Enantioselective aldol reaction using recyclable Montmorillonite-Entrapped N-(2-Thiophenesulfonyl)prolinamide

Article abstract of DOI:10.1002/adsc.201000214

N-(2-Thiophenesulfonyl)prolinamide Nould be easily introduced into Montmorillonite by a simple ion-exchange reaction. The asymmetric aldol reactions between various isatins with acetone or acetaldehyde using a heterogeneous Montmorillonite-entrapped organocatalyst afforded products with high enantioselectivity. The catalyst was readily reusable without significant loss of catalytic activity or enantioselectivity.

Full text of DOI:10.1002/adsc.201000214

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DOI: 10.1002/adsc.201000214
Enantioselective Aldol Reaction using Recyclable Montmorillon-
ite-Entrapped N-(2-Thiophenesulfonyl)prolinamide
Noriyuki Hara,a Shuichi Nakamura,a,* Norio Shibata,a and Takeshi Torua
a
Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku,
Nagoya 466-8555, Japan
Fax : (+81)-52-735-5245; e-mail: snakamur@nitech.ac.jp
Received: March 18, 2010; Revised: May 10, 2010; Published online: June 30, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000214.
Abstract:
N-(2-Thiophenesulfonyl)prolinamide
atives.[5] This organocatalyst is now commercially
available, but it is rather expensive.[6] Therefore, the
recovery and reuse of this expensive organocatalyst is
important from a cost and environmental standpoint.
Although recovery and reuse of organocatalysts using
polymer supports,[7] ionic liquid supports,[8] and fluo-
rous chemistry[9] have been developed, these anch-
ored organocatalysts have some disadvantages, includ-
ing multi-step syntheses and deactivation of the inher-
ent catalysis. Recently, Kaneda and co-workers have
reported a pioneering work for the entrapment of
MacMillanꢀs organocatalyst on Montmorillonite using
a cation exchange method, which allows facile separa-
tion from the reaction mixture and reuse of the en-
trapped catalyst.[10] However, to the best of our
knowledge, there is no report on Montmorillonite-en-
trapped organocatalysts for the asymmetric aldol re-
could be easily introduced into Montmorillonite by
a simple ion-exchange reaction. The asymmetric
aldol reactions between various isatins with acetone
or acetaldehyde using a heterogeneous Montmoril-
lonite-entrapped organocatalyst afforded products
with high enantioselectivity. The catalyst was readi-
ly reusable without significant loss of catalytic activ-
ity or enantioselectivity.
Keywords: aldol reaction; enantioselectivity;
hetero
ACHTUNGTRENNUNGarenesulfonyl group; Montmorillonite; orga-
nocatalysis
The enantioselective aldol reaction using organocata- action. Herein our ongoing interest was extended to a
lysts is recognized as one of the most powerful recyclable organocatalyst on Montmorillonite for the
carbon-carbon bond-forming reactions,[1] so the orga- asymmetric aldol reaction to isatins and the develop-
nocatalytic asymmetric aldol reaction to ketones as ment of an efficient synthetic method (Scheme 1).
electrophiles has been intensively investigated,[2] as it
The Montmorillonite-entrapped N-(2-thiophenesul-
was prepared by Kanedaꢀs
provides efficient access to chiral tertiary alcohols. In fonyl)prolinamide
1
particular, the utilization of isatin as an electrophile method.[10] The catalytic ability of the organocatalyst
has attracted much attention because the reaction af- entrapped in Montmorillonite was examined in the
fords chiral 3-hydroxy-2-oxyindole derivatives, which synthesis of convolutamydine A[11] as an asymmetric
are an important structure motif in biologically active aldol reaction to isatins. The reaction of 4,6-dibromo-
compounds.[3] However, organocatalytic aldol reac-
ACHTUNGTRENiNGNU satin 2a with acetone using 5 mol% of Montmorillon-
tions to ketones generally need a high catalyst loading ite-entrapped N-(2-thiophenesulfonyl)prolinamide 1
