Tetranitromethane as an efficient reagent for the conversion of epoxides into β-hydroxy nitrates

Article abstract of DOI:10.1016/j.tetlet.2008.04.050

A convenient regioselective method for the preparation of β-hydroxy nitrates based on the ring opening reaction of epoxides by tetranitromethane in the presence of triethylamine is described. A series of substituted β-hydroxy nitrates were obtained in high yields under mild conditions.

Full text of DOI:10.1016/j.tetlet.2008.04.050

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3935–3938
Tetranitromethane as an efficient reagent for the conversion
of epoxides into b-hydroxy nitrates
Yuliya A. Volkova a, Olga A. Ivanova a, Ekaterina M. Budynina a,
Elena B. Averina a,b,*, Tamara S. Kuznetsova a,b, Nikolai S. Zefirov a,b
a Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, 1-3, Moscow 119992, Russia
b IPhaC RAS, Severnyi Proezd, 1, Chernogolovka, Moscow Region, 142432, Russia
Received 19 February 2008; revised 21 March 2008; accepted 9 April 2008
Available online 12 April 2008
Abstract
A convenient regioselective method for the preparation of b-hydroxy nitrates based on the ring opening reaction of epoxides by
tetranitromethane in the presence of triethylamine is described. A series of substituted b-hydroxy nitrates were obtained in high yields
under mild conditions.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Tetranitromethane; Epoxides; b-Hydroxy nitrates
Nitrate esters are known to be a potentially useful class
of organic compounds, which have found widespread ther-
apeutic applications as drugs for the treatment of heart and
vascular diseases due to their NO-donor properties.1–3
Functionalized alkyl nitrates, especially b-hydroxy nitrates,
are utilized medicinally in the capacity of vasodilators.2
Also, the incorporation of an ONO2 group on a hydrocar-
bon skeleton is used in the design of many explosives.4,5
Moreover, in sugar chemistry the nitrato group is
employed as a protecting group, which can be removed eas-
ily by catalytic hydrogenation or under basic reaction con-
ditions.6 Therefore, the search for and development of new
efficient approaches to nitrate esters and their derivatives
are attracting extensive attention.
new method for the synthesis of b-hydroxy nitrates based
on the reaction of epoxides with cerium ammonium nitrate
in the presence of ammonium or tetra-n-butylammonium
nitrate as a source of nitrate ions was reported.9 However,
some methods are unsuitable for large-scale application
owing to their several limitations including the employment
of strongly acidic conditions7 or the need for expensive
reagents.8
We describe here a novel pathway to b-hydroxy nitrates
via epoxide ring opening with tetranitromethane (TNM),
which is known to be a smooth nitrating reagent in the syn-
thesis of nitro- and gem-dinitro substituted compounds,
nitroamines, etc.10 The trinitromethyl anion should play
the role of a nucleophilic agent to ring-open the epoxides.
Recently, we reported the first example of epoxide cleavage
by trinitromethyl anions generated from nitroform.11 Due
to the high polarity of the C–H bond, nitroform easily pro-
duces trinitromethyl anions without additional activation
under mild reaction conditions.12 In contrast, TNM was
found to be less active as a nucleophilic agent and does
not cleave an epoxide directly without activation with basic
reagents. Therefore, we employed triethylamine to increase
the nucleophilic properties of TNM.
There are several methods reported in the literature for
the synthesis of b-hydroxy nitrates. For example, b-
hydroxy nitrates are usually prepared in poor yields by
treating epoxides with concentrated nitric acid7 or via the
nitration of halohydrins with silver nitrate.8 Recently, a
*
Corresponding author. Tel./fax: +7 495 9393969.
E-mail address: elaver@org.chem.msu.ru (E. B. Averina).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.050

3936
Y. A. Volkova et al. / Tetrahedron Letters 49 (2008) 3935–3938
Table 1
HO
R1
ONO2
R2
O2NO
R1
OH
R2
O
Et3N
+
C(NO2)4
+
1,4-dioxane
20 ºC
R1
R2
1a-l
2a-i,l
3f,g,j,k
Entry
1
Epoxide 1
R1
H
R2
H
Reaction time, days
7
b-Hydroxy nitrate 2, 3
Yield 2, 3a (%)
HO
ONO2
a
93
2a
HO
ONO2
2
3
4
b
c
d
Me
Me
7
5
5
67
80
85
2b
HO
HO
ONO2
–(CH2)3–
2c
ONO2
–(CH2)4–
2d
HO
ONO2
5
e
–(CH2)6–
7
88
2e
HO
ONO2
O2NO
OH
6
f
Me
H
7
87c
2f
3f
65/35b
C6H13
C6H13
OH
ONO2
7
8
9
g
h
i
C6H13
H
H
H
7
5
6
85c
ONO2
OH
2g
80/20b
3g
Cl
ONO2
ClCH2
83
OH
2h
PhO
ONO2
PhOCH2
91
OH
2i

