Metal-free oxidative dehydrogenation of imidazolines and pyrazolines using silica-adsorbed peroxymonosulfate under aprotic and almost neutral conditions

Article abstract of DOI:10.1007/s10593-008-0112-7

Oxidative dehydrogenation of 1,3,5-trisubstituted pyrazolines and 2-substituted imidazolines to their corresponding pyrazoles and imidazoles is carried out effectively by treatment with benzyltriphenylphosphonium peroxymonosulfate as an oxidant silica-adsorbed under aprotic and almost neutral conditions.

Full text of DOI:10.1007/s10593-008-0112-7

Chemistry of Heterocyclic Compounds, Vol. 44, No. 7, 2008
METAL-FREE OXIDATIVE DEHYDRO-
GENATION OF IMIDAZOLINES AND
PYRAZOLINES USING SILICA-ADSORBED
PEROXYMONOSULFATE UNDER APROTIC
AND ALMOST NEUTRAL CONDITIONS
H. Adibi1, A. R. Hajipour2,3, and H. Jafari4
Oxidative dehydrogenation of 1,3,5-trisubstituted pyrazolines and 2-substituted imidazolines to their
corresponding pyrazoles and imidazoles is carried out effectively by treatment with
benzyltriphenylphosphonium peroxymonosulfate as an oxidant silica-adsorbed under aprotic and
almost neutral conditions.
Keywords: imidazoles, peroxymonosulfate, pyrazoles, silica, oxidative dehydrogenation.
1,3,5-Trisubstituted pyrazolines are important five-membered heterocyclic compounds, which can be
easily prepared from phenylhydrazine and chalcone derivatives [1-3], and their oxidative dehydrogenation
provides the corresponding pyrazoles, which are known to possess diverse biological activities, including anti-
inflammatory, antiarrhythmic, antidiabetic, and antibacterial activities [1-3]. For the oxidative aromatization of
pyrazolines various methods have been reported employing reagents such as Pb(OAc)4 [4], MnO2 [5], KMnO4
[6], Zr(NO3)4 [7], iodobenzene diacetate [8], AgNO3 [9], Pd/C in acetic acid [10], activated carbon [11],
N-hydroxyphthalimide (NHPI)/Co(OAc)2/O2 [12], 4-(p-chlorophenyl)-1,2,4-triazole-3,5-dione [13], cobalt soap
of fatty acids [14], mercury or lead oxide [15], HIO3 or I2O5 [16], trichloroisocyanuric acid [17], clay-supported
Cu(NO3)2⋅3H2O (claycop)/ ultrasound [18], p-chloranil [19], and DDQ [20]. However, many of these methods
suffer from disadvantages such as the use of expensive transition metal oxidants and reagents, which are highly
toxic, produce by-products that either destroy the sensitive pyrazoles or are difficult to remove, and the use of
acidic media and tedious work-up.
2-Imidazolines can be prepared from nitriles and ethylenediamine [21, 22].
Selective dehydrogenation of 2-imidazolines to their corresponding imidazoles is of importance from both
biological and pharmaceutical considerations since many imidazole derivatives possess anti-inflammatory,
antihypertensive, antibacterial, and antidiabetic activities [23-25]. Several reagents are available to perform this
transformation including KMnO4/Al2O3 [26], DMSO [27], Pd/C [28], Swern oxidation [29], trichloro-
__________________________________________________________________________________________
1Department of Medicinal Chemistry, Faculty of Pharmacy, Kermanshah University of Medical
2
Sciences, Kermanshah 67145-1673, IR Iran; e-mail: hadibi@kums.ac.ir. Pharmaceutical Research Laboratory,
College of Chemistry, Isfahan University of Technology, Isfahan 84156, IR Iran. 3Department of Pharmacology,
4
University of Wisconsin, Medical School, Madison, Wisconsin 53706-1532, USA. Islamic Azad University,
Sanandaj Branch, Sanandaj, IR Iran. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6,
pp. 1003-1008, June, 2008. Original article submitted February 24, 2008.
