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The cycloaddition reaction involving bicyclo[1.1.0]butanes (BCBs) offers a versatile and efficient synthetic platform for producing C(sp3)‐rich rigid bridged ring scaffolds, which act as phenyl bioisosteres. However, there is a scarcity of catalytic asymmetric cycloadditions of BCBs to fulfill the need for enantioenriched saturated bicycles in drug design and development. In this study, an efficient synthesis of valuable azabicyclo[2.1.1]hexanes (aza‐BCHs) by an enantioselective zinc‐catalyzed (3+2) cycloadditions of BCBs with imines is reported. The reaction proceeds effectively with a novel type of BCB that incorporates a 2‐acyl imidazole group and a diverse array of alkynyl‐ and aryl‐substituted imines. The target aza‐BCHs, which consist of α‐chiral amine fragments and two quaternary carbon centers, are efficiently synthesized with up to 94 % and 96.5:3.5 er under mild conditions. Experimental and computational studies reveal that the reaction follows a concerted nucleophilic ring‐opening mechanism of BCBs with imines. This mechanism is distinct from previous studies on Lewis acid‐catalyzed cycloadditions of BCBs. [ABSTRACT FROM AUTHOR]

We demonstrate that 2‐alkenylarylaldimines and ketimines undergo thermal 6π‐azaelectrocyclization to generate a wide range of azabicyclic o‐quinodimethanes (o‐QDMs). These o‐QDMs exist as a hybrid of a diene and a benzylic diradical. The diradical nature was confirmed by their ability to undergo dimerization and react with H‐atom donor, 2,2,6,6‐tetramethylpiperidin‐1‐yl)oxyl (TEMPO) and O2. In addition, the interception of the diradicaloid o‐QDMs by H‐atom transfer was used to synthesize five tetrahydroisoquinoline alkaloids and related bioactive molecules. The diene form can undergo [4+2] cycloaddition reactions with different dienophiles to generate bridged azabicycles in high endo:exo selectivity. The azabicyclic o‐QDMs can be generated for [4+2] cycloaddition from a wide range of electronically and sterically varied 2‐alkenylarylimines, including mono, di, tri and tetrasubstituted alkenes, and imines derived from arylamine, alkylamine (1°, 2°, 3°), benzylamine, benzylsulfonamide and Boc‐amine. [ABSTRACT FROM AUTHOR]

Given the tremendous success of (p‐cymene)RuII‐catalyzed C−H activation over the past 20 years, the community has long been aware that the development of chiral η6‐benzene (Ben) ligands should be a potent strategy for achieving the attractive but incredibly underdeveloped ruthenium(II)‐catalyzed asymmetric C−H activation. However, it has rarely been achieved due to the severe difficulty in developing proper chiral Ben ligands. In particular, designing chiral Ben ligands by connecting a benzene fragment to a chiral framework including benzene rings remained an unsolved challenge until this effort. Here we present a novel class of axially chiral Ben ligands derived from readily available (S)‐5,5′,6,6′,7,7′,8,8′‐octahydro‐1,1′‐bi‐2‐naphthol ((S)‐H8‐BINOL) in 4–8 steps. Notably, when coordinated with ruthenium, such chiral Ben ligand containing three benzene rings only forms one of the three possible isomeric BenRuII complexes. The related chiral BenRuII catalysts could effectively catalyze the asymmetric C−H activation of N‐sulfonyl ketimines with alkynes, affording a range of chiral spirocyclic sultams in up to 99 % yield with up to >99 % ee. These catalysts are expected to find broad applications in future. [ABSTRACT FROM AUTHOR]

A regio‐ and stereoselective stepwise (4+2) annulation of N‐propargylamides and α,β‐unsaturated imines/ketones has been accomplished with synergetic catalysis by a combination of a gold‐complex and a chiral quinine‐derived squaramide (QN‐SQA), leading to highly functionalized chiral tetrahydropyridines/dihydropyrans in good to high yields with generally excellent enantioselectivity. Mechanistic studies and DFT calculations indicate that the in situ formed alkylgold species is the key intermediate in this transformation, and the amide group served as a traceless directing group in this highly selective transformation. This method complements the enantioselective (4+2) annulation of allene reagents, providing the formal internal C−C π‐bond cycloaddition products, which is challenging and remains elusive. [ABSTRACT FROM AUTHOR]

A carbonyl‐assisted asymmetric 1,2‐migratory allylation through in situ generation of vicinal tetrasubstituted stereocenters is reported to access enantiopure α‐amino ketones and amino alcohols with excellent yields and diastereoselectivities. In a remarkable divergence, despite higher steric hindrance, the allylation exclusively occurs on ketones over imines in the first step, followed by a face‐selective 1,2‐allyl transfer, thus highlighting an exciting interplay between two distinct electrophiles. The methodology distinguishes itself through its adaptability to gram‐scale synthesis, showcasing broad functional‐group tolerance and stereodivergence. Density functional theory (DFT) analysis led to a deeper understanding of its selectivity and mechanistic framework. Highlighting its transformative potential, the method was applied to the total synthesis of hapalindole alkaloids. [ABSTRACT FROM AUTHOR]

