Sodium borohydride pyridinium salts

When a pyridinium salt such as (27) is treated with sodium borohydride, the final product is the tetrahydropyridine (30). The mechanism for this reaction was proposed by Katritzky (65) and experimentally verified by Anderson and Lyle (66-68). The sequence is visualized as reduction of the... 

Lithium aluminum hydride reduction of pyridinium salts is very similar to sodium horohydride reduction and gives similar products, but the ratio of 1,2- and 1,4-dihydro- or tetrahydropyridines differs considerably (5). Isoquinolinium salts are reduced hy sodium borohydride or lithium aluminum hydride in a manner identical to pyridinium salts (5). Quino-linium salts are reduced by sodium borohydride to give primarily tetra-hydroquinolines (72) as shown by the conversion of 33 to 34 and 35. When lithium aluminum hydride is used, the product is usually the dihydroquinoline (73) as shown in the conversion of 36 to 37 and 38. 

Thus the critical synthetic 1,6-dihydropyridine precursor for the unique isoquinuclidine system of the iboga alkaloids, was generated by reduction of a pyridinium salt with sodium borohydride in base (137-140). Lithium aluminum hydride reduction of phenylisoquinolinium and indole-3-ethylisoquinolinium salts gave enamines, which could be cyclized to the skeletons found in norcoralydine (141) and the yohimbane-type alkaloids (142,143). 

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,... 

Another classic reaction of pyridinium salts is reduction of the pyridine ring. Donohoe and co-workers reported the partial reduction of A-alkylpyridinium salts <060BC1071>, which is accompanied by subsequent alkylation and hydrolysis to furnish a range of 2,3-dihydropyrid-4-ones. This sequence has the potential to introduce a variety of functional groups at the C-2 position of 2,3-dihydropyrid-4-ones. Reduction of pyridinium ylides with sodium borohydride has also been reported in fair to good yields <06JHC709>. 

The key intermediate 124 was prepared starting with tryptophyl bromide alkylation of 3-acetylpyridine, to give 128 in 95% yield (Fig. 37) [87]. Reduction of 128 with sodium dithionite under buffered (sodium bicarbonate) conditions lead to dihydropyridine 129, which could be cyclized to 130 upon treatment with methanolic HC1. Alternatively, 128 could be converted directly to 130 by sodium dithionite if the sodium bicarbonate was omitted. Oxidation with palladium on carbon produced pyridinium salt 131, which could then be reduced to 124 (as a mixture of isomers) upon reaction with sodium boro-hydride. Alternatively, direct reduction of 128 with sodium borohydride gave a mixture of compounds, from which cyclized derivative 132 could be isolated in 30% yield after column chromatography [88]. Reduction of 132 with lithium tri-f-butoxyaluminum hydride then gave 124 (once again as a mixture of isomers) in 90% yield. 

It is quite difficult to reduce benzene or pyridine, because these are aromatic stmctures. However, partial reduction of the pyridine ring is possible by using complex metal hydrides on pyridinium salts. Hydride transfer from lithium aluminium hydride gives the 1,2-dihydro derivative, as predictable from the above comments. Sodium borohydride under aqueous conditions achieves a double reduction, giving the 1,2,5,6-tetrahydro derivative, because protonation through the unsaturated system is possible. The final reduction step requires catalytic hydrogenation (see Section 9.4.3). The reduction of pyridinium salts is of considerable biological importance (see Box 11.2). 

According to the second way, thieno[3,2-c]pyridine undergoes N-alkylation using 2-chlorobenzylchloride, and the resulting pyridinium salt (24.2.2) is further reduced by sodium borohydride to the desired ticlopidine. 

Pyridine is difficult to reduce (as is benzene ), but pyridinium salts, e.g. alkylpyridinium halides, are partly reduced by hydride transfer reagents such as lithium aluminium hydride (LiAlH ) and sodium borohydride (NaBH4). LiAlH, which must be used in anhydrous conditions, only gives the 1,2-dihydro derivative, but the less vigorous reductant NaBH in aqueous ethanol yields the 1,2,5,6-tetrahydro derivative (Scheme 2.30)1... 

The preparation of conjugated dienes from pyridines is exemplified by the transformation of 2-picoline into the sex pheromone (669) of Lobesia botrana, a major pest of vineyards (Scheme 154) (80TL67). Thus, the lithio salt of 2-picoline was alkylated by 2-(5-chloropentyl-oxy)tetrahydropyran, the resulting pyridine (665) N-methylated, and the pyridinium salt reduced by sodium borohydride. Quaternization of the 1,2,3,6-tetrahydropyridine (666) and Hofmann elimination gave the (7 , 9Z)-undecadien-l-ol (667) as the sole isomer. Protection of the alcohol and treatment of the corresponding ammonium salt (668) of the amine with lithium dimethylcuprate gave pure (669) after hydrolysis, acetylation and HPLC purification. 

