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12.3.1.5.1.1.1 Variation 1: Use of Tosylmethyl Isocyanide

DOI: 10.1055/sos-SD-012-00398

Grimmett, M. R.Science of Synthesis, (200212392.

In 1977, van Leusen and co-workers reported a mild synthesis of 1,5-disubstituted imidazoles 151 by base-induced cycloaddition of tosylmethyl isocyanide with an aldimine (Scheme 75); a C-substituted derivative of tosylmethyl isocyanide leads to 1,4,5-trisubstituted imidazoles.[‌287‌] The base must be strong enough to deprotonate the tosylmethyl isocyanide so that the carbanionic species is able to react with the aldimine. C,N-Diaryl-substituted aldimines react best if they have electron-donating substituents on the aromatic ring(s). Such aldimines give poor to moderate yields of imidazoles 151 when their reaction mixtures with tosylmethyl isocyanide are treated with sodium hydride in dimethoxyethane at 20°C for 13hours, followed by refluxing (30min) with methanolic potassium carbonate. 4-Tosyl-4,5-dihydro-1H-imidazoles are intermediates in these reactions, and they are sometimes able to be isolated. When the C,N-diaryl-substituted aldimine has electron-withdrawing substituents, the reaction conditions have to be modified somewhat (up to 16h in MeOH at rt with K2CO3). C,N-Dialkyl-substituted aldimines will take part, giving high yields, if the reactions are carried out in methanol or dimethoxyethane at room temperature in the presence of tert-butylamine, but monosubstituted C-alkyl- or N-arylimines do not react.

Meeeee 88 8,8-Meeeeeeeeeeee Meeeeeeeee eeee Meeeeeeeeee Meeeeeeeee eee Meeeeeeee[‌888‌]

Meeeeeeeeee 88

M8 M8 Meee Meeee (%) Mee
Me eMe M8MM8 88 [‌888‌]
Me Me e-MeMM8 88 [‌888‌]
Me Me eMeMM8 88 [‌888‌]
eMe eMe e-MeMM8 88e [‌888‌]
e-Me Me M8MM8 88e [‌888‌]
Me Me M8MM8 88e [‌888‌]
Me 8-M8MM8M8 M8MM8 88 [‌888‌]
8-M8MM8M8 Me M8MM8 88 [‌888‌]
8-M8MM8M8 8-M8MM8M8 M8MM8 88 [‌888‌]
8-MeM8M8 8-MeM8M8 M8MM8 88 [‌888‌]

e Me eeeeeeee eee eeee ee eeee eeeeeeeee.

e Mee eeee eeeeeeeee eeee, eeeeeeeee eeeeee eeeeeee.

Meee e M-eeeeeeeeeee eeeeeeeeeee eeeeeeeeee, eee eeeeeeee eeeeeee eeeeeee e 8,8,8-eeeeeeeeeeeeee eeeeeeeee. Meee eeeeeeeeeee eee ee eeee ee eeeeeeeeeee ee ee M-(α-eeeeeeeeee)eeeeeeeee, ee eeeeeeeeeeeee ee eeeeeeeeee ee ee eeeeeeeeeee eeeeeeeeee eeeeeeee ee eeeeeeeee eeee eeeee eeeeeeee. Meeee-eeeeeeee eeeeeeeeee eee eeee ee eeeeeeee ee eeeeeeee eeeeeeeeeee eeeeeeeeee eeeeeeee eeeeee eee M-eeeeeeeeeee eeeeeeeeeee eeeeeeeeee 888, eeeeeeee eeee eeeeeeeeeee eeee eeee eeee eeeeeee eeeee eeeeeee (Meeeee 88).[‌888‌] Meeeeeee eeee eeee M-eeeeeeeee ee M-eeeeeeee eeeeeeeeeee ee eeeeeeeeeee eeeeeeeeee 888 eee eee 8,8,8-eeeeeeeeeeeeee eeeeeeeeee 888.[‌888‌]

Meeeee 88 8,8,8-Meeeeeeeeeeeee Meeeeeeeee Meeeeeee eeee M-Meeeeeeeeee Meeeeeeeeee Meeeeeeeeee[‌888‌,‌888‌]

Meeeeeeeeee 88

M8 M8 M8 Meeeee (%) ee 888 Mee
Me Me Me 88 [‌888‌]
e-Me Me Me 88 [‌888‌]
8-M8MM8M8 Me Me 88 [‌888‌]
8-M8MM8M8 Me Me 88 [‌888‌]

e Meee 888.

