Site selectivity in the addition of ketoximes to activated allenes and alkynes; N- versus O-alkylation

Article abstract of DOI:10.1039/a808167k

Reaction of ketoximes with methyl propiolate afforded geometrical isomers of the methyl 3-(hydroxyimino)-propanoates 4 and of the O-vinyl oximes 5 as well as the 2-isoxazoline 6. With dimethyl penta-2,3-diendioate 8c reaction progressed via an O-alkylatio

Full text of DOI:10.1039/a808167k

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Site selectivity in the addition of ketoximes to activated allenes
and alkynes; N- versus O-alkylation
Frances Heaney,* Bronwyn M. Kelly, Sharon Bourke, Oliver Rooney, Desmond Cunningham
and Patrick McArdle
Department of Chemistry, National University of Ireland, Galway, Ireland
Received (in Cambridge) 21st October 1998, Accepted 18th November 1998
Reaction of ketoximes with methyl propiolate afforded geometrical isomers of the methyl 3-(hydroxyimino)-
propanoates 4 and of the O-vinyl oximes 5 as well as the 2-isoxazoline 6. With dimethyl penta-2,3-diendioate 8c
reaction progressed via an O-alkylation to give the O-oxime ethers 9, only in the case of cyclopentanone oxime was
the spirocyclic dihydroazepinol 11 also obtained, its identity has been confirmed by an X-ray structure determination.
Introduction
methyl propiolate and each of the symmetrical oximes, cyclo-
pentanone oxime, cyclohexanone oxime and acetone oxime, 1a–
c (MeOH, 55–60 ЊC, 3 d) three groups of products were isolated
The preparation of nitrones from oximes falls into three broad
categories; i. thermal or catalytic proton transfer (generating an
1
NH-nitrone); ii. intramolecular cyclisation of a δ- or ε-alkenyl-
R
2
(
alkynyl) oxime (generating a cyclic nitrone); iii. inter- or
O –
R
intramolecular reaction with an electrophilic species (generat-
ing acyclic or cyclic dipoles).
is an electron deficient olefin the dipole forming reaction fol-
lows a 1,3-azaprotio cyclotransfer (APT) mechanism, a con-
certed equivalent of the Michael addition reaction and since
activated acetylenes and allenes make excellent Michael
acceptors (with carbon and heteronucleophiles), it was postu-
+
R1
R
N+
NOH
CO2Me
2b,3,4
When the electrophilic species
R
1
R
CO2Me
a. R,R = (CH2)4
b. R,R = (CH2)5
R1 = H, CO Me
2b
2
2
c. R = CH3
d. R,R = (CH2)2CH Bu(CH2)2
t
5
lated that they ought to react with oximes to furnish N-vinyl
nitrones (2 and 10). The current paper reports an investigation
of this hypothesis.
MeO2C
CO2Me
R
R
O
It is known that activated alkynes are more susceptible to
N
6
nucleophilic attack than the corresponding olefins and the
nitrone forming power of the intramolecular oxime–alkyne
cyclisation reaction has been shown to be considerably greater
than the comparative oxime–alkene process. Further, Holmes
MeO2C
CO Me
2
7
3b,c
and co-workers have reported that an enynylhydroxylamine
preferentially cyclises on the alkyne moiety to give an alkenyl
substituted dipole. Thus it was anticipated that methyl propiol-
ate and dimethyl acetylenedicarboxylate may be potent sub-
strates in an intermolecular APT reaction and that the N-vinyl
nitrones 2 may thus be readily accessible.
from the crude mixture. For each oxime the major products
were the isomeric oximes 4, present as a 1:1 mixture in 60–75%
yield, the stable E–Z O-addition products (5a–c) which were
8
MeO C
2
H
HO
H
OH
Reportedintermolecularreactionsbetweenoximesandacetyl-
enic substrates, in the presence of base, lead to products from
N
H
N
CH2CO2Me
CO Me
2
O
CO2Me
H
9
N
an initial O-alkylation. † Further, it has recently been reported
H
that conjugate addition of an oxime to ethyl propiolate, in neu-
(Z)-4
(E)-4
6
tral conditions, under the influence of triphenylphosphine,
1
0
gives E O-vinyl oximes. Only one example of a bimolecular
oxime–alkyne reaction resulting in the formation of nitrones
has been reported. Winterfeldt and Krohn have found that each
of cyclohexanone and acetone oxime react with 2 mol equiv-
alents of dimethyl acetylenedicarboxylate (DMSO, room tem-
perature) to afford the 4-isoxazolines 3b,c by a two step, one
CO Me
2
Ha
R
R
O
H
R
N
H
O
N
2
CO Me
R
Hb
(E)-5
(
Z)-5
a. R,R = (CH2)4
b. R,R = (CH2)5
c. R = R = CH3
11
pot, dipole formation–cycloaddition sequence.
