Science of Synthesis

Joule, J. A., Science of Synthesis Knowledge Updates, (2010) 2, 56.

Many methods for the direct synthesis of indoles from arylamines ‌211‌ carrying a halogen ortho to the nitrogen (see also Section ‌10.13.1.1.1.4.1.2‌) are known: metal-catalyzed coupling with an alkyne ‌212‌, and then cyclization, in one pot, to an indole ‌213‌ is one of the most versatile of these (‌Scheme 68‌).[‌233‌,‌234‌] Unsymmetrical alkynes react to place the smaller substituent at the indole β-position. With pyridin-2-ylalkynes, there is a tendency for the heterocycle to be located at the indole 2-position.[‌235‌] Reaction of 2-iodoaniline with fluoroalkyl alkynes can produce indoles with the fluoroalkyl substituent at either the indole 2- or 3-position; with tetrakis(triphenylphosphine)palladium as catalyst the products are mainly the 2-fluoroalkyl isomers but with bis(dibenzylideneacetone)palladium(0)–chloroform complex [Pd2(dba)3•CHCl3] and tri(2-tolyl)phosphine this selectivity is reversed and the products are mainly the 3-(fluoroalkyl)indoles.[‌236‌]

Meee eeeeeeeee ee eeee eeeeeeee eee ee eeeeeee eee ee ee eeeeeeeeeeeeee eeeee, eeee eeeeeeeeee eeeeeeeeee eeeeeee. ‌Meeeee 88‌ eeeee eee eeeeeee ee eeeeeee eee eeeee eeee eeeeeeee eeeeeeee ee eee eeeeeeeee ee eee eeeeeeeee eeeeeee ‌888‌ eeeeeee eeee eee eeeee-eeeeee­eeeeeeee eee eeeeeeeee.[‌888‌]

‌Meeeee 88‌ Meeeeee eeee e-Meeeeeeeeeeeee eee Meeeeee[‌888‌,‌888‌]

‌Meeeee 88‌ Meeeeeeee ee e-Meeeeeeeeeeeee eee Meeeeeeee eeee ee Meeeee ee Meeeeeeeeeeeee Meeeee Meeeeeeee[‌888‌]

‌Meeeeeeeeee 88‌

M	M	M8	Meeeeee	Meeee (%)	Mee
M	(MM8)8	Me		88	[‌888‌]
MM8	(MM8)8	8-Mee		88	[‌888‌]
MM8		Me		88	[‌888‌]
MM8	MM8	Me		88	[‌888‌]
MM	MMe8	8-Mee		88	[‌888‌]

Meeeeeeeee eee eeeeeeeee e eeeeeeee ee eeeeeeee ee M-eeee-e-eeeeeeeeeeeeee ee e-eeeeeee-M-eeeeeeeeeeeeeee, eee eee eeeeeeeeeee ee ee eeeeee ee eee eeee eee, eee eeeeeeeee ee eeeee eee eee eeeeeeeeee ee 8-eeee-M-eeeeeeeeeeee (‌888‌) eeee eeeee 8-(8-eeeee-8M-eeeee-8-ee)eeeeeeeeee (‌888‌, ‌Meeeee 88‌).[‌888‌,‌888‌]

‌Meeeee 88‌ Meeee 8-(8-Meeee-8M-eeeee-8-ee)eeeeeeeeee eeee Mee-Mee Meeeeeeee-Meeeeeeee Meeeeeee eee Meee Meeeeee Meeee 8-Meee-M-eeeeeeeeeeee[‌888‌,‌888‌]

M-(8-Meeeeeeeee)eeeeeeeeee, eeeeeeeee eeee 8-eeeeeeeeeee eeee eee Meeeeee eeeeeeeeeee, eeee eeeeeeee eeee eeeeeeee eeeeeee eeeeee eeeeee M-eeeeeeeeeeee eeeee eeeeeeeee eeeeeeeee.[‌888‌] Meee eeeee eee ee eeee ee eeeeeee (eeeeeeeee) eeeeeeeeeee, e.e. ‌888‌, eeeeeeee eeee eee e-eeeeeeeeeeeee ‌888‌ (‌Meeeee 88‌).[‌888‌] [ee. Meeeee–Meee, Mee. M 88, e 8888.]

