Regioselective 1,3-dipolar cycloaddition reactions of 4-methylene-2- oxazolidinones with benzonitrile oxide

Article abstract of DOI:10.1071/CH08111

Substituted 4-methylene-2-oxazolidinones were prepared in two steps by cyclizing O-propargyl carbamates, which in turn were prepared from propargyl alcohols and phenyl isocyanate. The 4-methylene-2-oxazolidinones underwent a 1,3-dipolar cycloaddition reac

Full text of DOI:10.1071/CH08111

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2008, 61, 432–437
www.publish.csiro.au/journals/ajc
Regioselective 1,3-Dipolar Cycloaddition Reactions of
4-Methylene-2-oxazolidinones with Benzonitrile Oxide
Rebecca NewtonA and G. Paul SavageA,B
ACSIRO Molecular and Health Technologies, Private Bag 10, Clayton South MDC, VIC 3169, Australia.
BCorresponding author. Email: paul.savage@csiro.au
Substituted 4-methylene-2-oxazolidinones were prepared in two steps by cyclizing O-propargyl carbamates, which in turn
were prepared from propargyl alcohols and phenyl isocyanate.The 4-methylene-2-oxazolidinones underwent a 1,3-dipolar
cycloaddition reaction with benzonitrile oxide to give the corresponding spiro heterocycles. Where the substitution pattern
on the oxazolidinone engendered facial asymmetry, the cycloadditon reaction proceeded with 5:1 selectivity for the less
hindered face of the dipolarophile.
Manuscript received: 19 March 2008.
Final version: 5 May 2008.
Introduction
carbonate.[16] Nitrile oxide generation can be carried out in
THF, dichloromethane, diethyl ether, or other aprotic solvents.
Benzohydroximoyl chloride can be conveniently prepared from
commercially available benzaldehyde oxime by treatment with
N-chlorosuccinimide.[17]
The 1,3-dipolar cycloaddition reaction of nitrile oxides with car-
bon dipolarophiles is a versatile and powerful synthetic method
to prepare ꢀ2-isoxazolines and isoxazoles, which in turn are use-
ful precursors to β-hydroxy ketones, β-amino alcohols, 1,3-diols,
and a range of other 1,3-disubstituted compounds.[1] We have
been interested in controlling the stereochemistry and regio-
chemistry of cycloaddition,[2,3] inhibiting the competing side
reaction of nitrile oxide dimerization,[3,4] novel methods of ring-
opening isoxazole cycloaddition products,[5–7] and subsequent
reactions on the ring-opened products.[8] In particular, we have
explored nitrile oxide cycloaddition reactions with exocyclic
methylene compounds, which lead to novel spiro heterocyclic
compounds (Scheme 1).[9–11]
Despite their ease of formation, and reported biological
activity,[12,13] substituted 4-methylene-2-oxazolidinones have
received relatively little attention in the literature. In particular,
there are no reports in the literature of nitrile oxide cycloaddition
reactions with 4-methylene-2-oxazolidinones, and the expected
spiro heterocyclic ring system is quite rare. There is one report
of nitrone cycloadditions to 4-methylene-2-oxazolidinones,[14]
and a single report of a nitrile oxide cycloaddition to a
related, if rather obscure, allene oxazolidinone derivative.[15] We
now describe the nitrile oxide cycloaddition of 4-methylene-2-
oxazolidinones to generate 1,8-dioxa-2,6-diazaspiro[4.4]non-2-
en-7-one systems.
Propargylalcoholsreactwithisocyanatestogive O-propargyl
carbamates, which in turn can undergo base-promoted cycliza-
tion. The direct, one-pot reaction to give 4-methylene-2-
oxazolidinones has long been established for some specific
analogues.[18–20] However, these reported procedures, gener-
ally catalyzed by sodium methoxide or pyridine, are extremely
exothermic and not well defined. Yields are moderate to poor
in most cases. A more recent report describes the addition
of a stoichiometric quantity of triethylamine to a solution of
the appropriate alcohol and phenylisocyanate in THF at room
temperature, to give improved yields of the oxazolidinones.[21]
However, although this procedure was satisfactory for propar-
gyl alcohol and monosubstituted derivatives, it is limited in that
disubstituted propargyl alcohols give poor yields and products
that are difficult to purify. In our hands, the most reliable proce-
dure for preparing disubstituted 4-methylene-2-oxazolidinones
was a two-step procedure, isolating the O-propargyl carbamate
intermediates.
