An effective and general method for the highly regioselective synthesis of 1-phenylpyrazoles from β-enaminoketoesters, tandem Blaise-acylation adducts

Article abstract of DOI:10.1039/b820324e

An effective and general route for the regioselective synthesis of 1-phenylpyrazoles has been developed from β-enaminoketoesters prepared by tandem Blaise-acylation. This method is applicable to a very broad range of substrates, generating a diverse set o

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www.rsc.org/obc | Organic & Biomolecular Chemistry
An effective and general method for the highly regioselective synthesis of
1-phenylpyrazoles from b-enaminoketoesters, tandem Blaise–acylation
adducts†
Young Ok Ko,a Yu Sung Chun,a Cho-Long Park,a Youngmee Kim,a Hyunik Shin,*b Sungho Ahn,c Jongki Hongc
and Sang-gi Lee*a
Received 13th November 2008, Accepted 3rd December 2008
First published as an Advance Article on the web 26th January 2009
DOI: 10.1039/b820324e
An effective and general route for the regioselective synthesis of 1-phenylpyrazoles has been developed
from b-enaminoketoesters prepared by tandem Blaise–acylation. This method is applicable to a very
broad range of substrates, generating a diverse set of 3-aryl-5-alkyl, 3-alkyl-5-aryl, 3,5-diaryl, and
3,5-dialkyl substituted pyrazoles regioselectively. The dichotomous regioselective synthesis of
isotopically discriminated 3-CD3-5-CH3 and 3-CH3-5-CD3 substituted pyrazoles showcases the power
of this protocol.
pyrazoles.9 In this case, simple arylation of 3,5-dialkyl pyrazoles
Introduction
with 4-fluoronitrobenzene resulted in poor regioselectivity, a prob-
Pyrazole is embedded as a prominent sub-structure in numerous
lem that was solved by the introduction of a chelating hydroxyalkyl
bioactive compounds exhibiting various activities1 such as anti-
group at the 3-position. However, this method required extra steps
inflammatory,1a–c analgesic,1d anti-bacterial,1e and anti-cancer.1f,g
such as protection, deprotection, and removal of the chelating
Moreover, recent blockbuster drugs verify pyrazole’s importance
hydroxy group. Thus, the development of a general route for
regiocontrolled synthesis of pyrazoles with broad substrate-scope
try has a longstanding interest in its synthesis. Starting with
is quite desirable.
Our own interest in the regioselective synthesis of pyrazoles
with hydrazine, where regiocontrol becomes poor with mono-
stems from our recent finding on an efficient and general synthetic
as a pharmacophore.2 Accordingly, the pharmaceutical indus-
the classical Knorr condensation3 of 1,3-dicarbonyl compounds
substituted hydrazines, various native synthetic methods have
been developed with the aim of enhancing regioselectivity in
the synthesis of 1,3,5-tri and 1,3,4,5-tetrasubstituted pyrazoles.4
Michael-type additions of monosubstituted hydrazines to alkynyl
or olefinic ketones followed by intramolecular condensation5
and regiospecific 1,3-dipolar cycloaddition of the hydrazones
with nitroolefin6 provides better control of the regioselectivity
than that of the original Knorr procedure. The cross-coupling
of 5-bromopyrazole derivatives with various nucleophiles7 or
the sequential Suzuki coupling of pyrazole boronate derivatives
generated by lithiation using a metal directing group8 also provide
an alternative choice for enhanced regioselectivity. However, most
of these methods have limited substrate-scope because either the
synthetic method lacks precursors or is incompatible with reac-
tion conditions. Particularly, regioselective synthesis of 1-aryl-3,
5-dialkyl pyrazoles having similar alkyl groups could not be
accomplished using the aforementioned methods as shown in
a recent report on the synthesis of N-arylation of 3,5-dialkyl
route to b-enaminoketoesters 1, which could be used as efficient
surrogates of ynones and 1,3-dicarbonyl compounds in pyrazole
synthesis. Although not fully recognized by synthetic chemists,
an earlier work by Veronese et al. indicated that reactions of
