The nickel-catalyzed: C 3-acylation of 2 H -indazoles with aldehydes

Article abstract of DOI:10.1039/c9ob01749f

A direct coupling of 2H-indazoles' C3 position and acyl groups has been achieved to produce 3-acyl-2H-indazoles. The Ni(ii)-catalyzed acylation might proceed through a radical pathway for the reaction of 2H-indazoles with either aryl or alkyl aldehydes in

Full text of DOI:10.1039/c9ob01749f

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DOI: 10.1039/C9OB01749F
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Nickel-Catalyzed C3-Acylation of 2H‑Indazoles with Aldehydes
Yan-Ling Liu, You-Lu Pan, Gang-Jian Li, Hai-Feng Xu, Jian-Zhong Chen a*
Received 00th January 20xx,
Accepted 00th January 20xx
A direct coupling of 2H‑Indazoles’ C3 position and acyl groups has been achieved to produce 3-acyl-2H-Indazoles. The Ni(II)-
catalyzed acylation might proceed through a radical pathway for the reaction of 2H‑Indazoles with either aryl or alkyl
aldehydes at the presence of the free radical initiator TBHP and additive PivOH. This method provided a superior approach
to fulfil the direct C3-acylation of 2H-indazoles with yields up to 91%. And various substituted 2H‑Indazoles were well
tolerated with this method that enriched the diversity of 2H-indazole derivatives. In comparison with previously reported
approaches of C3-acylation of 2H-indazoles , the developed reaction represented a more convenient and economical
method directly using aldehydes to be acylation agents.
DOI: 10.1039/x0xx00000x
molecular diversity and for the development of new bioactive
compounds.
It was no denying that the C3-acylation may expend the
Introduction
Indazoles, which are widely distributed in herb seeds, were
proved to have potentials in antitumor activity,1 anti-
inflammatory activity,2 and HIV protease inhibition.3 Generally,
there are two indazole isomers, 1H-indazoles and 2H-
indazoles.4 Over the past decades, 1H-indazoles have
molecular diversity of 2H-indazoles. A few studies have been
carried out on syntheses of 2H-indazoles with a C3-keto
substituent. As reported, Wang et al. developed the approach
for the synthesis of 3-acyl-2H-Indazoles using diazocarbonyl
reagents and benzynes through silver-catalyzed [3+2]-
cycloaddition reaction (Scheme 1, a),11 and Jeong et al.
demonstrated the direct C–H functionalization, accompanied
by the use of rhodium catalyst, of azobenzenes reacting with
ethyl glyoxalate or aryl glyoxals (Scheme 1, b).12 Moreover,
Bogonda et al. revealed a direct acyl radical addition to 2H-
indazole through AgNO3-catalyzed decarboxylative cross-
coupling of α-keto acid (Scheme 1, c).13 Obviously, all above
reactions need a noble metal participating to be the catalyst.
Herein, we reported a new approach (Scheme 1, d) of nickel-
catalyzed C3-acylation reaction of 2H-indazoles via directly
reacting with either aryl or alkyl aldehydes, obtaining
represented
a kind of important structures in clinical
treatments, such as Lonidamine,5 Granisetron,6 and Axitinib
(Figure 1).7 Coincidentally, 2H-indazoles were also verified of
pharmacological activities recently, and the applications of
which in pharmaceutical researches and clinical studies have
been realized, for instance, Pazopanib and MK-4827 (Figure 1).8,
9 On the other hand, synthetic routes of 2H-indazoles were less
prevalent than 1H-indazoles, although there were couples of
publications reporting syntheses of 2H-indazoles.10 It would be
valuable of developing new synthetic approaches to induce
different moieties on 2H-indazole core for the increase of
HO
O
Previous works:
N
H
N
N
H
O
O
O
N
N
O
R2
N
OTf
cat. AgOTf, TBAF
S
R2
R1
+
a
N
N
N
R1
TMS
N2
Cl
N
N
N
R1
H
Cl
O
X
O
N
H
cat. [Rh]
cat. [Ag]
X
N
Axitinib
Lonidamine
Granisetron
+
+
H
b
c
N
Ph
R3
O
N
X= OEt, Ar
O
NH2
O
O
S
H2N
H
O
N
N
N
N
R2
R1
NH
N
N
N
R3
O
N
s
HO
R1
N
R2
N
N
N
O
This work:
MK-4827
O
R3
Pazopanib
TBHP, NiCl2, PivOH
N
R2
d
R1
N
R2
R3 CHO
+
R1
N
Figure 1. Examples of bioactive indazoles
℃
Toluene, Ar, 80 , 10h
N
R3= aryl and alkyl
R1= F, OR
R2= aryl
a. Address here. College of Pharmaceutical Sciences, Zhejiang University, 866
Yuhangtang Rd., Hangzhou, Zhejiang 310058, China
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Scheme 1. Synthetic approaches to 3-acyl-2H-Indazoles
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corresponding products in yields of up to 91%. In this work, the dioxane, and toluene, to produce 3a in yields rangViniegw fArrtoicmle O3n3lin%e
preciously-used metal catalyst was replaced by a bivalent nickel to 86% at 80 C (Table 1, entries 1-7), andDtOoIl:u1e0n.1e03s9e/rCv9eOdB0a1s7t4h9eF
catalyst. Meanwhile, aldehydes with extensive commercial best solvent for the reaction to get the yield of 86% (Table 1,
sources took the place of hard-won accessed starting material, entry 7).
such as α-keto acids, which required to be particularly
Next, the role of metal catalyst was put into discussion to
synthesized. The developed reaction appeared more evaluate the most efficient one. Since it was reported that
convenient and economical method to synthesize 3-acyl-2H- palladium salt in combined with TBHP-PivOH catalysed C2-
indazoles in comparison with previously reported ones.
acylation of indoles reacting with aldehydes effectively,16 it was
supposed that the method could also work in the C3-acylation
of 2H-indazoles, too. As listed in Table 1, Pd(OAc)2 was tested to
catalyse the reaction in a yield of 60% in combination with
TBHP-PivOH (Table 1, entry 8), showing a lower reaction-
promoting efficiency than the catalyst NiCl2 (Table 1, entry 7).
