Synthesis of 2,3-Disubstituted NH Indoles via Rhodium(III)-Catalyzed C-H Activation of Arylnitrones and Coupling with Diazo Compounds

Article abstract of DOI:10.1021/acs.joc.7b02105

A rhodium-catalyzed intermolecular coupling between arylnitrones and diazo compounds by C-H activation/[4 + 1] annulation with a C(N₂)-C(acyl) bond cleavage is reported, and 2,3-disubstituted NH indoles are directly synthesized in up to a 94% yield. A variety of functional groups are applicable to this reaction to give the corresponding products with high selectivity. Compared to other previously reported Rh(III)-catalyzed synthesis of homologous series, this method is simpler, more general, and more efficient.

Full text of DOI:10.1021/acs.joc.7b02105

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Article
Synthesis of 2,3-Disubstituted NH Indoles via Rhodium(III)-Catalyzed
C–H Activation of Arylnitrones and Coupling with Diazo Compounds
Xin Guo, Jianwei Han, Yafeng Liu, Mingda Qin, Xueguo Zhang, and Baohua Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02105 • Publication Date (Web): 19 Sep 2017
Downloaded from http://pubs.acs.org on September 19, 2017
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Synthesis
of
2,3-Disubstituted
NH
Indoles
via
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Rhodium(III)-Catalyzed C–H Activation of Arylnitrones and
Coupling with Diazo Compounds
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Xin Guo,a Jianwei Han,a Yafeng Liu,a Mingda Qin,a Xueguo Zhang,a and Baohua
Chena,b*
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu, and Key
Laboratory of Nonferrous
Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou 730000, People’s Republic
of China
Fax: (+86)ꢀ931ꢀ891ꢀ2582; eꢀmail: chbh@lzu.edu.cn
b Zhongwei Highꢀtech Institute of Lanzhou University, Zhongwei, Ningxia, 755500, China
Abstract: A rhodiumꢀcatalyzed intermolecular coupling between
arylnitrones and diazo compounds by CꢀH activation/[4+1] annulation
with a C(N2) ꢀC(acyl) bond cleavage is reported, and 2,3ꢀdisubstituted NH
indoles are directly synthesized in up to a 94% yield. A variety of
functional groups are applicable to this reaction to give the corresponding
products with high selectivity. Compared to other previously reported
Rh(III)ꢀcatalyzed synthesis of homologous series, this method is simpler,
more general, and more efficient.
Introduction
As one of the most abundant and relevant heterocycles, the indole unit
has been found in many natural products, agrochemicals, pharmaceuticals,
and organic functional materials.1 In the last few decades, many efforts
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have been made to develop new synthetic methods for the generation of
indole models and a number of strategies have been reported.2ꢀ4 However,
via these methods, harsh reaction conditions, low atom economy and low
functionalꢀgroup tolerance often limit the versatility of indole synthesis.
Finding new synthetic methods to synthesis indoles is still in great
demand.
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Over the past few decades, transitionꢀmetalꢀcatalyzed direct CꢀH bond
activation has been extensively investigated as a powerful strategy for
direct synthesis of complexed structures.5 Therefore, a wide variety of
directing groups have been successfully explored.6 As a relatively weaker
ligating group, nitrones have been functioned as a directing group in
rhodiumꢀcatalyzed CꢀH activation reactions because of its easy
accessbility since 2013.7 Then, many heterocyclic compounds have been
synthesized by this building block.8 Yu and coꢀworkers demonstrated the
first rhodiumꢀcatalyzed intermolecular coupling of arenes with
diazomalonates via CꢀH activation.9 Subsequently, many groups have
made great progress in different heterocycleꢀspecies by such method.10
For example,
Zhou
and
Chang’s
groups developed
a
rhodiumꢀ(III)ꢀcatalyzed regioselective synthesis of 3HꢀindoleꢀNꢀoxides
from nitrones and diazo compounds (Scheme 1a).11 More recently, Li’s
group reported ruthenium(II)ꢀcatalyzed of synthesis 2,3ꢀdisubstituted NH
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indoles and 3Hꢀindoles with imidamides and diazo compounds in 2016
(Scheme 1b).12
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However, transformations on more challenging nitrones with diazo
compounds to access NH indoles are thus far unprecedented. Encouraged
by strategies above, we herein report the Rh(III)ꢀcatalyzed CꢀH
functionalization of nitrones with diazo compounds to deliver the
corresponding 2,3ꢀdisubstituted NH indoles under mild reaction
conditions (Scheme 1c).
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Scheme 1. Intermolecular Coupling with Diazo Com-pounds.
Zhou and chang's work. (a)
N2
N2
Ar
O
OH
N
O
N
R1 R2
R1 R2
N
Ar
Ar
R2
[Cp*RhCl2]2
AgOAc
[Cp*RhCl2]2
PivOH
R2
R1
R1
Li's work. (b)
CO2R2
R
RuII
N2
NH
R1OC
CO2R2
N
N
R
H
H
This work. (c)
Ar
O
CO2R2
Ar
N2
N
Rh(III)
R1OC
CO2R2
R
R
N
H
Results and Discussion Sections
We started our studies by testing different reaction conditions for the
desired product of 2,3ꢀdisubstituted NH indole 3a (Table 1). As we know,
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Pd(II), Ru(II), and Rh(III) catalysts can easily react with diazo
compounds to generate metal carbene intermediate.13 Our first
investigation began with nitrone (1a) and αꢀacyldiazoacetate (2a) in the
Table 1. Optimization of the Reaction Conditionsa
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entry
catalyst
additive (equiv.)
oxidant
(equiv.)
yield
(%)b
1
2
3
4
Pd(OAc)2
[Ru(pꢀcymene)Cl2]2
[RhCp*Cl2]2
NaOAc (0.2)
NaOAc (0.2)
NaOAc (0.2)
NaOAc (0.2)
ꢀ
0
0
ꢀ
ꢀ
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[RhCp*Cl2]2
Cu(OAc)2 (2.0)
5
6
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
NaOAc (1.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
AgOAc (2.0)
67
21
AcOH
(1.0)
7
8c
PivOH (1.0)
NaOAc (1.0)
NaOAc (1.0)
NaOAc (1.0)
NaOAc (1.0)
NaOAc (1.0)
NaOAc (1.0)
NaOAc (1.0)
NaOAc (1.0)
NaOAc (1.0)
NaOAc (1.0)
43
Trace
36
9
10
11d
12e
13f
14g
15h
16i
17j
CuO (2.0)
56
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
trace
32
24
trace
19
92
67
aUnless otherwise noted, all the reactions were carried out using nitrone (1a) (0.20 mmol) and diazo
compound (2a) (0.40 mmol) with metal catalysts (5 mol%) in the presence of additives in DCE (2.0
mL) at 100 C for 12 h under air in a sealed reaction tube. bIsolated yield. cWithout AgSbF6. dIn
DMF. eIn tꢀAmOH. In toluene. gIn CH3CN. hThe reaction temperature is 80 oC.iThe reaction
temperature is 120 oC. j2.5 mol % of [Cp*RhCl2]2 were used as catalyst, the reaction temperature is 120
oC .
