Synthesis of tri- and tetrasubstituted pyrazoles via Ru(II) catalysis: Intramolecular aerobic oxidative C-N coupling

Article abstract of DOI:10.1021/ol3022353

An unprecedented ruthenium(II)-catalyzed intramolecular oxidative C-N coupling method has been developed for the facile synthesis of a variety of synthetically challenging tri- and tetrasubstituted pyrazoles. Dioxygen gas is employed as the oxidant in this transformation. The reaction demonstrates excellent reactivity, functional group tolerance, and high yields.

Full text of DOI:10.1021/ol3022353

ORGANIC
LETTERS
2012
Vol. 14, No. 19
5030–5033
Synthesis of Tri- and Tetrasubstituted
Pyrazoles via Ru(II) Catalysis:
Intramolecular Aerobic Oxidative
CÀN Coupling
Jiantao Hu, Shi Chen, Yonghui Sun, Jing Yang, and Yu Rao*
Department of Pharmacology and Pharmaceutical Sciences, School of Medicine and
School of Life Sciences, Tsinghua University, Beijing 100084, China
yrao@mail.tsinghua.edu.cn
Received August 12, 2012
ABSTRACT
An unprecedented ruthenium(II)-catalyzed intramolecular oxidative CÀN coupling method has been developed for the facile synthesis of a variety
of synthetically challenging tri- and tetrasubstituted pyrazoles. Dioxygen gas is employed as the oxidant in this transformation. The reaction
demonstrates excellent reactivity, functional group tolerance, and high yields.
Pyrazoles are an important class of compounds that are
extensively used in today’s pharmaceutical industry.1
Compounds containing a pyrazole scaffold are being
developed for the treatment of metabolic, CNS, and
oncological diseases, etc.2 A number of pyrazole deriva-
tives have been successfully commercialized, such as Ce-
lebrex, Viagra, and Acomplia.3 Substituted pyrazoles have
also been utilized as useful ligands for some cross-coupling
reactions.4
Over the past decade, considerable research has focused
on the development of transition-metal-catalyzed CÀH
bond functionalization methods that can be applied to the
synthesis of biologically important aromatic and heteroaro-
matic compounds.5,6 Among these, ruthenium-catalyzed
(1) (a) Elguero, J. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 5.
(b) Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S. Targets Heterocycl.
Syst. 2002, 6, 52–98. (c) Fustero, S.; Rosell, M. S.; Barrio, P.; Fuentes, A. S.
Chem. Rev. 2011, 111, 6984.
(5) Selected recent reviews on CÀH bond functionalizations: (a)
Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (b) Ackermann,
L.; Potukuchi, H. K. Org. Biomol. Chem. 2010, 8, 4503. (c) Daugulis, O.
Top. Curr. Chem. 2010, 292, 57. (d) Sun, C. L.; Li, B. J.; Shi, Z. J. Chem.
Commun. 2010, 46, 677. (e) Colby, D. A.; Bergman, R. G.; Ellman, J. A.
Chem. Rev. 2010, 110, 624. (f) Ackermann, L. Chem. Commun. 2010, 46,
4866. (g) Fagnou, K. Top. Curr. Chem. 2010, 292, 35. (h) Giri, R.; Shi,
B. F.; Engle, K. M.; Maugel, N.; Yu, J. Q. Chem. Soc. Rev. 2009, 38,
3242. (i) Ackermann, L.; Vicente, R.; Kapdi, A. Angew. Chem., Int. Ed.
2009, 48, 9792. (j) Thansandote, P.; Lautens, M. Chem.;Eur. J. 2009,
15, 5874. (k) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(6) For reviews on heterocycle synthesis, see: (a) Zeni, G.; Larock,
R. C. Chem. Rev. 2006, 106, 4644. (b) Thansandote, P.; Lautens, M.
Chem.;Eur. J. 2009, 15, 5874. For intramolecular CÀH amidation, see:
(c) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005,
127, 14560. (d) Jordon-Hore, J. A.; Johansson, C. C. C.; Gulias, M.;
Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184. (e) Mei,
T. S.; Wang, X.; Yu, J. Q. J. Am. Chem. Soc. 2009, 131, 10806. (f) Wasa,
M.; Yu, J. Q. J. Am. Chem. Soc. 2008, 130, 14058. (g) Inamoto, K.; Saito,
T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org. Lett. 2007, 9, 2931. (h)
Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3676. (i) Neumann,
J. J.; Rakshit, S.; Droge, T.; Glorius, F. Angew. Chem., Int. Ed. 2009, 48,
6892.