802
0009-3122/08/4407-0802©2008 Springer Science+Business Media, Inc.

isocyanuric acid [30], KMnO4/SiO2 [31], KMnO4 [32], Zn/Al2O3 [33], Ni [34], Se [35], MnO2 [36], and BaMnO4
[37]. These reagents suffer from limitations such as low yields of the products, very long reaction times, toxicity
of transition metal oxidants, the use of large excess of the reagents, and harsh reaction conditions. Therefore, we
decided to introduce a new reagent to overcome these limitations.
Oxone® (2KHSO5·KHSO4·K2SO4) is an inexpensive, water-soluble, and stable oxidizing reagent that is
commercially available. However, this reagent is insoluble in organic solvents and buffering is needed due to its
acidity [38–40]. Recently, we reported benzyltriphenylphosphonium peroxymonosulfate (BTPPMS) as a mild,
inexpensive, and efficient reagent in organic transformations [41–44]. Over the last two decades, the use of solid
supports has become popular due to their characteristic properties such as enhanced selectivity and reactivity,
straightforward work-up procedure, milder reaction conditions, and associated ease of manipulation [45].
Following our continued interest in BTPPMS [41–44] and in the course of our studies on the dehydro- genation
of organic compounds [43], we herein report metal-free oxidative dehydrogenation of 1,3,5-tri-substituted
pyrazolines 1 and 2-substituted imidazolines 3 to their corresponding pyrazoles 2 and imidazoles 4 employing
BTPPMS as an oxidant silica-adsorbed as the supporting agent under non-aqueous and almost neutral
conditions. To the best of our knowledge, this is the first example of BTPPMS-mediated metal-free
dehydrogenation of pyrazolines and imidazolines.
We first examined the reaction of 1,3,5-trisubstituted pyrazolines 1 using BTPPMS as the oxidant.
During the course of the screening of a variety of reaction conditions such as solvent, time, reaction temperature,
and the amount of the oxidant, we found that the use of silica as a supporting agent was essential for the efficient
conversion of 1,3,5-trisubstituted pyrazolines 1 to pyrazoles 2. That is, the treatment of 1,3,5-triphenyl- pyrazoline
1a as a model compound (1 mmol) with BTPPMS (2 mmol) silica-adsorbed (0.5 g per mmol of pyrazoline) as
an inexpensive and readily available supporting agent in refluxing acetonitrile for 5 h afforded 1,3,5-
triphenylpyrazole 2a in 76% yield. The oxidation of compound 1a was investigated with BTPPMS alone in
refluxing acetonitrile and only 30% of compound 2a was obtained from the reaction mixture after 5 h. The
reactions in MeCN, which turned out to be one of the best choices in our previously organic transformations
[41–44], produced the corresponding pyrazoles 2 by simple filtration and evaporation of the solvent in good to
moderate yields. The results and reaction conditions are exemplified in Table 1. Having successfully achieved
the aromatization of pyrazolines, we applied this method to the oxidative aromatization of 2-substituted
imidazolines 3 to imidazoles 4. As shown in Table 1, the treatment of 2-substituted imidazolines 3 according to
the above mentioned-procedure led to the formation of the corresponding imidazoles 4 in refluxing acetonitrile
in good yields.
Oxidation of 2-alkylimidazolines to the corresponding imidazoles was achieved by this oxidation system
(Table 1, 3g–i), since 2-alkylimidazoles are used as intermediates for the synthesis of valuable nitroimidazole
drugs [32]. Some of the reported reagents such as DMSO [27] and Pd/C [28] were not effective for
dehydrogenation of 2-alkylimidazolines.
The actual role of BTPPMS and silica is not clear to us; however, according to a plausible mechanism
suggested in our previously reported literature for BTPPMS-oxidized aromatization of 1,4-dihydropyridines to
pyridines [43], we propose a possible mechanism for BTPPMS-mediated oxidative dehydrogenation of
pyrazolines according to a radical pathway upon homolytic cleavage of O–O bond in peroxymonosulfate anion
(–O3S–O–OH). It is believed that the presence of silica increases the decomposition rate of peroxymonosulfate
anion to form a hydroxyl radical and a sulfate radical anion.