o
f
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presence of various catalytic transitionꢀmetal salts with AgSbF6 (20 mol%)
o
and NaOAc (20 mol%) in 1,2ꢀdichloroethane (DCE) at 100 C under an
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air atmosphere for 12 h (entries 1ꢀ3). We soon found that only
[RhCp*Cl2]2 could afford the desired product in a 15% yield. Intriguingly,
when 2 equivalent of Cu(OAc)2 was used, the yield of 3a was excellently
improved to 52% (entry 4). Subsequently, with 1 equivalent of NaOAc as
an additive, the yield was increased to 67% whereas other additives
(AcOH and PivOH) were ineffective in this reaction (entries 5ꢀ7). A
further explored reaction was not occurred in the absence of AgSbF6.
When AgOAc and CuO were used as the oxidant, the yield was not
improved (entries 9ꢀ10). Screening of the solvents revealed that DCE was
optimal (entries 11ꢀ14). Under these conditions, by changing the reaction
temperature, we found that the yield could be enhanced to 92% at 120 oC.
Finally, decreasing the catalyst loading to 2.5 mol% resulted in a reduced
yield to 67%.
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Table 2. Synthesis of 2,3-Disubstituted NH Indoles.a
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aReaction condition: 1 (0.20 mmol), 2a (0.40 mmol), [RhCp*Cl2]2 (5 mol%), AgSbF6 (20 mol%), NaOAc (1
equiv), Cu(OAc)2 (2 equiv), and DCE (2 mL) at 120 oC for 12 h under air in a sealed reaction tube.
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Under the optimal reaction conditions, a variety of nitrones were used
as substrate to investigate the scope of the reaction. As we know, nitrones
can be prepared from readily available nitroarenes and aromatic
aldehydes. So we examined variation of arylaldehydes at first. As shown
in Table 2, arylaldehydes bearing an electronꢀdonating or
electronꢀwithdrawing group at para, or metaꢀposition of the phenyl ring
proceeded smoothly to give the ideal products in 78%ꢀ93% yields (3a, 3b,
3d, 3e, 3g, 3h, 3j, 3k). According to the experimental results, we found
that electronic effects are weak for this reaction. The yields of the
orthoꢀposition are relatively lower than others which may be due to the
steric effect (3c, 3f, 3i). To our delight, arylaldehydes bearing 2ꢀfuryl (1m)
and 1ꢀnaphthyl (1l) groups also can be expected to give a moderate yield
of the corresponding products (3m, 3l). In addition, the structure of 3a
was confirmed by Xꢀray crystal structure analysis (see the Supporting
Information).
Subsequently, we set out to explore the scope of nitrones bearing kinds
of Nꢀaryl substituents as summarized in Table 2. It was worth noting that
the Nꢀaryl moiety bearing both electronꢀrich groups and electronꢀdeficient
groups were all successfully engaged with good yields in this catalytic
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methodology. A cyanoꢀ group on the Nꢀaryl moiety was well tolerated
under this reaction but afforded the target product with a lower yield (3v).
Notably, substrates substituted by methyl, fluorine, chlorine, bromine,
methoxyl, trifluoromethyl and even acetyl groups on the paraꢀposition all
could provide very excellent yields (3n, 3qꢀ3u, 3w). Meanwhile, the
metaꢀmethylꢀsubstituted Nꢀaryl led to a regioselective formation of the
desired product which was at a less hindered position (3o), whereas the
metaꢀfluoro substrate was occurred at the more hindered position (3y).12
When a orthoꢀsubstituent is present, a slightly lower yield was observed
(3p). At last, when we reacted 1x with 2a, we also got the corresponding
product in a good yield (3x).
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Table 3. Reactions with Different Diazo Compounds.a
Entry
R1
R2
Yield(%)
1
2
3
4
5
6
7
ꢀAc (2z)
ꢀC(O)OMe
ꢀC(O)OtBu
ꢀC(O)OMe
ꢀC(O)OEt
ꢀC(O)OEt
ꢀC(O)OtBu
ꢀC(O)OEt
3z, 74
3aa, 65
3z, 84
3a, 92
3a, 25
3aa, 34
3a, 59
ꢀAc (2aa)
ꢀC(O)Ph (2ab)
ꢀC(O)Ph (2ac)
ꢀP(O)(OMe)2 (2ad)
ꢀP(O)(OEt)2 (2ae)
ꢀP(O)(OEt)2 (2af)
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ꢀC(O)OMe (2ag)
ꢀC(O)OMe
NR
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8
aReaction conditoin: 1a (0.20 mmol), 2 (0.40 mmol), [RhCp*Cl2]2 (5 mol%), AgSbF6 (20 mol%),
o
NaOAc (1 equiv), Cu(OAc)2 (2 equiv), and DCE (2 mL) at 120 C for 12 h under air in a sealed
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reaction tube.
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Then, we investigated the feasibility of different diazo esters (Table 3).
We found that the diazo compounds bearing both ester and ketone groups
(2z, 2aa, 2ab, 2ac) were successfully reacted with 1a to afford the
corresponding products with the cleavage of CꢀC bond, but bearing only
ester groups (2ag) were not engaged in this transformation to form
2,3ꢀdisubstituted NH indole. To our delight, when we reacted 1a with
other different diazo esters (2ad–2af), we could get the same products
with the cleavage of the CꢀP bonds in the diazo compound.
