A Polystyrene-Supported Phase-Transfer Catalyst for Asymmetric Michael Addition of Glycine-Derived Imines to α,β-Unsaturated Ketones

Article abstract of DOI:10.1002/adsc.201700155

A 2-oxopyrimidinium salt was immobilized onto a polystyrene-derived polymer to generate a heterogeneous catalyst that effectively promoted the asymmetric Michael addition of glycine-derived imines to α,β-unsaturated ketones. The reactions proceeded smooth

Full text of DOI:10.1002/adsc.201700155

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DOI: 10.1002/adsc.201700155
A Polystyrene-Supported Phase-Transfer Catalyst for Asymmetric
Michael Addition of Glycine-Derived Imines to a,b-Unsaturated
Ketones
Javier Miguꢀlez,a Hiroyuki Miyamura,a and Shu¯ Kobayashia,*
a
Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
Fax : (+81)-3-5684-0634; e-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Received: February 7, 2017; Revised: February 21, 2017; Published online: && &&, 0000
Supporting information for this article can be found under http://dx.doi.org/10.1002/adsc.201700155.
Abstract: A 2-oxopyrimidinium salt was immobi-
lized onto a polystyrene-derived polymer to gener-
ate a heterogeneous catalyst that effectively pro-
moted the asymmetric Michael addition of glycine-
derived imines to a,b-unsaturated ketones. The re-
actions proceeded smoothly to afford the desired
adducts, (S)-tert-butyl 2-[(diarylmethylidene)ami-
no]-5-oxoalkanoates, in high yields and with high
enantioselectivities (up to 92% ee). The polymer
catalyst could be recovered and reused at least five
times without significant loss of activity or selectivi-
ty.
a chiral catalyst in the alkylation of glycine deriva-
tives to afford the desired amino acids in high yields
and with high enantioselectivities. The Michael addi-
tion of glycine-derived imines to a,b-unsaturated ke-
tones can also provide amino acid derivatives and
precursors of alkaloid species.[6] In 2005, Ishikawa
et al. performed an asymmetric conjugate addition
using polymer-supported chiral guanidines.[8] Hii et al.
reported asymmetric Michael reactions using 2-oxo-
pyrimidinium salt 1 as a homogeneous catalyst with
a novel structure (Figure 1), achieving high yields and
high enantioselectivities under mild conditions.[8]
Keywords: asymmetric reaction; Michael addition;
organocatalysts; phase-transfer catalysts; polymers
In recent years, the development of environmentally
friendly chemical transformations has aroused great
interest.[1] Catalysts play a key role in this field, and
the use of chiral non-metal catalysts (organocatalysts)
in particular has undergone an exponential growth.[2]
Although a wide range of asymmetric reactions has
been developed, in many cases, catalyst loadings are
Figure 1. Oxopyrimidinium phase-transfer catalyst.
Inspired by this structure, we aimed to design and
high (20 mol% or more), and recovery of catalysts synthesize a novel heterogeneous chiral organocata-
from reaction mixtures is difficult. One possible solu- lyst 9 with a polystyrene backbone. Here we describe
tion to overcome these problems is the immobiliza- the synthesis of 9 and the 9-catalyzed asymmetric Mi-
tion of catalysts onto solid supports. Asymmetric chael addition of glycine-derived imines to a,b-unsa-
phase-transfer catalysts (PTCs) provide one of the turated ketones to afford the corresponding adducts,
most efficient routes to chiral molecules, and Cincho- (S)-tert-butyl 2-[(diarylmethylidene)amino]-5-oxoalka-
na alkaloid derivatives have been employed as noates (14), in high yields with high enantioselectivi-
PTCs[3] to achieve effective transformations in liquid- ties. To the best of our knowledge, this is the first im-
liquid or liquid-solid phases;[4] moreover, several poly- mobilization of an oxopyrimidinium-based PTC.
mer-supported catalysts have been prepared from
The synthesis of 9 is depicted in Scheme 1.[8] Inex-
Cinchona alkaloid derivatives. For example, Itsuno pensive 4-hydroxy-(S)-phenylglycine (2) was used as
et al. reported a novel polymer in which an ammoni- a starting material. After Boc protection of 2, the
um salt was attached to the support by ionic interac- neopentyl amide moiety was introduced by amidation
tions.[5] They found that this polymer worked well as followed by reduction with lithium aluminum hydride.
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Scheme 1. Preparation of the catalyst.
The linker 5a was attached under basic conditions attached through dipole-dipole interactions of both
and the amino hydrochloride 7 was obtained after polymers.[10]
