L-Benzyl-3,4-dihydroisoquinolines

To a solution of 460 mg (1.5 mmol) spiro-cyclopropene in 50 ml of dry ether an equimolar amount (32.2 mg =1.5 mmol) of l-benzyl-3,4-dihydroisoquinoline was slowly added at room temperature. After 24 h of stirring in the dark, the precipitate was filtered off. Column chromatography in Si02 with CH2CI2 and recrystallisation from ether afforded the tetrahydroindolizine. Yield 420 mg (53.2%) mp 238°C. 

Intermediacy of a zwitterionic peroxide was postulated also for the oxidation of l-benzyl-3,4-dihydroisoquinolines to the corresponding 1-benzoyl derivatives (Scheme 6). 

The synthesis of meconin has been referred to already (p. 201). Cotarnine has been synthesised by Salway from myristicin (I) as a starting-point. This was transformed into jS-3-methoxy-4 5-methylenedioxy-phenylpropionic acid (II), the amide of which was converted by Hofmann s reaction into j3-8-methoxy-4 5-methylenedioxyphenylethylamine, and the phenylacetyl derivative (III) of this condensed, by heating it in xylene solution with phosphoric oxide, giving rise to the two possible dihydroiso-quinoline derivatives. The first of these substances, 8-methoxy-6 7-methylenedipxy-l-benzyl-3 4-dihydroisoquinoline (IV), on conversion into methochloride and reduction with tin and hydrochloric acid, gave... 

Although 1-alkyl- and l-phenethyl-3,4-dihydroisoquinolines are stable in air, some l-benzyl-3,4-dihydroisoquinolines tend to undergo air oxidation to l-benzoyl-3,4-dihydroisoquinolines in neutral or alkaline solution, but usually not in acidic media. However, in the B-N reaction of amide 38, the oxidized product 39 is the only one which was isolated (67JPJ406) (Scheme 19) (81HC139). 

Agbalyan et al 9 recently employed this reaction in the synthesis of several 3,4-dihydroisoquinoline derivatives with unsaturated substituents in the 1-position. The Madrid group50 has shown that (with the exception of benzyl thiocyanate) aliphatic and aromatic thiocyanates yield 1-alkylthio- and l-arvlthio-3,4-dihydroisoquinolines as expected (cf. Table V). 

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. 

In order to demonstrate the transfer of a benzyl group to an acceptor under the rearrangement conditions, a mixture of the l-benzyl-3-ethyl-l,2-dihyd-roisoquinoline 110, a 3-substituted 1,2-dihydroisoquinoline that does not rearrange, and the l-ethyl-l,2-dihydroisoquinoline 111, which normally gives disproportionation, was treated with dilute acid. The 3,4-dihydroisoquino-linium salt 112 was obtained in 5% yield. This experiment demonstrated that the transfer of a benzyl group from a 1,2-dihydroisoquinoline (110), existing as a 1,4-dihydroisoquinolinium salt in acidic solution, to form the 3,4-dihydroisoquinolinium salt 112 is possible. The low yield of 112 can be... 

Applying the same methodology, Felpin et al. reported the selective synthesis of 4-benzyl-l,2-dihydroisoquinoline-3-ones by the reaction of 2-(2-cyanoaryl)acrylate instead of 2-(2-nifrophenyl) acrylafe and aryl diazonium salt [31]. 

---