Synthesis of 2,3-dihydro-1H-indazoles by Rh(iii)-catalyzed C-H cleavage of arylhydrazines

Article abstract of DOI:10.1039/c4ob00921e

A rhodium-catalyzed efficient method for the synthesis of 2,3-dihydro-1H-indazoles is described. The reaction of arylhydrazines with olefins results in the corresponding 2,3-dihydro 1H-indazoles with exclusive regioselectivity via C-H bond activation. The utility of the methodology is illustrated by a rapid synthesis of 1H-indazoles under mild reaction conditions in half an hour. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00921e

Organic &
Biomolecular Chemistry
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Synthesis of 2,3-dihydro-1H-indazoles by
Rh(III)-catalyzed C–H cleavage of arylhydrazines†
Jinzhong Yao,a Ruokun Feng,a Cong Lin,a Zhanxiang Liu*a and Yuhong Zhang*a,b
Cite this: Org. Biomol. Chem., 2014,
12, 5469
Received 5th May 2014,
Accepted 10th June 2014
A rhodium-catalyzed efficient method for the synthesis of 2,3-dihydro-1H-indazoles is described.
The reaction of arylhydrazines with olefins results in the corresponding 2,3-dihydro 1H-indazoles with
exclusive regioselectivity via C–H bond activation. The utility of the methodology is illustrated by a rapid
synthesis of 1H-indazoles under mild reaction conditions in half an hour.
DOI: 10.1039/c4ob00921e
www.rsc.org/obc
of Pd-, Fe-, and Cu-catalytic systems were reported to syn-
thesize 1H-indazoles through intramolecular C–H amination
Introduction
Heterocycles are frequently found in bioactive natural products by Hiroya, Bao and Jiang, respectively.8 Glorius reported a syn-
and have been intensively studied as drug candidates. Accord- thesis of 1H-indazoles from easily available arylimidates and
ingly, development of efficient and economic ways to construct organo azides via the Rh-catalyzed C–H activation/C–N bond
heterocycles has been a subject of considerable interest in formation and Cu-catalyzed N–N bond formation.9 Recently,
organic synthesis.1 In particular, the domino C–H activation/ the preparation of N-aryl-2H-indazoles initiated by Rh(III)-
cyclization method has emerged as a powerful tool for the syn- catalyzed direct addition of an azobenzene C–H bond to an
thesis of heterocycles.2–4
The indazole is an important heterocycle and the key motif demonstrated by Lavis and Ellman.10
aldehyde with subsequent cyclization and aromatization is
of anti-cancer, anti-inflammatory, anti-HIV, and anti-emetic
Arylhydrazine is a widely used chemical reagent and its
drugs (Scheme 1).5 Consequently, the diverse approach to derivatives can be readily prepared. However, the utilization of
indazoles has attracted much attention over the past few arylhydrazines in the direct functionalization of the C–H bond
decades.6 Besides the traditional methods of condensation is rarely studied.11 Herein, we wish to report a highly efficient
and transition metal-catalyzed intramolecular amination of method for the synthesis of 2,3-dihydro-1H-indazoles via the
o-halo arylhydrazones,7 synthesis of indazoles via transition rhodium-catalyzed C–H activation process. The corresponding
metal-catalyzed C–H functionalization has aroused much 1H-indazoles could be readily prepared by the treatment of 2,3-
attention recently. Starting from arylhydrazones, three examples dihydro-1H-indazoles with 2 N HCl in ethanol in half an hour.
Results and discussion
In the preliminary investigation, we examined the reaction of
N′-methyl-N′-phenyl-acetylhydrazide with ethyl acrylate in the
presence of [Cp*RhCl2]2 (5 mol%), Cu(OAc)2 (2.0 equiv.), and
DCE at 110 °C under nitrogen (Table 1, entry 1). To our
delight, the desired product 3aa was obtained in 61% yield.
Further studies showed that the addition of 1.0 equiv. AcOH
improved the yield to 73% (Table 1, entry 2). Other additives,
such as PivOH, CsOAc, and LiOAc, were found less effective
(Table 1, entries 3–5). No reaction was observed in the absence
Scheme 1 Some examples of biologically active 1H-indazoles.
of an oxidant or a catalyst (Table 1, entries 6–7). The desired
product was not observed when [Rh(COD)Cl2]2 and [RuCl2-
aDepartment of Chemistry, ZJU-NHU United R&D Center, Zhejiang University,
Hangzhou 310027, China. E-mail: liuzhanx@zju.edu.cn, yhzhang@zju.edu.cn
(p-cymene)]2 were used as catalysts (Table 1, entries 8–9). Among
bState Key Laboratory of Applied Organic Chemistry, Lanzhou University,
the solvents investigated, dichloroethane was the best. Other
Lanzhou 730000, China
solvents, such as t-AmOH, toluene, DME, and acetone, were
ineffective (Table 1, entries 10–13). In the case of decreasing
†Electronic supplementary information (ESI) available: Experimental details.
Spectral data and other ESI. See DOI: 10.1039/c4ob00921e
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Table 1 Optimization of reaction conditionsa
Table 2 Scope of olefinesa
Entry
1
Substrate (2)
Product (3)
Yieldb (%)
73
Entry
Catalyst
Additive
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
—
[Rh(COD)Cl2]2
[RuCl2(p-cymene)]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
—
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
61
73
68
57
AcOH
PivOH
CsOAc
LiOAc
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
55
N.D.c
N.D.
N.D.
N.D.
