Substrate-Controlled Transformation of Azobenzenes to Indazoles and Indoles via Rh(III)-Catalysis

Article abstract of DOI:10.1021/acs.joc.6b02548

Rh(III)-catalyzed substrate-controlled transformation of azobenzenes to indazoles and 2-acyl (NH) indoles is achieved via C-H functionalization. Generally, good functional groups tolerance, satisfying yields, and excellent regio-selectivity are achieved in this reaction. Mechanistically, the reaction with acrylates undergoes β-hydride elimination, while the reaction with vinyl ketones or acrylamides undergoes nucleophilic addition. Copper acetate was supposed to play different roles in the β-hydride elimination to furnish indazoles and nucleophilic addition of C-Rh bond to deliver 2-acyl (NH) indoles.

Full text of DOI:10.1021/acs.joc.6b02548

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Article
Substrate-Controlled Transformation of Azobenzenes
to Indazoles and Indoles via Rh(III)-Catalysis
Shangjun Cai, Songyun Lin, Xiangli Yi, and Chanjuan Xi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02548 • Publication Date (Web): 12 Dec 2016
Downloaded from http://pubs.acs.org on December 13, 2016
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Substrate-Controlled Transformation of Azobenzenes to Indazoles and Indoles
via Rh(III)-Catalysis
†
†
†
,†,‡
Shangjun Cai, Songyun Lin, Xiangli Yi and Chanjuan Xi*
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†
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry
of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China
‡
State Key Laboratory of ElementoꢀOrganic Chemistry, Nankai University, Tianjin
3
00071, China
ABSTRACT: Rh(III)ꢀcatalyzed substrateꢀcontrolled transformation of azobenzenes
to indazoles and 2ꢀacyl (NH) indoles is achieved via CꢀH functionalization. Generally,
good functional groups tolerance, satisfying yields, and excellent regioꢀselectivity are
achieved in this reaction. Mechanistically, the reaction with acrylates undergoes
βꢀhydride elimination, while the reaction with vinyl ketones or acrylamides undergoes
nucleophilic addition. Copper acetate was supposed to play different roles in the
βꢀhydride elimination to furnish indazoles and nucleophilic addition of CꢀRh bond to
deliver 2ꢀacyl (NH) indoles.
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INTRODUCTION
Indazoles and indoles represent two kinds of the most prevalent heterocycles in
1
pharmaceuticals and biologically active molecules. Consequently, numerous efforts
have been devoted to construct these biologically important skeletal motifs.
Traditionally, indazoles are formed by the condensation/cyclization of aryl ketone and
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hydrazine, or by the crossꢀcoupling/cyclization of oꢀhalo phenylacetylene and
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hydrazine. Indoles are prepared by Fisher, Larock, Buchwald, and Hegadus indole
synthesis.
Recently, remarkable progress in transitionꢀmetalꢀcatalyzed CꢀH bond
functionalization has enabled the generation of indazoles and indoles via selective
transformation of CꢀH bonds, which possesses gratifying atomꢀ and stepꢀeconomy.
The synthesis of indazoles via CꢀH functionalization strategy mostly relies on the
addition of CꢀH bond towards aldehydes, followed by the intramolecular cyclative
8
aꢀ8d
8e
8f
capture of azo group. Within this method, rhodium,
cobalt, and rhenium
catalysts have been employed to give indazole products (Scheme 1, set A). The
synthesis of indoles via CꢀH functionalization strategy often depends on
9
intramolecular annulation of Nꢀarylenamines or imines. or intermolecular cyclization
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11
of anilines and alkynes under oxidative or redox neutral conditions (Scheme 1, set
12a
12b
B). More recently, Glorius’ group
and Jana’s group,
respectively reported
intermolecular oxidative cyclization of anilines and alkenes to deliver indole skeleton
with substituent on the 1ꢀposition (Scheme 1, set C). To the best of our knowledge, no
catalytic CꢀH annulation method has ever been established to selectively deliver
2ꢀacyl (NH) indoles from simple starting materials. Herein, we would like to report a
substrateꢀcontrolled transformation of azobenzenes to indazoles and indoles via
rhodiumꢀcatalyzed CꢀH activation in the presence of Cu(OAc) . The reaction with
2
acrylates afforded indazole skeleton (Scheme 1, part 1). The reaction with vinyl
ketones or acrylamides afforded indole skeleton (Scheme 1, part 2).
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Scheme 1. Synthesis of Indazoles and Indoles via C-H Functionalization
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RESULTS AND DISCUSSION
Optimization Studies. Initially, we treated azobenzene 1a with methyl acrylate 2a
using [Cp*RhCl ] as a catalyst, Cu(OAc) as an oxidant, 1,2ꢀdichloroethane (DCE)
2
2
2
o
as a solvent, at 90 C under nitrogen atmosphere, product 3aa was obtained in 71%
yield (Table 1, entry 1). Encouragingly, the yield of the product was further improved
o
to 90% by increasing the reaction temperature to 130 C (entries 2ꢀ3). Reduction of
the catalyst or oxidant resulted in slightly lower yields (entries 4ꢀ5). Solvent screening
disclosed that DCE was the most efficient medium for this reaction (entries 6ꢀ9). No
product was observed when either [Cp*RhCl
0ꢀ11). Other catalysts, such as [(COD)RhCl]
Cp*IrCl ] and Pd(OAc) were proved to be of no activity for this transformation.
2
]
2
or Cu(OAc)
2
was used alone (entries
1
2
, [(pꢀcymene)RuCl
2 2
]
, RuCl (PPh
2
3 3
) ,
[
2
2
2
2
Other oxidants, such as CuCl and AgOAc failed to improve the reaction yields (see
SI). Therefore, entry 3 was chosen as the optimal reaction conditions for the indazole
synthesis.
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a
Table 1. Optimization of Reaction Condations
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Conditions: 1a (0.1 mmol), 2a (0.12 mmol), [Cp*RhCl
]
2 2
2
(5 mol%), Cu(OAc) (0.2
b
1
mmol), Solvent (0.5 mL) under nitrogen atmosphere. Yield determined by H NMR.
c
Isolation yield.
Substrates Scope and Limitations for Formation of Indazoles: Having arrived at
the optimal conditions, we next explored a diverse set of azobenzenes 1 and alkenes 2.
The representative results are shown in Table 2. First, a series of acrylates 2a-e were
examined. The acrylates 2a-e reacted with azobenzene 1a to generate indazoles
3
aa-3ae in good yields, yet phenyl vinyl sulfone and dimethyl vinyl phosphonate
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failed to react with azobenzene 1a under standard conditions. Then, a range of
azobenzenes were conducted and results are summarized in Table 2.
Electronꢀdonating and electronꢀwithdrawing substituents, such as Me, OMe, F, and Cl
on azobenzene led to the indazole products 3ba-3ea in moderate to good yields, while
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the stronger electronꢀwithdrawing group such as CF only give trace product detected
by GCꢀMS 3fa. Notably, crystals of 3da was suitable for single crystal analysis, and
its structure was fully characterized by Xꢀray diffraction analysis, which cleanly
confirmed formation of the indazole backbone. We further extended the reaction using
metaꢀ or orthoꢀsubstituted azobenzenes such as 1g-k. With the mꢀmethyl substituent
afforded the desired indazole 3ga exclusively at the less hindered site, while
mꢀmethoxyl substituent resulted in a mixture of two regio isomers in 65% combined
yield with 2:1 ratio favoring functionalization at the less hindered position such as
3ha. It is also significant that the indazole products 3ia-3ja can be obtained in good
yields from diꢀsubstituted azobenzenes. When an unsymmetric azobenzene was
employed, the reaction site satisfyingly focused on the less hindered position to give
product 3ka in 69% yield. When unsymmetric substrates such as
(E)ꢀ1ꢀphenylꢀ2ꢀ(4ꢀ(trifluoromethyl)phenyl)diazene
and
(E)ꢀmethyl
4
ꢀ(phenyldiazenyl)benzoate were used, trace products were observed in both reactions.
