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α,α-Diaryl primary amines are highly important chemical building blocks in agrochemical and pharmaceutical active ingredients. One of the limitations of current chromatographic methodologies for th...

The introduction of a trifluoromethyl (CF3) group can dramatically improve a compound’s biological properties. Despite the well-established importance of trifluoromethylated compounds, general methods for the trifluoromethylation of alkyl C–H bonds remain elusive. Here we report the development of a dual-catalytic C(sp3)–H trifluoromethylation through the merger of light-driven, decatungstate-catalysed hydrogen atom transfer and copper catalysis. This metallaphotoredox methodology enables the direct conversion of both strong aliphatic and benzylic C–H bonds into the corresponding C(sp3)–CF3 products in a single step using a bench-stable, commercially available trifluoromethylation reagent. The reaction requires only a single equivalent of substrate and proceeds with excellent selectivity for positions distal to unprotected amines. To demonstrate the utility of this new methodology for late-stage functionalization, we have directly derivatized a broad range of approved drugs and natural products to generate valuable trifluoromethylated analogues. Preliminary mechanistic experiments reveal that a ‘Cu–CF3’ species is formed during this process and the critical C(sp3)–CF3 bond-forming step involves the copper catalyst. Despite the importance of trifluoromethylated compounds, direct catalytic methods for the conversion of C(sp3)–H bonds into the corresponding C(sp3)–CF3 analogues have remained elusive. This transformation has now been achieved by the merger of copper catalysis with decatungstate photocatalysis, enabling the C(sp3)–H trifluoromethylation of abundant feedstocks, natural products and pharmaceuticals.

This Concept article highlights the development of a novel analytical tool, LED-NMR (a combination of in situ light illumination using a light-emitting diode and NMR spectroscopy) and its variant UVNMR (LED-NMR coupled with UV/Vis absorption spectroscopy), as well as their applications in the mechanistic investigation of light-induced transformations. The utility of these new tools has been demonstrated by providing rich kinetic and structural data of reaction species offering mechanistic insights into photochemical and photocatalytic reactions. Furthermore, NMR actinometry has been recently developed as a practical and simple method for quantum yield measurements. Quantum yield is an important parameter in photo-induced processes, but is rarely measured in practice because of the barriers associated with traditional actinometry. These new tools and techniques streamline measurements of the quantum efficiency while affording informative mechanistic insights into photochemical reactions. We anticipate these techniques will enable chemists to further advance the rapidly emerging photochemistry field.

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl3/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides., An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield.

Primary amines are an important structural motif in active pharmaceutical ingredients (APIs) and intermediates thereof, as well as members of ligand libraries for either biological or catalytic applications. Many chemical methodologies exist for amine synthesis, but the direct synthesis of primary amines with a fully substituted α carbon center is an underdeveloped area. We report a method which utilizes photoredox catalysis to couple readily available

Accessing hindered amines, particularly primary amines α to a fully substituted carbon center, is synthetically challenging. We report an electrochemical method to access such hindered amines starting from benchtop-stable iminium salts and cyanoheteroarenes. A wide variety of substituted heterocycles (pyridine, pyrimidine, pyrazine, purine, azaindole) can be utilized in the cross-coupling reaction, including those substituted with a halide, trifluoromethyl, ester, amide, or ether group, a heterocycle, or an unprotected alcohol or alkyne. Mechanistic insight based on DFT data, as well as cyclic voltammetry and NMR spectroscopy, suggests that a proton-coupled electron-transfer mechanism is operational as part of a hetero-biradical cross-coupling of α-amino radicals and radicals derived from cyanoheteroarenes.

Despite the widespread success of transition-metal-catalysed cross-coupling methodologies, considerable limitations still exist in reactions at sp3-hybridized carbon atoms, with most approaches relying on prefunctionalized alkylmetal or bromide coupling partners1,2. Although the use of native functional groups (for example, carboxylic acids, alkenes and alcohols) has improved the overall efficiency of such transformations by expanding the range of potential feedstocks3–5, the direct functionalization of carbon–hydrogen (C–H) bonds—the most abundant moiety in organic molecules—represents a more ideal approach to molecular construction. In recent years, an impressive range of reactions that form C(sp3)–heteroatom bonds from strong C–H bonds has been reported6,7. Additionally, valuable technologies have been developed for the formation of carbon–carbon bonds from the corresponding C(sp3)–H bonds via substrate-directed transition-metal C–H insertion8, undirected C–H insertion by captodative rhodium carbenoid complexes9, or hydrogen atom transfer from weak, hydridic C–H bonds by electrophilic open-shell species10–14. Despite these advances, a mild and general platform for the coupling of strong, neutral C(sp3)–H bonds with aryl electrophiles has not been realized. Here we describe a protocol for the direct C(sp3) arylation of a diverse set of aliphatic, C–H bond-containing organic frameworks through the combination of light-driven, polyoxometalate-facilitated hydrogen atom transfer and nickel catalysis. This dual-catalytic manifold enables the generation of carbon-centred radicals from strong, neutral C–H bonds, which thereafter act as nucleophiles in nickel-mediated cross-coupling with aryl bromides to afford C(sp3)–C(sp2) cross-coupled products. This technology enables unprecedented, single-step access to a broad array of complex, medicinally relevant molecules directly from natural products and chemical feedstocks through functionalization at sites that are unreactive under traditional methods. Direct coupling of aliphatic C–H nucleophiles to aryl electrophiles is described, through the combination of light-driven polyoxometalate hydrogen atom transfer and nickel catalysis.

