Rh(III)-Catalyzed C-H Cyclization of Arylnitrones with Diazo Compounds: Access to 3-Carboxylate Substituted N-Hydroxyindoles

Article abstract of DOI:10.1021/acs.joc.7b01393

Recently, N-hydroxyindole derivatives have received much interest because of their unique structural motif and various biological activities. In this study, we report the first example of a Rh(III)-catalyzed reaction of arylnitrones with α-diazoketoesters or α-diazodiketones to produce N-hydroxyindole derivatives. Intriguingly, we could build the N-hydroxyindole scaffold by blocking the cleavage of the N-O bond selectively, while eliminating the acyl group of α-diazoketoesters or α-diazodiketones preferentially.

Full text of DOI:10.1021/acs.joc.7b01393

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Article
Rh(III)-Catalyzed C-H Cyclization of Arylnitrones with Diazo
Compounds: Access to 3-Carboxylate Substituted N-Hydroxyindoles
Yazhou Li, Jian Li, Xiaowei Wu, Yu Zhou, and Hong Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01393 • Publication Date (Web): 31 Jul 2017
Downloaded from http://pubs.acs.org on July 31, 2017
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Rh(III)ꢀCatalyzed C−H Cyclization of Arylnitrones with Diazo
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Compounds:
Access
to
3ꢀCarboxylate
Substituted
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NꢀHydroxyindoles
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Yazhou Li,a, b Jian Li,b Xiaowei Wu,b Yu Zhou,* b and Hong Liu* b
a Department of Chemistry, Shanghai University , Shanghai 200444, China.
b
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
Eꢀmail: hliu@simm.ac.cn; zhouyu@simm.ac.cn
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Graphic Abstract
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Abstract
Recently, Nꢀhydroxyindole derivatives have received much interest because of their
unique structural motif and various biological activities. In this study, we report the
first example of a Rh (III)ꢀcatalyzed reaction of arylnitrones with αꢀdiazoketoesters or
αꢀdiazodiketones to produce Nꢀhydroxyindole derivatives. Intriguingly, we could
build the Nꢀhydroxyindole scaffold by blocking the cleavage of the NꢀO bond
selectively while eliminating the acyl group of αꢀdiazoketoesters or αꢀdiazodiketones
preferentially.
Introduction
Indoles represent an important structural motif that is found ubiquitously in a
diverse array of bioactive natural products, pharmaceuticals, and agrochemicals.1 In
particular, Nꢀhydroxyindole derivatives have received much interest recently2 because
of their unique structural motif and various biological activities, such as antibiotic,
antiproliferative, and platelet aggregation inhibitory activities (Figure 1).3 Despite
their pharmacological significance, only a few methods for the synthesis of these
Nꢀhydroxyindole derivatives have been reported.4 Therefore, it is desired to develop
highly efficient methods to directly access various Nꢀhydroxyindole derivatives.
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Figure 1. Selected examples of functional and bioactive Nꢀhydroxyindoles
In the past decades, Rh(III)ꢀcatalysts have played many important roles in the
activation of smart CꢀH bonds.5 Notably Rh(III)ꢀcatalyzed C−H functionalization has
been explored for the synthesis of a broad range of heterocycles,6 in which the nitrone
group7 has been applied widely in the synthesis of indoles and indolines because of
the polar nature of the NꢀO bond. For example, Chang’s group and Wan’s group both
reported an intriguing Rh(III)ꢀcatalyzed C−H functionalization of nitrones with diaryl
alkynes to give 2,3ꢀdiarylindole derivatives, in which the additive played an important
role in deciding which indole scaffolds could be established (Scheme 1a).8a,8b
Although it is a significant strategy to construct indole scaffolds, the production of the
pharmaceutically important Nꢀhydroxyindoles using this strategy has been reported
rarely, presumably because of the preferential cleavage of the NꢀO bond.9, 10 Recently,
Zhou et al. reported an interesting [4+1] cyclative capture approach to prepare
3HꢀindoleꢀNꢀoxides (Scheme 1b), in which the diazo compounds undergo migratory
insertion, and followed by intramolecular addition to the polarized C=N bond and in
situ oxidation.11 Similarly, Chang reported an interesting transformation to produce
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Scheme1. Rhodium(III)ꢀcatalyzed CꢀH functionalization.
Nꢀhydroxyindolines (Scheme 1b).12 However, the synthesis of Nꢀhydroxyindoles is
still a problematic by Rh (III)ꢀcatalyzed C−H direct cyclization of nitrones in reaction
with diazo compounds, because it is very difficult to control the cleavage of
C(N2)ꢀC(acyl) bond.
During our studies to develop direct C−H functionalization reactions,13 we found
that
treatment
of
arylnitrones
and
αꢀdiazoketoesters
with
the
Rh(III)/AgSbF6/Cu(OAc)2·H2O catalyst system could build 3ꢀcarboxylate substituted
Nꢀhydroxyindole scaffolds by eliminating the acyl group (Scheme 1c).
Results and discussion
Therefore, our investigations commenced with the treatment of a nitrone species 1a
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and diazoacetylacetate ester 2a under the complex catalytic system of
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o
Rh(III)/AgSbF6/PivOH at 100 C in 1,4ꢀdioxane. The results demonstrated that an
8
9
intriguing 3ꢀcarboxylate Nꢀhydroxyindole 3a could be obtained with 35% yield,
meanwhile a dehydroxylation byproduct 4a was also isolated in 14% yield (Table 1,
entry 1). Encouraged by these results, we further explored the reaction conditions to
prepare the desired product 3a selectively. First, different additives were screened;
however, replacement of the PivOH with AcONa or AcOH gave the desired product
3a in only trace amounts (Table 1, entries 2ꢀ3). However, introducing Cu(OAc)2 as an
additive resulted in a significant improvement in the yield of product 3a (Table 1,
entry 4). The yield was improved to 81% by replacement of Cu(OAc)2 with
Cu(OAc)2·H2O (Table 1, entry 5). Subsequently, screening other silver salts
demonstrated that AgSbF6 remained the best choice for this transformation (Table 1,
entries 6ꢀ8). An exploration of solvents revealed that no reaction took place in CH3CN,
and using THF gave a low yield of the target product. Additionally, performing the
reaction in MeOH and DCE only provided product 3a with moderate yields (Table 1,
entries 9−12). With these results in hand, we sought to further improve the yield of
desired product 3a. Our studies displayed that a lower loading of the Cu(OAc)2·H2O
(1 equiv ) increased the yield of 3a to 88% (Table 1, entry 13) and only a trace
amount of byproduct 4a was detected. Lowering the reaction temperature to 25°C or
40 °C showed that the rection no occur (Table 1, entry 14). In addition, the
requirement for two additives was also evaluated, and the results revealed that the
reaction did not proceed in the absence of AgSbF6 or Cu(OAc)2·H2O (Table 1, entries
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15ꢀ16). Briefly, the optimum results were obtained when nitrone species (0.1 mmol,
1a) and diethyl 2ꢀdiazomalonate (0.12 mmol, 2a) in 1, 4ꢀdioxane were treated with
the catalytic system of [RhCp*Cl2]2, AgSbF6, Cu(OAc)2·H2O at 100 °C for 2 h. The
structure of the product 3a was confirmed by Xꢀray crystallographic analysis.14
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Table 1. Optimization of reaction conditions.a
entry
additive 1
additive 2
(x equiv)
solvent
yield (%)
3a (4a)
35 (10)
Trace
Trace
57 (4)
81 (8)
46 (20)
0
1
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgOTf
AgOTs
AgNTf2
AgSbF6
AgSbF6
AgSbF6
AgSbF6
PivOH (2)
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
CH3CN
2
AcONa (2)
3
AcOH (2)
4
Cu(OAc)2 (2)
5
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
6
7
8
61 (18)
0
9
10
11
12
THF
27 (4)
52 (6)
53 (20)
MeOH
Cu(OAc)2·H2O (2)
DCE
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AgSbF6
Cu(OAc)2·H2O (1)
1,4ꢀdioxane
88
(trace)
0[b]
0
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AgSbF6
ꢀ
Cu(OAc)2·H2O (1)
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
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Cu(OAc)2·H2O (1)
ꢀ
AgSbF6
0
[a]Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), [RhCp*Cl2]2 (4
mol %), additive 1 ( 16 mol %), additive 2 (X equiv) in Solvent (3 mL) at
100 °C, 2 h. [b]At 25 °C or 40 °C. THF = tetrahydrofuran, DCE = 1,
2ꢀdichloroethane.
