Synthesis of pyrazoles, diazepines, enaminones, and enamino esters using 12-tungstophosphoric acid as a reusable catalyst in water

Article abstract of DOI:10.1055/s-0028-1083169

12-Tungstophosphoric acid (H₃PW₁₂O₄₀) is found to be an efficient and recyclable catalyst in promoting a chemo- and regioselective condensation of hydrazines/hydrazides, diamines, and primary amines with various 1,3-dicarbonyl compounds in pure water at room temperature to afford pyrazoles, diazepines, and enaminones/enamino esters, respectively, in high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083169

3478
PAPER
Synthesis of Pyrazoles, Diazepines, Enaminones, and Enamino Esters Using
12-Tungstophosphoric Acid as a Reusable Catalyst in Water
1
2-Tungstophosph
i
oric
A
c
a
id
a
s
a
Reu
n
sable Cataly
g
st in Wate
r
Chen,a Jin She,a Zhicai Shang,*a Jun Wu,*a Haifeng Wu,a Peizhi Zhangb
a
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87952379; E-mail: shangzc@zju.edu.cn
b
School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou 310012, P. R. of China
Received 4 June 2008; revised 3 July 2008
amount of the catalyst, and nonrecyclability of the cata-
lyst. Thus, there is still a need to develop greener and ef-
ficient pathways for the syntheses such compounds.
Abstract: 12-Tungstophosphoric acid (H3PW12O40) is found to be
an efficient and recyclable catalyst in promoting a chemo- and re-
gioselective condensation of hydrazines/hydrazides, diamines, and
primary amines with various 1,3-dicarbonyl compounds in pure wa-
ter at room temperature to afford pyrazoles, diazepines, and enami-
nones/enamino esters, respectively, in high yields.
In recent years, carrying out organic reactions in water has
become highly desirable.9 The use of an aqueous medium
as solvent is economic and safe, and also reduces the
harmful effects of organic solvents on the environment.
These advantages become even more attractive if such re-
actions can be performed using reusable catalysts. In this
respect, only few of the aforementioned catalysts meet
this criterion of green chemistry. To the best of our knowl-
edge, synthesis of pyrazoles, diazepines, and b-enamin-
ones/b-enamino esters using reusable catalysts in water
has not been published yet. Therefore, there is still room
for further search for recyclable catalysts to be used in
such synthesis. Heteropolyacids (HPAs), which are well-
known for their reusability, flexibility in modifying the
acid strength, ease of handling, environmental compati-
bility, nontoxicity, and experimental simplicity, have
been reported to efficiently catalyze many organic reac-
tions.10 Herein, we report a catalytic method for a chemo-
and regioselective synthesis of pyrazoles, diazepines, and
enaminones/enamino esters by room temperature conden-
sation of hydrazines/hydrazides, diamines, and primary
amines with various 1,3-dicarbonyl compounds in pure
Key words: 12-tungstophosphoric acid, recyclable catalyst, con-
densation, 1,3-dicarbonyl compounds, aqueous medium
Three kinds of nitrogen-containing compounds, pyra-
zoles, diazepines, and b-enaminones/b-enamino esters
have attracted considerable attention in organic synthesis
because of their prominent role. Pyrazoles and diazepines
are valuable bioactive heterocycles, which have been re-
ported to possess important biological and pharmaceutical
activities,1 such as antimicrobial, antiviral, antitumor,
anti-inflammatory, antifungal, antidepressant, and anti-
convulsantproperties. In addition, b-enaminones/b-enam-
ino esters are useful synthons for the synthesis of various
pharmaceuticals2 and bioactive heterocycles.3
A number of syntheses for these three kinds of com-
pounds have been developed. Among the synthesis of
pyrazoles reported,4 the most preferred ones are the reac-
tions of 1,3-dicarbonyl compounds with hydrazines in the
presence of acid, such as polystyrene supported sulfonic
acid (PSSA),4a sulfuric acid,4b etc. As for preparing diaz-
epines, several routes have been reported, including mi-
crowave heating of diazepine diones in boiling POCl3,5
hydrogen-transfer N-heterocyclization using the catalyst
[Cp*IrCl2]2/K2CO3,6 condensation of 1,3-diketones with
diamines using the catalyst PSSA,4a and others.7 More-
over, b-enaminones/b-enamino esters have been prepared
by condensation of amines and b-dicarbonyl compounds
utilizing Al2O3,8a SiO2/microwaves,8b montmorillonite
K-10,8c NaAuClO4,8d Bi(TFA)3,8e Zn(ClO4)2·6H2O,8f
CeCl3·7H2O,8g SiO2/HClO4,8h etc. However, most of the
methods to prepare these three kinds of compounds suffer
from certain drawbacks including tedious experimental
procedures, unsatisfactory yields, low selectivity, higher
temperatures, applications of nonavailable and costly re-
agents, use of hazardous solvents, employment of large
11
water using H3PW12O40 as an efficient, reusable, and
ecofriendly heterogeneous inorganic catalyst.
