Heterogeneous catalytic hydrogenation of unprotected indoles in water: A green solution to a long-standing challenge

Article abstract of DOI:10.1021/ol2019899

An environmentally benign procedure for the hydrogenation of unprotected indoles is described. The hydrogenation reaction is catalyzed by Pt/C and activated by p-toluenesulfonic acid in water as a solvent. The efficacy of the method is illustrated by the hydrogenation of a variety of substituted indoles to their corresponding indolines which were obtained in excellent yields.

Full text of DOI:10.1021/ol2019899

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5124–5127
Heterogeneous Catalytic Hydrogenation
of Unprotected Indoles in Water: A Green
Solution to a Long-Standing Challenge
ꢀ € €
Aditya Kulkarni, Weihong Zhou, and Bela Torok*
Department of Chemistry, University of Massachusetts Boston, 100 Morrissey
Boulevard, Boston, Massachusetts 02125, United States
bela.torok@umb.edu
Received July 23, 2011
ABSTRACT
An environmentally benign procedure for the hydrogenation of unprotected indoles is described. The hydrogenation reaction is catalyzed by Pt/C
and activated by p-toluenesulfonic acid in water as a solvent. The efficacy of the method is illustrated by the hydrogenation of a variety of
substituted indoles to their corresponding indolines which were obtained in excellent yields.
Hydrogenation of indole is a difficult task due to the
highly resonance-stabilizedaromaticnucleus.1 Inaddition,
the hydrogenated product, a cyclic secondary amine, could
poison the metal catalyst and hinder the progress of the
reaction,2 and the product indoline can undergo further
hydrogenation to form byproducts up to octahydroindole.
Over the years, extended efforts have been devoted to the
regioselective hydrogenation of indoles to indolines. The
most environmentally benign tool for this reaction is hetero-
geneous catalytic hydrogenation.3 However, challenges for
the use of this truly green tool for the selective hydrogenation
of indole still remain.4 One of the most effective methods for
this transformation utilizes NaBH3CN, which gives the
desired indolines in good yields. This method has its
major drawbacks; it uses superstoichiometric amounts
(up to 3 equiv) of the hydride reagent, and the reaction
generates large amounts of toxic byproducts such as
cyanides.5 Other reagents used for this transformation
include triethylamine/borane,6 triethylsilane/trifluoroace-
tic acid,7 or PhSiH3.8 All of these methods use stoichio-
metric amounts of reagents and generate an extensive
amount of waste. The reduction of indoles to indolines
was also reported by catalytic hydrogenation. The use of
hydrogen has advantages over H-transfer reagents, most
importantly that no waste is generated after the reaction
from hydrogen. The major challenge in catalytic hydro-
genation ofindoles is that it often proceeds further than the
indoline stage or occurs at positions other than the desired
2,3-double bond.9 Homogeneous catalytic methods for the
hydrogenation of N-protected indoles using hydrogen
involve the use of Rh,10 Ru,11 and Ir12 complexes.
(6) Berger, J. G. Synthesis 1974, 508.
(7) Lanzilotti, A. E.; Littell, R.; Fanshawe, W. J.; McKenzie, T. C.;
Lovell, F. M. J. Org. Chem. 1979, 44, 4809.
(1) Bird, C. W. Tetrahedron 1992, 48, 335.
(8) Tan, M.; Zhang, Y. Tetrahedron Lett. 2009, 50, 4912.
(9) Robinson, B. Chem. Rev. 1969, 69, 785.
(10) (a) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J.
Am. Chem. Soc. 2000, 122, 7614. (b) Kuwano, R.; Kaneda, K.; Ito, T.;
Sato, K.; Kurokawa, T.; Ito, T. Org. Lett. 2004, 6, 2213.
(11) Kuwano, R.; Kashiwabara, M. Org. Lett. 2006, 8, 2653.
(12) Baeza, A.; Pfaltz, A. Chem.;Eur. J. 2010, 16, 2036.