Meanwhile, another two nickel catalysts, Ni(dppp)Cl2 (Table 1,
entry 9) and Ni(OAc)24H2O (Table 1, entry 10), were individually
used to be the catalyst, making the reaction in a yield of 66%
and 43%, respectively. Typically, the reaction with
Ni(OAc)24H2O obtained the product 3a in a similar yield of
around 40% as to the one without a metal catalyst (Table1,
entry 11). By the way, when the usage of NiCl2 reduced to 10%
mol, the reaction yield decreased to 71% (Table 1, entry 7c).
Results and discussion
Based on forerunner's researches, it was hypothesized that a
metallaphotocatalysis protocol could contribute to acylation
reactions by a free radical pathway.14 Additionally, peroxides
were frequently applied for a radical initiator in such kind of
reactions.15 Therefore, we developed the method for the
acylation at the C3 position of 2H-indazoles reacting with an
aldehyde in the presence of both oxidant and metal catalyst.
Initially, the studies were commenced by investigating the
reaction of 2-(2-phenyl)-2H-indazole (1a) and benzaldehyde
(2a) using NiCl2, tert-butyl hydroperoxide (TBHP), and pivalic
acid (PivOH) to be the catalyst, oxidant, and additive,
respectively. At first, the reaction solvent was screened. Results
indicated that the reaction took place in various solvents, like
Table 1. Screening of Reaction Conditions a
CHO
O
oxidant, catalyst., additive
N
+
N
N
N
solvent, Ar, heat, 10h
1a
2a
3a
Entry
1
Solvent
Catalyst
Oxidant
Additive
Yield (%)b
MeCN
NiCl2
TBHP
PivOH
72
2
3
4
5
6
7c
8
EtOH
PhCl
PhBr
Xyl
Diox
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
Pd(OAc)2
Ni(dppp)Cl2
Ni(OAc)24H2O
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
BPO
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
-
33
60
54
53
60
86
60
66
43
40
NR
23
11
66
18
62
9
10
11
12d
13
14
15
16
17
-
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
-
-
-
PhI(OAc)2
TBHP
TBHP
TBHP
PhB(OH)2
AcOH
aReaction conditions:1a (0.26mmol), 2a (0.78mmol, 3 equiv), oxidant (0.52mmol, 2 equiv), catalyst (20% mol), additive (0.52mmol, 2 equiv), solvent (1mL), under
argon environment, 80C, for 10h. bIsolated yields after column chromatography. cReduce the usage of NiCl2 to 10% mol, the yield was 71%. dReacting at 120C,
the yield was 30%. TBHP = tert-Butyl hydroperoxide, PivOH = Pivalic acid, Xyl = Xylene, Diox= Dioxane, DTBP = Di-tert-butyl peroxide, NR= No reaction, BPO =
Dibenzoyl peroxide.
acetonitrile, ethanol, chlorobenzene, bromobenzene, xylene,
2 | J. Name., 2012, 00, 1-3
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Through above results, further optimizations of the reaction
condition were encouraged to focus on various oxidants
triggering off the free radical reaction. All the chosen oxidants,
including Di-tert-butyl peroxide (DTBP), Dibenzoyl peroxide
(BPO), PhI(OAc)2, and TBHP (Table 1, entries 12-15),
respectively, initiated the C3-acylation reaction of 1a and 2a
without an additive. Among these reactions, TBHP was the most
effective oxidant to produce 3a in a yield of 66% (Table 1, entry
15). In addition, it was found that the acylation reaction did not
take place using DTBP at the temperature of 80C, while the
yield increased to 30% at 120 C (Table 1, entry 12d). The results
suggested that the Ni-catalyzed reaction at the C3 position of
2H-indazoles with the aldehyde would be elicited by oxyradical,
since published data demonstrated that the appropriate
excitation temperature for DTBP was 100 to 120 C.17 In the
meantime, it was noticed that the additive PivOH was also
favorable to the acylation reaction by comparing entries 7
(reaction yield, 86%) and 15 (reaction yield, 66%) in Table 1.
Furthermore, it was indicated that the reaction yield was also
highly sensitive to Lewis acid additives. As illustrated in Table 1,
the reaction yields were 18% and 62%, respectively, in the
presence of phenyl boric acid (Table 1, entry 16) or acetic acid
(Table 1, entry 17) to be the additive. In comparison, PivOH was
proved to be the best additive for the Ni-catalyzed C3-acylation
reaction (yield, 86%) of 2H-indazoles reacting with aldehydes.
So far, the studies demonstrated that 2H-indazoles C3-acylation
reaction condition with the maximum yield of 86% was
obtained with toluene as solvent, involving TBHP (0.52mmol, 2
equiv.), anhydrous nickel chloride (20 mol %), and pivalic acid
(0.52mmol, 2 equiv.) under the argon atmosphere at 80 °C for
10 hours.
