Unexpected heterocyclization of electrophilic alkenes by tetranitromethane in the presence of triethylamine. Synthesis of 3-nitroisoxazoles

Article abstract of DOI:10.1021/jo100319p

Novel reaction of tetranitromethane (TNM) with electrophilic alkenes in the presence of triethylamine yielding substituted 3-nitroisoxazoles was found and studied. Triethylamine increases the reactivity of TNM toward electrophilic alkenes promoting their heterocyclization, and the reactions proceed in an unusual way. A variety of α,β-unsaturated aldehydes, ketones, esters, amides, phosphonates, and nitro and sulfur compounds was involved in the heterocyclization reaction, and a wide range of functionalized 3-nitroisoxazoles was obtained in good to high yields. The scope and limitations of the reaction and the mechanistic aspects are discussed.

Full text of DOI:10.1021/jo100319p

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Unexpected Heterocyclization of Electrophilic Alkenes by
Tetranitromethane in the Presence of Triethylamine. Synthesis of
3-Nitroisoxazoles
Yulia A. Volkova,† Elena B. Averina,*,† Yuri K. Grishin,† Per Bruheim,‡
Tamara S. Kuznetsova,† and Nikolai S. Zefirov†
†Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, 1-3, Moscow 119992,
Russia, and ‡Department of Biotechnology, Norwegian University of Science and Technology,
Sem Selands vei 6/8, N-7431 Trondheim, Norway
elaver@org.chem.msu.ru
Received February 20, 2010
Novel reaction of tetranitromethane (TNM) with electrophilic alkenes in the presence of triethyl-
amine yielding substituted 3-nitroisoxazoles was found and studied. Triethylamine increases the
reactivity of TNM toward electrophilic alkenes promoting their heterocyclization, and the reactions
proceed in an unusual way. A variety of R,β-unsaturated aldehydes, ketones, esters, amides,
phosphonates, and nitro and sulfur compounds was involved in the heterocyclization reaction,
and a wide range of functionalized 3-nitroisoxazoles was obtained in good to high yields. The scope
and limitations of the reaction and the mechanistic aspects are discussed.
Introduction
in the 1960s by the groups headed by Tartakovski2 and
Perekalin.3 These workers explored heterocyclizations of
alkenes using polynitromethanes and showed their potential
in the synthesis of mainly dinitroisoxazolidines. Only nucleo-
philic alkenes were used in these reactions.1 Moreover, it was
mentioned that4 “electron-withdrawing groups at double
bond dramatically reduce the nucleophilicity of alkene and
exclude its reaction...with tetranitromethane”.
Recently studying the reactions of polynitromethanes with
alkenes containing a small ring, we have developed one-pot
three component heterocyclization reaction with a variety of
alkenes and proposed a preparative approach to highly func-
tionalized nitro-substituted heterocycles, such as isoxazoli-
dines, as well as piperidones, aziridines, and isoxazolines.5
Nitronates generated from polynitromethanes have found
wide use in organic synthesis as versatile 1,3-dipoles for the
cycloaddition reaction with alkenes to yield five-membered
N,O-heterocyclic compounds.1 This reaction was discovered
(1) (a) Altukhov, K. V.; Perekalin, V. V. Usp. Khim. 1976, 45, 2050; Chem.
Abstr. 1977, 86, 71774s. (b) Fridman, A. L.; Surkov, V. D.; Novikov, S. S. Usp.
Khim. 1980, 49, 2159; Chem. Abstr. 1981, 94, 156194t. (c) Shvekhgeymer, G.
A.; Zvolinskii, V. I.; Kobrakov, K. I. Khim. Heterotsikl. Soed. 1986, 435; Chem.
Abstr. 1987, 106, 50078j. (d) Nielsen, A. T. In Nitronic Acids and Esters; Feuer,
H., Ed.; Wiley-VCH: New York, 1981; p 349. (e) Torssell, K. B. G. In Nitrile
oxides, nitrones and nitronates in organic synthesis; Feuer, H., Ed.; Wiley-
VCH:: New York, 1988; p 95. (f) Nielsen, A. T. In Nitrocarbons; Feuer, H., Ed.;
Wiley-VCH: New York, 1995; p 1. (g) Padwa, A.; Pearson, W. H. In Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry toward Heterocycles and
Natural Products; Feuer, H., Ed.; Wiley-VCH: New York, 2002; p 83. (h) Ioffe, S.
L. In Nitrile Oxide, Nitrones and Nitronates on Organic Synthesis; Feuer, H.,
Ed.; Wiley-VCH: New York, 2008; p 435. (i) Averina, E. B.; Ivanova, O. A.;
Budynina, E. M.; Volkova, Y. A.; Kuznetsova, T. S.; Zefirov, N. S. Moscow Univ.
