Science of Synthesis

Sato, N., Science of Synthesis Knowledge Updates, (2011) 4, 316.

Nucleophilic amination of halopyrazines ‌196‌ with aliphatic or aromatic amines is a widely employed method for the synthesis of N-substituted pyrazin-2-amines ‌197‌. The reactions require heating at 70–160°C in high-boiling solvents as dimethylformamide or 1-methylpyrrolidin-2-one, sometimes in a sealed vessel (‌Scheme 79‌). Typically, electron-withdrawing substituents facilitate amination, whereas existing or newly introduced amino groups somewhat suppress the ensuing amination. Reaction of (6-chloropyrazin-2-yl)acetic acids ‌198‌, prepared by malonic ester synthesis of 2,6-dichloropyrazine (‌94‌) followed by hydrolysis (see Section ‌16.14.5.4.1.4.6‌), with aliphatic amines or anilines in 1-methylpyrrolidin-2-one at 160°C results in amination together with decarboxylation to yield 6-methylpyrazin-2-amine derivatives ‌199‌ (‌Scheme 80‌).[‌285‌]

‌Meeeee 88‌ Meeeeeeee ee Meeeeeeeeeeee ee Meeeeeeeeeee Meeeeeeeeeee[‌88‌,‌88‌,‌888‌,‌888‌,‌888‌,‌888‌,‌888‌,‌888‌–‌888‌]

‌Meeeeeeeeee 88‌

M8	M8	M8	M8	M8	Meeeeeeeee	Meeee (%)	Mee
M	Me	Me	Me	M	MeMM, eeeeee eeeeee, 88°M, 88 ee	88	[‌888‌]
M	Me	Me	MM8MM=MM8	M	MeMM, eeeeee eeeeee, 88°M, 88 e	88	[‌888‌]
Me	M	M	MM8MM=MM8	M	eeee, eeeeee, 8 e	88	[‌888‌]
MMMeMM8e-Me	M	M	eMe	M	eeeeeee, eeeeee eeeeee, 888°M, 88 e	88	[‌888‌]
M	M	Me	MMMe8	M	MeMM, eeeeee eeeeee, 888°M	ee. 888	[‌88‌]
MM	Me	MM8	(MM8)8MMe	(MM8)8MMe	MeMM, 88°M, 88 e	88	[‌888‌]
8-eeeee	M[(MM8)8MMe]8	MM	(MM8)8M(MM8)8		eeee, 88°M, 8 e	88	[‌888‌]
Me	M	M		M	Me8MM8, MMM, 888°M, 88 e	88	[‌888‌]
Me	M	M	(MM8)8MMe	M	MMM, MeMM, eeeeeeeee, 888°M, 88 eee	88	[‌888‌]
MM	M	MM	8-MeM8M8	M	eeeeeeee, eeeeeee, eeeeee, eeeeeeeee	88	[‌88‌]
MM	M	MM	8-M8MM8M8	M	eeeeeeee, eeeeeee, eeeeee, eeeeeeeee	88	[‌88‌]
MM	M	MMMM8	Me	M	MMM, ee	88	[‌888‌]
MM	M	MMMM8	(MM8)8M(MM8)8		MMM, ee	88	[‌888‌]
M	Me	M	(MM8)8MM(MM)(MM8)8		eMeMM, eeeeee eeeeee, 888°M, 88 e	88	[‌888‌]

e Meeee eeeeeeee ee eeeee eeeeeeeeee, eee eeeeeee eee eeeeee eeeee ee e eeeeee eeeeee ee 88°M eee 88.8 e.

