Direct Displacement of Alkoxy Groups of Vinylogous Esters by Grignard Reagents

Abstract

The direct displacement of alkoxy groups from the beta position of aromatic and unsaturated esters and ketones is described. The reaction is chemo- and regioselective, displaying wide substrate scope.

Mechanism of Alkoxy Groups Substitution by Grignard Reagents on Aromatic Rings and Experimental Verification of Theoretical Predictions of Anomalous Reactions

“…Although ketones are generally viewed as incompatible with the high nucleophilicity of Grignard reagents, we have shown that the displacement reaction is facile at temperatures below which the ester or ketone products will undergo addition (Table 1, entries 2–5) 1 . As an exception, MeMgI in CH 2 Cl 2 undergoes complete addition to the carbonyl group as previously reported 31 and confirmed in our lab (Table 1, entry 1).…”

“…These theoretical results were not in accordance with the reported reactivity for this substrate, since a slower but still complete chemoselectivity towards methoxy group displacement was previously published. 1 Intrigued by these observations, we repeated the same reactions and re-examined the NMR data of the isolated compounds carefully. Thereafter, we concluded that our previous assessment of reactivity for this compound was wrong, and the ester carbonyl group indeed reacts exclusively to provide the corresponding isopropyl ketone 10 in good yield (85%, Scheme 4), which did not undergo further 1,2-addition.…”

“…In our previous study, 1 we reported that non-aromatic vinylogous esters such us Z -ethyl 3-methoxycinnamate 3 and methyl 1-methoxy-3,4-dihydro-2-naphthoate 5 (Scheme 3) readily react with Grignard reagents in a similar manner to the naphthalene counterparts, namely with complete selectivity towards alkoxy group displacement. However, treatment of the corresponding 1H-indene analogue 7 with 1 equiv of i -PrMgCl only yielded starting unreacted starting material after extractive workup, hence we decided to shed some light onto this behavior computationally.…”

“…1 Thus, a simple change in the location of the alkoxy group to provide other ortho isomer, namely methyl 3-methoxy-2-naphthoate 9 , disrupted its reactivity as demonstrated by competition experiments. In the course of our computational investigations to rationalize this reactivity, we found that although the methoxy displacement pathway was clearly disfavored using EtMgCl as Grignard reagent model (lowest energy barrier: ΔG ‡ OMe = +30.8 for 9-TS OMe ), the reactivity at the carbonyl group remained essentially unchanged (lowest energy barrier: ΔG ‡ OMe = +22.1 for 9-TS C=O ), providing a complete chemoselectivity towards 1,2-addition.…”

“…According to the experimental results (Table 1, entry 6), 1 the chemoselectivity calculated for the addition of EtMgCl (computational model n -BuMgCl) to 1-methoxy-2-naphthaldehyde 13c is reversed with respect to analogous ester 1a with a calculated ratio of 2:98 favoring the attack towards the carbonyl group. As can be seen in Figure 7, the contribution of the carbonyl carbon to the LUMO is larger in naphthyl aldehyde 13c than in the analogous methyl ester 1a , justifying the higher selectivity towards 1,2 carbonyl addition with Grignard reagents of the former.…”