Phase-transfer catalyzed alkylation and cycloalkylation of 3-substituted-1H-pyrazol-2-in-5-ones in the absence or presence of carbon disulphide

Article abstract of DOI:10.1080/104265090517208

PTC-alkylation of 3-substituted-1H-pyrazol-2-in-5-ones by different organohalogen reagents at 25°C in the presence of tetrabutylammonium bromide as-catalyst was investigated either in the absence or presence of CS ₂. This work aims to study the comparative reactivity of N-versus O-versus C-alkylation and cycloalkylation. Copyright Taylor & Francis Inc.

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Phosphorus, Sulfur, and Silicon
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Phase-Transfer Catalyzed
Alkylation and Cycloalkylation
of 3-Substituted-1H-pyrazol-2-
in-5-ones in the Absence or
Presence of Carbon Disulphide
A. Kh. Khalil a , M. A. Hassan a , M. M. Mohamed a &
A. M. El-Sayed a
a Chemistry Department , Faculty of Science, Ain
Shams University , Abbasia, Cairo, Egypt
Published online: 21 Dec 2010.
To cite this article: A. Kh. Khalil , M. A. Hassan , M. M. Mohamed & A. M. El-
Sayed (2005) Phase-Transfer Catalyzed Alkylation and Cycloalkylation of 3-
Substituted-1H-pyrazol-2-in-5-ones in the Absence or Presence of Carbon Disulphide,
Phosphorus, Sulfur, and Silicon and the Related Elements, 180:2, 479-496, DOI:
10.1080/104265090517208
To link to this article: http://dx.doi.org/10.1080/104265090517208
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Phosphorus, Sulfur, and Silicon, 180:479–496, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090517208
Phase-Transfer Catalyzed Alkylation and Cycloalkylation
of 3-Substituted-1H-pyrazol-2-in-5-ones in the Absence
or Presence of Carbon Disulphide
A. Kh. Khalil
M. A. Hassan
M. M. Mohamed
A. M. El-Sayed
Chemistry Department, Faculty of Science, Ain Shams University,
Abbasia, Cairo, Egypt
PTC-alkylation of 3-substituted-1H-pyrazol-2-in-5-ones by different organohalogen
reagents at 25◦C in the presence of tetrabutylammonium bromide as-catalyst was
investigated either in the absence or presence of CS2. This work aims to study the
comparative reactivity of N-versus O-versus C-alkylation and cycloalkylation.
Keywords 3-Substituted-1H-pyrazol-2-in-5-ones; alkylation; cycloalkylation; phase-
transfer catalysis (PTC)
INTRODUCTION
Phase-transfer catalysis (PTC) is one of the promising methods in or-
ganic synthesis of specialty chemicals. In the last 20 years, a steadily
increasing number of published articles and patents dealing with phase
transfer catalysis topics and their applications. PTC is not merely im-
portant for substitution reactions, but nowadays it is being extensively
applied in polymer chemistry, heterocyclic chemistry, organometal-
lic and agrochemicals dyes, flavors, perfumes, and pharmaceutical
manufacture.1−3
The technique of PTC has been extensively applied in the organic
synthesis via substitution, displacement, condensation, elimination, re-
dox, polymerization, and Ylide-mediated reactions. The most advan-
tages of using the PTC technique to synthesize organic chemicals are
the enhancement of the reaction rate, carrying out the reaction at
Received April 17, 2004; in final form July 25, 2004.
Address correspondence to A. Kh. Khalil, Chemistry Department, Faculty of Sci-
ence, King Abdul Aziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia. E-mail:
mahassan77@yahoo.com
479

