Synthesis of 2H-Indazoles via Tandem Palladium-Catalyzed Deacylative Cross-Coupling and Denitrogenative Cyclization of 2-Iodoazoarenes and 2-Iodoaryltriazenes with Acyldiazoacetates in One-Pot

Article abstract of DOI:10.1002/adsc.201600351

A synthetic method to prepare a wide range of 2H-indazoles was developed via a tandem palladium-catalyzed deacylative cross-coupling reaction of 2-iodoazoarenes and 2-iodoaryltriazenes with acyldiazoacetates and denitrogenative cyclization reaction of in

Full text of DOI:10.1002/adsc.201600351

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DOI: 10.1002/adsc.201600351
Very Important Publication
Synthesis of 2H-Indazoles via Tandem Palladium-Catalyzed
Deacylative Cross-Coupling and Denitrogenative Cyclization of
2-Iodoazoarenes and 2-Iodoaryltriazenes with Acyldiazoacetates
in One-Pot
Woo-Soon Yong,a Sangjune Park,a Hyunsik Yun,a and Phil Ho Leea,*
a
National Creative Research Initiative Center for Catalytic Organic Reactions, Department of Chemistry, Kangwon
National University, Chuncheon 24341, Republic of Korea
Fax: (+82)-33-259-5667; e-mail: phlee@kangwon.ac.kr
Received: April 2, 2016; Revised: April 15, 2016; Published online: May 24, 2016
This paper is dedicated to Professor Kyo Han Ahn (POSTECH) on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600351.
Abstract: A synthetic method to prepare a wide palladium-catalyzed denitrogenative cyclization to
range of 2H-indazoles was developed via a tandem produce 2H-indazoles. The present reaction is a good
palladium-catalyzed deacylative cross-coupling reac- example in which a Pd(0)-catalyst is involved in two
tion of 2-iodoazoarenes and 2-iodoaryltriazenes with catalytic cycles in one-pot.
acyldiazoacetates and denitrogenative cyclization re-
action of in situ generated diazoacetates having
azoaryl and triazenylaryl moieties in one-pot. Addi- Keywords: diazoacetates; 2H-indazoles; 2-iodoazoar-
tionally, azoaryl-substituted diazoacetates underwent enes; palladium catalysis; tandem reactions
Introduction
Azaheterocycles have been recognized as a highly im-
portant class of compounds in drug discovery due to
their biological activities and pharmaceutical, agricul-
tural, and industrial applications.[1] 2H-Indazoles are
useful privileged pharmacophores found in medicinal-
ly important molecules.[2] Although a large number of
synthetic methods for the thermodynamically favored
1H-indazole has been reported,[3] there is only a limit-
ed number of methods for the regioselective synthesis
of 2H-indazoles.[4] Thus, the development of efficient
synthetic methods for providing 2H-indazoles from
readily accessible starting material is required. To
date, [3+2] dipolar cycloaddition of arynes and syd-
nones [Eq (1), Scheme 1],[5a] Cu-catalyzed three-com-
ponent reactions of 2-bromobenzaldehydes, primary
amines, and sodium azides in one-pot [Eq (2)],[5b] and
À
Rh-, Co-, Re-, or Pd-catalyzed C H bond addition of
azobenzenes to aldehydes [Eq (3)][5c–f] have been de-
veloped. The preparation of 3-acyl-2H-indazoles has
been much less investigated due to the number of
synthetic steps, dialkylations, reaction yields, and con-
ditions. Therefore, a synthetic approach via a catalytic Scheme 1. Approaches for the synthesis of 2H-indazoles.
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Table 1. Reaction optimization.[a]
Entry Cat. Pd
Solvent
t [h] Yield [%][b]
1
2
Pd(dba)2
Pd2(dba)3
Pd2(dba)3CHCl3 EtOH
Pd2(dba)3CHCl3 EtOH
Pd2(dba)3CHCl3 EtOH
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
EtOH
EtOH
12
12
12
4
4
2
0
0
0
53
3[c]
4[d]
5[e]
6
Scheme 2. Synthesis of 2H-indazoles via tandem Pd-cata-
lyzed deacylative coupling and denitrogenative cyclization.
52
EtOH
t-amyl alcohol 12
n-propanol
MeCN
EtOH
85 (83)[f]
56
7
8
9
10
11
6
12
2
79
process represents a formidable challenge: Ag-cata-
79
50[g]
43[h]
lyzed [3+2] cycloaddition of benzynes with diazocar-
bonyl reagents [Eq (4)][5g] and Rh-catalyzed C H ad-
À
Pd(OAc)2/Ph3P EtOH
2
dition and cyclization of azobenzenes with a- keto al-
[a]
Reaction conditions: 1a (0.2 mmol, 1.0 equiv.),
2
dehydes [Eq (5)].[5h]
(0.4 mmol, 2.0 equiv.), Pd catalyst (5.0 mol%), and
NaOH (3.0 equiv.) in solvent (0.25M) at room tempera-
ture for 2 h and then 708C for x h under N2.
NMR yield using CH2Br2 as an internal standard.
PCy3 (20.0 mol%) was used.
Xantphos (10.0 mol%) was used.
dppf (10.0 mol%) was used.
Isolated yield.
Recently, Wang and co-workers reported Pd-cata-
lyzed deacylative cross-coupling of aryl iodides with
acyldiazoacetates for the synthesis of aryl diazoace-
tates.[6] On the basis of these results, we envisioned
that with the same Pd catalyst, a tandem deacylative
cross-coupling and denitrogenative cyclization reac-
tion starting from 2-iodoazoarenes and 2-iodoaryltri-
azenes may be achievable in one-pot, thus producing
3-acyl-2H-indazole scaffolds through the formation of
[b]
[c]
[d]
[e]
[f]
[g]
[h]
Under air.
Ph3P (20.0 mol%) was used.
