6-Chloro-4-phenylpyrimidine

Benzyl-9-phenyl-3,4-dihydro-27/,677-pyrimido[6,l-A [l,3]thiazine-6,8-(7//)-dione was prepared from 3-benzyl-6-chloro-l-(3-chloropropyl)-5-phenylpyrimidine-2,4-(17/,3//)-dione and NaSH hydrate in DMF in 27% yield <1995W035296>. 

The nature of the leaving halogeno atom. It has been observed that reaction of mono-labeled 6-fluoro-, 6-chloro-, and 6-iodo-4-phenyl[l(3)- Njpyrimidine with potassium amide/liquid ammonia leads to 6-amino-4-phenylpyrimidine in which the exocyclic amino group is N-labeled the percentages, however, strongly depend on the nature of the halogen atom, i.e., F (73 5%), Cl (93 5%), Br (83 5%), I (13 5%) (Scheme 11.12) (72RTC1414). 

In order to clarify the possible existence of these intermediates, 6-chloro-5-cyano-4-phenyl[l(3)- N]pyrimidine (20) (the label is scrambled over both nitrogens) and the radioactive 6-chloro-5-[ " C-cyano]-4-phenylpyrimidine (23) were synthesized as substrates. Because of the presence of the cyano function at C-5, one can expect that 20 (and 23) would undergo amination involving an Sn(ANRORC) mechanism. This has indeed been found. When 20 was reacted with potassium amide in liquid ammonia, two products were obtained as main product, 6-amino-5-cyano-4-phenylpyrimidine (21, 75%), and as minor product, a-amino-jS,jS -dicyanostyrene (22, about 20%) (Scheme 11.15). 

As one can see from the table, the degree to which this ANRORC process occurs is nearly independent of the temperature applied during the amination. For example, the amination of 2-chloro-4-phenylpyrimidine, when carried out at -33°C instead of -75°C, still occurs 90% according to the ANRORC mechanism. 

Fluoro-5-phenyl-l,2,4-triazine (109, X = F) reacts much faster than the 3-chloro-, 3-bromo-, or 3-iodo-compound. Moreover, the reaction mixture obtained is cleaner than that from the corresponding 3-chloro- or 3-bromo compounds 3-amino-5-phenyl-l,2,4-triazine (110) is formed in good yield. This conversion takes place to only a small extent (18%) via the ANRORC process the main part of the aminodefluorination seems to involve the Sn(AE) mechanism. This result is consistent with the observation that the aminodefluorination of 4,6-diphenyl-2-fluoropyrimidine follows the Sn(AE) process, whereas 2-fluoro-4-phenylpyrimidine (position 6 is vacant for addition of the nucleophile) reacts for the most part according to the Sn(ANRORC) mechanism (see Section II,C,l,c). 

Other workers confirmed the above results but did not isolate any of the 4-nitrophenyl product. The nitration of 5-bromo and 5-chloro-2-phenylpyrimidine was also shown to yield the ortho and meta products (in the ratio of about 3 7) with no para isomer being observed (80H1989). Further work has indicated that 5-nitro-2-phenylpyrimidine undergoes nitration in mixed acid at 0°C to give a similar mixture of ortho and meta products (1 7) with no para isomer, whereas 6-methyl-2-phenylpyrimidin-4-one (72) forms only a 3-nitro phenyl product (91UP1). 

When treated with potassium artiide in liquid ammonia, suitably substituted and activated pyrimidines are converted into imidazoles, a ring eontraction which has been shown by labelling to involve cleavage of the 5,6 bond (Scheme 6.1.6). 5-Amino-4-chloro-2-phenylpyrimidine is converted under the reaction conditions into 4-cyano-2-phenylimidazole in 30-35% yield, rather better than is achieved by Comforth s method (using aminoacetonitrile with... 

Amino-4-chloro-2-phenylpyrimidine (62) reacts with potassium amide in liquid ammonia to form 4-cyano-2-phenylimidazole (63) 4-chloro-5-methyl-2-phenylpyrimidine (64) gives 4-ethynyl-2-phenylimidazole (65) under the same conditions.These results are somewhat surprising in... 

The yields of the pyrimidines 147 and the pyridines 151 are not high and vary greatly, depending on the structure of the starting materials. The latter can also determine the nature of the product. Thus, a mixture of 2,4-dimethyl-6-phenylpyrimidine, 2,4-dimethyl-4,6-diphenyl-4//-l,3-oxazine and 1-chloro-l-phenylethene was obtained by refluxing a 1 3 3 ratio of the acetophenone-benzonitrile-phosphorus oxychloride mixture, followed by treatment of the crude product with sodium carbonate solution .It has been shown that addition of an additional ketone molecule to the iminium intermediate is an alternative to the formation of the A -acylenamines and this route is catalyzed by aluminum chloride. Auricchio and coworkers believe also that the reaction of ketones with nitriles catalyzed with both protic and Lewis acids must be considered as a Ritter reaction (see, however, Section V.C). The cationic intermediate 152 thus formed can undergo either a proton shift giving enamide 153 or addition of another ketone molecule... 

Cyclocondensation of the 2-amino-5-alkyl-4-chloro-5-phenylpyrimidines 41 with formylhydrazine gave the corresponding l,2,4-triazolo[4,3-c]pyrim-... 

In 4-chloro-2-methyl-6-phenylpyrimidine-5-carbonitrile, the reactivity of the chloro substituent allows the introduction of side chains which will cyclize with the adjacent nitrile function. Thus, cyanoacetamide yields 5-amino-2-methyl-7-oxo-7,8-dihydro-4-phenyipyrido[2,3-[Pg.110]

Treatment of 5-acetyl-4-chloro-6-methyl-2-phenylpyrimidine (38, R1 = Ph R2 = Me) with urea leads to the corresponding pyrimido[4,5-d]pyrimidine 39 (R1 = Ph, R2 = Me). On the other hand, the reaction with thiourea affords not the expected 4,5-dimethyl-7-phenylpyrimido[4,5-t/]pyrimidine-2-thiol, but instead 5-acetyl-6-methyl-2-phenylpyrimidine-4-thiol.116... 

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