Sodium borohydride, reaction with iminium salts

The Bischler-Napieralski reaction is one of the traditional methods for isoquinoline synthesis, and has been applied to the preparation of fused quinolizidine systems. One simple example is the transformation of compound 246 into a 9 1 mixture of diastereomers 247 and 248 by treatment with phosphorus oxychloride followed by sodium borohydride reduction of a nonisolated iminium salt resulting from the cyclization (Scheme 49) <2000BMC2113>. 

The key intermediate 21 is in principle accessible in any of several ways. Thus reaction of thiophenecarbox-aldehyde with amninoacetal would lead to the Schiff base treatment with acid would result in formation of the fused thiophene-pyridine ring (21). Alkylation of that intermediate with benzyl chloride gives the corresponding ternary iminium salt. Treatment with sodium borohydride leads to reduction of the quinolinium ring and thus formation of ticlopidine (24). ... 

It has been shown that phenylselenyl halides easily reacted with 0-allyl oximes 221 to give cyclic iminium salts 222, which by reaction with water afforded isoxazolidines 223 in moderate to good yields (equation 96) . Compounds 222 can be reduced in situ by sodium borohydride to produce Ai-alkyl-substituted isoxazolidines 224 in 50-95% yields . ... 

In the total synthesis of reserpine, Woodward and collaborators (10) have reported that the quaternary iminium salt J8 was reduced with aqueous metha-nolic sodium borohydride to methyl 0-acetyl isoreserpate 09). This is the anticipated product whether the stereochemical sense of the reaction is subject to steric or thermodynamic control as pointed out by Woodward. It is also the expected one on the basis of stereoelectronic control. 

The cyclization of O-allyl oximes 1, performed with diphenyl diselenide/ammonium thiosulfate/ trifluorosulfonic acid or phenylselenenyl bromide, gave cyclic iminium salts 2 via an intramolecular antt -addition mechanism. By addition of water to the reaction mixture, 3-substi-tuted isoxazolidines 3 are formed in good yield. When the salts 2 were prepared by using phenylselenenyl bromide, A-alkyl 3-substituted isoxazolidines 4 were afforded in good yield by reduction of 2 with sodium borohydride in methanol247-249. 

Also reported in Scheme 24 are the PhSeBr promoted cyclization reactions of alkenyl aldimines described by De Kimpe [93,94]. As indicated by the reactions of 158 and 161, both, the 5-exo-trig and the 5-endo-trig cyclizations, can take place. The initially formed iminium salts 159 and 162 are converted into the corresponding pyrrolidines 160 and 163 by reduction with sodium borohydride. Compound 163 was obtained as an almost equimolecular mixture of two diastereomers. 

The same methodology was employed by Tiecco to effect the cyclizations of 0-allyl oximes 164 indicated in Scheme 25. Treatment of the intermediate iminium salt 165 with sodium borohydride affords M-alkyl isoxazolidines 166 [95]. Alternatively, 165 can be treated with water to produce M-unsubstituted isoxazolidines 167 [96]. This synthesis of M-alkyl isoxazolidines represents a valid alternative to that described in Scheme 23. Moreover, the present cyclization reaction is much more stereoselective than the cyclization of 0-allyl hydro-xylamines. In fact, when the methyl derivative 168 was employed, the two isomeric isoxazolidines 153 and 154 were obtained in a ratio of 95 5. The same two products were, in contrast, formed in a 1 1 ratio when the reaction was carried out starting from the corresponding 0-allyl hydroxylamines. Clearly, the steric requirements for the selenium-induced cyclization of the 0-allyl oximes are much greater than those for the corresponding 0-allyl hydroxylamines. 

A further point of interest concerns the reaction of the iminium salts 118 and 120 with borohydride (65). The reduction of 118 or 120 with sodium borohydride gave an identical product mixture in which the major components were 6-0-methylmesembranol (121) and 6 -0-methyl-7a-epimesem-branol (122) in 78% and 16% yields, respectively (see Scheme 32). Two minor components representing less than 6% of the total products were identified as mesembrane and its C-7a epimer 123. While the structures of the compounds with a trans ring fusion rested on spectral evidence, the identity of 6-0-methylmesembranol was established by its synthesis from mesembranol by selective O-methylation of the sodium salt with methyl-p-toluenesulfonate, while that of c -mesembrane was identified by comparison with an authentic sample. 

Oxidative cyclization. The final step in a synthesis of racemic ajmalicine (2) required oxidative cyclization of (I). This reaction was carried out in 2.5% aqueous acetic acid with an excess of 1 1 mercuric acelale-ethylenediaminetetraacetic acid disodium salt (EDTA, I, 373-374) followed by sodium borohydride reduction of iminium intermediates. 

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