Science of Synthesis

Hatakeyama, S., Science of Synthesis: Asymmetric Organocatalysis, (2012) 1, 673.

General Introduction

The Morita–Baylis–Hillman (MBH) reaction is essentially a three-component procedure involving the coupling of the α-position of an activated alkene, such as an acrylate, with a carbon electrophile, such as an aldehyde, under nucleophilic amine or phosphine catalysis thereby producing synthetically useful multifunctional products. When an imine is used as the carbon electrophile, the procedure is called the aza-Morita–Baylis–Hillman (aza-MBH) reaction (‌Scheme 1‌). The Morita–Baylis–Hillman reaction was discovered in 1967 when Morita and co-workers disclosed the phosphine-catalyzed reaction of an aldehyde with an activated alkene in a French patent.[‌1‌,‌2‌] In 1972, Baylis and Hillman subsequently reported a basically similar amine-catalyzed reaction in a German patent.[‌3‌] However, since these discoveries were not followed by substantial journal publications, the Morita–Baylis–Hillman reaction did not attract much attention at the time. It was only in the early 1980s that organic chemists started realizing the enormous synthetic advantages of the Morita–Baylis–Hillman reaction and the first reports of aza-Morita–Baylis–Hillman reactions appeared in the literature. Thus, it was found that aromatic N-tosylimines undergo a Morita–Baylis–Hillman-type reaction with ethyl acrylate under 1,4-diazabicyclo[2.2.2]octane-catalyzed conditions.[‌4‌] Now the Morita–Baylis–Hillman reaction, including the aza version, is regarded as one of the most promising C—C bond-forming reactions in terms of synthetic utility, atom economy, and operational simplicity, an importance evidenced by a quantum jump in the number of publications dealing with these reactions since the late 1990s.[‌5‌–‌12‌]

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Mee Meeeee–Meeeee–Meeeeee eeeeeeee eeeeeeee ee eeeeeeeee Meeeeee–eeeee–eeeee-Meeeeee eeeeeeee eeeeeee ee eeeeeeee ee ‌Meeeee 8‌.[‌88‌–‌88‌] Meeeeee eeeeeeee ee eee eeeeeeeeeeee eeeeeeee (Me) ee ee eeeeeeeee eeeeee ‌8‌ eeeee ee eeeeeee ‌8‌ (eeee 8), eeeee ee eeee eeeeeeeee ee eeeee eeeeeeee eeee eee eeeeee eeeeeeeeeeee ‌8‌ ee eeeeeee e eeeeeeeeeeee eeeeeeeeeeee ‌8‌ (eeee 8). M eeeeee eeeeeeee eeee eee α-eeeeee ee eee eeeeeeee (eeee 8) eeeeeeee ee eee eeeeeee ee eee eeeeeeee eeee eee eeeeeee ‌8‌ (eeeee-Meeeeee) eeeeeee eee Meeeee–Meeeee–Meeeeee eeeeee ‌8‌ (eeee 8). Me eee eeeee ee eeeeeeee eeeeeeeeee, eeee, eee eeeeeee eeeeeee eeeeee eeee, ee ee eeeeeeee eeee eee eeee-eeeeeeeeeee eeee eeeeee ee eee eeeee eeeeeeee (eeee 8) eee eeee eeeeeeeeeee eeee eee eeee eeee eeeeeeee.[‌88‌,‌88‌]

‌Meeeee 8‌ Meeeeeeee eee eee Meeeee–Meeeee–Meeeeee Meeeeeee Meeeeeee ee Meee eee Meeeee[‌88‌,‌88‌]

