A new method for functionalizing α,γ-dinitro compounds at the β-position: Application to the cyclization of β-alkoxy-α, γ-dinitro compounds

Article abstract of DOI:10.1002/poc.3227

Treatment of 2,4-dinitropentane with bromine and sodium methoxide in methanol, affords formation of an ether product, 2,4-dibromo-3-methoxy-2,4- dinitropentane, in 59% yield as a mixture of three diastereomers. This observation has led to a general synthesis of 3-alkoxy-2,4-dibromo-2,4- dinitropentanes, obtained in 75-86% yield from 2,4-dibromo-2,4-dinitropentane as the preferred reactant. 4-Bromo-2,4-dinitro-2-pentene has been identified as an intermediate in these reactions. The nitroalkene has been isolated and undergoes conjugate addition with alkoxides to afford the same ether products after brominative work-up. The nitroalkene undergoes conjugate addition with sodium azide to give 3-azido-2,4-dibromo-2,4-dinitropentane in 38% yield as a mixture of two isomers in which the (R*,R*) isomer predominates. Sequential treatment of 2,4-dibromo-2,4-dinitropentane with sodium methoxide followed by sodium iodide and acetic acid gives 3-methoxy-2,4-dinitropentane in 63% yield, the overall product of simple methoxylation of 2,4-dinitropentane. However, attempted complete debromination of 2,4-dibromo-3-methoxy-2,4- dinitropentane with excess sodium iodide and acetic acid results only in monodebromination to give 2-bromo-3-methoxy-2,4-dinitropentane in 86% yield. Likewise, 2-bromo-3-ethoxy-2,4-dinitropentane is formed in 93% yield from the ethoxy analog. A mechanistic rationale is offered for condition-specific removal of the second Br atom in these reactions. Treatment of 3-methoxy-2,4- dinitropentane with potassium acetate/iodine in dimethyl sulfoxide affords formation of 4,5-dihydro-3,4-dimethyl-3-methoxy-4-nitroisoxazole 2-oxide in 30% yield as a single diastereomer. Conversion of 2-bromo-3-methoxy-2,4- dinitropentane in 15% yield to 4,5-dihydro-3,4-dimethyl-3-methoxy-4- nitroisoxazole 2-oxide is also possible by using potassium acetate in dimethyl sulfoxide. The mechanistic pathways for formation of 4,5-dihydro-3,4-dimethyl-3- methoxy-4-nitroisoxazole 2-oxide apparently involve unstable 3-methoxy-1,2-dimethyl-1,2-dinitrocyclopropane as the common intermediate. Similarly, 2-bromo-3-ethoxy-2,4-dinitropentane affords 4,5-dihydro-3-ethoxy-3,4- dimethyl-4-nitroisoxazole 2-oxide in 13% yield. Copyright 2013 John Wiley & Sons, Ltd. Ethers were obtained from the reaction of 2,4-dibromo-2,4- dinitro-pentane, NaOR, and Br₂. Selective removal of either one or two Br atoms from the products is described. Cyclization of 2,4-dinitro-3- methoxy-pentane gave a 4,5-dihydroisoxazole-2-oxide and not a cyclopropane. Copyright

Full text of DOI:10.1002/poc.3227

Research Article
Received: 20 July 2013,
Revised: 19 August 2013,
Accepted: 23 August 2013,
Published online in Wiley Online Library: 23 September 2013
(wileyonlinelibrary.com) DOI: 10.1002/poc.3227
A new method for functionalizing α,γ-dinitro
compounds at the β-position: application
to the cyclization of β-alkoxy-α,
γ-dinitro compounds
Peter A. Wadea*, Christopher E. Castilloa and Nicholas Paparoidamisa
Treatment of 2,4-dinitropentane with bromine and sodium methoxide in methanol, affords formation of an ether product,
2,4-dibromo-3-methoxy-2,4-dinitropentane, in 59% yield as a mixture of three diastereomers. This observation has led to a
general synthesis of 3-alkoxy-2,4-dibromo-2,4-dinitropentanes, obtained in 75-86% yield from 2,4-dibromo-2,4-
dinitropentane as the preferred reactant. 4-Bromo-2,4-dinitro-2-pentene has been identified as an intermediate in these
reactions. The nitroalkene has been isolated and undergoes conjugate addition with alkoxides to afford the same ether
products after brominative work-up. The nitroalkene undergoes conjugate addition with sodium azide to give
3-azido-2,4-dibromo-2,4-dinitropentane in 38% yield as a mixture of two isomers in which the (R*,R*) isomer predomi-
nates. Sequential treatment of 2,4-dibromo-2,4-dinitropentane with sodium methoxide followed by sodium iodide and
acetic acid gives 3-methoxy-2,4-dinitropentane in 63% yield, the overall product of simple methoxylation of
2,4-dinitropentane. However, attempted complete debromination of 2,4-dibromo-3-methoxy-2,4-dinitropentane with
excess sodium iodide and acetic acid results only in monodebromination to give 2-bromo-3-methoxy-2,4-dinitropentane
in 86% yield. Likewise, 2-bromo-3-ethoxy-2,4-dinitropentane is formed in 93% yield from the ethoxy analog. A
mechanistic rationale is offered for condition-specific removal of the second Br atom in these reactions. Treatment
of 3-methoxy-2,4-dinitropentane with potassium acetate/iodine in dimethyl sulfoxide affords formation of 4,5-dihydro-
3,4-dimethyl-3-methoxy-4-nitroisoxazole 2-oxide in 30% yield as a single diastereomer. Conversion of 2-bromo-3-
methoxy-2,4-dinitropentane in 15% yield to 4,5-dihydro-3,4-dimethyl-3-methoxy-4-nitroisoxazole 2-oxide is also possible
by using potassium acetate in dimethyl sulfoxide. The mechanistic pathways for formation of 4,5-dihydro-3,4-dimethyl-3-
methoxy-4-nitroisoxazole 2-oxide apparently involve unstable 3-methoxy-1,2-dimethyl-1,2-dinitrocyclopropane as the
common intermediate. Similarly, 2-bromo-3-ethoxy-2,4-dinitropentane affords 4,5-dihydro-3-ethoxy-3,4-dimethyl-4-
nitroisoxazole 2-oxide in 13% yield. Copyright © 2013 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: debromination; methoxylation; nitro; nitronate; push–pull cyclopropane
trans-1,2-dinitrospiro[2.2]pentane was also reported.[3] These
INTRODUCTION
compounds have potential uses as energetic materials.[4] Here,
The introduction of a new group at the β-site to an existing nitro
group is an important synthetic transformation not readily
accomplished. Nitroalkanes usually undergo reactions at the
α-position (i.e., the carbon bearing the nitro group) rather than
the β-position. There are, however, some known exceptions
where reaction does occur at the β-position. For instance,
heptanitrocubane undergoes substitution at the one remaining
unsubstituted C atom, a site that is located β to three nitro
groups.[1] Substitution of the H atom at this site by an eighth
nitro group is a key synthetic transformation in the synthesis
of octanitrocubane. Nevertheless, it is uncommon for H atom
substitution at the β-site of nitro compounds to occur readily.
Here, a new method for introducing alkoxy groups at the
central C atom of 2,4-dinitropentane is reported. This new
method amounts to substitution of an H atom located β to
two nitro groups.
we describe the corresponding cyclizations of 3-alkoxy-2,4-
dinitropentane derivatives. These reactions, however, take a much
different course than cyclization of simple 1,3-dinitro compounds.
RESULTS
During a routine bromination of 2,4-dinitropentane in the pres-
ence of sodium methoxide, we observed a surprising result.
The main product formed was the ether 2a–c, isolated in 59%
yield as a mixture of three separable diastereomers. (Scheme 1).
During the course of bromination, an H atom located β to both
nitro groups has been replaced by a methoxy group.
* Correspondence to: Peter A. Wade, Department of Chemistry, Drexel University,
Philadelphia, PA 19104, USA.
E-mail: wadepa@drexel.edu
Several methods for the cyclization of 1,3-dinitro compounds to
trans-1,2-dinitrocyclopropanes were previously reported.[2] Thus,
2,4-dinitropentane (1) can be converted to trans-1,2-dimethyl-1,2-
dinitrocyclopropane. A similar cyclization approach to synthesis of
a P. A. Wade, C. E. Castillo, N. Paparoidamis
Department of Chemistry, Drexel University, Philadelphia, PA 19104, USA
J. Phys. Org. Chem. 2014, 27 38–46
Copyright © 2013 John Wiley & Sons, Ltd.

β-ALKOXY-α,γ-DINITRO COMPOUNDS
(5a–b) is readily preparable. It was therefore
possible to probe pathway (b) as a potential
route to the observed ether products.