Y. A. Volkova et al. / Tetrahedron Letters 49 (2008) 3935–3938
3937
Table 1 (continued)
Entry
Epoxide 1
R1
Ph
R2
H
Reaction time, days
1
b-Hydroxy nitrate 2, 3
Yield 2, 3a (%)
ONO2
10
j
80
OH
3j
ONO2
Br
11
k
p-Br–C6H4
H
H
3
7
75
47
OH
3k
HO
OH
O
12
l
O2NO
ONO2
2l
a
Isolated yields for 2, 3.
b
c
The ratio of regioisomers was determined by 1H NMR.
Yield refers to both isomers.
We examined the reactions of epoxides 1a–l with TNM
the final b-hydroxy nitrates 2 after solvolysis (for regio-
isomer 2). The same type of nitronate transformation into
alcohols has been described earlier.15
High regioselectivity was observed in the reactions of
epoxides 1h,i with TNM, as a result, only regioisomers
2h,i bearing a primary ONO2 group were obtained. Such
a high regioselectivity may be explained in terms of anchi-
meric assistance by the neighbouring group (ClCH2 or
PhOCH2, entries 8 and 9) during the opening of oxonium
cation 4.
Unexpected results were obtained in the reactions of sty-
rene oxides 1j,k with TNM:b-hydroxy nitrates 3j,k bearing
a secondary ONO2 group were the products. It may be
assumed that in these cases the cleavage of the oxonium
cation 4 is accompanied by phenonium ion formation as
described previously.14 Attack of the trinitromethyl anion
at the less substituted methylene group of the phenonium
ion takes place leading to 3j,k exclusively.
in the presence of triethylamine in 1,4-dioxane at room
temperature.13 The results obtained are summarized in
Table 1.
We found that the reaction of epoxides 1a–l with TNM
led smoothly to b-hydroxy nitrates 2a–l in high yields.
Symmetrical di-substituted epoxides 1b–e (entries 2–5)
afforded b-hydroxy nitrates as single diastereomers in
accordance with the Furst-Plattner rule under which the
cleavage of the epoxide ring by nucleophiles affords the
products with trans configurations.14 The reactions of
unsymmetrical epoxides 1f and 1g with TNM led to the
mixtures of two regioisomers in 65:35 and 80:20 ratios,
respectively, in which the primary nitrates prevailed
(entries 6 and 7). The reactions of epoxides 1h–l were found
to be highly regioselective and only one isomer, either 2 or
3 was obtained (entries 8–12).
The mechanism of the process can be presented as fol-
lows (Scheme 1, Eqs. 1 and 2). The key stage of the reaction
is the O-alkylation of oxonium cation 4 by the trinitrom-
ethyl anion affording unstable nitronate 5, which gives
High regioselectivity was also observed in the reaction
of the butadiene diepoxide 1l with TNM in the presence
of triethylamine (in a 1:4:2 molar ratio). Erythritol 1,4-
-
C(NO2)4 + Et3N
[Et3NNO2]+ + C(NO2)3
(1)
C(NO2)2
N
NO2
HO
R1
ONO2
R2
O
O
-
O
O
C(NO2)3
[Et3NNO2]+
-Et3N
Solvent
(2)
ONO2
O
-alkylation
R1
R1
R2
R1
R2
2
1
4
R2
5
Scheme 1.

