Br?nsted-Acid-Promoted Rh-Catalyzed Asymmetric Hydrogenation of N-Unprotected Indoles: A Cocatalysis of Transition Metal and Anion Binding

Article abstract of DOI:10.1021/acs.orglett.8b00312

The incorporation of Br?nsted acid, thiourea anion binding, and transition metal catalysis enables an efficient method to synthesize chiral indolines via hydrogenation of indoles. Catalyzed by a rhodium/ZhaoPhos complex, asymmetric hydrogenation of unprotected indoles is performed smoothly with excellent enantioselectivities (up to 99% ee, up to 400 TON). Br?nsted acid HCl activates indoles to form iminium ion intermediates. Mechanistic studies support the assumption that anion binding plays a crucial role as a secondary interaction. DFT calculations reveal an outer-sphere mechanism in this chemical transformation.

Full text of DOI:10.1021/acs.orglett.8b00312

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Brønsted-Acid-Promoted Rh-Catalyzed Asymmetric Hydrogenation
of N‑Unprotected Indoles: A Cocatalysis of Transition Metal and
Anion Binding
Jialin Wen,†,‡ Xiangru Fan,† Renchang Tan,§ Hui-Chun Chien,§ Qinghai Zhou,† Lung Wa Chung,*,†
and Xumu Zhang*,†
†Department of Chemistry, Southern University of Science and Technology (SUSTech), 1088 Xueyuan Road, Shenzhen 518055,
China
‡Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, 1088 Xueyuan Road, Shenzhen
518055, China
§Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Road, Piscataway, New
Jersey 08854, United States
S
* Supporting Information
ABSTRACT: The incorporation of Brønsted acid, thiourea
anion binding, and transition metal catalysis enables an
efficient method to synthesize chiral indolines via hydro-
genation of indoles. Catalyzed by a rhodium/ZhaoPhos
complex, asymmetric hydrogenation of unprotected indoles
is performed smoothly with excellent enantioselectivities (up
to 99% ee, up to 400 TON). Brønsted acid HCl activates
indoles to form iminium ion intermediates. Mechanistic
studies support the assumption that anion binding plays a crucial role as a secondary interaction. DFT calculations reveal an
outer-sphere mechanism in this chemical transformation.
proton is the simplest and a powerful catalyst. The last
Atwo decades have witnessed the prosperity of Brønsted
acid catalysis.1 Asymmetric Brønsted acid catalysis has been
demonstrated as a powerful tool in organic synthetic method-
ologies.2 In the meanwhile, thiourea hydrogen bonding, with
unique characteristics, such as moderate bonding energy and
directionality,3 plays an important role in the field of
organocatalysis. The combination of thiourea/urea derivatives
and simple Brønsted acids offers a broader acidity range than
chiral phosphoric acids. Moreover, tunable substituents on
bifunctional thiourea/urea catalysts can introduce many kinds
of secondary interactions, such as cation−π interaction and
π−π stacking3c,d,4 (Figure 1). The strategy of cooperative
Figure 1. Chiral Brønsted acid catalysis and thiourea anion binding
with simple Brønsted acid and Zhaophos.
catalysis emerged in recent years, aiming to combine two or
more catalytic centers to achieve a single reaction.5 The
integration of transition-metal-catalyzed hydrogenation and
small-molecule organocatalysis has shown its potential
application in synthetic chemistry.6
quinolines, and quinolines11 are among its successful
applications in asymmetric catalysis.
Chiral indolines are ubiquitous N-heterocycles. This
structural motif could be widely found in natural alkaloids
and drugs.12 Efficient synthetic methods to prepare optically
pure indolines are in high demand. Compared with other
synthetic approaches, hydrogenation of indoles is a straightfor-
ward method to obtain chiral indolines (Scheme 1). N-
We recently developed a bisphosphine-thiourea ligand,
ZhaoPhos.7 Within this ligand, a covalent linker connects a
ferrocene-based bisphosphine unit with a thiourea moiety
(Figure 1). We aimed to utilize the hydrogen bonding between
the thiourea and substrate to introduce a secondary interaction,
enabling chemical transformations with high enantioselectiv-
ities. The hydrogenations of nitroolefins,7,8 N-unprotected
iminium ions,9 α,β-unsaturated carbonyl compounds,10 iso-
Received: January 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00312
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Asymmetric Hydrogenation of N-Unprotected
Indole
Table 1. Condition Optimization for 2-Methylindole
b
c
entry
ligand
solvent
MeOH
conversion
ee
1
2
3
4
5
6
7
8
(S,R)-ZhaoPhos
(S,R)-ZhaoPhos
(S,R)-ZhaoPhos
(S,R)-ZhaoPhos
(S,R)-ZhaoPhos
(S,R)-ZhaoPhos
(S,R)-ZhaoPhos
(S,R)-ZhaoPhos
(S,R)-ZhaoPhos
L1
56%
>99%
21%
26%
14%
trace
76%
71%
>99%
68%
65%
0
27%
60%
84%
91%
84%
N.D.