monosubstituted hydrazines with a b-enaminoketoester 1 (R1 =
Bn, R2 = CH3) afforded the corresponding pyrazoles 2 in a
regioselective manner.10 Unfortunately, this protocol has not
been extended further due to the limited availability of the
b-enaminoketoesters 1, which are prepared from Knoevenagel
condensation of b-ketoesters, commonly prepared by Blaise
reaction with nitrile by using a stoichiometric amount of toxic
tin(IV) chloride. In a similar work, Nielsen and Persson reported
recently that monosubstituted hydrazine reacted with N-methoxy-
N-methyl-b-enaminoketoesters, prepared by the reaction of ethyl-
propynoate with Weinreb amides, to afford the 3-carboxylated
pyrazoles regioselectively.11 During our ongoing study of the Blaise
reaction,12 we developed a new general route for the synthesis of
b-enaminoketoesters 1 removing this limitation completely. Quite
recently we reported that the Blaise reaction intermediate, zinc
bromide complexes of b-enaminoesters, could be activated in situ
by the addition of a stoichiometric or catalytic amount of n-BuLi
to allow chemoselective C2-acylation, which provides various
b-enaminoketoesters 1.13 Although limited b-enaminoketoesters
have been studied for the construction of the pyrazole ring
moiety,10,13 the full potential of b-enaminoketoesters 1 for the re-
gioselective synthesis of pyrazoles 2 remained to be verified. In this
work, we attempted to extend our tandem Blaise–acylation proto-
col to the regioselective synthesis of a variety 1-phenylpyrazoles 2,
aDepartment of Chemistry and Nano Science (BK21), Ewha Womans
University, Seoul 120-750, Korea. E-mail: sanggi@ewha.ac.kr; Fax: +82-
3277-3419; Tel: +82-2-3277-4505
bChemical Development Division, LG Life Sciences, Ltd./R & D, Daejeon
305-380, Korea. E-mail: hisin@lgls.com
cCollege of Pharmacy, Kyung Hee University, Seoul 130-701, Korea
† Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for 1a–1k, 2a–2k and 3, and their 1H
NMR and 13C NMR spectra. Crystallographic data for 2a, 2b, 2e, and 2f.
CCDC reference numbers 708928–708931. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/b820324e
1132 | Org. Biomol. Chem., 2009, 7, 1132–1136
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where R1 and R2 are aryl/alkyl, alkyl/aryl, aryl/aryl, alkyl/alkyl
groups including isotopically discriminated 3-CD3-5-CH3 and 3-
CH3-5-CD3 substituted pyrazoles. A mechanism for the regiose-
lective formation of pyrazole 2 has also been proposed.
phenyl group, and 0.25 ppm up-field shifted compared with that
in 2d (d = 1.03 ppm, d, J = 6.7 Hz, 6H). We next investigated the
regioselective synthesis of a set of 3,5-diaryl substituted pyrazoles
2e and 2f with sterically similar but electronically different phenyl
and 4-trifluoromethylphenyl substituents to obtain information
on the effects of substituent electronic properties on regioselec-
tivity. The tandem Blaise–benzoylations of benzonitrile with 4-
trifluoromethylbenzoic anhydride provided 1e in 84% yield with
a 1.2:1 ratio of E and Z isomers (entry 5, Table 1). Switching
the Blaise–acylation partners to 4-trifluoromethylbenzonitrile and
benzoic anhydride afforded 1f in 89% with E and Z in a 2:1
ratio (entry 6, Table 1). Reactions of the E/Z mixtures of b-
enaminoketoesters 1e and 1f with phenyl hydrazine showed perfect
regioselectivity providing the corresponding 1,3,5-triaryl substi-
tuted pyrazoles 2e and 2f in respective yields of 83% and 88%. The
structures of 2e and 2f were determined unambiguously by X-ray
analysis (Fig. 1). Finally, this b-enaminoketoester-based approach
was applied to the regioselective synthesis of unsymmetrical 3,5-
dialkyl substituted pyrazoles 2g (entry 7, Table 1) and 2h (entry
8, Table 1), having sterically and electronically less discernible
methyl and ethyl groups at the 3- and 5-positions. The tandem
Blaise–acylation with acetonitrile/propionic anhydride and propi-
onitrile/acetic anhydride partners provided the corresponding b-
enaminoketoesters 1g and 1h in respective yields of 82% and 86%.
