Sc(OTf)3-catalyzed, solvent-free domino synthesis of functionalized pyrazoles under controlled microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2011.12.094

An efficient, rapid, and green synthesis of functionalized pyrazoles has been accomplished under solvent-free conditions by the reaction of phenyl hydrazine, aldehydes and ethyl acetoacetate. This approach exploits the synthetic potential of microwave irr

Full text of DOI:10.1016/j.tetlet.2011.12.094

Tetrahedron Letters 53 (2012) 1130–1133
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sc(OTf)3-catalyzed, solvent-free domino synthesis of functionalized
pyrazoles under controlled microwave irradiation
Kumkum Kumari a, Dushyant Singh Raghuvanshi a, Viatcheslav Jouikov b, Krishna Nand Singh a,
⇑
a Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
b Université de Rennes 1, Chimie et Photonique Moléculaires, CNRS UMR 6510, Avenue du Général Leclerc, 35042 Rennes Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, rapid, and green synthesis of functionalized pyrazoles has been accomplished under solvent-
free conditions by the reaction of phenyl hydrazine, aldehydes and ethyl acetoacetate. This approach
exploits the synthetic potential of microwave irradiation and scandium triflate combination and offers
many advantages such as excellent product yields, shorter reaction time, easy isolation of products,
and environmentally benign reaction conditions.
Received 7 September 2011
Revised 19 December 2011
Accepted 22 December 2011
Available online 5 January 2012
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Green synthesis
Multicomponent reaction
Microwave
Sc(OTf)3
Functionalized pyrazoles
Green chemistry has come to the forefront of current chemical
research to develop efficient, sustainable, and environmentally be-
nign synthetic methodologies.1,2 Multicomponent reactions (MCRs)
have been recognized as a powerful tool for the expedient creation
of chemical libraries of drug-like compounds with high levels of
molecular complexity and diversity.3,4 Applicability of focused
microwave assisted organic synthesis (MAOS) is nowadays prac-
ticed for rapid and reliable production of chemical entities.5 Thus,
multicomponent procedures employing microwave (MW) irradia-
tion under solvent-free conditions are particularly welcome due
to their intrinsic advantages,6 particularly under the present para-
digm shift to green methodologies.
Transition metal catalyzed carbon–carbon and carbon–
heteroatom bond formations via multicomponent reactions are of
utmost importance in organic synthesis,7 because of their high
reactivity, selectivity, and mild reaction conditions. Of these, scan-
dium triflate [Sc(OTf)3] has emerged as a powerful Lewis acid cat-
alyst to perform many useful organic transformations8 under mild
reaction conditions. Due to easy handling, stability to moisture,
and reusability, Sc(OTf)3 is expected to solve some severe environ-
mental problems caused by mineral or Lewis acid promoted reac-
tions in the chemical industry.
EtOOC
R2
Sc(OTf)3 (5 mol%)
O
O
N R1
N
4
R2CHO
R1NHNH2
MW, 200 W, 100 °C
3-6 min.
OEt
3
2
1
Scheme 1. Sc(OTf)3-catalyzed synthesis of functionalized pyrazoles.
synthesis of heterocycles has always been a thread in the synthetic
community.9 The pyrazole core is a privileged heterocyclic scaf-
fold,10 and is a constituent of agro-chemicals,11 and polymeric
materials,12 besides its use as a unique ligand.13 Although pyra-
zoles are rarely found in natural products, they represent an
important motif of man-made biologically active compounds such
as celecoxib, fipronil, lonazolac, viagra, and many others.14
The most popular methods for the preparation of fully substi-
tuted pyrazoles involve 1,3-dipolar cycloaddition of diazoalkanes
or nitrile imines with olefins,15 the Knorr condensation of hydra-
zine with 1,3-dicarbonyl or their derivatives,16 the cross coupling
of 5-bromopyrazole derivatives with various nucleophiles or the
sequential Suzuki coupling of pyrazole boronate derivatives using
a metal directing group,17 and by N-arylation of functionalized pyr-
azoles.18 A one-pot synthesis of pyrazoles using Yb(PFO)3 is also
described under conventional conditions.19 While these methods
provide the synthetic chemists with a multitude of choices to con-
struct substituted pyrazoles, almost all of them suffer from one or
the other drawbacks such as regiochemical infidelity, multistep se-
quence, low product yield, or longer reaction time, which has
limited the exploitation of these methods in high throughput
Heterocycles are ubiquitous in natural products, pharmaceuti-
cals, organic materials, and numerous functional molecules. There-
fore, the interest for developing new, versatile, and efficient
⇑
Corresponding author. Tel.: +91 542 6702485; fax: +91 542 2368127.
