Isoxazoline derivatives from activated primary nitrocompounds and tertiary diamines

Article abstract of DOI:10.1016/j.tetlet.2005.09.110

Activated nitrocompounds, in the presence of dipolarophiles and a tertiary diamine (e.g., DABCO), undergo dehydration to afford directly isoxazoline derivatives, formal cycloadducts of nitrile oxides; this mild procedure is very efficient for the synthesi

Full text of DOI:10.1016/j.tetlet.2005.09.110

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7877–7879
Isoxazoline derivatives from activated primary nitrocompounds
and tertiary diamines
Luca Cecchi,a Francesco De Sarloa,* and Fabrizio Machettib,*
a
`
Dipartimento di chimica organica ‘U. Schiff’, Universita di Firenze, Via della Lastruccia 13, 50019 Sesto F.no, Firenze, Italy
bIstituto di Chimica dei Composti Organo Metallici del CNR, c/o Dipartimento di chimica organica ‘U. Schiff’,
Via Della Lastruccia 13, 50019 Sesto F.no, Firenze, Italy
Received 23 July 2005; revised 19 September 2005; accepted 19 September 2005
Abstract—Activated nitrocompounds, in the presence of dipolarophiles and a tertiary diamine (e.g., DABCO), undergo dehydration
to afford directly isoxazoline derivatives, formal cycloadducts of nitrile oxides; this mild procedure is very efficient for the synthesis
of the reported isoxazolines.
Ó 2005 Elsevier Ltd. All rights reserved.
Primary nitrocompounds have become a common
source of nitrile oxides since their dehydration with
phenylisocyanate was first reported.1 Several other
dehydrating procedures subsequently described include
treatment with strong acids or with other acylating
agents. ÔActivatedÕ primary nitrocompounds, that is,
those bearing an EWG geminal to the nitro group, are
reported to undergo dehydration, too, by reaction with
acids (sulfuric acid2 or PTSA3–6) or in acylating condi-
tions (aryl-sulfonyl chloride,7,8 acetyl chloride,9 ethyl
chloroformate,8 isocyanates10) or even on severe heat-
ing:10 cycloadducts are produced in the presence of
dipolarophiles. Some activated nitrocompounds have
also been reported to give the expected cycloadducts
on treatment with an excess of Ce(III) ammonium
nitrate in the presence of dipolarophiles.11 Most reactions
are carried out at elevated temperatures. The use of
di-tert-butyl dicarbonate (Boc2O)12 or 4-(4,6-dimeth-
oxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride
(DMTMM)13 and catalytic amounts of N,N-dimethyl-
aminopyridine (DMAP) allows the dehydration of
nitroalkanes under much milder conditions.
dipolarophiles under mild conditions, by treatment with
amines. Only tertiary amines can be used, since activated
nitrocompounds are known to be cleaved by other
amines.14 As soon as these nitrocompounds are mixed
in chloroform with tertiary amines, the salt is produced,
as evidenced by 1H NMR spectroscopy and as expected
from their acid strength:15 1a pKa(H2O) = 5.1; 1b, pKa
(H2O) = 5.19; 1c, pKa(H2O) = 5.82; 1d, pKa(MeOH–
H2O) = 5.69. With triethylamine (TEA), the addition
of a dipolarophile such as norbornene (3) or styrene
(4) causes the slow production of the dehydrated ad-
ducts 6a–b and 7a–b from nitroacetone (1a) as well as
benzoylnitromethane (1b). In the same conditions, ethyl
nitroacetate (1c) and phenylsulfonylnitromethane (1d)
do not react with dipolarophiles 3 and 4. However, if
tertiary diamines such as 1,4-diazabicyclo[2.2.2]octane
(DABCO, 2) or N,N,N0,N0-tetramethylethylenediamine
(TMEDA) are employed, not only cycloadducts 6a–b
and 7a–b, but 6c and 7c from 1c, as well as 6d from
1d are obtained, too, with the appropriate dipolaro-
philes. An induction period has been observed; for the
reaction to go to completion, prolonged warming at
60 °C is required. Results are summarised in Table 1, to-
gether with the yields obtained with other procedures,
shown for comparison.
Here we report the synthesis of isoxazoline derivatives
from activated primary nitrocompounds (1a–d) and
Our method directly converts activated nitroalkanes
1a–d into isoxazolidines 6a–d and 7a–c with higher
yields and an easier procedure compared to those previ-
ously reported. Normally, these procedures require an
excess of dipolarophile to reduce the dimerisation of
Keywords: Isoxazolines; Nitroalkanes; Diamines.
*
Corresponding authors. Tel.: +39 055 457 3484; fax: +39 055 457
3531 (F.D.S.); tel.: +39 055 457 3501; fax: +39 055 457 3531
(F.M.); e-mail addresses: francesco.desarlo@unifi.it; fabrizio.
machetti@unifi.it
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.110

