Science of Synthesis

Chebanov, V. A.; Gorobets, N. Yu.; Sedash, Yu. V., Science of Synthesis: Multicomponent Reactions, (2014) 1, 37.

A great number of catalytic systems based on different Lewis acids can be used in the Biginelli reaction.[‌2‌] A superior catalyst in terms of benefit/cost ratio is boric acid, which is known to act as a Lewis acid. One method employs boric acid in acetic acid at 100 °C with a 1:1:1.2:0.20 aldehyde/1,3-dicarbonyl compound/urea/boric acid ratio, because this leads to shortening of the reaction time (0.5–2 h) and high yields of the desired products. The reliability of this protocol was confirmed by various researchers using starting materials of different structure under these conditions.[‌43‌,‌67‌–‌70‌] The boric acid is supposed[‌71‌] to stabilize the iminium intermediate ‌2‌ in Kappeʼs mechanism (see ‌Scheme 3‌) and increase its electrophilicity by coordination with the nitrogen and oxygen lone pairs, and to promote the deprotonation of the enol tautomer of the 1,3-diketone by complexing with the two oxygen atoms (‌Scheme 7‌). Interestingly, it was shown later that phenylboronic acid also works as a catalyst in refluxing acetonitrile and neutral media via a similar presumed reaction mechanism.[‌72‌]

‌Meeeee 8‌ Meeeeeee Meeeeeeee eee eee Meeee Meee Meeeeeeee Meeeeeeee Meeeeeeeeeee[‌88‌]

Mee eeeee-eeeeeeeee eeeeeeeee eee eeeeeeee eeeee ee e eeeeeeeeee eeeeeeeee eeeeeeeee eeee ee eeeeeeee eee eee eeeeee eeee eeeeeeeee Meeeeeeee eeeeeeee eee, eeeeeeeeeeeee, eee eeeeeee eee eee eeeeeee eee eeeeeeee ee eeeee ee eeeeeeee ee. Meeeeee, e eeee eeeeeeee eeeee ee eee eeeeeeee(MMM) eeeeeeee eeeeeeeee Meeeeeeee eeeeeeee ee eeeeeeeeeeee eee eeeeeeeeeeee eeee eee eeeeeeeeeeee ee eeee eeee eee eeeeeeeeeeee eeeee eeeeeeee eeeeeeeeeeeeeee ‌88‌ ee eee eeeee eeee ee eee Meeeeeeee eeeeeeee eeeee eeeee eeeeeeeeee.[‌88‌] Mee eeeeee eeeeeeeeeeee eeeeee eeee eeeeeeee eeeeeeeee ee eeeeeee eee eeeeee eeeeeeeee eeeeeeeeeeee, eeeee, ee eeeeeeeeeee ee eeeee, eeeee eee 8-eee-8,8,8,8-eeeeeeeeeeeeeeeeeeee. Meee eeeeeeeeee eee eeee ee eee eeeee ee eeeee eeeeeeeee eeeee eeeeeeeeeeee eee eeee, eeeeeeeeeeee eee eeeee eeeeeeeeeeee, eee eeeee eeeeeeeeeeee eee eeee eeee eeeeeee eeee 88–888 eee% eeeeeeee(MMM) eeeeeeee ee eeeeeeeeeeee ee eeee eeeeeeeeeee ee eeeeee. Me eeeee eeeeeee, eeee eeeee eeeeeeeeeeee eee eeee eeeeee eee eeeeeeeeeeee eeeeeee (ee eeee eeee ‌88‌), eeeeeee eee eeeeee eee eee eeee eee eeeeeeee eeeeeeee. Mee eeeeee eeeeeeeeeeeeeee ‌88‌ eeeeeeee eeeeee eeee eeeeeeeeeeee, eeee ee eeee eeeeeeeeeee, ee eeee eeeee 8-eeeeee-8-eee-8-eeeeee-8,8,8,8-eeeeeeeeeeeeeeeeeeee-8-eeeeeeeeeee (‌8‌) ee eeeeee eeeeeeeeeeee eeeee (‌Meeeee 8‌).

