Direct C-3-arylations of 1H-indazoles

Article abstract of DOI:10.1002/ejoc.201200860

The first example of intermolecular C-H arylation of substituted 1H-indazoles is reported. Various 1-substituted indazoles were used as starting materials, and (hetero)aryl bromides and iodides were investigated as coupling partners. Different reaction co

Full text of DOI:10.1002/ejoc.201200860

FULL PAPER
DOI: 10.1002/ejoc.201200860
Direct C-3-Arylations of 1H-Indazoles
Ali Ben-Yahia,[a,b,c] Mohammed Naas,[b,c] Saïd El Kazzouli,*[a] El Mokhtar Essassi,[a,b] and
Gérald Guillaumet*[c]
Keywords: Synthetic methods / Nitrogen heterocycles / Homogeneous catalysis / C–C coupling / Cross-coupling /
Palladium / N ligands / Ligand effects
The first example of intermolecular C–H arylation of substi-
tuted 1H-indazoles is reported. Various 1-substituted indaz-
oles were used as starting materials, and (hetero)aryl brom-
ides and iodides were investigated as coupling partners. Dif-
ferent reaction conditions were investigated. The best results
were obtained using Pd(OAc)2 as catalyst, 1,10-phen-
anthroline as ligand, K2CO3 as base, and DMA as solvent.
The crucial role of the ligand on the C–H arylation of substi-
tuted 1H-indazoles is highlighted.
gram on indazole systems[7] and on C–H activation,[8] we
decided to develop a new method for the direct and selec-
tive C-3 arylation of substituted 1H-indazoles using
Pd(OAc)2 as catalyst, 1,10-phenanthroline as ligand, and
K2CO3 as base, and we report the results of this investiga-
tion in this paper. During the preparation of this manu-
script, a similar method for the C-3-selective arylation of
pyridine was reported.[9]
Introduction
3-Substituted indazoles obtained from different cross-
coupling reactions are common components of drugs, and
have been found to be of pharmaceutical interest in a vari-
ety of therapeutic areas.[1] Although several procedures have
been developed for the functionalization of the 3-position
of indazole ring systems, including palladium-catalyzed
cross-coupling methods such as Suzuki, Heck, Sonogashira,
Stille, and Negishi,[2] no examples of C-arylation in the 1H
series have been described. Only two examples of inter-[3]
and intramolecular[4] C-arylation at the 3-position in the
2H-indazole series have recently been reported.
Results and Discussion
We began our study by the investigation of standard re-
action conditions using 1-methylindazole 1[7,10] as starting
material and 4-iodotoluene (1.2 equiv.) as coupling partner.
Thus, we tested Pd(OAc)2 (10 mol-%) as catalyst in the
presence of K2CO3 (1.5 equiv.) as base in refluxing DMA
(conditions A), but no C-3 arylation was observed (Table 1,
entry 1). Only a small amount of the biaryl product (formed
in a homocoupling reaction) was detected. When testing
other (hetero)aryl bromides (2-bromotoluene, 3-bromotolu-
ene, and 3-bromopyridine) again, no C-3 arylation was ob-
served [Scheme 1, Equation (1) and Equation (2)]. Only
when using 2-bromopyridine as coupling partner did we
isolate the product of C-3 arylation in a very low yield. In
this case, a by-product, the 2,2Ј-bipyridine resulting from a
homocoupling reaction, was also isolated [Scheme 1, Equa-
tion (3)]. Guided by this observation, we suggested that the
C-3 arylation reaction was catalyzed by the 2,2Ј-bipyridine
in the role of the ligand. Thus, we directed our efforts
towards exploiting this newly observed reactivity to develop
a C-3-selective arylation of substituted 1H-indazoles.
To prove this hypothesis, we decided to investigate vari-
ous ligands such as PPh3 (L1), 2,2Ј-bipyridine (L2) and
1,10-phenanthroline (L3) for the C-3 arylation of indazole
1 (Figure 1).
The direct arylation of heteroarenes, achieved by cross-
coupling of (sp2) C–H bonds and haloarenes has been
widely investigated[5,6] by different research groups, includ-
ing our own.[7] Recently, Greaney et al. have described the
C–H arylation of substituted 2H-indazoles on water.[3] Al-
though the C-3 arylation of substituted 2H-indazoles
worked very well, no reaction was observed in the substi-
tuted 1H series, due to the low reactivity of the 3-position
towards substitution. In a continuation of our research pro-
[a] Institute of Nanomaterials and Nanotechnology (INANO-
TECH), MAScIR Foundation,
Avenue de l’Armée Royale, Madinat El Irfane 10 100 Rabat,
Morocco
Fax: +212-05-30300671
E-mail: s.elkazzouli@mascir.com
gerald.guillaumet@univ-orleans.fr
Homepage: www.mascir.ma
[b] Laboratoire de Chimie Organique Hétérocyclique URAC 21,
Pôle de Compétences Pharmacochimie, Université Mohammed
V-Agdal
BP 1014, Avenue Ibn Batouta, Rabat, Morocco
[c] Institut de Chimie Organique et Analytique, Université
d’Orléans, UMR CNRS 7311,
BP 6759, 45067 Orléans Cedex 2, France
Homepage: www.univ-orleans.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200860.
Eur. J. Org. Chem. 2012, 7075–7081
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7075

S. El Kazzouli, G. Guillaumet et al.
FULL PAPER
Table 1. Optimization of the C-3 arylation reaction on 1-methyl- the desired product (i.e., 3) was isolated in a very low yield
indazole 1.
