L-proline-catalyzed synthesis of novel 5-(1H-indol-3-yl-methylene)- thiazolidine-2,4-dione derivatives as potential antihyperglycemic agents

Article abstract of DOI:10.1080/00397911.2010.515352

Knoevenagel condensation between indole-3-aldehyde 1 and an active methylene group containing 2,4-thiazolidinedione 2 in refluxing toluene using L-proline as a catalyst yielded 3, which on alkylation using 2 equivalents of alkylating agent under phase-tra

Full text of DOI:10.1080/00397911.2010.515352

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L-Proline-Catalyzed Synthesis of
Novel 5-(1H-Indol-3-yl-methylene)-
thiazolidine-2,4-dione Derivatives as
Potential Antihyperglycemic Agents
S. Riyaz a , A. Naidu a & P. K. Dubey a
a Department of Chemistry, Jawaharlal Nehru Technological
University, Hyderabad College of Engineering, Kukatpally,
Hyderabad, India
To cite this article: S. Riyaz , A. Naidu & P. K. Dubey (2011): L-Proline-Catalyzed Synthesis of Novel 5-
(1H-Indol-3-yl-methylene)-thiazolidine-2,4-dione Derivatives as Potential Antihyperglycemic Agents,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:18, 2756-2762
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Synthetic Communications1, 41: 2756–2762, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515352
L-PROLINE-CATALYZED SYNTHESIS OF NOVEL
5-(1H-INDOL-3-YL-METHYLENE)-THIAZOLIDINE-
2,4-DIONE DERIVATIVES AS POTENTIAL
ANTIHYPERGLYCEMIC AGENTS
S. Riyaz, A. Naidu, and P. K. Dubey
Department of Chemistry, Jawaharlal Nehru Technological University,
Hyderabad College of Engineering, Kukatpally, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract Knoevenagel condensation between indole-3-aldehyde 1 and an active methylene
group containing 2,4-thiazolidinedione 2 in refluxing toluene using L-proline as a catalyst
yielded 3, which on alkylation using 2 equivalents of alkylating agent under phase-transfer-
catalyzed (PTC) conditions using K2CO3 as
a base in dimethylformamide gave
N,NI-symmetrically disubstituted 5-(1H-indol-3ylmethylene)-thiazolidine-2,4-diones 4.
Alternately, 4 can be synthesized by condensing 5 and 6 in a single step. Using this synthetic
strategy, N,NI-unsymmetricallydisubstituted derivatives 9a–f were prepared either by con-
densing 6 with N-substituted-2,4-thiazolidinedione 5 to obtain 7 followed by alkylation
under PTC conditions or condensing 6 with N-unsubstituted- 2,4-thiazolidinedione 2 to yield
8 followed by alkylation under PTC conditions. The latter are the dehydro analogs of the
dihydro-N-substituted-5-(1H-indol-3-yl-methylene)-thiazolidine-2,4-diones, which are
potential antihyperglycemic agents.
Keywords Indole-3-aldehyde; L-proline; N,NI-symmetrically=unsymmetrically disubsti-
tuted 5-(1H-indol-3ylmethylene)-thiazolidine-2,4-diones; 2,4-thiazolidinedione (TZD)
INTRODUCTION
Thiazolidinediones (TZDs), also referred to as glitazones, are a new class of
antidiabetic[1] pharmacophores that differ markedly from other oral antidiabetic
agents. Some 2,4-TZDs, such as pioglitazone and rosiglitazone,[2] have been mar-
keted for the treatment of type 2 diabetes. Some of the thiazolidinedione derivatives,
though effective therapeutic agents, have been reported to possess hepatotoxicity.
Received April 20, 2010.
Address correspondence to P. K. Dubey, Department of Chemistry, JNTUH College of
Engineering, Hyderabad 500 085, A. P., India. E-mail: riyazsd@gmail.com
2756