Chem. Bull. 2008, 63, 131.
(3) Altukhov, K. V.; Perekalin, V. V. Zh. Org. Khim. 1966, 2, 1902;
Chem. Abstr. 1967, 66, 46354j.
(4) Ratsino, E. V.; Altukhov, K. V. J. Org. Chem. USSR 1972, 8, 2327.
(5) For an account, see: Averina, E. B.; Kuznetsova, T. S.; Zefirov, N. S.
Synlett 2009, 1543.
(2) Tartakovskii, V. A.; Chlenov, I. E.; Smagin, S. S.; Novikov, S. S. Izv.
Akad. Nauk SSSR, Ser. Khim. 1964, 583; Chem. Abstr. 1964, 61, 4335e.
DOI: 10.1021/jo100319p
r
Published on Web 04/12/2010
J. Org. Chem. 2010, 75, 3047–3052 3047
2010 American Chemical Society

Volkova et al.
JOCArticle
What is more, we have found that combination of tetranitro-
methane (TNM) with triethylamine may be regarded as a
specific reagent, which was used for the ring-opening reaction
of oxiranes and N-tosylaziridines yielding β-hydroxy nitrate6
and β-tosylamino nitrates,7 respectively. It should be noted
that TNM itself does not cleave the epoxides and the aziridines
directly without activation with basic reagents (Et3N).
chloronitrolic acid with Grignard derivatives of acetylenes.13
An interesting example of 3-nitroisoxazole synthesis is the
reaction of tetranitroethylene and trimethylsilyl-substituted
acetylenes giving mono- and disilylsubstituted 3-nitroisox-
azoles.14
Here, we present the results of our study of heterocycliza-
tion of electrophilic alkenes under the action of TNM in the
presence of Et3N as well as the scope and limitations of this
protocol. In fact, eight classes of electrophilic alkenes were
studied in this reaction.
In this paper, we report a novel reaction of TNM in the
presence of triethylamine (Et3N) with conjugated functiona-
lized alkenes containing electron-withdrawing group at the
double bond, which, in turn, may be considered as a general
method for the synthesis of substituted 3-nitroisoxazoles.
It is well-known that isoxazoles constitute a class of
heterocyclic compounds possessing a remarkable variety
of applications as versatile building blocks in organic
synthesis.8 Their wide range of biological activity includes
antibacterial, antiviral, and antifungal activities; they can act
as various glutamate and GABA receptors ligands and
also display herbicide activity.8d,9 The construction of the
isoxazole ring can be achieved by two major synthetic
approaches, including 1,3-dipolar cycloaddition of unsatu-
rated compounds and the reaction of hydroxylamine with
1,3-diketones or R,β-unsaturated ketones.8 However, both
of these methods are not suitable for the synthesis of 3-nitro-
substituted isoxazoles.
Results and Discussion
We have started our studies by examination the reaction of
TNM-base complex with R,β-unsaturated compounds con-
taining a carbonyl group. Methyl vinyl ketone was chosen as
a model substrate for the optimization of the reaction
conditions. Full data concerning the optimization of the
type of base and solvent used and the amounts of the reagents
are presented in the Supporting Information. We tried
several tertiary amines (Et3N, Bu3N, Py, TMEDA, DBU,
DABCO) and triphenylphosphine as bases, which were used
in catalytic or equimolar amounts. In all cases, the principle
result was the following: we have observed the formation of
3-nitroizoxazole 1 in accordance with Scheme 1:
Only a few synthetic routes have been developed for
3-nitrosubstituted isoxazoles having antibacterial activity.10
3-Nitroisoxazoles cannot be obtained by the direct nitration
of isoxazoles or by the usual [3 þ 2]-cycloaddition reactions.
According to described methods, nitro group is introduced
in the 3-position of isoxazole at the step of intramole-
cular cyclization of substituted nitrolic acids generated
from propargyl halides11 or 1,3-dihalogenopropanes12 and
sodium nitrite. Another method is based on the reaction of
SCHEME 1. Heterocyclization of Methyl Vinyl Ketone under
the Action of TNM in the Presence of Base
However, in some cases, side product 5,5,5-trinitropentan-
2-one was isolated in 6-10% yields. The best result was
obtained with Et3N (80%). The use of other bases such as
Bu3N, Py, TMEDA, and DBU resulted in moderate yields of
isoxazole 1 (30-40%), and low yields were obtained when
DABCO and Ph3P were used (20 and 6%, respectively).
