Scientific paper
Synthesis and Biological Activity of New Series of JN-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-2-(substituted Phenyl)-3-Chloro-4-Oxo-1-Azetidinecarboxamide
Ritu Sharma,* Pushkal Samadhiya, Savitri D. Srivastava and Santosh K. Srivastava
Synthetic Organic Chemistry Laboratory, Department of Chemistry, Dr. H. S. Gour University (A Central University),
Sagar, Madhya Pradesh, India 470003
* Corresponding author: E-mail: ritusharmaic@rediffmail.com
Received: 24-09-2010
Abstract
The synthesis of a new series of N-[3-(1_ff-1,2,3-benzotriazol-1-yl)propyl]-2-(4-substituted phenyl)-3-chloro-4-oxo-1-azetidinecarboxamides 4a-s has been executed from 1,2,3-benzotriazole as a starting material by conventional method. Compounds 4a-s were screened for their antibacterial, antifungal and antitubercular activities. Structures of all the synthesized compounds were confirmed by chemical and spectroscopic analyses such as IR, 1H NMR, 13C NMR and FAB mass spectroscopy.
Keyword: Synthesis, 1,2,3-benzotriazole, azetidinone, antimicrobial, antitubercular.
1. Introduction
Heterocyclic compounds have captured our attention for many reasons, mainly due to their biological activities. A wide variety of 2-oxoazetidine derivatives have been described for their chemotherapeutic importance. 2-Oxoazeti-dine and its derivatives possess various types of biological activities, such as antibacterial,1-4 anticonvulsant,5 analgesic, antitubercular,6-8 antiinflammatory,9 antifungal,10-13 as synthetic precursors for amino acids,14 to mediate cholesterol absorption,15 for antiviral16 and CNS17 activity, etc. 2-Oxozetidines also serve as synthons for many biologically active compounds. Many antibiotics like penicillin and cep-halosporin contain 2-oxoazetidine ring.
Benzotriazole derivatives have pharmaceutical importance possessing several remarkable biological activities, such as antibacterial,11,18 antifungal,1,19 antihistamine, antiadrenergic and DNA cleavage,20 antitubercular,21 anticancer, antiemetic,22 antitumor, antiinflammatory,23,24 anticonvulsant,25 as protein kinase inhibitors26 and respiratory syndrome protease inactivators,27 analgesic,28 anti-viral29 etc. The biological activities of both 2-oxoazetidine and 1,2,3-benzotriazole aroused our interest in the synthesis of 2-oxoazetidine derivatives of 1,2,3-benzotriazole. 2-
Oxoazetidine derivatives were synthesized in four steps shown in Scheme 1. All synthesized compounds were screened against some selected bacteria and fungi for their antimicrobial activity and antitubercular activity screened against Mycobacterium tuberculosis using H37Rv strain. The structures of all the newly synthesized compounds were confirmed by elemental analysis, IR, 1H and 13C NMR and FAB mass spectroscopy.
Scheme 1
Comp.	X	Comp.	X	Comp.	X
3a, 4a	H	3h, 4h	4-NO2	3o, 4o	3-CH3
3b, 4b	4-Cl	3i, 4i	3-NO2	3p, 4p	2-CH33
3c, 4c	3-Cl	3j, 4j	2-NO2	3q, 4q	4-OH3
3d, 4d	2-Cl	3k, 4k	4-OCH3	3r, 4r	3-OH
3e, 4e	4-Br	3l, 41	3-OCH3	3s, 4s	2-OH
3f, 4f	3-Br	3m, 4m	2-OCH3		
3g, 4g	2-Br	3n, 4n	4-CH3		
Scheme 1. The synthesis of compounds 1, 2, 3a-s and 4a-s.
considerable and varied activity against the selected microorganisms. The new series of 4a-s prepared was screened for their antibacterial and antifungal activity against some selected bacteria and fungi and antitubercular activity against M. tuberculosis (H37Rv strain). The investigation of antimicrobial data revealed that the compounds 4b, 4d-f, 4h-j displayed high activity, the compounds 4c, 4g and 4r showed moderate activity and the rest of the compounds showed less activity against all the strains compared with standard drugs.
2. Results and Discussion
N-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-2-(sub-stituted phenyl)-3-chloro-4-oxo-1-azetidinecarboxamides 4a-s were synthesized in four steps (Scheme 1): 1,2,3-benzotriazole on reaction with Cl(CH2)3Br at room temperature afforded 1-(3-chloropropyl)-1H-1,2,3-benzotria-zole (1). IR spectrum of 1 displayed absorption at 1235 and 749 cm-1 for N-CH2 and C-Cl, respectively, clearly indicating the disappearance of NH absorption 3445 cm-1 of 1,2,3 benzotriazole. The compound 1 on reaction with urea at room temperature yielded N-[3-(1H-1,2,3-benzo-triazol-1-yl)propyl]urea (2). IR spectrum of 2 showed absorption for CO at 1658 cm-1 while absorption of C-Cl has disappeared. The 1H NMR spectrum of 2 displayed a signal for CH2-N at 5 3.30 ppm and in its 13C NMR spectrum a signal for CO group at 5 163.3 ppm. The compound 2 on further reaction with several substituted aromatic aldehydes produced 3a-s, for them a characteristic absorption for Schiff base (N=CH) in IR spectrum appeared at 1544-1572 cm-1 and in the 1H and 13C NMR spectrum a signal appeared in the range of 5 7.86-8.12 and 145.2-155.9 ppm, respectively. In the 1H NMR spectrum of 2 a broad signal for NH2 (previously at 5 5.96 ppm) has disappeared. The compounds 3a-s on treatment with ClCH2COCl in the presence of Et3N furnished final products 4a-s. In the IR spectrum of 4a-s carbonyl group of P-lactam ring showed characteristic absorption in the range of 1732-1765 cm-1 and 1H NMR spectrum of 4a-s showed two doublets for NCH and CHCl in the range of 5 5.15-5.54 and 4.45-4.66 ppm, respectively. However, the 13C NMR spectrum of 4a-s displayed three signal for NCH, CHCl and cyclic CO in the range of 5 58.8-68.8, 47-54.9 and 166-175 ppm, respectively. The IR absorption, 1H and 13C NMR signal of N=CH have disappeared.
3. Pharmacological Results and Discussion
The results of the antimicrobial (antibacterial, anti-fungal and antitubercular) activities are summarized in Tables 1, 2 and 3. The results of the antimicrobial screening data revealed that all the compounds 4a-s showed
4. Conclusion
The research study reports the successful synthesis of a new series of 4a-s. Biological testing of the newly synthesized systems bearing azetidinone moiety revealed that all the compounds tested showed moderate to good antibacterial, antifungal and antitubercular activities against selected microbial strains.
5. Experimental
Melting points were determined in open glass capillaries and are uncorrected. Progress of reaction was monitored by silica gel-G coated TLC plates using Me-OH:CHCl3 system (1:9). The spot was visualized by exposing dry plate at iodine vapours chamber. IR spectra were recorded as KBr discs on Schimadzu 8201 PC FTIR spectrophotometer (vmax in cm1); 1H and 13C NMR spectra were measured on a Bruker DRX-300 spectrometer in CDCl3 at 300 and 75 MHz, respectively using TMS as the internal standard. All chemical shifts are reported on 5 scale. The FAB mass spectra were recorded on a Jeol SX-102 mass spectrometer. Elemental analyses were performed on a Carlo Erba 1108 analyzer providing satisfactory results. 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 further purified before use.
Synthesis of the 1-(3-chloropropyl)-1_ff-1,2,3-benzotri azole (1)
A mixture of 1,2,3-benzotriazole and 1-bromo-3-chloropropane (1:1 mol) was dissolved in methanol at room temperature. The reaction mixture was continuously stirred on a magnetic stirrer for about 360 min. The product was filtered and purified with column chromato-graphy and recrystallized from ethanol at room temperature to yield 1.
CH,CH2CHjC<
1-(3-chloropropyl)-1H-1,2,3-benzotriazole. Yield: 60%; mp 77-79 °C; IR v 749 (C-Cl), 1235 (N-CH2), 1563 (C=C), 3020, 2836 (CH) cm-1. 1H NMR 5 2.13 (m, 2H, CH2CH2CH2), 3.49 (t, 2H, J = 7.5 Hz, CH2CH2CH2-Cl), 4.177 (t, 2H, J = 7.5 Hz, N-CH2CH2CH2), 7.29-7.96 (m, 4H, ArH). 13C NMR 5 36.2 (CH2CH2CH2), 43.7 (CH2CH2CH2-Cl), 49.3 (N-CH2CH2CH2), 118.5 (C-2), 120.2 (C25), 128.4 (C-3), 128.9 (C-4), 145.5 (C-6), 147.9 (C-1). Anal. Calcd for C9H10N3Cl: C, 55.25; H, 5.15; N, 21.47. Found: C, 55.21; H, 5.13; N, 21.41; MS-FAB: 195 (M+).