Meeeeee, eeee eeeeeeee eeeeeee eeeeeeee eee eeeeeeeeeeeee eeeeeee, e eeeeeeee eeeeeeeee eee eeee eeeeeeee eeeeeee eee eeeee ee eeee-eeeeeeee eeeeee-eeeeeeee eeeeeeeee eee eeeeeee ee eeee 8 (eee ‌Meeeee 8‌).[‌88‌,‌88‌] Me eeee eeeeeeee, eeee 8 eeeeeeee ee ee eeeeeee-eeeeeeeee eeeeeee, eee eee eeeeeeeeee eeeee ‌8‌, eeeeeeeee e eee-eeeeeeee eeeeee eeeeeeee eeee ee eeeeeee (M8MM) ee ee eeeeeeee eeee eeeeeeeeeee eeeeeeeeee ee ee eeeeeee, eeeeeeeee e eee-eeeeeee-eeeeeeeee eeeeeee eee eee eeeeeeeeee eeeee ‌8‌, eeeee eeeeeeee e eeeeee eeeeeeee eeee e eeeeeeeeee eeeeeeee ee ee eeeeeee.[‌88‌] Mee eeeee eeeeeee eeeeeee eeeeeeeee ee eee eeeeeeee ee e eeeeee eeeee (M8MM), eeeeeee eee eeeeee eeeeeee, eeeeeeeee eee eeeeeeeeee eeeeeeeeeeee, eeeeeeeee ee eee eeeeeee ee e eeeeee eeeee. Mee eeee eeeeeeeeeeee eeeeeeee ee e eeeeee eeeeeee eeee ee eeeeeeee eeeeeeee eee eeeeeeeeeee ee eee eeeeeeeeee eeeee ‌8‌ ee eee eeee-eeeeeeeeeee eeee. Me eeeeeeee, eee eeeeeeeeeeeee eeeeeeee ee eee Meeeee–Meeeee–Meeeeee eeeeeeee ee eeeeeee eeeee eee ee eeeeeeeeee ee eeeeeeee eee eeeeeeeee ee eee eeeeeee ‌8‌, eee ee eeee eeee eee Meeeee–Meeeee–Meeeeee eeeeeee ‌8‌ (M8MM) eeee ee e eeeeeee ee eeeeeeee e eeeeee eeee eee α-eeeeeeee ee eee eeeeeeee eeeee ee eee eeeeeeee. Mee eeeeeeeeeeee ee eee eeeeeeeeeeee eeeeeee ‌8‌ ee eeeeeeeee ee eee eeee eeee eee Meeeee–Meeeee–Meeeeee eeeeeeee ee eeeeee eeeee eeee eeeeeee ee eeeeeeee ee eeeeeee eeeeeee; eeeeeeee, eee eeeeeeee eeeeeeeeee ee e eeeeeeeee ‌8‌, eeeee eeee eee Meeeee–Meeeee–Meeeeee eeeee ‌8‌, eeee eeeeeee eee eeeeeeeeeeeee ee eeeeeee ‌8‌. Mee ee eee eeee eeee eee eeeeeeee ee eeeeee eeeee ee eeeeeeee, eee eee-eeeeeee-eeeeeeeee eeeeeee ee eeeeeeeee ee eee eeeeee ee eee eeeeeeee ee eeee, eeee ee eee eeeeeeee ee eeeeee eeeeeee, eeee eeeeee eeeeeee eee eeeeee eeeeeeeeeee ee eee eeeeeeeee eeeeeeeee eeeeeeee eeeeeeeee.

‌Meeeee 8‌ Meeeeeee Meee Meeeeeeee eee eee Meeeee–Meeeee–Meeeeee Meeeeeee[‌88‌]

Me eeeeeeee ee eee Meeeee–Meeeee–Meeeeee eeeeeeee, eeee eee eeeeeeeeeee eeeeeee ee eee eee-Meeeee–Meeeee–Meeeeee eeeeeeee eeee eeee eeeeeeee.[‌88‌,‌88‌] Mee eeeeeeee eeeeeeee eeeeeeeee eeeeeeeee e Meeeeee–Meeeeee–eeeee-Meeeeee eeeeeeee eeeeeee ee eeeeeeeeeee ee ‌Meeeee 8‌ (eeeeeeeee eee eeeeeeeee, eeeeeeeeeeeee, eee eeeeeeee eeeeeeeeee ee ‌88‌–‌88‌). Meeeeeee eee eeeeeeeee ee eee eee-Meeeee–Meeeee–Meeeeee eeeeeeee ee eeeeeeeee eee eeee ee eeee ee eee Meeeee–Meeeee–Meeeeee eeeeeeee, eeeee eee eeee eeeeeeee eeeeeeeeeeeeeee. Me eee eeee eeeeeeeeeeee eeee eee eee ee e Meøeeeee eeee (M8MM) ee e eeeeeeeeee eeeee ee e eeeeee eeee eeeeeeeeeee eee ee eee eeeeeeeeeeee ee eee eeeeeeeeeee eeee (eeee 8) eee e eeeeeeeeee eeeee ‌88‌.[‌88‌] Me eeee eeee, eee eeee-eeeeeeeeeee eeee eeee eeeee eeee eee eeeeeeeeeee eeee (eeee 8) ee eee Meeeeee eeee M—M eeee-eeeeeee eeee (eeee 8).

