Asymmetric Arylation of Imines Catalyzed by Heterogeneous Chiral Rhodium Nanoparticles

Article abstract of DOI:10.1021/acs.orglett.6b01172

Asymmetric arylation of aldimines catalyzed by heterogeneous chiral rhodium nanoparticles has been developed. The reaction proceeded in aqueous media without significant decomposition of the imines by hydrolysis to afford chiral (diarylmethyl)amines in high yields with outstanding enantioselectivities. This catalyst system exhibited the highest turnover number (700) in heterogeneous catalysts reported to date for these reactions. The reusability of the catalyst was also demonstrated.

Full text of DOI:10.1021/acs.orglett.6b01172

Letter
pubs.acs.org/OrgLett
Asymmetric Arylation of Imines Catalyzed by Heterogeneous Chiral
Rhodium Nanoparticles
Tomohiro Yasukawa, Tatsuya Kuremoto, Hiroyuki Miyamura, and Shu Kobayashi*
̅
Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
ABSTRACT: Asymmetric arylation of aldimines catalyzed by heteroge-
neous chiral rhodium nanoparticles has been developed. The reaction
proceeded in aqueous media without significant decomposition of the
imines by hydrolysis to afford chiral (diarylmethyl)amines in high yields
with outstanding enantioselectivities. This catalyst system exhibited the
highest turnover number (700) in heterogeneous catalysts reported to
date for these reactions. The reusability of the catalyst was also
demonstrated.
hiral (diarylmethyl)amines are important compounds that
are found in many pharmaceutical skeletons.1 Asymmetric
linking moieties and carbon black.10 We successfully developed
Rh/Ag bimetallic NP catalysts (PI/CB Rh/Ag), which were
utilized for asymmetric 1,4-addition of arylboronic acids to α,β-
unsaturated carbonyl compounds in the presence of a chiral
diene as a modifier.11 Notably, this heterogeneous chiral Rh NP
system showed superior performance over the corresponding
homogeneous metal complex for some substrates, and the
unique nature of the active species was found to be distinct
from that of a metal complex.11a These results demonstrated
the great potential of chiral metal NP catalysts. Herein, we
report the application of heterogeneous chiral Rh NP catalyst
systems for asymmetric arylation of aldimines.
We selected aryltosylimine (1a) and phenylboronic acid (2a)
as model substrates, and reaction conditions were optimized
(Table 1). Initially, the reaction was conducted with a chiral
metal NP system consisting of PI/CB Rh/Ag and secondary
amide-substituted chiral diene 412 under the optimal conditions
for asymmetric 1,4-addition to α,β-unsaturated esters.11a Under
these conditions, the desired product was obtained with
excellent enantioselectivity but in moderate yield (entry 1).
Aldehyde 5 and a significant amount of diarylmethanol adduct
6 were also observed, indicating that decomposition of 1a to 5
occurred in the presence of water with subsequent arylation of
5. The solvent ratio was then examined in an attempt to
suppress the hydrolysis of 1a (entries 2−6). When the ratio of
toluene and water was 4:1 or 8:1, the yield of 3aa was improved
(entries 2 and 3). Further decreases in the amount of water led
to a dramatic reduction in the catalytic activity (entries 4−6).
The presence of water might play a key role in accelerating part
of the catalytic cycle such as the catalytic turnover step, that is,
hydrolysis of a reaction intermediate after addition of an aryl
group to an imine to give the product. When water was
replaced by ethanol, formation of 6 was suppressed; however,
the yield was not improved (entry 3 vs 7). The inclusion of
C
arylation of aldimines can afford such compounds, and the use
of organoboron reagents as aryl donors is one of the most
promising strategies for the synthesis of these compounds
because of the stability, mild reactivity, and ease of handling of
organoboron reagents.2 Since the first examples of asymmetric
addition of arylboronic acids to aryl tosylimines catalyzed by
chiral Rh complexes were reported in 2004,3 numerous efforts
for the development of this type of reaction have focused on
improving the catalytic activities and substrate diversity to
include aliphatic imines and various types of protected
aldimines.1b,4 As alternatives to Rh catalysis, other metals
such as Pd5 and Ru6 catalyst systems were also investigated.
