Evaluation of novel coumarin-proline sulfonamide hybrids as anticancer and antidiabetic agents

Article abstract of DOI:10.1080/00397911.2019.1647439

Cancer and diabetes are considered as two major diseases affecting human health worldwide. Various therapies are available for treatment of cancer and diabetes individually, peptide linkage containing proline sulfonamide can be a promising therapy for treatment of both cancer as well as diabetes. Here, we report design and synthesis of novel coumarin-proline sulfonamide derivatives as anticancer and antidiabetic agents. All the synthesized compounds were screened for their anticancer activity against lungs cancer cell line (A549) and breast cancer cell line (MCF7) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye (MTT)assay and antidiabetic activity using DPP-IV inhibition assay. Compound 16b showed excellent activity against breast cancer cell line (MCF7) with IC₅₀ value of 1.07 μM. All compounds showed moderate DPP-IV inhibition.

Full text of DOI:10.1080/00397911.2019.1647439

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Evaluation of novel coumarin-proline sulfonamide
hybrids as anticancer and antidiabetic agents
Sunil Dutt Durgapal & Shubhangi S. Soman
To cite this article: Sunil Dutt Durgapal & Shubhangi S. Soman (2019): Evaluation of novel
coumarin-proline sulfonamide hybrids as anticancer and antidiabetic agents, Synthetic
Communications, DOI: 10.1080/00397911.2019.1647439
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https://doi.org/10.1080/00397911.2019.1647439
Evaluation of novel coumarin-proline sulfonamide hybrids
as anticancer and antidiabetic agents
Sunil Dutt Durgapal and Shubhangi S. Soman
Department of Chemistry, Faculty of Science, M. S. University of Baroda, Vadodara, India
ABSTRACT
ARTICLE HISTORY
Received 25 April 2019
Cancer and diabetes are considered as two major diseases affecting
human health worldwide. Various therapies are available for treat-
ment of cancer and diabetes individually, peptide linkage containing
proline sulfonamide can be a promising therapy for treatment of
both cancer as well as diabetes. Here, we report design and synthe-
sis of novel coumarin-proline sulfonamide derivatives as anticancer
and antidiabetic agents. All the synthesized compounds were
screened for their anticancer activity against lungs cancer cell line
(A549) and breast cancer cell line (MCF7) using 3-(4,5-dimethylthia-
zol-2-yl)-2,5-diphenyltetrazolium bromide dye (MTT)assay and antidia-
betic activity using DPP-IV inhibition assay. Compound 16b showed
excellent activity against breast cancer cell line (MCF7) with IC50
value of 1.07 mM. All compounds showed moderate DPP-IV inhib-
ition.
KEYWORDS
Aminocoumarin; anticancer;
DPP-IV inhibitor; proline;
sulfonamide
GRAPHICAL ABSTRACT
Introduction
Cancer and diabetes are two major diseases affecting human health worldwide. Cancer
is considered as fatal disease, while type 2 diabetes is considered as one of the major
threat to human health. According to WHO, around 18.1 million new cases of cancer
CONTACT Shubhangi S. Soman
shubhangiss@rediffmail.com
Department of Chemistry, Faculty of Science, M. S.
University of Baroda, Vadodara 390 002, India
Supplemental data for this article can be accessed on the publisher’s website.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
ß 2019 Taylor & Francis Group, LLC

2
S. D. DURGAPAL AND S. S. SOMAN
Figure 1. Sulfonamide derivatives 1–8 with anticancer and antidiabetic activity.
and 9.6 million cancer death was estimated to occur only in 2018.[1] In last few decades,
there are several reports on development of sulfonamide derivatives with various bio-
logical activities. Sulfonamide derivatives are known for its antimicrobial, carbonic
anhydrase, antitumor, and antidiabetic activities.[2–4] Various sulfonamide derivatives
1–8 having anticancer and antidiabetic activities are shown in Figure 1. Compound
1 (Figure 1) studied for histone deacetylase (HDAC) inhibitors that can induce
hyperacetylation of histones in human cancer cells, which blocks the cell cycle and
induce apoptosis in human cancer cells but not in normal cells.[5,6] Indisulam 4
(Figure 1) is a novel sulfonamide anticancer agent in clinical development for treat-
ment of solid tumor, which includes renal, breast and colorectal cancer.[7,8]
Dipeptidyl peptidase IV (DPP-IV E.C.3.3.145, CD 26) is a serine protease enzyme
formed in various tissues and body fluids of mammals. It plays important roles in
variety of disease like autoimmune disease, AIDS, and melanoma. DPP-IV is associ-
ated with glucose metabolism, immune regulation, signal transduction and apoptosis
and regulating cancer. Compounds 6–8 (Figure 1) have been reported as potent
DPP-IV inhibitors.[9–11]
The findings from meta-analysis indicated positive association between diabetes pri-
marily Type II diabetes and breast cancer risk. Results showed that women with dia-
betes may have 20% increased risk of breast cancer. The association between diabetes
and breast cancer was consistent for case–control and cohort studies and for studies
carried out in North America, Europe, and Asia.[12,13] In diabetic patients, cancer may
be favored by two types of mechanisms: (i) general mechanisms that promote cancer

