Synthesis ofN1-3-{(4-substituted aryl-3-chloro-2-oxo-azetidine)- iminocarbamyl}-propyl-6-nitroindazole derivatives and their biological significance

Article abstract of DOI:10.1002/cjoc.201180311

Synthesis ofN¹-3-{(4-substitute daryl-3-chloro-2-oxo-azetidine)- iminocarbamyl}-propyl-6-nitroindazole 4a-4s was conducted by a conventional method. All the compounds were synthesized and characterized by IR, ¹H NMR, ¹³C N

Full text of DOI:10.1002/cjoc.201180311

FULL PAPER
Synthesis of N1-3-{(4-Substituted aryl-3-chloro-2-oxo-
azetidine)-iminocarbamyl}-propyl-6-nitroindazole
Derivatives and Their Biological Significance
Samadhiya, Pushkal*
Sharma, Ritu
Srivastava, Santosh K.
Srivastava, Savitri D.
Synthetic Organic Chemistry Laboratory, Department of Chemistry, Dr. H. S. Gour University (A Central Univer-
sity), Sagar, M.P. 470003, India
Synthesis of N1-3-{(4-substitute daryl-3-chloro-2-oxo-azetidine)-iminocarbamyl}-propyl-6-nitroindazole 4a—
1
4s was conducted by a conventional method. All the compounds were synthesized and characterized by IR, H
NMR, 13C NMR, FAB-Mass techniques and chemical methods. All the final synthesized compounds were evalu-
ated for their antimicrobial activity and antitubercular activity with MIC values against some selected microorgan-
isms.
Keywords synthesis, 6-nitroindazole, 2-azetidinone, biological activity
Introduction
cal activity. Our research groups decide to synthesize
and explore their biological activities. A new series of
Indazole derivatives possess a wide variety of activi-
ties such as antimicrobial,1 nitric oxide synthesis,2 pro-
tein kinase inhibitor,3 antiproliferative,4 antiprotozoal5
and anesthesia.6 Despite many useful applications of
indazole derivatives, indazole chemistry remains less
studied compared to other heteroaromatic compounds,
such as indole or benzimidazole while pyridine, pyrrole
and pyrazole molecules have been well studied, chem-
ists still have interest for further study due to their
promising biological activities. β-Lactam antibiotics are
the most commonly used antimicrobial drug,7 the
2-carbonyl derivative of azetidine (four membered het-
erocyclic ring with nitrogen as the heteroatom) is des-
ignated as 2-azitidinone which possesses powerful anti-
inflammatoryl,8 anticonvulsnt,9 antibacterial10,11, anti-
fungal12 etc. activities. Thus 6-nitroindazole and
2-azetidinone derivative together may enhance biologi-
N1-3-{(4-substituted
aryl-3-chloro-2-oxo-azetidine)-
iminocarbamyl}-propyl-6-nitroinda-zole 4a—4s were
synthesized as shown in Scheme 1 and characterized by
IR, 1H NMR,13C NMR, FAB-Mass techniques and
chemical methods and their biological activities viz.
antibacterial, antifungal and antitubercular activities
have been investigated.
Experimental
Melting points were taken in open capillaries and
were uncorrected. Progress of reaction was monitored
by silica gel-G coated TLC plates using MeOH/CHCl3
system (V∶V＝1∶9). The spot was visualized by ex-
posing dry plate in iodine vapours chamber. IR spectra
were recorded in KBr disc on a Schimadzu 8201 PC,
Scheme 1 Synthesis of compounds 1, 2, 3a— 3s and 4a— 4s
* E-mail: pushkalsamadhiya@rediffmail.com.
Received December 23, 2010; revised February 14, 2011; accepted April 12, 2011.
Chin. J. Chem. 2011, 29, 1745— 1752 © 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1745

Samadhiya et al.
FULL PAPER
FTIR spectrophotometer (ν
－1
1
in cm ) and H NMR
to react. The reaction mixture was first continuously
stirred on a magnetic stirrer for about 2 to 3.5 h, then
kept on a steam bath for about 1.5 to 2.5 h. The products
were cooled and filtered at room temperature. The fil-
tered products were purified over a column chromatog-
raphy and recrystallized from ethanol at room tempera-
ture to yield compounds 3a—3s.
max
and 13C NMR spectra were measured on a Brucker
DRX-300 spectrometer in CDCl3 at 300 and 75 MHz
using TMS as an internal standard respectively. The
FAB-Mass spectra were recorded on a Jeol SX-102
mass spectrometer. Elemental analyses were performed
on a Carlo Erba-1108 analyzer. The analytical data of
all the compounds were highly satisfactory. For column
chromatographic purification of the products, Merck
silica Gel 60 (230—400 mesh) was used. The reagent
grade chemicals were purchased from the commercial
sources and were further purified before use.
N1-{3-(Benzylideniminocarbamyl)-propyl}-6-nitro-
1
indazole (3a): Yield 61%, m.p. 142—144 ℃; H NMR
(CDCl3, 300 MHz) δ: 2.25 (m, 2H, CH2CH2CH2), 3.32
(m, 2H, CH2CH2CH2-NH), 4.18 (t, J＝7.35 Hz, 2H,
N-CH2CH2CH2), 5.69 (br s, 1H, NH), 7.84 (s, 1H, N＝
CH), 7.40—7.71 (m, 9H, ArH); 13C NMR (CDCl3, 75
MHz) δ: 34.2 (CH2CH2CH2), 42.2 (CH2CH2CH2-NH),
46.1 (N-CH2CH2CH2), 145.8 (N＝CH), 169.9 (CO),
108.7, 120.9, 125.7, 126.6, 127.1, 128.3, 129.2, 134.6,
137.4, 138.3, 146.2 (A－r); IR ν: 1555 (N＝CH), 16＋52
Method for synthesis of compound 1
A mixture of 6-nitroindazole and 1-bromo-3-
chloropropane (1∶1 molar ratio) was dissolved in
methanol at room temperature. The reaction mixture
was continuously stirred on a magnetic stirrer for about
6.5 h. The product was filtered and purified over a col-
umn chromatography. The purified product was recrys-
tallized from ethanol at room temperature to yield com-
1
(C＝O), 3356 (NH) cm ; Mass (FAB) m/z: 351 (M ).
Anal. calcd for C18H17N5O3: C 61.53, H 4.87, N 19.93;
found C 61.51, H 4.80, N 19.85.
N1-{3-(4-Chlorobenzylideniminocarbamyl)-propyl}-
6-nitroindazole (3b): Yield 62%, m.p. 167—169 ℃; 1H
NMR (CDCl3, 300 MHz) δ: 2.38 (m, 2H, CH2CH2CH2),
3.48 (m, 2H, CH2CH2CH2-NH), 4.31 (t, J＝7.60 Hz, 2H,
N-CH2CH2CH2), 5.65 (br s, 1H, NH), 7.93 (s, 1H, N＝
CH), 7.28—7.81 (m, 8H, ArH); 13C NMR (CDCl3, 75
MHz) δ: 35.2 (CH2CH2CH2), 43.4 (CH2CH2CH2-NH),
47.3 (N-CH2CH2CH2), 152.5 (N＝CH), 173.1 (CO),
106.8, 113.9, 121.7, 126.4, 127.7, 128.9, 129.6, 134.7,
137.8, 139.3, 144.3 (Ar); IR ν: 742 (C—Cl) 1560 (N＝
1
pound 1. Yield 64%, m.p. 163—165 ℃; H NMR
(CDCl3, 300 MHz) δ: 2.20—2.26 (m, 2H, CH2CH2CH2),
3.40 (t, J＝7.45 Hz, 2H, CH2CH2CH2-Cl), 4.26 (t, J＝
7.45 Hz, 2H, N-CH2CH2CH2), 7.86—8.35 (m, 4H,
ArH); 13C NMR (CDCl3, 75 MHz) δ: 33.4
(CH2CH2CH2),
42.8
(CH2CH2CH2-Cl),
45.1
(N-CH2CH2CH2), 107.3, 114.2, 121.7, 126.2, 134.1,
138.7, 145.0 (Ar); IR ν: 752 (C—Cl), 872 (C—N), 1328
(N—CH2), 1523 (NO2), 1556 (C＝C), 2839, 3027 (CH)
－1
＋
－1
cm ; Mass (FAB) m/z: 239 (M ). Anal. calcd for
C10H10N3O2Cl: C 50.20, H 4.20, N 17.11; found C
50.17, H 4.13, N 17.08.
CH), 16＋74 (C＝O), 3372 (NH) cm ; Mass (FAB) m/z:
385 (M ). Anal. calcd for C18H16N5O3Cl: C 56.03, H
4.18, N 18.15; found C 55.97, H 4.15, N 18.12.
