Some Items of Interest to Process R&D Chemists and Engineers

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Terminal trisubstituted alkenyl boronates are highly important substrates in synthetic chemistry, with applications in a variety of useful transformations, including Suzuki–Miyaura cross-coupling, radical additions, and transition-metal-free cross-couplings. While various methodologies have been developed to synthesize trisubstituted alkenyl boronates, they typically require multiple steps and lack regioselectivity. Aggarwal and co-workers at the University of Bristol reported a simple protocol to convert terminal alkynes into trisubstituted alkenyl boronates ( Org. Lett. 2018, 20, 3136). The carboborations proceeded with high regio- and stereoselectivities and improved yields compared with previous approaches. The initial zirconium-catalyzed Negishi carboalumination with trimethylaluminum afforded an alkenyl alane, which was then reacted with i-PrOBin to afford the desired alkenyl boronate in high yield. The carboalumination proceeded faster and in higher yield with reagent-grade CH₂Cl₂ (∼500 ppm water), versus an anhydrous solvent. Alkynes bonded to primary, secondary, and even tertiary carbon centers reacted equally well. This one-pot protocol affords terminal trisubstituted alkenyl boronates generally in good yields from a broad range of nonactivated terminal alkynes.

Fused cyclic ketones are integral motifs in biologically active molecules. In particular, α-tetralones and their derivatives are important motifs in natural products and pharmaceuticals. Typically, different substitution patterns on the target molecules require redesign of the synthetic route. Hong and co-workers at Genentech reported a novel homoconjugate addition/decarboxylation Dieckmann annulation strategy that is both efficient and general ( J. Org. Chem. 2018, 83, 6225). The first step in the sequence is the formation of an aryl Grignard reagent by metal–halogen exchange of 2-iodoaryl esters and isopropylmagnesium chloride. This aryl organometallic, in the presence of copper(I) iodide–dimethyl sulfide complex, reacts with 1,1-cyclopropane diesters to afford the homoconjugate addition products in good to excellent yields. The resultant triesters are then cyclized under mild conditions with triethylamine/magnesium bromide to afford the corresponding β-keto esters. The best solvent for both steps was demonstrated experimentally to be 2-MeTHF. The additive 1,3-dimethyl-2-imidazolidinone (DMI) was found to improve the yield in the homoconjugate addition reaction. The key to the copper-mediated homoconjugate addition is the activation of both carbonyls of the target; monoesters, dinitriles, and nitrile esters were not effective substrates. The synthetic sequence was extended to include various heterocycles, including pyridine, indole, and benzothiophene. The reaction sequence generally affords good overall yields for a wide variety of substrates under mild conditions.

Azetidines are four-membered nitrogen-containing heterocycles that appear in a variety of natural products and pharmaceutical agents. 3-Substituted azetidines, in particular, are increasingly prevalent in medicinal chemistry as either linking fragments or rigidifying moieties. Despite the myriad uses for azetidines, methods for their synthesis and functionalization still lag behind approaches for their higher homologues (pyrrolidines and piperidines). Lopchuk and co-workers at the University of South Florida described a one-pot, gram-scale synthesis of protected 3-haloazetidines and their further functionalization ( ARKIVOC 2018, 2018 (iv), 195; DOI: 10.24820/ark.5550190.p010.549). 1-Azabicyclo[1.1.0]butane (ABB) was formed in situ and then ring-opened with a halide salt and an electrophile to form the protected 3-haloazetidines in good overall yields. The protected 3-cyano derivative was generated from the corresponding iodide. This nitrile could be hydrolyzed to the corresponding carboxylic acid or alkylated with various alkyl halides to form additional derivatives. Uniformly high yields were obtained in the various derivatization reactions. All of the reported syntheses were conducted on a minimum of gram scale to illustrate the utility of the methodology. All of the starting materials were commercially available. This methodology affords rapid access to a diverse range of protected 3-functionalized azetidines, which are finding increasing applications in medicinal chemistry.