Despite great advances in the development of this reaction, the
catalysts have all been homogeneous metal complexes and less
attention has been focused toward the development of
heterogeneous catalysts. This is a crucial issue for further
applications of the reaction considering the advantages of
heterogeneous catalysts, such as ease of recovery, reusability,
and prevention of metal contamination in the final products.7
Quite recently, heterogeneous Rh complex catalysts embedded
on chiral diene-based metal−organic frameworks were
developed, and asymmetric arylation of aldimines was
demonstrated.8 Although these reactions achieved a high
turnover number (TON = 275), a large catalyst loading was
necessary to obtain a quantitative yield (3 mol %) and to
maintain the activity upon reuse of the catalyst (6 mol %).
Therefore, more active heterogeneous catalysts for this reaction
are still required.
Chiral ligand-modified metal nanoparticles (chiral metal
NPs) provide promising strategies to construct active and
robust asymmetric catalyst systems as an alternative to
conventional metal complex catalysts.9 Metal NPs can be easily
immobilized on solid supports to form heterogeneous catalysts,
and our laboratory has also established polymer incarceration
methods to immobilize various metal NP catalysts on a
nanocomposite of polystyrene-based copolymers with cross-
Received: April 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01172
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Reaction Optimization
Table 2. Substrate Scope
yield
a
ee
(%)
b
entry
R
Ar
3
(%)
1
2
3
4
5
(4-Me)C6H4 (1a)
(3-Me)C6H4 (1b)
(2-Me)C6H4 (1c)
(4-F)C6H4 (1d)
(4-Cl)C6H4 (1e)
(4-Br)C6H4 (1f)
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
3aa
3ba
3ca
3da
3ea
3fa
87
85
91
79
84
84
86
99
99
96
99
99
99
99
a
b
yield (%)
ee (%)
entry
x/y
1:2
3aa
5
6
3aa
c
6
1
2
3
4
5
6
45
71
77
29
4
6
38
7
99
99
99
99
99
−
7
(4-OMe)C6H4
(1g)
3ga
4:1
12
8:1
<1
22
15
<1
8
16
<1
<1
2
8
9
C6H5 (1h)
(4-Me)C6H4
(3-Me)C6H4
(2-Me)C6H4
(4-F)C6H4
(4-Cl)C6H4
(4-Br)C6H4
(4-OMe)C6H4
C6H5
3hb
3ac
3ad
3ae
3af
75
81
84
93
77
80
86
96
93
73
89
33
19
33
99
99
95
99
99
99
99
99
99
99
99
99
99
99
16:1
100:1
1:0
(4-Me)C6H4 (1a)
(4-Me)C6H4 (1a)
(4-Me)C6H4 (1a)
(4-Me)C6H4 (1a)
(4-Me)C6H4 (1a)
(4-Me)C6H4 (1a)
1-naphthyl (1i)
2-naphthyl (1j)
2-furyl (1k)
c
10
3
c
11
12
13
14
15
16
17
18
7
1:0
77
2
99
d
8
e
8:1
<1
71
2
<1
5
−
99
99
f
f
3ag
3ah
3ia
9
8:1
96 (87)
74 (70)
g
10
8:1
8
10
a
b
1
Determined by H NMR analysis. Determined by HPLC analysis.
Toluene/EtOH (8:1) cosolvent system was used. K2CO3 (1 equiv)
was added. PI/CB Rh/Ag (Rh: 0.5 mol %) and 4 (0.1 mol %) were
used, and the concentration was 0.133 M. The concentration was
calculated based on the total amount of both solvents. Isolated yield.
PI/CB Rh/Ag (Rh: 0.1 mol %) and 4 (0.1 mol %) were used, and the
C6H5
3ja
c
d
e
C6H5
3ka
3la
2-thienyl (1l)
tBu (1m)
C6H5
cd
,
f
19
20
21
C6H5
3ma
3na
3oa
g
cd
,
Cy (1n)
C6H5
reaction time was 48 h.
