A Rapid, Convenient
Microwave assisted and Conventional Synthesis of novel azetidin-2-one derivatives
as Potent Antimicrobial agents
Jignesh P Raval1*,
Hemul V Patel1, Pradip
S. Patel1, Nilesh H Patel1 and Kishor R Desai2
1Department of Pharmaceutical Chemistry, Ashok and Rita Patel Institute of Integrated Study and Research in Biotechnology and Allied Sciences, New Vallabh vidyanagar (Gujarat-India)
2Department of Chemistry, Veer Narmad South Gujarat University, Udhna-Magdalla Road, Surat (Gujarat-India).
*Corresponding Author E-mail: drjpraval@yahoo.co.in, drjpraval@hotmail.com
ABSTRACT
We report efficient and extremely fast procedures for the synthesis of 3-chloro-4-(4-(diethylamino)-2-hydroxyphenyl)-1-(substitutedphenyl)-azetidin-2-one using 4-diethylamino-2-hydroxybenzaldehyde, various amines and chloroacetyl chloride in presence of triethylamine under microwave irradiation (μw) and similarly, conventional methods are used for comparison. A considerable increase in the reaction rate has been observed with better yield in microwave technique. The structures of the compounds were confirmed by elemental analysis and spectral analysis (1H-NMR, 13C-NMR and Mass). All the compounds have been screened for their antifungal activity and their antibacterial activity against various gram +ve and gram –ve bacteria.
KEY WORDS: 4-diethylamino-2-hydroxybenzaldehyde, azetidin-2-one, Microwave method, antimicrobial activity.
INTRODUCTION:
Recently, Microwave heating has emerged as a powerful technique to promote a variety of chemical reactions1. Microwave reactions under solvent-free conditions are attractive in offering reduced pollution, low cost and offer high yields together with simplicity in processing and handling2. The recent introduction of single-mode technology3 assures safe and reproducible experimental procedures and microwave synthesis has gained acceptance and popularity among the synthetic chemist community. The application of microwave irradiation to organic synthesis has been the focus of considerable attention in recent years and is becoming an increasingly popular technology4. Microwave irradiation has been also applied to carry out synthesis in open vessel5, using organic solvents such as ethanol, N,N–Dimethylformamide(DMF), 1,2–Dichloroethane (DCE), 1,2–dichlorobenzene etc. as energy transfer media which absorb microwave energy efficiently through dipole rotation. The salient features of microwave approach are shorter reaction times, simple reaction conditions and enhancements in chemical yields6,7,
further more it allows reaction in open vessels and synthesis on preparative scales. Under the work of Green Chemistry and in continuation to our earlier work8,9 on the application of
microwaves to organic synthesis we have developed an environmentally benign method for synthesizing azetidin-2-one, 4a–r(Scheme 1) and hope to obtain a few compounds having better anti–bacterial and anti–fungal activities.
The synthesis of novel 3-chloro-4-(4-(diethylamino)-2-hydroxyphenyl)-1-(substituted phenyl)-azetidin-2-one, 4a–r is achieved by cycloaddtion of Schiff base of 4-diethylamino-2-hydroxybenzaldehyde and various aromatic amines with chloroacetyl chloride in presence of catalytic amount of tiethylamine under microwaves irradiation (Scheme-1). The same compounds have been also synthesized using conventional approach. A comparative study9 in terms of yield and reaction period is also reported using conventional method (Table–2, 3 and 4). The reaction carried out using conventional method requires about 6.0–8.0 hr, while microwave irradiation method requires only 2.0–3.0min10-12. All the compounds synthesized were characterized by elemental analysis, IR, 1H-NMR , 13C-NMR and Mass data(Table-1, 5 and 6).
