Dess-Martin periodinane-mediated oxidative aromatization of 1,3,5-trisubstituted pyrazolines

Article abstract of DOI:10.1080/00397911.2011.563449

(Chemical Equation Presented) A general method for the oxidative aromatization of 1,3,5-trisubstituted pyrazolines under mild conditions has been developed using Dess-Martin periodinane as oxidant. Copyright Taylor & Francis Group, LLC.

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Dess–Martin Periodinane–Mediated
Oxidative Aromatization of 1,3,5-
Trisubstituted Pyrazolines
Sumit V. Gamapwar a , Nilesh P. Tale a & Nandkishor N. Karade a
a Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur
University, Nagpur, Maharashtra, India
Accepted author version posted online: 02 Jan 2012.Version of
record first published: 29 May 2012.
To cite this article: Sumit V. Gamapwar , Nilesh P. Tale & Nandkishor N. Karade (2012): Dess–Martin
Periodinane–Mediated Oxidative Aromatization of 1,3,5-Trisubstituted Pyrazolines, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
42:17, 2617-2623
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Synthetic Communications1, 42: 2617–2623, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.563449
DESS–MARTIN PERIODINANE–MEDIATED OXIDATIVE
AROMATIZATION OF 1,3,5-TRISUBSTITUTED
PYRAZOLINES
Sumit V. Gamapwar, Nilesh P. Tale, and
Nandkishor N. Karade
Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur
University, Nagpur, Maharashtra, India
GRAPHICAL ABSTRACT
Abstract A general method for the oxidative aromatization of 1,3,5-trisubstituted pyrazo-
lines under mild conditions has been developed using Dess–Martin periodinane as oxidant.
Keywords Aromatization; Dess–Martin periodinane; oxidation; 1,3,5-trisubstituted
pyrazolines
INTRODUCTION
The substructural unit of pyrazole is frequently present in various bioactive
molecules showing a wide range of pharmacological properties such as analgesic,
anti-inflammatory,[1] antipyretic, anti-arrhythmic, tranquilizing, muscle relaxant,
psychoanaletic, anticonvulsant, monoanineoxidase inhibitory, anticancer,[2] anti-
bacterial,[3] antiviral,[4] antidiabetic,[5] antimicrobial, and antifungal activities.[6]
Celecoxib[7] and rimonabant[8] are the most notable examples of commercial phar-
maceutical drugs with pyrazole as their core molecular entity. Celecoxib is a
non-steroidal anti-inflammatory drug (NSAID), whereas rimonabant is an anorectic
antiobesity drug. Some pyrazoles also display agrochemical properties (i.e.,
herbicidal and soil fungicidal activity) and have applications as pesticides and
insecticides.[9]
Received December 20, 2010.
Address correspondence to Nandkishor N. Karade, Department of Chemistry, Rashtrasant
Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra 440 033, India. E-mail: nnkarade@
gmail.com
2617

2618
S. V. GAMAPWAR, N. P. TALE, AND N. N. KARADE
Scheme 1. Strategy of 1,3,5-trisubstituted pyrazole synthesis.
1,3,5-Trisubstituted pyrazoles can be easily obtained by oxidation of their
corresponding pyrazolines (Scheme 1), which are, in turn, obtained from the cyclo-
condensation reaction of chalcones with arylhydrazines.[10]
There is obvious demand for oxidation of pyrazolines to pyrazoles because of
their importance both as pharmacological targets and synthetic intermediates. A num-
ber of methods have been previously reported for the oxidation of pyrazolines using a
variety of oxidants. These oxidizing agents can be broadly classified into two cate-
gories: (a) transition metal–based oxidizing agents such as Zr(NO3)4,[11] Pd=C=
AcOH,[12] Co(II)=O2,[13] Pb(OAc)4,[14] MnO2,[15] KMnO4,[16] Ag(NO3)2,[17] and
HgO;[18] and (b) halogen-derived oxidants such as PhI(OAc)2,[19] N-bromosuccinimide
(NBS),[20] I2O5=KBr,[21] and poly-1,3-dichloro-5-methyl-5(40-vinylphenyl)hydan-
toin.[22] Oxidation of 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazoles to the correspond-
ing pyrazoles have also been achieved by utilizing other miscellaneous oxidizing agents
such as carbon-activated oxygen,[23] N-hydroxyphthalimide (NHPI),[24] and silica-
supported 1,3-dibromo-5,5-dimethylhydantoin (DBH).[25] However, many reported
methods suffer from certain drawbacks such as the use of expensive reagents, longer
reaction times, high temperatures, poor yields, formation of side products, and toxicity
of certain elements embodied in these reagents. These limitations necessitate further
demand for new, environmentally benign, and easily accessible reagents for conversion
of 2-pyrazolines to pyrazoles.
Dess-Martin (DMP) is a pentavalent hypervalent iodine reagent most exten-
sively used for the oxidation of alcohols.[26] Its use for the dehydrogenation of 4,5-
dihydropyrazoles is hitherto unknown in the literature. Herein, we report a practical
and environmentally friendly method for the oxidative aromatization of 1,3,5-
trisubstituted pyrazolines using DMP as a versatile oxidizing agent (Scheme 2).
Scheme 2. Oxidative aromatization of 1,3,5-trisubstituted pyrazolines using DMP.

