When aryldiazonium salts meet vinyl diazoacetates: A cobalt-catalyzed regiospecific synthesis of N-arylpyrazoles

Article abstract of DOI:10.1021/ol5012339

A cobalt-catalyzed C-N bond formation between aryl diazonium salts and vinyl diazoacetates has been developed under relatively mild conditions. The N-arylpyrazoles have been prepared in moderate to high yields in a regiospecific way.

Full text of DOI:10.1021/ol5012339

Letter
pubs.acs.org/OrgLett
When Aryldiazonium Salts Meet Vinyl Diazoacetates: A
Cobalt‑Catalyzed Regiospecific Synthesis of N‑Arylpyrazoles
Haiheng Guo, Daming Zhang, Chenghao Zhu, Jian Li, Guangyang Xu, and Jiangtao Sun*
School of Pharmaceutical Engineering & Life Science, Changzhou University, Changzhou 213164, P. R. China
S
* Supporting Information
ABSTRACT: A cobalt-catalyzed C−N bond formation between
aryl diazonium salts and vinyl diazoacetates has been developed
under relatively mild conditions. The N-arylpyrazoles have been
prepared in moderate to high yields in a regiospecific way.
ryldiazonium salts are important active intermediates and
have found wide applications in various organic trans-
arylpyrazole relies on the condensation of aryl-hydrazines with
A
1,3-dicarbonyl compounds or synthetic equivalents (Scheme
formations1 such as in the construction of the C−Y bond (Y =
Cl, Br, CN, etc.) via a Sandmeyer-type reaction,1,2 as reactive
arylhalide surrogates in Pd-catalyzed3 as well as visible-light
mediated1b,4 C−C bond formation, and in generating C−B5
and C−S6 bonds (Figure 1). Recent reports highlighted the use
1A-a).13 Alternatively, the 1,3-dipolar cycloaddition of diazo
Scheme 1. Synthesis of N-Arylpyrazoles
compounds or surrogates with alkynes/alkenes14 followed by
metal-catalyzed cross-coupling15 has been another powerful
tool (Scheme 1A-b). However, regioselective control is often
problematic in these procedures. Nevertheless, the develop-
ment of an efficient protocol for the synthesis of N-
arylpyrazoles in a regiospecific way is still a challenging task.
Herein, we describe the development of a cobalt-catalyzed
approach in the use of aryldiazonium salts and vinyl
diazoacetates to achieve this goal.
Recently, we have been interested in the development of
novel synthetic protocols with diazo compounds.16 As often
observed and also reported by Davies and others,17 the vinyl
diazoacetates are unstable and would undergo a spontaneous
Figure 1. Aryldiazonium salts in organic transformation.
of aryldiazonium salts as efficient radical precursors in
trifluoromethylations,8 aminosulfonylation,9 trifluoromethyl-
thiolation,10 and stannylation11 via novel Sandmeyer-type
reactions. However, the utilization of aryldiazonium salts as
an aryl cation or aryl-metal cation precursor for C−N bond
formation is rare.7 Clearly, it is still highly desirable to develop a
novel transformation from inexpensive and readily available
aryldiazonium salts.
On the other hand, the N-arylpyrazole moiety has been
found in numerous synthetic pharmaceuticals and leading
compounds with a broad scope of pharmacological proper-
ties.12 Generally, the common approach for the synthesis of N-
Received: April 30, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
a
[1,5]-cycloaddition to produce pyrazole II, which occurred
more or less as a side reaction in vinyl diazoacetates involved in
transformations (Scheme 2, route A).17c Based on this
Table 1. Optimization of the Reaction Conditions
a
Scheme 2. Proposed Strategy
b
entry
catalyst
solvent
yield (%)
1
no
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
7 (1:1)
12 (10:1)
10 (5:1)
15 (10:1)
45 (8:1)
42
2
Rh(OAc)2
[Cp*RhCl2]2
[RuCl2(p-cymene)]2
Fe(acac)3
FeCl3
3
4
5
6
7
Pd(TFA)2
PdCl2
8 (2:3)
19 (10:1)
40 (10:1)
36 (7:1)
50 (12:1)
58 (10:1)
messy
8
9
Cu(OAc)2
CuBr
10
11
12
13
Mn(OAc)2
Co(OAc)2
CoCl2
c
14
CoBr2
51 (10:1)
54 (10:1)
68 (15:1)
54 (9:1)
−
−
−
−
messy
a
15
16
17
18
19
20
21
Co(acac)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
The atom hydrogen and substituents have been omitted for clarity.