Table 1 12-Tungstophosphoric Acid Catalyzed Condensation of
Pentane-2,4-dione and PhNHNH2 in Different Solventsa
H3PW12O40
O
O
(1 mol%)
+
NHNH2
N
r.t., 8 min
N
Entry
Solvent
Yield (%)b
1
2
3
4
5
THF
92
96
92
95
93
EtOH
MeCN
CH2Cl2
H2O
a Reactions were performed with pentane-2,4-dione (1.0 mmol),
PhNHNH2 (1.1 mmol), and H3PW12O40 (1 mol%) in solvent (2 mL)
by stirring the mixture for 8 min at r.t.
SYNTHESIS 2008, No. 21, pp 3478–3486
Advanced online publication: 16.10.2008
DOI: 10.1055/s-0028-1083169; Art ID: F12408SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8
b Isolated yields after column chromatography.

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12-Tungstophosphoric Acid as a Reusable Catalyst in Water
3479
Initially, the condensation of hydrazines/hydrazides and diketones to afford the desired pyrazoles in good to excel-
1,3-dicarbonyl compounds with H3PW12O40 was exam- lent yields (Table 2). All of the reactions between hydra-
ined. As a model study, we chose the condensation part- zines/hydrazides and symmetrical diketones gave single
ners pentane-2,4-dione (1 mmol) and PhNHNH2 (1.1 components (Table 2, entries 1–10). When an unsymmet-
mmol) with the catalyst H3PW12O40 (1 mol%) as a system, rical diketone, 1-phenylbutane-1,3-dione, was employed
and different solvents including THF, EtOH, MeCN, to react with PhNHNH2, two regioisomers were obtained
CH2Cl2, and H2O were tested. As summarized in Table 1, in the ratio of 18:1 (Table 2, entry 11). Moreover, b-keto
the yield of the condensation was excellent in water, ap- esters can also be used as a substitute for diketones in this
proximately equal to those of the reactions in the above synthesis (Table 2, entries 12–14). In such case, only sin-
organic solvents.
gle components were obtained, in low yields at room tem-
perature, while in high yields at 50 °C for 30 min.
Condensation of hydrazines/hydrazides (1.1 mmol) and
1,3-dicarbonyl compounds (1 mmol) with H3PW12O40 (1
mol%) in pure water (2 mL) was then examined. Hydra-
zines/hydrazides reacted efficiently with various 1,3-
Table 2 12-Tungstophosphoric Acid Catalyzed Synthesis of Pyrazolesa
R3
R3
O
O
N
N
H3PW12O40 (1 mol%)
H2O, r.t.
N N
R3NHNH2
+
+
R1
R1
R1
R2
R2
R2
R1 = Me, Ph, OEt; R2 = H, Me; R3 = Ph, 4-MeC6H4, 4-ClC6H4, H, MeCO
Entry
1
Hydrazine/hydrazide
Dicarbonyl compound
Time (min) Product
8
Yield (%)b
93
O
O
O
O
(41)c
NHNH2
N
N
N
N
2
3
4
5
8
85
95
89
87
NHNH2
O
O
O
O
6
Me
Me
Cl
NHNH2
NHNH2
NHNH2
NHNH2
Me
N
N
N
N
6
Me
O
O
O
O
10
Cl
N
N
6
7
8
10
81
96
93
Cl
Cl
N
N
N
N
NH
O
O
O
O
NH2NH2
10
10
NH
NH2NH2
O
O
O
O
9
60
89
N
NHNH2
N
Synthesis 2008, No. 21, 3478–3486 © Thieme Stuttgart · New York

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X. Chen et al.
PAPER
Table 2 12-Tungstophosphoric Acid Catalyzed Synthesis of Pyrazolesa (continued)
R3
R3
O
O
N
N
H3PW12O40 (1 mol%)
H2O, r.t.
N
N
R3NHNH2
+
+
R1
R1
R1
R2
R2
R2
R1 = Me, Ph, OEt; R2 = H, Me; R3 = Ph, 4-MeC6H4, 4-ClC6H4, H, MeCO
Entry
10
Hydrazine/hydrazide
Dicarbonyl compound
Time (min) Product
Yield (%)b
O
O
O
O
60
85
N
NHNH2
N
Ph
N
O
O
N
18
11
30
92d
NHNH2
..
Ph
1
N
N
Ph
EtO
N
O
O
O
O
O
O
20
12
13
14
60
60
60
86e
NHNH2
OEt
OEt
OEt
N
EtO
N
25
88e
Me
Cl
NHNH2
NHNH2
Me
Cl
N
EtO
15
80e
N
N
a Reactions were performed with the 1,3-dicarbonyl compound (1.0 mmol), hydrazine/hydrazide (1.1 mmol), and H3PW12O40 (1 mol%) in pure
H2O (2 mL) at r.t.
b Isolated yields after column chromatography.
c Without H3PW12O40.
d The regioisomers were formed in a ratio of 18:1.
e Yields of reactions performed at 50 °C for 30 min.
Next, the reactions of diamines with b-dicarbonyl com- one with PhNH2, two regioisomers were obtained in the
pounds under the same conditions were investigated ratio of 29:1 (Table 4, entry 12).