N1-{3-(3-Chlorobenzylideniminocarbamyl)-propyl}-
6-nitroindazole (3c): Yield 63%, m.p. 162—164 ℃; 1H
NMR (CDCl3, 300 MHz) δ: 2.33 (m, 2H, CH2CH2CH2),
3.40 (m, 2H, CH2CH2CH2-NH), 4.29 (t, J＝7.65 Hz, 2H,
N-CH2CH2CH2), 5.68 (br s, 1H, NH), 7.97 (s, 1H, N＝
CH), 7.15—7.93 (m, 8H, ArH); 13C NMR (CDCl3, 75
MHz) δ: 35.5 (CH2CH2CH2), 42.5 (CH2CH2CH2-NH),
48.2 (N-CH2CH2CH2), 151.2 (N＝CH), 172.9 (CO),
107.4, 116.8, 121.5, 124.2, 125.4, 127.5, 128.6, 129.7,
134.6, 134.9, 137.4, 138.5, 145.2 (Ar); IR ν: 745 (C—Cl)
Method for synthesis of compound 2
A mixture of compound 1 and urea (1∶1 molar ratio)
was dissolved in methanol at room temperature. The
reaction mixture was continuously stirred on a magnetic
stirrer for about 5.5 h. The product was filtered and pu-
rified over a column chromatography. The purified
product was recrystallized from ethanol at room tem-
perature to yield compound 2. Yield 71%, m.p. 145—
1
147 ℃; H NMR (CDCl3, 300 MHz) δ: 2.32 (m, 2H,
－1
CH2CH2CH2), 3.38 (m, 2H, CH2CH2CH2-NH), 4.28 (t,
J＝7.40 Hz, 2H, N-CH2CH2CH2), 5.69 (br s, 1H, NH),
5.94 (s, 2H, NH2), 6.86—7.72 (m, 4H, ArH); 13C NMR
(CDCl3, 75 MHz) δ: 33.7 (CH2CH2CH2), 41.1
(CH2CH2CH2NH), 45.7 (N-CH2CH2CH2), 163.4 (CO),
107.6, 114.2, 121.5, 126.3, 134.5, 137.7, 145.2 (Ar); IR
ν: 878 (C—N), 1234 (C—NH), 1523 (NO2), 1666 (C＝
1561 (N＝CH), 1675 (C＝O), 3365 (NH) cm ; Mass
(FAB) m/z: 385 (M＋). Anal. calcd for C18H16N5O3Cl: C
56.03, H 4.18, N 18.15; found C 55.99, H 4.17, N 18.11.
N1-{3-(2-Chlorobenzylideniminocarbamyl)-propyl}-
6-nitroindazole (3d): Yield 64%, m.p. 164—165 ℃; 1H
NMR (CDCl3, 300 MHz) δ: 2.36 (m, 2H, CH2CH2CH2),
3.38 (m, 2H, CH2CH2CH2-NH), 4.30 (t, J＝7.55 Hz, 2H,
N-CH2CH2CH2), 5.63 (br s, 1H, NH), 7.90 (s, 1H, N＝
CH), 7.2—7.9 (m, 8H, ArH); 13C NMR (CDCl3, 75
MHz) δ: 34.7 (CH2CH2CH2), 44.2 (CH2CH2CH2-NH),
48.6 (N-CH2CH2CH2), 152.6 (N＝CH), 172.4 (CO),
108.3, 115.2, 122.7, 126.8, 127.4, 128.2, 129.8, 130.5,
134.1, 135.2, 136.4, 139.6, 147.1 (Ar); IR ν: 750 (C－—
－1
O), 3342 (NH), 3456 (NH2) cm ; Mass (FAB) m/z: 263
(M＋). Anal. calcd for C11H13N5O3: C 50.18, H 4.97, N
26.60; found C 50.10, H 4.92, N 26.54.
General method for the synthesis of compound 3a—
3s
1
A mixture of compound 2 (1∶1 molar ratio) was
Cl), 1568 (N＝CH), 1674 (C＝O), 3374 (NH) cm ;
＋
dissolved in methanol at room temperature and allowed
Mass (FAB) m/z: 385 (M ). Anal. calcd for
1746
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1745— 1752

Synthesis of N1-3-{(4-Substituted aryl-3-chloro-2-oxo-azetidine)-iminocarbamyl}-propyl-6-nitroindazole
C18H16N5O3Cl: C 56.03, H 4.18, N 18.15; found C
55.97, H 4.15, N 18.14.
3.26 (m, 2H, CH2CH2CH2-NH), 4.26 (t, J＝7.45 Hz, 2H,
N-CH2CH2CH2), 5.72 (br s, 1H, NH), 7.89 (s, 1H, N＝
CH), 7.21—7.86 (m, 8H, ArH); 13C NMR (CDCl3, 75
MHz) δ: 41.7 (CH2CH2CH2), 47.2 (CH2CH2CH2-NH),
43.1 (N-CH2CH2CH2), 154.7 (N＝CH), 173.5 (CO),
110.5, 116.4, 121.7, 124.1, 126.7, 127.5, 128.3, 133.1,
134.6, 136.6, 139.8, 145.3, 150.6 (Ar); IR ν: 848 (C—
NH), 1524 (N＝O), 1572 (N＝CH), 1＋665 (C＝O), 3360
N1-{3-(4-Bromobenzylideniminocarbamyl)-propyl}-
6-nitroindazole (3e): Yield 66%, m.p. 159—161 ℃; 1H
NMR (CDCl3, 300 MHz) δ: 2.30 (m, 2H, CH2CH2CH2),
3.34 (m, 2H, CH2CH2CH2-NH), 4.26 (t, J＝7.55 Hz, 2H,
N-CH2CH2CH2), 5.58 (br s, 1H, NH), 7.99 (s, 1H, N＝
CH), 7.39—7.68 (m, 8H, ArH); 13C NMR (CDCl3, 75
MHz) δ: 33.1 (CH2CH2CH2), 43.2 (CH2CH2CH2-NH),
47.2 (N-CH2CH2CH2), 153.2 (N＝CH), 172.1 (CO),
107.9, 116.6, 122.1, 124.5, 126.7, 128.9, 129.3, 134.7,
137.6, 138.7, 146.3 (Ar); IR ν: 636 (C—Br), 1560 (N＝
CH), 1665 (C＝O), 3368 (NH); Mass (FAB) m/z: 430
(M＋). Anal. calcd for C18H16N5O3Br: C 50.24, H 3.74,
N 16.27; found C 50.21, H 3.71, N 16.22.
－1
(NH) cm ; Mass (FAB) m/z: 396 (M ). Anal. calcd for
C18H16N6O5: C 54.54, H 4.06, N 21.20; found C 54.49,
H 4.03, N 21.16.
N1-{3-(2-Nitrobenzylideniminocarbamyl)-propyl}-6-
1
nitroindazole (3j): Yield 61%, m.p. 100—161 ℃; H
NMR (CDCl3, 300 MHz) δ: 2.34 (m, 2H, CH2CH2CH2),
3.35 (m, 2H, CH2CH2CH2-NH), 4.23 (t, J＝7.50 Hz, 2H,
N-CH2CH2CH2), 5.53 (br s, 1H, NH), 8.17 (s, 1H, N＝
CH), 7.26—7.99 (m, 8H, ArH); 13C NMR (CDCl3, 75
MHz) δ: 35.9 (CH2CH2CH2), 44.7 (CH2CH2CH2-NH),
49.3 (N-CH2CH2CH2), 155.4 (N ＝ CH), 173 (CO),
107.7, 117.6, 120.3, 122.6, 125.8, 127.7, 130.4, 133.2,
134.6, 136.7, 138.5, 147.3, 150.4 (Ar); IR ν: 842 (C—
NH), 1531 (N＝O), 1575 (N＝CH), 1＋664 (C＝O), 3361
N1-{3-(3-Bromobenzylideniminocarbamyl)-propyl}-
1
6-nitroindazole (3f): Yield 63%, m.p. 157—160 ℃; H
NMR (CDCl3, 300 MHz) δ: 2.34 (m, 2H, CH2CH2CH2),
3.37 (m, 2H, CH2CH2CH2-NH), 4.28 (t, J＝7.50 Hz, 2H,
N-CH2CH2CH2), 5.46 (br s, 1H, NH), 7.83 (s, 1H, N＝
CH), 7.23—7.9 (m, 8H, ArH); 13C NMR (CDCl3, 75
MHz) δ: 33.3 (CH2CH2CH2), 42.4 (CH2CH2CH2-NH),
47.2 (NCH2CH2CH2), 151.6 (N＝CH), 171.8 (CO),
109.3, 114.5, 121.7, 126.2, 127.4, 127.7, 128.9, 132.3,
134.1, 134.5, 137.6, 138.7, 145.0 (Ar); IR ν: 641 (C－—
－1
(NH) cm ; Mass (FAB) m/z: 396 (M ). Anal. calcd for
C18H16N6O5: C 54.54, H 4.06, N 21.20; found C 54.47,
H 4.04, N 21.12.