Initially, dibromide 5a–b was prepared by
employing sodium n-butoxide as the base in
the bromination reaction.[2] Here, the main
product was 5a–b, although a small amount
of easily separated side product (likely the
ether but this was not confirmed) was also
present. Subsequently, conditions for bromi-
nation with sodium methoxide as base lead-
ing to dibromide 5a–b were developed and
were thereafter routinely employed.
When dibromide 5a–b is treated with so-
dium methoxide followed by bromine, ether
2a–c is obtained in 83% yield (Table 1). Thus,
pathway (b) is confirmed as a route to the
ether products. However, pathway (a) might
be a minor competing reaction when 2,4-
dinitropentane (1a–b) is the starting mate-
rial: this has not been excluded as a possibil-
ity. Similarly, treatment of 5a–b with other
sodium alkoxides in the corresponding alco-
hol followed by bromine gives the ether
Scheme 1. Pathways for formation of 2,4-dibromo-3-methoxy-2,4-dinitropentane (2a–b)
It seemed likely that formation of ether 2a–c involved a
nitroalkene intermediate formed by bromination and subsequent
dehydrobromination. Conjugate addition reactions of nitroalkenes
do indeed lead to β-functionalized nitro compounds.[5] However, it
was not clear whether monobromination or dibromination
occurred prior to nitroalkene formation. Thus, either nitroalkene
4 or nitroalkene 6 could be the precursor for incorporation of
the methoxy group. Initially, pathway (a) involving conversion of
2-bromo-2,4-dinitropentane (3) to nitroalkene 4 was considered
more likely. It was thought that conjugate addition to nitroalkene
4 was more plausible than conjugate addition to the more
hindered nitroalkene 6. Conjugate additions are usually quite
sensitive to the steric environment at the site undergoing attack,
and therefore, nitroalkene 6 seemed unlikely as the intermediate
in ether formation. However, 2,4-dibromo-2,4-dinitropentane
products 7–9 in 75–90% yield. This method is preferential to
direct reaction of 1a–b that also gives ethers 7–8, because it is
generally cleaner and gives better yields of the ether products.
The nitroalkene 6a–b can be isolated as a separable mixture of
E and Z isomers. Under optimized conditions using sodium
ethoxide as base and quenching with bromine after 7.5 min,
the E isomer 6a is obtained in 30% yield. The E isomer both
predominates and is more stable to storage, although early in
the reaction, a significant amount of Z isomer 6b is present.
Using a reaction time of only 15 s, the Z isomer 6b is obtained
in 3% yield accompanied by the E isomer in 5% yield. Structure
assignments are based in part by analogy to the known com-
pounds (E)-2-nitro-2-butene and (Z)-2-nitro-2-butene.[6] The vinyl
proton signals for 2-nitro-2-butene are at δ 7.20 for the E isomer
and δ 5.87 for the Z isomer, respectively. Nitroalkene isomers
Table 1. Products obtained from the reactions of 2,4-dibromo-2,4-dinitropentane (5a-b) and (E)-4-bromo-2,4-ditropentene (6a)
with NaX/bromine
Isomer ratios from 5a–b (from 6a)
Product
X
Yield, % from 5a–b
Yield, % from 6a
R*, R*
First meso
11 (13)
Second meso
6 (15)
2a–c
OMe
83a
72b
83 (72)
2a–c
7a–c
8a–c
9a–b
10a–c
11a–b
OMe
OEt
OPr
OCH2Ph
OPr-i
N3
59c
86b
90b
75d
0
40
85 (81)
75
5
55
6 (8)
12
75b
9 (10)
13
17
(29)
13 (40)
83
18b
38b
(42)
(29)
32e
87 (60)
b
d
e
a0.1 M NaOMe. 0.1-0.24 M NaX. c1.7 M NaOMe. 0.8 M NaOCH2Ph. 0.15 M NaN3 and 0.03 M NaOEt
J. Phys. Org. Chem. 2014, 27 38–46
Copyright © 2013 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/poc

P. A. WADE, C. E. CASTILLO AND N. PAPAROIDAMIS
6a–b exhibit somewhat more deshielded vinyl proton signals at
δ 7.57 and δ 6.34, respectively.
The kinetic equation log k = sN (E + N) has been used to correlate
nucleophile reactivity in conjugate addition reactions of
benzylidenemalonitriles.[8] The equation should be applicable to
conjugate addition reactions of 6a, at least for semi-quantitative
nucleophile comparison. In the equation, sN = a nucleophile-
dependent sensitivity factor, N = a nucleophilicity parameter, and
E = an electrophilicity parameter. Of paramount importance are
the pertinent values of N. The nucleophilicity parameters of
methoxide ion,[9] N = 14.51, and azide ion,[10] N = 14.54, are very
nearly equal (both values determined in 91:9 methanol–
acetonitrile). Sodium ethoxide has a slightly lower nucleophilicity
parameter, N = 16.08,[9] than does azide ion, N = 16.30,[10] (both
values in 91:9 ethanol–acetonitrile). It is therefore not surprising
that both alkoxide ions compete favorably with azide ion.
Considering the steric environment at C-3, the terminal C atom
of the conjugated system present in 6a, the linear azide ion might
be expected to perform somewhat better than less approachable
nonlinear alkoxide ions. Nevertheless, alkoxide ions proved to be
the better nucleophiles.
Nitroalkene 6a also undergoes reaction with alkoxides in the cor-
responding alcohols producing the same products after subse-
quent bromination during work-up as obtained from 5a–b. In
one case, reaction with sodium 2-propoxide, nitroalkene 6a
gives the ether product 10a–c in 18% yield, whereas 2,4-
dibromo-2,4-dinitropentane (5a–b) fails to give any 10a–c. Failure
to obtain 10a–c from 5a–b is attributed to failure of the elimination
step. The somewhat hindered base is apparently unable to
deprotonate the hindered central C atom of 5a–b.
The major diastereomer (2a and 7a–11a) produced in the
previous reactions is typically the (R*, R*) diastereomer (an enantio-
mer pair). Isomer structure assignment is based on the four sepa-
rate 13C NMR signals attributable to C-2/C-4 (diastereotopic) and
C-1/C-5 (diastereotopic) C atoms. There are also separate signals at-
tributable to the C 1 and C 5 methyl protons in the 1H NMR spec-
trum. The remaining meso isomers, (R,r,S) diastereomers and/or
(R,s,S) diastereomers, give just one 13C NMR signal for the C-2/C-4
enantiotopic atom pair and another signal for the C-1/C-5
enantiotopic atom pair. In each case, a single signal is present at-
tributable to the C-1 and C-5 methyl protons in the 1H NMR spec-
trum. However, the assignment of minor isomers as either the (R,r,
S) diastereomer or the (R,s,S) diastereomer is not unambiguous and
has not been made.
Although the (R*, R*) isomer is typically major from reac-
tions of both 5a–b and 6a, the isomer ratios are somewhat
different. The preference for the (R*, R*) isomer is somewhat
greater (2a/2b/2c 83:11:06, respectively) when 5a–b is used
as the starting material than when nitroalkene 6a is
employed (2a/2b/2c 72:13:15, respectively). There is also a marked
sodium methoxide concentration dependence for reaction of
5a–b. Concentrated methoxide gives a significantly different
isomer ratio (2a/2b/2c 40:05:55, respectively) compared with reac-
tion with dilute methoxide (2a/2b/2c 83:11:06, respectively). Thus
2c (one of the meso isomers) becomes the predominant product
from reaction of 5a–b with concentrated sodium methoxide. The
reason for this concentration dependence is unclear. Perhaps the
ratio favoring meso isomer 2c at high base concentration is
the kinetic product ratio, whereas the ratio with more dilute
base is the ratio after equilibration of the nitronate products
present before quenching with bromine.[7]
Reaction of nitroalkene 6a with sodium azide in aqueous
ethanol eliminates the competition for ether formation, allowing
11a-b to be isolated free from ether products. Even so, reaction
is slow and the best yield of 11a–b attainable is 38%.
Reaction of nitroalkene 6a with either sodium benzenethiolate or
sodium ethanethiolate gives none of the expected thioether prod-
uct. Thiolates are generally much better nucleophiles than alkox-
ides, so these results are unexpected. Sodium cyanide also fails
to give a nitrile product on reaction with 6a. Two possible expla-
nations have been considered, both centered on preferential re-
activity at the geminal bromonitro site rather than the C,C
double bond site. Possibly the bromonitro site is debrominated
giving nitronate formation. Geminal bromonitro compounds
transfer the Br atom to thiolate anions[11] and carbanions.[12,2]
Iodide ion also displaces bromine from geminal bromonitro
compounds, a reaction that will be described later. Displace-
ment of bromine from 6a would give a nitronate that is presum-
ably unstable based on the absence of identifiable products. It is
also possible that single-electron transfer at the bromonitro site
could occur. Geminal bromonitro compounds readily accept a
single electron from either thiolates[11] or cyanide,[13] although
synthetically useful reactions are normally carried out in polar
aprotic solvents.
