2- Trichloromethyl pyrimidines

By heating 4-amino-6-(cyanomethyl)-2-(trichloromethyl)pyrimidine-5-carbonitrile in a mixture of acetic and sulfuric acid the conversion into 4-aminopyrido[4,3-ring closure to the cyclic imide together with the substitution of the trichloromethyl group.516... 

A solution of 4-amino-6-(cyanomethyl)-2-(trichloromethyl)pyrimidine-5-carbonitrile (2.8 g, 10 mmol) in HOAc (50 mL) was treated with coned H2S04 (5 mL). The mixture was heated at reflux for 2 h after which the product was filtered off and crystallized. 

An attempt to generate 2-(trichloromethyl)pyrimidine 198, from 196 and phenyl vinyl sulfoxide 197, failed and produced 2-(trichloromethyl)-4-(dimethylamino)-l,3,5-triazine 203 as the only isolable product (20%) (Scheme 30). This compound is suggested to arise as a consequence of a partial fragmentation of 196 to A, A -dimethylformamidine 199 and trichloroacetonitrile 200 <1996JOC2470>. 

N-[6-dimethylamino)-5-aryl(alkyl)-2-(trichloromethyl)pyrimidin-4-yl]-4-aryl(alkyl)sulfonamides 63 in moderate-to-good yields starting from terminal alkynes, sulfonyl azides, trichloroacetonitrile, and 1,1,3,3-tetramethylguanidine (Scheme 27) (13SL165). 

Reaction of 4-cyano-3-trichloromethyl-lH-pyrido[l,2-c]pyrimidin-l-one with primary amines in boiling dioxane for 15 h gave 3-amino derivatives in 30-48% yields (05MI2). 

Azine approach. Cyclization of the oxime (48) (73G219) corresponds to a common method for the preparation of isoxazoles, viz. the reaction between 1,3-dicarbonyl compounds and hydroxylamine. Similarly a cyano group reacts with hydroxylamine to form an N-hydroxyamidine which can be cyclized to an isoxazole if the vicinal carbon is activated and carries a leaving group. The 5-cyanopyrimidine (49) perhaps behaves unexpectedly in that it is a trichloromethyl substituent which is the leaving group in the cyclization (79JHC11-09). This behavior may be attributed to its location in the activated pyrimidine 4-position. 

Pyrimidine 2,6-Bis-[trichloromethyl]-4-hydroxy- E9b/2, 24 [C13C-C(NH2) = CH —COOR SC12]... 

Pyrimidin 5-Ethoxycarbonyl-4-methyl-2-trichloromethyl- E9b/2, 135 [HN-C(CC13)-N = CR-NR2 4- HC = C-COOR]... 

T6429>. Pyrolysis of trispyrazolylmethane (94) alfords bispyrazolylmethane (88 R = H) and, probably, AT,iV -bipyrazole (14) while pyrolysis of bispyrazolylmethane (88 R = H) affords NH-pyrazole (7), trispyrazolylmethane (94), 1-methylpyrazole and, at higher temperatures, pyrimidine. To explain the formation of pyrimidine a radical mechanism involving the rearrangement of radical (70) was proposed. Trichloromethyl radicals react with 3(5)-methyl-pyrazole to afford 4-methylpyrimidine and its 2-chloro derivative <89PJS377>. 

Nitriles have also been used as cyclization partners. Thus, nicotinonitrile cyclizes with 2-amino-nicotinonitrile to give 2-(3-pyridyl)pyrido[2,3-r/]pyrimidin-4-amine (64).127 The electron-withdrawing effect of the pyridine group in nicotinonitrile, or of the trichloromethyl group in trichloroacetonitrile,128 appears to be essential for the reaction since benzonitrile does not react with 2-aminonicotinonitrile under the given conditions the dimer of 2-aminonicotinonitrile, 2-(2-amino-3-pyridyl)pyrido[2,3-r/]pyrimidin-4-amine,129 is obtained instead.127... 

The corresponding reaction of trichloroacetonitrile with 2-aminonicoti nonitriles in the presence of piperidine yields 2-(trichloromethyl)pyrido[2,3-rf]pyrimidin-4-ainines. Workup in boiling water or ethanol removes the trichloromethyl group to give corresponding hydroxy or ethoxy compounds, e.g. 65.128... 

Trichloromethyl groups in the 2-position of pyrido[2,3-t/]pyrimidines can be replaced by oxygen functionalities as shown by the reactions of 4-amino-6-thiocyanato-5-phenyl-2-(trichloromethyl)pyrido[2,3-t/]pyrimidin-7(8//)-one (38) and 7-ethoxy-6-thiocyanato-5-phenyl-2-(trichloromethyl)pyrido[2,3- /]pyrimidin-4-amine with water or ethanol.128... 

Ethyl 4,6-diamino-5-cyano-2-(trichloromethyl)nicotinate, obtained from ethyl 3-amino-4,4-dicyanobut-3-enoate and trichloroacetonitrile, reacts with benzoyl isothiocyanate in acetic acid to give ethyl 4,5-diamino-7-(trichloromethyl)-2-oxo-l,2-dihydropyrido[4,3-r/]pyrimidine-8-carboxylate (16).503... 

For other substitutions with trichloromethyl as the leaving group, see p 154 (pyrido[2,3-d]-pyrimidines). 

Bonacorso et al. reported that, P-alkoxyvinyl trichloromethyl ketones 72 (R i = H, Me,n-pr i-pr, i-Bu R2 = H, Me) are useful building bloeks for the synthesis of thiazolo[3,2-a]pyrimidin-5-ones 73 (Scheme 34) by reaetion with 2-aminothiazole [59]... 

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