Dehydrative intramolecular nitrone cycloaddition in confined aqueous media: A green chemical route to cis-fused chromano[4,3-c]isoxazoles

Article abstract of DOI:10.1016/j.tetlet.2010.09.111

An efficient synthetic route to the formation of cis-fused chromano[4,3-c]isoxazoles via dehydrative intramolecular 1,3-dipolar nitrone cycloaddition in organized aqueous media in the presence of a surfactant (viz. CTAB) as catalyst was developed, which indeed appeared to be green and a more sustainable method than the existing methods with the additional advantage of easy isolation of products.

Full text of DOI:10.1016/j.tetlet.2010.09.111

Tetrahedron Letters 51 (2010) 6700–6703
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Dehydrative intramolecular nitrone cycloaddition in confined aqueous media:
a green chemical route to cis-fused chromano[4,3-c]isoxazoles
Amrita Chatterjee a,b, , Sandip K. Hota a, Mainak Banerjee b, Pranab K. Bhattacharya a,z
⇑
a Chemistry Division, Indian Institute of Chemical Biology, Kolkata 700 032, India
b Chemistry Group, Birla Institute of Science and Technology, Pilani – K. K. Birla, Goa Campus, Goa 403 726, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic route to the formation of cis-fused chromano[4,3-c]isoxazoles via dehydrative
intramolecular 1,3-dipolar nitrone cycloaddition in organized aqueous media in the presence of a surfac-
tant (viz. CTAB) as catalyst was developed, which indeed appeared to be green and a more sustainable
method than the existing methods with the additional advantage of easy isolation of products.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 5 August 2010
Revised 17 September 2010
Accepted 24 September 2010
Available online 4 November 2010
Keywords:
Nanoreactor
Dehydration reaction in water
Intramolecular nitrone cycloaddition
Chromano[4,3-c]isoxazoles
Although nature uses aqueous environment in most of its chem-
ical transformations, water as solvent was totally neglected in or-
ganic reactions/syntheses till the end of the last century mostly
due to poor solubility of organic compounds. However, most of
the organic solvents and reagents are not environment benign sub-
stances, which is now a pronounced environmental concern. The
concept of ‘green chemistry’1 and its 12 principles2 have emerged
as a major solution to this problem with ways to develop clean
and more sustainable chemical processes. From this point of view
water is the solvent of choice for synthetic purposes3 because it
is environment friendly, cheap, non-toxic, non-flammable, widely
abundant in nature, and also provides easy synthetic approaches,
for example, no need for vigorous drying of the solvents or main-
taining tricky anhydrous reaction systems, and scope of easy isola-
tion of products. In addition, water has unique physical and
chemical properties, which sometimes lead to reactivity or selec-
tivity that cannot be attained in organic medium.3g,4 The problem
of insolubility and hydrolytic decomposition of many organic com-
pounds in water may be solved by the use of surfactants, which
form a colloidal, micellar or other organized phase that serves as
nanoreactors in aqueous media.5 The confined hydrophobic inte-
rior of the nanoreactor not only solubilizes the organic reagents
but also brings them in close proximity and in the process en-
hances the efficiency as well as the rate of a chemical reaction.
These nanoreactors have been proven as a useful tool to carry out
various types of catalytic reactions in water.3d–f,5,6 In particular,
dehydration reactions, which otherwise need anhydrous condi-
tions and thus one of the most challenging tasks to accomplish in
water, have been successfully carried out by our group7 and others8
in the confined nanoreactor systems under aqueous environment.
1,3-Dipolar nitrone cycloaddition is one of the most useful ways
for the construction of a variety of nitrogen-containing five-mem-
bered heterocycles, some of which are biologically and pharmaceu-
tically important compounds.9 In particular, intramolecular
nitrone-olefin cycloadditions have been utilized to obtain structur-
ally more complex bi- or tri-cyclic isoxazolidines of either biolog-
ical significance or as useful synthetic intermediates for target
molecules.10 Particularly, certain fused isoxazoline/isoxazole with
chromano moiety are known to possess antidepressant, antipsy-
chotic and antianxiolytic activities.11 The labile nature of NꢀO
bond of chromano-isoxazoles has also been exploited by several
groups of researchers and used as synthetic precursors for the con-
struction of pharmaceutically important amino alcohols.12 In spite
of their bioactivity and potential pharmacological utility not many
methods have been developed for chromano-isoxazoles.12a–c,13
Moreover, existing methods are based on conventional synthetic
protocols involving use of hazardous reagents, toxic solvents or rel-
atively harsh reaction conditions.12a–c,13 These facts prompted us
to develop a better, environment friendly alternative. As per our
current efforts on the development of safe and ‘green’ protocols
for organic reactions in aqueous media, we have reported one-
pot processes for nitrone formation followed by its intermolecular
cycloaddition to form various heterocyclic compounds.7a Herein,
we report an environment friendly synthetic route to chroma-
⇑
Corresponding author. Tel.: +91 832 2580 320; fax: +91 832 2557 031.
E-mail address: amrita@bits-goa.ac.in (A. Chatterjee).
z
Deceased.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.111