Additionally, to gain insight into the mechanism of this cyclization
process, a series of experiments were performed. First, a competitive
reaction was carried out to probe the electronic effect of the Nꢀaryl ring
(Scheme 2). An equimolar mixture of 1n, 1r, and 2a was allowed to react
under standard conditions for 5h. The products 3n and 3r were generated
in a 1.7:1 ratio by NMR analysis. We found that the reaction is more
favorable for Nꢀaryl bearing an electronꢀdonating substituent. The results
indicated that an electrophilic CꢀH activation is involved in the reaction
mechanism of this reaction (Scheme 2a). Moreover, To further probe the
CꢀH activation process, the kinetic isotope effect(KIE) was determined by
intermolecular competition experiments using an equimolar mixture of 1h
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and [D5]ꢀ1h. H NMR analysis of the product mixture gave an average
3h:3h-d4 ratio of 3.0. This result indicated that cleavage of the CꢀH bond
activation is involved in the rateꢀlimiting step (Scheme 2b).14
Scheme 2. Experiments for Mechanistic Studies.
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Referring to the preceding literature reports, and our experimental
findings. We propose a plausible reaction mechanism (Scheme 3). At the
first step, the cyclorhodium intermediate I is formed through CꢀH bond
activation of nitrone 1a reaction with the catalytically active rhodium
species which is initiated by AgSbF6 and NaOAc. Then,
αꢀacyldiazoacetate (2a) reacts with the rhodacycle I to form a rhodium
(III) carbene intermediate II. Migratory insertion of the RhꢀC bond into
the activated carbene generates the sixꢀmembered rhodacyclic
intermeditate III. Intermediate IV is furnished by intramolecular
electrophilic attack of the imino moiety.15 Then transmetalation of the Rh
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catalyst with the copper salt and subsequent βꢀhydride elimination
releases intermediate VI.16 At last, with the elimination of one acetic acid
unit, the desired product is obtained.
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Scheme 3. Proposed Catalytic Cycle.
Conclusion
In summary, we have developed a mild and efficient Rh(III)ꢀcatalyzed
oneꢀpot synthesis of 2,3ꢀdisubstituted NH indoles from arylnitrones and
diazo compounds. The scope of the nitrones substrates are sufficiently
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broad to deliver structurally diverse indoles in high yields. Based on the
above studies, further applications of this method in natural product
synthesis and a detailed mechanistic investigation are in progress.
Experimental Section
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1
13
General remarks. H NMR and C NMR spectra were recorded on
300MHz and 100MHz in CDCl3. All chemical shifts are given as δ value
(ppm) with reference to tetramethylsilane (TMS) as an internal standard.
The highꢀresolution mass spectra (HRMS) were recorded on an FTꢀICR
mass spectrometer using electrospray ionization (ESI). Products were
purified by flash chromatogrgraphy on 200ꢀ300 mesh silica gel. All
melting points were determined without correction. Unless otherwise
noted, commercially available reagents were used without further
purification.
The procedure for the synthesis of Arylnitrones: In a 100 ml round
bottomed flask, Nitroarene (1.0 equiv), aldehyde (1.1 equiv) and NH4Cl
(1.4 equiv) were added to a mixture of EtOH (2 mL/mmol of starting
material) and H2O (2 mL/mmol of starting material). Then the resulting
mixture was cooled to 0 °C. Then, zinc powder (2.0 equiv) was added at
0 °C, and the reaction mixture was allowed to warm to room temperature
and stirred over 1 d. The reaction mixture was filtered through a celite
pad and washed with CH2Cl2. The filtrate was extracted with CH2Cl2 and
the combined organic layers were dried over MgSO4, filtered and
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concentrated to give the crude nitrones. Pure nitrones were obtained by
recrystallization from ethanol.17
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The procedure for the synthesis of Diazo Compounds: To a solution of
ketonic ester or 1,3 diꢀketone (5 mmol) in CH3CN, 6 mmol TsN3 was
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o
added. Then the reaction mixture was cooled to 0 C and a solution of
DBU (6mmol) in CH3CN was added dropwise. Next, the reaction
temperature was raised to room temperature. After stirring for 5 hours,
the residue was extracted with ethyl acetate for 3 times. The combined
organic layers were washed with water and brine sequentially, dried over
Na2SO4, filtered and concentrated. The crude product was purified by
flash chromatography on silica gel to afford the corresponding product in
70ꢀ90% yields.18
The procedure for the synthesis of Compounds 3: A sealed reaction
tube was charged with nitrones (0.20 mmol), diazo compounds (0.40
mmol), [RhCp*Cl2]2 (5 mol%), AgSbF6 (20 mol%), NaOAc (0.2 mmol)
and Cu(OAc)2 (0.4 mmol) in DCE (2.0 mL). The mixture was stirred at
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120 C for 12 h under air. After that, the solvent was removed under
vacuum and the residue was purified by silica gel chromatography using
ethyl acetate/petroleum ether (20:1) to afford product 3.
ethyl 2-phenyl-1H-indole-3-carboxylate (3a). White solid (48.5 mg,
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92%); m.p. 157 – 159 C; H NMR (300 MHz, CDCl3) δ 8.67 (s, 1H),
8.22 (dd, J = 6.0, 3.1 Hz, 1H), 7.68 – 7.57 (m, 2H), 7.46 – 7.37 (m, 3H),
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7.37 – 7.30 (m, 1H), 7.29 – 7.22 (m, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.29 (t,
J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.7, 144.8, 135.4, 132.3,
129.8, 129.4, 128.3, 127.8, 123.4, 122.4, 122.3, 111.3, 104.9, 60.0, 14.6;
HRMS (ESI) calcd for C17H16NO2 [M+H]+ 266.1176; found: 266.1176.
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ethyl 2-(p-tolyl)-1H-indole-3-carboxylate (3b). Yellow solid (48.1 mg,
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86%); m.p. 175 – 178 C; H NMR (300 MHz, CDCl3) δ 8.72 (s, 1H),
8.19 (d, J = 6.8 Hz, 1H), 7.50 (d, J = 7.9 Hz, 2H), 7.35 – 7.22 (m, 3H),
7.17 (d, J = 7.9 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.35 (s, 3H), 1.32 (t, J =
13
7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ 165.5, 144.8, 139.1, 135.1,
129.4, 128.9, 128.7, 127.6, 122.9, 122.0, 121.9, 111.0, 104.2, 59.6, 21.3,
14.3; HRMS (ESI) calcd for C18H18NO2 [M+H]+ 280.1332; found:
280.1333.
ethyl 2-(o-tolyl)-1H-indole-3-carboxylate (3c). White solid (34.5 mg,
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62%); m.p. 76 – 79 C; 1H NMR (300 MHz, CDCl3) δ 8.98 (s, 1H), 8.19
(d, J = 7.9 Hz, 1H), 7.29 – 7.14 (m, 7H), 4.03 (q, J = 7.1 Hz, 2H), 2.15 (s,
13
3H); C NMR (75 MHz, CDCl3) δ 165.3, 144.4, 137.4, 135.1, 132.4,
129.7, 129.6, 128.9, 126.8, 125.1, 122.7, 121.8, 121.5, 111.3, 105.6, 59.4,
19.7, 14.0; HRMS (ESI) calcd for C18H18NO2 [M+H]+ 280.1132; found:
280.1132.
