Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Am. Chem. Soc. 2024, 146, 47, 32452-32462

ArticleNovember 8, 2024

Catalytic Concerted S_NAr Reactions of Fluoroarenes by an Organic Superbase
Click to copy article linkArticle link copied!

Masanori Shigeno*
Masanori Shigeno
Department of Biophysical Chemistry, Graduate School of Pharmaceutical Science, Tohoku University, Aoba, Sendai 980-8578, Japan
JST, PRESTO, Kawaguchi, Saitama 332-0012, Japan
*Email: [email protected]
More by Masanori Shigeno
https://orcid.org/0000-0002-9640-8283
Kazutoshi Hayashi
Kazutoshi Hayashi
Department of Biophysical Chemistry, Graduate School of Pharmaceutical Science, Tohoku University, Aoba, Sendai 980-8578, Japan
More by Kazutoshi Hayashi
Ozora Sasamoto
Ozora Sasamoto
Department of Biophysical Chemistry, Graduate School of Pharmaceutical Science, Tohoku University, Aoba, Sendai 980-8578, Japan
More by Ozora Sasamoto
Riku Hirasawa
Riku Hirasawa
Department of Biophysical Chemistry, Graduate School of Pharmaceutical Science, Tohoku University, Aoba, Sendai 980-8578, Japan
More by Riku Hirasawa
Toshinobu Korenaga*
Toshinobu Korenaga
Department of Chemistry and Biological Sciences, Faculty of Science and Engineering, Iwate University, Ueda, Morioka 020-8551, Japan
Soft-Path Science and Engineering Research Center (SPERC), Iwate University, Ueda, Morioka 020-8551, Japan
*Email: [email protected]
More by Toshinobu Korenaga
https://orcid.org/0000-0002-9156-536X
Shintaro Ishida
Shintaro Ishida
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
More by Shintaro Ishida
https://orcid.org/0000-0001-7832-912X
Kanako Nozawa-Kumada
Kanako Nozawa-Kumada
Department of Biophysical Chemistry, Graduate School of Pharmaceutical Science, Tohoku University, Aoba, Sendai 980-8578, Japan
Interdisciplinary Research Center for Catalytic Chemistry, National Institute of Advanced Industrial Science and Technology (AIST), Central 5, 1-1-1 Higashi, Tsukuba 305-8565, Ibaraki, Japan
More by Kanako Nozawa-Kumada
https://orcid.org/0000-0001-8054-5323
Yoshinori Kondo
Yoshinori Kondo
Department of Biophysical Chemistry, Graduate School of Pharmaceutical Science, Tohoku University, Aoba, Sendai 980-8578, Japan
More by Yoshinori Kondo

Open PDF Supporting Information (1)

Journal of the American Chemical Society

Cite this: J. Am. Chem. Soc. 2024, 146, 47, 32452–32462

Click to copy citationCitation copied!

https://doi.org/10.1021/jacs.4c09042

Published November 8, 2024

CC-BY 4.0 .

Abstract

Click to copy section linkSection link copied!

We herein propose that the catalytic concerted S_NAr reaction is a powerful method to prepare functionalized aromatic scaffolds. Classic stepwise S_NAr reactions involving addition/elimination processes require the use of electron-deficient aromatic halides to stabilize Meisenheimer intermediates, despite their widespread use in medicinal chemistry research. Recent efforts have been made to develop concerted S_NAr reactions involving a single transition state, allowing the use of electron-rich substrates based on the use of stoichiometric amounts of strong bases or reactive nucleophiles. This study demonstrates that, without the use of such reagents, the organic superbase t-Bu-P4 efficiently catalyzes the concerted S_NAr reactions of aryl fluorides regardless of their electronic nature. The key to establishing this system is the dual activation of aryl fluoride and anionic nucleophiles by the t-Bu-P4 catalyst. Furthermore, this catalysis allows excellent functional group tolerance, utilization of diverse nucleophiles, and late-stage functionalization of bioactive compound derivatives. These findings make possible diverse applications in chemical synthesis and pharmaceutical development.

This publication is licensed under

CC-BY 4.0 .

License Summary*
You are free to share(copy and redistribute) this article in any medium or format and to adapt(remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
- Creative Commons (CC): This is a Creative Commons license.
- Attribution (BY): Credit must be given to the creator.
View full license
*Disclaimer
This summary highlights only some of the key features and terms of the actual license. It is not a license and has no legal value. Carefully review the actual license before using these materials.
License Summary*
You are free to share(copy and redistribute) this article in any medium or format and to adapt(remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
- Creative Commons (CC): This is a Creative Commons license.
- Attribution (BY): Credit must be given to the creator.
View full license
*Disclaimer
This summary highlights only some of the key features and terms of the actual license. It is not a license and has no legal value. Carefully review the actual license before using these materials.

Subjects

Introduction

Click to copy section linkSection link copied!

The nucleophilic aromatic substitution (S_NAr) reaction of aryl halides involves regioselective ipso-substitution and generates functionalized aromatic compounds relevant to pharmaceuticals, agrochemicals, and functional materials. (1) Early studies on this reaction date back to at least the 1870s. (2) A 2016 report documented that the S_NAr reaction is the second most commonly used reaction in medicinal chemistry research, (3) appearing at least once in the synthetic route of many best-selling drugs. (4) Aryl fluorides are suitable substrates for this reaction, in which the fluorine atom of a strong C–F bond with high bonding energy is replaced. (1) Such C–F bond transformations of aryl fluorides have received considerable attention in organic synthesis due to scientific interest as well as their abundance, ready availability, and structural diversity. (5) Furthermore, this reaction enables the late-stage functionalization of complex molecules. (6) The classic S_NAr reaction mechanistically involves the addition of a nucleophile to form a Meisenheimer intermediate, followed by the elimination of fluorine along with rearomatization of the aryl ring (Figure 1A). Despite the widespread use of this reaction, an inherent and significant drawback is the need to use electron-deficient substrates possessing an electron-withdrawing group at the ortho- or para-position to stabilize the Meisenheimer intermediate and compensate for the loss of aromaticity. Although stepwise elimination and addition processes using strong bases via an aryne intermediate have also been reported as alternative pathways, regioselective control of the addition is not facile and affords a mixture of ipso- and ortho-substituted products. (7)

Figure 1. Overview of previous S_NAr reactions and this work.

As a recent prominent advance, the concerted nucleophilic aromatic substitution (CS_NAr) reaction through a single transition state has emerged (Figure 1B). (8) Theoretical and experimental studies by Jacobsen’s group and Murphy and Tuttle’s group highlighted the CS_NAr reactions and suggested the potential reaction scope. (9,10) Here, cation M⁺ (mainly, alkali-metal cations) undergoes a favorable electrostatic interaction with a fluorine atom to stabilize its negative charge in the transition state and assists in fluorine elimination. (10) Based on these findings, several groups have successfully demonstrated the applicability of nonelectrophilically activated aryl fluorides, even including electron-rich substrates, for these reactions. (11) This reaction, however, remains sporadically reported and understudied. Moreover, this reaction requires the use of stoichiometric amounts of strong bases {e.g., MHMDS (M = Li, Na, K) and KO-t-Bu} or reactive nucleophiles. Thus, the construction of a catalytic CS_NAr reaction system without the use of such reagents is attractive and merits investigation. To date, a few nucleophilic Lewis base catalysts have been demonstrated (Figure 1C). For example, Tobisu and co-workers reported that N-heterocyclic carbene catalyzes intramolecular cyclization of fluoroarenes bearing an acrylamide moiety to afford quinoline-2-ones (Figure 1C-a). (12) In addition, catalytic reduction and thiolation reactions of perfluoroarenes were described with silane and silylated thiol nucleophiles, respectively (Figure 1C-b,c). (13,14) However, these pioneering reactions have a limited scope of aryl fluorides (i.e., intramolecular cyclization substrates and electron-deficient substrates) and nucleophilic components (i.e., special C═C double bonds and organosilanes). Therefore, the development of a powerful and robust catalytic system that is compatible with a range of aryl fluorides, regardless of their electronic nature, and nucleophiles as well as diverse functional groups is highly desirable and is expected to lead to considerable advances in the chemistry of S_NAr reactions. In addition, other catalytic S_NAr reactions using cationic transition metals (Rh(III) and Ru(II)) (15) or (electro)photocatalysts (16) proceed through the electrophilic activation of aromatic rings (i.e., formation of a metal h⁶-fluoroarene complex or generation of an aryl radical cation intermediate by single-electron arene oxidation, respectively), which mainly focuses on the use of electron-rich aryl fluorides. Thus, based on the different mechanisms, the catalytic CS_NAr system proposed herein is complementary to those catalysis.

Our group has developed molecular transformations using the organic superbase t-Bu-P4, which was originally prepared by Schwesinger et al. (17,18) Deprotonation of a pronucleophile by t-Bu-P4 forms a reactive anion species because the electrostatic interaction of the anion with the large soft cation [t-Bu-P4]⁺H (∼500 Å³) is rather weak. (19) Based on this, we previously showed that t-Bu-P4 catalyzes the S_NAr reactions of electron-deficient methoxyarenes with alkyl cyanides, alcohols, and amines. (20) It was also reported that the reactions of electron-deficient aryl fluorides proceed with organosilicon. (21) In previous studies, we found that when 3-fluoro-4-methoxybenzonitrile was treated with 2-phenylpropionitrile (2a), not only methoxy substitution but also fluorine substitution occurred (Scheme S1). (20c) This result was notable because the electronically insufficiently activated aryl fluoride moiety reacted under the applied conditions, suggesting that t-Bu-P4 catalysis could be a potent catalytic S_NAr system for aryl fluorides. Here, the developed system based on this finding is reported (Figure 1D).

Results and Discussion

Click to copy section linkSection link copied!

Reaction Development

Initially, the reaction conditions were investigated using electron-neutral 4-fluorobiphenyl (1a) and 2-phenylpropionitrile (2a) as model substrates (Table 1). When the reaction was conducted with t-Bu-P4 (20 mol %) at 80 °C, target product 3aa was obtained in 39% yield (entry 1). Then, molecular sieves were added as a heterogeneous solid base to trap the generated HF, and the 4 Å MS greatly increased the product yield to 91% (entries 2–4). (22) The use of inorganic bases, such as Na₂CO₃, K₂CO₃, Cs₂CO₃, K₃PO₄, and KOH, resulted in modest to good yields (45–88%), while organic bases, such as NEt₃ and pyridine, were less effective (Table S1). Among the evaluated solvents, 1,4-dioxane and cyclohexane resulted in good yields (81 and 87%, respectively), but these values were inferior to that obtained in toluene (entries 5–7). A reduced amount of t-Bu-P4 (10 mol %) still afforded a good yield of 83% (entry 8). Decreasing the reaction temperature decreased the product yield (entry 9). t-Bu-P4 was found to be an exceptionally effective base catalyst compared with other catalysts (Table S2). This catalyst was amenable to a scaled-up reaction on the 1.0 mmol scale, furnishing the product in 91% yield (entry 10).

Table 1. Optimization of the Reaction Conditions of 1a and 2a^a

entry	deviation from standard conditions	3aa (%)^b
1	without 4 Å MS	39
2	3 Å MS instead of 4 Å MS	79
3	none	91
4	5 Å MS instead of 4 Å MS	71
5	1,4-dioxane as the solvent	81
6	cyclohexane as the solvent	87
7	DMF as the solvent	56
8	10 mol % t-Bu-P4	83
9	60 °C	55
10	scaled-up reaction^c	91

^{^a}

Standard conditions: 1a (0.20 mmol), 2a (0.22 mmol), t-Bu-P4 (0.04 mmol), 4 Å MS (100 mg), toluene (0.3 mL), 80 °C, and 18 h.

^{^b}

Isolated yields.

^{^c}

1a (1.0 mmol), 2a (1.1 mmol), t-Bu-P4 (0.20 mmol), 4 Å MS (500 mg), toluene (1.5 mL), 80 °C, and 18 h.

Substrate Scope with Respect to Fluoroarenes

With the optimized conditions in hand, we examined the substrate scope of fluoroarenes with 2a (Figure 2). First, electron-deficient substrates were tested (Figure 2A). Electrophilic functional groups (i.e., cyano, trifluoromethyl, (non)enolizable ketone, ester, and amide), which may be susceptible to nucleophilic addition or substitution, at the para position of the fluorine atom were well tolerated, and target products 3ba–3ga were furnished in high yields (72–93%). In addition, less electron-deficient meta-substituted substrates 1h–1k possessing cyano, benzoyl, sulfonyl, and sulfonamide moieties successfully afforded products 3ha–3ka, despite the potential side reaction, e.g., deprotonation of the relatively acidic C2-proton and subsequent aryne formation. Reactions of nitro-substituted substrates also proceeded smoothly. Perfluoroarenes bearing benzoyl and methyl groups, 1n and 1o, provided the monosubstitution products, while hexafluorobenzene (1p) gave the disubstitution product. Additionally, not only 2-fluoropyridine (1q) but also less electrophilic 3-fluoropyridine (1r) underwent reaction to generate products 3qa and 3ra, respectively, in high yields.

Figure 2. Scope of aryl fluorides and alkyl cyanides.^a,b aReactions were conducted on a 0.2 mmol scale. ^bIsolated yields. ^cReaction was conducted at 40 °C. ^dReaction was conducted at 60 °C. ^e2 (2 equiv) was used. ^fReaction was conducted at 120 °C. ^gReaction was conducted at 140 °C. ^hReaction was conducted in mesitylene at 160 °C. ⁱReaction was conducted in mesitylene at 180 °C.

Next, the scope of electron-neutral and electron-rich substrates was examined (Figure 2B). Regardless of the position of the phenyl group, the reactions proceeded smoothly to form target products 3sa and 3ta in high yields of 90 and 77%, respectively. 1-Fluoronaphthalene (1u) and fluorobenzene (1v) were also suitable substrates, producing the target products in excellent yields. Use of substrate 1w, bearing a mesityl group at the para-position, provided product 3wa in 97% yield. This is in contrast to previous reports of CS_NAr silylation and phosphinylation, which indicated that substrate 1w and related 4′-fluoro-2,4,6-triisopropyl-1,1′-biphenyl with large torsion angles are unfavorable substrates since their fluorine-ipso-carbons are shielded by the distal methyl and isopropyl substituents, respectively. (11f,h) Substrates 1x and 1y demonstrated the compatibility of alkene and alkyne moieties, respectively. Moreover, chemoselective reactions proceeded successfully in the presence of halogen atoms (Cl, Br, and I), affording products 3za–3Ba. Then, the electron-rich heteroaromatic fluorides 5-fluorobenzothiophene (1C) and 6-fluoro-1-methyl-1H-indole (1D) were tested, resulting in the formation of products 3Ca and 3 Da, respectively, in good yields. Substrates with alkyl groups (i.e., Me and Et) or heteroatom substituents (i.e., OPh, SMe, pyrazolyl, and 2-pyrrolidone groups) also generated target products 3Ea–3Ja in high yields (74–87%). Furthermore, substrates with strong electron-donating amino groups (i.e., NPh₂ and NMe₂) were suitable for this reaction, affording products 3Ka and 3La, respectively. In comparison to fluoroarenes, other (pseudo)halobenzenes such as chlorobenzene, bromobenzene, and nitrobenzene were unsuitable substrates (Table S3).

Substrate Scope with Respect to Alkyl Cyanides

The scope of alkyl cyanides was investigated with fluoroarene 1a (Figure 2C). 2-Arylpropionitriles 2b–2d with methyl, methoxy, and amide moieties on the phenyl ring and 2e with a 1-naphthyl group produced target products 3ab–3ae in high yields (75–94%). In addition, good to high yields were observed for substrates 2f–2i, containing ethyl, isopropyl, benzyl, and phenethyl groups, respectively, at the α-position of the cyano group and 2j and 2k, bearing Indane and tetrahydronaphthalene scaffolds, respectively. Heteroaromatic ring-containing substrates 2l–2o afforded products 3al–3ao in excellent yields (87–93%). Furthermore, alkyl cyanides 2p–2t without an aryl group, which have a higher pK_a value (e.g., propionitrile, 32.5, DMSO) (23a) than 2a (23.0, DMSO) (23b) and are less prone to deprotonation, furnished the corresponding products in good yields (58–75%). The use of carbon nucleophiles bearing ketone, ester, nitro, and trifluoromethyl moieties instead of a cyano group resulted in a low yield or no product formation (Table S4). The high reactivity of alkyl cyanides is considered to be due to the small size of the cyano group (24) and the formation of a less-stabilized carbanion intermediate. (25,26)

Extension to Transformations with Heteroatom Nucleophiles

The current system was extended to transformations with heteroatom nucleophiles (Figure 3; for optimization of the reaction conditions, see the Supporting Information). Specifically, etherification reactions of primary, secondary, and tertiary alcohols 4a–4c with fluoroarene 1a proceeded to provide products 8aa–8ac in high yields (76–86%) (Figure 3A). Benzyl alcohols 4d and 4e were also employed to form the target products. Moreover, β-citronellol and diacetone-d-galactose with intricate structures successfully afforded products 8af and 8ag, respectively, in excellent yields.

Figure 3. Scope of heteroatom nucleophiles in the reaction of 1a (A–D) and functionalization of bioactive compound derivatives (E).^a,b aReactions were conducted on a 0.2 mmol scale. ^bIsolated yields. ^cReaction was conducted at 200 °C. ^dDMI was used as a solvent. ^eReaction was conducted at 160 °C. ^fTHF was used as a solvent. ^gMesitylene was used as a solvent. ^hProducts were isolated after oxidation with H₂O₂. ⁱReaction was conducted at 140 °C. ^jReaction was conducted at 80 °C.

Next, amination reactions using nitrogen nucleophiles were investigated (Figure 3B). The reactions proceeded with various N-alkyl aniline derivatives {i.e., N-methylaniline (5a), its methyl- and chlorine-substituted derivatives 5b and 5c, N-ethylaniline (5d), N-benzylaniline (5e), diphenylamine (5f), and indoline (5g)}, producing target products 9aa–9ag in good to high yields (60–88%). 2-(Methylamino)- and 3-(methylamino)pyridines, 5h and 5i, were also suitable substrates. Additionally, high yields were obtained with nitrogen-containing heteroarenes, such as pyrrole (5j), imidazole (5k), and indole (5l). Pyrrolidine, which has a large pK_a value (pK_a = 44, DMSO; (23c) cf. 5a, pK_a = 29.5, DMSO), (23d) was also tested in the reaction but did not form the product (data not shown).

Furthermore, thiolation and phosphination reactions were surveyed (Figure 3C,D). (27) The use of primary, secondary, and tertiary thiols 6a–6c, benzyl mercaptan (6d), and p-toluenethiol (6e) resulted in the formation of the target products in good to excellent yields (65–95%). Phosphination using diphenylphosphine (7a) and di-o-tolylphosphine (7b) was also successful, and the products were isolated as phosphine oxide after oxidation. Thus, versatile nucleophiles were applicable, demonstrating the universality of this catalysis to access biologically important classes of functionalized aromatic compounds.

Synthetic Applications

We next examined the potential for the late-stage functionalization of bioactive compound derivatives with diverse structures (Figure 3E). Menthol, cholesterol, and α-tocopherol derivatives as well as blonanserin were employed in the reaction with 2a, successfully providing target products 3Ma–3Pa in excellent yields (74–91%). The results further illustrate the robustness of this catalytic protocol.

Proposed Mechanism

The reaction mechanism is shown in Figure 4. The t-Bu-P4 base initially deprotonates the nucleophile to form ionic intermediate A. Subsequently, A undergoes aryl fluoride substitution, generating the arylated product and fluoride salt B. Then, t-BuP4 is regenerated with the release of an HF molecule, which is trapped by the molecular sieves, thus completing the catalytic cycle (path a). Alternatively, it is also plausible that A is regenerated through deprotonation of the nucleophile by the fluoride anion in B (path b).

Hammett Analysis

A Hammett plot was constructed from the correlation of the kinetic data for the reactions of substrates 1a, 1z, 1B, and 1K with σ_p parameters (Figures S1 and S2 and Table S12). A positive reaction constant (ρ = 2.9) was obtained, indicating that a partial negative charge is built up on the aromatic ring in the transition state. This constant is within the range of those observed in previously reported CS_NAr reactions. (8a)

Density Functional Theory Calculations

Next, we conducted density functional theory (DFT) calculations to gain insight into the reaction mechanism (Figure 5; CPCM(toluene)/oniom(ωB97X-D/6-311+G(2d,p):B97-D/6-311G(d,p)) level of theory, and the division of layers is shown in the Supporting Information). The reaction coordinate diagram of PhF (1v) and PhCHMeCN (2a) with t-Bu-P4 was evaluated (Figure 5A-a). The pathway consists of the formation of a deprotonated intermediate of 2a (Int-1), a pretransition state (Int-2), and a transition state (TS-1) to afford a fluorine-substituted product (Int-3). Notably, the intrinsic reaction coordinate (IRC) calculation showed a single barrier of TS-1 between Int-2 and Int-3 and no formation of a Meisenheimer intermediate. In addition, attempts to locate the Meisenheimer intermediate did not afford a stable intermediate. (28) Thus, nucleophile attack and fluorine elimination occur in a synchronous manner in TS-1, supporting the involvement of the CS_NAr reaction mechanism.

