Straightforward α‐Amino Nitrile Synthesis Through Mo(CO)6‐Catalyzed Reductive Functionalization of Carboxamides

The selective reduction of amides into an intermediate hemiaminal catalyzed by Mo(CO)₆ together with the inexpensive and easy to handle TMDS (1,1,3,3‐tetramethyldisiloxane) as reducing agent, followed by subsequent trapping of the hemiaminal with a cyanide source, allows for the straightforward synthesis of α‐amino nitriles. The methodology presented here, displays high levels of chemoselectivity allowing for the reduction of amides in the presence of functional groups such as ketones, imines, aldehydes, and acids, which affords a simple route for the synthesis of α‐amino nitriles with a broad scope of functionalities in high yields. Furthermore, the applicability of this methodology is demonstrated by scale up experiments and by derivatization of the target compounds into synthetically interesting products. The selective cyanation is successfully applied in late stage functionalizations of amide containing drugs and prolinol derivatives.     

Enantio‐ and Site‐Selective α‐Fluorination of N‐Acyl 3,5‐Dimethylpyrazoles Catalyzed by Chiral π–CuII Complexes

Catalytic enantioselective α‐fluorination reactions of carbonyl compounds are among the most powerful and efficient synthetic methods for constructing optically active α‐fluorinated carbonyl compounds. Nevertheless, α‐fluorination of α‐nonbranched carboxylic acid derivatives is still a big challenge because of relatively high pK_a values of their α‐hydrogen atoms and difficulty of subsequent synthetic transformation without epimerization. Herein we show that chiral copper(II) complexes of 3‐(2‐naphthyl)‐l ‐alanine‐derived amides are highly effective catalysts for the enantio‐ and site‐selective α‐fluorination of N‐(α‐arylacetyl) and N‐(α‐alkylacetyl) 3,5‐dimethylpyrazoles. The substrate scope of the transformation is very broad (25 examples including a quaternary α‐fluorinated α‐amino acid derivative). α‐Fluorinated products were converted into the corresponding esters, secondary amides, tertiary amides, ketones, and alcohols with almost no epimerization in high yield.     

Polycyclic Indoline‐Benzodiazepines through Electrophilic Additions of α‐Imino Carbenes to Tröger Bases

Polycyclic indoline‐benzodiazepines can be accessed through the intermolecular reaction of Tröger bases with N‐sulfonyl‐1,2,3‐triazoles. Under Rh^II catalysis, α‐imino carbenes are generated and a subsequent cascade of [1,2]‐Stevens, Friedel–Crafts, Grob, and aminal formation reactions yield the polycyclic heterocycles as single isomers (d.r.>49:1, four stereocenters including two bridgehead N atoms). Further ring expansion by insertion of a second α‐imino carbene leads to elaborated polycyclic 9‐membered‐ring triazonanes.     

Umpolung Reactions of α‐Imino Esters: Useful Methods for the Preparation of α‐Amino Acid Frameworks

This paper summarizes our recent efforts toward the development of tandem reactions utilizing umpolung reactions of α‐imino esters. A highly diastereoselective tandem N‐alkylation–Mannich reaction of α‐imino esters was developed. A tandem N‐alkylation–addition reaction of α‐imino esters derived from ethyl glyoxylate with various aldehydes proceeded to give 1,2‐amino alcohols. The same reaction also proceeded efficiently using a novel flow system comprising two connected microreactors. Novel syntheses of α‐quaternary alkynyl amino esters and allenoates were developed through the use of umpolung N‐addition to β,γ‐alkynyl α‐imino esters, followed by regioselective acylation. In addition, a highly regioselective tandem N‐alkylation–vinylogous aldol reaction of β,γ‐alkenyl α‐imino esters was discovered. N‐Alkylation of α‐iminophosphonates followed by a Horner–Wadsworth–Emmons reaction with aldehydes occurred to afford enamines, which can be used in a four‐component coupling reaction with methyl vinyl ketone. α‐N‐Acyloxyimino esters served as highly efficient substrates for the N,N,C‐trialkylation reaction to introduce various nucleophiles at the imino nitrogen and carbon atoms.     

