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DOI: 10.1055/s-0030-1260976
Ethyl 3-[(Ethylthio)carbonyl]-4,4,5,5,5-pentafluoropentanoate: A Building Block towards Trifluoromethyl Pyrazoles and Pyrimidin-4-ones
Publication History
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
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References and Notes
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.
10Data 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.
11Data 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+].
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.
13Preparation 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.
14Data 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.