With the optimized reaction condition in hand, we then
investigated the scope with various aldehydes. As listed in Table
2, both aryl and alkyl aldehydes can react with compound 1a to
provide corresponding C3-acylated 2H‑Indazoles in good yields
over 50% under above condition. Typically, n-butyraldehyde
reacted with 1a to produce 3b in the highest yield of 91% (Table
2, entry 2). Similarly, another alkyl aldehyde propionaldehyde
produced 3c (Table 2, entry 3) in a good yield of 71%. Besides,
the reaction yields decreased to 74% (product 3d) and 58%
(product 3e), respectively, when benzaldehyde was replaced by
ortho-methyl-benzaldehyde (Table 2, entry 4) or para-chloro-
benzaldehyde (Table 2, entry 5). Furthermore, heterocyclic
thiophene-3-carbaldehyde was also tested to react with
compound 1a, producing 3f in a relatively low yield of 47%
(Table 2, entry 6). However, a limitation of current method
existed for pivalaldehyde, which did not make acylation but
introduced a tert-butyl group at the C3-position of compound
1a, obtaining the product 3-tert-butyl-2H-indazole 3g in a yield
of 60%. It could be on the reason of the unstability of tert-butyl
acyl radical, which might go further decarbonylation to a tert-
butyl radical, participating to the reaction with 2H-indazole.13
In order to further discuss the applicability of the developed
method, various substituted 2H-Indazoles and aldehydes were
chosen as substrates to produce different 3-acyl-2H-indazoles
4a-4l (Scheme 2). Gratifyingly, many substituents, such as
fluoro, chloro, methyl, and alcoxy, were well tolerated for the
View Article Online
DOI: 10.1039/C9OB01749F
Table 2. Scope of aldehydes in the NiCl2-Catalyzed Radical
Addition to 2H-Indazolea
O
R
TBHP, NiCl2, PivOH
N
+
R
CHO
N
N
℃
Toluene, Ar, 80 , 10h
N
3
1a
2
Entry
Aldehyde
Product
Yield(%)b
O
CHO
1
86
N
N
,3a
,3b
,3c
O
2
3
91
71
CHO
N
N
O
CHO
N
N
O
4
5
74
58
CHO
N
N
,3d
Cl
O
Cl
CHO
N
N
,3e
,3f
S
CHO
O
6
7
47
60
N
N
S
CHO
N
N
,3g
aReaction conditions:1a (0.26mmol), 2 (0.78mmol), TBHP
(2 equiv), NiCl2 (20%mol), PivOH (2 equiv), Toluene (1mL),
under argon atmosphere, 80C, 10h. Isolated yields after
b
column chromatography.
reaction, and electron properties did not show significant
effects on the reactivity. Moreover, it was found that aryl
aldehydes made the C3-acylation reactions of 2H-indazoles in
lower yields than alkyl aldehydes, for example, 4a (76%) vs 4c
(86%) and 4b (64%) vs 4d (85%), likely on the reason of steric
hindrance of aryl aldehydes. We also tested the C3-acylation
reactions of 2-(pyridin-2-yl)-2H-indazole with alkyl and aryl
aldehydes to get the C3-acylated 2-(pyridin-2-yl)-2H-indazoles
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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the oxidative addition of carbonyl radical B which was excited
by TBHP from aldehydes. This process may afford intermediate
C, and then the product 3-acyl-2H-Indazoles was obtained via
reductive elimination. At the same time, nickel intermediate C
View Article Online
DOI: 10.1039/C9OB01749F
O
R2
TBHP, NiCl2, PivOH
N
R1
+
R2 CHO
N R1
N
℃
Toluene, Ar, 80 , 10h
N
4
1
2
O
(i) Control experiments
O
O
O
N
Cl
N
N
N
N
Cl
O
N
N
N
CHO
a
b
standard condition
without TBHP
yield= 0%
+
+
N
N
N
N
4d (85%)
N
N
N
N
4b (64%)
4c (86%)
4a (76%)
O
O
O
O
O
O
CHO
CHO
F
O
O
standard condition
N
yield= 86%
yield= 60%
N
N
N
N
N
N
N
N
N
N
N
N
4h (41%)
4g (46%)
4f (42%)
4e (77%)
Cl
c
d
standard condition
2 equiv. TEMPO
S
N
O
+
O
O
N
N
F
O
N
N
N
N
N
N
N
N
N
N
N
O
CHO
4k (76%)
4l (45%)
4j (52%)
4i (38%)
standard condition
5 equiv. TEMPO
yield= 20%
yield= 0%
N
N
+
N
N
F
O
N
N
N
CHO
N
N
N
e
standard condition
10 equiv. TEMPO
+
N
N
4n (28%)
4m (29%)
N
N
Scheme 2. Substrate scope of 2H-indazoles
ate scope of 2H-indazoles
(ii)Plausible reaction mechanism
NiCl2
4f-4l. In the mean time, it was also noticed that pivalaldehyde
did not make acylation but had a substituent of tert-butyl group
(products 4m and 4n) at the C3-position of 2-(pyridin-2-yl)-2H-
indazole, either. Similar to the C3-acylation of 2-phenyl-2H-
indazole, straight chain alkyl aldehydes conducted higher yields
than branched alkyl aldehydes, such as 4f (42%) vs 4m (42%),4h
(41%) vs 4n(28%), which could also be induced by bigger steric
hindrance of branched alkyl group than straight alkyl
chain.Considering the wealth of 2H-Indazoles accessible, this
process represents a powerful and distinct approach toward
their construction under mild reaction conditions with readily
available starting materials.
