N-aryl modification in-lactam: Design and synthesis of novel monocyclic-lactam derivatives as inhibitor for bacterial propagation

Article abstract of DOI:10.1080/00397911.2011.574807

In search of novel γ-lactam antibacterial agents as non-lactam mimics of some γ-lactam antibiotics, N-aryl modification in the γ-lactam ring has been made to synthesize compounds 4-8 in two to six steps. Compound 4 was synthesized using the intermolecular

Full text of DOI:10.1080/00397911.2011.574807

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N-Aryl Modification in γ-Lactam: Design
and Synthesis of Novel Monocyclic γ-
Lactam Derivatives as Inhibitor for
Bacterial Propagation
Prasanta Patra a , Gandhi K. Kar a , Aparna Sarkar a , Jayanta K. Ray
b , Tista Dasgupta a , Mahua Ghosh c & Sugata Bhattacharya c
a Department of Chemistry and Biochemistry, Presidency University,
Kolkata, India
b Department of Chemistry, Indian Institute of Technology,
Kharagpur, India
c Department of Chemical Technology, University of Calcutta,
Kolkata, India
Accepted author version posted online: 10 Jan 2012.Version of
record first published: 21 Jun 2012.
To cite this article: Prasanta Patra , Gandhi K. Kar , Aparna Sarkar , Jayanta K. Ray , Tista
Dasgupta , Mahua Ghosh & Sugata Bhattacharya (2012): N-Aryl Modification in γ-Lactam: Design and
Synthesis of Novel Monocyclic γ-Lactam Derivatives as Inhibitor for Bacterial Propagation, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
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Synthetic Communications1, 42: 3031–3041, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.574807
N-ARYL MODIFICATION IN c-LACTAM: DESIGN AND
SYNTHESIS OF NOVEL MONOCYCLIC c-LACTAM
DERIVATIVES AS INHIBITOR FOR BACTERIAL
PROPAGATION
Prasanta Patra,1 Gandhi K. Kar,1 Aparna Sarkar,1
Jayanta K. Ray,2 Tista Dasgupta,1 Mahua Ghosh,3 and
Sugata Bhattacharya3
1Department of Chemistry and Biochemistry, Presidency University,
Kolkata, India
2Department of Chemistry, Indian Institute of Technology, Kharagpur, India
3Department of Chemical Technology, University of Calcutta, Kolkata, India
GRAPHICAL ABSTRACT
Abstract In search of novel c-lactam antibacterial agents as non-b-lactam mimics of some
c-lactam antibiotics, N-aryl modification in the c-lactam ring has been made to synthesize
compounds 4–8 in two to six steps. Compound 4 was synthesized using the intermolecular
Michael addition of diethyl N-(6-coumarinyl)-2-aminomalonate and 3-aryl=(2-heteroaryl)
acryloyl chloride followed by intramolecular amidification. Hydrolysis and stereoselective
decarboxylation of 4 resulted in the formation of trans- c-lactam carboxylic acids (5), which
on side chain homologation followed by saponification of the intermediate c-lactam monoester
(7) afforded c-lactam carboxylic derivatives 8. Moderate to good bacterial growth inhibition
was observed for some of the synthesized compounds against E. coli and S. aureus.
Keywords Antibacterial activity; c-lactam; Michael addition; N-aryl modification
INTRODUCTION
Several modifications on the tail and=or head of the penicillin antibiotics
(Fig. 1) have led to the development of many clinically useful b-lactam antibacterial
agents. However, untill the late 1980s, very limited efforts were taken to modify the
b-lactam ring (i.e., the body of the molecule) as it was believed that presence of the
b-lactam ring is necessary for showing the bioactivities of such compounds. After
the middle of the 1970s, many groups of scientists began to raise questions about
Received February 22, 2011.
Address correspondence to Gandhi K. Kar, Department of Chemistry and Biochemistry,
Presidency University, 86=1 College Street, Kolkata 700 073, India. E-mail: gandhikar41@hotmail.com
3031

3032
P. PATRA ET AL.
Figure 1. Tail, body, and head segments of bicyclic b-lactam antibiotics.
Figure 2. Monocyclic N-aryl c-lactam carboxylic acids.
Scheme 1. Reagents and conditions: (a) 140 ꢀC, 1 h, then at 125 ꢀC, 2 h. (b) ArCH¼CHCOCl, Et3N, dry
benzene, reflux, 7.5–8 h. (c) KOH (2.5 equiv.), EtOH, H2O, reflux, 4–4.5 h. (d) SOCl2, dry benzene, DMF
(cat.), reflux 4–4.5 h. (e) CH2N2 (excess) in ether-CH2Cl2, 0 ꢀC to r.t, overnight. (f) Ag2O, dry MeOH,
reflux, 2 h. (g) KOH (1.1 equiv.), EtOH, H2O, rt, 1.5 h.