E-mail addresses: knsingh@bhu.ac.in, knsinghbhu@yahoo.co.in (K.N. Singh).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.094

K. Kumari et al. / Tetrahedron Letters 53 (2012) 1130–1133
1131
Table 1
Optimization of reaction conditions for the synthesisa of pyrazole 4a
Entry
Catalyst (mol %)
Solvent
Conventional
Time (min)
180
Microwave
Power (Watt) Time (min)
Temp (°C)
Yieldb (%)
nrc
Temp (°C)
Yieldb (%)
1
—
100
100
200
8
Traces
L-Proline (10)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Zn-( -proline)2 (10)
Guanidinium chloride (10)
CdI2 (10)
L
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
100
100
100
100
100
100
100
100
100
100
100
100
100
100
90
180
180
120
180
180
150
180
120
180
120
180
75
75
75
75
75
75
75
75
75
nrc
nrc
51
46
12
31
29
59
Traces
54
47
73
74
70
64
74
63
65
53
60
55
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
200
200
200
200
200
200
200
200
200
200
200
200
200
200
150
250
200
200
200
200
200
8
8
8
8
8
8
8
8
8
8
8
5
5
5
5
5
5
5
5
5
5
nrc
nrc
60
56
24
42
41
67
19
65
69
84
84
71
79
84
72
73
64
69
65
p-TSA (10)
Co(OAc)2Á2H2O (10)
LiClO4 (10)
TiO2 (10)
P2O5 (10)
MnCl2Á4H2O (10)
Iodine (10)
Fe(SO4)2Á9H2O (10)
Sc(OTf)3 (10)
Sc(OTf3) (5)
Sc(OTf)3 (3)
Sc(OTf)3 (5)
Sc(OTf)3 (5)
Sc(OTf)3 (5)
Sc(OTf)3 (5)
Sc(OTf)3 (5)
Sc(OTf)3 (5)
120
100
100
80
80
100
Toluene
Chlorobenzene
Ethanol
Acetonitrile
[Bmim]BF4
80
100
Sc(OTf)3 (5)
75
a
b
c
Used phenyl hydrazine–aldehyde–ethyl acetoacetate (1:1:1.2).
Isolated yield based on benzaldehyde.
nr = no reaction.
Table 2
MW assisted one-pot synthesisa of pyrazoles using Sc(OTf)3 as a catalyst
Entry
Reactants
Product
Time (min)
Yieldb (%)
1
2
3
NHNH2
NHNH2
NHNH2
CHO
O
O
O
O
EtOOC
EtOOC
1
N
N
OEt
OEt
OEt
5
5
83
76
2a
4a
CHO
O
O
2
3
N
N
2b
4b
CHO
EtOOC
N
N
Br
4
5
83
88
2c
Br
4c
NHNH2
NHNH2
CHO
O
O
O
O
EtOOC
4
5
N
OEt
OEt
O2N
N
2d
CHO
O2N
EtOOC
4d
N
N
NO2
2e
3
4
92
NO2
4e
NHNH2
CHO
O
O
EtOOC
Cl
6
N
OEt
N
Cl
86
2f
4f
(continued on next page)

1132
K. Kumari et al. / Tetrahedron Letters 53 (2012) 1130–1133
Table 2 (continued)
Entry
Reactants
Product
Time (min)
Yieldb (%)
1
2
3
NHNH2
CHO
O
O
EtOOC
N
OEt
7
8
N
Br
4
85
2g
Br
4g
NHNH2
NHNH2
NHNH2
NHNH2
CHO
O
O
O
O
O
O
O
O
EtOOC
N
OEt
OEt
OEt
OEt
Cl
N
4
6
3
84
74
90
2h
Cl
4h
EtOOC
CHO
9
N
H3CO
N
2i
CHO
H3CO
4i
EtOOC
F
10
N
F
N
2j
4j
EtOOC
CHO
11
N
Me2N
N
5
81
2k
Me2N
4k
NHNH2
O
O
EtOOC
12
13
CHO
2l
O
S
N
OEt
N
4
4
82
84
O
4l
NHNH2
NHNH2
O
O
O
O
EtOOC
CHO
2m
N
OEt
OEt
N
S
4m
CHO
OH
2n
EtOOC
14
N
N
8
5
nrc
81
OH
4n
15
NHNH2
O
O
CHO
2o
EtOOC
N
N
4o
OEt
a
Reaction conditions: Aldehyde (1 mmol), phenyl hydrazine (1 mmol), ethyl acetoacetate (1.2 mmol), 200 W MW power, 100 °C.
