Palladium on carbon-catalyzed synthesis of 2- and 2,3-substituted indoles under heterogeneous conditions

Article abstract of DOI:10.1039/c004939e

A mild, efficient and LiCl-free synthetic method for indole derivatives based on the heteroannulation of alkynes with 2-iodoanilines was achieved using palladium on carbon (Pd/C) and NaOAc in heated NMP. The N-tosyl protection of 2-iodoaniline expedited the reaction progress, while other protecting groups, such as tert-butoxycarbonyl, acetyl, and benzyloxycarbonyl groups, underwent deprotection under the present conditions. A variety of di- and monosubstituted alkynes could effectively react with N-tosyl-2-iodoaniline to give the corresponding indoles in good to high yields. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c004939e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Palladium on carbon-catalyzed synthesis of 2- and 2,3-substituted indoles
under heterogeneous conditions†
Yasunari Monguchi,a Shigeki Mori,a Satoka Aoyagi,a Azusa Tsutsui,a Tomohiro Maegawaa,b and
Hironao Sajiki*a
Received 7th April 2010, Accepted 18th May 2010
First published as an Advance Article on the web 4th June 2010
DOI: 10.1039/c004939e
A mild, efficient and LiCl-free synthetic method for indole derivatives based on the heteroannulation of
alkynes with 2-iodoanilines was achieved using palladium on carbon (Pd/C) and NaOAc in heated
NMP. The N-tosyl protection of 2-iodoaniline expedited the reaction progress, while other protecting
groups, such as tert-butoxycarbonyl, acetyl, and benzyloxycarbonyl groups, underwent deprotection
under the present conditions. A variety of di- and monosubstituted alkynes could effectively react with
N-tosyl-2-iodoaniline to give the corresponding indoles in good to high yields.
reusability, and avoidance of residual metals in the desired
products.11 Palladium on carbon (Pd/C), which has been most
Introduction
commonly used as a heterogeneous hydrogenation catalyst,12 was
recently utilized for various kinds of carbon–carbon,13,14 carbon–
nitrogen,15 and carbon–oxygen16 bond forming reactions.
There are a few reports of 2-substituted indole syntheses from
monosubstituted alkynes using non-commercially heterogeneous
palladium17,18 or palladium–copper19 catalysts together with LiCl
as an additive, and only Djakovitch’s method does not require the
addition of LiCl.18,19 During the preparation of this manuscript,
an attractive annulation method using disubstituted alkynes
catalyzed by heterogeneous palladium species including Pd/C was
reported as a communication.20
The indole nucleus is one of the most prevalent heterocyclic
structural motifs found in biologically active compounds from
either natural or artificial origin.1 A variety of synthetic methods
to build the indole ring system has been developed for over
a hundred years,1,2 and the palladium-catalyzed annulation of
2-haloanilines with alkynes, in particular, is of great importance
due to the availability of substrates, the tolerance of a wide range
of functionalities, and a simple one-pot procedure (Scheme 1).3–10
Monosubstituted alkynes were first used for the annulation in
the presence of Pd(PPh3)2Cl2, CuI, and Et3N by Yamanaka to
directly afford the corresponding 2-substituted indole derivatives
through a domino Sonogashira coupling–cyclization process,3,4
while Larock used disubstituted alkynes together with Pd(OAc)2,
LiCl, and K2CO3 to obtain 2,3-disubstituted indoles in a highly
regioselective manner.5,6 Such annulation reactions have been
successfully applied to the synthesis of azaindoles,7 tryptophan
derivatives,8 bioactive materials,9,10 and natural products.10
In this paper, we describe an efficient and general protocol for
the LiCl-free Pd/C-catalyzed Yamanaka–Larock indole synthe-
sis using 2-iodoaniline derivatives and mono- or disubstituted
alkynes. The use of the base and alkyne were successfully reduced.
