R. Delatouche et al. / Tetrahedron 67 (2011) 401e407
407
1.5 equiv). After 2 h reflux, the solution was cooled down and the
solvent was removed under vacuum. The crude product was puri-
fied (flash chromatography, silica gel, PE/EA/Et3N 95/4/1 to 30/69/
1) affording the carbamate 7c as a colourless viscous oil with traces
of the starting alcohol 3c (195 mg, 0.31 mmol, 77%). 1H NMR (ac-
structures. All calculations were performed with the Gaussian 09
package (see Molecular modelling in Supplementary data).
Acknowledgements
etone-d6, 400 MHz):
d
¼8.01 (s, 1H), 7.73 (dd, 1H, J¼1.8, 7.7 Hz), 7.48
ꢁ
We thank CNRS, ANR and Universite de Poitiers for financial
support and ANR (Contract to R.D.).
(m, 5H), 7.24 (m, 11H), 7.08 (d, 1H, J¼8.4 Hz), 7.00 (dt, 1H, J¼0.8,
7.6 Hz), 4.51 (t, 2H, J¼7.1 Hz), 4.35 (m, 2H), 4.24 (d, 2H, J¼6.1 Hz),
4.07 (t, 2H, J¼6.1 Hz), 3.62 (m, 2H), 3.29 (s, 3H), 2.15 (m, 2H), 1.82
Supplementary data
(m, 2H); 13C NMR (acetone-d6, 100 MHz):
d¼166.8, 159.1, 155.4,
150.5, 145.7, 140.6, 134.2, 131.9, 129.1, 128.4, 128.3, 128.1, 127.9, 127.7,
125.7, 121.7, 120.9, 114.3, 83.6, 71.1, 68.7, 64.4, 58.8, 50.2, 44.9, 27.9,
26.8; HRMS (ESI): [MþNa]þ (C37H38N4O6Na) calculated: 657.26836,
found: 657.2687 (0 ppm).
Additional experimental procedure for compounds 1 and ana-
lytical data for all synthesized compounds, HPLC method and
analysis, graphical t1/2 determination of acidic hydrolysis of avail-
able compounds 7 and 9, details for calculations performed with
the Gaussian 09 package (energies, cartesian coordinates) and ad-
ditional references. Supplementary data associated with this article
4.1.6. 2-{4-[4-(Benzylamino-diphenyl-methyl)-[1,2,3]triazol-1-yl]-
butoxy}-benzoic acid 2-methoxy-ethyl ester (9c). To a solution of
alcohol 1c (0.2 g, 0.40 mmol, 1 equiv) in dry DCM (10 mL) at 0 ꢁC
under nitrogen atmosphere was added a 2 M solution of HCl in Et2O
(0.239 mL, 0.48 mmol, 1.2 equiv). The solution was stirred for 1 h
and Et3N (0.122 mL, 0.089 g, 0.88 mmol, 2.2 equiv) and benzyl-
amine (0.057 mL, 0.056 g, 0.52 mmol, 1.3 equiv) were added. After
2 h reflux, the solvent was evaporated under vacuum and the crude
product was purified (flash chromatography, silica gel, PE/EA/Et3N
80/19/1 to 30/69/1) affording the amine 9c as a colourless viscous
oil (47 mg, 0.0795 mmol, 20%). 1H NMR (acetone-d6, 400 MHz):
References and notes
1. Ulbrich, K.; Subr, V. Adv. Drug Delivery Rev. 2004, 56, 1023.
2. (a) Ringsdorf, H. J. Polym. Sci., Polym. Symp. 1975, 51, 135; (b) Duncan, R.; Gac-
Breton, S.; Keane, R.; Musila, R.; Sat, Y. N.; Satchi, R.; Searle, F. J. Controlled Release
2001, 74, 135; (c) Kopecek, J.; Nori, A. Adv. Drug Delivery Rev. 2005, 57, 609.
3. White, S.; Szewczyk, J. W.; Turner, J. M.; Baird, E. E.; Dervan, P. B. Nature 1998,
391, 468.
4. Guo, X.; Szoka, F. C., Jr. Bioconjugate Chem. 2001, 12, 291.
5. (a) Asokan, A.; Cho, M. J. Bioconjugate Chem. 2004, 15, 1166; (b) Heffernan, M. J.;
Murthy, N. Bioconjugate Chem. 2005, 16, 1340.
d
¼7.77 (s, 1H), 7.70 (dd, 1H, J¼1.8, 7.7 Hz), 7.58 (m, 4H), 7.46 (ddd,
6. Bachelder, E. M.; Beaudette, T. T.; Broaders, K. E.; Paramonov, S. E.; Dashe, J.;
Frechet, J. M. J. Mol. Pharmaceutics 2008, 5, 876.