This may be due to the decrease of coordination ability of the azo group.
a
Table 2. Scope of Indazoles Formation
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Conditions: 1 (0.1 mmol), 2 (0.12 mmol), [Cp*RhCl
2 2 2
] (5 mol%), Cu(OAc) (0.2
mmol), DCE (0.5 mL), under nitrogen atmosphere. All yields are isolated yields.
It was noteworthy that when the reaction was carried out under oxygen
atmosphere, 3ꢀacyl indazole product was yielded with the capture of molecular
oxygen. Some representative results are shown in Table 3.
a
Table 3. Capture of Molecular Oxygen in Indazole Formation
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a
Conditions: 1 (0.1 mmol), 2 (0.12 mmol), [Cp*RhCl
2 2 2
] (5 mol%), Cu(OAc) (0.2
mmol), DCE (0.5 mL), under oxygen atmosphere. All yields are isolated yields.
Scope and Limitations for Formation of Indoles: Further extension of this rhodium
catalytic system towards vinyl ketone substrates led to fascinating 2ꢀacyl (NH) indole
products and the corresponding anilines were obtained as byꢀproducts. Considering
the volatility of vinyl ethyl ketone, two equivalents of vinyl ethyl ketone was used to
enhance the yields. After optimization of the reaction conditions (see SI), this novel
indole synthesis reaction was next explored with a diverse set of azobenzenes and
vinyl ketones. The typical results are shown in Table 4. A broad range of synthetically
useful functional groups, such as Me, OMe, F, Cl, and Br on azobenzene were found
to be compatible with this reaction, and gave the expected indole products in
moderate to good yields. Notably, the tolerance of halides is particularly important
thanks to their great capabilities of further transformation via a traditional
crossꢀcoupling reaction. Encouragingly, the stronger electronꢀwithdrawing
substituents, such as trifluoromethyl and methoxycarbonyl are well tolerated in this
reaction. Moreover, sterically hindered azobenzene 1j also reacted smoothly to give
indole product 5jg in satisfying yield. Exclusive regioselectivity was also observed
when unsymmetrically substituted azobenzenes such as 1k, 1l, and 1n were employed
in this approach.
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a
Table 4. Scope for the Formation of 2-Propionyl (NH) Indoles
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R2
+
[Cp*RhCl2]2 (5 mol%)
Cu(OAc)2 (2 equiv.)
H
N
O
N
O
N
R1
R1
Et
DCE (0.5 mL)
Et
1
2g
o
N2, 130 C, 24 h
5
yield (%)b
azobenzene
product
H
N
O
N
N
5ag
76
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Et
1a
Me
H
N
O
N
N
N
5bg
80
73
Me
Et
1b
Me
OMe
H
N
O
N
5cg
Et
MeO
1
c
MeO
F
H
N
O
N
N
5dg
5eg
71
51
F
Et
O
1d
Cl
F
H
N
N
N
Cl
Et
1e
Cl
Br
H
N
O
N
N
5
Et
mgc
54
73
81
1m
Br
Br
CF3
H
N
O
N
N
fgc
5
Et
1
f
F3C
Me
F3C
Me
H
N
O
N
N
Me
Me
5gg
1g
Et
Me
H
N
Me
O
Me
N
N
N
5jg
72
67
Et
1
j
Me
Me
Me
OMe
Me
H
N
O
5kg
Et
N
MeO
1
k
MeO
Me
OH
H
N
O
N
5lgc
4
5
0
N
N
Me
MeO2C
Et
1l
MeO C
2
Me
OMe
Me
H
N
O
5lgc
Et
N
5
MeO C
2
1n
MeO C
2
a
Conditions: 1 (0.1 mmol), 2 (0.2 mmol), [Cp*RhCl
2
]
2
2
(5 mol%), Cu(OAc) (0.2
b
c
mmol), DCE (0.5 mL), under nitrogen atmosphere. Isolation yield. 20 mol %
AgSbF was added.
6
It was known that 2ꢀaroyl indole derivatives were identified as a new class of
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potent tubulinꢀinhibitory and antimitotic agents. Consequently, different kinds of
vinyl aryl ketones were investigated under the standard conditions. The representative
results are shown in Table 5. Both aryl and heteroaryl vinyl ketones can proceed
smoothly to furnish biologically valuable 2ꢀaroyl indoles in good yields, such as 5ah,
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5
ai and 5aj. Gratifyingly, antimitotic agent 5cl can also be obtained in gram scale
using this method. What is more, when N,Nꢀdimethyl acrylamide was treated with
azobenzenes under the standard conditions, the expected indole 2ꢀcarboxamides such
as 5ak, 5fk and 5gk were obtained successfully. However, when chalcone 2m was
used, the reaction did not proceed and starting materials remained.
a
Table 5. Scope for the Synthesis of 2-Acyl (NH) Indoles
a
Conditions: 1 (0.1 mmol), 2 (0.12 mmol), [Cp*RhCl
]
2 2
2
(5 mol%), Cu(OAc) (0.2
o
b
mmol), DCE (0.5 mL), 130 C for 24 h, under nitrogen atmosphere. Isolation yield.
c
d
e
6
In 5 mmol scale. 20 mol % AgSbF was added. A little amount of corresponding
indazole was detected as byꢀproduct in GCꢀMS.
MECHANISTIC INVESTIGATION
To gain some insights of the reaction mechanism, additional experiments were
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performed. For indazole formation process, the olefinated azobenzene 6 was prepared
(see SI) and treated with standard conditions to give a quantitative indazole 3aa,
indicating the olefinated azobenzene 6 is likely to be the key intermediate in the
formation of indazole (Scheme 2 a). For indole formation process, we firstly tried to
prepare (E)ꢀ1ꢀ(2ꢀ((E)ꢀphenyldiazenyl)phenyl)pentꢀ1ꢀenꢀ3ꢀone and it failed. So we
prepared (E)ꢀN,Nꢀdimethylꢀ3ꢀ(2ꢀ((E)ꢀphenyldiazenyl)phenyl)ꢀacrylamide 6'. When
the olefinated azobenzene 6' was treated under the standard conditions and a
quantitative yield of indazole 3ak was obtained, revealing that the olefinated
azobenzene 6' was unlikely to be the intermediate for indole formation (Scheme 2 b).
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To understand the role of Cu(OAc)
was carried out without the addition of Cu(OAc)
c). Replacing Cu(OAc) with KOAc also failed to give indole product, only trace
2
in the formation of indole, the model reaction
2
, no product was observed (Scheme
2
2
amount of indazole 3ag was detected by GCꢀMS (Scheme 2 d). Moreover, the
addition of catalytic amount of Cu(OAc) led to 65% of olefin insertion product 7,
2
rather than the expected indole product 5ag (Scheme 2 e), indicating that
2
stoichiometric amount of Cu(OAc) is undoubtly necessary for the indole formation.
Furthermore, when compound 7 was treated under the standard conditions, the
corresponding indole product 5ag was generated in moderate yield (47%) (Scheme 2
f), revealing that compound 7 is possibly to be the key intermediate in the indole
formation process. In order to gain more insights of the mechanism of indole
formation, a fiveꢀmembered cycloꢀrhodium intermediate 8 was prepared (see SI) and
2
treated with 2g in the presence of two equivalents of Cu(OAc) , and the expected
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indole 5ag was found to be the main product (Scheme 2 g).
