kinetics will occur and the concentration of benzylic radical 26 will become independent of styrene 6 concentration.

      There is no corresponding record for this reference.
    56. 56
      Bloh, J. Z. A Holistic Approach to Model the Kinetics of Photocatalytic Reactions. Front. Chem. 2019, 7, 128,  DOI: 10.3389/fchem.2019.00128
      56
      A holistic approach to model the kinetics of photocatalytic reactions
      Bloh, Jonathan Z.
      Frontiers in Chemistry (Lausanne, Switzerland) (2019), 7 (), 128CODEN: FCLSAA; ISSN:2296-2646. (Frontiers Media S.A.)
      Understanding and modeling kinetics is an essential part of the optimization and implementation of chem. reactions. In the case of photocatalytic reactions this is mostly done one-dimensionally, i.e., only considering the effect of one parameter at the same time. However, as discussed in this study, many of the relevant reaction parameters have mutual interdependencies that call for a holistic multi-dimensional approach to accurately model and understand their influence. Such an approach is described herein, and all the relevant equations given so that researchers can readily implement it to analyze and model their reactions.
    57. 57
      (a) Ji, Y.; DiRocco, D. A.; Kind, J.; Thiele, C. M.; Gschwind, R. M.; Reibarkh, M. LED-Illuminated NMR Spectroscopy: A Practical Tool for Mechanistic Studies of Photochemical Reactions. ChemPhotoChem. 2019, 3, 984– 992,  DOI: 10.1002/cptc.201900109
      57a
      LED-Illuminated NMR Spectroscopy: A Practical Tool for Mechanistic Studies of Photochemical Reactions
      Ji, Yining; Di Rocco, Daniel A.; Kind, Jonas; Thiele, Christina M.; Gschwind, Ruth M.; Reibarkh, Mikhail
      ChemPhotoChem (2019), 3 (10), 984-992CODEN: CHEMYH ISSN:. (Wiley-VCH Verlag GmbH & Co. KGaA)
      This Concept article highlights the development of a novel anal. tool, LED-NMR (a combination of in situ light illumination using a light-emitting diode and NMR spectroscopy) and its variant UVNMR (LED-NMR coupled with UV/Vis absorption spectroscopy), as well as their applications in the mechanistic investigation of light-induced transformations. The utility of these new tools has been demonstrated by providing rich kinetic and structural data of reaction species offering mechanistic insights into photochem. and photocatalytic reactions. Furthermore, NMR actinometry has been recently developed as a practical and simple method for quantum yield measurements. Quantum yield is an important parameter in photo-induced processes, but is rarely measured in practice because of the barriers assocd. with traditional actinometry. These new tools and techniques streamline measurements of the quantum efficiency while affording informative mechanistic insights into photochem. reactions. We anticipate these techniques will enable chemists to further advance the rapidly emerging photochem. field.
      (b) Tlahuext-Aca, A.; Candish, L.; Garza-Sanchez, R. A.; Glorius, F. Decarboxylative Olefination of Activated Aliphatic Acids Enabled by Dual Organophotoredox/Copper Catalysis. ACS Catal. 2018, 8, 1715– 1719,  DOI: 10.1021/acscatal.7b04281
      57b
      Decarboxylative Olefination of Activated Aliphatic Acids Enabled by Dual Organophotoredox/Copper Catalysis
      Tlahuext-Aca, Adrian; Candish, Lisa; Garza-Sanchez, R. Aleyda; Glorius, Frank
      ACS Catalysis (2018), 8 (3), 1715-1719CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      Herein, we demonstrate a dual organophotoredox/copper catalytic strategy toward challenging decarboxylative olefination processes proceeding in high yields and selectivities. This operationally simple method uses photoactive org. mols. and Cu(II)-complexes as catalysts to provide rapid access to a wide variety of olefins from inexpensive synthetic and biomass-derived carboxylic acids under mild light-mediated conditions. Mechanistic investigations suggest that the reaction rate for this process is controlled solely by the incident photon flux.
      (c) Le, C.; Wismer, M. K.; Shi, Z.-C.; Zhang, R.; Conway, D. V.; Li, G.; Vachal, P.; Davies, I. W.; MacMillan, D. W. C. A General Small-Scale Reactor To Enable Standardization and Acceleration of Photocatalytic Reactions. ACS Cent. Sci. 2017, 3, 647– 653,  DOI: 10.1021/acscentsci.7b00159
      57c
      A general small-scale reactor to enable standardization and acceleration of photocatalytic reactions
      Le, Chi "Chip"; Wismer, Michael K.; Shi, Zhi-Cai; Zhang, Rui; Conway, Donald V.; Li, Guoqing; Vachal, Petr; Davies, Ian W.; MacMillan, David W. C.
      ACS Central Science (2017), 3 (6), 647-653CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
      Photocatalysis for org. synthesis has experienced an exponential growth in the past 10 years. However, the variety of exptl. procedures that have been reported to perform photon-based catalyst excitation has hampered the establishment of general protocols to convert visible light into chem. energy. To address this issue, we have designed an integrated photoreactor for enhanced photon capture and catalyst excitation. Moreover, the evaluation of this new reactor in eight photocatalytic transformations that are widely employed in medicinal chem. settings has confirmed significant performance advantages of this optimized design while enabling a standardized protocol.
    58. 58

      We became aware that Professor Gaunt at the University of Cambridge was engaged in related studies toward photocatalytic amine synthesis. We are grateful to the Gaunt group for kindly agreeing to submit their results concurrently with our own studies, and thank them for their generosity and collegiality. See:

      Blackwell, J. H.; Harris, G. R.; Smith, M. A.; Gaunt, M. J. Modular Photocatalytic Synthesis of α-Trialkyl-α-Tertiary Amines. J. Am. Chem. Soc. 2021,  DOI: 10.1021/jacs.1c07402
      There is no corresponding record for this reference.

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