À
intermolecular C C bonds and sequential intramolec-
À
ular C N bonds on the carbon that possesses a diazo gave the deacylative cross-coupling product (E)-ethyl
group of the acyldiazoacetates. In continuation of our 2-diazo-2-[2-(phenyldiazenyl)phenyl]acetate (3a) in
recent studies on the synthesis of azaheterocycles,[7] 69% and 64% yields, respectively, in ethanol at room
we report an efficient synthetic method for a wide temperature for 2 h [Eq (6)].
range of 3-acyl-2H-indazoles via tandem Pd-catalyzed
deacylative cross-coupling from 2-iodoazoarenes and
2-iodoaryltriazenes with acyldiazoacetates and deni-
trogenative
(Scheme 2).
cyclization
reaction
in
one-pot
Results and Discussion
We initiated our investigations with the reaction of 2-
iodoazobenzene (1a) with ethyl 2-diazo-3-oxobuta-
noate (2) in the presence of a variety of Pd catalysts
Thus, we conceived that if the diazoacetate 3a
(Table 1). 2-Iodoazobenzenes were prepared from the having an azophenyl group was treated with a transi-
Pd-catalyzed iodination of aromatic azo compounds[8] tion metal or heated, the denitrogenative cyclization
and dehydration of 2-iodoanilines with nitrosoben- reaction would occur, producing 2H-indazole 4a.
zenes.[9] When Pd(dba)2 and Pd2(dba)3 (5.0 mol% Moreover, a direct synthesis of 2H-indazole 4a start-
each) were used as catalysts in the presence of NaOH ing from 2-iodoazobenzene (1a) and ethyl 2-diazo-3-
(3.0 equiv.) in ethanol at room temperature, the reac- oxobutanoate (2) was envisaged to be possible via the
tions were ineffective (entries 1 and 2). Next, a wide tandem Pd-catalyzed deacylative cross-coupling reac-
range of ligands, such as PCy3, Xantphos, and dppf, tion and the denitrogenative cyclization reaction in
was examined in the presence of Pd2(dba)3CHCl3 one-pot. The tandem reaction from 1a and 2 occurred
(5.0 mol%). Although PCy3 (20.0 mol%) was not ef- in one-pot, affording ethyl 2-phenyl-2H-indazole-3-
fective (entry 3), Xantphos and dppf (10.0 mol%) carboxylate (4a) in 53% and 52% yields, respectively
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(entries 4 and 5). These results indicate that the Pd-
Next, we examined the substrate scope and the
catalyzed deacylative cross-coupling reaction of 2-io- functional group tolerance in the reaction with
doazobenzene (1a) with ethyl 2-diazo-3-oxobutanoate a series of 2-iodoazobenzenes having substituents on
(2) and a sequential denitrogenative cyclization reac- one aryl ring (Scheme 4). Electronic modification of
tion in one-pot worked moderately well. The opti- substituents on the phenyl ring of 2-iodoazobenzenes
mum conditions were obtained from the reaction of (1) had little effect on the reaction efficiency. Several
1a (0.2 mmol, 1.0 equiv.) with 2 (2.0 equiv.) using 2H-indazoles (4j–4m) were obtained in good to excel-
Pd(PPh3)4 (5.0 mol%) and NaOH (3.0 equiv.) in lent yields from 2-iodoazobenzenes with electron-do-
EtOH at room temperature for 2 h followed by treat- nating methyl substituents. Although 3’-chloro-2-io-
ment at 708C for 2 h under N2, providing 4a in 83% doazobenzene (1n) was transformed to 4n in 53%
isolated yield (entry 6). Ethanol gave the best results yield, 4’-chloro, 3’-bromo-, and 4’-bromo-substituted
among the solvents, including t-amyl alcohol, n-propa- 2-iodoazobenzenes were converted to the desired 2H-
nol, and acetonitrile (entries 6–9). 2H-Indazole 4a was indazoles (4o–4q) in good yields ranging from 67% to
obtained in 50% yield under air (enry 10). Use of 87%. Electron-withdrawing groups, such as acetyl and
Pd(OAc)2 (5.0 mol%) and Ph3P (20.0 mol%) pro- ethoxycarbonyl, are tolerable in the tandem Pd-cata-
duced 4a in 43% yield (entry 11).
lyzed deacylative cross-coupling and denitrogenative
To show the efficiency and substrate scope of the cyclization reaction in one-pot, which makes the pres-
present method, several 2-iodoazobenzenes with the ent method useful.
same substituents on two aryl rings were subjected to
With the success of the tandem Pd-catalyzed deacy-
the optimum reaction conditions (Scheme 3). Varia- lative cross-coupling and denitrogenative cyclization,
tion of the electron demand of the substituents on the we attempted the synthesis of 2H-indazoles from 2-io-
aryl rings did not largely affect the efficiency of the doazobenzenes with different substituents on two aryl
tandem Pd-catalyzed deacylative cross-coupling and rings (Scheme 5). When 2-iodoazobenzenes (1t and
denitrogenative cyclization in one-pot. 2-Iodoazoben- 1u) with electron-withdrawing ethoxycarbonyl, chlo-
zenes bearing electron-donating methyl groups were ride, and bromide groups on each aryl ring were treat-
smoothly converted to 2H-indazoles (4b, 4c, and 4d) ed with a Pd-catalyst, the tandem reaction occurred
in good yields ranging from 60% to 85%. Additional- smoothly, affording 2H-indazoles 4t (63%) and 4u
ly, 2-iodo-5-methoxyazobenzene (1f) underwent Pd- (60%). In the case of the azo compound (1v) with tri-
catalyzed cross-coupling followed by cyclization to fluoromethyl and bromide groups on each aryl ring,
produce 2H-indazole 4f in a 60% yield. However, 6- the desired 2H-indazole 4v was obtained in a 71%
ethyl-substituted 2-iodoazobenzene (1e) lowered the yield. However, the presence of strong electron-with-
product yield (42%) due to steric congestion. 2-Iodo- drawing trifluoromethyl and ethoxycarbonyl groups
azobenzenes with electron-withdrawing chloride and on each aryl ring decreased the reaction efficiency.
bromide groups afforded the desired 2H-indazoles The combination of dimethyl and methyl or bromide
4g–4i in good yield without loss of halogen functional- groups on each aryl ring gave good results, providing
ity.
2H-indazoles 4x and 4y in 80% yields, respectively.
Scheme 3. Synthesis of 2H-indazoles from 2-iodoazoarenes with the same substituents on two aryl rings in one-pot. Reaction
conditions: 1 (0.2 mmol, 1.0 equiv.), 2 (2.0 equiv.), Pd(PPh3)4 (5.0 mol%), and NaOH (3.0 equiv.) in EtOH (0.8 mL) at room
temperature for 2 h and then 708C for 2–12 h under N2.
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Scheme 4. Synthesis of 2H-indazoles from 2-iodoazoarenes with substituents on one aryl ring in one-pot. Reaction condi-
tions: 1 (0.2 mmol, 1.0 equiv.), 2 (2.0 equiv.), Pd(PPh3)4 (5.0 mol%), and NaOH (3.0 equiv.) in EtOH (0.8 mL) at room tem-
perature for 2 h and then 708C for 1–7 h under N2.
Scheme 5. Synthesis of 2H-indazoles from 2-iodoazoarenes with different substituents on two aryl rings in one-pot. Reaction
conditions: 1 (0.2 mmol, 1.0 equiv.), 2 (2.0 equiv.), Pd(PPh3)4 (5.0 mol%), and NaOH (3.0 equiv.) in EtOH (0.8 mL) at room
temperature for 2 h and then 708C for 1–8 h under N2.
