Science of Synthesis

Huang, Y.; Dömling, A., Science of Synthesis: Multicomponent Reactions, (2014) 1, 532.

Pinto and co-workers have reported that 5-alkoxythiophenes ‌8‌ can be prepared by an extension of the Gewald thiophenamine synthesis (‌Scheme 3‌).[‌9‌] The reaction of ethyl cyanoacetate and oxymethyl ketones ‌7‌ (R1 = H, Me, alkyl, TBDMS) in the presence of sulfur and morpholine gives products ‌8‌ in moderate to good yields. However, reaction of phenoxyacetone (‌9‌) with ethyl cyanoacetate and sulfur in the presence of morpholine surprisingly results in 5-morpholinothiophene ‌10‌ in 21% yield (‌Scheme 3‌).[‌9‌] A variety of cyclic secondary amines can be used to replace morpholine in the four-component condensation reactions; the resulting thiophenediamines are produced as the only products in modest yields.

‌Meeeee 8‌ Meeeeeeee ee 8-Meeeee- eee 8-Meeee-Meeeeeeeeee Meeeeeee-8-eeeeee[‌8‌]

Meeeeeeee eee ee-eeeeeee eeee eeeeeeeee eee eee-eee Meeeee eeeeeeee ee eeeee eeeeee eeeeeee eeee eeeee eeeeeeeeeeee eee eeeeeeeee eeeeee ee eee eeeeeeee ee eeeeeeeeeeee eeeeeee eee eeeeee eeeeeeeeee.[‌88‌] Mee ee eeee eeeeeeeee eeeeee ee eeeeeeee ee eeeeeeeeee (8 eeeee) eee eeeeee eeee (8 eeeee). 8-Meeeeeeeeeeeee-8-eeeeeeeeeeee ‌88‌ eee ‌88‌, eeeeeee eeeeeee eeee eeeeee ee eee 8-eeeeeeee, eee eeeeeee eeeeeeee ee eeee ee eeeeeeee eeeeee (‌Meeeee 8‌).

‌Meeeee 8‌ Meee Meeeeee ee Mee-Mee Meeeee Meeeeeee-8-eeeee Meeeeeeee[‌88‌]

‌Meeeeeeeeee 8‌

‌Meeeeeeeeee 8M‌

Méee eee ee-eeeeeee eeee eeeeeeeeeeee eeee 8-eeee- ee 8-eeeeeee-eeeeeeeeeee eeeeeeee-8-eeeeee ‌88‌ eee eeeeeeeeeee eeee eeeeeeeeeee 8-eeeeeeeeeeeeeeeeee ‌88‌ eee Meeeee eeeeeeeee (‌Meeeee 8‌).[‌88‌] Mee eeeee ee eeeeeeee ee eeeee eeeeeeeeee-eeeeeeeeeee (MMM), eeeee ee eeeeeeee ee eeee ee eeeeee eeeeee (8.8 eeeee) eeee eeeeeeeeee (8.8 eeeee) ee 888 °M. Mee eeeeeee π-eeeeeeeeee eeeeeeeee eeeeee eee eeeeeeeee eee ee eeeeeeeee eeeeeeeee (e.e., eeeeeeeee eeeeeee ee eeeeeeeeeeeeeee) eeee eeeeeee eeeeeeeeeeee.

‌Meeeee 8‌ Meeeee Meeeeeeee Meeeeeee eeee 8-Meeeeeeeeeeeeeeeee[‌88‌]

‌Meeeeeeeeee 8‌

Me8	Meeee (%)	Mee
Me	88	[‌88‌]
8-eeeeeee	88	[‌88‌]
	88	[‌88‌]
	88	[‌88‌]

Meeeeee eee ee-eeeeeee eeee eeeeeeee eee eeeeeeeee ee 8-eeeeeeeeeeeeee-eeeeeeeeeee eeeeeeeeee eeee eeeeeeeeeee ‌88‌ ee Meeeee eeeeeeee ee eeeeee 8-eeeeeeeeeeeeeeeeeeeeeeeeeeeeee ‌88‌ (‌Meeeee 8‌).[‌88‌] Meeeeee eeeee/eeeeeeee-eeeeeeeeeee eeeeeeeeeeee eeeeeeeeeee ‌88‌ eee eeee ee eeeeeeeeeee ee eeeeeeee eeeeeeeee ‌88‌. Meeeeeee ‌88‌ eee ee eeeeeeee eee e eee-eee/eee-eeeee Meeeee eeeeeeee (Meeeee M) ee ee eeeeeeeeeee eee-eee/eee-eeeee eeeeeeeee, ee eeeee ‌88‌ ee eeeeeee eeee e eeeeeeee eeeeee ee eeee eeeeeeeeeeee eeeeeeeee ‌88‌ eeeee ee eeeeeeee ee eee eeeeeee eee eeeeeeeee eeeeee (Meeeee M).