An exception of eschweiler‐clarke methylation: Cyclocondensation of α‐amino amides with formaldehyde and formic acid

An exception of Eschweiler‐Clarke methylation was found for α‐amino amides. The α‐amino amides on treatment with formaldehyde and formic acid produce cyclocondensation products, imidazolidin‐4‐ones, but N‐methylation process becomes important when three substituents of the α‐amino amides are very bulky. On the other hand, N‐methylation is the only product for Eschweiler‐Clarke methylation of the α‐amino amides with N,N‐disubstituted amide.     

Recent Advances in the Synthesis of Heterocycles and Related Substances Based on α‐Imino Rhodium Carbene Complexes Derived from N‐Sulfonyl‐1,2,3‐triazoles

In recent years, α‐imino rhodium carbene complexes derived by ring‐opening of N‐sulfonyl‐1,2,3‐triazoles have attracted much attention from organic chemists. Many transformations of these species have been reported that involve, in most cases, nucleophilic attack at the carbene center of the α‐imino rhodium carbene, facilitating the synthesis of a wide range of novel and useful compounds, particularly heterocycles. This Minireview mainly focuses on advances in the transformation of N‐sulfonyl‐1,2,3‐triazoles during the past two years.     

Enantioselective Synthesis of α‐Hydroxy Amides and β‐Amino Alcohols from α‐Keto Amides

Synthesis of enantiomerically enriched α‐hydroxy amides and β‐amino alcohols has been accomplished by enantioselective reduction of α‐keto amides with hydrosilanes. A series of α‐keto amides were reduced in the presence of chiral Cu^II/(S)‐DTBM‐SEGPHOS catalyst to give the corresponding optically active α‐hydroxy amides with excellent enantioselectivities by using (EtO)₃SiH as a reducing agent. Furthermore, a one‐pot complete reduction of both ketone and amide groups of α‐keto amides has been achieved using the same chiral copper catalyst followed by tetra‐n‐butylammonium fluoride (TBAF) catalyst in presence of (EtO)₃SiH to afford the corresponding chiral β‐amino alcohol derivatives.     

Heteroatom‐Guided Torquoselective Olefination of α‐Oxy and α‐Amino Ketones via Ynolates

Ynolates were found to react with α‐alkoxy‐, α‐siloxy‐, and α‐aryloxyketones at room temperature to afford tetrasubstituted olefins with high Z selectivity. Since the geometrical selectivity was determined in the ring opening of the β‐lactone enolate intermediates, the torquoselectivity was controlled by the ethereal oxygen atoms. From experimental and theoretical studies, the high Z selectivity is induced by orbital and steric interactions rather than by chelation. In a similar manner, α‐dialkylamino ketones provided olefins with excellent Z selectivity. These products can be easily converted into multisubstituted butenolides and γ‐butyrolactams in good yield.     

Synthesis and X‐ray Crystal Structures of Zinc Complexes Supported by Chelating Ligands: Various Reactions of α‐Iminopyridines with ZnEt2

α‐Iminopyridine (α‐IP) is an important redox‐noninnocent ligand. The substituents on the imino function of α‐IPs have important impact on the reaction selectivity with diethylzinc. For the α‐IPs with a hydrogen substituent on the imino carbon, reduction occurred for the non‐bulky N‐substituents phenyl and 2‐methylphenyl groups, whereas alkyl addition and coupling reactions can be selectively achieved for the sterically bulky N‐substituents 2,6‐dimethylphenyl or 2,4,6‐trimethylphenyl group. However, for the α‐IPs with a CH₃ substituent on the imino carbon, the deprotonation reaction happened regardless of the N‐substituents of 2‐methylphenyl or 2,6‐dimethylphenyl group. All the products were isolated and characterized by single‐crystal X‐ray diffraction. The possible mechanisms of these reactions were also discussed.     

