Iridium-catalyzed asymmetric hydrogenation of N-protected indoles

Article abstract of DOI:10.1002/chem.200903105

Chiral indolines substituted at C-2 or C-3 can be prepared in high yield and excellent enantioselectivity by asymmetric hydrogenation of N-protected indoles by using Ir catalysts with chiral N,P ligands. With less reactive substrates, the reaction had to

Full text of DOI:10.1002/chem.200903105

DOI: 10.1002/chem.200903105
Iridium-Catalyzed Asymmetric Hydrogenation of N-Protected Indoles
Alejandro Baeza and Andreas Pfaltz*[a]
Chiral indolines are common structures occurring in alka-
loids and other natural or synthetic products that exhibit
biological activity.[1] In addition, indolines with a stereogenic
center at C-2 have been used as organocatalysts or chiral
auxiliaries in asymmetric transformations.[2] Different meth-
ods have been developed to obtain such molecules in an
enantioselective manner; however, only a few catalytic
methods have been reported, most of them based on enzy-
matic or nonenzymatic kinetic resolutions.[3] One of the best
methods in terms of simplicity and atom efficiency would be
the direct asymmetric hydrogenation of substituted indoles,
but this reaction, along with the hydrogenation of other het-
eroaromatic compounds, still represents a challenge.[4] The
only suitable catalysts for this transformation reported so
far are based on the trans-coordinating diphosphine (S,S)-
(R,R)-PhTRAP ligand paired with rhodium or ruthenium.[5]
Hydrogenation with these catalysts in the presence of base
allowed the preparation of 2- or 3-substituted indolines in
high enantiomeric purity. Herein we report another efficient
class of catalysts for the asymmetric hydrogenation of N-
protected indoles, cationic Ir complexes derived from
PHOX or other chiral N,P ligands.[6]
A1 and A2, along with catalyst B[8] and the pyridine-based
catalyst C[9] were identified as optimal catalysts for this reac-
tion, giving the best conversions and enantioselectivities.
After refinement of the reaction parameters, such as hydro-
gen pressure, catalyst loading, and solvent,[7] full conversion
and high enantioselectivities were achieved within 6 h at am-
bient temperature and 50 bar of hydrogen pressure in di-
chloromethane when using catalysts A1, A2, or
B
(Scheme 1).
Initial studies were carried out on unprotected 2-methyl
and 2-phenyl indoles, but only moderate conversions and
enantioselectivities were obtained. Methylation of the nitro-
gen atom improved the conversion but, disappointingly, the
enantioselectivity dropped sharply.[7] In contrast to the find-
ings of Kuwano and Ito,[5] addition of base or other additives
led to worse results. We next turned to N-Boc-protected in-
doles, using the 2-methyl derivative 1a as test substrate.
After an exhaustive screening of catalysts, we found that iri-
dium complexes bearing an electron-rich dialkyl-phosphane
group provided the best results.[7] Thus, Ir-PHOX complexes
Scheme 1. Asymmetric hydrogenation of indole 1a with catalysts A1, A2
and B. i) H2 (50 bar), cat. (1 mol%), CH2Cl2, 258C, 6 h.
With catalyst C, which had already proved to be effective
in the asymmetric hydrogenation of furans and benzofur-
ans,[9] perfect enantioselectivity was obtained (>99% ee), al-
though the conversion remained moderate. Increase of cata-
lyst loading, temperature and reaction time gave only minor
improvements.[7] Kinetic measurements showed that the re-
action came to a halt after 8 h; this implies that catalyst de-
activation was the problem. Consequently, the catalyst was
added in two portions, 2 mol% in the beginning and
2 mol% after 8 h. In this way, 89% conversion was achieved
at 608C and 100 bar hydrogen pressure, while the enantio-
meric excess remained at 99% despite the elevated reaction
temperature (Scheme 2).
[a] Dr. A. Baeza, Prof. A. Pfaltz
Department of Chemistry, University of Basel
St. Johanns Ring 19, 4056 Basel (Switzerland)
Fax : (+41)61-267-1103
E-mail: andreas.pfaltz@unibas.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903105 and contains details
and analytical data for the compounds.
Next the influence of different substituents at C-5 of the
indole nucleus was examined (Table 1). The presence of
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Chem. Eur. J. 2010, 16, 2036 – 2039