480
A. Kh. Khalil et al.
moderate conditions, and obtaining high selectivity of the main product
with high conversion of the reactants.4,5
In continuation of our current research in the field of organic syn-
thesis of some heterocyclic compounds under phase transfer catalysis
conditions (PTC),6−10 we aim here to study the reactivity of N-vs. O-vs.
C-alkylation of 3-substituted-1H-pyrazol-2-in-5-ones.
5-Pyrazolones are very important class of heterocycles due to their
biological and pharmacological activities11,12 which exhibit an anti-
inflammatory,13 herbicidal,14 fungicidal,15 and bactericidal,15 plant
growth regulating properties14 and antipyretic16 and protein kinase
inhibitors.17 Also, they are used as a key starting for the synthesis of
commercial arylazopyrazolone dyes.
RESULT AND DISCUSSION
The approach reported here is an extension and continuation of our in-
terest in alkylation of some heterocycles under phase-transfer catalysis
(PTC) conditions.18,19 This work is aiming to study the phase-transfer
catalyzed alkylation of 3-substituted-1H-pyrazol-2-in-5-ones and the
comparative reactivity towards N-versus O-versus C-alkylation upon
treatment with different organo–halogen reagents either under liquid-
solid or liquid-liquid phases in the presence of tetrabutylammonium
bromide (TBAB) as a catalyst in the absence or presence of CS2 at 25◦C.
3-substituted-1H-pyrazol-2-in-5-ones (1a–c) exist in three tau-
tomeric forms (I–III) due to their keto-enol or lactam-lactime tau-
tomerism, while the enol form (II) is the predominate one. This phe-
nomenon is confirmed by spectral data in addition to our results of
PTC-alkylation which are afforded O-monoalkylated products or O- and
N-dialkylated or cycloalkylated products.
SCHEME 1 Tautomers of 3-substituted-1H-pyrazol-2-in-5-ones (1a–c).
3-Substituted-1H-pyrazol-2-in-5-ones (1a–c) have been synthesized
by heating a mixture of β-ketoesters with hydrazine hydrate.

Alkylation of Pyrazolones
481
The optimized reaction conditions of our PTC-alkylation are the
treatment of 5-hydroxy-3-substituted-1H-pyrazoles (1a–c) with differ-
ent organo-halogen compounds in a 1:3 molar ratio either in (a) acetoni-
trile as a liquid phase and anhydrous potassium carbonate as a basic
solid phase in the presence of TBAB as a catalyst in the absence or pres-
ence of CS2 at 25◦C, and/or (b) acetonitrile as a liquid phase and a 30%
aqueous sodium hydroxide solution as an immiscible liquid phase in the
presence of TBAB as a catalyst at 25◦C. In both conditions the reaction
needs vigorous and efficient stirring for a limited short time where the
reaction progress was monitored by thin-layer chromatography (TLC).
Methylation of 5-hydroxy-3-phenyl-1H-pyrazole (1b) under the op-
timized PTC conditions in solid-liquid phases by methyl iodide under-
went O-methylation, predominantly to give 5-methoxy-3-phenyl-1H-
pyrazole (2) (Scheme 2), while methylation of 5-hydroxy-3-methyl/or
phenyl-1H-pyrazole (1a, b) by methyl iodide in the presence of carbon
disulphide under the same liquid-solid PTC conditions afforded methyl
5-hydroxy-1,3-dimethyl-1H-pyrazole-4-carbodithioate (3) or methyl 5-
hydroxy-1-methyl-3-phenyl-1H-pyrazole-4-carbodithioate (4), respec-
tively (Scheme 3). The reaction proceeds via nucleophilic addition of C4
of pyrazolone to CS2 followed by simultaneous N- and S-methylation of
the intermediate carbodithioate anion.
PTC-alkylation of 5-hydroxy-3-phenyl-1H-pyrazole (1b) by allyl bro-
mide using anhydrous K2CO3/acetonitrile as solid-liquid phases in the
presence of TBAB as a catalyst underwent O-alkylation only to give
5-(allyloxy)-3-phenyl-1H-pyrazole (5) (Scheme 2).
Benzylation of 5-hydroxy-3-methyl-1H-prazole (1a) under the solid-
liquid PTC conditions gave 1,4-dibenzyl-3-methyl-1H-2-pyrazolin-5-
one (6) via C- and N-dibenzylations and 5-benzyloxy-3-methyl-1H-
pyrazole (7) via O-benzylation that were separated by column chro-
matography using petroleum ether 60–80, ethyl acetate, chloroform
(6:3:1) as eluent, while benzylation of 5-hydroxy-3-methyl-1H-prazole
(1a) in the liquid-liquid PTC conditions gave three products are
1,4-dibenzyl-5-benzyloxy-3-methyl-1H-pyrazole (8) via C-, N- and O-
benzylation, 1,4-dibenzyl-3-methyl-1H-2-pyrazolin-5-one (6) and 5-
benzyloxy-3-methyl-1H- pyrazole (7) that are separated by column
chromatography, using petroleum ether 60–80, ethyl acetate, chloro-
form (5:3:1) as eluent. Moreover, benzylation of 5-hydroxy-3-phenyl-
1H-prazole (1b) using benzyl chloride in solid-liquid or liquid-
liquid phases under the same PTC reaction conditions gave N- and
O-monobenzylated products 1-benzyl-5-hydroxy-3-phenyl-1H-pyrazole
(9) and 5-benzyloxy-3-phenyl-1H-pyrazole (10) that were separated by
column chromatography using petroleum ether 60–80, ethyl acetate
(2:3) as eluent.