Isolated yield based on aldehyde.
nr = no reaction.
b
c
synthesis. Thus, an improved, efficient, and green alternative ap-
proach to functionalized pyrazoles is of current interest to organic
chemists.
develop a viable approach, the model reaction was investigated
by employing different catalysts both under conventional and
microwave conditions and the overall findings are given in Table
1. Gratifyingly, it was found that the reaction gave promising re-
sults in the presence of Sc(OTf)3 at 100 °C (Table 1, entry 13) both
under conventional as well as microwave conditions. Due to
advantages associated with organo-catalyzed reactions, an attempt
As part of our continued interest to develop efficient protocols
for the synthesis of biologically active molecular scaffolds via
one-pot multicomponent reactions,20 we report herein an efficient
use of Sc(OTf)3 and microwave combination for a benign, rapid,
and convenient synthesis of functionalized pyrazoles in excellent
yields (74–92%) through the one-pot three-component reaction
of phenyl hydrazine, aldehydes and ethyl acetoacetate under sol-
vent-free conditions (Scheme 1).
The studies were initiated to optimize the reaction conditions
for a model multicomponent reaction between phenyl hydrazine
(1), benzaldehyde (2a), and ethyl acetoacetate (3). As solvent-free
synthesis has gained much current interest, it was imperative to
investigate the reaction under solvent-free conditions. In order to
was made to study the reaction with L-proline, Zn-(L-proline)2 and
guanidinium chloride, but no observable product was formed (Ta-
ble 1, entries 1–3). The use of catalysts such as CdI2, p-TSA, LiClO4,
TiO2, P2O5, iodine and Fe(SO4)2Á9H2O also promoted the reaction to
a
considerable extent, but catalysts like Co(OAc)2Á2H2O and
MnCl2Á4H2O (Table 1, entries 6 and 10) provided rather poor yields.
In terms of catalyst concentration, 5 mol % of Sc(OTf)3 was neces-
sary and sufficient for the completion of model reaction (Table 1,
entry 14), as the reaction remains incomplete when 3 mol % of cat-

K. Kumari et al. / Tetrahedron Letters 53 (2012) 1130–1133
1133
4. (a) Weber, L. Curr. Med. Chem. 2002, 9, 2085–2093; (b) Hulme, C.; Gore, V. Curr.
Med. Chem. 2003, 10, 51–80; (c) Arya, P.; Chou, D. T. H.; Baek, M.-G. Angew.
Chem., Int. Ed. 2001, 40, 339–346.
5. (a) Loupy, A. Microwave in Organic Synthesis, 2nd ed.; Wiley-VCH: Weinheim,
2006; (b) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284; (c) Caddick,
S.; Fitzmaurice, R. Tetrahedron 2009, 65, 3325–3355; (d) Moseley, J. D.; Kappe,
C. O. Green Chem. 2011, 13, 794–806.
6. (a) Shore, G.; Morin, S.; Organ, M. G. Angew. Chem., Int. Ed. 2006, 45, 2761–
2766; (b) Kappe, C. O.; Stadler, A. Microwaves in Organic and Medicinal
Chemistry; Wiley-VCH: Weinheim, 2005; (c) Comer, E.; Organ, M. G. A. J. Am.
Chem. Soc. 2005, 127, 8160–8167.
7. (a) D’Souza, D. M.; Muller, T. J. J. Chem. Soc. Rev. 2007, 36, 1095–1108;
(b)Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH:
Weinheim, 2005; pp 33–75.
