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This report describes the site-selective α-functionalization of sulfonylamide derivatives through the in-situ generation of imine intermediates. The N-F sulfonylamides, which could facilitate the elimination to generate imines, are coupled with TBACN to efficiently and mildly afford α-amino cyanides. Comparing with Strecker reaction, this transformation offers a complementary strategy to efficiently construct α-amino cyanides from direct α C-H functionalization of sulfonylamindes. The reaction is also characterized by broad substrate scope and flash chromatography column free workup. More importantly, the new two-electron pathway to generate imines through manipulation of the leaving group allows us to achieve excellent α site-selectivity.

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. Agency for Science, Technology and Research (A*STAR) National Research Foundation (NRF) Accepted version We acknowledge financial supports from Singapore National Research Foundation under its NRF Investigatorship (NRF-NRFI2016-06) and Competitive Research Program (NRF-CRP22-2019-0002); the Ministry of Education, Singapore, under its MOE AcRF Tier 1 Award (RG108/16, RG5/19, RG1/18), MOE AcRF Tier 2 (MOE2019-T2-2-117), MOE AcRF Tier 3 Award (MOE2018-T3-1-003); the Agency for Science, Technology and Research (A*STAR) under its A*STAR AME IRG Award (A1783c0008, A1783c0010); GSK-EDB Trust Fund; Nanyang Research Award Grant, Nanyang Technological University; the National Natural Science Foundation of China (21772029, 21801051, 21807019, 21961006, 22071036, 22061007, 82360589, 81360589), Frontiers Science Center for Asymmetric Synthesis and Medicinal Molecules, Department of Education, Guizhou Province [Qianjiaohe KY number (2020)004]; The 10 Talent Plan (Shicengci) of Guizhou Province ([2016]5649); the Science and Technology Department of Guizhou Province ([2018]2802, [2019]1020); the Program of Introducing Talents of Discipline to Universities of China (111 Program, D20023) at Guizhou University; the Guizhou Province First-Class Disciplines Project [(Yiliu Xueke Jianshe Xiangmu)-GNYL(2017)008], NSFC Grant (81360589), Guizhou University of Traditional Chinese Medicine (China); and Guizhou University. X.Z. thanks the Institute of High Performance Computing (IHPC), A*STAR for financial support and acknowledges the use of super computers in the A*STAR Computational Resource Centre (ACRC) and the National Supercomputing Centre (NSCC), Singapore (https://www.nscc.sg), for computations performed in this work.

A carbene-catalyzed enantioselective cascade reaction of substituted methylenemalononitriles and α-bromoenals is disclosed. Key steps of this cascade process include a formal [4 + 2] cycloaddition, aldol reaction, and intramolecular lactonization. Our reaction offers streamlined and highly stereoselective access to complex tetrahydrocarbazole derivatives, with simultaneous formation of four chemical bonds and four chiral centers. Ministry of Education (MOE) National Research Foundation (NRF) Accepted version We thank Dr. Yongxin Li (NTU) for assistance with X-ray structure analysis. We acknowledge financial support by the Singapore National Research Foundation (NRF-NRFI2016- 06), the Ministry of Education of Singapore (RG 1/18; RG 5/ 19; MOE2018-T3-1-003), an A*STAR Individual Research Grant (A1783c0008; A1783c0010), GSK-EDB Trust Fund, a Nanyang Research Award Grant, and Nanyang Technological University; the Guizhou Province First-Class Disciplines Project (Yiliu Xueke Jianshe Xiangmu)-GNYL(2017)008, Guizhou University of Traditional Chinese Medicine (China), QMYY [2017]101 (China); the National Natural Science Foundation of China (Nos. 21772029, 21901233), the National Key Technologies R&D Program (No. 2014BAD23B01), the “Thousand Talent Plan”, the 10 Talent Plan (Shicengci) of Guizhou Province [2016]5649, and Guizhou University, Department of Science and Technology of Guizhou Province [2019]1020, Undergraduate Innovation and Pioneer Training Program, Guizhou University of Traditional Chinese Medicine 2018(31), Program of Introduc- ing Talents of Discipline to Universities of China (111 Program, D20023).