PivOH
N
N
Ni (OPiv)2
TBHP
Oxidation
PivOH
PivO
Ni
N
A N
Ni(I)OPiv
t-BuOO
O
O
Oxidation
Reductive
elimination
O
R
R
R
H
N
t-BuOOH
N
O
OPiv
To explore the mechanism of nickel-catalyzed C3-acylation of
2H-indazoles with aldehydes, we carried out control
experiments as illustrated in Scheme 3. As reported in
literatures, tert-butyl hydroperoxide (TBHP) has been validated
to serve as the radical initiator.18 In fact, our experiments
demonstrated that the reaction didn’t take place in the absence
of TBHP (Scheme 3, a). Furthermore, we attempted to capture
the radical species with increasing equivalent amount of
2,2,6,6-tetra-methylpiperidine-1-oxyl (TEMPO) (Scheme 3, b-
e).19 It was found that the yield sharply decreased as the
equivalent of TEMPO increased. Especially, the addition of 10
equivalent of TEMPO made the reaction failed (Scheme 3, e),
illustrating the involvement of radical species in the current
synthetic route to 3-acyl-2H-indazoles. Based on the results of
control experiments and previous publications,20 we proposed
a plausible pathway for this reaction. As depicted in Scheme 3,
Ni(II) and PivOH might firstly form [Ni(PivO)2]. Then, 2-(2-
phenyl)-2H-indazole was evolved into a complex A, followed by
TM
B
Ni
R
N
N
C
Scheme 3. Proposed mechanism
was converted to a Ni(I) specie. Finally, it was assumed that the
Ni(I) species might be converted back to a Ni(II) species, likely
through the involvement of THBP or PivOH, to continue the
catalytic cycle. We may suppose that the participating nickel
catalyst might promote the transfer of electrons to make the
reaction more efficient.20c-e Not only that, PivOH might favor the
formation of nickel complex with 2H-indazoles.20f, g
Experimental
4 | J. Name., 2012, 00, 1-3
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General methods. All reagents and solvents were purchased 132.80, 129.45, 129.20, 129.05, 126.93, 126.21, 126.11, 125.96,
View Article Online
DOI: 10.1039/C9OB01749F
from commercial sources and used without further purification. 122.93, 120.89, 119.00, 77.31, 77.06, 76.81, 35.80, 27.05, 7.91.
Reactions were monitored by analytical thin-layer
chromatography (TLC) on Silica gel plates (GF254). The TLC (2-Phenyl-2H-indazol-3-yl)-(o-tolyl)-methanone (3d). Milky
1
plates were isualized by shortwave (254 nm) or longwave (365 white solid in a yield of 74% (60 mg). H NMR and 13C NMR
nm) UV light. Column chromatography was carried out using spectra for this compound are consistent with previously
1
silica gel (200-300 mesh) to purify the product. H NMR (500 reported literature data.13 1H NMR (500 MHz, CDCl3): δ 8.31-
MHz) and 13C NMR (126 MHz) spectra were recorded in CDCl3 8.29 (m, 1H), 7.92 (td, J = 8.11, 0.88 Hz, 1H), 7.86-7.82 (m, 2H),
or DMSO-d6 on Bruker 500 MHz spectrometers using TMS as the 7.40-7.35 (m, 2H), 7.33 (ddd, J = 7.37, 3.72, 1.59 Hz, 2H), 7.27-
internal standard. Chemical shifts are given in ppm downfield 7.20 (m, 3H), 7.16 (q, 1H), 7.08 (t, J = 7.52 Hz, 1H), 2.58 (s, 3H).
from tetramethylsilane (TMS) as an internal reference, and 13C NMR (126 MHz, CDCl3): δ 188.06, 152.13, 148.99, 148.03,
coupling constants (J-values) are in Hertz (Hz). 1H NMR 138.76, 138.59, 138.30, 133.67, 132.74, 131.87, 131.56, 131.46,
assignment abbreviations are the following; singlet (s), doublet 129.73, 127.77, 125.82, 125.49, 125.18, 124.08, 123.48, 120.64,
(d), triplet (t), quartet (q), broad singlet (bs), doublet of doublets 118.51, 118.02, 77.32, 77.06, 76.81, 20.37.
(dd), triplet of doublets (td), doublet of a triplets (dt) and
multiplet (m). The high-resolution mass spectra (HRMS) were (4-Chlorophenyl)-(2-phenyl-2H-indazol-3-yl)-methanone (3e).
1
recorded in the FAB mode on Agilent 1290 HPLC-6224.
