Mixing with microwaves: Solvent-free and catalyst-free synthesis of pyrazoles and diazepines

Article abstract of DOI:10.1016/j.tetlet.2013.01.029

A simple and facile condensation of hydrazines/hydrazides and diamines with 1,3-diketones/β-ketoester leads to the preparation of pyrazoles and diazepines in high yields. This eco-friendly protocol is accelerated by microwave heating and efficiently carried out without any reaction solvent or catalyst in as little as 5 min.

Full text of DOI:10.1016/j.tetlet.2013.01.029

Tetrahedron Letters 54 (2013) 1538–1541
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Mixing with microwaves: solvent-free and catalyst-free synthesis of
pyrazoles and diazepines
⇑
⇑
Buchi Reddy Vaddula, Rajender S. Varma , John Leazer
Sustainable Technology Division, National Risk Management Research Laboratory, U.S. Environmental Protection Agency, 26 West Martin Luther King Drive, MS 443, Cincinnati,
OH 45268, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and facile condensation of hydrazines/hydrazides and diamines with 1,3-diketones/b-ketoester
leads to the preparation of pyrazoles and diazepines in high yields. This eco-friendly protocol is acceler-
ated by microwave heating and efficiently carried out without any reaction solvent or catalyst in as little
as 5 min.
Received 19 November 2012
Revised 4 January 2013
Accepted 8 January 2013
Available online 18 January 2013
Published by Elsevier Ltd.
Keywords:
1,3-Diketones
Aryl hydrazines
Aryl hydrazides
Catalyst-free
Condensation
1. Introduction
2. Results and discussion
Pyrazole derivatives are important biologically active com-
pounds. They are significant in the agrochemical and pharmaceuti-
cal industry. In medicinal chemistry, they are known for their
antitumor activity,1 angiotensin converting enzyme inhibitor
activity,2 antimicrobial activity,3 anti-inflammatory activity,4 anti-
viral activity,5 and anticonvulsant and antidepressant activities.6
Celecoxib, a pyrazole derivative, is used successfully as an analge-
sic in arthritis.7
The synthesis of pyrazoles can be achieved by several different
routes.8–13 The path involving 1,3-diketones and aryl hydrazines
is one of the prominent methods for the preparation of substituted
pyrazoles. The earlier reported reaction protocols include the use of
various acidic catalysts, such as hydrochloric acid,14 sulfuric acid,15
and phosphotungstic acid16 in solvents namely ethanol and water.
More recently, our room temperature synthesis of these molecules
has been accomplished using polystyrene sulfonic acid in water17
or using glutathione supported magnetic nanoparticles.18
The synthesis of these molecules is now achieved under sol-
vent-free and catalyst-free conditions to develop a greener and
useful protocol; the reactions under solvent-free conditions are
known to be rapid and chemo- or regioselective, resulting in high
yields of products that have both environmental and economic
advantages.19
In our efforts to develop greener and more facile organic trans-
formations, we have focused on the synthesis of pyrazoles under
solvent-free and catalyst-free conditions. Microwave (MW) irradi-
ation of a neat mixture of aryl hydrazines and 3-substituted-pen-
tane-2,4-diones resulted in the formation of pyrazoles in high
yields.
Initially, a neat mixture of phenyl hydrazine and pentane-2,4-
dione was ground via mortar and pestle at ambient temperature,
resulting in almost 40% conversion to the pyrazole product. The
mixture was subsequently heated in an oven at 80 °C for 30 min
to improve the conversion to 70%. In order to expedite the reaction,
a fresh equimolar mixture of the reactants was subjected to MW
irradiation at 100 °C for 5 min, affording complete conversion to
the desired product. The neat conversion to the product, as evi-
denced by the gas chromatography, avoided the need for further
work-up.
O
O
R1
Neat, MWI
R2
R1 NHNH2
N
N
+
120 oC, 5-15 min
R2
2
1
3
R1 = Ar, ArCO-
R2 = H, Cl, Et
⇑
Corresponding authors. Tel.: +1 513 487 2701; fax: +1 513 569 7677.
E-mail address: varma.rajender@epa.gov (R.S. Varma).
Scheme 1. Solvent-free and catalyst-free synthesis of pyrazoles 3.
0040-4039/$ - see front matter Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.01.029

