Synthesis of imidazo[4,5-c]pyrazoles via copper-catalyzed amidine cyclization

Article abstract of DOI:10.1021/jo300176f

A new synthetic approach to 4-substituted imidazo[4,5-c]pyrazoles is proposed on the basis of the N′-(4-halopyrazol-5-yl)amidine cyclization under the conditions of copper-catalyzed cross-coupling reactions. Using 5-aminopyrazoles and copper catalysts as

Full text of DOI:10.1021/jo300176f

Article
pubs.acs.org/joc
Synthesis of Imidazo[4,5-c]pyrazoles via Copper-Catalyzed Amidine
Cyclization
Kostiantyn Liubchak,*,† Andrey Tolmachev,‡ and Kostiantyn Nazarenko†
†Institute of Organic Chemistry of NAS of Ukraine, 5 Murmanska str., Kyiv, 02094, Ukraine
‡Research and Development Center for Chemistry and Biology, National Taras Shevchenko University of Kyiv, 62 Volodymyrska str.,
Kyiv, 01033, Ukraine
S
* Supporting Information
ABSTRACT: A new synthetic approach to 4-substituted
imidazo[4,5-c]pyrazoles is proposed on the basis of the N′-(4-
halopyrazol-5-yl)amidine cyclization under the conditions
of copper-catalyzed cross-coupling reactions. Using 5-amino-
pyrazoles and copper catalysts as starting materials, the
method is inexpensive and convenient and allows a wide range
of substituents at all positions of the imidazo[4,5-c]pyrazole
nucleus.
As a rule, imidazo[4,5-c]pyrazoles are synthesized by
annelation of imidazole to the [c] edge of the pyrazole ring.
An alternative pathway, construction of the pyrazole moiety at
the imidazole ring, was reported only once in the literature and
involved the addition of diazomethane to the CC bond of 5-
nitroimidazoles.6
INTRODUCTION
■
Many bicyclic pyrazole derivatives are well recognized for their
potent and diverse bioactivity, which can be exemplified by
simple indazoles contained in the antiemetic Granisetron1 or by
pyrazolo[4,3-d]pyrimidine, a basic component of the urology
drugs Sildenafil and Udenafil (Figure 1).2 Much interest has
The use of 4,5-diaminopyrazoles in the synthesis of
imidazo[4,5-c]pyrazole derivatives is restricted to condensa-
tions with aromatic carboxylic acids as well as with carbon
disulfide or thiophosgene. The former reactions afford 5-aryl
substituted imidazo[4,5-c]pyrazoles5,7and the latter 5-thio-
nes,8 which are desulfurized with Raney nickel to provide bare
heterocycles.9
4,5-Diaminopyrazoles can be replaced by more easily
accessible 4-carboxy-5-aminopyrazoles; they are converted via
standard reactions to 4-isocyanato-5-aminopyrazoles, which are
readily cyclizable to the corresponding imidazo[4,5-c]pyrazol-5-
ones.10
The most general synthetic approach to imidazo[4,5-c]-
pyrazoles is offered by the intramolecular cyclocondensation of
4-nitroso-5-alkylaminopyrazoles in which the nitroso group
reacts with the α-methylene unit of the alkyl substituent, thus
giving rise to the imidazole ring.1,10 Both 5-aryl and 5-alkyl sub-
stituted derivatives can be obtained by this method. However, it
cannot be considered as a convenient strategy since the pro-
cedure includes many steps with a low yield each, especially the
inefficient cyclization (20−40%).
Preparation of 4- and/or 6-substituted imidazo[4,5-c]-
pyrazoles presents a separate synthetic problem. These com-
pounds were reported to be alkylated with alkyl halides at
position 4 of the heterocyclic nucleus.4b However, the alkyl-
ation selectivity remains an open question, as does the possibility
Figure 1. Biologically active imidazo[4,5-c]pyrazoles.
also been focused on pyrazolo[3,4-b]pyridine derivatives
efficiently inhibiting p38α mitogen-activated protein kinase.3
However, one of the simplest pyrazole-containing nuclei,
imidazo[4,5-c]pyrazole, remains largely unexplored since
reliable synthetic routes to this heterocyclic system have
been lacking so far. At the same time, imidazo[4,5-c]pyrazole
derivatives show promise as antineurodegenerative (e.g., anti-
Alzheimer) drugs.4 Moreover, recent in vitro studies suggest
that 5-aryl substituted heterocycles of this class act as selective
Raf kinase inhibitors.5
Received: January 23, 2012
Published: March 2, 2012
© 2012 American Chemical Society
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to obtain N-aryl substituted imidazo[4,5-c]pyrazoles by direct
arylation.
Table 1. Synthesis of N-Pyrazolylamidines from 5-
Aminopyrazoles and Imidoyl Chlorides
a
As evident from the retrosynthesis of the imidazo[4,5-c]-
pyrazole system (see Scheme 1), it is obtainable by the intramolecular
Scheme 1. Retrosynthesis of Imidazo[4,5-c]pyrazoles
entry
amidine
R1
R2
R3
R4
yield, %
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
Ph
Ph
Ph
Ph
Me
Me
Ph
Ph
Me
Me
Me
Me
Me
Me
H
Me
Et
Ph
Ph
82
79
84
89
86
91
87
53
Me
Me
Me
Me
Me
Ph
4-MeO-phenyl
3-Cl-phenyl
Ph
cyclization of halopyrazolyl-substituted amidines 2, which are
derived from commercially available and inexpensive 5-
aminopyrazoles 3. The key step of the synthetic retroscheme
is the CN bond formation resulting from the nucleophilic
substitution of the halogen atom in the pyrazole nucleus.
In the recent years, much insight has been gained into such
N-arylation and heteroarylation reactions catalyzed by tran-
4-Me-phenyl
Ph
4g
4h
Me
Me
a
Reaction conditions: 1.0 mol of 3, 1 mol of 5, 2.0 mol of Et3N, dry
1,4-dioxane, rt, 24 h.
Table 2. Synthesis of N-Pyrazolylamidines from Imino Esters
and Amines
12
sition metals.11 Palladium(0) compounds such as Pd2(dba)3
a
or Pd(PPh3)413 are now extensively used as catalysts in the
synthesis of various heterocyclic systems including imidazole and
benzimidazole derivatives. Over the past decade, considerable
interest has been focused on the development of cheap and en-
vironmentally friendly nonpalladium catalysts. For instance,
complexes of copper rather than of palladium are employed to
catalyze N-arylation reactions. In particular, using the complexes of
Cu(I)14 and Cu(II)15 formed in situ or under ligand-free condi-
tions,16 benzimidazole derivatives can be obtained by the mild and
high-yield cyclization of o-halogenaryl substituted ureas, thioureas,
and amidines.
We are currently concerned with heterocyclic syntheses
starting from amino derivatives of electron-rich heterocycles,
e.g., 5-amino substituted pyrazoles, isoxazoles, and imidazoles,
2-aminothiophenes, etc.17 In view of our ongoing synthetic
efforts in this field and abundant literature on transition-metal-
catalyzed N-arylation and heteroarylation reactions, here we
report a novel approach to 4-substituted imidazo[4,5-c]-
pyrazoles based on the cyclization of N-halopyrazolylamidines
2 under conditions of copper catalysis.
entry
amidine
R3
R4
yield, %
1
2
3
4
4i
4j
4k
4l
Ph
H
H
H
H
76
54
81
62
4-Cl-phenyl
4-Me-phenyl
4-MeO-phenyl
a
Reaction conditions: 1.0 mol of 6, 1 mol of 7, 140 °C, 4 h.
aniline and its derivatives even on temperature elevation from
140 to 220 °C.
