Iodine catalyzed three-component synthesis of Î²-amino-Î² ... - NOPR

Indian Journal of Chemistry Vol. 52B, December 2013, pp 1505-1512

Iodine catalyzed three-component synthesis of β-amino-β-keto-esters and their antimicrobial activity Dolly Katakia, Pranabananda Bhattacharyyab, Manab Dekac, Dhruba Kumar Jha*b & Prodeep Phukan*a a

Department of Chemistry, Gauhati University, Guwahati 781 014, India b

Department of Botany, Gauhati University, Guwahati 781 014, India

c

Department of Biotechnology, Gauhati University, Guwahati 781 014, India E-mail: [email protected] Received 4 December 2012; accepted (revised) 29 April 2013

A series of β-amino-β-keto-esters have been prepared in moderate to good yields by a three-component Mannich reaction of aldehydes, benzyl carbamate and β-keto esters in the presence of iodine catalyst under solvent-free condition. All compounds have been tested for antibacterial and antifungal activities. Antagonistic activity of these compounds have been tested in vitro against three gram positive bacteria (Bacillus subtilis, Staphylococcus aureus and Staphylococcus epidermitidis), two gram negative bacteria (Escherichia coli, Klebsiella pneumoniae) and two pathogenic fungi (Candida albicans and Candida tropicalis) using agar-cup diffusion method. The bioassay result of these compounds in present investigation indicates promising antimicrobial activity against both the bacterial and fungal pathogens. The minimum inhibitory concentration (MIC) of the potent compounds range between 125 to 3000 µg/mL. Keywords: Three-component Mannich reaction, MCR, iodine, β-amino carbonyl compounds, solvent-free, antifungal, antibacterial

Multicomponent coupling reaction (MCR) is a very powerful synthetic tool in combinatorial chemistry and for generation of small-molecule libraries1. MCR strategies offer significant advantages over multi step syntheses. MCR’s can provide products with the diversity needed for the discovery of new lead compounds. β-Amino carbonyl compounds are important building blocks in organic synthesis for construction of bioactive molecules2. Moreover, a great number of nature’s molecules, including proteins and nucleic acids and most of the biologically active compounds, contain nitrogen. Consequently, development of new synthetic methods for the construction of nitrogenous molecules is considered as the frontiers of organic synthesis. Mannich reaction is one such method that provides β-amino carbonyl compounds3. However, only a few reports are in literature on Mannich reaction that uses β-keto esters4. In recent years, iodine has emerged as a very effective catalyst for various organic transformations5. As a part of our ongoing work on iodine catalyzed reactions6, we report herein a mild, convenient and three-component method for synthesis of a series of cbz-protected β-

amino carbonyl compounds using iodine as catalyst under solvent-free condition (Scheme I). Moreover, the antimicrobial activities of the β-amino carbonyl compounds are also presented in this work. Results and Discussion Synthesis of β-amino carbonyl compounds Initially, a systematic study was carried out for the three component condensation reaction to find out the optimum reaction condition. The reaction was carried out by taking benzaldehyde (1 mmol), iodine (10 mol%), benzyl carbamate (1.2 mmol) and ethylacetoacetate (1 mmol) and was stirred at 90°C. The same reaction was further carried out with varying concentrations of iodine, benzyl carbamate and ethylacetoacetate. The reaction in absence of iodine could produce only 19 % yield after 12h of reaction. The variation of yield of the product under different conditions is discussed in Table I. Finally, the best result was obtained when the reaction was carried out using 1 equivalent of benzaldehyde, 1.2 equivalent of benzyl carbamate, 1 equivalent of ethylacetoacetate and 0.1 equivalent of iodine.

INDIAN J. CHEM., SEC B, DECEMBER 2013

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O

O RCHO

+

H2N

O

1

O

+

O

EtO

2

I2(10mol%) 90 0C R'

R

EtO

O N H

O

O

R'

4

3

Scheme I ― Synthesis of β-amino carbonyl compounds from aldehydes, benzyl carbamates and β-keto esters in presence of iodine

Table I ― Preparation of β-amino carbonyl compounds under different conditions Entry 1 2 3 4 5 6

Benzaldehyde (mmol) 1 1 1 1 1 1 a Isolated yield

Ethylacetoacetate (mmol)

Benzyl carbamate (mmol)

Iodine (mol%)

Time (h)

Yielda (%)