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SYNTHETIC COMMUNICATIONSV
3
initiation or progression in any organ due to hyperglycemia, hyperinsulinemia or drugs
that affect all tissues, (ii) site-specific mechanisms affecting cancerogenesis of a particu-
lar organ.[14]
Metformin is one of the most widely prescribed drugs for the treatment for type 2
diabetes and also used in cardiovascular disease prevention.[15] Epidemiological observa-
tions have suggested that the use of metformin in diabetes mellitus patients is correlated
with a reduction in cancer incidence.[16]
Coumarin is a class of natural and synthetic compound which shows versatile
pharmacological activities like anticarcinogenic,[17] antiviral,[18] antimicrobial,[19] anti-
depressant,[20] antinflamatory,[21] antioxidant,[22] antidiabetic,[23] etc. Several compounds
containing coumarin scaffold are clinically well-known agents.[24–26]
In our previous study, we did several modifications on third and seventh position of
coumarin, which led to excellent anticancer activity and antidiabetic activity.[23,27,28]
Keeping in mind the activity of various coumarin derivatives and sulfonamides and in
continuation of our work on designing new compounds with anticancer and antidia-
betic activity, we have designed pharmacophore which can have binary application.
Hereby we report synthesis of coumarin proline sulfonamide hybrids to get a potent
compound having both anticancer and antidiabetic activity. All the compounds were
screened for their in vitro anticancer activity using MTT assay and antidiabetic activity
as DPP-IV inhibition assay.
Results and discussion
In search of some novel compounds with potent anticancer activity and antidiabetic
activity, compounds 16a–c have been synthesized from 7-amino-4-methylcoumarin 12
(Scheme 1). Compound 12 was synthesized in three steps starting with carbamate pro-
tected 3-aminophenol 10, which on Pechmann reaction with ethyl acetoacetate in 70%
ethanolic sulfuric acid gave 7-carboethoxy amino coumarin 11 followed by deprotection
in sulfuric acid/acetic acid (1:1) to give 7-amino-4-methyl coumarin 12. (L)-N-Boc-pro-
line 13 was first stirred with ethyl chloroformate in tetrahydrofuran (THF) at 0–5 ꢀC
followed by dropwise addition of solution of compound 12 and triethylamine (TEA) in
THF, which further refluxed for 8 hours to give compound 14. Deprotection of Boc
group in compound 14 was carried out using trifluoroacetic acid (TFA) to give com-
pound 15. Compound 15 was reacted with different benzene sulfonyl chloride deriva-
tives at room temperature using NaHCO3 in DCM:water (1:1) gave compounds 16a–c
(Scheme 1).
1H-NMR spectra of compound 14 showed peak at d 1.53 ppm for nine protons of
three methyl groups of Boc. Proline protons were observed in region from d 1.92 to
4.55 and methyl protons of coumarin at d 2.27. Aromatic protons were observed in
region from d 6.03 to 7.70 and amide proton was observed at 10.04 ppm. 13C-NMR
spectra of compound 14 showed peaks in region from 18.41 to 80.95 for aliphatic car-
bons of boc group and proline moiety, while aromatic carbons were observed from d
106.84 to 155.78 ppm and carbonyl carbon of amide and lactone ring of coumarin at
161.17 and 171.36 ppm, respectively. The proton NMR of Boc-deprotected compound
15 exhibited different peaks at d 1.77–2.81 ppm for aliphatic protons of proline, –NH

4
S. D. DURGAPAL AND S. S. SOMAN
Scheme 1. Synthesis of 7-Amino-4-methylcoumarin derivatives 16a–c.
proton as broad singlet around d 2.12 ppm, methyl group of coumarin at d 2.41 ppm.
Protons of proline next to nitrogen were observed at d 2.98–3.08, 3.01–3.14 and
3.91 ppm. Aromatic protons of coumarin ring were observed in the region of d
7.51–7.64 ppm and amide proton at d 10.05 ppm. In 13C-NMR spectrum of compound
15 showed peaks at d 18.67–61.02 ppm for carbons of methyl group and proline ring,
peaks at d 106.66–154.32 ppm for aromatic carbons and peak at d 161.24 ppm for amide
carbonyl and 174.08 ppm for carbonyl carbon of lactone ring. In IR spectrum of com-
pound 15 showed bands at 3304–3082 cmꢁ1 is for N–H and C–H stretching, bands at
1724 cmꢁ1 and 1679 cmꢁ1 corresponds to lactone carbonyl and amide functional groups
respectively.
1
The structures of compounds 16a–c were confirmed by its IR, H-NMR, 13C-NMR
1
and ESI-MS analyses. H-NMR of compound 16c exhibited peaks at d 1.61–4.21 for ali-
phatic protons, peaks at d 6.23–7.85 for aromatic protons and peak at d 9.02 ppm for
amide proton. 13C spectrum of compound 16c showed peaks at d 18.65–63.03 for ali-
phatic carbons and the peaks for aromatic carbons were observed in the range of
107.55–154.28 ppm. Amide carbonyl carbon was observed at 161.04 ppm and lactone
carbonyl carbon was observed at 169.09 ppm. IR spectrum of compound 16c showed
one band at 3338 cmꢁ1 for –NH stretching vibrations and band at 1716 and 1695 cmꢁ1
is for carbonyl stretching of lactone and amide, respectively. Sulfonamide group showed
peak at 1226–1201 cmꢁ1. Mass spectrum of compound 16c showed [M þ H]þ peak at
477. The structure of 16c was also confirmed by its single crystal analysis with CCDC
number 1876142.
Similar set of proline sulfonamide hybrid compounds 28a–c and 29a–c were synthe-
sized from 3–aminocoumarin 21–22 (Scheme 2). 3-Aminocoumarins 21–22 were

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Scheme 2. Synthesis of 3-Aminocoumarin derivatives 28a–c and 29a–c.
synthesized using Perkin reaction of o-hydroxy benzaldehyde 17 or b-hydroxy naphthal-
dehyde 18 with N-acetyl glycine in presence of sodium acetate and acetic anhydride to
give 3-acetamido coumarin derivatives 19–20, followed by hydrolysis of acetyl group
using ethanol: conc. HCl (7:3) to yield compounds 3-amino-2H-chromen-2-one (21)
and 2-amino-3H-benzo[f]chromen-3-one (22). Compounds 28a–c and 29a–c were syn-
thesized from compounds 21–22 using similar set of reaction conditions as discussed
for synthesis of 7-amino coumarin derivatives 16a–c from compound 15. All com-
1
pounds 28a–c and 29a–c were well characterized using spectral techniques such as H-
NMR, 13C-NMR, IR and ESI-MS.
1
The H-NMR spectrum of representative compound 28c showed multiplet at d 1.84
and singlet at d 2.27 for protons at third and fourth position of proline ring, multiplet
at d 3.30 and singlet at d 3.61 were observed for the protons at fifth position of proline
ring and doublet at d 4.31 was observed for second position proton of proline ring.
Aromatic protons were observed in the region from d 7.29 to 8.67 ppm and sharp sing-
let for amide proton at d 9.29 distinctively. 13C-NMR of compound 28c showed proline
ring carbons at d 24.69, 30.54, 49.89, 62.75, aromatic region carbons from d 116.45 to
150. Carbonyl carbon of amide and lactone were observed at d 158.41 and d
170.60 ppm, respectively.