Yellow solid in a yield of 58% (50 mg). H NMR and 13C NMR
spectra for this compound are consistent with previously
General procedure for the reaction of 2H-indazoles with reported literature data.13 1H NMR (500 MHz, CDCl3): δ 7.91-
aldehydes: 2-phenyl-2H-indazole (50mg, 0.26 mmol), aldehydes 7.87 (m, 1H), 7.81-7.78 (m, 2H), 7.52 (td, J = 5.64, 2.53, 2H),
(0.78mmol, 3 equiv), TBHP (71 µL, 2 equiv), NiCl2 (6.1 mg, 7.45-7.40 (m, 5H), 7.40-7.37 (m, 2H), 7.21 (q, 1H). 13C NMR (126
20%mol), PivOH (53.04 mg, 0.52 mmol) were reacted in Toluene MHz, CDCl3): δ 184.64, 148.64, 140.44, 140.07, 136.19, 131.89,
(1mL) under argon atmosphere at 80℃ for 10h. After cooling, 131.24, 129.13, 129.07, 129.02, 127.12, 125.56, 125.31, 124.07,
the mixture was poured into the EtOAc (5.0 mL) and washed 120.37, 118.69, 77.27, 77.01, 76.76.
with water (3 × 10.0 mL), brine (3 × 10.0 mL), then dried over
MgSO4. Evaporation of the solvent under reduced pressure (2-Phenyl-2H-indazol-3-yl)-(thiophen-3-yl)methanone
(3f).
provided the crude product, which was purified by column Yellow solid in a yield of 47% (37 mg). 1H NMR and 13C NMR
chromatography (Petroleum ether : EtOAc = 10:1) to afford the spectra for this compound are consistent with previously
final product.
reported literature data.13 1H NMR (500 MHz, CDCl3): 7.88 (d, J
= 8.76 Hz, 1H), 7.76 (dd, J = 4.93, 1.09 Hz, 1H), 7.67-7.61 (m, 2H),
Phenyl-(2-phenyl-2H-indazol-3-yl)-methanone (3a). Pale 7.59-7.56 (m, 2H), 7.47-7.37 (m, 4H), 7.25-7.20 (m, 1H), 7.12
1
yellow solid in a yield of 86% (67 mg). H NMR and 13C NMR (dd, J = 4.89, 3.85 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 177.90,
spectra for this compound are consistent with previously 148.63, 144.23, 140.37, 135.47, 135.43, 132.16, 129.16, 128.97,
reported literature data.13 1H NMR (500 MHz, CDCl3): δ 7.92- 128.21, 127.99, 127.13, 125.38, 124.83, 123.56, 120.42, 118.47,
7.84 (m, 3H), 7.62-7.58 (m, 1H), 7.55 (t, J = 1.90 Hz, 1H), 7.53 (t, 77.27, 77.01, 76.76.
1H), 7.41 (m., 7H), 7.18 (ddd, J = 8.62, 6.62, 0.86 Hz, 1H). 13C
NMR (101 MHz, CDCl3): δ 186.00, 148.60, 140.53, 137.84, 3-(tert-Butyl)-2-phenyl-2H-indazole (3g). Yellow solid in a yield
133.59, 132.30, 129.93, 129.10, 128.96, 128.66, 127.06, 125.57, of 60% (39 mg). 1H NMR and 13C NMR spectra for this compound
125.05, 124.10, 120.62, 118.57, 77.37, 77.05, 76.74.
are consistent with previously reported literature data.13 1H
NMR (500 MHz, CDCl3): δ 7.97-7.92 (m, 1H), 7.67 (td, J = 8.73,
1-(2-Phenyl-2H-indazol-3-yl)-butan-1-one (3b). Yellow solid in 0.95 Hz, 1H), 7.51-7.41 (m, 5H), 7.30-7.26 (m, 1H), 7.06-7.03 (m,
1
a yield of 91% (76 mg). H NMR and 13C NMR spectra for this 1H), 1.43 (s, 9H). 13C NMR (126 MHz, CDCl3): δ 148.48, 144.45,
compound are consistent with previously reported literature 142.95, 129.42, 128.50, 128.11, 126.00, 122.64, 120.81, 119.73,
data.13 1H NMR (500 MHz, CDCl3): δ 8.03 (dd, J = 8.40, 1.09 Hz, 117.84, 77.33, 77.08, 76.82, 34.78, 31.87.
1H), 7.89-7.86 (dt, 1H), 7.54-7.51 (m, 3H), 7.48-7.46 (m, 2H),
7.44-7.35 (m, 2H), 2.85 (t, J = 8.83, 5.68 Hz, 2H), 1.77-1.69 (m, Phenyl-(2-(p-tolyl)-2H-indazol-3-yl)-methanone (4a). Pale
1
2H), 0.94 (t, J = 7.41 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ yellow solid in a yield of 76% (62 mg). H NMR and 13C NMR
190.87, 148.49, 141.52, 129.42, 129.05, 126.93, 126.19, 125.91, spectra for this compound are consistent with previously
122.93, 120.84, 118.97, 77.34, 77.09, 76.83, 44.38, 17.44, 13.79. reported literature data.13 1H NMR (500 MHz, CDCl3): δ 7.90-
7.85 (m, 3H), 7.62-7.57 (m, 1H), 7.46 (t, J = 7.80 Hz, 2H), 7.43-
1-(2-Phenyl-2H-indazol-3-yl)-propan-1-one (3c). Yellow solid in 7.40 (m, 2H), 7.39-7.32 (m, 2H), 7.21 (d, J = 8.03 Hz, 2H), 7.16
1
a yield of 71% (51 mg). H NMR and 13C NMR spectra for this (ddd, J = 8.57, 6.62, 0.79 Hz, 1H), 2.38 (s, 3H). 13C NMR (126
compound are consistent with previously reported literature MHz, CDCl3): δ 186.01, 148.49, 139.02, 138.15, 137.94, 133.49,
data.13 1H NMR (500 MHz, CDCl3): δ 8.04 (d, J = 8.42 Hz, 1H), 132.21, 129.94, 129.65, 128.62, 126.86, 125.30, 124.86, 124.02,
7.88 (d, J = 8.53 Hz, 1H), 7.55-7.52 (m, 3H), 7.49-7.46 (m, 2H), 120.55, 118.53, 77.28, 77.03, 76.77, 21.16. HRMS (ESI) calcd. for
7.45-7.36 (m, 2H), 2.92 (q, J = 7.22 Hz, 2H), 1.18 (t, J = 7.22 Hz, C21H16N2O [M+H]+ 313.1296, found 313.1298.
