A Regioselective Approach to Trisubstituted Pyrazoles via Palladium-Catalyzed Oxidative Sonogashira-Carbonylation of Arylhydrazines

Article abstract of DOI:10.1021/acs.orglett.7b01447

A palladium-catalyzed oxidative carbonylation of arylhydrazines and alkynes with balloon pressure CO/O₂ to afford trisubstituted pyrazoles in a one-pot manner has been developed. The formation of trisubstituted pyrazoles involves a sequential C-N bond cleavage, carbonylation, Sonogashira coupling, Michael addition, and intramolecular condensation cyclization tandem process. An unprecedented oxidative Sonogashira-carbonylation reaction of arylhydrazine plays a key role for such a facile approach to pyrazoles.

Full text of DOI:10.1021/acs.orglett.7b01447

Letter
pubs.acs.org/OrgLett
A Regioselective Approach to Trisubstituted Pyrazoles via Palladium-
Catalyzed Oxidative Sonogashira-Carbonylation of Arylhydrazines
Yongliang Tu, Zhenming Zhang, Tao Wang,* Jiamei Ke, and Junfeng Zhao*
Key Laboratory of Chemical Biology of Jiangxi Province, College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang, 330022, Jiangxi, P. R. China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed oxidative carbonylation of
arylhydrazines and alkynes with balloon pressure CO/O2 to
afford trisubstituted pyrazoles in a one-pot manner has been
developed. The formation of trisubstituted pyrazoles involves a
sequential C−N bond cleavage, carbonylation, Sonogashira
coupling, Michael addition, and intramolecular condensation
cyclization tandem process. An unprecedented oxidative Sonogashira-carbonylation reaction of arylhydrazine plays a key role for
such a facile approach to pyrazoles.
yrazole is an important motif for large varieties of natural
Pproducts and biomolecules, which exhibit remarkable
biological and therapeutic activities.1 For example, PNU-
32945 (I) is used as a nonnucleoside reverse transcriptase
inhibitor for treatment of HIV.2 Polysubstituted pyrazoles are
the core structures of a broad range of commercial available
drugs such as Rimonabant (II),3 CDPPB (III),1b Zoniporide
(IV),4 Celecoxib (V),5 and PDE5 inhibitor (VI) (Figure 1).6
Consequently, searching for efficient synthetic methodology for
pyrazole derivatives has attracted much attention.7
afford pyrazoles through an ynone intermediate, which was
formed in situ via Sonogashira coupling reaction of alkynes with
acyl chlorides12 or aryl iodides in the presence of CO,13 have
also been developed. Theoretically, two regioisomers can be
produced via 1,2-addition of the terminal nitrogen and 1,4-
addition of the terminal or internal nitrogen of hydrazine,
respectively (Scheme 1). Although excellent regioselectivity
could be obtained for methylhydrazine due to the stronger
nucleophilicity of the internal nitrogen of methylhydrazine,12d
the regioselectivity of arylhydrazines is still a challenge and
unpredictable which might be attributed to the similar
nucleophilicity of both nitrogen atoms of arylhydrazines
(Scheme 1).14 It is highly desirable to develop efficient reaction
systems for the synthesis of aryl substituted pyrazoles from
arylhydrazines with high efficiency and regioselectivity under
mild reaction conditions.
Since Loh and co-workers’ pioneering work in 2011,15
arylhydrazines aroused much attention in palladium-catalyzed
crossing-coupling reactions as environmentally friendly aryla-
tion reagents under aerobic oxidative reaction conditions
because N2 and H2O were the only byproducts.16 On the
other hand, palladium-catalyzed carbonylation has evolved into
a useful and straightforward synthetic strategy for introducing
one carbon unit to construct various carbonyl-containing
compounds.17 We envisioned that arylhydrazines could be
applied as an arylation reagent under oxidative carbonylation
reaction conditions18 to provide ynone, which could be trapped
by another molecular arylhyrazine to furnish pyrazoles (Scheme
1). Herein, we reported a novel method for the synthesis of
pyrazoles with excellent regioselectivity by a palladium-
catalyzed tandem reaction based on an unprecedented oxidative
Sonogashira-carbonylation of arylhydrazines.
Figure 1. Examples of pyrazole-containing bioactive compounds.
