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15.5.1.1.1.5.2.1 Method 1: From N-Acyl-2-arylethylamines: The Bischler–Napieralski Synthesis

DOI: 10.1055/sos-SD-015-01146

Álvarez, M.; Joule, J. A.Science of Synthesis, (200515716.

The widely used BischlerNapieralski synthesis, first described in 1893,[‌176‌] has the advantage of easy preparation and access to starting materials, and generally efficient ring closure, although electron-withdrawing groups on the benzene ring are not conducive to efficient syntheses. The process has been reviewed.[‌177‌] A disadvantage is that it produces 3,4-dihydroisoquinolines that need to be dehydrogenated (Section 15.5.1.2.2). Scheme 94 illustrates the sequence from N-acyl-2-arylethylamine 203 to 3,4-dihydroisoquinoline 205 with a typical reagent used for the ring closure, phosphoryl chloride. This reagent was not used for all the examples summarized in Scheme 94, but it is certainly the most popular. Further examples are given in Table 1.

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Meeee Meeeeeee Meeeeeee Meeeeeeeee Meeeeee Me8 Meeee (%) Mee
8 MMM, eeee 88 [‌888‌]
8 MMMe8, MeMM, eeeeee 8,8-(M8M)8M8M8 88 [‌888‌]
8 MMMe8, MeMM, eeeeee 8-MeM8M8 88 [‌888‌]
8 MMMe8, MeMM, eeeeee 8,8-(M8M)8M8M8 88 [‌888‌]
8 MMMe8, MM8Me8, eeeeee [‌888‌]
8 M8M8, MMMe8, eeeeee, eeeeee 8-Me-8-M8MM8M8 88 [‌888‌]
8 MMMe8, MeMM, eeeeee 8-MeM8M8 88 [‌888‌]
8 MMMe8, eeeeeee, eeeeee 8-MeMM8M8 88 [‌888‌]
8 Me8M, MMMM, 888°M 88 [‌888‌]
88 M8M8, Meeeeeee, eeeeee 88 [‌888‌]
88 MMMe8, MeMM, eeeeee 88 [‌888‌]

Meeeeeeeeeee Meeeeeeeee

8,8-Meeeeeeee-8-(8,8-eeeeeeeeeeeeeee)-8,8-eeeeeeeeeeeeeeeeeee [888, M8=8,8-(MMe)8; M8=M8=M; M8=8,8-(MeM)8M8M8MM8]; Meeeeee Meeeeeeee:[‌888‌]

M eeeeeee ee 8-(8,8-eeeeeeeeeeeeeee)-M-(8,8-eeeeeeeeeeeeeeeeeeeee)eeeeeeeeee [888, M8=8,8-(MMe)8; M8=M8=M; M8=8,8-(MeM)8M8M8MM8; 88e, 88eeee] eee MMMe8 (88e, 8.8eee) eee eeeeee ee eeeeeeeee eee eeeeeee (88eM) eee 8e. M eeeeee eeeeeeeeeee eeeeeeee eeee eeeeeeeee. Me eee eeeeeeeee, eeeeee eeee eeeeeeeee eeeee eee eeeeeeeee ee M8M. Mee eeeeeeee eeee eee eeee eeeeeeee eee eeeeeeeee eeee Me8M, eeeeeeeeeee ee eeeee eeee eee eeeeeeeeeeeeeeeeeee; eeeee: 88e (88%); ee 8888°M.

8-Meeeee-8,8-eeeeeeeeeeeeeeeeeee (Meeee 8, Meeee 88); Meeeeee Meeeeeeee:[‌888‌]

M-Meeeee-8-eeeeeeeeeeeeeeee (8.8e, 8eeee) eee M8M8 (8.8e, 88eeee) eeee eeeeeeee ee eee Meeeeeee (88eM) eee 88eee. Meee M8M8 (8.8e) eee eeeee eee eeeeeee eeeeeeeee eee e eeeeeee 88eee. Mee Meeeeeee eee eeeeeeee eee eee eeeeeee eeeeeee eeee M8M eee eeeee eeeeeeeee ee eeeeee eeeeeeeee eeeeee ee Meeeeeee. Mee eeeeee eeee eee eeee eeeeeeee eeeeeeee eee eeeee eeeeeeeee. Mee eeeeeeeeee eee eeee eeeeeeee eeeeeeee eee eeeeeee eeeeeeeee eeee Me8M, eeeeeeeeeee ee eeeee eeee eee eeeeeee; eeeee: 8.88e (88%); ee 888°M/88Meee.

8-(Meeeeeeeeee)-8,8-eeeeeeeeeeeeeeeeeeeee (Meeee 8, Meeee 88); Meeeeee Meeeeeeee:[‌888‌]

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Mee eeeeeeeeeeeeeeeeeee (88e, 88.8eeee) eee eeeeee ee Meeeeee (888eM) eeee 88% Me/M (8.8e) eee 8e. Meeee eeeeeee, eee eeeeeee eee eeeeeeee eee eee eeeeeee eeeeeeeeee eeeeeee eeeeeeee eeeee eee eeeeeeeeeeee (MeMM) eeeeee 8,8-eeeeeeeee-8-(eeeeeeeeeeeeeee­ee)eee­eeeeeeeee; eeeee: 8e (88%); ee 888°M.

Mee 8,8-eeeeeeeee-8-(eeeeeeeeeeeeeeeee)eeeeeeeeeeee (8e, 88eeee) ee MeMM (888eM) eee eeeeeeee eeee eeeeeeeee eeeeeee (88eM) eee 8e. Mee eeeeeee eee eeeeeeeeee; eee eeeeeee eeeeeee eeee M8M eee eee eeeeeee eeeeeeeee eeee MM8Me8, Meeee eeeeee, eee eeeeeee eee eeeeeeeeee eee eee eeeeeee eeeeeeeeeeee (eeeeeeeeeee); eeeee: 8.8e (88%); ee 888°M.

References