α-Oximono-esters as precursors to heterocycles - generation of oxazinone N-oxides and cycloaddition to alkene dipolarophiles

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ꢀ-Oximono-esters as precursors to heterocycles – generation of

oxazinone N-oxides and cycloaddition to alkene dipolarophiles

Frances Heaney,*^aJulie Fenlon,^bColm OЈMahony,^bPatrick McArdle^band

Desmond Cunningham^b

^aDepartment of Chemistry, National University of Ireland, Maynooth, Ireland

^bDepartment of Chemistry, National University of Ireland, Galway, Ireland

Received 24th June 2003, Accepted 23rd September 2003

First published as an Advance Article on the web 29th October 2003

Preparation of a series of terminally and internally substituted δ-alkenyl and δ-alkynyl esters 6,7 and 9, potential

precursors to oxazin-2-one nitrones, has been attempted. Condensation between pyruvic or benzoylformic acid and the

appropriate alcohol proceeded smoothly in some cases whilst allylic transposition was a major feature in other cases –

most especially during reactions with α-vinylbenzyl alcohol. Oximation of pyruvic acid derivatives furnished E-oxime

isomers whilst benzoylformic acid derivatives aﬀorded mixed geometrical isomers. The E-oxime of 4a¹carrying an

internal Me group undergoes facile thermal cyclisation aﬀording nitrones 1c and 1d in good yield. Oximes E-5a,b

with a terminal methyl substituent on the alkene moiety furnish nitrone only under the inﬂuence of an external

electrophile [PhSeBr/AgBF₄]. A terminal Ph substituent on 5c,d prohibits formation of the cyclic dipole irrespective

of reaction conditions, and whilst 5d reacts to aﬀord a bicyclic isoxazolofuranone 13 by an IOOC reaction

(intramolecular oxime oleﬁn cyclisation) 5c remains thermally inert. Finally δ-alkynyl oximes 9c,d also failed to

cyclise. The regio- and stereochemical characteristics of the cycloadditions between the new dipoles and electron

poor oleﬁnic dipolarophiles have been investigated. The conditions needed for reaction were rather forcing since the

dipoles are somewhat stabilised by the adjacent alkoxycarbonyl group. All reactions proceeded regiospeciﬁcally to

give adducts with 5-substituted isoxazolidine rings whilst diastereoselectivity varied with the choice of dipolarophile

and the steric demands of the nitrone substituents. The phenylselenyl dipole 10a could not be trapped by any

dipolarophiles bar dimethyl acetylenedicarboxylate.

We have already reported that pyruvic acid and 3-buten-2-ol

condense upon heating in boiling benzene in the presence of a

Introduction

Intermolecular cycloaddition to nitrones is attractive for the

construction of N-containing compounds and indeed nitrones

catalytic amount of p-TsOH (Dean–Stark trap) to provide 6a in

80% yield.¹In contrast, under the same experimental condi-

have played an important role in the synthesis of various classes

tions benzoylformic acid reacted with this branched alcohol to

furnish, as an inseparable mixture, the terminally substituted

product 7b (23%) together with the expected ester 6b (59%).

Thermal, Lewis acid or transition metal catalysed [3,3]-sigma-

of drugs. Both the primary adducts – isoxazolidines/∆⁴-isoxazo-

lines and their derivatives have potential for biological interest.

We have recently reported the preparation of α-alkoxycarbonyl

nitrones 1a,b from cyclisation of E-oximino esters 2a,b, the

tropic rearrangement of allylic esters is well known. For

propensity with which the new dipoles cycloadd to acetylenic

example, treatment of either 1-but-2-enyl acetate or 2-but-3-

dipolarophiles and the tendency of the primary cycloadducts to

enyl acetate with 5 mol% Pd(PPh₃)₄in CDCl₃lead, after just

rearrange to pyrrolo-fused bicycles.^1,2In order to test the toler-

1 h, to a 58 : 42 equilibrium mixture in favour of the linear

ance of the oxime substrate to structural diversity we have since

isomer.⁴Allylic esters have also been shown to isomerise upon

prepared analogous oximino-amides 2c–e and found them to

standing in CHCl₃in the presence of an acid catalyst,

cyclise to the piperazinone nitrones 3.³To further explore the

rearrangement is slow at rt but fast at elevated temperatures, it

generality of the reaction we aimed to prepare nitrones substi-

tuted at C-2 and bearing a group, other than methyl, at the C-3

position. We now report our ﬁndings on the preparation the

can also be eﬀected by exposure to SiO₂or alumina.^5,6Thus, it

is likely that 7b arises from 6b by way of an allylic transposition.

Indeed we observe a signiﬁcant change in the ratio of 6b : 7b,

targeted oximes 4 and 5, and on novel cycloaddition reactions

from ∼2.5 : 1 to ∼1 : 1, when a neat sample was re-examined

of the dipoles 1 and 10 with monosubstituted alkenes.

following standing for 5 months at rt. Heating this equimolar

solution of 6b and 7b in reﬂuxing benzene (6 h) caused a further

Results and discussion

drift towards the terminally substituted isomer [6b : 7b 1 : 1.1].

However, in the presence of a catalytic amount of p-TsOH the

degree of isomerisation is more signiﬁcant and after 6 h the

isomeric ratio has changed to 1 : 1.3 in favour of 7b.

Reaction between α-vinylbenzyl alcohol and either of

pyruvic acid or benzoylformic acid failed to furnish the targeted

ester 6c/6d with an allylic phenyl substituent, instead the prod-

ucts were the terminally substituted α-keto esters 7c (31%) and

7d (37%). A second product accompaning the ester in the

case of 7c was shown by independent experimentation to be

dicinnamyl ether 8. Dicinnamyl ether is known in the literature

having been characterised by Frimer⁷following reaction of

cinnamyl bromide with superoxide. We have demonstrated that

α-vinylbenzyl alcohol is stable upon heating alone in boiling

Substrate preparation

Nitrones 1a and 1b, without a substituent at the C-2 position

were prepared following thermal activation of the E-isomer of

the parent oximes, 2a,b as reported earlier.²To introduce a

group at the C-2 position of the nitrone it is necessary to pre-

pare oximes of general structure 4 bearing a substituent at the

allylic position. If the group at the nitrone C-3 position is to be

other than methyl, then oximes of general structure 5, termin-

ally substituted on the alkene moiety are required. Accordingly

pyruvic acid and benzoylformic acid were reacted in turn

with 3-buten-2-ol, α-vinylbenzyl alcohol, 2-buten-1-ol (crotyl

alcohol) and cinnamyl alcohol.

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 0 2 – 4 3 1 6

T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3

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Scheme 1

benzene (75 min), however, in the presence of p-TsOH, (cat.)

In attaining the transition state [Fig. 1] for sigmatropic

rearrangement the esters 6 and 7 lose their O᎐C–C᎐O conju-

dicinnamyl ether is isolated as the only identiﬁable product

(26%). We propose the ether arises by way of an acid catalysed

rearrangement of α-vinylbenzyl alcohol leading to cinnamyl

alcohol, attack of this alcohol on the resonance stabilised

cation and deprotonation aﬀords dicinnamyl ether as summar-

ised in Scheme 1. If this mechanism is indeed operating then

reaction of the α-keto acids with “α-vinylbenzyl alcohol” may

aﬀord the terminally substituted allylic esters 7c/7d by either or

both of the following mechanisms: (i) a condensation between

the reactants followed by an allylic rearrangement of the

primary ester 6c/6d or (ii) an initial rearrangement of α-vinyl-

benzyl alcohol to cinnamyl alcohol followed by condensation to

give 7c/7d directly. The latter proposition is disfavoured on two

grounds. Firstly, a search of the chemical literature indicates

that there are no reports of simple thermal isomerisation of

cinnamyl alcohols to vinylbenzyl alcohols or vice versa, how-

ever, Crilly and co-workers do report an indirect isomerisation

of the m-chloro derivative of vinylbenzyl alcohol to m-chloro-

cinnamyl alcohol by way of a Pd() catalysed isomerisation

of the corresponding acetate.⁸Secondly when pyruvic acid

and cinnamyl alcohol were combined directly (p-TsOH, C₆H₆,

Dean–Stark) a mixture resulted from which the ester 7c could

be isolated in only 3% yield.

Reaction between pyruvic acid and 2-buten-1-ol furnished

the desired ester 7a in 93% yield. The same alcohol reacted with

benzylformic acid to yield inseparable isomeric esters with the

methyl substituent at the terminal 7b (72%) and the internal

position 6b (9%). Condensation between propargyl alcohol and

the α-ketoacids provided the alkynic esters 9a,b in moderate

yield with no side products.

It is apparent that esters 6a and 7a, derived from pyruvic

acid in reaction with either of the butenols, are thermally

stable whilst the corresponding esters, 6b and 7b, derived from

benzoylformic acid, are both subject to skeletal rearrangement.

᎐

gative stabilisation. This loss is more signiﬁcant for the methyl

derivatives than for the phenyl derivatives where Ph–C᎐O con-

᎐

jugation is possible. Hence the activation energy for rearrange-

ment of the phenyl substituted substrates 6b/7b is expected to

be lower than that for their methyl analogues 6a/7a.

Fig. 1

The α-keto esters 6a and 7a, bearing an allylic or terminal

methyl substitutent respectively, reacted smoothly with NH₂OH

furnishing the corresponding oximes E-4a¹(90%) and E-5a

(80%) in each case as a single geometrical isomer. The esters 6b

and 7b were available as impure samples (each carrying the

other as a contaminant), in each case following oximation,

[NH₂OHؒHCl, pyridine, EtOH, rt] puriﬁcation of the product

mixture was successful only in that it delivered separate samples

of E-4b/E-5b as well as Z-4b/Z-5b. For each reaction the ratio

of the oximes 4b:5b reﬂected that of the starting esters 6b:7b,

thus no skeletal rearrangement occurred during oxime form-

ation. The esters 7c and 7d, with a terminal phenyl substituent,

oximated smoothly and E-5c was isolated in 44% yield as a

single isomer whilst 5d formed as a mixture of geometrical

isomers, E-5d (29%) and Z-5d (41%). The terminal alkyne

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 0 2 – 4 3 1 6

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functionality on 9a,b did not interfere with oxime formation

and E-9c (68%), was formed from 9a whilst E-9d (86%) and

Z-9d (13%) resulted from reaction of 9b.

experimentation showed Z-5b to be stable to thermal activ-

ation, thus, all new products are attributed to reactivity of Z-4b.

Separation of the crude mixture after heating for 30 h (140 ЊC)

returned unreacted Z-5b and provided evidence for formation

of two diastereomeric nitrones 1e (19%) and 1f (3%) and three

diastereomeric bicyclic isoxazolofuranones of general structure

11a (11%, 20% and 17%). Whilst it was not possible to obtain

analytically pure samples of any of these new products ¹H

NMR spectral data clearly supports their existence. Further,

based on a comparison of the ¹H NMR resonance positions of

the 2-H and C-2 & C-3 methyl protons for the diastereomers of

1e with 1c [2-H, 4.45 ppm] and 1d [2-H, 4.82 ppm]¹it can be

concluded that the major nitrone 1e has, as expected, the C-2

and C-3 methyl groups trans-disposed, this arrangement results

in the 2-H proton resonating ∼0.4 ppm upﬁeld of the corre-

sponding proton in its diastereomeric nitrone. The C-2 and C-3

methyl protons in the trans-isomers, 1c and 1e, have a more

downﬁeld shift than the analogous protons on the cis-isomers

1d and 1f. It is somewhat surprising that Z-4b reacts without

selectivity since, under the same reaction conditions, its un-

substituted partner Z-2b furnishes the isoxazolofuranone 12

exclusively. It is apparent that the allylic methyl group on 4b

inﬂuences the relative activation energies for the steps involved

in oxime isomerisation, the IOOC reaction and the APT reac-

tion such that all paths of reactivity become possible [Fig. 2].

It is reported in the literature that α-oxo-oximes should have

s-trans-conformation about both the O᎐C–C᎐N moiety and the

᎐

oximino functionality,^9,10thus, the observation that the pyruvic

acid derivatives 4a, 5a and 5c are stereochemically pure oximes

with E-conﬁguration is as expected. That both E- and Z-oximes

arise from benzoylformic acid suggests the steric and electronic

factors promoting the E- over the Z-isomer are more ﬁnely

balanced in the case of 4b,5b and 5d. Cerfontain⁹has found

that E-α-oxo-oxime derivatives having a phenyl group on the

iminyl carbon experience a steric clash between the aryl ring

and the oxime oxygen atom which forces the phenyl ring to be

out of conjugation with the C᎐N whilst the C᎐N–C᎐O groups

᎐

are fully conjugated. In contrast no steric clash operates to

prevent a co-planar arrangement of the phenyl and the imine

groups of the Z-isomers of the same oxime (prepared from the

E-isomer by photoisomerisation), however, there is reduced

conjugation between C᎐O and C᎐N. The oximes 4 and 5 are

᎐

α-ester-oximes accordingly the stabilisation derived from C᎐N–

᎐

C(O)᎐O conjugation is less signiﬁcant than that aﬀorded to

᎐

Cerfontain’s α-oxo analogues and evidently it is the case that

planarity of the phenyl and C᎐N groups (available to the

᎐

Z-isomer only) is a good compromise for the full conjugation

of the C᎐N–C(O)᎐O moieties (available to the E-isomer only)

thus both E- and Z-isomers of the C-phenyl α-ester-oximes

4b,5b and 5d result.

᎐

Fig. 2

The oxime E-5b has a terminal methyl susbtituent and as

observed with E-5a this substituent eﬀectively blocks a

thermally induced APT reaction. However, the phenylselenyl

substituted nitrone 10b was obtained in 57% yield under the

combined inﬂuence of PhSeBr and AgBF₄. The solution con-

formation adopted by the oxazinone ring in nitrones 10 is such

that in the ¹H NMR spectrum of 10a and 10b (CDCl₃) both the

methylenic protons couple weakly to the 3-H proton, with 2a-H

appearing as a slightly broad doublet whilst 2b-H is observed as

a doublet of doublets [J ∼ 12 & 3 Hz].

Oxime reactivity

We have already reported that E-4a cyclises by an APT¹¹

(azaprotio cyclotransfer) reaction to a mixture of diastereo-

meric nitrones 1c (50%) and 1d (10%) upon heating in boiling

xylene,¹the major isomer has the C-2 and C-3 methyl groups

trans orientated. E-5a with a terminal methyl group is isomeric

with E-4a yet it failed to cyclise upon heating in boiling xylene.