Variation of the molar ratio of the reagents in the case of
triethylamine showed that the optimal yield of isoxazole 1
was achieved using alkene, TNM, and triethylamine in a
1:2.5:2 ratio. After screening the solvents, we found that the
heterocyclization proceeded smoothly in dioxane at room
temperature and complete conversion of starting olefins was
achieved in 12 h with a good yields of isoxazole 1. It should be
noted that if the reaction was carried out in methanol the
trinitropentanone was isolated exclusively. The reaction
protocol includes a slow addition of alkene at 5 °C to
previously prepared complex of TNM with Et3N. The reac-
tion was scaled up using 10 mmol of methyl vinyl ketone,
25 mmol of TNM, and 20 mmol of Et3N under standard
conditions to produce 80% yield of isoxazole 1.
(6) Volkova, Y. A.; Ivanova, O. A.; Budynina, E. M.; Averina, E. B.;
Kuznetsova, T. S.; Zefirov, N. S. Tetrahedron Lett. 2008, 49, 3935.
(7) Volkova, Y. A.; Averina, E. B.; Kuznetsova, T. S.; Zefirov, N. S.
Tetrahedron Lett. 2010, 51, 2254–2257.
(8) For reviews, see: (a) Lang, S. A.; Lin, Y.-I. In Comprehensive Hetero-
cyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984;
Vol. 6, p 1. (b) Gr€unanger, P.; Vita-Finzi, P. Isoxazoles, Part I, The Chemistry of
Heterocyclic Compounds; Taylor, E. C., Weissberger, A., Eds.; Wiley: New York,
1991; Vol. 49, p 1. (c) Teresa, M. V. D.; Pinho e, Melo Curr. Org. Chem. 2005, 9,
925. (d) Giomi, D.; Cordero, F. M.; Machetti, F. Isoxazoles. In Comprehensive
Heterocyclic Chemistry; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V.,
Taylor, R. J. K., Eds.; Elsevier: Oxford, 2008; Vol. 4, p 365.
(9) For selected examples on bioactivity: (a) Stein, P. D.; Floyd, D. M.;
Bisaha, S.; Dickey, J.; Girotra, R. N.; Gougoutas, J. Z.; Kozlowski, M. L.;
Lee, V. G.; Liu, E.C.-K.; Malley, M. F.; McMullen, D.; Mitchell, C.;
Moreland, S.; Murugesan, N.; Serafino, R.; Webb, M. L.; Zhang, R.; Hunt,
J. T. J. Med. Chem. 1995, 38, 1344. (b) Madsen, U.; Bang-Andersen, B.;
Brehm, L.; Christensen, I. T.; Ebert, B.; Kristoffersen, I. T. S.; Lang, Y.;
Krogsgaard-Larsen, P. J. Med. Chem. 1996, 39, 1682. (c) Solankee, A.;
Solankee, S.; Patel, G. Rasayan J. Chem. 2008, 1, 581. (d) Srinivas, A.;
Nagaraj, A.; Reddy, S. J. Heterocycl. Chem. 2009, 46, 497. (e) Kuz’min, V. E.;
Artemenko, A. G.; Muratov, E. N.; Volineckaya, I. L.; Makarov, V. A.;
Riabova, O. B.; Wutzler, P.; Schmidtke, M. J. Med. Chem. 2007, 50, 4205. (f)
Pieroni, M.; Lilienkampf, A.; Wan, B.; Wang, Y.; Franzblau, S. G.;
Kozikowski, A. P. J. Med. Chem. 2009, 52, 6287. (g) Dayan, F. E.; Duke,
S. O.; Reddy, K. N.; Hamper, B. C.; Leschinsky, K. L. J. Agric. Food Chem.
1997, 45, 967. (h) Zimecki, M.; Maczynski, M.; Ryng, S. Acta Polon. Pharm.
Drug Res. 2008, 65, 793. (i) Simoni, D.; Rondanin, R.; Baruchello, R.; Rizzi,
M.; Grisolia, G.; Eleopra, M.; Grimaudo, S.; Di Cristina, A.; Pipitone, M.
R.; Bongiorno, M. R.; Arico, M.; Invidiata, F. P.; Tolomeo, M. J. Med.
Chem. 2008, 51, 4796.
Having this general optimization of reaction conditions in
hand, we investigated a series of R,β-unsaturated ketones
and aldehydes under these conditions; the results are pre-
sented in Table 1.
Ketones smoothly reacted with TNM-Et3N complex at
room temperature forming 5-acyl-3-nitroisoxazoles 1-7 in
high yields. We also succeeded in heterocyclization with
(10) Uhr, H.; Kretschik, O.; Kugler, M.; Wachtler, K. US Patent 2003/
0166698, 2003.
