Diastereoselective synthesis of pyrazolines using a bifunctional Bronsted acidic ionic liquid under solvent-free conditions

Article abstract of DOI:10.1002/adsc.201200191

An efficient protocol for the excellent diastereoselective synthesis of pyrazolines via a three-component reaction of aldehydes, hydrazines and dimethyl acetylenedicarboxylate (DMAD) in the presence of a bifunctional Bronsted acidic ionic liquid as a reus

Full text of DOI:10.1002/adsc.201200191

FULL PAPERS
DOI: 10.1002/adsc.201200191
Diastereoselective Synthesis of Pyrazolines using a Bifunctional
Brønsted Acidic Ionic Liquid under Solvent-Free Conditions
Shirin Safaei,a Iraj Mohammadpoor-Baltork,a,* Ahmad R. Khosropour,a,*
Majid Moghadam,a Shahram Tangestaninejad,a and Valiollah Mirkhania
a
Department of Chemistry, Catalysis Division, University of Isfahan, Isfahan 81746-73441, Iran
Fax : (+98)-311-668-9732; phone: (+98)-311-7932705; e-mail: imbaltork@sci.ui.ac.ir or arkhosropour@sci.ui.ac.ir
Received: March 8, 2012; Revised: July 3, 2012; Published online: November 4, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200191.
Abstract: An efficient protocol for the excellent dia- yields of the products and an environmentally benign
stereoselective synthesis of pyrazolines via a three- procedure avoiding toxic organic solvents are other
component reaction of aldehydes, hydrazines and di- significant features of this method.
methyl acetylenedicarboxylate (DMAD) in the pres-
ence of a bifunctional Brønsted acidic ionic liquid as
a reusable catalyst under solvent-free conditions is Keywords: aldehydes; diastereoselectivity; heterocy-
reported. Easy work-up, short reaction times, high cles; ionic liquids; multicomponent reactions
Introduction
pensive chiral catalysts or substrates, long reaction
times, toxic organic solvents and high amounts of cat-
Among nitrogen-containing heterocyclic compounds, alysts to provide stereoselectivity. Further, unavaila-
pyrazolines have attracted a great interest due to bility of some starting materials, use of potentially
their diverse biological and pharmacological activi- toxic dipoles and their difficult handling limit the util-
ties.[1] A great number of compounds containing pyra- ity of some of these methods, especially in large-scale
zoline moieties are reported to exhibit a broad range operation, leading to serious economical and safety
of anti-microbial,[2] anti-inflammatory,[3] anti-depres- problems. Thus, the design of a simple, efficient, inex-
sant,[4] anti-diabetic,[5] anti-cancer[6] and anti-amoe- pensive and green approach for the synthesis of pyra-
bic[7] properties. These heterocyclic compounds are zolines with excellent diastereoselectivity is highly de-
also utilized as insecticides, fungicides[8] and as fluo- sirable.
rescent dyes.[9] Consequently, the synthesis of pyrazo-
lines is an important and useful task in organic media and catalyst in chemical and biochemical trans-
chemistry.[10]
formations has received much attention due to their
In recent years, the utility of ionic liquids as green
Several methods including [3+2]cycloaddition of favorable properties such as high polarity and ionic
active 1,3-dipoles such as diazoalkanes to olefins,[11] conductivity, high thermal and chemical stability, ease
photoactivated 1,3-dipolar cycloaddition of diarylte- of recovery and reuse, non-flammability and low
trazoles to electron-deficient alkenes,[12] addition of vapor pressure.[20] These properties make the ionic liq-
nitrones to 1,3-enynes[13], zirconium-catalyzed enan- uids as attractive alternatives to environmentally un-
tioselective [3+2]cycloaddition of hydrazones to ole- favorable toxic organic solvents. It is also noteworthy
fins,[14] BF3-catalyzed intramolecular [3+2]cycloaddi- that the physical properties of ionic liquids such as
tion of olefinic phenylhydrazones,[15] cycloaddition of melting point, solubility, viscosity, density and hydro-
nitrilimine to alkenes,[16] reaction of substituted phe- phobicity can be adapted by changing their cations
nylhydrazines with 3-butynol catalyzed by zinc tri- and/or anions, enabling the design of a useful and
flate,[17] chiral phosphoric acid-catalyzed electrocycli- convenient ionic liquid for a particular purpose.
zation of a,b-unsaturated arylhydrazones,[18] and Cin- Among the ionic liquids, sulfonic acid ( SO3H)-func-
À
chona alkaloid-catalyzed enantioselective amination tionalized Brønsted acidic ionic liquids have attracted
of a,b-unsaturated ketones[19] have been reported for extensive interest as they are non-volatile, non-corro-
the synthesis of pyrazolines. Most of the reported sive, air and water stable, and provide easy recovery
methods, in spite of their potential utility, require ex- and reuse.[21] These Brønsted acidic ionic liquids
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Shirin Safaei et al.
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which offer the advantages of both liquid acids and
solid acids, have emerged as useful alternatives to tra-
ditional mineral liquid acids such as sulfuric acid and
hydrochloric acid in chemical reactions. Because of
their unique properties, several organic transforma-
tions such as esterification reactions,[22] Beckmann re-
arrangement,[23] Ritter reaction,[24] biodiesel synthe-
sis,[25] Pechmann condensation[26] and Biginelli reac-
tion[27] have been reported to proceed efficiently in
the presence of these Brønsted acidic ionic liquid cat-
alysts.