A. Chatterjee et al. / Tetrahedron Letters 51 (2010) 6700–6703
6701
R
R
O
N
O
O
N
R4
R3
H
R1
R1
R1
CHO
O
R4
R4
surfactant (10 mol%)
water, rt
RNHOH
H
+
R3
R3
O
R2
R2
R2
2
4
1
3
Scheme 1. Synthesis of cis-fused chromano[4,3-c]isoxazoles in confined aqueous media.
Figure 1. (a) A typical optical micrograph of nanoreactors formed in an aqueous solution of CTAB, O-allyl salicylaldehyde and phenyl hydroxylamine. (b) DLS data of CTAB.
no[4,3-c]isoxazoles via intramolecular 1,3-dipolar cycloaddition by
in situ formation of nitrones derived from O-allyloxy salicylaldehy-
des in organized aqueous media (Scheme 1).
Table 2
Effect of co-solvents in cycloaddition reaction
Entry
Aa
Time (h)
Yield of 4a (%)
At the beginning of our study, we focused our attention on opti-
mizing the reaction conditions. In this direction, the formation of
the emulsion droplets, so called nanoreactors were confirmed by
taking an optical micrograph of a different surfactant containing
aqueous solutions of reactants before the reaction would actually
proceed (Fig. 1a). Dynamic light scattering (DLS) experiments of
those solutions revealed that the corresponding size of emulsion
droplets is in nanometre range (Fig. 1b).
1.
2.
3.
4.
5.
6.
7.
—
>48
>48
>48
>48
>48
>48
9
No rxn.
8
28
10
22
10% v/v MeOH
10% v/v MeOH + 10 mol% CTAB
15% v/v CH3CN
15% v/v CH3CN + 10 mol% CTAB
10% v/v THF
10 mol% CTAB
<5
92
a
An aqueous solution of 0.5 mmol of O-allyl salicylaldehyde (1a) and 0.52 mmol
of phenyl hydroxylamine (2a) was treated with A and the product was isolated after
To find out if a suitable surfactant that would act as a catalyst
for the cycloaddition reaction, a model reaction was carried out be-
tween O-allyl salicylaldehyde (1a) and phenyl hydroxylamine (2a)
using various surfactants as catalysts (Table 1). Although polyeth-
ylene oxide based surfactants afforded the desired product in mod-
erate yield after 48 h, reaction was much faster and high yielding in
the presence of anionic surfactants. However, acidic surfactant,
dodecylbenzene sulfonic acid (DBSA) was not useful in this reac-
tion (entry 8, Table 1). Among all the surfactants cetyl trimethy-
lammonium bromide (CTAB) was found to be most obvious
choice for further exploration of the methodology with other O-al-
lyl salicylaldehyde derivatives. In our next study, the role of the
surfactant as well as the nanoreactor was established by carrying
out the same reaction in the presence of organic co-solvents (Table
2). Although organic solvents ensure solubility of organic compo-
nents in water, only trace amount of product was obtained in the
absence of surfactant (viz. CTAB) after several hours. More impor-
tantly, the presence of surfactant could not boost the product for-
the said time.
mation; the reactions were very sluggish in different co-solvents.
This fact signifies the role of nanoreactor as well since it drives
the dehydration step forward by expelling the product water mol-
ecule out of its hydrophobic interior and consequently, shifting the
equilibrium towards the product side (Fig. 2). On the contrary, the
presence of co-solvent would presumably have taken the reactants
out of hydrophobic emulsion droplets into the solution phase
slowing down the rate of the dehydration reaction.
To study intramolecular cycloaddition reaction on various
substrates, phenolic –OH group of salicylaldehyde and its selective
derivatives were first alkylated with an allyl group or its
homologues adopting standard procedure. Next, O-allyl derivatives
Ph
O
CHO
O
N
O
Table 1
Study on catalytic activity of different surfactants in cycloaddition reaction
+
Entry
Surfactanta
Time (h)
Yield of 4a (%)
PhNHOH
- H2O
1.
2.
3.
4.
5.
6.
7.
8.
CTAB
SDS
SBDS
Triton X-100
Tween 20
Tween 80
Triton CF 10
DBSA
9
18
20
48
48
48
48
48
92
82
80
56
58
55
60
No pdt
Ph
O
N
O
a
The reaction was carried out between 0.5 mmol of O-allyl salicylaldehyde (1a)
and 0.52 mmol of phenyl hydroxylamine (2a) in presence of 0.05 mmol of surfac-
tants in 2 mL of water.
Figure 2. Nanoreactor promoted synthesis of chromano[4,3-c]isoxazole.

