Metal‐Bearing and Trifluoromethyl‐Substituted Pyrimidines: Generation and Functionalization

Abstract

Keywords: Functionalization / Halogen/metal permutation / Metalation / Nucleophilic addition / Pyrimidines / Single electron transfer / Trifluoromethyl groups 5-Pyrimidyllithium species are fairly stable when the metal is flanked by two electron-withdrawing substituents such as trifluoromethyl and chlorine or bromine. Thus, the corresponding 5-carboxylic acids are produced in high yields from 4,5-dibromo-6-(trifluoromethyl)pyrimidine and 5-bromo-4-chloro-6-(trifluoromethyl)pyrimidine upon halogen/metal permutation accomplished with isopropylmagnesium chloride or butyllithium followed by carboxylation. Satisfactory or excellent yields of 5-carboxylic acids are equally obtained when 4-chloro-, 2,4-dichloro-and 2,4-dibromo-6-(trifluoromethyl)pyrimidine are deprotonated with lithium diisopro-

CF3‐Bearing Aromatic and Heterocyclic Building Blocks

“…Thus, 2,4-dichloro-and 2,4-dibromo-6-(trifluoromethyl)pyrimidine are smoothly lithiated to afford the acids 61 (79 %) and 62 (89 %) after carboxylation (Scheme 24). [69] As previously with quinolines, bromine proves again to be a valuable auxiliary substituent with CF 3 -bearing pyrazoles. 1-Methyl-5-(trifluoromethyl)pyrazole, laboriously prepared from 4-ethoxy-1,1,1-trifluoro-3-buten-2-one and methylhydrazine in 26 % yield, reacts with butyllithium exclusively at the methyl group.…”

“…4-(Trifluoromethyl)-pyrimidine-2-carboxylic acid (58; 36 %) and 4-chloro-or 4-bromo-6-(trifluoromethyl)pyrimidine-5-carboxylic acid (59 and 60; 73 and 54 %, respectively) are isolated after carboxylation and neutralization (Schemes 22 and 23). [69] Doubly activated positions are acidic enough to undergo deprotonation already when treated with LITMP. Thus, 2,4-dichloro-and 2,4-dibromo-6-(trifluoromethyl)pyrimidine are smoothly lithiated to afford the acids 61 (79 %) and 62 (89 %) after carboxylation (Scheme 24).…”

Metalated heterocycles in organic synthesis: Recent applications

“…Thus, 5-pyrimidyllithium species are fairly stable when the metal is flanked by two electron-withdrawing substituents such as trifluoromethyl and chlorine or bromine, and can be generated by direct n-butyllithium-promoted metalation. 125 Another example of direct metalation on a pyrimidine ring is the LiTMP-promoted lithiation of 4-iodopyrimidine 50 to give 5-pyrimidinyllithium species 51, which has been formylated to afford the aldehyde 52 in a synthesis of 14-azacamptothecin, a water-soluble topoisomerase I poison (Scheme 16). 126 This lithiating agent has also been used for the DoM preparation of 5-lithio-2,4-di-tert-butoxypyrimidine, a useful heteroaryllithium used in the synthesis of pseudouridines.…”

CF3‐substituierte aromatische und heterocyclische Bausteine

“…Recht saubere Halogen/Metall-Permutationen gelingen bei der Reaktion von 2-Brom-4-(trifluormethyl)pyrimidin, [68] 5-Brom-4-chlor-6-(trifluormethyl)pyrimidin [68] sowie 4,5-Dibrom-6-(trifluormethyl)pyrimidin [68] mit Butyllithium oder Isopropyl- . [69] Doppelt aktivierte Stellungen sind hinreichend acid, um bereits von LITMP deprotoniert zu werden. 2,4-Dichlor-und 2,4-Dibrom-6-(trifluormethyl)pyrimidin lassen sich so glatt lithiieren und durch Carboxylieren in die Säuren 61 (79 %) und 62 (89 %) überführen (Schema 24).…”

“…2,4-Dichlor-und 2,4-Dibrom-6-(trifluormethyl)pyrimidin lassen sich so glatt lithiieren und durch Carboxylieren in die Säuren 61 (79 %) und 62 (89 %) überführen (Schema 24). [69] Wie schon vorher bei den Chinolinen, erweist sich Brom auch bei CF 3 -markierten Pyrazolen als wertvoller Hilfssubstituent. 1-Methyl-5-(trifluormethyl)pyrazol, mühsam in 26 % Ausbeute aus 4-Ethoxy-1,1,1-trifluor-3-buten-2-on und Methylhydrazin hergestellt, reagiert mit Butyllithium ausschließlich an der Methyl-Gruppe.…”