Laccase-catalyzed, aerobic oxidative coupling of 4-substituted urazoles with sodium arylsulfinates: Green and mild procedure for the synthesis of arylsulfonyl triazolidinediones

Article abstract of DOI:10.1016/j.tetlet.2017.12.048

The direct aerobic oxidation of 4-substituted urazoles using the laccase enzyme from Trametes versicolor in a phosphate buffer solution at ambient temperature, and subsequent cross-coupling with sodium benzenesulfinates was investigated to afford arylsulfonyl-1,2,4-triazolidine-3,5-dione derivatives in good to high yields.

Full text of DOI:10.1016/j.tetlet.2017.12.048

Accepted Manuscript
Laccase-catalyzed, aerobic oxidative coupling of 4-substituted urazoles with
sodium arylsulfinates: green and mild procedure for the synthesis of arylsulfonyl
triazolidinediones
Abdollah Rahimi, Davood Habibi, Amin Rostami, Mohammad Ali Zolfigol,
Shadpour Mallakpour
PII:
S0040-4039(17)31551-4
https://doi.org/10.1016/j.tetlet.2017.12.048
TETL 49550
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 November 2017
6 December 2017
12 December 2017
Please cite this article as: Rahimi, A., Habibi, D., Rostami, A., Ali Zolfigol, M., Mallakpour, S., Laccase-catalyzed,
aerobic oxidative coupling of 4-substituted urazoles with sodium arylsulfinates: green and mild procedure for the
synthesis of arylsulfonyl triazolidinediones, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.
2017.12.048
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Laccase-catalyzed, aerobic oxidative coupling of 4-substituted urazoles with
sodium arylsulfinates: green and mild procedure for the synthesis of
arylsulfonyl triazolidinediones
Abdollah Rahimi,a Davood Habibi,*a Amin Rostami,*b Mohammad Ali Zolfigol,a Shadpour Mallakpourc
a Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838683, Iran
b Department of Chemistry, Faculty of Sciences, University of Kurdistan, Sanandaj 6617715143, Iran
c Polymer Chemistry Research Laboratory, Department of Chemistry, Isfahan University of Technology, Isfahan, Iran
*email: davood.habibi@gmail.com, a.rostami@uok.ac.ir, Fax: (+98) 81-38380709; Tel: (+98) 81-38380922
ABSTRACT
The direct aerobic oxidation of 4-substituted urazoles using the laccase enzyme from Trametes versicolor in a phosphate buffer solution at
ambient temperature, and subsequent cross-coupling with sodium benzenesulfinates was investigated to afford arylsulfonyl-1,2,4-
triazolidine-3,5-dione derivatives in good to high yields.
Keywords: 4-substituted urazole, sodium benzenesulfinate, laccase enzyme, aerobic oxidation, arylsulfonyl triazolidindione
1. Introduction
Laccases (benzenediol: oxygen oxidoreductase, EC 1.10.3.2) belong to a group of polyphenol oxidases
containing copper atoms in the catalytic center. These multicopper oxidases catalyze oxidation reactions using
atmospheric oxygen as the oxidant and produce water as the only by-product. For example, Ragauskas and co-
workers reported the biocatalytic synthesis of phenothiazones and related compounds in an aqueous system
under mild conditions using laccase oxidation.1 Beifuss and co-workers reported various laccase-catalyzed
domino and oxidation reactions.2-6 Kidwai and co-workers investigated the enzymatic laccase oxidation of
catechols/hydroquinones in the presence of Meldrum's acid as a nucleophile in an aqueous solution.7 Kragl
and co-workers investigated the application of the fungal laccase from Myceliophthorathermophila
(Novozym®51003) for the oxidative C-C coupling of phenolic compounds.8
4-Substituted-1,2,4-triazolidine-3,5-dione derivatives are notable for their ability to participate in a wide
range of concerted and stepwise reactions.9-11 For example, the oxidation of urazoles represents one of the
best strategies for the preparation of these valuable intermediates. Several reagents have been reported for
this key transformation, including Ph3BiCO3,12 periodic acid/NaNO2,13 silica sulfuric acid/NaNO2,14
trichloroisocyanuric acid,15 silica chloride/ NaNO2,16 HNO3,17 N2O4,18 chlorine or bromine,19 Ca(OCl)2,20
K2Cr2O7/AlCl3,21 and p-toluenesulfonyl isocyanate/DMSO.22 However, these methods have disadvantages
including harsh reaction conditions, poor atom efficiency, the use of toxic and gaseous reagents, and the
production of large quantities of waste. Thus, from the viewpoint of green and sustainable chemistry, there is
significant motivation to develop both cleaner and milder methods for the oxidation of urazoles to the
corresponding triazolidindiones (TADs).
Although the direct laccase catalyzed, aerobic oxidation of a broad range of substrates, including mono-,
di-, and polyphenols, aminophenols, methoxyphenols and aromatic amines, have been studied,23,24 to the best
1

