Benzomorphans synthesis

Tetralone intermediates also offer approaches to 6,7-benzomorphan synthesis. The 1-tetralone (35, Scheme 4.4) may be prepared in five stages from 1-cyano-l-phenylmethane (a-methylphenylacetonitrile) (hydratropo-nitrile) (30).(7) Significant yield losses may occur during the reverse-addition LAH reduction of (31). From the tetralone (35) the synthesis proceeds in a... 

Using a similar synthetic concept as that described above (O Scheme 14 and O Scheme 16), utility of the per-O-pivaloylated D-galactosylamine 48 as a chiral auxiliary was broadened to the benzomorphan synthesis by the Kunz group [72] (O Scheme 17 and Scheme 18). The... 

A rather unusual reaction forms the key step in the preparation of a benzomorphan bearing a fatty side chain, The scheme used to form the benzomorphan nucleus, which is patterned after the Grewe synthesis originally developed for... 

The regiochemical course reacting saturated ketones depended on the substitution pattern of the a-positions. In most cases, the intermediate oxime had an anti N-OH function with respect to the chain branched a-position. Consequently, the more substituted alkyl group preferentially migrates. This advantage was utilized for synthesizing the spiro a-amino-e-caprolactam (202 203, Scheme 38) [12c], the Mexican bean beetle azamacrolide allomone (205 206, Scheme 39) [44 a], in a key step of the chiral synthesis of benzomorphanes... 

Omission of the phenolic group from cyclazocine results in a molecule which retains analgesic activity. In a classical application of the Grewe synthesis,15 the methylated pyridinium salt 54 is condensed with benzylmagnesium bromide. There is thus obtained the dihydropyridine 55. Treatment of that intermediate with sodium borohydride results in reduction of the iminium function to afford the tetrahydro derivative 56. Cyclization of 56 on treatment with acid leads to the desired benzomorphan nucleus. The cis compound (57) is separated from the mixture of isomers and demethylated by the cyanogen bromide procedure (58,... 

In recent years much attention has been paid to the synthesis of benzomorphane heteroanalogs in which a benzene ring has been replaced by a heteroaromatic one. Syntheses of substituted thieno[3,2-/]morphanes (derivatives of thieno[2,3-d]-azocine) described in Ref. 75JHC651 consists of the condensation of cyanopyri-dines 120 with 2-thienyllithium, reduction of the resulting ketones into thienylmethylpyridines, quaternization and reduction of the quaternary salts with sodium borohydride to form piperidines 124 and 125. Intramolecular cyclization of the latter leads to the formation of thieno[2,3-d]azocines 126 (Scheme 34). 

The double bond of A3-piperideines can be used to activate and control the functionalization of the six-membered ring. For example, studies on the synthesis of the benzomorphans require 2-benzyl-A3-piperideine derivatives. One approach to these compounds has been... 

Grauert, M., Bechtel, W. D., Ensinger, H. A., Merz, H., Carter, A. J. Synthesis and structure-activity relationships of 6,7-benzomorphan derivatives as antagonists of the NMDA receptor-channel complex, J. Med. Chem. 1997, 40, 2922-2930... 

SCHEME 24. General synthesis of moiphine, benzomorphans, and morphinans. 

The reduction of tri- and polysubstituted pyridinium ions has not received extensive attention, and generalizations are not available. A 1,2,4-trisubstituted pyridinium ion has been shown to form a 1,2,3,6-tetrahydropyridine,15 and 1,3,4-trisubstituted pyridinium salts (49) are reported to give 1,2,5,6-tetrahydropyridines (50) which were useful as intermediates in the synthesis of benzomorphans (51).40-43 As discussed above, those pyridinium ions having substituents on both the 3- and 5-positions usually lead to stable dihydro-pyridines on reduction with sodium borohydride.43 ... 

In the morphinan series, the preparation of 3-alkyl-morphinans222 and 3-mercapto-morphinans223 has been described. In the benzomorphan series, a novel cleavage of aryl benzyl ethers and of aryl allyl ethers has been described and used in an improved synthesis of pentazocine. The lactam (162), on hydrogenolysis, gives the benzomorphan (163 R1 = R2 = H). Treatment of this with dimethylallyl... 

