Rh(III)-Catalyzed C-H Cyanation of 2 H-Indazole with N-Cyano- N-phenyl- p-toluenesulfonamide

Article abstract of DOI:10.1021/acs.joc.0c01386

A Rh(III)-catalyzed direct cyanation of 2H-indazoles with N-cyano-N-phenyl-p-toluenesulfonamide has been realized via a chelation-assisted strategy. The methodology enables regioselective access to various ortho-cyanated phenylindazoles in good yields with a broad substrate scope and good functional group compatibility. The obtained cyanated indazoles could further be converted into other value-added chemicals. Importantly, the current protocol is featured with several characteristics, including a novel cyanating agent, good regioselectivity, and operational convenience.

Full text of DOI:10.1021/acs.joc.0c01386

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Article
Rh(III)-Catalyzed C-H Cyanation of 2H-Indazole
with N-Cyano-N-phenyl-p-toluenesulfonamide
Jing Li, Linlin Shi, Shu-Ping Zhang, Xu-Yan Wang, Xinju Zhu, Xin-Qi Hao, and Mao-Ping Song
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01386 • Publication Date (Web): 21 Jul 2020
Downloaded from pubs.acs.org on July 21, 2020
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Page 1 of 12
The Journal of Organic Chemistry
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Rh(III)-Catalyzed C−H Cyanation of 2H-Indazole with N-Cyano-N-phenyl-p-
toluenesulfonamide
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Jing Li, Linlin Shi, Shu-Ping Zhang, Xu-Yan Wang, Xinju Zhu,* Xin-Qi Hao, and Mao-Ping Song*
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College of Chemistry, Zhengzhou University, No. 100 of Science Road, Zhengzhou, Henan 450001, P. R. China
Email: zhuxinju@zzu.edu.cn (X.Z); mpsong@zzu.edu.cn (M.P.S)
KOAc (60 mol%)
AgSbF6 (40 mol%)
CN
H
NC
R1
[Cp*RhCl2]2 (5 mol%)
DCE, 120 oC, 24 h, air
R1
N
+
Ts
N
N
N
R2
N
R2
NCTS
Indazole-directed C-H cyanation
Operational convenience
Safe "nonmetallic" cyanating reagent
High efficiency
ABSTRACT: A Rh(III)-catalyzed direct cyanation of 2H-indazoles with N-Cyano-N-phenyl-p-toluenesulfonamide has been realized via
chelation-assisted strategy. The methodology enables regioselective access to various ortho-cyanated phenylindazoles in good yields with
broad substrate scope and good functional group compatibility. The obtained cyanated indazoles could further be converted into other value-
added chemicals. Importantly, the current protocol is featured with several characteristics, including novel cyanating agent, good
regioselectivity, and operational convenience.
applications. It is thus highly advisable to develop a cyanation
methodology assisted by an auxiliary moiety suitable for other
utility.
INTRODUCTION
Aromatic nitriles are versatile in nature products with diverse
applications in pharmaceuticals, dyes, agrochemicals, and
materials.1 In particular, the nitrile group allows multiple
transformations to other important functional groups, such as
amines, amidines, tetrazoles, aldehydes, and amides.2 Traditionally,
Rosenmund-von Braun reaction of aryl halides and Sandmeyer
reaction of aryldiazonium salts with a stoichiometric amount of
copper cyanide salt were the two most employed methods to access
aromatic nitriles.3 To date, various cyanide anion sources, including
KCN, CuCN, NaCN, Zn(CN)2, TMSCN, and K4Fe(CN)6 have
been reported via nucleophilic cyanation (Scheme 1a).4 However,
prefunctionalized substrates and potential toxic metal cyanating
reagents are required. Alternatively, the utilization of non-metallic
organic cyano-group sources, including cyanogen halides,5
cyanamides,6 cyanates,7 thiocyanates,8 and alkyl nitriles,9 would
Scheme 1. C−H functionalization of 2-arylindazoles
a) Nucleophilic cyanation and electrophilic cyanation
Electrophilic
cyanation
Nucleophilic
cyanation
CN
X
CN
Ar
Ar
Ar
ECN
MCN
E
M
= K, Cu, Na, Zn, etc.)
(
= Br, I, C, N, O, S)
(
b) C3-functionalizations of 2-arylindazoles
H
C3
R
C3
ref 23
N
N
N
N
c) Chelation-assisted C2'-functionalizations of 2-arylindazoles
H
C2'
R
C2'
ref 24
N
N
N
N
provide
a complementary synthetic route via electrophilic
d) Present work: C2'-cyanation of 2-arylindazoles with NCTS
cyanation (Scheme 1a).10 In addition, in situ generated cyano units
from readily available organic precursors have also been
successfully achieved for cyanation reactions.11
H
C2'
NC
C2'
R1
R1
Rh(III)
+
NCTS
N
N
under air
R2
N
R2
N
Very recently, transition-metal-catalyzed C−H activation has
emerged as a powerful approach to construct various chemical
bonds via a chelation-assisted strategy.12 In this context, N-cyano-
N-phenyl-p-methylbenzenesulfonamide (NCTS) have attracted
much attention in C−H cyanation reactions as a representative
non-toxic, bench-stable, and readily accessible electrophilic
cyanamide.13 Inspired by the pioneering work of Beller and Wang,14
the groups of Fu,15 Anbarasan,16 Ackermann,17 Chang,18 Glorius,19
and others20 have successfully developed C−H cyanation of
(hetero)arenes assisted by oxime, pyridine, pyrimidine, pyrazole,
ketone, and other directing groups. Despite the above progress,
deprotection of such directing groups is usually required for further
Indazoles have been recognized as an important class of N-
heterocycles due to their prevalence in natural products,
pharmaceutics, and bioactive compounds.21 Consequently, great
efforts have been made to synthesize and functionalize 2H-indazole
derivatives.22,23 However, most elaborations of 2H-indazoles are
reported at the C3 position (Scheme 1b).23 Recently, chelation-
assisted strategy has also been utilized for the selective
functionalization of 2-arylindazole moiety (Scheme 1c).24 For
example, the groups of Punniyamurthy and Fan have
independently developed annulation of 2-arylindazoles with
alkynes,24a azabenzonorbornadienes,24b maleimides,24c and α-diazo
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carbonyl compounds24d to access polyaromatic structures. Hajra
15bc
16bd
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2/AgSbF6
KOAc
KOAc
DCE
DCE
80
86
1
2
3
4
5
6
7
8
and co-workers have reported ortho-C–H functionalization of 2-
arylindazoles with dioxazolones and maleimides.24e,f On the other
hand, our group has developed N,O-bidentate directing group-
assisted C-H alkoxylation and alkynylation/annulation.25
Meanwhile, chelation-assisted C-H allylation and sulfonylation of
indolines have also been successfully achieved.26 As a continuation
of our previous work,25-27 we herein firstly report Rh-catalyzed
indazole-directed C-H cyanation using NCTS as the cyanating
agent (Scheme 1d). Importantly, as an intrinsic pharmacophore,
deprotection of indazole might be not required, which is more
atom economy.28
aReaction conditions: 1a (0.1 mmol), NCTS (0.25 mmol), Catalyst (5 mol%),
Ag salt (40 mol%), Base (50 mol%), Solvent (1.0 mL), 24 h, 120 oC. Isolated
yield. bBase (60 mmol%). c[Cp*RhCl2]2 (3 mmol%). d[Cp*RhCl2]2 (7 mmol%).
TCP = 1,2,3-Trichloropropane.
