Synthesis and application of a recyclable ionic liquid-supported imidazolidinone catalyst in enantioselective 1,3-dipolar cycloaddition

Article abstract of DOI:10.1039/c2cc31830j

The synthesis of recyclable ionic liquid-supported imidazolidinone catalyst I and its application in 1,3-dipolar cycloaddition of nitrone with α,β-unsaturated aldehyde with high performance were described. Most importantly, the catalyst I can be recovered

Full text of DOI:10.1039/c2cc31830j

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COMMUNICATION
Synthesis and application of a recyclable ionic liquid-supported
imidazolidinone catalyst in enantioselective 1,3-dipolar cycloadditionw
Zhi-Liang Shen,z Kau Kiat Kelvin Goh,z Colin Hong An Wong, Wan-Yi Loo,
Yong-Sheng Yang, Jun Lu and Teck-Peng Loh*
Received 12th March 2012, Accepted 5th April 2012
DOI: 10.1039/c2cc31830j
The synthesis of recyclable ionic liquid-supported imidazolidinone
catalyst I and its application in 1,3-dipolar cycloaddition of
nitrone with a,b-unsaturated aldehyde with high performance
were described. Most importantly, the catalyst I can be recovered
and recycled for up to five runs without observing significant
decrease in catalytic activity.
In recent years, there has been a tremendous increase in the use
of organocatalysts1 in asymmetric synthesis. Among them,
MacMillan’s imidazolidinone2 catalyst has emerged as one of
the most efficient organocatalysts for mediating a wide variety
of organic transformations with good to excellent enantio-
selectivities. Though the wide applicability of imidazolidinone
in asymmetric synthesis has been scientifically well-established
by MacMillan and others, the recovery and recycling of the
catalyst have been difficult. In light of the increasing impor-
tance of the imidazolidinone catalyst in organic synthesis and
the practical limitation of the recycling of the catalyst, the
Scheme 1 Synthetic route to ionic liquid-supported imidazolidinone
development of an imidazolidinone catalyst that can be recycled
in subsequent reactions is highly sought after in the chemical
industry.
catalysts I, II, and III.
runs without observing any significant decrease in catalytic
immobilizing chiral catalysts in ionic liquids.3–6 The special
activity.
Recently, our group and others have developed a strategy of
A strategy was proposed to synthesize the ionic liquid-
property of ionic liquid’s solubility in different organic solvents
supported imidazolidinone catalyst while maintaining the
allows easy recovery and recycling of expensive chiral catalysts
pivotal skeleton of the imidazolidinone catalyst untouched.
catalytic activity of catalysts.5,6a Therefore, we envision that
The synthetic route is summarized in Scheme 1. Starting from
and thus facilitates product isolation while maintaining high
the commercially available L-phenylalanine 1, protection of the
amino group with (Boc)2O, followed by DCC- or HOBt/EDC-
if an ionic liquid is tethered to the imidazolidinone catalyst,
we may be able to recycle the catalyst for further reactions
mediated coupling with N-(3-aminopropyl) imidazole 3 afforded
amide 4 in 75% and 82% yields, respectively. The Boc-protecting
group was subsequently removed using trifluoroacetic acid to
while maintaining the high enantioselectivity of the reaction
product. Herein, we describe an efficient synthetic route to
the synthesis of ionic liquid-supported imidazolidinone
catalyst I and its application in 1,3-dipolar cycloaddition2f,7,8
give 5 in 64% yield. Condensation of 5 with acetone was
successfully achieved by using a catalytic amount of D-(+)-10-
camphorsulfonic acid (CSA) under refluxing conditions, affording
with good to excellent endo enantioselectivities. In addition,
catalyst I can be recovered and recycled for at least five
the imidazolidinone framework 6 in 77% yield. After many trials,
it was found that the imidazolium unit of compound 6 could be
directly alkylated by 1-iodobutane (without tedious protection of
Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences,
the amino group) in refluxing CH3CN to generate the catalyst I in
80% yield. Finally, anion exchange of catalyst I with KBF4 and
KPF6 furnished catalysts II and III, respectively.
Nanyang Technological University, Singapore 637371, Singapore.