With the optimized reaction conditions established, we next investigated the
scope of different substituted arylnitrones in this [4+1] annulation reaction with
diethyl 2ꢀdiazomalonate 2a (Table 2). In general, nitrones bearing various
electronꢀdonating, electronꢀwithdrawing, and halide substituents at the
moiety all underwent smooth coupling with diethyl 2ꢀdiazomalonate 2a, and
the desired 3ꢀcarboxylate ꢀhydroxyindoles were obtained with moderate to
Nꢀaryl
N
excellent yields (3aꢀ3r, 48−80%). Introduction of electronꢀdonating groups
(ꢀMe, and ꢀOMe) to the benzene ring gave good yields (3b and 3c). The reaction
efficiency was maintained at a high level when halogens were introduced into the
para position of the Nꢀaryl moiety of the nitrones (3dꢀ3f). Similarly, introducing ethyl
carboxylate into the para position of the benzene ring also gave a good yield (3g).
However, the substrates substituted by a chlorine or trifluoromethyl moiety at the
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Table 2. Substrate Scope of Arylnitrones a
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[a]Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), [RhCp*Cl2]2 (4 mol %),
AgSbF6 (16 mol %), Cu(OAc)2·H2O (1 equiv) in 1,4ꢀdioxane (4 mL) at 100 °C, 2 h.
[b] At 80 °C, 30 min.
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meta or para position of the Nꢀaryl moiety resulted in slightly decreased yields (3h
and 3i). In addition, the cyclization reaction could be expanded to nitrones bearing
substituents on the phenylimino moiety. For example, diversified phenylnitrones
bearing methyl and methoxy groups at the para position of the phenylimino moiety
could undergo cyclization to give the corresponding products (3j and 3k) in good
yields under the standard reaction conditions. Notably, various functionalized
benzamides bearing cyano, trifluoromethyl, and halide moieties were compatible with
the standard reaction conditions (3lꢀ3o), which guaranteed further transformations.
Additionally, the nitrones substituted with naphthyl or thiophene groups were also
subjected to the standard reaction conditions, and the corresponding indole
products (3p and 3q) were obtained in good to excellent yields. Particularly
remarkable was the participation of nitrones bearing an alkyl group in this
reaction. Despite the instability of Cꢀalkyl nitrones,8, 15 we could still prepare the
corresponding 2ꢀalkylꢀsubstituted Nꢀhydroxyindole 3r effectively at 40% yield.
We next explored the scope of the diazo reactants (Table 3). The coupling of
nitrone 1a and various αꢀdiazoketoesters 2bꢀ2n gave the desired products in
moderate to excellent yields (3aꢀ4n). Dissymmetrical diazo compounds 2bꢀ2f
,
bearing various alkyl, cycloalkyl, and etherꢀalkyl ketone groups, could react
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Table 3. Scope of Diazo Compoundsa
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[a]Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), [RhCp*Cl2]2 (4 mol %),
AgSbF6 (16 mol %), Cu(OAc)2·H2O (1 equiv) in 1,4ꢀdioxane (4 mL) at 100 °C, 2 h.
with nitrone 1a to give the desired product 3a with satisfactory efficiency (60%
ꢀ79% yields). Interestingly, the αꢀdiazobenzoylacetate 2g was also tolerated in
the present cyclization reaction. In addition, when introducing
electronꢀdonating, electronꢀwithdrawing, and halide groups into the para
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Scheme 2. Scope of Symmetry Diazo Compounds
position of the benzene ring (2hꢀ2k), the desired product 3a was also obtained
in good yields. Additionally, the use of a thiophene ring instead of a benzene
ring produced 3a in moderate yield (2l). The scope of esters was further
examined: they were all converted into the desired products in reasonable yields
(
4m and 4n). Additionally, some symmetrical diazo compounds, such as
symmetrical αꢀdiazodiketones 2oꢀ2q, were also subjected to the standard
reactions, and the corresponding ꢀhydroxyindoles 5oꢀ5q were obtained at
N
moderate yields (Scheme 2a). Notably, a cyclic diketone diazo compound
2ꢀdiazocycloheptaneꢀ1,3ꢀdione (2r) was also tolerated in the present cyclization
reaction, and gave an interesting 3ꢀketonic acid substituted
Nꢀhydroxyindole
(
5r) at 35% yield (Scheme 2b). Besides, the nitrone 1a could also react with the
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simple ethyl diazoacetate 2s under the standard reaction conditions, but only
3,3ꢀdiꢀcarboxylate subsituted 3HꢀindoleꢀNꢀoxides 5s could detected in 72% yield
(Scheme 2c).
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To further evaluate the synthetic utility of
Nꢀhydroxyindole, a gramꢀscale
preparation of product 3a was carried out with 68% yield (Scheme 3a), and the
product 3a can also be transformed into diversified derivatives, such as
3ꢀmethyl substituted
Nꢀhydroxyindole (6) and indole (7) via different
hydrogenation reduction by DIBALꢀH and LiAlH4, respectively. In addition,
Compound 3a could conveniently be transformed into 3ꢀcarboxylate indole 4a
Scheme 3. Gramꢀscale preparation of 3a and Synthetic Utilities of Indole Products
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with dehydroxylation in a good yield (Scheme 3b). The resulting indole
scaffold 4a is an intriguing pharmacophore that can be transformed easily into
diverse bioactive molecules. Recently, a large number of studies reported that
Cꢀ7 substituted indoles exhibit interesting biological activities, such as
antibacterial, antiviral, and antidiabetic properties.16 Therefore, we attempted to
derivatize these 3ꢀcarboxylate indole 4a further. First, direct treatment of
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compound 4a with acetic anhydride produced
N
ꢀacetylindole (
8
) in 71% yield,
),
which was further converted into 7ꢀsulfamide substituted
Nꢀacetylindole (
9
using an iridium(III)ꢀcatalyzed amidation, in 50% yield (Scheme 3b).
