Cyano-6-methylpyridine

Submitted by Wayne E. Feely, Geoege Evanega, and Ellington M. Beavess.  

Checked by William E. Paeham, Stuart W. Fenton, and William W. Henderson. 

Caution All the operations should be carried out in a well-ventilated hood because of the toxic natures of dimethyl sulfate, hydrogen cyanide, and cyanide solutions. 

l-Methoxy-2-methylpyridinium methyl sulfate. In a 1-1. three-necked flask equipped with a Hirshberg stirrer, a thermometer which extends deep into the flask, and a 250-ml. pressureequalizing, dropping funnel fitted with a calcium chloride diying tube is placed 109 g. (1.0 mole) of diy powdered 2-picoline-l-oxide (Note 1). The stirrer is started at a slow rate, and 126 g. (1.0 mole) of dimethyl sulfate (Note 2) is added dropwise at a 

The preparation of 2-picoline-l-oxide is described by Boekel-heide and Linn. The oxide is hygroscopic, and best results are obtained if it is redistilled just before use. The submitters used 2-picoline-l-oxide, obtained from the Reilly Tar and Chemical Company, Indianapolis, Indiana, which was freshly redistilled and boiled at 118-120°/10 mm. 

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C7H6CIN02 2-chloro-4-methyl-1-nitrobenzene 38939-88-7 523.15 46.113 2 10345 C7H6N2 2-cyano-3-methylpyridine 20970-75-6 545.90 48.311 2... 

Additional support for this interpretation comes from work on isomeric lutidines 2,3-lutidine (X-82) is converted to 2-cyano-3-methylpyridine (X-83) and 3,5-lutidine (X-84) affords S-methylnicotinonitrile (X-8S). ... 

In a second synthesis the same authors start with ethyl 2 4-dihydroxy-6-methylpyridine-3-carboxylate, and by a shorter series of reactions reach 3-cyano-2 4-dimethoxypyridine (V), which is then converted into rieinine (VI) as before. 

A cyano group produces practical reactivity (methanolic CH30, 66°, < 3hr) by its presence in 2-chloro-3-cyano-6-methylpyridine, opposing the deactivating effect of a methyl group, and on other 2-chloropyridines (see references 3-6 in ref. 140). The cyano group activates 3-cyano-6,6-diphenyl-2-methoxypyrazine (168) (pre-... 

CYANO-6-METHYLPYRIDINE, 42, 30 2-Cyanopyridine, 42,33 4-Cyanopyridine, 42,33 2-CyanoquinoIine, 42,31 Cyclization, of a-acetoacetochloroanilide... 

Heating 6-[(2-carboxylphenyl)amino]-5-cyano-2-methylpyridine-3-carboxylate in refluxing POCI3 afforded 6-cyano-8-ethoxycarbonyl-9-methyl-ll//-pyrido[2,T3]quinazolin-ll-one, but in PPA at 135-145°C 2-methyl-3-ethoxycarbonyl-4-methyl-5-oxo-5,10-dihydrobenzo(3)-l,8-napthyridine-9-carboxylic acid formed <2004CHE510>. 

Denzel and Hans claimed that in the reaction of 3-aminocrotononitrile and EMME at 140-145°C for 2 hr, 4-hydroxy-5-cyano-6-methylpyridine-3-carboxylate (1317) was formed in 61% yield (73GEP2322073), but they later stated that the product was 2-hydroxy-5-cyano-6-methylpyridine-3-carboxylate (1318) (80USP4223142). 

N-Alkylpyridinium salts give mainly N,N -dialkyltetrahydro-4,4 -dipyridyl derivatives on reduction in neutral and slightly alkaline aqueous solution [76]. These products can be oxidised to the N,N -dialkyl-4,4 -dipyridyl. The radical-zwitterion derived from 4-cyano-l-methylpyridine couples and then loses cyanide ion to form N,N -dimethyl-4,4 -dipyridyl in 39 % yield [77]. 