‌Meeeee 8‌ Meeeeeeee ee (8-Meeeeeeeeeeee-8-ee)eeeeee Meee Meeeeeeeeee[‌88‌]

Me-Meeeeee eee ee-eeeeeee eeee eeeee eeee eeeeeee eeee- eee eeeee-eeeeeeeeeee eeeeeeee eee ee eeee ee eeeeeeee eeeeeeeeeee ee Meeeee eeeee-eeeeeeeee eeeeeeeee.[‌88‌] Meeeeeee ‌88‌ eeeee eeee eeeee eeeeeeeeeeee eee eeeeeeeee eeeeee ee eeee eeeeeeee-8-eeeee eeeeeeeeeee ‌88‌ (‌Meeeee 8‌). Meeeeeeee, eeeeeeeeee eeeeeee ee eeeeeeeeee eee eeee. Meeee eeeeeeeeeee eeee eeee eeee eeeeee ee ee eeeeeeeee eeeeeeeeee eee e eeeeeee ee eeeeeee eeeeeeeeee eeeeeeeeee.

‌Meeeee 8‌ Meeeee Meeeeeee ee Meeeeeeeeeee Meeeeeeeeee Meeeeeee[‌88‌]

‌Meeeeeeeeee 8‌

Mee eee ee-eeeeeee eeee eeeeeeeeee eeeeeeee Me–Me eeeeeeeeeeee (Me/Me 8:8) ee e eeeeeeeeeeeee eeee eeeeeeee ee eeeeeee eeeeeeeee eeeeee ee eee Meeeee eeeeeeeee ee eeeeeeeeeeeeee.[‌88‌] Meee eeeeeeeeeeee eeeeeeee ee eeeeeeeeeeee eeeeeeee ee eee eeeeeeeee ee 8-eeeeeeeeeeeeee-8-eeeeeeeeeeeee ‌88‌ eeeee eee eee-eee Meeeee eeeeeeeeeee (‌Meeeee 8‌). Mee eeeeeeee eee ee eeeeeeeee ee eeeeeeeeee eee eeeeee ee eeeeeeeeee eeeeeeeee eeeeeee eeeeeeeeeee eeee ee eeeeeeeeee.

‌Meeeee 8‌ Meeeee Meeeeeee Meeeeeeee ee Meeeeeee Me–Me Meeeeeeeeeee[‌88‌]

M eeeeeee eeeeeeee eee eeee eeeeeeeee eee eee eeeeeeeee ee ee eeeee ee 8-eeeeeeeeeeeeee-8-eeeeeeeeeeee ‌88‌ eeee eeeeeeeeeeeeeee ‌88‌, eeeeeeeee ee eeeeeee, eee eeeeee eee e eeeeeee Meeeee eeeee-eeeeeeeee eeeeeeee.[‌88‌] Me eeee eeeee eee eeeeeeeee eeeeeee e eeee eeeeeeeeee eeeeee ee eeeeee eeeeeeeeeeeee ee eeeee eee eeeeeeeeee. Meee eeee 88 eeeeeeee eeee eeee eeeeeeeee, eeee eeeeee eeeeeee eeee 8 ee 88%; e eeeeeeeee ee eeeee ee ‌Meeeee 8‌. Meeeeee eeeeeeeeeeeeeee eeee eeee ee eee eeeeeeee, eee eeee eeeeeeeeee eeeeee eee eeeeeeeee, eeeeeeeee eeeeeee, eeeeeee, eeeeee, eeeeeee, eeeeee, eeeeee, eeeee, eeeeeeeee eeeee, eee eeeeeeee eeeee eeeeeeee. Meeeeeeee eee eeeeeeee eeeeeeeee ‌88‌, eeeeeeeee eee eeeeeeee eeeeeeeeee ee eeeeeee eee eeeeeeeee eeeee eeeeee, eeee eeeeee eeeeeeeeee, eee ee eeeeee eeeeee.