N-ARYL MODIFICATION IN c-LACTAM
3033
the theory that presence of the b-lactam ring is needed to display the bioactivities of
b-lactam antibacterial agents, and in the search for biological surrogates of b-lactam
rings, significant attention was given to the design of c-lactam analogs by various
groups. As a result of these research works, syntheses of large number of c-lactam
derivatives[1] have appeared in literature in the past few decades. Many of these
c-lactam derivatives showed moderate to high biological activity. The research
toward the synthesis of novel c-lactam antibacterials have been further stimulated
by the isolation of many naturally occurring biologically active compounds such
as lactivicin,[2] virgineone,[3] salinosporamide,[4] ergobalansine,[5] thyrotropine-
releasing hormone (TRH),[6] and oleficine[7] bearing a c-lactam moiety within the
molecule. In the late 1990s, we have shown that the antibacterial activities of mono-
cyclic N-aryl c-lactam carboxylic acids[8] are dependent on the substituents present
on the N-aryl group as well as on the nature of C3-aryl group (Fig. 2). As an exten-
sion of this work in search of novel c-lactam antibacterial agents, the present article
describes the synthesis and biological evaluation of some novel c-lactam carboxylic
acid derivatives bearing 2-oxo-2H-chromen-6-yl functionality as the N-aryl part
(Scheme 1). We expected that presence of the weakly electron-withdrawing coumarin
moiety may enhance the reactivity of the c-lactam carbonyl to facilate its binding
with penicillin-binding proteins (PBP).
RESULTS AND DISCUSSION
The required starting material diethyl 2-(2-oxo-2H-chromen-6-yl-amino)-
malonate (3) was prepared, in 70% yield, by heating a mixture of 6-aminocoumarin
(1) and the bromomalonic ester (2) at 125–140 ꢀC in a solvent-free condition. Diethyl
2-(2-oxo-2H-chromen-6-yl-amino)malonate (3) on intermolecular Michael addition
followed by intramolecular amidification[9] with 2-(20-furyl)acryloyl chloride in the
presence of triethylamine produced the c-lactam diester derivative (4a) in the 68%
yield.
The diester derivative (4a) on hydrolysis with ꢁ2 equivalents of KOH in
refluxing aqueous ethanol underwent in situ decarboxylation to furnish the trans
c-lactam monocarboxylic acid derivative (5a) as a colorless solid in 75% yield
(100% diastreoselectivity). The trans geometry was assigned from the coupling
constant value of H2 and H3 protons (J ꢁ 3.4 Hz) as well as by analogy.[8,10]
Homologation of the carboxylic side chain was achieved via Arndt–Eistert method.
The c-lactam carboxylic acid was converted to the acid chloride by treatment with
thionyl chloride. The acid chloride on treatment with an excess of a solution of
diazomethane in Et2O afforded the diazoketone (6a) as a pale yellow viscous
liquid, which solidified on standing. The diazoketone on refluxing with Ag2O in
anhydrous MeOH afforded 7a in 56% yield. 1HNMR and 13CNMR spectra of
7a are in good agreement with the assigned structure. The ester derivative (7a),
when hydrolyzed with 1.1 equivalent of KOH in refluxing aqueous ethanol,
produced the carboxylic acid 8a in 70% yield.
Following a similar sequence of reactions, starting from diethyl 2-(2-oxo-2H-
chromen-6-yl-amino)malonate (2) and 2-(20-thienyl)acryloyl chloride or cinnamoyl
chloride, the C3-2-thienyl or C3-phenyl analogs 4b, 4c, 5b, 5c and 6b, 6c, 7b, 7c
8b, and 8c were prepared.

3034
P. PATRA ET AL.
The antibacterial properties of the c-lactam acids 5(a–c) as well as their methyl
ester derivatives were then tested by the cylinder plate method, using reference stan-
dard ampicillin sodium solution, against the growth of E. coli (NCTC 9002),
S. aureus (ATCC 29737), and P. aureginosa (ATCC 9027) with lactamase-producing
strains. Both compounds 5a and 5b were found to inhibit the growth of bacterial
propagation in moderate to good amounts, while the corresponding C3-phenyl
derivative 5c was poorly active in inhibiting the growth. For the corresponding
methyl ester derivatives of compound 5(a–b), bacterial growth inhibition was found
to be lesser compared to the free acid derivatives 5a or 5b. Unlike the N-aryl-3-
phenylpyrrolidine-2-carboxylic ester=acid derivatives,[8a] the N-coumarinyl-3-
phenylpyrrolidine-2-carboxylic ester=acid derivatives displayed weak but positive
activity in inhibiting the bacterial propagation. This may be due to the synergistic
effect of the coumarin moiety. All the compounds, however, showed either no
activity or poor activity in inhibiting the growth of P. aureginosa. The results are
summarized in Table 1.
