Oxidative Kinetic Resolution of Acyclic Amines Based on Equilibrium Control

Article abstract of DOI:10.1021/acs.orglett.0c00887

An oxidative kinetic resolution of racemic acyclic amines was developed using an imine derivative as the resolving reagent and chiral phosphoric acid as the catalyst to give enantiomers in good yields with high to excellent enantioselectivities. The key t

Full text of DOI:10.1021/acs.orglett.0c00887

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Letter
Oxidative Kinetic Resolution of Acyclic Amines Based on Equilibrium
Control
Kodai Saito, Hiromitsu Miyashita, Yui Ito, Masahiro Yamanaka, and Takahiko Akiyama*
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ABSTRACT: An oxidative kinetic resolution of racemic acyclic
amines was developed using an imine derivative as the resolving
reagent and chiral phosphoric acid as the catalyst to give
enantiomers in good yields with high to excellent enantioselectiv-
ities. The key to success of the title reaction was the equilibrium
control by adjusting the ratio of the resolving reagent, and unique
enantiodivergence was observed depending on the equilibrium displacement.
xidative kinetic resolution (OKR) is a kinetic resolution
method that is based on a dehydrogenative reaction of
have been applied to the enantioselective construction of
complex molecules, their reaction mechanisms are based on
intramolecular processes that are essential for efficient hydride
transfer. No intermolecular hydride transfer from acyclic
amines into electron-deficient unsaturated moieties has been
achieved until recently.8 Erker’s group reported an intermo-
lecular redox-neutral amine C−H functionalization induced by
B(C6F5)3.8a This attractive process was initiated by the hydride
transfer from amines into alkynes and resulted in the formation
of carbon−carbon bonds. However, there was no application
to a catalytic reaction because of the stable complex formation
of the product with B(C6F5)3. More recently, Wasa’s group
achieved a B(C6F5)3-catalyzed asymmetric direct Mannich
reaction using acyclic amines with electron-deficient α,β-
unsaturated olefins as hydride acceptors.8b Efficient carbon−
carbon bond formation proceeded to give a wide variety of β-
amino acid derivatives under convenient conditions, and an
optically active product could be synthesized by the combined
use of B(C6F5)3, the chiral magnesium complex, and
unsaturated olefins bearing oxazolidinone auxiliaries based on
substrate control.
O
racemic substrates. Although OKR of secondary alcohols has
been extensively studied,1 OKR of secondary amines
accompanied by oxidation to imines has posed several
challenges mainly because (1) the nitrogen atom generally
possesses a low oxidation potential and (2) the Lewis basic
amine frequently deactivates the catalyst. Because of these
issues, OKR of secondary amines based on a dehydrogenative
reaction has remained a challenge.2
The organocatalyzed hydrogen transfer (HT) reaction has
been extensively investigated in the asymmetric transfer
hydrogenation of ketimines3 using Hantzsch ester as the H2
donor in combination with chiral phosphoric acid.4 We have
demonstrated the utility of benzothiazoline as a hydrogen
donor in the chiral phosphoric acid catalyzed transfer
hydrogenation of ketimines.5 The aromatization of Hantzsch
ester and benzothiazoline would be the driving force for HT.
In contrast, the transfer hydrogenation of imines using other
amine-derived H2 donors, in which aromatization does not
proceed after the evolution of a hydrogen, has been
underexplored.6 For example, Nakajima and co-workers
reported that a tertiary amine functioned as a hydride donor
in the trichlorosilyl triflate mediated conjugate reduction of
unsaturated ketones.6a An asymmetric reduction of α,β-
unsaturated acylsilane using chiral lithium amides derived
from the corresponding secondary amines was also achieved by
Takeda et al.6e Under these circumstances, the development of
a catalytic method for asymmetric HT based on a hydride
transfer from an acyclic amine is a daunting task (see Scheme
1).
We have recently developed an organocatalyzed OKR of
cyclic amines, including indolines and tetrahydroquinolines.9
The HT processes proceeded to furnish chiral cyclic amines
accompanied by the formation of indole and quinoline,
respectively.10 However, OKR of simple acyclic amines was
not investigated at all. Therefore, we decided to examine OKR
of acyclic amines based on intermolecular HT. Despite viable
candidates for the reaction development, the accomplishment
Received: March 10, 2020
As related reactions, internal redox reactions involving a
[1,5]-hydride shift and a subsequent cyclization of a
zwitterionic intermediate have recently attracted much
attention. In these reactions, a C−H bond adjacent to a
nitrogen atom of an acyclic amine is, in many cases, activated
due to the t-amino effect.7 Although these cascade reactions
https://dx.doi.org/10.1021/acs.orglett.0c00887
© XXXX American Chemical Society
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Scheme 1. Background and Concept of This Work
Scheme 3. Proposed Reaction Mechanism
Scheme 2. Investigation of Reversibility of the HT Reaction
Figure 1. 3D structures and relative energies (kcal/mol, Gibbs free
energies in italics) of TSmajor and TSminor leading to (R) and (S)
enantiomers.
amine and (2) thermodynamic equilibrium between the
starting amine and the resulting imine. Although the first
issue is the ultimate problematic point, we have recently found
that an imine bearing an electron-rich aromatic ring on a
nitrogen atom could be strongly activated by a Brønsted acid
catalyst9a and envisioned that it would enable HT from an
acyclic amine to an imine (resolving reagent). Additionally, we
hypothesized that the thermodynamic equilibrium of this HT
process, the second issue, could be resolved by controlling the
ratio of the amine substrate to the resolving reagent because of
the inherent reactivity of an aldimine versus a ketimine.
