1 -Ethoxycarbonyl-1,2-dihydropyridine

H-NMR Data for 4-Adducts Obtained by Decomposition of 1-Ethoxycarbonyl-4,4-dlalkyl-1,4-dihydropyridines ... 

The negative charge distribution in the adducts was evaluated on the basis of the chemical shift values and found to be nearly 75% concentrated on the nitrogen atom. In the reactions of l-ethoxycarbonyl-l,4-dihydropyridines with organosodium and organopotassium compounds, the resulting metal-associated (j-adducts were not soluble in aliphatic hydrocarbons alone but were made so by addition of 18-crown-6. This behavior would support ionic structures for the potassium and sodium adducts. 

Adduct 110 has been obtained by decomposition of 1-ethoxycarbonyl-1,4-dihydropyridine with potassium terf-butoxide. It is the ti-adduct that would be expected to form by attack of the hydride ion on the 4-position of pyridine. H- and l3C-NMR studies suggest that 110 is planar and devoid of any homoaromatic character.155 The 13C chemical shifts [6 (in DMSO) 127.9... 

Oxidation of the dihydropyridine derivative is most conveniently carried out with an aqueous nitric-sulphuric acid mixture. Removal of the ethoxycarbonyl groups may be achieved by a stepwise hydrolysis and decarboxylation sequence, but the one-step reaction described in Expt 8.29 using soda-lime is convenient. 

Aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-l,4-dihydropyridine (amlodipine) was prepared from 2-(phthalimidoaminoethoxy)acetoacetate, 2-chlorobenzaldehyde and methyl-3-aminocrotonate under refluxing in ethanol for 24 hours. The ketoester was prepared by the method of Troostwijk and Kellog (JCS Chem. Comm., 1977, p.932). Methyl-3-aminocrotonate can be prepared by known method. Phthalimido-amino-protecting group was removed using hydrazine hydrate in ethanol at the reflux temperature. 

Aryl-l,4-dihydropyridine-3,5-dicarboxylates are widely studied due to their use in the treatment of cardiovascular diseases. Most of these compounds are synthesized using the Hantzsch method (Section 4.2.3.4.2) but this is less suitable for the synthesis of unsymmetrical or chiral derivatives. Enzymatic desymmetrization of bis(ethoxycarbonyl-methyl)-l,4-dihydropyridine-3,5-dicarboxylates, using Candida antarctica lipase B, can generate enantiopure 1,4-dihy-dropyridines in reasonable to high yields with good enantiomeric selectivity <2000TA4559>. 

Interestingly, 5-azaindole resists atmospheric-pressure hydrogenation with Adams catalyst in acidic medium. Also, 7-azaindole and its 1-ethoxycarbonyl derivatives are recovered from treatment with lithium aluminum hydride. This reagent readily reduced the dihydropyridine ring of 6,7-dihydro-4-methyl-7-azaindole to the corresponding 4,5,6,7-tetrahydro compound in 83% yield. ... 

A similar reaction is found in the formation of 5-amino-l-cyano-2,4-dimethyl-3.106-dihydrobenzo[c][2,7]naphthyridine by reduction of 3,5-dicyano-2,6-dimethyl-4-(2-nitro-phenyl)-l,4-dihydropyridine [87] and tetrahydroquino[2,l-c]benzodiazepines from 2-cyano-l-(2-nitrobenzyl)-l,2,3,4-tetrahydroquinoline [88], When the hydroxylamino group has a choice between a nitrile or an ester group, as in 3-ethoxycarbonyl-5-cyano-2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine, it condenses with the nitrile in acidic solution and with the ester in basic media [89]. 

Amlodipine (4-(2-chlorophenyl)-2-[2-(methylamino)ethoxymethyl]-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-f,4-dihydropyridine) is an antihypertensive, marketed... 

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... 

Photolysis of N-substituted dimethylacrylimides has boon shown to give head-to-tail adducts (25),34 correcting an earlier claim of head-to-head addition. N-Ethoxycarbonyl-2-alkyl-1.2-dihydropyridines react stereoselectively with phenyl... 

In what can be considered as a variant of the ring expansion of four-membered heterocycles, the thermal valence bond isomerization of 3,6-diazatricyclo[3.2.0.0 ]heptanes to 1,4-diazepines has been reported. The simplest example of this interesting reaction, illustrated in Scheme 29, starts with pyridine which is acylated with methyl chloroformate and reduced by sodium borohydride to the IV-methoxycarbonyl-2-dihydropyridine, photolysis of which produces 2-azabicyclo[2.2.0]hexa-5-ene in 24% yield (156). This is reacted with ethoxycarbonylnitrene to give a M% yield of 3-ethoxycarbonyl-3,6-diazatricyclo[3.2.0.0 ]heptane (1 ) which rearranges on heating under reflux in xylene for 6 hours to 4,5-dihydro-l-ethoxycarbonyl-4-methoxycarbonyl-l,4-diazepine in 84% yield (158) <85CPB4572>. 

Alkylidene-l-ethoxycarbonylmethyl-l,2-dihydropyridines, e.g. (92), cyclize either to 3-ethoxycarbonyl-indolizines (93) or to 2-acetoxy-l-ethenyl-indolizines (94), depending on the reaction conditions (Scheme 20). ... 

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