t
d. R,R = (CH2)2CH Bu(CH2)2
Results and discussions
a. Reactions with methyl propiolate
obtained in 10–16% yield, and the 2-isoxazoline 6 in 6–10%
yield. (E)–(Z ) Methyl 3-(hydroxyimino)propanoates 4 were
inseparable by flash chromatography, accordingly, stereochemi-
cal assignment is based on the deshielding of the hydroxyimino
proton of the Z-isomer (9.38 versus 8.92) due to its proximity
Following the reaction between the monoactivated acetylene,
(
and potential hydrogen-bonding) to the ester carbonyl group,
†
The addition of base favours O-addition by enhancing the nucleo-
further, in the E-isomer the imino proton is deshielded by the
proximate hydroxy group and resonates at 7.42 ppm, ~0.3 ppm
philicity of the oxygen atom. In the absence of base the equilibrium
concentration of the nitrone form may be expected to be greater.
J. Chem. Soc., Perkin Trans. 1, 1999, 143–148
143

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R
R
O
H
+
R
R
O
H
–
N+
H
N
H
CO2Me
CO Me
2
Intermediate A
+
R'OH
R'
R'
OH
CO2Me
+O
O
O H
N
R
+
R
N
H
R
H
R
–
CO2Me
+
R'OH
CO2Me
O
‡
OR'
OH
CO2Me
R
H
CO2Me
N
H
N
+
CO2Me
R
OR'
H
4
H2O
O
O
R
N
H
CO2Me
CO2Me
R
=
Isolated product,
6
‡
in the case of 1d only
Scheme 1
downfield of its Z-analogue. The O-vinyl oximes 5a–c were also
inseparable, their stereochemical assignment is reliably based
on the magnitude of the vicinal coupling constant between the
was isolated in 27% yield together with the oximes 4 (1:1 mix-
ture, 24%), the O-vinyl ethers (E)- and (Z)-5d, (combined
yield 17%) and the 2-isoxazoline 6 (3%). The isolation of 7
(which hydrolyses on standing to its parent ketone) implies
that the nucleophile attacking the intermediate A is a solvent
molecule (methanol) and not an extraneous water molecule.
That the dimethyl acetal 7 arises from 1d by a route more con-
voluted than straightforward methanolysis followed by trans-
fer of the hydroxylamine functionality is supported by the
observed stability of 1d following heating with cyclohex-
anone in boiling methanol. That the oximes 4 are the pre-
cursors to the 2-isoxazoline 6 has been illustrated by an
independent experiment, thus heating 4 with methyl propiolate
(1.4 equiv.) furnished 6 in 29% isolated yield (MeOH, 2 d,
65 ЊC).
3
3
olefinic protons [E-8 J ~ 12 Hz; Z-8 J ~ 7 Hz]. The assignment
1
of the third product as the 2-isoxazoline 6 is based on its H and
13
C NMR spectral data and the proposed structure is supported
by microanalytical data. Diagnostic spectral signals include the
C-3 proton which appears downfield at 7.19 ppm (1H, d, J 1.95)
and the corresponding C-3 carbon signal at 143 ppm. Irradi-
ation of the C-4 hydrogen atom failed to effect an enhancement
on the signal for the C-5 proton suggesting these protons have a
trans relationship; measurement of the coupling constant, J ,
4,5
as ~7.5 Hz does not help in stereochemical assignment since
12
coupling constants in 2-isoxazolines are not diagnostic.
Whilst the mechanistic route to the oximes 4 and the 2-
isoxazoline 6 is not obvious it is clear that their formation is
independent of the structure of the starting oxime (cyclo-
pentanone, cyclohexanone and acetone oxime all give the same
products in similar relative yields). Analysis of the structures of
The suggested mechanism involves a critical role for the sol-
vent in determining the product distribution, indeed acetone
oxime 1c reacts with methyl propiolate in dry C H (80 ЊC)
6
6
slowly, but specifically, to give (E)-5c only (14%) whilst in water
quantitative transformation to the O-vinyl adducts 5c was
observed (E:Z 1:3). In anhydrous ethanol, the reaction pro-
ceeded as with methanol but with a much reduced rate of con-
version. The nature and relative quantities of the products from
4
and 6 show that they are constructed from the hydroxyimino
portion of the oxime with one and two moles respectively of
methyl propiolate. A plausible mechanism, shown in Scheme 1,
requires the expulsion of one mole of carbonyl compound,
however, in no case could this be found amongst the reaction
products, perhaps this can be explained by the volatility of
the ketones arising from the deoximation of 1a–c. 4-tert-
Butylcyclohexanone, the parent carbonyl of the oxime 1d has a
bp of 113–116 ЊC at 20 mmHg and so, if formed in the reaction
of 1d with methyl propiolate, it should be easily detectable.
