15 Reviews: (a) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457;
(b) S. P. Stanforth, Tetrahedron, 1998, 54, 263; (c) S. Kotha, K. Lahiri
and D. Kashinath, Tetrahedron, 2002, 58, 9633; (d) A. Suzuki, in
Boronic Acids, D. G. Hall, (Ed.) Wiley-VCH, Weinheim, Germany,
2005; Chapter 3, pp. 123–170; (e) N. Miyaura, in Metal-catalysed Cross
Coupling Reactions. Wiley-VCH, Weinheim, Germany, 2004, Chapter
2; (f) I. J. S. Fairlamb, Chem. Soc. Rev., 2007, 36, 1036.
16 (a) A. M. Rouhi, Chem. & Eng. News, 2004, 82, 49; (b) J. S. Carey, D.
Laffan, C. Thomson and M. T. Williams, Org. Biomol. Chem., 2006, 4,
2337.
Pershin, J. Heterocycl. Chem., 2004, 41, 931; (d) D. L. Browne, M. D.
Helm, A. Plant and J. P. A. Harrity, Angew. Chem., Int. Ed., 2007, 46,
8656; (e) M. McLaughlin, K. Marcantonio, C. Chen and I. W. Davies,
J. Org. Chem., 2008, 73, 4309.
24 (a) A SciFinder search (May 2008) for trifluoromethyl-substituted
heterocyclic boronic acids and esters gave 49 results. Examples of
pyridylboronic acid derivatives: F. Stauffer, and F. Pascal, PCT Int.
Appl. WO2008012326, 2008; (b) Z.-J. Ni, S. Pecchi, M. Burger, W.
Han, A. Smith, G. Atallah, S. Bartulis, K. Frazier, J. Verhagen, Y.
Zhang, E. Iwanowicz, T. Hendrickson, M. Knapp, H. Merritt, C.
Voliva, M. Wiesmann, D. M. Legrand, I. Bruce, J. Dale, J. Lan, B.
Levine, A. Costales, J. Liu, T. Pick, and D. Menezes, PCT Int. Appl.
WO2007095588, 2007; (c) G. M. P. Gilbin, A. Hall, D. N. Hurst, I. R.
Kilford, X. Q. Lewell, A. Naylor, and R. Novelli, PCT Int. Appl.
WO2005037793, 2005; (d) C. D. Bayne, A. T. Johnson, S.-P. Lu, R.
Mohan, M. C. Nyman, E. J. Schweiger, W. C. Stevens, H. Wang, and
Y. Xie, US Patent US2005080111, 2005; (e) M. Nishida, T. Tagata,
and M. Shimada, Japanese Patent JP2003160586, 2003; (f) F. Rohl,
V. Harries, E. Ammermann, G. Lorenz, S. Strathmann, A. Ptock, H.
Sauter, W. Gammenos, T. Grote, H. Bayer, R. Kirstgen, K. Oberdorf, B.
Muller, and R. Muller, PCT Int. Appl. WO9812179, 1998. Examples of
pyrazolylboronic acid derivatives; (g) S. J. Woodhead, R. Downham,
C. Hamlett, S. Howard, H. F. Sore, M. L. Verdonk, D. W. Walker,
R. W. A. Luke, PCT Int. Appl. WO2006136830, 2006; (h) B. Teegarden,
H. Jayakumar, H. Li, S. Strah-Pleynet, and P. I. Dosa, PCT. Int., Appl.
WO2005012254, 2005; (i) A. Kleemann, and T. Maier, Eur. Pat. Appl.
EP1108720, 2001; (j) J. P. Chupp, J. Heterocycl. Chem., 1994, 31, 1377.
25 I. Bruce, J. F. Hayler, G. C. Bloomfield, L. Edwards, B. Cox, and C.
Howsham, PCT. Int., Appl. WO2007134828, 2007 reports the prepara-
tion of 4 and one example of a Suzuki–Miyaura cross-coupling reaction
(with 3-bromo-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-6-ylamine). The
only analytical data given for 4 was the mass spectrum of its
hydrochloride salt.