Figure 5. Theoretical mechanistic studies. (A) Energy diagram using Gibbs free energies calculated at the CPCM(toluene)/oniom(ωB97X-D/6-311+G(2d,p):B97-D/6-311G(d,p)) level of theory. (B) Chemical structures of intermediates and transition state. (C) 3D structures of intermediates and transition state.

We subsequently focused on the molecular state of TS-1. In TS-1, the C_aryl–F bond is bent from the phenyl plane by 32° with hydrogen bond formed between the fluorine of PhF and the proton of [(t-Bu-P4)H]⁺, and the carbanion nucleophile approaches the fluorine-ipso carbon from the opposite side of the phenyl ring (Figure 5C-a). Nucleus-independent chemical shift (NICS) calculations of TS-1 yielded NICS(1)_zz values of −19.7 ppm for the phenyl ring, indicating that the aromaticity is retained, although it is slightly weakened compared to that of 1v (−28.2 ppm) (Figure 6A). Natural population analysis (NPA) of TS-1 showed that the negative charges are located not only on the aromatic ring (C2: −0.373; C3: −0.199; C4: −0.348; C5: −0.205; C6: −0.354) but also on the eliminating fluorine atom (−0.452) and the nucleophilic carbon (−0.325) (Figure 6B). These are characteristic features of the transition state of CS_NAr reactions, unlike the case of the Meisenheimer structure that loses aromaticity and localizes the negative charge on the aromatic ring, contributing to the applicability of poorly reactive electron-rich aryl fluorides. (8b,29) Furthermore, natural bond orbital (NBO) analysis showed orbital interactions of the σ(C_ipso–C_α) bond orbital with aromatic π* orbitals as well as hydrogen-bond formation between the proton of [(t-Bu-P4)H]⁺ and the fluorine of PhF, which aid in stabilizing TS-1 (Figure S4).

Figure 6. (A) NICS_zz scan of (a) **TS-1**, (b) **TS-2**, and (c) 1v calculated at the GIAO/B3LYP/6-311+G(d) level of theory. The z axis for the NICS_zz-scan and z values are shown as purple dots. (B) Natural population analysis (NPA) of (a) **TS-1** and (b) **TS-2** calculated at the M06-2X/6-311+G(2d,p) level of theory using the optimized structures obtained at the CPCM(toluene)/oniom(ωB97X-D/6-311+G(2d,p):B97-D/6-311G(d,p)) level of theory.

Furthermore, for comparison, calculations were conducted for KO-t-Bu-18-crown-6, which is generally considered to generate a reactive anion species by the coordination of 18-crown-6 to potassium cation (Figure 5A-b). A reaction coordinate diagram similar to that for t-Bu-P4 was obtained; however, the activation energy of TS-2 was greater (27.0 kcal/mol) than that of TS-1 (24.8 kcal/mol). This result is consistent with the high reactivity of t-Bu-P4.

To understand the high reactivity achieved by the t-Bu-P4 base over KO-t-Bu-18-crown-6, we conducted the following studies. The nucleophilicity of the deprotonated intermediates (Int-1 and Int-5) was investigated. Specifically, natural energy decomposition analysis (NEDA) was conducted to evaluate the interaction energies between the cationic part ([(t-Bu-P4)H]⁺ and [K(18-crown-6)]⁺) and the anionic part in Int-1 and Int-5 by calculating the electrical interaction, charge transfer, and core repulsion (Figure 7A). A smaller interaction energy (−66.1 kcal/mol) and thus less stabilization were observed in the case of [(t-Bu-P4)H]⁺ than in the case of [K(18-crown-6)]⁺ (−81.9 kcal/mol). A weaker interaction was also observed for [(t-Bu-P4)H]⁺ by noncovalent interaction (NCI) analysis because the proton on [(t-Bu-P4)H]⁺ is embedded in the pocket of the t-Bu-P4 catalyst, surrounded by bulky t-Bu and NMe₂ groups, and thus is insufficient to stabilize the carbanion species, which is in contrast to the case of [K(18-crown-6)]⁺, which accepts anionic coordination (Figure 7B). Furthermore, the HOMO energy level of the anionic species of 2a is higher for [(t-Bu-P4)H]⁺ (−3.80 eV) than for [K(18-crown-6)]⁺ (−4.47 eV) (Figure 7C). Thus, t-Bu-P4 significantly enhances the nucleophilicity of the anionic moiety. Then, we also investigated the effect of the catalyst on the ArF reactivity in pretransition states Int-2 and Int-6 (Figure 7D). The proton on [(t-Bu-P4)H]⁺ forms a hydrogen bond with the fluorine atom in Int-2 and the LUMO + 5 of the PhF moiety, corresponding to the orbital that is subject to nucleophilic attack, possessing a lower energy level of −1.71 eV than the LUMO + 2 of PhF without a catalyst (0.53 eV), thus demonstrating the activation of PhF by [(t-Bu-P4)H]⁺. Nevertheless, this finding cannot sufficiently explain the high reactivity of t-Bu-P4 because the LUMO + 5 was lowered by [K(18-crown-6)]⁺ (−1.95 eV). Thus, t-Bu-P4 allows the dual activation of anionic nucleophile and ArF components, the former of which is more crucial for its high reactivity.

Figure 7. (A) Natural energy decomposition analysis (NEDA) for (a) **Int-1** ([(t-Bu-P4)H]⁺···[Ph(Me)CCN]⁻) and (b) **Int-5** ([K(18-crown-6)]⁺···[Ph(Me)CCN]⁻) (kcal/mol). In figures (A–D), all single point calculations were performed at the M06-2X/6-311+G(2d,p) level of theory using the optimized structures obtained at the CPCM(toluene)/oniom(ωB97X-D/6-311+G(2d,p):B97-D/6-311G(d,p)) level of theory. (B) Noncovalent interaction analyses of (a) **Int-1** and (b) **Int-5**. The red surface indicates strong repulsive interactions, while the green and blue surfaces show weak and strong attractive interactions, respectively. (C) Molecular states of (a) **Int-1**, (b) **Int-5**, and (c) [Ph(Me)CCN]⁻ (naked anion). The HOMOs of the anionic parts and their energies are shown. The natural charges of the anionic parts are also noted. (D) Molecular states of fluorobenzene moieties in (a) **Int-2** and (b) **Int-6** and the molecular state of (c) 1v. In molecular states **Int-2** and **Int-6**, the anionic part was omitted for simplicity. The π* orbitals of the aromatic rings (**Int-2**: LUMO+5; **Int-6**: LUMO + 5; 1v: LUMO + 2) and their energies are shown. The natural charges of the *ipso*-carbons attached to a fluorine atom are also noted.

Conclusions

Click to copy section linkSection link copied!

In summary, our study revealed a highly efficient method for catalytic CS_NAr reactions of aryl fluorides by t-Bu-P4. This catalytic reaction exhibited excellent functional group tolerance and allowed the use of diverse nucleophiles, thus making it a versatile tool for synthetic chemists. In addition, this system enabled the late-stage functionalization of bioactive compound derivatives. These findings demonstrate the promise of this approach in the development of new pharmaceuticals and the synthesis of complex molecules, offering exciting opportunities for future research and application.

Supporting Information

Click to copy section linkSection link copied!

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.4c09042.

Reaction of 3-fluoro-4-methoxybenzonitrile (12) and 2a (Scheme S1); effects of base additives in the reaction conditions of 1a and 2a (Table S1); effects of base catalysts in the reaction conditions of 1a and 2a (Table S2); reactions of (pseudo)halobenzenes (16) and 2a (Table S3); reactions of 1a and carbon nucleophiles other than alkyl cyanide (Table S4); optimization of the reaction conditions of 1a and heteroatom nucleophiles (Tables S5–S11); Hammet analysis (Figures S1 and S2 and Table S12); details for NICS_zz-scan of 1v, Int-2, TS-1, Int-6, and TS-2 (Figure S3); natural bond orbital (NBO) analysis of TS-1 (Figure S4); noncovalent interaction analyses of Int-1 and Int-5 (Figure S5); experimental procedures and spectra data for obtained products, and ¹H, ¹³C, ¹⁹F, and ³¹P NMR spectra (PDF)

ja4c09042_si_001.pdf (19.23 MB)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

Click to copy section linkSection link copied!

Corresponding Authors
- Masanori Shigeno - Department of Biophysical Chemistry, Graduate School of Pharmaceutical Science, Tohoku University, Aoba, Sendai 980-8578, Japan; JST, PRESTO, Kawaguchi, Saitama 332-0012, Japan; https://orcid.org/0000-0002-9640-8283; Email: [email protected]
- Toshinobu Korenaga - Department of Chemistry and Biological Sciences, Faculty of Science and Engineering, Iwate University, Ueda, Morioka 020-8551, Japan; Soft-Path Science and Engineering Research Center (SPERC), Iwate University, Ueda, Morioka 020-8551, Japan; https://orcid.org/0000-0002-9156-536X; Email: [email protected]
Authors
- Kazutoshi Hayashi - Department of Biophysical Chemistry, Graduate School of Pharmaceutical Science, Tohoku University, Aoba, Sendai 980-8578, Japan
- Ozora Sasamoto - Department of Biophysical Chemistry, Graduate School of Pharmaceutical Science, Tohoku University, Aoba, Sendai 980-8578, Japan
- Riku Hirasawa - Department of Biophysical Chemistry, Graduate School of Pharmaceutical Science, Tohoku University, Aoba, Sendai 980-8578, Japan
- Shintaro Ishida - Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan; https://orcid.org/0000-0001-7832-912X
- Kanako Nozawa-Kumada - Department of Biophysical Chemistry, Graduate School of Pharmaceutical Science, Tohoku University, Aoba, Sendai 980-8578, Japan; Interdisciplinary Research Center for Catalytic Chemistry, National Institute of Advanced Industrial Science and Technology (AIST), Central 5, 1-1-1 Higashi, Tsukuba 305-8565, Ibaraki, Japan; https://orcid.org/0000-0001-8054-5323
- Yoshinori Kondo - Department of Biophysical Chemistry, Graduate School of Pharmaceutical Science, Tohoku University, Aoba, Sendai 980-8578, Japan
Notes
The authors declare no competing financial interest.

Acknowledgments

Click to copy section linkSection link copied!

This work was financially supported by JST, PRESTO Grant Number JPMJPR22N7 (M.S.), Daicel Corporation (M.S.), Takeda Science Foundation (M.S.), Research Support Project for Life Science and Drug Discovery (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED under Grant Number JP23ama121040 (M.S.), and JSPS KAKENHI Grant Numbers 19H03346 (Y.K.) and 23K19419 (O.S.). We thank Professors Yoshiharu Iwabuchi and Yusuke Sasano (Graduate School of Pharmaceutical Science, Tohoku University) for the use of their HPLC apparatus.

References

Click to copy section linkSection link copied!

This article references 29 other publications.

