Nitration of α,β-unsaturated esters. Evidence for positive charge build-up adjacent to carbonyl carbon

Article abstract of DOI:10.1039/a607170h

Reactive intermediates formed in the nitration of certain α,β-unsaturated esters with nitronium tetrafluoroborate exhibit behaviour expected of highly reactive α-carbonyl cations. Three diagnostic reaction types have been observed which indicate the presence of these destabilised cations: (i) trapping in a Ritter reaction, (ii) cyclopropane formation from propyl cations, (iii) Wagner-Meerwein migration of alkyl groups. Semi-empirical calculations of the relative gas-phase stabilities of the proposed intermediate cations are useful in rationalising the observed chemistry.

Full text of DOI:10.1039/a607170h

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Nitration of á,â-unsaturated esters. Evidence for positive charge
build-up adjacent to carbonyl carbon
a
,
,a
b
c
Stuart A. Hewlins, John A. Murphy,* † J ian Lin, David E. Hibbs and
c
Michael B. Hursthouse
a
Department of Chemistry, University of Nottingham, University Park, Nottingham,
UK NG7 2RD
b
Shell Research and Technology Centre, Thornton, PO Box 1, Chester, UK CH1 3SH
EPSRC X-Ray Crystallography Service, Department of Chemistry, University of Wales,
c
Cardiff, PO Box 912, Cardiff, UK
Reactive intermediates formed in the nitration of certain á,â-unsaturated esters with nitronium
tetrafluoroborate exhibit behaviour expected of highly reactive á-carbonyl cations. Three diagnostic
reaction types have been observed which indicate the presence of these destabilised cations: (i) trapping in
a R itter reaction, (ii) cyclopropane formation from propyl cations, (iii) Wagner–M eerwein migration of
alkyl groups. Semi-empirical calculations of the relative gas-phase stabilities of the proposed intermediate
cations are useful in rationalising the observed chemistry.
ؒ
12
and this adds to the alkene forming a nitroalkyl radical.
Introduction
NO
2
ؒ
This could then be trapped by ONO to form the nitro nitrite 6,
The stabilisation of negative charge by an adjacent electron-
withdrawing carbonyl group, ‘enolate stabilisation’, underpins
modern synthetic chemistry. As positive charge is highly
destabilised by an adjacent electron-withdrawing group, the
cationic equivalent of an enolate anion is seldom described.
as for the reactions of alkenes with N O . Hydrolysis would
then afford the nitro alcohol 2.
The wish to distinguish between these and other possible
mechanisms prompted the current study of the nitration of α,β-
unsaturated esters; in particular we were keen to look for any
evidence for the involvement of α-carbonyl cations. We chose
2
4
1
–6
However, recent reviews
attest to the formation of such
‘destabilised’ cations adjacent to carbonyl and other electron-
withdrawing groups. Observations made in the literature and in
our own research on the regiochemistry of nitration of alkenes
prompted us to investigate this area to assess the relative acces-
sibility of such ‘cations’ both by experiment and using semi-
empirical computational methods. Throughout this paper, it is
recognised that naked cations are unlikely to exist in solution in
the solvent used (acetonitrile). Hence the term ‘carbocation’
will be used in the sense in which organic chemists normally use
it when speaking of reactions in solution, as a species which
may be heavily solvated, but which nevertheless bears signifi-
cant positive charge density on the carbon and is capable of
demonstrating this fact through its chemical behaviour.
7
,8
Shin et al. isolated α-hydroxy-β-nitro esters 2 and α-nitro-
α,β-unsaturated esters 3 from nitration of α,β-unsaturated
esters 1 with fuming nitric acid (Scheme 1). Although the authors
chose not to comment on the mechanism of the formation of
these compounds, the unusual regiochemistry of 2 would be
consistent with the intermediacy of an α-carbonyl cation. How-
ever, the nitration of alkenes with nitric acid can occur by a
9
variety of mechanisms, and hence a number of alternative
mechanisms may also be proposed for the α,β-unsaturated
esters. Below we consider three: mechanism 1 features a con-
certed addition of the nitronium ion and water to the double
bond. The mechanism would not require extensive build up of
positive charge α to the ester, but it would require the organis-
ation of three species in the transition state. A second possible
1
0
mechanism could involve a [2 ϩ 2] cycloaddition of the nitro-
nium ion to the alkene to give cyclic structure 4. Ring opening
1
1
by water would lead to the isolated nitro alcohol 5. A third
explanation might be that the nitric acid acts as a source of
†
Present address: Department of Pure and Applied Chemistry,
University of Strathclyde, 295 Cathedral Street, Glasgow, UK G1 1XL.
E-mail: John.Murphy@strath.ac.uk
Scheme 1
J. Chem. Soc., Perkin Trans. 1, 1997
1559

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the nitration of α,β-unsaturated esters in dry acetonitrile with
nitronium tetrafluoroborate for these studies.
been carried out using AM1. These showed that the tertiary α-
1
3
carbonyl cation 9 was of considerably lower energy (∆E = 21
Ϫ1
kcal mol ; 1 cal = 4.184 J) than the alternative primary carbo-
cation 14, mirroring the regiochemical findings of the experi-
ment (Scheme 3). Interestingly, however, the four-membered
Discussion
Nitration of methyl methacrylate afforded two products, the
allylic nitro compound 7 and the nitroacetamide 8. Three pos-
sible mechanisms can be proposed for the formation of 7
(Scheme 2). The first of these is a mechanism where addition of
Scheme 3
Ϫ1
ring system 10 is ca. 1 kcal mol lower in energy than 9. Hence
this may be in equilibrium with 9. Further, the four-membered
ring system 13 is apparently lower in energy than any of 9, 10 or
1
4. This implies that there are significant kinetic barriers to the
formation of 13.
Following this finding, a number of analogues of methyl
methacrylate were prepared and subjected to nitration. These
compounds were uniformly prepared from the corresponding
malonates. The first pair were ethyl substituted acrylates 15 and
1
6 (Scheme 4). Nitration of these compounds provided allylic
Scheme 2
the nitronium ion occurs to give the α-carbonyl cation 9;
A
deprotonation of H would give the allylic nitro compound 7.
On this mechanism one might expect to isolate product(s)
B
resulting from loss of H ; none was observed.
A second possible mechanism features the [2 ϩ 2] cyclo-
1
0
addition described above. Deprotonation would then occur
A
from the exocyclic site H rather than from the endocyclic site
B
H , accounting for the formation of 7 rather than 11.
A third mechanism would also account for the exclusive for-
mation of the allylic nitro compound 7 rather than the conju-
gated nitro compound 11. It involves an ene reaction, with the
nitronium ion acting as the enophile. Deprotonation of 12
would afford the observed product 7.
As for the formation of compound 8, the regiochemistry
suggested that an α-carbonyl cation 9 might be an intermediate
in its formation, which was then trapped by acetonitrile. To
obtain further understanding of the relative stabilities of the
possible intermediate cations in this reaction, calculations have
Scheme 4
1
0
nitro compounds, 17 and 18 respectively and cyclopropanes, 19
and 20 respectively. The identity of cyclopropane 20 was con-
firmed by an independent synthesis. Nitration of butyl meth-
acrylate afforded the allylic nitro compound 21. This was
cyclopropanated using the Corey ylide method to give the
cyclopropane 20. The formation of the cyclopropanes provided
1
4
1
560
J. Chem. Soc., Perkin Trans. 1, 1997

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excellent evidence for the high level of positive charge
developed on the α-carbon. It is proposed that the α-carbonyl
cations 22 cyclised via the protonated cyclopropanes 23.
The formation of cyclopropanes from propyl cations appears
to have been first reported by Skell and Starer, and Silver in
consecutive publications. Both publications were concerned
with the constituents of the hydrocarbon fractions obtained
from the deamination of aminopropane using aqueous nitrous
acid solution. The authors proposed that the propyl cation
cyclised via protonated cyclopropane to form the observed
product, cyclopropane.
see if Wagner–Meerwein rearrangements could be observed in
these nitration reactions, more highly substituted acrylates were
prepared. On nitration of the acrylate esters 31 and 32, the
predicted Wagner–Meerwein migration did occur. The products
isolated were the 1,3-nitroacetamides 33 and 34 and rather sur-
prisingly, the oxadiazoles 35 and 36 respectively (Scheme 6).
1
5
16
More recently, high level ab initio studies have been carried
1
7,18
ϩ
ϩ
out
on the C H7 and C H9 potential energy surfaces and
3 4
these calculations suggested that protonated cyclopropanes are
minima on these surfaces, which supports Skell’s proposal. Pro-
1
9–21
tonated cyclopropanes have been reviewed.
‡
Inspired by these cyclopropanation reactions, it was felt that
nitration of suitably substituted acrylates with longer alkyl
chains might lead to the formation of substituted cyclopro-
panes. To test this hypothesis, the esters 26 and 27 were pre-
pared (Scheme 5). However, on nitration, only the allylic nitro
Scheme 5
Scheme 6
compounds 28 and 29 were isolated, with no trace of the cor-
responding cyclopropanes.
There are two possible explanations as to why no cyclopro-
panation was seen in these reactions. The first considers steric
interactions in the transition state 30 for the formation of the
protonated cyclopropane. When R is methyl or ethyl, there may
be steric interactions between R and either the ester or the
nitromethyl group, preventing the cyclisation. With R = H, the
interactions would be much less serious allowing the cyclisation
to occur. The second explanation considers electronic distri-
bution in the transition state. There may be negative charge
build up on the γ-carbon and this will be destabilised by an
inductive effect where R is methyl or ethyl.
The structure of the oxadiazole 35 was determined by analysis
of the physical data. Combustion analysis suggested the
molecular formula C H N O and this was confirmed by the
1
0
15
3
6
ϩ
presence of (M ϩ H) in the FAB spectrum. The ester group
was clearly present from both NMR and IR spectra. The pres-
ence of the nitrate functional group was determined by absorb-
Ϫ1
ances at 1634 and 1280 cm in the IR spectrum, by the loss of
ONO in the EI spectrum and by the loss of NO and ONO in
2
2
2
the FAB mass spectrum. The oxadiazole ring was more difficult
to assign, but showed a characteristic IR absorbance at 1588
Ϫ1
cm . The UV spectrum showed no absorbance above 205 nm;
The formation of cyclopropanes indicates the intermediacy
of propyl cations. However a more commonly reported reaction
for carbocations is the Wagner–Meerwein rearrangement. To
weak UV absorbances are characteristic of 1,2,4-oxadiazoles.
The EI mass spectrum showed a peak at m/z 138 (59%), due to a
ϩ
molecular fragment (C H N O ) . Although the mechanism
6
6
2
2
᝽
of the formation of this ion may be quite complex, it is likely
that this fragment is formed by loss of the elements of OEt and
‡
Reference should be made at this stage to another published example
22
MeCHONO from the parent ion. This suggested oxadiazole 35
2
of cyclopropane formation from an α-carbonyl cation. This occurred
as a likely product structure and also suggested that a methyl
migration had occurred.
on solvolysis of the norbornyl methyl sulfonate 24. Presumably the
cyclopropane 25 was formed from the α-carbonyl cation which
cyclised via
a
protonated cyclopropane. Products resulting from
It was thought that the mass spectrum of the heptadeuteri-
ated analogue of the oxadiazole could confirm that the mi-
gration had occurred, thus providing important evidence for the
Wagner–Meerwein rearrangements were also isolated.
structure of this product. Accordingly, the acrylate ester 37 was
2
prepared, starting from 2-bromo[ H ]propane. As expected,
7
nitration afforded the deuteriated nitroacetamide 38 and oxa-
diazole 39. The EI mass spectrum of this oxadiazole showed a
peak at m/z 141 (66%), analogous to the fragment discussed
J. Chem. Soc., Perkin Trans. 1, 1997
1561

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Fig. 1 X-Ray crystal structure of 43
above, which backed up the suggestion that the methyl mi-
gration had occurred in the formation of the compound.
To confirm the structure of the oxadiazole 35, an X-ray crys-
tal structure determination of a derived compound was sought.
Compound 35 existed as a 3:1 mixture of diastereomers and so
to simplify this situation, it was reacted with tributyltin hydride
in benzene with a small amount of AIBN initiator. The tri-
2
3
butyltin radicals were predicted to attack the nitrate ester, and
form the alkoxyl radical 40 with loss of tributyltin nitrite.
Fragmentation, with loss of acetaldehyde would afford the
stabilised radical 41, which should abstract hydrogen from
tributyltin hydride to form the ester 42. The ester 42 was
indeed formed and was then converted via its acid and acid
chloride into the anilide 43. This was a white crystalline solid
and an X-ray crystal structure was determined (Fig. 1). §
With this confirmation of structure in hand, it remained to
explain the formation of nitroacetamide 33 and oxadiazole 35.
Nitration of the double bond in 31 occurs to form the α-carbonyl
cation 44 (Scheme 7). Methyl migration then occurs to form the
Fig. 2
1
3
followed by deprotonation would then form the bicyclic com-
pound 49, which on aromatisation would give the oxadiazole 50.
Subsequent nitration of the alcohol affords the nitrate ester 51.
AM1 calculations were performed on 44 and 45 (Fig. 2). The
Ϫ1
results showed the secondary cation 45 to be 35 kcal mol
more stable than the tertiary α-carbonyl cation 44, confirming
that the methyl migration was favourable. (Furthermore, AM1
calculations found that the minimised structure of the tertiary
Ϫ1
cation 53 was 36 kcal mol more stable than that of the tertiary
α-carbonyl cation 52 again in line with the observed migration
seen in the reaction of ester 32. In both 45 and 53, considerable
bonding is seen between the nitro oxygen and the carbocation;
these carbocations are substantially distorted from planarity
as a result; the nitro oxygen–carbocation distance is 1.51 Å in
4
5 and 1.54 Å in 53. Cations 44 and 52 appear to be between 1
Ϫ1
and 2 kcal mol more stable than their four-membered ring
counterparts 54 and 55).
