Soluble polymer-Supported organocatalysts: asymmetric reduction of imines with irichlorosilane catalyzed by an amino acid derived formamide anchored to a soluble polymer

Article abstract of DOI:10.1002/chem.200901573

A novel polymeric platform for catalyst immobilization has been developed, featuring inverted solubility pattern: soluble in a nonpolar and insoluble in a polar medium. Asymmetric reduction of imines with Cl₃SiH (see scheme), catalyzed by chira

Full text of DOI:10.1002/chem.200901573

COMMUNICATION
DOI: 10.1002/chem.200901573
Soluble Polymer-Supported Organocatalysts: Asymmetric Reduction of
Imines with Trichlorosilane Catalyzed by an Amino Acid Derived Form
Anchored to a Soluble Polymer
ACHTUNGTNERaNUNG mide
Andrei V. Malkov,*[a, b] Marek Figlus,[a] Mark R. Prestly,[a] Gouher Rabani,[a]
Graeme Cooke,*[a] and Pavel Kocˇovsky*[a]
´
ˇ
´
Dedicated to Professor Tomꢀs Hudlicky on the occasion of his 60th birthday
In the development of an efficient catalytic process, facile
separation of the product from the catalyst is one of the key
technological elements. In organocatalysis, where both the
product and the catalyst are small organic molecules, chro-
matography often represents the only option. Here, immobi-
lization of the catalyst may provide an elegant solution to
the problem.[1]
Asymmetric reduction of prochiral imines 1 is one of the
key reactions in synthetic organic chemistry (Scheme 1).[2]
Its organocatalytic version[3] is characterized by two funda-
mentally different approaches: 1) hydrosilylation with
Cl3SiH, catalyzed by chiral Lewis-bases,[4–9] and 2) reduction
with Hantzsch dihydropyridine, catalyzed by chiral Brønsted
acids.[10]
In the past few years, we have developed the amino acid-
based formamides 3–5 (Scheme 1) as chiral Lewis-basic or-
ganocatalysts for the reduction of imines 1 (ꢀ97% ee; 1–
5 mol% loading).[4] The practicality was then improved by
tagging the catalyst to a fluorous ponytail (7)[5] and by its
anchoring to a polymer support (8).[6,11] Catalyst 7, working
in a homogeneous solution, mirrored the enantioselectivities
of 3–5 and the products were separated from the catalyst by
Scheme 1. Catalysts for asymmetric reduction of imines; for a–j, see
Table 1.
filtration through a pad of fluorous silica.[5] The solid-sup-
ported catalysts 8 were separated even more easily via me-
chanical filtration.[6] However, the latter reactions were het-
erogeneous and that had a negative impact on the enantio-
selectivities, which reached ꢀ82% ee, that is, about 10–15%
ee below those of the homogeneous system.[6]
We reasoned that anchoring the catalyst to a soluble poly-
meric support might serve as a remedy to the problems as-
sociated with the heterogeneous systems. Recovery and re-
cycling of the soluble supported catalysts would then rely on
the switch of solubility induced either by changing the sol-
vent polarity (e.g., for PEG support) or the temperature
(for thermomorphic support).[1b,f,g] Traditionally, PEG poly-
mers are precipitated by non-polar solvents, which may also
lead to co-precipitation of the polar products, thereby affect-
ing the overall efficiency of the process. Herein, we report
[a] Prof. Dr. A. V. Malkov, Dr. M. Figlus, M. R. Prestly, Dr. G. Rabani,
ˇ
´
Dr. G. Cooke, Prof. Dr. P. Kocovsky
Department of Chemistry, WestChem
University of Glasgow, Glasgow G12 8QQ (UK)
Fax : (+44)141-330-4888
E-mail: graeme@chem.gla.ac.uk
pavelk@chem.gla.ac.uk
[b] Prof. Dr. A. V. Malkov
Present Address: Department of Chemistry
Loughborough University, Leicestershire, LE11 3TU (UK)
Fax : (+44)1509-22-3925
E-mail: a.malkov@lboro.ac.uk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901573.