The indole motif is one of the most prevalent heterocycles in natural products and drug molecules. The increasing interest in fluorinated indole derivatives toward drug discovery has led to the recent development of methods accessing trifluoromethylated indoles, an important class of trifluoromethylated heterocycles. Numerous synthetic methods for this class of heterocycles have been reported; however, they lack generality and regioselectivity. Tsui and co-workers at The Chinese University of Hong Kong described the novel regioselective preparation of 2-(trifluoromethyl)indoles ( Org. Lett. 2018, 20, 1676). The starting materials are readily accessible 2-alkynylanilines. The strategy relies on domino trifluoromethylation of the terminal alkyne followed by 5-endo-dig cyclization. The source of the trifluoromethyl moiety was Grushin’s fluoroform-derived CuCF₃. An electron-withdrawing group on the nitrogen atom facilitated the cyclization; in contrast, an −NHBn group afforded only alkynyl-CF₃ products. The addition of N,N,N′,N′-tetramethyl-1,2-ethylenediamine (TMEDA) was important to achieve high yields. Overall good yields were obtained; electron-donating substituents on the alkynylaniline generally afforded higher yields than electron-withdrawing substituents. When the reaction was performed at 80 °C, the corresponding 3-formyl-2-(trifluoromethyl)indoles were obtained in uniformly high yields. This synthetic methodology affords 2-(trifluoromethyl)indoles from readily accessible 2-alkynylanilines in good yields under very mild conditions.

The aldehyde group is a ubiquitous structural unit in biologically active compounds and organic functional materials and a key intermediate in chemical synthesis. Therefore, the development of direct C–H functionalization with an aldehyde group as a directing group is highly valuable. The transient directing group (TDG) strategy has recently been exploited for the construction of complex organic structures. Wang and co-workers at Northwest University in China described the development of a direct oxidative dehydrogenative arylation of benzaldehydes with arenes utilizing natural amino acids as TDGs ( Org. Lett. 2018, 20, 1794). Extensive screening of various amino acids identified the quaternary amino acid A as the most effective TDG. The bidentate chelation mode of the imine and carboxyl moieties in A was critical to the success of the reaction. The optimal reaction temperature was 60 °C. Electron-donating and electron-withdrawing substituents on the benzaldehyde were well-tolerated, and their reactivities did not exhibit a significant difference. Arenes bearing alkyl, ether, and halide substituents all reacted smoothly, affording the corresponding products in good yields. The TDG strategy was successfully exploited in the direct oxidative dehydrogenative arylation of benzaldehydes. The methodology featured mild reaction conditions, good functional group compatibility, and excellent regioselectivity.

An and co-workers reported an ammonia-free Birch reduction of aromatics and heteroaromatics utilizing sodium dispersion with the crown ether 15-crown-5 as a complexant ( Org. Lett. 2018, 20, 3439). The authors found that reacting a fine dispersion of sodium (5–10 μm) with 15-crown-5 in THF at 0 °C generated a solution of the electride salt, as confirmed by the intense blue color of the reaction mixture. This electride salt could be used to perform Birch-type reductions of aromatic systems upon addition of the substrate in IPA at 0 °C, generating 1,4-cyclohexadienes from benzenes as well as reducing benzannulated heteroaromatics and styrene derivatives. These reductions occur without the need for ammonia, strictly inert conditions, or cryogenic temperatures, making the protocol considerably more practical than the traditional Birch reduction. A protocol for the recovery and recycling of the crown ether is also described.

Yuan and Sigman reported the enantioselective relay heck arylation of enelactams to access α,β-unsaturated δ-lactams ( J. Am. Chem. Soc. 2018, 140, 6527). Enantiopure substituted lactams are important building blocks for a number of pharmaceutically active compounds, and the authors describe a novel method to access chiral δ-aryl lactams with high enantioselectivity through Pd(II)-catalyzed arylation with boronic acids. A catalytic Cu(II)/O₂ system was used to regenerate Pd(II) under the reaction conditions. The reaction results in a relay of the double bond around the lactam ring to give the more stable α,β-unsaturated lactams through successive migratory insertions and β-hydride eliminations. A wide variety of aromatics could be introduced onto six-membered lactams, including electron-rich and -poor boronic acids, although ortho substitution resulted in reduced enantioselectivity. Heteroaromatics could also be introduced, although again with reduced enantioselectivity. The corresponding seven-membered lactams also proved to be competent substrates as well as trisubstituted six-membered substrates, which generated the corresponding quaternary centers with excellent enantiocontrol.

