Palladium-catalyzed direct desulfitative C2 arylations of 3-halo-: N -protected indoles using (hetero)arenesulfonyl chlorides

Article abstract of DOI:10.1039/c6ob00584e

The direct arylation of N-protected 3-haloindole derivatives with benzenesulfonyl chlorides as coupling partners using 5 mol% of bis(acetonitrile)dichloropalladium(ii) catalyst and lithium carbonate as a base in 1,4-dioxane was investigated. We demonstrated that both iodo and chloro substituents at the indolyl C3 position act as temporary blocking groups allowing the formation of 2-arylindoles through a direct desulfitative arylation, followed by in situ dehalogenation. While, from 3-bromoindole derivatives, 2-aryl-3-bromoindoles were obtained without debromination, and could be converted into 2,3-diarylindoles through a second palladium coupling. This method allows one to prepare in a few steps a very wide variety of indole derivatives, which are of interest in the synthesis of bioactive molecules.

Full text of DOI:10.1039/c6ob00584e

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View Article Online
DOI: 10.1039/C6OB00584E
Organic & Biomolecular Chemistry
ARTICLE
Palladium-catalyzed direct desulfitative C2 arylations of 3-halo-N-
protected indoles using (hetero)arenesulfonyl chlorides
`
Received 00th January 20xx,
a, b, c
b
a*
a*
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Anoir Hfaiedh,
Hamed Ben Ammar, Jean-François Soulé, and Henri Doucet
The direct arylation of N-protected 3-haloindole derivatives with benzenesulfonyl chlorides as coupling partners using 5
mol% of bis(acetonitrile)dichloropalladium(II) catalyst and lithium carbonate as base in 1,4-dioxane was investigated. We
demonstrated that both iodo and chloro substituents at indolyl C3 position act as temporary blocking groups to allow the
formation of 2-arylindoles through a direct desulfitative arylation, followed by in-situ dehalogenation. While, from 3-
bromoindole derivatives, 2-aryl-3-bromoindoles were obtained without debromination, and could be converted into 2,3-
diarylindoles through a second palladium coupling. This method allows to prepare in a few steps a very wide variety of
indole derivatives, which are of interest in the synthesis of bioactive molecules.
Due to the ubiquitousness of this motif, the discovery of
environmentally friendly efficient protocols with a high
functional group tolerance allowing their preparation remains
an important research topic. Stille, Suzuki, or Negishi Pd-
catalyzed coupling reactions represent some of the most
efficient methods to prepare 2-arylindoles; however, such
reactions require the previous preparation of a metallated
indole or arene.
Introduction
The 2-arylindoles derivatives are an important class of
molecules because this motif is found in plenty of naturals
4
5
6
products and synthetic pharmaceuticals.
As examples,
Kenpaullone, which contains a bromine substituent at the C5
position, displays inhibition of Cyclin-Dependent Kinase (CDK)
1
activity. Rucaparib, a fluoroindole derivative, is a drug in
2
In 1985, Ohta et al. reported the Pd-catalyzed arylation of
heteroarenes via a C–H bond activation and, amongst others,
Phase II for the treatment of patients with ovarian cancers.
Diaplasinin is an anti-coagulant and Bazedoxifene is a selective
estrogen receptor modulator developed by Pfizer.
7
3
indole derivatives has been successfully used as substrates.
Since this discovery, this methodology has proven to be a very
powerful tool for a simpler and eco-friendly access to a very
wide variety of arylated heterocycles, as it saves synthetic
steps (i.e., no preparation of metallated derivatives) and as the
O
Br
NH
H
8
N
H
N
N
N
major by-products of the reaction are a base associated to HX.
HN
C H
5 11
O
Kenpaullone
H PO
O
N
Several examples of Pd-catalyzed direct arylations of indole
derivatives using aryl halides as coupling partners have been
3
4
HN
N
9
N
reported in recent years. Different coupling partners, such as
F
Ph
Diaplasinin
H Rucaparib
HO
10
11
12
arylboronic acids, aryl iodonium salts, aryldiazonium salts,
OH
13
14
15
N
arylsiloxanes, carboxylic acids, sodium sulfinates, acid
sulfinates, or even simple arenes through a double C–H
activation, have been successfully employed in Pd-catalyzed
direct C2-arylation of indoles. Among these diverse protocols,
only a few of them are tolerant towards the C–Br bonds.
N
16
Bazedoxifene
O
17
Figure 1. Pharmaceuticals containing a 2-arylindole motif.
Chemoselective
transformations
allowing
sequential
orthogonal transformations, especially involving sequential C–
H bond activations, has become a very promising synthetic
a.
UMR 6226 CNRS-Université de Rennes 1 " Organométalliques, Matériaux et
18
Catalyse", Campus de Beaulieu, 35042 Rennes, France.
E-mail: jean-
francois.soule@univ-rennes1.fr; henri.doucet@univ-rennes1.fr
strategy for the straightforward synthesis of complex
b.
19
Laboratoire de Synthèse Organique Asymétrique et Catalyse Homogène (UR
1ES56), Université de Monastir, Faculté des Sciences de Monastir, Avenue de
l’environnement, Monastir 5000, Tunisia.
structures. As example of chemoselective C2-arylation of
indoles, Sanford and co-workers reported the use of bis(4-
bromophenyl)iodonium tetrafluoroborate to allow the
synthesis of C2-arylated indoles, without the cleavage of the
1
c.
Université de Tunis El Manar, Faculté des Sciences de Tunis, Campus Universitaire
El-Manar, 2092 El Manar Tunis, Tunisia.
Footnotes relating to the title and/or authors should appear here.
†
11a
Electronic Supplementary Information (ESI) available: [details of any C–Br bond (Figure 1.a).
In 2012, Deng, Luo et al. reported a
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
chemoselective desulfitative direct arylation of N-methylindole
This journal is © The Royal Society of Chemistry 20xx
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Org. Biomol. Chem.
The bromides as starting materials in Pd-catalyzed direct indole C2-
15
using sodium 4-bromobenzenesulfinate (Figure 1.b).
View Article Online
DOI: 10.1039/C6OB00584E
28
reaction only involved the sulfinate function and the bromine arylation (Figure 1.e). The chlorine atom plays the role of
was untouched. On the other hand, Wang and al. extended blocking group to overcome the regioselectivity issue of this
this coupling to 4-bromobenzenesulfinic acid in acidic direct coupling. Hence, we decided to investigate the
1
6
conditions and microwave heating (Figure 1c).
reactivities of 3-chloro-, 3-bromo and 3-iodo-N-protected
indole derivatives in Pd-catalyzed desulfitative direct arylation
(Figure 1.f).
Results
Using our previous optimized reaction conditions for Pd-
catalyzed direct desulfitative arylation with heteroarenes –
namely, 5 mol% of PdCl (CH CN) catalyst associated to 3
2
3
2
equivalents of Li CO as base in 1,4-dioxane at 140 ºC over 48
2
3
h– we evaluated the reactivity of 1-benzyl-3-chloroindole in
the presence of 4-nitrobenzenesulfonyl chloride (Table 1, entry
1
). To our surprise, the desulfitative C2-arylation and the
dechlorination of the C3 position occurred at the same time to
afford directly the 2-arylindole in 74% yield. The fact that no
2
indole C3-arylation was observed suggests that the arylation
occurred first followed by dehalogenation. Hence, the
chlorine atom at indole C3-position acts as a trace-less
blocking group. Next, we investigated the reactivity of 1-
benzyl-3-bromoindole.
derivative, the C–Br bond was only partially cleaved under
these reaction conditions, as the 3-bromo-2-arylindole was
isolated in 64% yield, although the debrominated 2-arylindole
was also formed in 28% yield (Table 1, entry 2). Hence, we
decided to investigate a few reaction parameters in order to
improve the yield in (Table 1, entries 3-11). When the
In contrast to 3-chloroindole
3
2
3
reaction was performed at a lower temperature of 100 ºC, no
reaction occurred (Table 1, entry 3). The change of solvent to
diethylcarbonate (DEC) or cyclopentyl methyl ether (CPME) did
not allowed to improve the yield of
3
.
In addition, neat
condition did not afford any desired arylated product, but only
side products (Table 1, entries 4-6). The use of other
palladium sources, such as Pd(OAc) or Pd (dba) , only gave
2
2
3
the debrominated coupling product
entries 7 and 8). The use of 0.5 equivalent of CuBr as additive
also gave only the undesired product in 65% yield (Table 1,
entry 9). Finally, a shorter reaction time of 18 h allowed to
reach a high selectivity, and the desired 2-aryl-3-
bromoindole was isolated in 83% yield (Table 1, entry 10). A
reaction time of 5 h lead to a poor yield in , but without any
formation of (Table 1, entry 11). Finally, we evaluated the
2 in low yields (Table 1,
2
3:2
Figure 2. Palladium-catalyzed chemoselective direct arylation of indoles
3
3
During the last decade, benzenesulfonyl chloride coupling
partners have been used for the direct arylation of
2
reactivity of 1-benzyl-3-iodoindole under the same reaction
conditions. Similarly to the chloro substituent, an iodo
substituent at indolyl C3-position acts as a trace-less blocking
2
0
21
22
23
benzoquinoline, azoles, thiophenes, (benzo)furans and
pyrroles.
24
Recently, we reported on Pd-catalyzed
chemoselective direct desulfitative arylation of heteroarenes
group. Indeed, only the dehalogenated C-2-arylated indole
was obtained in 84% yield (Table 1, entry 12).
2
25
using (poly)halobenzenesulfonyl chlorides, which allowed
26
sequential arylations. It is important to note that in such
In summary, we found that both Cl and I substituents at the
indolyl C3 position are cleaved under our reaction conditions
and play the role of temporary blocking group, allowing the
regioselective C2-arylation of indoles. In contrast, 1-benzyl-3-
bromoindole was arylated at C2 position without the cleavage
of the C–Br bond.
couplings, even C–I bonds were tolerated by the optimized
conditions.
