Substituent‐Controlled Reactivity in the Nazarov Cyclisation of Allenyl Vinyl Ketones

Abstract

Alkyl substitution α to the ketone of an allenyl vinyl ketone enhances Nazarov reactivity by inhibiting alternative pathways involving the allene moiety and through electron donation and/or steric hindrance. This substitution pattern also accelerates Nazarov cyclisation by increasing the population of the reactive conformer and by stabilising the oxyallyl cation intermediate. Furthermore, α substitution by an alkyl group does not alter the regioselectivity of interrupted Nazarov reactions when the oxyallyl cation intermediate is intercepted by addition of an oxygen nucleophile, or by [4+3] cyclisation with acyclic dienes. The regioselectivity of the Nazarov process for allenyl vinyl ketones was determined to be a result of an electronic bias in the oxyallyl cation intermediate. Computational data are consistent with this observation.

Ambiphilic molecules for trapping reactive intermediates: interrupted Nazarov reaction of allenyl vinyl ketones with Me2PCH2AlMe2

“…Under these conditions, the 1 H and 13 C{ 1 H} NMR spectra are again in accordance with a cyclopentene core, however both the 1 H and 13 C C(c)-CH3 resonances now exhibit coupling with the phosphorous atom; 2 JC-P and 3 JH-P couplings of 3.6 and 1.2 Hz, respectively. The 1 JC-P coupling of 65.9 Hz is now observed for the C(c) 13 C resonance at δ 78.9. For compound 3, attack of the phosphine moiety on the face opposite of the phenyl group is supported by the dipolar coupling between one of the P-CH3 groups and the proton on the carbon atom also bearing the phenyl group (see ESI).…”

“…12 In a joint experimental and theoretical study, it was shown that the selectivity for nucleophilic addition at position (a) can be attributed to an electronic bias (the carbon at position (a) is a better electrophile) rather than steric effects (methyl group at position (c)). 13 Herein, we report not only that the Lewis acid alane moiety in ambiphilic compound (Me2PCH2AlMe2)2 efficiently initiates the Nazarov cyclization of AVK 2, but that the phosphine moiety can selectively trap the oxyallyl cation at 40 position (a) or (c), which to our knowledge is unprecedented. 14 (see ESI).…”

“…Attack at the (a) position was expected for AVK 2. 13 However, under kinetic control, trapping by the nucleophilic phosphine moiety was observed at position (c), going against both the electronic and steric bias expected for the oxyallyl cation. Immediately after mixing compounds 1 and 2 in dichloromethane-d2 at -25 °C, NMR spectroscopy at -50 °C allowed characterization of 3 as the predominant species (> 90 %).…”

“…Furthermore, it was previously established that the delocalization index obtained by QTAIM (quantum theory of atoms in molecules) calculations also favour "attack" at position C(a), although the charges on C(a) and C(c) are quite similar. 13 It appears that when reacting with ambiphilic phosphine-alane 1, stabilization of the oxyallyl cation occurs by electronic density transfer through an interaction between the intramolecular phosphine moiety and the methyl group on C(c). All attempts to find reaction intermediates using DFT calculations resulted either in interrupted Nazarov cyclization products 3 and 4, or in the structure depicted in Figure 2, in which the lone pair of the phosphine moiety is oriented towards one of the hydrogen atoms on the methyl group in position (c).The H-P distance of 2.54 Å falls in the range expected for a methyl group involved in a hydrogen bond (2.3 to 2.7 Å).…”

Recent Advances in the Interrupted Nazarov Reaction

“…The presence of α‐substituents facilitates the [3+4]‐cycloaddition of allenyl vinyl ketones 107 since the desired products 108a, b, d were isolated in high yields (Scheme ) . Unsubstituted substrates gave the [3+4]‐cycloaddition product 108c , but the Nazarov cyclization was not observed.…”