Iminium reduction

First, 91 was subjected to a Pt02-catalyzed iminium reduction to provide the amine as a single diastereomer (94, 83 %, Scheme 6.16). At this point 2D NMR techniques more clearly highlighted the correlations with the new me thine adjacent... 

Finally, the type IV chiral building block 15 was synthesized via the iminium reduction of the corresponding iminiun salt derived from the vinylogous urethane 14 as shown in Scheme 5. With all four stereoisomers of the chiral building blocks (I IV) for synthesis of 3-piperidinol alkaloid in hand, we examined the synthesis of prosafrinine,... 

Presumably the species that undergoes reduction here is a carbinolamine an iminium ion derived from it or an enamme... 

The reduction was studied in more detail by Cook and Schulz (52). They demonstrated conclusively that reduction of iminium salts by secondary amines is possible as illustrated in Eqs. (7) and (8). The oxidation... 

The reaction has been applied to more complex enamines 13) and to dienamines 19). The reduction may be rationalized by initial protonation at the enamine carbon and subsequent decarboxylation of formate ion and addition of the hydride ion to the iminium cation. This mechanism has been given support by the reaction of the enamine (205) with deuterated formic acid 143) to give the corresponding amines. The formation of 206 on reaction with DCOOH clearly indicates that protonation at the enamine carbon is the initial step. 

The reduction of the double bond of an enamine is normally carried out either by catalytic hydrogenation (MS) or by reduction with formic acid (see Section V.H) or sodium borohydride 146,147), both of which involve initial protonation to form the iminium ion followed by hydride addition. Lithium aluminum hydride reduces iminium salts (see Chapter 5), but it does not react with free enamines except when unusual enamines are involved 148). 

In most reviews of enamine chemistry the reactions of iminium salts are scattered throughout the review and are consequently not covered in a comprehensive manner. This chapter will be an attempt to look at reactions that, at one stage or another, proceed by nucleophilic addition to the iminium intermediate. The subject of enamines has been reviewed 1-4) and certain aspects of iminium salt chemistry such as reduction of aromatic quaternary salts have been treated in detail (5). Consequently, the reduction of aromatic quaternary salts with complex hydrides will be presented here only briefly. Although the literature (especially 1950-1967) has been checked with care, the author can make no claim to completeness. The... 

In some cases Grignard reagents cause reduction of the iminium salt to the corresponding saturated amine (51a). 

The reduction of iminium salts can be achieved by a variety of methods. Some of the methods have been studied primarily on quaternary salts of aromatic bases, but the results can be extrapolated to simple iminium salts in most cases. The reagents available for reduction of iminium salts are sodium amalgam (52), sodium hydrosulfite (5i), potassium borohydride (54,55), sodium borohydride (56,57), lithium aluminum hydride (5 ), formic acid (59-63), H, and platinum oxide (47). The scope and mechanism of reduction of nitrogen heterocycles with complex metal hydrides has been recently reviewed (5,64), and will be presented here only briefly. 

The reduction of simple iminium salts, as expected, occurs in an analogous way. The reduction of 39 and 40 are of particular interest since they show that attack of aluminohydride occurs from the less hindered side of the molecule (81). 

Further examples of reduction of simple iminium salts are given in Table 7. 

Reduction of iminium salts with diborane and by the Meerwein-Ponndorf method have been reported (89). 

There have been only a few examples of reduction of the C=N+ function of catalytic hydrogenation since the reductions with complex hydrides are so easy to do in the laboratory. A possible reduction of an iminium salt 45 to 46 with platinum oxide was reported by McKay et al. (91). A report that platinum oxide reduces 2l tio).jgj yjj.Qqyjp Qjj2idijjjujn perchlorate (25) in quantitative yield to 47 indicates that such reduction should be facile (47). 

Reduction of Iminium Salts with Complex Hydrides... 

The previous sections have dealt with stable C=N-I- functionality in aromatic rings as simple salts. Another class of iminium salt reactions can be found where the iminium salt is only an intermediate. The purpose of this section is to point out these reactions even though they do not show any striking differences in their reactivity from stable iminium salts. Such intermediates arise from a-chloroamines (133-135), isomerization of oxazolidines (136), reduction of a-aminoketones by the Clemmensen method (137-139), reductive alkylation by the Leuckart-Wallach (140-141) or Clarke-Eschweiler reaction (142), mercuric acetate oxidation of amines (46,93), and in reactions such as ketene with enamines (143). 

The reductive alkylation reaction under Clarke-Eschweiler conditions has been shown to proceed through an iminium intermediate (142). 

Clemmensen reductions of a-aminoketones that proceed with ring enlargement or ring contraction are presumed to proceed by an iminium intermediate. This reaction has been examined in detail (137-139), and an example is given in the conversion of (94) to an iminium intermediate (95), which is reduced to 96. 

The intermediate formation of iminium salts is postulated in the reduction of (x-amino ketones by the Clemmensen method, occurring with concomitant ring enlargement or contraction (244-246). Reduction of l,2,2-trimethyl-3-piperidone (154) in this manner gave l-methyl-2-iso-propylpyrrolidine (155). 

Cleavage of the chiral auxiliary is effected in a three-step procedure commencing with quatemization of the nitrogen with methyl fluorosulfonate, methyl trlfluoromethanesulfonate, or trimethyloxonium tetrafluoroborate. Reduction of the corresponding iminium salt 19 with NaBH4 and acidic hydrolysis of the resulting product affords substituted aldehyde 5 without epimerization of either stereocenter. 

The configuration of the amine was retained, except in the case of amino acid derivatives, which racemized at the stage of the pyridinium salt product. Control experiments showed that, while the starting amino acid was configurationally stable under the reaction conditions, the pyridinium salt readily underwent deuterium exchange at the rz-position in D2O. In another early example, optically active amino alcohol 73 and amino acetate 74 provided chiral 1,4-dihydronicotinamide precursors 75 and 76, respectively, upon reaction with Zincke salt 8 (Scheme 8.4.24). The 1,4-dihydro forms of 75 and 76 were used in studies on the asymmetric reduction of rz,>S-unsaturated iminium salts. 

Amide reduction occurs by nucleophilic addition of hydride ion to the amicle carbonyl group, followed by expulsion of the oxygen atom as an alumi-nate anion leaving group to give an iminium ion intermediate. The intermediate iminium ion is then further reduced by JL1AIH4 to yield the amine. 

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