A combined computational and experimental approach allowed us to develop overall the most selective catalyst for the direct hydrogenation of N‐methyl, N‐alkyl and N‐aryl imines described to date. Iridium catalysts with a cyclometallated cyclic imide group provide selectivity of up to 99 % enantiomeric excess. Computational studies show that the selectivity results from the combined effect of H‐bonding of the imide C=O with the substrate iminium ion and a stabilizing π–π interaction with the cyclometallated ligand. The cyclometallated ligand thus exhibits a unique mode of action, serving as a template for the H‐bond directed approach of the substrate which results in enhanced selectivity. The catalyst (2) has been synthesized and isolated as a crystalline air‐stable solid. X‐ray analysis of 2 confirmed the structure of the catalyst and the correct position of the imide C=O groups to engage in an H‐bond with the substrate. 19F NMR real‐time monitoring showed the hydrogenation of N‐methyl imines catalyzed by 2 is very fast, with a TOF of approx. 3500 h−1. [ABSTRACT FROM AUTHOR]

Chiral carboxylic acid production from renewable biomass by chemocatalysis is vitally important for reducing our carbon footprint, but remains underdeveloped. We herein establish a strategy that make use of a stereogenic center of biomass to achieve a rare example of D‐glyceric acid production with the highest yield (86.8 %) reported to date as well as an excellent ee value (>99 %). Unlike traditional asymmetric catalysis, chiral catalysts/additives are not required. Ample experiments combined with quantum chemical calculations established the origins of the stereogenic center and catalyst performance. The chirality at C4 in D‐xylose was proved to be retained and successfully delivered to C2 in D‐glyceric acid during C−C cleavage. The remarkable cooperative‐roles of Ag+ and Ag0 in the constructed Ag/γ‐Al2O3 catalyst are disclosed as the crucial contributors. Ag+ was responsible for low‐temperature activation of D‐xylose, while Ag0 facilitated the generation of active O* from O2. Ag+ and active O* cooperatively promoted the precise cleavage of the C2−C3 bond, and more importantly O* allowed the immediate fast oxidization of the D‐glyceraldehyde intermediate to stabilize D‐glyceric acid, thereby inhibiting the side reaction that induced racemization. This strategy makes a significant breakthrough in overcoming the limitation of poor enantioselectivity in current chemocatalytic conversion of biomass. [ABSTRACT FROM AUTHOR]

Bond activation and catalysis using s‐block metals are of great significance. Herein, a series of calcium pincer complexes with deprotonated side arms have been prepared using pyridine‐based PNP and PNN ligands. The complexes were characterized by NMR and X‐ray crystal diffraction. Utilizing the obtained calcium complexes, unprecedented N2O activation by metal‐ligand cooperation (MLC) involving dearomatization‐aromatization of the pyridine ligand was achieved, generating aromatized calcium diazotate complexes as products. Additionally, the dearomatized calcium complexes were able to activate the N−H bond as well as reversibly activate H2, offering an opportunity for the catalytic hydrogenation of various unsaturated molecules. DFT calculations were applied to analyze the electronic structures of the synthesized complexes and explore possible reaction mechanisms. This study is an important complement to the area of MLC and main‐group metal chemistry. [ABSTRACT FROM AUTHOR]

Geminal bis(boronates) are versatile synthetic building blocks in organic chemistry. The fact that they predominantly serve as nucleophiles in the previous reports, however, has restrained their synthetic potential. Herein we disclose the ambiphilic reactivity of α‐halogenated geminal bis(boronates), of which the first catalytic utilization was accomplished by merging a formal Heck cross‐coupling with a highly diastereoselective allylboration of aldehydes or imines, providing a new avenue for rapid assembly of polyfunctionalized boron‐containing compounds. We demonstrated that this cascade reaction is highly efficient and compatible with various functional groups, and a wide range of heterocycles. In contrast to a classical Pd(0/II) scenario, mechanistic experiments and DFT calculations have provided strong evidence for a catalytic cycle involving Pd(I)/diboryl carbon radical intermediates. [ABSTRACT FROM AUTHOR]

Modifying redox potential of substrates and intermediates to balance pairs of redox steps are important stages for multistep photosynthesis but faced marked challenges. Through co‐clathration of iridium photosensitizer and imine substrate within one packet of a metal‐organic capsule to shift the redox potentials of substrate, herein, we reported a multiphoton enzymatic strategy for the generation of heterocycles by intramolecular C−X hydrogen evolution cross‐couplings. The cage facilitated a pre‐equilibrium substrate‐involving clathrate that cathodic shifts the oxidation potential of the substrate‐dye‐host ternary complex and configuration inversion of substrate via spatial constraints in the confined space. The new two photon excitation strategy enabled the precise control of the multistep electron transfer between each pair (photosensitizer, substrate and the capsule), endowing the catalytic system proceeding smoothly with an enzymatic fashion. Three kinds of 2‐subsituted (−OH, −NH2, and −SH) imines and N‐aryl enamines all give the corresponding cyclization products efficiently under visible light irradiation, demonstrating the promising of the microenvironment driven thermodynamic activation in the host‐dye‐substrate ternary for synergistic combination of multistep photocatalytic transformations. [ABSTRACT FROM AUTHOR]

Azomethine imines, as a prominent class of 1,3‐dipolar species, hold great significance and potential in organic and medicinal chemistry. However, the reported synthesis of centrally chiral azomethine imines relies on kinetic resolution, and the construction of axially chiral azomethine imines remains unexplored. Herein, we present the synthesis of axially chiral azomethine imines through copper‐ or chiral phosphoric acid catalyzed ring‐closure reactions of N′‐(2‐alkynylbenzylidene)hydrazides, showcasing high efficiency, mild conditions, broad substrate scope, and excellent enantioselectivity. Furthermore, the biological evaluation revealed that the synthesized axially chiral azomethine imines effectively protect dorsal root ganglia (DRG) neurons by inhibiting apoptosis induced by oxaliplatin, offering a promising therapeutic approach for chemotherapy‐induced peripheral neuropathy (CIPN). Remarkably, the (S)‐ and (R)‐atropisomers displayed distinct neuroprotective activities, underscoring the significance of axial stereochemistry. [ABSTRACT FROM AUTHOR]