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ethyl 2-(4-chlorophenyl)-1H-indole-3-carboxylate (3d). White solid
(55.7 mg, 93%); m.p. 152 – 155 oC; 1H NMR (300 MHz, CDCl3) δ 8.84 (s,
1H), 8.24 – 8.15 (m, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.37 – 7.29 (m, 3H),
7.26 (dd, J = 6.5, 2.8 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz,
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3H); C NMR (75 MHz, CDCl3) δ 165.2, 142.9, 135.0, 130.6, 130.1,
128.0, 127.2, 123.1, 121.9, 110.9, 104.6, 59.6, 14.1; HRMS (ESI) calcd
for C17H15ClNO2 [M+H]+ 300.0786; found: 300.0786.
ethyl 2-(3-chlorophenyl)-1H-indole-3-carboxylate (3e). White solid
(51.3 mg, 86%); m.p.180 – 182 oC; 1H NMR (300 MHz, CDCl3) δ 8.72 (s,
1H), 8.28 – 8.17 (m, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.53 (dt, J = 6.8, 1.5
Hz, 1H), 7.41 – 7.32 (m, 3H), 7.31 – 7.22 (m, 2H), 4.30 (q, J = 7.1 Hz,
2H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 164.9, 142.3,
135.0, 133.7, 133.5, 129.5, 129.1, 128.9, 127.7, 127.3, 123.3, 122.0,
110.9, 105.0, 59.7, 14.1; HRMS (ESI) calcd for C17H15ClNO2 [M+H]+
300.0786; found: 300.0786.
ethyl 2-(2-chlorophenyl)-1H-indole-3-carboxylate (3f). Yellow solid
(49.9 mg, 84%); m.p. 141 – 143 oC; 1H NMR (300 MHz, CDCl3) δ 8.79 (s,
1H), 8.27 – 8.18 (m, 1H), 7.44 (dd, J = 10.0, 4.5 Hz, 2H), 7.40 – 7.33 (m,
2H), 7.32 (dd, J = 4.3, 1.8 Hz, 1H), 7.27 (dd, J = 6.0, 3.0 Hz, 2H), 4.19 (q,
13
J = 7.1 Hz, 2H), 1.17 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ
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164.9, 140.9, 135.1, 133.9, 132.0, 131.7, 130.3, 129.4, 126.7, 126.2,
123.3, 122.0, 121.9, 111.2, 106.6, 59.6, 14.1; HRMS (ESI) calcd for
C17H15ClNO2 [M+H]+ 300.0786; found: 300.0786.
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ethyl 2-(4-fluorophenyl)-1H-indole-3-carboxylate (3g). White solid
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(51.0 mg, 90%); m.p. 166 – 168 C; H NMR (300 MHz, CDCl3) δ 8.76
(s, 1H), 8.20 (dd, J = 5.4, 3.0 Hz, 1H), 7.66 – 7.52 (m, 2H), 7.34 (dd, J =
7.2, 2.0 Hz, 1H), 7.30 – 7.22 (m, 2H), 7.07 (t, J = 8.7 Hz, 2H), 4.28 (q, J
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= 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ
165.4, 164.8, 161.5, 143.4, 135.1, 131.5 (d, JCF = 8.4 Hz), 128.0, 127.4,
123.3, 122.1, 115.1 (d, JCF = 21.8 Hz), 111.0, 104.7, 59.8, 14.3; HRMS
(ESI) calcd for C17H15FNO2 [M+H]+ 284.1082; found: 284.1078.
ethyl 2-(4-methoxyphenyl)-1H-indole-3-carboxylate (3h). White solid
(46.3 mg, 78%); m.p. 147 – 150 oC; 1H NMR (300 MHz, CDCl3) δ 8.60 (s,
1H), 8.20 (dd, J = 5.9, 3.1 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.38 – 7.32
(m, 1H), 7.25 (dd, J = 6.4, 3.0 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 4.31 (q, J
= 7.1 Hz, 2H), 3.82 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 165.5, 160.3, 144.6, 135.0, 130.9, 127.7, 124.2, 122.9, 122.0,
121.9, 113.5, 110.9, 104.1, 59.6, 55.3, 14.4; HRMS (ESI) calcd for
C18H18NO3 [M+H]+ 296.1281; found: 296.1280.
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ethyl 2-(2-methoxyphenyl)-1H-indole-3-carboxylate (3i). White solid
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(41.2 mg, 70%); m.p. 167 – 169 C; H NMR (300 MHz, CDCl3) δ 8.87
(s, 1H), 8.28 – 8.14 (m, 1H), 7.56 (dd, J = 7.6, 1.5 Hz, 1H), 7.37 (dd, J =
7.8, 5.9 Hz, 2H), 7.24 (dd, J = 6.2, 2.9 Hz, 2H), 7.01 (dd, J = 16.8, 8.1 Hz,
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2H), 4.27 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); C
NMR (75 MHz, CDCl3) δ 165.3, 156.9, 141.0, 135.0, 132.7, 130.6, 127.1,
122.9, 121.8, 121.6, 120.5, 120.2, 111.0, 110.9, 105.5, 59.5, 55.6, 14.3;
HRMS (ESI) calcd for C18H18NO3 [M+H]+ 296.1281; found: 296.1287.
ethyl 2-(4-cyanophenyl)-1H-indole-3-carboxylate (3j). White solid
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(47.5 mg, 82%); m.p. 200 – 202 C; H NMR (300 MHz, CDCl3) δ 8.92
(s, 1H), 8.21 (dd, J = 6.2, 2.7 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.66 (d, J
= 8.1 Hz, 2H), 7.45 – 7.36 (m, 1H), 7.31 (dd, J = 6.2, 3.2 Hz, 2H), 4.33 (q,
13
J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ
165.1, 141.6, 136.5, 135.5, 131.7, 130.3, 127.2, 124.0, 122.5, 122.4,
118.5, 112.4, 111.2, 105.9, 60.1, 14.3; HRMS (ESI) calcd for C18H15N2O2
[M+H]+ 291.1128; found: 291.1126.
ethyl 2-(4-(trifluoromethyl)phenyl)-1H-indole-3-carboxylate (3k).