B. R. Vaddula et al. / Tetrahedron Letters 54 (2013) 1538–1541
1539
Table 1
Microwave-assisted neat synthesis of pyrazoles 3a
Entry
Hydrazine/Hydrazide 1
Diketone 2
Product 3b
Time (min)
5
Yieldb (%)
NHNH2
O
O
2a
2b
N
1
99
98
N
N
N
1a
3a
3b
NHNH2
O
O
Cl
2
3
4
1a
5
10
10
N
N
Cl
NHNH2
O
O
C2H5
1a
95.
98
C2H5
O
2c
2a
3c
NHNH2
O
O
N
N
N
N
Cl
Cl
1b
1b
Cl
Cl
3d
3e
NHNH2
NHNH2
O
Cl
5
6
10
15
97
98
Cl
N
2b
O
O
C2H5
Cl
1b
C2H5
N
2c
Cl
O
3f
O
O
O
O
O
O
O
2a
NHNH2
N
N
1c
1c
7
8
10
6
98
98
98
99
3g
O
O
N
N
NHNH2
O
Cl
Cl
O
2b
2a
3h
O
O
NHNH2
NHNH2
NHNH2
NHNH2
N
N
9
30
10
1d
3i
O
O
O
O
2a
2b
N
N
10
O
O
O
O
1e
1e
1e
1f
3j
O
O
O
O
N
N
11
12
13
10
15
10
98
97
Cl
O
O
S
Cl
O
3k
O
O
N
N
C2H5
C2H5
O
2c
2a
3l
O
O
NHNH2
N
N
98
S
3m
(continued on next page)

1540
B. R. Vaddula et al. / Tetrahedron Letters 54 (2013) 1538–1541
Table 1 (continued)
Entry
Hydrazine/Hydrazide 1
Diketone 2
Product 3b
Time (min)
10
Yieldb (%)
O
O
O
O
NHNH2
N
N
14
15
16
97
Cl
S
S
Cl
S
2b
1f
3n
O
O
O
O
N
NHNH2
N
N
15
10
10
97
95
94
C2H5
S
C2H5
O
1f
2c
3o
NHNH2
O
O
O
OC2H5
2d
2d
1a
N
3p
NHNH2
O
O
OC2H5
N
17
Cl
1b
N
Cl
3q
a
A mixture of 1 equiv of aryl hydrazine 1 and 1.1 equiv of diketone 2 was subjected to microwave irradiation at 120 °C for 5–15 min.
The progress of the reaction was monitored by GC–MS.
b
The reaction protocol was further extended to other hydrazines/
hydrazides 1 and diketones 2 resulting in products 3a–q in high
yields (94–99%). The aryl hydrazines 1a–b reacted efficiently with
1,3-diketones 2a–c affording the products 3a–f; however, the dike-
tone 2c was relatively less reactive than diketones 2a and 2b; it re-
quired more exposure time to MW irradiation for completion. The
hydrazides 1c–f were moderately reactive when compared to
hydrazines 1a–b. The phenyl hydrazide 1d was least reactive and
required 30 min of MW irradiation for completion of the reaction
(cf. Scheme 1 and Table 1).
O
O
NH2
NH2
N
Neat, MWI
R2
+
120 oC, 5-15 min
R2
N
4
2
5
R2 = H, Cl, Me, Et
Scheme 2. Solvent-free and catalyst-free synthesis of diazepines.
Table 2
Microwave-assisted neat synthesis of diazepines 5a
Entry
Diamine 4
NH2
Diketone 2
Product 5b
Time (min)
10
Yieldb (%)
96
O
O
O
O
O
O
O
O
N
2a
1
NH2
NH2
N
N
5a
Cl
2
3
4
10
10
15
NP
93
95
NH2
NH2
Cl
N
N
2b
2e
5b
CH3
NH2
NH2
CH3
O
N
N
5c
C2H5
NH2
NH2
C2H5
O
N
N
2c
5d
OH
OC2H5
5
10
NP
2d
NH2
N
5e
a
A mixture of 1 equiv of aryl hydrazine 1 and 1.1 equiv of diketone 2 was subjected to microwave irradiation at 120 °C for 5–15 min.
The progress of the reaction was monitored by GC–MS.
b

