Highly regioselective and practical synthesis of 1-acyl-5- hydroxypyrazolines and 1-acyl pyrazoles from 1,2-allenic ketones and hydrazides

Article abstract of DOI:10.1016/j.tet.2012.07.046

A mild and highly regioselective synthesis of 1-acyl-5-hydroxypyrazolines has been achieved through the condensation of 1,2-allenic ketones with hydrazides in the absence of any catalyst. Moreover, the obtained 1-acyl-5-hydroxypyrazolines can be easily tr

Full text of DOI:10.1016/j.tet.2012.07.046

Tetrahedron 68 (2012) 7768e7774
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Highly regioselective and practical synthesis of 1-acyl-5-hydroxypyrazolines
and 1-acyl pyrazoles from 1,2-allenic ketones and hydrazides
*
*
Shenghai Guo , Jiliang Wang, Dongqiang Guo, Xinying Zhang, Xuesen Fan
School of Chemistry and Environmental Science, Henan Key Lab for Environmental Pollution Control, Henan Normal University, Xinxiang, Henan 453007, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 May 2012
Received in revised form 6 July 2012
Accepted 13 July 2012
Available online 20 July 2012
A mild and highly regioselective synthesis of 1-acyl-5-hydroxypyrazolines has been achieved through
the condensation of 1,2-allenic ketones with hydrazides in the absence of any catalyst. Moreover, the
obtained 1-acyl-5-hydroxypyrazolines can be easily transformed into 1-acyl pyrazoles under the pro-
motion of BF3$Et2O. It was also found that 1-acyl pyrazoles can be produced directly from allenic ketones
and hydrazides through a one-pot procedure.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
1-Acyl-5-hydroxypyrazoline
1-Acyl pyrazole
Allenic ketone
Hydrazide
BF3$Et2O
1. Introduction
substrate scope. Therefore, the development of a more practical,
efficient, and regioselective access to 5-hydroxypyrazolines and 1-
Pyrazoline and pyrazole derivatives have been extensively
studied for decades since many of them are versatile synthetic
blocks, frequent structural skeleton of natural products, or potential
drug molecules.1 In particular, 5-hydroxypyrazolines have been
reported to possess anti-inflammatory,2 antimicrobial,3 antimalar-
ial,4 anti-PDE3,5 analgesic,6 and hypolipidemic7 activities. So far, the
most frequently used methods for the construction of 5-
hydroxypyrazolines involve the cyclocondensation of hydrazides
acyl pyrazoles remains an attractive task for organic chemists.
1,2-Allenic ketones, which are versatile synthetic intermediates,
can be widely used for many organic transformations.20 Recently, we
have reported an efficient synthetic route to 3,5-disubstituted pyr-
azoles through the cyclocondensation of 1,2-allenic ketones with
hydrazine hydrate.21 When phenyl substituted hydrazine was used,
the cyclocondensation reaction showed poor regioselectivity
(Scheme 1, eq. 1), which was plausibly attributed to the inherent
similar nucleophilicityof the two nitrogen atoms inphenyl hydrazine.
Based on the above results, we envisioned that if one of the nitrogen
atoms in hydrazine was attached with a strong electron-withdrawing
with
b a,b
-diketones,3a,8 -acetylenic ketones,9 chalcone dibromi-
des,3b,7 or 3-alkoxy-2-en-1-ones.2a,4,10 While these synthetic
methods are generally effective, they still suffer from low yields,
poor regioselectivity, harsh reaction conditions, or difficult-to-
obtain starting materials. On the other hand, 1-acyl pyrazoles ex-
hibit potent antifungal,11 anti-inflammatory,12 antimicrobial,13 and
anticonvulsant14 activities, and appear promising as potential cy-
totoxic,15 and antitumor16 agents, and inhibitors of human neu-
trophil elastase.17 Typical synthetic methods for 1-acyl pyrazoles
mostly involve the acylation of 1H-pyrazoles18 and the condensa-
tion of hydrazides with 1,3-diketones19a or
a,b-unsaturated keto-
nes.19b,c However, these known methods have several
disadvantages, such as high reaction temperature, poor regiose-
lectivity, use of expensive reagents, and/or catalysts, and limited
* Corresponding authors. Tel.: þ86 373 3329261; fax: þ86 373 3326336; e-mail
Scheme 1.
addresses: shguo@htu.cn (S. Guo), xuesen.fan@htu.cn (X. Fan).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.046

S. Guo et al. / Tetrahedron 68 (2012) 7768e7774
7769
substituent, such as a benzoyl group, the nucleophilicity of this ni-
trogen atom should be reduced more substantially than the another
one. As a result, the regioselectivity of the condensation between
substituted hydrazines and allenic ketones may be improved
accordingly.
To check the feasibility of this tentative idea, allenic ketone 1a
was treated with benzohydrazide 2a in ethanol in the absence of
any catalyst. We were pleased to find that the cyclocondensation
reaction of 1a and 2a proceeded smoothly and in a highly regio-
selective manner to afford pyrazoline 3a in high yield. Furthermore,
upon treatment with BF3$Et2O, 3a could be smoothly transformed
into pyrazole 4a (Scheme 1, eq. 2). In this paper, we would like to
report the details of our research work in this aspect.
with that procedure, higher temperature, longer reaction period
(6e24 h), and excess amounts of acetohydrazide were required.