3H). 13C NMR (126 MHz, CDCl3): δ 191.21, 148.49, 141.57,
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Organic & Biomolecular Chemistry
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(2-(4-Chlorophenyl)-2H-indazol-3-yl)-(phenyl)-methanone
Journal Name
148.40, 138.81, 133.46, 127.57, 125.44, 123.97, 122.31, 120.56,
View Article Online
(4b). Yellow solid in a yield of 64% (55 mg). 1H NMR (500 MHz, 118.80, 118.70, 77.32, 77.07, 76.81, 36D.4O6I,: 180..11083.9/HCR9MOBS01(7E4S9IF)
CDCl3): δ 7.82-7.77 (m, 3H), 7.55 (t, J = 7.46 Hz, 1H), 7.42-7.37 calcd. for C15H13N3O [M+H]+ 252.1092, found 252.1160.
(m, 5H), 7.34-7.30 (m, 2H), 7.23 (d, J = 8.61 Hz, 1H), 7.09 (m, 1H).
13C NMR (126 MHz, CDCl3): δ 185.81, 148.67, 139.02, 137.69,
134.93, 133.86, 133.63, 132.27, 130.18, 129.98, 129.73, 129.30, 1-(5-Fluoro-2-(pyridin-2-yl)-2H-indazol-3-yl)-butan-1-one (4h).
128.80, 128.47, 127.31, 126.78, 125.32, 124.07, 122.09, 120.59, Yellow solid in a yield of 41% (30 mg). 1H NMR (500 MHz, CDCl3):
118.56, 77.34, 77.09, 76.83. HRMS (ESI) calcd. for C20H13ClN2O δ 8.54 (ddd, J = 4.82, 1.73, 0.70 Hz, 1H), 7.99-7.94 (m, 1H), 7.85-
[M+H]+ 334.0687, found 334.0680.
7.80 (m, 2H), 7.48 (dd, J = 9.16, 1.93 Hz, 1H), 7.44 (ddd, J = 7.46,
4.87, 0.99 Hz, 1H), 7.21 (dt, J = 9.18, 2.38 Hz, 1H), 2.84 (t, J =
1-(2-(p-Tolyl)-2H-indazol-3-yl)-butan-1-one (4c). Yellow solid in 7.28 Hz, 2H), 1.82-1.74 (m, 2H), 0.98 (t, J = 7.43 Hz, 3H). 13C NMR
a yield of 86% (62 mg). 1H NMR (500 MHz, CDCl3): δ 8.02 (d, J = (126 MHz, CDCl3): δ 192.66, 161.56, 159.61, 152.73, 148.44,
8.44 Hz, 1H), 7.86 (td, J = 8.65, 0.92 Hz, 1H), 7.42-7.38 (m, 1H), 146.31, 138.86, 134.05, 133.98, 124.14, 122.31, 122.22, 121.16,
7.38-7.33 (m, 3H), 7.31 (d, J = 8.26 Hz, 2H), 2.82 (t, J = 7.23 Hz, 121.09, 119.52, 119.29, 118.74, 103.66, 103.45, 77.29, 77.04,
2H), 2.46 (s, 3H), 1.76-1.68 (m, 2H), 0.93 (t, J = 7.41 Hz, 3H). 13
C
76.78, 44.80, 17.61, 13.75. HRMS (ESI) calcd. for C16H14FN3O
NMR (126 MHz, CDCl3): δ 190.97, 148.42, 139.50, 139.05, [M+H]+ 284.1154, found 284.1204.
133.05, 129.61, 126.78, 125.91, 125.74, 122.97, 120.83, 118.92,
77.29, 77.04, 76.78, 44.35, 21.29, 17.46, 13.75. HRMS (ESI) (4-Chlorophenyl)-(2-(pyridin-2-yl)-2H-indazol-3-yl)-
calcd. for C18H18N2O [M+H]+ 279.1453, found 279.1519.
methanone (4i). Yellow solid in a yield of 38% (33 mg). 1H NMR
(500 MHz, DMSO- d6) δ 8.22-8.20 (m, 1H), 8.16-8.07 (m, 2H),
(4d). 7.91 (d, J = 8.84 Hz, 1H), 7.76-7.69 (m, 2H), 7.56-7.50 (m, 3H),
1-(2-(4-Chlorophenyl)-2H-indazol-3-yl)-butan-1-one
Yellow solid in a yield of 85% (66 mg). 1H NMR (500 MHz, CDCl3): 7.48 ( m, 1H), 7.41 (ddd, J = 7.17, 4.85, 1.24 Hz, 1H), 7.28 (ddd,
7.99 (dd, J = 8.31, 1.21 Hz, 1H), 7.87 (td, J = 5.14, 1.06, 1.06 Hz, J = 8.52, 6.60, 0.67 Hz, 1H). 13C NMR (126 MHz, DMSO-d6): δ
1H), 7.52-7.47 (m, 2H), 7.46-7.38 (m, 4H), 2.98 (t, J = 7.23, 7.23 185.77, 166.96, 151.36, 148.91, 148.39, 140.31, 138.74, 138.26,
Hz, 2H), 1.81-1.73 (m, 2H), 1.00 (t, J = 7.41, 7.41 Hz, 3H). 13C 136.60, 131.83, 131.61, 131.08, 130.13, 129.47, 129.20, 128.60,
NMR (126 MHz, CDCl3): δ 189.34, 147.57, 139.04, 134.22, 125.60, 124.60, 123.53, 120.51, 118.76, 117.69, 40.43, 40.36,
131.57, 128.08, 126.43, 126.00, 125.12, 121.70, 119.58, 118.08, 40.27, 40.19, 40.10, 39.93, 39.77, 39.60, 39.43. HRMS (ESI)
76.28, 76.03, 75.77, 43.40, 16.25, 12.78, 0.00. HRMS (ESI) calcd. calcd. for C19H12ClN3O [M+H]+ 334.0749, found 334.0810.