The combination of nickel metallaphotoredox catalysis, hydrogen atom transfer catalysis, and a Lewis acid activation mode, has led to the development of an arylation method for the selective functionalization of alcohol α-hydroxy C-H bonds. This approach employs zinc-mediated alcohol deprotonation to activate α-hydroxy C-H bonds while simultaneously suppressing C-O bond formation by inhibiting the formation of nickel alkoxide species. The use of Zn-based Lewis acids also deactivates other hydridic bonds such as α-amino and α-oxy C-H bonds. This approach facilitates rapid access to benzylic alcohols, an important motif in drug discovery. A 3-step synthesis of the drug Prozac exemplifies the utility of this new method.

A simplified approach to quantum yield ([Formula: see text]) measurement using in situ LED NMR spectroscopy has been developed. The utility and performance of NMR actinometry has been demonstrated for the well-known chemical actinometers potassium ferrioxalate and o-nitrobenzaldehyde. A novel NMR-friendly actinometer, 2,4-dinitrobenzaldehyde, has been introduced for both 365 and 440 nm wavelengths. The method has been utilized successfully to measure the quantum yield of several recently published photochemical reactions.

A weak Bronsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C2-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating α,β-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4-dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues.

Getting phosphorus into healthy shape ProTide therapeutics play a trick on the body, getting nucleoside analogs where they need to be by decorating them with unnatural phosphoramidates in place of ordinary phosphates. These compounds pose an unusual synthetic challenge because their configuration must be controlled at phosphorus; most methods have been refined to manipulate the geometry of carbon. DiRocco et al. report a metal-free, small-molecule catalyst that attains high selectivity for nucleoside phosphoramidation by activating both reaction partners. Kinetic studies with an early prototype revealed a double role for the catalyst that inspired the rational design of a more active and selective dimeric structure. Science , this issue p. 426

The introduction of a trifluoromethyl (CF

The emergence of visible light photoredox catalysis has enabled the productive use of lower energy radiation, leading to highly selective reaction platforms. Polypyridyl complexes of iridium and ruthenium have served as popular photocatalysts in recent years due to their long excited state lifetimes and useful redox windows, leading to the development of diverse photoredox-catalyzed transformations. The low abundances of Ir and Ru in the earth's crust and, hence, cost make these catalysts nonsustainable and have limited their application in industrial-scale manufacturing. Herein, we report a series of novel acridinium salts as alternatives to iridium photoredox catalysts and show their comparability to the ubiquitous [Ir(dF-CF3-ppy)2(dtbpy)](PF6).

Over the past two decades, there have been major developments in transition metal-catalyzed aminations of aryl halides to form anilines, a common structure found in drug agents, natural product isolates, and fine chemicals. Many of these approaches have enabled highly efficient and selective coupling through the design of specialized ligands, which facilitate reductive elimination from a destabilized metal center. We postulated that a general and complementary method for carbon-nitrogen bond formation could be developed through the destabilization of a metal amido complex via photoredox catalysis, thus providing an alternative approach to the use of structurally complex ligand systems. Here, we report the development of a distinct mechanistic paradigm for aryl amination using ligand-free nickel(II) salts, in which facile reductive elimination from the nickel metal center is induced via a photoredox-catalyzed electron-transfer event., National Institutes of Health (U.S.) (Award GM58160), National Institutes of Health (U.S.) (Award RO1-GM078201-05), National Institutes of Health (U.S.) (Award GM113311)

We report the development of a method for room-temperature C-H hydroxymethylation of heteroarenes. A key enabling advance in this work was achieved by implementing visible light photoredox catalysis that proved to be applicable to many classes of heteroarenes and tolerant of diverse functional groups found in druglike molecules.

