A mild and regioselective Ullmann reaction of indazoles with aryliodides in water

Article abstract of DOI:10.1016/j.tet.2016.11.066

A mild and regioselective Ullmann reaction of indazoles with aryliodides has been developed as a general method for the synthesis of 1-aryl-1H-indazoles. Water was used as the solvent wherein Tween 20 (2% w/w) was added to form aqueous micelles to improve

Full text of DOI:10.1016/j.tet.2016.11.066

Tetrahedron xxx (2016) 1e7
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A mild and regioselective Ullmann reaction of indazoles with
aryliodides in water
,
,
, *
Xiao Ding a 1, Jingtao Bai b 1, Hailong Wang a, Baowei Zhao a, Jian Li b, Feng Ren a
a Research and Development, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China
b Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237,
China
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and regioselective Ullmann reaction of indazoles with aryliodides has been developed as a general
method for the synthesis of 1-aryl-1H-indazoles. Water was used as the solvent wherein Tween 20 (2%
w/w) was added to form aqueous micelles to improve solubility of starting materials and accelerate
reaction rate. This aqueous protocol allows the Ullmann reaction to proceed at a mild temperature
(60 ꢀC) within a short reaction time (2 h), which typically requires high temperatures (ꢁ100 ꢀC) and
prolonged duration (ꢁ24 h). The protocol demonstrated broad substrate scopes with good isolated yields
and high regioselectivity (N-1 arylation over N-2 arylation) for 25 examples examined.
© 2016 Elsevier Ltd. All rights reserved.
Received 9 October 2016
Received in revised form
21 November 2016
Accepted 28 November 2016
Available online xxx
Keywords:
1-Aryl-1H-indazoles
Ullmann reaction
Aqueous micelles
Tween 20
Regioselective
1. Introduction
temperature (130 ꢀC) and completed in prolonged duration (24 h).
Teo and co-workers developed a milder Ullmann coupling condi-
1-Aryl-1H-indazole and its analogs are important building
blocks widely applied in a variety of biologically active compounds1
including Factor Xa inhibitors,2 GR agonists,3 KHK inhibitors,4 and
Nav1.7 blockers.5 Given its prevalence in pharmaceutical industry, a
number of strategies have been developed for the construction of
the 1-aryl-1H-indazole scaffold during the past years including the
palladium-catalyzed intramolecular amination of aryliodides,6 the
copper promoted Chan-Lam reaction,7 the Buchwald-Hartwig
coupling,8 and the Ullmann reaction.9 Among them, copper-
catalyzed Ullmann reaction of indazoles with aryliodides repre-
sents one of the most straightforward and atom-economic
methods. Buchwald's group10 described a regioselective synthesis
of 1-aryl-1H-indazole via copper-catalyzed Ullmann reaction in
toluene, wherein elevated temperature (110 ꢀC) and prolonged
reaction time (24 h) were required for good conversions. A ligand-
free Cu2O-catalyzed strategy for Ullmann coupling of indazoles in
water was reported by Lim and co-workers.11 Again, they observed
the same phenomenon that the reactions proceeded at high
tion at 60 ꢀC in water, but the addition of a second metal catalyst
(MnF2) and prolonged reaction time (24 h) were required in order
to achieve good conversions.12 Yao and Zhang's groups reported N-
(1-oxy-2-picolyl)oxalamic acids as the novel ligand for the Cu-
catalyzed N-arylation of indazoles and pyrazoles. Harsh reaction
conditions were observed (>90 ꢀC, 48 h) with limited examples
evaluated.13 A copper-catalyzed protocol for the cross-coupling of
indazole with p-tolyl boronic acid was reported to proceed at room
temperature, however with low regioselectivity (N-1 arylation over
N-2 arylation).7 Up to date, the reported protocols are often asso-
ciated with obvious disadvantages such as high reaction tempera-
ture, long reaction time, narrow functional group tolerance, and/or
low regioselectivity thus their synthetic utilities are limited. Herein,
we report a mild, efficient, and regioselective Ullmann reaction of
indazoles with aryliodides for the synthesis of 1-aryl-1H-indazoles
with a broad substrate scope. The protocol has been developed in
the most environmentally friendly and economical solvent, water,
which provides additional attractiveness of the methodology.
Replacing organic solvents especially hazardous ones with wa-
ter has intrigued great attention from both academia and industry
to address the significant health and environmental concerns.14 In
order to improve the solubility of organic reactants in water,
* Corresponding author.
E-mail address: feng.q.ren@gsk.com (F. Ren).
Contributed equally to this work.
1
http://dx.doi.org/10.1016/j.tet.2016.11.066
0040-4020/© 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ding X, et al., A mild and regioselective Ullmann reaction of indazoles with aryliodides in water, Tetrahedron
(2016), http://dx.doi.org/10.1016/j.tet.2016.11.066

2
X. Ding et al. / Tetrahedron xxx (2016) 1e7
surfactants are employed as additives to water to form aqueous
micelles which dissolve organics.15 Hydrophobic tails of surfactants
form micellar “nano-reactors” in water, which favor the compart-
mentalization of organic reactants in these “nano-reactors” thus
increasing the local reaction concentration.16 Hence, the aqueous
micellar solvent enables faster reaction rates and milder reaction
temperatures comparing with organic solvents.17 Our group has
successfully developed several novel protocols in this aqueous
micellar system with mild reaction conditions, wide scopes of
substrates and high yields, including selective N-alkylation of 2-
pyridones,18 carboxylate-directed C-H arylation19 and C2-selective
arylation of indoles.20 In our protocols, Tweens21 were used as
the surfactants due to their commercial availability and relatively
nontoxic profile.
spectroscopic data of 3a with those reported in literature.22 With
the encouraging preliminary result, we then investigated the effect
of different copper(I) catalysts on the reaction including CuI (entry
2), CuTC (entry 3), CuCN (entry 4), and Cu2O (entry 5) and the rest
copper catalysts resulted in much lower conversion even with
prolonged reaction time. In addition to the catalyst, the surfactants
were also observed to significantly impact on the reactivity of the
Ullmann coupling reaction. TPGS-750-M (entry 6), TritonX-100
(entry 7), Brij30 (entry 8) and PEG-600 (entry 9) resulted in
much decreased conversion (ꢂ27%) to the Ullmann coupling
product 3a comparing to that of Tween 20 (42%). Further, different
sizes of Tweens were evaluated and slightly lower reactivity rela-
tive to Tween 20 was observed when Tween 40 (entry 10), Tween
60 (entry 11), and Tween 80 (entry 12) were used as surfactants.
