2746
N. Cousaert et al. / Tetrahedron Letters 49 (2008) 2743–2747
5. Berellini, G.; Cruciani, G.; Mannhold, R. J. Med. Chem. 2005, 48,
4389–4399.
an imidazoline head for which a regioselective alkylation is
possible (unlike for losartan, bearing an ambident imidaz-
ole ring).6 Imidazolinone 14 was thus synthesized in three
steps as previously reported.21,22 Using our optimized con-
ditions, the synthesis of irbesartan was performed in five
steps as described in Scheme 2.23 First, anchoring of tetra-
zole 1 using Zn(OTf)2 was performed on a 4-hydroxy-
methyl-3-methoxyphenoxy TentagelÒ resin. Then, the
arylation of 2-bromophenyltetrazole was achieved using
our aqueous Suzuki conditions, and dehydrohalogenation
of the benzylalcohol was performed with P(C6H5)3Br2.24
Noteworthy, dichloromethane was carefully dried, to avoid
the cleavage of the product from the resin. Finally, bro-
mide was displaced by 14 in the presence of tetrabutylam-
monium iodide, and irbesartan 15 was released from the
resin using TFA 50% in dichloromethane. Irbesartan was
obtained in excellent purity and an overall yield of 64%
after five reaction steps, corresponding to an average yield
of 91% per synthesis step, including the arylation step.
We have developed an efficient anchoring of tetrazoles
on 4-hydroxymethyl-3-methoxyphenoxy resins. The use
of a water-compatible resin allowed maximizing the yield
of the Suzuki arylation step. The method was then success-
fully applied to the synthesis of irbesartan. Thanks to the
use of a polymer-supported technology, this linear scheme
is nonetheless very efficient and readily applicable to paral-
lel synthesis of biaryltetrazoles. Our method could thus be
extended to other bioactive series.
6. (a) Larsen, R. D.; King, A. O.; Chen, C. Y.; Corley, E. G.; Foster, B.
S.; Roberts, F. E.; Yang, C.; Lieberman, D. R.; Reamer, R. A.;
Tschaen, D. M.; Verhoeven, T. R.; Reider, P. J.; Lo, Y. S.; Romano,
L. T.; Brookes, A. S.; Meloni, D.; Moore, J. R.; Arnett, J. F. J. Org.
Chem. 1994, 59, 6391; (b) Ismail, M. A.; Barker, S.; Abou el-Ella, D.
A.; Abouzid, K. A.; Toubar, R. A.; Todd, M. H. J. Med. Chem. 2006,
49, 1526–1535.
7. Charton, J.; Cousaert, N.; Bochu, C.; Willand, N.; Deprez, B.;
Deprez-Poulain, R. Tetrahedron Lett. 2007, 48, 1479–1483.
8. Koppitz, M.; Eis, K. Drug Discovery Today 2006, 11, 561.
9. Matthews, D. P.; Green, J. E.; Shuker, A. J. J. Comb. Chem. 2000, 2,
19–23.
10. (a) Severinsen, R.; Lau, J. F.; Bondensgaard, K.; Hansen, B. S.;
Begtrup, M.; Ankersen, M. Bioorg. Med. Chem. Lett. 2004, 14, 317;
(b) Hamada, Y.; Igawa, N.; Ikari, H.; Ziora, Z.; Nguyen, J.-T.;
Yamani, A.; Hidaka, K.; Kimura, T.; Saito, K.; Hayashi, Y. Bioorg.
Med. Chem. Lett. 2006, 16, 4354; (c) Gunn, S.; Baker, A.; Bertram,
R.; Warriner, S. Synlett 2007, 2643–2646.
11. (a) Yoo, S.-E.; Seo, J.-S.; Yi, K.-Y.; Gong, Y.-D. Tetrahedron Lett.
1997, 38, 1203; (b) Yoo, S.-E.; Gong, Y.-D.; Choi, M.-Y.; Seo, J.-S.;
Yang Yi, K. Tetrahedron Lett. 2000, 41, 6415.
12. Chen, J. J.; Golebiowski, A.; Klopfenstein, S. R.; West, L. Tetra-
hedron Lett. 2002, 43, 4083.
13. (a) Kivrakidou, O.; Brase, S.; Hulshorst, F.; Griebenow, N. Org. Lett.
2004, 6, 1143–1146; (b) Alterman, M.; Hallberg, A. J. Org. Chem.
2000, 65, 7984–7989.
