One-Pot Reaction between N-Tosylhydrazones and 2-Nitrobenzyl Bromide: Route to NH-Free C2-Arylindoles

Article abstract of DOI:10.1021/acs.joc.8b02623

A one-pot Barluenga coupling between N-tosylhydrazones and nitro-benzyl bromide, followed by deoxygenation of ortho-nitrostyrenes, and subsequent cyclization has been developed, providing a new way to synthesize various C2-arylindoles. This method exhibits a good substrate scope and functional group tolerance, and it allows an access to NH-free indoles, which can present a potential utility in medicinal chemistry applications.

Full text of DOI:10.1021/acs.joc.8b02623

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Article
One-pot Reaction between N-tosylhydrazones and 2-
Nitrobenzyl Bromide: Route to NH-free C2-Arylindoles
Tourin Bzeih, Kena Zhang, Ali Khalaf, Ali Hachem, Mouad Alami, and Abdallah Hamze
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02623 • Publication Date (Web): 07 Dec 2018
Downloaded from http://pubs.acs.org on December 8, 2018
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One-pot Reaction between N-tosylhydrazones and
2-Nitrobenzyl Bromide: Route to NH-free C2-
Arylindoles
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†,‡,#
†,#
‡
‡
†
Tourin Bzeih, Kena Zhang, Ali Khalaf, Ali Hachem, Mouad Alami,* and Abdallah
†
Hamze*
†
Université Paris-Sud, CNRS, BioCIS–UMR 8076, LabEx LERMIT, Laboratoire de Chimie
Thérapeutique, Faculté de Pharmacie, rue J.-B. Clément, Châtenay-Malabry, F–92296,
France.
‡
Laboratory for Medicinal Chemistry and Natural Products, Lebanese University, Faculty of
Sciences (1) and PRASE-EDST, Hadath, Lebanon.
mouad.alami@u-psud.fr ; abdallah.hamze@u-psud.fr
CORRESPONDING AUTHOR. Tel.: (+33) 1 4683-5498. Fax: (+33) 1 4683-5827.
Abstract:
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A one-pot Barluenga coupling between N-tosylhydrazones and nitro-benzylbromide, followed
by deoxygenation of ortho-nitrostyrenes, and subsequent cyclization has been developed
providing a new way to synthesize various C2-arylindoles. This method exhibits a good
substrate scope and functional group tolerance, and it allows an access to NH-free indoles,
which can present a potential utility in medicinal chemistry applications.
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Introduction
N-Tosylhydrazones (NTH) have been emerged recently as a carbene precursors and
have been one of the most important achievements in the search for a new type of cross-
1
coupling partners in transition-metal catalysis. They serve as a versatile and powerful
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3
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synthetic tool for the formation of C-C, C-X (N, O, S ) bonds with a remarkable range of
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applications in medicinal chemistry. NTH are solid and stable reagents and are readily
accessible from ketones, and aldehydes. In comparison to classical cross-coupling reactions,
which employ stoichiometric organometallic reagents (such as boronic reagents, Grignard
reagents, organozinc reagents, organolithium) as a nucleophilic component, the use of NTH
represents an attractive alternative for metal-catalyzed cross-coupling processes that does not
involve the use of a stoichiometric organometallic species (R-MgX, RSnBu3, RLi).
Indoles constitute a privileged structure that can be found in a large number of drugs
approved for various diseases including cancer, cardiovascular diseases, and neurologic
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disorders. In the framework of our medicinal chemistry-screening program to discover new
5c, 7
anticancer compounds, recently, we developed a novel strategy for the effective synthesis of
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3-aryl-indoles from NTH, as antitubulin agents (Scheme 1), this approach has already proven
useful in the synthesis of potent antiproliferative agents compounds. Over the previous
decade, the access to molecular diversity has increased impressive enthusiasm within the
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community of synthetic chemists because of its vital role in drug discovery. In connection
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with the above and in order to use the NTH as a versatile building block in organic synthesis,
which enables further transformations of the carbene coupling product, we decided to explore
the reactivity of NTH derived from aldehydes in the cross-coupling reaction with 2-
nitrobenzyl bromide to form C2-arylated indoles in a one-pot reaction. This transformation
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consists firstly on the formation of a Csp -Csp bond between NTH and the benzyl bromide,
then in situ reduction of the nitroalkene to nitrene derivative, followed by annulation leading
to the formation of C2-arylated indoles.
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Over the past decades, many synthetic strategies have been developed to obtain C2
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arylated indoles.11 Among them, great efforts have been devoted to transition metal catalyzed
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direct C2-H arylations, Suzuki-Miyaura coupling (Scheme 1), and predominant metal-
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catalyzed preparation of indoles starting from 2-alkynylanilines. However, many of these
methods require activated indoles and arenes, some work better with N-methylated or
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protected indoles, and others suffer from regioselectivity issue (C2:C3). Hence, the
development of straightforward methodologies for synthesizing 2-aryl indoles remains highly
desirable. Highlighted features of this strategy are (a) the divergent synthesis of 2-arylindoles
can be achieved by changing the coupling partners; (b) functional-group tolerance; (c)
formation of NH-free arylindoles which can be interesting for biological activity.
Scheme 1. Different strategies for the access of C2-arylated indoles derivatives
Results and discussion
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Initially, the reaction of NTH 1a with 2-nitrobenzylbromide 2a under previously reported
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conditions (Pd2dba3/Xphos) or (Pd2dba3/ P(2-furyl)3) provided 3a in a low 25% and 50%
yields respectively (entries 1-2, Table 1). The low reactivity of 2-nitrobenzylbromide
derivative led to inefficient coupling and resulted in the concomitant formation of sulfone
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derivative resulted from decomposition of NTH. Performing the coupling by using a
combination of Pd2dba3/ P(2-furyl)3 in dioxane instead of toluene led to a slight increase in the
yield (cf. entry 2 and 3). We also tested other solvents such as THF and CPME but no
improvement in the yield was observed in comparison to dioxane. Surprisingly, the reduction
of the amount of ligand from 20 mol% (entry 3) to 10 mol% (entry 6) led to a significant
increase in the yield of the desired product 3a. Then, we turned toward the study of the
temperature parameter, and we found that the optimal range is at 110°C (entry 7). We
examined other palladium sources such as Pd(OAc)2 which was also effective, albeit affording
3a with slightly reduced yield (entry 8). Switching the P(2-furyl)3 by Sphos ligand led to
dramatically decrease in the yield (cf. entry 7 and 9). Finally, other inorganic bases were
tested such as NaOtBu and Cs2CO3 and we found them less efficient than LiOtBu in this
coupling (entries 10-11). As a result, the combination of Pd2dba3.CHCl3 (2.5 mol%), P(2-
furyl)3 (10 mol%), LiOtBu (2.2 equiv), dioxane in a sealed tube at 110 °C was fixed as
optimal condition.
Table 1. Optimization of Coupling Reaction of N-Tosylhydrazones 1a with 2-Nitrobenzyl bromide 2a under
Various Conditions.
a
entry
[Pd] X mol%
L mol%
solvent
base
Temp (°C)
yield (%)b
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Pd2dba3.CHCl3 (2.5)
Pd2dba3.CHCl3 (2.5)
Pd2dba3.CHCl3 (2.5)
Pd2dba3.CHCl3 (2.5)
Pd2dba3.CHCl3 (2.5)
Pd2dba3.CHCl3 (2.5)
XPhos (10)
dioxane
PhMe
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
NaOtBu
Cs2CO3
90
90
25
50
55
15
35
64
85
65
15
18
30
P(2-furyl)3 (20)
P(2-furyl)3 (20)
P(2-furyl)3 (20)
P(2-furyl)3 (20)
P(2-furyl)3 (10)
3
dioxane
THF
90
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90
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CPME
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
90
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90
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Pd2dba3.CHCl3 (2.5) P(2-furyl)3 (10)
110
110
110
110
110
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Pd(OAc)2 (5)
P(2-furyl)3 (10)
Sphos (10)
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Pd2dba3.CHCl3 (2.5)
Pd2dba3.CHCl3 (2.5)
Pd2dba3.CHCl3 (2.5)
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P(2-furyl)3 (10)
P(2-furyl)3 (10)
a The reactions were carried out in a sealed tube with 1a (0.6 mmol), 2a (0.6 mmol), [Pd] (X mol %), Ligand (Y
mol %), base (2.2 equiv) in 2.5 mL of solvent. b Yield of 3a.