1
(a) Bunnett, J. F.; Zahler, R. E. Aromatic Nucleophilic Substitution Reactions. Chem. Rev. 1951, 49, 273– 412, DOI: 10.1021/cr60153a002
Google Scholar
1a
Aromatic nucleophilic substitution reactions
Bunnett, Joseph F.; Zahler, Roland E.
Chemical Reviews (Washington, DC, United States) (1951), 49 (), 273-412CODEN: CHREAY; ISSN:0009-2665.
A review with 621 references.
(b) Miller, J. Aromatic Nucleophilic Substitution; Elsevier Sci. Ltd., Amsterdam, 1968.
Google Scholar
There is no corresponding record for this reference.
(c) Terrier, F. Modern Nucleophilic Aromatic Substitution; John Wiley & Sons, Inc., Weinheim, 2013.
Google Scholar
There is no corresponding record for this reference.
2
(a) Faust, A. Ueber das Verhalten des Monochlorphenols von 218° Siedepunkt in der Kalischmelze. Ber. Dtsch. Chem. Ges. 1873, 6, 1022– 1023, DOI: 10.1002/cber.18730060246
Google Scholar
There is no corresponding record for this reference.
(b) Fittig, R.; Mager, E. Beiträge zur Entscheidung der Stellungsfrage in der aromatischen Gruppe. Ber. Dtsch. Chem. Ges. 1874, 7, 1175– 1180, DOI: 10.1002/cber.18740070277
Google Scholar
There is no corresponding record for this reference.
3
Brown, D. G.; Boström, J. Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?. J. Med. Chem. 2016, 59, 4443– 4458, DOI: 10.1021/acs.jmedchem.5b01409
Google Scholar
3
Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?
Brown, Dean G.; Bostrom, Jonas
Journal of Medicinal Chemistry (2016), 59 (10), 4443-4458CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A review. An anal. of chem. reactions used in current medicinal chem. (2014), three decades ago (1984), and in natural product total synthesis has been conducted. The anal. revealed that of the current most frequently used synthetic reactions, none were discovered within the past 20 years and only two in the 1980s and 1990s (Suzuki-Miyaura and Buchwald-Hartwig). This suggests an inherent high bar of impact for new synthetic reactions in drug discovery. The most frequently used reactions were amide bond formation, Suzuki-Miyaura coupling, and SNAr reactions, most likely due to com. availability of reagents, high chemoselectivity, and a pressure on delivery. The authors show that these practices result in overpopulation of certain types of mol. shapes to the exclusion of others using simple PMI plots. The authors hope that these results will help catalyze improvements in integration of new synthetic methodologies as well as new library design.
4
Baumann, M.; Baxendale, I. R. An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles. Beilstein J. Org. Chem. 2013, 9, 2265– 2319, DOI: 10.3762/bjoc.9.265
Google Scholar
4
An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles
Baumann, Marcus; Baxendale, Ian R.
Beilstein Journal of Organic Chemistry (2013), 9 (), 2265-2319, 55 pp.CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
A review. This review which is the second in this series summarizes the most common synthetic routes as applied to the prepn. of many modern pharmaceutical compds. categorized as contg. a six-membered heterocyclic ring. The reported examples are based on the top retailing drug mols. combining synthetic information from both scientific journals and the wider patent literature. This compilation, in combination with the previously published review on five-membered rings, will form a comprehensive foundation and ref. source for individuals interested in medicinal, synthetic and preparative chem.
5
(a) Kiplinger, J. L.; Richmond, T. G.; Osterberg, C. E. Activation of carbon-fluorine bonds by metal complexes. Chem. Rev. 1994, 94, 373– 431, DOI: 10.1021/cr00026a005
Google Scholar
5a
Activation of Carbon-Fluorine Bonds by Metal Complexes
Kiplinger, Jaqueline L.; Richmond, Thomas G.; Osterberg, Carolyn E.
Chemical Reviews (Washington, DC, United States) (1994), 94 (2), 373-431CODEN: CHREAY; ISSN:0009-2665.
A review with 400 refs.
(b) Amii, H.; Uneyama, K. C–F Bond activation in organic synthesis. Chem. Rev. 2009, 109, 2119– 2183, DOI: 10.1021/cr800388c
Google Scholar
5b
C-F Bond Activation in Organic Synthesis
Amii, Hideki; Uneyama, Kenji
Chemical Reviews (Washington, DC, United States) (2009), 109 (5), 2119-2183CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review describes the various approaches to C-F bond activation in aliph., vinylic and arom. fluorides and their use in subsequent nucleophilic substitution, reductive defluorination, cross-coupling, dehydrofluorination and rearrangement reactions.
(c) Ahrens, T.; Kohlmann, J.; Ahrens, M.; Braun, T. Functionalization of fluorinated molecules by transition-metal-mediated C–F bond activation to access fluorinated building blocks. Chem. Rev. 2015, 115, 931– 972, DOI: 10.1021/cr500257c
Google Scholar
5c
Functionalization of Fluorinated Molecules by Transition-Metal-Mediated C-F Bond Activation To Access Fluorinated Building Blocks
Ahrens, Theresia; Kohlmann, Johannes; Ahrens, Mike; Braun, Thomas
Chemical Reviews (Washington, DC, United States) (2015), 115 (2), 931-972CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review that deals with transition-metal-mediated C1F bond activations which involve a cleavage of a C-F bond in polyfluorinated mols. and its transformation into carbon-element bonds, excluding hydrodefluorination or defluorination reactions.
(d) Ai, H.-J.; Ma, X.; Song, Q.; Wu, X.-F. C–F bond activation under transition-metal-free conditions. Sci. China Chem. 2021, 64, 1630– 1659, DOI: 10.1007/s11426-021-1040-2
Google Scholar
5d
C-F bond activation under transition-metal-free conditions
Ai, Han-Jun; Ma, Xingxing; Song, Qiuling; Wu, Xiao-Feng
Science China: Chemistry (2021), 64 (10), 1630-1659CODEN: SCCCCS; ISSN:1869-1870. (Science China Press)
A review. This review provided an overview of recent C-F bond activations and functionalizations under transition-metal-free conditions. The key mechanisms involved was demonstrated and discussed in detail. Finally, a brief discussion on the existing limitations of this field and our perspective was presented.
(e) Hooker, L. V.; Bandar, J. S. Synthetic Advantages of Defluorinative C–F Bond Functionalization. Angew. Chem., Int. Ed. 2023, 62, e202308880 DOI: 10.1002/anie.202308880
Google Scholar
5e
Synthetic Advantages of Defluorinative C-F Bond Functionalization
Hooker, Leidy V.; Bandar, Jeffrey S.
Angewandte Chemie, International Edition (2023), 62 (49), e202308880CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. Much progress has been made in the development of methods to both create compds. that contain C-F bonds and to functionalize C-F bonds. As such, C-F bonds are becoming common and versatile synthetic functional handles. This review summarizes the advantages of defluorinative functionalization reactions for small mol. synthesis. The coverage is organized by the type of carbon framework the fluorine is attached to for mono- and polyfluorinated motifs. The main challenges, opportunities and advances of defluorinative functionalization are discussed for each class of organofluorine. Most of the text focuses on case studies that illustrate how defluorofunctionalization can improve routes to synthetic targets or how the properties of C-F bonds enable unique mechanisms and reactions. The broader goal is to showcase the opportunities for incorporating and exploiting C-F bonds in the design of synthetic routes, improvement of specific reactions and advent of new methods.
(f) Zhou, J.; Zhao, Z.; Shibata, N. Transition-metal-free silylboronate-mediated cross-couplings of organic fluorides with amines. Nat. Commun. 2023, 14, 1847 DOI: 10.1038/s41467-023-37466-0
Google Scholar
5f
Transition-metal-free silylboronate-mediated cross-couplings of organic fluorides with amines
Zhou, Jun; Zhao, Zhengyu; Shibata, Norio
Nature Communications (2023), 14 (1), 1847CODEN: NCAOBW; ISSN:2041-1723. (Nature Portfolio)
Abstr.: C-N bond cross-couplings are fundamental in the field of org. chem. Herein, silylboronate-mediated selective defluorinative cross-coupling of org. fluorides with secondary amines via a transition-metal-free strategy is disclosed. The cooperation of silylboronate and potassium tert-butoxide enables the room-temp. cross-coupling of C-F and N-H bonds, effectively avoiding the high barriers assocd. with thermally induced SN2 or SN1 amination. The significant advantage of this transformation is the selective activation of the C-F bond of the org. fluoride by silylboronate without affecting potentially cleavable C-O, C-Cl, heteroaryl C-H, or C-N bonds and CF3 groups. Tertiary amines with arom., heteroarom., and/or aliph. groups were efficiently synthesized in a single step using electronically and sterically varying org. fluorides and N-alkylanilines or secondary amines. The protocol is extended to the late-stage syntheses of drug candidates, including their deuterium-labeled analogs.
6
Wencel-Delord, J.; Glorius, F. C–H bond activation enables the rapid construction and late-stage diversification of functional molecules. Nat. Chem. 2013, 5, 369– 375, DOI: 10.1038/nchem.1607
Google Scholar
6
C-H bond activation enables the rapid construction and late-stage diversification of functional molecules
Wencel-Delord, Joanna; Glorius, Frank
Nature Chemistry (2013), 5 (5), 369-375CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
A review. The beginning of the twenty-first century has witnessed significant advances in the field of C-H bond activation, and this transformation is now an established piece in the synthetic chemists' toolbox. This methodol. has the potential to be used in many different areas of chem., for example it provides a perfect opportunity for the late-stage diversification of various kinds of org. scaffolds, ranging from relatively small mols. like drug candidates, to complex polydisperse org. compds. such as polymers. In this way, C-H activation approaches enable relatively straightforward access to a plethora of analogs or can help to streamline the lead-optimization phase. Furthermore, synthetic pathways for the construction of complex org. materials can now be designed that are more atom- and step-economical than previous methods and, in some cases, can be based on synthetic disconnections that are just not possible without C-H activation. This Perspective highlights the potential of metal-catalyzed C-H bond activation reactions, which now extend beyond the field of traditional synthetic org. chem.
7
Bhunia, A.; Yetra, S. R.; Biju, A. T. Recent advances in transition-metal-free carbon–carbon and carbon–heteroatom bond-forming reactions using arynes. Chem. Soc. Rev. 2012, 41, 3140– 3152, DOI: 10.1039/c2cs15310f
Google Scholar
7
Recent advances in transition-metal-free carbon-carbon and carbon-heteroatom bond-forming reactions using arynes
Bhunia, Anup; Yetra, Santhivardhana Reddy; Biju, Akkattu T.
Chemical Society Reviews (2012), 41 (8), 3140-3152CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
A review. This tutorial review is aimed at highlighting recent developments in transition-metal-free carbon-carbon and carbon-heteroatom bond-forming reactions using a versatile class of reactive intermediates, viz., arynes, which hold the potential for numerous applications in org. synthesis. Key to the success of the resurgence of interest in the rich chem. of arynes is primarily the mild condition for their generation by the fluoride-induced 1,2-elimination of 2-(trimethylsilyl)aryl triflates. Consequently, arynes were employed for the construction of multisubstituted arenes with structural diversity and complexity. The versatile transition-metal-free applications of arynes include cycloaddn. reactions, insertion reactions and multicomponent reactions. Arynes found applications in natural product synthesis. Herein, the authors present a concise account of the major developments that occurred in this field during the past eight years.
8
(a) Rohrbach, S.; Smith, A. J.; Pang, J. H.; Poole, D. L.; Tuttle, T.; Chiba, S.; Murphy, J. A. Concerted Nucleophilic Aromatic Substitution Reactions. Angew. Chem., Int. Ed. 2019, 58, 16368– 16388, DOI: 10.1002/anie.201902216
Google Scholar
8a
Concerted Nucleophilic Aromatic Substitution Reactions
Rohrbach, Simon; Smith, Andrew J.; Pang, Jia Hao; Poole, Darren L.; Tuttle, Tell; Chiba, Shunsuke; Murphy, John A.
Angewandte Chemie, International Edition (2019), 58 (46), 16368-16388CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. Recent developments in exptl. and computational chem. have identified a rapidly growing class of nucleophilic arom. substitutions that proceed by concerted (cSNAr) rather than classical, two-step, SNAr mechanisms. Whereas traditional SNAr reactions require substantial activation of the arom. ring by electron-withdrawing substituents, such activating groups are not mandatory in the concerted pathways.
(b) Neumann, C. N.; Ritter, T. Facile C–F Bond Formation through a Concerted Nucleophilic Aromatic Substitution Mediated by the PhenoFluor Reagent. Acc. Chem. Res. 2017, 50, 2822– 2833, DOI: 10.1021/acs.accounts.7b00413
Google Scholar
8b
Facile C-F Bond Formation through a Concerted Nucleophilic Aromatic Substitution Mediated by the PhenoFluor Reagent
Neumann, Constanze N.; Ritter, Tobias
Accounts of Chemical Research (2017), 50 (11), 2822-2833CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
A review. Late-stage fluorination reactions aim to reduce the synthetic limitations of conventional organofluorine chem. with respect to substrate scope and functional group tolerance. C-F bond formation is commonly thermodynamically favorable but almost universally assocd. with high kinetic barriers. Apart from PhenoFluor chem., most modern arom. fluorination methods reported to date rely on the use of transition metal catalysts, with C-F bonds often formed through reductive elimination. Reductive elimination chem. to make C-X bonds becomes increasingly challenging when moving to higher at. nos. in the periodic table from C-C to C-F, in part because of higher metal-X bond dissocn. energies. The formation of C-C, C-N, and C-O bonds via reductive elimination has become routine in the 20/th century, but it took until the 21st century to develop complexes that could afford general C-F bond formation. The availability of such complexes enabled the substrate scope of modern fluorination chem. to exceed that of conventional fluorination.PhenoFluor chem. departs from conventional reaction mechanisms for arom. fluorination chem. Instead, we have revealed a concerted nucleophilic arom. substitution reaction (CSNAr) for PhenoFluor that proceeds through a single neutral four-membered transition state. Conceptually, PhenoFluor chem. is therefore distinct from conventional SNAr chem., which typically proceeds through a two-barrier process with Meisenheimer complexes as reaction intermediates. As a consequence, PhenoFluor chem. has a larger substrate scope than conventional SNAr chem. and can be performed on arenes as electron-rich as anilines. Moreover, PhenoFluor chem. is tolerant of protic functional groups, which sets it apart from modern metal-mediated processes. Primary and secondary amines, alcs., thiols, and phenols are often not tolerated under metal-catalyzed late-stage fluorination reactions because C-N and C-O reductive elimination can have lower activation barriers than C-F reductive elimination. The mechanism by which PhenoFluor chem. forms C-F bonds not only rationalizes the substrate scope and functional group tolerance but also informs the side-product profile. Fluorinated isomers are not obsd. because the four-membered transition state necessitates ipso substitution. In addn., no reduced product, e.g., H instead of F incorporation, as is often obsd. with metal-mediated methods, has ever been obsd. with PhenoFluor.PhenoFluor chem. can be used to deoxyfluorinate both phenols and alcs. PhenoFluor is an expensive reagent that must be used stoichiometrically and therefore cannot replace cost-efficient methods to make simple fluorinated mols. on a large scale. However, PhenoFluor is often successful when other fluorination methods fail. The synthesis of 18F-labeled mols. for positron emission tomog. (PET) is one application of modern fluorination chem. for which material throughput is not an issue because of the small quantities of PET tracers used in imaging (typically nanomoles). The high emphasis on functional group tolerance, side-product profiles, and reliability combined with less stringent cost requirements render PhenoFluor-based deoxyfluorination with 18F promising for human PET imaging.
9
Kwan, E. E.; Zeng, Y.; Besser, H. A.; Jacobsen, E. N. Concerted nucleophilic aromatic substitutions. Nat. Chem. 2018, 10, 917– 923, DOI: 10.1038/s41557-018-0079-7
Google Scholar
9
Concerted nucleophilic aromatic substitutions
Kwan, Eugene E.; Zeng, Yuwen; Besser, Harrison A.; Jacobsen, Eric N.
Nature Chemistry (2018), 10 (9), 917-923CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)
Nucleophilic arom. substitution (SNAr) is one of the most widely applied reaction classes in pharmaceutical and chem. research, providing a broadly useful platform for the modification of arom. ring scaffolds. The generally accepted mechanism for SNAr reactions involves a two-step addn.-elimination sequence via a discrete, non-arom. Meisenheimer complex. Here the authors use 12C/13C kinetic isotope effect (KIE) studies and computational analyses to provide evidence that prototypical SNAr reactions in fact proceed through concerted mechanisms. The KIE measurements were made possible by a new technique that leverages the high sensitivity of 19F as an NMR nucleus to quantitate the degree of isotopic fractionation. This sensitive technique permits the measurement of KIEs on 10 mg of natural abundance material in one overnight acquisition. As a result, it provides a practical tool for performing detailed mechanistic analyses of reactions that form or break C-F bonds.
10
Rohrbach, S.; Murphy, J. A.; Tuttle, T. Computational Study on the Boundary Between the Concerted and Stepwise Mechanism of Bimolecular S_NAr Reactions. J. Am. Chem. Soc. 2020, 142, 14871– 14876, DOI: 10.1021/jacs.0c01975
Google Scholar
10
Computational Study on the Boundary Between the Concerted and Stepwise Mechanism of Bimolecular SNAr Reactions
Rohrbach, Simon; Murphy, John A.; Tuttle, Tell
Journal of the American Chemical Society (2020), 142 (35), 14871-14876CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The text-book mechanism of bimol. nucleophilic arom. substitutions (SNAr) reactions is a stepwise process that proceeds via a so-called Meisenheimer intermediate. Only recently the alternative, concerted version of this mechanism has gained acceptance as more and more examples thereof have been reported. But so far only isolated examples of concerted SNAr reactions have been described and a coherent picture of when a SNAr reaction proceeds via a stepwise and when via a concerted mechanism has not yet been established. Here key factors are identified that influence the mechanistic choice of SNAr reactions. Moreover, the electron affinity is used as a simple descriptor to make a prediction on whether a given aryl fluoride substrate favors a concerted or stepwise mechanism.
11
(a) Matsuura, A.; Ano, Y.; Chatani, N. Nucleophilic aromatic substitution of non-activated aryl fluorides with aliphatic amides. Chem. Commun. 2022, 58, 9898– 9901, DOI: 10.1039/D2CC02999E
Google Scholar
There is no corresponding record for this reference.
(b) Caron, S.; Vazquez, E.; Wojcik, J. M. Preparation of Tertiary Benzylic Nitriles from Aryl Fluorides. J. Am. Chem. Soc. 2000, 122, 712– 713, DOI: 10.1021/ja9933846
Google Scholar
11b
Preparation of Tertiary Benzylic Nitriles from Aryl Fluorides
Caron, Stephane; Vazquez, Enrique; Wojcik, Jill M.
Journal of the American Chemical Society (2000), 122 (4), 712-713CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
An efficient method for the addn. of secondary nitriles to fluoroarenes was described. The reaction is specific to hexamethyldisilazane potassium salt, but proceeds with a variety of substrates. For example, the reaction of 1-fluoro-2-methoxybenzene with 2-methylpropanenitrile in the presence of hexamethyldisilazane potassium salt in toluene or THF gave 2-methoxy-α,α-dimethylbenzeneacetonitrile.
(c) Takeda, M.; Nagao, K.; Ohmiya, H. Transition-Metal-Free Cross-Coupling by Using Tertiary Benzylic Organoboronates. Angew. Chem., Int. Ed. 2020, 59, 22460– 22464, DOI: 10.1002/anie.202010251
Google Scholar
11c
Transition-Metal-Free Cross-Coupling by Using Tertiary Benzylic Organoboronates
Takeda, Mitsutaka; Nagao, Kazunori; Ohmiya, Hirohisa
Angewandte Chemie, International Edition (2020), 59 (50), 22460-22464CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
The transition-metal-free cross-coupling of alkyl or aryl electrophiles by using tertiary benzylic organoboronates is reported. This reaction involves the generation of tertiary alkyl anions from organoboronates in the presence of an alkoxide base and then their substitution reactions. This protocol allows the simple and efficient construction of quaternary carbon centers.