(Table 3). 1,2-Diaminobenzene reacted efficiently with
The condensation was found to be highly chemo- and re-
pentane-2,4-dione and 3-methylpentane-2,4-dione to
gioselective. NH2 group in RNH2 and RNHNH2 attacks
yield diazepines in a single step (Table 3, entries 1, 2).
only at the keto carbonyl of the b-keto esters (Table 2, en-
tries 12–14, Table 4, entries 13, 14). In the case of an un-
symmetrical diketone, priority of attack is given to the
The reaction proceeded at room temperature in excellent
yields. The reaction of 1,2-diaminobenzene with b-keto
esters, however, failed to give the desired products
ketone carbonyl connected with a relatively weaker elec-
(Table 3, entries 3, 4).
tron-donating group (Table 2, entry 11, Table 4, entry 12).
Finally, this protocol was also extended to the synthesis of Moreover, the Z-selectivity in the product b-enaminones/
various b-enaminones/b-enamino esters by condensing b-enamino esters (Table 4, entries 1–14) was secured by
primary amines with various 1,3-diketones and b-keto es- intramolecular hydrogen bonding. In the 1H NMR spectra,
ters at room temperature in aqueous medium and the re- the proton of the NH group appeared in the region of d =
sults are summarized in Table 4. All of the reactions 8.5–13.5.
between primary amines and symmetrical 1,3-diketones
and b-keto esters gave single components in good to high
The possibility of recycling the catalyst was examined
next. For this purpose, the reaction of pentane-2,4-dione
yields (Table 4, entries 1–11, 13, 14). In the case of the re-
and aniline in water at room temperature in the presence
action of unsymmetrical diketone 1-phenylbutane-1,3-di-
of H3PW12O40 was studied (Table 5). When the reaction
was complete, ethyl acetate was added and the organic
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12-Tungstophosphoric Acid as a Reusable Catalyst in Water
3481
materials were extracted and the aqueous solution was
saved. This solution, containing the used catalyst, could
be reused and subjected to a second run of the reaction.
The results of the first experiment and subsequent experi-
ments were almost consistent in yields. Even after five
runs for the condensation, the catalytic activity of
H3PW12O40 was almost the same as that of the freshly used
catalyst.
Table 3 12-Tungstophosphoric Acid Catalyzed Synthesis of Diaz-
epinesa
R1
NH2
NH2
N
N
O
O
H3PW12O40 (1 mol%)
H2O, r.t., 5 h
R2
+
R1
R2
R1 = Me, OMe, OEt; R2 = H, Me
Entry
Dicarbonyl compound Product
Yield (%)b
In conclusion, we have developed a green and efficient
approach for the synthesis of pyrazoles, diazepines, and b-
enaminones/b-enamino esters by room temperature con-
densation of hydrazines/hydrazides, diamines, and prima-
ry amines with various 1,3-dicarbonyl compounds in pure
water in the presence of a catalytic amount of H3PW12O40
as a heterogeneous inorganic catalyst, which may provide
a useful route for drug discovery. The aqueous medium,
simple experimental procedure, mildness of the conver-
sion, high yields and chemo- and regioselectivities and re-
usability of the catalyst are the noteworthy advantages of
the protocol.
N
92
O
O
O
O
1
(31)c
N
N
2
3
4
89
N
OMe
N
O
O
O
O
NR
NR
OMe
OEt
N
N
All chemicals were purchased from Aldrich. NMR spectra were re-
corded on a Bruker Avance DMX 500 MHz (1H, 500 MHz; 13C, 125
MHz) spectrometer in CDCl3 solution. Low-resolution MS analyses
were measured on a Bruker Esquire 3000 spectrometer using ESI
(electrospray ionization) technique. Petroleum ether used refers to
the fraction boiling at 60–90 °C.
OEt
N
a Reactions were performed with the 1,3-dicarbonyl compound (1.0
mmol), diamines (1.1 mmol), and of H3PW12O40 (1 mol%) in pure
H2O (2 mL) by stirring the mixture for 5 h at r.t.
b Isolated yields after column chromatography.
c Without H3PW12O40.
Table 4 12-Tungstophosphoric Acid Catalyzed Synthesis of b-Enaminones/b-Enamino Estersa
R3
R3
O
O
NH
O
H3PW12O40 (1 mol%)
H2O, r.t., 1 h
NH
O
R3NH2
+
+
R1
R1
R1
R2
R2
R1 = Me, Ph, OEt; R2 = H, Me; R3 = 4-MeOC6H4, 4-MeC6H4, Ph, 4-ClC6H4, 2-MeC6H4, Bn, alkylm
R2
Entry
Amine
Dicarbonyl compound
Product
Yield (%)b
O
O
96
O
O
O
O
MeO
NH
NH
1
(11)c
MeO
NH2
NH2
MeO
Me
2
3
4
5
92
93
88
90
MeO
Me
O
O
O
O
O
NH
NH2
O
Me
NH
Me
NH2
O
O
O
NH
NH2
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3482
X. Chen et al.
PAPER
Table 4 12-Tungstophosphoric Acid Catalyzed Synthesis of b-Enaminones/b-Enamino Estersa (continued)
R3
R1
R3
O
O
NH
O
H3PW12O40 (1 mol%)
H2O, r.t., 1 h
NH
O
R3NH2
+
+
R1
R1
R2
R2
R1 = Me, Ph, OEt; R2 = H, Me; R3 = 4-MeOC6H4, 4-MeC6H4, Ph, 4-ClC6H4, 2-MeC6H4, Bn, alkylm
R2
Entry
Amine
Dicarbonyl compound
Product
Yield (%)b
O
O
O
NH
6
86
85
80
NH2
O
O
O
O
O
O
7
8
Cl
Cl
NH
NH
O
Cl
Cl
NH2
NH2
Me
Me
O
O
O
O
9
85
94
NH
NH2
NH2
NH
O
10
O
O
O
O
11d
95
HN
O
H2N
NH2
O
NH
O
O
NH
Ph
29
12
92e
NH2
..
