A novel method for direct C-H functionalization of saturated N-heterocycles allowing easy access to synthetically as well as biologically important and structurally diverse ring-fused oxazines is developed. The method is operationally simple and highly diastereoselective. Moreover, it is efficient in functionalizing broad classes of both cyclic and acyclic amines including the substrates that are otherwise difficult to functionalize.

Arylated aliphatic N-heterocycles, and particularly arylated pyrrolidines, have a wide range of applications in medicine as well as in chemistry. Arylation of pyrrolidines mainly relies on metal-mediated couplings, which produce unwanted toxic metal waste. In this Communication, we report an oxidant-and metal-free method for direct sp 3 C À H arylation of pyrrolidine employing a highly atom economic three-component reaction. The method, operating under very simple and mild conditions, is highly selective and very efficient in producing single regioisomer of the arylated product even on a multigram scale. As an alternative to the metal-mediated reaction, this method has the potential to be used in production at an industrial scale. Moreover, a new approach for C À H arylation based on a novel reactivity that differs from the reactivity in Mannich or Betti reactions of iminium ion is presented.The dependence of human society on functional molecules that serve as advanced materials and medicine is increasing tremendously with time. Accordingly, huge progress has been made for the development of novel methods and strategies to synthesize those functional molecules. During synthesis, excess atomic units in the form of reactants, reagents, solvents or catalysts required to achieve chemical selectivity and molecular complexity are eliminated as chemical waste, which becomes a major problem for the environment. Enormous effort is ongoing to modify known methods and/or to develop new methods for minimizing the production of the chemical waste. Various concepts such as atom economy, [1] redox economy, [2] and step economy [3] were introduced and accepted by the synthetic chemistry community as some of the important parameters for evaluating the practicability of synthetic methods. [4] In this respect, the reaction that involves simple addition of reactants without any other aid from metal-based catalysts, oxidants, and so on, and provides the desired product would be better suited. A very few reactions of this kind (e.g. Diels-Alder, [5] Mannich, [6] Betti reactions, [7] and so on), in comparison with the pool of known chemical processes, are precedented in literature. Therefore, innovative design for the development of new reactions or reformatting the known ones to minimize the waste, keeping the essential features intact (selectivity, yields etc.), is intensely needed.In view of such development, evolutionary efforts are continuing in the context of direct C À H-arylation of saturated N-heterocycles, as a-arylated heterocycles such as arylated pyrrolidines have a wide range of applications in chemistry as well as in medicine. [8, 9] All of the known protocols for efficient direct arylation of saturated N-heterocycles generally involve the use of organometallic reactants either in stoichiometric and/or catalytic amount (Scheme 1, Eq. (1)). [10,11] The metal-mediated reactions are highly efficient in terms of selectivity and reactivity in producing wide variety of valuable C À H arylated heterocyclic compounds. Howev...

Optically active 5-aryl 2,5-disubstituted pyrrolidines are the principal structural moiety of many bioactive compounds including natural products and catalysts for asymmetric synthesis. A highly regio- and diastereoselective and enantiospecific method for direct C-H arylation of aliphatic amine has been developed. Structurally diverse enantiopure arylated pyrrolidines were synthesized from commercially available starting materials, through a single-step three-component reaction under metal- and oxidant-free conditions. Furthermore, the complex analogous structure of CCK antagonist RP 66803 and angiotensin-converting enzyme inhibitors was easily constructed using the synthesized arylated pyrrolidine derivative. Detailed theoretical calculations (M06-2X/TZVPP/SMD//M06-2X/6-31+G(d,p) level) were also carried to investigate the mechanism and high level of stereocontrol involved in this direct sp(3) C-H arylation reaction. Preference for a given regio- and stereoselectivity in the arylated product can be explained through elucidation of the mechanism for dehydration, generating azomethine ylide, and for the final re-aromatization step. The calculated energies reveals that the re-aromatization step is essentially rate determining, accompanying an activation barrier of Δ(≠) G=25.6 kcal mol(-1) .

Direct arylation and heteroarylation of unprotected tetrahydroisoquinolines were achieved under conditions free of metals, oxidants and solvents.

An unprecedented stereoselective C–H functionalization enabled Ugi-azide (CH-Ugi-azide) reaction to access α-tetrazolyl alicyclic amines directly from N-heterocycles is reported.