7878
L. Cecchi et al. / Tetrahedron Letters 46 (2005) 7877–7879
Table 1. Reaction of some nitroalkanes with dipolarophiles in the presence of tertiary diamines16
R1
R3
R1
+
R3
R2
R3
NO2
N
R2
1a-d
O
Producta
R1
R2
Conv. (%)b
Quantitative
74
Yield (%)c
(100) 90
(77) 60
(91) 90d
(75) 75e
(100) 100
(89) 91
(39) 35
—
Other methods (%)
6a
7a
6b
7b
6c
7c
6d
7d
MeCO
MeCO
PhCO
PhCO
EtOCO
EtOCO
PhSO2
PhSO2
—
Ph
Ph
Ph
Ph
H
H
H
H
266
Quantitative
Quantitative
Quantitative
Quantitative
38
62, 8317,18
21;17,19 70;6,17 50;17,20
8317,21
6621
20–2822
—
18–2522,23
a General conditions: dipolarophile (40 mg, 0.425 mmol), nitrocompound (1.06 mmol), base (0.216–0.318 mmol) in CHCl3 (1.4 mL) at 60 °C (sealed
tube), 20–40 h.
b Conversion of dipolarophile determined by 1H NMR.
c Isolated yields, based on dipolarophile, spectroscopic yields (in parentheses) determined by 1H NMR using an internal standard.
d Quantitative yield including a side product (10%).
e Quantitative yield including a side product (25%).
the intermediate nitrile oxide. For example the reaction
of styrene (4) with nitroacetone (1a) in the presence of
DABCO gives isoxazolidine 7a in one step and 60%
yield as compared to the lower yield (26%) of the
reported transformation of 1a into 7a using a nitronic
ester intermediate. Furthermore the reaction of styrene
(4) with ethyl nitroacetate (1c) in the presence of DAB-
CO gives isoxazolidine 7c in one step and 91% yield
(66% yield in previously reported synthesis). Cycload-
ducts can be easily isolated from the reaction mixture
after usual work-up and the amine completely recov-
ered. However, in the reactions of benzoylnitromethane
(1b) minor side products were obtained and the isolation
of the adducts required an additional chromatographic
separation. These side products are not isomers of
adducts 6b and 7b and their structure is at present
under investigation.
In the extensive literature on dehydration of primary
nitro compounds (hinted at the beginning) the identifi-
cation of nitrile oxides as possible intermediates has
received the attention of several authors.24,6 In the
absence of dipolarophile, either the spectroscopic identi-
fication of the nitrile oxide25 or the isolation of its dimer,
the corresponding furoxan,2,3 have been taken as evi-
dence for the formation of the nitrile oxide as an inter-
mediate. When furoxan is not detected in the absence
of dipolarophile, the problem actually exists and it has
been discussed in detail.24,6 In the present reaction, does
the dehydration step precede or follow cycloaddition? In
other words, is the nitrile oxide a reaction intermediate?
Minor amounts of furoxan 8a have been observed
beside adducts 6a and 7a only in the reactions of nitro-
acetone 1a, while furoxans were not detected in the reac-
tions of 1b–d, even in the absence of dipolarophile.
R1
N
R1
O
O
R1
N
O
R1
N
O
R1
H
N O
-H2O
N
O
O
1a-d
8a
H
R1
R1
2
R3
R1
R2
R3
H
N
R3
+
N
O
H+
N
H
N
N
N
-H2O
-H+
N
R2
N
N
O
O
O
O
H
H
R2
5
6a-d
7a-c
H+
a R1=MeCO
b R1=PhCO
R1
-H2O
R2-R3=
R2= P h , R 3= H
H
O
H
R3
R2
c R1=EtOCO
d R1=PhSO2
N
H
N
N
O
H
5'
Scheme 1.

L. Cecchi et al. / Tetrahedron Letters 46 (2005) 7877–7879
7879
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Scheme 1 is based on the observations reported above: a
pre-equilibrium is slowly established between the nitro-
nate (possibly H-bonded to the ammonium ion) and
the dipolarophile, thus accounting for the induction per-
iod. Adduct 5 is assumed to be in equilibrium with its
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cycloadduct). The dehydration, requiring heterolysis of
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basicity), while the irreversible dehydration step leading
to the final cycloadducts 6 and 7 depends on the Transi-
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nium ion to deliver water is much easier for the diamine
that loses a proton from one N atom while binding
another proton to the other N atom (the TS is illustrated
with curly arrows). Further investigations are necessary
to add support to this mechanism.
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22. Wade, P. A.; Bereznak, J. F. J. Org. Chem. 1987, 52, 2973–
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Acknowledgements
Financial support by the Ente Cassa di Risparmio di
Firenze for the purchase of the 400 MHz NMR instru-
ment is gratefully acknowledged. L.C. thanks Universita
`
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di Firenze for Doctoral fellowship.
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