Scheme 4. Preliminary Mechanistic Studies
To gain further insight into the mechanism of this cyclization process, preliminary
experiments were performed (Scheme 4). To probe the CꢀH activation process
further, the kinetic isotope effect was determined by intermolecular competition
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experiments using an equimolar mixture of 1a and [D5]ꢀ1a. A notable kinetic
isotopic effect was detected (kH/kD = 3.3), suggesting that C−H bond cleavage
might be involved in the turnoverꢀlimiting step (Scheme 4a).17 In addition, we
performed an illustrative competition reaction with an equimolar amount of 1c
and 1d to determine the electronic preference of the reaction. The results
showed that 3c and 3d were produced in a ratio of 4.3 : 1, which indicated that
the reaction favored the electronꢀrich arene (Scheme 4b).18 A control experiment
involving Nꢀhydroxyindolin 10 synthesized by Chang,s reaction12 condition from
1a and 2a was treated with Cu(OAc)2•H2O in dioxane at 100 °C indicates that the
desired product 3a could be obtained in 80% yield, suggesting that Cu slat play
an important role to elimimate the acyl group (Scheme 4c).
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On the basis of the preliminary mechanistic experiments and the published
literature,8b,12 a possible mechanism was proposed (Scheme 5
). The
fiveꢀmembered rhodacycle intermediate is first generated by the
A
Rh(III)ꢀmediated ortho CꢀH bond activation of nitrone 1a, followed by a diazo
. As reported by Yu,19 Lee, 20
and Chang12 et al., the subsequent diazo insertion produced the rhodacycle
compound
2 coordination to give intermediate B
C.
Intramolecular electrophilic attack of the imino moiety delivers intermediate E
presumably via D, 12 in which transmetalation of the Rh catalyst with the copper
salt,21 and subsequent
γ Nꢀoxides
ꢀhydrogen elimination,8b provided 3Hꢀindoleꢀ
G
. Finally, a nucleophilic attack of H2O toward COR results an elimination of
the carboxylic group, further preparing the desired product 3a. To explore the
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eliminated carboxylic group, we employed the cyclic diketon diazo compound
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2ꢀdiazocycloheptaneꢀ1, 3 ꢀ dione 2r as the substrate. As expected, the 3ꢀketonic
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acid substituted Nꢀhydroxyindole 5r was produced 35% yield.
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Scheme 5. Proposed Mechanism
Conclusion
In summary, we have developed the first synthetic route for Nꢀhydroxyindole
derivatives via the rhodium (III)ꢀcatalyzed C−H annulation of arylnitrones with
αꢀdiazoketoesters or αꢀdiazodiketones. The intermolecular coupling between
nitrones and diazo compounds produced
Nꢀhydroxyindoles by the selective
cleavage of the C(N2)ꢀC(acyl) bond. This study will provide new opportunities
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to enrich indole chemistry and will have applications in the synthesis of
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pharmaceutically important Nꢀhydroxyindole derivatives.
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Experimental Section
General Information. The reagents (chemicals) were purchased from commercial
sources (J&K, TCI, SigmaꢀAldrich, Adamasꢀbeta, etc.), and used without further
purification. Analytical thin layer chromatography (TLC) was HSGF 254 (0.15ꢀ0.2
1
mm thickness). All products were characterized by their NMR and MS spectra. H
and 13C {1H} NMR spectra were recorded on a 400 MHz, 500 MHz or 600MHz
instrument. Chemical shifts were reported in parts per million (ppm, δ) downfield
from tetramethylsilane. Proton coupling patterns are described as singlet (s), doublet
(d), triplet (t), quartet (q), multiplet (m), doublet of doublets (dd) and broad (br).
Highꢀresolution mass spectra (HRMS) were measured on Micromass Ultra QꢀTOF
spectrometer.
Representative procedures for the synthesis of product 3
A mixture of Arylnitrones 1 (0.2 mmol; 1 equiv), diazo compounds 2 (0.24 mmol; 1.2
equiv), [RhCp*Cl2]2 (4.9 mg, 0.008 mol, 0.04 equiv), AgSbF6 (11 mg, 0.032 mol,
0.16 equiv), and Cu(OAc)2·H2O (33 mg, 0.2 mmol, 1 equiv) in 1,4ꢀdioxane (4.0 mL)
was stirred at 100°C for 2 h. The reaction mixture was filtered through a pad of celite
washing with CH2Cl2 (5 mL x 3). The combined organic layers were dried with
Na2SO4, filtered, concentrated and purified by column chromatography on silica gel
(PE/EA = 10/1, v/v) to give desired product.
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Analytical Characterization Data of Products.
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Ethyl 1ꢀhydroxyꢀ2ꢀphenylꢀ1Hꢀindoleꢀ3ꢀcarboxylate (3a)
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Following general procedure, Compound 3a: 46 mg, 81% yield; white solid , mp 137
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– 139 C; H NMR (400 MHz, DMSOꢀd6) δ 11.54 (s, 1H), 8.11 (d, J = 7.9 Hz, 1H),
7.59 (dd, J = 6.5, 3.0 Hz, 2H), 7.56 – 7.44 (m, 4H), 7.28 (dt, J = 22.9, 7.1 Hz, 2H),
4.13 (q, J = 7.1 Hz, 2H), 1.15 (t, J = 7.1 Hz, 3H) ppm. 13C {1H} NMR (126 MHz,
DMSOꢀd6) δ 163.9, 142.1, 133.3, 131.0, 128.9, 128.7, 127.4, 122.8, 122.3, 121.9,
120.9, 109.2, 98.9, 58.9, 14.0 ppm. HRMS (ESI) m/z: [M ꢀ H]ꢀ calcd for C17H14NO3
280.0979; Found 280.0972.
Ethyl 1ꢀhydroxyꢀ5ꢀmethylꢀ2ꢀphenylꢀ1Hꢀindoleꢀ3ꢀcarboxylate (3b)
Following general procedure, Compound 3b: 36 mg, 61% yield; brown solid, mp 140
o
– 141 C; 1H NMR (400 MHz, DMSOꢀd6) δ 11.48 (s, 1H), 7.90 (s, 1H), 7.57 (dd, J =
6.5, 3.2 Hz, 2H), 7.52 – 7.45 (m, 3H), 7.41 (d, J = 8.3 Hz, 1H), 7.13 (dd, J = 8.3, 1.2
Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 2.45 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H) ppm. 13C{1H}
NMR (151 MHz, DMSOꢀd6) δ 164.1, 142.0, 131.9, 131.1, 130.9, 129.2, 128.7, 127.4,
124.4, 122.7, 120.6, 109.0, 98.5, 58.9, 21.5, 14.1 ppm. HRMS (ESI) m/z: [M ꢀ H]ꢀ
calcd for C18H16NO3 294.1136; Found 294.1130.
