1,2,5,6-Tetrahydropyridines, synthesis, sodium

A stereoselective total synthesis of ( )-hirsutine has been developed by Brown et al. (179). Catalytic hydrogenation of hydroxycyclopentenone 327, prepared previously (180), afforded a mixture of isomeric diols 328, which were quantitatively cleaved by sodium periodate to supply 329. Reductive amination of 329 with tryptamine resulted in tetrahydropyridine 330, which upon treatment with aqueous methanol in the presence of hydrochloric acid gave indolo-[2,3-a]quinolizine 321 with pseudo stereochemistry. Conversion of 321 to ( )-hirsutine was accomplished in a similar manner by Wenkert et al. (161) via selective reduction with diisobutylaluminum hydride and methylation with methanol (179). 

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 ... 

In a general annulation method, 4-aminonicotinonitriles are treated with ethyl orthoformate to give the corresponding (ethoxymethylene)amino compounds. The nitrile group is then converted with sodium hydrogen sulfide into a thioamide function which cyclizes to yield the 2-sulfanylpyrimidine moiety. An application of this method is the synthesis of 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-t/]pyrimidine-2-thiol (3) from l-benzyl-4-[(ethoxymethylene)amino]-l,2,5,6-tetrahydropyridine-3-carbonitrile (2).491 492... 

In the presence of sodium ethoxide in ethanol, the urethane synthesis starting from 4-amino-l-benzyl-i,2,5,6-tetrahydropyridine-3-carbonitrile and diethyl carbonate affords as a byproduct 6-benzyl-4-ethoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2(lA/)-one (6).496... 

Lounasmaa et al. ° have continued their investigations into the synthesis of indoloquinolizidine derivatives, with particular reference to vallesiachotamine models. The most advanced work in this area to date involves synthesis (Scheme 9) of the closely related vallesiachotamine derivative (75). The critical stage in this synthesis was the reduction of the pyridinium salt (76) by means of sodium dithionite, which, in buffered (NaHC03) solution, allowed the isolation of the dihydropyridine derivative (77). Cyclization of (77) in the presence of acid gave, preferentially, the desired 3H,15H-trans-isomer (75), as had previously been established " in model systems. Alternatively, alkylation of the unsaturated ester (78) with tryptophyl bromide gave the pyridinium salt (79), which, on reduction with sodium dithionite in aqueous methanol, gave a mixture of (75) and the uncyclized tetrahydropyridine derivative (80). >yhen the sodium dithionite reduction medium was buffered (with NaHCOa), and the dihydropyridines so obtained were cyclized in acid, the products were the tetracyclic geometrical isomers of structure (81) (Scheme 9). 

Sodium hydride Michael-type ring synthesis 1,2,3,4-Tetrahydropyridine ring... 

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