With optimized conditions in hand (Table 1, entry 10), the
substrate scope of 2-phenyl-2H-indazoles was investigated (Table
2). Initially, N2-substituted 2-arylindazoles were systematically
examined. Both electron-donating (Me, OMe and tBu,) and
electron-withdrawing (CO2Me, Br, Cl, and CF3) groups at the
para-position were well tolerated to afford the corresponding
products 2a-h in 53-90% yields. For meta-substituted 2-phenyl-2H-
indazoles, regioselective cyanation took place at the sterically less
hindered position to provide cyanated products 2i-2o in 55-95%
yields. When Me or OMe substituents locate at the ortho position,
the desired cyanated product 2p and 2q could also be obtained in
94% and 73% yield, respectively. Overall, compared with electron-
deficient 2-arylindazoles, the ones bearing electron-donating
groups exhibited increased reactivity. Nevertheless, when 2-
arylindazoles bearing electron-withdrawing groups were heated in
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RESULTS AND DISCUSSION
Our initial investigation started with reaction of 2-phenyl-2H-
indazole 1a and NCTS using [Cp*RhCl2]2/AgSbF6 as the catalyst
and NaOAc as the base (Table 1). To our delight, the desired
cyanated product 2a was isolated in 27% yield in MeCN at 120 °C
for 24 h (Table 1, entry 1). Subsequently, the effect of solvent was
investigated, and DCE displayed the best activity to afford 2a in
81% yield (Table 1, entry 4). Next, other base and base loading
were systematically employed (Table 1, entries 6-10). When 60
mmol% KOAc was employed, product 2a could be obtained in 90%
yield (Table 1, entry 10). In addition, replacement of [Cp*RhCl2]2
and AgSbF6 by other catalysts all gave inferior results (Table 1,
entries 11-14). Moreover, when the catalyst loading was modulated,
cyanated product 2a was also isolated in in decreased yield (Table 1,
entries 15 and 16). Finally, either elevating or lowering temperature
was detrimental to the reaction efficiency (see the Supporting
Information). The molecular structure of 2a was further confirmed
by X-ray diffraction (see the supporting information).
o
TCP at 130 C using t-BuOK as the base, satisfied yields could still
be obtained, probably due to the comparable reactivity and high
boiling point of TCP (Table 1, entry 5).
Table 2. Substrate Scope of N2-substituted 2H-indazolesa
KOAc (60 mol%)
AgSbF6 (40 mol%)
[Cp*RhCl2]2 (5 mol%)
DCE, 120 oC, 24 h, air
CN
N
NC
2
H
Ts
N
N
R1
R1
N
N
1
NCTS
NC
NC
NC
Table 1. Optimization of reaction conditionsa
N
N
Me
N
OMe
Base (50 mol%)
Ag salt (40 mol%)
Catalyst (5 mol%)
Solvent, 120 oC, 24 h
N
N
N
CN
N
H
NC
2a,
2b,
2c,
90%
70%
66%
Ts
N
N
N
N
NC
NC
NC
under air
1a
NCTS
2a
N
tBu
N
CO2Me
N
Cl
N
N
N
b
b
Entry
1
Catalyst/Ag salt
Base
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOH
DABCO
NaCO3
KOAc
Solvent
Yield(%)
27
2d,
2e,
2f,
80%
71%
67%
NC
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2/AgSbF6
[Cp*IrCl2]2/AgSbF6
[Cp*RuCl2]2/AgSbF6
RhCl3/AgSbF6
MeCN
Dioxane
DMF
DCE
TCP
NC
NC
N
2
65
N
N
Br
N
CF3
N
N
Me
3
14
b
b
2g,
2h,
2i,
66%
53%
95%
NC
N
4
81
NC
NC
5
74
N
N
N
N
N
6
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
18
OMe
F
Cl
b
b
2j,
78%
NC
N
2k,
2l,
55%
80%
7
55
NC
NC
8
37
N
N
N
N
N
9
84
CO2Et
CF3
Br
b
b
10b
11b
12b
13b
14b
KOAc
90
2m,
2n,
2o,
62%
76%
63%
NC
NC
KOAc
N.R.
N.R.
N.R.
83
N
N
KOAc
N
N
MeO
94%
Me
KOAc
2p,
2q,
73%
[Cp*RhCl2]2/AgOTf
KOAc
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The Journal of Organic Chemistry
aReaction conditions: 1a (0.1 mmol), NCTS (0.25 mmol), [Cp*RhCl2]2 (5
KOAc (60 mol%)
AgSbF6 (40 mol%)
[Cp*RhCl2]2 (5 mol%)
DCE, 120 oC, 24 h, air
mol%), AgSbF6 (40 mol%), KOAc (60 mol%), DCE (1.0 mL), 24 h, 120 oC.
CN
N
H
NC
1
2
3
4
5
6
7
8
Isolated yield. bt-BuOK (60 mol%), 1,2,3-Trichloropropane (1 mL), 130 oC.
Ts
R2
R2
N
N
N
N
Encouraged by the above results, the generality of the current
protocol was further expanded by employing substrates bearing
substitutions on the indazole ring (Table 3). In general, various
functional groups, including methoxyl, halogen, and ester, at either
C5 or C6 positions were all compatible to deliver the
corresponding products 4a-j in 62-83% yields irrespective of
electronic effect. No dehalogenation was observed during the
reaction for halo-substituted indazoles, which enabled further
3
4
NCTS
NC
NC
NC
MeO
F
Cl
N
N
N
N
N
N
4a,
4b,
4c,
62%
83%
NC
66%
NC
NC
9
Br
N
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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60
functionalizations.
Notably,
2-phenyl-2H-[1,3]dioxolo[4,5-
N
N
N
Me
Cl
MeO
f]indazole bearing two oxygen atom at both C5 and C6 positions
could furnish the desired product 4k in 87% yield. With substrates
bearing substituents at both indazole ring and N2-phenyl ring,
products 4l-o could also be isolated in 68-82% yields. Next,
pyrazole was also utilized as the directing group, which provided
product 4p in 84% yield with comparable efficiency15a and identical
regioselectivity29 compared with previous literatures. Finally, 1-
phenyl-1H-indazole and 1-methyl-3-phenyl-1H-indazole were also
proved as suitable
b
4e,
4h,
4k,
4f,
4i,
80%
NC
80%
4d,
4g,
4j,
76%
NC
NC
N
N
N
N
N
N
F
Br
80%
66%
NC
75%
NC
NC
Cl
O
O
N
N
N
Me
N
N
N
MeO2C
4l,
63%
87%
NC
81%
NC
Table 3. Substrate Scope of 2H-indazoles bearing substitutions on
the indazole ringa
NC
N
F
Br
N
N
Me
Me
N
N
N
MeO
Cl
4m,
4n,
4o,
72%
68%
82%
N
CN
N
NC
CN
N
N
N
N
4p,
4q,
4r,
92%
84%
92%
N
N
Unsuccessful substrates
N
N
N
N
2-methyl-2H-indazole
2-methyl-7-phenyl-2H-indazole 1-methyl-1H-indazole
aReaction conditions: 1a (0.1 mmol), NCTS (0.25 mmol), [Cp*RhCl2]2 (5
mol%), AgSbF6 (40 mol%), KOAc (60 mol%), DCE (1.0 mL), 24 h, 120 oC.
btBuOK (60 mol%), 1,2,3-Trichloropropane (1 mL), 130 oC.
substrates to give the corresponding products 4q and 4r in both
92% yields. Unfortunately, for 2-methyl-2H-indazole, 2-methyl-7-
phenyl-2H-indazole, and 1-methyl-1H-indazole, no desired
cyanated products could be detected.
To gain insight in the cyanation mechanism, a set of control
experiments were conducted (Scheme 2). First, an H/D
exchangeexperiment was carried out under the optimized
conditions using CD3OD or MeOH as a co-solvent. Analysis of the
1H NMR spectra showed that 71% of the ortho-C-H in 1a was
deuterated and 97% of the ortho-C-D in 1a-d5 was hydrogenated
after 3 h, indicating cleavage of C-H bond is reversible (Scheme 2a).
Subsequently, the kinetic isotope effect (KIE) parallel and
competitive experiments of substrate 1a or/and 1a-d5 with NCTS
was performed (Scheme 2b). KIE values of 1.34 and 1.18 were
obtained, respectively, by NMR analysis, suggesting C-H activation
may not be involved in the rate-determining step. Finally, an
intermolecular competition reaction between 1c and 1e was
performed (Scheme 2c). Compared with the electron-poor group
(CO2Me), the electron-rich one (OMe) exhibit a higher reactivity.
3
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Scheme 2. Mechanistic Studies
a) H/D Exchange Experiment
reversible C−H rodation. Subsequently, coordination and
1
2
3
4
5
6
7
8
subsequent migratory insertion of the CN group of NCTS into the
C−Rh bond affords intermediates B and C, which are generally
considered to be the key intermediates in the cyanation reaction.
Then, β-amine elimination from C provides cyanated intermediate
D. Finally, after treatment with HOAc, the cyanated product 2a was
obtained accompanied by regeneration of reactive rhodium species
to fulfill the catalytic cycle.