Scheme 2. Mechanistic Experiments
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Based on the preliminarily mechanistic experiments (see more details in SI) and
12a
reported literature, we proposed a mechanism as shown in Scheme 3. First, the CꢀH
bond of azobenzene is activated by Rh(III) species to give a fiveꢀmembered
cycloꢀrhodium species 8, which is followed by alkene coordination and insertion to
afford the sevenꢀmembered rhodacycle 9. Following the insertion, if the substituent is
an ester group (ꢀCOOR'), the βꢀhydride elimination occured to give an olefined
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azobenzene, which subsequently undergoes insertion of C=C bond into RhꢀN bond,
and then aromatization to yield indazole. If the substituent is an acyl group (ꢀCOR'')
or acylamino group (ꢀCONR
2
'), the weaker electronꢀwithdrawing inductive effect of
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carbon, nitrogen (electronegativity: CH = 2.55, NH = 3.12, OH = 3.55) possibly
3
2
inhibited competitive βꢀhydride elimination, allowing the rearrangement of
intermediate 9 to give more stable sixꢀmembered coordinately saturated Rh species 12
with the assistance of copper acetate. The CꢀRh bond of intermediate 12 presumably
undergoes nucleophilic addition towards N=N bond to afford intermediate 13, which
further undergoes NꢀN bond cleavage and aromatization to give free indole products.
In this part, copper acetate possibly acts as Lewis acid to accelerate nucleophilic
addition by coordinating with azo group, which is different from previous NꢀBoc
12a
strategy.
Scheme 3. Proposed catalytic cycles
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CONCLUSION
In summary, we reported a selective transformation of azobenzenes to indazoles
and indoles via rhodiumꢀcatalyzed CꢀH functionalization. The reaction of azobenzene
and acrylates provided a method for the construction of the indazole skeleton. The
reaction of azobenzenes with vinyl ketones or acrylamides represented a novel and
efficient route for synthesis of 2ꢀacyl (NH) indoles from simple starting material. It
was noteworthy that good functional groups tolerance, satisfying yields, and excellent
regioselectivity were achieved in this reaction.
EXPERIMENTAL SECTION
General Information. Toluene, 1,2ꢀdichloroethane, 1,4ꢀdioxane, MeCN, and DMSO
were fresh distilled. Unless otherwise indicated, all materials were obtained from
1
13
commercial sources and used as received. H NMR and C NMR spectra were
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3 6
recorded by 400 MHz spectrometer using CDCl or DMSOꢀD as the solvent. The
melting points were measured on Xꢀ4 digital melting point apparatus and were
uncorrected. HRMS were obtained with ESI in positive or negetive ion mode on
ITꢀTOF instrument.
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General procedure for the synthesis of azo compounds (1b-1j, 1m). According to
15
the literature, the following azo compounds were prepared by this procedure: CuBr
(34.4 mg, 0.24 mmol), pyridine (58.0 µL, 0.72 mmol), and corresponding aniline (4
2
mmol) were mixed in toluene (20 mL). Under O atmosphere, the reaction mixture
o
was stirred vigorously at 60 C for 24 h. After completion, the reaction mixture was
cooled down to room temperature and concentrated under vacuum. Then, the residue
was purified by flash chromatography on a short silica gel (eluent: petroleum ether) to
afford the corresponding azo compounds.
General procedure for the synthesis of azo compounds (1k, 1l, 1n). According to
16
the literature, the asymmetric azo compounds were prepared by this procedure:
aqueous HCl solution (25 mL, 1M) was added to a round bottom flask equipped with
o
a stir bar. After cooling to 0 C, the indicated aniline (10.0 mmol, 1.0 equiv) was
2
added to the reaction mixture, and stirred for 10 minutes. Then, NaNO (0.725 g, 10.5
mmol, 1.05 equiv) in water (35 mL) was added dropwise. The solution was stirred for
additional 10 minutes and then was transferred into a round bottom flask containing
o
1
,3ꢀdimethylphenol (1.22 g, 10.0 mmol, 1.0 equiv). At 0 C, NaOH (0.400 g, 10.0 1.0
equiv) in a mixture of water (100 mL) and ethanol (35 mL) was added via cannula.
o
Red precipitate formed instantly, and the solution was stirred for 6 h at 0 C. The
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mixture was filtered, and the red solid residue was purified by flash column
chromatography with hexanes/ethyl acetate (9:1) to afford the azobenzene as a red
powder.
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The methylation of phenol was proceeded by the following procedure: the
phenolꢀcontaining azo compound (752.6mg, 2.94 mmol) was treated with K
2 3
CO (492
mg, 3.56 mmol). Under N , acetone (8.5 mL) was added to the reaction mixture, and
2
the reaction mixture was stirred for 3 min. Then, MeI (500 µL, 8.03 mmol) was added
o
to the reaction mixture, which was refluxed at 70 C for 24 h. After completion, the
reaction mixture was cooled to room temperature, and extracted with ethyl acetate for
three times. After concentration under vacuum, the residue was purified by flash
chromatography on a short silica gel (eluent: petroleum ether/ ethyl acetate = 20:1) to
afford the corresponding product.
General procedure for the synthesis of vinyl ketone substrates (2h-2j, 2l). The
17
vinyl ketone substrates were prepared according the literature : to a solution of
aldehyde (10 mmol) in dry THF (50 mL), vinyl magnesium bromide (10 mL, 1 equiv.,
1
M in THF) was added dropwise at 0 °C. After stirring for 20 min, the reaction
mixture was allowed to warm to room temperature, and stirred for additional 3 h.
Then, the reaction was quenched by addition of saturated aqueous NH Cl and
4
extracted with EtOAc for three times. The organic phase was washed with brine, dried
over magnesium sulfate, filtered and concentrated under reduced pressure to provide
the respective allylic alcohol.
2 2
To a solution of the allylic alcohol (8 mmol) in CH Cl (10 mL), iodobenzene
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diacetate (2.84 g, 1.1 equiv.) and TEMPO (125 mg, 0.1 equiv.) were added. The
mixture was stirred at room temperature for 3 h. After completion, the reaction was
quenched by saturated aqueous Na
2 2 3
S O . The aqueous phase was extracted with
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CH Cl for three times. The combined organic phases were washed with saturated
2
2
3
aqueous NaHCO and brine, dried over magnesium sulfate, filtered and concentrated.
Purification by column chromatography (silica, petrol ether/ethyl acetate = 20/1)
afforded the corresponding vinyl ketone.
Preparation for cyclorhodium intermediate 8. A 25 mL sealed tube was charged
with azobenzene (36.4 mg, 0.2 mmol), [Cp*RhCl ] (60 mg, 0.1 mmol), and NaOAc
2 2
(
32.8 mg, 0.4 mmol). Under nitrogen atmosphere, DCE (1 mL) were added, then the
tube was sealed. The mixture was allowed to stir at 130 °C for 24 h. After completion,
the mixture was cooled to room temperature, and diluted with 1 mL CH Cl . The
2
2
resulting mixture was filtered over a pad of celite, and further washed with 5 mL
CH Cl . The combined organic phase was concentrated and purified by column
2
2
chromatography (silica, petrol ether/ethyl acetate = 3/1) to afforded the cyclo rhodium
five member ring as a dark brown solide.