(4-Me)C6H4
C6H5
e
(1o)
a
b
c
Isolated yield. Determined by HPLC analysis. PI/CB Rh/Ag (Rh:
d
either acidic or basic additives did not work well and led to
decomposition of 1a (entry 8; see also the Supporting
Information). Finally, reducing the concentration and increas-
ing the catalyst loading gave both satisfactory yield and
outstanding enantioselectivity (entry 9). The highest TON
(700) was achieved when the catalyst loading was 0.1 mol %
(entry 10). Notably, the catalytic activity of the present chiral
NP catalyst system was higher than that of the reported
heterogeneous catalysts,8 although a similar type of chiral
ligand, secondary amide-substituted chiral dienes with a
bicyclo[2.2.2]octadiene structure,11a was used.
Substrate generality was then surveyed by using the
optimized conditions (Table 2). Substituents including
electron-donating or -withdrawing groups on aryl tosylimines
did not affect the reactivity significantly; all the products were
obtained in high yields and with outstanding enantioselectiv-
ities, irrespective of the position of the substituents (entries 1−
7). Whereas arylboronic acids bearing substituents on the meta-
or para-position could be utilized without a decrease in yields
(entries 8 and 9), the use of o-tolylboronic acid required a slight
increase in the catalyst and ligand loadings to achieve a high
yield (entry 10). Arylboronic acids with either electron-
donating or -withdrawing groups reacted smoothly to afford
the desired products in high yields with outstanding
enantioselectivities (entries 11−14). A range of aryl tosylimines
including naphthyl imines (entries 15 and 16) and heteroarenes
(entries 17 and 18) were also suitable for this catalytic system,
and the desired products were obtained in high yields and with
outstanding enantioselectivities under the standard conditions.
The reaction with an aliphatic imine under the optimized
conditions was unsuccessful, presumably because aliphatic
imines are generally more sensitive to water than aromatic
1.0 mol %) and 4 (0.2 mol %) were used. The reaction mixture
before 1k and 4 were added was heated at 100 °C for 6 h. 4-
Nitrobenzenesulfonyl-protected imine was used.
e
imines. Therefore, we changed the reaction procedure to
improve the yield. In our previous study of chiral NP catalyst
systems for asymmetric 1,4-addition to α,β-unsaturated esters,
an induction period was observed that could be shortened by
heating PI/CB Rh/Ag at 100 °C for several hours in the
presence of arylboronic acid and solvents before starting the
reaction.11a,13 It was assumed that most aliphatic imines might
decompose during the induction period and the “preheating”
treatment described above might minimize this effect. Indeed,
when a mixture of the catalyst and arylboronic acid was heated
at 100 °C for 6 h prior to the addition of imine 1m to diene 4,
the desired product was obtained in 33% yield with 99% ee
(entry 19). The same protocol was applied to more unstable
aliphatic imine 1n, and the product was obtained in excellent
enantioselectivity despite the low yield (entry 20). Notably, the
chiral NP system could be used to catalyze the reaction with a
relatively unstable aliphatic imine in aqueous media. Finally, the
effect of protecting groups on the nitrogen was surveyed. The
reactivity of 4-nitrobenzenesulfonyl group-protected imine 1o
was relatively lower than that of tosyl imines under the
optimized conditions, and the product was obtained in low
yield with excellent enantioselectivity (entry 21). We also tested
tert-butoxycarbonyl protected imine; however, no desired
product was observed probably due to rapid hydrolysis of the
imine.
The recovery and reuse of the heterogeneous NP catalyst
were examined (Table 3). The catalyst was readily recovered by
simple filtration, and a new portion of chiral diene 4 was added
B
DOI: 10.1021/acs.orglett.6b01172
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(2) Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem. Soc.
Rev. 2006, 35, 454.
Table 3. Recovery and Reuse of the Catalyst
(3) (a) Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.;
Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.
(b) Kuriyama, M.; Soeta, T.; Hao, X. Y.; Chen, O.; Tomioka, K. J. Am.
Chem. Soc. 2004, 126, 8128.
(4) (a) Sieffert, N.; Boisson, J.; Py, S. Chem. - Eur. J. 2015, 21, 9753.
(b) Chen, Y.-J.; Cui, Z.; Feng, C.-G.; Lin, G.-Q. Adv. Synth. Catal.
