Enantioselective hydrogenation of indoles derivatives catalyzed by Walphos/rhodium complexes

Article abstract of DOI:10.1016/j.tetasy.2010.06.030

The enantioselective hydrogenation of indole esters has been carried out efficiently in the presence of a rhodium catalyst modified by Walphos-type chiral ligands. The addition of a base can be beneficial in some catalytic conditions.

Full text of DOI:10.1016/j.tetasy.2010.06.030

Tetrahedron: Asymmetry 21 (2010) 2010–2014
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective hydrogenation of indoles derivatives catalyzed
by Walphos/rhodium complexes
Anna M. Maj a,c, Isabelle Suisse a,b,c, Catherine Méliet a,c,d, Francine Agbossou-Niedercorn a,c,d,
*
a Université Lille Nord de France, F-59000 Lille, France
b Université Lille 1, Sciences et Technologies, F-59655 Villeneuve d’Ascq, France
c ENSCL, CCM-CCCF, F-59652 Villeneuve d’Ascq, France
d CNRS, UCCS UMR 8181, F-59655 Villeneuve d’Ascq, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective hydrogenation of indole esters has been carried out efficiently in the presence of a
rhodium catalyst modified by Walphos-type chiral ligands. The addition of a base can be beneficial in
some catalytic conditions.
Received 12 May 2010
Accepted 22 June 2010
Available online 24 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The enantioselective hydrogenation of heteroaromatic com-
pounds constitutes a very powerful method to access chiral cyclic
skeletons with a high potential for asymmetric synthesis.1,2 How-
ever, the hydrogenation of heteroatomic derivatives has been less
investigated than that of other classes of substrates such as ena-
mides, b-keto esters, imines, and other olefins.3 If quinoline, quinox-
aline, and pyridine compounds have been reduced with excellent
selectivities,1,2 the five-membered heteroaromatic compounds,
such as indole derivatives, have only been hydrogenated efficiently
recently4 in the presence of another catalytic system than that con-
taining the trans-chelating bisphosphines of the Ph-TRAP family.5
The Ph-TRAP-based catalytic systems suffer from a non-straightfor-
ward access to the chiral ligands.6 Thus, the efficient hydrogenation
of indole derivatives still remains a challenge with regard to the
application of easily accessible chiral auxiliaries.4
Enantiomerically pure amino acids and their derivatives are
well known as versatile building blocks for pharmaceutical appli-
cations and the efforts devoted to prepare non-proteinogenic ami-
no acids remain relevant.7 In order to carry out the hydrogenation
of indole derivatives, the nitrogen atom needs to be derivatized in
order to lower the aromaticity of the heterocycle. Thus, we focused
on the preparation of enantiomerically enriched indoline carbox-
ylic acid and specifically targeted the hydrogenation of N-Boc-in-
dole esters. Generally, the Boc residue can be easily attached to
an indole derivative and, subsequently, very easy to cleave.8 Here-
in, we report on the enantioselective hydrogenation of N-Boc-2-
substituted indole derivatives in the presence of rhodium catalysts
generated from easily accessible bisphosphine ligands.
For our initial experiments, we selected the 1-tert-butyl 2-
methyl 1H-indole-1,2-dicarboxylate 1 as the model substrate. We
first examined the cationic precursor [Rh(nbd)2]SbF6 in association
with four selected commercially available chiral bisphosphines
(Fig. 1).
The reactions were carried out according to Ito’s5a reported con-
ditions in iPrOH, at 60 °C, under 50 bar of hydrogen, and in the
presence of a base (Scheme 1). The addition of a base has been
found to be essential for the reaction to proceed.5a The results
are reported in Table 1. All reactions were complete under our con-
ditions. However, in addition to the expected indoline product 2,
we also observed the transesterified substrate 3, two N-deprotec-
ted derivatives 4 and 5, and the hydrogenated product 6 bearing
an isopropyl ester (Scheme 1).