EXPERIMENTAL
All melting points are uncorrected and were checked with one-side-open
glass capillary using a sulfuric acid bath. Solvents were dried following standard
literature procedure. 1HNMR spectra were recorded on Brucker 500-MHz (at
Chemgen Pharma, Kolkata) and Brucker 200-MHz (at IIT Kharagpur) instru-
ments. 13CNMR spectra were recorded respectively in 50 or 125 MHz NMR spec-
trometer (Brucker) respectively. Electrospray ionization (ESI)-mass spectra were
recorded on a Micro mass Q-TOF mass spectrometer (serial no. YA 263) at
Indian Association for the Cultivation of Sciences (IACS), Kolkata. Infrared (IR)
spectral data was obtained on a Jasco FT=IR680 Plus spectrometer.
2-(2-Oxo-2H-chromen-6-yl-amino)malonic Acid Diethyl Ester (3)
6-Aminocoumarin (1) (8.05 g, 0.05 mol) and 6.0 g (0.025 mol) of diethyl 2-
bromomalonate (2) were taken in a 100-mL, round-bottomed flask fitted with a
Table 1. Zone of inhibition with standard solution of c-lactam carboxylic acids 5(a–c) and the
corresponding methyl ester derivatives against E coli, S. aureus, and P. aureginosa
Zone of inhibition (diameter in cm) (% with respect to ampicillina)
E. coli (NCTC 9002)
(ampicillin resistant)
S. aureus (ATCC 29737)
(ampicillin resistant)
P. aureginosa
(ATCC 9027)
c-Lactam derivative
5a
5b
0.2 (ꢁ24%)
0.3 (ꢁ35%)
0.1 (ꢁ12%)
0.2 (ꢁ24%)
0.1 (ꢁ12%)
Not significant
0.3 (ꢁ25%)
0.5 (ꢁ42%)
0.2 (ꢁ17%)
0.1 (ꢁ8%)
0.1 (ꢁ8%)
0.1 (ꢁ8%)
Not significant
0.1 (ꢁ12%)
5c
Not significant
Not significant
0.1 (ꢁ8%)
Methyl ester derivative of 5a
Methyl ester derivative of 5b
Methyl ester derivative of 5c
Not significant
aSample concentration and ampicillin concentration used: 100 mg=mL of acetonitrile.

N-ARYL MODIFICATION IN c-LACTAM
3035
two-way stopcock. It was then evacuated and the stopcock was closed. The mixture
was then heated on an oil bath, first at 135–140 ꢀC for 1 h and then at 125 ꢀC for 2 h.
After cooling to room temperature, the vacuum was released, and the dark brown
residue was digested with dry benzene (toluene also can be used) and filtered to sep-
arate the 6-aminocoumarin hydrobromide salt. The filtrate was washed once with 5%
diluted HCl and then thoroughly with water and dried (anhydrous Na2SO4). The
benzene layer was treated with a little active charcoal and filtered. Removal of the
solvent afforded the crude product, which was recrystallized from ethanol to furnish
the title compound (3) as a pale yellow solid. Yield, 5.6 g (70%); mp 101–102 ꢀC
1
(EtOH). IR (KBr) nmax: 1715, 1748 and 3411 cmꢂ1; H NMR (CDCl3=500 MHz)
d: 1.30 (t, 6H, J ¼ 7.0 Hz), 4.29 (q, 4H, J ¼ 7.0), 4.74 (d, 1H, J ¼ 7.5 Hz), 4.91 (d,
1H, J ¼ 7.5 Hz), 6.39 (d, 1H, J ¼ 9.5 Hz), 6.65 (d, 1H, J ¼ 2.5 Hz), 6.90 (dd, 1H,
J ¼ 2.5 and 9.0 Hz), 7.20 (d, 1H, J ¼ 9.0 Hz), 7.59 (d, 1H, J ¼ 9.5 Hz) ppm; 13C
NMR (CDCl3=125 MHz) d: 14.05, 60.96, 62.62, 109.70, 117.08, 117.79, 118.68,
119.41, 142.27, 143.22, 147.60, 161.06, 167.32 ppm.