Therefore, by controlling the ratio of aldimine, the reverse
reaction pathway could be suppressed. We wish to report
herein a Brønsted acid catalyzed OKR based on HT between
acyclic amines and imines.
At the outset, we examined the enantioselective HT reaction
of N-3,4,5-trimethoxyphenyl (TMP)-substituted amine rac-1a
and imine 3a. When the reaction of 1a (1 equiv) and 3a (0.5
equiv) was first tested in the presence of a catalytic amount of
(R)-TRIP11−13 in toluene at 110 °C, the conversion of 1a was
of OKR using HT of acyclic amines would be precluded by
such issues as (1) low hydrogen donating ability of the acyclic
B
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d
Table 1. Screening for Amine and Imine in Catalytic Kinetic
Resolution
Scheme 4. Substrate Scope
a
bc
,
entry
amine
imine
yield/ee
1
2
3
4
5
6
1a (1 equiv)
1a (1 equiv)
1a (1 equiv)
1b (1 equiv)
1b (1 equiv)
1a (1 equiv)
3a (0.5 equiv)
3a (2 equiv)
3b (2 equiv)
3a (2 equiv)
3a (2 equiv)
4a (2 equiv)
(S)-1a 60%/14% ee
(S)-1a 40%/91% ee
(S)-1a 51%/86% ee
(S)-1b 46%/97% ee
(S)-1b 48%/97% ee
1a 90%/0% ee
d
a
Conditions: Resolutions were carried out on a 0.1 mmol scale with
racemic amine, imine, (R)-TRIP (10 mol %), and 5 Å MS (50 mg) in
b
toluene (0.1 M) at 110 °C (oil bath) for 7d. Isolated yields.
c
d
Determined by chiral HPLC analysis. Reaction time was 2 d.
moderate with 14% ee. Use of 2 equiv of 3a as the resolving
reagent dramatically improved the efficiency of OKR to furnish
1a in 40% yield with 91% ee. Next, we checked the reaction of
imine 4a and an excess amount of 2a to elucidate the
reversibility of the HT process between 1a and 3a and found
that the HT reaction preferentially occurred to give (R)-1a in
33% yield with 99% ee (Scheme 2). These results suggest that
this HT reaction of the imines and the amines is in
thermodynamic equilibrium. Furthermore, the loading of
resolving reagent (aldimine) 3a is critical for the present OKR.
The proposed mechanism of this HT reaction is shown in
Scheme 3. Under OKR conditions, the reaction of a large
amount of 3a and rac-1a would produce amine 2a and
ketimine 4a. Two reaction pathways A and B would occur
(paths A and B, Scheme 3). Path A would regenerate 2a and
3a. On the other hand, path B would proceed to give 3a and
(R)-1a, which would decrease the efficiency of this OKR.
Therefore, the addition of an excess amount of 3a would make
it possible to repeat the reaction of path A while suppressing
path B, and as a result, highly selective OKR would be
achieved. In the transfer hydrogenation of 4a (Scheme 3), HT
from amine 2a to imine 4a would furnish imine 3a and (R)-1a
with excellent enantioselectivity. During this reaction, the
reaction of 3a and (R)-1a would also proceed to give amine 2a
and imine 4a. In these processes, the production of (S)-1a
would not occur; therefore, (R)-1a would be finally obtained
with high enantioselectivity.
To elucidate the preferential reaction and formation of (R)-
1a in OKR and HT, respectively, DFT calculations were
conducted (B3LYP/6-31G*, Figure 1).14 The transition state
(TS) models reported previously allow us to employ (Z)-
ketimine, which is structurally preferred in the chiral space of
the catalyst. Therefore, we explored TS models that
correspond to the enantiofacial selection of 4a [leading to
(R) and (S) enantiomers of 1a, TSmajor, and TSminor] and
two transferable hydrogen atoms of 2a (see the Supporting
Information). In agreement with the experimental observation
(Scheme 2), TSmajor is energetically more stable than
a
b
c
Isolated yields. Determined by chiral HPLC analysis. The reaction
was run on a 1 mmol scale, and the yield is given in parentheses.
d
Conditions: Resolutions were carried out on a 0.1 mmol scale with
racemic 1 (0.1 mmol), 3a (0.2 mmol), (R)-TRIP (10 mol %), and 5 Å
MS (50 mg) in benzene (0.1 M) at 110 °C (oil bath) for 7 d.