Versatile One‐Pot Synthesis of Polysubstituted Cyclopent‐2‐enimines from α,β‐Unsaturated Amides: Imino‐Nazarov Reaction

The imino‐Nazarov cyclization of the polysubstituted pentan‐1,4‐diene‐3‐imines was realized. To this aim, a one‐pot procedure involving reductive alkenyliminylation of α,β‐unsaturated secondary amides with potassium organotrifluoroborates, followed by acid‐catalyzed imino‐Nazarov cyclization of the polysubstituted pentan‐1,4‐diene‐3‐imine intermediates, was studied systematically. This mild, operationally simple, flexible, and high‐yielding protocol efficiently affords polysubstituted pentan‐1,4‐diene‐3‐imines, cyclopentenimines, and α‐amino cyclopentenones, which are useful scaffolds in organic synthesis. The substituent effect at the C2 position of the polysubstituted pentan‐1,4‐diene‐3‐imines was studied by means of density‐functional theory calculations. Results suggested that the electron‐donating group facilitates the imino‐Nazarov cyclization process.     

Ring Expansion and 1,2‐Migration Cascade of Benzisoxazoles with Ynamides: Experimental and Theoretical Studies

Demonstrated herein is an Au^I‐catalyzed annulation of sulfonyl‐protected ynamides with substituted 1,2‐benzisoxazoles for the synthesis of E‐benzo[e][1,3]oxazine derivatives. The transformation involves the addition of benzisoxazole to the gold‐activated ynamide, ring expansion of the benzisoxazole fragment to provide an α‐imino vinylic gold intermediate, and 1,2‐migration of the sulfonamide motif to the masked carbene center to deliver the respective ring‐expanded benzo[e][1,3]oxazine of predominant E configuration. A trapping experiment justifies the participation of the α‐imino masked gold carbene. DFT computations also support the hypothesized mechanism and rationalize the product stereoselectivity.     

1,2‐N‐Migration in a Gold‐Catalysed Synthesis of Functionalised Indenes by the 1,1‐Carboalkoxylation of Ynamides

Unique α‐hemiaminal ether gold carbene intermediates were accessed by a gold‐catalysed 1,1‐carboalkoxylation strategy and evolved through a highly selective 1,2‐N‐migration. This skeletal rearrangement gave functionalised indenes, and isotopic labelling confirmed the rare C?N bond cleavage of the ynamide moiety. The effect of substituents on the migration has been explored, and a model is proposed to rationalise the observed selectivity.     

Au(Ⅰ)-Catalyzed Annulation of Benzofurazan N-oxides with Ynamides: From Predicting the Chemo-Selectivity to the Synthesis of 7-Nitroindole Derivatives

Summaryof main observation and conclusion It could be proposed that gold(I)-catalyzed reactions of ynamides with benzofurazan N-oxidesmightproceed through eitherO-attack or N-attack to affordα-oxo orα-imino Au(I)-carbenoidintermediates.Computational studies were performed to predict that benzofurazan N-oxides are ready to undergo the chemoselective N-attack tothe Au(I)-activatedynamides to generate theα-imino Au(I)-carbenoid intermediate.Experimental studies were carried out to confirm the computational results and the 7-nitroindole derivatives were synthesized in a concise and efficient manner.The unfavored O-attack for benzofurazan N-oxides,which is in contrast to nitrones and pyridine/quinoline N-oxides,in the Au(I)-catalyzed reactions with ynamides is rationalized.     

Diastereoselective Cyanation of α‐Keto Amides Derived from N‐Phenyl Camphorpyrazolidinone and Camphorsultam

The diastereoselective cyanation of α‐keto amides using trimethylsilyl cyanide in the presence of a Lewis acid is described. The corresponding O‐acetylated cyanohydrins are obtained in good to high levels of stereoselectivities. The predominance of products with the S absolute configuration at the newly generated stereogenic center was deduced from single crystal X‐ray analysis. ¹³C NMR data suggest that a preferential s‐cis conformation was formed by the chelation of a Lewis acid to the dicarbonyl oxygen atoms.     

Enantioselective Synthesis of Acyclic α‐Quaternary Carboxylic Acid Derivatives through Iridium‐Catalyzed Allylic Alkylation

The first highly enantioselective iridium‐catalyzed allylic alkylation that provides access to products bearing an allylic all‐carbon quaternary stereogenic center has been developed. The reaction utilizes a masked acyl cyanide (MAC) reagent, which enables the one‐pot preparation of α‐quaternary carboxylic acids, esters, and amides with a high degree of enantioselectivity. The utility of these products is further explored through a series of diverse product transformations.     