Compounds 4 and 5 result from the alcoholysis of 1 and 3,
respectively. The major products were the desired hydrogenated
species 2 and the transesterified hydrogenated derivative 6. For a
test experiment, substrate 1 was heated at 60 °C for 2 h in pro-
pan-2-ol in the presence of 10 equiv of Cs2CO3. We observed up
to 78% overall transesterification (3, 14% and 5, 64%). Without a
base, substrate 1 remained unchanged during heating in dry pro-
pan-2-ol for 2 h. The transesterification process could be entirely
suppressed just by adding a few drops of water into the medium
containing the base.9 The base Cs2CO3 was thus identified as par-
ticipating in both unwanted side reactions, that is, transesterifica-
tion and alcoholysis. We were unable to determine the
enantiomeric purity of 2 and 6 in the reaction mixtures as the HPLC
signals overlapped. The next series of experiments were carried out
under the aforementioned conditions, but in methanol instead of
propan-2-ol. The results are given in Table 2. The crude reaction
mixtures were composed of the hydrogenated product 2, the
* Corresponding author. Tel.: +33 (0) 32 04 34 927; fax: +33 (0) 32 04 36 585.
E-mail address: francine.agbossou@ensc-lille.fr (F. Agbossou-Niedercorn).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.06.030

A. M. Maj et al. / Tetrahedron: Asymmetry 21 (2010) 2010–2014
2011
CF3
CF3
Me
F3C
Et
Me
Me
CF3
Et
Et
P
P
P
P
P
P
P
H
Fe
Me
Me
P
Et
Me
Fe
CH3
Me
Me
(R,R)-MeDUPHOS
EtFerroTANE
(R,R)-MeBPE
SL-W008-1
Figure 1. Chiral bisphosphine ligands applied in the asymmetric hydrogenation of 1-tert-butyl-2-methyl 1H-indole-1,2-dicarboxylate 1.
H
COOMe
COOiPr
N
N
Boc
Boc
2
4
3
[Rh(nbd)2]SbF6
chiral bisphosphine ligand
COOMe
Boc
COOMe
H2
50 bar
COOiPr
Cs2CO3
iPrOH, 60ºC
N
N
N
H
H
1
5
*
COOiPr
N
Boc
6
Scheme 1. Asymmetric hydrogenation of 1-tert-butyl-2-methyl 1H-indole-1,2-dicarboxylate 1.
Table 1
(Table 2, entries 1 and 3). The chiral ligands MeDUPHOS and
MeBPE induced lower yields of 2 (13% and 8.6%) and lower selec-
tivities (3% and 20% ee, respectively) (Table 2, entries 2 and 4).
As the Walphos ligand SL-W008-1 furnished the best compro-
mise between enantioselectivity and magnitude of alcoholysis
and because of the large variety of congeners easily available,10
we studied other ligands of that family. We also varied the source
of rhodium precursors. We found that the neutral rhodium dimer
[Rh(OH)(COD)]2 provided more efficient catalysts than the cationic
[Rh(nbd)2]SbF6. Finally, we altered the hydrogen pressure and the
temperature and found that running the hydrogenations at room
temperature under 100 bar of dihydrogen and in the presence of
Cs2CO3 was the most appropriate conditions. The selected Walphos
ligands are presented in Figure 2 and the hydrogenation results are
summarized in Table 3.
Enantioselective hydrogenation of 1-tert-butyl-2-methyl 1H-indole-1,2-dicarboxylate
1a
Entry Chiral
auxiliary
Time Conv.b 2b
3b
(%)
4b
(%)
5b
(%)
6b
(%)
(h)
(%)
(%)
1
2
3
4
SL-W008-1
18
100
99
100
100
32
13
39
2
2
1.2
2
0.5
0.3
0
1.4 55
6.4 65
2.2 49
(R,R)-MeDUPHOS 90
EtFerroTANE
(R,R)-MeBPE
18
70
0.5
2.6 51
37
a
1/[Rh(nbd)2]SbF6/ligand/Cs2CO3: 100/1/1/10; PH2 = 50 bar, 60 °C; 17 h, reaction
time not optimized.
b
Yield determined by GC.