Bromination of amidines 4a−g,i,j with NBS in boiling
acetonitrile occurs at the C(4) atom of the pyrazole ring to give
compounds 2 (see Table 3). The procedure used, though
simple and affording high yields of the final products, has,
however, some limitations. As an example, treatment of
compound 4h with NBS gives rise to a complex product
mixture, which is likely to result from additional bromination of
the methyl group in acetamidine. Moreover, attempted
bromination of N-arylamidines 4k,l bearing electron-donor
substituents on the benzene ring caused resinification. In these
cases, N′-halopyrazolyl derivatives 2 of amidines 4 were
obtained under milder conditions; namely, halogenation with
elementary iodine was carried out in the presence of KOH at
room temperature. Iodopyrazolyl-substituted amidines 2h,k,l
were thus prepared in yields of 65−85%, with the reaction
being complete within 48−96 h.
Reaction conditions for intramolecular cross-coupling were
designed using a microwave-assisted reaction with model
compound 2a; as a result, the experiment time was reduced
to 15 min. Experiments were performed at 150 °C in all
solvents. The reaction products were not isolated, and the
conversion degree was determined by LC−MS analysis of the
reaction mixture. The study of the model compound provided
an insight into the effect caused by the solvent, ligand, and base
RESULTS AND DISCUSSION
■
First, we attempted the preparation of desired pyrazoles 2 by
the reaction of 4-bromo-1-phenyl-3-methyl-5-aminopyrazole 8
with imidoyl chlorides. However, compound 8 proved
unreactive toward imidoyl chlorides even on long boiling in
dry dioxane. To circumvent this limitation, we chose to
synthesize C(4)-unsubstituted pyrazolylamidines 4, followed by
C(4)-halogenation. Compounds 4 were obtained via two
pathways: (A) the reaction of 5-aminopyrazoles 3 with imidoyl
chlorides18 and (B) the reaction of imino esters 6 with amines.
C(4)-Unsubstituted 5-aminopyrazoles 3 react with imidoyl
chlorides 5 in dry 1,4-dioxane already at room temperature to
give products 4 in high yields (see Table 1, entries 1−7). A
lower yield of acetamidine derivative 4h is probably due to the
lability of the starting imidoyl chloride (see Table 1, entry 8).
N-Aryl substituted amidines 4i−l were prepared in yields of
54−87% by the reaction of imino esters19 6 with anilines 7
(Table 2). Imino ester 6b synthesized from N-phenyl-5-
aminopyrazole and triethyl orthoacetate does not react with
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a
Table 3. Synthesis of N′-(4-Halopyrazol-5-yl)amidines
a
Reaction conditions: (i) 1 mol of 7, 1.05 mol of NBS, CH3CN, heating, 2−5 h; (ii) 1 mol of 7, 1 mol of I2, 2 mol of KOH, DMF, rt,
48−96 h.
on the course of copper-catalyzed intramolecular arylation (see
Table 4). The nature of the solvent proves to be the most
significant parameter controlling the reaction efficiency; in all
cases, using DMSO or DMF instead of acetonitrile or toluene
leads to a drastically increased yield of the target product.
Another major factor of reaction optimization is an appropriate
choice of ligands; as seen from entries 9, 10, 15, and 16 of
Table 4, DMEDA and L-Pro appear most advantageous among
the compounds conventionally used in such syntheses (cf. with
phenanthroline and 8-hydroxyquinoline). Though cesium
carbonate used as a base affords the highest conversion degree,
potassium carbonate, causing only a slight yield reduction,
offers a cheaper and competitive alternative to it, whereas
potassium phosphate turns out to be quite inefficient (cf. Table 4,
entries 9−11 and 15−16).
suitable boiling solvents for 6 h. As shown, the reaction of
intramolecular cross-coupling does not proceed without a
catalyst (see Table 4, entry 21). On the other hand, DMF−
DMEDA−K2CO3 appears to be the optimum system both
with and without microwave irradiation (see Table 4, entries 9
and 19).
N′-halopyrazolylamidines 2a−g were cyclized to the
corresponding 4-alkyl substituted imidazo[4,5-c]pyrazoles
1a−g using 0.05 mol of CuI, 0.1 mol of DMEDA, and an
excess of K2CO3 under microwave irradiation (method A) and
conventional heating in boiling DMF (method B) or CH3CN
(method C); see Table 5. The procedures with and without
microwave assistance furnished much the same yields of the
desired products (83−95%). At the same time, cyclization of
N′-(4-bromopyrazolyl) and N′-(4-iodopyrazolyl) deriva-
tives 2h−l of N-aryl substituted amidines both by methods
A and B was accompanied by complete decomposition of starting
For reliability, some selected experiments were repeated
without microwave assistance so that the cyclization was run in
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all positions of the imidazo[4,5-c]pyrazole nucleus; because of
high intermediate yields, the desired products can be obtained
in multigram amounts.
Table 4. Condition Optimization for the Cu-Catalyzed
Cyclization
EXPERIMENTAL PROCEDURES
■
Condensation of Aminopyrazoles with Orthoesters. Amino-
pyrazole (6.0 mmol) was boiled with 30 mmol of triethyl ortoformate
for 6a or triethyl orthoacetate for 6b for 6 h. The mixture was
evaporated (boiling water bath, 12 Torr), and after that, the crude
product was dissolved in minimum amount of EtOAc and applied to
the SiO2. The silica was washed by hexane (about 100 mL) to remove
the residues of triethyl ortoformate/acetate. Then, the product was
eluated by the mixture EtOAc/hexane (1:1).
c
entry
solvent
ligand
base
conversion, %
a
Microwave Assisted
1
toluene
toluene
toluene
toluene
toluene
toluene
CH3CN
CH3CN
DMF
DMEDA
K2CO3
Cs2CO3
K2CO3
Cs2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
K2CO3
K2CO3
K2CO3
Cs2CO3
0
4
2
DMEDA
8-Oxy
3
2
Ethyl N-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)methanimidoate
1
4
8-Oxy
0
(6a). Yield: 0.65 g (71%); reddish oil; H NMR (500 MHz, CDCl3)
δ 7.97 (1H, s), 7.67 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H),
7.29−7.19 (m, 1H), 5.82−5.75 (m, 1H), 4.26 (q, J = 7.1 Hz, 2H), 2.28
(s, 3H), 1.31 (dt, J = 1.3 Hz, 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 157.3, 148.9, 147.0, 139.6, 128.5, 126.1, 123.5, 93.6, 63.2,
14.11, 14.09. Anal. Calcd for C13H15N3O: C 68.10; H 6.59; N 18.33.
Found C 68.08; H 6.60; N 18.31.
5
Phen
18
16
4
6
Phen
7
DMEDA
Phen
8
5
9
DMEDA
DMEDA
DMEDA
8-Oxy
92
97
29
15
54
76
81
10
11
13
14
15
16
DMF
Ethyl N-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)ethanimidoate
(6b). Yield: 0.91 g (93%); mp 45−46 °C; 1H NMR (500 MHz,
CDCl3) δ 7.60 (d, J = 9.0 Hz, 2H), 7.36 (t, J = 9.5 Hz, 2H), 7.23 (t, J =
9.0 Hz, 1H), 5.61 (s, 1H), 4.18 (q, J = 8.5 Hz, 2H), 2.29 (s, 3H), 2.02
(s, 3H), 1.26 (t, J = 8.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
154.3, 148.8, 146.5, 139.7, 128.4, 125.9, 123.5, 96.6, 62.3, 17.5, 14.2,
14.1. Anal. Calcd for C14H17N3O: C 69.11; H 7.04; N 17.27. Found C
69.13; H 7.02; N 17.25.