Methyl propiolate and 1d were heated in anhydrous methanol
for 3 d at 65 ЊC; following flash chromatographic analysis of
the reaction mixture 1,1-dimethoxy-4-tert-butylcyclohexane 7
the reaction in CHCl appeared very sensitive to the method by
3
which the solvent was purified and dried, however, in each case,
following the reaction with cyclohexanone oxime, inspection of
1
the crude H NMR spectra revealed the presence of the isox-
azoline 6 and (E)-5b. Methyl but-2-ynoate, a disubstituted
acetylene, failed to take part in reaction with any of the
chosen oximes. The observed lack of reactivity is presumably
due to problems of steric access between the reactants.
b. Reactions with electron deficient allenes
Nitrone generation from the reaction between oximes and
allenes has thus far been demonstrated only in the intra-
molecular variant; Lathbury and Gallagher have shown that
ω-allenyl oximes undergo a Ag() promoted cyclisation yielding
O
MeO
OMe
13a,b
5
- and 6-membered cyclic dipoles.
The success of the reac-
tBu
tBu
tion is related to the geometry of the oxime and the length of
the tether connecting the oxime and allene functionalities with
7
1
44
J. Chem. Soc., Perkin Trans. 1, 1999, 143–148

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certain oximes preferentially reacting via their oxygen atom to
13b,c
give the corresponding oxazepines.
The allenes
8
were prepared according to literature
H
R1
R
H
O
N
2
CO Me
C
C
C
R
H
COR2
CO2Me
8
9
a. R1 = H, R2 = OMe
a. R,R = (CH2)4
b. R,R = (CH2)5
c. R = CH3
1
2
b. R = H, R = Me
1
2
c. R = CO2Me, R = OMe
14a–c
methods,
and their reaction with the ketoximes 1a–c
studied. The monoactivated allenes 8a,b failed to give any useful
results in this investigation and products from reaction with
oximes in various solvents, over a range of temperatures, varied
between returned starting material and complicated mix-
tures of unidentifiable compounds. However heating a solution
Fig. 1 X-Ray crystallographic projection of 11.
14d
of the symmetrically activated allene 8c, [recognised as a
superior Michael acceptor due to the strong cationic nature of
the centre (sp) carbon atom] and cyclopentanone oxime (0.5
equiv.) in each of C H , CHCl , MeOH and DMSO resulted in
12 may undergo a 3,3-sigmatropic shift (hetero Cope) to the
spirocyclic azepinone 13, which following two 1,3-proton
transfers (keto
enol and imine
enamine] results in the
conjugated dihydroazepine 11 (Scheme 2). 1-Aza-1Ј-oxa Cope
6
6
3
greater reactivity and the O-alkylation product 9a was formed
in 0, 30, 35 and 42% yield respectively. Analogous behaviour
was observed for cyclohexanone and acetone oxime and in
DMSO the adducts 9b and 9c were formed in 55 and 43% yield
respectively. H NMR measurements indicated that in each case
the alkylation proceeded stereospecifically and indeed π-facial
CO2Me
CO2Me
1
CO Me
2
N+
CO2Me
N
O–
10
MeO2C
O
selectivity in the addition of nucleophiles to allene carboxylates
MeO2C
H
H
H
15
is a recognised characteristic. E-Geometry is assigned to the
adducts 9 following comparison of the resonance position of
C
C
C
CO2Me
2
MeO C
the vinylic proton (δ 5.81–5.84 ppm) with that observed for the
H
8c
12
corresponding proton (H ) in the acetylenic adducts (E)- and
a
(
Z)-5. In (E)-5, where the terminal vinylic proton is cis to the
hetero Cope
oxygen atom, resonance is in the range 5.45–5.55 ppm whilst for
the Z-adducts the analogous proton resonates upfield at 4.77–
4
.80 (br) 4.04 & 3.41
CO2Me
4
.84 ppm. No trace of N-alkylated products (nitrones, 10) or
(2×d, J 16)
CO2Me
the corresponding cycloadducts could be detected in any of the
crude reaction mixtures and only in the case of cyclopentanone
oxime was any other reaction product noted. A yellow solid,
isolated in 14% yield, has tentatively been identified as the spiro-
cyclic dihydroazepine 11. Microanalytical data indicate it is
made up of two moles of the allene and one mole of the oxime.