EXPERIMENTAL:
All reagents, solvents and catalyst used are of analytical grade from a commercial source and used directly. All the melting points were determined in PMP-DM scientific melting point apparatus and are uncorrected. UV spectra are determined on Perkin Elmer model 550S spectrophotometer. IR spectra (υmax in cm-1) were recorded on a Shimadzu FT-IR 8300 spectrophotometer using KBr or Nujol technique; 1H-NMR spectra on a Bruker’s WM 400FT 400 MHz NMR instrument using CDCl3 or DMSO-d6 as solvent and TMS as internal reference (chemical shifts in δ, ppm); 13C-NMR on a Varian AMX 400 (100 MHz) spectrometer as solutions in CDCl3 and Mass spectra on a Jeol JMS D-300 spectrometer operating at 75 eV. Column chromatography was performed with silica gel 60 (70-230 mesh) purchased from E. Merck AG. The purities of
the obtained substances and the composition of the reaction mixtures were monitoring by thin layer chromatography on silica gel 60 F254 plates (Merck) with fluorescent indicator (Merck No. 5554). Solvents and common reagents obtained from Merck and Aldrich, were reagent grade. The elemental analysis (C, H, N) of compounds was performed on Carlo Erba-1108 elemental analyzer. The values established by elemental analysis were within = 0.4% in comparison to calculated values. The microwave assisted reactions are carried out in a “QPro-M Microwave Synthesis System” manufactured by Questron Technologies Corporation, Ontario L4Z 2E9, Canada, where in microwaves are generated by magnetron at a frequency of 2450 MHz having an output energy range of 100 to 500 watts and individual sensor for temperature control with
|
Table – 1 : Analytical and Characterisation data of compounds 4a – r. |
||||||
|
Cpd No. |
R |
m.p. (oC) |
Molecular formula |
% Elemental Analysis Calcd. (Found) |
||
|
C |
H |
N |
||||
|
4a |
H |
154-58 |
C19H21 N2O2Cl |
66.18 (66.11) |
6.14 (6.11) |
8.12 (8.01) |
|
4b |
2 – CH3 |
178-82 |
C20H23 N2O2Cl |
67.94 (67.49) |
6.46 (6.29) |
7.81 (7.78) |
|
4c |
3 – CH3 |
180-84 |
C20H23 N2O2Cl |
67.94 (67.41) |
6.46 (6.18) |
7.81 (7.68) |
|
4d |
4 – CH3 |
200-01 |
C20H23 N2O2Cl |
67.94 (67.77) |
6.46 (6.34) |
7.81 (7.72) |
|
4e |
2 – Cl |
181-84 |
C19H20 N2O2Cl2 |
60.17 (60.11) |
5.32 (5.21) |
7.39 (7.21) |
|
4f |
3 – Cl |
178-80 |
C19H20 N2O2Cl2 |
60.17 (60.09) |
5.32 (5.27) |
7.39 (7.32) |
|
4g |
4 – Cl |
198-01 |
C19H20 N2O2Cl2 |
60.17 (60.07) |
5.32 (5.29) |
7.39 (7.34) |
|
4h |
2,4 – (Cl)2 |
177-79 |
C19H19 N2O2Cl3 |
55.16 (55.12) |
4.63 (4.79) |
6.77 (6.84) |
|
4i |
2,5 – (Cl)2 |
155-57 |
C19H19 N2O2Cl3 |
55.16 (55.09) |
4.63 (4.81) |
6.77 (6.83) |
|
4j |
2 – NO2 |
133-35 |
C19H20 N3O4Cl |
58.54 (58.69) |
5.17 (5.27) |
10.78 (10.71) |
|
4k |
3 – NO2 |
145-46 |
C19H20 N3O4Cl |
58.54 (58.71) |
5.17 (5.29) |
10.78 (10.71) |
|
4l |
4 – NO2 |
188-90 |
C19H20 N3O4Cl |
58.54 (58.72) |
5.17 (5.29) |
10.78 (10.77) |
|
4m |
2 – OCH3 |
165-67 |
C20H23 N2O3Cl |
64.08 (64.09) |
6.18 (6.11) |
7.47 (7.41) |
|
4n |
3 – OCH3 |
157-58 |
C20H23 N2O3Cl |
64.08 (64.11) |
6.18 (6.14) |
7.47 (7.61) |
|
4o |
4 – OCH3 |
178-80 |
C20H23 N2O3Cl |
64.08 (64.19) |
6.18 (6.18) |
7.47 (7.72) |
|
4p |
3,4 – (OCH3)2 |
185-87 |
C21H25 N2O4Cl |
62.30 (62.31) |
6.22 (6.21) |
6.92 (6.91) |
|
4q |
3 – Br |
193-95 |
C19H20 N2O2BrCl |
53.86 (53.77) |
4.76 (4.82) |
6.61 (6.69) |
|
4r |
4 – F |
210-12 |
C19H20 N2O2ClF |
62.90 (62.69) |
5.56 (5.79) |
7.72 (7.77) |