Chem. Eur. J. 2009, 15, 9651 – 9654
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9651

on development of a novel polymeric platform for catalyst
immobilization, featuring inverted solubility pattern: the
catalyst soluble in a non-polar and insoluble in a polar
medium.
In our previous work, the solid-supported catalysts 8 were
prepared by constructing an ether link between the phenolic
group in 6 and a suitable group on the polymer, namely P-
C6H4-CH2Cl or P-C6H4-CH2OH, using the Williamson and
Mitsunobu conditions, respectively.[6] In the present study,
we have adopted a different strategy, which aimed at the
preparation of the anchored catalyst by copolymerization of
methacrylates 10 and 11 (Scheme 2).
copolymers 9a and 9b was ~7800 and 6000 gmolÀ1, respec-
tively, as revealed by gel permeation chromatography
(GPC). Their poly-dispersity index (PDI) varied from 1.35
(9a) to 1.18 (9b), indicating a fairly narrow distribution of
molecular masses for the polymers.
The reactivity of our immobilized catalysts in the reduc-
tion of imines was investigated by using the same reaction
conditions as those employed for 3–7 (1 equiv of imine,
2 equiv of Cl3SiH, and catalyst 9 at room temperature). Re-
duction of imine 1a in toluene (an optimized solvent for ho-
mogeneous conditions[4,5]), catalyzed by 9a, afforded amine
(S)-2a in 85% ee (Table 1, entry 3). Catalyst 9b, with the
higher content of the active component, turned out to
be an optimum in terms of its preparation and perfor-
mance, since high conversions and enantioselectivities
were attained (86–88% ee; entries 4–6) even with grad-
ually decreasing catalyst loading (from 7 to 1 mol%).
The practicality of the protocol was demonstrated by
more than 25-fold scale-up experiment (entry 7). Signif-
icantly, enantioselectivity of the supported catalyst 9b
remained at the same level as that observed for its
monomeric congeners 4 and 6 (entries 1 and 2). When
the reaction was complete, as indicated by TLC, the re-
action mixture (in toluene) was poured into an excess
of a vigorously stirred MeOH, resulting in the precipi-
tation of ꢁ95% of the catalyst, which was then filtered
off.[13]
The scope of the homogeneous catalysts 3–5 has been
shown by us to be quite broad, spanning from a range of ar-
omatic to heteroaromatic and to some aliphatic substrates,
while tolerating various functionalities.[4,5] Therefore, only a
small set of imines, namely 1b–j, was explored in the pres-
ent study (Table 1). In agreement with the previous observa-
tions, high enantioselectivities were attained for imines de-
rived from aromatic ketones 1b–d with both electron-with-
drawing and electron-donating groups (entries 8–10). Imine
1e with the b-thiophene nucleus (entry 11) exhibited lower
enantioselectivity, consistent with the general behavior of ar-
omatic heterocycles.[4,5] By contrast, the presence of heteroa-
toms in the alkyl part (1 f,g) did not have any adverse effect
(entries 12 and 13), reaching the maximum of 91% ee. The
cyclopropyl and cyclobutyl derivatives 1h,i still exhibited
acceptable enantioselectivities (entries 14 and 15), whereas a
larger decrease was observed for the bulkier cyclohexyl de-
rivative 1j (entry 16).
Scheme 2. Synthesis of the supported catalyst.
Treatment of the phenolic derivative 6[6] with methacrylo-
yl chloride afforded the monomer 10 (83%), which was co-
polymerized with benzyl methacrylate 11 using atom trans-
fer radical polymerization (ATRP) methodology,[12] namely
by heating a mixture of 10 and 11 (1:99 to 10:90) in the pres-
ence of CuCl (1 mol% with respect to 11), 2,2’-bipyridine
(3 mol%), and ethyl 2-bromo-isobutyrate (1 mol%) in
DMSO at 908C for 4 h. The resulting copolymer 9 was pre-
cipitated by pouring the cooled mixture into an excess of
MeOH.