SYNTHESIS OF INDOLE DERIVATIVES
2757
Furthermore, many of the moieties that are reported in literature have the
TZD pharmacophore attached to a carbocyclic ring.[3–5] Hence, it was our endeavor
to condense the heterocyclic ring with the TZD to obtain novel antidiabetic
agents devoid of hepatotoxicity. As per the literature survey, it follows that the N-
substituted analogs’ antihyperglycemic activity is greater than that of N-unsubstituted
analogs.[6]
Indole is the prime constituent moiety in various drugs such as tryptophan,
sumatryptan, and indomethacin, and several of its derivatives have various biologi-
cal activities such as anticancer,[7] anti-inflammatory,[8] antimigraine,[9] and anti-
biotic[10] activities. Therefore, it was considered worthwhile to synthesize the
2,4-thiazolidinedione moiety attached to the indole ring, which may prove to be a
potential antihyperglycemic agent. The results of this study are described.
RESULTS AND DISCUSSION
To realize the strategy shown in Scheme 1, indole-3-aldehyde (1) was con-
densed with 2,4-thiazolidinedione 2 in the presence of L-proline in toluene medium
for 2–3 h at refluxing temperature, resulting in the formation of 5-(1H-indolyl-
3-ylmethylene)-thiazolidine-2,4-dione (3) in 92% yield. L-Proline is an effective
organocatalyst in several powerful asymmetric transformations such as aldol,
Michael, and Knoevenagel reactions. Proline is an abundant bifunctional molecule,
inexpensive, and available in both enantiomeric forms. The two functional groups of
proline can act as both acidic and basic catalysts and can also facilitate chemical
transformations in concert.
The condensation between 1 and 2 in refluxing toluene in the absence of
L-proline for several hours gave no detectable amount of 3 as checked by thin-layer
chromatography (TLC), thereby showing the wonderful catalytic effect of proline in
this condensation. The structure of 3 was assigned on the basis of its infrared (IR),
1H NMR, and liquid chromatography–tandem mass spectrometry (LC-MS=MS)
data. The peaks at 3325 and 3288 cmꢀ1 in IR strongly support the presence of two
1
–NH groups of thiazolidine-2,4-dione as well as indole. In the H NMR, the signal
at d 7.00–9.30 (m, 6H) corresponds to 4H aromatic þ 1H a-indolyl þ 1H vinylic pro-
ton, and the signals at d 10.0 and 10.2 belong to TZD–NH proton and –NH of
indole respectively. The molecular ion peak at 245 corresponding to M.þH in
LC-MS=MS is in concurrence with the actual molecular weight of 244 of 3.
Treatment of 3 with 2 equivalents of alkylating agent (DMS, DES, PhCH2Cl)
in dimethylformamide (DMF) at rt using tetrabutylammonium bromide (TBAB) as
Scheme 1. Condensation TZD with indole-3-aldehyde and its alkylation.

2758
S. RIYAZ, A. NAIDU, AND P. K. DUBEY
Table 1. Characterization data of the products
Substrate
Alkylating agent
Product
Mp (ꢁC)
Yield (%)
1
=
=
CH3)
=
C2H5)
3
3
3
3
DMS
DES
4a (R
4b (R
R
>200
195–199
>200
75
77
82
85
1
=
R
1
=
=
CH2Ph)
Ph-CH2Cl
C6H5SO2Cl
4c (R
4d (R
R
1
R
=
=
SO2Ph)
>200
phase-transfer catalyst (PTC) and K2CO3 as a base resulted in the formation of
N,NI-symmetrically disubstituted alkyl derivatives (4a–c) in very good yields (see
Table 1). This reaction could also be done with PhSO2Cl to get N,NI-disulfonylated
derivative 4d of 3. The structures of all the products 4a to 4d have been assigned on
the basis of spectral data (see Experimental section for details).
Alternately, 4 could be synthesized in a single step by condensing N-substituted
indole-3-aldehyde (5) and N-substituted-2,4-thiazolidinedione (6) in refluxing tolu-
ene using L-proline as a catalyst. Compound 4 obtained previously was found to
be identical in melting point and TLC with the corresponding derivatives prepared
earlier in the route 1 ! 3.
Using the strategy described, N,NI-unsymmetrically disubstituted derivatives
9a–f (Table 2) were prepared either by condensation with NI-substituted-2,4-thiazo-
lidinedione 5 to obtain 7 followed by alkylation under PTC conditions using K2CO3
as a base in DMF reaction medium or by condensation 6 with N-unsubstituted
2,4-thiazolidinedione 2 to yield 8 followed by alkylation under PTC conditions using
K2CO3 as a base in DMF medium (Scheme 2). The structures of 9a–f have been
1
established on the basis of IR, H NMR, and LC-MS (Q þ 1) spectral data (see
Experimental section for details).
Mechanism for the Formation of 3 from 1 and 2 (Scheme 2)
The following mechanism is proposed to account for the formation of 3 by
condensation of 1 with 2 using L-proline as catalyst (Scheme 3). The step 1 ! 3
can be regarded as Knoevengel condensation. Initially, 1 reacts with L-proline to
form an iminium carboxylate ion (1A). Then, 1A abstracts the proton from the active
methylene group of 2 to afford the carboxylic acid containing iminium ion 1B and
thiazolidinedione anion 2A as ion pairs. The ion pairs combine to form the adduct
3A, which loses proline to form 3. The liberated Proline brings about further conden-
sation of 1 and 2 in a repetitive cyclical form.
Table 2. Characterization data of the products
Substrate
Alkylating agent
Product
Mp (ꢁC)
Yield (%)
1
9a (R C2H5, R CH3)
=
=
7
7
8
8
8
8
DMS
DES
174–178
190–195
178–183
>200
86
84
77
81
84
86
1
9b (R CH3, R C2H5)
=
=
1
= =
9c (R CH2Ph,R CH3)
DMS
Ph-CH2Cl
DMS
DES
1
9d (R CH3,R CH2Ph)
=
=
1
9e (R SO2Ph,R CH3)
=
=
188–190
>200
1
9f (R SO2Ph,R C2H5)
=
=