Moreover, to further expand the scope of allenic ketones, we also
studied the cyclocondensation of 2-substituted allenic ketone with
benzohydrazide. This cyclocondensation proceeded smoothly under
the optimized conditions, to afford two diastereoisomers of pyrazo-
line 3p with a ratio of 2:1 in 70% total yield (Table 1, entry 16).
With 1-acyl-5-hydroxypyrazolines 3 in hand, we were then in-
terested in their dehydration to give the corresponding 1-acyl pyr-
azoles 4. Literature searching revealed that although the dehydration
of 1-acyl-5-hydroxypyrazolines has been extensively studied, mild
and efficient methods without using strong acidic conditions and
thus avoiding deacylation are still highly desirable.9c,23,24 Recently,
BF3$Et2O has emerged as a mild catalyst for the dehydration of
secondary and/or tertiary alcohols.25 This promoted us to try the
dehydration of 3a under the catalysis of BF3$Et2O. When 3a was
treated with BF3$Et2O in THF at 25 ꢀC for 12 h, the corresponding
pyrazole 4a was obtained in 82% yield (Table 2, entry 1). With CH3CN
or ethanol as the medium, the dehydration of 3a also proceeded
smoothly to provide 4a in 72% or 71% yield (Table 2, entries 2e3).
However, when it was run in DCM, the reaction was less efficient and
some unknown by-products were generated (Table 2, entry 4).
Based on the above results, THF was used as the solvent for
subsequent substrate scope studies. The representative examples are
summarized in Table 3. It showed that 1-acyl-5-hydroxypyrazolines
3 with various substitution patterns underwent the dehydration
process smoothly to give the corresponding pyrazoles 4 in good
yields under the promotion of BF3$Et2O (Table 3, entries 1e9).
As a further aspect, it has been well demonstrated that the
combination of two or more synthetic steps in one-pot not only
saves time and energy, but also reduces the use of solvents in the
isolation and purification of intermediates. Therefore, the feasibility
of one-pot synthesis of 1-acyl pyrazoles 4 directly from allenic
ketones 1 and hydrazides 2 was studied. For this purpose, 1a and 2a
were used as model substrates and two operation methods were
tried (Scheme 2). Encouragingly, our following studies showed that
4a could be obtained in a yield of 75% directly from 1a and 2a by
using Method A (Scheme 2). On the other hand, with Method B, two
2. Results and discussion
Initially, we chose 1,2-allenic ketone 1a and benzohydrazide 2a as
model substrates. After the mixture of 1a (0.5 mmol) and 2a
(0.5 mmol) in ethanol21 being stirred at 25 ꢀC for 1 h, 5-
hydroxypyrazoline 3a was obtained exclusively in a yield of 93%
(Scheme 1, eq. 2). Considering the easy nature and high efficiency of
the above process, no further optimization of the reaction conditions
was tried. Next, the scope of allenic ketones was examined by using
benzohydrazide 2a as nucleophile. When 1-aryl substituted allenic
ketones with different substituents on the aromatic ring were
employed as substrates, the desired pyrazolines 3ae3d22 were
formed in 89e93% yields (Table 1,entries 1e4). 1-Benzyl substituted
allenic ketone also reacted very well with 2a to generate 3e (Table 1,
entry 5). In addition, the reaction of 1-alkyl-4-aryl or 1,4-diaryl
substituted allenic ketones with 2a proceeded smoothly to provide
3fe3i in 61e83% yields (Table 1, entries 6e9). We also investigated
the scope of hydrazides. With p-methylbenzohydrazide or p-chlor-
obenzo-hydrazide, 3je3l were obtained in 70e79% yields (Table 1,
entries 10e12). In addition, acetohydrazide showed good reactivity
and regioselectivity to give 1-acetyl-5-hydroxypyrazolines 3me3o in
moderate to good yields (Table 1, entries 13e15). We noticed that 1-
acetyl-5-hydroxypyrazolines have been previously synthesized
through the reaction of acetohydrazide with alkynones.9a However,
Table 1
Synthesis of 1-acyl-5-hydroxypyrazolines 3a
Entry
R1
R2
R3
R4
Time (h)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
10
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
93
91
90
89c
82
80
83
61
71
79
70
78
60
83
61
70d
o-FC6H4
o-ClC6H4
o-BrC6H4
C6H5CH2
CH3
CH3
CH3
C6H5
C6H5
C6H5
o-ClC6H4
C6H5
o-ClC6H4
p-ClC6H4
C6H5
H
C6H5
p-FC6H4
p-CH3OC6H4
C6H5
H
H
H
H
9
C6H5
10
11
12
13
14
15
16
p-CH3C6H4
p-ClC6H4
p-ClC6H4
CH3
CH3
CH3
H
H
H
C6H5
a
All reactions were carried out using 0.5 mmol of allenic ketone, 0.5 mmol of hydrazide in ethanol (5 mL) at 25 ꢀC.
Isolated yields.
X-ray crystal structure of compound 3d is available in Supplementary data.