482
A. Kh. Khalil et al.
SCHEME 2 Alkylated products (2–20) of pyrazolones (1a–c) in the absence of
CS2.
PTC-benzylation of 1c by benzyl chloride using anhydrous K2CO3 as
a solid phase and acetonitrile as liquid phase in the presence of TBAB
as a catalyst underwent only N-monobenzoylation to give 1-benzyl-5-
hydroxy-3-pyrid-3-yl-1H-pyrazole (11) (Scheme 2).
On the other hand, benzylation of 5-hydroxy-3-methyl-1H-pyrazole
(1a) uses benzyl chloride in the presence of carbon disulphide TBAB
as a catalyst and anhydrous K2CO3/dry acetonitrile as solid-liquid
phases. The benzylation reaction was monitored by TLC and the

Alkylation of Pyrazolones
483
SCHEME 3 Alkylated products (3, 4 and 12–14) of pyrazolones (1a–c) in the
presence of CS2.
products obtained were separated by column chromatography us-
ing petroleum ether 60–80 and ethyl acetate (7:6) as eluent. The
benzylation reaction was believed to proceed via nucleophilic ad-
dition of C4 of pyrazolone to CS2 followed by S-benzylation of
the carbodithioate anion as intermediate to give benzyl 5-hydroxy-
3-methyl-1H-pyrazole-4-carbodithioate (12) and benzyl 1-benzyl-5-
hydroxy-3-methyl-1H-pyrazole-4-carbodithioate (13) via subsequent S-
and N- benzylations. Moreover, Benzylation of 1b, in the presence of
carbon disulphide under the same PTC conditions afforded S- and N-
dibenzylation to give benzyl 1-benzyl-5-hydroxy-3-phenyl-1H-pyrazole-
4-carbodithioate (14) (Scheme 3).
PTC-cyclohexylation of 5-hydroxy-3-phenyl/or-3-(pyrid-3-yl)-1H-
pyrazole (1b, c) by cyclohexyl bromide either in solid K2CO3/acetonitrile
phases or NaOH solution/acetonitrile phases and TBAB as a catalyst
affords O-alkylation only to give 5-cyclohexyloxy-3-phenyl/or-3(pyrid-
3-yl)1H-pyrazoles (15a, b), respectively (Scheme 2).
Alkylation of 5-hydroxy-3-phenyl/or-3-(pyrid-3-yl)-1H-pyrazoles
(1b, c) by chloroacetonitrile in solid K2CO3 and acetonitrile as solid/
liquid phases in the presence of TBAB as a catalyst at room temper-
ature affords, simultaneous O- and N-dialkylations, 1-cyanomethyl-
5-cyanomethyloxy-3-phenyl/or-3-(pyrid-3-yl)-1H-pyrazoles (16a, b)
and O-alkylation, and 5-cyanomethyloxy-3-phenyl/or-3-(pyrid-3-yl)-
1H-pyrazoles (17a, b), respectively. The products 16a and 17a are

