Iridium-Catalyzed Enantioselective Hydrogenation of Oxocarbenium Ions: A Case of Ionic Hydrogenation

Article abstract of DOI:10.1002/anie.201916677

Ionic hydrogenation has not been extensively explored, but is advantageous for challenging substrates such as unsaturated intermediates. Reported here is an iridium-catalyzed hydrogenation of oxocarbenium ions to afford chiral isochromans with high enantioselectivities. A variety of functionalities are compatible with this catalytic system. In the presence of a catalytic amount of the Br?nsted acid HCl, an α-chloroether is generated in situ and subsequentially reduced. Kinetic studies suggest first-order kinetics in the substrate and half-order kinetics in the catalyst. A positive nonlinear effect, together with the half kinetic order, revealed a dimerization of the catalyst. Possible reaction pathways based on the monomeric iridium catalyst were proposed and DFT computational studies revealed an ionic hydrogenation pathway. Chloride abstraction and the cleavage of dihydrogen occur in the same step.

Full text of DOI:10.1002/anie.201916677

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Accepted Article
Title: Iridium-catalyzed enantioselective hydrogenation of
oxocarbenium ions: a case of ionic hydrogenation
Authors: Tilong Yang, Yongjie Sun, Heng Wang, Zhenyang Lin, Jialin
Wen, and Xumu Zhang
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10.1002/anie.201916677
Angewandte Chemie International Edition
RESEARCH ARTICLE
Iridium-catalyzed enantioselective hydrogenation of
oxocarbenium ions: a case of ionic hydrogenation
Tilong Yang[a],[b],[d], Yongjie Sun[a],[d], Heng Wang[a], Zhenyang Lin*[b], Jialin Wen*[a],[c] and Xumu Zhang[a]
Dedication ((optional))
[a]
[b]
T. Yang, Y. Sun, H. Wang, Dr. J. Wen and Prof. Dr. X. Zhang
Shenzhen Grubbs Institute and Department of chemistry,
Southern University of Science and Technology,
1088 Xueyuan Road, Shenzhen, 518055, China.
E-mail: wenjl@sustech.edu.cn
T. Yang and Prof. Dr. Z. Lin
Department of chemistry,
The Hong Kong University of Science and Technology,
Clear Water Bay, Kowloon, Hong Kong, China.
E-mail: chzlin@ust.hk
[c]
[d]
Dr. J. Wen
Academy for Advanced Interdisciplinary Studies
Southern University of Science and Technology
1088 Xueyuan Road, Shenzhen, 518055, China.
Tilong Yang and Yongjie Sun contributed equally.
Supporting information for this article is given via a link at the end of the document.
Abstract: Compared to the classic “inner-sphere” transition metal
catalyzed homogeneous hydrogenation reactions, ionic
different reaction pattern typically requires a metal hydride
complex and a Brønsted acid: an in situ formed carbenium
intermediate is prone to be reduced by a hydride species.
Compared to “inner-sphere[4]” hydrogenation reactions which
dominate the asymmetric hydrogenation processes, ionic
hydrogenation is far less developed. Advantages of ionic
hydrogenation include: (1) noninvolvement of change in the
valence of the transition metal having the potential to enable a
high turnover number (TON); (2) chemoselectivity for polar C=O
and C=X bonds over nonpolar C=C bonds. The formation of a
carbenium species generally requires an acid, under which
hydrogenation has been a far less explored area. This type of
hydrogenation reaction, however, has its advantages for some
challenging substrates such as unsaturated intermediates. We herein
report an iridium-catalyzed hydrogenation of oxocarbenium ions to
afford chiral isochromans smoothly with high enantioselectivities. A
variety of functionalities are compatible with this catalytic system. In
the presence of catalytic amount of Brønsted acid HCl, α-chloroether
was in situ generated and subsequentially reduced. Kinetic studies
suggested 1st-order kinetics in the substrate and half-order kinetics in
the catalyst. A positive nonlinear effect, together with the half kinetic
order, revealed a dimerization off the catalytic cycle. Several possible
reaction pathways based on the monomeric iridium catalyst were
proposed and DFT computational studies revealed an ionic
hydrogenation pathway. Chloride abstraction and the cleavage of
dihydrogen occur at the same step.
condition
a majority of metal hydride complexes are not
compatible.