Propargyl alcohols 1a–g were converted to the correspond-
ing phenyl carbamates 2a–g using a modification of literature
procedures,[21,22] whereby the alcohol was reacted with phenyl
isocyanate at room temperature in THF with an equivalent of
triethylamine and a catalytic amount of dimethylaminopyridine
(DMAP) (Scheme 2). Yields were very good to quantitative
(Table 1), and in most cases the unpurified products could be
used for the next step.
Results and Discussion
The most convenient precursors to nitrile oxides are the cor-
responding hydroximoyl chlorides, which eliminate HCl on
treatment with mild bases such as triethylamine and sodium
A recent publication reports rapid and efficient cyclization
of carbamates 2 to the requisite oxazolidinones 3 under mild
conditions (10 mol-% LiOH in DMF).[23] Under these condi-
tions, cyclization of 2a and 2b was very facile, as reported.
Althoughthereportdidnotincludecyclizationofanycarbamates
derived from tertiary alcohols, we found that carbamates 2c–g
also underwent cyclization, albeit somewhat more sluggishly.
N
O
ϩ
N
Ϫ
O
R
C
R
Scheme 1.
© CSIRO 2008
10.1071/CH08111
0004-9425/08/060432

Reactions of 4-Methylene-2-oxazolidinones with Benzonitrile Oxide
433
R2
R2
R1
Table 2. Yields of cycloaddition reactions
R1
R2
(i)
(ii)
H
N
R1
N
O
O
Ph
Entry
R1
R2
Yield of spiro
Ph
OH
cycloadduct 6
O
O
1
2
3
a
b
c
d
e
f
H
H
Me
H
Et
Me
86%
75%A
64%
(i) PhNCO, Et3N, DMAP (0.12 eq), THF, room temp., 90 h;
(ii) LiOH·H2O (0.1 eq), DMF, room temp., 1–90 h
—(CH2)4—
—(CH2)5—
63%
50%
58%B
53%C
Scheme 2.
Me
Me
Et
Ph
g
Table 1. Yields of carbamates 2 and oxazolidinone 3 formation
AMixture of anti and syn addition products, 4.4:1.
BMixture of anti and syn addition products, 5:1.
CMixture of anti and syn addition products, 5:1.
Entry
R1
R2
Yield of carbamate 2 Yield of oxazolidinone 3
a
b
c
d
e
f
H
H
H
Et
Me
100%
84%
88%
90%
94%
100%
100%
80%
Me
—(CH2)4—
—(CH2)5—
Me
Me
R2
R2
CH3
OH
N
89%
Et3N
ϩ
100%
100%
74%
N
N
O
O
Cl
Ph
Ph
Et
Ph
92%
100%
O
O
g
3a R2 ϭ H
3b R2 ϭ Et
7a R2 ϭ H
7b R2 ϭ Et
5
OH
OH
N
N
Scheme 4.
(i)
H
Cl
In the case of cycloaddition reactions with oxazolidinones
3a and 3b, where R1 = H, the order of reagent addition was
critical.Typically, withnitrileoxidecycloadditionreactions, base
is added to a preformed mixture of hydroximoyl chloride and
the cycloaddition substrate.[1] However, when triethylamine was
added to a solution of benzohydroximoyl chloride and oxazolidi-
nones 3a or 3b, acid-catalyzed isomerization of the exocyclic
double bond to give the endo-isomers 7a, b was observed
(Scheme 4). The resulting tri- or tetra-substituted double bonds
were resistant to cycloaddition through steric hindrance. Adding
benzohydroximoylchlorideslowlytoasolutionofoxazolidinone
containing a slight excess of triethylamine ensured the reaction
medium was basic throughout, thereby circumventing unwanted
isomerization.
N
R2
R1
O
Ph
5
4
(ii)
N
O
Ph
R2
O
R1
6
N
O
Ph
O
3
(i) NCS, DMF;
(ii) triethylamine, dichloromethane, 0°C room temp. over 16 h, aqueous
workup
Scheme 3.
