Unprecedented conversion of (Z)-3-chloro-3-arylacrylic acids to benzoic acids: Synthesis of s-triazolo[3,4-b][1,3,4]thiadiazoles

Article abstract of DOI:10.1016/j.tetlet.2014.05.059

An unprecedented method for the conversion of (Z)-3-chloro-3-arylacrylic acids to corresponding benzoic acids by stirring in POCl₃ at 80 °C is reported. The benzoic acids formed in situ undergo condensation with 4-amino-5-aryl-3-mercapto-1,2,4-

Full text of DOI:10.1016/j.tetlet.2014.05.059

Tetrahedron Letters 55 (2014) 3809–3812
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Tetrahedron Letters
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Unprecedented conversion of (Z)-3-chloro-3-arylacrylic acids to
benzoic acids: synthesis of s-triazolo[3,4-b][1,3,4]thiadiazoles
⇑
Seema Sahi, Madhvi Bhardwaj, Satya Paul
Department of Chemistry, University of Jammu, Jammu 180 006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An unprecedented method for the conversion of (Z)-3-chloro-3-arylacrylic acids to corresponding ben-
zoic acids by stirring in POCl3 at 80 °C is reported. The benzoic acids formed in situ undergo condensation
with 4-amino-5-aryl-3-mercapto-1,2,4-triazoles to yield s-triazolo[3,4-b][1,3,4]thiadiazoles in high
yields.
Received 1 April 2014
Revised 13 May 2014
Accepted 14 May 2014
Available online 22 May 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
(Z)-3-Chloro-3-aryl acrylic acid
Benzoic acids
s-Triazolo-thiadiazoles
POCl3
Unprecedent conversion
(Z)-Haloenoic acids1 are functionalized building blocks for the
construction of various pyrrole2 containing marine natural
products such as (Z)-5-benzylidene-4-arylpyrrol-2(5H)-ones. (Z)-
3-Aryl-3-haloenoic acids are known to form (Z)-ylidenefuran-
2(5H)-2-ones3 via Sonogashira type reactions, and are present as
a core structure in a variety of naturally occurring alkaloids, and
are represented in the ningalin4 and baculiferin5 family of marine
natural products. Several of the ningalins have been known to pos-
sess very good cytotoxic activity6 against a variety of cancer cell
lines, and very significant multidrug resistance reversal activity.7
Benzoic acids are commonly synthesized by the oxidation of
alcohols and aldehydes. This transformation has been carried out
using a variety of conventional oxidants like PCC, KMnO4/MnO2,
HNO3, DMSO/TMDB/(CuClO4)2, and CrO3, which produce a profuse
amount of undesirable wastes.8,9 However, to the best of our
knowledge, the conversion of 2-haloenoic acids into benzoic acids
has not been reported. As a synthon, benzoic acids are the building
blocks for the synthesis of a wide range of biologically active mol-
ecules.10–12 Literature survey revealed that s-triazolo-thiadiazole13
ring system substituted at 3- and 6-positions by aryl, alkyl, or het-
erocyclic moiety, has received much attention in recent years on
account of its prominent utilization for developing pharmaceuti-
cally important molecules.14,15
antitubercular activity against Mycobacterium tuberculosis H37Rv
strain.16 Triazolo-thiadiazole17,18 system was also viewed as a cyc-
lic analog of two very important components, thiosemicarbazide
and biguanide, which often display diverse biological activities.
In addition, it was mentioned that thiadiazole nucleus possesses
antimicrobial activity due to the presence of @NACAS moiety.19,20
Prompted by these observations, it was decided to synthesize some
substituted triazolo-thiadiazole derivatives possessing ArAC(Cl)
@CA unit with a view to explore their potency as better antimicro-
bial agents.
We attempted the synthesis of s-triazolo-thiadiazoles possessing
ArAC(Cl)@CA unit by the condensation of 4-amino-3-mercapto-
5-methyl-1,2,4-triazole21,22 with (Z)-3-chloro-3-(4-bromophenyl)
acrylic acid1 in phosphorus oxychloride at 80 °C23 (Scheme 1). To
our surprise, instead of (Z)-6-chloro-2-(4-bromophenyl)vinyl-
3-methyl-s-triazolo[3,4-b][1,3,4]thiadiazole, we ended up with
6-(4-bromophenyl)-3-methyl-s-triazolo[3,4-b][1,3,4]thiadiazole.
The formation of 6-(4-bromophenyl)-3-methyl-s-triazolo[3,4-b]
[1,3,4]thiadiazole indicated that the condensation might have taken
place between 4-amino-3-mercapto-5-methyl-1,2,4-triazole and
4-bromobenzoic acid with the same substitution which was present
in the corresponding (Z)-3-chloro-3-(4-bromophenyl) acrylic acid.
Since we have not used 4-bromobenzoic acid, the only possibility
is that this may have been generated in situ from (Z)-3-chloro-
3-(4-bromophenyl) acrylic acids during the reaction in POCl3.
From the NMR spectral data, it was found that there is no peak
corresponding to vinylic proton, which is the only distinguishing
part between the two possible structures, 3 and 4 (Scheme 1). Fur-
ther, mass spectra showed the absence of Cl (1:3 peak ratio).
Ilango et al. have evaluated dichlorofluorophenyl containing
triazolothiadiazoles and 6-(2,4-difluorophenyl)-3-(4-isopropylthi-
azol-2-yl)-5,6-dihydro-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazoles for
⇑
Corresponding author. Tel.: +91 191 2453969; fax: +91 191 2431365.
E-mail address: paul7@rediffmail.com (S. Paul).
http://dx.doi.org/10.1016/j.tetlet.2014.05.059
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

