INTRODUCTION:

Even more than 70 years after the discovery of Penicillin, β-lactam antibiotics remain as one of the most important contributions of science to humanity¹. The chemistry of ß-lactams has taken an important place in organic chemistry since the discovery of Penicillin by Sir Alexander Fleming in 1928 and shortly thereafter Cephalosporin which were both used as successful antibiotics. Even now the research in this area is stimulated because of development of bacterial resistance to widely used antibiotics of this type². As part of interest in hetrocycles that have been explored for developing pharmaceutically important molecules, 2-azetidinones have played an important role in medicinal chemistry. Moreover they have been studied extensively because of their ready accessibility, diverse chemical reactivity and broad spectrum of biological activity³. 2-azetidinone exhibits anticonvulsant⁴, helmintic⁵, sedative⁶, tryptase inhibitory⁷, antiparkinsonism⁸, chymase inhibitory activity⁹, antitubercular¹⁰ activity.

Cycloaddition of monochloroacetylchloride with imine (schiff base) result in formation of 2-azetidinone (β-lactam).The reaction involves direct acylation of imine with monochloroacetylchloride. The reaction is carried out with base as triethylamine gives β- lactam¹¹.

MATERIALS AND METHODS:

Equipments:

Melting points were taken in an open capillary tube. The microwave assisted synthesis of 2-azetidinone derivatives were carried out in Godrej SLGX –20 E Microwave oven at 80% power 1H NMR spectra of the synthesized compounds were recorded on a Bruker-Avance (300 MHz) spectrophotometer using DMSO solvent and TMS as a internal standard. All the synthesized compounds are purified by recrystallization. The reactions were followed up and purity of compounds was monitored on pre-coated TLC plates using different solvent system and visualizing the spots in iodine chamber.

Materials:

All the chemicals and solvents were obtained from E-Merck and S.D. Fine India (AR grade) and were used without further purification.

Methodology:

Microwave-enhanced chemistry is based on the efficient heating of materials by “microwave dielectric heating” effects. This phenomenon is dependent on the ability of a specific material (solvent or reagent) to absorb microwave energy and convert it into heat¹². Microwave irradiation has gained popularity in the past decade as a powerful tool for rapid and efficient synthesis of a variety of compounds because of selective absorption of microwave energy by polar molecules. The application of Microwave irradiation to provide enhanced reaction rate and improved product field in chemical synthesis and it is providing quite successful in the formation of a variety of carbon-heteroatom bonds¹³. Many researchers have described accelerated reaction rates, with a large number of papers that have appeared proving the synthetic utility of MORE chemistry in day to day organic synthesis. It can be termed as ‘e- chemistry’ because it is easy, effective, economical, and eco-friendly, and is believed to be a step toward achieving green chemistry objectives¹⁴. Within the framework of ‘Green Chemistry’ we have now developed an environmentally benign and novel approach for the synthesis of azetidine-2-ones.

General Procedure:

STEP 1: Synthesis of 4-chloro benzohydrazide

To a solution of 4-chloro ethyl benzoate (0.01mole) in ethanol (25 ml) , hydrazine hydrate (99% 0.012 mole) was added drop wise .The resultant mixture was kept in domestic microwave oven for 3-4 min then resultant mixture is cooled at room temperature to obtained clear solution which is poured on ice to obtained solid 4-chloro benzohydrazide which is filtered off and washed thoroughly with water and recrystallized from ethanol to give product.

STEP 2: General Procedure for synthesis of N-substituted arylidene 4-chloro benzohydrazide (Schiff base) (1a-j)

4-chloro benzohydrazide (0.01mol) is treated with substituted aromatic aldehydes (0.01mol) in DMSO in microwave oven for 2-3 min and then mixture is cooled and poured in ice cold water to obtain Schiff bases.

STEP 3: General Procedure for synthesis of 3-chloro-4(substituted phenyl)-N-(4-chloro benzamido)-2-azetidinone (2a-j).

Schiff bases obtained in step 2 (0.01mol) in DMF on further treatment with base triethyl amine N(C₂H₅)₃(0.01mol) and acylatedwith monochloroacetyl chloride(0.01 mol) as cyclising agent in microwave oven for 3 – 4 mins to form 2-azetidinone.

The synthesis of 3-chloro-4(substituted phenyl)-N-(4-chloro benzamido)-2-azetidinone (2a-j) was carried out as per the reaction scheme of synthesis , scheme 1

Scheme 1

Where R is

Sr. No.	Compound	Structure
a	3,4,5- trimethoxy benzaldehyde
b	4- hydroxy benzaldehyde
c	4- methoxy benzaldehyde
d	3-bromo benzaldehyde
e	4-chloro benzaldehyde
f	3,5-Dimethoxy-4-hydroxy benzaldehyde
g	2-hydroxy benzaldehyde

Antimicrobial Activity:

All the prepared compounds were screened for antimicrobial activity. From the microbial study it can be concluded that compounds bearing chloro, methoxy groups are more potent than remaining substituted compounds against Gram (+) and Gram (-) bacteria. All the synthesized compounds have structure activity relationship (SAR) because activity of compounds varies with substitution. On the basis of SAR it can be concluded that activity of compounds depends on electron withdrawing nature of substituted group. The sequence of the activity was as follow

O₂ > Cl > Br > OH > OCH₃ > H > CH₃

RESULT AND DISCUSSION:

Today’s environmental conscious days microwave irradiation technique is becoming popular method of heating , offers significant improvements over existing conventional procedures and thus helps facile entry into a synthesis of variety of azetidin-2-one derivatives. Also, greener microwave technique affords various azetidin-2-one derivatives with short reaction times, excellent yields, and without formation of undesirable side products. The yields of different synthesized compounds were found to be in the range of 65-80% and the characterization was done by melting point, thin layer chromatography which confirms the completion of reaction. All the tested compounds shown good, moderate and poor biological activity.

