Regioselective Cyanation of Six‐Membered N‐Heteroaromatic Compounds Under Metal‐, Activator‐, Base‐ and Solvent‐Free Conditions

Abstract

A regioselective cyanation of heteroaromatic N-oxides with trimethylsilyl cyanide has been developed to obtain 2-substituted N-heteroaromatic nitrile without the requirement of any external activator-, metal-, base-, and solvent. The present protocol is a straightforward, one-pot heteroaromatic CÀ H cyanation process, and proceeds smoothly in conventional heating but also under microwave irradiation with shorter reaction times. This approach now allows access to a broad class of quinoline N-oxides and other heteroarene N-oxides with high to good yields and can also be scaled up to obtain gram quantities. Further application of this process was observed and utilized in late-stage cyanation of the anti-malarial drug quinine as well as transformation of the 2-cyanoazines to a series of biologically important molecules. Based on the experimental observations, a plausible mechanism has also been proposed highlighting the dual role of trimethylsilyl cyanide as a nitrile source and as an activating agent.

Recent Advances in the Synthesis of C2‐Functionalized Pyridines and Quinolines Using N‐Oxide Chemistry

“…Das's group successfully prepared 2‐cyanated pyridines and quinolines 317 under neat conditions at high temperatures either by conventional heating or microwave treatment (Scheme 96). [128] …”

Transition Metal Free α−C−H Functionalization of Six Membered Heteroaromatic‐N‐Oxides

“…Finally, again activation followed by rearomatization afforded the final product 130 (Scheme 50). [72] In 2019, Antonchick and co-workers reported the crosscoupling of six membered heteroaromatic N-oxide with organosilanes as a coupling partner under transition-metal-free conditions. Treatment of quinoline N-oxides 18 with benzyltrimethylsilane in the presence of catalytic amount of tetrabutylammonium fluoride and triethylsilane as an additive produced the 2-benzylated quinolines 134 in good to excellent yields (Scheme 51).…”

“…N‐ heteroaromatic compounds 18 converted to 2‐substituted N ‐heteroaromatic nitrile 130 in the presence of trimethylsilyl cyanide under solvent free conditions at 130 °C (Scheme 50). [72] Also, they performed the same reaction under the microwave irradiation condition. Both electron‐donating and electron withdrawing substituents at quinoline N ‐oxides afforded the products in good to high yields.…”

Recent Progress in Non‐Catalytic C–H Functionalization of Heterocyclic N‐Oxides

“…The introduction of the cyano group [54,55] can be effectively accomplished in the absence of additional promoters and bases by trimethylsilyl cyanide (TMSCN), [54] which is both an activating agent and a source of the CN nucleophile, in the absence of additional promoters and bases (Scheme 30). The process is carried out without solvent under heating (or under microwave activation conditions), with high C2-selectivity and tolerance to many functional groups, including acetal and hydroxy groups.…”