Trace
36
2
69
9
DCE
10
11
12
13
14
15
16
t-AmOH
Toluene
DME
Acetone
DCE
DCE
DCE
50
58
41d
50e
49f
3
4
71
59
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (5 mol%),
Cu(OAc)2 (2.0 equiv.), additive (1.0 equiv.), solvent (2 mL), 110 °C,
24 h, under N2. b Isolated yield. c Without Cu(OAc)2. d 2.5 mol%
[RhCp*Cl2]2 was used. e The reaction time was 12 h. f The reaction was
conducted at 90 °C.
the catalyst amount by half, the yield dropped to 41% (Table 1,
entry 14). The reaction time and temperature influenced the
reaction. The yield dropped to 50% when the reaction time
was decreased to 12 h (Table 1, entry 15). Lower temperature
was unsuitable for the reaction (Table 1, entry 16). Thus, the
optimal reaction conditions were [RhCp*Cl2]2 (5.0 mol%),
Cu(OAc)2 (2.0 equiv.), and HOAc (1.0 equiv.) under nitrogen in
DCE (2.0 mL) at 110 °C for 24 h.
With the optimized reaction conditions in hand, the scope
and limitation of olefins were examined as shown in Table 2. A
series of acrylates, ethyl acrylate, methyl acrylate, n-butyl acry-
late, t-butyl acrylate, phenyl acrylate, and benzyl acrylate (2a–f)
participated in the reaction smoothly to give the products in
good yields (Table 2, entries 1–6). It is noteworthy that acrylo-
nitrile and 1-arylprop-2-en-1-ones were also effective in this
reaction, providing the desired products in moderate yields
(Table 2, entries 7–11).
5
6
57
66
7
8
45
55
Next, we evaluated the scope of the reaction with regard to
a range of the N′-alkyl-N′-arylacetohydrazides as shown in
Table 3. In general, the reaction occurred smoothly to give the
N1,N2-disubstituted-2,3-dihydro-1H-indazoles in moderate to
good yields. A variety of functional groups, including methyl,
methoxy, fluoro, chloro and bromo on the aryl ring, were
compatible under the optimal reaction conditions (Table 3,
entries 1–9). Notably, the reaction presented regioselectivity at
the ortho-position of the less steric side of the arenes furnish-
ing the corresponding products in good yields (Table 3,
entries 2, 9). N′-Methyl-N′-arylacetohydrazide with ortho-substituents
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Table 2 (Contd.)
Table 3 Scope of N’-alkyl-N’-arylacetohydrazidesa
Entry
9
Substrate (2)
Product (3)
Yieldb (%)
49
Entry
1
Substrate (1)
Product (3)
Yieldb (%)
70
10
11
52
54
2
3
75
32
a Reaction conditions: 1a (0.2 mmol), olefin (0.4 mmol), [Cp*RhCl2]2
(5 mol%), Cu(OAc)2 (2.0 equiv.), AcOH (1.0 equiv.), DCE (2.0 mL),
110 °C, 24 h, under N2. b Isolated yield.
4
5
61
71
gave a 32% yield, illustrating that the steric hindrance played a
role in the reaction (Table 3, entry 3). Various halogen substitu-
ents showed good compatibility, which added flexibility to
further elaborate the indazole derivatives (Table 3, entries
7–9). The protective group other than methyl in the N-atom
was also investigated. Ethyl and n-butyl substituted 2-phenyl-
acetohydrazides were compatible with the reaction conditions
and provided the products in moderate yields (Table 3, entries
10–11).
The acid-mediated deprotection protocol can be success-
fully applied for the synthesis of 1H-indazoles. For example,
the above prepared 3aa and 3ah products could be easily trans-
formed to 4a and 4b 1H-indazoles in 2 N HCl in ethanol in
half hour in good yields (Scheme 2).
Based on previous studies of rhodium catalysis, a plausible
mechanism is proposed as illustrated in Scheme 3. First, the
rhodacycle intermediate A was formed through the reaction of
N′-methyl-N′-phenyl-acetohydrazide with the acetohydrazide-
assisted C–H activation process. The subsequent coordination
of the intermediate A with the olefin afforded the intermediate
B, which was transformed into C by 1,2-migratory insertion.
The β-hydride elimination of the intermediate C gives the
intermediate D followed by reductive elimination to yield the
Rh(I) species. An intramolecular aza-Michael addition of the
6
7
63
72
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Table 3 (Contd.)
Entry
8
Substrate (1)
Product (3)
Yieldb (%)
64
Scheme 3 Proposed reaction mechanism.
9
67
62
intermediate E affords the product 3. The oxidation of Rh(I) by
Cu(OAc)2 generates Rh(III) species to fulfill the catalytic cycle.
Conclusions
10
In summary, we have developed a facile and efficient strategy
for the construction of 2,3-dihydro-1H-indazoles via rhodium(III)-
catalyzed C–H activation of arylhydrazines.12 The reaction
exhibits a good tolerance for a broad range of functional
groups. Starting from simple hydrazine substrates, this
method provides an easy alternative to the synthesis of
1H-indazoles.
11
46
Experimental
General
Unless stated otherwise, all reactions were performed under
air atmosphere. All solvents were used without further purifi-
cation. Spectra were recorded for 1H NMR at 400 MHz, and 13
C
a Reaction conditions: N′-alkyl-N′-arylacetohydrazide (0.2 mmol), 2a
(0.4 mmol), [Cp*RhCl2]2 (5 mol%), Cu(OAc)2 (2.0 equiv.), AcOH
(1.0 equiv.), DCE (2.0 mL), 110 °C, 24 h, under N2. b Isolated yield.