Acylation of Aminopyrazoles with Imidoyl Chlorides. To a
stirred solution of 6.0 mmol of aminopyrazole in 50 mL of dry 1,4-
dioxane with 12.0 mmol of Et3N was added 6.0 mmol of imidoyl
chloride at room temperature. After stirring for 12 h, the sus-
pension was evaporated under a vacuum, diluted with 50 mL of
water, and extracted with 100 mL of dichloromethane. The organic
layer was washed with water, dried over Na2SO4, and evaporated.
The crude product was purified by crystallization from the mixture
EtOAc/hexane.
N-Methyl-N′-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-
benzimidamide (4a). Yield: 1.43 g (82%); mp 207−208 °C (Lit.18
203−204 °C); 1H NMR (500 MHz, DMSO-d6) δ 7.79 (d, J = 7.3 Hz,
2H), 7.62−7.45 (m, 1H), 7.45−7.33 (m, 5H), 7.24−7.14 (m, 3H),
4.69 (br, 1H), 2.88 (d, J = 4.6 Hz, 3H), 1.94 (s, 3H); 13C NMR (125
MHz, DMSO-d6) δ 161.1, 150.4, 147.5, 140.8, 135.3, 129.9, 128.80,
128.78, 128.1, 125.3, 122.6, 96.1, 28.9, 14.4; IR (KBr) νmax 3061, 2964,
1588, 1497, 1468, 1381. Anal. Calcd for C18H18N4: C 74.46; H 6.25; N
19.30. Found C 74.58; H 6.11; N 19.31.
DMF
DMF
DMF
Phen
DMSO
DMSO
L-Pro
L-Pro
b
Not Assisted
17
18
19
20
21
CH3CN
CH3CN
DMF
DMEDA
K2CO3
Cs2CO3
K2CO3
Cs2CO3
K2CO3
0
15
93
76
0
DMEDA
DMEDA
DMSO
DMF
L-Pro
no ligand and CuI
a
Conditions: 1 mol of amidine, 2 mol of base, 0.05 mol of CuI, 0.1
mol of ligand, 3 mL of solvent, vial tube, microvawe irradiation,
stirring, 15 min, 150 °C. Conditions: 1 mol of amidine, 2 mol of base,
0.05 mol of CuI, 0.1 mol of ligand, 5 mL of solvent, stirring, 6 h, and
heating at solvent boiling point. The conversion value given as the
average of three independent experiments.
b
c
compounds to form a mixture of unidentifiable products.
However, the reaction conducted under milder conditions by
method C afforded 4-aryl substituted imidazo[4,5-c]pyrazoles
1h−l in yields of 90−95% (see Table 5, entries h−l). A higher
reactivity of N′-halopyrazolylamidines 2h−l in copper-catalyzed
intramolecular cross-coupling reactions may be attributable to
the aromatic ring at one of the amidine nitrogens, which in-
creases the NH-acidity of these compounds compared to 2a−g.
A similar effect was described previously for the cyclization of
o-haloaryl amidines and guanidines to the corresponding
benzimidazole derivatives,14a,15 thus suggesting that not
amidines themselves but their conjugate anions coordinate
with the copper−ligand system in the reactions concerned.
Going from bromine to iodine evidently has a much weaker
effect on the reaction course since both bromo derivative 2j and
iodo derivatives 2h−l readily cyclize under mild conditions to
the corresponding imidazo[4,5-c]pyrazoles.
N-Ethyl-N′-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-
1
benzimidamide (4b). Yield: 1.44 g (79%); mp 158−159 °C; H
NMR (500 MHz, CDCl3) δ 7.73 (d, J = 7.6 Hz, 2H), 7.37 (t, J = 7.1
Hz, 3H), 7.34−7.28 (m, 2H), 7.24−7.18 (m, 1H), 7.18−7.10 (m, 2H),
4.89 (s, 1H), 4.81 (br, 1H), 3.60−3.35 (m, 2H), 2.10 (s, 3H), 1.26 (m,
3H); 13C NMR (125 MHz, CDCl3) δ 159.7, 149.5, 148.5, 140.3,
135.0, 129.8, 128.5, 128.3, 127.5, 125.2, 123.2, 96.3, 36.7, 14.7, 14.1; IR
(KBr) νmax 3060, 2972, 1497, 1464, 1381. Anal. Calcd for C19H20N4: C
74.97; H 6.62; N 18.41. Found C 74.90; H 6.67; N 18.43.
4-Methoxy-N-methyl-N′-(3-methyl-1-phenyl-1H-pyrazol-5-
1
yl)benzimidamide (4c). Yield: 1.61 g (84%); mp 127−128 °C; H
NMR (500 MHz, CDCl3) δ 7.73 (d, J = 7.8 Hz, 2H), 7.36 (t, J = 7.8
Hz, 2H), 7.19 (t, J = 7.8 Hz, 1H), 7.15−7.00 (m, 2H), 6.80 (d, J = 8.1
Hz, 2H), 4.97 (s, 1H), 4.85 (s, 1H), 3.82 (s, 3H), 3.02 (s, 3H), 2.14 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 160.6, 160.4, 148.5, 140.3,
129.0, 128.,3 127.0, 125.2, 123.1, 113.8, 96.3, 55.3, 28.9, 14.1; IR
(KBr) νmax 2964, 1597, 1563, 1501, 1460, 1380, 1246, 1038. Anal.
Calcd for C19H20N4O: C 71.23; H 6.29; N 17.49. Found C 71.38; H
6.20; N 17.57.
CONCLUSIONS
■
We have found a new synthetic access to 4-substituted
imidazo[4,5-c]pyrazole derivatives based on the cyclization of
N′-(4-halopyrazol-5-yl)amidines under the conditions of
copper-catalyzed cross-coupling reactions. The facile and
inexpensive method using 5-aminopyrazoles and copper
catalysts allows a variety of substituents to be introduced at
3-Chloro-N-methyl-N′-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-
1
benzimidamide (4d). Yield: 1.73 g (89%); mp 182−183 °C; H
NMR (500 MHz, DMSO-d6) δ 7.74 (d, J = 7.6 Hz, 2H), 7.69 (s, 1H),
7.54−7.32 (m, 4H), 7.32−7.15 (m, 2H), 7.11 (d, J = 6.1 Hz, 1H), 4.83
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a
Table 5. Synthesis of 4-Substituted Imidazo[4,5-c]pyrazoles
a
Reaction conditions. Method A: vial tube, 1 mol of 2, 2 mol of K2CO3, 0.05 mol of CuI, 0.1 mol of DMEDA, DMF, microvawe irridation, 30 min,
150 °C. Method B: 1 mol of 2, 2 mol of K2CO3, 0.05 mol of CuI, 0.1 mol of DMEDA, DMF, 8 h, heating. Method C: 1 mol of 2, 2 mol of K2CO3,
0.05 mol of CuI, 0.1 mol of DMEDA, CH3CN, 12 h, heating.
(br, 1H), 2.88 (d, J = 3.7 Hz, 3H), 1.98 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 159.3, 149.9, 147.6, 140.6, 137.2, 133.5, 130.6, 129.9,
127.9, 126.8, 125.4, 122.6, 96.3, 28.8, 14.4; IR (KBr) νmax 3064, 1602,
1580, 1496, 1467, 1381. Anal. Calcd for C18H17ClN4: C 66.56; H 5.28;
N 17.25. Found C 66.68; H 5.11; N 17.13.