OXIDATION OF 1,3,5-TRISUBSTITUTED PYRAZOLINES
2619
The methodology is characterized by good yields of the product and easy separation
of the product from the reaction mixture.
RESULTS AND DISCUSSION
DMP-mediated oxidative aromatization of 4,5-dihydropyrazolines to pyrazole
was investigated using 1,3,5-triphenylpyrazoline 1a as the model substrate. DMP (1
mmol) was added to a solution of 1,3,5-triphenylpyrazoline 1 (1 mmol) in MeCN
(10 ml), and the reaction mixture was stirred for 2 h at room temperature. The reac-
tion did not proceed to the formation of aromatized product in satisfactory yield.
When the reaction mixture was subjected to reflux, the formation of aromatized pro-
duct, 1,3,5-triphenylpyrazole, took place in 1.5 h with 59% yield. However, the use of
2.2 equivalents of DMP with respect to the substrate resulted in 87% yield of the aro-
matized product. Of the solvents tested for this reaction (CHCl3, CH2Cl2, MeOH
and MeCN), MeCN was found to be the most efficient for maximum yield of the
oxidation product. Apart from DMP, we tried to investigate the oxidation of
1,3,5-triphenylpyrazoline using molecular iodine as well as I2=K2CO3. However,
the formation of any oxidation product was not observed.
Using these optimized reaction conditions, a wide range of 1,3,5-triarylpyrazo-
lines were subjected to the oxidative aromatization using DMP. In all cases, good to
excellent yields of the products were obtained. All the reactions were complete within
Scheme 3. Mechanism of oxidative aromatization of 1,3,5-trisubstituted pyrazolines using DMP.

2620
S. V. GAMAPWAR, N. P. TALE, AND N. N. KARADE
1–2 h. The structures of all the products were established from infrared (IR), NMR,
and mass spectral analysis. The 1H NMR spectra of all the products showed
a characteristic singlet peak around at d ¼ 6.67–6.82 due to aromatic C-H at the
4-position of the pyrazole ring. Also, in 13C NMR, C-4 carbon resonates around
d 104–105, indicating the formation of pyrazole.
Mechanistically, the reaction will take place around the coordination sphere of
iodine (Scheme 3). The ligand exchange reaction between 4,5-dihydropyrazole and
DMP may form the intermediate 3. The tendency of iodine for the reductive elimin-
ation in 3 may induce the concomitant oxidation of 4,5-dihydropyrazole to form
aromatized pyrazole 4.
CONCLUSION
In conclusion, we have developed a new and mild transition metal–free method
for the oxidative aromatization of 1,3,5-trisubstituted pyrazolines to corresponding
pyrazoles using DMP.
EXPERIMENTAL
A mixture of 1,3,5-triaryl pyrazolines (2 mmol) and Dess–Martin periodinane
(4.4 mmol) in CH3CN (20 ml) was refluxed for the time as mentioned in Table 1.
The progress of the reaction was monitored by thin-layer chromotography(TLC).
After completion of reaction, it was treated with NaHCO3 (2 ꢀ 10 ml) and extracted
with CH2Cl2 (3 ꢀ 15 ml). The combined organic layers were dried over anhydrous
sodium sulfate, filtered, and concentrated under vacuum, and the residue was puri-
fied by column chromatography using the ethyl acetate=petroleum ether (1:9) as
eluent to obtain the highly pure product.
1,3,5-Triphenyl-1H-pyrazole (2a)
Yellow solid, mp 142–146 ꢁC (lit.[19] mp 139–140 ꢁC); IR (KBr): 3019, 1596,
1
1500, 1458, 1431, 1362, 1215, 1067, 1027, 928, 758, 669 cmꢂ1. H NMR (CDCl3,
400 MHz): d 6.82 (s, 1H), 7.27–7.38 (m, 11H, ArH), 7.43 (t, 2H, J ¼ 6.72 Hz,
ArH), 7.92 (d, 2H, J ¼ 7.04 Hz, ArH). 13C NMR (CDCl3, 100 MHz): d 105.25,
125.24, 125.85, 127.46, 128.04, 128.33, 128.52, 128.69, 128.78, 128.95, 130.61,
133.08, 140.17, 144.17, 144.42, 152.00. MS (ESI) m=z (M þ H)þ calculated for
C21H16N2: 296.13. Found: 297.2.
3-(4-Chlorophenyl)-1,5-diphenyl-1H-pyrazole (2d)
Whitesolid, mp 156–160 ꢁC. IR (KBr): 3017, 1597, 1499, 1458, 1360, 1215,
1
1093, 1015, 972, 834, 756, 693 cmꢂ1. H NMR (CDCl3, 400 MHz): d 6.79 (s, 1H),
7.26–7.29 (m, 2H, ArH), 7.30–7.36 (m, 8H, ArH), 7.36 (d, 2H, J ¼ 8.52 Hz, ArH),
7.86 (d, 2H, J ¼ 8.52 Hz, ArH). 13C NMR (CDCl3, 100 MHz): d 105.13, 125.30,
127.08, 127.61, 128.45, 128.56, 128.76, 128.86, 128.99, 130.40, 131.63, 133.74,
140.03, 144.63, 150.87. MS (ESI) m=z (M þ H)þ calculated for C21H15ClN2:
330.09. Found: 331.2.