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S. D. DURGAPAL AND S. S. SOMAN
Table 1. Anticancer activity against A549 (Lungs cancer cell
line), MCF-7 (Breast cancer cell line) for coumarin-proline sul-
fonamide hybrid derivatives.
IC50 in mMa
Compound
R
A549
MCF-7
15
16a
16b
16c
26
2.34
18.09
27.54
27.32
12.40
9.34
5.42
2.58
1.07
7.05
17.14
4.39
H
–CH3
–Cl
28a
H
28b
28c
27
29a
29b
29c
–CH3
–Cl
NA
7.39
3.75
19.95
11.95
23.09
11.13
7.759
3.81
11.74
22.94
7.37
50.99
45.04
H
ꢁCH3
ꢁCl
Fluorouracil
NA: not active.
aIC50 values were determined based on MTT assay using GraphPad
Prism software.
In IR spectrum of compound 28c bands for N-H and C-H stretching were observed
at 3311 and 3093 cmꢁ1, carbonyl stretching for lactone at 1724 and amide at 1693 cmꢁ1
,
respectively. The ESI-MS at 433.00 [M þ H]þ confirms the formation of desired com-
pound 28c. Formation of compound 29a was also confirmed by its single crystal X-ray
analysis (CCDC NO: 1876145)
Anticancer activity
Coumarin-proline sulfonamide hybrids 16a–c, 28a–c and 29a–c were synthesized from
7-amino-4-methyl coumarin and 3-amino coumarin having one electron withdrawing
group, electron releasing group and without any group on benzene sulfonamide. All
compounds 16a–c, 28a–c and 29a–c were screened initially for their anticancer activity
using MTT assay against A549 (Lungs cancer cell line), MCF-7 (Breast cancer cell line)
and compared with fluorouracil. Anticancer activity of coumarin-proline sulfonamide
hybrids were also compared with their precursor coumarin-proline derivatives 15
and 26–27.
Compound 15 with proline linked to 7-amino-4-methyl coumarin, showed good
activity against both A549 and MCF7 cancer cell line with IC50 values 2.34 mM and
5.42 mM (Table 1). Compound 16a with benzene sulfonamide group, showed drop in
activity against A549 cell line, while showed good activity in MCF7 cell line with IC50
value of 2.58 mM. Methyl substitution on benzene ring at para to sulfonamide group in
compound 16b resulted in loss of activity against A549 cell line, but showed excellent
activity with IC50 1.07 mM against MCF7 cell line (Table 1). Compound 16c with
4-chlorobenzene sulfonamide, showed moderate activity against both tested cell lines.
3-Aminocoumarin-proline hybrid compound 26 showed moderate activity against
both the tested cell lines. While benzene sulfonamide derivative 28a showed relatively
good activity compared to compound 26 against both tested cell lines. Compound 28b

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7
Table 2. DPP-IV inhibition activity of amino coumarin-proline sul-
fonamide derivative 16a–c, 28a–c and 29a–c.
% DPP-4 enzyme inhibition activitya
Compounds
25 mM
50 mM
100 mM
16a
16b
16c
28a
28b
28c
29a
29b
11.11
5.05
10.90
9.87
13.76
13.04
7.06
16.29
7.54
17.08
13.60
19.36
18.67
10.44
12.90
15.31
19.36
13.96
20.76
20.17
20.73
22.00
14.32
16.02
19.79
9.12
11.68
29c
Vildagliptin
56.3 % at 0.1mM
aDPP-IV inhibitory activity determined by fluorescence-based assay was measured
using Spectra Max fluorometer (Molecular Devices, CA). Values of % inhibition
are mean of three independent determinations at 25, 50 and 100 mM concentra-
tions of the test samples.
showed moderate activity against MCF7 cell line and lost the activity against A549 cell
line (Table 1).
However, 4-chlorobenzene sulfonamide compound 28c exhibited good activity with
IC50 value of 7.39 mM and 3.81 mM against A549 and MCF7 cell lines, respectively.
Compound 27 with extension of aromatic ring on amino coumarin part as compared to
compound 26, showed good activity against A549 cell line with IC50 value of 3.75 mM
and moderate activity against MCF7 cancer cell line (Table 1). Interestingly, conversion
of compound 27 to substituted benzene sulfonamide derivatives 29a–c resulted in loss
of activity against both tested cancer cell lines.
DPP-IV inhibition activity
Recently, coumarin containing compounds have been reported with very good DPP-IV
inhibition activity. Interestingly, position of attachment with coumarin moiety and type
of attachment showed drastic effect on DPP-IV inhibition activity of coumarin contain-
ing compounds. Proline containing derivatives as substrate like inhibitors are known
and reported with excellent DPP-IV inhibition activity. As these compounds 16a–c,
28a–c and 29a–c are hybrid of coumarin-proline and sulfonamide, they were also
selected to screen for their initial DPP-IV inhibition activity at three different concen-
trations of 25, 50 and 100 mM and compared with Vildagliptin.
Compound with 7-amino-4-methyl coumarin with proline sulfonamide 16a showed
poor activity with 19.36% DPP-IV inhibition at 100 mM concentration, substituting
methyl group on para position of benzene ring of sulfonamide resulted in compound
16b with decrease in activity with 13.96% DPP-IV inhibition at 100 mM (Table 2).
Change of methyl group by chloro resulted in compound 16c slightly increase in DPP4
inhibition of 20.76% in 100 mM concentration. Change of attachment of proline-sulfona-
mide moiety with coumarin from seventh positions to third position did not show
much change in DPP-IV inhibition activity for compounds 28a–c. 3-Aminocoumarin
analogs of proline-sulfonamide derivatives compound 28a showed poor activity with
20.17% inhibition at 100 mM concentration. Compound 28b with para-methyl and 28c

