Solvent-controlled, regio-switchable formation of 3-/5-arylaminopyrazole isomer in cyclocondensation of β-aminoenones with hydrazides: Intermolecular hydrogen bonding plays a role

Article abstract of DOI:10.1039/c2ra22647b

An unprecedented solvent-controlled, regio-switchable Knorr-type reaction for the synthesis of pyrazoles has been realized in the cyclocondensation of β-aminoenones with hydrazides. Single regioisomer of 3- or 5-arylaminopyrazole can be obtained simply by changing the reaction solvent. Using hydrazine hydrate, only 3-arylaminopyrazoles were produced.

Full text of DOI:10.1039/c2ra22647b

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Solvent-controlled, regio-switchable formation of 3-/5-
arylaminopyrazole isomer in cyclocondensation of
b-aminoenones with hydrazides: intermolecular
hydrogen bonding plays a role3
Cite this: RSC Advances, 2013, 3, 386
Received 25th October 2012,
Accepted 13th November 2012
DOI: 10.1039/c2ra22647b
Dexuan Xiang,a Xihe Bi,*bc Peiqiu Liao,b Guichun Fang,b Zikun Wang,b Xiaoqing Xina
and Dewen Dong*ab
www.rsc.org/advances
An unprecedented solvent-controlled, regio-switchable Knorr-
type reaction for the synthesis of pyrazoles has been realized in
the cyclocondensation of b-aminoenones with hydrazides. Single
regioisomer of 3- or 5-arylaminopyrazole can be obtained simply
by changing the reaction solvent. Using hydrazine hydrate, only
3-arylaminopyrazoles were produced.
Junjappa6b individually report a switchable Knorr-type pyrazoles
synthesis by changing the reaction sequence, and choosing an
appropriate base, respectively. Despite these elegant achievements,
new approaches for complete regio-switchable formation of single
pyrazole regioisomer is highly desirable.
The solvent is commonly considered an important parameter
that significantly influences the process of organic reactions such
as regioselectivity.7,8 However, to our knowledge, a complete
switch between two pyrazole isomers obtained simply by changing
the reaction media has not been reported.9 Herein, we describe
the first example of solvent-controlled and regio-switchable
formation of single regioisomer in cyclocondensation of b-ami-
noenones with hydrazides. A plausible mechanism is proposed
based on theoretical calculations of the intermolecular hydrogen
bonding interaction between b-aminoenones and the protic
solvent to cause a decrease in electrophilicity of the b-carbon in
b-aminoenones, thus leading to the regio-switch.
Pyrazole is a ubiquitous structural unit that presents in a broad
range of biologically active compounds, for example, CDK2/cyclin
A inhibitor PNU-292137, GPR109b agonist and EP1 receptor
antagonist bearing a characteristic 3- or 5-aminopyrazole struc-
tural unit (Scheme 1, a).1 Numerous synthetic methods have been
developed for pyrazole with particular emphasis on the regiose-
lective synthesis.2,3 Among these methods, Knorr-type reaction
represents the most common synthetic method for the prepara-
tion of pyrazoles; it involves cyclocondensation of a hydrazine with
a 1,3-electrophile such as 1,3-dicarbonyl compounds, a,b-unsatu-
rated carbonyl compounds bearing a leaving group, and ynones
(Scheme 1, b).4 Unfortunately, these methods generally produce
mixtures of regioisomers due to unsymmetrical reactants, which
leads to poor yields of the desired regioisomer partly due to the
difficult separation of these two isomers. This issue can be solved
by strategically using sterically or electronically biased reactants,
yet at best only one regioisomer is formed.5 Because these two
regioisomers constitute the most valuable regioisomeric pairs for
the comparison of functions such as in the study of structure-
activity relationship (SAR), switchable formation of each isomer by