N-Methyl-N′-(1-methyl-1H-pyrazol-5-yl)benzimidamide
1
(4g). Yield: 1.12 g (87%); mp 146−147 °C; H NMR (500 MHz,
DMSO-d6) δ 7.60−7.45 (m, 1H), 7.45−7.35 (m, 3H), 7.30−7.15 (m,
2H), 4.50 (br, 1H), 3.61 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ
161.1, 150.4, 147.5, 140.8, 135.3, 129.9, 128.80, 128.78, 128.1, 125.3,
122.6, 96.1, 28.9; IR (KBr) νmax 2963, 1596, 1469, 1392. Anal. Calcd
for C12H14N4: C 67.27; H 6.59; N 26.15. Found C 67.25; H 6.63;
N 26.13.
N′-(1,3-Dimethyl-1H-pyrazol-5-yl)-N-methylbenzimidamide
1
(4e). Yield: 1.18 g (86%); mp 136−137 °C; H NMR (500 MHz,
DMSO-d6) δ 7.47−7.37 (m, 4H), 7.25−7.15 (m, 1H), 4.32 (s, 1H),
3.53 (s, 3H), 3.36 (s, 3H), 2.89 (s, 3H).1.82 (s, 3H); 13C NMR (125
MHz, DMSO-d6) δ 160.6, 149.3, 144.7, 135.8, 129.8, 128.8, 128.1,
93.3, 34.1, 28.6, 14.3; IR (KBr) νmax 3030, 1381, 1347. Anal. Calcd
for C13H16N4: C 68.39; H 7.06; N 24.54. Found C 68.51; H 7.00;
N 24.49.
N′-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-N-phenyletanimid-
1
amide (4h). Yield: 922 mg (53%); mp 169−171 °C; H NMR (500
MHz, DMSO-d6) δ 7.68 (d, J = 7.3 Hz, 2H), 7.51 (d, J = 5.1 Hz, 2H),
7.36 (t, J = 7.4 Hz, 2H), 7.25 (t, J = 7.8 Hz, 3H), 7.06 (t, J = 7.1 Hz,
1H), 6.69 (br, 1H), 5.64 (s, 1H), 2.33 (s, 3H), 2.12 (s, 3H); 13C NMR
(125 MHz, DMSO-d6) δ 155.1, 147.9, 147.3, 139.1, 138.5, 127.8,
127.5, 124.9, 122.8, 122.6 M 119.7, 95.6, 17.7, 12.6; IR (KBr) νmax
1602, 1588, 1497, 1377. Anal. Calcd for C18H18N4: C 74.46; H 6.25;
N 19.30. Found C 74.51; H 6.18; N 19.31.
N′-(1,3-Dimethyl-1H-pyrazol-5-yl)-N,4-dimethylbimidamide
1
(4f). Yield: 1.32 g (91%); mp 167−169 °C; H NMR (500 MHz,
DMSO-d6) δ 7.33 (s, 1H), 7.19 (d, J = 7.7 Hz, 2H), 7.12 (d, J = 7.5
Hz, 2H), 4.40 (br, 1H), 3.51 (s, 3H), 2.87 (d, J = 4.2 Hz, 3H), 2.33 (s,
3H), 1.83 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 160.6, 149.4,
144.7, 139.4, 132.3, 129.3, 128.1, 93.3, 34.1, 28.6, 21.4, 14.3; IR (KBr)
νmax 3030, 1596, 1487, 767, 728. Anal. Calcd for C14H18N4: C 69.39;
H 7.49; N 23.12. Found C 68.97; H 7.65; N 23.38.
Condensation of Imino Esters of Aminopyrazoles with
Anilines. A round-bottom flask with a magnetic stirrer was charged
with 6.0 mmol of 5-aminopyrazole, 6.0 mmol of aniline, and 5 mL of
MeOH. The mixture was stirred until all reagents dissolved. Then the
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mixture was heated at 140 °C without stirring for 6 h. The crude
product was purified by flash chromatography.
N′-(4-Bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-chloro-
N-methyl-benzimidamide (2d). Yield: 1.55 g (96%); mp 124−
125 °C; 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 7.1 Hz, 2H), 7.34
(t, J = 7.6 Hz, 2H), 7.31−7.15 (m, 2H), 7.15−6.98 (m, 1H), 6.98−
6.52 (br, 2H), 5.47−5.19 (br, 1H), 3.02 (s, 3H), 2.13 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 160.5, 147.3, 146.7, 139.7, 136.4, 134.2,
131.2, 130.1, 129.5, 128.7, 127.3, 126.0, 125.2, 123.9, 122.7, 86.2, 29.1,
12.8; IR (KBr) νmax 1590, 1499, 1363. Anal. Calcd for C18H16BrClN4:
C 53.55; H 3.99; N 13.88. Found C 53.50; H 3.90; N 13.82.
N-(Phenyl-N′-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-
1
mehtanimidamide (4i). Yield: 1.25 g (76%); mp 169−171 °C; H
NMR (500 MHz, DMSO-d6) δ 7.68 (d, J = 7.3 Hz, 2H), 7.51 (d, J =
5.1 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.25 (t, J = 7.8 Hz, 3H), 7.06 (t,
J = 7.1 Hz, 1H), 6.81−6.49 (br, 1H), 5.64 (s, 1H), 2.33 (s, 3H), 2.12
(s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 151.8, 150.9, 148.3, 140.3,
129.5, 128.9, 125.9, 123.5, 123.0, 119.3, 116.8, 93.0, 14.6; IR (KBr)
νmax 3042, 1497, 1381. Anal. Calcd for C17H14N4: C 74.46; H 6.25;
N 19.30. Found C 74.51; H 6.18; N 19.31.
N′-(4-Bromo-1,3-dimethyl-1H-pyrazol-5-yl)-N-methylbenz-
1
imidamide (2e). Yield: 1.07 g (87%); mp 120−122 °C; H NMR
(500 MHz, CDCl3) δ 7.41−7.18 (m, 5H), 5.28−5.12 (br, 1H), 3.57 (s,
3H), 3.10 (s, 3H), 2.04 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
162.2, 147.1, 145.3, 135.0, 130.2, 129.1, 128.4, 127.3, 83.3, 35.1, 29.1,
12.7; IR (KBr) νmax 1377. Anal. Calcd for C13H15BrN4: C 50.83; H
4.92; N 18.24. Found C 50.76; H 4.87; N 18.34.
N-(4-Chlorophenyl)-N′-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-
1
mehtanimidamide (4j). Yield: 1.01 g (54%); mp 178−179 °C; H
NMR (500 MHz, CDCl3) δ 8.23 (br, 1H), 7.70 (t, J = 7.8 Hz, 2H),
7.40 (t, J = 8.1 Hz, 2H), 7.30−7.20 (m, 3H), 7.20−6.75 (m, 2H), 5.87
(s, 1H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 150.1, 149.2,
139.5, 137.7, 129.4, 128.5, 126.3, 123.9, 117.7, 92.5, 14.2; IR (KBr)
νmax 1495, 1380. Anal. Calcd for C17H15ClN4: C 65.70; H 4.86; N
18.03. Found C 65.73; H 4.80; N 18.05.
N′-(4-Bromo-1,3-dimethyl-1H-pyrazol-5-yl)-N,4-dimethyl-
1
benzimidamide (2f). Yield: 1.21 g (94%); mp 159−160 °C; H
NMR (500 MHz, CDCl3) δ 7.20−7.01 (m, 4H), 5.32−4.99 (br, 1H),
3.54 (s, 3H), 3.07 (s, 3H), 2.31 (s, 3H), 2.04 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 162.2, 145.3, 140.4, 132.0, 129.2, 127.2, 83.4, 35.2,
29.2, 21.4, 12.7; IR (KBr) νmax 2964, 1602. Anal. Calcd for
C14H17BrN4: C 52.35; H 5.33; N 17.44. Found C 52.47; H 5.40;
N 17.37.