Presumably the oxidation of pyrazoline I is initiated by a single electron transfer on the nitrogen of
pyrazoline I to the hydroxyl radical that produces hydroxide anion and a radical cation II, which subsequently
loses a proton to generate the radical III and water. The radical III transfers an electron to the sulfate radical
anion to form the cation IV and sulfate anion, subsequently resulting in the aromatized pyrazoline(s) V and
hydrogen sulfate anion. The suggested mechanism for BTPPMS-mediated oxidative dehydrogenation of
imidazolines is similar to that of pyrazolines.
803

TABLE 1. Oxidative dehydrogenation of 1,3,5-trisubstituted pyrazolines
1 and 2-substituted imidazolines 3 using BTPPMS/silica* under aprotic
conditions*2
R 1
R
R 1
–
R
/
HSO5
SiO2
N
N
N
N
refluxing MeCN
Ph
Ph
1
2
N
N
–
HSO5
/ SiO2
R
R
refluxing MeCN
N
H
N
H
3
4
Substrate
R
R1
Time, h
Yield, %*3
1a
1b
1c
1d
1e
1f
Ph
Ph
5
76
70
65
68
66
69
70
72
62
60
81
80
78
75
82
75
70
72
78
Ph
Ph
Ph
p-O2NC6H4
p-MeOC6H4
m-ClC6H4
p-ClC6H4
m-MeC6H4
2-Furyl
6.5
4.5
3.5
8
2-Naphthyl
2-Naphthyl
p-MeC6H4
p-MeOC6H4
p-MeOC6H4
p-MeC6H4
Ph
7
1g
1h
1i
6
p-ClC6H4
Ph
6
5
1j
m-MeC6H4
4.5
5
3a
3b
3c
3d
3e
3f
3g
3h
3i
p-MeOC6H4
2-Py
3
2.5
6
p-ClC6H4
m-ClC6H4
p-MeC6H4
Me
5
4.5
0.6
1
Ph
n-Bu
1.2
_______
* Molar ratio: BTPPMS−imidazoline (2:1 and 0.5 g silica per mmol of
pyrazoline (for 1a−j) and imidazoline (for 3a−i) was used).
*2 Confirmed by comparison with authentic samples [2].
*3 Yield of isolated pure product after purification.
In conclusion, we have disclosed a facile and environmentally benign oxidative aromatization process to
convert 1,3,5-trisubstituted pyrazolines and 2-substituted imidazolines to the corresponding pyrazoles and
imidazoles using silica-adsorbed BTPPMS as an interesting alternative to liquid and transition metal oxidants.
The advantages of the present reaction are the elimination of metals and toxic reagents, operational simplicity,
and easy work-up. Extension of this procedure to other substrates is under way in our laboratory.
EXPERIMENTAL
The products were characterized by comparing their spectral and physical data with those of authentic
samples reported in the literature [4-20, 26-37]. The reagent BTPPMS was prepared according to our previously
reported procedures [41–44]. 1,3,5-Trisubstituted pyrazolines 1 were synthesized according to the reported
procedure [13]. 2-Substituted imidazolines 3 were synthesized according to the reported procedure [21, 22].
804

.
.
– O3S–O–O–H
– O3S–O + OH
.
R1
H2O
R1
–
R
H
R1
–
OH
R
OH
OH R
H
H
N
N
N
N
H
+
N
N
N
H
.
.
..
Ph
Ph
Ph
III
I
II
.
–
R1
R
R1
2–
SO4
R
R
H
R1
SO4
+
–H
H
III
N
N
+
N
N
N
2–
–
..