This lack of reactivity can be attributed to a more crowded

transition state for the APT reaction. The eﬀect of increasing

pressure on the reactivity of organic substrates is well recog-

nised¹²and to this end E-5a was heated in toluene in a sealed

tube. As a control experiment 2a, which cyclises to 1a upon

heating in boiling xylene (30 h) at atmospheric pressure, was

heated in toluene at 210 ЊC. After 16 h the reaction mixture

comprised a 2 : 1 mixture of nitrone and unreacted oxime.

However, the terminally substituted oxime E-5a failed to react

under these conditions. In a further eﬀort to facilitate cyclis-

ation the electrophile induced approach pioneered by Grigg¹³

and others^14–17was exploited. I₂, NBS, AgBF₄, PhSeCl, PhSeBr

and Ph₂Se₂have all been reported in the literature as activators

of electron rich double bonds/allenes towards intramolecular

attack by oximes. Of this selection only PhSeBr aﬀorded any

promise of reactivity with the substrate, E-5a however, the

complexity of the reaction mixture precluded isolation of any

pure products. When PhSeBr was paired with AgBF₄reaction

was more selective and the nitrone 10a was isolated in 67%

yield.

The oximes 5c and 5d both have a terminal Ph substituent, 5c

was obtained solely as the E-isomer and it failed to react follow-

ing heating or activation with PhSeBr/AgBF₄. Oxime 5d is the

only oxime bearing a terminally substituted alkene moiety

which showed reactivity under simple thermal conditions.

Following heating a solution of either E-5d or Z-5d in boiling

xylene the isoxazolofuranone 13 was the only isolable product,

yields varied with E-5d furnishing 13 in 36% yield and Z-5d

yielding 13 in 74% yield. Oxime 2b, the terminally unsubsti-

tuted analogue of 5d shows conﬁgurational stability with its

E-isomer cyclising to nitrone 1b and, as reported above, its

Z-isomer participating in the IOOC reaction leading to the

The C-phenyl oximes E-4b and Z-4b responded quite

diﬀerently to thermal activation. Thus, Z-4b, taken together

with Z-5b as a 25% contaminant, yielded a complex mixture of

products following heating in boiling xylene. Independent

1

bicycle 12. The H NMR spectral data of 13 showed broad

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 0 2 – 4 3 1 6

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resonance signals for the protons attached to the bicyclic ring.

Spectra recorded over the range Ϫ60 ЊC to ϩ50 ЊC indicate a

persistence in conformational mobility at the lower temper-

atures and a failure to reach coalescence at ϩ50 ЊC.

We oﬀer a three-pronged explanation for the observed diﬀer-

ence in reactivity of 5d with that of 5b and 5c. The arguments

centre around the enhanced dipolarophilic power of an alkene

bearing a terminal phenyl [as in 5c and 5d] over a terminal

methyl substituent [as in 5a and 5b] – indeed styrene is recog-

nised as a superior dipolarophile to propene.¹⁸The second con-

sideration is the ease with which geometrical oxime isomers

may interconvert. Isomerisation may occur by one of two

modes (i) in-plane inversion or (ii) out-of-plane rotation.¹⁹

Delocalisation of electron density from the aryl ring to the

Fig. 3

demanding exo-approach. The same dipoles failed to react

with N-methyl maleimide suggesting the cycloadditions to be

LUMO nitrone controlled.²⁴

Under thermal activation, both 1a and 1b failed to react with

any of ethyl vinyl ether, methoxypropene, cyclohexene or

norbornylene. Thus, the electronic and steric factors permitting

cycloaddition to the electron rich dipolarophiles must be so

ﬁnely balanced that the steric bulk of C-5 methyl/phenyl

substituent on nitrones 1a/b is suﬃcient to prevent reaction

taking place. Cycloaddition also failed with either N-methyl or

N-phenyl maleimide, in contrast styrene and acyclic mono-

substituited electron poor alkenes made good traps for these

dipoles.

The nitrones 1a and 1b cycloadded to styrene following heat-

ing with a large excess of the dipolarophile. For each dipole,

regiospeciﬁc formation of a 5-substituted isoxazolidine unit

resulted and the 2-H proton in each adduct resonated as a

doublet of doublets close to 5 ppm. Reaction with the methyl

substituted dipole was complete after 5.5 h and 14a was

furnished as a single diastereomer, analysis of NOEDS data

indicates 14a results from a transition state involving an exo-

addition of the dipolarophile to the face of the dipole opposite

the C-3 methyl group – designated the α-face, Fig. 4. The phenyl

substituted dipole 1b reacted selectively to aﬀord, after 8 h heat-

ing, the exo-adduct 14b (86%); the minor adduct 15 (8%) was

obtained as an enriched mixture, its relative stereochemistry

could not be assigned using the NOEDS approach as the

protons of the C-2 and the C-3a phenyl groups are coincidient.

The strong preference for an exo-addition of styrene to cyclic

nitrones is expected.^26,27

oxime C᎐N bond may decrease the double bond character of

᎐

the later so facilitating the isomerisation of the C-phenyl

oximes 5b and 5d by out-of-plane rotation. The ﬁnal consider-

ations takes cognizance of the energetics of the steps involved

in the IOOC reaction which has two distinct steps, prototropic

dipole formation and intramolecular dipolar cycloaddition.

Given that oximes exist with a small equilibrium concentration

of the corresponding NH nitrone^20,21the rate determining

step in the formation of isoxazolofuranones should be the

cycloaddition step.

Thus, E-5b fails to undergo a thermally induced APT reac-

tion since the terminal alkene substituent raises the activation

energy for cyclisation to nitrone and yet whilst E-/Z-oxime

isomerisation is likely a viable option for the C-phenyl substrate

no products result from the IOOC reaction as the RCH᎐CHMe

᎐

is not a suﬃciently reactive dipolarophilic moiety, indeed Z-5b

is independently shown to be unreactive.

That E-5c is immune to thermal treatment is in keeping with

the failure of terminally substituted derivatives to undergo APT

reaction. That no IOOC products result – even though this

substrate carries a “good” dipolarophilic unit (RCH᎐CHPh)

᎐

suggests a prohibitively higher barrier to E-/Z-oxime isomeris-

ation for the pyruvic acid derivative.

The apparent ease with which E-/Z-5d participate in a ther-

mal IOOC reaction is explained on the basis that (i) the APT

reaction is unfavourable due to the presence of the terminal

alkene substituent (ii) E-/Z-oxime isomerisation is facile for

benzoylformic acid derivatives and (iii) this substrate has a

good internal dipole trap (viz. RCH᎐CHPh).

᎐

The oxime 9c with a terminal alkyne functionality failed to

cyclise under simple thermal conditions or upon heating in a

sealed tube (toluene, 210 ЊC, 9.5 h). Nitrone formation by

intramolecular attack of oximes¹¹or hydroxylamines²²onto

triple bonds is known, however 9c was returned unchanged

following treatment with AgBF₄(CH₂Cl₂, rt or reﬂux).

Fig. 4

Cycloaddition reactions

The electron withdrawing eﬀect of the α-alkoxycarbonyl group

suggested that the dipoles 1 may participate in inverse electron

demand cycloaddition reactions and indeed Katagiri has suc-

cessfully trapped related 5-membered dipoles with electron rich

dipolarophiles albeit under the inﬂuence of high reaction pres-

sure or Lewis acid catalysis, Fig. 3(a).²³It has also been reported

recently^24,25that analogous six-membered nitrones, with a C-3

phenyl group and C-5 unsubstituted, can be trapped under mild

reaction conditions by dipolarophiles, e.g. ethyl vinyl ether,

Fig. 3(b). In all cases the selectivity of the cycloaddition is

attributed to a transition state involving the least sterically

Reaction between phenyl vinyl sulfone and the dipoles 1a–d

proceeded with high regio- and stereoselectivity, in each case

only a single diastereomeric cycloadduct, 16a–d, was isolated.

The product yield varied with the substitution pattern on the

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 0 2 – 4 3 1 6

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Table 1 Reaction between nitrones 1 and phenyl vinyl sulfone

Nitrone

Solvent

Temperature

Time/h

Product (%)

Returned nitrone (%)

1a

1b

1c

1d

Xylene

Toluene

140 ЊC

110 ЊC

36

42

72

16a (85)

16b (44)

16c (30)

16d (29)

8

48

60

56

192

Fig. 5

dipole (Table 1). The enhanced conjugation of the aryl substi-

tuted dipole 1b with respect to its methyl analogue 1a accounts

for its reduced reactivity²⁸and the sluggish reactivity of 1c and

1d, with their additional site of substitution is likely due to the

increased steric demands of these dipoles.

Characterisation of the cycloadducts 16 as having 5-substi-

1

tuted isoxazolidine rings rests with the appearance in the H

NMR spectrum of the 2-H proton as doublets of doublets,

δ 4.71 to 5.05.²⁹That all four adducts share the same relative

stereochemistry is known from analysis of NOEDS data as well

as X-ray crystallographic analysis.^30–33The OSCAIL represen-

tation of 16a and 16c, crystallised from benzene and Et₂O–

petroleum ether respectively, are shown in Figs 5a and 5b. The

crystallographic data for 16a reveals that ﬁve of the atoms in

the oxazinone ring (N-1, C-1, C-2, O-2 C-3) approximate a

plane, C-1 has the greatest deviation from this plane (0.055 Å)

and C-4 lies out of the plane by 0.692 Å. The dihedral angle for

H-4a C-4 C-5 H-5 is 177.8Њ and for H-4b C-4 C-5 H-5 (crystal

numbering) is 60.5Њ, inspection the ¹H NMR spectrum of

the same adduct shows the magnitude of J_6b,7(11 Hz) and J_6a,7

(3.3 Hz) (structure numbering) to be in good agreement with

that predicted by the Karplus curve³⁴. That the bicyclic frame-

work of 16c has the same solid state conformational preference

can be clearly seen from Fig. 5c which shows a ﬁt of the two

structures based on the atoms of the isoxazolidine ring and the

peripheral sulfur atom; the mean error on ﬁtting the six pairs of

atoms pairs is 0.0199 Å. The data for 16a reveals that there are

two molecules in each asymmetric unit and these are held

together by two weak C-H---O(4) H-bonds to a molecule of

benzene of crystallization [Fig. 6]; the interatomic H---O(4) dis-

tance is 2.648 Å and the C–H---O(4) angle is 98.02Њ (crystal

numbering) (Tables 2 and 3). The relative stereochemistry of

16b could not be assigned from NOEDS studies as unambigu-

ous discrimination between the SO₂Ph and the 3a aryl protons

was not possible. On the other hand, the structure of 16d was

readily available from NOEDS studies, pertinent results are

summarised in the drawing. The relative conﬁguration of 16a–d

indicates cycloaddition occurred by way of an endo-addition

of phenyl vinyl sulfone to the α-face of the nitrone. The endo-

preference is as may be expected on the basis of secondary

orbital considerations.

Fig. 6

17c and 17d the 6b-H is signiﬁcantly deshielded, appearing

∼0.8 ppm downﬁeld of the corresponding proton in 17a and

17b. Analysis of NOEDS data indicates the relative stereo-

chemistry of these adducts to be as shown in the drawings, thus,

the major adducts 17a (endo-) and 17b (exo-) are products of

addition to the least hindered face of the dipole whilst 17c and

17d result, respectively, from exo- and endo-addition to the

β-face of the dipole. Indeed it may be the case that a downﬁeld

resonance for 6b-H characterises adducts in this series which

result from dipolarophile addition to the more hindered face of

the nitrone.

Reaction between methyl vinyl ketone and the C-phenyl

nitrone 1b in boiling toluene (100 h) gave samples of all possible

diastereoisomeric cycloadducts. Separation by ﬂash chromato-

graphy yielded a pure sample of the major adduct only 18a

(67%) with the remaining diastereomers 18b (12%), 18c (7%)

and 18d (2%) being obtained as enriched mixtures. NOEDS

studies on the major adduct 18a indicate that it arises from an

endo-approach of the dipolarophile to the α-face of the dipole.

The complete relative stereochemistry of all the minor products

remains unknown hence no comment can be made concerning

their origin.

The C-methyl nitrone 1a reacts with methyl vinyl ketone in

boiling xylene (140 ЊC) to furnish four diastereomers 17a–d in

38, 12, 10 and 5% yield respectively. Repeating the reaction

in toluene (110 ЊC) saw an improvement in selectivity and 17a

(68%) and 17b (10%) were the only isolable adducts. An exam-

1

ination of the H NMR spectral data of 17 indicates that for

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 0 2 – 4 3 1 6

4306

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Table 2 Crystal data and structure reﬁnement for 16a

Table 3 Crystal data and structure reﬁnement for 16c

Identiﬁcation code

fh1

Identiﬁcation code

Empirical formula

jf1

C₁₅H₁₉NO₅S

Empirical formula

Formula weight

Temperature/K

Wavelength/Å

Crystal system

Space group

C₁₄H₁₇NO₅S.1/2(C₆H₆)

350.40

293(2)

0.71069

Monoclinic

P21/c

a = 9.286(2)

b = 18.246(2) β = 90.77(2)Њ

c = 10.204(2)

1728.7(5)

Formula weight

Temperature/K

Wavelength/Å

Crystal system

Space group

325.37

293(2)

0.71069

Orthorhombic

P212121

a = 8.3850(10)

b = 11.2710(10)

c = 16.603(2)

1569.1(3)

4

Unit cell dimensions/Å

Volume/Å³

Z

Volume/Å³

Z

4

Density (calculated)/Mg m^Ϫ3

Absorption coeﬃcient/mm^Ϫ1

F(000)

1.346

0.213

740

Density (calculated)/Mg m^Ϫ3

Absorption coeﬃcient/mm^Ϫ1

F(000)

1.377

0.229

688

Crystal size/mm

Theta range for data collection/Њ

Index ranges

0.39 × 0.35 × 0.22

2.19 to 27.97

0<=h<=12; Ϫ10<=k<=24;

Ϫ13<=l<=13

4975

Crystal size/ mm

Theta range for data collection/Њ

Index ranges

0.45 × 0.32 × 0.28

2.18 to 21.17

Ϫ8<=h<=8; Ϫ11<=k<=11;

Ϫ16<=l<=16

6779

Reﬂections collected

Independent reﬂections

Reﬂections observed (>2σ)

Data Completeness

Absorption correction

Reﬁnement method

4154 [R(int) = 0.0531]

Independent reﬂections

Reﬂections observed (>2σ)

Data Completeness

Absorption correction

Reﬁnement method

Data/restraints/parameters

Goodness-of-ﬁt on F ²

Final R indices [I>2σ(I )]

R indices (all data)

1683 [R(int) = 0.0241]

3062

1641

1.000

None

0.976

None

Full-matrix least-squares on F ²

4154/0/219

Full-matrix least-squares on F ²

1683/0/202

Data/restraints/parameters

Goodness-of-ﬁt on F ²

Final R indices [I>2σ(I )]

R indices (all data)

1.035

0.859

R₁= 0.0696 wR₂= 0.1830

R₁= 0.0856 wR₂= 0.1956

0.680 and Ϫ0.878

R₁= 0.0256 wR₂= 0.0667

R₁= 0.0283 wR₂= 0.0680

Ϫ0.02(8)

Largest diﬀ. peak and hole/e Å^Ϫ3

Absolute structure parameter

Largest diﬀ. peak and hole/e Å^Ϫ3

0.200 and Ϫ0.289

R indices; R₁= [Σ ||F_o|Ϫ |F_c| |]/Σ |F_o| (based on F),wR₂= [[Σ_w(|F_o²Ϫ F_c²

2

|) ]/[Σ_w(F_o²)²]]^1/2(based on F ²).w = 1/[(σF_o)²ϩ (.1501*P)²].Goodness-

R indices; R₁= [Σ ||F_o| Ϫ|F_c| |]/Σ |F_o| (based on F), wR₂= [[Σ_w(|F_o²Ϫ F_c²

of-ﬁt = [Σ_w(F_o²Ϫ F_c²)²/(Nobs Ϫ Nparameters)]^1/2

|) ]/[Σ_w(F_o²)²]]^1/2(based on F ²). w = 1/[(σF_o)²ϩ (.0579*P)²ϩ .41*P)].