Synthesis of the N-[3-(1H-1,2,3-benzotriazol-1-yl)pro pyl]urea (2)
A mixture of 1 and urea (1:1 mole) was dissolved in methanol at room temperature. The reaction mixture was continuously stirred on a magnetic stirrer for about 270 min. The product was filtered and purified with a column chromatography and recrystallized from ethanol at room temperature to yield 2.
V
2 CH2CH2CH2NHCONH2
Yield: 71%; mp 60-63 °C; IR v 1234 (C-NH), 1658 (CO), 3340 (NH), 3415 (NH2) cm-1. 1H NMR 5 2.17 (m, 2H, CH2CH2CH2), 3.30 (t, 2H, J = 7.4 Hz, CH2CH2CH2 NH), 4.12 (t, 2H, J = 7.4 Hz, N-CH2CH2CH2), 5.64 (s, 1H, NH), 5.96 (s, 2H, NH2), 6.80-7.70 (m, 4H, ArH). 13C NMR 5 39.5 (CH2CH2CH2), 47.2 (CH2CH2CH2-NH), 48.2 (N-CH2CH2CH2), 117.6 (C-2), 121.3 (C-5), 127.8 (C-3), 128.2 (C-4), 144.7 (C-6), 146.7 (C-1), 163.3 (CO). Anal. Calcd for C10H13N5O: C, 54.78; H, 5.97; N, 31.94. Found: C, 54.79; H, 5.90; N, 31.88; MS-FAB: 219 (M+).
Synthesis of 3a-s
A mixture of compound 2 and appropriate substituted benzaldehydes (1:1 mole) was dissolved in methanol at room temperature and allowed to react. The reaction mixture was first continuously stirred on a magnetic stirrer for about 120-180 min then refluxed on a steam bath for about 90-135 min. The products were filtered and cooled at room temperature. The filtered products were purified with a column chromatography and recrystallized from ethanol at room temperature to yield 3a-s.
!	CH,CH,CH,a
N-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-N'-[(phenyl) methylidenejurea (3a). Yield: 58%; mp 70-72 °C; IR v 1553 (N=CH), 1662 (CO), 3360 (NH) cm-1. 1H NMR 5
2.06 (m, 2H, CH2CH2CH2), 3.36 (t, 2H, J = 7.4 Hz, CH2CH2CH2-NH), 4.15 (t, 2H, J = 7.4 Hz, N-CH2CH2 CH2), 5.79 (s, 1H, NH), 7.40-7.74 (m, 9H, ArH), 7.85 (s, 1H, N=CH). 13C NMR 5 38.4 (CH2CH2CH2), 45.3 (CH2CH2CH2-NH), 51.3 (N-CH2CH2CH2), 115.3 (C-2),
120.0	(C-5), 125.8 (C-3), 126.3 !C-8, C-12), 127.5 (C-9, C-11), 128.5 (C-4), 129.2 (C-10), 131.2 (C-7), 136.2 (C-6), 145.2 (N=CH), 146.1 (C-1), 149.3 (12C, Ar), 162.6 (CO). Anal. Calcd for C17H17N5O: C, 66.43; H, 5.57; N, 22.78. Found: C, 66.40; H, 5.48; N, 22.72. MS-FAB: 307 (M+).
N-[3-(1H-1,2,3-BenzotriazoM-yl)propyl]-N'-[(4-chlo roophenyl)methylidene]urea (3b). Yield: 66%; mp 81-82 °C; IR v 740 (C-Cl), 1566 (N=CH), 1675 (CO), 3372 (NH) cm-1. 1H NMR 5 2.28 (m, 2H, CH2CH2CH2), 3.36 (t, 2H, J = 7.4 Hz, CH2CH2CH2-NH), 4.28 (t, 2H, / = 7.4 Hz, N-CH2CH2CH2), 5.76 (s, 1H, NH), 7.32-7.81 (m, 8H, ArH), 7.92 (s, 1H, N=CH). 13C NMR 5 38.9 (CH2CH2CH2), 44.5 (CH2CH2CH2-NH), 47.3 (N-CH2CH2CH2), 112.5 (C-2), 121.0 (C-5), 125.4 (C-3),
127.7	(C-8, C-12), 128.8 (C-4), 129.2 (C-9, C-11), 132.3 (C-6), 135.5 (C-10), 137.8 (C-7), 144.1 (C-1), 152.6 (N=CH), 163.5 (CO). Anal. Calcd for C17H16N5OCl: C, 59.73; H, 4.71; N, 20.48. Found: C, 59.62; H, 4.62; N, 20.35. MS-FAB: 341 (M+).
N-[3-(1H-1,2,3-BenzotriazoM-yl)propyl]-N'-[(3-chlo rophenyl)methylidene]urea (3c). Yield: 67%; mp 76-78 °C; IR v 735 (C-Cl), 1559 (N=CH), 1673 (CO), 3363 (NH) cm-1. 1H NMR 5 2.27 (m, 2H, CH2CH2CH2), 3.37 (t, 2H, J = 7.4 Hz, CH2CH2CH2-NH), 4.25 (t, 2H, J= 7.4 Hz, N-CH2CH2CH2), 5.79 (s, 1H, NH), 7.10-7.90 (m, 8H, ArH), 7.98 (s, 1H, N=CH). 13C NMR 5 38.5 (CH2CH2CH2), 43.7 (CH2CH2CH2-NH), 52.2 (N-CH2CH2CH2), 113.3 (C-2), 120.5 (C-5), 125.3 (C-3), 126.4 (C-8), 127.7 (C-12), 128.3 (C-4), 129.4 (C-10), 131.2 (C-11), 132.7 (C-6), 135.6 (C-9), 139.2 (C-7),
146.1	(C-1), 150.7 (N=CH), 162.9 (CO). Anal. Calcd for C17H16N5OCl: C, 59.73; H, 4.71; N, 20.48. Found: C, 59^3; H, 4.62; N, 20.44. MS-FAB: 341 (M+).
N-[3-(1H-1,2,3-Benzotriazol-1-yl)propyl]-N'-[(2-chlo rophenyl)methylidene]urea (3d).
Yield: 66%; mp 80-81 °C; IR v 734 (C-Cl), 1567 (N=CH), 1672 (CO), 3371 (NH) cm-1. 1H NMR 5 2.22 (m, 2H, CH2CH2CH2), 3.31 (t, 2H, J = 7.4 Hz, CH2CH2CH2-NH), 4.24 (t, 2H, J = 7.4 Hz, N-CH2CH2CH2), 5.73 (s, 1H, NH), 7.20-7.90 (m, 8H, Ar-H), 8.07 (s, 1H N=CH). 13C NMR 5 38.7 (CH2CH2CH2), 44.2 (CH2CH2CH2-NH), 50.1 (N-CH2CH2CH2), 113.4 (C-2), 118.3 (C-5), 125.8 (C-3), 126.7, 127.4. (C-11),
128.2	(C-4), 129.2 (C-9), 130.2 (C-12), 133.2 (C-6),
133.8	(C-8), 138.2 (C-7), 147.2 (C-1), 151.6 (N=CH), 161.0 (CO). Anal. Calcd for C17H16N5OCl: C, 59.73; H, 4.71; N, 20.48. Found: C, 59^5; H, 4.70; N, 20.40. MS-FAB: 341 (M+).
N-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-N'-[(4-bro mophenyl)methylidene]urea (3e). Yield: 65%; mp 78-79 °C; IR v 636 (C-Br), 1560 (N=CH), 1667 (CO), 3374 (NH) cm-1. 1H NMR 5 2.27 (m, 2H, CH2CH2CH2), 3.30 (t, 2H, J = 7.5 Hz, CH2CH2CH2-NH), 4.29 (t, 2H, J =
7.5	Hz, N-CH2CH2CH2), 5.77 (s, 1H, NH), 7.41-7.69 (m, 8H, ArH), 7.97 (s, 1H, N=CH). 13C NMR 5 36.2 (CH2CH2CH2), 44.3 (CH2CH2CH2-NH), 50.3 (N-CH2CH2CH2), 114.1 (C-2), 1221.3 (C-5), 123.2 (C-10),
125.1	(C-3), 128.4 (C-8, C-12), 129.3 (C-4), 132.4 (C-9, C-11), 134.5 (C-6), 136.9 (C-7), 148.2 (C-1), 152.7 (N=CH), 163.8 (CO). Anal. Calcd for C17H16N5OBr: C, 52.86; H, 4.17; N, 18.13. Found: C, 52.82; H, 4.13; N, 18.07. MS-FAB: 386 (M+).