~71%D
KOAc (60 mol%)
AgSbF6 (40 mol%)
[RhCp*Cl2]2 (5 mol%)
D/H
H
H
H
N
H
D
N
H
MD3OD
DCE, 3 h, 120 o
C
N
N
D/H
H
H
1a
H
D
~71%D
1a-
d2
~97%H
KOAc (60 mol%)
AgSbF6 (40 mol%)
[RhCp*Cl2]2 (5 mol%)
D
D/H
D
MeOH
N
D
N
DCE, 3 h, 120 o
C
N
N
Scheme 4. The possible reaction mechanism
D
D
D/H
D
9
~97%H
1a-
d3
1a-
d5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
b) KIE experiment
N
N
KOAc (60 mol%)
AgSbF6 (40 mol%)
[RhCp*Cl2]2 (5 mol%)
[Cp*Rh(III)]
AgCl
2a
1a
CN
H
H4
D4
H4/D4
HOAc
or
H
N
N
N
N
N
NCTS
(0.25 mmol)
AgSbF6
[RhCp*Cl2]2
N
N
N
DCE, 30-70 min
120 oC, KH/KD = 1.34
H
D
NC
1a
1a
2a 2a
-d5
or -d4
N
N
N
N
KOAc (60 mol%)
AgSbF6 (40 mol%)
[RhCp*Cl2]2 (5 mol%)
Proposed
Mechanism
Rh
Cp*
CN
H4
D4
H4/D4
Rh
A
*Cp
D
N
N
N
N
NC
NCTS
DCE, 40 min, 120 o
(0.25 mmol)
Ph
NH
Ts
NCTS
C
H
D
KH/KD = 1.18
1a
1a
2a
2a
-d5
and -d4
N
N
c) Intermolecular Competition Experiment
H
N
N
NC
Ph
Ph
Rh
N
Rh
N
standard conditions
N
C N
*Cp
*Cp
NCTS
N
R
N
R
Ts
Ts
N
N
C
B
1c 1e
/
R = OMe/COOMe
2c/2e =
10/1
= 1/1
CONCLUSION
In conclusion, we have firstly developed a useful synthetic
method to prepare aryl nitriles through Rh-catalyzed indazole-
directed cyanation using NCTS as the cyano source. Under
optimized conditions, a broad range of substrates was well tolerated
to regioselectively afford ortho-cyanated phenylindazole scaffolds
in good to excellent yields. The H/D exchange and KIE
experiments indicate that a reversible C-H activation is not the rate-
determining step. Considering the importance of the indazole
pharmacophore, deprotection of the directing group is not
required, which would provide an alternative way of thinking in
chelation-assisted strategies.
To demonstrate the synthetic utility of this Rh-catalyzed
cyanation reaction, a gram-scale reaction was performed to give
C2’-cyanated product 2a in 85% yield (Scheme 3). This protocol
was further highlighted by successful conversion of cyanated
phenylindazole 2a into aminomethyl 5 in 82% yield, which is very
difficult to realize from indazole.15a During the course of these
studies, we also did derivatization reactions to transform cyanated
product 2a to its corresponding amide 6 and ester 7 in 67% and
52%, respectively.15a,17b
EXPERIMENTAL SECTION
Scheme 3. Gram-scale synthesis and derivatization reactions
General Information All the reagents were commercially obtained
and used without further purification unless otherwise noted. 2H-
Indazoles and NCTS are known compounds and synthesized
according to previous references.14,30 1H-Indazoles 2q and 2r,23b,31
2-methyl-2H-indazole,32 2-methyl-7-phenyl-2H-indazole,32 and 1-
methyl-1H-indazole31 have also been prepared according known
literatures. Melting points were measured by XT4A melting point
apparatus without correction. Silica gel of 200-300 mesh was used
to perform flash column chromatography. Analytical and
preparative thin-layer chromatography (TLC) plates coated with
commercial silica gel GF254 were used to monitor reaction and
purify products. 1H NMR, 13C NMR and 19F NMR spectra were
recorded at 400 MHz or 600 MHz, 101 MHz or 151 MHz, and 376
MHz respectively on a Bruker DPX instrument using TMS as an
internal standard. Data are reported as follows: chemical shift (δ
ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet), integration, and coupling constants (J) in hertz
(Hz). HRMS were determined on a Q-Tof Micro or AB SCIEX
H
N
N
1a
, 1g
Gram scale
standard condition
NH2
NH2
CN
O
N
KOH, tBuOH
60 °C, 4 h
LiAlH4
N
N
THF, 0 °C
N
N
N
5
2a
6
, 67%
, 82%
, 965 mg (85%)
H2SO4(conc)
MeOH, H2O, 90 °C, 24 h
CO2Me
N
N
7
, 52%
Based on the above discussion and relevant literature, a plausible
reaction mechanism was proposed (Scheme 4). First, an in situ
generated active cationic Rh(III) species coordinates with 2-
phenyl-2H-indazole 1a to afford a five-membered rodacycle A via
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MHz, CDCl3) δ 8.73 (d, J = 0.6 Hz, 1H), 8.52 (d, J = 1.8 Hz, 1H),
TripleTOF 6600 MS/MS System ESI spectrometer. The structure
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of product 2a (CCDC number 1974597) was further confirmed by
X-ray diffraction collected on a diffractometer with graphite-
monochromated Cu Kα radiation.
8.40 (dd, J = 8.6, 1.9 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 7.78 (dd, J
= 8.9, 0.7 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.39 – 7.35 (m, 1H),
7.16 (dd, J = 8.2, 6.9 Hz, 1H), 4.00 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 164.3, 150.6, 145.0, 136.2, 134.9, 130.0, 128.3,
125.6, 123.6, 123.4, 123.1, 120.8, 118.1, 116.1, 106.2, 53.0; HRMS
(ESI) m/z: [M + H]+ Calcd for C16H12N3O2 278.0924; Found
278.0925.
General Procedure for Cyanation. To a 35 mL oven-dried sealed
tube, 2H-Indazole 1 or 3 (0.1 mmol), NCTS (63 mg, 0.25 mmol)
and [Cp*RhCl2]2 (3.1 mg, 5 mol%) were added under open air
conditions. AgSbF6 (13.7 mg, 40 mol %) and KOAc (5.9 mg, 60
mol %) were weighed and added to the tube in the glove box. And
then DCE (1 mL) was added to the tube under air. The tube was
5-Chloro-2-(2H-indazol-2-yl)benzonitrile (2f). Purified by TLC
on silica gel with PE/acetone = 9/1 as an eluent (Rf = 0.52); white
solid (17 mg, 67%); mp 152-153 oC; 1H NMR (400 MHz, CDCl3)
δ 8.59 (d, J = 0.8 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 2.3
Hz, 1H), 7.77 (dd, J = 8.9, 0.9 Hz, 1H), 7.75 – 7.73 (m, H), 7.72 –
7.71 (m, 1H), 7.38 – 7.34 (m, 1H), 7.17 – 7.13 (m, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 150.4, 140.9, 134.3, 133.9, 128.0,
127.1, 123.4, 123.3, 123.0, 120.7, 118.0, 115.4, 107.7; HRMS (ESI)
m/z: [M + H]+ Calcd for C14H9ClN3 254.0480; Found 254.0481.
5-Bromo-2-(2H-indazol-2-yl)benzonitrile (2g). purified by TLC
on silica gel with PE/acetone = 7/1 as an eluent (Rf = 0.48); faint
yellow solid (19.6 mg, 66%); mp 127-128 oC; 1H NMR (400 MHz,
CDCl3) δ 8.60 (d, J = 0.8 Hz, 1H), 7.97 – 7.96 (m, 1H), 7.89 – 7.88
(m, 2H), 7.77 (dd, J = 8.9, 0.9 Hz, 1H), 7.74 – 7.71 (m, 1H), 7.39 –
7.34 (m, 1H), 7.17 – 7.13 (m, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 150.4, 141.3, 137.3, 136.8, 128.0, 127.2, 123.4, 123.3,
123.0, 121.7, 120.7, 118.0, 115.3, 107.9; HRMS (ESI) m/z: [M +
H]+ Calcd for C14H9BrN3 297.9974; Found 297.9973.
9
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sealed and placed in a preheated oil bath at 120 C for 24 h. After
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the reaction was completed, the reaction mixture was cooled to
room temperature and concentrated under vacuo. The crude
mixture was purified by preparative thin-layer chromatography to
give the desired product 2 or 4.
2-(2H-indazol-2-yl)benzonitrile (2a). Purified by TLC on silica gel
with petroleum ether (PE)/acetone = 10/1 as an eluent (Rf = 0.37);
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faint yellow solid (19.7 mg, 90% yield); mp 136-137 C; H NMR
(400 MHz, CDCl3) δ 8.60 (d, J = 0.7 Hz, 1H), 7.96 (dd, J = 8.2, 0.5
Hz, 1H), 7.85 (dd, J = 7.8, 1.3 Hz, 1H), 7.80 – 7.73 (m, 3H), 7.53
(td, J = 7.7, 1.0 Hz, 1H), 7.38 - 7.34 (m, 1H), 7.17 – 7.13 (m, 1H);
13C{1H} NMR (151 MHz, CDCl3) δ 150.3, 142.4, 134.5, 134.0,
128.4, 127.7, 126.0, 123.4, 123.1, 122.9, 120.7, 118.1, 116.6, 106.9;
HRMS (ESI) m/z: [M + H]+ Calcd for C14H10N3 220.0869; Found
220.0870.