Total isolated yield of two diastereoisomers of pyrazoline 3p.
b
c
d

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S. Guo et al. / Tetrahedron 68 (2012) 7768e7774
Table 2
regioisomers 4a and 5a were formed in 31% and 22% yields, re-
Optimization studies for the dehydration of compound 3aa
spectively. The poor regioselectivity observed with Method B might
result from the much enhanced electrophilicity and thus reduced
selectivity of 1a toward the two nitrogen atoms in 2a by co-
ordinating with BF3$Et2O.
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
THF
12
1
8
82
72
71
52
CH3CN
EtOH
DCM
2
a
All reactions were run at 25 ꢀC on 0.5 mmol scale.
Isolated yields.
b
Scheme 2. Optimization studies for one-pot synthesis of 4a.
Table 3
Synthesis of pyrazoles 4 via the dehydration of pyrazolines 3a
The generality of this one-pot synthesis of 1-acyl pyrazoles was
then investigated. A variety of allenic ketones and hydrazides were
found to be well compatible with the one-pot procedure to provide
the corresponding pyrazoles 4 in moderate to good yields (Table 4,
entries 1e11). It was also found that the dehydration rate of in-
termediates 3 strongly depended on the electronic effect of R1. When
R1 is an electron-donating substituent, much shorter reaction period
is required to complete the dehydration process (Table 4, entries 9 vs
10e11). This observation might be explained by the stabilization
effect of the electron-donating group on the proposed cationic in-
termediate involved in the dehydration process.
Entry
1
Substrate
Product
Time (h) Yieldb (%)
12
5
82
70
78
4a
4b
2
3
3. Conclusion
In summary, we have developed a highly regioselective protocol
for the synthesis of 1-acyl-5-hydroxypyrazolines and 1-acyl pyr-
azoles. Catalyst-free cyclocondensation of allenic ketones with
hydrazides affords 1-acyl-5-hydroxypyrazolines in good to excel-
lent yields with high regioselectivity under extremely mild reaction
conditions. The thus formed 1-acyl-5-hydroxypyrazolines can be
further converted into 1-acyl pyrazoles via BF3$Et2O-catalyzed
dehydration. In addition, 1-acyl pyrazoles can also be obtained di-
rectly from allenic ketones and hydrazides through a one-pot
procedure. Compared with literature methods, advantages of the
present protocol include high regioselectivity, good yields, mild
reaction conditions, and simple operation process.
8
4c
4
24
69
4d
5
6
12
12
70
66
4e
4. Experimental section
4.1. General
4f
THF was distilled from sodium/benzophenone. DCM and CH3CN
were distilled from CaH2. Unless noted, all commercial reagents
were used without further purification. 1,2-Allenic ketones were
prepared from commercially available reagents according to liter-
ature procedures.26 1H and 13C NMR spectra were recorded at 400
and 100 MHz, respectively. All reactions were monitored by thin-
layer chromatography (TLC) using silica gel plates (silica gel 60
F254 0.25 mm) and components were visualized by observation
under UV light (254 and 365 nm).
7
8
12
75
4g
3
5
82
81
4h
4.2. General procedure for the preparation of 1-acyl-5-
hydroxypyrazolines 3 from 1,2-allenic ketones 1 and hydra-
zides 2
9
4i
a
All reactions were conducted in dry THF on 0.3e0.5 mmol scale using
20 mol % BF3$Et2O as catalyst.
To a solution of 1,2-allenic ketone 1 (0.5 mmol) in EtOH (5 mL)
was added hydrazide 2 (0.5 mmol) and then stirred at 25 ꢀC until
b
Isolated yields.

S. Guo et al. / Tetrahedron 68 (2012) 7768e7774
7771
Table 4
One-pot synthesis of pyrazoles 4 starting from allenic ketones 1 and hydrazides 2a
Entry
R1
R2
R3
R4
Time 1 (h)
Time 2 (h)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
C6H5
C6H5CH2
CH3
C6H5
C6H5
C6H5
CH3
C6H5
H
H
H
H
H
H
H
CH3
H
H
H
C6H5
H
H
H
C6H5
C6H5
C6H5
p-CH3C6H4
p-ClC6H4
CH3
C6H5
C6H5
1
1
1
1
1
1
1
10
1
1
8
3
2
12
12
12
3
5
24
3
4a
4b
4c
4e
4f
4g
4h
4i
75
64
81
60
60
50
47
52
53
75
66
p-CH3OC6H4
H
H
H
H
9
10
11
p-NCC6H4
p-CH3OC6H4
3,4-(CH3O)2C6H3
C6H5
C6H5
C6H5
4j
4k
4l
H
H
1
4
a
Allenic ketones 1 (0.5 mmol) and hydrazide 2 (0.5 mmol) were stirred at 25 ꢀC for the time 1 in EtOH, and then BF3$Et2O (0.1 mmol) was added into the reaction mixture
and the resulting mixture was stirred for the time 2.
b
Isolated yields.
allenic ketone 1 was consumed completely. The solvent was re-
moved under reduced pressure and the residue was purified by
chromatography on silica-gel to afford the corresponding 1-acyl-5-
hydroxypyrazoline 3.
168.3. HRMS (ESI) calcd for C17H16BrN2O2 [MþH]þ: 359.0395,
found: 359.0393.