Ph
NH
Ph
1
O
O
O
O
O
13
14
90
89
MeO
NH
OEt
MeO
NH2
OEt
OEt
NH2
NH
O
OEt
a Reactions were performed with the 1,3-dicarbonyl compound (1.0 mmol), primary amines (1.1 mmol), and H3PW12O40 (1 mol%) in pure H2O
(2 mL) by stirring the mixture for 1 h at r.t.
b Isolated yields after column chromatography.
c Without H3PW12O40.
d Reactions were performed with the 1,3-dicarbonyl compound (2.0 mmol), primary amines (1.1 mmol), and H3PW12O40 (1 mol%) in pure H2O
(2 mL).
e The regioisomers were formed in a ratio of 29:1.
Pyrazole, Diazepines, and b-Enaminones/b-enamino Esters;
General Procedure
NaHCO3 (2 mL). After drying the organic layer (Na2SO4) and evap-
oration of the solvent, the product was purified by column chroma-
tography (EtOAc–petroleum ether, 1:10).
The 1,3-dicarbonyl compound (1 mmol) and hydrazine/hydrazide
(diamine, primary amine) (1.1 mmol) were placed in a 5 mL glass
tube charged with pure H2O (2 mL). H3PW12O40 (1 mol%) was then
added and the mixture was stirred at r.t. for the time indicated in
Tables 2– 4. The products were extracted with EtOAc (3 × 2 mL)
and the combined EtOAc extracts were washed with aq 5%
3,5-Dimethyl-1-phenyl-1H-pyrazole (Table 2, entry 1)4b
1H NMR (CDCl3): d = 2.29 (s, 3 H, CH3), 2.30 (s, 3 H, CH3), 5.99
(s, 1 H, CH), 7.31–7.44 (m, 5 H, C6H5).
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12-Tungstophosphoric Acid as a Reusable Catalyst in Water
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Table 5 Recycling Experiments with 12-Tungstophosphoric Acida
(s, 1 H, CH), 7.37–7.42 (m, 4 Harom).
13C NMR (CDCl3): d = 12.62, 13.70, 107.57, 125.99, 129.34,
H3PW12O40
(1 mol%)
O
O
O
133.04, 138.74, 139.60, 149.56.
+
NH2
NH
MS (ESI): m/z = 208 ([M + H]+).
H2O, r.t., 1 h
1-(4-Chlorophenyl)-3,4,5-trimethyl-1H-pyrazole (Table 2,
entry 6)
Run
1
Yield (%)b
IR (KBr): 3064, 2920, 2862, 1596, 1576, 1500, 1437, 1407, 1383,
90
89
91
90
91
91
1366, 1137, 1093, 1012, 943, 833, 762, 734, 702, 670, 574 cm–1.
2
1H NMR (CDCl3): d = 1.98 (s, 3 H, CH3), 2.22 (s, 3 H, CH3), 2.24
(s, 3 H, CH3), 7.34–7.36 (d, J = 8.8 Hz, 2 Harom), 7.39–7.41 (d,
J = 8.8 Hz, 2 Harom).
13C NMR (CDCl3): d = 8.40, 11.22, 12.11, 113.92, 125.84, 129.31,
132.67, 136.17, 139.01, 148.73.
3
4
5
MS (ESI): m/z = 222 ([M + H]+).
6
Anal. Calcd for C12H13ClN2: C, 65.31; H, 5.94; N, 12.69. Found: C,
65.15; H, 5.86; N, 12.86.
a Reactions performed with pentane-2,4-dione (1.0 mmol), aniline
(1.1 mmol), and H3PW12O40 (1 mol%) in pure H2O (2 mL) and stirred
for 1 h at r.t.
3,5-Dimethyl-1H-pyrazole (Table 2, entry 7)12a
1H NMR (CDCl3): d = 2.28 (s, 6 , CH3), 5.82 (s, 1 H, CH), 10.41 (s,
1 H, NH).
b Isolated yields after column chromatography.
13C NMR (CDCl3): d = 12.38, 104.17, 144.50.
MS (ESI): m/z = 97 ([M + H]+).
13C NMR (CDCl3): d = 12.53, 13.68, 107.07, 124.89, 127.37,
129.13, 139.51, 140.08, 149.09.
MS (ESI): m/z = 173 ([M + H]+).
3,4,5-Trimethyl-1H-pyrazole (Table 2, entry 8)12b
1H NMR (CDCl3): d = 1.91 (s, 3 H, CH3), 2.20 (s, 6 H, CH3), 11.06
(s, 1 H, NH).
13C NMR (CDCl3): d = 7.71, 12.40, 104.09, 142.13.
MS (ESI): m/z = 111 ([M + H]+).
3,4,5-Trimethyl-1-phenyl-1H-pyrazole (Table 2, entry 2)
IR (KBr): 3064, 2920, 2862, 2740, 1598, 1578, 1505, 1433, 1384,
1367, 1320, 1138, 1073, 1020, 943, 880, 795, 762, 721, 696, 670,
661, 640, 576 cm–1.