8. (a) Yadav, J. S.; Reddy, B. V. S.; Chandrasekhar, K. Tetrahedron Lett. 2001, 42,
4405–4407; (b) Yadav, J. S.; Reddy, B. V. S.; Chand, P. K. Tetrahedron Lett. 2001,
42, 4057–4059; (c) Yadav, J. S.; Reddy, B. V. S.; Srihari, P. Synlett 2001, 673–675;
(d) Yadav, J. S.; Reddy, B. V. S.; Reddy, J. S. S. J. Chem. Soc., Perkin Trans. 1 2002,
2390–2394; (e) Yadav, J. S.; Reddy, B. V. S.; Rao, K. V. R.; Kumar, G. G. K. S. N.
Tetrahedron Lett. 2007, 48, 5573–5576.
9. (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell: Oxford, 2000;
(b) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles; Wiley-VCH:
Weinheim, 2003; (c) Katrizky, A. R.; Pozharskii, A. F. Handbook of Heterocyclic
Chemistry, 2nd ed.; Pergamon: Amsterdam, 2000.
10. Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S. In Pyrazoles as Drugs: Facts and
Fantasies in Targets in Heterocyclic Systems; Attanasi, O. A., Spinelli, D., Eds.;
Italian Society of Chemistry: Roma, 2002; Vol. 6, pp 52–98.
11. (a) Lamberth, C. Heterocycles 2007, 71, 1467–1502; (b) Nikolaus, M.
PharmaChem 2007, 6, 25–27.
12. (a) Navarro, J. A. R.; Lippert, B. Coord. Chem. Rev. 2001, 222, 219–250; (b) Danel,
A.; He, Z.; Milburn, G. H. W.; Tomasik, P. J. Mater. Chem. 1999, 9, 339–342.
13. (a) Klingele, J.; Dechert, S.; Meyer, F. Coord. Chem. Rev. 2009, 253, 2698–2741;
(b) Dias, H. V. R.; Lovely, C. J. Chem. Rev. 2008, 108, 3223–3238.
14. (a) Strecker, A. Liebigs Ann. Chem. 1850, 75, 27; (b) Dömling, A.; Ugi, I. Angew.
Chem., Int. Ed. 2000, 39, 3168; (c) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879.
15. (a) Vuluga, D.; Legros, J.; Crousse, B.; Bonnet-Delpon, D. Green Chem. 2009, 11,
156–159; (b) Sibi, M. P.; Stanley, L. M.; Soeta, T. Org. Lett. 2007, 9, 1553–1556;
(c) Bonini, B. F.; Franchini, M. C.; Gentili, D.; Locatelli, E.; Ricci, A. Synlett 2009,
2328–2332.
16. (a) Knorr, L. Ber. 1883, 16, 2587; (b) Patel, M. V.; Bell, R.; Majest, S.; Henry, R.;
Kolasa, T. J. Org. Chem. 2004, 69, 7058–7065; (c) Peruncheralathan, S.; Khan, T.
A.; Ila, H.; Junjappa, H. J. Org. Chem. 2005, 70, 10030–10035; (d) Gosselin, F.;
O’Shea, P. D.; Webster, R. A.; Reamer, R. A.; Tillyer, R. D.; Grabowski, E. J. J.
Synlett 2006, 3267–3270; (e) Ko, Y. O.; Chun, Y. S.; Park, C.; Kim, Y.; Shin, H.;
Ahn, S.; Hong, J.; Lee, S. Org. Biomol. Chem. 2009, 1132–1136.
alyst was used (Table 1, entry 15). In order to screen the effect of
solvent and temperature, the model reaction was undertaken both
under conventional and microwave conditions using 5 mol % of
Sc(OTf)3 in different solvents at varying temperatures. The opti-
mum conversion was achieved under solvent-free conditions at
100 °C. The model reaction was also studied by varying microwave
power (150, 200 and 250 W) and it was concluded that 200 W
power output at 100 °C was needed to accomplish maximum con-
version to product 4a.
