An investigation of structure-reactivity relationships of δ-alkenyl oximes; Competitive thermal reactions leading to cyclic nitrones and/or N-unsubstituted bicyclic isoxazolidines

Article abstract of DOI:10.1016/j.tet.2010.06.005

Thermal reactions of C-aryl δ-alkenyl oximes give N-unsubstituted bicylic lactone, lactam and pyrrolidine fused isoxazolidines by an intramolecular oxime olefin cycloaddition pathway (IOOC) and/or cyclic nitrones by an azaprotio cyclotransfer (APT) route; a number of factors, including the nature of the aryl group, the oxime geometry and the structure of the linker between the oxime and the terminal alkene, contribute to the competition. The nature of the aryl group, oxime geometry, and the structure of the linker between the oxime and the alkene influence the reactivity of C-aryl δ-alkenyl oximes.

Full text of DOI:10.1016/j.tet.2010.06.005

Tetrahedron 66 (2010) 7041e7049
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An investigation of structure-reactivity relationships of d-alkenyl oximes;
competitive thermal reactions leading to cyclic nitrones and/or N-unsubstituted
bicyclic isoxazolidines
*
Linda Doyle, Frances Heaney
Department of Chemistry, National University of Ireland, Maynooth, Co. Kildare, Republic of Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Thermal reactions of C-aryl d-alkenyl oximes give N-unsubstituted bicylic lactone, lactam and pyrrolidine
Received 8 March 2010
Received in revised form 13 May 2010
Accepted 1 June 2010
fused isoxazolidines by an intramolecular oxime olefin cycloaddition pathway (IOOC) and/or cyclic ni-
trones by an azaprotio cyclotransfer (APT) route; a number of factors, including the nature of the aryl
group, the oxime geometry and the structure of the linker between the oxime and the terminal alkene,
contribute to the competition.
Available online 17 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
N-Unsubstituted isoxazolidines
Oxime geometry
Intramolecular oxime olefin cycloaddition
(IOOC)
azaprotio Cyclotransfer (APT)
1. Introduction
benzyl21 or Troc21 groups from N-substituted heterocycles has
been demonstrated.
The isoxazolidine nucleus has long been recognized in its own
right as a key structural component in biologically active mole-
cules,1,2 as an important synthon for the construction of
1,3-aminoalcohols or saturated nitrogen heterocycles3e5 and as
a chiral auxiliary.6 Recently, isoxazolidines have attracted atten-
tion as nucleoside analogues7a,8 and as synthetic transcriptase
activators.9 However, our current interests are concerned with
the preparation of a family of isoxazolo-bicycles with potential as
organocatalysts. 1,3-Dipolar cycloaddition of nitrones to alkenes
represents a key route to the isoxazolidine framework.10 How-
ever, N-substituted nitrones produce isoxazolidines with N-sub-
stituents, which are often difficult to remove without
simultaneous cleavage of the labile NeO bond. In addition to
those systems formed by intramolecular oxime olefin cyclo-
addition (IOOC) routes11e14 approaches to N-unsubstituted
isoxazolidines have frequently exploited Vasella’s carbohydrate-
derived auxiliaries;15 a more recent contribution to this area is
Partridge’s easily hydrolyzed N-nosyl auxiliary.16 In certain cases
the resonate tetrahydropyran,17 diphenyl methyl,18 trityl,19 Boc,20
We were interested in 5,5-bicycles incorporating an N-unsub-
stituted isoxazolidine with a second ring, fused proximal to the
nitrogen and report herein the synthesis of lactone, lactam and
pyrrolidine fused systems 1e3 (Fig. 1).
H
H
H
O
O
O
N
H
NCH3
O
NR
N
N
Ar
O
Ar
Ph
H
O
H
1
3
2
a. Ar = Ph
a R = Me
b R = Ph
a Ar = Ph
b. Ar = 2-furyl
c. Ar = 2-thienyl
d. Ar = 2-(NO2C6H4)CH2
e. Ar = CH2Ph
f. Ar = 2,4,6-(CH3)3C6H2
b Ar = 2-furyl
c Ar = 2-thienyl
Figure 1. Isoxazolo-fused bicycles 1e3.
We have previously reported the preparation of two members of
these families, 1a and 2a, from -alkenyl oximes and have reported
d
a relationship between the oxime geometry and the observed
reactivity.22e24 The reterosynthetic analysis outlined in Scheme 1
summarises our approach to the target bicycles. The
oximes 4 were to be accessed from their parent ketones 5 in turn
d-alkenyl
* Corresponding author. Tel.: þ353 1708 3802; fax: þ353 1708 3815; e-mail
address: mary.f.heaney@nuim.ie (F. Heaney).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.005

7042
L. Doyle, F. Heaney / Tetrahedron 66 (2010) 7041e7049
obtained from the condensation between the a-ketoacids 6 with
O
either allyl alcohol (X¼O) or N-methyl allylamine (X¼NMe) 7, or by
reaction between bromoacetophenone 8 and allylamine 9. Com-
petition between the desired IOOC reaction pathway, furnishing
1e3 and an alternative azaprotio cyclotransfer (APT) route,25
leading to the cyclic nitrones 10, depends on a number of para-
meters including a favourable equilibrium between the oximes 4
and the unsubstituted heteroaryl nitrones, their NH-tautomers, 4-T.
Whilst heteroaryl nitrones are known to be excellent peroxyl free
radical absorbance agents and potentially useful neuroprotective
agents,26,27 there are relatively few reports on their utility as
building blocks for the construction of isoxazolidines. In particular,
heteroaryl N-unsubstituted isoxazolidines are rare and direct
access to this framework has been realized by either thermal28 or
Pd(II) assisted cascade cycloadditions,29 indirect access by
N-deprotection strategies,30 and by reaction of 2-isoxazolines with
arylorganolithium reagents2, 31 have been successful.
O
Ar
O
5(I)
a. Ar = Ph; b. Ar = 2-furyl,
c. Ar = 2-thienyl, d. Ar = 2-(NO2C6H4)CH2,
e. Ar = CH2Ph, f. Ar = 2,4,6-(CH3)3C6H2
O
OH
Ph
O
Ph
O
H H
4.16 ppm
H
O
O
6.62 ppm
5(I)e (keto)
5(I)e (enol)
Figure 2. Key 1H NMR data for the tatuomers of 5(I)e.
the products are summarised in Table 1. For substrates 5(I)bee
reaction proceeded rapidly in EtOH at reflux and 4(I)b,c presented
as a mixture of geometrical isomers whilst 4(I)d39,e formed as
single isomers. The mesityl substrate 5(I)f was more sluggish to
H
O
N
Ar
X
4-T
i
R2
R3
react and heating in PrOH at reflux for 56 h furnished the desired
products, in 70% yield. A freshly prepared sample of the oximes 4
(I)f existed as an w1:8 mixture of geometrical isomers, however,
upon standing in solution (CDCl3) a gradual conversion of the
major to the minor isomer, completed after 17 days, at rt, was
observed. However, pure samples of 4(I)f stored at ꢀ20 ꢁC proved
to be conformationally stable.
IOOC
O
NOH
X
R2 R1
O
X
X
Ar
R1
N
R2 R1
Ar
2
H Ar
R
5
1-3
4
APT
OH
OH
H3
HO
Ar
N
N
HX
O
N
H
O
O
N
R
N+
R1
O
O
H4
Ar
7
9
X
R2
X
O
O
O
O
Ar
H5
OH
Ar
Br
8
10
Z-4(I)
E-4(I)
a. Ar = Ph; b. Ar = 2-furyl,
c. Ar = 2-thienyl, d. Ar = 2-(NO2C6H4)CH2,
e. Ar = CH2Ph, f. Ar = 2,4,6-(CH3)3C6H2
4(I)b,c
Ph
6
O
4/5/10(I) R1R2 = (=O), X = O;
4/5/10(II) R1R2 = (=O), X = NMe;
4/5(III) R1 = R2 = H, X = NR
Figure 3. Structures of the geometrical oxime isomers 4(I).
Scheme 1. Retrosynthetic approach to isoxazolo-fused bicycles 1-3 including optional
reaction pathways for alkenyl oximes 4.
Table 1
Yields and Geometrical ratios of the oximes 4(I), 4(II) and 4(III)
2. Results and discussions
Compound Z/E-ratio Isolated yield, % Compound Z/E-ratio Isolated yield, %
No.
Z, E-isomers
No.
Z,E-isomers
The lactone-fused isoxazolidines 1bef were targeted by a route
directly parallel to that described previously.22,24 In all cases
esterification of the commercially available ketoacids with allyl
alcohol proceeded to yield 5(I)bef in good yield (81e91%). The
benzyl substituted ester 5(I)e initially seemed difficult to purify,
however 1H NMR spectroscopy (CDCl3) subsequently revealed it to
exist as a mixture of keto and enol tautomers in solution. The enol
CHPh proton resonated ate6.62 ppm whilst the benzylic protons of
the keto tautomer appeared at 4.16 ppm, minor signals in the
spectrum are consistent with the presence of isomers about the
enol double bond (Fig. 2). This phenomenon was not observed with
the 2-(NO2C6H4)CH2 analogue 5(I)d.
4(I)b
4(I)c
4(I)e
4(I)f
1:1.4a
w1:1
99a
40, 43
75
4(II)b
4 (II)c
1:1.1a,c 76a,d
1:1.2c
20,d 24d
w1:8
8, 62b
4(III)a
4(III)b
2:5
17, 45
100a
1:1.3a
a
Geometrical isomers could not be separated.
Oxime isomers were not stable at rt.
Two rotamers presented for each oxime isomer.
b
c
d
It was not possible to separate individual rotameric forms.