of organocatalysts (normally 10–50 mol%) in which in the presence of 10 equivalents of H2O at room tem-
turnover numbers (TONs) are 2–10. Therefore, the perature afforded (R)-convolutamydine A 3a in 99%
design and development of highly active organocata- yield with 84% ee (Table 1, entry 1). Although the ad-
lysts aimed at lowering catalyst loading and an appro- dition of TsOH or CF3SO3H inhibited the reaction,
priate catalyst recovery technique for organocatalysts the addition of carboxylic acids as a Brønsted acid im-
have proved to be a significant challenge task and proved the enantioselectivity of the reaction (en-
only limited success has been achieved.[4] Recently, tries 2–6). The addition of 10 mol% TFA afforded 3a
we have reported that N-(2-thiophenesulfonyl)prolin- in 99% yield with 93% ee (entry 6).[12] The reaction
ACHTUNGTRENNUNG
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Noriyuki Hara et al.
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Scheme 1. Recyclable catalyst for the asymmetric aldol reaction to isatins
Table 1. Enantioselective addition of acetone to 4,6-dibro-
moisatin in the presence of Montmorillonite-entrapped N-
(2-thiophenesulfonyl)prolinamide 1.
Table 2. Enantioselective synthesis of convolutamydine A
derivatives 3a–h.
Entry Additive (mol%) Time [h] Yield [%][a] ee [%][b]
Entry Isatin Reaction Time [h] Yield [%][a] ee [%][b]
1
2
3
4
none
8
99
42
6
99
99
99
94
86
84
91
81
89
90
93
95
91
p-TolSO3H (10)
CF3SO3H (10)
PhCO2H (10)
CH3CO2H (10)
TFA (10)
72
72
10
10
20
48
168
1
2a
2a[c]
2b
2c
2d
2e
2f
20
30
40
80
24
20
20
35
50
99
95
99
93
96
99
98
95
93
96
2
92
96
95
91
94
-
2[d]
3
5
4[d]
5
6
7
8
6
7[c]
8[d]
TFA (10)
TFA (10)
[a]
2g
2h
Yield of isolated 3a after filtration and purification on
silica gel.
The ee was determined by HPLC analysis.
The reaction was carried out at 08C.
Catalyst loading is 2 mol%.
9
Trace
[b]
[c]
[d]
[a]
Yield of isolated 3a–g after filtration and purification on
silica gel.
[b]
[c]
[d]
The ee was determined by HPLC analysis.
N-Benzylated 2a was used.
At 08C.
3a in 92% yield with 93% ee,[5a] therefore, the hetero-
geneous organocatalyst 1 did not lose its catalytic
ability from the inherent homogeneous organocata-
lyst. Although the reactivity was lowered, the enantio-
We next examined the reaction of 4,6-dibromoisatin
selectivity was improved in the reaction performed at 2a with acetaldehyde in the presence of Montmoril-
a lower temperature (entry 7). Furthermore, the cata- lonite-entrapped organocatalyst 1 (Scheme 2). The re-
lyst loading of 1 can be reduced to 2 mol% without a action was carried out using 10 mol% of 1 and
significant loss of enantioselectivity (entry 8).
5 equivalents of acetaldehyde at room temperature.
With these optimized conditions, the preparation of After the aldol reaction, the obtained intermediate al-
various convolutamydine A derivatives 3b–h using dehyde was reduced by NaBH3CN in acetic acid to
5 mol% of Montmorillonite-entrapped organocatalyst give (R)-convolutamydine E 4[13,14] with high enantio-
1 is shown in Table 2. The reaction of N-Bn-protected selectivity.
dibromoisatin also afforded good enantioselectivity
The Montmorillonite-entrapped organocatalyst 1
(entry 2). The reaction of substituted isatins such as could be easily separated from the reaction mixture
4,6-dichloro-, 4,6-diiode-, 4-bromo, 4-chloro, and 4-io- by simple filtration.[15] Therefore, we next examined a
doisatins 2c–g gave products 3c–g in high yields with more efficient synthetic method for preparing convo-
high enantioselectivity (entries 4–8), although the re- lutamydine A without column chromatography purifi-
action of non-substituted isatin 2b afforded product cation. After the aldol reaction between 4,6-dibromo-
3b with low enantioselectivity (entry 3). Unfortunate-
ly, 4,6-dimethylisatin 2h has low reactivity (entry 9).
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Adv. Synth. Catal. 2010, 352, 1621 – 1624