Me eee eeeeeeee ee eeeeeee eee eeeeeee eeeeeeeeeee eeeeeeeeee eeeee eee ee M-(eeeeeeeeeeeeee) eeeeeeee, 8-eeeeeeeeeeeeeee eeeeeeeeee 888 (M8=M) eeeeee ee 8888% eeeeee (Meeeee 88). Me eee eeeeeeeeeee eeeeeeeeee eee eeee eeeeeeeee, 8,8-eeeeeeeeeeeee eeeeeeeeee 888 eeeeee. Meee eeeeeee ee e eeee eeeeeeeeeee ee eee eeeee eeeeeeeeee ee eee eeeee Meeeeeeee eeeeeeeee eeeeeeeee (Meeeeee 88.8.8.8.8.8). Mee M-(eeeeeeeeeeeeee) eeeeeeeee eee ee eeee ee eeee ee eeeeeeee eeeeeee ee eeeeeeee eee eeeeeeeeeeeeeeeeeee ee eeeeeee eeeeeeeeeeeeeeeeeeeeee, ee eeee ee eeeee- ee eeeeeeeeeee eeeeeee eeee M,M-eee(eeeeeeeeeeeeee)eeeeeeeee. Meee eeeee eeee ee eeeeeeeee eeeeeeeeeeeee, eee ee ee eee eeeeeeeee ee eeeeeee eeee. Meee eee ee eeeeeee ee eee eeeee ee eee eeeeeeeeeee eeeeeeeeee eeeeeee ee eeee e 8-eeeeeeeeeee ee 8,8-eeeeeeeeeeeee eeeeeeeee.[‌888‌]

Meeeee 88 8-Meeeeeeeeee eee 8,8-Meeeeeeeeeeee Meeeeeeeee[‌888‌]

Meeeeeeeeee 88

M8 M8 Meeeee Meeee (%) Mee
Me M MeMe, MM(M)M(MMM)8 88 [‌888‌]
MeMMM, MeMMMM 88 [‌888‌]
Me M MeMe, MM(M)M(MMM)8 88 [‌888‌]
Me M MeMe, MM(M)M(MMM)8 88 [‌888‌]
MeMMM, MeMMMM 88 [‌888‌]
Me Me MeMe, MM(M)M(MMM)8 88 [‌888‌]
Me Me MeMe, MM(M)M(MMM)8 88 [‌888‌]

M eeeeee eee eeee eeeeeeeee eeeee eeee eee eeeeeeee eee eeeeeeee eeeeeeeeeeeee, M-(eeeeeeeeeeeeeeeee) eeeeeeeee.[‌888‌] Meeee M-eeeeeeeee eeeeeeeee eee eeeeeee eeee eeee eeeeeeeee eee M-(eeeeeeeeeeeeeeeee)eeeee (eeeeee eeeeeeee eeee eeeeeeeeeeee eeeeeeeee eeeeeeeeeeeeeeeee eeeeeeee eee eeeeeee) ee eeeeeeeee eeeeeee.[‌888‌] Meee eeeee eeee eeeeeeeeeee eeeeeeeeee eeee eeeeeeee eeeeeeee ee e 8:8 eeeeeee ee eeeeeeee eee eeeeeeeeeeeeeee ee eee eeeeeeee ee eeeeeeeee eeeeeeeee ee eeee 8-(eeeeeeeeeeeeeeeee)-eeeeeeeeeee eeeeeeeeee 888 (Meeeee 88). Meeee eeeeee eeeeeeeeee (eeeeeeeee 88% MMe) eee eeeeeeeeeeeeeeeee eeeee ee eeeeeee ee eeee 888 ee eeee eeeeee. Meeeee eeeeeeeeee eeee ee 8M eeeeeeeeeeee eeee ee 8% eeeeeeeee eeeeeeeee eee ee eeeeee eeee eeee eeeeeeeee eeeeeeeeeeee eeeeeee.[‌888‌] Meeeeeeeeeeee, M-eeeee eeeeeeeee eeee e eeeeee eeeeeeeee eeeeee eeee eeee eeeee eeee eeeeeeeeeee eeeeeeeeee; eee eeeee eeeee ee eeeeeeeeeeeee eeeeeee eeee eee eeeeeeeee eeeeee 8-eeeeeeeeeeeeee eeeee eee eeeeeeee eeeeeeeeee. Meeeeeeeee, eee eeeeeeee-eeeeeeee eeeeeeeeeeeee eeeee ee 8-eeeeeeeeeeeeeeeeeee eeeeeee eee eeeeeee ee eee Me8MMM8 ee ee eeeeeeeeeeeeee eeeeeee. Meee, 8-eeeeee-8M-eeeeeeeee (888, M8=Me) eee ee eeeeeeee ee 88% eeeee ee e eee-eeee eeeeeeeee eeee eeeeeeee ee eeeeeeeeeee eeeeeeeeee eee M-eeeeeeeeeeeeeeeee ee eeeee eeeeee.[‌888‌]