H
N
CH2CO2Me
CO2Me
H
3
.46 (s)
N
H
13
MeO2C
CO2Me
MeO C
2
H
H
1,3-H shifts
12.42 (br)
HO
2
CO Me
O
1
11
The H NMR spectrum displays two exchangeable protons, at
1
2.4 and 4.8 ppm, assigned as the enolic OH and the NH sig-
nals respectively. The CH methine proton resonates as a singlet
3.46 ppm) and the methylene protons as doublets at 4.04 and
.41 ppm (J ~ 16 Hz), their magnetic non-equivalence is attrib-
uted to restricted rotation of the side chain in the highly substi-
Scheme 2
(
3
rearrangements are known for O-aryl oximes and O-vinyl
N-phenylhydroxylamines (preparative routes to benzofurans
and indoles respectively). There is also precedent for this
rearrangement with substrates like 12 where the N–O bond
is within a ring, an in situ rearrangement of 5-methylene-N-
phenylisoxazoline is reported to afford Z-configured 2-vinyl-
indoles. The factors promoting the formation of 11 from
cyclopentanone oxime and 8c appear not to operate with cyclo-
hexanone or acetone oxime, the explanation for this divergence
of reactivity between the three ketoximes is not clear.
13
tuted spirocyclic ring skeleton. In the C NMR spectrum there
are eight downfield signals, representing four ester carbonyl
groups and four olefinic carbon atoms, two of which are
deshielded and two which are not. Confirmation of the struc-
ture as the spirocyclic dihydroazepine rests with a single crystal
X-ray structure analysis of a triclinic crystal grown from
CH Cl –hexane (Fig. 1). The 2,3-dihydro-1H-azepin-4-ol ring
18
2
2
skeleton is rare and heretofore has been seen only as part of a
16
benzo fused bicyclic ring system. Examination of the struc-
ture gives evidence for an intramolecular hydrogen bond
between the enolic hydrogen atom H-3 and the adjacent carb-
onyl oxygen atom O-4, the O-4–O-3 distance is 2.524(3) Å,
this hydrogen bond is the likely stabilising factor in the
adoption of the enolic structure. A second interesting structural
feature is the extent of planarity in the dihydroazepine ring with
five ring atoms C-1, N-1, C-16, C-13 and C-10 falling in a plane.
We postulate that formation of 11 may involve the N-vinyl
nitrone 10, which following cycloaddition to a second molecule
Conclusions
The ambifunctional nucleophilicity of oximes is well known
and, in contrast to their behaviour with simple electron deficient
olefins, ketoximes react with a symmetrically activated allene to
form products arising from oxa- and not aza-addition. It may
be that the different topological requirements of the transition
states leading to N- and O-alkylation dictate chemoreactivity
(Fig. 2). The APT mechanism, leading to 10, involves a
5-membered cyclic framework with initial attack of the oxime
nitrogen atom on the central carbon of the allene and the steric
2b
17
of 8c gives the spirocyclic isoxazolidine 12; being a 1,5-diene
J. Chem. Soc., Perkin Trans. 1, 1999, 143–148
145

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R
R
MHz), 7.23 (d, 1H, J 7.33, H-a), 4.77 (d, 1H, J 7.33, H-b),
3.71 (s, 3H, OMe), 2.56 (m, 4H, CH (C᎐N)CH ), 1.75 (m, 4H,
N
C
H
R
O
2
᎐
2
O
C
N
H
C
CH CH ); δ (67.5 MHz), 172.6, 159.9, 134.1, 92.8, 50.3, 29.3,
R1
R
R1
2
2
C
H
9
10
H
27.7, 25.3, 23.5. The isomeric oximes 4 were obtained as an
inseparable mixture of E- and Z-isomers (1:1.5) 65% (Found:
C 43.69; H 6.39; N 6.42. C H NO requires C 43.33; H 6.40; N
C
C
C
COR2
COR2
H
H
4
7
3
Fig. 2
6
.36%). (E)-4 δH (400 MHz), 8.92 (br s, 1H, OH), 7.42 (t, 1H,
J 6.13, HC᎐N), 3.69 (s, 3H, OMe), 3.12 (d, 2H, J 6.13, CH );
δC (100 MHz), 168.4, 146.2, 52.1, 31.9; (Z)-4 δH (400 MHz),
᎐
2
hindrance encountered in this transtition state may be sufficient
to prohibit nitrone formation. On the other hand generation of
the O-addition product 9 involves a two step process and is
sterically uninhibited. Formation of the spirocyclic dihydro-
azepinol 11 was unexpected and its unusual structure has been
confirmed by a single crystal X-ray structure determination.