In the case of the oxime 4(I)b geometrical isomers, present in
a 1:1.4 ratio, were inseparable by flash column chromatography,
however, for 4(I)c it was possible to obtain individual samples of
each oxime isomer.z The aryl protons of the furyl and thienyl
oximes are readily assigned on the basis of their different coupling
Conversion to the oximes 4(I) was effected by treatment with
NH2OH (Fig. 3); the ensuing yields and geometrical make-upy of
2
2
constants; thus for a typical furan J3,4 is e3.5 Hz whilst J4,5 is
2
smaller at w1.5 Hz; corresponding values for a thiophene are J3,4
w3.4 Hz and 2J4,5 w4.7 Hz.32 A comparison of the 1H NMR spectral
y
In the interest of uniformity, the C- phenyl, furyl and thienyl oxime isomers of 4
(I), 4(II) and 4(III) are designated Z- if the hydroxyl group is on the same side as the
aryl group and E- if the aryl and the hydroxyl groups are on opposite sides of the
oxime C]N.
z
Overlaps with the other conformer.

L. Doyle, F. Heaney / Tetrahedron 66 (2010) 7041e7049
7043
data, for the geometrical isomers of 4(I)b with that of the precursor
H
O
N+
5(I)b show a marked upfield shift (w1 ppm) in the resonance po-
sition of H-3 for one isomer only. The same pattern, also observed
for the resonance position of the H-3 protons of the thienyl ana-
logues, Z- and E-4(I)c, is mirrored in the 13C resonance position of
the corresponding carbon atoms (AreC3). Whilst one can assume
the upfield shift correlates with oxime configuration the ability to
distinguish between geometrical oxime isomers is more reliably
based on the shielding effects of the oxime oxygen atom on the
4
O23 65O
3a
N1
6a
O
Ar
H Ar
O
O
10(I)
1
a. Ar = Ph; b. Ar = 2-furyl,
c. Ar = 2-thienyl, d. Ar = 2-(NO2C6H4)CH2,
e. Ar = CH2Ph, f. Ar = 2,4,6-(CH3)3C6H2
a. Ar = Ph
b. Ar = 2-furyl
c. Ar = 2-thienyl
a
-carbon atom where the oxime hydroxyl group is Z to that carbon
Figure 4. Structures of the bicycles 1 and the cyclic nitrones 10(I) arising from reaction
of oximes 4(I).
atom.33 In the case of the isomers of 4(I)b the
a-carbon/carbon
atom, AreC2 of the Z-isomer resonates at 140 ppm upfield bye3 ppm
of the corresponding carbon atom in the E-isomer. For the Z-isomer,
the a
0-carbon atom (C]O) appears downfield, w0.6 ppm, from the
same atom in the E-isomer. The resonance position of the oxime
carbon atom (C]N) of the E-isomer is also found w3 ppm down-
field of its Z-analogue. The oximes of 4(I)c display the same pattern,
pertinent chemical shifts are summarised in Table 2.
isomers and the composition of the reaction products rules
out a simple correlation between oxime geometry and reactivity
for 4(I)b.
The individual isomers of the analogous thienyl oximes 4(I)c
were separately heated in xylenes at reflux in. The Z-isomer
Table 2
Selected NMR spectral data for the ketones 5(I), 5(II) and 5(III) and the oximes 4(I), 4(II) and 4(III)
Compound Number
H-3/C-3
H-4/C-4
H-5/C-5
a
-AreCQ
C]N
a
-C]O
OH
5(I)b
Z-4(I)b
E-4(I)b
7.73/124.8
7.45/119.8
6.68/113.1
6.64/113.1
6.57/111.9
6.48/111.8
7.78/149.6
7.57/144.1
7.52/144.9
149.7
140.0
142.6
d
142.3
145.1
161.9
161.3
10.23
10.21
5(I) c
Z-4(I)c
E-4(I)c
8.12/130.7
8.16/133.5
7.19/129.1
7.19/128.7
7.15/126.5
7.05/127.5
7.83/137.3
7.62/131.1
7.37/128.4
139.1
127.9
133.7
d
161.3
162.9
162.7
141.8
146.9
10.69
9.37
5(II)b
7.15/122.3, 121.9
6.43/112.8, 112.9
7.57/148.9, 148.8
150.1, 149.9
d
165.6
165.2
Z-4(II)b and E-4(II)b
7.44 and 6.62 119.7
and 119.6
6.54 and 6.47 122.3,
112.8 and 111.7
7.50 and 7.48 144.8,
155.7, 143.6 and
143.5e143
146.0e142.5 (8 signals)
163.8, 163.6, 162.8
9.30 and 8.89
5(II) c
7.80/136.5, 135.4
7.40/131.8, 131.8
7.17/127.8, 127.6
7.22/128.7, 128.6
7.11/126.2, 126.1
7.00/126.5, 126.4
7.80/136.2, 136.1
7.58/131.1, 130.9
7.30/126.8, 126.7
140.3, 140.2
Z-4(II)c
E-4(II)c
5(III)a
128.8, 128.7
133.7, 133.5
136.7
146.8, 146.7
147.9
d
165.1 164.8
163.3
10.22
9.89
d
3.69/63.1a
3.38/60.3a
3.77/54.8a
Z-4(III)a
E-4(III)a
132.6
135.7
155.5
154.2
8.75
12.38
a
1H and 13C NMR positions of the C(]NOH)CH2 atoms.
We had previously observed that upon thermal activation the
individual oxime isomers of 4(I)a reacted chemospecifically, with
the Z-isomer cyclising to the nitrone 10(I)a by an APT route and the
E-isomer yielding the isoxazole-bicycle 1a by the IOOC pathway
(Fig. 4).22,24 Thus, in search of analogous bicycles 1bef we wished
to establish if the oximes 4(I)bef shared the reactivity profile of 4(I)
a. As the oximes 4(I)b were inseparable, a solution of a 1:1.4 (Z/E-)
mixture was heated to reflux in xylenes under an N2 atmosphere.
Following purification by flash column chromatography the nitrone
10(I)b and the bicycle 1b, were isolated in 56 and 20% yield,
respectively, together with unreacted oxime (15%) (Table 3). The
relationship between the relative amounts of the starting oxime
converted solely to the nitrone 10(I)c in 79% yield. However, the
E-isomer of 4(I)c reacted to furnish the desired bicycle 1c (22%) as
the minor component in a product mixture, which included the
nitrone 10(I)c (41%), together with unreacted oxime. Thus it is
apparent that replacing the phenyl substituent in 4(I)awith a thienyl
group has a significant influence on the balance of reactivity. Thus,
whilst Z-4(I)c does react chemospecifically by the APT route, E-4(I)c
does not share the conformational stability displayed by E-4(I)a.
Both 1b and 1c formed regio- and diastereospecifically and
similarities in their pmr data with that reported for 1a22 permit
assignment of the 5,5-bicycles as having the expected cis-ring
stereochemistry.
Table 3
Reactivity profiles of the oximes 4(I), 4(II) and 4(III)a
Oxime No
Geometry
Bicycle (%)
Nitrone (%)
Oxime No
Geometry
Bicycle (%)
Nitrone (%)
4(I)a22
4(I)a22
4(I)b
4(I)c
Z-
E-
10(I)a (85)
4(II)a23
4(II)b
4(II)c
E
2a (91)
2b (44)
1a (66)
1b (20)
1c (22)
Z/E-1:1.1
Z
E
10(II)bb,c
10(II)c (71)
Z/E-1:1.4
10(I)b (56)
10(I)c (41)
10(I)c (79)
10(I)d (50)
10(I)e (24)
10(I)f (89)
E-
Z-
Z-
Z-
Z-
4(II)c
2c (86)
4(I)c
4(I)d
4(I)e
4(I)f
4(III)a
Z/E- 1:1.6
Z/E- 1:1
3a (62)c
d
4(III)bc
3b (89)11b
a
A solution of the oxime(s) was heated to reflux in xylene under an N2 atmosphere.
Nitrone 10(II)b could not be obtained pure and was found in an enriched mixture together with bicycle.
Reaction conducted in boiling toluene.
b
c

7044
L. Doyle, F. Heaney / Tetrahedron 66 (2010) 7041e7049
In keeping with the observation for 4(I)c, the Z-oximes of 4(I)d,
comprised both the desired bicycle 2b, as a single diastereoisomer
and the nitrone 10(II)b (Fig. 6). The crude products, together with
unreacted oxime, were found in an w5:2:3 ratio. Bicycle 2b was
isolated in 44% yield and the relative stereochemistry is assigned
with reference to 2a;23 the nitrone 10(II)b was obtained as an
enriched sample together with bicycle (Table 3). The relationship
between the relative amounts of the starting oxime isomers and the
composition of the crude reaction products does not permit any
conclusion regarding structure and reactivity for the oximes of 4(II)
b. In sharp contrast, the individual isomers of the thienyl analogues 4
(II)c react chemoselectively upon heating to reflux in xylene; thus,
the Z-isomer furnished the nitrone 10(II)c in 71% yield by the APT
pathway, whilst the E-isomer delivered the desired bicycle 2c (86%)
by the IOOC route (Table 3). This observation demonstrates the
importance of the structure of the tether connecting the oxime and
the terminal alkene in determination of the preferred mode of
reactivity. Thus, replacement of the ester tether of the thienyl oxime
E-4(I)c with the amide tether of E-4(II)c is sufficient to restore
chemospecific reactivity to the C-thienyl oxime.
e,f upon heating in xylenes at reflux chemospecifically cyclised to
yield the corresponding nitrones. Whilst yields could be poor 10(I)
d, 50%; 10(I)e, 24%; 10(I)f 89% in no case was there evidence for any
reactivity by way of an IOOC pathway. As may have been antici-
pated on the grounds of its ease of geometrical isomerisation in
solution under ambient conditions, a pure sample of E-4(I)f also
failed to furnish the corresponding bicycle. Thus, of the anticipated
lactone-fused isoxazolidine series the interplay between the geo-
metrical make-up and the differential reactivity of the oxime iso-
mers of 4(I), conspired to facilitate access only to the furyl- and
thienyl bearing bicyclic isoxazolidines 1b,c (Table 3).
An IOOC approach to the synthesis of lactam-fused iso-
xazolidines has previously been demonstrated with substrates
bearing an amido functionality tethered either directly7b or more
remotely23 to the alkene bond affording isomeric 5,5-bicycles
illustrated, respectively, by 11 and 2a.