(2) (a) Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of
Heterocycles, 2nd ed.; Wiley & Sons: New York, 2004; pp 179À184. (b)
Sperandeo, N. R.; Brun, R. ChemBioChem 2003, 4, 69. (c) 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, 601–604. (d) Bekhit, A. A.; Abdel- Aziem, T. Bioorg. Med.
Chem. 2004, 12, 1935–1945. (e) Selvam, C.; Jachak, S. M.; Thilagavathi,
R.; Chakraborti, A. K. Bioorg. Med. Chem. Lett. 2005, 15, 1793–1797.
(3) (a) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson,
G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.;
Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson,
P. C. J. Med. Chem. 1997, 40, 1347–1365. (b) Terrett, N. K.; Bell, A. S.;
Brown, D.; Ellis, P. Bioorg. Med. Chem. Lett. 1996, 6, 1819–1824.
(4) (a) Singer, R. A.; Caron, S.; McDermott, R. E.; Arpin, P.; Do,
N. M. Synthesis 2003, 1727–1732. (b) Singer, R. A.; Dore, M.; Sieser,
J. E.; Berliner, M. A. Tetrahedron Lett. 2006, 47, 3727–3731.
r
10.1021/ol3022353
Published on Web 09/18/2012
2012 American Chemical Society

reactions have proven themselves to be highly selective and
atom economical.7,8 In this area, to date, most research has
focused on the catalytic conversion of CÀH bonds to CÀC
bonds. In contrast, the application of ruthenium catalysis
to the construction of carbonÀheteroatom bonds, espe-
cially for oxidative carbonÀnitrogen bond formation, has
been rarely reported.9 Thus far, major research efforts into
CÀN oxidative coupling have focused on using other
metals such as Pd, Cu, etc.5,6 In our ongoing studies into
the preparation of multisubstituted pyrazoles, we have
proposed that “a ruthenium catalyst, under proper condi-
tions, allows CÀH bond cleavage via an orthometalation
process that involves chelation with the nitrogen from
hydrazones”10 Consequently, the formation of a CÀN
bond is possible via reductive elimination to generate
the corresponding pyrazole products11 (Scheme 1). A
terminal oxidant could oxidize the Ru(0) species to
Ru(II) to complete the catalytic cycle. To the best
of our knowledge, intramolecular oxidative carbonÀ
nitrogen bond formation using ruthenium(II) has
not yet been achieved. In this paper, we report a new
example of ruthenium(II)-catalyzed oxidative CÀN
coupling with molecular oxygen as the oxidant for the
preparation of pyrazole derivatives.
used oxidants such as PhI(OAc)2,12 BQ,13 Cu(OAc)2,14
AgOAc,15 K2S2O8,16 TBHP, and Oxone, we are particu-
larly interestedhere in the applicability of dioxygen,17 since
it is an ideal oxidant and offers attractive industrial pros-
pects in terms of green and sustainable chemistry. Accord-
ingly, to test our hypothesis, a model study was initiated
with hydrazone 1 in the presence of [RuCl2(p-cymene)]2 in
DCE underoneatmosphereofO2. The results areshownin
Table 1. Encouragingly, a 10% yield of the desired product
2 was achieved (entry 1) after stirring for 6 h at 80 °C.
Encouraged by this preliminary result, we proceeded to
optimize the reaction conditions. After comprehensive
screening, we found DMSO to be highly efficient and
superior to other solvents, such as DCM, MeCN, THF,
DMF, DMA, EtOH, and 1,4-dioxane. It was observed
that higher temperatures could speed up the reactions
and improve the yields. There were only slight differences
in terms of reaction rates and conversion ratios when
higher catalyst loadings were used. Generally, a 0.05 equiv
amount of [RuCl2(p-cymene)]2 was sufficient to effec-
tively promote the reaction. Moreover, we found that
the yields notably increased with the addition of a base
such as NaHCO3. It was believed that the base would
serve as a proton shuttle and assist in the transforma-
tion. Attempts to use other ruthenium catalysts, such
as RuCl2(PPh)3, RuHCl(PPh)3, and Ru3(CO)12, were
not as successful as [RuCl2(p-cymene)]2. Interestingly, a
36% yield of product 2 was also achieved by using air as
the oxidant (entry 21). Typically, the reaction will proceed
to completion in DMSO within 8 h, in a clean manner,
under 1 atm of O2 at 100 °C.