varying reaction conditions would be highly useful. However, this
remains a challenging task for organic chemists, and only scarce
reports are found in the literature. For example, Kennedy6a and
As our continued interest is in developing new cyclization
reactions from b-ketoamides-derivatized multifunctional groups-
integrated synthon,10 we have previously reported exploration of
aChangchun Institute of Applied Chemistry, Chinese Academy of Sciences,
Changchun, 130022, China. E-mail: dwdong@ciac.jl.cn
bDepartment of Chemistry, Northeast Normal University, Changchun, 130024,
China. E-mail: bixh507@nenu.edu.cn
cState Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, China
Electronic supplementary information (ESI) available: Experimental, analytical data
3
and spectra. CCDC 819257, 830538. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2ra22647b
Scheme 1
386 | RSC Adv., 2013, 3, 386–389
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the synthetic utility of b-aminoenones 1 that were easily prepared
by base-promoted cyclization of b-ketoamides with 1,4-dibromo-
butane.10c, j,k We discovered that base-controlled, regioselective
synthesis of 3- or 5-arylaminoisoxazoles occurred via cyclization of
b-aminoenones 1 with hydroxylamine.10c Further investigation of
the reactions with hydrazides resulted in a solvent-controlled,
regio-switchable cyclization. As shown in Scheme 2, the reaction of
1a with methyl hydrazine mainly afforded 3-phenylaminopyrazole
2a in 85% yield, while replacement of DMF with EtOH exclusively
yielded 5-phenylaminopyrazole 3a in 87% yield. The structure of
2a was unambiguously confirmed by X-ray diffraction.
Subsequently, a range of solvents were screened (Table 1). Weak
polar aprotic solvents including CH3NO2 and CH3CN all give
regioisomer 2a as the major product along with low yields of
regioisomer 3a (entries 1 and 2). Strong polar aprotic solvents
DMSO and DMF favoured the formation of 2a, only with trace
amount of 3a (entries 3 and 4). Non-polar solvent toluene only
gave trace amounts of 2a and 3a, with the recovery of most of
reactant 1a (entry 5). Interestingly, regioisomer 3a was exclusively
produced in water in the presence of 10 mol% of tetrabutylam-
monium bromide (TBAB). Other protic solvents including CH3OH,
C2H5OH, and tBuOH either only or mainly afforded the
regioisomer 3a in excellent yields. Therefore, optimal conditions
for solvent-controlled regioselective synthesis of isomers 2a and 3a
have been established (entries 4 and 6).
Table 1 Solvent screening
Yield (%)a
Entry
Solvent
Recovered 1a
2a
3a
1
2
3
4
5
6b
7
8
9
CH3NO2
CH3CN
DMSO
DMF
Toluene
H2O
CH3OH
C2H5OH
tBuOH
0
0
0
0
84
0
0
0
0
69
76
81
85
12
10
trace
trace
trace
94
trace
0
0
0
91
87
84
trace
a
b
Isolated yields. TBAB (10 mol%) was added.
The NBO charge density of C2 is found to be higher than that of
C1 (0.624 vs. 0.511, and 0.632 vs. 0.510, respectively). Besides, there
exists an intramolecular hydrogen bonding interaction between
the carbonyl group and the amino group. These results might
account for the observed regioselectivity that the nucleophilic NH2
group of methyl hydrazine preferentially attacks the C2, and
therefore produces regioisomer 3-phenylaminopyrazole 2a. By
contrast, substrate 1a exhibits a significantly different geometry
structure in H2O, in which an intermolecular hydrogen bonding
interaction occurs between the amino group of 1a and the solvent
H2O. The NBO charge density of C2 decreases to 0.568 at a level
close to that of C1 (0.529). The similar electrophilicity of C1 and C2
as well as the steric hindrance of C2 may lead to the regioselective
attack of methyl hydrazine to C1, thus giving 5-phenylaminopyr-
azole 3a.