condensation with 6a. 2-Oxopyrimidinium salt 8 was
As a model reaction to test the activity of this het-
prepared after reaction with triphosgene. Monomer 8 erogeneous catalyst, the addition of OꢂDonnell sub-
contains two styrene moieties and plays the role of strate 11 to methyl vinyl ketone (MVK) 12 was
a cross-linker to generate the insoluble polymer cata- chosen, and several sets of reaction conditions were
lyst 9. In the presence of styrene under suspension examined (Table 1). It was found that the polarity of
polymerization conditions using dimethyl 2,2’- the solvent had a dramatic effect on the enantioselec-
azobis(2-methylpropionate) (V-601) as radical initia- tivity of the product, possibly because polar solvents
tor, the cross-linked polymer 9 was obtained. The provided a large distance between charges in the tran-
loading of the catalyst 9 was determined by calculat- sition state of this heterogeneous catalysis system
ing the amount of nitrogen by elemental analysis, (entry 1 vs. entries 2–4).[11] o-Xylene gave the best
which indicated a loading of 0.147 mmolgÀ1. We de- result (entries 1 vs. 5), and almost no difference was
cided to combine 9 with insoluble polydimethylsilane observed between Cs2CO3 and K3PO4 as base (en-
(DMPSi) to prevent the polymer from sticking on the tries 5 and 6). The desired product was obtained in
surface of the flask.[9] Polydimethylsilane is an insolu- 95% ee when the reaction was conducted at 08C
ble and inert polymer material. When this was com- (entry 7). We also prepared a polymer-immobilized
bined with the immobilized catalyst in a ratio of 2:1 oxopyrimidinium catalyst without the tetraethylene
(w/w), the mixture gave a fine composite material 10, glycol linker as a less sticky polymer than 9. Its activi-
ty was, however, lower than that of 10.[12]
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Table 1. Optimization of the model reaction to afford (S)-
tert-butyl 2-[(diphenylmethylidene)amino]-5-oxohexanoate
(14a).
The substrate scope of this asymmetric reaction was
then investigated with o-xylene or mesitylene as sol-
vent at 0 to À208C. Pleasingly, we found very good
activity of the catalyst for chalcone (Table 2, entry 1).
Table 2. Substrate scope.
Entry[a]
Solvent
Time [min]
Yield [%][b]
ee [%][c]
1
2
3
4
toluene
DCM
THF
MeCN
o-xylene
o-xylene
o-xylene
120
60
100
150
90
83
74
78
89
88
85
90
80
1
14
0
88
87
95
En-
try
R1/R2
Time
[h]
Yield
[%][b]
ee
Prod-
uct
[%][c]
5
6[d]
7[e]
90
300
1
2
3
4
5
6
7
Ph/Ph
24
24
3
24
24
24
24
24
6
82
82
86
84
88
90
87
86
88
89
87
87
82
93
93
88
82
92
14b
14c
14d
14e
14f
14g
14h
14i
Ph/2-pyridyl
Ph/4-ClC6H4
Ph/2-thienyl
3-pyridyl/Ph
4-NO2C6H4/Ph
2-pyridyl/Ph
Ph/4-MeOC6H4
H/ethyl
[a]
Reaction was performed using 11 (0.05 mmol), 12
(0.1 mmol), and 10 (5 mol%).
Yield of the isolated product.
Determined by HPLC analysis. The absolute configura-
tion was established by comparison with reported data.
K3PO4 (0.75 mmol) was used as base.
At 08C.
[b]
[c]
8
[d]
[e]
9[d]
14j
[a]
Reaction was performed with 11 (0.05 mmol), 13
(0.1 mmol), and 10 (5 mol%).
Yield of the isolated product.
Determined by HPLC analysis using a chiral stationary
phase. The absolute configuration was established by
comparison with reported data.
[b]
[c]
With the optimized conditions in hand, we studied
the recovery and reuse of the catalyst (Scheme 2). We
conducted five runs and found that the activity did
not decrease significantly, with excellent enantioselec-
tivity being maintained throughout all runs. After
each run, the catalyst was recovered by filtration, fol-
[d]
o-Xylene was used as solvent at 08C.
lowed by washing with brine and an acetone/water For chalcone derivatives with electron-deficient aro-
mixture, and then drying. Brine was used to ensure matic rings (entries 3 and 6), the enantioselectivities
that the chlorine counter anion was retained in the were very high. Good enantioselectivities were also
catalyst because carbonate ion might remain in the observed for substrates with an electron-rich aromatic
polymer.
ring and a sulfur-containing heterocyclic ring (en-
tries 4 and 8). Pyridine derivatives were also success-
fully employed (entries 2, 5, and 7). These compounds
have special interest from the viewpoint of medicinal
chemistry because further transformations can give
analogues of nicotine.[13] To the best of our knowl-
edge, this is the first report of a heterogeneous PTC
that can be used to perform Michael additions with
these types of substrates with performance compara-
ble to that of homogeneous catalysts.[6] Only one dia-
