Cyanopyridines oxidation

P-Cyanopyridine. Mix 25 g. of powdered nicotinamide with 30g. of phosphoric oxide in a 150 ml. distilling flask by shaking. Immerse the flask in an oil bath and arrange for distillation under a pressure of about 30 mm. Raise the temperature of the oil bath rapidly to 300°, then remove the oil bath and continue the heating with a free flame as long as a distillate is obtained. The nitrile crystallises on cooling to a snow-white solid. Redistil the solid at atmospheric pressure practically all of it passes over at 201° and crystallises completely on cooling. The yield of p-cyanopyridine, m.p. 49°, is 20 g. 

The pyridine-N-oxide 245 was converted into the cyanopyridine 246 and its isomer (Scheme 80). Grignard reaction, Fischer s indole synthesis, and N-protection gave a pyridinyl indole 247. Selenium dioxide selectively oxidized the methyl group to give the isonicotinic acid. The synthesis of Flavocarpine (244) was finally accomplished by a set of standard reactions as outlined in Scheme 80 (87TL5259). 

Heterocyclic N-oxides such as pyridine, quinoline, or isoquinoline N-oxides can be converted into a mixture of 2- and some 4-cyanopyridines, 2- or 4-cyanoquino-lines, or 1-cyanoisoquinolines, in 40-70% yield, in a Reissert-Henze reaction, by activation of the N-oxide function by O-acylation [1] or O-alkylation [2, 3] followed by treatment with aqueous alkali metal cyanide in H2O or dioxane. 

In two publications [36, 37] and a subsequent review [38], a closely related alternative procedure for conversion of pyridine-N-oxides into cyanopyridines was reported in 1983. This used a combination of the mild Lewis acid Me2NCOCl and trimethylsilyl cyanide 18 for the cyanation of pyridine N-oxides such as 860, affording, in CH2CI2, via 932 and 933, 2-cyanopyridine 862 in 94% yield and apparently no 4-cyanopyridine 864 [36-38] (Scheme 7.13). With 3-substituted pyridine N-oxides such as methyl nicotinate N-oxide a mixture of 40% methyl 2-cyanonico-tinate and 60% methyl 6-cyanonicotinate is obtained. 

The solid 4-cyanopyridine N-oxide was burned in pellet form. To avoid incomplete combustion, it was necessary to burn the compound in conjunction with n-hexadccanc. The bomb of 340 cm3 internal volume was charged... 

Table 7.1 Auxiliary data for the Washburn corrections associated with the combustion of 4-cyanopyridine N-oxide (see text and figures 7.5 and 7.6)... 

Once the values of A t/mp and A Ut, are known, the standard massic energy of combustion of 4-cyanopyridine N-oxide can be derived from... 

Table 7.3 shows a summary of the results of six independent combustion calorimetry experiments with 4-cyanopyridine N-oxide [47]. Note that the value of A t/jgn, which represents the energy change associated with ignition (equation 7.20), is included in the value of A C/ibp-... 

The mean value of the standard molar energy of combustion of 4-cyanopyridine N-oxide indicated refers to reaction 7.58 at 298.15 K ... 

In order to illustrate the application of LSV in mechanistic analysis we can look at the redox behavior of the formazan-tetrazolium salt system which we studied some years ago [17], 1,3,5-Triphenyl formazane was oxidized at controlled potential in CH3CN-Et4NC104 solution to 2,3,5-triphenyl tetrazolium perchlorate which was then isolated in quantitative yield. Coulometry showed that the overall electrode reaction was a two-electron oxidation. It has been shown that the rate of variation of Ep with log v was 30 mV per decade of sweep rate and that there was no variation of the peak potential with the concentration of 1,3,5-triphenylformazan. According to Saveant s diagnostic criteria (Table 1), four mechanistic schemes were possible e-C-e-p-p, e-C-d-p-p, e-c-P-e-p and e-c-P-d-p. If cyclization is the rate-determining step, then the resulting e-C-e-p-p and e-C-d-p-p mechanisms would not imply variation of Ep with the concentration of base. However, we have observed the 35 mV shift of Ep cathodically in the presence of 4-cyanopyridine as a b e. These observations ruled out the first two mechanisms. The remaining possibilities were then e-c-P-e and e-c-P-d, as shown in Scheme 3. 

The reaction proceeds via ANRORC-recyclization induced by alkoxide ion, and subsequent oxidative aromatization. Authors believe that aroma-tization occurs at the expense of disproportionation of the intermediate dihydropyridine because yields never exceed 50%. These results were reproduced and expanded (00PHA269), and used in a synthesis of 4,6-diaryl-2-methoxy-3-cyanopyridines and annulated methoxypyridines (88TL2703) (with low yields). 

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