The pyridinium salts have been shown to have electrophilic positions at the 2-, 4-, and 6-carbon atoms. Of these, the 2- and 6-positions should be the more positive because of the proximity to the quaternary nitrogen. From the ultraviolet absorption spectra of the reaction mixtures during the reduction and of the isolated products, it can be demonstrated that the predominant attack of the hydride ion from sodium borohydride occurs at these two positions.5,6 The 1,6-dihydro-pyridine (such as 5) formed from the reduction of a 1,3-disubstituted pyridinium ion appears to be stable toward further reduction, for a number of such compounds have been isolated from sodium borohydride reductions containing sufficient borohydride to complete the reduction to the tetrahydro-state.7"10 Since 1,4-dihydropyridines having a 3-substituent which is electron-withdrawing have also been... 

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 ... 

The reduction of 2-substituted-isoquinolinium salts has been reported by Torossian65 with potassium borohydride in water, by Mirza,68 and by Durmand et al.,87,68 using sodium borohydride in aqueous methanol to yield 1,2,3,4-tetrahydroisoquinolines. The reduction of the second double bond appears to arise from a mechanism similar to that leading to tetrahydropyridines from pyridinium ions (see Section I). Mirza66 (see also Bose60) found that the reduction of berberine (60) with sodium borohydride could be stopped at the 1,2-dihydro-intermediate (61), and Karrer and Brook70 showed that the 1,2-dihydroisoquinoline formed by the lithium aluminum hydride reduction of l-phenyl-2-methylisoquinolinium iodide (62) could be further reduced to the 1,2,3,4-tetrahydroisoquinoline (63) with sodium borohydride in methanol. Awe et al.71,72 and Huffman73... 

A systematic study of the reduction of thiazolium salts by complex metal hydrides has been promised in a preliminary communication on the mechanism of the reduction with sodium borohydride. The formation of 3-benzyl-4-methylthiazolidine from the reaction of 3-benzyl-4-methylthiazolium bromide and sodium borohydride was shown to occur in a manner similar to the reduction of pyridinium ions.158... 

Somewhat less useful is the aluminum hydride reduction of quaternary pyridinium salts. Reduction of the salts may be more conveniently performed by the use of sodium borohydride (see Section II, B, 6). Moreover, the aluminum hydride reductions of some dialkyl-pyridinium salts are accompanied by reductive cleavage of the pyridine ring,77 For example, methiodides of 2,5-dimethylpyridine,77 2-methyl-5-ethylpyridine,77 and 2-ethyl-5-methylpyridine61 afford mixtures of the corresponding tetrahydro and hexahydro bases along with a secondary amine, viz., 5-methylaminomethyl-2,4-hexadiene, 5-methylaminomethyl-2,4-heptadiene, and 7-methylamino-6-methyl-2,4-heptadiene, respectively. 

Reductions of quaternary pyridinium salts to 1-alkyl-3-piperideines may be performed preferably with the use of sodium or potassium borohydride in aqueous or alcoholic solutions. Lithium aluminum... 

In contrast to aluminum hydride reductions (see Section II, B, 4), no ring openings have been observed in reductions of quaternary pyridinium salts by means of sodium borohydride. Whenever possible, both isomeric tetrahydropyridines are formed, as it may be seen from the following examples (aluminum hydride, electrolytic, and formic acid reductions are included for comparison). 

In addition to compounds quoted by Lyle and Anderson," the following quaternary salts have recently been reduced with sodium borohydride ethiodides of pyridine and its homologs, methiodides of 3-ethylpyridine, 4-ethylpyridine, 2-methyl-5-ethylpyridine, and 3-methyl-4-ethylpyridine,102 and the methiodide of 2-benzyl-4-methylpyridine.103 Reductions (NaBH4) of l,2-dimethyl-5-ethyl-pyridinium iodide and l,3-dimethyl-4-ethylpyridinium iodide afford as principal products those 3-piperideines (94, 95) which carry the maximum number of substituents on the double bond, presumably due to hyperconjugation.102... 

Attempts to reduce the 3-oxo-group in the ketol pyridinium sulphate (181), using sodium borohydride in anhydrous methanol, afforded instead the stable 3,3-dimethoxy-derivative (182), The pyridinium ion is sufficiently acidic to promote this acetalization, although alkali-metal salts of the ketol sulphate were... 

The reduction of pyridinium salts 86 with borohydride in methanolic sodium hydroxide gives mixtures of di- and tetrahydropyridines (87-91). Over time, the dimeric species 91 increased, while 87 decreased. 

Sodium and potassium borohydrides are above all used for reducing aldehydes and ketones (Sections 3.2.1, 3.2.2) a,p-ethylenic ketones are converted to mixtures [W3]. In alcoholic media or THF, they leave epoxides, esters and lactones, acids, amides, and most nitro compounds unreacted, but they reduce halides (Section 2.1), anhydrides (Section 3.2.6), quartemary pyridinium salts (Section 3.3), double bonds conjugated to two electron-withdrawing groups (Sections 3.2.9, 4.4), and CUPd... 

Catalytic reduction of pyridinium salts to piperidines is particularly easy in ethanol at room temperature and pressure they are also susceptible to hydride addition by complex metal hydrides or formate, and lithium/ammonia reduction. In the reduction with sodium borohydride in protic media, the main product is a tetrahydro derivative with the double bond at the allylic, 3,4-position, formed by initial hydride addi-... 

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