1 1 1 1 1 1.5

1.2 1.2 1.2 1.2 1.1 1.1

5 10 20 0 10 10

3 3 3 12 3 3

55 66 49 19 60 61

The scope of the reaction was examined for various aromatic aldehydes using ethyl aceoacetate as well as diethyl malonate (Table II). Aromatic aldehydes bearing either electron-donating or electronwithdrawing group could be converted into the corresponding products in moderate to good yields. para-Substituted aldehydes produced better results over ortho- and meta-substituted aldehydes. In most cases, the reaction (with ethyl acetoacetate) gave only the anti isomer of the product. However, in some cases (Table II, entry 2 and 6), a mixtures of syn and anti isomers were formed in 1:1 ratio as evident by the analysis of 1H NMR data. Formation of cbzprotected β-amino carbonyl compounds was confirmed by NMR, mass, IR and elemental analysis. Antimicrobial activity All the synthesized compounds were screened for antimicrobial activity against three gram-positive bacteria (Bacillus subtilis, Staphylococcus epidermitidis and Staphylococcus aureus), two gram negative bacteria (Klebsiella pneumoniae and Escherichia coli) and two pathogenic fungi (Candida albicans and C. tropicalis) by agar-cup diffusion method7. Standard antibacterial tetracycline (30 µg/disc) and ciprofloxacin (10 µg/disc) and antifungal fluconazole (10 µg/disc) were also screened under similar conditions for comparison (Table III). DMSO was used as negative control. For antibacterial

bioassay, nutrient agar plates were inoculated with 0.2 mL of overnight grown culture of each bacterial suspension containing 1.0 × 109 cells. Similarly, Sabouraud's agar plate was inoculated with 0.2 mL of cultured test fungi containing 1.0 × 109 cells. The plates were evenly spread out with the help of a sterile cotton swab. Agar cups were prepared by scooping out the media with a sterile cork borer. Each cup was then loaded with 100 µL of the compound dissolved in DMSO. The compounds were tested at a concentration of 2 mg/mL. Along with this, disc containing tetracycline (30 µg/disc), and ciprofloxacin (10 µg/disc) antibacterial activity and fluconazole (10 µg/disc) for antifungal activity was also placed on the surface of inoculated media as a positive control. Agar cup filled with only DMSO was used as negative control. The plates were incubated at 37±1°C for 24 hr and zone of inhibition was recorded and compared with the control (i.e. both positive and negative). Three replicates were maintained in each case. Among all these compounds, 4d and 4j showed good antimicrobial activity against all the bacterial pathogens (Table III). The different activities shown by these compounds may be due to the nature of the substituents attached to the aromatic ring of these compounds. These results are compared with standard antibiotics i.e. tetracycline (30 µ g/disc) and ciprofloxacin (10 µ g/disc) as antibacterial and antifungal agent i.e. fluconazole (10 µg/disc) (Table III).

KATAKI et al.: THREE-COMPONENT SYNTHESIS OF β-AMINO-β-KETO-ESTERS

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Table II ― Preparation of β-amino carbonyl compounds from various aromatic aldehydes in presence of iodine catalyst under solvent-free condition Entry

β-amino carbonyl compounds 4

Aldehyde 1

CHO

O

Time (hr)

Yielda (%)

3

66b

2

74c

1.5

62b

3.5

56b

1

68b

1

61c

3

58b

O

1 O

N H

O

O

4a

O

O

CHO

2 O

N H

O

4b

O

OMe CHO

O

3 MeO

O

O

N H

O

4c

O

OMe CHO

O

O

4 O OMe

N H O

O

4d Cl

CHO O

5 O

Cl

CHO

O N H

O

O

4e

O

Cl O

6

Cl

O

N H

O

4f

O

Cl

CHO O

7

O

Cl

O N H

O

O

4g — Contd


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Table II ― Preparation of β-amino carbonyl compounds from various aromatic aldehydes in presence of iodine catalyst under solvent-free condition— Contd Entry

β-amino carbonyl compounds 4

Aldehyde 1

Time (hr)

Yielda (%)

4.5

65b

3

79b

3

69b

3.5

60b

4

60b

2.5

66

F

CHO O

8

O

O

F

N H

O

4h

O

Br CHO

O

9 Br

O

O

N H O

O

4i NO2

CHO O

10

O

O

O2N

N H O

CHO

4j NO2 O

O

11

O

NO2

O

N H O

O

4k NO2

CHO

O

O

12 O

N H

NO2

CHO 13

O

O

4l

O

O

O

N H O

O

O

4m a

b

c

Isolated yield; syn:anti = >99%; syn:anti=1:1; Entry 1-12: reaction carried out with ethyl acetoacetate Entry 13-15: reaction carried out with diethylmalonate