Oxocarbenium ions are a special class of carbocations. With a
resonance structure of the C=O+ unit, the carbon cation could be
stabilized with the conjugation from the adjacent oxygen atom.
This feature makes them much more stable and therefore in a
higher concentration. Asymmetric transformations based on
oxocarbenium ions have drawn chemical practitioners’ attention
in the recent decade. Since Jacobsen and co-workers’ studies on
Introduction
thiourea-catalyzed
addition
reaction[5],
many
catalytic
methodologies based on oxocarbenium ions have been
developed, such as nucleophilic addition of enolate[6],
alkynylation[7], acetalization[8], oxa-Pictet-Springler reaction[9] and
reduction[10]. A practical and commonly applied method to access
oxocarbenium ions is the elimination of a leaving group. In this
equilibrium, if the leaving anion could be trapped by another
molecule via molecular recognition, the formation of
oxocarbenium ions will be favored. We recently developed a
bifunctional ligand, ZhaoPhos[11], aiming to incorporate a thiourea
moiety on a bisphosphine ligand to render a secondary interaction
with a substrate. Anion binding of thiourea with substrates assists
to achieve high efficiencies and high enantioselectivities in
homogeneous hydrogenation of cationic C=N bonds present in
Platinum group metal catalyzed hydrogenation of C=C, C=O
and C=N bonds plays a crucial role in the realm of homogeneous
catalysis[1]. The addition of dihydrogen to unsaturated compounds
has undoubtedly found its merit in both pharmaceutical and
chemical industries[2]. The mechanisms of the above-mentioned
hydrogenation catalyzed by various transition metals (namely
rhodium, ruthenium and iridium) have been well studied and
documented, which could be summarized as the classic “inner-
sphere” hydrogenation reactions having a coordinating-insertion
pattern (Figure 1a). On the other hand, ionic hydrogenation[2-3]
,
which delivers proton and hydride separately, shows a different
reaction pattern that does not involve the coordination of substrate
and the insertion of the unsaturated bond (Figure 1b, 1c). This
iminium[12]
, . We
(iso)quinolinium[13] and indolinium ions[14]
1
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10.1002/anie.201916677
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RESEARCH ARTICLE
envisioned that this type of highly reactive intermediates could be
captured by thiourea[15] and be reduced by metal hydride
complexes in an ionic hydrogenation manner[16]. Herein, we report
an iridium catalyzed hydrogenation of oxocarbenium ions to afford
chiral isochromans smoothly with high enantioselectivities.
Figure 1. Ionic hydrogenation of carbocation intermediate. a, General mechanism of the classic “inner-sphere” hydrogenation of olefins. b, A stepwise ionic
hydrogenation reaction. c, Resonance structures of oxocarbenium ions. d, A practical strategy to generate oxocarbenium ions and ionic hydrogenation.
Results and Discussion
Condition optimization. 1-Methyl-1-methoxy isochroman
entry
1
metal precursor
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
Pd(TFA)2
acid
solvent
DCM
conv. [a]
>95%[e]
>95%[e]
>95%[e]
>95%[e]
>95%[e]
>95%[e]
>95%[e]
>95%
ee [b]
12%
36%
39%
<2%
97%
97%
92%
99%
99%
N.A.
(ketal 1a) was selected as the oxocarbenium precursor. Initially,
trimethylsilyl triflate[7c] (TMSOTf) was applied as Lewis acid and
[Rh(COD)Cl]2 as the transition metal precursor. Commonly used
chiral ligands in asymmetric hydrogenation reactions, such as
DuanPhos, BINAP, QuinoxP* and the Josiphos family, failed to
catalyze this reaction. In contrast, catalyzed by a Rh/ZhaoPhos
complex, the hydrogenation reaction proceeded with full
conversion, although the enantioselectivity was poor (only 12%
ee, Table 1, entry 1). Lewis acid boron trichloride and Brønsted
acid HCl also worked in this reaction with a minor improvement of
ee. Alternation of transition metal to palladium and iridium resulted
in two different enantioselectivities: Pd(TFA)2 gave almost
racemic product while [Ir(COD)Cl]2 boosted the ee up to 97%.
