Design and Synthesis of Novel Trichloromethylated N-Azolylmethyl-1H-­pyrimidin-2-ones and Related N-Methylenaminones

Abstract

Reaction of 4-trichloromethyl-1H-pyrimidin-2-ones with 5-bromo-1,1,1-trichloro(fluoro)-4-methoxy-alk-3-en-2-ones affords 1-[5,5,5-trichloro(fluoro)-2-methoxy-4-oxopent-2-en-1-yl]-4-trichloromethyl-1H-pyrimidin-2-ones. Reaction of the latter trichloromethylated compound with amines, hydroxylamine, and hydrazines affords a series of 1-(2-alkylamine-5,5,5-trichloro-4-­oxopent-2-en-1-yl)-4-trichloromethyl-1H-pyrimidin-2-ones and 1-(5-trichloromethyl-5-hydroxy-4,5-dihydro-3-azol-3-ylmethyl)-4-trichloromethyl-1H-pyrimidin-2-ones, respectively.

N-pyrazolylmethylpyrimidinones - pyrimidines - pyrazoles - enamino ketones - halogenated heterocycles

References

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<A NAME="RS09105ST-23">23</A>

Pyrimidine 5 - General Procedure.
A mixture of 3 (3.0 g, 10.12 mmol), pyrimidinone 1 (2.16 g, 10.12 mmol) and K₂CO₃ (1.4 g, 10.12 mmol) was refluxed in anhyd acetone (30 mL) or anhyd MeCN for compound 2, for 16 h under vigorous stirring. The reaction was carried out in two phases. The crude product, a white solid, precipitated and was collected under vacuum filtration. The white solid was washed with cold distilled H₂O (2 × 15 mL), acetone (2 × 10 mL), dried, and recrystallized from CHCl₃-MeOH (3:1). White powder, yield 60%; mp 208 °C (decomp.).
IR (KBr): ν_max = 1669, 1617, cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ (pyrimidinone) = 7.06 (d, 1 H, ³ J _H5-H6 = 7.0 Hz, H-5), 8.50 (d, 1 H, ³ J _H6-H5 = 7.0 Hz, H-6); δ (enone) = 3.82 (s, 3 H, OMe), 5.35 (s, 2 H, CH₂), 6.22 (s, 1 H, H-3). ¹³C NMR (100 MHz, DMSO-d ₆): δ (pyrimidinone) = 95.2 (CCl₃), 98.3 (C-5), 153.8 (C-2), 153.4 (C-6), 170.8 (C-4); δ (enone) = 51.9 (CH₂), 56.0 (OMe), 90.1 (C-3), 96.7 (CCl₃), 174.9 (C-2), 179.8 (C-4). Anal. Calcd for C₁₁H₈Cl₆N₂O₃ (428.91): C, 30.80; H, 1.88; N, 6.53. Found: C, 30.69; H, 1.94; N, 6.55.

<A NAME="RS09105ST-24">24</A>

N -Isoxazolylmethylpyrimidinone 9.
A mixture of 5 (0.5 g, 1.17 mmol), hydroxylamine hydrochloride (0.15 g, 2.12 mmol), pyridine (0.1 mL, 2.12 mmol), and anhyd MeOH (15 mL) was stirred under reflux for 24 h. The solvent was removed under reduced pressure and a yellow oil was obtained. To this oil was added cold H₂O (10 mL) and the mixture was stirred for 20 min in order to precipitate the compound 9. The white powder precipitated and was filtrated and dried under vacuum. The product was purified by recrystallization from CHCl₃-MeOH (3:1). Yield 80%; mp 229 °C (decomp.). IR (KBr): ν_max = 3196, 1638 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ (pyrimidinone) = 7.09 (d, 1 H, ³ J _H5-H6 = 7.0 Hz, H-5), 8.50 (d, 1 H, ³ J _H6-H5 = 7.0 Hz, H-6); δ (isoxazole) = 3.30 (d, 1 H, ² J _4Hb-4Ha = 19.0 Hz, 4-Hb), 3.70 (d, 1 H, ² J _4Ha-4Hb = 19.0 Hz, 4-Ha), 4.95 (s, 2 H, CH₂), 8.60 (s, 1 H, OH). ¹³C NMR (100 MHz, DMSO-d ₆): δ (pyrimidinone) = 95.3 (CCl₃), 99.0 (C-5), 153.3 (C-6), 153.7 (C-2), 170.8 (C-4); δ (isoxazole) = 44.7 (C-4), 46.9 (CH₂), 101.4 (CCl₃), 111.5 (C-5), 155.7 (C-3). Anal. Calcd for C₁₀H₇Cl₆N₂O₃ (429.90): C, 27.94; H, 1.64; N, 9.77. Found: C, 27.87; H, 1.72; N, 9.71.

<A NAME="RS09105ST-25">25</A> Bonacorso HG. Bittencourt SRT. Wastowski A. Wentz AP. Zanatta N. Martins MAP. J. Heterocycl. Chem.  1999,  36:  45 

<A NAME="RS09105ST-26">26</A>

Selected Spectroscopic Data and Elemental Analysis of 11d.
Yield 70%; mp 139 °C (decomp.). IR (KBr): ν_max = 3472, 3405, 1668, 1618 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ (pyrimidinone) = 7.03 (d, 1 H, ³ J _H5-H6 = 7.0 Hz, H-5), 8.47 (d, 1 H, ³ J _H6-H5 = 7.0 Hz, H-6); δ (pyrazole) = 3.47 (d, 1 H, ² J _4Hb-4Ha = 20.0 Hz, 4-Hb), 3.78 (d, 1 H, ² J _4Ha-4Hb = 20.0 Hz, 4-Ha), 5.02 (d, 1 H, ² J = 16.0 Hz, CH₂), 5.13 (d, 1 H, ² J _H-H = 16.0 Hz, CH₂), 8.05 (s, 1 H, OH), 8.15 (s, 1 H, CONH₂). ¹³C NMR (100 MHz, DMSO-d ₆): δ (pyrimidin-one) = 95.4 (CCl₃), 99.1 (C-5), 153.4 (C-2), 152.6 (C-6), 170.7 (C-4); δ (pyrazole) = 47.5 (C-4), 48.5 (CH₂), 104.4 (CCl₃), 100.6 (C-5), 153.9 (C-3), 157.3 (CONH₂). Anal. Calcd for C₁₁H₉Cl₆N₅O₃ (471.94): C, 27.99; H, 1.92; N, 14.84. Found: C, 27.66; H, 1.83; N, 14.95.

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<A NAME="RS09105ST-28D">28d</A> Bonacorso HG. Wastowski AD. Muniz MN. Zanatta N. Martins MAP. Synthesis  2002,  1079