Substituted Benzomorphans

Benzomorphans substituted in the 11-position are readily derived via the 2-tetralone route (Scheme 4.1, p. 156) or from pyridines possessing a 3-substituent, usually alkyl (Scheme 4.9, p. 165). Synthesis from 1-tetralones is less useful. Compounds without an 11-position substituent are best prepared by the Grewe route (Scheme 4.9, p. 165), although the 1-tetralone route may be exploited. Eddy and May(1) have summarized work prior to 1965. 

Few benzomorphans substituted in the piperidine bridge 4- and 5-positions have been reported. 4,6-Dimethyl- and 5,6-dimethylbenzomorphans with both agonist and antagonist N-substituents have been synthesized 119) and the products demonstrated by H-nmr to bear the 4- and 5-methyl substituents in an equatorial conformation on the piperidine chair (193 and 194, respectively.) Traces of the axial epimers were also detected. 

The synthesis of benzomorphans substituted in the 11-position from a 2-tetralone (Scheme 4.2, p. 157) involves either thionyl chloride dehydration of an 11-methylcarbinol (13a)(9) or a pyrolysis of the corresponding acetate perchlorate (136)methylene derivative (14). Carbocation-mediated processes in bridged compounds of this type are likely to give rearrangement byproducts. Kugita and Takeda(124) isolated from the thionyl chloride route an unstable chloride (203), and the indenotetrahydropyridine (204). Other reports(30 96a,125) of unidentified products from these reactions resulted in an investigation 126 127 of both pathways (Scheme 4.20). 

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... 

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recent years much attention has been paid to the synthesis of benzomorphane heteroanalogs in which a benzene ring has been replaced by a heteroaromatic one.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 acid-catalyzed cyclization of A3-piperideines has proven to be a valuable approach to the benzomorphans (equation 42) (77CRV1). This is a general reaction and, with simple alkyl substitution on the double bond, anti addition to the double bond gives the predominant if not exclusive product. This has led to speculation that the reaction occurs in a concerted fashion. 

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. 

Similarly, Bosch and co-workers(39) isolated from the potassium hydroxide-induced rearrangement of l,3,4-trimethyl-l-(3,4,5-trimethoxy-benzyl)-l,2,5,6-tetrahydropyridinium chloride, products corresponding to 73, 99, and by inference 101, together with a Hofmann-elimination product. An unambiguous method for preparing 2-benzyltetrahydropyridines from 2-bromopyridine, thus affording a wide selection of substituted benzomorphans has been published.(39a)... 

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. 

Generation of benzomorphan secondary amines, for conversion to appropriate N-substituted derivatives, usually requires N-demethylation of the corresponding tertiary amine. This may be effected by the von Braun reaction with cyanogen bromide or by the use of alkyl-, halogenated alkyl-, and arylchloroformates or diethylazodicarboxylate. Methods for N-demethylation in the series have been summarized by Rice.(62) Removal of an N-benzyl substituent affords an alternative path to norbenzomorphans and is exemplified by Michne and co-workers(63) and Kametani and Aoyama.(s4)... 

Encouraged by the potential of the 8-position to influence both analgesic potency and toxicity in benzomorphans, Jacobson and May(85) prepared a series of 8-nitro, 8-amino-, and 8-halogeno-substituted compounds by standard methods. All derivatives reported were weaker analgesics and were more toxic than the corresponding 8-OH or unsubstituted compounds. 

A series of 4-substituted and 4,4-disubstituted benzomorphans has been evaluated for analgesic activity (MHP).(122) The best activity (ED5Q, 3.7) was exhibited by 202. Several 5-ethyl and one 5-methylbenzomorphan also exhibited low analgesic activity.<123)... 

Benzomorphans lacking a 6-substituent and diastereomeric about positions 1- and 2- have been reported/172 The 1-position substituent configuration was fixed from the coupling constant between the protons at the 1- and 2-positions (JH, , H2 = 6 Hz JHlfi, H2 = 1.0 Hz). Other 1-substituted series have been examined in this manner/115 116 128 ... 

Most attempts to design narcotic antagonists based on 4-phenylpiperidine by linking the basic center to groups such as allyl, substituted allyl, and cyclopropyl methyl (CPM) that confer such properties on fused cyclic systems as possessed by morphine and 6,7-benzomorphans have led to agonists that have no power to block opiate receptors examples include TV-allyl derivatives of norpethidine and norprodine (18)34 and the TV-3-chloroallyl reversed ester 19.(56) Essentially similar results were found for a group of TV-substituted... 

Benzo-fused isoquinuclidines have been synthesized via benzyne (generated from anthranilic acid) addition to the appropriate N-substituted-A -alkyl-2-pyridones to produce benzomorphan-type analgesics (e.g., 28a,b) [28,78]. 

In this study, as a first step in modeling opiate receptor interactions, we have considered the interaction of an ammonium ion and methyl sulfate or phosphate with the series of compounds shown in Figure 1. These compounds, as N-substitutents in rigid opiates such as 5,9 dimethyl, 2 hydroxy, 6,7 benzomorphans, exhibit a broad spectrum of pharmacological behavior from... 

Antagonist potencies measured in vitro in the guinea pig ileum system or in vivo by extent of withdrawal in addicted animals should closely parallel the affinity of opiates for the receptor site. Both antagonist potencies and stero-specific binding constants have been measured for a number of N-substituted 5,9 dimethyl 2 hydroxy 6,7 benzomorphan analogues (14, 15, 32). Table III gives these values for the compounds studied and shows the extent of correlation between the known affinities and potencies for four analogues. 

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