(2) Maxted, E. B.; Biggs, M. S. J. Chem. Soc. 1957, 3844.
(3) Nishimura, S. Handbook of Heterogeneous Catalytic Hydrogena-
tion for Organic Synthesis; Wiley: New York, 2001.
(4) Zhou, Y. G. Acc. Chem. Res. 2007, 40, 1357.
(5) (a) Gribble, G. W.; Lord, P. D.; Skotnicki, J.; Dietz, S. E.; Eaton,
J. T.; Johnson, J. J. Am. Chem. Soc. 1974, 96, 7812. (b) Gribble, G. W.;
Hoffman, J. H. Synthesis 1977, 859.
r
10.1021/ol2019899
Published on Web 09/08/2011
2011 American Chemical Society

Heterogeneous catalysts are easy to store and handle,
usually are not moisture sensitive, and are easy to separate
and recycle.13 Despite some progress in selective hydro-
genationofindoles toindolinesbyheterogeneouscatalysis,
the available examples are mostly limited to N-protected
indoles.14 The only available report, to the best of our
knowledge, for the hydrogenation of unprotected indole
by catalytic heterogeneous hydrogenation using hydrogen
gas requires very harsh conditions such as hydrogen
pressure of 150 bar and temperature of 227 °C giving
moderate yield.15
Scheme 1. Synthetic Strategy for the Catalytic Heterogeneous
Hydrogenation of Indoles in Water
Under acidic conditions, indole can be protonated at the
C-3 position generating an iminium ion with disrupted
aromaticity.16 This iminium ion could be efficiently hydro-
genated by homogeneous catalytic hydrogenation to
obtain asymmetric indolines using the Pd(OCOCF3)2
catalyst.17 The method appeared tobe efficient; however, it
was limited to 2-substituted indoles that are less prone
to polymerization. Thus, while the application of a coacid
is a reasonable idea, it also raises further problems. As
indole is a highly activated aromatic compound, evenweak
electrophiles initiate polymerization that results in signifi-
cant amount of byproducts.18 The other problem is over-
hydrogenation, mainly to octahydroindole.
The topic has undoubtedly attracted significant atten-
tion due to the importance of the indoline moiety that can
be found in a number of naturally occurring, biologically
active, and pharmaceutically important compounds.19
Aside from the above-discussed hydrogenations,10À12,14,15,17
indolines can be synthesized by direct ring closure through
amination reactions.20
Continuing our efforts toward developing sustainable
organic transformations, herein we report a robust meth-
odology for highly regioselective, Brønsted acid-induced
heterogeneous catalytic hydrogenation of unprotected in-
doles (Scheme 1). The reaction is catalyzed by the inexpen-
sive and commercially available Pt/C catalyst and occurs
under mild conditions such as moderate hydrogen pres-
sure, at room temperature, generally requires short reac-
tiontimes, and mostimportantly utilizeswater asa solvent.
Hydrogenation of indole was selected as a model reac-
tion. The reaction was carried out in ethanol using a Pt/C
catalyst and hydrogen gas. The reaction revealed sig-
nificant selectivity issues such as over hydrogenation to
octahydroindole and polymerization. As our goal was to
develop a green reduction to produce indolines from
unprotected indoles, we decided to further explore this
reaction. We adopted the use of the acid additive even
though that method had failed for unprotected indoles,
since protonation appears to be a reasonable strategy to
disrupt the aromatic system of indole. In order to deter-
mine optimum conditions, a detailed investigation of the
effect of various experimental variables was undertaken.
The results are presented in Table 1.
When carried out without an acid additive, the reaction
yielded the product in traces (entry 1). Using 1 equiv of
trifluoroacetic acid (TFA), however, a substantial amount
of the desired product was observed with octahydroindole
and polymerized byproducts. When carried out in hexane,
the reaction resulted in 61% conversion and 13% selectiv-
ity for the desired product. A similar phenomenon was
observed in toluene, although the selectivity (38%) was
higher than in hexane. The conversion and selectivity
increased in ethanol (62% conversion, 77% selectivity)
and methanol (66% conversion, 76% selectivity). Thus, it
was concluded that the selectivity of product increased
with increasing nucleophilicity of the solvent (entries 2À5).