Table 2
Evaluation of chiral ligands in the asymmetric hydrogenation of 1 in MeOHa
Based on the observations detailed above and in order to limit
the transesterification process, we applied three solvent/base sys-
tems: MeOH/Cs2CO3 (Table 3, entries 1–5); propan-2-ol without
base (Table 3, entries 6–10); and propan-2-ol/H2O/Cs2CO3 (Table 3,
entries 11–15). The Walphos ligand SL-W008-1 combined with
[Rh(OH)(COD)]2 in MeOH in the presence of Cs2CO3 provided the
most enantioselective catalytic system as 2 was obtained in 87%
yield and 77% ee (Table 3, entry 4). The alcoholysis process oc-
curred only in 1.6%. Ligand SL-W002-1 provided the highest yield
of 2 (>98% conversion, >96.5% selectivity) (Table 3, entries 1, 6,
and 11). The lowest level of alcoholysis was generally observed
in the presence of this ligand as well (<0.4%). The chiral ligand
inducing both the highest chemoselectivity and enantioselectivity
of 2 was SL-W006-1 (100% conversion, 98% yield in 2, 72% ee, no
alcoholysis detected) (Table 3, entry 8). In this case, the reaction
was carried out in dry propan-2-ol without the base. In a pro-
pan-2-ol/H2O/Cs2CO3 solvent system, the enantioselectivity
Entry
Chiral
auxiliary
Time
(h)
Conv.b
(%)
2b
(%)
4b
(%)
ee of 2 (%)c
(conf.)
1
2
3
4
SL-W008-1
2
2
17
17
100
80
100
100
71
13
45
26
61
54
91
38 (R)
3 (R)
44 (R)
20 (R)
(R,R)-MeDUPHOS
EtFerroTANE
(R,R)-MeBPE
8.6
a
1/[Rh(nbd)2]SbF6/ligand/Cs2CO3: 100/1/1/10; PH2 = 50 bar, 60 °C; 17 h, reaction
time not optimized.
b
Determined by GC analysis.
Determined by HPLC analysis.
c
N-deprotected derivative 4 and some unreacted substrate 1. The
alcoholysis side reaction became significantly more important in
methanol (26–91%) than in propan-2-ol (0.3–2.6%, Table 1). In
the presence of the Walphos ligand SL-W008-1 and EtFerroTANE,
product 2 was obtained in 71% and 45% yield and 38% and 44%
ee, accompanied by compound 4 in 26% and 54% yield, respectively

2012
A. M. Maj et al. / Tetrahedron: Asymmetry 21 (2010) 2010–2014
O
CF3
Ph
Ph
CF3
F3C
Ph
Ph
P
Ph
P
Ph
CF3
Ph
Ph
P
O
P
P
Fe
P
CH3
P
H
P
H
H
Fe
Fe
Fe
H3C
CH3
CH3
H
SL-W022-2
SL-W002-1
SL-W006-1
SL-W005-1
Figure 2. The Walphos ligands used in asymmetric hydrogenation of 1-tert-butyl-2-methyl 1H-indole-1,2-dicarboxylate 1.
Table 3
Evaluation of Walphos-type ligands in the asymmetric hydrogenation of 1a
Entry
Chiral auxiliary
Solvent
Cs2CO3 (equiv)
Conv.b (%)
2b (%)
4b (%)
ee of 2 (%)c (config.)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
SL-W002-1
SL-W005-1
SL-W006-1
SL-W008-1
SL-W022-2
SL-W002-1
SL-W005-1
SL-W006-1
SL-W008-1
SL-W022-2
SL-W002-1
SL-W005-1
SL-W006-1
SL-W008-1
SL-W022-2
MeOH
MeOH
MeOH
MeOH
MeOH
iPrOH
iPrOH
iPrOH
50
50
50
50
50
—
—
—
—
—
50
50
50
50
50
99
100
94
89
69
100
100
100
97
89
99
99
97
90
87
66.5
97
95.5
98
86.5
83.5
96.5
99
0
66 (R)
37 (R)
27 (S)
77 (R)
34 (R)
66 (R)
0
0.2
1.5
1.6
1.5
0
0.1
0
72 (S)
9 (R)
iPrOH
iPrOH
1.1
1.6
0.4
0.4
0.1
2
34 (R)
46 (R)
35 (R)
51 (S)
16 (R)
71 (R)
iPrOH/H2O
iPrOH/H2O
iPrOH/H2O
iPrOH/H2O
iPrOH/H2O
99
100
65
99
63
83
85
0.5
a
b
c
1/[Rh(OH)(COD)]2/ligand/Cs2CO3: 80/1/1/50; PH2 = 100 bar, room temperature; 17 h, reaction time not optimized.