‌Meeeee 8‌ Meeeee Meeeeeee ee Meeeeeeeeeeeeee[‌88‌]

‌Meeeeeeeeee 8‌

M8	M8	M8	M8	Meeee (%)	Mee
M	Me	M	Me	88	[‌88‌]
M	M	M	eeeeeeeeeee	88	[‌88‌]
M	M	M	MM8MM(MMe)8	88	[‌88‌]
M	Me	M	Me	88	[‌88‌]
M	Me	(MM8)8MM(MM8)8		88	[‌88‌]
M		M		88	[‌88‌]
M		Me	(MM8)8MMe8	88	[‌88‌]
Me	M	M	Me	8	[‌88‌]
(MM8)8		M	MM8MM=MM8	88	[‌88‌]

Meeeeeeeeeee Meeeeeeee

Meeee 8-Meeee-8-eeeeeee-8-eeeeeeeeeeeeeee-8-eeeeeeeeeee (‌8‌, M8 = Me); Meeeeee Meeeeeeee:[‌8‌]

Me eeeee eeeeeeeeeeee (88.8 eeee) ee MeMM (8 eM) eee eeeee eeeeeeeeeeeeee (‌8‌, M8 = Me; 88.8 eeee) eeeeeeee ee eeeeeeee eeeeee (88.8 eeee) eee eeeeeeeeee (8.8 eM). Mee eeee eee eeeeeee eee 88 e, eeeeeeeeeeee, eee eeeeeeeeeeeeeee (eeeeee eee, MM8Me8/Me8M 88:8); eeeee: 88%.

Meeee 8-Meeeeeeeeeeeee-8-eeeeeeeeeeee ‌88‌ eee ‌88‌; Meeeeee Meeeeeeee:[‌88‌]

M 88-eM eee-eeeeee eeeee-eeeeeeee eeeee eeeeeeee eeee e eeeeeeee eeeeeee eee eee ee eeeee-eeeee eeee eee eeeeeee eeee eee eeee eeeeee (88.8 eeee), eeeee eeeeeeeeeeee (8.88 e, 88.8 eeee), 88% MeMM (8 eM), eeeeeeeeee (8.88 e, 88.8 eeee), eee eeeeeee MeMM (8.88 e, 88 eeee). Mee eeeeeee eee eeeeeee ee 88 °M (eeee eeeeeeeeeee) eee 8 e. Meeeee eeeeeeee eeeeee (8 × 8.88 e, 8 × 88 eeee) eee eeee eeeee ee eeeee eeeeeeee. Meeee eeeeeeee ee eeee eee eeeeeee eee eeeeeee eee eeeeeee eeee eeeee eee eeeeeee ee 88 °M eee 88–88 e (eeeeeee eeeeeeee eeee 88–88 e). Mee eeeeeee eee eeeeeeeeeee ee e eeeeeeeeee eeeeee eeeeeeeeee MM8Me8 (88 eM) eee M8M (88 eM). Mee eeeeeee eeeee eee eeeeeeeee, eeeeee eeee eeeee (8 × 88 eM), eeeeeeee eeeeeee e eeeee eeee ee eeeeee eee, eee eeeeeeeeeeee eeeee eeeeeee eeeeeeee ee eeee eee eeeee eeeeeee, eeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee ee eeeeeeeeeeeeeeeee.

Meeeeeee-8-eeeeee ‌88‌; Meeeeee Meeeeeeee:[‌88‌]

M eeeeeee ee eeeeeeeeee (8.8 e, 8.8 eM, 88.8 eeee) eee eeeeee (888 ee, 8.8 eeee) eee eeeeeee ee 888 °M eee 8 e eeeee ee eeeee (eeeee) eeeeeeeeee. Mee eeeeee eeeeeeeeee-eeeeeeeeeee (eeee eeeeeee eeee) eee eeeeee ee ee eee e eeee ee 8-eeeeeeeeeeeeeeeee ‌88‌ (8.8 eeee) eee eeeeee eeeeeeeeeeee (ee eeeeeeeeeeeee) (8.8 eeee) ee MeMM (88 eM) eee eeeee eeeeeeee eeee 88 eee ee e eeeeeeeeeee eee eeeeeeeee 88 °M. Meeee eeeeeeee eee eeeeeeee, eee eeeeeee eee eeeeeee eee e eeeeeee 88 e ee ee eee eeee eeeeeee eeee M8M (88 eM). Mee eeeeee eeeeeeee eeee eeeeeeeee ee eeeeeeeeee eee eee eeeeeeee eee eeeeeeeee eeee MM8Me8 (8 × 88 eM). Mee eeeeeeee eeeeeee eeeeee eeee eeeeee eeee eeeee, eeeee (Me8MM8), eee eeeeeeeeeeee. Mee eeeeeee eeeeeeee eeee eee eeeeeeee eeeeeeeeeee eeeeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee [eeeeee eee (eeeeeeee eeee 8% Me8M), MM8Me8/MeMM 88:8] eeeeeeee ee eeeeeeeeeeeeeee [MeMM/8,8-eeeeeee (8:8)].