Theyieldofcycloadductsdropsoffsignificantlyasstericbulk
at the 5-position increases. We have previously observed that the
stereochemical course of nitrile oxide cycloaddition reactions
can be especially sensitive to steric influences.[10,11] In the three
dipolarophile substrates (3b, 3f, and 3g), facial asymmetry gives
rise to potential diastereomers. In all three cases, a selectivity of
∼5:1 was observed. Not surprisingly, the major diastereomer
formed from approach of the nitrile oxide to the least hindered
face. This was established by nuclear Overhauser enhancement
spectroscopy (NOESY). Dipolar couplings observed between
the methylene protons of the isoxazoline ring and the substituent
on the oxazolidinone served to ascertain the relative stereochem-
istry of the system. In the cases of isoxazolines 6b and 6g, single
crystal X-ray structures were also obtained to confirm the rel-
ative stereochemistry of the cycloaddition adducts (Fig. 1 and
Fig. 2, respectively).
Whereas unhindered carbamates 2a and 2b cyclized within 1 h
at room temperature, the more hindered derivatives 2c–g took
up to 90 h to cyclize. After modifying the reported procedure
to incorporate an aqueous workup, oxazolidinones 2a–g were
prepared in excellent yields (Scheme 2).
Benzaldehyde oxime 4 was converted to benzohydroxi-
moyl chloride 5 with N-chlorosuccinimide in DMF, according
to the literature procedure.[17] Benzonitrile oxide, generated
in situ by treating benzohydroximoyl chloride with triethyl-
amine in either THF or dichloromethane, reacted with oxazo-
lidinones 3a–g to give the corresponding spiro cycloadducts
(Scheme 3). The yields were similar with either solvent; how-
ever, dichloromethane led to an easier workup (Table 2). In each
case, the cycloaddition was regiospecific, in that the oxygen of
the nitrile oxide became attached to the disubstituted end of the
double bond.[1] This was established by observing the 1H NMR
chemical shifts for the methylene protons of the newly formed
isoxazoline rings. In each case, the characteristic AB system
of these diastereotopic protons fell in the range of 3.0–3.5 ppm,
which is indicative of protons on C4 of the isoxazoline ring rather
than C5(4.5–5.0 ppm),[11] hence establishing theregiochemistry
of cycloaddition as shown (Scheme 3).
Conclusion
Substituted 4-methylene-2-oxazolidinones have been shown
to readily undergo 1,3-dipolar cycloaddition reactions with
benzonitrile oxide to give the corresponding 1,8-dioxa-2,6-
diazaspiro[4.4]non-2-en-7-one systems with complete regio-
selectivity. In the cases where the dipolarophile exhibited facial

434
R. Newton and G. P. Savage
General Method of Carbamate Synthesis
O(2)
C(1)
Phenyl isocyanate (1.3 mL, 12 mmol) was added to a solu-
tion of the appropriate acetylenic alcohol 1a–g (10 mmol),
triethylamine (2.1 mL, 15 mmol) and N,N-dimethylamino-
pyridine (146 mg, 1.2 mmol) in THF (10 mL) at room tempera-
ture.The reaction mixture was stirred for 90 h before adding 2 M
HCl (25 mL) and extracting with EtOAc (3 × 25 mL). The com-
bined organic phases were washed with saturated NaCl (25 mL),
dried (MgSO4), filtered, and concentrated under reduced pres-
sure to return the crude product.[21,22] The crude products were
sufficiently pure for subsequent cyclization reactions, but they
could be purified by either recrystallization or flash column
chromatography.
N(1)
O(3)
C(4)
O(1)
C(2)
N(2)
C(3)
C(5)
Prop-2-ynyl Phenylcarbamate 2a
Prepared on a 20-mmol scale to give carbamate 2a (3.50 g,
100%) as a pale yellow solid, which was purified by flash
column chromatography, eluting with 9:1 petrol/EtOAc, mp
60.6–61.8◦C (lit.[23,24] 62◦C), δH (400 MHz, CDCl3) 7.41–7.06
(6H, m, Ar and NH), 4.78 (2H, d, J 2.3, CH2) and 2.52 (1H, t,
J 2.3, CH). δC (100 MHz, CDCl3) 152.7 (C=O), 137.5 (ArC),
129.1, 123.8, 118.9 (ArCH), 77.9 (C), 75.1 (CH) and 52.8 (CH2).