|
Table – 2: Comparison of Conventional and Microwave synthesis for 4a – r. |
|||||||
|
Compd. |
Conventional method |
Microwave method |
|||||
|
% yield |
t/hrs |
% yield |
t1/min |
p1/watt |
t2/min |
p2/watt |
|
|
4a |
65-67 |
3 |
91-93 |
3.0 |
350 |
2.0 |
500 |
|
4b |
72-74 |
2.5 |
89-91 |
2.5 |
350 |
2.0 |
500 |
|
4c |
65-67 |
2.5 |
92-93 |
2.5 |
350 |
2.0 |
500 |
|
4d |
72-74 |
2.5 |
91-92 |
3.0 |
350 |
2.0 |
500 |
|
4e |
65-67 |
2.5 |
88-90 |
3.0 |
350 |
2.0 |
500 |
|
4f |
72-74 |
2.5 |
92-93 |
2.5 |
350 |
2.1 |
500 |
|
4g |
65-66 |
2.5 |
91-93 |
2.5 |
350 |
2.2 |
500 |
|
4h |
72-74 |
2.5 |
87-89 |
2.5 |
350 |
2.0 |
500 |
|
4i |
65-66 |
2.5 |
85-87 |
3.0 |
350 |
2.2 |
500 |
|
4j |
72-74 |
2.5 |
90-91 |
3.0 |
350 |
2.0 |
500 |
|
4k |
65-67 |
3 |
86-87 |
3.0 |
350 |
2.2 |
500 |
|
4l |
72-73 |
3 |
91-93 |
3.0 |
350 |
2.0 |
500 |
|
4m |
65-66 |
2.5 |
82-84 |
2.5 |
350 |
2.2 |
500 |
|
4n |
72-73 |
2.5 |
91-93 |
3.0 |
350 |
2.0 |
500 |
|
4o |
65-66 |
2.5 |
81-83 |
3.0 |
350 |
2.2 |
500 |
|
4p |
72-74 |
2.5 |
95-96 |
3.0 |
350 |
2.0 |
500 |
|
4q |
65-65 |
2.5 |
87-89 |
2.5 |
350 |
2.2 |
500 |
|
4r |
72-74 |
2.5 |
91-93 |
2.5 |
350 |
2.0 |
500 |
|
Table – 3 : The Effect of Microwave Irradiation Power* for 4a |
||||||
|
Irradiation Power(W) |
250 |
300 |
350 |
400 |
450 |
500 |
|
Yield |
75 |
77 |
82 |
83 |
89 |
92 |
|
* Irradiation time is 2 min |
||||||
|
Table – 4 : The Effect of Microwave Irradiation Time* for 4a |
||||||
|
Irradiation time(min) |
5.0 |
4.5 |
4.0 |
3.0 |
2.5 |
2.0 |
|
Yield |
75 |
77 |
82 |
83 |
89 |
92 |
|
* Irradiation power is 500 W |
||||||
Table – 5: IR and 1NMR Spectral data of
compound 4a – r
|
||
|
Compd. No |
IR-Spectra(cm-1 KBr-pellets) |
1NMR – Spectra (CDCl3 – DMSO - D6 ) ( d ppm) |
|
4a |
3359, 3035, 2977, 1769, 1660, 1560, 690 |
1.31 (t,3H, J = 6.9, N(CH2CH3)2), 4.13 (q, 2H, J = 7.0, N(CH2CH3)2), 4.95 ( d, ,1H, J = 9, – N – CH ), 6.64( d, 1H, J = 9.1, – CH – Cl), 7.40 – 7.85 ( m, 8H, Ar – H), 12.85 ( s, 1H, - OH). |
|
4b |
3350, 3030, 2980, 2950, 1767, 1660, 1560, 1310, 687 |
1.28 (t,3H, J = 7.0, N(CH2CH3)2), 4.11 (q, 2H, J = 7.0, N(CH2CH3)2), 2.03 (s, 3H, CH3), 2.20 (s, 3H, Ar – CH3), 4.92 ( d, ,1H, J = 9, – N – CH ), 6.64( d, 1H, J = 9.1, – CH – Cl), 7.20 – 7.65 ( m, 7H, Ar – H), 12.85 ( s, 1H, - OH). |
|
4c |
3350, 3037, 2980, 2945, 1769, 1660, 1560, 1315, 687 |
1.29 (t,3H, J = 7.0, N(CH2CH3)2), 4.11 (q, 2H, J = 7.1, N(CH2CH3)2), 2.00 (s, 3H, CH3), 2.18 (s, 3H, Ar – CH3), 4.92 ( d, ,1H, J = 9, – N – CH ), 6.64( d, 1H, J = 9.1, – CH – Cl), 7.20 – 7.65 ( m, 7H, Ar – H), 12.85 ( s, 1H, - OH). |
|
4d |
3360, 3039, 2980, 2950, 1760, 1660, 1560, 1310, 687 |
1.30 (t,3H, J = 7.0, N(CH2CH3)2), 4.11 (q, 2H, J = 7.0, N(CH2CH3)2), 2.00 (s, 3H, CH3), 2.15 (s, 3H, Ar – CH3), 4.92 ( d, ,1H, J = 9, – N – CH ), 6.62( d, 1H, J = 9.1, – CH – Cl), 7.20 – 7.65 ( m, 7H, Ar – H), 12.82 ( s, 1H, - OH). |
|
4e |
3367, 3040, 2985, 1765, 1667, 1569, 695 |
1.34 (t,3H, J = 6.7, N(CH2CH3)2), 4.12 (q, 2H, J = 7.0, N(CH2CH3)2), 4.92 ( d, ,1H, J = 9, – N – CH ), 6.62( d, 1H, J = 9.1, – CH – Cl), 7.60 – 7.80 ( m, 7H, Ar – H), 12.82 ( s, 1H, - OH). |
|
4f |
3350, 3040, 2989, 1767, 1669, 1568, 695 |
1.35 (t,3H, J = 6.7, N(CH2CH3)2), 4.12 (q, 2H, J = 7.1, N(CH2CH3)2), 4.94 ( d, ,1H, J = 9, – N – CH ), 6.62( d, 1H, J = 9.1, – CH – Cl), 7.60 – 7.80 ( m, 7H, Ar – H), 12.82 ( s, 1H, - OH). |
|
4g |
3350, 3030, 2980, 1760, 1660, 1560, 680.