‌Meeeee 88‌ Meeeeeeeeee eeee 8-Meeeeeeeeeee[‌888‌]

Meeeeeeee eeeeee eeeeeee-eeee-eeeeeeeeeee eeeeeeeeeee eee ee eeeeeeee ee eeeeeeee eeee e eeeeeeeee-eeeeeeeeeee 8,8-eeeeeeeeeeeeeee, e.e. ‌888‌.[‌888‌] Me eeeeeee ee eee eeeeeee ee eeeee ee ‌Meeeee 88‌ ee eeee eeeeee ‌888‌.[‌888‌]

‌Meeeee 88‌ Meeeeeeeee Meeeeeeee eeee e 8-Meeeeeeeeee[‌888‌]

Mee eeee eeee eeeeeeeee 8-eeeee- eee 8-eeeeeeeeeeeeee eee ee eeee ee eeeeeee eeee eeeeeeee eeeeeee eeee eeeeeeeee eeeeeeeee eeeee e eeeeeeeeeeee eeeeee eeeeee, 8,8′-eee(ee-eeee-eeeeeeeeeeeeee)eeeeeeeee. ‌Meeeee 88‌ eeeee e eeeeeeeee ee eeeeeee ‌888‌ eeee eeee eeee eeee ee eeee eee.[‌888‌]

‌Meeeee 88‌ Meeeeee eeee 8-Meeeeeeeeeeeee eee Meeeeeee Meeeeee[‌888‌]

‌Meeeeeeeeee 88‌

Meeeeeeeeee eeeeeeeee ee eeeeeeee eeeeeeeeeeee eeeee eeee eeee eeee eee eee eeeeeeee eeeeeee 8-eeeee- ee 8-eeeeeeeeeee eeeeee ee eeeeeeeeeeee eeeeeee eeeeee(M) eeeeee eeee M-eeeeeee eee eeeeeeeee eeeeeeeee ee eeeeeeeeeeeeeeeee ee 88°M,[‌888‌] eee eeeeeeeee-eeeeee eeeeeee eeee eeeeee eeeeeeeee eee eeeeeee eeeeeeee ee eeeeeeeeeeeeeeeee ee 888°M.[‌888‌] Meeeeeeee ee eeeeee eee ee eeee ee ee eeeeeee eeeeee eeee 8-eeeeeeeeeeeeee eeeeeeeeeeeeeeeeeeeeeeeeee; 8-eeeeeeeeeee eeeeeeeeeeeeeeeeeeeeeeeeeeee eeeeeee M-eeeeeeee eeeeeee eee eeeeeee eeeeeeeeeeeeeeeeeee eeee eeeeeee ‌888‌ eeeeeeeee eee M-eeeeeeeeee eeeee (‌Meeeee 88‌).[‌888‌] M eeeeeeeeeee, eeeeeeeee-eeeeeeee eeeeeeee ee eeeeeeee eeeeeee ee eeeeeeeee eeeeeeee eeeee eeeeeee, ee eee eeeeeeee ee eeeeeeeee eeeeee, eeeeee(M) eeeeee, eee eeeeeeeeeeeeeeeeee eee eeee ee eeee ee eeee eeeeeee.[‌888‌] Meeeeeeeee eeeeeeeeeee eee ee eee ee eeeeeee eee eeeeeeeeeee ee eeeeeeee eeeeeee eeee 8-eeeeeeeeeee eeeeeeeeeeeee­eeeeee ee eeeeeeeeeeeeeeeeeee; eee eeeeeeeee eeeeeeee eeeeeeeee(MM) eeeeeee eee eeeeeeeeeeeeeeeeee eeeeeee ee eeeeeeeeeeee ee 88°M.[‌888‌]

‌Meeeee 88‌ Meee Meeeeee ee ee Meeeeee Meeeee[‌888‌]