The chemistry of 1,2,4-oxadiazoles has been reviewed by
2
4
Eloy. He reported that these heterocycles may be prepared by
reaction of a nitrile, a nitro compound, phenyl isocyanate and
catalytic triethylamine. For a previous report of this synthesis
2
5
see Mukaiyama and Hoshino. This reaction involves a
dehydration of the nitro compound to a nitrile oxide by phenyl
isocyanate followed by a cycloaddition reaction (Scheme 8).
(
The reaction only worked for nitriles which were activated by
26
electron-withdrawing groups.) Anneser et al. have also
reported that the cycloaddition of nitriles to nitrile oxides
requires an activated nitrile. A similar mechanism might apply
in this case. [We are grateful to Drs M. J. E. Hewlins (Cardiff)
and W. J. Kerr (Strathclyde) for independently making this sug-
gestion.] The Scheme shows that 31 may react to afford a
nitronitrate 56. Further reaction with the nitronium ion act-
ing as dehydrating agent could form nitrile oxide 57. The cyclo-
addition then occurs with acetonitrile to give the oxadiazole 51.
To investigate this pathway, nitroethane was reacted with
nitronium tetrafluoroborate in acetonitrile. No trace of the
oxadiazole 58 was seen under these conditions, suggesting that
this type of reaction is not related to our oxadiazole formation.
Finally, the cyclic substrates 59 and 60 were prepared to test
the generality of the Wagner–Meerwein migrations (Scheme 9).
Nitration of these compounds afforded the ring expanded
nitroacetamides 61 and 62 and the oxadiazoles 63 and 64.
In conclusion, these studies show three strands of evidence
for the build-up of considerable positive charge on the carbon
adjacent to the carbonyl group in the nitration of α,β-
unsaturated esters, namely (i) the Ritter reaction seen in the
Scheme 7
more stable secondary cation 45. This is trapped by acetonitrile
in a Ritter reaction to give 46. Alternatively, the cation is trapped
by the intramolecular nitro group, forming the cyclic structure
7. Tautomerism of this intermediate, followed by attack of
acetonitrile gives the nitrilium species 48. 5-endo-dig Cyclisation
4
§
Atomic coordinates, thermal parameters and bond lengths and angles
have been deposited at the Cambridge Crystallographic Data Centre
CCDC). See Instructions for Authors, J. Chem. Soc., Perkin Trans. 1,
997, Issue 1. Any request to the CCDC for this material should quote
the full literature citation and the reference number 207/101.
(
1
1
562
J. Chem. Soc., Perkin Trans. 1, 1997

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and are uncorrected. Microanalyses were determined using a
Perkin-Elmer 240B elemental analyser. IR spectra were meas-
ured using a Perkin-Elmer 1600 series FTIR spectrometer. UV
1
spectra were recorded on a Philips PU8720 instrument.
H
NMR spectra were recorded at 250 MHz with a digital reso-
lution of 0.25 Hz per point on a Bruker WM250, at 270 MHz
with a digital resolution of 0.33 per Hz point or at 400 MHz
with a digital resolution of 0.31 Hz per point on a Bruker
1
3
AM400 machine. C NMR spectra were recorded at 67.8 MHz
on a JEOL EX270 or at 100 MHz on a Bruker AM400
machine. These were run as decoupled spectra and assigned
using DEPT and correlation spectroscopy. All NMR experi-
ments were carried out in deuteriochloroform with tetramethyl-
silane as internal reference. Coupling constants (J) are reported
in hertz (Hz). In several cases, where mixtures of diastereomers
were obtained, the overlapping signals have been reported as
multiplets, unless the coupling constant of each isomer could be
ascertained. In cases where one isomer was formed in excess,
wherever possible the minor isomer has been marked (*). The
following abbreviations have been used to assign the multi-
1
plicity of the signals observed in the H NMR spectra; s singlet,
d doublet, t triplet, q quartet, m m, br broad. Mass spectra
[
electron impact (EI) and fast atom bombardment (FAB)] were
recorded on VG AE1 MS902, VG Micromass 70E or VG Auto-
spec spectrometers. Some of the high resolution FAB spectra
were recorded at the EPSRC Mass Spectrometry Service, Swan-
sea on a VG Autospec. FAB mass spectra were recorded for
positive ions in a m-nitrobenzyl alcohol matrix. The X-ray crys-
tal structure was recorded at the EPSRC X-ray crystallography
service, Cardiff.
Where necessary, solvents were dried and/or distilled before
use. THF was dried over sodium wire and distilled freshly from
potassium–benzophenone. Acetonitrile was dried over 4 Å
molecular sieves and distilled from calcium hydride. Dichloro-
methane was distilled from calcium hydride. DMSO was dried
over 4 Å sieves and vacuum distilled. Benzene was dried over
sodium wire. All light petroleum (petrol) was of boiling range
4
0–60 ЊC and was distilled before use. Hexane was a mixture of
isomeric hexanes and was distilled before use. Flash column
chromatography was performed using Sorbsil C60 (May &
Baker), Kieselgel 60 (Art 9385) or Kieselgel HF254 silica gels.
AM1 calculations were performed on a Silicon Graphics
Indy R5000, using the Spartan calculational package available
from Wavefunction Inc.
Scheme 8
Nitration of methyl methacrylate in acetonitrile
Nitronium tetrafluoroborate (458 mg, 3.44 mmol) was added to
dry acetonitrile (20 ml) in a flame-dried flask flushed with
argon. The stirred solution was cooled in a salt–ice bath at
Ϫ16 ЊC and methyl methacrylate (688 mg, 6.88 mmol) was
added rapidly. The reaction was stirred for 2 h, water (50 ml)
was added and the reaction mixture extracted with dichloro-
methane (3 × 30 ml). The combined organic layers were dried
over sodium sulfate and evaporated to give a pale yellow oil
(369 mg).
Scheme 9
formation of 8, (ii) the formation of cyclopropanes 19 and 20
and (iii) the Wagner–Meerwein rearrangements of intermedi-
ates derived from 31, 32, 37, 59 and 60. The mechanisms pro-
posed in Scheme 1 avoid mandatory accumulation of positive
charge α to a carbonyl group, but the results presented here
clearly demonstrate that a tertiary carbon adjacent to an ester
carbonyl may indeed bear significant positive charge and such
cases are likely to be widely encountered in synthetic chemistry.
Compound 7 and related allylic nitro compounds may arise
by an ene reaction; the ene reaction could feature considerable
positive charge adjacent to the carbonyl group. However,
intermediates such as 10 appear from our AM1 calculations
to be comparable in energy to 9 and so may feature in our
reactions.
Column chromatography (50% ethyl acetate–petrol) led to
2
7,28
the isolation of methyl 2-methylene-3-nitropropanoate
7 as
a colourless oil (200 mg, 1.38 mmol, 40%) (Found: C, 41.3; H,
5.1; N, 9.9. C H NO requires C, 41.4; H, 4.8; N, 9.7%) [Found:
5
7
4
ϩ
ϩ
M
Ϫ OMe (EI), 114.0193. C H NO requires M Ϫ OMe,
5 7 4
Ϫ1
114.0191]; νmax(film)/cm 3014, 2958 (CH), 1724 (C᎐O), 1644
᎐
(C᎐C), 1560 (N᎐O), 1348 (N᎐O), 899 (᎐CH ); δ (250 MHz,
᎐
᎐
᎐
᎐
2
H
CDCl ) 3.82 (3 H, s, CO Me), 5.20 (2 H, d, J 0.9, CH ), 6.06 (1
3
2
2
H, br s, ᎐CH), 6.64 (1 H, br s, ᎐CH); δ (67.8 MHz, CDCl ) 52.2
᎐
᎐
C
3
(OMe), 74.9 (CH NO ), 130.2 (᎐C), 133.9 (CH ), 164.7 (C᎐O);
2
2
᎐
2
᎐
ϩ
ϩ
m/z (EI) 114 (M Ϫ OMe, 29%), 99 (M Ϫ NO , 55), 59
(CO Me , 100); and methyl 2-acetamido-2-methyl-3-nitro-
2
ϩ
Experimental
2
propanoate 8 as a white solid which was recrystallised from
diethyl ether (56 mg, 0.28 mmol, 8%); mp 84–87 ЊC [Found:
General information
ϩ
ϩ
Melting points were measured on a Kofler hot-stage apparatus
(M ϩ H) (FAB) 205.0819. C H N O requires (M ϩ H) ,
7 12 2 5
J. Chem. Soc., Perkin Trans. 1, 1997
1563

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Ϫ1
2
05.0824]; νmax(CHCl )/cm 3411 (N᎐H), 1748 (C᎐O), 1681
(CH), 1727 (C᎐O), 1564 (N᎐O), 1345 (N᎐O), 1160 (C᎐O);
᎐ ᎐ ᎐
3
᎐
(
C᎐O), 1558 (N᎐O), 1357 (N᎐O); δ (250 MHz, CDCl ) 1.66 (3
δ (250 MHz, CDCl ) 1.06 (2 H, dd, J 7.6, 4.8, CH ), 1.24 (3 H,
H 3 2
᎐
᎐
᎐
H
3
H, s, Me), 2.02 (3 H, s, Me), 3.85 (3 H, s, Me), 4.95 (1 H, d, J
t, J 7.1, Me), 1.57 (2 H, dd, J 7.6, 4.8, CH ), 4.17 (2 H, q, J 7.1,
2
1
3.4, CH NO ), 5.43 (1 H, d, J 13.4, CH NO ), 6.66 (1 H, br s,
OCH ), 4.53 (2 H, s, CH NO ); δ (100 MHz, CDCl ) 14.1 (Me),
2
2
2
2
2
2
2
C
3
NH); δ (67.8 MHz, CDCl ) 20.9 (Me), 23.4 (Me), 53.5 (Me),
15.5 (2 CH ), 21.6 (C), 61.7 (CH ), 78.2 (CH ), 171.9 (C᎐O);
2 2 2
ϩ ϩ
C
3
5
8.2 (C), 76.9 (CH ), 170.2 (C᎐O), 171.6 (C᎐O); m/z (FAB) 205
m/z (EI) 128 (M Ϫ NO ϩ H, 16%), 127 (M Ϫ NO , 6), 99
2
2
2
ϩ
ϩ
ϩ
ϩ
[
(M ϩ H) , 33%], 158 (M Ϫ NO , 7), 43 (Ac , 85).
(M Ϫ CO Et, 100).
2
2
29
30
Synthesis of ethyl 2-methylenebutanoate 15
Synthesis of butyl 2-methylenebutanoate 16
Potassium hydroxide (4.48 g, 80.0 mmol) in dry ethanol (70 ml)
was added dropwise over 2 h to a stirred solution of diethyl 2-
ethylpropanedioate (15.0 g, 80.0 mmol) in dry ethanol (25 ml).
The solution was stirred at room temperature for 24 h and the
alcohol evaporated off. The high viscosity residue was dissolved
in water (30 ml) and extracted with dichloromethane (2 × 20
ml). The aqueous layer was cooled in ice and concentrated
hydrochloric acid (6.6 ml) was added dropwise. The reaction
mixture was extracted with diethyl ether (3 × 30 ml). The com-
bined organic extracts were dried over sodium sulfate and
evaporated to give ethyl hydrogen 2-ethylpropanedioate as a
colourless oil (9.34 g, 58.4 mmol, 73%). Piperidine (600 mg,
Potassium hydroxide (4.00 g, 71.4 mmol) in dry ethanol (70 ml)
was added dropwise over 2 h to a stirred solution of diethyl 2-
ethylpropanedioate (13.4 g, 71.4 mmol) in dry butan-1-ol (25
ml). The solution was stirred at room temperature for 30 h and
the alcohol evaporated off. The high viscosity residue was dis-
solved in water (30 ml) and extracted with dichloromethane
(2 × 20 ml). The aqueous layer was cooled in ice and concen-
trated hydrochloric acid (5.95 ml) was added dropwise. The
reaction mixture was extracted with diethyl ether (3 × 30 ml).
The combined organic extracts were dried over sodium sulfate
and evaporated to give butyl hydrogen 2-ethylpropanedioate as
a colourless oil (11.8 g, 62.7 mmol).
7
.06 mmol) and paraformaldehyde (1.74 g, 58.0 mmol) were
Piperidine (600 mg, 7 mmol) and paraformaldehyde (1.89 g,
63 mmol) were added to a solution of butyl hydrogen 2-
ethylpropanedioate in pyridine (15 ml). The solution was
heated under reflux until the end of evolution of carbon dioxide.
After cooling, the reaction was poured onto water (50 ml)
and extracted with pentane (3 × 50 ml). The pentane phases
were washed successively with water (20 ml), 2  hydrochloric
acid (20 ml), water (20 ml), saturated aqueous sodium hydrogen
carbonate (20 ml) and brine (20 ml). The combined organic
extracts were dried over sodium sulfate and evaporated to give a
pale yellow oil. Column chromatography (8% diethyl ether–
pentane) led to the isolation of butyl 2-methylenebutanoate 16
added to a solution of the ethyl hydrogen 2-ethylpropanedioate
in pyridine (15 ml). The solution was heated under reflux until
the end of evolution of carbon dioxide.
After cooling, the reaction was poured onto water (50 ml)
and extracted with pentane (3 × 50 ml). The pentane phases
were washed successively with water (20 ml), 2  hydrochloric
acid (20 ml), water, saturated aqueous sodium hydrogen car-
bonate (20 ml) and brine (20 ml). The combined organic
extracts were dried over sodium sulfate and evaporated to give
ethyl 2-methylenebutanoate 15 as a colourless oil (4.45 g, 39.0
ϩ
mmol, 49%, 67% from half ester) [Found: M (EI), 128.0810.