As an extension of this work, the synthesis of 2H- Heating of diazoacetate 3a in EtOH to 708C without
indazoles from 2-iodoaryltriazenes was investigated a Pd catalyst and NaOH gave 2H-indazole 4a in
(Scheme 6). When (E)-4-[(2-iodophenyl)diazenyl]- a 23% yield (entry 1).[10] Treatment of 3a with the op-
morpholine (5a) was subjected to a Pd catalyst, the timum reaction conditions gave 4a in a 5% yield
tandem reaction occurred smoothly, resulting in the (entry 2). However, when 3a was subjected to
formation of (E)-4-{[2-iodo-4-(trifluoromethyl)-phe- 5.0 mol% Pd(PPh3)4 without NaOH in EtOH, the cyc-
nyl]diazenyl}morpholine (6a) in 73% yield. Ethoxy- lization occurred to afford 4a in an 80% yield
carbonyl- and trifluoromethyl-substituted 2-iodoaryl- (entry 3), indicating that the Pd-catalyst was essential
triazenes are applicable to the present transformation, for the cyclization of diazoacetate. Exposure of 3a to
affording the corresponding 2H-indazoles (6b and 6c). 5.0 mol% Pd(PPh3)4 and NaOH (1.0 equiv.) in EtOH
Several control experiments were performed to ex- resulted in the formation of 4a in 82% yield (entry 4).
amine what kind of factor leads to cyclization of These results indicate that the NaOH (2.0 equiv.) was
diazoacetate 3a in situ generated from 2-iodoazoben- used in the cross-coupling reaction and the NaOH
zene and ethyl 2-diazo-3-oxobutanoate (Table 2). (1.0 equiv.) that remained in the reaction mixture
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lative cross-coupling reaction of 2-iodoazoarenes and
2-iodoaryltriazenes (1) with ethyl 2-diazo-3-oxobuta-
5 (0.2 mmol, noate (2) in one-pot is shown in Scheme 7. At the
Scheme 6. Synthesis of 2H-indazoles from 2-iodoaryltri-
azenes in one-pot. Reaction conditions:
1.0 equiv.), 2 (2.0 equiv.), Pd(PPh3)4 (5.0 mol%), and NaOH
(3.0 equiv.) in EtOH (0.8 mL) at room temperature for 2 h
and then 708C for 2 h under N2.
outset, oxidative addition of 2-iodoazoarenes and 2-
iodoaryltriazenes (1) to Pd catalyst provides the inter-
mediate A, which makes a complex with diazoacetate
2 to afford the intermediate B (pathway a).[6] Next,
nucleophilic attack by hydroxide anion gives rise to
intermediate C. When 2 initially reacts with hydroxide
anion, intermediate D might be produced, and then
coordination of D to A generates C (pathway b).
Then, deacylation from C followed by reductive elimi-
nation from E produces the deacylative cross-coupling
product 3 and regenerates the Pd catalyst. In pathway
c, liberation of molecular nitrogen from 3 would pro-
vide Pd-carbene complex F. Next, intramolecular nu-
cleophilic attack by the azoarene and triazene moiet-
ies produces G, and subsequent depalladation affords
the 2H-indazoles 4 and regenerates the Pd catalyst.
The present reaction is a good example in which the
Pd(0) catalyst is involved in two catalytic cycles in
one-pot. Heating of diazoacetates 3 to 708C partially
produces carbene intermediate H through the evolu-
tion of nitrogen gas (entry 1, Table 2).[10] Nucleophilic
attack of the diazo moiety affords nitrogen ylide I
and subsequent resonance delivered the 2H-indazoles
4 (pathway d). In addition to the free carbene path-
way d under 708C conditions, pathway e cannot be
ruled out.
Table 2. Cyclization of azophenyl-substituted diazoacet-
ates.[a]
Entry
Cat. Pd
Additive (equiv.)
Yield [%][b]
1
2
3
4
5
6
–
23
5
80
82
4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
–
–
NaOH (3.0)
–
NaOH (1.0)
NaOH (3.0)
NaOH (1.0)
9
[a]
Reaction conditions: 3a (0.2 mmol, 1.0 equiv.), Pd(PPh3)4
(5.0 mol%), and NaOH in EtOH (0.25M) at 708C for
2 h under N2.
[b]
NMR yield using CH2Br2 as an internal standard.
after cross-coupling reaction did not affect the effi-
ciency of the denitrogenative cyclization. In addition,
NaOH (1.0 and 3.0 equiv.) was totally ineffective, in- Conclusions
dicating that Pd catalyst is essential to the denitroge-
native cyclization (entries 5 and 6).
In conclusion, we have developed a synthetic method
Encouraged by these results, the cyclization of to prepare a wide range of 2H-indazoles via the
diazoacetates was attempted. Diazoacetate 3b with tandem Pd-catalyzed deacylative cross-coupling reac-
methyl substituents on two aryl rings was cyclized to tion of 2-iodoazoarenes and 2-iodoaryltriazenes with
produce 2H-indazole 4d in a 60% yield [Eq. (7)]. Di- acyldiazoacetate and denitrogenative cyclization reac-
azoacetate (3c) possessing trifluoromethyl and bro- tion of in situ generated diazoacetates having the
mide groups on each aryl ring is applicable to the azoaryl and triazenylaryl moieties in one-pot. A Pd-
present transformation, affording the corresponding catalyzed intramolecular cyclization occurred effi-
2H-indazole 4v in a 56% yield [Eq (8)].
ciently with diazoacetates having azoaryl moieties to
A plausible reaction mechanism for the synthesis of produce 2H-indazoles. The two catalytic cycles are
2H-indazoles 4 from the tandem Pd-catalyzed deacy- promoteded by one Pd catalyst.
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Scheme 7. A plausible mechanism.
Synthetic Procedure for 2H-Indazoles
Experimental Section
To
a long test tube were added 2-iodoazoarene (1)
General
(0.2 mmol), Pd(PPh3)4 (11.5 mg, 5.0 mol%) and NaOH
(24.0 mg, 0.6 mmol) in EtOH (0.4 mL) at room temperature
under N2. Subsequently, ethyl diazoacetoacetate (2)
(62.5 mg, 0.4 mmol) in EtOH (0.4 mL) was added dropwise
into the long test tube and the resulting mixture was stirred
at room temperature for 2 h under N2. After 2 h, the result-
ing mixture was heated at 708C for 1 h. After evaporation
of the solvents under vacuum, the reaction mixture was pu-
rified by column chromatography on silica gel to give the
corresponding 2H-indazole derivatives.
