Facile Route to Tetrasubstituted Pyrazoles Utilizing Ceric Ammonium Nitrate

Abstract

A convenient approach for the synthesis of tetrasubstituted pyrazoles is described. The method involves the treatment of 1,3-diketones and allyltrimethylsilane with CAN followed by cerium-catalyzed addition of substituted hydrazines to construct pyrazoles in good yields.

Key words

heterocycles - pyrazoles - ceric ammonium nitrate - allyl­ation - hydrazines

References and Notes

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15

All reactions were run at room temperature unless specified otherwise.

16

One-Pot Procedure for 4-Allyl-1,3,5-trisubstituted Pyrazoles To a mixture of 1,3-dione (1 equiv) and allyltrimethylsilane (1.3 equiv) in MeCN, CAN (2.1 equiv) dissolved in MeCN was added dropwise. The solution was stirred at r.t. until the color disappeared completely (20-45 min). Hydrazine (1.4 equiv) was added and stirred at r.t. for 3.5-6 h (monitored by GC). Solvent was removed by rotary evaporation. Ice-cold water was added to the solid residue and extracted with CH₂Cl₂. The combined organic extract was dried over MgSO₄ and concentrated by rotary evaporation. The residue was purified with SiO₂ column chromatography eluting with hexanes-EtOAc.
4-Allyl-1-(4-methoxy-phenyl)-3,5-dimethyl-1 H -pyrazole (3c)
Yield 74% (0.89 g). ^¹H NMR (500 MHz, CDCl₃): δ = 2.13 (s, 3 H, Me), 2.21 (s, 3 H, Me), 3.14 (d, J = 5.0 Hz, 2 H, CH₂), 3.82 (s, 3 H, OMe), 4.98 (d, J = 8.5 Hz, 1 H, CH), 4.99 (br s, 1 H, CH), 5.85 (m, 1 H), 6.93 (d, J = 8.2 Hz, 2 H, ArH), 7.28 (d, J = 8.5 Hz, 2 H, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 10.65, 11.87, 27.99, 55.51, 114.09, 114.51, 114.54, 126.36, 133.31, 136.50, 136.61, 147.6, 158.67. HRMS-FAB: m/z = calcd for C₁₅H₁₉N₂O [MH]⁺: 243.1497; found: 243.1488.
4-Allyl-1-(2,4-dinitro-phenyl)-3,5-dimethyl-1 H -pyrazole (3d)
Yield 63% (0.48 g). ^¹H NMR (500 MHz, CDCl₃): δ = 2.15 (s, 3 H, Me), 2.16 (s, 3 H, Me), 3.15 (d, J = 5.7 Hz, 2 H, CH₂), 4.75 (d, J = 17.2 Hz, 1 H, CH), 5.03 (d, J = 10.0 Hz, 1 H, CH), 5.85 (m, 1 H), 7.67 (d, J = 8.7 Hz, 1 H, ArH), 8.49 (d, J = 7.9 Hz, 1 H, ArH), 8.76 (s, 1 H, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 10.2, 11.9, 27.56, 115.25, 117.39, 121.0, 127.26, 129.18, 135.25, 137.82, 138.11, 145.44, 145.95, 151.92. HRMS-FAB: m/z calcd for [MH]⁺ C₁₄H₁₅N₄O₄: 303.1093; found: 303.1071.
4-Allyl-1-(4-toluenesulfonyl)-3,5-dimethyl-1 H -pyrazole (3e)
Yield 67% (0.68 g). ^¹H NMR (500 MHz, CDCl₃): δ = 2.10 (s, 3 H, Me), 2.36 (br s, 6 H, 2 × Me), 2.98 (d, J = 5.7 Hz,
2 H, CH₂), 4.75 (dd, J = 1.7, 17.1 Hz, 1 H, CH), 4.92 (dd, J = 1.5, 10.1 Hz, 1 H, CH), 5.69 (m, 1 H), 7.25 (d, J = 8.4 Hz, 2 H, ArH), 7.77 (d, J = 8.8 Hz, 2 H, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 11.23, 12.29, 22.6, 27.18, 115.30, 118.79, 127.41, 129.77, 134.74, 135.44, 140.33, 144.91, 153.49. HRMS-FAB: m/z calcd for [MH]⁺ C₁₅H₁₉N₂O₂S: 291.1167; found: 291.1178.
4-(4-Allyl-3,5-dimethyl-pyrazol-1-yl)-benzoic Acid (3f)
Yield 65% (0.58 g). ^¹H NMR (500 MHz, CDCl₃): δ = 2.26 (s, 3 H, Me), 2.27 (s, 3 H, Me), 3.15 (d, J = 5.8 Hz, 2 H, CH₂), 4.98 (d, J = 17.1 Hz, 1 H, CH), 5.0 (d, J = 10.1 Hz, 1 H, CH), 5.85 (m, 1 H), 7.54 (d, J = 8.4 Hz, 2 H, ArH), 8.15 (d, J = 8.5 Hz, 2 H, ArH), 9.98 (br s, 1 H, OH). ^¹³C MR (125 MHz, CDCl₃): δ = 11.21, 11.73, 27.76, 114.93, 116.53, 123.71, 127.77, 131.13, 135.85, 136.89, 143.92, 149.37, 170.42. HRMS-FAB: m/z calcd for [MH]⁺: C₁₅H₁₇N₂O₂: 257.1290; found: 257.1287.
4-Allyl-3,5-diethyl-1-methyl-1 H -pyrazole (3g) Yield 76% (0.68 g). ^¹H NMR (500 MHz, CDCl₃): δ = 1.09 (t, J = 7.5 Hz, 3 H, Me), 1.18 (t, J = 7.5 Hz, 3 H, Me), 2.49-2.52 (two quart are overlapping, 2 × 2 H, 2 × CH₂), 3.08 (dd, J = 1.6, 4.7 Hz, 2 H, CH₂), 3.71 (s, 3 H, Me), 4.91 (d, J = 7.3 Hz, 1 H, CH), 4.93 (d, J = 7.8 Hz, 1 H, CH), 5.86 (m, 1 H). ^¹³C NMR (125 MH_Z, CDCl₃): δ = 13.55, 13.89, 17.4, 19.81, 27.67, 35.73, 113.1, 114.26, 137.53, 141.92, 151.26. HRMS-FAB: m/z calcd for C₁₁H₁₉N₂ [MH]⁺: 179.1548; found: 179.1572.

