Bischler-Napieralski reaction Mechanism

Despite the synthetic utility of this transformation, nearly eighty years elapsed between the discovery of the Bischler-Napieralski reaction and the first detailed studies of its mechanism. " Early mechanistic proposals regarding the Bischler-Napieralski reaction involved protonation of the amide oxygen by traces of acid present in P2O5 or POCI3 followed by electrophilic aromatic substitution to provide intermediate 5, which upon dehydration would afford the observed product 2. However, this proposed mechanism fails to account for the formation of several side products that are observed under these conditions vide infra), and is no longer favored. 

Bischler-Napieralski reactions of N-acyl tryptamine derivatives 16 are believed to proceed via a related mechanism involving the initial formation of intermediate spiroindolenines (17) that rearrange to the observed 2-carboline products (18). The presence of these intermediates has been inferred by the observation of dimerized products that are presumably formed by the intermolecular trapping of the spiroindolenine by unreacted indole present in the reaction mixture." ... 

What is the mechanism of the Bischler-Napieralski reaction of step b ... 

The closure of the new 6-membered lactam ring to give 16 from 15 is based on extensive literature precedent from synthetic work in the yohimbane-type indole alkaloids.The mechanism of this Bischler-Napieralski reaction involves conversion of the amide function to an imidoyl chloride, which makes Cn electrophilic enough to add to the two position of the indole. ... 

The mechanism has been further supported by the isolation and characterization of retro-Ritter by-products observed from the Bischler— Napieralski reaction. The retro-Ritter by-products are formed by decomposition of the proposed nitrilium salts. 

It is believed that this reaction proceeds via initial formation of hydrochloric salts of imidoyl chloride when POCI3, PCI5, or SOCI2 is used as a reagent, followed by the formation of imidoyl chloride by the loss of hydrogen chloride, which is in equilibrium with nitrilium salt. Then the 3,4-dihydroisoquinoline is formed via the ring closure of nitrilium salt, as indicated in the direct formation of such dihydroisoquinoline via alkylation of nitrile with phenylethyl halide in the presence of a Lewis acid. An exemplary mechanism of the Bischler-Napieralski reaction is illustrated here. 

Isoquinolines can be prepared by a Bischler-Napieralski reaction involving a tertiary formamide 1555, which reacts with the dehydration reagent triphosgene to form the anti-tumor active nitidine chloride 1557 [1184]. As regards the reaction mechanism, it can be suggested that the first step affords the same intermediate chloroformate 1556 as the isocyanide-generating process. Then, a Friedel-Crafts acylation-like attack of the iminium cation at the benzene moiety affords the isoquinoline nitidine chloride 1557 in 91% yield. 

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... 

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.)... 

The catalytic and chemical reduction of the 3-methyl-3,4-dihydrobenzyliso-quinoline (56) has been studied (Scheme 2)3 Catalytic hydrogenation of (56) in acidic ethanol gave the ds-l,2,3,4-tetrahydroisoquinoline, c/5-(57), as the sole product whereas reduction with NaBH4 produced a 25 1 mixture in favour of trans- Sl). The same report also describes the Bischler-Napieralski cyciization of N-2-[l-(2,5-dimethoxy-4-methylphenyl)propyl]-3,4-dimethoxyphenylaceta-mide to give, in addition to the normal product (56), a number of neutral compounds which shed some light on the mechanism of this reaction." One of... 

The mechanism of the Staudinger reaction was mentioned above in another computational study of this reaction, a biradical transition structure has been predicted. Finally, the Bischler-Napieralski synthesis of isoquinolines is well-known experimentally the activation energy for the cyclization process has been calculated by ab initio means, together with the effect on this energy of various substituents. ... 

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