(8%, Table 1, entry 2). When using 20 mol-% Pd(OAc)2 and
40 mol-% L1, the yield of the isolated product was slightly
improved but was still very low (17%, Table 1, entry 3).
Using 10 mol-% L2 and 20 mol-% Pd(OAc)2 led to the for-
mation of the C-3-arylated product in a moderate yield
(51%, Table 1, entry 4). By increasing the amount of both
ligand and catalyst to 20 mol-% and 40 mol-%, respectively,
no notable improvement of the reaction yield was observed.
In this case, compound 3 was isolated in 58% yield (Table 1,
entry 5). The use of L3 (10 mol-%) and Pd(OAc)2 (5 mol-
%) under reaction conditions A, resulted in the formation
of C-3-arylated product in low yield (23%, Table 1, entry 6).
When increasing the amount of Pd(OAc)2 and L3 to 10 and
20 mol-%, respectively, the yield of desired product 3 was
improved (53%, Table 1, entry 7).
Then, we tested other inorganic bases. Using Cs2CO3 in-
stead of K2CO3 did not enhance the reaction yield; in this
case, the desired product was isolated in 45% yield (Table 1,
entry 8). Ag2CO3 was also tested, and gave a similar yield
to that obtained using K2CO3 (Table 1, entry 9). We then
decided to test various solvents. Neither 1,4-dioxane alone,
nor a mixture of 1,4-dioxane/ethanol, gave any C-3-arylated
product (Table 1, entries 10 and 11). In contrast, xylene af-
forded the desired product but in a very low yield (10%,
Table 1, entry 12).
Entry
Ligand
[mol-%]
Pd
[mol-%]
Base
Solvent
%
Yield
1
2
3
4
5
6
7
8
none
10
10
20
10
20
5
10
10
10
10
10
10
20
K2CO3 DMA
K2CO3 DMA
K2CO3 DMA
K2CO3 DMA
K2CO3 DMA
K2CO3 DMA
K2CO3 DMA
Cs2CO3 DMA
Ag2CO3 DMA
K2CO3 1,4-dioxane
K2CO3 dioxane/EtOH[a]
K2CO3 xylene
K2CO3 DMA
0
8
L1 (20)
L1 (40)
L2 (20)
L2 (40)
L3 (10)
L3 (20)
L3 (20)
L3 (20)
L3 (20)
L3 (20)
L3 (20)
L3 (40)
17
51
58
23
53
45
50
0
9
10
11
12
13
0
10
68
[a] Diox./EtOH = 1,4-dioxane/EtOH (3:1, v/v).
Finally when the amounts of both ligand and catalyst
were increased to 40 and 20 mol-%, respectively, total con-
version of the starting material was observed, and the de-
sired product was isolated in 68% yield (Table 1, entry 13).
We next decided to compare, on the one hand, the effect
of ligands L2 and L3, and on the other hand, the effect of
using different (hetero)aryl bromides and iodides as cou-
pling partners. We continued our optimization using 1-
methylindazole 1 as starting material, but now 4-bromotol-
uene, 4-iodotoluene, 4-bromopyridine, and 4-iodopyridine
were used as coupling partners. In all cases, the (hetero)aryl
iodides gave better yields than the corresponding bromides.
In addition, L3 as ligand gave notably better yields than L2
(Table 2).
Then, we decided to study the scope and limitations of
our method. For this reason, in addition to starting mate-
rial 1, other N-1-arylated indazoles were prepared and used
(Figure 2, compounds 4, 5, and 6). All the reactions were
carried out using the optimized reaction conditions[11]
[Pd(OAc)2 (20 mol-%), L3 (40 mol-%), K2CO3 (1.5 equiv.)
in refluxing DMA].
Scheme 1. C-3 arylation on 1-methylindazole 1 under classical reac-
tion conditions using various (hetero)aryl bromides.
Using starting material 1 and iodobenzene as coupling
partner, the expected product (i.e., 7) was isolated in 60%
yield (Table 3, entry 1). When using 2-iodotoluene and 3-
idodotoluene, the C-3-arylated products (i.e., 8 and 9) were
isolated in 63 and 65% yields, respectively. These yields are
slightly lower than those obtained using 4-iodotoluene
(Table 1, entry 13). Then, various aryl iodides bearing elec-
tron-withdrawing groups were used, and the desired prod-
Figure 1. Ligands used during the optimization of the C-3 arylation
reaction.
The cross-coupling reaction between 1 and 4-iodotoluene ucts (i.e., 10 and 11) were formed in 70 and 68% yields,
was used again for the following optimization study. When respectively (Table 3, entries 4 and 5). In addition, aryl iod-
adding L1 (20 mol-%) to reaction conditions A (see above), ides bearing electron-donating groups were coupled
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Eur. J. Org. Chem. 2012, 7075–7081

Direct C-3-Arylations of 1H-Indazoles
Table 2. Effect of aryl iodides and aryl bromides using either L2 or elimination, the desired product 3 is obtained, and complex
L3 as ligand.
D is formed. Finally, complex D is transformed into com-
plex A.
Scheme 2. Plausible mechanism for C-3 arylation.
Conclusions
In conclusion, we have shown for the first time that Pd-
catalyzed direct C-3 arylation of substituted 1H-indazoles
is feasible using 1,10-phenanthroline as a ligand. The func-
tional group tolerance for groups such as ester, cyano, and
chloro functionalities was good. These groups could be
used for future transformations. C-3 arylation was also ef-
fective using heteroaryl halides as coupling partners.
