Water Exclusion Reaction in Aqueous Media: Nitrone Formation and Cycloaddition in a Single Pot

Article abstract of DOI:10.1021/ol035535m

(Equation Presented) The formation of nitrone (a water exclusion reaction) in aqueous media using surfactant and subsequent cycloaddition in the same pot, a new example of green chemistry, is reported. The control of regioselectivity favors the formation

Full text of DOI:10.1021/ol035535m

ORGANIC
LETTERS
2
003
Vol. 5, No. 21
967-3969
Water Exclusion Reaction in Aqueous
Media: Nitrone Formation and
Cycloaddition in a Single Pot
3
Amrita Chatterjee, Dilip Kumar Maiti, and Pranab Kumar Bhattacharya*
Medicinal Chemistry DiVision, Indian Institute of Chemical Biology,
4, Raja S.C. Mullick Road, JadaVpur, Kolkata 700032, India
pranabbhatta@iicb.res.in
Received August 14, 2003
ABSTRACT
The formation of nitrone (a water exclusion reaction) in aqueous media using surfactant and subsequent cycloaddition in the same pot, a new
example of green chemistry, is reported. The control of regioselectivity favors the formation of trans-5-substituted isoxazolidine. This work
not only may lead to an environmentally benign system but also will provide a new aspect of reactions in water.
Environmentally benign reactions have now become the
target of the synthetic organic chemists. The development
of the concept of green chemistry and its 12 principles
common. The reaction studies in the media mainly focused
on kinetic studies. However, some preparative studies have
been done.
1
1c
2
act as guidelines. Catalysis plays a significant role for this
purpose,1d and so development of alternative pathways
becomes of interest. Replacement of toxic organic solvents
by a nontoxic one, e.g., water,1 which is also cheap and
safe, becomes one of the main features of green chemistry.
However, the majority of the organic compounds are
insoluble in water, and one answer to this problem is the
use of surfactants, which help to solubilize the organic
compounds in water.
Our studies on surfactant-catalyzed reactions revealed that
emulsion droplets were formed under the reaction condition
from the catalytic amount of the catalyst and the substrate.
These emulsion droplets are sufficiently hydrophobic and
can protect water-labile components from the hydrolytic
e-g
2
b
decomposition. Therefore, dehydration reaction can be
carried out in water.
Nitrones are very important due to their various uses. As
3
therapeutic agents, they are well recognized. The synthetic
uses and reactions of nitrones are also well documented.4
Organized media is the border between homogeneous
(
solution phase) and heterogeneous phases. It is a gray area
consisting of micellar, reverse micellar, microheterogeneous,
colloidal phase, etc. Studies of the media are very common,
but studies of new reactions in the media are not that
(2) (a) Manabe, K.; Limura, S.; Sun, Xiang-Min.; Kobayashi, S. J. Am.
Chem. Soc. 2002, 124, 11971. (b) Manabe, K.; Mori, Y.; Kobayashi, S.
Synlett 1999, 9, 1401.
(3) (a) Floyd, R. A.; Hensley, K.; Forster, M. J.; Kelleher-Andersson, J.
A.; Wood, P. L. Mech. Ageing DeV. 2002, 123, 1021. (b) Floyd, R. A.
AdV. Pharmarcol. 1997, 38, 361. (c) Floyd, R. A.; Hensley, K.; Chiuch, C.
C. (Ed.) Ann. New. York. Acad. Sci. 2000, 899, 222. (d) Kotake, Y. Antioxid.
Redox Signaling 1999, 1, 481. (e) Hensley, K.; Carney, J. M.; Tabatabaie,
T.; Pye, Q.; Floyd, R. A. Inter. ReV. Neurobiol. 1999, 40, 299. (f) Durand,
G.; Polidori, A.; Salles, J.-P.; Pucci, B. Bioorg. Med. Chem. Lett. 2003, 13,
859.