A broader range of nucleophiles has been
examined for the functionalization of
dibromide 5a–b and nitroalkene 6a. This has
met with only limited success. When 5a–b is
treated with a solution of sodium ethoxide
and sodium azide followed by bromine, a
mixture of the azide 11a–b (two diastereo-
mers) and ethyl ether 7a–c is obtained. Azide
11a–b is the minor product, obtained as a
45:55 mixture with the ether. The azide minor
diastereomer 11b is obtained pure in 5%
yield, but the major diastereomer 11a cannot
be chromatographically separated from the
ether. Using sodium methoxide as the base,
azide competition with ether formation is less
successful. Here the product ratio is 28:72
azide 11a–b/ether 2a–c. It is thought that
the ether/azide ratios in these reactions
reflect the difference in nucleophilicity of the
salts involved.
Scheme 2. Debromination of 3-alkoxy-2,4-dibromo-2,4-dinitropentanes 2a–c and 7a–c
wileyonlinelibrary.com/journal/poc
Copyright © 2013 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2014, 27 38–46

β-ALKOXY-α,γ-DINITRO COMPOUNDS
Treatment of ether 2a–c with sodium iodide in methanolic
acetic acid leads to mono debromination and formation of
2-bromo-3-methoxy-2,4-dinitropentane (15a–c) in 81% yield as
an inseparable mixture of diastereomers. Four diastereomers are
possible, but only three were detected by nuclear magnetic reso-
nance (NMR). Of these three, one is major (81:13:6 ratio, Scheme 2).
Ether 7a–c behaves similarly to give 2-bromo-2,4-dinitro-3-
ethoxypentane (16a–c) in 93% yield again as an inseparable
mixture of three discernible diastereomers where one predomi-
nates (77:15:08 ratio). Surprisingly, neither of the monobromo
ethers undergoes a second debromination with sodium iodide.
Treatment of 2,4-dibromo-2,4-dinitropentane (5a–b) proceeds
similarly to give 2-bromo-2,4-dinitropentane (3) as a 5:1 mixture
of two diastereomers and without removal of the second bro-
mine atom. However, successive treatment of 5a–b with sodium
methoxide and excess methanolic sodium iodide/acetic acid at an
appropriate concentration affords 3-methoxy-2,4-dinitropentane
13a–b as the major product (13a/13b/15 52:36:11 ratio) from
which 13a–b can be isolated as a 66:34 mixture. Only two of the
three theoretically possible diastereomers have been observed,
the racemic diastereomer 13a and one of the two meso diastereo-
mers 13b for which the configuration at C-3 was not readily
assignable by NMR. In conjunction with the initial dibromination
of 2,4-dinitropentane, this sequence provides an overall method
for methoxylating 2,4-dinitropentane at the 3-position.
Figure 1. Electron donation to the C–Br σ* orbital
the nitro compound 15a–c, it is intercepted by an iodide ion
ultimately affording the nonbromo ether 13a–b. However, if
14a tautomerizes first, the second debromination fails to occur.
Consistent with this explanation, it is possible to favor formation
of monobromo ether 15a–c or nonbromo ether 13a-b simply by
manipulating the amount of acetic acid present (Table 2). The initial
results where 14 equivalents of acetic acid were employed are
optimum for formation of 13a–b. If either less acid (9 equivalents)
or more acid (24 equivalents or above) is employed, 15a–c
becomes the major product. These results indicate a window
where the conversion of nitronic acid is sufficiently slow for iodide
ion to intercept the nitronic acid and displace the second Br atom.
Low acid concentration would appear to favor a significant con-
centration of nitronate 12a in equilibrium with 14a, a base-cata-
lyzed tautomerization process for rapid formation of 15a–c
(Scheme 3). At high acetic acid concentrations, protonation of
14a would lead to rapid formation of 15a–c. If, indeed, the rate
of nitronic acid tautomerization can be controlled by the amount
of acetic acid present, general application to the synthesis of
nitronic acids might be possible. However, that matter has not
yet been investigated.
The pathway followed for complete debromination is unusual.
Monobromo ether 15a–c cannot lie on the pathway to 13a–b
because it is not converted to 13a–b by treatment with excess
sodium iodide/acetic acid. We offer the following series of events
as
a
probable explanation. Dehydrobromination of 5a–b
Simple α-bromonitro compounds are readily debrominated by
sodium iodide/acetic acid. The nonreactivity of monobromo dinitro
compounds is exceptional and seems inconsistent with a mechanis-
tic pathway involving simple nucleophilic displacement of bromine
by iodide. A stereoelectronic effect whereby the second nitro group
donates electron density to the Br-lobe of the C–Br σ* orbital has
been considered (Fig. 1). Such donation would presumably protect
bromine from displacement by iodide ion. However, the infrared
stretching frequencies for 3 and 15–16 assigned to the nitro groups
are not atypical. Significant electron donation from the nitro group
might be expected to alter these frequencies. Further study is
underway to elucidate the actual pathway.
One goal of the current project was to obtain starting materials
for the synthesis of functionalized dinitrocyclopropanes. Pursuant
to that goal, we have now developed improved methods for
preparation of trans-1,2-dimethyl-1,2-dinitrocyclopropane (17)
(Scheme 4). Treatment of 2,4-dinitropentane (1a–b) with a DMSO
solution of potassium acetate/iodine affords 17 in 56% yield.
Conversion of 2,4-dinitropentane (1a-b) to 17 in 36% yield using
dimsylsodium/iodine was previously reported.[2] Treatment of
dibromide 5a-b with sodium iodide/dimethyl sulfoxide (DMSO)
gives cyclopropane 17 in 25% yield. We previously reported[2]
followed by conjugate addition should give the nitronate 12a
as an intermediate. Reaction of 12a with methanolic sodium
iodide/acetic acid should give initially the kinetic protonation
product, nitronic acid 14a. Before 14a is able to tautomerize to
Table 2. Debromination dependence on quantity of acetic
acid
HOAc mol equiva
13a
13b
15a–c
9
<5
52
<2
36
>93
11
14
20
24
57
108
34
21
45
19
16
65
<5
<2
<2
<2
>93
>96
aReaction of 5a–b and NaOMe in MeOH/Et2O followed by
NaI/HOAc.
Scheme 3. Tautomerization of 14a
J. Phys. Org. Chem. 2014, 27 38–46
Scheme 4. New methods of preparing 1,2-dimethyl-1,2-dinitrocyclopropane
Copyright © 2013 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/poc

P. A. WADE, C. E. CASTILLO AND N. PAPAROIDAMIS
Scheme 7. Selected 13C chemical shifts
Scheme 5. Ring-opening reactions of push–pull nitrocyclopropane
derivatives
Scheme 8. Proposed ring opening of 23a
two different ethyl ether starting materials (Scheme 6). Treatment
of 13a–b with potassium acetate/iodine in DMSO, treatment of
15a–c with potassium acetate/DMSO, and treatment of 2a–c
with sodium iodide/DMSO all gave 22a as the major component
of the crude product. No other new product has been identified
in these reactions. Treatment of 16a–c with potassium acetate/
DMSO and treatment of 7a–c with sodium iodide/DMSO give
22b as the major material present in the crude product. Here,
too, no other new product has been identified. These cyclic
nitronates are relatively unstable and consequently difficult to
characterize. During chromatographic purification on silica gel,
they decompose, although rapid flash chromatography does
afford a low yield of substantially purified samples (85% and 90%
pure by 1H NMR, respectively) of 22a–b.
Scheme 6. Reactions generating 4,5-dihydroisoxazole-2-oxides
Two different routes were considered that could result in the
formation of cyclic nitronate products. Formation of 22a–b likely
requires the intermediacy of β,β’-dinitrocyclopropyl ethers
23a–b. Direct internal O-alkylation of the nitronate intermedi-
ates would produce the isomeric cyclic nitronates 24a–b. The
structure assignment for nitronates 22a–b rests on a combination
of typical spectral data. Thus, compounds 22a–b each have a
strong IR absorption at 1652 cmÀ1 assigned as the nitronate C,N
double bond stretching frequency based on published values for
related five-member cyclic nitronates.[17] Additional IR bands
characteristic of a nitro compound are present for compounds
the conversion of 5a–b in 25% yield to 17 by using lithium
2-nitropropanate/DMSO. That procedure, however, requires
separation of 2,3-dimethyl-2,3-dinitrobutane formed as the side
product. Is it then possible that the ethers 2a–c, 7a–c, and 13a–b
can be converted similarly to β,β’-dinitrocyclopropyl ethers by
any of these methods?