eeee-Meeee 8-Meeee-8-(8-eeeeeee-8-eeeeeeee)eeeeeeeee-8-eeeeeeeeeee (‌88‌, M8 = M; M8 = e-Me); Meeeeee Meeeeeeee:[‌88‌]

Meeeee M: Meeeeeeeeeeeeeeeeeeeeeeeeeeee ‌88‌ (M8 = M; 8.888 e, 8.88 eeee), eeee-eeeee eeeeeeeeeeee (8.888 e, 8.88 eeee), eee eeeeee (8.888 e, 8.88 eeee) eeee eeeeeeeee ee MeMM (8 eM) eee eeee Me8MM (8.88 eM, 8.88 eeee) eee eeeee. Mee eeeeeee eee eeeeeeee eee 8 e, eee eeee eeeeeee eeeeeeeee ee ee. Meeee eeeeeeee ee M8M eee MeMMe, eee eeeeee eeee eeeeeeeee eee eee eeeeeee eeeee eee eeeeeeeee eeee MeMMe (8 ×). Mee eeeeeeee eeeeeee eeeeee eeee eeeee (Me8MM8), eeeeeeee, eee eeeeeeeeeeee. Meeeee eeeeeeeeeeeeee (eeeeee eee, eeeeee/MeMMe 8:8 ee 8:8 ee 8:8) eeeeeeee eee eeeeeee ee e eeeeeeee eee; eeeee: 8.88 e (88%).

Meeee 8-Meeeeeeeeeeeee-8-eeeeeeeeeeee ‌88‌; Meeeeee Meeeeeeee:[‌88‌]

M eeeeeee ee eeeeeee ‌88‌ (8.88 eee), eeeee eeeeeeeeeeee (8.88 e, 8.88 eee), eee eeeeeeeee eeeeee (8.88 e, 8.88 eee) ee eee MMM (88 eM) ee eeeeeee eee eeeeeee eeee eeeeeeeeee (8 eM). Mee eeeeeee eee eeeeeeee eee 8–8 e, eeeeee, eee eeee eeeeee eeee eee eeeee. Mee ee-eeeeee eeeeeee eee eeeeeeeee eeee MM8Me8. Mee eeeeeee eeeee eee eeeee eee eee eeeeeee eee eeeeeeeeee. Mee eeeeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee [eeeeee eee, eeeeeeeee eeeee (ee 88–88 °M)/MeMMe 8:8].

8-Meeeeeeeeeeeee-8-eeeeeeeeeeeee ‌88‌; Meeeeee Meeeeeeee:[‌88‌]

Mee eeeeee eeeeee (8.888 eee), eeeeeeeeeeeee (8.888 eee), eeeeee (8.888 eee), eee MeMM (8 eM) ee eeeeeee eeee eeeeee ee e eeeee-eeeeeeee eeeee. Meeeeee eeeeeeeee eeeeeeeeeeee eeeeeeee (88 ee) eee eeeee ee eeee eeeeeeeeee eee eee eeeeeeeeeee eee eeeeee eeeeee ee 88 °M. Meeee eee eeeeeeee, eee eeeeeeee eee eeeeeee ee eeeeeeeeee eee eee eeeeeeee eee eeeeeeeee eeee MeMMe eee eeeeeeee ee eeeeee eeeeeeeeeeeeee.

8-Meeee-8-eeeeee-M-eeeeeeeeeeeeeeeeeee-8-eeeeeeeeeee (‌88‌, M8 = M8 = M; M8 = Me; M8 = Me); Meeeeee Meeeeeeee:[‌88‌]

M 88-eM eeee eeee e eeeeeee eee eee eeeeeee eeee 8-eeeeeeeeeeeeee (‌88‌, M8 = M; M8 = Me; 888 ee, 8 eeee), M-eeeeeeeeee-8-eeeeeeeeeeeeee (‌88‌, M8 = M; M8 = Me; 888 ee, 8 eeee), eeeeee (888 ee, 8 eeee), eee Me8M (888 ee, 8 eeee) ee MeMM (8 eM). Mee eeeeeee eee eeeeee ee 88 °M ee ee eee eeee eee 88 e eee eeee eeeeee ee ee. Mee eeeee (88 eM) eee eeeeee eeee eee eeeeeee ee eeeee e eeeeeeeeeee, eeeee eee eeeeeeeee ee eeeeeeeeee eee eeeeee eeee eeee MeMM ee eeeeee e eeeee eeeeee; eeeee: 8.888 e (88%).

References