of our knowledge there are no reports regarding the use of laccase for the aerobic oxidation of urazoles to
TADs. Therefore, in continuation of our studies on applications of the laccase enzyme in organic synthesis,25,26
herein we disclose the use of laccase from Trametes versicolor as a biocatalyst for the synthesis of arylsulfonyl-
1,2,4-triazolidine-3,5-dione derivatives via the direct aerobic oxidative coupling reaction between 4-
substituted urazole derivatives and sodium arylsulfinates in a phosphate buffer solution (PBS) using air as an
oxidant.
2. Results and Discussion
The laccase catalyzed, aerobic oxidative coupling reaction of 4-phenylurazole 1a with sodium
benzenesulfinate 2a was initially examined in aqueous media and a range of organic solvents (Table 1), where
it was determined that PBS (0.1 M, pH = 5.0) was optimal (Entry 3). In water, ethanol and water/ethanol (1:1),
the reaction proceeded with moderate yields (40-57%; entries 8-10). No reaction took place in MeCN, DMF
and DMSO, probably due to denaturation of the laccase enzyme (Entries 11-13).
Table 1. Solvent optimization for the synthesis of phenylsulfonyl triazolidinedione 3aa
Entry Solvent
GC Yield 3a (%)b
1
2
PBS (0.1 M, pH = 7.0)
82
PBS (0.1 M, pH = 6.0)
75
>99
77
65
57
50
40
52
57
-
3
PBS (0.1 M, pH = 5.0)
4
PBS (0.1 M, pH = 4.0)
5
acetate buffer solution (0.1 M, pH = 5.0)
6
phosphate/citrate buffer solution (0.1 M, pH = 7.0)
7
phosphate/citrate buffer solution (0.1 M pH = 5.0)
8
H2O
9
EtOH
10
11
12
13
H2O/EtOH (1:1)
MeCN
DMF
-
DMSO
-
aReagents and conditions: laccase (57.5 mg, 50 U), 1a (1.0 mmol), 2a (1.0 mmol), solvent (10 mL), air, r.t., 4 h.
bGC yield.
The effect of the laccase amount on the reaction rate was also studied (Table 2). A blank reaction was
carried out to determine the catalytic effectiveness of laccase; no product formation occurred even after 20 h
2