A new strategy to access α‐functionalized alicyclic amines via their corresponding imine‐BF3 complexes is reported. Isolable imine‐BF3 complexes, readily prepared via dehydrohalogenation of N‐bromoamines in a base‐promoted/18‐crown‐6 catalyzed process followed by addition of boron trifluoride etherate, undergo reactions with a wide range of organometallic nucleophiles to afford α‐functionalized azacycles. Organozinc and organomagnesium nucleophiles add at ambient temperatures, obviating the need for cryogenic conditions. In situ preparation of imine‐BF3 complexes provides access to α‐functionalized morpholines and piperazines directly from their parent amines in a single operation. α‐Functionalized morpholines can be elaborated further, for instance by installing a second substituent in the α′‐position. [ABSTRACT FROM AUTHOR]

A new phosphine‐catalyzed reaction of α‐substituted allenes with aryl imines, in stark contrast to classic cycloaddition reactions, has been developed. This reaction delivers valuable highly functionalized itaconimides with excellent stereoselectivities by a new «un‐cyclizing» reaction mode involving β′‐carbon of α‐substituted allenes. Moreover, the present «un‐cyclizing» reaction can also be carried out in a one‐pot fashion and scaled up to the gram scale by using aryl aldehydes, without the need to isolate the aryl imines. Mechanistic studies and control experiments reveal the crucial role of H2CO3 for the present reaction mode. In addition, density functional theory (DFT) calculations were performed to understand the possible mechanism. [ABSTRACT FROM AUTHOR]

Although the development of radical chain and photocatalytic borylation reactions using N‐heterocyclic carbene (NHC)‐borane as boron source is remarkable, the persistent problems, including the use of hazardous and high‐energy radical initiators or the recyclability and photostability issues of soluble homogeneous photocatalysts, still leave great room for further development in a sustainable manner. Herein, we report a conceptually different approach toward highly functionalized organoborane synthesis by using recoverable ultrathin cadmium sulfide (CdS) nanosheets as a heterogeneous photocatalyst, and a general and mild borylation platform that enables regioselective borylation of a wide variety of alkenes (arylethenes, trifluoromethylalkenes, α,β‐unsaturated carbonyl compounds and nitriles), alkynes, imines and electron‐poor aromatic rings with NHC‐borane as boryl radical precursor. Mechanistic studies and density functional theory (DFT) calculations reveal that both photogenerated electrons and holes on the CdS fully perform their own roles, thereby resulting in enhancement of photocatalytic activity and stability of CdS. [ABSTRACT FROM AUTHOR]

Dynamic covalent chemistry (DCC) has, in recent years, provided valuable tools to synthesize molecular architectures of increasing complexity. We have also taken advantage of imine DCC chemistry to prepare TPMA‐based supramolecular cages for molecular recognition applications. However, the versatility of this approach has as a major drawback the intrinsic hydrolytic lability of imines, which hampers some applications. We present herein a synthetic strategy that combines the advantages of a thermodynamic‐driven formation of a supramolecular structure using imine chemistry, together with the possibility to synthetize chiral hydrolytically stable structures through a [3,3]‐sigmatropic rearrangement. A preliminary mechanistic analysis of this one‐pot synthesis and the scope of the reaction are also discussed. [ABSTRACT FROM AUTHOR]

Catalytic reduction of a representative set of imines, both aldimines and ketimines, to amines has been studied using transfer hydrogenation from 1,4‐dicyclohexadiene. Unusually, this has been achieved using s‐block pre‐catalysts, namely 1‐metallo‐2‐tert‐butyl‐1,2‐dihydropyridines, 2‐tBuC5H5NM, M(tBuDHP), where M=Li–Cs. Reactions have been monitored in C6D6 and tetrahydrofuran‐d8 (THF‐d8). A definite trend is observed in catalyst efficiency with the heavier alkali metal tBuDHPs outperforming the lighter congeners. In general, Cs(tBuDHP) is the optimal pre‐catalyst with, in the best cases, reactions producing quantitative yields of amines in minutes at room temperature using 5 mol % catalyst. Supporting the experimental study, Density Functional Theory (DFT) calculations have also been carried out which reveal that Cs has a pathway with a significantly lower rate determining step than the Li congener. In the postulated initiation pathways DHP can act as either a base or as a surrogate hydride. [ABSTRACT FROM AUTHOR]

N‐heterocyclic carbene (NHC)‐catalyzed enantioselective Mannich‐type reactions of the biomass‐derived platform compound 5‐(chloromethyl)furfural (CMF) with imines were developed. A series of high‐value‐added chiral amines were afforded in good to high yields with excellent regio‐ and enantioselectivities. The bifunctional NHC derived from ʟ‐pyroglutamic acid efficiently steered the remote addition of the trienolate intermediate to the imine in a highly stereocontrolled manner. This represents the first enantioselective reaction proceeding via an NHC‐bound trienolate intermediate. [ABSTRACT FROM AUTHOR]