(d) Bizier, N. P.; Wm Wackerly, J.; Braunstein, E. D.; Zhang, M.; Nodder, S. T.; Carlin, S. M.; Katz, J. L. An Alternative Role for Acetylenes: Activation of Fluorobenzenes toward Nucleophilic Aromatic Substitution. J. Org. Chem. 2013, 78, 5987– 5998, DOI: 10.1021/jo400668v
Google Scholar
11d
An Alternative Role for Acetylenes: Activation of Fluorobenzenes toward Nucleophilic Aromatic Substitution
Bizier, Nicholas P.; Wackerly, Jay Wm.; Braunstein, Eric D.; Zhang, Mengfei; Nodder, Stephen T.; Carlin, Stephen M.; Katz, Jeffrey L.
Journal of Organic Chemistry (2013), 78 (12), 5987-5998CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Acetylenes are increasingly versatile functional groups for a range of complexity-building org. transformations and for the construction of desirable mol. architectures. Herein we disclose a previously underappreciated aspect of arylacetylene reactivity by utilizing alkynes as electron-withdrawing groups (EWG) for promoting nucleophilic arom. substitution (SNAr) reactions. Reaction rates for the substitution of 4-(fluoroethynyl)benzenes by p-cresol were detd. by 1H NMR spectroscopy, and these rate data were used to det. substituent (Hammett) consts. for terminal and substituted ethynyl groups. The synthetic scope of acetylene-activated SNAr reactions is broad; fluoroarenes bearing one or two ethynyl groups undergo high-yielding substitution with a variety of oxygen and arylamine nucleophiles.
(e) Diness, F.; Fairlie, D. P. Catalyst-Free N-Arylation Using Unactivated Fluorobenzenes. Angew. Chem., Int. Ed. 2012, 51, 8012– 8016, DOI: 10.1002/anie.201202149
Google Scholar
11e
Catalyst-Free N-Arylation Using Unactivated Fluorobenzenes
Diness, Frederik; Fairlie, David P.
Angewandte Chemie, International Edition (2012), 51 (32), 8012-8016, S8012/1-S8012/65CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A valuable and simple novel catalyst-free protocol for the N-arylation of azole and indole derivs. has been described using direct SNAr substitution of fluorine on unactivated benzene derivs. is presented. Reaction conditions have been optimized to effect facile, rapid, versatile, and high-yielding, one-step reactions which tolerate a wide range of substituents on the fluorobenzene and azole/indole deriv., including chloro, bromo, and iodo substituents which result in halogenated N-aryl derivs. This catalyst-free N-arylation reaction is also compatible with metal-catalyzed cross-coupling reactions performed in the same pot simultaneously with, or subsequent to, SNAr substitution of fluorine in fluorobenzene derivs. We predict that these new methods may have wide synthetic utility across org., medicinal, agricultural, and polymer chem. as well as in materials science applications.
(f) Mallick, S.; Xu, P.; Würthwein, E.-U.; Studer, A. Silyldefluorination of Fluoroarenes by Concerted Nucleophilic Aromatic Substitution. Angew. Chem., Int. Ed. 2019, 58, 283– 287, DOI: 10.1002/anie.201808646
Google Scholar
11f
Silyldefluorination of Fluoroarenes by Concerted Nucleophilic Aromatic Substitution
Mallick, Shubhadip; Xu, Pan; Wuerthwein, Ernst-Ulrich; Studer, Armido
Angewandte Chemie, International Edition (2019), 58 (1), 283-287CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
The reaction of readily generated silyl Li reagents with various aryl fluorides to provide the corresponding aryl silanes is reported. DFT calcns. reveal that the nucleophilic arom. substitution of the fluoride anion by the silyl Li reagent proceeds through concerted ipso substitution. In contrast to the classical nucleophilic arom. substitution, this concerted ionic silyldefluorination also occurs on more electron-rich aryl fluorides.
(g) Liu, L. W.; Zarata, C.; Martin, R. Base-Mediated Defluorosilylation of C(sp²)–F and C(sp³)–F Bonds. Angew. Chem., Int. Ed. 2019, 58, 2064– 2068, DOI: 10.1002/anie.201813294
Google Scholar
11g
Base-Mediated Defluorosilylation of C(sp2)-F and C(sp3)-F Bonds
Liu, Xiang-Wie; Zarate, Cayetana; Martin, Ruben
Angewandte Chemie, International Edition (2019), 58 (7), 2064-2068CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
The ability to selectively forge C-heteroatom bonds by C-F scission is typically accomplished by metal catalysts, specialized ligands and/or harsh reaction conditions. Described herein is a base-mediated defluorosilylation of unactivated C(sp2)-F and C(sp3)-F bonds that obviates the need for metal catalysts. This protocol was characterized by its simplicity, mild reaction conditions, and wide scope, even within the context of late-stage functionalization, constituting a complementary approach to existing C-Si bond-forming protocols.
(h) You, Z.; Higashida, K.; Iwai, T.; Sawamura, M. Phosphinylation of Non-activated Aryl Fluorides through Nucleophilic Aromatic Substitution at the Boundary of Concerted and Stepwise Mechanisms. Angew. Chem., Int. Ed. 2021, 60, 5778– 5782, DOI: 10.1002/anie.202013544
Google Scholar
11h
Phosphinylation of Non-activated Aryl Fluorides through Nucleophilic Aromatic Substitution at the Boundary of Concerted and Stepwise Mechanisms
You, Zhensheng; Higashida, Kosuke; Iwai, Tomohiro; Sawamura, Masaya
Angewandte Chemie, International Edition (2021), 60 (11), 5778-5782CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Non-activated aryl fluorides reacted with potassium diorganophosphinites through a nucleophilic arom. substitution (SNAr) reaction. Remarkably, both electron-neutral and electron-rich aryl fluorides participated in the reaction with substantially stabilized anionic P nucleophiles to form the corresponding tertiary phosphine oxides. Quantum chem. calcns. suggested a nucleophile-dependent mechanism that involves both concerted and stepwise SNAr reaction pathways.
12
(a) Yasui, K.; Kamitani, M.; Tobisu, M. N-Heterocyclic Carbene Catalyzed Concerted Nucleophilic Aromatic Substitution of Aryl Fluorides Bearing α,β-Unsaturated Amides. Angew. Chem., Int. Ed. 2019, 58, 14157– 14161, DOI: 10.1002/anie.201907837
Google Scholar
12a
N-Heterocyclic Carbene Catalyzed Concerted Nucleophilic Aromatic Substitution of Aryl Fluorides Bearing α,β-Unsaturated Amides
Yasui, Kosuke; Kamitani, Miharu; Tobisu, Mamoru
Angewandte Chemie, International Edition (2019), 58 (40), 14157-14161CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Concerted nucleophilic arom. substitution (CSNAr) has emerged as a powerful mechanistic manifold, in which nucleophilic arom. substitution can proceed in one step without the need to form a Meisenheimer intermediate. However, all of the CSNAr reactions reported thus far require a stoichiometric strong base or activating reagent, and no catalytic variants have yet been reported. Herein, we report an N-heterocyclic carbene (NHC)-catalyzed intramol. cyclization of acrylamides that contain a 2-fluorophenyl group on the nitrogen through a CSNAr reaction. By using this catalytic method, it is possible to synthesize an array of quinolin-2-one derivs., which are common structural motifs in pharmaceuticals and org. materials. DFT calcns. unambiguously revealed that this reaction proceeds through the concerted nucleophilic arom. substitution of aryl fluorides, in which a stereoelectronic σ (Cipso-Cβ)→ σ*(Cipso-F) interaction critically contributes to the stabilization of the transition state for the cyclization.
(b) Ito, S.; Fujimoto, H.; Tobisu, M. Non-Stabilized Vinyl Anion Equivalents from Styrenes by N-Heterocyclic Carbene Catalysis and Its Use in Catalytic Nucleophilic Aromatic Substitution. J. Am. Chem. Soc. 2022, 144, 6714– 6718, DOI: 10.1021/jacs.2c02579
Google Scholar
12b
Non-stabilized Vinyl Anion Equivalents from Styrenes by N-Heterocyclic Carbene Catalysis and Its Use in Catalytic Nucleophilic Aromatic Substitution
Ito, Sora; Fujimoto, Hayato; Tobisu, Mamoru
Journal of the American Chemical Society (2022), 144 (15), 6714-6718CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
A protocol for the catalytic nucleophilic activation of unactivated styrenes was reported, which enables the generation of a non-stabilized alkenyl anion equiv. as a transient intermediate. In the reaction, N-heterocyclic carbenes add across styrenes to generate ylide intermediates, which could then be used in intramol. nucleophilic arom. substitution reactions of aryl fluorides, chlorides and Me ethers. The method allowed for straightforward access to complex polyarom. compds.
13
Kikushima, K.; Grellier, M.; Ohashi, M.; Ogoshi, S. Transition-Metal-Free Catalytic Hydrodefluorination of Polyfluoroarenes by Concerted Nucleophilic Aromatic Substitution with a Hydrosilicate. Angew. Chem., Int. Ed. 2017, 56, 16191– 16196, DOI: 10.1002/anie.201708003
Google Scholar
13
Transition-Metal-Free Catalytic Hydrodefluorination of Polyfluoroarenes by Concerted Nucleophilic Aromatic Substitution with a Hydrosilicate
Kikushima, Kotaro; Grellier, Mary; Ohashi, Masato; Ogoshi, Sensuke
Angewandte Chemie, International Edition (2017), 56 (51), 16191-16196CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Polyfluorinated arenes underwent regioselective transition metal-free hydrodefluorination with Ph3SiH or Et2SiH2 in the presence of tetrabutylammonium difluorotriphenylsilicate (TBAT) in THF. For example, hexafluorobenzene underwent hydrodefluorination with Et2SiH2 at 60° to yield pentafluorobenzene in 19% yield, 1,2,4,5-tetrafluorobenzene in 70% yield, and 1,2,3,5-tetrafluorobenzene and 1,2,3,4-tetrafluorobenzene in 2% yields. The reaction involves direct hydride transfer from a hydrosilicate as the key intermediate, which is generated from a hydrosilane and a fluoride salt; the eliminated fluoride regenerates the hydrosilicate to complete the catalytic cycle. The mechanism was studied using stoichiometric reactions of silicates and using dispersion-cor. DFT calcns.; hydrodefluorination likely proceeds via concerted nucleophilic arom. substitution.
14
Park, N. H.; dos Passos Gomes, G.; Fevre, M.; Jones, G. O.; Alabugin, I. V.; Hedrick, J. L. Organocatalyzed synthesis of fluorinated poly(aryl thioethers). Nat. Commun. 2017, 8, 166 DOI: 10.1038/s41467-017-00186-3
Google Scholar
14
Organocatalyzed synthesis of fluorinated poly(aryl thioethers)
Park Nathaniel H; Fevre Mareva; Jones Gavin O; Hedrick James L; Gomes Gabriel Dos Passos; Alabugin Igor V
Nature communications (2017), 8 (1), 166 ISSN:.
The preparation of high-performance fluorinated poly(aryl thioethers) has received little attention compared to the corresponding poly(aryl ethers), despite the excellent physical properties displayed by many polysulfides. Herein, we report a highly efficient route to fluorinated poly(aryl thioethers) via an organocatalyzed nucleophilic aromatic substitution of silyl-protected dithiols. This approach requires low catalyst loadings, proceeds rapidly at room temperature, and is effective for many different perfluorinated or highly activated aryl monomers. Computational investigations of the reaction mechanism reveal an unexpected, concerted SNAr mechanism, with the organocatalyst playing a critical, dual-activation role in facilitating the process. Not only does this remarkable reactivity enable rapid access to fluorinated poly(aryl thioethers), but also opens new avenues for the processing, fabrication, and functionalization of fluorinated materials with easy removal of the volatile catalyst and TMSF byproducts.Fluorinated poly(aryl thioethers), unlike their poly(aryl ethers) counterparts, have received little attention despite excellent physical properties displayed by many polysulfides. Here the authors show a highly efficient route to fluorinated poly(aryl thioethers) via an organocatalyzed nucleophilic aromatic substitution of silyl-protected dithiols.
15
(a) Otsuka, M.; Endo, K.; Shibata, T. Catalytic S_NAr reaction of non-activated fluoroarenes with amines via Ru η⁶-arene complexes. Chem. Commun. 2010, 46, 336– 338, DOI: 10.1039/B919413D
Google Scholar
15a
Catalytic SNAr reaction of non-activated fluoroarenes with amines via Ru η6-arene complexes
Otsuka, Maiko; Endo, Kohei; Shibata, Takanori
Chemical Communications (Cambridge, United Kingdom) (2010), 46 (2), 336-338CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
Ru-catalyzed SNAr reaction of non-activated fluoroarenes with secondary amines proceeded through η6-arene complexes to give aminated products in up to 79% yield. E.g., in presence of Ru(cod)(2-methylallyl)2, 1,5-bis(diphenylphosphino)pentane, trifluoromethanesulfonic acid, triethylamine, and triethylsilane, reaction of 4-fluorotoluene and morpholine gave 72% aminated product I.
(b) Kang, Q.-K.; Lin, Y.; Li, Y.; Xu, L.; Li, K.; Shi, H. Catalytic S_NAr Hydroxylation and Alkoxylation of Aryl Fluorides. Angew. Chem., Int. Ed. 2021, 60, 20391– 20399, DOI: 10.1002/anie.202106440
Google Scholar
15b
Catalytic SNAr Hydroxylation and Alkoxylation of Aryl Fluorides
Kang, Qi-Kai; Lin, Yunzhi; Li, Yuntong; Xu, Lun; Li, Ke; Shi, Hang
Angewandte Chemie, International Edition (2021), 60 (37), 20391-20399CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A reliable method for accessing phenols ArOH (Ar = C6H5, 4-CH3OC6H4, 9H-fluoren-2-yl, etc.) and Ph alkyl ethers Ar1OR (Ar1 = 4-CH3C6H4, 9H-fluoren-2-yl, 1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl, etc.; R = Me, cyclohexylmethyl, oxan-4-yl, etc.) via catalytic SnAr reactions has been described. The method is applicable to a broad array of electron-rich and neutral aryl fluorides ArF and Ar1F, which are inert under classical SnAr conditions. Although the mechanism of SNAr reactions involving metal arene complexes is hypothesized to involve a stepwise pathway (addn. followed by elimination), exptl. data that support this hypothesis is still under exploration. Mechanistic studies and DFT calcns. suggest either a stepwise or stepwise-like energy profile. Notably, a rhodium η5-cyclohexadienyl complex intermediate with an sp3-hybridized carbon bearing both a nucleophile and a leaving group was isolated.
16
(a) Pistritto, V. A.; Liu, S.; Nicewicz, D. A. Mechanistic Investigations into Amination of Unactivated Arenes via Cation Radical Accelerated Nucleophilic Aromatic Substitution. J. Am. Chem. Soc. 2022, 144, 15118– 15131, DOI: 10.1021/jacs.2c04577
Google Scholar
16a
Mechanistic Investigations into Amination of Unactivated Arenes via Cation Radical Accelerated Nucleophilic Aromatic Substitution
Pistritto, Vincent A.; Liu, Shubin; Nicewicz, David A.
Journal of the American Chemical Society (2022), 144 (33), 15118-15131CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
A mechanistic investigation into the amination of electron-neutral and electron-rich arenes using org. photoredox catalysis is presented. Kinetic and computational data support rate-limiting nucleophilic addn. into an arene cation radical using both azole and primary amine nucleophiles. This finding is consistent with both fluoride and alkoxide nucleofuges, supporting a unified mechanistic picture using cation radical accelerated nucleophilic arom. substitution (CRA-SNAr). Electrochem. and time-resolved fluorescence spectroscopy confirm the key role solvents play in enabling selective arene oxidn. in the presence of amines. The synthetic limitations of xanthylium salts are elucidated via photophys. studies. An alternative catalyst scaffold with improved turnover nos. is presented.
(b) Huang, H.; Lambert, T. H. Electrophotocatalytic SNAr Reactions of Unactivated Aryl Fluorides at Ambient Temperature and Without Base. Angew. Chem., Int. Ed. 2020, 59, 658– 662, DOI: 10.1002/anie.201909983
Google Scholar
16b
Electrophotocatalytic SNAr Reactions of Unactivated Aryl Fluorides at Ambient Temperature and Without Base
Huang, He; Lambert, Tristan H.
Angewandte Chemie, International Edition (2020), 59 (2), 658-662CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
The electrophotocatalytic SNAr reaction of unactivated aryl fluorides at ambient temp. without strong base is demonstrated.
(c) Sheng, H.; Liu, Q.; Zhang, B.-B.; Wang, Z.-X.; Chen, X.-Y. Visible-Light-Induced N-Heterocyclic Carbene-Catalyzed Single Electron Reduction of Mono-Fluoroarenes. Angew. Chem., Int. Ed. 2023, 62, e202218468 DOI: 10.1002/anie.202218468
Google Scholar
There is no corresponding record for this reference.
(d) Wu, S.; Schiel, F.; Melchiorre, P. A General Light-Driven Organocatalytic Platform for the Activation of Inert Substrates. Angew. Chem., Int. Ed. 2023, 62, e202306364 DOI: 10.1002/anie.202306364
Google Scholar
16d
A General Light-Driven Organocatalytic Platform for the Activation of Inert Substrates
Wu, Shuo; Schiel, Florian; Melchiorre, Paolo
Angewandte Chemie, International Edition (2023), 62 (32), e202306364CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A readily available indole thiolate organocatalyst that, upon excitation with 405 nm light, acquires a strongly reducing power was reported. This excited-state reactivity served to activate, by single-electron redn., strong C-F, C-Cl, and C-O bonds in both arom. and aliph. substrates. This catalytic platform was versatile enough to promote the redn. of generally recalcitrant electron-rich substrates (Ered<-3.0 V vs SCE), including arenes that afforded 1,4-cyclohexadienes. The protocol was also useful for the borylation and phosphorylation of inert substrates with a high functional group tolerance. Mechanistic studies identified an excited-state thiolate anion as responsible of the highly reducing reactivity.
17
Schwesinger, R.; Schlemper, H. Peralkylated Polyaminophosphazenes─ Extremely Strong, Neutral Nitrogen Bases. Angew. Chem., Int. Ed. 1987, 26, 1167– 1169, DOI: 10.1002/anie.198711671
Google Scholar
There is no corresponding record for this reference.
18
Puleo, T. R.; Sujansky, S. J.; Wright, S. E.; Bandar, J. S. Organic Superbases in Recent Synthetic Methodology Research. Chem. - Eur. J. 2021, 27, 4216– 4229, DOI: 10.1002/chem.202003580
Google Scholar
18
Organic Superbases in Recent Synthetic Methodology Research
Puleo, Thomas R.; Sujansky, Stephen J.; Wright, Shawn E.; Bandar, Jeffrey S.
Chemistry - A European Journal (2021), 27 (13), 4216-4229CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. Recent applications of com. org. superbases in modern synthetic methodologies were discussed. Examples of the advantages of org. superbases in three areas were highlighted, including the discovery of new base-catalyzed reactions, the optimization of reactions that require stoichiometric Bronsted base, and in high-throughput experimentation technol.
19
(a) Mamdani, H. T.; Hartley, R. C. Phosphazene bases and the anionic oxy-Cope rearrangement. Tetrahedron Lett. 2000, 41, 747– 749, DOI: 10.1016/S0040-4039(99)02123-1
Google Scholar
19a
Phosphazene bases and the anionic oxy-Cope rearrangement
Mamdani, Hassan T.; Hartley, Richard C.
Tetrahedron Letters (2000), 41 (5), 747-749CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)
Compds. contg. a 1,5-hexadien-3-ol system undergo anionic oxy-Cope rearrangement when treated with the phosphazene super-base, P4-t-Bu. The [3,3] sigmatropic rearrangement occurs in hexane as well as in THF. The weaker phosphazene base, P2-Et, fails to induce rearrangement. This is the first example of the use of a metal-free base to induce anionic oxy-Cope rearrangement.
(b) Seebach, D.; Beck, A. K.; Studer, A. Modern Synthetic Methods; Ernst, B.; Leumann, C., Eds.; VCH: Weinheim, 1995; Vol. 7.
Google Scholar
There is no corresponding record for this reference.
20
(a) Shigeno, M.; Hayashi, K.; Nozawa-Kumada, K.; Kondo, Y. Phosphazene Base tBu-P4 Catalyzed Methoxy–Alkoxy Exchange Reaction on (Hetero)Arenes. Chem. - Eur. J. 2019, 25, 6077– 6081, DOI: 10.1002/chem.201900498
Google Scholar
20a
Phosphazene Base tBu-P4 Catalyzed Methoxy-Alkoxy Exchange Reaction on (Hetero)Arenes
Shigeno, Masanori; Hayashi, Kazutoshi; Nozawa-Kumada, Kanako; Kondo, Yoshinori
Chemistry - A European Journal (2019), 25 (24), 6077-6081CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
The org. superbase tBu-P4 catalyzed methoxy-alkoxy exchange reactions on (hetero)arenes with alcs was reported. The catalytic reaction proceeded efficiently with electron-deficient methoxy(hetero)arenes as well as with a variety of alcs., including 3-amino-1-propanol, β-citronellol, menthol and cholesterol. An intramol. version of this reaction furnished six- and seven-membered ring compds.
(b) Shigeno, M.; Hayashi, K.; Nozawa-Kumada, K.; Kondo, Y. Organic Superbase t-Bu-P4 Catalyzes Amination of Methoxy(hetero)arenes. Org. Lett. 2019, 21, 5505– 5508, DOI: 10.1021/acs.orglett.9b01805
Google Scholar
20b
Organic Superbase t-Bu-P4 Catalyzes Amination of Methoxy(hetero)arenes
Shigeno, Masanori; Hayashi, Kazutoshi; Nozawa-Kumada, Kanako; Kondo, Yoshinori
Organic Letters (2019), 21 (14), 5505-5508CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