17

Typical Procedure for Pyrazole Synthesis An MeCN soln of 2-substituted diketone (1 equiv), hydrazine (1.4 equiv), and CAN (3 mol%) was refluxed for 3 h. Reaction mixture was cooled down to r.t. Solvent was removed by rotary evaporation. The residue was dissolved with CH₂Cl₂, and washed with H₂O. The organic layer was separated, dried over anhyd MgSO₄, and concentrated by rotary evaporation. The crude reaction mixture was purified by SiO₂ column chromatography eluted with hexanes-EtOAc.
4-Allyl-1,3,5-triphenyl-1 H -pyrazole (8b) Yield 72% (0.24 g). ^¹H NMR (500 MHz, CDCl₃): δ = 3.34 (dd, J = 1.9, 3.3 Hz, 2 H, CH₂), 5.02 (dd, J = 1.8, 17.0 Hz, 1 H, CH), 5.11 (dd, J = 1.8, 10.3 Hz, 1 H, CH), 6.00 (m, 1 H), 7.24-7.25 (m, 1 H, ArH), 7.27-7.30 (m, 4 H, ArH), 7.31-7.33 (m, 6 H, ArH), 7.34 (t, 2 H, J = 6.5 Hz, ArH), 7.42 (d, 2 H, J = 6.7 Hz, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 28.16, 115.85, 115.93, 124.7, 126.76, 127.7, 127.93, 128.32, 128.37, 128.42, 128.66, 129.91, 130.61, 133.65, 137.61, 140.13, 142.0, 151.48. HRMS-FAB: m/z calcd for C₂₄H₂₁N₂ [MH]⁺: 337.1705; found: 303.1721.
4-Allyl-1-(4-methoxyphenyl)-3,5-diphenyl-1 H -pyrazole (8c) Yield 76% (0.63 g). ^¹H NMR (500 MHz, CDCl₃): δ = 3.34 (br s, 2 H, CH₂), 3.76 (s, 3 H, OMe), 5.00 (d, 1 H, J = 18.4 Hz, CH), 5.08 (d, 1 H, J = 9.3 Hz, CH), 5.98 (m, 1 H), 6.79 (br d, 2 H, J = 6.1 Hz, ArH), 7.22-7.25 (m, 4 H, ArH), 7.29-7.32 (m, 4 H, ArH), 7.42 (br d, 2 H, ArH), 7.81 (d, 2 H, J = 6.7 Hz, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 28.22, 55.39, 113.86, 115.44, 115.75, 126.15, 127.59, 127.93, 128.20, 128.34, 128.36, 128.57, 128.86, 129.96, 130.67, 133.52, 133.79, 137.67, 141.98, 151.06, 158.36. HRMS-FAB: m/z calcd for C₂₅H₂₃N₂O [MH]⁺: 367.1810; found: 367.1826.