Determined by GC analysis.
Determined by HPLC analysis.
dropped significantly (51% ee, Table 3, entry 13). The most selec-
tive system in propan-2-ol/H2O/Cs2CO3 was obtained with SL
W022-2 (71% ee, Table 3, entry 15). It can be proposed that the
alcoholysis process remains minor as long as the hydrogenation
proceeds at a sufficiently high rate. The ability of the rhodium cat-
alysts bearing Walphos-type ligands to perform efficient hydroge-
nations at room temperature is the key point as the alcoholysis is
most probably inhibited at that temperature. For the asymmetric
hydrogenation of the N-Boc indole derivative 1, the catalytic sys-
tem developed here compares well with the Rh/Ph-TRAP catalysts
developed by Kuwano and Ito (78% ee).5a
Next, we applied our catalytic systems to other indole esters
especially the ethyl 7 and tert-butyl 8 derivatives (Scheme 2) in or-
der to improve the catalytic performance by increasing the steric
demand of the substrate. To the best of our knowledge, the hydro-
genation of 7 and 8 had not been carried out. We attempted a large
variety of experimental conditions including different catalytic
precursors, solvents, the presence of a base, and ferrocenyl ligands.
The best results are summarized in Table 4.
to improve this result (Table 4, entries 2 and 4). Again, the most
enantioselective catalytic system for the ethyl substrate is the
same as that used for the methyl derivative. Next, we turned our
attention to the tert-butyl ester 8. As tert-butanol was prohibited
as the solvent, we performed hydrogenations in 2-methylbutan-
2-ol. The major product was the deprotected substrate 8b (entry
5). We consequently decided to use MeOH or iPrOH. In addition
to the hydrogenated product 8a and the deprotected substrate
8b, a small amount of deprotected transesterified derivative 9
was obtained (in the presence of water, entries 6 and 7, without
the base, entry 8, Table 4). The various experiments including var-
iation of the chiral ligand and the catalytic conditions (with or
without water and with or without the base) shaved the catalytic
system SL-W002-/8/[Rh(OH)COD]2 in MeOH (Table 4, entry 8) to
be the most effective catalytic system. An 85% yield of 8a with
an ee of 80% could be reached under these conditions, which pro-
vided the best result for an easy to implement hydrogenation of
N-Boc-indole derivatives.
In all cases, in addition to the hydrogenation product 7a or 8a,
we also observed the deprotected derivatives 7b or 8b and eventu-
ally the transesterified, non-hydrogenated, and deprotected prod-
uct 9. Under our experimental conditions, for the two substrates,
[Rh(OH)COD]2 complex appeared to be the most suitable precata-
lyst at once in terms of activity and enantioselectivity. The first
experiments with substrate 7 were performed in ethanol in order
to avoid the transesterification (Table 4, entries 1 and 3) but con-
versions remained low (<37%) although the enantioselectivity
was interesting (85%) with the SL-W008-1 ligand (Table 4, entry
1). Other combinations of solvents and ligands did not allow us
3. Conclusion
In conclusion, we have developed a new efficient catalytic system
based on rhodium and chiral ligands of the Walphos family for the
enantioselective hydrogenation of indole derivatives. These easily
accessible catalytic systems are prepared in situ from commercially
available diphosphines and readily accessible rhodium precursors.
These new catalytic systems are efficient at room temperature in
the presence of water. Small variations of the catalytic conditions al-
low optimizing of the system according to the properties desired

A. M. Maj et al. / Tetrahedron: Asymmetry 21 (2010) 2010–2014
2013
[Rh(OH)(cod)]2
chiral ligand
*
H2
100 bar
COOR
COOR
COOR
Boc
solvent R'OH
RT
N
N
N
Boc
H
7a or 8a
7b or 8b
7 R = Et
8 R = tBu
COOR'
N
H
9
Scheme 2. Asymmetric hydrogenation of the 2-substituted indole esters 7 and 8.
