Palladium-catalyzed double C-H activation: One-pot synthesis of benzo[c]pyrazolo[1,2-a]cinnolin-1-ones from 5-pyrazolones and aryl iodides

Article abstract of DOI:10.1039/c3cc47989g

A palladium-catalyzed dual C-H activation to construct C-C/C-N bonds for one-pot synthesis of benzo[c]pyrazolo[1,2-a]cinnolin-1-ones is successfully developed. This approach involves using a pyrazolone moiety as an internal directing group for C-H activation, and provides a flexible strategy to access this polycyclic skeleton.

Full text of DOI:10.1039/c3cc47989g

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Palladium-catalyzed double C–H activation:
one-pot synthesis of benzo[c]pyrazolo[1,2-a]-
cinnolin-1-ones from 5-pyrazolones and aryl
iodides†
Cite this: Chem. Commun., 2014,
0, 1682
5
Received 17th October 2013,
Accepted 5th December 2013
a
b
c
b
a
Zhoulong Fan, Kui Wu, Li Xing, Qizheng Yao and Ao Zhang*
DOI: 10.1039/c3cc47989g
www.rsc.org/chemcomm
A palladium-catalyzed dual C–H activation to construct C–C/C–N the difficulty in synthesis, especially the harsh reaction condi-
bonds for one-pot synthesis of benzo[c]pyrazolo[1,2-a]cinnolin- tions and limited availability of the starting materials 2 (Fig. 1).
1-ones is successfully developed. This approach involves using a Therefore, to fully disclose the pharmacological potential of
pyrazolone moiety as an internal directing group for C–H acti- benzo[c]pyrazolo[1,2-a]cinnolin-1-ones, new and flexible synthetic
vation, and provides a flexible strategy to access this polycyclic methods are highly desirable.
skeleton.
In view of the advances in the directing-group (DG) assisted
palladium-catalyzed C–H activation, especially the achieve-
2
Benzo[c]pyrazolo[1,2-a]cinnolin-1-ones 1 represent a unique ments in the synthesis of many natural and synthetic complex
1
3,4
class of polycycles possessing potential anti-inflammatory activity.
molecules through a multiple C–H activation process,
we
The synthesis of these compounds was initially reported in the envisioned that benzo[c]pyrazolo[1,2-a]cinnolin-1-ones 1 might
0
1
960s through a four-step synthetic process from 2,2 -dinitro- be prepared from 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (3a)
1a,b
biphenyl 2 in 36% overall yield (Fig. 1).
However, very limited and aryl iodides through a Pd-catalyzed double C–H activation
pharmacological studies have been reported so far largely due to process. Although many N-heterocycles are known to be capable
5
,6
of directing C–H activation, to the best of our knowledge,
Pd-catalyzed C–H activation directed by a pyrazol-5(4H)-one
moiety (as in 3a) has not been reported yet. Herein, we wish to
report a Pd-catalyzed one-pot synthesis of benzo[c]pyrazolo[1,2-a]-
cinnolin-1-ones 1 through a double C–H activation approach
from diversified 1-aryl-1H-pyrazol-5(4H)-ones and aryl iodides.
Notably, compound 3a itself is a neuroprotective drug marketed
7
,8
as Edaravone in 2001 in Japan and used for neurological
recovery following acute brain ischemia and subsequent
cerebral infarction. Derivatives of 3a are also rare due to its
9
limited synthetic starting materials, aryl hydrazines. Therefore,
our current C–H activation study on compound 3a will not only
lead to facile synthesis of target skeleton 1, but also generate new
analogues of 3a.
Fig. 1 Conventional processes and our proposal.
To test our assumption, we first treated pyrazol-5(4H)-one 3a
2
with phenyl iodide 5a in the presence of Pd(OAc) /AgOAc in
a
CAS Key Laboratory of Receptor Research, and Synthetic Organic & Medicinal
10
refluxing TFA, a widely used procedure for C–H activation.
It was found that arylation product 4aa was formed as the
major product in 2.5 h, and the expected cyclization product
1a appeared when the reaction time was extended to 3 h.
Further extension of the reaction time did not significantly
increase the yield of 1a, instead dual arylation product 6 was
formed (Scheme 1). Although our target compound 1a was not
obtained as the major product, this result confirmed the
feasibility of using pyrazol-5(4H)-one moiety as an internal
Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM),
Chinese Academy of Sciences, Shanghai 201203, China.
