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M. Mabrour et al. / Tetrahedron Letters 48 (2007) 443–447
Table 2. PM3 calculations of reagents, products and transition states
(TS)
References and notes
a
DH0f
E act.b
lc
1. (a) Varma, R. S. Tetrahedron 2002, 58, 1235; (b) Tanaka,
K. Solvent-free Organic Synthesis; Wiley-VCH: Weinheim,
Germany, 2003.
2. (a) Kappe, C. O.; Stadler, A. In Microwaves in Organic
and Medicinal Chemistry; Wiley-VCH, Ed.; Weinheim:
Germany, 2005; (b) Microwaves in Organic Synthesis, 2nd
ed.; Loupy, A., Ed., Wiley-VCH: Weinheim, Germany,
2006.
Phenylnitrile oxide
Allyl saccharin 2
Cycloadduct 4a
Cycloadduct 6a
TS toward 4a
55.57
2.57
3.65
6.97
6.98
4.83
3.60
ꢀ54.34
ꢀ27.40
ꢀ23.28
37.44
36.21
37.07
TS toward 6a
38.30
a Standard enthalpy formation in kcal/mol.
b Energy of activation in kcal/mol.
c Dipole moment in Debyes.
3. (a) Colinas, P. A.; Ja¨ger, V.; Lieberknecht, A.; Bravo, R.
D. Tetrahedron Lett. 2003, 44, 1071; (b) Giacomelli, G.;
De Luca, L.; Porcheddu, A. Tetrahedron 2003, 59, 5437;
(c) Das, B.; Holla, H.; Mahender, G.; Banerjee, J.; Reddy,
M. R. Tetrahedron Lett. 2004, 45, 7347.
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R.; Bougrin, K.; El Akri, K.; Benhida, R. Tetrahedron
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Bashiardes, G. In Microwaves in Organic Synthesis;
Loupy, A., Ed.; Wiley-VCH: Weinheim, Germany, 2006,
Chapter 11.
Finally, in order to check the possible intervention of
specific (nonthermal) microwave effects,2,15 the best
results obtained under microwave irradiation were
extrapolated to conventional heating by carrying out
the reactions under similar conditions (time, tempera-
ture, pressure, and vessel). It was found that the reaction
did not occur and the reactants remained unchanged
even on extended reaction times (Table 1), thus suggest-
ing that the effect of microwaves is not simply
thermal.2,16,17
5. (a) Wagner, E.; Becan, L.; Nowakowska, E. Bioorg. Med.
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Chem. 2004, 12, 265; (b) Pastor, J.; Alcazar, J.; Alvarez, R.
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M.; Andres, J. I.; Cid, J. M.; De Lucas, A. I.; Dıaz, A.
Bioorg. Med. Chem. Lett. 2004, 14, 2917; (c) Sadashiva, B.
P. S.; Nanjunda, S. S.; Mahendra, M.; Shashidhara, P. J.;
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Lett. 2004, 14, 3679.
The nonthermal MW effects evidenced here can be easily
explained by considering the evolution of polarities
between ground state and transition state. The values
of dipole moments as given in Table 2 clearly indicate
that the polarity is significantly increased from starting
materials toward transition state and even toward the
final product. Indeed, as the polarity is enhanced with
the reaction progress, the dipole–dipole stabilization
with the electric field is increased and consequently a
positive MW effect is expected.2,17
6. (a) Bashiardes, G.; Safir, I.; Barbot, F.; Laduranty, J.
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In conclusion, we have developed, by coupling solvent-
free conditions and microwave assistance, a new,
efficient and green method for the synthesis of novel
isoxazoline and isoxazole N-substituted saccharins.
The process involves regiospecific [3+2] cycloaddition
between alkenes or alkynes and arylnitrile oxides.
The biological activity and inhibitory effect of such
analogues against human leukocyte elastase (HLE),
cathepsin G (Cat G), and proteinase 3 (PR 3) is under
examination.
Acknowledgments
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Besch, A.; Loose, J.; Otto, H. H. Pharmazie 2005, 60, 723;
(c) Ersanli, C. C.; Odabasoglu, M.; Sari, U. Acta
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Wei, L.; Alliston, K. R.; Yu, H.; Li, Y. H.; Groutas, W. C.
Arch. Biochem. Biophys. 2004, 429, 191; (e) Brooke, C. G.;
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Chem. Lett. 2003, 13, 2527; (f) Elgazwy, A.-S. S. H.
Tetrahedron 2003, 59, 7445; (g) Soubh, L.; Besch, A.; Otto,
H. H. Pharmazie 2002, 57, 384; (h) Nerenberg, J. B.; Erb,
J. M.; Thompson, W. J.; Lee, H. Y.; Guare, J. P.;
Munson, P. M.; Bergman, J. M.; Huff, J. R.; Broten, T. P.;
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´
We acknowledge CNRS-CNRST (convention d’echange
´
France-Maroc CHIMIE 04/06), Region PACA and
Ministry of Education, Government of Morocco
(PROTARS III, D13/57) for financial support. We are
´
especially thankful to Dr. F. Maurel (Itodys, Universite
Paris VII) for the theoretical calculations.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.11.067.