4.2.5. Pyrazoline 3e. Column chromatography on silica-gel (petro-
leum ether/ethyl acetate¼6:1e4:1) afforded 3e as colorless oil in
4.2.1. Pyrazoline 3a. Column chromatography on silica-gel (petro-
leum ether/ethyl acetate¼8:1e5:1) afforded 3a as yellow solid in
82% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 1.81 (s, 3H), 2.88 (d,
J¼18.0 Hz, 1H), 3.03 (d, J¼18.4 Hz, 1H), 3.42 (d, J¼14.0 Hz, 1H), 3.81
93% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 1.97 (s, 3H), 2.90 (d,
(d, J¼14.0 Hz,1H), 5.58 (s,1H), 7.28e7.33 (m, 5H), 7.41e7.51 (m, 3H),
J¼18.4 Hz, 1H), 3.20 (d, J¼18.4 Hz, 1H), 5.38 (s, 1H), 7.18e7.22 (m,
7.85 (d, J¼7.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
d 16.0, 44.1, 47.7,
1H), 7.28e7.34 (m, 4H), 7.38e7.41 (m, 3H), 7.85 (d, J¼8.0 Hz, 2H);
95.2, 127.1, 127.8, 128.5, 129.8, 130.2, 131.3, 134.4, 135.8, 155.7, 169.1.
HRMS (ESI) calcd for C18H19N2O2 [MþH]þ: 295.1447, found:
295.1441.
13C NMR (CDCl3, 100 MHz)
d 16.0, 53.6, 94.5, 123.9, 127.7, 127.9,
128.6, 129.9, 131.5, 133.7, 143.6, 154.9, 168.1. HRMS (ESI) calcd for
C17H17N2O2 [MþH]þ: 281.1290, found: 281.1288.
4.2.6. Pyrazoline 3f. Column chromatography on silica-gel (petro-
leum ether/ethyl acetate¼5:1e4:1) afforded 3f as colorless oil in
4.2.2. Pyrazoline 3b. Column chromatography on silica-gel (pe-
troleum ether/ethyl acetate¼8:1e5:1) afforded 3b as yellow solid
80% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 1.91 (s, 3H), 2.72 (d,
in 91% isolated yield. 1H NMR (CDCl3, 400 MHz)
d
2.10 (s, 3H), 3.20
J¼18.4 Hz, 1H), 2.97 (d, J¼18.0 Hz, 1H), 3.65 (d, J¼15.2 Hz, 1H), 3.71
(d, J¼18.8 Hz, 1H), 3.26 (d, J¼18.8 Hz,1H), 5.73 (s, 1H), 7.02e7.07 (m,
1H), 7.18e7.21 (m, 1H), 7.28e7.33 (m, 1H), 7.39e7.49 (m, 3H),
7.76e7.80 (m, 1H), 7.90 (d, J¼8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
(d, J¼14.8 Hz, 1H), 5.03 (brs, 1H), 7.22e7.36 (m, 5H), 7.42e7.52 (m,
3H), 7.92 (d, J¼7.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
d 26.7, 37.0,
48.7, 92.9,127.2,127.7,128.86,128.91,130.0,131.3,134.3,135.7,157.4,
168.7. HRMS (ESI) calcd for C18H19N2O2 [MþH]þ: 295.1447, found:
295.1446.
d
16.0, 52.3, 91.3, 116.1 (d, J¼22.1 Hz, 1C), 123.9 (d, J¼3.8 Hz, 1C),
127.5 (d, J¼2.3 Hz, 1C), 127.7, 130.0, 130.1, 130.2, 131.6, 133.6, 155.1,
159.4 (d, J¼245.4 Hz, 1C), 168.3. HRMS (ESI) calcd for C17H16FN2O2
[MþH]þ: 299.1196, found: 299.1192.
4.2.7. Pyrazoline 3g. Column chromatography on silica-gel (petro-
leum ether/ethyl acetate¼4:1e3:1) afforded 3g as colorless oil in
4.2.3. Pyrazoline 3c. Column chromatography on silica-gel (petro-
leum ether/ethyl acetate¼6:1e4:1) afforded 3c as white solid in 90%
83% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 1.91 (s, 3H), 2.70 (d,
J¼19.2 Hz, 1H), 2.95 (d, J¼18.4 Hz, 1H), 3.58e3.66 (m, 2H), 5.18 (brs,
isolated yield. 1H NMR (CDCl3, 400 MHz)
d 2.13 (s, 3H), 3.14 (d,
1H), 7.01 (t, J¼8.0 Hz, 2H), 7.15e7.19 (m, 2H), 7.39e7.49 (m, 3H), 7.90
J¼19.2 Hz,1H), 3.33 (d, J¼18.4Hz,1H), 5.58(s,1H), 7.26(t, J¼7.2 Hz, 1H),
(d, J¼7.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
d 26.7, 36.1, 48.7, 92.9,
7.33e7.43 (m, 4H), 7.48 (t, J¼7.2 Hz, 1H), 7.91 (d, J¼7.2 Hz, 2H), 7.96 (d,
115.7 (d, J¼21.4 Hz, 2C), 127.7, 130.0, 130.4 (d, J¼8.4 Hz, 2C), 131.3,
131.4 (d, J¼3.0 Hz, 1C), 134.2, 157.1, 162.0 (d, J¼243.9 Hz, 1C), 168.7.
HRMS (ESI) calcd for C18H18FN2O2 [MþH]þ: 313.1352, found:
313.1355.
