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3. Harger, M. J. P. J. Chem. Soc., Perkin Trans. I 1983, 2699±
2702.
4.2.1. 4-Amino-2-methoxycarbonylaminobenzoic acid
ꢀ6b). Melting point 125.6±129.38C; H NMR +CDCl3) d
1
4. Fahmy, A. F. M.; Aly, N. F.; Nada, A.; Aly, N. Y. Bull. Chem.
Soc. Jpn. 1977, 50, 2678±2681.
5. KuÈhle, E.; Wegler, R. Justus Leibigs Ann. Chem. 1958, 616,
183±206.
10.75 +s, 1H), 7.80 +d, J8.8 Hz, 1H), 7.74 +d, J2.2 Hz,
1H), 6.28 +dd, J8.8, 2.2 Hz, 1H), 4.17 +s, 2H), 3.86 +s, 3H),
3.78 +s, 3H); 13C NMR +CDCl3) d 168.6, 154.3, 152.4,
143.8, 133.0, 108.1, 104.7, 103.0, 52.3, 51.8; MS m/z
224.0 +M1); Anal. calcd. for C10H12N2O4: C, 53.57; H,
5.39; N, 12.49. Found: C, 53.74; H, 5.37; N, 12.28.
6. Berndt, D. C.; Shechter, H. J. Org. Chem. 1964, 29, 916±918.
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1967, 19, 578±583.
4.2.2. 4-Acetylamino-2-methoxycarbonylaminobenzoic
acid ꢀ7b). Melting point 191.5±191.78C; 1H NMR
+CDCl3) d 10.60 +s, 1H), 8.19 +d, J1.8 Hz, 1H), 8.01 +d,
J8.8 Hz, 1H), 7.74 +d, J8.1 Hz, 1H), 7.61 +s, 1H), 3.88
+s, 3H), 3.70 +s, 3H), 2.21 +s, 3H); 13C NMR +CDCl3) d
185.7, 168.2, 154.3, 143.6, 142.6, 132.7, 112.7, 110.2,
108.0, 52.4, 52.2, 24.9; MS m/z 266.1 +M1); Anal. calcd.
for C12H14N2O5: C, 54.13; H, 5.30; N, 10.52. Found: C,
54.04; H, 5.31; N, 10.27.
9. Rozeboom, M. D.; Tegmo-Larsson, I. M.; Houk, K. N. J. Org.
Chem. 1981, 46, 2338±2345.
10. Kerrigan, J. E.; Shirley, J. J. Bioorg. Med. Chem. Lett. 1996, 6,
451±456.
11. Entwistle, I. D.; Johnstone, R. A. W.; Povall, T. J. J. Chem.
Soc., Perkin Trans. I 1975, 1300±1301.
12. Ogata, Y.; Sawaki, Y.; Isono, M. Tetrahedron 1969, 25,
2715±2721.
4.2.3. 4-Phenacetylamino-2-methoxycarbonylamino-
benzoic acid methyl ester ꢀ8b). Melting point 209.9±
13. Fleming, I. Frontier Orbitals and Organic Chemical
Reactions; Wiley: New York, 1976.
1
210.28C; H NMR +CDCl3) d 10.60 +s, 1H), 8.10 +d, J
14. Rosenberg, R. E.; Mohrig, J. R. J. Am. Chem. Soc. 1997, 119,
487±492.
2.3 Hz, 1H), 7.95 +d, J9.2 Hz, 1H), 7.69 +dd, J9.2,
2.1 Hz, 1H), 7.28±7.47 +m, 6H), 3.89 +s, 3H), 3.77 +s,
3H), 3.75 +s, 2H); 13C NMR +CDCl3) d 169.6, 168.2,
154.2, 143.4, 142.5, 134.0, 132.5, 129.5, 129.3, 127.9,
112.9, 110.4, 108.3, 52.4, 45.1; MS m/z 342.0 +M1); Anal.
calcd. for C18H18N2O5´+H2O)0.5: C, 61.83; H, 5.45; N, 7.97.
Found: C, 61.74; H, 5.27; N, 7.95.
15. Schlegel, H. J. Comput. Chem. 1982, 3, 214±218.
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6105±6109.
18. Wong, M. W.; Frisch, M. J.; Wiberg, K. B. J. Am. Chem. Soc.
1991, 113, 4776±4782.
19. Wong, M. W.; Wiberg, K. B.; Frisch, M. J. J. Am. Chem. Soc.
1992, 114, 1645±1652.
4.3. Molecular modeling
20. Wiberg, K. B.; Wong, M. W. J. Am. Chem. Soc. 1993, 115,
1078±1084.
All computations were carried out on a Dell Precision
620 Workstation using TITAN +Wavefunction, Inc. and
Schroedinger, Inc.). All structure models were initially
geometry optimized using the Merck Molecular Force
Field +MMFF94).25 The structure models for compounds 1
and 2 depicted in Figs. 3 and 4 were geometry optimized at
the RHF/6-31Gp level of theory.26 All single point and
SCRF calculations employing the RHF/6-31Gp, RHF/
6-311Gp and B3LYP/6-311Gp methods were performed
in Gaussian 98 using `tight' convergence criteria.27
21. Kohn, W.; Becke, A. D.; Parr, R. G. J. Phys. Chem. 1996, 100,
12974±12980.
22. Perrin, D. D.; Armarego, W. L. F. Puri®cation of Laboratory
Chemicals; 3rd; Pergamon Press: New York, 1988.
23. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923±2925.
24. Makosza, M.; Bialecki, M. J. Org. Chem. 1998, 63, 4878±
4888.
25. Halgren, T. J. Comput. Chem. 1996, 17, 490±519.
26. Hehre, W.; Radom, L.; Schleyer, P.; Pople, J. Ab Initio
Molecular Orbital Theory; Wiley: New York, 1986.
27. Frisch, M.; Trucks, G.; Schlegel, H.; Scuseria, G.; Robb, M.;
Cheeseman, J.; Zakrzewski, V.; Montgomery, J.; Stratmann,
R.; Burant, J.; Dapprich, S.; Millam, J.; Daniels, A.; Kudin,
K.; Strain, M.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.;
Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford,
S.; Ochterski, J.; Petersson, G.; Ayala, P.; Cui, Q.; Morokuma,
K.; Malick, D.; Rabuck, A.; Raghavachari, K.; Foresman, J.;
Cioslowski, J.; Ortiz, J.; Baboul, A.; Stefanov, B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.;
Martin, R.; Fox, D.; Keith, T.; Al-Laham, M.; Peng, C.;
Nanayakkara, A.; Challacombe, M.; Gill, P.; Johnson, B.;
Chen, W.; Wong, M.; Andres, J.; Gonzalez, C.; Head-Gordon,
M.; Replogle, E.; Pople, J.; Gaussian 98, Revision A.9,
Gaussian, Inc., Pittsburgh, PA, 1998.
Acknowledgements
The authors wish to thank the New Jersey Thoracic Society
of the American Lung Association and the Charles and
Johanna Busch Foundation for their generous support. In
addition, the authors wish to thank the referees of this
journal for their intuitive comments and suggestions.
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