for C17H15ClN2O [M+H]+ 300.0843, found 300.0798.
(2-(Pyridin-2-yl)-2H-indazol-3-yl)-(thiophen-3-yl)-methanone
1
1-(2-Phenyl-2H-[1,3]dioxolo[4,5-f]indazol-3-yl)-butan-1-one
(4j). Yellow solid in a yield of 52% (41 mg). H NMR (500 MHz,
(4e). Yellow solid in a yield of 77% (62 mg). 1H NMR (500 MHz, CDCl3) δ 8.23 (dd, J = 4.84, 1.01 Hz, 1H), 7.97 (d, J = 8.13 Hz, 1H),
CDCl3): 7.54-7.49 (m, 3H), 7.47-7.43 (m, 2H), 7.28 (s, 1H), 7.07 7.86-7.79 (m, 2H), 7.76 (d, J = 8.83 Hz, 1H), 7.53-7.48 (m, 2H),
(s, 1H), 6.05 (s, 2H), 2.65 (t, J = 7.27, 7.27 Hz, 2H), 1.72-1.63 (m, 7.31 (ddd, J = 8.80, 6.60, 0.99 Hz, 1H), 7.26 (dd, J = 5.10, 2.93 Hz,
2H), 0.89 (t, J = 7.40, 7.40 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 1H), 7.20-7.17 (m, 1H), 7.11 (ddd, J = 8.56, 6.60, 0.73 Hz, 1H).
191.13, 149.51, 148.84, 145.99, 141.46, 133.15, 129.14, 129.07, 13C NMR (126 MHz, CDCl3): δ 180.37, 167.32, 151.92, 149.03,
126.12, 119.98, 101.57, 96.25, 94.90, 77.32, 77.06, 76.81, 44.11, 148.16, 142.57, 138.77, 134.60, 134.38, 133.02, 128.15. HRMS
17.50, 13.74. HRMS (ESI) calcd. for C18H16N2O3 [M+H]+ 309.1194, (ESI) calcd. for C17H11N3OS [M+H]+ 306.0605, found 306.0758.
found 309.1219.
Phenyl-(2-(pyridin-2-yl)-2H-indazol-3-yl)-methanone
(4k).
1-(2-(Pyridin-2-yl)-2H-indazol-3-yl)-butan-1-one (4f). Yellow Yellow solid in a yield of 76% (59 mg). 1H NMR (500 MHz, CDCl3)
solid in a yield of 42% (29 mg). 1H NMR (400 MHz, CDCl3): δ 8.53 δ 8.21 (dd, J = 4.82, 1.04 Hz, 1H), 8.05 (d, J = 8.15 Hz, 1H), 7.88-
(dd, J = 4.84, 1.03 Hz, 1H), 7.96 (dt, J = 7.77, 7.61, 1.82 Hz, 1H), 7.83 (m, 4H), 7.53 (t, J = 7.42, 7.42 Hz, 1H), 7.48 (d, J = 8.60 Hz,
7.87 (d, J = 8.64 Hz, 2H), 7.83 (d, J = 8.76 Hz, 1H), 7.44-7.38 (m, 1H), 7.43-7.35 (m, 3H), 7.20 (dd, J = 7.36, 4.88 Hz, 1H), 7.15 (q,
2H), 7.30 (ddd, J = 8.46, 6.65, 0.72 Hz, 1H), 2.92 (dd, J = 8.83, 1H). 13C NMR (126 MHz, CDCl3): δ 187.13, 171.60, 151.81,
5.76 Hz, 2H), 1.88-1.73 (m, 2H), 0.99 (t, J = 7.42, 7.42 Hz, 3H). 149.10, 148.02, 138.72, 137.94, 133.73, 133.25, 132.52, 130.21,
13C NMR (126 MHz, CDCl3): δ 193.35, 152.83, 148.95, 148.36, 129.52, 129.41, 128.58, 128.49, 127.86, 124.72, 123.69, 123.36,
138.80, 133.68, 127.57, 125.41, 123.94, 122.31, 120.53, 118.79, 120.60, 118.42, 117.37, 77.31, 77.05, 76.80. HRMS (ESI) calcd.
118.67, 77.32, 77.06, 76.81, 45.05, 17.67, 13.79. HRMS (ESI) for C19H13N3O [M+H]+ 300.1092, found 300.1124.
calcd. for C16H15N3O [M+H]+ 266.1249, found 266.1318.