8
S. D. DURGAPAL AND S. S. SOMAN
with para-chloro on benzene sulfonamide showed moderate DPP4 inhibition at 100 mM
(Table 2).
Further, extension of aromatic ring on 3-aminocoumarin resulted in compound
29a–c with 3-aminobenzocoumarin proline-sulfonamide derivatives. Compounds 29a–c
were also showed similar trend of inhibitions with moderate activity at all three tested
concentrations. All synthesized compounds were compared with standard drug vilda-
gliptin with 56.3% inhibition at 0.1 mM concentration.
Conclusion
In this work, novel amino coumarin-proline sulfonamide hybrids were synthesized and
their in vitro anticancer activity and DPP-IV inhibition activity were evaluated. Among
the tested compounds almost all compounds showed moderate activity in A549 cell line
and excellent activity in MCF7 cancer cell line. Compounds were also screened for their
DPP-IV inhibition activity, Compounds 16a–c, 28a–c and 29a–c were found to be
inactive. The active compounds could be considered as useful templates for further
development to obtain more potent anticancer agents.
Experimental
General procedure for preparation of coumarin tert-butyl pyrrolidine-1-
carboxylate derivatives (14, 24, 25)
To an ice cold solution of ethyl chloroformate (2.55 mmol) in THF, the mixture of N-
Boc proline 13 (1.5 mmol) and TEA (1.5 mmol) in THF (10 mL) was added dropwise
followed by stirring for 10–15 min. To this mixture, the solution of aminocoumarin
12/21/22 (1.5 mmol) and TEA (1.5 mmol) in THF (20 mL) was added dropwise over a
period of 30 min at 0–5 ꢀC. The resulting mixture was stirred for another 30 min at
0–5 ꢀC, brought to room temperature and then refluxed for 8 h at 60 ꢀC. The comple-
tion of reaction was monitored by TLC. After completion of reaction, solvents were
removed under reduced pressure to give residue. The residue was dissolved in dichloro-
methane (DCM). The organic layer was washed with water, dil. HCl and sodium bicar-
bonate. The organic layer was dried over sodium sulfate, and concentrated to give
compound. The product was used in next step without any further purification.
Characterization data for Boc-protected compounds 14, 24, and 25
Tert-Butyl 2-((4-methyl-2-oxo-2H-chromen-7-yl)carbamoyl)pyrrolidine-1-carboxylate (14).
Pale yellow solid, Yield: 78%; M.P: 165–168 ꢀC; IR (KBr) 3312, 3055, 2976, 2891, 1718,
1689, 1622, 1577, 1531, 1448, 1406, 1390, 1369, 1269, 1215, 1174, 1126, 1068, 1016, 904,
1
881, 829, 773, 754, 711, 638, 576, 524 cmꢁ1; H-NMR(400 MHz, CDCl3): d 1.53 (s, 9 H),
1.92–1.98 (m, 1 H), 2.08 (br s, 2 H), 2.27 (br s, 1 H) 2.34 (s, 3 H), 3.43–3.45 (m, 1 H),
3.56–3.61 (m, 1 H), 4.56 (br s, 1 H), 6.03 (s, 1 H), 6.99 (d, J ¼ 7.6 Hz, 1 H), 7.33 (d,
J ¼ 8.4 Hz, 1 H), 7.70 (s, 1 H), 10.04 (s, 1 H); 13C-NMR(100 MHz, CDCl3): d ppm 18.41,
24.56, 28.48, 29.12, 47.35, 60.57, 80.95, 106.84, 112.83, 115.14, 115.31, 124.57, 141.74,