1
Br), 1562 (N＝CH), 1661 (C＝O), 3366 (NH) cm ;
N1-{3-(4-Methoxybenzylideniminocarbamyl)-
propyl}-6-nitroindazole (3k): Yield 62%, m.p. 150—
＋
Mass (FAB) m/z: 430 (M ). Anal. calcd for
1
C18H16N5O3Br: C 50.24, H 3.74, N 16.27; found C
50.18, H 3.72, N 16.23.
153 ℃; H NMR (CDCl3, 300 MHz) δ: 2.27 (m, 2H,
CH2CH2CH2), 3.28 (t, J ＝ 7.35 Hz, 2H,
CH2CH2CH2-NH), 4.17 (s, 3H, OCH3), 5.31 (br s, 1H,
NH), 3.63 (m, 2H, N-CH2CH2CH2), 7.85 (s, 1H, N＝
CH), 7.34—7.52 (m, 8H, ArH); 13C NMR (CDCl3, 75
MHz) δ: 45.2 (CH2CH2CH2), 47.6 (CH2CH2CH2-NH),
47 (N-CH2CH2CH2), 51.7 (OCH3), 154.2 (N＝CH),
170.6 (CO), 106.4, 115.7, 118.6, 119.6, －131.5, 133.2,
N1-{3-(2-Bromobenzylideniminocarbamyl)-propyl}-
6-nitroindazole (3g): Yield 61%, m.p. 158—159 ℃; 1H
NMR (CDCl3, 300 MHz) δ: 2.36 (m, 2H, CH2CH2CH2),
3.41 (m, 2H, CH2CH2CH2-NH), 4.26 (t, J＝7.50 Hz, 2H,
N-CH2CH2CH2), 5.59 (br s, 1H, NH), 7.95 (s, 1H, N＝
CH), 7.31—7.63 (m, 8H, ArH); 13C NMR (CDCl3, 75
MHz) δ: 33.8 (CH2CH2CH2), 43.8 (CH2CH2CH2-NH),
47.4 (N-CH2CH2CH2), 153.2 (N＝CH), 171.5 (CO),
108.3, 115.2, 122.7, 125.2, 125.4, 127.7, 128.9, 130.6,
133.7, 134.5, 137.6, 141.7, 146.5 (Ar); IR ν: 632 (C—
Br), 1555 (N＝CH＋), 1668 (C＝O), 3364 (NH); Mass
(FAB) m/z: 430 (M ). Anal. calcd for C18H16N5O3Br: C
50.24, H 3.74, N 16.27; found C 50.18, H 3.70, N 16.21.
N1-{3-(4-Nitrobenzylideniminocarbamyl)-propyl}-6-
1
135.7, 136.3, 137.9, 148.4, 160.4 (Ar) cm ; IR ν: 1561
(N＝CH), 2947 (OCH3), 3363 (NH); Mass (FAB) m/z:
381 (M＋). Anal. calcd for C19H19N5O4: C 59.83, H 5.02,
N 18.36; found C 59.80, H 4.98, N 18.32.
N1-{3-(3-Methoxybenzylideniminocarbamyl)-
propyl}-6-nitroindazole (3l): Yield 60%, m.p. 149—151
1
℃; H NMR (CDCl3, 300 MHz) δ: 2.21 (m, 2H,
CH2CH2CH2), 3.51 (m, 2H, CH2CH2CH2-NH), 3.61 (s,
3H, OCH3), 4.18 (t, J＝7.35 Hz, 2H, N-CH2CH2CH2),
5.59 (br s, 1H, NH), 7.96 (s, 1H, N＝CH), 7.41—7.82
(m, 8H, ArH); 13C NMR (CDCl3, 75 MHz) δ: 33.7
1
nitroindazole (3h): Yield 65%, m.p. 162—164 ℃; H
NMR (CDCl3, 300 MHz) δ: 2.37 (m, 2H, CH2CH2CH2),
3.39 (m, 2H, CH2CH2CH2-NH), 4.24 (t, J＝7.45 Hz, 2H,
N-CH2CH2CH2), 5.41 (br s, 1H, NH), 8.10 (s, 1H, N＝
CH), 7.32—7.91 (m, 8H, ArH); 13C NMR (CDCl3, 75
MHz) δ: 36.1 (CH2CH2CH2), 44.3 (CH2CH2CH2-NH),
48.3 (N-CH2CH2CH2), 155.9 (N＝CH), 174.1 (CO),
109.6, 117.5, 121.5, 123.2, 127.7, 129.3, 131.1, 134.5,
137.6, 145.6, 148.5 (Ar); IR ν: 847 (C—NH), 1528 (N
＝O), 1568 (N＝CH), 1638 (C＝O), 3358 (NH); Mass
(FAB) m/z: 396 (M＋). Anal. calcd for C18H16N6O5: C
54.54, H 4.06, N 21.20; found C 54.51, H 4.02, N 21.17.
N1-{3-(3-Nitrobenzylideniminocarbamyl)-propyl}-6-
(CH2CH2CH2),
43.6
(CH2CH2CH2-NH),
47.7
(N-CH2CH2CH2), 54.2 (OCH3), 153.7 (N＝CH), 170.9
(CO), 105.4, 112.3, 115.2, 118.9, 120.7, 123.4, 127.1,
130.5, 134.5, 136.7, 137.1, 139.3, 149.7 (Ar); IR ν:
－1
1557 (N＝CH), 2943 (OCH3), 3358 (NH) cm ; Mass
(FAB) m/z: 381 (M＋). Anal. calcd for C19H19N5O4: C
59.83, H 5.02, N 18.36; found C 59.79, H 4.99, N
18.32.
N1-{3-(2-methoxybenzylideniminocarbamyl)-
propyl}-6-nitroindazole (3m): Yield 61%, m.p. 147—
1
1
nitroindazole (3i): Yield 62%, m.p.165—166 ℃; H
148 ℃; H NMR (CDCl3, 300 MHz) δ: 2.09 (m, 2H,
NMR (CDCl3, 300 MHz) δ: 2.36 (m, 2H, CH2CH2CH2),
CH2CH2CH2), 3.37 (m, 2H, CH2CH2CH2-NH), 3.67 (s,
Chin. J. Chem. 2011, 29, 1745— 1752
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1747

Samadhiya et al.
FULL PAPER
3H, OCH3), 4.15 (t, J＝7.35 Hz, 2H, N-CH2CH2CH2),
5.34 (br s, 1H, NH), 7.76 (s, 1H, N＝CH), 7.22—7.72
(m, 8H, ArH); 13C NMR (CDCl3, 75 MHz) δ: 42.1
(m, 8H, ArH); 13C NMR (CDCl3, 75 MHz) δ: 39.9
(CH2CH2CH2),
51.1
(CH2CH2CH2-NH),
47.1
(N-CH2CH2CH2), 153.3 (N＝CH), 169.2 (CO), 109.3,
114.5, 118.6, 123.5, 125.4, 127.2, 130.2, 133.8, 136.7,
141.5, 156.1 (Ar); IR ν: 1557 (N＝CH), 3385 (NH),
(CH2CH2CH2),
49.3
(CH2CH2CH2-NH),
48.1
(N-CH2CH2CH2), 53.7 (OCH3), 151 (N＝CH), 170.6
(CO), 107.2, 113.5, 118.9, 124.6, 127.4, 128.3, 129.0,
130.2, 132.5, 137.4, 139.2, 140.1, 146.8 (Ar); IR ν:
＋
－1
3472 (OH) cm ; Mass (FAB) m/z: 367 (M ). Anal.
calcd for C18H17N5O4: C 58.85, H 4.68, N 19.06; found
C 58.81, H 4.63, N 19.02.
－1
1559 (N＝CH), 2949 (OCH3), 3366 (NH) cm ; Mass
(FAB) m/z: 381 (M＋). Anal. calcd for C19H19N5O4: C
59.83, H 5.02, N 18.36; found C 59.77, H 4.96, N 18.30.
