Highly diastereoselective condensation of α-nitro-esters with aldehydes catalyzed by zinc complexes of amino acids

Article abstract of DOI:10.1016/S0040-4039(02)01047-X

Zinc complexes of amino acids efficiently catalyze the condensation between α-nitro-esters and a variety of aldehydes. An unusual domino reaction sequence leads to the diastereoselective formation of substituted isoxazoline N-oxides in high yields.

Full text of DOI:10.1016/S0040-4039(02)01047-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5287–5289
Highly diastereoselective condensation of a-nitro-esters with
aldehydes catalyzed by zinc complexes of amino acids
A. Chatterjee, S. C. Jha and N. N. Joshi*
Division of Organic Synthesis, National Chemical Laboratory, Pune 411008, India
Received 22 March 2002; revised 21 May 2002; accepted 31 May 2002
Abstract—Zinc complexes of amino acids efficiently catalyze the condensation between a-nitro-esters and a variety of aldehydes.
An unusual domino reaction sequence leads to the diastereoselective formation of substituted isoxazoline N-oxides in high yields.
© 2002 Elsevier Science Ltd. All rights reserved.
Nitroaldol condensation, or the Henry reaction, is one
of the classical methods for carbon–carbon bond form-
ing reactions.1 A more specialized case of the reaction
involves an a-nitro-ester as one of the reactants.2 The
reaction of a-nitro-esters with aldehydes provides three
types of products depending upon the reaction condi-
tions: (a) a Henry addition providing a-nitro-b-hydroxy
esters 2,3 or (b) in situ dehydration of these addition
products leading to a-nitroacrylates 3,4 or (c) the
Michael addition of 1 to 3 producing 2,4-dinitroglu-
tarates 4.5
carried out in the presence of 10 mol% zinc glycinate
using methanol as the solvent. Indeed, the condensation
proceeded smoothly at room temperature giving a com-
pound which was not the expected nitroaldol, but a
diastereomeric mixture of isoxazoline N-oxides 5.
The two diastereomers of 5 could be separated by
column chromatography, the major product being the
trans isomer.6 Their ratio was found to be highly depen-
dent on the solvent chosen (Table 1). The highest
selectivity was realized in DMSO as the solvent giving a
single trans diastereomer. A small amount of water in
the solvent did not hamper the reaction. However, the
reaction stops halfway to give 4 (R%=Ph; R=Me) in
the presence of a large amount of water. Variation in
the reaction temperature did not cause significant dif-
ferences in the outcome of the reaction; comparable
yields and selectivity were obtained at 0, 25 and 50°C.
As expected, the concentration of the catalyst affected
the rate of the reaction. The reaction was very slow
when 1 mol% zinc glycinate was employed. No particu-
lar advantage was realized by increasing the catalyst
We were interested in a stereoselective nitroaldol reac-
tion between a-nitro-esters and aldehydes. The reaction
did not take place either in the presence of a Lewis acid
(e.g. ZnCl2) or a Lewis base (e.g. Et3N). We then
envisaged that zinc complexes of amino acids could act
as dual-site (Lewis acidic and Lewis basic) catalysts for
the condensation. Thus the zinc center would activate
the aldehyde whereas the amino group would abstract
the proton from the nitro-ester. Zinc glycinate was
chosen as the preliminary catalyst. The reaction was
* Corresponding author. Fax: +91-20-5893153; e-mail: joshi@ems.ncl.res.in
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01047-X