All commercially available reagents were used as received
without purification. All reaction mixtures were stirred mag-
netically and were monitored by thin-layer chromatography
using silica gel pre-coated glass plates, which were visualized
with UV light and then developed using either iodine or
a solution of anisaldehyde. Flash column chromatography
was carried out using silica gel (230–400 mesh). 1H NMR
(400 MHz) and 13C{1H} NMR (100 MHz) spectra were re-
corded on NMR spectrometers. Deuterated chloroform was
used as the solvent and chemical shift values (d) are report-
ed in parts per million relative to the residual signals of this
Ethyl 2-phenyl-2H-indazole-3-carboxylate (4a): yield:
44.2 mg (83%); Rf =0.30 (Et2O:CH2Cl2:hexane=1:1:20);
white solid; m.p. 81–838C; H NMR (400 MHz, CDCl3): d=
1
solvent [d=7.26 for H (chloroform-d) and d=77.16 for 13C
1
8.13 (dt, J=8.5 Hz, 1.1 Hz, 1H), 7.85 (dt, J=8.6 Hz, 1.0 Hz,
1H), 7.53 (s, 5H), 7.43 (ddd, J=8.6 Hz, 6.7 Hz, 1.2 Hz, 1H),
7.36 (ddd, J=8.4 Hz, 6.7 Hz, 1.0 Hz, 1H), 4.36 (q, J=7.1 Hz,
2H), 1.35 (t, J=7.1 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): d=159.6, 148.5, 141.1, 129.5, 128.8, 127.2, 126.5,
125.6, 125.2, 124.1, 121.7, 118.7, 61.2, 14.3; IR (film): n=
3065, 2978, 1719, 1597, 1501, 1287 cmÀ1; HR-MS (FAB):
m/z=267.1135, calcd. for C16H14N2O2: 267.1134.
(chloroform-d)]. Infrared spectra were recorded on an FT-
IR spectrometer as either a thin film pressed between two
sodium chloride plates or as a solid suspended in a potassium
bromide disk. High resolution mass spectra (HR-MS) were
obtained by fast atom bombardment (FAB) using a double
focusing magnetic sector mass spectrometer and electron
impact (EI) ionization technique (magnetic sector – electric
sector double focusing mass analyzer) from the KBSI
(Korea Basic Science Institute). Melting points were deter-
mined in open capillary tubes.
Ethyl 7-methyl-2-(o-tolyl)-2H-indazole-3-carboxylate (4b):
yield: 35.5 mg (60%); Rf =0.20 (Et2O:CH2Cl2:hexane=
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1
1:1:20); red oil; H NMR (400 MHz, CDCl3): d=7.97 (d, J=
8.4 Hz, 1H), 7.45–7.41 (m, 1H), 7.36–7.25 (m, 4H), 7.18 (dt,
J=6.8 Hz, 1.0 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 2.69 (s,
3H), 2.01 (s, 3H), 1.28 (t, J=7.1 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): d=159.5, 148.9, 140.9, 135.0, 130.6,
129.7, 129.0, 127.1, 126.4, 126.2, 126.1, 125.8, 123.3, 119.1,
61.0, 17.2, 17.1, 14.2; IR (film): n=3032, 2978, 1714, 1650,
1501, 1228 cmÀ1; HR-MS (EI): m/z=294.1369, calcd. for
C18H18N2O2: 2 9 4.1368.
7.7 Hz, 1.7 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 7.42 (dt, J=
7.8 Hz, 1.7 Hz, 1H), 7.30 (dd, J=9.0 Hz, 1.6 Hz, 1H), 4.38
(q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): d=159.0, 148.8, 141.6, 134.5, 133.5,
129.9, 129.7, 127.4, 126.9, 125.8, 124.8, 123.1, 122.5, 117.6,
61.6, 14.2; IR (film): n=2987, 2918, 1721, 1484, 1172,
781 cmÀ1
;
HR-MS (EI): m/z=334.0274, calcd. for
C16H12Cl2N2O2: 334.0276.
Ethyl 5-chloro-2-(4-chlorophenyl)-2H-indazole-3-carbox-
Ethyl
6-methyl-2-(m-tolyl)-2H-indazole-3-carboxylate
ylate
(4h):
yield:
43.8 mg
(65%);
Rf =0.20
(4c): yield: 44.0 mg (75%); Rf =0.20 (Et2O:CH2Cl2:hexane=
1:1:20); white solid; m.p. 99–1018C; 1H NMR (400 MHz,
CDCl3): d=7.99 (d, J=9.0 Hz, 1H), 7.58 (d, J=9.0 Hz, 1H),
7.39 (t, J=7.7 Hz, 1H), 7.34–7.28 (m, 3H), 7.18 (dd, J=
8.7 Hz, 1.2 Hz, 1H), 4.35 (q, J=7.1 Hz, 2H), 2.50 (s, 3H),
2.44 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): d=159.6, 149.1, 141.1, 138.8, 137.1,
130.1, 128.5, 128.4, 127.0, 125.0, 123.6, 122.5, 121.1, 117.0,
61.1, 22.2, 21.4, 14.3; IR (film): n=2988, 2925, 1714, 1637,
1501, 1116 cmÀ1; HR-MS (EI): m/z=294.1368, calcd. for
C18H18N2O2: 294.1368.
(Et2O:CH2Cl2:hexane=1:1:20); yellow solid; mp 184–
1868C; H NMR (400 MHz, CDCl3): d=8.08 (dd, J=2.0 Hz,
1
0.7 Hz, 1H), 7.78 (dd, J=9.1 Hz, 0.7 Hz, 1H), 7.50 (d, J=
9.0 Hz, 2H), 7.47 (d, J=9.0 Hz, 2H), 7.37 (dd, J=9.1 Hz,
2.0 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): d=159.1, 147.0,
139.2, 135.7, 131.9, 129.03, 128.99, 127.7, 124.9, 124.6, 120.6,
120.2, 61.6, 14.4; IR (film): n=2987, 2918, 1716, 1498, 1124,
771 cmÀ1
;
HR-MS (EI): m/z=334.0274, calcd. for
C16H12Cl2N2O2: 334.0276.