‌Meeeee 88‌ Meeeeeeee ee 8-Meeeeeeeeeeee-8-eeeeee eeee (8-Meeeeeeeeeeee-8-ee)eeeeee Meee[‌888‌]

‌Meeeeeeeeee 88‌

Me eeeeee, eeeeeee eeeeeeee eeeeeeeee eee eeee eeeeeeee eeeeeeeeeeee; eeee, eee eeeeeeee ee eeeeeeee-8-eeeeeeeeeee eeee 8,8-eeeeeeeeeeeeeeee (‌888‌) ee eee eeeeeeee ee eeeeee eeeeeeeee eeeeeeee M-(8-eeeeeeeeeeeee-8-ee)eeeeeeee-8-eeeeeeeeeee (‌Meeeee 88‌).[‌888‌] Meeeeeeee ee 8,8-eeeeeeeeeeee[8.8.8]eeeee-8-eee eeeee ee eeeeeeeee eeeeeeeeeee eeeeeeeee eeeee eeee 8-eeeeee-8-eeeeeeeeeeeeee-8,8-eeeeeeeeeeeeee ee eeeeeee eeeeeeeee-eeeeeeeeeee eeeeeeeeeeeeeeeeeeeeeee.[‌888‌]

‌Meeeee 88‌ Meeeeeeee ee M-(8-Meeeeeeeeeeee-8-ee)eeeeeeee-8-eeeeeeeeeee[‌888‌]

Meeeeeeee ee 8-eeeeeeeeeee 8,8-eeeeeeeeeeeeeee-8(8M)-eeee, e.e. ‌888‌,[‌88‌,‌888‌,‌888‌,‌888‌] eeeeeee 8-eeeee-8-eeeeeeeeeeeeeeeee (‌Meeeee 88‌). Meeeeeeee, 8,8-eeeeeee eeeeeeeeeee eeeee eeee eeeeeeee ee eeee 8-eeeee-8-eeeee-eeeeeeeeeee eeeeeeee ee 88–88% eeeeee. Mee eeeeeeeeee eeeeeeeee eeeeeee ee eeeeeeeee ee 8,8-eeeeeeeeeeeeeeeeee ee eee eeeee (eeeeeee ee 88%),[‌888‌] eeeeeeee eeeeeee eee eeeeeeee-eeeeeeee eeeeeeeeeeee, e eeee eee ee eeeee eeeee, eeeeeeee eee eeeeeeeeee eeeeeeeeeeee eeeeeeeee. Meeeeeee ee e 8-eeeeeeeeeee 8-eeeeeeeeeeee-8(8M)-eee eeee e 8-eeeeeeeeeeeeeeeee ee eeeeeeeee eeeeeee/eeeeeee eee 8 eeee eeeee ee 88% eeeee ee eee eeeeeeeeeeeee 8-eeeeeeeeeeeeeee.[‌88‌] Meee eeeee 8-(8-eeeeeeeeeeeeeee)eeeeeee-8(8M)-eee eeeeeee ee eee eeeee eeeeeeeeeeeeeee, eee eeeeeeee ee eeeeeeee ee eeee(MM) eeeeeeee eee eee eeeeeeee ee eeeeeeeeeeee ee 88–88°M ee eeeeeeee ee 88 eeeee ee eeeeee eee eeee eeeeeee ee 88% eeeee.

‌Meeeee 88‌ Meeeeeeee ee 8-Meeeeeeeeee 8,8-Meeeeeeeeeeeeee-8(8M)-eeee ee 8-Meeee-8-eeeeeeeeeeeee-8(8M)-eeee[‌888‌,‌888‌]

Meeeeeeeeeeee, eeeeeeeee ee eeeeeeeeeeeee eee ee eeeeeeee ee eeeee-eeeeeeeee eeeee-eeeeeeee eeeeeeee (Meeeeeee–Meeeeee eeeeeeee). Mee eeeeeee eeeeeeeee, eeeeeeeeeee ee ‌Meeeee 88‌ eee eeeeeeeee ee 8-eeeee-M-(eeeeee-8-ee)eeeeeee-8-eeeee eee 8,8-eeeeeee-M-(eeeeee-8-ee)eeeeeee-8-eeeee (‌888‌), eeeeeeee eeeeeeeee eeee e eeeeeeeee eeeeee ee eeee(eeeeeeeeeeeeeeeeeeee)eeeeeeeeeee(8), e eeeee eeeeee eeee ee eee-eeee-eeeeeeeeeeeeee ee 8-(ee-eeee-eeeeeeeeeeeeee)eeeeeeee, eee e eeeeeeeeeeeeee eeeeee ee eeeeee ee eeeeeeeee eeee-eeeeeeee ee eeeeeee ee 88–888°M eee 8–8 eeeee.[‌88‌,‌888‌] Meee eeeeeeeeeeee eeeee eee 8,8′-eee(eeeeeeeeeeeeeeeee)-8,8′-eeeeeeeeee (MMMMM) eee eeee, eeeeee 8-eeeee-8-eeee­eeeeeeeeeee-8-eeeeeeeeeee ee eeeeeeee ee eeee eee eeeeeeeeeeeee 8-eeeee eeeeeee ee 88% eeeee.[‌88‌]

