Integration of aerobic oxidation and intramolecular asymmetric aza-Friedel-Crafts reactions with a chiral bifunctional heterogeneous catalyst

Article abstract of DOI:10.1039/C6SC03849B

A new class of chiral bifunctional heterogeneous materials composed of Au/Pd nanoparticles and chiral phosphoric acids as active orthogonal catalysts was prepared by utilizing a facile pseudo-suspension co-polymerization method. It was found that this heterogeneous catalyst was capable of facilitating the sequential aerobic oxidation-asymmetric intramolecular aza-Friedel-Crafts reaction between benzyl alcohols and N-aminoethylpyrroles. Moreover, the designed chiral heterogeneous catalyst could be recovered and reused several times without significant loss of activity or enantioselectivity.

Full text of DOI:10.1039/C6SC03849B

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Integration of Aerobic Oxidation and Intramolecular Asymmetric
aza–Friedel–Crafts Reactions with a Chiral Bifunctional
Heterogeneous Catalyst†
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
a
DOI: 10.1039/x0xx00000x
Hong-Gang Cheng,‡ Javier Miguélez,‡ Hiroyuki Miyamura, Woo-Jin Yoo and Shū Kobayashi*
www.rsc.org/
A new class of chiral bifunctional heterogeneous materials bearing Au/Pd nanoparticles and chiral phosphoric acid as
active orthogonal catalysts was prepared by utilizing a facile pseudo-suspension co-polymerization method. It was found
that this heterogeneous catalyst was capable of facilitating the sequential aerobic oxidation-asymmetric intramolecular
aza-Friedel-Crafts reaction between benzyl alcohols and N-aminoethylpyrroles. Moreover, this designed chiral
heterogeneous catalyst could be recovered and reused several times without significant loss of activity and
enantioselectivity.
polymeric materials (PI(Au/Pd)-CO, polymer-incarcerated
Au/Pd NP-coated organocatalyst), and its application as a
Introduction
1
Multicatalyst-promoted asymmetric tandem reactions are an
2
emerging subset in the family of one-pot processes that can
catalyst for the sequential aerobic oxidation-asymmetric
Michael reactions of primary allylic alcohols and dibenzyl
3
c
malonate (Scheme 1a). While we were able to demonstrate
that our fabrication method prevented catalyst deactivation
between the Au/Pd NPs and the chiral organocatalyst to
enable the asymmetric TOP, it was discovered that the chiral
secondary amine catalyst was neutralized under aerobic
conditions and that the heterogeneous catalyst could not be
reused. Based on our preliminary experimental studies and
provide access to complex organic substrates of high
enantiopurity in an efficient and practical manner. Despite the
promise of these reactions, one of the major challenges, which
have limited its development, is the problem associated with
catalyst incompatibility. A potential strategy to overcome this
obstacle is by applying the principle of site separation to
prevent mutual deactivation of catalysts, and successful
tandem asymmetric processes have been achieved with chiral
8
related literatures, we concluded that the use of chiral
3
heterogeneous secondary amines as organocatalysts for
asymmetric TOPs was not a viable strategy due to the
propensity of its covalent intermediates to undergo aerobic
oxidation and become degraded. Therefore, we hypothesized
that the use of chiral organocatalysts, which activated the
organic substrates through non-covalent interactions, would
lead to a more robust heterogeneous system that could be
recovered and reused even under aerobic conditions.
catalysts immobilized or encapsulated on polymers and sol-
4
gel materials. Another challenge faced in multicatalyst-
promoted tandem reactions is the unselective interaction of
starting materials and reaction intermediates with the
catalysts to generate unwanted by-products. While it is
difficult to achieve catalyst selectivity in one-pot reaction
process, the use of heterogeneous catalysts in continuous-flow
5
systems is a potential solution to overcome this problem.
Over the past decade, chiral phosphoric acids (CPAs) have
been proven to be highly efficient catalysts for a wide range of
Our group has
a
long-standing interest in the
immobilization of metal nanoparticles (NPs) onto polymer
6
supports and its application to tandem oxidation processes
9
,10
asymmetric transformations.