Among the surfactants evaluated, Tween 20 proved to be superior
considering both conversion and regioselectivity, notwithstanding
a higher regioselectivity observed for PEG-600 (lower conversion
however). On the other hand, the reaction proceeded with low
conversion without the addition of surfactant (entry 13), which was
likely due to low solubility of starting materials as well as the
copper catalyst in water. Increasing the catalyst loading from
10 mol% to 20 mol% resulted in accelerated reaction rate, providing
60% conversion (entry 14). When the temperature was increased to
60 ꢀC, a full conversion was observed (99%, entry 15) at the same
time the regioselectivity was maintained (N-1/N-2 arylation
ratio ¼ 5:1). The optimal condition for the Ullmann reaction was
thus concluded using Tween 20/water (2% w/w) as the solvent, CuI
(20 mol%) as the catalyst, and at elevated temperature (60 ꢀC).
The optimal reaction condition was then applied to the Ullmann
reaction of indazole (1a) with a broad scope of aryliodides (2). As
showed in Table 2, iodobenzenes with a variety of different sub-
stitutions were well tolerated for the reaction. Overall, high con-
versions were observed and good isolated yields of desired 1-aryl-
1H-indazole products (3) were obtained with a couple of excep-
tions (3h and 3i). In addition, the regioselectivity (N-1/N-2 aryla-
tion ratio) was observed high (5:1 to 10:1) as determined by
integration of the characteristic protons for products 3 and 4 in 1H
NMR spectra of the crude reaction mixtures. Para-substituted
iodobenzenes bearing both electron-donating substitutions such as
eCH3, eOCH3 and electron-withdrawing substitutions including
eCl, eCN, eCOOMe, or eCF3 resulted in good to excellent conver-
sions (entries 1e6, 61%e98%) and provided the desired 1-aryl-1H-
indazole products (3ae3f) with good isolated yields (50%e83%).
The methyl ester substitution was tolerated with the reaction
condition even though a relatively lower yield was obtained (entry
5), which might due to partial hydrolysis of the methyl ester under
the basic condition in water. Iodobenzene with meta-substitution
(1-iodo-3-trifluoromethylbenzene, entry 7) demonstrated similar
reactivity to provide the Ullmann product (3g) in excellent con-
version (100%), high N-2/N-1 arylation ratio (10:1), and good iso-
lated yield (91%). On the other hand, when the trifluoromethyl
substitution was on the ortho-position (2h) no coupling product
was observed even after prolonged reaction time (entry 8), indi-
cating the reactivity was sensitive to steric effect. Low yield of the
Ullmann coupling product 3i (38%) was obtained when 4-iodo-1,1'-
biphenyl was used as the starting material (entry 9), which might
due to its low solubility. Furthermore, heteroaromatic halides were
also examined including 2-iodopyrazine (2j), 2-bromothiazole (2k),
and 4-iodo-1-methyl-1H-pyrazole (2l), and all of them provided
good conversions and isolated yields. It is noteworthy that the five-
membered heteroaromatic halides (2k and 2l) resulted in very high
regioselectivity, with the N-1/N-2 arylation ratios greater than 99:1
(entries 11 and 12) based on HPLC-MS analysis of the crude reaction
mixtures.
2. Results and discussion
We initiated our exploration of Ullmann reaction using indazole
(1a) and iodobenzene (2a) as model substrates, and Tween 20 as
the surfactant to construct the 1-aryl-1H-indazole scaffold.
(Table 1). It was encourging to find that 20% conversion to the
desired product was observed within 2 h using CuBr (10 mol %) as
the catalyst, Cs2CO3 as the base, and trans-N1,N2-
dimethylcyclohexane-1,2-diamine as the ligand in Tween 20/wa-
ter micellar solvent (2% w/w) at room temperature (entry 1). Based
on HPLC-MS analysis, the ratio of N-1 arylation product 3a and N-2
arylation product 4a was observed to be 6:1 (entry 1), consistent
with the kinetically preferred coppereindazole (N-1) intermediate
during the reaction.10 The structure assignment of 3a was indirectly
confirmed from 2D NMR spectroscopy based on the NOESY cross-
peaks between Ha and Hb of 4a (Supporting Information). The
structure assignment was further confirmed by comparison of the
Table 1
Optimization of reaction conditions for Ullmann reaction of indazole.a
Entry Catalyst Surfactant
Temp (ꢀC) Conversion (%)b 3a/4a ratiob
1
2
3
CuBr
CuI
CuTC
CuCN
Cu2O
CuI
CuI
CuI
CuI
CuI
Tween 20
Tween 20
Tween 20
Tween 20
Tween 20
TPGS-750-M rt
TritonX-100
Brij30
PEG-600
Tween 40
Tween 60
Tween 80
/
rt
rt
rt
rt
rt
20
42
25
0
0
15
6
6:1
6:1
6:1
NDd
NDd
6:1
5:1
6:1
8:1
6:1
6:1
6:1
6:1
4:1
5:1
4c
5c
6
7
8
9
10
11
12
13
14e
15e
rt
rt
rt
rt
rt
rt
rt
rt
60
9
27
22
35
15
14
60
99
CuI
CuI
CuI
CuI
Tween 20
Tween 20
CuI
a
Reaction conditions: indazole 1a (47 mg, 1.0 eq), iodobenzene 2a (105 mg, 1.2
eq), Cs2CO3 (326 mg, 2.5 eq), catalyst (10 mol%), trans-N1,N2-dimethylcyclohexane-
1,2-diamine (40 mol%), surfactant/H2O (2% w/w, 2 mL), 2 h.
b
Conversion and N-1/N-2 arylation ratio were determined by HPLC peak areas at
254 nm for indazole 1a and the regioisomeric products (3a and 4a) in the crude
reaction mixture.
c
24 h.