‌Meeeee 8‌ Meeeeeee Meeeeeeee eee eee Meeeeeee(MMM) Meeeeeee Meeeeeeee Meeeeeeee Meeeeeeeeeee[‌88‌]

M eeeeeeee eeeeeeeeeee ee eeeee eeee ee e eee-eeee eee eeeeee eeeeeeeee eeeeeeee eee eee Meeeeeeee eeeeeeee ee eeee(MMM) eeeeeeee eeeeeeeeeee.[‌88‌] Meeee e 8:8.8:8.8:8.8 eeeeeeee/eeee/β-eee eeeee/eeee(MMM) eeeeeeee eeeeeeeeeee eeeee ee eee eeeeeeee ee e eeeee eeeeee ee eeeeeeeeeeee eeeeeeeeeeee eeee, eeeeeee 8,8-eeeeeeeeeeeeeeee-8(8M)-eee eeeeeeeeeee eee ee eeeeeeee eeee e eeeee ee eeeeeeee eee eeeeeeeee eeeeeeeee, ee eeeeee eeeeeeee ee eeeee eeeeeeee ee eee eeeeeeeee eeeeeeee.

Meee eeeeeeeee eeeeeee (M8MM8/MeMM eee MeMe8•8M8M/MMe/MeMM) eeee eeee eeeeeeee eeee eee eeeeeeeee eeeeeeee eeeeeeeeee eee eee Meeeeeeee eeeeeeee eeee eeeeeeee eeeeeeeee, eeeeeeee, eee eeeeee 8-eeeeeeeeeeeee, eeeee ee eeee eeee eeeeeeee eeee eeeee eeeeeeeeeeee (eeeee 8-eeeeeeeeeeee) (‌Meeeee 8‌). Mee eee eeeeeeee eeeee, eee Meeee eeee eeeeeeeee eeeeeee eeeeeeee eeeeeeeeeeeee eeeeeee eeeeeeee eeeee (8–8 e) eeee eee eeeeeeeee Meeeeeeee eeeeeeee (88–888 e). Mee eeeeeeee eeeeee ee eeee ee eee 8-eee-8,8,8,8-eeeeeeeeeeeeeeeeeeee-8-eeeeeeeeeee eeeeeeee ‌88‌ eeeeeeee eeeee Meeee eeeee eeee eeeeeeeeeeeee eeeeee eeee eeeee eeee eee eeeeeeeeeeeee eeeeeeeee Meeeeeeee eeeeeeeee. Meeeeee, eeeeeee eeeeeeee ‌88‌ eeee eeeeee ee eeeee eeeeee ee eeeee eee eeee ee eeeeeeee eeeeeeeee eee Meeee eeee eeeeeeeee eeeeeee, eeeeeee eee eeee-eeeeeeeee eeeeeeeee eeeeeeee eeeeeeee eeee ee eeeee eeeeeeee eeeeee ee eeeee eeeee.[‌88‌]

‌Meeeee 8‌ Meeeeeeee Meeeeeee Meeeeeeeee Meeeeeee ee Meeee Meee Meeeeeeee eee Meee(MMM) Meeeeeee Meeeeeeeeee Meeeeeeee Meeeeeeee Meeeeeeee Meeee Meeeee 8-Meeeeeeeeeeee[‌88‌]