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White solid (56.4 mg, 85%); m.p. 150 – 152 C; H NMR (300 MHz,
CDCl3) δ 8.83 (s, 1H), 8.26 – 8.15 (m, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.63
(d, J = 8.2 Hz, 2H), 7.41 – 7.32 (m, 1H), 7.32 – 7.20 (m, 2H), 4.28 (q, J =
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7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.3,
142.5, 135.5, 135.3, 130.0, 127.3, 125.9 (d, JCF = 3.7 Hz), 123.7, 122.3,
122.2, 111.2, 105.5, 60.0, 14.2; HRMS (ESI) calcd for C18H15F3NO2
[M+H]+ 334.1050; found: 334.1049.
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ethyl 2-(naphthalen-1-yl)-1H-indole-3-carboxylate (3l). White solid
(37.9 mg, 60%); m.p. 166 – 168 oC;1H NMR (300 MHz, CDCl3) δ 8.71 (s,
1H), 8.30 (d, J = 6.8 Hz, 1H), 7.90 (dd, J = 11.3, 8.3 Hz, 2H), 7.66 (d, J =
8.2 Hz, 1H), 7.56 – 7.44 (m, 3H), 7.41 – 7.27 (m, 4H), 3.96 (q, J = 7.1 Hz,
2H), 0.81 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.0, 142.5,
135.2, 133.2, 132.2, 130.5, 129.4, 128.2, 127.9, 127.1, 126.5, 126.0,
125.7, 124.8, 123.2, 122.1, 121.8, 111.1, 107.1, 59.3, 13.6; HRMS (ESI)
calcd for C21H18NO2 [M+H]+ 316.1332; found: 316.1334.
ethyl 2-(furan-2-yl)-1H-indole-3-carboxylate (3m). White solid (17.9
mg, 35%); m.p. 123 – 126 oC; 1H NMR (300 MHz, CDCl3) δ 9.15 (s, 1H),
8.26 – 8.12 (m, 1H), 7.88 (d, J = 3.4 Hz, 1H), 7.51 (s, 1H), 7.43 – 7.34 (m,
1H), 7.26 (dt, J = 4.4, 3.4 Hz, 2H), 6.58 (dd, J = 3.4, 1.7 Hz, 1H), 4.46 (q,
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J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ
165.2, 145.6, 142.7, 134.7, 133.8, 127.4, 123.5, 122.4, 122.0, 114.6, 112.7,
110.9, 103.1, 59.9, 14.6; HRMS (ESI) calcd for C15H14NO3 [M+H]+
256.0968; found: 256.0964.
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ethyl 5-methyl-2-phenyl-1H-indole-3-carboxylate (3n). White solid
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(52.5 mg, 94%); m.p. 136 – 139 C; H NMR (300 MHz, CDCl3) δ 8.68
(s, 1H), 8.00 (s, 1H), 7.63 – 7.53 (m, 2H), 7.40 – 7.33 (m, 3H), 7.23 –
7.17 (m, 1H), 7.04 (d, J = 8.3 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 2.47 (s,
3H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.5, 144.5,
133.5, 132.2, 131.4, 129.7, 129.5, 128.9, 127.9, 124.6, 121.6, 110.7,
104.0, 59.6, 21.7, 14.2; HRMS (ESI) calcd for C18H18NO2 [M+H]+
280.1332; found: 280.1331.
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ethyl 6-methyl-2-phenyl-1H-indole-3-carboxylate (3o). yellow oil
(44.7 mg, 80%); 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.08 (d, J =
8.2 Hz, 1H), 7.61 (dd, J = 6.6, 3.0 Hz, 2H), 7.42 – 7.36 (m, 3H), 7.14 –
7.05 (m, 2H), 4.26 (q, J = 7.1 Hz, 2H), 2.45 (s, 3H), 1.29 (t, J = 7.1 Hz,
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3H); C NMR (75 MHz, CDCl3) δ 165.4, 143.9, 135.5, 133.0, 132.1,
129.5, 128.9, 128.0, 125.4, 123.7, 121.7, 110.9, 104.4, 60.0, 21.6, 14.3;
HRMS (ESI) calcd for C18H18NO2 [M+H]+ 280.1332; found: 280.1329.
ethyl 7-methyl-2-phenyl-1H-indole-3-carboxylate (3p). White solid
(22.6 mg, 41%); m.p. 155– 157 oC; 1H NMR (300 MHz, CDCl3) δ 8.58 (s,
1H), 8.06 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 3.7 Hz, 2H), 7.41 (d, J = 3.7 Hz,
3H), 7.19 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 7.0 Hz, 1H), 4.27 (dd, J = 14.2,
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7.1 Hz, 2H), 2.49 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); C NMR (75 MHz,
CDCl3) δ 165.4, 144.18, 134.7, 132.2, 130.7, 129.6, 129.5, 129.0, 128.8,
128.0, 127.2, 123.7, 122.2, 120.2, 119.8, 105.2, 59.6, 16.5, 14.3; HRMS
(ESI) calcd for C18H18NO2 [M+H]+ 280.1332; found: 280.1330.
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ethyl 5-fluoro-2-phenyl-1H-indole-3-carboxylate (3q). White solid
(52.6 mg, 93%); m.p.153 – 155 oC; 1H NMR (300 MHz, CDCl3) δ 8.97 (s,
1H), 7.83 (dd, J = 10.1, 2.3 Hz, 1H), 7.56 (dd, J = 6.5, 2.8 Hz, 2H), 7.42 –
7.28 (m, 3H), 7.19 (dd, J = 8.8, 4.4 Hz, 1H), 6.95 (td, J = 9.0, 2.4 Hz, 1H),
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4.22 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H); C NMR (75 MHz,
CDCl3) δ 165.4, 159.2 (d, J = 236.4 Hz), 146.2, 131.7 (d, J = 4.1 Hz),
129.5, 129.3, 128.3 (d, J = 11.1 Hz), 128.1, 112.1, 112.0, 111.5(d, J = 26.6
Hz), 107.3 (d, J = 25.3 Hz), 104.6 (d, J = 4.4 Hz), 59.9, 14.3; HRMS (ESI)
calcd for C17H15FNO2 [M+H]+ 284.1082; found: 284.1081.
ethyl 5-chloro-2-phenyl-1H-indole-3-carboxylate (3r). White solid
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(51.4 mg, 86%); m.p. 122 – 125 C; H NMR (300 MHz, CDCl3) δ 8.89
(s, 1H), 8.17 (d, J = 1.9 Hz, 1H), 7.64 – 7.55 (m, 2H), 7.39 (dd, J = 4.2,
2.4 Hz, 3H), 7.26 – 7.16 (m, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.0, 145.6, 133.5, 131.5, 129.5,
129.3, 128.6, 128.1, 127.7, 123.4, 121.6, 112.1, 104.3, 59.9, 14.3; HRMS
(ESI) calcd for C17H15ClNO2 [M+H]+ 300.0786; found: 300.0784.
