Dihydropyridines reduction

The mechanism of 1,4-dihydropyridine reductions is actively being pursued (B-78MI20702). A mechanism involving hydride transfer is attractive because of its simplicity (80JA4198). However, many workers in the area prefer an electron transfer as the first step (79JA7402). The hydride mechanism can be completed by the transfer of a proton followed by an electron or by the transfer of a hydrogen atom (Scheme 29). It is unlikely that the mechanistic question will be resolved in the near future. It may be that the mechanistic pathway that these reactions follow is very sensitive to both the structure of the dihydropyridine and the compound being reduced. 

When pyridine is treated with zinc dust and acetic anhydride, a type of reductive coupling occurs and the product is diacetyltetrahydrodipyridyl (I) this undergoes a curious change on heating yielding pyridine and a new diacetyl compound, 1 4 diacetyl 1 4-dihydropyridine (II). The latter is reduced by zinc and acetic acid to 4-ethylpyridine (III). 

Butyroin has been prepared by reductive condensation of ethyl butyrate with sodium in xylene, or with sodium in the presence of chloro-trimethylsilane. and by reduction of 4,5-octanedlone with sodium l-benzyl-3-carbamoyl-l,4-dihydropyridine-4-sulfinate in the presence of magnesium chloride or with thiophenol in the presence of iron polyphthalocyanine as electron transfer agent.This acyloin has also been obtained by oxidation of (E)-4-octene with potassium permanganate and by reaction of... 

Even more highly selective ketone reductions are earned out with baker s yeast [61, 62] (equations 50 and 51) Chiral dihydronicotinamides give carbonyl reductions of high enantioselectivity [63] (equation 52), and a crown ether containing a chiral 1,4-dihydropyridine moiety is also effective [64] (equation 52). 

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). 

Analogous to DPNH (144-146), 1,4-dihydropyridines (147) act as reducing agents. For instance, the conversion of aromatic nitro compounds to amines (148) and reduction of enones to ketones (749) has been achieved. 

A limitation of this approach was the fact that the cyclization could not be accomplished on the resin. This would preclude further functionalization of the core. Therefore an alternate approach was to link the resin to the core via an aminoalcohol spacer as in 93. Furthermore, since linkage was conducted through the P-ketoester component rather than through the nitrogen atom, dihydropyridines 94 could now be formed on the solid support. When the 4-aryl substituent of 94 was nitro, on-resin reduction to the corresponding amine was possible. This allowed for further addition of diversity elements to the core scaffold before cleavage from the resin. 

The Zincke reaction has also been adapted for the solid phase. Dupas et al. prepared NADH-model precursors 58, immobilized on silica, by reaction of bound amino functions 57 with Zincke salt 8 (Scheme 8.4.19) for subsequent reduction to the 1,4-dihydropyridines with sodium dithionite. Earlier, Ise and co-workers utilized the Zincke reaction to prepare catalytic polyelectrolytes, starting from poly(4-vinylpyridine). Formation of Zincke salts at pyridine positions within the polymer was achieved by reaction with 2,4-dinitrochlorobenzene, and these sites were then functionalized with various amines. The resulting polymers showed catalytic activity in ester hydrolysis. ... 

Utilizing the Zincke reaction of salts such as 112 (Scheme 8.4.38), Binay et al. prepared 4-substituted-3-oxazolyl dihydropyridines as NADH models for use in asymmetric reductions. They found that high purity of the Zincke salts was required for efficient reaction with R-(+)-l-phenylethyl amine, for example. As shown in that case (Scheme 8.4.38), chiral A-substituents could be introduced, and 1,4-reduction produced the NADH analogs (e.g. 114). 