Of particular note is their
7
TOPs) with oxygen gas as the terminal oxidant. Previously,
ability to activate imine derivatives, via hydrogen bonding or
ion pair interactions (non-covalent interactions), and to
promote high levels of stereoinduction of the prochiral
electrophiles. Based on these considerations, we rationalized
that CPAs might represent the ideal chiral component for a
recyclable heterogeneous catalyst that could facilitate
asymmetric TOPs. Herein, we report the preparation of a
heterogeneous chiral bifunctional catalyst, consisting of Au/Pd
NPs and a CPA, and its application for the sequential aerobic
oxidation-asymmetric aza-Friedel-Crafts (FC) reaction (Scheme
(
we reported the fabrication of a layered heterogeneous
bifunctional chiral catalyst consisting of Au/Pd NPs and a
Jørgensen-Hayashi-type organocatalyst supported on separate
1b).
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a) Previous work
modifications, the asymmetric TOP proceeded well to deliver
chiral piperazine 3a in high yield and enantioselectivity
(Scheme 2, eqn 2).
PI(Au/Pd)-CO
CHO
CO
Bn
CO
2
Bn
(
2 mol% wrt Au)
*
2
Bn
Au/Pd
NPs
+
R
OH
AcOH (20 mol%), EtOH:H
0 °C, O (1 atm)
2
O
R
n
CO
2
Bn
With these results in hand, we began the process of
fabricating chiral bifunctional heterogeneous catalysts that
would be capable of facilitating the sequential aerobic
oxidation-asymmetric aza-FC reaction. We began by
3
2
CO
2
N
Polymer-Incarcerated (Au/Pd)-Coated Organocatalyst
H
OTMS
b) Present work
R1
IOC-PI/CB (Au/Pd)
2 mol% wrt Au)
R
1
OH
developing
monomer 4,
a
13
reliable synthetic route for (S)-TRIP-type
(
Ar
O
+
*
R2
NH
2
R
2
NH
O
and then utilize this as a chiral feedstock to
O
2
(1 atm)
P
N
N
Au/Pd
NPs
O
OH
construct the chiral composite material
8 through a pseudo-
Ar
Immobilized Organocatalyst-Coated Polymer-Incarcerated/
Carbon Black (Au/Pd)
suspension co-polymerization method (Fig 1a). With this
heterogeneous bifunctional chiral catalyst in hand, we
examined the asymmetric TOP between benzyl alcohol (1a
)
Scheme 1 Chiral bifunctional heterogeneous catalysts for TOPs
and N-aminoethylpyrrole 2a (Scheme 3). It was found that
after slight modification of the optimized reaction conditions
previously determined for the combined catalyst system of
PI/CB-Au/Pd and (S)-TRIP, the desired piperazine 3a could be
obtained in excellent yield and enantioselectivity. We also
examined our model reaction using the layered heterogeneous
catalyst 10 with the inversed placement of the Au/Pd NPs and
CPA (Fig 1c), and it was found to catalyze the asymmetric TOP
with similar results (85%, 88% ee of 3a).
Results and discussion
We began our investigations by examining the feasibility of a
TOP that integrated aerobic oxidation with the aza-FC reaction
using benzyl alcohol (1a) and N-aminoethylpyrrole (2a) as
model substrates, and PI/CB-Au/Pd and p-toluenesulfonic acid
as co-catalysts (Scheme 2, eqn 1). It was found that the
expected piperazine 3a was not obtained under our initial
conditions. This was unexpected given that control studies
showed that both the aerobic oxidation of 1a and the aza-FC
reaction between 2a and benzaldehyde occurred in good
After establishing the optimal reaction conditions for the
sequential aerobic oxidation-asymmetric aza-FC reaction, we
IOC-PI/CB(Au/Pd) 8
Ph
1
1
(
1.5 mol% wrt Au)
THF:H O (14:1, 0.5 M)
(1 atm), 25 °C, 24 h
2a
yields under these initial conditions. It was later revealed
that the aerobic oxidation of 1a did not occur in the presence