N-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-N'-[(3-bro mophenyl)methylidene]urea (3f). Yield: 64%; mp 80-81 °C; IR v 643 (C-Br), 1568 (N=CH), 1664 (CO), 3366 (NH) cm-1. 1H NMR 5 2.24 (m, 2H, CH2CH2CH2), 3.37 (t, 2H, J = 7.6 Hz, CH2CH2CH2-NH), 4.30 (t, 2H, / =
7.6	Hz, N-CH2CH2CH2), 5.73 (s, 1H, NH), 7.23-7.90 (m, 8H, ArH), 7.98 (s, 1H, N=CH). 13C NMR 5 36.5 (CH2CH2CH2), 44.74 (CH2CH2CH2-NH), 48.4 (NCH2CH2CH2), 114.2 (C-2), 119.6 (C-5), 123.8 (C-9),
125.5	(C-3), 126.8 (C-12), 128.4 (C-4), 129.5 (C-8),
131.6	(C-11), 132.4 (C-10), 134.6 (C-6), 139.1 (C-7),
146.3	(C-1), 152.6 (N=CH), 162.5 (CO). Anal. Calcd for C17H16N5OBr: C, 52.86; H, 4.17; N, 18.13. Found: C, 52.76; H, 4.10; N, 18.05. MS-FAB: 386 (M+).
N-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-N'-[(2-bro mophenyl)methylidene]urea (3g). Yield: 62%; mp 74-75 °C; IR v 638 (C-Br), 1559 (N=CH), 1666 (CO), 3368 (NH) cm-1. 1H NMR 5 2.26 (m, 2H, CH2CH2CH2), 3.32 (t, 2H, J = 7.6 Hz, CH2CH2CH2-NH), 4.22 (t, 2H, J = 7.6 Hz, N-CH2CH2CH2), 5272 (s, 1H, NH), 7.31-7.63 (m, 8H, ArH), 8.02 (s, 1H, N=CH). 13C NMR 5 38.5 (CH2CH2CH2), 44.5 (CH2CH2CH2-NH), 51.4 (N-CH2CH2CH2), 115.4 (C-2), 121.5 (C-5), 121.7 (C-8),
124.2	(C-3), 128.3 (C-11), 129.4 (C-4), 130.5 (C-12),
131.4	(C-10), 133.9 (C-9), 134.2 (C-6), 142.3 (C-7),
149.7	(C-1), 152.8 (N=CH), 161.9 (CO). Anal. Calcd for C17H16N5OBr: C, 52.86; H, 4.17; N, 18.13. Found: C, 52780; H 4.08; N, 18.12. MS-FAB: 386 (M+).
N- [3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-N'- [(4-nitro phenyl)methylidene]urea (3h). Yield: 66%; mp 73-74 °C; IR v 847 (C-NH), 1530 (N=O), 1568 (N=CH), 1668 (CO), 3358 (NH) cm-1. 1H NMR 5 2.24 (m, 2H, CH2CH2CH2), 3.28 (t, 2H, J = 7.6 Hz, CH2CH2CH2-NH), 4.242 (t, 2 H, J= 7.6 Hz, N-CH2CH2CH2), 5.81 (s, 1H, NH), 7.32-7.91 (m, 8H, ArH), 8.10 (s, 1H, N=CH). 13C NMR 5 40.1 (CH2CH2CH2), 45.7 (CH2CH2CH2-NH), 50.8 (NCH2CH2CH2), 110.2 (C-2), 120.4 (C-5)2 123.4 (C-9, C-11), 125.2 (C-3), 128.4 (C-4), 130.3 (C-8, C-12), 133.6 (C-6), 138.2 (C-7), 144.3 (C-1), 149.5 (C-10), 155.9
(N=CH), 162.3 (CO). Anal. Calcd for C17H16N6O3: C, 57.94; H, 4.57; N, 23.85. Found: C, 57.81; H, 4.51; N, 23.73. MS-FAB: 352 (M+).
N-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-N'-[(3-ni-trophenyl)methylidene]urea (3i). Yield: 63%; mp 70-71 °C; IR v 840 (C-NH), 1528 (N=O), 1572 (N=CH), 1665 (CO), 3351 (NH) cm-1. 1H NMR 5 2.26 (m, 2H, CH2CH2CH2), 3.20 (t, 2H, J = 7.6 Hz, CH2CH2CH2-NH), 4.22 (t, 2 H, J= 7.6 Hz, N-CH2CH2CH2), 5.83 (s, 1H, NH), 7.21-7.86 (m, 8H, ArH), 8.07 (s, 1H, N=CH). 13C NMR 5 39.7 (CH2CH2CH2), 44.2 (CH2CH2CH2-NH), 49.4 (N-CH2CH2CH2), 111.2 (C-2), 119.5 (C-5), 121.5 (C-8), 124.2 (C-10), 125.4 (C-3), 129.3 (C-4), 129.9 (C-11),
133.5	(C-6), 133.9 (C-12), 139.8 (C-7), 146.9 (C-1),
149.6	(C-9), 154.3 (N=CH), 160.2 (CO). Anal. Calcd for C17H16N6O3: C, 57.94; H, 4.57; N, 23.85. Found: C, 57^0; H, 4.55; N; 23.60. MS-FAB: 352 (M+).
N-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-N'-[(2-ni trophenyl)methylidene]urea (3j). Yield: 62%; mp 73-75 °C; IR v 841 (C-NH), 1533 (N=O), 1572 (N=CH), 1664 (CO), 3350 (NH) cm-1. 1H NMR 5 2.17 (m, 2H, CH2CH2CH2), 3.35 (t, 2H, J = 7.6 Hz, CH2CH2CH2-NH), 4.182 (t, 2H, J= 7.6 Hz, N-CH2CH2CH2), 5.87 (s, 1H, NH), 7.26-7.99 (m, 8H, ArH), 8.12 (s, 2H, N=CH). 13C NMR 5 40.2 (CH2CH2CH2), 45.1 (CH2CH2CH2-NH), 48.9 (NCH2CH2CH2), 110.6 (C-2), (C-5), 123.6 (C-9), 125.2 (C-3), 127.3 (C-12), 129.1 (C-4), 130.4 (C-10), 132.9 (C-6), 134.2 (C-7), 135.6 (C-11), 145.3 (C-1), 146.2 (C-8), 155.4 (N=CH), 162.2 (CO). Anal. Calcd for C17H16N6O3: C, 57.94; H, 4.57; N, 23.85. Found: C, 5750; H 4.40; N, 23.75. MS-FAB: 352 (M+).
N- [3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-N'- [(4-meth oxyphenyl)methylidene]urea (3k). Yield: 61%; mp 68-69 °C; IR v 1561 (N=CH), 2947 (OCH3), 3351 (NH) cm-1. 1H NMR 5 2.15 (m, 2H, CH2CH2CH2), 3.28 (t, 2H, J = 7.6 Hz, CH2CH2CH2-NH), 3.427 (s, 3H, OCH3), 4.16 (t, 2H, J = 7.6 Hz, NCH2CH2CH2), 5.78 (s, 1H, NH), 7.34-7.52 (m, 8H, ArH), 7.88 (s, 1H, N=CH). 13C NMR 5 37.2 (CH2CH2CH2), 42.6 (CH2CH2CH2-NH), 47.2 (N-CH2CH2 CH2), 51.7 (OCH3), 111.3 (C-2), 114.5 (C-9, C-11), 119.6 (C-5), 122.9 (C-3), 128.2 (C-8, C-12), 130.0 (C-4), 131.1 (C-7), 132.8 (C-6), 148.6 (C-1), 154.2 (N=CH), 159.6 (C-10), 161.5 (CO). Anal. Calcd for C18H19N5O2: C, 64.08; H, 5.67; N, 20.75. Found: C, 63.96; H 5.56; N, 20.65. MS-FAB: 337 (M+).
N- [3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-N'- [(3-meth oxyphenyl)methylidene]urea (3l). Yield: 62%; mp 67-68 °C; IR v 1559 (N=CH), 2942 (OCH3), 3355 (NH) cm-1. 1H NMR 5 2.17 (m, 2H, CH2CH2CH2), 3.30 (t, 2H, J = 7.6 Hz, CH2CH2CH2-NH), 3.61 (s, 3H, OCH3), 4.18 (t, 2H, J = 7.6 Hz, N-CH2CH2CH2), 5.69 (s, 1H NH), 7.41-7.82 (m, 8H, ArH), 7.96 (s, 1H, N=CH). 13C NMR 5
37.7	(CH2CH2CH2), 42.9 (CH2CH2CH2-NH), 47.7 (N-CH2CH2CH2), 544.7 (OCH3), 110.2 (C-2), 114.1 (C-8),
115.4	(C-10), 117.2 (C-12), 119.5 (C-5), 125.3 (C-3),
128.7	(C-11), 129.6 (C-4), 133.4 (C-6), 140.4 (C-7),
146.5	(C-1), 153.7 (N=CH), 160.7 (C-9), 161.9 (CO). Anal. Calcd for C18H19N5O2: C, 64.08; H, 5.67; N, 20.75. Found: C, 63.98; H, 5.64; NT, 20.62. MS-FAB: 337 (M+).