2

Goodness-of-ﬁt = [Σ_w(F_o²Ϫ F_c²)²/(Nobs Ϫ Nparameters)]^1/2

.

data with that of the adducts 17 the signiﬁcant deshielding of

the axial methylene proton 6b-H (4.96 ppm) characterises the

adduct as arising from an attack of the dipolarophile to the

β-face of the nitrone. NOE data for the adducts 21a (C₆D₆)

and 21b indicate they arise, respectively, from an endo- and

exo-addition of the dipolarophile to the α-face of the dipole.

Nitrone 10a with a bulky 1-(phenylselenyl)ethyl substituent

at the C-3 position failed to react with oleﬁnic substrates and it

was only following heating with dimethyl acetylenedicarboxyl-

ate (72 h) that any products were isolated. The trimethoxy-

pyrrolo-fused adduct 23 was found in 45% yield, it likely arises

by rearrangement of the primary cycloadduct 22. We have pre-

viously noted thermal lability of C-7 methyl analogues, e.g. 24,

and we propose that 23 arises from 22 by a mechanism parallel

to that suggested earlier.¹

Conclusion

In conclusion eﬀorts to prepare variously substituted oxazin-

2-one nitrones by cyclization of a series of δ-alkenyl and

δ-alkynyl α-oximino esters were somewhat thwarted by an

allylic transposition which conspired to reduce the number of

available precursors. Not with standing this complication

nitrones carrying a Me or ^tBu substituent at C-2 or a 1-(phenyl-

selenyl)ethyl substituent at C-3 have been synthesised. 1,3-Di-

polar cycloaddition of the oxazinone N-oxides 1 to oleﬁnic

dipolarophiles proceeded regiospeciﬁcally and only 5-substi-

tuted isoxazolidine rings were formed. The facial selectivity was

for addition of the dipolarophile to the least hindered (α-)face

of the dipole. Endo–exo selectivity varied with the choice of

dipolarophile with endo-speciﬁcity being observed with phenyl

vinyl sulfone and a strong exo-selectivity with styrene. In the

cases of methyl vinyl ketone and methyl acrylate both endo-

and exo-adducts resulted and minor products arising from

addition to the β-face of the dipole were observed. The steric

bulk of nitrone substituents was also important in controlling

The rate and the selectivity of the cycloaddition between 1

and methyl acrylate in boiling toluene varied signiﬁcantly with

the substitution pattern on the dipole. Thus, reaction of 1g,²

carrying a ^tBu substituent at the C-2 position progressed slowly

(110 h) to aﬀord the exo-adduct 19 (68%). The preference

for the exo-approach is likely a reﬂection of the steric bulk of

the ^t-Bu substituent in 1g, this hypothesis is supported by

the ﬁnding that the C-2 unsubstituted analogue 1b, displays

endo-selectivity with 20a being isolated in 67% yield. A second

diastereoisomer, 20b was found in 22% yield. NOEDS data

failed to aﬀord reliable information on the relative stereo-

chemistry of the minor adduct.

The C-methyl nitrone 1a, like 1b has its C-2 position unsub-

stituted, it reacted rapidly with methyl acrylate (45 h) and the

diastereomeric adducts 21a,b,c were found in, 39, 25 and 7%

yield respectively. NOEDS data for the minor adduct 21c were

inconclusive, however, following a comparison of ¹H NMR

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 0 2 – 4 3 1 6

4307

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spectrometer or a JOEL JNM-LA400 FT NMR spectrometer

at probe temperatures with tetramethylsilane as internal refer-

ence and deuteriochloroform as solvent, J values are given in

Hertz. DEPT 135 assignments, where presented, immediately

follow individual ¹³C resonance signals as positive signals (ϩ,

CH or CH₃), negative signals (Ϫ, CH₂) or absent signals (abs.,

quaternary carbon). Flash column chromatography was carried

out on silica gel 60 (Merck 9385, 70–230 mesh, 40–60 mesh),

analytical TLC plates were purchased from Merck. Samples

were located by UV illumination using a portable Spectroline

Hanovia lamp (λ, 254nm) or by the use of iodine staining.

Crotyl alcohol was obtained from Aldrich Chemical Company

as a mixture of isomers and was used as such.

1-Methyl-2-propenyl 2-oxo-2-phenylacetate 6b

Benzoylformic acid (5.02 g, 33.5 mmol) and 3-buten-2-ol

(2.93 g, 40.7 mmol) were heated for 7 h at reﬂux in C₆H₆

(120 cm³) in the presence of a catalytic amount of p-TsOH

(0.33 g, 1.74 mmol) using a Dean–Stark apparatus. The reac-

tion was allowed to cool to rt and was washed with sat.

NaHCO₃(2 × 100 cm³) and then with water (2 × 100 cm³). The

organic layers were collected and dried (anh. Na₂SO₄), ﬁltered

and concentrated to yield the crude product as a yellow mobile

oil (5.58 g, 82%) which was not puriﬁed further. Compound 6b

(59%) obtained as an enriched mixture with 7b (23%). Spectral

data reported for 6b only; R_f0.8 Et₂O; δ_H(400 MHz) 1.47 (3H,

d, J 6.3, Me), 5.25 (1H, d, J 10.3, ᎐CH ), 5.38 (1H, d, J 17.1,

᎐

2

᎐CH ), 5.65 (1H, m, OCH), 5.94 (1H, m, CH᎐), 7.49 (2H, m,

᎐

2

2 × ArH), 7.65 (1H, m, ArH), 7.97 (2H, m, 2 × ArH).

3-Phenyl-2-propenyl 2-oxopropanoate (from ꢀ-vinylbenzyl

alcohol) 7c and dicinnamyl ether 8

Pyruvic acid (0.44 g; 5.0 mmol) and α-vinylbenzyl alcohol

(1.0 g, 7.5 mmol) were heated at reﬂux for 75 min in C₆H₆

(20 cm³) in the presence of a catalytic amount of p-TsOH

(0.05 g; 0.26 mmol) using a Dean–Stark apparatus. The reac-

tion was allowed to cool to rt and was washed with sat.

NaHCO₃(2 × 10 cm³) and then with water (2 × 10 cm³). The

organic layer was collected and dried (anh. Na₂SO₄), ﬁltered

and concentrated to yield the crude product, a viscous orange

oil. Puriﬁcation by column chromatography (Et₂O : petroleum

ether; 1 : 10) yielded two major products; dicinnamyl ether 8

(158 mg; 15.8%) and the ester 7c, a yellow mobile oil (310 mg;

31%) which was not puriﬁed further.

t

diastereoselectivity, in particular a C-2 Bu substituent on 1g

directed cycloaddition to occur by an exo-attack whilst the

preference for endo-selectivity observed for 1b was retained with

the C-2 methyl substituted dipole 1d. Synthetic manipulation of

the new cycloadducts, viz. reductive cleavage of the isoxazol-

idine ring and hydrolysis of the lactone moiety potentially pro-

vides access to unusual N,α-bis(2-hydroxyethyl) α-amino acids

which may serve as novel chelating agents.

Experimental

Melting points were determined on an Electrothermal melting

point apparatus and are uncorrected. Elemental analyses were

performed on a Perkin-Elmer model 240 CHN analyser. IR

spectra (nujol mull and liquid ﬁlm) were measured on a Perkin

Elmer 1600 series (FT) or a Perkin Elmer 983G spectrometer.

NMR spectra were recorded using a JOEL EX270 FT NMR

8 δ_H(400 MHz) 4.22 (4H, dd, J 1.5 and 5.9, OCH₂), 6.31 (2H,

dt, J 5.9 and 16.0, CH᎐CH–Ph), 6.63 (2H, d, J 16.0, CH᎐CH–

᎐

Ph), 7.21–7.40 (10H, 10 × ArH); δ_C(100 MHz) 70.72 (Ϫve)

(OCH₂), 125.96 (ϩve) (ArC), 126.46 (ϩve) (ArC), 127.65 (ϩve)

(CH᎐CH–Ph), 128.50 (ϩve) (ArC), 132.58 (ϩve) (CH᎐CH–

᎐

Ph), 136.65 (abs.) (n-ArC).

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 0 2 – 4 3 1 6

4308

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7c δ_H(400 MHz) 2.49 (3H, s, Me), 4.90 (2H, d, J 6.6, OCH₂),

2-Propynyl 2-oxopropanoate 9a

6.31 (1H, dt, J 6.6 and 15.7, OCH CH᎐), 6.73 (1H, d, J 15.7,

CH–Ph), 7.33 (m, 5 × ArH).

᎐

2

Pyruvic acid (3.00 g, 34.1 mmol) and propargyl alcohol (2.29 g,

40.9 mmol) were heated for 4 h at reﬂux in C₆H₆(120 cm³) in the

presence of a catalytic amount of p-TsOH (0.32 g, 1.7 mmol)

using a Dean–Stark apparatus. The reaction was allowed to

cool to rt and was washed with sat. NaHCO₃(2 × 100 cm³) and

then with water (2 × 100 cm³). The organic layer was collected

and dried (anh. Na₂SO₄), ﬁltered and concentrated to yield the

crude product as an odourless mobile yellow oil (2.08 g, 49%)

which was not puriﬁed further. δ_H(400 MHz) 2.39 (3H, s, CH₃),

2.51 (1H, t, J 2.5, CH), 4.73 (2H, d, J 2.5, CH₂).

3-Phenyl-2-propenyl 2-oxo-2-phenylacetate (from ꢀ-vinylbenzyl

alcohol) 7d

Benzoylformic acid (0.49 g; 3.27 mmol) and α-vinylbenzyl alco-

hol (0.53 g; 3.99 mmol) were heated at reﬂux in C₆H₆(10 cm³)

for 90 min in the presence of a catalytic amount of p-TsOH

(0.03 g; 0.158 mmol) using a Dean–Stark trap. The reaction

mixture was allowed to cool to rt and was washed with sat.

NaHCO₃(3 × 10 cm³) and water (2 × 10 cm³). The organic layer

was collected and dried (anh. Na₂SO₄), ﬁltered and concen-

trated to aﬀord the crude product, an orange oil. Puriﬁcation

by column chromatography (Et₂O : petroleum ether; 1 : 3)

aﬀorded 7d, a colourless mobile oil (245 mg, 37%) (Found: C,

77.30; H, 5.23. C₁₇H₁₄O₃requires: C, 76.69; H, 5.26%); δ_H(400

MHz) 4.96 (2H, dd, J 1.1 and 6.6, OCH₂), 6.30 (1H, dt, J 6.6

2-Propynyl 2-oxo-2-phenylacetate 9b

Benzoylformic acid (3 g, 20 mmol) and propargyl alcohol

(1.34 g, 24 mmol) were heated for 5 h at reﬂux in C₆H₆(72 cm³)

in the presence of a catalytic amount of p-TsOH (0.19 g,

0.1 mmol) using a Dean–Stark apparatus. The reaction was

allowed to cool to rt and was washed with sat. NaHCO₃(2 ×

50 cm³) and then with water (2 × 50 cm³). The organic layer was

collected and dried (anh. Na₂SO₄), ﬁltered and concentrated to

yield the crude product as a viscous non-mobile yellow oil (2.61

g, 69%) which was not puriﬁed further (Found: C, 69.77; H,

4.51. C₁₁H₈O₃requires: C, 70.21; H, 4.26%); δ_H(400 MHz)

2.54 (1H, t, J 2.4, CH), 4.87 (2H, d, J 2.4, –CH₂–), 7.42 (2H, m,

and 15.9, OCH CH᎐), 6.70 (1H, d, J 15.9, CH–Ph), 7.23 (3H,

᎐

2

m, 3 × ArH), 7.35 (2H, m, 2 × ArH), 7.44 (2H, m, 2 × ArH),

7.57 (1H, m, 1 × ArH), 7.95 (2H, m, 2 × ArH); δ_C(100 MHz)

66.68 (Ϫve) (OCH ), 121.50 (ϩve) (CH᎐), 126.76 (ϩve) (CH–

᎐

2

Ph), 128.42, 128.67, 128.93, 130.07, 134.96, 135.98, (ϩve)

(10 × ArC), 132.45 (abs.) (n-ArC), 135.81 (abs.) (n-ArC), 163.53

(abs.) (C᎐O, ester), 185.95 (abs.) (C᎐O, ketone).

᎐

2 × o-ArH), 7.57 (1H, m, p-ArH), 7.91 (2H, m, m-ArH); δ_C(100

᎐

MHz) 53.18 (Ϫve) (–CH –), 76.19 (abs.) (C᎐CH), 128.21 (ϩve)

᎐

2

3-Phenyl-2-propenyl 2-oxopropanoate (from cinnamyl alcohol) 7c

᎐

(C᎐CH), 128.84 (ϩve) (ArC), 129.95 (ϩve) (ArC), 132.07 (abs.)