2015, 357, 2815. (c) Chen, C.-C.; Gopula, B.; Syu, J.-F.; Pan, J.-H.;
Kuo, T.-S.; Wu, P.-Y.; Henschke, J. P.; Wu, H.-L. J. Org. Chem. 2014,
79, 8077. (d) Shintani, R.; Narui, R.; Tsutsumi, Y.; Hayashi, S.;
Hayashi, T. Chem. Commun. 2011, 47, 6123. (e) Korenaga, T.; Ko, A.;
Uotani, K.; Tanaka, Y.; Sakai, T. Angew. Chem., Int. Ed. 2011, 50,
10703. (f) Hao, X.; Chen, Q.; Yamada, K.-I.; Yamamoto, Y.; Tomioka,
K. Tetrahedron 2011, 67, 6469. (g) Hao, X.; Chen, Q.; Kuriyama, M.;
Yamada, K.-I.; Yamamoto, Y.; Tomioka, K. Catal. Sci. Technol. 2011, 1,
62. (h) Cui, Z.; Yu, H.-J.; Yang, R.-F.; Gao, W.-Y.; Feng, C.-G.; Lin, G.-
Q. J. Am. Chem. Soc. 2011, 133, 12394. (i) Yang, H.-Y.; Xu, M.-H.
Chem. Commun. 2010, 46, 9223. (j) Shao, C.; Yu, H.-J.; Wu, N.-Y.;
Feng, C.-G.; Lin, G.-Q. Org. Lett. 2010, 12, 3820. (k) Cao, Z.; Du, H.
Org. Lett. 2010, 12, 2602. (l) Okamoto, K.; Hayashi, T.; Rawal, V. H.
Chem. Commun. 2009, 4815. (m) Kurihara, K.; Yamamoto, Y.;
Miyaura, N. Adv. Synth. Catal. 2009, 351, 260. (n) Hao, X.; Kuriyama,
M.; Chen, Q.; Yamamoto, Y.; Yamada, K.-I.; Tomioka, K. Org. Lett.
2009, 11, 4470. (o) Bishop, J. A.; Lou, S.; Schaus, S. E. Angew. Chem.,
Int. Ed. 2009, 48, 4337. (p) Trincado, M.; Ellman, J. A. Angew. Chem.,
Int. Ed. 2008, 47, 5623. (q) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin,
G.-Q. J. Am. Chem. Soc. 2007, 129, 5336. (r) Nakagawa, H.; Rech, J.
C.; Sindelar, R. W.; Ellman, J. A. Org. Lett. 2007, 9, 5155. (s) Marelli,
C.; Monti, C.; Gennari, C.; Piarulli, U. Synlett 2007, 2007, 2213.
(t) Jagt, R. B. C.; Toullec, P. Y.; Geerdink, D.; de Vries, J. G.; Feringa,
B. L.; Minnaard, A. D. J. Angew. Chem., Int. Ed. 2006, 45, 2789.
(u) Duan, H.-F.; Jia, Y.-X.; Wang, L.-X.; Zhou, Q.-L. Org. Lett. 2006, 8,
2567. (v) Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org.
Lett. 2005, 7, 307.
c
c
c
cycle
1
2
3
4
5
a
yield (%)
85(92)
99
77(80)
99
94(97)
99
88(92)
99
85(89)
99
b
ee (%)
a
The yield was determined by isolation from a small fraction of a
crude mixture. The yield determined by 1H NMR analysis was shown
b
c
in parentheses. Determined by HPLC analysis. The recovered
catalyst was heated at 150 °C for 6 h before use.
in every cycle. The yield decreased slightly in the second cycle
after washing the recovered catalyst with water and an organic
solvent followed by drying. The recovered catalyst was then
reactivated by heating at 150 °C for 6 h, which resulted in the
high yield and outstanding enantioselectivity being maintained
for the following three cycles (cycles 3−5).
In summary, heterogeneous chiral Rh NP catalysts for
asymmetric addition of arylboronic acids to aldimines have
been developed. The catalyst worked efficiently in aqueous
media, and the highest TON (700) in heterogeneous catalysts
yet described for this reaction was achieved. A wide variety of
substrates could be utilized to afford the desired products in
high yields and with outstanding enantioselectivities. Remark-
ably, in spite of the aqueous conditions, even water-unstable
aliphatic imines could be converted into the desired products
with excellent enantioselectivities. Moreover, the reusability of
the catalyst was confirmed and a simple heating treatment
could be used to maintain the catalytic activity for five cycles.
