Dihydropyridines, from pyridine

Lithium ammonia ethanol N-Subst. 1,4-dihydropyridines from pyridines... 

A variation of an approach developed by Meyers was used to prepare nifedipine-type 1,4-dihydropyridines 35 from pyridine 34 using an oxazoline-directed aryllithium 1,4-addition reaction <96H(43)2425>. 

Turning from pyridine to dihydropyridine, we find another interesting structural type represented by SKF 24260 (XXXVII). 

There are several significant ring syntheses for pyridines, of which the most important is the Hantzsch synthesis of dihydropyridines (Section 4.2.3.4.2). However, the majority of substituted pyridines are prepared from pyridine itself or from a simple alkyl derivative. 

Chiral aminals 1,4-dihydropyridine-3-carboxaldehydes.1 The chiral aminal 2 prepared from pyridine-3-carboxylaldehyde and (S,S)-12 reacts with organocopper reagents in the presence of methyl chloroformate to give almost exclusively products of 1,4-addition, as expected from reactions of the free aldehyde.3 No products of 1,2-addition are formed, but 1,6-adducts are minor products in some cases. The 1,4-adducts are formed in 82-93% de (R-configuration). Addition of butyl and ethyl groups is best effected with lithium cuprates, but addition of methyl, vinyl, or aryl groups is best effected with organomagnesium cuprates. Under these conditions,... 

The relative reactivities of pyridine, 3-picoline, and 3-ethylpyridine toward phenyllithium have been measured under various conditions by a competitive technique and found to be in the order 3-pico-line > pyridine > 3-ethylpyridine.252 By carrying out reactions using an equimolar mixture of pyridine and 3-picoline and a large excess of phenyllithium, it has been possible to obtain yields of the phenyl-pyridines of over 80%, provided short reaction times and low temperatures are used. It has also been shown that the low yields usually obtained in such reactions are due to the fact that the dihydropyridyl-lithium intermediates form by-products, probably by polymerization (the intermediate dihydropyridine is a ct s-butadiene-like system and, in the presence of a Ziegler-type catalyst, can be expected to polymerize readily). The a-complexes from 3-picoline and phenyllithium polymerize faster than that from pyridine and phenyllithium, but there is no selective removal of the isomeric dihydropicolyllithium intermediates to form by-products, both isomers undergoing side-reactions at virtually the same rate. 

The Hantzsch pyridine synthesis gives initially a dihydropyridine from the cyclization reaction. Adaptation of this reaction to the use of a 2-methylenethiazolidine yields the fused tetrahydro derivative (502) (77LA1888). Perhydro derivatives are simply prepared from 2-substituted thiazolidines by cycloalkylation as for (503) (80S387). The thiazolidine may also be generated in situ as in the reaction between y-benzoylbutyric acid and 2-mercaptoethylamines under azeotropic conditions to yield (504) (65JOC1506). 

There are numerous variations in the Hantzsch protocol deriving from variations in the aldehydes, ammonia derivatives and active methylene compounds employed. The final products are 1,4-dihydropyridine and pyridine derivatives as well as pyrroles. 

A mechanism has been proposed which involves dihydropyridine intermediates. Pyridines (173) are also obtained from the reaction of butadiyne with f3-aminocrotonale esters in the presence of sodium . 

A novel method for the synthesis of 2-alkylpyridines and 2-pyridine-carbinols starts from pyridine and involves the pyridine Reissert analog 175. Anion formation with sodium hydride and alkylation with alkyl halides afford the 2-alkyl-l-ethoxycarbonyl-2-cyano-1,2-dihydropyridines 176, which on heating with HMPT/Nal (HMPT = hexamethylphosphorous triamide) give 2-alkylpyridines 177. Condensation of the anion with benzaldehyde or o-tolualdehyde leads to 2-pyridinecarbinols (85CI(L)125). The reaction of 1,4-bis(trimethylsilyl)-1,4-dihydropyridine (178) with aldehydes (and ketones) in... 

Ring fission similar to Zincke fission is occasionally applied to other N-heterocycles to afford aldehydes. For instance, in an alkaline medium containing hydroxylamine pyrrole is converted into succindialdehyde dioxime,1140 and dihydropyridine (prepared from pyridine by sodium and methanol) affords glutardialdehyde dioxime analogously.1141... 

Note that the classical syntheses of dihydropyridines (eg, Hantzsch synthesis) employ de novo construction of the rings by multicomponent reactions rather than starting from pyridines, and that some of the pyridine reduction processes are actually reductions of pyridinium cations (eg, Fowler s sodium borohydride reduction of the N-acylpyridinium salts produced in situ by the reaction of pyridines with chloroformate esters). 

Highly nucleophilic aromatic compounds are capable of arylating acyl-pyridinium salts. The first example of this striking reaction was described by Koenigs and Ruppelt s ho observed the formation of 4-(/>-dimethyl-aminophenyl) pyridine from pyridine, benzoyl chloride and dimethyl-aniline in the presence of copper. Benzaldehyde is also formed s, 736 and the copper is not necessaryThe dihydropyridine (105) is probably an intermediate. Other examples of the reaction are known s, 493 but attempts to isolate the intermediates have failed , though that from dimethyl-m-toluidine may have been obtained. In contrast, the dihydropyridines (106) were isolated when indole was the nucleophile. Skatole reacted similarly, at the 2-position of the indole nucleus, giving the fully aromatic 3-methyl-2-(4 -pyridyl)indole. These reactions failed with 2- and 4-picoline . Similar reactions occur between acylpyridinium salts and pyrroles (p. 71). 

Apparently, the intermediate O-vinyl oxime rearranges to nitrone A [328], which is further fused with acetophenone to generate triene nitrone B (Scheme 1.156). Electrocyclization of the latter gives dihydropyridine-N-oxide C, which rearranges in N-hydroxydihydropyridine D. 1,4-Abstraction of methanol from pyridine D leads to 2,4,6-triphenylpyridine via the intermediate 1,4-biradical E (analog of 1,4-benzoid Bergman biradical [329,330]). 

An alternative asymmetric Diels-Alder reaction was reported by the Fukuyama group in which a dihydropyridine derivative and acrolein were used to build the cyclohexene ring (Scheme 16.2). Dihydropyridine 10 was synthesized from pyridine 9 by NaBH4 reduction in the presence of Cbz-Cl. An asymmetric Diels-Alder reaction between the dihydropyridine 10 and the acrolein in the presence of MacMillan catalyst 11 at room temperature... 

Another important reaction of diketene derivatives is the Hant2sch pyridine synthesis (101). This synthesis is the preparation of 1,4-dihydropyridines (14) starting either from two acetoacetic esters, which react with an aldehyde and ammonia or a primary amine or from 3-aminocrotonates and 2-alkyhdene acetoacetic esters, both diketene derivatives. Several such dihydropyridines such as nifedipine [21829-25-4] (102), nimodipine [66085-59-4] and nicardipine [55985-32-5] exhibit interesting pharmaceutical activity as vasodilators (blood vessel dilation) and antihypertensives (see Cardiovascularagents). 

The Hantzsch pyridine synthesis involves the condensation of two equivalents of a 3-dicarbonyl compound, one equivalent of an aldehyde and one equivalent of ammonia. The immediate result from this three-component coupling, 1,4-dihydropyridine 1, is easily oxidized to fully substituted pyridine 2. Saponification and decarboxylation of the 3,5-ester substituents leads to 2,4,6-trisubstituted pyridine 3. 

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. ... 

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