N- [3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-N'- [(2-meth oxyphenyl)methylidene]urea (3m). Yield: 64%; mp 62-64 °C; IR v 1558 (N=CH), 2945 (OCH3), 3361 (NH) cm-1. 1H NMR 5 2.12 (m, 2H, CH2CH2CH2), 3.32 (t, 2H, J = 7.6 Hz, CH2CH2CH2-NH), 3.67 (s, 3H, OCH3), 4.16 (t, 2H, J = 7.6 Hz, N-CH2CH2CH2), 5.74 (s, 1H, NH), 7.22-7.72 (m, 8H, ArH), 7.86 (s, 1H, N=CH). 13C NMR 5
38.3	(CH2CH2CH2), 43.2 (CH2CH2CH2-NH), 48.1 (N-CH2CH2CH2), 53.7 (OCH3), 1132.2 (C-2), 118.4 (C-5),
123.5	(C-3), 126.7 (C-9), 127.7 (C-8), 128.6 (C-10),
129.6	(C-4), 130.9 (C-11), 132.5 (C-6), 135.9 (C-12),
138.8	(C-7), 147.4 (C-1), 151.0 (N=CH), 158.1 (CO). Anal. Calcd for C18H19N5O2: C, 64.08; H, 5.67; N, 20.75. Found: C, 63.90; H, 5.57; N, 20.61. MS-FAB: 337 (M+).
N-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-N'-[(4- meth ylphenyl)methylidene]urea (3n). Yield: 60%; mp 57-58 °C; IR v 1548 (N=CH), 2917 (CH3), 3342 (NH) cm-1. 1H NMR 5 2.11 (m, 2H, CH2CH2CH2), 2.64 (s, 3H, CH3), 3.22 (t, 2H, J = 7.4 Hz, CH2CH2CH2-NH), 4.03 (t, 2H, / = 7.4 Hz, N-CH2CH2CH2), 5.67 (s, 1H, NH), 7.39-7.79 (m, 8H, ArH), 7.89 (s, N=CH). 13C NMR 5 24.9 (CH3), 36.6 (CH2CH2CH2), 42.6 (CH2CH2CH2-NH), 463.8 (N-CH2CH2CH2), 113.2 (C-2), 120.3 (C-5), 124.5 (C-3), 126.4 (C-8, C-12), 128.6 (C-4), 129.9 (C-9, C-11), 132.7 (C-6), 134.7 (C-7), 137.6 (C-10), 146.3 (C-1), 151.2 (N=CH), 159.8 (CO). Anal. Calcd for C18H19N5O: C, 67.27; H, 5.95; N, 21.79. Found: C, 67.18; H, 5.90; N, 21.72. MS-FAB: 321 (M+).
N- [3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-N'- [(3-met hylphenyl)methylidene]urea (3o). Yield: 61%; mp 54-56 °C; IR v 1544 (N=CH), 2923 (CH3), 3345 (NH) cm-1. 1H NMR 5 4.05 (m, 2H, CH2CH2CH23), 2.58 (s, 3H, CH3), 3.17 (t, 2H, J = 7.5 Hz, CH2CH2CH2-NH), 4.05 (t, 2H, J = 7.5 Hz, N-CH2CH2CH2), 5.78 (s, 1H, NH), 7.31-7.84 (m, 8H, ArH), 77.91 (s, 1H, N=CH). 13C NMR 5
22.4	(CH3), 36.5 (CH2CH2CH2), 42.5 (CH2CH2CH2-NH),
45.8	(N-CH2CH2CH2), 112.4 (C-2), 121.5 (C-5), 125.2 (C-12), 126.6 (C-3), 127.1 (C-8), 128.2 (C-4), 129.2 (C-11), 130.6 (C-10), 132.4 (C-6), 137.5 (C-7), 139.5 (C-9), 147.5 (C-1), 152.0 (N=CH), 160.8 (CO). Anal. Calcd for C18H19N5O: C, 67.27; H, 5.95; N, 21.79. Found: C, 67.11; H, 5.88; N, 21.76. MS-FAB: 321 (M+).
N- [3-(1_ff-1,2,3-Benzotriazol-1-yl)propyl]-N'- [(2-meth ylphenyl)methylidene]urea (3p). Yield: 62%; mp 52-54 °C; IR v 1553 (N=CH), 2908 (CH3), 3341 (NH) cm-1. 1H
NMR 5 2.08 (m, 2H, CH2CH2CH2), 2.60 (s, 3H, CH3), 3.22 (t, 2H, J = 7.4 Hz, CH2CH2CH2-NH), 4.00 (t, 2H, J = 7.4 Hz, N-CH2CH2CH2), 5J2 (s, 1H, NH), 7.34-7.76 (m, 8H, ArH), 7.88 (s, N=CH). 13C NMR 5 21.9 (CH3), 38.7 (CH2CH2CH2), 43.4 (CH2CH2CH2-NH), 453.7 (N-CH2CH2CH2), 113.3 (C-2), 120.5 (C-5), 124.5 (C-3), 126.1 (C-9), 126.8 (C-8), 128.9 (C-4), 129.7 (C-10),
130.3	(C-11), 133.6 (C-6), 136.5 (C-12), 138.6 (C-7), 145.5 (C-1), 154.0 (N=CH), 159.2 (CO). Anal. Calcd for C18H19N5O: C, 67.27; H, 5.95; N, 21.79. Found: C, 67.21; H, 5.89; N, 21.70. MS-FAB: 321 (M+).
N-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-N'-[(4-hydro xyphenyl)methylidene]urea (3q). Yield: 64%; mp 72-73 °C; IR v 1557 (N=CH), 3385 (NH), 3472 (OH) cm-1. 1H NMR 5 2.22 (m, 2H, CH2CH2CH2), 3.36 (t, 2H, J = 7.7 Hz, CH2CH2CH2-NH), 4.15 (s, 1H, OH), 4.17 (t, 2H, J = 7.7 Hz, N-CH2CH2CH2), 5.84 (s, 1H, NH), 7.32-7.79 (m, 8H, ArH), 8.07 (s, 1H, N=CH). 13C NMR 5 39.9 (CH2CH2CH2), 45.7 (CH2CH2CH2-NH), 50.4 (N-CH2CH2 CH2), 111.3 2C-2), 118.9 (C-9, C211), 120.7 (C-5), 124.3 (C-3), 127.9 (C-8, C-12), 128.4 (C-4), 130.8 (C-7), 132.2 (C-6), 147.1 (C-1), 153.3 (N=CH), 154.6 (C-10), 163.7 (CO). Anal. Calcd for C17H17N5O2: C, 63.14; H, 5.29; N, 21.65. Found: C, 63.07; H, 5.22; N, 21.50. MS-FAB: 323
(M+).
N-[3-(1tf-1,2,3-Benzotriazol-1-yl)propyl]-N'-[(3-hy droxyphenyl)methylidene]urea (3r). Yield: 60%; mp 70-72 °C; IR v 1561 (N=CH), 3379 (NH), 3464 (OH) cm-1. 1H NMR 5 2.18 (m, 2H, CH2CH2CH2), 3.39 (t, 2H, J = 7.6 Hz, CH2CH2CH2-NH), 4.24 (s, 1H, OH), 4.25 (t, 2H, J = 7.6 Hz, N-CH2CH2CH2), 5.89 (s, 1H, NH), 7.36-7.74 (m, 8H, ArH), 8.01 (s, 1H, N=CH). 13C NMR 5 39.9 (CH2CH2CH2), 44.7 (CH2CH2CH2-NH), 49.7 (N-CH2CH2CH2), 112.6 (C-2), 114.2 (C-8), 116.3 (C-4), 119.5 (C-12), 120.6 (C-5), 125.4 (C-3), 128.4 (C-4), 130.8 (C-11), 132.4 (C-6), 139.3 (C-7), 146.4 (C-1),
151.4	(N=CH), 155.6 (C-9), 160.7 (CO). Anal. Calcd for C17H17N5O2: C, 63.14; H, 5.29; N, 21.65. Found: C, 63.11; H, 5.18; N, 21.58. MS-FAB: 323 (M+).
N-[3-(1tf-1,2,3-Benzotriazol-1-yl)propyl]-N'-[(2-hy droxyphenyl)methylidene]urea (3s). Yield: 62%; mp 68-69 °C; IR v 1565 (N=CH), 3381 (NH), 3460 (OH) cm-1. 1H NMR 5 2.28 (m, 2H, CH2CH2CH2), 3.33 (t, 2H, J = 7.7 Hz, CH2CH2CH2-NH), 4.36 (s, 1H, OH), 4.21 (t, 2H, J = 7.7 Hz, N-CH2CH2CH2), 5.86 (s, 1H, NH), 7.25-7.69 (m, 8H, ArH), 77.97 (s, 1H, N=CH). 13C NMR 5 38.4 (CH2CH2CH2), 43.5 (CH2CH2CH2-NH), 49.2 (N-CH2CH2CH2), 114.2 (C-2), 116.5 (C-9), 120.7 (C-5), 122.7 (C-11), 125.9 (C-3), 126.4 (C-7), 128.8 (C-12),
129.5	(C-4), 130.3 (C-10), 132.9 (C-6), 147.8 (C-1), 151.7 (N=CH), 154.2 (C-8), 161.1 (CO). Anal. Calcd for C17H17N5O2: C, 63.14; H, 5.29; N, 21.65. Found: C, 63^9; H 5.23; N, 21.57. MS-FAB: 323 (M+).