SYNTHESIS OF INDOLE DERIVATIVES
2759
Scheme 2. Plausible mechanism for the formation of 3 from 1 and 2.
Scheme 3. Alternative approaches for unsymmetrical indolylidine thiazolidinediones.
EXPERIMENTAL
Melting points are uncorrected and were determined in open capillary tubes in
a sulfuric acid bath. Thin-layer chromatography (TLC) was performed on silica gel
G, and spotting was done using iodine or ultraviolet light. IR spectra were recorded
1
with a Jasco Fourier transform (FT)–IR 5300 instrument, H NMR on a Varian
400-MHz instrument, and mass spectra on an Agilent LC-MS instrument, giving
only M þ values in Q þ 1 mode. Starting materials 1 and 2 were prepared using
literature methods.[11,12]
Preparation of 3 from 1 and 2
A mixture of 1 (0.735 g, 5 mmol), 2 (0.585 g, 5 mmol), and a catalytic amount of
L-proline (10 mg) were refluxed in toluene (30 ml) for 2–3 h. At the end of this period,
a yellow-colored solid separated out and was filtered, washed, and dried to obtain
crude 3. The latter, on recrystallization from hot ethanol–DMF, gave pure 3. Yield
83%; mp 180–184 ꢁC.

2760
S. RIYAZ, A. NAIDU, AND P. K. DUBEY
Preparation of 4 from 3 (General Procedure)
A mixture of 3 (1.22 g, 5 mmol), K2CO3 (2.07 g, 15 mmol), TBAB (10 mg),
DMF (20 mL), and 2 equivalents of an appropriate alkylating agent were stirred
at rt for 2–3 h. At the end of this period, the mixture was poured into ice-cold water
and neutralized with AcOH. The separated solid was filtered, washed, and dried to
obtain crude 4, which on recrystallization from ethyl acetate gave pure 4.
Characterization Data
Compound 4a. IR (KBr): 1728 and 1674 cmꢀ1 (both s, sharp, two ꢀC O
=
1
groups); H NMR (400 MHz, DMSO-d6=TMS): d 3.16 (s, 3H, ꢀNCH3 of TZD),
3.60 (s, 3H, ꢀNCH3 of indole), 6.22–8.85 (m, 6H, 4H aromatic þ 1H a -indolyl þ 1H
vinylic proton); m=z (Mþ þ 1): 273. Anal. calcd. for C14H12N2O2S requires C, 61.75;
H, 4.44; found C, 61.72; H, 4.42%.
Compound 4b. IR (KBr): 1748 and 1656 cmꢀ1 (both s, sharp, two ꢀC O
=
1
groups); H NMR (400 MHz, DMSO-d6=TMS): d 1.20 (q, 2H, ꢀNCH2 of TZD),
1.51 (q, 2H, ꢀNCH2 of indole), 3.82 (t, 3H, -CH3 of TZD), 4.19 (t, 3H, -CH3 of
indole), 6.42–8.91 (m, 6H, 4H aromatic þ 1H a-indolyl þ 1H vinylic proton); m=z
(Mþ þ 1): 301. Anal. calcd. for C16H16N2O2S requires C, 63.98; H, 5.37; found C,
63.72; H, 5.42%.
Compound 4c. IR (KBr): 1739 and 1647 cmꢀ1 (both s, sharp, two ꢀC O
=
1
groups); H NMR (400 MHz, DMSO-d6=TMS): d 4.74 [s, 2H, ꢀNCH2 of benzyl
(TZD)], 5.34 [s, 2H, ꢀNCH2 of benzyl (indole) of TZD], 7.01–8.96 (m,15H, 10H aro-
matic benzyl þ 4H aromatic indolyl þ 1H vinylic proton þ 1H a-indolyl); m=z
(Mþ þ 1): 425. Anal. calcd. for (C26H20N2O2S) requires C, 73.56; H, 4.75; found
C,73.2; H, 4.72%.
Compound 4d. IR (KBr): 1739 and 1647 cmꢀ1 (both s, sharp, two ꢀC O
=
groups); 1H NMR (400 MHz, DMSO-d6=TMS): d 7.01–9.06 (m, 16H, 10H aromatic
benzyl þ 4H aromatic indolyl þ 1H vinylic proton þ 1H a-indolyl); m=z (Mþ þ 1): 525.
Anal. calcd. for C24H16N2O6S3 requires C, 54.96; H, 3.07; found C, 54.85; H,
3.10%.
Preparation of 9 from 7/8 (General Procedure)
A mixture of 7/8 (5 mmol), K2CO3 (2.07 g, 15 mmol), TBAB (10 mg), DMF
(20 mL), and appropriate alkylating agent were stirred at rt for 2–3 h. At the end
of this period, the mixture was poured into ice-cold water and neutralized with
AcOH. The separated solid was filtered, washed, and dried to obtain crude 9, which
on recrystallization from ethyl acetate gave pure 9.
Characterization Data
Compound 9a. IR (KBr): 1758 and 1648 cmꢀ1 (both s, sharp, two ꢀC O
=
groups); 1H NMR (400 MHz, DMSO-d6=TMS): d 1.51 (t, 3H, -CH3 of ethyl),
3.16 (s, 3H, ꢀNCH3 of TZD), 3.89 (q, 2H, ꢀNCH2 of TZD), 4.19 (t, 3H, -CH3

