A Convenient Synthesis of 4-Trifluoromethyl-(2H)-pyridazin-3-ones from Methyl 3,3,3-Trifluoropyruvate

Abstract

A convenient two-step synthesis of 4-CF₃-(2H)-pyridazin-3-ones starting from methyl 3,3,3-trifluoropyruvate ­(MeTFP) and carbonyl compounds has been elaborated. As a result, a set of various 4-CF₃-(2H)-pyridazin-3-ones was obtained. The scope and limitations of the methodology is defined.

methyl 3,3,3-trifluoropyruvate - pyridazinones - tri­fluoromethyl - aldol condensation - cyclocondensation

References

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2a Yoshinori K, Tomoyuki K, Hiromichi S, Hideo Y, Takahiro K, Shunji T, Kyoko Y, Junko T, and Seiichi S. inventors; U.S. Pat. Appl. Publ. US  2004002497.  ; Chem. Abstr. 2004, 140, 77155

2b Matyus P. Maes BUW. Riedl Z. Hajos G. Lemiere GLF. Tapolcsanyi P. Monsieurs K. Elias O. Dommisse RA. Krajsovszky G. Synlett  2004,  1123 ; and references therein

3a Brule C. Bouillon J.-P. Nicolai E. Portella C. Synthesis  2003,  436 

3b Kamitori Y. Sekiyama T. Heterocycles  2004,  63:  707 

4a Fluorine in Bioorganic Chemistry   Filler R. Kobayasi Y. Yagupolskii LM. Elsevier; Amsterdam: 1993. 

4b Hudlicky M. Chemistry of Organic Fluorine Compounds   Ellis Horwood; Chichester: 1992. 

4c Kukhar VP. Soloshonok VA. Fluorine-Containing Amino Acids, Synthesis and Properties   Wiley; New York: 1995. 

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10

Typical Procedure for Preparation of Compounds 7a-k.
A neat mixture of ketone 6 (1 equiv) and MeTFP (1 equiv) in a pressure tube was heated at 100 °C 1-5 h (reaction mixture was monitored by ¹⁹F NMR). After cooling the tube was opened (Caution! Excessive pressure inside!) and the residue was triturated with n-hexane yielding targeted compound 7.

11

Typical ¹H NMR data (Varian Mercury-300 spectrometer) of aldols 7.
Compound 7f: ¹H NMR (300 MHz, CDCl₃): δ = 3.59 and 3.71 (2 H, AB-syst., ² J _HH = 18.0 Hz, CH₂), 3.83 (3 H, s, OCH₃), 4.18 (1 H, br s, OH), 7.48 (1 H, dd, ³ J _HH = 7.8 Hz, ³ J _HH = 4.8 Hz, CH), 8.13 (1 H, dt, ³ J _HH = 7.8 Hz, ⁴ J _HH = 2.5 Hz, CH), 8.72 (1 H, dd, ³ J _HH = 4.8 Hz, ⁴ J _HH = 2.5 Hz, CH), 9.07 (1 H, d, ⁴ J _HH = 2.5 Hz, CH).
Compound 7g: ¹H NMR (300 MHz, DMSO-d ₆): δ = 3.77 (3 H, s, OCH₃), 3.83 (2 H, s, CH₂), 7.05, (1 H, s, OH), 7.87 (2 H, d, ³ J _HH = 6.0 Hz, CH), 8.20 (2 H, d, ³ J _HH = 6.0 Hz, CH).
Compound 7i: ¹H NMR (300 MHz, CDCl₃): δ = 3.64 and 3.70 (2 H, AB-syst., ² J _HH = 17.1 Hz, CH₂), 3.93 (3 H, s, OCH₃), 4.24 (1 H, br s, OH), 7.17 (1 H, t, ³ J _HH = 4.8 Hz, CH), 7.72 (1 H, d, ³ J _HH = 4.8 Hz, CH), 7.76 (1 H, d, ³ J _HH = 4.8 Hz, CH).

12

Typical ¹³C NMR data (Varian Mercury-400 spectrometer) of aldols 7.
Compound 7f: ¹³C NMR (100 MHz, CDCl₃): δ = 41.0, 54.2, 74.9 (CCF₃, ² J _CF = 32.9 Hz), 123.1 (CF₃, ¹ J _CF = 285.1 Hz), 123.8, 128.3, 131.2, 135.5, 149.4, 154.1, 169.1, 193.6.
Compound 7g: ¹³C NMR (100 MHz, DMSO-d ₆): δ = 42.1, 53.2, 73.2 (CCF₃, ² J _CF = 28.2 Hz), 121.3, 123.7 (CF₃, ¹ J _CF = 285.7 Hz), 141.8, 151.0, 168.5, 195.2.
Compound 7i: ¹³C NMR (100 MHz, CDCl₃): δ = 41.0, 54.2, 75.2 (CCF₃, ² J _CF = 29.5 Hz), 122.1 (CF₃, ¹ J _CF = 285.3 Hz), 128.4, 133.1, 135.1, 142.7, 169.2, 187.4.