However, when we applied our reaction
conditions to the desulfitative arylation of indoles, using 2-
bromobenzenesulfonyl chloride, a mixture of C2 and C3
24b, 27
arylated products was obtained (Figure 1.d).
Fagnou and
coworkers have used 3-chloro-1-methylindole with aryl
2
| Org. Biomol Chem., 2016, 00, 1-3
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Org. Biomol. Chem.
ARTICLE
Table 1. Reactivity of 1-Benzyl-3-haloindoles in Palladium-Catalyzed Desulfitative tolerated affording methyl 3-(1-benzyl-3-bromoindo 2-
l-li
10.1039/C6OB00584E
View Article On ne
30
Arylation with 4-Nitrobenzenesulfonyl Chloride.
yl)thiophene-2-carboxylate (13) in 81% yie .
D
O
ldI:
Modifications to
conditions
Entry
X
Conv.
Yield of 1, 3 or 4
Yield of 2
1
2
3
4
5
6
7
8
9
Cl
Br
–
–
100% 1, traces
100% 3, 64%
73%
28%
0%
30%
24%
Br 100 ºC
0%
0%
Br DEC as solvent
Br CPME as solvent
Br neat, 18 h
Br Pd(OAc)
Br Pd (dba)
Br CuBr (50 mol%)
Br 18 h
Br 5 h
52%
25%
75%
15%
15%
69%
3, 22%
3, traces
3, traces
3, traces
3, traces
3, traces
2
15%
15%
65%
5%
0%
84%
2
3
1
1
1
0
1
2
100% 3, 83%
28% 3, 28%
100% 4, traces
I
–
2 3 2 2 3
i) PdCl (CH CN) (5 mol%), Li CO (3 equiv.), 1,4-dioxane, 140 ºC, 48 h. DEC =
diethylcarbonate; CPME = cyclopentyl methyl ether.
Scheme 1. Scope of Benzenesulfonyl Chlorides in Pd-Catalyzed Desulfitative C2-
Arylation of 1-Benzyl-3-bromoindole.
Then, we studied the scope of the benzenesulfonyl chlorides in
Pd-catalyzed desulfitative arylation of 1-benzyl-3-bromoindole
using 5 mol% of PdCl (CH CN) catalyst associated to 3 Next, we employed 1-benzyl-3-chloroindole or 1-benzyl-3-
2
3
2
equivalents of Li CO as base in 1,4-dioxane at 140ºC over 18h iodoindole, in which the halo substituents were used as
2
3
(
Scheme 1). Benzenesulfonyl chlorides substituted at para- traceless blocking groups, with
a
wide range of
position by an electron-withdrawing group, such as benzenesulfonyl chlorides for the one-step synthesis of 2-
trifluoromethyl or chloro, allowed the formation of desired C2- arylindole derivatives (Scheme 2). Overall, better yields in
arylated indoles
4 and 5
in 62% and 72% yields, respectively, favor of the desired C2-arylated indole derivatives were
without cleavage of the C–Br bonds. A meta-substituent on obtained when the reaction was performed from 1-benzyl-3-
the benzenesulfonyl chloride has no influence on the yield, as iodoindole. Benzenesulfonyl chlorides substituted at para-
the coupling product
,5-bis(trifluoromethyl)benzenesulfonyl chloride displayed a trifluoromethyl or cyano allowed the formation of the desired
moderate reactivity, as the 2-arylated 3-bromoindole C2-arylated indoles 14 and 15 in 71% and 44% yields, with the
derivative
was obtained in only 42% yield. However, the cleavage of C–X bonds. Then, we investigated the reactivity of
coupling product
resulting from the use of 3,5- benzenesulfonyl chlorides bearing a C–X bond. 4-bromo- and
6
was isolated in 73% yield. In contrast, position by an electron-withdrawing group such as
3
7
8
,
dichlorobenzenesulfonyl chloride as aryl source, was isolated 4-iodo-benzenesulfonyl chlorides smoothly reacted with 1-
in 61%. The reaction seems to be sensitive to steric hindrance, benzyl-3-iodoindole to afford the C2-arylated products 16 and
as the reaction between 2-nitrobenzenesulfonyl chloride and 17 in 63% and 54% yields, respectively. It is important to note
1
4
-benzyl-3-bromoindole afforded the desired indole 9
in only that, unlike indolyl C–I bond, both phenyl C–Br and C–I bonds
5% yield. Polyfluorinated molecules are ubiquitous in remained untouched at the end of the reactions, allowing
medicinal chemistry as well as in materials owing to fluorine further Pd-catalyzed orthogonal transformations. A meta-
atom properties (i.e., electronegativity, size, lipophilicity, and trifluoromethyl group on the benzenesulfonyl chloride
electrostatic interactions), which induces a dramatic change in resulted in a moderate reactivity; as from 1-benzyl-3-
2
9
the molecules behavior. Hence, we studied the reactivity of chloroindole, the arylated product 18 was obtained in
a couple of polyfluorinated benzenesulfonyl chlorides as moderate yield. Again, polyfluorinated benzenesulfonyl
coupling partners with 1-benzyl-3-bromoindole under the chlorides smoothly reacted, whatever the coupling partners, to
18c
same reaction conditions.
We were pleased to find that deliver the tri-, di- and mono-fluorophenylindoles 19-21 in 62-
arylation occurred again at the indolyl C2 position without the 67% yields. As seen previously, an ortho-substituent on the
cleavage of both C–Br and C–F bonds to afford the penta-, tri- benzenesulfonyl chloride resulted in a moderate reactivity in
and difluophenylindoles 10-
12 in 65-86% yields. Finally, desulfitative coupling with 3-haloindoles. Indeed, the reaction
methyl 3-(chlorosulfonyl)thiophene-2-carboxylate was also between 1-benzyl-3-chloroindole and 2-nitrobenzenesulfonyl
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ARTICLE
Org. Biomol. Chem.
chloride afforded the arylated product 22 in only 38% yield. As also coupled to 3,5-dibromo-1-methylindole afforVdieiwngArttichleeO3n,li5ne-
one of the major advantage of the desulfitative coupling is the dibromoindoles 28 and 29 in 54% and 52D%OIy: i1e0l.d10s3,9r/eCs6pOeBc0t0iv5e8l4yE.
chemoselectivity in the presence of halo-benzenesulfonyl In addition, we evaluated the reactivity of 3-bromo-1-(2-
chlorides, we investigated other (poly)bromobenzenesulfonyl bromobenzyl)indole
chlorides as aryl sources. The reaction between 2-bromo-4- cyanobenzenesulfonyl chloride. The 2-arylindole 31 was
trifluoromethyl)benzenesulfonyl chloride and 1-benzyl-3- obtained in good yield, albeit we observed the cleavage of the
30
in
the
presence
of
4-
(
chloroindole afforded the 2-arylindole 23 in 64% yield, without indolyl C–Br bond, whereas the benzyl C–Br was untouched.
cleavage of the C–Br bond. A similar result was observed in
the case of 2,5-dibromobenzenesulfonyl chloride affording 24
in 67% yield. Thiophene-3-sulfonyl chloride derivatives were
also used as coupling partners giving the heteroarenes diads
25 and 26 in 73% and 58% yields. Importantly, the thienyl C–
Br and C–Cl bonds were untouched.
Scheme 3. Scope of Benzenesulfonyl chlorides in Pd-Catalyzed Desulfitative Arylation
of 3,5-dibromo-1-methylindole and 3-Bromo-1-(2-bromobenzyl)indole.
We further demonstrated the potential of this methodology
with the introduction of a second aryl group, for the two steps
synthesis of 2,3-diarylindole derivatives containing two
different aryl units (Scheme 4). From a mixture of 2-aryl-3-
bromoindole
9 and phenylboronic acid (1.2 equivalents) in the
presence of 2 mol% of a diphosphine-palladium catalyst and 2
equivalent of K PO in dioxane at 80 ºC over 18h, the 2,3-
3
4
diarylindole 32 was obtained in 81% yield. Other 2,3-
diarylindoles, with different substituents (e.g., Cl, CF ) on the
3
C2-aryl group, were subjected to the same reaction conditions
and allowed the formation of the desired coupling products 33
and 34 in similar yields. Finally, an heteroarylboronic acid,
such as thiophen-3-ylboronic acid, was coupled with
4 to
afford the 2,3-diarylindole 35 in 73% yield.
Scheme 2. Scope of Benzenesulfonyl Chlorides in Pd-Catalyzed Desulfitative C2-
Arylation of 1-Benzyl-3-chloroindole or 1-Benzyl-3-iodoindole.
Polybrominated indoles are important building blocks in
pharmaceutical synthesis, as C–Br bonds provide
complementary platforms for further elaboration via, among
others, Pd-catalyzed cross-coupling reactions. Therefore, we
investigated the reactivity of polybrominated indoles in such
desulfitative couplings. Under the previous optimized reaction
conditions, 3,5-dibromo-1-methylindole was arylated at C2-
Scheme 4. Pd-Catalyzed Functionalizations of the 2-Aryl-3-bromoindole Derivatives
position using 4-bromobenzenesulfonyl chloride to give the Through Suzuki Coupling Reaction.
tribromoindole 27 in 57% yield, without the cleavage of the
three C–Br bonds. Two other benzenesulfonyl chlorides were
4
| Org. Biomol Chem., 2016, 00, 1-3
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ARTICLE
As many natural products and pharmaceuticals contain NH- General procedure for synthesis of heteroarylated heteroaVrieewneArst:icTleoOanli2n5e
free indole motif, we demonstrated that the N-benzyl mL oven dried Schlenk tube, arylsulfonyl chlorideD(O1.I:2150m.10m3o9l/)C, 36-OhaBl0o0in5d8o4lEe
2 3
substituent of indole derivative 14 can be easily removed derivative (1 mmol), Li CO (0.222 g, 3 mmol), 1,4-dioxane (2 mL) and
(
Scheme 5). We used slightly modified conditions described by PdCl
2 3 2
(CH CN) (12.9 mg, 0.05 mmol) were successively added. The reaction
31
Deaton-Rewolinski, namely a large excess of tBuOK (5 equiv.) mixture was evacuated by vacuum-argon cycles (5 times) and stirred at 140
in DMSO at 60 °C under oxygen bubbling. Using these ºC (oil bath temperature) for 18-48 h (see tables and schemes). After cooling
conditions, the indole derivative 14 affords the desired NH- the reaction at room temperature and concentration, the crude mixture was
free indole 36 in 92% yield.
purified by silica column chromatography to afford the 2-arylated indoles.