Figure 2. Starting materials 4, 5, and 6 used for C-3 arylation reac-
tions.
Experimental Section
smoothly to give the expected products (i.e., 12 and 13) in
57 and 59% yields, respectively (Table 3, entries 6 and 7). 4-
Iodopyridine was also used, which led to compound 14 in
61% yield (Table 3, entry 8).
We then investigated other 1-aryl-1H-indazoles (com-
pounds 4, 5 and 6, Figure 2) as starting materials. These
compounds were prepared using CuI as catalyst, L2 as li-
gand and K2CO3 as base. The N-arylation reactions were
carried out in NMP at 200 °C under microwave irradiation
for 35 min.[12,13] Then, products 4–6 and various aryl iod-
ides were subjected to the optimized reaction conditions,
which led to desired products 15–21 in yields between 58
and 66% (Table 3, entries 9–15).
Sensitive groups such as chloro, cyano, and ethyl ester
were stable under the cross-coupling reaction conditions.
These groups could be used for future transformations
(Table 3, entries 4, 6, 7, 11, 14, and 15).
Based on the recently reported studies on the C-3 aryl-
ation reaction, we propose a plausible mechanism for the
C-3 arylation on indazole (Scheme 2). Pd(OAc)2 and ligand
form a PdII intermediate (complex A, Scheme 2) followed
by a PdII-indazole complex (complex B, Scheme 2). Then
an oxidative addition of aryl halide (X = I or Br) leads to
1-Methyl-1H-indazole (1): White solid; m.p. 57–59 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.00 (s, 1 H), 7.74 (d, J = 8 Hz, 1 H), 7.40
(d, J = 8 Hz, 2 H), 7.32–7.02 (m, 1 H), 4.09 (s, 3 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 139.85, 132.68, 126.17, 123.99,
121.04, 120.40, 108.87, 35.48 ppm. HRMS: calcd. for C8H9N2 [M
+ H]+ 133.0766; found 133.0764.
1-Methyl-3-(pyridin-2-yl)-1H-indazole (2): Yellow oil. IR (neat): ν =
˜
3050.84, 1592.77, 1296.91, 1104.19, 739.34, 662.09 cm–1. H NMR
1
(400 MHz, CDCl3): δ = 8.77 (d, J = 4.8 Hz, 1 H), 8.65 (d, J =
8.2 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 7.78 (td, J = 7.8, 1.8 Hz, 1
H), 7.49–7.39 (m, 2 H), 7.33–7.22 (m, 2 H), 4.16 (s, 3 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 153.57, 149.47, 142.71, 141.55,
136.31, 126.47, 123.58, 122.31, 122.07, 121.61, 120.77, 108.89,
35.77 ppm. HRMS (ESI): calcd. for C13H12N3 [M + H]+ 210.1031;
found 210.1031.
1-Methyl-3-(pyridin-2-yl)-1H-indazole (3): Yellow solid; m.p. 52–
54 °C. IR (neat): ν = 2921.85, 1492.50, 1334.14, 1254.05, 790.26,
˜
1
740.01, 698.41 cm–1. H NMR (400 MHz, [D4]methanol): δ = 7.97
(d, J = 7.8 Hz, 1 H), 7.80 (d, J = 8.1 Hz, 2 H), 7.54 (d, J = 9.0 Hz,
1 H), 7.45 (t, J = 7.8 Hz 1 H), 7.32 (d, J = 8.3 Hz, 2 H), 7.21 (t, J
= 7.8 Hz, 1 H), 4.10 (s, 3 H), 2.41 (s, 3 H) ppm. 13C NMR
(101 MHz, [D4]methanol): δ = 143.59, 141.41, 137.64, 130.36,
129.07 (2 C), 126.94 (2 C), 126.39, 121.06, 120.81 (2 C), 109.12,
34.05, 19.92 ppm. HRMS: calcd. for C15H15N2 [M + H]+ 223.1235;
a PdIV complex (complex C, Scheme 2). After a reductive found 223.1235.
Eur. J. Org. Chem. 2012, 7075–7081
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7077

S. El Kazzouli, G. Guillaumet et al.
FULL PAPER
Table 3. Scope and limitation study of C-3 arylation.
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Eur. J. Org. Chem. 2012, 7075–7081

Direct C-3-Arylations of 1H-Indazoles
1-Phenyl-1H-indazole (4):[14,16] White solid; m.p. 78–79 °C. IR
1-Methyl-3-[4-(trifluoromethyl)phenyl]-1H-indazole (11): White so-
(neat): ν = 2914.73, 1498.11, 1341.17, 1257.04, 779.88, 747.79, lid; m.p. 70–73 °C. IR (neat): ν = 2930.11 1496.10, 1343.81,
˜
˜
1
702.12 cm–1. H NMR (400 MHz, [D6]DMSO): δ = 8.37 (s, 1 H),
1171.10, 1112.97, 841.66, 772.22, 668.07 cm–1. 1H NMR (400 MHz,
7.88 (d, J = 8 Hz, 1 H), 7.83 (d, J = 8 Hz, 1 H), 7.76 (d, J = 7.8 Hz, [D6]DMSO): δ = 8.21 (d, J = 8.2 Hz, 2 H), 8.12 (d, J = 8.3 Hz, 1
2 H), 7.58 (t, J = 7.8 Hz, 2 H), 7.48 (t, J = 7.8 Hz, 1 H), 7.39 (t, J H), 7.85 (d, J = 8.2 Hz, 2 H), 7.73 (d, J = 8.3 Hz, 1 H), 7.49 (t, J
= 8 Hz, 1 H), 7.26 (t, J = 8 Hz, 1 H) ppm. 13C NMR (101 MHz, = 8.3 Hz, 1 H), 7.28 (t, J = 8.3 Hz, 1 H), 4.14 (s, 3 H) ppm. 13C
[D6]DMSO): δ = 140.13, 138.53, 136.13, 130.10, 127.93, 126.99,
125.50, 122.58, 122.11, 121.92, 110.87 ppm. HRMS: calcd. for
C13H11N2 [M + H]+ 195.0922; found 195.0920.