Pyruvic acid (3.16 g, 35.9 mmol) and cinnamyl alcohol (5.77 g,

43.1 mmol) were heated for 4 h at reﬂux in C₆H₆(120 cm³) in the

presence of a catalytic amount of p-TsOH (0.34 g, 1.80 mmol)

using a Dean–Stark apparatus. The reaction was allowed to

cool to rt and was washed with sat. NaHCO₃(2 × 100 cm³) and

then with water (2 × 100 cm³). The organic layer was collected

and dried (anh. Na₂SO₄), ﬁltered and concentrated to yield

the crude product, a complex mixture 5.71 g, 78%, which was

puriﬁed by ﬂash column chromatography (petroleum ether)

to yield 7c as a colourless mobile oil (0.219 g, 3%), much

decomposed material was also obtained. Spectral data as

reported above.

(n-ArC), 135.08 (ArC), 162.64 (abs.) (C᎐O, ester), 185.10 (abs.)

(C᎐O).

᎐

1-Methyl-2-propenyl 2-(hydroxyimino)-2-phenylacetates E- and

Z-4b

α-Keto ester 6b (as a mixture with 7b, 2.5 : 1) (3.20 g, 15.7

mmol), NH₂OHؒHCl (1.64 g, 23.6 mmol) and pyridine (1.86 g,

23.6 mmol) were stirred in EtOH (170 cm³) at rt for 15 h. The

mixture was concentrated, taken up in CH₂Cl₂(200 cm³)

and washed with water (2 × 100 cm³). The organic layer was

collected, dried (Na₂SO₄anh.), ﬁltered and concentrated to

aﬀord the crude product as a mixture of Z-4b : E-4b : Z-5b :

1

E-5b (ratio by H NMR spectral analysis 18 : 4 : 6 : 1). Puriﬁ-

2-Butenyl 2-oxopropanoate 7a

cation by column chromatography aﬀorded Z-4b as an insepar-

able mixture with Z-5b [1.75 g, 51% – combined yield, Z-4b :

Z-5b 3 : 1] and E-4b as an inseparable mixture with E-5b [0.62 g,

18% – combined yield, E-4b : E-5b 3 : 1].

Pyruvic acid (6 g, 68.2 mmol) and crotyl alcohol (5.89 g, 81.9

mmol) were heated for 5 h at reﬂux in C₆H₆(200 cm³) in the

presence of a catalytic amount of p-TsOH (0.65 g, 3.41 mmol)

using a Dean–Stark apparatus. The reaction was allowed to

cool to rt and was washed with sat. NaHCO₃(2 × 100 cm³) and

then with water (2 × 100 cm³). The organic layer was collected

and dried (anh. Na₂SO₄), ﬁltered and concentrated to yield the

crude product as a yellow mobile oil (7.51 g, 93%) which was

not puriﬁed further. δ_H(400 MHz) 1.65 (3H, d, J 6.6, CH₃), 2.36

Z-4b a colourless mobile oil (Found: C; 65.75, H; 6.06, N;

6.36. C₁₂H₁₃NO₃requires: C; 65.74, H; 5.98, N; 6.39%.); δ_H(400

MHz) 1.47 (3H, d, J 6.8, Me), 5.23 (1H, d, J 10.7, ᎐CH ), 5.40

᎐

2

(1H, d, J 17.1, ᎐CH ), 5.72 (1H, m, OCH), 5.93 (1H, m, CH᎐),

᎐

2

7.41 (3H, m, o- & p-ArH), 7.69 (2H, m, m-ArH), 9.63 (1H, br s,

OH); δ_C(100 MHz) 19.94 (ϩve) (Me), 73.39 (ϩve) (OCH),

(3H, s, CH ), 4.57 (2H, d, J 6.6, OCH ), 5.55 (1H, m, CH᎐CH–

117.21 (Ϫve) (᎐CH ), 126.29 (ϩve) (ArC), 128.84 (ϩve) (ArC),

᎐

2

᎐

3

2

CH ), 5.81 (1H, m, CH᎐CH–CH ).

130.03 (abs.) (n-ArC), 130.50 (ϩve) (ArC), 136.53 (ϩve) (CH᎐),

᎐

3

151.73 (abs.) (C᎐N), 163.11 (abs.) (C᎐O).

᎐

2-Butenyl 2-oxo-2-phenylacetate 7b

E-4b a white powder mp 115–116 ЊC (from benzene–hexane)

(Found: C; 65.04, H; 6.03, N; 6.31. C₁₂H₁₃NO₃requires: C;

65.74, H; 5.98, N; 6.39%.); δ_H(400 MHz) 1.38 (3H, d, J 6.8,

Benzoylformic acid (6 g, 40 mmol) and crotyl alcohol (3.46 g,

48 mmol) were heated for 6 h at reﬂux in C₆H₆(120 cm³) in the

presence of a catalytic amount of p-TsOH (0.38 g, 2 mmol)

using a Dean–Stark apparatus. The reaction was allowed to

cool to rt and was washed with sat. NaHCO₃(2 × 100 cm³) and

then with water (2 × 100 cm³). The organic layer was collected

and dried (anh. Na₂SO₄), ﬁltered and concentrated to yield the

crude product as a colourless mobile oil (6.57 g, 81%) which

was not puriﬁed further. 7b (72%) obtained as an enriched mix-

ture with 6b (9%). Spectral data reported for 7b only. δ_H(400

MHz) 1.75 (3H, d, J 6.1, Me), 4.80 (2H, d, J 6.8, OCH₂), 5.70

Me), 5.16 (1H, d, J 10.7, ᎐CH ), 5.28 (1H, d, J 17.6, ᎐CH ),

᎐

2

5.52 (1H, m, OCH), 5.84 (1H, m, CH–Ph), 7.44 (3H, br m,

3 × ArH), 7.52 (2H, br s, 2 × ArH), 10.6 (1H, br s, NOH);

δ (100 MHz) 19.81 (Me), 73.35 (OCH), 116.95 (᎐CH ), 127.91

᎐

C

2

(ArC), 128.50 (n-ArC), 129.39 (ArC), 129.73 (ArC), 136.74

(CH᎐), 149.05 (C᎐N), 162.60 (C᎐O).

᎐

3-Phenyl-2-propenyl-2-(hydroxyimino)propanoate 5c

α-Keto acid 7c (0.64 g, 3.15 mmol), NH₂OHؒHCl (0.39 g,

4.73 mmol) and pyridine (0.37 g, 4.73 mmol) were stirred

in EtOH (50 cm³) at rt for 15 h. The mixture was concen-

trated, taken up in CHCl₃(60 cm³) and washed with water

(1H, m, CH᎐CH–CH ), 5.92 (1H, m, CH᎐CH–CH ), 7.34 (2H,

᎐

3

m, 2 × o-ArH), 7.63 (1H, m, 1 × p-ArH), 7.99 (2H, d, J 4.9,

2 × p-ArH)

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 0 2 – 4 3 1 6

4309

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(2 × 20 cm³). The organic layer was dried (Na₂SO₄anh.),

ﬁltered and concentrated to aﬀord the crude product, which

crystalised to colourless cubic crystals (0.306 g; 44%), mp 116–

118ЊC (from CHCl₃–hexane) (Found: C, 65.62; H, 6.18; N, 6.10.

C₁₂H₁₃NO₃requires: C, 65.75; H, 5.94; N, 6.39%); δ_H(400

MHz) 2.12 (3H, s, Me), 4.91 (2H, dd, J 1.1 and 6.6, OCH₂), 6.33

(Na₂SO₄anh.), ﬁltered and concentrated to aﬀord the crude

product. Examination of the ¹H NMR spectral data of the

crude reaction mixture indicated a Z-5b : E-5b : Z-4b : E-4b

ratio of 12 : 5 : 3.5 : trace. Puriﬁcation by ﬂash column chrom-

atography (petroleum ether with Et₂O, 1% gradient) aﬀorded

Z-5b as an inseparable mixture with Z-4b (1.75 g, 74% –

combined yield, Z-5b : Z-4b, 7 : 2) and E-5b (0.26 g, 11%).

Spectral data reported for title compounds only. Data for Z-4b

matches that as previously reported.

Z-5b a colourless, odourless, mobile oil, [R_f0.9 (Et₂O), 0.28

(Et₂O : petroleum ether; 1 : 1)] (Found: C, 65.49; H, 6.16; N,

6.59. C₁₂H₁₃NO₃requires: C, 65.75; H, 5.94; N, 6.39%); δ_H(400

MHz) 1.75 (3H, d, J 5.9, Me), 4.85 (2H, d, J 6.4, CH₂), 5.70

(1H, dt, J 6.6 and 15.7, CH᎐CH–Ph), 6.71 (1H, d, J 15.7, CH᎐

᎐

CH–Ph), 7.41 (5H, m, ArH), 9.84 (1H, br s, N–OH); δ_C(100

MHz) 10.55 (ϩve) (CH₃), 66.34 (Ϫve) (OCH₂), 122.22 (ϩve)

(OCH₂CH), 126.68, 128.21, 128.59, 135.13 (ϩve) (5 × ArC and

CHPh), 136.02 (abs.) (n-ArC), 149.52 (abs.) (C᎐N), 163.36

᎐

(abs.) (C᎐O).

᎐

(1H, m, CH᎐CH–CH ), 5.93 (1H, m, CH᎐CH–CH ), 7.41 (3H,

m, o- & p-ArH), 7.58 (2H, m, m-ArH), 9.45 (1H, br s, OH);

δ_C(100 MHz) 17.77 (ϩve) (CH₃), 66.64 (Ϫve) (CH₂), 123.92

᎐

1-Phenyl-2-propenyl-2-(hydroxyimino)-2-phenylacetates, E- and

Z-5d

3

α-Keto ester 7d (0.15 g, 0.56 mmol), NH₂OHؒHCl (0.067 g,

0.85 mmol) and pyridine (0.061 g, 0.85 mmol) were stirred in

EtOH (9 cm³) at rt for 2.5 h. The mixture was concentrated,

taken up in CHCl₃(20 cm³), and washed with water (2 × 10

cm³). The organic layer was collected, dried (Na₂SO₄anh.), ﬁl-

tered and concentrated to aﬀord the crude products. Separation

by column chromatography (Et₂O : petroleum ether; 1 : 3)

aﬀorded Z-5d (0.065 g, 41%) and E-5d (46 mg; 29%).

(ϩve) (CH-CH ), 126.34 (ϩve) (CH᎐CH–CH ), 128.76 (ϩve)

᎐

3

(ArC), 129.99 (abs.) (n-ArC), 130.46 (ϩve) (ArC), 133.00 (ϩve)

(ArC), 151.60 (abs.) (C᎐N), 163.49 (abs.) (C᎐O), ν_max/cm^Ϫ13427

᎐

(OH), 1733 (C᎐O).

᎐

E-5b ﬁne colourless needles, mp 121–123 ЊC (from C₆H₆–

petroleum ether) (Found: C, 65.55; H, 5.59; N, 6.15. C₁₂H₁₃NO₃

requires: C, 65.75; H, 5.94; N, 6.39%); δ_H(400 MHz) 1.70 (3H,

d, J 5.4, CH ), 4.70 (2H, d, J 6.4, CH ), 5.63 (1H, m, CH᎐CH–

᎐

3

2

Z-5d a yellow viscous oil (Found: C, 72.27; H, 5.51; N, 4.48.

C₁₇H₁₅NO₃requires: C, 72.58; H, 5.37; N, 4.98%); δ_H(400

MHz) 4.96 (2H, dd, J 1.3 and 6.5, OCH₂), 6.28 (1H, dt, J 6.5

and 15.9, OCH₂CH ), 6.67 (1H, d, J 15.9, CHPh), 7.26 (8H, m,

ArH), 7.49 (2H, m, ArH), 8.92 (1H, s, OH); δ_C(100 MHz) 66.43

(Ϫve) (OCH₂), 121.84 (ϩve) (OCH₂CH), 126.42, 126.72,

128.29, 128.59, 128.80, 129.22, 130.50 (ϩve) (10 × ArC), 130.07

(abs.) (n-ArC), 135.42 (ϩve) (CHPh), 135.89 (abs.) (n-ArC),

CH ), 5.85 (1H, m, CH᎐CH–CH ), 7.39–7.53 (5H, m, 5 ×

᎐

3

ArH), 10.05 (1H, br s, NOH); δ_C(100 MHz) 17.73 (ϩve) (CH₃),

66.77 (Ϫve) (CH ), 124.17 (ϩve) (CH᎐CH–CH ), 127.95 (ϩve)

᎐

2

3

(CH᎐CH–CH ), 128.46 (abs.) (n-ArC), 129.31 (ϩve) (ArC),

᎐

3

129.78 (ϩve) (ArC), 132.75 (ϩve) (ArC), 149.26 (abs.) (C᎐N),

᎐

163.15 (abs.) (C᎐O), ν_max/cm^Ϫ13240 (OH), 1723 (C᎐O), 1677

᎐

(C᎐N), 1462, 1546, 684, 617 (mono sub. aryl ring).

᎐

151.60 (abs.) (C᎐N), 163.36 (abs.) (C᎐O), m/z 219, 133

᎐

2-Propynyl 2-(hydroxyimino)propanoate 9c

(^ϩOCH CH᎐CHPh), 117 (^ϩCH CH᎐CHPh).

᎐

2

α-Keto ester 9a (1.5 g, 11.9 mmol), pyridine (1.41 g, 17.85

mmol) and NH₂OHؒHCl (1.24 g, 17.85 mmol) in EtOH

(190 cm³) were stirred at rt for 15 h. The reaction mixture was

concentrated, taken up in CHCl₃(200 cm³) and washed with

water (2 × 100 cm³). The organic layer was collected, dried

(anh. Na₂SO₄), ﬁltered and concentrated to aﬀord the crude

product (1.14 g, 68%) which crystalised to ﬁne colourless

needles, mp 92–94 ЊC (from C₆H₆–petroleum ether) (R_f0.8

Et₂O) (Found: C, 51.21; H, 4.95; N, 9.58. C₆H₇NO₃requires: C,

51.06; H, 5.00; N, 9.93%); δ_H(400 MHz) 2.12 (3H, s, CH₃), 2.51

(1H, t, J 2.4, CH), 4.83 (2H, d, J 2.4, CH₂); δ_C(100 MHz) 10.47

(ϩve) (CH₃), 53.05 (Ϫve) (CH₂), 75.51 (ϩve) (CH), 148.76

(abs.) (C᎐N), 162.81 (abs.) (C᎐O); m/z 142 (M^ϩϩ 1), 96, 86, 68,

E-5d colourless plates, mp 175–177 ЊC (from CHCl₃–hexane)

(Found: C, 72.19; H, 4.84; N, 5.34. C₁₇H₁₅NO₃requires: C,

72.58; H, 5.37; N, 4.98%); δ_H(400 MHz) 4.92 (2H, dd, J 0.9

and 6.5, OCH₂), 6.30 (1H, dt, J 15.7 and 6.5, OCH₂CH ), 6.68

(1H, d, J 15.7, CHPh), 7.30 (5H, m, 5 × ArH), 7.42 (3H, m,

3 × ArH), 7.52 (2H, m, 2 × ArH), 10.03 (1H, br s, OH);

δ_C(100 MHz) 66.60 (Ϫve) (OCH₂), 122.01(ϩve) (OCH₂CH),

126.68, 127.99, 128.16, 128.55, 129.27, 129.82 (ϩve) (10 ×

ArC), 128.33 (abs.) (n-ArC), 135.21 (ϩve) (CHPh), 135.93

(abs.) (n-ArC), 149.26 (abs.) (C᎐N), 163.06 (abs.) (C᎐O).