CH3CN
dioxane
DMF
DMSO
toluene
DCE
phenomenon and the nature of the three resonance structures
of vinyl diazoacetates, we envisaged that the introduction of an
in situ formed cation [M−X] would probably prioritize
coupling with diazo to afford intermediate III, which then
might relay the cyclization to yield IV along with the recovery
of the metal catalyst (Scheme 2, route B). However, to realize
this hypothesis, the potential reaction system would be inactive
toward the rapid decomposition of vinyl diazoacetates to avoid
side reactions (Scheme 2, route C). Also, this system should
reduce or suppress route A if II was stable and unable to
undergo direct coupling with the cation precursor (Scheme 2,
route D). So with a view to maximize route B and increase the
yield of IV, a suitable catalytic system must be developed not
only to promote this relay cyclization but also to minimize the
undesired side reactions.
Based on the above hypothesis, we utilized a diazonium salt
(1a) and vinyl diazoacetate (2a) as model substrates for the
initial investigation in the presence of various metal complexes
(10 mol %) (Table 1). Among the metal complexes examined,
the use of Co(OAc)2 provided 3a in the highest yield with also
better selectivity (Table 1, entry 12) and Co(acac)2 gave a
slightly lower yield (Table 1, entry 13), while Fe(acac)3 and
Mn(OAc)2 displayed moderate catalytic activity (Table 1,
entries 5 and 11). However, the commonly used metal
complexes for diazo decomposition such as rhodium,
ruthenium, and palladium gave poor results, which probably
attributed to the strong ability for rapid decomposition of the
diazo moiety to bring about undesired side reactions (Table 1,
entries 2 to 4). Next, after screening a variety of solvents, we
were pleased to find dichloroethane (DCE) was the best choice
(Table 1, entry 16), while acetonitrile (CH3CN) afforded a
slightly lower yield (Table 1, entry 17). However, the reaction
was totally inert when dioxane, DMF, DMSO, and toluene were
used (Table 1, entries 18 to 21). In addition, a higher
temperature was detrimental to the transformation (Table 1,
entry 22) and a lower catalyst loading also gave a lower yield
(Table 1, entry 23). A lower reaction temperature gave almost
the same result (Table 1, entry 24). It is of note that 3a and 3a′
were obtained almost in a 1:1 ratio in very low yield without
c
22
d
23
DCE
60 (15:1)
67 (15:1)
e
24
DCE
a
All reactions were carried out with 1a (0.3 mmol), 2a (0.25 mmol),
metal complex (0.025 mmol, 0.1 equiv), and solvent (3 mL) under a
nitrogen atmosphere at rt for 12 h unless otherwise noted. Isolated
yields of 3a. The ratios in parentheses were determined by NMR
b
c
analysis of crude products. Reaction was performed at 60 °C for 3 h.
d
e
With 5 mol % Co(OAc)2. Reaction was performed at 0 °C for 12 h.
addition of any metal catalyst (Table 1, entry 1). Also, 3a′ was
detected in a low ratio for most of the cobalt-catalyzed
processes. Moreover, the use of FeCl3 made the reaction very
clean but resulted in a lower yield (Table 1, entry 6).
Under the above optimized conditions, the scope of the vinyl
diazoacetates was evaluated with regard to diazonium salt 1a as
the standard substrate (Scheme 3). As observed, all of the
reactions proceeded smoothly and appeared to tolerate a wide
range of vinyl diazoacetates. In general, for the arylvinyl
diazoacetates examined, the phenyl ring bearing electron-
withdrawing substituents gave higher yields than the electron-
donating substituted substrates. The thiophene vinyl diazo-
acetate was also subjected to this reaction and delivered the
corresponding pyrazole in 68% yield (Scheme 3, 3i). In
addition, the use of alkyl vinyl diazoacetates also led to the
pyrazoles in moderate yields (Scheme 3, 3j−3l).
Next, we explored the reaction of different phenyl diazonium
salts, such as para-methyl-phenyl, para-chloro-phenyl, ortho-
bromo-phenyl, and 1,5-ditrifluoromethyl-phenyl diazonium
salts, with a variety of vinyl diazoacetates under the optimal
reaction conditions. The results were summarized in Scheme 4.