After further screening, the optimal condition was obtained: 1-
methylisochromane was cleanly formed with remarkably high
enantioselectivity and full conversion (99% ee in toluene).
Isochroman ketal was also fully consumed in DCM, DCE, and
THF but by-products, which we were unable to identify, were
observed in these solvents. We hypothesize that a cation-π
interaction could stabilize the highly reactive oxocarbenium ion,
making the hydrogenation reaction proceeding smoothly[17]. Other
commercial HCl solutions, such as HCl in dioxane, do not show
noticeable differences (entry 9). However, there was no
hydrogenation product in the reaction without acid (entry 10).
TMSOTf (1.0 eq)
BCl3 (0.35 eq)
HCl (1.0 eq) [c]
HCl (1.0 eq) [c]
HCl (1.0 eq) [c]
HCl (1.0 eq) [c]
HCl (1.0 eq) [c]
HCl (1.0 eq) [c]
HCl (1.0 eq) [d]
No acid
2
DCM
3
DCM
4
DCM
5
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
DCM
6
DCE
7
THF
8
toluene
toluene
toluene
9
>95%
10
0
[a] Reaction condition: 1a (0.1 mmol) in 1.0 mL solvent, 1a/metal/ligand
ratio=100/0.50/1.0. Conversion was determined by 1H NMR analysis. [b] The ee
value was determined by HPLC on a chiral stationary phase. [c] 0.10 mL of HCl
(1.0 M in AcOH) was added. [d] 0.025 mL of HCl (4.0 M in dioxane) was added;
[e] Detectable impurities were observed in the reaction mixture.
The reactive nature of oxocarbenium ion favors a high TON in
this chemical transformation and the experimental results
approved the hypothesis mentioned above: under a minor-
modified condition, the TON could approximately reach 8600 at a
large scale. In addition, at a lower hydrogen pressure (e.g. 10
atm) or even at ambient condition, 1-methylisochroman was
formed with high enantioselectivity (99% ee). In addition, lowering
Table 1. Condition optimization for hydrogenation: from isochroman ketal to
isochroman.
2
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10.1002/anie.201916677
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RESEARCH ARTICLE
the loading of the Brønsted acid HCl to 10% did not diminish the
conversion or enantiomeric excess dramatically. [For reaction
details, see supporting information.]
afforded various chiral isochromans with this method. However,
isochroman acetal with a phenyl group led to an eroded
enantioselectivity (2j). Ethyl or isopropyl acetal was prepared
when the acetal cyclization was conducted in different alcoholic
media (1k and 1l). No obvious difference in enantioselectivity was
observed when performing this hydrogenation reaction using
methyl, ethyl or isopropyl isochroman ketal (2a, 2k or 2l).
Functional groups like ether and ester could tolerate the reaction
condition (2m and 2n). Interestingly, a C≡C bond, which is often
sensitive in many transition metal catalyzed hydrogenation
systems[2], is finely compatible in this system (2p and 2q). This
chemoselectivity suggests an ionic hydrgeonation mechanism.
In order to exploit the potential application of this method in
synthetic communities, robustness of the catalyst and
compatibility with different functionalities should be evaluated. We
applied Glorius’ method[18] to carry out a fast screening (see
supporting information). This chemical transformation showed
compatibility with many functionalities, such as carboxylic acid,
amide, nitro, nitrile, phenol and ketone. In accordance with the
reaction of alkynyl substrates, various alkynes survived in this
reaction. Moreover, the introduction of thiophene did not influence
this reaction, while pyridine made it sluggish and less
enantioselective. The excellent chemoselectivity demonstrated
the potential application of this method in synthetic chemistry.
Figure 3. Examination of the role of the thiourea-chloride anion binding. a,
control experiments with ferrocene-based bisphosphine ligands analogical to
ZhaoPhos demonstrated the importance of the double hydrogen donor. b.
introduction of various counterions indicates the superiority of chloride.