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ethyl 5-bromo-2-phenyl-1H-indole-3-carboxylate (3s). Yellow solid
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(57.0 mg, 83%); m.p. 102 – 104 C; H NMR (300 MHz, CDCl3) δ 8.86
(s, 1H), 8.34 (d, J = 1.9 Hz, 1H), 7.63 – 7.54 (m, 2H), 7.39 (dd, J = 4.3,
2.3 Hz, 3H), 7.32 (dd, J = 8.6, 1.9 Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 4.30
– 4.22 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
164.8, 145.3, 133.6, 131.2, 129.3, 129.2, 129.0, 127.9, 125.9, 124.5,
115.3, 112.3, 104.0, 59.7, 14.1; HRMS (ESI) calcd for C17H15BrNO2
[M+H]+ 344.0281; found: 344.0281.
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ethyl 2-phenyl-5-(trifluoromethyl)-1H-indole-3-carboxylate (3t).
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White solid (53.3 mg, 80%); m.p. 166 – 168 C; H NMR (300 MHz,
CDCl3) δ 9.17 (d, J = 17.3 Hz, 1H), 8.51 (s, 1H), 7.63 – 7.54 (m, 2H),
7.46 (d, J = 8.5 Hz, 1H), 7.37 (dd, J = 4.5, 2.0 Hz, 4H), 4.27 (dd, J = 7.1,
3.2 Hz, 2H), 1.30 (td, J = 7.1, 1.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
165.0, 146.1, 136.5, 131.2, 129.9, 129.5, 128.8, 128.1, 127.0, 124.4,
119.8, 111.5, 105.1, 60.0, 14.2; HRMS (ESI) calcd for C18H15F3NO2
[M+H]+ 334.1050; found: 334.1049.
ethyl 5-methoxy-2-phenyl-1H-indole-3-carboxylate (3u). Yellow solid
(44.8 mg, 76%); 1H NMR (300 MHz, CDCl3) δ 8.80 (s, 1H), 7.73 (d, J =
2.4 Hz, 1H), 7.60 (d, J = 3.3 Hz, 2H), 7.39 (d, J = 3.0 Hz, 3H), 7.24 (dd, J
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= 7.4, 4.8 Hz, 1H), 6.88 (dd, J = 8.7, 2.4 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H),
3.88 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.5,
155.7, 144.8, 132.1, 130.2, 129.5, 129.0, 128.5, 127.9, 113.3, 111.9, 104.2,
103.5, 59.6, 55.6, 14.2; HRMS (ESI) calcd for C18H18NO3 [M+H]+
296.1281; found: 296.1278.
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ethyl 5-cyano-2-phenyl-1H-indole-3-carboxylate (3v). White solid
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(26.8 mg, 46%); m.p. 124 – 126 C; H NMR (300 MHz, CDCl3) δ 9.37
(s, 1H), 8.54 (s, 1H), 7.63 (dd, J = 6.6, 3.0 Hz, 2H), 7.47 (dd, J = 8.4, 1.4
Hz, 1H), 7.44 – 7.36 (m, 4H), 4.30 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz,
13
3H); C NMR (75 MHz, CDCl3) δ 164.6, 146.6, 136.9, 130.8, 129.7,
129.5, 128.2, 127.7, 127.3, 126.0, 120.5, 112.1, 105.0, 60.2, 14.3; HRMS
(ESI) calcd for C18H15N2O2 [M+H]+ 291.1128; found: 291.1138.
ethyl 5-acetyl-2-phenyl-1H-indole-3-carboxylate (3w). White solid
(38.4 mg, 63%); m.p. 184 –186 oC; 1H NMR (300 MHz, CDCl3) δ 9.23 (s,
1H), 8.81 (s, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.57 (s, 2H), 7.32 (d, J = 8.7
Hz, 4H), 4.23 (q, J = 7.0 Hz, 2H), 2.61 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 198.7, 165.0, 145.9, 137.9, 131.6, 131.4,
129.6, 129.5, 128.1, 127.2, 124.5, 123.1, 111.3, 105.6, 60.0, 26.6, 14.2;
HRMS (ESI) calcd for C19H18NO3 [M+H]+ 308.1281; found: 308.1272.
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ethyl (E)-2-styryl-1H-indole-3-carboxylate (3x). White solid (29.7 mg,
o
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8.05 (m, 2H), 7.51 (d, J = 6.8 Hz, 2H), 7.40 – 7.15 (m, 6H), 7.06 (d, J =
16.9 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 165.9, 141.5, 136.2, 135.7, 131.3, 128.8, 128.6, 127.5,
126.9, 123.8, 122.1, 121.9, 118.0, 110.7, 59.9, 14.6; HRMS (ESI) calcd
for C19H18NO2 [M+H]+ 292.1332; found: 292.1331.
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ethyl 4-fluoro-2-(4-methoxyphenyl)-1H-indole-3-carboxylate (3y).
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White solid (43.9 mg, 70%); m.p.168 –170 C; H NMR (400 MHz, ) δ
9.02 (s, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.10 (ddd, J = 19.4, 9.9, 6.2 Hz,
2H), 6.92 – 6.83 (m, 1H), 6.79 (d, J = 8.5 Hz, 2H), 4.24 (q, J = 7.1 Hz,
2H), 3.75 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
165.5, 160.2, 157.2, 154.7, 143.4, 137.8 (d, JCF = 10.2 Hz), 130.5, 123.4
(d, JCF = 8.0 Hz), 115.6 (d, JCF = 18.9 Hz), 113.6 ,107.6, 107.2 (d, JCF =
3.8 Hz), 103.5, 60.4, 55.2, 14.0; HRMS (ESI) calcd for C18H17FNO3
[M+H]+ 314.1187; found: 314.1187.
methyl 2-phenyl-1H-indole-3-carboxylate 3z). White solid (37.3 mg,
74%); m.p.136 –139 oC; 1H NMR (300 MHz, CDCl3) δ 8.87 (s, 1H), 8.23
– 8.13 (m, 1H), 7.63 – 7.53 (m, 2H), 7.36 (dd, J = 6.8, 3.6 Hz, 3H), 7.30
(dd, J = 6.5, 2.4 Hz, 1H), 7.27 – 7.18 (m, 2H), 3.77 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 165.9, 144.7, 135.1, 131.8, 129.4, 129.1, 128.0, 127.4,
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123.1, 122.0, 111.1, 104.1, 50.8; HRMS (ESI) calcd for C16H14NO2
[M+H]+ 252.1019; found: 252.1019.