C H O requires M, 128.0837]; νmax(film)/cm 2973, 2878
Ϫ1
ϩ
as a colourless oil (1.90 g, 13.4 mmol, 19%) [Found: M (EI),
7
12
2
(
CH), 1719 (C᎐O), 1631 (C᎐C), 1176 (C᎐O), 818 (᎐CH ); δ (250
156.1141. C H O requires M, 156.1150] (Found: C, 69.3; H,
9 16 2
Ϫ1
᎐
᎐
᎐
2
H
MHz, CDCl ) 1.08 (3 H, t, J 7.4, Me), 1.30 (3 H, t, J 7.0, Me),
10.7. C H O requires C, 69.2; H, 10.3%); νmax(film)/cm
9 16 2
3
2
5
1
1
.33 (2 H, qdd, J 7.4, 1.5, 0.4, CH ), 4.21 (2 H, q, J 7.0, OCH ),
2963, 2875 (CH), 1720 (C᎐O), 1632 (C᎐C), 1168 (C᎐O), 817
(᎐CH); δ (250 MHz, CDCl ) 0.96 (3 H, t, J 7, Me), 1.09 (3 H, t,
2
2
.51 (1 H, m, ᎐CH), 6.13 (1 H, m, ᎐CH); δ (67.8 MHz, CDCl )
᎐
᎐
C
3
H
3
2.6 (Me), 14.2 (Me), 24.8 (CH ), 60.5 (OCH ), 123.2 (᎐CH ),
J 7, Me), 1.41 (2 H, m, CH ), 1.67 (2 H, m, CH ), 2.34 (2 H, m,
2
2
2
2
2
ϩ
42.5 (᎐C), 167.2 (C᎐O); m/z (EI) 128 (M , 14%), 113
CH ), 4.17 (2 H, t, J 7, OCH ), 5.52 (1 H, dd, J 3.1, 1.2, ᎐CH),
2 2
᎐
᎐
ϩ
ϩ
ϩ
(M
Ϫ Me, 27), 100 (M Ϫ C H , 34), 55 (M Ϫ CO Et, 100).
6.14 (1 H, dd, J 2.3, 1.3, ᎐CH); δ (67.8 MHz, CDCl ) 12.4 (Me),
2
4
2
C
3
1
3.4 (Me), 19.0 (CH ), 24.6 (CH ), 30.5 (CH ), 64.0 (OCH ),
2 2 2 2
ϩ
Nitration of ethyl 2-methylenebutanoate 15
122.8 (᎐CH ), 142.3 (᎐C), 166.9 (C᎐O); m/z (EI) 156 (M , 1%),
2
ϩ ϩ ϩ
127 (M Ϫ Et, 2), 101 (CO Bu , 100), 83 (M Ϫ OBu, 82), 55
(M Ϫ CO Bu, 75).
Nitronium tetrafluoroborate (687 mg, 5.16 mmol) was added to
dry acetonitrile (20 ml) in a flame-dried flask flushed with nitro-
gen. The stirred solution was cooled in a salt–ice bath at Ϫ16 ЊC
and ethyl 2-methylenebutanoate (1.32 g, 10.3 mmol) was added
rapidly. The reaction was stirred for 2 h, water (30 ml) was
added and the reaction mixture extracted with dichloromethane
2
ϩ
2
Nitration of butyl 2-methylenebutanoate 16
Nitronium tetrafluoroborate (367 mg, 2.75 mmol) was added to
dry acetonitrile (20 ml) in a flame-dried flask flushed with nitro-
gen. The stirred solution was cooled in a salt–ice bath at Ϫ16 ЊC
and butyl 2-methylenebutanoate (850 mg, 5.51 mmol) was
added rapidly. The reaction was stirred for 2 h, water (50 ml)
was added and the reaction mixture extracted with dichloro-
methane (3 × 30 ml). The combined organic layers were washed
with water (30 ml), dried over sodium sulfate and evaporated to
give a pale orange oil (795 mg). Column chromatography
(8–100% ethyl acetate, hexane) led to the separation of a mix-
ture of isomers (200 mg, 0.99 mmol, 36%). HPLC [(4% ethyl
(3 × 30 ml). The combined organic layers were washed with
water (30 ml), dried over sodium sulfate and evaporated to give
a pale yellow oil (954 mg). Column chromatography (6–10–
1
00% ethyl acetate–petrol) led to the isolation of a mixture of
isomers (348 mg, 4.02 mmol, 39%). HPLC [(3% ethyl acetate–
Ϫ1
hexane) (3 ml min ), Waters Porasil 125 Å 15–20 µm, 9 × 300
mm] led to the isolation of ethyl 2-nitromethylbut-2-enoate 17 as
a colourless oil (Found: C, 48.5; H, 6.6; N, 7.8. C H NO
requires C, 48.5; H, 6.4; N, 8.1%) [Found: M Ϫ NO2 (EI),
7
11
4
ϩ
Ϫ1
1
27.0746. C H NO requires M Ϫ NO2, 127.0759]; νmax
-
acetate–hexane) (3 ml min ), Waters Porasil 125 Å, 15–20 µm,
7
Ϫ1
11
4
(CHCl )/cm 2990, 2928, 2853 (CH), 1712 (C᎐O), 1658 (C᎐C),
9 × 300 mm] led to the isolation of butyl 2-nitromethylbut-2-
enoate 18 as a colourless oil (NMR yield 28%) [Found:
3
1
1
7
564 (N᎐O), 1347 (N᎐O), 1145 (C᎐O); δ (400 MHz, CDCl )
᎐ ᎐
H
3
ϩ
ϩ
.30 (3 H, t, J 7.1, Me), 1.97 (3 H, d, J 7.3, Me), 4.25 (2 H, q, J
.1, OCH ), 5.26 (2 H, s, CH NO ), 7.39 (1 H, q, J 7.3, ᎐CH);
(M ϩ H) (FAB), 202.1065. C H NO requires (M ϩ H) ,
9 15 4
202.1079] (Found: C, 54.0; H, 7.7; N, 7.0. C H NO requires
2
2
2
9
15
4
Ϫ1
δ (67.8 MHz, CDCl ) 14.1 (Me), 15.0 (Me), 61.5 (CH ), 70.0
C, 53.7; H, 7.1; N, 7.0%); νmax(CHCl )/cm 2934 (CH), 1710
C
3
2
3
(
(
CH ), 123.7 (᎐C), 147.1 (᎐CH), 165.2 (C᎐O); m/z (EI) 127
(C᎐O), 1658(C᎐C), 1561(N᎐O), 1348(N᎐O), 1146(C᎐O);δ (250
2
H
ϩ
ϩ
ϩ
M
Ϫ NO , 100%), 99 (C H NO , 92), 81 (C H O , 60); and
MHz, CDCl ) 0.94 (3 H, t, J 7.3, Me), 1.39 (2 H, tq, J 7.3, 7.3,
2
4
5
2
5
5
3
ethyl 1-nitromethylcyclopropanecarboxylate 19 as a colourless
CH ), 1.65 (2 H, m, CH ), 1.97 (3 H, d, J 7.3, Me), 4.19 (2 H, t, J
2
2
oil (Found: C, 48.6; H, 6.7; N, 8.0. C H NO requires C, 48.5;
7.3, OCH ), 5.26 (2 H, s, CH NO ), 7.37 (1 H, q, J 7.3, ᎐CH);
δ (67.8 MHz, CDCl ) 13.6 (Me), 14.9 (Me), 19.1 (CH ), 30.5
C 3 2
7
11
4
2
2
2
ϩ
H, 6.4; N, 8.1%) [Found: M Ϫ NO (EI), 127.0763. C H NO
2
7
11
4
Ϫ1
requires M Ϫ NO , 127.0759]; ν (CHCl )/cm 2945, 2837
(CH ), 65.3 (CH ), 69.9 (CH ), 123.8 (C), 147.0 (CH), 165.2
2
max
3
2 2 2
1
564
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
ϩ
ϩ
(
1
4
C᎐O); m/z (FAB) 403 [(2 M ϩ H) , 4%], 202 [(M ϩ H) , 100],
g, 56.0 mmol) were added to a solution of ethyl hydrogen 2-
᎐
ϩ
ϩ
ϩ
55 (M Ϫ NO , 23), 154 (M Ϫ HNO , 23), 128 (M Ϫ OBu,
8); and butyl 1-nitromethylcyclopropanecarboxylate 20 as a
colourless oil (NMR yield 22%) [Found: (M ϩ H) (FAB),
02.1072. C H NO requires (M ϩ H) , 202.1079] (Found: C,
3.6; H, 7.7; N, 6.8. C H O N requires C, 53.7; H, 7.5; N,
.0%); νmax(CHCl )/cm 2934 (CH), 1725 (C᎐O), 1562 (N᎐O),
347 (N᎐O), 1169 (C᎐O); δ (250 MHz, CDCl ) 0.92 (3 H, t, J
.2, Me), 1.07 (2 H, dd, J 6.1, 4.8, CH ), 1.34 (2 H, m, CH ),
.60 (4 H, m, CH ), 4.11 (2 H, t, J 6.6, OCH ), 4.52 (2 H, s,
CH NO ); δ (67.8 MHz, CDCl ) 13.6 (Me), 15.5 (2 CH ), 19.0
CH ), 21.6 (C), 30.5 (CH ), 65.5 (CH ), 78.1 (CH NO ), 171.9
2 2 2 2 2
ϩ ϩ
C᎐O); m/z (FAB) 403 [(2 M ϩ H) , 4%], 202 [(M ϩ H) , 100],
propylpropanedioate in pyridine (15 ml). The solution was
heated under reflux until the end of evolution of carbon
dioxide.
2
2
ϩ
ϩ
2
5
7
1
7
1
After cooling, the reaction was poured onto water (50 ml)
and extracted with pentane (3 × 50 ml). The pentane phases
were washed successively with water, 2  hydrochloric acid (20
ml), water (20 ml), saturated aqueous sodium hydrogen carbon-
ate (20 ml) and brine (20 ml). The combined organic extracts
were dried over sodium sulfate and evaporated to give a colour-
less oil. Kugelrohr distillation led to the isolation of ethyl 2-
methylenepentanoate 26 as a colourless oil (4.80 g, 37.5 mmol,
9
15
4
9
15
4
Ϫ1
3
᎐
H
3
2
2
2
2
2
2
C
3
2
(
(
1
31
47%, 67% from half ester); bp 25 ЊC/0.2 mmHg (lit., 48 ЊC/8
᎐
ϩ
ϩ
ϩ
55 (M Ϫ NO , 23), 128 (M Ϫ OBu, 60).
mmHg) [Found: M (EI), 142.0996. C H O requires M,
2
8
14
2
1
42.0994] (Found: C, 67.8; H, 10.3. C H O requires C, 67.6;
8 14 2
Ϫ1
Nitration of butyl methacrylate
H, 9.9%); νmax(film)/cm 2961, 2874 (CH), 1718 (C᎐O), 1631
᎐
Nitronium tetrafluoroborate (541 mg, 4.07 mmol) was added to
dry acetonitrile (20 ml) in a flame-dried flask flushed with nitro-
gen. The stirred solution was cooled in a salt–ice bath at Ϫ16 ЊC
and butyl methacrylate (578 mg, 648 µl, 4.07 mmol) was added
rapidly. The reaction was stirred for 2 h, water (50 ml) was
added and the reaction mixture extracted with dichloromethane
(C᎐C), 1160 (C᎐O), 818 (᎐CH); δ (250 MHz, CDCl ) 0.93
᎐ ᎐
H 3
(3 H, t, J 7.3, Me), 1.30 (3 H, t, J 7.1, Me), 1.50 (2 H, m, CH ),
2
2.28 (2 H, t, J 7.3, CH ), 4.21 (2 H, q, J 7.1, OCH ), 5.51 (1 H,
2
2
bd, J 1.4, ᎐CH), 6.14 (1 H, d, J 1.4, ᎐CH); δ (67.8 MHz,
C
CDCl ) 13.5 (Me), 14.1 (Me), 21.5 (CH ), 33.8 (CH ), 60.4
3
2
2
(OCH ), 124.1 (᎐CH ), 140.8 (᎐C), 167.2 (C᎐O); m/z (EI) 142
2
2
ϩ
ϩ
ϩ
(3 × 30 ml). The combined organic layers were washed with
(M , 11%), 114 (M Ϫ C H , 36), 97 (M Ϫ OEt, 75), 69
(M Ϫ CO Et, 100).
2
4
ϩ
water (30 ml), dried over sodium sulfate and evaporated to give
a pale yellow oil (615 mg). Column chromatography (10% ethyl
acetate–hexane) led to the isolation of butyl 2-methylene-3-
2
3
1
Synthesis of ethyl 2-methylenehexanoate 27
2
7
nitropropanoate 21 as a colourless oil (260 mg, 1.39 mmol,
Potassium hydroxide (2.98 g, 53.2 mmol) in dry ethanol (32 ml)
was added dropwise over 30 min to a solution of diethyl 2-
butylpropanedioate (11.5 g, 11.6 ml, 53.0 mmol) in dry ethanol
(32 ml). The solution was stirred at room temperature for 12 h
and the alcohol evaporated off. The high viscosity residue was
dissolved in water (10 ml) and then concentrated hydrochloric
acid (4.4 ml) was added dropwise. The reaction mixture was
extracted with diethyl ether (3 × 30 ml). The combined organic
extracts were dried over sodium sulfate and evaporated to give
ethyl hydrogen 2-butylpropanedioate as a colourless oil.
3
5
4%) (Found: C, 51.4; H, 7.3; N, 7.3. C H NO requires C,
8 13 4
Ϫ1
1.3; H, 7.0; N, 7.5%); νmax(CHCl )/cm 2962, 2875 (CH), 1722
3
(
C᎐O), 1645 (C᎐C), 1562 (N᎐O), 1341 (N᎐O); δ (250 MHz,
᎐ ᎐ ᎐ ᎐
H
CDCl ) 0.94 (3 H, t, J 7, Me), 1.67 (2 H, m, CH ), 3.81 (2 H, m,
3
2
CH ), 4.22 (2 H, t, J 7, OCH ), 5.17 (2 H, s, CH NO ), 6.00 (1
2
2
2
2
H, s, ᎐CH), 6.63 (1 H, s, ᎐CH); δ (67.8 MHz, CDCl ) 13.4 (Me),
᎐
᎐
C
3
1
1
8.9 (CH ), 30.3 (CH ), 65.4 (CH ), 75.2 (CH NO ), 130.7 (᎐C),
2 2 2 2 2
ϩ
33.5 (᎐CH ), 164.3 (C᎐O); m/z (FAB) 46 (NO , 73%).