Covalent organic nanotubes (CONTs) are porous one‐dimensional frameworks connected through imine bonds via Schiff base condensation between aldehydes and amines. The presence of two amine groups at the ortho position in the structurally demanding tetraaminotriptycene (TAT) building block leads to multiple reaction pathways between the ditopic aldehyde and the tetratopic amine. We have synthesized five different monomers of CONT‐1 by the Schiff base condensation reaction between TAT and o‐anisaldehyde. The conversion of imine to imidazole bonding in a monomer is probed using NMR, mass spectrometry, and X‐ray diffraction techniques. Solid‐state NMR provide insights into the CONTs' structural connectivity. A theoretical investigation suggests that the π‐π stacking could be the driving force for rapid imine to imidazole conversion within the CONT‐1. Microscopic imaging sheds further light on the self‐assembly process of the CONTs, indicating both head‐to‐head and side‐by‐side assembly. [ABSTRACT FROM AUTHOR]

Homologation of trisubstituted fluoroalkenes followed by allylboration of aldehyde, ketone and imine substrates is suitable for synthesis of β‐fluorohydrin and amine products. In the presence of (R)‐iodo‐BINOL catalyst enantioselectivities up to 99 % can be achieved by formation of a single stereoisomer with adjacent stereocenters, of which one is a tertiary C−F center. [ABSTRACT FROM AUTHOR]

Transition‐metal‐catalyzed enantioselective addition of aryl organometallic reagents to imines has emerged as one of the most powerful tools for the formation of optically active diarylmethylamines. Here, we report the first asymmetric reductive (hetero)arylations of imines using aryl and heteroaryl halides enabled by a chiral cobalt‐bisphosphine catalyst. This approach shows good functional group compatibility and complements the reported strategy without use of organometallic reagents. Mechanistic investigations supported that aryl‐cobalt, instead of an arylzinc reagent, was formed in situ in this reductive aryl‐addition event. [ABSTRACT FROM AUTHOR]

We herein describe the chiral diboron‐templated asymmetric homocoupling of aryl alkyl ketimines, providing for the first time a series of chiral vicinal tetrasubstituted diamines with excellent ee values and good to high yields. The powerful and efficient diboron‐participated [3,3]‐sigmatropic rearrangement is successfully demonstrated by the homocoupling of a variety of ketimines thanks to the rational design and engineering of chiral diborons. Systematic DFT studies suggest that two chiral diborons adopt different conformational assembling strategies to couple the diboron template with ketimine substrates in their tight concerted transition states to ensure the excellent enantioselectivities. The synthetic value of chiral vicinal tetrasubstituted diamines is demonstrated by the asymmetric α‐bromination of aliphatic aldehydes by employing a chiral vicinal tetrasubstituted diamine‐based organocatalyst. [ABSTRACT FROM AUTHOR]

A divergent asymmetric total synthesis of voacafricines A and B, hexacyclic monoterpene indole alkaloids, has been accomplished featuring the following key steps: a) a catalyst‐controlled asymmetric Pictet–Spengler reaction of 6‐methoxytryptamine with a chiral α‐ketoester affording a 1,1‐disubstituted tetrahydro‐β‐carboline in excellent yield and diastereoselectivity; b) oxidative cleavage of a 3,5‐disubstituted cyclopentene furnishing a dialdehyde intermediate, which was effectively differentiated through spontaneous cyclization with the neighboring hydroxy and secondary amine functions; c) intramolecular nucleophilic addition of a tertiary amino nitrogen atom to the in situ generated oxonium species generating stereoselectively an unprecedented 8‐alkyl octahydro‐2H‐5,8‐methanofuro[2,3‐b]azepin‐8‐ium motif bearing five contiguous stereocenters. The synthesis confirmed the absolute configuration of these two natural products. [ABSTRACT FROM AUTHOR]

Compared to γ‐addition, the α‐addition of α‐branched β,γ‐unsaturated aldehydes faces larger steric hindrance and disrupts the π–π conjugation, which might be why very few examples are reported. In this article, a highly diastereo‐ and enantioselective α‐regioselective Mannich reaction of isatin‐derived ketimines with α‐, β‐ or γ‐branched β,γ‐unsaturated aldehydes, generated in situ from Meinwald rearrangement of vinyl epoxides, is realized by using chiral N,N′‐dioxide/ScIII catalysts. A series of chiral α‐quaternary allyl aldehydes and homoallylic alcohols with vicinal multisubstituted stereocenters are constructed in excellent yields, good d.r. and excellent ee values. Experimental studies and DFT (density functional theory) calculations reveal that the large steric hindrance of the ligand and the Boc (tButyloxy carbonyl) protecting group of imines are critical factors for the α‐regioselectivity. [ABSTRACT FROM AUTHOR]

We report herein the first examples of chiral phosphoric acid‐catalyzed enantioselective Diels–Alder reactions between 2‐trifluoroacetamido‐1,3‐dienes 1 and α,β‐unsaturated carbonyl compounds 2. Polysubstituted 1‐acetamido cyclohexenes 3 were formed in high yields with excellent diastereo‐ and enantioselectivities. The reaction proceeds through a stepwise process as shown by deuterium labelling experiments. A catalytic enantioselective three‐component reaction of 1, 2 and ortho‐hydroxybenzhydryl alcohols 4 was subsequently developed furnishing the densely functionalized hexahydroxanthenes 5 in a highly stereoselective manner. This multicomponent reaction generates four chemical bonds with concurrent creation of five contiguous stereocenters. [ABSTRACT FROM AUTHOR]