1H NMR (CDCl3): d = 1.98 (s, 3 H, CH3), 2.21 (s, 3 H, CH3), 2.26
1-(3,5-Dimethyl-1H-pyrazol-1-yl)ethanone (Table 2, entry 9)4b
1H NMR (CDCl3): d = 2.24 (s, 3 H, CH3), 2.54 (s, 3 H, CH3), 2.66
(s, 3 H, CH3), 5.96 (s, 1 H, CH).
13C NMR (CDCl3): d = 14.02, 14.82, 23.77, 111.37, 144.22, 152.21,
171.71.
(s, 3 H, CH3), 7.30–7.43 (m, 5 H, C6H5).
13C NMR (CDCl3): d = 8.30, 11.06, 12.00, 113.32, 124.71, 127.01,
129.04, 139.09, 140.27, 148.14.
MS (ESI): m/z = 187 ([M + H]+).
Anal. Calcd for C12H14N2: C, 77.38; H, 7.58; N, 15.04. Found: C,
77.25; H, 7.50; N, 15.25.
MS (ESI): m/z = 139 ([M + H]+).
1-(3,4,5-Trimethyl-1H-pyrazol-1-yl)ethanone (Table 2, entry
3,5-Dimethyl-1-p-tolyl-1H-pyrazole (Table 2, entry 3)4b
1H NMR (CDCl3): d = 2.28 (s, 3 H, CH3), 2.30 (s, 3 H, CH3), 2.40
(s, 3 H, CH3), 5.98 (s, 1 H, CH), 7.23–7.25 (d, J = 8.2 Hz, 2 Harom),
7.29–7.31 (d, J = 8.2 Hz, 2 Harom).
13C NMR (CDCl3): d = 12.50, 13.72, 21.27, 106.78, 124.88, 129.72,
137.30, 137.69, 139.52, 148.87.
10)
IR (KBr): 2985, 2928, 2868, 2748, 1724, 1611, 1563, 1494, 1434,
1378, 1333, 1289, 1177, 1105, 1037, 997, 967, 934, 800, 719, 671,
630, 564 cm–1.
1H NMR (CDCl3): d = 1.88 (s, 3 H, CH3), 2.17 (s, 3 H, CH3), 2.43
(s, 3 H, CH3), 2.61 (s, 3 H, CH3).
13C NMR (CDCl3): d = 7.78, 12.49, 12.89, 23.66, 117.54, 139.59,
152.40, 171.46.
MS (ESI): m/z = 187 ([M + H]+).
3,4,5-Trimethyl-1-p-tolyl-1H-pyrazole (Table 2, entry 4)
IR (KBr): 3062, 2920, 2860, 2740, 1596, 1578, 1503, 1438, 1384,
1368, 1138, 1083, 1018, 943, 850, 762, 736, 699, 670, 576 cm–1.
1H NMR (CDCl3): d = 1.98 (s, 3 H, CH3), 2.20 (s, 3 H, CH3), 2.25
(s, 3 H, CH3), 2.39 (s, 3 H, CH3), 7.22–7.24 (d, J = 8.2 Hz, 2 Harom),
7.28–7.29 (d, J = 8.4 Hz, 2 Harom).
13C NMR (CDCl3): d = 8.42, 11.10, 12.10, 21.27, 113.13, 124.81,
124.90, 129.72, 136.25, 137.03, 137.92, 147.94.
MS (ESI): m/z = 201 ([M + H]+).
MS (ESI): m/z = 153 ([M + H]+).
Anal. Calcd for C8H12N2O: C, 63.13; H, 7.95; N, 18.41. Found: C,
63.00; H, 7.87; N, 18.55.
3-Methyl-1,5-diphenyl-1H-pyrazole (Table 2, entry 11a)12c,d
1H NMR (CDCl3): d = 2.39 (s, 3 H, CH3), 6.55 (s, 1 H, CH), 7.32–
7.91 (m, 10 H, C6H5).
13C NMR (CDCl3): d = 13.76, 107.97, 125.41, 127.40, 128.34,
128.63, 128.87, 129.09, 130.89, 140.27, 143.37, 149.70.
Anal. Calcd for C13H16N2: C, 77.96; H, 8.05; N, 13.99. Found: C,
77.84; H, 7.99; N, 14.17.
MS (ESI): m/z = 235 ([M + H]+).
5-Methyl-1,3-diphenyl-1H-pyrazole (Table 2, entry 11b)12e
1H NMR (CDCl3): d = 2.40 (s, 3 H, CH3), 6.33 (s, 1 H, CH), 7.22–
7.32 (m, 10 H, C6H5).
1-(4-Chlorophenyl)-3,5-dimethyl-1H-pyrazole (Table 2, entry
5)4a
1H NMR (CDCl3): d = 2.289 (s, 3 H, CH3), 2.294 (s, 3 H, CH3), 6.00
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(Z)-4-(4-Methoxyphenylamino)-3-methylpent-3-en-2-one
13C NMR (CDCl3): d = 12.75, 104.57, 125.16, 125.90, 127.79,
127.94, 128.75, 129.27, 133.52, 140.10, 140.36, 151.67.
