Copper(I)-catalyzed synthesis of pyrazoles from phenylhydrazones and dialkyl ethylenedicarboxylates in the presence of bases

Article abstract of DOI:10.1055/s-0030-1260552

An easy and efficient copper-catalyzed reaction for the synthesis of polysubstituted pyrazoles from phenylhydrazones and dialkyl ethylenedicarboxylates is described. This reaction can tolerate a range of functionalities, and the corresponding adducts can

Full text of DOI:10.1055/s-0030-1260552

LETTER
1321
Copper(I)-Catalyzed Synthesis of Pyrazoles from Phenylhydrazones and
Dialkyl Ethylenedicarboxylates in the Presence of Bases
P
yrazole
s
from
P
h
henylhydraz
o
nes and D
i
o
alkyl Ethyle
w
nedicarboxylates ei Ma, Yanmei Li, Ping Wen, Rulong Yan, Zhiyong Ren, Guosheng Huang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8912582; E-mail: hgs@lzu.edu.cn
Received 5 March 2011
through C–H activation,14 examples of the reactions under
copper-catalyzed conditions are rare.15 In addition, be-
cause of the economic attractiveness and potential large-
scale application of copper catalysts, during the past few
years there have been remarkable advances in the use of
copper catalysis in organic chemistry.16 As a part of our
continuing study on the utilization of copper catalysis in
organic synthesis,17 herein we wish to report an easy and
efficient one-pot synthesis of pyrazoles from phenylhy-
drazones and dialkyl ethylenedicarboxylates. The reac-
Abstract: An easy and efficient copper-catalyzed reaction for the
synthesis of polysubstituted pyrazoles from phenylhydrazones and
dialkyl ethylenedicarboxylates is described. This reaction can toler-
ate a range of functionalities, and the corresponding adducts can be
obtained in moderate to good yields.
Key words: heterocycles, copper catalysis, hydrazones, dialkyl
ethylenedicarboxylates, pyrazoles
Pyrazoles are a well-known class of nitrogen containing
heterocycles that find extensive use in the pharmaceutical
and agrochemical substances.1 For instance, pyrazoles
constitute the core structures of some well-known drugs
such as Celebrex, Viagra, and Acomplia,2 as well as in
therapeutic areas such as anti-inflammatory,3 analgesic,4
and anticancer.5 Due to the attractive medicinal properties
of the pyrazole skeleton, easy and efficient methods for
the preparation of such compounds are of considerable in-
terest in synthetic organic chemistry. By far the classical
methods for synthesis of these heterocycles are reactions
between 1,3-diketones with hydrazines.6 However, such
procedures suffer a major drawback in that there is a lack
of regioselectivity with unsymmetrically substituted 1,3-
diketones (Scheme 1).7 Other methods of obtaining pyra-
zoles that do not require 1,3-diketones have been report-
ed,8 but often have serious drawbacks such as being step
intensive. Recently, several new approaches to access
pyrazoles have been reported.9–11 Hence, the development
of new and more efficient procedures is a subject of great
importance.
Table 1 Survey of Catalysts, Bases, and Solvent Effects of the
Reactiona
Ph
COOMe
COOMe
H
catalyst, base
solvent, r.t.
N
+
N
COOMe
Ph
N
Ph
N
COOMe
Ph
1a
2a
3aa
Entry
1
Catalyst
CuI
Base
Solvent
DME
DME
DME
DME
DME
DME
DME
DME
DME
THF
Yield (%)b
NaOAc
NaOAc
–
73
44
trace
75
75
0
2c
3
CuI
CuI
4d
5e
6
CuI
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
Na2CO3
K2CO3
KOH
CuI
–
7
CuCl
CuBr
CuBr2
CuI
27
trace
0
8
Ar3
R
Ar2
R
O
O
9
H
and
+
N
N
N
Ar2
Ar3
Ar1
NH2
Ar3
Ar2
N
N
10
11
12
13
14
15
0
Ar1
Ar1
R
CuI
MeCN
DCE
66
0
Scheme 1 Pyrazoles synthesis from 1,3-diketones and hydrazines
CuI
With the emergence of the concepts of atom economy12
and green chemistry,13 new methods to construct hetero-
cycles with simple and readily accessible substances are
both important and highly desirable. Although there were
a lot of excellent results about C–N bond formation
CuI
DME
DME
DME
53
57
54
CuI
CuI
a Reaction conditions: 1a (0.24 mmol), 2a (0.2 mmol), base (0.2
mmol), catalysts (0.02 mmol) in 2 mL of solvent for 2 h under air.
b Isolated yield.
SYNLETT 2011, No. 9, pp 1321–1323
x
x.
x
x.
