Silver(I)-catalyzed facile synthesis of pyrazoles from propargyl N-sulfonylhydrazones

Article abstract of DOI:10.1021/jo800663g

(Chemical Equation Presented) A silver(I)-catalyzed facile formation of pyrazoles from propargyl N-sulfonylhydrazones has been disclosed. During the reaction, a migration of sulfonyl groups (Ts, Ms) was observed. Good functional group compatibility was observed under mild reaction conditions (at room temperature for 3-5 h). This methodology allows for the efficient and regioselective synthesis of 1,3- and 1,5-disubstituted and 1,3,5-trisubstituted pyrazoles.

Full text of DOI:10.1021/jo800663g

developed.3 Among them, the condensation of hydrazine with
1,3-dicarbonyl compounds and the nitrene insertion reaction are
widely employed strategies.4 However, the generality of these
reactions is debased by the severe reaction conditions or
multistep sequences usually required to access the starting
materials. Moreover, the frequent formation of regioisomeric
mixtures of unsymmetrical pyrazoles vitiates the appealing
generality of the methods. As a result, efforts have been and
are still being made to find and develop more general and
versatile synthetic methodologies for pyrazoles.
Silver(I)-Catalyzed Facile Synthesis of Pyrazoles
From Propargyl N-Sulfonylhydrazones
Young Tak Lee and Young Keun Chung*
Intelligent Textile System Research Center, Department of
Chemistry, College of Natural Sciences, Seoul National
UniVersity, Seoul 151-747, Korea
ykchung@snu.ac.kr
While we studied a synthesis of Grubbs’ catalyst, we found
that a reaction of propargyl N-tosylhydrazone 1a in the presence
of ruthenium and silver salt led to an isolation of 2a (eq 1).10
ReceiVed March 27, 2008
1
The formation of 2a was confirmed by H and 13C NMR,
HRMass, and an X-ray diffraction study. However, very
recently, the X-ray crystal structure of 2a was reported by
Makhova and his co-workers.11The formation of 2a suggested
that water molecules would take part in the reaction, presumably
due to the handling of the chemicals in the air. We closely
reexamined the reaction and found that the reaction was
catalyzed by the silver salt alone in the presence of moisture.
Thus, the formation of 2a involves a 5-endo-dig ring closure
A silver(I)-catalyzed facile formation of pyrazoles from
propargyl N-sulfonylhydrazones has been disclosed. During
the reaction, a migration of sulfonyl groups (Ts, Ms) was
observed. Good functional group compatibility was observed
under mild reaction conditions (at room temperature for 3-5
h). This methodology allows for the efficient and regiose-
lective synthesis of 1,3- and 1,5-disubstituted and 1,3,5-
trisubstituted pyrazoles.
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10.1021/jo800663g CCC: $40.75 2008 American Chemical Society
Published on Web 05/20/2008