3810
S. Sahi et al. / Tetrahedron Letters 55 (2014) 3809–3812
Finally, single crystal X-ray crystallography24 confirmed the forma-
tion of 4-bromobenzoic acid and 6-(4-bromophenyl)-3-methyl-
1,2,4-triazolo[3,4-b][1,3,4] thiadiazole as co-crystal (Fig. 1).
The reaction was then performed with different 4-amino-
5-substituted-3-mercapto-1,2,4-triazoles with (Z)-3-chloro-3-aryl-
acrylic acids, and similar results were obtained (Table 1). To
confirm the formation of substituted benzoic acids in situ from
(Z)-3-chloro-3-arylacrylic acids, (Z)-3-chloro-3-arylacrylic acids
were treated by POCl3 at 80 °C (Table 2) and found that corre-
sponding substituted benzoic acids were obtained in each case.
This further confirmed the in situ conversion of (Z)-3-chloro-3-
arylacrylic acids into corresponding benzoic acids.
N
N
N
R'
S
N
N
N
Cl
R
R'
SH
N
+
3, 80 oC
R
POCl
R'
3
NH2
HOOC
1
2
N
N
N
S
N
Cl
The possible mechanism was also explored for the conversion of
(Z)-3-chloro-3-arylacrylic acids into benzoic acids. This involves
the cycloaddition of (Z)-3-chloro-3-arylacrylic acid with phospho-
rous oxochloride leading to the formation of 6-aryl-6-chloro-2,2,2-
trimethyl-6H-1,3,2-dioxaphosphinin-4-ol A, which then undergoes
4
R
Scheme 1. Synthesis of 3,6-disubstituted-s-triazolo[3,4-b][1,3,4]thiadiazoles in
POCl3 at 80 °C.
Figure 1. ORTEP view of the asymmetric unit of the 4-bromobenzoic acid and 6-(4-bromophenyl)-3-methyl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole cocrystal.
Table 1
Synthesis of s-triazolo[3,4-b][1,3,4]thiadiazoles by the condensation of (Z)-3-chloro-3-arylacrylic acids and 4-amino-5-substituted-3-mercapto-1,2,4-triazoles in POCl3 at 80 °Ca
Entry
1
2
3
Time (h)
Yieldb (%)
N
N
N
N
Cl
N
N
N
N
N
N
Cl
H3C
H3C
SH
SH
SH
SH
SH
S
S
S
S
N
N
N
N
N
1
3
86
N
N
NH2
HOOC
C6H4(4-Cl)
C6H4(4-Br)
Cl
N
Br
H3C
H3C
H3C
C2H5
H3C
H3C
H3C
C2H5
N
2
3
4
5
0.75
89
86
84
88
N
N
NH2
HOOC
Cl
Cl
N
H3CO
O2N
Cl
N
1
N
N
NH2
HOOC
C6H4(4-OCH3)
C6H4(4-NO2)
N
N
1.5
2.5
N
NH2
HOOC
Cl
N
N
N
N
S
N
N
N
NH2
HOOC
C6H4(4-Cl)