2-(2H-indazol-2-yl)-5-methylbenzonitrile (2b). Purified by TLC
on silica gel with PE/ethyl acetate (EA) = 6/1 as an eluent (Rf =
2-(2H-indazol-2-yl)-5-(trifluoromethyl)benzonitrile (2h). Purified
by TLC on silica gel with PE/acetone = 6/1 as an eluent (Rf =
o
1
0.46); white solid (16.3 mg, 70%); mp 129-129 C; H NMR (400
MHz, CDCl3) δ 8.55 (d, J = 0.6 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H),
7.78 (dd, J = 8.9, 0.9 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.63 (s,
1H), 7.56 (dd, J = 8.3, 1.2 Hz, 1H), 7.37 – 7.33 (m, 1H), 7.16 –
7.12 (m, 1H), 2.47 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
150.1, 140.1, 139.1, 134.8, 134.6, 127.5, 125.8, 123.4, 122.9, 122.8,
120.7, 118.0, 116.7, 106.6, 20.8; HRMS (ESI) m/z: [M + H]+
Calcd for C15H12N3 234.1026; Found 234.1025.
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0.54); faint yellow solid (15.2 mg, 53%); mp 91-92 C ; H NMR
(400 MHz, CDCl3) δ 8.72 (d, J = 0.8 Hz, 1H), 8.21 (d, J = 8.6 Hz,
1H), 8.11 (d, J = 1.3 Hz, 1H), 8.02 (dd, J = 8.7, 1.6 Hz, 1H), 7.78
(dd, J = 8.9, 0.9 Hz, 1H), 7.75 – 7.72 (m, 1H), 7.40 – 7.36 (m, 1H),
7.19 – 7.15 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 150.7,
144.6, 131.9 (JC-F = 3.8 Hz), 130.9 (JC-F = 3.5 Hz), 130.6 (JC-F
=
34.1 Hz), 128.4, 126.3, 123.7, 123.3, 123.2, 122.6 (JC-F = 272.2 Hz),
120.8, 118.1, 115.6, 106.6; 19F NMR (376 MHz, CDCl3) δ -63.5;
HRMS (ESI) m/z: [M + H]+ Calcd for C15H9F3N3 288.0743;
Found 288.0745.
2-(2H-indazol-2-yl)-4-methylbenzonitrile (2i). Purified by TLC on
silica gel with PE/EA = 9/1 as an eluent (Rf = 0.34); faint yellow
solid (22.1 mg, 95%); mp 137-138 oC . 1H NMR (400 MHz,
CDCl3) δ 8.60 (d, J = 0.8 Hz, 1H), 7.80 – 7.77 (m, 2H), 7.74 – 7.71
(m, 2H), 7.38 – 7.32 (m, 2H), 7.16 – 7.12 (m, 1H), 2.51 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 150.1, 145.7, 142.2, 134.3,
129.3, 127.7, 126.6, 123.5, 123.0, 122.8, 120.7, 117.9, 116.9, 103.6,
21.9; HRMS (ESI) m/z: [M + H]+ Calcd for C15H12N3 234.1026;
Found 234.1025.
2-(2H-indazol-2-yl)-5-methoxybenzonitrile (2c). Purified by TLC
on silica gel with PE/acetone = 14/1 as an eluent (Rf = 0.41);
yellow solid (16.4 mg, 66%); mp 120-121 oC; 1H NMR (400 MHz,
CDCl3) δ 8.48 (s, 1H), 7.83 – 7.80 (m, 1H), 7.78 (dd, J = 8.8, 0.9
Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.37 – 7.33 (m, 1H), 7.27 (d, J =
8.5 Hz, 2H), 7.16 – 7.12 (m, 1H), 3.90 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 159.1, 150.0, 135.8, 127.5, 127.4, 123.5,
122.8, 122.7, 120.6, 120.3, 118.3, 117.9, 116.3, 107.9, 56.1; HRMS
(ESI) m/z: [M + H]+ Calcd for C15H12N3O 250.0975; Found
250.0976.
5-(tert-Butyl)-2-(2H-indazol-2-yl)benzonitrile (2d). Purified by
TLC on silica gel with PE/acetone = 6/1 as an eluent (Rf = 0.52);
colorless oil (22 mg, 80%); 1H NMR (400 MHz, CDCl3) δ 8.57 (d,
J = 0.8 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 2.1 Hz, 1H),
7.80 – 7.79 (m, 1H), 7.78 – 7.77 (m, 1H), 7.75 – 7.72 (m, 1H),
7.37 – 7.33 (m, 1H), 7.16 – 7.12 (m, 1H), 1.39 (s, 9H); 13C{1H}
NMR (101 MHz, CDCl3) δ 152.3, 150.1, 139.9, 131.4, 131.3,
127.5, 125.6, 123.3, 122.9, 122.8, 120.7, 118.0, 117.0, 106.3, 35.0,
31.0; HRMS (ESI) m/z: [M + H]+ Calcd for C18H18N3 276.1495;
Found 276.1494.
2-(2H-indazol-2-yl)-4-methoxybenzonitrile (2j). Purified by TLC
on silica gel with PE/acetone = 8/1 as an eluent (Rf = 0.43); yellow
o
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solid (19.4 mg, 78%); mp 90-91 C ; H NMR (400 MHz, CDCl3)
δ 8.65 (s, 1H), 7.78 (dd, J = 8.9, 0.7 Hz, 1H), 7.73 (dd, J = 8.7, 0.7
Hz, 2H), 7.51 – 7.50 (m, 1H), 7.38 – 7.34 (m, 1H), 7.14 (dd, J =
8.5, 6.6 Hz, 1H), 7.04 – 7.01 (m, 1H), 3.95 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 163.8, 150.1, 144.2, 135.7, 127.8, 123.6,
123.1, 122.8, 120.8, 117.9, 117.1, 115.2, 111.0, 97.9, 56.1; HRMS
(ESI) m/z: [M + H]+ Calcd for C15H12N3O 250.0975; Found
250.0974.
Methyl 3-cyano-4-(2H-indazol-2-yl)benzoate (2e). purified by
TLC on silica gel with PE/acetone = 7/1 as an eluent (Rf = 0.54);
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faint yellow solid (19.7 mg, 71%); mp 160-161 C ; H NMR (400
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4-Fluoro-2-(2H-indazol-2-yl)benzonitrile (2k). Purified by TLC NMR (101 MHz, CDCl3) δ 154.6, 149.7, 131.8, 130.7, 127.0,
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on silica gel with PE/acetone = 8/1 as an eluent (Rf = 0.49); brown
solid (13 mg, 55%); mp 107-108 oC; 1H NMR (600 MHz, CDCl3)
δ 8.62 (d, J = 0.8 Hz, 1H), 7.82 – 7.72 (m, 4H), 7.39 – 7.35 (m,
1H), 7.31 (td, J = 8.2, 1.2 Hz, 1H), 7.17 – 7.14 (m, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 165.5 (JC-F = 267.1 Hz), 150.4, 143.3,
135.2 (JC-F = 9.9 Hz), 128.1, 123.4 (JC-F = 11.7 Hz), 123.0, 121.2
(JC-F = 3.5 Hz), 120.7, 118.1, 115.5, 115.3, 111.6; 19F NMR (376
MHz, CDCl3) δ -102.9; HRMS (ESI) m/z: [M + H]+ Calcd for
C14H9FN3 238.0775; Found 238.0776.
4-Chloro-2-(2H-indazol-2-yl)benzonitrile (2l). Purified by TLC
on silica gel with PE/acetone = 8/1 as an eluent (Rf = 0.53); faint
yellow solid (20.2 mg, 80%); mp 166-167 oC ; 1H NMR (400 MHz,
CDCl3) δ 8.66 (d, J = 0.8 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.77
(dd, J = 8.3, 1.4 Hz, 2H), 7.73 (d, J = 8.6 Hz, 1H), 7.50 (dd, J = 8.4,
2.0 Hz, 1H), 7.39 – 7.35 (m, 1H), 7.17 – 7.13 (m, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 150.4, 143.1, 140.7, 135.4, 128.7,
128.2, 126.2, 123.5, 123.4, 123.0, 120.8, 118.0, 116.1, 104.5;
HRMS (ESI) m/z: [M + H]+ Calcd for C14H9ClN3 254.0480;
Found 254.0481.