In the initial polymerizations, the amount of 10 in the
mixture was varied in the range of 1, 5, and 10 mol% with
respect to 11, whereas the amount of CuCl was kept con-
stant (1 mol%). Co-polymerization of 10 (1 mol%) with 11
produced 9a in 46% yield, which contained 0.13 mmolgÀ1
of the active moiety, as revealed by elemental analysis.
However, when the amount of 10 in the initial mixture was
increased to 5 mol%, the polymerization afforded the copo-
lymer in only 9% yield and a further decrease (to 4%) was
observed with 10 mol% of 10. Clearly, 10 had a negative
effect on the activity of the catalyst. Therefore, in the subse-
quent experiments, the amount of CuCl was increased to
match that of 10, which proved to have a beneficial effect.
In a scaled-up, optimized experiment, carried out with a
5:95 mixture of 10 and 11 in the presence of CuCl
(5 mol%), 2,2’-bipyridine (15 mol%), and ethyl 2-bromo-
isobutyrate (1 mol%), copolymer 9b (0.19 mmolgÀ1) was
obtained in 48% yield. Further increase in the content of 10
in the mixture did not lead to any significant increase in its
incorporation, showing that the copolymerization reached
its saturation point. The average molecular weight (Mn) of
The solid-supported, insoluble catalysts 8 retained their
activity when re-used;[6] in fact, we have observed an in-
crease in selectivity in the second run by ~5% ee, which was
maintained in the subsequent runs; this behavior was attrib-
uted to a “conditioning” effect.[6] By contrast, the soluble
catalyst 9b (Table 2) exhibited the same activity in runs 1–5;
hence, no “conditioning” was taking place here, which is ap-
parently confined to the heterogeneous protocol.
In conclusion, a new soluble polymeric platform for im-
mobilization of organocatalysts has been developed, which
may, a priori, be applied to a wide variety of other catalytic
systems. The asymmetric reduction of imines 1a–j with
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Chem. Eur. J. 2009, 15, 9651 – 9654

Soluble Polymer-Supported Organocatalysts
COMMUNICATION
Table 1. Reduction of ketimines 1a–j with trichlorosilane, catalyzed by the valine-derived N-methyl forma-
mides (S)-9a/b.[a]
Experimental Section
Entry
Catalyst
(mol%)
Imine
R1
R2
Catalyst
recovery [%]
Yield [%][b]
ee[d] 2[c] [%]
Catalyst 9b: Copper(I) chloride
(80 mg, 0.82 mmol), 2,2’-bipyridine
(384 mg, 2.46 mmol), benzyl methacry-
late 11 (2.70 mL, 16 mmol), and ethyl
G
1
2
3
4
5
6
7
8
4 (10)[e]
6 (10)[e]
9a (20)
9b (7)
9b (3)
9b (1)
9b (1)[f]
9b (7)
9b (7)
9b (7)
9b (7)
9b (7)
9b (7)
9b (7)
9b (7)
9b (7)
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
CH2Cl
CH2CO2Et
c-Pr
c-Bu
c-Hex
–
–
85
94
90
90
90
90
90
88
75
87
78
70
77
71
81
85
91
86
85
86
86
88
88
86
86
82
65
91
81
73
75
55
2-bromoisobutyrate
(24 mL,
99
99
98
99
98
90
92
85
96
94
99
99
99
98
0.16 mmol) were successively added to
a solution of 10 (282 mg, 0.82 mmol)
in DMSO (7 mL) and the mixture was
stirred under nitrogen for 5 min. This
heterogeneous mixture was then de-
gassed by freeze–pump–thaw and
stirred under nitrogen at 908C for 3 h.