Reaction between methyl propiolate and ketoximes in MeOH
is complex and the simple O-addition products 5, present in
rather small yield, are accompanied by the isomeric oximes 4
9
.38 (br s, 1H, OH), 7.13 (t, 1H, J 6.03, HC᎐N), 3.71 (s, 3H,
᎐
OMe), 3.44 (d, 2H, J 6.13, CH ); δ (100 MHz), 169.2, 144.0,
2
C
5
2.2, 30.3. The isoxazoline 6 was obtained as a pale yellow oil
(
10%) (Found: C 47.88; H 5.13; N 6.25. C H NO requires C
8
11
5
4
5
7.76; H 5.47; N 6.96%). δ (400 MHz), 7.19 (d, 1H, J 3.2, H-2),
.17 (q, 1H, J 7.67, H-5), 4.21 and 4.19 (2 × d, 2 × 1H, J 7.67,
H
CH ), 3.79 and 3.71 (2 × s, 2 × 3H, 2 × OMe), 2.75 (m, 1H,
2
H-4); δ (100 MHz), 169.3, 167.3, 144.2, 58.2, 52.3, 37.2, 29.4;
C
(
the major products) and the 2-isoxazoline 6 as the reaction
Ϫ1
IR 1739.9, 1628.0, 1602.8 1202.4 cm .
products. A mechanism postulating the origin of these unex-
pected products is presented in Scheme 1. Since the allene and
the alkyne are electronically activated towards nucleophilic
attack, the disparate reactivity encountered with these species
with respect to similarly activated alkenes, is a likely con-
sequence of the differing topological requirements for the
Reaction of cyclohexanone oxime 1b with methyl propiolate
afforded the methyl 3-[(cyclohexylideneamino)oxy]prop-2-
enoates 5b (10%) as an inseparable mixture of E- and Z-isomers
(
7
1.1:2), mixed melting point 114–118 ЊC (Found: C 61.10; H
.30; N 7.40. C H NO requires C 60.90; H 7.66; N 7.10%).
10
15
3
(
E)-5b δH (270 MHz), 7.88 (d, 1H, J 12.45, H-a), 5.45 (d, 1H,
J 12.45, H-b), 3.63 (s, 3H, OMe), 2.42 (m, 2H, CH (C᎐N)), 2.22
m, 2H, CH (C᎐N)), 1.90 (m, 6H (CH ) ); δ (67.5 MHz), 168.3,
interaction of the oxime with the allenic (sp hybridised), alkynic
2
2
(
sp hybridised), and olefinic carbon atoms (sp hybridised). In
(
2
2
3
C
particular, aza attack, to result in nitrone formation, requires a
1
66.5, 159.9, 95.9, 51.2, 32.8, 32.0, 29.8, 26.9, 25.8; (Z)-5b
5
-membered cyclic transition state (APT mechanism) and is
δH (270 MHz), 7.25 (d, 1H, J 7.33, H-a), 4.77 (d, 1H, J 7.33,
more spatially demanding than the alternate conjugate (two
step) addition. The latter mechanism can proceed with either
the oxime O- or N-atom as the attacking centre.
H-b), 3.63 (s, 3H, OMe), 2.56 (m, 2H, CH (C᎐N)), 2.20 (m, 2H,
2
CH (C᎐N)), 1.90 (m, 6H, (CH ) ); δ (67.5 MHz), 166.6, 162.4,
2
2
3
C
1
59.9, 92.8, 51.0, 32.7, 31.8, 29.3, 26.7, 25.5. The isomeric
oximes 4 were obtained as an inseparable mixture of E- and
Z-isomers (1:1) (75%) and the isoxazoline 6 was obtained as a
pale yellow oil (6%).
Reaction of acetone oxime 1c with methyl propiolate
afforded the methyl 3-[(methylethylideneamino)oxy]prop-2-
enoates 5c (10%) as an inseparable mixture of E- and Z-isomers
Experimental
Mps were determined on an Electrothermal melting point
apparatus and are uncorrected. Elemental analyses were per-
formed on a Perkin-Elmer model 240 CHN analyser. NMR
Spectra were recorded using JEOL JNM-LA400 and JEOL
EX270 FT NMR spectrometers at probe temperatures with
(
1:1), mixed melting point 96–100 ЊC (Found: C 53.22; H 7.01;
N 8.80. C H NO requires C 53.49; H 7.05; N 8.90%). (E)-5c
7
11
3
tetramethylsilane as internal reference and CDCl as solvent,
3
δH (270 MHz), 7.89 (d, 1H, J 12.53, H-a) 5.49 (d, 1H, J 12.53,
H-b), 3.73 (s, 3H, OMe), 2.00 and 1.99 (2 × s, 2 × 3H, 2 × Me);
δC (67.5 MHz), 168.3, 162.2, 144.3, 96.0, 51.2, 22.2, 21.4; (Z)-5c
δH (270 MHz), 7.26 (d, 1H, J 7.26, H-a), 4.83 (d, 1H, J 7.26,
H-b), 3.73 (s, 3H, OMe), 2.00 and 1.99 (2 × s, 2 × 3H, 2 × Me);
δC (67.5 MHz), 168.3, 163.3, 144.9, 94.3, 51.2, 17.1, 16.4. The
isomeric oximes 4 were obtained as an inseparable mixture of
E- and Z-isomers (1:1.3) (60%) and the isoxazoline 6 was
obtained as a pale yellow oil (6%).