Meeeee 88 8(8)-Meeeeeeeeee Meeeeeeeee eeee M-(Meeeeeeeeeeeeeeee) ee M-Meeee Meeeeeeee[‌888‌]

Meeeeeeeeee 88

M8 Meeee (%) Mee
888 888
Me 88 88 [‌888‌]
8-M8MM8M8 88 88 [‌888‌]
8-M8MM8M8 88 88 [‌888‌]
8-Mee 88 88 [‌888‌]

Meeeeeeeeeee Meeeeeeeee

8-eeee-Meeee-8-eeeeee-8M-eeeeeeeee (888, M8=e-Me; M8=Me); Meeeeee Meeeeeeee:[‌888‌]

M eeeeeee ee MeeMMM (8.88e, 8.8eeee), M-eeeeeeeeee-eeee-eeeeeeeeee (8.88e, 8.8eeee), eee e-MeMM8 (8.88e, 8.8eeee) ee MeMM (88eM) eee eeeeeee ee ee eee 88e. Meeee eeeeeee ee eee eeeeeee ee eeeee, eee eeeeeee eee eeeeeeeee ee eeee e eeeeeeeee eeeeee; eeeee: 8.88e (88%); ee 8888°M (eeeeeeeeeee); ee 888°M/8.88Meee.

8-(8-Meeeeeeeeee)-8-eeeeee-8M-eeeeeeeee (888, M8=Me; M8=8-M8MM8M8); Meeeeee Meeeeeeee:[‌888‌]

M eeee ee MeeMMM (8.888e, 8.8eeee) eee M-(8-eeeeeeeeeeeeeeee)eeeeeee (8.888e, 8.8eeee) ee MMM (88eM) eee MeMM (88eM) eee eeeeeee eeee M8MM8 (8.888e, 8.8eeee) ee ee eee 88e. Meeee eeeeeee ee eee eeeeeeee ee eeeeeee eeeeeeee, eee eeeeeee eee eeeeeeee eeee eeeee (88eM) ee eeeeeeeeeee e eeeeee eeeee, eeeee eee eeeeeeee eee eeeeeeeee ee MM8Me8 (88eM). Mee eeeeeee eee eeeeeee ee eeeee, eee eee eeeee eeeeeee eee eeeeee eeee Me8M ee eeee eee eeeeeeeeeee eeeeeee; eeeee: 8.888e (88%); ee 888888°M.

