3-Cyano-4-methoxy-pyridine

Cyano-4-methoxy-pyridine XIII XIII. 1 H. nymphaeifolia (Presl.) Leaf Iriomote 60... 

A solution of the crude cyanohydrin (94a ca. 1 g) in pyridine (15 ml) and acetic anhydride (15 ml) is allowed to stand at room temperature for 52 hr. The solvents are evaporated under reduced pressure below 60°. The residue is dissolved in ether, and the ether solution is washed successively with 5 % hydrochloric acid, water and saturated salt solution. The solvent is evaporated under reduced pressure to give a crystalline residue. Recrystallization of the crude product from cyclohexane-acetone gives 3-methoxy-17a-cyano-estra-l,3,5(10)-trien-17i5-ol acetate (94b 0.9 g), mp 130-132°, as large prisms. 

Substituted pyrimidine N-oxides such as 891 are converted analogously into their corresponding 4-substituted 2-cyano pyrimidines 892 and 4-substituted 6-cya-no pyrimidines 893 [18]. Likewise 2,4-substituted pyrimidine N-oxides 894 afford the 2,4-substituted 6-cyano pyrimidines 895 whereas the 2,6-dimethylpyrimidine-N-oxide 896 gives the 2,6-dimethyl-4-cyanopyrimidine 897 [18, 19] (Scheme 7.6). The 4,5-disubstituted pyridine N-oxides 898 are converted into 2-cyano-4,5-disubsti-tuted pyrimidines 899 and 4,5-disubstituted-6-cyano pyrimidines 900 [19] (Scheme 7.6). Whereas with most of the 4,5-substituents in 898 the 6-cyano pyrimidines 900 are formed nearly exclusively, combination of a 4-methoxy substituent with a 5-methoxy, 5-phenyl, 5-methyl, or 5-halo substituent gives rise to the exclusive formation of the 2-cyanopyrimidines 899 [19] (Scheme 7.6). The chemistry of pyrimidine N-oxides has been reviewed [20]. In the pyrazine series, 3-aminopyrazine N-ox-ide 901 affords, with TCS 14, NaCN, and triethylamine in DMF, 3-amino-2-cyano-pyrazine 902 in 80% yield and 5% amidine 903 [21, 22] which is apparently formed by reaction of the amino group in 902 with DMF in the presence of TCS 14 [23] (Scheme 7.7) (cf. also Section 4.2.2). Other 3-substituted pyrazine N-oxides react with 18 under a variety of conditions, e.g. in the presence of ZnBr2 [22]. 

Halogen atoms in pyrones and pyridones e.g. 902) are unreactive toward SAE nucleophilic displacement. 3-Halopyridines are less reactive than the a- and 7-isomers but distinctly more reactive than unactivated phenyl halides. Thus, a bromine atom in the 3-position of pyridine or quinoline can be replaced by methoxy (NaOMe-MeOH, 150°C), amino (NH3-H20-CuS04, 160°C) or cyano (CuCN, 165°C). 5-Halogens in pyrimidines are also relatively unreactive. 

Isonicotinic acid hydrazide (isoniazid 275), a drug used in treating tuberculosis269, has been 1 -labelled264 by introduction of a [nC]cyano group at the 2-position of the pyridine ring of l-methoxy-4-methoxcarbonyl pyridinium methyl sulphate and subsequent treatment of the 1 -labelled methyl ester 276 with hydrazine hydrate. The reaction has been carried out on a solid support (silica gel) to yield methyl 2[11C]cyano-isonicotinate in 32.4+12% (EOB) yield. 275 was obtained in 10% (EOB), radiochemical... 

Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid (0.29 mmol) dissolved in 2 ml DMF was treated with A-ethylmorpholine (1.16 mmol), 1 -pyridin-4-ylmethyl-piperazine (0.29 mmol), and 0-((cyano(ethoxycarbonyl)methylene)amino)-l, 1,3,3-tetramethyluronium tetrafluoroborate (0.3 mmol), then stirred 60 minutes at ambient temperature. The mixture was concentrated, then dissolved in CH2C12, washed three times with saturated NaHC03 solution, dried with Na2S04, and reconcentrated. The residue was purified by chromatography with silica gel using n-heptane/EtOAc, 1 1, then EtOAc, and finally EtOAc/methyl alcohol, 10 1, and 102 mg product isolated. MS ES+, m/z = 500 (M+)... 

The position of the substituents on the pyridine moiety also affects the activity of the initiator. For example, p-MeO benzyl o-CN pyridinium salt 2k is 100 times more reactive than the corresponding p-CN derivative 2f. Thus, introduction of the o-cyano group into pyridine nucleo causes a large enhancement of the initiator activity. The reason for the activity enhancement by this modification can be accounted for by both electronic and steric effects of the o-cyano group of the pyridine group. In a typical comparison of the initiation activities of p-CN 2f and m-COOMe 21 substituted p-methoxy benzyl pyridinium salts in the polymerization of GPE, it was observed that p-substituted salt 2f is approximately 10 times more reactive than the corresponding o-substituted salt 21. In this case the steric effect of the substituents is negligible. A similar... 

Pyrazine 1-oxide and 3-amino- and 3-chloropyrazine 1-oxide with tosyl chloride in the presence of pyridine gave 2-pyridiniopyrazine chloride (14) and 2-amino- or 2-chloro-3-pyridiniopyrazine chloride, respectively and 3-methoxycarbonyl(or morpholinocarbonyl or cyano)pyrazine 1 -oxide treated similarly gave 2-methoxy-... 

Some successful syntheses have also been effected with triethyl ortho acetate and acetic anhydride leading to 2-methyl-213 and 2,6-dimethylpteridin-4-one244 from the relevant pyrazine, as well as to 2-methyl-6-cyano-7-methoxy-pyrido[2,3-d]pyrimidin-4-one (see 3) from the corresponding pyridine.245... 

Triethylamine added to a soln. of 2-cyano-5-methoxythiophene in pyridine, a stream of dry HgS passed in for 2-4 hrs., and allowed to stand 24 hrs. 5-methoxy-2-thiophenecarboxylic acid thioamide (Y 98%) dissolved in dry acetone, the theoretical amount of methyl iodide added, and allowed to stand for 24 hrs. methyl 5-methoxythiophene-2-carboximinothiolate hydriodide (Y 93%) dissolved in ethanol, and refluxed 6 hrs. with aniline —> crude N-phenyl-5-methoxythiophene-2-carboxamidine hydriodide (Y ca. 100%). F. e. s. M. Ber ot-Vatteroni, A. ch. 7, 312 (1962). 

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