J¼7.2 Hz, 1H); 13C NMR (CDCl3,100 MHz)
d 15.9, 51.4, 92.4, 126.8, 127.7,
128.1,129.5,130.3,131.06,131.09,131.6,133.5,139.4,155.3,168.2. HRMS
(ESI) calcd for C17H16ClN2O2 [MþH]þ: 315.0900, found: 315.0902.
4.2.4. Pyrazoline 3d. Column chromatography on silica-gel (pe-
troleum ether/ethyl acetate¼6:1e4:1) afforded 3d as white solid in
4.2.8. Pyrazoline 3h. Column chromatography on silica-gel (pe-
troleum ether/ethyl acetate¼5:1e4:1) afforded 3h as colorless oil
89% isolated yield. 1H NMR (CDCl3, 400 MHz)
d
2.14 (s, 3H), 3.12 (d,
in 61% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 1.90 (s, 3H), 2.70
J¼18.0 Hz, 1H), 3.36 (d, J¼18.4 Hz, 1H), 5.60 (s, 1H), 7.15e7.19 (m.
(d, J¼18.4 Hz, 1H), 2.95 (d, J¼18.4 Hz, 1H), 3.58 (d, J¼14.8 Hz, 1H),
3.64 (d, J¼15.2 Hz, 1H), 3.79 (s, 3H), 6.85e6.89 (m, 2H), 7.13 (d,
J¼8.4 Hz, 2H), 7.41e7.51 (m, 3H), 7.90e7.92 (m, 2H); 13C NMR
1H), 7.37e7.44 (m, 3H), 7.49 (t, J¼7.2 Hz, 1H), 7.60 (d, J¼8.4 Hz, 1H),
7.95e7.97 (m, 3H); 13C NMR (CDCl3, 100 MHz)
d 16.0, 51.4, 93.1,
120.0,127.4,127.7,128.4,129.7,130.4,131.7,133.4,134.7,140.6,155.5,
(CDCl3, 100 MHz) d 26.7, 36.1, 48.6, 55.3, 92.9, 114.3, 127.6, 127.7,

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S. Guo et al. / Tetrahedron 68 (2012) 7768e7774
129.8, 130.0, 131.3, 134.2, 157.8, 158.7, 168.7. HRMS (ESI) calcd for
diastereoisomers of pyrazoline 3p as colorless oil in 70% total yield.
1H NMR (CDCl3, 400 MHz)
C19H21N2O3 [MþH]þ: 325.1552, found: 325.1551.
d
0.72 (d, J¼7.6 Hz, 1H), 1.30 (d, J¼7.6 Hz,
2H), 2.03 (s, 3H), 3.02 (q, J¼7.6 Hz, 0.66H), 3.34 (q, J¼7.6 Hz, 0.33H),
5.33 (brs, 0.6H), 5.49 (brs, 0.3H), 7.30e7.33 (m, 1H), 7.37e7.54 (m,
4.2.9. Pyrazoline 3i. Column chromatography on silica-gel (petro-
leum ether/ethyl acetate¼6:1e4:1) afforded 3i as yellow oil in 71%
7H), 7.97e7.80 (m, 2H); 13C NMR (CDCl3, 100 MHz)
d 8.9, 13.3, 14.2,
isolated yield. 1H NMR (CDCl3, 400 MHz)
d
2.92 (d, J¼18.0 Hz, 1H),
14.5, 54.8, 56.3, 94.3, 97.5, 123.9, 127.8, 127.9, 128.2, 128.5, 128.7,
130.0, 130.1, 131.5, 131.6, 133.8, 133.9, 139.9, 144.5, 159.1, 159.7, 168.1,
168.9. HRMS (ESI) calcd for C18H19N2O2 [MþH]þ: 295.1447, found:
295.1450.
3.24 ( d, J¼18.8 Hz, 1H), 3.77 (s, 2H), 5.48 (s, 1H), 7.26e7.40 (m, 8H),
7.47e7.57 (m, 5H), 8.05 (d, J¼7.2 Hz, 2H); 13C NMR (CDCl3,100 MHz)
d
36.9, 51.4, 94.7, 124.0, 127.2, 127.9, 128.0, 128.7, 128.8, 129.0, 130.2,
131.7, 133.7, 135.5, 143.6, 157.2, 168.3. HRMS (ESI) calcd for
C23H21N2O2 [MþH]þ: 357.1603, found: 357.1603.
4.3. General procedure for the preparation of 1-acyl pyrazoles
4 via the dehydration of pyrazolines 3
4.2.10. Pyrazoline 3j. Column chromatography on silica-gel (petro-
leum ether/ethyl acetate¼6:1e5:1) afforded 3j as yellow solid in 79%
To a solution of 1-acyl-5-hydroxypyrazoline 3 (0.3e0.5 mmol) in
dry THF (3e5 mL) was added BF3$Et2O (20 mol %) and then stirred
at 25 ꢀC for the time indicated in Table 3. THF was removed under
reduced pressure and the residue was purified by chromatography
on silica-gel to afford the corresponding 1-acyl pyrazole 4.
isolated yield. 1H NMR (CDCl3, 400 MHz)
d 2.07 (s, 3H), 2.41 (s, 3H),
2.99 (d, J¼18.4 Hz, 1H), 3.30 (d, J¼18.4 Hz, 1H), 5.56 (s, 1H), 7.25 (d,
J¼7.2 Hz, 2H), 7.31e7.32 (m,1H), 7.38 (t, J¼7.2 Hz, 2H), 7.52 (d, J¼7.2 Hz,
2H), 7.90 (d, J¼7.2 Hz, 2H); 13C NMR (CDCl3,100 MHz)
d 16.1, 21.6, 53.6,
94.5, 124.1, 128.0, 128.5, 128.7, 130.2, 130.9, 142.1, 143.9, 154.9, 168.2.
