Regioselective 1,4-Conjugate Addition of Grignard Reagents to α,β–γ,δ-Dienones and α,β–γ,δ-Dienyl Thiol Esters

Abstract

Alkyl Grignard reagents (Et, Bu,Pr, cyclohexyl), with the exception of BuMgCl, undergo exclusive or exceptionally highly regioselective 1,4-addition reactions to α,β-γ,δ-unsaturated ketones, while aryl and heteroaryl Grignard reagents give mixed results ranging from exclusive 1,4-addition (1-naphthyl, 2-N-methylpyrrolyl) to regioselective 1,2-addition (2-furyl, 2:1). All alkyl, aryl, and heteroaryl Grignard reagents examined gave exclusive 1,4-addition reactions with α,β-γ,δ-unsaturated thiol esters, with the exception ofBuMgCl, which gave an 80:20 mixture of 1,4:1,6-addition products. The high chemo- and regioselectivity observed for these reactions is attributed to a radical or radical-like pathway for the alkyl Grignard reagents and possibly a carbanion pathway for aryl Grignard reagents. The α,γ-dienyl thiol esters provide for a one-pot tandem 1,4-addition-nucleophilic acyl substitution reaction sequence to afford 3-substituted 4-enone moieties.

Regioselectivity Issues in the Addition of Grignard Reagents to Trifluoromethylated α‐Bromoenones

“…Surprisingly, no 1,4‐addition product was observed in the latter case. The reasons for the differences in the reactivity of alkyl‐ and aryl Grignard reagents as well as the mechanism of these reactions were recently discussed ,…”

“…The reasons for the differences in the reactivity of alkyl-and aryl Grignard reagents as well as the mechanism of these reactions were recently discussed. [23,24] In order to study the influence of the arylic substitution pattern of the substrate on the regioselectivity of the Grignard addition, we prepared α-bromoenones featuring either an electron-withdrawing 4-chloro substituent (1b) or an electrondonating, 4-methyl (1c) and 4-methoxy (1d), substituent on the aryl moiety. Here again, various types of Grignard reagents were engaged with these substrates 1b-d.…”

Gram-scale preparation of negative-type liquid crystals with a CF2CF2-carbocycle unit via an improved short-step synthetic protocol

“…From the above insight into the reaction mechanism, if the 1,2-addition reaction of Int-I proceeds in preference to the conjugate addition reaction, the desired octa-1,7-diene 5a should be produced in higher yield. However, no significant improvement was observed after various attempts such as employing a more nucleophilic lithium reagent instead of the Grignard reagent [ 20 ] or the addition of a Lewis acid to the reaction mixture [ 21 – 22 ]. Fortunately, 5a and 8a are easily separable by silica gel column chromatography, and the obtained octa-1,7-diene 5a was employed in the ensuing reaction without further attempts to improve its yield.…”

Tales of the Unexpected: Selectivity of Nucleophilic Additions to Zigzag Nanographene Diones

“…The formation of A7 is unexpected considering that the size of nucleophile (Ar) did not change compared to ArMgBr and organolithiums are known to favor 1,2-additions. 30 Because in ArLi the C-M bond is more polarized than in ArMgBr, ArLi is more basic and reactive, which might give an impression that it is also harder. In our reactions,…”