We report that the org. superbase t-Bu-P4 efficiently catalyzes the amination of methoxy(hetero)arenes with amine nucleophiles such as aniline, indoline, and aminopyridine derivs. This catalytic reaction is effective for the transformation of electron-deficient methoxyarenes possessing diverse functionalities (carbonyl, cyano, nitro, and halogen) as well as methoxyheteroarenes, including pyrazine, quinoline, isoquinoline, and pyridine derivs. Intramol. reactions provide six- and seven-membered ring cyclic amine products.
(c) Shigeno, M.; Hayashi, K.; Nozawa-Kumada, K.; Kondo, Y. Catalytic C(sp²)–C(sp³) Bond Formation of Methoxyarenes by the Organic Superbase t-Bu-P4. Org. Lett. 2020, 22, 9107– 9113, DOI: 10.1021/acs.orglett.0c03507
Google Scholar
20c
Catalytic C(sp2)-C(sp3) Bond Formation of Methoxyarenes by the Organic Superbase t-Bu-P4
Shigeno, Masanori; Hayashi, Kazutoshi; Nozawa-Kumada, Kanako; Kondo, Yoshinori
Organic Letters (2020), 22 (22), 9107-9113CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
The org. superbase catalyst t-Bu-P4 achieves nucleophilic arom. substitution of methoxyarenes with alkanenitrile pronucleophiles. A variety of functional groups [cyano, nitro, (non)enolizable ketone, chloride, and amide moieties] are allowed on methoxyarenes. Moreover, an array of alkanenitriles with/without an aryl moiety at the nitrile α-position can be employed. The system also features no requirement of a stoichiometric base, MeOH (not salt waste) formation as a byproduct, and the prodn. of congested quaternary carbon centers.
(d) Shigeno, M.; Hayashi, K.; Korenaga, T.; Nozawa-Kumada, K.; Kondo, Y. Organic superbase t-Bu-P4-catalyzed demethylations of methoxyarenes. Org. Chem. Front. 2022, 9, 3656– 3663, DOI: 10.1039/D2QO00483F
Google Scholar
20d
Organic superbase t-Bu-P4-catalyzed demethylations of methoxyarenes
Shigeno, Masanori; Hayashi, Kazutoshi; Korenaga, Toshinobu; Nozawa-Kumada, Kanako; Kondo, Yoshinori
Organic Chemistry Frontiers (2022), 9 (14), 3656-3663CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)
The org. superbase t-Bu-P4 catalyzes the demethylation reactions of methoxyarenes ROMe [R = 4-cyanophenyl, 1-oxo-2,3-dihydro-1H-inden-5-yl, 1-benzothiophen-5-yl, etc.] in the presence of alkanethiol and hexamethyldisilazane was reported. The system can efficiently convert a variety of substrates, including electron-deficient, -neutral, and -rich substrates and heteroarom. substrates, and displays excellent functional group tolerance. Computational studies show that the high reactivity achieved by t-Bu-P4 is due to the formation of the nucleophilic naked thiolate species.
21
(a) Ueno, M.; Hori, C.; Suzawa, K.; Ebisawa, M.; Kondo, Y. Catalytic Activation of Silylated Nucleophiles Using tBu-P4 as a Base. Eur. J. Org. Chem. 2005, 2005, 1965– 1968, DOI: 10.1002/ejoc.200500087
Google Scholar
There is no corresponding record for this reference.
(b) Ueno, M.; Yonemoto, M.; Hashimoto, M.; Wheatley, A. E. H.; Naka, H.; Kondo, Y. Nucleophilic aromatic substitution using Et₃SiH/cat. t-Bu-P4 as a system for nucleophile activation. Chem. Commun. 2007, 2264– 2266, DOI: 10.1039/b700140a
Google Scholar
21b
Nucleophilic aromatic substitution using Et3SiH/cat. t-Bu-P4 as a system for nucleophile activation
Ueno, Masahiro; Yonemoto, Misato; Hashimoto, Masahiro; Wheatley, Andrew E. H.; Naka, Hiroshi; Kondo, Yoshinori
Chemical Communications (Cambridge, United Kingdom) (2007), (22), 2264-2266CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
A novel type of deprotonative arylation of nucleophiles was conducted using Et3SiH/cat. t-Bu-P4 and the powerful SNAr reactions of aryl fluorides were accomplished using alcs. and malonates as nucleophiles.
22
(a) Okachi, T.; Fujimoto, K.; Onaka, M. Practical Carbonyl-Ene Reactions of α-Methylstyrenes with Paraformaldehyde Promoted by a Combined System of Boron Trifluoride and Molecular Sieves 4A. Org. Lett. 2002, 4, 1667– 1669, DOI: 10.1021/ol025719l
Google Scholar
22a
Practical Carbonyl-Ene Reactions of α-Methylstyrenes with Paraformaldehyde Promoted by a Combined System of Boron Trifluoride and Molecular Sieves 4A
Okachi, Takahiro; Fujimoto, Katsuhiko; Onaka, Makoto
Organic Letters (2002), 4 (10), 1667-1669CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
A combined system of boron trifluoride and mol. sieves is an efficient promoter for the carbonyl-ene reaction of α-methylsyrenes with paraformaldehyde. The coexistence of BF3·OEt2 and mol. sieves 4A is essential for obtaining high yields of ene products.
(b) Ono, F.; Ohta, Y.; Hasegawa, M.; Kanemasa, S. Molecular sieve 4 Å generates nitrile oxides from hydroximoyl chlorides. Development of catalyzed enantioselective nitrile oxide cycloadditions to monosubstituted alkenes. Tetrahedron Lett. 2009, 50, 2111– 2114, DOI: 10.1016/j.tetlet.2009.02.178
Google Scholar
22b
Molecular sieve 4 Å generates nitrile oxides from hydroximoyl chlorides. Development of catalyzed enantioselective nitrile oxide cycloadditions to monosubstituted alkenes
Ono, Fumiyasu; Ohta, Yasuaki; Hasegawa, Masayuki; Kanemasa, Shuji
Tetrahedron Letters (2009), 50 (18), 2111-2114CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
The effective generation of nitrile oxide 1,3-dipoles from hydroximoyl chlorides can be achieved with powd. mol. sieves 3 Å and 4 Å as mild solid bases. Rate of nitrile oxide generation depends upon the choice of reaction solvents, among which alcs. are the best media. A catalytic process is achieved by use of a catalytic amt. of amine in the presence of MS 4 Å leading to the amine-catalytic generation of nitrile oxides. This new synthetic method can be applied to the catalytic enantioselective nitrile oxide 1,3-dipolar cycloaddn. reactions with monosubstituted alkenes.
(c) Shigeno, M.; Shishido, Y.; Soga, A.; Nozawa-Kumada, K.; Kondo, Y. Defluorinative Transformation of (2,2,2-Trifluoroethyl)arenes Catalyzed by the Phosphazene Base t-Bu-P2. J. Org. Chem. 2023, 88, 1796– 1802, DOI: 10.1021/acs.joc.2c02034
Google Scholar
There is no corresponding record for this reference.
23
(a) Bordwell, F. G.; Van der Puy, M.; Vanier, N. R. Carbon acids. 9. The effects of divalent sulfur and divalent oxygen on carbanion stabilities. J. Org. Chem. 1976, 41, 1885– 1886, DOI: 10.1021/jo00872a050
Google Scholar
23a
Carbon acids. 9. The effects of divalent sulfur and divalent oxygen on carbanion stabilities
Bordwell, F. G.; Van der Puy, Michael; Vanier, Noel R.
Journal of Organic Chemistry (1976), 41 (10), 1885-6CODEN: JOCEAH; ISSN:0022-3263.
The effect of replacement of Me or Me3C by Me3N+ on equil. acidities in Me2SO in the C acid systems MeCH2CN, MeCH2SO2Ph, MeCH2COPh, and 9-tert-butylfluorene are used to est. the size of the polar effect. The ρ values estd. from these results (ΔpK = σρ) are used, in combination with the σ values for MeO, PhO, MeS, and PhS groups, to est. the polar effects of these groups. For the MeO and PhO groups, the acidifying effects obsd. are in every instance smaller than those calcd. for polar effects. This is attributed to a destabilizing effect in the anion caused by lone pair-lone pair repulsions in the carbanions. For MeS and PhS groups the acidifying effects obsd. are in every instance much larger than the calcd. values. This cannot be attributed solely to the polarizability of S; conjugative stabilization of α carbanions by divalent S appears to be significant.
(b) Bordwell, F. G.; Bartmess, J. E.; Hautala, J. A. Alkyl effects on equilibrium acidities of carbon acids in protic and dipolar aprotic media and the gas phase. J. Org. Chem. 1978, 43, 3095– 3101, DOI: 10.1021/jo00410a001
Google Scholar
23b
Alkyl effects on equilibrium acidities of carbon acids in protic and dipolar aprotic media and the gas phase
Bordwell, F. G.; Bartmess, John E.; Hautala, Judith A.
Journal of Organic Chemistry (1978), 43 (16), 3095-101CODEN: JOCEAH; ISSN:0022-3263.
The effects on acidity of substitution of Me or H at C in 28 weak acids are divided into 4 types: (a) acid-weakening hyperconjugative and polar Me effects; (b) acid-strengthening hyperconjugative Me effects (on ketones, nitroalkanes and 9-methylfluorene); (c) acid-weakening polar Me effects (on sulfones and nitriles); and (d) acid-weakening steric Me effects. Decreasing acidities of nitroalkanes RCH2NO2 (R = Me, Et, Me2CH, CMe3) were alike in 50% aq. MeOH and Me2SO. These alkyl effects are the result of a complex blend of hyperconjugative, polar, polarizability and steric effects. Ph and vinyl groups exhibit substantial conjugative effects which are larger in Me2SO than in aq. MeOH. The cyclopropyl group exhibits no observable conjugative effect in the RCH:NO2- anion (R = cyclopropyl). Substitution of R for H in RCH2NO2 produces, for the most part, the same relative effects as obsd. for substitution of R for H in HCH2NO3. However, substitution of cyclopropyl for H in HCH2NO2 and MeCH2NO2 is acid strengthening, whereas substitution of cyclopropyl for H in RCH2NO2 (R = cyclopropyl) is acid weakening.
(c) Bordwell, F. G.; Drucker, G. E.; Fried, H. E. Acidities of carbon and nitrogen acids: the aromaticity of the cyclopentadienyl anion. J. Org. Chem. 1981, 46, 632– 635, DOI: 10.1021/jo00316a032
Google Scholar
23c
Acidities of carbon and nitrogen acids: the aromaticity of the cyclopentadienyl anion
Bordwell, Frederick G.; Drucker, George E.; Fried, Herbert E.
Journal of Organic Chemistry (1981), 46 (3), 632-5CODEN: JOCEAH; ISSN:0022-3263.
The equil. acidities in Me2SO of 1,3-cyclopentadiene, indene, and fluorene decrease in that order, the pKa values being 18.0, 20.1, and 22.6, resp., whereas those of the corresponding nitrogen acids, pyrrole, indole, and carbazole, change in the opposite order, the pKa values being 23.05, 20.95, and 19.90, resp. These pKa values, together with approx. intrinsic acidities of carbon vs. nitrogen acids, are used to est. arom. stabilization energies of 26, 20, and 14.5 kcal/mol for the cyclopentadienyl, indenyl, and fluorenyl anions, resp. Other ests. based on acidity data give values of 24 and 27 kcal/mol for the arom. stabilization energy of the cyclopentadienyl anion.
(d) Bordwell, F. G.; Cheng, J.-P.; Ji, G.-Z.; Satish, A. V.; Zhang, X. Bond dissociation energies in DMSO related to the gas phase values. J. Am. Chem. Soc. 1991, 113, 9790– 9795, DOI: 10.1021/ja00026a012
Google Scholar
23d
Bond dissociation energies in DMSO related to the gas phase values
Bordwell, F. G.; Cheng, Jinpei; Ji, Guo Zhen; Satish, A. V.; Zhang, Xianman
Journal of the American Chemical Society (1991), 113 (26), 9790-5CODEN: JACSAT; ISSN:0002-7863.
Ests. have been made of the homolytic bond dissocn. energies (BDEs) for (a) the benzylic or allylic H-C bonds in 14 hydrocarbons, (b) the acidic H-C bonds in 12 hydrocarbons contg. one or more heteroatoms, and (c) the H-N bonds in five nitrogen acids as well as thiophenol and phenol. For the 18 compds. where literature gas-phase values were available, agreement to within ±2 kcal/mol was obsd. for all but three (Ph3CH, PhNH2, and PhOH). For Ph3CH and PhNH2, the literature values were shown to be in error. For the BDEs of the acidic H-A bonds in 17 compds., error limits of ±2 kcal/mol, or better, were established from BDE ests. made for three or more derivs. in which remote substituents were placed on the benzene ring of the parent compd. In all, the BDEs of the acidic H-A bonds of 32 compds. have been established to ±2 kcal/mol or better.
24
(a) Eliel, E. L.; Wilen, S. H.; Doyle, M. P. Basic Organic Stereochemistry; Wiley: New York, 2001.
Google Scholar
There is no corresponding record for this reference.
(b) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley: New York, 1994.
Google Scholar
There is no corresponding record for this reference.
25
(a) Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.; Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.; McCollum, G. J.; Vanier, N. R. Equilibrium acidities of carbon acids. VI. Establishment of an absolute scale of acidities in dimethyl sulfoxide solution. J. Am. Chem. Soc. 1975, 97, 7006– 7014, DOI: 10.1021/ja00857a010
Google Scholar
25a
Equilibrium acidities of carbon acids. VI. Establishment of an absolute scale of acidities in dimethyl sulfoxide solution
Matthews, Walter S.; Bares, Joseph E.; Bartmess, John E.; Bordwell, F. G.; Cornforth, Frederick J.; Drucker, George E.; Margolin, Zafra; McCallum, Robert J.; McCollum, Gregory J.; Vanier, Noel R.
Journal of the American Chemical Society (1975), 97 (24), 7006-14CODEN: JACSAT; ISSN:0002-7863.
An accurate spectrophotometric method of detg. relative equil. acidities of C acids in Me2SO was developed; the pK scale was anchored by comparisons of values obtained by the spectrophotometric method with those obtained potentiometrically in the 8 to 11 pK range. The pK's were correlated with heats of deprotonation by K dimisyl, and evidence was presented to show that the pK measurements were free from ion assocn. effects. C acids wherein the charge on the anion resides mainly on O, such as ketones and nitroalkanes, were weaker Me2SO than in H2O by 5.5 to 9.6 pK units, while C acids wherein the charge on the anion is delocalized over a large hydrocarbon matrix, such as in the anion derived from 9-cyanofluorene were stronger acids in Me2SO than in H2O. A list of 13 indicators covering the pK range 8.3 to 30.6 in Me2SO was given.
(b) Zhang, X. M.; Bordwell, F. G.; Van Der Puy, M.; Fried, H. E. Equilibrium Acidities and Homolytic Bond Dissociation Energies of the Acidic Carbon-Hydrogen Bonds in N-Substituted Trimethylammonium and Pyridinium Cations. J. Org. Chem. 1993, 58, 3060– 3066, DOI: 10.1021/jo00063a026
Google Scholar
25b
Equilibrium acidities and homolytic bond dissociation energies of the acidic carbon-hydrogen bonds in N-substituted trimethylammonium and pyridinium cations
Zhang, Xian Man; Bordwell, Frederick G.; Van Der Puy, Michael; Fried, Herbert E.
Journal of Organic Chemistry (1993), 58 (11), 3060-6CODEN: JOCEAH; ISSN:0022-3263.
Equil. acidities (pKHA) of the cations in 16 N-substituted trimethylammonium salts, one N-phenacylquinuclidinium salt, 8 N-substituted pyridinium salts, and N-(ethoxycarbonyl)isoquinolinium bromide, together with the oxidn. potentials of their conjugate bases, have been detd. in Me2SO. The acidifying effects of the α-trimethylammonium groups (α-Me3N+) and the α-pyridinium groups (α-PyN+) on the adjacent acidic C-H bonds in these cations were found to av. about 10 and 18 pKHA units, resp. The homolytic bond dissocn. energies of the acidic C-H bonds in these cations, estd. by the combination of the equil. acidities with the oxidn. potentials of their corresponding conjugate bases (ylides), show that the α-trimethylammonium groups destabilize adjacent radicals by 2-6 kcal/mol, whereas α-pyridinium groups stabilize adjacent radicals by 3-6 kcal/mol. The effects of α-pyridinium groups on the stabilization energies of the radicals derived from these cations were ca. 4-10 kcal/mol smaller than those of the corresponding Ph groups, whereas their effects on the equil. acidities of the cations were 5.4-13.1 pKHA units larger. The pKHA value of tetramethylammonium cation (Me4N+) was estd. by extrapolation to be about 42 in Me2SO.
26
Yang, X.; Fleming, F. F. C- and N-Metalated Nitriles: The Relationship Between Structure and Selectivity. Acc. Chem. Res. 2017, 50, 2556– 2568, DOI: 10.1021/acs.accounts.7b00329
Google Scholar
26
C- and N-Metalated Nitriles: The Relationship between Structure and Selectivity
Yang, Xun; Fleming, Fraser F.
Accounts of Chemical Research (2017), 50 (10), 2556-2568CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
A review. Metalated nitriles are exceptional nucleophiles capable of forging highly hindered stereocenters in cases where enolates are unreactive. The excellent nucleophilicity emanates from the powerful inductive stabilization of adjacent neg. charge by the nitrile, which has a miniscule steric demand. Inductive stabilization is the key to understanding the reactivity of metalated nitriles because this permits a continuum of structures that range from N-metalated ketenimines to nitrile anions. Soln. and solid-state analyses reveal two different metal coordination sites, the formally anionic carbon and the nitrile nitrogen, with the site of metalation depending intimately on the solvent, counterion, temp., and ligands. The most commonly encountered structures, C- and N-metalated nitriles, have either sp3 or sp2 hybridization at the nucleophilic carbon, which essentially translates into two distinct organometallic species with similar but nonidentical stereoselectivity, regioselectivity, and reactivity preferences. The hybridization differences are particularly important in SNi displacements of cyclic nitriles because the orbital orientations create very precise trajectories that control the cyclization selectivity. Harnessing the orbital differences between C- and N-metalated nitriles allows selective cyclization to afford nitrile-contg. cis- or trans-hydrindanes, decalins, or bicyclo[5.4.0]undecanes. Similar orbital constraints favor preferential SNi displacements with allylic electrophiles on sp3 centers over sp2 centers. The strategy permits stereoselective displacements on secondary centers to set contiguous tertiary and quaternary stereocenters or even contiguous vicinal quaternary centers. Stereoselective alkylations of acyclic nitriles are inherently more challenging because of the difficulty in creating steric differentiation in a dynamic system with rotatable bonds. However, judicious substituent placement of vicinal di-Me groups and a trisubstituted alkene sufficiently constrains C- and N-metalated nitriles to install quaternary stereocenters with excellent 1,2-induction. The structural differences between C- and N-metalated nitriles permit a rare series of chemoselective alkylations with bifunctional electrophiles. C-Magnesiated nitriles preferentially react with carbonyl electrophiles, whereas N-lithiated nitriles favor SN2 displacement of alkyl halides. The chemoselective alkylations potentially provide a strategy for late-stage alkylations of polyfunctional electrophiles en route to bioactive targets. In this Account, the bonding of metalated nitriles is summarized as a prelude to the different strategies for selectively prepg. C- and N-metalated nitriles. With this background, the Account then transitions to applications in which C- or N-metalated nitriles allow complementary diastereoselectivity in alkylations and arylations, and regioselective alkylations and arylations, with acyclic and cyclic nitriles. In the latter sections, a series of regiodivergent cyclizations are described that provide access to cis- and trans-hydrindanes and decalins, structural motifs embedded within a plethora of natural products. The last section describes chemoselective alkylations and acylations of C- and N-metalated nitriles that offer the tantalizing possibility of selectively manipulating functional groups in bioactive medicinal leads without recourse to protecting groups. Collectively, the unusual reactivity profiles of C- and N-metalated nitriles provide new strategies for rapidly and selectively accessing valuable synthetic precursors.
27
Thiolation and phosphination reactions proceeded at lower reaction temperatures compared to etherification and amination reactions. This is presumably due to the higher acidities of thiol and phosphine nucleophiles, which facilitate the generation of anionic species more efficiently, as well as their higher HOMO levels, which contribute to increased nucleophilicity.
Google Scholar
There is no corresponding record for this reference.
28
The attempts were made using electron-deficient 4-fluoronitrobenzene (see the Supporting Information). The absence of the Meisenheimer intermediate suggests that the CS_NAr reaction process might also be involved in the reactions of electron-deficient substrates, although the stepwise addition and elimination processes cannot be entirely excluded.
Google Scholar
There is no corresponding record for this reference.
29
Mauksch, M.; Tsogoeva, S. B. Hückel and Möbius Aromaticity in Charged Sigma Complexes. Chem. - Eur. J. 2019, 25, 7457– 7462, DOI: 10.1002/chem.201900849
Google Scholar
29
H.ovrddot.uckel and M.ovrddot.obius Aromaticity in Charged Sigma Complexes
Mauksch, Michael; Tsogoeva, Svetlana B.
Chemistry - A European Journal (2019), 25 (31), 7457-7462CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
In sigma complexes, intermediates in nucleophilic and electrophilic arom. substitution and other reactions, delocalization in the arom. ring is formally disrupted. Unexpectedly, computational evidence is presented that favorable processes contain arom. sigma complexes. Tetracoordinated carbon therein surprisingly employs orbitals that are more similar to sp2 than to sp3 hybrids in sigma bonds with adjacent ring atoms. Both leaving groups and nucleo- or electrophiles may donate electrons to the π-system depending on the availability of p-type orbitals to fulfill H.ovrddot.uckel (4+2) or M.ovrddot.obius (4N) rules of aromaticity in analogy to conjugated transition-metal metallacycles.