᎐

2-Butenyl 2-(hydroxyimino)propanoate 5a

᎐

α-Keto ester 7a (3 g, 21.13 mmol), pyridine (2.51 g, 31.7 mmol)

and NH₂OHؒHCl (2.30 g, 31.7 mmol) were stirred in EtOH

(250 cm³) at rt for 15 h. The mixture was concentrated, taken up

in CH₂Cl₂(200 cm³) and washed with H₂O (2 × 150 cm³). The

organic layer was collected, dried (anh. Na₂SO₄), ﬁltered and

concentrated to aﬀord the crude product. Puriﬁcation by

column chromatography (petroleum ether with Et₂O 1% gradi-

ent) aﬀorded 5a (2.66 g, 80%) which crystalised to colourless

plates, mp 42–45 ЊC (from Et₂O–petroleum ether), R_f0.7 (Et₂O)

(Found: C, 53.91; H, 7.04; N, 8.79. C₇H₁₁NO₃requires: C,

53.50; H, 7.01; N, 8.92%); δ_H(400 MHz) 1.72 (3H, d, J 6.2,

CH₃), 2.10 (3H, s, CH₃), 4.67 (2H, d, J 6.2, CH₂), 5.64 (1H, m,

58.

2-Propynyl 2-(hydroxyimino)-2-phenylacetate 9d

α-Keto ester 9b (3 g, 15.9 mmol), pyridine (1.89 g, 23.9 mmol)

and NH₂OHؒHCl (1.66 g, 23.9 mmol) were stirred in EtOH

(240 cm³) at rt for 15 h. The mixture was concentrated, taken up

in CH₂Cl₂(300 cm³), and washed with water (2 × 150 cm³). The

organic layer was collected, dried (anh. Na₂SO₄), ﬁltered and

concentrated to aﬀord crude product. Puriﬁcation by column

ﬂash chromatography (Et₂O–petroleum ether; 1 : 5) aﬀorded

E-9d (2.77 g, 86%) and Z-9d (0.43 g, 13%).

E-9d a colourless viscous odourless oil (R_f0.5, Et₂O) (Found:

C, 64.78; H, 4.37; N, 6.99. C₁₁H₉NO₃requires: C, 65.02; H,

4.43; H, 6.90%); δ_H(400 MHz) 2.48 (1H, t, J 2.4, CH), 4.87 (2H,

d, J 2.4, CH₂), 7.30 (3H, m, o- and p-ArH), 7.46 (2H, m,

CH᎐CH–CH ), 5.84 (1H, m, CH᎐CH–CH ), 10.18 (1H, br s,

᎐

3

OH); δ (100 MHz) 10.47 (ϩve) (Me), 17.73 (ϩve) (᎐CHCH ),

᎐

C

3

66.43 (Ϫve) (CH ), 124.30 (ϩve) (CH᎐CH-CH ), 132.45 (ϩve)

᎐

2

3

(CH᎐CH–CH ), 149.39 (abs.) (C᎐N), 163.49 (abs.) (C᎐O).

᎐

3

m-ArH), 9.23 (1H, s, NOH); δ_C(100 MHz) 53.39 (Ϫve) (CH₂),

᎐

76.36 (ϩve) (CH), 76.75 (abs.) (C᎐CH), 126.55 (ϩve) (ArC),

᎐

2-Butenyl 2-(hydroxyimino)-2-phenylacetate 5b

129.14 (ϩve) (ArC), 129.82 (abs.) (n-ArC), 130.97 (ϩve) (ArC),

α-Keto ester 7b (as a mixture with 6b, 8 : 1) (2.2 g, 10.78 mmol),

NH₂OHؒHCl (1.12 g, 16.2 mmol) and pyridine (1.28 g, 16.2

mmol) were stirred at rt in EtOH (200 cm³) for 16 h. The mix-

ture was concentrated, taken up in CH₂Cl₂(200 cm³) and

washed with water (2 × 200 cm³). The organic layer was dried

151.26 (abs.) (C᎐N), 163.06 (abs.) (C᎐O).

᎐ ᎐

Z-9d colourless plates, mp 124–127 ЊC (Et₂O–petroleum

ether) (Found: C, 64.93; H, 4.18; N, 6.45. C₁₁H₉NO₃requires:

C, 65.02; H, 4.46; N, 6.89%); δ_H(400 MHz) 2.42 (1H, t, J 2.4,

CH), 4.78 (2H, d, J 2.4, CH₂), 7.37 (3H, m, o- and p-ArH), 7.45

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 0 2 – 4 3 1 6

4310

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(2H, m, m-ArH); δ_C(100 MHz) 53.41 (Ϫve) (CH₂), 75.83 (ϩve)

aﬀord the crude product which was shown by ¹H NMR spectral

analysis to comprise starting material. When the reaction was

repeated on the same scale in CH₂Cl₂at reﬂux temperature, a

complex mixture resulted.

᎐

(CH), 77.40 (abs.) (C᎐CH), 128.09 (ϩve) (ArC), 129.41 (ϩve)

᎐

(ArC), 130.09 (ϩve) (ArC), 132.20 (abs.) (n-ArC), 148.86

(C᎐N), 162.61 (C᎐O).

᎐

Attempted cyclisation of oximes 2a, 9a and 9c by heating under

pressure

Preparation of 5-methyl-6-oxo-3-[1-(phenylselenyl)ethyl]-3,6-

dihydro-2H-1,4-oxazin-4- ium-4-olate 10a

(i) A solution of oxime 2a (0.05 g, 0.35 mmol) in toluene

(10 cm³) was heated at 210 ЊC in a sealed tube for 16 h. The

reaction was allowed to cool to rt and the solvent removed. ¹H

NMR analysis of the crude mixture showed nitrone 1a²

together with starting oxime in a 2 : 1 ratio.

(ii) A solution of oxime E-5a (0.05 g, 0.35 mmol) in toluene

(10 cm³) was heated at 190 ЊC in a sealed tube for 24 h. The

reaction was allowed to cool to rt and the solvent removed. ¹H

NMR analysis of the crude mixture showed returned starting

material only.

PhSeBr (0.75 g, 3.18 mmol) and AgBF₄(0.62 g, 3.18 mmol)

were stirred in CH₂Cl₂anh. (25 cm³) in the dark at 0 ЊC, for 10

min. Oxime E-5a (0.50 g, 3.18 mmol) was added at 0 ЊC and the

mixture was stirred for 3 h. K₂CO₃(0.48 g, 3.50 mmol) was

added and stirring continued at rt for a further 15 h, after which

time the mixture was ﬁltered with suction. The inorganic resi-

due was extracted several times [CH₂Cl₂] and the organic layers

collected. The solvent was removed from the combined organic

layers under reduced pressure, to yield the crude product as a

blue–green oil. Puriﬁcation by column chromatography (Et₂O–

petroleum ether, 1 : 2) aﬀorded 10a (0.66 g, 67%) as a viscous

yellow oil (R_f0.3 Et₂O), which solidiﬁed on standing in the cold

to a yellow amorphous solid, mp 48–51 ЊC (Found: C, 49.80; H,

4.78; N, 4.80. C₁₃H₁₅NO₃Se requires: C; 50.00, H; 4.81, N;

4.49%); δ_H(400 MHz) 1.55 (3H, d, J 7.3, Me), 2.17 (3H, s,

5-Me), 3.75 (1H, m, 1 : -H), 4.02 (1H, m, 3-H), 4.60 (1H, dd,

J 2.3 and 12.3, 2b-H), 4.86 (1H, d, J 12.3, 2a-H), 7.30 (3H, m,

3 × ArH), 7.55 (2H, m, 2 × ArH); δ_C(100 MHz) 11.78 (ϩve)

(5-Me), 19.68 (ϩve) (Me), 36.75 (ϩve) (CHSePh), 64.64 (Ϫve)

(2-C), 72.33 (ϩve) (3-C), 127.02 (abs.) (n-ArC), 128.67 (ϩve)

(ArC), 129.39 (ϩve) (ArC), 135.38 (ϩve) (ArC), 135.93 (abs.)

(5-C), 159.07 (abs.) (6-C); m/z 314 (M^ϩϩ 2), 312 (M^ϩ).

NOEDS: irradiation of 3-H caused an enhancement the signals

representing 2b-H (2.8%) and 1Ј-H (1.5%). Irradiation of 2b-H

caused the following enhancements 3-H (4.5%) and 2a-H

(26.7%).

(iii) A solution of oxime 9c (0.05 g, 0.34 mmol) in toluene

(10 cm³) was heated at 210 ЊC in a sealed tube with times vary-

ing from 1 to 9.5 h. The reaction was allowed to cool to rt and

1

the solvent removed. H NMR analysis of the crude mixture

showed returned starting material only.

Attempted electrophile induced cyclisation of oximes 5a and 9c

(i) Procedure employing I₂. Oxime E-5a (0.1 g, 0.64 mmol)

and I₂(0.16 g, 0.64 mmol) were stirred in CH₂Cl₂anh. (10 cm³)

at rt for 5 min. Anhydrous K₂CO₃(0.10 g, 0.701 mmol) was

added whereupon the colour of the reaction mixture turned

from purple to a brown. The mixture stirred at rt for a further

2 h, ﬁltration and concentration aﬀorded the crude product. ¹H

NMR spectral analysis of which showed returned starting

oxime. The reaction was repeated varying iodine concentration

(0.56–2.0 mol eq.) and reaction time following addition of base

(2–15 h). ¹H NMR spectral analysis of the crude reaction mix-

tures showed returned starting material when less than a one

mole eq. of I₂is employed, with an excess of I₂, mixtures were

returned in which the starting oxime is the major component.

6-Oxo-5-phenyl-3-[1-(phenylselenyl)ethyl]-3,6-dihydro-2H-1,4-

oxazin-4-ium-4-olate 10b

PhSeBr (0.058 g, 0.245 mmol) and AgBF₄(0.052 g, 0.268

mmol) were stirred at 0 ЊC in CH₂Cl₂(5 cm³) in the dark for

10 min. Oxime E-5b (0.05 g, 0.242 mmol) was added and the

reaction mixture stirred for 3 h in the dark at 0 ЊC. K₂CO₃

(0.042 g, 0.313 mmol) was added and the reaction stirred at rt

for a further 15 h. The reaction mixture was ﬁltered with

suction and the inorganic residue was extracted several times

with CH₂Cl₂. The organic layers were collected and the solvent

was removed under reduced pressure, to yield the crude product

as a blue–green oil. Puriﬁcation by ﬂash column chromato-

graphy (Et₂O–petroleum ether; 1 : 2) aﬀorded 10b (0.052 g,

57%) as a ﬂuﬀy white solid, mp 119–120 ЊC, (C₆H₆–petroleum

ether) (Found: C, 57.47; H, 4.47; N, 3.68. C₁₈H₁₇NO₃Se

requires: C, 57.75; H, 4.55; N, 3.74%); δ_H(400 MHz) 1.65 (3H,

d, J 7.3, Me), 3.79 (1H, m, H), 4.11 (1H, m, 3-H), 4.75 (1H, dd,

J 12.5 and 3.2, 2b-H), 4.98 (1H, d, J 12.5, 2a-H), 7.31–7.67

(10H, m, 10 × ArH); δ_C(100 MHz) 19.74 (ϩve) (Me), 36.56

(ϩve) (CHSePh), 64.56 (Ϫve) (2-C), 74.40 (ϩve) (3-C), 126.72

and 127.15 (abs.) (2 × n-ArC), 127.91, 128.86, 129.52, 130.08,

130.28, 135.68 (ϩve) (10 × ArC), 135.05 (abs.) (5-C), 158.61

(ii) Procedure employing N-bromosuccinimide (NBS).

Oxime E-5a (0.05 g, 0.32 mmol) and NBS (0.017 g, 0.1 mmol)

were stirred in anh. CH₂Cl₂(5 cm³) at rt for 2 h. The reaction

mixture was concentrated to aﬀord the crude product. ¹H

NMR spectral analysis of the crude reaction mixture showed

returned oxime. The reaction was repeated varying duration

between 5 min and 8 h with NBS concentration over the range

1

0.18–1 molar. H NMR spectral analysis of the crude reaction

mixtures showed that with less than one equivalent of NBS

the starting material is returned. Complex mixtures of an

undetermined nature resulted when molar equivalents of NBS

were employed.

(iii) Procedure employing AgBF₄. Oxime 9c (0.20 g, 1.42

mmol) and a catalytic amount of AgBF₄(0.014 g, 0.07 mmol)

were stirred in CH₂Cl₂(5 cm³) for 6 h. The reaction mixture was

washed with H₂O (2 × 5 cm³) and the water washings extracted

with CH₂Cl₂(3 × 5 cm³). The combined organic layers were

washed with brine (5 cm³). The organic layer was collected and

dried (anh. Na₂SO₄), ﬁltered and concentrated to aﬀord the

(abs.) (6-C), ν_maxcm^Ϫ11712 (C᎐O), m/z 374 (M^ϩ), 376 (M^ϩϩ 2).

᎐

1

crude product which was shown by H NMR spectral analysis

2,3-Dimethyl-6-oxo-5-phenyl-3,6-dihydro-2H-1,4-oxazin-4-ium-

4-olates 1e and 1f and 4-methyl-6a-phenyltetrahydro-3H,6H-

furo[3,4-c]isoxazol-6-ones 11(i), 11(ii) and 11(iii)

to comprise starting material. The above reaction was repeated

at rt for 24 h and at reﬂux temperature for 6 h, however only

starting material was returned.

α-Keto oxime Z-4b (as an enriched mixture with Z-5b [3 : 1])

(1 g, 4.56 mmol) was heated at reﬂux in xylene (300 cm³) in the

presence of hydroquinone (1%, ^w/_v, 3 g) under N₂for 30 h. The

reaction mixture was allowed to cool to rt and the precipitated

hydroquinone was ﬁltered oﬀ with suction. The ﬁltrate was

concentrated, taken up in CHCl₃(10 cm³) and further hydro-

quinone which precipitated was again removed by ﬁltration.