It appears that the decreasing nucleophilicity of the medi-
um increases the acidity of the system, thus promoting
polymerization.
Therefore, in order to minimize the polymerization, it
was envisioned that further increasing the nucleophilicity
of the medium would alleviate the acidity of the Brønsted
acid, thereby minimizing the possibility of polymerization.
One obvious choice to increase solvent nucleophilicity
was the selection of water as a solvent. When the reaction
was carried out in aqueous medium, polymerization was
completely hindered and only indoline and indole were
observed (entry 7). Then, it was decided to test different
Brønsted acid additives. When camphorsulfonic acid
(CSA) and p-toluenesulfonic acid (p-TSA) were used as
additives (entries 8 and 9), complete conversion was
observed and the selectivity of indoline increased substan-
tially with octahydroindole being the only byproduct.
It appears that there is an acidity optimum for the reaction.
The selectivity decreased when a weaker acid (formic acid)
(13) (a) Horvath, I., Ed. Encyclopedia of Catalysis; Wiley: New York,
€ €
2003. (b) Kulkarni, A.; Torok, B. Curr. Org. Synth. 2011, 8, 187.
(14) (a) Gilchrist, T. L.; Graham, K. Tetrahedron 1997, 53, 791. (b)
Chandrasekhar, S.; Basu, D.; Reddy, C. R. Synthesis 2007, 1509.
(15) Shaw, J. E.; Stapp, P. R. J. Heterocycl. Chem. 1987, 24, 1477.
(16) (a) Chen, C. B.; Wang, X. F.; Cao, Y. J.; Cheng, H. G.; Xiao,
W. J. J. Org. Chem. 2009, 74, 3532. (b) Gilchrist, T. L. Heterocyclic
Chemistry, 3rd ed.; Pearson: Essex, 1997; p 240.
(17) (a) Wang, D. S.; Chen, Q. A.; Li, W.; Yu, C. B.; Zhou, Y. G.;
Zhang, X. J. Am. Chem. Soc. 2010, 132, 8909. (b) Wang, D. S.; Tang, J.;
Zhou, Y. G.; Chen, M. W.; Yu, C. B.; Duan, Y.; Jiang, G. F. Chem. Sci.
2011, 2, 803.
(18) Ishii, H.; Murakami, K.; Sakurada, E.; Hosoya, K.; Murakami,
Y. J. Chem. Soc., Perkin Trans. 1 1988, 2377.
(19) (a) Boger, D. L.; Boyce, C. W.; Garbaccio, R. M; Goldberg, J. A.
Chem. Rev. 1997, 97, 787. (b) Dounay, Z. A. B.; Overman, L. E.;
Wrobleski, A. D. J. Am. Chem. Soc. 2005, 127, 10186. (c) Natesh, R.;
Schwager, S. L. U.; Evans, H. R.; Sturrock, E. D.; Acharya, K. R.
Biochemistry 2004, 43, 8718. (d) Gruenfeld, N.; Stanton, J. L.; Yuan,
A. M.; Ebetino, F. H.; Browne, J. J.; Gude, C.; Huebner, C. F. J. Med.
Chem. 1983, 26, 1277.
(20) (a) Anas, S.; Kagan, H. B. Tetrahedron: Asymmetry 2009, 20,
2193. (b) Liu, D.; Zhao, G.; Xiang, L. Eur. J. Org. Chem. 2010, 3975. (c)
Viswanathan, R.; Prabhakaran, E. N.; Plotkin, M. A.; Johnston, J. N.