᎐
2
2
Cyclopropanation of butyl 2-methylene-3-nitropropanoate 21
Sodium hydride (47.2 mg of 60% dispersion, 1.18 mmol) was
washed with tetrahydrofuran (2 × 3 ml) and then DMSO (5 ml)
was added. Trimethylsulfoxonium iodide (259 mg, 1.18 mmol)
was added in one portion. After stirring for 45 min, butyl 2-
methylene-3-nitropropanoate (200 mg, 1.07 mmol) in DMSO (1
ml) was added rapidly. After stirring for 1.5 h, the reaction was
quenched with 3% cold hydrochloric acid (10 ml). The reaction
was extracted with diethyl ether (3 × 30 ml). The combined
ether extracts were dried over sodium sulfate and evaporated to
give a brown oil. Column chromatography (10% ethyl acetate–
hexane) led to the isolation of butyl 1-nitromethylcyclo-
propanecarboxylate contaminated with iodine. The mixture
was taken up in dichloromethane (5 ml) and washed with aque-
ous sodium thiosulfate (5 ml). This led to the isolation of butyl
Piperidine (430 mg, 5.06 mmol) and paraformaldehyde (1.25
g, 42.5 mmol) were added to a solution of ethyl hydrogen 2-
butylpropanedioate in pyridine (15 ml). The solution was
heated under reflux until the end of evolution of carbon dioxide.
After cooling, the reaction was poured onto water (50 ml)
and extracted with pentane (4 × 30 ml). The pentane phases
were washed successively with water, hydrochloric acid (2 ),
water, saturated aqueous sodium hydrogen carbonate and
brine. The combined organic extracts were dried over sodium
sulfate and evaporated to give a colourless oil. Column chroma-
tography (2% ethyl acetate–petrol) led to the isolation of ethyl
2-methylenehexanoate 27 as a colourless oil (5.84 g, 38.0 mmol,
ϩ
72%) [Found: M (EI), 156.1130. C H O requires M,
9
16
2
156.1150] (Found: C, 69.1; H, 10.6. C H O requires C, 69.2;
9
16
2
Ϫ1
H, 10.3%); νmax(film)/cm 2958, 2873 (CH), 1719 (C᎐O), 1631
(C᎐C), 1158 (C᎐O), 818 (᎐CH); δ (250 MHz, CDCl ) 0.91 (3 H,
1
-nitromethylcyclopropanecarboxylate 20 as a colourless oil (22
H
3
mg, 0.11 mmol, 10%). This compound was identical to the
compound produced from the nitration of butyl 2-methylene-
propanoate by TLC, H NMR and IR spectroscopy.
t, J 7.0, Me), 1.30 (3 H, t, J 7.1, Me), 1.43 (4 H, m, CH ), 2.30 (2
2
H, t, J 6.8, CH ), 4.20 (2 H, q, J 7.1, OCH ), 5.50 (1 H, d, J 1.2,
2
2
1
᎐CH), 6.12 (1 H, s, ᎐CH); δ (67.8 MHz, CDCl ) 13.5 (Me), 13.8
C
3
(
Me), 22.0 (CH ), 30.4 (CH ), 31.3 (CH ), 60.1 (OCH ), 123.6
2 2 2 2
ϩ
Synthesis of ethyl 2-methylenepentanoate 26
(᎐CH ), 140.9 (᎐C), 166.8 (C᎐O); m/z (EI) 156 (M , 37%), 128
2
᎐ ᎐ ᎐
ϩ ϩ
(M Ϫ C H , 31), 111 (M Ϫ OEt, 63).
2 4
Potassium hydroxide (4.48 g, 80.0 mmol) in dry ethanol (70 ml)
was added dropwise over 2 h to a stirred solution of diethyl 2-
propylpropanedioate (16.1 g, 80 mmol) in dry ethanol (25 ml).
The solution was stirred at room temperature for 24 h and the
alcohol evaporated off. The high viscosity residue was dissolved
in water (30 ml) and extracted with dichloromethane (2 × 20
ml). The aqueous layer was cooled in ice and concentrated
hydrochloric acid (6.6 ml) was added dropwise. The reaction
mixture was extracted with diethyl ether (3 × 30 ml). The com-
bined organic extracts were dried over sodium sulfate and
evaporated to give ethyl hydrogen 2-propylpropanedioate as a
colourless oil (9.74 g, 56.0 mmol, 70%).
Nitration of ethyl 2-methylenepentanoate 26
Nitronium tetrafluoroborate (532 mg, 4.00 mmol) was added to
dry acetonitrile (20 ml) in a flame-dried flask flushed with nitro-
gen. The stirred solution was cooled in a salt–ice bath at Ϫ16 ЊC
and ethyl 2-methylenepentanoate (1.14 g, 8.03 mmol) was
added rapidly. The reaction was stirred for 3 h, water (30 ml)
was added and the reaction mixture extracted with dichloro-
methane (3 × 30 ml). The combined organic layers were washed
with water (30 ml), dried over sodium sulfate and evaporated to
give a pale yellow oil (992 mg). Column chromatography (10%
ethyl acetate–hexane) led to the isolation of ethyl 2-
Piperidine (600 mg, 7.06 mmol) and paraformaldehyde (1.68
J. Chem. Soc., Perkin Trans. 1, 1997
1565

View Article Online
nitromethylpent-2-enoate 28 as a colourless oil (171 mg, 0.91
mmol, 23%, NMR yield 21.4%) (Found: C, 51.4; H, 7.1; N, 7.6.
C H NO requires C, 51.3; H, 7.0; N, 7.5%) [Found:
was extracted with diethyl ether (3 × 30 ml). The combined
organic extracts were dried over sodium sulfate and evaporated.
Piperidine (430 mg, 5.06 mmol) and paraformaldehyde
(1.25 g, 42.5 mmol) were added to a solution of ethyl hydrogen
2-isopropylpropanedioate in pyridine (9 ml). The solution was
heated under reflux until the end of evolution of carbon
dioxide.
8
ϩ
13
4
M
Ϫ NO2 (EI), 141.0898. C H NO requires M Ϫ NO2,
8 13 4
Ϫ1
1
41.0916]; νmax(CHCl )/cm 2938, 2853 (CH), 1712 (C᎐O),
3
1
653 (C᎐C), 1564 (N᎐O), 1353 (N᎐O), 1152 (C᎐O); δ (400
᎐
᎐
᎐
H
MHz, CDCl ) 1.13 (3 H, t, J 7.5, CH ), 1.31 (3 H, t, J 7.3, CH ),
3
3
3
2
.32 (2 H, dq, J 7.5, 7.5, CH ), 4.25 (2 H, q, J 7.1, OCH ), 5.24
After cooling, the reaction was poured onto water (50 ml) and
extracted with pentane (3 × 50 ml). The pentane phases were
washed successively with water, 2  hydrochloric acid (20 ml),
water (20 ml), saturated aqueous sodium hydrogen carbonate
(20 ml) and brine (20 ml). The combined organic extracts were
dried over sodium sulfate and evaporated to give a colourless
oil. Column chromatography (2% ethyl acetate–petrol) led to
the isolation of ethyl 2-methylene-3-methylbutanoate 31 (3.19 g,
2
2
(2 H, s, CH NO ), 7.27 (1 H, t, J 7.8, ᎐CH); δ (67.8 MHz,
2
2
C
CDCl ) 12.7 (Me), 14.1 (Me), 25.6 (CH ), 61.4 (CH ), 70.1
3
2
2
(
(
(
CH ), 122.1 (᎐C), 153.3 (᎐CH), 165.3 (C᎐O); m/z (EI) 141
M
M
2
ϩ
ϩ
Ϫ NO2, 35%), 113 (M Ϫ NO Ϫ C H , 100), 95
2 2 4
ϩ
Ϫ OEt Ϫ HNO , 81), 67 (M Ϫ HNO Ϫ CO Et, 100);
ϩ
2
2
2
ϩ
ϩ
m/z (FAB) 188 [(M ϩ H) , 11%], 141 (M Ϫ NO , 12).
2
ϩ
Nitration of ethyl 2-methylenehexanoate 27
22.5 mmol, 42%) [Found: M (EI), 142.0968. C H O requires
8
14
2
Nitronium tetrafluoroborate (516 mg, 3.88 mmol) was added to
dry acetonitrile (20 ml) in a flame-dried flask flushed with nitro-
gen. The stirred solution was cooled in a salt–ice bath at Ϫ16 ЊC
and ethyl 2-methylenehexanoate (1.10 g, 7.05 mmol) was added
rapidly. The reaction was stirred for 3 h, water (30 ml) was
added and the reaction mixture extracted with dichloromethane
M, 142.0994] (Found: C, 67.3; H, 10.2. C H O requires C,
8 14 2
Ϫ1
67.6; H, 9.9%); νmax(film)/cm 2965, 2874 (CH), 1719 (C᎐O),
1626 (C᎐C), 1183 (C᎐O); δ (250 MHz, CDCl ) 1.08 (6 H, d, J
H
3
6.8, Me), 1.31 (3 H, t, J 7.1, Me), 2.82 (1 H, br qq, J 6.8, 6.8,
CH), 4.21 (2 H, q, J 7.1, OCH ), 5.50 (1 H, dd, J 1.1, 1.1, ᎐CH),
2
6.12 (1 H, br s, ᎐CH); δ (67.8 MHz, CDCl ) 13.9 (Me), 21.4 (2
C
3
(
3 × 30 ml). The combined organic layers were washed with
Me), 29.0 (CH), 60.0 (OCH ), 121.0 (᎐CH ), 147.1 (᎐C), 166.9
2 2
ϩ ϩ
water (30 ml), dried over sodium sulfate and evaporated to give
a pale yellow oil (1.30 g). Column chromatography (10% ethyl
acetate–hexane) led to the isolation of ethyl 2-nitromethylhex-2-
enoate 29 as a colourless oil (94.1 mg, 0.47 mmol, 12%) (Found:
C, 53.8; H, 7.8; N, 6.9. C H NO requires C, 53.7; H, 7.5; N,
(C᎐O); m/z (EI) 142 (M , 8%), 127 (M Ϫ Me, 6), 114
ϩ ϩ ϩ
(M Ϫ C H , 24), 97 (M Ϫ OEt, 47), 69 (M Ϫ CO Et, 100).
2
4
2
Nitration of ethyl 2-methylene-3-methylbutanoate 31
Nitronium tetrafluoroborate (504 mg, 3.79 mmol) was added to
dry acetonitrile (20 ml) in a flame-dried flask flushed with nitro-
gen. The stirred solution was cooled in a salt–ice bath at Ϫ16 ЊC
and ethyl 2-methylene-3-methylbutanoate (1.07 g, 7.57 mmol)
was added rapidly. The reaction was stirred for 2 h, water (50
ml) was added and the reaction mixture extracted with dichlo-
romethane (3 × 30 ml). The combined organic layers were
washed with water (30 ml), dried over sodium sulfate and evap-
orated to give a pale yellow oil (852 mg). Column chroma-
tography (8–70–100% ethyl acetate–pentane) led to the isolation
of 3-ethoxycarbonyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)butan-2-
yl nitrate 35 as a 2:3 mixture of diastereomers, as a colourless
9
15
4
ϩ
7
.0%) [Found: M Ϫ OEt (EI), 156.0723. C H NO requires
9 15 4
Ϫ1
M Ϫ OEt, 156.0661]; νmax(CHCl )/cm 2935, 2874 (CH), 1713
(
δ (250 MHz, CDCl ) 0.97 (3 H, t, J 7.4, Me), 1.31 (3 H, t, J 7.0,
Me), 1.55 (2 H, m, CH ), 2.27 (2 H, m, CH ), 4.25 (2 H, q, J 7.0,
OCH ), 5.25 (2 H, s, CH NO ), 7.28 (1 H, t, J 7.6, ᎐CH); δ (67.8
MHz, CDCl ) 13.6 (Me), 14.0 (Me), 21.5 (CH ), 31.0 (CH ),
6
3
C᎐O), 1652 (C᎐C), 1565 (N᎐O), 1353 (N᎐O), 1151 (C᎐O);
᎐ ᎐ ᎐ ᎐
H
3
2
2
2
2
2
C
3
2
2
1.3 (CH ), 70.2 (CH NO ), 122.7 (C), 151.8 (CH), 165.2
2 2 2
ϩ ϩ
(C᎐O); m/z (EI) 156 (M Ϫ OEt, 16%), 155 (M Ϫ NO , 28),
᎐
2
ϩ
ϩ
1
27 (M Ϫ NO Ϫ C H , 27), 109 (C H N , 79).
2 2 4 7 11
32
ϩ
Synthesis of diethyl 2-isopropylpropanedioate
oil (176 mg, 0.64 mmol, 17.0%) [Found: (M ϩ H) (EI),
ϩ
Sodium (960 mg, 41.7 mmol) was added to dry ethanol (20 ml)
in a flask flushed with nitrogen. When the sodium had dis-
solved, the stirred solution was brought to 55 ЊC and diethyl
propanedioate (6.50 g, 6.16 ml, 40.7 mmol) was added over 30 s.
After stirring for 1 h, 2-bromopropane (3.61 ml, 5 g, 40.65
mmol) was added over 1 min. The solution was stirred at 55 ЊC
for 44 h and the alcohol evaporated off. The residue was taken
up in water (30 ml) and extracted with dichloromethane (3 × 30
ml). The combined organic extracts were dried over sodium
sulfate and evaporated to give a pale yellow liquid (6.79 g).