(iv) Procedure employing PhSeBr. A solution of the oxime

E-5a (0.10 g, 0.637 mmol) and PhSeBr (0.15 g, 0.634 mmol)

were stirred at rt in either CH₃CN or CH₂Cl₂(5 cm³) for 3 h.

K₂CO₃(0.10 g, 0.70 mmol) was added and the reaction mixture

was stirred for a further 15 h. The crude reaction mixture was

ﬁltered and solvent was removed under reduced pressure to

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 0 2 – 4 3 1 6

4311

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The ﬁltrate was concentrated to yield the crude product, which

was puriﬁed by ﬂash chromatography (Et₂O–petroleum ether,

1 : 10) to aﬀord a pure sample of Z-5b (12%) – all other

products were obtained as enriched mixtures – 1e (19%), 11(i)

(11%), 1f (3%), 11(ii) (20%) and 11(iii) (17%).

combined and concentrated. Chromatography of the yellow

solid residue on SiO₂with Et₂O-petroleum ether (1 : 3) as eluant

gave the title adduct as a white solid (1.56 g, 90%).

14a Colourless plates, mp 90–92 ЊC (benzene–petroleum

ether) (Found: C, 68.11; H, 7.01; N, 5.89. C₁₄H₁₇NO₃requires

C, 68.02; H, 6.88; N, 5.67%); δ_H(270 MHz) 1.22 (3H, d, J 6.2,

7-Me), 1.68 (3H, s, 3a-Me), 2.35 (1H, dd, J 13.2 & 8.2, 3a-H),

3.18 (1H, dd, J 8.2 & 13.2, 3b-H), 3.29 (1H, m, 7-H), 4.02 (1H,

dd, J 11.0 & 11.0, 6b-H), 4.20 (1H, dd, J 3.1 & 11.0 6a-H), 5.16

(1H, dd, J 8.1 & 8.1, 2-H), 7.36 (5H, m, ArH); δ_C(67.5 MHz)

15.2 (7-Me), 28.4 (3a-Me), 49.8 (3-C), 53.2 (7-C), 69.8 (3a-C),

70.7 (6-C), 78.0 (2-C), 126.9–138.8 (4 × Ar–C), 172.9 (4-C).

NOEDS results: irradiation of 2-H caused the following

enhancements 3b-H (6.4%), 7-H (7.0%), ArH (6.3%). Irradi-

ation of 3a-Me caused 1.0% enhancement on 2-H, 1.1% on

6b-H and 2.8% on 3a-H.

Z-5b spectral data as previously reported, all other returned

products obtained as mixtures.

1e (¹H NMR data taken from an enriched sample of 1e with

11 (i), 4 : 1); δ_H(400 MHz) 1.58 (3H, d, J 6.6, 2-Me), 1.60 (3H,

d, J 6.6, 3-Me), 4.09 (1H, m, 3-H), 4.60 (1H, m, 2-H), 7.37–7.70

(5H, m, 5 × ArH).

11(i) (¹H NMR data taken from a fraction composed of

11(i) : 1e; 1 : 4); δ_H(400 MHz) 1.36 (3H, d, J 6.2, Me), 3.09 (1H,

br m, 3a-H), 4.39 (2H, m, 3-H and 3Ј-H), 4.54 (1H, m, 4-H),

6.12 (1H, br s, NH), 7.37–7.70 (5H, m, 5 × ArH).

1f (¹H NMR data taken from a sample comprising 11(ii) : 1e :

11(i) : 1f; 1.2 : 1.3 : 2.1 : 1.1); δ_H(400 MHz) 1.48 (3H, d, J 7.0, 2-

Me), 1.52 (3H, d, J 6.6, 3-Me), 4.11 (1H, m, 3-H), 5.00 (1H, m,

2-H), 7.38–7.72 (5H, m, 5 × ArH).

2,3,6,7-Tetrahydro-7-methyl-2,3a-diphenyl-3aH-isoxazolo[3,2-c]-

[1,4]oxazin-4-one 14b and 2,3,6,7-tetrahydro-7-methyl-2,3a-

diphenyl-3aH-isoxazolo[3,2-c][1,4]oxazin-4-one 15

11(ii) (¹H NMR data taken from a fraction containing trace

amounts of 1f and 11(i)); δ_H(400 MHz) 1.52 (3H, d, J 6.6,

Me), 3.44 (1H, br m, 3a-H), 4.00 (1H, m, 3-H), 4.46 (1H, m,

3Ј-H), 4.85 (1H, m, 4-H), 7.43 (3H, m, 3 × ArH), 7.55 (2H, m,

2 × ArH).

Freshly recrystallised nitrone 1b (0.45 g, 2.20 mmol) and hydro-

quinone (0.20 g, 18.0 mmol) were stirred in deoxygenated

styrene (6 cm³) at 110 ЊC under a constant ﬂow of N₂. After 8 h

heating the reaction mixture was cooled to rt, and excess styr-

ene was removed under reduced pressure (100 ЊC, 0.50 mmHg).

The residue was taken up in CHCl₃(1 cm³) and allowed to

stand at rt for 15 min, the precipitated hydroquinone was

ﬁltered in vacuo. The ﬁltrate was collected and concentrated.

Flash chromatography with Et₂O–petroleum ether (1 : 5) as the

eluant yielded a pure sample of 14b (0.58 g, 86%) 15 was

obtained as an enriched mixture (0.07 g, 10%).

11(iii) (¹H NMR data taken from a fraction comprising

11(ii) : 11(iii); 5 : 3); δ_H(400 MHz) 1.44 (3H, d, J 6.2, Me), 3.23

(1H, br m, 3a-H), 4.12 (1H, m, 3-H), 4.28 (1H, m, 3Ј-H), 4.59

(1H, m, 4-H), 5.80 (br s, NH), 7.41–7.60 (5H, m, 5 × ArH).

3,6a-Diphenyltetrahydro-3H,6H-furo[3,4-c]isoxazol-6-one 13

(i) Z-5d (0.367 g; 1.30 mmol) was heated at reﬂux in xylene

(80 cm³) in the presence of hydroquinone (1% ^w/_v, 0.8 g) under a

nitrogen atmosphere for 24 h. The mixture was allowed to cool

to rt and concentrated. The residue was taken up in CHCl₃

(5 cm³) and the hydroquinone which precipitated was removed

with suction, concentration of the ﬁltrate aﬀorded the crude

product. Puriﬁcation by ﬂash column chromatography (Et₂O–

petroleum ether, 1 : 3) aﬀorded 13 (0.303 g; 83%) which crystal-

ised to colourless needles (0.270 g; 74%), mp 94–95.5 ЊC (from

CHCl₃–petroleum ether) (Found: C, 72.37; H, 4.91; N, 4.90.

C₁₇H₁₅NO₃requires: C, 72.60; H, 5.34, N, 4.98%); δ_H(400

MHz) (rt) 3.67 (1H, br s, 3a-H), 4.62 (2H, m, 4-H and 4Ј-H),

5.25 (1H, br s, 3-H), 6.30 (1H br s, NH), 7.32–7.50, 10 H, m,

10 × ArH); δ_H(400 MHz) (50 ЊC) 3.64 (1H, slightly (sl.) br. t,

J 4.8, 3a-H), 4.62 (2H, m, 4-H and 4Ј-H), 5.22 (1H, sl. br d,

J 4.8, 3-H), 6.33 (br s, NH), 7.32–7.50 (10H, m, 10 × ArH);

δ_C(100 MHz) 58.92 (ϩve) (3a-C), 68.13 (Ϫve) (4-C), 76.20

(abs.) (6a-C), 89.96 (ϩve) (3-C), 126.43, 126.64, 127.75, 128.00,

128.21, 128.42, 128.81, 128.89, 129.15 (ϩve) (10 × ArC), 135.69

(abs.) (n-ArC), 139.08 (abs.) (n-ArC), 176.11 (abs.) (6-C); m/z

M^ϩ281.

14b Colourless cubic crystals, mp 94–96 ЊC (benzene–petrol-

eum ether) (Found: C, 74.01; H, 6.10; N, 4.72. C₁₉H₁₉NO₃

requires C, 73.79; H, 6.15; N, 4.53%); δ_H(270 MHz) 1.34 (3H, d,

J 6.2, Me), 2.55 (1H, dd, J 12.7 & 7.2, 3a-H), 3.52 (1H, m, 7-H),

3.74 (1H, dd, J 12.7 & 8.3 3b-H), 3.90 (1H, dd, J 11.4 & 11.4 6b-

H), 4.13 (1H, dd, J 11.4 & 3.7, 6a-H), 5.12 (1H, dd, J 7.2 & 8.3,

2-H), 7.37–7.25 (8H, 2 × m, ArH), 7.73 (d, 2H, 3a-ArH);

δ_C(67.5 MHz) 16.5 (Me), 52.6 (3-C), 56.8 (7-C), 68.2 (6-C),

77.9 (3a-C), 78.9 (2-C), 140.0–126.3 (8 × Ar–C), 171.1 (4-C).

NOEDS results: irradiation of 2-H caused the following

enhancements 3b-H (8.5%), 7-H (8.8%), 6a-H (1.8%). Irradi-

ation of 3a-H caused 3.7% enhancement on 3a-ArH, 2.8% on

2-H, 3.4% on the 2-ArH/3a-ArH multiplet and 25.2% on its

partner 3b-H. Irradiation of 3b-H caused 8.9% enhancement

on 2-H, 3.2 % on 6a-H and 27.9% on its partner 3a-H.

15; δ_H(270 MHz) 1.30 (3H, d, J 6.8, Me), 2.88 (1H, dd, J 5.9

& 13.0 3-H), 3.20 (1H, dd, J 10.6 & 13.0, 3-H), 3.48 (1H, m,

7-H) 4.25 (1H, dd, J 11.2 & 5.0 6a-H), 4.85 (1H, dd, J 11.2 &

11.9 6b-H,), 4.92 (1H, dd, J 10.6 & 5.9 2-H), 7.51–7.25 (10H m,

ArH).

(ii) The above reaction was repeated on one third the scale

1

with E-5d, H NMR spectral analysis of the crude reaction

2,3,6,7-Tetrahydro-3a,7-dimethyl-2-phenylsulfonyl-3aH-

isoxazolo[3,2-c][1,4]oxazin-4-one 16a

mixture indicated 13 as the only reaction product with much

decomposed material, puriﬁcation by ﬂash chromatography

aﬀorded 13 (36%), physical and spectral data as previously

reported.

Freshly distilled nitrone 1a (0.5 g, 3.50 mmol) and phenyl vinyl

sulfone (0.74 g, 4.40 mmol) were stirred in xylene (100 cm³) at

reﬂux under N₂for 36 h. The reaction mixture was cooled to rt

and the solvent was removed under reduced pressure (100 ЊC,

0.2 mmHg). Chromatography of the yellow gummy residue

[Et₂O–petroleum ether, 1 : 1] gave the title compound (0.92 g,

85%), unreacted nitrone (8%) was returned.

16a Colourless needles, mp 170–172 ЊC (benzene–hexane)

(Found; C, 53.94; H, 5.64; N, 4.61. C₁₄H₁₇NO₅S requires C,

54.0; H, 5.47; N, 4.50%); δ_H(270 MHz) 1.27 (3H, d, J 5.9,

7-Me), 1.56 (3H, s, 3a-Me), 2.84 (1H, dd, J 7.7 & 13.6 3a-H),

3.21 (1H, dd, J 9.0 & 13.6, 3b-H), 3.61 (1H, m, 7-H), 4.00 (1H,

dd, J 11.1 & 11.1, 6b-H), 4.24 (1H, dd, J 3.3 & 11.1, 6a-H), 5.05

(1H, dd, J 9.0 & 7.7, 2-H), 7.27 (2H, m, 2 × m-ArH), 7.74 (1H,

m, p-ArH), 7.89 (2H, m, 2 × o-ArH); δ_C(67.5 MHz) 14.4

2,3,6,7-Tetrahydro-3,7-dimethyl-2-phenyl-3aH-isoxazolo-[3,2-c]-

[1,4]oxazin-4-one 14a

Nitrone 1a (1.0 g, 7.0 mmol) and hydroquinone (0.15g, 1.40

mmol), were stirred in deoxygenated styrene (15 cm³) at 100 ЊC,

under a constant ﬂow of N₂gas. After 5.5 h the reaction mix-

ture was cooled to rt and excess styrene was removed under

high vacuum (100 ЊC, 0.20 mmHg). The yellow solid residue

was, with the aid of sonication, taken up in CHCl₃(1 cm³), this

solution was allowed to stand at rt (0.5 h), and the precipitated

hydroquinone was removed by vacuum ﬁltration and washed

with petroleum ether (20 cm³). The ﬁltrate and washings were

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(7-Me), 24.9 (3a-Me), 39.7 (3-C), 55.0 (7-C), 69.4 (3a-C), 70.2

(6-C), 92.7 (2-C), 136.9–128.8 (4 × Ar–C), 170.1 (4-C). NOEDS

results: irradiation of 2-H caused the following enhancements

3a-H (8.1%), 3a-Me (2.4%) and ArH (3.3%). Irradiation of

3b-H caused 3.7% enhancement on 2-H, 25.1% on 3a-H and

9.7% on 7-H. Irradiation of 3a-H caused 28.8% enhancement

on 3b-H, 10.6% on 2-H and 4.2% on 3a-Me.

16d Fine colourless needles, mp 178–179 ЊC (from Et₂O–

petroleum ether), R_f0.7 (Et₂O, 100%) (Found: C, 55.37; H,

5.78; N, 4.56. C₁₅H₁₉NO₅S requires: C, 55.38; H, 5.85; N,

4.31%); δ_H(400 MHz) 1.31 (3H, d, J 6.4, 7-Me), 1.37 (3H, d,

J 6.8, 6-Me), 1.55 (3H, s, 3a-Me), 2.80 (1H, dd, J 13.7 and 7.8,

3a-H), 3.19 (1H, dd, J 13.7 and 9.0, 3b-H), 3.60 (1H, m, 7-H),

4.51 (1H, m, 6-H), 5.04 (1H, dd, J 9.0 and 7.8, 2-H), 7.61 (2H,

m, 2 × ArH), 7.72 (1H, m, 1 × ArH), 7.94 (2H, m, 2 × ArH);

δ_C(100 MHz) 15.16 (7-Me), 24.50 (6-Me), 29.55 (3a-Me), 40.00

(3-C), 57.23 (7-C), 69.25 (3a-C), 78.25 (6-C), 92.73 (2-C),

128.82 (ArC), 129.54 (ArC), 134.55 (ArC), 137.18 (n-ArC),

170.26 (4-C). NOEDS results: irradiation of 3a-H caused the

following enhancements 3a-Me (2.0%), 3b-H (28.4%), 2-H

(10.6%). Irradiation of 3b-H caused 7.5% enhancement on 7-H

and 23.4% on 3a-H. Irradiation of 7-H caused 7.9% enhance-

ment on 3b-H and 9.3% on 6-H.