(11) (a) Rossi, S.; Duranti, E. Tetrahedron Lett. 1973, 14, 485. (b)
Mechkov, Ts. D.; Sulimov, I. G.; Usik, N. V.; Mladenov, I.; Perekalin, V. V.
Zh. Org. Khim. 1980, 16, 1328; J. Org. Chem. USSR 1980, 16, 1148.
(12) Diamantini, G.; Duranti, E.; Tontini, A. Synthesis 1993, 1104.
(13) Bravo, P.; Gaudiano, G. Gazz. Chim. Ital. 1966, 96, 454.
(14) Baum, K.; Tzeng, D. J. Org. Chem. 1985, 50, 2736.
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TABLE 1. Reaction of R,β-Unsaturated Ketones and Aldehydes with
TNM-Et3N Complex
TABLE 2. Synthesis of 3-Nitroisoxazole-5-carboxylates
entry
3-nitroisoxazole
R1
R2
yield,a %
1
2
3
4
5
6
7
8
9
8
9
H
H
H
H
H
Me
Et
(CH2)3Cl
CH2Ph
Me
Et
Bu
t-Bu
CH2Ph
Et
Et
Et
62
75
60
46
60
50
40
46
21
10
11
12
13
14
15
16
Et
aIsolated yield.
TABLE 3. Reaction of Acrylamides with TNM-Et3N Complex
aIsolated yield.
TNM-Et3N levoglucosenone, a highly functionalized chiral
synthon, which is an excellent starting material and building
block for the synthesis of natural compounds.15 A new chiral
3-nitroisoxazole 5 was obtained in a good yield (Table 1,
entry 5). It was found that acrolein and crotone aldehyde also
reacted with TNM under the same conditions, producing
5-carbaldehyde-3-nitroisoxazoles 6 and 7 in 40 and 49%
yields, respectively. Lower yields of compounds 6 and 7
related to partial polymerization of starting aldehydes
under reaction conditions.
Next, we tried to involve R,β-unsaturated esters in the
heterocyclization reaction with TNM-Et3N complex. We
have found that the simplest vinyl ester-methyl acrylate
reluctantly reacted with TNM-Et3N at room temperature
for 12 h leading to the corresponding 3-nitroisoxazole 8 in
poor yield (10%).16 However, further investigation revealed
that this reaction proceeded smoothly when heated at 70 °C
for 2 h, and the yield of 8 increased to 62%. These conditions
were found to be optimal for R,β-unsaturated esters, and a
series of 3-nitroisoxazole-5-carboxylates 8-16 was thus
obtained (Table 2).
compds 17 and 18
R1
R2
yield of 17,a % yield of 18,a %
a
b
c
d
e
f
H
H
H
H
H
C3H7
H
Bu
CH2Ph
cy-hexyl
Ph
64
29
20
41
24
23
18
-
21
23
38
19
25
25
C3H7
g
-(CH2)5-
aIsolated yield.
Moreover, it was found that hindered cumarin and (E)-ethyl
4-methylpent-2-enoate do not react with complex TNM-
Et3N under the stated conditions. With R2 = Bu (Table 2,
entry 3), the corresponding isoxazole 10 was obtained in 60%
yield, while with R2 = t-Bu (Table 2, entry 4) the reaction
proceeded affording the product 11 in 46% yield.
We have further extended the heterocyclization to acryl
amides. The results of the heterocyclization of N-substituted
acryl amides upon the action of TNM-Et3N are summar-
ized in Table 3. We have found that the complex TNM-
Et3N at 20 °C clearly converted acryl amide into a single
product, 3-nitroisoxazole-5-carboxamide 17a, in 64% yield
in 48 h. However, the heterocyclization of N-substituted
acryl amides led to the mixtures of the desired nitroisoxazoles
17b-f and the products of formal trinitromethane Michael
addition to the starting amides: N-substituted 4,4,4-trinitro-
butanamides 18b-f. Optimization of the reaction conditions
for selective preparation of 3-nitroisoxazole carbamides was
not successful. Mixtures of compounds 17c and 18c in nearly
equal ratio were obtained in the reaction of N-benzyl acryl
amide with TNM-Et3N complex at room temperature in
It is worth noting that increasing the size either substituent
R1 or R2 led to a moderate decrease of isoxazole yields. For
instance, if R1 in the starting ester was changed from H
(Table 2, entry 2) to Et (Table 2, entry 7) and then to PhCH2
(Table 2, entry 9), the yields of the corresponding isoxazoles
9, 14, and 16 decreased from 75 to 40 and 20%, respectively.
(15) (a) Miftakhov, M. S.; Valeev, F. A.; Gaisina, I. N. Russ. Chem. Rev.