Elbasvir is a potent NS5A antagonist for the treatment of chronic hepatitis C. A seemingly trivial indoline oxidation en route to the target compound was complicated by epimerization of a stereogenic hemiaminal center under most standard oxidation conditions. To address this issue, a novel visible light photoredox process for indoline oxidation was developed involving an iridium photosensitizer and environmentally-benign perester oxidant. The reaction was discovered through a high-throughput experimentation campaign and the optimized process was demonstrated on 100 g scale in flow to afford a key intermediate towards the target compound. A battery of kinetic, electrochemical, and spectroscopic studies of this process indicates a radical chain mechanism of dehydrogenation involving selective HAT from the substrate by an alkoxy radicals. Notably, isotope effects were used to validate the chain mechanism when quantum yield data proved ambiguous.

Major new advances in synthetic chemistry methods are typically reported using simple, non-standardized reaction substrates, and reaction failures are rarely documented. This makes the evaluation and choice of a synthetic method difficult. We report a standardized complex molecule diagnostic approach using collections of relevant drug-like molecules which we call chemistry informer libraries. With this approach, all chemistry results, successes and failures, can be documented to compare and evolve synthetic methods. To aid in the visualization of chemistry results in drug-like physicochemical space we have used an informatics methodology termed principal component analysis. We have validated this method using palladium- and copper-catalyzed reactions, including Suzuki–Miyaura, cyanation and Buchwald–Hartwig amination.

INTRODUCTION The invention of new chemical reactions provides new bond construction strategies for improved access to diverse regions of structural space. However, a pervasive, long-standing bias toward reporting successful results means that the shortcomings of even mature reaction methods remain poorly defined, making practical syntheses of structurally diverse targets far from certain. Distinct tools and experimental approaches are required to expose and record the problematic structural elements that limit different synthetic methods. The experimental space required to systematically survey reaction failure is vast, and existing ultrahigh-throughput (uHT) reaction screening approaches are inadequate for exploring the diversity of conditions pertaining in modern synthetic methods. Additionally, analytical approaches must continuously improve to meet the throughput demands of this expansive reaction screening. RATIONALE We report a nanomole-scale screening protocol that can be used to execute heterogeneous reactions with heating and agitation, use of volatile solvents, and capacity for photoredox chemistry. These advances in miniaturized chemistry screening were combined with the use of matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry (MALDI-TOF MS), enabling analysis of 1536 reactions in ~10 min. Together, these advances create a platform that can enable systematic reaction evaluation and data capture to survey the dark space of chemical reactions. RESULTS Using the Buchwald-Hartwig C–N coupling reaction to exemplify this process, an uHT Glorius fragment additive poisons diagnostic approach was first applied to demonstrate that MALDI-MS could provide adequate data quality to monitor the formation of a single product under a wide variety of different synthetic conditions. Four catalytic methods—Ir/Ni and Ru/Ni dual-metal photoredox catalysis, as well as heterogeneous and high-temperature Cu and Pd catalysis—with extended nanomole chemistry requirements were evaluated for the synthesis of a single product in the presence of 383 structurally diverse simple and complex potential poisons. Using a normalizing internal standard that was closely related to the product and optimized operating parameters, MALDI-MS provided good correlation with existing ultra performance liquid chromatography (UPLC)–MS approaches (coefficient of determination R2 up to 0.85), allowing correct binning of “hits” and “misses” (defined as >50% product signal knockdown) up to 95% of the time. Next, the more challenging goal of exploring diverse whole-molecule C–N couplings was explored. In this case, it was not practical to have either product standards or closely related internal standards to enable analytical quantitation. A “simplest-partner test” was employed, in which 192 aryl bromides and 192 secondary amines were each coupled with a MS-active “simplest partner,” guaranteeing a somewhat normalized MS response for all products. The formation of 384 different products using the four aforementioned synthetic methods was monitored by MALDI-MS, with pass-fail binning of results correlating well with UPLC-MS in the identification of common structural elements (such as functional group counts, H-bond donors and acceptors, and polar surface area) that lead to reaction failure. CONCLUSION In the near future, each problematic structural element that is identified through systematic dark-space exploration can be promoted for in-depth examination to precisely define the specific parameters that determine reaction outcome at the atomic and quantum molecular level. Predictive machine learning models will use this focused data to enable synthetic practitioners to select the most appropriate reactions for use in a particular synthetic setting. In addition, functionality that persistently fails across synthetic methods can sharply define important challenges for the invention of improved chemical reactions.