2
0
1
1
c Reaction was carried out with 0.2 equiv of base.
d Reaction was carried out with 2 equiv of base.
e Reaction was carried out with 1.0 equiv of base under nitrogen.
Advanced online publication: 05.05.2011
DOI: 10.1055/s-0030-1260552; Art ID: W06311ST
© Georg Thieme Verlag Stuttgart · New York

1322
C. Ma et al.
LETTER
Table 2 Synthesis of Pyrazoles from Phenylhydrazones and Dialkyl
tions proceeded smoothly, and the corresponding adducts
were achieved in moderate to good yields.
Ethylenedicarboxylates18
R1
COOR2
COOR2
We initiated our study by examining the reaction of ben-
zaldehyde phenylhydrazone (1a) and dimethyl acetylene-
dicarboxylate (2a) in the presence of 1.0 equivalent of
NaOAc in dimethyl ether (DME) at room temperature un-
der air. To our delight, the desired dimethyl 1,3-diphe-
nylpyrazole-4,5-dicarboxylate (3aa) was obtained in 73%
yield in the reaction catalyzed by CuI after two hours
(Table 1, entry 1). When the base loading was reduced, a
lower yield of 3aa was obtained (Table 1, entries 2 and 3).
By increasing the base loading to 2 equivalents, the yield
of 3aa only had a slight change (Table 1, entry 4). Fur-
thermore, different copper salts such as CuCl, CuBr, and
CuBr2 were examined (Table 1, entries 7–9), but no better
results were obtained. In addition, in the absence of metal
salts, no desired product was found (Table 1, entry 6).
Among the solvent systems examined, changing the sol-
vent to THF, MeCN, and 1,2-dichloroethane (DCE) did
not improve the yields (Table 1, entries 10–12). The re-
sults indicated that the choice of DME as a solvent was
crucial for the reaction. Other bases such as Na2CO3,
K2CO3, and KOH were also evaluated (Table 1, entries
13–15), NaOAc was found to provide the product in the
highest yield. It is worth mentioning that when the reac-
tion was carried out under nitrogen, product 3aa was iso-
lated in good yield too (Table 1, entry 5). Thus, the most
suitable reaction conditions for the formation of 3aa were
established, and optional conditions featured 10 mol%
CuI, DME, room temperature, and 1.0 equivalent of
NaOAc (Table 1, entry 1), which provide product 3aa in
good yield.
H
CuI, NaOAc
DME, r.t.
N
+
N
R1
COOR2
N
Ph
N
COOR2
Ph
3
1
2
Entry
1
R1
R2
Product Yield (%)a
1a Ph
1a Ph
2a Me
2b Et
2a Me
2b Et
2a Me
2b Et
2a Me
2b Et
2a Me
2b Et
2a Me
2a Me
2a Me
2a Me
2a Me
2a Me
2a Me
3aa
3ab
3ba
3bb
3ca
3cb
3da
3db
3ea
3eb
3fa
73
78
85
88
76
78
81
86
68
87
72
75
53
52
58
57
61
2
3
1b 4-ClC6H4
1b 4-ClC6H4
1c 4-BrC6H4
1c 4-BrC6H4
1d 4-NCC6H4
1d 4-NCC6H4
4
5
6
7
8
9
1e 4-O2NC6H4
1e 4-O2NC6H4
1f 2-ClC6H4
10
11
12
13
14b
15
1g 2,4-Cl2C6H3
1h 4-MeC6H4
1h 4-MeC6H4
1i 3,4-Me2C6H3
1j 2-furan
3ga
3ha
3ha
3ia
With these optimized conditions in hand, we then attempt- 16
ed to extend the scope of this reaction to test the generality
3ja
17
1k 4-CHOC6H4
3ka
of this method, and the results are illustrated in Table 2.
Generally, reaction of phenylhydrazones with dialkyl eth- a Isolated yield.
b The reaction was carried out at reflux temperature for 10 h.
ylenedicarboxylates proceeded smoothly and led to the
desired polysubstituted pyrazoles in moderate to good
yields. Gratifyingly, the reaction was found to tolerate a
range of functionalities, including aryl- and heterocyclic-
substituted phenylhydrazones. Good yields of pyrazole
products 3 were usually obtained with electron-withdraw-
ing-group-substituted phenylhydraz-ones (Table 2, en-
tries 3–12). However, even at reflux temperature and a
longer reaction time, electron-donating-group-substituted
phenylhydrazones gave lower yields of pyrazole products
(Table 2, entries 13–15). Phenylhydrazones bearing het-
erocycles, such as 2-furan-carboxaldehyde phenylhydra-
zone (1j) could also react to give 3ja in 57% yield
(Table 2, entry 16). Further investigations demonstrated
that the reaction of phenylhydrazone and diethyl acety-
lenedicarboxylate (2b) gave higher yields than the dime-
thyl acetylenedicarboxylate (2a). The substrates 1e and 1k
reacted with 2a to form the corresponding products 3ea
and 3ka in 68% and 61% yields, respectively (Table 2, en-
tries 9 and 17).
