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8.1.14.12.1 Variation 1: By Direct Deprotonation

DOI: 10.1055/sos-SD-008-00213

Gribble, G. W.Science of Synthesis, (20068387.

Like pyrrole (see Section 8.1.14.5.1), N-substituted indoles are preferentially deprotonated at C2, a position acidified by the inductive electron-withdrawing ability of nitrogen. Following studies on the lithiation of 1-methylindole with butyllithium (Et2O, reflux, 8h) and carboxylation to give 1-methylindole-2-carboxylic acid (78%),[‌323‌] Sundberg explored the use of N-protecting/activating groups that permit C2 lithiation under milder conditions and whereby the N-protecting group can be removed (unlike N-methyl).[‌324‌] Snieckus has summarized the use of indole N-protecting groups in C2 lithiation,[‌236‌] and a selected list of indole C2 lithiation reactions (e.g., to give 75) is shown in Table 5. This list is not complete, but depicts only a few examples with each N-protecting group. Depending on the end use, all of these N-protecting groups have utility in synthesis; with the exception of N-methyl, all of the protecting groups are usually easily removed.

Meeee 8 M8 Meeeeeeeee Meeeeeeee ee Meeeee[‌888‌,‌888‌‌888‌]

M8 Meeeeeeeee M+ M Meeee (%) Mee
Me MeMe, Me8M, eeeeee, 8e MM8 MM8M 88 [‌888‌]
Me MeMe, Me8M/eeeeee, eeeeee, 8e (MM8Me)8 MMMM8M 88e [‌888‌]
Me MeMe, Me8M/eeeeee, eeeeee, 8e M8 M 88 [‌888‌]
Me MeMe, Me8M/eeeeee, eeeeee, 8e eeeeeee M(MM)Me8 88 [‌888‌]
MM8Me e-MeMe, eeeeeee, MMMMM, ee, 88eee MeMMM MM(MM)Me 88 [‌888‌]
MM8Me e-MeMe, eeeeeee, MMMMM, 88°M, 88eee MeMMMM8Me M(MM)MeMM8Me 88 [‌888‌]
MM8Me MMM, MMM/eeeeee, 88 ee 8°M, 8e MeM Me 88 [‌888‌]
MM8Me MMM, MMM/eeeeee, 88 ee 8°M, 8e MeMMM MM(MM)Me 88 [‌888‌]
MM8Me MMM, MMM/eeeeee, 88 ee 8°M, 8e e-MeMMM MMMMe-Me 88 [‌888‌]
MM8Me MMM, MMM/eeeeee, 88 ee 8°M, 8e MeMM Me 88 [‌888‌]
MM8Me MMM, MMM/eeeeee, 88 ee 8°M, 8e MeMM8Me Me 88 [‌888‌]
MM8Me e-MeMe, MMM/eeeeeeeeeee, 88°M ee ee, 8e Me8M Me 88 [‌888‌]
MM8Me e-MeMe, MMM, 88°M, 8e M8M8 MM8 88 [‌888‌]
MM8MMe e-MeMe, eeeeee/Me8M, 8°M ee ee, 8e MeMM Me 88 [‌888‌]
MM8MMe e-MeMe MeM(Me)MMM MMM 88 [‌888‌]
MM(MMe)8 e-MeMe, eeeeeee/MMM, 8°M ee ee, 88eee MeMM=MMMM8 MM(Me)MM8MM8 88 [‌888‌]
Mee e-MeMe, eeeeee/MMM, 88°M, 88eee (MM8Me)8 MMMM8Me 88 [‌888‌]
Mee e-MeMe, MMMMM, 88°M Me8MeMe MeMe8 88 [‌888‌]
Mee e-MeMe, MMM, 88°M, 8e M8M8 MM8 88 [‌888‌]
Mee MeMe, eeeeeee/MMM, 88°M, 8e MeMM8Me MM8Me 88 [‌888‌]
Mee MMM, MMM, 88°M, 8e M(MeMe)8 M(MM)8 88 [‌888‌]
MM8MMe8 MeMe, Me8M, ee, 8e Me8MM M(MM)Me8 88 [‌888‌]
MM8MMe8 MeMe, eeeeee/MMM, 88 ee 8°M, 88eee (MeM)8 MMe 88 [‌888‌]
MM8Me MeMe, eeeeee/MMM, 88°M; eeee MM8, eeee e-MeMe, 88°M, 8e MeMe Me 88 [‌888‌]
MMMMe-Me e-MeMe (8.8 eeeee), MMM, 88 ee 8°M, 88eee MMMMe MMM 88 [‌888‌]
MMMMe8 e-MeMe, e-MeMM, MMM, 88°M, 8e MeM Me 88 [‌888‌]

e Mee eeeeeee eeeee eeeeeee eee eeeeeeeeee.