1994, 63, 869. (b) Witczak, Z. J. In Chemicals and Materials from Renewable
Resources; Bozell, J. J., Ed.; American Chemical Society: Washington DC, 2001;
No. 784, Chapter 7, p 81.
(16) If the mixture of 1,4-dioxane-CH3CN was used as a solvent only
methyl 4,4,4-trinitrobutanoate in 36% yield was evolved as a reaction
product.
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SCHEME 2. Reaction of Vinylsulfonylbenzene with TNM-Et3N Complex
SCHEME 3. Reaction of Vinyl Benzenesulfonate with TNM-
Et3N Complex
SCHEME 4. Synthesis of 3-Nitro-5-phosphonate Isoxazole
In the case of vinyl benzenesulfonate, when the reaction with
TNM-Et3N was carried out in hot dioxane, trinitromethyl
derivative 21 was obtained in good yield (Scheme 3), whereas
when the reaction was run at 110 °C in chlorobenzene, only
isoxazole 22 was isolated from the reaction mixture.
On the other hand, vinyl sulfinyl benzene in the reaction
with TNM-Et3N did not afford the expected isoxazole, and
only benzenesulfonic acid was formed obviously as a result
of the oxidation of starting vinylsulfinyl compound by
TNM. This result was the same at room temperature and
upon heating at 70 °C in dioxane.
We were encouraged to find that vinyl phosphonate ester
smoothly reacted with TNM- Et3N complex in dioxane
upon heating at 70 °C to form the desired 3-nitroisoxazole-
5-phosphonate 23 in high yield (Scheme 4).
Finally, R,β-unsaturated nitroalkenes were investigated
in the reaction with TNM-Et3N complex. A series of
nitroethylenes were found to be active in this reaction
at 70 °C in dioxane, and 3,5-dinitroisoxazoles 24-28
were isolated in good yields (Table 4). The yield of 24
48 h or upon heating at 70 °C in dioxane in 2 h. The use of
methylene chloride as a solvent in the reaction of N-benzyl
acryl amide with TNM-Et3N complex at room temperature
led to trinitroamide 18c as the sole product in 54% yield in
72 h. The products 17 and 18 were isolated by column
chromatography.
A similar result was observed in the reaction of R,β-
unsaturated organic sulfur compounds in the reaction with
TNM-Et3N complex. It was found that vinylsulfonyl ben-
zene reacted with TNM in the presence of Et3N, and the
desired 3-nitro-5-(phenylsulfonyl)isoxazole 19 was obtained
along with the side product trinitroethylsulfonylbenzene 20
(Scheme 2). The reaction proceeded at 70 °C in dioxane for
5 h. When the reaction was conducted at 20 °C in dioxane for
14 days, only compound 20 was obtained in 38% yield.
Increasing the reaction temperature to 100 °C using chloro-
benzene as a solvent afforded 19 and 20 in tiny 2% and 3%
yields, respectively, and a number of unidentified byproducts.
TABLE 4. Synthesis of 3,5-Dinitroisoxazoles
(17) The isoxazole fragments of the compounds present characteristic
spectral patterns with small variations of the 1H and 13C chemical shift
values. The C(4)H protons of heterocycles give singlets at 7.3-7.6 ppm. The
signals of the corresponding carbon atoms (C4) are observed in the typical
region at 100-104 ppm that reveal weak dependence on substituent at C5.
Introduction of the substituent at C4 causes an expected downfield shift
(14-20 ppm). Relatively narrow ranges of 13C chemical shifts in a series of
compounds are found for carbon atoms C3 (at 162 to 167 ppm) and C5 (at
154 to 164 ppm). It is interesting to note the peculiarity of the signals of
quaternary carbon atoms C3 bonded to nitro group due to scalar relaxation
mechanism ( Becker, E. D. High Resolution NMR. Theory and Chemical
Applications, 2nd ed.; Academic Press: London, 1980; p 192). Relaxation of
14N nuclei causes appreciable resonance line broadening for these carbon
atoms. In contrast, in the case of 3,5-dinitroisoxazole 24 resolved 13C-14N
splitting was observed for both CNO2 groups with JCN equal to 18 and 16 Hz.
Nitro groups of this compound give rather narrow resonance signals in 14N
NMR spectrum at -33.7 and -38.4 ppm with respect to CH3NO2. The 13
C
resonance of C(NO2)3 group (at ca. 130 ppm) in trinitrosubstituted adducts
18 and 21 is upfield shifted compared to the CNO2 group of 3-nitroisox-
azoles. The weak 13C signal of this group was not found for compounds
18c-e and 20.
aIsolated yield.