(4) (a) Lombardo, M.; Trombini, C. Synthesis 2000, 6, 759. (b) Wade,
P. A. In ComprehensiVe Organic Synthesis, SelectiVity, Strategy, and
Efficiency in Modern Organic Chemistry; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 4, p 1120. (c) Little, D. R. In
(
1) (a) Anastas, P.; Willimson, T. C. Green Chemistry: Frontiers in
Benign Chemical Synthesis and Process; Oxford University Press: New
York, 1998. (b) Lectures presented at International Symposium on Green
Chemistry. Clark, J. H. Pure. Appl. Chem. 2001, 73, 77. (c) Hjeresen, D.
L.; Kirchhoff, M. M.; Lankey, R. L. Corporate EnViron. Strategy 2002, 9
(3), 259. (d) Centi, G.; Perathoner, S. Catal. Today 2003, 77, 287. (e)
Engberts, J. B. F. N.; Blandamer, M. J. Chem. Commun. 2001, 1701. (f)
Cave, G. W. V.; Raston, C. L.; Scott, J. L. Chem. Commun. 2001, 2159.
(g) Lindstrom, U. M. Chem. ReV. 2002, 102, 2751.
1
0.1021/ol035535m CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/17/2003

There are some standard synthetic routes to nitrones.4,5 The
majority of the reactions forming nitrones are dehydration
reactions of substituted hydroxylamine and carbonyl com-
pounds using anhydrous conditions and/or a dehydrating
agent.
Table 1. Nitrone Formation Reaction in Water
We hereby report for the first time the formation of nitrone
in water followed by its cycloaddition. The proposed model
of nitrone formation, the dehydration reaction, using sub-
stituted hydroxylamine and aldehydes in the presence of
surfactant (both anionic, i.e., SDS and cationic, i.e., CTAB)
as a catalyst is shown in Figure 1.
entry
A
time (h)
yield (%)
1
2
3
surfactant
1
>48
>48
>90
10% MeOH
10
cycloaddition reaction, the control of regioselctivity favors
the formation of 5-substituted isomer.
In our reaction system, phenyl hydroxylamine was reacted
with various aldehydes (5 min of sonication followed by
stirring; without sonication, the reaction took a longer time)11
to form nitrone. The disappearance of aldehyde and appear-
ance of nitrone was monitored by TLC. In the case of
1
cinnamaldehyde, nitrone was isolated and detected by H
NMR and mass spectrometry. In other cases, after the
formation of nitrone, the dipolarophile (ethyl acrylate) was
directly added to the system and the reaction was allowed
Figure 1. Proposed model of the dehydration reaction in water in
the presence of catalyst (surfactant SDS or CTAB).
6
,11
to take place at room temperature (Table 2).
Yields are generally very good (71-91%), except in one
case, i.e., the 2,5-dimethoxy phenyl system. This may be
due to the activated ring system, which reduces the carbonyl
character. Between the sodium dodecyl sulfate (SDS) and
cetyl trimethylammonium bromide (CTAB), the latter cata-
lyzes the reaction better, presumably due to stronger binding
of the CTAB with the substrate, which is expected as CTAB
has much more hydrocarbon content in its core region than
The emulsion droplets have a hydrophobic interior, through
hydrophobic interaction. Therefore, the equilibrium position
for the hydrophobic substrate would lie at the product side
because, as the water molecule forms under the reaction
conditions, it would be ejected from the core of the droplets.
The formation of emulsion droplets in the reaction medium
was confirmed by optical microscopy (Figure 2).
(
5) (a) Tennant, G. In ComprehensiVe Organic Chemistry; Barton, D.,
Ollis, W. D., Eds.; Pergamon Press: Oxford. 1979; Vol. 2, p 385. (b) Padwa,
A. In New Synthetic Methods; Verlag Chemie: New York; 1979; Vol. 5.
(c) Voinov, M. A.; Grigorev, I. A. Tetrahedron Lett. 2002, 43, 2445. (d)
Alibe, R.; Blanco, P.; March, P.; Figueredo, M.; Font, J.; Alvarez-Larena,
A.; Piniella, J. F. Tetrahedron Lett. 2003, 44, 523. (e) Iwasa, S.; Maeda,
H.; Nishiyama, K.; Tsusima, S.; Tsukamoto, Y.; Nishiyama, H. Tetrahedron
2
002, 58, 8281.