There is reason to doubt that β,β’-dinitrocyclopropyl ethers
would be stable compounds because of the push–pull vicinal sub-
stituents. In a prior study, Pollitzer et al. reported computational
results that indicate high instability for β-nitrocyclopropyl amine
18.[14] They concluded that facile ring cleavage will occur affording
conversion of 18 to open-chain zwitterion 19 (Scheme 5). One can
imagine a similar cleavage process for β,β’-dinitrocyclopropyl
ethers, although this cleavage may be slowed by the reduced
stability of an oxonium zwitterion relative to the corresponding
ammonium zwitterion.
While our work was in progress, a computational study was pub-
lished by Schneider and Werz indicating that β-nitrocyclopropyl
ether 20 is unstable and should spontaneously convert to the
cyclic nitronate 21.[15] Such rearrangements are known to occur
both thermally and by acid catalysis.[16] Finally, an unsuccessful
attempt to prepare β-nitrocyclopropyl ethers via rhodium cata-
lyzed cycloaddition of α-nitrodiazo compounds to vinyl ethers
has been reported.[16]
Attempts to prepare and isolate the β,β’-dinitrocyclopropyl
ether 23a did prove unsuccessful. However, the cyclic nitronate
22a is obtained from three different methyl ether starting
materials and the corresponding nitronate 22b is obtained from
1
22a–b. The H NMR and 13C NMR data are consistent with the
structure assignments for 22a–b. In particular, the observed 13C
NMR chemical shifts for CH signals attributed to C-5 (δ 100.7 and
δ 99.7, respectively) are consistent with structures 22a–b but are
inconsistent with the isomeric structures 24a–b in which the CH
signals would be attributed to C-4. Chemical shift values for
compounds 25[17] and 26a–b[18] are illustrative (Scheme 7). For
24a–b, the CH chemical shifts should be δ 77–85 by comparison
to C-4 signals of 26a–b. The actual values of the CH signals are
similar to the value for C-5 in compound 25 (δ 96.3). Finally, a
nuclear Overhauser effect (NOE) experiment supports struc-
ture 22a. Irradiation centered at δ 5.7 to saturate the H-5 atom of
22a results in enhancement of the methoxy protons (δ 3.6, 7.9%
enhancement) and C-4 methyl protons (δ 1.8, 3.1% enhancement:
presumably cis to H-5) but not the C-3 methyl signal at δ 2.1. For
structure 24a, irradiation at δ 5.7 would saturate the H-4 atom.
Enhancement of the C-3 methyl protons (δ 2.1) as well as the
methoxy protons (δ 3.6) would be anticipated, but only the latter
enhancement was observed.
wileyonlinelibrary.com/journal/poc
Copyright © 2013 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2014, 27 38–46

β-ALKOXY-α,γ-DINITRO COMPOUNDS
0.080 g, 0.25 mmol) in anhydrous diethyl ether (1 mL), and the resulting
solution was stirred for 7.5 min. A solution of bromine (0.15 g, 0.94 mmol)
in dichlormethane (1 mL) was then added over 30 s followed by 25%
aqueous acetic acid (1 mL). Solvents were removed at high vacuum over
10 min, and the residue was taken up in dichloromethane (three 10-mL
portions). The combined organic layer was filtered, washed with water
(5 mL), dried over anhydrous MgSO4, and concentrated at reduced pres-
sure. The crude product amounted to 0.068 g of an oil. 1H NMR indicated
that this was a 35:60:5 mixture of 6a, ether isomers (7a/7b/7c, 85:6:9
ratio) and starting material 5a–b, respectively. Under these conditions, 6b
was not detected. Flash chromatography on silica gel (hexanes/EtOAc,
95:05 elution) gave a mixture of ether 7a–c and starting material 5a–b as
the most mobile fraction followed by pure 6a as an oil. Rf 0.30 (95:5
hexanes/EtOAc). IR (film) 1568 (NO2, νas), 1539 cmÀ1 (conj NO2, νas). 1H
CONCLUSIONS
The formation of 3-alkoxy-2,4-dibromo-2,4-dinitropentane deriv-
atives in the presence of bromine and base involves conjugate
addition to 4-bromo-2,4-dinitro-2-pentene and subsequent
bromination of the nitronate intermediate. This is a syntheti-
cally useful reaction and can be extended to the preparation
of 3-azido-2,4-dibromo-2,4-dintropentane. Partial and complete
debromination of the ether products is possible and can be con-
trolled by proper choice of conditions. A variety of 3-alkoxy-2,4-
dintropentane dervivatives can be converted to cyclic nitronates,
a process that appears to involve β,β’-dinitrocyclopropyl ethers as
intermediates. This provides experimental verification of the pre-
diction[15] made that compounds such as 1-methoxy-2-methyl-3-
nitrocyclopropane (20) should rearrange to cyclic nitronates. On
the basis solely of the NOE enhancement of the C-4 methyl group
in 22a, it would seem that cyclopropane ring-opening occurs
between the methoxy donor group and the trans-nitro acceptor
group (Scheme 8).
NMR (CDCl3): δ 7.57 (s, 1H), 2.50 (s, 3H), 2.29 (s, 3H). 13C NMR (CDCl3):
79
δ153.1, 131.6, 86.7, 32.5, 14.0. HRMS CI (NH3) m/z calcd for C5H BrN3O4
11
(M+ NH4)+ 255.9933, found 255.9939.
(Z)-4-bromo-2,4-dinitro-2-pentene (6b)
The preceding experiment for preparation of 6a was repeated except
that the bromine solution was added to the reaction solution after only
15 s. After work-up, 1H NMR showed that the crude product consisted
of a 10:8:71:11 mixture of 6a, 6b, ethyl ethers 7a/7b/7c (73:4:23 ratio),
and starting material 5a–b, respectively. Chromatography on silica gel
(95:5, hexanes/EtOAc elution) afforded a mixture of 7a–c and 5a–b as
the most mobile fraction followed by 6a and finally 6b. The fraction
containing 6b was subjected to preparative TLC (80:20 hexanes/EtOAc
elution) to obtain a pure sample as an oil. Rf 0.17 (95:5 hexanes/EtOAc).
IR (film) 1567 (NO2, νas), 1533 cmÀ1 (conj NO2, νas). 1H NMR (CDCl3): δ
6.34 (s, 1H), 2.48 (s, 3H), 2.33 (s, 3H). 13C NMR (CDCl3): δ148.2, 127.1,
EXPERIMENTAL SECTION
General
Alkoxide solutions were prepared under nitrogen from the reaction of the
appropriate anhydrous alcohol with pre-cleaned sodium cut into small
pieces. After the initially exothermic reaction, the mixture was refluxed
briefly until all sodium was consumed, and the resulting homogenous
solution was then cooled. 2,4-Dinitropentane (1) (1:1 mixture of meso and
racemic diastereomers) was prepared by a published procedure[2] and
was normally used as the mixture (chromatographic separation of the
two diastereomers was previously described).
85.5, 30.7, 19.8. HRMS CI (NH3) m/z calcd for C5H BrN3O4 (M + NH4)+
79
11
255.9933, found 255.9940.
General procedure A for synthesis of 3-alkoxy-2,4-dibromo-2,4-
dinitropentane derivatives. Preparation of 2,4-dibromo-3-methoxy-
2,4-dinitropentane (2a–c) from 5a–b
Synthesis
2,4-dibromo-2,4-dinitropentane (5a–b)
A cold (0–5 °C) 0.1-M solution of sodium methoxide in methanol (10 mL, 1
mmol NaOMe) was added to compound 5a–b (0.130 g, 0.4 mmol; 45:55
a/b). The resulting solution was stirred for 15 min and then a cold (0–
5 °C) solution of bromine (0.096 g, 0.6 mmol) in dichloromethane
(10 mL) was added. The resulting solution was stirred for 10 min and
was poured into a solution of sodium bisulfite (0.1 g, 1 mmol) in water
(35 mL). The layers were separated, and the aqueous layer was extracted
with dichloromethane (three 10-mL portions). The combined organic
layers were washed with water (25 mL), dried over anhydrous MgSO4,
and concentrated at reduced pressure. The crude light yellow product
(0.109 g, 83% yield, 83:11:06 2a/2b/2c ratio) was purified by flash
chromatography on silica gel thin-layer chromatography (TLC) (elution
with hexanes/EtOAc, 95:5) to give the three separate isomers.