|
1.34 (t,3H, J = 6.7, N(CH2CH3)2), 4.12 (q, 2H, J = 6.9, N(CH2CH3)2), 4.90 ( d, ,1H, J = 9, – N – CH ), 6.60( d, 1H, J = 9.1, – CH – Cl), 7.40 – 7.85 ( m, 7H, Ar – H), 12.80 ( s, 1H, - OH). |
|
4h |
3360, 3040, 2990, 1770, 1667, 1570, 695 |
1.35 (t,3H, J = 7.0, N(CH2CH3)2), 4.15 (q, 2H, J = 7.0, N(CH2CH3)2), 4.95 ( d, ,1H, J = 9, – N – CH ), 6.62( d, 1H, J = 9.1, – CH – Cl), 7.70 – 7.90 ( m, 6H, Ar – H), 12.84 ( s, 1H, - OH). |
|
4i |
3367, 3040, 2985, 1760, 1660, 1570, 699 |
1.35 (t,3H, J = 7.0, N(CH2CH3)2), 4.14 (q, 2H, J = 7.1, N(CH2CH3)2), 4.95 ( d, ,1H, J = 9, – N – CH ), 6.65( d, 1H, J = 9.1, – CH – Cl), 7.70 – 7.90 ( m, 6H, Ar – H), 12.84 ( s, 1H, - OH). |
attachment of reflux condenser with constant stirring (thus avoiding the risk of high pressure development) and synthesis on preparative scales.
Method for preparation of 4-diethylamino-2-hydroxybenzaldehyde(1):
The starting compound was synthesized according to reported literature13.
Representative process: Conventional Preparation of Schiff’s Base derivatives (3a-r):
The starting compound was synthesized according to reported literature14.
Equimolar amount of 4-diethylamino-2-hydroxybenzaldehyde (1) (1.93 g, 0.01 mole) and 4–chloroaniline(2g) (1.27 g, 0. 01 mole) was refluxed in ethanol (10 mL) in the presence of catalytic amount of acetic acid for 2.5-3.0 hrs. On cooling the reaction
mixture a yellow solid was crystallized from dimethylformamide – ethanol mixture (60:40).
Representative process: Microwave Preparation of Schiff’s Base derivatives (3a–r):
Equimolar amount of 4-diethylamino-2-hydroxybenzaldehyde (1) (1.93g, 0.01mole), 4–chloroaniline (2g) (1.27 g, 0. 01 mole) and ethanol (10 mL) in the presence of catalytic amount of acetic acid(1mL) were put in an Erlenmeyer flask and irradiated under microwaves in two stages (t1= 2.5-3.0 min and t2 = 2.0-2.5 min) at two different power levels (p1 = 350w and p2 = 500w) respectively. (Table 2)8,15. Upon completion of reaction (monitored by tlc), The solvent was removed, and the residue was recrystallized from dimethylformamide–ethanol mixture (60: 40) to give yellow solid. C17H19N2ClO; M.p. 110–112C. IR-Spectra(cm-1 KBr-pellets): 1626(-N=CH-), 2990(Alkyl CH stretching), 3370 (OH stretching), 3030(Aromatic CH stretching); 1NMR–Spectra (CDCl3–DMSO-d6)(
|
Table – 5 : Continue……….. |
||
|
Compd. No |
IR-Spectra(cm-1 KBr-pellets) |
1NMR – Spectra (CDCl3 – DMSO - D6 ) ( d ppm) |
|
4j |
3350, 3030, 2980, 1760, 1660, 1560, 1500,1340, 685 |
1.28 (t,3H, J = 7.0, N(CH2CH3)2), 4.12 (q, 2H, J = 7.1, N(CH2CH3)2), 4.95 ( d, ,1H, J = 9, – N – CH ), 6.65( d, 1H, J = 9.1, – CH – Cl), 7.45 – 7.80 ( m, 7H, Ar – H), 12.84 ( s, 1H, - OH). |
|
4k |
3340, 3035, 2985, 1750, 1650, 1545, 1505,1345,685 |
1.29 (t,3H, J = 7.0, N(CH2CH3)2), 4.11 (q, 2H, J = 7.1, N(CH2CH3)2), 4.95 ( d, ,1H, J = 9, – N – CH ), 6.66( d, 1H, J = 9.1, – CH – Cl), 7.45 – 7.80 ( m, 7H, Ar – H), 12.85 ( s, 1H, - OH). |
|
4l |
3345, 3030, 2985, 1755, 1655, 1560, 1510,1350,685 |
1.28 (t,3H, J = 7.0, N(CH2CH3)2), 4.11 (q, 2H, J = 7.1, N(CH2CH3)2), 4.94 ( d, ,1H, J = 9, – N – CH ), 6.66( d, 1H, J = 9.1, – CH – Cl), 7.45 – 7.80 ( m, 7H, Ar – H), 12.83 ( s, 1H, - OH). |