A novel one-pot approach for the synthesis of multi-substituted 2-imidazolylimidazoles, 2-pyrazolylimidazoles and 2-indazolylimidazoles was developed through a domino addition/A3 coupling/cyclization process under copper catalysis. A variety of aminoethyl- or hydroxylethyl-tethered 2-azolylimidazole derivatives were conveniently and efficiently assembled in one pot using N-propargylcarbodiimides, azoles, paraformaldehyde and secondary amines as starting materials. The products containing an o-iodoaryl group could be further converted to imidazo[1,2-c]imidazo[1,2-a]quinazoline derivatives through a copper-catalyzed intramolecular C-H arylation.

A catalyst- and metal-free electrochemical hydrodehalogenation of aryl halides is disclosed. Our reaction by a flexible protocol is operated in an undivided cell equipped with an inexpensive graphite rod anode and cathode. Trialkylamines nBu3 N/Et3 N behave as effective reductants and hydrogen atom donors for this electrochemical reductive reaction. Various aryl and heteroaryl bromides worked effectively. The typically less reactive aryl chlorides and fluorides can also be smoothly converted. The utility of our method is demonstrated by detoxification of harmful pesticides and hydrodebromination of a dibrominated biphenyl (analogues of flame-retardants) in gram scale. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) MOE (Min. of Education, S’pore) Accepted version

Herein, we disclosed a highly efficient strategy of enantioselective synthesis of 2,3-furan-fused carbocycles bearing three-contiguous stereocenters. This transformation is catalyzed by dual catalysis of PtCl4/chiral amines via tandem dehydrogenative annulation/Diels–Alder reaction of 2-(1-alkynyl)-2-alken-1-ones and enals. The in situ generation of the furan-based ortho-quinodimethane intermediates and the iminium activation of enals are crucial to this transformation.

The dominated approaches for asymmetric aldol reactions have primarily focused on the aldol carbon-carbon bond-forming events. Here we postulate and develop a new catalytic strategy that seeks to modulate the reaction thermodynamics and control the product enantioselectivities via post-aldol processes. Specifically, an NHC catalyst is used to activate a masked enolate substrate (vinyl carbonate) to promote the aldol reaction in a non-enantioselective manner. This reversible aldol event is subsequently followed by an enantioselective acylative kinetic resolution that is mediated by the same (chiral) NHC catalyst without introducing any additional substance. This post-aldol process takes care of the enantioselectivity issues and drives the otherwise reversible aldol reaction toward a complete conversion. The acylated aldol products bearing quaternary/tetrasubstituted carbon stereogenic centers are formed in good yields and high optical purities. Ministry of Education (MOE) National Research Foundation (NRF) Accepted version

An enantioselective functionalization of the indole NH group is developed. The reaction stereoselectivity is controlled by an N-heterocyclic carbene catalyst that adds to an aldehyde moiety at the C7-carbon of indole. The NH group participating in the carbene-catalyzed reaction is part of the heteroaromatic rings of the indole substrate. Our reactions afford multicyclic products bearing pyrroloquinazoline or oxazinoindole scaffolds widely present in bioactive molecules. Our study will encourage further exploration of carbene-catalyzed reactions of aromatic molecules and asymmetric transformation of heteroatoms in various functional molecules. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) MOE (Min. of Education, S’pore) Accepted version

A new catalytic approach for rapid asymmetric access to spirocycles is disclosed. The reaction involves a carbene- and thiourea-cocatalyzed desymmetrization process with the simultaneous installation of a spirocyclic core. The use of a thiourea cocatalyst is critical to turn on this reaction, as no product was formed in the absence of a thiourea. Our study constitutes the first success in the carbene-catalyzed enantioselective synthesis of all-carbon spirocycles. The reaction products can be readily transformed into sophisticated multicyclic molecules and chiral ligands. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) MOE (Min. of Education, S’pore) Accepted version