HRMS (ESI) calcd for C18H19N2O2 [MþH]þ: 295.1447, found: 295.1443.
4.3.1. Pyrazole 4a. Column chromatography on silica-gel (petro-
leum ether/ethyl acetate¼15:1e10:1) afforded 4a as white solid in
4.2.11. Pyrazoline 3k. Column chromatography on silica-gel (pe-
troleum ether/ethyl acetate¼6:1e5:1) afforded 3k as yellow solid
82% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 2.36 (s, 3H), 6.38 (s,
1H), 7.39e7.51 (m, 7H), 7.60 (t, J¼8.0 Hz, 1H), 8.04 (d, J¼7.2 Hz, 2H);
in 70% isolated yield. 1H NMR (CDCl3, 400 MHz)
d
2.08 (s, 3H), 3.00
13C NMR (CDCl3, 100 MHz)
d
14.0, 112.1, 128.1, 128.3, 128.4, 128.6,
(d, J¼19.2 Hz, 1H), 3.30 (d, J¼18.0 Hz, 1H), 5.40 (s, 1H), 7.31e7.41 (m,
130.9, 131.7, 132.7, 133.1, 148.1, 152.1, 167.4. HRMS (ESI) calcd for
5H), 7.47 (d, J¼7.2 Hz, 2H), 7.92 (d, J¼8.0 Hz, 2H); 13C NMR (CDCl3,
C17H15N2O [MþH]þ: 263.1184, found: 263.1175.
100 MHz) d 16.1, 53.6, 94.6, 123.9, 128.07, 128.12, 128.7, 131.6, 132.0,
137.7, 143.5, 155.5, 166.9. HRMS (ESI) calcd for C17H16ClN2O2
4.3.2. Pyrazole 4b. Column chromatography on silica-gel (petro-
leum ether/ethyl acetate¼15:1e10:1) afforded 4b as colorless oil in
[MþH]þ: 315.0900, found: 315.0910.
70% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 2.21 (s, 3H), 4.42 (s,
4.2.12. Pyrazoline 3l. Column chromatography on silica-gel (pe-
troleum ether/ethyl acetate¼6:1e5:1) afforded 3l as yellow solid in
2H), 5.85 (s, 1H), 7.23e7.35 (m, 5H), 7.45 (t, J¼8.0 Hz, 2H), 7.55 (t,
J¼7.2 Hz, 1H), 7.98 (d, J¼8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
78% isolated yield. 1H NMR (CDCl3, 400 MHz)
d
2.13 (s, 3H), 3.13 (d,
d 13.9, 34.4, 111.6, 126.7, 127.9, 128.6, 129.1, 131.4, 132.5, 133.3, 138.0,
J¼18.4 Hz, 1H), 3.32 (d, J¼18.4 Hz, 1H), 5.55 (brs, 1H), 7.24e7.38 (m,
148.8, 152.1, 168.4. HRMS (ESI) calcd for C18H17N2O [MþH]þ:
5H), 7.86 (d, J¼8.4 Hz, 2H), 7.94 (d, J¼7.6 Hz, 1H); 13C NMR (CDCl3,
277.1341, found: 277.1336.
100 MHz)
d 15.9, 51.4, 92.4, 126.8, 128.0, 128.1, 129.6, 131.0, 131.1,
131.77, 131.82, 137.8, 139.1, 155.7, 166.9. HRMS (ESI) calcd for
4.3.3. Pyrazole 4c. Column chromatography on silica-gel (petro-
leum ether/ethyl acetate¼15:1e10:1) afforded 4c as colorless oil in
C17H15Cl2N2O2 [MþH]þ: 349.0511, found: 349.0509.
78% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 2.65 (s, 3H), 4.00 (s,
4.2.13. Pyrazoline 3m. Column chromatography on silica-gel (pe-
troleum ether/ethyl acetate¼4:1e3:1) afforded 3m as white solid
2H), 6.04 (s, 1H), 7.26e7.38 (m, 5H), 7.52 (t, J¼7.2 Hz, 2H), 7.60e7.63
(m, 1H), 8.09 (d, J¼7.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
d 14.5,
in 60% isolated yield. 1H NMR (CDCl3, 400 MHz)
d
2.04 (s, 3H), 2.31
34.9, 110.4, 126.6, 127.9, 128.6, 128.9, 131.6, 132.6, 133.3, 138.7, 145.4,
155.2, 168.5. HRMS (ESI) calcd for C18H17N2O [MþH]þ: 277.1341,
found: 277.1340.
(s, 3H), 2.91 (d, J¼19.2 Hz, 1H), 3.27 (d, J¼18.0 Hz, 1H), 5.13 (s, 1H),
7.26e7.30 (m, 1H), 7.35e7.36 (m, 4H); 13C NMR (CDCl3, 100 MHz)
d
16.0, 22.2, 54.2, 93.4, 123.8, 128.0, 128.7, 143.8, 154.2, 170.3. HRMS
(ESI) calcd for C12H15N2O2 [MþH]þ: 219.1134, found: 219.1135.