7. Etrych, S.; Sirova, M.; Starovoytova, L.; Rihova, B.; Ulbrich, K. Mol. Pharmaceutics
1H, J¼1.8, 7.4, 8.4 Hz), 7.39 (m, 2H), 7.30 (m, 6H), 7.21 (m, 3H), 7.08
(dd, 1H, J¼1.1, 8.4 Hz), 6.98 (dt, 1H, J¼1.0, 7.6 Hz), 4.54 (t, 2H,
J¼7.1 Hz), 4.30 (m, 2H), 4.09 (t, 2H, J¼6.0 Hz), 3.61 (m, 2H), 3.50
(d, 2H, J¼7.2 Hz), 3.29 (s, 3H), 2.76 (br t, 1H), 2.19 (m, 2H), 1.84 (m,
ꢁ
2010, 7, 1015.
ꢁ
8. Frechet, J. M. J.; Gillies, E. R.; Goodwin, A. P. Bioconjugate Chem. 2004, 15, 1254.
2H); 13C NMR (acetone-d6, 100 MHz):
d
¼166.8, 159.1, 153.5, 147.0,
9. Patel, V. F.; Hardin, J. N.; Mastro, J. M.; Law, K. L.; Zimmermann, J. L.; Ehlhardt,
W. J.; Woodland, J. M.; Starling, J. J. Bioconjugate Chem. 1996, 7, 497.
10. (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565; (b) Huisgen, R. Angew.
Chem., Int. Ed. Engl. 1963, 2, 633.
11. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004.
12. Majireck, M. M.; Weinreb, S. M. J. Org. Chem. 2006, 71, 8680.
13. (a) Wan, Q.; Chen, J.; Chen, G.; Danishefsky, S. J. J. Org. Chem. 2006, 71, 8244; (b)
Srinivasachari, S.; Liu, Y.; Zhang, G.; Prevette, L.; Reineke, T. M. J. Am. Chem. Soc.
2006, 128, 8176.
14. Kirshenbaum, K.; Jang, H.; Fafarman, A.; Holub, J. Org. Lett. 2005, 7, 1951.
15. Englert, B. C.; Bakbak, S.; Bunz, U. H. F. Macromolecules 2005, 38, 5868.
16. (a) Wang, Q.; Sivakumar, K.; Xie, F.; Cash, B. M.; Long, S.; Barnhill, H. N. Org. Lett.
2004, 6, 4603; (b) Deiters, A.; Cropp, T. A.; Muckherji, M.; Chin, J. W.; Anderson,
J. C.; Schultz, P. G. J. Am. Chem. Soc. 2003, 125, 11782.
142.15, 134.2, 132.0, 129.1, 129.0, 128.8, 128.6, 127.5, 127.4, 124.6,
121.8, 120.9, 114.3, 71.1, 68.7, 67.0, 64.4, 58.8, 50.3, 48.8, 27.9, 26.9;
HRMS (ESI): [MþNa]þ (C36H38N4O4Na) calculated: 613.27853,
found: 613.2788 (0 ppm).
4.1.7. 2-(4-{4-[Benzylamino-bis-(4-methoxy-phenyl)-methyl]-[1,2,3]
triazol-1-yl}-butoxy)-benzoic acid 2-methoxy-ethyl ester (9d). To
a two-neck flask solution of alcohol 1d (0.050 g, 0.089 mmol,
1 equiv) in 2 mL dry DCM under nitrogen atmosphere was added
89
mL HCl/Et2O 2 M (0.178 mmol, 2 equiv). The solution was
17. Zhou, Z.; Li, S.; Zhang, Y.; Liu, M.; Li, W. J. Am. Chem. Soc. 2005, 127, 10824.
18. Bertrand, P.; Gesson, J.-P. J. Org. Chem. 2007, 72, 3596.
refluxed for 2 h and then 37
mL Et3N (0.267 mmol, 3 equiv) and 11 mL
19. Stella, V. J.; Borchart, R. T.; Hageman, M. J.; Oliyai, R.; Maag, H.; Tilley, J. W.
Prodrugs: Challenges and Rewards; Springer: New York, NY, 2007, Part 1.
