Bischler-Napieralski cyclizations, amides

In some instances the attack of the arene on the nitrilium salt occurs at the ipso carbon rather than the ortho carbon. For example, the Bischler-Napieralski cyclization of phenethyl amide 10 affords a 2 1 mixture of regioisomeric products 11 and 12. The formation of 12 presumably results from attack of the ipso aromatic carbon on the nitrilium salt 13 followed by rearrangement of the spirocyclic carbocation 14 to afford 15, which upon loss of a proton vields product 12. ... 

One of these products (49) was used as a key intermediate for the synthesis of the Amaryllidaceae alkaloids a- and /-lycorane (Scheme 12)53. A copper-catalyzed Grignard reaction with 49 afforded 50 via a selective y-anti displacement of the chloride. Hydrogenation followed by Bischler-Napieralski cyclization gave 51. Interestingly, reversal of the latter two steps gave the isomer 52 where an epimerization at the benzylic carbon had occurred in the cyclization step (>99% selectivity). Subsequent reduction of the amide in each case afforded the target molecules a- and y-lycorane, respectively. The purity of the final product was very high with respect to the opposite stereoisomer. Thus <0.2% of /-lycorane was present in a-lycorane and vice versa. 

Similarly to 8-lactone 260, y-lactone 263, prepared also from ( )-norcamphor (228), proved to be another useful intermediate for the synthesis of all four corynantheidol stereoisomers as well as of the corresponding 18,19-didehydro derivatives. Cleavage of the a-diketone monothioketal moiety in 263 and the formation of amide 265 by its reaction with tryptamine, followed by Bischler-Napieralski cyclization and sodium borohydride reduction, resulted in a mixture... 

Amides are often cleaved with strong alkali. Fabio Prati of the University di Modena has reported (Organic Lett. 2004,6,3885) that treatment of triphenyl phosphite with chlorine at -30 "C gives a substance that reacts smoothly with amides such as 5 to give the amine 6 as the HC1 salt. The imino chloride is the intermediate, so this also provides a convenient entry to Bischler-Napieralski cyclization. 

The first total synthesis of ( + )-dauricine was reported by Kametani and Fukumoto in 1964 (18,19). Arndt-Eistert reaction of homoveratryl-amine with the acid chloride XIX afforded the amide XXII. Bischler-Napieralski cyclization of the above amide gave the dihydro isoquinoline derivative XXIV, the methiodide of which when reduced with zinc dust and ethanol-hydrochloric acid afforded + )-dauricine. The identity of the synthetic product with ( )-dauricine w as concluded through a comparison of its physical properties (spectra and chromatographic behavior) with those of an authentic sample of the alkaloid. Melting-point determination of a mixture of derivatives of the two specimens is not recorded. 

Bischler-Napieralski cyclization of amide 8, readily obtained by reaction of 5-methyl-tryptamine with 2-cyclohexyl acetyl chloride (75%)... 

In the catalytic Lonza process reported in Fig. 23, the unstable imine 67 was prepared in two steps from 2-cyclohexen-l -yl ethylamine and 4-methoxyphenylacetic acid via amide formation and Bischler-Napieralski cyclization to the hexahydroisoquinoline. To obtain more... 

The Bischler-Napieralski cyclization can be properly directed by means of bromination of ring a of the amide precursor, and a biogenetically patterned... 

Treatment of the oxygenated biphenyl (842) with lead(iv) acetate affords the complex benzofuran (843), as shown by X-ray analysis. The benzylidene-isoindolinone (844) cyclizes to compound (845) in polyphosphoric acid. The novel l,2-dihydroindolo[l,7-fl6][l,5]benzodiazepines (847 R = H, Me, or Ph) are formed by Bischler-Napieralski cyclization of the amides (846)/ iV-Acyl-... 

Angular, e.g. (197), rather than linear isoquinolines are formed by Bischler-Napieralski cyclization of (2-naphthylethyl)amides of type (196) (Scheme 80). ... 

There are two problems to be solved in perfecting the benzylisoquinoline approach synthesis of 7,8-substituted benzylisoquinolines with appropriate functional groups and formation of the oxepine ring. Bischler-Napieralsky cyclization of amides (66) is known to afford 6,7-substituted benzylisoquinolines. To avoid this unwanted reaction, two new approaches have been developed, namely, activating position C-2 and blocking position C-6. 

Acyliminium ions are also derived from rearrangement of Bischler-Napieralski cyclization products, which are obtained from amide product of reaction of arylethylamines and 2-methoxycarbonyl benzoyl chloride. These can be captured, for example, with methoxide anion (Scheme 43) (94TL(35)2751). 

As with the PictetASpengler reaction, the Bischler-Napieralski cyclization has been used in alkaloid synthesis. For example, a synthesis of yohimbine and related alkaloids began with enantiomerically pure amide [364],... 

It is relevant to point out that Fodor and co-workers have shown that nitrilium cations are intermediates in the Bischler-Napieralski cyclization whenever secondary amides are used. A nitrilium ion was trapped as its crystalline hexafluoroantimonate salt. ... 

