Development of an efficient route to CF₃-substituted pyrrolopyrimidines through understanding the competition between Michael and aza-Henry reactions

Abstract

The regioselective base-catalyzed addition of nitromethane to 2-oxo-4-trifluoromethyl-1,2-dihydropyrimidine-5-carboxylates is reported. It was found that the Michael-like pathway is highly reversible and substantially dominating under conditions of kinetic control (0-5 °C, 10 h) whereas the aza-Henry reaction leads to thermodynamically stable adducts after 8-24 h exposure at room temperature. The adjacent nitro and alkoxycarbonyl groups were exploited to demonstrate the synthetic potential of the obtained products by converting to the isomeric trifluoromethylated pyrrolo[3,4-d]pyrimidine-2,5-diones. With this aim an efficient protocol for selective reduction of nitro-derivatives to the corresponding 4- or 6-aminomethyl-2-oxo-4-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates and their subsequent thermal cyclocondensations was applied.

Regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1H)-ones

“…These compounds are unique heterocyclic conjugated trifluoromethylketimines with two competing electrophilic centers which can enable either Michael- or Mannich-type nucleophilic additions. As found in our previous studies, organocatalytic addition of acetone [ 37 ], nitromethane [ 38 ] and trimethylsilyl cyanide [ 39 ] in most cases can be performed regioselectively after optimization of the reaction conditions (temperature, solvent, time and catalyst nature). In general, under kinetic reaction control, the Michael-type 1,4-adducts are the predominant products while under thermodynamic control, the regioisomeric Mannich-type 1,2-adducts are more likely to be formed.…”

Substituent-Driven Selective N-/O-Alkylation of 4-(Trihalomethyl)pyrimidin-2(1H)-ones Using Brominated Enones

“…27 The brominated enones/enaminones were synthesized in accordance with previously reported procedures. 28,29 For the initial tests, we considered the pyrimidin-2(1H)ones 1a (R = Ph) and 2a (R = H) and 5-bromo enone 3, using K 2 CO 3 in refluxing acetone for 16 the pyrimidin-2(1H)-one and the 5-bromo enone] had been prepared previously by our research group. 25 However, the expected alkylated (N-or O-) product was not observed in any test done (when varying the solvent, temperature, and base).…”

“…Several derivatization techniques have already been reported for the synthesis of trihalomethyl (−CCl 3 or −CF 3 ) pyrimidines, − with the most widely explored derivatization technique being alkylation (usually N - or O -) using alkyl halides or esters . However, the selectivity of the reaction (to furnish N - or O -alkylated products) in the absence of protecting groups or catalysts is still a problem .…”

Chan–Evans–Lam N1-(het)arylation and N1-alkеnylation of 4-fluoroalkylpyrimidin-2(1H)-ones

“…Our interest in the development of N-arylation methods resonated with recent studies focused on the addition of various C-nucleophilic reagents to 4-trifluoromethylpyrimidin-2(1H)ones I, heterocyclic analogues of activated ketimines (Figure 1), thus offering potential applications in the design of new heterocyclic chemotypes [21][22][23][24][25]. Compounds I are precursors of trifluoromethyl-substituted dihydropyrimidine derivatives which appear as original and potent scaffolds in medicinal chemistry, given the great importance of fluorinated groups in drug discovery [26][27][28][29].…”