Efficient C-7 or C-3/C-7 direct arylation of tri- or disubstituted imidazo[1,2- b ]pyrazoles

Article abstract of DOI:10.1055/s-0033-1339657

A novel and efficient method of C-7 direct arylation of the imidazo[1,2-b]pyrazole core, never described to date, is presented in this paper. Series of electron-rich or electron-poor aryl and heteroaryl groups were easily introduced. The corresponding products were obtained in moderate to excellent yields thanks to this pallado-catalyzed and microwave-assisted process. A one-pot double C-3 and C-7 direct coupling is also reported. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339657

LETTER
▌2095
letter
Efficient C-7 or C-3/C-7 Direct Arylation of Tri- or Disubstituted Imidazo-
[1,2-b]pyrazoles
Efficient Direct Arylation of Tri- or Disubstituted Imidazo[1,2-b]pyrazoles
Sandrine Grosse,a Christelle Pillard,b Philippe Bernard,b Gérald Guillaumet*a
a
Institut de Chimie Organique et Analytique (ICOA), Université d’Orléans, UMR-CNRS 7311, BP 6759, rue de Chartres, 45067 Orléans cedex
2, France
Fax +33(38)417281; E-mail: gerald.guillaumet@univ-orleans.fr
b
Greenpharma S.A.S, 3, allée du Titane, 45100 Orléans, France
Received: 24.06.2013; Accepted after revision: 24.07.2013
constructing the 5-5 fused ring system with the desired
Abstract: A novel and efficient method of C-7 direct arylation of
substituents in appropriate positions.1a,b,2b,5 Strategies of
the imidazo[1,2-b]pyrazole core, never described to date, is present-
direct functionalization of the heterobicyclic moiety have
rarely been reported. Developing new synthetic and func-
ed in this paper. Series of electron-rich or electron-poor aryl and
heteroaryl groups were easily introduced. The corresponding prod-
ucts were obtained in moderate to excellent yields thanks to this tionalization strategies therefore continues to be essential
pallado-catalyzed and microwave-assisted process. A one-pot
double C-3 and C-7 direct coupling is also reported.
in generating diversified libraries of potentially bioactive
molecules.
Key words: C–C coupling, arylation, fused-ring systems, micro-
At the beginning of our research in this field, we devel-
wave chemistry, palladium
oped an original synthesis of the imidazo[1,2-b]pyrazole
core through a three-step route. We then reported the first
regioselective C-3 direct arylation of the imidazo[1,2-
In recent years, polycyclic scaffolds containing heteroat-
oms such as nitrogens have attracted much attention in the
field of drug discovery. More precisely, imidazo[1,2-
b]pyrazole derivatives have been designed, prepared and
b]pyrazole system.6 The methodology allows rapid access
to a wide range of trisubstituted imidazo[1,2-b]pyrazole
compounds. To pursue our objectives,7 we now envision
studying the reactivity of carbon C-7 toward direct C–H
studied as anticancer,1 antifungal2 and anti-inflammatory
arylation (Scheme 1).
agents.3 They can also play an important role in the treat-
The direct C–H arylation of aromatic and heteroaromatic
compounds has been successfully accomplished in recent
years. Such cross-couplings are very attractive compared
to more classical palladium-catalyzed reactions such as
Suzuki, Stille and Negishi coupling as they do not require
ment of neurodegenerative disorders.4
The synthesis of the imidazo[1,2-b]pyrazole skeleton,
therefore, provides an interesting challenge. Current syn-
thetic methods of such compounds generally consist in
previous work (ref. 6)
Ph
Ph
7
7
Ph
3 steps
7
C-3 regioselective
direct arylation
N
N
Me
Me
N
N
N
N
N
3
N
NH2
3
H
Ar(Het)
R
R
this work
Ph
R3
Ph
7
7
N
N
N
Me
Me
C-7 direct arylation
N
N
N
3
3
R1 = MeO, CF3, Me
R2 = Ar, 4-py
R2
R2
R3 = Ar, 4-py
R1
R1
Scheme 1 Previous versus current work
SYNLETT 2013, 24, 2095–2101
Advanced online publication: 28.08.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339657; Art ID: ST-2013-B0578-L
© Georg Thieme Verlag Stuttgart · New York

2096
S. Grosse et al.
LETTER
7
X
7
N
catalyst, ligand, base
solvent, 160 °C, MW
Me
N
N
3
N
Me
+
N
N
3
OMe
OMe
1
1a
Scheme 2 Screening of the palladium-catalyzed direct C-7 arylation conditions
the preliminary preparation of organometallic reagents.8 applied the conditions optimized for C-3 direct arylation,
Noticeably, arylation of electron-poor heterocycles such namely palladium acetate (10 mol%), tricyclohexylphos-
as five-membered heterocycles bearing two or three het- phine (20 mol%), potassium carbonate (2.0 equiv).6 How-
eroatoms, is a compelling challenge in this field today.9 ever, two equivalents of 4-bromotoluene were used.
