Bischler-Napieralski conditions

Synthesis of 216, an analog of the amide alkaloids, starting with ketone 214 was performed by Ishii et al. (176) (Scheme 33). The initial step involved the formation of cis secondary amine 215, which on N-formylation and dehydrogenation led to 216. Under Bischler-Napieralski conditions 216 could be recyclized to chelirubine (217). 

The seco amide alkaloids have been subjected to various transformations, mainly for structure elucidation purposes. When treated with lithium aluminium hydride, arnottianamide (206) was converted to the tertiary amine, deoxyarnottianamide (224), which on methylation with the Rodionow reagent gave deoxy-O-methylarnottianamide (225) (172,175). Arnottianamide (206) could be O-acetylated (174) as well as O-methylated with diazomethane in HMPA (172). Isoarnottianamide (208) was O-methylated to trimethoxy derivative 226, which under Bischler-Napieralski conditions recyclized to the benzophenantridine alkaloid, chelilutine (227) (176) (Scheme 33). 

Electrophilic cyclodimerization (to 26) also results when (25) is subjected to Bischler-Napieralski conditions (POCI3, reflux), presumably through reaction of pyrazole with the imino chloride intermediate (78JHC1339). 

Starting from resin-bound N-acylated dipeptides 11 having tryptophan or a tryptophan analog as the C-terminal amino acid, a mixture-based combinatorial library of 46,750 indolepyridoimidazoles 12 was synthesized by double cyclodehydration under Bischler-Napieralski conditions (POCl3, dioxane, 100°) (Fig. 4).23 Twenty-two tryptophan analogs, 25 amino acids, and 85 carboxylic acids were used for the library synthesis. 

Hydroxy-substituted A -(2-arylethy)amides 51 lead to isoquinolines 48 under Bischler-Napieralski conditions. In this case, dehydrogenation is not required Pictet-Gams synthesis), because H2O elimination occurs at the dihydroisoquinoline step. The starting materials 51 are available e.g. from aryl-4,5-dihydrooxazoles (e.g. 57). 

The tetracyclic core of the berbane and alloyohimbane alkaloids has been accessed using xanthate-based radical chemistry [111]. The precursor xanthate 197 was prepared from tryptamine and then subjected to reflux conditions (1,2-dichloroethane or 2-propanol) in the presence of a catalytic amount of DLP. The resultant piperidones (198 and 200) generated via a 6-exo-trig cyclization were obtained in reasonable yields and accompanied by azepinone 199, the product of presumed radical attack on the 2-position of the indole. The alloyohimbane core was finally accessed through reductive Bischler-Napieralski conditions. 

The use of quinone methides in the synthesis of spirobenzylisoquinolines has been extended by Kametani and his colleagues who have utilized substituted benzocyclobutenes as precursors for o-quinodimethides. They converted the known benzocyclobutene 10 to the amide 11 which upon treatment under Bischler-Napieralski conditions furnished the known spirobenzyliso-quinoline 13 probably via the o-quinodimethide 12 ° ... 

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 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... 

Studies on the Bischler-Napieralski cyclization of A -acetyltryptamine in the presence of indole have led to the isolation of numerous products, among which the indolocarbazole 186 could be found in 3.5% yield. This outcome was rationalized as a result of the intermediacy of a spiroindolenine species formed under these conditions [89H(28)175]. During detailed studies on the polymerization of indole, formation of a low yield of the related indolo[3,2-h]carbazole 187 was discovered in the product mixture originating from the treatment of indole with p-toluenesulfonic acid at elevated temperature [88JCS(P1)2387]. In an investigation of the condensation of p-benzoquinone with 4-substituted anilines, an indolo[3,2-h]carbazole derivative has been reported to be formed in 2% yield (80JOC1493). 

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). 

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). 

As part of a programme designed to produce compounds with axial chirality, double Bischler-Napieralski reactions were carried out with oxamide derivatives of co-arylalkylamines. Thus, treatment of the oxamide derived from 3,4-dimethoxy- P -pheny lethylamine with pyrophosphoryl chloride in acetonitrile gave 1 in 84% yield, as expected. An attempt was then made to extend this double cyclisation protocol to the oxamide derived from 2-(3-methoxyphenoxy)ethylamine. Reaction of this latter compound under the same conditions used for the formation of 1, however, gave 2 in 81% yield instead of the expected product of a double Bischler-Napieralski reaction. 

The Pictet-Spengler and Bischler-Napieralski reactions are used to prepare biologically and pharmocologically important isoquinoline ring systems. Versions of these reactions have also been proposed in biosynthetic pathways. Under mildly to strongly acidic conditions, the cyclizations... 

Bischler-Napieralski cyclodehydration of amides.1 This reaction is traditionally effected with P205 or ZnCl2. It can also be effected under neutral conditions with (C6H5)3P and CCU (equation I). 

Acylation of the well-known Bischler-Napieralski product, 1-benzyl-3,4-dihydroisoquinoline, with ethyl chloroformate gave a mixture of two carbamates, E isomer 118 and Z isomer 119 in the ratio of 1 2, which were readily assigned from their UV and NMR spectra and underwent cycliza-tion on irradiation under either nonoxidative or oxidative conditions to afford the 8-oxoberbine 120 or aporphine skeleton 121 (104,105). Irradiation of either the E or Z enamide, (118 or 119) or their mixture quickly... 

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