With the optimal conditions for the first step in hand, we subsequently investigated the one-
pot reaction in order to perform reduction of the nitro function to nitrenes, and then
spontaneous annulation led to C2-aryl indole 4. To our delight, we found that the optimal
conditions were compatible with the one-pot reaction and when the first coupling was
achieved (3 hours), PPh3 was added allowing the formation of C2-aryl indole 4a in 70% yield
(Table 2, entry 1). This yield represents an average of 84% for each step. Next, we examined
the scope of NTH partner in this one-pot sequence. Most of these NTH were prepared from
the corresponding aldehydes and used without further purification. Electron-donating groups
on the phenyl ring of NTH were compatible, affording the desired C2-aryl indole derivatives
with good yields (Table 2, entries 1-4). However moderate to low yield was obtained when
the reaction was performed with NTH having electron-withdrawing groups (entries 5-7).
Different substituents at various positions on the arenes, including 3,4,5-trimethoxy group did
not hamper the coupling. Also, the reaction was successfully carried out with N-
tosylhydrazones derived from benzaldehyde, 2-naphthaldehyde, and biphenyl-4-
carboxaldehyde (entries 8-10). When the coupling was performed between NTH derived from
alkyl aldehyde 1k and benzyl bromide 2a, we were unable to isolate the desired compound
4k, and only a trace of the intermediate 3 was obtained. Finally, our standard conditions was
useful for NTH generated from heterocyclic NTH, and the desired compound 4l was obtained
in 40% isolated yield.
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Table 2. Substrate scope of NTH, synthesis of C2-aryl indoles.
entry
1
NTH 1
Benzyl bromides 2
product
yield (%)a
70
1a
2a
2a
4a
2
65
1b
1c
1d
1e
1f
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1g
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a Yield of products 4. b Only a trace of intermediate 3 was obtained.
In order to gauge the performance of this one-pot procedure, the substrate scope has been
investigated with respect to the substituted ortho-nitro-benzylbromide 2 (Table 3). These aryl
halides derivatives were prepared easily by bromination of the corresponding 1-methyl-2-
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nitroaryls in the presence of AIBN/NBS.
Under the optimized reactions conditions, the electrophilic coupling partner ortho-nitro-
benzylbromide having an EDG (OMe), in ortho (2b), meta (2c), and para (2d) positions to
NO2 were coupled to a diverse range of N-tosylhydrazones 1, and the corresponding 2-aryl
indole derivatives were obtained in satisfactory yields (Table 3, entries 1-6). Also, the
coupling was successful in the presence of EWG (F) on the benzylbromide partner (entries 7-
9). Remarkably, functional groups, such as fluoro (compounds 4r-u), and cyano (4n and 4v)
were tolerated, providing the possibility for further transformations. It should be noted that
under our standard conditions, we were able to realize the coupling between hydrazones
derivated from cinnamaldehyde and benzylbromide 2a, which lead to the corresponding (E)-
2-styryl-1H-indole (4w) in a 32% yield. Finally, coupling with NTH (1g) and 2-nitrobenzyl
bromide partner (2e) having both EWG led successfully to the formation of the desired
compound 4x.
Table 3. Substrate scope of NTH and nitro-benzylbromide.
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entry
1
NTH 1
1d
Benzyl bromides 2
product
yield (%)a
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2b
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4m
4n
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3
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1g
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4p
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4u
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4w
4x
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1m
1g
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a Yield of products 4.
After the success in the coupling of NTH derived from aldehydes, we finally intended to
perform the one-pot reaction between NTH derived from benzophenone 1n (R = H) (Scheme
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2) and nitrobenzyl bromide 2a which would lead to the intermediate 6i and then the reductive
cyclization normally would give rise to a compound with seven-member azepin heterocycle
7i (Scheme 2). When the reaction has performed, a new compound was obtained in 55%
yield and was expected to be the desired 7-member ring compound. Even if we obtained the
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+
desired peak of mass for this product 7: HRMS (ESI): for C20H16N (M + H) : m/z calcd
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270.1283, found 270.1274, however the H and C NMR analysis did not fit with this already
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known compound 7. After careful analysis (MS, H, and C NMR), we deduced that the
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obtained compound corresponds to 2,3-diphenyl-1H-indole 8a (Scheme 2). To validate this
observation, we studied the same reaction with another NTH derived from benzophenone (R
= OMe), again no traces of 7-member ring compound was observed and we isolated
compound 8b in a 30% yield. However, NTH having EWG (R = F) was not suitable for this
transformation, in this case the corresponding intermediate 6 was not obtained. Finally, to
study the selectivity of this rearrangement, we performed this coupling with dissymmetrical
NTH 1q, in this case, the rearrangement was also successful, and, the indole 8c was obtained
in a poor yield.
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Scheme 2. Unexpected 2,3 diphenyl indoles formation from NTH derived from
acetophenone and nitrobenzyl bromide
Conclusion
In summary, we have developed a new one-pot method for the synthesis of C2-aryl indoles.
This method implies the formation of ortho-nitrostyrenes intermediates from N-
tosylhydrazones and nitro-benzylbromides. Then, nitrenes derivatives were generated in situ
after deoxygenation of nitrostyrenes, followed by annulation leading to the formation of C2-
arylated indoles. We anticipate that this method may quickly find use in medicinal chemistry
programmes as it allows the synthesis of NH-free indoles libraries for direct biological tests,
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and which can be alkylated thereafter in order to increase the molecular diversity and enables
drug discovery.
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EXPERIMENTAL SECTION
General Methods. Solvent peaks were used as reference values, with CDCl3 at 7.26 ppm
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for H NMR and 77.16 ppm for C NMR. Chemical shifts δ are given in ppm, and the
following abbreviations are used: singlet (s), doublet (d), doublet of doublet (dd), triplet (t),
multiplet (m) and broad singlet (bs). Reaction courses and product mixtures were routinely
monitored by TLC on silica gel, and compounds were visualized with under a UVP
Mineralight UVGL-58 lamp (254 nm) and with phosphomolybdic acid/Δ, anisaldehyde/Δ, or
vanillin/Δ. Flash chromatography was performed using silica gel 60 (40–63 mm, 230–400
mesh) at medium pressure (200 mbar). Dioxane, dichloromethane, cyclohexane and
tetrahydrofuran were dried using the procedures described in D. Perrin Purification of
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Laboratory Chemicals. Organic extracts were, in general, dried over MgSO4 or Na2SO4. High-
resolution mass spectra were recorded with the aid of a MicrOTOF-Q II. All products
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reported showed H and C NMR spectra in agreement with the assigned structures.
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General procedure for preparation of hydrazone
To a rapidly stirred suspension of p-toluenesulphonohydrazide (930 mg, 5 mmol) in dry
methanol (10 mL) at 60 °C, the ketone (5 mmol) was added dropwise. Within 5-60 min the N-
tosylhydrazone began to precipitate. The mixture was cooled to 0 °C and the product was
collected on a Büchner funnel, washed by petroleum ether then was dried in vacuo to afford
the pure product.
(E)-N'-(3,5-Dimethoxybenzylidene)-4-methylbenzenesulfonohydrazide (1a).25 The title
compound was isolated as a white solid, m.p. = 114-116 ˚C (1.58 g, 4.75 mmol, yield 95%).
1H NMR (300 MHz, acetone-d6) δ (ppm): 10.11 (s, 1H), 7.90 (s, 1H), 7.84 (d, J = 8.3 Hz,
2H), 7.40 (d, J = 8.2 Hz, 2H), 6.77 (d, J = 2.3 Hz, 2H), 6.51 (t, J = 2.3 Hz, 1H), 3.79 (s, 6H),
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2.39 (s, 3H). 13C{1H} NMR (75 MHz, acetone-d6) δ (ppm): 162.0, 147.9, 144.7, 137.4, 137.0,
130.4, 128.6, 105.7, 103.0, 55.8, 21.5.