Hülscher, Bera, and co-workers reported the double dehydrogenation of primary amines to nitriles catalyzed by a Ru(II) complex ( J. Am. Chem. Soc. 2018, 140, 8662). The presence of a β-protic pyrazole unit on the ligand was found to be key to the desired reactivity, and DFT calculations showed that the β-nitrogen facilitates proton/hydride transfer in the catalytic cycle. Aromatic and aliphatic primary amines were successfully dehydrogenated to give the corresponding nitriles in toluene at 70 °C when catalytic KOtBu was added. A nitrogen sweep was used to remove the released hydrogen, and reaction in a sealed tube resulted in poor conversion (<50%). The dehydrogenation of disubstituted amines resulted in the formation of N-alkyl imines. Oxidation of indoline to indole in high yield was also demonstrated.

Yu and co-workers reported the palladium(II)-catalyzed arylation of free carboxylic acids to access cyclopropane and amino acid derivatives with high enantiocontrol ( J. Am. Chem. Soc. 2018, 140, 6545). The combination of a chiral monoprotected diamine ligand with Pd(OAc)₂ allowed for enantioselective functionalization of prochiral cyclopropanecarboxylic acids and phthalyl-protected α,α-dimethylglycine with aryl and heteroaryl iodides. Although a moderate racemic background reaction was observed in the absence of ligand, the Pd/ligand combination was able to overcome this and afford significant enantioselectivity. Cyclopropanecarboxylic acids were generated as single cis diastereomers with excellent stereocontrol (≥90:10 er). α-Substituted cyclopropanes were also competent substrates, again generating cis diastereomers with consistently high stereocontrol (≥95:5 er). The amino acids proved to be more challenging, with lower enantioselectivities observed for electron-poor iodides (≥86:14 er). However, these studies show promise for the rapid generation of pharmaceutically relevant monomers without the need for carboxylic acid protection or the installation of a directing group that is typical of many C(sp³)–H functionalizations.

Chiral transition-metal-free catalysts for enantioselective catalytic transformations—“organocatalysts”—are often nucleophilic in nature and frequently operate by initially attacking a carbonyl, generating key reactive intermediates like enamines and imines. Recently, Yuan, Zhao, and co-workers reported a complementary approach wherein a chiral carbonyl-bearing catalyst activates an amine-bearing substrate and organizes a transition state leading to significant enantioinduction. In their report ( Science 2018, 360, 1438), an N-methyl-4-formylpyridinium salt bearing both axial and point chirality condenses with the tert-butyl ester of glycine hydrochloride, and the resulting activated imino glycine is easily deprotonated; the derived anion enters into enantioselective Mannich reactions with the N-phosphinoylamine cosubstrates. This set of events results in trans-α,β-diaminodihydrocinnamates and dihydrocinnamate-like products with excellent levels of diastereo- and enantiocontrol. The products may be selectively deprotected and provide facile access to chiral 1,2-diamines. More generally, this work paves the way for further advances with chiral carbonyl organocatalysts.

The formation of C–N bonds is an enduring research problem in synthetic organic chemistry whose history spans several decades. Nevertheless, despite the myriad advances made, new methods of broad utility continue to be invented. MacMillan and co-workers have reported the latest significant entry in this field, reporting on C–N bond formation catalyzed by Cu- and Ir-based catalysts under photoirradiation ( Nature 2018, 559, 83). The photocatalyst serves to reduce a mixed carboxy–Ir(III) complex, resulting in decarboxylation and free radical formation while also oxidizing Cu(I) to Cu(II). Independently, the Cu(II) in the system forms amido complexes with the amine substrate, and this complex, after intercepting the carbon-centered radical, undergoes reductive elimination to generate the product and regenerate Cu(I). The substrate scope is impressively broad, and numerous acidic azaheterocycles can be used as nucleophiles, as can other acidic nitrogen-based functionalities (anilines, sulfonamides, etc.). The methodology also tolerates a wide range of carboxylic acids, including those bearing sensitive functional groups.