NMR at 100 MHz using TMS as an internal standard. The fol-
lowing abbreviations were used to describe peak patterns
where appropriate: singlet (s), doublet (d), doublet of doublets
(dd), triplet (t), quartet (q), multiplet (m), broad resonances
(br). Mass spectroscopy data of the products were collected on
an HRMS-APCI instrument or a low-resolution MS instrument
using EI or ESI ionization.
General procedure for the starting materials
N′-Alkyl-N′-arylacetohydrazide were prepared according to pub-
lished procedures.11,13 To a solution of arylhydrazine hydro-
chloride salt (20 mmol) in 1 N NaOH (40 mL) and THF
(10 mL) was added acetic anhydride (2.0 g, 20 mmol) drop-
wise. After stirring for 30 min the mixture was extracted with
EtOAc three times. The combined organic layer was dried over
Na2SO4 and filtered through the pad of silica gel. The filtrate
was concentrated to afford a solid residue. Recrystallization
from a mixture of petroleum ether–ethyl acetate (5 : 1) gave
2-acetyl-1-arylhydrazine.
Scheme 2 Transformation of products.
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Freshly cut Na (0.23 g, 10 mmol) was added to absolute 18.6; HRMS (EI) Calcd for C11H16N2O (M)+ 192.1263; Found,
ethanol (6 mL) in a sealed tube to obtain a clear solution. 192.1267.
N′-(4-Fluorophenyl)-N′-methylacetohydrazide (1h).13 White solid;
2-Acetyl-1-arylhydrazine (10 mmol) was added to the resulting
solution, and then halogenated alkane (iodomethane for
1H NMR (400 MHz, CDCl3, TMS) δ 7.36 (br s, 1H), 7.00–6.88
(m, 2H), 6.80–6.68 (m, 2H), 3.09 and 3.05 (2 × s, 3H), 2.04 and
1.96 (2 × s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.9, 169.3,
1a–1j, bromoethane for 1k and n-butyl chloride for 1l) was
added. The resulting solution was sealed and kept at 100 °C in
the dark for 20 h. The solution was concentrated and the
residue was dissolved in ethyl acetate (20 mL), and then
washed with water, dried over Na2SO4 and filtered through the
pad of silica gel. The filtrate was concentrated and the result-
ing residue was purified by flash column chromatography
(silica gel, ethyl acetate–petroleum ether = 1 : 2, v/v) to obtain
the desired products.
158.4 (JC–F = 53.6 Hz), 156.1 (JC–F = 53.1 Hz), 145.8 (JC–F
=
1.6 Hz), 145.7 (JC–F = 2.2 Hz), 115.7 (JC–F = 22.4 Hz), 115.4
(JC–F = 22.0 Hz), 114.7 (JC–F = 53.6 Hz), 114.3 (JC–F = 53.6 Hz),
42.6, 41.0, 20.9, 19.0; HRMS (EI) Calcd for C9H11FN2O (M)+
182.0855; Found, 182.0857.
N′-(4-Chlorophenyl)-N′-methylacetohydrazide (1i).13 White solid;
1H NMR (400 MHz, CDCl3, TMS) δ 7.26–7.18 (m, 2H), 6.90
(br s, 1H), 6.80–6.75 (m, 2H), 3.18 and 3.16 (2 × s, 3H), 2.06
and 2.06 (2 × s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.9, 169.2,
147.9, 147.8, 129.2, 128.9, 125.7, 124.6, 114.5, 114.1, 42.1, 40.7,
20.9, 19.1; HRMS (EI) Calcd for C9H11ClN2O (M)+ 198.0560;
Found, 198.0564.
Characterization data of the starting materials
1
N′-Methyl-N′-phenylacetohydrazide (1a).13 White solid; H NMR
(400 MHz, CDCl3, TMS) δ 7.34–7.24 (m, 2H), 6.89–6.83 (m,
3H), 3.20 and 3.18 (2 × s, 3H), 2.09 and 2.07 (2 × s, 3H);
13C NMR (100 MHz, CDCl3) δ 175.8, 168.9, 149.3, 149.0, 129.4,
129.1, 120.7, 120.0, 113.2, 113.0, 42.1, 40.9, 21.1, 19.1; HRMS
(EI) Calcd for C9H12N2O (M)+ 164.0950; Found, 164.0948.
N′-(4-Bromophenyl)-N′-methylacetohydrazide (1j).2 White solid;
1H NMR (400 MHz, CDCl3, TMS) δ 7.91 (br s, 1H), 7.38–7.26
(m, 2H), 6.71–6.62 (m, 2H), 3.12 and 3.10 (2 × s, 3H), 2.03 and
2.00 (2 × s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.8, 169.2,
148.3, 148.2, 132.1, 131.7, 114.8, 114.5, 112.9, 111.7, 42.0, 40.6,
20.9, 19.0; HRMS (EI) Calcd for C9H11BrN2O (M)+ 242.0055;
Found, 242.0057.
N′-(3-Chlorophenyl)-N′-methylacetohydrazide (1k). Colorless
oil; 1H NMR (400 MHz, CDCl3, TMS) δ 7.94 (br s, 1H),
7.19–7.08 (m, 1H), 6.90–6.61 (m, 3H), 3.13 and 3.11 (2 × s, 3H),
2.03 and 2.00 (2 × s, 3H); 13C NMR (100 MHz, CDCl3) δ 176.0,
169.4, 150.5, 150.3, 135.3, 135.0, 130.5, 130.2, 120.5, 119.4,
113.3, 112.8, 111.3, 110.9, 42.0, 40.6, 21.0, 19.1; HRMS (EI)
Calcd for C9H11ClN2O (M)+ 198.0560; Found, 198.0560.