Ethyl 1ꢀhydroxyꢀ5ꢀmethoxyꢀ2ꢀphenylꢀ1Hꢀindoleꢀ3ꢀcarboxylate (3c)
Following general procedure, at 80 °C, 30 min. Compound 3c: 42 mg, 68% yield;
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brown solid, mp 150– 151 C; H NMR (400 MHz, DMSOꢀd6) δ 11.51 (s, 1H), 7.60
(d, J = 2.4 Hz, 1H), 7.57 (dd, J = 6.5, 3.2 Hz, 2H), 7.50 – 7.45 (m, 3H), 7.43 (d, J =
8.8 Hz, 1H), 6.95 (dd, J = 8.8, 2.4 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H),
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1.14 (t, J = 7.1 Hz, 3H) ppm. 13C {1H} NMR (151 MHz, DMSOꢀd6) δ 164.1, 155.5,
141.9, 131.1, 129.1, 128.7, 128.6, 127.4, 123.3, 112.9, 110.3, 102.6, 98.5, 58.9, 55.3,
14.0 ppm. HRMS (ESI) m/z: [M ꢀ H]ꢀ calcd for C18H16NO4 310.1085; Found
310.1077.
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Ethyl 5ꢀfluoroꢀ1ꢀhydroxyꢀ2ꢀphenylꢀ1Hꢀindoleꢀ3ꢀcarboxylate (3d)
Following general procedure, Compound 3d: 45 mg, 75% yield; brown solid, mp 138
– 140 oC; 1H NMR (600 MHz, DMSOꢀd6) δ 11.71 (s, 1H), 7.77 (dd, J = 10.1, 2.3 Hz,
1H), 7.59 (dd, J = 6.5, 2.9 Hz, 2H), 7.55 (dd, J = 8.8, 4.5 Hz, 1H), 7.52 – 7.46 (m, 3H),
7.18 (td, J = 9.2 Hz, 2.4 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H)
ppm. 13C {1H} NMR (151 MHz, DMSOꢀd6) δ 163.7, 158.7 (d, J = 234.6 Hz), 143.4,
131.0, 130.2, 129.1, 128.7, 127.5, 122.9 (d, J = 11.1 Hz), 111.3 (d, J = 26.3 Hz), 110.8
(d, J = 9.9 Hz), 105.9 (d, J = 25.3 Hz), 99.1(d, J = 4.3 Hz), 59.1, 14.1 ppm. HRMS
(ESI) m/z: [M ꢀ H]ꢀ calcd for C17H13FNO3 298.0885; Found 298.0884.
Ethyl 5ꢀbromoꢀ1ꢀhydroxyꢀ2ꢀphenylꢀ1Hꢀindoleꢀ3ꢀcarboxylate (3e)
Following general procedure, Compound 3e: 54 mg, 80 % yield; brown solid, mp 149
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– 152 C; H NMR (400 MHz, DMSOꢀd6) δ 11.75 (s, 1H), 8.23 (d, J = 1.3 Hz, 1H),
7.59 (dd, J = 6.2, 2.8 Hz, 2H), 7.52ꢀ7.49 (m, 4H), 7.44 (dd, J = 8.6, 1.5 Hz, 1H), 4.14
(q, J = 7.1 Hz, 2H), 1.13 (t, J = 7.1 Hz, 3H) ppm. 13C {1H} NMR (151 MHz,
DMSOꢀd6) δ 163.6, 143.2, 132.2, 131.0, 129.1, 128.5, 127.6, 125.6, 123.9, 123.1,
114.7, 111.5, 98.7, 59.2, 14.0 ppm. HRMS (ESI) m/z: [M ꢀ H]ꢀ, [M + H]+ calcd for
C17H13BrNO3, C17H15BrNO3 358.0084, 360.0063; Found 358.0080, 360.0060.
Ethyl 5ꢀchloroꢀ1ꢀhydroxyꢀ2ꢀphenylꢀ1Hꢀindoleꢀ3ꢀcarboxylate (3f)
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Following general procedure, Compound 3f: 47 mg, 74% yield; brown solid, mp 159
– 161oC; 1H NMR (400 MHz, DMSOꢀd6) δ 11.75 (s, 1H), 8.08 (d, J = 1.8 Hz, 1H),
7.62 – 7.54 (m, 3H), 7.51 (dd, J = 6.6, 3.4 Hz, 3H), 7.33 (dd, J = 8.7, 2.0 Hz, 1H),
4.14 (q, J = 7.1 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H) ppm. 13C {1H} NMR (126 MHz,
DMSOꢀd6) δ 164.0, 143.8, 132.4, 131.5, 129.6, 128.9, 128.0, 127.1, 123.8, 123.5,
120.5, 111.5, 99.2, 59.7, 14.5 ppm. HRMS (ESI) m/z: [M ꢀ H]ꢀ calcd for C17H13ClNO3
314.0589; Found 314.0587.
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Diethyl 1ꢀhydroxyꢀ2ꢀphenylꢀ1Hꢀindoleꢀ3,5ꢀdicarboxylate (3g)
Following general procedure, Compound 3g: 44 mg, 62% yield; brown solid, mp 153
– 154 oC; 1H NMR (400 MHz, DMSOꢀd6) δ 11.83 (s, 1H), 8.84 (s, 1H), 7.93 (dd, J =
8.6, 1.3 Hz, 1H), 7.62 (dd, J = 10.1, 5.8 Hz, 3H), 7.57 – 7.40 (m, 3H), 4.35 (q, J = 7.1
Hz, 2H), 4.15 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H)
ppm. 13C {1H} NMR (126 MHz, DMSOꢀd6) δ 166.8, 164.0, 144.3, 136.0, 131.5,
129.6, 128.9, 128.0, 124.2, 124.1, 123.9, 122.2, 109.8, 100.8, 60.9, 59.7, 14.7, 14.3
ppm. HRMS (ESI) m/z: [M ꢀ H]ꢀ calcd for C20H18NO5 352.1190; Found 352.1198.
Ethyl 1ꢀhydroxyꢀ2ꢀphenylꢀ5ꢀ(trifluoromethyl)ꢀ1Hꢀindoleꢀ3ꢀcarboxylate (3h)
Following general procedure, Compound 3h: 36 mg, 52% yield; brown solid, mp
o
151– 152 C; 1H NMR (400 MHz, DMSOꢀd6) δ 11.90 (s, 1H), 8.44 (s, 1H), 7.75 (d, J
= 8.6 Hz, 1H), 7.63ꢀ7.60 (m, 3H), 7.58 – 7.46 (m, 3H), 4.16 (q, J = 7.1 Hz, 2H), 1.14
(t, J = 7.1 Hz, 3H) ppm. 13C {1H} NMR (151 MHz, DMSOꢀd6) δ 163.5, 144.2, 134.8,
131.1, 129.3, 128.3, 127.6, 126.1, 122.7 (d, J = 31.5 Hz), 121.6, 119.4 (d, J = 3.0 Hz),
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118.4 (d, J = 4.5 Hz), 110.4, 100.0, 59.4, 13.9 ppm. HRMS (ESI) m/z: [M ꢀ H]ꢀ
calcd for C18H13F3NO3 348.0853; Found 348.0843.
