A convenient imino aldol reaction in ethyl alcohol catalyzed by a cation-exchange resin

Article abstract of DOI:10.1039/b106662e

Imino aldol reaction of ketene silyl acetals with imines proceeds smoothly to give β-amino esters in good yields under the influence of a cation-exchange resin in ethanol, and the work-up of the reaction consists only of a simple filtration followed by co

Full text of DOI:10.1039/b106662e

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A convenient imino aldol reaction in ethyl alcohol catalyzed by a
cation-exchange resin
Makoto Shimizu,* Susumu Itohara and Emi Hase
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan
Received (in Cambridge, UK) 24th July 2001, Accepted 26th September 2001
First published as an Advance Article on the web 25th October 2001
Imino aldol reaction of ketene silyl acetals with imines
proceeds smoothly to give b-amino esters in good yields
under the influence of a cation-exchange resin in ethanol,
and the work-up of the reaction consists only of a simple
filtration followed by concentration of the crude mixture and
purification.
Examples of the Amberlyst® 15 DRY catalyzed imino aldol
reactions of ketene silyl acetals with imines in ethyl alcohol are
shown in Table 2.† In the reactions of ketene silyl acetal 1a with
the imines derived from aromatic amines, the addition reaction
proceeded smoothly to afford b-amino esters 3 in moderate to
high yields. However, the imine derived from benzyl amine did
not give the addition product in good yield (entry 7). A
moderate diasteroselectivity was observed in the reaction of the
ketene silyl acetal 1b derived from propionate (entry 8). Ketene
silyl thioacetals also worked well to give the corresponding
adducts in good yields (entries 9 and 10).
The present reaction conditions were also effective for the
addition of ketene silyl acetal 1a to the imine equivalent 2h
derived from formaldehyde,6 and the b-amino ester was
obtained in 66% yield. As shown in Scheme 1, the in situ
preparation of a relatively unstable imine could be used for the
present addition, and the adduct was formed in good yield.
Furthermore, Amberlyst® 15 DRY was recovered by simple
filtration after the reaction, and could be reused at least four
times without loss of activity.‡ The results are shown in
Table 3.
Cation-exchange resins have been found to be excellent
activators for imino aldol reaction of ketene silyl acetals with
imines in dichloromethane or in some cases in isopropyl
alcohol.1 Although a variety of activators for such transforma-
tions have been reported,2 polymer supported catalysts such as
ion-exchange resins have not received much attention for
promotion of imino aldol reaction until recently.3 Use of ion-
exchange resins offers several advantages in organic synthesis,4
e.g. simplification of reaction procedures, easy separation of
products without discharging harmful waste water, repeated
use, and so on. In our previous report, a cation-exchange resin,
in particular Amberlyst® 15 DRY, having a large surface area
(45 m2 g21), was found to be one of the most useful resins that
promoted aldol type reaction, where the addition reactions
proceeded with high chemoselectivity in the presence of two
kinds of imines and/or nucleophiles. From an environmental
point of view, however, this reaction needs modifications,
because it is carried out in dichloromethane as a solvent and an
equimolar amount of a cation-exchange resin is needed in most
cases. Recent papers describing imino aldol reaction carried out
in water or organic solvent–water as a convenient system5
prompted us to report our approach which reduces harmful
wastes such as waste water containing metal ions and organic
wastes. We wish to report herein a convenient imino aldol
reaction using a cation-exchange resin as a recyclable catalyst in
ethanol as a solvent.
Regarding the chemoselectivity, the ketene silyl acetal 1a
reacted with the anisyl imine 2a preferentially even in the
presence of benzaldehyde to give b-amino ester 3aa in 83%
yield, and none of the adduct 4 arising from benzaldehyde was
detected.7
Competition reactions between two kinds of imines were
examined next. Amberlyst® 15 DRY selectively promoted the
Table 2 Imino aldol reaction promoted by Amberlyst® 15 DRY in
EtOHa
First, reaction of the imine 2a and the ketene silyl acetal 1a
was chosen as a model for comparison of solvents, and the
results are shown in Table 1. Among the alcohols examined the
use of ethyl alcohol proved to be the most effective, whereas in
methyl alcohol the ketene silyl acetal 1a hydrolized to some
extent and in tert-butyl alcohol the desired reaction proceeded
very slowly.
Table 1 Effects of solventa
Entry
1
2
Time/h
Yield (%)b
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
2a
2b
2c
2d
2e
2f
2g
2a
2a
2a
10.5
24.5
18.0
23.5
9.0
99
73
81
69
57
94
27
60c
96d
86
Entry
Solvent
Time/h
Yield (%)b
1
EtOH
10.5
11.0
11.5
12.5
99
81
30
66
4.0
2
3c
4
i-PrOH
t-BuOH
MeOH
24.0
16.5
9.0
10
20.5
a The reaction was carried out according to the typical experimental
p
procedure. An = p-anisyl (p-methoxyphenyl). b Isolated yield. c Amber-
a The reaction was carried out according to the typical experimental
procedure. b Isolated yield. c syn+anti = 39+61. d syn+anti = 48+52.
lyst® 15 DRY (0.2 eq.) was used.
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Chem. Commun., 2001, 2318–2319
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106662e