Results and discussion
We first investigated the 10% Pd/C-catalyzed Larock annula-
tion using various N-substituted 2-iodoanilines and 2 equiv of
diphenylacetylene in the presence of 1 equiv of LiCl and 5
equiv of Na2CO3 in heated 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone (DMPU) (Table 1). Without the N-substituent, the
reaction proceeded to give the corresponding 2,3-diphenylindole
(3), and the yield was improved to 67% by increasing the
temperature from 100 ◦C to 120 ◦C (Entries 1 and 2). When
N-Boc-2-iodoaniline (1b) was used as the substrate, the complete
deprotection of the Boc moiety was observed, and the correspond-
ing non-N-substituted indole 3 was obtained in 77% yield as
the sole product at 120 ◦C (Entry 4). The N-acetyl and N-Cbz
protective groups of 2-iodoanilines (1c and 1d) were also found
to be labile under the present conditions (Entries 5 and 6). To
avoid the removal of the substituents, N-tosyl-2-iodoaniline (1e)
was chosen as the substrate.21 Thus, the annulation proceeded
without decomposition of the tosylamide moiety (Entry 7), and
the desired N-tosylindole (2e) was afforded in quantitative yield
at 120 ◦C (Entry 8).
Scheme 1 Palladium-catalyzed annulation of 2-haloaniline derivatives
with alkynes.
The useofheterogeneous catalysts has recentlybeen investigated
in a variety of organic chemical fields from sustainable and
industrial standpoints due to their air-stability, recoverability,
aLaboratory of Organic Chemistry, Department of Organic and Medicinal
Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-
1196, Japan
bCurrent address: Graduate School of Pharmaceutical Sciences, Osaka
University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
† Electronic supplementary information (ESI) available: Compound
characterization data and 1H and 13C NMR spectra. See DOI:
10.1039/c004939e
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Table 1 Pd/C-catalyzed annulation of N-substituted 2-iodoanilines and
diphenylacetylene
Table 3 Pd/C-catalyzed annulation of alkynes with N-tosyl-2-
iodoaniline (1e)
Yield (%)
Entry
R1
R2
Time/h
Yield (%)a
Entry
R1
Temp./◦C
2
3
1
2
Et
Et
24
7
6
24
3
8
97 (2g)
1
2
3
4
5
6
7
8
H (1a)
100
120
100
120
100
100
100
120
—
—
55 (2b)
0
15 (2c)
0
46 (2e)
46
67
34
77
33
64
0
n-Pr
n-Pr
C5H11
C5H11
Ph
Ph
H
H
H
n-Bu
n-Bu
Me
Me
n-Pr
n-Pr
C5H11
C5H11
Ph
Ph
Ph
Ph
n-Bu
Ph
96 (2h)
H (1a)
3b
90 (2h)
Boc (1b)
Boc (1b)
Ac (1c)
Cbz (1d)
Ts (1e)
4
100 (2f)
5b
100 (2f)
6c
69 (2e)
7b,c
8
8
94 (2e)
12
12
2
24
24
10
2
69 (2i)
Ts (1e)
100 (2e)
0
9b
70 (2i)
10b
11
12b
13
14b
92 (89 : 11) d(2j)
90 (72 : 28) d(2k)
84 (77 : 23) d(2k)
84 (64 : 36) d(2l)
90 (68 : 32) d(2l)
Table 2 Screening of bases and solvents for the Pd/C-catalyzed annula-
tion using N-tosyl-2-iodoaniline (1e) and 6-dodecynea
Ph
Ph
Ph
a Isolated yield. b LiCl was not added. c 2.0 equiv of alkynes were used.
d The ratio of 2 and its regioisomer is indicated in parentheses.
kinds of polar aprotic solvents, such as DMPU, DMF, NMP, and
DMA, without any influence of the solvent grades (Entries 11–15).