J values are given in Hertz. Flash column chromatography was
carried out on silica gel (200–400 mesh; Kieselgel 60, E Merck)
with air pump pressure; analytical TLC plates were purchased
from Merck. Samples were located by UV illumination using
a portable Spectroline Hanovia lamp (λ, 254 nm) or by the use
of iodine staining. All solvents used were purified by standard
procedures and pet. spirit refers to that fraction of light petrol-
eum boiling between 40–60 ЊC.
General procedure for the reaction of ketoximes with methyl
propiolate. Preparation of (E)- and (Z)-methyl 3-[(alkylidene-
amino)oxy]prop-2-enoates 5, (E)- and (Z)-methyl 3-(hydroxy-
imino)propanoates 4 and 4,5-dihydro-4-methoxycarbonyl-5-
methoxycarbonylmethylisoxazole 6
Reaction of 4-tert-butylcyclohexanone oxime 1d with methyl
propiolate
4
-tert-Butylcyclohexanone oxime 1d (0.500 g, 2.95 mmol) and
methyl propiolate (0.496 g, 5.90 mmol) were heated at reflux in
dried methanol (65 ЊC) for 3 d under a nitrogen atmosphere.
The reaction was monitored by TLC (pet. spirit–diethyl ether;
10:3). Removal of the solvent yielded a brown oil. Purification
by flash chromatography (silica gel, pet. spirit–diethyl ether;
10:2) afforded the pure products. 1,1-Dimethoxy-4-tert-butyl-
cyclohexane 7 was isolated as a clear oil (160 mg, 27.1%)
(Found: C 71.63; H 12.74. C H O requires C 72.00; H
A solution of methyl propiolate (2 mmol) and the oxime (1
3
mmol) in anhydrous MeOH (3 cm ) was heated to 55–65 ЊC
under a N atmosphere for 3 d. The cooled reaction solution
2
was concentrated to yield the crude products, the O-vinyl oxime
ethers 5, the oximes 4 and the 2-isoxazoline 6. Purification by
flash chromatography [SiO , ethyl acetate–pet. spirit (for reac-
2
tion of 1a, 2:3; 1b, 2:3; 1c, 1:1)] afforded the products.
12
24
2
Reaction of cyclopentanone oxime 1a with methyl propiolate
afforded the methyl 3-[(cyclopentylideneamino)oxy]prop-2-
enoates 5a (10%), as an inseparable mixture of E- and
Z-isomers (1:1.5), mixed melting point 99–104 ЊC (Found:
C 58.77; H 7.90; N 7.66. C H NO requires C 59.00; H 7.10; N
12.00%); δ (400 MHz), 3.16 (s, 3H, OMe), 3.11 (s, 3H, OMe),
H
2.05 (d, 2H, J 11.1, 2 × CHC(OMe) ), 1.61 (d, 2H, J 11.1,
2
2 × CHC(OMe) ), 1.21 (m, 2H, 2 × CHCH C(OMe) ), 1.10 (m,
2
2
2
2H, 2 × CHCH C(OMe) ), 1.00 (m, 1H, CH CHCH ), 0.82 (s,
2
2
2
2
9H, 3 × CH ); δ (100 MHz), 47.51, 47.28, 32.71, 32.21, 27.57,
9
13
3
3
C
7
(
(
.64%). (E)-5a δH (270 MHz), 7.27 (d, 1H, J 12.45, H-a), 5.45
d, 1H, J 12.45, H-b), 3.71 (s, 3H, OMe), 2.65 (m, 4H, CH2-
C᎐N)CH ), 1.72 (m, 4H, CH CH ); δ (67.5 MHz), 173.1,
23.52. Methyl (E)-3-[(4-tert-butylcyclohexylideneamino)oxy]-
prop-2-enoate (E)-5d was isolated as a clear oil (70 mg, 9.6%)
᎐
2
2
2
C
(Found: C 66.51; H 8.53; N 5.23. C H N O requires C 66.66;
18 19 3 6
1
62.3, 136.8, 95.8, 50.1, 29.7, 27.8, 24.9, 23.4; (Z)-5a δH (270
H 8.73; N 5.55%); δ (400 MHz), 7.95 (d, 1H, J 12.2, OCH᎐C),
H
᎐
1
46 J. Chem. Soc., Perkin Trans. 1, 1999, 143–148

View Article Online
5
2
2
1
.55 (d, 1H, J 12.2, CHCO Me), 3.71 (s, 3H, OMe), 2.44 (m,
Table 1 Crystal data and structure refinement for 11
2
H, 2 × CHC᎐N), 2.24 (m, 2H, 2 × CHC᎐N), 2.01 (m, 5H,
᎐
᎐
× CH(CH ) ), 0.88 (s, 9H, 3 × CH ); δ (100 MHz), 168.33,
Identification code
Empirical formula
Formula weight
Temperature
11
19 25
2
2
3
C
C H NO
62.23, 144.49, 96.11, 51.24, 47.15, 31.49, 27.44, 26.45, 26.02.