3-Aryl/heteroaryl-5-oxo-1-(2-oxo-2H-chromen-6-yl)pyrrolidine-2,2-
dicarboxylic Acid Diethyl Ester 4(a–c)
A solution of 0.012–0.013 mol of 2-(2-furoyl=thienyl)acryloyl chloride or cinna-
moyl chloride in 25 mL dry benzene was added drop wise to a stirred solution of
compound 3 (3.19 g, 0.01 mol) and triethylamine (3.03 g or 4.2 mL, 0.03 mol) in
60 mL dry benzene. The reaction mixture warmed up and a white precipitate sepa-
rated out. The mixture was then refluxed on water bath for 7–8 h with protection
from moisture (completion of the reaction was monitored with thin-layer chromato-
graphy). It was then cooled to room temperature, and the reaction mixture was
transferred to a separatory funnel. The mixture was successively washed with cold
5% HCl, 5% NaHCO3 solution, and finally thoroughly with water. The organic layer
was collected and dried (anhydrous Na2SO4), and removal of solvent furnished a
highly viscous brownish yellow oil, which solidified on standing. It was further
purified by recrystallization from EtOH or by column chromatography [silica gel;
petroleum ether (60–80 ꢀC)–EtAc mixture] to furnish the c-lactam derivatives 4 in
66–72% yield.
Compound 4a. White solid; yield, 68%, mp 132–133 ꢀC (EtOH). IR (KBr)
n
max: 1610, 1624, 1730 (strong & broad) cmꢂ1 1H NMR (CDCl3=500 MHz) d:
;
1.00 (t, 3H, J ¼ 7.0 Hz), 1.05 (t, 3H, J ¼ 7.0 Hz), 2.94 (dd, 1H, J ¼ 9.0 & 17.0 Hz),
3.09 (dd, 1H, J ¼ 11.0 & 17.0 Hz), 3.83 (m, 1H), 4.05 (m, 1H), 4.11 (m, 1H), 4.17
(m, 1H), 4.69 (dd, 1H, J ¼ 9.0 and 11.0 Hz), 6.33 (d, 1H, J ¼ 3.0 Hz), 6.38 (br t,
1H, J ꢁ 2.5 Hz), 6.46 (d, 1H, J ¼ 9.5 Hz), 7.35 (d, 1H, J ¼ 8.5 Hz), 7.41–7.42 (m,
2H), 7.52 (d, 1H, J ¼ 2.5 Hz), 7.69 (d, 1H, J ¼ 9.5 Hz) ppm.; 13C NMR (CDCl3=
125 MHz) d: 13.62, 33.21, 39.97, 62.63, 62.75, 109.15, 110.59, 117.17, 117.44,
119.07, 128.31, 132.26, 132.85, 142.69, 143.00, 149.39, 153.44, 160.28, 166.14,
167.19, 173.91 ppm. HRMS (ESI, 70 eV): m=z ¼ 440.1055 (Mþ þ H), 462.1004
(Mþ þ Na) [calculated mass for C23H22NO8 440.1345 (Mþ þ H), C23H21 NO8Na:
462.1165 (Mþ þ Na)].

3036
P. PATRA ET AL.
Compound 4b. White solid; yield, 66%, mp 163–164 ꢀC (EtOH). IR (KBr)
1
n
max: 1622, 1693, 1720, 1751 (strong & broad) cmꢂ1; H NMR (CDCl3=500 MHz)
d: 0.91 (t, 3H, J ¼ 7.2 Hz), 0.99 (t, 3H, J ¼ 7.2 Hz), 3.06 (d, 1H, J ¼ 9.8 Hz),
3.64–3.80 (m, 1H), 3.95–4.21 (m, 3H), 4.84 (t, 1H, J ¼ 9.8 Hz), 6.44 (d, 1H,
J ¼ 9.6 Hz), 6.97–7.04 (m, 2H), 7.27–7.41 (m, 3H), 7.47 (d, 1H, J ꢁ 2.5 Hz), 7.60
(d, 1H, J ¼ 9.6 Hz) ppm; 13C NMR (CDCl3=125 MHz) d: 13.39, 13.58, 35.89,
40.98, 62.54, 62.58, 78.80, 117.09, 117.38, 119.00, 125.55, 126.62, 126.83, 128.24,
132.17, 132.97, 138.35, 142.96, 153.35, 160.24, 166.16, 167.00, 173.90 ppm. HRMS
(ESI, 70 eV): m=z ¼ 456.1054 (Mþ þ H) [calculated mass for C23H22NO7S:
456.1117 (Mþ þ H)].
Compound 4c. White solid; yield, 72%, mp 120–122 ꢀC (cold EtOH, ꢁ5 ꢀC).
