Bischler—Napieralski cyclization reaction

Af-Aroyl derivatives of a-aminonicotyrine (99) underwent the Bischler-Napieralski cyclization reaction to give l/f-pyrrolo[3,2-c][l,8]naphthyridine products (38) in excellent yield, the first example of the preparation of pyrrolonaphthyridine compounds being reported in 1960 (Equation (26)) <60JCS1509>. 

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. ... 

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... 

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). 

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 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 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. 

A total synthesis of a mixture of diastereoisomers having the constitution of magnolamine was reported recently by Kametani and Yagi 26). Arndt-Eistert reaction of 3-methoxy-4-benzyloxyphenethylamine with the diazoketone prepared from the acid chloride XLVII furnished the diamide LI. Bischler-Napieralski cyclization of the latter afforded the dihydroisoquinoline derivative XLIX, whose methiodide was reduced with sodium borohydride to the stereoisomers of constitution XLV. Debenzylation of the latter mixture gave a noncrystalline product which behaved similarly on paper chromatography to magnolamine and had IR- and UV-spectra which were superimposable on those of the alkaloid. 

Regarding synthetic studies, the syntheses of ( )-latifine (437) (200), of ( )-cherylline (440) and ( )-latifine (437) (201), and of ( )-0,0-dimethylcherylline (445) and ( )-6>,0-dimethyllatifine (446) (202) have been performed using the Pomeranz-Fritsch-type cyclization (Scheme 51), the Bischler-Napieralski-type reaction (Scheme 52), and intramolecular nucleophilic addition of aryllithium (generated by butyllithium) to a carbonyl group (Scheme 53). 

The open-chain tautomers 24b and 25 of precursor incipient imidazolidine and perhydropyrimidine derivatives, which bear a six carbon transferable fragment, on acid-catalyzed reactions with tryptamine formed the diester 85. A similar reaction of 24a leads to quantitative formation of 86 and the reaction of 25 with tryptamine is appreciably faster than that of 24b. Sodium cyanoborohydride/acetic acid reduction of 85 was accompanied by intramolecular aminolysis to form piperidone 87. Its Bischler-Napieralski cyclization followed by borohydride reduction gave cis- and trara-isomers of indoloquinolizine ester 88, which on hydrolysis to acid and subsequent methylene lactam rearrangement gave methylene lactam 89. Its DIBAL reduction gave 18- or-deplancheine 84a (88T6187). 

Related work not directly dealing with total synthesis of proaporphine, aporphine, or homoproaporphine alkaloids has appeared. A series of homopro-aporphine-type compounds (110) have been prepared, as shown in Scheme 9.12 7 Compound (106), readily prepared from 3,4-dimethoxy-/ -phenethylamine and the appropriate keto-acid derivative, was transformed by reduction and acetylation to (107). Acetylation effectively blocked any complications from the cyclohexane oxygen function during the subsequent Bischler-Napieralski cyclization. Consecutive reduction, alkylation, and hydrolysis gave the key intermediate (109) which was transformed into the tetracyclic spiro-system (110) by reaction with polyphosphate ester under strictly defined conditions. Other conditions and... 

Total syntheses of ( )-capaurine (194 R1 = R2 = R4 = R5 = Me, R3 = OH),209 ( )-isocorybulbine (195 R1 = Me, R2 = R3 = H, R4 = R5 = OMe),202 ( )-kikemanine (194 R1 = R2 = R4 = Me, R3 = R5 = H),210 and ( )-0-methylcaseadine (202)211 have been reported. In all cases, conventional routes involving Bischler-Napieralski cyclization to form benzylisoquinoline derivatives and subsequent insertion of the C(8)-carbon by reaction with formaldehyde were adopted. A further example of para-activation by an ethoxycarbonyl-amino-function for the Bischler-Napieralski reaction may be noted.211 In the synthesis of capaurine, the presence of the bromo-function in compound (203) forced the Mannich reaction with formaldehyde to produce the tetracyclic derivative (204) rather than the normally more favourable mode of cyclization para to the hydroxy-group. Debromination was effected at a later stage with zinc powder in 50 % acetic acid solution.209... 

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

Meutermans and Alewood [48] reported the solid-phase synthesis of tetrahydroisoquinolines 13 and dihydroisoquinolines 13a using the Bischler-Napieralski reaction (Fig. 5). The polystyrene resin-bound deprotected L-3,4-dimethoxyphenylalanine was acylated with acetic acid derivatives using N- [(IH-benzotriazol-1 -yl)(dimethylamino)methylene] -iV-methylmethana-minium hexafluorophosphate A-oxide (HBTU) as a coupling reagent. The product obtained was then treated with phosphorus oxychloride under optimized conditions to afford a Bischler-Napieralski cyclization. Hutchins and Chapman [49] reported the synthesis of tetrahydroisoquinolines 13b and 4,5,6,7-tetrahydro-3H-imidazol[4,5-c]pyridines 14 via cyclocondensation of the appropriate dipeptidomimetic with various aldehydes (Fig. 6). 

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],... 

The Bischler-Napieralski cyclization is a classic reaction for the synthesis of heterocycles such as quinolines and isoquinolines. Thus, early efforts were devoted to the application of this transformation within this series of compounds (via activation of a carbamate or an analogue), along with known variants (using Vilsmeier-like intermediates, isocyanates, or activated ami-dines). These types of cyclization would produce the desired 6-azaindole at the correct oxidation state. To our dismay, none of these approaches provided the desired target. Instead, they resulted in either no reaction, decomposition, or unproductive reaction. 

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