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

Abstract

The Chan–Evans–Lam reaction of 1-unsubstituted 4-fluoroalkylpyrimidin-2(1Н)-ones with arylboronic acids is reported as a facile synthetic route to hitherto unavailable N1-(het)aryl and N1-alkenyl derivatives of the corresponding pyrimidines. An efficient C–N bond-forming process is also observed by using boronic acid pinacol esters as coupling partners in the presence of Cu(II) acetate and boric acid. The 4-fluoroalkyl group on the pyrimidine ring significantly assists in the formation of the target N1-substituted products, in contrast to the 4-methyl and 4-unsubstituted substrates which do not undergo N1-arylation under similar reaction conditions.

Hydroaminoalkyl Functionalization of Pyrimidin‐2(1H)‐ones by Visible Light Organophotocatalysis: A Radical Approach to Biginelli‐Type Dihydropyrimidines

“…In order to further broaden our reaction scope, we also investigated the photocatalytic aminoalkylation of various substituted pyrimidin-2(1H)-one substrates (Scheme 5). [27,56,57] Using the most reactive trifluoroborate 1 a, the reaction was shown to have good substituent tolerance at the N-1 position of the starting pyrimidines 2 b-t (substituent R 1 ): N-benzyl, allyl, phenyl, vinyl, styryl, and benzoylmethyl; all of these compounds provided the corresponding products 3 i-l, n, o in uniformly good 61-73% isolated yields (except for the N-unsubstituted product 3 m in a moderate 37% yield). Interestingly, the trans-styryl substrate 2 n gave rise to a mixture of cis and trans isomers of 3 n (isolated as individual pure compounds).…”

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

“…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 . For instance, selective N -substituted derivatives have been achieved by using the following special strategies: (i) using TMS-protected pyrimidines, (ii) heterocyclization of carbamates with 4-aminoesters, (iii) direct cyclocondensation of 4-alkoxy­(amino)­vinyl trifluoromethyl ketones with substituted ureas (Scheme a), , and (iv) coupling of aryl boronic acids using Cu­(OAc) 2 ·H 2 O (Scheme b) . The direct alkylation of 4-(trihalomethyl)­pyrimidin-2­(1 H )-ones with methyl iodide or allyl bromide furnished a mixture of N -/ O -alkylated products in accordance with the chosen substrate (Scheme c). ,, However, when the reaction was done with a more complex alkylating agent (5-bromo-1,1,1-trichloro-4-methoxypent-3-en-2-one or brominated enone), the same reaction furnished only the N -alkylated pyrimidine (Scheme b) …”

Chemoselective O-Alkylation of 4-(Trifluoromethyl)pyrimidin-2(1H)-ones Using 4-(Iodomethyl)pyrimidines

“…There have been several studies regarding the chemoselectivity between N - and O -alkylation − (or S -alkylation in pyrimidine-2­(1 H )-thiones − ) when preparing alkyl/aryl derivatives; however, directing the reaction toward furnishing one sole product in the absence of protecting groups or specific catalysts is a problem yet to overcome . More specifically, several derivatization techniques have already been reported for the synthesis of trifluoromethyl-containing pyrimidines; − however, the most widely explored one is still alkylation using alkyl halides or esters, and others are based on the application of TMS-protected pyrimidines, cyclocondensation strategies using starting materials that allow the desired substitution pattern, − and copper-mediated coupling reactions with aryl boronic acids …”

“…23 More specifically, several derivatization techniques have already been reported for the synthesis of trifluoromethyl-containing pyrimidines; 24−28 however, the most widely explored one is still alkylation using alkyl halides or esters, 29 and others are based on the application of TMS-protected pyrimidines, 29 cyclocondensation strategies using starting materials that allow the desired substitution pattern, 30−32 and copper-mediated coupling reactions with aryl boronic acids. 33 The direct alkylation of the 4-(trifluoromethyl)pyrimidin-2(1H)-ones with alkyl or allyl halides furnishes a mixture of Nand O-alkylated products in ratios that depend mostly on the substrate choice. 18,23,34 When the same reaction was performed with a more complex alkylating agent (5-bromo-1,1,1-trichloro-4-methoxypent-3-en-2-one, a brominated enone), only the N-alkylated pyrimidine was observed.…”