Photochemically induced cyclization of N-[2-(o-styryl)phenylethyl]acetamides and 5-styryl-1-methyl-1,2,3,4-tetrahydroisoquinolines: new total syntheses of 1-methyl-1,2,3,4- tetrahydronaphtho[2,1-f]isoquinolines Elena Martõ Ânez, Juan C. Este Âvez, Ramo Ân J. Este Âvez p and Luis Castedo Departamento de Quõ Âmica Orga Ânica and Unidad Asociada al Instituto de Investigaciones Quõ Âmicas (C.S.I.C.), Universidad de Santiago, 15706 Santiago de Compostela, Spain Received 25 February 2000; revised 20 December 2000; accepted 11 January 2001 Abstract ÐTwo new total syntheses of 1-methyl-1,2,3,4-dihydronaphtho[1,2-f]isoquinolines are based on the construction of their phenanthrene ring system by photochemically induced cyclization of N-{2-[(E)-2-phenyl-1-ethenyl]phenylethyl}acetamides or 1-methyl- 5-[(E)-2-phenyl-1-ethenyl]-1,2,3,4-tetrahydroisoquinolines. q 2001 Elsevier Science Ltd. All rights reserved. Our previous paper 1 reported the ®rst total syntheses of naphtho[2,1-f]isoquinolines (1), a class of isoquinolines that received negligible attention until the recent isolation of litebamine 2 and annoretine, 3 and two subsequent partial syntheses of litebamine 4,5 from its probable biogenetic precusor, 4 the aporphine boldine. Here, we describe two additional total syntheses of naphthoisoquinolines 1. Like those described in Ref. 1, they are both based on a sequential construction of rings C and A, but start from styrylphenylethylacetamides 3, these latter include a stilbene-like system allowing construc- tion of the phenanthrene ring system of acetamides 2 trans- formation of which into the target compounds 1 is described in Ref. 1. Alternatively, ring A can be constructed ®rst, giving 5-styrylisoquinolines 4, 5 that can be transformed into naphthoisoquinolines 1 by electrocyclic cyclization (Scheme 1). We ®rst studied the preparation of starting o-styrylphenyl- ethylacetamide 3a by Heck 6 coupling of an appropriate halobenzene to styrene (Scheme 2). When a deoxygenated solution of phenylethylacetamide 6a, 7 styrene (5a), triethyl- amine and palladium acetate was heated at 1358C in a sealed tube for 3 days, the desired unsubstituted o-styryl- phenylethylacetamide 3a was obtained in 81% yield. Its mass spectrum con®rmed the expected molecular weight (m/z265) and its 1 H NMR spectrum the E con®guration of the stilbene double bond showing two doublets at 7.03 (1H, J16.1 Hz) and 7.27 ppm (1H, J16.1 Hz). We next studied the preparation of dimethoxystyrylphenyl- ethylacetamide 3b by this route. Since Heck coupling between 6b 8 and styrene in the above conditions furnished 3b in only 25% yield, we explored a longer but, as it turned out, more ef®cient route based on the opening of benzylideneisoquinolines 10 to o-phenylacetylphenylethyl- acetamides 11 9 (Scheme 2). Reaction between homo- veratrylamine (6c) and phenylacetyl chloride (7a) gave phenylacetylphenylethylamine 8a, which was cyclized to benzyldihydroisoquinoline 9a under typical Bichler± Napieralski conditions. 10 Treatment of this isoquinoline with Ac 2 O gave N-acetyl-1-benzylideneisoquinoline 10a, which upon treatment with 10% aqueous HCl solution opened to the desired phenylacetylphenylacetamide 11a. 9 Reduction of this latter with NaBH 4 gave its hydroxy derivative 12a, which was directly dehydrated to styryl- phenylethylacetamide 3b. The overall yield for this indirect route to 3b was 70%. Finally, tetramethoxystyrylphenylethylacetamide 3c was prepared by the above both routes. Heck coupling of o-bromohomoveratrylamine (6b) with dimethoxystyrene 5b 11 afforded 3c in 47% yield. The indirect route from previously prepared o-acetylphenylethylacetamide 11b 1 via hydroxyacetamide 12b gave a yield of 75%. Tetrahedron 57 (2001) 1981±1986 Pergamon TETRAHEDRON 0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved. PII: S0040-4020(01)00041-2 Keywords: alkaloids; biaryls; isoquinolines; electrocyclic reactions; photo- chemistry. p Corresponding author. Tel.: 134-981-563100, ext. 14242; fax: 134-981- 591014; e-mail: qorjec@usc.es