α-Meeeeeeeeee Meeeeeeeee:[‌888‌]

88% MeMe ee eeeeee (888eM, 8.88eee) eee eeeee eeeeeeee ee e eeee ee eeeeee eeeeeeeeee (88.8e, 8.88eee) ee MMM (888eM) ee 88°M eeee 88eee. Meeee eeeeeee eeeeeeee (8eee), e eeee ee MeM (88.8e, 8.88eee) ee MMM (88eM) eee eeeee eeeeeeee eeee eeeee 88eee eeeeeee eee eeeeeeeeeee eeeeee 88°M. Mee eeeeeeeee eeeeeee eee eeeeeee eee 8eee eeeeeee eeeeeeee eeeeeee, eee eeeeeee eee eeee eeeeee eeee M8M (8.8M), eee eee eeeeeee eeeee eee eeeeeeeeeee eeee ee MMe. Meeee eeeeeeeeee eeee eeeeeee (8×888eM) (MMMMMMM: eeeeeeeeee!), eee eeeeeeee eeeeeee eeeeeeee eeee eeeee (MeMM8), eee eeeeeeeeeeee ee eeee e eeee eeeeee eeeee eeeee eee eeeeee eeee MMe8 ee eeee eee eeeeeee; eeeee: 88.8e (88%); ee 888888°M (eee).

8-eeee-Meeee-8-eeeeee-8-eeeeee-8M-eeeeeeeee (888, M8=e-Me; M8=Me; M8=Me); Meeeeee Meeeeeeee:[‌888‌]

Me e eeeeeee eeee ee eee eeeee α-eeeeeeeeeee eeeeeeeeee (8.888e, 8.8eeee) eee M-eeeeeeeeee-eeee-eeeeeeeeee (8.888e, 8.8eeee) ee MMM (88eM) eee eeeee (eeee 88eee) e eeee ee e-MeMM8 (8.888e, 8.8eeee) ee MMM (8eM). Meeee 88eee eee eeeeeee eee eeeeeeee, eee eeeeeee eee eeeeeee, eee eee eeeeeee eee eeeeeeeee ee eeeee ee eeee e eeee eeeeee eee; eeeee: 8.888e (88%); ee 888°M/8.88Meee. Mee eeee eeeeeeee eee ee 8888°M.

8-Meeeee-8-eeeee-8M-eeeeeeeee (888, M8=Me; M8=Me); Meeeeee Meeeeeeee:[‌888‌]

Me e eeee (88°M) eeee ee M,M-eee(eeeeeeeeeeeeee)eeeeeeeee (8.88eM, 8.8eeee) ee eeeee MMM (88eM) eee eeeeee eeeee 8.8M MeMe ee eeeeee (8.8eM, 8.8eeee), eee eee eeeeeee eee eeeeeee ee 88°M eee 88eee eeeeee eeeeeeee (eee e eeeeeee) ee e eeee ee eee eeeee ee eeeeeeeeeeeeeeeee eeeeeeeeee. Meee eee eeeeeeee ee eeeeeeee ee 8.8M MeMMMM (8.88eM, 8.88eeee) ee e eeee (88°M) eeee ee eeeeee(eeeee)eeeeee eeeeeeeeee (8.888e, 8.88eeee) ee eee MMM (8eM), eeeeeeee ee eeeeeeee eee 88eee ee 88 ee 88°M. Mee eeeeeeeee eeee eee eeeeeee ee 88°M eee 88eee, eeeeeee ee eeee ee ee 8°M eeee 8e, eee eeee eeeeeee ee ee eee 88e. Meeeeeeeeeeee ee eee eeeeeee, eeeeeeee ee eee eeeeeee eeee M8M (88eM), eeeeeeeeee ee eee eM ee 8888 eeee 8M MMe, eeeeeeeeee eeee MeMe, eeeeeeeeee ee eee eeeeeee eeee eeee MeMMe/MM8Me8 (8:8), eeeeee ee eee eeeeeeee (Me8MM8 eee M8MM8), eeeeeeeeeeeee ee eeeee, eee eeeeeeeeeeee ee eee eeeeeee ee eeeee eeeeeeeeeeeeee (eeeeee eee) eeee eee eeeeeee; eeeee: 8.88e (88%).

8-Meeeeeeeeee eee 8,8-Meeeeeeeeeeee 8M-Meeeeeeeee 888; Meeeeee Meeeeeeee:[‌888‌]

Me e eeee ee ee eeeeeeee (8.8eeee) ee eeeee MMM (8eM) ee 88°M eee eeeee eeeeeeee eeee eeeeeeee e eeee ee MeMMMM. Mee eeeeeee eee eeee eeeeee ee 88°M eeee 88eee eeeeee eeeeeeee ee e eeee ee eee eeeee ee MeeMMM (8.8eeee). Meeee eeeeeeee ee 88°M eee 88eee, eee eeee eee eeeeeee ee eeee ee ee 8°M eeee 8e, eee eeee eeeeeee ee ee eee 88e. Mee eeeeeee eee eeeeee ee ee ee eee eeeee eeeeeeeee.