2,4-Dinitropentane (50:50 diastereomer mixture, 0.352 g, 2.2 mmol) was
added dropwise over 1 min to a cold (0–5 °C) solution of sodium
methoxide (0.329 g, 6.1 mmol) in methanol (5 mL), and the resulting solu-
tion was stirred for an additional 19 min. This cold solution was then
added dropwise over 5 min to a second cold (0–5 °C) solution of bromine
(1.04 g, 6.5 mmol) in dichloromethane (5 mL). Sufficient 10% sodium
bisulfite solution was added to decolorize excess bromine. Water (25mL)
was added, and the mixture was extracted with dichloromethane (three
10-mL portions). The combined organic extracts were washed with water
(25mL), dried over anhydrous MgSO4, and concentrated at a reduced pres-
sure affording 0.485g (70% yield) of an oil consisting of 5 as a 45:55 a/b
1
mixture by H NMR. Flash chromatography on silica gel (hexanes, EtOAc,
95:5 elution) provided racemic isomer 5b as the more mobile fraction and
meso isomer 5a as the less mobile fraction. Both isomers were obtained
as oils that crystallized after protracted storage at À20 °C. Recrystallization
from ethanol gave the analytical samples.
(R*, R*)-2,4-dibromo-3-methoxy-2,4-dinitropentane (2a). Viscous
oil, Rf 0.51 (95:5 hexanes/EtOAc). IR (film) 1565 cm-1 (NO2, νas). 1H NMR
(CDCl3): δ 5.38 (s, 1H), 3.51 (s, 3H), 2.48 (s, 3H), 2.37 (s, 3H). 13C NMR
(CDCl3): δ98.6, 90.3, 86.8, 63.7, 29.4, 25.5. HRMS CI (NH3) m/z calcd for
C6H Br81BrN3O5 (M + NH4)+ 367.9280, found 367.9279.
79
(R, S)-2,4-dibromo-2,4-dinitropentane (5a). White solid, mp 64–65.5 °C,
14
1
Rf 0.43 (80:20 hexanes/EtOAc). H NMR2 (CDCl3): δ 4.06 (d, 1H, J= 16.6Hz),
3.92 (d, 1H, J= 16.6 Hz), 2.28 (s, 6H). 13C NMR (CDCl3): δ 89.4, 52.3, 29.8.
(R,r,S or R,s,S)-2,4-dibromo-3-methoxy-2,4-dinitropentane (2b). Vis-
cous oil, Rf 0.38 (95:5 hexanes/EtOAc). IR (film) 1571 cmÀ1 (NO2, νas). 1H
NMR (CDCl3): δ 5.42 (s, 1H), 3.48 (s, 3H), 2.42 (s, 6H). 13C NMR (CDCl3):
(R*, R*)-2,4-dibromo-2,4-dinitropentane (5b). White solid, mp 62–62.5 °
C, Rf 0.50 (80:20 hexanes/EtOAc). 1H NMR2 (CDCl3): δ 4.07 (s, 2H), 2.17
(s, 6H); 13C NMR (CDCl3): δ 87.1, 52.8, 27.4.
δ92.1, 87.4, 63.7, 27.2. HRMS CI (NH3) m/z calcd for C6H Br81BrN3O5
79
14
(M+ NH4)+ 367.9280, found 367.9281.
(E)-4-bromo-2,4-dinitro-2-pentene (6a)
(R,r,S or R,s,S)-2,4-dibromo-3-methoxy-2,4-dinitropentane (2c). Vis-
cous oil, Rf 0.55 (95:5 hexanes/EtOAc). IR (film) 1560 cmÀ1 (NO2, νas). 1H
NMR (CDCl3): δ 5.14 (s, 1H), 3.74 (s, 3H), 2.27 (s, 6H). 13C NMR (CDCl3):
A cold (0–5 °C) solution of sodium ethoxide (0.051 g, 0.75 mmol) in etha-
nol (6 mL) was added to a cold (0–5 °C) solution of 5a–b (45:55 ratio;
J. Phys. Org. Chem. 2014, 27 38–46
Copyright © 2013 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/poc

P. A. WADE, C. E. CASTILLO AND N. PAPAROIDAMIS
δ96.8, 86.9, 64.7, 27.4. HRMS CI (NH3) m/z calcd for C6H Br81BrN3O5
79
84.9, 78.1, 69.6 (weak), 29.5, 27.2 (weak), 25.7 (weak signals are assignable
to isomer 9b). HRMS CI (NH3) m/z calcd for C12H18Br2N3O5 (M + NH4)+
443.9593, found 443.9611.
14
(M+ NH4)+ 367.9280, found 367.9279.
Preparation of 2,4-dibromo-3-methoxy-2,4-dinitropentane (2a-c)
using concentrated base
General procedure B for synthesis of 3-alkoxy-2,4-dibromo-2,4-
dinitropentane derivatives. Preparation of 2,4-dibromo-3-ethoxy-
2,4-dinitropentane (7a–c) from 6a
A cold (0–5 °C) 1.7-M solution of sodium methoxide in methanol (1.5 mL, 2.5
mmol NaOMe) was added to 5a–b (0.13g, 0.4mmol; 45:55 a/b). Further
reaction and work-up as described in general procedure A gave 0.08 g
(59% yield) of 2 (2a/2b/2c 5:40:55 ratio, respectively, by 1H NMR).
A cold (0–5 °C) 0.6-M solution of sodium ethoxide in ethanol (3.5 mL,
2.1 mmol of NaOEt) was added to a cold solution of E-nitroalkene 6a
(0.17 g, 0.7 mmol) in ethanol (4 mL). The resulting solution was stirred
for 10 min and then poured into a cold (0–5 °C) solution of bromine
(0.27 g, 1.7 mmol) in dichloromethane (17 mL). This solution was added
to a solution of sodium bisulfite (0.2 g, 2 mmol) in water (100 mL), and
the resulting mixture was extracted with dichloromethane (three 20-mL
portions). The combined extracts were washed with water (3 mL), dried,
concentrated, and flash chromatographed on silica gel to give 0.19 g
(75% yield) of an oil that by 1H NMR consisted of 7a/7b/7c (81:10:08,
respectively).
2,4-Dibromo-3-ethoxy-2,4-dinitropentane (7a–c)
Prepared in 86% yield as a mixture of 7a/7b/7c (85:6:9, respectively) fol-
lowing general procedure A, but the alkoxide concentration was 0.24 M
(less solvent). Repetitive preparative TLC (elution with hexanes/EtOAc,
95:5) on the product mixture gave enriched (>90% purity) samples of
7a and 7b. The sample of 7c was obtained as a 50:50 7c/7a mixture.
(R*, R*)-2,4-dibromo-3-ethoxy-2,4-dinitropentane (7a). Viscous oil,
Rf 0.57 (95:5 hexanes/EtOAc). IR (film) 1566 cmÀ1 (NO2, νas). 1H NMR
(CDCl3): δ 5.44 (s, 1H), 3.78 (ABX3, 1H, J = 7.1, 8.8 Hz), 3.56 (ABX3, 1H,
J = 7.1, 8.8 Hz), 2.48 (s, 3H), 2.38 (s, 3H), 1.10 (t, 3H, J = 7.1 Hz). 13C NMR
(CDCl3) δ98.7, 90.6, 85.7, 72.5, 29.2, 25.4, 15.2. HRMS CI (NH3) m/z calcd
2,4-Dibromo-3-(1-methylethoxy)-2,4-dinitropentane (10a–c)
Prepared following general procedure B by using a 0.16-M alkoxide
solution for a reaction time of 40 min. The crude product consisted of a
30:30:20:20 mixture of 6a/10a/10b/10c, respectively, by 1H NMR. Flash
chromatography (hexanes/EtOAc, 95:05) afforded a mixture of 10a–c in
18% yield. Repetitive preparative TLC (elution with hexanes/EtOAc,
95:5) on the product mixture gave pure samples of 10a and 10c. A
sample of 10b (88:12, 10b/10a by 1H NMR) was also obtained.
for C7H Br81BrN3O5 (M + NH4)+ 381.9436, found 381.9423.
79
16
(R,r,S or R,s,S)-2,4-dibromo-3-ethoxy-2,4-dinitropentane (7b). Viscous
oil, Rf 0.50 (95:5 hexanes/EtOAc). IR (film) 1567 cmÀ1 (NO2, νas). 1H NMR
(CDCl3): δ 5.49 (s, 1H), 3.62 (q, 2H, J= 6.8 Hz), 2.42 (s, 6H), 1.07 (t, 3H,
J= 6.8 Hz) (signals assigned to 7b). 13C NMR (CDCl3): δ 92.3, 86.4, 27.1, 15.4
(signals assigned to 7b; a signal at 72.6 was coincident with a signal of 7a).