To the best of our knowledge, this work constitutes the These conditions led to a poor conversion of 27% (Table
first successful palladium-catalyzed direct C-7 functional- 1, entry 1). The conversion was based on the ratio of NMR
ization of the imidazo[1,2-b]pyrazole core.
integrations of the NMe signal from the product and the
starting material. Using a stronger base such as cesium
carbonate enhanced the conversion to 47% (Table 1, entry
2), whereas the use of a non-carbonate base such as potas-
sium acetate was unsuccessful (Table 1, entry 3). Adding
pivalic acid10 as additive did not improve the conversion
Our study was initiated by working on 2-(4-methoxyphe-
nyl)-1-methyl-6-phenyl-3-(p-tolyl)-1H-imidazo[1,2-b]-
pyrazole (1, Scheme 2). This starting material was easily
synthesized in a four-step process from the commercially
available 3(5)-phenyl-1H-pyrazol-5(3)-amine.6 We first
Table 1 Screening of the Palladium-Catalyzed Direct C-7 Arylation Conditionsa
Entry
Catalyst
(mol%)
Ligand
(mol%)
Base (2.0
equiv)
X
Solvent
Time (h)
Conversion (%)b
[Yield (%)]c
(equiv)
1
2
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (15)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
PCy3 (20)
K2CO3
Br (2.0)
Br (2.0)
Br (2.0)
Br (2.0)
Br (2.0)
Br (2.0)
Br (2.0)
Br (2.0)
Br (4.0)
Br (2.0)
Br (2.0)
Br (2.0)
Br (2.0)
Br (2.0)
Cl (2.0)
I (2.0)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
1
1
1
1
1
1
1
1
1
1
2
3
4
4
4
4
27
47
PCy3 (20)
Cs2CO3
KOAc
3
PCy3 (20)
24
4
PCy3 (20)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
42d
32
5
t-Bu3PHBF4 (20)
PCy3HBF4 (20)
PCy3HBF4 (20)
PCy3HBF4 (20)
PCy3HBF4 (20)
PCy3HBF4 (30)
PCy3HBF4 (20)
PCy3HBF4 (20)
PCy3HBF4 (20)
PCy3HBF4 (10)
PCy3HBF4 (20)
PCy3HBF4 (20)
6
69
7
58
8
DMA
52
9
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
67
10
11
12
13
14
15
16
72
84
92
100 (95)
70
100 (89)
10
a The reactions were carried out with 1 (0.254 mmol), 4-halogenotoluene (specified quantities), palladium acetate (specified quantities), ligand
(specified quantities), and base (2.0 equiv) in solvent (2 mL).
b 1H NMR ratio based on the integration of NMe.
c Isolated yields after column chromatography.
d Pivalic acid (20 mol%) was added.
Synlett 2013, 24, 2095–2101
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LETTER
Efficient Direct Arylation of Tri- or Disubstituted Imidazo[1,2-b]pyrazoles
2097
R3
Ph
7
Ph
7
N
Me
Pd(OAc)2 (10 mol%), PCy3HBF4 (20 mol%)
N
N
N
Me
X
R3
N
N
+
3
Cs2CO3 (2.0 equiv), 1,4-dioxane
MW, 160 °C, 4 h
3
R2
R1
R2
R1
R1 = Ar R2 = Ar, 4-py
R3 = Ar, 4-py
X = Br, Cl
1–5
products 1a–5b
Scheme 3 Synthesis of products 1a–5b
(Table 1, entry 4). Furthermore, a rapid survey of different hexylphosphine tetrafluoroborate (20 mol%), 4-bromo- or
ligands showed that tricyclohexylphosphine tetrafluorob- 4-chlorotoluene (2.0 equiv) and cesium carbonate (2.0
orate was the best candidate because a 69% conversion equiv) in 1,4-dioxane at 160 °C under microwave irradia-
was achieved (Table 1, entry 6). Switching the solvent tion during four hours.
system to toluene or a more polar solvent such as dimeth-
ylacetamide was not beneficial (Table 1, entries 7 and 8).