Preparation for olefinated azobenzene 6. A 25 mL sealed tube was charged with
2 3 2 2
oꢀbromo aniline (0.86g, 5 mmol) and PdCl (PPh ) (175 mg, 5 mol%). Under N
atmosphere, methyl acrylate (0.55 mL, 6 mmol) and Et N (10 mL) were added, then
3
the tube was sealed. The mixture was allowed to stir at 100 °C for 24 h. After
2
completion, the mixture was cooled to room temperature, then H O (20 mL) was
2 4
added and the mixture was extracted with EtOAc, dried by anhydrous Na SO .
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Evaporation of the solvent followed by purification by column chromatography (silica,
petrol ether/ethyl acetate = 4/1) gave the olefinated aniline in 75% yield.
The olefinated aniline (654.4 mg, 3.7 mmol) was further treated with
nitrosobenzene (399.4 mg, 3.7 mmol) in the presence of acetic acid (35 mL). The
reaction was protected from light by wrapping with foil. The resulting mixture was
then allowed to stir at room temperature for 48 h. After completion, the reaction
mixture was extracted with petrol ether for 4ꢀ6 times to extract the desired olefinated
azobenzene. Then, the extract was combined and washed with saturated aqueous
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Na CO , brine, dried over magnesium sulfate, filtered and concentrated. Purification
2
3
by column chromatography (silica, petrol ether/ethyl acetate = 30/1) afforded the
desired olefinated azobenzene as yellow solid in 88% yield.
Preparation for olefinated azobenzene 6'. A 25 mL sealed tube was charged with
2 3 2 2
oꢀbromo aniline (0.86 g, 5 mmol) and PdCl (PPh ) (175 mg, 5 mol%). Under N
atmosphere, N,Nꢀdimethyl acrylamide (0.62 mL, 6 mmol) and Et N (10 mL) were
3
added, then the tube was sealed. The mixture was allowed to stir at 100 °C for 24 h.
After completion, the mixture was cooled to room temperature, then H
2
O (20 mL)
4
SO .
was added and the mixture was extracted with EtOAc, dried by anhydrous Na
2
Evaporation of the solvent followed by purification by column chromatography (silica,
petrol ether/ethyl acetate = 1/1) gave the olefinated aniline in 46% yield.
The olefinated aniline (440 mg, 2.3 mmol) was further treated with
nitrosobenzene (247 mg, 2.3 mmol) in the presence of acetic acid (35 mL). The
reaction was protected from light by wrapping with foil. The resulting mixture was
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then allowed to stir at room temperature for 48 h. After completion, the reaction
mixture was diluted with EtOAc (100 mL), and neutralized by adding saturated
2 3
aqueous Na CO slowly until no bubble was generated. Then, the resulting mixture
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was further extracted with EtOAc. The combined organic phase was washed with
brine, dried over magnesium sulfate, filtered and concentrated. Purification by column
chromatography (silica, petrol ether/ethyl acetate = 1/1) afforded the desired
olefinated azobenzene as yellow solid in 73% yield.
General procedure for the synthesis of 3-alkyl indazole product 3. A 25 mL sealed
tube was charged with azobenzene (0.1 mmol), [Cp*RhCl ] (5 mol %, 3 mg), and
2 2
2
Cu(OAc) (2 equiv., 36.4 mg). Under nitrogen atmosphere, acrylate 2 (1.2 equiv.) and
DCE (0.5 mL) were added, then the tube was sealed. The mixture was allowed to stir
at 130 °C for 24 h. After completion, the mixture was cooled to room temperature,
2
then H O (5 mL) was added and the mixture was extracted with EtOAc (5 mL x 3),
dried by anhydrous Na SO . Evaporation of the solvent followed by purification on
2
4
TLC preparative plates (petroleum ether/ethyl acetate = 4/1) provided the
corresponding 3ꢀalkyl indazole product 3.
General procedure for the synthesis of 3-acyl indazole product 4. A 25 mL sealed
2 2
tube was charged with azobenzene (0.1 mmol), [Cp*RhCl ] (5 mol %, 3 mg), and
Cu(OAc) (2 equiv., 36.4 mg). Under oxygen atmosphere, acrylate 2 (1.2 equiv.) and
2
DCE (0.5 mL) were added, then the tube was sealed. The mixture was allowed to stir
at 130 °C for 24 h. After completion, the mixture was cooled to room temperature,
then H
2
O (5 mL) was added and the mixture was extracted with EtOAc (5 mL x 3),
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2 4
dried by anhydrous Na SO . Evaporation of the solvent followed by purification on
TLC preparative plates (petroleum ether/ethyl acetate = 4/1) provided the
corresponding 3ꢀacyl indazole product 4.
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General procedure for the synthesis of 3-acyl indole product 5. A 25 mL sealed
2 2
tube was charged with azobenzene (0.1 mmol), [Cp*RhCl ] (5 mol %, 3 mg), and
Cu(OAc) (2 equiv., 36.4 mg). Under nitrogen atmosphere, vinyl ketones or
2
acrylamides 2 (1.2 equiv.) and DCE (0.5 mL) were added, then the tube was sealed.
The mixture was allowed to stir at 130 °C for 24 h. After completion, the mixture was
cooled to room temperature, then H O (5 mL) was added and the mixture was
2
2 4
extracted with EtOAc (5 mL x 3), dried by anhydrous Na SO . Evaporation of the
solvent followed by purification on TLC preparative plates (petroleum ether/ethyl
acetate = 4/1) provided the corresponding 3ꢀacyl indole product 5.
Methyl 2-(2-phenyl-2H-indazol-3-yl) acetate (3aa): Yellow Solid, 22.1 mg (83%
o
1
yield), mp: 79ꢀ81 C; H NMR (CDCl , 400 MHz): δ 7.76 (d, J = 8.8 Hz, 1H), 7.66 (d,
3
J = 8.6 Hz, 1H), 7.61ꢀ7.49 (m, 5H), 7.35 (ddd, J = 8.6, 6.5, 0.8 Hz, 1H), 7.14 (dd, J =
13
8
.4, 6.6 Hz, 1H), 4.06 (s, 2H), 3.68 (s, 3H); C NMR (CDCl
3
, 100 MHz): δ 169.4,
148.7, 139.5, 129.4, 129.3, 128.2, 127.0, 126.3, 122.1, 122.0, 119.8, 118.0, 52.6, 31.5;
+
GCꢀMS found for 266. HRMS calcd for C16
H
15
N
2
O
2
[M+H] , 267.1128; found,
267.1128.
1
Ethyl 2-(2-phenyl-2H-indazol-3-yl) acetate (3ab): Oil, 23.5 mg (84% yield); H
NMR (CDCl
3
, 400 MHz): δ 7.75 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H),
7
.63ꢀ7.59 (m, 2H), 7.57ꢀ7.49 (m, 3H), 7.35 (dd, J = 7.9, 7.2 Hz, 1H), 7.14 (dd, J = 8.4,
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6
.7 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 4.05 (s, 2H), 1.21 (t, J = 7.1 Hz, 3H); C NMR
(
CDCl , 100 MHz): δ 169.0, 148.8, 139.6, 129.4, 129.3, 128.4, 127.0, 126.3, 122.1,
3
1
22.0, 119.9, 118.0, 61.7, 31.8, 14.2; GCꢀMS found for 280. HRMS calcd for
0
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+
C H N O [M+H] , 281.1285; found, 281.1281.