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SYNTHETIC COMMUNICATIONSV
9
152.52, 153.76, 155.78, 161.17, 171.36; Anal. Calc. for C20H24N2O5; C,64.50; H, 6.50; N,
7.52; found: C, 64.58; H, 6.61; N, 7.45%; ESI-MS: 373.10 [M þ H]þ.
Tert-Butyl 2-((2-oxo-2H-chromen-3-yl)carbamoyl)pyrrolidine-1-carboxylate (24). Pale yel-
low solid, Yield: 81%; M.P: 138–140 ꢀC; IR (KBr) 3365, 3250, 3211, 3045, 2972, 2931,
2877, 2866, 1730, 1697, 1674, 1626, 1608, 1537, 1477, 1458, 1452, 1404, 1352, 1294,
1263, 1197, 1188, 1172, 1126, 1101, 1030, 981, 956, 923, 910, 881, 856, 763, 721 cmꢁ1
;
1H-NMR(400 MHz, CDCl3): d 1.50 (s, 9 H), 1.95–2.06 (m, 2 H), 2.23–2.36 (m, 2 H),
3.40–3.54 (m, 2 H), 4.33–4.49 (m, 1 H), 7.42 (br s, 2 H), 7.47 (m, 2 H), 8.65 (s, 1 H),
9.39 (s, 1 H); 13C-NMR (100 MHz, CDCl3): d ppm 24.60, 28.32, 47.15, 61.03, 61.81,
81.11, 116.32, 119.78, 123.35, 124.23, 125.04, 127.73, 129.51, 150.02, 158.42, 171; Anal.
Calc. for C19H22N2O5; C,63.68; H, 6.19; N, 7.82; found: C, 63.61; H, 6.31; N, 7.96%;
ESI-MS: 359.10 [M þ H]þ.
Tert-Butyl 2-((3-oxo-3H-benzo[f]chromen-2-yl)carbamoyl)pyrrolidine-1-carboxylate (25).
Pale yellow solid, Yield: 76%; M.P: 192–196 ꢀC; IR (KBr) 3382, 3340, 3069, 2972, 2897,
1715, 1687, 1589, 1575, 1516, 1462, 1437, 1408, 1344, 1253, 1220, 1193, 1111, 1088, 996,
1
974, 951, 806, 779 cmꢁ1; H-NMR(400 MHz, CDCl3): d 1.55 (s, 9 H), 1.68 (s, 2 H),
1.97–2.32 (m, 1 H), 2.44 (s, 1 H), 3.46–3.60 (m, 2 H), 4.41–4.56 (m, 1 H), 7.46
(d, J ¼ 8.8 Hz, 1 H), 7.58–7.61 (m, 1 H), 7.68–7.72 (m, 1 H), 7.91 (d, J ¼ 8.4 Hz, 2 H),
8.33 (d, J ¼ 8.0 Hz, 1 H), 9.53 (s, 1 H); 13C-NMR(100 MHz, CDCl3): d ppm 24.69, 24.91,
28.38, 47.24, 61.08, 81.20, 114.14, 116.35, 116.43, 119.50, 119.61, 122.36, 124.06, 126.15,
126.25, 127.92, 128.81, 129.07, 130.66, 130.89, 148.93, 158.59, 169.59.; Anal. Calc. for
C23H24N2O5; C, 67.63; H, 5.92; N, 6.86; found: C, 67.68; H, 5.99; N, 6.93%.
General procedure for Boc-deprotection
To a solution of compound 14/24/25 (1.0 mmol), DCM (10 mL) was added trifloroacetic
acid (TFA) (0.1 mL). The resulting solution was stirred at room temperature for over-
night. The completion of reaction was monitored by TLC. After completion of reaction,
reaction mixture was concentrated to give residue. The residue was taken in water, neu-
tralized with saturated NaHCO3 solution, and extracted with DCM (3 ꢂ 15 mL). The
organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give com-
pound 15/26/27 as solid. The product was used in next step without any further purifi-
cation. (Yield ¼ 96–98%).
Characterization data for Boc-deprotected compounds 15, 26, and 27
N-(4-Methyl-2-oxo-2H-chromen-7-yl)pyrrolidine-2-carboxamide (15). Light pink solid,
Yield: 98%; M.P: 152–154 ꢀC; IR (KBr) 3304, 3272, 3173, 3082, 2961, 2930, 2864, 1689,
1616, 1595, 1524, 1443, 1392, 1347, 1326, 1272, 1222, 1177, 1112, 1020, 963, 873, 845,
719 cmꢁ1 1H-NMR(400 MHz, CDCl3): d 1.77–1.85 (m, 2 H), 2.04–2.12 (m, 2 H),
;
2.21–2.28 (m, 1 H), 2.41 (d, J ¼ 1.2 Hz, 3 H), 2.99–3.05 (m, 1 H), 3.10–3.14 (m, 1 H),
3.91 (dd, J ¼ 9.2, 5.2 Hz, 1 H), 6.19 (s, 1 H), 7.53 (d, J ¼ 8.4 Hz, 1 H), 7.59 (dd, J ¼ 8.4,
2.0 Hz, 1 H), 7.64 (d, J ¼ 1.6 Hz, 1 H), 10.05 (s,1H); 13C-NMR (100 MHz, CDCl3): d ppm
18.67, 26.41, 30.76, 47.42, 61.02, 106.66, 113.26, 115.27, 115.94, 125.22, 141.09, 152.31,

