Synthesis of polysubstituted pyrazoles by a platinum-catalyzed sigmatropic rearrangement/cyclization cascade

Article abstract of DOI:10.1021/ol502968c

A highly efficient Pt-catalyzed [3,3] sigmatropic rearrangement/cyclization cascade of N-propargylhydrazones is reported. The process provides expedient access to a variety of highly functionalized pyrazoles. The substrate has good substituted group compa

Full text of DOI:10.1021/ol502968c

Letter
pubs.acs.org/OrgLett
Synthesis of Polysubstituted Pyrazoles by a Platinum-Catalyzed
Sigmatropic Rearrangement/Cyclization Cascade
Jia-Jie Wen, Hai-Tao Tang, Kai Xiong, Zong-Cang Ding, and Zhuang-Ping Zhan*
Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, Fujian, P. R. China
S
* Supporting Information
ABSTRACT: A highly efficient Pt-catalyzed [3,3] sigmatropic rearrange-
ment/cyclization cascade of N-propargylhydrazones is reported. The
process provides expedient access to a variety of highly functionalized
pyrazoles. The substrate has good substituted group compatibility, and the
bioactive 3-CF3 pyrazoles could be synthesized easily with this method.
he [3,3] sigmatropic rearrangement of N-allylhydrazones,
first reported in 1973 by Stevens and co-workers,1 is an
efficient method for the assembly of complex molecules from
simple fragments such as hydrazines and aldehydes. The
rearrangement of these structures usually leads to a diazo
intermediate II (Scheme 1), which can eliminate a molecule of
Scheme 2. [3,3]-Rearrangement of N-Propargylhydrazones
T
Scheme 1. [3,3]-Rearrangement of N-Allylhydrazones
cascade (Scheme 2), demonstrating an alternative pathway in
which the diazo moiety of the intermidate 3 was retained to
allow the formation of a series of highly functionalized
pyrazoles.7
We first used the reaction conditions that we previously
employed to convert tosylhydrazone 4 to diene 5 (Scheme 2)
as a starting point for the optimization of reaction conditions.
Hence, the model substrate 1a was treated with a catalytic
amount of [CuPPh3I]4 (5 mol %) in PhCH3 under reflux for 24
h (Table 1, entry 1). However, no reaction occurred. We then
tested a range of other transition-metal catalysts, including
N2 to generate a variety of functionalized alkenes. Since the
initial discovery, various efforts have been made, mainly by
Thomson and co-workers, to expand the application scope of
these reactions.2−5 In comparison, similar reactions involving
N-propargylhydrazones were less studied. In 2013, we reported
the only set of examples of the [3,3] sigmatropic rearrangement
of N-propargylhydrazones for the stereoselective synthesis of
sufonyldienes 5 (Scheme 2).6 All of these reactions shared the
same mechanistic feature that included the labile diazo
intermediate invariably undergoing N2 extrusion and generating
an open-chain carbon backbone. Here, We report the synthesis
of polysubstituted pyrazoles7 from N-propargylhydrazones via a
PtCl4-catalyzed [3,3] sigmatropic rearrangement/cyclization
Received: October 8, 2014
Published: November 10, 2014
© 2014 American Chemical Society
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Letter
determined to comprise 5 mol % of PtCl4 as the catalyst,
toluene as the solvent, and heating the mixture to 120 °C for 7
h.
Table 1. Optimization of the Reaction Conditions
We next evaluated the scope of the reaction under the
optimal conditions by placing different substituents (R1, R2, R3,
R4) on various positions of the N-propargylhydrazone 1 (Table
2). The alkynyl position R2 was found to tolerate a diverse
Table 2. Synthesis of Polysubstituted Pyrazoles
a
Reaction conditions: 1a (50 mg), solvent (3 mL), in Schlenk tube.
NR = no reaction. Unstable product. Isolated yield.
b
c
d
a
CuBr, Cu(OTf)2, ZnCl2, NiCl2, Pd(OAc)2, PdCl2, AgOAc, and
AgOTf, all of which either did not lead to any detectable
product formation or resulted in unstable or complex
byproducts (Table 1, entries 2−9). However, the treatment
of 1a with PtCl2 furnished pyrazole 2a in 27% yield (Table 1,
entry 10). Experimentation with other Pt-based catalysts
revealed that the choice of PtCl4 could dramatically improve
the yield to 65% and shorten the reaction time necessary to 5 h
(Table 1, entry 11). Attempts to further enhance the efficiency
of product formation by screening different solvents were
unsuccessful (Table 1, entries 12−19). Additionally, lowering
the usage of PtCl4 to 5 mol % boosted the yield to 82% at the