IR (KBr) nmax: 1626, 1696, 1731 (strong & broad), 1747 (strong & broad) cmꢂ1
;
1H NMR (CDCl3=500 MHz) d: 0.79 (t, 3H, J ¼ 7.2 Hz), 0.99 (t, 3H, J ¼ 7.2 Hz),
3.04 (d, 1H, J ¼ 9.2 Hz), 3.51 (m, 1H), 3.86 (m, 1H), 4.00 (m, 1H), 4.17 (m, 1H),
4.60 (t, 1H, J ¼ 9.2 Hz), 6.44 (d, 1H, J ¼ 9.6 Hz), 7.33–7.34 (m, 6H), 7.40 (dd, 1H,
J ¼ 2.1 and 8.8 Hz), 7.52 (d, 1H, J ¼ 2.0 Hz), 7.67 (d, 1H, J ¼ 9.6 Hz) ppm;
13C NMR (CDCl3=125 MHz) d: 13.28, 13.63, 35.18, 45.18, 62.09, 62.50, 79.17,
117.12, 117.38, 119.03, 128.31, 128.39, 128.48, 128.57, 132.38, 133.15, 136.42,
142.99, 153.41, 160.28, 166.81, 167.13, 174.98 ppm. HRMS (ESI, 70 eV): m=z ¼
450.2034 (Mþ þ H), 472.2255 (Mþ þ Na) [calculated mass for C25H24NO7:
450.1553(Mþ þ H), C25H23 NO8Na: 472.1372 (Mþ þ Na)].
3-Aryl/heteroaryl-5-oxo-1-(2-oxo-2H-chromen-6-yl)pyrrolidine-2-
carboxylic Acid 5(a–c)
To a solution of the c-lactam diester derivative (4) (5.0 mmol) in 20 mL EtOH,
20 mL of aqueous solution of KOH (700 mg, 12.5 mmol) was added. The mixture was
refluxed on a water bath for 4.0–4.5 h. Excess ethanol was distilled out, and crushed
ice was added to the residue and then acidified with concentrated HCl. The separated
solid was filtered or extracted with ethyl acetate, washed with water, and dried
(anhydrous Na2SO4), and the solvent was removed. The crude trans acid derivative
thus obtained was redissolved in saturated aqueous NaHCO3 solution and extracted
with EtAc to remove the neutral part (if any). The aqueous part was treated with a
pinch of active charcoal (if required) and filtered. The filtrate was cooled in ice and
on acidification produced the carboxylic acid 5 as a white precipitate, which was
filtered under suction to furnish the title compound 5 in 70–75% yield. An analytical
sample was prepared by recrystallization from ethyl acetate–petroleum ether mixture.
[NMR spectra=HRMS data of the samples were recorded as methyl ester derivative
(prepared by treatment of the sample with diazomethane).]
Compound 5a. White solid; yield, 75%, mp 148–149 ꢀC. IR (KBr) nmax: 1730
(strong & broad), 3443 (broad) cmꢂ1 1H NMR of the methyl ester derivative
;
(CDCl3=200 MHz) d: 2.82 (dd, 1H, J ¼ 4.4 and 17.2 Hz), 3.12 (dd, 1H, J ¼ 8.8 and
17.2 Hz), 3.77 (s, 3H), 3.78 (m, 1H), 4.83 (d, 1H, J ¼ 3.4 Hz), 6.25 (d, 1H, J ¼ 3.4 Hz),
6.36 (dd,1H, J ¼ 1.8 and 3.4 Hz), 6.44 (d, 1H, J ¼ 9.6 Hz), 7.32 (d, 1H, J ¼ 8.8 Hz),
7.41 (dd, 1H, J ¼ 0.8 and 1.8 Hz), 7.46 (dd, 1H, J ¼ 2.6 and 8.8 Hz), 7.90 (d, 1H,
J ¼ 9.6 Hz), 8.0 (d, 1H, J ¼ 2.5 Hz) ppm; 13C NMR of the methyl ester derivative

N-ARYL MODIFICATION IN c-LACTAM
3037
(CDCl3=50 MHz) d: 35.94, 36.17, 53.49, 66.83, 106.91, 110.99, 117.80, 117.96,
119.55, 122.26, 125.99, 134.54, 143.13, 143.51, 152.01, 153.37, 160.78, 171.25,
173.20 ppm; HRMS of the methyl ester derivative (ESI, 70 eV): m=z ¼ 353.9624
(Mþ þ H), 375.9337 (Mþ þ Na) [calculated mass for C19H16NO6 354.0987 (Mþ þ H),
C19H15 NO6Na: 376.0797 (Mþ þ Na)].
