Pyrimidine ring nitriles

The formation of the adduct between 86 and the nitrile, i.e., 89, occurs more readily than that between 86 and ketones, since an activated nitrile is a better nucleophile than a ketone. Since the ce-proton in the adduct 89 is more acidic than the ce-proton in the ketonic adduct, also the ring opening will occur more easily. The interchange of a nitrile carbon with the ring carbon of a pyrimidine ring was also observed with the 3-benzyloxymethyl-l-ribosyl-5-cyanouracil. With a series of activated nitriles, the protected bi-cyclic nucleosides are formed. After deprotection, the corresponding bi-cyclic nucleosides are obtained (Scheme IV.35). 

When 4-imino-9-methyl-4//-pyrido[l, 2-a]pyrimidine-3-nitrile reacted with sodium azide in a solvent at 60-70°C for 3-6 hours, ring-opened 3 - [(3 - methyl-2- py ridy l)amino]-2- (1 -H- tetrazol-5- yl)-2- propenenitrile was obtained, but the bicyclic 4-imino-9-methyl-3-(l//-tetrazol-5-yl)-4//-pyrido[l,2-a]pyrimidine could be isolated when the reaction was carried out in acetic acid at 115°C (90EUP385634). The latter product was also obtained from the ring-opened product by heating in IN hydrochloric acid at 100°C for 1 hour, or in IN potassium hydroxide at 100°C for 3.5 hours. Reaction in acetic acid was also extended to 9-phenoxymethyl, 9-(4-acetyl-... 

A halogen substituent at C-4 of the pyrazolo[3,4-c ]pyrimidine ring system is readily replaced by active methylene reagents (76S824, 76YZ1352). For example, treatment of the derivatives (207) with active methylene reagents in the presence of sodium hydride results in the formation of derivatives (208) in 70-80% yield (Equation (21)). The methylsulfonyl derivative (209) is converted into the carboxamide (211) when treated with cyanide ion intermediacy of the nitrile (210) seems most likely (Scheme 16) <82JMC1334>. 

Amidino and amino groups are converted in high yield into a fused pyrimidine ring on stirring the compound with (in this example, labelled) acetic formic anhydride (review of this compound [3823]. Amidino-nitriles react with either ammonium acetate or methylamine to give fairly good yields of the amino-pteridines (reviews of pteridines [3454, 3594, 3669]). Formic acid provides a carbon atom to complete the pyrimidine ring of a purine in this example of cyclization of an amino-amidine [2431]. No additional atoms are needed in the cyclization of the pyrazine (43.1) to a dihydropteridine [2159]. 

The imino-amine (51.6) reacts at room temperature with aldehydes or ketones with the formation of purines. The products obtained from aldehydes are slowly oxidized (by loss of two hydrogen atoms from the pyrimidine ring) at room temperature, but the ketone-derived purines are stable and are accompanied by smaller amounts of an imidazo[l,S-c]imidazoIe. During cyclization, the nitrile group is converted into a carboxamide. Pentane-2,4-dione, 2-furfuraldehyde and but-2-enal give the fully aromatized purine as the main or only product isolated (in 38-49% yield). Stirring an imino-nitrile for several hours or heating it for a few minutes with an anhydride converts it into a fused pyrimidine. 

The nitrile group of another malonic acid derivative (65.7) forms a pyrimidine ring by reaction with a ring-nitrogen. 

The starting materials for these syntheses are 2-aminonicotinic acids and derivatives such as esters. Examples of 2-aminonicotinamides and -onitriles are cited here if the amide or nitrile nitrogen is not incorporated into the pyrimidine ring, although in cyclizations with carboxamides or urea there are ambiguities. 

Most pyrimidine carbonitriles show normal nitrile chemistry reductive reactions to methylamines by metal hydrides, hydrolytic reactions, reduction to aldehydes and formation of ketones with Grignard reagents. However, in highly electron-deficient pyrimidines, competition may arise between addition to an electrophilic substituent and the electrophilic pyrimidine ring. In the 5-cyano derivative (426), specific attack of organometallics is in the 4-position, with formation of the dihydro derivatives (427) instead of a ketone <83ACS(B)6I3>. 

Kinetically stabilized azetes (575) react with acceptor-substituted nitriles in a [4 -I- 2] cycloaddition step (Scheme 91). The initially formed Dewar pyrimidine (576) is subsequently isomerized to the pyrimidine (577). The sterically demanding substituents necessary for the stabilization of the azetes are thus introduced into the pyrimidine ring <90SL40i>. 

This gives the 4-pyrimidone ring, which is converted into the 4,5-dichloro-6-(l-fluoroethyl)pyrimidine by the action of sulfuryl chloride in the presence of dimethylformamide (DMF) [68]. The chlorine on the 4-position of the pyrimidine ring is substituted with the side chain 2-[4-(trifluoromethyl)phenyl]ethylamine through a nucleophilic substitution reaction [63]. The side chain 2-[4-(trifluoro-methoxy)phenyl]ethylamine is prepared by chloromethylation of trifluorome-thoxybenzene followed by displacement of the chlorine atom with cyanide and reduction of the nitrile with Raney nickel [69]. 

Ethyl 3-azido-l-methyl-177-indole-2-carboxylate 361 is prepared in 70% yield by diazotization of amine 360 followed by substitution of the created diazonium group with sodium azide. In cycloadditions with nitrile anions, azide 361 forms triazole intermediates 362. However, under the reaction conditions, cyclocondensation of the amino and ethoxycarbonyl groups in 362 results in formation of an additional ring. This domino process provides efficiently 4/7-indolo[2,3-i ]l,2,3-triazolo[l,5- ]pyrimidines 363 in 70-80% yield (Scheme 57) <2006TL2187>. 

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