484
A. Kh. Khalil et al.
separated by column chromatography using petroleum ether 60–80,
ethyl acetate, chloroform (3:2:5) as eluent. However, products 16a
and 17a are separated by column chromatography using petroleum
ether 60–80 and ethyl acetate (3:2) as an eluent. Also, PTC-alkylation
of 5-hydroxy-3-phenyl-1H-pyrazoles (1b) by chloroacetonitrile in
NaOH solution/acetonitrile as liquid-liquid phases in the presence of
TBAB at room temperature affords O-alkylation product (17a) with
a simultaneous O-, N- and C4-trialkyled product 5-cyanomethyloxy-
1,4-dicyanomethyl-3-phenylpyrazole (18) that is separated by column
chromatography using petroleum ether 60–80, ethyl acetate, and
chloroform (3:2:5) as eluent. However, alkylation of 5-hydroxy-3-(pyrid-
3-yl)-1H-pyrazoles (1c) under the same PTC conditions affords the
O-alkylation product, 5-cyanomethyloxy-3-(pyrid-3-yl)-1H-pyrazoles
(17b) only (Scheme 2).
On the other hand, treatment of 5-hydroxy-3-phenyl/or-3-(pyrid-3-
yl)-1H-pyrazoles (1b, c) with ethyl bromoacetate (1:3 molar ratio) un-
der the same optimized PTC conditions of liquid-solid phases affords
O-alkylated products only to give ethyl 3-phenyl/or-3-(pyrid-3-yl)-1H-
pyrazol-5-yloxy acetate (19b, c). Treatment of 5-hydroxy-3-methyl-1H-
pyrazoles (1a) with ethyl bromoacetate under the same PTC conditions
affords O-alkylated product (19a) and the N-, O-dialkylated product,
diethyl 3-methyl-1H-pyrazol-5-yloxy-1,5-diacetate (20), that separates
by column chromatography using petroleum ether 60–80 and ethyl ac-
etate (7:3) as eluent (Scheme 2).
Treatment of equimolar amounts of 5-hydroxy-3-methyl-1H-
pyrazole (1a) and 1,2-dibromoethane in acetonitrile/anhydrous K2CO3
as liquid-solid phases and in the presence of TBAB as a catalyst
at 25◦C yielded 5-(2-bromoethoxy)-3-methyl-1H-pyrazole (21a) and 6-
methyl-2,3-dihydropyrazolo[5,1-b]-oxazole (22a) which are separated
by column chromatography using ethyl acetate:petroleum ether 60–
80 (3:2) as eluent. Whenever under the same PTC reaction conditions,
5-hydroxy-3-phenyl-1H-pyrazole (1b) yields only 6-phenyl-2,3-dihydro-
pyrazolo[5,1-b]-oxazole (22b). Moreover, 5-hydroxy-3-(pyrid-3yl)-1H-
pyrazole (1c) yields a mixture of 5-(2-bromoethoxy)-3-(pyrid-3yl)-1H-
pyrazole (21c) and 6-(pyrid-3-yl)-2,3-dihydro-pyrazolo[5,1-b]-oxazole
(22c) which are separated by column chromatography using petroleum
ether 60–80, ethyl acetate, and chloroform (2:8:1) as eluent
(Scheme 4).
On the other hand, under the same PTC-reaction conditions, alky-
lation of pyrazole (1a) by ethylene dibromide in acetonitrile/NaOH
solution as liquid-liquid phases affords the corresponding O-mono-
alkylation product (21a) while pyrazole (1c) yields a mixture of 21c
and 22c.