N1-{3-(4-Methylbenzylideniminocarbamyl)-propyl}-
6-nitroindazole (3n): Yield 60%, m.p. 145—146 ℃; 1H
NMR (CDCl3, 300 MHz) δ: 2.12 (m, 2H, CH2CH2CH2),
2.67 (s, 3H, CH3), 3.42 (m, 2H, CH2CH2CH2-NH), 4.12
(t, J＝7.30 Hz, 2H, NCH2CH2CH2), 5.62 (br s, 1H, NH),
7.89 (s, 1H, N＝CH), 7.39—7.79 (m, 8H, ArH); 13C
NMR (CDCl3, 75 MHz) δ: 24.9 (CH3), 32.6
N1-{3-(3-Hydroxybenzylideniminocarbamyl)-pro-
pyl}-6-nitroindazole (3r): Yield 61%, m.p. 162—163
1
℃; H NMR (CDCl3, 300 MHz) δ: 2.28 (m, 2H,
CH2CH2CH2), 3.29 (m, 2H, CH2CH2CH2-NH), 4.12 (t,
J＝7.60 Hz, 2H, N-CH2CH2CH2), 4.26 (s, 1H, OH),
5.36 (br s, 1H, NH), 8.01 (s, 1H, N＝CH), 7.36—7.74
(m, 8H, ArH); 13C NMR (CDCl3, 75 MHz) δ: 42
(CH2CH2CH2),
52.7
(CH2CH2CH2-NH),
46
(N-CH2CH2CH2), 151 (N＝CH), 168.9 (CO), 107.3,
114.2, 121.7, 123.2, 127.7, 128.9, 129.3, 134.1, 134.5,
137.6, 138.7, 145.2, 155.6 (Ar); IR ν: 1561 (N＝CH),
(CH2CH2CH2),
43.3
(CH2CH2CH2-NH),
46.7
(N-CH2CH2CH2), 151.2 (N＝CH), 170.1 (CO), 113.5,
121.8, 124.9, 126.4, 127.6, 130.3, 133.2, 134.5, 138.6,
140.2, 146.2 (Ar); IR ν: 1549 (N＝CH), 2917 (CH3),
－1
3379 (NH), 3464 (OH) cm ; Mass (FAB) m/z: 367
(M＋). Anal. calcd for C18H17N5O4: C 58.85, H 4.68, N
19.06; found C 58.77, H 4.62, N 19.05.
－1
＋
3340 (NH) cm ; Mass (FAB) m/z: 365 (M ). Anal.
calcd for C19H19N5O3: C 62.45, H 5.24, N 19.16; found
C 62.41, H 5.20, N 19.11.
N1-{3-(2-Hydroxybenzylideniminocarbamyl)-pro-
pyl}-6-nitroindazole (3s): Yield 64%, m.p. 167—168
N1-{3-(3-Methybenzylideniminocarbamyl)-propyl}-
6-nitroindazole (3o): Yield 62%, m.p. 143—145 ℃; 1H
NMR (CDCl3, 300 MHz) δ: 2.04 (m, 2H, CH2CH2CH2),
2.58 (s, 3H, CH3), 3.13 (m, 2H, CH2CH2CH2-NH), 4.11
(t, J＝7.30 Hz, 2H, N-CH2CH2CH2), 5.39 (br s, 1H,
NH), 7.81 (s, 1H, N＝CH), 7.31—7.83 (m, 8H, ArH);
13C NMR (CDCl3, 75 MHz) δ: 22.9 (CH3), 45.7
℃; H NMR (CDCl3, 300 MHz) δ: 2.24 (m, 2H,
1
CH2CH2CH2), 3.14 (m, 2H, CH2CH2CH2-NH), 4.19 (t,
J＝7.55 Hz, 2H, N-CH2CH2CH2), 4.36 (s, 1H, OH),
5.33 (br s, 1H, NH), 7.97 (s, 1H, N＝CH), 7.25—7.69
(m, 8H, ArH); 13C NMR (CDCl3, 75 MHz) δ: 38.4
(CH2CH2CH2),
52.3
(CH2CH2CH2-NH),
42.1
(N-CH2CH2CH2), 151.3 (N＝CH), 168.6 (CO), 106.1,
(N-CH2CH2CH2),
40.1
(CH2CH2CH2),
52.1
113.5, 120.6, 122.4, 125.1, 127.6, 130.3, 133.2, 134.6,
－1
(CH2CH2CH2-NH), 169.8 (CO), 152 (N＝CH), 111.5,
117.2, 121.7, 126.6, 127.4, 127.7, 128.9, 129.3, 134.1,
135.3, 137.6, 139.7, 145.4 (Ar); IR ν: 1544 (N＝CH),
136.2, 139.2, 146.5, 158.7 (Ar) cm ; IR ν: 1567 (N＝
－1
CH), 3381 (NH), 3468 (OH) cm ; Mass (FAB) m/z:
367 (M＋). Anal. calcd for C18H17N5O4: C 58.85, H 4.68,
N 19.06; found C 58.79, H 4.62, N 19.01.
－1
2921 (CH3), 3345 (NH) cm ; Mass (FAB) m/z: 365
(M＋). Anal. calcd for C19H19N5O3: C 62.45, H 5.24, N
19.16; found C 62.44, H 5.22, N 19.13.
General method for the synthesis of compounds 4a—
4s
N1-{3-(2-Methylbenzylidincarbamyl)-propyl}-6-
1
A mixture of compounds 3a—3s and chloroacetyl
chloride in the presence of Et3N (1∶1∶1 molar ratio)
was dissolved in methanol at room temperature and al-
lowed to react. The reaction mixture was first continu-
ously stirred on a magnetic stirrer for about 2 to 3.6 h,
then kept on a steam bath for about 1.5 to 2.25 h. The
products were cooled and filtered at room temperature.
The filtered products were purified over a column
chromatography and recrystallized from ethanol at room
temperature to yield compounds 4a—4s.
nitroindazole (3p): Yield 61%, m.p. 139—141 ℃; H
NMR (CDCl3, 300 MHz) δ: 2.08 (m, 2H, CH2CH2CH2),
2.60 (s, 3H, CH3), 3.34 (m, 2H, CH2CH2CH2-NH), 4.14
(t, J＝7.35 Hz, 2H, N-CH2CH2CH2), 5.52 (br s, 1H,
NH), 7.78 (s, 1H, N＝CH), 7.34—7.76 (m, 10H, ArH);
13C NMR (CDCl3, 75 MHz) δ: 21.9 (CH3), 38.2
(CH2CH2CH2),
43.3
(CH2CH2CH2-NH),
45.7
(N-CH2CH2CH2), 154 (N＝CH), 169.5 (CO), 109.4,
116.7, 119.5, 123.3, 124.5.4, 126.7, 127.3, 130.2, 133.4,
134.5, 137.4, 138.7, 147.5 (Ar); IR ν: 1551 (N＝CH),
N1-[3-{4-(Phenyl)-3-chloro-2-oxo-azetidine}-imino-
carbamyl]-propyl]-6-nitroindazole (4a): Yield 67%, m.p.
－1
2908 (CH3), 3341 (NH) cm ; Mass (FAB) m/z: 365
(M＋). Anal. calcd for C19H19N5O3: C 62.45, H 5.24, N
19.16; found C 62.39, H 5.17, N 19.11.
1
155—157 ℃; H NMR (CDCl3, 300 MHz) δ: 2.27 (m,
N1-{3-(4-Hydroxybenzylideniminocarbamyl)-pro-
pyl}-6-nitroindazole (3q): Yield 65%, m.p. 162—164
2H, CH2CH2CH2), 3.42 (m, 2H, CH2CH2CH2-NH),
4.20 (t, J＝7.40 Hz, 2H, N-CH2CH2CH2), 4.46 (d, J＝
4.75 Hz, 1H, CH—Cl), 5.19 (d, J＝4.75 Hz, 1H, N—
CH), 5.42 (br s, 1H, NH), 6.85—7.72 (m, 8H, ArH); 13C
NMR (CDCl3, 75 MHz) δ: 51.2 (CH-Cl), 62.4 (N-CH),
170.7 (CO cyclic), 109.5, 120.9, 125.5, 126.6, 127.9,
1
℃; H NMR (CDCl3, 300 MHz) δ: 2.25 (m, 2H,
CH2CH2CH2), 3.37 (m, 2H, CH2CH2CH2-NH), 4.21 (t,
J＝7.50 Hz, 2H, N-CH2CH2CH2), 4.15 (s, 1H, OH),
5.42 (br s, 1H, NH), 8.07 (s, 1H, N＝CH), 7.32—7.79
1748
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1745— 1752

Synthesis of N1-3-{(4-Substituted aryl-3-chloro-2-oxo-azetidine)-iminocarbamyl}-propyl-6-nitroindazole
－1
128.8, 130.2, 135.2, 137.8, 138.9, 147.4 (Ar); IR ν:
(CO cy＋clic), 2892 (CH—Cl) cm ; Mass (FAB) m/z:
507 (M ). Anal. calcd for C20H17N5O4BrCl: C 47.40, H
3.38, N 13.82; found C 47.36, H 3.34, N 13.78.
－1
1327 (C—NH), 1730 (CO cyclic), 2908 (CH—Cl) cm ;
＋
Mass (FAB) m/z: 428 (M ). Anal. calcd for
C20H18N5O4Cl: C 56.14, H 4.24, N 16.36; found C
56.11, H 4.20, N 16.33.