TABLE 1. Screening the Reaction Conditionsa
TABLE 2. AgSbF6-Catalyzed Synthesis of Pyrazoles from
Propargyl N-Sulfonylhydrazonesa
time yieldb
entry
catalyst
solvent T (°C) (h)
(%)
1
2
3
4
5
6
7
8
10 mol % of AgSbF6
5 mol % of AgSbF6
5 mol % of AgBF4
5 mol % of AgOTf
5 mol % of AgPF6
5 mol % of AgClO4
CH2Cl2 15-20
CH2Cl2 15-20
CH2Cl2 15-20
CH2Cl2 15-20
CH2Cl2 15-20
CH2Cl2 15-20
3
3
3
3
3
3
3
18
89
88
83
66
53
76
n.r.c
55
10 mol % of [Au(PPh3)2]SbF6 CH2Cl2 15-20
10 mol % of PtCl2 toluene 80
a 0.5 mmol of 1f (0.169 g) in 5 mL of CH2Cl2 was used. b Isolated
yield. c n.r. ) no reaction.
followed by addition of water to the iminium ion intermediate
with a concomitant elimination of benzaldehyde. Under an
exclusion of water, pyrazole 3a was obtained in high yield
(eq 2).
Compound 3a was derived from an unprecedented sulfon-
amide migration to an alkenyl group. This is the first example
of silver(I)-catalyzed formation of pyrazoles from propargyl
N-sulfonylhydrazones. Four decades ago, a base-induced trans-
formation of dypnone tosylhydrazone to pyrazole was reported
by Sato and Watanabe.5 They used tosylhydrazones as diazo
precursors in the presence of base. The diazo compounds were
induced to react directly with alkenes or alkynes to synthesize
pyrazoles after additional step.6 We herein report our recent
results. Our newly developed reaction provides an efficient and
selective formation of 1,3,5-trisubstituted pyrazoles in high
yield.7
a 0.5 mmol of propargyl N-sulfonylhydrazone in 5 mL of CH2Cl2 was
used. b Isolated yield. c n.r. ) no reaction. d Reaction run using 10 mol
% of AgSbF6.
in high yields. Styrenyl hydrazones (entries 6, 7, 10, 11, and
12) were good substrates. The formation of a pyrazole derivative
was confirmed by an X-ray diffraction study of single crystals
of 3h (Figure 2, Supporting Information).10 For a reaction of
an aryl hydrazone containing a doubly substituted imine moiety
(entry 13), a higher loading of the catalyst (10 mol %) was
needed and two pyrazole compounds were obtained; the
expected product (3m) was isolated in 45% yield and the other
(3m′) derived from the expected product by elimination of
toluenesufinic acid (TsH) was obtained in 41%. When the
hydrazones possessing an alkyl group (entries 14 and 15) were
subjected to the reaction conditions, the expected products were
also obtained in high yields. The reaction also worked well with
an alkylsulfonyl group (entries 7 and 12). However, with the
N-benzoyl- or N-phenylhydrazones (entries 16 and 17, respec-
tively) treatment with AgSbF6 gave none of the desired products.
Using propargyl N-tosylhydrazone (1f) as a model compound,
we screened silver catalysts, including AgClO4, AgPF6, AgOTf,
AgBF4, and AgSbF6 (Table 1).
The reaction could be carried out under mild conditions: at
room temperature for 3 h. After the reaction, pyrazole 3f was
obtained in reasonable to high yield. The formation of 3f was
confirmed by 1H and 13C NMR. The yield was highly dependent
upon the counteranion and the best yield (88%) employs only
5 mol % of the catalyst with AgSbF6. We also used
[Au(PPh3)2]SbF6. However, no reaction was observed with it.
When PtCl2 was as a catalyst in toluene at 80 °C for 18 h, the
product was obtained in 55% yield. Thus, the reaction was
unique to silver catalysts. Formation of 3f suggested a reaction
involving a migration of the tosyl group.8 However, the
migration of the tosyl group is not common as a detosylation.9
Using AgSbF6 as a catalyst, we screened various propargyl
N-sulfonylhydrazones with a terminal alkyne (Table 2).
The reactions of aryl hydrazones with various functional
groups such as -Br, -F, -OMe, and -OH (entries 2-5)
afforded the pyrazole products in high yields without forming
any side reaction products. Treatment of alkenyl hydrazones
(entries 8 and 9) with silver catalyst also produced pyrazoles
We next investigated the synthesis of 1,3- and 1,5-disubsti-
tuted and 1,3,5-trisubstituted pyrazoles (Table 3).
Treatment of styrenyl hydrazones (entries 1-3) in the
presence of 5 mol % of the catalyst gave reasonable to high
yields. Introduction of a methyl group to propargyl in styrenyl
hydrazones (entry 3, 77%) slightly decreased the yield of the
reaction. Interestingly, reactions of p-methoxystyrenyl hydra-
zones (entries 4-6) gave higher yields with shortening of the
reaction time. Any side products were not isolated. Thus, 1,3-
and 1,5-disubstituted and 1,3,5-trisubstituted pyrazoles were
readily synthesized under mild reaction conditions.
J. Org. Chem. Vol. 73, No. 12, 2008 4699

