Bischler-Napieralski cyclisation

Of the well-known methods to prepare isoquinolines, including the Pictet-Spengler and Bischler-Napieralski cyclisation, the Pomeranz-Fritsch reaction is the only direct generally accepted method for the construction of the fully unsaturated isoquinoline ring system. 

Trisphaeridine, [8]. The synthesis [9] of trisphaeridine (17) (Scheme 4) involved the known aryl boronic acid 18 and the sterically unencumbered o-bromophenylcaibamate 19 as coupling partners in the Suzuki reaction. The biaryl 20, thus obtained in customary good yield, underwent a Bischler-Napieralsky cyclisation with phosphorus oxychloride to afford the chlorophenanthridine 21. The latter on catalytic dechlorination furnished 17. 

The latter when subjected to a second Ullmann condensation with bromomethoxyphenylacetic acid produces the acid (83). Removal of the /v-butyry1 group and internal amide formation, followed by Bischler-Napieralski cyclisation, A -methy1ation and reduction gives a mixture of diastereoisomeric bases of structure (84), one of which has been reduced to the 4 -benzyl compound and completely 0-demethylated to the tetrahydric phenol (85). This is cyclised to the dioxin by hydrobromic acid at 140°, methylated with diazomethane and reductively debenzy-lated to trilobine (86). The other isomer of the base (84) has been similarly converted into obaberine, the C-1 epimer of trilobine (Y. Inubushi et al.. Tetrahedron Letters, 1976, 2857 Chem.Pharm.Bull., 1977,, 1636). 

Isochromanones on condensation with p-phenylethyl amines, followed by Bischler-Napieralski cyclisation and NaBH reduction furnish berbine alkaloids in good to excellent yields. The 7,8-dimethoxy and mcthylenedioxy isochromanones prepared by lithiation methods provide the 9,10-oxygenated berbine alkaloids, such as tetra-hydropalmatine 51a canadine stylopine 57c , sinactine... 

Condensation of isochromanones with tryptamine followed by Bischler-Napieralski cyclisation and NaBH reduction provide the Yohimbane skeleton... 

With the related 6-methoxy compound shown the cyclisation to a morphinan with hydrochloric acid proceeded to the unwanted product C in 37% yield and the desired one in only a 3% yield (ref. 179). The same precursor, synthesised from 2-(3-methoxyphenyl)ethylamine and 3,4-dimethoxyphenylacetic acid by amide formation and ring closure by the Bischler-Napieralski cyclisation, followed by reduction, methylation and Birch reduction, was used by others with similar results (ref. 180). The route constitutes a synthesis of morphine by the use of the final steps of earlier work (refe. 169,171), albeit in low yield, although in considerably fewer steps than the earlier syntheses. 

Catalytic hydrogenation of alkene 62 proceeded in a completely facially selective manner to give the C7-arylated perhydroindole 63 (quant.) that was then subjected to treatment with phosphoms oxytrichloride and so effecting a Bischler-Napieralski cyclisation reaction to give the lactam 64 (81%). Upon reduction with lithium aluminium hydride this lactam provided ( )-y-lycorane [( )-54] in 84% yield. 

From this key intermediate various alkaloids could be obtained by two separate routes. Firstly, Bischler-Napieralski cyclisation, reduction and hydrolysis of the hydrazone by the method of Corey and Knapp (1976) afforded protoemetine (11), which was converted via cephaeline into emetine (3) (Brossi et al. 1971). Condensation of (10) with tryptamine gave a 3 1 mixture of deoxytubulosine(12a)and deoxy-isotubulosine (12b) identical with authentic samples. Alternatively, the hydrazone in (10) was hydrolysed first, and the aldehyde condensed with tryptamine to give two epimers (14a,b) which were then converted into (12a) and (12b). 

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. 

Anhydrolycorinone, Hippadine, Oxoassoanine. The recent syntheses [14] of anhydrolycorinone (201), hippadine (202) and oxoassoanine (203) once again made use of the Suzuki reaction and a very mild and efficient reagent for effecting Bischler-Napieralsky type cyclisations (Scheme 37). Thus the 7-arylindole 223 obtained from the arylboronic acid 224 and the bromoindole 225 in high yield, was reduced with sodium cyanoborohydride in acetic acid to provide the indoline 226, which was converted into the methylcaibamate 227. 

A novel syrTEhesis of the aporphine system has been achieved from the diphenylethylamine (149) by condensation with diethyl oxalate followed by Bischler-Napieralski ring closure to the dihydroisoquinoline (150) and further cyclisation with polyph-osphoric acid to the oxoaporphine (151). A -methylation and reduction of this gave the trimethoxyaporphine 0,iV-dimethyl-tuduranine (M. Grecke and A. Brossi, Helv., 1979, 62. 1549). 

An alternate approach to the fused heterocyclic compounds is the intramolecular cyclisation at an aromatic position. The Bischler-Napieralski reaction for the synthesis of the isoquinoline ring system illustrates this approach. 

The failure of the usual acid-catalysed cyclisation methods to furnish specific methoxy substituted heteroaromatic compounds may be illustrated with the synthesis of 8-methoxy isoquinoline by Bischler-Napieralski reaction. In this, the starting compound is the acyl derivative of meta methoxy p-phenylethylamine. This, in the acid catalysed ring closure reaction, furnishes the 6-methoxy isoquinoline (5) rather than the 8-methoxy isomer (6). 

The preparation of some novel pyrimido[4,5-6][l,4]benzothiazepines has been described employing a Bischler-Napieralski-type cyclisation on pyrimidine amide derivatives... 

Condncting the Bischler-Napieralski seqnence with a potentially unsaturated aryl-ethanamine, a fully aromatic isoquinoline can be obtained directly. The amide of a 2-methoxy- or 2-hydroxy-2-aryl-ethanamine is heated with the nsnal type of cyclisation catalyst. It is not clear whether dehydration to an unsaturated amide or to an oxazolidine is an initial stage in the overall sequence. 

Arylethanamines react with aldehydes easily and in good yields to give imines. 1,2,3,4-Tetrahydroisoquinolines result from their cyclisation with acid catalysis. Note that the lower oxidation level imine, versus amide, leads to a tetrahydro- not a dihydroisoquinoline. After protonation of the imine, a Mannich-type electrophile is generated since these are intrinsically less electrophilic than the intermediates in Bischler-Napieralski closure, a strong activating substituent must be present, and appropriately sited on the aromatic ring, for efficient ring closure. 

The synthetic plan devised for lavendamycin (40) by Kende and Ebetino was based on Bischler-Napieralski reaction. The key synthon (42) representing the AB fragment, was obtained by a straightforward preparation from 8-meth-oxyquinaldic acid (41) by sequential nitration at C-5 and bromination at C-7. Subsequent coupling reaction of 42 and P-methyltryptophan (43) formed the amide 44 which was cyclised to the pentacyclic intermediate (45) as present in the skeleton of lavendamycin. The desired functionalisations of ring A in 45 to obtain the methyl ester of 40 are summarised in Scheme 5. 

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