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tert-butyl 2-phenyl-1H-indole-3-carboxylate (3aa). White solid (38.1
mg, 65%); m.p.189 – 192 oC; 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H),
8.26 – 8.17 (m, 1H), 7.59 (dd, J = 6.4, 3.0 Hz, 2H), 7.40 (dd, J = 4.9, 1.7
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Hz, 3H), 7.37 – 7.31 (m, 1H), 7.29 – 7.20 (m, 2H), 1.49 (s, 9H); C
NMR (75 MHz, CDCl3) δ 164.6, 143.9, 135.0, 132.4, 129.6, 128.9, 128.0,
127.7, 123.0, 122.0, 121.8, 110.9, 106.1, 80.0, 28.4; HRMS (ESI) calcd
for C19H20NO2 [M+H]+ 294.1489; found: 294.1488.
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Copies of 1H and 13C NMR spectra for all reaction products.
Xꢀray crystal structure of compound 3a (CIF)
Corresponding Author:
*Fax: (+86)ꢀ931ꢀ891ꢀ2582. Eꢀmail: chbh@lzu.edu.cn
References
(1) (a) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005, 22, 761. (b) Somei, M.; Yamada, F.
Nat. Prod. Rep. 2005, 22, 73. (c) Ertl, P.; Jelfs, S.; Muhlbacher, J.; Schuffenhauer, A.; Selzer,
P. J. Med. Chem. 2006, 49, 4568. (d) KochanowskaꢀKaramyan, A. J.; Hamann, M. T. Chem.
Rev. 2010, 110, 4489. (e) Patil, S. A.; Patil, R.; Miller, D. D. Future. Med.Chem. 2012, 4,
ACS Paragon Plus Environment

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1
2
3
4
2085. (f) Vicente, R. Org. Biomol. Chem. 2011, 9, 6469.
5
6
7
8
(2) (a) Cacchi,S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (b) Inman, M.; Moody, C. J. Chem.
Sci. 2013, 4, 29. (c) Lu, B. Z.; Zhao, W.; Wei, H. X.; Dufour, M.; Farina, V.; Senanayake, C.
H. Org. Lett. 2006, 8, 3271. (d) Shen, M.; Li, G.; Lu, B. Z.; Hossain, A.; Roschangar, F.;
Farina, V.; Senanayake, C. H. Org. Lett. 2004, 6, 4129. (e) Tokuyama, H.; Yamashita, T.;
Reding, M. T.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 1999, 121, 3791. (f) Zhang, G.;
Yu, H.; Qin, G.; Huang, H. Chem. Commun. 2014, 50, 4331. (g) Ackermann, L. Acc. Chem.
Res. 2014, 47, 281. (h) Larock, R.C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J.Org.
Chem. 1996, 61, 3584. (i) Stuart, D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc.
2010, 132, 18326. (j) Zhou, S.; Wang, J.; Chen, P.; Chen, K.; Zhu, J. Chem. ꢀ Eur. J. 2016, 22,
14508.
9
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
(3) (a) Chen, J.; Pang, Q.; Sun, Y.; Li, X. J. Org. Chem. 2011, 76, 3523. (b) Jensen, T.;
Pedersen, H.; BangꢀAndersen, B.; Madsen, R.; Jorgensen, M. Angew. Chem., Int. Ed. 2008,
47, 888. (c) Lian, X. L.; Ren, Z. H.; Wang, Y. Y.; Guan, Z. H. Org. Lett. 2014, 16, 3360. (d)
Wang, C.; Huang, Y. Org. Lett. 2013, 15, 5294. (e) He, Z.; Liu, W.; Li, Z. Chem. Asian J.
2011, 6, 1340. (f) Breazzano, S. P.; Poudel, Y. B.; Boger, D. L. J. Am. Chem. Soc. 2013, 135,
1600. (g) Cai, S.; Yang, K.; Wang, D. Z. Org. Lett. 2014, 16, 2606. (h) Chen, J.; Song, G.;
Pan, C.ꢀL.; Li, X. Org. Lett. 2010, 12, 5426. (i) Stuart, D. R.; BertrandꢀLaperle, M.; Burgess,
K. M. N.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474.
(4) (a) Huang, F.; Wu, P.; Wang, L.; Chen, J.; Sun, C.; Yu, Z. J. Org. Chem. 2014, 79, 10553.
(b) Bernini, R.; Fabrizi, G.; Sferrazza, A.; Cacchi, S. Angew. Chem., Int. Ed. 2009, 48, 8078.
(c) Zhou, B.; Yang, Y.; Tang, H.; Du, J.; Feng, H.; Li, Y. Org. Lett. 2014, 16, 3900. (d) Zhang,
H. J.; Lin, W.; Su, F.; Wen, T. B. Org. Lett. 2016, 18, 6356. (e) Zhang, B.; Zhang, X.; Hao, J.;
Yang, C. Org. Lett. 2017, 19, 1780. (f) Yang, K.; Zhou, F.; Kuang, Z.; Gao, G.; Driver, T. G.;
Song, Q. Org. Lett. 2016, 18, 4088. (g) Vaitla, J.; Bayer, A.; Hopmann, K. H. Angew. Chem.,
Int. Ed. 2017, 129, 4341. (h) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N.