4-Bromo-2-(2H-indazol-2-yl)benzonitrile (2m). Purified by TLC
on silica gel with PE/acetone = 8/1 as an eluent (Rf = 0.44); yellow
solid (22.6 mg, 76%); mp 178-179 oC; 1H NMR (400 MHz,
CDCl3) δ 8.65 (d, J = 0.8 Hz, 1H), 8.23 (d, J = 1.6 Hz, 1H), 7.77
(dd, J = 8.9, 0.9 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 8.3
Hz, 1H), 7.66 (dd, J = 8.3, 1.7 Hz, 1H), 7.39 – 7.35 (m, 1H), 7.18 -
7.14 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 150.4, 142.9,
135.3, 131.6, 129.1, 128.8, 128.2, 123.5, 123.4, 123.0, 120.8, 118.0,
116.2, 104.9; HRMS (ESI) m/z: [M + H]+ Calcd for C14H9BrN3
297.9974; Found 297.9973.
Ethyl 4-cyano-3-(2H-indazol-2-yl)benzoate (2n). Purified by TLC
on silica gel with PE/EA = 8/1 as an eluent (Rf = 0.40); light green
solid (18.3 mg, 63%); mp 121-122 oC; 1H NMR (400 MHz,
CDCl3) δ 8.61 (s, 1H), 8.58 (s, 1H), 8.17 (dt, J = 8.1, 1.5 Hz, 1H),
7.93 (dd, J = 8.1, 1.1 Hz, 1H), 7.82 – 7.79 (m, 1H), 7.74 (dd, J =
8.6, 1.0 Hz, 1H), 7.39 – 7.35 (m, 1H), 7.18 – 7.14 (m, 1H), 4.45 (q,
J = 7.1, 2H), 1.43 (td, J = 7.1, 0.6 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 164.0, 150.4, 142.5, 135.8, 134.8, 128.9, 127.9,
126.5, 123.4, 123.3, 123.0, 120.7, 118.1, 116.0, 110.3, 62.3, 14.2;
HRMS (ESI) m/z: [M + H]+ Calcd for C17H14N3O2 292.1081;
Found 292.1082.
125.9, 125.2, 122.6, 122.1, 120.5, 118.2, 116.8, 115.5, 112.7;
HRMS (ESI) m/z: [M + H]+ Calcd for C15H12N3O 250.0975;
Found 250.0976.
2-(2H-indazol-2-yl)-3-methylbenzonitrile (2q). Purified by TLC
on silica gel with PE/EA = 7/1 as an eluent (Rf = 0.32); faint yellow
1
oil (17 mg, 73%); H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 0.8
Hz, 1H), 7.80 (dd, J = 8.8, 0.9 Hz, 1H), 7.77 – 7.74 (m, 1H), 7.67
(dd, J = 7.7, 0.9 Hz, 1H), 7.62 (dd, J = 7.8, 0.6 Hz, 1H), 7.52 (t, J =
7.7 Hz, 1H), 7.39 – 7.35 (m, 1H), 7.19 – 7.15 (m, 1H), 2.16 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 149.9, 141.9, 137.6,
135.6, 131.1, 129.8, 127.1, 125.0, 122.8, 122.2, 120.6, 118.1, 115.5,
111.8, 17.6; HRMS (ESI) m/z: [M + H]+ Calcd for C15H12N3
234.1026; Found 234.1027.
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2-(5-Methoxy-2H-indazol-2-yl)benzonitrile (4a). Purified by TLC
on silica gel with PE/EA = 5/1 as an eluent (Rf = 0.40); white solid
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(20.7 mg, 83%); mp 143-144 C; H NMR (400 MHz, CDCl3) δ
8.47 (d, J = 0.9 Hz, 1H), 7.95 (dd, J = 8.3, 0.8 Hz, 1H), 7.83 (dd, J
= 7.8, 1.3 Hz, 1H), 7.78 – 7.74 (m, 1H), 7.68 (d, J = 9.4 Hz, 1H),
7.50 (td, J = 7.7, 1.1 Hz, 1H), 7.06 (dd, J = 9.4, 2.4 Hz, 1H), 6.90
(d, J = 2.2 Hz, 1H), 3.86 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 155.9, 147.4, 142.4, 134.5, 134.0, 128.1, 125.6, 123.4,
123.0, 122.1, 119.4, 116.8, 106.4, 96.1, 55.4; HRMS (ESI) m/z: [M
+ H]+ Calcd for C15H12N3O 250.0975; Found 250.0976.
2-(5-Fluoro-2H-indazol-2-yl)benzonitrile (4b). Purified by TLC
on silica gel with PE/acetone = 6/1 as an eluent (Rf = 0.43); white
solid (15.6 mg, 66%); mp 164-165 oC; 1H NMR (400 MHz,
CDCl3) δ 8.54 (s, 1H), 7.94 (dd, J = 8.2, 0.7 Hz, 1H), 7.87 (dd, J =
7.8, 1.3 Hz, 1H), 7.81 - 7.76 (m, 2H), 7.56 (td, J = 7.7, 1.1 Hz, 1H),
7.31 (dd, J = 8.9, 2.3 Hz, 1H), 7.17 (td, J = 9.2, 2.4 Hz, 1H);
13C{1H} NMR (101 MHz, CDCl3) δ 158.9 (JC-F = 242.4 Hz),
147.7, 142.2, 134.6, 134.1, 128.7, 125.8, 123.5 (JC-F = 9.0 Hz),
122.1 (JC-F = 11.9 Hz), 120.3 (JC-F = 9.9 Hz), 119.7 (JC-F = 29.4
Hz), 116.4, 106.9, 102.9 (JC-F = 24.5 Hz); 19F NMR (376 MHz,
CDCl3) δ -117.9; HRMS (ESI) m/z: [M + H]+ Calcd for
C14H9FN3 238.0775; Found 238.0774.
2-(5-Chloro-2H-indazol-2-yl)benzonitrile (4c). Purified by TLC
on silica gel with PE/acetone = 6/1 as an eluent (Rf = 0.33); faint
yellow solid (15.7 mg, 62%); mp 131-132 oC; 1H NMR (400 MHz,
CDCl3) δ 8.53 (d, J = 0.8 Hz, 1H), 7.94 (dd, J = 8.2, 0.8 Hz, 1H),
7.87 (dd, J = 7.8, 1.3 Hz, 1H), 7.79 (td, J = 7.9, 1.5 Hz, 1H), 7.75 –
7.72 (m, 2H), 7.57 (td, J = 7.7, 1.1 Hz, 1H), 7.29 (dd, J = 9.2, 2.0
Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 148.5, 142.0, 134.6,
134.1, 129.2, 128.8, 125.9, 123.1, 123.0, 119.6, 119.3, 116.4, 107.0;
HRMS (ESI) m/z: [M + H]+ Calcd for C14H9ClN3 254.0480;
Found 254.0479.
2-(2H-indazol-2-yl)-4-(trifluoromethyl)benzonitrile (2o). Purified
by TLC on silica gel with PE/EA = 8/1 as an eluent (Rf = 0.39);
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yellow solid (17.8 mg, 62%); mp 97-98 C; H NMR (400 MHz,
CDCl3) δ 8.70 (d, J = 0.7 Hz, 1H), 8.33 (s, 1H), 7.99 (d, J = 8.1 Hz,
1H), 7.80 – 7.76 (m, 2H), 7.74 (d, J = 8.6 Hz, 1H), 7.40 – 7.36 (m,
1H), 7.19 – 7.15 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ
2-(5-Bromo-2H-indazol-2-yl)benzonitrile (4d). Purified by TLC
on silica gel with PE/acetone = 7/1 as an eluent (Rf = 0.55); faint
150.6, 142.8, 136.1 (JC-F = 33.7 Hz), 135.4, 128.3, 124.8 (JC-F
=
1
3.5Hz), 123.7, 123.3, 123.2, 123.0 (JC-F = 3.8 Hz), 122.5 (JC-F = 275
Hz), 120.8, 118.1, 115.6, 109.4; 19F NMR (376 MHz, CDCl3) δ -
63.5; HRMS (ESI) m/z: [M + H]+ Calcd for C15H9F3N3 288.0743;
Found 288.0744.
yellow solid (22.6 mg, 76%); 151-152 oC ; H NMR (400 MHz,
CDCl3) δ 8.53 (d, J = 0.7 Hz, 1H), 7.94 (dd, J = 8.3, 0.7 Hz, 1H),
7.91 (d, J = 1.2 Hz, 1H), 7.86 (dd, J = 7.8, 1.3 Hz, 1H), 7.79 (td, J =
7.9, 1.5 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.57 (td, J = 7.7, 1.1 Hz,
1H), 7.41 (dd, J = 9.2, 1.8 Hz, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 148.5, 142.0, 134.6, 134.1, 131.4, 128.8, 125.9, 123.9,
122.9, 122.7, 119.8, 116.7, 116.4, 107.0; HRMS (ESI) m/z: [M +
H]+ Calcd for C14H9BrN3 297.9974; Found 297.9976.