3938
Y. A. Volkova et al. / Tetrahedron Letters 49 (2008) 3935–3938
7. (a) Nichols, P. L.; Magnusson, A. B.; Ingham, J. D. J. Am. Chem.
Soc. 1953, 75, 4255; (b) Ingham, J. D.; Nichols, P. L. J. Am. Chem.
Soc. 1954, 76, 4477.
8. Marans, N. S.; Zelinski, R. P. J. Am. Chem. Soc. 1950, 72, 5330.
9. Iranpoor, N.; Salehi, P. Tetrahedron 1995, 51, 909.
dinitrate 2l was the only product of this reaction (Table 1,
entry 12).
The structures of all the synthesized nitrates were estab-
1
lished unequivocally by H and 13C NMR spectroscopy
and elemental analysis.
10. (a) Nielsen, A. T. Nitrocarbons; Wiley: New York, 1995; pp 1–76 ; (b)
Rathore, R.; Kochi, J. K. J. Org. Chem. 1996, 61, 627; (c) Baum, K.;
Berkowitz, P. T.; Grakauskas, V.; Archibald, T. G. J. Org. Chem.
1983, 48, 2953; (d) Mayants, A. G.; Pyreseva, K. G.; Gordeichuk, S.
S. Zh. Org. Khim. (Russ.) 1986, 22, 2120; . Russ. J. Org. Chem. (Engl.
Transl.) 1986, 22, 1900.
11. (a) Volkova, Yu. A.; Ivanova, O. A.; Budynina, E. M.; Averina, E. B.;
Kuznetsova, T. S.; Zefirov, N. S. Tetrahedron 2008, 64, 3548–3553; (b)
Volkova, Yu. A.; Ivanova, O. A.; Averina, E. B.; Budynina, E. M.;
Kuznetsova, T. S.; Zefirov, N. S. Dokl. Akad. Nauk (Russ.) 2008,
419, 500–503.
The method suggested for the nitration of epoxides with
TNM has a remarkable advantage: even simple epoxides
such as 1a,f did not polymerize under the action of
TNM, although this problem arises when other nitrating
agents are employed for epoxide opening.
In conclusion, the good regioselectivity, high yields of
products and the mildness of the reaction conditions, sim-
plicity of the work-up and availability of the reagents make
this method an efficient and useful alternative to other
methods for the preparation of b-hydroxy nitrates.
Caution: Although we have not met any problems in
handling these compounds, full safety precautions should
be taken due to their potentially explosive nature.
12. The chemistry of the nitro and nitroso groups; Feuer, H., Ed.;
Part II, R. E. Krieger Publishing Company: New York, 1981; p
292.
13. General procedure: Triethylamine (0.14 ml, 1 mmol) after cooling in
an ice bath was added gradually to a solution of TNM (0.22 ml,
2 mmol) in 1,4-dioxane (2 ml). The mixture was stirred for 5 min with
cooling, and then the corresponding epoxide (1 mmol) was added.
The resulting mixture was stirred at room temperature for the
specified time according to Table 1. TLC and NMR spectra were used
to monitor the progress of the reactions. The solvent was evaporated
and the product was isolated by column chromatography (hexane–
ethyl acetate, 5:1).
Acknowledgements
We thank the Division of Chemistry and Materials Sci-
ence RAS (Program N 1.5), the President’s grant ‘Support
of Leading Scientific School’ N 5538.2008.3 (academician
N.S. Zefirov) and the Russian Foundation for Basic Re-
search (Project 07-03-00685-a) for financial support of this
work.
2-Hydroxyoctyl nitrate (2g), major isomer. Yellow oil, Rf 0.1 (CHCl3).
3
1H NMR (400 MHz, CDCl3): d 0.89 (t, J = 7.1 Hz, 3H, CH3), 1.30–
1.52 (m, 10H), 2.22 (br s, 1H, IH), 3.91–3.96 (m, 1H, CH), 4.35 (dd,
2J = 11.1, 3J = 7.6 Hz, 1 H, CH2), 4.50 (dd, 2J = 11.1, 3J = 3.0 Hz,
1H, CH2). 13C NMR (100 MHz, CDCl3): d 14.0 (CH3), 22.6, 25.2,
29.1, 31.7, 33.2 (CH2), 68.3 (CH), 76.8 (CH2).
1-Hydroxyoctan-2-yl nitrate (2g), minor isomer. Yellow oil, Rf 0.1
(CHCl3). 1H NMR (400 MHz, CDCl3): d 0.89 (t, 3J = 7.1 Hz, 3H,
CH3), 1.30–1.68 (m, 10H), 2.25 (br s, 1H, IH), 3.74 (dd, 2J = 12.7,
3J = 6.3 Hz, 1 H, CH2), 3.83 (dd, 2J = 12.7, 3J = 3.2 Hz, 1H, CH2),
5.09–5.15 (m, 1H, CH). 13C NMR (100 MHz, CDCl3): d 14.0 (CH3),
22.5, 25.2, 29.0, 31.6, 33.2, 62.5 (CH2), 84.9 (CH).
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