(Entry 7). The rate of product formation was enhanced with increasing catalyst amount, and the optimum
enzyme concentration was found to be 50 U (Entry 5).
Table 2. Optimization of the amount of laccase for the synthesis of phenylsulfonyl triazolidinedione 3aa
O
O
O
NH
HN
S
Laccase (10-60U), air
N
Na
O
+
O2S
Ph
N
O
N
NH
3a
PBS (0.1 M, 10 mL, pH=5.0),
r.t., 4 h
Ph
1a
2a
O
Entry
Laccase amount (U)
GC Yield 3a (%)b
1
2
3
4
5
6
7
10
20
30
40
50
60
-
21
50
70
85
>99%
>99%
-
aReagents and conditions: laccase (10-60 U), 1a (1.0 mmol), 2a (1.0 mmol), PBS (0.1 M, 10 mL, pH=5.0), air r.t., 4 h.
bGC yield
Finally, the effect of reaction temperature was investigated using various temperatures ranging from 25 ᵒC
to 65 ᵒC; the optimum temperature found to be the room temperature (25 ᵒC).
The scope of the aerobic oxidative coupling reaction between various urazole derivatives and sodium
arylsulfinates (Table 3) were examined using the optimized conditions: laccase (57.5 mg, 50 U) in PBS (0.1 M,
10 mL, pH = 5.0) at room temperature.
Table 3. Synthesis of various arylsulfonyl triazolidinedione derivativesa
Sodium
arylsulfinate
Entry
1
Urazole
HN
Products
Time (h) Yield (%)b
95
NH
4
O
O
N
1a
3

2
6
88
3
4
2
2
92
95
5
6
2
3
95
97
7
8
3.5
5.5
87
85
9
2
93
4

10
11
2
2
90
96
12
13
14
2.5
97
86
87
O
O
5
H
S
N
N
O
N
Cl
O
3m
7
15
16
17
O
O
2.5
2.6
2.5
93
87
92
H
S
N
N
O
CH3
N
Cl
O
3o
5

18
4
89
a Reagents and conditions: laccase (57.5 mg, 50 U), 1a-f (1 mmol), 2a-c (1 mmol), PBS (0.1 M, 10 mL, pH=5.0), air, r.t., 4 h.
b Isolated yield
The laccase catalyzed, aerobic oxidative coupling reaction between similar aza-heterocyclic compounds,
such as phthalhydrazide and succinic hydrazide, with sodium phenyl sulfinate under various reaction
conditions did not give the desired products and the starting materials remained intact.
The greenness of this method was compared with previously reported methods for the oxidation of
urazoles (ESI, Table S1). In contrast to the reported procedures, the laccase/air system has attractive features
including mild conditions, the use of laccase as a biodegradable catalyst which is derived from renewable
resources, and an environmentally compatible solvent.
3. Conclusion
In summary, we have reported the synthesis of a range of 1-sulfonyl-1,2,4-triazolidine-3,5-dione
derivatives via the aerobic oxidative coupling of 4-substituted urazoles with sodium arylsulfinates in good to
high yields, using air as a terminal oxidant and laccase as an eco-friendly biocatalyst in PBS as a green solvent.
Acknowledgements
The authors gratefully acknowledge financial support from Bu-Ali Sina University, Hamedan 6517838683,
Iran.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/....
References
1. Cannatelli M. D., Ragauskas A. J., Tetrahedron Lett. 2016, 57, 3749-3753.
2. Hajdok S., Conrad J., Leutbecher H., Strobel S., Schleid T., Beifuss U., J. Org. Chem. 2009, 74, 7230-
7237.
3. Hajdok S., Conrad J., Beifuss U., J. Org. Chem. 2012, 77, 445-459.
4. Abdel-Mohsen H. T., Conrad J., Beifuss U., Green Chem. 2012, 14, 2686-2690.
5. Constantin, M-A.; Conrad, J.; Meris, E.; Koschorreck, K.; Urlacher, V. B.; Beifuss, U. J. Org. Chem. 2012,
77, 4528-4543.
6. Constantin, M-A.; Conrad, J.; Beifuss, U. Tetrahedron Lett. 2012, 53, 3254-3258.
7. Kidwai M., Jain A., Sharma A., Kuhad R. C., CR. Chim. 2013, 16, 728-735.
6