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4-Methyl-N'-(3,4,5-trimethoxybenzylidene)benzenesulfonohydrazide (1b).26 The title
compound was isolated as a white solid, m.p. = 141-143 ˚C (1.67 g, 4.6 mmol, yield 92%). 1H
NMR (300 MHz, CDCl3) δ (ppm): 8.05 (s, 1H), 7.76 (s, 1H), 6.76–7.81 (m, 6H), 3.74 (s, 9H),
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2.25 (s, 3H). C{1H} NMR (75 MHz, CDCl3) δ (ppm): 154.9, 148.8, 141.4, 137.3, 135.5,
129.6, 125.8, 125.5, 107.9, 56.7, 20.6.
N'-(4-Methoxybenzylidene)-4-methylbenzenesulfonohydrazide
(1c).27
The
title
1
compound was isolated as a yellow solid, m.p. = 103-105 ˚C (1.29 g, 4.25 mmol, 85%). H
NMR (300 MHz, CDCl3) δ (ppm): 8.12 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.73 (s, 1H), 7.51
(d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H), 2.39 (s,
3H). 13C{1H} NMR (75 MHz, CDCl3) δ (ppm): 161.4, 148.3, 144.2, 135.3, 129.7, 129.0,
127.9, 125.9, 114.1, 55.4, 21.6.
4-Methyl-N'-(4-methylbenzylidene)benzenesulfonohydrazide (1d).28 The title compound
was isolated as a white solid, m.p. = 139-141 ˚C (1.3 g, 4.5 mmol, 90%). 1H NMR (300 MHz,
CDCl3) δ (ppm): 8.08 (br s, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.73 (s, 1H), 7.47 (d, J = 8.2 Hz,
2H), 7.30 (d, J = 8.0 Hz, 2H), 7.16 (d, 2H, J = 8.0 Hz), 2.36 (s, 3H, CH3), 2.32 (s, 3H, CH3).
13C{1H} NMR (75 MHz, CDCl3) δ (ppm): 148.3, 144.1, 140.7, 135.2, 130.5, 129.6, 129.2,
127.8, 127.2, 21.5 (CH3), 21.4 (CH3).
N'-(4-Fluorobenzylidene)-4-methylbenzenesulfonohydrazide (1e).29 The title compound
1
was isolated as a white solid, m.p. = 133-135 ˚C (1.24 g, 4.25 mmol, 85%). H NMR (300
MHz, CDCl3) δ (ppm): 8.56 (br s, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.78 (s, 1H), 7.54 (dd, J1 =
8.9, J2 =5.6 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 7.04 (t, J = 8.6 Hz, 2H), 2.39 (s, 3H). 13C{1H}
NMR (75 MHz, CDCl3) δ (ppm): 165.5 (JC-F = 251.2 Hz), 148.4, 144.2, 135.3, 129.7, 129.5,
129.2 (JC-F = 8.3 Hz), 127.9, 115.7 (JC-F = 22.3 Hz), 21.5.
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4-Methyl-N'-(4-(trifluoromethyl)benzylidene)benzenesulfonohydrazide (1f).27 The title
compound was obtained as white solid, m.p. = 148-150 ˚C (1.33 g, 3.9 mmol, yield 78%). 1H
NMR (300 MHz, DMSO-d6) δ (ppm): 11.72 (s, 1H), 8.00 (s, 1H), 7.80-7.70 (m, 6H), 7.39 (d,
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J = 8.0 Hz, 2H), 2.34 (s, 3H). C{1H} NMR (75 MHz, DMSO-d6) δ (ppm): 145.0, 143.5,
137.5, 136.1, 129.7 (q, J C-F = 31.7 Hz), 129.9, 127.3, 127.2, 125.6 (q, J C-F = 4.0 Hz), 123.9
(q, J C-F = 270.0 Hz), 20.9.
N'-(4-Cyanobenzylidene)-4-methylbenzenesulfonohydrazide (1g).30 The title compound
was isolated as a white solid, m.p. = 161-163 ˚C (1.2 g, 4.0 mmol, 80%). 1H NMR (300 MHz,
CDCl3) δ (ppm): 8.87 (br s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.80 (s, 1H), 7.64 (m, 4H), 7.32 (d,
J = 8.0 Hz, 2H), 2.40 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ (ppm): 144.9, 144.8, 137.4,
134.9, 132.4, 129.9, 127.9, 127.6, 118.4, 113.4, 21.7.
N'-Benzylidene-4-methylbenzenesulfonohydrazide (1h).28 The title compound was
1
isolated as a white solid, m.p. = 119-121 ˚C (1.01 g, 3.7 mmol, 74%). H NMR (300 MHz,
CDCl3) δ (ppm): 8.12 (br s, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.79 (s, 1H), 7.61-7.58 (m, 2H),
7.38-7.28 (m, 5H), 2.42 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ (ppm): 148.2, 144.4,
135.3, 133.3, 130.5, 129.8, 128.7, 128.0, 127.5, 21.7.
4-Methyl-N'-(naphthalen-2-ylmethylene)benzenesulfonohydrazide (1i).18b The title
1
compound was isolated as a white solid, m.p. = 128-130 ˚C (1.36 g, 4.2 mmol, 84%). H
NMR (300 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.94 – 7.91 (m, 3H), 7.89 – 7.76 (m, 5H), 7.52 –
13
7.47 (m, 2H), 7.32 (d, J = 8.1 Hz, 2H), 2.39 (s, 3H). C{1H} NMR (75 MHz, DMSO-d6) δ
147.0, 143.4, 136.2, 133.6, 132.7, 131.4, 129.6, 128.6, 128.4, 128.2, 127.7, 127.3, 127.1,
126.7, 122.1, 20.9.
N'-([1,1'-Biphenyl]-4-ylmethylene)-4-methylbenzenesulfonohydrazide (1j).31 The title
compound was obtained as white solid, m.p. = 198-200 ˚C (1.5 g, 4.3 mmol, yield 86%).1H
NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1H), 7.97 (s, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.67 (q, J
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= 8.2 Hz, 6H), 7.48-7.34 (m, 5H), 2.35 (s, 3H). 13C{1H} NMR (75 MHz, DMSO-d6) δ 146.5,
143.4, 141.5, 139.2, 136.2, 132.7, 129.6, 128.9, 127.8, 127.3, 127.2, 126.9, 126.6, 20.9
4-Methyl-N'-(3-phenylpropylidene)benzenesulfonohydrazide (1k).27 The title compound
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was obtained as white solid, m.p. = 112-114 ˚C (0.8 g, 2.7 mmol, yield 53%). H NMR (300
MHz, DMSO-d6) δ (ppm): 10.93 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H),
7.27 (t, J = 5.1 Hz, 2H), 7.23-7.14 (m, 3H), 7.11 (d, J = 7.4 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H),
2.43-2.40 (m, 2H), 2.38 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δ (ppm): 150.9, 143.1, 140.7,
136.3, 129.5, 128.2, 128.2, 127.1, 125.8, 33.2, 31.5, 21.0.
4-Methyl-N'-(pyridin-3-ylmethylene)benzenesulfonohydrazide
(1l).32
The
title
compound was obtained as white solid, m.p. = 154-156 ˚C (1.35 g, 4.9 mmol, yield 98%). 1H
NMR (300 MHz, DMSO-d6) δ (ppm): 11.63 (s, 1H), 8.70 (s, 1H), 8.55 (d, J = 4.6 Hz, 1H),
7.94 (m, 7.95-7.93, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.1 Hz, 3H), 2.36 (s, 3H).
13C{1H} NMR (75 MHz, DMSO-d6) δ (ppm): 150.6, 148.3, 144.1, 143.5, 136.0, 133.2, 129.7,
129.6, 127.2,123.9, 21.0.