Cited By

Click to copy section linkSection link copied!

Explore this article's citation statements on scite.ai

This article is cited by 2 publications.

Nicolò Tampellini, Brandon Q. Mercado, Scott J. Miller. Enantiocontrolled Cyclization to Form Chiral 7- and 8-Membered Rings Unified by the Same Catalyst Operating with Different Mechanisms. Journal of the American Chemical Society 2025, 147 (5) , 4624-4630. https://doi.org/10.1021/jacs.4c17080
. Superbase-Catalyzed Concerted SNAr Reactions on Unbiased Arenes. Synfacts 2025, 184-184. https://doi.org/10.1055/a-2496-8997

Download PDF

Get e-Alerts

Journal of the American Chemical Society

Cite this: J. Am. Chem. Soc. 2024, 146, 47, 32452–32462

Click to copy citationCitation copied!

https://doi.org/10.1021/jacs.4c09042

Published November 8, 2024

CC-BY 4.0 .

Article Views

Altmetric

Citations

Learn about these metrics

Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

Abstract
High Resolution Image
Download MS PowerPoint Slide
Figure 1
Figure 1. Overview of previous S_NAr reactions and this work.
High Resolution Image
Download MS PowerPoint Slide
Figure 2
Figure 2. Scope of aryl fluorides and alkyl cyanides.^a,b aReactions were conducted on a 0.2 mmol scale. ^bIsolated yields. ^cReaction was conducted at 40 °C. ^dReaction was conducted at 60 °C. ^e2 (2 equiv) was used. ^fReaction was conducted at 120 °C. ^gReaction was conducted at 140 °C. ^hReaction was conducted in mesitylene at 160 °C. ⁱReaction was conducted in mesitylene at 180 °C.
High Resolution Image
Download MS PowerPoint Slide
Figure 3
Figure 3. Scope of heteroatom nucleophiles in the reaction of 1a (A–D) and functionalization of bioactive compound derivatives (E).^a,b aReactions were conducted on a 0.2 mmol scale. ^bIsolated yields. ^cReaction was conducted at 200 °C. ^dDMI was used as a solvent. ^eReaction was conducted at 160 °C. ^fTHF was used as a solvent. ^gMesitylene was used as a solvent. ^hProducts were isolated after oxidation with H₂O₂. ⁱReaction was conducted at 140 °C. ^jReaction was conducted at 80 °C.
High Resolution Image
Download MS PowerPoint Slide
Figure 4
Figure 4. Proposed mechanism.
High Resolution Image
Download MS PowerPoint Slide
Figure 5
Figure 5. Theoretical mechanistic studies. (A) Energy diagram using Gibbs free energies calculated at the CPCM(toluene)/oniom(ωB97X-D/6-311+G(2d,p):B97-D/6-311G(d,p)) level of theory. (B) Chemical structures of intermediates and transition state. (C) 3D structures of intermediates and transition state.
High Resolution Image
Download MS PowerPoint Slide
Figure 6
Figure 6. (A) NICS_zz scan of (a) TS-1, (b) TS-2, and (c) 1v calculated at the GIAO/B3LYP/6-311+G(d) level of theory. The z axis for the NICS_zz-scan and z values are shown as purple dots. (B) Natural population analysis (NPA) of (a) TS-1 and (b) TS-2 calculated at the M06-2X/6-311+G(2d,p) level of theory using the optimized structures obtained at the CPCM(toluene)/oniom(ωB97X-D/6-311+G(2d,p):B97-D/6-311G(d,p)) level of theory.
High Resolution Image
Download MS PowerPoint Slide
Figure 7
Figure 7. (A) Natural energy decomposition analysis (NEDA) for (a) Int-1 ([(t-Bu-P4)H]⁺···[Ph(Me)CCN]⁻) and (b) Int-5 ([K(18-crown-6)]⁺···[Ph(Me)CCN]⁻) (kcal/mol). In figures (A–D), all single point calculations were performed at the M06-2X/6-311+G(2d,p) level of theory using the optimized structures obtained at the CPCM(toluene)/oniom(ωB97X-D/6-311+G(2d,p):B97-D/6-311G(d,p)) level of theory. (B) Noncovalent interaction analyses of (a) Int-1 and (b) Int-5. The red surface indicates strong repulsive interactions, while the green and blue surfaces show weak and strong attractive interactions, respectively. (C) Molecular states of (a) Int-1, (b) Int-5, and (c) [Ph(Me)CCN]⁻ (naked anion). The HOMOs of the anionic parts and their energies are shown. The natural charges of the anionic parts are also noted. (D) Molecular states of fluorobenzene moieties in (a) Int-2 and (b) Int-6 and the molecular state of (c) 1v. In molecular states Int-2 and Int-6, the anionic part was omitted for simplicity. The π* orbitals of the aromatic rings (Int-2: LUMO+5; Int-6: LUMO + 5; 1v: LUMO + 2) and their energies are shown. The natural charges of the ipso-carbons attached to a fluorine atom are also noted.
High Resolution Image
Download MS PowerPoint Slide
References
This article references 29 other publications.
1. 1
  (a) Bunnett, J. F.; Zahler, R. E. Aromatic Nucleophilic Substitution Reactions. Chem. Rev. 1951, 49, 273– 412, DOI: 10.1021/cr60153a002
  1a
  Aromatic nucleophilic substitution reactions
  Bunnett, Joseph F.; Zahler, Roland E.
  Chemical Reviews (Washington, DC, United States) (1951), 49 (), 273-412CODEN: CHREAY; ISSN:0009-2665.
  A review with 621 references.
  (b) Miller, J. Aromatic Nucleophilic Substitution; Elsevier Sci. Ltd., Amsterdam, 1968.
  There is no corresponding record for this reference.
  (c) Terrier, F. Modern Nucleophilic Aromatic Substitution; John Wiley & Sons, Inc., Weinheim, 2013.
  There is no corresponding record for this reference.
2. 2
  (a) Faust, A. Ueber das Verhalten des Monochlorphenols von 218° Siedepunkt in der Kalischmelze. Ber. Dtsch. Chem. Ges. 1873, 6, 1022– 1023, DOI: 10.1002/cber.18730060246
  There is no corresponding record for this reference.
  (b) Fittig, R.; Mager, E. Beiträge zur Entscheidung der Stellungsfrage in der aromatischen Gruppe. Ber. Dtsch. Chem. Ges. 1874, 7, 1175– 1180, DOI: 10.1002/cber.18740070277
  There is no corresponding record for this reference.
3. 3
  Brown, D. G.; Boström, J. Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?. J. Med. Chem. 2016, 59, 4443– 4458, DOI: 10.1021/acs.jmedchem.5b01409
  3
  Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?
  Brown, Dean G.; Bostrom, Jonas
  Journal of Medicinal Chemistry (2016), 59 (10), 4443-4458CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A review. An anal. of chem. reactions used in current medicinal chem. (2014), three decades ago (1984), and in natural product total synthesis has been conducted. The anal. revealed that of the current most frequently used synthetic reactions, none were discovered within the past 20 years and only two in the 1980s and 1990s (Suzuki-Miyaura and Buchwald-Hartwig). This suggests an inherent high bar of impact for new synthetic reactions in drug discovery. The most frequently used reactions were amide bond formation, Suzuki-Miyaura coupling, and SNAr reactions, most likely due to com. availability of reagents, high chemoselectivity, and a pressure on delivery. The authors show that these practices result in overpopulation of certain types of mol. shapes to the exclusion of others using simple PMI plots. The authors hope that these results will help catalyze improvements in integration of new synthetic methodologies as well as new library design.
4. 4
  Baumann, M.; Baxendale, I. R. An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles. Beilstein J. Org. Chem. 2013, 9, 2265– 2319, DOI: 10.3762/bjoc.9.265
  4
  An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles
  Baumann, Marcus; Baxendale, Ian R.
  Beilstein Journal of Organic Chemistry (2013), 9 (), 2265-2319, 55 pp.CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
  A review. This review which is the second in this series summarizes the most common synthetic routes as applied to the prepn. of many modern pharmaceutical compds. categorized as contg. a six-membered heterocyclic ring. The reported examples are based on the top retailing drug mols. combining synthetic information from both scientific journals and the wider patent literature. This compilation, in combination with the previously published review on five-membered rings, will form a comprehensive foundation and ref. source for individuals interested in medicinal, synthetic and preparative chem.
5. 5
  (a) Kiplinger, J. L.; Richmond, T. G.; Osterberg, C. E. Activation of carbon-fluorine bonds by metal complexes. Chem. Rev. 1994, 94, 373– 431, DOI: 10.1021/cr00026a005
  5a
  Activation of Carbon-Fluorine Bonds by Metal Complexes
  Kiplinger, Jaqueline L.; Richmond, Thomas G.; Osterberg, Carolyn E.
  Chemical Reviews (Washington, DC, United States) (1994), 94 (2), 373-431CODEN: CHREAY; ISSN:0009-2665.
  A review with 400 refs.
  (b) Amii, H.; Uneyama, K. C–F Bond activation in organic synthesis. Chem. Rev. 2009, 109, 2119– 2183, DOI: 10.1021/cr800388c
  5b
  C-F Bond Activation in Organic Synthesis
  Amii, Hideki; Uneyama, Kenji
  Chemical Reviews (Washington, DC, United States) (2009), 109 (5), 2119-2183CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review describes the various approaches to C-F bond activation in aliph., vinylic and arom. fluorides and their use in subsequent nucleophilic substitution, reductive defluorination, cross-coupling, dehydrofluorination and rearrangement reactions.
  (c) Ahrens, T.; Kohlmann, J.; Ahrens, M.; Braun, T. Functionalization of fluorinated molecules by transition-metal-mediated C–F bond activation to access fluorinated building blocks. Chem. Rev. 2015, 115, 931– 972, DOI: 10.1021/cr500257c
  5c
  Functionalization of Fluorinated Molecules by Transition-Metal-Mediated C-F Bond Activation To Access Fluorinated Building Blocks
  Ahrens, Theresia; Kohlmann, Johannes; Ahrens, Mike; Braun, Thomas
  Chemical Reviews (Washington, DC, United States) (2015), 115 (2), 931-972CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review that deals with transition-metal-mediated C1F bond activations which involve a cleavage of a C-F bond in polyfluorinated mols. and its transformation into carbon-element bonds, excluding hydrodefluorination or defluorination reactions.
  (d) Ai, H.-J.; Ma, X.; Song, Q.; Wu, X.-F. C–F bond activation under transition-metal-free conditions. Sci. China Chem. 2021, 64, 1630– 1659, DOI: 10.1007/s11426-021-1040-2
  5d
  C-F bond activation under transition-metal-free conditions
  Ai, Han-Jun; Ma, Xingxing; Song, Qiuling; Wu, Xiao-Feng
  Science China: Chemistry (2021), 64 (10), 1630-1659CODEN: SCCCCS; ISSN:1869-1870. (Science China Press)
  A review. This review provided an overview of recent C-F bond activations and functionalizations under transition-metal-free conditions. The key mechanisms involved was demonstrated and discussed in detail. Finally, a brief discussion on the existing limitations of this field and our perspective was presented.
  (e) Hooker, L. V.; Bandar, J. S. Synthetic Advantages of Defluorinative C–F Bond Functionalization. Angew. Chem., Int. Ed. 2023, 62, e202308880 DOI: 10.1002/anie.202308880
  5e
  Synthetic Advantages of Defluorinative C-F Bond Functionalization
  Hooker, Leidy V.; Bandar, Jeffrey S.
  Angewandte Chemie, International Edition (2023), 62 (49), e202308880CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. Much progress has been made in the development of methods to both create compds. that contain C-F bonds and to functionalize C-F bonds. As such, C-F bonds are becoming common and versatile synthetic functional handles. This review summarizes the advantages of defluorinative functionalization reactions for small mol. synthesis. The coverage is organized by the type of carbon framework the fluorine is attached to for mono- and polyfluorinated motifs. The main challenges, opportunities and advances of defluorinative functionalization are discussed for each class of organofluorine. Most of the text focuses on case studies that illustrate how defluorofunctionalization can improve routes to synthetic targets or how the properties of C-F bonds enable unique mechanisms and reactions. The broader goal is to showcase the opportunities for incorporating and exploiting C-F bonds in the design of synthetic routes, improvement of specific reactions and advent of new methods.
  (f) Zhou, J.; Zhao, Z.; Shibata, N. Transition-metal-free silylboronate-mediated cross-couplings of organic fluorides with amines. Nat. Commun. 2023, 14, 1847 DOI: 10.1038/s41467-023-37466-0
  5f
  Transition-metal-free silylboronate-mediated cross-couplings of organic fluorides with amines
  Zhou, Jun; Zhao, Zhengyu; Shibata, Norio
  Nature Communications (2023), 14 (1), 1847CODEN: NCAOBW; ISSN:2041-1723. (Nature Portfolio)
  Abstr.: C-N bond cross-couplings are fundamental in the field of org. chem. Herein, silylboronate-mediated selective defluorinative cross-coupling of org. fluorides with secondary amines via a transition-metal-free strategy is disclosed. The cooperation of silylboronate and potassium tert-butoxide enables the room-temp. cross-coupling of C-F and N-H bonds, effectively avoiding the high barriers assocd. with thermally induced SN2 or SN1 amination. The significant advantage of this transformation is the selective activation of the C-F bond of the org. fluoride by silylboronate without affecting potentially cleavable C-O, C-Cl, heteroaryl C-H, or C-N bonds and CF3 groups. Tertiary amines with arom., heteroarom., and/or aliph. groups were efficiently synthesized in a single step using electronically and sterically varying org. fluorides and N-alkylanilines or secondary amines. The protocol is extended to the late-stage syntheses of drug candidates, including their deuterium-labeled analogs.
6. 6
  Wencel-Delord, J.; Glorius, F. C–H bond activation enables the rapid construction and late-stage diversification of functional molecules. Nat. Chem. 2013, 5, 369– 375, DOI: 10.1038/nchem.1607
  6
  C-H bond activation enables the rapid construction and late-stage diversification of functional molecules
  Wencel-Delord, Joanna; Glorius, Frank
  Nature Chemistry (2013), 5 (5), 369-375CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
  A review. The beginning of the twenty-first century has witnessed significant advances in the field of C-H bond activation, and this transformation is now an established piece in the synthetic chemists' toolbox. This methodol. has the potential to be used in many different areas of chem., for example it provides a perfect opportunity for the late-stage diversification of various kinds of org. scaffolds, ranging from relatively small mols. like drug candidates, to complex polydisperse org. compds. such as polymers. In this way, C-H activation approaches enable relatively straightforward access to a plethora of analogs or can help to streamline the lead-optimization phase. Furthermore, synthetic pathways for the construction of complex org. materials can now be designed that are more atom- and step-economical than previous methods and, in some cases, can be based on synthetic disconnections that are just not possible without C-H activation. This Perspective highlights the potential of metal-catalyzed C-H bond activation reactions, which now extend beyond the field of traditional synthetic org. chem.
7. 7
  Bhunia, A.; Yetra, S. R.; Biju, A. T. Recent advances in transition-metal-free carbon–carbon and carbon–heteroatom bond-forming reactions using arynes. Chem. Soc. Rev. 2012, 41, 3140– 3152, DOI: 10.1039/c2cs15310f
  7
  Recent advances in transition-metal-free carbon-carbon and carbon-heteroatom bond-forming reactions using arynes
  Bhunia, Anup; Yetra, Santhivardhana Reddy; Biju, Akkattu T.
  Chemical Society Reviews (2012), 41 (8), 3140-3152CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  A review. This tutorial review is aimed at highlighting recent developments in transition-metal-free carbon-carbon and carbon-heteroatom bond-forming reactions using a versatile class of reactive intermediates, viz., arynes, which hold the potential for numerous applications in org. synthesis. Key to the success of the resurgence of interest in the rich chem. of arynes is primarily the mild condition for their generation by the fluoride-induced 1,2-elimination of 2-(trimethylsilyl)aryl triflates. Consequently, arynes were employed for the construction of multisubstituted arenes with structural diversity and complexity. The versatile transition-metal-free applications of arynes include cycloaddn. reactions, insertion reactions and multicomponent reactions. Arynes found applications in natural product synthesis. Herein, the authors present a concise account of the major developments that occurred in this field during the past eight years.
8. 8
  (a) Rohrbach, S.; Smith, A. J.; Pang, J. H.; Poole, D. L.; Tuttle, T.; Chiba, S.; Murphy, J. A. Concerted Nucleophilic Aromatic Substitution Reactions. Angew. Chem., Int. Ed. 2019, 58, 16368– 16388, DOI: 10.1002/anie.201902216
  8a
  Concerted Nucleophilic Aromatic Substitution Reactions
  Rohrbach, Simon; Smith, Andrew J.; Pang, Jia Hao; Poole, Darren L.; Tuttle, Tell; Chiba, Shunsuke; Murphy, John A.
  Angewandte Chemie, International Edition (2019), 58 (46), 16368-16388CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. Recent developments in exptl. and computational chem. have identified a rapidly growing class of nucleophilic arom. substitutions that proceed by concerted (cSNAr) rather than classical, two-step, SNAr mechanisms. Whereas traditional SNAr reactions require substantial activation of the arom. ring by electron-withdrawing substituents, such activating groups are not mandatory in the concerted pathways.
  (b) Neumann, C. N.; Ritter, T. Facile C–F Bond Formation through a Concerted Nucleophilic Aromatic Substitution Mediated by the PhenoFluor Reagent. Acc. Chem. Res. 2017, 50, 2822– 2833, DOI: 10.1021/acs.accounts.7b00413
  8b
  Facile C-F Bond Formation through a Concerted Nucleophilic Aromatic Substitution Mediated by the PhenoFluor Reagent
  Neumann, Constanze N.; Ritter, Tobias
  Accounts of Chemical Research (2017), 50 (11), 2822-2833CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
  A review. Late-stage fluorination reactions aim to reduce the synthetic limitations of conventional organofluorine chem. with respect to substrate scope and functional group tolerance. C-F bond formation is commonly thermodynamically favorable but almost universally assocd. with high kinetic barriers. Apart from PhenoFluor chem., most modern arom. fluorination methods reported to date rely on the use of transition metal catalysts, with C-F bonds often formed through reductive elimination. Reductive elimination chem. to make C-X bonds becomes increasingly challenging when moving to higher at. nos. in the periodic table from C-C to C-F, in part because of higher metal-X bond dissocn. energies. The formation of C-C, C-N, and C-O bonds via reductive elimination has become routine in the 20/th century, but it took until the 21st century to develop complexes that could afford general C-F bond formation. The availability of such complexes enabled the substrate scope of modern fluorination chem. to exceed that of conventional fluorination.PhenoFluor chem. departs from conventional reaction mechanisms for arom. fluorination chem. Instead, we have revealed a concerted nucleophilic arom. substitution reaction (CSNAr) for PhenoFluor that proceeds through a single neutral four-membered transition state. Conceptually, PhenoFluor chem. is therefore distinct from conventional SNAr chem., which typically proceeds through a two-barrier process with Meisenheimer complexes as reaction intermediates. As a consequence, PhenoFluor chem. has a larger substrate scope than conventional SNAr chem. and can be performed on arenes as electron-rich as anilines. Moreover, PhenoFluor chem. is tolerant of protic functional groups, which sets it apart from modern metal-mediated processes. Primary and secondary amines, alcs., thiols, and phenols are often not tolerated under metal-catalyzed late-stage fluorination reactions because C-N and C-O reductive elimination can have lower activation barriers than C-F reductive elimination. The mechanism by which PhenoFluor chem. forms C-F bonds not only rationalizes the substrate scope and functional group tolerance but also informs the side-product profile. Fluorinated isomers are not obsd. because the four-membered transition state necessitates ipso substitution. In addn., no reduced product, e.g., H instead of F incorporation, as is often obsd. with metal-mediated methods, has ever been obsd. with PhenoFluor.PhenoFluor chem. can be used to deoxyfluorinate both phenols and alcs. PhenoFluor is an expensive reagent that must be used stoichiometrically and therefore cannot replace cost-efficient methods to make simple fluorinated mols. on a large scale. However, PhenoFluor is often successful when other fluorination methods fail. The synthesis of 18F-labeled mols. for positron emission tomog. (PET) is one application of modern fluorination chem. for which material throughput is not an issue because of the small quantities of PET tracers used in imaging (typically nanomoles). The high emphasis on functional group tolerance, side-product profiles, and reliability combined with less stringent cost requirements render PhenoFluor-based deoxyfluorination with 18F promising for human PET imaging.
9. 9
  Kwan, E. E.; Zeng, Y.; Besser, H. A.; Jacobsen, E. N. Concerted nucleophilic aromatic substitutions. Nat. Chem. 2018, 10, 917– 923, DOI: 10.1038/s41557-018-0079-7
  9
  Concerted nucleophilic aromatic substitutions
  Kwan, Eugene E.; Zeng, Yuwen; Besser, Harrison A.; Jacobsen, Eric N.
  Nature Chemistry (2018), 10 (9), 917-923CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)
  Nucleophilic arom. substitution (SNAr) is one of the most widely applied reaction classes in pharmaceutical and chem. research, providing a broadly useful platform for the modification of arom. ring scaffolds. The generally accepted mechanism for SNAr reactions involves a two-step addn.-elimination sequence via a discrete, non-arom. Meisenheimer complex. Here the authors use 12C/13C kinetic isotope effect (KIE) studies and computational analyses to provide evidence that prototypical SNAr reactions in fact proceed through concerted mechanisms. The KIE measurements were made possible by a new technique that leverages the high sensitivity of 19F as an NMR nucleus to quantitate the degree of isotopic fractionation. This sensitive technique permits the measurement of KIEs on 10 mg of natural abundance material in one overnight acquisition. As a result, it provides a practical tool for performing detailed mechanistic analyses of reactions that form or break C-F bonds.
10. 10
  Rohrbach, S.; Murphy, J. A.; Tuttle, T. Computational Study on the Boundary Between the Concerted and Stepwise Mechanism of Bimolecular S_NAr Reactions. J. Am. Chem. Soc. 2020, 142, 14871– 14876, DOI: 10.1021/jacs.0c01975
  10
  Computational Study on the Boundary Between the Concerted and Stepwise Mechanism of Bimolecular SNAr Reactions
  Rohrbach, Simon; Murphy, John A.; Tuttle, Tell
  Journal of the American Chemical Society (2020), 142 (35), 14871-14876CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The text-book mechanism of bimol. nucleophilic arom. substitutions (SNAr) reactions is a stepwise process that proceeds via a so-called Meisenheimer intermediate. Only recently the alternative, concerted version of this mechanism has gained acceptance as more and more examples thereof have been reported. But so far only isolated examples of concerted SNAr reactions have been described and a coherent picture of when a SNAr reaction proceeds via a stepwise and when via a concerted mechanism has not yet been established. Here key factors are identified that influence the mechanistic choice of SNAr reactions. Moreover, the electron affinity is used as a simple descriptor to make a prediction on whether a given aryl fluoride substrate favors a concerted or stepwise mechanism.
