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Synlett 2013; 24(16): 2095-2101
DOI: 10.1055/s-0033-1339657
letter
© Georg Thieme Verlag Stuttgart · New York

Efficient C-7 or C-3/C-7 Direct Arylation of Tri- or Disubstituted Imidazo[1,2-b]pyrazoles

Sandrine Grosse
a   Institut de Chimie Organique et Analytique (ICOA), Université d’Orléans, UMR-CNRS 7311, BP 6759, rue de Chartres, 45067 Orléans cedex 2, France   Fax: +33(38)417281   Email: gerald.guillaumet@univ-orleans.fr
,
Christelle Pillard
b   Greenpharma S.A.S, 3, allée du Titane, 45100 Orléans, France
,
Philippe Bernard
b   Greenpharma S.A.S, 3, allée du Titane, 45100 Orléans, France
,
Gérald Guillaumet*
a   Institut de Chimie Organique et Analytique (ICOA), Université d’Orléans, UMR-CNRS 7311, BP 6759, rue de Chartres, 45067 Orléans cedex 2, France   Fax: +33(38)417281   Email: gerald.guillaumet@univ-orleans.fr
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Further Information

Publication History

Received: 24 June 2013

Accepted after revision: 24 July 2013

Publication Date:
28 August 2013 (online)

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Abstract

A novel and efficient method of C-7 direct arylation of the imidazo[1,2-b]pyrazole core, never described to date, is presented in this paper. Series of electron-rich or electron-poor aryl and heteroaryl groups were easily introduced. The corresponding products were obtained in moderate to excellent yields thanks to this ­pallado-catalyzed and microwave-assisted process. A one-pot ­double C-3 and C-7 direct coupling is also reported.

Key words

C–C coupling - arylation - fused-ring systems - microwave chemistry - palladium

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  • References and Notes

    • 1a Baviskar AT, Madaan C, Preet R, Mohapatra P, Jain V, Agarwal A, Guchhait SK, Kundu CN, Banerjee UC, Bharatam PV. J. J. Med. Chem. 2011; 54: 5013
      CrossrefPubMed
    • 1b Zhang J, Singh R, Goff D, Kinoshita T. U.S. Patent US20100316649(A1), 2010 ; Chem. Abstr. 2010, 154, 64825
    • 1c Keshi O, Bahar I, Jernigan RL, Beutler JA, Shoemaker RH, Sansville EA, Covell DG. Anti-Cancer Drugs 2000; 15: 79
    • 1d Kinnamon KE, Engle RR, Poon BT, Ellis WY, MacCall JW, Pzimianski MT. Proc. Soc. Exp. Biol. Med. 2000; 224: 45
      CrossrefPubMed
    • 2a Abdelhamid AO, Abdelall EK. A, Zakic YH. J. Heterocycl. Chem. 2010; 47: 477
    • 2b Li M, Zhao G, Wen L, Cao W, Zhang S, Yang H. J. Heterocycl. Chem. 2005; 42: 209
      Crossref
    • 2c Chen YF, Huang NY, Ding MW. Chin. J. Chem. 2004; 24: 1413
  • 3 Terada A, Wachi K, Myazawa H, Lizuka Y, Hagesawa K, Tabata K. (Sankyo Co) Jpn. Patent 07278148, 1995 ; Chem. Abstr. 1996, 124, 8700
    • 4a Bhatia G, Graczyk P, Khan A, Medland DP, Numata H, Oinuma H, Palmer V. Int. Patent WO02081475A1, 2002 ; Chem. Abstr. 2002, 137, 310918
    • 4b Vanotti E, Fiorentini F, Villa M. J. Heterocycl. Chem. 1994; 31: 737
      Crossref
    • 5a Rahmati A, Eskandari-Vashareh M, Alizadeh-Kouzehrash M. Tetrahedron 2013; 69: 4199
      Crossref
    • 5b Rahmati A, Alizadeh-Kouzehrash M. Synthesis 2011; 2913
      Article in Thieme Connect
    • 5c Shawali AS, Mosseelhi MA, Altablawy FM. A, Farghaly TA. F, Tawfik NM. Tetrahedron 2008; 64: 5524
      Crossref
    • 5d Barsy MA, El-Rady EA. J. Heterocycl. Chem. 2006; 43: 523
      Crossref
    • 5e Ming L, Guilong Z, Lirong W, Huazheng Y. Synth. Commun. 2005; 35: 493
      Crossref
    • 5f Shawali AS, Abdelkader MH, Eltalbawy FM. A. Tetrahedron 2002; 58: 2875
      Crossref
    • 5g Langer P, Wuckelt J, Döring M, Schreiner PR, Görls H. Eur. J. Org. Chem. 2001; 2257
    • 5h Seneci P, Nicola M, Inglesi M, Vanotti E, Resnati G. Synth. Commun. 1999; 29: 311
      Crossref
    • 5i Cho N, Kubo K, Furuya S, Sugiura Y, Yasuma T, Kohara Y, Ojima M, Inada Y, Nishikawa K, Naka T. Bioorg. Med. Chem. Lett. 1994; 4: 35
      Crossref
    • 5j Hammouha HA, El-Barbary AA, Sharaf MA. F. J. Heterocycl. Chem. 1984; 21: 945
      Crossref
    • 5k Wood SG, Dalley NK, George RD, Robins RK, Revankar GR. J. Org. Chem. 1984; 49: 3534
      Crossref
    • 5l Hiroshi K, Masaaki H, Toshihiko O. Chem. Pharm. Bull. 1974; 22: 482
      Crossref
  • 6 Grosse S, Pillard C, Massip S, Léger JM, Jarry C, Bourg S, Bernard P, Guillaumet G. Chem. Eur. J. 2012; 18: 14943
    CrossrefPubMed
    • 7a Bassoude I, Berteina-Raboin S, Massip S, Leger JM, Jarry C, Essassi EM, Guillaumet G. Eur. J. Org. Chem. 2012; 2572
    • 7b El Akkaoui A, Berteina-Raboin S, Mouaddib A, Guillaumet G. Eur. J. Org. Chem. 2010; 862
    • 7c Koubachi J, El Kazzouli S, Berteina-Raboin S, Mouaddib A, Guillaumet G. J. Org. Chem. 2007; 72: 7650
      Crossref
    • 7d Koubachi J, El Kazzouli S, Berteina-Raboin S, Mouaddib A, Guillaumet G. Synlett 2006; 3237
      Article in Thieme Connect