On the basis of the results obtained above, a plausible
pathway for this reaction is illustrated in Scheme 2. The
reaction of 1 and 2 under reaction conditions presumably
led to the formation of intermediates A and C. The next
step involved the coupling of B, another resonance form
of A, and C to produce intermediate D. Then, the interme-
diate E was formed via tautomerization in the presence of
bases. Subsequently, protonation of E led to the formation
of intermediate F which then underwent reductive elimi-
nation of CuH, which further reacted with the conjugate
acid of the base to afford hydrogen and regenerated the
catalyst.19
In conclusion, an efficient copper-catalyzed approach to
the construction of a polysubstituted pyrazole skeleton in
the presence of base from phenylhydrazones and dialkyl
ethylenedicarboxylates has been developed. A range of
functionalities including aryl- and heterocyclic-substitut-
ed phenylhydrazones were proven possible. This reaction
Synlett 2011, No. 9, 1321–1323 © Thieme Stuttgart · New York

LETTER
Pyrazoles from Phenylhydrazones and Dialkyl Ethylenedicarboxylates
1323
Katzenellenbogen, J. A. J. Med. Chem. 2000, 43, 4934.
(b) Stauffer, S. R.; Huang, Y.; Coletta, C. J.; Tedesco, R.;
Katzenellenbogen, J. A. Bioorg. Med. Chem. 2001, 9, 141.
(6) (a) Knorr, L. Ber. Dtsch. Chem. Ges. 1883, 16, 2587.
(b) Kost, A. N.; Grandberg, I. I. Adv. Heterocycl. Chem.
1966, 6, 347.
(7) (a) Silva, V. L. M.; Silva, A. M. S.; Pinto, D. C. G. A.;
Cavaleiro, J. A. S.; Elguero, J. Eur. J. Org. Chem. 2004,
4348. (b) Heller, S. T.; Natarajan, S. R. Org. Lett. 2006, 8,
2675.
(8) (a) Huang, Y. R.; Katzenellenbogen, J. A. Org. Lett. 2000, 2,
2833. (b) Katritzky, A. R.; Wang, M.; Zhang, S.; Voronkov,
M. V.; Steel, P. J. J. Org. Chem. 2001, 66, 6787. (c) Singer,
R. A.; Caron, S.; McDermott, R. E.; Arpin, P.; Do, N. M.
Synthesis 2003, 1727. (d) Aggarwal, V. K.; De Vicente, J.;
Bonnert, R. V. J. Org. Chem. 2003, 68, 5381. (e) Ahmed,
M. S. M.; Kobayashi, K.; Mori, A. Org. Lett. 2005, 7, 4487.
(9) Monteiro, N.; Balme, G.; Delaunay, T. Org. Lett. 2010, 12,
3328.
(10) Moses, J.; Spiteri, C.; Keeling, S. Org. Lett. 2010, 12, 3368.
(11) Wada, A.; Okitsu, T.; Sato, K. Org. Lett. 2010, 12, 3506.
(12) (a) Trost, B. M. Acc. Chem. Res. 2002, 35, 695. (b) Trost,
B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259.
(13) Winterton, N. Green Chem. 2001, 3, G73.
(14) (a) Davies, H. M. L.; Long, M. S. Angew. Chem. Int. Ed.
2005, 44, 3518. (b) Wasa, M.; Yu, J. Q. J. Am. Chem. Soc.
2008, 130, 14058. (c) Brasche, G.; Buchwald, S. L. Angew.
Chem. Int. Ed. 2008, 47, 1932. (d) Hamada, T.; Ye, X.;
Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833. (e) Inamoto,
K.; Hasegawa, C.; Hiroya, K.; Doi, T. Org. Lett. 2008, 10,
5147. (f) Reed, S.; White, M. C. J. Am. Chem. Soc. 2008,
130, 3316.
(15) (a) Stahl, S. S. Angew. Chem. Int. Ed. 2004, 43, 3400.
(b) Tsang, W. C. P.; Munday, R.; Brasche, G.; Zheng, N.;
Buchwald, L. L. J. Org. Chem. 2008, 73, 7603.
(c) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org.
Lett. 2009, 11, 1607.
(16) (a) Brasche, G.; Buchwald, S. L. Angew. Chem. Int. Ed.