Figure 2. Asymmetric hydrogenation of oxocarbenium ions: from isochroman
ketals to chiral isochromans. Reaction condition:
1
(0.2 mmol),
1/[Ir(COD)Cl]2/ZhaoPhos = 400:1.0:2.05/2.0, 0.1 mL HCl (1 M in acetic acid) in
1.0 mL toluene, Isolated yields. Enantiomeric excesses were determined by
HPLC on a chiral stationary phase.
Control experiments. To evaluate the role of anion binding
between thiourea and chloride in this catalysis, we conducted a
series of control experiments: iridium with dppf fails to catalyze
this hydrogenation, resulting in a recovery of most of the
substrate; methylation of thiourea leads to a sharp decrease in
both yield and enantioselectivity (Figure 3a, L1 and L2). The
hydrogen bond donor, thiourea, undoubtedly plays a crucial role
in this reaction. In addition, counter-ion effect was also evaluated:
triflate ion gives poor enantioselectivity when using TMSOTf as
the Lewis acid; the introduction of various anions in this reaction
alters both the conversion and the ee (Figure 3b). Chloride gives
the highest enantioselectivity (92% ee, close to the result from the
Scope of asymmetric hydrogenation of oxocarbenium ions.
Various isochroman ketals were prepared and tested under the
optimal condition (Figure 2). Different substituents did not bring
significant change in reactivities or enantioselectivities.
Isochroman ketals with either electron-donating group (-OMe) or
electron-withdrawing group (-F) on the benzene ring could be
transformed to chiral isochroman with high enantioselectivities.
Other halogen atoms (Cl, Br) on the benzene ring did not bring
significant changes. Altering the substituents on 1-position
3
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10.1002/anie.201916677
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optimized condition), showing its superiority over other
counterions.
neither the isochroman acetal (δ ~1.6 ppm) nor a carbenium ion
intermediate[20] (δ > 3 ppm), suggesting that this compound is
likely to be chloroisochroman (1a’)[21]. In addition, each set of
diastereotopic protons on the ring merged to one triplet peak
(Figure 4a, marked red and blue), indicating an equilibrium
between the two enantiomers of 1-chloro-1-methylisochroman via
an oxocarbenium intermediate. The broadened methyl peak at δ
2.0 also indicated the existence of this equilibrium. The mixture of
1a and HCl in benzene-d6 gave a similar spectrum (see
supporting information). Variating the ratio of HCl to 1a makes the
methyl peak shift from 1.6 to 2.0 (Figure 4b), suggesting a fast
equilibrium between 1a + HCl and 1a’ + MeOH. DFT calculation
results (vide infra) showed that the formation of 1a’ and MeOH is
thermodynamically favored by 2.1 kcal/mol in toluene.
Reaction pathway. A question emerged after the success of
this enantioselective chemical transformation: what is the reaction
pathway? Hydrogen chloride was applied in the formation of α-
chloroamide via a proposed SN1 pathway[19]. In this case, we
hypothesized that the formation of chloroisochroman occurs
before the oxocarbenium ion[5]. To verify our assumption, many
attempts were made to isolate 1-chloro-1-methylisochroman. To
our disappointment, we failed to obtain a pure form of it, probably
because it is less stable than 1-chloroisochroman in Jacobsen’s
case[5]. However, evidences were still collected to support this
reaction pathway. The mixing of HCl (4.0 M in dioxane, 1.0 eq.)
and 1a yielded a product with a methyl signal at δ 2.0 ppm (Figure
1
4a, marked purple) in H NMR spectrum. The signal belongs to
Figure 4. The transformation of acetal 1a to α-chloroether.
Scheme 1. Deuterium labelling experiments and proposed reaction pathway.