As a part of our ongoing research on the develop-
ment of efficient protocols for the synthesis of hetero-
cyclic compounds,[28] herein, we report a novel, facile
and environmentally benign one-pot three-component
synthesis of pyrazolines from arylaldehydes, hydra-
zines and DMAD with excellent diastereoselectivity
using a bifunctional Brønsted acidic ionic liquid as
Scheme 2. Synthesis of the bifunctional Brønsted acidic
ionic liquid.
a safe, inexpensive and reusable catalyst under sol- these conditions, the desired product was obtained in
vent-free conditions (Scheme 1). To the best of our low yield and poor diastereoselectivity (Table 1, en-
knowledge, this is the first report on the use of an tries 2–5). Performing the reaction in the presence of
ionic liquid as catalyst for the one-pot three-compo- stronger Lewis acids such as Bi
ACHUTNGTNERNUG(OTf)3 and ZnACHTUNGTRENNUNG(OTf)2,
nent synthesis of pyrazolines under solvent-free con- and p-TSA as Brønsted acid afforded the desired
ditions.
product in high yield but still with insignificant diaste-
reoselectivity (Table 1, entries 6–8). To improve both
the yield and diastereoselectivity, we examined this
reaction using different ionic liquids. The reaction cat-
alyzed by ionic liquids such as [Hmim]HSO4,
Results and Discussion
The bifunctional Brønsted acidic ionic liquid was [Bmim]BF4, [Bmim]PF6 or [mim
easily prepared in two steps. First, 1,4-diazabicyclo- provided the corresponding product in low yield and
ACHTUNGTRENNUNG[2.2.2]octane (DABCO) was reacted with 1,3-pro- excellent diastereoselectivity (Table 1, entries 9–12).
ACHTUGNERTN(NGNU CH2)3SO3H]HSO4
panesultone in THF to produce a white solid zwitter- It is noteworthy that, even in the presence of
ion. Then, treatment of this zwitterion with sulfuric 60 mol% of monofunctional ionic liquid, [mim-
acid afforded the desired ionic liquid in quantitative
yield (Scheme 2).
ACHTUNGTRENNUNG
In order to optimize the conditions, the reaction of uct was obtained in 70% yield (Table 1, entry 13).
benzaldehyde, phenylhydrazine and DMAD was se- But, interestingly, the bifunctional Brønsted acidic
lected as a model. A control experiment demonstrat- ionic liquid revealed exceptional catalytic activity, af-
ed that the reaction did not proceed in the absence of fording the desired product in excellent yield and ex-
catalyst (Table 1, entry 1). Then, the model reaction cellent diastereoselectivity (Table 1, entry 14). En-
was performed in the presence of Lewis acids such as couraged by this result, we then focused on optimiz-
InCl3, ZnCl2, ZrOCl2·8H2O and BiACTHNUTRGNEG(NU TFA)3. Under
Scheme 1. Diastereoselective synthesis of pyrazolines.
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Diastereoselective Synthesis of Pyrazolines using a Bifunctional Brønsted Acidic Ionic Liquid
Table 1. Optimization of the reaction conditions for diastereoselective synthesis of pyrazoline 4a.[a]
Entry
Catalyst
Time [h]
Yield [%][b]
dr (4a:5a)[c]
1
2
3
4
5
6
7
8
no catalyst
InCl3
ZnCl2
10
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
–
–
52
44
46
42
88
87
73
30
32
28
47
70
90
82
90
72
90
83
90
56:44
57:43
60:40
57:43
55:45
60:40
55:45
97:3
96:4
97:3
97:3
97:3
98:2
98:2
98:2
98:2
98:2
98:2
98:2
ZrOCl2·8H2O
Bi
Bi
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ZnACHTUNTGRENNUNG
9
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
10
11
12
13[d]
14
15[e]
16[f]
17[g]
18[h]
19[i]
20[j]
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
present catalyst
present catalyst
present catalyst
present catalyst
present catalyst
present catalyst
present catalyst
[a]
Benzaldehyde (1 mmol), phenylhydrazine (1 mmol) and DMAD (1.2 mmol), catalyst (30 mol%), under solvent-free con-
ditions, at 1008C.
Isolated yield.
[b]
[c]
[d]
[e]
[f]
1
The dr (trans:cis) was determined by H NMR analysis of the crude reaction mixture.
Reaction was performed in the presence of 60 mol% of catalyst.
Reaction was performed in the presence of 20 mol% of catalyst.
Reaction was performed in the presence of 40 mol% of catalyst.
Reaction was performed at 808C.
Reaction was performed at 1108C.
Benzaldehyde (1 mmol), phenylhydrazine (1 mmol) and DMAD (1 mmol), catalyst (30 mol%), under solvent-free condi-
tions, at 1008C.
[g]
[h]
[i]
[j]
Benzaldehyde (1 mmol), phenylhydrazine (1 mmol) and DMAD (1.4 mmol), catalyst (30 mol%), under solvent-free con-
ditions, at 1008C.
ing the reaction conditions using this novel bifunc- benzaldehyde and phenylhydrazine. Consequently,
tional Brønsted acidic ionic liquid catalyst. the optimum conditions were found to be a 1:1:1.2:0.3
To optimize the catalyst loading, the model reaction molar ratio of benzaldehyde, phenylhydrazine,
was performed in the presence of different bifunction- DMAD and catalyst at 1008C under solvent-free con-
al Brønsted acidic ionic liquid percentages (20 mol%, ditions.