Crystal structure determination for 16a†

The structure was solved by direct methods, SHELXS-97,³¹

and reﬁned by full matrix least squares using SHELXL-97.³²

SHELX operations were automated using OSCAIL which was

also used to obtain the drawings.³⁰The XDS program was used

for data reduction and the data was corrected for Lorentz and

polarization eﬀects but not for absorption.³³Hydrogen 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 calcu-

lations were performed on a Pentium PC.

2-Acetyl-3a,7-dimethyltetrahydroisoxazolo[3,2-c][1,4]-

oxazine-4(2H)-ones 17a–d. Freshly distilled nitrone 1a (0.97 g,

6.80 mmol) and methyl vinyl ketone (6 cm³, 5.05 g, 72.0 mmol),

w

were stirred in the presence of hydroquinone (2% /_v, 4.0 g) in

2,3,6,7-Tetrahydro-7-methyl-3a-phenyl-2-phenylsulfonyl-3aH-

isoxazolo[3,2-c][1,4]oxazin-4-one 16b. Freshly recrystallised

nitrone 1b (2.0 g, 10.0 mmol), and phenyl vinyl sulfone (2.10 g,

12.5 mmol) were stirred in xylene (250 cm³) at reﬂux under a N₂

atmosphere. After 42 h the reaction solvent was removed under

reduced pressure. Chromatography of the yellow solid resi-

due with Et₂O–petroleum ether, (10 : 19) as eluant yielded the

title compound 16b (1.60 g, 44%), unreacted nitrone 1b was

returned (0.96 g, 48%).

16b Cubic crystals, mp 119–121 ЊC (benzene–hexane)

(Found; C, 60.94; H, 5.25; N, 3.64; C₁₉H₁₉NO₅S requires C,

61.13; H, 5.09; N, 3.75%); δ_H(270 MHz) 1.39 (3H, d, J 6.0 Me),

3.52 (2H, m, 3a-H & 3b-H), 3.84 (1H, m, 7-H), 4.11 (1H, dd,

J 10.6 & 11.5, 6b-H), 4.28 (1H, dd, J 3.1 & 11.5, 6b-H), 4.71

(1H, dd, J 7.9 & 8.6, 2-H), 7.35 (3H, m, ArH), 7.70–7.58 (3H,

ArH), 7.83 (2H, m, ArH), 7.92 (2H, m, ArH); δ_C(67.5 MHz),

15.9 (Me), 42.0 (3-C), 56.7 (7-C), 71.6 (6-C), 75.8 (3a-C), 93.4

(2-C), 138.4–128.3 (8 × Ar–C), 169.8 (4-C).

xylene (200 cm³) at reﬂux under N₂for 32 h (using a double

sided water condenser). The reaction mixture was allowed to

cool to rt, both the reaction solvent and excess dipolarophile

were removed under reduced pressure (100 ЊC, 0.5 mmHg). The

brown gummy residue was taken up in CHCl₃(2.5 cm³) and

allowed to stand at rt (0.5 h), the precipitated hydroquinone was

ﬁltered oﬀ (in vacuo). Puriﬁcation of the crude products by

ﬂash chromatography (Et₂O : petroleum ether, 1.3 : 1.0), yielded

17d, a yellow oil (0.073 g, 5%) which solidiﬁed upon standing

and was crystallised (Et₂O–hexane) to give colourless needles;

17b an oﬀ white solid (0.17 g, 12%); 17a a white solid (0.55 g,

38%); 17c oﬀ white solid (0.15 g, 10%). Following a strip of the

column (Et₂O) unreacted dipole (0.23 g, 24%) was obtained.

17d Colourless needles, mp 96–98 ЊC (Et₂O–hexane) (Found:

C, 56.45; H, 6.94; N, 6.37. C₁₀H₁₅NO₄requires: C, 56.34; H,

7.04; N, 6.57%); δ_H(270 MHz) 1.34 (3H, d, J 6.6, 7-Me), 1.50

(3H, s, 3a-Me), 2.31 (3H, s, COMe), 2.57 (1H, dd, J 4.2 & 13.4,

3b-H), 3.09 (1H, dd, J 9.5 & 13.2, 3a-H), 3.56 (1H, m, 7-H),

4.24 (2H, m, 2-H & 6a-H), 4.76 (1H, dd, J 11.4 & 11.4, 6b-H);

δ_C(67.5 MHz) 14.6 (7-Me), 22.6 (3a-Me), 25.4 (COMe), 44.1

(3-C), 49.1 (7-C), 66.6 (3a-C), 69.0 (6-C), 78.4 (2-C), 173.3

(4-C), 211.1 (COMe). NOEDS results: irradiation of 7-H

caused the following enhancements 2- & 6a-H (3.9%), 3a-Me

(2.7%), 7-Me (6.3%) and 6b-H (1.8%). Irradiation of 3b-H

caused 23.0% enhancement on its partner 3a-H, 2.6%

enhancement on 6b-H and 2.1% on 3a-Me.

3a,6,7-Trimethyl-2-(phenylsulfonyl)tetrahydroisoxazolo-[3,2-c]-

[1,4]oxazin-4-(2H)-one 16c. Nitrone 1c (0.10 g, 0.637 mmol)

and phenyl vinyl sulfone (0.128 g, 0.764 mmol) were stirred in

toluene (60 cm³) at reﬂux under N₂for 72 h. The reaction mix-

ture was allowed to cool to rt, concentrated and puriﬁed by

ﬂash chromatography (Et₂O–petroleum ether; 1 : 2) yielding 16c

(63 mg, 30%) and returned dipole (59.5 mg, 60%).

16c Colourless needles, mp 182–183 ЊC (from Et₂O–petrol-

eum ether) (Found: C, 55.29; H, 5.78; N, 3.92. C₁₅H₁₉NO₅S

requires: C, 55.38; H, 5.85; N, 4.31%); δ_H(400 MHz) 1.27 (3H,

d, J 5.9, 7-Me), 1.42 (3H, d, J 6.4, 6-Me), 1.55 (3H, s, 3a-Me),

2.82 (1H, dd, J 13.6 and 7.8, 3a-H), 3.19 (1H, dd, J 13.6 and 9.2,

3b-H), 3.26 (1H, m, 7-H), 4.16 (1H, m, 6-H), 5.03 (1H, dd, J 9.2

and 7.8, 2-H), 7.62 (2H, m, 2 × ArH), 7.73 (1H, m, 1 × ArH),

7.94 (2H, m, 2 × ArH); δ_C(100 MHz) 14.76 (7-Me), 17.43

(6-Me), 24.82 (3a-Me), 39.81 (3-C), 61.12 (7-C), 69.15 (3a-C),

78.06 (6-C), 92.79 (2-C), 128.88 (ArC), 129.52 (ArC), 134.57

(ArC), 137.12 (n-ArC), 169.94 (4-C).

17b Colourless needles, mp 93–94 ЊC (Et₂O, hexane) (Found:

C, 56.59; H, 7.21; N, 6.64. C₁₀H₁₅NO₄requires: C, 56.34; H,

7.04; N, 6.57%); δ_H(270 MHz) 1.23 (3H, d, J 5.9, 7-Me), 1.48

(3H, s, 3a-Me), 2.30 (3H, s, COMe), 2.60 (1H, dd, J 13.4 & 5.1,

3a-H), 2.87 (1H, dd, J 13.4 & 9.8, 3b-H), 3.13 (1H, m, 7-H),

4.01 (1H, dd, J 11.5 & 10.1, 6b-H), 4.23 (1H, dd, J 11.5 & 3.5,

6a-H), 4.49 (1H, dd, J 9.8 & 5.1, 2-H); δ_C(67.5 MHz) 14.7

(7-Me), 26.4 (3a-Me), 27.4 (COMe), 42.7 (3-C), 53.5 (7-C), 68.3

(3a-C), 70.1 (6-C), 80.6 (2-C), 171.8 (4-C), 206.6 (COMe).

NOEDS results: irradiation of 3a-H caused 15.4% enhance-

ment on its partner 3b-H and 12.9% on 3a-Me. Irradiation of

2-H caused 6.7% enhancement on 3b-H and 7.0% on 7-H.

Irradiation of 6b-H caused 2.7% enhancement on 7-H, 15.0%

on 6a-H, 3.6% on 7-Me and 2.2% on 3a-Me. Irradiation of

6a-H caused 7.6% enhancement on 7-H, 18.8% on 6b-H and

3.3% on 7-Me. Irradiation of 7-H caused 5.1% enhancement on

2-H, 4.9% on 3b-H and 5.4% on 7-Me.

Crystal structure determination for 16c as for 16a

3a,6,7-Trimethyl-2-(phenylsulfonyl) tetrahydroisoxazolo-[3,2-c]-

[1,4] oxazin-4-(2H)-one 16d. Nitrone 1d (0.04 g, 0.26 mmol)

and phenyl vinyl sulfone (0.05 g, 0.31 mmol) were stirred in

toluene (25 cm³) at reﬂux under N₂for 192 h. The mixture was

allowed to cool to rt, concentrated and puriﬁed by ﬂash

chromatography (Et₂O–petroleum ether, 1 : 1) yielding 16d

(25 mg, 29%) and returned dipole (23 mg, 56%).

17a Colourless plates, mp 100–101 ЊC (CHCl₃–hexane)

(Found: C, 56.24; H, 6.89; N, 6.29. C₁₀H₁₅NO₄requires: C,

56.34; H, 7.04; N, 6.57%); δ_H(270 MHz) 1.25 (3H, d, J 5.9,

7-Me), 1.60 (3H, s, 3a-Me), 2.30 (3H, s, COMe), 2.62 (1H, dd,

J 13.0 & 8.4, 3a-H), 2.72 (1H, dd, J 12.8 & 8.8, 3b-H), 2.96 (1H,

m, 7-H), 3.99 (1H, dd, J 11.5 & 10.4, 6b-H), 4.18 (1H, dd, J 11.5

† CCDC reference numbers 213558 and 213559. See http://

www.rsc.org/suppdata/ob/b3/b307077h/ for crystallographic data in .cif

or other electronic format.

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& 3.3, 6a-H), 4.60 (1H, dd, J 8.8 & 8.8, 2-H); δ_C(67.5 MHz)

14.4 (7-Me), 25.1 (3a-Me), 27.4 (COMe), 41.1 (3-C), 54.5 (7-C),

69.5 (3a-C), 70.0 (6-C), 81.7 (2-C), 171.3 (4-C), 205.7 (COMe).

NOEDS results: irradiation of 2-H caused 6.8% enhancement

on 3a-H, 3.1% on 3a-Me and 2.2% on 7-Me. Irradiation of

3a-Me caused an enhancement on 2-H (2.1%) and 7-Me (1.1%).

Irradiation of 7-H caused 2.1% enhancement on 3b-H, 3.4% on

6a-H and 8.6% on 7-Me. Irradiation of 3a-H caused an

enhancement on 2-H (5.0%), 3b-H (10.9%) and 3a-Me (7.4%).

17c Colourless needles, mp 92–93 ЊC (CHCl₃, hexane)

(Found: C, 56.30; H, 7.09; N, 6.49. C₁₀H₁₅NO₄requires: C,

56.34; H, 7.04; N, 6.57%); δ_H(270 MHz) 1.29 (3H, d, J 6.6,

7-Me), 1.55 (3H, s, 3a-Me), 2.16 (3H, s, COMe), 2.53 (1H, dd,

J 13.6 & 9.9, 3b-H), 2.85 (1H, dd, J 13.6 & 6.5, 3a-H), 3.53 (1H,

m, 7-H), 4.25 (1H, dd, J 11.3 & 4.4, 6a-H), 4.39 (1H, dd, J 9.1 &

6.6, 2-H), 4.83 (1H, dd, J 11.3 & 11.3, 6b-H); δ_C(67.5 MHz)

14.7 (7-Me), 22.8 (3a-Me), 26.3 (COMe), 44.0 (3-C), 49.6 (7-C),

66.6 (3a-C), 69.2 (6-C), 79.4 (2-C), 172.8 (4-C), 205.6 (COMe).

NOEDS results: irradiation of 7-H caused 2.3% enhancement

on 3a-Me, 2.3% on 6b-H, 1.8% on 6a-H and 10.9% on 7-Me.

Irradiation of 3a-Me caused 1.7% enhancement on 3b-H and

2.4% on 6b-H. Irradiation of 3a-H caused 13.1% enhancement

on its partner 3b-H and 4.6% on 2-H. Irradiation of 3b-H

caused an enhancement on 2-H (2.3%), 3a-H (19.1%) and

3a-Me (4.1%).

NOEDS results: irradiation of 3a-H caused the following

enhancements 3a-Ph (7.8%), 3b-H (24.5%), 2-H (6.4%). Irradi-

ation of 3b-H caused 2.7% enhancement on 7-H and 20.9% on

3a-H. Irradiation of 7-H caused 1.7% enhancement on 3b-H,

4.4% on 7-Me and 3.5% on 6a-H.

2-Methyloxycarbonyl-6-tert-butyl-2,3,6,7-tetrahydro-7-

methyl-3a-phenyl-3aH-isoxazolo[3,2-c][1,4]oxazin-4-one

19.

Freshly recrystallised nitrone 1g (0.21 g, 0.81 mmol), methyl

acrylate (2.25 cm³, 2.15 g, 25.00 mmol) and hydroquinone

(0.10% ^w/_v, 0.03 g) were stirred in toluene (30 cm³) at reﬂux

under N₂for 110 h (using a double sided water condenser). The

reaction mixture was allowed to cool to rt, both the reaction

solvent and excess dipolarophile were removed under reduced

pressure (100 ЊC, 0.50 mmHg). The highly viscous residue was

taken up in chloroform and allowed to stand at rt for 0.5 h, the

precipitated hydroquinone material was ﬁltered oﬀ in vacuo and

the ﬁltrate was concentrated. Puriﬁcation of the crude mixture

by ﬂash chromatography (Et₂O : petroleum ether, 1 : 2) yielded

19 as a highly viscous colourless oil (0.19 g, 68%), unchanged

dipole was returned (0.05 g, 24%).

