Bischler Reaction

The Bischler synthesis, first described in 1893, involves the fusion of A-acylanthranilic acid and ammonia to generate the corresponding 2-substituted quinazolinone, which exists in equilibrium with the 4-hydroxy quinazoline tautomer. Bischler s original synthesis, shown below, involved direct conversion of ammonium-A-acetylanthranilate to the corresponding 2-alkyl-2,3,4-dihydro-4-quinazolinone under thermal conditions. 

The mechanism of the Bischler synthesis is illustrated below. Fusion of ammonium-iV-acetylanthranilate generates the diamide, which then undergoes cyclodehydration to form tiie corresponding quinazolinone. The quinazolinone then tautomerizes to the 4-hydroxyquinazoline.  

The Bischler synthesis is still practical today for the synthesis of 2-substituted quinazolines and quinazolinones. However, it has been largely replaced by the Neimentowksi reaction, which can be conducted under milder conditions and is therefore more practical for synthesis highly functionalized quinazolines and quinazolinones. 

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The aminouracil (196) reacts with a-bromoacetophenone in DMF to give only the product of initial C- alkylation (197). In acetic acid the product of N- alkylation (198) is formed as well (73CPB473). 2,6-Diaminopyridine hydrochloride reacts with acyloins under melt conditions (Bischler reaction). The product (199) or (200) depends on the molar ratio of the reactants <74JCS(Pl)l852). 

In order to probe the reactivity of the C-7 position, without the possible complication of the formation of regioisomers, 4,6-dimethoxy-2,3-diphenylindole 3a was prepared by the Bischler reaction from 3,5-di-methoxyaniline and benzoin.3 Vilsmeier formylation occurred smoothly to give the 7-carbaldehyde 4a in 82% yield. In a related manner, the other 2,3-disubstituted-4,6-dimethoxyindoles 3b-d3 were converted in yields of 62-70% to the corresponding 7-carbaldehydes 4b-d4,5 (Scheme 2). More recently, the tetrahydrocarbazole 3e6,7 was also formylated at the equivalent 8-position in 82% yield.7... 

The classical Bischler reaction has received relatively little attention in comparison with other methods for indole synthesis because of the harsh reaction conditions that it requires. The milder modifications involve the use of lithium bromide as a catalyst <2005T77> and a procedure under microwave irradiation conditions <2006SL91>. 

Other references related to the Bischler reaction are cited in the literature. 

In 1881, Mohlau first disclosed this reaction, which was followed by further study carried out by Bischler in 1892-1893. Typically, this indole synthesis of heating excess anilines with a-haloketones is referred to as the Bischler reaction, however naming the transformation the Bischler-Mdhlau indole synthesis is more appropriate. Despite its long history, this classical reaction... 

AMNES - AMINES, AROMATIC - ANILINE AND ITS DERIVATIVES] (Vol 2) Bischler-Napieralski reaction... 

Aromatic amines react with 1-haloketones or 1-hydroxyketones to yield substituted indoles. This reaction is known as the Bischler indole synthesis (30). 

Bischler-ISlapieralski Reaction. This synthetic method involves the cyclodehydration of N-acyl derivatives of p-phenethjlamines (26) to... 

The preparation of benzo fused pyrido[3,2- i]pyrimidines has furnished the only examples of the classic reaction of this type, the Bischler-Napieralski, involving the cyclization of 5-aryl-4-acylaminopyrimidines to 6-alkylpyrimido[4,5-c]isoquinolines, e.g. (157)->(158) (73YZ330). As often found in this reaction, the presence of activating substituents appears necessary (78CPB245). 

The only reactions of this type noted in the pyridopyridazine series are two classic Bischler-Napieralski type closures in benzo fused systems in which 3- or 4-benzamidopyridazines are cyclized to an adjacent phenyl group to give a 6-aryIpyridazino-[3,4-c]- (e.g. 361—> 362) or -[4,5-c]- isoquinoline respectively (59JCS1, 59JCS6). 

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. 

Formally analogous to the foregoing Grignard additions are the intramolecular condensations of amides with aromatic systems, found in the Bischler-Napieralski reaction 101), which is of particular interest in isoquinoline and indole alkaloid syntheses (102). Condensations of amidines with reactive methylene compounds also led to enamines (103-106). 

The Bischler-Napieralski reaction involves the cyclization of phenethyl amides 1 in the presence of dehydrating agents such as P2O5 or POCI3 to afford 3,4-dihydroisoquinoline products 2. This reaction is one of the most commonly employed and versatile methods for the synthesis of the isoquinoline ring system, which is found in a large number of alkaloid natural products. The Bischler-Napieralski reaction is also frequently used for the conversion of N-acyl tryptamine derivatives 3 into p-carbolines 4 (eq 2). 