NMR (100 MHz, [D6]DMSO): δ = 141.74, 140.76, 137.74, 128.17
2
3
(q, JCq,F = 32.3 Hz), 127.51, 126.87, 126.25 (q, JCH,F = 4 Hz),
1
124.80 (q, JCq,F = 272 Hz), 122.23, 121.08, 121.05, 110.90,
36.14 ppm. HRMS: calcd. for C15H12F3N2 [M + H]+ 277.0950;
found 277.0948.
1-(p-Tolyl)-1H-indazole (5): White solid; m.p. 61–63 °C. IR (neat):
ν
=
2921.97, 1493.05, 1332.98, 1255.11, 788.90, 742.10,
˜
1
699.22 cm–1. H NMR (400 MHz, [D6]DMSO): δ = 8.34 (s, 1 H),
4-(1-Methyl-1H-indazol-3-yl)benzonitrile (12): Yellow solid; m.p.
7.88 (d, J = 8.4 Hz, 1 H), 7.78 (d, J = 8.4 Hz, 1 H), 7.63 (d, J = 153–155 °C. IR (neat): ν = 2224.79, 1257.56, 856.68, 752.93,
˜
8.3 Hz, 2 H), 7.47 (t, J = 8.4 Hz, 1 H), 7.39 (d, J = 8.3 Hz, 2 H),
7.25 (t, J = 8.4 Hz, 1 H), 2.39 (s, 3 H) ppm. 13C NMR (101 MHz,
[D6]DMSO): δ = 138.6, 137.7, 136.4, 135.7, 130.5, 127.8, 125.3,
122.6, 121.9, 121.8, 110.8, 21 ppm. HRMS: calcd. for C14H13N2 [M
+ H]+ 209.1079; found 209.1076.
668.70 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 8.3 Hz,
2 H), 8.00 (d, J = 8.3 Hz, 1 H), 7.77 (d, J = 8.3 Hz, 2 H), 7.47 (d,
J = 3.9 Hz, 2 H), 7.28 (dd, J = 8.2, 4.0 Hz, 1 H), 4.15 (s, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 141.59, 141.44, 138.60 (2 C),
127.45 (2 C), 126.63, 121.84, 121.51, 120.78, 119.06, 118.32, 110.92,
109.63, 35.82 ppm. HRMS (ESI): calcd. for C15H12N3 [M + H]+
234.1031; found 234.1026.
1-(4-Chlorophenyl)-1H-indazole (6): White solid; m.p. 71–72 °C. IR
(neat): ν = 2932.12, 1489.96, 1340.13, 1250.54, 790.44, 740.09,
˜
1
700.05 cm–1. H NMR (400 MHz, [D6]DMSO): δ = 8.40 (s, 1 H),
Ethyl 4-(1-Methyl-1H-indazol-3-yl)benzoate (13): White solid; m.p.
7.90 (d, J = 7.5 Hz, 1 H), 7.85 (d, J = 8.6 Hz, 1 H), 7.81 (d, J = 71–73 °C. IR (neat): ν = 2981.84, 1706.60, 1267.77, 1100.03,
˜
8.6 Hz, 2 H), 7.63 (d, J = 8.6 Hz, 2 H), 7.50 (t, J = 7.7 Hz, 1 H),
7.31–7.25 (m, 1 H) ppm. 13C NMR (101 MHz, [D6]DMSO): δ =
136.6, 130, 128.2, 124, 122.3, 122, 110.9 ppm. HRMS: calcd. for
C13H10ClN2 [M + H]+ 229.0533; found 229.0529.
752.64, 701.35, 666.96 cm–1. 1H NMR (250 MHz, CDCl3): δ = 8.17
(d, J = 8.7 Hz, 2 H), 8.06–8.02 (m, 2 H), 7.45 (d, J = 3.4 Hz, 2 H),
7.31–7.21 (m, 2 H), 4.42 (q, J = 7.2 Hz, 2 H), 4.15 (s, 3 H), 1.43
(t, J = 7.2 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 166.54,
142.49, 141.53, 138.10, 130.12, 130.08 (2 C), 129.45, 126.93 (2 C),
126.45, 121.46, 121.14, 109.42, 60.99, 35.71, 14.39 ppm. HRMS
(ESI): calcd. for C17H17N2O2 [M + H]+ 281.1290; found 281.1287.
