Bischler-Napieralski condensation

The first homopavine, ( )-homoargemonine (174), was synthesized in 1973 in an attempt to construct pavine analogs with improved analgesic activity (Scheme 38) (777). The corresponding 1-phenethylisoquinoline 173 was obtained by a Bischler-Napieralski condensation of 2-(3,4-dimethoxyphenyl)-ethylamine (170) and 3-(3,4-dimethoxyphenyl)propionic acid (171) via the hy-droxyamide intermediate 172. Compound 173 was then successively quater-nized, reduced by lithium aluminum hydride, and treated with acid to afford the tetracyclic compound ( )-174. 

The retro-synthetic analysis ouflined in Scheme 6.1 shows that in addition to the Pictet-Spengler route previously used by discovery, several others are also possible. The Bischler-Napieralski condensation of 5-methyltryptamine and 2-cyclohexylacetic acid chloride as well as the Friedel-Crafts reaction of the N-protected 5-methyltryptamine allows preparation of the prochiral imine derivative 7. The 2-cyclohexylmethyl side chain may also be introduced via alkylating an unsubstituted THpC by 2-cyclohexylmethyl chloride. As shown in Scheme 6.1, all of these routes involve 5-methyltryptamine as a common building block. 

A number of synthetic methods have been developed, the most useful being extensions of those used to prepare isoquinolines. The Bischler-Napieralski condensation is carried out on the... 

By a modified Bischler-Napieralsky reaction, 6 -nitrophenylaceto-jS-3 4-methylenedioxyphenylethylamide, resulting from the condensation of -3 4-methylenedioxyphenylethylamine with 2-nitrophenylacetyl chloride, was converted into 6 nitro-l-benzyl-6 7-methylenedioxy-3 4-dihydroisoquinoline. The methiodide of the latter was reduced with zinc and hydrochloric acid to 6 -amino-l-benzyl-2-methyl-6 7-methylenedioxy-1 2 3 4-tetrahydro/soquinoline dihydrochloride, which by the Pschorr ring-closure reaction, produced dZ-roemerine (IV, p. 317), m.p. 85-7°. By treatment in succession with d- and Z-tartaric acids, the dZ-base was resolved into Z- and tZ-forms. Synthetic Z-roemerine is dimorphic, m.p. 85-7° and 102°, and has [aju — 79-9° (EtOH), these constants being in good agreement with those of the natural base. 

Formally analogous to the foregoing Grignard additions are the intramolecular condensations of amides with aromatic systems, found in the Bischler-Napieralski reaction 101), which is of particular interest in isoquinoline and indole alkaloid syntheses (102). Condensations of amidines with reactive methylene compounds also led to enamines (103-106). 

Studies on the Bischler-Napieralski cyclization of A -acetyltryptamine in the presence of indole have led to the isolation of numerous products, among which the indolocarbazole 186 could be found in 3.5% yield. This outcome was rationalized as a result of the intermediacy of a spiroindolenine species formed under these conditions [89H(28)175]. During detailed studies on the polymerization of indole, formation of a low yield of the related indolo[3,2-h]carbazole 187 was discovered in the product mixture originating from the treatment of indole with p-toluenesulfonic acid at elevated temperature [88JCS(P1)2387]. In an investigation of the condensation of p-benzoquinone with 4-substituted anilines, an indolo[3,2-h]carbazole derivative has been reported to be formed in 2% yield (80JOC1493). 

One of the earliest syntheses of lavendamycin methyl ester, however, did not employ either the Pictet-Spengler or the Bischler-Napieralski reactions for construction of the /J-carboline ring system. Instead, a palladium-promoted ring closure of aryl pyridine 36 (Fig. 12) was used to prepare /1-carboline 37 by Boger and coworkers [35]. Unfortunately, stoichiometric palladium was found to be necessary, in this case 1.5 equivalents of the tetrakis(triphenylphosphine)palladium(0) being used. Friedlander condensation with aldehyde 38 in the presence of benzyltrimethylammonium hydrox-... 