9
411.40
293(2) K
0.71069 Å
Methyl (Z)-3-[(4-tert-butylcyclohexylideneamino)oxy]prop-2-
enoate, (Z)-5d was isolated as a clear oil (50 mg, 7.3%) (Found:
C 66.32; H 8.45; N 5.33. C H N O requires C 66.66; H 8.73;
Wavelength
18
19
3
6
Crystal system
Space group
Unit cell dimensions
Triclinic
N 5.55%); δH (400 MHz), 7.32 (d, 1H, J 7.32, OCH᎐C), 4.84
d, 1H, J 7.32, CHCO Me), 3.70 (s, 3H, OMe), 2.43 (m, 2H,
P1¯
(
a = 8.7445(11) Å, α = 69.045(12)Њ
b = 10.6180(12) Å, β = 78.645(12)Њ
c = 12.083(2) Å, γ = 82.861(11)Њ
2
2
2
1
× CHC᎐N), 2.24 (m, 2H, 2 × CHC᎐N), 2.00 (m, 5H,
᎐ ᎐
× CH(CH ) ), 0.86 (s, 9H, 3 × CH ); δ (100 MHz), 168.33,
2
2
3
C
3
Volume
1025.4(2) Å
63.31,144.73,95.12,51.23,47.11,31.44,27.40,26.41,25.00.The
Z
2
oximes 4 (1:1, 24%) and the isoxazoline 6 (3%) were isolated,
data agreed with that reported above.
Ϫ3
Density (calculated)
Absorption coefficient
F(000)
1.332 Mg m
0.107 mm
436
Ϫ1
Crystal size
θ range for data collection
Index ranges
0.54 × 0.20 × 0.14 mm
2.06 to 25.97Њ
0 р h р 10; Ϫ12 р k р 13;
Ϫ14 р l р 14
4434
4006 [R(int) = 0.0253]
2563
Full-matrix least-squares on F
4006/0/267
1.071
General procedure for the reaction of ketoximes with dimethyl
penta-2,3-dienedioate. Preparation of dimethyl (Z)-3-[(cyclo-
pentylideneamino)oxy]pent-2-enedioate, 9a, dimethyl (Z)-3-
[
(
(cyclohexylideneamino)oxy]pent-2-enedioate, 9b and dimethyl
Z)-3-[(1-methylethylideneamino)oxy]pent-2-enedioate, 9c
Reflections collected
Independent reflections
Reflections observed (>2σ)
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
14
A solution of the allene 8c (2 mmol) and the oxime 1a–c (1
2
3
mmol) in anhydrous DMSO (12 cm ) was heated to 55 ЊC under
2
a N atmosphere for 15 h. To the cooled reaction solution was
2
3
added distilled water (10 cm ) and the aqueous layer was
extracted with CH Cl (10 cm ). The organic layer was col-
lected, washed with water (2 × 8 cm ), dried (MgSO ) and con-
R = 0.0462, wR = 0.1338
1
2
3
R = 0.0785, wR = 0.1446
1 2
Ϫ3
2
2
3
0.371 and Ϫ0.208 e Å
4
2
R indicies; R = [Σ F | Ϫ |F ]/Σ|F | (based on F ), wR = [[Σ (|F
Ϫ
centrated to yield a brown coloured residue which was purified
1
2
o
c
o
2
w
o
2
2
2
o
¹
2
2
2
F |) ]/[Σ (F ) ]] �² (based on F ). w = 1/[(σF ) ϩ (0.0842P) ]. Goodness-
by flash chromatography (SiO ; 9a, ethyl acetate–hexane 3:7;
c
w
o
2
2
2
c
2
¹
of-fit = [Σ (Fo Ϫ F ) /(N Ϫ Nparameters)] �² .
