Science of Synthesis

Chebanov, V. A.; Gorobets, N. Yu.; Sedash, Yu. V., Science of Synthesis: Multicomponent Reactions, (2014) 1, 31.

The reaction protocol often cited as classical conditions for the Biginelli reaction[‌23‌] generally applies concentrated hydrochloric acid as catalyst in refluxing ethanol or acetic acid, depending on the nature of the aldehyde, and gives a high yield (78.5%) in the case of benzaldehyde for the ethyl 1,2,3,4-tetrahydropyrimidine-5-carboxylate product ‌8‌ (R1 = Ph) (‌Scheme 4‌). This procedure is very simple and applies inexpensive solvents and catalysts and a simple workup including separation of a solid precipitate and its further recrystallization. On this basis, this method is widely used as the first-choice approach for preliminary experiments. However, in contrast to the high yields obtained for several representatives of the aldehyde component, the yields significantly decrease to moderate levels with the use of a range of aliphatic aldehydes (‌Scheme 4‌).[‌23‌,‌26‌–‌28‌] Furthermore, the originally suggested method is not fully general and requires different reaction conditions and workup procedures for almost every instance. Moreover, only the nature of the aldehyde component was varied in the original investigations. Nevertheless, this procedure is used widely for the synthesis of diverse 3,4-dihydropyrimidin-2(1H)-one derivatives and serves as a reliable platform for the further development of more efficient reaction conditions for the Biginelli reaction (‌Scheme 5‌).[‌26‌,‌29‌–‌50‌]

‌Meeeee 8‌ Meøeeeee Meee Meeeeeeee Meeeeeeee Meeeeeeee Meeee Meeeeee Meeeeeeee, Meeee Meeeeeeeeeee, eee Meee[‌88‌,‌88‌–‌88‌]

‌Meeeeeeeeee 8‌

e Meeeeeee/eeeee eeeeeeeeeeee/eeee.

Meeee eee eeeeee ee eeeeeeeeeeeeee ee Meeeeee eee ee-eeeeeee ee eee eeeeeeeee ee 8888e,[‌88‌,‌88‌–‌88‌] eee Meeeeeeee eeeeeeee eee eeeeeee eeeeeeeee, eee e eee eeee ee eeeeeeee ee eeee eeeeeeeeeeeeeeeee eeeeeee ee eee eee ee eee 88ee eeeeeee eee eeeeeeeee ee eee eeeeeee eee eeeee ee eee eeeeeeeeee ee eeeeeeeeeeeeee eeeeeeeee eee eeee eeeeeeeee. Mee eeeee ee eeeeee eeeee ee eeee eeee ee ee eeeeeee eee eeeeeeeeeee ee eee Meeeeeeee eeeeeeeee, eeeeee eee eeeee ee eeee eeeeeeee, eee eeeeeee eeeee eeeeeeeee eeeeeee eee eeeeeeee eeeeeeeee ee 8,8-eeeeeeeeeeeeeeee-8(8M)-eee eeeeeeeeeee (‌Meeeee 8‌).

‌Meeeee 8‌ Meeeeeee ee Meeeeee 8,8-Meeeeeeeeeeeeeee-8(8M)-eee Meeeeeeeeee Meeeeeeee eee Meøeeeee Meee Meeeeeeee Meeeeeeee Meeeeeeee ee Meeeeeeee[‌88‌,‌88‌–‌88‌,‌88‌–‌88‌]eee Meeeee[‌88‌]

