One-pot synthesis of 2,4-disubstituted indoles from N-tosyl-2,3- dichloroaniline using palladium-dihydroxyterphenylphosphine catalyst

Article abstract of DOI:10.1021/ol500711z

4-Chloroindoles were synthesized from readily available 2,3-dichloroaniline derivatives and terminal alkynes. The catalyst composed of palladium and dicyclohexyl(dihydroxyterphenyl)phosphine (Cy-DHTP) enabled ortho-selective Sonogashira coupling, and subsequent cyclization afforded 4-chloroindoles in high yields. This transformation was successfully applied to the one-pot synthesis of 2,4-disubstituted indoles via Suzuki-Miyaura coupling after indole formation.

Full text of DOI:10.1021/ol500711z

Letter
pubs.acs.org/OrgLett
One-Pot Synthesis of 2,4-Disubstituted Indoles from N‑Tosyl-2,3-
dichloroaniline Using Palladium−Dihydroxyterphenylphosphine
Catalyst
Miyuki Yamaguchi and Kei Manabe*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
S
* Supporting Information
ABSTRACT: 4-Chloroindoles were synthesized from readily
available 2,3-dichloroaniline derivatives and terminal alkynes.
The catalyst composed of palladium and dicyclohexyl-
(dihydroxyterphenyl)phosphine (Cy-DHTP) enabled ortho-
selective Sonogashira coupling, and subsequent cyclization
afforded 4-chloroindoles in high yields. This transformation
was successfully applied to the one-pot synthesis of 2,4-disubstituted indoles via Suzuki−Miyaura coupling after indole formation.
Scheme 1. Synthetic Strategies of 2,4-Disubstituted Indoles
from 2,3-Dihaloaniline Derivatives
he indole nucleus is a common heterocycle found in
1
Tbiologically active natural compounds and pharmaceut-
icals;2 accordingly, many synthetic methods for these
compounds have been developed owing to its ubiquity and
wide range of biological activities.3 Among the various
substitution patterns of the indole skeleton, indoles bearing
4-substitution, in particular, are challenging synthetic targets4
due to the scarcity of efficient synthetic methods for
introducing a substituent at the C-4 position of the indole
ring. The main synthetic strategy for 4-substituted indoles is
heteroannulation of substituted aromatic derivatives.5 A more
direct strategy, although less frequently used, is functionaliza-
tion at C-4, which often requires a directing group at the C-3
position.6 The synthesis of 4-haloindoles would be a promising
strategy to provide various 4-substituted indoles through
synthetic transformations such as cross-coupling.7 Recently, a
few methods for the catalytic synthesis of 4-haloindoles have
been reported.8 Among them, the Sonogashira coupling of 2,3-
dihaloanilines and terminal alkynes followed by cyclization and
subsequent cross-coupling is a promising route for synthesizing
2,4-disubstituted indoles.9 However, substrates are limited to
2,3-dihaloanilines bearing different halogen atoms in order to
achieve site-selective Sonogashira coupling at the position ortho
to the amino group in the first step (Scheme 1). In addition, the
presence of Br or I at the ortho position is crucial to achieving
high reactivities; however, such dihaloanilines require multistep
preparations. No examples of this sequential coupling/
cyclization transformation exist using commercially available
and inexpensive 2,3-dichloroaniline as the starting material. To
realize the reactions of 2,3-dichloroaniline, however, two
problems must be overcome: (i) the low reactivity of 2-
chloroanilines due to the strong electron-donating ability of the
amino group, which retards the turnover-limiting oxidative
addition step, and (ii) difficulty of the site-selective Sonogashira
coupling10 that enables the reaction at the electronically
deactivated and sterically hindered 2-chloro group.
We have previously reported the synthesis of benzofurans
from 2-chlorophenols and terminal alkynes using Pd catalysts
bearing hydroxyterphenylphosphine (HTP)11 with cyclohexyl
groups on the phosphorus atom (Cy-HTP, 1a) (Figure 1).12 In
addition, the use of a dihydroxyterphenylphosphine such as 1b
Figure 1. Hydroxylated terphenylphosphines.