Compound 5b. White solid; yield, 74%, mp 138–140 ꢀC. IR (KBr) nmax: 1609,
1730 (strong & broad) cmꢂ1 1H NMR of the methyl ester derivative (CDCl3=
;
500 MHz) d: 2.79 (dd, 1H, J ¼ 3.7 and 17.2 Hz), 3.23 (dd, 1H, J ¼ 8.8 and
17.2 Hz), 3.78 (s, 3H), 4.00 (m, 1H), 4.75 (d, 1H, J ¼ 3.0 Hz), 6.44 (d, 1H, J ¼ 9.6 Hz),
6.98–7.0 (m, 2H), 7.25 (d, 1H, J ¼ 4.9 Hz), 7.32 (d, 1H, J ¼ 8.9 Hz), 7.49 (dd, 1H,
J ¼ 2.5 and 8.9 Hz), 7.69 (d, 1H, J ¼ 9.6 Hz), 7.74 (d, 1H, J ¼ 2.0 Hz) ppm;
13C NMR of the methyl ester derivative (CDCl3=125 MHz) d: 37.96, 39.65, 53.51,
70.00, 117.81, 118.00, 119.58, 122.37, 125.03, 125.13, 126.11, 127.62, 134.48,
143.50, 144.67, 152.08, 160.75, 171.09, 173.07 ppm. HRMS of the methyl ester
derivative (ESI, 70 eV): m=z ¼ 370.0054 (Mþ þ H), 392.0514 (Mþ þ Na) [calculated
mass for C19H16NO5S 370.0749 [(Mþ þ H), C19H15 NO5SNa: 392.0569 (Mþ þ Na)].
Compound 5c. White solid, yield 70%, m.p. 140–141 ꢀC. IR (KBr) nmax
:
1610, 1649, 1731 (strong & broad) cmꢂ1; H NMR of the methyl ester derivative
(CDCl3=200 MHz) d: 2.76 (dd, 1H, J ¼ 4.0 and 17.4 Hz), 3.21 (dd, 1H, J ¼ 9.0 &
17.4 Hz), 3.66 (dt, 1H, J ¼ 3.6 & 9.0 Hz), 3.76 (s, 3H), 4.70 (d, 1H, J ¼ 3.0 Hz),
6.44 (d, 1H, J ¼ 9.6 Hz), 6.26–7.40 (m, 6H), 7.44 (d, 1H, J ¼ 2.5 & 9.0 Hz), 7.90 (d,
1H, J ¼ 9.6 Hz), 8.0 (d, 1H, J ¼ 2.5 Hz) ppm; HRMS of the methyl ester derivative
(ESI, 70 eV): m=z ¼ 364.2425 (Mþ þ H) [calculated mass for C21H18NO5,
364.1185(Mþ þ H)].
1
4-Aryl/heteroaryl-1-(2-oxo-2H-chromen-6-yl)-5-diazoacetylpyrrolidine-
2-one 6(a–c)
To a solution of c-lactam monocarboxylic acid (4) (3.8 mmol) in 60 ml of dry
benzene, 570 mg (0.35 mL, 4.8 mmol) of SOCl2 was added followed by addition of
catalytic amount of dry dimethylformamide (DMF). The mixture was refluxed on
a water bath for 4–4.5 h protecting from moisture. Removal of solvent and excess
thionyl chloride afforded the crude acid chloride as viscous light yellow oil in almost
quantitative yield. The crude acid chloride was immediately dissolved in a dry
dichloromethane–ether mixture and was added dropwise with stirring to an ice-cold
solution of diazomethane in ether (generated from 6.5 g of nitrosomethylurea). The
mixture was left overnight at room temperature. Removal of the solvent left a brown
oil. It was redissolved in anhydrous ether and filtered through a column of neutral
alumina. Evaporation of the solvent afforded the diazoketone as a pale yellow
viscous mass, which solidified on standing. Yield, 60–65%.
Compound 6a. White solid; yield, 65%, mp 151–152 ꢀC (diethyl ether,
0–5 ꢀC). IR (KBr) nmax: 1632, 1713 (strong & broad), 2112 (strong) cmꢂ1
;
1H NMR (CDCl3=500 MHz) d: 2.84 (dd, 1H, J ¼ 4.9 and 17.3 Hz), 3.10 (dd, 1H,
J ¼ 9.2 and 17.3 Hz), 3.72 (m, 1H), 4.73 (d, 1H, J ¼ 2.5 Hz), 5.40 (s, 1H), 6.26 (br

3038
P. PATRA ET AL.
s, 1H), 6.37 (br s, 1H), 6.43 (d, 1H, J ¼ 10.0 Hz), 7.32 (d, 1H, J ¼ 8.9 Hz), 7.42 (br s,
1H), 7.48 (br d, 1H, J ¼ 8.7 Hz), 7.68 (d, 1H, J ¼ 10.0 Hz), 7.73 (br s, 1H) ppm.