(R*, R*)-2,4-dibromo-3-(1-methylethoxy)-2,4-dinitropentane (10a). Vis-
cous oil, Rf 0.54 (95:5 hexanes/EtOAc). IR (film) 1560cmÀ1 (NO2, νas). 1H NMR
(CDCl3): δ 5.58 (s, 1H), 3.81 (septet, 1H, J = 5.9Hz), 2.49 (s, 3H), 2.35 (s, 3H),
1.14 (d, 3H, J= 5.9Hz), 1.03 (d, 3H, J= 5.9Hz). 13C NMR (CDCl3): δ 83.1,
77.1, 30.1, 26.1, 22.6, 21.7 (C atoms indirectly from HMQC spectra) and δ
100.4, 91.7 (quat C atoms indirectly from HMBC). HRMS CI (NH3) m/z calcd
HRMS CI (NH3) m/z calcd for C7H Br81BrN3O5 (M + NH4)+ 381.9436, found
79
16
381.9434.
(R,r,S or R,s,S)-2,4-dibromo-3-ethoxy-2,4-dinitropentane (7c). Vis-
cous oil, Rf 0.62 (95:5 hexanes/EtOAc). IR (film) 1563 (NO2, νas) cmÀ1 1H
.
for C8H Br81BrN3O5 (M+ NH4)+ 395.9593, found 395.9593.
79
18
NMR (CDCl3): δ 5.21 (s, 1H), 3.93 (q, 2H, J = 6.8 Hz), 2.29 (s, 6H), 1.25 (t,
3H, J = 6.8 Hz). 13C NMR (CDCl3): δ97.2, 85.8, 73.4, 27.5, 15.3. HRMS CI
16
(NH3) m/z calcd for C7H Br81BrN3O5 (M + NH4)+ 381.9436, found
79
(R,r,S or R,s,S)-2,4-dibromo-3-(1-methylethoxy)-2,4-dinitropentane
(10b). Viscous oil: an 88:12 mixture of 10b/10a, Rf 0.49 (95:5
hexanes/EtOAc). IR (film) 1566 cmÀ1 (NO2, νas). 1H NMR (CDCl3): δ 5.72
(s, 1H), 3.73 (septet, 1H, J = 6.3 Hz), 2.40 (s, 6H), 1.09 (d, 6H, J = 6.3 Hz).
13C NMR (CDCl3): δ 93.8, 83.4, 77.0, 28.0, 22.2. HRMS CI (NH3) m/z calcd
381.9429.
2,4-Dibromo-2,4-dinitro-3-propoxypentane (8a–c)
Prepared in 90% yield as a mixture (8a/8b/8c, 75:12:13, respectively, by
1H NMR) following general procedure A, but the alkoxide concentration
was 0.14 M, and the isomers were not separated. Viscous oil, IR (film)
for C8H Br81BrN3O5 (M + NH4)+ 395.9593, found 395.9603.
79
18
1567 cmÀ1 (NO2, νas). H NMR (CDCl3): δ 5.50 (s, 1H of 8c), 5.45 (s, 1H of
1
(R,r,S or R,s,S)-2,4-dibromo-3-(1-methylethoxy)-2,4-dinitropentane
(10c). Viscous oil, Rf 0.61 (95:5 hexanes/EtOAc). IR (film) 1567 cmÀ1
(NO2, νas). 1H NMR (CDCl3): δ 5.32 (s, 1H), 4.06 (septet, 1H, J = 5.9 Hz),
2.28 (s, 6H), 1.22 (d, 6H, J = 5.9 Hz). 13C NMR (CDCl3): δ 82.7, 77.0, 27.8,
22.3 (C atoms indirectly from HMQC spectra) and δ 98.4 (quat C atom
8a), 5.22 (s, 1H of 8b), 3.82 (t, 2H of 8b, J = 6.3 Hz), 3.67 (ABX2, 1H of 8a,
J = 6.6, 8.8 Hz), 3.51 (t, 2H of 8c, J = 6.3 Hz), 3.45 (ABX2, 1H of 8a, J = 6.6,
8.8 Hz), 2.49 (s, 3H of 8a), 2.42 (s, 6H of 8c), 2.38 (s, 3H of 8a), 2.28 (s,
6H of 8b), 1.62 (app sextet, 2H of 8c, J = 6.8 Hz), 1.48 (app sextet, 2H of
8a, J = 6.8 Hz) overlapping 1.44 (m, 2H of 8b), 0.93 (t, 3H of 8c,
J = 7.3 Hz), 0.84 (t, 3H of 8a, J = 7.3 Hz) overlapping 0.81 (t, 3H of 8b).
13C NMR δ 99.3, 97.2, 92.2, 90.6 (C2,4 all isomers), 85.8, 85.3 (C3 all isomers),
78.9, 78.2, 78.1 (C6 all isomers), 29.8, 27.5, 27.1, 25.6 (C1,5 all isomers), 23.1
(C7 all isomers), 10.4, 10.2, 10.1 (C8 all isomers). HRMS CI (NH3) m/z calcd
indirectly from HMBC). HRMS CI (NH3) m/z calcd for C8H Br81BrN3O5
79
18
(M + NH4)+ 395.9593, found 395.9593.
Preparation of azide 11a–b from nitroalkene 6a
for C8H Br81BrN3O5 (M + NH4)+ 395.9593, found 395.9586.
79
18
A cold (0–5 °C) solution of sodium azide (41 mg; 0.63 mmol) in water
(1 mL) was added dropwise over 3 min to a cold (0–5 °C) solution
containing 6a (27 mg; 0.11 mmol), methanol (4 mL), and water (1 mL).
The resulting solution was stirred for 1 h and a solution of bromine
(56 mg, 0.35 mmol) in dichloromethane (3.5 mL) was added followed by
10% sodium bisulfite (5 mL). The layers were separated, and the aqueous
layer was extracted with dichloromethane (three 10-mL portions). The
combined organic layers were washed with water (10 mL), dried, and con-
centrated to give an oil consisting of 11a/11b/6a (52:35:13, respectively,
by 1H NMR). Preparative TLC (95:5 hexanes/EtOAc elution) gave in order
1-(1-Bromo-1-nitroethyl)-2-bromo-2-nitropropoxybenzene (9a–b)
Prepared in 90% yield as a mixture (9a–b, 83:17, respectively, by 1H NMR)
following general procedure A, but the alkoxide concentration was 0.8 M,
and the isomers were not separated. Viscous oil, IR (film) 1564 cmÀ1 (NO2,
νas). 1H NMR (CDCl3): δ 7.14–7.36 (m, 5H, both isomers), 5.75 (s, 1H of 9b),
5.70 (s, 1 H of 9a), 4.78 (d, 1H of 9a, J = 10.3 Hz), 4.66 (s, 2H of 9b), 4.51(d,
1H of 9a, J = 10.3 Hz), 2.51 (s, 3 H of 9a), 2.42 (s, 6H of 9b), 2.38 (s, 3H, of
9a). 13C NMR (CDCl3): δ 135.5, 128.6, 128.5, 128.3, 98.7, 90.4, 85.5 (weak),
wileyonlinelibrary.com/journal/poc
Copyright © 2013 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2014, 27 38–46

β-ALKOXY-α,γ-DINITRO COMPOUNDS
of elution 6mg (13% yield) of 11b, 9 mg (23% yield) of 11a, and 5 mg of
recovered 6a. No third azide isomer was detected.
(weak signals attributed to two minor isomers (greater b and lesser c)).
13C NMR (CDCl3): δ 91.3 (quat), 84.3, 83.0, 61.8, 23.4, 14.8 (prominent signals
15
only). HRMS CI (NH3) m/z calcd for C6H BrN3O5 (M+ NH4)+ 288.0195, found
79
288.0194.
(R*, R*)-3-azido-2,4-dibromo-2,4-dinitropentane (11a). Viscous oil,
Rf 0.44 (95:5 hexanes/EtOAc). IR (film) 2123 (N3, νas), 1568 cmÀ1 (NO2,
νas), 1388 cmÀ1 1H NMR (CDCl3): δ 5.80 (s, 1H), 2.46 (s, 3H), 2.37 (s, 3H).
.