30 mol%, and 40 mol%, Table 1, entries 14–16);
The generality and synthetic scope of this novel cat-
30 mol% loading provided the maximum yield. alytic method for the preparation of pyrazolines have
Higher loading of the catalyst did not affect the yield been investigated and the results are shown in
or the reaction time, whereas, reducing the catalyst Table 2. A series of aromatic aldehydes and arylhy-
loading decreased the product yield. In examining the drazines with electron-donating as well as electron-
reaction temperature in the range of 80–1108C withdrawing substituents reacted smoothly with
(Table 1, entries 14, 17, 18), 1008C was found to be DMAD to afford the corresponding pyrazolines in
the optimum temperature. Finally, the influence of high yields and excellent diastereoselectivity (Table 2,
the molar ratio of the starting materials was evaluated entries 1–13). It is noteworthy that in some cases, the
(Table 1, entries 14, 19, 20); the best result was trans-diastereomer was produced as the sole product
achieved employing 1.2 mmol of DMAD per mmol of (Table 2, entries 4, 5, 8–11). Also, as an acid-sensitive
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Shirin Safaei et al.
Table 2. Diastereoselective synthesis of pyrazolines catalyzed by Brønsted acidic ionic liquid under solvent-free conditions.[a]
FULL PAPERS
Entry
Aldehyde (1)
Hydrazine (2)
Product (4)
Time [min]
Yield [%][b]
dr (4:5)[c]
1
60
90
98:2
2
3
4
5
6
7
8
60
60
45
75
75
60
30
85
91
92
87
93
90
93
94:6
94:6
100:0
100:0
98:2
99:1
100:0
9
60
60
60
87
83
85
100:0
100:0
100:0
10
11
12
13
14
15
60
60
60
60
90
86
66
90
98:2
97:3
98:2
100:0
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Diastereoselective Synthesis of Pyrazolines using a Bifunctional Brønsted Acidic Ionic Liquid
Table 2. (Continued)
Entry
Aldehyde (1)
Hydrazine (2)
Product (4)
Time [min]
60
Yield [%][b]
83
dr (4:5)[c]
16
100:0
[a]
Arylaldehyde (1 mmol), hydrazine (1 mmol) and DMAD (1.2 mmol), catalyst (30 mol%) under solvent-free conditions,
at 1008C.
Isolated yield.
[b]
[c]
1
The dr (trans:cis) was determined by H NMR analysis of crude reaction mixture.
aldehyde, thiophen-2-carbaldehyde participated effi- corresponding pyrazoles were obtained in high yields
ciently in this reaction to produce the desired pyrazo- (Scheme 3). Finally, two of these reactions were inves-
line in good yield and excellent diastereoselectivity tigated with ethyl propiolate (an alkyne containing
(Table 2, entry 14). Under the same conditions, meth- only one activating group) instead of DMAD. Under
ylhydrazine as an alkylhydrazine took part in the re- these conditions, the corresponding pyrazoles were
action efficiently to give the desired pyrazoline in also produced in high yields (Scheme 4). Therefore,
high yields and excellent diastereoselectivity (Table 2, the present method can be used as an efficient
entries 15 and 16). In contrast, phenylhydrazide did method for the diastereoselective preparation of pyra-
not give the desired product under the same reaction zolines from aromatic aldehydes, aryl- and/or alkyl-
conditions. This may be attributed to the reduced re-
activity of the hydrazide as a result of the strong elec-
ACHTUNGTRENNUNG
tron-withdrawing effect of the acyl group in the hy- reoselectivity is due to the epimerization of the cis
drazide. It is worth noting that, when aliphatic alde- product or not, a control experiment was carried out
hydes such as butanal and heptanal were used in in the presence of the bifunctional Brønsted acidic
place of aromatic aldehydes in these reactions, the ionic liquid catalyst. For instance, the isolated mixture
Scheme 3. Synthesis of pyrazoles with aliphatic aldehydes.
Scheme 4. Synthesis of pyrazoles with ethyl propiolate.
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A plausible mechanism for the diastereoselective
formation of pyrazoline is proposed in Scheme 5.
Firstly, arylhydrazone 6 is formed by condensation of
arylaldehyde 1 with hydrazine 2. Nucleophilic attack
of hydrazone to the triple bond of DMAD 3 in the
presence of the catalyst provides 7 which upon cycli-
zation gives 8. Double bond migration in 8 affords the
pyrazoline 4 as the major diastereomer and releases
the catalyst for the next catalytic cycle.
Finally, the possibility for recovery and reuse of the
ionic liquid catalyst was examined in the reaction of
benzaldehyde, phenylhydrazine and DMAD under
solvent-free conditions at 1008C. After completion of
the reaction, the mixture was cooled to room temper-
ature and water was added. The product was separat-
ed by simple filtration and washed with water. Then
water was evaporated, the catalyst was dried at 808C
under reduced pressure for 2 h and reused for the
subsequent reaction. The data shown in Table 3 illus-
Figure 1. Crystal structure of compound 4h.
of cis- and trans-product (from entry 2 of Table 1) was trate that the ionic liquid catalyst can be reused at
resubjected to the reaction conditions using the pres-
ent catalyst; no change in diastereomeric ratio of the
product was observed after 1 h, indicating that epime-
rization of the product did not occur during the reac-
tion course.