Catellani’s finding three decades ago that norbornene could “walk” a Pd(II) center ortho to the initial site of palladium oxidative addition or metalation led to an explosion of interest in modulating the activity and regioselectivity of traditional and cutting-edge Pd-catalyzed transformations. In the latest advance in this still-burgeoning area, the Yu group has reported that a chiral norbornene cocatalyst can induce enantioselective C–H arylations and alkylations as well as the corresponding kinetic resolutions ( Nature 2018, 558, 581). The authors examined chiral strained alkenes based on norbornene as well as several chiral acidic additives to arrive at a reaction system capable of kinetically resolving functionalized diarylmethanes by either C–H arylation (with aryl iodide electrophiles) or alkylation (with alkyl iodide electrophiles); the desymmetrization is also effective on protected, symmetric homobenzylic amines. Finally, the authors also demonstrated kinetic resolution of unsymmetrical homobenzylic amines. While some stoichiometry values and the necessity for stoichiometric AgOAc may prevent immediate adoption on-scale, this study may represent the starting point for application.

While the attractiveness of Ni for catalysis of reactions typically catalyzed by Pd is virtually unquestioned, the fine mechanistic details of such transformations are only now beginning to be elucidated. Along these lines, Gómez-Bengoa, Burés, Martin, and co-workers have published a full article on the mechanism of C–Si bond formation starting from aryl pivalates; their work implicates a Ni–Ni dinuclear resting complex that undergoes disproportionation prior to productive transmetalation, reductive elimination, and regeneration of the resting complex ( J. Am. Chem. Soc. 2018, 140, 8771). The authors began by investigating the stoichiometric oxidative addition complexes derived from 1-naphthyl pivalate and either Ni(cod)₂/PCy₃ or [Ni(PCy₃)₂]₂(N₂) and found that the resulting product bears two Ni centers at a distance supporting a Ni–Ni interaction. With this complex isolated and structurally characterized by X-ray crystallography, the authors subjected the complex to a variety of stoichiometric reaction conditions. Their observations support the beneficial effect of fluoride additives for C–Si bond formation, argue for a disproportionation mechanism en route to transmetalation, and demonstrate the formation of monomeric Ni complexes when bidentate bisphosphines are used in lieu of monodentate monophosphines. Beyond these stoichiometric studies, the authors demonstrated the catalytic relevance of the oxidative addition complexes and performed detailed DFT calculations to further bolster their understanding of elementary events in the overall C–OC(O)t-Bu to C–Si transformation.

Despite the prevalence of aryl sulfonamides across numerous synthetic-chemistry-based fields, their synthesis is usually accomplished by the reaction of sulfonyl chlorides with amines. However, unless the sulfonyl chloride component is commercially available, it must be made through (harsh) chemical pathways. Now, Willis and co-workers have reported a new modular synthesis using arylboronic acids, DABSO, and amines ( J. Am. Chem. Soc. 2018, 140, 8781). The chemistry was specifically designed to be modular to have the greatest impact on medicinal chemistry and other areas where diverse sulfonamides would be desirable. Because their previous Pd-catalyzed variant proved ineffective with amine coupling partners, they switched to Cu-based catalysis. The method leverages the considerable commercial availability of arylboronic acids and secondary amines as well as the convenience of DABSO as a source of SO₂. Although the chemistry does not work with primary aliphatic amines, primary anilines are effective coupling partners. Overall, the chemistry is an exciting advance since sulfonamides have been made for decades following the same sulfonyl chloride-based protocol.