N′-Ethyl-N′-phenylacetohydrazide (1k). White solid; 1H NMR
(400 MHz, CDCl3, TMS) δ 7.31–7.27 (m, 1H), 7.22–7.21
(m, 1H), 6.94–6.82 (m, 3H), 3.54–3.49 (m, 2H), 2.06 and 2.04
(2 × s, 3H), 1.20 (2 × t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 176.5, 169.4, 148.6, 148.2, 129.4, 129.1, 120.6, 119.7,
113.9, 113.3, 48.6, 46.4, 20.9, 19.2, 11.2, 10.5; HRMS (EI) Calcd
for C10H14N2O (M)+ 178.1106; Found, 178.1104.
1
N′-Methyl-N′-p-tolylacetohydrazide (1b).13 White solid; H NMR
(400 MHz, CDCl3, TMS) δ 7.93 (br s, 1H), 7.09 and 7.01 (2 × d,
J = 8.4, 8.0, 2H), 6.75–6.70 (m, 2H), 3.08 (s, 3H), 3.28 and 3.22
(2 × s, 3H), 2.04 and 1.98 (2 × s, 3H); 13C NMR (100 MHz,
CDCl3) δ 175.9, 169.0, 147.2, 147.1, 130.0, 129.8, 129.5, 129.1,
113.5, 113.3, 42.3, 40.9, 20.9, 20.2, 19.0; HRMS (EI) Calcd for
C10H14N2O (M)+ 178.1106; Found, 178.1106.
N′-Methyl-N′-m-tolylacetohydrazide (1c). White solid; 1H NMR
(400 MHz, CDCl3, TMS) δ 7.20–7.04 (m, 2H), 6.75–6.70
(m, 3H), 3.13 and 3.12 (2 × s, 3H), 2.33 and 2.29 (2 × s, 3H),
2.06 and 2.02 (2 × s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.9,
169.0, 149.4, 149.2, 139.3, 138.8, 129.2, 128.9, 121.5, 120.7,
114.0, 113.7, 110.4, 110.2, 42.1, 40.8, 21.7, 21.7, 21.0, 19.1;
HRMS (EI) Calcd for C10H14N2O (M)+ 178.1106; Found,
178.1107.
1
N′-Methyl-N′-o-tolylacetohydrazide (1d). White solid; H NMR
(400 MHz, CDCl3, TMS) δ 7.26–7.15 (m, 4H), 3.10 and 2.91
(2 × s, 3H), 2.36 and 2.28 (2 × s, 3H), 2.13 and 1.94 (2 × s, 3H);
13C NMR (100 MHz, CDCl3) δ 174.9, 167.8, 149.8, 148.0, 132.0,
131.3, 131.1, 130.7, 126.8, 126.0, 124.8, 123.8, 118.8, 117.4,
46.4, 41.9, 20.9, 19.7, 18.4, 17.9; HRMS (EI) Calcd for
C10H14N2O (M)+ 178.1106; Found, 178.1110.
N′-Butyl-N′-phenylacetohydrazide (1l). White solid; 1H NMR
(400 MHz, CDCl3, TMS) δ 7.31–7.22 (m, 2H), 6.94–6.82
(m, 3H), 3.51–3.42 (m, 2H), 2.08–2.03 (2 × s, 3H), 1.63–1.59
(m, 2H), 1.42–1.36 (m, 2H), 0.97 (t, J = 7.2, 3H); 13C NMR
(100 MHz, CDCl3) δ 176.2, 169.1, 148.9, 148.3, 129.4, 129.2,
120.5, 119.8, 113.7, 113.1, 54.6, 52.3, 28.5, 27.7, 21.0, 20.9,
20.2, 19.2, 13.9, 13.9; HRMS (EI) Calcd for CH18N2O (M)+
206.1419; Found, 206.1418.
N′-(4-Methoxyphenyl)-N′-methylacetohydrazide (1f).13 Color-
1
less oil; H NMR (400 MHz, CDCl3, TMS) δ 6.83–6.75 (m, 4H),
3.74 and 3.70 (2 × s, 3H), 3.04 and 3.03 (2 × s, 3H), 2.05 and
1.94 (2 × s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.8, 169.1,
154.2, 153.6, 143.5, 115.1, 114.9, 114.5, 114.3, 55.5, 55.4, 42.8,
41.2, 20.9, 19.0; HRMS (EI) Calcd for C10H14N2O2 (M)+
194.1055; Found, 194.1057.
General procedure for the reaction of N′-methyl-N′-arylaceto-
hydrazide 1 with olefine. To a 25 mL sealed tube containing a
N′-(3,4-Dimethylphenyl)-N′-methylacetohydrazide (1g). White magnetic stir bar, were added 1 (0.2 mmol), olefine 2
1
solid; H NMR (400 MHz, CDCl3, TMS) δ 7.06 and 7.01 (2 × d, (0.4 mmol), [Cp*RhCl2] (6 mg, 5 mol%), Cu(OAc)2 (72 mg,
2
J = 8.4, 8.0, 1H), 6.72 (br s, 1H), 6.68–6.60 (m, 2H), 3.16 and 0.4 mmol), AcOH (12 mg, 0.2 mmol), and DCE (2 mL). The
3.12 (2 × s, 3H), 2.25 and 2.22 (2 × s, 3H), 2.20 and 2.17 (2 × s, tube was sealed under nitrogen and heated to 110 °C with stir-
3H), 2.09 and 2.06 (2 × s, 3H); 13C NMR (100 MHz, CDCl3) ring for 24 h. Then the reaction mixture was cooled to room
δ 175.8, 168.9, 147.6, 147.5, 137.5, 137.0, 130.3, 130.0, 128.8, temperature and diluted with ethyl acetate. The reaction
127.9, 114.9, 114.9, 110.8, 110.8, 42.3, 41.0, 21.0, 20.1, 19.0, mixture was filtered through a plug of Celite and the residue
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was washed with ethyl acetate (2 × 5 mL). The combined CDCl3) δ 173.1, 169.8, 150.0, 135.6, 130.6, 128.7, 128.5, 128.5,
organic layer was concentrated under vacuum and the residue 128.3, 123.9, 123.3, 113.7, 66.7, 57.9, 48.7, 43.2, 21.0; HRMS
was purified by flash column chromatography (silica gel, ethyl (EI) Calcd for C19H20N2O3 (M)+ 324.1474; Found, 324.1472.