The thermal condensation of p-benzyloxyphenylacetic acid and of 3-methoxy-4-hydroxyphenethylamine occurs and gives, with a yield of 86% to 92%, the N-(3-methoxy-4-hydroxyphenethyl-p-benzyloxyphenyl)acetamide from this latter, by cyclization according to Bischler-Napieralski with phosphorus oxychloride in acetonitrile, followed by reduction with sodium borohydride, there is obtained with a yield of 75% to 80% the l-(p-benzyloxybenzyl)-6-methoxy-7-hydroxy-l,2,3,4-tetrahydroisoquinoline, which is methylated with... 

Closely related to the Bischler-Napieralski synthesis is the Pictet-Spengler synthesis, which utilises aldehydes rather than acylating species. Condensation of (3-arylethylamines with aldehydes produces imines such as... 

Psychotrine (6) has already been synthesized by condensation of the (—)-tricyclic ester 29 with 3-benzyloxy-4-methoxyphenethylamine, followed by Bischler-Napieralski cyclization and debenzylation (76). Thus, the syntheses of (—)-29 reviewed last in Section III,B constitute formal syntheses of this alkaloid. 

Nagubandi, S., Fodor, G. Novel condensing agents for Bischler-Napieralski type cyclodehydration. Heterocycles 1981, 15,165-177. 

Bischler-Napieralski reaction.1 Cyclization of the nitroamide (1) with the usual condensation reagents2 failed, but was realized in moderate yield with polyphosphate ester prepared according to Cafva (3, 229). The reaction was used in one step of a total synthesis of the thalictrum alkaloid adiantifoline. 

Bischler-Napieralski reaction. Cyclodehydration of (i-phcncthylamidcs to 3,4-dihydroisoqui-nohne derivatives by means of condensing agents such as phosphorus pentoxide or zinc chloride. 

The latter when subjected to a second Ullmann condensation with bromomethoxyphenylacetic acid produces the acid (83). Removal of the /v-butyry1 group and internal amide formation, followed by Bischler-Napieralski cyclisation, A -methy1ation and reduction gives a mixture of diastereoisomeric bases of structure (84), one of which has been reduced to the 4 -benzyl compound and completely 0-demethylated to the tetrahydric phenol (85). This is cyclised to the dioxin by hydrobromic acid at 140°, methylated with diazomethane and reductively debenzy-lated to trilobine (86). The other isomer of the base (84) has been similarly converted into obaberine, the C-1 epimer of trilobine (Y. Inubushi et al.. Tetrahedron Letters, 1976, 2857 Chem.Pharm.Bull., 1977,, 1636). 

A novel syrTEhesis of the aporphine system has been achieved from the diphenylethylamine (149) by condensation with diethyl oxalate followed by Bischler-Napieralski ring closure to the dihydroisoquinoline (150) and further cyclisation with polyph-osphoric acid to the oxoaporphine (151). A -methylation and reduction of this gave the trimethoxyaporphine 0,iV-dimethyl-tuduranine (M. Grecke and A. Brossi, Helv., 1979, 62. 1549). 

Isochromanones on condensation with p-phenylethyl amines, followed by Bischler-Napieralski cyclisation and NaBH reduction furnish berbine alkaloids in good to excellent yields. The 7,8-dimethoxy and mcthylenedioxy isochromanones prepared by lithiation methods provide the 9,10-oxygenated berbine alkaloids, such as tetra-hydropalmatine 51a canadine stylopine 57c , sinactine... 

Condensation of isochromanones with tryptamine followed by Bischler-Napieralski cyclisation and NaBH reduction provide the Yohimbane skeleton... 

Eudistomidin A (11) and eudistomins H (7), I (8) and P (9) have been made (127, 128) by the Bischler-Napieralski (BN) reaction, a method used extensively by the Hino group. Appropriately substituted tryptamine was condensed with BOC-prolinoyl chloride, then treated under BN conditions (POCl3 or polyphosphoric ester (PPE)) to produce a 5,7-disubstituted eudistomin skeleton (163). Eudistomin I thus results when starting from tryptamine (Scheme 9, R = R = H), eudistomin H from 5-bromotryptamine (Scheme 9, R = Br, R = H), eudistomidin A from 5-bromo-7-hydroxytryptamine (Scheme 9, R = Br, R = tosylate) eudistomin P is obtained from the use of 6-bromo-5-methoxytryptamine. 

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