SO4
HSO4
Ph
Ph
Ph
V
IV
Oxidative aromatization of 1,3,5-triphenylpyrazoline 1a to 1,3,5-triphenylpyrazole 2a (Typical
procedure). BTPPMS (0.932 g, 2 mmol) and silica (0.5 g) were shaken together by a mini-shaker (vortex) until a
fine homogeneous powder was obtained. To a solution of 1,3,5-triphenylpyrazoline 1a (1 mmol) in MeCN
(10 ml), silica-adsorbed BTPPMS (1.432 g, 2 mmol) was added and the mixture was stirred under reflux for 5 h.
The progress of the reaction was monitored by TLC (eluent EtOAc–cyclohexane, 2:8). The mixture was cooled
to room temperature and then filtered off, and the solid material was washed with MeCN (10 ml). The filtrate
was evaporated and the resulting crude material was purified by chromatography on silica gel (eluent
acetone/petroleum ether, 1:5) to afford the pure 1,3,5-triphenylpyrazole 2a as a pale yellow solid in 76% yield,
mp 133-135ºC (mp 133-134ºC [13]).
Oxidative aromatization of 2-phenylimidazoline 3a to 2-phenylimidazole 4a (Typical procedure).
A mixture of silica-adsorbed BTPPMS (1.432 g, 2 mmol) and 2-phenylimidazole 3a (1 mmol) in MeCN (10 ml)
was heated under reflux conditions. After disappearance of the starting imidazoline monitored by TLC using
EtOAc–cyclohexane, 2:8, the mixture was cooled to room temperature and then filtered off through a sintered
glass funnel, and the solid material was washed with MeCN (2×10 ml). The combined organic layer was
evaporated and the crude product was purified by column chromatography on silica gel (eluent acetone–
petroleum ether, 1:5) to afford the pure 2-phenylimidazole 4a in 81% yield as revealed from TLC and 1H NMR
analysis, mp 141-144ºC (mp 140-142ºC [31]).
We gratefully acknowledge the Kermanshah University of Medical Sciences Research Council for financial
support.
REFERENCES
1.
E. Takabata, R. Kodama, Y. Tanaka, R. Dohmori, H. Tachizawa, and T. Naito, Chem. Pharm. Bull., 16,
1900 (1979).
2.
3.
S. S. Parmar, B. R. Pandey, C. Dwivedi, and R. D. Harbison, J. Pharm. Sci., 63, 1152 (1974).
N. Soni, K. Pande, R. Kalsi, T. K. Gupta, S. S. Parmer, and J. P. Barthwal, Res. Commun. Mol. Pathol.
Pharmacol., 56, 129 (1987).
4.
5.
6.
7.
W. A. F. Goldstone and R. O. C. Norman, J. Chem. Soc., Chem. Commun., 1536 (1966).
I. Bhatnagar and M. V. George, Tetrahedron, 24, 1293 (1968).
L. I. Smith and K. L. Howard, J. Am. Chem. Soc., 65, 159 (1943).
G. Sabitha, G. S. Reddy, C. S. Reddy, N. Fatima, and J. S. Yadav, Synthesis, 1267 (2003).
805

8.
9.
10.
11.
12.
13.