2-(2-Acetyl-1-methyl-2,3-dihydro-1H-indazol-3-yl)acetonitrile
(3ag). Yellow oil; H NMR (400 MHz, CDCl3, TMS) δ 7.35–7.30
acetate–petroleum ether = 1 : 2, v/v) to afford the corres-
ponding products.
1
(m, 2H), 7.15–7.11 (m, 1H), 6.95 (d, J = 8.0 Hz, 1H), 5.56 (t, J =
4.8 Hz, 1H), 3.16 (s, 3H), 2.98–2.95 (m, 2H), 2.30 (s, 3H);
Characterization data of the products
Ethyl 2-(2-acetyl-1-methyl-2,3-dihydro-1H-indazol-3-yl)acetate
1
(3aa). Yellow oil; H NMR (400 MHz, CDCl3, TMS) δ 7.30–7.26 13C NMR (100 MHz, CDCl3) δ 174.0, 150.0, 129.6, 127.1, 124.1,
(m, 2H), 7.08–7.04 (m, 1H), 6.92 (d, J = 7.6 Hz, 1H), 5.72 (t, J = 122.7, 117.2, 113.7, 58.0, 48.7, 26.0, 21.1; HRMS (EI) Calcd for
6.0 Hz, 1H), 4.21–4.17 (m, 2H), 3.07 (s, 3H), 2.95 (dd, J = 15.2, C12H13N3O (M)+ 215.1059; Found, 215.1055.
2-(2-Acetyl-1-methyl-2,3-dihydro-1H-indazol-3-yl)-1-phenylethanone
(3ah). Yellow oil; 1H NMR (400 MHz, CDCl3, TMS) δ 8.01
(d, J = 7.2 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.49–7.45 (m, 2H),
7.32 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.02 (t, J =
7.6 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 5.93–5.90 (m, 1H),
3.77–3.73 (m, 1H), 3.30 (dd, J = 15.6, 9.6 Hz, 1H), 3.08 (s, 3H),
5.2 Hz, 1H), 2.68 (dd, J = 15.2, 8.4 Hz, 1H), 2.26 (s, 3H), 1.26
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.0, 170.0,
150.0, 130.8, 128.6, 123.9, 123.3, 113.7, 60.7, 57.8, 48.7, 43.2,
21.0, 14.1; HRMS (EI) Calcd for C14H18N2O3 (M)+ 262.1317;
Found, 262.1320.
Methyl 2-(2-acetyl-1-methyl-2,3-dihydro-1H-indazol-3-yl)acetate
(3ab). Yellow oil; H NMR (400 MHz, CDCl3, TMS) δ 7.30–7.26 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 196.9, 172.6, 149.9,
(m, 2H), 7.06 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 5.70 136.5, 133.3, 131.3, 128.6, 128.5, 128.2, 124.1, 124.0, 113.6,
(s, 1H), 3.72 (s, 3H), 3.07 (s, 3H), 2.95 (dd, J = 15.2, 5.2 Hz, 1H), 57.8, 48.9, 47.3, 21.0; HRMS (EI) Calcd for C18H18N2O2 (M)+
2.70 (dd, J = 15.2, 8.0 Hz, 1H), 2.26 (s, 3H); 13C NMR (100 MHz, 294.1368; Found, 294.1373.
1
2-(2-Acetyl-1-methyl-2,3-dihydro-1H-indazol-3-yl)-1-p-tolyletha-
none (3ai). Yellow oil; H NMR (400 MHz, CDCl3, TMS) δ 7.91
(d, J = 7.6 Hz, 2H), 7.32–7.23 (m, 4H), 7.02 (t, J = 7.6 Hz, 1H),
6.92 (d, J = 7.6 Hz, 1H), 5.91–5.89 (m, 1H), 3.74–3.70 (m, 1H),
CDCl3) δ 173.1, 170.4, 150.0, 130.7, 128.7, 123.9, 123.3, 113.7,
57.9, 51.8, 48.7, 43.1, 21.0; HRMS (EI) Calcd for C13H16N2O3 (M)+
248.1161; Found, 248.1162.
1
n-Butyl 2-(2-acetyl-1-methyl-2,3-dihydro-1H-indazol-3-yl)acetate
1
(3ac). Yellow oil; H NMR (400 MHz, CDCl3, TMS) δ 7.30–7.26 3.27 (dd, J = 15.2, 10.0 Hz, 1H), 3.07 (s, 3H), 2.40 (s, 3H), 2.27
(m, 2H), 7.06 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 5.71 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 196.6, 172.7, 149.9,
(s, 1H), 4.13–4.10 (m, 2H), 3.06 (s, 3H), 2.96 (dd, J = 15.2, 144.2, 134.1, 131.4, 129.3, 128.5, 128.3, 124.2, 124.0, 113.6,
5.2 Hz, 1H), 2.68 (dd, J = 15.2, 8.0 Hz, 1H), 2.26 (s, 3H), 58.0, 48.9, 47.3, 21.6, 21.0; HRMS (EI) Calcd for C19H20N2O2 (M)+
1.64–1.57 (m, 2H), 1.39–1.33 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H); 308.1525; Found, 308.1523.