Column chromatography of a 500 mg aliquot (10% ethyl
acetate–hexane) led to the isolation of diethyl 2-isopropylpro-
panedioate as a colourless oil (320 mg, 1.58 mmol, 52%)
274.0987. C H N O requires (M ϩ H) , 274.1039] (Found:
1
0
15
3
6
C, 44.3; H, 5.8; N, 15.3. C H N O requires C, 44.0; H, 5.5; N,
1
0
15
3
6
Ϫ1
15.4%); νmax(film)/cm 2989, 2907 (CH), 1743 (C᎐O), 1634
(ON᎐O), 1588 (C᎐N), 1280 (ON᎐O); δ (250 MHz, CDCl ) 1.22
H
3
(t, J 7.1, Me), 1.24 (t, J 7.1, Me)*, 1.36 (d, J 6.5, Me), 1.41 (d, J
6.5, Me)*, 1.70 (s, Me)*, 1.71 (s, Me), 2.59 (s, Me)*, 2.61 (s,
Me), 4.20 (2 H in 2 diastereomers, m, OCH ), 5.96 (q, J 6.5,
2
CH)*, 6.04 (q, J 6.5, CH); δ (67.8 MHz, CDCl ) 12.4 (Me),
C
3
13.9 (Me), 13.9 (Me)*, 14.6 (Me), 15.6 (Me), 16.7 (Me)*, 50.6
(C), 50.8 (C)*, 62.4 (CH ), 62.4 (CH )*, 80.2 (CHONO )*, 80.4
2
2
2
(CHONO ), 169.3 (᎐C), 169.7 (᎐C)*, 169.8 (᎐C), 176.9 (᎐C)*,
2
ϩ
ϩ
177.2 (᎐C); m/z (EI) 274 [(M ϩ H) , 2%], 211 (M Ϫ ONO , 5),
183 (M Ϫ ONO Ϫ C H , 9), 155 (C H N O , 21), 138
2
ϩ
ϩ
2
2
4
7
11
2
2
ϩ
ϩ
(Found: C, 59.7; H, 9.3. C H O requires C, 59.4; H, 9.0%)
(C H N O , 59), 43 (C H O , 100); m/z (FAB) 547 [(2
6 6 2 2 2 3
ϩ ϩ ϩ
1
0
18
4
ϩ
[
Found:
M
Ϫ C H6 (EI), 160.0733. C H O requires
Ϫ C H , 160.0736]; νmax(film)/cm 2939, 2876 (CH), 1735
M ϩ H) , 3%], 274 [(M ϩ H) , 100], 227 (M Ϫ NO , 9), 211
2
ϩ ϩ
3
10 18
4
ϩ
Ϫ1
M
(M Ϫ ONO2, 16), 138 (C H N O , 51); and ethyl 2-
6 6 2 2
3
6
(
C᎐O); δ (250 MHz, CDCl ) 1.00 (6 H, d, J 6.7, Me), 1.27 (6 H,
nitromethyl-2-methyl-3-acetamidobutanoate 33 as a 1:4 mixture
᎐
H
3
t, J 7.2, Me), 2.38 (1 H, m, CH), 3.10 (1 H, d, J 8.6, CH), 4.19 (4
of diastereomers, as a white solid (343 mg, 1.39 mmol, 37%);
ϩ
H, J 7.2, OCH ); δ (67.8 MHz, CDCl ) 13.7 (2 Me), 20.0 (2
mp 92–95 ЊC [Found: (M ϩ H) (FAB), 247.1292. C H N O
2
C
3
10 18
2
5
ϩ
Ϫ1
Me), 28.3 (CH), 58.7 (CH), 60.6 (2 CH ), 168.4 (2 C᎐O); m/z
requires (M ϩ H) , 247.1294]; ν (CHCl )/cm 3434 (N᎐H),
2
max 3
ϩ
ϩ
(
EI) 160 (M Ϫ C H , 100%), 157 (M Ϫ OEt, 76).
2991 (CH), 2942 (CH), 1737 (C᎐O), 1674 (C᎐O), 1558 (N᎐O),
᎐ ᎐ ᎐
3
6
1
373 (N᎐O); δ (250 MHz, CDCl ) 1.08 (d, J 6.9, Me), 1.12 (d, J
᎐
H
3
31
Synthesis of ethyl 2-methylene-3-methylbutanoate 31
6.9, Me)*, 1.23 (s, Me), 1.27 (t, J 7.1, Me), 1.30 (t, J 7.1, Me)*,
1.97 (s, Me)*, 1.99 (s, Me), 4.21 (2 H in 2 diastereomers, q, J 7.1,
OCH ), 4.30 (d, J 13.5, CH NO ), 4.35 (1 H in 2 diastereomers,
Potassium hydroxide (2.98 g, 53.2 mmol) in dry ethanol (32 ml)
was added dropwise over 30 min to a solution of diethyl 2-
isopropylpropanedioate (10.8 g, 10.9 ml, 53.5 mmol) in dry
ethanol (32 ml). The solution was stirred at room temperature
for 12 h and the alcohol evaporated off. The high viscosity resi-
due was dissolved in water (30 ml) and concentrated hydro-
chloric acid (4.4 ml) was added dropwise. The reaction mixture
2
2
2
m, CH), 4.91 (d, J 13.5, CH NO )*, 4.96 (d, J 13.5, CH NO ),
2
2
2
2
6.29 (br d, J 8.5, NH)*, 6.43 (br d, J 8.5, NH); δ (67.8 MHz,
C
CDCl ) 14.2 (Me), 14.3 (Me), 16.7 (Me), 16.9 (Me)*, 18.0
3
(Me)*, 23.5 (Me), 23.6 (Me)*, 48.3 (CH), 49.7 (CH)*, 49.9 (C)*,
51.2 (C), 62.2 (CH ), 62.3 (CH )*, 81.3 (CH NO ), 81.4
2
2
2
2
1
566
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
(
(
(
CH NO )*, 170.0 (C᎐O)*, 170.6 (C᎐O), 172.6 (C᎐O), 172.9
oil (700 mg). Column chromatography (8–70% ethyl acetate–
2
2
᎐
᎐
᎐
ϩ
ϩ
C᎐O)*; m/z (EI) 247 [(M ϩ H) , 2%], 189 (C H NO , 7), 86
hexane) led to the isolation of 3-ethoxycarbonyl-3-(5-methyl-
᎐
8
15
4
ϩ
ϩ
2
C H NO , 100); m/z (FAB) 493 [(2 M ϩ H) , 11%], 247
4
1,2,4-oxadiazol-3-yl)[ H ]butan-2-yl nitrate 39 as a 3:4 mixture
8
7
ϩ
ϩ
[
(M ϩ H) , 100], 200 (M Ϫ NO , 10).
of diastereomers, as a colourless oil (228 mg, 0.80 mmol,
2
ϩ
1
7.3%) [Found: (M ϩ H) (FAB), 281.1476. C H D N O
1
0
8
7
3
6
2
33
ϩ
Ϫ1
Synthesis of diethyl 2-([ H ]isopropyl)propanedioate
requires (M ϩ H) , 281.1478]; ν (CHCl )/cm 2915 (CH),
7
max 3
Sodium (980 mg, 42.6 mmol) was added to dry ethanol (20 ml)
in a flask flushed with nitrogen. When the sodium had dis-
solved, the solution was brought to 52 ЊC and diethyl propane-
2247 (C᎐D), 1738 (C᎐O), 1644 (ON᎐O), 1587 (C᎐N), 1298
᎐ ᎐ ᎐
3 Ϫ1 Ϫ1
(ON᎐O); λ /nm 217.7 (ε/dm mol cm 290); δ (400 MHz,
᎐
max
H
CDCl ) 1.23 (t, J 7.1, Me), 1.25 (t, J 7.1, Me)*, 2.59 (s, Me),
3
dioate (6.50 g, 6.16 ml, 40.7 mmol) was added over 5 min. After
2.60 (s, Me), 4.21 (2 H in 2 diastereomers, m, OCH ); δ (100
2
C
2
stirring for 1 h, 2-bromo[ H ]propane (3.61 ml, 5.00 g, 40.7
MHz, CDCl ) 12.2 (Me), 13.7 (Me), 13.7 (Me)*, 15.0 (m, CD ),
7
3
3
mmol) was added over 1 min. The solution was stirred at 52 ЊC
for 44 h and the alcohol distilled off. The residue was taken up
in water (40 ml) and extracted with dichloromethane (3 × 40
ml). The combined organic extracts were washed with water,
dried over sodium sulfate and evaporated to give an orange
62.2 (OCH ), 62.2 (CH )*, 79.5 (m, CD), 169.1 (᎐C)*, 169.5
2 2
(᎐C), 169.6 (᎐C), 176.8 (᎐C)*, 177.0 (᎐C); m/z (FAB) 281
ϩ
ϩ
[(M ϩ H) , 15%], 219 (M Ϫ ONO ϩ H, 4); m/z (EI) 235
2
ϩ
ϩ
(M Ϫ OEt, 2%), 141 (C H D O N , 66); and two separable
diastereomers of ethyl 2-nitromethyl-2-[ H ]methyl-3-aceta-
mido[ H ]butanoate 38. Diastereomer 1 was a white solid (45.1
mg, 0.18 mmol, 3.8%) [Found: (M ϩ H) (EI), 254.1749.
6
3
3
2
2
2
3
2
liquid (8.44 g). Column chromatography (10% ethyl acetate–
4
2
ϩ
hexane) led to the isolation of diethyl 2-([ H ]isopropyl)pro-
7
ϩ
panedioate as a colourless oil (6.33 g, 30.3 mmol, 75%);
C H D N O requires (M ϩ H) , 254.1733]; ν (CHCl )/
1
0
Ϫ1
12
7
2
5
max
3
Ϫ1
νmax(film)/cm 2983, 2939 (CH), 2222 (C᎐D), 1733 (C᎐O);
cm 3436 (N᎐H), 1722 (C᎐O), 1682 (C᎐O), 1561 (N᎐O), 1373
(N᎐O); δ (400 MHz, CDCl ) 1.30 (3 H, t, J 7.1, Me), 1.95 (3 H,
δ (250 MHz, CDCl ) 1.27 (6 H, t, J 7.1, Me), 3.10 (1 H, s, CH),
H
3
᎐
H
3
4
1
.19 (4 H, q, J 7.1, OCH ); δ (100 MHz, CDCl ) 13.9 (2 Me),
s, Me), 4.21 (2 H, q, J 7.1, OCH ), 4.55 (1 H, d, J 14.5, CH ),
4.85 (1 H, d, J 14.5, CH ), 5.67 (1 H, br s, NH); δ (100 MHz,
2 C
2
C
3
2
2
9.1 (m, CD ), 27.8 (m, CD), 58.7 (CH), 60.9 (2 OCH ), 168.7
3
2
ϩ
ϩ
(2 C᎐O); m/z (FAB) 210 [(M ϩ H) , 15%], 164 (M Ϫ OEt, 12),
CDCl ) 14.1 (Me), 24.2 (Me), 24.8 (m, CD ), 49.5 (m, CD), 53.5
᎐
3
3
ϩ
1
36 (M Ϫ CO Et, 47).
(C), 61.6 (OCH ), 73.4 (CH NO ), 170.2 (C᎐O), 171.1 (C᎐O);
2 2 2
ϩ ϩ
2
m/z (EI) 254 [(M ϩ H) , 5%], 223 (M Ϫ NO, 10). Diastereo-
mer 2 was a white solid (151 mg, 0.60 mmol, 13%) [Found:
2
2
Synthesis of ethyl 2-methylene-3-[ H ]methyl[ H ]butanoate 37
3
4
ϩ
Potassium hydroxide (1.67 g, 29.8 mmol) in dry ethanol was
added over 5 min to stirred solution of diethyl 2-
[ H ]isopropyl)propanedioate in dry ethanol (15 ml). After
(M ϩ H) (FAB), 254.1747. C H D N O requires (M ϩ
1
0
12
7
2
5
ϩ
Ϫ1
a
H) , 254.1733]; ν (CHCl )/cm 3435 (N᎐H), 2992 (CH),
max 3
2
(
2360, 2238 (C᎐D), 1735, 1675 (C᎐O), 1557 (N᎐O), 1376 (N᎐O);
δ (400 MHz, CDCl ) 1.31 (3 H, t, J 7.1, Me), 2.02 (3 H, s, Me),
7
stirring for 2.5 days, the ethanol was evaporated off. The vis-
cous residue was taken up in water (25 ml) and extracted with
dichloromethane (2 × 25 ml). To the aqueous layer was added
concentrated hydrochloric acid (1.6 ml) and the reaction stirred
for 15 min. The reaction was extracted with dichloromethane
H
3
4.25 (2 H, q, J 7.1, OCH ), 4.35 (1 H, d, J 13.5, CH ), 4.99 (1 H,
2
2
d, J 13.5, CH ), 6.37 (1 H, br s, NH); δ (100 MHz, CDCl )
2
C
3
13.02 (m, CD ), 13.92 (Me), 15.46 (m, CD ), 23.17 (Me), 47.43
3
3
(m, CD), 50.48 (C), 61.83 (CH ), 80.94 (CH ), 170.14 (C᎐O),
2
2
ϩ
(3 × 25 ml), dried over sodium sulfate and evaporated to give
172.20 (C᎐O); m/z (FAB) 254 [(M ϩ H) , 100%].
2
ethyl hydrogen 2-([ H ]isopropyl)propanedioate as a colourless
7
oil (4.67 g, 25.8 mmol, 87%).
Synthesis of ethyl 2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoate
42
2
Ethyl hydrogen 2-([ H ]isopropyl)propanedioate (4.67 g, 25.8
7
mmol) was dissolved in pyridine (15 ml) and then piperidine
To a solution of the nitrate ester 35 (300 mg, 1.10 mmol) in dry
benzene (60 ml), was added tributyltin hydride (294 µl, 320 mg,
1.10 mmol) and AIBN (60.0 mg, 0.36 mmol, 0.3 equiv.). The
solution was refluxed for 3.5 h and the solvent was evaporated to
give a pale yellow oil. Column chromatography (10% ethyl
acetate–hexane) led to the isolation of ethyl 2-(5-methyl-1,2,4-
(336 mg, 3.95 mmol) and paraformaldehyde (774 mg, 25.8
mmol) were added. The suspension was refluxed until the end
of evolution of carbon dioxide (ca. 3 h). After cooling, water
(
(
30 ml) was added and the reaction extracted with pentane
3 × 30 ml). The combined organic extracts were washed with
water (20 ml), 2  hydrochloric acid (20 ml), water (20 ml),
saturated aqueous sodium hydrogen carbonate (20 ml), brine
oxadiazol-3-yl)propanoate 42 as a colourless oil (124 mg, 0.67
Ϫ1
mmol, 61%); νmax(CHCl )/cm 2988, 2943 (CH), 1742 (C᎐O),
3
(20 ml), dried over sodium sulfate and evaporated to give
1589 (C᎐N); δ (400 MHz, CDCl ) 1.26 (3 H, t, J 7.1, Me), 1.59 (3
H
3
a colourless oil (3 g). Column chromatography (3% diethyl
H, d, J 7.2, Me), 2.59 (3 H, s, Me), 3.95 (1 H, q, J 7.2, CH), 4.19 (2
H, m, OCH ); δ (67.8 MHz, CDCl ) 12.3 (Me), 14.0 (Me), 15.0
ether–pentane) led to the isolation of ethyl 2-methylene-3-
2
C
3
2
2
[
H ]methyl[ H ]butanoate 37 as a colourless oil (2.60 g, 12.4
(Me), 37.9 (CH), 61.5 (CH ), 169.2 (᎐C), 170.8 (᎐C), 176.7 (᎐C).