2-(2H-indazol-2-yl)-3-methoxybenzonitrile (2p). Purified by TLC
on silica gel with PE/acetone = 6/1 as an eluent (Rf = 0.42); yellow
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solid (23.4 mg, 94%); mp 90 C; H NMR (400 MHz, CDCl3) δ
8.21 (d, J = 0.9 Hz, 1H), 7.81 (dd, J = 8.8, 0.9 Hz, 1H), 7.73 (d, J =
8.5 Hz, 1H), 7.56 – 7.52 (m, 1H), 7.42 (dd, J = 7.8, 1.2 Hz, 1H),
7.36 – 7.30 (m, 2H), 7.15 – 7.12 (m, 1H), 3.83 (s, 3H); 13C{1H}
2-(6-Methyl-2H-indazol-2-yl)benzonitrile (4e). Purified by TLC
on silica gel with PE/acetone = 15/1 as an eluent (Rf = 0.38); white
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121.9, 120.8, 116.3, 107.1, 52.3; HRMS (ESI) m/z: [M + H]+
solid (18.6 mg, 80%); mp 127-128 oC; 1H NMR (400 MHz,
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CDCl3) δ 8.53 (d, J = 0.7 Hz, 1H), 7.96 (dd, J = 8.2, 0.7 Hz, 1H),
7.83 (dd, J = 7.8, 1.3 Hz, 1H), 7.78 – 7.74 (m, 1H), 7.62 (d, J = 8.7
Hz, 1H), 7.53 – 7.49 (m, 2H), 6.99 (dd, J = 8.7, 1.1 Hz, 1H), 2.47
(d, J = 0.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 150.9,
142.4, 137.8, 134.5, 134.0, 128.2, 126.2, 125.8, 123.2, 121.3, 120.2,
116.7, 116.1, 106.6, 22.3; HRMS (ESI) m/z: [M + H]+ Calcd for
C15H12N3 234.1026; Found 234.1027.
Calcd for C16H12N3O2 278.0924; Found 278.0926.
2-(2H-[1,3]dioxolo[4,5-f]indazol-2-yl)benzonitrile (4k). Purified
by TLC on silica gel with PE/EA = 4/1 as an eluent (Rf = 0.30);
o
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faint yellow solid (22.9 mg, 87%); mp 177-178 C; H NMR (600
MHz, CDCl3) δ 8.41 (s, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.81 (d, J =
7.8 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.01
(s, 1H), 6.90 (s, 1H), 5.99 (s, 2H); 13C{1H} NMR (101 MHz,
CDCl3) δ 150.5, 148.2, 146.6, 142.3, 134.6, 134.0, 127.6, 125.1,
122.5, 119.0, 116.9, 105.7, 101.2, 94.8, 93.9; HRMS (ESI) m/z: [M
+ H]+ Calcd for C15H10N3O2 264.0768; Found 264.0769.
2-(6-Methoxy-2H-indazol-2-yl)benzonitrile (4f). Purified by TLC
on silica gel with PE/EA = 5/1 as an eluent (Rf = 0.30); hazel solid
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(19.9 mg, 80%); mp 132-133 C; H NMR (400 MHz, CDCl3) δ
8.51 (d, J = 0.4 Hz, 1H), 7.94 (d, J = 8.1, 0.7 Hz, 1H), 7.83 (dd, J =
7.8, 1.3 Hz, 1H), 7.75 (td, J = 8.0, 1.5 Hz, 1H), 7.58 (d, J = 9.2 Hz,
1H), 7.49 (td, J = 7.7, 1.0 Hz, 1H), 6.99 (d, J = 1.8 Hz, 1H), 6.84
(dd, J = 9.2, 2.1 Hz, 1H), 3.89 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 159.9, 151.4, 142.3, 134.6, 134.0, 127.9, 125.4, 123.3,
121.5, 118.9, 118.8, 116.8, 106.2, 94.3, 55.3; HRMS (ESI) m/z: [M
+ H]+ Calcd for C15H12N3O 250.0975; Found 250.0976.
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2-(5-Chloro-2H-indazol-2-yl)-5-methylbenzonitrile (4l). Purified
by TLC on silica gel with PE/EA = 7/1 as an eluent (Rf = 0.36);
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faint yellow solid (21.6 mg, 81%); mp 174-175 C; H NMR (400
MHz, CDCl3) δ 8.48 (d, J = 0.8 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H),
7.74 – 7.71 (m, 1H), 7.71 – 7.70 (m, 1H), 7.64 (d, J = 1.0 Hz, 1H),
7.58 – 7.55 (m, 1H), 7.29 – 7.27 (m, 1H), 2.48 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 148.3, 139.8, 139.4, 134.9, 134.6,
129.0, 128.6, 125.7, 123.0, 119.6, 119.2, 116.5, 106.7, 20.8; HRMS
(ESI) m/z: [M + H]+ Calcd for C15H11ClN3 268.0636; Found
268.0637.
2-(6-Fluoro-2H-indazol-2-yl)benzonitrile (4g). Purified by TLC
on silica gel with PE/acetone = 7/1 as an eluent (Rf = 0.40); faint
yellow solid (14.9 mg, 63%); mp 173-174 oC; 1H NMR (400 MHz,
CDCl3) δ 8.61 (d, J = 0.6 Hz, 1H), 7.97 (dd, J = 8.2, 0.7 Hz, 1H),
7.86 (dd, J = 7.8, 1.3 Hz, 1H), 7.80 (td, J = 8.0, 1.5 Hz, 1H), 7.73
(dd, J = 9.2, 5.3 Hz, 1H), 7.56 (td, J = 7.7, 1.1 Hz, 1H), 7.38 – 7.35
(m, 1H), 6.98 (td, J = 9.1, 2.2 Hz, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 162.5 (JC-F = 249.2 Hz), 150.1 (JC-F = 13.3 Hz), 142.1,
134.5, 134.1, 128.6, 125.9, 124.0, 122.7 (JC-F = 10.9 Hz), 120.1,
116.5, 115.3 (JC-F = 28.9 Hz), 106.7, 101.0 (JC-F = 24.0 Hz); 19F
NMR (376 MHz, CDCl3) δ -111.3; HRMS (ESI) m/z: [M + H]+
Calcd for C14H9FN3 238.0775; Found 238.0776.
2-(6-Chloro-2H-indazol-2-yl)benzonitrile (4h). Purified by TLC
on silica gel with PE/acetone = 6/1 as an eluent (Rf = 0.42); white
solid (16.7 mg, 66%); mp 165-166 oC; 1H NMR (400 MHz,
CDCl3) δ 8.59 (d, J = 0.9 Hz, 1H), 7.95 (dd, J = 8.2, 0.8 Hz, 1H),
7.86 (dd, J = 7.8, 1.3 Hz, 1H), 7.82 – 7.77 (m, 2H), 7.68 (dd, J =
9.0, 0.6 Hz, 1H), 7.56 (td, J = 7.7, 1.1 Hz, 1H), 7.10 (dd, J = 9.0, 1.7
Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 150.2, 142.0, 134.6,
134.1, 133.7, 128.8, 126.0, 124.8, 124.0, 122.0, 121.2, 117.0, 116.4,
106.8; HRMS (ESI) m/z: [M + H]+ Calcd for C14H9ClN3
254.0480; Found 254.0478.
2-(6-Bromo-2H-indazol-2-yl)benzonitrile (4i). Purified by TLC on
silica gel with PE/acetone = 6/1 as an eluent (Rf = 0.38); white
solid (22.3 mg, 75%); mp 148-149 oC; 1H NMR (400 MHz,
CDCl3) δ 8.57 (d, J = 0.8 Hz, 1H), 7.98 – 7.97 (m, 1H), 7.94 (dd, J
= 8.2, 0.8 Hz, 1H), 7.86 (dd, J = 7.8, 1.3 Hz, 1H), 7.81 – 7.77 (m,
1H), 7.62 (dd, J = 8.9, 0.5 Hz, 1H), 7.56 (td, J = 7.7, 1.2 Hz, 1H),
7.22 (dd, J = 9.0, 1.6 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ
150.7, 142.0, 134.6, 134.2, 128.8, 127.0, 126.0, 124.0, 122.1, 121.8,
121.3, 120.4, 116.4, 106.9; HRMS (ESI) m/z: [M + H]+ Calcd for
C14H9BrN3 297.9974; Found 297.9973.