10
S. D. DURGAPAL AND S. S. SOMAN
154.32, 161.24, 174.08; Anal. Calc. for C15H16N2O3; C, 66.16; H, 5.92; N, 10.29; found:
C, 66.29; H, 5.98; N, 10.38%
N-(2-Oxo-2H-chromen-3-yl)pyrrolidine-2-carboxamide (26). Pale yellow solid, Yield: 96%;
M.P: 145–158 ꢀC; IR (KBr) 3187, 3073, 2947, 2876, 1724, 1679, 1619, 1546, 1501, 1453,
1
1415, 1361, 1317, 1293, 1200, 1131, 1039, 1005, 947, 884, 863, 832, 799, 751 cmꢁ1; H-
NMR(400 MHz, CDCl3): d 1.79–1.86 (m, 2 H), 2.01–2.09 (m, 1 H), 2.25–2.33 (m, 1 H),
3.13–3.16 (m, 2 H), 4.06 (br s, 1 H), 7.25–7.33 (m, 2 H), 7.41–7.46 (m, 2 H), 8.68 (s,
1 H), 10.41 (s, 1 H); 13C-NMR (100 MHz, CDCl3): d ppm 26.16, 30.87, 47.33, 61.00,
116.32, 119.84, 123.19, 123.91, 125.02, 127.71, 129.54, 150.14, 158.59, 174.97; Anal. Calc.
for C14H14N2O3; C, 65.11; H, 5.46; N, 10.85; found: C, 65.19; H, 5.58; N, 10.98%
N-(3-Oxo-3H-benzo[f]chromen-2-yl)pyrrolidine-2-carboxamide (27). Pale white solid,
Yield: 92%; M.P: 250–255 ꢀC; IR (KBr) 3390, 3111, 2881, 2710, 2649, 2559, 2505, 2442,
1722, 1689, 1587, 1548, 1513, 1461, 1438, 1420, 1402, 1387, 1338, 1315, 1248, 1227,
1
1197, 1128, 1101, 900, 813, 782, 754 cmꢁ1; H-NMR(400 MHz, CDCl3): d 1.94–2.05 (m,
3 H), 2.49–2.50 (m, 1 H), 3.34 (m, 2 H), 4.64–4.68 (m, 1 H), 7.59–7.67 (m, 2 H), 7.76 (t,
J ¼ 7.2 Hz, 1 H), 8.08 (d, J ¼ 8 Hz 1 H), 8.13 (d, J ¼ 8.8 Hz 1 H), 8.23 (d, J ¼ 8.8 Hz 1 H),
9.36 (s, 1 H), 10.69 (s, 1 H); 13C-NMR (100 MHz, CDCl3): d ppm 24.04, 30.44, 46.27,
59.88, 113.45, 116.82, 122.03, 122.52, 124.34, 126.66, 128.76, 128.83, 129.49, 130.68,
131.88, 149.66, 157.57, 169.49; Anal. Calc. for C18H16N2O3; C, 70.12; H, 5.23; N, 9.09;
found: C, 70.24; H, 5.34; N, 9.15%; ESI-MS: 309 [M þ H]þ.
General procedure for synthesis of coumarin-benzenesulphonamide derivatives
16a–c, 28a–c, and 29a–c
To a solution of compound 15 (1.0 mmol) and sodium bicarbonate (3.0 mmol) in
dichloro methane (DCM): water (1:1) (25 mL) un/substituted benzenesulphonyl chloride
(1.1 mmol) was added. The resulting mixture was stirred at room temperature for 18 h.
The completion of reaction was monitored by TLC. After completion of the reaction,
the reaction mixture was concentrated to give residue. The residue was neutralized with
dil HCl, filtered, washed with water (3 ꢂ 5 mL), pet.ether (5 mL) and dried to give com-
pounds 16a–c. 3-Aminocoumarin derivatives 28a–c and 29a–c were synthesized using
same procedure as used for compound16a–c.
Characterization data for compounds 16a–c, 28a–c, and 29a–c
N-(4-Methyl-2-oxo-2H-chromen-7-yl)-1-(phenylsulfonyl)pyrrolidine-2-carboxamide (16a).
Pale white solid, Yield: 89%; M.P: 225–228 ꢀC; IR (KBr) 3313, 3194, 3068, 2953, 2872,
1718, 1695, 1616, 1579, 1570, 1523, 1444, 1417, 1390, 1348, 1309, 1217, 1166, 1093,
1
1070, 1008, 995, 893, 854, 752, 723 cmꢁ1; H-NMR (400 MHz, CDCl3): d 1.29–1.81
(m, 3 H), 2.45 (s, 4 H), 3.29–3.33 (m, 1 H), 3.70 (s, 1 H), 4.24–4.27 (m, 1 H), 6.24 (s,
1 H), 7.31–7.47 (m, 1 H), 7.56–7.74 (m, 4 H), 7.85–7.95 (m, 3 H), 9.11 (s, 1 H); 13C-
NMR (100 MHz, CDCl3): d ppm 19.15, 25.10, 30.09, 50.80, 63.60, 77.00, 78.27, 108.10,
114.21, 116.35, 116.99, 125.69, 128.47, 130.16, 134.39, 135.96, 141.32, 152.70,

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SYNTHETIC COMMUNICATIONSV
11
154.87,161.60, 169.96;; Anal. Calc. for C21H20N2O5S; C, 61.15; H, 4.89; N, 6.79; S, 7.77;
found: C, 61.23, H, 4.92; N, 6.91; S, 7.86; ESI-MS: 413.05 [M þ H]þ.
N-(4-Methyl-2-oxo-2H-chromen-7-yl)-1-tosylpyrrolidine-2-carboxamide
(16b).
Pale
white solid, Yield: 86%; M.P: 216–220 ꢀC; IR (KBr) 3562, 3369, 3290, 3140, 3059, 2987,
2953, 2891, 1724, 1697, 1689, 1618, 1597, 1568, 1523, 1506, 1440, 1411, 1396, 1346,
1332, 1313, 1294, 1157, 1182, 1093, 1003, 966, 941, 871, 827, 756, 725 cmꢁ1 1H-
;
NMR(400 MHz, CDCl3): d 1.60–1.70 (m, 2 H), 1.82–1.84 (m, 1 H), 2.35–2.43 (m, 1 H),
2.44 (s, 3 H), 2.48 (s, 3 H), 3.25–3.30 (m, 1 H), 3.64–3.69 (m, 1 H), 4.20 (dd, J ¼ 8.8,
2.8 Hz, 1 H), 6.24 (s,1H), 7.40–7.44 (m, 3 H), 7.56 (d, J ¼ 8.4 Hz, 1 H), 7.78 (d,
J ¼ 8.0 Hz, 2 H), 7.84 (d, J ¼ 2.0 Hz, 1 H), 9.11 (s, 1 H); 13C-NMR (100 MHz, CDCl3): d
ppm 18.65, 21.67, 24.52, 29.42, 50.27, 62.99, 107.52, 113.66, 115.75, 116.41, 125.11,
127.95, 130.22, 132.14, 140.71, 144.95, 152.12, 154.30, 161.09, 169.45; Anal. Calc. for
C22H22N2O5S; C, 61.96; H, 5.20; N, 6.57; S, 7.52; found: C, 61.81; H, 4.98; N, 6.34; S,
7.48% ESI-MS: 427.10 [M þ H]þ.
1-((4-Chlorophenyl)sulfonyl)-N-(4-methyl-2-oxo-2H-chromen-7-yl)pyrrolidine-2-carboxa-
mide (16c). Pale white solid, Yield: 87%; M.P: ꢁ230–234 ꢀC; IR (KBr) 3338, 3196, 3111,
3059, 2991, 2868, 1716, 1695, 1622, 1579, 1533, 1475, 1460, 1437, 1415, 1388, 1338,
1267, 1226, 1180, 1157, 1087, 1064, 1026, 1008, 974, 922, 850, 860, 761 cmꢁ1
;
1H-NMR(400 MHz, CDCl3): d 1.61–1.76 (m, 2 H), 1.87 (br s, 1 H) 2.43 (s, 4 H),
3.21–3.27 (m, 1 H), 3.67–3.71 (m, 1 H), 4.19 (d, J ¼ 6.8 Hz, 1 H), 6.23 (s, 1 H), 7.44 (d,
J ¼ 7.6 Hz, 1 H), 7.55–7.60 (m, 3 H), 7.84–7.86 (m, 3 H), 9.01 (s, 1 H); 13C-NMR
(100 MHz, CDCl3): d ppm 18.65, 24.53, 29.59, 50.29, 63.03, 107.55, 113.72, 115.75,
116.49, 125.16, 129.30, 129.94, 133.73, 140.61, 152.12, 154.28, 161.04, 169.09; Anal. Calc.
for C21H19ClN2O5S; C, 56.44; H, 4.29; N, 6.27; S, 7.17, found: C, 56.60; H, 4.32; N, 6.18;
S, 7.30; ESI-MS: 447.00 [M þ H]þ.
N-(2-Oxo-2H-chromen-3-yl)-1-(phenylsulfonyl)pyrrolidine-2-carboxamide
(28a).
Pale
white solid, Yield: 92%; M.P: 186–188 ꢀC; IR (KBr) 3350, 3084, 3064, 3037, 2985, 2937,
2872, 1724, 1693, 1626, 1602, 1572, 1518, 1460, 1444, 1363, 1350, 1309, 1294, 1257,
1222, 1180, 1165, 1132, 1111, 1091, 1074, 1049, 1004, 995, 968, 947, 923, 904, 860, 850,
1
773, 759, 721 cmꢁ1; H-NMR(400 MHz, CDCl3): d 1.73 (m, 1 H), 1.86–1.88 (m, 2 H),
2.3–2.4 (m,1H), 3.29–3.36 (m, 1 H) 3.60–3.65 (m, 1 H), 4.34 (dd, J ¼ 8.4, 3.0 Hz, 1 H),
7.29–7.31 (dt, J ¼ 7.6, 1.2 Hz, 1 H), 7.35 (br, d, J ¼ 8.00 Hz, 1 H), 7.45–7.49 (m, 1 H),
7.51 (dd, J ¼ 8, 1.4 Hz, 1 H), 7.59–7.63 (m, 2 H), 7.67–7.70 (m, 1 H), 7.95–7.97 (m, 2 H),
8.69 (s, 1 H), 9.38 (s, 1 H); 13C-NMR (100 MHz, CDCl3): d ppm 24.66, 30.47, 49.91,
62.77, 116.44, 119.64, 123.70, 123.74, 125.11, 127.84, 128.10, 129.48, 129.87, 133.68,
135.94, 150.23, 158.37, 170.87; Anal. Calc. for C20H18N2O5S; C, 60.29; H, 4.55; N, 7.03;
S, 8.05; found: C, 60.33; H, 4.48; N, 6.98; S, 8.08; ESI-MS: 399.05 [M þ H]þ.
N-(2-Oxo-2H-chromen-3-yl)-1-tosylpyrrolidine-2-carboxamide (28b). Pale white solid,
Yield: 90%; M.P: 170–172 ꢀC; IR (KBr) 3367, 3088, 3066, 2955, 2879, 1728, 1718, 1697,
1629, 1597, 1514, 1485, 1458, 1354, 1294, 1163, 1111, 1091, 1058, 1004, 950, 923, 904,