COMMUNICATION
Other substituents at the 2 position were also examined.
Thus, 2-phenyl and 2-carboethoxy-substituted N-Boc-pro-
tected indoles 2a and 2b were subjected to hydrogenation
using the catalysts and conditions mentioned above. Howev-
er, the results were disappointing, especially with substrate
3b, which gave the corresponding deprotected indole as the
main product in most cases. To our delight, the Ir-Thre-
PHOX complex D[11] proved to be much more effective in
this case. The 2-phenyl derivative gave 94% conversion and
88% ee with this catalyst under the conditions shown in
Scheme 4. In the hydrogenation of substrate 3b, partial
Scheme 2. Asymmetric hydrogenation of indole 1a using catalysts C.
i) H2 (100 bar), C (4 mol%), CH2Cl2, 608C, 24 h.
Table 1. Effect of substituents in the asymmetric hydrogenation of in-
doles 1.
1b
1c
Catalyst
Conv. [%][a]
ee [%][b]
Conv. [%][a]
ee [%][b]
Scheme 4. Asymmetric Hydrogenation of 2-subsituted N-Boc indoles 3a
and 3b. i) H2 (75 bar), D (1 mol%), CH2Cl2, 258C, 24 h. [a] At 100 bar H2
pressure and with 2 mol% catalyst loading.
A1
A2
B
87
81
>99
90
95
95
58
43
98
84
88
84
1
[a] Determind by H NMR analysis after removal of the catalyst (see the
Supporting Information for details). [b] Determind by HPLC analysis on
a Daicel Chiralcel OD-H column (see the Supporting Information for de-
tails).
cleavage of the Boc group was observed. However, this
problem was overcome by simply increasing the catalyst
loading (up to 2 mol%) and the hydrogen pressure
(100 bar). Finally, 3-substituted indoles were also tested but,
disappointingly, gave only low or no conversion.
In addition to Boc, other common nitrogen protecting
groups were evaluated. N-Acetyl-2-phenylindole reacted
with high enantioselectivity, similar to the N-Boc-protected
analogue, but conversions were low.[7] In contrast, high con-
versions and excellent enantioselectivities were achieved
with the 2-carboethoxy derivative 5c (Scheme 5). Among
either an electron-donating group, like methoxy (1b), or an
electron-withdrawing substituent, like fluorine (1c), led to a
decrease in the conversion. The methoxy group had a posi-
tive effect on the enantioselectivity, whereas the fluoro de-
rivative gave somewhat lower ee values than the unsubstitut-
ed indole 1a (Table 1). Catalyst B turned out to be especial-
ly active as compared to PHOX complexes A1 and A2, and
excellent conversions were obtained even with these sub-
strates. The 5-nitro derivative 1d, on the other hand, did not
react under these conditions.
The same trend for the hydrogenation of indoles 1b and
1c was observed with catalyst C.[7] Since conversions were
even lower than with the standard substrate 1a, the sequen-
tial catalyst addition strategy was again adopted, leading to
moderate conversions and excellent enantioselectivities
(Scheme 3). In chlorobenzene at 1108C, the enantioselectivi-
ty was still very high, while the conversion increased to
85%.[10]
Scheme 5. Asymmetric hydrogenation of 2-subsituted N-Ac indole 5c.
i) H2 (100 bar), cat., CH2Cl2, 30 h.
the catalysts tested, the pyridine-based complex C gave the
highest enantiomeric excess (99% ee). However, more vigo-
rous conditions than for the more reactive catalyst D had to
be applied to achieve high conversion. N-Acetyl-3-carbome-
thoxyindole, on the other hand, did not react with these cat-
alysts, even under forcing conditions. N-Acetyl-3-methylin-
dole also proved to be very unreactive. Although ee values
of up to 93% were achieved, conversions remained low
(<35%).
Finally we turned our attention to N-tosyl-protected in-
doles. The 2-methylindole 7a was found to be less reactive
than the N-Boc derivative, requiring long reaction times and
Scheme 3. Effect of substituents in the asymmetric hydrogenation of in-
doles 1. i) H2 (100 bar), C (4 mol%), CH2Cl2, 608C, 24 h. [a] With PhCl
as solvent and at 1108C.
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A. Pfaltz and A. Baeza
high H2 pressure, but the enantioselectivities were consider-
ably higher (99% ee for catalysts A2 and B).[7] As observed
for the N-Boc derivative, complex B proved to be the most
reactive catalyst, giving high conversion under the condi-
tions shown in Scheme 6. The need for more forcing condi-
Scheme 8. Asymmetric hydrogenation of 3-subsituted N-tosyl indoles 9a.
i) H2 (100 bar), C (2.5 mol%), CH2Cl2, 608C, 30 h.
In summary, our results show that cationic Ir catalysts
with chiral N,P ligands are efficient catalysts for the asym-
metric hydrogenation of N-protected indoles. The ee values
are in the same range as those reported for Ru and Rh com-
plexes with the (S,S)-(R,R)-PhTRAP ligand, which were the
only suitable catalysts known for this substrate class up to
now.[5] However, in contrast to Rh- and Ru-catalyzed hydro-
genations, no base additives are needed. A further advant-
age of the Ir catalysts is their air and moisture stability. The
results obtained with N-Boc-, N-acetyl-, and N-tosylindoles
demonstrate that the protecting group influences both the
reactivity and enantiomeric excess. With the right combina-