1
-Benzyl-2-(4-nitrophenyl)indole (2): 1-Benzyl-3-chloroindole (0.241 g, 1
mmol) and 4-nitrobenzenesulfonyl chloride (0.277 g, 1.25 mmol) affords 2 in
7
3 % (0.241 g) or 84% (0.276 g) from 1-benzyl-3-iodoindole (0.333 g, 1
1
mmol) yield. H NMR (400 MHz, CDCl
3
) δ (ppm) 8.23 (d, J = 8.7 Hz, 2H), 7.71
Scheme 5. Debenzylation of the indole derivative 14.
(d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.33-7.22 (m, 5H), 7.22-7.16 (m,
13
1
H), 7.03 (dd, J = 1.9 and 7.3 Hz, 2H), 6.80 (s, 1H), 5.39 (s, 2H). C NMR (100
MHz, CDCl ) δ (ppm) 147.1, 139.2, 139.0, 137.5, 129.4, 129.0, 128.0, 127.6,
125.8, 123.9, 123.3, 121.2, 120.8, 110.7, 104.8, 48.1. Elemental analysis:
calcd (%) for C21 (328.37): C 76.81, H 4.91; found: C 77.13, H 4.82.
3
Conclusions
16 2 2
H N O
In summary, we reported herein on the reactivity of 3-halo-N-
protected-indoles in Pd-catalyzed desulfitative arylation using
benzenesulfonyl chlorides as aryl sources. We shown that a
bromo substituent at indolyl C3 position can be used as a
blocking group and then used in further chemical
transformation in orthogonal synthesis of 2,3-diarylindoles
containing two different aryl groups. On the contrary, both
indolyl chloro or iodo C3-substituents act as traceless blocking
groups to regioselectively afford the dehalogenated C2-
1
-Benzyl-3-bromo-2-(4-nitrophenyl)indole (3): 1-Benzyl-3-bromoindole
(0.286 g, 1 mmol) and 4-nitrobenzenesulfonyl chloride (0.277 g, 1.25 mmol)
1
affords 3 in 83% (0.338 g) yield. H NMR (400 MHz, CDCl
3
) δ (ppm) 8.28 (d, J
=
6
1
1
C
8.7 Hz, 2H), 7.70-7.66 (m, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.307.24 (m, 7H),
13
.95-6.90 (m, 1H), 5.30 (s, 2H). C NMR (100 MHz, CDCl
3
) δ (ppm) 147.7,
37.2, 137.0, 135.6, 131.4, 131.2, 129.0, 127.7, 127.5, 125.8, 124.3, 123.7,
21.4, 120.0, 110.8, 92.9, 48.6. Elemental analysis: calcd (%) for
21
H
15BrN O
2 2
(407.27): C 61.93, H 3.71; found: C 61.69, H 3.79.
arylated indoles in good yields.
A wide range of
benzenesulfonyl chloride was tolerated by the optimized
reaction conditions including those bearing C–Br and C–I
bonds. Thanks to this chemoselectivity, this Pd-catalyzed
orthogonal transformation scheme has the potential to
streamline pharmaceutical development, providing a new
rapid and efficient method to discover drug candidates.
1
-Benzyl-3-bromo-2-(4-(trifluoromethyl)phenyl)indole (4): 1-Benzyl-3-
bromoindole (0.286 g, 1 mmol) and 4-(trifluoromethyl)benzenesulfonyl
1
chloride (0.305 g, 1.25 mmol) affords 4 in 62% (0.267 g) yield. H NMR (400
MHz, CDCl
3
) δ (ppm) 7.70-7.66 (m, 3H), 7.55 (d, J = 8.2 Hz, 2H), 7.33-7.24 (m,
13
6
1
1
1
6
H), 6.97-6.93 (m, 2H), 5.28 (s, 2H). C NMR (100 MHz, CDCl
3
) δ (ppm)
37.3, 136.8, 136.5, 134.1, 131.0, 130.9 (q, J = 21.9 Hz), 128.9, 127.6, 127.5,
25.9, 125.5 (q, J = 3.2 Hz), 124.0 (q, J = 271.0 Hz), 123.8, 121.2, 119.8,
3
10.7, 92.0, 48.4. Elemental analysis: calcd (%) for C22H15BrF N (430.27): C
1.41, H 3.51; found: C 61.28, H 3.83.
Experimental Section
1
-Benzyl-3-bromo-2-(4-chlorophenyl)indole (5): 1-Benzyl-3-bromoindole
General: All reactions were carried out under argon atmosphere with
(
0.286 g, 1 mmol) and 4-chlorobenzenesulfonyl chloride (0.264 g, 1.25
standard Schlenk-tube techniques. HPLC grade 1,4-dioxane was stored
1
1
mmol) affords 5 in 72% (0.286 g) yield. H NMR (400 MHz, CDCl
3
) δ (ppm)
under argon and used without further purification. H NMR spectra were
7
.70-7.66 (m, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.31-7.23
recorded on Bruker GPX (400 MHz or 300 MHz) spectrometer. Chemical
shifts (d) were reported in parts per million relative to residual chloroform
13
(m, 6H), 6.99-6.94 (m, 2H), 5.30 (s, 2H). C NMR (100 MHz, CDCl
3
) δ (ppm)
37.4, 136.9, 136.6, 135.0, 131.9, 131.7, 128.8, 127.5, 125.9, 123.4, 121.0,
20.9, 119.6, 118.5, 110.7, 91.5, 48.3. Elemental analysis: calcd (%) for
15BrClN (396.71): C 63.58, H 3.81; found: C 63.73, H 3.89.
1
13
1
1
1
C
(7.26 ppm for H ; 77.0 ppm for C), constants were reported in Hertz. H
NMR assignment abbreviations were the following: singlet (s), doublet (d),
triplet (t), quartet (q), doublet of doublets (dd), doublet of triplets (dt), and
21
H
13
multiplet (m). C NMR spectra were recorded at 100 MHz on the same
spectrometer and reported in ppm. All reagents were weighed and handled
in air.
1
-Benzyl-3-bromo-2-(3-(trifluoromethyl)phenyl)indole (6): 1-Benzyl-3-
bromoindole (0.286 g, 1 mmol) and 3-(trifluoromethyl)benzenesulfonyl
1
chloride (0.305 g, 1.25 mmol) affords 6 in 73% (0.314 g) yield. H NMR (400
3
2
MHz, CDCl
3
) δ (ppm) 7.68-7.65 (m, 1H), 7.65-6.61 (m, 2H), 7.59 (d, J = 8.2 Hz,
Preparation of the PdCl(C
Schlenk tube equipped with
atmosphere, was charged with [Pd(C
426 mg, 1 mmol). 10 mL of anhydrous dichloromethane were added, then,
3 5
H
)(dppb) catalyst: An oven-dried 40 mL
magnetic stirring bar under argon
)Cl] (182 mg, 0.5 mmol) and dppb
1
H), 7.53 (t, J = 7.0 Hz, 1H), 7.28-7.21 (m, 6H), 6.94-6.88 (m, 2H), 5.26 (s, 2H).
a
13
C NMR (100 MHz, CDCl
q, J = 33.0 Hz), 129.0, 128.8, 127.5 (q, J = 3.0 Hz), 125.9, 125.5 (q, J = 3.0 Hz),
23.8 (q, J = 262.7 Hz), 123.6, 121.1, 120.9, 119.7, 118.7, 110.6, 91.9, 48.4.
3
) δ (ppm) 137.2, 136.7, 136.4, 133.8, 131.2, 130.9
3
H
5
2
(
(
1
the solution was stirred at room temperature for twenty minutes. The
solvent was removed in vacuum. The powder was used without
Elemental analysis: calcd (%) for C22
3
H15BrF N (430.27): C 61.41, H 3.51;
3
1
found: C 61.67, H 3.29.
3
purification. ( P NMR 381 MHz, CDCl ) δ = 19.3 (s).
This journal is © The Royal Society of Chemistry 20xx
Org. Biomol Chem., 2016, 00, 1-3 | 5
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Org aP nl ei ca s &e dB oi o nmo to al ed cj uu sl at rm Ca hr ge imn si stry
Page 6 of 9
ARTICLE
Org. Biomol. Chem.
1
-Benzyl-3-bromo-2-(3,5-bis(trifluoromethyl)phenyl)indole (7): 1-Benzyl-3- 135.8, 129.8, 127.5, 127.2, 127.0 (m), 125.8, 123.6, 121.0, 1V1i9e.w8A(rdti,clJe=O1nl8in.5e
DOI: 10.1039/C6OB00584E
bromoindole (0.286 g, 1 mmol) and 3,5-bis(trifluoromethyl)benzenesulfonyl Hz), 119.6, 117.5 (d, J = 16.2 Hz), 110.6, 91.8, 48.2. Elemental analysis: calcd
1
chloride (0.391 g, 1.25 mmol) affords 7 in 42% (0.209 g) yield. H NMR (400 (%) for C21
H
14BrF
2
N (398.25): C 63.33, H 3.54; found: C 63.67, H 3.91.
