One‐Pot, Atom and Step Economy (PASE) Assembly of Trifluoromethylated Pyrimidines from CF₃‐Ynones

Abstract

A highly efficient synthetic method for the preparation of of 6‐trifluoromethylated pyrimidines was developed. The reaction of CF3‐substituted ynones and nitrogen 1,3‐bis(nucleophile)s was employed for the one‐pot assembly of the pyrimidine core. The cascade route proceeded through an aza‐Michael addition, intramolecular cyclization, and dehydration reaction sequence to give the target heterocycles in excellent yields (up to 97 %). When acetamidine was used as the bis(nucleophile), the unexpected addition of two equivalents of the CF3‐substituted ynone to the acetamidine was observed.

Reaction of Bromoenones with Amidines: A Simple Catalyst-Free Approach to Trifluoromethylated Pyrimidines

“…Solvent or base in this case did not show a significant influence on the reaction course. Similar results were observed in the reaction of acetamidine hydrochloride with CF 3 -ynones 16 and -unsubstituted enones. 13 Both organic bases -Et 3 N and DABCO -were successfully used in the reaction.…”

“…Calcd for C 18 H 13 F 3 N 2 : C, 68.78; H, 4.17; N, 8.91. Found: C, 68.60; H, 3.92; N, 8.65.4-(4-Methoxyphenyl)-2-phenyl-6-(trifluoromethyl)pyrimidine (3fa)Light yellow solid; yield: 250 mg (76%); mp 114-115 °C; R f = 0.9 (CHCl 3 -MeOH 97:3).1 H NMR (CDCl 3 ):  = 8.63-8.58 (m, 2 H, C 6 H 5 ), 8.21 (d, J = 8.9 Hz, 2 H, Ar), 7.79 (s, 1 H, C 5 H), 7.54-7.49 (m, 3 H, C 6 H 5 ), 7.05 (d, J = 8.9 Hz, 2 H, Ar), 3.89 (s, 3 H, CH 3 ).The NMR data are in agreement with those in the literature 13,16. 2-Phenyl-4-(m-tolyl)-6-(trifluoromethyl)pyrimidine (3ga)Pale yellow solid; yield: 235 mg (75%); mp 56-57 °C (CHCl 3 ); R f = 0.9 (CHCl 3 -MeOH 97:3).IR (KBr): 1589 (C 6 =N), 1549 (C 2 =N-C 4 =C 5 ), 1174, 1148 cm -1 (C-F).1 H NMR (CDCl 3 ):  = 8.65-8.60 (m, 2 H, C 6 H 5 ), 8.04 (d, J = 10.1 Hz, 2 H, Ar), 7.86 (s, 1 H, C 5 H), 7.55-7.51 (m, 3 H, C 6 H 5 ), 7.44 (dd, J 1 = J 2 = 7.6 Hz, 1 H, Ar), 7.38 (d, J = 7.6 Hz, 1 H, Ar), 2.49 (s, 3 H, CH 3 ).…”

“…The alternative reaction pathway that involves the intermediate formation of CF 3 -ynones 7 can apparently be ruled out because their reactions with amidines proceeded in the presence of very strong bases (MeONa, EtONa, t-BuOK, DBU). 16 Moreover, when fluorinated bromoenones 1 were treated with acetamidine hydrochloride (2f) in the presence of triethylamine, the unusual adduct 8, which was always formed as a major by-product from the reaction of two molecules of CF 3 -ynone with one molecule of acetamidine, 16 was not detected in this case.…”

“…Very recently, we have developed an efficient synthesis of 6-trifluoromethylated pyrimidines from CF 3 -ynones and nitrogen 1,3-binucleophiles. 16 The emergence of new pharmaceutical drugs possessing broad spectrum of activities stimulates the search for novel reagents for the synthesis of pyrimidine derivatives.…”

One-Pot Metal-Free Synthesis of 3-CF3-1,3-Oxazinopyridines by Reaction of Pyridines with CF3CO-Acetylenes

“…α,β-Unsaturated CF 3 -ketones have been shown as versatile building blocks for the synthesis of various fluorinated heterocyclic compounds [36,37,38,39,40]. In a series of works, we have demonstrated a great potential of CF 3 -ynones in different heterocyclizations to prepare fluorinated derivatives of diazepines [41], pyrimidines [42], thiophenes [43], triazoles [44], pyrazoles [45,46,47]. Recently, we focused our attention on the reactions of CF 3 -ynones with azines.…”