Transition‐Metal‐Free Reductive Functionalization of Tertiary Carboxamides and Lactams for α‐Branched Amine Synthesis

A new method for the synthesis of α‐branched amines by reductive functionalization of tertiary carboxamides and lactams is described. The process relies on the efficient and controlled reduction of tertiary amides by a sodium hydride/sodium iodide composite, in situ treatment of the resulting anionic hemiaminal with trimethylsilyl chloride and subsequent coupling with nucleophilic reagents including Grignard reagents and tetrabutylammonium cyanide. The new method exhibits broad functional‐group compatibility, operates under transition‐metal‐free reaction conditions, and is suitable for various synthetic applications on both sub‐millimole and on multigram scales.     

Selective α‐Oxyamination and Hydroxylation of Aliphatic Amides

Compared to the α‐functionalization of aldehydes, ketones, even esters, the direct α‐modification of amides is still a challenge because of the low acidity of α‐CH groups. The α‐functionalization of N−H (primary and secondary) amides, containing both an unactived α‐C−H bond and a competitively active N−H bond, remains elusive. Shown herein is the general and efficient oxidative α‐oxyamination and hydroxylation of aliphatic amides including secondary N−H amides. This transition‐metal‐free chemistry with high chemoselectivity provides an efficient approach to α‐hydroxy amides. This oxidative protocol significantly enables the selective functionalization of inert α‐C−H bonds with the complete preservation of active N−H bond.     

Evidence for a Boat Conformation at the Transition State of GH76 α‐1,6‐Mannanases—Key Enzymes in Bacterial and Fungal Mannoprotein Metabolism

α‐Mannosidases and α‐mannanases have attracted attention for the insight they provide into nucleophilic substitution at the hindered anomeric center of α‐mannosides, and the potential of mannosidase inhibitors as cellular probes and therapeutic agents. We report the conformational itinerary of the family GH76 α‐mannanases studied through structural analysis of the Michaelis complex and synthesis and evaluation of novel aza/imino sugar inhibitors. A Michaelis complex in an ^OS₂ conformation, coupled with distortion of an azasugar in an inhibitor complex to a high energy B_2,5 conformation are rationalized through ab initio QM/MM metadynamics that show how the enzyme surface restricts the conformational landscape of the substrate, rendering the B_2,5 conformation the most energetically stable on‐enzyme. We conclude that GH76 enzymes perform catalysis using an itinerary that passes through ^OS₂ and B_2,5^≠ conformations, information that should inspire the development of new antifungal agents.     

A Reaction of Triazoles with Thioesters to Produce β‐Sulfanyl Enamides by Insertion of an Enamine Moiety into the Sulfur–Carbonyl Bond

N‐Sulfonyl‐1,2,3‐triazoles react with thioesters in the presence of a rhodium(II) catalyst to produce β‐sulfanyl enamides in a stereoselective manner. The reaction proceeds through generation of an α‐imino rhodium carbene complex, nucleophilic addition of the sulfur atom of a thioester onto the carbenoid carbon atom, and subsequent intramolecular migration of the acyl group from the sulfur atom to the imino nitrogen atom. The method is successfully applied to a ring‐expansion reaction of thiolactones, thus leading to the formation of sulfur‐containing lactams.     

C‐Selective and Diastereoselective Alkyl Addition to β,γ‐Alkynyl‐α‐imino Esters with Zinc(II)ate Complexes

Since umpolung α‐imino esters contain three electrophilic centers, regioselective alkyl addition with traditional organometallic reagents has been a serious problem in the practical synthesis of versatile chiral α‐amino acid derivatives. An unusual C‐alkyl addition to α‐imino esters using a Grignard reagent (RMgX)‐derived zinc(II)ate was developed. Zinc(II)ate complexes consist of a Lewis acidic [MgX]⁺ moiety, a nucleophilic [R₃Zn]^? moiety, and 2 [MgX₂]. Therefore, the ionically separated [R₃Zn]^? selectively attacks the imino carbon atom ,which is most strongly activated by chelation of [MgX]⁺. In particular, chiral β,γ‐alkynyl‐α‐imino esters can strongly promote highly regio‐ and diastereoselective C‐alkylation because of structural considerations, and the corresponding optically active α‐quaternary amino acid derivatives are obtained within 5 minutes in high to excellent yields.