18

Alternative Workup Procedure for Methylallylation (8e and 8f only) Upon completion of allylation, an excess of Et₃N was added dropwise to the reaction mixture. Solvent was removed by rotary evaporation. The residue was dissolved with CH₂Cl₂, and washed with H₂O. The organic layer was separated, dried over anhyd MgSO₄, and concentrated by rotary evaporation. The crude reaction mixture was purified by SiO₂ column chromatography eluted with hexanes-EtOAc. 1-Methyl-4-(2-methylallyl)-3,5-diphenyl-1 H -pyrazole (8e) Yield 84% (0.24 g), ^¹H NMR (500 MHz, CDCl₃): δ = 1.69 (s, 3 H, Me), 3.11 (s, 2 H, CH₂), 3.81 (s, 3 H, Me), 4.61 (s, 1 H, CH), 4.64 (s, 1 H, CH), 7.30 (d, J = 6.9 Hz, 1 H, ArH), 7.38-7.45 (m, 7 H, ArH), 7.71 (br d, J = 7.2 Hz, 2 H, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 23.06, 32.19, 37.26, 111.47, 114.1, 127.23, 127.44, 127.94, 128.26, 128.47, 128.5, 129.48, 130.35, 133.97, 143.01, 145.3, 149.71. HRMS-FAB: m/z calcd for C₂₀H₂₁N₂ [MH]⁺: 289.1705; found: 289.1722.
1-(4-Methoxyphenyl)-4-(2-methylallyl)-3,5-diphenyl-1 H -pyrazole (8f) Yield 70% (0.79 g). ^¹H NMR (500 MHz, CDCl₃): δ = 1.78 (s, 3 H, Me), 3.20 (s, 2 H, CH₂), 3.79 (s, 3 H, OMe), 4.75 (s, 1 H, CH), 4.95 (s, 1 H, CH), 6.81 (d, J = 7.2 Hz, 2 H, ArH), 7.25 (m, 4 H, ArH), 7.32 (br t, J = 7.1 Hz, 4 H, ArH), 7.42 (d, J = 7.4 Hz, 2 H, ArH), 7.81 (d, J = 7.1 Hz, 2 H, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 23.28, 32.33, 55.39, 111.87, 113.84, 115.78, 126.14, 127.52, 127.70, 128.14, 128.57, 129.68, 129.88, 133.51, 133.74, 142.03, 145.47, 151.19, 158.3. HRMS-FAB: m/z calcd for C₂₆H₂₄N₂O [M]⁺: 380.1889; found: 380.1891.
4-Allyl-1-(4-methoxyphenyl)-3-methyl-5-phenyl-1 H -pyrazole (10a) Yield 45% (0.30 g). ^¹H NMR (500 MHz, CDCl₃): δ = 2.29 (s, 3 H, Me), 3.15 (dt, J = 5.6, 1.7 Hz, 2 H, CH₂), 3.75 (s, 3 H, Me), 4.98 (ddt, J = 20.0, 1.8, 1.8 Hz, 1 H, CH), 5.03 (ddt, J = 10.3, 1.7, 1.7 Hz, 1 H, CH), 5.90 (ddt, J = 17.0, 10.0, 5.6 Hz, 1 H, CH), 6.75 (m, J = 9.1 Hz, 2 H, ArH), 7.09 (m, J = 9.1 Hz, 2 H, ArH), 7.13-7.15 (m, 2 H, ArH), 7.27-7.30 (m, 3 H, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 12.01, 27.85, 55.37, 113.82, 114.94, 115.94, 126.03, 127.97, 128.33, 129.75, 130.72, 133.50, 136.83, 140.81, 148.45, 158.12. HRMS-FAB: m/z calcd for C₂₀H₂₀N₂O [M]⁺: 304.1576; found: 304.1570.
