Guided desaturation of unactivated aliphatics

Abstract

The excision of hydrogen from an aliphatic carbon chain to produce an isolated olefin (desaturation) without over-oxidation is one of the most impressive and powerful biosynthetic transformations for which there are no simple and mild laboratory substitutes. The versatility of olefins and the range of reactions they undergo is unsurpassed in functional group space. Thus, the conversion of a relatively inert aliphatic system to its unsaturated counterpart can open new possibilities in retrosynthesis. In this article, the invention of a directing group to achieve such a transformation under mild, operationally simple, metal-free conditions is outlined. This “portable desaturase” (TzoCl) is a bench-stable, commercial entity (Aldrich, cat # L510092) that is facile to install on alcohol and amine functionalities to ultimately effect remote desaturation, while leaving behind a synthetically useful tosyl group.

Complementary Strategies for Directed C(sp3)−H Functionalization: A Comparison of Transition‐Metal‐Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer

“…A successful example has been reported by Baran and coworkers for the desaturation of aliphatic compounds (Scheme 64). [150] Another example has been reported by Nishio et al (Scheme 79) for the synthesis of amide 423 from ketone 422. [175] Irradiation of 422 with UV light results in the formation of diradical 424.T he oxygen radical abstracts ah ydrogen atom from the methyl C À Hb ond through 1,8-HAT, thereby leading to the formation of alkyl 425,w hich cyclizes to give 426.A mide 423 is formed via either intermediate 427 or 428.T he key to the success is the lack of hydrogen atoms for 1,5-, 1,6-, and 1,7-HATasw ell as the geometry constraint imposed by the sp 2 -hybridized atoms which significantly reduces the entropy cost for 1,8-HAT.…”

“…[150] In the proposed mechanism, the elimination of HNEt 2 from 358 yields diazonium 360,which is reduced by TEMPO to give aryl radical 361.A1,7-HATg ives tertiary radical 362.S ubsequent oxidation and deprotonation accounts for the formation of alkene 359.…”

Alcohols or Masked Alcohols as Directing Groups for C–H Bond Functionalization

“…33 In 2012, Baran and co-workers developed another guided radical protocol for alkane dehydrogenation using an o-tosyl triazene (Tz o ) moiety. 34 This well-designed, "portable desaturase"-like group (Tz o ) is easy to install on alcohols and amines, and can serve as a masked aryl radical to enable remote desaturation leaving behind a synthetically useful tosyl group (Scheme 22). In general, the desaturation reaction takes place via 1,7-H-abstraction when a tertiary carbon center is at the γ-position to the alcohol or amine.…”

Second-Generation Palladium Catalyst System for Transannular C–H Functionalization of Azabicycloalkanes

“…Instead, the major products were 12-ene (24% isolated yield) and 12-ene-OPiv (31% isolated yield), in which a single C–H arylation occurred along with a second, completely different transannular C–H functionalization reaction. In the formation of 12-ene , this second reaction involves dehydrogenation at the C-6–C-7 position, 32 presumably via transannular C–H activation and subsequent β-hydride elimination. 33 Product 12-ene-OPiv is then formed via an allylic C–H pivaloylation of 12-ene .…”