13C NMR (100 MHz, CDCl3) δ 173.0, 170.0, 150.0, 130.9, 128.6,
2-(2-Acetyl-1-methyl-2,3-dihydro-1H-indazol-3-yl)-1-(4-chlorophenyl)-
ethanone (3aj). Yellow oil; 1H NMR (400 MHz, CDCl3, TMS)
123.9, 123.3, 113.7, 64.6, 57.9, 48.7, 43.2, 30.45, 21.0, 19.1,
13.6; HRMS (EI) Calcd for C16H22N2O3 (M)+ 290.1630; Found,
δ 7.96 (d, J = 8.4 Hz, 2H), 7.46–7.43 (m, 2H), 7.31–7.25 (m, 2H),
7.04 (t, J = 7.2 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 5.87 (dd, J = 9.6,
3.6 Hz, 1H), 3.70 (dd, J = 16.0, 2.8 Hz, 1H), 3.28 (dd, J = 15.6,
290.1627.
tert-Butyl
2-(2-acetyl-1-methyl-2,3-dihydro-1H-indazol-3-yl)-
acetate (3ad). Yellow oil; 1H NMR (400 MHz, CDCl3, TMS) 9.6 Hz, 1H), 3.07 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz,
δ 7.33–7.25 (m, 2H), 7.05 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 8.0 Hz, CDCl3) δ 195.8, 172.8, 149.9, 139.8, 134.9, 131.0, 129.7, 129.0,
1H), 5.70 (s, 1H), 3.06 (s, 3H), 2.93 (dd, J = 15.2, 4.8 Hz, 1H), 129.0, 128.6, 124.0, 113.7, 57.9, 48.9, 47.3, 21.0; HRMS (EI)
2.56 (dd, J = 15.2, 8.8 Hz, 1H), 2.25 (s, 3H), 1.44 (s, 9H); Calcd for C18H17ClN2O2 (M)+ 328.0979; Found, 328.0970.
13C NMR (100 MHz, CDCl3) δ 173.0, 179.3, 150.0, 131.2, 128.5,
Ethyl 2-(2-acetyl-1,5-dimethyl-2,3-dihydro-1H-indazol-3-yl)-
acetate (3ba). Yellow oil; 1H NMR (400 MHz, CDCl3, TMS)
123.8, 123.6, 113.7, 81.1, 57.9, 48.6, 44.2, 28.1, 21.0; HRMS (EI)
Calcd for C16H22N2O3 (M)+ 290.1630; Found, 290.1629.
δ 7.09–7.07 (m, 2H), 6.81 (d, J = 8.0 Hz, 1H), 5.67 (s, 1H),
4.21–4.16 (m, 2H), 3.02 (s, 3H), 2.94 (dd, J = 15.2, 5.6 Hz, 1H),
Phenyl 2-(2-acetyl-1-methyl-2,3-dihydro-1H-indazol-3-yl)acetate
1
(3ae). Yellow oil; H NMR (400 MHz, CDCl3, TMS) δ 7.40–7.36 2.67 (dd, J = 15.2, 8.4 Hz, 1H), 2.32 (s, 3H), 2.25 (s, 3H), 1.27
(m, 3H), 7.31 (t, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.9, 170.1,
7.11–7.07 (m, 3H), 6.95 (d, J = 8.0 Hz, 1H), 5.84 (s, 1H), 3.14 147.7, 133.6, 131.0, 129.3, 123.8, 113.5, 60.7, 57.8, 48.9, 43.2,
(dd, J = 15.2, 6.0 Hz, 1H), 3.11 (s, 3H), 2.98 (dd, J = 15.2, 21.0 (2 C), 14.1; HRMS (EI) Calcd for C15H20N2O3 (M)+
7.2 Hz, 1H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.4, 276.1474; Found, 276.1475.
Ethyl 2-(2-acetyl-1,6-dimethyl-2,3-dihydro-1H-indazol-3-yl)-
acetate (3ca). Yellow oil; 1H NMR (400 MHz, CDCl3, TMS)
δ 7.15 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 6.74 (s, 1H),
5.67 (s, 1H), 4.20–4.14 (m, 2H), 3.00 (s, 3H), 2.94 (dd, J = 15.2,
168.5, 150.5, 150.1, 130.4, 129.4, 128.8, 125.9, 124.0, 123.4,
121.6, 113.8, 58.0, 48.7, 43.4, 21.1; HRMS (EI) Calcd for
C18H18N2O3 (M)+ 310.1317; Found, 310.1316.