Monodebromination of 5a–b
13C NMR (CDCl3): δ 89.0, 71.1, 28.4, 25.9. HRMS CI (NH3) m/z calcd for
11
Carried out on 5a–b (45:55 a/b mixture) similarly to debromination of
7a–c to give 0.89g (77% yield) of 3 as a 91:9 mixture of two isomers a–b
(by 1H NMR). Viscous oil. IR (film) 1550 cmÀ1 (NO2, νas). 1H NMR (CDCl3): δ
4.91 (ABMX3 pattern, 1H), 3.30 (dd, 1H, J = 7.8, 16.3Hz), 2.85 (dd, 1H,
J = 2.4, 16.3 Hz), 2.22 (s, 3H), 1.67 (d, 3H, J = 6.8 Hz) (prominent signals attrib-
uted to main isomer a) and δ 4.66 (ABMX3 pattern, 1H), 3.45 (dd, 1H, J= 8,
16.3Hz), 2.91 (dd, J = 2.2, 16.3Hz), 2.23 (s, 3H), 1.66 (d, 3H, J = 6.8Hz) (weak
signals attributed to minor isomer b). 13C NMR (CDCl3): δ 91.9 (quat), 80.9,
46.2, 30.4, 21.3 (prominent signals attributed to 3a) and δ 80.4, 47.0, 29.1,
21.6 (weak signals attributed to 3b). HRMS EI m/z calcd for C6H799BrNO2
(M–NO2)+ 193.9817, found 193.9826.
C5H Br81BrN6O4 (M + NH4)+ 378.9188, found 378.9203.
79
(R,r,S or R,s,S)-3-azido-2,4-dibromo-2,4-dinitropentane (11b). Vis-
cous oil, Rf 0.55 (95:5 hexanes/EtOAc). IR (film) 2122 (N3, νas), 1568 cmÀ1
(NO2, νas). 1H NMR (CDCl3): δ 5.62 (s, 1H), 2.25 (s, 6H). 13C NMR (CDCl3):
11
79
δ 71.4, 26.8. HRMS CI (NH3) m/z calcd for C5H Br81BrN6O4 (M + NH4)+
378.9188, found 378.9198.
Preparation of azide 11a–b from 5a–b
A 0.06-M solution of sodium ethoxide in ethanol (10mL, 0.6mmol NaOEt)
was added dropwise over 2 min to a cold (0–5 °C) solution of 5a–b
(0.124 g, 0.39 mmol; 45:55 a/b ratio), sodium azide (0.235g, 3.6mmol), eth-
anol (10 mL), and water (4mL). The resulting solution was stirred for 20 min,
and a solution of bromine (0.12 g, 0.76 mmol) in dichloromethane (10mL)
was added followed by 10% sodium bisulfite (10 mL). Water (10 mL) was
added, the layers were separated, and the aqueous layer was extracted with
dichloromethane (three 10-mL portions). The combined organic layers
were washed with water (10 mL), dried, and concentrated to give 0.11g
of an oil consisting of 11a/11b/7a–c/5a–b (35:5:50:10, respectively, by
1H NMR). The amount of azide 11a–b present was therefore 44 mg
(32% yield). Preparative TLC (95:5 hexanes/EtOAc elution) gave 7 mg
of pure isomer 11b as the most nonpolar fraction but isomer 11a
obtained as a more polar fraction was contaminated with ether 7a–c.
Preparation of 3-methoxy-2,4-dinitropentane (13a–b)
A cold (0–5 °C) solution of sodium methoxide (0.97 g, 18 mmol) in
methanol (50 mL) was rapidly added to a cold (0–5 °C) solution of 5a–b
(1.94 g, a/b 45:55 ratio, 6 mmol) in diethyl ether (50 mL), and the resulting
solution was stirred for 20 min. A cold solution of sodium iodide (3.38 g,
23 mmol) and acetic acid (5 mL, 87 mmol) in methanol (20 mL) was
rapidly added, and the resulting solution stirred at 0–5 °C for 30 min
and then concentrated at reduced pressure. Dichloromethane (50 mL)
was added, and the resulting mixture was filtered. The filtrate was
sequentially washed with saturated aqueous sodium bisulfite (50 mL)
and water (two 50-mL portions), dried over anhydrous MgSO4, and con-
centrated at reduced pressure. A 1.03-g portion of a mixture containing
13 and 15 was obtained (13a/13b/15 52:36:11 ratio). Partial separation
was obtained by flash chromatography (70:30 hexanes – EtOAc). An early
fraction containing 0.27 g (23% yield) of 13b contaminated with 15a–c
(85:15 13b/15a–c ratio) and a later fraction containing 0.56 g (48% yield)
of 13a/13b 66:34 ratio were obtained. Analytical data are for the latter
fraction. Viscous oil, Rf 0.77 (70:30 hexanes/EtOAc). IR (film) 1560 cmÀ1
(NO2, νas). 1H NMR (C6D6): δ 4.18 (dd, 1H, J = 2.9, 9.2 Hz), 3.88 (dq, 1H,
J = 6.8, 9.2 Hz), 3.50 (dq, 1H, J = 2.9, 6.8 Hz), 2.93 (s, 3H), 0.82 (d, 3H,
J = 6.8 Hz), 0.57 (d, 3H, J = 6.8 Hz) (signals attributed to 13a with confirma-
tion from the early fraction) and δ 4.06 (t, 1H, J = 5.4 Hz), 3.78 (dq, 2H,
J = 5.4, 6.8 Hz), 2.79 (s, 3H), 0.95 (d, 6H, J = 6.8 Hz) (signals attributed to
13b). 13C NMR (CDCl3): δ 84.5, 83.0, 81.6, 61.7 (two maxima), 16.2, 12.0
(signals attributed to 13a with confirmation from the early fraction and
HMQC spectra) and δ 82.6, 82.2, 61.7 (two maxima), 13.8 (signals attrib-
uted to 13b). HRMS CI (NH3) m/z calcd for C8H16N3O5 (M + NH4)+
210.1090, found 210.1092.
Monodebromination of 2,4-dibromo-3-ethoxy-2,4-dinitropentane
(7a–c)
A cold (0–5 °C) solution of sodium iodide (1.68 g, 11 mmol) in ethanol
(30 mL) was added to a second cold solution (0–5 °C) consisting of 7a–c
(1.64 g, 4.5 mmol, 85:9:6 7a/7b/7c ratio) dissolved in acetic acid (25 mL;
0.44 mol) and ethanol (25 mL). The resulting solution was stirred for
30 min at 0–5 °C. Water (500 mL) was added, and the organic products
extracted with dichloromethane (three 20-mL portions). The combined
organic layers were washed with water (three 25-mL portions), dried over
anhydrous MgSO4, and concentrated at reduced pressure. The crude
product was purified by flash chromatography (80:20, hexanes/EtOAc
elution) to give 1.2 g (93% yield) of 16 as a 77:15:08 mixture of three
diastereomers a–c by (1H NMR). Viscous oil, Rf 0.50 (80:20 hexanes/EtOAc).
IR (film) 1564 cmÀ1 (NO2, νas). 1H NMR (CDCl3):δ 5.11 (d, 1H, J = 2.4Hz), 4.99
(qd, 1 H, J= 2.4, 6.8Hz), 3.77 (dq, 1H, J= 6.8, 9.3Hz), 3.56 (dq, 1H, J = 6.8,
9.3Hz), 2.16 (s, 3H), 1.66 (d, 3H, J = 6.8Hz), 1.12 (t, 3H, J = 6.8Hz) (prominent
signals attributed to main isomer a) and δ 4.87–4.97 (m), 4.64 (d of b
J= 6.3Hz overlapping m of c), 3.84 (dq, J = 7.3, 9.3Hz), 3.61–3.72 (m), 2.29
(s, 3H of b), 2.27 (s, 3H of c), 1.77 (d, 3H of b, J = 7.3Hz), 1.67 (d of isomer
c overlapping signal of a), 1.20 (t, 3H of c, J = 6.8Hz), 1.05 (t, 3H of b,
J= 6.8Hz) (weak signals attributed to two minor isomers, b and c). 13C
NMR (CDCl3): δ91.7 (quat), 83.1, 83.0, 70.3, 23.5, 15.1, 14.9. (prominent
Preparation of 4,5-dihydro-5-methoxy-3,4-dimethyl-4-nitroisoxazole
N-oxide (22a)
A cool (16–18 °C) solution of potassium acetate (0.23 g, 2.3 mmol) in
DMSO (8 mL) was added to a cool (16–18 °C) solution containing 13a–b
(66:34 a/b ratio, 0.15 g, 0.77 mmol) in DMSO (8 mL). The resulting solution
was stirred at 16–18 °C for 5 min and iodine (0.4 g, 1.6 mmol) was added.
This mixture was stirred for 4 min and the resulting solution poured into
a solution of sodium bisulfite (0.52 g, 5 mmol) in water (100 mL). The
aqueous solution was extracted with dichloromethane (three 10-mL
portions). The combined extracts were washed with water (10 mL), dried
over anhydrous MgSO4, and concentrated at reduced pressure to give
0.074 g of oil. By 1H NMR this contained about 60% 22a (30% yield)
and several unidentified materials. Rapid flash chromatography gave an
analytical sample that was partially purified (85% pure, low recovery).