3
4
2
ϩ
mmol, 48% from half ester, 41.6% overall) [Found: M (EI),
Ϫ1
1
49.1421. C H D O requires M, 149.1424]; νmax(film)/cm
2-(5-Methyl-1,2,4-oxadiazol-3-yl)propanoic acid
8
7
7
2
2
982, 2937 (CH), 2221 (C᎐D), 1717 (C᎐O), 759 (C᎐CH ); δ (250
Potassium hydroxide (33.6 mg, 0.6 mmol) was added to a stirred
solution of ethyl 2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoate
42 (99.3 mg, 0.54 mmol) in ethanol (6 ml). After stirring for 20 h,
the ethanol was evaporated. The residue taken up in water and
extracted with dichloromethane (1 × 20 ml). The aqueous layer
was acidified with concentrated hydrochloric acid and then
extracted with dichloromethane (2 × 20 ml). The combined
organic layers were dried over sodium sulfate and evaporated to
give 2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoic acid as a pale
yellow oil (35.5 mg, 0.23 mmol, 42%); δ (250 MHz, CDCl ) 1.59
᎐
᎐
2
H
MHz, CDCl ) 1.31 (3 H, t, J 7.1, Me), 4.21 (2 H, q, J 7.1,
OCH ), 5.49 (1 H, d, J 1.1, ᎐CH ), 6.11 (1 H, d, J 1.1, CH );
3
2
2
2
δ (100 MHz, CDCl ) 14.1 (Me), 20.6 (m, 2 CD ), 28.5 (m, CD),
C
3
3
6
0.3 (CH ), 122.8 (᎐CH ), 147.3 (᎐C), 167.3 (C᎐O); m/z (EI)
2 2
ϩ ϩ ϩ ϩ
M , 149 (M , 35%), 121 (M Ϫ C H , 26), 104 (M Ϫ OEt,
2
4
ϩ
6
7), 76 (M Ϫ CO Et, 100).
2
2
2
Nitration of ethyl 2-methylene-3-[ H ]methyl[ H ]butanoate 37
3
4
Nitronium tetrafluoroborate (615 mg, 4.62 mmol) was added to
dry acetonitrile (20 ml) in a flask flushed with nitrogen. The
stirred solution was cooled in a bath at Ϫ16 ЊC, ethyl 2-
H
3
(3 H, d, J 7.3, Me), 2.59 (3 H, s, Me), 3.99 (1 H, q, J 7.3, CH),
9.29 (1 H, br s, CO H); δ (67.8 MHz, CDCl ) 12.3 (Me), 29.7
2
C
3
2
2
methylene-3-[ H ]methyl[ H ]butanoate (689 mg, 4.62 mmol)
(Me), 37.6 (CH), 168.6 (᎐C), 175.8 (᎐C), 177.1 (᎐C).
3
4
was added in one portion. After stirring for 4 h, water (30 ml)
was added and the reaction extracted with dichloromethane
Synthesis of 2-(5-methyl-1,2,4-oxadiazol-3-yl)propananilide 43
2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoic acid (54 mg, 0.346
mmol) was dissolved in dichloromethane (10 ml) and oxalyl
(3 × 30 ml). The combined organic extracts were washed with
water, dried over sodium sulfate and evaporated to give a yellow
J. Chem. Soc., Perkin Trans. 1, 1997
1567

View Article Online
Table 1 Crystal data and structure refinement for 43
ml), water (20 ml), saturated aqueous sodium hydrogen carbon-
ate (20 ml) and brine (20 ml). The combined organic extracts
were dried over sodium sulfate and evaporated to give a colour-
less oil. Column chromatography (15% dichloromethane–
petrol) led to the separation of ethyl 2-methylene-3,3-
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
C H N O
12 13 3 2
231.10
293(2) K
0.710 69 Å
Monoclinic
P2(1)/a
dimethylbutanoate 32 as a colourless oil (300 mg, 1.92 mmol,
Ϫ1
8.3%); νmax(film)/cm 2928 (CH), 1712 (C᎐O), 1115 (C᎐O);
᎐
Unit cell dimension
a 9.2294(11) Å
b 11.7100(11) Å
c 11.1879(9) Å
β 95.034(13)Њ
t
δ (250 MHz, CDCl ) 1.21 (9 H, s, Bu ), 1.31 (3 H, t, J 7.1, Me),
H
3
4
᎐
᎐
.20 (2 H, q, J 7.1, OCH ), 5.51 (1 H, s, ᎐CH), 5.92 (1 H, s,
2
t
CH); δ (67.8 MHz, CDCl ) 14.1 (Me), 29.3 (Bu ), 34.8 (C), 60.1
C 3
3
(CH ), 120.5 (CH ), 150.3 (᎐C), 167.9 (C᎐O).
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
Crystal size
θ Range for data collected
Index ranges
1204.5(2) Å
4
2
2
᎐ ᎐
Ϫ3
1.275 Mg m
Nitration of 2-methylene-3,3-dimethylbutanoate 32
Ϫ1
0.090 mm
Nitronium tetrafluoroborate (140 mg, 1.05 mmol) was added to
dry acetonitrile (12 ml) in a flame-dried flask flushed with nitro-
gen. The stirred solution was cooled in a salt–ice bath at Ϫ16 ЊC
and ethyl 2-methylene-3,3-dimethylbutanoate (200 mg, 1.30
mmol) was added rapidly. The reaction was stirred for 2 h,
water (30 ml) was added and the reaction mixture extracted
with dichloromethane (3 × 30 ml). The combined organic layers
were washed with water (30 ml), dried over sodium sulfate and
evaporated to give a colourless semi-solid (190 mg). Column
chromatography (30–70% ethyl acetate–hexane) led to the
488
0.27 × 0.19 × 0.16 mm
1.83 to 24.97Њ
Ϫ7 ≤ h ≤ 10, Ϫ12 ≤ k ≤ 13,
Ϫ12 ≤ l ≤ 11
4821
1771 (Rint = 0.0571)
Full-matrix least-squares on F
1771/0/156
Reflections collected
Independent reflections
Refinement method
Data/restraints/parameters
Goodness of fit on F
Final R indices [I > 2σ(I)]
R indices (all data)
Largest diff. peak and hole
2
2
0.891
R1 0.0489, wR2 0.1109
R1 0.0743, wR2 0.1164
0.188 and Ϫ0.195 e Å
isolation
of
2-methyl-3-ethoxycarbonyl-3-(5-methyl-1,2,4-
Ϫ3
oxadiazol-3-yl)butan-2-yl nitrate 36 as a colourless oil (24.2 mg,
ϩ
0
.084 mmol, 7.9%) [Found: (M ϩ H) (FAB), 288.1169.
ϩ Ϫ1
C H N O requires (M ϩ H) , 288.1196]; νmax/cm 2991,
1
1
17
3
6
chloride (220 mg, 1.73 mmol, 151 µl) was added. After stirring
for 1 h, the solvent was evaporated. The residue was taken up in
dichloromethane (10 ml) and aniline (50.0 mg, 0.54 mmol, 49 µl)
was added. After stirring for 1.5 h, 2  hydrochloric acid was
added and the reaction extracted with dichloromethane
2939 (CH), 1732 (C᎐O), 1633 (ON᎐O), 1590 (C᎐N), 1297
᎐ ᎐ ᎐
(ON᎐O); δ (250 MHz, CDCl ) 1.25 (3 H, t, J 7.1, Me), 1.79 (3
᎐
H
3
H, s, Me), 1.89 (3 H, s, Me), 2.60 (3 H, s, Me), 4.23 (2 H, m,
OCH ); δ (100 MHz, CDCl ) 12.1 (Me), 13.6 (Me), 18.7 (Me),
2
C
3
22.0 (Me), 22.1 (Me), 54.7 (C), 61.8 (OCH ), 92.8 (C), 169.5
2
ϩ
(3 × 10 ml). Column chromatography (50% ethyl acetate–
(᎐C), 169.7 (᎐C), 175.7 (᎐C); m/z (FAB) 288 [(M ϩ H) , 75%],
ϩ
ϩ
hexane) led to the isolation of 2-(5-methyl-1,2,4-oxadiazol-3-
yl)propananilide 43 as a white solid (35.7 mg, 0.15 mmol, 43%);
mp 105–107 ЊC (Found: C, 62.4; H, 5.9; N, 18.2. C H N O
225 (M Ϫ ONO , 100), 184 (M Ϫ ONO Ϫ MeCN, 49), 138
2 2
ϩ
(M Ϫ HNO Ϫ MeCN Ϫ OEt, 40); and ethyl 2,3-dimethyl-2-
3
nitromethyl-3-acetamidobutanoate 34 as a white solid (23 mg,
1
2
13
3
2
ϩ
ϩ
requires C, 62.3; H, 5.7; N, 18.2%) [Found: M (EI), 231.1005.
0.088 mmol, 8.4%); mp 78–80 ЊC [Found: (M ϩ H) (FAB),
Ϫ1
ϩ
C N N O requires M, 231.1008]; νmax(CHCl )/cm 3684,
261.1474. C H N O requires (M ϩ H) , 261.1450]; νmax-
1
2
13
3
2
3
11 20
Ϫ1
2
5
3
620, 3338 (N᎐H), 3028 (CH), 1693 (C᎐O), 1601, 1589, 1549
(CHCl )/cm 3434, 3367 (N᎐H), 2941, 2852 (CH), 1715 (C᎐O),
᎐
3
᎐
(
Ar C᎐C); δ (250 MHz, CDCl ) 1.69 (3 H, d, J 7.2, Me), 2.64 (3
1682 (C᎐O), 1564 (N᎐O), 1367 (N᎐O); δ (250 MHz, CDCl )
᎐ ᎐ ᎐
H 3
᎐
H
3
H, s, Me), 3.98 (1 H, q, J 7.2, CH), 7.10 (1 H, dd, J 7.6, 7.6,
ArH), 7.32 (2 H, dd, J 7.6, 7.6, ArH), 7.52 (2 H, d, J 7.6, ArH),
1.33 (3 H, t, J 7.1, Me), 1.33 (3 H, s, Me), 1.39 (3 H, s, Me), 1.51
(3 H, s, Me), 1.96 (3 H, s, Me), 4.27 (2 H, m, OCH ), 4.68 (1 H,
2
8
.33 (1 H, br s, NH); δ (67.8 MHz, CDCl ) 12.4 (Me), 15.8
d, J 13.8, CH ), 5.11 (1 H, d, J 13.8, CH ), 6.05 (1 H, s, NH);
C
3
2
2
(
Me), 39.9 (CH), 119.9 (CH), 124.5 (CH), 129.0 (CH), 137.6
δ (100 MHz, CDCl ) 13.4 (Me), 15.3 (Me), 22.5 (Me), 23.3
C
3
ϩ
(C), 167.6 (᎐C), 169.6 (᎐C), 177.1 (᎐C); m/z (EI) 231 (M , 50%),
(Me), 24.3 (Me), 52.7 (C), 57.1 (C), 61.5 (OCH ), 79.6
᎐
᎐
᎐
2
ϩ
ϩ
1
12 (C H N O , 63), 93 (PhNH , 100). Crystallisation from
(CH NO ), 169.5 (C᎐O), 172.6 (C᎐O); m/z (FAB) 261
5
8
2
2
2
2
ϩ
dichloromethane–ethyl acetate by slow evaporation led to the
isolation of white needles which allowed an X-ray crystal struc-
ture to be determined, see Table 1.§
[(M ϩ H) , 72%], 154 (57), 69 (81), 55 (100).
Synthesis of diethyl 2-cyclopentylpropanedioate
Sodium (1.60 g, 69.6 mmol) was added to dry ethanol (50 ml) in
a flask flushed with nitrogen. The solution was brought to reflux
and diethyl propanedioate (10.7 g, 10.2 ml, 67.0 mmol) was
added. After refluxing for 45 min, cyclopentyl bromide (10.0 g,
10.2 ml, 67.0 mmol) was added. After refluxing for 20 h, the
ethanol was distilled off and the residue taken up in water (30
ml) and extracted with dichloromethane (3 × 30 ml). The com-
bined organic extracts were dried over sodium sulfate and evap-
orated to give a colourless liquid (15.0 g). Distillation gave
diethyl 2-cyclopentylpropanedioate as a colourless liquid (12.6
Ethyl 2-methylene-3,3-dimethylbutanoate 32
Potassium hydroxide (1.29 g, 23.15 mmol) in dry ethanol (25
ml) was added dropwise over 2 h to a stirred solution of diethyl
2
-tert-butylpropanedioate (5.00 g, 23.2 mmol) in dry ethanol
(25 ml). The solution was stirred at room temperature for 5 days
and then the alcohol was evaporated off. The high viscosity
residue was dissolved in water (30 ml) and extracted with
dichloromethane (3 × 20 ml). The aqueous layer was cooled in
ice and concentrated hydrochloric acid (2.2 ml) was added drop-
wise. The reaction mixture was extracted with dichloromethane
3
4
g, 55.3 mmol, 79%); bp 102–105 ЊC/2 mmHg (lit., 115–117 ЊC/
(
3 × 30 ml). The combined organic extracts were dried over
2 mmHg) (Found: C, 63.1; H, 8.9. C H O requires C, 63.1; H,
1
2
20
4
ϩ
sodium sulfate and evaporated to give a colourless oil (3.0 g).