The structural complexity of pharmaceuticals presents a significant challenge to modern catalysis. Many published methods that work well on simple substrates often fail when attempts are made to apply them to complex drug intermediates. The use of high-throughput experimentation (HTE) techniques offers a means to overcome this fundamental challenge by facilitating the rational exploration of large arrays of catalysts and reaction conditions in a time- and material-efficient manner. Initial forays into the use of HTE in our laboratories for solving chemistry problems centered around screening of chiral precious-metal catalysts for homogeneous asymmetric hydrogenation. The success of these early efforts in developing efficient catalytic steps for late-stage development programs motivated the desire to increase the scope of this approach to encompass other high-value catalytic chemistries. Doing so, however, required significant advances in reactor and workflow design and automation to enable the effective assembly and agitation of arrays of heterogeneous reaction mixtures and retention of volatile solvents under a wide range of temperatures. Associated innovations in high-throughput analytical chemistry techniques greatly increased the efficiency and reliability of these methods. These evolved HTE techniques have been utilized extensively to develop highly innovative catalysis solutions to the most challenging problems in large-scale pharmaceutical synthesis. Starting with Pd- and Cu-catalyzed cross-coupling chemistry, subsequent efforts expanded to other valuable modern synthetic transformations such as chiral phase-transfer catalysis, photoredox catalysis, and C-H functionalization. As our experience and confidence in HTE techniques matured, we envisioned their application beyond problems in process chemistry to address the needs of medicinal chemists. Here the problem of reaction generality is felt most acutely, and HTE approaches should prove broadly enabling. However, the quantities of both time and starting materials available for chemistry troubleshooting in this space generally are severely limited. Adapting to these needs led us to invest in smaller predefined arrays of transformation-specific screening "kits" and push the boundaries of miniaturization in chemistry screening, culminating in the development of "nanoscale" reaction screening carried out in 1536-well plates. Grappling with the problem of generality also inspired the exploration of cheminformatics-driven HTE approaches such as the Chemistry Informer Libraries. These next-generation HTE methods promise to empower chemists to run orders of magnitude more experiments and enable "big data" informatics approaches to reaction design and troubleshooting. With these advances, HTE is poised to revolutionize how chemists across both industry and academia discover new synthetic methods, develop them into tools of broad utility, and apply them to problems of practical significance.

Aliphatic amines, oxygenated at remote positions within the molecule, represent an important class of synthetic building blocks to which there are currently no direct means of access. Reported herein is an efficient and scalable solution that relies upon decatungstate photocatalysis under acidic conditions using either H2 O2 or O2 as the terminal oxidant. By using these reaction conditions a series of simple and unbiased aliphatic amine starting materials can be oxidized to value-added ketone products. Lastly, NMR spectroscopy using in situ LED-irradiated samples was utilized to monitor the kinetics of the reaction, thus enabling direct translation of the reaction into flow.

An asymmetric intermolecular reaction between enals and nitroalkenes to yield δ-nitroesters has been developed, catalyzed by a novel chiral N-heterocyclic carbene. Key to this work was the development of a catalyst that favors the δ-nitroester pathway over the established Stetter pathway. The reaction proceeds in high stereoselectivity and affords the previously unreported syn diastereomer. We also report an operationally facile two-step, one-pot procedure for the synthesis of δ-lactams.

Over the past two decades, there have been major developments in transition metal–catalyzed aminations of aryl halides to form anilines, a common structure found in drug agents, natural product isolates, and fine chemicals. Many of these approaches have enabled highly efficient and selective coupling through the design of specialized ligands, which facilitate reductive elimination from a destabilized metal center. We postulated that a general and complementary method for carbon–nitrogen bond formation could be developed through the destabilization of a metal amido complex via photoredox catalysis, thus providing an alternative approach to the use of structurally complex ligand systems. Here, we report the development of a distinct mechanistic paradigm for aryl amination using ligand-free nickel(II) salts, in which facile reductive elimination from the nickel metal center is induced via a photoredox-catalyzed electron-transfer event.

A one-step photocatalytic fluorination of (S)-leucine methyl ester (I) is thoroughly elaborated which allows for the multi-gram preparation of (S)-γ-fluoroleucine methyl ester (II) under continuous flow conditions, thus representing a straightforward access to the critical intermediate (II) of odanacatib (III).

Cross-coupling reactions are some of the most widely utilized methods for C-C bond formation; however, the requirement for pre-activated starting materials still presents a major limitation. Methods that take direct advantage of the inherent reactivity of the C-H bond offer an efficient alternative to these methods, negating the requirement for substrate pre-activation. In this process two chemically distinct activation events culminate in the formation of the desired C-C bond with loss of H2 as the only by-product. Herein we report the catalytic asymmetric α-acylation of tertiary amines with aldehydes facilitated by the combination of chiral N-heterocyclic carbene catalysis and photoredox catalysis.

