T3P-DMSO mediated one pot cascade protocol for the synthesis of 4-thiazolidinones from alcohols

Article abstract of DOI:10.1016/j.tetlet.2012.08.020

Propylphosphonic anhydride (T3P)-DMSO mediated oxidation of alcohols to carbonyl compounds and their subsequent cyclization with aryl/hetero aryl amines and thioglycolic acid to afford 4-thiazolidinones has been reported. Synthesis of 4-thiazolidinones di

Full text of DOI:10.1016/j.tetlet.2012.08.020

Tetrahedron Letters 53 (2012) 5619–5623
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
T3PÒ-DMSO mediated one pot cascade protocol for the synthesis of
4-thiazolidinones from alcohols
Kothanahally S. Sharath Kumar, Toreshettahally R. Swaroop, Kachigere B. Harsha,
⇑
Kereyagalahally H. Narasimhamurthy, Kanchugarakoppal S. Rangappa
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India
a r t i c l e i n f o
a b s t r a c t
Propylphosphonic anhydride (T3PÒ)-DMSO mediated oxidation of alcohols to carbonyl compounds and
their subsequent cyclization with aryl/hetero aryl amines and thioglycolic acid to afford 4-thiazolidinon-
es has been reported. Synthesis of 4-thiazolidinones directly from alcohols has been carried out for the
first time. Mild reaction conditions, wide functional group tolerance, ease of work-up, and good yields
are the noteworthy features of this protocol.
Article history:
Received 16 June 2012
Revised 2 August 2012
Accepted 4 August 2012
Available online 14 August 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Propylphosphonic anhydride (T3PÒ
Cascade
)
4-Thiazolidinones
Thioglycolic acid (or mercaptoacetic acid)
4-Thiazolidinone represents an important class of heterocyclic
compounds in the view of its broad biological activities.1–9 Because
of its diverse pharmacological activities, several synthetic efforts
have been made to construct this ring. Most commonly employed
method is one-pot cyclocondensation of aldehydes, amines, and
mercaptoacetic acid.10 Many catalysts11–16 have been reported in
literature to accelerate the cyclocondensation and, in addition,
solid phase,17 micro wave heating,18 and polymer supported19
systems have also been developed.
However, the above mentioned methods advocate prolonged
heating, Dean-Stark removal of water, and tedious work-up proce-
dure. Hence, a protocol which circumvents these demerits attracts a
lot of attention of chemists. To the best of our knowledge, synthesis
of 4-thiazolidinones directly from alcohols has not been reported,
probably due to lack of reagent that oxidizes alcohol to carbonyl
compounds and mediates subsequent in-situ cyclocondensation
of carbonyl compounds with amines and mercaptoacetic acid.
On the other hand, several synthetic applications of T3PÒ have
been reported in the literature.20 Also, DMSO has been found to
be a good oxidizing agent in the presence of electrophilic reagent-
s.21a For instance, it oxidizes alcohols to carbonyl compounds in the
presence of polyphosphoric acid21b and T3PÒ.21c,d
Recently, we have reported an one pot tandem approach for the
synthesis of benzimidazoles and benzothiazoles from alcohols
using DMSO-propylphosphonic anhydride (T3PÒ) media22 as an
oxidizing as well as cyclodehydrating agent. In continuation of
our work toward the development of new synthetic methodologies
toward biologically important heterocyclic compounds, we report
herein an efficient T3PÒ-DMSO mediated one pot three-component
synthesis of 4-thiazolidinones directly from various alcohols.23
This process involves oxidation, condensation followed by cycliza-
tion under mild reaction conditions.
Initially, we selected the reaction between benzyl alcohol(1a),
aniline(2a) and thioglycolic acid(3) in the presence of T3PÒ (50%
solution in ethyl acetate) in ethyl acetate and DMSO solvent mix-
ture in the ratio 2:1 as a media of choice (Scheme 1). Thus, the
reaction between 1a, 2a, and 3 in the presence of T3PÒ (1 equiv)
gave the required product 4a in 15% yield after 10 h (Table 1 entry
1). We observed that increase in the quantity of T3PÒ in the
reaction would enhance yield up to 92% in 5 h (Table 1 entry 2
and 3). Further increase in the quantity of T3PÒ in the reaction does
not affect the reaction time and yield (Table 1 entry 4). Later, we
diverted our interest to explore the effect of various solvents on
the reaction with solvent: DMSO ratio being 2:1 as a choice. Thus,
the reaction was screened in various solvents – toluene, benzene,
dichloromethane, chloroform, acetonitrile, dioxane and THF gave
decreased yield of 4a (Table 1, entries 5–11). At this stage, we con-
verged our interest to study the effect of temperature on the
EtOAc: DMSO mediated reaction. Thus, increase in temperature
⇑
Corresponding author. Tel.: +91 821 2419661; fax: +91 821 2500846.
E-mail addresses: rangappaks@chemistry.uni-mysore.ac.in, rangappaks@gmail.-
com (K.S. Rangappa).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.020

