Haloacetylated Enol Ethers: a Way Out for the Regioselective Synthesis of Biologically Active Heterocycles

Abstract

This review describes advances in the synthesis of heterocyclic scaffolds (associated with their biological activity), using haloacetylated enol ethers as precursors. The wide variety of heterocycles that can be prepared using these precursors, together with the high regioselectivity they usually provide, in [3+2] and [3+3] cyclocondensation reactions, make these starting materials powerful tools. The biological evaluation is also highlighted, given that several analogues of commercially available drugs can be easily accessed.

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

“…When comparing to a less hindered and more labile alkoxy group (methoxy or ethoxy, usually used for these reactions) combined with a less reactive dinucleophile such as 2-methyl-2-thiopseudourea sulfate, this resulted in a significant decrease in the isolated yield of 4a . 24 With the aim of using a methoxy group at the β-position, the alkylation of pyrimidin-2(1 H )-one 1a with brominated enone 5a was performed. However, in the 1 H NMR analysis, only a mixture of starting materials along with peaks that could not be assigned to any plausible structure was obtained.…”

N‐Functionalization of 4‐amino‐2‐(trifluoromethyl)‐1H‐pyrroles: Synthesis of N‐alkyl derivatives and 1,2,3‐triazol‐4‐yl‐pyrrole scaffolds

“…13 C NMR (CDCl 3 , 150 MHz): δ = 136.4, 121.5 (q, 1 J C-F = 266.6 Hz), 119.1 (q, 2 J C-F = 36.8 Hz), 111.4 (q, 4 J C-F = 2.4 Hz), 102.1 (q, 3 J C-F = 3.5 Hz), 79.8, 72.2, 54.5, 49.6 (q, J C-F = 2.2 Hz), 41.8, 24.5, 20.5, 11.6, 11.1. GC-MS (EI, 70 eV): m/z (%) = 272 (44) [M + ], 244 (13), 243 (100), 229 (10), 204 (11), 201 (29), 181 (12), 174 (14), 161 (17) (m, 1H), 1.39 (d, 3H, J = 6.7 Hz), 1.10 (d, 3H, J = 6.7 Hz), 0.93 (t, 3H, J = 7.4 Hz), 0.82 (t, 3H, J = 7.4 Hz). 13 C NMR (CDCl 3 , 150 MHz): δ = 135.5, 121.6 (q, 1 J C-F = 266.5 Hz), 118.9 (q, 2 J C-F = 37.3 Hz), 107.4-107.3 (m), 101.4-101.3 (m), 82.0, 71.3, 54.7, 36.9, 30.8, 27.4, 22.2 (q, J C-F = 2.0 Hz), 16.5 (q, J C-F = 2.2 Hz), 11.5, 10.6.…”

“…19 F NMR (CDCl 3 , 564 MHz): δ = À57.05. GC-MS (EI, 70 eV): m/z (%) = 300 (37) [M + ], 272 (16), 271 (100), 215 (35), 187 (11), 176 (14), 161 (18) (d, 1H, J = 6.8 Hz), 0.94 (d, 6H, J = 6.6 Hz), 0.90 (d, 6H, J = 6.7 Hz). 13 C NMR (CDCl 3 , 150 MHz): δ = 136.8, 121.5 (q, 1 J C-F = 266.0 Hz), 119.2 (q, 2 J C-F = 37.4 Hz), 111.4-111.3 (m), 101.9-101.8 (m), 79.8, 72.0, 60.9, 42.2, 30.0, 26.7, 20.5 (2C), 19.9 (2C).…”

“…Thus, a more viable route would be the use of starting materials that enable this substitution pattern. The 5-bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one (brominated enone) has proven to be a suitable starting material for synthesizing 4-amino/alkoxy-(2-trifluoromethyl)-1Hpyrroles via intramolecular cyclocondensation approaches [7][8][9][10][11]. It is also important to note that the insertion of electron-donating substituents in pyrroles may furnish unstable products, due to the electron-rich character of the ring [12].…”

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

“…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 .…”