E-mail: teckpeng@ntu.edu.sg; Fax: +65-67911961
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data of products, and copies of 1H and
13C NMR spectra. See DOI: 10.1039/c2cc31830j
To evaluate the capacity of the ionic liquid-supported
imidazolidinone catalysts, we set out to investigate its catalytic
z These authors contributed equally to this work.
c
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Table 2 Application of catalyst I to 1,3-dipolar cycloadditiona
Table 1 Optimization of reaction conditions by using different
catalysts I–III and acid co-catalyst HXa
Entry
R
R0
Yieldb (%) endo : exoc endo eed (%)
Entry Catalyst HX
Yieldb (%) endo : exoc endo eed (%)
1
2
3
4
5
6
7
8
9
4-BrC6H4
4-ClC6H4
C6H5
4-MeC6H4
4-OMeC6H4 Me 97
2-Naphthyl Me 77
C6H5
C6H5
C6H5
Me 92
Me 97
Me 98
Me 88
95 : 5
96 : 4
90 : 10
86 : 14
96 : 4
86 : 14
80 : 20
86 : 14
88 : 12
93
93
94
92
92
94
82
85
84
1
2
3
4
5
6
7
8
I
CF3COOH 77
CF3COOH 70
CF3COOH 76
75 : 25
74 : 26
72 : 28
82 : 18
86 : 14
90 : 10
90 : 10
85 : 15
94
94
94
94
94
94
94
94
II
III
I
I
I
CSAe
TfOH
HBF4
HPF6
HCl
80
85
98
81
87
H
Et
73
79
I
I
n-Pr 81
a
b
See ESI for detailed experimental procedures. Isolated yield. c Endo/exo
a
The reactions were carried out at ꢀ20 1C for 120 h using catalyst
1
ratio was determined by H NMR analysis of the crude reaction mixture.
d Enantioselectivity was determined by chiral HPLC analysis.
(0.1 mmol), HX (0.1 mmol), nitrone (0.5 mmol), (E)-crotonaldehyde
b
(5.0 mmol), CH3NO2 (1.9 mL), and H2O (0.1 mL). Isolated yield.
c
Endo/exo ratio was determined by 1H NMR analysis of crude reaction
d
mixture. Product enantiometric ratios were determined by HPLC
aldehydes in the presence of ionic liquid-supported imidazol-
idinone catalyst I and acid co-catalyst HBF4 in CH3NO2–H2O
at ꢀ20 1C. The target products of isoxazolidines were obtained
in moderate to good yields with good to excellent endo ee,
which are comparable to the results obtained from the use of
imidazolidinone as reaction catalyst.2f For instance, the same
excellent endo enantioselectivity of 94% was obtained when
N-benzylidenebenzylamine N-oxide and (E)-crotonaldehyde
were used as substrates (Table 2, entry 3), by employing either
Macmillan’s imidazolidinone catalyst or the ionic liquid-
supported catalyst I in present protocol.
using chiralcel OD-H column (ꢁ2) after reduction of the aldehyde to
e
alcohol with NaBH4. CSA = D-(+)-10-camphorsulfonic acid.
efficiency in the synthesis of enantiomerically enriched
isoxazolidine via an enantioselective 1,3-dipolar cycloaddition
of nitrone with a,b-unsaturated aldehyde.2f Isoxazolidines are
useful chiral precursors to g-amino alcohols, b-amino acids
and b-lactams, which are widely employed in the pharma-
ceutical industry as antibacterial, antibiotics drugs, as well as
many other biological applications.9 N-Benzylidenebenzylamine
N-oxide and (E)-crotonaldehyde were chosen as model sub-
strates to explore the optimum conditions for the 1,3-dipolar
cycloaddition. The three catalysts I–III in conjunction with
various acid co-catalysts (HX) were tested in the reaction at
ꢀ20 1C for 120 hours.
With the success of the above reactions, next we explored
the recyclability of the chiral ionic liquid-supported imidazol-
idinone catalyst I in 1,3-dipolar cycloaddition. As illustrated in
Scheme 2, after reaction the remaining ionic liquid-supported
imidazolidinone catalyst I was recovered and recycled in
subsequent reactions with only a slight decrease in catalytic
activity being observed. For instance, the recycling procedure
involving N-benzylidenebenzylamine N-oxide and (E)-crotonalde-
hyde were found to afford the product in 98% yield, 94% endo
ee (1st run), 97% yield, 94% endo ee (2nd run), 95% yield,
92% endo ee (3rd run), 96% yield, 90% endo ee (4th run), and
92% yield, 88% endo ee (5th run).