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Volkova et al.
SCHEME 5. Proposed Mechanism for the Reaction of R,β-Unsaturated Carbonyl Compounds with TNM-Et3N Complex
JOCArticle
was substantially less due to a partial polymerization of
starting nitroethylene under the reaction conditions. The
bulky substituents at the double bond have an obvious
dilatory effect on the reactivity of starting olefins; e.g.,
the yield of cyclopropylmethyl substitued isoxazole 28
did not exceed 50%, while isopropylnitroethylene was
totally inert in the reaction with TNM under optimized
conditions.
Et3N HNO3 and N-nitrosodiethylamine from the reaction
3
mixture.
Trinitrosubstituted adducts of type VI could be formed
via path B, which is in fact the Michael addition of
trinitromethane to starting electrophilic alkenes. In turn,
trinitromethane can be generated in the reaction mixture
from trinitromethyl anion (its source is complex I) and free
proton (its source is the solvent or substrate). This is in a
good agreement with the fact that 5,5,5-trinitropentan-
2-one was the only product in the reaction of methyl vinyl
ketone with TNM-Et3N in methanol. Acrylic acid reacted
with TNM-Et3N complex at room temperature in 1,4-
dioxane to afford the sole product 4,4,4-trinitrobutyric
acid in 49% yield. Although the cyclization of 1,1,1,3-
tetranitropropane and 1,1,1,3-tetranitro-2-methylpropane
described in the literature18 led to the formation of the
corresponding 3,5-dinitroisoxazoles by treatment with di-
lute mineral acids, our attempts to cyclize the products of
the Michael addition of trinitromethane to electrophilic
alkenes under variety of conditions were all unsuccessful.
Structures of the obtained products were unambiguously
confirmed by NMR spectroscopy.17
Consider now the mechanistic aspects of the reaction of
electrophilic alkenes with TNM-Et3N complex. A proposed
mechanism for this reaction is outlined in Scheme 5 using
R,β-unsaturated carbonyl compounds as a model. In the first
step, the molecule of TNM is polarized upon the reaction
with triethylamine to give complex I, which can act in the
reaction as nitronic ester N (path A). It should be specially
emphasized that TNM does not react with electrophilic
alkenes in the absence of amine. The stoichiometry of this
reaction shows that the elimination of either 2NO2 þ H2O or
HNO3 þ HNO2 occurs. In other words, to get the aromatic
structure we need several elimination reactions of nitro
groups! Thus, triethylamine is needed not only to initiate
the reaction but also to bind the forming acids. Nitronic
ester N reacts further with electrophilic alkene; likewise,
the 1,3-dipole generates unstable 3,3-dinitroisoxazolidine
Conclusion
In conclusion, it is has been demonstrated that TNM
activated by Et3N possesses unusual properties and may be
used as an efficient and readily available reagent for numer-
ous synthetic purposes. The present investigation describes
the employment of TNM-Et3N complex for heterocycliza-
tion of electrophilic alkenes under mild conditions affording
hardly accessible 3-nitroisoxazoles in good isolated yields.
The reaction tolerates a variety of substituents in alkenes. We
have developed a simple, general, and in many cases pre-
parative method for the synthesis of functionalized 3-nitro-
isoxazoles, which are perspective pharmacologically active
compounds. Hopefully, this new reaction will find applica-
tion in the synthesis of heterocyclic compounds.
-
þ
II. Subsequent elimination of NO3 and NO2 produced
nitroisoxazoline III. Obviously, looking at the structure(s)
of the product(s), the next step must be some kind of
dehydrogenization reaction leading to an aromatic isoxa-
zole structure. While the reaction mixture contains some
potential oxidants, this stage is not thoroughly clear. We
suppose that the aromatization process is due to sub-
sequent nitration-elimination of nitrous acid of inter-
mediate III. We supposed that NO2þ may be participating
in this process to yield product IV. The final stage is the
formation of 3-nitroisoxazole V due to elimination of
HNO2. The indirect proof of elimination of molecules
HNO3 and HNO2 is the successful isolation of the salt
(18) Golod, E. L.; Novatskiy, G. N., Bagal, L. I. Zh. Org. Khim. 1973, 9,
1111; J. Org. Chem. USSR 1973, 9, 1139.