5620
K. S. Sharath Kumar et al. / Tetrahedron Letters 53 (2012) 5619–5623
n-pr
O
P
O
P
O
P
NH2
rp-n
O
n-pr
S
O
O
CO2H
N
DMSO/Ethyl acetate
0°C-rt
HS
O
OH
1a
2a
3
4a
Scheme 1. Synthesis of 2,3-diphenylthiazolidin-4-one (4a).
Table 1
T3PÒ-DMSO mediated synthesis of 4a under different reaction conditions
Sl. No.
Solventa
T3PÒ (equiv)b
Time (h)
Temperature (°C)
Yieldc (%) of 4a
1
2
3
4
5
6
7
8
EtOAc
EtOAc
EtOAc
EtOAc
Toluene
Benzene
CH2Cl2
CHCl3
CH3CN
Dioxane
THF
EtOAc
EtOAc
EtOAc
EtOAc
1.0
2.0
2.5
3.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
10
5
5
5
5
5
5
5
5
5
5
4.5
4
3
0–25
0–25
0–25
0–25
0–25
0–25
0–25
0–25
0–25
0–25
0–25
50
15
86
92
91
72
60
40
45
52
50
25
90
90
88
87
9
10
11
12
13
14
15
60
65
70
2
a
b
c
Solvent and DMSO were taken in 2:1 volume ratio.
T3PÒ (50% solution in EtOAc) was used to carry out the reactions.
Isolated yield.
O
T3P®/DMSO
OH
OH
Ethyl acetate
0°C to rt
S
R3
NH2
R1
N
O
R3
R2
R2
R1
SH
3
4
2
1
Scheme 2. Synthesis of 4-thiazolidinones (4).
of the reaction resulted in gradual decrease in reaction time with
very slight decrease in yield of 4a (Table 1, entry 12–15) as sum-
marized in Table 1.
throughout the reaction. Interestingly, secondary alcohols (1k,
1l, & 1m) also underwent smooth oxidation followed by cycliza-
tion to afford respective 4-thiazolidinones in high yields (Table 2,
entry 12–14).
The possible mechanism involves the reaction of DMSO with
T3PÒ followed by substitution reaction of alcohol and results in
the cleavage of phosphoester bond to form intermediate 5. Elimi-
nation of dimethyl sulfide gives carbonyl compound 6 which
undergoes condensation and cyclization with amine and mercap-
toacetic acid to afford thiazolidinone 4 as shown in Scheme 3.
In conclusion, we have demonstrated an excellent, mild, and high
yielding protocol for the synthesis of 4-thiazolidinones starting
With the optimized reaction condition in hand, we next ex-
plored the generality of the protocol by reacting various aryl/het-
eroaryl primary alcohols with aryl/heteroaryl amines and
thioglycolic acid as shown in Scheme 2. Thus, primary alcohols
and amines bearing various electron donating and electron with-
drawing substituents underwent reaction smoothly to give
respective 4-thiazolidinones in high yields (Table 2, entries 1–
11). It should be noted that many functional groups such as
hydroxyl, nitro, ester, methoxy, and Boc remain unaffected

K. S. Sharath Kumar et al. / Tetrahedron Letters 53 (2012) 5619–5623
5621
Table 2
Entrya
1
2
4
Time (h)
Yieldb,c (%)
NH2
O
OH
S
N
2a
9224
1a
1
5
4a
O
O
O
OH
S
N
HO
NH2
1b
2
4.5
93
2b
O
O
OH
4b
NH2
O
OH
S
N
F
1c
3
4
90
O
2c
O
F
4c
NH2
O
OH
O
N
O
NO2
2d
1d
4
4.5
94
S
NO2
O
4d
NH2
OH
F3C
N
1e
5
4
95
S
2e
F3C
Br
4e
NH2
OH
O
N
N
Br
1f
2f
6
5
88
S
N
4f
N
O
O
O
OH
Boc
N
N
NH2
S
N
N
O
2g
O
7
4.5
89
N
N
1g
Boc
O
O
4g
(continued on next page)