B. R. Vaddula et al. / Tetrahedron Letters 54 (2013) 1538–1541
1541
b-Ketoester 2d reacted efficiently generating the hydroxy pyra-
Acknowledgments
zoles 3p–q. The reaction progress, monitored by GC–MS, showed
clean and complete transformation. The reaction temperature of
120 °C was found to be optimum for all the substrates. Further
purification of the reaction mixture was not required in most of
the cases (for compounds 3a, 3b, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l,
3m, 3n, 3o, 3q, and 5a). If present, any residual starting material
can be removed from the crude products by passing through a
short silica gel column.
B.R.V. was supported in part by an appointment to the Research
Participation Program for the U.S. Environmental Protection
Agency, Office of Research and Development, administered by
the Oak Ridge Institute for Science and Education through an inter-
agency agreement between the U.S. Department of Energy and the
EPA.
The scope of this transformation was explored by extending the
reaction of diketones 2 with o-phenylenediamine 4 (Scheme 2)
which resulted in the formation of diazepines 5a,c, and d (Table 2)
in good yields (93–96%). However, the reaction of diamine 4 with
diketone 2b and b-ketoester 2d failed to deliver the desired prod-
ucts; instead mixtures of undesired entities were obtained.
A greener and more facile procedure for the preparation of pyr-
azoles and diazepines is developed from readily available dike-
tones and hydrazines/hydrazides/diamines. The eco-friendly
attributes of this process are catalyst-free and solvent-free condi-
tions. The advantages of the reaction protocol include short reac-
tion time and elimination of work-up or purification step (in
most of the demonstrated examples). Keeping in view the modular
and exploratory power of these transformations, the studies can be
extended to the construction of other heterocycles, especially
fused pyrazoles and diazepines ring systems.
Supplementary data
Supplementary data (experimental procedure and GC–MS pro-
files of all the compounds) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.01.029.
References and notes
1. Lv, P.-C.; Li, H.-Q.; Sun, J.; Zhou, Y.; Zhu, H.-L. Bioorg. Med. Chem. 2010, 18, 4606.
2. Bonesi, M.; Loizzo, M. R.; Statti, G. A.; Michel, S.; Tillequin, F.; Menichini, F.
Bioorg. Med. Chem. Lett. 2010, 20, 1990.
3. Bondock, S.; Fadaly, W.; Metwally, M. A. Eur. J. Med. Chem. 2010, 45, 3692.
4. Barsoum, F. F.; Girgis, A. S. Eur. J. Med. Chem. 2009, 44, 2172.
5. El-Sabbagh, O. I.; Baraka, M. M.; Ibrahim, S. M.; Pannecouque, C.; Andrei, G.;
Snoeck, R.; Balzarini, J.; Rashad, A. A. Eur. J. Med. Chem. 2009, 44, 3746.
6. Abdel-Aziz, M.; Abuo-Rahma, G. E.-D. A.; Hassan, A. A. Eur. J. Med. Chem. 2009,
44, 3480.
7. Clemett, D.; Goa, K. L. Drugs 2000, 59, 957.
8. Jackowski, O.; Lecourt, T.; Micouin, L. Org. Lett. 2011, 13, 5664.
9. Hari, Y.; Tsuchida, S.; Sone, R.; Aoyama, T. Synthesis 2007, 3371.
10. Ma, C.; Li, Y.; Wen, P.; Yan, R.; Ren, Z.; Huang, G. Synlett 2011, 1321.
11. Martín, R.; Rodríguezrivero, M.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45,
7079.
3. Experimental section
3.1.General procedure for the synthesis of pyrazoles and
diazepines
12. Babinski, D. J.; Aguilar, H. R.; Still, R.; Frantz, D. E. J. Org. Chem. 2011, 76,
5915.
The hydrazine/hydrazide/o-phenylenediamine (0.5 mmol) and
1,3-diketone (0.55 mmol) were mixed in a closed microwave tube
and subjected to microwave irradiation on a CEM Discover™ SP
microwave system in standard mode at 120 °C for 5–20 min. Upon
completion of the reaction, the crude product may be purified by
passing through silica gel column eluting with 20% ethyl acetate
in hexane to afford the pure products. The characterization data
of the synthesized compounds are in agreement with earlier re-
ported data (ESI).
13. Rosa, F. A.; Machado, P.; Vargas, P. S.; Bonacorso, H. G.; Zanatta, N.; Martins, M.
A. P. Synlett 2008, 1673.
14. Gutmann, B.; Obermayer, D.; Reichart, B.; Prekodravac, B.; Irfan, M.; Kremsner,
J. M.; Kappe, C. O. Chem. Eur. J. 2010, 16, 12182.
15. Chen, X.; She, J.; Shang, Z.-C.; Wu, J.; Zhang, P. Synth. Commun. 2009, 39, 947.
16. Chen, X.; She, J.; Shang, Z.; Wu, J.; Wu, H.; Zhang, P. Synthesis 2008, 3478.
17. Polshettiwar, V.; Varma, R. S. Tetrahedron Lett. 2008, 49, 397.
18. Varma, R. S.; Polshettiwar, V. U.S. Patent 2011/0054180 A1, 2009.
19. Loupy, A. In Modern Solvents in Organic Synthesis; Knochel, P., Ed.; Springer:
Berlin/Heidelberg, 1999; Vol. 206, p 153.