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Experimental Section
Ethyl 3-nitroisoxazole-5-carboxylate (9): yield 140 mg (75%);
pale yellow liquid; Rf 0.49 (CHCl3); H NMR (CDCl3) δ 1.46
1
Analytical thin-layer chromatography (TLC) was carried out
with “Silufol” silica gel plates (supported on aluminum); the
revelation was done by UV lamp (254 and 365 nm) and chemical
staining (iodine vapor and potassium permanganate solution in
water). Column chromatography was performed on silica gel 60
(230-400 mesh). Preparation of starting compounds is referred
to the Supporting Information. NMR spectra were recorded at
(t, J = 7.2 Hz, 3H, CH3), 4.52 (q, J = 7.2 Hz, 2H, CH2),
7.41 (s, 1H, CH); 13C NMR (CDCl3) δ 14.0 (CH3), 63.4
(CH2), 102.3 (CH), 157.6 (C), 158.3 (C), 165.6 (br s, CNO2);
IR (KBr) 1740 (s), 1552 (s), 1357 (s) cm-1. Anal. Calcd for
C6H6N2O5: C, 38.72; H, 3.25; N, 15.05. Found: C, 38.65; H,
3.24; N, 15.25.
Ethyl 4-(3-chloropropyl)-3-nitroisoxazole-5-carboxylate (15):
yield 120 mg (46%); pale yellow liquid; Rf 0.36 (petroleum
ether-EtOAc, 5:1); H NMR (CDCl3) δ 1.45 (t, J = 7.1 Hz,
3H, CH3), 2.08-2.15 (m, 2H, CH2), 3.18-3.24 (m, 2H, CH2),
3.63 (app t, J = 6.3 Hz, 2H, CH2), 4.51 (q, J = 7.1 Hz, 2H,
CH2); 13C NMR (CDCl3) δ 14.0 (CH3), 20.6, 31.5, 44.0, 63.2
(CH2), 118.5, 157.1, 158.4 (C), 162.1 (br s, CNO2); IR (film)
1730 (s), 1540 (s), 1335 (s) cm-1. Anal. Calcd for C9H11ClN2-
O5: C, 41.16; H, 4.22; N, 10.67. Found: C, 41.21; H, 4.13; N,
10.75.
400.1, 162.0, 100.6, and 28.9 MHz for H, 31P, 13C, and 14N,
1
respectively, at room temperature; the chemical shifts δ were
measured in ppm with respect to the solvent (1H: CDCl3, δ =
7.26 ppm, DMSO-d6, δ = 2.49 ppm, CD3OD, δ = 3.31 ppm;
13C: CDCl3, δ = 77.1 ppm, DMSO-d6, δ = 39.5 ppm, CD3OD,
δ = 49.0 ppm). Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, app = apparent, and br = broad), coupling
constants in hertz (Hz), and integration.
1
Typical Procedure for the Synthesis of 3-Nitroisoxazoles.
Triethylamine (0.28 mL, 2 mmol) was added dropwise to a
solution of tetranitromethane (0.3 mL, 2.5 mmol) in 1,4-dioxane
(2 mL) at 0 °C (ice bath). The reaction mixture was stirred for
5 min, and alkene (1 mmol) was added in one portion. Then the
cooling was removed, and the mixture was stirred either at room
temperature for 12 h (for isoxazoles 1-7) or at 70 °C for 2 h (for
isoxazoles 8-16 and 23-28). The solvent was removed under
reduced pressure, and the product was isolated by column
chromatography (petroleum ether-EtOAc, 10:1 for 2, 9, 15,
25, and 27; petroleum ether-EtOAc, 2:1 for 5 and 7;
CHCl3-MeOH for 23).
Diethyl 3-nitroisoxazol-5-ylphosphonate (23): colorless liquid;
Rf 0.67 (CHCl3-MeOH, 20:1); 1H NMR (CDCl3) δ 1.41 (t, J =
7.1 Hz, 6H, 2 ꢀ CH3), 4.29-4.34 (m, 4H, 2 ꢀ CH2), 7.27 (s, 1H,
CH); 13C NMR (CDCl3) δ 16.2 (d, J = 6 Hz, 2 ꢀ CH3), 64.6 (d,
J = 6 Hz, 2 ꢀ CH2), 104.2 (d, J = 19 Hz, CH), 159.5 (d, J = 211
Hz, C), 165.5 (br s, CNO2); 31P NMR (CDCl3) δ -0.12; IR
(KBr) 2987 (s), 1554 (s), 1355 (s), 1220 (s) cm-1. Anal. Calcd for
C7H11N2O6P: C, 33.61; H, 4.43; N, 11.20. Found: C, 33.35; H,
4.30; N, 11.15.
4-Methyl-3,5-dinitroisoxazole (25): yield 110 mg (63%); pale
yellow solid; mp 24-28 °C; Rf 0.81 (CHCl3); 1H NMR (CDCl3)
δ 2.71 (s, 3H, CH3); 13C NMR (CDCl3) δ 8.5 (CH3), 110.7 (C),
165.3 (br s, CNO2), 166.4 (br s, CNO2); IR (nujol) 1560 (s), 1315
(s) cm-1. Anal. Calcd for C4H3N3O5: C, 27.76; H, 1.75; N, 24.28.