Enantioselective Aldol Reaction using Recyclable Montmorillonite-Entrapped
Scheme 2. Enantioselective synthesis of convolutamydine E.
Scheme 3. Efficient synthetic method for preparing convolutamydine A.
Table 3. Recycling of catalyst 1 by simple filtration.
Scheme 4. Enantioselective reaction of p-nitrobenzaldehyde
with acetone.
Reuse
Time [h]
Yield [%][a]
ee [%][b]
zation of crude mixture afforded 3a in good yield as
an enantiomerically pure product (Scheme 3).
We also examined the reaction of p-nitrobenzalde-
hyde with acetone in the presence of 5 mol% of
Montmorillonite-entrapped organocatalyst 1 to give
the product 5 in high yield with high enantioselectivi-
ty (Scheme 4).
The next important aspect was to examine the cata-
lyst recovery and the possibility for catalyst reuse.
After the aldol reaction with 2a,d, catalyst 1 was
easily separated and quantitatively recovered by
simple filtration of the reaction mixture. The recov-
ered catalyst retained its high activity and high levels
1st (for 2a)
2nd (for 2a)
3rd (for 2a)
4th (for 2a)
1st (for 2d)
2nd (for 2d)
3rd (for 2d)
4th (for 2d)
20
20
24
40
24
24
48
80
99
94
95
89
96
97
78
51
93
93
91
89
96
94
94
92
[a]
Yield of isolated 3a,d after filtration and purification on
silica gel.
[b]
The ee was determined by the HPLC analysis.
of enantioselectivity (89–94% ee) even after four ite-entrapped N-(2-thiophenesulfonyl)prolinamide 1
cycles despite some degree of activity loss observed in acts as an environmentally friendly catalyst. Further
cycles 3 and 4 (Table 3).[16]
studies focusing on the scope of this recyclable cata-
In conclusion, we developed an immobilization lyst in asymmetric transformations are currently un-
method for a chiral organocatalyst on Montmorillon- derway and will be reported in due course.
ite using a cation-exchange method. The Montmoril-
lonite-entrapped N-(2-thiophenesulfonyl)prolinamide
1 did not lose its catalytic ability from the inherent
Experimental Section
homogeneous organocatalyst. To the best of our
knowledge, this is the first report for recyclable orga-
nocatalysts for use in the aldol reaction with ketones.
Furthermore, it was readily reusable without needing
to regenerate the catalyst. The total turnover numbers
(TONs) for the recyclable catalyst reached almost 80
Preparation of 1
Na+-Montmorillonite (300 mg), was added to N-(2-thio-
AHCTUNGTRENNUNG
with high enantioselectivity. Therefore Montmorillon- separated by filtration, washed with deionized water, and
Adv. Synth. Catal. 2010, 352, 1621 – 1624
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Noriyuki Hara et al.
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dried under vacuum at room temperature to provide the
Montmorillonite-entrapped N-(2-thiophenesulfonyl)prolina-
mide organocatalysts 1 as a white powder; yield: 325 mg.
[7] Reviews on the immobilization of organocatalysts, see:
a) M. Benaglia, A. Puglisi, F. Cozzi, Chem. Rev. 2003,
103, 3401–3429; b) M. Gruttadauria, F. Giacalone, R.
Noto, Chem. Soc. Rev. 2008, 37, 1666–1688.
ˇ
ˇ
ˇ
[8] S. Toma, M. Meciarovꢂ, R. Sebesta, Eur. J. Org. Chem.
2009, 321–327.
Acknowledgements
[9] a) J. A. Gladysz, D. P. Curran, I. T. Horvꢂth, Handbook
of Fluorous Chemistry; Wiley-VCH: Weinheim, 2004;
b) W. Zhang, C. Cai, Chem. Commun. 2008, 5686–
5694.
[10] T. Mitsudome, K. Nose, T. Mizugaki, K. Jitsukawa, K.
Kaneda, Tetrahedron Lett. 2008, 49, 5464–5466.
[11] a) Y. Kamano, H.-P. Zhang, Y. Ichihara, H. Kizu, K.
Komiyama, G. R. Pettit, Tetrahedron Lett. 1995, 36,
2783–2784; b) H.-P. Zhang, H. Shigemori, M. Ishibashi,
T. Kosaka, G. R. Pettit, Y. Kamano, J. Kobayashi, Tet-
rahedron 1994, 50, 10201–10206.
[12] The role of TFA is unclear, but TFA could change the
structure of the transition state to improve the enantio-
selectivity.
[13] H.-P. Zhang, Y. Kamano, Y. Ichihara, H. Kizu, K. Ko-
miyama, H. Itokawa, G. R. Pettit, Tetrahedron 1994, 50,
5523–5528.
This work was partly supported by a Grant-in-Aid for Young
Scientists B (20750074) from JSPS and the Toyoaki Scholar-
ship Foundation. We are grateful to Kunimine Industry Co.
Ltd., Japan for a gift of Na+-Montmorillonite.
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Adv. Synth. Catal. 2010, 352, 1621 – 1624