Traditional synthesis of multisubstituted pyrazoles usually
adopts addition condensation of hydrazines with carbonyl
derivatives,8 or cycloadditions of diazo compounds with alkenes
or alkynes.9 Moreover, hydrazones have also been employed as
starting materials in the synthesis of pyrazoles.10 Among the
reported methods, the addition condensation reaction of
hydrazine with ynones is featured as one of most efficient
strategies to construct pyrazoles.11 Recently, palladium-
catalyzed multicomponent cascade reactions of hyrdrazine to
Received: May 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01447
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Synthetic Strategies for Pyrazoles
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
ligand
solvent
yield (%)
1
Pd(OAc)2
Pd(dba)2
PdCl2
PPh3
PPh3
PPh3
PPh3
PPh3
Bpy
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
DMSO
EtOH
THF
59
2
47
3
49
4
Pd(TFA)2
Pd(acac)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
50
5
32
6
4
7
o-tol3P
Ph2PCy
DPPPy
DPPE
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
3
8
43
9
52
10
11
12
13
14
15
16
17
18
19
20
trace
ND
30
4
trace
3
c
DMF
DMF
DMF
DMF
DMF
DMF
d
e
40
62
ef
,
48
eg
,
72 (69)
81 (78)
egh
, ,
a
Initially, the Pd-catalyzed oxidative cascade carbonylation of
phenylhydrazine hydrochloride (1a) and phenylacetylene (2a)
with a balloon of CO/O2 (3:1) was investigated (Table 1; see
the Supporting Information for details). Fortunately, the
desired product 1,3,5-triphenyl-1H-pyrazole (3aa) was ob-
tained in 59% yield in the presence of Pd(OAc)2 (5 mol %) and
PPh3 (20 mol %) in DMF (Table 1, entry 1). Further screening
of the catalyst showed that other catalysts such as Pd(dba)2,
PdCl2, Pd(TFA)2, and Pd(acac)2 produced the corresponding
pyrazole (3aa) in lower yields (Table 1, entries 2−5).
Reaction condition: phenylhydrazine hydrochloride 1a (0.6 mmol),
phenylacetylene 2a (0.2 mmol), Et3N (2.0 equiv) in the presence of
Pd cat. (5 mol %), and ligand (20 mol %) in solvent (2.0 mL) at 100
°C for 8 h, with a balloon of CO/O2 (3:1). GC yield with
b
naphthalene as the internal standard. Isolated yield is in parentheses.
c
d
e
No Et3N. 1.0 equiv of Et3N was used. 4.0 equiv of Et3N was used.
f
g
h
2.0 equiv of 1a were used. 4.0 equiv of 1a were used. 50 mg of 4 Å
molecular sieve were used. Bpy = 2,2′-Dipyridyl, DPPPy = Diphenyl-2-
pyridylphosphine, DPPE = 1,2-Bis(diphenylphosphino)ethane, THF =
Tetrahydrofuran, DMF = N,N-Dimethylformamide, DMSO =
Dimethyl sulfoxide.
Ligand screening revealed that PPh3 was the best ligand in
this transformation (Table 1, entries 6−10). The solvent has a
remarkable effect on the reaction efficiency, and DMF was
identified as the best choice of solvent (Table 1, entries 11−
14). The base played a crucial role in this transformation, as a
higher yield up to 72% could be attained when 4.0 equiv of
Et3N were used (Table 1, entries 15−20). Gratifyingly, the
presence of 4 Å molecular sieve was helpful to improve the
reaction efficiency and 1,3,5-triphenyl-1H-pyrazole (3aa) could
be obtained in 78% isolated yield (Table 1, entry 20).
Under the optimized reaction conditions, the scope of
arylhydrazines 1 was investigated with alkyne 2a as the model
substrate (Scheme 2). It appears that the position of the
substituents on the phenyl ring has a very limited effect on the
reaction efficiency. The o-Me, m-Me, p-Me, p-Et, and p-tBu
substituted arylhydrazines all reacted smoothly and afforded the
pyrazole products (3ba−fa) in high yields (72%−84%).
Disubstituted substrates such as 3,4-dimethyl, 2,4-dimethyl,
and 3,5-dimethyl phenylhydrazines could also successfully
undergo the CO-insert cascade reaction with phenyl acetylene
to produce the corresponding products (3ga, 3ha, and 3ia) in
74%, 74%, and 73% yields, respectively. In addition, the strong
electron-donating group 4-OMe− is also tolerated. Moderate
electron-withdrawing substituent F− turned out to be
compatible under the standard reaction condition and gave
the corresponding pyrazole 3ka in moderate yield. However,
strong electron-withdrawing groups such as 4-cyano and 4-nitro
have a significant detrimental effect on the reaction efficiency
and prohibited the reaction completely (data not shown). It
should be noted that aliphatic hydrazines are also not valid
substrates for this transformation.
Next, the substrate scope regarding the alkyne partner was
further examined and the results are summarized in Scheme 3.
Generally, phenyl acetylenes with substituents such as p-Me, m-
Me, and p-tBu afforded the corresponding products (3ab−ad)
in good yields. In addition, phenyl acetylenes bearing a
methoxy group could afford the target products (3ae−af) in
50%−71% yields. The fluoro- and chloro-substituted phenyl
acetylene could also be used as valid substrates to produce 3ai
and 3aj in 63% and 61% yields. In addition, 4-bromophenyl
acetylene was also compatible with this reaction conditions to
afford the target product (3ak) albeit in low yield.19 The
structures of these pyrazoles were unambiguously assigned by
NMR and X-ray crystallography (see the Supporting
Information for details). Moreover, aliphatic alkynes could
also be tolerated to furnish pyrazoles (3am, 3an, and 3ao) in
moderate yields. However, phenyl acetylenes containing a
strong electron-withdrawing group such as a 4-cyano group
(3al) is not tolerated.
