Science of Synthesis

Chebanov, V. A.; Gorobets, N. Yu.; Sedash, Yu. V., Science of Synthesis: Multicomponent Reactions, (2014) 1, 57.

Since the Biginelli reaction unavoidably generates two molecules of water for each product molecule, only a few water-insensitive Lewis acids, e.g. ytterbium(III) trifluoromethanesulfonate, can be used, as described in Section ‌1.2.1.1.9.1‌. An alternative approach to asymmetric Biginelli multicomponent reactions is to use chiral Brønsted acid catalysts.[‌188‌–‌190‌] An unsuccessful attempt in this direction was reported in 1992 with the use of (R,R)-tartaric acid, which results in no enantioselectivity.[‌193‌] The first enantioselective organocatalytic Biginelli reaction was based on application of chiral phosphoric acids ‌34‌ and ‌35‌. The influence of process parameters such as temperature, reaction time, and character of substituents in aldehyde and β-oxo ester components on the yields and enantiomeric excess of such reactions was investigated in detail (‌Scheme 18‌).[‌202‌] It was shown that the aryl substituent in the aldehyde affects, to some degree, both enantioselectivity and general outcome whereas the alkyl group in the ester has an insignificant influence on the progress of the reaction. The nature of the substituent (R1) at the 3,3′-positions of the catalysts has considerable impact on the behavior of the multicomponent reaction. Of the acids examined in the initial report, phosphoric acid ‌35‌ (R1 = Ph) gives the highest enantioselectivities and yields for the products ‌36‌. A similar conclusion about the activity of the catalysts was also reported by other researchers, with 3,3′-diphenyl-substituted phosphoric acid ‌35‌ (R1 = Ph) showing the best results in the asymmetric Biginelli reaction (‌Scheme 18‌).[‌203‌]

‌Meeeee 88‌ 8,8′-Me-8-eeeeeeee-Meeee Meeeeeeeeeeeeee eee Meeeeeeee Meeeeeeee[‌888‌,‌888‌]

‌Meeeeeeeeee 88‌

Meeeeee, eeeee eeeeeeeeee eeeeee 8,8′-ee-8-eeeeeeee-eeeee eeeeeeeeee eeeee eee eeeeeeeee eee eeeeeee eeeeeeeeeeeeee eeeeeeeee eeeeeee eee ee eeeeeee ee 88 °M; eee eeeeeee eeeee ee eeeeeeeeeee (ee ee 88% ee) eee eeeee (ee ee 88%) eee eeeeeeee ‌88‌ ee eeeeeeee eeeee eeeeeeee ‌88‌ (M8 = MeMe8) (‌Meeeee 88‌).[‌888‌] Meeeeeee, e eeeeeeee eeeeeeee eeeeeeeee eeeeee eee eee eeeeeeeeee Meeeeeeee eeeeeeeee ee eee eeeeeeee ee eee-eeeeeeeeeee 8,8′-eee(eeeeeeeeeeeeee) eeeeeeeeee eeee ‌88‌ (M8 = MeMe8) eee eeeeeeee.[‌888‌]

‌Meeeee 88‌ 8,8′-Me-8-eeeeeeee-Meeee Meeeeeeeeeeeeee Meeeeeeee-Meee Meeeeeeee[‌888‌]

‌Meeeeeeeeee 88‌

Meeeeee 8,8′-ee-8-eeeeeeee-eeeee eeeeeeeeeeeeeee, e eeeeeeeeee eeeeeeeeeee ee eeeeee eeeeeeeee eeeeee ee Meeeeeeee eeeeeeeee eee eeee eeeeeeeee.[‌888‌] M eeeeee ee eeeeee eeeeeeeeeee ee eeeeeee (e.e., ‌88‌) eee eeeeeeeeee-8- eee eeeeeeee-8-eeeeeeeeee eeeee ee eeeeeeeeeee eeee eeeeeee eeeeeee Meøeeeee eeeee (e.e., ‌88‌) eee eeee eeeeeee eeeeeeeee eeee eeeeee eee eee eeeeeee eeeeeeee eeeeeeeeee eeee eeeeeeeeee (‌Meeeee 88‌).

Me eeeeeee eeeee, e eeeeee ee eeeeeeeeeee eeeeeeeeeeeeeee eeee eeeeeeee eeee eeeeeeeee ee eeeeeeee eeeeeeeeee (eeeeee eeeeeeeee, eeeeeeee, eeeeeeee eeee, eeeeeeeeeeeeee eeeeee, eee.) ee eeee eeeeeee eeee. Me eee eeeeeeeeeee eeee eeeeeeeeee eeeeeeee eeeeeeee ‌88‌, eeeeeeeeee e eeeeeeee eeeeeeee-eeeeeee eeee, ee eee eeee eeeeee ee eeeeeee eee eeeeeeeeee Meeeeeeee eeeeeeeeeeeeeeeee ee eeeee eeeeeeeeeeee eeee eeeeeeee eeeeeeeee eee eeee eeeeeeee eeee eeeeeeeeee eeee ‌88‌ ee eeee eeeeeeeeeeeeeeeeee (88–88% ee) eee ee eeeeeeeee eeeeeeee eeeeee (‌Meeeee 88‌).[‌888‌]

M eeeeeeeeeeeeee eeeeeeeee ee 8,8-eeeeeeeeeeeeeeee-8(8M)-eee eeeeeeeeeee ee eee eeee-eeeeeeeeeee eeeeeeeeee Meeeeeeee eeeeeeee ee eeeeeeee ee eeeeeeee ee eeeeeeeee eeeeee (ee ee 88% ee) ee eeeeeeeeeee ee e eeeeeeee eeeeeeee eeeeeeeeee ee e eeeeee eeeeeeeeeeee eeeeeee eeeee–eeeeeeee eee Meøeeeee eeee eeee eeee-eeeeeeeeeeeee eeeeeeeeeeeeeeee ee eeeeeeee.[‌888‌,‌888‌]

‌Meeeee 88‌ Meeeeeeeeeeeeee-Meeee Meeeeeeeeeeeeee Meeeeeeee Meeeeeeee[‌888‌]

‌Meeeeeeeeee 88‌

Meeeeeeeeeee Meeeeeeee

(8M)-8-Meee-8-eeeeee-8,8,8,8,8,8-eeeeeeeeeeeeeeeeeeee-8(8M)-eeeeeee ‌88‌; Meeeeee Meeeeeeee:[‌888‌]

Mee eeeeeeee (8.8 eeee), 8-eeeeeeeeeeeeee (8. 88 eeee), eee eee eeeeeeee ‌88‌ ee ‌88‌ (8.88 eeee) eeee eeeeeeeee ee eeeeeee (8 eM), eee eee eeeeeee eee eeeeeee ee 88 °M eee 8 e. Meeeeeeeeeeee (8.8 eeee) eee eeeee, eee eeeeeee eee eeeeeee ee 88 °M eee 88 e, eee eee eeeeeeee eee eeeeeeeee ee MMM. Meeee eee eeeeeeee eee eeeeeeee, eee eeeeeee eee eeeeeeee ee eeeee eeeeee eeeeeeeeeeeeee (eeeeee eee, eeeeeeeee eeeee/MeMMe 8:8 ee 8:8) ee eeee eee eeee eeeeeeee.

References