Indenobenzazepines

Hsynthesis from, 3, 767 Indenobenzazepines pharmacological properties, 7, 546 Indenone oxide, 2,3-diphenyl-photochromic compound, 1, 385 In deno[ 1,2-c][ 1,2,4]triazines synthesis, 3, 434 Indicated hydrogen nomenclature, 1, 33 Indigo, I, 317, 318-319, 4, 370 Baeyer synthesis, 1, 319 colour and constitution, 1, 344-345 molecular structure, 4, 162 photochromic compound, 1, 386 synthesis, 4, 247 Indigoid dyes... 

Bromination of the indenobenzazepine 9 with bromine in acetic acid produces a dibromo adduct which, on heating in nitrobenzene or in dimethylformamide, yields the 12-bromo derivative 10.97 The bromo compound 10 is also obtained directly from 9 with Af-bromosuccinimidc in hot nitrobenzene. 

Regioselective C-14—N bond cleavage of an 8,14-cycloberbine leads to the indenobenzazepine skeleton. This transformation was developed by Shamma et al. (100,101) and Hanaoka et al. (102-104) independently. 

Scheme 32. Indenobenzazepines from the 8,14-cycloberbine 146. Reagents a, H+, H20, or MeOH b, HCHO c, NaBH3CN d, TiCl4 or BF3 OEt2 e, I2, EtOH or AcOH or CF3COOH, benzene or p-TsOH, benzene. 

Scheme 33. Indenobenzazepines from the 8,14-cycloberbine 184. Reagents a, hv, N2, MeOH b, 10% HC1 c, Me2S04, THF d, BF3 OEt2 e, p-TsOH, benzene f, Me2SOt, NaH, HMPA.

Analogous results were obtained from the reaction of another cycloberbine (183), as depicted in Scheme 33 (102-104). These reactions were applied to synthesis of indenobenzazepine (Section V,F,5) and rhoeadine alkaloids (Section V,G,2). 

The indenobenzazepines 314, obtainable from the corresponding protoberberines (Sections V,F,2 and V,G,2), were converted to the spirobenzyliso-quinolinediones 315 in 76% yield through hydrolytic bond cleavage and recyclization by sequential treatment with 4 N hydrochloric acid, bromine in acetic acid, and triethylamine, via the indanediones (Scheme 58) (166). A one-step stereoselective rearrangement of an indenobenzazepine to a spirobenzylisoquinoline was developed by Blasko et ah (167). O-Methylfumarofine (316)... 

Scheme 58. Conversion of indenobenzazepines to spirobenzytisoquinolines via indanediones. Reagents a, 4 N- HC1 b, Br2, AcOH c, Et3N.

Regardless of the stereochemistry at C-14, both diasteroisomeric indenobenzazepines 176 and 177 afforded the same spiro compound 320. The stereochemistry at C-8 (or C-13) is retained, and the hydroxyl group newly... 

Scheme 59. One-step conversion of indenobenzazepines to spirobenzylisoquinolines. Reagents a, (CF3C0)20, py b, aq NH3 c, NaBH4. 

Orito et al. (206-208) developed an attractive conversion of indenobenzazepines to protopines through photosensitized oxygenation of the... 

Scheme 77. Synthesis of protopine alkaloids by photooxygenation of indenobenzazepines. Reagents a, hv, 02, Methylene Blue b, LAH c, Mn02.

Indenobenzazepines have been used as key intermediates for synthesis of rhoeadine, protopine, phthalideisoquinoline, and spirobenzylisoquinoline alkaloids. Several new alkaloids possessing an indenobenzazepine skeleton have been isolated, and they are presumably biosynthesized from proto-berberine alkaloids. 

An indenobenzazepine skeleton was constructed from a protoberberine through C-8—N and C-14—N bond cleavage followed by formation of C-13—N and C-8—C-14 bonds via a protopine analog according to a bio-... 

Scheme 79. Conversion of protopines to indenobenzazepines. Reagents a, BrCN, THF b, KOH, EtOH.

Rearrangement of spirobenzylisoquinolines, having a hydroxyl group on ring C trans to the nitrogen, to indenobenzazepines was first reported by Irie et al. (209,210) in their synthesis of rhoeadine alkaloids (Section V,G,1). This... 

Scheme 80. One-step conversion of 13-oxoallocryptopine (402) to indenobenzazepines. Reagents a, hv, /-BuOK, f-BuOH.

Holland et al. (214) reported a conversion of /Miydrastine to the corresponding indenobenzazepines. On treatment with p-nitrophenyl chlorofor-mate, /J-hydrastine (368) was converted to the ene lactone 425 through C—N bond cleavage (Scheme 84). Treatment of 425 with sodium methoxide in methanol afforded the indanedione 426a. Basic hydrolysis of 426a and... 

Scheme 84. Conversion of /3-hydrastine (368) to indenobenzazepines. Reagents a, p-nitrophenol chloroformate b, NaOMe, MeOH c, NaOH, DMSO d, p-TsOH, toluene.

On the basis of fundamental experiments (see Section IV,A,2) some indenobenzazepine alkaloids have been efficiently synthesized from the corresponding protoberberines via 8,14-cycloberbines. For example, the cycloberbine 428 derived from the protoberberine 427 was heated with methanesulfonic acid in aqueous tetrahydrofuran to afford a 2 1 mixture of cis- and trans-indenobenzazepines 429 in 92% yield (Scheme 85). The mixture was methylated with methyl iodide to give the cts-N-methyl derivative 430 and the unchanged trans secondary amine (21%), which was very difficult to methylate and which gave the /V-methyl derivative only in 6% yield even on treatment with dimethyl sulfate for 43 hr. Contrary to the ordinary cases (Section IV,A,2), the trans derivative did not isomerize to the cis isomer 430 under various acidic conditions. Debenzylation of 430 by hydrogenolysis afforded fumarofine (417), which was converted to O-methylfumarofine (316) by methylation with diazomethane (215). 

Epiberberine and berberine were stereoselectively converted to fumaritrine (421) and its analog via 8,14-cycloberbines 216). The cycloberbine 432, derived from epiberberine (431) in the established way, was treated with p-toluenesulfonic acid in methanol and then with methyl iodide to give stereoselectively the cis-fused indenobenzazepine 433 in excellent yield (Scheme 86). Deoxygenation of the hydroxyl group in 433 was accomplished by treatment with methanesulfonyl chloride and subsequent reduction with sodium borohydride in dimethoxyethane to give (+ )-fumaritrine (421) (216). 

The first synthesis of a rhoeadine alkaloid was achieved by Irie et al. (209,210) through skeletal rearrangement of a spirobenzylisoquinoline to an indenobenzazepine. The trans-alcohols 434 and 329 were treated with methanesulfonyl chloride and rearranged to the indenobenzazepine 435,... 

Scheme 91. Synthesis of rhoeadine analogs via indenobenzazepines. Reagents a, NaI04 b, NaBH4 c, HC1 d, DIBAL e, HC(OMe)3. ...

Ring D inversion seems to be a crucial step in biogenetic transformations of protoberberines to related alkaloids such as rhoeadine, retroprotoberberine, spirobenzylisoquinoline, and indenobenzazepine alkaloids. 8,14-Cyclober-bin-13-ol 478 derived from berberine (15) was successively treated with ethyl chloroformate, silver nitrate, and pyridinium dichromate (PDC) in dimethyl-formamide to give the keto oxazolidinone 479 (Scheme 98). Heating of 479 with 10% aqueous sodium hydroxide in ethanol effected hydrolysis, retro-aldol reaction, cyclization, and dehydration to provide successfully the... 

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