4-Methyl-N'-((2E)-3-phenylallylidene)benzenesulfonohydrazide (1m).32 The title
1
compound was isolated as a white solid, m.p. = 156-158 ˚C (750 mg, 2.5 mmol, 50%). H
NMR (300 MHz, DMSO-d6) δ (ppm): 7.93 (s, 1H), 7.82 (d, J = 7.5 Hz, 2H), 7.53 (d, J = 7.6
Hz, 1H), 7.37 – 7.22 (m, 7H), 6.84-6.70 (m, 2H), 2.34 (s, 3H). 13C{1H} NMR (75 MHz,
DMSO-d6) δ 149.2, 143.3, 139.1, 136.3, 135.6, 129.6, 128.8, 128.7, 127.2, 127.0, 124.7, 30.0.
N'-(Diphenylmethylene)-4-methylbenzenesulfonohydrazide (1n).33 The title compound
1
was isolated as a white solid, m.p. = 180-182 ˚C (1.58 g, 4.5 mmol, 90%). H NMR (300
MHz, CDCl3) δ (ppm): 7.86 (d, J = 8.3 Hz, 2H), 7.53 – 7.51 (m, 4H), 7.46 – 7.43 (m, 2H),
7.35 – 7.26 (m, 5H), 7.14-7.11 (m, 2H), 2.43 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ
(ppm): 154.3, 144.3, 136.6, 135.7, 131.3, 130.2, 130.0, 129.9, 129.8, 128.4, 128.4, 128.1,
127.7, 21.8.
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N'-(bis(4-Methoxyphenyl)methylene)-4-methylbenzenesulfonohydrazide (1o).34 The
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title compound was isolated as a white solid, m.p. = 138-140 ˚C (1.4 g, 3.4 mmol, 68%). H
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NMR (300 MHz, CDCl3) δ (ppm): 7.86 (d, J = 8.1 Hz, 2H), 7.49 (s, 1H), 7.36 (dd, J = 8.4 Hz,
4H), 7.04 (d, J = 8.7 Hz, 4H), 6.81 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 2.44 (s, 3H).
13C{1H} NMR (75 MHz, CDCl3) δ (ppm): 160.9, 160.5, 154.2, 143.9, 135.5, 129.8, 129.50,
129.47, 129.1, 127.8, 123.0, 115.0, 113.5, 55.4, 55.3, 21.7.
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N'-(bis(4-Fluorophenyl)methylene)-4-methylbenzenesulfonohydrazide (1p).33 The title
1
compound was isolated as a white solid, m.p. = 154-156 ˚C (1.16 g, 3.0 mmol, 60%). H
NMR (300 MHz, CDCl3) δ (ppm): 7.87 (d, J = 8.5 Hz, 2H), 7.50 (s, 1H), 7.43 – 7.35 (m, 4H),
13
7.31 (d, J = 8.9 Hz, 2H), 7.18-7.13 (m, 2H), 6.99 (t, J = 8.6 Hz, 2H), 2.46 (s, 3H). C{1H}
1
1
NMR (75 MHz, CDCl3) δ (ppm): δ 164.5 (d, JC-F = 247.5 Hz), 164.2 (d, JC-F = 246.3 Hz),
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3
3
153.0, 144.8, 137.5, 134.7 (d, JC-F = 2.6 Hz), 132.2 (d, JC-F = 8.5 Hz), 130.5 (d, JC-F = 8.5
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Hz), 130.4, 129.3 (d, JC-F = 3.2 Hz),128.9, 117.1 (d, JC-F = 21.8 Hz), 116.0 (d, JC-F = 21.9
Hz), 21.5.
N'-((4-Methoxyphenyl)(phenyl)methylene)-4-methylbenzenesulfonohydrazide (1q).35
The title compound was obtained as white solid, m.p. = 140- 142˚C (1.7 g, 4.5 mmol, yield
1
90%). H NMR (300 MHz, CDCl3) δ 7.84 (2H, d, J = 8.2 Hz) 7.54-7.42 (3H, m), 7.42-7.26
(m, 4H), 7.15-7.00 (2H, m), 6.8 (2H, d, J = 8.9 Hz), 3.78 (3H, s), 2.42 (3H, s); 13C NMR (75
MHz, CDCl3) δ 161.2, 154.4, 144.1, 135.7, 130.1, 129.9,. 129.7, 129.2, 128.4, 128.0, 113.7,
55.5, 21.7.
General procedure for the synthesis of 2-arylated NH-free indole derivatives
A 5 ml sealed tube under argon atmosphere was charged with N-tosylhydrazone (0.6 mmol,
1.0 eq), 2-nitrobenzylbromide (0.6 mmol, 1.0 eq), Pd2dba3·CHCl3 (2.5 mol%), and P(2-furyl)3
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(10 mol%). Then dioxane (2.5 mL) was added via syringe and the mixture was stirred at room
temperature for 1 min before the addition of LiOtBu (1.32 mmol, 2.2 eq). Then the flask was
put into a preheated oil bath (110 oC) and stirred. After 3 h, PPh3 (2.4 mmol, 4 eq) was added
to the same reaction mixture which was stirred at 160 oC for 24 h. The crude reaction mixture
was allowed to cool to room temperature. EtOAc was added to the mixture, which was
filtered through Celite®. The solvents were evaporated under reduced pressure, and the crude
residue was purified by column chromatography on silica gel.
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2-(3,5-Dimethoxyphenyl)-1H-indole (4a).36 Column chromatography on silica gel
afforded 106 mg of the desired compound (0.42 mmol, yield 70%), white solid, m.p.= 129-
130 ˚C. TLC: Rf = 0.4 (Cyclohexane/ Ethyl acetate 8/2). IR (film, cm-1): 3388, 2994, 2937,
1611, 1592, 1546, 1455, 1428, 1359, 1280, 1204, 1151, 1081. 1H NMR (300 MHz, CDCl3) δ
(ppm): 8.36 (s, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.24 (t, J = 7.7 Hz,
1H), 7.17 (t, J = 7.8 Hz, 1H), 6.84 (s, 1H), 6.83 (d, J = 2.1 Hz, 2H), 6.48 (t, J = 2.1 Hz, 1H),
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3.87 (s, 6H). C{1H} NMR (75 MHz, CDCl3) δ (ppm): 161.3 (2C), 137.9 (C), 136.8 (C),
134.4 (C), 129.2 (C), 122.5 (CH), 120.8 (CH), 120.4 (CH), 111.1 (CH), 103.7 (2CH), 100.4
(CH), 99.7 (CH), 55.5 (2OCH3). HRMS (ESI): for C16H16NO2 (M + H)+: m/z calcd 254.1181,
found 254.1182.
2-(3,4,5-Trimethoxyphenyl)-1H-indole (4b).37 Column chromatography on silica gel
afforded 109 mg of the desired compound (0.39 mmol, yield 65%), brown solid, m.p.= 178-
180˚C. TLC: Rf = 0.27 (Cyclohexane/ Ethyl acetate 8/2). IR (film, cm-1): 3332, 2923, 1591,
1501, 1462, 1363, 1285, 1261, 1239, 1184, 1127, 1077. 1H NMR (300 MHz, CDCl3) δ (ppm):
8.37 (s, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.20 (td, J = 7.7, 1.2 Hz, 1H),
7.13 (td, J = 7.8, 1.1 Hz, 1H), 6.87 (s, 2H), 6.76 (d, J = 2.0 Hz, 1H), 3.95 (s, 6H), 3.90 (s, 3H).
13C{1H} NMR (75 MHz, CDCl3) δ (ppm): 153.9 (2C), 138.3 (C), 138.2 (C), 136.9 (C), 129.4
(C), 128.5 (C), 122.5 (CH), 120.7 (CH), 120.5 (CH), 111.0 (CH), 102.9 (2CH), 100.1 (CH),
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61.2 (OCH3), 56.4 (2OCH3). HRMS (ESI): for C17H18NO3 (M + H)+: m/z calcd 284.1287,
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found 284.1280.
