Science of Synthesis

Huang, Y.; Dömling, A., Science of Synthesis: Multicomponent Reactions, (2014) 1, 542.

In recent years, the Gewald reaction has been adapted to polymer-supported or ionic liquid based protocols which produce thiophen-2-amines in good to excellent yields with high purity. The solid-phase Gewald protocol has been performed by the reaction of a poly(ethylene glycol) resin bound cyanoacetic ester with a ketone or an aldehyde, morpholine, and sulfur in ethanol (‌Scheme 15‌).[‌21‌] Direct isolation of the thiophenamine ‌35‌ is inefficient due to decomposition of the product during the cleavage step with trifluoroacetic acid; however, this problem is solved by acylating the resin-bound amino intermediates ‌34‌ with acetyl chloride prior exposure to trifluoroacetic acid.

‌Meeeee 88‌ Meeee-Meeee Meeeee Meeeeeeee ee Meeeeeeeeeeeee[‌88‌]

Meeeeeeee, eeeee-eeeee Meeeee eeeeeeee ‌88‌ eee ‌88‌ eeee eeeeeeeeeee ee eee eeeeeeeee ee eee eeeeeeeeeeee eeeeeeee eeeeeeeee (‌Meeeee 88‌).[‌88‌] Meeeeeee ‌88‌ ee e eeeee MMM8M (eeeeeee eeeeeeee eeeeeeeeeee 8M) eeeeeeeee,[‌88‌] eeeee eee ee eeeeeeeeeee ee eeeeeeeee ee ‌88‌ eeee eeeeee eeeeee(eee)eeeeeee, eeeeeeeeeeeeeee eeee eeeeeeee eeeeeeee, eee eeee-eeeeeeeeeeeeee eeeeeeeeeeee, eeeeeeee ee eeeeeee eeeeeeeee eeeeeeee eeeeeeeeee. Meeeeeee ‌88‌ eee eeee eeeee ee eeeeeee eee eeeeeeeee eeeeeeee M8 eeee ee MM88 ee 8.8 µM.[‌88‌] Me ee eeeeeeee ee eee eeeeeeee ee eee eeeeeeeeeeeeee-eeeeeeeee eeeeeeee ‌88‌ eeee eeeeeeeeeeee eeee eeeee eeeeeeeeeeeeeeeeeeeeeee/8-(eeeeeeeeeeeee)eeeeeeee, eeeeeeee eeee eee eeeee eeee eeeeeeeeeeeeeee eeee, eee eeeeeeeeee eeee eeeeeeeeee ee eeeeeeeeeeeeeeeee eeeee eeeeee eeeeeeeee.

‌Meeeee 88‌ Meeeeeeeeeeeeeeee ee Meeeeeee-8-eeeeee[‌88‌]

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

‌Meeeee 88‌ Meeee Meeeee Meeee Meeeeeeee Meeeee Meeee-Meeeeeeee Meeeeeee[‌88‌]

‌Meeeeeeeeee 88‌

M eeeeee ee eeee-eeeeeeeeeee eeeeeeee-8-eeeeee eeee eeee eeeeeeee eee eee-eee eeeeeeeee-eeeeeeee Meeeee eeeeeeeee ee e eeeee eeeeeee (‌Meeeee 88‌).[‌88‌] Mee eeeee ‌88‌ ee eeeeeeee ee eee eeeeeeee ee eeeeeeeeeee eeee Meee eeeee, eeeeeeeee eeeeee, 8,8-eeeeeeeeeeee[8.8.8]eeeee-8-eee, eee eee eeeeeeeeeeeee eeeeeeee ee eeeeee, eeeeeeee ee eeeeeeeee eeeee eeeeeeeee eeeeeeeeeee. 8-(Meeeeeeee)eeeeeeeeee ‌88‌ eee eeeeeeee ee eeee eeeeee ee eeeeeeee ee ‌88‌ eeee eeeeeeeeeeeeeee eeee. Mee eeeeeeee eee ee eeeeeeee ee eeeeeeeee-eeeeeeee Meeeee eeeeeeeee eeee e eeee eeeeee ee eeeeee eeeeee eeee e eee eeeee.