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Ethyl 6ꢀchloroꢀ1ꢀhydroxyꢀ2ꢀphenylꢀ1Hꢀindoleꢀ3ꢀcarboxylate(3i)
Following general procedure, Compound 3i: 30 mg, 48% yield; brown solid, mp 158
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– 161 C; H NMR (400 MHz, DMSOꢀd6) δ 11.72 (s, 1H), 7.59 (dd, J = 8.0, 1.6 Hz,
2H), 7.56 – 7.48 (m, 4H), 7.31 – 7.21 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H), 1.09 (t, J =
7.1 Hz, 3H) ppm. 13C {1H} NMR (151 MHz, DMSOꢀd6) δ 164.7, 139.0, 134.6, 130.0,
129.1, 128.4, 128.2, 124.5, 123.6, 122.1, 118.1, 108.5, 101.9, 60.4, 13.8 ppm. HRMS
(ESI) m/z: [M ꢀ H]ꢀ calcd for C17H13ClNO3 314.0589; Found 314.0586.
Ethyl 1ꢀhydroxyꢀ2ꢀ(pꢀtolyl)ꢀ1Hꢀindoleꢀ3ꢀcarboxylate (3j)
Following general procedure, Compound 3j: 37 mg, 63% yield; brown solid, mp 138
– 140 oC; 1H NMR (500 MHz, Acetoneꢀd6) δ 10.39 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H),
7.68 – 7.42 (m, 3H), 7.36 – 7.28 (m, 3H), 7.25 (t, J = 7.5 Hz, 1H), 4.18 (q, J = 7.1 Hz,
2H), 2.43 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H) ppm. 13C {1H} NMR (126 MHz, DMSOꢀd6)
δ 164.5, 142.8, 138.8, 133.9, 131.4, 128.5, 126.5, 123.2, 122.8, 122.4, 121.5, 109.7,
99.3, 59.4, 21.5, 14.6 ppm. HRMS (ESI) m/z: [M ꢀ H]ꢀ calcd for C18H16NO3 294.1136;
Found 294.1135.
Ethyl 1ꢀhydroxyꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ1Hꢀindoleꢀ3ꢀcarboxylate(3k)
Following general procedure, at 80 °C, 30 min. Compound 3k: 45 mg, 73% yield;
brown solid, mp 147– 150oC; The two isomers were inseparable under previous
purification conditions. 1H NMR (400 MHz, DMSOꢀd6) δ 11.49 (s, 1H), 8.09 (d, J =
7.9 Hz, 1H), 7.52 (dd, J = 14.5, 8.3 Hz, 3H), 7.26 (dt, J = 21.7, 7.1 Hz, 2H), 7.05 (d, J
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= 8.7 Hz, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H) ppm. 13C
{1H} NMR (126MHz, DMSOꢀd6) δ 164.5, 160.2, 142.7, 133.9, 133.0, 123.2, 122.9,
122.4, 121.4, 121.4, 113.4, 109.6, 99.1, 59.3, 55.7, 14.7 ppm. HRMS (ESI) m/z: [M ꢀ
H]ꢀ calcd for C18H16NO4 [M ꢀ H]ꢀ: 310.1085; Found 310.1091.
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Ethyl 2ꢀ(4ꢀcyanophenyl)ꢀ1ꢀhydroxyꢀ1Hꢀindoleꢀ3ꢀcarboxylate (3l)
Following general procedure, Compound 3l: 32 mg, 52% yield; brown solid, mp 163
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– 167 C; H NMR (500 MHz, DMSOꢀd6) δ 11.75 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H),
7.99 (d, J = 7.9 Hz,2H), 7.81 (d, J = 7.9 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.33 (dt, J
= 31.9, 7.2 Hz,2H), 4.16 (q, J = 6.9 Hz, 2H), 1.17 (t, J = 6.9 Hz, 3H) ppm. 13C {1H}
NMR (126 MHz, DMSOꢀd6) δ 164.2, 140.4, 134.4, 134.0, 132.6, 131.9, 123.9, 122.8,
122.6, 121.7, 119.2, 111.9, 109.9, 100.3, 59.7, 14.5 ppm. HRMS (ESI) m/z: [M ꢀ H]ꢀ
calcd for C18H13N2O3 305.0932; Found 305.0931.
Ethyl 1ꢀhydroxyꢀ2ꢀ(4ꢀ(trifluoromethyl)phenyl)ꢀ1Hꢀindoleꢀ3ꢀcarboxylate (3m)
Following general procedure, Compound 3m: 59 mg, 84% yield; brown solid, mp 146
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– 150 C; H NMR (400 MHz, DMSOꢀd6) δ 11.70 (s, 1H), 8.12 (d, J = 7.9 Hz, 1H),
7.88ꢀ7.81 (m, 4H), 7.56 (d, J = 8.0 Hz, 1H), 7.31 (dt, J = 25.3, 7.1 Hz, 2H), 4.14 (q, J
= 7.1 Hz, 2H), 1.15 (t, J = 7.1 Hz, 3H) ppm. 13C {1H} NMR (125 MHz, DMSOꢀd6) δ
164.2, 140.8, 133.9 (d, J = 24.2 Hz), 132.4, 129.6 (d, J = 32.1 Hz), 125.8, 124.8,
123.8, 123.6, 122.8, 122.6, 121.6, 109.9, 100.1, 59.6, 14.5 ppm. HRMS (ESI) m/z: [M
ꢀ H]ꢀ calcd for C18H13F3NO3348.0853; Found 348.0853.
Ethyl 2ꢀ(4ꢀfluorophenyl)ꢀ1ꢀhydroxyꢀ1Hꢀindoleꢀ3ꢀcarboxylate (3n)
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Following general procedure, Compound 3n: 38 mg, 63% yield; brown solid, mp
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160– 162 C; H NMR (400 MHz, DMSOꢀd6) δ 11.59 (s, 1H), 8.11 (d, J = 7.9 Hz,
1H), 7.65 (dd, J = 8.6, 5.6 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.43 – 7.16 (m, 4H), 4.14
(q, J = 7.1 Hz, 2H), 1.17 (t, J = 7.1 Hz, 3H) ppm. 13C {1H} NMR (126 MHz,
DMSOꢀd6) δ 164.4, 162.9 (d, J = 246.2 Hz), 141.5, 133.8 (d, J = 3.3 Hz), 133.8, 125.8
(d, J = 3.1 Hz), 123.5, 122.7, 122.6, 121.5, 115.0 (d, J = 21.7 Hz), 109.7, 99.6, 59.5,
14.6 ppm. HRMS (ESI) m/z: [M ꢀ H]ꢀ calcd for C17H13FNO3 298.0885; Found;
298.0883.