|
4m |
3340, 3030, 2990, 1760, 1655, 1560, 1250, 680 |
1.30 (t,3H, J = 6.9, N(CH2CH3)2), 4.09 (q, 2H, J = 7.1, N(CH2CH3)2), 3.82 (s, 3H, OCH3), 4.94 ( d, ,1H, J = 9, – N – CH ), 6.66( d, 1H, J = 9.1, – CH – Cl), 7.60 – 7.95 ( m, 7H, Ar – H), 12.84 ( s, 1H, - OH). |
|
4n |
3350, 3035, 2980, 1770, 1650, 1560, 1240, 680 |
1.31 (t,3H, J = 6.9, N(CH2CH3)2), 4.09 (q, 2H, J = 7.1, N(CH2CH3)2), 3.80 (s, 3H, OCH3), 4.92 ( d, ,1H, J = 9, – N – CH ), 6.66( d, 1H, J = 9.1, – CH – Cl), 7.60 – 7.95 ( m, 7H, Ar – H), 12.86 ( s, 1H, - OH). |
|
4o |
3345, 3030, 2977, 1770, 1650, 1570, 1245, 680 |
1.31 (t,3H, J = 6.9, N(CH2CH3)2), 4.09 (q, 2H, J = 7.1, N(CH2CH3)2), 3.80 (s, 3H, OCH3), 4.94 ( d, ,1H, J = 9, – N – CH ), 6.66( d, 1H, J = 9.1, – CH – Cl), 7.60 – 7.95 ( m, 7H, Ar – H), 12.86 ( s, 1H, - OH). |
|
4p |
3352, 3034, 2984, 1767, 1668, 1577, 1250, 680 |
1.31 (t,3H, J = 6.7, N(CH2CH3)2), 4.10 (q, 2H, J = 7.1, N(CH2CH3)2), 3.90 (s, 6H, OCH3), 4.94 ( d, ,1H, J = 9, – N – CH ), 6.62( d, 1H, J = 9.1, – CH – Cl), 7.60 – 7.95 ( m, 6H, Ar – H), 12.86 ( s, 1H, - OH) |
|
4q |
3350, 3035, 2989, 1769, 1670, 1560, 680, 603 |
1.33 (t,3H, J = 6.9, N(CH2CH3)2), 4.13 (q, 2H, J = 7.1, N(CH2CH3)2), 4.92 ( d, ,1H, J = 9, – N – CH ), 6.62( d, 1H, J = 9.1, – CH – Cl), 7.30 – 7.90 ( m, 7H, Ar – H), 12.84 ( s, 1H, - OH). |
|
4r |
3359, 3037, 2985, 1765, 1667, 1569, 1045, 680 |
1.35 (t,3H, J = 7.0, N(CH2CH3)2), 4.11 (q, 2H, J = 7.0, N(CH2CH3)2), 4.92 ( d, ,1H, J = 9, – N – CH ), 6.62( d, 1H, J = 9.1, – CH – Cl), 7.40 – 7.95 ( m, 7H, Ar – H), 12.86 ( s, 1H, - OH). |
Table – 6: UV, MS data and 13C - NMR – Spectra data of compound 4a – r |
|||
|
Compd. No |
uv (DMF) l max in nm |
MS (m/z) ; [M+] |
13C - NMR – Spectra (CDCl3 – DMSO - D6 ) ( d ppm) |
|
4a |
310 |
345 |
12.91(N(CH2CH3)2), 40.20(N(CH2CH3)2), 171.61 (cyclic, >C=O), 60.00 (>CH-N<), 51.00 (>CH-Cl), 129.70 – 139.07 (Ar – C) |
|
4b |
285 |
358 |
13.01(N(CH2CH3)2), 40.21(N(CH2CH3)2), 35.11 (CH3), 171.79 (cyclic, >C=O), 59.10 (>CH-N<), 49.18 (>CH-Cl), 121.81 – 143.04 (Ar – C) |
|
4c |
278 |
358 |
13.11(N(CH2CH3)2), 40.22(N(CH2CH3)2), 35.55 (CH3), 171.00 (cyclic, >C=O), 59.19 (>CH-N<), 49.88 (>CH-Cl), 127.91 – 142.77 (Ar – C) |
|
4d |
297 |
358 |
13.02(N(CH2CH3)2), 40.22(N(CH2CH3)2), 35.99 (CH3), 171.79 (cyclic, >C=O), 58.10 (>CH-N<), 49.19 (>CH-Cl), 124.09 – 149.99 (Ar – C) |
|
4e |
332 |
379 |
12.90(N(CH2CH3)2), 40.27(N(CH2CH3)2), 177.29 (cyclic, >C=O), 57.10 (>CH-N<), 47.78 (>CH-Cl), 124.37 – 137.71 (Ar – C) |
|
4f |
324 |
379 |
12.93(N(CH2CH3)2), 40.25(N(CH2CH3)2), 177.17 (cyclic, >C=O), 57.01 (>CH-N<), 47.77 (>CH-Cl),124.35 – 137.77 (Ar – C) |
|
4g |
335 |
379 |
12.97(N(CH2CH3)2), 40.26(N(CH2CH3)2), 179.19 (cyclic, >C=O), 57.99 (>CH-N<), 47.78 (>CH-Cl), 125.34 – 133.99 (Ar – C) |
|
4h |
291 |
413 |
13.91(N(CH2CH3)2), 40.21(N(CH2CH3)2), 177.70 (cyclic, >C=O), 58.89 (>CH-N<), 49.00 (>CH-Cl), 127.86 – 139.29 (Ar – C) |
|
4i |
295 |
413 |
13.97(N(CH2CH3)2), 40.22(N(CH2CH3)2), 177.99 (cyclic, >C=O), 59.89 (>CH-N<), 49.11 (>CH-Cl), 120.96 – 149.99 (Ar – C) |
ppm) : 1.42(t,3H, J=6.8, N(CH2CH3)2), 4.29(q, 2H, J=7.1, N(CH2CH3)2), 5.38(s, 1H, CH=N ), 6.97–7.71(m, 7H, Ar–H), 11.09( s, 1H, OH).