N-(4-Methylphenyl)-N′-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-
1
imidoformamide (4k). Yield: 1.41 g (81%); mp 159−160 °C; H
NMR (500 MHz, CDCl3) δ 8.37−8.10 (br, 1H), 7.70 (d, J = 8.1 Hz,
2H), 7.63−7.40 (m, 1H), 7.38 (t, J = 7.7 Hz, 2H), 7.25−7.20 (m, 1H),
7.09 (d, J = 8.1 Hz, 2), 7.00−6.20 (m, 1H), 5.83 (s, 1H), 2.30 (s, 6H);
13C NMR (125 MHz, CDCl3) δ 149.0, 139.5, 136.5, 133.2, 130.0,
128.5, 126.1, 123.9, 116.9, 92.3, 20.7, 14.2; IR (KBr) νmax 3031, 1601,
1505. Anal. Calcd for C18H18N4: C 74.46; H 6.25; N 19.29. Found C
74.51; H 6.23; N 19.26.
N′-(4-Bromo-1-methyl-1H-pyrazol-5-yl)-N-methylbenzimi-
1
damide (2g). Yield: 1.05 g (90%); mp 164−165 °C; H NMR (500
MHz, DMSO-d6) δ 7.86−7.69 (br, 1H), 7.46−7.26 (m, 3H), 7.26−
7.15 (m, 2H), 7.09 (s, 1H), 3.52 (s, 3H), 2.91 (d, J = 5.0 Hz, 3H); 13C
NMR (125 MHz, DMSO-d6) δ 162.6, 147.6, 137.5, 130.3, 128.6,
127.9, 81.2, 35.8, 29.9. ; IR (KBr) νmax 1596. Anal. Calcd for
C12H13BrN4: C 49.16; H 4.47; N 19.11. Found C 49.15; H 4.45;
N 19.13.
N-(4-Methoxyphenyl)-N′-(3-methyl-1-phenyl-1H-pyrazol-
1
5yl)imidoformamide (4l). Yield: 1.14 g (62%); mp 63−64 °C; H
NMR (500 MHz, CDCl3) δ 8.45−7.70 (m, 2H), 7.70−7.50 (m, 2H),
7.35 (t, J = 7.3 Hz, 2H), 7.20 (t, J = 7.1 Hz, 1H), 7.00−6.60 (m, 2H),
6.79 (d, J = 6.2 Hz, 2H), 5.80 (s, 1H), 3.76 (s, 3H), 2.30 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 156.5, 153.2, 150.7, 148.3, 139.6, 131.9,
128.9, 128.6, 126.5, 123.5, 118.9, 114.9, 55.6, 14.9; IR (KBr) νmax
2992, 2951, 1178, 1128, 1031. Anal. Calcd for C18H18N4O: C 70.57;
H 5.92; N 18.29. Found C 70.46; H 5.98; N 18.15.
N′-(4-Bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-phenyli-
1
midoformamide (2i). Yield: 1.19 g (81%); mp 112−113 °C; H
NMR (500 MHz, CDCl3) δ 8.92−8.55 (br, 1H), 8.37−7.93 (br, 1H),
7.62 (d, J = 7.1 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.32−7.16 (m, 3H),
7.06 (t, J = 7.3 Hz, 1H), 6.98−6.55 (br, 1H), 2.31 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 151.7, 147.8, 145.3, 139.6, 138.7, 129.7, 128.6,
126.6, 123.9, 123.7, 116.8, 13.0; IR (KBr) νmax 3033, 1594, 1496, 1383.
Anal. Calcd for C17H15BrN4: C 57.48; H 4.26; N 15.77. Found
C 57.00; H 4.39; N 15.67.
Bromination of Amidines with NBS. To a suspension of 4.0
mmol of amidine in 25 mL of dry acetonitrile was added 4.1 mmol of
NBS at room temperature. The mixture was refluxed and monitored
by TLC. Then the solution was evaporated, diluted with 100 mL of
dichloromethane, and washed twice with 25 mL of water. The organic
layer was dried over Na2SO4 and evaporated.
N′-(4-Bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-(4-
chlorophenyl)imidoformamide (2j). Yield: 1.18 g (76%); mp
1
182−183 °C; H NMR (500 MHz, CDCl3) δ 8.85−8.50 (br, 1H),
N′-(4-Bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-methyl-
7.60 (d, J = 9.0 Hz, 2H), 7.37 (t, J = 10.0 Hz, 2H), 7.32−7.13 (m, 2H),
7.11−6.60 (br, 2H), 2.30 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
152.1, 147.9, 144.9, 139.3, 137.4, 129.6, 129.0, 128.6, 123.6, 117.9,
83.9, 13.0; IR (KBr) νmax 3031, 1377. Anal. Calcd for C17H14BrClN4:
C 52.40; H 3.62; N 14.38. Found C 52.38; H 3.63; N 14.37.
Iodination of Amidines with Iodine. To 4.0 mmol of amidine
dissolved in 3 mL of dry DMF at room temperature were added 4.0
mmol of iodine and 8.0 mmol of KOH under stirring. The reaction
mixture was stirred for 2 h at room temperature and then left to stand
under TLC monitoring until the reaction was complete. Then the
mixture was poured into 100 mL of water and the precipitate was
filtered off. The crude product was used in the next step without
purification.
1
benzimidamide (2a). Yield: 1.37 g (93%); mp 106−107 °C; H
NMR (500 MHz, CDCl3) δ 7.56 (d, J = 6.8 Hz, 2H), 7.34 (t, J = 7.1
Hz, 2H), 7.30 (t, J = 7.8 Hz, 1H), 7.26−7.11 (m, 3H), 7.10−6.75 (m,
2H), 5.23−5.06 (br, 1H), 3.72−3.66 (m, 2H), 3.09 (s, 3H), 2.15 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 161.9, 147.2, 134.8, 129.9,
128.6, 128.3, 127.1, 125.7, 122.5, 86.0, 29.2, 12.9; IR (KBr) νmax 1497,
1381. Anal. Calcd for C18H17BrN4: C 58.55; H 4.64; N 15.17. Found
C 58.60; H 4.60; N 15.26.
N′-(4-Bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-ethyl-
benzimidamide (2b). Brown solid. Yield: 1.39 g (91%); mp 162−
163 °C; 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 7.5 Hz, 2H), 7.33
(t, J = 8.0 Hz, 2H), 7.31−7.25 (m, 1H), 7.25−7.09 (m, 3H), 7.09−
6.75 (m, 2H), 5.15 (s, 1H), 3.70−3.41 (m, 2H), 2.13 (s, 3H), 1.40−
1.12 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 161.1, 147.2, 140.0,
135.0, 129.9, 128.6, 128.2, 127.1, 125.7, 122.4, 86.0, 37.0, 14.6, 12.9; IR
(KBr) νmax 1594, 1378. Anal. Calcd for C19H19BrN4: C 59.54; H 5.00;
N 14.62. Found C 59.49; H 5.05; N 14.53.