The groups of Duan and Li at Nankai University in China recently reported that a combination of sodium trifluoromethanesulfinate (Langlois’ reagent) and Mn(OAc)₃ (oxidant) mediates the addition of a CF₃ radical to C═C bonds ( J. Org. Chem. 2018, 83, 6015). The authors reported that optimum yields were obtained when 2 equiv of Langlois’ reagent and 2 equiv of Mn(OAc)₃·2H₂O were employed under mild reaction conditions (room temperature). Both di- and trisubstituted alkenes were well-tolerated, with yields of up to 78% achieved. In one example, the reaction was scaled up to a gram scale, and only a small drop in yield (72% → 63%) was observed (see the graphic). Analysis of the reaction conditions revealed a radical-based process that involves addition of a CF₃ radical to the double bond (Markovnikov-type addition). The authors reported a total of 36 successful examples.

Chen, Liu, Wu, and co-workers at Zhejiang University in China recently disclosed a route to synthesize α-amino oxime ethers ( J. Org. Chem. 2018, 83, 5999). The authors reported that with catalytic copper(I) iodide (10 mol %) and K₂CO₃ (1 equiv) in dichloroethane as the solvent, yields of up to 99% could be achieved. The method allows variation of the N-alkoxybenzamide, with a variety of aryl, heteroaryl, cycloalkyl, and alkyl functionalities tolerated under the reaction conditions. The reaction benefits from high atom economy as well as excellent regio- and stereoselectivity. In a single example, the reaction was scaled to a gram scale, and a 21% drop in yield was observed. The authors reported detailed control experiments (free radical trapping and nucleophilic agent trapping experiments) to support a postulated mechanistic cycle. The authors reported 27 examples with yields of up to 99% achieved.

Ritter and co-workers from the Max-Planck-Institute für Kohlenforschung in Germany have recently reported their findings on aromatic carbon–hydrogen fluorination utilizing novel palladium(II) complexes and a mild electrophilic fluorinating agent (either NFSI or Selectfluor) ( Nature 2018, 554, 511). The reaction conditions generate the active fluorine transfer species, a palladium(IV)–fluoride complex, that is then capable of fluorinating a broad range of aromatic substrates; aryl bromides/chlorides, sulfonamides, ketones, amides, and esters were well-tolerated. The method was also extended to the fluorination of key pharmaceuticals and agrochemicals that were otherwise inaccessible utilizing conventional fluorination techniques (e.g., F-butyl ciprofibrate). The authors highlight a single example in which the fluorination of 4-cyanobiphenyl can be conducted on a gram scale (with successful separation of ortho- and para-fluorinated products). The authors conducted several experiments to corroborate that the fluorinating species is a Pd^IV–F complex, including determination of the X-ray structure of this species, and performed DFT studies of the fluorination of chlorobenzene.

A recent report by the List group at the Max-Planck-Institute für Kohlenforschung in Germany showed that complex chiral Brønsted acid catalysts can be used to activate olefins to undergo asymmetric catalytic reactions, more specifically asymmetric intramolecular hydroalkoxylation of unbiased olefins ( Science 2018, 359, 1501). The chosen imidodiphosphorimidate (IDPi) catalysts provided both excellent reactivity and enantioselectivity. The optimum reaction conditions were found to be 5 mol % Brønsted acid catalyst with cyclohexane as the reaction solvent at an elevated temperature of 60 °C for a reaction time of 2 days. The scope of the reaction was found to be broad: over 20 examples were reported, with yields of up to 94% and enantiomeric ratios of up to 98.5:1.5 observed. The group proposed a catalytic cycle that was supported by additional experimental data, including DFT analysis.

While decomposition of formic acid into carbon dioxide and hydrogen in the presence of a variety of transition metals is well-known, the generation of carbon monoxide from this C1 source generally requires the use of a stoichiometric activator such as an anhydride or a carbodiimide. Beller and co-workers at Universität Rostock in Germany recently succeeded in developing a palladium-catalyzed carboxylation of aryl and benzyl halides using unmodified formic acid as a CO surrogate ( Angew. Chem., Int. Ed. 2018, 57, 6910). A carefully designed supporting ligand, L1, with a “built-in base” was found to be optimal for the planned reaction to take place. The optimal conditions for benzyl and aryl halides differ only in the amount of TMEDA used as the base. Worthy of note is the fact that aryl chlorides can be transformed efficiently into the corresponding acids, although with relatively large loadings of the catalyst and ligand compared with bromides. In the mechanism proposed by the authors, the palladium catalyst acts both to activate the carbon–halogen bond in the substrate and to enable the decomposition of formic acid.