Received: March 6, 2014
Published: April 17, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
(Cy-DHTP), shown to be much more effective than HTP for
ortho-selective cross-coupling,13 enabled the one-pot synthesis
of disubstituted benzofurans bearing substituents at different
positions using various dichlorophenols.14 This preliminary
success prompted us to investigate the synthesis of 2,4-
disubstituted indoles from 2,3-dichloroanilines. We expected
that the use of 1b would enable the synthesis of 4-chloroindoles
and subsequent cross-coupling to afford 2,4-disubstituted
indoles in one pot (Scheme 1). Herein, we present the Pd-
catalyzed sequential one-pot synthesis of 2,4-disubstituted
indoles from N-tosyl-2,3-dichloroaniline via Suzuki−Miyaura
(SM) coupling of 4-chloroindoles with boronic acids.
limiting oxidative addition of the C−Cl bond presumably
through mixed aggregate formation similar to that proposed for
ortho-selective cross-coupling.12−14 Mesitylene was also a good
solvent, affording product 4a at 140 °C in higher yield (entry
10).
We then applied the conditions developed above to the
synthesis of 4-chloroindoles from N-tosyl-2,3-dichloroaniline
(7) and alkynes (Table 2). To our delight, the reaction of 7
Table 2. Synthesis of Chloroindoles from N-Tosyl-2,3-
dichloroaniline
First, we searched for catalytic conditions that sufficiently
activate the chloro group ortho to the amino group using 2-
chloroaniline derivatives 2a−f and ethynylbenzene (3) as the
model substrates (Table 1). According to our previous work
Table 1. Indole Synthesis from 2-Chloroaniline Derivatives
alkyne
a
entry
R
equiv
yield (%)
1
2
3
Ph (3)
1.05
2
74
88
83
Ph (3)
C10H21 (8)
2
a
Isolated yield.
a
yield (%)
with 3 gave the desired product in good yield (entry 1). The
yield was improved to 88% by increasing the amount of alkyne
(entry 2). Aliphatic alkyne 8 could also be used in the reaction
(entry 3). In all these cases, the Sonogashira coupling
proceeded selectively at the o-chloro group, and the products
formed through Sonogashira coupling at the m-chloro group
were not observed. These results again demonstrate the
effectiveness of the Pd−1b catalyst for accelerating the reaction
at the electronically deactivated and sterically hindered position.
It should be mentioned that this catalytic system was also
applicable to N-tosyl-2,4- and 2,5-dichloroanilines to give the
corresponding 5- and 6-chloroindoles 11−14 in moderate to
high yields (Figure 2).
entry
R
cosolvent
4a−f
5a−f
b
1
2
3
4
5
6
Ts (2a)
H (2b)
Ac (2c)
Ms (2d)
H2O
H2O
H2O
H2O
H2O
H2O
−
68
nd
nd
b
b
b
nd
c
nd (12)
trace
23
b
nd
d
b
b
Ns (2e)
nd
nd
b
b
Boc (2f)
Ts (2a)
Ts (2a)
Ts (2a)
nd
nd
e
7
trace
25
38
8
MeOH
trace
f
b
9
H2O
11
nd
g
h
b
10
Ts (2a)
H2O
87
nd
a
b
c
d
Isolated yield. Not detected. Yield of 2-phenyl-1H-indole (6). 2-
Nitrobenzenesulfonyl. t-BuOLi (3.6 equiv), 19 h. 1a instead of 1b.
Mesitylene instead of toluene, 140 °C, 2 h. Reflux, 1 h.
e
f
g
h
toward benzofurans,14 the Sonogashira coupling was conducted
using Pd−1b catalyst in the presence of t-BuOLi as a base.
Toluene was used as the solvent, and water was added as
cosolvent after the Sonogashira coupling step to promote
cyclization14 of the intermediate, 2-alkynylaniline derivative 5.
