PDF icon Download PDF
Synlett 2009(4): 615-619  
DOI: 10.1055/s-0028-1087922
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Protected Indazole Boronic Acid Pinacolyl Esters: Facile Syntheses and Studies of Reactivities in Suzuki-Miyaura Cross-Coupling and Hydroxydeboronation Reactions

François Crestey, Elodie Lohou, Silvia Stiebing, Valérie Collot*, Sylvain Rault
Université de Caen Basse-Normandie, U.F.R. des Sciences Pharmaceutiques, Centre d’Études et de Recherche sur le Médicament de Normandie (CERMN), UPRES EA-4258, FR CNRS INC3M, Boulevard Becquerel, 14032 Caen Cedex, France
Fax: +33(2)31931188; e-Mail: valerie.collot@unicaen.fr;
Further Information

Publication History

Received 8 October 2008
Publication Date:
16 February 2009 (online)

   Permissions and Reprints All articles of this category
Preview

Abstract

The paper describes a rapid and efficient synthesis for the isolation of protected indazolylboronic esters. These compounds were synthesized by reaction between prepared protected haloindazoles and bis(pinacolato)diboron. The effects of solvent, temperature, reaction time, and the nature of halogen atom as well as protecting group were investigated. Additionaly, these compounds reacted either with aryl halides in a Suzuki-Miyaura cross-coupling reaction or with hydrogen peroxide in a hydroxydeboronation reaction showing the potential access to new aryl and hydroxyindazole libraries.

Key words

indazole boronic acid pinacolyl esters - Suzuki-Miyaura cross-coupling reaction - palladium-mediated reaction - protected halo-1H-indazoles - hydroxydeboronation

