942
P. Sharma et al. / Bioorg. Med. Chem. Lett. 15(2005) 937–943
4.2. Synthesis of 5-[(30-chloro-40,40-disubstituted-2-
oxoazetidinyl)(N-nitro)amino]-6-hydroxy-3-alkyl/
aryl[1,3]azaphospholo[1,5-a]pyridin-1-yl-phosphorus
dichlorides (4a–r)
hydrofuran (25 mL) was added. All the contents were
stirred for 30 min at room temperature and resulted in
the formation of a solid compound. It was then washed
with diethyl ether (10 mL), filtered and dried in vacuum.
The resultant compound (0.01M) thus obtained was
then suspended in acetonitrile (20 mL) in a beaker and
cooled to 0–5 ꢁC. To this, triethylamine (4 mL,
0.04 M) was added and the mixture was stirred for
30 min. Further, a solution of phosphorus trichloride
(0.02 M) in acetonitrile (1mL) was added dropwise.
The reaction mixture gradually changes from pale yel-
low to brown and allowed to stand at room temperature
for 30 min and then stirred further for 10 h. The
compounds 5-[(30-chloro-40,40-disubstituted-2-oxoaze-
tidinyl)(N-nitro)amino]-6-hydroxy-3-alkyl/aryl[1,3]aza-
Disubstituted-3-chloro-1-[(3-hydroxypyridin-2-yl)(N-ni-
tro)amino]-4-oxoazetidine-2,2-dicarboxylates 3a–r (0.01
M) was taken in 250 cm3 round-bottom flask and an
equimolar quantity of a solution of an alkylating agent
viz. benzyl chloride, monochloroacetic acid in tetra-
O
OH
R'
N
NH
R"
phospholo[1,5-a]pyridin-1-yl-phosphorus
dichlorides
N
O
(4a–r) obtained were recrystallized from methanol.
Structures of all the synthesized compounds have been
ascertained on the basis of consistent physical and spec-
troanalytical data (Table 5). Synthetic pathway of all
sequential steps is depicted in Scheme 1.
1a-r
(i)
O
O
OH
R'
Conclusively, a series of compounds incorporating
azetidine and phosphaindolizine heterocyclic nuclei
viz., 5-[(30-chloro-40,40-disubstituted-2-oxoazetidinyl)-
(N-nitro)amino]-6-hydroxy-3-alkyl/aryl[1,3]azaphospho-
lo[1,5-a]pyridin-1-yl-phosphorus dichlorides has been
synthesized as potent antimicrobial agents. Further-
more, QSAR studies performed on these compounds
have revealed that the substitution of bulky group with
higher polarizability probably enhances the potency of
these compounds as antibacterial and antifungal agents.
Influence of other substituents at this site will be the
matter of further investigation.
N
N
R"
N
NO2
2a-r
(ii)
OH
R'
NO2
N
O
R"
N
N
O
O
Cl
3a-r
(iii)
References and notes
1. Akinori, K.; Tastuya, N.; Koizumi, K.; Yoshiyasu, K.;
Naoki, S. Heterocycles 1996, 42, 195.
2. Gundersen, L. L.; Negussie, A. H.; Rise, F.; Ostby, O. B.
Arch. Pharm. 2003, 336, 191.
3. Foster, C.; Ritchie, M.; Selwood, D. I.; Snowden, W.
Antiviral. Chem. Chemother. 1995, 6, 289.
4. Vaught, V. L.; Carson, J. R.; Carmosin, R. J.; Blum, P. S.;
Perisco, F. J.; Hageman, W. E.; Shank, R. P.; Raffa, R. B.
J. Pharmacol. Exp. Ther. 1990, 255, 1 .
5. Coutre, A.; Deniau, E.; Grandclaudon, P.; Leburn, S.;
Leonce, S.; Renard, P.; Pfeiffer, B. Bioorg. Med. Chem.
2000, 8, 2113.
OH
R'
Cl
NO2
O
R"
N
N
+
N
O
+
H2C
H
C
2
O
Cl -
R
Cl2P
6. Jorgenson, A. S.; Jacobson, P.; Chirstiansen, L. B.; Bury,
P. S.; Kanstrup, A.; Throp, S. M.; Bain, S.; Naerum, L.;
Wassermann, K. Bioorg. Med. Chem. Lett. 2000, 10, 399.
7. Holladay, M. W.; Bai, H.; Li, Y.; Lin, N. H.; Daanen, J.
F.; Ryther, K. B.; Wasicak, J. T.; Kincaid, J. F.; He, Y.;
Hettinger, A. M. Bioorg. Med. Chem. Lett. 1998, 8, 2797.
8. Nishiyama, S.; Kikuchi, Y.; Kurata, H.; Yamamura, S.;
Izawa, T.; Nagahata, T.; Ikeda, R.; Kato, K. Bioorg. Med.
Chem. Lett. 1995, 5, 2273.
9. Hosono, F.; Nishiyama, S.; Yamamura, S.; Izawa, T.;
Kato, K.; Terada, Y. Tetrahedron 1994, 50, 1335.
10. Cheng, Q.; Kiyota, H.; Yamaguchi, M.; Horiguchi, M.;
Oritani, T. Bioorg. Med. Chem. Lett. 2003, 13, 1075.
11. Smaele, D. D.; Dejaegher, Y.; Duvey, G.; Kimpe, N. D.
Tetrahedron Lett. 2001, 42, 2373.
(iv)
OH
R'
NO2
N
O
R"
N
N
O
Cl2P
R
O
P
Cl
4a-r
Scheme 1. Reagents and conditions: (i) HNO3/H2SO4, 0–5 ꢁC; (ii)
(C2H5)3N, 1,4-dioxane, ClCOCH2Cl, stirring, 4 h; (iii) RX, THF, PCl3;
(iv) CH3CN, PCl3, (C2H5)3N, stirring, 10 h.
Sharma, Pratibha