tion of catalyst and protecting group, high yields and excel-
lent enantioselectivities can be achieved for various 2- and
3-substituted indoles.
Scheme 6. Asymmetric hydrogenation of 2-subsituted N-tosyl indole 7a.
i) H2 (100 bar), B (2 mol%), CH2Cl2, 258C, 30 h.
tions could be due to coordination of the catalyst to the sul-
fone group, which could lower the activity of the catalyst,
but on the other hand cause the remarkable increase in
enantioselectivity (Scheme 6).
Next, other 2-substituted N-tosyl-indoles were examined.
As before, 2-phenyl and 2-carboethoxyindole 7b and 7c
were subjected to hydrogenation under the conditions used
for 7a. The best results were obtained with catalyst C but,
despite high enantioselectivities, the conversions remained
low. However, with higher catalyst loading and sequential
catalyst addition (see above), we were able to successfully
hydrogenate substrate 7c with high conversion and excellent
enantioselectivity when the temperature was raised to 608C
(Scheme 7). However, when the same conditions were ap-
Experimental Section
General procedure for the iridium-catalyzed asymmetric hydrogenation
of N-protected indoles: A solution of the N-protected indole (0.2 mmol)
and the iridium complex (1–2.5 mol%) in dry dichloromethane (1 mL,
previously filtered over basic alumina) under an inert atmosphere was
placed in an autoclave, which was sealed, purged with hydrogen, and
pressurized to the desired hydrogen pressure. After the mixture had been
stirred at the desired temperature for the indicated time, the solvent was
evaporated, and the catalyst was removed by filtration through a short
silica gel column (3ꢁ1 cm) with pentane/diethyl ether (1:1, 25 mL) as
eluent to give the corresponding N-protected indoline after evaporation
of the solvent.
When the reaction was carried out with sequential addition of catalyst,
the same procedure was followed, but after 8 h at the reported tempera-
ture, the autoclave was allowed to cool down to 30–408C and opened
after the hydrogen pressure had been released. Then a solution of the iri-
dium complex in the corresponding dry solvent (100 mL, previously fil-
tered over basic alumina) was syringed into the reaction vessel. The auto-
clave was sealed again, purged with hydrogen, and repressurized. Then
stirring was continued at the reported temperature for an additional 16 h.
Scheme 7. Asymmetric hydrogenation of 2-subsituted N-tosyl indoles 7b
and 7c. i) H2 (100 bar), C (4 mol%), solvent, 24 h.
plied to the 2-phenylindole 7b, conversion only reached
55%. Even at 1108C in chlorobenzene the conversion did
not exceed 70%. On the other hand, the enantiomeric
excess remained at 98% despite the high temperature
(Scheme 7).
Among the 3-substituted N-tosylindoles, the 3-methyl de-
rivative 9a reacted with perfect enantioselectivity (>99%
ee) when using catalyst C under standard conditions, but the
conversion was moderate (52%). Therefore, the reaction
was carried out at elevated temperature (Scheme 8). Most
gratifyingly, almost quantitative conversion was achieved at
608C, while the ee remained at very high level of 98%. N-
Tosylindoles with carboxylic ester groups at C-3 (9b, R=
CO2Me; 9c, R=CH2CO2Et) showed extremely low reactivi-
ty and gave only very low or no conversion at all, even
under forcing conditions.
For catalyst screening, reactions were performed on a 0.1 mmol scale.
A preparative experiment was also carried out by using 2-methyl-N-Boc-
protected indole 1a and catalyst A2. The general procedure was fol-
lowed, but using a 0.4m solution (instead of 0.2m) of 1a (578 mg,
2.5 mmol) in chlorobenzene (6.25 mL) and 1 mol% of A2 catalyst
(38 mg). After the mixture had been stirred at 258C under H2 (50 bar)
for 6 h. The solvent was evaporated, and the catalyst was removed by fil-
tration through a silica gel column (2ꢁ12 cm) with pentane/diethyl ether
(1:1, 100 mL) as eluent. The pure indoline 2a was obtained in 94% yield
(544 mg) with 92% ee.
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Hydrogenation of N-Protected Indoles
COMMUNICATION
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Acknowledgements
A.B. would like to thank the Spanish Ministerio de Educaciꢂn, Ciencia y
Deporte (MECD) and Fundaciꢂn EspaÇola para la Ciencia y la Tecnolo-
gꢃa (FECYT) for a Postdoctoral fellowship. Support of this work by the
Swiss National Science Foundation and the Federal Commission for
Technology and Innovation (KTI) is gratefully acknowledged.
Keywords: asymmetric catalysis · hydrogenation · indoles ·
indolines · iridium
[7] See the Supporting Information for details.
[8] For the use of these catalysts for the asymmetric hydrogenation of
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[10] When these conditions were applied to substrate 1c, partial depro-
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cates that cleavage of the N-Boc group occurs (at least in part)
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Received: November 12, 2009
Published online: January 26, 2010
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2039