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Synlett 2011(13): 1849-1852  
DOI: 10.1055/s-0030-1260976
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Ethyl 3-[(Ethylthio)carbonyl]-4,4,5,5,5-pentafluoropentanoate: A Building Block towards Trifluoromethyl Pyrazoles and Pyrimidin-4-ones

Cédric Brulé, Jean-Philippe Bouillon*, Charles Portella*
Institut de Chimie Moléculaire de Reims, UMR 6229 CNRS, Université de Reims Champagne-Ardenne, UFR Sciences, BP 1039, 51687 Reims Cedex 2, France
Fax: +33(326)913166; e-Mail: charles.portella@univ-reims.fr;
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Publication History

Received 12 May 2011
Publication Date:
25 July 2011 (online)

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Abstract

Reaction of the title substrate with methylhydrazine yields, via a domino process, HF elimination-β-addition/elimination-cyclocondensation, to 3-hydroxy-5-trifluoromethylpyrazol-4-ylacetic acid derivatives. In a similar domino process, reaction with benzamidine led mainly to ethyl 4-oxo-2-phenyl-6-trifluoromethylpyrimidin-4-yl acetate. While pyrazole was obtained in high yield via a totally chemo- and regioselective process, reaction with amidine led to a mixture of regioisomers.

Key words

fluorine - heterocycle - domino reaction - pyrazole - pyrimidin-4-one

    References and Notes

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1

Current address: Laboratoire Sciences et Méthodes Séparatives EA 3233, Université de Rouen, IRCOF, 76821 Mont Saint Aignan cedex, France. Email: jean-philippe.bouillon@univ-rouen.fr.

10

Data for Compound 3: oil. ¹H NMR (250 MHz, CDCl3): δ = 1.25 (t, ³ J H,H = 7.1 Hz, 3 H, CH 3CH2O or CH 3CH2S), 1.26 (t, ³ J H,H = 7.4 Hz, 3 H, CH 3CH2S or CH 3CH2O), 2.91 (q, ³ J H,H = 7.4 Hz, 2 H, CH3CH 2S), 3.46 (q, 5 J H,F = 1.4 Hz, 2 H, CH 2CO), 4.16 (q, ³ J H,H = 7.1 Hz, 2 H, CH3CH 2O), 7.30 (m, 2 H, NH2). ¹³C NMR (62 MHz, CDCl3): δ = 14.1, 14.5 (CH3CH2O, CH3CH2S), 23.5 (CH3 CH2S), 32.0 (CH2CO), 60.9 (CH3 CH2O), 99.2 (=CCH2CO), 120.5 (q, ¹ J C,F = 278.7 Hz, CF3), 143.8 (q, ² J C,F = 31.0 Hz, =CCF3), 171.1 (CO2), 193.5 (COS). ¹9F NMR (235 MHz, CDCl3): δ = -66.9 (s). IR (film): 3416, 3283, 2982, 1736, 1634, 1176 cm-¹. GC-MS (EI): m/z = 285 [M+], 224, 196, 168, 150, 54.

11

Data for Compound 4: oil. ¹H NMR (250 MHz, CDCl3): δ = 1.30, 1.31 (t, ³ J H,H = 7.3 Hz, 6 H, CH3CH2O, CH3CH2S), 3.03 (q, ³ J H,H = 7.3 Hz, 2 H, CH3CH 2S), 4.20 (m, 2 H, CH3CH 2O), 5.49 (dq, ² J H,F = 44.0 Hz, ³ J H,F = 6.0 Hz, 1 H, CHF), 6.39 (m, 1 H, =CH). ¹³C NMR (62 MHz, CDCl3): δ = 13.8, 14.0 (CH3CH2O, CH3CH2S), 24.2 (CH3 CH2S), 61.8 (CH3 CH2O), 85.8 (dq, ¹ J C,F = 196.6 Hz, ² J C,F = 36.0 Hz, CHF), 121.1 (qd, ¹ J C,F = 282.8 Hz, ² J C,F = 27.8 Hz, CF3), 126.4 (d, ³ J C,F = 10.7 Hz, =CH), 141.7 (d, ² J C,F = 16.7 Hz, =CCOS), 163.4 (CO2), 189.9 (d, ³ J C,F = 3.2 Hz, COS). ¹9F NMR (235 MHz, CDCl3): δ = -199.5 (dq, ² J F,H = 44.0 Hz, ³ J F,F = 12.1 Hz, 1 F, CHF),
-77.5 (dd, ³ J F,F = 12.1 Hz, ³ J F,H = 6.0 Hz, 3 F, CF3). IR (film): 2984, 2937, 1735, 1670, 1193, 1148 cm-¹. GC-MS (EI):
m/z = 288 [M+].

12

Treatment of compound 1 with hydrazine monohydrate or phenylhydrazine led to low conversions (<10-15%) even when the reaction mixture was refluxed for several hours.