Alkylation of Pyrazolones
485
SCHEME 4 Cycoalkylated products (21–27) of pyrazoles (1a–c) in the absence
or presence of CS2.
On the other hand, treatment of 3-phenyl-2-pyrazolin-5-one (1b)
with 1,2-dibromoethane in the presence of carbon disulphide in acetoni-
trile/anhydrous K2CO3 as liquid-solid phases and TBAB as a catalyst
at room temperature affords 4-(1,3-dithiolan-2-ylidene)-5-phenyl-2,4-
dihydro-3H-pyrazol-3-one (23) (Scheme 4).
PTC-Alkylation of 5-hydroxy-3-methyl/or-3-(pyrid-3-yl)-1H-pyraz-
oles (1a, c) by 1,4-dibromobutane in acetonitrile/anhydrous K2CO3
as liquid-solid phases or in acetonitrile/NaOH solution as liquid-
liquid phases in the presence of TBAB as a catalyst at room temper-
ature yields 2-methyl/or-3-(pyrid-3-yl)-5,6,7,8-tetrahydropyrazolo[5,
1-b][1,3]-oxazepines (24a, c). However, liquid-liquid PTC-alkylation of
5-hydroxy-3-phenyl-1H-pyrazole (1b) with 1,4-dibromobutane yields
either 2-phenyl-5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]oxazepine (24b),
while under solid-liquid PTC conditions affords 5-(4-bromobultyloxy)-
3-phenyl-1H-pyrazole (25) only as O-monoalkylated product. It’s wor-
thy to mention that oily crude products of 24a, c are first obtained
and passed through a column using petroleum ether 60–80, ethyl ac-
etate, chloroform (6:3:2), and petroleum ether 60–80, ethyl acetate (2:3)
as eluents. Then the organic solvents are evaporated to give the pure
crystalline solids.
On the other hand, treatment of 5-hydroxy-3-methyl/or phenyl-1H-
pyrazole (1a, b) with 1,4-dibromobutane in the presence of carbon
disulphide in dry acetonitrile/anhydrous K2CO3 as liquid-solid phases
and TBAB as a catalyst at room temperature probably proceeds via
nucleophilic addition of C4 of pyrazolone to CS2 followed by alkylation

486
A. Kh. Khalil et al.
of the intermediate carbodithiolate anion to give 4-(1,3-dithiepan-2-
ylidene)-5-methyl-2,4-dihydro-3H-pyrazol-3-one (26) and 2-(4-bromo-
butyl)-4-(1,3-dithiepan-2-ylidene)-5-phenyl-2,4-dihydro-3H-pyrazol-3-
one (27), respectively (Scheme 4).
EXPERIMENTAL
All melting points reported are uncorrected. IR spectra were recorded
using Perkin Elmer’s Spectrum RXIFT-IR spectrophotometer, USA (ν
in cm−1). The NMR spectra were recorded on Bruker Avance DPX400
spectrometer using deuterated chloroform (CDCl3) as a solvent and
TMS as an internal standard (chemical shifts in δ values in ppm. El-
emental analyses were preformed on Perkin Elmer 2400, series II mi-
croanalyzer, USA. The used 1R, NMR spectrophotometers and CHN-
microanalyzer are located at Chemistry Dept., Faculty of Science, King
Abdulaziz University, Jeddah, Saudi Arabia.
Condensation of β-Ketoester with Hydrazine Hydrate:
Synthesis of 5-Hydroxy-3-substituted-1H-pyrazoles (1a–c)
A solution of ethyl acetoacetate, (0.01 mol, 1.54 g), ethyl benzoylacetate
(0.01 mol, 1.92 mL) or ethyl nicotinoylacetate (0.01 mol, 1.94 g) and
hydrazine hydrate (0.01 mol, 0.48 g, 100%) in ethanol (50 mL) is refluxed
for 6 h then the solvent was evaporated. The solid residue is crystallized
from ethanol to give the corresponding pyrazole (1a–c), respectively as
white crystals. The results are listed in Tables I and II.
General Procedure of PTC-Alkylation
(A) Alkylation in the Absence of Carbon Disulphide
(1) In liquid-solid phases. In a 150 mL conical flask fitted with a rub-
ber stopper, a suspension of 5-hydroxy-3-substituted-1H-pyrazoles (1,
0.01 mol), anhydrous potassium carbonate (0.02 mol, 2.76 g) and tetra-
butylammonium bromide (TBAB, 0.003 mol, 0.9 g) in dry acetonitrile
(50 mL) stirred at 25◦C for 30 min, then the organo-halogen compound,
and the alkylating agent, (0.03 mol) was added and the reaction mixture
efficiently stirred at room temperature. The progress of the reaction
was monitored by TLC during the entire reaction time. After the reac-
tion completion, the organic layer was separated by filtration and the
solvent was evaporated. The residue crystallizes from the proper sol-
vent or separates by column chromatography using silica gel (80–120
mesh) and proper eluent to give one or more pure products. Also, the
K2CO3 precipitate dissolves in water (100 mL) and acidifies by dilute