OXIDATION OF 1,3,5-TRISUBSTITUTED PYRAZOLINES
2621
Table 1. Aromatization of 1,3,5-trisubstituted pyrazolines with Dess–Martin periodinanea
Mp (ꢁC)
Substrate Product
Ar1
Ar2
Time (h) Yield (%)a
Found
Lit.
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
C6H5
C6H5
C6H5
C6H5
4-CH3C6H4
4-NO2C6H5
C6H5
1.5
2
84
80
74
82
81
79
78
81
83
142–146 139–140[22]
78–80
78–80[22]
141–142 142–142[22]
2
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
2
156–157
160–162
113–114
110–112
132–133
81–82
—
—
4-CH3C6H4
4-CH3OC6H4
C6H5
2
2
—
—
1g
1h
1i
2g
2h
2i
2
4-ClC6H4
C6H5
2
—
80–82[22]
3
aIsolated yields.
3-(4-Chlorophenyl)-1-phenyl-5-p-tolyl-1H-pyrazole (2e)
Yellow solid, mp 160–162 ꢁC.IR (KBr): 3019, 2925, 1662, 1599, 1490, 1329,
1
1215, 1092, 1012, 984, 837, 755, 669 cmꢂ1. H NMR (CDCl3, 400 MHz): d 2.34 (s,
3H), 6.75 (s, 1H), 7.12–7.24 (m, 4H, ArH), 7.29–7.47 (m, 6H, ArH), 7.45–7.47 (m,
1H, ArH), 7.84 (d, 2H, J ¼ 9.16 Hz, ArH). 13C NMR (CDCl3, 100 MHz): d 21.38,
104.86, 125.31, 125.31, 127.05, 127.53, 128.60, 128.88, 128.96, 129.25, 129.92,
130.41, 131.67, 133.66, 138.41, 140.11, 144.70, 145.71, 150.80. MS (ESI) m=z
(M þ H)þ calculated for C22H17ClN2: 344.11. Found: 345.
1,5-Diphenyl-3-p-tolyl-1H-pyrazole (2f)
Yellow solid, mp 110–112 ꢁC. IR (KBr): 3041, 2913, 1684, 1593, 1457, 1422,
.
1359, 1175, 1114, 1085, 1027, 969, 826, 769, 691 cmꢂ1 1H NMR (CDCl3,
400 MHz): d 2.35 (s, 3H), 6.79 (s, 1H), 7.12 (d, 2H, J ¼ 8.12 Hz, ArH), 7.17 (d,
d, 2H, J ¼ 8.24 Hz, ArH), 7.25–7.38 (m, 6H, ArH), 7.42 (t, d, 2H, J ¼ 8.44 Hz,
ArH), 7.91 (d, t, 2H, J ¼ 8.04 Hz, ArH). 13C NMR (CDCl3, 100 MHz): d 21.21,
104.89, 125.24, 125.74, 127.27, 127.87, 128.55, 128.81, 129.12, 133.05, 138.16,
140.18, 144.39, 151.83.MS (ESI) m=z (M þ H)þ calculated for C22H18N2: 310.15.
Found: 311.