Compound 6b. White solid; yield, 64%, mp 153–154 ꢀC (diethyl ether,
0–5 ꢀC). IR (KBr) nmax: 1625, 1710 (strong & broad), 2108 (strong) cmꢂ1 1H
;
NMR (CDCl3=500 MHz) d: 2.77 (dd, 1H, J ¼ 4.6 and 17.2 Hz), 3.20 (dd, 1H,
J ¼ 8.8 and 17.2 Hz), 3.92 (quin, 1H, J ¼ 4.3 Hz), 4.61 (d, 1H, J ¼ 3.3 Hz), 5.34 (s,
1H), 6.44 (d, 1H, J ¼ 9.6 Hz), 6.96–6.98 (m, 2H), 7.23 (dd, 1H, J ¼ 1.7 and 4.5 Hz),
7.32 (d, 1H, J ¼ 9.0 Hz), 7.48 (dd, 1H, J ¼ 2.4 and 9.0 Hz), 7.68 (d, 1H, J ¼ 9.6 Hz),
7.74 (d, 1H, J ¼ 2.4 Hz) ppm.
Compound 6c. White solid; yield, 60%, mp 156–157 ꢀC. IR (KBr) nmax: 1646,
1
1701 (strong), 1727 (strong), 2111 (strong) cmꢂ1; H NMR (CDCl3=500 MHz) d:
2.78 (dd, 1H, J ¼ 4.0 and 17.5 Hz), 3.20 (dd, 1H, J ¼ 9.5 and 17.5 Hz), 3.61 (t, 1H,
J ¼ 4.0 Hz), 4.62 (br s, 3H), 5.29 (s, 1H), 6.45 (d, 1H, J ¼ 9.5 Hz), 7.29–7.39 (m,
6H), 7.52 (br d, 1H, J ¼ 8.5 Hz), 7.69 (d, 1H, J ¼ 9.5 Hz), 7.78 (br s, 1H) ppm.
trans-Methyl 2-[(3-Aryl)-5-oxo-1-(2-oxo-2H-chromen-6-yl)pyrrolidine-
2yl]acetate 7(a–c)
To a stirred solution of the diazoketone (6) (4.3 mmol) in 15 mL of dry meth-
anol at 50 ꢀC, 0.5 g of Ag2O was added in two to three batches. Immediate evolution
of N2 took place. When the nitrogen evolution ceased, a further quantity of Ag2O
(500 mg) was added, and the mixture was refluxed on a water bath for 2 h. It was
then filtered, and the solvent was removed. The brownish yellow oil obtained on
purification by column chromatography (silica gel, light petrol–EtAc mixture, 9:1)
afforded the title compound as a pale semisolid mass. Yield, 56–58%.
Compound 7a. White solid; yield, 56%, mp 135–136 ꢀC (diethyl ether,
1
0–5 ꢀC). IR (KBr) nmax: 1729 (strong & broad) cmꢂ1; H NMR (CDCl3=500 MHz)
d: 2.62 (dd, 1H, J ¼ 7.2 and 15.7 Hz), 2.71 (dd, 1H, J ¼ 4.6 and 15.7 Hz), 2.86 (dd,
1H, J ¼ 6.7 and 17.3 Hz), 3.02 (dd, 1H, J ¼ 9.2 and 17.3 Hz), 3.54 (s, 3H), 3.59 (m,
1H), 4.66 (m, 1H), 6.23 (d, 1H, J ¼ 3.2 Hz), 6.35 (dd, 1H, J ¼ 1.9 and 3.2 Hz), 6.46
(d, 1H, J ¼ 9.6 Hz), 7.36 (d, 1H, J ¼ 8.9 Hz), 7.41 (d, 1H, J ¼ 1.8 Hz), 7.48 (dd, 1H,
J ¼ 2.4 and 8.9 Hz), 7.58 (d, 1H, J ¼ 2.4 Hz), 7.69 (d, 1H, J ¼ 9.6 Hz) ppm; HRMS
(ESI, 70 eV): m=z ¼ 368.1574 (Mþ þ H), 390.1384 (Mþ þ Na) [calculated mass for
C20H18NO6 368.1134 [(Mþ þ H), C20H17 NO6Na: 390.0954 (Mþ þ Na)].