MHz, CDCl
3
) δ (ppm) 7.89 (brs, 1H), 7.81 (brs, 2H), 7.68 (d, J = 7.6 Hz, 1H),
Methyl 3-(1-benzyl-3-bromoindol-2-yl)thiophene-2-carboxylate (13): 1-
Benzyl-3-bromoindole (0.286 g, mmol) and methyl 3-
7
5
1
.36-7.32 (m, 2H), 7.32-7.27 (m, 1H), 7.27-7.23 (m, 3H), 6.92-6.88 (m, 2H),
13
1
.27 (s, 2H). C NMR (100 MHz, CDCl
3
) δ (ppm) 137.2, 137.0, 134.6, 132.6,
(
chlorosulfonyl)thiophene-2-carboxylate (0.301 g, 1.25 mmol) affords 13 in
32.1, 131.7, 130.7 (m), 129.0, 127.9, 127.2, 125.8, 124.4, 122.9 (q, J = 262.7
1
8
7
1% (0.345 g) yield. H NMR (400 MHz, CDCl
3
) δ (ppm) 7.63-7.60 (m, 1H),
Hz), 122.3 (m), 120.0, 110.5, 92.9, 48.6. Elemental analysis: calcd (%) for
.54 (d, J = 5.3 Hz, 1H), 7.51 (d, J = 5.3 Hz, 1H), 7.27-7.23 (m, 1H), 7.23-7.19
C
23
H
14BrF
6
N (498.27): C 55.44, H 2.83; found: C 55.42, H 2.81.
(m, 1H), 7.19-7.15 (m, 2H), 7.05 (d, J = 4.9 Hz, 1H), 6.98 (d, J = 4.9 Hz, 1H),
1
-Benzyl-3-bromo-2-(3,5-dichlorophenyl)indole (8):
1-Benzyl-3- 6.89 (dd, J = 2.8 and 5.5 Hz, 2H), 5.27 (d, J = 16.5 Hz, 1H), 5.15 (d, J = 16.4 Hz,
13
bromoindole (0.286 g, 1 mmol) and 3,5-dichlorobenzenesulfonyl chloride 1H), 3.74 (s, 3H). C NMR (100 MHz, CDCl
3
) δ (ppm) 161.6, 137.4, 136.3,
1
(0.307 g, 1.25 mmol) affords 8 in 61% (0.263 g) yield. H NMR (400 MHz, 135.7, 132.3, 132.0, 131.8, 130.7, 128.6, 127.4, 127.2, 126.4, 123.1, 120.6,
3 2
CDCl ) δ (ppm) 7.68-7.65 (m, 1H), 7.42 (t, J = 2.1 Hz, 1H), 7.29-7.26 (m, 5H), 119.5, 110.4, 92.3, 52.3, 48.5. Elemental analysis: calcd (%) for C21H16BrNO S
1
3
7
.26-7.24 (m, 3H), 6.94-6.90 (m, 2H), 5.28 (s, 2H). C NMR (100 MHz, CDCl
δ (ppm) 137.2, 136.8, 135.2, 135.1, 133.3, 129.0, 128.9, 128.8, 127.7, 127.3,
26.0, 123.9, 121.2, 119.9, 110.7, 92.3, 48.5. Elemental analysis: calcd (%)
N (431.15): C 58.50, H 3.27; found: C 58.21, H 3.14.
3
)
(426.32): C 59.16, H 3.78; found: C 59.36, H 4.02.
1
-Benzyl-2-(4-(trifluoromethyl)phenyl)indole (14): 1-Benzyl-3-iodoindole
1
(
0.333 g, 1 mmol) and 4-(trifluoromethyl)benzenesulfonyl chloride (0.305 g,
for C21H14BrCl
2
1
1
.25 mmol) affords 14 in 71% (0.249 g) yield. H NMR (400 MHz, CDCl
3
) δ
1
-Benzyl-3-bromo-2-(2-nitrophenyl)indole (9): 1-Benzyl-3-bromoindole (ppm) 8.15 (ddd, J = 1.3, 4.6 and 6.8 Hz, 1H), 8.09 (ddd, J = 1.7, 5.0 and 7.9
(
0.286 g, 1 mmol) and 2-nitrobenzenesulfonyl chloride (0.277 g, 1.25 mmol) Hz, 2H), 8.03-7.98 (m, 2H), 7.75-7.70 (m, 3H), 7.69-7.62 (m, 3H), 7.48 (dd, J =
1
13
affords 9 in 45% (0.183 g) yield. H NMR (400 MHz, CDCl
3
) δ (ppm) 8.15-8.12 4.7 and 7.2 Hz, 2H), 7.17 (s, 1H), 5.28 (s, 2H). C NMR (100 MHz, CDCl
3
) δ
(
m, 1H), 7.65-7.59 (m, 3H), 7.35-7.30 (m, 1H), 7.28-7.25 (m, 3H), 7.23-7.19 (ppm) 140.1, 138.4, 137.8, 136.2, 129.9 (q, J = 33.0 Hz), 129.2, 128.8, 129.1,
m, 3H), 6.94-6.90 (m, 2H), 5.36 (d, J = 16.8 Hz, 1H), 5.05 (d, J = 16.9 Hz, 1H). 127.4, 125.8, 125.5 (q, J = 2.1 Hz), 124.1 (q, J = 279.8 Hz), 122.6, 120.8,
(
1
3
C NMR (100 MHz, CDCl
28.7, 127.6, 127.1, 126.3, 125.7, 124.8, 123.5, 120.9, 119.6, 118.6, 110.6, (362.26): C 75.20, H 4.59; found: C 75.64, H 4.89.
2.0, 48.8. Elemental analysis: calcd (%) for C21 (407.27): C 61.93,
3 16 3
) δ (ppm) 149.7, 137.0, 136.5, 133.5, 132.9, 130.5, 120.5, 110.6, 103.5, 47.8. Elemental analysis: calcd (%) for C22H F N
1
9
H
2 2
15BrN O
4
-(1-Benzylindol-2-yl)benzonitrile (15): 1-Benzyl-3-chloroindole (0.242 g, 1
H 3.71; found: C 62.12, H 3.58.
mmol) and 4-cyanobenzenesulfonyl chloride (0.252 g, 1.25 mmol) affords 15
1
1
-Benzyl-3-bromo-2-(perfluorophenyl)indole (10): 1-Benzyl-3-bromoindole in 44% (0.136 g) yield. H NMR (300 MHz, CDCl
3
) δ (ppm) 7.70-7.63 (m, 3H),
(
0.286 g, 1 mmol) and 2,3,4,5,6-pentafluorobenzenesulfonyl chloride (0.333 7.51(d, J = 8.1 Hz, 2H), 7.29-7.15 (m, 6H), 7.00 (d, J = 7.2 Hz, 2H), 6.74 (s, 1H),
1
g, 1.25 mmol) affords 10 in 86% (0.388 g) yield. H NMR (400 MHz, CDCl
3
) δ 5.35 (s, 2H). This is a known compound and the spectral data are identical
33
(ppm) 7.68 (d, J = 7.4 Hz, 1H), 7.33-7.29 (m, 2H), 7.29-7.24 (m, 1H), 7.23-7.19 to those reported in literature.
13
(
m, 3H), 6.86 (ddd, J = 1.5, 3.1 and 5.9 Hz, 2H), 5.23 (s, 2H). C NMR (100
) δ (ppm) 144.9 (md, J = 251.2 Hz), 142.2 (md, J = 266.8 Hz), 137.8
md, J = 251.2 Hz), 137.1, 136.2, 128.8, 127.8, 127.0, 126.0, 124.3, 122.6,
1
-Benzyl-2-(4-bromophenyl)indole (16): 1-Benzyl-3-iodoindole (0.333 g, 1
MHz, CDCl
3
mmol) and 4-bromobenzenesulfonyl chloride (0.319 g, 1.25 mmol) affords
(
1
1
6 in 63% (0.228 g) yield. H NMR (400 MHz, CDCl
3
) δ (ppm) 7.71-7.67 (m,
1
21.1, 120.0, 110.6, 105.9 (t, J = 18.9 Hz), 95.7, 48.6. Elemental analysis:
N (452.22): C 55.78, H 2.45; found: C 55.98, H 2.38.
1
H), 7.53 (d, J = 8.5 Hz, 2H), 7.35-7.28 (m, 4H), 7.26-7.24 (m, 1H), 7.22-7.18
calcd (%) for C21H11BrF
5
(
m, 2H), 7l.18-7.14 (m, 1H), 7.03 (dd, J = 2.1 and 7.3 Hz, 2H), 6.67 (s, 1H),
13
1
-Benzyl-3-bromo-2-(2,3,4-trifluorophenyl)indole
(11):
3
1-Benzyl-3- 5.36 (s, 2H). C NMR (100 MHz, CDCl ) δ (ppm) 140.5, 138.2, 138.0, 131.7,
bromoindole (0.286 g, 1 mmol) and 2,3,4-trifluorobenzenesulfonyl chloride 131.6, 130.7, 128.8, 128.2, 127.3, 125.9, 122.4, 122.3, 120.7, 120.4, 110.5,
1
(
0.288 g, 1.25 mmol) affords 11 in 68% (0.283 g) yield. H NMR (400 MHz, 102.7, 47.8. Elemental analysis: calcd (%) for C21
H
16BrN (351.37): C 69.63, H
3
CDCl ) δ (ppm) 77.71-7.66 (m, 1H), 7.33-7.25 (m, 4H), 7.24-7.20 (m, 2H), 7.04 4.45; found: C 69.27, H 4.78.