N′-(4-Bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-4-methoxy-
N-methybenzimidamide (2c). Yield: 1.42 g (89%); mp 105−
106 °C; 1H NMR (500 MHz, CDCl3) δ 7.59 (d, J = 7.8 Hz, 2H), 7.33
(t, J = 7.8 Hz, 2H), 7.19 (t, J = 7.3 Hz, 1H), 7.03−6.80 (m, 2H), 6.68
(d, J = 8.0 Hz, 2H), 5.05 (s, 1H), 3.76 (s, 3H), 3.09 (s, 3H), 2.16
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 161.7, 160.7, 147.4, 147.2,
140.1, 128.7, 128.6, 127.2, 125.7, 122.4, 113.7, 85.9, 55.3, 29.2, 12.9; IR
(KBr) νmax 1598. Anal. Calcd for C19H19BrN4O: C 57.15; H 4.80;
N 14.03. Found C 57.10; H 4.92; N 14.15.
(1E)-N′-(4-Iodo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-phe-
nylethanimidamide (2h). Yield: 1.08 g (65%); mp 141−142 °C; 1H
NMR (500 MHz, DMSO-d6) δ 9.69−9.55 (m, 1H), 7.69 (d, J = 6.8
Hz, 2H), 7.58 (t, J = 7.7 Hz, 2H), 7.46 (d, J = 8.1 Hz, 1H), 7.40 (t, J =
6.8 Hz, 2H), 7.26 (m, 2H), 7.02 (t, J = 6.6 Hz, 1H), 2.19 (s, 3H), 2.01
(s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 158.73, 146.8, 140.3,
140.0, 131.9, 129.3, 129.0, 126.6, 123.5, 114.9, 85.3, 20.2, 13.2; IR
(KBr) νmax 1594, 1362. Anal. Calcd for C18H17IN4: C 51.94; H 4.12;
N 13.46. Found C 51.90; H 4.10; N 13.56.
N′-(4-Iodo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-(4-
methylphenyl)imidoformamide (2k). Yield: 1.46 g (88%); dark
brown oil; 1H NMR (500 MHz, CDCl3) δ 8.17 (m, 1H), 7.30 (d, J =
6.1 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.24 (t, J = 7.0 Hz, 1H), 6.84 (m,
1H), 6.83 (d, J = 8.1 Hz, 2H), 5.83 (s, 1H), 3.79 (s, 3H), 2.33 (s, 3H);
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13C NMR (125 MHz, CDCl3) δ 156.3, 150.5, 149.0, 139.7, 139.6,
132.2, 128.4, 126.1, 123.8, 119.0, 114.8, 92.2, 55.6, 14.2; IR (KBr) νmax
1602, 1502, 1456. Anal. Calcd for C18H17IN4: C 51.94; H 4.12;
N 13.46. Found C 51.90; H 4.11; N 13.47.
C18H15ClN4: C 66.98; H 4.68; N 17.36. Found C 66.93; H 4.65;
N 17.35.
1,3,4-Trimethyl-5-phenyl-1,4-dihydroimidazo[4,5-c]pyrazole
(1e). Method A. Yield: 169 mg (89%). Method B. Yield: 173 mg
1
(91%); mp 127−128 °C; H NMR (500 MHz, CDCl3) δ 7.72−7.62
N′-(4-Iodo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-(4-
methoxyphenyl)imidoformamide (2l). Yield: 1.45 g (84%); mp
64−65 °C; 1H NMR (500 MHz, CDCl3) δ 8.56−8.35 (m, 2H), 7.75−
7.57 (m, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 6.93−
6.72 (m, 3H), 3.79 (s, 3H), 2.34 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 156.5, 153.2, 150.7, 148.4, 139.6, 131.9, 128.6, 126.5, 123.5,
118.9, 114.9, 55.6, 14.9; IR (KBr) νmax 1601, 1452. Anal. Calcd for
C18H17IN4O: C 50.02; H 3.96; N 12.96. Found C 50.10; H 3.94;
N 12.93.
Cyclization of N′-(Halopyrazolyl)amidines to Imidazo[4,5-c]-
pyrazoles under Microwave Irridation (Method A). A vial was
charged with 0.84 mmol of N′-halopyrazolylamidine 2, 1.68 mol of
Cs2CO3, 0.084 mol of DMEDA, 3 mL of dry DMF, and 0.042 mol of
powdered CuI under Ar. The stirred mixture was heated for 30 min at
150 °C under microwave irridation, evaporated, diluted with 100 mL
of dichloromethane, and filtered. The organic layer was washed twice
with 50 mL of water, dried over Na2SO4, and evaporated. The crude
product was purified by flash chromatography (EtOAc/hexane).
Cyclization of N′-(Halopyrazolyl)amidines to Imidazo[4,5-c]
pyrazoles without Microwave Irridation (Methods B and C).
A round-bottom flask was charged with 0.84 mmol of N′-halopyrazoly-
lamidine 2, 1.68 mol of Cs2CO3, 0.084 mol of DMEDA, and 3 mL of
dry DMF (method B) or 10 mL of dry MeCN (method C). To the
stirred mixture was then added 0.042 mol of powdered CuI under Ar.
The stirred mixture was heated under Ar and monitored by TLC,
evaporated, diluted with 100 mL of dichloromethane, and filtered.
The organic layer was washed twice with 50 mL of water, dried over
Na2SO4, and evaporated. The crude product was purified by flash
chromatography (EtOAc/hexane).
(m, 2H), 7.55−7.43 (m, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 2.50 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 154.6, 151.2, 130.3, 129.4, 129.2,
128.6, 127.2, 123.5, 35.0, 33.2, 12.3; IR (CHCl3) νmax 1459, 1382.
Anal. Calcd for C13H14N4: C 69.00; H 6.24; N 24.76. Found C 69.02;
H 6.20; N 24.78.
1,3,4-Trimethyl-5-(4-methylphenyl)-1,4-dihydroimidazo-
[4,5-c]pyrazole (1f). Method A. Yield: 184 mg (91%). Method B.
Yield: 168 mg (83%); mp 75−76 °C; 1H NMR (500 MHz, CDCl3) δ
7.56 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 3.94 (s, 3H), 3.83
(s, 3H), 2.50 (s, 3H), 2.44 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
154.9, 151.8, 139.6, 129.3, 129.1, 127.4, 127.2, 123.4, 34.8, 33.1, 21.4,
12.2; IR (KBr) νmax 1500, 1376. Anal. Calcd for C14H16N4: C 69.67;
H 6.71; N 23.32. Found C 69.68; H 6.70; N 23.32.
1,4-Dimethyl-5-phenyl-1,4-dihydroimidazo[4,5-c]pyrazole
(1g). Method A. Yield: 169 mg (95%). Method B. Yield: 164 mg
(92%); mp 113−114 °C; 1H NMR (500 MHz, CDCl3) δ 7.68 (d, J =
6.5 Hz, 2H), 7.55−7.44 (m, 3H), 7.35 (s, 3H), 4.02 (s, 3H), 3.81 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 155.2, 151.1, 130.2, 129.6,
129.2, 128.7, 125.6, 117.6, 35.5, 33.8; IR (KBr) νmax 1595, 1458, 1365,
768, 732, 700. Anal. Calcd for C12H12N4: C 67.90; H 5.70; N 26.40.
Found C 67.89; H 5.71; N 26.40.
3,5-Dimethyl-1,4-diphenyl-1,4-dihydroimidazo[4,5-c]-
pyrazole (1h). Method C. Yield: 217 mg (90%); mp 124−125 °C;
1H NMR (500 MHz, CDCl3) δ 8.10 (dd, J = 1.0 Hz, 8.4 Hz, 2H),
7.60−7.51 (m, 2H), 7.51−7.42 (m, 3H), 7.42−7.31 (m, 2H), 7.14 (t,
J = 7.5 Hz, 1H), 2.50 (s, 3H), 2.25 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 152.0, 150.0, 139.8, 136.3, 129.9, 129.6, 129.2, 128.5, 126.1,
124.2, 117.2, 14.9, 12.6; IR (KBr) νmax 1594, 1460, 1384. Anal. Calcd
for C18H16N4: C 74.98; H 5.59; N 19.43. Found C 74.97; H 5.58;
N 19.45.
