Asymmetric Synthesis of Optically Active Spirocyclic Indoline Scaffolds through an Enantioselective Reduction of Indoles

Article abstract of DOI:10.1002/chem.201605450

An enantioselective synthesis of spirocyclic indoline scaffolds was achieved by applying an asymmetric iridium-catalyzed hydrogenation of 3H-indoles. Low catalyst loadings and mild reaction conditions provide a broad range of differently substituted products with excellent yields and enantioselectivities. The developed methodology allows an efficient synthesis of this important spirocyclic structural motif, which is present in numerous biologically active molecules and privileged structures in medicinal chemistry.

Full text of DOI:10.1002/chem.201605450

A Journal of
Accepted Article
Title: Asymmetric Synthesis of Optically Active Spirocyclic Indoline
Scaffolds Applying an Enantioselective Reduction of 3H-Indoles
Authors: Magnus Rueping
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To be cited as: Chem. Eur. J. 10.1002/chem.201605450
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Asymmetric Synthesis of Optically Active Spirocyclic Indoline
Scaffolds Applying an Enantioselective Reduction of Indoles
Ruediger Borrmann, Nils Knop, and Magnus Rueping*
Abstract: An enantioselective synthesis of spirocyclic indoline
scaffolds was achieved by applying an asymmetric iridium catalyzed
hydrogenation of 3H-indoles. Low catalyst loadings and mild reaction
conditions provide a broad range of differently substituted products
with excellent yields and enantioselectivities. The developed
methodology allows an efficient synthesis of this important
spirocyclic structural motif, which is present in numerous biologically
active molecules and privileged structures in medicinal chemistry.
Therefore, we decided to develop
a
metal catalyzed
hydrogenation of indoles for the enantioselective synthesis of
spirocyclic indoline scaffolds in which no protecting groups are
needed (Scheme 1).
Indoles and indolines are among the most widespread
motives in naturally occurring bioactive compounds, insecticides,
herbicides and drugs.[1,2] In particular, the 2-aryl-indoline
structural element represents an important and prevalent motive
in biologically and pharmaceutically active molecules with
antitumor, anti-infective and anti-proliferative activity.[3]
Additionally, chiral 2-aryl-indolines are privileged structures in
medicinal chemistry as they possess cardiovascular[4] and
nervous system[5] activity (Figure 1).
Asymmetric hydrogenation reactions employing molecular
hydrogen and transition metal catalysts are among the most
efficient and economic methods to generate chiral molecules.[6]
The enantioselective hydrogenation of imines, enamines and N-
heteroarenes in particular represents the most important access
towards chiral amines,[7,8] not only in academia, but importantly
in industry[9] and drug discovery.[10] Thus, the most direct
approach to synthesize chiral 2-aryl-indolines would be the
application of an asymmetric hydrogenation of the
corresponding indoles. However, indoles are challenging
substrates and their enantioselective hydrogenation remained
unsuccessful for a long time. Furthermore, the few existing
reports are limited to either N-protected indoles[11] or to alkyl and
benzyl substituents in 2-position of unprotected indoles.[12]
Except for an example of a cyclization strategy[13] and kinetic
resolution approaches,[14] the only direct access to unprotected
chiral 2-aryl-indolines to date is an organocatalytic procedure.[15]
Unfortunately, the latter procedures are as yet not efficient
enough to compete with the metal catalyzed hydrogenations, in
particular when larger amounts of product need to be prepared.
Figure 1. Bioactive and pharmacologically relevant indole and indoline
scaffolds.
The 2-aryl-indolenine substrates can be readily prepared via
a hindered Fischer-indole-synthesis from commercially available
hydrazines and alkyl-aryl-ketones in a one-pot procedure[16]
which provides a straightforward way to prepare a variety of 2-
aryl 3,3-disubstituted spirocyclic indoline substrates. Here, we
report a first successful asymmetric hydrogenation protocol for
the synthesis of 2-aryl 3,3-spirocyclic indolines.[17,18]
Scheme 1. Asymmetric hydrogenation of 3H-indoles.
[a]
Dr. Rüdiger Borrmann, M.Sc. Nils Knop, Prof. Dr. Magnus Rueping
Institute of Organic Chemistry, RWTH Aachen
Landoltweg 1, 52074 Aachen (Germany)
Fax: (+49) 241-809-2665
We commenced our studies with the asymmetric
hydrogenation of model substrate 2a applying different metal
catalysts (Table 1). While palladium, platinum and rhodium
BINAP complexes showed very low activity, ruthenium failed to
give satisfying enantioselectivity. Iridium complexes, however,
showed good reactivity and provided a promising selectivity of
56%ee (entry 7). Further reaction optimization involved the use
of different counterions which typically do have a great impact
on the reactivity or selectivity of the reaction. We screened
several counterions by addition of their corresponding sodium or
E-mail: magnus.rueping@rwth-aachen.de
Prof. Dr. M. Rueping
King Abdullah University of Science and Technology (KAUST)
KAUST Catalysis Center (KCC)
Thuwal, 23955-6900 (Saudi Arabia)
E-mail: magnus.rueping@Kaust.edu.sa
Supporting information for this article is given via a link at the end of
the document.