‌Meeeee 88‌ Meeeeeeee-Meeeeeee Meeeee Meeee-Meeeeeeee Meeeeeee ee e Meeee Meeeeee[‌88‌]

M eeeeeee ee eeeeeeeee eeeeeeeeeee eeee eeee eeeeeeeeeee eeeee Meeeee eeeeeeeee ee eeee(eeeeeeee eeeeee) (MMM-8888) ee e eeeeeee eeeeeee eeeeeee (‌Meeeee 88‌).[‌88‌] Meee(eeeeeeee eeeeee) eeeeee eeee eeeeeeeeeee eeee, eeeeeeeeeeeeeeeeeeeeeeee, eee 8-(eeeeeeeeeeeee)eeeeeeee eeeee eeeeeeeee eeeeeeeeeee ee eeee eeeeeee-eeeee eeeeeeeeeee eeeee ‌88‌. Mee Meeeee eeeeeeee ee ‌88‌, eeeeeeeee eeeeee, eeeeeee eeeeeeee eeeeeeeee, eee M,M-eeeeeeeeeeeeeeeeeeeee ee eeeeeee eee eeeee eeeeeeeee eeeeeeeeeee ee eeeeee eeeeeeee-8-eeeee ‌88‌, eeeee ee eeeeeeee ee eeee eeeeeee-eeeee eeeeeee ‌88‌. Mee eeeeeeeee eeeeeeeeeee ‌88‌ eee eeee eeeeeeee ee eeeeeeee ‌88‌ eeee 8% eeeeeeeee eeeeeee ee eeeeeeee. Meeeeeee eeee eeeeeeeeeeee eeeeee eeeee eeeeeeeee eeeeeee, eee eeeeeee-eeeee eeeeeeeeeeeee eee eeeeee eeeeeeee ee eeeeee eeeeeeeeeeeee eee eeeeeeeeee.

‌Meeeee 88‌ Meeeeeeee-Meeeeeee Meeeee Meeee-Meeeeeeee Meeeeeee ee e Meeeeee Meeeeee Meeeeee[‌88‌]

‌Meeeeeeeeee 88‌

Meeeeeeeeeee Meeeeeeee

8-(Meeeeeeeeee)eeeeeeeee-8-eeeeeeeeee Meeee ‌88‌; Meeeeee Meeeeeeee:[‌88‌]

Mee eeeee-eeeee eeeeeeeeeee eeeee eee eeeeeeeee ee MeMM eeeeeeeeee eee eeeeee ee eeeeeeee, eeeeeeeeee, eee eeeee eeeeee (8.88 M ee eeee eeeeeeeee) eee eeeeee ee eeeeee eee 88 e ee e 88-eM eeeeeeee eeeeee ee e Meeee 888 eeeeeeeeeee. Meeee eeeeeee ee ee, eee eeeee eee eeeeee eeeeeeeeeee eeee eeeeeeeeeee MeMM, MMM, eee MM8Me8. Meeeeeeee ee eee eeeee eeeee MeMe eeeeeeee ee MMM eeeeeeee eeeeeeee eee eeeeeee.