Over the past decade, N-heterocyclic carbenes (NHCs) have been used as catalysts in a variety of C-C bond forming reactions.[1] Our group has been interested in the development of chiral NHCs as catalysts for the asymmetric intra-molecular Stetter reaction[2,3] and more recently the inter-molecular variant.[4,5] We recently reported that hetaryl aldehydes and enals react efficiently with nitroalkenes in the Stetter reaction, leading to β-nitro ketones with high enantioselectivity.[4d] Crucial to the success of this method was the development of a fluorinated triazolium salt pre-catalyst that provides significantly enhanced enantioselectivity over des-fluoro analogues.[6] Although this new catalyst system greatly expands the scope of this method, these conditions are not amenable to the use of unactivated aliphatic aldehydes. Due to their lower electrophilicity than aryl aldehydes, aliphatic aldehydes have rarely been used successfully in the asymmetric inter-molecular Stetter reaction.[7,8]

An asymmetric intermolecular Stetter reaction of enals with nitroalkenes catalyzed by chiral N-heterocyclic carbenes has been developed. The reaction rate and efficiency are profoundly impacted by the presence of catechol. The reaction proceeds with high selectivities and affords good yields of the Stetter product. Internal redox products were not observed despite of the protic conditions. The impact of catechol has been found to be general, facilitating far lower catalyst loadings than were previously achievable.

Acryloyl and vinyl monomers functionalized with a chiral oxazolidinone auxiliary have been successfully polymerized in a stereospecific fashion to highly isotactic, optically active polymers, through either the previously established isospecific coordination polymerization (for acryloyl monomers) or a novel isospecific cationic polymerization (for vinyl monomers). Specifically, conjugated chiral acryloyloxazolidinones, N-acryloyl-(R or S)-4-phenyl-2-oxazolidinone [(R or S)-AOZ], are readily polymerized by chiral ansa-zirconocenium coordination catalysts, (R,R-, S,S-, or R,R/S,S)-[C2H4(η5-Ind)2]Zr+(THF)[OC(OiPr)═CMe2][MeB(C6F5)3]− (1), in an isospecific manner through a catalyst-site-controlled mechanism, producing the corresponding optically active chiral polymers, (R or S)-PAOZ. Owing to the nature of stereocontrol dictated by the chiral catalyst site, even the coordination polymerization of the parent AOZ, without the chiral side group, also affords PAOZ with nearly quantitative isotacticity. A series o...

The optimization of a palladium-catalyzed amidation reaction providing a new class of amino acid–tetrahydroanthranilic acid derivatives has been achieved. The scope of the reaction and preliminary conformational analysis of the resulting series of molecules is discussed.

Late-stage C–H fluorination is an appealing reaction for medicinal chemistry. However, the application of this strategy to process research appears less attractive due to the formation and necessary purification of mixtures of organofluorines. Here we demonstrate that γ-fluoroleucine methyl ester, an intermediate critical to the large-scale synthesis of odanacatib, can be accessed directly from leucine methyl ester using a combination of the decatungstate photocatalyst and N-fluorobenzenesulfonimide in flow. This efficient C–H fluorination reaction compares favorably with several generations of classical γ-fluoroleucine process syntheses.

Since Breslow's initial report on the thiamine mode of action, the study of catalytic acyl carbanion processes has been an area of immense interest. With the advent of azolylidene catalysis, a plethora of reactivtiy has been harnessed, but the crucial nucleophilic intermediate proposed by Breslow had never been isolated or fully characterized. Herein, we report the isolation and full characterization of nitrogen analogues of the Breslow intermediate. Both stable and catalytically relevant, these species provide a model system for the study of acyl carbanion and homoenolate processes catalyzed by triazolylidene carbenes.

The catalytic asymmetric intermolecular Stetter reaction of heterocyclic aldehydes and nitroalkenes has been developed. We have identified a strong stereoelectronic effect on catalyst structure when a fluorine substituent is placed in the backbone. X-ray structure analysis provides evidence that hyperconjugative effects are responsible for a change in conformation in the azolium precatalyst. This new N-heterocyclic carbene precursor bearing fluorine substitution in the backbone results in significantly improved enantioselectivities across a range of substrates.

A wide range of different substituted syn-δ-nitroesters are synthesized by using a novel NHC ligand.