2008, 47, 1932. (b) Ueda, S.; Nagasawa, H. Angew. Chem.
Int. Ed. 2008, 120, 6511.
(17) (a) Yan, R.; Huang, J.; Luo, J.; Wen, P.; Huang, G.; Liang,
Y. Synlett 2010, 1071. (b) Yan, R.; Luo, J.; Wang, C. X.;
Ma, C. W.; Huang, G.; Liang, Y. J. Org. Chem. 2010, 75,
5395.
(18) Typical Procedure for the Synthesis of Pyrazoles
An oven-dried reaction tube was charged with CuI (3.8 mg,
0.02 mmol), NaOAc (16.4 mg, 0.20 mmol), benzaldehyde
phenylhydrazone (1a, 47.0mg, 0.24 mmol), and dimethyl
acetylenedicarboxylate (2a, 28.4mg, 0.20 mmol). Then
DME (2 mL) was added to the reaction system. The mixture
was stirred at r.t. for 2 h. After removal of the solvent under
reduced pressure, the crude product was purified by column
chromatography on silica gel (EtOAc–PE, 1:8) to give 3aa
(49.0 mg, 73%) as white solid (Table 2, entry 1); mp 152–
154 °C. 1H NMR (400 MHz, CDCl3): d = 7.75 (dd, J = 7.4,
1.8 Hz, 2 H), 7.54 (dd, J = 8.2, 1.4 Hz, 2 H), 7.50–7.40 (m,
6 H), 3.85 (s, 3 H), 3.82 (s, 3 H). 13C NMR (100 MHz,
CDCl3): d = 163.37, 160.64, 151.98, 139.03, 136.82, 131.33,
129.16, 129.06, 128.87, 128.77, 128.16, 124.53, 114.13,
53.11, 52.12. IR (neat): 2952, 1733, 1499, 1447, 1266, 911,
732 cm–1. HRMS: m/z calcd for C19H16N2O4 [M + H]+:
337.1183; found: 337.1175.
–
N
+
BH
H
B
R1
N
Ph
N
R1
N
Ph
A
1
–
N
CO2R2
R1
N
Ph
CO2R2
CO2R2
B
+
Cu
CO2R2
Ph
Cu
CO2R2
C
1
N
N
Cu+
H-H
CO2R2
B
R1
D
+
BH
Cu-H
Ph
CO2R2
CO2R2
N
+
BH
CO2R2
N
H
CO2R2
CO2R2
–
Ph
Cu
Ph
Cu
N
N
R1
N
3
N
+
BH
CO2R2
B
R1
R1
E
F
Scheme 2 Possible reaction pathway
could proceed smoothly, and the corresponding products
were achieved in moderate to good yields.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the State Key Laboratory of Applied Organic Chemistry
for financial support. We also thank our reviewers’ suggestion.
References and Notes
(1) (a) Lamberth, C. Heterocycles 2007, 71, 1467. (b) Elguero,
J. In Comprehensive Heterocyclic Chemistry, Vol. 5;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1966. (c) Eicher, T.; Hauptmann, S.;
Speicher, A. The Chemistry of Heterocycles, 2nd ed.; J.
Wiley and Sons: New York, 2003, 179.
(2) Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S.
Pyrazoles as Drugs: Facts and Fantasies, In Targets in
Heterocyclic Systems Chemistry and Properties, Vol. 6;
Attanasi, O. A.; Spinelli, D., Eds.; Italian Society of
Chemistry: Rome, 2002, 52.
(3) (a) Sui, Z.; Guan, J.; Ferro, M. P.; Mccoy, K.; Wachter, M.
P.; Murray, W. V.; Singer, M.; Steber, M.; Ritchie, D. M.;
Argentieri, D. C. Bioorg. Med. Chem. Lett. 2000, 10, 601.
(b) Bekhit, A. A.; Abdelaziem, T. Bioorg. Med. Chem. 2004,
12, 1935. (c) Selvam, C.; Jachak, S. M.; Thilagavathi, R.;
Chakraborti, A. K. Bioorg. Med. Chem. Lett. 2005, 15, 1793.
(4) Katoch-Rouse, R.; Pavlova, L. A.; Caulder, T.; Hoffman, A.
F.; Mukhin, A. G.; Horti, A. G. J. Med. Chem. 2003, 46, 642.
(5) (a) Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishiguchi,
G.; Carlson, K.; Sun, J.; Katzenellenbogen, B. S.;
(19) Cacchi, S.; Bernini, R.; Fabrizi, G.; Sferrazza, A. Angew.
Chem. Int. Ed. 2009, 48, 8078.
Synlett 2011, No. 9, 1321–1323 © Thieme Stuttgart · New York