Pschorr aporphine synthesis

PSCHORR APORPHINE SYNTHESIS 6-Methoxy-7-hydroxy-3,4-dihydroisoquino-linium melhiodide. 

Pschorr aporphine synthesis, Kupchan el al.2 have reported an improved synthesis of aporphines by using (1) for condensation with o-nitrotoluenes (2) in the presence of potassium t-butoxide in DMA to give l-(2-nitrobenzyl)-6-methoxy-7-hydroxy-l,2,3,4-tetrahydroisoquinolines (3) in yields of 88-95%. These are hydrogenated to the... 

The Reissert method15—conversion of an isoquinoline to a 2-benzoyl-1,2-dihydroisoquinaldonitrile (Reissert compound), alkylation, and hydrolysis—has enjoyed wide success in the synthesis of benzyliso-quinoline and related alkaloids.16,17 In particular, aporphines are prepared conveniently by converting isoquinolines to I-(o-nitrobcnzyl)-isoquinolines via a Reissert sequence, followed by A7-alkylation, reduction, and Pschorr cyclization.17... 

The synthesis of three l,2,10,ll-tetrasubstituted./V-(n-propyl)noraporphines, using either the Bischler-Napieralski-Pschorr sequence or a Reissert alkylation-Pschorr cyclization, has been achieved.29 Patents have been taken out on the morphine-apomorphine rearrangement that is induced by phosphoric acid and which leads to N- alkylated norapomorphines.30 Other patents concern the vanadium-trichloride-induced cyclization of tetrahydrobenzylisoquinolines that are hydroxylated at C-7, to furnish a series of 1-hydroxylated aporphines such as thaliphorphine. 31,32... 

The use of 2-nitrobenzyl halides in the Reissert alkylation, followed eventually by the Pschorr cyclization, has provided an attractive route to various aporphines (31). Thus this procedure had led to the synthesis of apomor-phine, ° apomorphine derivatives, atheroline, imenine, N-methyl-ovigerine, oconovine, 8-hydroxyaporphines, 10-hydroxyaporphines, ... 

Some years ago a general synthetic method 52) for the morphinan-dienone-type alkaloids was discovered by modifying the Pschorr reaction which had been used widely for the synthesis of the aporphine alkaloids and this method was applied to a synthesis of the homo-morphinandienone-type compounds. 

One of the most important fields of application of the Pschorr reaction is the synthesis of isoquinoline alkaloids. The syntheses of thalicsimidine [72] (Scheme 46) and aporphine [73] are typical examples. 

Further studies of the synthesis of the aporphine alkaloids were carried out to find simpler procedures and to increase the yields. The most frequently applied methods are the Bischler-Napieralski reaction (91, 408, 408a, 449, 450), the Pschorr cyclization (451, 452), and the photocy-clization of various benzylisoquinoline precursors (416a, 453,454) (Scheme 10). 

Four major reactions (Pschorr, phenol oxidative coupling, photocyclization, and benzyne-mediated synthesis) continue to play key roles in the total synthesis of aporphine and proaporphine alkaloids. Coninnine (96) was synthesized according to Scheme 5, employing the Pschorr reaction as the key step. An... 

R = H) in 20% yield. Compound (111 R = OMe, R == H) has also been synthesized by a conventional Pschorr cyclization route.The photochemical oxidation of glaucine to 7-oxoglaucine has been reported. Photochemical synthesis of the unusual aporphine alkaloid thalphenine (113 N-Mel) has been achieved. Irradiation of (114) under basic conditions gave directly (113), presumably via the intermediate quinone methide (115), which results from the initially formed aporphine precursor by elimination of the elements of methanol. Quaternization of (113) provided ( )-thalphenine (113 A/-Mel), whose Hofmann elimination gave the alkaloid thaliglucine (93 R = H2). 

Structure. The structure of glaucine was arrived at by Gadamer (12) by a process of intuitive reasoning supplemented by a synthesis. Co-rytuberine dimethyl ether and glaucine were known to be isomeric, and if a relation to papaverine were admitted only two structures were available for the two alkaloids. Pschorr (13), utilizing his well-known phenanthrene synthesis, had attempted to convert papaverine into an aporphine (IV) via the nitro (II) and the amino (III) derivatives. When papaverine is nitrated it yields 6 -nitropapaverine (II), from which the methochloride... 

The synthesis of three new racemic aporphines (22)—(24), using either a Bischler-Napieralski-Pschorr sequence or a Reissert-Pschorr route, has been described. ... 

Introduction - Interest in the aporphine alkaloids continues at a rather high level, and a number of developments have been reported since the appearance of the last review (April, 1966) on this class of compounds-More than thirty new aporphines of varied structure have been isolated from natural sources the structures of a few members have been confirmed by total synthesis. The synthesis of aporphines by methods other than the classical Pschorr method continues to be e3q>lored, and some new ring systems related to the aporphines have been synthesized. Some new pharmacological studies employing aporphines have been reported. 

Laudanine has been obtained as a by-product in the synthesis of some aporphine bases. When the amino bases LXXIV (Ri = NH2, R2 = H) (129,130) and LXXIV (Ri = H, R2 = NH2) (131) were diazotized and submitted to the usual treatment of the Pschorr reaction, partial substitution of the diazo group by hydrogen took place and 0-benzyl-laudanine was obtained (LXXIV Ri = R2 = H) which on debenzylation produced laudanine. 

Neumeyer JL, Oh KH, Weinhardt KK, Neustadt BR (1969) The chemistry of aporphines. IV. Synthesis of aporphines via Reissert alkylation, photochemical cyclization OR the Pschorr cyclization route. J Org Chem 34 3786-3788... 

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