No data.
d
e
20 mol% CuI, 80 mol% trans-N1,N2-dimethylcyclohexane-1,2-diamine.
The substrate scope of indazoles was also investigated. As
Please cite this article in press as: Ding X, et al., A mild and regioselective Ullmann reaction of indazoles with aryliodides in water, Tetrahedron
(2016), http://dx.doi.org/10.1016/j.tet.2016.11.066

X. Ding et al. / Tetrahedron xxx (2016) 1e7
3
Table 2
Table 3
Scope of aryl halides for Ullmann reaction in Tween 20/water.a
Scope of indazoles for Ullmann reaction in Tween 20/water.a
Entry
1
2
Conversion (%)b
97
3/4 ratioc
6:1
Isolated
yield of 3 (%)
Entry
2
Conversion (%)b
5/6 ratioc
10:1
Isolated
yield of 5
(%)
3a, 73
2
95
5:1
3b, 79
1
2
98
87
3c, 76
3
4
98
91
10:1
10:1
3c, 76
3d, 81
7:1
5a, 75
3
60
4:1
5b, 46
5
6
61
97
7:1
7:1
3e, 50
3f, 83
4
5
89
72
8:1
3:1
5c,74
7
8
100
0
10:1
NDd
3g, 91
5d, 52
3h, NDd
6
7
8
95
6:1
5e, 80
5f, 86
5g,79
9
70
89
5:1
8:1
3i, 38
3j, 78
100
94
10:1
7:1
10
11
60
71
>99:1
>99:1
3k, 58
3l, 67
9
80
11:1
5h, 71
5i, 86
5j, 91
12
10
11
95
>99:1
30:1
a
Reaction conditions: indazole 1a (100 mg, 1.0 eq), arylhalides 2 (1.2 eq), Cs2CO3
(2.5 eq), catalyst (20 mol%), trans-N1,N2-dimethylcyclohexane-1,2-diamine (80 mol
%), surfactant/H2O (2% w/w, 2 mL), 2 h.
b
Conversion was determined by HPLC peak areas at 254 nm for indazole 1a and
100
both regioisomeric products (3 and 4) in the reaction mixture.
c
N-1/N-2 arylation ratio was determined by integration of the characteristic
protons for products 3 and 4 in 1H NMR spectra of the crude reaction mixture.
d
No data.
12
13
81
70
>99:1
>99:1
5k, 63
5l, 70
showed in Table 3, indazoles bearing the electron-donating sub-
stitution (methoxy) at different positions (4-, 5-, 6-, and 7-position)
underwent Ullmann reaction with 1-chloro-4-iodobenzene
smoothly, providing corresponding 1-aryl-1H-indazole products
in moderate to good yields (entries 2e5). Among them, the 7-
methoxy-1H-indazole (1e) provided the lowest regioselectivity
(N-1/N-2 arylation ratio ¼ 3:1) which might be the result of the
steric effect of the methoxy group.
We then focused the substrate explorations on 5-substituted
indazoles because of their commercial availability. The reaction
demonstrated good tolerability for different substitutions including
both electron-withdrawing (entries 6e11) and electron-donating
groups (entry 3). Excellent regioselectivity (>99:1 and 30:1) was
a
Reaction conditions: indazole 1 (100 mg, 1.0 eq), 1-chloro-4-iodobenzene 2 (1.2
eq), Cs2CO3 (2.5 eq), catalyst (20 mol%), trans-N1,N2-dimethylcyclohexane-1,2-
diamine (80 mol%), surfactant/H2O (2% w/w, 2 mL), 2 h.
b
Conversion was determined by HPLC peak areas at 254 nm for indazoles 1 and
both regioisomeric products (5 and 6) in the reaction mixture.
c
N-1/N-2 arylation ratio was determined by comparing integrations of charac-
teristic protons for product 5 and 6 in 1H NMR spectrum of the crude reaction
mixture.
Please cite this article in press as: Ding X, et al., A mild and regioselective Ullmann reaction of indazoles with aryliodides in water, Tetrahedron
(2016), http://dx.doi.org/10.1016/j.tet.2016.11.066

4
X. Ding et al. / Tetrahedron xxx (2016) 1e7
observed with the cyano and ester substitutions (1j and 1k), likely
due to its strong electron-withdrawing property rendering the
resulting coppereindazole (N-1) intermediate the most dominant
than all the other substituents. Similarly, aza-indazole (1l) also
provided excellent regioselectivity (N-1/N-2 arylation ratio > 99:1)
in good isolated yield (91%, entry 12). Further, introducing a methyl
group ortho to N-2 of indazole (entry 13) afforded a much improved
regioselectivity (>99:1) comparing with the un-substituted inda-
zole (10:1, entry 1). Again, the regiochemistry was confirmed from
2D NMR spectroscopy (e.g. observed NOESY cross-peaks between
Ha and Hb of 6d, Supporting Information).
The protocol was further extended to other bicyclic heterocycles
(Table 4) in addition to indazoles. To our delight, the reaction
worked smoothly on both indole (7) and indolin-2-one (9), and the
desired Ullmann coupling products 8 and 10 were obtained in
moderate to good yields (37% and 81%, respectively). The 1H NMR
spectrum of 10 was observed identical to that reported in litera-
ture,23 confirming the N-arylation regioselectivity over O-arylation.