Careful 1H NMR analysis indicated that an E/Z (1:1) mixture of
1h was formed, whereas 1g was formed as a single isomer. To our
delight, reactions of 1g and 1h with phenyl hydrazine afforded the
corresponding pyrazoles 2g (91%) and 2h (90%) regioselectively in
extremely high yield. 1H NMR analysis indicated that as observed
in 2c and 2d, the methyl protons (d = 1.17 ppm, t, J = 7.4 Hz, 3H)
in the ethyl group of 2g were 0.14 ppm up-field shifted compared
to those of 2h (d = 1.31 ppm, t, J = 7.5 Hz, 3H).
Results and discussion
In our previous study, the b-phenyl-b-enaminoketoester 1a was
synthesized in 82% yield, which reacted with phenyl hydrazine
in the presence of a catalytic amount of p-toluenesulfonic acid
to afford the corresponding 1,3-diphenyl-5-methyl pyrazole 2a
regioselectively in 91% yield (entry 1, Table 1).13 To determine
whether the opposite regioselectivity could be obtained with
the b-enaminoketoesters 1b in 81% yield with tandem Blaise–
benzoylation, the nitrile and anhydride partners were switched to
acetonitrile and benzoic anhydride (entry 2, Table 1). In contrast
to 1a forming a single isomer, an inseparable E/Z mixture of
1b was formed in 1:1 ratio. Reaction of the E/Z mixture of 1b
with phenyl hydrazine provided 1,5-diphenyl-3-methyl-pyrazole
2b in 88% yield. There was no sign of the formation of its
regioisomer 2a. In the 1H NMR spectra, the methyl proton
resonance peak for 2a (d = 2.59 ppm, s, 3H) appeared slightly up-
field compared with that for 2b (d = 2.60 ppm, s, 3H) indicating
that the methyl group in 2a is located in the shielding region
of the N-phenyl group. Later, their structures were determined
unambiguously by X-ray crystallographic analysis (Fig. 1). In
the same manner, dichotomous regioselectivity was obtained in
the reaction of phenyl hydrazine with b-enaminoketoesters 1c
(entry 3, Table 1) and 1d (entry 4, Table 1), having a sterically
bulky sec-butyl alkyl group. 1c and 1d were prepared in high
yields by Blaise–acylation of benzonitrile/isovaleric anhydride
and isovaleronitrile/benzoic anhydride partners. Reactions of 1c
and 1d with phenyl hydrazine afforded the corresponding 1,3-
diphenyl-5-sec-butyl pyrazole 2c (87%) and 1,5-diphenyl-3-sec-
butyl pyrazole 2d (85%) without any sign of the formation of other
regioisomers. As in 2a, the methyl group of 2c (d = 0.78 ppm, d,
J = 6.7 Hz, 6H) was observed in the shielding region of the N-
Based on these results, it would be reasonable to assume that
the Michael-type addition of the unsubstituted nitrogen of phenyl
hydrazine occurred at the b-carbon bearing an electronegative
free amine group followed by intramolecular condensation. To
elucidate the proposed reaction mechanism, we attempted to
isolate the reaction intermediate, the conjugated addition adduct,
without any success. However, the reaction of benzylamine
with 1a provided Michael addition product 3 in 64% yield,
thus indirectly supporting the Michael addition–condensation
mechanism (path a) (Scheme 1). The other possible pathway
Table 1 Tandem Blaise–acylation and regioselective synthesis of 1-
phenylpyrazoles 2a–2h
Entry
R1
R2
1 (yield, %)a
2 (yield, %)a
1
2
3
4
5
6
7
8
Ph
CH3
Ph
sec-Bu
Ph
4-CF4C6H4
CH3
CH3CH2
CH3
Ph
sec-Bu
Ph
4-CF3C6H4
Ph
CH3CH2
CH3
1a (82)b
1b (81)c
1c (94)b
1d (90)c
1e (84)d
1f (89)e
1g (82)
1h (86)c
2a (91)b
2b (88)
2c (87)
2d (85)
2e (83)
2f (88)
2g (91)
2h (90)
a Yield after silica column chromatography. b Data from reference 13.
c Mixture of E/Z = ca. 1:1 determined by 1H NMR. d Mixture of E/Z =
ca. 1.2:1 determined by 1H NMR. e Mixture of E/Z = ca. 2:1 determined
by 1H NMR.