of 2a, most likely due to the strong coordination of the primary
amine moiety of 2a to the Au/Pd NPs, to cause catalyst
deactivation. To overcome this limitation, we found that by
performing the TOP through a one-pot, sequential addition
process, in which the aerobic oxidation of 1a was allowed to
proceed prior to the addition of 2a, was key to successfully
obtain 3a. Optimization of the aerobic oxidation step and the
asymmetric TOP using (S)-3,3'-bis(2,4,6-triisopropylphenyl)-
Ph
OH
2
BnSCH
THF:H
Ar, 10 °C, 24 h
3
(0.1 eq.), CaSO
4
N
NH
1
a
O
2
2
O (49:1, 0.1 M)
3a
(
90%, 91% ee)
Scheme 3 Sequential aerobic oxidation of 1a-asymmetric aza-
FC reaction with 2a catalyzed by IOC-PI/CB(Au/Pd)
8
Ar
x
y
z
O
O
Me
CO
P
2
Bn
1
2
O
OH
1,1'-binaphthyl-2,2'diyl hydrogenphosphate ((S)-TRIP) as the
O
OH
4
Ar
O
O
CPA was performed in order to improve the yield and
enantioselectivity of the desired chiral piperazine 3a. It was
found that water was essential to promote the aerobic
4
5 (x:y:z = 1:1:1)
6
7
i
3 6 2
Ar = 2,4,6-( Pr) C H
a) IOC-PI/CB(Au/Pd) heterogeneous catalyst
3
oxidation of 1a, while the introduction of BnSCH as an
AIBN
PVA, MePh:H2O (1:2)
0 °C, 12 h, Ar
4
+
6
+
7
+
PI/CB-Au/Pd
additive to deactivate the Au/Pd NPs was important to prevent
(
5 eq.)
(60 eq.)
(6 eq.)
(1.5 eq.)
9
oxidation of 3a to its imine form. Based on these two major
IOC-PI/CB(Au/Pd) 8
b) Polymer-supported CPA
PI/CB-Au/Pd (1 mol%)
Ph
AIBN
4
+
6
+
7
NH
2
p-TsOH•H2O (10 mol%)
THF (0.1 M), 4Å MS, O (1 atm)
5 °C, 24 h
N.R.)
PVA, MePh:H2O (1:2)
90 °C, 12 h, Ar
Ph
OH
+
(1)
N
N
NH
(5 eq.)
(60 eq.)
(6 eq.)
2
polymer bead 9
2
1a
2a
c) PI(Au/Pd)-CO heterogeneous catalyst
PPh AuCl
3a
(
3
Ph
NH
CB
NaBH4
Pd(OAc)2
9
coacervate wash cross-link
Et2 Et2 150 °C
PI/CB-Au/Pd (1.5 mol%)
O
(S)-TRIP (5 mol%)
2a, BnSCH (0.1 eq.)
THF:H O (66:1, 0.1 M)
Å MS, Ar, 25 °C, 24 h
5
Ph
OH
(2)
diglyme
diglyme
diglyme
O
O
THF:H
2
O (9:1, 1.0 M)
Ph
H
3
N
1a
PI(Au/Pd)-CO 10
O
2
(1 atm), 25 °C, 24 h
2
4
3a
(
90%, 92% ee)
Fig 1 Fabrication procedure for a) IOC-PI/CB(Au/Pd)
8; b)
polymer-supported CPA 9; c) PI(Au/Pd)-CO 10. Blue represents
Scheme 2 Reaction integration of aerobic oxidation with aza-
the layer containing CPA while the red represents the layer
containing Au/Pd NPs
FC reaction
2
| J. Name., 2012, 00, 1-3
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Plea sC eh de om ni oc ta al dS j uc si et nm c ae rgins
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DOI: 10.1039/C6SC03849B
Journal Name
ARTICLE
examined the substrate scope for this one-pot process (Table oxidation-asymmetric aza-FC reaction for 4-substituted benzyl
). It was found that substituted benzyl alcohols 1a-h, bearing alcohols with a wide range of functional groups, such as F, Cl,
electron-donating substituents, could be utilized for the CF , CO Me, and CN, to furnish the corresponding chiral
1
3
2
asymmetric TOP to furnish the desired chiral piperazines 3a-h piperazines 3i-n in good yields and enantioselectivities (entries
in good yields and enantioselectivities (entries 1-8). On the 9-14). We also examined the asymmetric TOP with methyl
otherhand, when we examined 4-fluorobenzyl alcohol (1i) as a substituted N-aminoethylpyrroles 2b-c, and it was found that
substrate, only a trace amount of the expected product 3i was these substrates were also suitable to provide chiral bicyclic
detected under the current reaction conditions. Control heterocycles 3o-p with high yields and enantioselectivities
studies revealed that the origin of this problem was the (entries 15-16).