Isotope labeling experiments (Scheme 1a and 1b) were also
conducted to reveal the reaction pathway of this reaction. The
combination of hydrogen gas with deuterated solvents and acid
gave a methyl deuterated isochroman. High abundance of D
atoms on the methyl group suggested a fast equilibrium between
100%, suggesting a possible H-D exchange under the reaction
condition[22]. Based on these studies, we proposed a plausible
reaction pathway (Scheme 1c): in the presence of hydrogen
chloride, isochroman acetal is converted to chloroisochroman,
which forms a reactive oxocarbenium ion after anion abstraction
an oxocarbenium ion and a terminal enol ether. On the other hand, with thiourea catalyst[23]. An iridium hydride complex reduces this
the combination of deuterium gas with normal solvent and acid
gave expected C-1 deuterated compound. Noteworthy, the
abundance of H or D atoms at C-1 position in each case was not
oxocarbenium ion to afford the chiral isochroman product.
Kinetic and nonlinear effect experiments. Kinetic profiles
were obtained with in situ attenuated total reflectance Fourier-
4
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10.1002/anie.201916677
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RESEARCH ARTICLE
transform infrared (ATR FTIR) spectroscopy. In a minor-modified
condition (0.5 eq. HCl, 20 atm H2 pressure, see supporting
information), graphical rate equation[24] displayed a 1st order
dependence on the substrate. This reaction, however, has an
induction period with higher catalyst loading (e.g. S/C = 125).
Kinetic studies with different catalyst concentration revealed that
this reaction exhibits half-order kinetics in catalyst (see supporting
information). This behavior suggested a dimerization of the
catalyst and that Kagan’s reservoir effect[25] might apply in this
case. In other words, the monomeric species, rather than the
dimeric ones, catalyze this transformation[26]. Rate equation was
After mixing with [Ir(COD)Cl]2,
the bisphosphine ligand
Zhaophos is expected to replace COD to form a square planar
Ir(I) complex I (Figure 6). The Brønsted acid HCl oxidizes this d8
complex, giving an octahedral d6 Ir(III) hydride complex II′.
Isomerization of II′ occurs to give a thermodynamically more
stable trigonal bipyramidal Ir(III) complex II, which enters the
catalytic cycle (Figure 6a), with the Cl- anion binding to the
thiourea moiety. This isomerization offers a vacant coordinating
site, which facilitates the coordination of dihydrogen to form a
dihydrogen IrIII(η2-H2) complex III. From this dihydrogen complex
III, there are serval possible pathways for the H2 activation. The
most favorable pathway is the heterolytic cleavage of H2 with the
help of 1a′, having an energy barrier of 11.4 kcal/mol, to give the
intermediate IV (Figure 6b). Assembling III with 1a′ is
thermodynamically favorable to gives a van der Waals complex
III+1a′, suggesting that the van der Waals interaction can
counteract the entropy cost in this two-to-one process. Formation
of the intermediate IV accompanies the release of HCl that
functions as the reagent to convert the substrate 1a to 1a′. The
intermediate IV, which is a van der Waals complex of dihydride
IrIII(H)2 with the resulting carbenium ion, then undergoes a hydride
transfer reaction. This is the enantio-determining step: the hydride
reducing the carbenium ion gives the product (S)-2a via an overall
barrier of 11.9 kcal/mol (Figure 6b) while the formation of (R)-2a
incurs a higher overall barrier of 14.0 kcal/mol, giving a DFT-
calculated ee value of 94.5% (Figure 7).
derived and the constant was obtained (푘′
=
(
)
9.85 ± 0.18 ×
푐푎푡
1
10−3 M− · s−1). Catalytic monomeric species seemed in a very
low proportion in the reaction mixture. The potential aggregation
of the catalyst encouraged us to examine the relationship of
enantio-purity of the catalyst and the enantioselectivity. A
pronounced positive nonlinear effect was observed, which
suggested that the heterochiral dimer is much favored over the
homochiral ones in this equilibrium (K ≫ 1).
2
3.0
2.5
2.0
1.5
1.0
0.5
0.0
100
80
60
40
20
0
S/C = 2000
S/C = 1000
S/C = 500
S/C = 125
0
20
40
60
80
100
0.00
0.02
0.04
0.06
0.08
ee of ligand
[1a] (M)
Figure 7. Transition states calculated for the hydride transfer step to generate
both enantiomers of 2a.
