And the Bischler-Napieralski reaction

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 first two reported syntheses of manzamine C utilized the two most common approaches to the /J-carboline ring system—the Pictet-Spengler reaction [13,14] and the Bischler-Napieralski reaction [15]. These two reactions are illustrated in Fig. 3. 

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). 

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. 

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... 

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... 

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. 

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... 

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). 

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>. 

One of the earliest syntheses of lavendamycin methyl ester, however, did not employ either the Pictet-Spengler or the Bischler-Napieralski reactions for construction of the /J-carboline ring system. Instead, a palladium-promoted ring closure of aryl pyridine 36 (Fig. 12) was used to prepare /1-carboline 37 by Boger and coworkers [35]. Unfortunately, stoichiometric palladium was found to be necessary, in this case 1.5 equivalents of the tetrakis(triphenylphosphine)palladium(0) being used. Friedlander condensation with aldehyde 38 in the presence of benzyltrimethylammonium hydrox-... 

For the preparation of 3,4-dihydro-/3-carbolines the Bischler-Napieralski reaction is widely used (510R74). Since this reaction requires rather drastic conditions, A-acetyl tryptophan and its analogs yielded l-methyl-/8-carboline (harman) rather than l-methyl-3,3-dihydro-j8-carboline-3-carboxylic acid derivatives owing to accompanying decarboxylation and aromatization (41JCS153 50JA2962). 

The nitrile ylides were generated from amides via the imidoyl chloride-base method and hence the reaction is, overall, the electrocyclic equivalent of a Bischler-Napieralski type of process. However, it has the advantage that it is effective for cyclization on to both electron-rich and electron-poor aromatic rings, unlike the Bischler-Napieralski reaction itself, which is an electrophihc process and only works well for electron-rich rings. 

W. H. Whaley and T. R. Govindachari, The preparation of 3,4-dihydroisoquinolines and related compounds by the Bischler-Napieralski reaction, Organic Reactions, VI, 74, Wiley, New York (1951). 

The carbonyl unit involved in the cyclization process is not restricted to aldehydes and ketones. The carbonyl of acid derivatives, such as amides can also be utilized. One of the more important cyclodehydration reactions is applied to the formation of heterocychc systems via cyclization of p-aryl amides, in what is called the Bischler-Napieralski reaction In this reaction amides of the type 47 are... 

Under the conditions for Hofmann degradation, the quaternary salt (43) undergoes loss of the C-1 substituent as benzophenone, followed by further degradation to the o-vinylbenzylamine (44). The Bischler-Napieralski reaction used in the synthesis of (43) afforded the chlorinated by-product (45 R = Cl) which reacted rapidly with methanol to give (45 R=OMe). The l-(2 -picolyl)- and l-(6 -methyl-2 -picolyO-isoquinolines (46 R = H) and (46 R = Me), like their 3,4-... 

New C—C bonds to arenes can be made by Friedel-Crafts reactions. Friedel-Crafts alkylations are traditionally executed with an alkyl chloride and catalytic AICI3 or an alkene and a strong Brpnsted or Lewis acid the key electrophilic species is a carbocation. Friedel-Crafts acylations are usually executed with an acyl chloride and an excess of AICI3 the key electrophilic species is an acylium ion (RC=0+). In the Bischler-Napieralski reaction, intramolecular attack on a nitrilium ion (RC=NR) occurs. 

Reagent for cyclodehydration. A Japanese groups prepared PPE as above and used the chloroform solution as such and found it to be an excellent reagent for the Bischler-Napieralski reaction. Thus phenylethylamides (I) are cyclized smoothly to dihydroisoquinolines (2) by refluxing with PPE in chloroform. Phenylpropylamides (3) similarly yield 3.4-dihydro-5H-2-benzopines (4). The same workers report that... 

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