w
obs
9
b, ethyl acetate–hexane 1:1; 9c, diethyl ether–hexane 3:7). The
following O-vinyl oximes were prepared; 9a colourless oil (43%)
Found: C 56.52; H 6.69; N 5.50. C H NO requires C 56.46;
Ϫ3
19
(
and Ϫ0.208 e Å , software used, SHELXS-97, SHELXL-
20 21
12
17
5
H 6.71; N 5.48%); δH (270 MHz), 5.81 (s, 1H, C᎐CH), 3.83 (s,
H, CH ), 3.65 and 3.60 (2 × s, 2 × 3H, 2 × OMe), 2.43 (m, 4H,
97 and ORTEX. Data were corrected for Lorentz and polar-
ization effects but not for absorption. Hydrogen atoms were
included in calculated positions with thermal parameters 30%
larger than the atom to which they were attached. The non-
hydrogen atoms were refined anisotropically. All calculations
were performed on a Pentium PC (see Table 1).‡
2
2
CH (C᎐N)CH ), 1.72 (m, 4H, CH CH ); δ (67.5 MHz), 168.2,
2
2
2
2
C
1
67.3, 166.2, 161.5, 95.3, 52.4, 51.1, 36.5, 31.6, 27.2, 25.0, 23.4;
9
b colourless oil (42%) (Found: C 58.33; H 7.52; N 5.00.
C H NO requires C 57.96; H 7.10; N 5.20%); δ (270 MHz),
13
19
5
H
5
2
.85 (s, 1H, C᎐CH), 3.87 (s, 2H, CH ), 3.74 and 3.63 (2 × s,
᎐
2
× 3H, 2 × OMe), 2.49 (m, 2H, CH C᎐N), 2.27 (m, 2H,
2
Acknowledgements
CH C᎐N), 1.60 (m, 6H, (CH ) ); δ (67.5 MHz), 169.5, 168.2,
2
2
3
C
1
67.1, 165.4, 94.5, 52.3, 50.7, 36.1, 31.7, 26.6, 26.1, 25.5, 25.1;
c colourless oil (55%) (Found: C 52.00; H 6.83; N 6.26.
We acknowledge Forbairt grants for postgraduate research
(B. K. and S. B.) and a Forbairt Basic Science Grant SC/97/517
(F. H., O. R.), support from Galway County Co. (B. K., O. R.),
Mayo County Co. (S. B.) and the Chemistry Department,
University College, Galway.
9
C H NO requires C 52.40; H 6.60; N 6.10%); δ (270 MHz),
10
15
5
H
5
2
.84 (s, 1H, C᎐CH), 3.85 (s, 2H, CH ), 3.66 and 3.61 (2 × s,
᎐
2
× 3H, 2 × OMe), 1.92 and 1.91 (2 × s, 2 × 3H, 2 × Me); δC
(
67.5 MHz), 169.4, 168.3, 165.5, 162.3, 95.1, 52.2, 51.0, 36.4,
2
2.6, 21.8.
‡
Full crystallographic details, excluding structure factor tables, have
been deposited at the Cambridge Crystallographic Data Centre
CCDC). For details of the deposition scheme, see ‘Instructions for
In the reaction of 1a with 8c, trimethyl 10-hydroxy-7-(2-
methoxy-2-oxoethyl)-6-azaspiro[4.6]undeca-7,9-diene-8,9,11-
tricarboxylate 11 was isolated in 14% yield, mp 139–140 ЊC
(
Authors’, J. Chem. Soc., Perkin Trans. 1, available via the RSC web
page (http://www.rsc.org/authors). Any request to the CCDC for this
material should quote the full literature citation and the reference
number 207/285.
(
diethyl ether–pet. spirit) (Found: C 55.16; H 6.19; N 3.46.
C H NO requires C 55.47; H 6.08; N 3.41%); δ (400 MHz),
1
19
25
9
H
2.42 (br s, 1H, OH), 4.80 (br s, 1H, NH), 4.04 (d, 1H, J 15.7,
CH CO Me), 3.75 (s, 3H, OMe), 3.72 (s, 3H, OMe), 3.61 (s, 3H,
2
2
OMe), 3.60 (s, 3H, OMe), 3.46 (s, 1H, CHCO Me), 3.41 (d, 1H,
2
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¯
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J. Chem. Soc., Perkin Trans. 1, 1999, 143–148