E-mail: aozhang@simm.ac.cn
b
Department of Medicinal Chemistry, China Pharmaceutical University,
Nanjing 210009, China
c
Nano Science and Technology Institute, University of Science and Technology of
China, Suzhou 215123, China
†
Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data of all new compounds. CCDC 965248. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c3cc47989g
1
682 | Chem. Commun., 2014, 50, 1682--1684
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
Scheme 1 Reaction of pyrazol-5(4H)-one 3a and iodide 5a.
component of the substrate/product to direct the double C–H
activation process.
To promote compound 1a as the major product and to
suppress the formation of the dual arylation product 6, we
decided to investigate the two C–H activation steps separately.
First, we investigated the Pd-catalyzed C–H activation/arylation
on the model reaction of 3a with iodobenzene (5a). Systematic
screening of various Pd catalysts, amount of iodobenzene,
solvents and reaction temperature (see ESI,† Table S1) dis-
closed that the highest yield (82%) of the arylated product
4aa could be obtained when the reaction was conducted using
5
equiv. of iodide 5a in TFA (0.2 M) at 120 1C for 1.5 h with
2
Pd(OAc) (10 mol%) as the catalyst, and AgOAc (1.5 equiv.) as
the silver salt.
With the optimized reaction conditions for the first C–H
activation, we explored the substrate scope and limitation.
It was found that various pyrazol-5(4H)-one derivatives and sub-
stituted iodides were well tolerated providing corresponding
arylated products 4 in moderate to high yields (see ESI,†
Table S2). Next, we set out to explore the optimal conditions
for the second C–H activation/intramolecular C–N bond for-
mation to complete the construction of benzo[c]pyrazolo[1,2-a]-
cinnolin-1-ones 1. With Pd(OAc)
2
as the catalyst, different
bases, oxidants as well as various concentrations of the reaction
solution were tested (see ESI,† Table S3). It was found that high
conversion of 4aa to 1a (74%) could be achieved when the
reaction was conducted in a sealed tube with Pd(OAc)
as the catalyst, K (1.5 equiv.) as the oxidant and K
2 equiv.) as the base in refluxing TFA (0.1 M). Encouraged by
the results, we further evaluated the one-pot process to prepare
a directly from 3a and 5a by conducting the first C–H activation/ time was necessary for those substrates bearing an electron-
2
(10 mol%)
2
S
2
O
8
2
CO
3
Scheme 2 One-pot synthesis of benzo[c]pyrazolo[1,2-a]cinnolin-1-ones.
a
(
1
arylation reaction followed by directly subjecting the reaction withdrawing substituent (1e–h, 1m–n) and for those bearing
mixture to the optimized second C–H activation/cyclization multiple substituents (1r, 1q). In addition, substitution on the
condition. To our delight, compound 1a was obtained in 76% pyrazol-5(4H)-one ring was explored as well (1s–w). Substrates
yield through the one pot process, which is even more efficacious with non-substitution or with an alkyl group at C-3 gave
than that obtained from two separate reactions.
corresponding products 1s–u in 71–83% yields, whereas a C-4
To determine the generality and limitation of this one-pot substituent led to lower yield (1v, 37%). In the case of sub-
double C–H activation process, diversified pyrazol-5(4H)-ones 3 strates bearing an ester substituent, product 1w was obtained
and iodides 5 were tested, and the results are summarized in in 53% yield. Although the yield is moderate, the ester function
Scheme 2. It was found that a para-substituent on the aryl provides an additional platform for further structural mani-
iodides has a minor effect and compounds 1a–c were obtained pulation. All the structures were fully characterized and further
in nearly identical yields (73–76%). Similar to the observations confirmed by the X-ray single-crystal analysis of compound 1n
from the first step/arylation, the second C–H activation/cycliza- (see ESI†).
1
1
tion at the less steric site was favored and no other regio-
To gain insights into the reaction mechanism, additional
isomers of compounds 1d–g were isolated. A longer reaction experiments were performed. It was reported previously that
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 1682--1684 | 1683

View Article Online
ChemComm
Communication
This work was supported by grants from Chinese NSF
81125021, 81373277), and grants from the ‘‘Interdisciplinary
(
Cooperation Team’’ Program for Science and Technology
Innovation (CAS) are also appreciated.
Notes and references
1
(a) E. Andre, A. Georges and A. Serge, C. R. Seances Acad. Sci., Ser. C,
1967, 264, 1855; (b) E. Andre and I. Georges, Bull. Soc. Chim. Fr., 1964,
1
1, 2897; (c) E. Andre and P. Rene, Bull. Soc. Chim. Fr., 1962, 292.