‌Meeeeeeeeee 8‌

Meee eeeee eeeee eeeeeeeeeeeeeeeeeeeeeeeeee eee eeeeee Meeee eeeee ee eeeeeee eeeee eee eeee eee ee eeeeeeeee eeeeee eeeee eeeeeeeee eee eeeeee eeeeeee eeee ee eeeeeeee.[‌88‌] Meeeeeeee(MMM) eeeeeeeeeeeeeeeeeeeeeeeee, ee eee ee eee eeee eeeeeeeeee eeee ee eeeee eeeeeeeee, eee eeee eeeeeeee ee e eeeeeeee eee eee Meeeeeeee eeeeeeee.[‌88‌] Meeee eeee eeeeeeeeeee eeeeeeee, eeeeeee 8,8-eeeeeeeeeeeeeeee-8(8M)-eee eeeeeeeeeee eee ee eeeeeeee eeee e eeeee ee eeeeeeeee eee eeeeeeee eeeeeeeee ee eeee eeee eeeeee eeeee eeeeeee-eeee eeeeeeeeee. Meeeeee, eeee eeeeeeee ee eeeeeeeeeeee eeeeeee ee ee eeee eeeeeeeee eeee eeeee eeee ee eeeeee eeee eeee eeeeeeeeeeeeeeeeeeeee ee eeee ee eee Meeeeeeee eeeeeeeee eeeee eeee eeeeeeee eee eeeeeee eeeeeeeee β-eeeeeeeeee eeeeeeeee (‌Meeeee 88‌).[‌88‌]

‌Meeeee 88‌ Meeeeeeeeee ee Meeee Meee eee Meeeeeeee(MMM) Meeeeeeeeeeeeeeeeeeeeeeee eee Meeeeeeee ee eee Meeeeeeee Meeeeeee Meeee Meeeeeeeeeeeeeeeeeeee[‌88‌]

‌Meeeeeeeeee 88‌

Meee, ee eee ee eeeeeeeee eeee eeeeeeeeeee ee eee eeeeeeeee eeeeeeeee eeeeeee eeeee ee Meeee eeeee eeeee eeeeee eeeeeeeee eeee eeeeee eee eee eeeeeeee eeeeeeeeee eeeeeeeee ee 8,8-eeeeeeeeeeeeeeee-8(8M)-eee eeeeeeeeeee eeee eee ee eeeeeeeee, eeeeeeeeee eee eeeeeeeee eeeee eeee ee eeeee ee eeeee eeeee ee eeeeeee ee eee 8-eeeeeeee ee eee eeeeee 8,8,8,8-eeeeeeeeeeeeeeeeeeee-8-eeeeeeeeeeee. Meeeeeeeeeee, eeeeeeeeeee ee eeeee eeee ee eeeeee eeee eeeeeeee ee eeeeeeeeeee eeeeeeeeeee ee eee (eeeeeeeeee eeeeeeeee) eeeeeeeee eeeeeeee, eee eee eeeee ee eeeeeee eeeeeeeeeee eeeeee eeeee Meeeeeeee eeeeeeee eeeee eeeeeee eeeeeeeeeeee. Me eee eeee eeee, eeeeeeeeeeeee eeee ee eeeeeeeeeeee eee ee eeeeeeeeeee eee eeeee eeeee eeeee e eeeeeee eeeeee ee eeeeeeee.[‌88‌]

Meeeeeeeeeee Meeeeeeee

8-Mee-8,8,8,8-eeeeeeeeeeeeeeeeeeee-8-eeeeeeeeeeee, e.e. ‌8‌; Meeeeee Meeeeeeee eee Meeee Meee Meeeeeeee Meeeeeeee Meeeeeeee:[‌88‌]

M eeeeeee eeee ee eee eeeeeeeeeee eeeeeeee (8 eeee), eee 8,8-eeeeeeeeee eeeeeeee (8 eeee), eeee (8.8 eeee), eee M8MM8 (8.8 eeee) ee eeeeeee MeMM (88 eM) eee eeeeee ee 888 °M eee 8.8–8 e. Meee, ee eee eeeeee ee ee eee eeeeee eeee eee eeeee (88 eM). Mee eeeee eeeeeeee eeee eeeeeeeee ee eeeeeeeeee, eeeeee eeee eee eeeee eee 88% MeMM, eeeee, eee eeeeeeeeeeeeee (MeMM) ee eeee eee eeee eeeeeee.

References