N1-[3-{4-(3-Bromophenyl)-3-chloro-2-oxo-azeti-
dine}-iminocarbamyl]-propyl]-6-nitroindazole
(4f):
N1-[3-{4-(4-Chlorophenyl)-3-chloro-2-oxo-azeti-
Yield 61%, m.p. 159—161 ℃; H NMR (CDCl3, 300
MHz) δ: 2.31 (m, 2H, CH2CH2CH2), 3.37 (m, 2H,
CH2CH2CH2-NH), 4.26 (t, J ＝ 7.35 Hz, 2H,
N-CH2CH2CH2), 4.45 (d, J＝4.90 Hz, 1H, CHCl), 5.37
(d, J＝4.90 Hz, 1H, N-CH), 7.31—7.92 (m, 8H, ArH);
13C NMR (CDCl3, 75 MHz) δ: 48.7 (CHCl), 59.9
(NCH), 165.3 (CO cyclic), 107.5, 113.7, 122.4, 126.5,
127.3, 127.9, 128.7, 129.6, 134.9, 135.6, 137.8, 138.4,
146.2 (Ar); IR ν: 571 (C—Br), 1318 (C—NH), 1748
1
dine}-iminocarbamyl]-propyl]-6-nitroindazole
(4b):
1
Yield 65%, m.p. 172—175 ℃; H NMR (CDCl3, 300
MHz) δ: 2.28 (m, 2H, CH2CH2CH2), 3.34 (m, 2H,
CH2CH2CH2-NH), 4.22 (t, J ＝ 7.35 Hz, 2H,
N-CH2CH2CH2), 4.62 (d, J＝4.80 Hz, 1H, CH-Cl), 5.66
(d, J＝4.80 Hz, 1H, N-CH), 5.77 (s, 1H, NH), 6.86—
7.72 (m, 8H, Ar-H); 13C NMR (CDCl3, 75 MHz) δ: 54.8
(CH-Cl), 62.4 (N-CH), 166.2 (CO cyclic), 111.3, 116.2,
122.7, 126.0, 127.7, 128.9, 130.3, 135.1, 137.6, 138.7,
148.2 (Ar); IR ν: 762 (C—Cl), 1338 (C—NH), 1750
－1
(CO cy＋clic), 2896 (CH—Cl) cm ; Mass (FAB) m/z:
507 (M ). Anal. calcd for C20H17N5O4BrCl: C 47.40, H
3.38, N 13.82; found C 47.32, H 3.31, N 13.75.
－1
(CO cy＋clic), 2910 (CH—Cl) cm ; Mass (FAB) m/z:
462 (M ). Anal. calcd for C20H17N5O4Cl2: C 51.96, H
3.70, N 15.14; found C 51.92, H 3.65, N 15.10.
N1-[3-{4-(2-Bromophenyl)-3-chloro-2-oxo-azeti-
dine}-iminocarbamyl]-propyl]-6-nitroindazole
(4g):
N1-[3-{4-(3-Chlorophenyl)-3-chloro-2-oxo-azeti-
Yield 63%, m.p. 155—157 ℃; H NMR (CDCl3, 300
MHz) δ: 2.26 (m, 2H, CH2CH2CH2), 3.39 (m, 2H,
CH2CH2CH2-NH), 4.25 (t, J ＝ 7.35 Hz, 2H,
N-CH2CH2CH2), 4.44 (d, J＝5.10 Hz, 1H, CHCl), 5.35
(d, J＝5.10 Hz, 1H, N-CH), 7.27—7.84 (m, 8H, ArH);
13C NMR (CDCl3, 75 MHz) δ: 47.7 (CHCl), 58.1
(N-CH), 162.5 (CO cyclic), 108.4, 114.2, 121.7, 126.6,
127.4, 127.7, 128.9, 129.9, 134.6, 135.3, 137.6, 138.7,
145.1 (Ar); IR ν: 565 (C—Br), 1324 (C—NH), 1755
1
dine}-iminocarbamyl]-propyl]-6-nitroindazole
(4c):
1
Yield 62%, m.p. 166—168 ℃; H NMR (CDCl3, 300
MHz) δ: 2.23 (m, 2H, CH2CH2CH2), 3.36 (m, 2H,
CH2CH2CH2-NH), 4.20 (t, J ＝ 7.35 Hz, 2H,
N-CH2CH2CH2), 4.68 (d, J＝5.00 Hz, 1H, CH-Cl), 5.36
(d, J＝5.00 Hz, 1H, N-CH), 5.74 (s, 1H, NH), 6.79—
7.64 (m, 8H, ArH); 13C NMR (CDCl3, 75 MHz) δ: 55.8
(CH-Cl), 65.1 (N-CH), 165.5 (CO cyclic), 108.3, 115.7,
122.7, 126.5, 127.4, 127.7, 128.9, 130.2, 134.5, 134.8,
137.6, 138.7, 147.2 (Ar); IR ν: 774 (C—Cl), 1333 (C—
－1
(CO cy＋clic), 2884 (CH—Cl) cm ; Mass (FAB) m/z:
507 (M ). Anal. calcd for C20H17N5O4BrCl: C 47.40, H
3.38, N 13.82; found C 47.37, H 3.36, N 13.78.
－1
NH), 1755 (CO cyclic), 2918 (CH—Cl) cm ; Mass
(FAB) m/z: 462 (M＋). Anal. calcd for C20H17N5O4Cl2: C
51.96, H 3.70, N 15.14; found C 51.90, H 3.67, N 15.12.
N1-[3-{4-(2-Chlorophenyl)-3-chloro-2-oxo-azeti-
N1-[3-{4-(4-Nitrophenyl)-3-chloro-2-oxo-azetidine}-
iminocarbamyl]-propyl]-6-nitroindazole (4h): Yield
62%, m.p. 162—164 ℃; 1H NMR (CDCl3, 300 MHz) δ:
2.33 (m, 2H, CH2CH2CH2), 3.38 (m, 2H,
CH2CH2CH2-NH), 4.29 (t, J ＝ 7.35 Hz, 2H,
N-CH2CH2CH2), 4.38 (d, J＝4.80 Hz, 1H, CH-Cl), 5.47
(d, J＝4.80 Hz, 1H, N-CH), 7.1—7.71 (m, 8H, ArH);
13C NMR (CDCl3, 75 MHz) δ: 53.4 (CH-Cl), 68.8
(N-CH), 161 (CO cyclic), 113.3, 116.2, 123.7, 127.7,
129.3, 134.1, 134.5, 137.6, 138.7, 148.1, 147.5 (Ar); IR
ν: 869 (C—NO), 1351 (C—NH), 1540 (NO2), 1761
dine}-iminocarbamyl]-propyl]-6-nitroindazole
(4d):
1
Yield 63%, m.p. 165—166 ℃; H NMR (CDCl3, 300
MHz) δ: 2.29 (m, 2H, CH2CH2CH2), 3.30 (m, 2H,
CH2CH2CH2-NH), 4.23 (t, J ＝ 7.35 Hz, 2H,
N-CH2CH2CH2), 4.53 (d, J＝4.90 Hz, 1H, CH-Cl), 5.36
(d, J＝4.90 Hz, 1H, N-CH), 5.72 (s, 1H, NH), 6.81—
7.62 (m, 8H, ArH); 13C NMR (CDCl3, 75 MHz) δ: 55.4
(CH-Cl), 61.4 (N-CH), 165.2 (CO cyclic), 112.3, 114.2,
123.1, 126.7, 127.4, 128.2, 129.3, 130.2, 132.1, 134.5,
137.4, 138.5, 147.8 (Ar); IR ν: 771 (C—Cl), 1335 (C—
－1
(CO cyclic), 2928 (CH—Cl) cm ; Mass (FAB) m/z:
473 (M＋). Anal. calcd for C20H17N6O6Cl: C 50.80, H
3.62, N 17.77; found C 50.77, H 3.56, N 17.72.
－1
NH), 1757 (CO cyclic), 2919 (CH—Cl) cm ; Mass
(FAB) m/z: 462 (M＋). Anal. calcd for C20H17N5O4Cl2: C
51.96, H 3.70, N 15.14; found C 51.88, H 3.64, N 15.13.