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Ethyl 2ꢀ(4ꢀbromophenyl)ꢀ1ꢀhydroxyꢀ1Hꢀindoleꢀ3ꢀcarboxylate (3o)
Following general procedure, Compound 3o: 44 mg, 61% yield; brown solid, mp 148
– 150 oC; 1H NMR (400 MHz, DMSO) δ 11.64 (s, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.77
– 7.64 (m, 2H), 7.54 (dt, J = 4.5, 2.5 Hz, 3H), 7.36 – 7.29 (m, 1H), 7.28 – 7.23 (m,
1H), 4.15 (q, J = 7.1 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H) ppm. 13C {1H} NMR (101 MHz,
DMSO) δ 164.3, 141.3, 133.9, 133.6, 131.0, 128.7, 123.6, 123.0, 122.7, 122.6, 121.6,
109.8, 99.7, 59.5, 14.6. ppm. HRMS (ESI) m/z: [M ꢀ H]ꢀ, [M + H]+ calcd for
C17H13BrNO3, C17H15BrNO3 358.0084, 360.0063; Found 358.0090, 360.0072.
Ethyl 1ꢀhydroxyꢀ2ꢀ(naphthalenꢀ1ꢀyl)ꢀ1Hꢀindoleꢀ3ꢀcarboxylate (3p)
Following general procedure, at 80 °C, 30 min. Compound 3p: 47 mg, 71% yield;
o
brown solid, mp 138 – 140 C; 1H NMR (400 MHz, DMSOꢀd6) δ 11.54 (s, 1H), 8.18
(d, J = 7.7 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.69 – 7.54 (m,
4H), 7.50 ꢀ7.44 (m, 2H), 7.34 (dt, J = 19.4, 7.4 Hz, 2H), 3.90 (q, J = 7.1 Hz, 2H), 0.76
(t, J = 7.1 Hz, 3H) ppm. 13C {1H} NMR (101 MHz, DMSOꢀd6) δ 164.2, 140.9, 133.9,
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133.3, 132.6, 129.6, 129.4, 128.6, 128.2, 126.9, 126.4, 125.9, 125.4, 123.4, 122.8,
122.5, 121.3, 109.8, 101.3, 59.1, 14.0 ppm. HRMS (ESI) m/z: [M ꢀ H]ꢀ calcd for
C21H16NO3 330.1136; Found 330.1143.
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Ethyl 1ꢀhydroxyꢀ2ꢀ(thiophenꢀ2ꢀyl)ꢀ1Hꢀindoleꢀ3ꢀcarboxylate (3q)
Following general procedure, Compound 3q: 52 mg, 91% yield; brown solid, mp
o
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156– 157 C; H NMR (400 MHz, DMSOꢀd6) δ 11.83 (s, 1H), 8.08 (d, J = 7.9 Hz,
1H), 7.84 (dd, J = 5.1, 1.1 Hz, 1H), 7.73 (dd, J = 3.7, 1.1 Hz, 1H), 7.51 (d, J = 8.1 Hz,
1H), 7.37 – 7.28 (m, 1H), 7.25ꢀ7.22 (m, 2H), 4.24 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1
Hz, 3H) ppm. 13C {1H} NMR (126 MHz, DMSOꢀd6) δ 164.4, 135.4, 134.0, 132.4,
129.8, 128.4, 127.1, 123.7, 122.7, 122.8, 121.7, 109.6, 100.0, 59.7, 14.7 ppm. HRMS
(ESI) m/z: [M ꢀ H]ꢀ calcd for C15H12NO3S 286.0543; Found 286.0541.
Ethyl 2ꢀcyclohexylꢀ1ꢀhydroxyꢀ1Hꢀindoleꢀ3ꢀcarboxylate (3r)
1
Following general procedure, Compound 3r: 23 mg, 40% yield; brown oil; H NMR
(500 MHz, DMSOꢀd6) δ 11.56 (s, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.39 (d, J = 7.9 Hz,
1H), 7.29 – 6.99 (m, 2H), 4.27 (q, J = 7.1 Hz, 2H), 3.924ꢀ3.869 (m, 1H), 2.178ꢀ2.103
(m, 2H), 1.82 (d, J = 12.7 Hz, 2H), 1.731ꢀ1.654 (m, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.33
– 1.20 (m, 3H) ppm. 13C {1H} NMR (151 MHz, DMSOꢀd6) δ 164.8, 148.5, 133.2,
122.1, 122.0, 121.6, 120.9, 108.7, 97.0, 59.0, 35.1, 29.1, 26.5, 25.5, 14.5 ppm. HRMS
(ESI) m/z: [M ꢀ H]ꢀ calcd for C17H20NO3 286.1449; Found 286.1442.
Methyl 1ꢀhydroxyꢀ2ꢀphenylꢀ1Hꢀindoleꢀ3ꢀcarboxylate (4m)
Following general procedure, Compound 4m: 30 mg, 56% yield; brown solid, 1H
NMR (500 MHz, DMSOꢀd6) δ 11.57 (s, 1H), 8.10 (d, J = 7.9 Hz, 1H), 7.71 – 7.56 (m,
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2H), 7.56 – 7.42 (m, 4H), 7.37 – 7.30 (m, 1H), 7.30 – 7.23 (m, 1H), 3.68 (s, 3H) ppm.
13C {1H} NMR (126 MHz, DMSOꢀd6) δ 164.9, 142.7, 133.9, 131.5, 129.3, 128.0,
123.4, 122.7, 122.5, 121.5, 109.7, 99.3, 51.0 ppm. HRMS (ESI) m/z: [M ꢀ H]ꢀ calcd
for C16H12NO3 266.0823; Found 266.0821.
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Allyl 1ꢀhydroxyꢀ2ꢀphenylꢀ1Hꢀindoleꢀ3ꢀcarboxylate (4n)
Following general procedure, Compound 4n: 38 mg, 65% yield; 1H NMR (400 MHz,
DMSOꢀd6) δ 11.57 (s, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.64 – 7.57 (m, 2H), 7.54 (d, J =
8.1 Hz, 1H), 7.53 – 7.46 (m, 3H), 7.36 – 7.23 (m, 2H), 5.90 (ddt, J = 18.1, 10.4, 5.3
Hz, 1H), 5.14 (d, J = 1.3 Hz, 1H), 5.13 – 5.08 (m, 1H), 4.64 (dd, J = 5.3, 1.3 Hz, 2H)
ppm. 13C {1H} NMR (126 MHz, DMSOꢀd6) δ 164.1, 142.9, 133.9, 133.5, 131.5,
129.4, 129.3, 128.0, 123.4, 122.8, 122.6, 121.5, 117.5, 109.8, 99.2, 64.1 ppm. HRMS
(ESI) m/z: [M ꢀ H]ꢀ calcd for C18H14NO3 292.0979; Found 292.0987.