The mixture was then cooled to room
temperature and poured into a vigo-
rously stirred MeOH (1 L). The pre-
cipitated polymer was isolated by fil-
tration, washed with MeOH (300 mL),
dissolved in DMSO (7 mL), and the
solution was poured into a vigorously
stirred MeOH (1000 mL) again. The
precipitate was isolated by filtration,
washed with MeOH (300 mL), and
dried under high vacuum to afford a
crude product as a greenish powder
(3.19 g). The latter powder was dis-
solved in CH2Cl2 (100 mL) and vigo-
rously stirred with deionized water
(100 mL) for 30 min. The organic layer
2-naphthyl
4-CF3-C6H4
4-MeO-C6H4
thiophen-2-yl
Ph
Ph
Ph
Ph
Ph
9
10
11
12
13
14
15
16
1j
[a] The reaction was carried out at 0.2 mmol scale with 2.0 equiv of Cl3SiH at 258C for 16 h. [b] Isolated yield.
[c] The absolute configuration was established from the optical rotation by comparison with the literature data
(see Experimental Section) and by HPLC via comparison with authentic samples; the resulting amines 2a–j
were S configured. [d] Determined by chiral HPLC. [e] Ref. [6]. [f] The reaction was carried out at 5 mmol
scale.
Table 2. Asymmetric reduction of imine 1a with Cl3SiH catalyzed by the
was separated, dried, and evaporated and the residue was dissolved in
CHCl3 (7 mL) and the solution was poured into a vigorously stirred
MeOH (1 L). The precipitated polymer was isolated by filtration, washed
with MeOH (300 mL), and dried under high vacuum to furnish 9b
(2.48 g, 48%) as a white powder. 1H NMR (400 Hz, CDCl3): d = 0.72
(brs), 0.91 (brs), 1.07 (brs), 1.18 (brm), 1.31 (brm), 1.60 (brm), 1.78
(brs), 1.88–2.04 (brsignal), 2.48 (brm), 2.98 (brs), 3.44 (brm), 4.00
(brm), 4.35 (brd), 4.88 (brd), 5.09 (brm), 5.15 (brm), 7.08 (brm), 7.28
(brs), 7.47 (brm), 8.00 (brs), 8.14 ppm (brs); IR (KBr): n = 3437, 3064,
reused 9b (20 mol%) in toluene.[a]
Run
Catalyst recovery [%]
Yield [%][b]
ee[c] (S)-2a [%]
1
2
3
4
5
99
95
94
93
95
86
87
90
90
90
86
86
84
86
86
[a] For the conditions, see Table 1. [b] Isolated yield. [c] Determined by
chiral HPLC.
3032, 2959, 1728, 1487, 1482, 1455, 1388, 1367, 1262, 1142, 751, 697 cmÀ1
;
GPC: Mn =6000 gmolÀ1, Mw =7134 gmolÀ1, PDI=1.19; elemental analy-
sis (%) found: C 73.78, H 6.88, N 0.53, this corresponds to 0.19 mmolgÀ1
loading.
Procedure for a large scale asymmetric reduction of 1a catalyzed by 9b:
Cl3SiH (1.15 mL, 10 mmol) was added to a solution of imine 1a (1.15 g,
5.10 mmol) and the supported catalyst 9b (253 mg; containing 0.62% of
N, which corresponds to 1 mol% loading) in toluene (46 mL) at 08C and
the mixture was stirred at room temperature overnight. The mixture was
then poured into a rapidly stirred MeOH (900 mL), and the precipitated
polymer was separated by filtration, washed with MeOH (200 mL), and
dried in a vacuum to afford the regenerated catalyst 9b (249 mg, 98%).
The methanolic filtrate, containing the amine and inorganic impurities,
was evaporated and the residue was dissolved in CH2Cl2 (200 mL) and
the resulting solution was washed with aqueous saturated NaHCO3
(100 mL). The aqueous phase was extracted with CH2Cl2 (200 mL) and
the combined organic solutions were dried over MgSO4. Evaporation of
the solvent furnished amine 2a in ~95% purity as a brownish oil (1.05 g,
90%, 88% ee).