The result suggested this aqueous protocol could be generalized as
a mild method for the Ullmann reaction of heterocycles.
and used without further purification. 1H NMR, 13C NMR and 2D
NOESY spectra were recorded on a Bruker 400 or 600 NMR spec-
trometer using CDCl3 (deuterochloroform) as the solvents and TMS
(tetramethylsilane) as the internal standard. Chemical shifts (d)are
given in parts per million (ppm) downfield from the TMS signal.
The following abbreviations are used to indicate the multiplicity in
NMR spectra: s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet,
m ¼ multiplet, dd ¼ doublet of doublets, dt ¼ doublet of triplets,
app ¼ apparent, br ¼ broad. J indicates the NMR coupling constant
measured in Hertz. High resolution mass (HRMS) was operated in a
positive mode of electrospray ionization (ESI) at an orthogonal
acceleration time-of-flight (oa-TOF) SYNAPT G2 HDMSTM (Waters,
Manchester, UK). LCMS (Agilent 1200SL-6110) analysis was con-
ducted for all compounds under the acidic condition: acidic con-
dition refers to water containing 0.05% TFA/acetonitrile as the
mobile phase on Agilent SB-C18 column (1.8
mm, 4.6 ꢃ 30 mm),
with MS and photodiode array detector (PDA). The following con-
ditions were used: a gradient from 5 to 95% in 5 min (or 6 min) and
held at 95% for 1 min; UV detection at 214 and 254 nm; a flow rate
of 1.5 ml/min; full scan; mass range from 100 to 1000 amu. Column
chromatography was performed on ISCO or Biotage using a pre-
packed silica gel column, a detector with UV wavelength at
254 nm and 280 nm.
3. Conclusion
In summary, we have developed a mild, efficient, and regiose-
lective method for the preparation of 1-aryl-1H-indazole through
copper-catalyzed Ullmann reaction between indazoles and arylio-
dides in water with 2% (w/w) Tween 20. The aqueous micelles
formed enable improved solubility of starting materials and
increased local reaction concentration thus accelerated reaction
rate. This aqueous protocol allows a mild reaction temperature
(60 ꢀC) and a short reaction time (2 h) for the Ullmann reaction,
which otherwise requires high temperatures (ꢁ100 ꢀC) and pro-
longed duration (ꢁ24 h). The protocol also demonstrated broad
substrate scopes with good isolated yields and high regioselectivity
(N-1 over N-2 arylation) for the examples examined. In addition,
the protocol was further generalized to bicyclic heterocycles other
than indazole, such as indole and indolin-2-one, for Ullmann re-
action. Further application of this protocol to other heterocyclic
substrates is ongoing.
4.2. General procedures for the syntheses of compounds 3, 5, 8 and
10
To a mixture of indazoles, indoles, or indolin-2-ones (1 equiv),
aryl halides (1.2 equiv), cesium carbonate (2.5 equiv), copper (I)
iodide (0.2 equiv) in Tween 20/water (2%, w/w, 0.2 M) was added
trans-N1,N2-dimethylcyclohexane-1,2-diamine (0.8 equiv). The re-
action mixture was stirred at 60 ꢀC for 2 h. The reaction mixture
was extracted with ethyl acetate (20 mL ꢃ 3). The organic layers
were combined, washed with brine (50 mL), dried over anhydrous
Na2SO4 and concentrated. The residue was purified by flash chro-
matography on silica gel and eluted with PE/EA to afford the
desired product 3, 5, 8 and 10.
4.2.1. 1-(P-tolyl)-1H-indazole (3a)
129 mg (73% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3):
4. Experimental section
d
ppm 8.23 (d, J ¼ 0.8 Hz, 1H), 7.83 (d, J ¼ 8.0 Hz, 1H), 7.75 (dd,
J ¼ 0.8, 8.4 Hz, 1H), 7.64 (d, J ¼ 8.4 Hz, 2H), 7.44 (ddd, J ¼ 0.98, 7.2,
8.4 Hz, 1H), 7.37 (d, J ¼ 8.0 Hz, 2H), 7.21e7.28 (m, 1H), 2.47 (s, 3H).
4.1. General methods
13C NMR (101 MHz, CDCl3):
d
ppm 138.8, 137.8, 136.6, 135.1, 130.þ0,
All reactions were conducted under atmosphere without special
drying. All reagents were purchased from commercial suppliers
127.0, 125.2, 122.8, 121.3, 110.4, 21.1. LC-MS: 209.1 [MþH]
,
tR ¼ 3.85 min. HRMS (ESI): m/z calcd for C14H13N2 [MþH]þ
Table 4
Ullmann reaction of indole and indolin-2-one in Tween 20/water.
Please cite this article in press as: Ding X, et al., A mild and regioselective Ullmann reaction of indazoles with aryliodides in water, Tetrahedron
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X. Ding et al. / Tetrahedron xxx (2016) 1e7
5
209.1079, found [MþH]þ 209.1081.
(101 MHz, CDCl3, mixture):
d
ppm 140.3, 139.5, 138.8, 135.5, 128.9,
128.1, 127.5, 127.2, 127.1, 125.4, 122.9, 121.6, 121.4, 110.5. LC-MS: 271
[MþH]þ, tR ¼ 4.25 min. HRMS (ESI): m/z calcd for C19H15N2 [MþH]þ
271.1235, found [MþH]þ 271.1236.