1ꢀ(1ꢀHydroxyꢀ2ꢀphenylꢀ1Hꢀindolꢀ3ꢀyl)ethanone (5o)
Following general procedure, Compound 5o: 20 mg, 40% yield; brown solid, mp
o
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153– 157 C; H NMR (500 MHz, DMSOꢀd6) δ 11.56 (s, 1H), 8.30 (d, J = 7.9 Hz,
1H), 7.59 (br, 5H), 7.52 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.27 (t, J = 7.4
Hz, 1H), 1.95 (s, 3H) ppm. 13C {1H} NMR (126 MHz, DMSOꢀd6) δ 193.3, 143.0,
133.8, 131.4, 130.3, 130.0, 128.8, 123.7, 123.0, 122.7, 122.0, 110.5, 109.5, 26.9 ppm.
HRMS (ESI) m/z: [M ꢀ H]ꢀ calcd for C16H12NO2 250.0874; Found 250.0881.
1ꢀ(1ꢀHydroxyꢀ2ꢀphenylꢀ1Hꢀindolꢀ3ꢀyl)propanꢀ1ꢀone (5p)
Following general procedure, Compound 5p: 22 mg, 42% yield; brown solid, mp
152– 155 oC; 1H NMR (400 MHz, DMSOꢀd6) δ 11.49 (s, 1H), 8.28 (d, J = 7.8 Hz, 1H),
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7.63ꢀ7.53 (m, 5H), 7.50 (d, J = 8.0 Hz, 1H), 7.28 (dt, J = 25.5, 7.1 Hz, 2H), 2.27 (q, J
= 7.3 Hz, 2H), 0.86 (t, J = 7.3 Hz, 3H) ppm. 13C {1H} NMR (126 MHz, DMSOꢀd6) δ
196.6, 142.4, 133.8, 131.2, 130.5, 129.9, 128.8, 123.6, 122.9, 122.7, 122.0, 110.0,
109.5, 34.5, 9.2 ppm. HRMS (ESI) m/z: [M ꢀ H]ꢀ calcd for C17H14NO2 264.1030;
Found 264.1025.
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(1ꢀHydroxyꢀ2ꢀphenylꢀ1Hꢀindolꢀ3ꢀyl)(phenyl)methanone (5q)
Following general procedure, Compound 5q: 20 mg, 32% yield; brown solid, mp
o
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153– 155 C; H NMR (500 MHz, DMSOꢀd6) δ 11.67 (s, 1H), 7.88 (d, J = 8.0 Hz,
1H), 7.57 (d, J = 8.1 Hz, 1H), 7.47 – 7.39 (m, 2H), 7.37 – 7.30 (m, 3H), 7.31 – 7.25
(m, 1H), 7.25 – 7.18 (m, 4H), 7.13 (t, J = 7.7 Hz, 2H) ppm. 13C {1H} NMR (126 MHz,
DMSOꢀd6) δ 191.7, 142.7, 140.3, 134.3, 131.6, 131.4, 129.3, 129.2, 129.0, 128.1,
123.8, 123.6, 122.7, 121.2, 109.8, 108.9 ppm. HRMS (ESI) m/z: [M ꢀ H]ꢀ calcd for
C21H14NO2 312.103; Found: 312.1025.
6ꢀ(1ꢀHydroxyꢀ2ꢀphenylꢀ1Hꢀindolꢀ3ꢀyl)ꢀ6ꢀoxohexanoic acid (5r)
Following general procedure, Compound 5r: 24 mg, 35% yield; brown solid, mp 156
– 160oC; 1H NMR (500 MHz, DMSOꢀd6) δ 12.07 (s, 1H), 11.92 (s, 1H), 8.17 (d, J =
7.4 Hz, 1H), 7.76 – 7.49 (m,5H), 7.42 (d, J = 7.3 Hz, 1H), 7.32 – 7.04 (m, 2H), 2.39 (t,
J = 7.4 Hz, 2H), 2.05 (t, J = 7.4 Hz, 2H), 1.47 (br, 2H), 1.27 (br, 2H) ppm. 13C {1H}
NMR (126 MHz, DMSOꢀd6) δ 196.9, 174.7, 144.8, 135.9, 133.3, 130.3, 129.8, 128.9,
127.5, 123.3, 122.2, 122.0, 114.4, 112.1, 41.3, 33.9, 24.7, 24.5 ppm. HRMS (ESI) m/z:
[M ꢀ H]ꢀ calcd for C20H18NO4 336.1241; Found 336.1247.
3,3ꢀBis(ethoxycarbonyl)ꢀ2ꢀphenylꢀ3Hꢀindole ꢀ1ꢀoxide (5s)
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Following general procedure, Compound 5s: 51 mg, 72% yield; white solid, 1H NMR
(400 MHz, DMSOꢀd6) δ 8.42 (dd, J = 8.0, 1.8 Hz, 2H), 7.81 (d, J = 7.6 Hz, 1H), 7.76
(d, J = 7.6 Hz, 1H), 7.72 (dd, J = 7.7, 1.2 Hz, 1H), 7.66 (td, J = 7.4, 1.1 Hz, 1H), 7.59
– 7.49 (m, 3H), 4.22 – 4.09 (m, 4H), 1.01 (t, J = 7.1 Hz, 6H) ppm. 13C {1H} NMR
(101 MHz, DMSOꢀd6) δ 165.6, 147.5, 140.1, 131.4, 131.1, 130.9, 129.4, 128.8, 128.1,
127.8, 124.4, 115.5, 66.7, 63.5, 14.0 ppm. HRMS (ESI) m/z: [M + H]+ calcd for
C20H20NO5 353.1263; Found 353.1261.
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3ꢀMethylꢀ2ꢀphenylꢀ1Hꢀindolꢀ1ꢀol (6)
Diisobutylaluminium hydride 1M/toluene (1.1 mL, 1.1 mmol) is added dropwise to a
stirred solution of 3a (100 mg, 0.36 mmol) in THF (10 mL) at 0ºC. The reaction is
stirred at room temperature for 0.5 hours. Methanol (1 mL) is added over the mixture
at 0ºC and stirred for 10min. Then, water (3 mL) and EtOAc (15 mL) is added. The
precipitate formed is filtered through celite and all the solvents are removed in
vacuum to obtain a crude product. The crude product was purified by a silica gel
column chromatography (PE/EA = 8/1, v/v) to obtain 6 (64 mg, 81%). 1H NMR (400
MHz, DMSO) δ 10.80 (s, 1H), 7.61 (d, J = 7.2 Hz, 2H), 7.55 ꢀ 7.49 (m, 3H), 7.44 ꢀ
7.37 (m, 2H), 7.19 (t, J = 7.5 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 2.31 (s, 3H) ppm. 13C
{1H} NMR (101 MHz, DMSO) δ 135.1, 134.9, 130.9, 130.3, 128.7, 127.9, 124.3,
122.4, 119.5, 119.0, 109.1, 104.3, 9.9 ppm. HRMS (ESI) m/z: [M + H]+ calcd for
C15H14NO 224.107; Found 224.1066
3ꢀMethylꢀ2ꢀphenylꢀ1Hꢀindole (7)
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Lithium aluminum hydride (27 mg, 0.72 mmol) was added to a tetrahydrofuran
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solution (10 ml) of 3a (100 mg, 0.36 mmol) under iceꢀcooling. The resulting mixture
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was warmed up to 40 C and then stirred 2 h. After completion of the reaction, water
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and a 15 percent aqueous sodium hydroxide solution were added thereto and stirred.