Similarly, other compounds 3b–r were prepared in the above manner.
Representative process: Conventional Preparation of azetidin-2-one, 4a-r
A mixture of (3a) (0.01 mole) in benzene and chloroacetylchloride (0.01 mole) with a catalytic amount of triethylamine (1mL) was taken in a RBF. It was refluxed for 5 hr on a steam-bath. After completion of reaction (monitored by TLC). The benzene was distilled off to get product (4a). The solid product was filtered, dried and recrystallized from ethanol.
Table – 6: Continue……. |
|||
|
Compd. No |
uv (DMF) l max in nm |
MS (m/z) ; [M+] |
13C - NMR – Spectra (CDCl3 – DMSO - D6 ) ( d ppm) |
|
4j |
289 |
389 |
12.71(N(CH2CH3)2), 40.21(N(CH2CH3)2), 179.70 (cyclic, >C=O), 62.00 (>CH-N<), 48.18 (>CH-Cl), 111.18 – 196.84 (Ar – C) |
|
4k |
291 |
389 |
12.67(N(CH2CH3)2), 40.27(N(CH2CH3)2), 179.89 (cyclic, >C=O), 62.81 (>CH-N<), 48.77 (>CH-Cl), 111.19 – 196.84 (Ar – C) |
|
4l |
298 |
389 |
12.77(N(CH2CH3)2), 40.29(N(CH2CH3)2), 179.77 (cyclic, >C=O), 61.99 (>CH-N<), 47.89 (>CH-Cl), 111.79 – 196.84 (Ar – C) |
|
4m |
320 |
374 |
13.02(N(CH2CH3)2), 40.17(N(CH2CH3)2), 172.00 (cyclic, >C=O), 62.09 (>CH-N<), 50.19 (>CH-Cl), 58.69 (OCH3) 128.97 – 134.99 (Ar – C) |
|
4n |
300 |
374 |
13.07(N(CH2CH3)2), 40.18(N(CH2CH3)2), 172.11 (cyclic, >C=O), 62.19 (>CH-N<), 50.79 (>CH-Cl), 59.97 (OCH3) 129.91 – 139.89 (Ar – C) |
|
4o |
295 |
374 |
13.09(N(CH2CH3)2), 40.19(N(CH2CH3)2), 172.18 (cyclic, >C=O), 62.77 (>CH-N<), 50.99 (>CH-Cl), 59.22 (OCH3) 128.19 – 137.97 (Ar – C) |
|
4p |
277 |
404 |
13.11(N(CH2CH3)2), 40.21(N(CH2CH3)2), 177.77 (cyclic, >C=O), 61.89 (>CH-N<), 51.10 (>CH-Cl), 57.71 (OCH3) 124.19 – 139.77 (Ar – C) |
|
4q |
301 |
423 |
13.99(N(CH2CH3)2), 40.29(N(CH2CH3)2), 177.81 (cyclic, >C=O), 55.79 (>CH-N<), 51.08 (>CH-Cl), 128.30 – 154.19 (Ar – C) |
|
4r* |
298 |
362 |
12.91(N(CH2CH3)2), 40.20(N(CH2CH3)2), 179.99 (cyclic, >C=O), 59.99 (>CH-N<), 52.11 (>CH-Cl), 117.99 – 165.99 (Ar – C), J F – C = 2.8 Hz |
|
* 13C NMR Spectra was done on the basis of the long – range coupling constants 4J (C-F) in the fluorinated derivative Vr. |
|||
|
Compd. No |
Table – 7: In vitro antimicrobial activity of 4a-r. |
|||||||||
|
MIC, µg/mL |
||||||||||
|
B.s |
S.a |
S.p |
E.c |
S.f |
P.a |
C.v |
C.a |
A.n |
||
|
4a |
++ |
++++ |
++++ |
++++ |
+++ |
++ |
++ |
+++ |
+++ |
|
|
4b |
+ |
+++ |
+++ |
+++ |
+ |
++ |
+++ |
++ |
++ |
|
|
4c |
++ |
+++ |
+++ |
++ |
++ |
+ |
++ |
++ |
++ |
|
|
4d |
++ |
++ |
+++ |
++ |
++ |
++ |
+ |
+++ |
++ |
|
|
4e |
+++ |
+ |
++ |
++ |
++ |
++ |
++ |
++ |
++ |
|
|
4f |
+ |
++ |
+++ |
+++ |
+++ |
+++ |
+ |
+ |
++ |
|
|
4g |
++ |
+++ |
+++ |
+ |
+++ |
+++ |
++ |
++ |
++ |
|
|
4h |
++ |
+++ |
+++ |
++ |
+ |
+++ |
++ |
+ |
++ |
|
|
4i |
+ |
++ |
+++ |
++ |
+ |
++ |
+ |
++ |
++ |
|
|
4j |
+ |
++ |
++ |
++ |
++ |
+ |
- |
+ |
- |
|
|
4k |
- |
+++ |
+ |
++ |
++ |
++ |
+ |
+++ |
++ |
|
|
4l |
++ |
+++ |
++ |
++ |
+++ |
++ |
++ |
++ |
++ |
|
|
4m |
- |
+++ |
++ |
++ |
+++ |
+++ |
+++ |
++ |
+++ |
|
|
4n |
+ |
+++ |
+ |
++ |
+ |
++ |
++ |
- |
- |
|
|
4o |
++ |
++ |
+ |
++ |
++ |
+++ |
++ |
++ |
+++ |