2-(5-Bromo-2H-indazol-2-yl)-5-methylbenzonitrile (4m). Purified
by TLC on silica gel with PE/EA = 12/1 as an eluent (Rf = 0.34);
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faint yellow solid (21.2 mg, 68%); mp 194-195 C; H NMR (400
MHz, CDCl3) δ 8.48 (d, J = 0.8 Hz, 1H), 7.91 – 7.90 (m, 1H), 7.80
(d, J = 8.4 Hz, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 1.2 Hz,
1H), 7.57 (dd, J = 8.3, 1.3 Hz, 1H), 7.40 (dd, J = 9.2, 1.8 Hz, 1H),
2.48 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 148.4, 139.7,
139.5, 134.9, 134.6, 131.2, 125.7, 123.8, 122.8, 122.7, 119.7, 116.5,
116.4, 106.7, 20.8; HRMS (ESI) m/z: [M + H]+ Calcd for
C15H11BrN3 312.0131; Found 312.0133.
2-(6-Methoxy-2H-indazol-2-yl)-5-methylbenzonitrile
(4n).
Purified by TLC on silica gel with PE/acetone = 8/1 as an eluent
(Rf = 0.43); white solid (21.6 mg, 82%); mp 128-129 oC; 1H NMR
(400 MHz, CDCl3) δ 8.46 (d, J = 0.7 Hz, 1H), 7.81 (d, J = 8.4 Hz,
1H), 7.61 (d, J = 1.2 Hz, 1H), 7.59 – 7.57 (m, 1H), 7.55 – 7.53 (m,
1H), 6.99 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 9.1, 2.1 Hz, 1H), 3.89
(s, 3H), 2.46 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 159.8,
151.2, 140.1, 138.5, 134.8, 134.6, 125.3, 123.3, 121.4, 118.7, 118.6,
116.9, 106.0, 94.3, 55.3, 20.7; HRMS (ESI) m/z: [M + H]+ Calcd
for C16H14N3O 264.1131; Found 264.1133.
4-Chloro-2-(5-fluoro-2H-indazol-2-yl)benzonitrile (4o). Purified
by TLC on silica gel with PE/acetone = 7/1 as an eluent (Rf =
0.46); faint yellow solid (19.5 mg, 72%); mp 157-158 oC; 1H NMR
(600 MHz, CDCl3) δ 8.60 (s, 1H), 8.03 (s, 1H), 7.79 – 7.75 (m,
2H), 7.52 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.18 (t, J =
9.2 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 159.1 (JC-F
243.0 Hz), 147.9, 142.9, 140.7, 135.4, 128.9, 126.1, 123.4 (JC-F
=
=
9.3 Hz), 122.3 (JC-F = 12.1 Hz), 120.4, 120.1 (JC-F = 20.3 Hz),
116.0, 104.6, 102.9 (JC-F = 24.8 Hz); 19F NMR (376 MHz, CDCl3)
δ -117.1; HRMS (ESI) m/z: [M + H]+ Calcd for C14H8ClFN3
272.0385; Found 272.0387.
Methyl
2-(2-cyanophenyl)-2H-indazole-6-carboxylate
(4j).
Purified by TLC on silica gel with PE/EA = 6/1 as an eluent (Rf =
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0.33); white solid (17.4 mg, 63%); mp 156-157 C; H NMR (400
MHz, CDCl3) δ 8.63 (d, J = 0.9 Hz, 1H), 8.60 (d, J = 1.0 Hz, 1H),
7.97 (dd, J = 8.2, 0.7 Hz, 1H), 7.88 (dd, J = 7.8, 1.3 Hz, 1H), 7.83 –
7.81 (m, 1H), 7.78 (t, J = 1.3 Hz, 2H), 7.59 (td, J = 7.7, 1.1 Hz,
1H), 3.98 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.2,
149.4, 142.0, 134.6, 134.2, 129.5, 129.0, 126.0, 124.5, 123.8, 122.6,
2-(1H-Pyrazol-1-yl)benzonitrile (4p). Purified by TLC on silica gel
with PE/EA = 12/1 as an eluent (Rf = 0.24); colorless oil (14.3 mg,
o
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84%); mp 110-111 C; H NMR (600 MHz, CDCl3) δ 8.14 (d, J =
2.2 Hz, 1H), 7.81 – 7.77 (m, 3H), 7.71 (t, J = 7.9 Hz, 1H), 7.43 (t, J
= 7.6 Hz, 1H), 6.55 (s, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ
142.3, 142.1, 134.5, 134.0, 129.5, 127.2, 124.3, 117.0, 108.5, 105.4;
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HRMS (ESI) m/z: [M + H]+ Calcd for C10H8N3 170.0713; Found
170.0724.
quenched with EtOAc, filtered through a celite pad and the filtrate
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3
4
5
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7
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was concentrated under reduced pressure. The residue was purified
by preparative TLC (PE/acetone = 6/1) to recover the starting
material 1a-d2 (> 99%). The deuterium content of o-position was
71%. The content was determined by the 1H NMR. (See the
Supporting Information)
2-(1H-Indazol-1-yl)benzonitrile (4q). Purified by TLC on silica gel
with PE/acetone = 6/1 as an eluent (Rf = 0.33); yellow solid (20.2
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mg, 92%); mp 84-85 C; H NMR (600 MHz, CDCl3) δ 8.31 (s,
1H), 7.88 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.77 – 7.75
(m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.52 (dd, J = 15.0, 7.9 Hz, 2H),
7.47 (t, J = 7.6 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H); 13C{1H} NMR
(151 MHz, CDCl3) δ 141.8, 139.5, 137.0, 134.8, 133.7, 127.8,
127.7, 126.0, 125.4, 122.3, 121.6, 116.6, 110.1, 109.5; HRMS (ESI)
m/z: [M + H]+ Calcd for C14H10N3 220.0869; Found 220.0880.
2-(1-Methyl-1H-indazol-3-yl)benzonitrile (4r). Purified by TLC
on silica gel with PE/acetone = 6/1 as an eluent (Rf = 0.23); yellow
solid (18.4 mg, 92%); mp 110-111 oC; 1H NMR (600 MHz,
CDCl3) δ 7.84-7.80 (m, 3H), 7.69 (t, J = 7.6 Hz, 1H), 7.50 – 7.43
(m, 1H), 7.24 (dd, J = 10.0, 4.0 Hz, 1H); 13C{1H} NMR (151
MHz, CDCl3) δ 141.2, 140.7, 136.7, 134.3, 132.7, 130.3, 128.1,
126.7, 122.0, 121.5, 120.8, 118.8, 111.8, 109.5, 35.9; HRMS (ESI)
m/z: [M + H]+ Calcd for C15H12N3 234.1026; Found 234.1035.
General Procedure for the Synthesis of 2-phenyl-2H-indazole 1 and
3. To a 35 mL oven-dried sealed tube with a stir bar, 2-
nitrobenzaldehyde (3.25 mmol), aniline (3.58 mmol) and i-PrOH
(8.0 mL) were added in one portion. The reaction mixture was
To a 35 mL oven-dried sealed tube, 2-(Phenyl-d5)-2H-Indazole 1a-
d5 (19.9 mg, 0.1 mmol) and [Cp*RhCl2]2 (3.1 mg, 5 mol %) were
added under open air condition. AgSbF6 (13.7 mg, 40 mol %) and
KOAc (5.9 mg, 60 mol %) were weighed and added to the tube in
the glove box. And then DCE (1 mL) and MeOH (60 mg, 2.0
mmol) were added to the tube under air. The sealed tube was
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capped and placed in a preheated oil bath at 120 C for 3 h. And
then the reaction mixture was immediately quenched with EtOAc
and filtered through a celite pad. The filtrate was concentrated
under reduced pressure. The residue was purified by preparative
TLC (PE/acetone = 6/1) to recover the starting material 1a-d3 (>
99%). The hydrogen content of o-position was 97% and
determined by the 1H NMR. (See the Supporting Information).
Parallel KIE Experiment between 1a and 1a-d5. To a 35 mL oven-
dried sealed tube, 2-phenyl -2H-Indazole 1a (19.4 mg, 0.1 mmol)
or 1a-d5 (19.9 mg, 0.1 mmol) was added under the optimized
conditions. The sealed tube was capped and placed in a preheated
oil bath at 120 oC for 30, 40, 50, 60 or 70 minutes. Then the
reaction was quenched with EtOAc separately and filtered through
a celite pad. The filtrate was concentrated under reduced pressure.