Synthesis of 4a-s
A mixture of 3a-s and chloroacetyl chloride in the presence of Et3N (1:1:1 mole) was dissolved in methanol at room temperature and allowed to react. The reaction mixture was first continuously stirred on a magnetic stirrer for about 135-180 min, then refluxed on a steam bath for about 90-150 min. The products were filtered and cooled at room temperature. The filtered products were purified with a column chromatography and recrystallized from ethanol at room temperature to yield compounds 4a-s.
N-[3-(1_ff-1,2,3-Benzotriazol-1-yl)propyl]-2-phenyl-3-chloro-4-oxo-1-azetidinecarboxamide (4a). Yield: 68%; mp 78-79 °C; IR v 1329 (C-NH), 1732 (CO cyclic), 2908 (CH-Cl) cm-1. 1H NMR 5 2.10 (m, 2H, CH2CH2CH2), 3.28 (t, 2H, J = 7.5 Hz, CH2CH2CH2-NH), 4.11 (t, 2H, J = 7.5 Hz, N-CH2CH2CH2), 4.48 (d, J= 5.0 Hz, 1H, CH-Cl), 5.17 (d, J = 5.0 Hz, 1H, N-CH), 5.60 (s, 1H, NH), 6.85-7.72 (m, 9H, ArH). 13C NMR 5 34.4 (CH2CH2CH2),
40.5	(CH2CH2CH2-NH), 47.2 (N-CH2CH2CH2) 54.9 (CH-Cl), (52.7 (N-CH), 110.3 (C-2), 118.9 (C-5), 125.7 (C-3), 126.4 (C-8, C-12), 128.4 (C-4), 129.8 (C-10), 130.1 (C-9, C-11), 132.6 (C-6), 136.4 (C-7), 145.9 (C-1), 161.1 (CO), 168.7 (CO cyclic). Anal. Calcd for C19H18N5O2Cl: C, 59.45; H, 4.72; N, 18.24. Found: C, 591.38; H, 4251; N, 18.15. MS-FAB: 383 (M+).
N-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-2-(4-chloro phenyl)-3-chloro-4-oxo-1-azetidinecarboxamide (4b).
Yield: 64%; mp 85-87 °C; IR v 765 (C-Cl), 1337 (C-NH), 1752 (CO cyclic), 2915 (CH-Cl) cm-1. 1H NMR 5 2.17 (m, 2H, CRC^CR), 3.30 (t, 2H, J = 7.6 Hz, CRCRCH^NH), 4.12 (t, 2H, J = 7.6 Hz, N-C^^CR), 4.65 (d, 1H, J = 5.1 Hz, CH-Cl), 5.39 (d, 1H, J= 5.1 Hz, N-CH), 5.64 (s, 1H, NH), 6.86-7.75 (m, 8H, ArH). 13C NMR 5 38.2 (CH^RCR), 42.5 (CH(CH(CH(-NH), 49.3 (NC^CRCR), 53.7 2CH-Cl),
63.6	(N-CH), 116.2 (C-2), 120.9 (C-5), 123.7 (C-3), 127.7 (C-8, C-12), 128.6 (C-4), 129.4 (C-9, C-11), 132.8 (C-6), 135.5 (C-10), 136.7 (C-7), 146.9 (C-1), 164.1 (CO), 174.5 (CO cyclic). Anal. Calcd for C^H^O^: C, 54.55; H, 4.14; N, 16.74. Found: C, 5-4.418; H, 4.10; N, 16.60. MS-FAB: 418 (M+).
N-[3-(1_ff-1,2,3-Benzotriazol-1-yl)propyl]-2-(3-chlorop henyl)-3-chloro-4-oxo-1-azetidinecarboxamide (4c).
Yield: 65%; mp 82-84 °C; IR v 776 (C-Cl), 1333 (C-NH), 1754 (CO cyclic), 2920 (CH-Cl) cm-1. 1H NMR 5 2.15 (m, 2H, CRC^CHA 3.33 (t, 2H, J = 7.5 Hz,
CRCRCH^NH), 4.15 (t, 2H, J = 7.5 Hz, N-CH^RCH^, 4.63 (d, 1H, J = 5.1 Hz, CH-Cl), 5.34 (d, 1H, J = 5.1 Hz, N-CH), 5.64 (s, 1H, NH), 6.79-7.64 (m, 8H, ArH). 13C NMR 5 37.4 (CH^RCR), 42.9 (CH(CH(CH(-NH), 49.3 (N-CH(CH(CH(), 55.8 2^-0), 65.7 (N-CH), 114.2 (C-2), 118.4 (C-5), 124.3 (C-3), 126.7 (C-8), 128.3 (C-12), 129.1 (C-4), 129.9 (C-10), 131.4 (C-11), 134.4 (C-6), 135.3 (C-9), 138.1 (C-7), 147.9 (C-1), 164.3 (CO), 171.2 (CO cyclic). Anal. Calcd for C19H17N5O(Cl(: C, 54.55 H, 4.14; N, 16.74. Found: C, 5447; H, 4.08. N, 16.58. MS-FAB: 418 (M+).
N-[3-(1_ff-1,2,3-Benzotriazol-1-yl)propyl]-2-(2-chlorop henyl)-3-chloro-4-oxo-1-azetidinecarboxamide (4d).
Yield: 66%; mp 80-81 °C; IR v 773 (C-Cl), 1334 (C-NH), 1751 (CO cyclic), 2917 (CH-Cl) cm1. 1H NMR 5 2.13 (m, 2H, CRC^CH^, 3.28 (t, 2H, J = 7.6 Hz, CRCRCH^NH), 4.14 (t, 2H, J = 7.6 Hz, N-CH2CH(CH(), 4.62 (d, 1H, J = 5.1 Hz, CH-Cl), 5.33 (d, 1H, J = 5.1 Hz, N-CH), 5.68 (s, 1H, NH), 6.81-7.62 (m, 8H, ArH). 13C NMR 5 37.9 (CH^RCR), 43.1 (CH(CH(CH(-NH), 48.7 (N-CH(CH(CH(), 55.2 2^-0),
64.6	(N-CH), 114.5 (C-2), 119.9 (C-5), 124.7 (C-3), 127.6 (C-11), 128.9 (C-4), 129.4 (C-9), 130.4 (C-10), 132.2 (C-12), 133.3 (C-6), 135.1 (C-8), 137.9 (C-7), 147.4 (C-1), 163.6 (CO), 173.7 (CO cyclic). Anal. Calcd for C19H17N5O(Cl(: C, 54.55; H, 4.14; N, 16.74. Found: C, 5448; H, 4.05; N, 16.70. MS-FAB: 418 (M+).
N-[3-(1_ff-1,2,3-Benzotriazol-1-yl)propyl]-2-(4-bromop henyl)-3-chloro-4-oxo-1-azetidinecarboxamide (4e).
Yield: 61%; mp 78-80 °C; IR v 578 (C-Br), 1310 (C-NH), 1741 (CO cyclic), 2892 (CH-Cl) cm1. 1H NMR 5 2.15 (m, 2H, CHCH^H), 3.25 (t, 2H, J = 7.6 Hz, CHJCHCH^NH), 4.20 (t, 2H, J = 7.6 Hz, N-CH2CH(CH(), 4.63 (d, 1H, J = 5.2 Hz, CH-Cl), 5.44 (d, 1H, J = 5.2 Hz, N-CH), 5.70 (s, 1H, NH), 7.37-7.95 (m, 8H, ArH). 13C NMR 5 38.8 (CH^RCR), 43.2 (CH(CH(CH(-NH), 49.6 (NC^CRCR), 47.3 2^-0),
59.7	(N-CH), 112.4 (C-2), 119.4 (C-5), 123.9 (C-10), 124.5 (C-3), 128.6 (C-4), 130.8 (C-8, C-12), 131.4 (C-9, C-11), 132.6 (C-6), 136.5 (C-7), 147.9 (C-1), 164.2 (CO), 172.3 (CO cyclic). Anal. Calcd for C^H^O^rCl: C, 49.31; H, 3.70; N, 15.13. Found: C, 449.19; H, 3.65; N, 15.05. MS-FAB: 462 (M+).
N-[3-(1_ff-1,2,3-Benzotriazol-1-yl)propyl]-2-(3-bromop henyl)-3-chloro-4-oxo-1-azetidinecarboxamide (4f).
Yield: 64%; mp 81-82 °C; IR v 572 (C-Br), 1319 (C-NH), 1747 (CO cyclic), 2895 (CH-Cl) cm-1. 1H NMR 5 2.20 (m, 2H, CRC^CR), 3.35 (t, 2H, J = 7.7 Hz, CRCRCH^NH), 4.21 (t, 2H, J = 7.7 Hz, N-CH2CH(CH(), 5.38 (d, 1H, J = 5.2 Hz, N-CH), 5.57 (d, 1H, J = 5.2 Hz, CH-Cl), 5.72 (s, 1H, NH), 7.31-7.92 (m, 8H, ArH). 13C NMR 5 37.8 (CH^RCR), 42.8 (CH(CH(CH(-NH), 48.6 (CH-Cl), 49.2
59.9 (N-CH), 109.2 (C-2), 118.9 (C-5), 123.7 (C-9), 124.7 (C-3), 125.6 (C-12), 128.4 (C-4), 129.8 (C-8), 132.5 (C-11), 133.4 (C-10), 134.5 (C-6), 140.3 (C-7), 145.6 (C-1),
163.7	(CO), 172.6 (CO cyclic). Anal. Calcd for C19H17N5O2BrCl: C, 49.31; H, 3.70; N, 15.13. Found: C, 49.24; H, 3.59; N, 15.07. MS-FAB: 462 (M+).