2
For recent reviews on C–H activation, see: (a) X. Chen, K. M. Engle,
D.-H. Wang and J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094;
(
b) K. Muniz, Angew. Chem., Int. Ed., 2009, 48, 9412; (c) L. Ackermann,
R. Vicente and A. R. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792;
d) P. Sehnal, R. J. K. Taylor and I. J. S. Fairlamb, Chem. Rev., 2010,
10, 824; (e) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010,
110, 1147; ( f ) L.-M. Xu, B.-J. Li, Z. Yang and Z.-J. Shi, Chem. Soc.
Rev., 2010, 39, 712; (g) J. Wencel-Delord, T. Dr ¨o ge, F. Liu and F. Glorius,
Chem. Soc. Rev., 2011, 40, 4740; (h) C. S. Yeung and V. M. Dong, Chem.
Rev., 2011, 111, 1215; (i) C. Liu, H. Zhang, W. Shi and A. Lei, Chem. Rev.,
2011, 111, 1780; ( j) L. Ackermann, Chem. Rev., 2011, 111, 1315;
(k) S. R. Neufeldt and M. S. Sanford, Acc. Chem. Res., 2012, 45, 936;
(
1
Scheme 3 Proposed mechanism.
compound 3a is stable in CHCl
3
, and readily tautomerizes to
0
8
3
a in DMSO. To test the real isomer involved in our reaction
1
cycle, we conducted H-NMR analysis of 3a, and found it indeed
(
l) B.-J. Li and Z.-J. Shi, Chem. Soc. Rev., 2012, 41, 5588; (m) A. J.
Hickman and M. S. Sanford, Nature, 2012, 484, 177.
3 (a) L. McMurray, F. O’Hara and M. J. Gaunt, Chem. Soc. Rev., 2011,
0, 1885; (b) J. Yamaguchi, A. D. Yamaguchi and K. Itami, Angew.
0
existed as 3a in CDCl , but immediately converted to 3a when a
3
few drops of TFA was added to the CDCl solution (Scheme 3,
also see ESI†).
3
4
Chem., Int. Ed., 2012, 51, 8960; (c) J. Wencel-Delord and F. Glorius,
Meanwhile, two additional substrates, 4,4-dimethyl-1-phenyl-
Nature, 2013, 5, 369.
1
H-pyrazol-5(4H)-one and N-methyl 1,5-dimethyl-2-phenyl-1H-
4 For selected examples of C–C & C–N formation, see: (a) C. Zhu,
R. Wang and J. R. Falck, Chem.–Asian J., 2012, 7, 1502; (b) B.-J. Li,
S.-L. Tian, Z. Fang and Z.-J. Shi, Angew. Chem., Int. Ed., 2008, 47, 1115;
pyrazol-3(2H)-one, were employed as substrates for the Pd-catalyzed
C–H activation/arylation. Only the former substrate underwent the
reaction to provide the arylated product in 72% yield, whereas the
reaction with the latter substrate did not occur (see ESI†). This
result suggested that the imino N-2 other than the carbonyl-O
in pyrazol-5(4H)-ones 3 acted as the directing group in the
current reaction.
(c) D.-D. Li, T.-T. Yuan and G.-W. Wang, Chem. Commun., 2011,
47, 12789; (d) J.-H. Chu, P.-S. Lin, Y.-M. Lee, W.-T. Shen and M.-J.
Wu, Chem.–Eur. J., 2011, 17, 13613; (e) S. Rakshit, C. Grohmann,
T. Besset and F. Glorius, J. Am. Chem. Soc., 2011, 133, 2350; ( f ) G.-W.
Wang, T.-T. Yuan and D.-D. Li, Angew. Chem., Int. Ed., 2011, 50, 1380;
(g) J. Karthikeyan and C.-H. Cheng, Angew. Chem., Int. Ed., 2011,
5
0, 9880; (h) J. Karthikeyan, R. Haridharan and C.-H. Cheng, Angew.
Chem., Int. Ed., 2012, 51, 12343; (i) L. Wang, W. Guo, X.-X. Zhang,
Based on these experimental outcomes and by referring
X.-D. Xia and W.-J. Xiao, Org. Lett., 2012, 14, 740.
5 (a) D. Shabashov and O. Daugulis, Org. Lett., 2005, 7, 3657;
4
b,f,12,13
to the leading references,
proposed (Scheme 3, based on the model reaction of 3a and 5a).
First, substrate 3a tautomerized to 3a in TFA and then under-
a tentative mechanism was
(
b) K. L. Hull and M. S. Sanford, J. Am. Chem. Soc., 2007, 129, 11904.