13

Typical MS data (MX-1321 instrument) of aldols 7.
Compound 7f: MS (EI, 70 eV): m/z (%) = 277 (4) [M⁺], 218 (26) [M⁺ - CO₂Me], 106 (100) [3-pyridyl - CO⁺], 78 (40) [3-pyridyl⁺], 51 (17).
Compound 7g: MS (EI, 70 eV): m/z (%) = 277 (5) [M⁺], 218 (27) [M⁺ - CO₂Me], 106 (100) [4-pyridyl - CO⁺], 78 (42) [4-pyridyl⁺], 51 (21).
Compound 7i: MS (EI, 70 eV): m/z (%) = 282 (4) [M⁺], 223 (15) [M⁺ - CO₂Me], 111 (100) [2-thienyl - CO⁺], 39 (16).

14

Typical Procedure for Preparation of (2 H )-Pyridazine-3-ones 8. To a solution of aldol 7 (1 equiv) in HOAc (5 mL) NH₂NH₂·H₂O (3 equiv) was added. The reaction mixture was refluxed for 1 h. After cooling the solvent was evaporated in vacuum and the residue was triturated with H₂O affording 8.

15

Typical ¹H NMR data (Varian Mercury-300 spectrometer) of 4-trifluoromethyl-(2H)-pyridazine-3-ones 8.
Compound 8f: ¹H NMR (300 MHz, DMSO-d ₆): δ = 7.54 (1 H, t, ³ J _HH = 7.2 Hz, CH), 8.31 (1 H, d, ³ J _HH = 7.2 Hz, CH), 8.51 (1 H, s, CH), 8.66 (1 H, d, ³ J _HH = 3.6 Hz, CH), 9.12 (1 H, s, CH), 13.97 (1 H, br s, NH).
Compound 8g: ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.52 (2 H, d, ³ J _HH = 6.3 Hz, CH), 9.10 (1 H, s, CH), 9.29 (2 H, d, ³ J _HH = 6.3 Hz, CH).
Compound 8i: ¹H NMR (300 MHz, DMSO-d ₆): δ = 7.18 (1 H, s, CH), 7.69 (1 H, s, CH), 7.91 (1 H, s, CH), 8.47 (1 H, s, CH), 13.73 (1 H, s, NH).

16

Typical ¹³C NMR data (Varian Mercury-400 spectrometer) of 4-trifluoromethyl-(2H)-pyridazine-3-ones 8.
Compound 8f: ¹³C NMR (100 MHz, DMSO-d ₆): δ = 121.6 (CF₃, ¹ J _CF = 271.8 Hz), 123.8, 127.6 (CCF₃, ² J _CF = 31.9 Hz), 129.7, 130.4 (CCCF₃, ³ J _CF = 5.0 Hz), 133.6, 141.6, 147.1, 150.3, 156.1.
Compound 8g: ¹³C NMR (100 MHz, DMSO-d ₆): δ = 119.9, 121.5 (CF₃, ¹ J _CF = 270.9 Hz), 127.6 (CCF₃, ² J _CF = 31.6 Hz), 129.9 (CCCF₃, ³ J _CF = 4.9 Hz), 140.9, 141.2, 150.3, 156.3, 172.0.
Compound 8i: ¹³C NMR (100 MHz, DMSO-d ₆): δ = 121.3 (CF₃, ¹ J _CF = 271.4 Hz), 127.8, 127.9 (CCF₃, ² J _CF = 31.2 Hz), 128.4, 128.9, 129.5 (CCCF₃, ³ J _CF = 4.9 Hz), 138.3, 140.3, 156.0.

17

Typical MS data (MX-1321 instrument) of 4-trifluoromethyl-(2H)-pyridazine-3-ones 8.
Compound 8f: MS (EI, 70 eV): m/z (%) = 242 (9) [M + 1], 241 (100) [M⁺], 184 (37).
Compound 8g: MS (EI, 70 eV): m/z (%) = 242 (10) [M + 1], 241 (100) [M⁺], 184 (24).
Compound 8i: MS (EI, 70 eV): m/z (%) = 247 (9) [M + 1], 246 (100) [M⁺], 189 (54).