2622
S. V. GAMAPWAR, N. P. TALE, AND N. N. KARADE
5-(4-Methoxyphenyl)-1-phenyl-3-p-tolyl-1H-pyrazole (2g)
Orange solid, mp 105–110 ꢁC.IR (KBr): 3007, 2934, 1654, 1612, 1595, 1499,
.
1432, 1293, 1255, 1185, 1024, 969, 840, 805, 764 cmꢂ1 1H NMR (CDCl3,
400 MHz): d 2.35 (s, 3H), 3.85 (s, 3H OCH3), 6.72 (s, 1H), 6.96 (d, 2H, J ¼ 8.84 Hz,
ArH), 7.14 (dd, 2H, J ¼ 8.28 Hz, J ¼ 8.12 Hz, ArH), 7.20 (d,d, 2H, J ¼ 8.28 Hz,
ArH), 7.27–7.33 (m, 5H ArH), 7.84 (d, 2H, J ¼ 8.88 Hz, ArH). 13C NMR (CDCl3,
100 MHz): d 21.22, 55.22, 104.51, 113.96, 125.22, 125.63, 127.00, 127.16, 128.53,
128.80, 129.11, 129.96, 138.10, 140.23, 144.31, 151.67, 159.48. MS (ESI) m=z
(M þ H)þ calculated for C23H20N2O: 340.16. Found: 341.2.
5-(4-Chlorophenyl)-1-phenyl-3-p-tolyl-1H-pyrazole (2h)
Yellow solid, mp 132–133 ꢁC. IR (KBr): 3050, 3023, 2920, 1656, 1597, 1494,
1
1436, 1215, 1179, 1014, 971, 955, 835, 793, 760 cmꢂ1. H NMR (CDCl3, 400 MHz):
d 2.27 (s, 3H), 6.67 (s, 1H), 7.03 (d, 2H, J ¼ 8.16 Hz, ArH), 7.06 (d,d, 2H, J ¼ 8.36 Hz,
J ¼ 8.16 Hz, ArH), 7.16–7.28 (m, 5H, ArH), 7.30 (d, 2H, J ¼ 8.64 Hz, ArH), 7.76 (d,
2H, J ¼ 8.60 Hz, ArH). 13C NMR (CDCl3, 100 MHz): d 21.23, 104.79, 125.22, 126.98,
127.43, 128.53, 128.74, 128.87, 129.17, 131.62, 133.58, 138.32, 140.06, 144.63, 150.72.
MS (ESI) m=z (M þ H)þ calculated for C22H17ClN2: 344.11. Found: 345.
ACKNOWLEDGMENT
The authors are thankful to the Department of Science and Technology,
New Delhi, India (No. SR=S1=OC-72=2009), for the financial support.
REFERENCES
1. Rapposelli, S.; Lapucci, A.; Minutolo, F.; Orlandini, E.; Ortore, G.; Pinza, M.; Balsamo,
A. Farmaco 2004, 59, 25.
2. Shin, K. D.; Lee, M.-Y.; Shin, D.-S.; Lee, S.; Son, K. H.; Koh, S.; Paik, Y. K.; Kwon, B.
M.; Han, D. C. J. Biol. Chem. 2005, 280, 41439.
3. Cali, P.; Naerum, L.; Mukhija, S.; Hjelmencrantz, A. Bioorg. Med. Chem. Lett. 2004, 14,
5997.
4. Sechi, M.; Sannia, L.; Carta, F.; Palomba, M.; Dallocchio, R.; Dessi, A.; Derudas, M.;
Zawahir, Z.; Neamati, N. Antiviral Chem. Chemother. 2005, 16, 41.
5. Cottineau, B.; Toto, P.; Marot, C.; Pipaud, A.; Chenault, J. Bioorg. Med. Chem. Lett.
2002, 12, 2105.
6. Al-Omran, F.; El-Khair, A. A. J. Heterocycl. Chem. 2004, 41, 327.
7. (a) Bertagnolli, M.; Eagle, C.; Zauber, A.; Redston, M.; Solomon, S.; Kim, K.; Tang, J.;
Rosenstein, R.; Wittes, J.; Corle, D.; Hess, T.; Woloj, G.; Boisserie, F.; Anderson, W.;
Viner, J.; Bagheri, D.; Burn, J.; Chung, D.; Dewar, T.; Foley, T. Hoffman, N.; Macrae,
F.; Pruitt, R.; Saltzman, J.; Salzberg, B.; Sylwestrowicz, T.; Gordon, G.; Hawk, E. N.
Engl. J. Med. 2006, 355, 873; (b) Arber, N.; Eagle, C.; Spicak, J.; Racz, I.; Dite, P.; Hajer,
´
J.; Zavoral, M.; Lechuga, M.; Gerletti, P.; Tang, J.; Rosenstein, R.; Macdonald, K.;
Bhadra, P.; Fowler, R.; Wittes, J.; Zauber, A.; Solomon, S.; Levin, B. N. Engl. J. Med.
2006, 355 (9), 885.
8. (a) Deadwyler, S. A.; Goonawardena, A. V.; Hampson, R. E. Behav. Pharmacol. 2007, 18,
571; (b) Kim, A. H.; Kerchner, G. A.; Choi, D. W.; Blocking excitotoxicity, chapter 1 in