N1-[3-{4-(4-Bromophenyl)-3-chloro-2-oxo-azeti-
N1-[3-{4-(3-Nitrophenyl)-3-chloro-2-oxo-azetidine}-
iminocarbamyl]-propyl]-6-nitroindazole (4i): Yield 65%,
m.p. 167—168 ℃; 1H NMR (CDCl3, 300 MHz) δ: 2.30
(m, 2H, CH2CH2CH2), 3.35 (m, 2H, CH2CH2CH2-NH),
4.27 (t, J＝7.35 Hz, 2H, N-CH2CH2CH2), 4.39 (d, J＝
4.85 Hz, 1H, CHCl), 5.42 (d, J＝4.85 Hz, 1H, N-CH),
7.16—7.79 (m, 8H, ArH); 13C NMR (CDCl3, 75 MHz) δ:
54 (CHCl), 63.8 (NCH), 167 (CO cyclic), 112.8, 116.2,
122.7, 124.2, 127.7, 128.9, 129.3, 134.1, 134.5, 137.6,
138.7, 146.7, 147.5 (Ar); IR: 862 (C—NO), 1357 (C—
NH), 1542 (NO2), 1749 (CO cycl＋ic), 2914 (CH—Cl)
dine}-iminocarbamyl]-propyl]-6-nitroindazole
(4e):
1
Yield 61%, m.p. 160—161 ℃; H NMR (CDCl3, 300
MHz) δ: 2.30 (m, 2H, CH2CH2CH2), 3.42 (m, 2H,
CH2CH2CH2-NH), 4.28 (t, J ＝ 7.35 Hz, 2H,
N-CH2CH2CH2), 4.62 (d, J＝5.00 Hz, 1H, CHCl), 5.42
(d, J＝5.00 Hz, 1H, NCH), 5.67 (s, 1H, NH), 7.35—
7.95 (m, 8H, ArH); 13C NMR (CDCl3, 75 MHz) δ: 47.1
(CH-Cl), 59.1 (N-CH), 167.3 (CO cyclic), 108.3, 115.2,
120.7, 125.8, 127.4, 128.9, 129.5, 134.1, 37.6, 138.7,
145.8 (Ar); IR ν: 578 (C—Br), 1315 (C—NH), 1741
－1
cm ; Mass (FAB) m/z: 473 (M ). Anal. calcd for
C20H17N6O6Cl: C 50.80, H 3.62, N 17.77; found C
Chin. J. Chem. 2011, 29, 1745— 1752
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1749

Samadhiya et al.
FULL PAPER
50.73, H 3.58, N 17.74.
N1-[3-{4-(4-Methylphenyl)-3-chloro-2-oxo-azeti-
N1-[3-{4-(2-Nitrophenyl)-3-chloro-2-oxo-azetidine}-
iminocarbamyl]-propyl]-6-nitroindazole (4j): Yield
63%, m.p. 164—165 ℃; 1H NMR (CDCl3, 300 MHz) δ:
2.34 (m, 2H, CH2CH2CH2), 3.41 (m, 2H,
CH2CH2CH2-NH), 4.29 (t, J ＝ 7.35 Hz, 2H,
N-CH2CH2CH2), 4.41 (d, J＝4.80 Hz, 1H, CHCl), 5.54
(d, J＝4.80 Hz, 1H, N-CH), 7.05—7.71 (m, 8H, ArH);
13C NMR (CDCl3, 75 MHz) δ: 54.6 (CHCl), 64.8
(N-CH), 167 (CO cyclic), 107.3, 114.2, 121.7, 123.2,
127.7, 128.9, 129.3, 134.1, 134.5, 137.6, 138.7, 145,
147.5 (Ar); IR ν: 869 (C—NO), 1354 (C—NH), 1542
dine}-iminocarbamyl]-propyl]-6-nitroindazole
(4n):
1
Yield 63%, m.p. 151—152 ℃; H NMR (CDCl3, 300
MHz) δ: 2.19 (m, 2H, CH2CH2CH2), 2.68 (s, 3H, CH3),
3.33 (m, 2H, CH2CH2CH2-NH), 4.22 (t, J＝7.35 Hz, 2H,
N-CH2CH2CH2), 4.53 (d, J＝4.65 Hz, 1H, CHCl), 5.42
(d, J＝4.65 Hz, 1H, N-CH), 7.28—7.98 (m, 8H, ArH);
13C NMR (CDCl3, 75 MHz) δ: 24.7 (CH3), 51.7 (CHCl),
62.8 (NCH), 164.8 (CO cyclic), 107.8, 122.3, 126.2,
127.4, 127.7, 129.9, 134.1, 134.5, 137.6, 138.7, 146.3
(Ar); IR ν: 1328 (C—NH)－, 1740 (CO cyclic), 2889
1
(CH—Cl), 2924 (CH3) cm ; Mass (FAB) m/z: 442
－1
(NO2), 1745 (CO cyclic), 2918 (CH—Cl) cm ; Mass
(M＋). Anal. calcd for C21H20N5O4Cl: C 57.08, H 4.56,
N 15.84; found C 56.95, H 4.52, N 15.80.
(FAB) m/z: 473 (M＋). Anal. calcd for C20H17N6O6Cl: C
50.80, H 3.62, N 17.77; found C 50.75, H 3.60, N 17.73.
N1-[3-{4-(4-Methoxyphenyl)-3-chloro-2-oxo-azeti-
N1-[3-{4-(3-Methylphenyl)-3-chloro-2-oxo-azeti-
dine}-iminocarbamyl]-propyl]-6-nitroindazole
(4o):
1
di-ne}-iminocarbamyl]-propyl]-6-nitroindazole
(4k):
Yield 61%, m.p. 144—145 ℃; H NMR (CDCl3, 300
MHz) δ: 2.25 (m, 2H, CH2CH2CH2), 2.62 (s, 3H, CH3),
3.32 (m, 2H, CH2CH2CH2-NH), 4.20 (t, J＝7.35 Hz, 2H,
N-CH2CH2CH2), 4.57 (d, J＝4.65 Hz, 1H, CH-Cl), 5.34
(d, J＝4.65 Hz, 1H, NCH), 7.18—7.84 (m, 8H, ArH);
13C NMR (CDCl3, 75 MHz) δ: 23.5 (CH3), 51 (CHCl),
63.8 (NCH), 163.8 (CO cyclic), 108.3, 115.2, 121.7,
126.5, 127.4, 127.7, 128.9, 129.3, 134.1, 134.5, 137.6,
138.7, 145.5 (Ar); IR ν: 1322 (C—NH－), 1746 (CO cy-
1
Yield 65%, m.p. 158—160 ℃; H NMR (CDCl3, 300
MHz) δ: 2.22 (m, 2H, CH2CH2CH2), 3.35 (m, 2H,
CH2CH2CH2-NH), 3.64 (s, 3H, OCH3), 4.26 (t, J＝7.35
Hz, 2H, N-CH2CH2CH2), 4.31 (d, J＝4.75 Hz, 1H,
CH-Cl), 5.69 (d, J＝4.75 Hz, 1H, N-CH), 7.26—7.92
(m, 8H, ArH); 13C NMR (CDCl3, 75 MHz) δ: 49.1
(CHCl), 54 (OCH3), 64.4 (NCH), 162.5 (CO cyclic),
114.2, 122.7, 123.2, 128.9, 129.3, 134.1, 134.5, 138.7,
145.4, 147.5, 159.2 (Ar); IR －ν: 1326 (N—C), 1736 (CO
1
clic), 2894 (CH—Cl), 2927 (CH3) cm ; Mass (FAB)
cyclic), 2891 (CH—Cl) cm ; Mass (FAB) m/z: 458
m/z: 442 (M＋). Anal. calcd for C21H20N5O4Cl: C 57.08,
H 4.56, N 15.84; found C 57.05, H 4.49, N 15.78.
N1-[3-{4-(2-Methylphenyl)-3-chloro-2-oxo-azeti-
1
(M＋). Anal. calcd for C21H20N5O5Cl: C 55.08, H 4.40,
N 15.29; found C 55.01, H 4.36, N 15.22.