5622
K. S. Sharath Kumar et al. / Tetrahedron Letters 53 (2012) 5619–5623
Table 2 (continued)
Entrya
1
2
4
Time (h)
Yieldb,c (%)
O
OH
O
NH2
S
N
N
O
O
1h
8
4
90
O
N
2b
2h
O
4h
NH2
O
OH
S
N
O
O
O
1g
9
4
94
O
O
S
4i
NH2
O
O
OH
N
O
9525
2i
10
3
O
O
1i
O
O
4j
HO
N
O
Boc
N
N
NH2
N
Boc
N
N
N
S
2g
N
11
4
90
Boc
1j
N
Boc
4k
OH
NH2
O
Cl
Cl
N
S
S
12
5
89
Cl
Cl
2j
1k
4l
OH
N
NH2
O
N
N
N
13
14
4
96
97
2k
N
1l
4m
OH
O
N
O
F
NH2
O
F
F
S
3.5
F
2l
1m
4n
a
b
C
T3PÒ (2.5 equiv), Alcohol (1.1 equiv), Amine (1.0 equiv) and Thioglycolic acid (1.0 equiv).
Isolated yield.
Literature reported compounds.
directly from a variety of primary and secondary alcohols, aryl/het-
ero aryl amines, and thioglycolic acid. The main advantages of this
procedure are one pot operation, short reaction time, mild reaction
condition, broad functional group tolerance, ease of product purifi-
cation, and excellent yield. Further synthetic applications of T3PÒ
are currently underway in our laboratory.