4-Phenyl-1,4-dihydro-3-methyl-1-phenylimidazo[4,5-c]-
pyrazole (1i). Method C. Yield: 207 mg (90%); mp 132−133 °C; 1H
NMR (500 MHz, CDCl3) δ 8.12 (d, J = 7.7 Hz, 2H), 7.81 (s, 1H),
7.55−7.41 (m, 8H), 7.17 (t, J = 7.3 Hz, 1H), 2.47 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 141.9, 139.5, 136.5, 130.1, 130.0, 129.3, 127.8,
124.6, 122.4, 122.0, 117.3, 13.7; IR (KBr) νmax 1600, 1505, 1464, 1382.
Anal. Calcd for C17H14N4: C 74.43; H 5.14; N 20.42. Found C 74.42;
H 5.15; N 20.42.
4-(4-Chlorophenyl)-1,4-dihydro-3-methyl-1-phenylimidazo-
[4,5-c]pyrazole (1j). Method C. Yield: 240 mg (93%); mp 146−
147 °C; 1H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 8.0 Hz, 2H), 7.79
(s, 1H), 7.53 (d., J = 8.6 Hz, 2H), 7.51−7.39 (m, 4H), 7.20 (t, J =
7.1 Hz, 1H), 2.47 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 150.9,
140.8, 138.5, 134.1, 132.5, 129.2, 128.8, 128.3, 123.6, 122.5, 120.7,
116.3, 12.1; IR (KBr) νmax 1595, 1500, 1383. Anal. Calcd for
C17H13ClN4: C 66.13; H 4.24; 18.14. Found C 66.20; H 4.30; N 29.50.
3-Methyl-4-(4-methylphenyl)-1-phenyl-1,4-dihydroimidazo-
[4,5-c]pyrazole (1k). Method C. Yield: 230 mg (95%); mp 113−
115 °C; 1H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 8.7 Hz, 2H), 7.77
(s, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.40−7.27 (m, 4H), 7.17 (t, J =
7.5 Hz, 1H), 2.46 (s, 3H), 2.43 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 151.8, 141.9, 139.6, 137.8, 134.0, 130.5, 130.0, 129.2, 124.4, 122.4,
122.1, 117.2, 21.0, 13.6; IR (KBr) νmax 1596, 1460, 1380. Anal. Calcd
for C18H16N4: C 74.98; H 5.59; N 19.43. Found C 74.91; H 5.61;
N 19.48.
3,4-Dimethyl-1,5-diphenyl-1,4-dihydroimidazo[4,5-c]-
pyrazole (1a). Method A. Yield: 232 mg (96%). Method B. Yield:
225 mg (93%); mp 155−156 °C; 1H NMR (500 MHz, CDCl3) δ 8.18
(d, J = 7.8 Hz, 2H), 7.73 (d, J = 7.6 Hz, 2H), 7.60−7.48 (m, 3H), 7.45
(t, J = 7.8 Hz, 2H), 7.16 (t, J = 8.1 Hz, 1H), 3.87 (s, 3H), 2.60 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 154.6, 150.5, 139.9, 130.3, 130.1,
129.6, 129.4, 129.1, 128.7, 125.3, 124.0, 117.1, 33.1, 12.5; IR (KBr)
νmax 3027, 1597, 1501, 1379. Anal. Calcd for C18H16N4: C 74.98;
H 5.59; N 19.43. Found C 74.92; H 5.63; N 19.45.
4-Ethyl-3-methyl-1,5-diphenyl-1,4-dihydroimidazo[4,5-c]-
pyrazole (1b). Method A. Yield: 236 mg (93%). Method B. Yield:
1
220 mg (87%); mp 153−155 °C; H NMR (500 MHz, CDCl3) δ
8.20−8.17 (m, 1H), 8.17−8.14 (m, 1H), 7.70 (m, 2H), 7.53 (m, 3H),
7.45 (m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 2.62 (s, 3H), 1.52 (t, J = 7.3
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 154.2, 150.9, 139.9, 130.6,
129.9, 129.6, 129.4, 129.2, 128.7, 124.0, 123.9, 117.2, 40.9, 29.7, 17.0,
13.2; IR (CHCl3) νmax 1383. Anal. Calcd for C19H18N4: C 75.47;
H 6.00; N 18.53. Found C 75.48; H 6.02; N 18.50.
5-(4-Methoxyphenyl)-3,4-dimethyl-1-phenyl-1,4-dihydro-
imidazo[4,5-c]-pyrazole (1c). Method A. Yield: 235 mg (88%).
Method B. Yield: 246 mg (92%); mp 96−97 °C; 1H NMR (500 MHz,
CDCl3) δ 8.14 (d, J = 7.6 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H), 7.43 (t, J
= 7.6 Hz, 2H), 7.13 (t, J = 8.3 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 3.87
(s, 3H), 3.84 (s, 3H), 2.58 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
159.6, 153.6, 149.4, 138.9, 129.7, 129.0, 128.1, 124.0, 122.9, 121.7,
116.0, 113.2, 54.4, 32.0, 11.5; IR (KBr) νmax 1597, 1504, 1251, 1177.
Anal. Calcd for C19H18N4O: C 71.68; H 5.70; N 17.60. Found
C 71.63; H 5.72; N 17.59.
4-(4-Methoxyphenyl)-3-methyl-1-phenyl-1,4-dihydroimidazo-
[4,5-c]pyrazole (1l). Method C. Yield: 232 mg (91%); mp 167−
168 °C; 1H NMR (500 MHz, CDCl3) δ 8.15 (d, J = 7.6 Hz, 2H), 7.76
(s, 1H), 7.48 (t, J = 8.1 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.20 (t, J =
7.3 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 3.91 (s, 3H), 2.46 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 159.2, 161.6, 142.1, 139.7, 130.0, 129.6,
129.2, 124.4, 124.1, 122.5, 117.2, 115.1, 55.7, 13.4; IR (KBr) νmax
1597, 1460, 1383, 1158, 1028. Anal. Calcd for C18H16N4O: C 71.04;
H 5.30; N 18.41. Found C 71.04; H 5.30; N 18.39.
5-(3-Chlorophenyl)-3,4-dimethyl-1-phenyl-1,4-dihydro-
imidazo[4,5-c]pyrazole (1d). Method A. Yield: 254 mg (94%).
1
Method B. Yield: 244 mg (90%); mp 148−149 °C; H NMR (500
MHz, CDCl3) δ 8.15 (d, J = 7.6 Hz, 2H), 7.57 (s, 1H), 7.59 (d, J = 7.6
Hz, 1H), 7.50−7.40 (m, 4H), 7.17 (t, J = 7.6 Hz, 1H), 3.85 (s, 3H),
2.58 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 152.8, 150.3, 139.8,
134.8, 131.9, 130.1, 129.9, 129.6, 129.4, 129.2, 127.3, 125.4, 124.1,
117.0, 33.2, 12.5; IR (KBr) νmax 1600, 1499, 1379. Anal. Calcd for
3371
dx.doi.org/10.1021/jo300176f | J. Org. Chem. 2012, 77, 3365−3372

The Journal of Organic Chemistry
Article
Wang, X.; Wang, Y.; Chen, C. J. Org. Chem. 2011, 76, 716. (h) Wang, P.;
Wang, X.-J.; Li, Y.; Xiang, W.-S.; Zheng, G.-J.; Wang, Y.-P. Tetrahedron
2010, 66, 5402.
