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

doi:10.1055/s-0030-1260976

LETTER

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;

Abstract

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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

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References

References and Notes

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.

For general reviews, see:

2a Bégué J.-P. Bonnet-Delpon D. Bioorganic and Medicinal Chemistry of Fluorine Wiley-VCH; Weinheim: 2008.

2b Burger K. Wucherpfennig U. Brunner E. Adv. Heterocycl. Chem. 1994, 60: 1

2c Fluorine in Bioorganic Chemistry Welch JT. Eswarakrishnan S. John Wiley & Sons; New York: 1991.

3a Kumar V. Aggarwal R. Singh SP. Heterocycles 2008, 75: 2893

3b Sloop JC. Bumgardner CL. David Loehle W. J. Fluorine Chem. 2002, 118: 135

For some reviews, see:

4a Plantier-Royon R. Portella C. Targets Heterocycl. Syst. 2006, 10: 114

4b Zhu SZ. Wang YL. Peng WM. Song LP. Jin GF. Curr. Org. Chem. 2002, 6: 1057

4c Uneyama K. J. Fluorine Chem. 1999, 97: 11

5 Muzard M. Portella C. J. Org. Chem. 1993, 58: 29

6 Portella C. Bouillon J.-P. in ‘Fluorine-Containing Synthons’ Soloshonok VA. ACS Symposia in print No. 911, American Chemical SocietyOxford University Press; Washington / D.C.: 2005. Chap. 12. p.232-247

7a Huot JF. Muzard M. Portella C. Synlett 1995, 247

7b Hénin B. Huot JF. Portella C. J. Fluorine Chem. 2001, 107: 281

7c Bouillon JP. Hénin B. Huot JF. Portella C. Eur. J. Org. Chem. 2002, 1556

8 Brulé C. Bouillon J.-P. Portella C. Tetrahedron 2004, 60: 9849

9a Dondy B. Doussot P. Iznaden M. Muzard M. Portella C. Tetrahedron Lett. 1994, 35: 4357

9b Bouillon J.-P. Didier B. Dondy B. Doussot P. Plantier-Royon R. Portella C. Eur. J. Org. Chem. 2001, 187

9c Portella C. Iznaden M. J. Fluorine Chem. 1991, 51: 1

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.

15a Lakontseva E. Krasavin M. Tetrahedron Lett. 2010, 51: 4095

15b Bouillon J.-P. Ates C. Janousek Z. Viehe HG. Tetrahedron Lett. 1993, 34: 5075

16 Hamper BC. J. Fluorine Chem. 1990, 48: 123

17a Kees KL. Fitzgerald JJ. Steiner KE. Mattes JF. Mihan B. Tosi T. Mondoro D. McCaleb ML. J. Med. Chem. 1996, 39: 3920

17b Kees KL. inventors; U.S. Patent, US 5264451. ; Chem. Abstr. 1993, 120: 95803

18 Moedritzer K, and Rogers MD. inventors; Eur. Patent, EP0370990. ; Chem. Abstr. 1990, 114: 6497

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 (C_q 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 (C_q 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.