Synlett 2009(9): 1490-1494  
DOI: 10.1055/s-0029-1217163
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Facile Route to Tetrasubstituted Pyrazoles Utilizing Ceric Ammonium Nitrate

James J. Devery, III, Pramod K. Mohanta, Brian M. Casey, Robert A. Flowers, II*
Department of Chemistry, Lehigh University, Bethlehem, PA 18015, USA
Fax: +1(610)7586536; e-Mail: rof2@lehigh.edu;
Weitere Informationen

Publikationsverlauf

Received 7 January 2009
Publikationsdatum:
13. Mai 2009 (online)

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.

    References and Notes

  • 1 Shinkai I. In Comprehensive Heterocyclic Chemistry II:
    A Review of the Literature 1982-1995: The Structure, Reactions, Synthesis, and Uses of Heterocyclic Compounds   Vol. 3:  Shinkai I. Pergamon; Oxford UK: 1996.  p.1-75  
  • 2 Genin MJ. Biles C. Keiser BJ. Poppe SM. Swaney SM. Tarpley WG. Yagi Y. Romero DL. J. Med. Chem.  2000,  43:  1034 
  • 3 Bebernitz GR. Argentieri G. Battle B. Brennan C. Balkan B. Burkey BF. Eckhardt M. Gao J. Kapa P. Strohschein RJ. Schuster HF. Wilson M. Xu DD.
    J. Med. Chem.  2001,  44:  2601 
  • 4a Regan J. Breitfelder S. Cirillo P. Gilmore T. Graham AG. Hickey E. Klaus B. Madwed J. Moriak M. Moss N. Pargellis C. Pav S. Proto A. Swinamer A. Tong L. Torcellini C. J. Med. Chem.  2002,  45:  2994 
  • 4b Palomer A. Cabre F. Pascual J. Campos J. Trujillo MA. Entrena A. Gallo MA. Garcia L. Mauleon D. Espinosa A. J. Med. Chem.  2002,  45:  1402 
  • 4c Elzein E. Kalla RV. Li X. Perry T. Gimbel A. Zeng D. Lustig D. Leung K. Zablocki J. J. Med. Chem.  2008,  51:  2267 
  • 5 Slee DH. Moorjani M. Zhang X. Lin E. Lanier MC. Chen Y. Rueter JK. Lechner SM. Markison S. Malany S. Joswig T. Santos M. Gross RS. Williams JP. Castro-Palomino JC. Crespo MI. Prat M. Gual S. Díaz J.-L. Jalali K. Sai Y. Zuo Z. Yang C. Wen J. O’Brien Z. Petroski R. Saunders J. J. Med. Chem.  2008,  51:  1730 
  • 6 Wang H. Duffy RA. Boykow GC. Chackalamannil S. Madison VS. J. Med. Chem.  2008,  51:  2439 
  • 7 Li H. Li H.-y. McMillen WT. Heap CR. McCann DJ. Yan L. Campbell RM. Mundla SR. King C.-HR. Dierks EA. Anderson BD. Britt KS. Huss KL. Voss MD. Wang Y. Clawson DK. Yingling JM. Sawyer JS. J. Med. Chem.  2008,  51:  2302 
  • 8 Lauria A. Abbate I. Patella C. Gambino N. Silvestri A. Barone G. Almerico AM. Tetrahedron Lett.  2009,  in press
  • 9a Fink BE. Mortensen DS. Stauffer SR. Aron ZD. Katzenellenbogen JA. Chem. Biol.  1999,  6:  205 
  • 9b Kraichely D. Sun J. Katzenellenbogen J. Katzenellenbogen B. Endocrinology  2000,  141:  3534 
  • 9c Stauffer SR. Coletta CJ. Tedesco R. Nishiguchi G. Carlson K. Sun J. Katzenellenbogen BS. Katzenellenbogen JA. J. Med. Chem.  2000,  43:  4934 
  • 10a Molander GA. Chem. Rev.  1992,  92:  29 
  • 10b Nair V. Mathew J. Prabhakaran J. Chem. Soc. Rev.  1997,  26:  127 
  • 11a Zhang Y. Jiao J. Flowers RA. J. Org. Chem.  2006,  71:  4516 
  • 11b Jiao J. Zhang Y. Devery JJ. Xu L. Deng J. Flowers RA. J. Org. Chem.  2007,  72:  5486 
  • 12a Zhang Y. Raines AJ. Flowers RA. Org. Lett.  2003,  5:  2363 
  • 12b Zhang Y. Flowers RA. J. Org. Chem.  2003,  68:  4560 
  • 13 Sridharan V. Avendaño C. Menéndez JC. Synlett  2007,  881 
  • 14 Timmons C. Wipf P. J. Org. Chem.  2008,  73:  9168 
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 MHZ, 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.