Table 3. Reusability of catalyst for synthesis of 4a.[a]
Run
Cycle
Yield [%][b]
dr (4a:5a)[c]
1
2
3
4
5
0
1
2
3
4
90
90
88
87
85
98:2
98:2
97:3
96:4
95:5
The structures of new compounds were ascertained
by elemental analysis and spectral (IR, 1H NMR,
13C NMR, and MS) data. The known compounds
were identified by comparison of their mp, and IR
1
and H NMR spectra with authentic data.
[a]
Benzaldehyde (1 mmol), phenylhydrazine (1 mmol) and
DMAD (1.2 mmol), catalyst (30 mol%) at 1008C under
solvent-free conditions.
The diastereoselectivity of the reaction and configu-
ration of the stereogenic centers of the product 4h
were established by single crystal X-ray diffraction
analysis (Figure 1).[29]
[b]
[c]
Isolated yield.
The dr (trans:cis) was determined by 1H NMR analysis of
crude reaction product.
Scheme 5. A plausible mechanism.
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Diastereoselective Synthesis of Pyrazolines using a Bifunctional Brønsted Acidic Ionic Liquid
ture was stirred at 1008C under solvent-free conditions for
least four times without significant decreases in the
reaction yield and diastereoselectivity.
the appropriate time according to Table 2. The progress of
the reaction was monitored by TLC (eluent: n-hexane/ethyl
acetate, 5:1). After completion of the reaction, the mixture
was cooled to room temperature and water was added. The
product was separated by simple filtration and washed with
water. The resulting crude product was purified by recrystal-
lization from EtOH to afford the pure product. In the case
of liquid products, the purification was performed by
column chromatography on silica gel.
Conclusions
In conclusion, the present work describes a novel and
efficient protocol for the preparation of pyrazolines
through a three-component condensation reaction in
the presence of catalytic amounts of bifunctional
Brønsted acidic ionic liquid under solvent-free condi-
tions. The non-hazardous experimental conditions, re-
usable catalyst, short reaction times, high yields and
excellent diastereoselectivity are the remarkable fea-
tures of this procedure. Thus, it provides a better and
more convenient alternative to the existing methodol-
ogies for the synthesis of pyrazoline derivatives.
Dimethyl 4,5-dihydro-1,3-diphenyl-1H-pyrazole-4,5-dicar-
boxylate (4a):[30] mp 150–1528C; IR (KBr): nmax =3056, 2949,
1742, 1596, 1275, 1146, 1017, 740, 687 cmÀ1
;
1H NMR
(500 MHz, CDCl3): d=7.81 (d, J=8.5, 2H), 7.4 (t, J=
7.3 Hz, 2H), 7.36 (d, J=7.0 Hz, 1H), 7.31 (t, J=7.5 Hz,
2H), 7.16 (d, J=8.5 Hz, 2H), 6.92 (t, J=7.5 Hz, 1H), 5.19
(d, J=5.0 Hz, 1H), 4.58 (d, J=5.0 Hz, 1H), 3.76 (s, 3H),
3.72 (s, 3H); 13C NMR (125 MHz, CDCl3): d=170.1, 169.3,
143.7, 143.6, 131.1, 129.2, 129.0, 128.6, 126.3, 120.3, 113.3,
65.9, 55.7, 53.2, 53.1.
Dimethyl
3-(4-bromophenyl)-4,5-dihydro-1-phenyl-1H-
pyrazole-4,5-dicarboxylate (4b):[31] mp 189–1908C; IR
(KBr): nmax =3092, 2951, 1739, 1597, 1502, 1207, 1145, 747,
Experimental Section
690 cmÀ1
;
1H NMR (500 MHz, CDCl3): d=7.67 (d, J=
The chemicals used in this work were purchased from Fluka
and Merck chemical companies. The progress of the reac-
tion was monitored by TLC using 0.25 mm pre-coated silica
gel plates. Melting points were determined using Stuart Sci-
entific SMP2 apparatus. 1H NMR (400 and 500 MHz) and
13C NMR (100 and 125 MHz) spectra were recorded on
Bruker Avance 400 and 500 spectrometers, respectively. FT-
IR spectra were recorded on a Nicolet-Impact 400D instru-
ment in the range of 400–4000 cmÀ1. Mass spectra were re-
corded on a Platform II spectrometer from Micromass; EI
mode at 70 eV. Elemental analysis was done on a LECO,
CHNS-932 analyzer.
8.5 Hz, 2H), 7.51 (d, J=8.5 Hz, 2H), 7.31 (t, J=8.0 Hz,
2H), 7.14 (d, J=7.5 Hz, 2H), 6.93 (t, J=7.3 Hz, 1H), 5.21
(d, J=5.0 Hz, 1H), 4.54 (d, J=4.5 Hz, 1H), 3.76 (s, 3H),
3.73 (s, 3H).