(Table 4, entry 2)
IR (KBr): 3004, 2960, 2835, 1602, 1561, 1512, 1467, 1441, 1356,
MS (ESI): m/z = 235 ([M + H]+).
1290, 1269, 1244, 1182, 1105, 1035, 974, 843, 756, 592, 522 cm–1.
5-Ethoxy-3-methyl-1-phenyl-1H-pyrazole (Table 2, entry 12)12f
1H NMR (CDCl3): d = 1.42–1.45 (t, J = 7.0 Hz, 3 H, CH3), 2.28 (s,
3 H, CH3), 4.11–4.16 (q, J = 7.1 Hz, 2 H, CH2), 5.48 (s, 1 H, CH),
7.21–7.72 (m, 5 H, C6H5).
13C NMR (CDCl3): d = 14.77, 14.86, 68.01, 86.49, 121.97, 125.94,
128.96, 139.03, 148.94, 155.07.
1H NMR (CDCl3): d = 1.90 (s, 3 H, CH3), 1.95 (s, 3 H, CH3), 2.20
(s, 3 H, CH3), 3.80 (s, 3 H, CH3), 6.85–7.00 (m, 4 Harom), 13.33 (s,
1 H, NH).
13C NMR (CDCl3): d = 15.05, 17.11, 28.81, 55.67, 100.27, 114.40,
121.13, 132.51, 157.63, 159.75, 192.30.
MS (ESI): m/z = 220 ([M + H]+).
MS (ESI): m/z = 203 ([M + H]+).
Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C,
71.09; H, 7.76; N, 6.52.
5-Ethoxy-3-methyl-1-p-tolyl-1H-pyrazole (Table 2, entry 13)
IR (KBr): 3037, 2982, 2921, 2733, 1615, 1588, 1558, 1519, 1445,
1394, 1361, 1315, 1292, 1267, 1144, 1108, 1090, 1048, 1020, 1008,
976, 940, 906, 819, 776, 737, 655, 629, 616, 571 cm–1.
1H NMR (CDCl3): d = 1.41–1.44 (t, J = 7.0 Hz, 3 H, CH3), 2.28 (s,
3 H, CH3), 2.36 (s, 3 H, CH3), 4.10–4.14 (q, J = 7.1 Hz, 2 H, CH2),
5.47 (s, 1 H, CH), 7.20–7.21 (d, J = 8.2 Hz, 2 Harom), 7.56–7.58 (d,
J = 8.2 Hz, 2 Harom).
13C NMR (CDCl3): d = 14.76, 14.84, 21.17, 67.89, 86.25, 122.02,
129.49, 135.65, 136.62, 148.60, 154.89.
MS (ESI): m/z = 217 ([M + H]+).
(Z)-4-(p-Toluidino)pent-3-en-2-one (Table 4, entry 3)8e
1H NMR (CDCl3): d = 1.96 (s, 3 H, CH3), 2.09 (s, 3 H, CH3), 2.34
(s, 3 H, CH3), 5.17 (s, 1 H, CH), 6.99–7.00 (d, J = 8.2 Hz, 2 Harom),
7.13–7.15 (d, J = 8.2 Hz, 2 Harom), 12.40 (s, 1 H, NH).
13C NMR (CDCl3): d = 19.99, 21.13, 29.34, 97.41, 125.08, 129.87,
135.70, 136.28, 160.90, 196.13.
MS (ESI): m/z = 190 ([M + H]+).
(Z)-4-(p-Toluidino)-3-methylpent-3-en-2-one (Table 4, entry 4)
IR (KBr): 3291, 3066, 2944, 2920, 1610, 1551, 1511, 1455, 1402,
1365, 1265, 1181, 1113, 1041, 1015, 965, 821, 755, 620, 511 cm–1.
1H NMR (CDCl3): d = 1.92 (s, 3 H, CH3), 2.00 (s, 3 H, CH3), 2.22
(s, 3 H, CH3), 2.34 (s, 3 H, CH3), 6.94–6.96 (d, J = 8.2 Hz, 2 Harom),
7.12–7.14 (d, J = 8.1 Hz, 2 Harom), 13.41 (s, 1 H, NH).
13C NMR (CDCl3): d = 15.07, 17.21, 21.13, 28.87, 100.67, 125.45,
129.79, 135.20, 136.98, 159.14, 196.47.
MS (ESI): m/z = 204 ([M + H]+).
Anal. Calcd for C13H16N2O: C, 72.19; H, 7.46; N, 12.95. Found: C,
72.03; H, 7.39; N, 13.13.
1-(4-Chlorophenyl)-5-ethoxy-3-methyl-1H-pyrazole (Table 2,
entry 14)4a
1H NMR (CDCl3): d = 1.43–1.45 (t, J = 7.0 Hz, 3 H, CH3), 2.26 (s,
3 H, CH3), 4.11–4.15 (q, J = 7.0 Hz, 2 H, CH2), 5.47 (s, 1 H, CH),
7.35–7.69 (m, 2 Harom), 7.67–7.69 (m, 2 Harom).
13C NMR (CDCl3): d = 14.78, 14.86, 68.15, 86.68, 122.84, 129.03,
131.14, 137.74, 149.30, 155.13.
Anal. Calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C,
76.65; H, 8.37; N, 7.07.