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2-(4-Methoxyphenyl)-1H-indole (4c). Column chromatography on silica gel
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afforded 98 mg of the desired compound (0.44 mmol, yield 73%), yellow solid, m.p.= 228-
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230˚C. TLC: Rf = 0.51 (Cyclohexane/ Ethyl acetate 8/2). IR (film, cm ): 3431, 3054, 2361,
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2340, 1607, 1545, 1502, 1486, 1454, 1432, 1398, 1351, 1287, 1256, 1182, 1115. H NMR
(300 MHz, Acetone-d6) δ (ppm): 10.54 (s, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 7.7 Hz,
1H), 7.38 (d, J = 7.8 Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H), 7.02 (d, J = 8.7 Hz, 2H), 7.01 – 6.97
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(m, 1H), 6.76 (d, J = 2.1 Hz, 1H), 3.84 (s, 3H). C{1H} NMR (75 MHz, Acetone-d6) δ (ppm):
160.3 (C), 139.0 (C), 138.2 (C), 130.4 (C), 127.3 (2CH), 126.3 (C), 122.1 (CH), 120.8 (CH),
120.3 (CH), 115.2 (2CH), 111.8 (CH), 98.7 (CH), 55.6 (OCH3). HRMS (ESI): for C15H14NO
+
(M + H) : m/z calcd 224.1075, found 224.1086.
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2-(p-Tolyl)-1H-indole (4d). Column chromatography on silica gel afforded 87 mg of
the desired compound (0.42 mmol, yield 70%), yellow solid, m.p.= 214-216˚C. TLC: Rf = 0.6
-1
(Cyclohexane/ Ethyl acetate 8/2). IR (film, cm ): 3441, 1595, 1546, 1501, 1454, 1426, 1351,
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1298, 1264, 1205, 1155. H NMR (300 MHz, CDCl3) δ (ppm): 8.30 (s, 1H), 7.67 (d, J = 7.7
Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 7.9 Hz, 2H), 7.23 (t, J
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= 7.7 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 1.5 Hz, 1H), 2.44 (s, 3H). C{1H} NMR
(75 MHz, CDCl3) δ (ppm): 138.2 (C), 137.8 (2C), 136.8 (C), 129.8 (2CH), 129.5 (C), 125.2
(2CH), 122.2 (CH), 120.7 (CH), 120.3 (CH), 110.9 (CH), 99.5 (CH), 21.4 (CH3). HRMS
+
(ESI): for C15H14N (M + H) : m/z calcd 208.1126, found 208.1130.
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2-(4-Fluorophenyl)-1H-indole (4e). Column chromatography on silica gel afforded
70 mg of the desired compound (0.33 mmol, yield 55%), white solid, m.p.= 189-191 ˚C. TLC:
-1
Rf = 0.6 (Cyclohexane/ Ethyl acetate 8/2). IR (film, cm ): 3413, 1606, 1545, 1498, 1484, 1453,
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1428, 1347, 1298, 1233, 1160, 1100, 1011. H NMR (300 MHz, CDCl3) δ (ppm): 8.25 (s, 1H),
7.65 – 7.60 (m, 3H), 7.40 (d, J = 7.7 Hz, 1H), 7.21 (td, J = 7.7, 1.3 Hz, 1H), 7.18 – 7.15 (m,
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1H), 7.14 (t, J = 7.9 Hz, 2H), 6.77 (d, J = 2.0 Hz, 1H). C{1H} NMR (75 MHz, CDCl3) δ
(ppm): 162.5 (d, J = 247.4 Hz, C), 137.2 (C), 137.0 (C), 129.4 (C), 128.9 (d, J = 3.0 Hz, C),
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127.0 (d, J = 8.0 Hz, 2CH), 122.6 (CH), 120.8 (CH), 120.5 (CH), 116.2 (d, J = 21.8 Hz, 2CH),
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111.0 (CH), 100.1 (CH). F{1H} NMR (188 MHz, CDCl3) δ (ppm): -110.7 (s). HRMS (ESI):
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for C14H11NF (M + H) : m/z calcd 212.0876, found 212.0878.
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2-(4-(Trifluoromethyl)phenyl)-1H-indole (4f). Column chromatograph on silica
gel afforded 71 mg of the desired product (0.27 mmol, yield 45%), yellow solid, m.p.= 234-
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236 ˚C. TLC: Rf = 0.4 (cyclohexane/EA 8/2). H NMR (300 MHz, Acetone-d6) δ (ppm): 10.84
(s, 1H), 8.07 (d, J = 7.9 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 7.8 Hz, 1H), 7.45 (d, J
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= 8.1 Hz, 1H), 7.17 (t, J = 5.2 Hz, 1H), 7.08-7.06 (m, 2H). C{1H} NMR (75 MHz, Acetone-
d6) δ (ppm): 138.9 (C), 37.4 (C), 137.1 (C), 130.1 (C), 129.2 (q, C, JC-F=32 Hz), 129.1 (q, C, JC-
F=269 Hz), 126.8 (q, 2CH, JC-F=4 Hz), 126.3 (2CH), 123.6 (CH), 121.6 (CH), 120.9 (CH),
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112.4 (CH), 102.03 (CH). F{1H} NMR (188 MHz, Acetone-d6) δ (ppm): -62.98.
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4-(1H-indol-2-yl)benzonitrile (4g). Column chromatograph on silica gel afforded
55 mg of the desired product (0.25 mmol, yield 42%), yellow solid, m.p.= 192-194 ˚C. TLC:
1
Rf = 0.4 (cyclohexane/EA 8/2). H NMR (400 MHz, Acetone-d6) δ 10.88 (s, 1H), 8.04 (d, J =
8.6 Hz, 2H), 7.82 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.20–
13
7.15 (m, 1H), 7.12-7.11 (m, 1H), 7.08-7.04 (m, 1H). C{1H} NMR (101 MHz, Acetone-d6) δ
(ppm): 139.0 (C), 137.8 (C), 136.7 (C), 133.6 (2CH), 129.9 (C), 126.3 (2CH), 123.9 (CH),
121.7 (CH), 121.0 (CH), 119.5 (C), 112.4 (CH), 111.0 (C), 102.7 (CH). HRMS (ESI): for
+
C15H11N2 (M + H) : m/z calcd 219.0922, found 219.0926.
42
2-Phenyl-1H-indole (4h). Column chromatography on silica gel afforded 80 mg of the
desired compound (0.41 mmol, yield 68%), white solid, m.p.= 188-190˚C. TLC: Rf = 0.6
-1
(Cyclohexane/ Ethyl acetate 8/2). IR (film, cm ): 3446, 1603, 1480, 1458, 1446, 1403, 1352,
1
1299. H NMR (300 MHz, CDCl3) δ (ppm): 8.33 (s, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.66 (d, J =
7.2 Hz, 2H), 7.47 (d, J = 7.7 Hz, 1H), 7.42 (t, J = 7.2 Hz, 2H), 7.37 – 7.31 (m, 1H), 7.22 (t, J =
13
7.7 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.85 (d, J = 1.1 Hz, 1H). C{1H} NMR (75 MHz,
CDCl3) δ (ppm): 138.0 (C), 136.9 (C), 132.5 (C), 129.4 (C), 129.2 (2CH), 127.8 (CH), 125.3
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(2CH), 122.5 (CH), 120.8 (CH), 120.4 (CH), 111.0 (CH), 100.1 (CH). HRMS (ESI): for
+
C14H12N (M + H) : m/z calcd 194.0970, found 194.0970.
43
2-(Naphthalen-2-yl)-1H-indole (4i). Column chromatography on silica gel afforded
9
91 mg of the desired compound (0.37 mmol, yield 62%), white solid, m.p.= 196-197 ˚C. TLC:
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-1
Rf = 0.63 (Cyclohexane/ Ethyl acetate 8/2). IR (film, cm ): 3054, 1603, 1454, 1422, 1345,
1
1296, 1264. H NMR (300 MHz, CDCl3) δ ppm: 8.47 (s, 1H), 8.05 (s, 1H), 7.92 – 7.81 (m,
4H), 7.68 (d, J = 7.7 Hz, 1H), 7.56 – 7.46 (m, 2H), 7.44 (d, J = 7.8 Hz, 1H), 7.24 (t, J = 7.7
13
Hz, 1H), 7.16 (t, J = 7.7 Hz, 1H), 6.97 (s, 1H). C{1H} NMR (75 MHz, CDCl3) δ ppm: 138.0
(C), 137.2 (C), 133.7 (C), 133.0 (C), 129.8 (C), 129.5 (C), 129.0 (CH), 128.1 (CH), 127.9
(CH), 126.8 (CH), 126.3 (CH), 123.9 (CH), 123.2 (CH), 122.7 (CH), 120.9 (CH), 120.5 (CH),
+
111.0 (CH), 100.8 (CH). HRMS (ESI): for C18H14N (M + H) : m/z calcd 244.1126, found
244.1124.