8. Engelmann C., Illner S., Kragl U., Process Biochem. 2015, 50, 1591-1599.
9. De Bruycker K., Billiet S., Houck H. A., Chattopadhyay S., Winne J. M., Du Prez F. E., Chem. Rev. 2016,
116, 3919-3974.
10. (a) Breton G. W., Newton K. A., J. Org. Chem. 2000, 65, 2863-2869; (b) Henderson A. P., Mutlu E.,
Leclercq A., Bleasdale C., Clegg W., Henderson R. A., Golding B. T., Chem. Commun. 2002, 1956-1957.
11. Erden I., Song J., Cao W., Org. Lett. 2000, 2, 1383-1385.
12. Menard C., Doris E., Mioskowski C., Tetrahedron Lett. 2003, 44, 6591-6593.
13. Zolfingol M. A., Chehardoli G., Shirini F., Mallakpour S. E., Nasr-Isfahani H., Synth. Commun. 2001, 31,
1965-1970.
14. Zolfigol M. A., Chehardoli G., Mallakpour S. E., Synth. Commun. 2003, 33, 833-841.
15. Zolfigol M. A., Madrakian E., Ghaemi E., Mallakpour S., Synlett 2002, 10, 1633-1636.
16. Zolfigol M. A., Torabi M., Mallakpour S. E., Tetrahedron 2001, 57, 8381-8384.
17. Furdik M., Mikulase S., Livar M., Priehrad S., Chem. Zvesti. 1967, 21, 427-442.
18. Stickler J. C., Pirkle W. H., J. Org. Chem. 1966., 31, 3444-3445.
19. Read G., Richardson N. R., J. Chem. Soc., Perkin Trans. 1. 1996, 167-174.
20. Zolfigol M. A., Mallakpour S., Khazaiae A., Vaghaie R. G., Torabi M., Bull. Korean Chem. Soc. 2004, 25,
1251-1252.
21. Mohammadpoor-Baltork I., Sadeghi M. M., Mallakpour S. E., Reza Hajipour A., Adibi A.-H., Synth.
Commun. 2002, 32, 3445-3448.
22. Moore J. A., Muth R., Sorace R., J. Org. Chem. 1974, 39, 3799-3800.
23. Monti D., Ottolina G., Carrea G., Riva S., Chem. Rev. 2011, 111, 4111-4140.
24. Mogharebi M., Faramarzi M.A., Adv. Synth. Catal. 2014, 356, 897-927.
25. Rouhani S., Rostami A., Salimi A., RSC Adv. 2016, 6, 26709-26718.
26. Habibi D., Rahimi A., Rostami A., Moradi S., Tetrahedron Lett. 2017, 58, 289-293.
27. Mallakpour S. E., Zolfigol M. A., Indian J. Chem. 1999, 38B, 777-782.
28. Mallakpour S. E., J. Chem. Educ. 1992, 69, 238-241.
29. Bohlin C., Lundquist K., Jönsson L., J. Bioorg. Chem. 2009, 37, 143-148.
30. Varmaghani F., Nematollahi D., Mallakpour S., Esmaili R., New J. Chem. 2017, 41, 8279-8288.
31. Varmaghani F., Nematollahi D., Mallakpour S., Esmaili R., Green Chem. 2012, 14, 963-967.
7

Laccase-catalyzed, aerobic oxidative coupling of 4-substituted urazoles with sodium
arylsulfinates: green and mild procedure for the synthesis of sulfonyl
triazolidinediones
Abdollah Rahimi,a Davood Habibi,*a Amin Rostami,*b Mohammad Ali Zolfigol,a Shadpour Mallakpourc
8

Revised Highlights
1. Direct oxidation of 4-substituted urazoles by laccase enzyme from Trametes versicolor.
2. Cross-coupling reaction of oxidized form of urazoles with sodium benzenesulfinates.
3. Synthesis of arylsulfonyl-1,2,4-triazolidine-3,5-dione derivatives.
4. The use of air as an eco-friendly oxidant.
5. Working in green conditions (aqueous media and ambient temperature).
9