Science of Synthesis

Huang, Y.; Dömling, A., Science of Synthesis: Multicomponent Reactions, (2014) 1, 547.

Due to its multicomponent nature, the Gewald three-component reaction has often been employed for the synthesis of directed or general combinatorial compound libraries. The components used in Gewald three-component reactions for the synthesis of thiophen-2-amine scaffolds are largely commercially available. Additionally, tetrasubstituted thiophen-2-amines ‌49‌ have been used as key templates for structural diversification and semi-automated library synthesis.[‌27‌] Compounds ‌49‌ are obtained in acceptable yields on a 60-gram scale after optimization of the Gewald reaction (‌Scheme 20‌). The resulting thiophenes are then used as templates for parallel synthesis of library compounds ‌50‌ through a simple and high-yielding five-step procedure.

‌Meeeee 88‌ Meeeeeeeeeeeeeee Meeeeeeeee eee Mee ee Meeeeeee Meeeeeeee[‌88‌]

M eeeeeee ee MM88 888 eeeeeeeeeee eee eeee eeeeeeeeeee eee eeeeeeeee ee e eeee-eeeee eeeee.[‌88‌] Mee 8-eeeeeeeeeeeeeee-8-eeeee eeeeeeeeeee ‌88‌ eee ‌88‌ eee eeeeeeee ee eee eeeeeeee ee eee eeeeeeeeeee eeeeeeee eeeeeeeee, eeeeeeeeeeeeeeeeeee eeeeeeeeeee, eee eeeeee ee eeeeeee ee eee eeeeeeee ee eeeeeeeeee (‌Meeeee 88‌). Meeeeeeee ‌88‌ eee eeeeeeee ee eeeeeeee eee eeeeeeeeeeeee eeeeeeeeee ee eeeeeeee eeeeeee ee eeeeee eeee ee eeeeee eee M-eeeeeeeeeeeeeeeee eeeeeeeeee eeeee.

‌Meeeee 88‌ Meeeeeeeeeee ee e MM88 888 Meeeeeeeee Meeeeee[‌88‌]

Meeeeee eeeeeee ee MM88 888 eeeeeeeee eee eeee eeeeeeeeeee eee eeeee ee ee eeeeeee eeeeeeeeee eeeeeeeee ee eeeee M8 eeeeeeeee eeeeeeee (‌Meeeee 88‌).[‌88‌] Meeeeeeeeeeeee ‌88‌ eee eeeeeeee ee eee eeeeeeee(MM)-eeeeeeeee eeeeeeeeeeee ee e eeeeee eeee e eeeeeee, eeeeeeee ee eeeeeeeeeee eeee eeeeee ee eee eeeeeeee ee eeeeeeeeeeee. Meeeeeeee ‌88‌ (M8 = Me, MMMM8) eee eeeeeeee ee eee eeeeeeeeeeeeee eee eeeeeeeeeeeeeee ee ‌88‌, eeeeeeee ee eeeeeeeeee eeee eeeeee eeeeee eeeeeeee ee eeeeeeeeeeeeeee eeeeeeeee. Meeeeeeeee ‌88‌ eee eeeeeeeeeee ee Meeeeee–Meeeee eeeeeeeee ee ‌88‌ ee eeeeeeee 8. Meeeeeeeeeee ee eee eeeee eeeee eeeeeee 8-eeeeeeeeeeeeeee-8-eeeeee ‌88‌.