MS (ESI): m/z = 238 ([M + H]+).
(Z)-4-(Phenylamino)pent-3-en-2-one (Table 4, entry 5)8h
1H NMR (CDCl3): d = 1.99 (s, 3 H, CH3), 2.10 (s, 3 H, CH3), 5.19
(s, 1 H, CH), 7.10–7.36 (m, 5 H, C6H5), 12.48 (s, 1 H, NH).
13C NMR (CDCl3): d = 20.08, 29.42, 97.83, 124.99, 125.79, 129.32,
138.96, 160.48, 196.39.
(1Z,4Z)-2,4-Dimethyl-3H-benzo[b][1,4]diazepine (Table 3,
entry 1)4a
1H NMR (CDCl3): d = 2.34 (s, 6 H, CH3), 2.81 (s, 2 H, CH2), 7.20–
7.22 (m, 2 Harom), 7.35–7.38 (m, 2 Harom).
MS (ESI): m/z = 176 ([M + H]+).
13C NMR (CDCl3): d = 27.87, 43.38, 125.09, 127.68, 140.43,
157.99.
MS (ESI): m/z = 173 ([M + H]+).
(Z)-3-Methyl-4-(phenylamino)pent-3-en-2-one (Table 4, entry
6)
IR (KBr): 3280, 3052, 2960, 2890, 1606, 1558, 1512, 1450, 1410,
(1Z,4Z)-2,3,4-Trimethyl-3H-benzo[b][1,4]diazepine (Table 3,
entry 2)4a
1350, 1263, 1180, 1113, 1040, 1015, 970, 825, 755, 620, 522 cm–1.
1H NMR (CDCl3): d = 1.92 (s, 3 H, CH3), 2.02 (s, 3 H, CH3), 2.22
(s, 3 H, CH3), 7.04–7.34 (m, 5 H, C6H5), 13.45 (s, 1 H, NH).
13C NMR (CDCl3): d = 15.05, 17.27, 28.92, 101.15, 125.30, 125.36,
129.19, 139.64, 158.57, 196.82.
1H NMR (CDCl3): d = 1.58–1.59 (d, J = 7.0 Hz, 3 H, CH3), 2.00–
2.01 (q, J = 7.0 Hz, 1 H, CH), 2.23 (s, 6 H, CH3), 7.20–7.22 (m, 2
Harom), 7.36–7.38 (m, 2 Harom).
13C NMR (CDCl3): d = 13.04, 22.89, 44.99, 124.98, 127.23, 139.86,
157.79.
MS (ESI): m/z = 187 ([M+ H]+).
MS (ESI): m/z = 190 ([M + H]+).
Anal. Calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C,
76.00; H, 7.91; N, 7.58.
(Z)-4-(4-Methoxyphenylamino)pent-3-en-2-one (Table 4, entry
1)12g
(Z)-4-(4-Chlorophenylamino)pent-3-en-2-one (Table 4, entry
7)12g
1H NMR (CDCl3): d = 1.91 (s, 3 H, CH3), 2.09 (s, 3 H, CH3), 3.80
(s, 3 H, CH3), 5.16 (s, 1 H, CH), 6.86–6.88 (d, J = 8.8 Hz, 2 Harom),
7.03–7.05 (d, J = 8.8 Hz, 2 Harom), 12.30 (s, 1 H, NH).
1H NMR (CDCl3): d = 1.97 (s, 3 H, CH3), 2.10 (s, 3 H, CH3), 5.20
(s, 1 H, CH), 7.02–7.31 (m, 4 Harom), 12.48 (s, 1 H, NH).
13C NMR (CDCl3): d = 19.84, 29.28, 55.66, 97.03, 114.44, 126.88,
13C NMR (CDCl3): d = 20.02, 29.46, 98.34, 126.10, 129.45, 131.24,
131.71, 157.92, 161.45, 192.03.
137.59, 159.62, 196.79.
MS (ESI): m/z = 206 ([M + H]+).
MS (ESI): m/z = 211 ([M + H]+).
Synthesis 2008, No. 21, 3478–3486 © Thieme Stuttgart · New York

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12-Tungstophosphoric Acid as a Reusable Catalyst in Water
MS (ESI): m/z = 236 ([M + H]+).
3485
(Z)-4-(4-Chlorophenylamino)-3-methylpent-3-en-2-one (Table
4, entry 8)
IR (KBr): 3325, 3059, 2998, 2921, 1605, 1587, 1564, 1495, 1420,
1398, 1354, 1256, 1222, 1179, 1108, 1012, 976, 846, 809, 739, 699,
674, 625, 592 cm–1.
1H NMR (CDCl3): d = 1.91 (s, 3 H, CH3), 1.99 (s, 3 H, CH3), 2.21
(s, 3 H, CH3), 6.96–6.98 (d, J = 8.6 Hz, 2 Harom), 7.27–7.29 (d,
J = 8.6 Hz, 2 Harom), 13.37 (s, 1 H, NH).