As shown in Table 1, when CF3COOH was used as an acid
co-catalyst (Table 1, entries 1–3), the reactions employing
catalysts I–III proceeded smoothly to give the desired product
in moderate diastereoselectivity (B75 : 25 endo/exo ratio) and
excellent endo enantioselectivity (94% ee). Considering the
relatively good yield and diastereoselectivity obtained with
the use of catalyst I (Table 1, entry 1), it was chosen as a
catalyst in subsequent optimization by surveying different
acids as reaction co-catalysts.
In conclusion, we have described an efficient synthetic route
to the synthesis of ionic liquid-supported imidazolidinone
catalyst I and its application in enantioselective 1,3-dipolar
cycloaddition, providing the desired products of isoxazolidines
Six types of protic acids were screened as the reaction
co-catalysts (Table 1, entries 1, 4–8). In comparison to
CF3COOH, it was found that better yields and endo–exo
selectivities were obtained when CSA, TfOH, HBF4, HPF6,
and HCl were used as reaction co-catalysts, along with the
maintenance of the excellent endo ee of 94%. Whereas HBF4
was proven to be the most efficient one among all the acids
screened, excellent yield (98%) and good diastereoselectivity
(endo : exo 90 : 10) were produced under the reaction condi-
tions (Table 1, entry 6). Therefore, HBF4 was selected as a
reaction co-catalyst in further reactions.
Next, the substrate scope of the reaction was investigated. As
can be seen from Table 2, in all cases, various nitrones effectively
underwent the 1,3-dipolar cycloadditon with a,b-unsaturated
Scheme 2 Recycling of catalyst I in 1,3-dipolar cycloaddition.
Chem. Commun., 2012, 48, 5856–5858 5857
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in moderate to good yields with good to excellent endo
enantioselectivities. Most importantly, the recovery and recycling
of the ionic liquid-supported imidazolidinone catalyst I in
further reactions were successfully achieved and the catalyst
can be reused for at least five runs without observing signifi-
cant decrease in yield and enantioselectivity. We believed that
the immobilization of imidazolidinone to ionic liquid which
enables the easy recycling of the imidazolidinone organo-
catalyst in organic reactions will have great synthetic value
and potentially find wide applications in both organic synthesis
and the chemical industry.
Ionic liquid: a green solvent for organic transformations II, ACS
Symposium Series, vol. 950 (Ionic Liquids in Organic Synthesis),
2007, pp. 177–193.
4 For reviews concerning the use of ionic liquid as catalyst supporters,
see: (a) S. Z. Luo, L. Zhang and J. P. Cheng, Chem.–Asian J., 2009,
4, 1184; (b) A. Winkel, P. V. G. Reddy and R. Wilhelm, Synlett,
2008, 999; (c) K. Bica and P. Gaertner, Eur. J. Org. Chem., 2008,
3235; (d) W. S. Miao and T. H. Chan, Acc. Chem. Res., 2006,
39, 897; (e) X. W. Chen, X. H. Li, A. X. Hu and F. R. Wang,
Tetrahedron: Asymmetry, 2008, 19, 1; (f) S.-g. Lee, Chem. Commun.,
2006, 1049; (g) C. Baudequin, D. Bregeon, J. Levillain, F. Guillen,
J. C. Plaquevent and A. C. Gaumont, Tetrahedron: Asymmetry,
2005, 16, 3921; (h) J. Ding and D. W. Armstrong, Chirality, 2005,
17, 281; (i) P. Dominguez de Maria, Angew. Chem., Int. Ed., 2008,
47, 6960; (j) A. F. Trindade, P. M. P. Gois and C. A. M. Afonso,
Chem. Rev., 2009, 109, 418; (k) R. Sebesta, I. Kmentova and
S. Toma, Green Chem., 2008, 10, 484.
5 For leading references concerning the use of ionic liquid as catalyst
supporters, see: (a) S. Z. Luo, X. L. Mi, L. Zhang, S. Liu, H. Xu and
J. P. Cheng, Angew. Chem., Int. Ed., 2006, 45, 3093; (b) W. S. Miao
and T. H. Chan, Adv. Synth. Catal., 2006, 348, 1711; (c) S. Z. Luo,
L. Zhang, X. L. Mi, Y. P. Qiao and J. P. Cheng, J. Org. Chem.,
2007, 72, 9350; (d) N. Audic, H. Clavier, M. Mauduit and
J. C. Guillemin, J. Am. Chem. Soc., 2003, 125, 9248; (e) T. J.
Geldbach and P. J. Dyson, J. Am. Chem. Soc., 2004, 126, 8114;
(f) W. X. Qian, E. L. Jin, W. L. Bao and Y. M. Zhang, Angew.