Among the 2-chloroaniline derivatives tested, N-tosylaniline 2a
gave the desired indole 4a in good yield (entry 1).15 2-
Chloroaniline (2b) did not afford the product (entry 2). When
N-acetylated 2c was used, deacylated indole 6 was obtained in
low yield along with Sonogashira coupling product 5c (entry
3). Other protecting groups (2d−f) were not suitable for this
reaction (entries 4−6). A cosolvent is necessary to cyclize 2-
alkynylaniline 5; without the addition of water, cyclization of 5
did not proceed (entry 7). Methanol did not work well as the
cosolvent for cyclization (entry 8). The use of monohydrox-
yterphenylphosphine 1a instead of 1b resulted in a low yield of
the product (entry 9). In the case of other ligands commonly
used in the cross-coupling of chloroarenes (such as PCy3 or
XPhos16), Sonogashira coupling did not proceed at all, and 2a
was fully recovered.17 These results clearly demonstrate the
effectiveness of ligand 1b, which accelerates the turnover-
Figure 2. Synthesis of 5- and 6-chloroindoles under the conditions
shown in Table 2, entries 2 and 3. Alkyne 1.05 equiv, mesitylene
instead of toluene, 140 °C, 2 h; H2O, reflux, 1.5 h.
a
Next, we turned our attention to the transformation of the
chloro group of 4-chloroindole 9 by SM coupling, a highly
versatile carbon−carbon bond-forming method.18 Compound 9
was coupled with boronic acid 15 using Pd−1b catalyst in the
presence of K3PO4 as a base (Scheme 2). As expected, the
reaction proceeded smoothly to give desired 2,4-disubstituted
indole 16 in quantitative yield.19
With the optimized reaction conditions in hand, we
investigated the sequential one-pot synthesis of 2,4-disubsti-
tuted indole 16 from dichloroaniline 7, alkyne 3, and boronic
acid 15 (Table 3). We expected that the Pd−1b catalyst would
enable 4-chloroindole formation and subsequent SM cross-
coupling in one pot. First, the reaction was carried out by
combining the reaction conditions developed above. Unfortu-
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Organic Letters
Letter
Scheme 2. Suzuki−Miyaura Coupling of 4-Chloroindole
Table 3. One-Pot Synthesis of 2,4-Disubstituted Indole
a
yield (%)
entry
TBAX (equiv)
16
9
b
1
2
−
nd
29
13
1
15
19
TBAC (2)
Figure 3. Substrate scope. Conditions: (i) alkyne (2 equiv),
PdCl2(CH3CN)2 (2 mol %), 1b·HBF4 (4 mol %), t-BuOLi (2.4
equiv), toluene, reflux, 3 h; (ii) H2O, reflux, 3 h; (iii) boronic acid (2
equiv), K3PO4 (3 equiv), TBAC (0.5 equiv), reflux, 12 h. bBoronic acid
(3 equiv), K3PO4 (4.5 equiv), SM coupling 20 h. cAlkyne (1.05 equiv).
c
3
−
4
c
4
TBAC (2)
TBAC (1)
TBAC (0.5)
TBAC (0.25)
TBAB (0.25)
TBAOH (0.25)
2
5
6
7
8
9
16
52
61
49
24
69
41
11
<10
<10
25
d
d
synthesis of 2,4-disubstituted indoles via 4-chloroindole
formation followed by subsequent SM coupling. This work
provides a facile synthetic route for indoles with the less
explored 4-substitution pattern.
e
10
TBAC (0.5)
trace
a
b
c
Isolated yield. Not detected. XPhos (4 mol %) was added at the
d
e
1
beginning. Determined by H NMR. Alkyne (2 equiv).
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
nately, SM coupling did not proceed at all and 4-chloroindole 9
remained (entry 1). After a screening of additives, quaternary
ammonium salts were found to be effective for promoting the
SM coupling step.20 We assume that quaternary ammonium
salts work as a phase-transfer agent and transport boronic acid
back to the organic phase. The use of tetra-n-butylammonium
chloride (TBAC) afforded desired product 16 with an amount
of unreacted 9 (entry 2). When a two-ligand system consisting
of 1b and XPhos (effective in our benzofuran synthesis14) was
used, the yield of 16 was not improved (entries 3 and 4).
Decreasing the amount of TBAC gave better results (entries 5−
7). Examining the counteranions bromide and hydroxide gave
the product in moderate yields (entries 8 and 9). Finally,
conditions using 2 equiv of alkyne 3 and 0.5 equiv of TBAC led
to the best yield (69%) of 16 (entry 10).
The scope and generality of this method was next examined
by using various alkynes and boronic acids (Figure 3). Both
alkyl- and arylalkynes afforded the corresponding products (16,
21−23, and 31) in moderate to high yield. Phenylboronic acid
having either an electron-donating or electron-withdrawing
group at the para position reacted well (16−19, 23−26).