Substantially fewer studies have been published for the reactions of alkyl-substituted heteroaromatics, although these compounds also have implications for coal combustion. Several references discussed in the previous section contain information on methylated heteroaromatic rings. Mackie and coworkers completed experimental and theoretical studies of the pyrolytic decomposition of 2-picoline (2-methylpyridine). They concluded that decomposition proceeded mainly through o-pyridinyl and 2-picolinyl radicals. The former tended to decompose predominantly to yield cyanoacetylene, while the latter favored decomposition to a cyano-functionalized cyclopentadiene (Fig. 16). 

Recently, these principles have been put to good use in the synthesis of 4-cyano-2-methylpyridine in 60% yield from l-ethoxy-2-methylpyridine (Scheme 136) (81JHC1349). 

Intermolecular cycloadditions involving pyridinones are well known (80H(14)1793). 4-Cyano-l-methylpyridin-2-one undergoes Diels-Alder reaction with a suitable diene (equation 195) (79H(12)l). The pyridinone (307) forms 1 1 and 1 3 adducts on reaction with DMAD under pressure (Scheme 225) (82H(19)499). 2-Azabarrelenone (308) may be prepared by a sequence (Scheme 225), the first step of which is the addition of maleic anhydride to l-benzylpyridin-2-one (80AG(E)463). 

Cyclization of the piperidone derivative (158) gave rise to diastereomer-ically pure perhydropyrido[2,l-h][l,3]oxazin-6-one (159) (94JA10819). Heating l-(3-methoxy-l-propyl)-2-hydroxy-3-cyano-4-methylpyridin-6(l//)-one in 25% sulfuric acid at 80°C for 2 h gave 8-methyl-6-oxo-2,3,4,6-tetrahydropyrido[2,1 -fo][ 1,3]oxazine-9-carboxamide (89EUP316779). 8-(4-Methoxyphenyl)-2,3,4,6-tetrahydropyrido[2, -b [1,3]oxazine-2,6-dione was obtained by cyclization of 3-[4-(4-methoxyphenyl)-2,6-dioxo-l,2,3,6-... 

Okamoto et a/.156 cyclized the dinitriles (86 R = CN, R2 = H) by heating in 15° hydrochloric acid to obtain pyrido[l,2-a]pyrimidine-3-carboxylic acids (89 R2 = H). 2-Aminopyridinium chloride and ethoxymethylene-malononitrile at 110CC yielded 3-cyano-4-imino-4H-pyrido[l,2-a]pyrimi-dine (87 R1 = R2 = H, X = NH) and compound 91. Under similar conditions, 2-amino-3-methylpyridine gave a noncyclized product of type 91. 

Chlorination of 2,6-dihydroxy-3-cyano-4-methylpyridine with phosphorus oxychloride and successive reaction with amines yields 2,6 diaminopyridines. With these coupling components brilliant orange and red dyes with excellent lightfastness are obtained (e.g., 43 [4]). 

A solution of 2-amino-3-methylpyridine (5.0 g, 0.0462 mole) and ethyl ethoxymethylenecyanoacetate (7.82 g, 0.0462 mole) in toluene (4 ml) was heated for 15 min by means of an oil bath maintained at 100°C. The solution was cooled and the crude product (9.1 g, 85%) collected by filtration. The product was recrystallized from 2-propanol to give an analytical sample of ethyl 2-cyano-3-(3-methyl-2-pyridylamino)acrylate, melting point 144°-146°C. 

Treatment of 4-amino-3,5-dicyano-2-methylpyridine (509) with ammonium sulfide at 45°C for 10 h gave only 4-amino-3-cyano-2-methyl-5-thiocarbamoylpyridine (510). Oxidation of this thioam-ide (510) with hydrogen peroxide gave the 3-aminoisothiazolo[4,3-c]pyridine (511) in good yield (Scheme 63) <80BRP2074565>. 

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