1402
T. R. Rheault et al. / Tetrahedron Letters 50 (2009) 1399–1402
Table 2 (continued)
Entry
Compd
X
R2
R
Temperature (°C)
Microwave (Y/N)
N
Time (min)
600
Isolated yield (%) 2
N
12
3k
3l
Br
Cl
80
30d
N
N
13
Br
Br
Cl
Cl
80
80
N
N
60
58
13
N
N
BOC
14
3m
N
600
a
All reactions were carried out using a two-step procedure with purified 2 unless otherwise noted.
General reaction conditions: 2 (0.350 mmol), heteroaryl halide (0.60 mmol), Na2CO3 (1 M aq, 0.7 mL) and PdCl2(dppf) (10 mol %), 0.18 M, in DMA.
% Conversion by LC–MS. Attempted reaction with PdCl2(PPh3)2 as the catalyst resulted in minimal conversion to 3e, and multiple side products were noted.
Attempted reaction with 4-bromo-1H-imidazole did not provide any desired imidazole-coupled product.
Isolated yield over two steps. Reactions carried out according to simplified two-step procedure using crude 2 for Suzuki–Miyaura coupling reaction.
b
c
d
e
examples of benzimidazole-based IGF1R kinase inhibitors see: (a) Velaparthi,
to)diboron (0.25 g, 0.98 mmol), potassium acetate (0.20 g,
2.4 mmol), and dichlorobis(triphenylphosphine)palladium(II)
U.; Wittman, M.; Liu, P.; Carboni, J. M.; Lee, F. Y.; Attar, R.; Balimane, P.; Clarke,
W.; Sinz, M. W.; Hurlburt, W.; Patel, K.; Discenza, L.; Kim, S.; Gottardis, M.;
Greer, A.; Li, A.; Saulnier, M.; Yang, Z.; Zimmermann, K.; Trainor, G.; Vyas, D. J.
Med. Chem. 2008, 51, 5897; (b) Hubbard, R. D.; Bamaung, N. Y.; Palazzo, F.;
Zhang, Q.; Kovar, P.; Osterling, D. J.; Hu, X.; Wilsbacher, J. L.; Johnson, E. F.;
Bouska, J.; Wang, J.; Bell, R. L.; Davidsen, S. K.; Sheppard, G. S. Bioorg. Med. Chem.
Lett. 2007, 17, 5406.
(0.058 g, 0.083 mmol) were combined in N,N-dimethylformamide
(5.0 mL). The reaction mixture was heated in a Personal Chemistry
microwave reactor at 150 °C for 20 min, after which the mixture
was diluted with ethyl acetate and washed with water. The organic
layer was separated, dried over MgSO4, filtered, and concentrated.
The resulting crude residue was diluted with N,N-dimethylacet-
amide (10 mL), and 5 mL of this solution was carried into the sub-
sequent Suzuki–Miyaura coupling reaction. To this solution of
crude 2b in N,N-dimethylacetamide, 5-bromo-6-methyl-2-pyridin-
amine (0.15 g, 0.8 mmol) and sodium carbonate (1 N in water,
1.5 mL) were added, followed by 1,10-bisdiphenylphosphinoferro-
cene dichloropalladium(II) (0.033 g, 0.040 mmol). The reaction
mixture was stirred under nitrogen while heating at 80 °C for
15 h. The mixture was then cooled and partitioned between dichlo-
romethane and water. The aqueous layer was extracted twice with
dichloromethane. The combined organics were dried over MgSO4,
concentrated onto silica gel, and purified by column chromatogra-
phy (10–40% 1:9:90 NH4OH–MeOH–DCM in DCM) to afford
0.080 g (40%) of the title compound over two steps. 1H NMR
(400 MHz; CDCl3) d ppm 7.98 (s, 1H) 7.70 (s, 1H) 7.39–7.49 (m,
3H) 7.26–7.37 (m, 3H) 7.22 (d, J = 1.1 Hz, 2H) 6.63 (s, 1H) 6.42 (d,
J = 8.2 Hz, 1H) 5.87 (d, J = 6.4 Hz, 2H) 4.51 (br s, 2H) 2.35 (s, 3H)
1.77 (d, J = 6.2 Hz, 3H). MS (ESI): 504.2 [M+H]+.