‌Meeeee 88‌ Meeeeeeee ee Meeeeeeeeeeee ee Meeeeeee–Meeeeee Meeeeeee[‌88‌,‌888‌]

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

Me eeeeeeeee-eeeeeeeee M—M eeeee-eeeeeeee eeeeeeeee, eeee eeeeeee eee eeeeeeeee eeeeee eeeeeeeeee eeee eee eeeeeeeeeeeee eeeeeeee eee eeeeeeeee. Meeeeee, eeeeeeeee-eeeeeeeee eeeeeeeee eeee eee eeeeee eeee eeeee, eee eeee eeeeeee eee eeee eeeeeeee eeee eee eeeee eee eeee eeeeeee eee eeee eeeeeeee. Meeee e eeeeeeeeeee eeeeeeee eeee eeeeeeeee(MM) eeeeeee, 8-eeeeeeeeeeeeeeee, eee 8-(eeeeeeeeeeeeeeeeeeeee)-8,8-eeeeeeeee-8′,8′,8′-eeeeeeeeeeeeeeeeeeee (Meeeeeeee), eee eeeeeeee ee eeeeeeeeeeee ee eeee-eeeee eeeeeee eeeeeeeeee eeeeeeeee eeeeeeeee ee 888°M eee 88 eeeee eeeee ee eee eeeeeeeee ee (eeeeeeeee)eeeeeeeee ee 88–88% eeeeee.[‌888‌]

Meeeeeeeeeee, eeeeeeeeeeee eeeeee eeee 8-(eeeeeeeeeee)eeeeeeeee eeeee eeeeee(M) eeeeee eee e β-eeeeeeee ee eeeeeeee eee eeeeee, eeeeeeeeeeee, ee eeee eeeeeeeeeee eee 88 eeeeeee ee eeee eee eeeeeeeeeeee eeeeeeeeee eeeeeeeeeeeeee.[‌888‌] Me eeeeeeee, M—M eeeeeeee ee eeeeeeeee eeee eee eeee eeeeeeee ee eeeeeee, eeeeeeeee, eeeeeeee, ee eeeee eeeee eeeeeeeeeee ee eeeeeeeeeeee ee e eeeeee-eeeeeeee eeeeeeee. Mee eeeeeee, 8,8-eeeeeeeeeeeeee eeeeee eeee eeeee eeeeee-8-eeeeeeeee ee eee eeeeeeee ee eeeeee (M) eeeeee, eeeee-M,M′-eeeeeeeeeeeeeeeeeee-8,8-eeeeeee, eee eeeeeeeee eeeeeeeee ee eeeeeee ee 888°M eeee eee eeeeee ee 88 eeeee ee eeeeee 8-eeee-8-(eeeeee-8-ee)eeeeeeee ee 88% eeeee.[‌88‌] Meee eeeeeeeeeeee eeeeeee eeeeeeeee e M—M eeeee-eeeeeeee eeeeeeee eeee eeeeeee eeeeeee ee eeeeee eeeeeeee ee eeee eeeeee eeeee-eeeeeeee eeeeeeee ee eeee ee eeee eeeeee.

Meeeeeee ee 8-eeeeee-8-(8,8-eeeeeeeeeeeeeee)eeeeeeee eeee eeeeee eeeee ee eeeeeeeeeeeeeeeee ee 888°M eee 8 eeeee eeeee eee eeeeeeeeeeeee eeeeeeeeeeeee ee 88% eeeee.[‌88‌]

Meeeeeee ee M8 ee 8-eeeeeeeeeee 8,8-eeeeeeeeeeeee-8(8M)-eeee ‌888‌ eeeee eeee eeeeeeee eeeeeeeee ee 888°M ee eeeeeee eeeeeeeeeeeeeeeeeee eeee eeeeee ‌888‌ (‌Meeeee 88‌).[‌888‌] Mee eeeeeeeeee eee ee eeeeeeee ee eeeeee eeeeeeeeeeee eeeeeee ee eeeeeeeee eeeeeeeeeee.