94%
95%
95%
89%
80%
N.D.
98%
98%
N.D.
i-PrOH
CF3CH2OH
toluene
THF
1,4-dioxane
DCM
1,2-DCE
DCM
d
9
d
10
DCM
d
11
L2
DCM
Protected indoles have been successfully reduced with
ruthenium, iridium, or rhodium complexes.13 However, the
removal of protecting groups requires extra steps and leads to
loss of yields, thus increasing the cost for synthetic chemistry.
Due to their unique nature,13 N-unprotected indoles are still a
challenging class of hydrogenation substrates. The limited
successful examples for unprotected indoles were reported with
palladium,14 iridium,15 and ruthenium.16 In these cases, either
the relatively moderate enantioselectivity or the use of
expensive fluorinated alcohol limits their application in
industry. Therefore, we were looking forward to developing a
simple and economic synthetic method to afford chiral indoles
with excellent enantioselectivities and lower cost.
d
12
L3
DCM
e
13
(S,R)-ZhaoPhos
(S,R)-ZhaoPhos
(S,R)-ZhaoPhos
DCM
99%
97%
0
f
14
DCM
g
15
DCM
a
Reaction condition: 1a (0.1 mmol) in 1.0 mL of solvent, 1a/
[Rh(COD)Cl]2/ligand ratio = 100/0.50/1.0, 0.1 mL of HCl (2 M) in
b
1
Et2O solution was added. Conversion was determined by H NMR
analysis, and no side product was observed. ee was determined by GC
with a chiral stationary phase. 0.04 mL of HCl (5 M) in i-PrOH
solution was added. 0.2 mL of HCl (1 M) in AcOH solution was
c
d
e
f
g
applied. 0.25 mol % of Rh catalyst. No acid was added.
We envisioned that a strong Brønsted acid could activate this
kind of aromatic substrates, while the thiourea moiety of the
ligand forms a secondary interaction with the substrates. Based
on this theoretical rationale, we initiated our research with
hydrogenation of 2-methylindole with (S,R)-ZhaoPhos and
[Rh(COD)Cl]2. Hydrogen chloride in diethyl ether solution (2
M) was introduced as the Brønsted acid. After screening of
solvents, we found that dichloromethane and 1,2-dichloro-
ethane gave the highest conversion with the highest
make the ZhaoPhos/Rh catalytic system easy in organic
synthesis communities. However, without Brønsted acid HCl,
no product was observed, leading to almost 100% recovery of
starting material (entry 15).
The substrate scope of this chemical transformation was
explored under the optimized conditions (Scheme 2). By
adding hydrogen chloride in acetic acid as the Brønsted acid
source, 2-monosubstituted indoles and 2,3-disubstituted indoles
were hydrogenated smoothly with high enantioselectivities
(82% ∼ 99% ee). Various substituents at the C-2 position or on
the benzene ring brought no significant influence on the
enantioselectivity, while the yields vary from case to case. Due
to the extraordinary electron-withdrawing effect, the nitro
group on the fused benzo ring may cause difficulty in the
protonation step, leading to a low yield (2j). Substrate 2p
remains a challenge, and this might be caused by a highly stable
enamine structure conjugate with phenyl on the 2-position,
which is difficult to protonate. 2,3-Disubstituted indoles were
also hydrogenated successfully with both high diastereoselec-
tivities (>25:1) and high enantioselectivities.
In order to gain insight into the reaction pathway, isotope
labeling experiments (Scheme 3) were conducted. When the
reaction was performed in deuterated solvent with hydrogen
gas, D atoms were located only at the C-3 position and H
atoms at the C-2 position. When regular solvents and
deuterium gas were applied, D atoms were located exclusively
at the C-2 position, and no significant signal of D atoms was
observed at the C-3 position. These results suggested that it is
the CN bond, rather than CC, that is hydrogenated. A
1
enantiomeric excess (Table 1, entries 7 and 8). H NMR
analysis showed no byproducts (e.g., dimerization products),
which are usually found in acidic conditions. Diethyl ether,
however, is extraordinarily volatile, and therefore, its HCl
solution is difficult to handle and measure in a glovebox. In
addition, the concentration of HCl in ether can hardly be
maintained in the reaction condition. Isopropanol and acetic
acid, with much higher boiling point, might be desirable
alternatives. When we applied HCl (5 M) in isopropanol, the
conversion was driven up to nearly 100% with the retention of
high enantioselectivity (Table 1, entry 9). Finally, hydrochloric
acid in acetic acid was chosen to be the acid source (entry 10,
99% conversion and 98% ee). [For further acid screening and
the rationale, please see Supporting Information.] A series of
analogues of ZhaoPhos were prepared and tested afterward.