Easily accessible via a simple esterification of alcohols with formic acid, alkyl formates are used as a novel class of transfer hydroalkylation reagents, CO2 acting as a traceless linker. As a proof‐of‐concept, their reactivity in the transfer hydroalkylation of imines is investigated, using a ruthenium‐based catalyst and LiI as promoter to cleave the C−O σ‐bond of the formate scaffold. Providing tertiary amines, the reaction displays a divergent regioselectivity compared to previously reported transfer hydroalkylation strategies. [ABSTRACT FROM AUTHOR]

We disclose herein an atroposelective synthesis of novel bridged biaryls containing medium‐sized rings via N‐heterocyclic carbene organocatalysis. The reaction starts with addition of the carbene catalyst to the aminophenol‐derived aldimine substrate. Subsequent oxidation and intramolecular desymmetrization lead to the formation of 1,3‐oxazepine‐containing bridged biaryls in good yields and excellent enantioselectivities. These novel bridged biaryl products can be readily transformed into chiral phosphite ligands. Preliminary density function theory calculations suggest that the origin of enantioselectivity arises from the more favorable frontier molecular orbital interactions in the transition state leading to the major product. [ABSTRACT FROM AUTHOR]

Keywords: Bürgenstock Conference; Catalysis; Chemical Biology; Organic Chemistry; Stereochemistry EN Bürgenstock Conference Catalysis Chemical Biology Organic Chemistry Stereochemistry 1 10 10 12/16/22 20221223 NES 221223 The 55th edition of the Bürgenstock Conference took place in Brunnen (Switzerland) from May 1 to May 5, 2022. Chem. 2022, 87, 1934 - 1940; 28 D. Xu, N. Rivas-Bascón, N. M. Padial, K. W. Knouse, B. Zheng, J. C. Vantourout, M. A. Schmidt, M. D. Eastgate, P. S. Baran, J. Am. Chem. Soc. 2020, 142, 5785 - 5792; 29 J. C. Vantourout, S. R. Adusumalli, K. W. Knouse, D. T. Flood, A. Ramirez, N. M. Padial, A. Istrate, K. Maziarz, J. N. deGruyter, R. R. Merchant, J. X. Qiao, M. A. Schmidt, M. J. Deery, M. D. Eastgate, P. E. Dawson, G. J. L. Bernardes, P. S. Baran, J. Am. Chem. Soc. 2020, 142, 17236 - 17242. 51 D. C. Behenna, B. M. Stoltz, J. Am. Chem. Soc. 2004, 126, 15044 - 15045; 52 A. Q. Cusumano, B. M. Stoltz, W. A. Goddard, J. Am. Chem. Soc. 2020, 142, 13917 - 13933. 86 D. Parmar, H. Matsubara, K. Price, M. Spain, D. J. Procter, J. Am. Chem. Soc. 2012, 134, 12751 - 12757; 87 D. Parmar, K. Price, M. Spain, H. Matsubara, P. A. Bradley, D. J. Procter, J. Am. Chem. Soc. 2011, 133, 2418 - 2420. [Extracted from the article]

An extended class of stable mesoionic N‐heterocyclic imines (mNHIs), containing a highly polarized exocyclic imine moiety, were synthesized. The calculated proton affinities (PA) and experimentally determined Tolman electronic parameters (TEPs) reveal that these synthesized mNHIs have the highest basicity and donor ability among NHIs reported so far. The superior nucleophilicity of newly designed mNHIs was utilized in devising a strategy to incorporate CO2 as a bridging unit under reductive conditions to couple inert primary amides. This strategy was further extended to hetero‐couplings between amide and amine using CO2. These hitherto unknown catalytic transformations were introduced in the diversification of various biologically active drug molecules under metal‐free conditions. The underlying mechanism was explored by performing a series of control experiments, characterizing key intermediates using spectroscopic and crystallographic techniques. [ABSTRACT FROM AUTHOR]

An extended class of stable mesoionic N‐heterocyclic imines (mNHIs), containing a highly polarized exocyclic imine moiety, were synthesized. The calculated proton affinities (PA) and experimentally determined Tolman electronic parameters (TEPs) reveal that these synthesized mNHIs have the highest basicity and donor ability among NHIs reported so far. The superior nucleophilicity of newly designed mNHIs was utilized in devising a strategy to incorporate CO2 as a bridging unit under reductive conditions to couple inert primary amides. This strategy was further extended to hetero‐couplings between amide and amine using CO2. These hitherto unknown catalytic transformations were introduced in the diversification of various biologically active drug molecules under metal‐free conditions. The underlying mechanism was explored by performing a series of control experiments, characterizing key intermediates using spectroscopic and crystallographic techniques. [ABSTRACT FROM AUTHOR]

Direct asymmetric functionalization of the inert α C−H bonds of N‐unprotected propargylic amines is a big challenge in organic chemistry, due to the low acidity (pKa≈42.6) of the α C−H bonds and interruption of the nucleophilic NH2 group. By using a chiral pyridoxal as carbonyl catalyst, we have successfully realized direct asymmetric α‐C−H addition of N‐unprotected propargylic amines to trifluoromethyl ketones, producing a broad range of chiral alkynyl β‐aminoalcohols in 54–84 % yields with excellent stereoselectivities (up to 20 : 1 dr and 99 % ee). The α C−H bonds of propargylic amines are greatly activated by the pyridoxal catalyst via the formation of an imine intermediate, resulting in the increase of acidity by up to 1022 times (from pKa 42.6 to pKa 20.1), which become acidic enough to be deprotonated under mild conditions for the asymmetric addition. This work presented an impressive example for asymmetric functionalization of inert C−H bonds enabled by an organocatalyst. [ABSTRACT FROM AUTHOR]

