A new synthesis of pyrazoles through a Lewis acid catalyzed union of 3-ethoxycyclobutanones with monosubstituted hydrazines

Article abstract of DOI:10.1021/ol2002682

A new efficient and convenient approach toward the synthesis of pyrazoles is described. Through a Lewis acid catalyzed union of 3-ethoxycyclobutanones with monosubstituted hydrazines, a variety of pyrazole derivatives were prepared readily at ambient temp

Full text of DOI:10.1021/ol2002682

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1746–1749
A New Synthesis of Pyrazoles through a
Lewis Acid Catalyzed Union of
3-Ethoxycyclobutanones with
Monosubstituted Hydrazines
Gang Shan, Pengfei Liu, and Yu Rao*
Department of Pharmacology and Pharmaceutical Sciences, School of Life Sciences and
School of Medicine, Tsinghua University, Beijing 100084, China
yrao@mail.tsinghua.edu.cn
Received January 27, 2011
ABSTRACT
A new efficient and convenient approach toward the synthesis of pyrazoles is described. Through a Lewis acid catalyzed union of
3-ethoxycyclobutanones with monosubstituted hydrazines, a variety of pyrazole derivatives were prepared readily at ambient temperature
with complete regioselectivity.
Pyrazoles and their derivatives represent an important
class of compounds that find extensive use in the pharma-
ceutical industry.1 Compounds containing a pyrazole mo-
tif are being developed in a wide range of therapeutic areas
including metabolic, CNS, and oncological diseases.2 To
date, a number of pyrazole-containing compounds have
been successfully commercialized, such as Celebrex, Via-
gra, and Acomplia.3 Substituted pyrazole derivatives have
also been employed as ligands for transition-metal-cata-
lyzed cross-coupling reactions.4
Due to the important applications of pyrazoles, their
synthesis has been extensively studied.5,6 By far the two
most prevalent strategies for constructing pyrazole rings
are the classic Knorr pyrazole synthesis7 and 1,3-dipole
(1) (a) Elguero, J. Comprehensive Heterocyclic Chemistry; Katritzky,
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r
10.1021/ol2002682
Published on Web 03/07/2011
2011 American Chemical Society

cycloaddition of diazoalkanes or nitrile imines with olefins
or alkynes (Scheme 1a,b).8 The Knorr synthesis, however,
suffers from a lack of regiospecificity.9 On the other hand,
the difficulty in preparing and handling reactive 1,3-di-
poles often limitstheir synthetic application.10 Therefore, a
general, convenient, and complementary method for pyr-
azole synthesis is highly desired.
bond of the cyclobutanone ring to form a zwitterionic
intermediate,14 which then reacts with ketones, aldehydes,
silyl enol ethers, or allylsilanes to construct the corresponding
cyclic compounds. In those cases, 3-ethoxycyclobutanones
were used as a formal 1,4-dipole to afford a six-member ring.
To the best of our knowledge, 3-ethoxycyclobutanones have
never been employed as a 1,3-dicarbonyl synthon to prepare
heterocyclic compounds such as pyrazoles.
Here in this paper, we report a new efficient and
convenient approach to prepare pyrazole derivatives with
complete regioselectivity by employing 3-ethoxycyclobu-
tanones as 1,3-dicarbonyl synthons for reaction with
monosubstituted hydrazines (Scheme 1c). We postulate
that intramolecularly trapping this zwitterionic intermedi-
ate through a preformed or in situ generated NH-contain-
ing hydrazone that could be prepared from 3-ethoxycy-
clobutanone with hydrazine would result in the formation
of the corresponding pyrazole derivatives.
Scheme 1. General Strategies for Construction of Pyrazole
Rings
Accordingly, a model study was initiated with 2,2-dimethyl
3-ethoxycyclobutanone and TsNHNH2 as substrates. First,
we tried a two-step protocol to test our hypothesis (Scheme
2a). As a Lewis acid catalyst, 0.5 equiv of SnCl4 was added
to the preformed hydrazone 2. The reaction was very fast
and went to completion in 30 min at room temperature.
Delightfully the desired product was obtained in 80%
yield. Two one-pot protocols were then examined
(Scheme 2b) with different Lewis acid addition times. It
was observed that the one-pot synthesis also went
smoothlyand gavethe samepyrazoleproduct3 inexcellent
yields. Interestingly, even in the presence of SnCl4, hydra-
zone 2 was formed prior to the ring openning of 2,2-
dimethyl 3-ethoxycyclobutanone.
Cyclobutanones serve as important and versatile inter-
mediates in organic synthesis.11 Previous studies have
shown that 3-ethoxycyclobutanones can be utilized to
construct useful synthetic compounds such as silyloxy
dienes and bicyclobutanes.12 More recently, 3-ethoxycy-
clobutanones havebeen employed toprepare various types
of six-membered cyclic compounds.13 In those cases, it was
suggested that a Lewis acid activates 3-ethoxycyclobuta-
nones through cleavage of the more substituted C2-C3
Scheme 2. Preliminary Investigation with 2,2-Dimethyl
3-Ethoxycyclobutanone
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Chem. 2003, 68, 5381–5383. (c) Nakano, Y.; Hamaguchi, M.; Nagai, T.
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Tetrahedron Lett. 1999, 40, 2605–2606.
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After gaining these preliminary results, we started to
optimize this reaction by screening different conditions
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from cyclobutane derivatives: (a) Allart, E. A.; Christie, S. D. R.;
Pritchard, G. J.; Elsegood, M. R. J. Chem. Commun. 2009, 7339. (b)
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Org. Lett., Vol. 13, No. 7, 2011
1747