To probe the scope of the reaction, the use of different im-
idazo[1,2-b]pyrazole synthons and various aryl or hetero-
Increasing the amount of aryl bromide to four equivalents
aryl bromides was examined (Scheme 3). The expected
did not improve the reaction outcome (Table 1, entry 9).
products were cleanly obtained in good to excellent yields
using para electron-withdrawing groups such as CF3 or
Moreover, the increment in the catalyst loading induced
no noticeable change (Table 1, entry 10). However, in-
CN or soft electron-donating groups such as methyl onto
creasing the time of the reaction gradually improved the
aryl bromide (Table 2, entries 1, 2, 4, 5, 8, 9 and 13–16).
conversion (Table 1, entries 11 and 12). We were pleased
For unknown reasons, the presence of a methoxy group
to observe that the starting material was completely con-
affected the efficiency of the reaction because a partial
sumed after four hours heating and the expected product
conversion was noted (Table 2, entry 3). The increase in
was isolated in an excellent yield of 95% (Table 1, entry
the time of the reaction or the amount of coupling partner
13). Decreasing the catalyst loading to 5 mol% of
did not produce any improvement. The same behavior
Pd(OAc)2 and 10 mol% of PCy3 did not maintain the cou-
was observed with 4-bromopyridine. Compounds with a
pling efficiency (Table 1, entry 14). The reaction was also
pyridinyl group in C-7 (1d, 2c, 3c) were obtained in 41–
71% yield (Table 2, entries 4, 7 and 10). The starting ma-
performed using the corresponding 4-chlorotoluene as
coupling partner. A slightly lower yield was achieved (Ta-
terial was easily separated from the product and recycled.
ble 1, entry 15). The extension of our methodology to aryl
Fortunately, the efficiency of our methodology was main-
tained using ortho- or meta-substituted aryl bromides (Ta-
ble 2, entries 11 and 12). The compounds 3d and 3e were
chlorides is a powerful result as these substrates are gen-
erally less expensive and more readily available than their
bromo or iodo analogues.11 This suggests the possibility
isolated in good yields of 78% and 71%, respectively.
of introducing a larger range of functional groups. How-
Comparable yields were reached using various
ever, using the 4-iodotoluene only led to a low conversion
(hetero)aryl chlorides (Table 2, entries 1–4). This result
of 10% (Table 1, entry 16). To sum up, the best conditions
highlights the great versatility of our strategy.
were found to be palladium acetate (10 mol%), tricyclo-
Table 2 Scope of the Pd-Catalyzed C-7 Direct Arylation of 1–5
Yield (%)a
95 (89)b
R1
R2
R3
Entry
1
Starting material
Product
1
1a
OMe
2
1b
90 (87)b
CF3
3
4
1c
64c (68)b,d
41e (39)b,f
OMe
1d
N
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2095–2101

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S. Grosse et al.
LETTER
Table 2 Scope of the Pd-Catalyzed C-7 Direct Arylation of 1–5 (continued)
Yield (%)a
86
R1
R2
R3
Entry
5
Starting material
Product
2
2a
OMe
OMe
6
7
8
9
2b
2c
3a
3b
86
70g
91
82
CF3
N
3
CF3
OMe
CN
10
11
3c
66h
78
N
3d
12
3e
71
13
14
15
16
4
5
4a
4b
5a
5b
71
74
72
74
CF3
OMe
CN
N
OMe
CF3
a Isolated yields after column chromatography.
b The reaction was performed using the 4-chloro analogue as coupling partner.
c Amount of starting material recovered was 28%.
d Amount of starting material recovered was 25%.
e Amount of starting material recovered was 49%.
f Amount of starting material recovered was 45%.
g Amount of starting material recovered was 23%.
h Amount of starting material recovered was 25%.
