Catalytic enantioselective α-hydrazination of 1,3-dicarbonyl compounds with azodicarboxylates was investigated in the presence of our newly developed hydrogen bonding catalyst, squaramide 3j. High yields and high enantioselectivities were achieved with low catalyst loading under mild conditions.Hydrogen bond donor catalysis for asymmetric synthesis has attracted intense research efforts in recent years. 1 With the focus on substrate generality, catalyst practicality, and mildness of reaction conditions, our laboratory has been involved in the investigation of enantioselective transformations catalyzed by simple chiral hydrogen bond donors. 2 Recently we have developed a new family of catalysts based on the squaramide scaffold and demonstrated their utility in C-C bond 3a and C-P bond 3b formation. 4 In both cases nitroalkenes were successfully activated towards 1,4-addition reactions. In order to assess the range of electrophiles that would be compatible with squaramide-based catalysts, we have begun to examine other classes of reactants. In particular, we were drawn to electrophilic amination reactions, an important class of transformations that offers alternative and often attractive routes for the synthesis of nitrogen-containing compounds. 5 Among them, the asymmetric α-hydrazination of carbonyl compounds with azodicarboxylates is a powerful tool to install protected amino groups and set chiral centers during a synthetic sequence. When α-monosubstituted-1,3-dicarbonyl compounds are used as nucleophiles, quaternary α-amino acid derivatives are obtained as products. 6 These derivatives are of special interest for the synthesis of designer peptides with specific conformational and biological properties 7 and as building blocks of potential therapeutic agents such as metabotropic glutamate receptor ligands. 8 Although several examples of catalytic enantioselective α-hydrazination of 1,3-dicarbonyl compounds have already been reported, 9,10,11 there are still challenging issues that need to be addressed, particularly in the area of organocatalysis. These challenges include enantioselectivity, substrate generality, efficiency and ease of catalyst preparation, catalyst loading, and reaction time. Herein we describe our investigation of catalytic enantioselective α-hydrazination of 1,3-dicarbonyl compounds using a newly developed chiral squaramide catalyst. We report a wide substrate scope with several examples of reactions that proceed at ambient temperature and afford products in 93-96% ee.vrawal@uchicago.edu. Supporting Information Available: Procedures for catalyst preparation and hydrazination reaction, discussion and detail of the assignment of absolute stereochemistry, and analytical data for new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2011 May 7. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptTo confirm the ability of squaramides to catalyz...

Ynamides react with ketenes in [2+2] cycloadditions leading to a variety of substituted 3-aminocyclobut-2-en-1-ones. The ynamides employed in these reactions are readily available via the copper-promoted N-alkynylation of carbamates and sulfonamides with alkynyl bromides and iodides. The scope of the [2+2] cycloaddition with regard to both the ketene and ynamide component is described.

Highly substituted polycyclic aromatic and heteroaromatic compounds are produced via a two-stage tandem benzannulation/cyclization strategy. The initial benzannulation step proceeds via a pericyclic cascade mechanism triggered by thermal or photochemical Wolff rearrangement of a diazo ketone. The photochemical process can be performed using a continuous flow reactor which facilitates carrying out reactions on a large scale and minimizes the time required for photolysis. Carbomethoxy ynamides as well as more ketenophilic bissilyl ynamines and N-sulfonyl and N-phosphoryl ynamides serve as the reaction partner in the benzannulation step. In the second stage of the strategy, RCM generates benzofused nitrogen heterocycles, and various heterocyclization processes furnish highly substituted and polycyclic indoles of types that were not available by using the previous cyclobutenone-based version of the tandem strategy.

A two-stage “tandem strategy” for the synthesis of indoles with a high level of substitution on the six-membered ring is described. Benzannulation based on the reaction of cyclobutenones with ynamides proceeds via a cascade of four pericyclic reactions to produce multiply substituted aniline derivatives in which the position ortho to the nitrogen can bear a wide range of functionalized substituents. In the second stage of the tandem strategy, highly substituted indoles are generated via acid-, base-, and palladium-catalyzed cyclization and annulation processes.

Benzannulation via the Reaction of Ynamides and Vinylketenes. Application to the Synthesis of Highly Substituted Indoles. -A two-stage tandem strategy for the synthesis of indoles with a high level of substitution on the six-membered ring is described. Benzannulation based on the reaction of cyclobutenones with ynamides proceeds via a cascade of four pericyclic reactions to produce multiply-substituted aniline derivatives in which the position ortho to the nitrogen can bear a wide range of functionalized substituents. In the second stage of the tandem strategy, highly substituted indoles are generated via acid-, base-, and palladium-catalyzed cyclization and annulation processes. -(LAM, T. Y.; WANG, Y.-P.; DANHEISER*, R. L.; J. Org. Chem. 78 (2013) 18, 9396-9414, http://dx.