Ortho- or meta-substituted phenylboronic acid also gave the
corresponding 2,4-disubstituted indoles (27, 28) in good yield.
3-Thienyl (20, 29) and alkenyl (30) groups could also be
introduced.
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: manabe@u-shizuoka-ken.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partly supported by Grants-in-Aid for Young
Scientists (B) (Grant No. 24750036) from the Japan Society
for the Promotion of Science (JSPS) and Platform for Drug
Discovery, Informatics, and Structural Life Science from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan. We thank Haruka Katsumata (University of
Shizuoka) for the initial experiments and Kohei Suzuki
(University of Shizuoka) for the preparation of ligand 1b.
REFERENCES
■
(1) Bronner, S. M.; Im, G.-Y. J.; Garg, N. K. In Heterocycles in Natural
Product Synthesis; Majumdar, K. C., Chattopadhyay, S. K., Eds.; Wiley-
VCH: Weinheim, 2011; p 221.
(2) (a) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev.
2010, 110, 4489. (b) Sharma, V.; Kumar, P.; Pathak, D. J. Heterocycl.
Chem. 2010, 47, 491. (c) Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar,
N.; Kim, C. H.; Verma, A. K.; Choi, E. H. Molecules 2013, 18, 6620.
In summary, we have developed an efficient synthetic
method toward 4-chloroindoles from readily available 2,3-
dichloroaniline derivatives and terminal alkynes using the
dihydroxyterphenylphosphine-based catalyst Pd−1b. This
catalytic system was successfully applied to the one-pot
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(3) (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
(b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (c) Humphrey,
G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (d) Barluenga, J.;
F.; Desmurs, J.-R.; Schlama, T. J. Mol. Catal. A: Chem. 2002, 182−183,
481. (c) Amadio, E.; Scrivanti, A.; Bortoluzzi, M.; Bertoldini, M.;
Beghetto, V.; Matteoli, U.; Chessa, G. Inorg. Chim. Acta 2013, 405,
188.
Rodríguez, F.; Fananas
́
, F. J. Chem.Asian J. 2009, 4, 1036.
̃
(e) Inman, M.; Moody, C. J. Chem. Sci. 2013, 4, 29.
(4) (a) Kozikowski, A. P. Heterocycles 1981, 16, 267. (b) Schwarzer,
D. D.; Gritsch, P. J.; Gaich, T. Synlett 2013, 24, 1025.
(5) For example: (a) Tidwell, J. H.; Buchwald, S. L. J. Am. Chem. Soc.
1994, 116, 11797. (b) Stoll, A. H.; Knochel, P. Org. Lett. 2008, 10,
113.
(6) Selected examples: (a) Somei, M.; Yamada, F.; Kunimoto, M.;
Kaneko, C. Heterocycles 1984, 22, 797. (b) Iwao, M. Heterocycles 1993,
36, 29. (c) Brown, M. A.; Kerr, M. A. Tetrahedron Lett. 2001, 42, 983.
(d) Chauder, B.; Larkin, A.; Snieckus, V. Org. Lett. 2002, 4, 815.
(e) Davies, H. M. L.; Manning, J. R. J. Am. Chem. Soc. 2006, 128, 1060.
(f) Liu, Q.; Li, Q.; Ma, Y.; Jia, Y. Org. Lett. 2013, 15, 4528. (g) Lanke,
V.; Prabhu, K. R. Org. Lett. 2013, 15, 6262. (h) Gritsch, P. J.; Leitner,
C.; Pfaffenbach, M.; Gaich, T. Angew. Chem., Int. Ed. 2014, 53, 1208.
(7) (a) Harrington, P. J.; Hegedus, L. S. J. Org. Chem. 1984, 49, 2657.
(b) Kalinin, A. V.; Chauder, B. A.; Rakhit, S.; Snieckus, V. Org. Lett.
2003, 5, 3519.
(8) (a) Watanabe, M.; Yamamoto, T.; Nishiyama, M. Angew. Chem.,
Int. Ed. 2000, 39, 2501. (b) Willis, M. C.; Brace, G. N.; Findlay, T. J.