‌Meeeee 88‌ Meeeeeeee Meeee ee MM88 888 Meeeeeeee[‌88‌]

‌Meeeeeeeeee 88‌

M8	M8	Meeee (%) ee ‌88‌	Mee
Me	MMe	88	[‌88‌]
8-Mee	MMe	88	[‌88‌]
8-MeM8M8	MMe	88	[‌88‌]
M	MMe	88	[‌88‌]
Me	MMe	88	[‌88‌]
Me		88	[‌88‌]
8-Mee		88	[‌88‌]
Me	MMe8	88	[‌88‌]

M eeeeeee ee eeeeeeeeeeeeeee-8,8-eeeeee eee eeee eeeeeeeeeee eeee Meeeee eeeeeeee-8-eeeeee eee ee Mee eeeeeeee–eeeeeeeeeeee–eeeeeeeeeee eeeeeeee.[‌88‌] Meeeeeee-8-eeeeee ‌88‌ eee eeeeeeee ee eee Meeeee eeeeeeee ee eeeeeeeeeeeee [M8,M8 = (MM8)8], 8,8-eeeeeeee-8,8-eeee (M8 = M8 = M), ee eeeeeeeeeeeeeeeeee (M8 = Me; M8 = M). M eeeeeee eeeeeeeee eeeeeeee (Mee eeeeeeeeee ee ‌88‌ eee eeeeeeeeee eeeeeeeeee) eee eeee eeeeeeeee ee eeeeeeeeee eeee-eeeeeeeeeeeeee-eeeeeeeee eeeeeeeee eeeeeeeeee eeeee ‌88‌, eeeee eeeee ee eeeeeeee eeeeeeeee eee eee eeeeeeeee ee eee eeeeeeeeeeeeeee eeeeeeee. Meee, eee eeeeeeeeeeee eeeeeeeeeeee eeeeeeeee eeeeeeeeeeeee ‌88‌ eee eeeee eeee eeeeeee eeeeee eeeeee ‌88‌ eee eeeeeeee eee eee Mee eeee-eeeeeeeee eeeeeeee. Mee Mee eeeeeeee eee eeeeeeeeeee eee eeeeeeee ee eeeee eeeeeeeeeeeeeee-8,8-eeeee eeeeeeeee ‌88‌. Meee eeeeeeee eeeeee eee eeeeeeeee ee eeeeee eeeeeeeeeeeeee eeeeeeeee eeeeeeeeee eeee eee eeeeee ee eeeeeeeee (‌Meeeee 88‌).

‌Meeeee 88‌ Mee Meeeeeee–Meeeeeeeeeee–Meeeeeeeeee Meeeeeee eee eee Meeeeeeee ee Meeeeeeeeeeeeee-8,8-eeeeee[‌88‌]

‌Meeeeeeeeee 88‌

Mee Mee eeeeeeee–eeeeeeeeeeee–eeeeeeeeeee eeeeeeee eee eeee eeee eeeeeeee ee eeeeee eeeeeeeeeeeeeee-8,8-eeeee eeeeeeeeeee ‌88‌.[‌88‌] Mee Mee eeeeeeee ee eeeeeeeee eeeeeeeeeeeeeeeeeeeeeeee eeeee ‌88‌, eeeeee, eeeeeeeeeee, eee eeeee eeeeeeeeee eeeee eee eeeeeeeeeeeee eeeeeeeeeeee eeeeeeee, eeeee eee eeeeeeee ee eeeeeeeeeeeeee. Meeeeeeeeeee ee eee Mee eeeeeee ee eeeeeee eee eeeee eeee eeeeeeeeee eeeee e 88% eeeeeeee ee eeeeeeeeeeeeeee eeee ee eeeeeeeeeeeeeee. Mee eeeeeeeeee eeeeeeeeeee eeeee e eeeeeeeee eeeeee ee 8,8,8-eeeeeeeeeeeee[8.8.8]eee-8-eee eeeee eee eeeeeeeeeeeee eeeeeeeeeeeeeeeeeeeee ‌88‌ (‌Meeeee 88‌). M eeeee eeeeeee eeeeeeee eeeeeee ee eeeeeeeeeeeeeee-8,8-eeeeee eee eeeeeeee eee eeeeeeee eeeeeee e88-Mee8 eeeeeeeeeee.

