Grewe cyclization

A fair number of carbo-ammonium dicationic species and related systems have been reported. These distonic superelectrophiles have been directly observed and shown to be useful in synthetic methodologies. For example, the acid-catalyzed Grewe-cyclization is a well-known reaction used in the preparation of morphine analogues.37 The conversion involves formation of the distonic superelectrophile (102) from an appropriate... 

Acid-catalysed Grewe cyclization of the partially reduced benzylisoquinoline (38) resulted in the formation of aporphines (39)—(41).29... 

Further improvements of the Roche synthesis were made in Nutley where it was found that the Grewe cyclization of the optical active N-formyl protected isoquinoline (19) took place below 100 , and afforded the methyl ether (20) (R = CH3) in very high yield after hydrolysis of the N-formyl group and N4nethylation (Leim-gmber 1972). 

The Grewe synthesis of /V-methylmorphinan [3882-38-0] (40), which paved the way for the preparation of dextromethorphan and numerous analogues, follows standard reactions to 2-meth5l-l-benzyl-l,2,3,4,5,6,7,8-octahydroisoquinoline. Cyclization of this compound with phosphoric acid gave a mixture of isomers from which /V-methylmorphinan was separated. 

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,... 

Morphine is biosynthesized from norreticuline through intramolecular oxidative coupling of the electron-rich aromatic rings, transformation that is difficult to achieve with chemical oxidizing agents. The most convenient synthesis, illustrated in Scheme 23, consists of partial saturation of the aromatic ring by the Birch reaction followed by an acid-Catalyzed Grewe-type cyclization to form the required tetracyclic skeleton (48). 

Reinvestigation(87) of the Grewe/Stevens routes to 106, 148, and the corresponding 8-OH, 8-OMe, and 8-OAc homologs demonstrated that cycliz-ation of 2-benzyl-l-methyl-l,2,5,6-tetrahydropyridine to 148 occurs in PPA at an optimum temperature of 155°. At higher temperatures, degradation occurs in competition with cyclization, rendering the isolation of products difficult. 

Grewe first investigated the production of 13-substituted phenan-threne-derivatives by the cyclization of various derivatives of /3-phenylethylcycZohexene with phosphoric acid. The unsaturated acid [xlii] on heating with phosphoric acid yielded an unidentified mono-carboxylic acid C17H1808 [17], but on heating with copper powder in quinoline it was converted to [xun], which, like [xliv], yielded two isomers of the angular-substituted acid [xlv] on cyclization [18]. 

However, attempts to effect a similar cyclization of [xlvi] and [xlvh] appeared to result in an 8-substituted product [19-20], and Grewe concluded that only hydrocarbon residues can be introduced at C-13 in this way. This was subsequently found to be untrue. Cyclization of the allyl-derivative [xLvm] gave 13-allyloctahydrophenanthrene [xlix, R = CH2 CH=CH2], which was converted to the corresponding aldehyde [xlix, R = CH2 CHO] by ozonolysis [20]. 

In a study of the Grewe method of codeine synthesis, the p-bromophenol (98) and its N-methoxycarbonyl derivative failed to undergo acid-catalysed cyclization to a morphinan. Also, although 2-hydroxydihydronorthebainone (99) was readily obtained by cyclization of (100), removal of the 2-hydroxy-group could not be... 

Morphine Rice, 1980 In 1980, Rice achieved a short and highly efficient synthesis of morphine [144, 147]. The route, outlined in Scheme 12.41, closely follows the biosynthetic pathway and features an electrophilic cyclization reaction as first described by Grewe (233 to 234) as key step for the closure of the B ring [148]. Although this route was published nearly 35 years ago. Rice s synthesis of morphine stiU stands out in respect to brevity and overall efficiency and is considered a milestone achievement in morphine research. 

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