Regioselectively Controlled Synthesis of N-Substituted (Trifluoromethyl)pyrimidin-2(1H)-ones

Abstract

A simple and regioselectively controlled method for the preparation of both 1,4- and 1,6-regioisomers of 1-substituted 4(6)-trifluoromethyl-pyrimidin-2(1H)-ones is described. Both regioisomers were synthesized from the cyclocondensation reaction of 4-substituted 1,1,1-trifluoro-4-methoxybut-3-en-2-ones: with nonsymmetric ureas for the 1-substituted 4-(trifluoromethyl)pyrimidin-2(1H)-ones (1,4-isomer) and with nonsymmetric 1-substituted 2-methylisothiourea sulfates for the synthesis of 1-substituted 6-(trifluoromethyl)pyrimidin-2(1H)-ones (1,6-isomer). Each method furnished only the respective isomer in very good yields. The structure of the products was assigned based on the (1)H and (13)C NMR as well as 2D HMBC spectral analysis.

Trifluoromethyl β‐Enamino Diketones as Dual Substrates for the Synthesis of 5‐Benzoyl‐6‐(trifluoromethyl)pyrimidines and their Pyrimidin‐4(3H)‐one Analogues

“…for the optimization of reaction conditions (Table ). The solvents were based on previous reports . It was reported previously that, in the cyclocondensation reaction of β‐alkoxyvinyl trichloromethyl ketones (enones) with N ‐substituted 2‐methylisothiourea sulfates (pseudothioureas), the initial nucleophilic attack is from the iminic nitrogen on the β‐carbon of the enones, which furnishes the 1,6‐regioisomers, exclusively .…”

“…The regioselectivity was also confirmed by NMR methods, as reported previously. [33] During the optimization step, we observed the formation of a different unexpected product when the solvent was changed from CHCl 3 to MeCN: the corresponding 5-benzoyl-2-methylsulfanyl-pyrimidin-4(3H)-one, which originated from the elimination of the -CF 3 group. In order to explore this finding, we attempted to optimize the reaction conditions.…”

“…The solvents were based on previous reports. [33] It was reported previously that, in the cyclocondensation reaction of -alkoxyvinyl trichloromethyl ketones (enones) with N-substituted 2-methylisothiourea sulfates (pseudothioureas), the initial nucleophilic attack is from the iminic nitrogen on the -carbon of the enones, which furnishes the 1,6-regioisomers, exclusively. [32] In this present study, -enamino diketones were also shown to be extremely regioselective for obtaining the 1,6regioisomer (3a); and, no trace of 3a′ was detected under 1 H NMR analysis.…”

Design, Synthesis, and Cholinesterase Inhibitory Activity of 4‐Substituted‐6‐(trihalomethyl)‐2‐methylsulfanyl Pyrimidines

“…[9,10] β-Alkoxyvinyl trihalomethyl ketones have proven to be successful as CCC-building blocks in the regioselective synthesis of several heterocyclic scaffolds [11][12][13] (including pyrimidine rings), easily allowing the introduction of trihalomethyl groups. [14,15] On the other hand, allylic brominated β-alkoxyvinyl trihalomethyl ketones (enones) have been far less explored in heterocyclic synthesis, especially in regard to pyrimidines. [16] Given the high chemoselectivity that has been observed in the synthesis of several heterocycles, the use of these enones in heterocyclic synthesis is now well established.…”

Synthesis of Highly Functionalized 4-Amino-2-(trifluoromethyl)-1H-pyrroles

“…17 Additionally, pyrroles with electron-donating substituents (e.g., amino and alkoxy groups) are not very stable. 18 Over the last few years, our research group has been demonstrating the versatility of 4-alkoxy(or amino)vinyl trihalomethyl ketones in the synthesis of pyrimidines, [19][20][21] tetrahydropyridines, 22 1,4-diazacycles, 23 and several other compounds. 13,24,25 Scheme 1 Selected approaches for the synthesis of 1H-pyrroles from 5azido/bromo enones…”