Homoxylopinine, a synthetic B-homotetrahydroprotoberberine, was obtained along standard lines from the amide of a y-substituted propylamine via Bischler-Napieralski cyclization and subsequent Mannich condensation. ... 

The acid 17 was converted to its acid chloride using oxalyl chloride, and further reaction with A-methylhomopiperonylamine provided the amide 19. Bischler-Napieralski cyclization led to the key dehydrophthalideisoquinoline 20, and catalytic hydrogenation supplied the desired adlumidine and bicucul-line. ... 

The structure of the azafluoranthene telitoxine (31a) has now been confirmed by synthesis (Scheme 1.2). Condensation of 3,4-dimethoxyphenethy-lamine (36) with 2-nitro-5-benzoyloxybenzoyl chloride (37) gave an almost quantitative yield of an amide (38) which on Bischler-Napieralski cyclization afforded an excellent yield of the dihydroisoquinoline (39a). Catalytic reduction in ethanolic hydrochloric acid furnished the iminoaminophenol (39b). 

In the initial applications of Diels-Alder chemistry to yohimbine alkaloid synthesis, the Kametani (24-27) and Takano (28) groups have both examined reactions between furan derivatives and maleic anhydride. In the initial investigations of Kametani and his coworkers (24) (Scheme 3.10), the Diels-Alder adduct (57) of furan and maleic anhydride underwent bromolactonization to give the tricyclic carboxylic acid 58 (94). This compound has four [C(15), C(16), C(17), and C(18)] of the five contiguous stereocenters of the reserpine E-ring in place. Acid 58 was converted to diazoketone 59 which underwent Wolff rearrangement followed by tryptamine trapping to afford amide 60. Bischler-Napieralski cyclization of this substance afforded the tetracyclic... 

This methodology was initially applied to a synthesis of (—)-alloyohimbane (82) (Scheme 3.13) (29). Readily available levoglucosenone (75), a product of cellulose pyrolysis, was the starting material. Diels-Alder reaction of 75 with 1,3-butadiene afforded adduct 76 which underwent Wolff-Kishner elimination and subsequent acylation to provide the bicyclic enol ether 77. Hydrolysis followed by oxidation and saponification afforded hydroxymethyl lactone 78 which was then condensed with tryptamine to yield the amide diol 79. Periodate cleavage of the diol was followed by conversion to chloride 80 which was cyclized to afford lactam 81. Subsequent Bischler-Napieralski cyclization followed by hydrogenation of the olefin moiety afforded the target ( )-alloyohimbane (82). 

The synthesis began with the silver ion catalyzed reaction between diazoketone 453 and tryptamine which afforded amide 454. When 454 was subjected to Bischler-Napieralski cyclization conditions, tetracyclic ester 455 formed along with the pentacyclic lactam 456 containing a trans DE-ring fusion. Treatment of 455 with mild base effected cyclization to produce the cis-fused pentacyclic lactam 457 which was reduced to provide alloyohim-bane (82). Alternatively, lactam 456 was reduced to provide 458, a substance which Ninomiya had previously converted to yohimbane (120) (61). 

An interesting D-ring closure was used by Pakrashi and his coworkers to synthesize normalindine (466) and norisomalindine (467) (Scheme 3.81) (130). Imine 462, prepared by condensation of tryptamine and 3-acetylpyridine, was reduced and the formed amine was acetylated to afford amide 463. Bischler-Napieralski cyclization of 463 provided tetracyclic iminium bis-perchlorate salt 464 which when treated with triethylamine and pivaloyl chloride underwent a second cyclization to yield the pentacyclic enamine 465. Reduction of the olefinic group in 465 afforded the desired azayohimbines, 466 and 467. 

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). 

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. ... 

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 ... 

Enantiospecific syntheses of amino derivatives of benzo[ ]quinolizidine and indolo[2,3- ]quinolizidine compounds have also been achieved via A-acyliminium ion cyclization reactions, as an alternative to the more traditional Bischler-Napieralski chemistry (see Section 12.01.9.2.2). One interesting example involves the use of L-pyroglutamic acid as a chiral starting material to construct intermediates 240 via reaction with arylethylamine derivatives. Diisobutylaluminium hydride (DIBAL-H) reduction of the amide function in 240 and subsequent cyclization and further reduction afforded piperidine derivatives 241, which stereoselectively cyclized to benzo[ ]quinolizidine 242 upon treatment with boron trifluoride (Scheme 47) <1999JOC9729>. 

Alternatively, a P-methoxy-P-phenylethylamine can be used to circumvent the oxidation step after the conventional Bischler-Naperialski cyclization. Here, when treated with the phosphorus reagent the amide (R = OMe) undergoes both cyclization and the elimination of methanol to give the isoquinoline (R = H) directly. This is known as the Pictet-Gams modification of the Bischler-Napieralski synthesis. 

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. 

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