SYNTHESIS OF INDOLE DERIVATIVES
2761
of indole), 6.22–8.81 (m, 6H, 4H aromatic þ 1H a-indolyl þ 1H vinylic proton);
m=z (Mþ-1): 286. Anal. calcd. for C15H14N2O2S requires C, 62.92; H, 4.93; found
C, 62.93; H, 4.91%.
Compound 9b. IR (KBr): 1758 and 1648 cmꢀ1 (both s, sharp, two ꢀC O
=
1
groups); H NMR (400 MHz, DMSO-d6=TMS): d 1.21 (t, 3H, ꢀNCH3 of TZD),
3.52 (q, 3H, -CH2 of TZD), 3.62 (s, 3H, ꢀNCH3 of indole), 6.22–8.81 (m, 6H, 4H
aromatic þ 1H a-indolyl þ 1H vinylic proton); m=z (Mþ-1): 286. Anal. calcd. for
(C15H14N2O2S) requires C, 62.92; H, 4.93; found C, 62.93; H, 4.91%.
Compound 9c. IR (KBr): 1742 and 1643 cmꢀ1 (both s, sharp, two ꢀC O
=
1
groups); H NMR (400 MHz, DMSO-d6=TMS): d 3.16 (s, 2H, ꢀNCH3 of TZD),
5.14 [s, 2H, ꢀNCH2 of benzyl (indole)], 7.01–8.96 (m, 11H, 9H aromatic benzyl þ 1H
1H vinylic proton þ 1H a-indolyl); m=z (Mþ þ 1): 349. Anal. calcd. for C20H16N2O2S
requires C, 68.94; H, 4.63; found C, 68.91; H, 4.59%.
Compound 9d. IR (KBr): 1735 and 1645 cmꢀ1 (both s, sharp, two ꢀC O
=
1
groups); H NMR (400 MHz, DMSO-d6=TMS): d 3.60 (s, 3H, ꢀNCH3 of indole),
4.74 [s, 2H, ꢀNCH2 of benzyl (TZD)], 7.06–8.86 (m, 11H, 9H aromatic benzyl þ 1H
vinylic proton þ 1H a-indolyl); m=z (Mþ þ 1): 349. Anal. calcd. for C20H16N2O2S
requires C, 68.94; H, 4.63; found C, 68.91; H, 4.59%.
Compound 9e. IR (KBr): 1742 and 1643 cmꢀ1 (both s, sharp, two ꢀC O
=
1
groups); H NMR (400 MHz, DMSO-d6=TMS): d 3.16 (s, 3H, ꢀNCH3 of TZD),
7.01–9.30 (m, 11H, 9H aromatic þ 1H vinylic proton þ 1H a-indolyl); m=z
(Mþ þ 1): 399. Anal. calcd. for C19H14N2O4S2 requires C, 57.27; H, 3.54; found C,
57.32; H, 3.59%.
Compound 9f. IR (KBr): 1735 and 1645 cmꢀ1 (both s, sharp, two ꢀC O
=
1
groups); H NMR (400 MHz, DMSO-d6=TMS): d 1.20 (t, 3H, -CH3 of –N ethyl
of TZD), 3.52 [q, 2H, ꢀNCH2 of ethyl (TZD)], 7.06–8.86 (m, 11H, 9H
aromatic þ 1H vinylic proton þ 1H a-indolyl); m=z (Mþ þ 1): 413. Anal. calcd. for
C20H16N2O4S2 requires C, 58.24; H, 3.91; found C, 58.33; H, 4.02%.
ACKNOWLEDGMENTS
The authors are thankful to the authorities of Jawaharlal Nehru Technological
University, Hyderabad (A.P.), for providing laboratory facilities. They are also
indebted to the University Grants Commission, government of India, New Delhi,
for providing financial support.
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