The benzoin reaction has been studied for more than a century, since its initial report by Wohler and Liebig in 1832.[1,2] Nature has long utilized the concept of umpolung in the form of thiamine dependent enzymes that are required for life.[3] Despite this, a general method for the asymmetric cross-benzoin reaction has not yet been discovered.[ 4] The inherent problem with this transformation lies in the lack of chemoselectivity between aldehyde partners. A few elegant methodologies have addressed this problem making the synthesis of enantioenriched hetero-benzoin products accessible.[5,6] Related to the cross-benzoin reaction of aldehydes is the cross aza-benzoin reaction of aldehydes and imines.[7] This concept has a variety of advantages. The difference in reactivity between an aldehyde and an imine is inherently greater but can also be tuned due to the trivalency of nitrogen. Furthermore, α-amido ketones represent an important class of medicinal agents and are a synthon for the ubiquitous 1,2-amino-alcohol motif.[8,9] Murry, Frantz and coworkers reported the first example of an aldehyde-imine cross-benzoin reaction catalysed by thiazolylidene carbenes, using arylsulfonylamides as imine precursors.[10,11] Later, Miller and coworkers disclosed an asymmetric variant of this work implementing their peptide-derived thiazolium salt as a pre-catalyst to deliver aryl aldehyde derived α-amido ketones.[12] These workers further noted some epimerization of the newly formed stereocenter when using more activated coupling partners. There has been speculation in the literature about the reversibility of active catalyst addition to an imine which has led to the dogma that slow generation of the imine in situ, or attenuation of its electrophilicity would be necessary for catalyst turnover.[13] We have recently disclosed a study of aza-Breslow intermediates derived from the interaction of one of our chiral triazolylidene carbenes with iminium salts.[14] This study revealed that addition of these carbene species to an iminium salt is facile, leading to a stable intermediate; however, in the presence of weak acid this process is highly reversible. We wondered if we could take advantage of this reversibility when electrophilic acyl-imines are used as substrates, negating the requirement for a slow addition protocol. With the assumption that a less activated system would lead to increased stability of the newly formed stereocenter as well as a more synthetically valuable product, we began to evaluate the addition of butanal 1a to N-Boc imine 2a. In our study of aza-Breslow intermediates we found acetic acid to be a competent catalyst in regenerating the active carbene. Acetate salts have been used as bases in a variety of NHC-catalyzed processes and implementation of them in this system would generate catalytic amounts of the required acid in situ.[15] We were pleased to find that catalyst 3c in combination with cesium acetate provides the desired α-amido ketone 4a in good yield (89%) and excellent enantioselectivity (96%) (Table 1). Amine bases such as diisopropylethylamine are not effective, except in the case where catalytic amounts of acid are added to the reaction.[16] Addition of 4A molecular sieves is necessary to suppress imine hydrolysis, likely due to the hygroscopic-nature of cesium acetate, while lowering the temperature led to a significant reduction in post reaction epimerization. Table 1 Reaction optimization.a With an efficient catalyst system in hand we evaluated the scope of this transformation (Table 2). A variety of aliphatic aldehydes were examined containing a diverse range of functionality. Straight-chain aldehydes produce the desired products in high yield (71–93%) and excellent enantioselectivity (84–93% ee), while β-branched aldehydes participate in excellent enantioselectivity (98% ee) albeit lower yields (33%).[17] Heteroatoms can be incorporated into the tether without deleterious impact on yield or enantioselectivity, allowing for the incorporation of functionality such as thioethers, imides, and esters. Currently, α-branched aldehydes do not participate. The scope of the imine partner was assessed using N-Boc imines of varying electronic nature. Both electron rich and electron poor aryl derivatives work with equal utility (72–74% yield) despite some small variation in enantioselectivity (90–94% ee). The common methylenedioxyphenyl motif can be incorporated with high selectivity (94% ee) as well as heterocycles such as furan, albeit in lower selectivity (60% ee). Ortho-substituted aryl derivatives lead to an unexpected loss of reactivity. Table 2 Reaction Scopea The α-amido ketone products are useful intermediates in the synthesis of 1,2-aminoalcohols. Reduction of 3a provides quantitative yield of the anti-1,2-aminoalcohol as the sole diastereomer (Scheme 1).[18] Scheme 1 Diastereoselective Reduct ion of Amido-ketones. Upon devoloping an efficient catalyst system, we were interestested in probing the interaction between N-Boc imines and our active carbene to gain further evidence for the reversible formation of an aza-Breslow intermediate in the catalytic cycle. Subjection of pre-catalyst 3c to excess KOtBu shows clean formation of carbene 5 by 1H NMR. Addition of 1.0 equivalent of N-Boc imine 2a immediately produces a bright yellow solution and reveals the formation of a new species assigned by 1H NMR and HRMS to be aza-Breslow intermediate 6 (Scheme 2).[19] To test the reversibility of this process under the reaction conditions, 6 was treated with excess AcOH, regenerating a colorless solution. 1H NMR analysis confirms the disappearance of intermediate 6 but neither carbene 5 or imine 2a could be identified, suggesting that the carbene may not be the resting state under these conditions.[20] Scheme 2 NMR Studies of Catalyst/Substrate Interaction In conclusion, we have developed a highly enantioselective cross aza-benzoin reaction of aliphatic aldehydes and N-Boc imines. This transformation provides access to useful 1,2-amino alcohol synthons in a single step. Crucial insight pertaining to the reversible formation of aza-Breslow intermediates in the catalytic cycle has enabled the direct implementation of highly reactive imines as substrates, negating the requirement for a slow-addition protocol.

