Cyclization Bischler-Napieralski

The Bischler-Napieralski cyclization of a brominated tetrahydrobenzyl-isoquinoline formamide was employed to obtain the desired 2,3,9,10-substitution pattern required for a synthesis of cheilanthifoline  

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Bischler-Napieralski cyclizations azepine synthesis by, 7, 532 Bischler-Napieralski synthesis, 2, 72... 

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. ... 

Martin has achieved the synthesis of lycoramine (59) via a Bischler-Napieralski cyclization of 58 in the final step of the synthesis. Treatment of 58 with POCI3 followed by NaBHi provided the natural product 59 in 68% yield. 

The reactions of (174) with various amines has been studied." " Hydrolysis of the hexamine salt of (174) gave not the symmetric diamine but (184) via a cyclic intermediate. The pyrolysis of 5-methyl-2-thenyltrimethyl ammonium hydroxide (185) is claimed to give (186) through a 1,6 Hofmann elimination reaction. The Bischler-Napieralski cyclization has been applied to acetyl derivatives of 2-(2-thienyl) ethylamine and 2-(3-thienyl) ethylamine for the preparation of sulfur analogs of isoquinoline. ... 

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). 

Products of Bischler-Napieralski cyclizations discussed thus far have been reduced in order to afford the desired biologically active compounds. Occasionally, the products obtained directly from the... 

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... 

Bischler-Napieralski cyclization of pyridazin-6-one 134 with POCI3, and subsequent hydrogenation of the cyclized product 135 over Pt02, gave rise to 2,3,4,6,7,llZ -hexahydro-l//-pyridazino[6,l-fl]isoquinoline (51) (75CPB3056). Treatment of Reissert compound 136 with NaH gave 116-cyano-l, 2,3,116-tetrahydro-4//-pyrido[2,l-fl]phthalazin-4-one (137) (80JHC433). 

Bischler-Napieralski cyclization of N- formyl-3-phenylpropylamine yields not the desired 4,5-dihydro-3f/-2-benzazepine, but its dimer, 3,4,10,ll-dibenz-l,8-diazacyclotetradeca-1,3,8,10-tetraene (78) (73AP271). 

Bischler-Napieralski cyclizations of N-acyl-y-phenylpropylamines, with P2Os in xylene, with PPA (or its ester), or with POCl3 and A1C13 mixtures, are valuable routes to 4,5-dihydro-3//-2-benzazepines (76HCA623,77HCA1644), and to ll//-dibenz[6,e]azepines <76JCS(P1)1279>. 

Formation of this bond has been achieved in Bischler-Napieralsky cyclizations leading for example from (179) to (180) (68CRV747, p. 768) and from (181) to the dibenzo[6,e] [l,4]diazepine system (67AHC(8)21, p. 74). 

Benzothiazepines of type (401) can be prepared by the Bischler-Napieralsky cycliz-ation of N- (arylthioethyl)benzamides and reactions of the same type have been used in the synthesis of dibenzo[6,/][ 1,4]thiazepines (70JHC409). 

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. 

Immediate sodium borohydride (NaBfLt) reduction gave lactam 44. Bischler-Napieralski cyclization of 44 followed by NaBfLt reduction yielded ( )-methyl-0-acetyl-isoreserpate (45). The correct stereochemistry at C-3 was obtained by first lactonizing compound 45 epimerization with pivalic acid then resulted in ( )-reserpic acid lactone (47). Treatment with base followed by acylation with TMBCI yielded racemic reserpine. The stereochemical considerations involved in the epimerization reaction will be discussed later. 

The synthesis continued with the formation of the 2-azabicyclo[3.3.1]nonane ring (D, E-rings), and epimerization of the cyano group at C-20 to an axial position. Closure of the C ring using a Bischler-Napieralski cyclization gave the quaternary indole alkaloid, ( )-melinonine-E (159). A closely related analog, ( )-strychnoxanthine, was also synthesized by a similar method [67]. 

The cyclohexene 121, which was readily accessible from the Diels-Alder reaction of methyl hexa-3,5-dienoate and 3,4-methylenedioxy-(3-nitrostyrene (108), served as the starting point for another formal total synthesis of ( )-lycorine (1) (Scheme 11) (113). In the event dissolving metal reduction of 121 with zinc followed by reduction of the intermediate cyclic hydroxamic acid with lithium diethoxyaluminum hydride provided the secondary amine 122. Transformation of 122 to the tetracyclic lactam 123 was achieved by sequential treatment with ethyl chloroformate and Bischler-Napieralski cyclization of the resulting carbamate with phosphorus oxychloride. Since attempts to effect cleanly the direct allylic oxidation of 123 to provide an intermediate suitable for subsequent elaboration to ( )-lycorine (1) were unsuccessful, a stepwise protocol was devised. Namely, addition of phenylselenyl bromide to 123 in acetic acid followed by hydrolysis of the intermediate acetates gave a mixture of two hydroxy se-lenides. Oxidative elimination of phenylselenous acid from the minor product afforded the allylic alcohol 124, whereas the major hydroxy selenide was resistant to oxidation and elimination. When 124 was treated with a small amount of acetic anhydride and sulfuric acid in acetic acid, the main product was the rearranged acetate 67, which had been previously converted to ( )-lycorine (108). 

The structures of the ds-hydroindole 130 (Ar = Ph) and the trans-hydroindole 131 (Ar = Ph) were established by their conversion to ( )-a- and ( )-(3-lycorane (57 and 58), respectively. In the event, catalytic hydrogenation of the double bond in the hydroindoles 130 and 131 (Ar = Ph) over 5% Pd/C in AcOH proceeded with concomitant N-debenzylation to provide the corresponding secondary amines, which were then allowed to react with methyl chloroformate to furnish the corresponding carbamates 132 and 133. On heating in POCl3, 132 and 133 underwent Bischler-Napieralski cyclization to provide the 7-oxo-a- and -(3-lycoranes 134 and 135, which were then converted to 57 and 58, respectively, by reduction with LiAlH4. 

Ellipticine and olivacine have both been synthesized via a Bischler-Napieralski cyclization and subsequent aromatization of alkylamidocarbazoles, as shown for the preparation of compounds (181) (Equation (81)) <90JOC4528>. 

A synthesis of takatonine-like compounds (25 R = H) has been reported, by Bischler-Napieralski cyclization to (25 R = CH2Ph) followed by routine transformations, and the correlation between chemical shifts in the n.m.r. spectra and the conformation of the isoquinoline system has been examined.38... 

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