Dimethyl
3-(4-bromophenyl)-4,5-dihydro-1-p-tolyl-1H-
pyrazole-4,5-dicarboxylate (4c): mp 151–1538C; IR (KBr):
nmax =3004, 2949, 1742, 1615, 1516, 1275, 1149, 1018, 823,
639 cmÀ1
;
1H NMR (500 MHz, CDCl3): d=7.66 (d, J=
8.5 Hz, 2H), 7.51 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz,
2H), 7.05 (d, J=8.5 Hz, 2H), 5.19 (d, J=4.5 Hz, 1H), 4.53
(d, J=4.5 Hz, 1H), 3.76 (s, 3H), 3.72 (s, 3H), 2. 30 (s, 3H);
13C NMR (125 MHz, CDCl3): d=170.0, 169.1, 141.9, 141.3,
138.8, 131.7, 129.7, 128.4, 127.7, 122.9, 113.5, 66.1, 55.4, 53.2,
53.1, 20.6; MS: m/z (%)=432 (M+ +2, 33.8), 430 (M+, 54.0),
371 (35.0), 327 (18.0), 248 (23.5), 130 (48.7), 91 (100.0), 65
(82.0); anal. calcd. for C20H19BrN2O4: C 55.70, H 4.44, N,
6.50; found: C 55.64, H 4.49, N 6.48.
Synthesis of Bifunctional Brønsted Acidic Ionic
Liquid Catalyst
A
solution of 1,4-diazabicycloACTHUNGETRNNU[G 2.2.2]octane (DABCO)
(10 mmol) and 1,3-propanesultone (20 mmol) in dry THF
was refluxed for 24 h to afford a white solid zwitterion. The
resulting solid was washed with Et2O in order to remove the
unreacted starting materials and dried under vacuum. Then,
sulfuric acid (20 mmol) was added to the solid zwitterion
and the resulting mixture was stirred for 20 h at 1708C
during which time the solid zwitterion was liquefied and re-
sulted in the bifunctional Brønsted acidic ionic liquid; yield:
quantitative; mp 858C. IR (KBr): nmax =2924, 1471, 1398,
Dimethyl 3-(4-bromophenyl)-4,5-dihydro-1-(4-methoxy-
phenyl)-1H-pyrazole-4,5-dicarboxylate (4d): mp 158–1608C;
IR (KBr): nmax =3024, 2998, 1741, 1511, 1236, 1147, 1013,
821, 786 cmÀ1; H NMR (400 MHz, CDCl3): d=7.57 (d, J=
1
8.8 Hz, 2H), 7.52 (d, J=8.8 Hz, 2H), 7.10 (d, J=8.8 Hz,
2H), 6.88 (d, J=8.8 Hz, 2H), 5.31 (d, J=4.4 Hz, 1H), 4.56
(d, J=4.4 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.71 (s, 3H);
13C NMR (100 MHz, CDCl3): d=170.1, 169.2, 154.4, 141.9,
137.9, 131.7, 130.2, 127.6, 122.8, 115.1, 114.7, 66.7, 55.6, 55.5,
53.2, 53.1; MS: m/z (%)=447 (M+, 8.1), 415 (16.0), 352
(6.8), 183 (20.0), 123 (39.2), 56 (100.0); anal. calcd. for
C20H19BrN2O5: C 53.71, H 4.28, N 6.26; found: C 53.63, H
4.30, N 6.27.
1222, 1051, 853, 590 cmÀ1 1H NMR (400 MHz, D2O): d=
;
4.02 (s, 6H), 3.72 (t, J=8.0 Hz, 2H), 2.96 (t, J=8.0 Hz, 2H),
2.28–2.21 (m, 2H); 13C NMR (100 MHz, D2O): d=63.2,
51.1, 46.8, 17.8; anal. calcd. for C12H28N2O14S4: C 26.08, H
5.11, N 5.07, S 23.21; found: C 25.92, H 5.15, N 5.14, S,
23.04.
Dimethyl 3-(4-cyanophenyl)-4,5-dihydro-1-phenyl-1H-pyr-
azole-4,5-dicarboxylate (4e): mp 200–2018C; IR (KBr):
nmax =3043, 2952, 2224, 1746, 1596, 1499, 1214, 1151,
Diastereoselective Synthesis of Pyrazolines; General
Procedure
749 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=7.90 (d, J=
8.0 Hz, 2H), 7.67 (d, J=8.4 Hz, 2H), 7.34 (t, J=7.8 Hz,
2H), 7.18 (d, J=8.4 Hz, 2H), 6.98 (t, J=7.2 Hz, 1H), 5.32
(d, J=4.4 Hz, 1H), 4.58 (d, J=4.4 Hz, 1H), 3.75 (s, 3H),
3.74 (s, 3H); 13C NMR (100 MHz, CDCl3): d=169.6, 168.6,
First, a mixture of arylaldehyde 1 (1 mmol) and hydrazine 2
(1 mmol) was stirred for 20 min. Then, DMAD 3 (1.2 mmol)
and catalyst (0.3 mmol) were added and the resulting mix-
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Shirin Safaei et al.
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142.7, 141.1, 135.4, 132.3, 129.3, 126.5, 121.2, 118.8, 113.5,
111.6, 65.7, 54.8, 53.5, 53.3; MS: m/z (%)=363 (M+, 8.9),
304 (10.7), 260 (27.9), 244 (15.3), 143 (9.3), 116 (10.6), 92
(2.5), 77 (100.0); anal. calcd. for C20H17N3O4: C 66.11, H
4.72, N 11.56; found: C 66.05, H 4.80, N 11.55.