17 A SciFinder search (May 2008) for commercially available bromo-
(trifluoromethyl)-benzenes resulted in 704 compounds, for commer-
cially available bromo-(trifluoromethyl)-pyridines resulted in 40 com-
pounds. Commercially available chloro-(trifluoromethyl)-benzenes and
-pyridines resulted in 26140 and 5246 compounds, respectively.
18 A SciFinder search (May 2008) for (trifluoromethyl)phenylboronic
acids resulted in 71 commercially available compounds, from a number
of suppliers, for example, Frontier Scientific, Apollo, Fluorochem and
Sigma-Aldrich.
19 Examples of Suzuki-Miyaura cross-couplings of halo(trifluo-
romethyl)benzene derivatives; (a) E. Perissutti, F. Frecentese, A.
Lavecchia, F. Fiorino, B. Severino, F. De Angelis, V. Santagada and
G. Caliendo, Tetrahedron, 2007, 63, 12779; (b) A. E. Thompson, G.
Hughes, A. S. Batsanov, M. R. Bryce, P. R. Parry and B. Tarbit, J. Org.
Chem., 2005, 70, 388; (c) T. Katagiri, S. Ota, T. Ohira, T. Yamao and
S. Hotta, J. Heterocycl. Chem., 2007, 44, 853; (d) Examples of Suzuki–
Miyaura cross-couplings of halo(trifluoromethyl)pyridine derivatives:
K. Olofsson, E. Suna, B. Pelcman, V. Ozola, M. Katkevics, I. Kalvins,
and W. Schaal, PCT Int. Appl. WO2005123674, 2005; (e) J. Nishida,
H. Echisen, T. Iwata and Y. Yamashita, Chem. Lett., 2005, 34, 1378;
(f) R. Dunkel, H.-L. Elbe, B. Hartmann, J. N. Greul, U. Wachendorff-
Neumann, P. Dahmen, K.-H. Kuck, D. J. Mansfield, P.-Y. Coqueron,
H. Rieck, and P. Desbordes, PCT Int. Appl. WO2005004606, 2005. Ex-
amples of Suzuki-Miyaura cross-couplings of (trifluoromethyl)phenyl
boronic acid derivatives; (g) A. P. Skoumbourdis, S. Moore, M.
Landsman and C. J. Thomas, Tetrahedron Lett., 2007, 48, 9140; (h) R.
Epple, M. Azimioara, R. Russo, B. Bursulaya, S.-S. Tian, A. Gerken
and M. Iskandar, Bioorg. Med. Chem. Lett., 2006, 16, 2969; (i) M.
Bartoszek, M. Beller, J. Deutsch, M. Klawonn, A. Ko¨ckritz, N. Nemati
and A. Pews-Davtyan, Tetrahedron, 2008, 64, 1316; (j) E. Paunescu, N.
Matuszak and P. Melnyk, Tetrahedron, 2007, 63, 12791.
20 (a) P. R. Parry, C. Wang, A. S. Batsanov, M. R. Bryce and B. Tarbit,
J. Org. Chem., 2002, 67, 7541; (b) P. R. Parry, M. R. Bryce and B.
Tarbit, Synthesis, 2003, 1035; (c) A. E. Thompson, A. S. Batsanov,
M. R. Bryce, N. Saygili, P. R. Parry and B. Tarbit, Tetrahedron, 2005,
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21 (a) A. Bouillon, J.-C. Lancelot, V. Collot, P. R. Bovy and S. Rault,
Tetrahedron, 2002, 58, 2885; (b) A. Bouillon, J.-C. Lancelot, V. Collot,
P. R. Bovy and S. Rault, Tetrahedron, 2002, 58, 3323; (c) A. Bouillon,
J.-C. Lancelot, P. R. Bovy and S. Rault, Tetrahedron, 2002, 58, 4369;
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Bovy and S. Rault, Tetrahedron, 2003, 59, 10043; (e) Ref. 19a; (f) Ref.