N1-[3-{4-(3-Methoxyphenyl)-3-chloro-2-oxo-azeti-
dine}-iminocarbamyl]-propyl]-6-nitroindazole
(4p):
1
dine}-iminocarbamyl]-propyl]-6-nitroindazole
(4l):
Yield 60%, m.p. 148—149 ℃; H NMR (CDCl3, 300
MHz) δ: 2.22 (m, 2H, CH2CH2CH2), 2.72 (s, 3H, CH3),
3.35 (m, 2H, CH2CH2CH2-NH), 4.16 (t, J＝7.35 Hz, 2H,
N-CH2CH2CH2), 4.48 (d, J＝4.65 Hz, 1H, CH-Cl), 5.45
(d, J＝4.65 Hz, 1H, N-CH), 7.21—8.09 (m, 8H, ArH);
13C NMR (CDCl3, 75 MHz) δ: 23.4 (CH3), 50.9 (CHCl),
62.2 (NCH), 161.2 (CO cyclic), 108.1, 115.2, 121.7,
126.3, 127.4, 127.7, 128.9, 129.3, 134.6, 135.1, 137.3,
138.7, 146.1 (Ar); IR ν: 1321 (CNH), 1746 (CO cyclic),
1
Yield 62%, m.p. 155—157 ℃; H NMR (CDCl3, 300
MHz) δ: 2.20 (m, 2H, CH2CH2CH2), 3.34 (m, 2H,
CH2CH2CH2-NH), 3.59 (s, 3H, OCH3), 4.25 (t, J＝7.35
Hz, 2H, N-CH2CH2CH2), 4.49 (d, J＝4.70 Hz, 1H,
CHCl), 5.29 (d, J＝4.70 Hz, 1H, NCH), 7.36—8.02 (m,
8H, Ar-H); 13C NMR (CDCl3, 75 MHz) δ: 49.8 (CH-Cl),
54.8 (OCH3), 62.4 (N-CH), 164.5 (CO cyclic), 114.2,
122.7, 124.2, 127.7, 128.9, 134.7, 135.2, 138.7, 145.8,
147.5, 159.2 (13C, Ar); IR ν: 1322 (N—C), 1728 (CO
－1
2876 (CHCl), 2913 (CH3) cm ; Mass (FAB) m/z: 442
－1
cyclic), 2895 (CH—Cl) cm ; Mass (FAB) m/z: 458
(M＋). Anal. calcd for C21H20N5O4Cl: C 57.08, H 4.56,
N 15.84; found C 57.01, H 4.50, N 15.79.
(M＋). Anal. calcd for C21H20N5O5Cl: C 55.08, H 4.40,
N 15.29; found C 55.04, H 4.37, N 15.25.
N1-[3-{4-(4-Hydroxyphenyl)-3-chloro-2-oxo-azeti-
N1-[3-{4-(2-Methoxyphenyl)-3-chloro-2-oxo-azeti-
dine}-iminocarbamyl]-propyl]-6-nitroindazole
(4q):
1
dine}-iminocarbamyl]-propyl]-6-nitroindazole
(4m):
Yield 61%, m.p. 166—168 ℃; H NMR (CDCl3, 300
MHz) δ: 2.20 (m, 2H, CH2CH2CH2), 3.35 (m, 2H,
CH2CH2CH2-NH), 4.21 (t, J ＝ 7.35 Hz, 2H,
N-CH2CH2CH2), 4.31 (s, 1H, OH), 4.59 (d, J＝5.05 Hz,
1H, CHCl), 5.38 (d, J＝5.05 Hz, 1H, NCH), 7.09—8.1
(m, 8H, ArH); 13C NMR (CDCl3, 75 MHz) δ: 53.2
(CH-Cl), 63.7 (NCH), 166.4 (CO cyclic), 111.8, 116.2,
122.7, 124.2, 128.9, 129.8, 134.8, 135.8, 138.7, 147.5,
154.6 (Ar); IR ν: 1187 (C—O), 1355 (C—NH), 1768
1
Yield 60%, m.p. 152—153 ℃; H NMR (CDCl3, 300
MHz) δ: 2.21 (m, 2H, CH2CH2CH2), 3.30 (m, 2H,
CH2CH2CH2-NH), 3.52 (s, 3H, OCH3), 4.18 (t, J＝7.35
Hz, 2H, N-CH2CH2CH2), 4.45 (d, J＝4.80 Hz, 1H,
CH-Cl), 5.39 (d, J＝4.80 Hz, 1H, N-CH), 8.11—8.47
(m, 8H, ArH); 13C NMR (CDCl3, 75 MHz) δ: 47.4
(CH-Cl), 54.1 (OCH3), 63.1 (NCH), 163.2 (CO cyclic),
108.2, 116.2, 122.7, 124.2, 127.7, 128.9, 129.3, 134.1,
134.5, 138.7, 146.1, 147.5, 160.2 (Ar); IR ν: 1738 (CO
cyc－lic), 1328 (N—C), 2885 (CH—Cl), 1163 (C—O)
－1
(CO cyclic), 2917 ＋(CH—Cl), 3467 (OH) cm ; Mass
(FAB) m/z: 444 (M ). Anal. calcd for C20H18N5O5Cl: C
54.12, H 4.08, N 15.77; found C 54.08, H 4.01, N 15.73.
N1-[3-{4-(3-Hydroxyphenyl)-3-chloro-2-oxo-azeti-
＋
1
cm ; Mass (FAB) m/z: 458 (M ). Anal. calcd for
C21H20N5O5Cl: C 55.08, H 4.40, N 15.29; found C
54.98, H 4.36, N 15.21.
dine)-iminocarbamyl}-propyl]-6-nitroindazole
(4r):
1750
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1745— 1752

Synthesis of N1-3-{(4-Substituted aryl-3-chloro-2-oxo-azetidine)-iminocarbamyl}-propyl-6-nitroindazole
1
Yield 64%, m.p. 163—164 ℃; H NMR (CDCl3, 300
MHz) δ: 2.18 (m, 2H, CH2CH2CH2), 3.27 (m, 2H,
CH2CH2CH2-NH), 4.15 (t, J ＝ 7.35 Hz, 2H,
N-CH2CH2CH2), 4.28 (s, 1H, OH), 4.57 (d, J＝5.10 Hz,
1H, CH-Cl), 5.41 (d, J＝5.10 Hz, 1H, NCH), 7.12—
8.13 (m, 8H, ArH); 13C NMR (CDCl3, 75 MHz) δ: 51.2
(CHCl), 64.7 (NCH), 162.7 (CO cyclic), 112.3, 115.2,
120.7, 124.2, 127.7, 128.9, 129.3, 134.1, 135.5, 137.6,
138.7, 147.5, 154.6 (Ar); IR ν: 1182 (C—O), 1360 (C—
products compounds 4a—4s. In the spectrum of com-
pound 4a carbonyl group of β-lact－am ring showed
1
1
characteristic absorption at 1730 cm and H NMR
spectrum showed three doublet for N-CH and CH-Cl at
δ 5.19 and 4.46 respectively, but in the 13C NMR spec-
trum two signals appeared for (N-CH), (CH-Cl) and (Co
cyclic) at δ 62.4, 51.2 and 170.7 respectively. The IR
1
absorption and H NMR signal of N＝CH have disap-
peared. Compounds 4a — 4s were synthesized and
screened for their antimicrobial and antitubercular ac-
tivity. Data shown in Tables 1 and 2 revealed that all the
synthesized compounds 4a—4s have a structure activity
relationship (SAR) because activity of compounds var-
ies with substitution. Nitro group containing compounds
(4h, 4i and 4j) showed higher activity than chloro (4c,
4d), or bromo (4e, 4f) group containing compounds.
Chloro and bromo derivatives also have higher activity
than other rested compounds. On the basis of structure
activity relationship (SAR), it could be concluded that
the activity of compounds depends on electron with-
drawing nature of the substituted groups. The sequence
of the activity is as follows:
－1
N), 1762 (CO cyclic), 2923 (CH＋—Cl), 3469 (OH) cm ;
Mass (FAB) m/z: 444 (M ). Anal. calcd for
C20H18N5O5Cl: C 54.12, H 4.08, N 15.77; found C
54.10, H 4.03, N 15.75.
N1-[3-{4-(2-Hydroxyphenyl)-3-chloro-2-oxo-azeti-
dine}-iminocarbamyl]-propyl]-6-nitroindazole
(4s):
1
Yield 65%, m.p. 160—161 ℃; H NMR (CDCl3, 300
MHz) δ: 2.19 (m, 2H, CH2CH2CH2), 3.27 (m, 2H,
CH2CH2CH2-NH), 4.10 (t, J ＝ 7.35 Hz, 2H,
N-CH2CH2CH2), 4.25 (s, 1H, OH), 4.57 (d, J＝4.95 Hz,
1H, CHCl), 5.39 (d, J＝4.95 Hz, 1H, N-CH), 7.19—
8.21 (m, 8H, ArH); 13C NMR (CDCl3, 75 MHz) δ: 54
(CHCl), 63.2 (NCH), 161.9 (CO cyclic), 112.6, 115.2,
122.7, 124.2, 127.7, 128.9, 129.3, 134.1, 137.6, 138.7,
145.6, 147.5, 154.6 (Ar); IR ν: 1182 (C—O), 1359 (C—
NH), 1752 (CO cyclic), 2919 (CH—Cl), 3459 (OH)
NO2＞Cl＞Br＞OCH3＜OH＞CH3
On the basis of given data it could also be concluded
that compounds 4c—4f, 4h—4j displayed high activity,
compounds 4b, 4g and 4s showed moderate activity and
the rest compounds showed less activity compared with
standard drugs.
＋
－1
cm ; Mass (FAB) m/z: 444 (M ). Anal. calcd for
C20H18N5O5Cl: C 54.12, H 4.08, N 15.77; found C
54.06, H 4.03, N 15.70.