17
17
2
2
1
Butyl 2-(2-phenyl-2H-indazol-3-yl) acetate (3ac): Oil, 26.5 mg (86% yield); H
NMR (CDCl , 400 MHz): δ 7.75 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H),
.63ꢀ7.60 (m, 2H), 7.57ꢀ7.50 (m, 3H), 7.34 (ddd, J = 8.7, 6.5, 0.8 Hz, 1H), 7.16ꢀ7.11
m, 1H), 4.09 (t, J = 6.7 Hz, 2H), 4.05 (s, 2H), 1.59ꢀ1.51 (m, 2H), 1.28 (dq, J = 14.6,
3
7
(
13
7
1
.4 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H); C NMR (CDCl , 100 MHz): δ 169.1, 148.8,
3
39.6, 129.42, 129.3, 128.4, 127.0, 126.3, 122.1, 122.0, 119.9, 118.0, 65.6, 31.8, 30.6,
+
19.1, 13.7; GCꢀMS found for 308. HRMS calcd for C19
found, 309.1592.
H
21
N
2
O
2
[M+H] , 309.1598;
1
8a
tert-Butyl 2-(2-phenyl-2H-indazol-3-yl) acetate (3ad) : Oil, 24.0 mg (78% yield);
1
H NMR (CDCl , 400 MHz): δ 7.75 (d, J = 8.7 Hz, 1H), 7.71ꢀ7.68 (m, 1H), 7.65ꢀ7.62
3
(m, 2H), 7.57ꢀ7.49 (m, 3H), 7.34 (ddd, J = 8.7, 6.6, 1.0 Hz, 1H), 7.15ꢀ7.10 (m, 1H),
13
3
.96 (s, 2H), 1.39 (s, 9H); C NMR (CDCl
3
, 100 MHz): δ 168.1, 148.8, 139.7, 129.3,
129.1, 128.9, 126.9, 126.3, 122.0, 121.9, 120.0, 117.9, 82.2, 33.1, 28.0; GCꢀMS found
for 308.
1
Benzyl 2-(2-phenyl-2H-indazol-3-yl) acetate (3ae): Oil, 23.9 mg (70% yield); H
3
NMR (CDCl , 400 MHz): δ 7.75 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H),
7.56ꢀ7.53 (m, 2H), 7.48 (dd, J = 4.1, 2.6 Hz, 3H), 7.37ꢀ7.30 (m, 4H), 7.27ꢀ7.22 (m,
13
2
H), 7.14ꢀ7.09 (m, 1H), 5.12 (s, 3H), 4.09 (s, 2H); C NMR (CDCl
3
, 100 MHz): δ
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68.8, 148.8 139.5, 135.3, 129.4, 129.3, 128.7, 128.6, 128.5, 128.2, 127.0, 126.3,
1
22.2, 122.1, 119.8, 118.0, 67.4, 31.8; GCꢀMS found for 342. HRMS calcd for
+
C
22
H
19
N
2
O
2
[M+H] , 343.1441; found, 343.1443.
10
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Methyl 2-(5-methyl-2-(p-tolyl)-2H-indazol-3-yl) acetate (3ba): Yellow Solid, 24.1
o
1
mg (82% yield), mp: 147ꢀ149 C; H NMR (CDCl
3
, 400 MHz): δ 7.65 (d, J = 8.9 Hz,
1
H), 7.44 (d, J = 8.2 Hz, 2H), 7.37 (s, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.8
13
Hz, 1H), 4.00 (s, 2H), 3.68 (s, 3H), 2.45 (s, 6H); C NMR (CDCl
3
, 100 MHz): δ
1
5
2
69.7, 147.6, 139.3, 137.1, 131.4, 129.9, 129.8, 127.2, 126.0, 122.1, 117.7, 117.6,
+
2.6, 31.4, 22.0, 21.4; GCꢀMS found for 294. HRMS calcd for C H N O [M+H] ,
18 19
2
2
95.1441; found, 295.1439.
Butyl 2-(5-methoxy-2-(4-methoxyphenyl)-2H-indazol-3-yl) acetate (3cc): Oil, 30.9
1
mg (84% yield); H NMR (CDCl
3
, 400 MHz): δ 7.63 (d, J = 9.4 Hz, 1H), 7.49 (d, J =
8.9 Hz, 2H), 7.06ꢀ7.00 (m, 3H), 6.83 (d, J = 2.2 Hz, 1H), 4.09 (t, J = 6.7 Hz, 2H),
.95 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 1.60ꢀ1.52 (m, 2H), 1.29 (dt, J = 14.3, 7.2 Hz,
3
13
2H), 0.88 (t, J = 7.4 Hz, 3H); C NMR (CDCl
3
, 100 MHz): δ 169.3, 160.0, 155.3,
1
45.4, 132.7, 127.5, 127.3, 121.9, 121.7, 119.3, 114.4, 95.9, 65.5, 55.7, 55.5, 31.8,
+
30.7, 19.2, 13.8; GCꢀMS found for 368. HRMS calcd for C21
69.1809; found, 369.1810.
Methyl 2-(5-fluoro-2-(4-fluorophenyl)-2H-indazol-3-yl) acetate (3da): Yellow
25 2 4
H N O [M+H] ,
3
o
1
3
Solid, 23.6 mg (78% yield), mp: 128ꢀ130 C; H NMR (CDCl , 400 MHz): δ 7.73 (dd,
J = 9.3, 4.6 Hz, 1H), 7.62ꢀ7.57 (m, 2H), 7.29ꢀ7.23 (m, 3H), 7.17 (td, J = 9.2, 2.4 Hz,
13
1
H), 3.99 (s, 2H), 3.73 (s, 3H); C NMR (CDCl
3
, 100 MHz): δ 169.2, 162.9 (d, J =
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3
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50.1 Hz), 158.6 (d, J = 241.4 Hz), 146.2, 135.5, 128.5 (d, J = 8.8 Hz), 128.1 (d, J =
.7 Hz), 121.3 (d, J = 11.5 Hz), 120.1 (d, J = 9.8 Hz), 118.9 (d, J = 29.1 Hz), 116.5 (d,
8
J = 23.0 Hz), 102.3 (d, J = 24.4 Hz), 52.8, 31.4; GCꢀMS found for 302. HRMS calcd
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
for C H F N O [M+H] , 303.0940; found, 303.0940.
16
13
2
2
2
Methyl 2-(5-chloro-2-(4-chlorophenyl)-2H-indazol-3-yl) acetate (3ea): Yellow
o
1
3
Solid, 19.0 mg (57% yield), mp: 178ꢀ180 C; H NMR (CDCl , 400 MHz): δ 7.68 (d,
J = 9.2 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.54 (d, J = 1.6 Hz, 4H), 7.30ꢀ7.27 (m, 1H),
13
3
1
3
.99 (s, 2H), 3.72 (s, 3H); C NMR (CDCl
3
, 100 MHz): δ 169.1, 147.3, 137.8, 135.7,
29.8, 128.7, 128.1, 128.1, 127.5, 122.5, 119.6, 118.5, 52.9, 31.4; GCꢀMS found for
+
34. HRMS calcd for C16
H
13Cl
2
N
2
O
2
[M+H] , 335.0349; found, 335.0349.
Methyl 2-(6-methyl-2-(m-tolyl)-2H-indazol-3-yl) acetate (3ga): Oil, 23.8 mg (81%
1
yield); H NMR (CDCl
3
, 400 MHz): δ 7.54 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 0.7 Hz,
1H), 7.40 (t, J = 7.6 Hz, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 6.97
13
(dd, J = 8.6, 0.9 Hz, 1H), 4.02 (s, 2H), 3.68 (s, 3H), 2.47 (s, 3H), 2.44 (s, 3H); C
NMR (CDCl
3
, 100 MHz): δ 169.5, 149.3, 139.6, 139.5, 136.8, 129.9, 129.1, 127.9,
1
26.9, 125.0, 123.1, 120.4, 119.3, 116.2, 52.6, 31.6, 22.4, 21.4; GCꢀMS found for 294.