Ethyl 6-bromo-2-(3-bromophenyl)-2H-indazole-3-carbox-
Ethyl 5-methyl-2-(o-tolyl)-2H-indazole-3-carboxylate (4d):
yield: 44.2 mg (85%); Rf =0.30 (Et2O:CH2 Cl2:hexane=
1:1:20); white solid; m.p. 119–1218C; 1H NMR (400 MHz,
CDCl3): d=7.85 (dd, J=2.4 Hz, 1.0 Hz, 1H), 7.74 (d, J=
8.8 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.0 Hz,
2H), 7.25 (dd, J=8.9 Hz, 1.5 Hz, 1H), 4.37 (q, J=7.1 Hz,
2H), 2.51 (d, J=0.8 Hz, 3H), 2.45 (s, 3H), 1.36 (t, J=
7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): d=159.8,
147.4, 139.4, 138.8, 135.4, 129.9, 129.3, 126.2, 124.5, 124.3,
119.8, 118.3, 61.0, 22.3, 21.4, 14.4; IR (film): n=2975, 2918,
1715, 1514, 1287, 1120 cmÀ1; HR-MS (EI): m/z=294.1369,
calcd. for C18H18N2O2: 294.1368.
ylate
(4i):
yield:
56.7 mg
(67%);
Rf =0.20
(Et2O:CH2Cl2:hexane=1:1:20); pink solid; mp 148–1508C;
1H NMR (400 MHz, CDCl3): d=8.01 (dd, J=1.6 Hz, 0.7 Hz,
1H), 7.99 (dd, J=9.0 Hz, 0.7 Hz, 1H), 7.70 (t, J=1.8 Hz,
1H), 7.67 (ddd, J=7.9 Hz, 1.9 Hz, 1.2 Hz, 1H), 7.47 (ddd,
J=8.0 Hz, 2.0 Hz, 1.2 Hz, 1H), 7.42 (dd, J=9.0 Hz, 1.6 Hz,
1H), 7.40 (t, J=7.9 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 1.35
(t, J=7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): d=
159.0, 149.3, 141.7, 132.8, 130.0, 129.8, 129.7, 125.9, 125.3,
123.2, 122.8, 122.1, 121.6, 121.0, 61.7, 14.3; IR (film): n=
3095, 2987, 1716, 1484, 1124, 678 cmÀ1; HR-MS (EI): m/z=
621.9264, calcd. for C16H12Br2N2O2: 421.9266.
Ethyl 7-ethyl-2-(2-ethylphenyl)-2H-indazole-3-carboxylate
(4e): yield: 27.1 mg (42%); Rf =0.40 (Et2O:CH2Cl2:hexane=
1:1:20); colorless oil; H NMR (400 MHz, CDCl3): d=7.98
Ethyl 2-(o-tolyl)-2H-indazole-3-carboxylate (4j): yield:
49.0 mg (87%); Rf =0.20 (Et2O:CH2Cl2:hexane=1:1:20);
yellow solid; mp 114–1168C; H NMR (400 MHz, CDCl3):
1
1
(d, J=8.4 Hz, 1H), 7.47 (td, J=11.2 Hz, 1.4 Hz, 1H), 7.41
(dd, J=7.7 Hz, 1.0 Hz, 1H), 7.36–7.27 (m, 3H), 7.21 (dd, J=
6.8 Hz, 1.0 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 3.13 (t, J=
7.4 Hz, 2H), 2.29 (t, J=7.7 Hz, 2H), 1.40 (t, J=7.5 Hz, 3H),
1.26 (t, J=7.1 Hz, 3H), 1.07 (t, J=7.6 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3): d=159.5, 148.0, 140.7, 140.3,
135.1, 129.9, 129.0, 127.2, 126.3, 126.2, 125.9, 124.2, 123.5,
119.0, 60.9, 24.4, 23.9, 14.5, 14.4, 14.2; IR (film): n=3024,
2972, 1718, 1496, 1230, 1105 cmÀ1; HR-MS (EI): m/z=
322.1684, calcd for C20H22N2O2: 322.1681.
d=7.94 (d, J=8.4 Hz, 1H), 7.52 (s, 5H), 7.27–7.23 (m, 1H),
7.17 (dt, J=7.0 Hz, 1.1 Hz, 1H), 4.34 (q, J=7.1 Hz, 2H),
2.69 (s, 3H), 1.33 (t, J=7.1 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): d=159.7, 148.8, 141.3, 129.4, 128.9,
128.7, 126.6, 126.2, 125.9, 125.4, 124.0, 119.0, 61.1, 17.0, 14.2;
IR (film): n=3008, 2975, 1724, 1463, 1240, 1105 cmÀ1; HR-
MS (EI): m/z=280.1212, calcd for C17H16N2O2: 280.1212.
Ethyl 2-(m-tolyl)-2H-indazole-3-carboxylate (4k): yield:
50.4 mg (90%); Rf =0.30 (Et2O:CH2Cl2:hexane=1:1:20);
1
white solid; mp 78–808C; H NMR (400 MHz, CDCl3): d=
Ethyl 6-methoxy-2-(3-methoxyphenyl)-2H-indazole-3-car-
8.12 (dt, J=8.5 Hz, 1.0 Hz, 1H), 7.86 (dt, J=8.6 Hz, 1.0 Hz,
1H), 7.44–7.29 (m, 6H), 4.36 (q, J=7.1 Hz, 2H), 2.45 (s,
3H), 1.35 (t, J=7.1 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): d=159.6, 148.5, 141.0, 138.9, 130.2, 128.5, 127.1,
126.9, 125.5, 125.2, 124.0, 123.6, 121.7, 118.7, 61.2, 21.4, 14.3;
IR (film): n=3060, 2981, 1721, 1466, 1294, 1112 cmÀ1; HR-
MS (EI): m/z=280.1214, calcd. for C17H16N2O2: 280.1212.
Ethyl 2-(p-tolyl)-2H-indazole-3-carboxylate (4l): yield:
45.2 mg (81%); Rf =0.30 (Et2O:CH2Cl2:hexane=1:1:20);
white solid; mp 100–1028C; 1H NMR (400 MHz, CDCl3):
d=8.11 (dt, J=8.4 Hz, 1.0 Hz, 1H), 7.85 (dt, J=8.7 Hz,
1.0 Hz, 1H), 7.43–7.40 (m, 3H), 7.36–7.31 (m, 3H), 7.36–
7.31 (m, 3H), 4.37 (q, J=7.1 Hz, 2H), 2.46 (s, 3H), 1.37 (t,
J=7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): d=159.7,
148.4, 139.5, 138.6, 129.3, 127.1, 126.1, 125.5, 125.1, 124.0,
121.7, 118.7, 61.2, 21.5, 14.3; IR (film): n=3044, 2984, 1718,
boxylate
(4f):
yield:
39.2 mg
(60%);
Rf =0.20
(Et2O:CH2Cl2:hexane=1:1:20); white solid; mp 95–978C;
1H NMR (400 MHz, CDCl3): d=7.96 (dd, J=9.1 Hz, 0.6 Hz,
1H), 7.40 (td, J=7.7 Hz, 1.1 Hz, 1H), 7.09–7.01 (m, 5H),
4.35 (q, J=7.1 Hz, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 1.34 (t,
J=7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): d=159.8,
159.5, 159.4, 149.6, 142.1, 129.3, 125.3, 122.4, 120.6, 119.8,
118.9, 115.3, 112.2, 95.4, 61.2, 55.6, 55.4, 14.3; IR (film): n=
2997, 2832, 1719, 1501, 1316, 1218 cmÀ1; HR-MS (EI): m/z=
326.1267, calcd. for C18H18N2O4: 326.1267.