Table 1. Optimization of the Reaction Conditions
Table 3. Reaction Scope with Respect to 3-Ethoxycyclobuta-
nones and Monosubstituted Hydrazines
Entry
Catalyst
Condition
Yielda
1
BF3 OEt2
0.1 equiv, DCM, rt, 0.5 h
0.1 equiv, DCM, rt, 0.5 h
0.1 equiv, DCM, rt, 0.5 h
0.1 equiv, DCM, rt, 0.5 h
0.1 equiv, DCM, rt, 0.5 h
0.3 equiv, DCM, rt, 0.5 h
0.5 equiv, DCM, rt, 0.5 h
1.0 equiv, DCM, rt, 0.5 h
0.1 equiv, DCE, rt, 0.5 h
0.5 equiv, CH3CN, rt, 0.5 h
0.5 equiv, THF, rt, 0.5 h
0.1 equiv, DCM, 0 °C, 1 h
88%
82%
90%
53%
72%
88%
86%
74%
88%
79%
71%
85%
3
2
TiCl4
3
SnCl4
TMSOTf
TfOH
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
4
5
6
7
8
9
10
11
12
a Isolated yield.
Table 2. Reaction Scope with Respect to Monosubstituted
Hydrazines
a Isolated yield.
to apply these conditions to substituted aryl hydrazines such
as PhNHNH2, however, were not as successful as in the case
of TsNHNH2. After further screening of the conditions, we
a Isolated yield.
discovered that 0.5 equiv of BF3 OEt2 provided the most
suitable conditions for forming the pyrazole product with
PhNHNH2.
3
(Table 1). In the case of TsNHNH2, we found that in
addition to SnCl4, other Lewis acids, such as BF3 OEt2
Having identified these optimal conditions, we set out to
explore the scope for this new ring-opening-cyclization reac-
tion. As shown in Table 2, a variety of monosubstituted
hydrazines were reacted with 2,2-dimethyl 3-ethoxycyclobu-
3
and TiCl4, can catalyze pyrazole formation with almost
equally high levels of efficiency. In general, a small catalyst
amount, such as 0.10 or 0.30 equiv of SnCl4, can promote
the reaction as effectively as higher catalyst loadings. Itwas
observed that the reaction also proceeded smoothly in
various solvents, such as DCM, DCE, CH3CN, and
THF, and gave pyrazole 3 in good to excellent yields.
Lower temperatures only have a slight effect on the yield
and reaction time. Typically the reaction will proceed to
completion within 1 h in a fastand clean manner. Entry3in
Table 1 shows the best conditions for TsNHNH2. Attempts
tanone in the presence of either SnCl4 or BF3 OEt2. It was
3
found that both CbzNHNH2 and BzNHNH2 reacted readily
to furnish the corresponding pyrazole derivatives.15 Notably,
different aryl hydrazines produced the desired pyrazole pro-
ducts smoothly in good to excellent yields (Compounds 6-10,
(15) Highly sterically demanding tBuNHNH2 was also tried with
different Lewis acid catalysts. Only a trace amount of possible product
was observed by LC-MS analysis.
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Org. Lett., Vol. 13, No. 7, 2011

intermediate II ring-closes to form the less strained five-
membered ring intermediate III. Following this intramo-
lecular cyclization, a proton transfer provides intermediate
IV. Finally, elimination of one molecue of EtOH from IV
furnishes the pyrazole products.
Scheme 3. Plausible Mechanism
In conclusion, a concise, one-pot method has been
developed for the rapid synthesis of functionalized pyr-
azoles from easily accessible starting materials at ambient
temperature. This method has been found to be generally
useful for the preparation of a variety of pyrazole deriva-
tives some of which are difficult to make via conventional
approaches. The reaction demonstrates excellent reactiv-
ity, completeregioselectivity,16 andhighyields. By employ-
ing 3-ethoxycyclobutanones as synthons for a Lewis acid
catalyzed union withmonosubstitutedhydrazines, we have
shown, for the first time, that this 1,3-dicarbonyl synthon
acts as a complement to the four-carbon synthon of
3-ethoxycyclobutanones in [4 þ 2] cycloadditions.13
Further investigations using 3-ethoxycyclobutanones as a
three-carbon component in other chemical transforma-
tions are currently underway.
Table 2). In all cases, only one single product was isolated, and
no other regioisomer was obtained.
As illustrated in Table 3, the optimum reaction conditions
proved to be compatible with a variety of 3-ethoxycyclobu-
tanones which reacted with monosubstituted hydrazines to
readily provide different di- and trisubstituted pyrazole
derivatives in good to excellent yields. In particular, a
consistent complete regioselectivity of the reaction was
observed. Only single isomers were obtained in all examples.
A possible mechanism is demonstrated in Scheme 3.
Upon activation of the in situ generated hydrazone inter-
mediate I from 2,2-dimethyl 3-ethoxycyclobutanone (1)
with Lewis acids, the more substituted C2-C3 bond of the
hydrazone intermediate is broken down preferentially to
form a zwitterionic intermediate II. Subsequently the
Acknowledgment. This work was supported by the na-
tional ‘973’ grant from the Ministry of Science and Technol-
ogy (Grant No. 2011CB965300) and Tsinghua University
985 Phase II funds. We thank Dr. Y. Li (Massachusetts
Institute of Technology) and Prof. W. He (Tsinghua
University) for helpful discussions.
Supporting Information Available. Experimental pro-
cedures and characterization data of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Although NMR analysis of crude products did not reveal the
presence of the other regioisomers, theoretically the reaction could be
regioselective.
Org. Lett., Vol. 13, No. 7, 2011
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