In general, for the same vinyl diazoacetates employed, para-
chloro phenyl diazonium salt gave the corresponding N-
arylpyrazoles in higher yields than para-methyl phenyl
diazonium salt. The highest yield was obtained from the
B
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Organic Letters
Letter
a
,b
a
,b
Scheme 3. Substrate Scope
Scheme 4. Substrate Scope
a
All reactions were carried out with 1a (0.3 mmol), 2 (0.25 mmol),
and Co(OAc)2 (0.025 mmol), in DCE (3 mL) at room temperature
b
for 12 h. Isolated yields of 3.
reaction of para-chloro-phenyl diazonium salt and para-cyano-
phenyl vinyl diazoacetate, which afforded the corresponding
pyrazole in 82% isolated yield (Scheme 4, 4k). Additionally, the
alkyl vinyl diazoacetates were also tolerated in this procedure
(Scheme 4, 4f, 4l). Remarkably, the reaction of para-chloro-
phenyl diazonium salt with ethyl and tert-butyl styryldiazo-
acetates gave better yields than methyl styryldiazoacetate
(Scheme 4, 4q and 4r to 4p).
To better understand the reaction mechanism, we conducted
further investigations (Scheme 5). First, diazonium salt (1c)
treated with TEMPO and TEMPO-Ph was not isolated
(Scheme 5a). Second, when TEMPO was added to the
reaction mixture of 1c and ethyl-vinyl diazoacetate, N-
arylpyrazole (4l) was still isolated in 18% yield although most
of vinyl diazoacetate has been oxidized to the ketone ester
(Scheme 5b). These results suggested that the aryl radical is not
involved as a reactive species. Third, treated 1c with water
under the optimal conditions gave phenol in high yield
(Scheme 5c). The direct coupling between pyrazole (3a′) and
1c was investigated. The pyrazole was not obtained, and the
two staring materials had been recovered (Scheme 5d). Finally,
unlike the addition of rhodium and copper catalysts to the
solution of 2a, no bubble emission was observed even with 20
mol % of Co(OAc)2 and most of 2a was recovered (Scheme
5e). In contrast, slow gas emission was observed when 1c was
treated with Co(OAc)2 (Scheme 5f). These control experi-
ments indicated that the two nitrogen atoms of the N-
arylpyrazoles probably came from vinyl diazoacetates.
a
All reactions were carried out with 1 (0.3 mmol), 2 (0.25 mmol), and
Co(OAc)2 (0.025 mmol), in DCE (3 mL) at room temperature for 12
h. Isolated yields of 4.
b
Scheme 5. Further Exploration
Based on the above experiments, a plausible reaction
mechanism is proposed in Scheme 6. First, the oxidative
addition of Co(OAc)2 to phenyldiazonium salt (1a) generates
the cationic phenyl-cobalt complex A and simultaneously
releases one molecule of nitrogen. Second, coupling of vinyl
diazoacetate (2a) with cation A gives the formation of
intermediate B, which would subsequently undergo [1,5]-
cycloaddition to afford intermediate C. Then subsequent
tautomerization and loss of hydrogen deliver intermediate D.
Finally, reductive elimination would furnish the target product
as well as recover the cobalt catalyst.
C
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Organic Letters
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Scheme 6. Plausible Catalytic Cycle
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In summary, we have demonstrated a novel strategy for the
regiospecific synthesis of N-arylpyrazoles through the cobalt-
catalyzed coupling reactions of vinyl diazoacetates and aryl
diazonium salts. This protocol featured a very cheap cobalt
catalyst, mild reaction conditions, easily available starting
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useful synthetic methodology toward N-arylpyrazoles. More
importantly, a cobalt-catalyzed cation cyclization is crucial for
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures along with characterizing data and
copies of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
Int. Ed. 2013, 52, 7219. (e) Tang, M.; Zhang, Y.; Kong, Y. Org. Biomol.
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■
*E-mail: jtsun08@gmail.com or jtsun@cczu.edu.cn.
Notes
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Biomol. Chem. 2013, 11, 5998. (b) Liu, G.; Xu, G.; Li, J.; Ding, D.; Sun,
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J.; Wang, G.; Sun, J. Org. Biomol. Chem. 2014, 12, 2533. (d) Ding, D.;
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(No. 21172023), Applied Basic Research Plan of Changzhou
(CJ20120029), the Science & Technology department of
Jiangsu Province (BY0212096), and the Priority Academic
Program Development of Jiangsu Higher Education Institutions
for their financial support.
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