We believe that heterogeneous chiral NPs are active and
practical catalyst systems for the synthesis of important chiral
amine compounds.
(5) (a) Gao, X.; Wu, B.; Yan, Z.; Zhou, Y.-G. Org. Biomol. Chem.
2016, 14, 55. (b) Schrapel, C.; Peters, R. Angew. Chem., Int. Ed. 2015,
54, 10289. (c) Beisel, T.; Manolikakes, G. Org. Lett. 2015, 17, 3162.
(d) Marques, C. S.; Burke, A. J. Eur. J. Org. Chem. 2010, 2010, 1639.
(e) Liu, Z.; Shi, M. Tetrahedron 2010, 66, 2619. (f) Ma, G.-N.; Zhang,
T.; Shi, M. Org. Lett. 2009, 11, 875.
(6) Marques, C. S.; Burke, A. J. Eur. J. Org. Chem. 2012, 2012, 4232.
(7) (a) Lucarelli, C.; Vaccari, A. Green Chem. 2011, 13, 1941. (b) Yin,
L.; Liebscher, J. Chem. Rev. 2007, 107, 133. (c) Butters, M.; Catterick,
D.; Craig, A.; Curzons, A.; Dale, D.; Gillmore, A.; Green, S. P.;
Marziano, I.; Sherlock, J.-P.; White, W. Chem. Rev. 2006, 106, 3002.
(8) Sawano, T.; Ji, P.; McIsaac, A. R.; Lin, Z.; Abney, C. W.; Lin, W.
Chem. Sci. 2015, 6, 7163.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01172.
■
S
Experimental procedures, characterization data, and
copies of NMR and HPLC charts (PDF)
(9) (a) Yasukawa, T.; Miyamura, H.; Kobayashi, S. Chem. Soc. Rev.
2014, 43, 1450. (b) Ranganath, K. V. S.; Kloesges, J.; Schafer, A. H.;
̈
Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 7786. (c) Heitbaum, M.;
Glorius, F.; Escher, I. Angew. Chem., Int. Ed. 2006, 45, 4732. (d) Jansat,
AUTHOR INFORMATION
Corresponding Author
■
́
S.; Gomez, M.; Philippot, K.; Muller, G.; Guiu, E.; Claver, C.;
Castillon, S.; Chaudret, B. J. Am. Chem. Soc. 2004, 126, 1592.
(e) Orito, Y.; Imai, S.; Niwa, S.; Nguyen, G. H. Yuki Gosei Kagaku
Kyokaishi 1979, 37, 173.
*E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp.
Notes
(10) Kobayashi, S.; Miyamura, H. Aldrichimica Acta 2013, 46, 3.
(11) (a) Yasukawa, T.; Suzuki, A.; Miyamura, H.; Nishino, K.;
Kobayashi, S. J. Am. Chem. Soc. 2015, 137, 6616. (b) Yasukawa, T.;
Miyamura, H.; Kobayashi, S. J. Am. Chem. Soc. 2012, 134, 16963.
(12) The structure of the chiral diene was previously optimized in the
asymmetric 1,4-addition to α,β-unsaturated esters. See ref 11a.
(13) We assumed that a redox process between Rh/Ag NP and
arylboronic acids might occur during the “preheating” stage to
generate active species. A similar shorter induction period was
observed when preheating was carried out in the presence of the
catalyst and a catalytic amount of sodium citrate (5 mol%) as a
reductant. See ref 11a for more details.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for Science
Research from the Japan Society for the Promotion of Science
(JSPS), Global COE Program, The University of Tokyo,
MEXT, Japan, and the Japan Science and Technology Agency
(JST).
REFERENCES
■
(1) (a) Ameen, D.; Snape, T. J. MedChemComm 2013, 4, 893.
(b) Marques, C. S.; Burke, A. J. ChemCatChem 2011, 3, 635.
C
DOI: 10.1021/acs.orglett.6b01172
Org. Lett. XXXX, XXX, XXX−XXX