Cl3SiH, promoted by this new catalyst 9b, proceeds readily
at room temperature. This protocol simplifies the catalyst
recovery and produces chiral amines 2a–j in high yields and
with good enantioselectivity (ꢀ91% ee) at 1–7 mol% cata-
lyst loading, which is unprecedented in the realm of support-
ed organocatalysts. The catalyst can be recovered almost
quantitatively and re-used at least five times without loss of
activity, which demonstrates its suitability for multiple and
parallel use. The main advantage of the present system 9b
over our previous solid-supported catalysts 8 can be seen in
the homogeneous conditions that led to the increase of
enantioselectivity (by ꢀ10% ee). Furthermore, 9b with its
polymethacrylate backbone, is superior to other soluble
polymeric systems, based, for example, on ethylene glycol,[14]
in that it works in a non-polar solvent (toluene), can be
easily precipitated by a polar solvent (methanol) and
reused, and allows a higher concentration of the catalytic
moiety in the polymer. The narrow range of the molecular
weight of 9b undoubtedly contributes to the overall behav-
ior of this catalyst.
Acknowledgements
We thank the University of Glasgow for a fellowship to M.F. and the
EPSRC for grants No. GR/S87294/01 and EP/C53056X/2.
Chem. Eur. J. 2009, 15, 9651 – 9654
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9653

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´
A. V. Malkov, P. Kocovsky et al.
[9] H. Zheng, J. Deng, W. Lin, X. Zhang, Tetrahedron Lett. 2007, 48,
7934.
Keywords: asymmetric synthesis · imines · organocatalysis ·
polymer-supported catalysts · reduction
[10] a) S. Singh, U. K. Batra, Indian J. Chem. Sect. B 1989, 28, 1–2;
b) M. Rueping, E. Sugiono, C. Azap, T. Theissmann, M. Bolte, Org.
Lett. 2005, 7, 3781–3783; c) M. Rueping, A. P. Antonchick, T.
Theissmann, Angew. Chem. 2006, 118, 3765–3768; Angew. Chem.
Int. Ed. 2006, 45, 3683–3686; d) M. Rueping, A. P. Antonchick, T.
Theissmann, Angew. Chem. 2006, 118, 6903–6907; Angew. Chem.
Int. Ed. 2006, 45, 6751–6755; e) S. Hoffmann, A. M. Seayad, B. List,
Angew. Chem. 2005, 117, 7590–7593; Angew. Chem. Int. Ed. 2005,
44, 7424–7427; f) S. Hoffmann, M. Nicoletti, B. List, J. Am. Chem.
Soc. 2006, 128, 13074–13075; g) J. Zhou, B. List, J. Am. Chem. Soc.
2007, 129, 7498–7499; h) R. I. Storer, D. E. Carrera, Y. Ni, D. W. C.
MacMillan, J. Am. Chem. Soc. 2006, 128, 84–86; i) S. G. Ouellet,
A. M. Walji, D. W. C. MacMillan, Acc. Chem. Res. 2007, 40, 1327–
1339.
[1] For polymer-supported catalysts, see, e.g.: a) C. A. McNamara, M. J.
Dixon, M. Bradley, Chem. Rev. 2002, 102, 3275–3300; b) D. E. Berg-
breiter, Chem. Rev. 2002, 102, 3345–3384; c) M. Heitbaum, F. Glo-
rius, I. Escher, Angew. Chem. 2006, 118, 4850–4881; Angew. Chem.
Int. Ed. 2006, 45, 4732–4762; d) R. T. Baker, S. Kobayashi, W. Leit-
ner, Adv. Synth. Catal. 2006, 348, 1337–1340; e) F. Cozzi, Adv.
Synth. Catal. 2006, 348, 1367–1390; f) D. E. Bergbreiter, S. D. Sung,
Adv. Synth. Catal. 2006, 348, 1352–1366; g) D. E. Bergbreiter, J. Li,
Chem. Commun. 2004, 42–43.
[2] a) I. Ojima, Catalytic Asymmetric Synthesis, 2nd ed., Wiley, New
York, 2000; b) S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069–
1094; c) B. T. Cho, Tetrahedron 2006, 62, 7621–7643.
[3] a) A. Berkessel, H. Grçger, Asymmetric Organocatalysis, Wiley-
VCH, Weinheim, 2005; b) P. I. Dalko, Enantioselective Organo-catal-
ysis, Wiley-VCH, Weinheim, 2007.