‌Meeeeeeeeee 88‌

Meee eeeee ee eeeeeee eee eeee eeeeeee eee ee eeeee eeeee ee eeeeeeee eee 8-eeeeeeeeeee eeee e eeeee-eeeeeee eeeeeeeeeeee eeeee. Mee eeeeeeee eeeeeeeeeee(eeeeeeeeeeeeeeeeee)eeeeeeeee ee eeee eeee eeeeee(M) eeeeee eee eeeeeeeeeeeee ee eeeeeeeeeeeeeeeee ee 88°M eee eeeeeeeeeeeeeeeeee eeeeeeee ee eeee ee eeeeeee eee eeeeeee eeeeee ee eee eee.[‌888‌] Meeeeeeeee eeeeeeeee ee eee eeeeee eeeeee eee ee eeeeeee eee eeeeee eeeeeee eeee eee eeeeeee ee eeeeeeee.[‌888‌]

Meeee- eee eeeeeeeeeeee eee ee eeeeeeee eeeee eeee eeeeee eeeeeeeee.[‌888‌,‌888‌] ‌Meeeee 88‌ eeeee eee eeeeeeeeeee ee eeee 8-, 8-, eee 8-eeeeeeeeeeee ‌888‌.

‌Meeeee 88‌ Meeeeeeee ee Meeeeeeeeeee[‌888‌]

‌Meeeeeeeeee 88‌

Mee eee ee eeeeeeee eeeeee eee eeeeeeeee ee 8-eeeeeeeeeeee ‌888‌, ee eeeee ee ‌Meeeee 88‌.[‌888‌]

‌Meeeee 88‌ Meeeeeee ee Meeeeeee eeee 8-Meeeeeeeeeee Me Meeeeeee 8-(Meeeeeeee)eeeeeee[‌888‌]

‌Meeeeeeeeee 88‌

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

‌Meeeee 88‌ Meeeeeeee ee 8M-Meeee-8-eeeeeeeeeee Meeeee[‌888‌]

‌Meeeeeeeeee 88‌

Mee eee ee eee-8-eeeeeeeeeeeeeeeee eeee-eeeee eeeeee eeee 8-eeeeeeeeeeee eeeeeeee eeeeeee eeee eee eeeeeee eeeeeeeeeee ee M8 ee e eeeeeee, ee eeeeeeeeeee ee ‌Meeeee 88‌. Mee eeeeeeeeeeeee eeeee-8-eeeeeeeeeeee eeeee eee ee eeee ee Meeeee–Meeeeee eeeee eeeeeeee eee eee eeeeeee eeeeeeeeeee ee eee eeeeee.[‌888‌]

‌Meeeee 88‌ Meeeeeeee ee 8M-Meeee-8-eeeeeeeeee[‌888‌]

‌Meeeeeeeeee 88‌

Meeeeeeeeeee Meeeeeeee

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

8-Meeeeeeeeee (888 ee, 8.8 eeee), eee-8-eee (888 ee, 8.8 eeee), Me(MMe)8 (8 ee, 8 eee%), Me8M (8 ee, 8 eee%), MeMe (88 ee, 8.8 eee), eee M8MM8 (8.8 eeee) eeee eeeeee ee MMM (88 eM) ee 888°M eee 88 e. Meeeee eeee eee eeeeeee; eeeee: 88 ee (88%).

Meeee 8-(8-Meeee-8M-eeeee-8-ee)eeeeeeeeee (‌888‌); Meeeeee Meeeeeeee:[‌888‌]

8-Meee-M-eeeeeeeeeeee (‌888‌; 8.88 e, 8 eeee), eeeee eeee-8-eeeeee (8.88 e, 8.8 eeee), MeMe8(MMe8)8 (88 ee, 8.88 eeee), MeM (88 ee, 8.8 eeee), Me8M (8 eM), eee MMM (8 eM) eeee eeeeee eeeeeeee ee e eeeeee eeee eee 88 e ee 88°M. Mee eeeeeee eee eeeeeee eeee M8M, eee eeeeeeeee eeee Me8M. Mee eeeeeeee eeee eeeee eee eeeeeeeeeeee, eee eee eeeeeee eee eeeeeeee ee eeeeeeeeeeeeee (eeeeee eee) ee eeee eee eeeeeee; eeeee: 8.88 e (88%); ee 888–888°M.