M-(8-Meeeeee-8,8,8,8-eeeeeeeeeeeeeeee[8,8-e]eeeeeee-8-ee)eeeeee Meee (‌88‌); Meeeeee Meeeeeeee:[‌88‌]

Mee eeeee (888 ee, 8.88 eeee) eee eeeeeeeeeee eeee e Meeee 888 88-eM eeeeeeee eeeeee. 8-(eeee-Meeeeeeeeeeeee)eeeeeeeee-8-eee (888 ee, 8.8 eeee), eeeeeeeee eeeeee (88 ee, 8.8 eeee), eee eeeeeeeeee (888 µM, 8.8 eeee) ee MeMM (8 eM) eeee eeeee ee eee eeeeeeee eeeeee, eee eee eeeeeee eee eeeeeeee eee eeeeeeee eee 8 e. Mee eeeeee eee eeee eeeeeee eee eee eeeee ‌88‌ eee eeeeee. Meeeee eeeeee(eee)eeeeeee (888 µM, 8.8 eeee) eee eMe8MMe (888 µM, 8.8 eeee) eeee eeeee ee eee eeeeeeee eeeeee ee MM8Me8 (8 eM) ee eeeeeee eee eeee eeeee. Mee eeeeeee eee eeeeeeee eee 8 e, eeeeeee, eee eeeeee. Meeeeeee eeee eeeeeee eeee eee eeeee eeee 8 e ee e eeeeeee ee MMM, MM8Me8, eee M8M (88.8:8:8.8) ee eeeeee eee eeeeee eeeee eeeeeeeee eeeeeeeeee eee eeeeeeeeeeeee. MeMM•M8M (88 ee, 8.88 eeee) eee eeeee ee eee eeeee ee MMM/M8M (8:8; 8 eM). Mee eeeeeee eee eeeeeeee eee 8 e eee eeeeeeeeeeee. Mee eeeeeee eee eeeeeeeeeee ee M8M (8.8 eM), eeeeeeeeeeee ee eeeeeeee ee MeMM (8.88 eM), eee eeeeeeee ee eeee eee eeeee eeeeeeee; eeeee: 88 ee (88%).

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

Mee eeeeeeee eeeeeeee (8 eeee), eeeeee (8 eeee), eee eeeeeeeeeeeeeeeeee eeeeeeeee (8.8 eeee) eeee eeeee ee eeeeeeeee eeeeeeeeeeee ‌88‌ (8 eeee). Mee eeeeeee eee eeeeeee eeeee eeeeeee-eeee eeeeeeeeee eee 8–8 e ee 88 °M. Mee eeeeeeeee eeeeeee eee eeeeeeee eee eeeeee eeee eee Me8M (8 × 88 eM) eee eeee eeeee eeeee eeeeee ee eeee eee eeeee eeeeee eeeeeeeee eeeeeeee-8-eeeee ‌88‌. Meee eee eeeee ee e eeee ee MeMMe (8.8 eeee) ee MeMM (88 eM), eee eee eeeeeee eee eeeeeee ee ee eee 8 e. Meee eeeeeeeeee ee eee eeeeeeee, eee MeMM eee eeeeeee eeeee eeeeeee eeeeeeee, eee eee eeeeeee eee eeeeeeeee eeee Me8M (8 × 88 eM). Mee eeeeeeee eeeeeeee eeee eeeeeeeeeeee ee eeee eee eeeeeee eeee eeee eeeeee, eeeeeee eee eeee eee eeeeeee eeeeeeeeeeeeeee eeeeeeeeeeee.

8-(Meeeeeeeeeee)-8-eeeeeeeeeeeeeeeeee-8-eeeeeeeeee Meee (‌88‌, M8 = M; M8 = eMe; M8 = Me); Meeeeee Meeeeeeee:[‌88‌]

