Synthesis of phthalideisoquinolines by direct coupling of phthalide anions with 3,4-dihydroisoquinolinium salts

Abstract

, 306 (1984). The condensation of phthalide anions, derived from phthalide itself and from its 6,7-and 5,6-dimethoxy derivatives, with 6,7-dimethoxy-2-methyl-3.4-dihydroisoquinoine is described. The reaction products obtained in ca. 40% yield are easily separable mixtures of substituted (*)-erythro and (*)-threo-phthalidetetrahydroisoquinolines. The reaction is potentially useful for synthesis of naturally occurring akaloids of this family. RICHARD MARSDEN et DAVID B. MACLEAN. Can. J. Chem. 62, 306 (1984). On dtcrit la condensation des anions phtalides, provenant du phtalide lui-meme et de ses dtrivts dimtthoxy-6,7 et dimtthoxy-5,6 sur la dimtthoxy-6,7 mtthyl-2 dihydro-3,4 isoquinoltine. Les produits de la reaction obtenus avec un rendement d'environ de 40% sont des mtlanges facilement stparables de (+) trythro et de (*) thrto phtalidetttrahydroisoquinoltines substitutes. La reaction est potentiellement utile pour la synthkse des alcaloi'des naturels de cette famille.[Traduit par le journal]Perkin and Robinson (1) reported in 191 1 the first successful synthesis of a phthalideisoquinoline alkaloid, although in low yield, by treating cotarnine with meconin in boiling alcohol. Many synthetic approaches to these alkaloids have appeared in the intervening years, which are summarized in several reviews (2-6) and in a recent paper (7). Several reports describing new and efficient syntheses of these alkaloids based on the PerkinRobinson approach have recently appeared. In 1979 a preliminary account appeared of the reaction between 3-halophthalides and 2-methyl-3,4-dihydroisoquinolinium salts in the presence of Zn metal or Zn-Cu couple (8) and a full account of this reaction was published in 1981 (7). The validity of this approach to phthalideisoquinoline alkaloid synthesis has recently been confirmed by Shono et al. (9) who carried out the same reaction in a different solvent system. The electrochemical i coupling of bromophthalides and 3,4-dihydroisoquinolinium salts has also been reported (10). In another approach Prager et al. (I 1) have shown that 2-methylisoquinolinium salts condense with ~hthalides in the Dresence of sodium methoxide yielding adducts that may be reduced catalytically with hydrogen or with sodium cyanoborohydride to the 2-methylphthalidetetrahydroisoquinoline system present in the naturally occurring alkaloids. Prager et al.( 1 1) noted that they were unable to carry out a similar addition to 3,4-dihydroisoquinolinium salts. In this laboratory we had encountered similar difficulties in the past. Now, however, by preparation of the phthalide anions at low temperature using LDA, we are able to report the direct coupling of phthalide anions with 3,4-dihydroisoquinolinium salts. Phthalide anions have been prepared and used successfu!ly by Broom and Sammes (12) as Michael donors. Sammes' group has also shown that they add to acyclic imines forming isoquinolones (13) and we have shown that they add to 3,4-dihydroisoquinolines (cyclic imines), forming in one step the berberine ring system (14). Their add...

Synthesis of Phthalideisoquinoline and Protoberberine Alkaloids and Indolo[2,1-a]isoquinolines in a Divergent Route Involving Palladium(0)-Catalyzed Carbonylation1

“…( ± )-Isocordrastine II (1e): 87% yield from 19e ; mp 167−169 °C (EtOH) (lit . mp 157−159 °C; , 166−167 °C; 167−169 °C; 169−170 °C; 169−171 °C; 170−171 °C). 1 H NMR (270 MHz) δ 2.28−2.40 (m, 1H), 2.57−2.72 (m, 2H), 2.93−3.03 (m, 1H), 2.60 (s, 3H), 3.72, 3.79, 3.86, 3.91 (each s, each 3H), 4.12, 5.58 (each d, J = 4.0 Hz, each 1H), 6.23, 6.42, 6.62, 7.23 (each s, each 1H). ,− …”