A wide range of alkynes (3 equiv to 1e) was examined for the
preparation of the indole derivatives using 10% Pd/C (5 mol%),
LiCl (1 equiv), and NaOAc (5 equiv) in heated NMP (120 ◦C). The
reactions of symmetrical dialkylacetylenes gave the corresponding
2,3-disubstituted indoles (2e–2g) in good to quantitative yields,
regardless of the alkyl chain length (Table 3, Entries 1, 2, 4, and 6).
Phenylacetylene, a monosubstituted acetylene, was cyclized in a
completely regioselective manner to give N-tosyl-2-phenylindole
(2i) as the sole product (Entry 8), while the use of 1-hexyne gave
a mixture of regioisomers, i.e., the 2- and 3-butyl-1-tosylindoles
in the ratio of 89 : 11 (Entry 10). This result indicates that the
pathway for the indole formation from monosubstituted alkynes
would be the same as the proposed mechanism for the synthesis of
2,3-disubstituted indoles from the disubstituted alkynes by
Larock, which involves the insertion of an alkyne into the arene–
palladium bond to form the vinylic palladium intermediate,5
although the two step process including the Sonogashira coupling
process could not be thoroughly excluded (Scheme 2).3,4,23 Unsym-
metrical disubstituted acetylenes, such as 1-phenyl-1-hexyne and
1-phenyl-1-propyne, were also smoothly cyclized, but a complete
regioselectivity was not achieved (Entries 11 and 13). During the
investigation of the annulation using a variety of alkynes, we found
that LiCl was not essential for the efficient reaction progress; the
reaction effectively proceeded in the absence of LiCl (Entries 3, 5,
7, 9, 10, 12, and 14).
Yield (%)b
Entry
Base
Solventa
2f
Recovered 1e
c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Na2CO3
K2CO3
Cs2CO3
DMPU
DMPU
DMPU
DMPU
DMPU
DMF
—
0
0
70
69
0
0
0
0
0
0
0
18
17
25
100
100
65
Na3PO4·12H2O
KOAc
KOAc
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
DMPU
DMF
98
DMFd
NMP
100
100
100
100
100
100
100
DMPU
DMF
0
0
0
0
DMFd
NMPd
DMAd
a Reagent grade solvent was used unless mentioned. b Isolated yield. c The
generation of 2f was observed in the reaction mixture. d A commercial
anhydrous solvent was used.
We next examined the indole synthesis using 1e and 6-dodecyne,
a dialkylacetylene. Although the formation of the corresponding
indole was obtained, it was quite difficult to isolate from the
reaction mixture containing byproducts, which were generated by
polymerization of the alkynes (Table 2, Entry 1).22 The base and
solvent, therefore, were optimized using 10% Pd/C (5 mol%) and
LiCl (1 equiv) to avoid the formation of any intractable byproducts.
When K2CO3, Cs2CO3, or Na3PO4·12H2O was used as the base, the
desired N-tosyl-2,3-dipentylindole (2f) was obtained in low yields
(Entries 2–4). The reaction was dramatically improved by the use
of KOAc in DMPU or DMF, although the polymerization of
6-dodecyne was still observed (Entries 5 and 6). On the other hand,
the use of either NaHCO3 or NaOAc led to the clean formation of
2f (Entries 7–15), and NaOAc could be successfully used in various
Decreased amounts of the alkyne, NaOAc, and 10% Pd/C
were next investigated using 1e and 1-phenyl-1-propyne as the
substrates from an environmental point of view (Table 4).