+
19 2 2
HRMS calcd for C18H N O [M+H] , 295.1441; found, 295.1440.
Methyl 2-(2-(2,4-dimethylphenyl)-5,7-dimethyl-2H-indazol-3-yl) acetate (3ia): Oil,
1
24.1 mg (75% yield); H NMR (CDCl , 400 MHz): δ 7.23 (s, 1H), 7.20 (d, J = 7.9 Hz,
3
1
H), 7.17 (s, 1H), 7.11 (d, J = 7.9 Hz, 1H), 6.96 (s, 1H), 3.81 (s, 2H), 3.62 (s, 3H),
13
2.61 (s, 3H), 2.42 (s, 3H), 2.40 (s, 3H), 1.97 (s, 3H); C NMR (CDCl
3
, 100 MHz): δ
1
69.4, 147.9, 139.9, 135.9, 131.8, 131.6, 128.7, 128.1, 127.7, 127.6, 127.2, 121.0,
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15.2, 52.4, 31.1, 22.0, 21.4, 17.2, 17.2; GCꢀMS found for 322. HRMS calcd for
+
C
20
H
23
N
2
O
2
[M+H] , 323.1754; found, 323.1755.
Methyl 2-(2-(3,5-dimethylphenyl)-4,6-dimethyl-2H-indazol-3-yl) acetate (3ja):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
1
Yellow Solid, 16.7 mg (52% yield), mp: 94ꢀ96 C; H NMR (CDCl , 400 MHz): δ
3
7
3
1
.31 (s, 1H), 7.11 (s, 3H), 6.69 (s, 1H), 4.11 (s, 2H), 3.70 (s, 3H), 2.57 (s, 3H), 2.40 (s,
13
3
H), 2.38 (s, 6H); C NMR (CDCl , 100 MHz): δ 170.3, 149.7, 139.4, 139.2, 136.7,
30.9, 130.1, 128.4, 125.4, 124.2, 120.1, 114.1, 52.6, 32.6, 22.2, 21.4, 19.6; GCꢀMS
+
found for 322. HRMS calcd for C20
H
23
N
2
O
2
[M+H] , 323.1754; found, 323.1753.
Methyl 2-(5-methoxy-2-(4-methoxy-3,5-dimethylphenyl)-2H-indazol-3-yl) acetate
1
(
3ka): Oil, 24.4 mg (69% yield); H NMR (CDCl
3
, 400 MHz): δ 7.62 (d, J = 9.3 Hz,
1H), 7.20 (s, 2H), 7.03 (dd, J = 9.3, 2.3 Hz, 1H), 6.81 (d, J = 2.1 Hz, 1H), 3.99 (s, 2H),
13
3
.86 (s, 3H), 3.77 (s, 3H), 3.70 (s, 3H), 2.34 (s, 6H); C NMR (CDCl
3
, 100 MHz): δ
169.7, 157.5, 155.3, 145.4, 135.0, 132.2, 126.8, 126.4, 121.8, 121.7, 119.4, 95.8, 60.0,
+
5
5.6, 52.6, 31.6, 16.3; GCꢀMS found for 354. HRMS calcd for C H N O [M+H] ,
20
23
2
4
355.1652; found, 355.1651.
Methyl 2-oxo-2-(2-phenyl-2H-indazol-3-yl) acetate (4aa): Oil, 22.6 mg (81% yield);
1
H NMR (CDCl
3
, 400 MHz): δ 8.11 (dd, J = 7.7, 1.7 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H),
13
7
.56 (s, 5H), 7.51ꢀ7.43 (m, 2H), 3.53 (s, 3H); C NMR (CDCl
3
, 100 MHz): δ 175.9,
162.9, 148.9, 140.2, 130.0, 129.5, 129.5, 127.9, 127.5, 126.2, 125.5, 120.8, 119.1,
+
5
2.9; GCꢀMS found for 280. HRMS calcd for C16
H
13
N
2
O
3
[M+H] , 281.0921; found,
281.0919.
Methyl
2-(5-fluoro-2-(4-fluorophenyl)-2H-indazol-3-yl)-2-oxoacetate
(4da):
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5
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o
1
Yellow Solid, 23.4 mg (74% yield), mp: 129ꢀ131 C; H NMR (CDCl
3
, 400 MHz): δ
7
2
.90 (dd, J = 9.4, 4.7 Hz, 1H), 7.68 (dd, J = 8.9, 2.3 Hz, 1H), 7.53 (dd, J = 8.9, 4.6 Hz,
1
3
3
H), 7.31ꢀ7.22 (m, 3H), 3.65 (s, 3H); C NMR (CDCl , 100 MHz): δ 175.3, 163.3 (d,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J = 251.5 Hz), 162.9, 162.1 (d, J = 248.4 Hz), 146.2, 136.3, 129.9 (d, J = 8.2 Hz),
28.1 (d, J = 8.8 Hz), 125.7 (d, J = 12.7 Hz), 121.5 (d, J = 10.1 Hz), 119.6 (d, J = 28.8
1
Hz), 116.5 (d, J = 23.2 Hz), 104.4 (d, J = 26.3 Hz), 53.2; GCꢀMS found for 316.
+
HRMS calcd for C16
H
11
F
2
N
2
O
3
[M+H] , 317.0732; found, 317.0732.
Methyl 2-(5-methoxy-2-(4-methoxy-3,5-dimethylphenyl)-2H-indazol-3-yl)-2-oxo
o
1
acetate (4ka): Yellow Solid, 23.1 mg (63% yield), mp: 97ꢀ99 C; H NMR (CDCl ,
3
4
00 MHz): δ 7.78 (d, J = 9.3 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.20 (s, 2H), 7.13 (dd,
1
3
J = 9.3, 2.4 Hz, 1H), 3.93 (s, 3H), 3.77 (s, 3H), 3.47 (s, 3H), 2.36 (s, 6H); C NMR
CDCl , 100 MHz): δ 176.4, 163.3, 159.9, 158.1, 145.3, 135.6, 132.5, 129.0, 127.0,
(
3
126.2, 122.7, 120.4, 97.7, 60.0, 55.9, 52.5, 16.2; GCꢀMS found for 368. HRMS calcd
+
for C H N O [M+H] , 369.1445; found, 369.1444.
20
21
2
5
1
8b
1-(1H-indol-2-yl)propan-1-one (5ag) : Yellow Solid, 13.1 mg (76% yield), mp:
o
1
1
3
52ꢀ154 C; H NMR (CDCl , 400 MHz): δ 9.28 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H),
7.45 (d, J = 8.3 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 1.7 Hz, 1H), 7.16 (t, J =
13
7
.5 Hz, 1H), 3.01 (q, J = 7.4 Hz, 2H), 1.29 (t, J = 7.4 Hz, 3H); C NMR (CDCl
3
, 100
MHz): δ 194.2, 137.3, 135.1, 127.7, 126.3, 123.1, 121.0, 112.3, 109.0, 31.6, 8.9;
GCꢀMS found for 173.
1-(5-Methyl-1H-indol-2-yl)propan-1-one (5bg): Yellow Solid, 14.9 mg (80% yield),
o
1
3
mp: 174ꢀ176 C; H NMR (CDCl , 400 MHz): δ 9.12 (s, 1H), 7.47 (s, 1H), 7.33 (d, J
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=
8.4 Hz, 1H), 7.17 (dd, J = 8.5, 1.0 Hz, 1H), 7.12 (d, J = 1.4 Hz, 1H), 2.99 (q, J = 7.4
13
Hz, 2H), 2.44 (s, 3H), 1.28 (t, J = 7.4 Hz, 3H); C NMR (CDCl
3
, 100 MHz): δ 194.1,
1
35.7, 135.1, 130.3, 128.3, 128.0, 122.3, 112.0, 108.5, 31.6, 21.6, 8.9; GCꢀMS found
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
for 187. HRMS calcd for C H NO [M+H] , 188.1070; found, 188.1069.