B
DOI: 10.1021/acs.orglett.7b01447
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Substrate Scope of Arylhydrazines
Scheme 4. Control Experiments
when phenylhydrazine reacted with ynone substrates (Scheme
4, eq 2). Therefore, we proposed that ynone should be a key
intermediate in this transformation. α,β-Alkynic hydrazones 5a
and 5b were synthesized and treated with the standard reaction
conditions. As expected, pyrazoles 3aa and 6a were obtained in
moderate yields. This experimental result unambiguously
excluded the possibility that the tandem process proceeded
with hydrazone as the intermediate (Scheme 4, eq 3).
a
Reaction conditions: 1 (0.8 mmol), 2a (0.2 mmol), 5 mol % of
Pd(OAc)2, 20 mol % of PPh3, 4.0 equiv of Et3N, and 4 Å molecular
sieve (50 mg) in 2.0 mL of DMF with a balloon of CO/O2 (3:1) at
100 °C for 8 h.
On the basis of the above experimental results, a plausible
reaction mechanism is proposed in Scheme 5. Arylpalladium
a
Scheme 5. Proposed Reaction Mechanism
Scheme 3. Substrate Scope of Terminal Alkynes
species A is formed in situ via an oxidative C−N cleavage of
arylhydrazine with the Pd(II) catalyst under atmospheric O2.
Subsequently, CO insertion of complex A results in
acylpalladium B. Then, the acyl palladium B reacts with the
terminal alkyne to afford ynone C and Pd(0). The active Pd(II)
species is regenerated by oxidation of Pd(0) with O2, and the
catalytic cycle is closed.20 On the other hand, the ynone C
undergoes a Michael addition reaction with another molecule
arylhydrazine via the terminal amino group to yield enamine
intermediate D. Finally, intramolecular condensation cycliza-
tion of intermediate D provides the target pyrazole product.21
In conclusion, we have developed a highly efficient
multicomponent reaction system for the synthesis of
trisubstituted pyrazoles with the unprecedented palladium-
catalyzed aerobic oxidative Sonogashira-carbonylation of
arylhydrazines with terminal alkynes and CO as the key step.
The reaction is believed to proceed through a five-step tandem
reaction including C−N cleavage, CO insertion, Sonogashira
coupling, Michael addition, and cyclization. Arylhydrazines
played two roles in this transformation. Importantly, excellent
regioselectivity was observed, and only one regioisomer was
a
Reaction conditions: 1 (0.8 mmol), 2a (0.2 mmol), 5 mol % of
Pd(OAc)2, 20 mol % of PPh3, 4.0 equiv of Et3N, and 4 Å molecular
sieve (50 mg) in DMF (2.0 mL) with a balloon of CO/O2 (3:1) at 100
°C for 8 h.
To highlight the utility of the synthetic method for pyrazoles,
we successfully scaled the reaction up to 5 mmol and obtained
product 3aa in 69% yield under standard conditions (Scheme 4,
eq 1). In order to gain insight into the reaction mechanism,
several control experiments were conducted. Under the
standard reaction conditions, the pyrazole products 3aa and
3ad could be obtained in 40% and 69% yields, respectively,
C
DOI: 10.1021/acs.orglett.7b01447
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01447.
Experimental procedures, compound characterization
data, copies of NMR spectra (PDF)
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Crystallographic data for compound 3ak (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhaojf@jxnu.edu.cn.
*E-mail: wangtao@jxnu.edu.cn.
ORCID
Junfeng Zhao: 0000-0003-4843-4871
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The National Natural Science Foundation of China (21462023,
21562026) and the Natural Science Foundation of Jiangxi
Province (20143ACB20007, 20153BCB23018, 20161BAB
213069) are acknowledged for support of this research.
(18) Tu, Y.; Yuan, L.; Wang, T.; Wang, C.; Ke, J.; Zhao, J. J. Org.
Chem. 2017, 82, 4970.
(19) The CCDC number of compound 3ak is 1548912. For more
details, see the Supporting Information.
(20) Tan, C.; Wang, P.; Liu, H.; Zhao, X. L.; Lu, Y.; Liu, Y. Chem.
Commun. 2015, 51, 10871.
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12104. (b) Zora, M.; Kivrak, A. J. Org. Chem. 2011, 76, 9379.
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DOI: 10.1021/acs.orglett.7b01447
Org. Lett. XXXX, XXX, XXX−XXX