Benzyl 2-(2-acetyl-1-methyl-2,3-dihydro-1H-indazol-3-yl)acetate
1
(3af). Yellow oil; H NMR (400 MHz, CDCl3, TMS) δ 7.35–7.32 5.2 Hz, 1H), 2.64 (dd, J = 15.2, 8.4 Hz, 1H), 2.35 (s, 3H), 2.24
(m, 5H), 7.28–7.24 (m, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.01 (t, J = (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 5.73 (s, 1H), 5.15 (dd, δ 173.0, 170.0, 150.2, 138.8, 128.0, 124.8, 123.0, 114.3, 60.7,
J = 17.2, 12 Hz, 2H), 3.03 (s, 3H), 2.98 (dd, J = 15.2, 5.6 Hz, 1H), 57.8, 48.7, 43.3, 21.5, 21.0, 14.1; HRMS (EI) Calcd for
2.74 (dd, J = 14.8, 8.0 Hz, 1H), 2.24 (s, 3H); 13C NMR (100 MHz, C15H20N2O3 (M)+ 276.1474; Found, 276.1473.
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Ethyl 2-(2-acetyl-1,7-dimethyl-2,3-dihydro-1H-indazol-3-yl)- δ 7.21 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H),
acetate (3da). Yellow oil; 1H NMR (400 MHz, CDCl3, TMS)
5.67 (s, 1H), 4.19–4.14 (m, 2H), 3.07 (s, 3H), 2.94 (dd, J = 15.2,
δ 7.16 (d, J = 7.6 Hz, 1H), 7.09–7.07 (m, 1H), 7.04–7.00 (m, 1H),
5.70–5.67 (m, 1H), 4.23–4.17 (m, 2H), 3.00 (s, 3H), 2.97 (dd, J =
15.2, 5.6 Hz, 1H), 2.70 (dd, J = 15.2, 8.4 Hz, 1H), 2.32 (s, 3H),
2.27 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 172.4, 170.0, 148.6, 130.4, 127.8, 124.7, 124.1, 120.9,
60.8, 57.4, 46.9, 43.3, 20.9, 17.4, 14.1; HRMS (EI) Calcd for
C15H20N2O3 (M)+ 276.1474; Found, 276.1471.
4.8 Hz, 1H), 2.66 (dd, J = 15.2, 8.4 Hz, 1H), 2.24 (s, 3H), 1.26
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.2, 169.8,
151.2, 134.3, 129.3, 124.3, 124.0, 114.0, 60.8, 57.6, 48.4, 42.9,
21.0, 14.1; HRMS (EI) Calcd for C14H17ClN2O3 (M)+ 296.0928;
Found, 296.0932.
Ethyl 2-(2-acetyl-1-ethyl-2,3-dihydro-1H-indazol-3-yl)acetate (3ka).
Yellow oil; 1H NMR (400 MHz, CDCl3, TMS) δ 7.29–7.24
(m, 2H), 7.04 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 5.74
(s, 1H), 4.25–4.18 (m, 2H), 3.34 (d, J = 6.8 Hz, 2H), 2.91 (dd, J =
15.2, 5.2 Hz, 1H), 2.66 (dd, J = 15.2, 8.8 Hz, 1H), 2.25 (s, 3H),
1.30 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 174.3, 170.1, 148.2, 131.6, 128.5, 123.7,
123.2, 113.8, 60.8, 58.1, 54.3, 42.4, 21.3, 14.1, 11.7; HRMS (EI)
Calcd for C15H20N2O3 (M)+ 276.1474; Found, 276.1472.
Ethyl 2-(2-acetyl-1-ethyl-2,3-dihydro-1H-indazol-3-yl)acetate
Ethyl 2-(2-acetyl-5-methoxy-1-methyl-2,3-dihydro-1H-indazol-
1
3-yl)acetate (3ea). Yellow oil; H NMR (400 MHz, CDCl3, TMS)
δ 6.79–6.76 (m, 3H), 5.61 (s, 1H), 4.13–4.10 (m, 2H), 3.70
(s, 3H), 2.93 (s, 3H), 2.90 (dd, J = 15.2, 5.2 Hz, 1H), 2.60 (dd, J =
15.2, 8.4 Hz, 1H), 2.17 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 172.9, 170.1, 156.8, 143.5, 132.3, 114.8,
114.6, 108.6, 60.8, 58.0, 55.7, 49.3, 43.2, 21.0, 14.2; HRMS (EI)
Calcd for C15H20N2O4 (M)+ 292.1423; Found, 292.1421.
Ethyl 2-(2-acetyl-1,5,6-trimethyl-2,3-dihydro-1H-indazol-3-yl)-
acetate (3fa). Yellow oil; 1H NMR (400 MHz, CDCl3, TMS)
δ 7.04 (s, 1H), 6.72 (s, 1H), 5.64 (s, 1H), 4.21–4.16 (m, 2H), 3.02
(s, 3H), 2.93 (dd, J = 15.2, 5.6 Hz, 1H), 2.64 (dd, J = 15.2,
8.4 Hz, 1H), 2.25 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 1.27 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.9, 170.1, 148.1,
137.2, 132.3, 128.4, 124.1, 114.8, 60.7, 57.8, 48.9, 43.4,
21.0, 20.1, 19.5, 14.1; HRMS (EI) Calcd for C16H22N2O3 (M)+
290.1630; Found, 290.1626.
1
(3la). Yellow oil; H NMR (400 MHz, CDCl3, TMS) δ 7.29–7.24
(m, 2H), 7.04 (t, J = 7.2 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 5.73
(s, 1H), 4.24–4.19 (m, 2H), 3.23 (d, J = 8.8 Hz, 2H), 2.91 (dd, J =
15.2, 6.0 Hz, 1H), 2.66 (dd, J = 15.2, 8.8 Hz, 1H), 2.25 (s, 3H),
1.69–1.48 (m, 2H), 1.36 (t, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz,
3H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 174.2, 170.1, 148.7, 129.5, 128.4, 123.7, 123.3, 113.9, 60.8,
60.5, 58.0, 42.5, 28.8, 21.3, 20.1, 14.1, 13.8; HRMS (EI) Calcd
for C17H24N2O3 (M)+ 304.1787; Found, 304.1791.