4.2.2. 2-(P-tolyl)-2H-indazole (4a)
20 mg (11% yield) as a white solid. 1H NMR (400 MHz, CDCl3):
d
ppm 8.40 (s, 1H), 7.78e7.85 (m, 3H), 7.73 (d, J ¼ 8.4 Hz, 1H),
7.31e7.38 (m, 3H), 7.13 (dd, J ¼ 6.8, 8.0 Hz,1H), 2.45 (s, 3H). 13C NMR
4.2.10. 1-(Pyrazin-2-yl)-1H-indazole (3j)
(101 MHz, CDCl3):
d
ppm 149.7, 138.3, 137.9, 130.1, 126.7, 122.7,
130 mg (78% yield) as colorless oil. 1H NMR (400 MHz, CDCl3):
122.3, 120.9, 120.3, 117.9, 21.0. LC-MS: 209.1 [MþH] þ, tR ¼ 3.61 min.
d
ppm 9.43 (s, 1H), 8.74 (d, J ¼ 8.8 Hz, 1H), 8.43 (d, J ¼ 9.2 Hz, 2H),
8.25 (s, 1H), 7.80 (d, J ¼ 8.0 Hz, 1H), 7.55 (t, J ¼ 7.6 Hz, 1H), 7.33 (t,
4.2.3. 1-(4-Methoxyphenyl)-1H-indazole (3b)
J ¼ 7.6 Hz, 1H). 13C NMR (101 MHz, CDCl3):
d ppm 150.3,141.3, 139.8,
150 mg (79% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3):
139.0, 138.1, 136.5, 128.4, 126.1, 123.2, 121.0, 115.0. LC-MS: 197
[MþH]þ, tR ¼ 3.15 min. HRMS (ESI): m/z calcd for C11H9N4 [MþH]þ
197.0827, found [MþH]þ 197.0827.
d
ppm 8.20 (s, 1H), 7.82 (d, J ¼ 8.0 Hz, 1H), 7.62e7.71 (m, 3H), 7.43 (t,
J ¼ 7.6 Hz, 1H), 7.24 (t, J ¼ 7.6 Hz, 1H), 7.09 (d, J ¼ 9.2 Hz, 2H), 3.91 (s,
3H). 13C NMR (101 MHz, CDCl3):
d ppm 158.4, 139.0, 134.8, 133.4,
126.9, 125.0, 124.5, 121.3, 114.6, 110.2, 55.6. LC-MS: 225.1 [MþH]þ,
tR ¼ 3.47 min. HRMS (ESI): m/z calcd for C14H13N2O [MþH]þ
225.1028, found [MþH]þ 225.1031.
4.2.11. 2-(1H-indazol-1-yl)thiazole (3k)
99 mg (58% yield) as a white solid. 1H NMR (400 MHz, CDCl3):
d
ppm 8.65 (d, J ¼ 8.4 Hz, 1H), 8.22 (s, 1H), 7.80 (d, J ¼ 8.0 Hz, 1H),
7.65 (d, J ¼ 3.6 Hz, 1H), 7.61 (t, J ¼ 7.8 Hz, 1H), 7.35 (t, J ¼ 7.4 Hz, 1H),
4.2.4. 1-(4-Chlorophenyl)-1H-indazole (3c)
7.08 (d, J ¼ 3.6 Hz, 1H). 13C NMR (101 MHz, CDCl3):
d ppm 162.7,
150 mg (76% yield) as a white solid. . 1H NMR (400 MHz, CDCl3):
140.3, 138.3, 138.0, 128.9, 125.8, 123.4, 121.1, 114.1, 113.9. LC-MS: 202
[MþH]þ, tR ¼ 3.41 min. HRMS (ESI): m/z calcd for C10H8N3S [MþH]þ
202.0439, found [MþH]þ 202.0446.
d
ppm 8.23 (s, 1H), 7.84 (d, J ¼ 8.4 Hz, 1H), 7.68e7.77 (m, 3H),
7.51e7.57 (m, 2H), 7.44e7.51 (m, 1H), 7.26e7.31 (m, 2H). 13C NMR
(101 MHz, CDCl3):
d ppm 138.8, 138.7, 135.8, 132.0, 129.6, 127.4,
125.5, 123.8, 121.8, 121.5, 110.2. LC-MS: 229 [MþH]þ, tR ¼ 3.85 min.
HRMS (ESI): m/z calcd for C13H10N2Cl [MþH]þ 229.0533, found
[MþH]þ 229.0535.
4.2.12. 1-(1-Methyl-1H-pyrazol-4-yl)-1H-indazole (3l)
115 mg (67% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3):
d
ppm 8.16 (s, 1H), 7.89 (s, 1H), 7.77e7.83 (m, 2H), 7.58 (d, J ¼ 8.4 Hz,
1H), 7.47 (t, J ¼ 7.8 Hz, 1H), 7.24 (t, J ¼ 7.6 Hz, 1H), 4.04 (s, 3H). 13
C
4.2.5. 4-(1H-indazol-1-yl)benzonitrile (3d)
NMR (151 MHz, CDCl3): d ppm 139.4,134.9,132.7,127.2,124.5,124.4,
160 mg (81% yield) as a white solid. 1H NMR (400 MHz, CDCl3):
123.7, 121.4, 121.3, 109.8, 39.6. LC-MS: 198.9 [MþH]þ, tR ¼ 2.60 min.
HRMS (ESI): m/z calcd for C11H11N4 [MþH]þ 199.0984, found
[MþH]þ 199.0984.
d
ppm 8.28 (s, 1H), 7.93e8.00 (m, 2H), 7.79e7.90 (m, 4H), 7.54 (t,
J ¼ 7.6 Hz, 1H), 7.33 (t, J ¼ 7.6 Hz, 1H). 13C NMR (101 MHz, CDCl3):
d
ppm 143.8,138.5,137.3,133.6,128.1,126.1,122.5,121.9,118.5,110.4,
109.1. LC-MS: 219.9 [MþH]þ, tR ¼ 3.44 min. HRMS (ESI): m/z calcd
4.2.13. 1-(4-Chlorophenyl)-4-methoxy-1H-indazole (5a)
for C14H10N3 [MþH]þ 220.0875, found [MþH]þ 220.0871.