(
dquint., J = 2.4 and 5.3 Hz, 2H), 6.88 (dd, J = 2.7 and 5.5 Hz, 2H), 5.34 (d, J =
13
1
-Benzyl-2-(4-iodophenyl)indole (17): 1-Benzyl-3-iodoindole (0.333 g, 1
1
1
6.8 Hz, 1H), 5.16 (d, J = 16.7 Hz, 1H). C NMR (100 MHz, CDCl
3
) δ (ppm)
mmol) and 4-iodobenzenesulfonyl chloride (0.378 g, 1.25 mmol) affords 17
51.9 (ddd, J = 3.9, 10.2 and 256.3 Hz), 149.6 (ddd, J = 3.9, 10.2 and 256.3
1
in 54% (0.221 g) yield. H NMR (400 MHz, CDCl
3
) δ (ppm) 7.72 (d, J = 8.2 Hz,
Hz), 140.3 (td, J = 14.7 and 247.9 Hz), 136.8, 136.6, 130.2, 128.7, 127.6,
2
H), 7.70-7.68 (m, 1H), 7.32-7.24 (m, 3H), 7.21-7.13 (m, 5H), 7.02 (d, J = 7.4
1
1
27.2, 126.7 (m), 126.0, 123.8, 121.0, 119.7, 116.1 (dd, J = 2.8 and 12.0 Hz),
12.4 (dd, J = 3.2 and 17.4 Hz), 110.6, 93.5, 48.4. Elemental analysis: calcd
13
Hz, 2H), 6.66 (s, 1H), 5.35 (s, 2H). C NMR (100 MHz, CDCl
3
) δ (ppm) 140.5,
38.2, 137.9, 137.7, 132.1, 130.8, 128.8, 128.2, 127.3, 125.8, 122.2, 120.6,
20.3, 110.5, 102.7, 93.9, 47.7. Elemental analysis: calcd (%) for C21
1
1
(%) for C21
H
13BrF
3
N (416.24): C 60.60, H 3.15; found: C 60.84, H 3.29.
H
16IN
1
-Benzyl-3-bromo-2-(3,4-difluorophenyl)indole (12):
1-Benzyl-3- (409.27): C 61.63, H 3.94; found: C 69.89, H 4.13.
bromoindole (0.286 g, 1 mmol) and 3,4-difluorobenzenesulfonyl chloride
1
1
-Benzyl-2-(3-(trifluoromethyl)phenyl)indole (18): 1-Benzyl-3-iodoindole
(
0.266 g, 1.25 mmol) affords 12 in 65% (0.259 g) yield. H NMR (400 MHz,
(
0.333 g, 1 mmol) and 3-(trifluoromethyl)benzenesulfonyl chloride (0.305 g,
CDCl
3
) δ (ppm) 7.90 (dddd, J = 2.4, 6.7, 9.0 and 15.5 Hz, 1H), 7.69-7.65 (m,
1
1
.25 mmol) affords 18 in 48% (0.169 g) yield. H NMR (400 MHz, CDCl
3
) δ
1
6
H), 7.44 (dt, J = 7.1 and 9.3 Hz, 1H), 7.34-7.19 (m, 6H), 7.17-7.13 (m, 1H),
13
(ppm) 7.71-7.66 (m, 2H), 7.59 (dd, J = 7.9 and 10.2 Hz, 2H), 7.49 (t, J = 7.7 Hz,
3
.97-6.89 (m, 2H), 5.29 (s, 2H). C NMR (100 MHz, CDCl ) δ (ppm) 150.6
1
H), 7.31-7.22 (m, 5H), 7.19 (d quint., J = 2.2 and 7.3 Hz, 2H), 7.01 (d, J = 7.1
(dd, J = 17.7 and 148.8 Hz), 150.0 (dd, J = 17.7 and 148.8 Hz), 137.2, 136.5,
6
| Org. Biomol Chem., 2016, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 9
Org aP nl ei ca s &e dB oi o nmo to al ed cj uu sl at rm Ca hr ge imn si stry
Org. Biomol. Chem.
ARTICLE
13
Hz, 2H), 6.71 (s, 1H), 5.35 (s, 1H). C NMR (100 MHz, CDCl
3
) δ (ppm) 140.0, 104.0, 47.8. Elemental analysis: calcd (%) for C22
H
15BrF
3
N (430.26): C 61.41,
View Article Online
DOI: 10.1039/C6OB00584E
1
1
1
C
38.3, 137.8, 133.5, 132.2, 131.0 (q, J = 31.5 Hz), 129.0, 128.8, 128.1, 127.4, H 3.51; found: C 61.75, H 3.87.
26.0 (q, J = 3.0 Hz), 125.8, 124.6 (q, J = 3.0 Hz), 123.9 (q, J = 266.9 Hz),
1
-Benzyl-2-(2,5-dibromophenyl)indole (24): 1-Benzyl-3-iodoindole (0.333 g,
22.5, 120.8, 120.4, 110.5, 103.3, 47.8. Elemental analysis: calcd (%) for
1
mmol) and 2,5-dibromobenzenesulfonyl chloride (0.418 g, 1.25 mmol)
22
H
16
F
3
N (351.37): C 75.20, H 4.59; found: C 75.59, H 4.42.
1
affords 24 in 67% (0.296 g) yield. H NMR (400 MHz, CDCl
3
) δ (ppm) 7.72 (d,
1
-Benzyl-2-(2,3,4-trifluorophenyl)indole (19):
1-Benzyl-3-chloroindole J = 7.7 Hz, 1H), 7.56 (d, J = 9.3 Hz, 1H), 7.43 (s, 1H), 7.32-7.27 (m, 4H), 7.27-
13
(0.242 g, 1 mmol) and 2,3,4-trifluorobenzenesulfonyl chloride (0.288 g, 1.25 7.17 (m, 4H), 6.92-6.88 (m, 2H), 5.24 (s, 2H). C NMR (100 MHz, CDCl
3
) δ
1
mmol) affords 19 in 67% (0.226 g) yield. H NMR (400 MHz, CDCl
3
) δ (ppm) (ppm) 137.8, 137.5, 136.9, 135.9, 135.6, 134.0, 133.0, 128.5, 127.8, 127.3,
7
7
1
.69 (dd, J = 1.5 and 7.7 Hz, 1H), 7.24-7.18 (m, 5H), 7.15 (t, J = 8.2 Hz, 1H), 126.3, 123.8, 122.3, 121.0, 120.8, 120.1, 110.4, 103.7, 47.8. Elemental
.07-6.98 (m, 1H), 6.98-6.92 (m, 1H), 6.9 (dd, J = 2.3 and 6.9 Hz, 2H), 6.68 (s, analysis: calcd (%) for C21 N (441.17): C 57.17, H 3.43; found: C 57.39, H
H
15Br
2
13
3
H), 5.27 (s, 2H). C NMR (100 MHz, CDCl ) δ (ppm) 151.2 (md, J = 256.3 3.91.
Hz), 149.3 (md, J = 256.3 Hz), 140.2 (md, J = 256.3 Hz), 137.7, 137.4, 132.6,
28.6, 128.0, 127.3, 126.0, 125.6 (m), 122.6, 120.9, 120.3, 118.4 (dd, J = 3.8
and 12.4 Hz), 112.1 (dd, J = 4.0 and 17.9 Hz), 110.6, 104.7, 47.9. Elemental
analysis: calcd (%) for C21 N (337.35): C 74.77, H 4.18; found: C 74.96, H
1
-Methyl 3-(1-benzylindol-2-yl)thiophene-2-carboxylate (25): 1-Benzyl-3-
1
iodoindole (0.333 g, 1 mmol) and methyl 3-(chlorosulfonyl)thiophene-2-
1
carboxylate (0.301 g, 1.25 mmol) affords 25 in 73% (0.254 g) yield. H NMR
14 3
H F
(400 MHz, CDCl
3
) δ (ppm) 7.69 (d, J = 7.7 Hz, 1H), 7.50 (d, J = 5.2 Hz, 1H),
4
.36.
7
.28 (t, J = 7.6 Hz, 2H), 7.25-7.11 (m, 4H), 7.01 (d, J = 5.0 Hz, 1H), 6.93 (d, J =
13
1
3
-Benzyl-2-(3,4-difluorophenyl)indole (20): 1-Benzyl-3-iodoindole (0.333 g, 2.8 Hz, 2H), 6.66 (s, 1H), 5.26 (s, 2H), 3.77 (s, 3H). C NMR (100 MHz, CDCl )
1
mmol) and 3,4-difluorobenzenesulfonyl chloride (0.266 g, 1.25 mmol) δ (ppm) 161.8, 138.4, 137.9, 137.2, 134.1, 132.2, 130.3, 128.4, 127.9, 127.1,
1
affords 20 in 62% (0.198 g) yield. H NMR (400 MHz, CDCl
3
) δ (ppm) 7.69- 126.3, 121.9, 120.7, 119.8, 110.4, 110.3, 103.4, 52.1, 47.7. Elemental
S (347.43): C 72.60, H 4.93; found: C 72.99,
7
6
2
1
1
.65 (m, 1H), 7.31-7.21 (m, 5H), 7.21-7.10 (m, 4H), 6.99 (d, J = 7.5 Hz, 2H), analysis: calcd (%) for C21
H
17NO
2
13
.63 (s, 1H), 5.34 (s, 2H). C NMR (100 MHz, CDCl
3
) δ (ppm) 150.3 (dm, J = H 5.13.
53.1 Hz), 150.5 (dm, J = 253.1 Hz), 139.4, 138.1, 137.7, 129.7 (t, J = 6.8 Hz),
28.9, 128.0, 127.4, 125.8, 125.3 (dd, J = 3.0 and 6.0 Hz), 122.4, 120.7,
20.4, 118.2 (d, J = 17.7 Hz), 117.4 (d, J = 17.3 Hz), 110.5, 103.0, 47.7.
1
-Benzyl-2-(4-bromo-2,5-dichlorothiophen-3-yl)indole (26): 1-Benzyl-3-
iodoindole (0.333 g, 1 mmol) and 4-bromo-2,5-dichlorothiophene-3-sulfonyl
1
chloride (0.301 g, 1.25 mmol) affords 26 in 58% (0.253 g) yield. H NMR (400
Elemental analysis: calcd (%) for C21
15 2
H F N (319.35): C 78.98, H 4.73; found:
MHz, CDCl
3
) δ (ppm) 7.77 (d, J = 7.7 Hz, 1H), 7.36 (dd, J = 1.6 and 7.5 Hz, 1H),
C 79.24, H 5.01.