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Table III ― Antibacterial activity (zone of inhibition) of the potent compounds against a host of clinically significant human pathogens Compd B. subtilis 11.3±1.3 4a 10.5±0.5 4b 10.7±0.58 4c 11.2±0.24 4d 12.3±0.47 4e 9.0±0.94 4f 8.5±1.3 4g 10.3±0.72 4h 9.3±1.5 4i 11.8±0.85 4j 10.0±0.47 4k 8.7±0.7 4l 10.8±1.6 4m 10.0±2.2 4n 9.2±1.9 4o Control (DMSO) 0 Tetracycline 25 Ciprofloxacin ND Fluconozole ND ND: not determined

S. epidermitidis 10.3±0.72 9.8±0.12 10.3±0.35 10.7±0.47 12.7±0.94 9.7±0.72 10.0±1.7 11.6±1.5 10.2±0.29 11.8±0.24 7.7±0.7 8.0±0.47 10.0±1.7 9.2±1.4 10.7±1.9 0 22 ND ND

Zone of inhibition (mm) S. aureus K. pneumoniae E. coli

C. albicans

C. tropicalis

11.0±0.82 11.7±1.2 13.2±2.0 14.3±1.2 8.0±1.41 6.0±0.47 7.8±1.6 6.3±0.15 6.7±1.3 13.2±0.62 6.7±0.99 9.3±0.98 10.7±1.9 10.5±1.7 6.0±0.87 0 24 ND ND

12.7±0.94 12.2±0.41 12.5±0.87 13.0±0.82 19.3±1.2 11.0±0.47 13.2±1.8 12.3±0.47 11.6±1.5 12.3±1.0 10.0±0.47 10.0±0.47 11.5±1.3 11.3±1.5 11.3±2.1 0 ND 24 29

14.7±0.47 11.7±0.47 12.2±1.8 12.3±1.7 11±0.94 10.3±0.72 10.7±1.5 10.2±0.29 11.2±0.24 15.0±0.82 8.3±0.7 10.7±0.72 12.0±2 11.0±1.8 9.5±2.2 0 ND ND 22

Minimum inhibitory concentration was also determined by tube dilution method (Table IV). MIC was determined as the least concentration of the compound inhibiting the growth of the test organisms. The minimum inhibitory concentration varied for different compounds against different test pathogens. Experimental Section General procedure for synthesis of β-amino carbonyl compounds A mixture of aldehyde (1 mmol), benzyl carbamate (1.2 mmol), ethylacetoacetate/diethyl malonate (1 mmol) and iodine (10 mol%) was heated in an oil bath at 90°C. After completion of the reaction, iodine was destroyed by adding aqueous solution of sodium thiosulfate. The mixture was then extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography over silica gel (60-120 mesh) with ethyl acetate-petroleum ether (10-20%) as eluent. 2-(Benzyloxycarbonylamino-phenyl-methyl)-3oxo-butyric acid ethyl ester, 4a: m.p. 89-92°C; IR

9.2±0.73 9.3±1.6 10.8±0.29 11.3±0.94 8.3±1.2 5.3±0.72 6.7±1.5 8.0±0.5 8.3±1.5 12.0±0.41 6.0±0.47 5.3±0.72 8.5±1.3 8.7±1.5 7.5±1.3 0 ND 25 ND

11.3±0.47 10.8±0.58 11.8±0.29 12.2±1.3 11.7±0.47 8.7±0.72 9.3±0.58 10.2±0.76 6.2±1.04 11.8±0.24 10.3±0.7 7.7±0.98 10.5±0.5 10.0±1.3 9.3±1.9 0 ND 27 ND