11. 11
  (a) Matsuura, A.; Ano, Y.; Chatani, N. Nucleophilic aromatic substitution of non-activated aryl fluorides with aliphatic amides. Chem. Commun. 2022, 58, 9898– 9901, DOI: 10.1039/D2CC02999E
  There is no corresponding record for this reference.
  (b) Caron, S.; Vazquez, E.; Wojcik, J. M. Preparation of Tertiary Benzylic Nitriles from Aryl Fluorides. J. Am. Chem. Soc. 2000, 122, 712– 713, DOI: 10.1021/ja9933846
  11b
  Preparation of Tertiary Benzylic Nitriles from Aryl Fluorides
  Caron, Stephane; Vazquez, Enrique; Wojcik, Jill M.
  Journal of the American Chemical Society (2000), 122 (4), 712-713CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  An efficient method for the addn. of secondary nitriles to fluoroarenes was described. The reaction is specific to hexamethyldisilazane potassium salt, but proceeds with a variety of substrates. For example, the reaction of 1-fluoro-2-methoxybenzene with 2-methylpropanenitrile in the presence of hexamethyldisilazane potassium salt in toluene or THF gave 2-methoxy-α,α-dimethylbenzeneacetonitrile.
  (c) Takeda, M.; Nagao, K.; Ohmiya, H. Transition-Metal-Free Cross-Coupling by Using Tertiary Benzylic Organoboronates. Angew. Chem., Int. Ed. 2020, 59, 22460– 22464, DOI: 10.1002/anie.202010251
  11c
  Transition-Metal-Free Cross-Coupling by Using Tertiary Benzylic Organoboronates
  Takeda, Mitsutaka; Nagao, Kazunori; Ohmiya, Hirohisa
  Angewandte Chemie, International Edition (2020), 59 (50), 22460-22464CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The transition-metal-free cross-coupling of alkyl or aryl electrophiles by using tertiary benzylic organoboronates is reported. This reaction involves the generation of tertiary alkyl anions from organoboronates in the presence of an alkoxide base and then their substitution reactions. This protocol allows the simple and efficient construction of quaternary carbon centers.
  (d) Bizier, N. P.; Wm Wackerly, J.; Braunstein, E. D.; Zhang, M.; Nodder, S. T.; Carlin, S. M.; Katz, J. L. An Alternative Role for Acetylenes: Activation of Fluorobenzenes toward Nucleophilic Aromatic Substitution. J. Org. Chem. 2013, 78, 5987– 5998, DOI: 10.1021/jo400668v
  11d
  An Alternative Role for Acetylenes: Activation of Fluorobenzenes toward Nucleophilic Aromatic Substitution
  Bizier, Nicholas P.; Wackerly, Jay Wm.; Braunstein, Eric D.; Zhang, Mengfei; Nodder, Stephen T.; Carlin, Stephen M.; Katz, Jeffrey L.
  Journal of Organic Chemistry (2013), 78 (12), 5987-5998CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Acetylenes are increasingly versatile functional groups for a range of complexity-building org. transformations and for the construction of desirable mol. architectures. Herein we disclose a previously underappreciated aspect of arylacetylene reactivity by utilizing alkynes as electron-withdrawing groups (EWG) for promoting nucleophilic arom. substitution (SNAr) reactions. Reaction rates for the substitution of 4-(fluoroethynyl)benzenes by p-cresol were detd. by 1H NMR spectroscopy, and these rate data were used to det. substituent (Hammett) consts. for terminal and substituted ethynyl groups. The synthetic scope of acetylene-activated SNAr reactions is broad; fluoroarenes bearing one or two ethynyl groups undergo high-yielding substitution with a variety of oxygen and arylamine nucleophiles.
  (e) Diness, F.; Fairlie, D. P. Catalyst-Free N-Arylation Using Unactivated Fluorobenzenes. Angew. Chem., Int. Ed. 2012, 51, 8012– 8016, DOI: 10.1002/anie.201202149
  11e
  Catalyst-Free N-Arylation Using Unactivated Fluorobenzenes
  Diness, Frederik; Fairlie, David P.
  Angewandte Chemie, International Edition (2012), 51 (32), 8012-8016, S8012/1-S8012/65CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A valuable and simple novel catalyst-free protocol for the N-arylation of azole and indole derivs. has been described using direct SNAr substitution of fluorine on unactivated benzene derivs. is presented. Reaction conditions have been optimized to effect facile, rapid, versatile, and high-yielding, one-step reactions which tolerate a wide range of substituents on the fluorobenzene and azole/indole deriv., including chloro, bromo, and iodo substituents which result in halogenated N-aryl derivs. This catalyst-free N-arylation reaction is also compatible with metal-catalyzed cross-coupling reactions performed in the same pot simultaneously with, or subsequent to, SNAr substitution of fluorine in fluorobenzene derivs. We predict that these new methods may have wide synthetic utility across org., medicinal, agricultural, and polymer chem. as well as in materials science applications.
  (f) Mallick, S.; Xu, P.; Würthwein, E.-U.; Studer, A. Silyldefluorination of Fluoroarenes by Concerted Nucleophilic Aromatic Substitution. Angew. Chem., Int. Ed. 2019, 58, 283– 287, DOI: 10.1002/anie.201808646
  11f
  Silyldefluorination of Fluoroarenes by Concerted Nucleophilic Aromatic Substitution
  Mallick, Shubhadip; Xu, Pan; Wuerthwein, Ernst-Ulrich; Studer, Armido
  Angewandte Chemie, International Edition (2019), 58 (1), 283-287CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The reaction of readily generated silyl Li reagents with various aryl fluorides to provide the corresponding aryl silanes is reported. DFT calcns. reveal that the nucleophilic arom. substitution of the fluoride anion by the silyl Li reagent proceeds through concerted ipso substitution. In contrast to the classical nucleophilic arom. substitution, this concerted ionic silyldefluorination also occurs on more electron-rich aryl fluorides.
  (g) Liu, L. W.; Zarata, C.; Martin, R. Base-Mediated Defluorosilylation of C(sp²)–F and C(sp³)–F Bonds. Angew. Chem., Int. Ed. 2019, 58, 2064– 2068, DOI: 10.1002/anie.201813294
  11g
  Base-Mediated Defluorosilylation of C(sp2)-F and C(sp3)-F Bonds
  Liu, Xiang-Wie; Zarate, Cayetana; Martin, Ruben
  Angewandte Chemie, International Edition (2019), 58 (7), 2064-2068CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The ability to selectively forge C-heteroatom bonds by C-F scission is typically accomplished by metal catalysts, specialized ligands and/or harsh reaction conditions. Described herein is a base-mediated defluorosilylation of unactivated C(sp2)-F and C(sp3)-F bonds that obviates the need for metal catalysts. This protocol was characterized by its simplicity, mild reaction conditions, and wide scope, even within the context of late-stage functionalization, constituting a complementary approach to existing C-Si bond-forming protocols.
  (h) You, Z.; Higashida, K.; Iwai, T.; Sawamura, M. Phosphinylation of Non-activated Aryl Fluorides through Nucleophilic Aromatic Substitution at the Boundary of Concerted and Stepwise Mechanisms. Angew. Chem., Int. Ed. 2021, 60, 5778– 5782, DOI: 10.1002/anie.202013544
  11h
  Phosphinylation of Non-activated Aryl Fluorides through Nucleophilic Aromatic Substitution at the Boundary of Concerted and Stepwise Mechanisms
  You, Zhensheng; Higashida, Kosuke; Iwai, Tomohiro; Sawamura, Masaya
  Angewandte Chemie, International Edition (2021), 60 (11), 5778-5782CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Non-activated aryl fluorides reacted with potassium diorganophosphinites through a nucleophilic arom. substitution (SNAr) reaction. Remarkably, both electron-neutral and electron-rich aryl fluorides participated in the reaction with substantially stabilized anionic P nucleophiles to form the corresponding tertiary phosphine oxides. Quantum chem. calcns. suggested a nucleophile-dependent mechanism that involves both concerted and stepwise SNAr reaction pathways.
12. 12
  (a) Yasui, K.; Kamitani, M.; Tobisu, M. N-Heterocyclic Carbene Catalyzed Concerted Nucleophilic Aromatic Substitution of Aryl Fluorides Bearing α,β-Unsaturated Amides. Angew. Chem., Int. Ed. 2019, 58, 14157– 14161, DOI: 10.1002/anie.201907837
  12a
  N-Heterocyclic Carbene Catalyzed Concerted Nucleophilic Aromatic Substitution of Aryl Fluorides Bearing α,β-Unsaturated Amides
  Yasui, Kosuke; Kamitani, Miharu; Tobisu, Mamoru
  Angewandte Chemie, International Edition (2019), 58 (40), 14157-14161CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Concerted nucleophilic arom. substitution (CSNAr) has emerged as a powerful mechanistic manifold, in which nucleophilic arom. substitution can proceed in one step without the need to form a Meisenheimer intermediate. However, all of the CSNAr reactions reported thus far require a stoichiometric strong base or activating reagent, and no catalytic variants have yet been reported. Herein, we report an N-heterocyclic carbene (NHC)-catalyzed intramol. cyclization of acrylamides that contain a 2-fluorophenyl group on the nitrogen through a CSNAr reaction. By using this catalytic method, it is possible to synthesize an array of quinolin-2-one derivs., which are common structural motifs in pharmaceuticals and org. materials. DFT calcns. unambiguously revealed that this reaction proceeds through the concerted nucleophilic arom. substitution of aryl fluorides, in which a stereoelectronic σ (Cipso-Cβ)→ σ*(Cipso-F) interaction critically contributes to the stabilization of the transition state for the cyclization.
  (b) Ito, S.; Fujimoto, H.; Tobisu, M. Non-Stabilized Vinyl Anion Equivalents from Styrenes by N-Heterocyclic Carbene Catalysis and Its Use in Catalytic Nucleophilic Aromatic Substitution. J. Am. Chem. Soc. 2022, 144, 6714– 6718, DOI: 10.1021/jacs.2c02579
  12b
  Non-stabilized Vinyl Anion Equivalents from Styrenes by N-Heterocyclic Carbene Catalysis and Its Use in Catalytic Nucleophilic Aromatic Substitution
  Ito, Sora; Fujimoto, Hayato; Tobisu, Mamoru
  Journal of the American Chemical Society (2022), 144 (15), 6714-6718CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A protocol for the catalytic nucleophilic activation of unactivated styrenes was reported, which enables the generation of a non-stabilized alkenyl anion equiv. as a transient intermediate. In the reaction, N-heterocyclic carbenes add across styrenes to generate ylide intermediates, which could then be used in intramol. nucleophilic arom. substitution reactions of aryl fluorides, chlorides and Me ethers. The method allowed for straightforward access to complex polyarom. compds.
13. 13
  Kikushima, K.; Grellier, M.; Ohashi, M.; Ogoshi, S. Transition-Metal-Free Catalytic Hydrodefluorination of Polyfluoroarenes by Concerted Nucleophilic Aromatic Substitution with a Hydrosilicate. Angew. Chem., Int. Ed. 2017, 56, 16191– 16196, DOI: 10.1002/anie.201708003
  13
  Transition-Metal-Free Catalytic Hydrodefluorination of Polyfluoroarenes by Concerted Nucleophilic Aromatic Substitution with a Hydrosilicate
  Kikushima, Kotaro; Grellier, Mary; Ohashi, Masato; Ogoshi, Sensuke
  Angewandte Chemie, International Edition (2017), 56 (51), 16191-16196CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Polyfluorinated arenes underwent regioselective transition metal-free hydrodefluorination with Ph3SiH or Et2SiH2 in the presence of tetrabutylammonium difluorotriphenylsilicate (TBAT) in THF. For example, hexafluorobenzene underwent hydrodefluorination with Et2SiH2 at 60° to yield pentafluorobenzene in 19% yield, 1,2,4,5-tetrafluorobenzene in 70% yield, and 1,2,3,5-tetrafluorobenzene and 1,2,3,4-tetrafluorobenzene in 2% yields. The reaction involves direct hydride transfer from a hydrosilicate as the key intermediate, which is generated from a hydrosilane and a fluoride salt; the eliminated fluoride regenerates the hydrosilicate to complete the catalytic cycle. The mechanism was studied using stoichiometric reactions of silicates and using dispersion-cor. DFT calcns.; hydrodefluorination likely proceeds via concerted nucleophilic arom. substitution.
14. 14
  Park, N. H.; dos Passos Gomes, G.; Fevre, M.; Jones, G. O.; Alabugin, I. V.; Hedrick, J. L. Organocatalyzed synthesis of fluorinated poly(aryl thioethers). Nat. Commun. 2017, 8, 166 DOI: 10.1038/s41467-017-00186-3
  14
  Organocatalyzed synthesis of fluorinated poly(aryl thioethers)
  Park Nathaniel H; Fevre Mareva; Jones Gavin O; Hedrick James L; Gomes Gabriel Dos Passos; Alabugin Igor V
  Nature communications (2017), 8 (1), 166 ISSN:.
  The preparation of high-performance fluorinated poly(aryl thioethers) has received little attention compared to the corresponding poly(aryl ethers), despite the excellent physical properties displayed by many polysulfides. Herein, we report a highly efficient route to fluorinated poly(aryl thioethers) via an organocatalyzed nucleophilic aromatic substitution of silyl-protected dithiols. This approach requires low catalyst loadings, proceeds rapidly at room temperature, and is effective for many different perfluorinated or highly activated aryl monomers. Computational investigations of the reaction mechanism reveal an unexpected, concerted SNAr mechanism, with the organocatalyst playing a critical, dual-activation role in facilitating the process. Not only does this remarkable reactivity enable rapid access to fluorinated poly(aryl thioethers), but also opens new avenues for the processing, fabrication, and functionalization of fluorinated materials with easy removal of the volatile catalyst and TMSF byproducts.Fluorinated poly(aryl thioethers), unlike their poly(aryl ethers) counterparts, have received little attention despite excellent physical properties displayed by many polysulfides. Here the authors show a highly efficient route to fluorinated poly(aryl thioethers) via an organocatalyzed nucleophilic aromatic substitution of silyl-protected dithiols.
15. 15
  (a) Otsuka, M.; Endo, K.; Shibata, T. Catalytic S_NAr reaction of non-activated fluoroarenes with amines via Ru η⁶-arene complexes. Chem. Commun. 2010, 46, 336– 338, DOI: 10.1039/B919413D
  15a
  Catalytic SNAr reaction of non-activated fluoroarenes with amines via Ru η6-arene complexes
  Otsuka, Maiko; Endo, Kohei; Shibata, Takanori
  Chemical Communications (Cambridge, United Kingdom) (2010), 46 (2), 336-338CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  Ru-catalyzed SNAr reaction of non-activated fluoroarenes with secondary amines proceeded through η6-arene complexes to give aminated products in up to 79% yield. E.g., in presence of Ru(cod)(2-methylallyl)2, 1,5-bis(diphenylphosphino)pentane, trifluoromethanesulfonic acid, triethylamine, and triethylsilane, reaction of 4-fluorotoluene and morpholine gave 72% aminated product I.
  (b) Kang, Q.-K.; Lin, Y.; Li, Y.; Xu, L.; Li, K.; Shi, H. Catalytic S_NAr Hydroxylation and Alkoxylation of Aryl Fluorides. Angew. Chem., Int. Ed. 2021, 60, 20391– 20399, DOI: 10.1002/anie.202106440
  15b
  Catalytic SNAr Hydroxylation and Alkoxylation of Aryl Fluorides
  Kang, Qi-Kai; Lin, Yunzhi; Li, Yuntong; Xu, Lun; Li, Ke; Shi, Hang
  Angewandte Chemie, International Edition (2021), 60 (37), 20391-20399CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A reliable method for accessing phenols ArOH (Ar = C6H5, 4-CH3OC6H4, 9H-fluoren-2-yl, etc.) and Ph alkyl ethers Ar1OR (Ar1 = 4-CH3C6H4, 9H-fluoren-2-yl, 1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl, etc.; R = Me, cyclohexylmethyl, oxan-4-yl, etc.) via catalytic SnAr reactions has been described. The method is applicable to a broad array of electron-rich and neutral aryl fluorides ArF and Ar1F, which are inert under classical SnAr conditions. Although the mechanism of SNAr reactions involving metal arene complexes is hypothesized to involve a stepwise pathway (addn. followed by elimination), exptl. data that support this hypothesis is still under exploration. Mechanistic studies and DFT calcns. suggest either a stepwise or stepwise-like energy profile. Notably, a rhodium η5-cyclohexadienyl complex intermediate with an sp3-hybridized carbon bearing both a nucleophile and a leaving group was isolated.
16. 16
  (a) Pistritto, V. A.; Liu, S.; Nicewicz, D. A. Mechanistic Investigations into Amination of Unactivated Arenes via Cation Radical Accelerated Nucleophilic Aromatic Substitution. J. Am. Chem. Soc. 2022, 144, 15118– 15131, DOI: 10.1021/jacs.2c04577
  16a
  Mechanistic Investigations into Amination of Unactivated Arenes via Cation Radical Accelerated Nucleophilic Aromatic Substitution
  Pistritto, Vincent A.; Liu, Shubin; Nicewicz, David A.
  Journal of the American Chemical Society (2022), 144 (33), 15118-15131CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A mechanistic investigation into the amination of electron-neutral and electron-rich arenes using org. photoredox catalysis is presented. Kinetic and computational data support rate-limiting nucleophilic addn. into an arene cation radical using both azole and primary amine nucleophiles. This finding is consistent with both fluoride and alkoxide nucleofuges, supporting a unified mechanistic picture using cation radical accelerated nucleophilic arom. substitution (CRA-SNAr). Electrochem. and time-resolved fluorescence spectroscopy confirm the key role solvents play in enabling selective arene oxidn. in the presence of amines. The synthetic limitations of xanthylium salts are elucidated via photophys. studies. An alternative catalyst scaffold with improved turnover nos. is presented.
  (b) Huang, H.; Lambert, T. H. Electrophotocatalytic SNAr Reactions of Unactivated Aryl Fluorides at Ambient Temperature and Without Base. Angew. Chem., Int. Ed. 2020, 59, 658– 662, DOI: 10.1002/anie.201909983
  16b
  Electrophotocatalytic SNAr Reactions of Unactivated Aryl Fluorides at Ambient Temperature and Without Base
  Huang, He; Lambert, Tristan H.
  Angewandte Chemie, International Edition (2020), 59 (2), 658-662CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The electrophotocatalytic SNAr reaction of unactivated aryl fluorides at ambient temp. without strong base is demonstrated.
  (c) Sheng, H.; Liu, Q.; Zhang, B.-B.; Wang, Z.-X.; Chen, X.-Y. Visible-Light-Induced N-Heterocyclic Carbene-Catalyzed Single Electron Reduction of Mono-Fluoroarenes. Angew. Chem., Int. Ed. 2023, 62, e202218468 DOI: 10.1002/anie.202218468
  There is no corresponding record for this reference.
  (d) Wu, S.; Schiel, F.; Melchiorre, P. A General Light-Driven Organocatalytic Platform for the Activation of Inert Substrates. Angew. Chem., Int. Ed. 2023, 62, e202306364 DOI: 10.1002/anie.202306364
  16d
  A General Light-Driven Organocatalytic Platform for the Activation of Inert Substrates
  Wu, Shuo; Schiel, Florian; Melchiorre, Paolo
  Angewandte Chemie, International Edition (2023), 62 (32), e202306364CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A readily available indole thiolate organocatalyst that, upon excitation with 405 nm light, acquires a strongly reducing power was reported. This excited-state reactivity served to activate, by single-electron redn., strong C-F, C-Cl, and C-O bonds in both arom. and aliph. substrates. This catalytic platform was versatile enough to promote the redn. of generally recalcitrant electron-rich substrates (Ered<-3.0 V vs SCE), including arenes that afforded 1,4-cyclohexadienes. The protocol was also useful for the borylation and phosphorylation of inert substrates with a high functional group tolerance. Mechanistic studies identified an excited-state thiolate anion as responsible of the highly reducing reactivity.
17. 17
  Schwesinger, R.; Schlemper, H. Peralkylated Polyaminophosphazenes─ Extremely Strong, Neutral Nitrogen Bases. Angew. Chem., Int. Ed. 1987, 26, 1167– 1169, DOI: 10.1002/anie.198711671
  There is no corresponding record for this reference.
18. 18
  Puleo, T. R.; Sujansky, S. J.; Wright, S. E.; Bandar, J. S. Organic Superbases in Recent Synthetic Methodology Research. Chem. - Eur. J. 2021, 27, 4216– 4229, DOI: 10.1002/chem.202003580
  18
  Organic Superbases in Recent Synthetic Methodology Research
  Puleo, Thomas R.; Sujansky, Stephen J.; Wright, Shawn E.; Bandar, Jeffrey S.
  Chemistry - A European Journal (2021), 27 (13), 4216-4229CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. Recent applications of com. org. superbases in modern synthetic methodologies were discussed. Examples of the advantages of org. superbases in three areas were highlighted, including the discovery of new base-catalyzed reactions, the optimization of reactions that require stoichiometric Bronsted base, and in high-throughput experimentation technol.
19. 19
  (a) Mamdani, H. T.; Hartley, R. C. Phosphazene bases and the anionic oxy-Cope rearrangement. Tetrahedron Lett. 2000, 41, 747– 749, DOI: 10.1016/S0040-4039(99)02123-1
  19a
  Phosphazene bases and the anionic oxy-Cope rearrangement
  Mamdani, Hassan T.; Hartley, Richard C.
  Tetrahedron Letters (2000), 41 (5), 747-749CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)
  Compds. contg. a 1,5-hexadien-3-ol system undergo anionic oxy-Cope rearrangement when treated with the phosphazene super-base, P4-t-Bu. The [3,3] sigmatropic rearrangement occurs in hexane as well as in THF. The weaker phosphazene base, P2-Et, fails to induce rearrangement. This is the first example of the use of a metal-free base to induce anionic oxy-Cope rearrangement.
  (b) Seebach, D.; Beck, A. K.; Studer, A. Modern Synthetic Methods; Ernst, B.; Leumann, C., Eds.; VCH: Weinheim, 1995; Vol. 7.
  There is no corresponding record for this reference.
20. 20
  (a) Shigeno, M.; Hayashi, K.; Nozawa-Kumada, K.; Kondo, Y. Phosphazene Base tBu-P4 Catalyzed Methoxy–Alkoxy Exchange Reaction on (Hetero)Arenes. Chem. - Eur. J. 2019, 25, 6077– 6081, DOI: 10.1002/chem.201900498
  20a
  Phosphazene Base tBu-P4 Catalyzed Methoxy-Alkoxy Exchange Reaction on (Hetero)Arenes
  Shigeno, Masanori; Hayashi, Kazutoshi; Nozawa-Kumada, Kanako; Kondo, Yoshinori
  Chemistry - A European Journal (2019), 25 (24), 6077-6081CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The org. superbase tBu-P4 catalyzed methoxy-alkoxy exchange reactions on (hetero)arenes with alcs was reported. The catalytic reaction proceeded efficiently with electron-deficient methoxy(hetero)arenes as well as with a variety of alcs., including 3-amino-1-propanol, β-citronellol, menthol and cholesterol. An intramol. version of this reaction furnished six- and seven-membered ring compds.
  (b) Shigeno, M.; Hayashi, K.; Nozawa-Kumada, K.; Kondo, Y. Organic Superbase t-Bu-P4 Catalyzes Amination of Methoxy(hetero)arenes. Org. Lett. 2019, 21, 5505– 5508, DOI: 10.1021/acs.orglett.9b01805
  20b
  Organic Superbase t-Bu-P4 Catalyzes Amination of Methoxy(hetero)arenes
  Shigeno, Masanori; Hayashi, Kazutoshi; Nozawa-Kumada, Kanako; Kondo, Yoshinori