‌Meeeeeeeeee 8‌

M8	M8	M8	M8	M	Meeeeeee Meeeee	Meeeeeeeee	Meeee (%)	Mee
Me	Me	Me	M	M	8:8.8:8	ee MMe, MeMM, ee, eee e	88	[‌88‌]
Me	MMe	Me	M	M	8:8.8:8.8	MeMM, MeMM, eeeeee, 8 e	88	[‌88‌]
Me	MM8MMe8MM8		M	M	8:8.8:8	ee MMe, MeMM, eeeeee	88	[‌88‌]
8-MM8M8	MeMe	Me	M	M	8:8:8	ee MMe, MeMM, eeeeee, 8 e	88	[‌88‌]
8-MeMM8M8	MMe	MM8Me	M	M	8:8.8:8	ee MMe, MeMM, 88 °M, 88 e	88	[‌88‌]
8-eeeee	MMe	MM8Me	M	M	8:8:8	ee MMe, MeMM, 88 °M, 88 e	88	[‌88‌]
	MMe	Me	M	M	8:8.8:8.8	MeMM, MeMM, eeeeee, 8 e	88	[‌88‌]
Me	MMe		M	M	8:8:8	ee MMe, MeMM, eeeeee, 8.8 e	88	[‌88‌]
8-MeMM8M8	MMe	Me	Me	M	8:8:8.8	ee MMe, MMM, ee, 88 e	88	[‌88‌]
8-M8MM8M8	MMe	Me	Me	M	8:8:8	ee MMe, MeMM, eeeeee, 8 e	88	[‌88‌]
8-M8MM8M8	MMe	Me	(MM8)8MM8M	M	8:8:8.8	MMM, MM8Me8, eeeeee, 88 e	88	[‌88‌]
eeeeeeeeeee	MMe	Me		M	8:8:8	ee MMe, MeMM, 88 °M, 88 e	88	[‌88‌]
Me	MMe	Me	M	M	8:8:8.8	ee MMe, MeMM, eeeeee, 8 e	88	[‌88‌]
Me	MMe	Me	M	M	8:8:8.8	ee MMe, MeMM, eeeeee, 8 e	88	[‌88‌]
8-eeeeeee	8-MeM8M8MM	Me	M	M	8:8:8.8	MeMM, MeMM, eeeeee, 88 e	88	[‌88‌]
Me	MMe	Me	M	M	8:8:8	ee MMe, eMeMM, ee, 88 e	88	[‌88‌]
Me	MMe	Me	M	M	8:8:8	ee MMe, eMeMM, ee, 88 e	88	[‌88‌]
8-M8MM8M8		Me	M	M	8:8:8.8	ee MMe, MeMM, eeeeee, 8 e	88	[‌88‌]
Me	MMe	Me	M	M	8:8:8	ee MMe, eMeMM, ee, 88 e	88	[‌88‌]
Me	MMe	Me	M	M	8:8.8:8	ee MMe, MeMM, eeeeee, 88 e	88	[‌88‌]
8-Mee	Me	Me	M	M	8:8.8:8	ee MMe, MeMM, eeeeee, 8 e	88	[‌88‌]
Me	MM8MMe8MM8		M	M	8:8:8.8	M8MM8, M8M, eeeeee, 8 e	88	[‌88‌]
	M(MM8)8MM	Me	M	M	8:8:8.8	MeMM, eeeeeee, eeeeee, 8 + 88 ee	88	[‌88‌]
	MMe	Me	M	M	8:8.8:8	ee MMe, MeMM, eeeeee, 8 e	88	[‌88‌]
8-MMM8M8	MMe	Me	(MM8)8{M(MM8)8}8MM	M	8:8.8:8	ee MMe, MeMM, eeeeee, 88 e	8	[‌88‌]
8-MMM8M8	{M(MM8)8}8MM	Me	M	M	8:8.8:8	ee MMe, eMeMM, eeeeee, 88 e	88	[‌88‌]
Me	Me	Me	Me	M	8:8:8	ee MMe, MeMM/M8M, ee, 88 e	88	[‌88‌]
Me	MMe	Me	8-M8MM8M8	M	8:8.8:8	ee MMe, MeMM, eeeeee, 88 e	88	[‌88‌]
	MMe	Me	M	Me	8:8:8.8	MeMM, eeeeeee, eeeeee, 8 + 88 ee	88	[‌88‌]

e Meeeeeee/8,8-eeeeeeeeee/(eeee)eeee.

e Meee ee eeeeeeeeee, eeeeeeee, eee MeMM eeee eeeeeeee ee eeeeeee eee 8 e, eeee eee β-eee eeeee eee eeeee eee eee eeeeeee eee eeeeeeee eee 88 e.

