Intermolecular sp3-C–H Amination for the Synthesis of Saturated Azacycles

Abstract

The preparation of substituted azetidines and larger-ring, nitrogen-containing saturated heterocycles is enabled through efficient and selective intermolecular sp<sup>3</sup>-C–H amination of alkyl bromide derivatives. A range of substrates is demonstrated to undergo C–H amination and subsequent sulfamate alkylation in good to excellent yield. <i>N</i>-Phenoxysulfonyl-protected products can be unmasked under neutral or mild basic conditions to yield the corresponding cyclic 2° amines. The preparative convenience of this protocol is demonstrated through gram-scale and telescoped multi-step procedures. Application of this technology is highlighted in a nine step total synthesis of an unusual azetidine-containing natural product, penaresidin B.

Aerobically-initiated C(sp3)–H bond amination through the use of activated azodicarboxylates

“…Buchwald-Hartwig amination), 5,6 (ii) the overreliance of directing groups, especially in the case of C(sp 3 )-H bond activation, resulting in synthetic routes requiring additional installation and removal steps of the protecting/directing group, 7,8 (iii) the current standard of using nitrene insertion reactions as a means for C(sp 3 )-H amination suffers from suboptimal regioselectivity and requires the use of specialised reagents such as organic azides [9][10][11] or azoles 12 as the nitrogen source, and (iv) the prevalent use of toxic/expensive transition metal reagents in the activation of inert C-H bonds. 13,14 Despite providing a direct route to C-N bond formation, the existence of these limitations and the current quantity of external additives 15,16 required for efficient reaction means that there is a need to develop C-H bond activation methodologies that are more attractive from a green chemistry standpoint. 17 The use of radical intermediates in C-H bond activation reactions has seen major developments in the past few decades owing to improvements in indiscriminate C-H bond abstraction and reaction regioselectivity.…”

Regio- and Diastereoselective Synthesis of 2-Arylazetidines: Quantum Chemical Explanation of Baldwin’s Rules for the Ring-Formation Reactions of Oxiranes

“…Only a few approaches have been developed for the synthesis of 2-phenylazetidines. N -Protected 2-arylazetidines can be synthesized by stereospecific cross-coupling reactions, 52 by selective intermolecular sp 3 -C–H amination, 53 or by [2+2] photocycloaddition. 1 A few efficient synthetic methods of diversely substituted N -aryl-2-cyanoazetidines have also been published, based on an anionic ring-closure reaction, which requires the presence of an electron-withdrawing group (EWG) in the starting material.…”