Scheme 1. Preparation of Pyrazole through Ru(II)-Mediated
CÀH Activation
Table 1. Optimization of the Reaction Conditions
The oxidant plays an essential role in the catalytic
cycle of CÀH activation. While there are many commonly
(7) For reviews, see: (a) Ackermann, L. Chem. Rev. 2011, 111, 1315.
(b) Ackermann, L. Pure Appl. Chem. 2010, 82, 1403. (c) Ackermann, L.;
Vicente, R. Top. Curr. Chem. 2010, 292, 211.
entry
condition
1 atm O2, DCE, 80 °C, 6 h
yielda (%)
(8) For illustrative examples, see: (a) Lakshman, M. K.; Deb, A. C.;
Chamala, R. R.; Pradhan, P.; Pratap, R. Angew. Chem., Int. Ed. 2011, 50,
11400. (b) Seki, M.; Nagahama, M. J. Org. Chem. 2011, 76, 10198. (c)
Miura, H.; Wada, K.; Hosokawa, S.; Inoue, M. Chem.;Eur. J. 2010, 16,
4186. (d) Ackermann, L.; Born, R.; Vicente, R. ChemSusChem. 2009, 546.
(e) Ozdemir, I.; Demir, S.; Cetinkaya, B.; Gourlaouen, C.; Maseras, F.;
Bruneau, C.; Dixneuf, P. H. J. Am. Chem. Soc. 2008, 130, 1156. (f) Oi, S.;
Sasamoto, H.; Funayama, R.; Inoue, Y. Chem. Lett. 2008, 37, 994. (g)
Ackermann, L.; Born, R.; Alvarez-Bercedo, P. Angew. Chem., Int. Ed. 2007,
46, 6364. (h) Ackermann, L. Org. Lett. 2005, 7, 3123. (i) Oi, S.; Aizawa, E.;
Ogino, Y.; Inoue, Y. J. Org. Chem. 2005, 70, 3113. (j) Ackermann, L.; Lygin,
A. V.; Hofmann, N. Angew. Chem., Int. Ed. 2011, 50, 6379.
(9) (a) Leung, S. K. Y.; Tui, W. M.; Huang, J. S.; Che, C. M.; Liang,
J. L.; Zhu, N. J. Am. Chem. Soc. 2005, 127, 16629. (b) Liang, J. L.; Yuan,
S. X.; Huang, J. S.; Yu, W. Y.; Che, C. M. Angew. Chem., Int. Ed. 2002,
41, 3465. (c) Liang, J. L.; Huang, J. S.; Yu, X. Q.; Zhu, N.; Che, C. M.
Chem.;Eur. J. 2002, 8, 1563. (d) He, L.; Chan, P.; Tsui, W.; Yu, W.;
Che, C. Org. Lett. 2004, 6, 2405.
1
2
3
4
5
6
7
8
9
10
21
10
27
11
35
49
41
67
71
66
1 atm O2, 1,4-dioxane, 80 °C, 6 h
1 atm O2, MeCN, 80 °C, 6 h
1 atm O2, EtOH, 80 °C, 6 h
1 atm O2, t-AmOH, 80 °C, 6 h
1 atm O2, DMSO, 80 °C, 6 h
1 atm O2, DMF, 100 °C, 6 h
1 atm O2, DMA, 100 °C, 6 h
1 atm O2, DMSO, 100 °C, 6 h
10 1 atm O2, 2.0 equiv Et3N, DMSO, 100 °C, 6 h
11 1 atm O2, 2.0 equiv DIPEA, DMSO, 100 °C, 6 h
12 1 atm O2, 2.0 equiv Pyridine, DMSO, 100 °C, 6 h 47
13 1 atm O2, 2.0 equiv DBU, DMSO, 100 °C, 6 h
14 1 atm O2, 2.0 equiv DABCO, DMSO, 100 °C, 6 h
59
61
(10) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K
Org. Lett. 2007, 9, 2931.