Ph
O
O
NMe
N
H
H
-O
11
N
O
NMe
Ar O
N
N
Ar
The lactam-fused isoxazolidines 2b,c were accessed by a parallel
route to that described for 2a. Condensation between the acid
H
O
2
10(II)
chloride derivatives of the commercially available
a-ketoacids 6b,c
prepared by reaction with
a,a
-dichloromethly methyl ether34 and
a. Ar = Ph; b. Ar = 2-furyl; c. Ar = 2-thienyl
N-methylamine furnished the amides 5(II)b,c in good yield. In both
cases, 1H NMR spectroscopy (CDCl3) revealed the amides to exist as
an w1:1.1 mixture of rotamers in solution. Conversion to the ox-
imes 4(II)b,c followed from treatment with NH2OH, in refluxing
EtOH (Fig. 5). The 1H and 13C NMR spectra for the reaction products
were quite busy as in both cases the products presented as a mix-
ture of Z- and E-oxime isomers with each isomer showing evidence
for both rotameric forms in solution. The geometrical isomers of 4
(II)b were inseparable and the 1H NMR data shows multiple reso-
nance signals for many of the protons, for example, the N-methyl
protons present as four singlets at 3.06, 3.05, 2.93 2.92 ppm, in
w1.1:1:1:1.1 ratio; four distinct signals represent the corresponding
C-atom in the 13C NMR data (32.4, 31.4, 35.5, 34.6 ppm). It was not
possible to deconvolute the NMR data to unambiguously assign the
observed resonances to the individual conformers present (Table
2). In keeping with the analogous thienyl ester oximes 4(I)c the
amido oximes 4(II)c could be obtained as individual compounds. A
comparison of the 1H/13C NMR spectral data for each oxime of 4(II)c
with the data for Z- and E-4(I)c reveals a similar pattern. Specifi-
Figure 6. Structures of the bicycles 2 and the cyclic nitrones 10(II) arising from
reaction of 4(II).
Allylamines possessing an appropriately positioned oxime are
known to undergo a thermally-induced IOOC sequence to give
bicyclic pyrrolidine fused isoxazolidines.11,35,36 Olefin bearing
O-tert-butyldimethylsilyl oximes, under the influence of BF3$OEt2,
also react efficiently to generate N-unsubstituted bicycles.37,38
Stirring a solution of 2-bromoacetophenone 9 and N-methyl allyl-
amine in DCM for 10 min furnished the desired tertiary amine 5(III)
a in quantitative yield, the already known 5(III)b required longer to
reach the same extent of conversion (30 h).11b Each substrate
reacted with NH2OH$HCl in ethanolic NaHCO3 to furnish the
corresponding oximes as pairs of geometrical isomers (Fig. 7).
Analytical samples of Z- and E-isomers of the N-methyl amino
oximes 4(III)a were obtained. Geometrical assignment is based on
the 13C NMR resonance data. In the case of the Z-isomer the
a
-carbon carbon atom, AreCQ, resonates at w132 ppm upfield by
w3 ppm of the corresponding carbon atom in the E-isomer. For the
Z-isomer the
0-carbon atom (NCH2) appears downfield, w6 ppm,
from the same atom in the E-isomer. The resonance position of
the
0-protons (NCH2) reflect this pattern with the methylene
cally, the
at w129 ppm, w5 ppm upfield of the corresponding carbon atom
in the E-isomer. For the Z-isomer the
0-carbon atom (C]O) ap-
a
-carbon carbon atom, AreCQ, of the Z-isomer resonates
a
a
pears downfield,e1.7 ppm, from the same atom in the E-isomer. The
resonance position of the oxime carbon atom of the E-isomer is also
founde1 ppm downfield of its Z-analogue (Table 2).
a
protons of E-isomer resonating w0.4 ppm downfield of those in the
Z-analogue (Table 2). Flash column chromatography was not able
to separate the N-phenyl amido oximes 4(III)b, which we obtained
as a 1:1.3 mixture of Z- and E-isomers. This ratio reflects a slight
preference for the E-isomer over an earlier synthesis conducted
in H2O.11b
HO
Ar
OH
Me
N
N
Me
N
N
O
Me
N
Ar
Ar
O
O
O
5(II)
E-4(II)
Z-4(II)
OH
HO
Ph
O
R
N
N
R
N
N
R
a. Ar = Ph; b. Ar = 2-furyl; c. Ar = 2-thienyl
N
Ph
Ph
Figure 5. Structures of the amido esters 5(II) and the geometrical oxime isomers 4(II).
E-4(III)
5(III)
Z-4(III)
a. R = Me; b. R = Ph
As the furyl bearing oximes 4(II)b were impossible to separate by
flash column chromatography, thermal activationwas performed on
the mixture of E-and Z-isomers. The resulting reaction products
Figure 7. Structures of the amido esters 5(III) and the geometrical oxime isomers 4(III).

L. Doyle, F. Heaney / Tetrahedron 66 (2010) 7041e7049
7045
The N-methylpyrrolidine fused isoxazolidine 3a (Fig.1) resulted in
62% yield following heating to reflux a toluene solution of the mixed
oximes Z-/E-4(III)a, Table 3. As has been observed for the N-phenyl
analogue 3b11b pmr spectroscopy revealed an equilibrium between
two major conformers. Spectra of 3a were very broad at ambient
temperaturewhilstsharpsignalsrepresentingindividualconformers,
in a ratio of w6:1, were evident at ꢀ50 ꢁC. The individual conformers
are most likely associated with pyramidal inversion of both N-atoms
and flipping of the two five-membered rings.11b
nucleus. Coupling constants are measured in hertz. Mass spectra
were obtained on a LC/TOF-MS model 6210. Infrared spectra were
recorded on a Perkin Elmer System 2000 FT spectrometer as thin
films or as Nujol mulls. Melting points were measured on a Stuart
Scientific (Bibby) Melting Point SMPI apparatus and are uncorrected.
Microanalytical data were recorded on an Exeter Analytical CE-440
elemental analyser. Flash column chromatography was performed
using silica gel 60 (Merck, 0.040e0.063 mm) on a Buchi Automated
Flash system. Analytical thin layer chromatography was carried out
on aluminium sheets pre-coated with Merck TLC Silica gel 60 F254
Developed chromatograms were visualised using a portable UVItec
CV-006 lamp ( 254). Mixed, and not individual xylene isomers were
.
3. Conclusion
l
used in all reactions.
Facile thermal oxime/NH-nitrone tautomerisation is a requisite
for IOOC reactivity and appropriately positioned functional groups
within the rest of the molecule, for example, a carbonyl oxygen atom
capable of forming of a stabilizing H-bond with the new dipole, are
known to facilitate this process.28 Whilst the oximes 4(I) and 4(II) do
bear this type of functionality they are not conformationally con-
strained molecules and it may be the case that, even if dipole for-
mation is facilitated by the proximal ester or amide carbonyl group,
that it is difficult to attain the necessary alignment for an intra-
molecular cycloaddition between the transient NH-nitrone and the
pendant alkene moiety. In addition to the possibility of presenting as
geometrical isomers about the C]N double bond the oximes 4(I)b,c
and 4(II)b,c and their tautomeric NH-nitrones 4(I)b,c-T and 4(II)b,c-
T, have additional restrictions to their conformational freedom. S-cis-
or S-trans-relationships are possible about the CeC single bond
connecting the heteroaryl and the oxime functionalities, and about
the bond connecting the oxime carbon atom to the adjacent carbonyl
group. The presentation of distinct rotameric forms about the amide
functionality adds a further layer of structural complexity for the
oximes of 4(II), Figure 8. Whilst our results demonstrate enhanced
chemoselectivity for the amide tethered alkenyl oximes over their
ester analogues, the multitude of possible reacting conformations
makes it difficult to be prescriptive about any relationship between
oxime structure and reactivity. However, this survey does indicate
4.2. General procedure for preparation of allyl esters
of
a
-ketoacids, 5(I)
A solution of the
a-keto acid 6 (18.0 mmol) and allyl alcohol 7
(X¼O) (27.0 mmol) in toluene (75 mL) in the presence of a catalytic
amount of p-TsOH was stirred with heating at reflux using a Dean-
eStark apparatus for 15 min-20 h. The solution was washed with
satd aq NaHCO3 (20 mL) and H2O (20 mL) and the organic layer was
dried (MgSO4), filtered and evaporated to yield the crude product.
4.2.1. Allyl 2-(2-furyl)-2-oxoacetate, 5(I)b. Prepared from 6b, the
product 5(I)b was obtained as a dark yellow oil (2.80 g, 87%) after
a reaction time of 20 h and was used without further purification;
Rf (10% EtOAc/Hex) 0.25; nmax (Nujol) 5793, 2951, 1675, 1576,
1457 cmꢀ1 dH 7.78e7.77 (1H, dd J 1.6 and 0.6, AreH5), 7.73e7.72
;
(1H, dd J 3.7 and 0.6 AreH3), 6.64e6.63 (1H, dd J 3.7 and 1.6,
AreH4), 6.09e5.95 (1H, m, CH]CH2), 5.49e5.32 (2H, m, CH]CH2),
4.85 (2H, d, J 5.9, OCH2); dC, 170.8 (ArC]O), 160.7 (C]O), 149.7 (Q
ArC), 149.6 (ArC5), 130.6 (CH]CH2), 124.8 (ArC3), 120.1 (CH2]CH),
113.1 (ArC4) 67.0 (OCH2); LC/TCOF-MS found 181.0495(MþNH4)þ;
C9H8O4 requires 181.0501.