Under optimized conditions using RuCl2(bipy)3 as the photocatalyst, MDNB as weak organic oxidant, chiral carbene catalyst TBT, and blue light irradiation, tetrahydroisoquinolines are acylated at the α-position with aliphatic aldehydes to give the products in a highly enantioselective manner (up to 92% e.e.).

The benzoin reaction has been studied for more than a century, since its initial report by Wohler and Liebig in 1832.[1,2] Nature has long utilized the concept of umpolung in the form of thiamine dependent enzymes that are required for life.[3] Despite this, a general method for the asymmetric cross-benzoin reaction has not yet been discovered.[ 4] The inherent problem with this transformation lies in the lack of chemoselectivity between aldehyde partners. A few elegant methodologies have addressed this problem making the synthesis of enantioenriched hetero-benzoin products accessible.[5,6] Related to the cross-benzoin reaction of aldehydes is the cross aza-benzoin reaction of aldehydes and imines.[7] This concept has a variety of advantages. The difference in reactivity between an aldehyde and an imine is inherently greater but can also be tuned due to the trivalency of nitrogen. Furthermore, α-amido ketones represent an important class of medicinal agents and are a synthon for the ubiquitous 1,2-amino-alcohol motif.[8,9] Murry, Frantz and coworkers reported the first example of an aldehyde-imine cross-benzoin reaction catalysed by thiazolylidene carbenes, using arylsulfonylamides as imine precursors.[10,11] Later, Miller and coworkers disclosed an asymmetric variant of this work implementing their peptide-derived thiazolium salt as a pre-catalyst to deliver aryl aldehyde derived α-amido ketones.[12] These workers further noted some epimerization of the newly formed stereocenter when using more activated coupling partners. There has been speculation in the literature about the reversibility of active catalyst addition to an imine which has led to the dogma that slow generation of the imine in situ, or attenuation of its electrophilicity would be necessary for catalyst turnover.[13] We have recently disclosed a study of aza-Breslow intermediates derived from the interaction of one of our chiral triazolylidene carbenes with iminium salts.[14] This study revealed that addition of these carbene species to an iminium salt is facile, leading to a stable intermediate; however, in the presence of weak acid this process is highly reversible. We wondered if we could take advantage of this reversibility when electrophilic acyl-imines are used as substrates, negating the requirement for a slow addition protocol. With the assumption that a less activated system would lead to increased stability of the newly formed stereocenter as well as a more synthetically valuable product, we began to evaluate the addition of butanal 1a to N-Boc imine 2a. In our study of aza-Breslow intermediates we found acetic acid to be a competent catalyst in regenerating the active carbene. Acetate salts have been used as bases in a variety of NHC-catalyzed processes and implementation of them in this system would generate catalytic amounts of the required acid in situ.[15] We were pleased to find that catalyst 3c in combination with cesium acetate provides the desired α-amido ketone 4a in good yield (89%) and excellent enantioselectivity (96%) (Table 1). Amine bases such as diisopropylethylamine are not effective, except in the case where catalytic amounts of acid are added to the reaction.[16] Addition of 4A molecular sieves is necessary to suppress imine hydrolysis, likely due to the hygroscopic-nature of cesium acetate, while lowering the temperature led to a significant reduction in post reaction epimerization. Table 1 Reaction optimization.a With an efficient catalyst system in hand we evaluated the scope of this transformation (Table 2). A variety of aliphatic aldehydes were examined containing a diverse range of functionality. Straight-chain aldehydes produce the desired products in high yield (71–93%) and excellent enantioselectivity (84–93% ee), while β-branched aldehydes participate in excellent enantioselectivity (98% ee) albeit lower yields (33%).[17] Heteroatoms can be incorporated into the tether without deleterious impact on yield or enantioselectivity, allowing for the incorporation of functionality such as thioethers, imides, and esters. Currently, α-branched aldehydes do not participate. The scope of the imine partner was assessed using N-Boc imines of varying electronic nature. Both electron rich and electron poor aryl derivatives work with equal utility (72–74% yield) despite some small variation in enantioselectivity (90–94% ee). The common methylenedioxyphenyl motif can be incorporated with high selectivity (94% ee) as well as heterocycles such as furan, albeit in lower selectivity (60% ee). Ortho-substituted aryl derivatives lead to an unexpected loss of reactivity. Table 2 Reaction Scopea The α-amido ketone products are useful intermediates in the synthesis of 1,2-aminoalcohols. Reduction of 3a provides quantitative yield of the anti-1,2-aminoalcohol as the sole diastereomer (Scheme 1).[18] Scheme 1 Diastereoselective Reduct ion of Amido-ketones. Upon devoloping an efficient catalyst system, we were interestested in probing the interaction between N-Boc imines and our active carbene to gain further evidence for the reversible formation of an aza-Breslow intermediate in the catalytic cycle. Subjection of pre-catalyst 3c to excess KOtBu shows clean formation of carbene 5 by 1H NMR. Addition of 1.0 equivalent of N-Boc imine 2a immediately produces a bright yellow solution and reveals the formation of a new species assigned by 1H NMR and HRMS to be aza-Breslow intermediate 6 (Scheme 2).[19] To test the reversibility of this process under the reaction conditions, 6 was treated with excess AcOH, regenerating a colorless solution. 1H NMR analysis confirms the disappearance of intermediate 6 but neither carbene 5 or imine 2a could be identified, suggesting that the carbene may not be the resting state under these conditions.[20] Scheme 2 NMR Studies of Catalyst/Substrate Interaction In conclusion, we have developed a highly enantioselective cross aza-benzoin reaction of aliphatic aldehydes and N-Boc imines. This transformation provides access to useful 1,2-amino alcohol synthons in a single step. Crucial insight pertaining to the reversible formation of aza-Breslow intermediates in the catalytic cycle has enabled the direct implementation of highly reactive imines as substrates, negating the requirement for a slow-addition protocol.