N-[3-(1_ff-1,2,3-Benzotriazol-1-yl)propyl]-2-(2-bromop henyl)-3-chloro-4-oxo-1-azetidinecarboxamide (4g).
Yield: 65%; mp 77-78 °C IR v 566 (C-Br), 1327 (C-NH), 1753 (CO cyclic), 2882 (CH-Cl) cm-1. 1H NMR 5 2.22 (m, 2H, CH2CH2CH2), 3.38 (t, 2H, J = 7.6 Hz, CH2CH2CH2-NH), 4.16 (t, 2H, J = 7.6 Hz, N-CH2CH2CH2), 4.66 (d, 1H, J = 5.2 Hz, CH-Cl), 5.15 (d, 1H, J = 5.2 Hz, N-CH), 5.69 (s, 1H, NH), 7.27-7.84 (m, 8H, ArH). 13C NMR 5 38.2 (CH2CH2CH2), 43.0 (CH2CH2CH2-NH), 47.8 (CH-Cl), 49.5 (2N-C2H2C2H2CH2), 58.8 (N-CH), 111.1 (C-2), 119.5 (C-5), 120.3 (C-8), 125.7 (C-3), 127.2 (C-11), 128.4 (C-4), 130.1 (C-12), 131.5 (C-10), 132.2 (C-6), 133.2 (C-9), 142.6 (C-7), 147.9 (C-1), 161.1 (CO), 172.5 (CO cyclic). Anal. Calcd for C19H17N5O2BrCl: C, 49.31; H, 3.70; N, 15.13. Found: C, 49925; H, 3.43; N, 15.24. MS-FAB: 462 (M+).
N-[3-(1#-1,2,3-BenzotriazoM-yl)propyl]-2-(4-nitrop-henyl)-3-chloro-4-oxo-1-azetidinecarboxamide (4h).
Yield: 63%; mp 81-83 °C; IR v 868 (C-NO), 1352 (C-NH), 1540 (NO2), 1745 (CO cyclic), 2923 (CH-Cl) cm-1. 1H NMR 5 2.26 (m, 2H, CH2CH2CH2), 3.65 (t, 2H, J = 7.4 Hz, CH2CH2CH2-NH), 4.20 (t, 2H, J = 7.4 Hz, N-CH2CH2CH2), 5.44 (d, 1H, J = 5.3 Hz, N-CH), 4.59 (d, 1H, J= 5.3 Hz, CH-Cl), 5.72 (s, 1H, NH), 7.10-7.71 (m, 8H, ArH). 13C NMR 5 37.8 (CH2CH2CH2), 42.7 (CH2CH2CH2-NH), 50.2 (N-CH2CH2CH2), 51.0 2CH-Cl), 68.8 (N-CH), 112.2 (C-2), 118.5 (C-5), 122.6 (C-9, C-11),
124.8	(C-3), 127.9 (C-8, C-12), 128.3 (C-4), 132.4 (C-6), 139.8 (C-7), 145.9 (C-1), 147.9 (C-10), 163.7 (CO), 173.6 (CO cyclic). Anal. Calcd for C19H17N6O4Cl: C, 53.21; H, 3.99; N, 19.59. Found: C, 53.15; H, 3.79; N, 19.49. MS-FAB: 428 (M+).
N-[3-(1ff-1,2,3-BenzotriazoM-yl)propyl]-2-(3-nitrop henyl)-3-chloro-4-oxo-1-azetidinecarboxamide (4i).
Yield: 64%; mp 79-81 °C; IR v 864 (C-NO), 1358 (C-NH), 1542 (NO2), 1749 (CO cyclic), 2916 (CH-Cl) cm-1. 1H NMR 5 2.28 (m, 2H, CH2CHtCH2), 3.39 (t, 2H, J = 7.6 Hz, CH2CH2CHt-NH), 4.19 (t, 2H, J = 7.6 Hz, N-CHtCH2CH2), 4.47 (d, 1H, J = 5.2 Hz, CH-Cl), 5.45 (d, 1H, J = 5.2 Hz, N-CH), 5.74 (s, 1H, NH), 7.16-7.79 (m, 8H, ArH). 13C NMR 5 38.9 (CH2CH2CH2), 43.6 (CH2CH2CH2-NH), 49.9 (N-CH2CH2CH2), 51.3 2CH-Cl), 68.8 (N-CH), 113.3 (C-2), 118.9 (C-5), 122.7 (C-8), 124.8 (C-10), 125.9 (C-3), 128.8 (C-4), 129.4 (C-11), 132.6 (C-6), 132.9 (C-12), 139.7 (C-7), 146.9 (C-1), 147.9 (C-9), 163.1 (CO), 175.6 (CO cyclic). Anal. Calcd for C19H17N6O4Cl: C, 53.21, H, 3.99; N, 19.59. Found: C,
53.12; H, 3.87; N, 19.54. MS-FAB: 428 (M+).
N-[3-(1_ff-1,2,3-Benzotriazol-1-yl)propyl]-2-(2-mtrop henyl)-3-chloro-4-oxo-1-azetidinecarboxamide (4j).
Yield: 62%; mp 80-82 °C; IR v 869 (C-NO), 1355 (C-NH), 1542 (NO2), 1747 (CO cyclic), 2917 (CH-Cl) cm-1. 1H NMR 5 2.17 (m, 2H, CH2CH2CH2), 3.30 (t, 2H, J = 7.5 Hz, CH2CH2CH2-NH), 4.12 (2, 2H, J = 7.5 Hz, N-CH2CH2CH2), 4.45 (d, 1H, J = 5.3 Hz, CH-Cl), 5.54 (d, 1H, J = 5.3 Hz, N-CH), 5.64 (s, 1H, NH), 7.05-7.71 (m, 8H, ArH). 13C NMR 5 38.4 (CH2CH2CH2), 43.5 (CH2CH2CH2-NH), 49.2 (N-CH2CH2CH22), 524.6 (2CH-Cl), 64.8 (N-CH), 112.4 (C-2), 117.4 (C-5), 122.5 (C-9), 123.8 (C-3), 127.6 (C-12), 128.6 (C-4), 130.8 (C-10), 132.9 (C-6), 133.5 (C-7), 135.3 (C-11), 145.7 (C-1), 146.5 (C-8), 161.1 (CO), 174.5 (CO cyclic). Anal. Calcd for C19H17N6O4Cl: C, 53.21; H, 3.99; N, 19.59. Found: C, 53.18; H, 3.90; N, 19.50. MS-FAB: 428 (M+).
N-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-2-(4-met hoxyphenyl)-3-chloro-4-oxo-1-azetidinecarboxamide (4k). Yield: 65%; mp 74-75 °C; IR v 1165 (C-O), 1329 (N-C), 1738 (CO cyclic), 2891 (CH-Cl) cm-1.1H NMR 5 2.10 (m, 2H, CH2CH2CH2), 3.25 (t, 2H, J = 7.6 Hz, CH2CH2CH2-NH), 3.677 (s, 3H, OCH3), 4.10 (t, 2H, J = 7.6 Hz, N-CH2CH2CH2), 4.45 (d, 1H, 3= 5.1 Hz, CH-Cl), 5.30 (d, 1H, J = 5.1 Hz, N-CH), 5.55 (s, 1H, NH), 7.26-7.92 (m, 8H, ArH). 13C NMR 5 34.4 (CH2CH2CH2), 41.5 (CH2CH2CH2-NH), 47.2 (N-CH2CH2CH2), 49.4 (CH-Cl), 524.5 (OCH3), 64.8 (N-CH), 112.3 (C-2), 114.4 (C-9, C-11), 120.1 (C-5), 124.8 (C-3), 126.9 (C-8, C-12), 128.5 (C-4), 131.7 (C-7), 132.4 (C-6), 145.3 (C-1), 159.8 (C-10), 162.6 (CO), 171.5 (CO cyclic). Anal. Calcd for C20H20N5O3Cl: C, 58.04; H, 4.87; N, 16.92. Found: C, 577.95; H, 4.78; N, 16.85. MS-FAB: 413 (M+).