    References and Notes

  • 1a Crestey F. Stiebing S. Legay R. Collot V. Rault S. Tetrahedron  2007,  63:  419 
    Search in Google Scholar
  • 1b Collot V. Bovy PR. Rault S. Tetrahedron Lett.  2000,  41:  9053 
    Search in Google Scholar
  • 1c Collot V. Dallemagne P. Bovy PR. Rault S. Tetrahedron  1999,  55:  6917 
    Search in Google Scholar
  • 2a Crestey F. Collot V. Stiebing S. Lohier J.-F. Sopkova-de Oliveira Santos J. Rault S. Tetrahedron Lett.  2007,  48:  2457 
    Search in Google Scholar
  • 2b Crestey F. Collot V. Stiebing S. Rault S. Synthesis  2006,  3506 
  • 2c Crestey F. Collot V. Stiebing S. Rault S. Tetrahedron  2006,  62:  7772 
    Search in Google Scholar
  • 2d Witulski B. Azcon JR. Alayrac C. Arnautu A. Collot V. Rault S. Synthesis  2005,  771 
  • 2e Arnautu A. Collot V. Calvo Ros J. Alayrac C. Witulski B. Rault S. Tetrahedron Lett.  2002,  43:  2695 
    Search in Google Scholar
  • 2f Collot V. Varlet D. Rault S. Tetrahedron Lett.  2000,  41:  4363 
    Search in Google Scholar
  • 3a Herradura PS. Pendola KA. Guy RK. Org. Lett.  2000,  2:  2019 
    Search in Google Scholar
  • 3b Chan DMT. Monaco KL. Wang R.-P. Winters MP. Tetrahedron Lett.  1998,  39:  2933 
    Search in Google Scholar
  • 3c Lam PYS. Clark CG. Saubern S. Adams J. Winters MP. Chan DMT. Combs A. Tetrahedron Lett.  1998,  39:  2941 
    Search in Google Scholar
  • 4a Kotha S. Lahiri K. Kashinath D. Tetrahedron  2002,  58:  9633 
    Search in Google Scholar
  • 4b Suzuki A. J. Organomet. Chem.  1999,  576:  147 
    Search in Google Scholar
  • 4c Miyaura N. Suzuki A. Chem. Rev.  1995,  95:  2457 
    Search in Google Scholar
  • 5 Webb KS. Levy D. Tetrahedron Lett.  1995,  36:  5117 
    CrossrefSearch in Google Scholar
  • 6 Salzbrunn S. Simon J. Prakash GKS. Petasis NA. Olah GA. Synlett  2000,  1485 
    Thieme Connect
  • 7 Thiebes C. Prakash GKS. Petasis NA. Olah GA. Synlett  1998,  141 
    Thieme Connect
  • 8 Urawa Y. Ogura K. Tetrahedron Lett.  2002,  44:  271 
    Search in Google Scholar
  • 9 Petasis NA. Goodman A. Zavialov IA. Tetrahedron  1997,  53:  16463 
    CrossrefSearch in Google Scholar
  • 10a Hall DG. Boronic Acids - Preparation and Applications in Organic Synthesis   Wiley-VCH; Weinheim: 2005. 
  • 10b Chincilla R. Najera C. Yus M. Chem. Rev.  2004,  104:  2667 
    Search in Google Scholar
  • 11 For a recent review on heterocyclic boronic acids, see: Tyrell E. Brookes P. Synthesis  2003,  469 
    Thieme Connect
  • For the main references at this time to obtain 4-indazolyl-boronic acids and esters, see:
  • 12a Folkes AJ. Ahmadi K. Alderton WK. Alix S. Baker ST. Box G. Chuckowree IS. Clarke PA. Depledge P. Eccles SA. Friedman LS. Hayes A. Hancox TC. Kugendradas A. Lensun L. Moore P. Olivero AG. Pang J. Patel S. Pergl-Wilson GH. Raynaud FI. Robson A. Saghir N. Salphati L. Sohal S. Ultsch MH. Valenti M. Wallweber HJA. Wan NC. Wiesmann C. Workman P. Zhyvoloup A. Zvelebil MJ. Shuttleworth S. J. Med. Chem.  2008,  51:  5522 
    Search in Google Scholar
  • 12b Chuckowree I, Folkes A, Hancox T, and Shuttleworth S. inventors; WO  07129161.  ; Chem. Abstr. 2007, 147, 541901
  • 12c Shuttleworth SJ, Folkes AJ, Chuckowree IS, Wan NC, Hancox TC, Baker SJ, Sohal S, and Latif MA. inventors; WO  06046040.  ; Chem. Abstr. 2006, 144, 450724
  • 12d Yoon T, Yuan J, Lee K, Maynard GD, and Liu N. inventors; WO  06004589.  ; Chem. Abstr. 2006, 144, 128985
  • 12e Lee K, Yuan J, Maynard GD, Hutchison A, and Mitchell S. inventors; WO  05110991.  ; Chem. Abstr. 2005, 144, 6683
  • For the main references at this time to obtain 5-indazolyl-boronic acids and esters, see:
  • 13a Alberti MJ, and Jung DK. inventors; WO  06044753.  ; Chem. Abstr. 2006, 144, 432843
  • 13b Yamashita DS, Lin H, and Wang W. inventors; WO  05085227.  ; Chem. Abstr. 2005, 143, 306183
  • 13c Hagihara M, Komori K.-I, Sunamoto H, Nishida H, Matsugi T, Nakajima T, Hatano M, Kido K, and Hara H. inventors; WO  05035506.  ; Chem. Abstr. 2005, 142, 411353
  • 13d McAlpine IJ, Deal JG, Johnson MC, Kephart SE, Park JY, Romines WH, and Tikhe JG. inventors; US  05090529.  ; Chem. Abstr. 2005, 142, 430272
  • 13e Shoda M, and Kuriyama H. inventors; WO  03070686.  ; Chem. Abstr. 2003, 139, 214465
  • For the main references at this time to obtain 6-indazolyl-boronic acids and esters, see:
  • 14a Frazee JS, Hammond M, Kano K, Manns S, Nakamura H, Thompson SK, and Washburn DG. inventors; WO  06063167.  ; Chem. Abstr. 2006, 145, 62865
  • 14b Lu T, Thieu TV, Player MR, Lee Y.-K, Parks DJ, Markotan TP, Pan W, and Milkiewicz KL. inventors; WO  06047415.  ; Chem. Abstr. 2006, 144, 450703
  • 14c Bamborough P, Campos SA, Patel VK, Swanson S, and Walker AL. inventors; WO  05073189.  ; Chem. Abstr. 2005, 143, 211906
  • For the main references at this time about 7-indazolyl-boronic acids and esters, see:
  • 15a Shipps GW, Cheng CC, Huang X, Fischmann TO, Duca JS, Richards M, Zeng H, Sun B, Reddy PA, Wong TT, Tadikonda PK, Siddiqui MA, Labroli MM, Poker C, and Guzi TJ. inventors; WO  08054702.  ; Chem. Abstr. 2008, 148, 552346
  • 15b Kelly M, Lee Y, Liu B, Fujimoto T, Freundlich J, Dorsey BD, Flynn GA, and Husain A. inventors; US  06270686.  ; Chem. Abstr. 2006, 146, 7835
  • 16 Boulouard M. Schumann-Bard P. Butt-Gueulle S. Lohou E. Stiebing S. Collot V. Rault S. Bioorg. Med. Chem. Lett.  2007,  17:  3177 
    CrossrefSearch in Google Scholar
  • 17 Kania RS, Bender SL, Borchardt AJ, Braganza JF, Cripps SJ, Hua Y, Johnson MD, Johnson TO, Luu HT, Palmer CL, Reich SH, Tempczyk-Russell AM, Teng M, Thomas C, Varney MD, and Wallace MB. inventors; WO  0102369.  ; Chem. Abstr. 2001, 134, 100864
  • 18 Gérard A.-L. Bouillon A. Mahatsekake C. Collot V. Rault S. Tetrahedron Lett.  2006,  47:  4665 
    CrossrefSearch in Google Scholar
  • 19 Primas N. Mahatsekake C. Bouillon A. Lancelot J.-C. Sopkova-de Oliveira Santos J. Lohier J.-F. Rault S. Tetrahedron  2008,  64:  4596 
    CrossrefSearch in Google Scholar
  • 20 Young MB. Barrow JC. Glass KL. Lundell GF. Newton CL. Pellicore JM. Rittle KE. Selnick HG. Stauffer KJ. Vacca JP. Williams PD. Bohn D. Clayton FC. Cook JJ. Krueger JA. Kuo LC. Lewis SD. Lucas BJ. McMasters DR. Miller-Stein C. Pietrak BL. Wallace AA. White RB. Wong B. Yan Y. Nantermet PG. J. Med. Chem.  2004,  47:  2995 
    CrossrefPubMedSearch in Google Scholar
  • For example, see:
  • 21a Jiang Q. Ryan M. Zhichkin P.
    J. Org. Chem.  2007,  72:  6618 
    Search in Google Scholar
  • 21b Lee IYC. Jung MH. Lim H.-J. Lee HW. Heterocycles  2005,  65:  2505 
    Search in Google Scholar
  • 21c Organ MG. Bilokin YV. Bratovanov S. J. Org. Chem.  2002,  67:  5176 
    Search in Google Scholar
  • 21d Schinazi RF. Prusoff WH. J. Org. Chem.  1985,  50:  841 
    Search in Google Scholar
  • 22a Voisin A.-S. Bouillon A. Lancelot J.-C. Rault S. Tetrahedron  2005,  61:  1417 
    Search in Google Scholar
  • 22b Bouillon A. Lancelot J.-C. Sopkova-de Oliveira Santos J. Collot V. Bovy PR. Rault S. Tetrahedron  2003,  59:  10043 ; and references cited therein
    Search in Google Scholar
  • 23 Ishiyama T. Murata M. Miyaura N. J. Org. Chem.  1995,  60:  7508 
    CrossrefSearch in Google Scholar
  • 24 Reich SH, Bleckman TM, Kephart SE, Romines WH, and Wallace MB. inventors; WO  01053268.  ; Chem. Abstr. 2001, 135: 137505
  • For Suzuki-Miyaura cross-coupling reactions using K3PO4 as base in DMF, see:
  • 26a Cailly T. Fabis F. Rault S. Tetrahedron  2006,  62:  5862 
    Search in Google Scholar
  • 26b Watanabe T. Miyaura N. Suzuki A. Synlett  1992,  207 
  • For Suzuki-Miyaura cross-coupling reactions using Na2CO3 or Cs2CO3 as base in dioxane, see:
  • 27a Song YS. Lee Y.-J. Kim BT. Heo J.-N. Tetrahedron Lett.  2006,  47:  7427 
    Search in Google Scholar
  • 27b Heo Y. Song YS. Kim BT. Heo J.-N. Tetrahedron Lett.  2006,  47:  3091 
    Search in Google Scholar
  • 27c Littke AF. Fu GC. Angew. Chem. Int. Ed.  1999,  37:  3387 
    Search in Google Scholar
  • 29 Schumann P. Collot V. Hommet Y. Gsell W. Dauphin F. Sopkova J. McKenzie ET. Duval D. Boulouard M. Rault S. Bioorg. Med. Chem. Lett.  2001,  11:  1153 
    CrossrefSearch in Google Scholar
25