4-Allyl-1-(4-methoxyphenyl)-5-methyl-3-phenyl-1 H -pyrazole (10b) Yield 27% (0.16 g). ^¹H NMR (500 MHz, CDCl₃): δ = 2.21 (s, 3 H, Me), 3.34 (dt, J = 5.5, 1.8 Hz, 2 H, CH₂), 3.84 (s, 3 H, Me), 5.02 (ddt, J = 17.0, 1.8, 1.8 Hz, 1 H, CH), 5.08 (ddt, J = 10.3, 1.8, 1.6 Hz, 1 H, CH), 5.99 (ddt, J = 17.3, 10.5, 5.5 Hz, 1 H, CH), 6.97 (m, J = 8.9 Hz, 2 H, ArH), 7.30-7.34 (m, J = 7.5 Hz, 1 H, ArH), 7.37-7.41 (m, 4 H, ArH), 7.66-7.68 (m, 2 H, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 10.85, 28.28, 55.61, 113.83, 114.19, 115.20, 126.63, 127.97, 128.33, 133.17, 133.88, 136.72, 138.05, 150.76, 159.00, 195.65. HRMS-FAB: m/z calcd for C₂₀H₂₀N₂O [M]⁺: 304.1576; found: 304.1577.
4-Allyl-1,3-dimethyl-5-phenyl-1 H -pyrazole (11a) Yield 78% (0.63 g). ^¹H NMR (500 MHz, CDCl₃): δ = 2.21(s, 3 H, Me), 3.05 (m, 2 H, CH₂), 3.69 (s, 3 H, NMe), 4.88 (dd, J = 1.8, 7.0 Hz, 1 H, CH), 4.95 (dd, J = 1.7, 11.0 Hz, 1 H, CH), 5.82 (m, 1 H), 7.26-7.28 (m, 2 H, ArH), 7.37-7.45 (m, 3 H, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 11.85, 27.81, 36.77, 114.41, 114.61, 128.4, 128.55, 129.6, 130.52, 136.99, 141.85, 146.68. HRMS-FAB: m/z calcd for C₁₄H₁₇N₂ [M]⁺: 213.1392; found: 213.1387.
1-(4-Methoxyphenyl)-3,4-dimethyl-5-phenyl-1 H -pyrazole (12a) Yield 68% (0.37 g). ^¹H NMR (500 MHz, CDCl₃): δ = 2.01 (s, 3 H, CH₃), 2.31 (s, 3 H, Me), 3.71 (s, 3 H, OMe), 6.74 (d, J = 7.2 Hz, 2 H, ArH), 7.12 (m, 4 H, ArH), 7.27 (m, 3 H, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 8.52, 11.84, 55.21, 113.69, 113.93, 125.91, 127.65, 128.21, 129.63, 130.83, 133.40, 140.13, 148.06, 157.94. HRMS-FAB: m/z calcd for C₁₈H₁₈N₂O [M]⁺: 278.1419; found: 278.1412. 1-(4-Methoxyphenyl)-4,5-dimethyl-3-phenyl-1 H -pyrazole (12b) Yield 11% (0.06 g). ^¹H NMR (500 MHz, CDCl₃): δ = 2.19 (s, 3 H, Me), 2.23 (s, 3 H, Me), 3.84 (s, 3 H, OMe), 6.96 (d, J = 9.0 Hz, 2 H, ArH), 7.27-7.31 (m, 2 H, ArH), 7.37-7.41 (m, 3 H, ArH), 7.71 (d, J = 8.0 Hz, 2 H, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 9.76, 10.85, 55.58, 114.19, 125.41, 126.59, 127.28, 127.81, 127.90, 128,34, 134.25, 137.34, 150.30, 158.92. HRMS-FAB: m/z calcd for C₁₈H₁₈N₂O [M]⁺: 278.1419; found: 278.1422. 4-Allyl-1-(4-methoxyphenyl)-5-phenyl-3-(trifluoromethyl)-1 H -pyrazole (13) Yield 68% (0.49 g). ^¹H NMR (500 MHz, CDCl₃): δ = 3.27 (d, J = 3.6 Hz, 2 H, CH₂), 3.75 (s, 3 H, Me), 4.94 (d, J = 17.2 Hz, 1 H, C=CH), 5.03 (d, J = 10.5 Hz, 1 H, C=CH), 5.89 (m, 1 H, C=CH), 6.77 (d, J = 8.8 Hz, 2 H, ArH), 7.14 (m, 4 H, ArH), 7.33 (m, 3 H, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 27.38, 55.16, 113.98, 115.58, 116.63, 122.25 (q, J = 271 Hz, CF₃), 126.40, 128.65, 128.96, 129.07, 129.99, 132.45, 136.43, 141.05 (q, J = 37 Hz), 142.83, 159.17. HRMS-FAB: m/z calcd for C₂₀H₁₇F₃N₂O [M]⁺: 358.1293; found: 358.1301.