[11] The p-ether substituent in 7 and its congeners proved to have no
effect on the catalyst reactivity.[4b,5] On the other hand, the introduc-
tion of the 3,5-alkyl groups, as in 4 and 5, resulted in a minor but
consistent increase of enantioselectivity by ꢂ5% ee.[4b,5]
ˇ
´
[4] a) A. V. Malkov, A. Mariani, K. N. MacDougall, P. Kocovsky, Org.
[12] For authoritative reviews on this method, see: a) K. Matyjaszewski,
J. Xia, Chem. Rev. 2001, 101, 2921–2990; b) K. Matyjaszewski,
W. A. Braunecker in Macromolecular Engineering. Precise Synthesis
Materials Properties, Applications, Vol. 1 (Eds.: K. Matyjaszewski, Y.
Gnanou, L. Leibler), Wiley-VCH, Weinheim, 2007, pp. 161–215;
c) W. A. Braunecker, K. Matyjaszewski, Prog. Polym. Sci. 2007, 32,
93–146.
ˇ
Lett. 2004, 6, 2253–2256; b) A. V. Malkov, S. Stoncius, K. N. Mac-
ˇ
´
Dougall, A. Mariani, G. D. McGeoch, P. Kocovsky, Tetrahedron
ˇ
ˇ
´
2006, 62, 264–284; c) A. V. Malkov, S. Stoncius, P. Kocovsky, Angew.
Chem. 2007, 119, 3796–3798; Angew. Chem. Int. Ed. 2007, 46, 3722–
ˇ
3724; d) A. V. Malkov, S. Stoncius, K. Vrankovꢁ, M. Arndt, P. Ko-
ˇ
´
covsky, Chem. Eur. J. 2008, 14, 8082–8085; e) A. V. Malkov, K.
ˇ
ˇ
´
Vrankovꢁ, S. Stoncius, P. Kocovsky, J. Org. Chem. 2009, 74, 5839–
5849.
[13] In the small-scale experiments, a small amount of the catalyst (ꢀ
5%) remained in the filtrate due to the presence of toluene, in
which it is soluble. Therefore, the filtrate was evaporated and the
solid residue was treated with MeOH, which dissolved the product,
leaving the remaining supported catalyst undissolved. For details see
Supporting Information.
ˇ
ˇ
´
[5] A. V. Malkov, M. Figlus, S. Stoncius, P. Kocovsky, J. Org. Chem.
2007, 72, 1315–1325.
[6] A. V. Malkov, M. Figlus, P. Kocovsky, J. Org. Chem. 2008, 73, 3985–
ˇ
´
3996.
[7] a) F. Iwasaki, O. Omonura, K. Mishima, T. Kanematsu, T. Maki, Y.
Matsumura, Tetrahedron Lett. 2001, 42, 2525–2527; b) O. Onomura,
Y. Kouchi, F. Iwasaki, Y. Matsumura, Tetrahedron Lett. 2006, 47,
3751–3754. For a related reduction of ketones, see: c) F. Iwasaki,
O, Onomura, K. Mishima, T, Maki, Y. Matsumura, Tetrahedron
Lett. 1999, 40, 7507–7511; d) Y. Matsumura, K. Ogura, Y. Kouchi, F.
Iwasaki, O. Onomura, Org. Lett. 2006, 8, 3789–3792.
[14] For reviews on other soluble polymers, see: a) T. J. Dickerson, N. N.
Reed, K. D. Janda, Chem. Rev. 2002, 102, 3325–3344. For the prob-
lems associated with nonpolar solvents, see: b) T. S. Reger, K. D.
Janda, J. Am. Chem. Soc. 2000, 122, 6929–6934.
[8] a) Z. Wang, X. Ye, S. Wei, P. Wu, A. Zhang, J. Sun, Org. Lett. 2006,
8, 999–1001; b) Z. Wang, M. Cheng, P. Wu, S. Wei, J. Sun, Org. Lett.
2006, 8, 3045–3048.
Received: June 9, 2009
Published online: August 26, 2009
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