1.4- Dihydropyridines, stability

Formation of Pyridine and Dihydropyridine-Stabilized Alkylidene Complexes of W° and Cr° from Fischer Carbene Complexes Stracture and Reactivity,... 

The basic metal salts and soaps tend to be less cosdy than the alkyl tin stabilizers for example, in the United States, the market price in 1993 for calcium stearate was about 1.30— 1.60, zinc stearate was 1.70— 2.00, and barium stearate was 2.40— 2.80/kg. Not all of the coadditives are necessary in every PVC compound. Typically, commercial mixed metal stabilizers contain most of the necessary coadditives and usually an epoxy compound and a phosphite are the only additional products that may be added by the processor. The requited costabilizers, however, significantly add to the stabilization costs. Typical phosphites, used in most flexible PVC formulations, are sold for 4.00— 7.50/kg. Typical antioxidants are bisphenol A, selling at 2.00/kg Nnonylphenol at 1.25/kg and BHT at 3.50/kg, respectively. Pricing for ESO is about 2.00— 2.50/kg. Polyols, such as pentaerythritol, used with the barium—cadmium systems, sells at 2.00, whereas the derivative dipentaerythritol costs over three times as much. The P-diketones and specialized dihydropyridines, which are powerful costabilizers for calcium—zinc and barium—zinc systems, are very cosdy. These additives are 10.00 and 20.00/kg, respectively, contributing significantly to the overall stabilizer costs. Hydrotalcites are sold for about 5.00— 7.00/kg. 

A -Alkyl-l,2-dihydropyridines that are not stabilized by electron-withdrawing groups on the ring could behave as dienophiles towards alkynes. For example, N-methyl-l,2-dihydropyridine 41a reacts with dimethyl acetylenedicarboxylate (32) to give [2 + 2] cycloaddition product 42, which rearranges to give the azocine derivative 43 [74JCS(P1)2496],... 

The reaction is of wide scope. Instead of ester groups as substituents at C-3 and C-5, other acceptor substituents—e.g. oxo, cyano, sulfonyl or nitro groups—can be employed in order to stabilize the 1,4-dihydropyridine system. 

The resonance mechanism shown in Fig. 8.15 accounts for the greater stability of dihydropyridine pro-prodrugs vs. their pyridinium metabolites in base-catalyzed and enzymatic reactions of hydrolysis, but it also suggests a decreased stability of the former in acid-catalyzed hydrolysis. Indeed, the carbonyl O-atom is deduced from Fig. 8.15 to be more nucleophilic in dihydropyridine (A) than in pyridinium derivatives (B). The stability of dihydropyridine pro-prodrugs under the acidic conditions of the stomach and small intestine should, therefore, be examined further. 

Silylcuprates have been reported to undergo reactions with a number of miscellaneous Michael acceptors [65]. Conjugate addition to 3-carbomethoxy acyl pyri-dinium salts [65a] affords 4-silyl-l,4-dihydropyridines. Oxidation with p-chlorand generates a 4-acyl pyridinium salt that gives the 4-silylnicotinate upon quenching with water, and methyl 4-silyl-2-substituted dihydronicotinates upon quenching with nucleophiles (nucleophilic addition at the 6-position). The stabilized anion formed by conjugate addition to an a, j8-unsaturated sulfone could be trapped intramolecularly by an alkyl chloride [65b]. 

Fig. 26. Compounds (in oxidized form) analyzed for the stability of the corresponding dihydropyridines...

The relative stabilities of the dihydropyridines have also attracted attention over the years. Because of the reactivity of the dihydropyridines much of the research concerning the relative stabilities has been of a theoretical nature (78JA4946, 81CCC2068). Although the stability series is a sensitive function of the method of calculation, there is agreement that the 1,4-dihydropyridine is more stable than the 1,2-isomer. There is disagreement with... 

The reductive cleavage of the C—O bond in 2- and 4-substituted hydroxy-methylpyridines was mentioned in Part I. The optically active l-(4-pyridyl)-alkanols are reduced in good yield to the optically inactive alkylpyridine, whereas the 2-substituted derivatives were reduced in lower yield to the optically active alkylpyridine (and some tetrahydropyridine derivatives).384,385 The difference in behavior was explained by orientation of the adsorbed pro-tonated pyridine, allowing contact between the electrode and the 2-substituent, but not the 4-substituent. This model was used in later work however, not excluded was the possibility that the higher stability of the p-quinonoid dihydropyridine intermediate, compared to the o-quinonoid dihydropyridine, played a role in the relative ease of reduction of the 4- and 2-substi-tuted pyridines. 

With Aralkyl- or Wacylpyridinium salts, the addition of isonitriles takes place efficiently when a carboxamido group is present in the 3-position. The outcome of the reaction involves the stabilization of the nitrilium intermediates by the amide, which suffers a mild dehydration providing 3-cyano-4-carbamoyl-l,4-dihydropyridines. This method also works with the corresponding Wacylquinolinium and Wacylisoquinolinium salts (Equation 58) <2006OL5789, 2004JOC3550>. 

Dihydropyridines are inherently unstable and rapidly isomerize to other dihydropyridine isomers many also rapidly eliminate H2 to form pyridines. The exceptions are 3,4-dihydropyridines substituted at the 2- and 5-positions with electron-donating groups. However, even stable 3,4-dihydropyridines can be oxidized to the corresponding pyridine by the use of 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) <1995T7161>. An example of the stability of these substituted 3,4-dihydropyridines is in the unexpected formation of 2-methoxy-3,4-dihydropyridine 45 rather than the expected pyridine 46 from the [3+3] cyclization of 4-amino-l-azabutadiene 44 with Fischer alkynylcarbene complex 43 (Equation 1) <2001NJC8>. The 2-methoxy group was proposed to stabilize an intermediate and result in elimination of the metal without aromatization. 

Various 2-substituted iV-phenyl-6-phenylimino-3,6-dihydro-2//-thiopyran-4-amines, which are available from 6-substitutcd-5,6-dihydro-2//-thiopyran-2-thioncs, thermally rearrange to 5,6-dihydropyridine-2(l//)-thiones. A resonance stabilized thioamide anion is proposed as the intermediate (Scheme 107) <2001T8305>. 

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