Typical Experimental Procedure for the Synthesis of Indazolylboronic Esters
To a solution of 1-(4-bromoindazol-1-yl)ethanone (3a, 1.5 g, 6.3 mmol) in 1,4-dioxane (25 mL) were added successively bis(pinacolato)diboron (1.8 g, 7.2 mmol, 1.15 equiv) and KOAc (2.8 g, 23.8 mmol, 4.6 equiv) at r.t. The reaction mixture was degassed under vacuum with argon replacement three times, then PdCl2 (dppf)-CH2Cl2 (0.3 g, 0.5 mmol, 0.08 equiv) was added, and the degassing procedure was repeated twice. The reaction was heated under reflux conditions for 15 min then concentrated in vacuo. After the addition of EtOAc, the organic layer was washed successively with H2O and brine, dried over MgSO4, and the solvent evaporated in vacuo. The crude material was purified by flash column chromatography on SiO2 (EtOAc-cyclohexane, 1:3) to give 1-[4-(4,4,5,5-tetramethyl[1,3,2]-
dioxaborolan-2-yl)indazol-1-yl)ethanone (7a); yield 1.8 g (98%); pink solid; mp 128 ˚C. TLC: R f  = 0.6 (EtOAc-cyclohexane, 1:4). IR (KBr): 2976, 1713, 1601, 1415, 1349, 1325, 1174, 1151, 932, 756 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.42 (s, 12 H), 2.80 (s, 3 H), 7.55 (t, J = 8.3 Hz, 1 H), 7.82 (d, J = 7.1 Hz, 1 ), 8.54 (d, J = 7.1 Hz, 1 H), 8.55 (s, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 23.1, 25.0, 84.2, 118.3, 128.6, 130.6, 132.0, 138.3, 141.7, 171.1. MS (EI): m/z (%) = 286 (53) [M+], 244 (100), 243 (39), 229 (14), 158 (70), 145 (34), 144 (68), 134 (67). Anal. Calcd for C15H19BN2O3: C, 62.96; H, 6.69; N, 9.79. Found: C, 62.39; H, 6.48; N, 9.23.