1-Methyl-3-phenyl-1H-indazole (7): Yellow solid; m.p. 71–73 °C. IR
(neat): ν = 2932.10, 1489.90, 1337.12, 1261.02, 779.98, 734.76,
˜
696.91 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 8.06 (d, J =
9.0 Hz, 1 H), 7.97 (d, J = 8.2 Hz, 2 H), 7.68 (d, J = 8.5 Hz, 1 H), 1-Methyl-3-(pyridin-4-yl)-1H-indazole (14): Yellow solid; m.p. 88–
7.51 (t, J = 7.7 Hz, 2 H), 7.45 (d, J = 8.0 Hz, 1 H), 7.39 (t, J = 90 °C. IR (neat): ν = 1517.57, 1088.36, 826.53, 737.21, 665.92 cm–1.
˜
7.9 Hz, 1 H), 7.27–7.19 (m, 1 H), 4.10 (s, 3 H) ppm. 13C NMR 1H NMR (400 MHz, CDCl3): δ = 8.71 (d, J = 5.9 Hz, 2 H), 8.04
(101 MHz, [D6]DMSO): δ = 142.40, 141.63, 133.81, 129.35, 128.14,
(d, J = 8.2 Hz, 1 H), 7.89 (d, J = 6.0 Hz, 2 H), 7.46 (d, J = 3.6 Hz,
127.14, 126.61, 121.62, 121.24, 121.07, 110.57, 35.92 ppm. HRMS: 2 H), 7.28 (dd, J = 10.1, 5.8 Hz, 1 H), 4.15 (s, 3 H) ppm. 13C
calcd. for C14H13N2 [M + H]+ 209.1079; found 209.1075.
NMR (101 MHz, CDCl3): δ = 150.28 (2 C), 141.55, 141.17, 140.58,
126.57, 121.83, 121.63, 121.29 (2 C), 120.78, 109.62, 35.82 ppm.
HRMS (ESI): calcd. for C13H12N3 [M + H]+ 210.1031; found
210.1029.
1-Methyl-3-(m-tolyl)-1H-indazole (8): White solid; m.p. 241–
243 °C. IR (neat): ν = 3059.94, 2923.96, 1514.95, 1238.42, 757.10,
˜
747.34, 672.88, 577.64 cm–1. 1H NMR (250 MHz, CDCl3): δ = 7.68
(dt, J = 8.1, 1.0 Hz, 1 H), 7.55 (t, J = 4.0 Hz, 1 H), 7.48–7.45 (m,
1-Phenyl-3-(p-tolyl)-1H-indazole (15): Yellow solid; m.p. 95–97 °C.
2 H), 7.41–7.32 (m, 3 H), 7.24–7.15 (m, 1 H), 4.17 (s, 3 H), 2.44 (s, 3 IR (neat): ν = 3046.34, 2914.46, 1610.05, 1530.16, 1499.93, 1346.39,
˜
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 144.49, 140.66, 137.19,
132.39, 130.67, 130.51, 128.06, 126.17, 125.65, 123.02, 121.42,
120.45, 108.97, 35.51, 20.53 ppm. HRMS (ESI): calcd. for
C15H15N2 [M + H]+ 223.1235; found 223.1232.
1228.96, 1211.11, 772.48, 739.46, 697.58 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 8.11 (d, J = 8.2 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 2 H),
7.82 (t, J = 8.4 Hz, 3 H), 7.58 (t, J = 7.8 Hz, 2 H), 7.50–7.45 (m,
1 H), 7.33–7.28 (m, 1 H), 2.47 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 146.17, 140.30, 140.19, 138.14, 130.36, 129.55 (2 C),
129.44 (2 C), 127.66 (2 C), 127.05, 126.58, 123.18, 122.98 (2 C),
121.79, 121.68, 110.64, 21.40 ppm. HRMS (ESI): calcd. for
C20H17N2 [M + H]+ 285.1392; found 285.1388.
1-Methyl-3-(m-tolyl)-1H-indazole (9): Yellow oil. IR (neat): ν =
˜
2921.88, 1492.64, 1333.95, 1254.09, 790.32, 740.04, 698.35 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 8.06 (dd, J = 7.8, 3.6 Hz, 1 H), 7.83
(d, J = 9.1 Hz, 2 H), 7.51–7.35 (m, 3 H), 7.29–7.19 (m, 2 H), 4.14
(s, 3 H), 2.50 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
143.88, 141.44, 138.49, 133.60, 128.71, 128.65, 128.02, 126.26,
124.57, 121.67, 121.45, 120.86, 109.19, 35.52, 21.60 ppm. HRMS
(ESI): calcd. for C15H15N2 [M + H]+ 223.1235; found 223.1235.
1,3-Diphenyl-1H-indazole (16):[14,15] White solid; m.p. 93–95 °C. IR
(neat): ν = 3025.18, 2916.45, 1615.78, 1528.10, 1510.16, 1350.84,
˜
1227.79, 1239.08, 770.43, 754.30, 680.95 cm–1. 1H NMR (250 MHz,
[D4]methanol): δ = 8.12 (d, J = 8.2 Hz, 1 H), 8.04 (d, J = 7.5 Hz,
2 H), 7.81 (d, J = 7.5 Hz, 3 H), 7.70–7.41 (m, 7 H), 7.35 (d, J =
7.5 Hz, 1 H) ppm. 13C NMR (63 MHz, [D4]methanol): δ = 145.9,
140.3, 139.8, 132.8, 129.3, 128.5, 128.1, 127.4, 127.3, 126.7, 122.8,
122.6, 122, 121.2, 110.3 ppm. HRMS: calcd. for C19H15N2 [M +
H]+ 271.1230; found 271.1230.
3-(4-Chlorophenyl)-1-methyl-1H-indazole (10): White solid; m.p.