K.; Holmes, I. P. Adv. Synth. Catal. 2006, 348, 851. (c) Taber, D. F.;
Tian, W. J. Am. Chem. Soc. 2006, 128, 1058. (d) Sanz, R.; Escribano, J.;
Pedrosa, M. R.; Aguado, R.; Arnai
́
z, F. J. Adv. Synth. Catal. 2007, 349,
, C. J. Am.
713. (e) Barluenga, J.; Jimenez-Aquino, A.; Aznar, F.; Valdes
́
́
Chem. Soc. 2009, 131, 4031. (f) Stokes, B. J.; Liu, S.; Driver, T. G. J.
Am. Chem. Soc. 2011, 133, 4702. (g) Wang, Y.-Z.; Ye, L.-W.; Zhang, L.-
M. Chem. Commun. 2011, 47, 7815. (h) Huleatt, P. B.; Lau, J.; Chua,
S.; Tan, Y. L.; Duong, H. A.; Chai, C. L. L. Tetrahedron Lett. 2011, 52,
1339. (i) Flanagan, J. C. A.; Dornan, L. M.; McLaughlin, M. G.;
McCreanor, N. G.; Cook, M. J.; Muldoon, M. J. Green Chem. 2012, 14,
1281.
(9) (a) Sanz, R.; Guilarte, V.; García, N. Org. Biomol. Chem. 2010, 8,
3860. (b) Guilarte, V.; Castroviejo, M. P.; García-García, P.;
Fernan
́
dez-Rodríguez, M. A.; Sanz, R. J. Org. Chem. 2011, 76, 3416.
(10) Reviews of site-selective cross coupling: (a) Schroter, S.; Stock,
̈
C.; Bach, T. Tetrahedron 2005, 61, 2245. (b) Fairlamb, I. J. S. Chem.
Soc. Rev. 2007, 36, 103. (c) Wang, J.-R.; Manabe, K. Synthesis 2009,
1405.
(11) (a) Ishikawa, S.; Manabe, K. Chem. Lett. 2007, 36, 1302.
(b) Ishikawa, S.; Manabe, K. Chem. Lett. 2007, 36, 1304. (c) Ishikawa,
S.; Manabe, K. Org. Lett. 2007, 9, 5593. (d) Manabe, K.; Ishikawa, S.
Chem. Commun. 2008, 3829. (e) Ishikawa, S.; Manabe, K. Tetrahedron
2010, 66, 297.
(12) Wang, J.-R.; Manabe, K. J. Org. Chem. 2010, 75, 5340.
(13) (a) Ishikawa, S.; Manabe, K. Angew. Chem., Int. Ed. 2010, 49,
772. (b) Ishikawa, S.; Manabe, K. Tetrahedron 2011, 67, 10156.
(14) Yamaguchi, M.; Katsumata, H.; Manabe, K. J. Org. Chem. 2013,
78, 9270.
(15) An early example of the use of an N-sulfonylaniline for indole
synthesis: Sakamoto, T.; Kondo, Y.; Iwashita, S.; Nagano, T.;
Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 1305.
(16) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(17) For details of optimization studies, see Tables S1 and S2
(Supporting Information).
(18) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
Examples of SM coupling of 4-chloroindole: (b) Tanaka, M.; Li, X.;
Hikawa, H.; Suzuki, T.; Tsutsumi, K.; Sato, M.; Takikawa, O.; Suzuki,
H.; Yokoyama, Y. Bioorg. Med. Chem. 2013, 21, 1159. (c) Tichy, M.;
́
̌ ́
Pohl, R.; Tloust’ova, E.; Weber, J.; Bahador, G.; Lee, Y.-J.; Hocek, M.
Bioorg. Med. Chem. 2013, 21, 5362.
(19) SM coupling also proceeded quantitatively when XPhos was
used as the ligand.
(20) Selected examples of uses of quaternary ammonium salts for SM
coupling: (a) Badone, D.; Baroni, M.; Cardamone, R.; Ielmini, A.;
Guzzi, U. J. Org. Chem. 1997, 62, 7170. (b) Castanet, A.-S.; Colobert,
2389
dx.doi.org/10.1021/ol500711z | Org. Lett. 2014, 16, 2386−2389