|
|
4p |
+ |
+ |
+++ |
++ |
+ |
+ |
+++ |
+ |
- |
|
|
4q |
+ |
++ |
+++ |
++ |
++ |
+ |
++ |
++ |
+++ |
|
|
4r |
++ |
++ |
+++ |
+++ |
++ |
+ |
+ |
++ |
+++ |
|
|
20 mg/mL = ++++, 50 mg/mL = +++, 100 mg/mL = ++, 150 mg/mL = + , Not active upto 200 mg/mL = – *Benzyl Penicillin, Streptomycine and Gentamycin £ 20 mg/mL |
||||||||||
|
B.s : Bacillus subtilis, S.a : Staphylococcus aureus, S.p : Salomonella paratyphi A |
E.c: Escherichia coli, P.a: Pseudomonas aerugenosa, S.f: Shigella flexneri, |
C.v: Cerevesae vitae, C.a: Candida albicans, A.n: Aspergillus niger |
||||||||
Representative process: Microwave Preparation of azetidin-2-one, 4a-r:
A mixture of (3a) (0.01 mole) in DMF and chloroacetylchloride (0.01 mole) with a catalytic amount of triethylamine (1mL) (as a reaction mediator)10 were put in an Erlenmeyer flask and irradiated under microwaves in two stages (t1= 3.0 to 3.5 min and t2 = 2.0 to 2.5 min) at two different power levels (p1 = 350w and p2 = 500w) at 120-125 oC respectively. (Table 2) 8,15. After completion of reaction (monitored by tlc.). It was then diluted with ice cold water. The separated solid was crystallized from methanol to give compound 4a
The minimum inhibitory concentrations (MIC) of various newly synthesized azetidin-2-one derivatives were tested against representative Gram-positive organisms viz. Bacillus subtilis, Staphylococcus aureus, and Gram-negative organisms viz. Salmonella paratyphi, Escherichia coli, Shigella flexneri, Pseudomonas auregenosa, and fungi such as Cerevesae vitae, Candida albicans, Aspergillus niger by broth dilution method recommended by National Committee for Clinical Laboratory (NCCL) standards16. Standard antimicrobial agents like Benzylpenicillin, Streptomycin and Gentamycin were also screened under identical conditions for comparison. The minimum inhibitory concentration (MIC) values are presented in Table-7. The MIC of the compounds was defined, as the lowest concentration at which there was 80% inhibition of growth compared with the growth for a drug free control. Standard inhibition of zone size for Benzylpenicillin, streptomycin and for Gentamycin is (++++) at ≤ 20 µgm/mL against all microbes.
RESULTS AND DISCUSSION:
Various Schiff’s Base derivatives 3a–r were prepared using 4-diethylamino-2-hydroxybenzaldehyde(1) and various aromatic amines which on cycloaddition with chloracetyl chloride in presence of triethylamine gave 3-chloro-4-(4-(diethylamino)-2-hydroxyphenyl)-1-(substituted phenyl)-azetidin-2-one, 4a–r. (Scheme 1).
All the reactions under microwave irradiation were completed within 2.0–3.5 min, whereas similar reactions under conventional heating (steam bath) at refluxed temperature gave poor yields with comparatively longer reaction time periods (Table 2), demonstrating that the effect of microwave irradiation is not purely thermal. Actually, Microwave irradiation facilitates the polarization of the molecules under irradiation causing rapid reaction to occur. This is consistent with the reaction mechanism, which involves a polar transition state6.