Results and discussion
Pharmacology
Synthesis
Antibacterial and antifungal activity All the fi-
nal synthesized compounds 4a—4s have been screened
for their antibacterial and antifungal activity using filter
paper disc diffusion method against B. subtilis, E. coli, S.
aureus and K. pneumoniae bacterial strain and A. niger,
A. flavus, F. oxisporium and C. albicans fungal strain
respectively. The MIC values of standard Streptomycin
for all bacterial strain and Griseofulvin for all fungal
strain were in the range of 6.25—12.5 and 6.25—25
µg/mL respectively. The MIC values of compounds 4a
—4s are presented in Table 1.
N1-[3-{(4-Substituted
aryl-3-chloro-2-oxo-azeti-
dine)-iminocarbamyl}-propyl]-6-nitroindazole 4a — 4s
were synthesized in four different steps. 6-Nitroindazole
on reaction with Cl(CH2)3Br at room temperature af-
forded N1-(3-chloropropyl)-6-nitroindazole (1). IR
spectrum of 1 displayed absorption at 1328 and 752 cm
－1
for N—CH2 and C—Cl respectively, clearly indicat-
－1
ing the disappearance of NH absorption (3415 cm ) of
6-nitroindazole. Compound 1 reacted with urea at room
temperature yielding N1-{3-(aminocarbamyl)-propyl}-6-
nitroindazole (2). IR spectrum of compound 2 showed
absorption for NH, NH2 and for CO at 3342, 3456 and
Antitubercular activity Synthesized compounds
4a—4s were screened against M. tuberculosis using L. J.
medium (Conventional) method at 50 µg/mL and lower
concentrations using M. tuberculosis H37Rv strain. The
results are shown in Table 2. The standard antitubercu-
lar drugs Streptomycin, Isoniazid, Rifampicin and
Ethambutol (MIC range 0.2—4 µg/mL) were taken as
standards.
－1
1666 cm respectively, while absorption of C—Cl dis-
appeared. The 1H NMR spectra of 2 displayed signal for
(CH2-N), NH and NH2 appearing at δ 3.38, 5.69 and
5.94 respectively and its 13C NMR value of CO group
appeared at δ 163.4. The compound 2 on further reac-
tion with selected several substituted aromatic alde-
hydes produced N1-{3-(substituted arylidene-iminocar-
bamyl)-propyl-6-nitroindazole 3a—3s. for the com-
pound 3a characteristic absorption for Shi－ff base (N＝
CH) in IR spectrum appeared at 1555 cm 1 and in the
1H NMR chemical shift at δ 7.84 while in its 13C NMR
Acknowledgement
The authors are thankful to SAIF, Central Drugs
Research Institute, Lucknow (India) for providing spec-
tral and analytical data of the compounds. We are
thankful to Head, Department of Biotechnology, Dr. H.
S. Gour University, Sagar (India) for antimicrobial (an-
tibacterial and antifungal) and Microcare Laboratory
1
signal found at δ 145.8. In the H NMR signal for NH2
has disappeared. The compounds 3a—3s on treatment
with ClCH2COCl in the presence of Et3N furnished final
Chin. J. Chem. 2011, 29, 1745— 1752
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1751

Samadhiya et al.
FULL PAPER
Table 1 Antibacterial and antifungal activity (µg/mL) of compounds 4a— 4s
Antibacterial activity Antifungal activity
Compd.
B. subtilis
E. coli
S. aureus
25
K. pneumoniae
A. niger
A. flavus
F. oxisporium
C. albicans
4a
4b
4c
4d
4e
4f
25
＞
＞
25
25
＞
25
＞
50
50
100
100
25
v100
50
12.5
12.5
12.5
12.5
＞
＞
＞
＞
＞
12.5
12.5
12.5
12.5
12.5
25
＞
＞
＞
＞
25
25
50
25
＞
12.5
＞
＞
6.25
6.25
50
25
25
50
12.5
12.5
12.5
＞
＞
＞
50
25
25
＞
＞
＞
＞
25
50
25
25
＞
12.5
12.5
＞
＞
25
25
50
12.5
12.5
＞
＞
＞
＞
25
50
4g
4h
4i
＞
25
＞
＞
＞
12.5
6.25
6.25
＞
＞
＞
25
25
50
＞
＞
6.25
12.5
6.25
12.5
12.5
6.25
12.5
＞
＞
25
25
25
25
25
25
25
100
50
50
100
100
100
50
100
12.5
＞
25
25
100
＞
＞
4j
6.25
50
12.5
25
＞
＞
＞
25
4k
4l
25
50
25
25
25
50
＞
＞
25
25
＞
＞
50
50
＞
100
50
＞
＞
＞
25
＞
＞
100
50
4m
4n
4o
4p
4q
4r
4s
25
25
100
100
100
100
25
＞
＞
＞
＞
100
100
50
＞
＞
25
25
25
50
＞
＞
＞
50
25
25
＞
＞
＞
＞
＞
25
50
＞
50
＞
＞
＞
50
100
＞
25
25
100
50
50
25
50
25
＞
＞
12.5
12.5
25
＞
＞
12.5
25
25
＞
＞
＞
＞
＞
＞
25
50
50
＞
＞
12.5
12.5
25
25
25
＞
＞
＞
12.5
＞
12.5
＞
50
Table 2 Antitubercular activity (µg/mL) of compounds 4a— 4s
Compd.
4a
Conc.
Comp.
Conc.
6.25
12.5
12.5
12.5
Comp.
4i
Conc.
12.5
12.5
12.5
25
Comp.
4m
4n
Conc.
25
Comp.
4q
Conc.
＞
25
6.25
6.25
12.5
4e
4f
＞
＞
＞
＞
＞
＞
＞
25
25
4b
4j
＞
＞
25
50
4r
4c
＞
4g
4h
4k
4o
4s
25
4d
4l
4p
50
and Tuberculosis Research Center, Surat, Gujrat (India)
for antituberculosis activity. We are also thankful to
Head, Department of Chemistry, Dr. H. S. Gour Uni-
versity, Sagar (India) for giving the facilities to carry
out the work.
5
Gerpe, A.; Aguirre, G.; Boiani, L.; Cerecetto, H.; Gonzalez,
M.; Olea-Azar, C.; Rigol, C.; Maya, J. D.; Morello, A.; Piro,
O. E.; Aran, V. J.; Azqueta, A.; Cerain, A.; Lopez de Cerain,
A.; Monge, A.; Rojas, M. A.; Yaluff, G. Bioorg. Med. Chem.
2006, 14, 3467.
6
7
Doris, M.; Ulf, G.; Carsten, T.; Hans, F. Brain Res. 1998, 78,
353.
References
Sharma, M. C.; Kohli, D. V.; Sahu, N. K.; Sharma, S.;
Chaturvedi, S. C. Digest J. Nanomater. Biostruct. 2009, 4,
339.
1
Upadhyay, A.; Srivastava, S. K.; Srivastava, S. D.; Yadav,
R. Proc. Nat. Acad. Sci. India 2010, 80, 131.
2
Cottyn, B.; Acher, F.; Ramassamy, B.; Alvey, L.; Lepoivre,
M.; Frapart, Y.; Stuehr, D.; Mansuy, D.; Boucher, J.-L.;
Vichard, D. Bioorg. Med. Chem. 2008, 16, 5962.
8
9
Srivastava, S. K.; Srivastava, S. L.; Srivastava, S. D. Indian
J. Chem. 2000, 39B, 464.
3
Woods, K. W.; Fischer, J. P.; Claiborne, A.; Li, T.; Thomas,
S. A.; Zhu, G.-D.; Diebold, R. B.; Liu, X.; Shi, Y.; Kling-
hofer, V.; Han, E. K.; Guan, R.; Magnone, S. R.; Johnson, E.
F.; Bouska, J. J.; Olson, A. M.; de Jong, R.; Oltersdorf, T.;
Luo, Y.; Rosenberg, S. H.; Giranda, V. L.; Lia, Q. Bioorg.
Med. Chem. 2006, 14, 6832.
Srivastava, S. K.; Srivastava, S.; Srivastava, S. D. Indian J.
Chem. 1999, 38B, 183.
10 Raval, J. P.; Patel, H. V.; Patel, P. S.; Patel, N. H.; Desai, K.
R Asian J. Res. Chem. 2009, 2(2), 171.
11 Patel, K. H.; Mehta, A. G. E-Journal Chem. 2006, 3(11),
103.
4
Pinna, G. A.; Pirisi, M. A.; Mussinu, J.-M.; Murineddu, G.;
Loriga, G.; Pau, A.; Grella, G. E. Ll Farmaco 2003, 58, 749.
12 Desai, K. G.; Desai, K. R. Indian J. Chem. 2005, 44B, 2093.
(E1012233 Zhao, C.)
1752
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1745— 1752