12
14
1
8c
1
-(5-Methoxy-1H-indol-2-yl)propan-1-one (5cg) : Yellow Solid, 14.8 mg (73%
o
1
3
yield), mp: 166ꢀ168 C; H NMR (CDCl , 400 MHz): δ 9.31 (s, 1H), 7.34 (d, J = 9.0
Hz, 1H), 7.12 (s, 1H), 7.08 (d, J = 1.7 Hz, 1H), 7.02 (dd, J = 9.0, 2.3 Hz, 1H), 3.85 (s,
13
3
H), 2.99 (q, J = 7.4 Hz, 2H), 1.28 (t, J = 7.4 Hz, 3H); C NMR (CDCl
3
, 100 MHz):
δ 194.0, 154.8, 135.5, 132.8, 128.0, 118.1, 113.3, 108.6, 102.8, 55.8, 31.6, 8.9;
+
GCꢀMS found for 203. HRMS calcd for C12
H
14NO
2
[M+H] , 204.1019; found,
204.1019.
1
-(5-Fluoro-1H-indol-2-yl)propan-1-one (5dg): Yellow Solid, 13.6 mg (71% yield),
o
1
mp: 182ꢀ184 C; H NMR (CDCl
3
, 400 MHz): δ 9.37 (s, 1H), 7.39 (dd, J = 9.0, 4.3
Hz, 1H), 7.34 (dd, J = 9.1, 2.3 Hz, 1H), 7.16 (d, J = 1.9 Hz, 1H), 7.11 (td, J = 9.1, 2.4
1
3
3
Hz, 1H), 3.00 (q, J = 7.4 Hz, 2H), 1.29 (t, J = 7.4 Hz, 3H); C NMR (CDCl , 100
MHz): δ 194.1, 158.3 (d, J = 236.9 Hz), 136.4, 133.9, 127.9, 115.5 (d, J = 27.2 Hz),
113.3 (d, J = 9.6 Hz), 108.7 (d, J = 5.0 Hz), 107.2 (d, J = 23.1 Hz), 31.7, 8.8; GCꢀMS
+
found for 191. HRMS calcd for C11
H
11FNO [M+H] , 192.0819; found, 192.0821.
1-(5-Chloro-1H-indol-2-yl)propan-1-one (5eg): Yellow Solid, 10.5 mg (51% yield),
o
1
3
mp: 195ꢀ197 C; H NMR (CDCl , 400 MHz): δ 9.29 (s, 1H), 7.68 (d, J = 1.6 Hz, 1H),
7.37 (d, J = 8.8 Hz, 1H), 7.29 (dd, J = 8.8, 1.9 Hz, 1H), 7.13 (d, J = 1.7 Hz, 1H), 3.00
13
(
q, J = 7.4 Hz, 2H), 1.28 (t, J = 7.4 Hz, 3H); C NMR (CDCl
3
, 100 MHz): δ 194.1,
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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4
4
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5
5
5
5
5
5
6
1
2
1
36.1, 135.5, 128.6, 126.8, 126.6, 122.2, 113.5, 108.1, 31.7, 8.7; GCꢀMS found for
ꢀ
07. HRMS calcd for C11
H
9
ClNO [MꢀH] , 206.0378; found, 206.0377.
-(5-Bromo-1H-indol-2-yl)propan-1-one (5mg): Yellow Solid, 13.6 mg (54% yield),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
mp: 193ꢀ195 C; H NMR (CDCl , 400 MHz): δ 9.28 (s, 1H), 7.84 (s, 1H), 7.42 (dd, J
3
=
8.7, 1.8 Hz, 1H), 7.33 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 1.0 Hz, 1H), 3.00 (q, J = 7.4
13
Hz, 2H), 1.28 (t, J = 7.4 Hz, 3H); C NMR (CDCl
3
, 100 MHz): δ 194.1, 135.9, 135.8,
1
29.3, 129.2, 125.4, 114.1, 113.9, 108.0, 31.7, 8.7; GCꢀMS found for 251, 253.
ꢀ
9
HRMS calcd for C11H BrNO [MꢀH] , 249.9873; found, 249.9872.
1
-(5-(Trifluoromethyl)-1H-indol-2-yl)propan-1-one (5fg): White Solid, 17.5 mg
o
1
3
(73% yield), mp: 167ꢀ169 C; H NMR (CDCl , 400 MHz): δ 9.92 (s, 1H), 8.02 (s,
1H), 7.57 (s, 2H), 7.29 (d, J = 0.9 Hz, 1H), 3.06 (q, J = 7.3 Hz, 2H), 1.32 (t, J = 7.4
13
Hz, 3H); C NMR (CDCl
3
, 100 MHz): δ 194.4, 138.5, 136.4, 126.8, 125.0 (q, J =
271.5 Hz), 123.5 (q, J = 32.3 Hz), 122.7 (q, J = 3.0 Hz), 121.0 (q, J = 4.4 Hz), 113.0,
ꢀ
1
09.6, 31.8, 8.7; GCꢀMS found for 241. HRMS calcd for C H F NO [MꢀH] ,
12
9 3
240.0642; found, 240.0644.
1
-(6-Methyl-1H-indol-2-yl)propan-1-one (5gg): Yellow Solid, 15.1 mg (81% yield),
o
1
mp: 141ꢀ143 C; H NMR (CDCl
3
, 400 MHz): δ 9.13 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H),
7
.22 (s, 1H), 7.16 (s, 1H), 6.99 (d, J = 8.2 Hz, 1H), 2.98 (q, J = 7.4 Hz, 2H), 2.47 (s,
13
3H), 1.28 (t, J = 7.5 Hz, 3H); C NMR (CDCl , 100 MHz): δ 194.0, 137.9, 136.7,
3
1
34.7, 125.6, 123.2, 122.7, 111.9, 109.1, 31.5, 22.2, 9.0; GCꢀMS found for 187.
+
HRMS calcd for C12
H
14NO [M+H] , 188.1070; found, 188.1069.
1
-(4,6-Dimethyl-1H-indol-2-yl)propan-1-one (5jg): Yellow Solid, 14.5 mg (72%
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o
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yield), mp: 171ꢀ173 C; H NMR (CDCl
3
, 400 MHz): δ 9.15 (s, 1H), 7.19 (d, J = 1.1
Hz, 1H), 7.05 (s, 1H), 6.79 (s, 1H), 3.00 (q, J = 7.4 Hz, 2H), 2.54 (s, 3H), 2.43 (s, 3H),
13
1
1
3
.29 (t, J = 7.4 Hz, 3H); C NMR (CDCl , 100 MHz): δ 193.9, 137.8, 136.9, 134.2,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
32.3, 125.9, 123.2, 109.4, 107.8, 31.4, 22.2, 18.7, 9.1; GCꢀMS found for 201. HRMS
+
calcd for C13
H
16NO [M+H] , 202.1226; found, 202.1226.