(KBr): nmax =3059, 2953, 1752, 1599, 1502, 1241, 1210, 889,
754 cmÀ1 1H NMR (500 MHz, CDCl3): d=7.33–7.28 (m,
;
4H), 7.15 (d, J=8.0 Hz, 2H), 7.09–7.07 (m, 1H), 6.94 (t, J=
7.5 Hz, 1H), 5.35 (d, J=6.0 Hz, 1H), 4.73 (d, J=6.0 Hz,
1H), 3.81 (s, 3H), 3.64 (s, 3H); 13C NMR (125 MHz,
CDCl3): d=170.3, 167.7, 162.5, 160.5, 143.8, 136.4, 130.7 (d,
Dimethyl 3-(4-cyanophenyl)-4,5-dihydro-1-p-tolyl-1H-pyr-
azole-4,5-dicarboxylate (4f): mp 186–1888C; IR (KBr):
nmax =3035, 2955, 2225, 1742, 1516, 1278, 1150, 1014,
J
C,F =9.37 Hz), 129.2, 125.72, 125.70, 120.9, 114.2 (d, JC,F =
22.13 Hz), 113.7, 64.5, 58.2, 53.1; MS: m/z (%)=392 (M+ +
2, 73.9), 390 (M+, 89.5), 331 (97.7), 287 (93.2), 272 (69.5),
237 (71.5), 143 (58.2), 117 (90.4), 104 (81.5), 91 (86.8), 77
(100.0); anal. calcd. for C19H16ClFN2O4: C 58.39, H 4.13, N
7.17; found: C 58.33, H 4.20, N 7.19.
837 cmÀ1
;
1H NMR (500 MHz, CDCl3): d=7.88 (d, J=
8.5 Hz, 2H), 7.65 (d, J=8.5 Hz, 2H), 7.13 (d, J=8.5 Hz,
2H), 7.07 (d, J=9.0 Hz, 2H), 5.27 (d, J=4.5 Hz, 1H), 4.55
(d, J=4.5 Hz, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 2.31 (s, 3H);
13C NMR (125 MHz, CDCl3): d=169.7, 168.7, 140.63,
140.57, 135.6, 132.2, 130.8, 129.9, 126.4, 118.8, 113.7, 111.5,
66.1, 54.9, 53.4, 53.2, 20.6; MS: m/z (%)=377 (M+, 17.9),
318 (15.8), 274 (43.9), 130 (12.1), 91 (31.1), 59 (100.0); anal.
calcd. for C21H19N3O4: C 66.83, H 5.07, N 11.13; found: C
66.78, H 5.09, N 11.14.
Dimethyl
pyrazole-4,5-dicarboxylate (4l): mp 168–1698C; IR (KBr):
nmax =3095, 2952, 1740, 1602, 1501, 1269, 1209, 747 cmÀ1
3-(4-chlorophenyl)-4,5-dihydro-1-phenyl-1H-
;
1H NMR (400 MHz, CDCl3): d=7.76 (d, J=8.8 Hz, 2H),
7.38 (d, J=8.8 Hz, 2H), 7.33 (dd, 1J=8.2 Hz , 2J=7.2 Hz,
2H), 7.16 (dd, 1J=8.8 Hz , 2J=1.2 Hz, 2H), 6.95 (t, J=
7.4 Hz, 1H), 5.24 (d, J=4.4 Hz, 1H), 4.56 (d, J=4.4 Hz,
1H), 3.78 (s, 3H), 3.74 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=170.0, 168.9, 143.3, 142.3, 134.8, 129.6, 129.3,
128.8, 127.5, 120.5, 113.3, 65.7, 55.4, 53.3, 53.1; MS: m/z
(%)=376 (M+ +4, 2.7), 374 (M+ +2, 80.2), 372 (M+, 100.0),
313 (99.1), 254 (83.8), 218 (48.2), 131 (40.5), 117 (76.1), 104
(86.0), 77 (98.7), 59 (93.7); anal. calcd. for C19H17ClN2O4: C
61.21, H 4.60, N 7.51; found: C 61.19, H 4.66, N 7.45.
Dimethyl
3-(4-cyanophenyl)-4,5-dihydro-1-(4-methoxy-
phenyl)-1H-pyrazole-4,5-dicarboxylate (4g): mp 184–1868C;
IR (KBr): nmax =3039, 2931, 2224, 1742, 1509, 1238, 1153,
1
1011, 820 cmÀ1; H NMR (500 MHz, CDCl3): d=7.86 (d, J=
8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 7.12 (d, J=9.0 Hz,
2H), 6.89 (d, J=9.0 Hz, 2H), 5.26 (d, J=4.5 Hz, 1H), 4.55
(d, J=5.0 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.74 (s, 3H);
13C NMR (125 MHz, CDCl3): d=169.7, 168.8, 154.8, 140.5,
137.0, 135.7, 132.2, 126.3, 118.9, 115.3, 114.8, 111. 3, 66.6,
55.7, 54.9, 53.4, 53.2; MS: m/z (%)=393 (M+, 0.9), 334 (1.2),
273 (1.0), 130 (1.9), 102 (5.0), 59 (100); anal. calcd. for
C21H19N3O5: C 64.12, H 4.87, N 10.68; found: C 64.05, H
4.90, N 10.64.