Ethyl 6-chloro-2-(3-chlorophenyl)-2H-indazole-3-carbox-
ylate
(4g):
yield:
49.5 mg
(74%);
Rf =0.20
(Et2O:CH2Cl2:hexane=1:1:20); ivory solid; mp 159–1618C;
1H NMR (400 MHz, CDCl3): d=8.05 (d, J=9.0 Hz, 1H),
7.82 (d, J=0.9 Hz, 1H), 7.55 (t, J=1.7 Hz, 1H), 7.52 (dt, J=
Adv. Synth. Catal. 2016, 358, 1958 – 1967
1964
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1457, 1290, 1118 cmÀ1; HR-MS (EI): m/z=280.1210, calcd.
for C17H16N2O2: 280.1212.
Ethyl 2-(3,5-dimethylphenyl)-2H-indazole-3-carboxylate
Ethyl 2-(3-acetylphenyl)-2H-indazole-3-carboxylate (4r):
yield: 47.0 mg (76%); Rf =0.20 (Et2O:CH2Cl2:hexane=
1:1:20); ivory solid; mp 112–1148C; 1H NMR (400 MHz,
CDCl3): d=8.14–8.13 (m, 2H), 8.12 (t, J=1.2 Hz, 1H), 7.86
(dt, J=8.6 Hz, 1.0 Hz, 1H), 7.75 (ddd, J=7.9 Hz, 2.1 Hz,
1.2 Hz, 1H), 7.65 (t, J=8.1 Hz, 1H), 7.45 (ddd, J=8.4 Hz,
6.9 Hz, 1.4 Hz, 1H), 7.38 (ddd, J=8.4 Hz, 6.7 Hz, 1.0 Hz,
1H), 4.38 (q, J=7.1 Hz, 2H), 2.66 (s, 3H), 1.37 (t, J=
7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): d=196.8,
159.5, 148.7, 141.2, 137.6, 131.0, 129.1, 129.0, 127.5, 126.5,
125.9, 125.2, 124.1, 121.7, 118.7, 61.4, 26.9, 14.3; IR (film):
3075, 2981, 1718, 1688, 1484, 1292 cmÀ1; HR-MS (EI): m/z=
308.1163, calcd. for C18H16N2O3: 308.1161.
(4m):
yield:
50.2 mg
(85%);
Rf =0.30
(Et2O:CH2Cl2:hexane=1:1:20); white solid; mp 72–748C;
1H NMR (400 MHz, CDCl3): d=8.11 (dt, J=8.4 Hz, 1.1 Hz,
1H), 7.84 (dt, J=8.6 Hz, 1.0 Hz, 1H), 7.41 (ddd, J=8.5 Hz,
6.8 Hz, 1.3 Hz, 1H), 7.34 (ddd, J=8.4 Hz, 6.7 Hz, 1.0 Hz,
1H), 7.14 (d, J=0.6 Hz, 1H), 7.13 (d, J=0.6 Hz, 2H), 4.37
(q, J=7.1 Hz, 2H), 2.39 (s, 6H), 1.36 (t, J=7.1, Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): d=159.6, 148.4, 140.9,
138.5, 131.1, 127.1, 125.5, 125.1, 124.1, 124.0, 121.6, 118.7,
61.1, 21.4, 14.3; IR (film): n=3014, 2924, 1721, 1477, 1303,
1072 cmÀ1
;
HR-MS (EI): m/z=294.1364, calcd. for
Ethyl
2-[4-(ethoxycarbonyl)phenyl]-2H-indazole-3-car-
(4s): yield: 48.0 mg (71%); Rf =0.40
C18H18N2O2: 294.1368.
boxylate
Ethyl 2-(3-chlorophenyl)-2H-indazole-3-carboxylate (4n):
yield: 31.0 mg (53%); Rf =0.20 (Et2O:CH2Cl2:hexane=
1:1:20); pink solid; mp 120–1228C; 1H NMR (400 MHz,
CDCl3): d=8.12 (dt, J=8.5 Hz, 1.1 Hz, 1H), 7.84 (dt, J=
8.6 Hz, 0.9 Hz, 1H), 7.57–7.56 (m, 1H), 7.51 (dt, J=7.1 Hz,
2.1 Hz, 1H), 7.48–7.42 (m, 3H), 7.36 (ddd, J=8.4 Hz,
6.8 Hz, 1.0 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 1.37 (t, J=
7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): d=159.4,
148.7, 141.9, 134.4, 129.6, 127.5, 127.0, 125.9, 125.3, 124.9,
124.2, 121.7, 118.7, 61.4, 14.3; IR (film): n=3068, 2981, 1710,
1482, 1129, 776 cmÀ1; HR-MS (EI): m/z=300.0667, calcd.
for C16H13ClN2O2: 300.0666.
(Et2O:CH2Cl2:hexane=1:1:20); ivory solid; mp 119–1218C;
1H NMR (400 MHz, CDCl3): d=8.22 (d, J=8.7 Hz, 2H),
8.12 (dt, J=8.5 Hz, 1.1 Hz, 1H), 7.86 (dt, J=8.6 Hz, 1.0 Hz,
1H), 7.63 (d, J=8.7 Hz, 2H), 7.44 (ddd, J=8.6 Hz, 6.7 Hz,
1.2 Hz, 1H), 7.37 (ddd, J=8.5 Hz, 6.7 Hz, 1.0 Hz, 1H), 4.43
(q, J=6.8 Hz, 2H), 4.38 (q, J=6.8 Hz, 2H), 1.43 (t, J=
7.1 Hz, 3H), 1.37 (t, J=7.1 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): d=165.8, 159.5, 148.8, 144.4, 131.3,
130.1, 127.5, 126.5, 126.0, 125.3, 124.2, 121.7, 118.7, 61.5,
61.4, 14.5, 14.3; IR (film): n=3051, 2975, 1718, 1457, 1294,
1127 cmÀ1
C19H18N2O4: 338.1267.