The solid formed was removed by filtration, and the solvent was distilled off under
reduced pressure to obtain a crude product. The crude product was purified by a silica
gel column chromatography (PE/EA = 10/1, v/v) to obtain 7 (67 mg, 90%). 1H NMR
(400 MHz, DMSOꢀd6) δ 11.15 (s, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.54 ꢀ 7.49 (m, 3H),
7.43 ꢀ 7.31 (m, 2H), 7.10 (t, J = 7.5 Hz, 1H), 7.01 (t, J = 7.4 Hz, 1H), 2.41 (s, 3H)
ppm. 13C {1H} NMR (101 MHz, DMSOꢀd6) δ 136.4, 134.2, 133.6, 129.9, 129.2,
128.0, 127.4, 122.0, 119.0, 111.5, 107.2, 118.9, 10.3 ppm. HRMS (ESI) m/z: [M +
H]+ calcd for C15H14N 207.1043; Found 207.1036.
A GramꢀScale Synthesis of ethylꢀ2ꢀphenylꢀ1Hꢀindoleꢀ3ꢀcarboxylate(4a)
The dry 50 mL round bottom flask were added 1a (1.0 g, 5.07 mmol, 1 equiv), 2a
(0.950 g, 6.08 mmol, 1.2 equiv), [RhCp*Cl2]2 (125 mg, 0.203 mmol, 0.04 equiv),
AgSbF6 (279 mg, 0.812 mmol, 0.16 equiv), CuOAc·H2O (1.01g, 5.07 mmol, 1 equiv )
and 20 mL 1, 4ꢀdioxane. The mixture was stirred at 100 °C for 15 min with a
condenser pipe. After that, the mixture was added 2ꢀBromoacetophenone (1.01 g, 5.07
mol, 1 equiv), Triethylamine (1.18 g, 11.6 mol, 2.3 equiv) and 10 ml MeOH and
was stirred at r.t. for 12 h. After that, the reaction mixture was filtered through a pad
of celite washing with CH2Cl2 (15 mL x 3). The combined organic layers were dried
with Na2SO4, filtered, concentrated and purified by column chromatography on silica
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gel (PE/EA = 10/1, v/v) to give desired product 4a (0.97 g, 57% yield). White solid;
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mp 118 – 120 C; 1H NMR (400 MHz, DMSOꢀd6) δ 12.11 (s, 1H), 8.05 (dd, J = 6.5,
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2.1 Hz, 1H), 7.78 – 7.58 (m, 2H), 7.57 – 7.40 (m, 4H), 7.30 – 7.11 (m, 2H), 4.19 (q, J
= 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H) ppm. 13C {1H} NMR (150 MHz, DMSOꢀd6) δ
197.5, 144.6, 135.9, 133.4, 130.3, 129.7, 128.9, 127.5, 123.2, 122.1, 121.9, 114.2,
112.0, 34.8, 9.2 ppm. HRMS (ESI) m/z: [M + H]ꢀ calcd for C17H16NO2 266.1176;
Found 266.1171.
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Synthesis of ethyl 1ꢀacetylꢀ2ꢀphenylꢀ1Hꢀindoleꢀ3ꢀcarboxylate (8)
4a (100 mg, 0.377 mmol, 1equiv), triethylamine (57.21 mg, 1.5 equiv) and N,
Nꢀdimethylꢀ4ꢀaminopyridine (1 mg, 0.02 equiv) were dissolved in acetic anhydride
(10 mL). The reaction mixture was reflux at 140 °C for 5 h. After the reaction, the
reaction mixture was concentrated under reduced pressure and purified by column
chromatography on silica gel (PE/EA = 8/1, v/v) to give desired product 8. (82.2 mg,
71% yield). 1H NMR (400 MHz, CDCl3) δ 8.35 – 8.29 (m, 1H), 8.24 – 8.18 (m, 1H),
7.54 – 7.45 (m, 5H), 7.45 – 7.35 (m, 2H), 4.20 (q, J = 7.1 Hz, 2H), 1.91 (s, 3H), 1.16
(t, J = 7.1 Hz,3H) ppm.13C {1H} NMR (150 MHz, DMSOꢀd6) δ 172.1, 163.8, 144.4,
136.0, 132.6, 130.9, 129.8, 128.5, 126.9, 125.8, 124.7, 121.5, 115.9, 111.5, 60.1, 27.9,
14.1 ppm. HRMS (ESI) m/z: [M + Na]+ calcd for C19H17NO3Na 330.1101; Found
330.1099.
Synthesis of Compound 9
The dry sealed tube was charged with indole 8 (30.7 mg, 0.1 mmol), tosyl azide (29.6
mg, 0.15 mmol, 1.5 equiv), [IrCp*Cl2] 2 (4.0 mg, 5 mol %), AgSbF6 (6.9 mg, 20
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mol %), AgOAc (33.4 mg, 2 equiv), HOAc (12 mg, 2 equiv) and 1, 2ꢀdichloroethane
(1 mL). The mixture was stirred at 80 oC for 24 h, and organic solvent was evaporated
under reduced pressure. The residue was purified by column chromatography on silica
gel (PE/EA = 4/1, v/v) to give the product 9 (23.8 mg, 50%). 1H NMR (600 MHz,
DMSOꢀd6) δ 10.87 (s, 1H), 7.90 (dd, J = 6.9, 2.5 Hz, 1H), 7.59 – 7.49 (m, 5H), 7.44
(dd, J = 5.1, 3.3 Hz, 2H), 7.43 – 7.32 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 3.99 (q, J =
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7.1 Hz, 2H), 2.32 (s, 3H), 1.87 (s, 3H), 0.74 (t, J = 7.1 Hz, 3H) ppm. C {1H} NMR
(100 MHz, DMSOꢀd6) δ 172.2, 167.2, 145.2, 144.1, 137. 0, 136.6, 132.5, 130.7,
130.63, 130.2, 130.0, 128.6, 127.2, 126.5, 118.3, 116.4, 112.0, 110.4, 61.8, 28.1, 21.4,
13.4 ppm. HRMS (ESI) m/z: [M ꢀ H]ꢀ calcd for C26H23N2O5S 475.1333; Found
475.1339.
ASSOCIATED CONTENT
Author Information
Corresponding Authors
Eꢀmail: hliu@simm.ac.cn.
Eꢀmail: zhouyu@simm.ac.cn
.
Notes
The authors declare no competing financial interests.
Acknowledgments
We gratefully acknowledge financial support from the National Natural Science
Foundation of China (21632008, 21672232 and 21372235）the Major Project of
Chinese National Programs for Fundamental Research and Development
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