The efficient construction of small heterocyclic fluorinated building blocks continues to be a major topic of interest for the synthetic community. Novák and co-workers at Eötvös University in Budapest described a new methodology for the synthesis of trifluoromethylated aziridines that expands for the first time the scope of substrates to nonaromatic amines ( Angew. Chem., Int. Ed. 2018, 57, 6643). For that purpose, the authors designed and synthesized trifluoropropenyl iodonium salts as new C2–CF₃ synthons. Under the best conditions, dichloromethane as the solvent with 2 equiv of sodium carbonate as the base, an array of substituted alkylamines as well as (hetero)arylamines were converted into trifluoromethylated aziridines in moderate to high yields. An impressive number of functional groups, including alcohols and unprotected anilines, are well-tolerated. DFT calculations were performed to provide insight into the mechanism of the reaction.

With only few exceptions, the cross-coupling of organozinc reagents with thioesters, known as Fukuyama coupling, is a palladium-catalyzed process. Fleischer and co-workers at Eberhard Karls Universität Tübingen were recently able to identify a nickel catalyst that promotes the reaction over a large range of substrates ( Chem.—Eur. J. 2018, 24, 8774). Initially focusing on finding a suitable ligand with nickel dichloride as the metal source, the optimization work led to the choice of Jamison Ni^II–Xantphos precatalyst C2 as optimal promoter for the reaction. The scope was demonstrated to be exceptionally large in terms of substrates, with a number of sensitive functional groups such as ketones and indole NH being well-tolerated. Mechanistic studies did not allow the authors to draw conclusions about the exact reaction pathway but led to the hypothesis of a classical two-valence-electron cross-coupling mechanism involving single electron transfer (SET) steps.

Reductive amination is a fundamental transformation in organic chemistry for which catalytic processes with low environmental impact are of interest. Taddei and co-workers at Università degli Studi di Siena in Italy recently developed a new protocol for this reaction that relies on the use of an iron catalyst and an isopropyl alcohol/water mixture as the hydrogen source ( Adv. Synth. Catal. 2018, 360, 2560). The optimal reaction conditions were found to require a combination of N,N-dimethylaminopyridine and sodium hydroxide in catalytic amounts (0.2 and 0.5 equiv, respectively). The developed methodology relies on the use of nonacarbonyldiiron as the catalyst under microwave heating, but the reaction can be carried out with the same level of efficiency under conventional heating by shifting to dodecacarbonyltriiron as the catalyst. Although only a restricted number of examples were provided, preventing a full assessment of the chemoselectivity of the protocol, the presence of a conjugated alkene is well-tolerated.

“Click chemistry” is a term that was introduced by Sharpless in 2001 and describes pairs of functional groups that rapidly and selectively react with each other under mild conditions. Sulfur(VI)–fluoride exchange (SuFEx) is a new embodiment of click chemistry that generates the sulfur(VI)–heteroatom linkage. Sulfuryl fluoride (SO₂F₂) was identified as a versatile SuFEx hub to selectively derivatize phenols to fluorosulfates in high yields. Although SO₂F₂ possesses ideal reactivity and selectivity as a SuFEx connector, it is a harmful gas and inconvenient to handle at laboratory scale. A team led by Sharpless and Dong at Shanghai Institute of Organic Chemistry in China discovered a stable fluorosulfuryl imidazolium salt as a new portal to SuFEx click chemistry ( Angew. Chem., Int. Ed. 2018, 57, 2605). The fluorosulfuryl imidazolium salt could be easily prepared in two steps, a reaction of 2-methylimidazole with SO₂F₂ followed by N-methylation with methyl trifluoromethanesulfonate. The salt melts at 58–60 °C, decomposes at 228 °C, and has a half-life of 30 min in deionized water. As a surrogate for SO₂F₂, this reagent can react with phenols in the presence of triethylamine to give the corresponding fluorosulfates and displays high reactivity toward primary and secondary amines to produce sulfonamides:

Indoline and its derivatives are important intermediates for the synthesis of pharmaceutically active compounds and natural products. Various methods have been developed to access such N-heterocycles, including transition-metal-catalyzed approaches. Recently, Wang and co-workers at Shandong University in China developed a transition-metal-free approach to synthesize indolines that utilizes an iodonium ylide as a novel cyclization agent ( Angew. Chem., Int. Ed. 2018, 57, 3792). Iodonium ylides are reactive species and can be employed as both nucleophiles and electrophiles to participate in a range of chemical transformations. The Wang research team found that iodonium ylide can activate the C(sp³)–H bond in tertiary arylamines via an SET process. In addition, the iodonium ylide reacts as a nucleophile in this process to couple with an iminium intermediate. The drawbacks of the method are the moderate indoline product yields and the requirement of 2 equiv of the iodonium ylide.

Radical cyclizations and subsequent hydrogen atom abstractions are frequently used to synthesize five- or six-membered-ring compounds. In contrast, cyclization via radical substitution reactions are rare; unlike ionic substitution reactions, radical substitutions have to proceed through a highly organized and less polar transition state. Knowing these challenges, a research team led by Zhang at Boston College in Massachusetts developed an enantioselective radical cyclization involving hydrogen atom abstraction followed by a radical substitution process ( J. Am. Chem. Soc. 2018, 140, 4792). This metalloradical catalysis was utilized to prepare various five-membered heterocyclic compounds in good yields with high enantioselectivity. For example, 2-arylpyrrolidines 1 and 2 were synthesized in 87% yield with 91% ee and 91% yield with 95% ee, respectively, while 2-(pyridin-3-yl)pyrrolidine 3 was obtained in 73% yield with 92% ee. Furthermore, other heterocycles such as phenyl-substituted tetrahydrothiophene 4 could also be prepared.

α-Alkylation of ketones is usually realized via S_N2 substitution with alkyl halides in the presence of a base. This reaction does have limitations, especially during the late-stage synthesis of active pharmaceutical ingredients (APIs) because of the (likely) genotoxicity of the alkyl halides. Control of genotoxic impurity levels in APIs can be a rather challenging task in the pharmaceutical industry. Shao, Zhu, and co-workers at Zhengzhou University in China developed a Ru(II)-catalyzed α-alkylation of ketones with alcohols ( J. Org. Chem. 2018, 83, 3657). This method avoids using the genotoxic alkyl halides, allowing alkylation of ketones without concerns about genotoxic impurities. This reaction is carried out with an NNN pincer–Ru(II) complex as the catalyst and alcohols as both the alkylation agent and hydrogen source for the subsequent 1,4-reduction of the α,β-unsaturated intermediates A. The NNN pincer–Ru(II) catalyst could be conveniently prepared in three steps: initial bromination of ketone with NBS, then cyclization with 2-aminopyridine, and finally cyclometalation with RuCl₂(Ph₃P)₃.

Pyridines are an important class of organic compounds in the design and synthesis of drug molecules, and therefore, the development of practical synthetic methods to access pyridine derivatives is of continuing interest to synthetic chemists. Pyridine N-oxides are stable organic compounds and often serve as synthetic intermediates. Miura and co-workers at Kyoto University in Japan disclosed a photocatalyzed ortho-alkylation of pyridine N-oxides using alkenes as the alkylation reagent ( Angew. Chem., Int. Ed. 2018, 57, 5139). This approach features mild reaction conditions with moderate to good product yields. This approach addresses the challenging regioselectivity issues during the alkylation of pyridines and was applied in the synthesis of ortho-alkylated pyridines with complex alkenes. For example, a commercially available phytyl acetate and propionate were successfully used to synthesize ortho-substituted pyridines in 31% and 41% yield, respectively. A drawback of this approach is the long reaction time.