18

Procedure for Preparation of 1,6-Dihydro-6-oxo-5-(trifluoromethyl)-3-pyridazineacetonitrile ( 10). To a solution of aldol 9a (1 g, 4.2 mmol) in HOAc (10 mL) NH₂NH₂·H₂O (0.63 g, 12.6 mmol) was added. The reaction mixture was refluxed for 3 h (reaction mixture was monitored by ¹⁹F NMR). After cooling the solvent was evaporated in vacuum and the residue was triturated with H₂O and extracted with Et₂O (10 mL). The Et₂O was evaporated in vacuum affording 10 (0.68 mg, 81%). Mp 175 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 4.15 (2 H, s, CH₂), 7.93 (1 H, s, CH), 13.8 (1 H, br s, NH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 23.1, 117.1, 121.4 (CF₃, ¹ J _CF = 270.8 Hz), 127.8 (CCF₃, ² J _CF = 31.2 Hz), 132.8, 139.1, 156.5. MS (EI, 70 eV): m/z (%) = 204 (100) [M⁺], 148 (15), 120 (39), 106 (14), 75 (19).

19

Procedure for Preparation of Methyl α-Hydroxy-5-phenyl-α-(trifluoromethyl)-1 H -pyrazole-3-propanoate ( 11). To a solution of aldol 9b (1 g, 3.1 mmol) in HOAc (10 mL) NH₂NH₂·H₂O (0.47g, 9.3 mmol) was added. The reaction mixture was refluxed for 1 h (reaction mixture was monitored by ¹⁹F NMR). After cooling the solvent was evaporated in vacuum and the residue was triturated with H₂O affording 11 (0.83 mg, 84%). Mp 98 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 3.11 and 3.33 (2 H, AB-syst., ² J _HH = 14.1 Hz, CH₂), 3.76 (3 H, s, OCH₃), 6.46 (1 H, s, CH), 7.04 (1 H, br s, OH), 7.32-7.41 (3 H, m, CH), 7.72 (2 H, d, ³ J _HH = 6.3 Hz, CH), 12.94 (1 H, br s, NH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 31.2 (br, Δν_1/2 ca. 30 Hz), 53.7, 78.1 (CCF₃, ² J _CF = 27.7 Hz), 102.9, 124.6 (CF₃, ¹ J _CF = 288.0 Hz), 125.4, 128.1, 129.3, 132.0 (br, Δν_1/2 ca. 65 Hz), 141.2 (br, Δν_1/2 ca. 300 Hz), 146.6 (br, Δν_1/2 ca. 270 Hz), 168.6. MS (EI, 70 eV): m/z (%) = 314 (38) [M⁺], 255 (40) [M⁺ - CO₂Me], 157 (100) [M⁺ - MeTFP].

20

Procedure for Preparation of Ethyl 1,6-Dihydro-6-oxo-5-(trifluoromethyl)-3-pyridazineacetate ( 12) and Methyl α,5-Dihydroxy-α-(trifluoromethyl)-1 H -pyrazole-3-propanoate ( 13).
To a solution of aldol 9c (1 g, 3.5 mmol) in HOAc (10 mL) NH₂NH₂·H₂O (0.53 g, 10.5 mmol) was added. The reaction mixture was refluxed for 1 h (reaction was monitored by ¹⁹F NMR). After cooling the solvent was evaporated in vacuum and the residue was triturated with Et₂O. The solvent was evaporated and the residue was dissolved in CH₂Cl₂ (10 mL). The insoluble precipitate was filtered affording 13 (0.43 g, 48%). The mother liquid was evaporated and the residue was triturated with hexane giving 12 (0.41 g, 47%).
Compound 12: mp 87 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.3 (3 H, t, ³ J _HH = 7.2 Hz, CH₃), 3.75 (2 H, s, CH₂), 7.71 (1 H, s, CH), 10.02 (1 H, br s, NH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 14.4, 20.9, 39.5, 53.6, 61.3, 120.1 (CF₃, ¹ J _CF = 272.9 Hz), 127.3 (CCF₃, ² J _CF = 31.4 Hz), 133.9, 141.8, 156.5, 168.4, 170.0. MS (EI, 70 eV): m/z (%) = 250 (35) [M⁺], 178 (86) [M⁺ - CO₂Et], 158 (40), 120 (20), 101 (49), 97 (33), 75 (20), 74 (43), 69 (24) [CF₃], 51 (25), 43 (100).
Compound 13: mp 196 °C ¹H NMR (300 MHz, DMSO-d ₆): δ = 2.94 and 3.16 (2 H, AB-syst., ² J _HH = 14.4 Hz, CH₂), 3.73 (3 H, s, OCH₃), 5.24 (1 H, s, CH), 7.0 (1 H, br s, OH), 10.6 (1 H, br s, NH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 30.8, 53.6, 77.8 (CCF₃, ² J _CF = 27.5 Hz), 89.8, 124.4 (CF₃, J _CF = 285.6 Hz), 137.3, 160.5, 168.4. MS (EI, 70 eV): m/z (%) = 254 (10) [M⁺], 195 (10) [M⁺ - CO₂Me], 98 (100) [M⁺ - MeTFP].