Piperidine (225 mg, 2.65 mmol) and paraformaldehyde (570
mg, 19.0 mmol) were added to a solution of the ethyl hydrogen
8.8%) [Found: M Ϫ OEt (EI), 183.1015. C H O requires
12 20 4
Ϫ1
M Ϫ OEt, 183.1021]; νmax(film)/cm 2958, 2871 (CH), 1753
and 1734 (C᎐O), 1147 (C᎐O); δ (270 MHz, CDCl ) 1.27 (8 H,
H
3
2
-tert-butylpropanedioate in pyridine (7 ml). The solution was
m, CH and Me), 1.57 (4 H, m, CH ), 1.84 (2 H, m, CH ), 2.48
2
2
2
heated under reflux until the end of evolution of carbon
dioxide.
(1 H, m, CH), 3.17 (1 H, d, J 10.3, CH), 4.19 (4 H, q, J 7.2,
OCH ); δ (67.8 MHz, CDCl ) 13.5 (2 Me), 24.2 (2 CH ), 30.2 (2
2
C
3
2
After cooling, the reaction was poured onto water (30 ml)
and extracted with pentane (3 × 50 ml). The pentane phases
were washed successively with water, 2  hydrochloric acid (20
CH ), 39.1 (CH), 56.8 (CH), 60.4 (2 OCH ), 168.3 (2 C᎐O);
2 2
ϩ ϩ
m/z (EI) 183 (M Ϫ OEt, 25%), 160 (M Ϫ C H , 100), 133
5
8
ϩ
(C H O , 31).
5
9
4
1
568
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
Synthesis of diethyl 2-cyclohexylpropanedioate
hydrogen 2-cyclohexylpropanedioate as a colourless oil (4.79 g,
Sodium (1.54 g, 66.9 mmol) was added to dry ethanol (50 ml) in
a flask flushed with nitrogen. The solution was brought to
reflux and diethyl propanedioate (10.7 g, 10.17 ml, 67.0 mmol)
was added. After refluxing for 30 min, cyclohexyl bromide (10.9
g, 18.3 ml, 67.0 mmol) was added. After refluxing for 20 h, the
ethanol was distilled off, the residue taken up in water (30 ml)
and extracted with dichloromethane (3 × 30 ml). The combined
organic extracts were dried over sodium sulfate and evaporated
to give a yellow liquid (13.3 g). Distillation gave diethyl 2-
cyclohexylpropanedioate as a colourless liquid (6.50 g, 26.8
22.4 mmol, 90%).
Ethyl hydrogen 2-cyclohexylpropanedioate (4.79 g, 22.4
mmol) was dissolved in pyridine (25 ml) and piperidine (35.0
mg, 0.42 mmol) and paraformaldehyde (890 mg, 22.4 mmol)
were added. The suspension was refluxed until the end of evolu-
tion of carbon dioxide. After cooling, water (30 ml) was added
and the reaction extracted with pentane (3 × 30 ml). The com-
bined pentane extracts were washed with water (30 ml), dilute
hydrochloric acid (30 ml), water (30 ml), saturated aqueous
sodium hydrogen carbonate (30 ml) and brine (30 ml) then
dried over sodium sulfate and evaporated to give a colourless
liquid (2.98 g).
3
5
mmol, 40%); bp 94–96 ЊC/0.6 mmHg (lit., 122–123 ЊC/4
ϩ
mmHg) [Found: M Ϫ OEt (EI), 197.1193. C H O requires
1
3
22
4
Ϫ1
M Ϫ OEt, 197.1178]; νmax(film)/cm 2981, 2929, 2854 (CH),
732 (C᎐O); δ (250 MHz, CDCl ) 1.08 (4 H, m, CH ), 1.27 (6
Column chromatography (4% diethyl ether–pentane) led to
the isolation of ethyl 2-cyclohexylprop-2-enoate 60 as a colour-
less liquid (2.90 g, 15.9 mmol, 64% overall, 72% from half ester)
1
᎐
H
3
2
H, t, J 7.2, Me), 1.27 (2 H, m, CH ), 1.69 (6 H, m, CH ), 2.07 (1
2
2
ϩ
H, m, CH), 3.13 (1 H, d, J 9.2, CH), 4.18 (4 H, q, J 7.2, OCH );
[Found: M (EI), 182.1305. C H O requires M, 182.1307];
2
11 18
2
Ϫ1
δ (67.8 MHz, CDCl ) 13.7 (2 Me), 25.6 (2 CH ), 25.7 (CH ),
νmax(film)/cm 2926, 2980, 2852 (CH), 1716 (C᎐O), 1627
(C᎐C); δ (400 MHz, CDCl ) 1.13 (2 H, m, CH ), 1.33 (2 H, m,
C
3
2
2
3
0.3 (2 CH ), 37.5 (CH), 57.9 (CH), 60.5 (2 OCH ), 168.9 (2
2 2
ϩ ϩ
᎐
H
3
2
C᎐O); m/z (EI) 197 (M Ϫ OEt, 16%), 160 (M Ϫ C H , 100),
1
CH ), 1.76 (6 H, m, CH ), 2.44 (1 H, m, CH), 4.20 (2 H, q, J 7.1,
᎐
6
10
2
2
ϩ
15 (C H O , 35).
OCH ), 5.46 (1 H, dd, J 1.0, 1.0, ᎐CH ), 6.09 (1 H, d, J 1.0,
2 2
5
7
3
᎐
᎐
CH ); δ (67.8 MHz, CDCl ) 14.0 (Me), 26.1 (CH ), 26.5 (2
2 C 3 2
Synthesis of ethyl 2-cyclopentylprop-2-enoate 59
CH ), 32.4 (2 CH ), 38.9 (CH), 60.3 (OCH ), 121.5 (᎐CH ),
2 2 2 2
᎐
ϩ
Potassium hydroxide (2.88 g, 51.3 mmol) in dry ethanol (30 ml)
was added to a stirred solution of diethyl 2-cyclopentyl-
propanedioate (11.7 g, 51.3 mmol) in dry ethanol (15 ml) over
146.4 (᎐C), 167.2 (C᎐O); m/z (EI) 182 (M , 57%), 153
᎐ ᎐
ϩ ϩ ϩ
(M Ϫ Et, 23), 137 (M Ϫ OEt, 52), 67 (C H , 100).
5
7
1
0 min. After stirring for 24 h, the ethanol was evaporated off
Nitration of ethyl 2-cyclopentylprop-2-enoate 59
and the viscous residue taken up in water (50 ml) and then
extracted with dichloromethane (2 × 20 ml). The aqueous layer
was acidified with concentrated hydrochloric acid (2.9 ml) and
extracted with dichloromethane (3 × 20 ml). The combined
organic extracts were dried over sodium sulfate and evaporated
to give ethyl hydrogen 2-cyclopentylpropanedioate as a colour-
less oil (8.79 g, 43.9 mmol, 86%).
Ethyl hydrogen 2-cyclopentylpropanedioate (8.79 g, 43.9
mmol) was dissolved in pyridine (32 ml) and piperidine (60.0
mg, 0.71 mmol) and paraformaldehyde (1.32 g, 44.0 mmol)
were added. The suspension was refluxed until the end of
evolution of carbon dioxide. After cooling, water (40 ml) was
added and the reaction extracted with pentane (3 × 75 ml). The
combined pentane extracts were washed with water (30 ml), 2 
hydrochloric acid (30 ml), water (30 ml), saturated aqueous
sodium hydrogen carbonate (30 ml) and brine (30 ml) then
dried over sodium sulfate and evaporated to give a colourless
liquid.
Nitronium tetrafluoroborate (995 mg, 7.48 mmol) was added to
dry acetonitrile (30 ml) in a flask flushed with nitrogen. The
stirred solution was cooled in an ice bath at Ϫ16 ЊC and ethyl 2-
cyclopentylprop-2-enoate (1.26 g, 7.48 mmol) was added in one
portion. The reaction was stirred for 4 h, water (30 ml) was
added and the reaction was extracted with dichloromethane
(3 × 30 ml). The combined organic extracts were washed with
water, dried over sodium sulfate and evaporated to give a yellow
oil (1.76 g). Column chromatography (10–30–50–70–100% ethyl
actate–hexane) led to the recovery of ethyl 2-cyclopentylprop-2-
enoate 59 as a colourless oil (180 mg, 1.07 mmol; 14.5%); and to
the isolation of 2-ethoxycarbonyl-2-(5-methyl-1,2,4-oxadiazol-3-
yl)cyclohexyl nitrate 63 as a 1:4 mixture of diastereomers, as a
colourless oil (234 mg, 0.78 mmol, 10.5%, 16% based on
ϩ
recovered starting material) [Found: (M ϩ H) (FAB),
ϩ
300.1159. C H N O
requires (M ϩ H) , 300.1196];
1
2
17
3
6
3
Ϫ1
Ϫ1
Ϫ1
λmax(EtOH)/nm 212 (ε/dm mol cm 1760); νmax(film)/cm
2944, 2869 (CH), 1738 (C᎐O), 1633 (ON᎐O), 1588 (C᎐N), 1281
(ON᎐O); δ (400 MHz, CDCl ) 1.19 (t, J 7.1, Me)*, 1.25 (t, J 7.2,
Column chromatography (10% diethyl ether–pentane), fol-
lowed by Kugelrohr distillation led to the isolation of ethyl 2-
cyclopentylprop-2-enoate 59 as a colourless liquid (4.80 g, 28.3
mmol, 55% overall, 64% from half ester); bp 135 ЊC/12 mmHg
H
3
Me), 1.45 (m, CH ), 1.65 (m, CH ), 2.02 (m, CH ), 2.22 (m,
2
2
2
CH ), 2.47 (m, CH ), 2.62 (s, Me), 2.66 (s, Me)*, 4.15 (m,
2
2
OCH )*, 4.26 (m, OCH ), 5.97 (m, CHONO ), 6.10 (m,
2
2
2
3
6
ϩ
(
lit., 50–51 ЊC/0.5 mmHg) [Found: M (EI), 168.1148;
CHONO )*; δ (100 MHz, CDCl ) 12.1 (Me), 13.7 (Me)*, 13.7
2
C
3
Ϫ1
C H O requires M, 168.1150]; νmax(film)/cm 2955, 2871
(Me), 19.7 (CH )*, 20.4 (CH ), 20.7 (CH )*, 21.5 (CH ), 25.9
2 2 2 2
1
0
16
2
(
CH), 1717 (C᎐O), 1628 (C᎐C); δ (250 MHz, CDCl ) 1.30 (3 H,
(CH )*, 26.3 (CH ), 27.9 (CH )*, 28.8 (CH ), 50.4 (C)*, 50.8 (C),
᎐
᎐
H
3
2 2 2 2
t, J 7.1, Me), 1.40 (2 H, m, CH ), 1.63 (4 H, m, CH ), 1.92 (2 H,
61.9 (OCH )*, 62.1 (OCH ), 79.8 (CH)*, 80.0 (CH), 168.4 (᎐C)*,
2 2
2
2
m, CH ), 2.86 (1 H, m, CH), 4.21 (2 H, q, J 7.1, OCH ), 5.52 (1
168.9 (᎐C), 168.9 (᎐C)*, 169.2 (᎐C), 176.7 (᎐C), 177.1 (᎐C)*; m/z
᎐ ᎐ ᎐ ᎐ ᎐
ϩ ϩ
2
2
H, dd, J 1.1, 1.1, CH ), 6.10 (1 H, dd, J 1.1, 1.1, CH ); δ (67.8
(FAB) 300 [(M ϩ H) , 100%], 253 (M Ϫ NO , 9), 237
2
ϩ ϩ
2
2
C
MHz, CDCl ) 13.9 (2 Me), 24.7 (2 CH ), 31.6 (2 CH ), 41.2
(M Ϫ ONO , 5), 226 (M Ϫ NO Ϫ C H ϩ H, 17); and two
2 2 2 4
3
2
2
(
CH), 60.1 (OCH ), 121.1 (᎐CH ), 144.6 (᎐C), 167.2 (2 C᎐O);
separable diastereomers of ethyl 2-acetamido-1-nitromethyl-
cyclohexanecarboxylate 61. Diastereomer 1 was a white crystal-
line solid (127 mg, 0.47 mmol, 6.3%, 9.7% based on recovered
2
2
ϩ
ϩ
ϩ
m/z (EI) 168 (M , 32%), 140 (M Ϫ C H , 28), 123 (M Ϫ OEt,
4
2
4
ϩ
6), 95 (C H , 100).