Ethyl (Z)-3-(Benzylamino)but-2-enoate (Table 4, entry 14)8h
1H NMR (CDCl3): d = 1.25–1.28 (t, J = 7.0 Hz, 3 H, CH3), 1.92 (s,
3 H, CH3), 4.09–4.13 (q, J = 7.1 Hz, 2 H, CH2), 4.43–4.44 (d,
J = 6.4 Hz, 2 H, CH2), 4.55 (s, 1 H, CH), 7.26–7.36 (m, 5 H, C6H5),
8.96 (s, 1 H, NH).
13C NMR (CDCl3): d = 14.83, 19.54, 47.00, 58.57, 83.45, 126.92,
127.54, 128.98, 138.98, 161.97, 170.79.
13C NMR (CDCl3): d = 15.04, 17.22, 28.99, 101.83, 126.41, 129.48,
130.66, 138.32, 157.89, 197.37.
MS (ESI): m/z = 220 ([M + H]+).
MS (ESI): m/z = 225 ([M + H]+).
Anal. Calcd for C12H14ClNO: C, 64.63; H, 6.31; N, 6.26. Found: C,
64.50; H, 6.24; N, 6.41.
References
(1) (a) Behr, L. C.; Fusco, R.; Jarboe, C. H. In Pyrazoles,
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(b) Elguero, J. In Comprehensive Heterocyclic Chemistry II,
Vol. 3; Katritzky, A. R.; Rees, C. W.; Scriven, E. F., Eds.;
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(Z)-4-(o-Toluidino)pent-3-en-2-one (Table 4, entry 9)12h
1H NMR (CDCl3): d = 1.87 (s, 3 H, CH3), 2.11 (s, 3 H, CH3), 2.29
(s, 3 H, CH3), 5.20 (s, 1 H, CH), 7.07–7.24 (m, 4 Harom), 12.34 (s, 1
H, NH).
13C NMR (CDCl3): d = 18.24, 19.78, 29.26, 97.23, 126.47, 126.58,
126.60, 130.98, 133.92, 137.72, 161.35, 196.22.
MS (ESI): m/z = 190 ([M + H]+).
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(Z)-4-(Benzylamino)pent-3-en-2-one (Table 4, entry 10)12g
1H NMR (CDCl3): d = 1.91 (s, 3 H, CH3), 2.03 (s, 3 H, CH3), 4.45–
4.46 (d, J = 6.5 Hz, 2 H, CH2), 5.05 (s, 1 H, CH), 7.25–7.35 (m, 5
H, C6H5), 11.17 (s, 1 H, NH).
13C NMR (CDCl3): d = 19.05, 29.10, 46.92, 96.10, 126.90, 127.61,
129.00, 138.26, 163.24, 195.57.
MS (ESI): m/z = 190 ([M + H]+).
(3Z,3¢Z)-4,4¢-[Ethane-1,2-diylbis(azanediyl)]dipent-3-en-2-one
(Table 4, entry 11)8h
1H NMR (CDCl3): d = 1.89 (s, 6 H, CH3), 1.98 (s, 6 H, CH3), 3.40–
3.41 (t, J = 3.0 Hz, 4 H, CH2), 4.98 (s, 2 H, CH), 10.89 (s, 2 H, NH).
13C NMR (CDCl3): d = 18.91, 29.12, 43.74, 96.39, 163.06, 195.79.
MS (ESI): m/z = 225 ([M + H]+).
(Z)-1-Phenyl-3-(phenylamino)but-2-en-1-one (Table 4, entry
12a)12h
1H NMR (CDCl3): d = 2.16 (s, 3 H, CH3), 5.92 (s, 1 H, CH), 7.19–
7.95 (m, 10 H, C6H5), 13.13 (s, 1 H, NH).
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13C NMR (CDCl3): d = 20.66, 94.48, 124.98, 125.99, 127.28,
128.50, 129.38, 131.12, 138.85, 140.23, 162.44, 188.88.
MS (ESI): m/z = 238 ([M + H]+).
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(Z)-4-Phenyl-4-(phenylamino)but-3-en-2-one (Table 4, entry
12b)12i
1H NMR (CDCl3): d = 2.24 (s, 3 H, CH3), 5.44 (s, 1 H, CH), 6.77–
7.35 (m, 10 H, C6H5), 9.71 (s, 1 H, NH).
13C NMR (CDCl3): d = 29.62, 100.33, 122.98, 123.79, 127.64,
128.20, 128.59, 129.18, 135.40, 139.60, 159.50, 197.36.
MS (ESI): m/z = 238 ([M + H]+).
Ethyl (Z)-3-(4-Methoxyphenylamino)but-2-enoate (Table 4,
entry 13)12g
1H NMR (CDCl3): d = 1.27–1.30 (t, J = 7.1 Hz, 3 H, CH3), 1.88 (s,
3 H, CH3), 3.80 (s, 3 H, CH3), 4.12–4.16 (q, J = 7.0 Hz, 2 H, CH2),
4.65 (s, 1 H, CH), 6.84–6.86 (d, J = 8.8 Hz, 2 Harom), 7.01–7.03 (d,
J = 8.8 Hz, 2 Harom), 10.16 (s, 1 H, NH).
13C NMR (CDCl3): d = 14.82, 20.30, 55.63, 58.83, 84.91, 114.38,
127.03, 132.33, 157.65, 160.23, 170.71.
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X. Chen et al.
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stabilities and low reducibilities. The acidity strength
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Synthesis 2008, No. 21, 3478–3486 © Thieme Stuttgart · New York