Angew. Chem. 2009, 121, 4642. (i) Taber, D. F.; Tirunahari, P. K. Tetrahedron Lett. 2011, 67,
7195. (j) Liu, W. Q.; Lei, T.; Song, Z. Q.; Yang, X. L.; Wu, C. J.; Jiang, X.; Chen, B.; Tung,
C. H.; Wu, L. Z. Org. Lett. 2017, 19, 3251.
(5) (a) Ackermann, L. Acc. Chem. Res. 2014, 47, 281. (b) Alonso, F.; Beletskaya, I. P.; Yus,
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1
2
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6
7
8
9
M. Chem.Rev. 2004, 104, 3079. (c) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc.
Rev. 2011, 40, 5068. (d) Guo, X. X.; Gu, D. W.; Wu, Z.; Zhang, W. Chem.Rev. 2015, 115,
1622. (e) McMurray, L.; O'Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885. (f)
Yamamoto, Y. Chem.Rev. 2012, 112, 4736 (g) Kuhl, N.; Hopkinson, M. N.; WencelꢀDelord,
J.; Glorius, F. Angew. Chem. 2012, 124, 10382. (h) Zhao, Y. S.; Li, S. Q.; Zheng, X. S.; Tang,
J. B.; She, Z. J.; Gao, G.; You, J. S. Angew. Chem., Int. Ed. 2017, 56, 4286.
10
11
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13
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16
17
18
19
20
21
22
23
24
25
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27
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50
51
52
53
54
55
56
57
58
59
60
(6) (a) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem.Rev. 2012, 112, 5879. (b) Chen, Z.;
Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Org. Chem. Front. 2015, 2, 1107. (c) Ros, A.;
Fernandez, R.; Lassaletta, J. M. Chem. Soc. Rev. 2014, 43, 3229. (d) WencelꢀDelord, J.;
Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (e) Zhang, M.; Zhang, Y.; Jie,
X.; Zhao, H.; Li, G.; Su, W. Org. Chem. Front. 2014, 1, 843. (f) Liu, G.; Shen, Y.; Zhou, Z.;
Lu, X. Angew. Chem., Int. Ed. 2013, 52, 6033. (g) Hu, F.; Xia, Y.; Ye, F.; Liu, Z.; Ma, C.;
Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2014, 126, 1388.
(7) Qi, Z.; Wang, M.; Li, X. Org. Lett. 2013, 15, 5440.
(8) (a) Huang, X.; Huang, J.; Du, C.; Zhang, X.; Song, F.; You, J. Angew. Chem., Int. Ed.
2013, 52, 12970. (b) Manna, S.; Narayan, R.; Golz, C.; Strohmann, C.; Antonchick, A. P.
Chem. Commun. 2015, 51, 6119. (c) Wang, H.; Moselage, M.; González, M. J.; Ackermann,
L. ACS Catalysis 2016, 6, 2705. (d) Xie, F.; Yu, S.; Qi, Z.; Li, X. Angew. Chem., Int. Ed.
2016, 55, 15351. (e) Zhou, B.; Chen, Z.; Yang, Y.; Ai, W.; Tang, H.; Wu, Y.; Zhu, W.; Li, Y.
Angew. Chem., Int. Ed. 2015, 54, 12121. (f) Yan, H.; Wang, H.; Li, X.; Xin, X.; Wang, C.;
Wan, B. Angew. Chem., Int. Ed. 2015, 54, 10613. (g) Chen, X.; Ruider, S. A.; Hartmann, R.
W.; González, L.; Maulide, N. Angew. Chem., Int. Ed. 2016, 128, 15650.
(9) Chan, W. W.; Lo, S. F.; Zhou, Z.; Yu, W. Y. J. Am. Chem. Soc. 2012, 134, 13565.
(10) (a) Bai, P.; Huang, X. F.; Xu, G. D.; Huang, Z. Z. Org. Lett. 2016, 18, 3058. (b) Kim, J.
H.; Greßies, S.; Glorius, F. Angew. Chem., Int. Ed. 2016, 128, 5667. (c) 1. Kim,
J.
H.;
Gressies, S.; Glorius, F. Angew. Chem., Int. Ed. 2016, 55, 5577. (d) Yu, K.; Liang, Y.; Li, B.;
Wang, B. Adv. Synth. Catal. 2016, 358, 661. (e) Chan, W. W.; Lo, S. F.; Zhou, Z.; Yu, W. Y.
J. Am. Chem. Soc. 2012, 134, 13565. (f) Li, J.; Tang, M.; Zang, L.; Zhang, X.; Zhang, Z.;
Ackermann, L. Org. Lett. 2016, 18, 2742. (g) Li, X. G.; Sun, M.; Jin, Q.; Liu, K.; Liu, P. N. J.
Org. Chem. 2016, 81, 3901.
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(11) (a) Dateer, R. B.; Chang, S. Org. Lett. 2016, 18, 68. (b) Yang, Y.; Wang, X.; Li, Y.;
Zhou, B. Angew. Chem., Int. Ed. 2015, 54, 15400.
7
8
9
(12) Li, Y.; Qi, Z.; Wang, H.; Yang, X.; Li, X. Angew. Chem. 2016, 128, 12056.
(13) (a)Li, X. G.; Sun, M.; Jin, Q.; Liu, K.; Liu, P. N. J. Org. Chem. 2016, 81, 3901. (b) Xiao,
Q.; Zhang, Y.; Wang, J. Acc. Chem. Res. 2013, 46, 236. (c) Liang, Y.; Yu, K.; Li, B.; Xu, S.;
Song, H.; Wang, B. Chem. Commun. 2014, 50, 6130. (d) Zhao, D.; Kim, J. H.; Stegemann, L.;
Strassert, C. A.; Glorius, F. Angew. Chem., Int. Ed. 2015, 54, 4508.
10
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48
49
50
51
52
53
54
55
56
57
58
59
60
(14) (a) Qi, Z.; Wang, M.; Li, X. Org. Lett. 2013, 15, 5440. (b) Muralirajan, K.; Parthasarathy,
K.; Cheng, C.ꢀH. Angew. Chem., Int. Ed. 2011, 123, 4255.
(15) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51, 3066.
(16) (a) Patureau, F. W.; Besset, T.; Kuhl, N.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2154.
(b) Yan, H.; Wang, H.; Li, X.; Xin, X.; Wang, C.; Wan, B. Angew. Chem., Int. Ed. 2015, 54,
10613.
(17) Wang, C.; Wang, D.; Yan, H.; Wang, H.; Pan, B.; Xin, X.; Li, X.; Wu, F.; Wan, B.
Angew. Chem., Int. Ed. 2014, 53, 11940.
(18) Sun, P.; Wu, Y.; Yang, T.; Wu, X.; Xu, J.; Lin, A.; Yao, H. Adv. Synth. Catal.2015, 357, 2469.
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