(5-Fluoro-2-(pyridin-2-yl)-2H-indazol-3-yl)-(phenyl)-
1-(2-(Pyridin-2-yl)-2H-indazol-3-yl)-propan-1-one (4g). Yellow methanone (4l). Yellow solid in a yield of 45% (37 mg). 1H NMR
solid in a yield of 46% (30 mg).1H NMR (500 MHz, CDCl3): δ 8.54 (500 MHz, CDCl3): δ 8.15 (dd, J = 4.84, 1.01 Hz, 1H), 7.93 (d, J =
(td, J = 5.32, 2.66, 2.66 Hz, 1H), 7.99-7.92 (m, 1H), 7.90-7.85 (m, 8.13 Hz, 1H), 7.80 (dt, J = 8.03, 7.81, 1.81 Hz, 1H), 7.78-7.74 (m,
2H), 7.83 (d, J = 8.76 Hz, 1H), 7.44-7.37 (m, 2H), 7.33-7.27 (m, 3H), 7.51-7.46 (m, 1H), 7.38-7.33 (m, 2H), 7.15 (ddd, J = 7.46,
1H), 2.96 (q, J = 7.24, 7.24, 7.23 Hz, 2H), 1.25 (t, J = 7.24, 7.24 4.88, 0.91 Hz, 1H), 7.12 (dt, J = 9.21, 9.18, 2.41 Hz, 1H), 6.99 (dd,
Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 193.79, 152.87, 148.96, J = 8.96, 1.90 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 186.62,
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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99, 891-904; (b) D. D. Gaikwad, A. D. Chapolikar, C. G.
160.97, 159.02, 151.70, 148.08, 146.48, 138.76, 137.74, 133.67,
133.36, 130.19, 129.43, 128.66, 128.47, 123.53, 120.81, 120.73,
119.91, 119.67, 117.38, 103.38, 103.18, 77.31, 77.05, 76.80.
HRMS (ESI) calcd. for C19H12FN3O [M+H]+ 318.0998, found
318.1073.
View Article Online
Devkate, K. D. Warad, A. P. TayadDeO, RI:.10P..10P3a9w/Ca9rOaBn0d17A4.9JF.
Domb, European Journal of Medicinal Chemistry, 2015, 46,
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and D. Distefano, Bioorganic & Medicinal Chemistry
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Laynez, J. Gomez, P. Jimenez, F. Tomas and J. Elguero,
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Alkorta and J. Elguero, Journal of Physical Organic
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Transactions, 1996, 1, 57-60.
3-(tert-Butyl)-2-(pyridin-2-yl)-2H-indazole (4m). Yellow solid in
a yield of 29% (19 mg). 1H NMR (500 MHz, CDCl3): δ 8.60 (ddd, J
= 4.87, 1.86, 0.76 Hz, 1H), 7.95 (td, J = 8.82, 0.94, Hz, 2H), 7.90
(td, J = 7.75, 1.91 Hz, 1H), 7.68 (td, J = 8.75, 0.94 Hz, 1H), 7.54
(td, J = 7.91, 0.89, Hz, 1H), 7.28 (ddd, J = 8.73, 6.55, 0.98 Hz, 1H),
7.04 (ddd, J = 8.79, 6.55, 0.97 Hz, 1H), 1.46 (s, 9H). 13C NMR (126
MHz, CDCl3) δ 155.43, 148.26, 138.21, 126.32, 124.50, 122.72,
121.04, 118.04, 116.56, 77.32, 77.07, 76.81, 34.86, 31.57,
31.25.HRMS (ESI) calcd. for C16H17N3 [M+H]+ 252.1456, found
252.1552.
4.
5.
3-(tert-Butyl)-5-fluoro-2-(pyridin-2-yl)-2H-indazole
(4n).
Yellow solid in a yield of 28% (20 mg). 1H NMR (500 MHz, CDCl3):
δ8.62-8.60 (m, 1H), 7.92 (dt, J = 7.73, 7.70, 1.87 Hz, 1H), 7.64
(td, J = 14.95, 7.42, 7.42 Hz, 1H), 7.57-7.50 (m, 2H), 7.50-7.45
(m, 1H), 7.10 (dt, J = 9.08, 9.06, 2.36 Hz, 1H), 1.43 (s, 9H). 13C
NMR (126 MHz, CDCl3): δ 158.45, 156.55, 155.25, 148.36,
146.30, 138.34, 124.62, 122.57, 120.04, 119.96, 118.78, 118.14,
117.91, 105.25, 105.05, 77.29, 77.03, 76.78, 31.40. HRMS (ESI)
calcd. for C16H16FN3 [M+H]+ 270.1362, found 270.1431.
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8.
Conclusions
In summary, it was achieved an economic and efficient method
for the direct C3-acylation of 2H-indazoles to react with
aldehydes at 80C using catalyst NiCl2, oxidant TBHP, additive
PivOH in the argon environment. The developed approach may
increase the molecular diversity of 2H-indazoles, promoting the
development of biological and pharmaceutical applications of
2H-indazole derivatives to some extent.
9.
10.
Conflicts of interest
There are no conflicts to declare.
11.
12.
C. D. Wang and R. S. Liu, Organic & Biomolecular Chemistry,
2012, 10, 8948-8952.
Acknowledgements
Support for this project was provided by the National Natural
Science Foundation of China (81773638, 81473135) and the
Natural Science Foundation of Zhejiang Province
(LZ18H300001). We thank Ms Jianyang Pan, Research and
Service Center, College of Pharmaceutical Sciences of Zhejiang
University, for performing NMR spectrometry for structure
elucidation.
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13.
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Notes and references
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H and B. Keppler, Journal of Inorganic Biochemistry, 2006,
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