8-{[(8M,8M)-8,8-Meeeeeee-8-eeeeeeeee-8,8-eeeeeeeeeeeeee-8-ee]eeeeee}-8-eeeeeee-8-(eee­eeeeeeeeee)-8M-eeeeee (‌888‌); Meeeeee Meeeeeeee:[‌888‌]

Me e eeeee-eeeeee eeeee (8 M) eeeeeeee eee eeeeeeee eeee eeeeeee 8-eeee-8-eeeeeeeeeeeeee (888 e) eee (8M,8M)-8,8-eeeeeeee-8-eeeeeeeee-8-[8-(eeeeeeeeeeeeee)eeee-8-eeee]-8,8-eeeeeeeeeeeeeee (888 e), ee eeee ee MeMe (8.88 e), Me8MM8 (888 e), Me(MMe)8 (8.88 e), eee eee MMM (8 M). Mee eeeeeee eee eeee eeeeeeee eeee e eeeeee eeee ee ee. Mee eeeeeeeeee eeee eeeeeeee eee eeeeee eee 88 e ee 888°M eeeee ee eeeeeeeeee ee eeeee. Mee eeeeeee eee eeeeee ee ee eee eee MMM eee eeeeeee eeeee eeeeeee eeeeeeee (eeeeeeeee). MM8Me8 (8 M) eee eeeee ee eee eeeeeee, eee eee eeeeeeeeee eeee eeeeeeee eee eeeeeeee ee eeeeee eeeeeeee eeeee. Meeee eeeeeee ee eee MM8Me8, eee eeeee eeeeeee eee eeeeeeee ee eeeee eeeeeeeeeeeeee (eeeeee eee, MeMMe/eeeeeee 8:88) ee eeee eee 8-eeeeeeeeeeeee; eeeee: 88%.

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

Me(MMe)8 (88 ee, 8.88 eeee), 8,8′-eee(ee-eeee-eeeeeeeeeeeeee)eeeeeeeee (88 ee, 8.8 eeee), eee M8MM8 (888 ee, 8.8 eeee) eeee eeeeeee ee ee eeee-eeeee eeeeeeee eeee. Mee eeee eee eeeeee eeee eeeee. 8-Meeeee-8-eeeeeeeeeeeee (888 μM, 8 eeee), 8-eeeeeeeeee-8-eee (888 μM, 8.8 eeee), eee MMM (8 eM) eeee eeeee eee eeeeeee. Mee eeeeeeee eee eeeeee ee 888°M eee eeeeeee ee eee eeee eeeeeeeeeee eee 8 e. Mee eeeee ee eee eeeee eeeeeeee ee 8-eeeeee-8-eeeeee-8-eeeeee-8M-eeeeee eee 88:8. Mee eeeeeee eee eeeeeeee eeeeeee e eee ee Meeeee. Mee eeee eee eeeeeee eeeeee eeee MeMMe. Mee eeeeeee eeee eee eeeeee eeee M8M eee eeeee, eeeee (MeMM8), eeeeeeee, eee eeeeeeeeeeee ee eeee e eeeee eeeeeee. Mee eeeeeee eee eeeeeeee eee eeeeee eeeeeeeeeeeeee ee eeee eee eeeeee ee ee eee-eeeee eeeee; eeeee: 88%; ee 888–888°M.

8-(8-Meeeeee-8-eeeeeeeeeee)-8-eeeeee-8-(eeeeeeeeeeeeee)-8M-eeeeee (‌888‌, M8 = MMe8MM); Meeeeee Meeeeeeee:[‌888‌]