103–105 °C. IR (neat): ν = 3021.78, 2913.92, 1618.30, 1530.16,
˜
1349.22, 1225.98, 1241.31, 772.47, 758.11, 677.76 cm–1. 1H NMR
(400 MHz, [D6]DMSO): δ = 8.05 (d, J = 8 Hz, 1 H), 7.99 (d, J =
8.7 Hz, 2 H), 7.69 (d, J = 8 Hz, 1 H), 7.55 (d, J = 8.7 Hz, 2 H),
7.46 (t, J = 8 Hz, 1 H), 7.24 (t, J = 8 Hz, 1 H), 4.10 (s, 3 H) ppm. 3-(4-Chlorophenyl)-1-phenyl-1H-indazole (17): White solid; m.p.
13C NMR (100 MHz, [D6]DMSO): δ = 141.6, 141.2, 132.7, 132.6, 126–129 °C. IR (neat): ν = 3018.90, 2920.11, 1612.60, 1521.88,
˜
129.4, 128.7, 126.7, 121.8, 121.1, 120.9, 110.7, 35.9 ppm. HRMS:
1344.90, 1225.79, 1205.66, 761.85, 686.90 cm–1. 1H NMR
(400 MHz, [D6]DMSO): δ = 8.17 (d, J = 8.2 Hz, 1 H), 8.08 (d, J
calcd. for C14H12ClN2 [M + H]+ 243.0689; found 243.0685.
Eur. J. Org. Chem. 2012, 7075–7081
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7079

S. El Kazzouli, G. Guillaumet et al.
FULL PAPER
L. H. Jones, G. Allan, O. Barba, C. Burt, R. Corbau, T. Du-
pont, T. Knöchel, S. Irving, D. S. Middleton, C. E. Mowbray,
M. Perros, H. Ringrose, N. A. Swain, R. Webster, M. Westby,
C. Phillips, J. Med. Chem. 2009, 52, 1219; d) E. Barile, S. K.
De, C. B. Carlson, V. Chen, C. Knutzen, M. Riel-Mehan, L.
Yang, R. Dahl, G. Chiang, M. Pellecchia, J. Med. Chem. 2010,
53, 8368.
= 8 Hz, 2 H), 7.89 (d, J = 8.6 Hz, 1 H), 7.84 (d, J = 8 Hz, 2 H),
7.62 (m, 4 H), 7.55 (t, 7.6, 1 H), 7.45 (t, J = 7.4 Hz, 1 H), 7.37 (t,
J = 7.4 Hz, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
144.2, 140.2, 139.8, 133.5, 131.8, 130.2, 129.5, 129.4, 128.2, 127.4,
123.1, 123.1, 122.6, 121.7, 111.4 ppm. HRMS: calcd. for
C19H14ClN2 [M + H]+ 305.0846; found 305.0843.
[2]
[3]
a) W. M. Welch, C. E. Hanau, W. M. Whalen, Synthesis 1992,
937; b) D. W. Gordon, Synlett 1998, 1065; c) V. Collot, P. R.
Bovy, S. Rault, Tetrahedron Lett. 2000, 41, 9053; d) V. Collot,
D. Varlet, S. Rault, Tetrahedron Lett. 2000, 41, 4363; e) A.
Amautu, V. Collot, J. C. Ros, C. Alayrac, B. Witulski, S. Rault,
Tetrahedron Lett. 2002, 43, 2695; f) A. Fraile, M. R. Martín,
J.-L. García Ruano, J.-A. Díaz, E. Arranz, Tetrahedron 2011,
67, 100; g) A. Unsinn, P. Knochel, Chem. Commun. 2012, 48,
2680.
1-Phenyl-3-[4-(trifluoromethyl)phenyl]-1H-indazole (18): White so-
lid; m.p. 140–141 °C. IR (neat): ν = 1494.89, 1339.56, 1168.50,
˜
1158.98, 1115.21, 1108.09, 1098.32, 845.80, 767.13, 745.78, 706.05,
666.67 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 8.29 (d, J =
8.1 Hz, 2 H), 8.22 (d, J = 8.2 Hz, 1 H), 7.90 (dd, J = 8.4, 1.9 Hz,
3 H), 7.85 (d, J = 7.5 Hz, 2 H), 7.63 (t, J = 8.1 Hz, 2 H), 7.60–7.54
(m, 1 H), 7.47 (t, J = 7.9 Hz, 1 H), 7.40 (t, J = 7.8 Hz, 1 H) ppm.
13C NMR (101 MHz, [D6]DMSO): δ = 143.80, 140.31, 139.67,
136.99, 130.19, 128.42 (q, 2JCq,F = 32.3 Hz), 128.33, 128.25, 127.63,
S. A. Ohnmacht, A. J. Culshaw, M. F. Greaney, Org. Lett. 2010,
12, 224.
1
3
127.42 (q, JCq,F = 271 Hz), 126.36 (q, JCH,F = 3.3 Hz), 123.38,
123.21, 122.62, 121.65, 111.55 ppm. HRMS: calcd. for C20H13F3N2
[M + H]+ 339.1109; found 339.1108.
[4]
[5]
B. Laleu, M. Lautens, J. Org. Chem. 2008, 73, 9164.
For recent reviews of arylation of heteroarenes, see: a) I. V.
Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007, 36, 1173; b) D.
Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174;
c) T. Satoh, M. Miura, Chem. Lett. 2007, 36, 200; d) L. Acker-
mann, R. Vicente, A. R. Kapdi, Angew. Chem. 2009, 121, 9976;
Angew. Chem. Int. Ed. 2009, 48, 9792; e) F. Bellina, R. Rossi,
Tetrahedron 2009, 65, 10269; f) G. P. McGlacken, L. M. Bate-
man, Chem. Soc. Rev. 2009, 38, 2447.
For selected examples of arylation of heteroarenes, see: a) F.
Shibahara, E. Yamaguchi, T. Murai, Chem. Commun. 2010, 46,
2471; b) K. Ueda, S. Yanagisawa, J. Yamaguchi, K. Itami, An-
gew. Chem. Int. Ed. 2010, 49, 8946; c) S. Potavathri, K. C. Per-
eira, S. I. Gorelsky, A. Pike, A. P. LeBris, B. DeBoef, J. Am.
Chem. Soc. 2010, 132, 14676; d) D. Roy, S. Mom, M. Beaupé-
rin, H. Doucet, J.-C. Hierso, Angew. Chem. Int. Ed. 2010, 49,
6650; e) H. Hachiya, K. Hirano, T. Satoh, M. Miura, Angew.
Chem. 2010, 122, 2248; Angew. Chem. Int. Ed. 2010, 49, 2202;
f) J. Huang, J. Chan, Y. Chen, C. J. Borths, K. D. Baucom,
R. D. Larsen, M. M. Faul, J. Am. Chem. Soc. 2010, 132, 3674;
g) M. Kitahara, N. Umeda, K. Hirano, T. Satoh, M. Miura, J.
Am. Chem. Soc. 2011, 133, 2160; h) J. Kwak, M. Kim, S.
Chang, J. Am. Chem. Soc. 2011, 133, 3780; i) R. Takita, D.
Fujita, F. Ozawa, Synlett 2011, 959; j) H. Cao, H. Zhan, Y.
Lin, X. Lin, Z. Du, H. Jiang, Org. Lett. 2012, 14, 1688; k) D.
Roy, S. Mom, S. Royer, D. Lucas, J.-C. Hierso, H. Doucet, ACS
Catal. 2012, 2, 1033; l) H. Y. Fu, L. Chen, H. Doucet, J. Org.
Chem. 2012, 77, 4473.
3-[4-(Trifluoromethyl)phenyl]-1-(p-tolyl)-1H-indazole (19): White
solid; m.p. 91–93 °C. IR (neat): ν = 1535.25, 1515.99, 1367.22,
˜
1321.68, 1104.11, 1066.15, 845.67, 770.48, 740.95 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 8.19 (d, J = 8.0 Hz, 2 H), 8.09 (d, J =
8.2 Hz, 1 H), 7.78 (t, J = 8.4 Hz, 3 H), 7.68 (d, J = 8.4 Hz, 2 H),
7.49 (dd, J = 11.2, 4.2 Hz, 1 H), 7.42–7.30 (m, 3 H), 2.48 (s, 3 H)
ppm. 13C NMR (101 MHz, CDCl3): δ = 144.11, 140.53, 137.37,
137.06, 136.93, 130.07 (2 C), 129.74, 127.75 (2 C), 127.17 (2 C),
125.75, 125.71, 123.14 (2 C), 122.74, 122.29, 121.07, 110.93,
21.12 ppm. HRMS (ESI): calcd. for C21H16F3N2 [M + H]+
353.1266; found 353.1262.
[6]
1,3-Bis(4-chlorophenyl)-1H-indazole (20): White solid; m.p. 132–
134 °C. IR (neat): ν = 1496.64, 1325.41, 1066.62, 838.13, 745.75,
˜
665.21 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 8.18 (d, J =
8.2 Hz, 1 H), 8.09 (d, J = 8.5 Hz, 2 H), 7.90 (t, J = 8.3 Hz, 3 H),
7.77–7.51 (m, 5 H), 7.40 (t, J = 7.5 Hz, 1 H) ppm. 13C NMR
(101 MHz, [D6]DMSO): δ = 146.08, 141.58, 140.09, 135.12, 133.08,
132.86, 131.55 (2 C), 131.00 (2 C), 130.88 (2 C), 129.90, 125.97 (2
C), 124.75, 124.14, 123.26, 112.88 ppm. HRMS (ESI): calcd. for
C19H13Cl2N2 [M + H]+ 339.0456; found 339.0451.
1-(4-Chlorophenyl)-3-[4-(trifluoromethyl)phenyl]-1H-indazole (21):
White solid; m.p. 135–137 °C. IR (neat): ν = 1496.64, 1325.41,
˜
1174.61, 1163.55, 1114.93, 1106.50, 1097.93, 1090.51, 846.65,
[7]
[8]
a) L. Bouissane, S. El Kazzouli, E. M. Rakib, M. Khouili, G.
Guillaumet, Tetrahedron 2005, 61, 8218; b) S. El Kazzouli, L.
Bouissane, M. Khouili, G. Guillaumet, Tetrahedron Lett. 2005,
46, 6163; c) L. Bouissane, S. El Kazzouli, S. Léonce, B. Pfeiffer,
E. M. Rakib, M. Khouili, G. Guillaumet, Bioorg. Med. Chem.
2006, 14, 1078.
a) J. Koubachi, S. El Kazzouli, S. Berteina-Raboin, A. Mouad-
dib, G. Guillaumet, Synlett 2006, 3237; b) J. Koubachi, S.