The transition‐metal‐catalyzed C−P bond cleavage has emerged as a powerful tool for the formation of both C−C and C−P bond. However, the transition‐metal‐catalyzed stereoselective cleavage of C−P bond is still undeveloped. Herein, we report a palladium‐catalyzed stereoselective cleavage of C−P bond for the construction of P‐stereogenic phosphines and stereogenic axis. This protocol enables the quick synthesis of atropisomers bearing a P‐stereogenic center in high yields, diastereo‐ and enantioselectivities of up to 98 % ee, >25 : 1 dr. The product is able to serve as chiral catalyst in phosphine catalyzed [3+2] cycloaddition of allenoates to imines, showing the great potential of the present methodology. [ABSTRACT FROM AUTHOR]

Here we report a new type of chiral all‐carbon tetrasubstituted VQMs generated via chiral phosphoric acids catalyzed nucleophilic addition of 2‐alkynylnaphthols to o‐quinone methides or imines, which can be captured intramolecularly as a result of cycloaddition reaction. A new class of naphthyl‐2H‐chromenes bearing axially and centrally chiral elements and axially chiral quinone‐naphthols were prepared efficiently with good to excellent yields, diastereoselectivities and enantioselectivities. Noteworthy, the enantioselective cycloaddition of alkynylnaphthols with o‐quinone methides proceeded via a [2+2] cycloaddition, followed by a retro‐4π‐electrocyclization and a 6π re‐cyclization. While the cycloaddition of alkynylnaphthols with imines proceeded via a sequential [2+4] cycloaddition and an auto oxidation reaction. Moreover, the obtained axially chiral naphthols can be converted into valuable phosphine ligands and other functional molecules. [ABSTRACT FROM AUTHOR]

The preparation of heterobenzylic amines by a Ni‐catalyzed reductive cross‐coupling between heteroaryl imines and C(sp3) electrophiles is reported. This umpolung‐type alkylation proceeds under mild conditions, avoids the pre‐generation of organometallic reagents, and exhibits good functional group tolerance. Mechanistic studies are consistent with the imine substrate acting as a redox‐active ligand upon coordination to a low‐valent Ni center. The resulting bis(2‐imino)heterocycle⋅Ni complexes can engage in alkylation reactions with a variety of C(sp3) electrophiles, giving heterobenzylic amine products in good yields. [ABSTRACT FROM AUTHOR]

Stabilizing water‐sensitive reaction intermediates is challenging but desirable for guiding reactions to desired products in water. Herein, we report that labile imine and hemiaminal functional groups can be stabilized inside a synthetic container compound, a water‐soluble naphthotube. The naphthotube features a primary amine group anchored in a cavity with both hydrogen bonding sites and hydrophobic surfaces. Aldehydes in bulk aqueous solution are trapped in the cavity by the amine to form hemiaminals stabilized through hydrogen bonding and hydrophobic effects. Dehydration of the hemiaminal to the imine is favored by the release of water from the hydrophobic microenvironment. Both the hemiaminals and imines can be detected at room temperature by NMR spectroscopy and mass spectrometry. [ABSTRACT FROM AUTHOR]

The partial reduction of amides is a challenging transformation that must overcome the intrinsic stability of the amide bond and exhibit high chemoselective control to avoid overreduction to amine products. To address this challenge, we describe a zirconium‐catalysed synthesis of imines by the reductive deoxygenation of secondary amides. This reaction exploits the excellent chemoselectivity of Schwartz's reagent (Cp2Zr(H)Cl) and utilises (EtO)3SiH as a mild stoichiometric reductant to enable catalyst turnover. The reaction generally proceeds with high yields (19 examples, 51 to 95 % yield) and tolerates a variety of functional groups (alkene, ester, nitro, etc.). Stoichiometric mechanistic investigations suggest the regeneration of the active [Zr]−H catalyst is achieved through the metathesis of Si−H and Zr−OR σ‐bonds. [ABSTRACT FROM AUTHOR]

We report here "sandwich" diimine‐copper(I) catalysts for C(sp3)−H bond functionalization. Reactions of alkanes and ethers with trimethylsilyldiazomethane, ethyl diazoacetate, and trifluoromethyl‐diazomethane have been demonstrated. We also report C(sp3)−H bond methylation, benzylation, and diphenylmethylation by diazomethane, aryldiazomethanes, and diphenyldiazomethane. These reactions are rare examples of base‐metal catalyzed, intermolecular C(sp3)−H functionalizations by employing unactivated diazo compounds. Electrophilicity and unique steric environment of "sandwich"‐copper catalysts are likely reasons for their catalytic efficiency. [ABSTRACT FROM AUTHOR]

Ionic (2 e−) nucleophilic addition of allylmetal regents to imines dominates the synthesis of homo‐allyl amine; however, single electron (1 e−) mediated imine allylation with feedstocks butadiene as an alternative allyl source remains unexplored. In this work, we report a conceptually different radical–radical cross‐coupling strategy for the synthesis of a homoallyl amine between an α‐amino alkyl radical and a transient allylic radical. This metal‐free method provided a novel approach for the synthesis of homoallylic amines (>80 examples) from readily available materials with excellent regioselectivity and exceptional broad functional group compatibility. [ABSTRACT FROM AUTHOR]