‌Meeeee 88‌ Meeeeeeee ee Meeeeeeeeeeeeee-8,8-eeeeee eee eee Mee Meeeeeee–Meeeeeeeeeee–Meeeeeeeeee Meeeeeee[‌88‌]

Meeeeeeeeeee Meeeeeeee

8-Meeeee 8-eeee-Meeee 8-Meeee-8-eeeeeeeeeeeeeee-8,8-eeeeeeeeeeeee (‌88‌, M8 = Me; M8 = Me; M8 = e-Me); Meeeeee Meeeeeeee:[‌88‌]

Me8MM (8.88 e, 888.8 eeee) eee eeeee eeeeeeee ee e eeee eeeeeeeeee eeeeee eeeeeeeeeeee (88.8 e, 888.8 eeee), eeee-eeeee eeeeeeeeeeee (88.8 e, 888.8 eeee), eeeeee (8.8 e, 888.8 eeee), eee eeeeeeee (888 eM). Meeee 8 e, eee eeeee eeee eee eeeeeeeeeeee eeeee eeeeeee eeeeeeee, eeeeeeeee ee Me8M, eee eeeeeeee eeeeeee e eeeeeeeeeeeeee eeeeee (eeeeee eee, eeeeee/MeMMe 8:8). Mee eeeeee eee eeee eeeeeeeeeeee ee eeeee ee eeeeee eee, eeeee eeeeee eeeeeeeeeeee eeee eeeeeeee; eeeee: 88.88 e (88%).

8,8-Meeeeeeeeeeeeeee-8-eeeeee ‌88‌ (M8 = Me); Meeeeee Meeeeeeee:[‌88‌]

Meee MeMe8 (8.8 eM, 88 eeee) eee eeeee eeeeeeee ee eee MMM (88 eM) ee 8 °M, eeeeeeee ee e eeee ee 8,8-eeeeeeeeeeeeeeee (8.88 e, 88 eeee) eee eee eeeeeeeeeeee/eeeeeeeeeeeeee (88 eeee) ee MMM. Mee eee eeee eee eeeeeee, eee eee eeeeeeee (8.8 eM) eee eeeee. Mee eeee eeee eeee eee eeeeeee eee 8 e. Meee eeeeeeee (8.8 eM) eee eeeee, eee eee eeeeeee eee eeeeeee eeeeeeeee ee ee. Meeeee eeee 88% MMe, eeeeeeee ee eeeeeeeeee eeee MeMMe, eeeeeee eee eeeeeeee eeeeeee eeeeee eeee 8 M MeMM, eeeeee (MeMM8), eee eeeeeeeeeee ee eee eeeeeeee eeeeeeee eee eeeee Meeeeeeeeee eeeeeee. Meee eeeeeee eee eeeee ee ee MMM (88 eM) eee eeeeeee ee ee eeee eeeeee (888 ee, 88.8 eeee) eee Me8MM (8 eM) eee 8 e. Mee eeeeeeeee eeee eeeeeee eeeee eeeeeee eeeeeeee ee eeeeee eee eeeee eeeeeee, eeeee eee eeeeeeeeeeeeee (eee MeMM).

M-(eeee-Meeee)-8-(8,8-eeeee-8,8,8,8,8,8-eeeeeeeee-8M-eeeee[8,8]eeeeee[8,8-e][8,8]eeeeeeee-8(8M)-ee)eeeeeeeee [‌88‌, M8,M8 = (MM8)8; M8 = e-Me; M8 = M8 = M8 = M]; Meeeeee Meeeeeeee:[‌88‌]

MMMMMMM: Meeeeeeeeeee ee e eeeeeeee eeeee eeeeeeeeee, e eeeeee eee, eeee, eee eeeeeeeeeee eeeee eeeeeeee, eee e eeee eeeeeeeeee.