(KBr): 3352, 3025, 2995, 2946, 1730, 1688, 1530, 1452, 1408, 1348, 1312, 1294, 1249, 1167, 1071 cm-1; 1 H NMR (400 MHz, CDCl3): δ 7.35-7.29 (m, 10H), 6.3 (br s, 1H), 5.51-5.46 (m, 1H), 5.09-5.06 (m, 2H), 4.09-4.05 (m, 3H), 2.14 (s, 3H), 1.12 (t, J = 6.8 Hz, 3H); 13C NMR(100 MHz, CDCl3): δ 203.4, 167.3, 155.8, 139.5, 136.5, 128.8, 128.7, 128.6, 128.2, 127.9, 126.7, 126.4, 67.0, 63.3, 62.0, 54.6, 30.8, 14.0; Mass (m/z, % rel. intensity): 370 (3), 240 (100), 196 (25), 91 (29). Anal. Calcd. for C21H23NO5: C, 68.28; H, 6.28; N, 3.79. Found: C, 68.36; H, 6.10; N, 3.83%. 2-(Benzyloxycarbonylamino-4-tolyl-methyl)-3oxo-butyric acid ethyl ester, 4b: m.p. 76-78°C; IR (KBr): 3341, 3263, 3037, 2949, 2811, 1734, 1693, 1523, 1448, 1406, 1347, 1288, 1252, 1177, 1071 cm-1; 1 H NMR (400 MHz, CDCl3): δ 7.32-7.31 (m, 5H), 7.2-7.09 (m, 4H), [6.38 (d, J = 8.0 Hz), 6.11 (d, J = 8.0 Hz), 1H], [5.59-5.5 (m), 5.5-5.38 (m), 1H], 5.085.05 (m, 2H), 4.13-4.03 (m, 3H), 2.30 (s, 3H), [2.28 (s), 2.13 (s), 3H], 1.16-1.11 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 201.8, 168.6, 155.8, 137.5, 136.3, 136.2, 129.4, 126.1, 67.0, 64.2, 63.1, 61.8(61.5), 28.9, 21.0, 13.9; Mass (m/z, % rel. intensity): 384 (2), 254 (100), 210 (22), 91 (13). Anal. Calcd. for C22H25NO6:


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Table IV ― Minimum inhibitory concentration (MIC) of the potent compounds against a host of human pathogens Compd B. subtilis 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o

250 500 500 250 500 1000 1000 500 1000 250 500 1000 500 500 1000

Minimum inhibitory concentration (MIC, µg/mL) S. epidermitidis S. aureus K. pneumoniae E. coli C. albicans 500 500 500 500 500 1000 500 500 500 500 1000 1000 500 1000 500

500 500 500 125 250 1000 2000 3000 3000 125 1000 2000 500 500 2000

C, 68.91; H, 6.57; N, 3.65. Found: C, 68.86; H, 6.40; N, 3.58%. 2-[Benzyloxycarbonylamino-(4-methoxy-phenyl)-methyl]-3-oxo-butyric acid ethyl ester, 4c: m.p. 91-94°C; IR (KBr): 3048, 2979, 2930, 2852, 1725, 1660, 1602, 1543, 1500, 1445, 1423, 1376, 1346, 1266, 1219, 1147, 1057 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.34-7.31 (m, 5H), 7.22-7.20 (m, 2H), 6.82 (d, J = 8.0 Hz, 2H), 6.13 (d, J = 8.0 Hz, 1H), 5.43 (d, J = 8.0 Hz, 1H), 5.07-5.02 (m, 2H), 4.11-4.06 (m, 2H), 4.0 (d, J = 7.2 Hz, 1H), 3.77 (s, 3H), 2.15 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 202.2, 167.2, 159.0, 155.6, 136.3, 132.2, 128.5, 128.1, 127.7, 114.0, 70.8, 66.9, 63.4, 61.8, 55.2, 30.6, 13.8. Anal. Calcd. for C22H25NO6: C, 68.15; H, 6.31; N, 3.51. Found: C, 68.27; H, 6.38; N, 3.61%. 2-[Benzyloxycarbonylamino-(3-methoxy-phenyl)-methyl]-3-oxo-butyric acid ethyl ester, 4d: m.p. 74°C; IR (KBr): 3342, 3274, 3036, 2960, 2837, 1734, 1691, 1602, 1533, 1489, 1455, 1401, 1347, 1298, 1254, 1180, 1141, 1072, 1043 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.39-7.22 (m, 6H), 6.90-6.80 (m, 3H), 6.25 (br s, 1H), 5.55-5.42 (m, 1H), 5.13-5.09 (m, 2H), 4.2-4.05 (m, 3H), 3.79 (s, 3H), 2.17 (s, 3H), 1.18 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 203.3, 167.1, 159.8, 155.7, 141.0, 136.3, 129.7, 128.4, 128.1, 128.0, 118.6, 113.2, 112.3, 66.9, 62.8, 61.9, 55.2, 54.3, 30.9, 13.8; Mass (m/z, % rel. intensity): 400 (4), 270 (100), 226 (24), 91 (22). Anal. Calcd. for