Table 4
Evaluation of ferrocenyl ligands in asymmetric hydrogenation of 7 and 8a
Entry Substrate Chiral auxiliary Solvent
Cs2CO3 (equiv/Rh) Conv.b (%) 7a or 8ab (%) 7b or 8bb (%) 9b (%) ee of 7a or 8a (%)c (config.)
1
2
3
4
5
6
7
8
7
7
7
7
8
8
8
8
SL-W008-1
SL-W006-1
SL-W008-1
SL W002-1
EtOH
iPrOH/H2O
EtOH
50
50
50
—
37
80
28
100
96
97
26
28
3
99
27
51
25
85
6
49
2
—
—
—
—
—
9
85 (R)
71 (R)
5 (S)
53 (R)
83 (R)
71 (R)
56 (R)
80 (R)
iPrOH
0
2-Methyl-butan-2-ol 50
60
35
56
3
MeOH/H2O
iPrOH/H2O
MeOH
50
50
—
86
100
3
8
a
b
c
7 or 8/[Rh(OH)(COD)]2/ligand/Cs2CO3: 80/1/1/50; PH2 = 100 bar, room temperature; 17 h, reaction time not optimized.
Determined by GC analysis.
Determined by HPLC analysis.
(chemoselectivity and enantioselectivity). Research is currently
underway to apply such catalytic systems to the hydrogenation of
other heteroaromatic substrates.
1.65 (s, 9H), 7.23 (m, 1H), 7.38 (m, 1H), 7.58 (m, 1H), 8.03 (m,
1H) ppm; 13C NMR (300 MHz, CDCl3) 27.9, 28.2, 81.90, 84.40,
114.73, 114.85, 122.09, 123.10, 126.53, 127.52, 132.22, 137.87,
149.44, 160.67 ppm.
4. Experimental
4.4. Di-tert-butyl indoline-1,2-dicarboxylate 8a
4.1. General and materials
1H NMR (300 MHz, CDCl3) 1.45 (s, 9H), 1.46 (s, 9H), 2.95 (m,
1H), 3.40 (m, 1H), 4.79 (m, 1H), 7.22 (m, 1H), 7.34 (m, 1H), 7.55
(m, 1H), 7.99 (m, 1H) ppm; 13C NMR (300 MHz, CDCl3) 27.97,
28.31, 43.47, 60.76, 81.20, 81.55, 114.59, 122.39, 125.10, 127.89,
128.10, 132.24, 151.80, 170.99 ppm.
The conversions of the substrates and selectivities were deter-
mined by GC analysis on a capillary CP Sil 5CB column (25 m,
N2 = 1 mL/min, 120–250 °C, oven rise = 10 °C/min). The enantio-
meric excesses were determined by HPLC analysis using
a
Chiralpak AD column (hexane/iPrOH = 90/10, flow = 0.8 ml/min).
All the hydrogenation experiments were prepared under a nitrogen
atmosphere. Propan-2-ol and MeOH were degassed with nitrogen
prior to use. The 1-tert-butyl 2-methyl 1H-indole-1,2-dicarboxyl-
ate 1 was prepared according to a reported procedure.4a The same
procedure was used for the ethyl 711 and tert-butyl 8 ester.
Acknowledgments
This work was supported by the Oril Industries (A. M. Maj).
The authors thank G. Servant, J.-P. Lecouve, N. Pinault, and M.
Sawamura for the fruitful discussions.
4.2. General procedure for the catalytic asymmetric
hydrogenation of 1-tert-butyl 2-methyl 1H-indole-1,2-
dicarboxylate 1
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A 50 ml Schlenk flask equipped with a magnetic stirrer bar was
charged with [Rh(OH)(COD)]2 (2.8 mg; 6.25 Â 10À3 mmol) and a
selected chiral ligand (12.5 Â 10À3 mmol). Then the mixture was
degassed by three vacuum/N2 cycles and the degassed solvent
(15 ml) was added. The mixture with the precatalyst was stirred
at room temperature for 1 h before cannula transfer into a 50 ml
double-walled stainless steel autoclave containing substrate 1
(0.96 mmol) and Cs2CO3 (202 mg; 0.614 mmol). The autoclave
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reaction was performed at the specified temperature over 17 h.
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