Alkylation of Pyrazolones
487
TABLE I The Physical Data of Alkylated Products Compounds 1–27
Elemental analysis
Reaction
period
(in h)
Solvent
cryst.
(yield %)
calc./found %
Compd
no.
M. formula
(m. wt.)
m. p.◦C
(color)
C
H
N
1a
1b
1c
2
—
—
—
8
C4H6N2O
(98.10)
C9H8N2O
(160.18)
C8H7N3O
(161.16)
C10H10N2O
(174.20)
C7H10N2OS2
(202.30)
C12H12N2OS2
(264.37)
C12H12N2O
(200.24)
218–220
238–240
260–261
E
(60)
E
(65)
E
(55)
P 80–100
(37)
P 80–100
(57)
E
(66)
P 80–100
(67)
E
(44)
E
(17)
E
(8)
E
(45)
E
(35)
P 80–100
(42)
E
(16)
E
(28)
E
48.97
48.72
67.49
67.31
59.62
59.44
68.94
68.78
41.56
41.37
54.52
54.38
71.98
71.90
77.67
77.46
70.19
70.03
81.49
81.33
76.78
76.67
76.78
76.69
71.70
71.53
54.52
54.38
64.38
64.19
69.20
71.22
74.35
74.27
69.11
69.03
65.54
65.41
60.25
60.16
66.32
66.17
60.00
59.77
6.16
6.03
5.03
4.96
4.38
4.32
5.78
5.73
4.98
4.90
4.58
4.49
6.04
6.00
6.52
6.49
6.43
6.41
6.57
6.52
5.64
5.53
5.64
5.60
5.21
5.19
4.58
4.50
5.12
5.08
4.84
5.13
7.49
7.43
7.04
7.00
4.23
4.20
3.79
3.72
4.55
4.50
4.03
4.01
28.55
28.41
17.49
17.33
26.07
25.92
16.08
15.94
13.85
13.76
10.60
10.46
13.99
13.81
10.06
9.97
188–120
(White)
152–154
(Yellow)
187–188
(Yellow)
141–142
(Yellow)
88–89
(White)
135–136
(White)
184–185
(White)
149–150
(White)
167–169
(White)
159–160
(white)
208–210
(Yellow)
149–150
(Yellow)
155–156
(yellow)
128–130
(White)
140–141
(White)
84–85
(White)
123–124
(White)
149–150
(White)
152–153
(White)
3
6
4
6
5
12
24
24
24
26
26
24
18
18
12
48
36
24
35
18
35
6
C
18H18N2O
(278.36)
7
C
11H12N2O
(188.23)
14.88
14.67
7.60
8
C25H24N2O
(368.48)
7.51
9
C
C
C
16H14N2O
(250.30)
16H14N2O
(250.30)
15H13N3O
(251.29)
11.19
11.02
11.19
11.07
16.72
16.58
10.60
10.47
7.90
10
11
12
13
14
15a
15b
16a
16b
17a
17b
C
12H12N2OS2
(264.37)
C19H18N2OS2
(354.50)
C24H20N2OS2
(416.55)
C15H18N2O
(242.32)
7.72
6.72
6.88
(28)
P 60–80
(65)
P 80–100
(35)
E
(37)
E
(34)
E
11.56
11.49
17.27
17.08
23.52
23.42
29.27
29.14
21.09
21.00
27.99
27.76
C
14H17N3O
(243.31)
C
13H10N4O
(238.24)
C
12H9N5O
(239.24)
C11H9N3O
(199.21)
C10H8N4O
(200.20)
(44)
E
(25)
(Continued on next page)