The target compounds are prepared with high dia- and enantioselectivities from the unactivated α,β-unsaturated imines and enals using a catalytic system consisting of the cyclohexyl-substituted azolium salt and sodium o-chlorobenzoate as a weak base.

Aldehyde umpolung, the inversion of the electrophilicity of the carbonyl group into a nucleophile, has its origins in Wohler and Liebig’s 1832 paper describing the cyanide catalyzed benzoin reaction.1 One hundred years later, Ukai demonstrated the same transformation using thiazolium precatalysts in the presence of base. 2 In 1958, Breslow first proposed the currently accepted mechanism of this transformation, building on Lapworth’s mechanism for the cyanide catalyzed benzoin.3 In 1974, Stetter showed that Michael acceptors may also be used as electrophiles for the acyl anion equivalent. 4 With the advent of N-heterocyclic carbenes, there has been a huge upsurge in reactivity associated with these systems, with chiral catalysts, novel reactions, new modes of reactivity and their applications to synthesis all making an appearance.5

The title reaction is performed with aromatic and aliphatic enals in the presence of chiral fluorinated triazolium salt FTB as precatalyst and catechols as additives, which significantly enhance the reactivity and chemical yields.

An efficient enantioselective approach to form trans-γ-lactams in up to 99% yield, 93% ee, and >20/1 dr using unactivated imines has been developed. The cyclohexyl-substituted azolium and the weak base sodium o-chlorobenzoate are most suitable for this transformation. Notably, the process involves cooperative catalysis by an N-heterocyclic carbene and a Bronsted acid.

The asymmetric intermolecular Stetter reaction was investigated using the B3LYP and M06-2X functionals. Fluorination of a triazolium bicyclic catalyst had been found to significantly influence reaction yields and enantiomeric ratios. Computations indicate that the improved reactivity of the fluorinated catalyst is due to better electrostatic interactions between the nitroalkene and catalyst. Computational investigations of preferred conformations of the ground state catalyst and acyl anion equivalent, and the transition structures leading to both enantiomers of the products, are reported.

Aldehyde umpolung, the inversion of the electrophilicity of the carbonyl group into a nucleophile, has its origins in Wohler and Liebig’s 1832 paper describing the cyanide catalyzed benzoin reaction.1 One hundred years later, Ukai demonstrated the same transformation using thiazolium precatalysts in the presence of base. 2 In 1958, Breslow first proposed the currently accepted mechanism of this transformation, building on Lapworth’s mechanism for the cyanide catalyzed benzoin.3 In 1974, Stetter showed that Michael acceptors may also be used as electrophiles for the acyl anion equivalent. 4 With the advent of N-heterocyclic carbenes, there has been a huge upsurge in reactivity associated with these systems, with chiral catalysts, novel reactions, new modes of reactivity and their applications to synthesis all making an appearance.5

A study on the mechanism of the asymmetric intramolecular Stetter reaction is reported. This investigation includes the determination of the rate law, kinetic isotope effects, and competition experiments. The reaction was found to be first order in aldehyde and azolium catalyst or free carbene. A primary kinetic isotope effect was found for the proton of the aldehyde. Taken together with a series of competition experiments, these results suggest that proton transfer from the tetrahedral intermediate formed upon nucleophilic attack of the carbene onto the aldehyde is the first irreversible step.

Amino-anthranilic acid derivatives have been identified as a new class of low serum shifted, high affinity full agonists of the human orphan G-protein-coupled receptor GPR109a with improved ADME properties.