12
S. D. DURGAPAL AND S. S. SOMAN
1
850, 754, 665 cmꢁ1; H-NMR(400 MHz, CDCl3): d 1.66 (br s, 1 H), 1.75–1.85 (m, 2 H),
2.24 (br s, 1 H), 2.46 (s, 3 H) 3.29–3.31 (m, 1 H), 3.60 (br s, 1 H),4.31 (br d, 1 H),
7.28–7.40 (m, 4 H), 7.45–7.52 (m, 2 H), 7.83 (d, J ¼ 7.6 Hz, 2 H), 8.69 (s, 1 H), 9.40 (s,
1 H); 13C-NMR (100 MHz, CDCl3): d ppm 21.64, 24.67, 30.45, 49.90, 62.74, 116.44,
119.66, 123.69, 123.74, 125.09, 127.83, 128.17, 129.84, 130.08, 132.93, 144.68, 150.23,
158.37, 171.01; Anal. Calc. for C21H20N2O5S; C, 61.15; H, 4.89; N, 6.79; S, 7.77, found:
C, 61.31; H, 4.91; N, 6.79; S, 7.77; ESI-MS: 413.05 [M þ H]þ.
1-((4-Chlorophenyl)sulfonyl)-N-(2-oxo-2H-chromen-3-yl)pyrrolidine-2-carboxamide (28c).
Pale white solid, Yield: 95%; M.P: 202–206 ꢀC; IR (KBr) 3311, 3248, 3093, 3084, 2955,
2875, 1722, 1693, 1626, 1604, 1537, 1487, 1460, 1448, 1356, 1329, 1296, 1276, 1222,
1205, 1157, 1101, 1085, 1070, 1022, 1006, 949, 904, 881, 856, 767, 756 cmꢁ1 1H-
;
NMR(400 MHz, CDCl3): d 1.71 (s, 1 H), 1.81–1.91 (m, 2 H), 2.27 (br s, 1 H), 3.26–3.32
(m, 1 H) 3.61 (br s, 1 H), 4.32–4.33 (br d, 1 H), 7.29–7.36 (m, 2 H), 7.45–7.57 (m, 2 H)
7.58 (d, J ¼ 8.4 Hz, 2 H), 7.90 (d, J ¼ 8.4 Hz, 2 H), 8.68 (s, 1 H), 9.30 (s, 1 H); 13C-NMR
(100 MHz, CDCl3): d ppm 24.69, 30.54, 49.89, 62.75, 116.45, 119.60, 123.62, 123.83,
125.16, 127.87, 129.51, 129.81, 129.94, 134.57, 140.38, 150.21, 158.41, 170.60; Anal. Calc.
for C20H17ClN2O5S; C, 55.49; H, 3.96; N, 6.47; S, 7.41; found: C, 55.58; H, 3.89; N, 6.39;
S, 7.30; ESI-MS: 433.00 [M þ H]þ.
N-(3-Oxo-3H-benzo[f]chromen-2-yl)-1-(phenylsulfonyl)pyrrolidine-2-carboxamide (29a).
Pale white solid, Yield: 90%; M.P: 206–208 ꢀC; IR (KBr) 3068, 2956, 2889, 1713,
1691, 1536, 1516, 1503, 1463, 1445, 1328, 1237, 1222, 1203, 1192, 1164, 1185, 1090,
994, 814 cmꢁ1 1H-NMR(400 MHz, CDCl3): d 1.80–1.84 (m, 1 H), 1.86–1.95 (m,
;
2 H), 2.29–2.33 (m, 1 H), 3.32–3.39 (br m, 1 H), 3.64–3.69 (m, 1 H), 4.39 (dd, J ¼ 8.4,
3.2 Hz, 1 H), 7.48 (d, J ¼ 8.8 Hz, 1 H), 7.57–7.64 (m, 3 H), 7.67–7.71 (m, 2 H), 7.92
(d, J ¼ 8.8 Hz, 2 H), 7.98–8.00 (m, 2 H), 8.31 (d, J ¼ 8.4 Hz, 1 H), 9.46 (s, 1 H), 9.52
(s, 1 H); 13C-NMR (100 MHz, CDCl3): d ppm 24.72, 30.47, 49.94, 62.83, 113.97,
116.48, 119.92, 122.30, 123.66, 126.20, 127.89, 128.13, 128.86, 129.07, 129.51, 130.66,
131.09, 133.70, 135.96, 149.18, 158.30, 170.98; Anal. Calc. for C24H20N2O5S; C, 64.27;
H, 4.50; N, 6.25; S, 7.15; found: C, 64.34; H, 4.47; N, 6.18; S, 7.30; ESI-MS:
449.01 [M þ H]þ.
N-(3-Oxo-3H-benzo[f]chromen-2-yl)-1-tosylpyrrolidine-2-carboxamide (29b). Pale white
solid, Yield: 87%; M.P: 202–206 ꢀC; IR (KBr) 2918, 2887, 1706, 1702, 1696, 1516, 1504,
1464, 1347, 1319, 1237, 1137, 1192, 1158, 1089, 898, 814 cmꢁ1 1H-NMR(400 MHz,
;
CDCl3): d 1.76–1.84 (m, 1 H), 1.86–1.94 (m, 2 H), 2.29–2.31 (m, 1 H), 2.47 (s, 3 H),
3.30–3.37 (br m, 1 H), 3.62–3.66 (m, 1 H), 4.37 (dd, J ¼ 8.4, 3.2 Hz, 1 H), 7.41
(d, J ¼ 8.0 Hz, 2 H), 7.49 (d, J ¼ 8.8 Hz, 1 H), 7.58–7.62 (m, 1 H), 7.68–7.72 (m, 1 H),
7.87 (d, J ¼ 8.0 Hz, 2 H), 7.92 (d, J ¼ 2.0 Hz, 1 H), 7.94 (d, J ¼ 2.8 Hz, 1 H), 8.33–8.36 (m,
1 H), 9.50 (s, 1 H), 9.55 (s, 1 H); 13C-NMR (100 MHz, CDCl3): d ppm 21.67, 24.72,
30.44, 49.93, 62.79, 114.01, 116.37, 116.51, 119.92, 122.33, 122.42, 123.72, 126.19, 127.89,
128.20, 128.86, 129.10, 130.11, 130.67, 130.92, 131.07, 132.94, 144.70, 149.20, 158.32,
171.13; Anal. Calc. for C25H22N2O5S; C, 64.92; H, 4.79; N, 6.06; S, 6.93; found: C, 64.99;
H, 4.72; N, 6.12; S, 7.09; ESI-MS: 463.13 [M þ H]þ.