2. Lindberg, P. Comp. Med. Chem. II 2006, 8, 213.
3. Hirashima, S.; Suzuki, T.; Ishida, T.; Noji, S.; Yata, S.; Ando, I.; Komatsu, M.;
Ikeda, S.; Hashimoto, H. J. Med. Chem. 2006, 49, 4721.
4. (a) Lansing, T. J.; McConnell, R. T.; Duckett, D. R.; Spehar, G. M.; Knick, V.
B.; Hassler, D. F.; Noro, N.; Furuta, M.; Emmitte, K. A.; Gilmer, T. M.; Mook,
R. A., Jr.; Cheung, M. Mol. Cancer Ther. 2007, 6, 450; (b) For the synthesis of
ester and amide substrates
1 see: (a) Hornberger, K. R.; Badiang, J. G.;
Salovich, J. M.; Kuntz, K. W.; Emmitte, K. A.; Cheung, M. Tetrahedron Lett.
2008, 49, 6348. (b) Kuntz, K.; Emmitte, K. A.; Rheault, T. R.; Smith, S.;
Hornberger, K.; Dickson, H.; Cheung, M. PCT Int. Appl. WO2007143456,
2007.
5. (a) Bilodeau, M. T.; Cunningham, A. M.; Koester, T. J.; Ciecko, P. A.; Coll, K. E.;
Huckle, W. R.; Hungate, R. W.; Kendall, R. L.; McFall, R. C.; Mao, X.; Rutledge, R.
Z.; Thomas, K. A. Bioorg. Med. Chem. Lett. 2003, 13, 2485; (b) Liu, H.; Pan, W.; Xu,
Y.-J. PCT Int. Appl. WO2005042496, 2005.
6. For an example where the reactivity of the coupling partners is reversed see:
Bonjouklian, R.; Dally, R. D.; De Dios, A.; Del Prado Catalina, M. F.; Dominguez-
Fernandez, C.; Jaramillo Aguado, C.; Lopez de Uralde-Garmendia, B.; Montero
Salgado, C.; Shepherd, T. A. PCT Int. Appl. WO2005080380, 2005.
7. Ishiyama, T.; Chen, H. 4,4,40,40,5,5,50,50-Octamethyl-2,20-bi-1,3,2-dioxaborolane.
e-EROS Encyclopedia of Reagents for Organic Synthesis, 2001.
8. For examples of microwave-assisted boronate ester formation see: (a)
DiMauro, E. F.; Vitullo, J. R. J. Org. Chem. 2006, 71, 3959; (b) De Borggraeve,
W. M.; Appukkuttan, P.; Azzam, R.; Dehaen, W.; Compernolle, F.; Van der
Eycken, E.; Hoornaert, G. Synlett 2005, 777; (c) Appukkuttan, P.; Van der
Eycken, E.; Dehaen, W. Synlett 2003, 1204; (d) Fürstner, A.; Seidel, G. Org. Lett.
2002, 4, 541.
9. The LC–MS data included in Table 1 were obtained using LC–MS systems
calibrated on a daily basis with a system-suitability seven-component test mix
to ensure fit for purpose (identity and purity).
Acknowledgments
The authors thank Melissa Gomez, James Mack, Nicholas
Adams, and Art Shu for helpful comments in the preparation of this
Letter.
10. In addition to unreacted 1, the following by-products were also routinely
observed: X = H, 2–12% by LC–MS; unreacted boronic acid, 7–11% by LC–MS;
and dimers formed from homocoupling of 1, 0–6% by LC–MS.
11. (a) Fleckenstein, C. A.; Plenio, H. Chem. Eur. J. 2008, 14, 4267. and references
cited therein; For examples of pyrazole and imidazole moieties functioning as
Pd ligands in Suzuki–Miyaura reactions see: (b) Mukherjee, A.; Sarkar, A.
Tetrahedron Lett. 2004, 45, 9525; (c) Zeng, F.; Yu, Z. J. Org. Chem. 2006, 71,
5274.
References and notes
1. For examples of benzimidazole-based Raf kinase inhibitors see: Smith, R. A.;
Dumas, J.; Adnane, L.; Wilhelm, S. M. Curr. Top. Med. Chem. 2006, 6, 1071; For