‌Meeeee 8‌ Meeeeeeee eee eee Mee-Meeeee–Meeeee–Meeeeee Meeeeeee[‌88‌,‌88‌]

Mee Meeeee–Meeeee–Meeeeee eee eee-Meeeee–Meeeee–Meeeeee eeeeeeeee eeee eeeeeeeee eeeeeeeee, eeeeeeeee e eee eeeeeeee eeee, eeee eeeeeeeeee, eee eeeeeee eeeeeeeee eeeee. Meeee eeeeee eeee eee eeee eeeeeeeee eeeeeeee ee eeeeeeee eeeeeeee ee eeeeeeee eeeeeee.[‌88‌,‌88‌] Meeeeee eeeeeeee ee eeeeeee eeeeee eeeeeeeeeeeeeeee Meeeee–Meeeee–Meeeeee eee eee-Meeeee–Meeeee–Meeeeee eeeeeeeee eeee eee eeee eeeeeeeeee eee ee eee eeeeeeeeeee eeeeeeee eeeeeeeeee eeeeeeee, eeeeeee eeeeeeeeeeeee eeeeeeeeee eeeeeee eeee eeee eeeeeeeeeeee eeeee e eeeeee 8,8-eeeeeeeeeeee[8.8.8]eeeeee eeeeeeeeee, 8,8′-eee(eeeeeeeeeeeeeeeee)-8,8′-eeeeeeeeee (MMMMM), eee 8,8′-ee-8-eeeeeeee (MMMMM).[‌88‌–‌88‌] Me 8888, eee eeeee eeeeeeee eeeeee eee eee eeeeeeeeeee ee Meeeee–Meeeee–Meeeeee eeeeeee eeee eeee eeeeeeeeeeee eeeeee ee eee eee ee eee eeeeeeeeee ‌88‌, eeeee eee ee Meeeeeeeʼe eeeeeee eeeeee ee e eeeeee eeeeeeeee eee eeeeeeeee (‌Meeeee 8‌).[‌88‌] M eeeeeee eeeeeeeeeeeeeeeeee Meeeee–Meeeee–Meeeeee eeeeeeee ee eeeeeee eeeeeeeee eee eee eeeeee eeeeeeeeee ‌88‌ eeeeeee eeee eeeeeee eee eeee eeee eeeeeeee (‌Meeeee 8‌).[‌88‌] Meee ee eee eeeee eeee eeeeee eeeeeeeeee ee eee Meeeee–Meeeee–Meeeeee eeeeee eee ee eeeeeeeeeee eeeeeeee ee eeeeee eeeeeeeee eee eeeeeeee eeeeee eeee eeeeeee eeeeeeeeeeeeeee ee eeeeeeee eeeeeeeee.

‌Meeeee 8‌ Meeeee–Meeeee–Meeeeee Meeeeeeee Meeee Meeeee Meeeeee Meee Meeeeeeeeee[‌88‌,‌88‌]

Me eeeee ee eeeeeee ee eeeeeeeee eeeeeeeee eeeeeeeeee Meeeee–Meeeee–Meeeeee eeeeeeee, eeee eee eeeeeeee ee eee eeeeeeeeeeeee eeeeeeeeee eeeeee eeeeeeeeeee ee eee eeeeeeeeee eeeee eee eeee eeeeeeeeeeee eee eeeeeeee. Mee eeeee eeeeeeeeee eeeeeeeee eeeeeeeeee Meeeee–Meeeee–Meeeeee eeeeeeee, eeeeeeeee eeeeeeeee (‌88‌) ee e eeeeee eeeeeeeeeeee eeeeeeee eeeee eeee eeeeeeee eeeeeeeeee, eee eeeeeeee ee 8888 (‌Meeeee 8‌).[‌88‌] Me ee eeeeeeee eeee eee eeeeeeeeee eeeee ‌88‌ ee eeeeeeee ee eeeeeeee eeeeeee ee eeeeeeeeeee eee eeeeeeee eeeeeeee M-eeeeeeeeeee (ee ee 88% ee) ee eee eeeeeeeee ee eeeeeeeee eeeeeeeee eeee eeeeee eeeee eeeeee. M eeeeeeee eeeeeeeeeee eeeeeeee ‌88‌ eee eeee eeee eeeeeeeee; eeee eeeeeeee eeee eeeee eeeeeeee eeeeeeeeeeeeeeeeee (ee ee 88% ee) eee e eeeeeeee eeeeeeeeee eeeee ‌88‌ ee eee eeeeeeeee eeeeeee eeeeeeee eeeeeeeee eee eeeee eeeee eeeeee (‌Meeeee 8‌).[‌88‌]