TSminor. Both OKR and HT proceed via the same TS, in
which amine and imine are simultaneously activated through
the two-point hydrogen bonding interaction with a phosphoric
acid moiety. The transferring hydrogen atom is positioned in
between the amine (aldimine) and ketimine parts. The amine
part is located at a similar position in both TSmajor and
TSminor, avoiding the steric repulsion with the 3,3′-
substituents of the catalyst. In contrast, the arrangement of
ketimine is significantly changed in TSmajor and TSminor. In
TSminor, to reduce the steric repulsion, ketimine is positioned
far from the phosphoric acid moiety, and the N-Ph group of
C
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ketimine is located parallel to the 3,3′-substituents of the
catalyst. Such a structural requirement by the steric repulsion
in TSminor weakens the hydrogen bonding interaction
between the ketimine part and the phosphoric acid moiety
(TSmajor: 1.782 Å, TSminor: 1.898 Å), destabilizing
TSminor. Thus, the inactivity of (S)-1a for the hydrogen
transfer to imines under the reaction conditions was also
confirmed by the theoretical approach.
Next, we examined the effect of the combination of amine
(1a, 1b, 2a) and imine (3a, 3b, 4a) (Table 1). When 1a and
N-PMP-imine 3b were subjected to these reaction conditions,
low conversion was observed (entry 3). From this result, we
elucidated that electron-rich N-TMP-aldimine 3a is more
suitable than N-PMP-aldimine 5a for the efficient HT, as we
had expected.15 We found that N-PMP amine 1b and N-TMP
imine 3a are the combination of choice for the present KR,
furnishing (S)-1b in 46% yield with 97% ee, and this yield was
further increased to 48% when the reaction time was shortened
without loss of ee (entries 4 and 5).16 The reaction of 1a and
ketimine 4a resulted in very low conversion (entry 6),
indicating that the steric hindrance of the hydrogen acceptor
is also important for HT.
In order to examine the scope of this OKR, a range of
amines 1c−1s was subjected to the optimized reaction
conditions (Scheme 4). All of the amines reacted to give the
corresponding chiral amines in high yields with good to
excellent enantioselectivities. Amines bearing electron-donat-
ing and -withdrawing groups on aromatics and heteroaromatics
(1b−1m) were also suitable substrates, affording the
corresponding chiral amines in high yields with high to
excellent enantioselectivities. Sterically hindered group-sub-
stituted amines (o-tolyl (1n), 1-naphthyl (1o)), cyclic
secondary amine 1p, and propylamine derivative 1q also
participated successfully. Simple acyclic amines 1r and 1s were
also found to be suitable substrates.17
Chemistry, Faculty of Science and Technology, Keio University,
Yokohama, Kanagawa 223-8522, Japan; orcid.org/0000-
0001-5867-2713
Hiromitsu Miyashita − Department of Chemistry, Faculty of
Science, Gakushuin University, Tokyo 171-8588, Japan
Yui Ito − Department of Chemistry, Faculty of Science, Rikkyo
University, Tokyo 171-8501, Japan
Masahiro Yamanaka − Department of Chemistry, Faculty of
Science, Rikkyo University, Tokyo 171-8501, Japan;
orcid.org/0000-0001-7978-620X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00887
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Trans-
formation Organocatalysis” from MEXT, Japan, JSPS KA-
KENHI (17H03060 for T.A. and 17KT0011 for M.Y.), and the
MEXT-supported Program for the Strategic Research
Foundation at Private Universities.
REFERENCES
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00887.
Detailed experimental procedures and characterization
data (1H NMR, 13C NMR, HRMS, IR, etc.) (PDF)
AUTHOR INFORMATION
Corresponding Author
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́
́
imines, see: (a) Fleury-Bregeot, N.; de la Fuente, V.; Castillon, S.;
Claver, C. Highlights of Transition Metal-Catalyzed Asymmetric
Hydrogenation of Imines. ChemCatChem 2010, 2, 1346. (b) Xie, J.-
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Takahiko Akiyama − Department of Chemistry, Faculty of
Science, Gakushuin University, Tokyo 171-8588, Japan;
orcid.org/0000-0003-4709-4107;
Email: takahiko.akiyama@gakushuin.ac.jp
Authors
Kodai Saito − Department of Chemistry, Faculty of Science,
Gakushuin University, Tokyo 171-8588, Japan; Department of
D
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(13) When we examined the substituent effect at the 3,3′-position of
the phosphoric acid catalyst for this reaction, the use of the SiPh3
group or p-NO2C6H4 group substituted catalysts resulted in no
reactions. Therefore, the selection of the phosphoric acid catalyst is
also an important factor to proceed this OKR.
(14) Computational details are shown in the SI.
(15) As we previously reported in ref 6a, the N-TMP group could be
more strongly activated by the phosphoric acid catalyst.
(16) However, this reaction condition could not be widely applied
for this OKR. Therefore, we examined the substrate scope based on
the condition of entry 4 (Table 1), mainly.
(17) Selectivity factor of the reaction of substrates 1r and 1s showed
negative values. The reason for this is considered to be that the
selectivity of the reverse reaction is low, resulting in the induction of
the enantiomerization of substrates. Reist, M.; Testa, B.; Carrupt, P.-
A.; Jung, M.; Schurig, V. Racemization, Enantiomerization, Diaster-
eomerization, and Epimerization: Their Meaning and Pharmaco-
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G
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