The [2 + 2] cycloaddition reaction of A -benzyl-l,4-dihydropyridine 34b with acrylonitrile, followed by catalytic reduction gave two pairs of diastereoisomeric amides 36 and 37 with a low diastereomeric excess, probably due to the large distance between the asymmetric center and the site of acrylonitrile attack. Compounds 36 and 37 were resolved into the four individual diastereoisomers (ca 5% for compound 36 and 15% for 37) [97JCR(M)321], Irradiation of 1,4-dibenzyl-1,4,5,6-tetrahydropyridine 38 in the presence of 29 gave two stereoisomers. 

Further elaboration of 152 resulted in the synthesis of (derived from the reduction of pyridinium salt 150b with excess of LiAlFt4 in THE Acid-catalyzed cyclization of 154 led to indoloquino-lizidine 155 (25% yield from 150b), a precursor of deplancheine (80TL2341) (Scheme 5). 

Introduction of an oxygen substituent at C-6 of a Hantzsch-type dihydropyridine having a sulfinyl group at C-5 affects the reduction of ketones with respect to both reactivity and stereoselectivity <96CC2535>. 

Two-electron reduction of 4,4 -(l,3-propanediyl)bis-(iV-methylpyridinium) dibromide with sodium amalgam affords bis-l,4-dihydropyridine 46 <96CL151>. 

The nondihydropyridine calcium channel blockers have been shown to also decrease protein excretion in patients with diabetes,20 but the reduction in proteinuria appears to be related to the reductions in blood pressure. The maximal effect of nondihydropyridine calcium channel blockers on proteinuria is seen with a blood pressure reduction to less than 130/80 mm Hg and no additional benefit is seen with increased doses. Dihydropyridine calcium channel blockers, however, do not have the same effects on protein excretion, and may actually worsen protein excretion.17... 

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,... 

Methyl-8-(2-chlorophenyl)-3,4-dihydro-177,877-pyrido[2,l-f][l,4]oxazine-7,9-carboxylate was obtained by cyclization of l,4-dihydropyridine-3,5-dicarboxylate 338 in the presence of 3M HC1 <1997CAP2188071>. Mild catalytic hydrogenation of oxazinone 339 over 5% Pd/C catalyst afforded 3,4-diphenyl-9-hydroxyperhydropyrido[2,l-f][l,4]oxazin-l-one via sequential iV-carbobenzyloxy (fV-Cbz) deprotection and reductive amination <1998TL3659>. 

The above examples show the ability of microsome reductases to oxidize substrates in the processes where the first step is a one-electron reduction, which may or may not be accompanied by superoxide formation. However, cytochrome P-450 can directly oxidize some substrates including amino derivatives. For example, mitochondrial oxidation (dehydrogenation) of 1,4-dihydropyridines apparently proceeds by two mechanisms via hydrogen atom abstraction or one-electron oxidation [48 50]. Guengerich and Bocker [49] have shown that... 

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. 

After its isolation, the structure of alkaloid deplancheine (7) was unambiguously proved by several total syntheses. In one of the first approaches (14), 1,4-dihydropyridine derivative 161, obtained by sodium dithionite reduction of A-[2-(indol-3-yl)ethyl]pyridinium salt 160, was cyclized in acidic medium to yield quinolizidine derivative 162. Upon refluxing 162 with hydrochloric acid, hydrolysis and decarboxylation took place. In the final step of the synthesis, the conjugated iminium salt 163 was selectively reduced to racemic deplancheine. 

Asymmetric reduction of ketones. Pioneering work by Ohno et al. (6, 36 7, 15) has established that l-benzyl-l,4-dihydronicotinamide is a useful NADH model for reduction of carbonyl groups, but only low enantioselectivity obtains with chiral derivatives of this NADH model. In contrast, this chiral 1,4-dihydropyridine derivative (1) reduces a-keto esters in the presence of Mg(II) or Zn(II) salts in >90% ee (equation I).1 This high stereoselectivity of 1 results from the beneficial effect... 

Dihydropyridines and their /V-alkyl derivatives undergo anodic oxidation in basic medium to the corresponding pyridines (reaction 27). The process may be complicated by the presence of other moieties for example, a nitro group may reductively condense... 

---