TABLE-1: Physical Data of the Synthesized Azetidinone Compounds

Compd.	M.P	Yield	Molecular formula	Molecular weight
SDT20	100 ⁰C	80 %	C₁₈H₁₆ N₂ O₅Cl₂	410
SDT21	140⁰C	72 %	C₁₆H₁₂N₂ O₃Cl₂	350
SDT22	80 ⁰C	74 %	C₁₆H₁₁N₂ O₂ Cl₂Br	412
SDT23	180 ⁰C	68 %	C₁₆H₁₁ N₂O₂Cl₃	368
SDT24	140 ⁰C	76%	C₁₇H₁₄N₂ O₃Cl₂	364
SDT25	190 ⁰C	71 %	C₁₆H₁₂N₂ O₃Cl₂	350
SDT26	90 ⁰C	81%	C₁₉H₁₈N₂ O₅Cl₂	424

TABLE -2 : SPECTRAL ANALYSIS

Code	Compound	¹H NMR (DMSO, δ ppm)	IR (KBr Pellets, cm^-1)
SDT20	3-chloro-4(3,5-dimethoxy-4-hydroxy phenyl)-N(4-chloro benzamido)-2-azetidinone	6.9-8.8(m,6 H, Ar-H), 11.7(s,1H,CONH), 3.8(s,6H, OCH3), 4.6(d,1H, CH-Cl)	3001(Ar-H), 1463,1488,1515 (C=C), 3437 (N-H), 726 (C-Cl), 1768 (C=O of β lactam), 3203 (Ar-OH),1330 (C-N),
SDT21	3-chloro-4(2-hydroxy phenyl)-N(4-chloro benzamido)-2-azetidinone	6.8-8.6(m,8 H, Ar-H), 12.2 (s,1H,CONH), 11.3(s,1H, OH), 4.2(d,1H, CH-Cl)	3031 (Ar-H), 1487,1571 (C=C), 3514 (N-H),749(C-Cl), 1643 (C= O of β lactam), 1307(C-N), 3217 (Ar-OH),
SDT22	3-chloro-4(3-bromo phenyl)-N(4-chloro benzamido)-2-azetidinone	7.2-8.4(m,8 H, Ar-H), 12.0(s,1H,CONH), 2.5(d,1H, CH), 4.7(d,1H, CH-Cl)	3034 (Ar-H) 1478,1479,1566(C=C), 3523(N-H),716(C-Cl), 1686(C= O of β lactam), 1325(C-N),
SDT23	3-chloro-4(4-chloro phenyl)-N(4-chloro benzamido)-2-azetidinone	7.2 – 8.4(m,8 H, Ar-H), 11.9 (s,1H,CONH), 2.5(d,1H, CH), 4.5(d,1H, CH-Cl)	3040 (Ar-H), 1487,1571 (C=C), 3520 (N-H),760(C-Cl), 1650 (C= O of β lactam), 1310(C-N),
SDT24	3-chloro-4(4-methoxy phenyl)-N(4-chloro benzamido)-2-azetidinone	6.9 – 8.4(m,8 H, Ar-H), 11.7 s,(1H,CONH), 2.5(d,1H, CH), 3.8(d,1H, CH-Cl), 3.4(s,1H,OCH₃)	3030 (Ar-H), 1463,1488,1512(C=C), 3493(N-H),747(C-Cl), 1656(C= O of β lactam), 1315(C-N), 1033,1259 (C-O-C),
SDT25	3-chloro-4(4-hydroxy phenyl)-N(4-chloro benzamido)-2-azetidinone	6.8-8.3(m,8 H, Ar-H), 11.7 (s,1H,CONH), 2.5(d,1H, CH), 4.5(d,1H, CH-Cl), 9.9(s,1H,OH)	3030(Ar-H), 1488,1513(C=C), 3302(N-H),732(C-Cl), 1770(C= O of β lactam), 1305(C-N), 3186(Ar-OH),
SDT26	3-chloro-4(3,4,5-tri methoxy phenyl)-N(4-chloro benzamido)-2-azetidinone	6.7-8.4(m,6 H, Ar-H), 11.9 (s,1H,CONH), 2.5(d,1H, CH), 4.7(d,1H, CH-Cl), 9.0(s,1H,OCH₃)	3060(Ar-H), 1433,1466,1505(C=C), 3467(N-H),720(C-Cl), 1674(C= O of β lactam), 1330(C-N), 1065,1238 (C-O-C)

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Received on 15.03.2014 Modified on 25.04.2014

Asian J. Research Chem. 7(5): May 2014; Page 483-486