The amount of the 1-phenyl-1-propyne could be decreased to
1.2 equiv to 1e without any significant reduction in the indole
production, although the reaction progression was significantly
delayed (Entries 1 and 2). Lowering the temperature from 120 to
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Table 4 Optimization of the LiCl-free conditions
Entry
Alkyne (equiv)
NaOAc (equiv)
10% Pd/C (mol%)
Temp./◦C
Time/h
Yield (%)a
1
2
3.0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
5.0
5.0
5.0
5.0
1.5
1.1
1.0
0.7
1.1
1.1
1.1
1.1
1.1
1.1
1.1
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
4.0
3.0
2.0
1.0
0.5
3.0
3.0
120
120
110
100
110
110
110
110
110
110
110
110
110
110
110
2
24
24
24
24
24
24
24
24
24
24
24
24
8
90 (68 : 32)
91 (73 : 27)
94 (71 : 29)
56 (62 : 38)
88 (71 : 29)
91 (72 : 28)
84 (71 : 29)
63 (73 : 27)
97 (71 : 29)
99 (70 : 30)
88 (72 : 28)
63 (67 : 33)
0
3
4b
5
6
7c
8d
9
10
11e
12f
13
14
15g
79 (71 : 29)
100 (73 : 27)
12
a Yield as a mixture of 3-methyl-2-phenyl-1-tosylindole (2l) and its regioisomer (2-methyl-3-phenyl-1-tosylindole). The ratio of the regioisomers is indicated
in parentheses. b 1e was recovered in 18% yield. c 1e was observed in the TLC analysis. d 1e was recovered in 28% yield. e 1e was recovered in 12% yield.
f 1e was recovered in 37% yield. g Compounds 2l and its regioisomer were isolated in 52% and 23% yields, respectively, using preparative TLC.
Table 5 Pd/C-catalyzed annulation using the N-tosyl-2-iodoaniline derivatives and alkynes
N-Ts-2-iodoaniline (1)
Alkyne
R1
Entry
R
R2
Temp./◦C
Time/h
Yield (%)a
1
2
3
H (1e)
H (1e)
H (1e)
H (1e)
H (1e)
H (1e)
H (1e)
H (1e)
H (1e)
H (1e)
H (1e)
MeO2C (1f)
C5H11
C5H11
C4H9
n-Pr
Ph
H
H
H
H
H
H
C5H11
C5H11
C4H9
n-Pr
Ph
4-MeO-Ph
3-Me-Ph
4-Me-Ph
1-naphthyl
6-MeO-naphth-2-yl
1-cyclohexenyl
C5H11
110
120
120
120
130
120
120
120
120
120
120
120
12
3
6
24
24
24
24
24
24
5
88 (2f)c
99 (2f)
86 (2m)
86 (2h)
87 (2e)
64 (2n)
72 (2o)
63 (2p)
52 (2q)
66 (2r)
77 (2s)
70 (2t)
4
5b
6
7
8
9
10
11
12
24
24
C5H11
a Isolated yield. b 2 equiv of NaOAc were used. c A trace amount of the unchanged 1e was observed by the TLC analysis.
110 ◦C gave no change in the reaction efficiency (Entry 3), but a
further decrease in the temperature to 100 ◦C caused an extensive
drop in the yield to 56% of 2l (Entry 4). We next investigated
the optimal amounts of NaOAc and 10% Pd/C. NaOAc could be
decreased to 1.1 equiv to 1e (Entries 5 and 6), although the reaction
was incomplete using 1.0 or 0.7 equiv of NaOAc (Entries 7 and
8). Furthermore, the reaction efficiently proceeded with 3.0 mol%
of 10% Pd/C to afford 2l in a quantitative yield (Entries 6, 9, and
10), while the use of less than 3.0 mol% of the 10% Pd/C was not
sufficient to complete the reaction (Entries 11–13). Furthermore,
the reaction using 1.2 equiv of 1-phenyl-1-propyne in the presence
of 10% Pd/C (3.0 mol%) and NaOAc (1.1 equiv) at 110 C was
◦
completed within 12 h (Entries 14 and 15). Considering both the
reduction of the alkyne and catalyst usage and the reaction time,
the Entry 15 conditions was chosen as the appropriate for the
present annulation.
Table 5 summarizes the results of the annulation of various
alkynes and N-tosyl-2-iodobenzene derivatives. When the annula-
tion of 1e with 6-dodecyne as a symmetrical alkyne was carried out
under the optimal reaction conditions as shown in Table 4, Entry
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(100–210 mm, Kanto Chemical Co., Inc.). 1H and 13C NMR spectra
were recorded by a JEOL JNM EX-400 or AL-400 spectrometer
(400 MHz for 1H NMR and 100 MHz for 13C NMR) using CDCl3
as the solvent. Chemical shifts (d) are expressed in ppm based on
internal standards (TMS for 1H NMR and CDCl3 for 13C NMR).