expense of the reaction time which was prolonged to 7 h (Table
1, entry 20). Hence, the optimum reaction conditions were
Reaction conditions: 1 (50 mg), PhCH3 (3 mL), in Schlenk tube.
Isolated yield. NR = no reaction.
b
c
range of phenyl groups (Table 2, entries 1−4) substituted with
a halogen (Br), an electron-donating group (OMe), or an
electron-withdrawing group (NO2), and alkyl or alkenyl
substituents (Table 2, entries 5−6), such as butyl and
cyclohexenyl. Introducing a trimethylsilyl group, however,
seemed to completely abolish the pyrazole formation (Table
2, entry 7). The structure of 2b is further confirmed by single
crystal X-ray structure analysis (Figure 1).
Hydrazones derived from both aryl (including hereoaryls)
and alkyl aldehydes were suitable substrates (Table 2, entries
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A proposed mechanism for the Pt-catalyzed rearrangement/
cyclization cascade is illustrated in Scheme 4. First, the Pt-based
Scheme 4. Proposed Mechanism
Figure 1. X-ray crystal structure of 2b.
8−11, products 2h−2k, 53−71% yield). Branching at the
proparglic position was tolerated (R1 = n-penyl), and the
desired pyrazole was obtained in 58% yield (Table 2, entry 12).
The reaction seemed to be very sensitive to the substituent R4.
While substrate 1m carrying an electron-rich phenyl ring
afforded the product in 85% yield (Table 2, entry 13), the ones
with electron-withdrawing substituents, such as p-NO2Ph, Ts,
and Boc, either failed to react or led to a complex product
mixture (Table 2, entries 14, 16−17). Replacing the R4 phenyl
group with a cyclohexyl ring significantly lowered the product
yield to 38% (Table 2, entry 15).
3-Trifluoromethyl-substituted pyrazole is the core structure
of many bioactive molecules.8,9 As shown in Scheme 3, the
current method is highly efficient for the synthesis of these
structures with different substituents along the pyrazole ring,
but requires a longer reaction time (12 h). Of note is that a
terminal alkyne also reacted to give the desired pyrazole in 51%
yield (product 2u).
catalyst complexes with the triple bond of the reactant render
the latter electrophilic and therefore vulnerable to the
nucleophilic addition of the proximal hydrazone. The ensuing
cyclization results in vinylplatinum 6, which opens up to
generate diazoallene 7. Instead of decomposition via nitrogen
extrusion, the diazo nitrogen cyclizes onto the Pt-activated
allene to furnish the cyclic intermediate 8, which then converts
to the final product 2 and regenerates the Pt catalyst through
proton transfer. The cyclization efficiency of 7 hinges largely on
the nucleophilicity and the stability of the diazo group. If R4 is
Ts or Boc, we proposed intermediate 7 to be unstable and its
nitrogen atom to exhibit weak nucleophilicity, which would
lead to the complex reaction result here. In contrast, if R4 is
phenyl or alkyl, the conjugation or electron-donating effect will
stabilize the intermediate 7 as well as enhance the
nucleophilicity of its nitrogen atom, which will undergo a
further cyclization process to furnish the cyclic intermediate 8.
In addition, the stabilization effect of the alkyl group compared
to the phenyl is less, resulting in the related substrate giving the
low yield of the cyclic product.
a
,b
Scheme 3. Synthesis of 3-Trifluoromethylpyrazoles
In conclusion, we have reported a novel method for the
synthesis of pyrazoles from N-propargylhydrazones via a Pt-
catalyzed [3,3] rearrangement/cyclization cascade. The method
is applicable to a wide range of substrates and provides
convenient access to a variety of highly functionalized
pyrazoles, including medically important 3-trifluoromethyl-
pyrazoles.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all compounds and crystallographic
data (CIF) of 2b. This material is available free of charge via the
Internet at http://pubs.acs.org.
a
b
Reaction conditions: 1 (50 mg), PhCH3 (3 mL), in Schlenk tube.
Isolated yield.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zpzhan@xmu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from National Natural Science Foundation of
China (No. 21272190) and PCSIRT in University. We
sincerely thank Ting Li (Department of Chemistry, College
of Chemistry and Chemical Engineering, Xiamen University)
for his kindly help on the crystal structure analysis.
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