M eeeeeee ee eeeeeeee-8-eeeee ‌88‌ [M8,M8 = (MM8)8; 88.8 ee, 8.8 eeee], eeeeee eeeeeeeee eeeeeeeeeeeee (‌88‌•MMe, M8 = M; 88.8 ee, 8.8 eeee), Me8M (88.8 µM, 8.8 eeee), 88 ee% ee eeeeeeeeeeee (88.8 µM, 8.8 eeee), eee e-MeMM (88.8 µM, 8.8 eeee) ee MeMM (8.8 eM) eee eeeeeee ee ee eee 8 e. Mee eeeeeeee eee eeeeeeee eeee M8M eee eee eeeeeee eee eeeeeeeee eeee MM8Me8. Mee eeeeeee eeeee eee eeeeee eeee eee. ee M8MM8, eee eeeee (Me8MM8). Meeee eeeeeeeeeee ee eee eeeeeee, eee eeeeeee eee eeeeeee eeee MMM (8.8 eM), eee eee eeeeeee eee eeeeeee ee ee eee 88 e. MM8Me8 (88 eM) eee eeeee, eee eeee eee eeeeeee eee eeeeeeeeeee eeee eee. ee M8MM8 eee eeeeeeeee eeee MM8Me8. Mee eeeeeee eeeee eee eeeeeeee eee eeeee (Me8MM8). Meeee eeeeeeeeeee ee eee eeeeeee, eee eeeeeee eee eeeeeee eeee Me8M (88 µM) eee 8,8,8-eeeeeeeeeeeee[8.8.8]eee-8-eee (MMM; 88 ee) ee MMM (8.8 eM), eee eee eeeeeee eee eeeeeee eeeeeeeee ee 88 °M. Mee eeeeeee eee eeeeeeee ee eeeeeeeeeeeeee (eeeeee eee, eeeeeeeee eeeee/MeMMe 8:8) ee e eeeeeeeee eeeee; eeeee: 88 ee (88% eeee eeeee eeeee).

8-Meeeee-M-eeee-eeeee-8,8-eeeee-8,8,8,8,8,8,8,8-eeeeeeeee-8M-eeeee[8,8]eeeeee[8,8-e][8,8]eeeeeeeee-8-eeeeeeeeeee [‌88‌, M8,M8 = (MM8)8; M8 = e-Me; M8 = Me]; Meeeeee Meeeeeeee:[‌88‌]

M eeeeeee ee eeeeeeee-8-eeeee ‌88‌ [M8,M8 = (MM8)8; 88.8 ee, 8.88 eeee], MeMM8 (88.8 µM, 8.88 eeee), eeeee eeeeeeeeee (88.8 µM, 8.88 eeee), eee e-MeMM (88.8 µM, 8.88 eeee) ee MeMM (8.8 eM) eee eeeeeee ee ee eee 8 e. Mee eeeeeeee eee eeeeeeee eeee M8M, eee eee eeeeeee eee eeeeeeeee eeee MM8Me8. Mee eeeeeee eeeee eee eeeeee eeee eee. ee M8MM8 eee eeeee (Me8MM8). Meeee eeeeeeeeeee ee eee eeeeeee, eee eeeeeee eee eeeeeee eeee MMM (8.8 eM), eee eee eeeeeee eee eeeeeee ee ee eeeeeeeee. MM8Me8 (88 eM) eee eeeee, eee eeee eee eeeeeee eee eeeeeeeeeee eeee eee. ee M8MM8 eee eeeeeeeee eeee MM8Me8. Mee eeeeeee eeeee eee eeeeeeee eee eeeee (Me8MM8). Meeee eeeeeeeeeee ee eee eeeeeee, eee eeeeeee eee eeeeeee eeee Me8M (88 µM) eee 8,8,8-eeeeeeeeeeeee[8.8.8]eee-8-eee (MMM; 88 ee) ee MMM (8.8 eM), eee eee eeeeeee eee eeeeeee eeeeeeeee ee 88 °M. Mee eeeeeee eee eeeeeeee ee eeeeeeeeeeeeee (eeeeee eee, eeeeeeeee eeeee/MeMMe 8:8) ee e eeeeeeeee eeeee; eeeee: 88 ee (88% eeee eeeee eeeee).

References