Chem., Int. Ed., 2005, 44, 952; (g) L. Zhang, L. Y. Cui, X. Li,
J. Y. Li, S. Z. Luo and J. P. Cheng, Chem.–Eur. J., 2010, 16, 2045;
(h) M. Lombardo, M. Chiarucci and C. Trombini, Chem.–Eur. J.,
2008, 14, 11288; (i) H. Hagiwara, T. Kuroda, T. Hoshi and
T. Suzuki, Adv. Synth. Catal., 2010, 352, 909.
6 (a) T. P. Loh, L. C. Feng, H. Y. Yang and J. Y. Yang, Tetrahedron
Lett., 2002, 43, 8741; (b) S. L. Chen, S. J. Ji and T. P. Loh,
Tetrahedron Lett., 2003, 44, 2405; (c) J. Lu, S. J. Ji, R. Qian,
J. P. Chen, Y. Liu and T. P. Loh, Synlett, 2004, 534;
(d) Z. L. Shen, W. J. Zhou, Y. T. Liu, S. J. Ji and T. P. Loh, Green
Chem., 2008, 10, 283; (e) S. L. Chen, S. J. Ji and T. P. Loh,
Tetrahedron Lett., 2004, 45, 375; (f) Z. L. Shen, S. J. Ji and
T. P. Loh, Tetrahedron Lett., 2005, 46, 3137; (g) J. Lu, S. J. Ji and T. P.
Loh, Chem. Commun., 2005, 2345; (h) F. Fu, Y. C. Teo and T. P. Loh,
Org. Lett., 2006, 8, 5999; (i) J. F. Zhao, B. H. Tan, M. K. Zhu, T. B.
W. Tjan and T. P. Loh, Adv. Synth. Catal., 2010, 352, 2085.
7 For reviews relating to 1,3-dipolar cycloaddition, see: (a) J. J.
Tufariello, in 1,3-Dipolar Cycloaddition Chemistry, ed. A. Padwa,
John Wiley and Sons, Chichester, 1984, vol. 2, p. 83; (b) K. B. G.
Torssell, Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis,
Wiley-VCH, Weinheim, 1988; (c) K. V. Gothelf and K. A. Jørgensen,
Chem. Rev., 1998, 98, 863; (d) R. Huisgen, Angew. Chem., Int. Ed.,
1963, 2, 565; (e) K. V. Gothelf and K. A. Jorgensen, in Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry toward Hetero-
cycles and Natural Products, ed. A. Padwa, Wiley, New York, 2002;
(f) K. V. Gothelf, in Cycloaddition Reactions in Organic Synthesis,
ed. S. Kobayashi and K. A. Jorgensen, Wiley-VCH, Weinheim,
2002, pp. 211–247.
8 For recent examples concerning the asymmetric organocatalyzed
1,3-dipolar cycloaddition reactions, see: (a) S. Karlsson and H.-E.
Hogberg, Tetrahedron: Asymmetry, 2002, 13, 923; (b) S. Karlsson
and H.-E. Hogberg, Eur. J. Org. Chem., 2003, 2782; (c) S. S. Chow,
M. Nevalainen, C. A. Evans and C. W. Johannes, Tetrahedron Lett.,
2007, 48, 277; (d) M. Lemay, J. Trant and W. W. Ogilvie, Tetra-
hedron, 2007, 63, 11644; (e) L. Weselinski, P. Stepniak and
J. Jurczak, Synlett, 2009, 2261; for application of solid-supported
imidazolidinone catalyst in 1,3-dipolar cycloaddition, see:
(f) A. Puglisi, M. Benaglia, M. Cinquini, F. Cozzi and G. Celentano,
Eur. J. Org. Chem., 2004, 567.
We gratefully acknowledge Nanyang Technological
University (NTU), NTU New Initiative Funding, Ministry
of Education (No. M45110000), and A*STAR SERC Grant
(No. 0721010024) for the funding of this research.