      For selected recent reviews on direct C–H arylation, see:
    • 8a Ackermann L. Chem. Commun. 2010; 46: 4866
    • 8b Fisch-Meister C, Doucet H. Green Chem. 2011; 13: 741
      Crossref
    • 8c Roger J, Gottumukkala AL, Doucet H. ChemCatChem 2010; 2: 20
      Crossref
    • 8d Jazzar R, Hitce J, Renaudat A, Sofack-Kreutzer J, Baudoin O. Chem. Eur. J. 2010; 16: 2654
    • 8e Ackermann L, Vicente R, Kapdi AR. Angew. Chem. Int. Ed. 2009; 48: 9792
      CrossrefPubMed
    • 8f Daugulis O, Do HQ, Shabashov D. Acc. Chem. Res. 2009; 42: 1074
      CrossrefPubMed
    • 8g McGlacken GP, Bateman LM. Chem. Soc. Rev. 2009; 38: 2447
      CrossrefPubMed
    • 8h Bellina F, Rossi R. Tetrahedron 2009; 65: 10269
      Crossref
    • 8i Li BJ, Yang SD, Shi ZJ. Synlett 2008; 949
      Article in Thieme Connect
    • 8j Alberico D, Scott ME, Lautens M. Chem. Rev. 2007; 107: 174
      CrossrefPubMed
    • 8k Seregin IV, Gevorgyan V. Chem. Soc. Rev. 2007; 36: 1173
      CrossrefPubMed
    • 8l Campeau LC, Stuart DR, Fagnou K. Aldrichimica Acta 2007; 40: 35
    • 8m Catellani M, Motti E, Della Ca’ N, Ferracioli R. Eur. J. Org. Chem. 2007; 4153
    • 8n Satoh T, Miura M. Chem. Lett. 2007; 36: 200
      Crossref
    • 9a See ref 7.
    • 9b Fu HY, Chen L, Doucet H. J. Org. Chem. 2012; 77: 4473
      Crossref
    • 9c Beladhriaa A, Beydounb K, Ammar HB, Salemc RB, Doucet H. Synthesis 2011; 2553
      Article in Thieme Connect
    • 9d Basolo L, Beccalli EM, Borsini E, Broggini G. Tetrahedron 2009; 65: 3486
      Crossref
    • 9e Basolo L, Beccalli EM, Borsini E, Broggini G, Pellegrino S. Tetrahedron 2008; 64: 8182
      Crossref
    • 9f Li W, Nelson DP, Jensen MS, Hoerrner RS, Javadi GJ, Cai D, Larsen RD. Org. Lett. 2003; 5: 4835
      CrossrefPubMed
    • 10a Liégault B, Lapointe D, Caron L, Vlassova A, Fagnou K. J. Org. Chem. 2009; 74: 1826
      CrossrefPubMed
    • 10b Lafrance M, Fagnou K. J. Am. Chem. Soc. 2006; 128: 16496
      CrossrefPubMed
    • 11a See Ref 8e.
    • 11b Daugulis O. Chem. Heterocycl. Compd. 2012; 48: 21
      Crossref
    • 11c Ackermann L, Vicente R, Borna R. Adv. Synth. Catal. 2008; 350: 741
      Crossref
    • 11d Campeau LC, Parisien M, Jean A, Fagnou K. J. Am. Chem. Soc. 2006; 128: 581
      CrossrefPubMed