28

7-(4-Methoxyphenyl)-1-(tetrahydro-2 H -pyran-2-yl)-1 H -indazole (17)
Yield 0.3 g (73%); white solid. TLC: R f  = 0.1 (EtOAc-cyclohexane, 1:10). IR (KBr): 3428, 2932, 1611, 1497, 1245, 1078, 1032, 824 cm-¹. ¹H NMR (400 MHz, CDCl3):
δ = 1.37-1.42 (m, 2 H), 1.76-1.78 (m, 1 H), 1.90-1.95 (m,
1 H), 2.56-2.58 (m, 1 H), 2.91-2.96 (m, 1 H), 3.74-3.80 (m, 1 H), 3.91 (s, 3 H), 4.04-4.07 (m, 1 H), 5.00 (dd, J = 12.7, 2.2 Hz, 1 H), 7.02 (dd, J = 7.3, 1.4 Hz, 2 H), 7.18-7.19 (m, 2 H), 7.23-7.26 (m, 2 H), 7.64-7.70 (m, 1 H), 8.12 (s, 1 H). MS (EI): m/z (%) = 308 (22) [M + ], 224 (100), 209 (26), 192 (2), 182 (8), 154 (7), 85 (8). Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C, 74.30; H, 6.74; N, 9.28.

30

The use of Oxone® (2KHSO5-KHSO4-K2SO4) as oxidative reagent in the presence of Na2CO3 in a mixture of H2O-acetone (1:1) at 0 ˚C led to the desired compounds but in lower yields.