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22 T. Cailly, F. Fabis, A. Bouillon, S. Lemaˆıtre, J. Sopkova, O. de Santos
and S. Rault, Synlett, 2006, 53.
26 The crystal structures are shown in the ESI.† For leading references to
the discussion of the crystal structures of aryl/heteroaryl boronic acids
see: (a) ref. 20a; (b) V. R. Pedireddi and N. Seethalekshmi, Tetrahedron
Lett., 2004, 45, 1903.
27 H.-J. Cristau, P. P. Cellier, J.-F. Spindler and M. Taillefer, Eur. J. Org.
Chem., 2004, 695.
3
28 1-Aryl-3-substituted pyrazoles exhibit JH,H = 2.4–2.9 Hz, while 1-
aryl-5-substituted pyrazoles exhibit 3JH,H = 1.5–1.9 Hz. See Ref. 27 and
references therein.
29 (a) R. G. Micetich, Can. J. Chem., 1970, 48, 2006; (b) For examples of
the lithiation of 3-(trifluoromethyl)pyrazole see: B. Jiang, Y.-Y. Xu and
J. Yang, J. Fluorine Chem., 1994, 67, 83; (c) M. Schlosser, J.-N. Volle,
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30 W. D. Miller, A. H. Fray, J. T. Quatroche and C. D. Sturgill, Org. Process
Res. Dev., 2007, 11, 359.
31 A variety of systems were screened: [Pd(dppf)Cl2·DCM, 1,4-dioxane,
K3PO4, 80 ◦C]; [Pd(dppf)Cl2·DCM, 1,4-dioxane, KOAc, 80 ◦C];
[Pd(PPh3)4, DMF, Na2CO3, 80 ◦C]; [Pd(PPh3)4, 1,4-dioxane/H2O,
Na2CO3, 80 ◦C]; [Pd(PPh3)4, BuOH/H2O, Na2CO3, 100 ◦C];
[Pd2(dba)3, XPhos, i-PrOH, K3PO4, 80 ◦C]; [Pd(PPh3)4, THF, Cy2NH,
60 ◦C].
32 Protodeboronation is known to occur with heteroarylboronic acids,
especially electron-deficient derivatives: (a) S. Gronowitz, V. Bobosik
and K. Lawitz, Chem. Scr., 1984, 23, 120; (b) C. Coudret and V. Mazenc,
Tetrahedron Lett., 1997, 38, 5293; (c) When the boron is attached to
a carbon adjacent to a heteroatom the stability of the boronic acid is
further decreased: B. Abarca, R. Ballesteros, F. Blanco, A. Bouillon,
V. Collot, J.-R. Dom´ınguez, J.-C. Lancelot and S. Rault, Tetrahedron,
2004, 60, 4887 and references therein. Pyrazolylboronic acids and esters
are known to be prone to protodeboronation: Ref. 23c and 23e.
33 By-products obtained alongside product 52 were the product obtained
from homo-coupling of the boronic acid, and debrominated compound
36 (which co-eluted during column chromatography), and unreacted
starting material 50 (16%).
23 (a) M. B. Young, J. C. Barrow, K. L. Glass, G. F. Lundell, C. L. Newton,
J. M. Pellicore, K. E. Rittle, H. G. Selnick, K. J. Stauffer, J. P. Vacca, P. D.
Williams, D. Bohn, F. C. Clayton, J. J. Cook, J. A. Krueger, L. C. Kuo,
S. D. Lewis, B. J. Lucas, D. R. McMasters, C. Miller-Stein, B. L. Pietrak,
A. A. Wallace, R. B. White, B. Wong, Y. Yan and P. G. Nantermet,
J. Med. Chem., 2004, 47, 2995; (b) A.-L. Ge´rard, A. Bouillon, C.
Mahatsekake, V. Collot and S. Rault, Tetrahedron Lett., 2006, 47, 2995;
(c) A. V. Ivachtchenko, D. V. Kravchenko, V. I. Zheludeva and D. G.
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