8-Meeeeeeeeeeee (888 µM, 8.88 eeee) eee MMM (88 µM, 8.88 eeee) eeee eeeee ee eeeeeeeeeee eeee Meee eeeee (88 ee, 8.88 eeee · e−8) eee eeeeeeeee eeeeee (888 ee, 8.88 eeee) ee eeeeeee (8 eM). Mee eeeeeee eee eeeeee ee 888 °M ee e eeeeee 8-eM Meeee Meeeeee eeeee eeee ee e eeeeeeeee eeee, eeee eeeeeeee, eee 88 eee. eMe8MMe (888 µM, 8.88 eeee) eee eeee MeMe (888 µM, 8.88 eeee) eeee eeeee eee eee eeeeeee eee eeeeee ee 888 °M eee 88 eee ee eee eeeeeeeee eeee. Meeee eeeeeee ee ee, eee eeeeeee eee eeeeeeee eee eee eeeee eee eeeeee eeee MeMM (8 ×), MM8Me8 (8 ×), MMM (8 ×), eee eeeee eeee MM8Me8. Mee eeeee eee eeeeeeeeeee eeeeeee eeee M8M/MM8Me8/MMM (8:8:88) eee 8 e ee ee ee eeeeee eee eeeeeee eeeee eeeeeeeeee eee eeeeeeeeeeeee; eeeee: 88 ee (88%).

Meeeee 8-(Meeeeeeee)eeeeeeeee-8-eeeeeeeeeeee ‌88‌; Meeeeee Meeeeeeee:[‌88‌]

MMMMMMM: Meeeeee eeeee eee ee eeeeeeee eeeeeee eee eeee eee eee eeeeeeeee eeeee.

Mee eeeeeeee eeeeeeee (8 eeee), eeeeeeeee eeeeee (8.88 e, 8 eeee), eee eMe8MMe (8.88 eM, 8.8 eeee) eeee eeeee ee eeeee eeeeeeee ‌88‌ (8.88 e). Mee eeeeeee eee eeeeeeeeee eeee eeeeeeeeee eeeee eeeeeee-eeee eeeeeeeeee eee 88 eee ee e eeeee ee 888 M eeeee M8. Mee eeeeeeeee eeeeeee eee eeeeee ee ee, eeeeeeeee ee MM8Me8 (88 eM), eee eeeeeeee ee eeeeee eee eeeeee eeeeee. Mee eeeeeeee eee eeeeeeeeeeee eee eeeeeeeeeeee eeee eeee Me8M (8 × 88 eM). Meee, eee eeeee eeeeeeeeeee eee eeeee eeeee eeeeee ee eeeeee eee MMM-eeeeeeeee eeeeeeeee ‌88‌. M eeee ee eeee eeeeeeee (8 eeee) ee MM8Me8 (88 eM) eee eeeee eeeeeeee ee e eeee ee ‌88‌ (8.88 e) eee eMe8MMe (8.88 eM, 8 eeee) ee MM8Me8 (88 eM) ee 8 °M eee eee eeeeeee eee eeeeeee ee ee eee 8 e. Mee eeeeeeeee eeeeeee eee eeeeee eeee M8M eee eee eeeeeee eeeee eee eeee-eeeeeeeee eeee MM8Me8 (8 × 88 eM). Mee eeeeeeee eeeeeee eeeeee eeee eeeeee eeee 88% MeMMM8 eeeee eM 8 eee eeeeeeee, eeeee (MeMM8), eeeeeeee, eee eeeeeeeeeeee. Meeeeeeeeeeee eee eeeeeee eeee eeee Me8M, eee eee eeeeeeeeeee eee eeeeeeeee ee eeeeeeeeee, eeeeee eeee eeee Me8M (8 × 88 eM), eee eeeee eeeee eeeeee ee eeeeee eeeeeee ‌88‌, eeeee eee eeeeeee eeee 8% MMM ee MeMM ee ee eeeeeeeee. Meeee eeeeeeeeeee ee MeMM, eee eeeeeee eee eeeeeeeeeee ee MM8Me8 (8 eM), eee eee eeeeeeee MMM eee eeeeeeeeeeee ee eeeeee eeee Me8M eee eeeeeee ee eeeeeeeeee. Meee, eee eeeeeeee eeeeeeee eee eeeeeeeeeeee ee eeee eee eeeee eeeeeeeee eeeeeeeeee ‌88‌, eeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee (eeeeee eee, MeMMe/eeeeeeeee eeeee 8:8).

References