In Situ Generation of Nitrilimines from Aryldiazonium Salts and Diazo Esters: Synthesis of Fully Substituted Pyrazoles under Room Temperature

Article abstract of DOI:10.1021/acs.orglett.8b00750

A novel one-pot synthesis for fully substituted pyrazoles has been well developed via the in situ generation of nitrilimines from aryldiazonium salts and diazo esters and a subsequent cycloaddition with 1,3-dicarbonyl compounds. High yields, mild conditio

Full text of DOI:10.1021/acs.orglett.8b00750

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
In Situ Generation of Nitrilimines from Aryldiazonium Salts and
Diazo Esters: Synthesis of Fully Substituted Pyrazoles under Room
Temperature
Ying Shao,*,†,‡ Hao Zheng,† Junfeng Qian,‡ and Xiaobing Wan*,‡
†Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Advanced Catalysis and Green Manufacturing
Collaborative Innovation Center, Changzhou University, Changzhou 213164, P. R. China
‡Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, P. R. China
S
* Supporting Information
ABSTRACT: A novel one-pot synthesis for fully substituted
pyrazoles has been well developed via the in situ generation of
nitrilimines from aryldiazonium salts and diazo esters and a
subsequent cycloaddition with 1,3-dicarbonyl compounds.
High yields, mild conditions, wide substrate scope, and
operational simplicity are the significant advantages of this
methodology.
Scheme 1. In Situ Generation of Nitrilimines
yrazole compounds are ubiquitous in natural products and
drug molecules.1 Due to their unique pharmacological
P
properties and biological activity, they occupy important
positions in heterocyclic compounds.2 Many pesticides, small
molecule drugs, and natural products contain the fragment of
pyrazoles, such as insecticide Pyrolan,3a Fipronil,3b anti-
inflammatory Celecoxib,3c and analgesic Novalgin.3d Unfortu-
nately, cyclocondensation of hydrazines with 1,3-dicarbonyl
compounds, the classic approach toward pyrazoles, often
suffered from poor regioselectivity.4 Recently, 1,3-dipolar
cycloadditions of diazo compounds with alkynes or alkenes has
shown excellent regioselectivity to produce pyrazoles.5 However,
in the majority of these methods, the access to fully substituted
pyrazoles was usually missed. Recently, Sun and co-workers
described an elegant cobalt-catalyzed synthesis of N-arylpyr-
azoles from aryldiazonium salts and vinyl diazoacetates in which
the two nitrogen atoms of pyrazoles were derived from the diazo
compounds.6 In general, the development of new and efficient
methods for the construction of fully substituted pyrazoles has
been both a challenge and a focus of synthetic chemistry.
Notably, nitrilimines as a 1,3-dipole have shown unique
potential, which could build diverse fully substituted pyrazoles.7
The most frequent method for the formation of nitrilimines was
the dehydrohalogenation of hydrazonoyl halides (Scheme 1a).8
However, the difficulties of preparing starting materials and the
necessity of bases cannot be underestimated. Apart from the
dehydrohalogenation methods, decomposition of tetrazolium9
or dehydrogenation of hydrazones10 also have been well explored
to generate nitrilimines, which suffered from the requirement of
complex raw materials, expensive and toxic catalysts, and harsh
conditions (Scheme 1b,c). Herein, we developed a fundamen-
tally different strategy to nitrilimines through the room
temperature coupling of aryldiazonium salts and diazo
compounds under mild conditions (Scheme 1d), leading to
fully substituted pyrazoles after its condensation with 1,3-
dicarbonyl compounds.
We chose acetylacetone 1a, ethyl diazoacetate 2a, and 4-
bromobenzenediazonium tetrafluoroborate 3a as model sub-
strates for the formation of fully substituted pyrazole 4a. After
extensive screening of different kinds of transition-metal salts,
Co3(PO4)2 was found to be the best catalyst and gave the desired
product 4a in 67% yield under room temperature (Table 1,
entries 1−7). The choice of solvent was also crucial for this
transformation: replacing CH3CN with other common solvents,
such as DCM, DCE, DMF, and i-PrOH, decreased the yield of
product 4a significantly (Table 1, entries 8−11). Fortunately,
when we increased the amounts of ethyl diazoacetate 2a and 4-
bromobenzenediazonium tetrafluoroborate 3a, the desired fully
substituted pyrazole 4a was obtained in a high yield of 85%
Received: March 6, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00750
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
substrate, the desired product 4q was obtained in moderate
50% yield. Naphthalene and polysubstituted aryldiazonium salt
could deliver the corresponding products 4r and 4s in moderate
yields, respectively. The exact structure of pyrazole 4e has been
conclusively confirmed by the single-crystal X-ray diffraction.
To further explore the diversity of this transformation, the
assessment of various diazo esters was performed, as shown in
Scheme 3. A variety of α-diazo esters could react well with acetyl-
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
Cu(OAc)2
solvent
yield (%)
1
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCM
49
53
28
54
50
45
67
42
45
<5
11
85
<5
ab
2
Fe(OTf)3
Scheme 3. Scope of Diazo Esters
3
MnCl4·4H2O
Co(OAc)2·4H2O
CoI2
4
5
6
Co(ClO4)2·6H2O
Co3(PO4)2
Co3(PO4)2
Co3(PO4)2
Co3(PO4)2
Co3(PO4)2
Co3(PO4)2
7
8
9
DCE
10
11
DMF
i-PrOH