43
2-([1,1'-Biphenyl]-4-yl)-1H-indole (4j). Column chromatograph on silica gel
afforded 59 mg of the desired product (0.22 mmol, yield 36%), light brown solid, m.p.= 296-
1
298 ˚C. TLC: Rf = 0.4 (cyclohexane/EA 8/2). H NMR (300 MHz, DMSO-d6) δ (ppm): 11.56
(brs, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.81-7.71 (m, 4H), 7.46-7.38 (m, 5H), 7.11 (t, J = 7.1 Hz,
13
1H), 7.02 (d, J = 7.7 Hz, 1H), 6.95 (s, 1H). C{1H} NMR (101 MHz, DMSO) δ 139.5 (C),
138.8 (C), 137.21 (C), 137.20 (C), 131.3 (C), 129.0 (2CH), 128.7 (C), 127.5 (CH), 127.1
(2CH), 126.4 (2CH), 125.5 (2CH), 121.7 (CH), 120.0 (CH), 119.4 (CH), 111.3 (CH), 98.9
+
(CH). HRMS (ESI): for C20H16N (M + H) : m/z calcd 270.1283, found 270.1281.
36
2-(Pyridin-3-yl)-1H-indole (4l). Column chromatograph on silica gel afforded 48
mg of the desired product (0.25 mmol, yield 40%), yellow solid, m.p.= 175-177 ˚C. TLC: Rf =
1
0.3 (cyclohexane/EA 5/5). H NMR (300 MHz, Acetone-d6) δ (ppm) 10.80 (s, 1H), 9.10 (d, J
= 2.3 Hz, 1H), 8.52-8.50 (m, 1H), 8.21-8.06 (m, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.45-7.41 (m,
13
2H), 7.14 (t, J = 7.6 Hz, 1H), 7.07-7.01 (m, 2H). C NMR (75 MHz, Acetone-d6) δ (ppm):
149.4 (CH), 147.6 (CH), 138.4 (C), 135.7 (C), 132.9 (CH), 130.2 (C), 129.6 (C), 124.7 (CH),
123.4 (CH), 121.5 (CH), 120.9 (CH), 112.4 (CH), 101.3 (CH). HRMS (ESI): for C13H11N2
+
(M+H) : m/z calcd. 195.0922, found 195.0920.
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7-Methoxy-2-(p-tolyl)-1H-indole (4m). Column chromatography on silica gel
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afforded 83 mg of the desired compound (0.35 mmol, yield 58%), brown solid, m.p.= 106-
-1
108 ˚C. TLC: Rf = 0.6 (Cyclohexane/ Ethyl acetate 8/2). IR (film, cm ): 3783, 3451, 2925,
1
2375, 2061, 1634, 1420, 1332, 1255, 1097. H NMR (300 MHz, CDCl3) δ ppm:8.55 (s, 1H),
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7.59 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.8 Hz, 1H), 7.05 (t, J = 7.8 Hz,
13
1H), 6.78 (d, J = 2.4 Hz, 1H), 6.66 (d, J = 7.8 Hz, 1H), 4.00 (s, 3H), 2.40 (s, 3H). C{1H}
NMR (75 MHz, CDCl3) δ ppm: 146.1 (C), 137.9 (C), 137.7 (C), 130.8 (C), 130.7 (C), 129.8
(2CH), 127.3 (C), 125.2 (2CH), 120.6 (CH), 113.4 (CH), 102.2 (CH), 99.8 (CH), 55.5
+
(OCH3), 21.4 (CH3). HRMS (ESI): for C16H16NO (M + H) : m/z calcd 238.1232, found
238.1240.
4-(7-Methoxy-1H-indol-2-yl)benzonitrile (4n). Column chromatography on silica
gel afforded 84 mg of the desired compound (0.34 mmol, yield 56%), yellow solid, m.p.=
-1
133-135 ˚C. TLC: Rf = 0.34 (Cyclohexane/ Ethyl acetate 8/2). IR (film, cm ): 3781, 3449,
1
2925, 2853, 2223, 1634, 1425, 1335, 1257, 1173, 1094. H NMR (300 MHz, Acetone-d6) δ
ppm: 10.73 (s, 1H), 8.14 (d, J = 8.7 Hz, 2H), 7.81 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 7.9 Hz,
1H), 7.09 (d, J = 2.0 Hz, 1H), 6.98 (t, J = 7.9 Hz, 1H), 6.72 (d, J = 7.8 Hz, 1H), 3.96 (s, 3H).
13
C{1H} NMR (75 MHz, CDCl3) δ ppm: 147.5 (C), 137.9 (C), 136.7 (C), 133.5 (2CH), 131.2
(C), 129.4 (C), 126.6 (2CH), 121.6 (CH), 119.5 (C), 114.3 (CH), 111.0 (C), 103.8 (CH),
+
103.3 (CH), 55.7 (OCH3). HRMS (ESI): for C16H13N2O (M + H) : m/z calcd 249.1028, found
249.1026.
2-(3,5-Dimethoxyphenyl)-6-methoxy-1H-indole (4o). Column chromatography
on silica gel afforded 113 mg of the desired compound (0.40 mmol, yield 66%), yellow oil.
-1
TLC: Rf = 0.29 (Cyclohexane/ Ethyl acetate 8/2). IR (film, cm ): 3853, 3779, 3415.31, 2925,
1
2851, 2372, 2051, 1727, 1618, 1439, 1356, 1236, 1201, 1155, 1063. H NMR (300 MHz,
acetone-d6) δ ppm: 10.63 (s, 1H), 7.42 (d, J = 8.6 Hz, 1H), 6.99 (d, J = 2.2 Hz, 2H), 6.94 (d, J
= 2.2 Hz, 1H), 6.83 (d, J = 2.2 Hz, 1H), 6.70 (dd, J = 8.6, 2.2 Hz, 1H), 6.42 (t, J = 2.2 Hz,
13
1H), 3.84 (s, 6H), 3.79 (s, 3H). C{1H} NMR (75 MHz, acetone-d6) δ ppm: 162.3 (2C),
157.6 (C), 139.1 (C), 137.7 (C), 135.7 (C), 124.3 (C), 121.7(CH), 110.7 (CH), 103.6 (2CH),
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100.3 (CH), 99.9 (CH), 95.2 (CH), 55.7 (2OCH3), 55.6 (OCH3). HRMS (ESI): for C17H18NO3
+
(M + H) : m/z calcd 284.1287, found 284.1280.
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2-(3,5-Dimethoxyphenyl)-5-methoxy-1H-indole (4p). Column chromatography
9
on silica gel afforded 121 mg of the desired compound (0.43 mmol, yield 71%), yellow oil.
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-1
TLC: Rf = 0.32 (Cyclohexane/ Ethyl acetate 8/2). IR (film, cm ): 3854, 3779 3414, 2925,
1
2852, 2376, 2051, 1726, 1616, 1459, 1355, 1295, 1205, 1153, 1064. H NMR (300 MHz,
CDCl3) δ ppm: 8.24 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 2.2 Hz, 1H), 6.83 (dd, J =
8.8, 2.3 Hz, 1H), 6.76 (d, J = 2.2 Hz, 2H), 6.71 (d, J = 2.3 Hz, 1H), 6.41 (t, J = 2.2 Hz, 1H),
13
3.83 (s, 3H), 3.82 (s, 6H). C{1H} NMR (75 MHz, CDCl3) δ ppm: 161.4 (2C), 154.6 (C),
138.7 (C), 134.6 (C), 132.1 (C), 129.7 (C), 112.9 (CH), 111.8 (CH), 103.6 (2CH), 102.4
(CH), 100.3 (CH), 99.8 (CH), 56.0 (OCH3), 55.6 (2OCH3). HRMS (ESI): for C17H18NO3 (M +
+
H) : m/z calcd 284.1287, found 284.1281.