130 mg (75% yield) as a white solid. 1H NMR (400 MHz, CDCl3):
d
ppm 8.29 (s, 1H), 7.70 (d, J ¼ 8.8 Hz, 2H), 7.52 (d, J ¼ 8.8 Hz, 2H),
4.2.6. Methyl 4-(1H-indazol-1-yl)benzoate (3e)
7.34e7.42 (m, 1H), 7.31 (m, 1H), 6.59 (d, J ¼ 7.6 Hz, 1H), 4.02 (s, 3H).
110 mg (50% yield) as a white solid. 1H NMR (400 MHz, CDCl3):
13C NMR (151 MHz, CDCl3):
d ppm 154.0, 140.4, 138.9, 133.6, 132.0,
d
ppm 8.19e8.30 (m, 1H), 7.78e7.96 (m, 1H), 7.51 (t, J ¼ 7.6 Hz, 1H),
129.5, 128.8, 123.7, 117.3, 103.0, 100.7, 55.5. LC-MS: 259 [MþH]þ,
tR ¼ 3.94 min. HRMS (ESI): m/z calcd for C14H12N2OCl [MþH]þ
259.0638, found [MþH]þ 259.0644.
7.29e7.33 (m, 1H), 3.99 (s, 3H). 13C NMR (101 MHz, CDCl3):
d
ppm
166.5, 144.0, 138.6, 136.6, 131.1, 127.7, 125.9, 122.1, 121.6, 121.5, 110.6,
51.5. LC-MS: 252.9 [MþH]þ, tR ¼ 3.67 min. HRMS (ESI): m/z calcd for
C
15H13N2O2 [MþH]þ 253.0977, found [MþH]þ 253.0980.
4.2.14. 1-(4-Chlorophenyl)-5-methoxy-1H-indazole (5b)
81 mg (46% yield) as a white solid. 1H NMR (400 MHz, CDCl3):
4.2.7. 1-(4-(Trifluoromethyl)phenyl)-1H-indazole (3f)
d
ppm 8.13 (s, 1H), 7.69 (d, J ¼ 8.4 Hz, 2H), 7.64 (d, J ¼ 9.2 Hz, 1H),
193 mg (83% yield) as a white solid. 1H NMR (400 MHz, CDCl3):
7.52 (d, J ¼ 8.4 Hz, 2H), 7.09e7.18 (m, 2H), 3.91 (s, 3H). 13C NMR
d
ppm 8.27 (s, 1H), 7.93 (d, J ¼ 8.4 Hz, 2H), 7.78e7.88 (m, 4H), 7.51 (t,
(151 MHz, CDCl3): d ppm 155.2, 138.9, 135.1, 134.5, 131.9, 129.6,
J ¼ 8.0 Hz, 1H), 7.21e7.36 (m, 1H). 13C NMR (101 MHz, CDCl3):
d
ppm
126.0, 123.4, 121.6, 119.3, 111.3, 100.7, 55.7. LC-MS: 259 [MþH]þ,
tR ¼ 3.84 min. HRMS (ESI): m/z calcd for C14H12N2OCl [MþH]þ
259.0638, found [MþH]þ 259.0641.
143.1, 138.6, 136.6, 127.8, 125.9, 122.1, 121.6, 110.3. LC-MS: 263
[MþH]þ, tR ¼ 3.98 min. HRMS (ESI): m/z calcd for C14H10N2F3
[MþH]þ 263.0796, found [MþH]þ 263.0799.
4.2.15. 1-(4-Chlorophenyl)-6-methoxy-1H-indazole (5c)
4.2.8. 1-(3-(Trifluoromethyl)phenyl)-1H-indazole (3g)
130 mg (74% yield) as a white solid. 1H NMR (400 MHz, CDCl3):
ppm 8.11 (s, 1H), 7.68 (d, J ¼ 8.4 Hz, 3H), 7.54 (d, J ¼ 8.8 Hz, 2H),
205 mg (91% yield) as colorless oil. 1H NMR (400 MHz, CDCl3):
d
d
ppm 8.27 (s, 1H), 8.07 (s, 1H), 7.99 (d, J ¼ 8.0 Hz, 1H), 7.86 (d,
7.06 (s, 1H), 6.92 (dd, J ¼ 2.0, 8.8 Hz, 1H), 3.90 (s, 3H). 13C NMR
J ¼ 8.0 Hz, 1H), 7.79 (d, J ¼ 8.8 Hz, 1H), 7.66e7.74 (m, 1H), 7.60e7.66
(151 MHz, CDCl3): d ppm 160.2, 140.2, 138.8, 135.8, 132.0, 129.6,
(m, 1H), 7.52 (t, J ¼ 7.6 Hz, 1H), 7.29e7.34 (m, 1H). 13C NMR
123.9, 122.1, 121.5, 120.0, 113.4, 91.7, 55.6. LC-MS: 259 [MþH]þ,
tR ¼ 3.89 min. HRMS (ESI): m/z calcd for C14H12N2OCl [MþH]þ
259.0638, found [MþH]þ 259.0638.
(101 MHz, CDCl3):
d ppm 140.8, 138.6, 136.3, 130.1, 127.7, 125.7,
125.3, 122.0, 121.6, 110.1. LC-MS: 263 [MþH]þ, tR ¼ 4.10 min. HRMS
(ESI): m/z calcd for C14H10N2F3 [MþH]þ 263.0796, found [MþH]þ
263.0802.