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silver salts and in situ formation of the active catalysts. To our
surprise, none of the tested additives improved the
enantioselectivity, neither halide sources for catalyst activation
nor acid additives for substrate activation were beneficial for the
reaction outcome.
on the enantioselectivity. On one hand, high reactivity is
observed at elevated temperatures, which is desirable in order
to
minimize
catalyst
loading
and
reaction
time.
Table 2. Survey of solvents and ligands.
[Ir(cod)Cl]2
Table 1. Survey of metal precursors and additives.
ligand
metal
(R)-BINAP
additive
solvent, 50 °C
100 bar, 12 h
N
H
N
2a
3a
N
N
DCM, 50 °C
H
100 bar, 12 h
3a
2a
Conv.
[%]
ee[c]
[%]
abs.
config.
Entry[a]
Solvent
Ligand[b]
Catalyst
precursor
Additive
(6 mol%)
Conv.
[%]
ee[b]
[%]
abs.
config.
Entry[a]
1
2
DCM
BINAP
BINAP
>95
56
66
(R)
(R)
CHCl3
>95
76
1
2
Rh(cod)2BF4
Rh(cod)acac
--
--
5
12
14
(R)
(S)
10
3
DCE
toluene
acetone
MeCN
MeOH
dioxane
Et2O
BINAP
71
62
34
12
16
12
69
79
79
79
83
69
82
91
96
97
98
98
97
(R)
(S)
(S)
(R)
(R)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
3
[Rh(cod)Cl]2
Ir(cod)2BF4
Ir(cod)acac
[Ir(cod)OMe]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
--
<5
n.d.[c]
n.d.[c]
4
BINAP
>95
5
4
--
44
24
(S)
5
BINAP
5
--
<5
n.d.[c]
1
n.d.[c]
(R)
6
BINAP
75
6
--
>95
>95
89
7
BINAP
18
7
--
56
(R)
8
BINAP
>95
>95
35
8
AgBF4
AgPF6
AgAsF6
AgSbF6
NaBArF[d]
AgTFA[e]
33
(R)
9
BINAP
9
>95
90
33
(R)
10
THF
BINAP
10
11
12
13
14
28
(R)
11
THF
MeO-BIPHEB
P-Phos
73
88
22
(R)
12
THF
>95
86
92
3
(S)
13
THF
SYNPHOS
SEGPHOS
DIFLUORPHOS
DTBM-SEGPHOS
DM-SEGPHOS
DM-SEGPHOS
DM-SEGPHOS
DM-SEGPHOS
DM-SEGPHOS
>95
>95
19
(R)
14
THF
88
[f]
AgNTf2
48
(R)
15
THF
>95
94
16
THF
[a] Reaction conditions: 2a (0.1 mmol), metal precursor (5 mol%; 2.5 mol% for
the dimeric species [Rh(cod)Cl]2 and [Ir(cod)Cl]2), (R)-BINAP (6 mol%), DCM
(2 mL, 0.05 M), 50 °C, 100 bar H2, 12 h, additive (none or 6 mol%); [b]
Determined by SFC using Chiralcel OD-H column; [c] Not determined; [d]
17
THF
>95
>95
>95
>95
>95
18[d]
19[d,e]
20[d,e,f]
21[d,e,f,g]
THF
Sodium
trifluoroacetate; [f] Silver bis(trifluoromethylsulfonyl)-imide.
tetrakis-[3,5-bis(trifluoromethyl)-phenyl]borate;[19]
[e]
Silver
THF
THF
THF
Subsequently, we evaluated various solvents (Table 2) and
the use of chlorinated solvents including chloroform and 1,2-
dichloroethane improved the enantioselectivity to 71% ee (entry
3). Polar solvents such as alcohols, acetonitrile, and dioxane
gave inferior results. However, toluene, etheric solvents, and
THF turned out to be efficient, with the latter one providing the
best result (79% ee, entry 10). Typically, the chiral ligand has a
tremendous impact on the enantioinduction, especially in
asymmetric hydrogenations. Among various tested ligands,
axially chiral diphosphines derived from the BINAP framework
proved to be efficient. SYNPHOS (83% ee, entry 13),
DIFLUORPHOS (82% ee, entry 15) and SEGPHOS based
structures with substituents on the phosphorous aryl rings (91%
ee, 96% ee, entries 16 and 17) were superior. Overall, the m-
xylyl substituted DM-SEGPHOS was found to be the best ligand
showing high reactivity and excellent enantioselectivity (96% ee,
entry 17). Having a promising catalytic system in hands, we
evaluated additional parameters including temperature,
hydrogen pressure, and concentration (Table 2, entries 18-21).