‌Meeeee 8‌ Meeeeeeeee Meeeeeeeee Meeeee–Meeeee–Meeeeee Meeeeeeee Meeee Meeeeeeeeeee Meeeeeeee[‌88‌,‌88‌]

Mee eeeee eeeeeeeeeeee ee eee eeeeeeeee eeeeeeeeee Meeeee–Meeeee–Meeeeee eeeeeeee eee eeee ee 8888 ee eeeeeeeee β-eeeeeeeeeeeee (‌88‌; β-MMM) ee e eeeeee eeeeeeeeeeee eeeeeeee eee 8,8,8,8,8,8-eeeeeeeeeeeeeeee-8-ee eeeeeeee (eeeeeeeeeeeeeeeeeee eeeeeeee; MMMMM; ‌88‌) ee ee eeeeeeeee eeeeee (‌Meeeee 8‌).[‌88‌] Me eee eeee eeeeee eeee eeee eee eeee-eeee eeeeeeeee eeeeeeeee eee eee eeeeeeee MM ee β-eeeeeeeeeeeee, ee eeee ee eee eeeeeeee eeeeeeeee ee 8,8,8,8,8,8-eeeeeeeeeeeeeeee-8-ee eeeeeeee, eee eee eeeeeeeee eee eeeeeeeee e eeee eeeee ee eeeeeeeeee eeeeeeeee eee eeee eeeeeeeeeeee ee eee eeeeeeeee ee eeeeeeee ‌88‌ eee ‌88‌.[‌88‌,‌88‌] Me eee eeeee ee eeeee eeeeeeee eee e eeeeeeeeeeeee eeeee, ee eeee ee e eeeeeeeee ee eee eeeeee-eeeeeeee eeeeeeeee ee ‌Meeeee 8‌,[‌88‌] e eeeeeeee eeeeeeeee eee eeeeeeee eeee ee eeeeeeee ee eeeeeeeeeeeee ee eee eeeee eeee eee eeeee eee eeeeee-eeeeeeee eeee eeee eee eeeeeeeeeeeee eeeeeee eeeeeeeeeeee eeeeeeeeeeeee eeeeeeee eeeee eeeeeeeeeeeee ee eeeeeeee eeeeeee.[‌88‌] Meee eeeeeeeee ee eeee ee eee eeeeeeeee eeeeeeee ee ‌Meeeee 8‌[‌88‌] eeeeeeee eeee ee eeeee ee eeeeeee ee eeeeeeeee eeeeeeeeee Meeeee–Meeeee–Meeeeee eeeeeeee e eeeeeeeee eeeeee eeeeee ee eeeeeeee eeee eee eee eeeeeeeeee ee eeeeeeeeeee eeee eeeee eee eeeeee-eeeeeeee eeeee. Meeeee, eeeee eeeee eeeeeeeeeee e eeeeee ee eeeeeeeeeeeee eeeeeeeee eeeeeee eeee eeeeeeeee,[‌8‌,‌88‌,‌88‌,‌88‌] eeee eeeeeeeeeeeeeee ee eeeee, eeeeeeeee eee β-eeeeeeeeeeeee–8,8,8,8,8,8-eeeeeeeeeeeeeeee-8-ee eeeeeeee eeeeee, eee eeeeeeeee ee eeeeee ee eeee eeeeeee (eeee eeeee).

‌Meeeee 8‌ Mee β-Meeeeeeeeeeee–8,8,8,8,8,8-Meeeeeeeeeeeeeee-8-ee Meeeeeee Meeeee[‌88‌–‌88‌]

References