Fig. 1. Molecular diagram of (5S∗,9S∗)-9-ethyl-3,6-diphenyl-1,8-dioxa-
2,6-diazaspiro[4.4]non-2-en-7-one 6b, shown with 50% thermal ellipsoids
and hydrogen atoms as spheres of arbitrary size. The molecule crystallizes
in a centrosymmetric space group (P21/c), which means that the inverted
structure is also present in the crystal.
O(2)
C(1)
Pent-1-yn-3-yl Phenylcarbamate 2b
Prepared on a 20-mmol scale to give carbamate 2b (3.43 g, 84%)
as a pale yellow oil that very slowly solidified, and was subse-
quently purified by flash column chromatography, eluting with
9:1 petrol/EtOAc, mp 46.6–48.2◦C. δH (400 MHz, CDCl3) 7.40–
7.29 (4H, m, Ar), 7.07 (1H, t, J 7.3, Ar), 6.71 (1H, br s, NH),
5.37 (1H, dt, J 2.0 and 6.4, CH2CH), 2.49 (1H, d, J 2.0, C≡CH),
1.86 (2H, p, J 7.2, CH3CH2CH) and 1.07 (3H, t, J 7.4, CH3).
δC (100 MHz, CDCl3) 152.5 (C=O), 137.7 (ArC), 129.2, 123.8,
118.8 (ArCH), 81.3 (C), 74.0 (C≡CH), 66.1 (CH2CH), 28.2
(CH3CH2) and 9.3 (CH3CH2). Compound 2b is referred to in a
table in one literature reference[21] but no details are recorded in
the experimental section.
N(1)
O(1)
C(2)
O(3)
N(2)
C(3)
C(4) C(5)
Fig. 2. Molecular diagram of (5S∗,9S∗)-9-methyl-3,6,9-triphenyl-1,8-
dioxa-2,6-diazaspiro[4.4]non-2-ene-7-one 6g, shown with 50% thermal
ellipsoids and hydrogen atoms as spheres of arbitrary size. The molecule
crystallizes in a centrosymmetric space group (P21/c), which means that the
inverted structure is also present in the crystal.
2-Methylbut-3-yn-2-yl Phenylcarbamate 2c
Prepared on a 10-mmol scale and purified by flash column chro-
matography, eluting with 9:1 petrol/EtOAc to return carbamate
2c (1.78 g, 88%) as a pale yellow solid, which was recrystal-
lized from toluene to give colourless needles, mp 102◦C (lit.[24]
102–103◦C). δH (200 MHz, CDCl3) 7.42–7.24 (4H, m,Ar), 7.05
(1H, t, J 7.2, Ar), 6.63 (1H, br s, NH), 2.58 (1H, s, C≡CH)
and 1.75 (6H, s, 2 × CH3). δC (50 MHz, CDCl3) 151.7 (C=O),
137.9 (ArC), 129.1, 123.4, 118.7 (ArCH), 84.0 (C≡CH), 72.5
(C≡CH), 72.3 ((CH3)2C) and 29.3 (2 × CH3).
asymmetry, the cycloaddition proceeded on the less-hindered
face in a diastereomeric ratio of ∼5:1.
Experimental
General
1-Ethynylcyclopentyl Phenylcarbamate 2d
For general details, see ref. [3].The Cambridge Crystallographic
Data Centre contains the supplementary crystallographic data
for the present paper. These data for (5S∗,9S∗)-9-ethyl-
3,6-diphenyl-1,8-dioxa-2,6-diazaspiro[4.4]non-2-en-7-one 6b
(CCDC 680920) and (5S∗,9S∗)-9-methyl-3,6,9-triphenyl-1,8-
dioxa-2,6-diazaspiro[4.4]non-2-ene-7-one 6g (CCDC 680921)
can be obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html (verified 12 March 2008) or from the Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44(0)1223–336033; email:
deposit@ccdc.cam.ac.uk.
Prepared on a 2.5-mmol scale to return carbamate 2d
(510 mg, 89%) as a pale yellow solid, which was recrystal-
lized from toluene to give colourless needles, mp 93.8–94.1◦C.