J. Am. Chem. Soc. 2003, 125, 163.
Org. Lett., Vol. 13, No. 19, 2011
5125

Table 1. Synthesis of Indoline from Indole under Various Experimental Conditionsa
entry
catalyst
HA
solvent
EtOH
H2 (bar)
time (h)
convn (%)
selectivity (%)
1
2
Pt/C
Pt/C
Pt/C
Pt/C
Pt/C
Pt/C
Pt/C
Pt/C
Pt/C
Pt/C
Pt/C
Pt/Al2O3
Pd/C
Pt/C
Pt/C
Pt/C
Pt/C
Pt/C
Pt/C
50
50
50
50
50
50
50
50
50
50
50
50
50
10
20
30
40
30
30
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
2
62
100/0
77/23
76/24
38/62
13/87
71/29
100/0
81/19
87/13
85/15
100/0
100/0
100/0
100/0
100/0
100/0
100/0
100/0
100/0
TFA
EtOH
MeOH
toluene
hexane
CF3CH2OH
H2O
3
TFA
66
4
TFA
53
5
TFA
61
6
TFA
100
67
7
TFA
8
CSA
H2O
100
100
52
9
p-TSA
HCOOH
CF3SO3H
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
H2O
10
11
12
13
14
15
16
17
18
19
H2O
H2O
78
H2O
88
H2O
56
H2O
36
H2O
56
H2O
78
H2O
82
H2O
100
3
H2O
a Conversions and selectivities were determined by GC. Major byproducts include octahydroindole, dimer and trimer of indole, and their
corresponding hydrogenated products. TFA = trifluoroacetic acid. CSA = camphorsulfonic acid. p-TSA = p-toluenesulfonic acid. The reactions
were carried out on a 1 mmol scale.
or a stronger acid (triflic acid) were used as additives
(entries 10 and 11). The use of different catalysts such as
Pt/Al2O3 (entry 12) or Pd/C (entry 13) increased the
selectivity, but these were less active than the Pt/C catalyst
and resulted in incomplete conversion of indole. After the
optimum solvent and acid additive were determined, atten-
tion was focused on optimizing the hydrogen pressure and
reaction time. It was observed that the reaction proceeded
with 100% selectivity even at 10 bar pressure, however,
with a relatively low rate (entry 14, 36% yield in 2 h). The
optimum hydrogen pressure of 30 bar gave 100% selectiv-
ity for indoline and quantitative conversion of indole
(entry 18). To confirm the effect of the acid additive, a
reaction was carried out under the optimized conditions
but without using p-TSA. As indicated, there was only 3%
product formation, and indole was recovered after the
reaction (entry 19). This observation confirmed the role of
the acid additive. Even though the reaction is catalytic with
respect to p-TSA, 1.2 equiv of p-TSA was required to
ensure short reaction times. As the reaction progresses, the
indoline formed tends to decrease the concentration of free
p-TSA in the solution by the formation of an ammonium
ion, and the reaction gets sluggish if less than 1 equiv of
p-TSA is used. This side reaction, however, has a rather
positive effect on the overall process; the formation of an
ammonium ion occupies the lone pair of the secondary
amine, therefore completely suppressing its catalyst poi-
soning effect that greatly inhibited the heterogeneous
catalytic hydrogenation earlier. Using the optimized con-
ditions, the method was applied to a variety of indoles with
different substituents on the carbocyclic as well as the
heterocyclic ring in order to study the steric and electronic
effects on the outcome of the reaction. The results are
summarized in Scheme 2.
A variety of indoles gave indolines in good yields with
excellent selectivities. C-5 electron-donating substituents
such as 5-methyl and 5-methoxy gave the desired products
in excellent yields (96% and 95%, respectively). 5-Fluo-
roindolealsoaffordedthe desiredproductinexcellentyield
(93%). However, a 5-chloro substituent was not comple-
tely tolerated, and the product (46%) was obtained along
with the dehalogenated derivative (42%) as well as octahy-
droindole (12%). A less active Pt/Al2O3 catalyst, however,
was found to effectively catalyze the reaction with high
selectivity and gave the desired product in 72% yield.