4.2.2. Allyl 2-oxo-2-(2-thienyl)acetate, 5(I)c39. Prepared from 6c,
the product 5(I)c was obtained as a yellow oil (1.06 g, 84%). dH
8.13e8.11 (1H, dd J 3.9 and 1.1, AreH3), 7.84e7.82 (1H, dd J 4.9 and
1.1, AreH5), 7.21e71.18 (1H, dd J 4.9 and 3.9, AreH4), 6.09e5.96 (1H,
m, CH]CH2), 5.48e5.42 (1H, dd J 17.2 and 1.3, H C]CH trans),
5.37e5.33 (1H, dd J 10.4 and 1.3, H C]CH cis), 4.85 (2H, d, J 5.9,
OCH2); dC 176.1 (ArC]O), 161.3 (C]O), 139.1 (Q ArC), 137.5 (CH]
CH2), 137.3, 130.7, 128.7 (3ꢂArC), 120.1 (CH2]CH), 67.0 (OCH2).
that thermal activation of amino or amido linked d-alkenyl oximes
can be an acceptable route to N-unsubstituted bicyclic isoxazolidines
overcoming the difficulties associated with the most commonly
employed routes to the N-unsubstituted hetrocycle, i.e., removal of
N-substituent from those isoxazolidines prepared from cycloaddi-
tion of N-alkyl nitrones.
H
O
HO
N
N
4.2.3. Allyl 2-oxo-3-phenylpropanoate, 5(I)e. Prepared from 6e, the
product 5(I)e was obtained as a dark yellow oil (3.11 g, 81%) after
a reaction time of 25 min and was used without further purifica-
O
O
Ar
Ar
O
O
E-/Z-4(I)b,c-T
E-/Z-4(I)b,c
tion; nmax (Nujol) 3225, 2952, 2587, 1736, 1455, 1274, 1177 cmꢀ1
; dH
O
H
Me
N
7.85e7.26 (10H, m, ArH[keto and enol]), 6.63 (1H, br s, OH[enol]),
6.62 (1H, s, CHPh[enol]), 6.11e5.88 (2H, m, CH]CH2[keto and
enol]), 5.48e5.30 (4H, CH2]CH [keto and enol]), 4.85e4.73 (4H,
OCH2[keto and enol]), 4.16 (2H, s, CH2Ph[keto]); dC 190.1 (COH
[enol]), 164.9, 159.5 (OC]O[keto and enol]), 156.3 (CH2C]O[keto]),
143.8 (CHPh[enol]), 138.1, 137.5 (Q ArC[keto and enol]), 131.4, 130.6
(CH]CH2[keto and enol]), 130.4, 130.1, 129.4, 129.2, 129.1, 128.8,
128.5, 128.1, 128.0, 127.6 (10ꢂArC[keto and enol]), 111.4 (CHPh
[enol]), 118.8, 118.2 (CH2]CH [keto and enol]), 66.4, 66.1 (OCH2[-
keto and enol]), 44.8 (CH2Ph[keto]).
HO
Me
N
N
N
Ar
Ar
O
O
E-/Z-4(II)b,c-T
E-/Z-4(II)b,c
Figure 8. Degrees of conformational freedom for ester and amido linked heteroaryl
oximes 4(I) and 4(II).
4. Experimental
4.1. General
4.2.4. Allyl 2-mesityl-2-oxoacetate, 5(I)f. Prepared from 6f, the
product 5(I)f was obtained as a yellow oil (90%) after a reaction time
of 15 min and was used without further purification; [found: C, 72.19;
H, 6.90. C14H16O3 requires, C, 72.39; H, 6.95%]; Rf (25% EtOAc/Hex)
All 1H and 13C nuclear magnetic resonance spectra were recorded
in CDCl3, with TMS as internal standard, on a Bruker Avance spec-
trometer at a probe temperature of 25 ꢁC, unless otherwise stated,
operating at 300 MHz for the 1H nucleus and 75.5 MHz for the 13C
0.33; nmax (Nujol) 2854, 1737, 1610, 1460, 1377, 1297, 1201 cmꢀ1
;
dH
6.86 (2H, s, ArH), 5.99e5.88 (1H, m, CH]CH2), 5.40e5.34 (1H, dd, J

7046
L. Doyle, F. Heaney / Tetrahedron 66 (2010) 7041e7049
17.2 and 1.0, C]CH trans), 5.30e5.26 (1H, dd, J 10.4 and 1.0, C]CH
cis), 4.75 (2H, d, J 5.9, OCH2), 2.27 (3H, s, p-ArCH3), 2.24 (6H, s, 2ꢂo-
ArCH3); dC 191.7 (ArC]O), 162.4 (C]O), 141.1 (p-ArC), 136.3 (o-ArC),
133.1 (Q ArC), 130.7 (CH]CH2), 129.1 (m-ArC), 120.0 (CH2]CH), 66.8
(CH2O), 21.2 (p-ArCH3), 19.4 (o-ArCH3); LC/TCOF-MS found 233.1182
(MþH)þ C14H16O3 requires 233.1172.
5ꢂArH), 5.98e5.89 (1H, m, CH]CH2), 5.36e5.30 (1H, dd, J 17.0 and
1.1, C]CH trans), 5.28e5.25 (1H, dd, J 10.6 and 1.1, C]CH cis), 4.71
(2H, d, J 5.8, CH2O), 3.99 (2H, s, CH2Ph); dC 163.0 (C]O), 151.1 (C]
N),135.6 (Q ArC), 131.3 (CH]CH2), 129.2, 128.6, 126.7 (3ꢂArC),119.3
(CH2]CH), 66.5 (OCH2), 30.6 (CH2Ph); LC/TCOF-MS found 242.0779
(MþNa)þ C12H13NO3 requires 242.0787.
4.3. General procedures for oxime formation
4.3.4. Allyl 2-(hydroxyimino)-2-mesitylacetates, Z-4(I)f and E-4(I)f.
Prepared by method B. The crude product was purified by flash
column chromatography (5% EtOAc/Hex) to yield Z-4(I)f as a cream
solid (42.0 mg, 8%) and E-4(I)f as a yellow oil (0.31 g, 62%); Z-4(I)f
[found: C, 68.10; H, 7.04; N, 5.62; C14H17NO3 requires C, 67.98; H,
6.93; N, 5.66; mp 83e87 ꢁC; nmax (KBr) 3258, 2923, 1735, 1410,
Method A. A solution of the allyl ester 5(I) (15 mmol), NH2OH$HCl
(1.61 g, 23.0 mmol) and pyridine (2.71 g, 23.0 mmol) in EtOH
(140 mL) was stirred with heating at reflux for 3 h. Following cooling
to rt the solution was evaporated and the residue taken up in DCM
(50 mL), washed with satd aq NaHCO3 (50 mL) and H2O (50 mL). The
organic layer was dried (MgSO4), filtered and evaporated to yield the
crude product, which was purified as noted below.
Method B. A mixture of the allyl ester 5(I) (2.4 mmol), pyridine
(0.42 g, 5.3 mmol) and NH2OH$HCl (0.37 g, 5.3 mmol) in iPrOH
(11 mL) was heated with stirring at reflux for 56 h. The mixture was
allowed to cool to rt prior to evaporation to dryness. The residue
was taken up in DCM (10 mL), washed with satd aq NaHCO3 (5 mL)
and H2O (5 mL), dried (MgSO4), filtered and evaporated to yield the
crude product, which was purified as described below.
1199 cmꢀ1
;
dH 8.65 (1H, br s, NOH), 6.91 (2H, s, 2ꢂArH), 6.00e5.87
(1H, m, CH]CH2), 5.34e5.28 (1H, dd, J 17.2 and 1.3, C]CH trans),
5.27e5.23 (1H, dd, J 10.4 and 1.3, C]CH cis), 4.75 (2H, d, J 5.8,
OCH2), 2.30 (3H, s, p-CH3), 2.14 (6H, s, o-CH3); dC 162.8 (C]O), 151.9
(C]N),139.2 (p-ArC),135.6 (o-ArC),131.3 (CH]CH2),128.2 (m-ArC),
126.6 (Q ArC), 119.2 (CH2]CH), 66.4 (OCH2), 21.2 (p-CH3), 19.5 (o-
CH3); LC/TCOF-MS found 248.1285 (MþNa)þ C14H17NO3 requires
248.1281. Compound E-4(I)f Rf (20% EtOAc/Hex) 0.40; nmax (Nujol)
3266, 2924, 1736, 1612, 1456, 1287 cmꢀ1
; dH 11.11 (1H, br s, NOH),
6.89 (2H, s, m-ArH), 5.93e5.80 (1H, m, CH]CH2), 5.30e5.26 (1H,
dd, J 12.7 and 1.4, C]CH trans), 5.24e5.22 (1H, dd, J 5.9 and 1.4, C]
CH cis), 4.72 (2H, d, J 5.7, OCH2), 2.29 (3H, s, p-ArCH3), 2.23 (6H, s, o-
CH3).; dC 163.0 (C]O), 148.7 (C]N), 139.1 (p-ArC), 137.4 (o-ArC),
130.6 (CH]CH2), 128.5 (m-ArC), 128.0 (Q ArC), 119.5 (CH2]CH),
66.2 (OCH2), 21.1 (p-ArCH3), 19.8 (o-ArCH3); LC/TCOF-MS found
270.1108 (MþNa)þ found 270.1101, C14H17NO3 requires 270.1108.
4.3.1. Allyl 2-(2-furyl)-2-(hydroxyimino)acetates, Z-4(I)b and E-4(I)
b. Prepared by method A. The product, a brown oil (2.90 g, 99%),
comprised Z- and E-oxime isomers (Z/E 1:1.4), which could not be
separated by flash column chromatography; Rf 0.39 (40% EtOAc/Hex)
0.39; nmax 3152, 2854, 1737, 1649, 1461, 1377, 1308, 1225, 1157,
1052 cmꢀ1 dH Z-4(I)b 10.23 (1H, br s, OH), 7.57 (1H, d, J 1.5, AreH5),
;
7.45 (1H, d, J 3.5, AreH3), 6.58e6.56 (1H, dd, J 3.5 and 1.5, AreH4),
6.08e5.94 (1H, m, CH]CH2), 5.46e5.40 (1H, dd, J 17.2 and 1.3, C]CH
trans), 5.33e5.29 (1H, dd J 10.4 and 1.3, C]CH cis), 4.84 (2H, d, J 5.8,
OCH2); dC Z-4(I)b 161.9 (C]O), 144.1 (ArC5), 142.3 (C]N), 140.0 (Q
ArC),131.2 (CH2]CH),119.8 (ArC3),119.4 (CH2]CH),111.9 (ArC4), 66.7
(CH2O); dH E-4(I)b 10.21 (1H, br s, OH), 7.52 (1H, d, J 1.5, AreH5), 6.68
(1H, d, J 3.5, AreH3), 6.49e6.47 (1H, dd, J 3.5 and 1.5, AreH4),
6.08e5.94 (1H, m, CH]CH2), 5.48e5.43 (1H, dd, J 17.2 and 1.3, C]CH
trans), 5.35e5.31 (1H, dd J 10.4 and 1.3, C]CH cis), 4.88 (2H, d, J 5.8,
OCH2); dC E-4(I)b 161.3 (C]O), 145.1 (C]N), 144.9 (ArC5), 142.6 (Q
ArC),130.9 (CH2]CH),119.7 (CH2]CH),113.1 (ArC3),111.8 (ArC4), 66.8
(CH2O); LC/TCOF-MS found 219.0464; (MþNa)þ requires 219.0456.