15 1 atm O2, 2.0 equiv NaHCO3, DMSO, 100 °C, 6 h 72b
(11) Recent examples about synthesis of pyrazole: (a) Mohanan, K.;
Martin, A. R. Angew. Chem., Int. Ed. 2010, 49, 3196. (b) Neumann, J. J.;
Suri, M. Angew. Chem., Int. Ed. 2010, 49, 7790. (c) Lin, Q. Y.; Meloni, D.
Org. Lett. 2009, 11, 1999. (d) Gerstenberger, B. S.; Rauckhorst, M. R.
Org. Lett. 2009, 11, 2097. (e) Shan, G.; Liu, P. F.; Rao, Y. Org. Lett.
2011, 13, 1746. (f) Hu, J. T.; Cheng, Y. F.; Yang, Y. Q.; Rao, Y. Chem.
Commun. 2011, 47, 10133.
16 1 atm O2, 2.0 equiv Na2CO3, DMSO, 100 °C, 6 h
17 without Ru, 1 atm O2, DMSO, 100 °C, 24 h
18 1 atm air, 2.0 equiv NaHCO3, DMSO, 100 °C, 6 h 36
59
tracec
a Conversion ratio. b Isolated yield. c LCÀMS analysis.
Org. Lett., Vol. 14, No. 19, 2012
5031

Having identified these optimal conditions, we set out
to explore the scope for this new reaction. A variety of
aromatic hydrazines, R,β-unsaturated aldehydes, and ke-
tones were surveyed to prepare different trisubstituted
pyrazoles. As shown in Figure 1, not only 1,3,5-trisubsti-
tuted pyrazole derivatives (3À22) but also 1,3,4- and 1,4,5-
trisubstituted pyrazole derivatives (23À27) were prepared
readily from the corresponding aromatic hydrazones. The
scope ofthe pyrazoleringsubstituentswasfoundtobe very
broad. In terms of R1 substituents, the ortho-, meta-, and
para-substituted aryl groups, as well as the electron-rich
and electron-deficient aryl groups, were well tolerated,
while the various aryl hydrazines easily produced good
to excellent yields of the corresponding pyrazole products.
Notably, 2-pyridyl hydrazine was also successfully em-
ployed to provide compound 20. It was found that R2, R3,
and R4 can be either H, alkyl, or aryl groups togivevarious
substituted pyrazoles. For example, if R2 is H, the products
will be 1,4,5-trisubstituted pyrazoles, respectively, such as
25 and 26. However, when R4 is H, the 1,3,4-trisubstituted
pyrazole 27 can be readily generated in a yield of 92%.
Both alkyl and aryl groups were well tolerated to provide
multifunctionalized pyrazole derivatives. It is particularly
worth noting that pyrazoles (4À7, 16, 17, 21) containing
different heteroaromatic rings, such as pyridine, thio-
phene, and furan, were also smoothly prepared in good
to excellent yields. Besides the alkyl and aryl substituents,
vinyl functional groups were presented as well to give
olefinated product 18.
The scope ofthisintramolecular cyclization reactionwas
further expanded to the preparation of synthetically chal-
lengingtetrasubstituted pyrazole derivatives. Asillustrated
in Figure 2, the optimum reaction conditions also proved
to be successful in providing highly diversified tetrasub-
stituted pyrazoles (compounds 28À36) with satisfactory
yields, respectively. It is noteworthy to point out that these
novel tetrasubstituted pyrazoles and most trisubstituted
pyrazoles are either difficult or need extra and tedious steps
to prepare via traditional methods (Scheme 2).18 Compared
with the usual ways, our new method has the advantages of
less steps, milder reaction conditions, and higher overall
yields.
Figure 1. Synthesis of trisubstituted pyrazoles. aIsolated yield.
This unique method provides new opportunities for
the construction of some biologically important molecules,
as exemplified in Scheme 3. A sulfa nonsteroidal anti-
inflammatory drug, Celebrex, and its structural ana-
logues (37À40) were smoothly prepared in good to excellent
yields.