1,1,2,2-Tetrachloroethane (16.8 mg, 0.1 mmol) was added to the
residue as internal standard and the yield of 2a or 2a-d4 was
determined by 1H NMR. The calculated KH/KD = 0.0047/0.0035 =
1.34. (See the Supporting Information)
o
stirred in a preheated oil bath at 80 C for 4 h. Then the mixture
was cooled down to room temperature and tri-n-butylphosphine
o
(1.98 g, 9.78 mmol) was added to the tube. After stirred at 80 C
for another 16 h, the reaction mixture was cooled down to room
temperature and diluted with EtOAc (60 mL). The organic layer
was washed with saturated ammonium chloride solution (30 mL ×
3) and brine (30 mL × 3). After that, the organic layer was dried
over MgSO4 and then filtered. Filtrate was concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (0-25% EA/PE) to afford 2H-indazole 1 and 3.
Mechanistic Experiment. Procedure for Preparation of 1a-d5. To a
35 mL oven-dried sealed tube with a stir bar, 2-nitrobenzaldehyde
1a (491 mg, 3.25 mmol), aniline-d5 (351 mg, 3.58 mmol) and i-
PrOH (8.0 mL) were added in one portion. The reaction mixture
was stirred in a preheated oil bath at 80 oC for 4 h. Then the
mixture was cooled down to room temperature and tri-n-
butylphosphine (1.98 g, 9.78 mmol) was added to the tube. After
Competitive KIE Experiment between 1a and 1a-d5. To a 35 mL
oven-dried sealed tube, 2-phenyl-2H-Indazole 1a (9.7 mg, 0.05
mmol) and p 1a-d5 (9.9 mg, 0.05 mmol) were added under the
optimized conditions. The sealed tube was capped and placed in a
preheated oil bath at 120 oC for 40 minutes. Then the reaction was
quenched with EtOAc immediately and filtered through a celite
pad. The filtrate was concentrated under reduced pressure and the
crude mixture was purified by preparative TLC (PE/acetone =
6/1) to get the desired product which was mixed by 2a and 2a-d4 in
1
35% yield. The ratio of 2a and 2a-d4 was determined by H NMR.
o
stirred at 80 C for another 16 h, the reaction mixture was cooled
The calculated KH/KD = 0.541/0.459 = 1.18. (See the Supporting
Information)
down to room temperature and diluted with EtOAc (60 mL). The
organic layer was washed with saturated ammonium chloride
solution (30 mL × 3) and brine (30 mL × 3). After that, the organic
layer was dried over MgSO4 and then filtered. Filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (0-25% EA/PE) to afford 1a-d5 (542 mg,
84%).1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 0.8 Hz, 1H), 7.79
(dd, J = 8.8, 0.9 Hz, 1H), 7.73 – 7.68 (m, 1H), 7.35 – 7.31 (m, 1H),
7.14 – 7.10 (m, 1H).
H/D Exchange Experiment. To a 35 mL oven-dried sealed tube, 2-
phenyl-2H-indazole 1a (19.4 mg, 0.1 mmol) and [Cp*RhCl2]2 (3.1
mg, 5 mol %) were added under open air condition. AgSbF6 (13.7
mg, 40 mol %) and KOAc (5.9 mg, 60 mol %) were weighed and
added to the tube in the glove box. And then DCE (1 mL) and
MD3OD (72.1 mg, 2.0 mmol) were added to the tube under air.
The sealed tube was capped and placed in a preheated oil bath at
120 oC for 3 h. And then the reaction mixture was immediately
Intermolecular Competition Experiment between 1c and 1e. To a
35 mL oven-dried sealed tube, 1c (22.4 mg, 0.1 mmol) and 1e
(26.6 mg, 0.1 mmol) were added under optimized conditions. The
sealed tube was capped and placed in a preheated oil bath at 120 oC
for 24 h. After the reaction was completed, the reaction mixture was
cooled down to room temperature and filtered through a celite pad.
Then the filtrate was concentrated under vacuo. 1,1,2,2-
tetrachloroethane (16.8 mg, 0.1 mmol) was added to the residue as
1
internal standard and the ratio of 2c and 2e was determined by H
NMR. The calculated ratio was 2c/2e = 10 : 1. (See the Supporting
Information)
Gram Scale Reaction for Synthesis of 2a. To a 150 mL oven-dried
sealed bottle, 2-phenyl-2H-indazole 1a (1.001g, 5.16 mmol),
NCTS (3.252 g, 12.9 mmol) and [Cp*RhCl2]2 (159.5 mg, 5 mol
%) were added under open air condition. AgSbF6 (709 mg, 40 mol
%) and KOAc (303.8 mg, 60 mol %) were weighed and added in
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The Journal of Organic Chemistry
(ESI) m/z: [M + H]+ Calcd for C15H13N2O2 253.0972; Found
the glove box. And then DCE (52 mL) was added to the bottle
1
2
under air. The sealed bottle was capped and placed in a preheated
oil bath at 120 C for 24 h. After the reaction was completed, the
253.0973.
o
ASSOCIATED CONTENT
Supporting Information
3
4
5
6
7
8
9
reaction mixture was cooled down to room temperature and
concentrated under vacuo. The crude mixture was purified by silica
gel chromatography (0-15% PE/acetone) to give the desired
product 2a (965 mg, 85%).
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental procedures and spectra data for 2, 4-7 (PDF)
Singly-crystal X-ray diffraction data for compounds 2a (CIF)
Synthesis of (2-(2H-indazol-2-yl)phenyl)methanamine 5. To a 25
mL oven-dried Schlenk tube with a stir bar, 2-(2H-indazol-2-
yl)benzonitrile 2a (0.2 mmol, 43.8 mg) and 2mL THF was added
under Ar. Suspensions of LiAlH4 (0.6 mmol, 22.8 mg) and 0.6 mL
THF was added afterwards. After stirred at 0 oC for 0.5 h, the
reaction mixture was warmed to room temperature and refluxed in
a preheated oil bath for 8 h. After cooling to room temperature, the
reaction mixture was diluted with THF and quenched with water
(200 µL) and NaOH (15%, 100 µL). Then the reaction mixture
was stirred at room temperature for 1 h and dried with Na2SO4.
After filtration and evaporation of the solvent, the crude mixture
was purified by column chromatography on silica gel
(dichloromethane/methanol = 10/1) to give 5. (36.7 mg, 82%);
AUTHOR INFORMATION
Corresponding Author
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Email: zhuxinju@zzu.edu.cn (X.Z)
Email: mpsong@zzu.edu.cn (M.P.S)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
1
Financial support from the National Natural Science Foundation of
China (Grant Nos. 21672192, 21803059, U1904212 and 21929101
is gratefully appreciated.
Light green oil; H NMR (600 MHz, CDCl3) δ 8.24 (s, 1H), 7.76
)
(dd, J = 15.9, 8.6 Hz, 2H), 7.63 (d, J = 7.2 Hz, 1H), 7.49 – 7.46 (m,
3H), 7.37 – 7.34 (m, 1H), 7.17 – 7.15 (m, 1H), 4.36 (s, 2H), 3.82
(s, 2H); 13C{1H} NMR (151 MHz, CDCl3) δ 149.5, 139.9, 135.6,
131.3, 129.6, 128.7, 127.0, 125.9, 124.4, 122.6, 122.2, 120.3, 117.8,
42.3; HRMS (ESI) m/z: [M + H]+ Calcd for C14H14N3 224.1182;
Found 224.1185.
REFERENCES
(1) (a) Miller J. S.; Manson, J. L. Designer Magnets Containing
Cyanides and Nitriles. Acc. Chem. Res. 2001, 34, 563. (b) Fleming,
F. F.; Wang, Q. Z. Unsaturated Nitriles: Conjugate Additions of
Carbon Nucleophiles to a Recalcitrant Class of Acceptors. Chem.
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J = 0.7 Hz, 1H), 7.91 – 7.90 (m, 1H), 7.74 – 7.72 (m, 2H), 7.61 –
7.58 (m, 2H), 7.52 – 7.50 (m, 1H), 7.39 – 7.75 (m, 1H), 7.18 –
7.14 (m, 1H), 6.35 (s, 1H), 5.61 (s, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 168.0, 149.7, 137.9, 132.2, 131.4, 130.2, 129.8, 127.4,
127.3, 126.1, 122.7, 122.5, 120.6, 117.5; HRMS (ESI) m/z: [M +
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