(a) N. R. Deprez and M. S. Sanford, J. Am. Chem. Soc., 2009, 131, 11234;
b) C. S. Yeung, X. Zhao, N. Borduas and V. M. Dong, Chem. Sci., 2010,
6
0
(
went the first C–H activation to generate a palladacycle inter-
1, 331; (c) C. S. Yeung and V. M. Dong, Synlett, 2011, 974; (d) D. Kalyani,
K. B. McMurtrey, S. R. Neufeldt and M. S. Sanford, J. Am. Chem. Soc.,
4
f
mediate I. Oxidative addition of iodide 5a to the palladacycle I
2011, 133, 18566; (e) S. R. Neufeldt and M. S. Sanford, Adv. Synth.
IV
yielded a Pd species II which then underwent a reductive
Catal., 2012, 354, 3517.
elimination in the presence of AgOAc to produce compound
7 (a) T. Watanabe, M. Tahara and S. Todo, Cardiovasc. Ther., 2008,
26, 101; (b) R. Tabrizch, Curr. Opin. Invest. Drugs, 2000, 1, 347;
0
II
4
aa and AgI, along with regeneration of the Pd species for the
(
c) Y.-J. Jin, T. Mima, V. Raicu, K. C. Park and K. Shimizu, Neurosci.
0
next catalytic cycle. Compound 4aa shifted to the tautomer 4aa
Res., 2002, 43, 75; (d) The Edaravone Acute Brain Infarction Study
Group (Chair: E. Otomo, MD), Cerebrovasc. Dis., 2003, 15, 222.
8 S. Pal, J. Mareddy and N. S. Devi, J. Braz. Chem. Soc., 2008, 19, 1207.
in CDCl
3
. Meanwhile, further C–H activation and palladation of
0
4aa resulted in a seven-membered palladacycle III, which was
9
For selected examples, see: (a) M. Desroses, M.-C. Jacques-Cordonnier,
S. Llona-Minguez, S. Jacques, T. Koolmeister, T. Helleday and M. Scobie,
Eur. J. Org. Chem., 2013, 5879; (b) M. S. Chande, P. A. Barve and
V. Suryanarayan, J. Heterocycl. Chem., 2007, 44, 49; (c) Z.-L. Tao, W.-Q.
Zhang, D.-F. Chen, A. Adele and L.-Z. Gong, J. Am. Chem. Soc., 2013,
then followed by a reductive elimination/C–N bond formation
0
to produce Pd and the cyclized product 1a. With the assistance
0
II
2 2 8
of K S O , the produced Pd was then oxidized to Pd for
further reaction.
135, 9255; (d) N. Uramaru, H. Shigematsu, A. Toda, R. Eyanagi,
In conclusion, we have successfully developed a novel one-
pot cascade synthesis to conveniently construct the unique
class of benzo[c]pyrazolo[1,2-a]cinnolin-1-ones in good yields.
This strategy includes a two-step/double C–H activation process:
first C–H activation/arylation coupled with second C–H activation/
intramolecular C–N bond formation. This approach not only
offers the first example using the pyrazolone moiety as an
internal directing group for C–H activation/functionalization,
but also provides a new access to re-investigate this polycyclic
skeleton since its first synthesis reported in the 1960s.
S. Kitamura and S. Ohta, J. Med. Chem., 2010, 53, 8727; (e) L. Liu,
M. H. Norman, M. Lee, N. Xi, A. Siegmund, A. A. Boezio, S. Booker,
D. Choquette, N. D. D’ Angelo, J. Germain, K. Yang, Y. Yang, Y. Zhang,
S. F. Bellon, D. A. Whittington, J.-C. Harmange, C. Dominguez, T.-S. Kim
and I. Dussault, J. Med. Chem., 2012, 55, 1868.
0 O. Daugulis and V. G. Zaitsev, Angew. Chem., Int. Ed., 2005, 44, 4046.
1 M. D. K. Boele, G. P. F. van Strijdonck, A. H. M. de Vries, P. C. J. Kamer,
J. G. de Vries and P. W. N. M. van Leeuwen, J. Am. Chem. Soc., 2002,
124, 1586.
1
1
1
2 (a) C. S. Yeung, X. Zhao, N. Borduas and V. M. Dong, Chem. Sci.,
2
2
010, 1, 331; (b) W.-W. Chan, Z. Zhou and W.-Y. Yu, Chem. Commun.,
013, 49, 8214.
13 H. Li, R.-Y. Zhu, W.-J. Shi, K.-H. He and Z.-J. Shi, Org. Lett., 2012, 14, 4850.
1
684 | Chem. Commun., 2014, 50, 1682--1684
This journal is ©The Royal Society of Chemistry 2014