4.2.16. 1-(4-Chlorophenyl)-7-methoxy-1H-indazole (5d)
90 mg (52% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3):
4.2.9. 1-([1,10-Biphenyl]-4-yl)-1H-indazole (3i)
d ppm 8.18 (s, 1H), 7.50e7.57 (m, 2H), 7.37e7.47 (m, 3H), 7.18 (t,
92 mg (38% yield) as a white solid. 1H NMR (400 MHz, CDCl3):
J ¼ 8.0 Hz, 1H), 6.84 (d, J ¼ 7.8 Hz, 1H), 3.84 (s, 3H). 13C NMR
d
ppm 8.23 (s, 1H), 7.73e7.86 (m, 7H), 7.66 (d, J ¼ 7.6 Hz, 2H),
(151 MHz, CDCl3): d ppm 146.1, 139.8, 135.8, 132.6, 130.3, 128.1,
7.43e7.53 (m, 3H), 7.35e7.42 (m, 1H), 7.24 (br s, 1H). 13C NMR
127.4, 127.1, 122.4, 113.2, 106.8, 55.4. LC-MS: 259 [MþH],
Please cite this article in press as: Ding X, et al., A mild and regioselective Ullmann reaction of indazoles with aryliodides in water, Tetrahedron
(2016), http://dx.doi.org/10.1016/j.tet.2016.11.066

6
X. Ding et al. / Tetrahedron xxx (2016) 1e7
tR ¼ 3.79 min. HRMS (ESI): m/z calcd for C14H12N2OCl [MþH]þ
259.0638, found [MþH]þ 259.0640.
d
ppm 9.21 (s, 1H), 8.54 (d, J ¼ 6.0 Hz, 1H), 8.38 (s, 1H), 7.70 (d,
J ¼ 8.8 Hz, 2H), 7.62 (d, J ¼ 6.0 Hz, 1H), 7.57 (d, J ¼ 8.8 Hz, 2H). 13
C
NMR (151 MHz, CDCl3): d ppm 145.9, 145.2, 141.4, 137.8, 135.7, 133.0,
4.2.17. 2-(4-Chlorophenyl)-7-methoxy-2H-indazole (6d)
129.9, 123.7, 122.6, 105.0. LC-MS: 230[MþH]þ, tR ¼ 2.08 min. HRMS
(ESI): m/z calcd for C12H9N3Cl [MþH]þ 230.0485, found [MþH]þ
230.0489.
27 mg (16% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3):
d
ppm 8.35 (s, 1H), 7.84e7.98 (m, 2H), 7.39e7.53 (m, 2H), 7.20e7.32
(m, 1H), 7.05 (dd, J ¼ 7.4, 8.4 Hz,1H), 6.61 (d, J ¼ 7.34 Hz,1H), 4.07 (s,
3H). 13C NMR (151 MHz, CDCl3, mixture):
ppm 150.4, 143.5, 138.9,
d
4.2.25. 1-(4-Chlorophenyl)-3-methyl-1H-indazole (5l)
130 mg (70% yield) as a white solid. 1H NMR (400 MHz, CDCl3):
133.5, 129.5, 124.5, 123.4, 122.1, 120.5, 112.3, 103.4, 55.5. LC-MS: 259
[MþH], tR ¼ 3.58 min.
d
ppm 7.76 (d, J ¼ 8.0 Hz, 1H), 7.69 (d, J ¼ 8.8 Hz, 3H), 7.42e7.54 (m,
3H), 7.21e7.27 (m, 1H), 2.68 (s, 3H). 13C NMR (151 MHz, CDCl3):
4.2.18. 1-(4-Chlorophenyl)-5-fluoro-1H-indazole (5e)
d
ppm 144.4, 139.4, 138.9, 131.4, 129.5, 127.4, 125.1, 123.3, 121.1,
140 mg (80% yield) as an orange solid. 1H NMR (400 MHz,
120.8, 110.1, 11.9. LC-MS: 243[MþH]þ, tR ¼ 4.07 min. HRMS (ESI): m/
z calcd for C14H12N2Cl [MþH]þ 243.0689, found [MþH]þ 243.0689.
CDCl3):
d
ppm 8.19 (s, 1H), 7.68 (d, J ¼ 8.8 Hz, 3H), 7.54 (d, J ¼ 8.4 Hz,
2H), 7.45 (dd, J ¼ 2.0, 8.4 Hz, 1H), 7.20e7.28 (m, 2H). 13C NMR
(151 MHz, CDCl3,):
d ppm 159.4, 157.0, 138.4, 135.7, 135.4, 132.4,
4.2.26. 1-(4-Chlorophenyl)-1H-indole (8)
129.7, 123.7, 117.0, 116.7, 111.3, 105.5.19F NMR (376 MHz, CDCl3):
72 mg (37% yield) as yellow oil. 1H NMR (400 MHz, CDCl3):
ppm 7.71 (d, J ¼ 7.6 Hz, 1H), 7.41e7.58 (m, 5H), 7.32 (d, J ¼ 3.2 Hz,
d
ppm 121.60 (s, 1F). LC-MS: 247 [MþH]þ, tR ¼ 4.00 min. HRMS
d
(ESI): m/z calcd for C13H9N2ClF [MþH]þ 247.0438, found [MþH]þ
1H), 7.17e7.27 (m, 2H), 6.72 (d, J ¼ 2.8 Hz, 1H). 13C NMR (151 MHz,
247.0444.
CDCl3):
d ppm 138.4, 135.7, 132.0, 129.8, 129.4, 127.7, 125.5, 122.6,
121.3, 120.6, 110.3, 104.1. LC-MS: 228[MþH]þ, tR ¼ 2.08 min. HRMS
(ESI): m/z calcd for C14H11NCl [MþH]þ 228.058, found [MþH]þ
228.0578.