Found: C, 27.90; H, 1.67; N, 24.10.
4-(3-Chloropropyl)-3,5-dinitroisoxazole (27): yield 120 mg
(51%); pale yellow liquid; Rf 0.42 (petroleum ether-EtOAc,
10:1); 1H NMR (CDCl3) δ 2.16-2.23 (m, 2H, CH2), 3.27-3.31
(m, 2H, CH2), 3.69 (app t, J = 6.1 Hz, 2H, CH2); 13C NMR
(CDCl3) δ 20.4 (CH2), 31.0 (CH2), 43.8 (CH2), 113.5 (C), 162.3
(br s, CNO2), 166.2 (br s, CNO2); IR (film) 1540 (s), 1345 (s)
cm-1. Anal. Calcd for C6H6ClN3O5: C, 30.59; H, 2.57; N, 17.84.
Found: C, 30.77; H, 2.56; N, 17.69.
Caution: Although we did not experience any problem in handling
tetranitromethane, full safety precautions should be taken due to its
toxicity and explosive nature.
1-(3-Nitroisoxazol-5-yl)propan-1-one (2): yield 150 mg (86%);
1
pale yellow solid; mp 53-54 °C; Rf 0.67 (CHCl3); H NMR
(CDCl3) δ 1.20 (t, J = 7.3 Hz, 3H, CH3), 3.08 (q, J = 7.3 Hz, 2H,
CH2), 7.34 (s, 1H, CH); 13C NMR (CDCl3) δ 7.0 (CH3), 33.1
(CH2), 100.4 (CH), 162.9 (C), 165.7 (br s, CNO2), 192.7 (CO); IR
(KBr) 1710 (s), 1546 (s), 1359 (s) cm-1. Anal. Calcd for
C6H6N2O4: C, 42.36; H, 3.55; N, 16.47. Found: C, 42.45; H,
3.54; N, 16.32.
(4S,7R)-3-Nitro-4,5-dihydro-4,7-epoxyoxepino[4,5-d]isoxazol-
8-one (5): yield 110 mg (53%); colorless solid; mp 110-112 °C; Rf
0.25 (petroleum ether-EtOAc, 2:1); 1H NMR (CDCl3) δ 4.09 (d,
J = 7.8 Hz, 1H, CH2), 4.20 (dd, J = 4.3, 7.8 Hz, 1H, CH2), 5.65
(s, 1H, CH), 6.02 (d, J = 4.3 Hz, 1H, CH); 13C NMR (CDCl3)
δ 68.6 (JCH = 156 Hz, CH2), 69.9 (JCH = 165 Hz, CH), 99.9
(JCH = 185 Hz, CH), 117.1 (C), 156.4 (CON), 158.4 (br s,
Acknowledgment. We thank the Division of Chemistry
and Materials Science RAS (Program N 4), the President’s
grant “Support of Leading Scientific School” N 5538.2008.3,
and the Russian Foundation for Basic Research (projects 07-
03-00685-a and 10-03-00820-a) for financial support of this
work. We are indebted to Dr. L. D. Konyushkin for a sample
of levoglucosenone.
CNO2), 179.0 (CO); IR (Nujol) 1730 (s), 1535 (s), 1340 (s) cm-1
.
Anal. Calcd for C7H4N2O6: C, 39.64; H, 1.90; N, 13.21. Found:
C, 39.81; H, 2.07; N, 13.29.
4-Methyl-3-nitroisoxazole-5-carbaldehyde (7): yield 70 mg
(49%); pale yellow liquid; Rf 0.76 (petroleum ether-EtOAc,
2:1); 1H NMR (CDCl3) δ 2.58 (s, 3H, CH3), 10.14 (s, 1H, CH);
13C NMR (CDCl3) δ 8.0 (CH3), 114.1 (C), 161.2 (C), 162.3 (br s,
Supporting Information Available: General experimental
procedures and complete characterization data, copies of
NMR spectra for all reaction products, and tables with the
information on the optimization of reaction conditions. This
material is available free of charge via the Internet at http://
pubs.acs.org.
CNO2), 184.4 (CO); IR (KBr) 1718 (s), 1542 (s), 1359 (s) cm-1
.
Anal. Calcd for C5H4N2O4: C, 38.47; H, 2.58; N, 17.95. Found:
C, 38.31; H, 2.60; N, 17.86.
3052 J. Org. Chem. Vol. 75, No. 9, 2010