A phosphine‐catalyzed highly enantioselective and diastereoselective (up to 98 % ee and >20 : 1 dr) (3+2) annulation between vinylcyclopropanes and N‐tosylaldimines has been developed, which allows facile access to a range of highly functionalized chiral pyrrolidines. Notably, this method makes use of vinylcyclopropanes as a synthon for phosphine‐mediated asymmetric annulation reaction, which will offer new opportunities for potential applications of cyclopropanes substrates in phosphine‐catalyzed organic transformations. [ABSTRACT FROM AUTHOR]

In contrast to the well‐established [3+2] cycloaddition reactions, the catalytic enantioselective [3+n] (n≥3) cycloaddition reaction of activated isocyanides for the preparation of six‐membered or larger ring systems has remained underdeveloped. Herein, we report the first example of highly diastereo‐ and enantioselective [3+3] cycloaddition of activated isocyanides with azomethine imines. By employing silver catalysis, a wide range of biologically important bicyclic 1,2,4‐triazines were obtained in high yields (up to 99 %) with good to excellent stereoselectivities (up to >20 : 1 dr, 99 % ee). In addition, the same catalytic system could be applied to both the late‐stage functionalization of complex bioactive molecules and the kinetic resolution of racemic azomethine imines, further highlighting its versatility and synthetic utility. [ABSTRACT FROM AUTHOR]

While continuous‐flow reactions with chiral heterogeneous catalysts provide a highly efficient method to synthesize optically active compounds, chiral heterogeneous Lewis acid catalysis has been less extensively explored. We have developed the first example of chiral heterogeneous Sc catalysts, which demonstrated excellent activity and selectivity for continuous‐flow enantioselective Friedel–Crafts reactions of isatins with indoles. Noncovalent interactions between chiral Sc complexes and heteropoly acid‐anchored amine‐functionalized SiO2 as support were utilized for the synthesis. The heteropoly acid was found to be crucial for the preparation, activity, and selectivity of the catalysts. The chiral ligand could be easily tuned without chemical modification and the continuous‐flow synthesis of a biologically active compound was achieved. [ABSTRACT FROM AUTHOR]

An O2‐assisted, four‐component reaction has been developed to synthesize a wide range of syn‐1,3‐amino alcohols in one step. The reaction proceeds by oxygenation of vinyl magnesium bromide (component‐I) with O2 (component‐II) to give a magnesium enolate of acetaldehyde, which undergoes addition to a chiral N‐tert‐butanesulfinyl imine (component‐III) followed by a sequential addition with excess vinyl magnesium bromide (component‐IV). The approach allows diastereoselective synthesis of anti/syn‐ and syn/syn‐3‐amino‐1,5‐diols in good yields with high diastereoselectivity. The method was illustrated in an efficient, four‐step synthesis of piperidine alkaloid (−)‐2′‐epi‐ethylnorlobelol. [ABSTRACT FROM AUTHOR]

A reagent‐controlled stereodivergent carbocyclisation of aryl aldimine‐derived, photocatalytically generated, α‐amino radicals possessing adjacent conjugated alkenes, affording either bicyclic or tetracyclic products, is described. Under net reductive conditions using commercial Hantzsch ester, the α‐amino radical species underwent a single stereoselective cyclisation to give trans‐configured amino‐indane structures in good yield, whereas using a substituted Hantzsch ester as a milder reductant afforded cis‐fused tetracyclic tetrahydroquinoline frameworks, resulting from two consecutive radical cyclisations. Judicious choice of the reaction conditions allowed libraries of both single and dual cyclisation products to be synthesised with high selectivity, notable predictability, and good‐to‐excellent yields. Computational analysis employing DFT revealed the reaction pathway and mechanistic rationale behind this finely balanced yet readily controlled photocatalytic system. [ABSTRACT FROM AUTHOR]

Ethynylbenziodoxolones (EBXs) are commonly used as radical traps in photocatalytic alkynylations. Herein, we report that aryl‐substituted EBX reagents can be directly activated by visible light irradiation. They act as both oxidants and radical traps, alleviating the need for a photocatalyst in several reported EBX‐mediated processes, including decarboxylative and deboronative alkynylations, the oxyalkynylation of enamides and the C−H alkynylation of THF. Furthermore, the method could be applied to the synthesis of alkynylated quaternary centers from tertiary alcohols via stable oxalate salts and from tertiary amines via aryl imines. A photocatalytic process using 4CzIPN as an organic dye was also developed for the deoxyalkynylation of oxalates. [ABSTRACT FROM AUTHOR]

Covalent organic frameworks (COFs) have emerged as an important class of organic semiconductors and photocatalysts for the hydrogen evolution reaction (HER)from water. To optimize their photocatalytic activity, typically the organic moieties constituting the frameworks are considered and the most suitable combinations of them are searched for. However, the effect of the covalent linkage between these moieties on the photocatalytic performance has rarely been studied. Herein, we demonstrate that donor‐acceptor (D‐A) type imine‐linked COFs can produce hydrogen with a rate as high as 20.7 mmol g−1 h−1 under visible light irradiation, upon protonation of their imine linkages. A significant red‐shift in light absorbance, largely improved charge separation efficiency, and an increase in hydrophilicity triggered by protonation of the Schiff‐base moieties in the imine‐linked COFs, are responsible for the improved photocatalytic performance. [ABSTRACT FROM AUTHOR]