Compound 7b. White solid; yield, 58%, mp 146–147 ꢀC. IR (KBr) nmax: 1622,
1693, 1715 (strong & broad), 1751 (strong & broad) cmꢂ1 1H NMR (CDCl3=
;
500 MHz) d: 2.55 (dd, 1H, J ¼ 7.5 and 15.8 Hz), 2.64 (dd, 1H, J ¼ 4.5 and
15.8 Hz), 2.73 (dd, 1H, J ¼ 5.8 and 17.4 Hz), 3.08 (dd, 1H, J ¼ 8.9 and 17.4 Hz),
3.48 (s, 3H), 3.72 (m, 1H), 4.53 (m, 1H), 6.39 (d, 1H, J ¼ 9.6 Hz), 6.92–6.94 (m,
2H), 7.18 (dd, 1H, J ¼ 1.9 and 4.5 Hz), 7.29 (d, 1H, J ¼ 8.9 Hz), 7.43 (dd, 1H,
J ¼ 2.5 and 8.9 Hz), 7.54 (d, 1H, J ¼ 2.5 Hz), 7.61 (d, 1H, J ¼ 9.6 Hz) ppm; 13C
NMR (CDCl3=125 MHz) d: 37.60, 38.76, 43.06, 51.89, 64.45, 117.45, 117.69,
119.25, 123.51, 126.88, 127.46, 127.66, 129.21, 133.25, 141.91, 142.93, 151.90,
160.30, 170.35, 173.10 ppm; HRMS (ESI, 70 eV): m=z ¼ 384.2672 (Mþ þ H),

N-ARYL MODIFICATION IN c-LACTAM
3039
406.2572 (Mþ þ Na) [calculated mass for C20H18NO5S 384.0906 [(Mþ þ H), C20H17
NO5SNa: 306.0725 (Mþ þ Na)].
Compound 7c. White solid; yield, 58%, mp 122–123 ꢀC.(diethyl ether,
0–5 ꢀC). IR (KBr) nmax: 1693 (strong & broad), 1715 (strong & broad), 1751 (strong
1
& broad) cmꢂ1; H NMR (CDCl3=500 MHz) d: 2.58 (dd, 1H, J ¼ 7.9 and 15.6 Hz),
2.69 (dd, 1H, J ¼ 4.4 and 15.6 Hz), 2.77 (dd, 1H, J ¼ 5.9 and 17.6 Hz), 3.14 (dd, 1H,
J ¼ 9.2 and 17.6 Hz), 3.45 (m, 1H), 3.50 (s, 3H), 4.57 (m, 1H), 6.45 (d, 1H,
J ¼ 9.6 Hz), 7.27–7.40 (m, 6H), 7.51 (dd, 1H, J ¼ 2.5 and 8.9 Hz), 7.62 (d, 1H, J ¼
2.4 Hz), 7.69 (d, 1H, J ¼ 9.6 Hz) ppm; HRMS (ESI, 70 eV): m=z ¼ 378.0778
(Mþ þ H) [calculated mass for C22H20NO5 364.1341 (Mþ þ H).
trans-Methyl 2-[(3-Aryl)-5-oxo-1-(2-oxo-2H-chromen-6-yl)pyrrolidine-
2yl]acetic Acid 8(a–c)
A mixture of the ester derivative (7) (0.27 mmol), KOH (0.3 mmol), ethanol
(5.0 ml), and water (5.0 mL) was refluxed on a water bath for 1.5 h. The solvent
was removed as much as possible. The residue was the cooled to 0–5 ꢀC and acidified
with concentrated HCl. The residue was the extracted with ethyl acetate thoroughly.
The organic layer was washed with saturated NaHCO3 solution. The sodium bicar-
bonate layer was collected, cooled to 0–5 ꢀC, and acidified with concentrated HCl.
The white precipitate formed was extracted with ethyl acetate, washed with cold
brine solution, and dried (anhydrous Na2SO4), and the solvent was removed. The
carboxylic acid 8 was obtained as a white powder. Yield, 70–75%.
Compound 8a. White solid; yield, 70%, mp 140–142 ꢀC. IR (KBr) nmax: 1693,
1715, 1751 cmꢂ1 (all are strong & broad). (Mp and 1H NMR spectra of methyl ester
derivative, prepared by treatment of the sample with diazomethane, were identical
with those of 7a.)
Compound 8b. White solid; yield, 72%, mp 148–150 ꢀC. IR (KBr) nmax: 1693,
1715, 1751 cmꢂ1 (all are strong & broad). (Mp and 1H NMR spectra of methyl ester
derivative, prepared by treatment of the sample with diazomethane, were identical
with those of 7b.)
Compound 8c. White solid; yield, 75%, mp 131–132 ꢀC. IR (KBr) nmax: 1699,
1736 cmꢂ1 (both strong & broad). (Mp and 1H NMR spectra of methyl ester deriva-
tive, prepared by treatment of the sample with diazomethane, were identical with
those of 7c.)
ACKNOWLEDGMENTS
Financial help from the Department of Science and Technology (Project
No. SR=S-1=OC-10), New Delhi, is gratefully acknowledged. Thanks to the Council
of Scientific and Industrial Research, New Delhi, for providing a NET fellowship to
one of the author (P. P.).

3040
P. PATRA ET AL.
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