Remarkably, the optimized palladium-catalyzed process electron-rich (MeO, Me) or electron-poor (CF3) substitu-
was successfully applied to a large variety of imidazo[1,2- ents or heterocycles such as pyridine in C-2 or C-3 posi-
b]pyrazoles bearing different groups in C-2 and C-3 posi- tion are well tolerated.
tions. Indeed, we were pleased to notice that aryl-bearing
Synlett 2013, 24, 2095–2101
© Georg Thieme Verlag Stuttgart · New York

LETTER
Efficient Direct Arylation of Tri- or Disubstituted Imidazo[1,2-b]pyrazoles
2099
As the last part of this work, we also extended the meth- presence of pivalate or potassium acetate13 and the low
odology to a double and one-pot C-3 and C-7 direct aryla- conversion observed when the aryl iodide14 is used may
tion of the disubstituted imidazo[1,2-b]pyrazole 6 not discard the carbonate-assisted metalation–deproton-
prepared according to the strategy previously described ation mechanism (CMD). Further studies (DFT calcula-
by our group.6 The amounts of aryl bromide and base were tions, kinetic isotopic effect, etc.) are necessary to draw
increased to three and four equivalents, respectively (see more precise conclusions.
Scheme 4). Gratifyingly, the strategy proved to be highly
In conclusion, we have disclosed herein the first strategy
effective because 3,7-bis(4-trifluoromethyl)phenyl and
for C-7 direct arylation of C-3-substituted imidazo[1,2-
3,7-bis(4-tolyl)imidazo[1,2-b]pyrazole derivatives were
b]pyrazoles.15 The method enables the synthesis of a large
obtained in 78% and 89% yields, respectively. The C–C
variety of tetra(hetero)arylated imidazopyrazole deriva-
coupling was also accomplished with aryl bromides bear-
tives. Moderate to excellent yields were achieved from
ing meta and ortho substituents. Interestingly, the meta-
readily available electron-poor or electron-rich aryl or
benzonitrile group was successfully introduced. Unfortu-
heteroaryl bromides or chlorides.
nately, in the case of the ortho-substituted cyano com-
pound, only the mono C-3 arylated product was isolated.
Acknowledgment
Ar
Ph
This work was supported by the Greenpharma Company and the
Conseil Général du Loiret.
7
Ph
7
ArBr (3.0 equiv)
Pd(OAc)2 (10 mol%)
PCy3HBF4 (20 mol%)
N
N
Me
Me
N
N
N
N
3
Cs2CO3 (4 equiv)
1,4-dioxane
160 °C, MW, 4 h
Supporting Information for this article is available online at
3
Ar
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
6
OMe
OMe
References and Notes
(1) (a) Baviskar, A. T.; Madaan, C.; Preet, R.; Mohapatra, P.;
Jain, V.; Agarwal, A.; Guchhait, S. K.; Kundu, C. N.;
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Patent US20100316649(A1), 2010; Chem. Abstr. 2010, 154,
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Cancer Drugs 2000, 15, 79. (d) Kinnamon, K. E.; Engle, R.
R.; Poon, B. T.; Ellis, W. Y.; MacCall, J. W.; Pzimianski, M.
T. Proc. Soc. Exp. Biol. Med. 2000, 224, 45.
CF3
N
N
Me
Me
N
N
N
N
(2) (a) Abdelhamid, A. O.; Abdelall, E. K. A.; Zakic, Y. H.
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OMe
CN
OMe
F3C
1a (89%)
6a (78%)
Ph
Ph
CN
Me
N
N
Me
(4) (a) Bhatia, G.; Graczyk, P.; Khan, A.; Medland, D. P.;
Numata, H.; Oinuma, H.; Palmer, V. Int. Patent
N
N
N
N
NC
WO02081475A1, 2002; Chem. Abstr. 2002, 137, 310918
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OMe
(5) (a) Rahmati, A.; Eskandari-Vashareh, M.; Alizadeh-
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A.; Alizadeh-Kouzehrash, M. Synthesis 2011, 2913.
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CN
6b (79%)
6c (0%)a
a
Scheme 4 One-pot C-3 and C-7 direct arylation. Only the C-3
mono-arylated compound was obtained (64%).
Several mechanistic scenarios have been proposed to ex-
plain palladium-catalyzed direct arylation outcomes in-
cluding SEAr, Heck-like addition, CMD (concerted
metalation–deprotonation) and nCMD (non-concerted
metalation–deprotonation) mechanism.12
The set of experiment achieved here is insufficient to ex-
plain the mechanism involved in this direct C–H aryla-
tion. In fact, the non-improvement of the reactivity in
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2095–2101

2100
S. Grosse et al.
LETTER
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mechanism may not be excluded. See ref. 11d.