13

Preparation of Pyrazole 6: To a solution of compound 1 (0.20 g, 0.6 mmol) in toluene (5 mL), was added methylhydrazine (76 µL, 1.2 mmol). The resulting mixture was heated at 80 ˚C for 1 h. After evaporation of volatiles under reduced pressure, the crude was purified by silica gel column chromatography (eluent: petroleum ether-EtOAc (80:20)] affording 0.10 g (yield: 66%, conversion: 88%) of pyrazole 6 as a solid; mp 92-94 ˚C. ¹H NMR (250 MHz, CDCl3): δ = 1.27 (t, ³ J H,H = 7.1 Hz, 3 H, CH 3CH2O), 3.53 (s, 2 H, CH 2CO2), 3.80 (s, 3 H, NCH3), 4.18 (q, ³ J H,H = 7.1 Hz, 2 H, CH3CH 2O), 11.1 (br s, 1 H, OH). ¹³C NMR (62 MHz, CDCl3): δ = 14.1 (CH3CH2O), 27.6 (CH2CO2), 37.5 (NCH3), 61.2 (CH3 CH2O), 99.9 (CCH2CO2), 120.0 (q, ¹ J C,F = 269.9 Hz, CF3), 130.2 (q, ² J C,F = 37.8 Hz, CCF3), 159.3 (COH), 170.5 (CO2). ¹9F NMR (235 MHz, CDCl3): δ = -59.9 (s). IR (KBr): 3058, 2991, 2648, 1736, 1553, 1294, 1129 cm-¹. GC-MS (EI): m/z = 252 [M+], 206, 179, 110. Anal. Calcd for C9H11F3N2O3: C, 42.86; H, 4.40; N, 11.11. Found: C, 43.14; H, 4.49; N, 10.56.

14

Data for compound 7: solid; mp 210-213 ˚C. ¹H NMR (250 MHz, acetone-d 6): δ = 3.51 (s, 2 H, CH 2CO2H), 3.77 (s, 3 H, NCH3). ¹³C NMR (62 MHz, acetone-d 6): δ = 27.6 (CH2CO2H), 38.0 (NCH3), 101.3 (CCH2CO2H), 121.3 (q, ¹ J C,F = 268.8 Hz, CF3), 129.7 (q, ² J C,F = 37.2 Hz, CCF3), 159.4 (COH), 172.0 (CO2H). ¹9F NMR (235 MHz, acetone-d 6): δ = -58.7 (s). IR (KBr): 3062, 2966, 2644, 1712, 1185, 1123, 1037 cm-¹. HRMS (ESI): m/z [M + H]+ calcd for C7H8F3N2O3: 225.0487; found: 225.0488.

19

Preparation of Pyrimidin-4-ones 8 and 9: To a suspension of benzamidine hydrochloride (1.20 g, 6.5 mmol) in a mixture of CH2Cl2-H2O (5:1; 6 mL) was added KOH (0.32 g, 5.7 mmol). The resulting mixture was stirred at r.t. for 30 min. Compound 1 (0.50 g, 1.6 mmol) was then added and the mixture was stirred at r.t. for 10 h. The crude mixture was washed with H2O (3 mL) and the organic layer was separated. The aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The combined organic phases were dried over Na2SO4, filtered off and concentrated in vacuo leading to a mixture (6:1) of pyrimidin-4-ones 8 and 9. Pure compounds 8 (0.20 g, yield: 39%) and 9 (0.04 g, yield: 7%) were obtained by preparative TLC [(Merck silica gel 60 PF254 with gypsum), eluent: petroleum ether-EtOAc (70:30)].
Compound 8: solid; mp 218-221 ˚C. ¹H NMR (250 MHz, CDCl3): δ = 1.24 (t, ³ J H,H = 7.1 Hz, 3 H, CH 3CH2O), 3.83 (s, 2 H, CH 2CO2), 4.17 (q, ³ J H,H = 7.10 Hz, 2 H, CH3CH 2O), 7.50-7.70 (m, 3 H, Ph), 8.20-8.40 (m, 2 H, Ph), 13.30 (br m, 1 H, NH). ¹³C NMR (62 MHz, CDCl3): δ = 14.1 (CH3CH2O), 30.7 (CH2CO2), 61.4 (CH3 CH2O), 119.4 (CCH2CO2), 121.2 (q, ¹ J C,F = 277.0 Hz, CF3), 127.9 (2 × CH of Ph), 129.1 (2 × CH of Ph), 130.6 (Cq of Ph), 132.8 (CH of Ph), 150.8 (q, ² J C,F = 34.0 Hz, CCF3), 155.9 (C-2), 165.4 (CON), 169.3 (CO2). ¹9F NMR (235 MHz, CDCl3): δ = -65.9 (s). IR (KBr): 3084, 2997, 1741, 1652, 1555 cm-¹. Anal. Calcd for C15H13F3N2O3: C, 55.22; H, 4.02; N, 8.59. Found: C, 54.99; H, 3.92; N, 8.39.
Compound 9: solid; mp 222-225 ˚C. ¹H NMR (250 MHz, CDCl3): δ = 1.45 (t, ³ J H,H = 7.1 Hz, 3 H, CH 3CH2O), 3.89 (q, ³ J H,F = 10.5 Hz, 2 H, CH2CF3), 4.49 (q, ³ J H,H = 7.1 Hz, 2 H, CH3CH 2O), 7.50-7.70 (m, 3 H, Ph), 8.20-8.30 (m, 2 H, Ph), 13.3 (br m, 1 H, NH). ¹³C NMR (62 MHz, CDCl3): δ = 14.0 (CH3CH2O), 28.8 (q, ² J C,F = 31.7 Hz, CH2CF3), 62.6 (CH3 CH2O), 115.3 (q, ³ J C,F = 2.7 Hz, CCH2CF3), 120-130 (m, CF3), 128.0 (2 × CH of Ph), 129.0 (2 × CH of Ph), 130.8 (Cq of Ph), 132.9 (CH of Ph), 155.0, 156.8 (C-2, C-6), 164.9, 165.2 (CON, CO2). ¹9F NMR (235 MHz, CDCl3): δ = -65.0 (t, ³ J F,H = 10.5 Hz). IR (KBr): 3432, 2969, 1745, 1547 cm-¹. GC-MS (EI): m/z = 327 [M+], 281, 220, 205, 145.