Under the optimized set of MW reaction conditions (5 mol % of
Sc(OTf)3, 200 W, 100 °C), a number of aldehydes 2 were subse-
quently allowed to react with phenyl hydrazine 1 and ethyl aceto-
acetate
3 to afford various pyrazole derivatives (4a–4o) in
reasonably good to excellent yields in 3–6 min (Table 2).21 Interest-
ingly, aromatic aldehydes with electron withdrawing groups gave
products with higher yields in comparison to those having electron
donating groups. It is worth noting that the reaction with o-salicyl-
aldehyde did not provide the expected product, and the reaction
stopped at the condensation stage with no further reaction with
ethyl acetoacetate. Heteroaromatic and aliphatic aldehydes such
as furan-2-carboxaldehdye, thiophene-2-carboxaldehyde, and
propionaldehyde also participated well in the reaction (Table 2,
entries 12, 13 and 15).
After completion of the reaction, dichloromethane (DCM) was
added to the reaction mixture and the catalyst was recovered by
filtration. After washing with DCM and drying in air, the recovered
catalyst was reused without any loss in its catalytic activity.
In conclusion, we have successfully developed a simple, green,
and efficient microwave assisted one-pot multicomponent synthe-
sis of pyrazole derivatives from easily available starting materials
using Sc(OTf)3 as a catalyst under solvent-free conditions. This pro-
tocol is attractive in terms of, atom economy, shortened reaction
time, simple and clean reaction profiles, tolerance of various func-
tional groups, and reusability of the catalyst.
17. Clapham, K. M.; Batsanov, A. S.; Bryce, M. R.; Tarbit, B. Org. Biomol. Chem. 2009,
7, 2155–2161.
Acknowledgments
18. (a) Goikhman, R.; Jacques, T. L.; Sames, D. J. Am. Chem. Soc. 2009, 131, 3042–
3048; (b) Wang, X.-j.; Tan, J.; Zhang, L. Org. Lett. 2000, 2, 3107–3109.
19. Shen, L.; Cao, S.; Liu, N.; Wu, J.; Zhu, L.; Qian, X. Synlett 2008, 1341–1344.
20. (a) Raghuvanshi, D. S.; Singh, K. N. Synlett 2011, 373–377; (b) Singh, N.; Singh,
S. K.; Khanna, R. S.; Singh, K. N. Tetrahedron Lett. 2011, 52, 2419–2422; (c)
Raghuvanshi, D. S.; Singh, K. N. Tetrahedron Lett. 2011, 52, 5702–5705.
21. Experimental procedure: A mixture of appropriate aldehyde (1 mmol), phenyl
hydrazine (1 mmol) and 5 mol % Sc(OTf)3 was placed in a 10-mL pressurized
vial and stirred for 5 min. To it was then added ethyl acetoacetate (1.2 mmol)
and was put in the ‘‘snap-on’’ cap. The reaction contents were irradiated in a
mono-mode CEM Discover microwave synthesis system using 200 W MW
power at 100 °C for appropriate time. After completion of the reaction (as
indicated by TLC), the mixture was cooled to rt and to it was added DCM and
stirred. The catalyst was recovered by filtration. The filtrate was washed with
satd aq brine solution, dried over anhydrous Na2SO4, filtered and evaporated
under reduced pressure. The crude product was purified by silica gel column
chromatography using ethyl acetate/hexane (1:10) to afford the pure product.
We are thankful to the Council of Scientific and Industrial Re-
search, New Delhi for financial assistance.
References and notes
1. Anastas, P.; Williamson, T. Green Chemistry, Frontiers in Benign Chemical
Synthesis and Procedures; Oxford Science Publications, 1998.
2. (a) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.; Machado, P. Chem.
Rev. 2009, 109, 4140–4182; (b) Choudhary, G.; Peddinti, R. K. Green Chem. 2011,
13, 276–282; (c) Yan, S.; Chen, Y.; Liu, L.; He, N.; Lin, J. Green Chem. 2010, 12,
2043–2052; (d) Polshettiwar, V.; Varma, R. S. Tetrahedron Lett. 2008, 49, 879–
883.
3. (a) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46–58; (b) Tan,
D. S. Nat. Chem. Biol. 2005, 1, 74–84; (c) Spandl, R. J.; Bender, A.; Spring, R. D.
Org. Biomol. Chem. 2008, 6, 1149–1158.