37
5-Methoxy-2-(3,4,5-trimethoxyphenyl)-1H-indole
(4q).
Column
chromatography on silica gel afforded 119 mg of the desired compound (0.38 mmol, yield
63%), brown solid, m.p.= 151-152 ˚C. TLC: Rf = 0.26 (Cyclohexane/ Ethyl acetate 7/3). IR
-1
(film, cm ): 3783, 3417, 2926, 2851, 2378, 2054, 1727, 1624, 1460, 1353, 1231, 1127, 1033,
1
1001. H NMR (300 MHz, CDCl3) δ ppm: 8.23 (s, 1H), 7.29 (d, J = 8.6 Hz, 1H), 7.08 (d, J =
2.2 Hz, 1H), 6.87 (dd, J = 8.6, 2.2 Hz, 1H), 6.85 (s, 2H), 6.68 (d, J = 2.1 Hz, 1H), 3.94 (s, 6H),
13
3.89 (s, 3H), 3.87 (s, 3H). C{1H} NMR (75 MHz, CDCl3) δ ppm: 154.7 (C), 153.9 (2C),
139.0 (C), 138.1 (C), 132.1 (C), 129.9 (C), 128.6 (C), 112.6 (CH), 111.7 (CH), 102.8 (2CH),
102.4 (CH), 99.9 (CH), 61.2 (OCH3), 56.4 (2OCH3), 56.0 (OCH3). HRMS (ESI): for C18H20NO4
+
(M + H) : m/z calcd 314.1392, found 314.1390.
45
2-(4-Fluorophenyl)-5-methoxy-1H-indole (4r). Column chromatography on silica
gel afforded 98 mg of the desired compound (0.41 mmol, yield 68%), yellow oil. TLC: Rf =
-1
0.47 (Cyclohexane/ Ethyl acetate 8/2). IR (film, cm ): 3853, 3781, 3415, 2925, 2854, 2378,
1
2037, 1885, 1728, 1620, 1448, 1381, 1221, 1156, 1112, 1028. H NMR (300 MHz, Acetone-
d6) δ ppm: 9.70 (s, 1H), 7.85 (dd, J = 8.9, 5.3 Hz, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.30 (t, J =
8.9 Hz, 2H), 7.16 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 8.8, 2.4 Hz, 1H), 6.82 (d, J = 1.6 Hz, 1H),
13
3.91 (s, 3H). C{1H} NMR (75 MHz, Acetone-d6) δ ppm: 162.7 (d, J = 244.8 Hz, C-F), 154.9
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(C), 138.2 (C), 132.9 (C), 130.2 (C), 129.6 (C), 129.6 (d, J = 3.3 Hz, C), 127.5 (d, J = 8.2 Hz,
2CH), 116.3 (d, J = 21.9 Hz, 2CH), 112.8 (CH), 112.4 (CH), 102.3 (CH), 99.4 (CH), 55.7
7
8
19
(OCH3). F{1H} NMR (188 MHz, CDCl3) δ (ppm): -110.7 (s). HRMS (ESI): for C15H13NOF
9
+
(M + H) : m/z calcd 242.0981, found 242.0984.
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7-Fluoro-2-(4-methoxyphenyl)-1H-indole (4s). Column chromatography on silica
gel afforded 75 mg of the desired compound (0.31 mmol, yield 52%), brown solid, m.p.=
-1
117-118 ˚C. TLC: Rf = 0.47 (Cyclohexane/ Ethyl acetate 8/2). IR (film, cm ): 3782, 3419,
1
2925, 2854, 2376, 2037, 1634, 1438, 1334, 1240, 1179, 1111, 1025. H NMR (300 MHz,
CDCl3) δ ppm: 8.41 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.03 – 7.01 (m,
1H), 7.00 (d, J = 8.8 Hz, 2H), 6.88 (dd, J = 11.1, 7.8 Hz, 1H), 6.74 – 6.71 (m, 1H), 3.87 (s,
13
3H). C{1H} NMR (75 MHz, CDCl3) δ ppm: 159.8 (C), 149.5 (d, J = 242.9 Hz, C-F), 139.0
(d, J = 0.9 Hz, C), 133.1 (d, J = 5.3 Hz, C), 126.8 (2CH), 125.0 (d, J = 13.0 Hz, C), 124.8 (C),
120.5 (d, J = 6.2 Hz, CH), 116.2 (d, J = 3.4 Hz, CH), 114.7 (2CH), 106.9 (d, J = 16.2 Hz,
19
CH), 99.5 (d, J = 2.4 Hz, CH), 55.5 (OCH3). F{1H} NMR (188 MHz, CDCl3) δ (ppm): -135.7
+
(s). HRMS (ESI): for C15H13NOF (M + H) : m/z calcd 242.0981, found 242.0982.
6-Fluoro-2-(naphthalen-2-yl)-1H-indole (4t). Column chromatography on silica
gel afforded 113 mg of the desired compound (0.43 mmol, yield 72%), white solid, m.p.=
-1
178-180 ˚C. TLC: Rf = 0.47 (Cyclohexane/ Ethyl acetate 8/2). IR (film, cm ): 3781, 3441,
1
2924, 2854, 2375, 2035, 1625, 1498, 1442, 1393, 1348, 1249, 1141, 1107. H NMR (300
MHz, CDCl3) δ ppm: 8.49 (s, 1H), 8.02 (d, J = 1.3 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.87 (d, J
= 8.2 Hz, 1H), 7.85 – 7.77 (m, 2H), 7.59 – 7.54 (m, 1H), 7.53 – 7.45 (m, 2H), 7.11 (dd, J =
13
8.5, 2.2 Hz, 1H), 6.95 – 6.88 (m, 2H). C{1H} NMR (75 MHz, CDCl3) δ ppm: 160.3 (d, J =
238.5 Hz, C-F), 138.5 (d, J = 3.7 Hz, C), 137.1 (d, J = 12.5 Hz, C), 133.7 (C), 133.0 (C),
129.6 (C), 129.0 (CH), 128.1 (CH), 128.0 (CH), 126.9 (CH), 126.3 (CH), 126.0 (d, J = 0.7
Hz, C), 123.7 (CH), 123.0 (CH), 121.6 (d, J = 12.2 Hz, CH), 109.2 (d, J = 24.5 Hz, CH),
19
100.7 (d, J = 0.7 Hz, CH), 97.5 (d, J = 24.8 Hz, CH). F{1H} NMR (188 MHz, CDCl3) δ
+
(ppm): -120.0 (s). HRMS (ESI): for C18H13NF (M + H) : m/z calcd 262.1032, found 262.1037.
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5-Fluoro-2-(p-tolyl)-1H-indole (4u). Column chromatography on silica gel afforded
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88 mg of the desired compound (0.39 mmol, yield 65%), yellow oil. TLC: Rf = 0.47
-1
(Cyclohexane/ Ethyl acetate 8/2). IR (film, cm ): 3781, 3437, 2924, 2854, 2375, 2053, 1635,
1
1447, 1262, 1200, 1111. H NMR (300 MHz, CDCl3) δ ppm: 8.30 (s, 1H), 7.54 (d, J = 7.8 Hz,
9
10
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2H), 7.29 (d, J = 4.4 Hz, 1H), 7.29 – 7.25 (m, 1H), 7.25 (d, J = 7.8 Hz, 2H), 6.91 (td, J = 8.6,
13
2.5 Hz, 1H), 6.73 (d, J = 2.2 Hz, 1H), 2.39 (s, 3H). C{1H} NMR (75 MHz, CDCl3) δ ppm:
158.3 (d, J = 234.4 Hz, C-F), 140.0 (C), 138.1 (C), 133.4 (C), 129.9 (2CH), 129.8 (C), 129.4
(C), 125.3 (2CH), 111.5 (d, J = 9.7 Hz, CH), 110.5 (d, J = 25.4 Hz, CH), 105.4 (d, J = 24.6
19
Hz, CH), 99.6 (d, J = 4.6 Hz, CH), 29.9 (CH3). F{1H} NMR (188 MHz, CDCl3) δ (ppm): -
+
124.3 (s). HRMS (ESI): for C15H13NF (M + H) : m/z calcd 226.1032, found 226.1040.