(Found: [M+] 229.1098. C14H15NO2 requires [M+] 229.1103).
νmax/cm−1 (CHCl3 solution, NaCl) 3300, 2960, 1710, 1601,
1531, 1443, 1316, 1229, 1048. δH (200 MHz, CDCl3) 7.41
(2H, d, J 8.0, Ar), 7.28 (2H, t, J 7.4, Ar), 7.04 (1H, t, J 7.3,
Ar), 6.67 (1H, br s, NH), 2.60 (1H, s, C≡CH), 2.42–2.10 (4H,
m, cyclopentyl (cp)) and 1.90–1.70 (4H, m, cp). δC (50 MHz,
CDCl3) 152.0 (C=O), 137.9 (ArC), 129.1, 123.4, 118.7 (ArCH),
84.4 and 80.9 (CC≡CH), 73.1 (C≡CH), 40.7 and 23.4 (cp).

Reactions of 4-Methylene-2-oxazolidinones with Benzonitrile Oxide
435
1-Ethynylcyclohexyl Phenylcarbamate 2e
(5H, m, Ar), 5.17–5.09 (1H, br m, CH2CHC=CHH), 4.22–4.19
(1H, br m, C=CHH), 4.08–4.06 (1H, br m, C=CHH), 2.06–
1.96 (1H, m, CH3CHHCH), 1.89–1.79 (1H, m, CH3CHHCH)
and 1.11 (3H, t, J 7.4, CH3). δC (100 MHz, CDCl3) 155.7
(C=O), 146.1 (C4), 134.0 (ArC), 129.7, 128.5, 127.2 (ArCH),
Prepared on a 10-mmol scale to return carbamate 2e (2.42 g,
100%) as a pale yellow solid, which was purified by flash column
chromatography, eluting with 9:1 petrol/EtOAc to give carba-
mate 2e as an off-white solid, mp 94◦C (lit.[24] 94–96◦C). δH
(200 MHz, CDCl3) 7.38 (2H, d, J 8.0, Ar), 7.27 (2H, t, J 7.4,
Ar), 7.03 (1H, t, J 7.3, Ar), 6.82 (1H, br s, NH), 2.61 (1H, s,
C≡CH), 2.25–2.15 (2H, m, cyclohexyl (cy)), 2.0–1.85 (2H, m,
cy), and 1.7–1.6 (6H, m, cy). δC (50 MHz, CDCl3) 151.5 (C=O),
138.0 (ArC), 128.9, 123.2, 118.6 (ArCH), 83.9 (C≡CH), 75.6
and 74.5 (cy C and C≡CH), 27.3, 25.1 and 22.5 (cy).
1
82.2 (=CH2), 79.6 (C5), 28.5 (CH3CH2) and 8.0 (CH3). H
NMR spectral data were in agreement with those previously
reported.[21] Theproductwasnotpurifiedfurtherduetoconcerns
over exo-endo isomerization.
5,5-Dimethyl-4-methylene-3-phenyloxazolidin-2-one 3c
Prepared on a 5-mmol scale (reaction stirred at room tem-
perature for 16 h) to return oxazolidinone 3c (1.02 g, 100%)
as a colourless solid, which was recrystallized from ethanol,
mp 119.3–122.6◦C (lit.[26] 121–123◦C). νmax/cm−1 (CHCl3
solution, NaCl disc) 1751, 1654. δH (400 MHz, CDCl3) 7.50–
7.30 (5H, m, Ar), 4.14 (1H, d, J 2.7, C=CHH), 4.04 (1H,
d, J 2.7, C=CHH) and 1.63 (6H, s, 2 × CH3). δC (100 MHz,
CDCl3) 154.6 (C=O), 152.0 (C4), 134.2 (ArC), 129.7, 128.4,
127.2 (ArCH), 82.6 (C5), 81.3 (=CH2) and 28.2 (2 × CH3).
1H NMR spectral data were in agreement with those previously
reported.[26] Oxazolidinone 3c was typically used for further
reactions without purification.