stereoisomer was observed, and a similar tendency
was observed under the previously reported homoge-
neous conditions.[8] The substrate with a terminal
alkene also gave excellent enantioselectivity (entry 9).
In conclusion, we have developed a novel chiral
heterogeneous catalyst in which 2-oxopyrimidinium
PTC was immobilized in a polystyrene-based poly-
mer. This catalyst was used to perform asymmetric
Michael additions of OꢂDonnell substrate to several
a,b-unsaturated ketones under mild conditions with
low catalytic loadings (5 mol%). High yields and
Scheme 2. Recovery and reuse of the catalyst.
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[3] a) M. J. OꢂDonnell, W. D. Bennett, S. Wu, J. Am.
Chem. Soc. 1989, 111, 2353–2355; b) S. E. Denmark,
Heterocycles 2010, 82, 1527.
[4] a) A. Nelson, Angew. Chem. 1999, 111, 1685–1687;
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Maruoka, Org. Proc. Res. Dev. 2008, 12, 679–697; c) B.
Lygo, B. I. Andrews, Acc. Chem. Res. 2004, 37, 518–
525; d) K. Maruoka, T. Ooi, Chem. Rev. 2003, 103,
3013–3028.
enantioselectivities were obtained, and recovery and
reuse of the catalyst were attained without significant
reduction of activity while maintaining high enantio-
selectivity. Further applications of this catalyst to
other asymmetric reactions and continuous-flow syn-
thesis are ongoing.
Experimental Section
[5] Y. Arakawa, N. Haraguchi, S. Itsuno, Angew. Chem.
2008, 120, 8356–8359; Angew. Chem. Int. Ed. 2008, 47,
8232–8235.
General Procedure for Reaction using 10 to Afford
(S)-tert-Butyl 2-[(Diarylmethylidene)amino]-5-oxo-
alkanoates (14)
[6] a) S. S. Jew, H. G. Park, Chem. Commun 2009, 7090–
7103; b) B. Lygo, B. Allbutt, E. H. M. Kirton, Tetrahe-
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Beynon, M. C. McLeod, C.-E. Roy, C. E. Wade, Tetra-
hedron 2010, 66, 8832–8836.
[7] a) D. Wannaporn, T. Ishikawa, Mol. Divers. 2005, 9,
321–331; b) T. Ishikawa, T. Heima, M. Yoshida, T. Ku-
mamoto, Helv. Chim. Acta 2014, 97, 307–314.
[8] A. E. Sheshenev, E. V. Boltukhina, A. J. P. White, K. K.
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Schiff base 11 (15.0 mg, 0.05 mmol, 1.0 equiv.), 10 (51 mg,
2.5 mmol, 5 mol%), and Cs2CO3 (32 mg, 0.08 mmol,
1.5 equiv.) were placed in a two-neck flask. Anhydrous o-
xylene (0.5 mL) was added and the reaction mixture was
stirred at room temperature for 10 min, then at 08C for an-
other 10 min, followed by addition of a,b-unsaturated
ketone 12 (0.10 mmol, 2.0 equiv.) in one portion. The mix-
ture was stirred (1000 rpm) at 08C and the progress of the
reaction was monitored by TLC. Upon complete consump-
tion of 11, the reaction mixture was directly filtered and
washed with toluene. After evaporation under vacuum, the
residue was loaded on a silica gel column and eluted with
hexane/ethyl acetate (95:5) to afford the desired product;
yield: 18.2 mg (0.043 mmol, 86%).
[9] Polystyrene polymer tends to swell in aromatic solvents
such as toluene, xylene and mesitylene, making the cat-
alyst more sticky.
[10] T. Kitao, S. Bracco, A. Comotti, P. Sozzani, M. Naito, S.
Seki, T. Uemura, S. Kitagawa, J. Am. Chem. Soc. 2015,
137, 5231–5238.
Reuse of 10
After filtration, the solid resin was washed with dichlorome-
thane and brine (1:1 v/v, 4 mL) for 5 h with stirring at room
temperature. After filtration and washing with H2O (20 mL)
and then acetone (20 mL), the catalyst was dried under
vacuum for 12 h and directly used in the next reaction.
[11] K. Brak, E. N. Jacobsen, Angew. Chem. 2013, 125, 558–
588; Angew. Chem. Int. Ed. 2013, 52, 534–561.
[12] Polymer immobilized catalyst 9’ without the tetraethy-
lene glycol linker was also prepared. The catalytic ac-
tivity of 9’ was lower than that of 10 (under the same
reaction conditions as Table 1, entry 5, 9’: 68% yield for
6 h vs. 10: 88% yield for 1.5 h), whereas the ee was
comparable (87% vs. 88%).
Acknowledgements
This work was partially supported by a Grant-in-Aid for Sci-
entific Research from theJapan Society for the Promotion of
Science (JSPS) and the Japan Science and Technology
Agency (JST).
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These are not the final page numbers!

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A Polystyrene-Supported Phase-Transfer Catalyst for
Asymmetric Michael Addition of Glycine-Derived Imines
to a,b-Unsaturated Ketones
5
Adv. Synth. Catal. 2017, 359, 1 – 5
Javier Miguꢀlez, Hiroyuki Miyamura, Shu¯ Kobayashi*
Adv. Synth. Catal. 0000, 000, 0 – 0
5
ꢁ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!