4.4. General procedure for thermal reactivity of oximes,
4(I)bef
A solution of the oxime 4(I)bef (5.0 mmol) in xylenes (300 mL)
was heated with stirring at reflux in the presence of hydroquinone
(1.0%, w/v, 3.0 g) under N2 for 24e46 h. The solution was allowed to
cool to rt, the solvent was removed under vacuum and the crude
product was taken up in CHCl3 (150 mL) and left to stand at rt for
30 min. After any remaining hydroquinone had precipitated the
solution was filtered and evaporated to yield the crude products,
which were purified as detailed below.
4.4.1. 6a-(2-Furyl)tetrahydro-3H,6H-furo[3,4-c]isoxazol-6-one, 1b and
5-(2-furyl)-5-methyl-6-oxo-3,6-dihydro-2H-1,4-oxazin-4-ium-4-olate,
10(I)b. Title products 1b, a brown solid (0.20 g, 20%) and 10(I)b, also
a brown solid (0.55 g, 56%), were obtained following heating a 1:1.4
mixture of Z- and E-4(I)b for 24 h, Separation was achieved by flash
column chromatography (50% Hex/EtOAc); 1b mp 69e74 ꢁC; nmax
4.3.2. Allyl 2-(hydroxyimino)-2-(2-thienyl)acetates, Z-4(I)c and E-4
(I)c39. The Z- (0.21 g, 40%) and E-oximes 4(I)c (0.23 g, 43%) were
purified by flash column chromatography; dH Z-4(I)c 10.69 (1H, br s,
OH), 8.18e8.15 (1H, dd, J 4.0 and 0.9, AreH3), 7.63e7.61 (1H, dd, J 5.0
and 0.9, AreH5), 7.17e7.14 (1H, dd, J 5.0 and 4.0, AreH4), 6.12e6.01
(1H, m, CH]CH2), 5.49e5.42 (1H, dd, J 17.2 and 1.2, C]CH trans),
5.36e5.32 (1H, dd, J 10.4 and 1.2, C]CH cis), 4.86 (2H, d, J 5.9, OCH2);
dC Z-4(I)c 162.9 (C]O), 141.8 (C]N), 133.5 (AreC3), 131.1 (AreC5),
131.2 (CH]CH2), 127.9 (Q ArC), 126.5 (AreC4), 119.7 (CH2]CH), 66.9
(OCH2); dH E-4(I)c 9.37 (1H, br s, OH), 7.37e7.35 (1H, dd, J 5.1 and 1.0,
AreH5), 7.21e7.19 (1H, dd, J 3.8 and 1.0, AreH3), 7.05e7.02 (1H, dd, J
5.1 and 3.8, AreH4), 6.08e5.95 (1H, m, CH]CH2), 5.45e5.42 (1H, dd, J
17.2 and 1.3, C]CHtrans), 5.35e5.31 (1H, dd, J 10.4 and 1.3, C]CHcis),
4.89 (2H, d, J 5.9, OCH2); dC E-4(I)c 162.7 (C]O),146.9 (C]N),133.7 (Q
ArC), 130.9 (CH]CH2), 129.1 (AreC3), 128.4 (AreC5), 127.5 (AreC4),
119.9 (CH2]CH), 66.7 (OCH2).
(KBr) 3384, 2849, 1766, 1377, 1194 cmꢀ1 dH 7.46 (1H, d, J 1.9, AreH5),
;
6.64 (1H, d, J 3.3, AreH3), 6.43e6.41 (1H, dd, J 3.3 and 1.9, AreH4),
5.79 (1H, br s, NH), 4.62e4.56 (1H, dd, J 9.6 and 8.3, H4), 4.33e4.26
(2H, m, H3 and 4), 4.20e4.14 (1H, dd, J 9.1 and 6.5, H3), 3.75e3.67 (1H,
m, H3a); dC 173.1 (C]O), 144.2 (C6a), 143.9 (AreC5), 111.3 (AreC4),
110.8 (AreC3), 70.2 (Q ArC), 69.9 (C4), 48.1 (C3a), 29.7 (C3); LC/TCOF-
MS found 196.0540 (MþH)þ C9H9NO4 requires 196.0540 g. Com-
pound 10(I)b [found: C, 55.78; H, 4.76; N, 6.94; C9H9NO4 requires C,
55.37; H, 4.65; N, 7.18%]; mp 68e72 ꢁC; nmax (KBr) 3426, 2837, 1716,
1526, 1286, 1280, 1207; dH 7.80 (1H, d, J 3.5, AreH3), 7.63 (1H, d, J 1.6,
AreH5), 6.57e6.56 (1H, dd, J 3.5 and 1.6, AreH4), 4.70e4.63 (1H, m,
CHCH3), 4.37e4.26 (2H, m, CH2), 1.61 (3H, d, J 6.7, CH3); dC 156.5 (C]
O), 144.7 (AreC5), 143.6 (C]N), 127.2 (Q ArC), 118.3 (AreC3), 111.6
(AreC4), 67.0 (CH2), 64.0 (CHCH3), 14.2 (CH3); LC/TCOF-MS found
196.0613 (MþH)þ C9H9NO4 requires 196.0604.
4.3.3. Allyl 2-(hydroxyimino)-3-phenylpropanoate, Z-4(I)e. Pre-
pared by method A. The crude product was purified by flash column
chromatography (50% Hex/Et2O) to yield the title oxime as a white
solid (1.27 g, 75%); [found: C, 68.08; H, 7.21; N, 5.15. C12H13NO3
requires C, 67.98; H, 6.93; N, 5.66%; mp 59e62 ꢁC; nmax (KBr) 3243,
4.4.2. 6a-(2-Thienyl)tetrahydro-3H,6H-furo[3,4-c]isoxazol-6-one,1c and
3-methyl-6-oxo-5-(2-thienyl)-3,6-dihydro-2H-1,4-oxazin-4-ium-4-
1726, 1449, 1311 cmꢀ1
;
dH 9.45 (1H, br s, NOH), 7.33e7.21 (5H, m,

L. Doyle, F. Heaney / Tetrahedron 66 (2010) 7041e7049
7047
olate,10(I)c. Title products 1c, a pale brown solid (51.0 mg, 22%) and
10(I)c, also a brown solid (96.0 mg, 41%), were obtained following
heating E-4(I)c for 46 h, Separation was achieved by flash column
chromatography (22% Hex/EtOAc); 1c mp 135e140 ꢁC; nmax(KBr)
(4.0 equiv) was added dropwise, addition was accompanied by
evolution of HCl. The mixture was heated in an oil bath at 50 ꢁC for
30 min and then allowed to cool to rt. Methyl formate was removed
on a rotatory evaporator using an ice-cooled water bath to afford the
products in quantitative yield as a pungent brown oils, which
were immediately used without further purification. Obtained from
6b, 2-(chlorooxy)-1-(2-furyl)-2-oxo-1-ethanone 0.226 g; from 6c
2-(chlorooxy)-1-(2-thienyl)-2-oxo-1-ethanone 1.126 g.
Step 2. To a mixture of N-methyl allylamine (1.44 g, 20.0 mmol)
and NaHCO3 (1.71 g, 20.0 mmol) in DCM (30 mL) at 0 ꢁC was added
dropwise a solution of freshly prepared acid chloride (15.0 mmol)
in DCM (8 mL). The mixture was stirred at rt for 1 h prior to
washing with H2O (20 mL). The organic layer was dried (MgSO4),
filtered and the solvent was removed by rotary evaporation to yield
the crude product, which required no further purification.
3197, 3070, 2923, 1764, 1481, 1384, 1234, 983 cmꢀ1
; dH 7.40e7.38
(1H, dd, J 5.1 and 1.2, AreH5), 7.29e7.27 (1H, br dd, J 3.5 and 1.2,
AreH3), 7.07e7.04 (1H, dd, J 5.1 and 3.8, AreH4), 5.76 (1H, br s, NH),
4.65e4.59 (1H, dd, J 9.7 and 7.1, H3), 4.39e4.34 (1H, dd, J 9.7 and 2.4,
H3), 4.30e4.19 (2H, m, H4), 3.63e3.57 (1H, m, H3a); dC 175.3 (C]O),
134.6 (Q ArC),127.7 (AreC4),127.3 (AreC3 and 5), 78.7 (C4), 72.5 (C6a),
70.6 (C3), 50.51 (C3a); LC/TCOF-MS found 249.9937 (MþK)þ
C9H9NO3S requires 249.9935. Compound 10(I)c mp 119e123 ꢁC; dH
8.49e8.47 (1H, dd, J 4.2 and 1.1, AreH3), 7.53e7.51 (1H, dd, J 5.1 and
1.1, AreH5), 7.24e7.21 (1H, dd, J 5.1 and 4.2, AreH4), 4.70e4.64 (2H,
m, CH2), 4.44e4.33 (1H, m, CHCH3), 1.66 (3H, d, J 6.6, CH3); dC 157.5
(C]O), 132.8 (AreC3), 130.6 (C]Nþ), 129.2 (AreC5), 129.0 (Q ArC),
127.2 (AreC4), 67.0 (CHCH3), 63.2 (CH2), 14.4 (CH3); LC/TCOF-MS
found 234.0202 (MþNa)þ C9H9NO3S requires 234.0195.