3-Methylpent-1-yn-3-yl Phenylcarbamate 2f
Prepared on a 10-mmol scale to return carbamate 2f (2.16 g,
100%) as a pale yellow solid, which was purified by flash column
chromatography, eluting with 9:1 petrol/EtOAc to give carba-
mate 2f as an off-white solid, mp 67–68◦C (lit.[25] 68–69◦C). δH
(200 MHz, CDCl3) 7.38 (2H, d, J 8.0,Ar), 7.27 (2H, t, J 7.4,Ar),
7.03 (1H, t, J 7.3, Ar), 6.71 (1H, br s, NH), 2.58 (1H, s, C≡CH),
2.04 and 1.92 (2H, m, J 7.4, CH3CH2) and 1.08 (3H, t, J 7.4,
CH3). δC (50 MHz, CDCl3) 151.6 (C=O), 137.9 (ArC), 128.9,
124.0, 118.6 (ArCH), 83.9 (C≡CH), 75.9 and 73.4 (CC≡CH),
34.6 (CH2), 26.3 (CH3), 8.5 (CH2CH3).
4-Methylene-3-phenyl-1-oxa-3-azaspiro[4.4]nonan-
2-one 3d
2-Phenylbut-3-yn-2-yl Phenylcarbamate 2g
Prepared on a 5-mmol scale to return carbamate 2g (980 mg,
74%) as a pale yellow solid, which was purified by flash column
chromatography, eluting with with 9:1 petrol/EtOAc. A sample
was recrystallized from toluene, mp 119.8–122.1◦C. (Found: C
76.8, H 5.6, N 5.4. C17H15NO2 requires C 77.0, H 5.7, N 5.3%).
δH (200 MHz, CDCl3) 7.69–7.65 (2H, m, Ar), 7.44–7.23 (7H,
m, Ar), 7.05 (1H, t, J 7.2, Ar), 6.83 (1H, br s, NH), 2.89 (1H,
s, C≡CH) and 1.98 (3H, s, CH3). δC (50 MHz, CDCl3) 151.1
(C=O), 142.3and137.8(ArC), 129.0, 128.5, 128.1, 124.9, 123.4
and 118.6 (ArCH), 83.2 and 76.0 (CC≡CH), 75.9 (C≡CH) and
32.3 (CH3).
Prepared on a 5-mmol scale (reaction stirred at room tem-
perature for 16 h) to return oxazolidinone 3d (1.15 g, 100%)
as a colourless solid, which was recrystallized from ethanol,
mp 150.8–151.0◦C. (Found: C 73.2, H 6.6, N 6.1, [M+]
229.1097. C14H15NO2 requires C 73.3, H 6.6, N 6.1%, [M+]
229.1103). νmax/cm−1 (CHCl3 solution, NaCl disc) 1760, 1648.
δH (400 MHz, CDCl3) 7.49–7.34 (5H, m, Ar), 4.15 (1H, d, J
2.8, C=CHH), 4.07 (1H, d, J 2.8, C=CHH), 2.36–2.19 (2H,
m, cp) and 2.10–1.80 (6H, m, cp). δC (50 MHz, CDCl3) 154.8
(C=O), 150.7 (C4), 134.3 (ArC), 129.6, 128.4, 127.2 (ArCH),
92.5 (C5), 81.2 (=CH2), 41.3 and 24.5 (cp). Oxazolidinone 3d
was typically used for further reactions without purification.
General Method for Cyclization to Oxazolidinones 3[23]
Lithium hydroxide monohydrate (21 mg, 0.5 mmol) was added
to a solution of the appropriate carbamate 2a–g (5.0 mmol) in
DMF (5 mL) at room temperature and the reaction stirred for
1 h (unless otherwise stated). The reaction was diluted with
water (20 mL) and extracted with diethyl ether (3 × 20 mL).
The combined organic extracts were then washed with water
(3 × 10 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure to return the oxazolidinones 3a–g.