125 250 500 500 125 3000 3000 2000 2000 500 2000 3000 1000 1000 1000

500 500 250 250 250 2000 1000 500 2000 500 500 1000 500 500 1000

250 250 250 125 500 500 250 250 500 250 500 500 500 500 500

C. tropicalis 125 250 250 250 500 500 500 500 500 250 1000 500 500 500 1000

C22H25NO6: C, 68.15; H, 6.31; N, 3.51. Found: C, 68.22; H, 6.34; N, 3.57%. 2-[Benzyloxycarbonylamino-(4-chloro-phenyl)methyl]-3-oxo-butyric acid ethyl ester, 4e: m.p. 96100°C; IR (KBr): 3223, 3056, 2968, 2919, 2860, 1728, 1675, 1503, 1449, 1263, 1165, 1118, 1032 cm-1; 1 H NMR (400 MHz, CDCl3): δ 7.32-7.25 (m, 9H), 6.21 (br s, 1H), 5.46-5.41 (m, 1H), 5.12-5.07 (m, 2H), 4.12 (q, J = 7.2 Hz, 2H), 4.01 (d, J = 6.6 Hz, 1H), 2.14 (s, 3H), 1.17 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 202.9, 166.9, 155.6, 138.0, 136.2, 133.6, 128.8, 128.0, 67.0, 62.7, 62.0, 53.8, 30.8, 13.0. Anal. Calcd. for C21H22ClNO5: C, 62.45; H, 5.49; N, 3.4. Found: C, 62.29; H, 5.20; N, 3.31%. 2-[Benzyloxycarbonylamino-(2-chloro-phenyl)methyl]-3-oxo-butyric acid ethyl ester, 4f: IR (KBr): 3058, 2970, 2930, 1727, 1502, 1450, 1345, 1278, 1223, 1146, 1053 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.397.19 (m, 9H), [6.84 (d, J = 8.0 Hz), 6.55 (d, J = 8.0 Hz), 1H], [5.88 (dd, J 1 = 4.0 Hz, J 2 = 8.0 Hz), 5.78 (dd, J 1 = 4.0 Hz, J 2 = 8.0 Hz), 1H], 5.10-5.06 (m, 2H), 4.33 (d, J = 8 Hz, 1H), 4.17-4.0 (m, 2H), [2.39 (s), 2.07 (s), 3H], [1.18 (t, J = 8.0 Hz), 1.09 (t, J = 8.0 Hz), 3H]; 13C NMR (100 MHz, CDCl3): δ 200.9, 168.7, 155.7, 136.1, 132.0, 129.9, 129.8, 129.1, 128.5, 128.1, 127.1, 67.1, 61.5, 61.3, 50.9, 28.5, 13.8. Anal. Calcd. for C21H22ClNO5: C, 62.45; H, 5.49; N, 3.4. Found: C, 62.26; H, 5.28; N, 3.38%. 2-[Benzyloxycarbonylamino-(2-chloro-phenyl)methyl]-3-oxo-butyric acid ethyl ester, 4g: m.p.