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SYNTHETIC COMMUNICATIONSV
13
1-((4-Chlorophenyl)sulfonyl)-N-(3-oxo-3H-benzo[f]chromen-2-yl)pyrrolidine-2-carboxa-
mide (29c). Pale white solid, Yield: 91%; M.P: 230–234 ꢀC; IR (KBr) 2870, 2848, 1715,
1706, 1694, 1533, 1516, 1464, 1343, 1238, 1224, 1203, 1187, 1166, 1102, 1089, 1010,
812 cmꢁ1 1H-NMR(400 MHz, CDCl3): d 1.81–1.90 (m, 1 H), 1.92–2.01 (m, 2 H),
;
2.31–2.35 (m, 1 H), 3.30–3.36 (m, 1 H), 3.63–3.67 (m, 1 H), 4.38 (dd, J ¼ 8.0, 2.8 Hz,
1 H), 7.50 (d, J ¼ 8.8 Hz, 1 H), 7.58–7.62 (m, 3 H), 7.70 (t, J ¼ 7.2 Hz, 1 H), 7.92–7.95 (m,
4 H), 8.33 (d, J ¼ 8.4 Hz, 1 H), 9.39 (s, 1 H), 9.54 (s, 1 H); 13C-NMR (100 MHz, CDCl3):
d ppm 24.74, 30.54, 49.93, 62.80, 113.96, 116.48, 120.05, 122.30, 123.59, 126.24, 127.94,
128.88, 129.08, 129.54, 129.84, 130.68, 131.18, 134.58, 140.41, 149.21, 158.36, 170.72;
Anal. Calc. for C24H19ClN2O5S; C, 59.69; H, 3.97; N, 5.80; S, 6.64, found: C, 59.38; H,
3.95; N, 5.75; S, 6.44%; ESI-MS: 483.06 [M þ H]þ.
1
Full experimental detail, IR, H and 13C NMR spectra. This material can be found via
the “Supplementary Content” section of this article’s webpage
Acknowledgements
Authors are thankful to The Head, Department of Chemistry, Faculty of Science, The M. S.
University of Baroda for providing laboratory facilities, Department of Zoology for screening
compounds for anticancer activity and Zydus Research Center, Ahmedabad, for the ESI-MS anal-
yses and antidiabetic activity. DST purse, M.S University of Baroda for single crystal analyses.
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