A New Synthesis of "Schöpf's Base VI" and Related 10H-Isoindolo[2,3-c] benzazepines

Abstract

The IOH-isoindol0[2,3-c~)I~3]benzazepines, "Schopfs base VI" (4a) and its 4-methoxy derivative 4b, have been prepared by a new and facile synthesis which utilized intermediates derived from phthalideisoquinoline alkaloids.Les IOH-isoindole[2,3-c][3]benzaztpines, la base VI (4a) de Schopf et son 4-methoxy derive 4b, ont ete prepares par une nouvelle synthtse et facile qui a utilisb des produits intermediaires derives des alcaloides phthalideisoquinoleniques.Canadian Journal of Chemistry, 50,2022Chemistry, 50, (1972 The tetracyclic base, obtained as a minor product by reduction of neooxyberberine2 with zinc and acetic acid (I), was shown by Schopf and Schweickert (2) to be 8,9-dimethoxy-2,3-methylenedioxy-5,5a, 12,13-tetrahydro-1 OH-isoindolo[2,3-c)[3]benzazepine (4a). Commonly referred to as "Schopf s base VI", 4a is of interest because of its relationship with the papaverrubine alkaloids (3). We now describe a novel and facile synthesis of 4a as well as its 4-methoxy derivative 4b. This was accomplished by reaction sequences which utilized the dihydrobenzazepine sodium salts 1 previously obtained from the phthalide alkaloids (-)-b-hydrastine and (-)-a-narcotine (4, 5). The key intermediate lactams 3 were prepared from the saturated amino acids 2 by N-demethylation and cyclization with acetic anhydride (6, 7).3Consecutive treatment of the dihydrobenzazepine sodium salt l a (4) with acetic acid4 and lithium borohydride in tetrahydrofuran afforded the saturated benzazepine carboxylic acid 2a. Reaction of 2a with refluxing acetic anhydride formed the lactam 3a which was reduced with 'Visiting Professor, Institute of Organic and Pharmaceutical Chemistry, University of Innsbruck, Austria. uOMe 3An alternative synthesis of 4a involving photocyclization was recently reported (8).4Mineral acid effects conversion to the phthalideisoquinoline (5). diborane in tetrahydrofuran to provide the tetracyclic base 4a. The physical and spectral properties of 4a were identical with an authentic sample5 of "Schopf s base VI" (2). By the same reaction sequences, the methoxy-substituted dihydrobenzazepine sodium salt 1b (5) was transformed into the corresponding substituted tetracyclic base 4b. ExperimentalMelting points were taken on a Kofler microscope hot stage and are uncorrected. The U.V. spectra were measured in ethanol with a Cary recording spectrophotometer Model 14M and the i.r. spectra were determined with a Beckman Infrared Model IR-9 in KBr, unless otherwise noted. The n.m.r. spectra were obtained on a Varian HA-100 spectrophotometer using tetramethylsilane as internal reference. Chemical shifts are reported in 6 with the following abbreviations: (s) singlet, (d) doublet, (m) multiplet, (b) broad. The mass spectra were taken with a CEF 21-1 10 mass spectrometer at 70 eV using a direct insertion probe. Extracts of products in organic solvents were washed with water and dried over anhydrous sodium sulfate prior to evaporation. Water of crystallization in compounds Za, hydrobromide of 4a, Zb, and hydrochloride of 26 was deter...

Vinyl azides in heterocyclic synthesis. Part 10. Synthesis of the isoindolobenzazepine alkaloid lennoxamine

“…), our initial studies on the benzazepine-forming reaction were carried out with a slightly simpler substrate. Thus the monoprotected dialdehyde (7), prepared from 6-bromoveratraldehyde l 6 as shown in Scheme 2, underwent Wittig reaction with the ylide derived from 2-bromobenzyltriphenylphosphonium bromide to give a mixture of the (2)-and (E)-stilbenes (8) and (9) in good yield (90%) in the ratio of 4:1, from which the pure (2) isomer (8) could be separated by chromatography. The pure (E)-stilbene (9) was better obtained by a Wadsworth-Emmons reaction on the aldehyde (7) using dimethyl (2-bromobenzy1)phosphonate.…”

“…dimethoxystilbene (8) and (9).-A solution of sodium ethoxide [prepared from sodium (2.0 g, 87 mmol) in ethanol (100 ml)] was added during 0.5 h to a stirred mixture of the benzaldehyde (7) (20.0 g, 84.0 mmol) and 2-bromobenzyl(triphenyl)phosphonium bromide (43.0 g, 84.0 mmol) in ethanol (200 ml) at room temperature. The mixture was stirred for a further 0.5 h and concentrated under reduced pressure.…”

“…76-78 "C (from hexane) (Found: C, 58.2; H, 5.1. C ,gHl gBrO, requires C, 58.3; H, 4.9%); v,,,(Nujol) 1 601, 1 511, 1 205, 1 110, 1001, 880, 776, and 750 cm-'; GH(CDC13) (data for 2-isomer) (8) A small sample was subjected to chromatography (SO,; ether-hexane) to afford the pure (2)-stilbene (8), m.p. 98-99 "C. (9).-A solution of dimethyl 2-bromobenzylphosphonate (1 1 .O g, 36.0 mmol) in THF (40 ml) was added dropwise at 0 "C to a mixture of the benzaldehyde (7) (8.50 g, 35.7 mmol) and sodium hydride (80% dispersion in oil) (1.08 g, 36 mmol) in THF (100 ml).…”

The aporhoeadane alkaloids

“…Reduction of the olefin yielded the cyclization substrate (167), and cyclization was achieved by treatment with acetyl chloride followed by zinc chloride. An additional hydrogenation yielded lennoxamine (11), and literature precedent, 19 allowed conversion to chilenamine (15).…”

Differential nitrogen–carbon bond cleavages in architecturally complex molecular scaffolds containing a bridge-head nitrogen atom

“…Compound 1 was accessed by following a literature reported procedure [7]. Once in hand, refluxing the compound 1 with excess ethyl chloroformate over a period of 24 h resulted in no appreciable change of the starting material.…”