Self‐assembly of host molecules in aqueous media via metal–ligand coordination is well developed. However, the preparation of purely covalent counterparts in water has remained a formidable task. An anionic tetrahedron cage was successfully self‐assembled in a [4+4] manner by condensing a trisamine and a trisformyl in water. Even although each individual imine bond is rather labile and apt to hydrolyze in water, the tetrahedron is remarkably stable or inert due to multivalence. The tetrahedral cages, as well as its neutral counterparts dissolved in organic solvent, have homochirality, namely that their four propeller‐shaped trisformyl residues adopt the same rotational conformation. The cage is able to take advantage of hydrophobic effect to accommodate a variety of guest molecules in water. When a chiral guest was recognized, the formation of one enantiomer of the cage became more favored relative to the other. As a consequence, the cage could be produced in an enantioselective manner. The tetrahedron is able to maintain its chirality after removal of the chiral guest—probably on account of the cooperative occurrence of intramolecular forces that restrict the intramolecular flipping of phenyl units in the cage framework. [ABSTRACT FROM AUTHOR]

The enantioselective aza‐Diels–Alder reaction is efficient for constructing chiral tetrahydropyridines, but the catalytic asymmetric aza‐Diels–Alder reaction of ketimines with unactivated dienes is still a challenging topic. Herein, guided by computational screening, a highly enantioselective aza‐Diels–Alder reaction of 2‐aryl‐3H‐indol‐3‐ones with unactivated dienes was realized by using a B(C6F5)3/chiral phosphoric acid catalyst system under mild conditions. The reaction has a broad scope with respect to both aza‐Diels–Alder reaction partners and hence offers rapid access to an array of tetrahydropyridine derivatives with pretty outcomes (up to 99 % yield, >20:1 dr and 98:2 er). The reaction is very efficient: lowering catalyst loadings for the model reaction to 0.1 mol %, enantioselectivity is still maintained. The synthetic utility was confirmed by transformations of the products. DFT calculations provide convincing evidence for the interpretation of stereoselection. [ABSTRACT FROM AUTHOR]

Imine‐based covalent organic frameworks (COFs) are a widely studied class of functional, crystalline, and porous nanostructures which combine a relatively facile crystallization with tuneable compositions and porosities. However, the imine linkage constitutes an intrinsic limitation due to its reduced stability in harsh chemical conditions and its unsuitability for in‐plane π‐conjugation in COFs. Urgent solutions are therefore required in order to exploit the full potential of these materials, thereby enabling their technological application in electronics, sensing, and energy storage devices. In this context, the advent of a new generation of linkages derived from the chemical conversion and locking of the imine bond represents a cornerstone for the synthesis of new COFs. A marked increase in the framework robustness is in fact often combined with the incorporation of novel functionalities including, for some of these reactions, an extension of the in‐plane π‐conjugation. This Minireview describes the most enlightening examples of one‐pot reactions and post‐synthetic modifications towards the chemical locking of the imine bond in COFs. [ABSTRACT FROM AUTHOR]

A new mode of carbene‐catalyzed heteroatom activation and asymmetric reactions is disclosed. The reaction starts with addition of a carbene catalyst to a (benz)imidazole‐derived aldimine substrate. Subsequent oxidation and proton transfer lead to the formation of a catalyst‐bound triaza‐diene as the key intermediate, in which the nitrogen atom at a site remote to the catalyst‐substrate bond is activated. This unusual triaza‐diene intermediate then undergoes highly enantioselective reactions with activated ketones through a concerted asynchronous pathway, as supported by mechanistic studies and preliminary density function theory calculation. [ABSTRACT FROM AUTHOR]

A non‐catalytic, mild, and easy‐to‐handle protecting group switched 1,3‐dipolar cycloaddition (1,3‐DC) between bi‐ or mono‐N‐protected Dha and C,N‐cyclic azomethine imines, which afford various quaternary amino acids with diverse scaffolds, is disclosed. Specifically, normal‐electron‐demand 1,3‐DC reaction occurs between bi‐N‐protected Dha and C,N‐cyclic azomethine imines, while inverse‐electron‐demand 1,3‐DC reaction occurs between mono‐N‐protected Dha and C,N‐cyclic azomethine imines. Above all, the reactions can be carried out between peptides with Dha residues at the position of interest and C,N‐cyclic azomethine imines, both in homogeneous phase and on resins in SPPS. It provides a new toolkit for late‐stage peptide modification, labeling, and peptide–drug conjugation. To shed light on the high regioselectivity of the reaction, DFT calculations were carried out, which were qualitatively consistent with the experimental observations. [ABSTRACT FROM AUTHOR]

Self‐assembly by imine condensation in aqueous media is a formidable task because of the labile nature of imines in the presence of water. Here, by taking advantage of multivalence and ligand preorganization, basket‐shaped triscationic cage molecules are self‐assembled in high yields in both water and organic solvent, by condensing a hexaformyl and bisamine. These cages, especially the chiral ones, are stable or inert in aqueous solution, that is, no decomposition was observed upon dilution, precipitation, or exposure to competitive amines or aldehydes. Such water‐compatibility allows the hosts to take advantage of the hydrophobic effect to accommodate hydrophobic guests. The chiral cage S‐23+ selectively binds and distinguishes one of two enantiomers, opening up opportunities for applications such as chiral compound separation. Chiral narcissistic self‐sorting and sergeants‐and‐soldiers effects occur during cage formation when two amino precursors are involved in self‐assembly. [ABSTRACT FROM AUTHOR]