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(15) General Procedure A; C-7 Direct Arylation of the
Imidazo[1,2-b]pyrazoles 1–5: A microwave vial containing
a stirring bar was loaded with imidazo[1,2-b]pyrazole 1–5 in
1,4-dioxane, (hetero)aryl bromide or chloride (2.0 equiv),
tricyclohexylphosphine tetrafluoroborate (0.20 equiv) and
cesium carbonate (2.0 equiv). The tube was evacuated and
backfilled with dry argon twice. Palladium acetate (0.10
equiv) was added and the mixture was submitted to
microwave irradiation with stirring at 160 °C for 4 h. It was
then cooled to r.t., and 1,4-dioxane was removed under
reduced pressure. The residue was purified by flash
chromatography to provide the desired products 1a–5b.
2-(4-Methoxyphenyl)-1-methyl-6-phenyl-3-(4-tolyl)-7-
[4-(trifluoromethyl)phenyl]-1H-imidazo[1,2-b]pyrazole
(1b): The reaction was carried out as described in general
procedure A using imidazo[1,2-b]pyrazole 1 (100 mg, 0.254
mmol), palladium acetate (5.7 mg, 0.0254 mmol),
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Chem. 2012, 77, 4473. (c) Beladhriaa, A.; Beydounb, K.;
Ammar, H. B.; Salemc, R. B.; Doucet, H. Synthesis 2011,
2553. (d) Basolo, L.; Beccalli, E. M.; Borsini, E.; Broggini,
G. Tetrahedron 2009, 65, 3486. (e) Basolo, L.; Beccalli, E.
M.; Borsini, E.; Broggini, G.; Pellegrino, S. Tetrahedron
2008, 64, 8182. (f) Li, W.; Nelson, D. P.; Jensen, M. S.;
Hoerrner, R. S.; Javadi, G. J.; Cai, D.; Larsen, R. D. Org.
Lett. 2003, 5, 4835.
(10) (a) Liégault, B.; Lapointe, D.; Caron, L.; Vlassova, A.;
Fagnou, K. J. Org. Chem. 2009, 74, 1826. (b) Lafrance, M.;
Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.
(11) (a) See Ref 8e. (b) Daugulis, O. Chem. Heterocycl. Compd.
2012, 48, 21. (c) Ackermann, L.; Vicente, R.; Borna, R. Adv.
Synth. Catal. 2008, 350, 741. (d) Campeau, L. C.; Parisien,
M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581.
(12) For reviews providing mechanistic discussions on
palladium(0)-catalyzed direct C–H coupling, see:
tricyclohexylphosphine tetrafluoroborate (18.7 mg, 0.0508
mmol), cesium carbonate (142 mg, 0.508 mmol) and
4-bromobenzotrifluoride (114 mg, 72 μL, 0.508 mmol) in
1,4-dioxane (2 mL). Standard workup followed by flash
chromatography (CH2Cl2–petroleum ether, 1:1) yielded 1b
as a pale yellow solid (123 mg, 90%); mp 226–228 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.71 (d, J = 8.1 Hz, 2 H, HAr),
7.58 (d, J = 8.4 Hz, 2 H, HAr), 7.53 (d, J = 7.9 Hz, 2 H, HAr),
7.47 (d, J = 8.1 Hz, 2 H, HAr), 7.33 (d, J = 8.5 Hz, 2 H, HAr),
7.25–7.29 (m, 3 H, HAr), 7.12 (d, J = 8.1 Hz, 2 H, HAr), 7.00
(d, J = 8.5 Hz, 2 H, HAr), 3.88 (s, 3 H, OMe), 3.30 (s, 3 H,
NMe), 2.32 (s, 3 H, Me). 13C NMR (101 MHz, CDCl3): δ =
160.31 (Cq), 152.26 (Cq), 140.07 (Cq), 137.17 (Cq), 136.82
(Cq), 134.27 (Cq), 132.46 (CHAr), 130.97 (CHAr), 129.19
(Cq), 129.03 (CHAr), 128.87 (CHAr), 128.18 (CHAr), 127.87
(2JC–F = 33.0 Hz, Cq), 127.42 (CHAr), 127.14 (CHAr), 125.63
(Cq), 125.14 (3JC–F = 3.72 Hz, CHAr), 124.41 (1JC–F = 273 Hz,
Cq), 121.13 (Cq), 118.42 (Cq), 114.64 (CHAr), 94.33 (Cq),
55.34 (OMe), 31.73 (NMe), 21.29 (Me). IR (neat): 1603,
1322, 1118, 1066, 838, 697 cm–1. HRMS (ESI): m/z [M +
H]+ calcd for C33H27F3N3O: 538.21007; found: 538.21007.