Dimethyl
1,3-bis(4-chlorophenyl)-4,5-dihydro-1H-pyra-
zole-4,5-dicarboxylate (4m): mp 187–1908C; IR (KBr):
1
nmax =3022, 2951, 1742, 1493, 1277, 1147, 820 cmÀ1; H NMR
(500 MHz, CDCl3): d=7.73 (d, J=8.5 Hz, 2H), 7.37 (d, J=
8.5 Hz, 2H), 7.26 (d, J=9.0 Hz, 2H), 7.08 (d, J=9.0 Hz,
2H), 5.19 (d, J=4.5 Hz, 1H), 4.56 (d, J=4.5 Hz, 1H), 3.76
(s, 3H), 3.73 (s, 3H); 13C NMR (125 MHz, CDCl3): d=
169.6, 168.8, 143.1, 142.1, 135.1, 129.4, 129.2, 128.9, 127.6,
125.5, 114.6, 65.7, 55.5, 53.3, 53.2; MS: m/z (%)=408 (M+ +
2, 2.4), 406 (M+, 4.3), 287 (2.9), 149 (13.8), 111 (35.8), 57
(100.0); anal. calcd. for C19H16Cl2N2O4: C 56.04, H 3.96, N
6.88; found: C 55.92, H 4.03, N 6.90.
Dimethyl 4,5-dihydro-3-(4-methoxyphenyl)-1-phenyl-1H-
pyrazole-4,5-dicarboxylate (4h):[32] mp 151–1528C; IR
(KBr): nmax =3053, 2953, 1744, 1595, 1500, 1242, 1143, 1015,
834 cmÀ1
;
1H NMR (500 MHz, CDCl3): d=7.75 (d, J=
7.0 Hz, 2H), 7.30 (t, J=8.5 Hz, 2H), 7.13 (d, J=8.0 Hz,
2H), 6.93–6.88 (m, 3H), 5.15 (d, J=5.0 Hz, 1H), 4.55 (d, J=
4.5 Hz, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 3.72 (s, 3H).
Dimethyl 3-(2,4-dichlorophenyl)-4,5-dihydro-1-phenyl-1H-
pyrazole-4,5-dicarboxylate (4i):[33] mp 107–1098C; IR (KBr):
nmax =3004, 2951, 1742, 1595, 1500, 1384, 1141, 1013, 747,
Dimethyl 4,5-dihydro-3-(thiophen-2-yl)-1-p-tolyl-1H-pyra-
zole-4,5-dicarboxylate (4n): oil; IR (neat): nmax =3105, 2951,
1
1740, 1515, 1233, 1013, 811, 703 cmÀ1; H NMR (500 MHz,
683 cmÀ1 1H NMR (500 MHz, CDCl3): d=7.70 (dd, 1J=
;
2
CDCl3): d=7.31 (dd, 1J=5.0 Hz , J=1.0 Hz, 1H), 7.3 (d,
8.5 Hz , 2J=1.0 Hz, 1H), 7.44 (s, 1H),7.33–7.28 (m, 3H),
7.14 (d, J=8.0 Hz, 2H), 6.95 (t, J=7.0 Hz, 1H), 5.26 (d, J=
5.0 Hz , 1H), 5.04 (d, J=5.0 Hz, 1H), 3.79 (s, 3H), 3.66 (s,
3H).
J=1.0 Hz, 1H), 7.10 (d, J=8.5 Hz, 2H), 7.03–7.01 (m, 3H),
5.16 (d, J=5.0 Hz, 1H), 4.50 (d, J=5.0 Hz, 1H), 3.77 (s,
3H), 3.76 (s, 3H), 2.29 (s, 3H); 13C NMR (125 MHz,
CDCl3): d=170.1, 168.9, 141.5, 138.9, 135.0, 129.7, 127.4,
127.0, 126.7, 123.2, 113.5, 66.2, 56.5, 53.2, 53.1, 20.6; MS: m/z
(%)=360 (M+ +2, 7.3), 358 (M+, 100.0), 325 (56.3), 299
(50.9), 255 (49.7), 130 (34.2), 91 (89.7), 57 (75.9); anal. calcd.
for C18H18N2O4S: C 60.32, H 5.06, N 7.82, S 8.95; found: C
60.26, H 5.11, N 7.88, S 8.89.
Dimethyl 1-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-4,5-
dihydro-1H-pyrazole-4,5-dicarboxylate (4j): mp 144–1468C;
IR (KBr): nmax =3056, 2955, 1739, 1495, 1281, 1144, 821,
791 cmÀ1
;
1H NMR (500 MHz, CDCl3): d=7.66 (d, J=
1
8.5 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.29 (dd, J=8.5 Hz ,
2J=2.0 Hz, 1H), 7.25 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0 Hz,
2H), 5.24 (d, J=5.0 Hz, 1H), 5.04 (d, J=5.0 Hz, 1H), 3.79
(s, 3H), 3.66 (s, 3H); 13C NMR (125 MHz, CDCl3): d=
169.7, 168.4, 142.4, 142.1, 135.5, 133.2, 131.7, 130.3, 129.2,
128.9, 127.3, 125.9, 114.8, 65.2, 57.2, 53.2; MS: m/z (%)=444
(M+ + 2, 24.9), 442 (M+, 72.7), 440 (75.8), 403 (79.4), 381
(88.7), 337 (85.1), 252 (41.3), 111 (100.0), 75 (84.0); anal.
calcd. for C19H15Cl3N2O4: C 51.67, H 3.42, N 6.34; found: C
51.60, H 3.46, N 6.28.