1
(
6) All the isoxazolidine products in Table 2 were characterized by H
Figure 2. Optical micrograph of the reaction mixture.
13
and C NMR. The spectral data are included in Supporting Information.
7) (a) Rispens, T.; Engberts, J. B. F. N. J. Org. Chem. 2002, 67, 7369.
b) Sepulveda, L. AdV. Collid. Interface Sci. 1986, 25, 1.
8) (a) Confalone, P. N.; Huie, E. M. In Organic Reactions; Kende, A.
(
(
(
We selected the reaction of o-nitro benzaldehyde and
phenyl hydroxylamine for the nitrone formation as a model
reaction in water (Table 1). This ensures that the surfactant
has the major role for the nitrone formation. During
S., Ed.; John Wiley & Sons: New York, 1988; Vol. 36, pp 1-173. (b)
Tufariello, J. J.; Ali, S. A.; Klingele, H. O. J. Org. Chem. 1979, 44, 4213.
(
9) (a) Kanemasa, S.; Ueno, N.; Shirahase, M. Tetrahedron Lett. 2002,
3, 657. (b) Merino, P.; Anoro, S.; Cerrada, E.; Laguna, M.; Moreno, A.;
Tejero, T. Molecules 2001, 6, 208.
10) Denis, C.; Laignel, B.; Plusquellec, D.; Marouille, J.-Y. Le.; Botrel,
4
(
A. Tetrahedron Lett. 1996, 37, 53.
ComprehensiVe Organic Synthesis, SelectiVity, Strategy, and Efficiency in
Modern Organic Chemistry; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 5, p 247. (d) Padwa, A. In ComprehensiVe
Organic Synthesis, SelectiVity, Strategy, and Efficiency in Modern Organic
Chemistry; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 4, p 1076. (e) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley-Interscience: New York, 1984; p 83. (f) Padwa, A.
In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley-Inter-
science: New York, 1984; p 277. (g) Balasubramanian, N. Org. Prep. Proc.
Int. 1985, 17, 23. (h) Gothelf, K. V.; Jorgensen, K. A. Chem. ReV. 1988,
(11) General Reaction Procedure. To a solution of surfactant (SDS or
CTAB, 0.05 mmol) in H2O (2 mL) were added an aldehyde (0.5 mmol)
and phenyl hydroxylamine (0.6 mmol, 1.2 equiv) successively at room
temperature in a 25 mL round-bottom flask. The reaction was sonicated
for 5 min and then stirred at room temperature. The reaction was monitored
by TLC. After the disappearance of aldehyde, ethyl acrylate (1 mmol, 0.1
mL) was added and the reaction mixture was stirred at room temperature.
After stirring at the same temperature for the period of time listed in Table
2, the product was extracted with ethyl acetate, washed with brine, dried
over Na2SO4, and concentrated, and purification by silica gel chromatog-
raphy gave the desired product(s). In the reaction in which no sonication
was used, the reaction required more time (5-6 times) for completion. It
is well-known that sonication favors the formation of organized media.
88, 863. (i) Kanemasa, S.; Uemura, T.; Wada, E. Tetrahedron Lett. 1992,
33, 7889. (j) Kanemasa, S.; Tsuruoka, T.; Yamamoto, H. Tetrahedron Lett.
1995, 36, 5019.