They did not show superiority to ZhaoPhos (L1, L2, and L3).
This reaction was conducted smoothly with catalyst loading as
low as 0.25% (entry 14), giving a turnover number of
approximately 400. In addition, the equivalent of hydrogen
chloride to indole substrate is wide-ranging.17 These advantages
B
DOI: 10.1021/acs.orglett.8b00312
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Scheme 2. Substrate Scope for Asymmetric Hydrogenation
of Indoles
Scheme 4. Control Experiments to Demonstrate the
Importance of Thiourea
a
the thiourea dominates the anion binding, while the less acidic
one contributes much less.19 Counterion effect was also
examined:20 fluoride anion dose not bring a significant
influence to this asymmetric reaction, while bromide and
iodide ions lower both the reactivity and enantioselectivity.
These results demonstrated that the thiourea−chloride anion
binding plays a crucial role in this chemical transformation.
Further investigation on binding manner between ZhaoPhos
and the chloride ion was undertaken. A Job plot was drawn, and
the curve suggests a 1:1 binding pattern (Figure 2).21 In
addition, high-resolution mass spectroscopy supports this
ZhaoPhos−chloride ion complex.22
a
Reaction condition: 1 (0.1 mmol) in 1.0 mL of solvent, 1/
[Rh(COD)Cl]2/ligand ratio = 100/0.50/1.0; isolated yields ee’s were
determined by HPLC with a chiral stationary phase.
Scheme 3. Deuterium Labeling Experiments and Proposed
Reaction Pathway
Figure 2. Job plot and NMR titration curves.
To gain insight into the reaction mechanism, DFT (PCM
B3LYP-D3/def2-SVP method) calculations have been per-
formed by using the Rh(I)/ZhaoPhos complex and substrate
1a. The computed possible pathway was initiated with oxidative
addition of H2 to the Rh(I) to form an active Rh(III) dihydride
intermediate. A five-coordinate Rh(III) is less usual than an
octahedral one in homogeneous hydrogenation reaction,23 but
it will be highly crowded (much higher in energy) if another
ligand is introduced in this rhodium complex. After the
protonation of indole by HCl, a catalyst−substrate complex is
formed (INT4). Hydride transfer then preferentially occurs to
the Re- face at C-2 of the protonated indole in an outer-sphere
manner24 (TS2OS). TS2OS is computed to be lower in free
energy than TS2IS (inner-sphere) and TS2OR by 2.3−6.9
kcal/mol in solution, partly due to a larger distortion of the
metal−ligand part in TS2OR (Scheme 5 and Figure S1). The
chloride ion forms hydrogen bonds with the thiourea of
ZhaoPhos and the protonated indole NH group in TS2OS.
After dissociation of indoline and coordination of another H2
protonation and the following enamine−iminium transforma-
tion probably occur prior to the hydrogenation. A noteworthy
finding is the reduced abundance of the deuterium atom at the
2-position in exp. 2, which is probably caused by H/D
exchange.18
The anion binding of ZhaoPhos with the chloride ion was
already observed in our previous NMR studies.9,11 Control
experiments were conducted to examine the cooperation of the
thiourea moiety and the bisphosphine scaffold. Each unit of
ZhaoPhos was demonstrated to be necessary for efficient
asymmetric hydrogenation of 2-methylindole. [For experimen-
tal details of ligand evaluation, see SI.] Substitution of the less
acidic proton in the thiourea with the methyl group (Scheme 4,
L4) led to only a minor decrease of ee. Replacement of both
protons (L5), however, lead to a sharp decrease in both
conversion and ee. We assume that the more acidic proton in
C
DOI: 10.1021/acs.orglett.8b00312
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Scheme 5. Proposed Possible Mechanism with Computed
Relative Free Energies (kcal·mol−1) by the B3LYP-D3
Method in Solution
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: zhangxm@sustc.edu.cn.
*E-mail: oscarchung@sustc.edu.cn.
ORCID
Jialin Wen: 0000-0003-3328-3265
Lung Wa Chung: 0000-0001-9460-7812
Xumu Zhang: 0000-0001-5700-0608
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for Prof. Warmuth’s constructive discussion
about hydrogen bonding, Mr. Yang Gao’s technical support,
and Dr. Tian Zhou’s computational support for modeling study
(all at Rutgers University). We gratefully acknowledge the
financial support from the NSFC and SUSTech.
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dihydrogen to regenerate the active dihydride species and HCl,
which was computed to be the rate-determining step. Our
computational results are qualitatively consistent with the
experimental observations and support the cooperative effect of
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In summary, we developed an efficient catalytic system that
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suggested an outer-sphere mechanism in the hydrogenation
step.
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