The electron impact (EI) and fast-atom bombardment (FAB) mass
spectra were taken using a JEOL JMS-SX 102A instrument.
General procedure for the LiCl-free Pd/C-catalyzed annulation of
alkynes with N-Ts-2-iodoaniline (for Table 5)
A
mixture of N-Ts-2-iodoaniline (0.250 mmol), alkyne
(0.300 mmol), 10% Pd/C (8.0 mg, 3 mol% of N-Ts-2-iodoaniline)
and NaOAc (22.5 mg, 0.275 mmol) in NMP (1.00 cm3) in a
15 cm3-test tube was sealed with a septum and the air inside
was replaced with Ar by five vacuum/Ar (balloon) cycles. The
mixture was stirred at 110–130 ◦C for 24 h using a Chemist Plaza
personal organic synthesizer (Shibata Scientific Technology, Ltd.,
Tokyo). The suspension was vigorously stirred with additional
EtOAc (40 cm3) and saturated NH4Cl solution (10 cm3), and
Scheme 2 Proposed reaction pathways for the annulation of the mono-
substituted alkyne with 2-iodoaniline.
15 (110 ◦C), 1e was not completely consumed (Table 5, Entry 1),
although the reaction was completed at 120 ◦C within 3 h to give 2f
in quantitative yield. Since the reaction progress was slightly influ-
enced by the subtle difference in the alkyne structure, the reactions
were performed after minor tuning of the conditions. Symmetrical
alkynes were effectively reacted with 1e to give the corresponding
2,3-disubstituted indoles (2m, 2h, and 2e) in excellent yields
(Entries 3–5). Phenylacetylenes bearing a methyl or methoxy
functionality cyclized into the corresponding 2-arylindoles in a
completely regioselective manner (Entries 6–8). The reaction of
the 1-naphthyl- and 1-cyclohexenyl acetylene derivatives also gave
the desired 2-naphthyl- (2q and 2r) and 2-cyclohexenylindole
(2s) derivatives in practically applicable yields (Entries 9–11).
Furthermore, N-tosyl-2-iodo-4-methoxycarbonylaniline (1f) was
found to be a good substrate for the present indole synthesis
(Entries 12).
R
filtered through a membrane filter (Millipore, Millexꢀ-LH, 0.45
mm). The filtered aqueous layers were separated and the water
layer was extracted with another EtOAc (20 cm3). The EtOAc
layer was combined with the filtered organic layer and washed
with saturated NH4Cl solution (20 cm3 ¥ 2), H2O (5 cm3 ¥ 2),
and brine (5 cm3), and dried over anhydrous Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by silica gel
column chromatography.
Acknowledgements
We sincerely thank the N.E. Chemcat Co. for the gift of the 10%
Pd/C.
Conclusions
Notes and references
We have established a practical and efficient protocol for the
Yamanaka–Larock indole synthesis, which requires 3.0 mol% of
heterogeneous 10% Pd/C as the catalyst, alkynes and NaOAc
as a mild base in the absence of LiCl. Symmetrical disubstituted
alkynes reacted with N-tosyl-2-iodoaniline to give the correspond-
ing 2,3-disubstituted indoles in excellent yields, and a variety of
2-monoarylsubstituted indole derivatives were synthesized from
monoarylalkynes in a completely regioselective manner. The
method will provide a facile, efficient, and environmentally-benign
process for the preparation of indole derivatives due to the wide
applicability of the substrates, easy access to the catalyst, easy
removal of the N-tosyl protection on the indole nucleus24 and
mild reaction conditions.
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3342 | Org. Biomol. Chem., 2010, 8, 3338–3342
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