With optimal conditions in hand, the reaction scope was
examined. As listed in Table 2, a range of b-enaminones 1 with the
variation of aromatic substituents were applied to these two
conditions in parallel. Corresponding regioisomers including
3-arylaminopyrazoles 2b–2f and 5-arylaminopyrazoles 3b–3f were
produced, respectively, in high to excellent yields (entries 1–5). It is
worth mentioning that pyrazoles 2 and 3 have a characteristic
hydroxypropyl group on the pyrazole ring, thus providing an
opportunity for further synthetic modification.11
Based on the above results and analysis, a plausible reaction
mechanism was proposed for divergent formation of regioisomers
2 and 3 (Scheme 3). The amino group of methyl hydrazide first
selectively attacks the b-carbon of substrate 1 and displaces the
alkoxy group to give b-aminoenone intermediate i9. Following a
one step intramolecular dehydration reaction, the 3-arylaminopyr-
To uncover the mechanism of solvent-regulating effect on
regioselectivity, we performed theoretical calculations (at B3LYP/6-
311+G(d) level) on the natural bond orbital (NBO) charge
distributions of compound 1a under different conditions, includ-
ing solvent-free, in DMF, and in H2O (Fig. 1). The calculated
results showed that the optimized geometry structures of 1a and
the distribution of NBO charge on C1 and C2 in DMF are nearly
equal to those under solvent-free conditions, which means that
the effect of solvent DMF on the reactivity of 1a can be neglected.
Table 2 Solvent-controlled regioselective synthesis of 3-arylamino- and 5-ary-
laminopyrazoles
Entry
2
Yield (%)a
Ar
3
Yield (%)a
1
2
3
4
5
2b
2c
2d
2e
2f
82
86
91
78
80
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-CF3C6H4
2,4-Me2C6H3
3b
3c
3d
3e
3f
86
88
91
84
83
Scheme 2 Cyclocondensation of b-aminoenone 1a with methyl hydrazide in
a
Isolated yields.
different solvents.
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Scheme 4 Reaction of b-aminoenone 1a with hydrazine hydrate in different
solvents.
Table 3 Cyclocondensation of b-aminoenones 1 with hydrazine hydrate
Entry
1
R
4
Yield (%)a
Fig. 1 Optimized geometry structures and NBO charge distributions of b-phenyla-
minoenone 1a under different conditions.
1
2
3
4
5
1b
1c
1d
1e
1f
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-CF3C6H4
2,4-Me2C6H3
4b
4c
4d
4e
4f
84
93
94
86
95
azoles 2 were produced. In contrast, an intermolecular hydration
of substrates 1 with the solvent H2O first takes place, leading to
the intermediate i. Methyl hydrazine selectively attacks the
carbonyl group to give the hydrazone ii through 1,2-addition/
elimination sequence, and finally afforded 5-arylaminopyrazoles 3
by intramolecular substitution.
a
Isolated yields.
In conclusion, a regio-switchable, divergent synthesis of 3- and
5-arylaminopyrazoles has been developed through the cyclocon-
densation of b-aminoenones with hydrazides. This protocol is
synthetically useful because a single pyrazole regioisomer can be
obtained by varying the solvents. Our findings further promote the
utilization of the classic Knorr-type pyrazoles synthesis.
Encouraged by this solvent-controlled regioselectivity, we
studied the cyclocondensation of b-aminoenone 1a with hydrazine
hydrate, with the aim to make 1H-pyrazole isomers because of
their interesting biological activity.12 3-Phenylaminopyrazole 4a
was exclusively formed in 92% yield when using DMF as the
solvent (Scheme 4). Unexpectedly, performing the reaction in H2O
in the presence of 10 mol% TBAB, product 4a was formed in 90%
yield as the single isomer. Formation of the single isomer 4a,
irrespective of the type of solvent, may be due to the prototropic
tautomerism of pyrazoles leading to the tautoisomer 4a, a
thermodynamically more stable isomer.13 Using water as the
solvent, b-aminoenones 1b–1f were applied in the reaction with
hydrazine hydrate, thus affording 3-arylamino-1H-pyrazoles 4b–4f
in excellent yields (Table 3). The structures of 4d and 4f were
confirmed by single-crystal X-ray diffraction.
Acknowledgements
This work was supported by NSFC (21172211, 21172029,
21202016), ‘‘Hundred Talents Program’’ of the Chinese
Academy of Sciences and FRFCU (11CXPY005).
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