;
HR-MS (EI): m/z=338.1269, calcd. for
Ethyl 2-(4-chlorophenyl)-2H-indazole-3-carboxylate (4o):
yield: 40.1 mg (67%); Rf =0.20 (Et2O:CH2Cl2:hexane=
1:1:20); white solid; mp 139–1418C; 1H NMR (400 MHz,
CDCl3): d=8.11 (dt, J=8.5 Hz, 1.0 Hz, 1H), 7.84 (dt, J=
8.7 Hz, 1.0 Hz, 1H), 7.52–7.47 (m, 2H), 7.43 (ddd, J=
8.4 Hz, 6.9 Hz, 1.3 Hz, 1H), 7.36 (ddd, J=8.2 Hz, 6.9 Hz,
1.1 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): d=159.6, 148.7,
139.5, 135.5, 129.0, 127.8, 127.5, 125.9, 125.2, 124.1, 121.7,
118.7, 61.4, 14.3; IR (film): n=3048, 2978, 1713, 1493, 1124,
Diethyl
2-(3-chlorophenyl)-2H-indazole-3,5-carboxylate
(4t): yield: 46.6 mg (63%); Rf =0.20 (Et2O:CH2Cl2:hexane=
1:1:20); yellow solid; mp 157–1598C; 1H NMR (400 MHz,
CDCl3): d=8.92 (dd, J=1.5 Hz, 0.9 Hz, 1H), 8.05 (dd, J=
9.1 Hz, 1.6 Hz, 1H), 7.85 (dd, J=9.1 Hz, 0.9 Hz, 1H), 7.58
(td, J=1.8 Hz, 0.4 Hz, 1H), 7.54 (dt, J=7.4 Hz, 1.9 Hz, 1H),
7.50–7.44 (m, 2H), 4.45 (q, J=7.1 Hz, 2H), 4.42 (q, J=
7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H), 1.40 (t, J=7.1 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): d=166.6, 158.9, 149.7,
141.5, 134.5, 130.0, 129.8, 127.9, 127.4, 127.2, 126.9, 125.9,
124.8, 123.3, 118.6, 61.8, 61.4, 14.5, 14.2; IR (film): n=2987,
1710, 1466, 1230, 1102, 762 cmÀ1; HR-MS (EI): m/z=
372.0877, calcd. for C19H17ClN2O4: 372.0877.
752 cmÀ1
;
HR-MS (EI): m/z=300.0664, calcd. for
C16H13ClN2O2: 300.0666.
Ethyl 2-(3-bromophenyl)-2H-indazole-3-carboxylate (4p):
yield: 53.4 mg (77%); Rf =0.30 (Et2O:CH2Cl2:hexane=
1:1:20); ivory solid; mp 121–1238C; 1H NMR (400 MHz,
CDCl3): d=8.12 (dt, J=8.4 Hz, 1.1 Hz, 1H), 7.84 (dt, J=
8.6 Hz, 1.0 Hz, 1H), 7.72 (t, J=1.9 Hz, 1H), 7.66 (ddd, J=
8.0 Hz, 1.9 Hz, 1.1 Hz, 1H), 7.49 (ddd, J=8.0 Hz, 2.0 Hz,
1.1 Hz, 1H), 7.46–7.34 (m, 3H) 4.39 (q, J=7.1 Hz, 2H), 1.37
(t, J=7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): d=
159.7, 148.7, 142.0, 132.5, 129.9, 129.8, 127.5, 125.9, 125.4,
125.3, 124.2, 122.0, 121.7, 118.7, 61.4, 14.3; IR (film): n=
3071, 2981, 1713, 1480, 1287, 684 cmÀ1; HR-MS (EI): m/z=
344.0158, calcd. for C16H13BrN2O2: 344.0160.
Ethyl 2-(4-bromophenyl)-2H-indazole-3-carboxylate (4q):
yield: 60.3 mg (87%); (Rf =0.20 (Et2O:CH2Cl2:hexane=
1:1:20); white solid; mp 136–1388C; 1H NMR (400 MHz,
CDCl3): d=8.11 (dt, J=8.5 Hz, 1.1 Hz, 1H), 7.84 (dt, J=
8.6 Hz, 1.0 Hz, 1H), 7.66 (d, J=8.8 Hz, 2H), 7.45–7.40 (m,
3H) 7.36 (ddd, J=8.4 Hz, 6.7 Hz, 1.0 Hz, 1H), 4.39 (q, J=
7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): d=159.6, 148.7, 140.0, 131.9, 128.1,
127.5, 126.0, 125.1, 124.1, 123.6, 122.0, 118.7, 61.4, 14.3; IR
(film): n=3048, 2978, 1713, 1493, 1290, 665 cmÀ1; HR-MS
(EI): m/z=344.0162, calcd. for C16H13BrN2O2: 344.0160.
Diethyl 2-(4-bromophenyl)-2H-indazole-3,5-dicarboxylate
(4u):
yield:
50.0 mg
(60%);
Rf =0.20
(Et2O:CH2Cl2:hexane=1:1:20); white solid; mp 164–1668C;
1H NMR (400 MHz, CDCl3): d=8.90 (dd, J=1.5 Hz, 0.9 Hz,
1H), 8.05 (dd, J=9.1 Hz, 1.6 Hz, 1H), 7.85 (dd, J=9.1 Hz,
0.9 Hz, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.43 (d, J=8.9 Hz,
2H), 4.45 (q, J=7.1 Hz, 2H), 4.42 (q, J=7.1 Hz, 2H), 1.45
(t, J=7.1 Hz, 3H), 1.41 (t, J=7.1 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): d=166.6, 159.0, 149.7, 139.6, 132.0,
128.0, 127.8, 127.3, 127.1, 125.9, 123.9, 123.3, 118.6, 61.8,
61.4, 14.5, 14.2; IR (film): n=2981, 1716, 1463, 1290, 1099,
684 cmÀ1
;
HR-MS (EI): m/z=416.0374, calcd. for
C19H17BrN2O4: 416.0372.
Ethyl 2-(3-bromophenyl)-5-(trifluoromethyl)-2H-indazole-
3-carboxylate (4v): yield: 58.3 mg (71%); Rf =0.20
(Et2O:CH2Cl2:hexane=1:1:20); pink solid; mp 168–1708C;
1H NMR (400 MHz, CDCl3): d=8.47 (t, J=0.8 Hz, 1H),
7.95 (dt, J=9.1 Hz, 0.8 Hz, 1H), 7.72 (t, J=1.8 Hz, 1H),
7.70 (ddd, J=8.0 Hz, 1.7 Hz, 1.4 Hz, 1H), 7.60 (dd, J=
9.1 Hz, 1.7 Hz, 1H), 7.49 (ddd, J=8.0 Hz, 2.0 Hz, 1.2 Hz,
1H), 7.43 (t, J=7.9 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 1.38
(t, J=7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): d=
Adv. Synth. Catal. 2016, 358, 1958 – 1967
1965
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158.7, 148.9, 141.5, 133.0, 130.0, 129.7, 127.8 (q, JCF
32.0 Hz), 127.1, 125.2, 124.4 (q, JC,F =272.2 Hz), 123.5 (q,
C,F =2.9 Hz), 122.7, 122.2, 120.6 (q, JC,F =5.0 Hz), 119.9,
61.9, 14.2; IR (film): n=2989, 1713, 1482, 1262, 1112,
678 cmÀ1
HR-MS (EI): m/z=412.0034, calcd. for
C17H12BrF3N2O2: 412.0034.