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addition to anisyl imine in the presence of the tosyl 2j or
ethoxycarbonyl imine 2k with an electron-withdrawing N-
substituent. One of the reasons for the chemoselectivity may be
due to the difference in the ability of the imino nitrogen to be
protonated by the catalyst. A better chemoselectivity between
the imines 2a and 2k was observed in the present case than that
in the previous report, showing that the present reaction
conditions are much milder than the previous ones.
In conclusion, we have developed a convenient imino aldol
reaction catalyzed by a cation-exchange resin. The present
reaction has the following several advantages. (1) The cation-
exchange resin was recovered by simple filtration without
discharging harmful waste water from the reaction medium and
it was used repeatedly without loss of activity. (2) The reaction
could be carried out in ethyl alcohol, which is a relatively safe
organic solvent. (3) High chemoselectivity was observed.
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports, and
Culture, Japan, and a grant from the Nagase Science and
Technology Foundation.
Notes and references
Scheme 1
† A typical experimental procedure is as follows: to a suspension of
Amberlyst® 15 DRY (4.3 mg, 0.02 mmol of the sulfonic acid portion,
washed with EtOH and dried in vacuo at 100 °C) and aldimine 2a (42.3 mg,
0.2 mmol) in EtOH (1.0 ml) was added a solution of ketene silyl acetal 1a
(45.2 mg, 0.24 mmol) in EtOH (1.0 ml) at room temperature under an argon
atmosphere. After being stirred at room temperature for 10.5 h, the
suspension was filtered through a Celite pad. The filtrate was concentrated
in vacuo to afford a crude oil. Purification on preparative silica gel TLC (n-
hexane–AcOEt = 10+1, as an eluent) gave the adduct 3aa (64.7 mg, 99%)
as a colorless oil.
Table 3 Reuse of Amberlyst® 15 DRYa
‡ The sulfonic acid groups on the recovered resin are involved in the salt
formation with amine moieties,8 and therefore, such salts may be also
responsible for the present imino aldol reaction. We are currently
investigating such salt formation in more detail.
Run
1st
98
2nd
93
3rd
97
4th
94
3aa (%)b
1 M. Shimizu and S. Itohara, Synlett, 2000, 1828.
a The reaction was carried out according to the typical experimental
procedure. b Isolated yield.
2 I. Ojima, S. Inaba and K. Yoshida, Tetrahedron Lett., 1977, 18, 3643; R.
A. Pilli and D. Russowsky, Chem. Commun., 1987, 1053; G. Guanti, E.
Narisano and L. Banfi, Tetrahedron Lett., 1987, 28, 4331; T. Mukaiyama,
K. Kashiwagi and S. Matsui, Chem. Lett., 1989, 1397; T. Mukaiyama, H.
Akamatsu and J. S. Han, Chem. Lett., 1990, 889; M. Onaka, R. Ohno, N.
Yanagiya and Y. Izumi, Synlett, 1993, 141; K. Ishihara, M. Miyata, K.
Hattori, T. Tada and H. Yamamoto, J. Am. Chem. Soc., 1994, 116,
10 520; S. Kobayashi, M. Araki, H. Ishitani, S. Nagayama and I. Hachiya,
Synlett, 1995, 233; M. Shimizu, K. Kume and T. Fujisawa, Chem. Lett.,
1996, 545; R. Hayakawa and M. Shimizu, Chem. Lett., 1999, 591.
3 S. Kobayashi, S. Nagayama and T. Busujima, Tetrahedron Lett., 1996,
37, 9221; L. Yu, D. Chen, J. Li and P. G. Wang, J. Org. Chem., 1997, 62,
3575; S. Kobayashi and S. Nagayama, J. Am. Chem. Soc., 1998, 120,
2985; N. Tanaka and Y. Masaki, Synlett, 2000, 406.
4 A. Akelah and D. C. Sherrington, Chem . Rev., 1981, 81, 557; S. J.
Shuttleworth, S. M. Allin and P. K. Sharma, Synthesis, 1997, 1217; B.
Baruah, M. P. Dutta, A. Boruah, D. Prajapati and J. S. Sandhu, Synlett,
1999, 409; J.-J. Young, L.-J. Jung and K.-M. Cheng, Tetrahedron Lett.,
2000, 41, 3415.
5 T.-P. Loh and L.-L. Wei, Tetrahedron Lett., 1998, 39, 323; S. Kobayashi,
T. Busujima and S. Nagayama, Synlett, 1999, 545; T. Akiyama, J. Takaya
and H. Kagoshima, Synlett, 1999, 1045; K. Manabe, Y. Mori and S.
Kobayashi, Synlett, 1999, 1401; T. Akiyama, J. Takaya and H.
Kagoshima, Synlett, 1999, 1426; K. Manabe and S. Kobayashi, Org.
Lett., 1999, 1, 1965; T. Akiyama, J. Takaya and H. Kagoshima,
Tetrahedron Lett., 2001, 42, 4025.
6 D. D. Reynolds and B. C. Cossar, J. Heterocycl. Chem., 1971, 597.
7 Preferential activation of aldimine in the presence of aldehyde, see: H.
Nakamura, H. Iwama and Y. Yamamoto, J. Am. Chem. Soc., 1996, 118,
6641; S. Kobayashi and S. Nagayama, J. Org. Chem., 1997, 62, 232; S.
Kobayashi and S. Nagayama, Synlett, 1997, 653; S. Kobayashi and S.
Nagayama, J. Am. Chem. Soc., 1997, 119, 10 049; T. Akiyama and J.
Iwai, Synlett, 1998, 273.
8 Y.-S. Liu, C. Zhao, D. E. Bergbreiter and D. Romo, J. Org. Chem., 1998,
63, 3471.
Scheme 2
Chem. Commun., 2001, 2318–2319
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