Methyl 2-propionyl-1H-indole-5-carboxylate (5lg): Yellow Solid, 10.3 mg (45%
o
1
yield), mp: 212ꢀ214 C; H NMR (CDCl
3
, 400 MHz): δ 9.39 (s, 1H), 8.49 (s, 1H),
8
3
.03 (dd, J = 8.7, 1.6 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.29ꢀ7.27 (m, 1H), 3.94 (s,
13
H), 3.02 (q, J = 7.3 Hz, 2H), 1.29 (t, J = 7.4 Hz, 3H); C NMR (CDCl , 100 MHz):
3
δ 194.0, 167.7, 139.5, 136.3, 127.3, 127.1, 126.4, 123.3, 112.1, 110.0, 52.2, 31.7, 8.7;
+
GCꢀMS found for 231. HRMS calcd for C13
32.0965.
(1H-indol-2-yl)(phenyl)methanone (5ah) : Yellow Solid, 18.1 mg (82% yield), mp:
H
14NO
3
[M+H] , 232.0968; found,
2
1
8d
o
1
1
50ꢀ152 C; H NMR (CDCl , 400 MHz): δ 9.52 (s, 1H), 8.01 (dd, J = 5.2, 3.4 Hz,
3
2H), 7.75ꢀ7.71 (m, 1H), 7.66ꢀ7.61 (m, 1H), 7.57ꢀ7.48 (m, 3H), 7.39 (ddd, J = 8.2, 7.1,
13
1
.0 Hz, 1H), 7.20ꢀ7.16 (m, 2H); C NMR (CDCl
3
, 100 MHz): δ 187.4, 138.1, 137.7,
134.5, 132.5, 129.4, 128.6, 127.9, 126.7, 123.4, 121.2, 113.0, 112.4; GCꢀMS found
+
for 221. HRMS calcd for C15
H
12NO [M+H] , 222.0913; found, 222.0916.
1
8b,18d
(4-Fluorophenyl)(1H-indol-2-yl)methanone (5ai)
: Yellow Solid, 16.7 mg (70%
o
1
yield), mp: 181ꢀ183 C; H NMR (CDCl
3
, 400 MHz): δ 9.47 (s, 1H), 8.08ꢀ8.02 (m,
2H), 7.73 (d, J = 8.2 Hz, 1H), 7.53ꢀ7.46 (m, 1H), 7.42ꢀ7.37 (m, 1H), 7.25ꢀ7.14 (m,
13
4
H); C NMR (CDCl
3
, 100 MHz): δ 185.8, 165.5 (d, J = 253.8 Hz), 137.7, 134.4 (d,
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1
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1
1
1
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2
2
2
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2
2
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5
5
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J = 2.9 Hz), 134.2, 131.9 (d, J = 8.9 Hz), 127.8, 126.8, 123.4, 121.3, 115.8 (d, J =
2
1.8 Hz), 112.8, 112.3; GCꢀMS found for 239.
Benzo[b]thiophen-2-yl(1H-indol-2-yl)methanone (5aj): Yellow Solid, 18.0 mg (65%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
yield), mp: 258ꢀ260 C; H NMR (DMSOꢀD , 400 MHz): δ 12.05 (s, 1H), 8.58 (s,
6
1
7
H), 8.11 (t, J = 7.5 Hz, 2H), 7.78 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H),
13
6
.59ꢀ7.49 (m, 3H), 7.37ꢀ7.31 (m, 1H), 7.17ꢀ7.11 (m, 1H); C NMR (DMSOꢀD , 100
MHz): δ 178.6, 142.1, 141.1, 139.3, 138.1, 133.7, 130.8, 127.6, 127.2, 126.5, 126.0,
1
25.3, 122.9, 120.6, 112.8, 110.9; GCꢀMS found for 277. HRMS calcd for
+
C H NOS [M+H] , 278.0634; found, 278.0635.
17 12
18e
N,N-dimethyl-1H-indole-2-carboxamide (5ak) : White Solid, 12.2 mg (65%
o
1
yield), mp: 185ꢀ187 C; H NMR (CDCl
3
, 400 MHz): δ 9.64 (s, 1H), 7.67 (d, J = 8.1
Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.28 (dd, J = 12.8, 4.8 Hz, 1H), 7.13 (t, J = 7.5 Hz,
1
3
3
1H), 6.86 (d, J = 2.0 Hz, 1H), 3.45 (s, 3H), 3.22 (s, 3H); C NMR (CDCl , 100 MHz):
δ 163.3, 135.6, 129.8, 127.9, 124.5, 122.1, 120.5, 111.9, 106.0; GCꢀMS found for 188.
ꢀ
HRMS calcd for C11
11
H N
2
O [MꢀH] , 187.0877; found, 187.0879.
N,N-dimethyl-5-(trifluoromethyl)-1H-indole-2-carboxamide (5fk): Yellow Solid,
o
1
13.3 mg (52% yield), mp: 224ꢀ226 C; H NMR (DMSOꢀD
6
, 400 MHz): δ 11.98 (s,
1
H), 8.03 (s, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.47 (dd, J = 8.7, 1.6 Hz, 1H), 7.03 (d, J =
1
3
1.6 Hz, 1H), 3.31 (s, 3H), 3.06 (s, 3H); C NMR (DMSOꢀD , 100 MHz): δ 162.3,
6
1
37.2, 132.5, 126.4, 125.5 (q, J = 271.2 Hz), 120.6 (q, J = 31.2 Hz), 119.5 (q, J = 9.5
Hz), 119.5 (q, J = 10.5 Hz), 113.0, 105.7; GCꢀMS found for 256. HRMS calcd for
+
C
12
H
12
F
3
N
2
O [M+H] , 257.0896; found, 257.0896.
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8f
N,N,6-trimethyl-1H-indole-2-carboxamide (5gk) : Yellow Solid, 12.7 mg (63%
o
1
yield), mp: 206ꢀ208 C; H NMR (CDCl
3
, 400 MHz): δ 9.44 (s, 1H), 7.54 (d, J = 8.2
Hz, 1H), 7.23 (s, 1H), 6.97 (d, J = 7.9 Hz, 1H), 6.81 (s, 1H), 3.33 (s, 6H), 2.47 (s, 3H);
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
C NMR (CDCl , 100 MHz): δ 136.1, 134.7, 129.2, 125.8, 122.6, 121.7, 111.6, 106.0,
3
+
2
2.1; GCꢀMS found for 202. HRMS calcd for C12
03.1177.
H
15
N
2
O [M+H] , 203.1179; found,
2
1
8g
(5-Methoxy-1H-indol-2-yl)(3-methoxyphenyl)methanone (5cl) : Yellow Solid,
o
1
8
10 mg (57% yield), mp: 146ꢀ148 C; H NMR (CDCl
3
, 400 MHz): δ 9.41 (s, 1H),
7
.59 (d, J = 7.6 Hz, 1H), 7.51ꢀ7.49 (m, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.38 (d, J = 8.8
Hz, 1H), 7.16 (dd, J = 8.2, 2.1 Hz, 1H), 7.11ꢀ7.04 (m, 3H), 3.89 (s, 3H), 3.85 (s, 3H);
1
3
3
C NMR (CDCl , 100 MHz): δ 186.9, 159.8, 155.0, 139.5, 134.9, 133.2, 129.6, 128.2,
1
22.0, 118.8, 118.6, 113.9, 113.3, 112.5, 102.9, 55.8, 55.6; GCꢀMS found for 281.
ꢀ
HRMS calcd for C17
H
14NO
3
[MꢀH] , 280.0979; found, 280.0978.
ASSOCIATED CONTENT
Supporting Information
Procedure for preparation of starting materials, optimization conditions, mechanistic
experiments, spectra for all compounds, and cif data for compound 3da are all
available on the ACS Publications website at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
cjxi@tsinghua.edu.cn
Notes
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