  Organic Letters (2019), 21 (14), 5505-5508CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  We report that the org. superbase t-Bu-P4 efficiently catalyzes the amination of methoxy(hetero)arenes with amine nucleophiles such as aniline, indoline, and aminopyridine derivs. This catalytic reaction is effective for the transformation of electron-deficient methoxyarenes possessing diverse functionalities (carbonyl, cyano, nitro, and halogen) as well as methoxyheteroarenes, including pyrazine, quinoline, isoquinoline, and pyridine derivs. Intramol. reactions provide six- and seven-membered ring cyclic amine products.
  (c) Shigeno, M.; Hayashi, K.; Nozawa-Kumada, K.; Kondo, Y. Catalytic C(sp²)–C(sp³) Bond Formation of Methoxyarenes by the Organic Superbase t-Bu-P4. Org. Lett. 2020, 22, 9107– 9113, DOI: 10.1021/acs.orglett.0c03507
  20c
  Catalytic C(sp2)-C(sp3) Bond Formation of Methoxyarenes by the Organic Superbase t-Bu-P4
  Shigeno, Masanori; Hayashi, Kazutoshi; Nozawa-Kumada, Kanako; Kondo, Yoshinori
  Organic Letters (2020), 22 (22), 9107-9113CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  The org. superbase catalyst t-Bu-P4 achieves nucleophilic arom. substitution of methoxyarenes with alkanenitrile pronucleophiles. A variety of functional groups [cyano, nitro, (non)enolizable ketone, chloride, and amide moieties] are allowed on methoxyarenes. Moreover, an array of alkanenitriles with/without an aryl moiety at the nitrile α-position can be employed. The system also features no requirement of a stoichiometric base, MeOH (not salt waste) formation as a byproduct, and the prodn. of congested quaternary carbon centers.
  (d) Shigeno, M.; Hayashi, K.; Korenaga, T.; Nozawa-Kumada, K.; Kondo, Y. Organic superbase t-Bu-P4-catalyzed demethylations of methoxyarenes. Org. Chem. Front. 2022, 9, 3656– 3663, DOI: 10.1039/D2QO00483F
  20d
  Organic superbase t-Bu-P4-catalyzed demethylations of methoxyarenes
  Shigeno, Masanori; Hayashi, Kazutoshi; Korenaga, Toshinobu; Nozawa-Kumada, Kanako; Kondo, Yoshinori
  Organic Chemistry Frontiers (2022), 9 (14), 3656-3663CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)
  The org. superbase t-Bu-P4 catalyzes the demethylation reactions of methoxyarenes ROMe [R = 4-cyanophenyl, 1-oxo-2,3-dihydro-1H-inden-5-yl, 1-benzothiophen-5-yl, etc.] in the presence of alkanethiol and hexamethyldisilazane was reported. The system can efficiently convert a variety of substrates, including electron-deficient, -neutral, and -rich substrates and heteroarom. substrates, and displays excellent functional group tolerance. Computational studies show that the high reactivity achieved by t-Bu-P4 is due to the formation of the nucleophilic naked thiolate species.
21. 21
  (a) Ueno, M.; Hori, C.; Suzawa, K.; Ebisawa, M.; Kondo, Y. Catalytic Activation of Silylated Nucleophiles Using tBu-P4 as a Base. Eur. J. Org. Chem. 2005, 2005, 1965– 1968, DOI: 10.1002/ejoc.200500087
  There is no corresponding record for this reference.
  (b) Ueno, M.; Yonemoto, M.; Hashimoto, M.; Wheatley, A. E. H.; Naka, H.; Kondo, Y. Nucleophilic aromatic substitution using Et₃SiH/cat. t-Bu-P4 as a system for nucleophile activation. Chem. Commun. 2007, 2264– 2266, DOI: 10.1039/b700140a
  21b
  Nucleophilic aromatic substitution using Et3SiH/cat. t-Bu-P4 as a system for nucleophile activation
  Ueno, Masahiro; Yonemoto, Misato; Hashimoto, Masahiro; Wheatley, Andrew E. H.; Naka, Hiroshi; Kondo, Yoshinori
  Chemical Communications (Cambridge, United Kingdom) (2007), (22), 2264-2266CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  A novel type of deprotonative arylation of nucleophiles was conducted using Et3SiH/cat. t-Bu-P4 and the powerful SNAr reactions of aryl fluorides were accomplished using alcs. and malonates as nucleophiles.
22. 22
  (a) Okachi, T.; Fujimoto, K.; Onaka, M. Practical Carbonyl-Ene Reactions of α-Methylstyrenes with Paraformaldehyde Promoted by a Combined System of Boron Trifluoride and Molecular Sieves 4A. Org. Lett. 2002, 4, 1667– 1669, DOI: 10.1021/ol025719l
  22a
  Practical Carbonyl-Ene Reactions of α-Methylstyrenes with Paraformaldehyde Promoted by a Combined System of Boron Trifluoride and Molecular Sieves 4A
  Okachi, Takahiro; Fujimoto, Katsuhiko; Onaka, Makoto
  Organic Letters (2002), 4 (10), 1667-1669CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  A combined system of boron trifluoride and mol. sieves is an efficient promoter for the carbonyl-ene reaction of α-methylsyrenes with paraformaldehyde. The coexistence of BF3·OEt2 and mol. sieves 4A is essential for obtaining high yields of ene products.
  (b) Ono, F.; Ohta, Y.; Hasegawa, M.; Kanemasa, S. Molecular sieve 4 Å generates nitrile oxides from hydroximoyl chlorides. Development of catalyzed enantioselective nitrile oxide cycloadditions to monosubstituted alkenes. Tetrahedron Lett. 2009, 50, 2111– 2114, DOI: 10.1016/j.tetlet.2009.02.178
  22b
  Molecular sieve 4 Å generates nitrile oxides from hydroximoyl chlorides. Development of catalyzed enantioselective nitrile oxide cycloadditions to monosubstituted alkenes
  Ono, Fumiyasu; Ohta, Yasuaki; Hasegawa, Masayuki; Kanemasa, Shuji
  Tetrahedron Letters (2009), 50 (18), 2111-2114CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
  The effective generation of nitrile oxide 1,3-dipoles from hydroximoyl chlorides can be achieved with powd. mol. sieves 3 Å and 4 Å as mild solid bases. Rate of nitrile oxide generation depends upon the choice of reaction solvents, among which alcs. are the best media. A catalytic process is achieved by use of a catalytic amt. of amine in the presence of MS 4 Å leading to the amine-catalytic generation of nitrile oxides. This new synthetic method can be applied to the catalytic enantioselective nitrile oxide 1,3-dipolar cycloaddn. reactions with monosubstituted alkenes.
  (c) Shigeno, M.; Shishido, Y.; Soga, A.; Nozawa-Kumada, K.; Kondo, Y. Defluorinative Transformation of (2,2,2-Trifluoroethyl)arenes Catalyzed by the Phosphazene Base t-Bu-P2. J. Org. Chem. 2023, 88, 1796– 1802, DOI: 10.1021/acs.joc.2c02034
  There is no corresponding record for this reference.
23. 23
  (a) Bordwell, F. G.; Van der Puy, M.; Vanier, N. R. Carbon acids. 9. The effects of divalent sulfur and divalent oxygen on carbanion stabilities. J. Org. Chem. 1976, 41, 1885– 1886, DOI: 10.1021/jo00872a050
  23a
  Carbon acids. 9. The effects of divalent sulfur and divalent oxygen on carbanion stabilities
  Bordwell, F. G.; Van der Puy, Michael; Vanier, Noel R.
  Journal of Organic Chemistry (1976), 41 (10), 1885-6CODEN: JOCEAH; ISSN:0022-3263.
  The effect of replacement of Me or Me3C by Me3N+ on equil. acidities in Me2SO in the C acid systems MeCH2CN, MeCH2SO2Ph, MeCH2COPh, and 9-tert-butylfluorene are used to est. the size of the polar effect. The ρ values estd. from these results (ΔpK = σρ) are used, in combination with the σ values for MeO, PhO, MeS, and PhS groups, to est. the polar effects of these groups. For the MeO and PhO groups, the acidifying effects obsd. are in every instance smaller than those calcd. for polar effects. This is attributed to a destabilizing effect in the anion caused by lone pair-lone pair repulsions in the carbanions. For MeS and PhS groups the acidifying effects obsd. are in every instance much larger than the calcd. values. This cannot be attributed solely to the polarizability of S; conjugative stabilization of α carbanions by divalent S appears to be significant.
  (b) Bordwell, F. G.; Bartmess, J. E.; Hautala, J. A. Alkyl effects on equilibrium acidities of carbon acids in protic and dipolar aprotic media and the gas phase. J. Org. Chem. 1978, 43, 3095– 3101, DOI: 10.1021/jo00410a001
  23b
  Alkyl effects on equilibrium acidities of carbon acids in protic and dipolar aprotic media and the gas phase
  Bordwell, F. G.; Bartmess, John E.; Hautala, Judith A.
  Journal of Organic Chemistry (1978), 43 (16), 3095-101CODEN: JOCEAH; ISSN:0022-3263.
  The effects on acidity of substitution of Me or H at C in 28 weak acids are divided into 4 types: (a) acid-weakening hyperconjugative and polar Me effects; (b) acid-strengthening hyperconjugative Me effects (on ketones, nitroalkanes and 9-methylfluorene); (c) acid-weakening polar Me effects (on sulfones and nitriles); and (d) acid-weakening steric Me effects. Decreasing acidities of nitroalkanes RCH2NO2 (R = Me, Et, Me2CH, CMe3) were alike in 50% aq. MeOH and Me2SO. These alkyl effects are the result of a complex blend of hyperconjugative, polar, polarizability and steric effects. Ph and vinyl groups exhibit substantial conjugative effects which are larger in Me2SO than in aq. MeOH. The cyclopropyl group exhibits no observable conjugative effect in the RCH:NO2- anion (R = cyclopropyl). Substitution of R for H in RCH2NO2 produces, for the most part, the same relative effects as obsd. for substitution of R for H in HCH2NO3. However, substitution of cyclopropyl for H in HCH2NO2 and MeCH2NO2 is acid strengthening, whereas substitution of cyclopropyl for H in RCH2NO2 (R = cyclopropyl) is acid weakening.
  (c) Bordwell, F. G.; Drucker, G. E.; Fried, H. E. Acidities of carbon and nitrogen acids: the aromaticity of the cyclopentadienyl anion. J. Org. Chem. 1981, 46, 632– 635, DOI: 10.1021/jo00316a032
  23c
  Acidities of carbon and nitrogen acids: the aromaticity of the cyclopentadienyl anion
  Bordwell, Frederick G.; Drucker, George E.; Fried, Herbert E.
  Journal of Organic Chemistry (1981), 46 (3), 632-5CODEN: JOCEAH; ISSN:0022-3263.
  The equil. acidities in Me2SO of 1,3-cyclopentadiene, indene, and fluorene decrease in that order, the pKa values being 18.0, 20.1, and 22.6, resp., whereas those of the corresponding nitrogen acids, pyrrole, indole, and carbazole, change in the opposite order, the pKa values being 23.05, 20.95, and 19.90, resp. These pKa values, together with approx. intrinsic acidities of carbon vs. nitrogen acids, are used to est. arom. stabilization energies of 26, 20, and 14.5 kcal/mol for the cyclopentadienyl, indenyl, and fluorenyl anions, resp. Other ests. based on acidity data give values of 24 and 27 kcal/mol for the arom. stabilization energy of the cyclopentadienyl anion.
  (d) Bordwell, F. G.; Cheng, J.-P.; Ji, G.-Z.; Satish, A. V.; Zhang, X. Bond dissociation energies in DMSO related to the gas phase values. J. Am. Chem. Soc. 1991, 113, 9790– 9795, DOI: 10.1021/ja00026a012
  23d
  Bond dissociation energies in DMSO related to the gas phase values
  Bordwell, F. G.; Cheng, Jinpei; Ji, Guo Zhen; Satish, A. V.; Zhang, Xianman
  Journal of the American Chemical Society (1991), 113 (26), 9790-5CODEN: JACSAT; ISSN:0002-7863.
  Ests. have been made of the homolytic bond dissocn. energies (BDEs) for (a) the benzylic or allylic H-C bonds in 14 hydrocarbons, (b) the acidic H-C bonds in 12 hydrocarbons contg. one or more heteroatoms, and (c) the H-N bonds in five nitrogen acids as well as thiophenol and phenol. For the 18 compds. where literature gas-phase values were available, agreement to within ±2 kcal/mol was obsd. for all but three (Ph3CH, PhNH2, and PhOH). For Ph3CH and PhNH2, the literature values were shown to be in error. For the BDEs of the acidic H-A bonds in 17 compds., error limits of ±2 kcal/mol, or better, were established from BDE ests. made for three or more derivs. in which remote substituents were placed on the benzene ring of the parent compd. In all, the BDEs of the acidic H-A bonds of 32 compds. have been established to ±2 kcal/mol or better.
24. 24
  (a) Eliel, E. L.; Wilen, S. H.; Doyle, M. P. Basic Organic Stereochemistry; Wiley: New York, 2001.
  There is no corresponding record for this reference.
  (b) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley: New York, 1994.
  There is no corresponding record for this reference.
25. 25
  (a) Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.; Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.; McCollum, G. J.; Vanier, N. R. Equilibrium acidities of carbon acids. VI. Establishment of an absolute scale of acidities in dimethyl sulfoxide solution. J. Am. Chem. Soc. 1975, 97, 7006– 7014, DOI: 10.1021/ja00857a010
  25a
  Equilibrium acidities of carbon acids. VI. Establishment of an absolute scale of acidities in dimethyl sulfoxide solution
  Matthews, Walter S.; Bares, Joseph E.; Bartmess, John E.; Bordwell, F. G.; Cornforth, Frederick J.; Drucker, George E.; Margolin, Zafra; McCallum, Robert J.; McCollum, Gregory J.; Vanier, Noel R.
  Journal of the American Chemical Society (1975), 97 (24), 7006-14CODEN: JACSAT; ISSN:0002-7863.
  An accurate spectrophotometric method of detg. relative equil. acidities of C acids in Me2SO was developed; the pK scale was anchored by comparisons of values obtained by the spectrophotometric method with those obtained potentiometrically in the 8 to 11 pK range. The pK's were correlated with heats of deprotonation by K dimisyl, and evidence was presented to show that the pK measurements were free from ion assocn. effects. C acids wherein the charge on the anion resides mainly on O, such as ketones and nitroalkanes, were weaker Me2SO than in H2O by 5.5 to 9.6 pK units, while C acids wherein the charge on the anion is delocalized over a large hydrocarbon matrix, such as in the anion derived from 9-cyanofluorene were stronger acids in Me2SO than in H2O. A list of 13 indicators covering the pK range 8.3 to 30.6 in Me2SO was given.
  (b) Zhang, X. M.; Bordwell, F. G.; Van Der Puy, M.; Fried, H. E. Equilibrium Acidities and Homolytic Bond Dissociation Energies of the Acidic Carbon-Hydrogen Bonds in N-Substituted Trimethylammonium and Pyridinium Cations. J. Org. Chem. 1993, 58, 3060– 3066, DOI: 10.1021/jo00063a026
  25b
  Equilibrium acidities and homolytic bond dissociation energies of the acidic carbon-hydrogen bonds in N-substituted trimethylammonium and pyridinium cations
  Zhang, Xian Man; Bordwell, Frederick G.; Van Der Puy, Michael; Fried, Herbert E.
  Journal of Organic Chemistry (1993), 58 (11), 3060-6CODEN: JOCEAH; ISSN:0022-3263.
  Equil. acidities (pKHA) of the cations in 16 N-substituted trimethylammonium salts, one N-phenacylquinuclidinium salt, 8 N-substituted pyridinium salts, and N-(ethoxycarbonyl)isoquinolinium bromide, together with the oxidn. potentials of their conjugate bases, have been detd. in Me2SO. The acidifying effects of the α-trimethylammonium groups (α-Me3N+) and the α-pyridinium groups (α-PyN+) on the adjacent acidic C-H bonds in these cations were found to av. about 10 and 18 pKHA units, resp. The homolytic bond dissocn. energies of the acidic C-H bonds in these cations, estd. by the combination of the equil. acidities with the oxidn. potentials of their corresponding conjugate bases (ylides), show that the α-trimethylammonium groups destabilize adjacent radicals by 2-6 kcal/mol, whereas α-pyridinium groups stabilize adjacent radicals by 3-6 kcal/mol. The effects of α-pyridinium groups on the stabilization energies of the radicals derived from these cations were ca. 4-10 kcal/mol smaller than those of the corresponding Ph groups, whereas their effects on the equil. acidities of the cations were 5.4-13.1 pKHA units larger. The pKHA value of tetramethylammonium cation (Me4N+) was estd. by extrapolation to be about 42 in Me2SO.
26. 26
  Yang, X.; Fleming, F. F. C- and N-Metalated Nitriles: The Relationship Between Structure and Selectivity. Acc. Chem. Res. 2017, 50, 2556– 2568, DOI: 10.1021/acs.accounts.7b00329
  26
  C- and N-Metalated Nitriles: The Relationship between Structure and Selectivity
  Yang, Xun; Fleming, Fraser F.
  Accounts of Chemical Research (2017), 50 (10), 2556-2568CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
  A review. Metalated nitriles are exceptional nucleophiles capable of forging highly hindered stereocenters in cases where enolates are unreactive. The excellent nucleophilicity emanates from the powerful inductive stabilization of adjacent neg. charge by the nitrile, which has a miniscule steric demand. Inductive stabilization is the key to understanding the reactivity of metalated nitriles because this permits a continuum of structures that range from N-metalated ketenimines to nitrile anions. Soln. and solid-state analyses reveal two different metal coordination sites, the formally anionic carbon and the nitrile nitrogen, with the site of metalation depending intimately on the solvent, counterion, temp., and ligands. The most commonly encountered structures, C- and N-metalated nitriles, have either sp3 or sp2 hybridization at the nucleophilic carbon, which essentially translates into two distinct organometallic species with similar but nonidentical stereoselectivity, regioselectivity, and reactivity preferences. The hybridization differences are particularly important in SNi displacements of cyclic nitriles because the orbital orientations create very precise trajectories that control the cyclization selectivity. Harnessing the orbital differences between C- and N-metalated nitriles allows selective cyclization to afford nitrile-contg. cis- or trans-hydrindanes, decalins, or bicyclo[5.4.0]undecanes. Similar orbital constraints favor preferential SNi displacements with allylic electrophiles on sp3 centers over sp2 centers. The strategy permits stereoselective displacements on secondary centers to set contiguous tertiary and quaternary stereocenters or even contiguous vicinal quaternary centers. Stereoselective alkylations of acyclic nitriles are inherently more challenging because of the difficulty in creating steric differentiation in a dynamic system with rotatable bonds. However, judicious substituent placement of vicinal di-Me groups and a trisubstituted alkene sufficiently constrains C- and N-metalated nitriles to install quaternary stereocenters with excellent 1,2-induction. The structural differences between C- and N-metalated nitriles permit a rare series of chemoselective alkylations with bifunctional electrophiles. C-Magnesiated nitriles preferentially react with carbonyl electrophiles, whereas N-lithiated nitriles favor SN2 displacement of alkyl halides. The chemoselective alkylations potentially provide a strategy for late-stage alkylations of polyfunctional electrophiles en route to bioactive targets. In this Account, the bonding of metalated nitriles is summarized as a prelude to the different strategies for selectively prepg. C- and N-metalated nitriles. With this background, the Account then transitions to applications in which C- or N-metalated nitriles allow complementary diastereoselectivity in alkylations and arylations, and regioselective alkylations and arylations, with acyclic and cyclic nitriles. In the latter sections, a series of regiodivergent cyclizations are described that provide access to cis- and trans-hydrindanes and decalins, structural motifs embedded within a plethora of natural products. The last section describes chemoselective alkylations and acylations of C- and N-metalated nitriles that offer the tantalizing possibility of selectively manipulating functional groups in bioactive medicinal leads without recourse to protecting groups. Collectively, the unusual reactivity profiles of C- and N-metalated nitriles provide new strategies for rapidly and selectively accessing valuable synthetic precursors.
27. 27
  Thiolation and phosphination reactions proceeded at lower reaction temperatures compared to etherification and amination reactions. This is presumably due to the higher acidities of thiol and phosphine nucleophiles, which facilitate the generation of anionic species more efficiently, as well as their higher HOMO levels, which contribute to increased nucleophilicity.
  There is no corresponding record for this reference.
28. 28
  The attempts were made using electron-deficient 4-fluoronitrobenzene (see the Supporting Information). The absence of the Meisenheimer intermediate suggests that the CS_NAr reaction process might also be involved in the reactions of electron-deficient substrates, although the stepwise addition and elimination processes cannot be entirely excluded.
  There is no corresponding record for this reference.
29. 29
  Mauksch, M.; Tsogoeva, S. B. Hückel and Möbius Aromaticity in Charged Sigma Complexes. Chem. - Eur. J. 2019, 25, 7457– 7462, DOI: 10.1002/chem.201900849
  29
  H.ovrddot.uckel and M.ovrddot.obius Aromaticity in Charged Sigma Complexes
  Mauksch, Michael; Tsogoeva, Svetlana B.
  Chemistry - A European Journal (2019), 25 (31), 7457-7462CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  In sigma complexes, intermediates in nucleophilic and electrophilic arom. substitution and other reactions, delocalization in the arom. ring is formally disrupted. Unexpectedly, computational evidence is presented that favorable processes contain arom. sigma complexes. Tetracoordinated carbon therein surprisingly employs orbitals that are more similar to sp2 than to sp3 hybrids in sigma bonds with adjacent ring atoms. Both leaving groups and nucleo- or electrophiles may donate electrons to the π-system depending on the availability of p-type orbitals to fulfill H.ovrddot.uckel (4+2) or M.ovrddot.obius (4N) rules of aromaticity in analogy to conjugated transition-metal metallacycles.
Supporting Information
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.4c09042.
- Reaction of 3-fluoro-4-methoxybenzonitrile (12) and 2a (Scheme S1); effects of base additives in the reaction conditions of 1a and 2a (Table S1); effects of base catalysts in the reaction conditions of 1a and 2a (Table S2); reactions of (pseudo)halobenzenes (16) and 2a (Table S3); reactions of 1a and carbon nucleophiles other than alkyl cyanide (Table S4); optimization of the reaction conditions of 1a and heteroatom nucleophiles (Tables S5–S11); Hammet analysis (Figures S1 and S2 and Table S12); details for NICS_zz-scan of 1v, Int-2, TS-1, Int-6, and TS-2 (Figure S3); natural bond orbital (NBO) analysis of TS-1 (Figure S4); noncovalent interaction analyses of Int-1 and Int-5 (Figure S5); experimental procedures and spectra data for obtained products, and ¹H, ¹³C, ¹⁹F, and ³¹P NMR spectra (PDF)
- ja4c09042_si_001.pdf (19.23 MB)
Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Catalytic Concerted SNAr Reactions of Fluoroarenes by an Organic SuperbaseClick to copy article linkArticle link copied!

Journal of the American Chemical Society

License Summary*

Abstract

License Summary*

License Summary*

License Summary*

Introduction

Figure 1

Results and Discussion

Reaction Development

Substrate Scope with Respect to Fluoroarenes

Figure 2

Substrate Scope with Respect to Alkyl Cyanides

Extension to Transformations with Heteroatom Nucleophiles

Figure 3

Synthetic Applications

Proposed Mechanism

Figure 4

Hammett Analysis

Density Functional Theory Calculations

Figure 5

Figure 6

Figure 7

Conclusions

Supporting Information

Terms & Conditions

Author Information

Acknowledgments

References

Cited By

Journal of the American Chemical Society

License Summary*

Article Views

Altmetric

Citations

Recommended Articles

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

References

Supporting Information

Supporting Information

Terms & Conditions

Catalytic Concerted S_NAr Reactions of Fluoroarenes by an Organic Superbase
Click to copy article linkArticle link copied!