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A. Chatterjee et al. / Tetrahedron Letters 43 (2002) 5287–5289
Table 1. Catalyzed condensation of a-nitro-esters with benzaldehyde
Entry
R
Solventa
Time (h)
Isomeric ratiob
trans
cis
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Et
MeOH
CH3CN
DMF
DMSO
MeOH
DMSO
MeOH
DMSO
3
6
1
2
8
3
6
2
56
71
92
\99
88
\99
85
44
29
8
0
12
0
Et
iPr
iPr
15
0
\99
a All reactions were carried out at room temperature using 10 mol% of zinc glycinate as the catalyst.
b Estimated by HPLC.
by the oxygen atom of the nitronate ion subsequently
concentration from 10 to 20 mol%. A very significant
effect on the stereochemical outcome was seen when the
size of the ester group was changed, thus ethyl and
isopropyl esters resulted in much higher selectivity even
in MeOH as the solvent (Table 1).
provides the isoxazoline N-oxide.7
Having optimized the reaction parameters, we then
examined the reaction with a variety of aldehydes. All
the reactions were over within 3 h at room temperature.
Consistently high yields were obtained in all cases
(Table 2). It is interesting to note that structural varia-
tion in the aldehydes had little influence on the reaction
rates or yields. The present reaction is thus not only
mechanistically interesting, but is a preparative proce-
dure for a variety of isoxazolines. Some of these com-
pounds (entries 1, 2, 4–8) have been obtained earlier,
via a different protocol.6
As we had predicted at the outset of the investigation,
zinc glycinate does indeed act as a dual-site catalyst.
Both the amino group (for the abstraction of protons)
and the zinc atom (as the Lewis acid center) are prereq-
uisites for the catalysis. This was evident from the fact
that neither zinc acetate nor sodium glycinate catalyzed
the reaction. The following domino reaction sequence
provides the pathway to isoxazoline N-oxide as the end
product. The first step is the expected nitroaldol reac-
tion. The resulting product then undergoes dehydration
to the corresponding nitroacrylate. A second equivalent
of the nitro-ester then undergoes Michael addition
yielding a dinitroglutamate. Substitution of nitrite ion
We were curious to know whether the use of homochi-
ral amino acids would impart any enantioselectivity to
the reaction. For this purpose, zinc prolinate, zinc
valinate and zinc phenylglycinate were prepared and
Table 2. Synthesis of trans-3,5-bis(alkoxycarbonyl)-4-substituted isoxazoline N-oxide
Entry
R
Aldehydea
Time (h)
Yield (%)b
Mp (°C)
1
2
3
4
5
6
7
8
9
Me
Et
Benzaldehyde
Benzaldehyde
Benzaldehyde
4-Tolualdehyde
4-Chlorobenzaldehyde
4-Methoxybenzaldehyde
4-Nitrobenzaldehyde
1-Naphthaldehyde
2-Furaldehyde
2
3
2
2
2
2
2
2
1
2
88
80
79
78
77
86
77
79
66
86
97 (lit.6 96)
76 (lit.6 74)
75
iPr
Me
Me
Me
Me
Me
Me
Me
100 (lit.6 98)
150 (lit.6 148)
104 (lit.6 94)
176 (lit.6 177)
163 (lit.6 164)
103
10
Cyclohexanecarboxaldehyde
83
a All the reactions were carried out using 10 mol% zinc glycinate in DMSO.
b Yield of isolated and purified trans-isomer.

A. Chatterjee et al. / Tetrahedron Letters 43 (2002) 5287–5289
5289
examined as the catalysts. Unfortunately, no significant
Acknowledgements
enantioselectivity was provided by any of these,
although all catalyzed the reaction efficiently. Efforts
are now in progress to design an enantioselective cata-
lyst for this transformation.
We are thankful to CSIR for the award of Research
Fellowships to A.C. and S.C.J.
In conclusion, we have shown that a-nitro-esters can be
efficiently condensed with a variety of aldehydes in the
presence of zinc complexes of amino acids as the cata-
lysts. The products were the outcome of a domino
reaction sequence resulting in isoxazoline N-oxides.
The protocol should prove to be a valuable tool for the
diastereoselective synthesis of a variety of substituted
isoxazoline N-oxides and their derivatives.
References
1. (a) Henry, C. R. Acad. Sci. Paris 1985, 120, 1265; (b)
Luzzio, F. A. Tetrahedron 2001, 57, 915.
2. Shipchandler, M. T. Synthesis 1979, 666.
3. Weisblat, D. I.; Lyttle, D. A. US Patent 2570297, 1951; C.
A. 1952, 46, 5077.
4. Lehnert, W. Tetrahedron 1972, 28, 663.
5. Dornow, A.; Frease, A. Justus Liebigs Ann. Chem. 1953,
581, 211.
6. Melot, J.; Texier-Boullet, F.; Foucaud, A. Synthesis 1988,
558.
Typical experimental procedure: To a solution of nitro-
ester (4 mM) in DMSO (5 ml), zinc glycinate (0.4 mM)
and aldehyde (2 mM) were added. The resulting solu-
tion was stirred at room temperature until TLC analy-
sis indicated the disappearance of starting materials.
The reaction mixture was diluted with water (20 ml)
and extracted with dichloromethane. The extract was
washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The resulting
product was purified by flash chromatography using
hexane/ethyl acetate (4:1) as the eluent and then crystal-
lized from the same combination of solvents. All the
compounds provided satisfactory analytical data.8
7. Kaji, E.; Zen, S. Chem. Pharm. Bull. 1980, 28, 479.
8. trans-3,5-Bis(methoxycarbonyl)-4-phenyl-4,5-dihydroiso-
1
xazole N-oxide: H NMR l 3.75 (s, 3H), 3.88 (s, 3H), 4.85
(d, J=2.2 Hz, 1H), 4.95 (d, J=2.9, 1H), 7.32–7.44 (m,
5H); 13C NMR l 52.4, 52.5, 53.1, 78.6, 108.8, 126.8, 128.6,
129.2, 137.6, 158.4, 168.4; MS m/z 279 (M+), 261, 248, 116
(base peak). Anal. Calcd for C13H13NO6: C, 55.91; H,
4.70; N, 5.02. Found: C, 55.72; H, 4.60; N, 5.00.