K. S. Sharath Kumar et al. / Tetrahedron Letters 53 (2012) 5619–5623
5623
..
..
OH
S
O
O
O
rp-n
O
R1
R2
S
O
O
P
P
O
R1
n-pr
P
O
P
O
P
O
P
O
H
S
O
O
n-pr
R2
rp-n
O
rp-n
O
5
rp-n
-Me2S
R1
O
O
S
R3-NH2, T3P®
N
R2
R3
R2
HS
CO2H
R1
6
4
Scheme 3. Possible mechanism of the T3PÒ-DMSO mediated 4-thiazolidinone synthesis.
12. Kumar, R. C.; Kumar, D. J. Ind. Chem. Soc. 2002, 77, 492.
13. Rawal, R. K.; Srivastava, T.; Haq, W.; Katti, S. B. J. Chem. Res. 2004, 5, 368–
369.
Acknowledgments
The authors are grateful to the DST-IFCPAR Project, Govt. of In-
dia for financial support to K.S.R. for the project vide NO. IFC/4303-
1/2010-11 Dated 22-12-2010.
14. Srivastava, T.; Haq, W.; Katti, S. B. Tetrahedron 2002, 58, 7619–7624.
15. (a) Yadav, A. K.; Kumar, M.; Yadav, T.; Jain, R. Tetrahedron Lett. 2009, 50, 5031–
5034; (b) Zhang, X.; Li, X.; Li, D.; Qu, G.; Wang, J.; Loiseau, P. M.; Fan, X. Bioorg.
Med. Chem. Lett. 2009, 19, 6280–6283.
16. Kanagarajana, V.; Thanusua, J.; Gopalakrishnana, M. Green Chem. Lett. Rev.
2009, 2, 161–167.
17. Holmes, C. P. WO 96/ 00148, 1996.
Supplementary data
18. Gududuru, V.; Nguyen, V.; Dalton, J. T.; Miller, D. D. Synlett 2004, 2357–2358.
19. Stephanie, E.; Justus, A.; Hodges, J. C.; Wilson, M. W. Biotech. Bioeng. 2000, 61,
17–22.
20. (a) Meudt, A.; Scherer, S.; Nerdinger, S. PCT Int. Appl. WO 2005070879, 2005;
Chem. Abstr. 2005, 143, 172649.; (b) Meudt, A.; Scherer, S.; Böhm, C. PCT Int.
Appl. WO 2005123632, 2005; Chem. Abstr. 2005, 144, 69544.;.; (c) Burkhart, F.;
Hoffmann, M.; Kessler, H. Angew. Chem. Int. Ed. 1997, 36, 1191; (d) Wedel, M.;
Walter, A.; Montforts, F.-P. Eur. J. Org. Chem. 2001, 1681; Augustine, J. K.;
Sharmila, v. v.; Alagarsamy, N. P.; Radhakrishnan, A. Tetrahedron 2009, 65,
9989–9996.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
020.
References and notes
1. Desai, K. G.; Desai, K. R. J. Sulfur Chemistry 2006, 27, 315–328.
2. (a) Barreca, M. L.; Balzsarini, J.; Chimirri, A.; De Clercq, E.; De Luca, L.; Höltje, H.
D.; Höltje, M.; Monforte, A. M.; Monforte, P.; Pannecouque, C.; Rao, A.; Zapalla,
M. J. Med. Chem. 2002, 45, 5410–5413; (b) Rao, A.; Balzarini, J.; Carbone, A.;
Chimirri, A.; De Clercq, E.; Monforte, A. M.; Monforte, P.; Pannecouque, C.;
Zapallà, M. Antivir. Res. 2004, 63, 79–84; (c) Rawal, R. K.; Tripathi, R.; Katti, S. B.;
Pannecouque, C.; De Clercq, E. Bioorg. Med. Chem. 2007, 15, 3134–3142.
3. (a) Archana; Srivastava, V. K.; Kumar, A. Eur. J. Med. Chem. 2002, 37, 873–882;
(b) Dwivedi, C.; Gupta, S. S.; Parmar, S. S. J. Med. Chem. 1972, 15, 553–554.
4. Hongyu, Z.; Wu, S.; Zhai, S.; Liu, A.; Sun, Y.; Li, R.; Zhang, Y.; Ekins, S.; Swaan, P.
W.; Fang, B.; Zhangand, B.; Yan, B. J. Med. Chem. 2008, 51, 1242–1251.
5. Diurno, M. V.; Mazzoni, O.; Calignano, P. E.; Giorodano, F.; Bolognese, A. J. Med.
Chem. 1992, 35, 2910–2912.
6. Solomon, V. R.; Haq, W.; Srivastava, K.; Puri, S. K.; Katti, S. B. J. Med. Chem. 2007,
50, 394–398.
7. Jackson, C. M.; Blass, B.; Coburn, K.; Djandjighian, L.; Fadayel, G.; Fluxe, A. J.;
Hodson, S. J.; Janusz, J. M.; Murawsky, M.; Ridgeway, J. M.; White, R. E.; Wu, S.
Bioorg. Med. Chem. Lett. 2007, 17, 282–284.
8. Kucukguzel, G. C.; Shchullek, J. R.; Kaocatepe, A.; De Clercq, E.; Sahinv, F.;
Gulluce, M. Eur. J. Med. Chem. 2006, 41, 353–359.
9. Look, G. C.; Schullek, J. R.; Homes, C. P.; Chinn, J. P.; Gordon, E. M.; Gallop, M. A.
Bioorg. Med. Chem. Lett. 1996, 6, 707–712.
21. (a) Mancuso, A. J.; Swern, D. Synthesis 1981, 165; (b) Sato, T.; Takatsu, A.; Saito,
Y.; Tohyama, T.; Hata, K. Bull. Chem. Soc. Japan 1968, 41, 221; (c) Meudt, A.;
Scherer, S.; Böhm, C. PCT Int. Appl. WO 2005102978, 2005.; (d) Chem. Abstr.
2005, 143, 440908.
22. Raghavendra, G. M.; Ramesha, A. B.; Revanna, C. N.; Nandeesh, K. N.;
Mantelingu, k.; Rangappa, K. S. Tetrahedron Lett. 2011, 52, 5571–5574.
23. General procedure for one pot synthesis of 4-thiazolidinones (4): To a solution of
alcohol (1.1 mmol) in a mixture of solvents EtOAc: DMSO (4 ml: 2 ml), was
added T3PÒ (2.5 mmol, 50% solution in ethyl acetate) at 0 °C, and the resulting
mixture was stirred at room temperature for 1–2 h under nitrogen
atmosphere. The reaction was monitored by TLC, amine (1.0 mmol) and
thioglycolic acid (1.0 mmol) were added once and stirred further for 1–3 h at
room temperature. After completion of the reaction, the mixture was diluted
with water (20 ml) and neutralized by adding 10% NaHCO3 solution. The
product was extracted with ethyl acetate (10 ml  2) and the combined
organic layers were washed with water followed by brine solution. The organic
phase was dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure to afford a crude product which was purified by column
chromatography using hexane: ethyl acetate mixture (8:2) as an eluent.
24. Dinesh, L.; Dhanaji, J.; Rahul, W.; Ramrao, M. Synth. Commun. 2010, 40, 2397–
2401.
10. Homes, C. P.; Chinn, J. P.; Look, C. G.; Gordon, E. M.; Gallop, M. A. J. Org. Chem.
1995, 60, 7328–7333.
11. Srivastava, S. K.; Srivastava, S. L. J. Ind. Chem. Soc. 2002, 77, 104.
25. Zuhal, T.; Cigdem, Y.; Feray, A.; Emine, B.; Nuket, O. Molecules 2007, 12, 2151–
2159.