A carbene and sulfinate co-catalyzed intermolecular Rauhut-Currier reaction between enals and nitrovinyl indoles is disclosed. The carbene catalyst activates the enal and the sulfinate co-catalyst activates the nitrovinyl indole. Both activation processes are realized via the formation of covalent bonds between the catalysts and substrates to generate catalyst-bound intermediates. The dual catalytic reaction affords azepino[1,2-a]indole products with excellent stereoselectivity. Our study demonstrates the unique involvement of sulfinate as an effective nucleophilic catalyst in activating electron-deficient alkenes for asymmetric reactions. This dual catalytic approach should also encourage future explorations of both sulfinate and carbene catalysts for new reactions. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) MOE (Min. of Education, S’pore) Accepted version

3-Aryl-1,2,4-benzotriazines were conveniently prepared in moderate to good yields from 1,l-bis(benzotriazol-1-yl)methylarenes with allylsamarium bromide/hexamethylphosphramide (allylSmBr/HMPA). Preliminary results indicate that HMPA may enhance the reducing ability as well as prohibit the nucleophicility of allylSmBr, thus making allylSmBr/HMPA as a promising single-electron transfer (SET) reagent.

Efficient regioselective conjugate additions of thiophenols and benzotriazole to 4-aryl-4-oxobut-2-enoates have been achieved under mild conditions. Thus a variety of 2-arylthio-4-oxo-4-arylbutanoates and 2- benzotriazolyl-4-oxo-4-arylbutanoates were conveniently synthesized in good to excellent yields.

Facile and efficient conjugate additions of carbon nucleophiles, such as ?-dicarbonyl compounds and nitroalkanes, to 4-aryl-4-oxobut-2-enoates have been achieved under simple base catalysis. A variety of multi-functional ?-keto esters could be conveniently obtained in good to excellent yields with complete regioselectivity.

Benzotriazole adducts methoxycarbonylamino-1-(1-benzotriazolyl)alkanes 1 were derived from the condensation of an aldehyde, benzotriazole, and methylcarbamate. The leaving tendency of methoxycarbonylamino group (MeOCONH) and benzotriazole group (Bt) was investigated by treatment of the adducts with active methylene compounds under either Lewis acid-catalyzed or basic conditions. In the presence of SmI3, MeOCONH take priority over Bt in the leaving process, whereas in the presence of MeONa, the Bt was substituted in preference. Thus, the tunable substitution of the two leaving groups could be used for different synthetic purposes. J. Heterocyclic Chem., 00, 00 (2011).

Intermediary o-quinodimethanes are trapped with alkenes and alkynes, respectively, to provide highly functionalized furan derivatives.

A strategy for in situ generation of furan-based ortho-quinodimethanes (o-QDMs) by the gold(I)-mediated dehydrogenative heterocyclization of 2-(1-alkynyl)-2-alken-1-ones in the presence of pyridine N-oxide under mild reaction conditions was developed. These in situ furan-based o-QDMs were trapped by electron-deficient olefins and alkynes, thus furnishing various 2,3-furan-fused carbocycles in good yields with high diastereo- and regioselectivities.

The authors state that HMPA enhances the reducing ability of samarium as well as it prohibits the nucleophilicity of allyl-SmBr generated in situ.

HMPA and water as additives inhibit the nucleophilicity and enhance the SET ability of the Sm agent.

The leaving tendency of either methoxycarbonylamino or benzotriazole group by treatment of adducts (IV) with active methylene compounds (V) is studied.

The radical cyclization between aliphatic acyclic esters and alkenes was achieved unprecedentedly in the presence of allylsamarium bromide with HMPA and H(2)O as additives. The cascade radical cyclization-ring-opening-anionic cyclization allowed facile and efficient access to 2-(2-hydroxyalkyl)cyclopropanols from readily available materials.