S. Sahi et al. / Tetrahedron Letters 55 (2014) 3809–3812
3811
Table 1 (continued)
Entry
1
2
3
Time (h)
0.5
Yieldb (%)
N
N
N
Cl
N
N
N
N
Br
C2H5
C2H5
SH
SH
SH
SH
SH
S
N
N
6
7
8
9
92
89
83
90
NH2
HOOC
C6H4(4-Br)
Cl
Cl
N
N
N
H3CO
O2N
Cl
C2H5
C2H5
C6H5
C6H5
C2H5
C2H5
C6H5
C6H5
S
S
N
N
N
1.15
N
N
NH2
HOOC
C6H4(4-OCH3)
C6H4(4-NO2)
N
N
N
1
N
NH2
HOOC
Cl
N
N
N
N
N
S
N
N
3
N
N
NH2
HOOC
C6H4(4-Cl)
N
Cl
N
Br
S
N
N
10
11
12
0.75
93
89
86
N
N
NH2
HOOC
HOOC
C6H4(4-Br)
N
N
Cl
N
N
H3CO
O2N
C6H5
C6H5
C6H5
C6H5
SH
SH
S
N
N
1
N
N
NH2
C6H4(4-OCH3)
Cl
N
N
S
N
N
1.5
N
NH2
HOOC
Cl
C6H4(4-NO2)
N
N
N
N
Cl
(H3CO-4)C6H4
(H3CO-4)C6H4
(H3CO-4)C6H4
SH
SH
(H3CO-4)C6H4
(H3CO-4)C6H4
(H3CO-4)C6H4
(H3CO-4)C6H4
N
NH2
S
S
S
S
N
N
N
N
13
14
15
3
88
92
87
82
N
N
HOOC
C6H4(4-Cl)
N
Cl
N
N
Br
N
NH2
0.5
1
N
N
HOOC
HOOC
HOOC
C6H4(4-Br)
N
Cl
Cl
N
N
N
H3CO
O2N
SH
N
N
NH2
N
N
C6H4(4-OCH3)
C6H4(4-NO2)
N
(H3CO-4)C6H4
SH
N
16
2
N
NH2
a
Reaction conditions: 4-amino-5-substituted-3-mercapto-1,2,4-triazole 1 (1 mmol) and (Z)-3-chloro-3-arylacrylic acid 2 (1 mmol) were stirred in POCl3 (3 mL) at 80 °C.
Isolated yields.
b
Table 2
Conversion of (Z)-3-chloro-3-arylacrylic acids into benzoic acids in POCl3 at 80 °Ca
Entry
1
Reactant
Product
Time (h)
3
Yieldb (%)
92
M.P./lit. M.P. (°C)
Cl
Cl
COOH
COOH
Cl
240–241/24025
HOOC
Cl
Br
Br
2
0.5
94
255–256/25825
HOOC
(continued on next page)

