Arylation of Halogenated Pyrimidines via a Suzuki Coupling Reaction

Abstract

The Suzuki coupling reaction has been used extensively for the synthesis of a wide variety of unsymmetrical biaryl compounds. We have extended this reaction to demonstrate the utility of preparing monophenyl-, diphenyl-, or triphenylpyrimidine depending on the reaction conditions. Further, it has been shown that chloropyrimidine substrates are preferable over iodo-, bromo-, or fluoropyrimidines.

Recent applications of the Suzuki–Miyaura cross-coupling reaction in organic synthesis

“…In addition, chloropyrimidine substrates are reported to be more preferable over iodo-, bromo-and fluoropyrimidines. 178 In connection with synthesis of heteroaryl dendrimers, Kotha and co-workers have prepared mixed aryl-heteroaryl C 3 -symmetric compounds such as 152 and 153 starting from 4-bromo-or 4-iodoacetophenone 179 using a trimerisation reaction and the SM cross-coupling as key steps.…”

Chemical and biological effects of substitution of the 2-position of ring-expanded (‘fat’) nucleosides containing the imidazo[4,5-e][1,3]diazepine-4,8-dione ring system: The role of electronic and steric factors on glycosidic bond stability and anti-HCV activity

“…As our SAR model I described earlier calls for a hydrophobic group at position-2, we decided to replace the bromo group with a phenyl substituent, which should be less electron-wihdrawing, but more bulky and hydrophobic than the bromo group. To that end, ZP-35 was converted into two 2-phenyl (ZP-45) and 2-p-methoxyphenyl (ZP-73) analogues via Suzuki coupling 15 with the appropriate phenylboronic acids (Scheme 4). Compound ZP-45 indeed underwent smooth sugar deprotection with t-butylamine in methanol to form the expected nucleoside ZP-52.…”

“…1,2 To this end, we synthesized the required diester precursors in the ribose series, namely ZP-115 and ZP-77, by standard Vorbrüggen ribosylation [17][18][19] of ZP-32 and ZP-72, respectively (Scheme 5). Whereas an attempted condensation reaction of ZP-115 with N-octylguanidine resulted in the formation of the deglycosylated, ring-closed heterocycle (ZP-16), the conversion of the 2-bromo group of ZP-77 into the corresponding p-methoxyphenyl derivative (ZP-108) via Suzuki coupling, 15 proceeded with no problem. The ring-closure of ZP-108 with guanidine provided the desired ZP-110, representing our first successful synthesis of a 2-substituted ring-expanded nucleoside.…”

“…The necessary diester nucleoside precursors for guanidine ringclosures were successfully prepared, as before, from ZP-115 or ZP-77, using Suzuki coupling. 15 These precursors include (Scheme 6) 2-phenyl (ZP-78), 2-p-F-phenyl (ZP-118), 2-mmethoxyphenyl (ZP-119), 2-p-phenylphenyl (ZP-123), 2-p-tert-butylphenyl (ZP-124), 2-mnitrophenyl (ZP-129), 2-p-trifluoromethylphenyl (ZP-132 and ZP-175), and 2-thienyl (ZP-128) derivatives. However, the attempted ring-closures of these precursors with guanidine or substituted guanidines were successful only in a limited number of cases, in addition to the mentioned p-methoxyphenyl (ZP-110), which included p-fluorophenyl (ZP-121), mmethoxyphenyl (ZP-122), and unsubstituted phenyl (NZ-53) derivatives.…”

Crystal structure of 4-chloro-6-phenylpyrimidine, C10H7ClN2

“…Therefore, the syntheses of pyrimidines have received a great deal of attention. Compared to conventional methods [9,10], the direct coupling of halopyrimidine is an alternative approach which does not involve the preparation of product-specific intermediates [11][12][13]. Here we report the crystal structure of the title compound, derived from the coupling reaction of 4,6-dichloropyrimidine and phenyl boronic acid.…”