Aliphatic Radical Relay Heck Reaction at Unactivated C(sp3 )-H Sites of Alcohols

Abstract

The Mizoroki-Heck reaction is one of the most efficient methods for alkenylation of aryl, vinyl, and alkyl halides. Given its innate nature, this protocol requires the employment of compounds possessing a halogen atom at the site of functionalization. However, the accessibility of organic molecules possessing a halogen atom at a particular site in aliphatic systems is extremely limited. Thus, a protocol that allows a Heck reaction to occur at a specific nonfunctionalized C(sp³ )-H site is desirable. Reported here is a radical relay Heck reaction which allows selective remote alkenylation of aliphatic alcohols at unactivated β-, γ-, and δ-C(sp³ )-H sites. The use of an easily installed/removed Si-based auxiliary enables selective I-atom/radical translocation events at remote C-H sites followed by the Heck reaction. Notably, the reaction proceeds smoothly under mild visible-light-mediated conditions at room temperature, producing highly modifiable and valuable alkenol products from readily available alcohols feedstocks.

Keywords: C−H activation; Heck reaction; palladium; photochemistry; radicals.

Scheme 1.

Development of radical relay Heck reaction.

Scheme 2.

Scope of radical relay Heck reaction. Experimental details are provided In the supplementary material, a) γ-Heck reactions, b) β-Heck reactions. c) δ-Heck reactions, d) Heck reaction at secondary C–H sites, d.r. = diastereomeric ratio, e) Inefficient substrates, R = iPr for 1a–z, 1ad–am, 1 ao, 1 ap, 1 au, R = Me for 1 aa–ac, 1 an, 1 aq–at, [a] Different deprotection procedures were applied depending on the products: TBAF in THF; CSA in MeOH; or AcCI and Montmorillonite K10 in CH₂Cl₂, See the Supporting Information for details, [b] Methyl vinyl ketone was used in the radical relay Heck reaction followed by reduction with NaBH₄ [c] Premature coupling product was observed as a major product (66%), [d] Desaturation product was observed as a major product (57%), CSA = camphorsulfonic acid, TBAF = tetra-n-butylammonium fluoride, THF = tetrahydrofuran.

Scheme 3.

Transformations of alkenol products. Experimental details are provided in the Supporting Information. a) 10 mol% OsO₄, 1.2 equiv NMO, acetone/water. b) 1.5 equiv mCPBA, CH₂Cl₂. c) 2 equiv LiBr, 0.5 equiv NaIO₄, CH₃CN. d) O₃, 2 equiv Me₂S, acetone. e) O₃, 2 equiv Me₂S, acetone, then NaBH₄ in MeOH. f) 5 equiv HBr, CHCI₃/DMSO. g) 1.2 equiv LiAlH₄, Et₂O. h) 10 mol% NiCl₂, 7 equiv NaBH₄, MeOH. *≈1:1 d.r. DMSO = dimethylsulfoxide, mCPBA=m-chloroperbenzoic acid, NMO = N-methylmorpholine N-oxide.

Scheme 4.

Proposed mechanism.