aerobic oxidation step, and we found that Au/Pt NPs in
Finally, we examined the possibility of recycling our chiral
DCM:H O (1:1) was more effective for the aerobic oxidation of bifunctional heterogeneous catalyst, and found that it could be
2
benzyl alcohols possessing electron-withdrawing substituents. recovered and reused several times without significant loss in
Thus, we prepared a new chiral bifunctional heterogeneous yield and enantioselectivity for the asymmetric TOP with
catalyst, IOC-PI/CB(Au/Pt) 11, and found that this new chiral benzyl alcohol 1a and N-aminoethylpyrrole 2a as substrates
composite material could effectively catalyze the sequential
(Scheme 4). The key to recycling the heterogeneous catalyst
was the treatment of the spent IOC-PI/CB(Au/Pd) with an
8
Table 1 Substrate scope for the IOC-PI/CB(Au/Pd)
8
or IOC- aqueous solution of H
2
O
2
to remove BnSCH
3
and reactivate the
PI/CB(Au/Pt) 11-catalyzed asymmetric TOP between benzyl Au/Pd NP catalyst.
a
alcohols 1a-n and N-aminoethylpyrroles 2a-c
IOC-PI/CB(Au/Pd) 8
Ph
R2
NH
(1.5 mol% wrt Au)
2a
2
cat. IOC-PI/CB(Au/Pd) 8
R1
2
a-c
Ph
OH
N
THF:H O (14:1, 0.5 M)
2
B
n
S
C
H
(
0
.
1
e
q
.
)
,
C
a
S
O
N
NH
or cat. IOC-PI/CB(Au/Pt) 11
3
4
R1
OH
a-n
R2
NH
1a
O
(1 atm), 25 °C, 24 h
THF:H
2
2
O (49:1, 0.1 M)
THF or DCM:H
2
O (0.5 M)
BnSCH
3
(0.1-0.3 eq.), CaSO
4
3a
N
Ar, 10 °C, 24 h
1
O
(1 atm), 25 °C, 24-48 h
THF or DCM:H O (0.1 M)
2
2
1st: 92%, 89% ee, 2nd: 90%, 88% ee, 3rd: 90%, 88% ee, 4th: 87%, 87% ee
5th: 88%, 88% ee, 6th: 85%, 84% ee
Ar, 10 °C, 24 h
3a-p
1
: R ;
2
: R
e
Entry
1
2
3
Yield
d
ee (%)
(
%)
Scheme 4 Recovery and reuse of IOC-PI/CB(Au/Pd)
8
1
2
3
4
1a: Ph; 2a: H
3a
3b
3c
3d
3e
3f
89
89
91
80
83
85
84
85
91
88
83
82
89
84
91
83
94
84
92
80
93
91
73
93
90
91
90
86
95
90
85
70
1b: 4-Me-C H ; 2a: H
6
4
1c: 2-Me-C H ; 2a: H
6
Conclusions
4
1d: 4-MeO-C H ; 2a: H
4
6
In conclusion, we have developed a new chiral bifunctional
heterogeneous catalyst, composed of metal NPs and CPAs,
that was capable of performing the sequential, one-pot
aerobic oxidation-intramolecular asymmetric aza-FC reaction
to provide chiral 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines 3a-
b
5
1e: 3-MeO-C H ; 2a: H
6 4
b
6
1f: 2-MeO-C H ; 2a: H
6 4
7
1g: piperonyl; 2a: H
1h: 1-naphthyl; 2a: H
1i: 4-F-C H ; 2a: H
3g
3h
3i
b
8
c
9
6
4
p
in high yields and enantioselectivities. Interestingly, we
c
10
11
12
13
14
15
16
1j: 2-F-C H ; 2a: H
4
3j
6
found a chemical system (H /BnSCH ) to switch on/off the
2
O
2
3
c
c
c
c
1k: 4-Cl-C H ; 2a: H
4
3k
3l
14
6
catalytic activity of the Au/Pd and Au/Pt NPs. By controlling
the catalytic activity of the heterogeneous catalyst through the
use of a chemical modifier, the undesired oxidation of chiral
piperazines 3a-p was avoided, and the facile reactivation of
the deactivated catalyst enabled the chiral composite material
to be recovered and reused several times without significant
losses in yields and enantioselectivities of the desired product
1l: 4-CF -C H ; 2a: H
3 6 4
1m: 4-CN-C H ; 2a: H
6
3m
3n
3o
3p
4
1n: 4-CO Me-C H ; 2a: H
2 6 4
1a: Ph; 2b: 2-Me
1a: Ph; 2c: 2,4-(Me)2
a
Reaction conditions: benzyl alcohol
1 (0.3 mmol), IOC-
3
a
.