N-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-2-(3-met hoxyphenyl)-3-chloro-4-oxo-1-azetidinecarboxamide (4l). Yield: 61%; mp 76-77 °C; IR v 1168 (C-O), 1325 (N-C), 1732 (CO cyclic), 2895 (CH-Cl) cm-1. 1H NMR 5 2.09 (m, 2H, CH2CH2CH2), 3.26 (t, 2H, J = 7.5 Hz, CH2CH2CH2-NH), 3.592 (s, 3H, OCH3), 4.06 (t, 2H, J = 7.5 Hz, N-CH2CH2CH2), 4.49 (d, 1H, 3= 5.1 Hz, CH-Cl), 5.27 (d, 1H, J = 5.1 Hz, N-CH), 5.59 (s, 1H, NH), 7.36-8.02 (m, 8H, ArH). 13C NMR 5 35.9 (CH2CH2CH2), 40.5 (CH2CH2CH2-NH), 48.2 (N-CH2CH2C2H2),2 492.8 (CH-Cl), 524.8 (OCH3), 62.7 (N-CH), 112.4 (C-2), 113.2 (C-8), 115.6 (C-10), 120.2 (C-12), 123.6 (C-5), 124.5 (C-3), 127.5 (C-11), 128.4 (C-4), 132.6 (C-6), 138.4 (C-7), 147.5 (C-1), 159.6 (C-9), 160.4 (CO), 170.7 (CO cyclic). Anal. Calcd for C20H20N5O3Cl: C, 58.04; H, 4.87; N, 16.92. Found: C, 57.94; H, 4.72; N, 16.87. MS-FAB: 413
(M+).
N-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-2-(2-met hoxyphenyl)-3-chloro-4-oxo-1-azetidinecarboxamide
(4m). Yield: 61%; mp 73-75 °C; IR v 1162 (C-O), 1325 (N-C), 1738 (CO cyclic), 2885 (CH-Cl) cm-1. 1H NMR 5 2.12 (m, 2H, CH2CH2CH2), 3.22 (t, 2H, J = 7.4 Hz, CH2CH2CH2-NH), 3.522 (s, 3H, OCH3), 4.05 (t, 2H, J =
7.4	Hz, N-CH2CH2CH2), 4.47 (d, 1H, J = 5.1 Hz, CH-Cl), 5.39 (d, 1H, J = 5.1 Hz, N-CH), 5.60 (s, 1H, NH), 7.04-7.87 (m, 8H, ArH). 13C NMR 5 35.3 (CH2CH2CH2), 41.1 (CH2CH2CH2-NH), 47.6 (N-CH2CH2CH2), 47.5 (CH-Cl), 524.6 (OCH3), 63.5 (N-CH), 112.4 (C-2), 115.4 (C-9), 121.3 (C-5), 121.8 (C-11), 123.8 (C-7), 124.5 (C-3), 127.5 (C-12), 128.4 (C-4), 129.9 (C-10), 132.4 (C-6), 147.8 (C-1), 157.4 (C-8), 160.1 (CO), 169.7 (CO cyclic). Anal. Calcd for C20H20N5O3Cl: C, 58.04; H, 4.87; N, 16.92. Found: C, 57.97; H, 4.82; N, 16.88. MS-FAB: 413 (M+).
N-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-2-(4-methyl phenyl)-3-chloro-4-oxo-1-azetidinecarboxamide (4n).
Yield: 62%; mp 72-73 °C; IR v 1330 (C-NH), 1742 (CO cyclic), 2889 (CH-Cl), 2927 (CH3) cm-1. 1H NMR 5 2.07 (m, 2H, CH2CH2CH2), 2.67 (s, 3H, CH3), 3.19 (t, 2H, J =
7.5	Hz, CH2CH2CH2-NH), 4.01 (t, 2H, J = 7.5 Hz, N-CH2CH2CH2), 4.53 (d, 1H, J = 5.0 Hz, CH-Cl), 5.45 (d, 1H, J = 5.0 Hz, N-CH), 5.64 (s, 1H, NH), 7.28-7.98 (m, 8H, ArH). 13C NMR 5 24.7 (CH3), 38.4 (CH2CH2CH2), 43.5 (CH2CH2CH2-NH), 49.2 (N-CH2CH2CH2), 52.7 (CH-Cl), (52.8 (N-CH), 110.4 (C-2), 118.9 (C-5), 125.7 (C-3), 127.7 (C-8, C-12), 128.5 (C-4), 129.5 (C-9, C-11), 133.5 (C-6), 134.8 (C-7), 138.6 (C-10), 146.4 (C-1), 161.1 (CO), 166.8 (CO cyclic). Anal. Calcd for C20H20N5O2Cl: C, 60.37; H, 5.06; N, 17.60. Found: C, 6(2.27; H, 4.97; N, 17.54. MS-FAB: 397 (M+).
N-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-2-(3-methy lphenyl)-3-chloro-4-oxo-1-azetidinecarboxamide (4o).
Yield: 60%; mp 70-71 °C; IR v 1324 (C-NH), 1748 (CO cyclic), 2894 (CH-Cl), 2929 (CH3) cm-1. 1H NMR 5 2.02 (m, 2H, CH2CH2CH2), 2.62 (s, 3H, CH3), 3.15 (t, 2H, J = 7.5 Hz, CH2CH2CH2-NH), 4.00 (t, 2H, J = 7.5 Hz, N-CH2CH2CH2), 4.55 (d, 1H, J = 5.0 Hz, CH-Cl), 5.38 (d, 1H, J = 5.0 Hz, N-CH), 5.60 (s, 1H, NH), 7.18-7.84 (m, 8H, ArH). 13C NMR 5 23.5 (CH3), 33.4 (CH2CH2CH2), 39.5 (CH2CH2CH2-NH), 47.2 (N-CH2CH2CH2), 51.0 (CH-Cl), 63.8 (N-CH), 110.5 (C-2), 118.2 2C-5), 122.7 (C-12), 123.3 (C-3), 126.5 (C-8), 128.7 (C-4), 129.3 (C-11), 129.9 (C-10), 132.2 (C-6), 137.6 (C-7), 139.1 (C-9), 147.9 (C-1), 159.8 (CO), 167.8 (CO cyclic). Anal. Calcd for C20H20N5O2Cl: C, 60.37; H, 5.06; N, 17.60. Found: C, 60.25; H, 4.95; N, 17.58. MS-FAB: 397 (M+).
N-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-2-(2-methy lphenyl)-3-chloro-4-oxo-1-azetidinecarboxamide (4p).
Yield: 58%; mp 68-69 °C; IR v 1325 (C-NH), 1749 (CO cyclic), 2876 (CH-Cl), 2917 (CH3) cm-1. 1H NMR 5 2.03 (m, 2H, CH2CH2CH2), 2.76 (s, 3H, CH3), 3.10 (t, 2H, J =
7.4 Hz, CH2CH2CH2-NH), 4.06 (t, 2H, J = 7.4 Hz, N-CH2CH2CH2), 4.50 (d, 1H, J = 5.1 Hz, CH-Cl), 5.47 (d, 1H, J = 5.1 Hz, N-CH), 5.50 (s, 1H, NH), 7.21-8.09 (m, 8H, ArH). 13C NMR 5 23.6 (CH3), 35.7 (CH2CH2CH2), 40.6 (CH2CH2CH2-NH), 47.1 (N-CH2CH2CH2), 50.9 (CH-Cl), (52.4 (N-CH), 109.4 (C-2), 118.7 (C-5), 124.3 (C-3), 125.7 (C-9), 126.5 (C-8), 127.4 (C-10), 128.5 (C-4), 129.8 (C-11), 132.8 (C-6), 137.4 (C-12), 138.4 (C-7), 145.4 (C-1), 161.4 (CO), 168.2 (CO cyclic). Anal. Calcd for C20H20N5O2Cl: C, 60.37; H, 5.06; N, 17.60. Found: C, 60.29; H, 4.90; N, 17.49. MS-FAB: 397 (M+).
N-[3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-2-(4-hydro xyphenyl)-3-chloro-4-oxo-1-azetidinecarboxamide (4q). Yield: 60%; mp 78-79 °C; IR v 1188 (C-O), 1358 (C-NH), 2914 (CH-Cl), 1758 (CO cyclic), 3467 (OH) cm-1. 1H NMR 5 2.27 (m, 2H, CH2CH2CH2), 3.38 (t, 2H, J = 7.7 Hz, CH2CH2CH2-NH), 4.19 (t, 2H, J = 7.7 Hz, N-CH2CH2CH2), 4.26 (s, 1H, OH), 4.59 (d, 1H, J = 5.2 Hz, CH-Cl), 5.38 (d, 1H, J = 5.2 Hz, N-CH), 5.74 (s, 1H, NH), 7.09-8.10 (m, 8H, ArH). 13C NMR 5 38.9 (CH2CH2CH2), 43.8 (CH2CH2CH2-NH), 50.2 (N-CH2CH2CH2), 53.5 (CH-Cl), 63.9 (N-CH), 111.3 (C-2), 117.4 2C-9, C-11), 120.5 (C-5), 124.4 (C-3), 127.5 (C-8, C-12), 128.6 (C-4), 131.4 (C-7), 133.5 (C-6), 145.6 (C-1), 155.2 (C-10),
163.7	(CO), 172.4 (CO cyclic). Anal. Calcd for C19H18N5O3Cl: C, 57.07; H, 4.53; N, 17.51. Found: C, 56.91; H, 4.47; N, 17.45. MS-FAB: 399 (M+).