The synthesis of 3,4-dihydroisoquinolines via intramolecular reactions of phenethyl amides was first reported by August Bischler and Bernard Napieralski in 1893. The authors described the conversion of A-acyl phenethylamide (1, R = Me) and A-benzoyl phenethylamide (1, R = Ph) to 1-methyl-3,4-dihydroisoquinoline (2, R = Me) and 1-phenyl-3,4-dihydroisoquinoline (2, R = Ph), respectively, in the presence of P2O5. This reaction has subsequently proven to be one of the most general methods ever developed for the synthesis of dihydroisoquinolines. 

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. 

Detailed mechanistic studies by Fodor demonstrated the intermediacy of both imidoyl chlorides (6) and nitrilium salts (7) in Bischler-Napieralski reactions promoted by a variety of reagents such as PCI5, POCI3, and SOCh)/ For example, amide 1 reacts with POCI3 to afford imidoyl chloride 6. Upon heating, intermediate 6 is converted to nitrilium salt 7, which undergoes intramolecular electrophilic aromatic substitution to afford the dihydroisoquinoline 2. Fodor s studies showed that the imidoyl chloride and nitrilium salt intermediates could be generated under mild conditions and characterized spectroscopically. Fodor also found that the cyclization of the imidoyl chlorides is accelerated by the addition of Lewis acids (SnCU, ZnCh), which provides further evidence to support the intermediacy of nitrilium salts. ... 

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." ... 

A common modification of the Bischler-Napieralski reaction involves reduction of the dihydroisoquinoline product 2 to provide a tetrahydroisoquinoline derivative 19. A variety of different reducing agents have been employed, with NaBHi used with the greatest frequency. In many cases the reduction is carried out on the crude product of the Bischler-Napieralski reaction purification of the dihydroisoquinoline prior to reduction is usually not necessary. 

An interesting synthesis of quinolizidines was achieved using a vinylogous variation of the Bischler-Napieralski reaction. Angelastro and coworkers reported that treatment of amide 26 with PPSE (polyphosphoric acid trimethylsilyl ester) followed by reductive... 

Phenethyl carbamate derivatives 30 have also been employed in Bischler-Napieralski reactions cyclization of these substrates affords 3,4-dihydroisoquinolones 31. These reactions have been conducted using a variety of different promoters including PPA, POCl3, and Tf20. Mixtures of P2O5 and POCI3 appear to afford the best results in some cases. 

The adaptation of the Bischler-Napieralski reaction to solid-phase synthesis has been described independently by two different groups. Meutermans reported the transformation of Merrifield resin-bound phenylalanine derivatives 32 to dihydroisoquinolines 33 in the presence of POCI3. The products 34 were liberated from the support using mixtures of HF/p-cresol. In contrast, Kunzer conducted solid-phase Bischler-Napieralski reactions on a 2-hydroxyethyl polystyrene support using the aromatic ring of the substrate 35 as a point of attachment to the resin. The cyclized products 36 were cleaved from the support by reaction with i-butylamine or n-pentylamine to afford 37. 

One important variation of the Bischler-Napieralski reaction is the Pictet-Gams modification, in which p-hydroxy or -alkoxy phenethylamides 38 are converted to isoquinolines 39. This transformation is covered in detail in section 9.12 of this text. 

Racemization has been reported to occur in some Bischler-Napieralski reactions of 1-substituted phenethylamides. However, this racemization can be suppressed by conducting the reactions at lower temperatures (0 °C-rt). For example, the product 49 obtained in reaction of 48 with P2O5 at 140 °C was found to be racemic, whereas the product obtained from a reaction conducted at room temperature retained optical activity. ... 

The Bischler-Napieralski reaction is one of the most widely used methods for the construction of dihydro- and tetrahydroisoquinoline units in the synthesis of alkaloid natural products. A few representative examples of the Bischler-Napieralski reaction in complex alkaloid syntheses are shown below. 

Wender and Aube have independently described the use of the Bischler-Napieralski reaction in the synthesis of Yohimban alkaloids. Aube s approach involved the cyclization of indole 50 followed by reduction of the resulting dihydroisoquinoline... 

A related route to the protoberberine skeleton was reported by Lete, in which substrate 54 underwent Bischler-Napieralski reaction followed by intramolecular alkylation of an in situ generated alkyl chloride to afford 55. °... 

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