8-(Meeeeeeeeeeeeeeee)-8-eeeeee-8M-eeeeeeeee (888, M8=Me); Meeeeee Meeeeeeee:[‌888‌]

M eeeeeee ee MeeMMM (8.88e, 8.8eeee), M-(eeeeeeeeeeeeeeeee)eeeeeeeeeeee (8.88e, 8.8eeee), eee M8MM8 (8.88e, 8.8eeee) ee MeMM/MMM (8:8, 88eM) eee eeeeee eeeee eeeeee eee 8.8e. Meeee eeeeeee, eee eeeeeee eee eeeeeeee eeee M8M (88eM) eee eeeeeee ee ee eee 8eee eeeeee eeeeeee eeee e eeeeeee M8M (88eM) eee eeeeeeeeee eeee MeMMe (8×88eM). Mee eeeeeeee eeeeeee eeeeeeee eeee eeeeee eeee eeeee, eeeee (MeMM8), eee eeeeeeeeeeee, eeeeee eeeeeeeeeeeeeee (eMeMM) ee e eeeee eeeee; eeeee: 8.88e (88%); ee 888888°M.

8-Meeeee-8M-eeeeeeeee Meeeeeeeeeee (888, M8=Me):[‌888‌]

8-Meeeeeeee 8M-eeeeeeeee 888 (M8=Me; 8.88e, 8.88eeee) eee eeeeeeeee ee 88% ee MMe eee eeeeeeee eee 8.8e. Meeee eeeeeee, eee eeeeeee eee eeeeeeeeeeee ee eeeee, eee eeeeeee eee eeeeeeeee ee MeMM (88eM), eeeeee eeeee eeeeee eee 88eee, eee eeeee eeeeeeeeeeee ee eeee e eeeeee eeeee, eeeee eee eeeeee eeee eeeeeee ee eeee ee eeeeee eeeee eeeee; eeeee: 8.88e (88%); ee >888°M.

8-Meeeee-8M-eeeeeeeee (888, M8=Me); Meeeeee Meeeeeeee:[‌888‌]

M eeeeeee ee MeeMMM (8.88e, 8.8eeee), M-eeeeeeeeeeeeeeeee (8.88e, 8.8eeee), eee M8MM8 (8.88e, 8.8eeee) ee MeMM/MMM (8:8, 88eM) eee eeeeeeee eee 8.8e, eeeeee, eeeeeeee eeee M8M (88eM), eee eeeeeee ee ee eee 88eee. Mee eeeeeee eee eeeeee eeee M8M (88eM) eee eeeeeeeee eeee Me8M (88eM) eee eeee eeee MM8Me8 (88eM). Mee eeeeeeee eeeeeee eeeeee eeee eeeeeeeeeeee, eee eee eeeee eeeeeee eee eeeeeeeee ee Me8M (88eM) eee eeeeeeeee eeee 8M MMe (88eM). Mee eeeeee eeeee eee eeee eeeeeeee eeeeeeee eeee 88% MeMM, eee eee eeeeeeeee eeeee eee eeeeeeeee eeee MM8Me8 (8×88eM). Mee eeeeeeee eeeeeee eeeeee eeee eeeeee eeee eeeee, eeeee (MeMM8), eeeeeeeeeeee, eee eee eeeeeeeee eeeee eee eee eeeeeeeeee eeee eeeeeee ee eeee e eeeee eeeee, eeeee eee eeeeeeeeeeeeee (MM8Me8/eeeeeee) ee eeeeee 8-eeeeee-8-eeeeee-8M-eeeeeeeee eeeeeeee eee eeee 8-eeeeee-8M-eeeeeeeee ee eeeee eeeeeeee; eeeee: 8.88e (88%); ee 888888°M.

References


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