2-(3,5-Dimethoxyphenyl)-1H-indole-6-carbonitrile
(4v).
Column
chromatography on silica gel afforded 92 mg of the desired compound (0.33 mmol, yield
55%), white solid, m.p. = 189-191 ˚C. TLC: Rf = 0.22 (Cyclohexane/ Ethyl acetate 8/2). IR
-1
(film, cm ): 3852, 3780, 3428, 2925, 2854, 2373, 2050, 1728, 1625, 1439, 1356, 1240, 1201,
1
1162. H NMR (300 MHz, CDCl3) δ (ppm): 7.80 (s, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.32 (dd, J
= 8.2, 1.3 Hz, 1H), 7.08 (d, J = 2.2 Hz, 2H), 7.07 (d, J = 1.5 Hz, 1H), 6.54 (t, J = 2.2 Hz, 1H),
13
3.87 (s, 6H). C{1H} NMR (75 MHz, CDCl3) δ (ppm): 162.4 (2C), 143.0 (C), 137.0 (C),
134.2 (C), 133.1 (C), 123.6 (CH), 122.0 (CH), 121.1 (C), 116.6 (CH), 104.7 (C), 104.6
+
(2CH), 101.4 (CH), 101.0 (CH), 55.8 (2OCH3). HRMS (ESI): for C17H15N2O2 (M + H) : m/z
calcd 279.1134, found 279.1132.
46
(E)-2-Styryl-1H-indole (4w). Column chromatography on silica gel afforded 42 mg
of the desired compound (yield 32%), white solid, m.p. = 188-190 ˚C. TLC: Rf = 0.4
1
(Cyclohexane/ Ethyl acetate 8/2. H NMR (300 MHz, Acetone-d6) δ (ppm): 10.52 (s, 1H),
7.58 (d, J = 7.6 Hz, 2H), 7.53 (d, J = 8.0 Hz,1H), 7.41-7.34 (m, 3H), 7.30-7.18 (m, 3H), 7.12
13
(t, J = 7.5 Hz, 1H), 7.03-6.98 (m, 1H), 6.63 (s, 1H). C{1H} NMR (75 MHz, Acetone-d6) δ
(ppm): 138.3 (C), 137.8 (C), 135.3 (C), 130.0 (C), 129.6 (2CH), 128.3 (CH), 128.1 (CH),
127.1 (2CH), 123.1 (CH), 121.1 (CH), 120.4 (CH), 120.3 (CH), 111.7 (CH), 104.1 (CH).
+
HRMS (ESI): for C16H14N (M + H) : m/z calcd 220.1126, found 220.1125.
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4-(7-Fluoro-1H-indol-2-yl)benzonitrile (4x). Column chromatograph on silica gel
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6
7
8
afforded 49 mg of the desired product (0.21 mmol, yield 35%), white solid, TLC: Rf = 0.4
1
(cyclohexane/EA 8/2). H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.79-7.73 (m, 4H), 7.42 (d,
9
13
J = 7.9 Hz, 1H), 7.06 (td, J1 = 7.9, J2=4.8 Hz, 1H), 6.98-6.94 (m, 2H). C{1H} NMR (101
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MHz, CDCl3) δ (ppm): 149.5 (d, JC-F= 244.2 Hz, C), 136.5 (C), 136.2 (C), 133.1 (2CH), 132.5
(d, JC-C-C-F = 4.9 Hz, C), 125.6 (2CH) , 121.2 (d, JC-C-C-F = 6.1 Hz, CH), 118.8 (C) , 117.1 (d, J
=
C-C-C-C-F
19
3.6 Hz, CH) , 111.3 (C) , 108.4 (d, JC-C-F = 16.0 Hz, CH), 103.2 (d, JC-C-C-C-F = 2.5 Hz, CH). F{1H}
+
NMR (188 MHz, CDCl3) δ (ppm): -134.85. HRMS (ESI): for C15H10FN2 (M + H) : m/z calcd
237.0828, found 237.0820.
22a
2,3-Diphenyl-1H-indole (8a). Column chromatography on silica gel afforded 90 mg
1
of 8a, white solid m.p. = 122-124 ˚C, (0.33 mmol, yield 55%). H NMR (300 MHz, CDCl3) δ
(ppm): 8.25 (s, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.48-7.43 (m, 5H), 7.40-7.34 (m, 2H), 7.35 –
13
7.24 (m, 5H), 7.23 – 7.12 (m, 1H). C{1H} NMR (75 MHz, CDCl3) δ (ppm): 136.0 (C), 135.2
(C), 134.2 (C), 132.9 (C), 130.3 (2CH), 128.9 (C), 128.8 (2CH), 128.7 (2CH), 128.3 (2CH),
127.8 (CH), 126.4 (CH), 122.8 (CH), 120.6 (CH), 119.8 (CH), 115.2 (C), 111.0 (CH). HRMS
+
(ESI): for C20H16N (M + H) : m/z calcd 270.1283, found 270.1274.
2,3-bis(4-Methoxyphenyl)-1H-indole (8b).46 Column chromatography on silica gel
afforded 119 mg of the desired compound (yield 30%), slight yellow solid, m.p.= 151-152 ˚C.
TLC: Rf = 0.4 (Cyclohexane/ Ethyl acetate 8/2). IR (film, cm-1): 3376, 3333, 2835, 1610,
1
1555, 1517, 1242, 1231, 1175, 1033, 906, 727. H NMR (300 MHz, CDCl3) δ (ppm): 8.23
(bs, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.49 – 7.28 (m, 5H), 7.25-7.14 (m, 2H), 6.96 (d, J = 8.6 Hz,
13
2H), 6.85 (d, J = 8.6 Hz, 2H), 3.85 (s, 3H), 3.79 (s, 3H). C{1H} NMR (75 MHz, CDCl3) δ
(ppm): 159.1(C), 158.1 (C), 135.8 (C), 133.9 (C), 131.2 (2CH), 129.4 (2CH), 129.1 (C), 127.7
(C), 125.4 (C), 122.3 (CH), 120.2(CH), 119.4 (CH), 114.2 (2CH), 114.1 (2CH), 113.7 (C),
110.9 (CH), 55.3 (2OCH3). HRMS (ESI): for C22H20NO2 (M + H)+: m/z calcd 330.1494,
found 330.1495.
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2-(4-Methoxyphenyl)-3-phenyl-1H-indole (8c).47 Column chromatography on silica gel
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6
afforded 27 mg of the desired compound (yield 15%), yellow solid, m.p.= 151-152 ˚C. TLC: Rf
7
8
1
= 0.4 (Cyclohexane/ Ethyl acetate 8/2). H NMR (300 MHz, CDCl3) δ (ppm): 8.20 (brs, 1H),
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7.65 (d, J = 7.9 Hz, 1H), 7.45-7.41 (m, 3H), 7.37-7.28 (m, 5) 7.24-7.12 m, 1H), 7.17-7.12 (m,
13
1H), 6.97-6.91 (m, 2H), 3.86 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ (ppm): 158.3 (C),
136.0 (C), 133.8 (C), 133.0 (C), 131.3 (2CH), 129.1 (C), 128.8 (2CH), 128.2 (2CH), 127.6
(CH), 127.5 (C), 122.7 (CH), 120.4 (CH), 119.8 (CH), 114.8 (C), 114.2 (2CH), 111.0 (CH),
55.3 (OCH3).
Author Contributions
#T.B. and K.Z. contributed equally to this work.
AKNOWLEDGMENT
T. Bzeih thanks Lebanese University for her Ph.D grant. K. Zhang thanks the Chinese
Scholarship Council for Ph.D. funding. The authors gratefully acknowledge support of this
project by CNRS, University Paris-Sud and “La Ligue Contre le Cancer” throughout an
“Equipe Labellisée 2014” grant. Our laboratory (Biocis UMR 8076 is a member of the
laboratory of excellence LERMIT supported by a grant from ANR (ANR-10-LABX-33).
Supporting Information
1 13
Copies of H and C NMR spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org
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