4.5.1. N-Allyl-2-(2-furyl)-N-methyl-2-oxo acetamide, 5(II)b. The
title product was obtained as a brown oil (2.66 g, 88%); rotamer ra-
tio: 1.1:1; Rf 0.31 (20% EtOAc/Hex); nmax (Nujol) 2854, 1654, 1568,
4.4.3. 3-Methyl-6-oxo-5-(2-thienyl)-3,6-dihydro-2H-1,4-oxazin-4-
ium-4-olate, 10(I)c. The nitrone 10(I)c was obtained as a brown
solid (0.16 g, 79%) following heating Z-4(I)c for 24 h.
1462, 1377 cmꢀ1 dH 7.57e7.56 (2.1H, m, AreH5), 7.15 (2.1H, d, J 3.5,
;
AreH3), 6.44e6.42 (2.1H, m, AreH4), 5.65e5.50 (2.1H, m, CH]CH2),
5.48e4.97 (4.2H, m, CH2]CH), 3.90 (2.2H, d, J 5.8, NCH2 major rot.),
3.68 (2H, d, J 5.8, NCH2[minor rot.]), 2.81 (3H, s, NCH3[minor rot.]),
2.75 (3.3H, s, NCH3 major rot.); dC 178.4 and 178.3 (ArC]O), 165.6
and 165.2 (NC]O), 150.1 and 149.9 (2ꢂQ ArC), 148.9, 148.8 (AreC5),
131.9 and 131.6 (CH]CH2), 122.3, 121.9 (AreC3), 119.3 and 119.2
(CH2]CH), 112.8, 112.9 (AreC4), 52.1 (NCH2 major rot.), 48.8
(NCH2[minor rot.]), 34.5 (NCH3[minor rot.]), 31.7 (NCH3 major rot.);
LC/TCOF-MS found 216.0639 (MþNa)þ C10H11NO3 requires 216.0631.
4.4.4. 3-Methyl-5-(2-nitrobenzyl)-6-oxo-3,6-dihydro-2H-1,4-oxazin-
4-ium-4-olate, 10(I)d. The nitrone 10(I)d was obtained as a yellow
solid (0.15 g, 50%) following heating Z-4(I)d for 24 h. Purification
was by flash column chromatography (50% Hex/EtOAc); mp
68e74 ꢁC; nmax (KBr) 2923, 1727, 1520, 1342, 1265 cmꢀ1
; dH
7.94e7.91 (1H, dd, J 8.7 and 1.7, AreH3), 7.55e7.52 (1H, ddd J 9.4, 7.5
and 1.7, AreH5), 7.42e7.37 (2H, m, AreH4 and 6), 4.63e4.58 (1H, dd, J
12.2 and 3.6, H2), 4.35 (2H, s, CH2Ar), 4.32e4.26 (1H, dd, J 12.2 and
4.5.2. N-Allyl-N-methyl-2-oxo- 2-(2-thienyl)acetamide, 5(II)c. The
title product was obtained as a brown oil (1.01 g, 75%); rotamer ratio:
1.1:1; Rf (10% EtOAc/Hex) 0.33; nmax (Nujol) 3286, 3086, 2932, 1852,
5.9, H2), 4.20e4.10 (1H, m, CHCH3), 1.53 (3H, d, J 6.8, CH3); dC 159.0
0
(C]O), 149.6 (Q ArC), 135.7 (C]Nþ), 133.0 (AreC5 ), 131.7 and 128.0
(AreC4/6), 130.2 (QAreC), 124.8 (AreC3), 67.3 (C2), 63.7 (CHCH3),
28.6 (CH2Ph), 14.3 (CH3); LC/TCOF-MS found 288.0678 (MþNa)þ
C12H12N2O5 requires 288.0669.
1760, 1659, 1408, 1355, 1287 cmꢀ1 dH 7.83e7.78 (4.2H, m, AreH3 and
;
5), 7.28e7.16 (2.1H, m, AreH4), 5.89e5.73 (2.1H, m, CHCH2),
5.32e5.18 (4.2H, m, CH2]CH), 4.13 (2H, d, J 6.0, NCH2[minor rot.]),
3.90 (2.2H, d, J 5.9, NCH2 major rot.), 3.05 (3.3H, s, CH3 major rot.),
2.98 (3H, s, CH3[minor rot.]); dC 183.4, 183.3 (ArC]O), 166.1, 165.7
(NC]O), 140.3, 140.2 (2ꢂQ ArC), 136.5, 136.4 (AreC3), 136.2, 136.1
(AreC5), 132.2, 131.4 (CH]CH2), 128.7, 128.6 (AreC4), 119.0, 118.7
(CH2]CH), 52.5, 49.1 (NCH2), 34.8, 32.0 (NCH3); LC/TCOF-MS found
248.0148 (MþK)þ C10H11NSO2 requires 248.0142.
4.4.5. 5-Benzyl-3-methyl-6-oxo-5,6-dihydro-2H-1,4-oxazin-4-ium-
4-olate, 10(I)e. The nitrone 10(I)e was obtained as a yellow solid
(38.0 mg, 24%) following heating Z-4(I)e for 24 h. Purification was
by flash column chromatography (20% Hex/EtOAc); mp 88e94 ꢁC;
nmax (KBr) 3402, 1703, 1553, 1495, 1453, 1382, 1362 cmꢀ1
; dH
7.37e7.19 (5H, m, ArH), 4.57e4.52 (1H, dd, J 12.0 and 3.5, H2),
4.26e4.20 (1H, dd, J 12.0 and 5.8, H2), 4.19e4.11 (1H, m, CHCH3),
4.02 (2H, s, CH2Ph), 1.53 (3H, d, J 6.8, CH3); dC 158.2 (C]O), 134.6
(C]Nþ), 133.7 (Q ArC), 128.6, 127.6, 124.7 (3ꢂArC), 66.6 (C2), 62.8
(CHCH3), 29.9 (CH2Ph), 13.4 (CH3); LC/TCOF-MS found 220.0964
(MþH)þ C12H13NO3 requires 220.0968.
4.6. General procedure for formation of oximes, 4(II)
A mixture of the a-keto amide 5(II) (2.6 mmol), pyridine (2.24 g,
2.8 mmol) and NH2OH$HCl (1.97 g, 2.8 mmol) in EtOH (500 mL)
was stirred with heating at reflux in for 18e20 h. The solution was
cooled to rt prior to evaporation under reduced pressure. The res-
idue was taken up in DCM (150 mL) and the organics were washed
with satd aq NaHCO3 (50 mL) and H2O (50 mL). The organic layer
was dried (MgSO4), filtered and evaporated to yield the crude
product, which was purified as detailed below.
4.4.6. 5-Mesityl-3-methyl-6-oxo-3,6-dihydro-2H-1,4-oxazin-4-ium-
4-olate, 10(I)f. The nitrone 10(I)f was obtained as a pale brown
solid (45.0 mg, 89%) following heating Z-4(I)f for 24 h; mp
101e109 ꢁC; nmax (KBr) 3415, 2920, 1722, 1611, 1722, 1534, 1464,
1350, 1282, 1201, 1142 cmꢀ1
; dH 6.92 (2H, s, m-ArH), 4.74e4.68 (1H,
dd, J 12.2 and 3.4, H2), 4.38e4.23 (1H, dd, J 12.2 and 4.0, H2),
4.29e4.20 (1H, m, CHCH3), 2.29 (3H, s, p-CH3), 2.12 (3H, s, o-CH3),
2.09 (3H, s, o-CH3), 1.66 (3H, d, J 6.9, CHCH3); dC 157.6 (C]O), 139.2
(C]Nþ), 136.2, 135.6, 134.9 (4ꢂQ ArC), 127.9 (ArCH), 66.1 (CH2),
63.6 (CHCH3), 20.2 (p-CH3), 18.3, 17.9 (2ꢂo-CH3), 13.8 (CH3); LC/
TCOF-MS found 239.1304 (MþH)þ C14H17NO3 requires 249.1314.
4.6.1. N-Allyl-2-(2-furyl)-2-(hydroxyimino)-N-methylacetamides,
Z-4(II)b and E-4(II)b. The title products, obtained as a brown oil
(4.09 g, 76%) after 20 h reaction time, presented a pair of geo-
metrical oxime isomers in a 1:1.1 ratio. Each oxime presented as
a pair of rotamers. The oximes were inseparable by flash column
chromatography. Rf (30% EtOAc/Hex) 0.18, 0.41; nmax (Nujol) 2924,
1654,1463,1377,1154, 963 cmꢀ1
; dH 9.30 and 8.89 (1.1H and 1H br s,
4.5. General procedure for formation of
a
-keto amides, 5(II)
major and minor NOH), 7.51e7.47 (2.1H, m, major and minor
AreH5), 7.45e7.43, 6.64e6.61 (2.1H, 2ꢂm, major and minor AreH3),
6.56e6.45 (2.1H, m, major and minor AreH4), 5.91e5.76 (1.1H, m,
major CH]CH2) 5.75e6.62 (1H, m, minor CH]CH2) 5.33e5.15
(4.4H, m, major and minor CH2]CH) 4.17 (2.2H, d, J 5.5, major
Step 1dPreparation of the acid chlorides of 6b and 6c.
furanacetic acid 6b or thiophene-2-glyoxylic acid 6c was stirred neat
under Ar or N2 at rt for 10e15 min. -Dichloromethylmethyl ether
a-Oxo-2-
a,a

7048
L. Doyle, F. Heaney / Tetrahedron 66 (2010) 7041e7049
NCH2) 3.84 (2H, dd, J 6.2, minor NCH2) 3.06 and 3.05 (3H, s, NCH3)
2.93 and 2.92 (3.3H, s, major NCH3); dC 163.8, 163.6, 162.8 (C]O),
146.0, 145.9, 145.8, 145.6, 143.55, 143.3, 142.6, 142.5 (C]N and Q
ArC), 144.8, 144.7, 143.6, 143.5 (AreC5), 131.9, 131.6; 132.6, 132.4
(CH]CH2), 119.1, 118.6 (major CH2]CH), 117.9, 117.8 (minor CH2]
CH), 119.7, 119.6 (AreC3), 112.8, 122.3, 111.7 (AreC4), 49.6, 49.0
(major NCH2), 53.4, 53.0 (minor NCH2), 35.5, 34.6 (major NCH3)
32.4, 31.4 (minor NCH3); LC/TCOF-MS found 247.0488 (MþK)þ
C12H13NO3 requires 247.0480.