Analytical data are for this sample. Small samples could also be purified
by rapid preparative TLC. Samples of crude 22a were completely con-
sumed when chromatography was insufficiently rapid.
signals only). HRMS CI (NH3) m/z calcd for C7H BrN3O5 (M+ NH4)+
79
17
302.0352, found 302.0343.
Monodebromination of 2a–c
Carried out on 2a–c (83:11:06 2a/2b/2c ratio) similarly to debromination
of 7a–c to give 0.91 g (81% yield) of 15 as an 81:13:06 mixture of three
isomers a–c (by 1H NMR). Viscous oil, Rf 0.50 (80:20 hexanes/EtOAc). IR
(film) 1560 cmÀ1 (NO2, νas). 1H NMR (CDCl3): δ 5.03 (d, 1H, J = 2.4Hz), 4.99
(qd, 1H, J = 2.4, 7.3Hz), 3.50 (s, 3H), 2.15 (s, 3H), 1.67 (d, 3H, J= 7.3Hz) (prom-
inent signals attributed to main isomer a) and δ 4.87–4.97 (m), 4.58 (d of b
J= 6.3Hz) overlapping m of c), 3.60 (s, 3H of c, 3.46 (s, 3H of b), 2.28 (s, 3H of
b), 2.26 (s, 3H of c), 1.67 (d, 3H of b, J = 6.8 Hz) 1.69 (d, 3H of c, J = 7.3Hz)
J. Phys. Org. Chem. 2014, 27 38–46
Copyright © 2013 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/poc

P. A. WADE, C. E. CASTILLO AND N. PAPAROIDAMIS
Treatment of 15a–c with a cool DMSO solution of potassium acetate
afforded 22a in 50% purity and 15% yield. Addition of a cool DMSO
solution of 2a–c to a cool DMSO solution of sodium iodide gave 22a in
60% purity and 7% yield.
Acknowledgements
We thank Dr. S. Sivasubramanian, formerly of Madurai Kamaraj
Univsersity, for performing preliminary experiments. We also thank
Dr. G. T. Furst (University of Pennsylvania) for obtaining NOE spectra.
4,5-Dihydro-5-methoxy-3,4-dimethyl-4-nitroisoxazole N-oxide (22a).
Viscous oil, Rf 0.31 (88:12 hexanes/EtOAc). IR (film) 1652 (C= N), 1558 cmÀ1
(NO2, νas). 1H NMR (CDCl3): δ 5.68 (s, 1 H), 3.61 (s, 3 H), 2.10 (s, 3 H), 1.80
(s, 3 H). 13C NMR (CDCl3): δ 110.6, 100.7, 100.0, 57.2, 16.9, 9.5 (signals
confirmed indirectly from HMQC and HMBC spectra). HRMS CI (CH4)
m/z calcd for C6H11N2O5 (M + H)+ 191.0668, found 191.0665.
REFERENCES
[1] M.-X. Zhang, P. E. Eaton, R. Gilardi, Angew. Chem. Internat Edit. 2000,
39, 401.
[2] P. A. Wade, W. P. Dailey, P. J. Carroll J. Am. Chem. Soc. 1987, 109, 5452.
[3] P. A. Wade, P. A. Kondracki, P. J. Carroll, J. Am. Chem. Soc. 1991, 113,
8807.
[4] J. D. Sullivan, Jr., P. A. Wade, A. L. Turetsky, U.S. patent 6007648
(1999)
A 19991228 “Chemically and mechanically sensitized
Preparation of 4,5-dihydro-5-ethoxy-3,4-dimethyl-4-nitroisoxazole
N-oxide (22b)
nitromethane-based liquid explosive”.
[5] a) For an example of alkoxide conjugate addition to nitroalkenes,
see: G. Trewartha, J. N. Burrows, A. G. M. Barrett, Tetrahedron Lett.
2005, 46, 3553. b) For a review of asymmetric conjugate addition
to nitroalkenes, see: O. M. Berner, L. Tedeschi, D. Enders, Eur. J.
Org. Chem. 2002, 1877.
[6] N. Ono, A. Kamimura, H. Sasatani, A. Kaji, J. Org. Chem. 1987, 52, 4133.
[7] This equilibration could occur as a result of reversible Br-atom trans-
fer reactions between 5a–b and the initial nitronate products. In a
dilute base, 5a–b would be present for much of the reaction. In a
concentrated base, 5a–b would be converted much more rapidly
to the nitroalkene intermediate and would be largely unavailable
for Br-atom transfer.
A cool (16–18°C) solution of potassium acetate (0.56 g, 5.7mmol) in DMSO
(40 mL) was added to a cool (16–18 °C) solution containing 16a–c (77:15:08
a/b/c ratio, 0.52 g, 1.81 mmol) in DMSO (60mL). The resulting solution was
stirred at 16–18 °C for 8min and was poured into ice water (500 mL). The
aqueous solution was extracted with dichloromethane (three 30-mL por-
tions). The combined extracts were washed with water (30 mL), dried over
anhydrous MgSO4, and concentrated at reduced pressure to give 0.094g
of a oil. By 1H NMR, this contained about 50% 22b (13% yield) and several
unidentified materials. Rapid flash chromatography gave an analytical sam-
ple that was substantially purified (90% pure, low recovery). Analytical data
are for this sample. Addition of a cool DMSO solution of 7a–c to a cool
DMSO solution of sodium iodide also gave 22b in 50% purity and 5% yield.
[8] T. Lemek, H. Mayr, J. Org. Chem. 2003, 68, 6880 and references cited
therein.
[9] T. B. Phan, H. Mayr, Can. J. Chem. 2005, 83, 1554.
[10] T. B. Phan, H. Mayr, J. Phys. Org. Chem. 2006, 19, 706.
[11] W. R. Bowman, G. D. Richardson Tetrahedron Lett. 1981, 22, 1551.
[12] a) G. A. Russell, R. K. Norris, E. J. Panek, J. Am. Chem. Soc. 1971, 93,
5839. b) E. E. van Tamelen, G. van Zyl, J. Am. Chem. Soc. 1949, 71,
835.
4,5-Dihydro-5-ethoxy-3,4-dimethyl-4-nitroisoxazole N-oxide (22b). Vis-
cous oil, Rf 0.4 (88:12 hexanes/EtOAc). IR (film) 1652(C = N), 1559 cmÀ1
(NO2, νas). 1H NMR (CDCl3): δ 5.76 (s, 1H), 3.98 (dq, 3H, J= 7.1, 9.8Hz), 3.73
(dq, 3H, J = 7.1, 9.8Hz), 2.10 (s, 3H), 1.80 (s, 3H), 1.28 (t, 3H, J = 7.1Hz). 13C
NMR (CDCl3): δ 99.7, 66.2, 17.1, 14.8, 9.7 (C atoms indirectly from HMQC
spectra) and δ 110.9 (one quat C atom indirectly from HMBC; a second quat
C atom was not detected). HRMS CI (CH4) m/z calcd for C7H13N2O5 (M+ H)+
205.0824, found 205.0826.
[13] Z. Matacz, H. Piotrowska, M. Poplawska, Bull. Pol. Acad. Sci., Chem.
1989, 36, 33.
[14] P. Pollitzer, G. P. Kirschenheuter, J. Alster J. Am. Chem. Soc. 1987,
109, 1033.
[15] T. B. Schneider, D. B. Werz, Org. Lett. 2011, 13, 1848.
[16] P. E. O’Bannon, W. P. Dailey, Tetrahedron 1990, 46, 7341 and
references cited therein.
[17] R. A. Kunetsky, A. D. Dilman, S. L. Ioffe, M. I. Struchkova, Y. A. Strelenko,
SUPPORTING INFORMATION
V. A. Tartakovsky Org. Lett. 2003, 5, 4907.
[18] a) E. Marotta, M. Baravelli, L. Maini, P. Righi, G. Rosini, J. Org.
Chem. 1998, 63, 8235. b) See also signals at δ 74–76 in related
compound 4a: Q. Zhang, J. Sun, F. Zhang, B. Yu, Eur. J. Org.
Chem. 2010, 3579.
1H NMR spectra of 2a–c, 3, 6a–b, 7a–c, 8–9, 10a-c, 11a–b,
13, 15–16, 22a–b and 13C NMR spectra of 2a–c, 3, 6a–b,
7a–c, 8–9, 10b, 11a–b, 13, 15–16, 22a.
wileyonlinelibrary.com/journal/poc
Copyright © 2013 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2014, 27 38–46