Ethyl 2-(2-acetyl-5-fluoro-1-methyl-2,3-dihydro-1H-indazol-3-yl)-
acetate (3ga). Yellow oil; 1H NMR (400 MHz, CDCl3, TMS)
δ 7.04–6.96 (m, 2H), 6.87–6.84 (m, 1H), 5.69 (s, 1H), 4.22–4.16
(m, 2H), 3.03 (s, 3H), 2.98 (dd, J = 15.6, 4.8 Hz, 1H), 2.67 (dd,
J = 15.6, 8.4 Hz, 1H), 2.25 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H);
Transformation of products. To a solution of compound 3
(0.2 mmol) in ethanol (1.0 mL) was added 2 N HCl (0.3 mL).
The mixture was refluxed for 0.5 h. Then the reaction mixture
was allowed to cool to room temperature. Water (10 mL) was
added, and the resulting mixture was extracted with ethyl
acetate (3 × 10 mL). The combined organic layer was dried over
Na2SO4 and filtered through the pad of silica gel. The filtrate
was concentrated and the resulting residue was purified
by flash column chromatography (silica gel, ethyl acetate–
petroleum ether = 1 : 3, v/v) to obtain the desired product.
Ethyl 2-(1-methyl-1H-indazol-3-yl)acetate (4a). Yellow oil;
1H NMR (400 MHz, CDCl3, TMS) δ 7.71 (d, J = 8.4 Hz, 1H),
7.38–7.34 (m, 2H), 7.16–7.12 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H),
4.03 (s, 3H), 4.00 (s, 2H), 1.25 (t, J = 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.3, 140.9, 137.7, 126.3, 122.8, 120.4,
120.2, 109.0, 61.1, 35.3, 33.5, 14.1; HRMS (EI) Calcd for
C12H14N2O2 (M)+ 218.1055; Found, 218.1052.
2-(1-Methyl-1H-indazol-3-yl)-1-phenylethanone (4b). Yellow oil;
1H NMR (400 MHz, CDCl3, TMS) δ 8.13–8.11 (m, 2H),
7.69–7.67 (m, 1H), 7.54–7.52 (m, 1H), 7.46–7.43 (m, 2H),
7.36–7.33 (m, 2H), 7.13–7.09 (m, 1H), 4.64 (s, 2H), 4.02 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 196.0, 140.9, 138.2, 136.3, 133.2,
128.8, 128.5, 126.3, 123.1, 120.7, 120.3, 108.9, 38.2, 35.3; HRMS
(EI) Calcd for C16H14N2O (M)+ 250.1106; Found, 250.1102.
13C NMR (100 MHz, CDCl3) δ 173.0, 169.8, 159.6 (d, JC–F
239.8 Hz), 146.1, 132.7 (d, JC–F = 7.4 Hz), 115.6 (d, JC–F
=
=
22.9 Hz), 114.7 (d, JC–F = 8.1 Hz), 110.8 (d, JC–F = 24.1 Hz), 60.9,
57.7, 49.1, 42.9, 21.0, 14.1; HRMS (EI) Calcd for C14H17FN2O3
(M)+ 280.1223; Found, 280.1222.
Ethyl 2-(2-acetyl-5-chloro-1-methyl-2,3-dihydro-1H-indazol-3-yl)-
acetate (3ha). Yellow oil; 1H NMR (400 MHz, CDCl3, TMS)
δ 7.21–7.15 (m, 2H), 6.76 (d, J = 8.4 Hz, 1H), 5.61 (s, 1H), 4.11
(q, J = 7.2 Hz, 2H), 2.97 (s, 3H), 2.88 (dd, J = 15.6, 5.2 Hz, 1H),
2.60 (dd, J = 15.6, 8.4 Hz, 1H), 2.17 (s, 3H), 1.19 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 173.1, 169.8, 148.7, 132.7,
129.1, 128.8, 123.7, 114.7, 60.8, 57.7, 48.6, 42.8, 21.0, 14.1;
HRMS (EI) Calcd for C14H17ClN2O3 (M)+ 296.0928; Found,
296.0931.
Ethyl 2-(2-acetyl-5-bromo-1-methyl-2,3-dihydro-1H-indazol-3-yl)-
acetate (3ia). Yellow oil; 1H NMR (400 MHz, CDCl3, TMS)
δ 7.43 (s, 1H), 7.40–7.37 (m, 1H), 6.79 (d, J = 8.4 Hz, 1H), 5.69
(s, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.07 (s, 3H), 2.95 (dd, J = 15.6,
5.2 Hz, 1H), 2.67 (dd, J = 15.6, 8.4 Hz, 1H), 2.24 (s, 3H), 1.27
(t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.1, 169.7,
149.2, 133.0, 131.6, 126.6, 116.4, 115.1, 60.8, 57.6, 48.5, 42.9,
21.0, 14.1; HRMS (EI) Calcd for C14H17BrN2O3 (M)+ 296.0928;
Found, 340.0419.
Acknowledgements
We gratefully acknowledge the National Basic Research
Program of China (no. 2011CB936003), NSFC (no. 21272205)
Ethyl 2-(2-acetyl-6-chloro-1-methyl-2,3-dihydro-1H-indazol-3-yl)-
acetate (3ja). Yellow oil; 1H NMR (400 MHz, CDCl3, TMS)
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and the National Key Technology Research and Development
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5476 | Org. Biomol. Chem., 2014, 12, 5469–5476
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