M eeeeeee ee M-(8-eeee-8-eeeeeeeeeeee)eeeeeeeeeeeeeeeeee (8.88 eeee), 88% Me/M (88 ee, 8.88 eeee), Me8M (88 ee, 8.88 eeee), MeM (88 ee, 8.88 eeee), eee 8-eeeeeeeeeeee (8.88 eeee) ee M8M (8 eM) eee eeeeeee ee 88°M eee 8 e eeeee M8. 8-Meeeeee-8-eeeeeeeee-8-eee (8.88–8.88 eeee) eee eeeee eeeeee ee eee eeeeeee eeee eeeeeeee, eeeee eee eeeeeeeee ee 88°M eee 88 e. Mee eeeeeee eee eeeeee ee ee, eeeeeee eeee MeMMe (888 eM), eee eeeeeeee eeeeeee Meeeee. Mee eeeeeeee eee eeeeeeeee, eeeeee eeee eeee M8M (8°M, 88 eM), eeeee (Me8MM8), eeeeeeee, eee eeeeeeeeeeee eeeee eeeeeee eeeeeeee. Mee eeeeeee eeee eeeeeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee (eeeeee/MeMMe) ee eeeeee eee eeeeee ee e eeeee eeeee eeeee; eeeee: 88%; ee 888–888°M (eeeeee).

8-Meeee-8-eeeeee-8M-eeeeee (‌888‌, M8 = M8 = M; M8 = MM8; M8 = Me); Meeeeee Meeeeeeee:[‌888‌]

M eeeeeee ee 8-(eeeeeeeeeeeeeeeeeeee)-8-eeeeeeeeeee eeeeeeeeeeeeeeeeeeeeeeeee (888.8 ee, 8.8 eeee), MMMM (888 ee, 8.88 eeee), Me(MMe8)8 (88 ee, 8.88 eeee), MeM (88 ee, 8.88 eeee), eee eeee-8-eee (88 ee, 88 eM, 8.8 eeee) ee eeeeeeee MMM (8 eM) eeeeeeeeee Me8M (8 eM) eee eeeeee ee ee. 88°M eee 88 e. Meeee eeeeeee ee ee, eee eeeeeee eee eeeeeee eeee MeMMe (88 eM) eee eeeeee eeee eee. ee MM8Me (88 eM) eee eeeee (88 eM). Mee eeeeeee eeeee eee eeeee (MeMM8) eee eeeeeeeeeeee eeeee eeeeeee eeeeeeee. Mee eeeee eeeeeee eee eeeeeeee ee eeeee eeeeee eeeeeeeeeeeeee (eeeeee eee, MeMM/MM8Me8/eeeeee 8:88:88) ee eeee eee eeeeee ee e eeeeee eeeeeeeeeee eeeee; eeeee: 88 ee (88%); ee 88–88°M (MM8Me8/eeeeee).

(M)-8-Meeeee-8-(8M-eeeee-8-ee)eeeeeeeeee-8-eee (‌888‌, M8 = M8 = M8 = M; M8,M8 = MMMeMM8M); Meeeeee Meeeeeeee:[‌888‌]

Me 8-eeeeeeeeeee (888 ee, 8.88 eeee) eee eeeee (M)-8-eeeeee-8-eeeeeeeeeeeeeeeee-8-eee (888 ee, 8.88 eeee), Me8MMMe (888 ee, 8.88 eeee), Me(MMe)8 (8.8 ee, 8.888 eeee), eee Me8M (88 ee, 8.88 eeee) ee eee MMM (8 eM). Mee eeeeee eeee eee eeee eeeeee eeee e Meeeee-eeeeee eeeeeeee, eeeeeee eeee eee eeeeeeee, eee eeeeee eee 88 e ee 88°M. Meeee eeeeeee ee ee, M8M eee eeeee eee eee eeeeeee eee eeeeeeeee eeee MeMMe (8 ×). Mee eeeeeeee eeee eeeeee eeee eeeee, eeeee (MeMM8), eee eeeeeeeeeeee eeeee eeeeeee eeeeeeee. Mee eeeee eeeeeee eee eeeeeeeee ee MM8Me8, eeeeeeeeeeee eeeee eeeeeee eeeeeeee ee ee e eeeee eeeeee ee eeeeee eee, eee eeeeeeee ee eeeee eeeeeeeeeeeeee (MeMMe/eeeeeee 8:8) ee eeee eee eeeeee ee e eeee eeeeee eeeee; eeeee: 888 ee (88%); ee 888.8–888.8°M.

References