85-87°C; IR (KBr): 3362, 3274, 3029, 2970, 2931, 1715, 1691, 1534, 1460, 1406, 1337, 1253, 1223, 1142, 1026 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.37.10 (m, 9H), 6.19 (d, J = 8.0 Hz, 1H), 5.38 (br s, 1H), 5.05-4.95 (m, 2H), 4.07-4.03 (m, 2H), 3.96 (d, J = 4.0 Hz, 1H), 2.07 (s, 3H), 1.09 (t, J = 8.0 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 203.0, 166.9, 155.6, 141.5, 136.2, 134.6, 129.9, 128.5, 128.1, 128.0, 126.8, 124.7, 67.0, 62.6, 62.1, 53.9, 30.9, 13.8; Mass (m/z, % rel. intensity): 404 (10), 274 (100), 230 (20), 91 (35). Anal. Calcd. for C21H22ClNO5: C, 62.45; H, 5.49; N, 3.4. Found: C, 62.30; H, 5.26; N, 3.29%. 2-[Benzyloxycarbonylamino-(4-fluoro-phenyl)methyl]-3-oxo-butyric acid ethyl ester, 4h: m.p. 9396°C; IR (KBr): 3362, 3045, 2976, 1710, 1693, 1527, 1458, 1422, 1364, 1288, 1227, 1157, 1028 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.35-7.24 (m, 7H), 6.98 (t, J = 8.4 Hz, 2H), 6.16 (d, J = 7.6 Hz, 1H), 5.43 (t, J = 7.2 Hz, 1H), 5.09-5.02 (m, 2H), 4.14-4.07 (m, 2H), 3.99 (d, J = 4.8 Hz, 1H), 2.14 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 203.0, 166.9, 164.6, 155.6, 137.3, 136.2, 135.2, 128.4, 128.1, 115.7, 115.3, 66.9, 63.1, 61.9, 53.8, 30.7, 13.8; Mass (m/z, % rel. intensity): 388 (2.5), 258 (100), 214 (28), 91 (28). Anal. Calcd. for C21H22FNO5: C, 65.11; H, 5.72; N, 3.62. Found: C, 65.02; H, 5.79; N, 3.53%. 2-[Benzyloxycarbonylamino-(4-bromo-phenyl)-methyl]-3-oxo-butyric acid ethyl ester, 4i: m.p. 120123°C; IR (KBr): 2919, 2860, 1719, 1655, 1596, 1493, 1449, 1380, 1253, 1165, 1032 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.41 (d, J = 8 Hz, 2H), 7.357.24 (m, 5H), 7.14 (d, J = 8 Hz, 2H), 6.18 (d, J = 8.0 Hz, 1H), 5.41 (t, J = 8.0 Hz, 1H), 5.09-5.02 (m, 2H), 4.11 (q, J = 7.2 Hz, 2H), 4.00 (d, J = 3.6 Hz, 1H), 2.12 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 202.9, 166.9, 155.6, 138.6, 136.2, 131.7, 128.3, 128.1, 128.0, 121.7, 67.0, 62.7, 62.1, 53.9, 30.8, 13.9. Anal. Calcd. for C21H22BrNO5: C, 56.26; H, 4.95; N, 3.12. Found: C, 56.08; H, 5.04; N, 3.24%. 2-[Benzyloxycarbonylamino-(4-nitro-phenyl)-methyl]-3-oxo-butyric acid ethyl ester, 4j: m.p. 11720°C; IR (KBr): 3351, 3273, 3027, 2949, 1715, 1685, 1542, 1517, 1459, 1347, 1307, 1238, 1155, 1071, 1031 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.35-7.24 (m, 5H), 6.33 (d, J = 8.4 Hz, 1H), 5.54 (t, J = 6.0 Hz, 1H), 5.1-5.03 (m, 2H), 4.17-4.06 (m, 3H), 2.15 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 202.9, 166.9, 155.6, 138.6, 136.2, 131.7,