7
.32-7.20 (m, 5H), 7.02-6.98 (m, 2H), 6.70 (s, 1H), 5.32 (d, J = 16.3 Hz, 1H),
13
1
3
-Benzyl-2-(2-fluorophenyl)indole (21): 1-Benzyl-3-chloroindole (0.242 g, 1 5.23 (d, J = 16.7 Hz, 1H). C NMR (100 MHz, CDCl ) δ (ppm) 137.2, 137.1,
mmol) and 2-fluorobenzenesulfonyl chloride (0.243 g, 1.25 mmol) affords 21 131.3, 130.5, 128.5, 127.8, 127.7, 127.4, 126.5, 123.6, 122.6, 121.2, 120.1,
1
in 66% (0.199 g) yield. H NMR (400 MHz, CDCl
3
) δ (ppm) 7.71-7.68 (m, 1H), 113.4, 110.5, 105.4, 48.0. Elemental analysis: calcd (%) for C19
H
12BrCl
2
NS
7
5
1
1
1
5
.42-7.34 (m, 2H), 7.25-7.14 (m, 8H), 6.95 (d, J = 7.5 Hz, 2H), 6.69 (s, 1H), (437.17): C 52.20, H 2.77; found: C 52.45, H 3.14.
13
3
.30 (s, 2H). C NMR (100 MHz, CDCl ) δ (ppm) 160.2 (d, J = 250.9 Hz),
3
,5-Dibromo-2-(4-bromophenyl)-1-methylindole (27): 3,5-Dibromo-1-
37.9, 137.6, 135.0, 132.4, 130.4 (d, J = 8.5 Hz), 128.6, 128.3, 127.1, 126.2,
24.2 (d, J = 2.8 Hz), 122.1, 120.7, 120.6, 120.1, 116.0 (d, J = 22.0 Hz), 110.6,
methylindole (0.289 g, 1 mmol) and 4-bromobenzenesulfonyl chloride
1
(0.319 g, 1.25 mmol) affords 27 in 57% (0.253 g) yield. H NMR (400 MHz,
04.0, 47.9. Elemental analysis: calcd (%) for C21H16FN (301.36): C 83.70, H
6 6
C D ) δ (ppm) 8.11 (s, 1H), 7.45 (dd, J = 2.0 and 8.7 Hz, 1H), 7.35 (d, J = 8.3
.35; found: C 83.99, H 5.18.
13
Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 6.66 (d, J = 8.7 Hz, 1H) , 2.73 (s, 3H). C NMR
-Benzyl-2-(2-nitrophenyl)indole (22): 1-Benzyl-3-chloroindole (0.242 g, 1 (100 MHz, C ) δ (ppm) 138.2, 136.2, 132.7, 132.2, 129.7, 129.0, 126.6,
1
6 6
D
mmol) and 2-nitrobenzenesulfonyl chloride (0.277 g, 1.25 mmol) affords 22 123.9, 122.8, 114.9, 112.0, 90.2, 31.2. Elemental analysis: calcd (%) for
1
in 38% (0.125 g) yield. H NMR (400 MHz, CDCl
3
) δ (ppm) 7.99-7.86 (m, 1H),
C
15 3
H10Br N (443.96): C 40.58, H 2.27; found: C 40.75, H 2.12.
7
6
.65 (d, J = 7.8 Hz, 1H), 7.57-7.51 (m, 2H), 7.37-7.33 (m, 1H), 7.25-7.12 (m,
13
3
,5-Dibromo-1-methyl-2-(4-(trifluoromethyl)phenyl)indole
(0.289 g, mmol)
(28):
and
3,5-
4-
H), 6.92 (dd, J = 2.9 and 5.5 Hz, 2H), 6.55 (s, 1H), 5.21 (s, 2H). C NMR (100
) δ (ppm) 150.0, 137.6, 137.5, 135.3, 133.5, 132.2, 129.6, 128.6,
28.0, 127.3, 126.3, 124.1, 122.4, 120.9, 120.2, 110.5, 103.3, 48.0.
Dibromo-1-methylindole
1
MHz, CDCl
3
(trifluoromethyl)benzenesulfonyl chloride (0.305 g, 1.25 mmol) affords 28 in
1
1
5
4% (0.234 g) yield. H NMR (400 MHz, C
6
D
6
) δ (ppm) 8.02 (s, 1H), 7.38-7.31
Elemental analysis: calcd (%) for C21
16 2 2
H N O (328.37): C 76.81, H 4.91; found:
13
(
m, 3H), 6.98 (d, J = 7.8 Hz, 2H), 6.56 (d, J = 8.9 Hz, 1H), 2.60 (s, 3H). C NMR
100 MHz, C ) δ (ppm) 137.7, 136.3, 134.1, 131.5, 130.8 (q, J = 29.8 Hz),
C 77.2, H 5.12.
(
6 6
D
1
-Benzyl-2-(2-bromo-4-(trifluoromethyl)phenyl)indole (23): 1-Benzyl-3- 129.6, 126.9, 125.8 (q, J = 4.0 Hz), 122.9, 120.6 (q, J = 259.1 Hz), 115.0,
chloroindole (0.242 g, mmol) and 2-bromo-4- 112.1, 90.7, 31.5. Elemental analysis: calcd (%) for C16 N (433.07): C
1
2 3
H10Br F
(
trifluoromethyl)benzenesulfonyl chloride (0.404 g, 1.25 mmol) affords 23 in 44.38, H 2.33; found: C 44.19, H 2.61.
1
6
=
4% (0.275 g) yield. H NMR (400 MHz, CDCl
3
) δ (ppm) 7.96 (s, 1H), 7.72 (d, J
3
,5-Dibromo-1-methyl-2-(2,3,4-trifluorophenyl)indole (29): 3,5-Dibromo-1-
7.5 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.3 (d, J = 7.3
methylindole (0.289 g, 1 mmol) and 2,3,4-trifluorobenzenesulfonyl chloride
Hz, 1H), 7.23 (dt, J = 0.9 and 7.1 Hz, 1H), 7.21-7.16 (m, 4H), 6.88-6.84 (m,
1
13
(0.288 g, 1.25 mmol) affords 29 in 52% (0.218 g) yield. H NMR (400 MHz,
2
1
1
3
H), 6.65 (s, 1H), 5.22 (s, 2H). C NMR (100 MHz, CDCl ) δ (ppm) 137.8,
6 6
C D ) δ (ppm) 7.97 (s, 1H), 7.32 (dd, J = 1.9 and 8.7 Hz, 1H), 6.52 (d, J = 8.7
37.5, 137.1, 133.1, 132.1 (q, J = 32.1 Hz), 129.8 (m), 128.6, 127.8, 127.3,
26.2, 125.4, 123.9 (m), 123.0 (q, J = 276.5 Hz), 122.5, 121.0, 120.3, 110.5,
Hz, 1H), 6.50-6.45 (m, 1H), 6.34 (ddt, J = 1.9, 7.1 and 9.3 Hz, 1H), 2.65 (s,
Org. Biomol Chem., 2016, 00, 1-3 | 7
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Page 8 of 9
ARTICLE
Org. Biomol. Chem.
13
13
3
H). C NMR (100 MHz, C
6 6
D
) δ (ppm) 152.4 (md, J = 249.1 Hz), 150.0 (md, 5.38 (s, 2H). C NMR (100 MHz, CDCl
3
) δ (ppm) 137.9, 137.2, 136.5, 135.8,
View Article Online
J = 249.1 Hz), 141.0 (td, J = 8.0 and 252.8 Hz), 136.2, 131.7, 129.4, 127.3 (m), 134.8, 134.3, 132.3, 130.3, 129.9, 129.3, 128.8, D12O8I.:71,01.12083.39,/C162O7.B30, 0152864.0E,
1
1
27.1, 123.0, 116.4 (dd, J = 4.8 and 12,1 Hz), 115.0, 112.8 (dd, J = 3.6 and 125.8, 122.7, 120.6, 119.8, 110.5, 47.6. Elemental analysis: calcd (%) for
7.5 Hz), 112.1, 91.9, 31.0. Elemental analysis: calcd (%) for C15
H
Br
8 2
F
3
N
C
27
H
20ClN (393.91): C 82.33, H 5.12; found: C 82.58, H 5.29.
(419.04): C 42.99, H 1.92; found: C 43.26, H 2.27.
1
-Benzyl-3-phenyl-2-(4-(trifluoromethyl)phenyl)indole (34): The reaction of
3
-Bromo-1-(2-bromobenzyl)indole (30): To a solution of 3-bromoindole (1 1-benzyl-3-bromo-2-(4-(trifluoromethyl)phenyl)indole (4) (0.215 g, 0.5
PO (0.212 g, 1 mmol)
NaH (0.25 g, 6.43 mmol, 1.25 mmol) at 0 ºC. The resulting mixture was at 80°C over 15 h in 1,4-dioxane (1 mL) in the presence of PdCl(C )(dppb)
g, 5.15 mmol, 1 equiv.) in DMF (10 ml) was added in small portions 60% oil mmol), phenylboronic acid (0.073 g, 0.6 mmol) and K
3
4
3 5
H
stirred at room temperature over 1 h before adding 2-bromobenzyl bromide (6 mg, 0.01 mmol) under argon affords, after evaporation of the solvent and
1
(
1.60 g, 6.43 mmol, 1.25 mmol). Then, the mixture was stirred at room purification on silica gel, product 34 in 84% (0.180 g) yield. H NMR (400
temperature for 4 h. The resulting solution was pourred in NH
4 3
Cl aqueous MHz, CDCl ) δ (ppm) 7.81 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 7.8 Hz, 2H), 7.35 (d, J
solution (100 ml). The mixture was extracted with three 100-ml. portions of = 8.8 Hz, 2H), 7.32-7.29 (m, 4H), 7.28-7.24 (m, 5H) 7.24-7.18 (2H), 7.01 (d, J =
13
diethyl ether, and each ether layer was washed with three 50-ml. portions 7.4 Hz, 2H), 5.29 (s, 2H). C NMR (100 MHz, CDCl
of water. The combined ether layers were dried over MgSO , and the 136.0, 134.5, 133.3 (q, J = 34.7 Hz), 131.2, 130.0, 128.8, 128.4, 128.1, 127.4,
solvent was removed under slightly reduced pressure. The crude mixture 127.3, 126.0, 125.9, 125.3 (q, J = 1.8 Hz), 123.6 (q, J = 275.1 Hz), 123.0,
3
) δ (ppm) 137.8, 137.3,
4
was purified by silica column chromatography to afford 30 in 89% yield (1.87 120.7, 119.9, 116.8, 110.5, 47.7. Elemental analysis: calcd (%) for C28
H
20
F
3
N
1
g). H NMR (400 MHz, C
6 6
D ) δ (ppm) 7.76 (d, J = 7.9 Hz, 1H), 7.26 (dd, J = 1.6 (427.47): C 78.67, H 4.72; found: C 78.98, H 4.49.