      For reviews providing mechanistic discussions on palladium(0)-catalyzed direct C–H coupling, see:
    • 12a Théveau L, Querolle O, Dupas G, Hoarau C. Tetrahedron 2013; 69: 4375
      Crossref
    • 12b Verrier C, Lassalas P, Théveau L, Quéguiner G, Trécourt F, Marsais F, Hoarau C. Beilstein J. Org. Chem. 2011; 7: 1584
      Crossref
    • 12c Bellina F, Rossi R. Adv. Synth. Catal. 2010; 352: 1223
      Crossref
    • 12d Balcells D, Clot E, Eisenstein O. Chem. Rev. 2010; 110: 749
      CrossrefPubMed
    • 12e Fagnou K. Top. Curr. Chem. 2010; 292: 35
    • 12f Bellina F, Cautericcio S, Rossi R. Curr. Org. Chem. 2008; 12: 774
      Crossref
    • 12g Seregin IV, Gevorgyan V. Chem. Soc. Rev. 2007; 36: 1173
      CrossrefPubMed
  • 13 Pivalic acid and potassium acetate should enhance the reactivity in the case of a CMD mechanism but in our case no improvement in the conversion was observed (Table 1, entry 4). See: Lafrance M, Fagnou K. J. Am. Chem. Soc. 2006; 128: 16496
    CrossrefPubMed
  • 14 Iodide poisoning effect of catalyst is known to inhibit CMD reactivity. A low conversion of 10% is noted using 4-iodotoluene (Table 1, entry 16). Consequently the CMD mechanism may not be excluded. See ref. 11d.
  • 15 General Procedure A; C-7 Direct Arylation of the Imidazo[1,2-b]pyrazoles 1–5: A microwave vial containing a stirring bar was loaded with imidazo[1,2-b]pyrazole 1–5 in 1,4-dioxane, (hetero)aryl bromide or chloride (2.0 equiv), tricyclohexylphosphine tetrafluoroborate (0.20 equiv) and cesium carbonate (2.0 equiv). The tube was evacuated and backfilled with dry argon twice. Palladium acetate (0.10 equiv) was added and the mixture was submitted to microwave irradiation with stirring at 160 °C for 4 h. It was then cooled to r.t., and 1,4-dioxane was removed under reduced pressure. The residue was purified by flash chromatography to provide the desired products 1a–5b. 2-(4-Methoxyphenyl)-1-methyl-6-phenyl-3-(4-tolyl)-7-[4-(trifluoromethyl)phenyl]-1H-imidazo[1,2-b]pyrazole (1b): The reaction was carried out as described in general procedure A using imidazo[1,2-b]pyrazole 1 (100 mg, 0.254 mmol), palladium acetate (5.7 mg, 0.0254 mmol), tricyclohexylphosphine tetrafluoroborate (18.7 mg, 0.0508 mmol), cesium carbonate (142 mg, 0.508 mmol) and 4-bromobenzotrifluoride (114 mg, 72 μL, 0.508 mmol) in 1,4-dioxane (2 mL). Standard workup followed by flash chromatography (CH2Cl2–petroleum ether, 1:1) yielded 1b as a pale yellow solid (123 mg, 90%); mp 226–228 °C. 1H NMR (400 MHz, CDCl3): δ = 7.71 (d, J = 8.1 Hz, 2 H, HAr), 7.58 (d, J = 8.4 Hz, 2 H, HAr), 7.53 (d, J = 7.9 Hz, 2 H, HAr), 7.47 (d, J = 8.1 Hz, 2 H, HAr), 7.33 (d, J = 8.5 Hz, 2 H, HAr), 7.25–7.29 (m, 3 H, HAr), 7.12 (d, J = 8.1 Hz, 2 H, HAr), 7.00 (d, J = 8.5 Hz, 2 H, HAr), 3.88 (s, 3 H, OMe), 3.30 (s, 3 H, NMe), 2.32 (s, 3 H, Me). 