20. Hegarty, A. F.; Frost, L. N.; Coy, J. H. J. Org. Chem. 1974, 39, 1089.
21. Bergon, M.; Calmon, J.-P. Tetrahedron Lett. 1981, 22, 937.
BnNH2 (0.098 mmol, 1.1 equiv) were added. The solution was
refluxed overnight. The solution was then cooled down and the
solvent was evaporated under reduced pressure. The crude residue
was separated by preparative chromatography on silica gel plates
by slow elution with a mixture of PE/EA/Et3N (59/39/2) affording
16 mg of the desired compound as a colourless viscous oil
22. Savolainen, J.; Leppanen, J.; Forsberg, M.; Taipale, H.; Nevalainen, T.; Huusko-
nen, J.; Gynther, J.; Mannisto, P. T.; Jarvinen, T. Life Sci. 2000, 67, 205.
€
23. Voelter, W.; Muller, J. Liebigs Ann. Chem. 1983, 248.
24. Moulin, F. Helv. Chem. Acta 1952, 35, 167.
25. Gabbutt, C. D.; Herin, B. M.; Instone, A. C.; Thomas, D. A.; Partington, S. M.;
Hursthouse, M. B.; Gelbrich, T. Eur. J. Org. Chem. 2003, 1220.
(0.025 mmol, 30% yield). 1H NMR (acetone-d6, 400 MHz):
d¼7.71
(m, 2H), 7.46 (m, 5H), 7.38 (d, 2H, J¼7.4 Hz), 7.28 (t, 2H, J¼7.4 Hz),
7.20 (m, 1H), 7.07 (d, 1H, J¼8.4 Hz), 6.98 (dt, 1H, J¼0.9, 7.6 Hz), 6.84
(m, 4H), 4.53 (t, 2H, J¼7.1 Hz), 4.30 (m, 2H), 4.09 (t, 2H, J¼6.0 Hz),
3.76 (s, 6H), 3.61 (m, 2H), 3.51 (br s, 2H), 3.29 (s, 3H), 2.68 (br s, 1H),
2.18 (m, 2H), 1.83 (m, 2H); 13C NMR (acetone-d6, 100 MHz):
26. (a) Francis, T.; Thorne, M. P. Can. J. Chem. 1976, 54, 24; (b) Dillard, R. D.; Poore,
G.; Cassady, D. R.; Easton, N. R. J. Org. Chem. 1967, 10, 40.
27. Martell, M. J., Jr.; Boothe, J. H. J. Med. Chem. 1967, 10, 44.
28. Da Silva, E. F.; Svendsen, H. F. Ind. Eng. Chem. Res. 2006, 45, 2497.
29. Abboud, J.-L. M.; Foces-Foces, C.; Notario, R.; Trifonov, R. E.; Volovodenko, A. P.;
Ostrovskii, V. A.; Alkorta, I.; Elguero, J. Eur. J. Org. Chem. 2001, 16, 3013.
30. (a) Riley, K. E.; Op’t Holt, B. T.; Merz, K. M., Jr. J. Chem. Theory Comput. 2007, 3,
407; (b) Tirado-Rives, J.; Jorgensen, W. L. J. Chem. Theory Comput. 2008, 4, 297;
(c) Guner, V.; Khuong, K. S.; Leach, A. G.; Lee, P. S.; Bartberger, M. D.; Houk, K. N.
J. Phys. Chem. A 2003, 107, 11445.
31. Vandenabeele-Trambouze, O.; Garrelly, L.; Mion, L.; Boiteau, L.; Commeyras, A.
Adv. Environ. Res. 2001, 6, 67.
32. (a) Becke’s three parameters hybrid method using the LYP correlation func-
tional of Lee et al. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648; (c) Lee, C.; Yang,
W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
d¼166.8, 159.2, 159.1, 154.2, 142.3, 139.2, 134.2, 132.1, 130.2, 129.1,
128.9, 127.4, 124.3, 121.8, 120.9, 114.3, 113.9, 71.1, 68.8, 66.0, 64.4,
58.8, 55.5, 50.3, 48.8, 27.9, 26.9; HRMS (ESI): [MþNa]þ
(C38H42N4O6Na) calculated: 673.29966, found: 673.3000 (0 ppm).
All structures were studied using the B3LYP method32 of the
density functional theory. The structures were fully optimized using
the 6-31G(d,p) basis sets (B3LYP/6-31G(d,p)). In the gas phase, free
energies were computed at 298.15 K without scaling vibrational
frequencies. Solvent effects were calculated using the Polarizable
Continuum SMD model33 (solvent¼water) as single point energy
calculations at the B3LYP/6-31G(d) level on the gas phase optimized
33. (a) The Polarizable Continuum SMD model was used with water as solvent. (b)
Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113, 6378; (c)
Calculations performed with the Gaussian 09 package. See Supplementary data
for additional details (energies, cartesian coordinates) and references for
Gaussian 09.