HRMS (ESI): m/z [M + Na]+ calcd for C33H27F3N3O:
560.19202; found: 560.19113.
General Procedure B; One-Pot C-3 and C-7 Direct
Arylation of Imidazo[1,2-b]pyrazole 6: A microwave vial
containing a stirring bar was loaded with imidazo[1,2-
b]pyrazole 6 in 1,4-dioxane, (hetero)aryl bromide (3.0
equiv), tricyclohexylphosphine tetrafluoroborate (0.20
equiv) and cesium carbonate (4.0 equiv). The tube was
evacuated and back-filled with dry argon twice. Palladium
acetate (0.10 equiv) was added and the mixture was
submitted to microwave irradiation with stirring at 160 °C
for 4 h. It was then cooled to r.t., and 1,4-dioxane was
removed under reduced pressure. The residue was purified
by flash chromatography to provide the desired products 1a,
6a and 6b.
(a) Théveau, L.; Querolle, O.; Dupas, G.; Hoarau, C.
Tetrahedron 2013, 69, 4375. (b) Verrier, C.; Lassalas, P.;
Théveau, L.; Quéguiner, G.; Trécourt, F.; Marsais, F.;
Hoarau, C. Beilstein J. Org. Chem. 2011, 7, 1584.
(c) Bellina, F.; Rossi, R. Adv. Synth. Catal. 2010, 352, 1223.
(d) Balcells, D.; Clot, E.; Eisenstein, O. Chem. Rev. 2010,
110, 749. (e) Fagnou, K. Top. Curr. Chem. 2010, 292, 35.
(f) Bellina, F.; Cautericcio, S.; Rossi, R. Curr. Org. Chem.
2008, 12, 774. (g) Seregin, I. V.; Gevorgyan, V. Chem. Soc.
Rev. 2007, 36, 1173.
2-(4-Methoxyphenyl)-1-methyl-6-phenyl-3,7-bis[4-
(trifluoromethyl)phenyl]-1H-imidazo[1,2-b]pyrazole
(6a): The reaction was carried out as described in general
procedure B using imidazo[1,2-b]pyrazole 6 (100 mg, 0.329
mmol), palladium acetate (8.04 mg, 0.0329 mmol),
tricyclohexylphosphine tetrafluoroborate (24.0 mg, 0.0658
mmol), caesium carbonate (369 mg, 1.32 mmol) and 4-
bromobenzotrifluoride (222 mg, 138 μL, 0.987 mmol) in
(13) Pivalic acid and potassium acetate should enhance the
reactivity in the case of a CMD mechanism but in our case
no improvement in the conversion was observed (Table 1,
Synlett 2013, 24, 2095–2101
© Georg Thieme Verlag Stuttgart · New York

LETTER
Efficient Direct Arylation of Tri- or Disubstituted Imidazo[1,2-b]pyrazoles
2101
1,4-dioxane (2 mL). Standard workup followed by flash
(2JC–F = 32.6 Hz, Cq), 128.27 (CHAr), 128.20 (2JC–F = 32.8
Hz, Cq), 127.64 (CHAr), 126.73 (CHAr), 125.25 (3JC–F = 3.70
chromatography (CH2Cl2–petroleum ether, 3:7) yielded 6a
as a white solid (151 mg, 78%); mp 220–222 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.01 (d, J = 8.4 Hz, 2 H, HAr), 7.47–
7.64 (m, 8 H, HAr), 7.29–7.41 (m, 5 H, HAr), 7.07 (d, J = 8.4
Hz, 2 × CHAr), 124.36 (1JC–F = 273 Hz, Cq), 124.18 (1JC–F
=
273 Hz, Cq), 120.39 (Cq), 117.03 (Cq), 114.99 (CHAr), 94.65
(Cq), 55.39 (OMe), 31.74 (NMe). IR (neat): 1613, 1320,
1249, 1162, 1103, 1076, 1064, 1016, 834 cm–1. HRMS
(ESI): m/z [M + H] calcd for C33H24F6N3O: 592.18181;
found: 592.18163.
Hz, 2 H, HAr), 3.92 (s, 3 H, OMe), 3.33 (s, 3 H, NCH3). 13
C
NMR (101 MHz, CDCl3): δ = 160.76 (Cq), 152.49 (Cq),
140.08 (Cq), 136.81 (Cq), 133.96 (Cq), 132.34 (CHAr), 132.28
(Cq), 131.09 (Cq), 131.05 (CHAr), 128.78 (CHAr), 128.37
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2095–2101

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