Notes and references
1 For reviews on organocatalysis, see: (a) A. Berkessel and H. Groger,
Asymmetric Organocatalysis, Wiley-VCH, Weinheim, 2005; (b) P. I.
Dalko, Enantioselective Organocatalysis, Wiley-VCH, Weinheim,
2007; (c) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004,
43, 5138; (d) B. List, Chem. Commun., 2006, 819; (e) M. Marigo and
K. A. Jogensen, Chem. Commun., 2006, 2001; (f) A. Dondoni and
A. Massi, Angew. Chem., Int. Ed., 2008, 47, 4638; (g) X. H. Yu
and W. Wang, Org. Biomol. Chem., 2008, 6, 2037; (h) L. W. Xu,
J. Luo and Y. Lu, Chem. Commun., 2009, 1807; (i) S. K. Tian,
Y. Chen, J. Hang, L. Tang, P. Mcdaid and L. Deng, Acc. Chem. Res.,
2004, 37, 621; (j) T. Ooi and K. Maruoka, Acc. Chem. Res., 2004,
37, 526; (k) B. List, Acc. Chem. Res., 2004, 37, 548; (l) W. Notz,
F. Tanaka and C. F. Barbas, Acc. Chem. Res., 2004, 37, 580.
2 For reviews, see: (a) G. Lelais and D. W. C. MacMillan, Aldrichi-
mica Acta, 2006, 39, 79; (b) A. Erkkila, I. Majander and
P. M. Pihko, Chem. Rev., 2007, 107, 5416; for selected examples,
see: (c) K. A. Ahrendt, C. J. Borths and D. W. C. MacMillan, J. Am.
Chem. Soc., 2000, 122, 4243; (d) A. B. Northrup and D. W. C.
MacMillan, J. Am. Chem. Soc., 2002, 124, 2458; (e) R. M. Wilson,
W. S. Jen and D. W. C. MacMillan, J. Am. Chem. Soc., 2005,
127, 11616; (f) W. S. Jen, J. J. M. Wiener and D. W. C. MacMillan,
J. Am. Chem. Soc., 2000, 122, 9874; (g) M. T. Hechavarria Fonseca
and B. List, Angew. Chem., Int. Ed., 2004, 43, 3958; (h) N. A. Paras
and D. W. C. MacMillan, J. Am. Chem. Soc., 2002, 124, 7894;
(i) S. P. Brown, N. C. Goodwin and D. W. C. MacMillan, J. Am.
Chem. Soc., 2003, 125, 1192; (j) T. D. Beeson, A. Mastracchio,
J.-B. Hong, K. Ashton and D. W. C. MacMillan, Science, 2007,
316, 582; (k) M. Reiter, S. Torssell, S. Lee and D. W. C. MacMillan,
Chem. Sci., 2010, 1, 37.
3 For selected reviews concerning the use of ionic liquid as reaction
solvent or catalyst, see: (a) R. A. Sheldon, Chem. Commun., 2001,
2399; (b) C. M. Gordon, Appl. Catal., A, 2001, 222, 101;
(c) P. Wasserscheid and W. Keim, Angew. Chem., Int. Ed., 2000,
39, 3772; (d) J. D. Holbrey and K. R. Seddon, Clean Prod.
Processes, 1999, 1, 223; (e) T. Welton, Chem. Rev., 1999, 99, 2071;
(f) H. Zhao and S. V. Malhotra, Aldrichimica Acta, 2002, 35, 75;
(g) C. E. Song, Chem. Commun., 2004, 1033; (h) C. Baudequin,
J. Baudoux, J. Levillain, D. Cahard, A. C. Gaumont and
J. C. Plaquevent, Tetrahedron: Asymmetry, 2003, 14, 3081;
(i) J. Dupont, R. F. Souza and P. A. Z. Suarez, Chem. Rev., 2002,
102, 3667; (j) S. L. Chen, G. L. Chua, S. J. Ji and T. P. Loh, Ionic
liquid: a green solvent for organic transformations I, 2007, ACS
Symposium Series, vol. 950 (Ionic Liquids in Organic Synthesis),
pp. 161–176; (k) S. L. Chen, G. L. Chua, S. J. Ji and T. P. Loh,
9 M. Frederickson, Tetrahedron, 1997, 53, 403.
c
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