N - [3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-2-(3-hy droxyphenyl)-3-chloro-4-oxo-1-azetidinecarboxamide (4r). Yield: 63%; mp 80-81 °C; IR v 1185 (C-O), 1362 (C-NH), 1765 (CO cyclic), 2925 (CH-Cl), 3469 (OH) cm-1. 1H NMR 5 2.25 (m, 2H, CH2CH2CH2), 3.40 (t, 2H, J = 7.7 Hz, CH2CH2CH2-NH), 4.26 (-, 2H, J = 7.7 Hz, N-CH2CH2CH2), 4.22 (s, 1H, OH), 4.58 (d, 1H, J = 5.2 Hz, CH-Cl), 5.45 (d, 1H, J = 5.2 Hz, N-CH), 5.74 (s, 1H, NH), 7.12-8.13 (m, 8H, ArH). 13C NMR 5 37.8 (CH2CH2CH2), 43.9 (CH2CH2CH2-NH), 49.8 (N-CH2CH2CH2), 51.2 (CH-Cl), 64.7 2N-CH), 111.9 (C-2), 113.6 (C-8), 116.6 (C-10), 118.6 (C-12), 120.5 (C-5), 124.6 (C-3), 128.7 (C-4), 130.9 (C-11), 132.7 (C-6), 139.9 (C-7), 146.8 (C-1), 156.3 (C-9), 165.7 (CO),
173.8	(CO cyclic). Anal. Calcd for C19H18N5O3Cl: C, 57.07; H, 4.53; N, 17.51. Found: C, 56.79; H, 4.35; N, 17.39. MS-FAB: 399 (M+).
N - [3-(1#-1,2,3-Benzotriazol-1-yl)propyl]-2-(2-hy droxyphenyl)-3-chloro-4-oxo-1-azetidinecarboxamide (4s). Yield: 61%; mp 77-78 °C; IR v 1186 (C-O), 1359 (C-NH), 1755 (CO cyclic), 2917 (CH-Cl), 3459 (OH) cm-1. 1H NMR 5 2.26 (m, 2H, CH2CH2CH2), 3.32 (t, 2H, J = 7.7 Hz, CH2CH2CH2-NH), 4.22 (-, 2H, J = 7.7 Hz, N-CH2CH2CH2), 4.25 (s- 1H, OH), 4.62 (d, 1H, J = 5.2 Hz, CH-Cl), 5.51 (d, 1H, J = 5.2 Hz, N-CH), 5.76 (s, 1H,
NH), 7.19-8.21 (m, 8H, ArH). 13C NMR 5 38.9 (CH2CH2CH2), 43.1 (CH2CH2CH2-NH), 49.6 (N-CH2CH2CH2), 54.5 (CH-Cl), 63.6 2N-CH), 113.7 (C-2), 114.8 (C-9), 120.5 (C-5), 122.6 (C-11), 124.5 (C-3), 125.6 (C-7), 127.8 (C-12), 128.5 (C-4), 130.6 (C-10), 133.5 (C-6), 146.6 (C-1), 154.6 (C-8), 163.6 (CO), 173.2 (CO cyclic). Anal. Calcd for C19H18N5O3Cl: C, 57.07; H, 4.53; N, 17.51. Found: C, 56.81; H, 4.46; N, 17.43. MS-FAB: 399 (M+).
6. Pharmacological Experimental Section
The synthesized compounds were screened against some selected microorganisms and determined their percentage inhibition zones. The percentage inhibition zone values were determined using the filter paper disc diffusion method and the concentrations have been used in ppm. All the final synthesized compounds 4a-s have been screened in vitro for their antibacterial activity against Bacillus subtilis, Escherichia coli and Staphylococcus au-reus and antifungal activity against Aspergillus niger, As-pergillus flavus, Candida albicans. Streptomycin and gri-seofulvin were used as standards for antibacterial and an-tifungal activity, respectively, and also screened under the similar conditions for comparison. The antitubercular activity was screened against the M. tuberculosis. For the antitubercular activity isoniazid and rifampicin were used as standards and also screened under the similar conditions for comparison.
6. 1. Antibacterial Activity
The antibacterial activity of compounds 4a-s has been assayed in vitro at two concentrations (50 and 100 ppm) against B. subtilis, E. coli and S. aureus. The percentage inhibition zones of the compounds 4a-s were determined by the filter paper disc diffusion method. Streptomycin used as standard showed 100% inhibition at both above concentrations. The percentage inhibition zones of the tested compounds are given in Table 1.
Table 1. In vitro antibacterial activity of compounds 4a-s and their inhibition zone (%).
Comp. B. subtilis	E. coli	S. aureus
50 ppm 100 ppm 50 ppm 100 ppm 50 ppm 100 ppm
4a	35	52	29	42	32	47
4b	47	78	53	75	42	65
4c	40	65	48	59	42	64
4d	64	76	61	76	47	62
4e	58	72	57	69	54	70
4f	55	77	54	66	55	70
4g	62	76	60	68	58	78
4h	26	62	67	82	64	82
4i	24	71	56	78	62	80
4j	27	73	54	79	70	86
4k	38	55	40	52	32	45
41	50	60	41	56	30	42
4m	48	58	43	53	30	48
4n	47	55	38	52	31	44
4o	40	52	32	48	29	48
4p	41	54	35	50	38	48
4q	44	62	45	64	41	59
4r	48	68	48	66	40	62
4s	40	62	43	60	46	62
Streptomycin used as standard showed 100% inhibition at both 50 and 100 ppm.
6. 2. Antifungal Activity
The antifungal activity of compounds 4a-s has been assayed in vitro at two concentrations (50 and 100 ppm) against A. niger, A. flavus and C. albicans. The percentage inhibition zones of the compounds 4a-s were determined by the using filter paper disc diffusion method. Griseoful-vin used as standard showed 100% inhibition at both above concentrations. The percentage inhibition zones of the tested compounds are given in Table 2.
Table 2. In vitro antifungal activity of compounds 4a-s and their inhibition zone (%).
Comp. A. niger	A. flavus	C. albicans
50 ppm 100 ppm 50 ppm 100 ppm 50 ppm 100 ppm
4a	38	50	40	50	30	49
4b	50	68	58	70	45	63
4c	43	65	40	65	42	62
4d	58	76	48	73	50	70
4e	50	72	59	71	51	66
4f	50	77	50	67	58	65
4g	45	76	44	56	50	62
4h	60	82	53	78	54	69
4i	61	81	54	75	52	70
4j	60	86	55	72	50	72
4k	40	54	30	44	38	47
41	45	52	30	48	45	52
4m	40	59	31	46	38	48
4n	39	48	24	38	29	44
4o	30	45	25	34	28	40
4p	33	48	27	32	28	38
4q	36	52	33	54	36	49
4r	42	59	41	58	54	62
4s	40	52	43	50	46	52
Griseofulvin used as standard showed 100% inhibition at both 50 and 100 ppm.
6. 3. Antitubercular Activity
The synthesized compounds 4a-s were screened against M. tuberculosis using L. J. medium (conventional)
method at two concentration (50 and 100 ppm) against M. tuberculosis H37Rv strain. The results are shown in Table 3. The standard antitubercular drugs isoniazid and rifam-picin were taken as standards showing 100% inhibition at both above concentrations.
Table 3. Antitubercular percentage inhibition activity at 50 ng/mL concentration.
Comp. % Comp. % Comp. % Comp. % Comp. %
activity activity activity activity activity
4a	59	4e	85	4i	79	4m	63	4q	55
4b	78	4f	8G	4j	8G	4n	6G	4r	75
4c	82	4g	76	4k	72	4o	55	4s	6G
4d	84	4h	8G	4l	7G	4p	52		
Isoniazid and rifampicin were used as standard showed 100% inhibition at both 50 and 100 ppm.
7. Acknowledgement
The authors are thankful to SAIF, Central Drugs Research Institute Lucknow (India) for providing spectral and analytical data of the compounds. We are thankful to Head, Department of Biotechnology, Dr. H. S. Gour, University (A Central University), Sagar (India) for antimicrobial (antibacterial and antifungal) and Microcare laboratory and Tuberculosis Research Center Surat, Gujarat (India) for antituberculosis activity. We are also thankful to Head, Department of Chemistry Dr. H. S. Gour, University (A Central University), Sagar (India) for giving the facilities to carryout the work.
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Povzetek
Za klasično sintezo nove serije N-[3-(1H-1,2,3-benzotriazol-1-il)propil]-2-(4-substituiranih fenil)-3-kloro-4-okso-1-azetidinekarboksamidov 4a-s smo kot izhodno spojino uporabili 1,2,3-benzotriazol. Spojinam 4a-s smo določili delovanje proti bakterijam, glivam in tuberkulozi. Strukture pripravljenih spojin smo potrdili s kemijsko analizo in spektroskopskimi metodami kot so IR, 1H NMR, 13C NMR ter FAB masno spektroskopijo.