Bischler-Napieralski synthesis

Bischler-Napieralski cyclizations azepine synthesis by, 7, 532 Bischler-Napieralski synthesis, 2, 72... 

This approach to the isoquinoline ring, albeit a reduced isoquinoline, is mechanistically similar to the Bischler-Napieralski synthesis, in that it involves electrophilic attack of an iminium cation on to an aromatic ring. In this case, the imine intermediate is formed by reacting a phenylethylamine with an aldehyde. 

Alternatively, a P-methoxy-P-phenylethylamine can be used to circumvent the oxidation step after the conventional Bischler-Naperialski cyclization. Here, when treated with the phosphorus reagent the amide (R = OMe) undergoes both cyclization and the elimination of methanol to give the isoquinoline (R = H) directly. This is known as the Pictet-Gams modification of the Bischler-Napieralski synthesis. 

The Pictet-Gams modification of the Bischler-Napieralski synthesis has also been reviewed (5loR(6)74, 81HC(38-l)l6i). As shown in equation (32), the additional unsaturation is achieved by elimination of ROH before the cyclization. The commonest examples use j8-hydroxy or /3-methoxy substituents on the phenethylamide. Papaverine (107) is an example of an isoquinoline obtained from both precursors (09CB2943, 27AP(265)l). The precursors can be made from 5-aryloxazolines by reaction with an acid chloride and... 

Problem 20.40 Outline a mechanism for the Bischler-Napieralski synthesis of 1-methylisoquinoline from N-acetylphenylcthylamine by reaction with strong acid and P,0, and then oxidation of the dihydroisoquinoline intermediate. 4... 

Isoquinoline synthesis Bischler-Napieralski synthesis is used to synthesize isoquinolines. (3-phenylethylamine is acylated, and then cyclodehy-drated using phosphoryl chloride, phosphorus pentoxide or other Lewis acids to yield dihydroisoquinoline, which can be aromatized by dehydrogenation with palladium, for example in the synthesis of papaverine, a pharmacologically active isoquinoline alkaloid. 

The synthesis of solefinacin (2) as shown in Scheme 14.7 [27] starts with 1-substi-tuted 1,2,3,4-tetrahydroisoquinoline (S)-30 which was synthesized from the corresponding N-(2-phenylethyl)carboxamide 29 using a Bischler-Napieralski synthesis. A resolution afforded desired enantiomer (S)-30, which was reacted with ethyl chloro forma te/potas slum carbonate to afford the carbamate. 

As in the Skraup quinoline synthesis, loss of two hydrogen atoms is necessary to reach the fully aromatic system. However, this is usually accomplished in a separate step, utilising palladium catalysis to give generalised isoquinoline 6.14. This is known as the Bischler-Napieralski synthesis. The mechanism probably involves conversion of amide 6.12 to protonated imidoyl chloride 6.15 followed by electrophilic aromatic substitution to give 6.13. (For a similar activation of an amide to an electrophilic species see the Vilsmeier reaction, Chapter 2.)... 

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... 

Step 4. This isoquinoline formation is of course an example of the Bischler-Napieralski synthesis, although phosphorus trichloride was actually used in this example, not phosphorus oxychloride. 

Bischler-Napieralsky synthesis of the benzylisoquinoline (39), iV-formylation, cyclization, and oxidation has given the pentamethoxy-compound (40), identical with glabrine dimethyl ether and glabrinine methyl ether.114 Reticuline N-oxide has... 

This method [Eq. (10)] was first used in 1930 by Kondo and Tanaka60 for the preparation of 4-hydroxy-5-methoxytetrahydroisoquinoline from j8-hydroxy-j8-(o-methoxyphenyl)ethylamine and methylal (mixed in aqueous HC1). Such ethanolamine derivatives are frequently used in the Bischler-Napieralski synthesis of isoquinolines61 as the Pictet-Gams modification. In this case, the reaction proceeds with dehydration to yield completely aromatic isoquinolines directly. Preparations of the ethanolamines have been reviewed.62... 

An important method for making derivatives of isoquinoline is the Bischler-Napieralski synthesis. Acyl derivatives of /3-phenylcthylaminc arc cyclized by treatment with acids (often P2O5) to yield dihydroisoquinolines, which can then be aromatized. 

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