14. Fortin, R.; Broch, C. Tetrahedron Lett. 1994, 35, 9681–9684.
15. General procedure for anchoring tetrazoles on hydroxyl resin using
Zn(OTf)2: A reactor was loaded with tetrazole (10 equiv, 0.3 M) and
zinc triflate (0.1 equiv, 0.003 M) in dry acetonitrile and hydroxyl resin
(1 equiv). The mixture was refluxed under argon during 24 h. Resin
was filtered and washed with acetonitrile (3 ꢀ 5 mL), methanol
(3 ꢀ 5 mL), DMF (5 ꢀ 3 mL), DCM (5 ꢀ 3 mL), and diethyl ether
(5 ꢀ 3 mL). This protocol was validated for the following quantities
of resin: 75, 150 or 300 lmol, either using SynPhase Lanterns
(Mimotopes, Pty, Clayton, Australia) or classical resins.
16. While the procedure described in Ref. 14 was successful for the
attachment of 5-phenyltetrazoles on the HMPB-BHA resin, it was not
suitable for anchoring 5-phenyl-1,2,4-oxadiazole-5-one, another
classical acidic heterocycle: 7% overall yield.
17. The synthesis of 5-(40-methyl-biphenyl-2-yl)-1H-tetrazole 5 was per-
formed using conditions described in Wittenberger, S. J., Donner, B.
G. J. Org. Chem. 1993, 58, 4139. 40-Methyl-biphenyl-2-carbonitrile
(1 equiv, 22 mmoL; 4.28 g) and (CH3)3SiN3 (5.45 equiv, 120 mmol,
16.8 mL) are dissolved in toluene (44 mL). (nC4H9)2SnO (0.18 equiv,
4 mmol, 996 mg) is then added and the reaction mixture is refluxed for
72 h. 1H NMR (DMSO-d6) 300 MHz d 2.27 (s, 3H); 7.05 (d;
J = 8.1 Hz, 2H); 7.15 (d, J = 8.2 Hz, 2H); 7.50–7.70 (m, 4H); mp:
148–149 °C; LCMS (EI): m/z = 237 [MH+].
Acknowledgment
We are grateful to the institutions that support our lab-
´
oratory (Inserm, Universite de Lille2 and Institut Pasteur
de Lille). This project was supported by the European
Commission—ERDF funds, Grant No. OBJ2—2006/
364.1 No. 302. The authors would also like to thank
ARH Nord Pas de Calais for the financial support of N.
Cousaert. Data management was performed using Pipeline
PilotTM from Scitegic. We thank also the following institu-
tions or companies: CAMPLP and VARIAN.Inc.
Supplementary data
18. Lee, J.; Kang, S. U.; Kim, S. Y.; Kim, S. E.; Kang, M. K.; Jo, Y. J.;
Experimental details and characterization biphenyl-
tetrazoles 6–13, heterocycle 14 and irbesartan 15 are avail-
able. Supplementary data associated with this article can be
Kim, S. Bioorg. Med. Chem. Lett. 2001, 11, 961.
19. Cousaert, N.; Toto, P.; Willand, N.; Deprez, B. Tetrahedron Lett.
2005, 46, 6529–6532.
20. General procedure for Suzuki conditions to load 4-hydroxymethyl-
phenylboronic acid: A reactor was loaded with boronic acid (12 equiv,
0.3 M), Na2CO3 (8 equiv, 0.2 M), PdCl2(dppf) (0.6 equiv, 0.015 M) in
DME/H2O (2:1), and Tentagel S AC resin grafted with 1 (1 equiv).
The mixture was refluxed during 24 h under argon. Resin was filtrated
and washed with DME (3 ꢀ 5 mL), methanol (3 ꢀ 5 mL), DMF
(5 ꢀ 3 mL), DCM (5 ꢀ 3 mL) and diethyl ether (5 ꢀ 3 mL). This
protocol was validated for the following quantities of resin 30 or
300 lmol.
21. See supporting information section: Bernhart, C. A.; Perreaut, P. M.;
Ferrari, B. P.; Muneaux, Y. A.; Assens, J. L. A.; Clement, J.;
Haudricourt, F.; Muneaux, C. F.; Taillades, J. E., et al. J. Med.
Chem. 1993, 36, 3371–3380.
References and notes
1. Wermuth, C. G. In The Practice of Medicinal Chemistry, 2nd ed.;
Wermuth, C. G., Ed.; Academic Press: London, 2003; pp 189–214.
2. For case histories and a review of solution-phase synthesis of
tetrazoles see: Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379–3393.
3. Huskey, S. W.; Doss, G. A.; Miller, R. R.; Schoen, W. R.; Chiu, S. H.
Drug Metab. Dispos. 1994, 22, 651–658.
4. Johnston, C. I. Lancet 1995, 346, 1403–1407.