Temperature is an important parameter with noticeable impact
[a] Reaction conditions: 2a (0.1 mmol), [Ir(cod)Cl]2 (2.5 mol%), ligand (6 mol%),
solvent (2 mL, 0.05 M), 50 °C, 100 bar H2, 12 h; [b] All ligands in
(R)-configuration; [c] Determined by SFC using Chiralcel OD-H column;
[d] 30 °C; [e] 150 bar H2; [f] solvent (1 mL, 0.1 M); [g] [Ir(cod)Cl]2 (0.5 mol%),
ligand (1.2 mol%).
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On the other hand, lower temperatures ensure
a better
enantiofacial discrimination resulting in higher ee values, but
often at the expense of moderate reactivity. By screening
several temperatures, we found an optimum between reactivity
and enantioselectivity at 30 °C (97% ee, entry 18). Higher
temperatures of up to 70 °C resulted in a slight decrease in
enantioselectivity (95% ee), while lower temperatures of 25 °C
and 20 °C resulted in a dramatic loss of reactivity (20% and <5%
conversion, respectively). Subsequently, we investigated the
influence of hydrogen pressure. Interestingly, low pressure of
20 bar still gave full conversion and 95% ee, which represents
remarkably mild conditions for such a hydrogenation. However,
high pressures had a positive effect on the enantioselectivity
(98% ee, entry 19). Additionally, concentration effects were
studied. Diluted solutions resulted in lower reactivity and
enantioselectivity, while higher concentrations provided better
results (98% ee, entry 20). Finally, we lowered the catalyst
loading to 0.5 mol% [Ir(cod)Cl]2 still achieving full conversion and
satisfying 97% ee (entry 21).
With the best conditions in hand, we applied this newly
developed asymmetric hydrogenation to differently substituted 2-
aryl 3,3-disubstituted indolenines (Scheme 2). In general, the
hydrogenation protocol can be applied to various substituted
indolenines and the products are obtained in good yields and
with acceptable enantioselectivities. Substituents in 3-position
(3a-c, 96-98%, 94-97% ee) are not limited to methyl groups but
also tolerate cyclic alkyl residues giving rise to highly valuable
spirocyclic indolines in excellent yields. Notably, indoline 3c was
synthesized on a 2 mmol scale (>500 mg), demonstrating the
potential of upscaling our protocol. We retained the spiro-
cyclohexyl motif and investigated substitutions in 5-position (3d-
h, 92-96%, 92-95% ee). To our delight, halides including fluorine,
chlorine and bromine were tolerated without showing
dehalogenated side products. This fact is most likely caused by
the selective catalyst and the comparatively mild reaction
conditions. Further variations of the substrate scope were
achieved by modification of the substituents in 2-position of the
indolenine framework. Para-substituted phenyl rings (3i-m, 93-
97%, 92-96% ee) with electron donating and electron
withdrawing
groups
provided
excellent
yields
and
enantioselectivities as well as halides, again showing no
dehalogenation. We were also interested in different substitution
patterns and found equally good results for meta-substituted
phenyl rings (3n-q, 93-96%, 91-96% ee) and more complex
substituents (3s-u, 92-95%, 92-94% ee) including biphenyl or
annulated bicycles. Substrates with ortho-substituted phenyl
rings in 2-position however are sterically hindered. However,
their hydrogenated products are still obtained with a high level of
enantiomeric excess (3r, 93%, 98% ee).
Scheme 2. Substrate scope of the iridium catalyzed enantioselective
hydrogenation of 2-aryl-3H-indoles. Reaction conditions:
2 (0.1 mmol),
[Ir(cod)Cl]2 (1 mol%), (R)-DM-Seg-Phos (2.4 mol%), THF (1 mL, 0.1 M), 35 °C,
150 bar, 12 h; enantiomeric ratios determined by SFC using Chiralcel OD-H
column; [a] 30 °C; [b] 2 mmol scale (>500 mg substrate).
In summary, we have developed a highly enantioselective
synthesis of valuable disubstituted and spirocyclic 2-aryl-indoline
scaffolds which represent an important class of biologically
active molecules and privileged structures in medicinal
chemistry. The hydrogenation protocol shows good functional
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Keywords: indole · asymmetric reduction · iridium catalyzed ·
spirocycle · pharmacophore
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