Regiospecific inverse electron demand Diels-Alder reactions of enamines with 1,3-diazines or 1,2,3- and 1,2,4-triazines (see Section III.D.l), which on elimination of HCN or N2, respectively, produce a pyridine ring, can be used with 1,3,5-triazines and 1,2,4,5-tetrazines as a useful method for the synthesis of pyrimidines214-216 (1,3-diazines) and pyridazines217-219 (1,2-diazines). Examples of the use of this methodology are the preparation of the pyrimidine substituted benzomorphane 356 (equation 77)219 and the pyridazine 359 (equation 78), intermediate in the total synthesis of cis- and trans-trikentrin A216. 

Some l-alkyl-2-benzyl-3-piperideines (185) were used in the Grewe synthesis of the benzomorphane-like analgesics (186). The ring closure between the ortho position of the benzyl residue and position 4 of the 3-piperideine nucleus was usually accomplished by heating in 48% hydrobromic acid or 85% phosphoric acid.41,103,188-193... 

The chemistry of such bridged naphthalenes-benzomorphans and some related compounds has been reviewed previously.<1 3) The first synthesis of a benzomorphan was achieved by Barltrop(4) however, prior to that synthesis, Schopf,(5) in his investigations of the structure of morphine, had isolated the benzomorphan, 2, from a thionyl chloride-induced, second-order Beckmann rearrangement of dihydrocodeinone oxime, 1. Reinvestigation(5a,5b) of the Beckmann rearrangement and a study of the Schmidt reaction of 6-oxomor-phinans confirmed Schopf s work and led to the isolation of the anticipated lactam (2a). 

Inoue and May(21) later modified the preceding synthesis with the presence of an 8-methoxyl substituent (Scheme 4.8). The key intermediate dihydronaphthalene (66) gave on treatment with mercuric acetate 8-methoxy-2,lla-dimethyl- la-hydroxybenzomorphan (67) in 49% yield, 5% of the 11/3-methyl isomer (69) and 13% of the la-acetate (68) corresponding to 67. Transformation to the desired 11-epimeric benzomorphans 70 and 71 was by standard methods. 

In analogy to a synthesis of morphinans from 1,2,3,4,5,6,7,8-octahy-droisoquinolines by Grewe,(22,23) May and Fry<24) prepared benzomorphans (Scheme 4.9). Treatment of 3,4-dialkyl or 4-alkylpyridinium methiodides with either benzyl or p-methoxybenzylmagnesium chloride in ether readily gives... 

Other substituted piperidines, particularly piperidinols, have been exploited as benzomorphan precursors. The first 6,7-benzomorphan lacking a 6-alkyl substituent, the parent heterocycle, was reported by May et al. in 1968<43,44) in a synthesis from 2-cyano-4-phenylpyridine (102) (Scheme 4.15). The 2-carbomethoxypiperidine (103) was prepared readily, but it proved resistant to direct cyclization to 3-methylbenzomorphan-l-one (105) with polyphosphoric acid, presumably because the more stable 2,4-diequatorial isomer is not favorable for ring closure for geometric reasons. Hydrolysis to the corresponding acid (104), however, gives an intermediate that closes to 105 in 94% yield. The parent heterocycle 106 is produced by standard techniques. 

A series of unusual amidinium benzomorphans has been described by Strauss et a/.<53 55) where some members of the series exhibit narcotic antagonist properties. Their synthesis involves a meta bridging process of di- and trinitronaphthalenes (116) with a-phenyl N,N-dimethylacetamidine (117) to produce two isomeric benzazocine amidinium nitronates as their a-phenyl-N,N-dimethylacetamidinium salts (AmH+). The benzomorphan 118 is formed in ethanolic solution, whereas the isomeric benzazocine (119) results from reaction in dimethylsulfoxide. 

Considerable difficulties were encountered in attempts to apply standard synthetic routes to the synthesis of the parent nucleus, 1,2,3,4,5,6-hexahy-drobenzazocine (or benzomorphan) (106). Ultimately, a route based upon 2-cyano-4-phenylpyridine (102) was successful (Scheme 4.15, p. 173). 

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