3968
Org. Lett., Vol. 5, No. 21, 2003

Table 2. Surfactant-Catalyzed Dehydrative Nitrone Formation from Phenyl Hydroxyl Amine and Aldehydes Followed by
Cycloaddition Reaction with Ethyl Acrylate in Water at Room Temperature
RCHO
time
(h)
yield (%)
4
5
entry
R ) (a-i)
surfactant
(4 + 5)
(exo:endo)
(cis:trans)j
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
a ) o-NO2C6H4-
a ) o-NO2C6H4-
b ) m-NO2C6H4-
b ) m-NO2C6H4-
c ) p-NO2C6H4-
c ) p-NO2C6H4-
d ) p-OMeC6H4-
d ) p-OMeC6H4-
e ) 2,5-diOMe-C6H3-
e ) 2,5-diOMe-C6H3-
f ) p-ClC6H4-
f ) p-ClC6H4-
g ) 3-pyridyl-
g ) 3-pyridyl-
h ) PhCHdCH-
h ) PhCHdCH-
i ) CH3(CH2)2-
i ) CH3(CH2)2-
SDS
CTAB
SDS
CTAB
SDS
CTAB
SDS
CTAB
SDS
CTAB
SDS
CTAB
SDS
CTAB
SDS
18
18
30
26
16
16
76
72
121
121
40
40
74
70.5
50
50
48
48
79
85
81
89
76
81
84
89
27
38
90
91
89
91
87
90
85
85
32:68
32:68
46:54
46:54
100:0
100:0
100:0k
100:0k
100:0k
100:0k
0:100
0:100
49:51l
49:51l
42:54
42:54
31:69m
31:69m
43:57
43:57
1
1
1
1
1
1
1
1
1
100:0l
100:0l
35:65m
35:65m
CTAB
SDS
CTAB
j
Cis:trans ratio determined with the help of NOE. k Ratio of 4:5 ) 39:61. l Ratio of 4:5 ) 60:40. m Ratio of 4:5 ) 31:69.
7
8
SDS. Cycloaddition of nitrone in organic solvent leads to
four different isomers, cis/trans for 5-substituted and exo/
endo for 4-substituted isoxazolidine in 2:1 ratio. In our case,
except for p-OMe, control of regioselectivity favors the trans-
When the reaction with cinnamaldehyde was conducted
in the presence of sucrose (presumably capable of forming
10
organized media ) and SDS (10 mol % for both cases), only
one regioisomer, i.e., the 4-carbethoxy isoxazolidine system,
1
2
5
-substituted product as the major one. In a few cases, the
was produced (Scheme 2).
endo-4-substituted product predominates. Spectral studies
identified the isomers. The proton attached with the carbe-
thoxy group of structure 5 was much more downfield
compared to that of structure 4. For the p-nitro compound
Scheme 2
(entries 5 and 6), the other regioisomer (structure 4) was
formed exclusively.
Scheme 1
In summary, water exclusion reaction in water media with
the help of surfactant catalysis led to nitrone formation, and
in the same pot, a cycloaddition reaction was conducted. The
regio- and stereocontrol was determined. In the case of
cinnamaldehyde, a similar type of experiment conducted in
the presence of sucrose led to one regioisomer only. Research
along this line is now under way.
Acknowledgment. We thank CSIR (India) and UGC
(India) for financial assistance, as well as for research
fellowships to two of the authors (A.C. & D.K.M.), and
finally Director, IICB, for various forms of help.
In the case of the p-chloro compound (entries 11 and 12),
the isomer is favored slightly (60%). In all the cases of
isomer 4, except cinnamaldehyde (entries 15 and 16), the
endo isomer is the sole product, which was confirmed by
9
Supporting Information Available: Spectral data for the
characterization of the isoxazolidine products. This material
is available free of charge via the Internet at http://pubs.acs.org.
J
3-4 (5.5-6.0 Hz). For entries 9 and 10, the lack of NOE
enhancement of the C3 H for the irradiation of C5 H, and
vice versa, revealed that the stereochemistry of structure 5
is trans. Comparing one of the C4 methylene protons of the
above with the other products helped to determine the cis/
trans isomer ratio.
OL035535M
(12) Optical rotation [R]D ) 43°.
Org. Lett., Vol. 5, No. 21, 2003
3969