OXIDATION OF 1,3,5-TRISUBSTITUTED PYRAZOLINES
2623
CNS Neuroproteciton; F.W. Marcoux and D.W. Choi, (Ed.).; Springer: New York; 2002.
pp. 3–36.
9. (a) Li, Y.; Zhang, H. Q.; Liu, J.; Yang, X. P.; Liu, Z. J. J. Agric. Food Chem. 2006, 54,
3636; (b) Siddall, T. L.; Ouse, D. G.; Benko, Z. L.; Garvin, G. M.; Jackson, J. L.;
McQuiston, J. M.; Ricks, M. J.; Thibault, T. D.; Turner, J. A.; Van Heertum, J. C.;
Weimer, M. R. Pest Manage. Sci. 2002, 58, 1175.
10. (a) Azarifar, D.; Shaebanzadeh, M. Molecules 2002, 7, 885; (b) Azarifar, D.;
Ghasemnejad, H. Molecules, 2003, 8, 642; (c) Azarifar, D.; Maleki, B. J. Heterocycl.
Chem. 2005, 42, 157.
11. Sabitha, G.; Kumar Reddy, G. S. K.; Reddy, C. S.; Fatima, N.; Yadav, J. S. Synthesis
2003, 1267.
12. Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett. 2002, 4, 3955.
13. Shah, J. N.; Shah, C. K. J. Org. Chem. 1978, 43, 1266.
14. Gladstone, W. A. F.; Norman, R. O. C. J. Chem. Soc. Chem. Commun. 1966, 1536.
15. Bhatnagar, I.; George, M. V. Tetrahedron 1968, 24, 1293.
16. Smith, L. I.; Howard, K. L. J. Am. Chem. Soc. 1943, 65, 159.
17. Dodwadmath, R. P.; Wheeler, T. S. Proc. Ind. Acad. Sci. 1935, 2A, 438.
18. Auwers, K.; Heimke, P. Liebigs Ann. 1927, 458, 186.
19. Singh, S. P.; Kumar, D.; Prakash, O.; Kapoor, R. P. Synth. Commun. 1997, 27, 2683.
20. Ried, W.; Lantzsch, R. Chem. Ber. 1969, 102, 378.
21. Chai, F. L.; Zhao, Y.; Sheng, O.; Liu, Z. O. Tetrahedron Lett. 2006, 47, 9283.
22. Azarifar, D.; Maleki, B.; Setayeshnazar, M. Heterocycles 2008, 75, 669.
23. Han, B.; Liu, Z.; Liu, Q.; Yang, L.; Li-Liu, Z.; Yu, W. Tetrahedron 2006, 62, 2492.
24. Azarifar, D.; Zolfigol, M. A.; Maleki, B. Synthesis 2004, 11, 1744.
25. Nakamichi, N.; Kawashita, Y.; Hayashi, M. Synthesis 2004, 1015.
26. (a) Dess, D. B.; Martin, J. S. J. Org. Chem. 1983, 48, 4155; (b) Becker, H. D.; Amin, K. A.
J. Org. Chem. 1989, 54, 3182; (c) Linderman, R. J.; Graves, D. M. J. Org. Chem. 1989, 54,
661; (d) Dess, D. B.; Martin, J. S. J. Am. Chem. Soc. 1991, 113, 7277.