Scheme 1 Aminolysis of 1a and proposed pathway for regioselective
pyrazole ring formation.
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Fig. 1 X-ray structures of 1-phenylpyrazoles 2a, 2e, 2e, and 2f.‡
(path b), i.e. imine formation between the carbonyl group and
hydrazine followed by ring-closure via a 5-endo-trig cyclization,
would appear to be unfavorable since only one regioisomer was
formed.
noketoesters 1j and 1k, a set of the tandem Blaise–acylations
was carried out with deuterated acetonitrile (CD3CN)/acetic
anhydride and acetonitrile/deuterated (CD3CO)2O combinations.
Compared with the Blaise–acylation of acetonitrile with acetic
anhydride for 1i (83%), acylation with deuterated acetic anhydride
(CD3CO)2O providing 1j decreased the yield to 68%. The yield was
more dramatically decreased in the Blaise–acylation of CD3CN
with acetic anhydride, providing 20% of 1k in 3 h, which could be
ascribed to the secondary kinetic isotope effect. Fortunately, the
yield was increased to 70% as the reaction time was prolonged to
12 h. Reactions of 1i, 1j and 1k with phenyl hydrazine afforded the
corresponding 3,5-dimethylated pyrazoles 2i (97%), 2j (79%), and
2k (78%). We observed only one singlet resonance peak for methyl
in the 1H NMR spectrum of 2j, at d = 2.50 ppm (s, 3H). In contrast,
the methyl proton peak for 2k was observed at d = 2.52 ppm
The highlight of our methodology is the regioselective synthesis
of isotopically labelled pyrazoles 2j and 2k, which could only
be accomplished through the discrimination of sterically and
electronically indiscernible CH3 and CD3 groups (Scheme 2). To
determine whether the two methyl groups can be differentiated
1
in H NMR, the 3,5-dimethyl pyrazole 2i was synthesized first
in 80% overall yield. We found that the two methyl protons
resonated with slightly different chemical shifts (d = 2.50 and 2.52
ppm) (Fig. 2). For the synthesis of isotopically labelled b-enami-
‡ CCDC numbers: 2a:708928; 2b:708929; 2e:708930; 2f:708931.†
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materials for the tandem Blaise–acylation combined with the
highly regioselective synthesis of pyrazoles provide high potential
for diversity-oriented synthesis.
Experimental
General procedure for the synthesis of pyrazoles 2
To a solution of b-enaminoketoesters 1 (0.5 mmol) in absolute
ethanol (1 mL) was added phenyl hydrazine (2.5 mmol) and p-
toluenesulfonic acid (5 mg, 5 mol%) followed by stirring at room
temperature for 1 h. The reaction mixture was refluxed for 1 h,
and cooled to room temperature. After evaporation of solvent,
the residue was dissolved in ethyl acetate, and the organic layer
was washed subsequently with saturated aqueous NaHCO3, 1 N
HCl, and brine, and then dried with anhydrous MgSO4. After
concentration under reduced pressure, the residue was purified by
column chromatography on silica gel to afford the product 2 with
the yield in Table 1.
Scheme
2 Regioselective synthesis of isotopically discriminated
3,5-dimethyl-1-phenylpyrazoles 2i, 2j, and 2k.
Acknowledgements
This work was supported by the Korean Research Foundation
(KRF-2006-312-C00587).
Notes and references
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broad substrate-scope, are the highly useful reagent of choice for
the regioselective synthesis of pyrzoles 2.
Conclusion
We developed an effective route for the synthesis of pyra-
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enaminoketoesters. This method is very broad in substrate
scope, generating a diverse set of 3,5-aryl/alkyl, 3,5-alkyl/aryl,
3,5-diaryl, and 3,5-dialkyl substituted pyrazoles regioselectively.
Moreover, the indiscernible CH3 and CD3 groups could be
discriminated using our method leading to 3-CD3-5-CH3 and 3-
CH3-5-CD3 substituted pyrazoles in a completely regiocontrolled
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