(15) Saha, P.; Ramana, T.; Purkait, N.; Ali, M. A.; Paul, R.;
Punniyamurthy, T. J. Org. Chem. 2009, 74, 8719.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) (a) Szczepankiewicz, B. G.; Rohde, J. J.; Kurukulasuriya, R. Org.
Lett. 2005, 7, 1833. (b) Kurukulasuriya, R.; Rohde, J. J.;
Szczepankiewicz, B. G.; Basha, F.; Lai, C.; Jae, H.-S.; Winn, M.;
Stewart, K. D.; Longenecker, K. L.; Lubben, T. W.; Ballaron, S. J.; Sham,
H. L.; von Geldern, T. M. Bioorg. Med. Chem. Lett. 2006, 16, 6226.
(c) Zhu, J.; Xie, H.; Chen, Z.; Li, S.; Wu, Y. Chem. Commun. 2009, 2338.
(d) Hirano, K.; Biju, A. T.; Glorius, F. J. Org. Chem. 2009, 74, 9570.
(17) (a) Volochnyuk, D. M.; Kovaleva, S. A.; Chernega, A. N.;
Chubaruk, N. G.; Kostyuk, A. N.; Pinchuk, A. M.; Tolmachev, A. A.;
Schmutzler, R. Synthesis 2006, 1613. (b) Iaroshenko, V. O.;
Volochnyuk, D. M.; Wang, Y.; Vovk, M. V.; Boiko, V. J.; Rusanov,
E. B.; Groth, U. M.; Tolmachev, A. A. Synthesis 2007, 3309.
(c) Volochnyuk, D. M.; Ryabukhin, S. V.; Plaskon, A. S.; Dmytriv,
Y. V.; Grygorenko, O. O.; Mykhailiuk, P. K.; Krotko, D. G.; A., P.;
Tolmachev, A. A. J. Comb. Chem. 2010, 12, 510.
AUTHOR INFORMATION
Corresponding Author
*Tel.: +380 50 707 12 10. E-mail: kliubchak@gmail.com.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by Enamine Ltd.
■
REFERENCES
■
(1) Vernekar, S. K. V.; Hallaq, H. Y.; Clarkson, G.; Lochner, M.;
Thompson, A. J.; Silvestr, L.; Lummis, S. C. R. J. Med. Chem. 2010, 53,
2324.
(2) Toque, H. A. F.; Priviero, F. B. M.; Teixeira, C. E.; Perissutti, E.;
Fiorino, F.; Severino, B.; Frecentese, F.; Lorenzetti, R.; Baracat, J. S.;
Santagada, V.; Caliendo, G.; Antunes, E.; Nucci, G. D. J. Med. Chem.
2008, 51, 2807.
(18) Kovaleva, S. A.; Chubaruk, N. G.; Tolmachev, A. A.; Pinchuk,
A. M. Chem. Heterocycl. Compd. (N. Y., NY, U. S.) 2001, 37, 1183.
(19) Lazaro, R.; Elguero, J. J. Heterocycl. Chem. 1978, 15, 715.
(3) (a) Wurz, R. P.; Pettus, L. H.; Xu, S.; Henkle, B.; Sherman, L.;
Plant, M.; Miner, K.; McBride, H.; Wong, L. M.; Saris, C. J. M.; Lee,
M. R.; Chmait, S.; Mohr, C.; Hsieh, F.; Tasker, A. S. Bioorg. Med.
Chem. Lett. 2009, 19, 4724. (b) Pettus, L. H.; Wurz, R. P.; Xu, S.;
Herberich, B.; Henkle, B.; Liu, Q.; McBride, H. J.; Mu, S.; Plant,
M. H.; Saris, C. J. M.; Sherman, L.; Wong, L. M.; Chmait, S.; Lee,
M. R.; Mohr, C.; Hsieh, F.; Tasker, A. S. J. Med. Chem. 2010, 53, 2973.
(c) Milburn, R. R.; Thiel, O. R.; Achmatowicz, M.; Wang, X.;
Zigterman, J.; Bernard, C.; Colyer, J. T.; DiVirgilio, E.; Crockett, R.;
Correll, T. L.; Nagapudi, K.; Ranganathan, K.; Hedley, S. J.; Allgeier,
A.; Larsen, R. D. Org. Process Res. Dev. 2011, 15, 31.
(4) (a) Vicentini, C. B.; Veronese, A.; Guarneri, M., Patent EP
190457A1. Aug. 13, 1986; Chem. Abstr., 1986, 105, 226578t; (b) Beck,
J. P.; Gilligan, P. J., Patent US 6714912B1. Jan. 16, 2001; Chem. Abstr.,
1999, 130, 223271.
(5) Yu, H.; Jung, Y.; Kim, H.; Lee, J.; Oh, C.-H.; Yoo, K. H.; Sim, T.;
Hah, J.-M. Bioorg. Med. Chem. Lett. 2010, 20, 3805.
(6) Sudarsanamr, V.; Nagarajan, K.; Rao, K. R.; Shenoy, S. J.
Tetrahedron Lett. 1980, 21, 4757.
(7) Barraclough, P.; Black, J. W.; Cambridge, D.; Firmin, D.;
Gerskowitch, V. P.; Glen, R. C.; Giles, H.; Gillam, J. M.; Hull, R. A. D.;
Lyer, R.; Randall, P.; Shah, G. P.; Smith, S.; Whiting, M. V. Pharmazie
1992, 325, 225.
(8) (a) Grandberg, I. I.; Klyuchko, G. V. Zh. Obshch. Chim. 1963, 33,
244; Chem. Abstr. 1963, 58, 13934a. (b) Vicentini, C. B.; Ferretti, V.;
Veronese, A. C.; Guarneri, M.; Manfrini, M.; Giori, P. Heterocycle
1995, 41, 497. (c) Vicentini, C. B.; Manfrini, M.; Mazzanti, M.;
Scatturin, A.; Romagnoli, C.; Mares, D. Pharmazie 1999, 332, 337.
(9) Vicentini, C. B.; Veronese, A. C.; Manfrini, M.; Guarneri, M.
Tetrahedron 1996, 52, 7179.
(10) Alfred, D.; Ehrhard, H. Chem. Ber. 1958, 91, 1834.
(11) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108,
3054.
(12) Brain, C. T.; Steer, J. T. J. Org. Chem. 2003, 68, 6814.
(13) (a) Brain, C. T.; Brunton, S. A. Tetrahedron Lett. 2002, 43, 1893.
(b) Travins, J. M.; Bernotas, R. C.; Kaufman, D. H.; Wrobel, J.;
Quinet, E.; Nambi, P.; Feingold, I.; Huselton, C.; Wilhelmsson, A.;
Goos-Nilsson, A. Bioor. Med. Chem. Lett. 2010, 20, 526.
(14) (a) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133. (b) Evindar,
G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802. (c) Barbero, N.; Carril,
M.; SanMartin, R.; Dominguez, E. Tetrahedron 2007, 63, 10425.
(d) Li, Z.; Sun, H.; Jiang, H.; Liu, H. Org. Lett. 2008, 10, 3263.
(e) Viirre, R. D.; Evinder, G.; Batey, R. A. J. Org. Chem. 2008, 73,
3452. (f) Murru, S.; Le Bras, J.; Muzart, J.; Patel, B. K. J. Org. Chem.
2009, 74, 2217. (g) Peng, J.; Ye, M.; Zong, C.; Hu, F.; Feng, L.;
3372
dx.doi.org/10.1021/jo300176f | J. Org. Chem. 2012, 77, 3365−3372