and 7.7 Hz, 1H), 7.12 (dd, J = 6.8 and 8.0 Hz, 1H), 7.03 (dd, J = 6.8 and 8.3 Hz,
H), 6.79 (d, J = 8.3 Hz, 1H), 6.59-6.49 (m, 2H), 6.47 (s, 1H), 6.14 (dd, J = 1.9
1
-Benzyl-3-(thiophen-3-yl)-2-(4-(trifluoromethyl)phenyl)indole (35): The
reaction of 1-benzyl-3-bromo-2-(4-(trifluoromethyl)phenyl)indole (4) (0.215
g, 0.5 mmol), thiophen-3-ylboronic acid (0.077 g, 0.6 mmol) and K PO
0.212 g, 1 mmol) at 80°C over 15 h in 1,4-dioxane (1 mL) in the presence of
PdCl(C )(dppb) (6 mg, 0.01 mmol) under argon affords, after evaporation
1
13
and 7.5 Hz, 1H), 4.70 (s, 2H). C NMR (100 MHz, C
6 6
D ) δ (ppm) 136.9, 136.6,
1
33.1, 129.5, 129.0, 127.9, 123.8, 122.5, 121.4, 120.2, 110.5, 91.4, 50.5.
3
4
(
2
Elemental analysis: calcd (%) for C15H11Br N (365.06): C 49.35, H 3.04; found:
3 5
H
C 49.59, H 2.81.
of the solvent and purification on silica gel, product 35 in 73% (0.158 g)
1
4
-(1-(2-Bromobenzyl)indol-2-yl)benzonitrile
(31):
3-bromo-1-(2- yield. H NMR (400 MHz, CDCl
3
) δ (ppm) 7.87 (d, J = 7.2 Hz, 1H), 7.59 (d, J =
bromobenzyl)indole (30) (0.365 g, 1 mmol) and 4-cyanobenzenesulfonyl 8.2 Hz, 2H), 7.4 (d, J = 8.2 Hz, 2H), 7.30-7.22 (m, 7H), 7.16 (d, J = 3.1 Hz, 1H),
1
13
chloride (0.252 g, 1.25 mmol) affords 31 in 62% (0.240 g) yield. H NMR 6.99 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 5.2 Hz, 1H), 5.38 (s, 2H). C NMR (100
400 MHz, C ) δ (ppm) 7.71 (d, J = 7.9 Hz, 1H), 6.32-7.29 (m, 1H), 7.20 (t, J MHz, CDCl ) δ (ppm) 137.7, 137.2, 136.0, 135.7, 134.6, 131.2, 130.3 (q, J =
7.5 Hz, 1H), 7.1 (dd, J = 6.9 and 8.5 Hz, 1H), 6.92 (d, J = 8.3 Hz, 2H), 6.82 (d, 32.1 Hz), 128.8, 128.6, 127.4, 125.9, 125.8, 125.3 (m), 125.0, 123.9 (q, J =
J = 8.6 Hz, 1H), 6.77 (d, J = 8.3 Hz, 2H ) 6.67-6.54 (m, 2H), 6.54 (s, 1H), 6.46- 279.5 Hz), 123.0, 121.7, 120.7, 120.0, 111.8, 110.5, 47.7. Elemental analysis:
(
D
6 6
3
=
1
3
6
1
1
.40 (m, 1H), 5.00 (s, 2H). C NMR (100 MHz, C
6 6
D
) δ (ppm) 140.0, 139.5, calcd (%) for C26
H
18
F
3
NS (433.49): C 72.04, H 4.19; found: C 71.89, H 3.96.
37.3, 136.7, 133.4, 132.7, 129.5, 129.1, 129.0, 128.5, 128.0, 124.0, 122.1,
21.8, 121.7, 118.9, 112.3, 111.2, 105.0, 49.0. Elemental analysis: calcd (%)
2
-(4-(Trifluoromethyl)phenyl)indole
trifluoromethyl)phenyl)indole (14) (0.181 g, 0.5 mmol) was dissolved in
DMSO (5 mL) and added to a flame-dried flask. While stirring the solution at
-Benzyl-2-(2-nitrophenyl)-3-phenylindole (32): The reaction of 1-benzyl-3- room temperature, tBuOK (0.280 g, 2.5 mmol) was added. The solution was
bromo-2-(2-nitrophenyl)indole (9) (0.204 g, 0.5 mmol), phenylboronic acid heated at 60 ºC, then oxygen was then bubbled into the solution over 2 h.
0.073 g, 0.6 mmol) and K PO (0.212 g, 1 mmol) at 80°C over 15 h in 1,4- The reaction was quenched with saturated ammonium chloride. The
dioxane (1 mL) in the presence of PdCl(C )(dppb) (6 mg, 0.01 mmol) under product was extracted three times with EtOAc. The organics were
(36): 1-Benzyl-2-(4-
(
2
for C22H15BrN (387.28): C 68.23, H 3.90; found: C 68.37, H 4.15.
1
(
3
4
3 5
H
argon affords, after evaporation of the solvent and purification on silica gel, combined, dried over Na
2
SO
4
and concentrated. The crude mixtuire was
1
1
product 32 in 81% (0.164 g) yield. H NMR (400 MHz, CDCl
3
) δ (ppm) 7.98 purified on silica gel to afford the product 36 in 92% (0.120 g) yield. H NMR
6
(dd, J = 1.8 and 7.8 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.55-5.45 (m, 2H), 7.34- (400 MHz, d -DMSO) δ (ppm) 11.72 (br, 1H), 8.07 (d, J = 8.3 Hz, 2H), 7.81 (d,
7
.17 (m, 12H), 7.00-6.97 (m, 2H), 5.39 (d, J = 16.7 Hz, 1H), 5.08 (d, J = 16.7 J = 8.3 Hz, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.17-7.13 (m,
13
3
Hz, 1H). C NMR (100 MHz, CDCl ) δ (ppm) 150.3, 137.4, 134.5, 134.1, 1H), 7.07 (s, 1H), 7.05-7.01 (m, 1H). This is a known compound and the
34
1
1
32.6, 132.3, 129.7, 129.4, 128.6, 128.3, 127.3, 127.1, 127.0, 126.3, 126.0, spectral data are identical to those reported in literature.
24.4, 122.8, 120.5, 119.9, 117.0, 110.4, 102.9, 48.0. Elemental analysis:
(404.47): C 80.18, H 4.98; found: C 80.35, H 5.17.
20 2 2
calcd (%) for C27H N O
Acknowledgements
1
-Benzyl-2-(4-chlorophenyl)-3-phenylindole (33): The reaction of 1-benzyl-
-bromo-2-(4-chlorophenyl)indole (5) (0.198 g, 0.5 mmol), phenylboronic
PO (0.212 g, 1 mmol) at 80°C over 15 h in
,4-dioxane (1 mL) in the presence of PdCl(C )(dppb) (6 mg, 0.01 mmol)
A. H. is grateful to “Université de Tunis El Manar” for a
research fellowship. We also thank the CNRS, “Rennes
Metropole” and French Scientific Ministry of Higher Education
for providing financial support.
3
acid (0.073 g, 0.6 mmol) and K
3
4
1
3 5
H
under argon affords, after evaporation of the solvent and purification on
1
silica gel, product 33 in 79% (0.156 g) yield. H NMR (400 MHz, CDCl
3
) δ
(
ppm) 7.81 (dd, J = 1.7 and 7.5 Hz, 1H), 7.32-7.28 (m, 4H), 7.28-7.19 (m, 7H),
Notes and references
7
.23-7.18 (m, 2H), 7.16 (d, J = 8.5 Hz, 2H), 7.00 (dd, J = 2.1 and 7.4 Hz, 2H),
8
| Org. Biomol Chem., 2016, 00, 1-3
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Org aP nl ei ca s &e dB oi o nmo to al ed cj uu sl at rm Ca hr ge imn si stry
Org. Biomol. Chem.
ARTICLE
1
. D. W. Zaharevitz, R. Gussio, M. Leost, A. M. Senderowicz, T. Lahusen, C. Campbell, E. B. Meyer and S. S. Stahl, Chem. Commun., 20V1ie1w, A4rt7ic,le1O02n5lin7e-
Kunick, L. Meijer and E. A. Sausville, Cancer Res., 1999, 59, 2566-2569. 10259.
. R. Plummer, P. Lorigan, N. Steven, L. Scott, M. R. Middleton, R. H. Wilson, 18. (a) F. Shibahara, T. Yamauchi, E. Yamaguchi and T. Murai, J. Org. Chem.,
E. Mulligan, N. Curtin, D. Wang, R. Dewji, A. Abbattista, J. Gallo and H. 2012, 77, 8815-8820; (b) S. Suzuki, Y. Segawa, K. Itami and J. Yamaguchi,
DOI: 10.1039/C6OB00584E
2
Calvert, Cancer Chemother. Pharmacol., 2013, 71, 1191-1199.
Nat Chem, 2015, 7, 227-233; (c) F. Abdelmalek, F. Derridj, S. Djebbar, J.-F.