CH3CN
CH3CN
c
12
c
13
a
All reactions were carried out with 1a (0.2 mmol), 2a (0.8 mmol), 3a
(0.28 mmol), catalyst (0.04 mmol), and solvent (1 mL) at room
b
temperature under air for 12 h unless otherwise noted. Isolated yields.
c
The molar ratio of 1a/2a/3a was 1:6:2.
(Table 1, entry 12). The control experiment suggested that
transition-metal catalyst was necessary for this pyrazole
formation reaction (Table 1, entry 13). For details on optimizing
reaction conditions, see Supporting Information.
With the optimized conditions in hand, we next explored the
substrate scopes of our reaction by screening different
aryldiazonium salts (Scheme 2). Aryldiazonium salts bearing
ab
Scheme 2. Scope of Aryldiazoium Salts
a
Reaction conditions: 1a (0.2 mmol), 2 (1.2 mmol), 3a (0.4 mmol),
Co3(PO4)2 (0.04 mmol, 20 mol %), and CH3CN (1 mL) for 12 h
b
under air. Isolated products.
acetone 1a and 4-bromobenzenediazonium tetrafluoroborate 3a,
leading to the corresponding products in moderate to high yields
(5a−5m). Notably, fully substituted pyrazoles bearing an alkenyl
or alkynyl group could also be prepared in moderate yields (5g−
5h), which can undergo further synthetic transformations.
Finally, we evaluated the scope of 1,3-dicarbonyl compounds
for this transformation (Scheme 4). Symmetrical 1,3-dicarbonyl
compounds, such as heptane-3,5-dione and 1,3-diphenylpro-
pane-1,3-dione, delivered the corresponding products 6a and 6b
in moderate yields. When unsymmetrical 1,3-dicarbonyl
compounds, such as 1-phenylbutane-1,3-dione, were used as
substrate, two isomers of pyrazoles 6c and 6c′ were generated
with good yields. Notably, the use of 1-phenylbutane-1,3-dione
generated the single product 6d in 40% yield.
Further experiments were conducted to gain insight into the
reaction mechanism, as shown in Scheme 5. When 15N-labeled
diazonium salt 3b′ was subjected to the model reaction, the 15N-
labeled product 4b′ was obtained in 61% yield (Scheme 5a). It
suggested that the nitrogen atom in the product was derived from
diazonium salts, rather than diazo compounds, which was
significantly different from Sun’s work.6 The condensation
product 7 of 1,3-dicarbonyl compound 1a and aryldiazoium salt
2a did not produce compound 4a under the standard conditions,
thus indicating that the condensation/cyclization was not
a
Reaction conditions: 1a (0.2 mmol), 2a (1.2 mmol), 3 (0.4 mmol),
Co3(PO4)2 (0.04 mmol, 20 mol %), and CH3CN (1 mL) for 12 h
under air. Isolated products.
b
either electron-donating groups or electron-withdrawing groups
at the para-position of the benzene rings produced the
corresponding pyrazoles in moderate to excellent yields (4b−
4k). In addition, aryldiazonium salts bearing electron-with-
drawing substituents at the meta-position of the benzene rings
also gave the corresponding products with good yields (4l−4o).
When ortho-methoxyl aryldiazonium salt was used as the
B
DOI: 10.1021/acs.orglett.8b00750
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
ab
which undergoes elimination to afford the desired fully
substituted pyrazole product 4.
Scheme 4. Scope of 1,3-Dicarbonyl Compounds
In conclusion, we have successfully developed a simple and
efficient approach for the synthesis of fully substituted pyrazoles
through the in situ generation of nitrilimines from aryldiazonium
salts and diazo esters and a subsequent 1,3-dipolar cycloaddition
with 1,3-dicarbonyl compounds. This reaction allows broad
functional group compatibility, mild and neutral reaction
conditions, easily available starting materials, and operational
simplicity. Further investigations will focus on the discovery of
other 1,3-dipolar cycloaddition reaction of nitrilimines generated
in situ from diazo compounds and aryldiazonium salts.
ASSOCIATED CONTENT
* Supporting Information
■
S
a
Reaction conditions: 1 (0.2 mmol), 2a (1.2 mmol), 3a (0.4 mmol),
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00750.
Co3(PO4)2 (0.04 mmol, 20 mol %), and CH3CN (1 mL) for 12 h
under air. Isolated products.
b
Experimental procedure, characterization data, copies of
1H and 13C NMR spectra (PDF)
Scheme 5. Probe for the Possible Mechanism
Accession Codes
CCDC 1813978 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yingshao@cczu.edu.cn.
*E-mail: wanxb@suda.edu.cn.
ORCID
Ying Shao: 0000-0002-7379-8266
Xiaobing Wan: 0000-0001-9007-2128
Notes
involved in this pyrazole formation reaction (Scheme 5b).
Notably, the nitrilimine generated in situ from hydrazonoyl
halide 8 resulted in the desired product 4a in 21% yield. When
Lewis acid Zn(OTf)2 was added to the reaction to promote the
enolization of 1,3-dicarbonyl, the product 4a was obtained in
72% yield (Scheme 5c).
Based upon the above results, and the literature, a plausible
catalytic cycle for this transformation was proposed, as shown in
Scheme 6. Initially, the reaction between diazo ester 2 and
aryldiazonium salt 3 forms intermediate A, which then converts
to intermediate B by releasing one molecule of N2. Next, B is
converted to a more stable intermediate C and then decomposes
to the nitrilimines D via the loss of HBF4.11 The 1,3-dipolar
cycloaddition between D and enol tautomer of 1,3-dicarbonyl
compound 1 stabilized by Co3(PO4)2 afforded intermediate E,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD)
and the NSFC (21572148 and 21272165).
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