13C NMR (101 MHz, CDCl3): δ = 160.31 (Cq), 152.26 (Cq), 140.07 (Cq), 137.17 (Cq), 136.82 (Cq), 134.27 (Cq), 132.46 (CHAr), 130.97 (CHAr), 129.19 (Cq), 129.03 (CHAr), 128.87 (CHAr), 128.18 (CHAr), 127.87 (2 J C–F = 33.0 Hz, Cq), 127.42 (CHAr), 127.14 (CHAr), 125.63 (Cq), 125.14 (3 J C–F = 3.72 Hz, CHAr), 124.41 (1 J C–F = 273 Hz, Cq), 121.13 (Cq), 118.42 (Cq), 114.64 (CHAr), 94.33 (Cq), 55.34 (OMe), 31.73 (NMe), 21.29 (Me). IR (neat): 1603, 1322, 1118, 1066, 838, 697 cm–1. HRMS (ESI): m/z [M + H]+ calcd for C33H27F3N3O: 538.21007; found: 538.21007. HRMS (ESI): m/z [M + Na]+ calcd for C33H27F3N3O: 560.19202; found: 560.19113. General Procedure B; One-Pot C-3 and C-7 Direct Arylation of Imidazo[1,2-b]pyrazole 6: A microwave vial containing a stirring bar was loaded with imidazo[1,2-b]pyrazole 6 in 1,4-dioxane, (hetero)aryl bromide (3.0 equiv), tricyclohexylphosphine tetrafluoroborate (0.20 equiv) and cesium carbonate (4.0 equiv). The tube was evacuated and back-filled with dry argon twice. Palladium acetate (0.10 equiv) was added and the mixture was submitted to microwave irradiation with stirring at 160 °C for 4 h. It was then cooled to r.t., and 1,4-dioxane was removed under reduced pressure. The residue was purified by flash chromatography to provide the desired products 1a, 6a and 6b. 2-(4-Methoxyphenyl)-1-methyl-6-phenyl-3,7-bis[4-(trifluoromethyl)phenyl]-1H-imidazo[1,2-b]pyrazole (6a): The reaction was carried out as described in general procedure B using imidazo[1,2-b]pyrazole 6 (100 mg, 0.329 mmol), palladium acetate (8.04 mg, 0.0329 mmol), tricyclohexylphosphine tetrafluoroborate (24.0 mg, 0.0658 mmol), caesium carbonate (369 mg, 1.32 mmol) and 4-bromobenzotrifluoride (222 mg, 138 μL, 0.987 mmol) in 1,4-dioxane (2 mL). Standard workup followed by flash chromatography (CH2Cl2–petroleum ether, 3:7) yielded 6a as a white solid (151 mg, 78%); mp 220–222 °C. 1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 8.4 Hz, 2 H, HAr), 7.47–7.64 (m, 8 H, HAr), 7.29–7.41 (m, 5 H, HAr), 7.07 (d, J = 8.4 Hz, 2 H, HAr), 3.92 (s, 3 H, OMe), 3.33 (s, 3 H, NCH3). 13C NMR (101 MHz, CDCl3): δ = 160.76 (Cq), 152.49 (Cq), 140.08 (Cq), 136.81 (Cq), 133.96 (Cq), 132.34 (CHAr), 132.28 (Cq), 131.09 (Cq), 131.05 (CHAr), 128.78 (CHAr), 128.37 (2 J C–F = 32.6 Hz, Cq), 128.27 (CHAr), 128.20 (2 J C–F = 32.8 Hz, Cq), 127.64 (CHAr), 126.73 (CHAr), 125.25 (3 J C–F = 3.70 Hz, 2 × CHAr), 124.36 (1 J C–F = 273 Hz, Cq), 124.18 (1 J C–F = 273 Hz, Cq), 120.39 (Cq), 117.03 (Cq), 114.99 (CHAr), 94.65 (Cq), 55.39 (OMe), 31.74 (NMe). IR (neat): 1613, 1320, 1249, 1162, 1103, 1076, 1064, 1016, 834 cm–1. HRMS (ESI): m/z [M + H] calcd for C33H24F6N3O: 592.18181; found: 592.18163.