Bischler—Napieralski reaction

Reaction of phenylethyl amides with a dehydrating agent, such as P2O5 or POCI3, was first described by August Bischler and Bernard Napieralski in 1893 to afford 3,4-dihydro-isoquinolines in good yields. 

Detailed mechanistic studies by Fodor revealed that the reaction is initiated by a nucleophilic attack of phenylethylamide to the dehydrating agent to afford intermediate imidoyl chlorides. Upon heating, these compounds are converted to nitrilium salts, which were cyclized through an intramolecular electrophilic aromatic substitution, providing the desired dihydroisoquinolines. Fodor prepared imidoyl chlorides using mild condition and promoted their cyclization to dihydroisoquinolines by using Lewis acids. His results supported the intermediacy of nitrilium salts as the key intermediates for the synthesis of dihydroisoquinolines.  

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. 

As it would be expected, the Bischler-Napieralski reaction as an intramolecular electrophilic substitution reaction is accelerated in the presence of an electron-donating group on the aromatic ring. With respect to that, electronic effects influence the regioselectivity of the reaction, leading the substitution typically to the carbon bearing the higher electron density. On the other hand, substitution on the phenylethyl side chain is usually well tolerated.  

The tricyclic isoquinoline compound tetrabenazine, a drug that has been used as an anti-psychotic agent and was also being studied for the treatment of some of the deleterious effects of the anti-psychotic dopamine 

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.  

Side reactions consistent with decomposition of intermediate nitrilium salt 7 have also been observed, including retro-Ritter reactions that afford alkenes (8), and VonBraun reactions that provide alkyl chlorides (9).  

Dihydroisoquinolines from P-phenethylamides using phosphorus oxychloride. 

Bischler, A. Napieralski, B. Ber. Dtsch. Chem. Ges. 1893, 26, 1903. Augustus Bis-chler (1865—1957) was born in South Russia. He studied in Zurich with Arthur Hantzsch. He discovered the Bischler-Napieralski reaction while studying alkaloids at Basel Chemical Works, Switzerland with his coworker, B. Napieralski. 

Bischler-Napieralski Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J. Eds. Wiley Sons Hoboken, NJ, 2005, 376—385. (Review). 

Dihydroisoquinolines from P-phenethylamides in refluxing phosphorus oxychloride. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 23, Springer-Verlag Berlin Heidelberg 2009 

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

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). 

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. °... 

The Bischler-Napieralski reaction was employed by Bonjoch in the synthesis of melinonine-E and strychnoxanthine. The preparation of polycyclic compound 57 was achieved in 53% yield by treating 56 with POCI3 followed by reduction of the dihydroisoquinoline with NaBIii. 

Bischler-Napieralski reaction conditions can be attributed, again, to the destabilizing ability of the trifluoromethyl group to the cationic transition state of the acid catalyzed elimination. Formation of compound 29 was ultimately accomplished by base catalyzed methanol elimination-conditions conditions that are quite unusual for isoquinoline formation. 

Application of the Bischler-Napieralski reaction to amides of tryptophan has been investigated. The cyclodehydration of acetyltrypto-phan under conventional conditions proved unsuccessful. Attempted ring closure of acetyltryptophan or its ethyl ester was accompanied by decarboxylation and aromatization, yielding... 

A synthetic approach to the same tetracyclic y-carboline nucleus (235) is the consecutive Fischer indole and Bischler-Napieralski ring closure of o-acetamidoacetophenone methylphenyUiydrazone (234). The Bischler-Napieralski reaction has also been used in the synthesis of 3,4-benz-j8-carbolines (236) and 3,4-benz-3-carbolines, e.g. 237... 

Bischler-Napieralski reaction of 139 to a 3,4-dihydroisoquinoline, oxidation, dehydrogenation and reduction of the nitro to the amino function gave 140 which was subjected to a Pschorr reaction (Scheme 49). Quaternization was accomplished by methyl iodide to furnish the isoquinolininium salt 141 which underwent an ether cleavage on heating a solid sample or benzene or DMF solution to Corunnine (127) (73TL3617). 

For the synthesis of quinolines and isoquinolines the classical approaches are the Skraup and the Bischler-Napieralski reactions. The reaction of substituted anilines with different carbonyl compounds in acid medium has been reported to be accelerated under microwave irradiation to give differently substituted quinolines and dihydro quinolines [137]. Although the yields are much better and the conditions are milder than under conventional heating, the acidity of the medium may prevent the preparation of acid-sensitive compounds. Thus, alternative approaches have been investigated. Substituted anilines and alkyl vinyl ketones reacted under microwave irradiation on the surface of sihca gel doped with InCU without solvent [137] to furnish good yields of quinohnes 213 (Scheme 77). 

The Bischler-Napieralski reaction has been described to proceed imder microwave irradiation to give very good yields of dihydroisoquinolines [140] and other polycyclic compounds (see below) in the presence of POCI3 and P2O5 (classical conditions) in toluene (10 cycles of 60 s each using a dedicated microwave reactor). 

Among the many applications of cyclodehydration to the formation of heterocyclic systems is the Bischler-Napieralski reaction. In this reaction, amides of the type 35 are cyclized with phosphorous oxychloride ... 

The Bischler-Napieralski reaction is one of the traditional methods for isoquinoline synthesis, and has been applied to the preparation of fused quinolizidine systems. One simple example is the transformation of compound 246 into a 9 1 mixture of diastereomers 247 and 248 by treatment with phosphorus oxychloride followed by sodium borohydride reduction of a nonisolated iminium salt resulting from the cyclization (Scheme 49) <2000BMC2113>. 

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