4.2.19. 5-Chloro-1-(4-chlorophenyl)-1H-indazole (5f)
149 mg (91% yield) as an orange solid. 1H NMR (400 MHz,
CDCl3): d ppm 8.17 (s, 1H), 7.80 (br s, 1H), 7.63e7.71 (m, 3H), 7.54 (d,
J ¼ 8.8 Hz, 2H), 7.42 (dd, J ¼ 2.0, 9.2 Hz, 1H). 13C NMR (151 MHz,
4.2.27. 1-(4-Chlorophenyl)indolin-2-one (10)
148 mg (81% yield) as a white solid. 1H NMR (400 MHz, CDCl3):
CDCl3):
d ppm 138.4, 137.2, 135.0, 132.5, 129.7, 128.0, 127.4, 126.3,
123.8, 120.6, 111.3. LC-MS: 263 [MþH]þ, tR ¼ 4.17 min. HRMS (ESI):
d
ppm 7.53 (d, J ¼ 8.8 Hz, 2H), 7.31e7.43 (m, 3H), 7.25 (t, J ¼ 8.0 Hz,
13H9N2Cl2 [MþH]þ 263.0143, found [MþH]þ
1H), 7.06e7.16 (m, 1H), 6.81 (d, J ¼ 8.0 Hz, 1H), 3.74 (s, 2H). 13C NMR
m/z calcd for
263.0142.
C
(151 MHz, CDCl3):
d ppm 174.3, 144.8, 133.7, 133.1, 129.9, 127.9,
124.8, 124.3, 123.1, 109.3, 36.0. LC-MS: 244[MþH]þ, tR ¼ 4.20 min.
HRMS (ESI): m/z calcd for C14H11NOCl [MþH]þ 244.0529, found
[MþH]þ 244.0529.
4.2.20. 5-Bromo-1-(4-chlorophenyl)-1H-indazole (5g)
123 mg (79% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3):
d
ppm 8.17 (s, 1H), 7.97 (s, 1H), 7.67 (d, J ¼ 8.8 Hz, 2H), 7.60 (s, 1H),
7.49e7.57 (m, 3H). 13C NMR (151 MHz, CDCl3):
d
ppm 138.3, 137.4,
Acknowledgements
134.9, 132.6, 130.5, 129.7, 127.0, 123.9, 123.8, 122.1, 114.8, 111.6. LC-
MS: 306.9 [MþH]þ, tR ¼ 4.26 min. HRMS (ESI): m/z calcd for
We thank Dr. Ruina Gao (GlaxoSmithKline) for HRMS analysis,
and Dr. Yingxia Sang (GlaxoSmithKline) for helpful discussions.
C
13H9N2ClBr [MþH]þ 306.9638, found [MþH]þ 306.9643.
4.2.21. 1-(4-Chlorophenyl)-5-(trifluoromethyl)-1H-indazole (5h)
Appendix A. Supplementary data
113 mg (71% yield) as a white solid. 1H NMR (400 MHz, CDCl3):
d
ppm 8.33 (s, 1H), 8.16 (s, 1H), 7.80 (d, J ¼ 8.8 Hz, 1H), 7.69 (d,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2016.11.066.
J ¼ 8.0 Hz, 3H), 7.57 (d, J ¼ 8.8 Hz, 2H). 13C NMR (151 MHz, CDCl3):
d
ppm 139.7, 138.1, 136.5, 133.0, 129.8, 124.1, 124.0, 119.6, 110.8.19
F
NMR (376 MHz, CDCl3):
d
ppm ꢄ61.08 (s, 1F). LC-MS: 297[MþH]þ,
References
tR ¼ 4.23 min. HRMS (ESI): m/z calcd for C14H9N2ClF3 [MþH]þ
297.0406, found [MþH]þ 297.0407.
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4.2.22. 1-(4-Chlorophenyl)-1H-indazole-5-carbonitrile (5i)
152 mg (86% yield) as a white solid. 1H NMR (400 MHz, CDCl3):
d
ppm 8.34 (s, 1H), 8.24 (s, 1H), 7.78 (d, J ¼ 8.8 Hz, 1H), 7.67 (d,
J ¼ 8.8 Hz, 3H), 7.50e7.61 (m, 2H). 13C NMR (151 MHz, CDCl3):
d ppm
139.5,137.7,136.3,133.4,129.9,129.6,127.8,125.0,124.3,119.2,111.4,
105.4. LC-MS: 254 [MþH]þ, tR ¼ 3.63 min. HRMS (ESI): m/z calcd for
C
14H9N3Cl [MþH]þ 254.0485, found [MþH]þ 254.0491.
4.2.23. Methyl 1-(4-chlorophenyl)-1H-indazole-5-carboxylate (5j)
148 mg (91% yield) as a white solid. 1H NMR (400 MHz, CDCl3):
d
ppm 8.60 (s, 1H), 8.33 (s, 1H), 8.15 (d, J ¼ 8.8 Hz, 1H), 7.67e7.79 (m,
(b) Bryan MC, Dillon B, Hamann LG, et al. J Med Chem. 2013;56:6007.
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Rev. 2012;56:62;
3H), 7.56 (d, J ¼ 8.8 Hz, 2H), 3.99 (s, 3H). 13C NMR (151 MHz, CDCl3):
d
ppm 166.9, 140.5, 138.2, 137.1, 129.7, 128.3, 125.2, 124.8, 124.0,
ꢀ
(b) Salome C, Wagner P, Bollenbach M, Bihel F, Bourguignon J-J, Schmitt M.
109.2, 52.2. LC-MS: 287[MþH]þ, tR ¼ 3.87 min. HRMS (ESI): m/z
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4.2.24. 1-(4-Chlorophenyl)-1H-pyrazolo[4,3-c]pyridine (5k)
122 mg (63% yield) as a white solid. 1H NMR (400 MHz, CDCl3):
Please cite this article in press as: Ding X, et al., A mild and regioselective Ullmann reaction of indazoles with aryliodides in water, Tetrahedron
(2016), http://dx.doi.org/10.1016/j.tet.2016.11.066

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Please cite this article in press as: Ding X, et al., A mild and regioselective Ullmann reaction of indazoles with aryliodides in water, Tetrahedron
(2016), http://dx.doi.org/10.1016/j.tet.2016.11.066