6702
A. Chatterjee et al. / Tetrahedron Letters 51 (2010) 6700–6703
Table 3
Studies on intramolecular nitrone cycloaddition (refer to Scheme 1) with CTAB as catalyst
Entry
Salicylaldehyde derivative (1)
RNHOH
Product (4)
Time (h)
Yield (%)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
1a: R1 = R2 = R3 = R4 = H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
9
14
20
12
22
11
22
9
21
11
15
24
12
12
11
92
86
85
88
84
91
85
88
86
94
89
79
82
88
86
1b: R1 = R2 = R3 = H, R4 = CH3
4b
4ca
4d
4ea
4f
1c: R1 = R2 = H, R3 = R4 = CH3
1d: R1 = Br, R2 = R3 = R4 = H
1e: R1 = Br, R2 = H, R3 = R4 = CH3
1f: R2 = OMe, R1 = R3 = R4 = H
1g: R2 = OMe, R1 = H, R3 = R4 = CH3
4ga
4h
4ia
4j
1h: R1 = NO2, R2 = R3 = R4 = H
1i: R1 = NO2, R2 = H, R3 = R4 = CH3
Ph
1a
1b
1c
1d
1f
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
4k
4la
4m
4n
4o
1h
a
Reported elsewhere; see Ref. 13a.
of salicylaldehyde (1a–i) were treated with N-substituted hydrox-
ylamine in an aqueous medium in the presence of 10 mol % CTAB
to afford corresponding nitrones, which undergo in situ stereose-
lective intramolecular cycloaddition to produce cis-fused 1-aryl-
1,3a,4,9b-tetrahydro-3H-chromano[4,3-c]isoxazoles (4a–o) as the
only isolated product in excellent yields (Table 3). It is worthy to
note that after the reaction was over the products were isolated
by cooling the reaction mixture at 5 °C for several hours and then
by filtering off the crude product.14 The sufficiently pure crude
products were further purified by recrystallization. Although the
current method competes equally in terms of yield and stereose-
lectivity, a combination of clean reaction profile and easy isolation
of the product has a sheer advantage over the other available con-
ventional methods.12a–c,13 Noticeably, substituents in the aromatic
ring of the O-allyl salicylaldehyde derivatives did not show any sig-
nificant effect in the yield of chromano[4,3-c]isoxazoles (entry 4–9
and 11–13, Table 3), whereas, doubly substituted allyl moiety (i.e.,
prenyl group) although it did not reduce the yield but slowed down
the reaction due to steric reason (entry 3, 5, 7, 9, 12, Table 3). The
expected cis stereochemistry13 of chromano[4,3-c]isoxazoles was
initially determined by 2D NMR studies (COSY and NOESY). For
example, 4c showed the presence of a NOESY cross peak between
H2 and H3 protons and a coupling constant (JH2–H3) of 6.6 Hz, which
clearly indicates that the five- and six-membered rings are cis-
fused (Fig. 3).13a The six-membered ring presumably adopts a
twisted structure,13a consistent with the observed coupling con-
Figure 4. ORTEP diagram of 4j.
molecules was reconfirmed by determining the X-ray crystal struc-
ture of a representative compound, 4j (Fig. 4).
In conclusion, we have demonstrated a useful and ‘green’ meth-
od for the preparation of cis-fused chromano[4,3-c]isoxazoles via
dehydrative intramolecular nitrone cycloaddition reaction in orga-
nized aqueous media. The method is more advantageous over
existing methods due to a clean reaction profile, high yield, use
of safe chemicals and easy isolation of the products.
0
stant values JH1 –H2 = 4.8 Hz and JH1–H2 = 9.8 Hz. The presence of
NOESY cross peaks between H1–CH3 (60), H01–CH3 (60), H3–CH3
(6) and H2–CH3 (6) as well as NOESY cross peaks between HA of
the phenyl and Ha of the N-phenyl with CH3 (6) further indicated
the twisted structure of the six-membered ring of 4c. The H2 and
H3 coupling constant values of the other compounds are also in
accordance with cis stereochemistry. The actual structure of these
Supplementary data
Crystallographic data (excluding structure factor) for the struc-
ture of 4j have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication no. CCDC
784802. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.09.111.
Acknowledgements
HB
HC
Hb
A.C. and S.K.H. thank the CSIR (India) for research fellowships.
The authors thank Mr. S. Samanta, IICB Kolkata and Dr. R. Banerjee,
NCL, Pune for the help in X-ray analysis.
Ha
Hc
Hb
HA
HD
O5
6
2
4
N
H
6'
4
H3
O
H
3
N
H
H1'
Ha
2
References and notes
CH3
1
O
H1
O
6'
H3C
5
6
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Figure 3. nOe interaction between the protons of 4c.

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6703
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14. General procedure for the syntheses of chromeno[4,3-c]isoxazoles: To a
solution of surfactant (0.05 mmol) in H2O (2 mL) were added an O-allyl
derivative of salicylaldehyde (0.5 mmol) and hydroxylamine (0.52 mmol,
1.05 equiv) successively at room temperature. The reaction was sonicated for
5 min and then stirred at room temperature for several hrs (see Table 3). The
reaction mixture was then refrigerated at 5 °C overnight. The solid separated
was filtered off and subsequently washed with distiled water (3 ꢁ 10 mL),
dried and desiccated. The sufficiently pure crude product was recrystallized
from a mixture of ethyl acetate and petrolium spirit (30:70).