7 11
ϩ
starting material); mp 130–132 ЊC [Found: (M ϩ H) (FAB),
37
ϩ
Synthesis of ethyl 2-cyclohexylprop-2-enoate 60
273.1418. C H N O
requires (M ϩ H) , 273.1450];
1
2
20
2
5
Ϫ1
Potassium hydroxide (1.39 g, 24.8 mmol) in dry ethanol (10 ml)
was added to a stirred solution of diethyl 2-cyclohexyl-
propanedioate (6.00 g, 24.8 mmol) in dry ethanol (22 ml) over
νmax(CHCl )/cm 3429 (N᎐H), 2945, 2862 (CH), 1726, 1667
3
(C᎐O), 1563, 1372 (N᎐O); δ (400 MHz, CDCl ) 1.32 (3 H, t, J
᎐
᎐
H
3
7.1, Me), 1.35 (3 H, m, CH ), 1.67 (4 H, m, CH ), 1.95 (3 H, s,
2
2
1
5 min. After stirring for 24 h, the ethanol was evaporated off,
Me), 2.23 (1 H, m, CH ), 4.04 (1 H, m, CH), 4.28 (2 H, q, J 7.1,
2
the viscous residue taken up in water (30 ml) and extracted with
dichloromethane (2 × 20 ml). The aqueous layer was acidified
with concentrated hydrochloric acid (1.5 ml) and extracted with
dichloromethane (3 × 30 ml). The combined organic extracts
were dried over sodium sulfate and evaporated to give ethyl
OCH ), 4.50 (1 H, d, J 12.6, CH ), 4.66 (1 H, d, J 12.6, CH ), 6.60
2
2
2
(1 H, br d, J 9.0, NH); δ (100 MHz, CDCl ) 13.8 (Me), 21.7
C
3
(CH ), 23.0 (Me), 24.5 (CH ), 30.0 (CH ), 32.4 (CH ), 50.4 (C),
2
2
2
2
52.3 (CH), 61.7 (CH ), 82.1 (CH ), 169.7 (C᎐O), 172.1 (C᎐O);
2
2
ϩ
ϩ
m/z (FAB) 273 [(M ϩ H) , 100%]; m/z (EI) 226 (M Ϫ NO2,
J. Chem. Soc., Perkin Trans. 1, 1997
1569

View Article Online
ϩ
5
0%), 184 (M Ϫ NO Ϫ Ac ϩ H, 65), 138 (C H NO, 100);
1.98 (1 H, m, CH ), 1.93 (3 H, s, Me), 2.05 (1 H, m, CH ),
2 2
2
8
12
and diastereomer 2 was a white crystalline solid (96 mg, 0.35
4.15 (1 H, t, J 9.1, CH), 4.30 (2 H, q, J 7.1, OCH ), 4.52 (1
2
mmol, 4.7%, 7.2% based on recovered starting material); mp
H, d, J 12.9, CH ), 4.69 (1 H, d, J 12.9, CH ), 6.41 (1 H, br
2
2
ϩ
1
58–159 ЊC [Found: (M ϩ H) , 273.1463. C H N O requires
d, J 9.1, NH); δ (67.8 MHz, CDCl ) 14.0 (Me), 22.3 (CH ),
1
2
21
2
5
C
3
2
ϩ
Ϫ1
(
M ϩ H) , 273.1450]; ν (CHCl )/cm 1733, 1680 (C᎐O),
23.3 (Me), 25.1 (CH ), 27.0 (CH ), 32.4 (CH ), 33.1 (CH ),
2 2 2 2
max
3
1
557, 1376 (ON᎐O); δ (250 MHz, CDCl ) 1.22 (3 H, t, J 7.1,
53.0 (C), 54.2 (CH), 61.9 (CH ), 82.0 (CH ), 169.4 (C᎐O),
᎐
H
3
2
2
Me), 1.50 (6 H, m, CH ), 1.73 (2 H, m, CH ), 1.95 (3 H, s, Me),
172.8 (C᎐O).
2
2
᎐
4
.14 (2 H, m, OCH ), 4.45 (1 H, m, CH), 4.53 (1 H, d, J 13.8,
2
CH ), 4.85 (1 H, d, J 13.8, CH ), 6.73 (1 H, br d, J 9.4, NH);
2
2
References
δ (100 MHz, CDCl ) 13.9 (Me), 20.9 (CH ), 21.9 (CH ),
C
3
2
2
2
3.1 (Me), 28.0 (CH ), 28.3 (CH ), 49.1 (C), 50.1 (CH), 61.7
1 P. G. Gassman and T. T. Tidwell, Acc. Chem. Res., 1983, 16, 279.
T. T. Tidwell, Angew. Chem., Int. Ed. Engl., 1984, 23, 20.
3 X. Creary, Chem. Rev., 1991, 91, 1625.
2
2
2
(CH ), 77.4 (CH ), 170.2 (C᎐O), 172.0 (C᎐O); m/z (FAB)
2
2
ϩ
ϩ
2
73 [(M ϩ H) , 100%], 226 (M Ϫ NO , 13); m/z (EI) 226
2
4
X. Creary, A. C. Hopkinson and E. Lee-Ruff, in Advances in
Carbocation Chemistry, ed. X. Creary, JAI Press Inc., Greenwich,
1989, vol. 1, pp. 45–92.
ϩ
ϩ
(M
Ϫ NO2, 50%), 184 (M Ϫ NO Ϫ Ac ϩ H, 55), 138
2
(C H NO, 100).
8
12
5
J.-P. Bégué and M. Charpentier-Morize, Acc. Chem. Res., 1980, 13,
207.
Nitration of ethyl 2-cyclohexylprop-2-enoate 60
6
7
X. Creary, Acc. Chem. Res., 1985, 18, 3.
C.-G. Shin, M. Masaki and M. Ohta, Bull. Chem. Soc. Jpn., 1970,
Nitronium tetrafluoroborate (565 mg, 4.65 mmol) was added
to dry acetonitrile (20 ml) in a flask flushed with nitrogen. The
stirred solution was cooled in an ice bath at Ϫ16 ЊC and ethyl
4
3, 3219.
8
C.-G. Shin, Y. Yonezawa, H. Narukawa, K. Nanjo and
J. Yoshimura, Bull. Chem. Soc. Jpn., 1972, 45, 3595.
2
-cyclohexylprop-2-enoate (774 mg, 4.25 mmol) was added in
one portion. The reaction was stirred for 4 h, water (30 ml)
was added and the reaction was extracted with dichloro-
methane (3 × 30 ml). The combined organic extracts were
washed with water, dried over sodium sulfate and evaporated to
give a yellow oil (1.04 g). Column chromatography (10–30–50–
9 A. I. Titov, Tetrahedron, 1963, 19, 557.
10 A. A. Borisenko, A. V. Nikulin, S. Wolfe, N. S. Zefirov and N. V.
Zyk, J. Am. Chem. Soc., 1984, 106, 1074.
ϩ
1
1 For computational studies of the addition of NO2 to ethene, see
F. Bernardi and W. J. Hehre, J. Am. Chem. Soc., 1973, 95, 3078;
J. T. Gleghorn and G. Torossian, J. Chem. Soc., Perkin Trans. 2,
7
0–100% ethyl acetate–hexane) led to the recovery of ethyl 2-
1
987, 1303; F. Bernardi, M. A. Robb, I. Rossi and A. Venturini,
J. Org. Chem., 1993, 58, 7074.
12 M. V. R. Reddy, B. Mehrotra and Y. D. Vankar, Tetrahedron Lett.,
995, 36, 4861.
cyclohexylprop-2-enoate 60 as a colourless oil (233 mg, 1.38
mmol, 18.5%) and to the isolation of 2-ethoxycarbonyl-2-(5-
methyl-1,2,4-oxadiazol-3-yl)cycloheptyl nitrate 64 as a 3:4 mix-
ture of two diastereomers, as a colourless oil (227 mg, 0.73
mmol, 15.6%, 40% based on recovered starting material)
1
1
3 For a preliminary account of this work, see S. A. Hewlins, J. A.
Murphy and J. Lin, Tetrahedron Lett., 1995, 36, 3039; J. A. Murphy,
S. A. Hewlins, M. Hursthouse, D. Hibbs and J. Lin, J. Chem. Soc.,
Chem. Commun., 1995, 559.
14 E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 1962, 84, 867.
15 P. S. Skell and I. Starer, J. Am. Chem. Soc., 1960, 82, 2971.
16 M. S. Silver, J. Am. Chem. Soc., 1960, 82, 2971.
(
Found: C, 50.1; H, 6.5; N, 13.3. C H N O requires C, 49.8;
13 19 3 6
ϩ
H, 6.1; N, 13.4%) [Found:
M
Ϫ NO2 (EI), 251.1420.
C H O N requires M Ϫ NO , 251.1396]; λmax(EtOH)/nm
1
3
19
6
3
2
3
Ϫ1
Ϫ1
Ϫ1
2
14 (ε/dm mol cm 1005); νmax(film)/cm 2937 and 2867
1
7 W. Koch, B. Liu and P. v. R. Schleyer, J. Am. Chem. Soc., 1989, 111,
479.
(
CH), 1738 (C᎐O), 1632 (ON᎐O), 1588 (C᎐N), 1279 (ON᎐O);
᎐
᎐
᎐
᎐
3
δ (400 MHz, CDCl ) 1.12 (t, J 7.1, Me), 1.14 (t, J 7.2, Me),
H
3
1
8 S. Sieber, P. Buzek, P. v. R. Schleyer, W. Koch and J. Walkimar de
M. Carneiro, J. Am. Chem. Soc., 1993, 115, 259.
19 C. J. Collins, Chem. Rev., 1969, 69, 543.
1
2
.58 (m, CH ), 1.90 (m, CH ), 2.22 (m, CH ), 2.49 (s, Me),
2
2
2
.50 (s, Me), 4.14 (2 H in 2 diastereomers, m, OCH ), 5.86
2
(
1 H in 2 diastereomers, dd, J 10.0, 8.5, CHONO ); δ (100
20 C. C. Lee, Prog. Phys. Org. Chem., 1970, 7, 129.
2
C
2
1 M. Saunders, P. Vogel, E. L. Hagen and J. Rosenfeld, Acc. Chem.
Res., 1973, 6, 53.
MHz, CDCl ) 12.11 (Me), 13.7 (Me), 22.3 (CH ), 22.8 (CH ),
2
2
3
2
2
3.0 (CH ), 23.1 (CH ), 27.4 (CH ), 28.0 (CH ), 28.6 (CH ),
2 2 2 2 2
2
2
2 X. Creary and C. C. Geiger, J. Am. Chem. Soc., 1982, 104, 4151.
3 J. C. Lopez, R. Alonso and B. Fraser-Reid, J. Am. Chem. Soc., 1989,
111, 6471; G. D. Vite and B. Fraser-Reid, Synth. Commun., 1988, 18,
1339. A. S. Batsanov, M. J. Begley, R. J. Fletcher, J. A. Murphy and
M. S. Sherburn, J. Chem. Soc., Perkin Trans. 1, 1995, 1281.
4 F. Eloy, Fortschr. Chem. Forsch., 1965, 4, 807.
8.9 (CH ), 32.1 (2 CH ), 54.4 (C), 54.7 (C), 62.0 (CH ), 62.1
2
2
2
(
(
(
CH ), 83.6 (CH), 84.2 (CH), 169.3 (2᎐C), 170.2 (2᎐C), 176.4
2
ϩ
᎐C), 176.7 (᎐C); m/z (EI) 267 (M Ϫ NO , 12%), 251
᎐
᎐
2
ϩ
M
Ϫ ONO , 3), 151 (C H O , 83); and two separable dia-
2 9 11 2
2
2
2
stereomers of ethyl 2-acetamido-1-nitromethylcycloheptane-
carboxylate 62. Diastereomer 1 was a white crystalline solid
(
material); mp 120–121.5 ЊC (Found: C, 54.8; H, 8.1; N, 9.7.
C H O N requires C, 54.6; H, 7.7; N, 9.8%) [Found:
(
5 T. Mukaiyama and T. Hoshino, J. Am. Chem. Soc., 1960, 82, 5339.
6 R. Huisgen, W. Mack and E. Anneser, Tetrahedron Lett., 1961, 2,
16.9 mg, 0.06 mmol, 1.3%, 3.2% based on recovered starting
5
87.
2
7 A. A. Stotskii, V. V. Kirichenko and L. I. Bagal, Zh. Org. Khim.,
1973, 9, 2464.
1
3
22
5
2
ϩ
ϩ
M ϩ H) (EI), 287.1641. C H N O requires (M ϩ H) ,
87.1607]; νmax(CHCl )/cm 3438 (N᎐H), 2933, 2859 (CH),
28 A. A. Stotskii and V. V. Kirichenko, Zh. Org. Khim., 1981, 17, 1373.
29 H. Amri, M. Rambaud and J. Villiéras, J. Organomet. Chem., 1990,
1
3
22
2
5
Ϫ1
2
1
3
3
84, 1.
726 (C᎐O), 1679 (C᎐O), 1558 (N᎐O), 1373 (N᎐O); δ (250
᎐
᎐
᎐
᎐
H
3
0 G. A. Marshalok, I. I. Yatchishin and D. K. Tolopko, Zh. Org.
Khim., 1981, 17, 694.
MHz, CDCl ) 1.30 (3 H, t, J 7.1, Me), 1.38 (1 H, m, CH ),
1
4
H, m, CH), 4.83 (1 H, d, J 13.1, CH ), 5.81 (1 H, br d, J
1
3
2
.78 (8 H, m, CH ), 2.00 (3 H, s, Me), 2.21 (1 H, m, CH ),
2
2
31 H. Stetter and H. Kuhlmann, Synthesis, 1979, 29.
32 G. Cahiez and M. Alami, Tetrahedron, 1989, 45, 4163.
33 K. Lipinski, T. Lipinska, A. Suszko-Purzycka and A. Rykowski, Pol.
J. Chem., 1993, 67, 667.
.22 (2 H, q, J 7.1, OCH ), 4.53 (1 H, d, J 13.1, CH ), 4.67 (1
2
2
2
1.1, NH); δ (67.8 MHz, CDCl ) 13.7 (Me), 22.7 (CH ), 22.9
C
3
2
34 G. R. Yohe and R. Adams, J. Am. Chem. Soc., 1928, 50, 1503.
35 G. S. Hiers and R. Adams, J. Am. Chem. Soc., 1926, 48, 2385.
36 D. S. Deorha and P. Gupta, Chem. Ber., 1965, 98, 1722.
(
(
(
(
Me), 23.9 (CH ), 27.6 (CH ), 31.1 (CH ), 31.2 (CH ), 51.8
C), 52.9 (CH), 61.5 (CH ), 79.0 (CH ), 169.7 (C᎐O), 172.7
2 2 2 2
2
2
ϩ
ϩ
C᎐O); m/z (EI) 287 [(M ϩ H) , 1], 240 (M Ϫ NO , 21), 198
᎐
M
2
37 J. A. Marshall, N. H. Andersen and A. R. Hochstetler, J. Org.
Chem., 1967, 32, 113.
ϩ
ϩ
Ϫ NO Ϫ Ac ϩ H, 77), 152 (M Ϫ OEt Ϫ NO Ϫ Ac,
2 2
ϩ
9
5), 43 (Ac , 100); and diastereomer 2 was a white crystalline
solid (167 mg, 0.58 mmol, 12.6%, 31.8% based on recovered
Paper 6/07170H
Received 21st October 1996
Accepted 7th February 1997
starting material); mp 128–131 ЊC; δ (400 MHz, CDCl ) 1.27
H
3
(
1 H, m, CH ), 1.33 (3 H, t, J 7.1, Me), 1.61 (7 H, m, CH ),
2
2
1
570
J. Chem. Soc., Perkin Trans. 1, 1997