Increased catalyst loading and hydrogen pressure were
required for 7-ethyl- and 2-methylindole, most likely be-
cause the alkyl group adjacent to the nitrogen hindered
adsorption on the surface of the catalyst and resulted in a
rate decrease. The rate of hydrogenation was compara-
tively low in the case of methyl indole-5-carboxylate
probably due to the electron-withdrawing nature of the
substituent and also required increased catalyst loading. In
the case of ethyl indole-2-carboxylate, the substrate was
completely deactivated.
Selectivity was a major problem for N-methylindole
since it was easily overreduced to the octahydro pro-
duct; thus, both catalyst loading and hydrogen pressure
were decreased. 2,3-Disubstituted indoles required
higher pressure and catalyst loading (Scheme 2).
5126
Org. Lett., Vol. 13, No. 19, 2011

formation associated with them. (ii) The reaction is carried
out in water, the most benign, readily available, and
inexpensive solvent. (iii) The use of a heterogeneous Pt/C
catalyst allows easy catalyst recovery and makes use of a
continuous flow process possible. (iv) Reactions were
carried out at room temperature over short reaction times,
and the temperatures and hydrogen pressures in this
process are significantly lower than those previously re-
ported in heterogeneous systems. (v) The atom economy is
near100%inthe reactionasbothstarting materials(indole
and hydrogen) are completely used up and there is no
byproduct formation. (vi) The acid additive is not con-
sumed in the reaction, and p-TSA can be recovered and
reused. (vii) With consideration of the previous points, the
reaction does not generate waste.
Scheme 2. Scope of the Pt/C-Catalyzed Hydrogenation of Sub-
stituted Indoles in Watera
a The reactions were carried out on a 1 mmol scale. b Determined by
1H NMR.
Both hexahydrocyclopentaindole and hexahydrocarba-
zole exclusively formed the cis products, whereas 2,3-
dimethylindoline was observed as a mixture of cis and
trans isomers in a 6:1 ratio.21 Tryptamine, which contains
two nitrogen atoms, required 2.2 equiv of p-TSA to give
2,3-dihydrotryptamine in good isolated yield (68%).
In the reaction mechanism, the acid additive has a
crucial role; it temporarily disrupts the aromaticity of the
heterocyclic ring of the indole forming an iminium ion
(Figure1). Thisstepoccursbyp-TSAprotonatingthemost
nucleophilic C-3 position of indole. Once the iminium ion
is formed, it dissolves in the aqueous medium and the
solvation in water prevents further nucleophilic attack by
another indole molecule, thus preventing polymerization.
The attack is prevented in part due to phase separation
between the water-soluble iminium ion and the insoluble
indole. In addition, the iminium ion is solvated by water
molecules that further eliminates the steric availability for
subsequent attack by excess indole. The iminium ion
quickly undergoes hydrogenation to form indoline. The
methodology described here is a highly green synthesis
design.22 The major advantages are as follows:
Figure 1. Mechanism for acid-induced Pt/C-catalyzed hydroge-
nation of indole to indoline in water.
In summary, a heterogeneous catalytic hydrogenation
methodology for the direct synthesis of indolines from
unprotected indoles in water was developed. In the
presence of a readily available Brønsted acid such as
p-toluenesulfonic acid, a broad variety of unprotected
indoles were hydrogenated to their corresponding indo-
lines by a heterogeneous Pt/C catalyst. The reactions were
carried out at room temperature at a moderate hydrogen
pressure. Products were obtained in excellent yields in
short reaction times. The process, with its highly effective,
inexpensive, and selective design, provides a green solution
to a long-standing challenge, the selective hydrogenation
of indoles to indolines.
Acknowledgment. Financial support provided by Uni-
versity of Massachusetts Boston and the National
Institute of Health (R-15 AG025777-03A1) is grate-
fully acknowledged.
(i) The reaction is carried out on unprotected indoles,
which eliminates the protection and deprotection steps
required in all previous attempts and the losses and waste
Supporting Information Available. General procedure
along with spectroscopic data of all products. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
(21) See the Supporting Information for details.
(22) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: Oxford, 1998.
Org. Lett., Vol. 13, No. 19, 2011
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