4.3.4. Pyrazole 4d. Column chromatography on silica-gel (petro-
leum ether/ethyl acetate¼15:1e10:1) afforded 4d as colorless oil in
4.2.14. Pyrazoline 3n. Column chromatography on silica-gel (pe-
troleum ether/ethyl acetate¼5:1e4:1) afforded 3n as white solid in
69% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 4.08 (s, 2H), 6.33 (s,
1H), 7.28e7.29 (m, 1H), 7.35e7.44 (m, 9H), 7.53 (t, J¼8.0 Hz, 2H),
83% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 2.09 (s, 3H), 2.26 (s,
7.65 (t, J¼7.6 Hz, 1H), 8.12 (d, J¼7.2 Hz, 2H); 13C NMR (CDCl3,
3H), 3.11 (d, J¼18.8 Hz, 1H), 3.17 (d, J¼18.8 Hz, 1H), 5.15 (s, 1H),
100 MHz) d 34.9, 111.3, 126.7, 128.16, 128.24, 128.4, 128.7, 129.0,
7.21e7.30 (m, 2H), 7.34 (d, J¼7.6 Hz, 1H), 7.75 (d, J¼7.6 Hz, 1H); 13C
130.8, 131.8, 132.5, 133.3, 138.6, 148.3, 155.3, 167.5. HRMS (ESI) calcd
NMR (CDCl3, 100 MHz)
d
15.7, 21.9, 52.1, 91.2, 126.7, 127.6, 129.3,
for C23H19N2O [MþH]þ: 339.1497, found: 339.1505.
130.9, 131.0, 139.5, 154.6, 170.2. HRMS (ESI) calcd for C12H14ClN2O2
[MþH]þ: 253.0744, found: 253.0750.
4.3.5. Pyrazole 4e. Column chromatography on silica-gel (petro-
leum ether/ethyl acetate¼15:1e10:1) afforded 4e as colorless oil in
4.2.15. Pyrazoline 3o. Column chromatography on silica-gel (pe-
troleum ether/ethyl acetate¼5:1e4:1) afforded 3o as white solid in
70% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 2.28 (s, 3H), 2.36 (s,
3H), 6.29 (s, 1H), 7.21 (d, J¼8.4 Hz, 2H), 7.30e7.37 (m, 5H), 7.89 (d,
61% isolated yield. 1H NMR (CDCl3, 400 MHz)
d
2.03 (s, 3H), 2.30 (s,
J¼7.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
d 13.9, 21.8, 111.8, 128.2,
3H), 2.87 (d, J¼18.0 Hz, 1H), 3.25 (d, J¼18.0 Hz, 1H), 5.15 (s, 1H),
128.3, 128.5, 128.9, 129.8, 131.0, 131.9, 144.1, 148.0, 151.9, 167.4.
HRMS (ESI) calcd for C18H17N2O [MþH]þ: 277.1341, found:
277.1345.
7.26e7.29 (m, 4H); 13C NMR (CDCl3, 100 MHz)
d
15.9, 22.2, 54.1,
92.9, 125.4, 128.8, 133.8, 142.4, 154.2, 170.4. HRMS (ESI) calcd for
C12H14ClN2O2 [MþH]þ: 253.0744, found: 253.0741.
4.3.6. Pyrazole 4f. Column chromatography on silica-gel (petro-
leum ether/ethyl acetate¼15:1e10:1) afforded 4f as colorless oil in
4.2.16. Pyrazoline 3p. Column chromatography on silica-gel (pe-
troleum
ether/ethyl
acetate¼10:1e6:1)
afforded
two
66% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 2.35 (s, 3H), 6.37 (s,

S. Guo et al. / Tetrahedron 68 (2012) 7768e7774
7773
1H), 7.39e7.47 (m, 7H), 7.99e8.01 (m, 2H); 13C NMR (CDCl3,
100 MHz) 13.9, 112.3, 128.2, 128.35, 128.40, 128.7, 130.7, 131.0,
2H); 13C NMR (CDCl3, 100 MHz)
111.7, 121.2, 123.4, 128.1, 131.6, 132.7, 133.1, 147.9, 148.5, 149.4, 152.1,
167.5. HRMS (ESI) calcd for C19H19N2O3 [MþH]þ: 323.1396, found:
323.1405.
d
13.9, 55.85, 55.91, 110.7, 111.6,
d
133.1, 139.5, 148.1, 152.4, 166.3. HRMS (ESI) calcd for C17H14ClN2O
[MþH]þ: 297.0795, found: 297.0781.
4.3.7. Pyrazole 4g. Column chromatography on silica-gel (petro-
leum ether/ethyl acetate¼15:1e10:1) afforded 4g as colorless oil in
4.5. Preparation of pyrazoles 4a and 5a by using Method B
(Scheme 2)
75% isolated yield. 1H NMR (CDCl3, 400 MHz)
d
2.34 (s, 3H), 2.70 (s,
13.8, 23.8,
3H), 6.21 (s, 1H), 7.39 (s, 5H); 13C NMR (CDCl3, 100 MHz)
d
To a solution of 1,2-allenic ketone 1a (0.5 mmol) in EtOH (5 mL)
were added hydrazide 2a (0.5 mmol) and BF3$Et2O (0.1 mmol) and
then stirred at 25 ꢀC for 8 h. When the reaction was completed, the
solvent was removed under reduced pressure and the crude
products were purified by chromatography on silica-gel to afford
pyrazoles 4a and 5a in 31% and 22% yields, respectively.