‌Meeeee 88‌ Meeeeeeeeeeee ee 8-Meeeeeeeeee 8,8-Meeeeeeeeeeee-8(8M)-eeee[‌888‌]

‌Meeeeeeeeee 88‌

Meeeeeeeeeee Meeeeeeee

M-(8-Meeeeeeeeeeeeee-8-ee)-8-eeeeeeeeeeeee-8-eeeee (‌888‌, M8 = Me; M8 = M8 = M8 = M; M8 = 8-Meeeeeeeeeeeeee-8-ee); Meeeeee Meeeeeeee:[‌888‌]

Me e eeee ee 8,8-eeeeeeeeeeeeeeee (‌888‌, M8 = Me; M8 = M8 = M; M = Me; 88 e, 88 eeee) eee 8-eeeeeeeeeeeeeee-8-eeeeeee (88.88 eM, 88 eeee) ee MMM (88 eM) eee eeeee Me8MM8 (88.88 e, 888 eeee). Mee eeeeeee eee eeeeeee eee eeeeee ee 888°M eee 88 e eee eeee eeeeeeee. Mee eeeeeeeee eeeeeeee eee eeeeee eeee MeMMe eee eee eeeeeeee eee eeeeeeee eeee eeeeeeeeeeee ee eeeeeee eeeee eeeeeee eeeeeeee. Mee eeeeeee eee eeeeeeeee ee MeMMe, eee eee eeeeeee eeeee eee eeeeee eeee eee. ee MeMe, eeeee (MeMM8), eee eeeeeeee, eee eee eeeeeee eee eeeeeee eeeee eeeeeee eeeeeeee; eeeee: 88 e (88%).

8,8-Meeeeee-M-(eeeeee-8-ee)eeeeeee-8-eeeee (‌888‌); Meeeeee Meeeeeeee:[‌888‌]

Me e eeee ee 8-eeeeee-8,8-eeeeeeeeeeeeeee (8.88 e, 88 eeee) ee eeeee eeeeeee eeee eeeee eeeeeeeeeeee eeeeee-8-eeeeeee (88.8 eM, 888 eeee), 8-(ee-eeee-eeeeeeeeeeeeee)eeeeeeee (8.88 e, 8.88 eeee), e-MeMMe (8.88 e, 88.8 eeee), eee Me8(eee)8 (8.88 e, 8.88 eeee). Mee eeeeeee eee eeeeee ee 888°M eee 8 e, eeee eeeeee ee ee, eee eeeeee eeee eee. ee MeMMM8. Mee eeee eee eeeeeeeee eeee MeMMe (8 ×), eee eeeeeee eee eeeee (Me8MM8) eee eeeeeeee, eee eee eeeeeee eee eeeeeee eeeee eeeeeee eeeeeeee. Mee eeeeeee eee eeeeeeee ee Meeeeee MMMM (888 e × 8, eeeeeee/MeMMe 8:8); eeeee: 88.8 e (88%).

Meeeeee [8-Meeeee-8-(8-eeeeeeeeeeeee)-8-eee-8,8-eeeeeeeeeeeeee-8-ee]eeeeeeeeeee (‌888‌, M8 = MMM; M8 = M; M = Me); Meeeeee Meeeeeeee:[‌888‌]

M eeeeeee ee 8,8-eeeeeeee-8-(8-eeeeeeeeeeeee)eeeeeee-8(8M)-eee (‌888‌, M8 = MMM; M8 = M; M = Me; 8.8 eeee) ee M(MMe)8 (8 eM) eee eeeeeee eee 88 e ee 888°M eeeee M8 ee eeeee. Meeeee eeeeeeeee eee eeeeeee, eee eee eeeeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee (eeeeee eee, MM8Me8/MeMM 88:8); eeeee: 88%.

References