488
A. Kh. Khalil et al.
TABLE I The Physical Data of Alkylated Products Compounds 1–27
(Continued)
Elemental analysis
Reaction
period
(in h)
Solvent
cryst.
(yield %)
calc./found %
Compd
no.
M. formula
(m. wt.)
m. p.◦C
(color)
C
H N
18
18
36
6
C15H11N5O
(277.29)
C8H12N2O3
(184.20)
142–143
(White)
79–80
E
(23)
E
64.98 4.00 25.26
64.83 3.98 25.12
52.17 6.57 15.21
52.03 6.52 15.08
19a
19b
19c
20
(White)
(38
C13H14N2O3
166–167 P 80–100 63.40 5.73 11.38
(246.27)
(White)
120–121
(Yellow)
199–120
(White)
171–172
(White)
111–113
(White)
162–163
(White)
(65)
E
(41)
E
(25)
E
(35)
E
63.28 5.64 11.19
58.29 5.30 16.99
58.11 5.25 16.74
53.33 6.71 10.36
53.17 6.68 10.23
35.15 4.42 13.66
35.04 4.37 13.51
44.80 3.76 15.67
44.68 3.71 15.43
58.05 6.50 22.57
57.87 6.46 22.27
24
36
16
36
16
12
36
10
24
14
36
18
6
C
12H13N3O3
(247.25)
C12H18N2O5
(270.29)
C6H9N2OBr
(205.06)
21a
21c
22a
22b
22c
23
C
10H10N3OBr
(268.11)
(37)
E
(25)
C6H8N2O
(124.14)
C
11H10N2O
(186.21)
102–103 P 80–100 70.95 5.99 15.04
White
139–140
(White)
173–175
(yellow)
—
(60)
E
(24)
P 60–80
(55)
E
70.37 5.87 14.93
64.16 4.85 22.45
64.02 4.80 22.27
54.94 3.84 10.68
54.77 3.78 10.41
63.13 7.95 18.41
63.99 7.48 18.22
C10H9N3O
(187.20)
C
12H10N2OS2
(262.36)
24a
24b
24c
25
C8H12N2O
(152.20)
Oil
(55)
C
13H14N2O
(214.27)
95–96
(Yellow)
88–89
(White)
P 80–100 72.87 6.59 13.07
(60)
E
72.66 6.51 12.99
66.96 6.09 19.52
66.74 6.02 19.37
C12H13N3O
(215.26)
(25)
C
13H15N2OBr
(295.18)
135–136 P 80–100 52.90 5.12
(White) (67) 52.73 5.04
195–196 P 80–100 47.34 5.30 12.27
9.49
9.27
26
C9H12N2S2O
(228.34)
18H21N2OS2Br 173–175
(Yellow)
(54)
P 60–80
(65)
44.26 5.53 12.73
27
6
C
50.82 4.98
50.68 4.90
6.58
6.40
(425.41) (Yellow)
P: petroleum ether; E: ethanol.
hydrochloric acid (10%) to separate and identify the acidic products in
the solid phase, if any. The results are listed in Tables I and II.
(2) In liquid-liquid phases. A solution of 5-hydroxy-3-substituted-
1H-pyrazoles (1a–c, 0.01 mol) in dry acetonitrile (50 mL) was mixed
with sodium hydroxide solution (10 mL, 30% aqueous solution), and

489

490

491

492

493

494

Alkylation of Pyrazolones
495
tetrabutylammonium bromide (TBAB, 0.003 mol, 0.90 g) was stirred
for 30 min. Next, the organo-halogen compound (0.03 mol) was added
and the reaction mixture was vigorously stirred at room temperature.
The progress of the reaction was monitored by TLC over the entire
reaction period. After completion of the reaction, the organic layer was
separated, dried by anhydrous MgSO4, and the solvent was evaporated.
The residue was crystallized from the proper solvent or separated by
column chromatography using silica gel and the proper eluent. The
results are listed in Tables I and II.
(B) Alkylation in the Presence of Carbon Disulphide
In a round bottle flask (100) fitted with a condenser, a suspension of
5-hydroxy-3-substituted-1H-pyrazoles (1, 0.01 mol), anhydrous K2CO3
(0.02 mol, 2.76 g), tetrabutylammonium bromide (TBAB, 0.003 mol,
0.90 g) and carbon disulphide (10 ml) in dry acetonitrile (50 ml) was
efficiently stirred at room temperature for 30 min. The organo-halogen
compound (0.03 mol) was added and the reaction mixture was vigor-
ously stirred at 25◦C. The progress of the reaction was monitored by
TLC over the entire reaction period. After the reaction completion, the
organic layer was separated by filtration and the solvent was evapo-
rated. The residue was crystallized from the proper solvent or separated
by column chromatography. The results are listed in Tables I and II.
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