Nþ), 143.0 (AreC3), 129.8 (Q ArC), 118.1 (AreC5), 110.5 (AreC4), 64.9
(CHCH3), 52.9 (NCH2), 34.8 (NCH3), 15.6 (CCH3).
4.6.4. 5-Methyl-6a-(2-thienyl)hexahydro-6H-pyrrolo[3,4-c]isoxazol-
6-one, 2c. A solution of E-4(II)c (0.08 g, 3.5 mmol) in xylenes
(24 mL) was heated at reflux under N2 in the presence of
hydroquinone (0.240 g, 1 mol % w/v). After 90 h reaction time the
solution was allowed to cool to rt prior to evaporation. The res-
idue was taken up in CHCl3 (15 mL) and left at rt for 30 min. After
any remaining hydroquinone, which precipitated was filtered
and the solvent was evaporated to yield the crude product, which
was purified by flash column chromatography (20% Hex/EtOAc)
to yield 2c as a brown oil (0.067 g, 86%); Rf (20% Hex/EtOAc) 0.36;
4.6.2. N-Allyl-2-(hydroxyimino)-N-methyl-2-(2-thienyl)acetamides,
Z-4(II)c and E-4(II)c. The title products were obtained after 20 h
reaction time. Following separation by flash column chromato-
graphy (30% Hex/EtOAc) individual samples of each oxime isomer
were obtained, Z-4(II)c, a yellow oil (0.23 g, 20%) and E-4(II)c,
a brown oil, (0.29 g, 24%). Each oxime presented as a pair of
rotamers; Z-4(II)c rotamer ratio: 1:1; E-4(II)c rotamer ratio: 1.3:1;
Z-4(II)c Rf (50% Hex/EtOAc) 0.27; nmax (Nujol) 3233, 1737, 1627,
nmax (KBr) 3436, 3183, 2924, 1677, 1503, 1404, 1678 cmꢀ1
; dH
7.32e7.30 (1H, dd, J 5.1 and 1.0, AreH5), 7.22e7.21 (1H, br d, J 3.7,
AreH3), 7.01e6.98 (1H, dd, J 5.1 and 3.7, AreH4), 4.19e4.08 (2H,
m, H3), 3.79e3.73 (1H, dd, J 10.3 and 7.8, H4), 3.41e3.37 (1H, m,
H
3a), 3.32e3.27 (1H, dd, J 10.3 and 2.0, H4), 2.91 (3H, s, NCH3); dC
1394, 1417, 1342, 982 cmꢀ1
;
dH 10.22 (1H, br s, OH), 7.58 (1H, d, J
170.4 (C]O), 136.9 (Q ArC), 126.2 (AreC4), 125.0 (AreC5), 123.1
(AreC3), 79.4 (C3), 73.1 (C6a), 51.4 (C4), 47.1 (C3a), 29.8 (NCH3);
LC/TCOF-MS found 242.0951 (MþNH4)þ C10H12N2O2S requires
242.0958.
5.1, AreH5), 7.40 (1H, d, J 3.8, AreH3), 7.11e7.06 (1H, m, AreH4),
5.94e5.81 (0.5H, m, CH]CH2 rot. a), 5.74e5.61 (0.5H, m, CH]CH2
rot. b), 5.31e5.13 (2H, m, CH2]CH), 4.17 (1H, d, J 5.9, NCH2 rot. a),
3.88 (1H, d, J 6.0, NCH2 rot. b), 3.08 (1.5H, s, NCH3 rot. a), 2.93
(1.5H, s, NCH3 rot. b); dC 165.1 and 164.8 (C]O), 146.8 and 146.7
(C]N), 132.5 (CH]CH2 rot. b), 132.0 (CH]CH2rot. a), 131.9 and
131.8 (AreC3), 131.1 and 130.9 (AreC5), 128.8 and 128.7 (Q ArC)
126.2 and 126.1 (AreC4), 118.9 and 118.3 (CH2]CH), 53.7 (NCH2
rot. a), 49.8 (NCH2rot. b), 35.9 (NCH3 rot. a), 32.5 (NCH3 rot. b); LC/
TCOF-MS found 225.0702 (MþH)þ C10H12N2O2S2 requires
225.0692.
4.6.5. 2,4-Dimethyl-5-oxo-6-(2-thienyl)-2,3,4,5-tetrahydropyrazin-
1-ium-1-olate, 10(II)c. A solution of Z-4(II)c (0.08 g, 3.5 mmol) in
xylenes (24 mL) was heated to reflux under N2 in the presence of
hydroquinone (0.240 g, 1 mol % w/v). After 90 h reaction time the
solution was allowed to cool to rt and left to stand prior to
evaporation. The residue was taken up in CHCl3 (15 mL) and left at
rt for 30 min. After any remaining hydroquinone had precipitated
the solution was filtered and the solvent evaporated to yield the
crude product. Separation by flash column chromatography (20%
Hex/EtOAc) yielded 10(II)c as a brown oil (0.056 g, 71%); Rf 0.27
(12.5% Hex/EtOAc); nmax (KBr) 3585, 2980, 2244, 1652, 1485, 1389,
E-4(II)c Rf (50% Hex/EtOAc) 0.33; nmax (Nujol) 3244, 2246, 1622,
1488, 1416, 1348, Compound 1265 cmꢀ1
; dH 9.89 (2.3H, br s, OH),
7.31e7.29 (2.3H, dd, J 4.7 and 1.0, AreH5), 7.17e7.16 (2.3H, dd, J 3.4
and 1.0, AreH3), 7.02e6.98 (2.3H, m, AreH4), 5.88e5.75 (1.3H, m,
CH]CH2 major rot.), 5.72e5.54 (1H, m, CH]CH2 minor rot.),
5.32e5.11 (4.6H, m, CH2]CH), 4.16 (2.6H, d, J 5.3, NCH2 major rot.),
3.80 (2H, d, J 5.9, NCH2 minor rot.), 3.04 (3H, s, NCH3 minor rot.),
2.88 (3.9H, s, CH3 major rot.); dC 163.3 (C]O), 147.9 (C]N), 133.7
and 133.5 (Q ArC) 131.5 (CH]CH2 minor rot.), 130.2 (CH]CH2
major rot.), 127.8 and 127.6 (AreC3), 126.8 and 126.7 (AreC5), 126.5
and 126.4 (AreC4), 118.2 and 117.0 (CH2]CH), 52.1 (NCH2 minor
rot.), 48.0 (NCH2 major rot.), 33.6 (NCH3 major rot.), 30.5 (NCH3
minor rot.); LC/TCOF-MS found 225.0702 (MþH)þ C10H12N2O2S2
requires 225.0692.
1056, 913 cmꢀ1 dH 8.66 (1H, d, J 4.2, AreH3), 7.46 (1H, d, J 5.1,
;
AreH5), 7.20e7.17 (1H, dd, J 5.1 and 4.2, AreH4), 4.36e4.26 (1H, m,
CHCH3), 3.89e3.83 (1H, dd, J 13.5 and 4.4, H2), 3.36e3.30 (1H, dd, J
13.5 and 5.4, H2), 3.19 (3H, s, NCH3), 1.59 (3H, d, J 6.8, CH3); dC
158.5 (C]O), 133.0 (C]Nþ), 132.8 (AreC3), 130.4 (Q ArC), 128.7
(AreC5), 126.8 (AreC4), 63.6 (CHCH3), 49.9 (CH2), 35.2 (NCH3), 15.6
(CHCH3); LC/TCOF-MS found 226.0720 (MþH)þ C10H12N2SO2
requires 225.0698.
4.6.6. 2-[Allyl(methyl)
amino]-1-phenyl-1-ethanone,
5(III)a. A
solution of 2-bromoacetophenone 9 (2.03 g, 10.2 mmol) in DCM
(23 mL) was injected slowly to a stirred solution of N-methyl
allylamine (5.00 g, 70.4 mmol) in DCM (68 mL) at rt. After complete
addition and a further 10 min stirring at rt the solution was washed
with H2O (3ꢂ30 mL), dried (MgSO4), filtered and evaporated to
yield the title product as a yellow oil (1.82 g, 98%), which required
no further purification; Rf (40% EtOAc/Hex) 0.27, 0.41; nmax (Nujol)
4.6.3. 6a-(2-Furyl)-5-methylhexahydro-6H-pyrrolo[3,4-c]isoxazol-6-
one, 2b and 6-(2-furyl)-2,4-dimethyl-5-oxo-2,3,4,5-tetrahydropyr-
azin-1-ium-1-olate, 10(II)b. A solution of Z- and E-4(II)b (1.00 g,
4.8 mmol) in toluene (310 mL) was heated to reflux under a N2
atmosphere for 100 h. The solution was allowed to cool to rt prior to
evaporation. The crude products were purified by flash column
chromatography (20% DCM/EtOAc) to afford the bicycle 2b as a or-
ange solid (0.441 g, 44%) and the nitrone 10(II)b as an enriched
sample together with the bicycle. 2b; mp 109e115 ꢁC; nmax (KBr)
3451, 2960, 2572, 1741, 1647, 1455, 1169, 1040 cmꢀ1
; dH 7.89e7.85
(2H, m, m-ArH), 7.44e7.38 (1H, m, p-ArH), 7.34e7.25 (2H, m, o-
ArH), 5.88e5.74 (1H, m, CH]CH2), 5.13e5.03 (2H, m, CH2]CH),
3.69 (2H, s, NCH2CO), 3.05 (2H, d, J 6.6, NCH2CH), 2.25 (3H, s, NCH3);
dC 197.3 (C]O), 136.7 (Q ArC), 135.5 (CH2]CH), 132.7 (p-ArC), 128.8
(o-ArC), 128.4 (m-ArC), 118.2 (CH2]CH), 63.1 (CH2C(O)), 60.9
(NCH2CH), 42.7 (NCH3); LC/TCOF-MS found 190.1219 (MþH)þ
C12H15NO requires 190.1226.