Moreover, we were able to demonstrate that
heterogeneous CPAs could retain its catalytic ability in the
presence of metal NPs under oxidative conditions (O and
). Further investigations into the use of these robust chiral
PI/CB(Au/Pd)
mL) under a balloon of oxygen gas at room temperature for 24
h (aerobic oxidation step). Then N-aminoethylpyrrole (0.2
mmol), CaSO (200 mg), BnSCH (2.8 mg) and THF (1.4 mL)
8
(1.5 mol% wrt Au) in THF:H O (v:v = 0.56:0.04
2
2
2
2 2
H O
4
3
heterogeneous catalysts in other types of asymmetric TOPs are
currently underway in our laboratory.
were added under a balloon of Ar at 10 °C for 24 h (aza-FC
b
step). Standard reaction conditions except for the use of IOC-
PI/CB(Au/Pd) 8 (3.0 mol% wrt Au) for 48 h (aerobic oxidation
c
step) and BnSCH (5.6 mg) (aza-FC step). Standard reaction
3
Acknowledgements
conditions except for the use of IOC-PI/CB(Au/Pt) 11 (3.0 mol%
This work was partially supported by Grant-in-Aids for
Scientific Research from JSPS, the Global COE Program, the
University of Tokyo, MEXT (Japan), and the Japan Science and
wrt Au) in DCM:H O (v:v = 0.54:0.06 mL) (aerobic oxidation
2
d
step) and BnSCH (5.6 mg) (aza-FC step). Isolated yield based
3
on 2a-c and determined by weight of the isolated product 3a-
e
. The ee value was determined by chiral HPLC analysis.
p
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Technology Agency (JST). We also thank Noriaki Kuramitsu 10 Multicatalyst promoted asymmetric tandem reactions
involving homogeneous CPAs and metal complexes have
(
The University of Tokyo) for STEM and EDS analysis.
been reported. For representative examples, please see: (a)
P.-S. Wang, H.-C. Lin, Y.-J. Zhai, Z.-Y. Han, L.-Z. Gong, Angew.
Chem., Int. Ed., 2014, 53, 12218; (b) S.-Y. Yu, H. Zhang, Y.
Notes and references
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(
(
j) S. Mukherjee, B. List, J. Am. Chem. Soc., 2007, 129, 11336;
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,
1
1
1 Details regarding reaction optimization and control studies
can be found in the Supporting Information.
2 For asymmetric intramolecular aza-FC reactions of N-
aminoethylpyrroles with aldehydes catalyzed by (R)-TRIP,
please see: Y. He, M. Lin, Z. Li, X. Liang, G. Li, J. C. Antilla, Org.
Lett., 2011, 13, 4490.
1
M. A. Pericàs, Chem. Eur. J., 2014, 20, 13089; (c) H.
Miyamura, G. C. Y. Choo, T. Yasukawa, W.-J. Yoo, S.
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2
013, 19, 10814; (e) Y. Chi; S. T. Scroggins; J. M. J. Fréchet, J.
1
3 Relatively few examples of immobilized CPAs have been
reported, please see: (a) B. Zhang, L. Shi, R. Guo, Catal. Lett.,
Am. Chem. Soc., 2008, 130, 6322; (f) S. L. Poe, M. Kobašlija,
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5
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,
3
1
4 The modulation of the catalytic activity of metal NPs using an
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