S. P. Singh, D. Kumar, O. Prakash, and R. P. Kapoor, Synth. Commun., 27, 2683 (1997).
R. P. Dodwadmath and T. S. Wheeler, Proc. Ind. Acad. Sci., 2A, 438 (1935).
N. Nakamichi, Y. Kawashita, and M. Hayashi, Org. Lett., 4, 3955 (2002).
N. Nakamichi, Y. Kawashita, and M. Hayashi, Synthesis, 1015 (2004).
B. Han, Z. Liu, Q. Liu, L. Yang, Z.-L. Liu, and W. Yu, Tetrahedron, 62, 2492 (2006).
M. A. Zolfigol, D. Azarifar, S. Mallakpour, I. Mohammadpoor-Baltork, A. Forghaniha, B. Maleki, and
M. Abdollahi-Alibeik, Tetrahedron Lett., 47, 833 (2006).
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
J. N. Shah and C. K. Shah, J. Org. Chem., 43, 1266 (1978).
K. Auwers and P. Hemke, Lieb. Ann. Chem., 458, 186 (1927).
L. Chai, Y. Zhao, Q. Sheng, and Z-Q. Liu, Tetrahedron Lett., 47, 9283 (2006).
M. A. Zolfigol, D. Azarifar, and M. Maleki, Tetrahedron Lett., 45, 2181 (2004).
S. Mallouk, K. Bougrin, H. Doua, R. Benhida, and M. Soufiaoui, Tetrahedron Lett., 45, 4143 (2004).
R. Huisgen, M. Seidel, G. Wallbillich, and H. Knupfer, Tetrahedron, 17, 3 (1962).
D. Walker and J. D. Hiebert, Chem. Rev., 67, 153 (1967).
G. Levesque, J.-C. Gressier, and M. Proust, Synthesis, 963 (1981).
I. Mohammadpoor-Baltork and M. Abdollahi-Alibeik, Bull. Korean Chem. Soc., 24, 1354 (2003).
M. R. Grimmett, in: K. T. Potts (editor), Comprehensive Heterocyclic Chemistry; Pergamon: Oxford,
1984, Vol. 4, p. 345.
24.
25.
26.
J. G. Lambardino and E. H. Wiseman, J. Med. Chem., 17, 1182 (1974).
H. G. Kim, J. K. Lee, J. T. Lee, and C. S. Lee, Bull. Korean Chem. Soc., 21, 345 (2000).
M. Abdollahi-Alibeik, I. Mohammadpoor-Baltork, and M. A. Zolfigol, Bioorg. Med. Chem. Lett., 14,
6079 (2004).
27.
28.
29.
30.
31.
M. Anastassiadou, G. Baziard-Mouysset, and M. Payard, Synthesis, 1814 (2000).
Y. Amemiya, D. D. Miller, and F. L. Hsu, Synth. Commun., 20, 2483 (1990).
D. H. Huh, H. Ryu, and Y. G. Kim, Tetrahedron, 60, 9857 (2004).
I. Mohammadpoor-Baltork, M. A. Zolfigol, and M. Abdollahi-Alibeik, Synlett, 2803 (2004).
I. Mohammadpoor-Baltork, M. A. Zolfigol, and M. Abdollahi-Alibeik, Tetrahedron Lett., 45, 8687
(2004).
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
M. E. Campos, R. Jimenez, F. Martinez, and H. Salgado, Heterocycles, 40, 841 (1995).
T. Dockner and A. Frank, Ger. Offen. 2,729,017 (1979), Chem. Abstr., 204100 (1979).
L. P. Kyrides, F. B. Zienty, G. W. Steahly, and H. L. Morrill, J. Org. Chem., 12, 577 (1947).
R. E. Klem, H. F. Skinner, H. Walba, and R. W. Isensee, J. Heterocycl. Chem., 7, 403 (1970).
P. K. Martin, H. R. Matthews, H. Rapoport, and G. Thyagarajan, J. Org. Chem., 33, 3758 (1968).
J. L. Hughey, S. Knapp, and H. Schudar, Synthesis, 489 (1980).
A. R. Hajipour, Indian J. Chem., 36B, 1069 (1997).
A. R. Hajipour and N. Mahboubkhah, Org. Prep. Proced. Int., 31, 112 (1999).
B. Meunier, New J. Chem., 16, 203 (1992).
A. R. Hajipour, S. E. Mallakpour, and H. Adibi, J. Org. Chem., 67, 8666 (2002).
A. R. Hajipour and H. Adibi, J. Chem. Res., Synop., 274 (2004).
H. Adibi and A. R. Hajipour, Bioorg. Med. Chem. Lett., 17, 1008 (2007).
H. Adibi and A. R. Hajipour, M. Hashemi, Tetrahedron Lett., 48, 1255 (2007).
J. H. Clark, in Catalysis of Organic Reactions by Supported Inorganic Reagents, VCH: Weinheim
(1994).
806