The impact of microwave irradiation and conventional heating for the synthesis of compound 3a–r and 4a–r has been compared. Moreover, the effects of irradiation power and time on the reaction were also studied and the results summarized in (Tables 1). The effects of irradiation power and time on the reaction were also studied and the results summarized in (Tables 3 and 4). It was found the higher yield of compounds 3a–r and 4a–r can be obtained in 500 watt for 2.0 – 2.5 min under microwave irradiation conditions. All the compounds synthesized were adequately characterized by their elemental analyses and spectral IR, 1H-NMR, 13C-NMR and Mass data. All, the structures of the above compounds were in good agreement with spectral and analytical data(Tables 1, 5 and 6)..
CONCLUSION:
A new method for the synthesis of 3-chloro-4-(4-(diethylamino)-2-hydroxyphenyl)-1-(substituted phenyl)-azetidin-2-one, 4a–r using microwave irradiation, offers significant improvements over existing procedures and thus helps facile entry into a synthesis of variety of azetidin-2-one derivatives. Also, this simple and reproducible technique affords various azetidin-2-one derivatives with short reaction times, excellent yields, and without formation of undesirable side products. From data of antimicrobial activity, it could be observed that compounds of the series, 4a-r showed activity ranging from 20 g/mL to 200 g/mL, i.e. compounds synthesized are showing comparable activity against standard drugs.
One of the author (JPR) is thankful to South Gujarat University, Surat for providing research facilities, Mr. P. R. Raval of Cyanamid India Ltd., Atul for providing Spectral facilities of the newly synthesized compounds.
1. Lidstrom P., Tierney J., Wathey B and Westman J. Microwave assisted organic synthesis-a review.; Tetrahedron. 2001; 57: 9225–9283.
2. Adam D. Out of the kitchen. Nature. 2003; 421: 571–572.
3. Hayes B L.. Microwave Synthesis: Chemistry at the Speed of Light, CEM Publishing, Matthews; NC; 2002.
4. Kidwai M. Dry media reactions. Pure Appl. Chem., 2001, 73(1), 147–151.
5. Varma R S. Solvent-free organic synthesis using supported reagents and microwave irradiation. Green Chem.; 1999; 1; 43-55.
6. Loupy A., Perreux L., Liagre M., Burle, K., Moneuse M. Reactivity and selectivity under microwaves in organic chemistry. Relation with medium effects, and reaction mechanisms. Pure Appl. Chem.; 2001; 73(1); 161–166.
7. Anastas P T., Warner J C., Green Chemistry: Theory and Practice, Oxford Science Publications, New York, 1998; b) Anastas P T., Williamson T.; Green Chemistry: Frontiers in Benign Chemical Synthesis and Processes, Oxford Science Publications, New York, 1998.
8. Raval J P., Desai K G and Desai K R. Neat Reaction Technology for the Synthesis of 4-Oxo-thiazolidines Derived from 2-SH-Benzothiazole and Antimicrobial Screening of Some Synthesized 4-Thiazolidinones; J. Iran. Chem. Soc.; 2006; 3(3); 233-241.
9. Raval J P., Desai J T., Desai C K and Desai K R. A comparative study of microwave assisted and conventional synthesis of 2,3-dihydro-2-aryl-4-[4-(2–oxo–2H–chromen–3–yl)–1,3-thiazol–2–ylamino]-1,5–benzothiazepines and its antimicrobial activity. ARKIVOC; 2008; xii; 233-244.
10. Desai K G and Desai K. R. Rapid and efficient synthesis of some biological active 2 – azetidinones under microwave irradiation. Indian J. Chem. (Sec B); 2005; 44B(10); 2093 – 2096.
11. Desai A. R., Roy R U and Desai K R. Synthesis and antimicrobial screening of quinazolone containing novel heterocyclic schiff base and azetidinone by niementowski reaction. E-Journal of Chemistry; 2005; 2(7); 101-108. ;
12. Naik B D and Desai K. R. Novel approach for the rapid and efficient synthesis of heterocyclic Schiff bases and azetidinones under microwave irradiation. Indian J. Chem. (Sec B); 2006;45B; 267-271;.
13. G. A. F., US Patent 1957, 2,789,125; Chem. Abstr. 1957, 51, 13410.
14. Raval J P, Desai K R. A Comparative study of Microwave assisted and Conventional Synthesis of novel 2-(4-diethylamino-2-hydroxyphenyl)-3-substituted-thiazolidin-4-one derivatives. Chemija (Accepted for publication, MS.No.08-30).
15. Desai K G and Desai K R. Green route for the heterocyclization of 2-mercaptobenzimidazole into β-lactam segment derivatives containing –CONH- bridge with benzimidazole: Screening in vitro antimicrobial activity with various microorganism. Bioorg. and Med. Chem. 2006; 14; 8271-8279.
16. National Committee for Clinical Laboratory Standards
(NCCLS)., Nat. Comm. Clini. Lab. Stands, Villanova; 1982; 242.
Received on 20.04.2009 Modified on 12.05.2009
Accepted on 12.06.2009 © AJRC All right reserved
Asian J. Research Chem. 2(2): April.-June, 2009 page 171-177