Meeeeeee eeeeeeeeeeee ee eeeee eeeeee M8 eeeeeeeeeee ee eeeeeeeee eee eeeee, eeeeeeeee eee eeeeeeeee ee 8-eeeeeeeeeeeeeee,[‌888‌] eeeeeeeeeee eee eeeee eeeeeeeeeeeeeeee,[‌888‌‌888‌] eeeeeeeeeeeeeee,[‌888‌] 8,8-eeeeeeeeee,[‌888‌] 8-(8-eeeeeee)eeeeeee,[‌888‌] eeeeeeeeeee,[‌888‌] eeeeeeeee-8,8-eeeeeeee,[‌888‌] eeee[8,8-e]eeeeeee,[‌888‌‌888‌] β-eeeeeeeeee,[‌888‌] eeeeeeeeeeeee[8,8-e]eeeeeee,[‌888‌] 8,8-eeeeeeeeeeeee,[‌888‌,‌888‌,‌888‌‌888‌] 8-eeeeeeeeeee 8-eeeeeeeeee,[‌888‌] eee 8,8-eeeeeeeeeeeee eeeeeee eeee eeeee ee eeeeeeeee ee eeeeeee eeeeeeeee.[‌888‌,‌888‌‌888‌] Mee eeeeeee, M8 eeeeeeeeee ee M-eeeeeeeee eeeeee-8-eeeeeeeeee eeee ee eeeeee-8-eeeeeeeeeeee eeeeeeee ee eeeeeeeeeeeee eeeeee eeeee eee eeeeeeeeeeeee 8-eeeeeeeeeee eeeeeee [MMM, Me, MM(MM)Me, M(MM)Me8, M(MM)Me8, Me, M(MM)MeMe] ee eeee eeee ee eeeeeeeee eeeeee.[‌888‌] Meeeeeeeeee ee M8 eee eeeeeeeee eee eeeeeeeee ee eeeeeeeeeeee ee eee eeeeeee eeee, e.e. 8-Me, 8-Me, 8-Me, 8-MMe, 8-MM, 8-M [8-(eeee-eeeeeeeeeeeeee)eeeeee eeee eeeeeee eeeeeeeeeeeeeeee],[‌888‌] eee 8-eeeeeee-8-eeeeeeeeeeee eeee eeeeeeeeeeee (eee eee eeee-eeeeeeeeeeee) eeeeeeeee eeeeeeeeee ee M8, M8, eee M8.[‌888‌] M eeeeeeeeee eeee eeee 8-(eeeeeeeeeeeeee)eeeeee eee eeeeeeeeeeee eeeeeeee ee eeee eee eeeeeeeeeeeeee eeeee eee ee eeeeeeeee eeeee ee eeeeeeee,[‌888‌,‌888‌] e eeee eeeeeeee eeeeeee eeee eeeeeee eeeeeeeeeeeeeeee.[‌888‌] Mee 8-eeeeeeeee eeeeeee eee eeeeeee eeeeeeeeeeeeee eeee eeeee,[‌888‌,‌888‌] eeee,[‌888‌] eee eee[‌888‌] eee eeeee-eeeeeeee eeeeeeeee.

Meeeeeeeeeee Meeeeeeee

8-[8-(Meeeeeeeeeeeee)eeeee-8-ee]eeeeeee [88, M8=MM8Me; M=MM(MM)Me]; Meeeeee Meeeeeeee:[‌888‌]

Me e eeee ee MMM (8.88eeee) [eeeeeeee eeee eMe8MM (8.88eeee) eee e 8.88M eeee ee MeMe ee eeeeee (8.88eM, 8.88eeee) ee eee MMM (88eM) eeeee eeeee ee 88°M] eee eeeee eeeeeeee, eee eeeeeee, eeee 8eee e eeee ee 8-(eeeeeeeeeeeeee)eeeeee (8.88e, 8.88eeee) ee eee MMM (88eM), eeeeeee eee eeeeeeee eeeeeeeeeee eeeee 88°M. Mee eeeeeee eee eeeeeee eee 8.8e eeeee 88°M eee eeee eeeeeee ee eeee eeeeee ee 8°M eeee 8e. Mee eeeeeeeee eeeeee eee eeee eee eeeeee ee 88°M. M eeeeeeeeeeee eeeeeee eeee ee eee 8-(eeeeeeeeeeeeee)eeeee-8-eeeeeeeee (88.88eeee) ee eee MMM (88eM) ee 88°M eeeee eeeee eee eeeeeee eeeeeee eee eeeeeee eeee e eeee ee eeeeeee eeeeeeeee MeMMM (8.88e, 88.8eeee) ee eee MMM (8eM). Mee eeeeeee eee eeeeeee ee eeee eeeeee ee ee eeeeeeeee, eeeeee eeee 8% ee MMe (888eM), eee eee eeeee eee eeeeeeeee eeee MM8Me8 (8×888eM). Mee eeeeeeee eeeeeeee eeee eeeeee eeee M8M (888eM) eee eeeee (8×888eM), eeeee (M8MM8), eee eeeeee eeeeeeeeee ee eeeeee e eeeee eeeeee eee. Meeee eeeeeeeeeeeeee (eeeeee eee, MM8Me8) eeee e eeeee eeeee eeeeeee eee eeeee eee eeeeeee eeeee (88°M/8.8Meee) eee 8e ee eeeeeee eee eeeeeeeeeeee eeee eeeee eeeeeeee ee eeeeeeeee eeeeeeee; eeeee: 8.88e (88%); ee 888888°M.

References


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