19 Bp 90–94 ЊC, 0.025 mmHg (Found: C, 65.86; H, 7.28; N,

3.89. C₁₉H₂₅NO₅requires: C, 65.71; H, 7.21; N, 4.04%); δ_H(270

MHz) 1.01 (9H, s, Me₃C), 1.42 (3H, d, J 5.9, Me), 2.93 (1H, dd,

J 13.2 & 8.1, 3b-H), 3.38 (1H, dd, J 13.2 & 7.3, 3a-H), 3.52 (1H,

m, 7-H), 3.58 (d, 1H, J 11.0, 6-H), 3.77 (3H, s, OMe), 4.51 (1H,

dd, J 8.1 & 7.3, 2-H), 7.35 (3H, m, ArH), 7.28 (2H, ArH);

δ_C(67.5 MHz) 18.1 (Me), 26.6 (3 × Me), 34.5 (CMe₃), 46.7 (3-

C), 52.5 (OMe), 60.4 (7-C), 68.6 (6-C), 75.2 (3a-C), 86.8 (2-C),

138.5–126. (4 × ArC), 170.5 (CO₂Me), 171.3 (4-C). NOEDS

results: irradiation of the signal representing the CMe₃protons

caused the following enhancements 2.1% on 2-H, 1.2% on

3a-H, 7.4% on 7-H and 1.2% on o-ArH. Irradiation of 7-Me

caused an enhancement on 7-H (10.4%), on 6-H (2.3%) and

7.4% on o-ArH. Irradiation of 2-H caused 5.9% enhancement

on 3b-H and 4.2% on CMe₃. Irradiation of 3a-H caused an

enhancement on 3b-H (32.1%) and ArH (6.2%).

2-Acetyl-7-methyl-3a-phenyltetrahydroisoxazolo[3,2-c][1,4]-

oxazine-4(2H)-ones 18a–d. Nitrone 1b (0.30 g, 1.46 mmol) and

methyl vinyl ketone (3.26 g, 46.5 mmol) were stirred in toluene

w

(50 cm³) in the presence of hydroquinone (0.1%, /_v, 0.05 g) at

reﬂux under N₂for 100 h (using a double sided water con-

denser). The mixture was allowed to cool to rt and the solvent

and excess dipolarophile were removed under reduced pressure

leaving a viscous brown oil which was taken up in CHCl₃and

allowed to stand at rt for 0.5 h. The precipitated hydroquinone

was removed by ﬁltration with suction and the ﬁltrate concen-

trated, yielding the crude product. ¹H NMR analysis of

the crude reaction mixture indicated a 33 : 6 : 4 : 2 mixture of

18a : 18b : 18c : 18d. Puriﬁcation by ﬂash chromatography

(Et₂O–petroleum ether; 1 : 4), aﬀorded, as enriched mixtures,

18d (0.006 g, 2%), 18c (0.030 g, 7%), 18b (0.047 g, 12%) and as a

pure sample, 18a (0.269 g, 67%).

Methyl 3a-methyl-7-phenyl-4-oxohexahydroisoxazolo[3,2-c]-

[1,4]oxazine-2-carboxylates 20a & 20b. Freshly recrystallised

nitrone 1b (1.12 g, 5.50 mmol), methyl acrylate (15 cm³, 14.34 g,

w

0.17 mol) and hydroquinone (0.10% /_v, 0.20 g) were stirred in

18d δ_H(400 MHz) 1.23 (3H, d, J 6.3, 7-Me), 1.75 (3H, s,

COMe), 3.41 (1H, m, 7-H), 3.63 (1H, dd, J 12.0 and 11.7, 6b-

H), 4.04 (2H, m, 3-H/6a-H), 4.36 (1H, dd, J 9.0 and 8.3, 3-H),

4.47 (1H, dd, J 8.3 and 7.2, 2-H), 7.36 (3H, m, o- & p-ArH),

7.54 (2H, m, m-ArH).

18c A colourless, mobile oil. δ_H(400 MHz) 1.26 (3H, d, J 6.8,

7-Me), 2.23 (3H, s, COMe), 2.85 (1H, dd, J 13.4 and 10.1, 3-H),

3.25 (1H, dd, J 13.4 and 6.1, 3-H), 3.48 (1H, m, 7-H), 4.28 (1H,

dd, J 11.4 and 4.9, 6a-H), 4.62 (1H, dd, J 10.1 and 6.1, 2-H),

4.85 (1H, dd, J 11.5 and 11.4, 6b-H), 7.35 (3H, m, o- & p-ArH),

7.52 (2H, m, m-ArH).

toluene (200 cm³) at reﬂux under N₂for 110 h (using a double

sided water condenser). The reaction mixture was allowed to

cool to rt, and the reaction solvent and excess dipolarophile

were removed under reduced pressure (100 ЊC, 0.50 mmHg).

The highly viscous residue was taken up in CHCl₃and allowed

to stand at rt for 0.5 h, the precipitated hydroquinone was ﬁl-

tered oﬀ in vacuo and the ﬁltrate was concentrated. Puriﬁcation

of the crude products by ﬂash chromatography (Et₂O : petrol-

eum ether, 1.0 : 1.3) yielded 20a (1.06 g, 67%) and 20b (0.35 g,

22%) both as highly viscous colourless oils, unreacted dipole

(0.08 g, 7%) was returned.

18b A colourless mobile oil. δ_H(400 MHz) 1.32 (3H, d, J 6.4,

Me), 2.23 (3H, s, COMe), 2.79 (1H, dd, J 4.2 and 13.3, 3-H),

3.52 (1H, m, 7-H), 3.56 (1H, dd, J 9.2 and 13.3, 3-H), 3.80 (1H,

dd, J 11.7 and 11.7, 6b-H), 4.15 (1H, dd, J 4.2 and 11.7, 6a-H),

4.38 (1H, dd, J 4.2 and 9.2, 2-H), 7.33 (3H, m, o- & p-ArH),

7.53 (2H, m, m-ArH).

18a A colourless mobile oil (Found: C, 65.39; H, 6.09; N,

5.01. C₁₅H₁₇NO₄requires: C, 65.46; H, 6.18; N, 5.09%); δ_H(400

MHz) 1.32 (3H, d, J 6.4, 7-Me), 2.22 (3H, s, COMe), 2.93 (1H,

dd, J 7.8 and 13.1, 3a-H), 3.15 (1H, dd, J 9.1 and 13.1, 3b-H),

3.40 (1H, m, 7-H), 3.91 (1H, dd, J 11.6 and 11.2, 6b-H), 4.13

(1H, dd, J 11.6 and 3.7, 6a-H), 4.35 (1H, dd, J 7.8 and 9.1, 2-H),

7.34 (3H, m, o- & p-ArH), 7.74 (2H, m, m-ArH); δ_C(100 MHz)

15.43 (ϩve) (7-Me), 26.73 (ϩve) (COMe), 44.01 (Ϫve) (3-C),

56.49 (ϩve) (7-C), 69.40 (Ϫve) (6-C), 73.99 (abs.) (3a-C), 81.33

(ϩve) (2-C), 126.55, 128.50, 128.76 (ϩve) (5 × ArC), 138.40

20a Bp 154–156 ЊC, 0.03 mmHg (Found: C, 61.82; H, 5.80; N,

4.79. C₁₅H₁₇NO₅requires: C, 61.86; H, 5.84; N, 4.81%); δ_H(270

MHz) 1.35 (3H, d, J 5.9, Me), 3.13 (1H, dd, J 13.2 & 8.1, 3b-H),

3.25 (1H, dd, J 13.2 & 8.1, 3a-H), 3.63 (1H, m, 7-H), 3.76 (3H,

s, OMe), 3.96 (1H, dd, J 11.5 & 11.0, 6b-H), 4.16 (1H, dd, J 11.5

& 3.3, 6a-H), 4.40 (1H, dd, J 8.1 & 8.1, 2-H), 7.36 (3H, m,

ArH), 7.77 (2H, d, ArH); δ_C(67.5 MHz) 15.1 (Me), 45.4 (OMe),

56.2 (7-C), 52.56 (3-C), 69.7 (6-C), 74.2 (3a-C), 75.6 (2-C),

138.4–126.7 (4 × Ar–C), 169.9 (CO₂Me), 171.5 (4-C). NOEDS

results: irradiation of 2-H caused 6.7% enhancement on 3a-H

and 2.4% on ArH. Irradiation of 3a-H caused an enhancement

on 2-H (2.3%), 3b-H (8.5%) and ArH (3.9%). Irradiation of Me

caused the following enhancements 6b-H (6.5%), 6a-H (4.1%),

7-H (15.2%) and ArH (1.1%). Irradiation of 6b-H caused

14.6% enhancement on 6a-H, 6.8% on 7-H and 2.5% on ArH.

20b (Found: C, 61.99; H, 5.72; N, 4.96. C₁₅H₁₇NO₅requires:

C, 61.86; H, 5.84; N, 4.81%); δ_H(270 MHz) 1.31 (3H, d, J 6.6,

(abs.) (n-ArC), 170.24 (abs.) (C᎐O), 205.44 (abs.) (COMe).

᎐

O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 0 2 – 4 3 1 6

4314

View Article Online

Me), 2.90 (1H, dd, J 13.2 & 5.1, 3-H), 3.45 (1H, m, 7-H), 3.57

(1H, m, 3-H), 3.61 (3H, s, OMe), 3.82 (1H, dd, J 11.7 & 11.0,

6b-H), 4.11 (1H, dd, J 11.7 & 3.7, 6a-H), 4.64 (1H, dd, J 8.8 &

5.1, 2-H), 7.34 (3H, m, ArH), 7.65 (2H, d, ArH); δ_C(67.5 MHz)

16.0 (Me), 46.0 (OMe), 52.3 (3-C), 56.8 (7-C), 68.7 (6-C), 73.6

(3a-C), 74.5 (2-C), 138.1–126.4 (4 × Ar–C), 169.7 (CO₂Me),

170.6 (4-C).

chromatography (Et₂O–petroleum ether,

unreacted dipole and the adduct 23 (0.0704 g, 45%) together

with a complex mixture of compounds.

23, A viscous yellow oil, R_f0.2 (Et₂O). δ_H(400 MHz) 1.38

(3H, d, J 7.6, Me), 3.60 (1H, quintet, J 7.3, CH-Se), 3.78, 3.86,

3.91 (3 × 3H, 3 × s, 3 × OMe), 4.61 (1H, dd, J 12.5 and 2.7,

4-H), 5.03 (1H, d, J 12.7, 3a-H), 5.21 (1H, dd, J 8.3 and 2.9,

3b-H), 7.30 (3H, m, o- & p-ArH), 7.47 (2H, m, 2 × m-ArH),

δ_C(100 MHz) 19.23 (CH₃), 39.01 (CH-Se), 39.10 (4-C), 52.69

1

:

1) returned

Methyl 3a,7-dimethyl-4-oxohexahydroisoxazolo[3,2-c][1,4]-

oxazine-2-carboxylates 21a, 21b & 21c. Nitrone 1a (0.27 g;

1.9 mmol) and methyl acrylate (2.88 g; 33.5 mmol) were stirred

in toluene (100 cm³) in the presence of hydroquinone (0.1% ^w/_v,

0.1 g) at reﬂux under N₂for 45 h (using a double sided water

condenser). The reaction mixture was allowed to cool to rt and

was concentrated under reduced pressure leaving a brown

gummy residue, which was taken up by CHCl₃(5 cm³) and

allowed to stand at rt for 0.5 h, the precipitated hydroquinone

was removed by ﬁltration with suction and the ﬁltrate concen-

trated. Puriﬁcation by ﬂash chromatography (Et₂O–petroleum

ether, 1.5 : 1.0), aﬀorded 21a (0.169 g, 39%), 21b (0.105 g, 25%),

21c (0.029 g, 7%) and returned dipole (0.097 g, 36%).

(2 × OMe), 57.10 (OMe), 67.63 (3-C), 120.88 (C᎐N), 122.15,

123.68, 127.24 (6-C, 7-C, 8-C), 128.43, 129.24, 135.10 (ArC),

᎐

155.10, 159.51, 162.40, 163.42 (3 × CO Me and C᎐O); m/z 495

᎐

2

(M ϩ 1), 493, 306, 236, 184 (CH(CH₃)SePh), 182, 156, 105.

Acknowledgements

We thank the National University of Ireland, Maynooth and

the National University of Ireland, Galway for support of this

work and Cork County V.E.C. and Enterprise Ireland for

student grants (C. O. M., J. F.).

21a Colourless needles, mp 90–93 ЊC (from Et₂O–hexane)

(Found: C, 52.58; H, 6.73; N, 6.09. C₁₀H₁₅NO₅requires: C,

52.43; H, 6.55; N, 6.11%); δ_H(400 MHz) 1.26 (3H, d, J 6.1,

7-Me), 1.57 (3H, s, 3a-Me), 2.76 (2H, d, J 8.6, 3a-H/3b-H), 3.23

(1H, m, 7-H), 3.78 (3H, s, OMe), 4.02 (1H, dd, J 11.4 and 10.7,

6b-H), 4.20 (1H, dd, J 11.4 and 3.2, 6a-H), 4.62 (1H, t, J 8.6,

2-H); δ_H(C₆D₆, 400 MHz) 0.97 (3H, d, J 6.1, 7-Me), 1.37 (3H, s,

3a-Me), 2.22 (1H, dd, J 12.9 and 8.7, 3a-H), 2.43 (1H, dd, J 12.9

and 8.7, 3b-H), 2.84 (1H, m, 7-H), 3.21 (3H, s, OMe), 3.38 (2H,

m, 6a/6b-H), 4.10 (1H, t, J 8.7, 2-H); δ_C(C₆D₆, 100 MHz) 14.22

(7-Me), 24.84 (3a-Me), 43.44 (3-C), 51.84 (OMe), 54.30 (7-C),

69.76 (3a-C), 70.01 (6-C), 75.79 (2-C), 170.43 and 172.21

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᎐

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3a-Me caused the following enhancements 3a-H (1.5%) and

2-H (1.0%). Irradiation of 7-H caused 1.7% enhancement on

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᎐

2

irradiation of 2-H caused 4.1% enhancement on 3b-H and 3.6%

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ether). Microanalytical data and ¹³C NMR spectral data were

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(7-C), 68.93 (6-C), 72.63 (3a-C), 170.71 and 172.45 (CO₂Me

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᎐

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4316

Article Doi

α-Oximono-esters as precursors to heterocycles - generation of oxazinone N-oxides and cycloaddition to alkene dipolarophiles

DOI: 10.1039/b307077h

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