3812
S. Sahi et al. / Tetrahedron Letters 55 (2014) 3809–3812
Table 2 (continued)
Entry
Reactant
Product
Time (h)
1
Yieldb (%)
91
M.P./lit. M.P. (°C)
Cl
Cl
H3CO
COOH
COOH
H3CO
3
245–246/24725
HOOC
O2N
O2N
4
1.5
93
235–236/23725
HOOC
a
Reaction conditions: (Z)-3-chloro-3-arylacrylic acid (1 mmol) was stirred in POCl3 (3 mL) at 80 °C.
Isolated yields.
b
Cl
O
P
Cl
Cl
P
Cl
Cl
Cl
O
Cl
Cl
Cl
O
O
Cl
O
O
P
OH
OH
Cl
Cl
OH
X
X
X
A
B
O
O
Cl
P
Cl
Cl
H3O
OH
Cl
OH
X
X
O
HCl
H3PO3
Unstable
D
C
Figure 2. Proposed mechanism for the conversion of (Z)-3-chloro-3-arylacrylic acids to benzoic acids in POCl3.
4. Kang, H.; Fenical, W. J. Org. Chem. 1997, 62, 3254–3262.
ring contraction to 4-aryl-2,2,2,4-tetrachloro-1,2-oxaphosphetane-
3-carboxylic acid B. The four membered intermediate B undergoes
ring cleavage to give substituted benzoyl chloride C and intermedi-
ate D. Finally C under the reaction conditions was converted to
benzoic acid, phosphoric acid, and hydrochloric acid (Fig. 2).
In summary, we have developed an unprecedented method for
the conversion of (Z)-3-chloro-3-arylacrylic acids to the corre-
sponding benzoic acids, which undergo in situ condensation with
4-amino-5-aryl-3-mercapto-1,2,4-triazoles to give s-triazolo[3,
4-b][1,3,4]thiadiazoles in good to excellent yields.
5. Fan, G.; Li, Z.; Shen, S.; Yang, Y.; Xu, M.; Brihn, T.; Bruhn, H.; Morschhauser, J.;
Bringmann, G.; Lin, W. Bioorg. Med. Chem. 2010, 18, 5466–5470.
6. Hamasaki, A.; Zimpleman, J.; Hwang, I.; Boger, D. J. Am. Chem. Soc. 2005, 127,
10767–10770.
7. Soenen, D.; Hwang, I.; Hedrick, M.; Boger, D. Bioorg. Med. Chem. Lett. 2003, 13,
1775–1777.
8. Das, R.; Chakraborty, D. Appl. Organomet. Chem. 2011, 25, 437–442.
9. Choudhary, V. R.; Dumbre, D. K.; Narkhede, V. S. J. Chem. Sci. 2012, 124, 835–
839.
10. Mannam, S.; Sekar, G. Tetrahedron Lett. 2007, 49, 1083–1085.
11. Purohit, N. V.; Yadav, P. Res. J. Chem. Sci. 2012, 2, 57–61.
12. Filho, J. M. B.; Silva, E. C.; Bhattacharyya, J. Quim. Nova 1990, 13, 332–334.
13. Sharma, M.; Deekshith, V.; Semwal, A.; Sriram, D.; Yogeeswari, P. Pain Ther.
2012, 1, 1–17.
Acknowledgment
14. Lal, H.; Sharma, N.; Agarwal, T. P.; Sharma, N. J. Appl. Pharm. Sci. 2012, 2, 104–
112.
15. Khan, I.; Ibrar, A.; Abbas, N. Eur. J. Med. Chem. 2013, 63, 854–868.
16. Ilango, K.; Valentina, P. Der. Pharma Chemica 2010, 2, 16–22.
17. Demirbas, N.; Demirbas, A.; Karaoglu, S. A.; Çelik, E. ARKIVOC 2005, i, 75–91.
18. Farghalya, A. R.; Clercq, E. D.; El-Kashefa, H. ARKIVOC 2006, x, 137–151.
19. Shah, B. A.; Shah, A. V.; Shah, P. M. Iran. Polym. J. 2006, 15, 809–819.
20. Gomha, S. M.; Riyadh, S. M. Molecules 2011, 16, 8244–8256.
21. Dhaka, K. S.; Jagmohan; Chadha, V. K.; Pujari, H. K. Indian J. Chem. 1974, 12,
287–289.
We gratefully acknowledge the Department of Science and
Technology, Government of India for NMR spectrometer (Bruker
Avance III, 400 MHz) under PURSE program to the University of
Jammu, and IIIM, Jammu for mass spectral data. One of the authors
(M.B.) thanks UGC, New Delhi for awarding J.R.F.
22. Jagmohan; Anjaneyulu, G. S. R.; Kiran Indian J. Chem. 1988, 27B, 346–349.
Supplementary data
23. General Procedure:
A mixture of 4-amino-5-substituted-3-mercapto-1,2,4-
triazoles 1 (1 mmol) and (Z)-3-chloro-3-arylacrylic acids 2 (1 mmol) in POCl3
(3 mL) was stirred at 80 °C for 0.5–3 h. After completion of the reaction
(monitored by TLC), the reaction mixture was poured into crushed ice (5 g).
The solid formed was filtered, washed with 10% aq. NaOH (15 mL), dried and
crystallized from methanol. The structure of the products were confirmed by
IR, 1H, 13C and mass spectral data and comparison with authentic samples
prepared according to the literature methods.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.05.
059.
References and notes
Spectroscopic data for entry 2 (Table 1): IR (KBr, m
max in cmÀ1): 2918 (alph. CH
stretch), 1605 (C@N), 1113 (C-S); 1H NMR (400 MHz, DMSO): d 2.66 (s, 3H,
CH3), 7.15–7.17 (d, J = 8.0 Hz, 2H, Harom), 7.90–7.92 (d, J = 8.0 Hz, 2H, Harom);
13C NMR (100 MHz, DMSO): d 14.1 (CH3), 123.5, 129.6, 132.1, 134.0 (aromatic
carbons), 141.4 (N@CAS), 149.6 (C3), 178.5 (C6); MS (ESI): 294.88, (M+), 215,
182.
1. Gupton, J. T.; Telang, N.; Banner, E. J.; Kluball, E. J.; Hall, K. E.; Finzel, K. L.; Jia, X.;
Bates, S. R.; Welden, R. S.; Giglio, B. C.; Eaton, J. E.; Barelli, P. J.; Firich, L. T.;
Stafford, J. A.; Coppock, M. B.; Worrall, E. F.; Kanters, R. P. F.; Keertikar, K.;
Osterman, R. Tetrahedron 2010, 66, 9113–9122.
2. Gupton, J.; Giglio, B.; Eaton, J.; Rieck, E.; Smith, K.; Keough, M.; Barelli, P.; Firich,
L.; Hempel, J.; Smith, T.; Kanters, R. Tetrahedron 2009, 65, 4283–4292.
3. Prim, D.; Fuss, A.; Kirsch, G.; Silva, A. J. Chem. Soc Perkin Trans. II 1999, 1175–
1180.
24. Kapoor, K.; Gupta, V. K.; Paul, S.; Sahi, S.; Kant, R. Acta Crystallogr. 2012, E68,
o1185–o1186.
25. Aldrich Advancing Science Handbook of Fine Chemicals, 2007.