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128.3, 128.1, 128.0, 121.7, 67.0, 62.7, 62.1, 53.9, 30.8, 13.9. Anal. Calcd. for C21H22N2O7: C, 60.86; H, 5.35; N, 6.76. Found: C, 60.95; H, 5.33; N, 6.69%. 2-[Benzyloxycarbonylamino-(2-nitro-phenyl)methyl]-3-oxo-butyric acid ethyl ester, 4k: m.p. 120-23°C; IR (KBr): 3196, 3048, 2970, 2921, 2862, 1724, 1533, 1489, 1450, 1386, 1342, 1263, 1224, 1126, 1067 cm-1; 1H NMR (400 MHz, CDCl3: δ 7.347.19 (m, 7H), 6.98 (t, J = 8 Hz, 2H), 6.18 (d, J = 8.4 Hz, 1H), 5.42 (t, J = 7.6 Hz, 1H), 5.08-5.01 (m, 2H), 4.13-4.07 (m, 2H), 4.0 (s, 1H), 2.13 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 202.9, 166.9, 155.6, 139.4, 137.9, 136.1, 133.6, 128.4, 127.9, 66.9, 62.8, 62.0, 54.3, 30.7, 13.8. Anal. Calcd. for C21H22N2O7: C, 60.86; H, 5.35; N, 6.76. Found: C, 60.90; H, 5.28; N, 6.66%. 2-[Benzyloxycarbonylamino-(3-nitro-phenyl)methyl]-3-oxo-butyric acid ethyl ester, 4l: m.p. 10709°C; IR (KBr): 3363, 3070, 3019, 2970, 2937, 1737, 1718, 1676, 1533, 1458, 1420, 1352, 1290, 1258, 1180, 1052 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.2 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.5 (t, J = 8.0 Hz, 1H), 7.37-7.26 (m, 5H), 6.38 (d, J = 8.4 Hz, 1H), 5.57 (br s, 1H), 5.12-5.05 (m, 2H), 4.2-4.08 (m, 3H), 2.18 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 202.4, 166.6, 155.6, 148.3, 141.8, 135.9, 133.0, 129.6, 128.5, 128.0, 122.7, 121.6, 67.2, 62.4, 62.3, 53.7, 30.6, 13.8. Anal. Calcd. for C21H22N2O7: C, 60.86; H, 5.35; N, 6.76. Found: C, 60.92; H, 5.31; N, 6.66%. 2-(Benzyloxycarbonylamino-phenyl-methyl)malonic acid diethyl ester, 4m: m.p. 76-78°C; IR (KBr): 3333, 3264, 3029, 2950, 2813, 1692, 1610, 1406, 1347, 1209, 1121, 1074, 1058 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.45-7.2 (m, 10H), 6.52 (d, J = 7.6 Hz, 1H), 5.58 (br s, 1H), 5.17-5.05 (m, 2H), 4.224.02 (m, 4H), 3.92 (s, 1H), 1.20 (t, J = 6.4 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 168.6, 167.0, 156.4, 139.1, 133.2, 128.6, 128.4, 128.1, 127.7, 126.2, 66.9, 62.0, 61.7, 56.8, 13.9, 13.8. Anal. Calcd. for C21H25NO6: C, 66.15; H, 6.31; N, 3.51. Found: C, 65.99; H, 6.49; N, 3.23%. 2-(Benzyloxycarbonylamino-p-tolyl-methyl)-malonic acid diethyl ester, 4n: IR (KBr): 3350, 3234, 3056, 2947, 1720, 1683, 1521, 1440, 1400, 1337, 1291, 1242, 1078, 1015 cm-1; 1H NMR (400 MHz, CDCl3): δδ 7.36-7.24 (m, 5H), 7.17 (d, J = 8.4 Hz, 2H), 7.1 (d, J = 8.0 Hz, 2H), 6.44 (d, J = 9.6 Hz, 1H), 5.50 (d, J = 4.8 Hz, 1H), 5.11-5.03 (m, 2H), 4.16-4.02 (m, 4H), 3.87 (d, J = 4.4 Hz, 1H). 2.29 (s, 3H), 1.18

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(t, J = 7.2 Hz, 3H), 1.12 (s, J = 7.2 Hz, 3H). Anal. Calcd. for C23H27NO6: C, 66.81; H, 6.58; N, 3.39. Found: C, 66.57; H, 6.44; N, 3.20%. 2-(Benzyloxycarbonylamino-(4-fluoro phenyl)malonic acid diethyl ester, 4o: IR (KBr): 3349, 3052, 2945, 2820, 1716, 1684, 1528, 1440, 1356, 1290, 1258, 1022 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.3-7.19 (m, 5H), 7.1-7.06 (m, 2H), 6.95-6.91 (m, 2H), 6.44 (d, J = 8.4 Hz, 1H), 5.46 (d, J = 4.0 Hz, 1H), 5.06-4.96 (m, 2H), 4.16-3.95 (m, 4H), 3.78 (d, J = 4 Hz, 1H), 1.13 (t, J = 7.2 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H). Anal. Calcd. for C22H24FNO6: C, 63.30; H, 5.80; N, 3.36. Found C, 63.40; H, 5.62; N, 3.28%. Conclusion Synthesis of various β-amino carbonyl compounds has been achieved via three component reaction of aldehydes, benzyl carbamate and ethyl acetoacetate / diethyl malonate in presence of iodine catalyst. Antiisomer is obtained in most of the reactions with ethylacetoacetate. All the synthesized compounds are found to have antibacterial as well as antifungal activity. Compounds 4d and 4j show good antimicrobial activity against all the bacterial pathogens, however, their activity are not at par with the standard antimicrobial agents. Acknowledgement Financial support from CSIR, India (Grant no. 01(1933)/04/EMR-II) is gratefully acknowledged. One of the authors (DK) is thankful to Council of Scientific & Industrial Research (India) for a senior research fellowship. The authors also thank, CDRI Lucknow, IIT Guwahati and NEHU Shillong for analytical data.

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