El Kazzouli, S. Berteina-Raboin, A. Mouaddib, G. Guillaumet,
J. Org. Chem. 2007, 72, 7650; c) J. Koubachi, S. El Kazzouli,
S. Berteina-Raboin, A. Mouaddib, G. Guillaumet, Synthesis
2008, 2537; d) A. El Akkaoui, S. Berteina-Raboin, A. Mouad-
dib, G. Guillaumet, Eur. J. Org. Chem. 2010, 5, 862; e) I. Bas-
soude, S. Berteina-Raboin, S. Massip, J.-M. Leger, C. Jarry,
E. M. Essassi, G. Guillaumet, Eur. J. Org. Chem. 2012, 13,
2572.
M. Ye, G.-L. Gao, A. J. F. Edmunds, P. A. Worthington, J. A.
Morris, J.-Q. Yu, J. Am. Chem. Soc. 2011, 133, 19090.
Methylation of indazole: The indazole (1 g, 8.46 mmol) was
dissolved in acetone (10 mL) at 0 °C in a 50 mL flask. KOH
(1.4 g, 25.38 mmol) was added, and then CH3I (1.8 g,
12.69 mmol, 1.5 equiv.) was added dropwise. The reaction mix-
ture was filtered and separated by flash chromatography on
silica gel.
1
771.13, 745.75, 711.87, 665.21 cm–1. H NMR (400 MHz, CDCl3):
δ = 8.17 (d, J = 8.1 Hz, 2 H), 8.09 (d, J = 8.1 Hz, 1 H), 7.84–7.74
(m, 5 H), 7.53 (dd, J = 16.2, 8.0 Hz, 3 H), 7.36 (t, J = 7.5 Hz, 1
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 144.86, 140.33, 138.43,
136.54, 132.48, 130.18 (q, 2JCq,F = 32.5 Hz), 129.66 (2 C), 127.81 (2
C), 127.61, 125.80 (q, 3JCH,F = 3.8 Hz), 124.19 (q, 1JCq,F = 273 Hz),
124.07 (2 C), 123.07, 122.66, 121.30, 110.70 ppm. HRMS (ESI):
calcd. for C20H13ClF3N2 [M + H]+ 373.0719; found 373.0714.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H NMR and 13C NMR spectra for all key
intermediates and final products.
[1] Some recent publications on biological applications of substi-
tuted indazoles: a) F. Saczewski, A. Kornicka, A. Rybczynska,
A. L. Hudson, S. Sean Miao, M. Gdaniec, K. Boblewski, A.
Lehmann, J. Med. Chem. 2008, 51, 3599; b) J. Wrobel, R. Stef-
fan, S. M. Bowen, R. Magolda, E. Matelan, R. Unwalla, M.
Basso, V. Clerin, S. J. Gardell, P. Nambi, E. Quinet, J. I. Remin-
ick, G. P. Vlasuk, S. Wang, I. Feingold, C. Huselton, T. Bonn,
M. Farnegardh, T. Hansson, A. G. Nilsson, A. Wilhelmsson,
E. Zamaratski, M. J. Evans, J. Med. Chem. 2008, 51, 7161; c)
[9]
[10]
7080
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 7075–7081

Direct C-3-Arylations of 1H-Indazoles
[11] General procedure for C-3 arylation: In a 10 mL flask, a solu-
tion of phenanthroline (57 mg, 0.31 mmol) in DMA (5 mL)
was degassed by bubbling argon through the solution, and then
palladium acetate (31 mg, 0.14 mmol) was added. The solution
was stirred at room temperature for 3 min, then K2CO3
(290 mg, 2.1 mmol), 1-methylindazole (92.5 mg, 0.7 mmol) and
an aryl iodide (0.9 mmol) were successively added. The reac-
tion mixture was heated at reflux under argon for 48 h, and
then it was allowed to cool. The mixture was filtered through
Celite and the DMA phase was extracted three times with ethyl
acetate, dried with magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by flash chromatog-
raphy on silica gel.
(NMP; 10 mL), in a microwave tube with stirring, and then
CuI (160 mg, 0.84 mmol), bipyridine (262.4 mg, 1.68 mmol),
K2CO3 (1.75 g 12.69 mmol), and an aryl iodide (10.15 mmol)
were added to the reaction mixture. The reaction mixture was
sealed with a silicone septum and subjected to microwave irra-
diation at 200 °C with stirring for 45 min. The reaction mixture
was diluted with ethyl acetate and extracted three times with
ethyl acetate. The organic phase was dried with MgSO4 and
concentrated under reduced pressure. The product was purified
by column chromatography on silica gel (diethyl ether/
CH2Cl2).
[14]
[15]
X. Xiong, Y. Jiang, M. Dawei, Org. Lett. 2012, 14, 2552.
C. Spiteri, S. Keeling, J. E. Moses, Org. Lett. 2010, 12, 3368.
[12] a) J. M. Salovich, C. W. Lindsley, C. R. Hopkins, Tetrahedron
Lett. 2010, 51, 3796; b) Y.-C. Teo, F.-F. Yong, G. S. Lim, Tetra-
hedron Lett. 2011, 52, 7171.
[13] General procedure for the N-arylation of indazole: The ind-
azole (1 g, 8.46 mmol) was dissolved in N-methylpyrrolidine
[16] B. C. Wray, J. P. Stambuli, Org. Lett. 2010, 12, 4576.
Received: June 28, 2012
Published Online: November 7, 2012
Eur. J. Org. Chem. 2012, 7075–7081
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7081