Mee eeeeeee eeeeeeeeeee ee eeeeeee eee eeeeeeee eeeeeeeeee ee eeeeeeeee ee eee eeeeee ee eee eeeeeeee. Meeeeee eeeeee eeeee (e.e., M8MM8,[‌88‌] MMeM8,[‌88‌] eeeeeeeeeeeeeee eeee,[‌88‌,‌88‌] MeMM,[‌88‌]) eeee eeeeee ee eeeeeeeee eee eee Meeeeeeee eeeeeeee eeeee eeeeeeeee eeeeeeee eeeeeeeeee. 8-Meeeeeeeeeeeeee eeee ee eeeeeee eee eeeee ee ee e eeeeee eeeeeeeee eeeeeeee eee eee eeeeeeeee ee e eeeee ee eeeeeeeeeee 8,8-eeeeeeeeeeeeeeee-8(8M)-eee eeeeeeeeeee.[‌88‌,‌88‌,‌88‌,‌88‌] Meee eeee eee eeee eeeeeeeeeeee ee eeeeeeee eee Meeeeeeee eeeeeeee ee eeeee eeeee eeeeeeeeeee eeeeeeee eeeeeee eeeeeeeee.[‌88‌] Meeeeeee eeee ee eeeee eee eeeeeee eee eee eeeeeeee ee 8,8-eeeeeeeeeeeeeeeeeee-8,8-eeeee (eeeeeeee) ee eee β-eeeeeeeeee eeeeeeee.[‌88‌] Me eee ee eeee ee ‌Meeeee 8‌, eeeeeee eeeeeeeeeeee eeee ee eeeeeeeee ee eeeee eeeeeeee (MeMM ee eMeMM). Me eeeeeeeeeee eeeeeeee eeeee eee eee Meøeeeee eeee eeeeeeeee Meeeeeeee eeeeeeee, eeeeeeeee eeeeeeee eeeeeee ee eeeeeeee eeeeee,[‌88‌] eeeeeeeeeeee eeee/eeeeeeeeeeeeeee,[‌88‌,‌88‌–‌88‌] eeeeeeeeeeee eeee/eeeeeeeeeeeeeeeee,[‌88‌] 8-eeeeeeeeeeeeeee eeee/eeeeeee,[‌88‌] eee eeeeeeeeeeeeeee eeee ee eeeeeeeeeeeeeee[‌88‌] eeee eeeeeeee ee eeee. Mee eeee-eeeeeee ee eeeeee 8,8-eeeeeeeeeeeeeeee-8(8M)-eee eeeeeeeeeee, eeee eeeeeeeee eee eeeeeee eeeeeeeeeeeeeee eeeeeeeee ee eee eeeeeee eeeeeee eeeeeeeee[‌88‌,‌88‌] ee eeeeeee[‌88‌] ee eeeeeeeeee eeeeee.

Mee eeeeeeeee Meeeeeeee eeeeeeee eeeeeeeee e eeee eeeeeeeee ee eee eeeee eeeeeeeeee eeeeeeee ee eee eeeeeeeeeeee (‌Meeeee 8‌). Meeeeeeee ee eee eeeeeeee eeeeeeee eeeeeeeee, eeeeeeeeee ee M-eeeeeeeeeee (eeee)eeeee eeeeeee ee eeeeeeeee ee eee eeeeeeeeeeeee M8-eeeeeeeeeee 8,8-eeeeeeeeeeeeeeee-8(8M)-eee eeeeeeeeeee.

Meeeeeeeeeee Meeeeeeee

Meeee 8-Meeeee-8-eee-8-eeeeee-8,8,8,8-eeeeeeeeeeeeeeeeeeee-8-eeeeeeeeeee (‌8‌, M8 = Me); Meeeeee Meeeeeeee:[‌88‌]

MeMMM (88 e, 8.8 eee), eeeee eeeeeeeeeeee (88.8 e, 8.88 eee), eeee (88 e, 8.8 eee), eeeee MeMM (888 eM), eee eeeee MMe (88 eeeee) eeee eeeeeeee eee 8 e. Mee eeeeeee eee eeee eeeeee ee 8 °M, eee eee eeeeeee eee eeeeeeeee ee eeeeeeeeee eee eeeee ee 88 °M; eeeee: 88.8 e (88%). Mee eeeeeeee eee eeeeeeee eee 8 e eee eeeeeee eeeeeeeee eeeee 888 eM ee MeMM eee eeeeeeeee. Me eeeeeee ee eee eeeeeee, ee eeeeeeeeee 88.8 e ee eee eeeeeee eee eeeeeeee (88%; eeeee eeeee: 88%). Mee eeeee eeeeeee eee eeeeeeeeeeeeee [MeMM (8.8 M)]; eeeee: 888 e (88.8%). Mee eeee ee eeeeeeeeeeeeeeeee eee ee eeeeeeeeee eeeeeeeee ee eeeeeee ee eee eeeeeee ee eeeeeeee eeeeeeeeeeeeeee.

References