3435, 3224, 3118, 2876, 1676, 1496, 1403 cmꢀ1
; dH 7.41e7.40 (1H,
dd, J 1.9 and 0.8, AreH5), 6.60 (1H, d, J 3.3, AreH3), 6.38e6.36 (1H,
dd, J 3.3 and 1.9, AreH4), 5.74 (1H, br s, NH), 4.15e4.11 (2H, m, H3),
3.75e3.68 (1H, dd, J 10.1 and 8.3, H4), 3.65e3.44 (1H, m, H3a),
3.28e3.24 (1H, dd, J 10.1 and 2.6, H4), 2.92 (3H, s, NCH3); dC 170.2
(C]O), 148.2 (Q ArC), 143.0 (AreC5), 110.9 (AreC4), 109.8 (AreC3),
79.2 (C3), 72.8 (C6a), 52.5 (C4), 44.8 (C3a), 30.3 (NCH3); LC/TCOF-MS
found 247.0280 (MþK)þ C10H12N2O3 requires 247.0280; 10(II)b dH
7.81 (1H, d, J 3.5, AreH3), 7.62 (1H, d, J 1.8, AreH5), 6.55e6.53 (1H,
dd, J 3.5 and 1.8, AreH4), 4.28e4.18 (1H, m, CHCH3), 3.91e3.86 (1H,
dd, J 13.7 and 4.3, H2), 3.37e3.30 (1H, dd, J 13.7 and 5.2, H2), 3.17
(3H, s, NCH3), 1.57 (3H, d, J 6.8, CHCH3); dC 153.8 (C]O), 144.5 (C]
4.6.7. 2-[Allyl(methyl) amino]-1-phenyl-1-ethanone oximes, Z-4(III)
a and E-4(III)a. To a solution of 5(III)a (0.314 g, 1.7 mmol) in EtOH
(5 mL) was added NH2OH$HCl (0.128 g, 1.8 mmol) and NaHCO3
(0.157 g, 1.8 mmol). The mixture was heated at 80 ꢁC for 3.5 h. The
solution was cooled to rt, concentrated in vacuo and the residue
taken up in DCM (10 mL). The organic layer was washed with H2O

L. Doyle, F. Heaney / Tetrahedron 66 (2010) 7041e7049
7049
(2ꢂ10 mL), dried (MgSO4), filtered and concentrated to yield the
title product as a yellow oil (0.289 g, 85%). The oximes presented
as a 1:2 mixture of Z- and E-isomers, separation was achieved by
flash column chromatography (30% EtOAc/Hex). Compound Z-4
(III)a, a yellow oil (0.026 g, 17%), E-4(III)a (0.152 g, 45%) also
a yellow oil; Z-4(III)a; Rf (50% Hex:EtOAc) 0.32; nmax (Nujol) 2854,
from the National University of Ireland, Maynooth for a John and
Pat Hume Scholarship to LD is gratefully acknowledged.
Supplementary data
The Supplementary data associated with this article can be
found in the online version at doi:10.1016/j.tet.2010.06.005.
1463, 1377, 1154 cmꢀ1
; dH 8.75 (1H, br s, OH), 7.58e7.50 (2H, m, o-
ArH), 7.44e7.36 (3H, m, m- and p-ArH), 5.86e5.72 (1H, m, CH]
CH2), 5.16e5.09 (2H, m, CH2]CH), 3.38 (2H, s, CH2C]N), 3.03 (2H,
d, J 6.5, NCH2CH), 2.24 (3H, s, NCH3); dC 155.5 (C]N), 135.4 (CH]
CH2), 132.6 (Q ArC), 129.0, 128.1 (m- and p-ArC), 126.5 (o-ArC),
117.8 (CH2]CH), 60.6 (NCH2CH), 60.3 (NCH2C]N), 42.1 (NCH3);
LC/TCOF-MS found 227.1164 (MþNa)þ C12H16N2O requires
227.1155; E-4(III)a; Rf (40% EtOAc/Hex 3:2) 0.39; nmax (Nujol) 2854,
References and notes
1. Christensen, B.G.; Foley, M.A.; Georges Evangelinos, A.T.; Liu, T.; Porter, J.R.;
Ripka, A.S.; Zhang, L. PCT Int. Appl. WO 2006009907, 2006; Chem. Abstr. 1995,
144, 170976.
2. Buhrlage, S. J.; Chen, B.; Mapp, A. K. Tetrahedron Lett. 2009, 65, 3305e3313.
3. Bates, R. W.; Boonsombat, J.; Lu, Y.; Nemeth, J. A.; Sa-Ei, K.; Song, P.; Cai, M. P.;
Cranwell, P. B.; Winbush, S. Pure Appl. Chem. 2008, 80, 681e685.
4. Tufariello, J. J. In In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley-
Interscience: New York, NY, 1984; 2, pp 83e168.
5. Confalone, P. N.; Huie, E. M. Org. React. 1988, 36, 1e173.
6. Abiko, A. Rev. Heteroat. Chem. 1997, 17, 51e71.
7. (a)Merino, P.; Tejero, T.; Mates, J.;Chiacchio, U.; Corsaro, A.;Romeo, G. Tetrahedron:
Asymmetry 2007,18,1517e1520;(b)Chiacchio, U.;Corsaro, A.;Pistara, V.;Rescifina,
A.; Romeo, G.; Romeo, R. Tetrahedron 1996, 52, 7875e7884.
1463, 1377, 1154 cmꢀ1
; dH 12.38 (1H, br s, OH), 7.66e7.60 (2H, m, o-
ArH), 7.38e7.33 (3H, m, m- and p-ArH), 5.96e5.82 (1H, m, CH]
CH2), 5.26e5.20 (2H, m, CH2]CH), 3.77 (2H, s, CH2C]N), 3.13 (2H,
d, J 6.7, NCH2CH), 2.34 (3H, s, NCH3); dC 154.2 (C]N), 135.7 (Q
ArC), 133.5 (CH]CH2), 129.1, 128.5 (m- and p-ArCH), 126.5 (o-
ArCH), 119.6 (CH2]CH), 60.3 (NCH2), 54.8 (NCH2C]N), 41.8
(NCH3); LC/TCOF-MS found 227.1603 (MþNH4)þ C12H16N2O re-
quires 222.1601.
8. Coutouli-Argyropoulou, E.; Lianis, P.; Mitakou, M.; Giannoulis, A.; Nowak, J.
Tetrahedron 2006, 62, 1494e1501.
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4(III)b. To a stirred solution of 5(III)b (0.310 g, 1.0 mmol) in EtOH
(8 mL) were added NH2OH$HCl (0.109 g, 2.0 mmol) and NaHCO3
(0.132 g, 2.0 mmol). The mixture was stirred with heating at reflux
for 3 h, following cooling to rt, the solution was concentrated and
the residue dissolved in DCM (10 mL). The organic layer was
washed with H2O (2ꢂ5 mL), dried (MgSO4), filtered and evaporated
to yield the title products as a yellow solid (0.325 g, 100%); Z-4(III)
b and E-4(III)b were obtained in a ratio of 1:1.3. 1H NMR spectral
data were in agreement with the literature.11b
10. Jones, R. C. F.; Martin, J. N. In Nitrones, Synthetic Applications of 1,3-Dipolar
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4.6.9. 5-Methyl-6a-phenylhexahydro-1H-pyrrolo[3,4-c]isoxazole,
3a. A solution of Z- and E-4(III)a (1.08 g, 5.3 mmol) in toluene
(370 mL) was heated at reflux. After 15 h it was cooled to rt and
concentrated to yield the crude product, purificationwas achieved by
flash column chromatography (10% MeOH/Et2O) and 3awas obtained
as a yellow solid (0.660 g, 62%). [Found: C, 70.40; H, 7.63; N, 13.43;
C12H16N2O requires C, 70.55; H, 7.90;N, 13.72%]; mp 77e80 ꢁC; nmax
(KBr) 3420, 2972, 2795,1663,1448,1264,1164 cmꢀ1
; dC 142.3 (Q ArC),
128.4, 127.0, 125.6 (3ꢂArC), 78.4 (CH2), 77.9 (C6a), 65.4, 60.5 (2ꢂCH2),
55.0 (C3a), 40.1 (NCH3), 28.6; LC/TCOF-MS found 205.1335 (MþH)þ
C12H16N2O requires 205.1335. NMR spectral data was poorly resolved
at rt and signals, in ane6:1 ratio, attributable to two distinct con-
formers emerged at ꢀ50 ꢁC. dH (300 MHz, CDCl3, ꢀ50 ꢁC) major
conformer 7.61e7.27 (5H, 3ꢂm, 5ꢂArHz), 5.48 (1H, s, NH), 4.60e4.55
(1H, dd, J 8.4 and 8.4, H3), 3.62e3.57 (1H, dd, J 8.4 and 8.0, H3),
3.25e3.18 (2H, m, H3a and 4z), 3.14 (1H, d, J 10.8, H6), 3.01 (1H, d, J 10.8,
H6), 2.62e2.57 (1H, dd, J 9.7 and 6.8, H4z), 2.42 (3H, s, NCH3); minor
conformer 7.62e7.27 (5H, 3ꢂm, 5ꢂArHz), 5.22 (1H, s, NH), 4.22 (1H, d,
J 9.0, H3), 3.83e3.78 (1H, dd, J 9.0 and 7.7, H3), 3.45e3.39 (1H, m, H3a),
3.25e3.18 (1H, m, H4/6z), 2.92 (2H, m, H4/6), 2.62e2.57 (1H, m, H4/6z),
2.35 (3H, s, NCH3).
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Acknowledgements
Financial support from the Embark Postgraduate Research
Scholarship Scheme (Grant reference number RS/2005/37) and
39. Armstrong, P.; Grigg, R.; Heaney, F.; Surendrakumar, S.; Warnock, W. J. Tetra-
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