Dimethyl 4,5-dihydro-1-methyl-3-phenyl-1H-pyrazole-4,5-
dicarboxylate (4o): mp 65–668C; IR (KBr): nmax =3025,
1
2953, 1736, 1628, 1225, 1069, 756 cmÀ1; H NMR (400 MHz,
CDCl3): d=7.19–7.27 (m, 5H), 4.70 (d, J=11.6 Hz, 1H),
4.53 (d, J=11.2 Hz, 1H), 3.69 (s, 3H), 3.57 (s, 3H), 3.48 (s,
3H); 13C NMR (100 MHz, CDCl3): d=170.9, 166.8, 138.4,
129.7, 128.8, 128.5, 126.7, 68.2, 52.6, 51.5, 44.3; MS: m/z
(%)=275 (M+, 2.2), 229 (100.0), 167.0 (80.9), 149 (96.3), 127
(64.3), 105 (75.1), 77 (83.4); anal. calcd. for C14H16N2O4: C
60.86, H 5.84, N 10.14; found: C 60.90, H 5.88, N 10.17.
Dimethyl
3-(2-chloro-6-fluorophenyl)-4,5-dihydro-1-
phenyl-1H-pyrazole-4,5-dicarboxylate (4k): mp 89–908C; IR
3102
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 3095 – 3104

Diastereoselective Synthesis of Pyrazolines using a Bifunctional Brønsted Acidic Ionic Liquid
Dimethyl
pyrazole-4,5-dicarboxylate (4p): mp 87–898C; IR (KBr):
nmax =3071, 2954, 1734, 1693, 1438, 1225, 1090, 833 cmÀ1
3-(4-chlorophenyl)-4,5-dihydro-1-methyl-1H-
Acknowledgements
;
The authors are grateful to the Center of Excellence of
Chemistry and Research Council of the University of Isfahan
for financial support of this work.
1H NMR (400 MHz, CDCl3): d=7.87 (d, J=8.8 Hz, 2H),
7.70 (d, J=8.0 Hz, 2H), 4.74 (d, J=11.6 Hz, 1H), 4.57 (d,
J=11.2 Hz, 1H), 3.78 (s, 3H), 3.66 (s, 3H), 3.56 (s, 3H);
13C NMR (100 MHz, CDCl3): d=167.8, 166.7, 138.3, 130.9,
128.8, 128.6, 127.9, 68.2, 59.5, 52.7, 51.6, 44.3; MS: m/z
(%)=311 (M+, 3.0), 279 (74.5), 265 (100.0), 204 (46.7), 149
(100.0), 139 (98.8), 111 (98.0), 77 (52.6); anal. calcd. for
C14H15ClN2O4: C 54.11, H 4.87, N 9.02, found: C 54.05, H
4.88, N 9.09.
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late (Scheme 3): oil; IR (neat): nmax =3024, 2957, 1744, 1724,
1597, 1504, 1255, 1106, 761 cmÀ1
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CDCl3): d=7.42–7.51 (m, 5H), 3.87 (s, 6H), 2.92 (t, J=
8 Hz, 2H), 1.72–1.82 (m, 2H), 1.02 (t, J=7.2 Hz, 3H);
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131.3, 129.3, 128.8, 123.8, 114.2, 53.3, 51.73, 29.5, 22.4, 14.1;
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1.68–1.74 (m, 2H), 1.26–1.32 (m, 6H), 0.89 (s, 3H);
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Ethyl 1,3-diphenyl-1H-pyrazole-4-carboxylate (Scheme 4):
mp 102–1048C; IR (KBr): nmax =3080, 2987, 1716, 1561,
1
1259, 1133, 1059, 756 cmÀ1; H NMR (400 MHz, CDCl3): d=
8.43 (s, 1H), 7.81 (d, J=7.6 Hz, 2H), 7.73 (d, J=7.6 Hz,
2H), 7.43–7.72 (m, 5H), 7.38 (t, J=7.2 Hz , 1H), 4.31 (q, J=
7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=163.0, 142.2, 132.3, 130.0, 129.6, 129.6, 129.4,
128.7, 127.9, 127.6, 127.5, 119.6, 60.5, 14.3; MS: m/z (%)=
293 (M+ +1, 47.2), 292 (M+, 98.6), 247 (97.2), 219 (38.0), 149
(34.3), 104 (48.2), 77 (100.0); anal. calcd. for C18H16N2O2: C
73.95, H 5.52, N 9.58; found: C 73.90, H 5.56, N 9.59.
Ethyl 3-(4-methoxyphenyl)-1-phenyl-1H-pyrazole-4-car-
boxylate (Scheme 4): mp 92–938C; IR (KBr): nm1ax =3067,
2959, 1696, 1526, 1276, 1177, 1027, 839, 756 cmÀ1; H NMR
(400 MHz, CDCl3): d=8.51 (s, 1H), 7.86 (d, J=8.8 Hz, 2H),
7.80 (d, J=6.8 Hz, 2H), 7.51 (t, J=7.6 Hz, 2H), 7.37 (t, J=
7.6 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 4.32 (q, J=7.2 Hz,
2H), 3.88 (s, 3H), 1.35 (t, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=160.1, 139.3, 132.6, 132.2, 130.7,
129.7, 129.6, 127.4, 124.6, 120.8, 119.5, 113.3, 60.3, 55.3, 14.4;
MS: m/z (%)=323 (M+ +1, 77.3), 322 (M+, 100.0), 277
(82.8), 235 (38.8), 125 (49.0), 111 (73.7), 95 (78.8), 77 (83.2);
anal. calcd. for C19H18N2O3: C 70.79, H 5.63, N 8.69; found:
C 70.87, H 5.66, N 8.66.
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Adv. Synth. Catal. 2012, 354, 3095 – 3104