The characterization data of 4a obtained via this procedure is
the same as the one obtained through the direct dehydration of
pyrazolines 3a.
112.9, 127.8, 128.6, 128.9, 131.3, 146.6, 152.0, 170.2. HRMS (ESI) calcd
for C12H13N2O [MþH]þ: 201.1028, found: 201.1025.
4.3.8. Pyrazole 4h. Column chromatography on silica-gel (petro-
leum ether/ethyl acetate¼15:1e10:1) afforded 4h as colorless oil in
82% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 2.62 (s, 3H), 3.80 (s,
3H), 3.90 (s, 2H), 6.00 (s, 1H), 6.86e6.89 (m, 2H), 7.19 (d, J¼8.8 Hz,
2H), 7.47e7.51 (m, 2H), 7.57e7.61 (m, 1H), 8.04e8.06 (m, 2H); 13C
NMR (CDCl3, 100 MHz)
d 14.4, 33.9, 55.2, 110.2, 114.0, 127.9, 129.8,
130.8, 131.5, 132.5, 133.3, 145.3, 155.6, 158.3, 168.5. HRMS (ESI) calcd
4.5.1. Pyrazole 5a. Column chromatography on silica-gel (petro-
leum ether/ethyl acetate¼15:1e10:1) afforded 5a as colorless oil in
for C19H19N2O2 [MþH]þ: 307.1447, found: 307.1445.
22% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 2.74 (s, 3H), 6.60 (s,
4.3.9. Pyrazole 4i. Column chromatography on silica-gel (petro-
leum ether/ethyl acetate¼20:1e15:1) afforded 4i as colorless oil in
1H), 7.37e7.43 (m, 3H), 7.50 (t, J¼7.6 Hz, 2H), 7.61 (t, J¼8.0 Hz, 1H),
7.82 (d, J¼7.2 Hz, 2H), 8.12 (d, J¼7.2 Hz, 2H); 13C NMR (CDCl3,
81% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 2.02 (s, 3H), 2.32 (s,
100 MHz) d 14.6, 108.0, 126.3, 127.8, 128.7, 129.0, 131.7, 132.0, 132.6,
133.1, 145.8, 153.4, 168.6. HRMS (ESI) calcd for C17H15N2O [MþH]þ:
3H), 7.36e7.49 (m, 7H), 7.56e7.60 (m, 1H), 8.03 (d, J¼6.8 Hz, 2H);
13C NMR (CDCl3, 100 MHz)
d
8.2, 12.4, 119.2, 128.0, 128.21, 128.24,
263.1184, found: 263.1188.
129.1, 131.3, 131.5, 132.7, 133.1, 143.4, 152.5, 167.1. HRMS (ESI) calcd
for C18H17N2O [MþH]þ: 277.1341, found: 277.1338.
Acknowledgements
4.4. General procedure for the one-pot synthesis of 1-acyl
pyrazoles 4 from 1,2-allenic ketones 1 (Scheme 2, Method A)
We thank the NSF of China (20972042, 21172057), PCSIRT
(IRT1061), 2012IRTSTHN006, and the Scientific Research Founda-
tion of HNU (01036500507, 01036400104) for financial support.
To a solution of 1,2-allenic ketone 1 (0.5 mmol) in EtOH (5 mL)
was added hydrazide 2 (0.5 mmol) and then stirred at 25 ꢀC until
Supplementary data
allenic ketone
1 was consumed completely. Next, BF3$Et2O
The X-ray crystal structure of 3d and the copies of 1H NMR and
13C NMR spectra of 3ae3p, 4ae4l, and 5a. Supplementary data
related to this article can be found online at http://dx.doi.org/
10.1016/j.tet.2012.07.046.
(0.1 mmol) was added into the resulting mixture and stirred at the
same temperature for the time 2 indicated in Table 4. And then the
solvent was removed under reduced pressure and the residue was
purified by chromatography on silica-gel to afford the corre-
sponding 1-acyl pyrazole 4.
The characterization data of 4ae4c and 4ee4i obtained via the
one-pot procedure is the same as the one obtained through the
direct dehydration reaction of pyrazolines 3.
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53% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 2.36 (s, 3H), 6.44 (s,
1H), 7.46e7.54 (m, 4H), 7.60e7.68 (m, 3H), 8.03e8.09 (m, 2H); 13C
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€
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75% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 2.32 (s, 3H), 3.79 (s,
3H), 6.30 (s,1H), 6.90 (d, J¼8.8 Hz, 2H), 7.35 (d, J¼8.8 Hz, 2H), 7.45 (t,
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(CDCl3, 100 MHz)
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66% isolated yield. 1H NMR (CDCl3, 400 MHz)
d 2.32 (s, 3H), 3.84 (s,
3H), 3.87 (s, 3H), 6.33 (s, 1H), 6.85 (d, J¼7.6 Hz, 1H), 6.94e6.98 (m,
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7774
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