=
1H), 7.30 (ddd, J=8.3 Hz, 6.9 Hz, 1.0 Hz, 1H), 4.49 (q, J=
7.1 Hz, 2H), 3.99 (t, J=4.7 Hz, 4H) 3.46 (t, J=4.4 Hz, 4H)
1.50 (t, J=7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3):
d=158.9, 144.9, 126.6, 125.2, 122.1, 121.6, 121.4, 118.2, 66.9,
61.1, 55.8, 14.6; IR (film): n=2981, 2854, 1724, 1463, 1265,
J
;
1082 cmÀ1
;
HR-MS (EI): m/z=275.1267, calcd. for
Ethyl
2-[4-(ethoxycarbonyl)phenyl]-5(trifluoromethyl)-
C14H17N3O3: 275.1270.
Diethyl 2-morpholino-2H-indazole-3,5-dicarboxylate (6b):
yield: 49.3 mg (71%); Rf =0.30 (Et2O:CH2Cl2:hexane=
2H-indazole-3-carboxylate (4w): yield: 38.9 mg (48%); Rf =
0.20 (Et2O:CH2Cl2:hexane=1:1:20); brown solid; mp 133–
1358C; H NMR (400 MHz, CDCl3): d=8.47 (s, 1H), 8.24
1
1
1:1:20); colorless oil; H NMR (400 MHz, CDCl3): d=8.80
(d, J=8.7 Hz, 2H), 7.96 (dt, J=9.0 Hz, 0.7 Hz, 1H), 7.63 (d,
J=8.7 Hz, 2H), 7.60 (dd, J=9.0 Hz, 1.6 Hz, 1H), 4.44 (q,
J=7.1 Hz, 2H), 4.41 (q, J=7.1 Hz, 2H), 1.44 (t, J=7.1 Hz,
3H), 1.38 (t, J=7.1 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): d=165.6, 158.8, 149.0, 143.9, 131.8, 130.3, 127.8 (q,
(dd, J=1.5 Hz, 0.9 Hz, 1H), 8.80 (dd, J=9.0 Hz, 1.6 Hz,
1H), 7.77 (dd, J=9.0 Hz, 0.8 Hz, 1H), 4.53 (q, J=7.1 Hz,
2H), 4.42 (q, J=7.1 Hz, 2H), 4.00 (t, J=4.6 Hz, 4H), 3.47
(dd, J=5.1 Hz, 3.7 Hz, 3H), 1.53 (t, J=7.1 Hz, 3H), 1.44 (t,
J=7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): d=166.7,
158.3, 146.1, 127.1, 126.5, 125.5, 123.5, 121.2, 118.0, 66.8,
61.5, 61.2, 55.8, 14.4; IR (film): n=2981, 1716, 1468, 1273,
1224, 1102 cmÀ1; HR-MS (EI): m/z=347.1483, calcd. for
C17H21N3O5: 347.1481.
J
C,F =31.9 Hz), 127.1, 126.5, 124.4 (q, JC,F =272.2 Hz), 123.6
(q, JC,F =2.9 Hz), 122.8, 120.7 (q, JC,F =4.9 Hz), 120.0, 62.0,
61.6, 14.5, 14.3; IR (film): n=2987, 1721, 1463, 1317, 1107,
1067 cmÀ1
;
HR-MS (EI): m/z=40 6.1143, calcd. for
C20H17F3N2O4: 406.1140.
Ethyl
2-morpholino-5-(trifluoromethyl)-2H-indazole-3-
Ethyl 5,7-dimethyl-2-(o-tolyl)-2H-indazole-3-carboxylate
(4x): yield: 49.2 mg (80%); Rf =0.30 (Et2O:CH2Cl2:hexane=
1:1:20); white solid; mp 77–798C; 1H NMR (400 MHz,
CDCl3): d=7.71 (s, 1H), 7.44–7.40 (m, 1H), 7.35–7.28 (m,
3H), 7.04 (t, J=1.4 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 2.65
(s, 3H), 2.48 (d, J=0.8 Hz, 3H), 2.06 (s, 3H), 1.26 (t, J=
7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): d=159.6,
147.9, 141.0, 135.8, 135.1, 130.6, 129.6, 129.1, 128.6, 127.1,
126.4, 125.2, 123.8, 117.2, 60.9, 22.3, 17.2, 17.1, 14.2; IR
(film): n=3062, 2978, 1716, 1498, 1278, 1099 cmÀ1; HR-MS
(EI): m/z=308.1526, calcd. for C19H20N2O2: 308.1525.
Ethyl 2-(4-bromophenyl)-5,7-dimethyl-2H-indazole-3-car-
carboxylate (6c): yield: 36.4 mg (53%); Rf =0.40 (Et2O:
CH2Cl2:hexane=1:1:20); white solid; mp 80–828C; H NMR
1
(400 MHz, CDCl3): d=8.36 (t, J=0.8 Hz, 1H), 7.86 (dt, J=
9.0 Hz, 0.8 Hz, 1H), 7.55 (dd, J=9.0 Hz, 1.6 Hz, 1H), 4.52
(q, J=7.1 Hz, 2H), 4.52 (q, J=7.1 Hz, 2H), 4.00 (t, J=
7.1 Hz, 4H), 3.47 (dd, J=5.0 Hz, 3.8 Hz, 4H), 1.51 (t, J=
7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): d=158.2,
145.3, 127.1 (q, JC,F =32.0 Hz), 124.5 (q, JC,F =272.4 Hz),
123.4, 122.6 (q, JC,F =3.0 Hz), 120.8, 120.3 (q, JC,F =4.9 Hz),
119.3, 66.8, 61.6, 55.9, 14.5; IR (film): n=2861, 1729, 1488,
1311, 1107, 1088 cmÀ1; HR-MS (EI): m/z=343.1144, calcd.
for C15H16F3N3O3: 343.1144.
boxylate
(4y):
yield:
59.8 mg
(80%);
Rf =0.30
(Et2O:CH2Cl2:hexane=1:1:20); white solid; mp 167–1698C;
1H NMR (400 MHz, CDCl3): d=7.66 (s, 1H), 7.64 (d, J=
8.6 Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 7.26 (s, 1H), 4.36 (q,
J=7.1 Hz, 2H), 2.63 (s, 3H), 2.47 (s, 3H), 1.36 (t, J=7.1 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): d=159.9, 148.1,
140.3, 136.2, 131.9, 129.4, 128.5, 128.3, 124.6, 124.5, 123.3,
117.2, 61.2, 22.3, 16.9, 14.4; IR (film): n=3011, 2978, 1710,
1493, 1275, 662 cmÀ1; HR-MS (EI): m/z=372.0469, calcd.
for C18H17BrN2O2: 372.0473.
Acknowledgements
This work was supported by the National Research Founda-
tion of Korea (NRF) grant funded by the Korea government
(MSIP) (2011-0018355) and Kangwon National University
(520150437).
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