Thiourea-assisted anion abstraction has been demonstrated
effective in the in-situ formation of oxocarbenium ions[5, 23a]. In the
current system, thiourea-assisted chloride abstraction would first
require to generate a thiourea-coordinated complex, such as the
dihydride Ir(III) complex V shown in Figure 6a. However, the
thiourea-Cl- complexation with a six-member-ring structure, is
very stable, indicating that the regeneration of free thiourea is
challenging. To generate the Ir(III) complex V, H2 activation may
go through other pathways, which were calculated to have
noticeably higher energy barriers compared to the most favorable
pathway shown in Figure 6b. Other H2 activation pathways,
including homolytic (oxidative addition of H2 to Ir(III) in III) and
heterolytic (the coordinated S acting as a base for deprotonation),
were also calculated and found to have noticeably higher energy
barriers (15.3 and 15.2 kcal/mol for TS2-1 and TS2-2 shown in
Figure S6). A HCl-assisted heterolytic split of dihydrogen, which
involves an external HCl as a proton shuttle to protonate the
thiourea needs a much higher barrier of 24.8 kcal/mol (Figure S6,
TS2-3). After HCl elimination from the protonated thiourea, the
Figure 5 Kinetic profiles of asymmetric hydrogenation of oxocarbenium ions. a.
Graphical rate equation with different catalyst concentration at 20 atm H2
pressure. b. Nonlinear relationship between ligand ee and product ee. c.
Proposed catalytic model involving dimerization of the catalyst.
DFT calculation to reveal an ionic hydrogenation
mechanism. Due to the non-coordinating feature of
oxocarbenium ions, classic “inner-sphere” model could not
explain this reaction. The ionic hydrogenation pattern is therefore
highly favored in this case[16, 27]. The H2 activation and hydride
transfer are two key steps involved in the mechanism of
hydrogenation reactions. Here, we report the results of our DFT
calculations of the reaction mechanism. For simplicity, the results
for some unfavorable pathways are given in the supporting
information.
5
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10.1002/anie.201916677
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RESEARCH ARTICLE
reactive thiourea-coordinated complex V would be generated.
Clearly, the formation of V is both thermodynamically and
dynamically unfavorable, suggesting that thiourea-assisted
chloride abstraction is not possible in the current catalytic system.
Figure 6. DFT calculated reaction mechanism. a. Proposed catalytic cycle in this reaction. b. Energy profile for the most favorable reaction pathway. Ar = 3,5-di-
CF3Ph, the phenyl groups on the phosphorus atoms are omitted for clarity, and the relative Gibbs free energies and electronic energies (in parentheses) are given
in kcal/mol.
the substrate and a half-order dependence on the catalyst.
Dimerization of the catalyst was proposed for this reaction. DFT
computational studies revealed that the cleavage of C-Cl bond
and the split of dihydrogen occurred in one single step, which is
Conclusion
different from previous studies that the thiourea plays a crucial
role in the in situ formation of oxocarbenium ions via chloride
abstraction. Moreover, this acid-tolerant catalytic system provides
us a tool to hydrogenate reactive intermediates in an acidic
condition.
Oxocarbenium ions have been brought into transition metal
catalyzed ionic hydrogenation in this work. In the presence of
Brønsted acid HCl, the isochroman acetal substrate and α-
chloroisochroman are in fast equilibrium.
Highly reactive
oxocarbenium ions, which are in situ formed from chloride
abstraction, is then reduced by an iridium hydride complex. High
enantioselectivities were achieved in this chemical transformation.
A remarkable efficiency and excellent chemoselectivities indicate
its potential application in synthetic chemistry. Mechanistic
studies, both experimental and computational, were carried out.
Kinetic profile of this reaction suggests a 1st order dependence on
Acknowledgements
We are grateful for the constructive discussion with Prof. Wei
Jiang (SUSTech) and Dr. Jean-Nicolas Desrosiers (Pfizer). This
6
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10.1002/anie.201916677
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project was financially supported by the NSF of China (21801118
and 21602172), the Science, Technology and Innovation
Commission of Shenzhen (KQTD20150717103157174) and the
Research Grants Council of Hong Kong (HKUST 16304017 and
16302418).
Keywords: asymmetric catalysis • ionic hydrogenation •
oxocarbenium • iridium • mechanistic study
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