As shown inScheme4, to probe the reactionmechanism,
an intermolecular isotope effect study wasconducted and a
KIE value of 2.4 was obtained. These results indicated that
CÀH activation might be involved in the rate-limiting step
of this transformation.19
Although details about the mechanism are not clear yet,
on the basis of our results, a plausible mechanism for this
reaction is depicted as follows: step i involves the chelation
of a ruthenium to nitrogen atom from the hydrazone sub-
strate. In the subsequent step (ii), chelate-directed CÀH
activation of the substrate could afford a six-membered
(12) (a) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7, 4149. (b)
Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8, 1141.
(13) Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler,
ꢀ
S. N. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I.
Angew. Chem., Int. Ed. 2009, 48, 1830.
(14) (a) Cai, G.; Fu, Y.; Li, Y.; Wan, X.; Shi, Z. J. J. Am. Chem. Soc.
2007, 129, 7666. (b) Chen, X.; Li, J. J.; Hao, X. S.; Goodhue, C. E.; Yu,
J. Q. J. Am. Chem. Soc. 2006, 128, 78.
(15) (a) Dhabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657. (b)
Chiong, H. A.; Pham, Q. N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129,
9879.
(16) Thu, H. Y.; Yu, W. Y.; Che, C. M. J. Am. Chem. Soc. 2006, 128,
9048.
(17) For some reviews, see: (a) Punniyamurthy, T.; Velusamy, S.;
Iqbal, J. Chem. Rev. 2005, 105, 2329. (b) Stahl, S. S. Angew. Chem., Int.
Ed. 2004, 43, 3400. For some palladium-catalyzed examples, see: (c)
Stahl, S. S. Science 2005, 309, 1824. (d) Li, B.; Tian, S. L.; Fang, Z.; Shi,
Z. J. Angew. Chem., Int. Ed. 2008, 47, 1115. (e) Shi, Z.; Zhang, C.; Tang,
C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3381.
(19) An other possible pathway: (i) coordination of Ru species to the
carbonÀcarbon double bond, (ii) trans addition of the nitrogen nucleo-
phile, (iii) elimination of RuH species, and (iv) oxidation of the Ru-H
species with molecular oxygen.
(18) Huang, Y. R.; Katzenellenbogen, J. A. Org. Lett. 2000, 2, 2833.
5032
Org. Lett., Vol. 14, No. 19, 2012

Scheme 3. Synthesis of Celebrex and Its Analogues
Scheme 4. Kinetic Isotope Effect
(1 atm) is employed as the oxidant in this transformation.
This method has been found to be generally useful for
making a variety of multisubstituted pyrazoles, most of
which are difficult to access with conventional methods.
The reaction demonstrates excellent reactivity, broad
scope, high tolerance of functional groups, and high yields,
which has been further exemplified in one synthetic applica-
tion. By employing a combination of [RuCl2(p-cymene)]2,
molecular O2, and bases, we have discovered a highly effi-
cient catalyst system for this unique intramolecular CÀN
bond formation reaction. Further investigations into the
mechanism and synthetic applications of this method are
currently underway in our laboratory.
Figure 2. Synthesis of tetrasubstituted pyrazoles. aIsolated yield.
Scheme 2. Comparsions of Conventional Approaches and Our
Methodology for Access to Tetrasubstituted Pyrazoles
Acknowledgment. This work was supported by a na-
tional “973” grant from the Ministry of Science and
Technology (Grant No. 2011CB965300), a grant from
the National Natural Science Foundation of China (Grant
No. 21142008), Tsinghua University 985 Phase II funds, and
the Tsinghua University Initiative Scientific Research Pro-
gram. We thank Prof. Lei Liu (Tsinghua University) for
helpful discussions.
cycloruthenium(II) intermediate. The final step (iii) in-
volves carbonÀnitrogen bond-forming reductive elimina-
tion to generate the product. Molecular oxygen could be
involved in the reoxidation step of Ru(0).
In summary, a novel Ru(II)-catalyzed oxidative CÀN
coupling method has been developed for the facile synthe-
sis of highly diversified tri- and tetrasubstituted pyrazoles
from easily accessible starting materials. Dioxygen gas
Supporting Information Available. Experimental pro-
cedures and characterization data of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 19, 2012
5033