TABLE 3. AgSbF6-Catalyzed Synthesis of Substituted Pyrazoles
SCHEME 1. Proposed Mechanism for Ag-Catalyzed
Pyrazole Synthesis
from Propargyl N-Sulfonylhydrazonesa
a 0.5 mmol of propargyl N-sulfonylhydrazone in 5 mL of CH2Cl2 was
used. b Isolated yield.
To find out whether the migration of the sulfonyl group occurs
in an intramolecular or intermolecular fashion, we performed a
crossover experiment (eq 3).
The reaction of a 1:1 mixture of 1g and 1k in the presence
of a catalytic amount of AgSbF6 gave the corresponding
products 3g and 3k in 31% and 30% yields, respectively, and
the crossover products 3l and 3f in 16% and 18% yields,
respectively. This result clearly indicates that migration of the
sulfonyl group proceeds in an intermolecular manner.
To get some insight about the reaction mechanism, a
deuterated substrate 1f(D) was subjected under the same reaction
conditions (eq 4).
SCHEME 2. Proposition of a Ag(I)-Substituted Allene
Intermediate
of the liberated deuterium to E leads to G through an
intermediate F and the intermediate G will undergo a subsequent
nucleophilic cyclization to give pyrazole derivatives with a
deuterium in 4 and 5 positions. An allenic intermediate was
proposed in the some Cu(I) and Au(I)-catalyzed reactions.12
In summary, we have reported a simple and efficient
procedure for the silver(I)-catalyzed formation of pyrazoles from
propargyl N-sulfonylhydrazone, especially affording 1,3,5-
trisubstituted pyrazoles. The procedures introduced here are
practically useful and good functional group-compatibility was
observed under mild reaction conditions. Further development
of the silver(I) catalyzed reactions and extension of the approach
to a wider range of valuable nitrogen heterocycles is underway.
The 1H NMR spectrum of the reaction product 3f(D) showed
two peaks at 7.59 and 6.37 ppm corresponding to the positions
4 and 5 of the pyrazole moiety, respectively, with a ratio of
0.3:0.7. Thus, the ratio of the deuterium at the positions at 3, 4,
and 5 was 1:0.7:0.3. The 2H NMR of 3f(D) showed two peaks
at 7.65 and 6.40 ppm with a ratio of 1.5:0.7. Because of
broadening, the two peaks corresponding to the positions 3 and
5 was merged in one peak at 7.65 ppm.
Although little mechanistic information has been obtained,
the following mechanism is proposed on the basis of the above
results (Scheme 1).
Upon coordination of the triple bond of 1, the enhancement
of electrophilicity of the alkyne gives rise to a subsequent
nucleophilic attack of the imine nitrogen atom on the electron-
deficient alkyne to yield the cyclized silver(I) intermediate B.
Deprotonation leads to the generation of ion pairs C. An attack
of the tosyl anion to the electron-deficient imine carbon followed
by protonation give the product 3.
The scrambling of the deuterium in the positions 4 and 5 of
pyrazole in eq 4 can be understood by proposition of a Ag(I)-
substituted allene intermediate, E (Scheme 2).
Experimental Section
General Procedure for AgSbF6-Catalyzed Synthesis of
Pyrazoles from Propargyl N-Sulfonylhydrazones. To a flame-
dried 10 mL Schlenk flask capped with a rubber septum containing
5 mL of dry CH2Cl2 were added 8.6 mg (5 mol %) of AgSbF6 and
0.5 mmol of propargyl N-sulfonylhydrazone sequentially in a
glovebox. The disappearance of the starting material was checked
by TLC analysis. After the starting material had disappeared, the
(12) Kuninobu, Y.; Inoue, Y.; Takai, K. Chem. Lett. 2007, 36, 1422–1423.
(a) Marion, N.; Diex-Gonzalez, S.; de Fremont, P.; Noble, A. R.; Nolan, S. P.
Angew. Chem., Int. Ed. 2006, 45, 3647–3650.
Removal of a deuterium allows the π-intermediate A to
rearrange to a silver-substituted allene intermediate, E. Addition
4700 J. Org. Chem. Vol. 73, No. 12, 2008

solvent was removed under reduced pressure. Flash chromatography
on silica gel eluting with hexane and ethyl acetate (v/v, 5:1) gave
the product.
helpful discussions. Y.T.L. thanks the Seoul Science Fellowship
and BK21 fellowship.
Supporting Information Available: Detailed experimental
procedures, new characterization data, 1H and 13C NMR spectra
of all compounds, and crystallographic data (CIF) of 3h. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported by the Korea
Research Foundation grant funded by the Korean Government
(MOEHRD) (KRF-2008-341-C00022 and KRF-2005-070-
C00072) and the SRC/ERC program of MOST/KOSEF (R11-
2005-065). We thank Prof. B. M. Kim and S. B. Park for their
JO800663G
J. Org. Chem. Vol. 73, No. 12, 2008 4701