Soulé and H. Doucet, Beilstein J. Org. Chem., 2015, 11, 2012-2020.
3
4
. D. M. Biskobing, Clin. Interv. Aging., 2007, 2, 299-303.
. (a) S. S. Labadie and E. Teng, J. Org. Chem., 1994, 59, 4250-4254; (b) R. L. 19. C.-H. Wong and S. C. Zimmerman, Chem. Commun., 2013, 49, 1679-1695.
20. X. Zhao, E. Dimitrijević and V. M. Dong, J. Am. Chem. Soc., 2009, 131,
. (a) N. Kudo, M. Perseghini and G. C. Fu, Angew. Chem., 2006, 118, 1304- 3466-3467.
306; (b) G. A. Molander, B. Canturk and L. E. Kennedy, J. Org. Chem., 2008, 21. M. Zhang, S. Zhang, M. Liu and J. Cheng, Chem. Commun., 2011, 47,
4, 973-980. 11522-11524.
. (a) Q.-D. Liu, M. S. Mudadu, R. Thummel, Y. Tao and S. Wang, Adv. Funct. 22. K. Yuan and H. Doucet, Chem. Sci., 2014, 5, 392-396.
Hudkins, J. L. Diebold and F. D. Marsh, J. Org. Chem., 1995, 60, 6218-6220.
5
1
7
6
Mater., 2005, 15, 143-154; (b) S.-F. Liu, Q. Wu, H. L. Schmider, H. Aziz, N.-X. 23. (a) L. Loukotova, K. Yuan and H. Doucet, ChemCatChem, 2014, 6, 1303-
Hu, Z. Popovic and S. Wang, J. Am. Chem. Soc., 2000, 122, 3671-3678; (c) Q. 1309; (b) A. Beladhria, K. Yuan, H. Ben Ammar, J.-F. Soulé, R. Ben Salem and
Liu, M. S. Mudadu, H. Schmider, R. Thummel, Y. Tao and S. Wang, H. Doucet, Synthesis, 2014, 46, 2515-2523.
Organometallics, 2002, 21, 4743-4749.
24. (a) F. Jafarpour, M. B. A. Olia and H. Hazrati, Adv. Synth. Catal., 2013,
7
. Y. Akita, A. Inoue, K. Yamamoto, A. Ohta, T. Kurihara and M. Shimizu, 355, 3407-3412; (b) R. Jin, K. Yuan, E. Chatelain, J.-F. Soulé and H. Doucet,
Heterocycles, 1985, 23, 2327-2333.
Adv. Synth. Catal., 2014, 356, 3831-3841.
8
7
. (a) F. Bellina, S. Cauteruccio and R. Rossi, Curr. Org. Chem., 2008, 12, 774- 25. A. Skhiri, A. Beladhria, K. Yuan, J.-F. Soulé, R. Ben Salem and H. Doucet,
90; (b) F. Kakiuchi and T. Kochi, Synthesis, 2008, 3013-3039; (c) L. Eur. J. Org. Chem., 2015, 4428-4436.
Ackermann, R. Vicente and A. R. Kapdi, Angew. Chem. Int. Ed., 2009, 48, 26. W. Hagui, K. Yuan, N. Besbes, E. Srasra, J.-F. Soulé and H. Doucet,
792-9826; (d) F. Bellina and R. Rossi, Chem. Rev., 2009, 110, 1082-1146; ChemCatChem, 2015, 7, 3544-3554.
e) F. Bellina and R. Rossi, Tetrahedron, 2009, 65, 10269-10310; (f) X. Chen, 27. A. Hfaiedh, K. Yuan, H. Ben Ammar, B. Ben Hassine, J.-F. Soulé and H.
K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem. Int. Ed., 2009, 48, 5094- Doucet, ChemSusChem, 2015, 8, 1794-1804.
115; (g) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147-1169; 28. B. Liégault, I. Petrov, S. I. Gorelsky and K. Fagnou, J. Org. Chem., 2010,
h) E. M. Beck and M. J. Gaunt, Top. Curr. Chem., 2010, 292, 85-121; (i) J. 75, 1047-1060.
9
(
5
(
Roger, A. L. Gottumukkala and H. Doucet, ChemCatChem, 2010, 2, 20-40; (j) 29. K. Müller, C. Faeh and F. Diederich, Science, 2007, 317, 1881-1886.
T. Satoh and M. Miura, Synthesis, 2010, 3395-3409; (k) C.-L. Sun, B.-J. Li and 30. B. Saoudi, A. Debache, J.-F. Soulé and H. Doucet, RSC Adv., 2015, 5,
Z.-J. Shi, Chem. Commun., 2010, 46, 677-685; (l) S. H. Cho, J. Y. Kim, J. Kwak 65175-65183.
and S. Chang, Chem. Soc. Rev., 2011, 40, 5068-5083; (m) N. Kuhl, M. N. 31. A. A. Haddach, A. Kelleman and M. V. Deaton-Rewolinski, Tetrahedron
Hopkinson, J. Wencel-Delord and F. Glorius, Angew. Chem. Int. Ed., 2012, 51, Lett., 2002, 43, 399-402.
1
0236-10254; (n) B.-J. Li and Z.-J. Shi, Chem. Soc. Rev., 2012, 41, 5588-5598; 32. T. Cantat, E. Génin, C. Giroud, G. Meyer and A. Jutand, J. Organomet.
(o) M. C. White, Synlett, 2012, 23, 2746-2748; (p) S. I. Kozhushkov and L. Chem., 2003, 687, 365-376.
Ackermann, Chem. Sci., 2013, 4, 886-896; (q) M. He, J.-F. Soulé and H. 33. D. Nandi, Y.-M. Jhou, J.-Y. Lee, B.-C. Kuo, C.-Y. Liu, P.-W. Huang and H. M.
Doucet, ChemCatChem, 2014, 6, 1824-1859; (r) R. Rossi, F. Bellina, M. Lessi Lee, J. Org. Chem., 2012, 77, 9384-9390.
and C. Manzini, Adv. Synth. Catal., 2014, 356, 17-117; (s) M. R. Yadav, R. K. 34. L. Ackermann, S. Barfüßer and H. K. Potukuchi, Adv. Synth. Catal., 2009,
Rit, M. Shankar and A. K. Sahoo, Asian J. Org. Chem., 2015, 4, 846-864; (t) K. 351, 1064-1072.
Yuan, J.-F. Soulé and H. Doucet, ACS Catal., 2015, 5, 978-991; (u) C. B.
Bheeter, L. Chen, J.-F. Soulé and H. Doucet, Catal. Sci. Technol., 2016, 6,
2
9
005-2049.
. (a) B. B. Touré, B. S. Lane and D. Sames, Org. Lett., 2006, 8, 1979-1982;
(b) F. Bellina, C. Calandri, S. Cauteruccio and R. Rossi, Tetrahedron, 2007, 63,
1
2
6
3
970-1980; (c) N. Lebrasseur and I. Larrosa, J. Am. Chem. Soc., 2008, 130,
926-2927; (d) L. Joucla and L. Djakovitch, Adv. Synth. Catal., 2009, 351,
73-714; (e) L. Joucla, N. Batail and L. Djakovitch, Adv. Synth. Catal., 2010,
52, 2929-2936; (f) T. C. Boorman and I. Larrosa, Progress in Heterocyclic
Chemistry, 2011, 22, 1-20; (g) L. Wang, W.-b. Yi and C. Cai, Chem. Commun.,
2
1
1
011, 47, 806-808; (h) S. Islam and I. Larrosa, Chem. Eur. J., 2013, 19, 15093-
5096.
0. (a) G. A. Molander and N. Ellis, Acc. Chem. Res., 2007, 40, 275-286; (b)
S. D. Yang, C. L. Sun, Z. Fang, B. J. Li, Y. Z. Li and Z. J. Shi, Angew. Chem., Halo-substituents at indolyl C3 position act as temporary blocking groups
2
008, 120, 1495-1498; (c) J. Zhao, Y. Zhang and K. Cheng, J. Org. Chem., allowing the regioselective formation of 2-arylindoles through a direct
2
008, 73, 7428-7431; (d) S. Kirchberg, R. Fröhlich and A. Studer, Angew. desulfitative arylation. This method allows to prepare a wide variety of
Chem., Int. Ed. Engl., 2009, 48, 4235-4238.
1. (a) N. R. Deprez, D. Kalyani, A. Krause and M. S. Sanford, J. Am. Chem.
indole derivatives in a few steps.
1
Soc., 2006, 128, 4972-4973; (b) D. T. D. Tang, K. D. Collins, J. B. Ernst and F.
Glorius, Angew. Chem. Int. Ed., 2014, 53, 1809-1813.
1
1
1
1
2. A. F. P. Biajoli, E. T. da Penha and C. R. D. Correia, RSC Advances, 2012, 2,
1930-11935.
3. Z. Liang, B. Yao and Y. Zhang, Org. Lett., 2010, 12, 3185-3187.
4. (a) M. Miyasaka, A. Fukushima, T. Satoh, K. Hirano and M. Miura, Chem.
Eur. J., 2009, 15, 3674-3677; (b) J. Zhou, P. Hu, M. Zhang, S. Huang, M.
Wang and W. Su, Chem. Eur. J., 2010, 16, 5876-5881.
1
5. M. Wu, J. Luo, F. Xiao, S. Zhang, G. J. Deng and H. A. Luo, Adv. Synth.
Catal., 2012, 354, 335-340.
1
3
1
1
6. T. Miao, P. Li, G. W. Wang and L. Wang, Chem. Asian J., 2013, 8, 3185-
190.
7. (a) D. R. Stuart, E. Villemure and K. Fagnou, J. Am. Chem. Soc., 2007, 129,
2072-12073; (b) S. Potavathri, K. C. Pereira, S. I. Gorelsky, A. Pike, A. P.
LeBris and B. DeBoef, J. Am. Chem. Soc., 2010, 132, 14676-14681; (c) A. N.
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