4-Methylene-3-phenyl-1-oxa-3-azaspiro[4.5]decan-
2-one 3e
Prepared on a 10-mmol scale (reaction stirred at room temper-
ature for 16 h) and purified by flash column chromatography,
eluting with 9:1 petrol/EtOAc to return oxazolidinone 3e (1.95 g,
80%) as a pale yellow solid, which was recrystallized from
ethanol, mp 168.6–168.7◦C (lit.[18] 167–167.5◦C). (Found: C
74.0, H 7.1, N 5.8, [M+] 243.1246. C15H17NO2 requires C 74.1,
H 7.0, N 5.8%, [M+] 243.1259). νmax/cm−1 (CHCl3 solution,
NaCl disc) 1761, 1645. δH (200 MHz, CDCl3) 7.53–7.28 (5H, m,
Ar), 4.11 (1H, d, J 2.7, C=CHH), 4.00 (1H, d, J 2.7, C=CHH),
2.12–1.96 (2H, m, cy), 1.94–1.51 (7H, m, cy) and 1.47–1.16 (1H,
m, cy). δC (50 MHz, CDCl3) 154.9 (C=O), 152.0 (C4), 134.2
(ArC), 129.6, 128.4, 127.2 (ArCH), 84.3 (C5), 81.5 (=CH2),
37.2, 24.8 and 21.8 (cy).
4-Methylene-3-phenyloxazolidin-2-one 3a
Prepared on a 5-mmol scale to return oxazolidinone 3a (790 mg,
90%) as a pale yellow solid. δH (400 MHz, CDCl3) 7.50–7.33
(5H, m, Ar), 5.03 (2H, d, J 2.0, CH2C=CHH), 4.23 (1H, app.
t, J 2.5, CH2C=CHH) and 4.14 (1H, d, J 2.1, C=CHH). δC
(100 MHz, CDCl3) 156.1 (C=O), 141.9 (C4), 133.7 (ArC),
1
129.7, 128.5, 127.1 (ArCH), 82.1 (=CH2) and 67.3 (C5). H
and 13C NMR spectral data were in agreement with those pre-
viously reported.[23] The product was not purified further owing
to concerns over exo-endo isomerization.
5-Ethyl-5-methyl-4-methylene-3-phenyloxazolidin-
2-one 3f
Prepared on a 10-mmol scale (reaction stirred at room tempera-
ture for 90 h) to return oxazolidinone 3f (2.00 g, 92%) as a pale
yellow solid, which was recrystallized from ethanol, mp 80–
86◦C (lit.[24] 87–89◦C). (Found: [M+] 217.1098. C13H15NO2
requires [M+] 217.1103). νmax/cm−1 (CHCl3 solution, NaCl
5-Ethyl-4-methylene-3-phenyloxazolidin-2-one 3b
Prepared on a 5-mmol scale to return oxazolidinone 3b (960 mg,
94%) as a pale yellow solid. δH (400 MHz, CDCl3) 7.40–7.27

436
R. Newton and G. P. Savage
disc) 1751, 1645. δH (400 MHz, CDCl3) 7.49–7.31 (5H, m,
Ar), 4.16 (1H, d, J 2.7, C=CHH), 3.99 (1H, d, J 2.7, C=CHH),
1.94 (1H, dq, J 14.5 and 7.3, CH3CHH), 1.79 (1H, dq, J 14.5
and 7.3, CH3CHH), 1.59 (3H, s, CCH3) and 1.02 (3H, t, J 7.3,
CH3CH2). δC (50 MHz, CDCl3) 155.0 (C=O), 150.4 (C4), 134.2
(ArC), 129.7, 128.4, 127.2 (ArCH), 85.3 (C5), 81.4 (=CH2),
34.0 (CH2CH3), 26.7 (CCH3) and 7.5 (CH2CH3). 1H NMR
spectral data are in agreement with those previously reported.[26]
C 70.8, H 5.7, N 8.8, [M+] 322.1314. C19H18N2O3 requires C
70.8, H 5.6, N 8.7%, [M+] 322.1317). νmax/cm−1 (CHCl3 solu-
tion, NaCl disc) 1764, 1658, 1641, 1382. δH (200 MHz, CDCl3)
7.52–7.20 (10H, m, Ar), 4.79 (1H, dd, J 8.7 and 4.1, C8–H),
3.49 (1H, d, J 18.3, C4–Ha), 3.20 (1H, d, J 18.3, C4–Hb), 2.06–
1.67 (2H, m, CH3CH2CH) and 1.16 (3H, t, J 7.3, CH3CH2).
δC (50 MHz, CDCl3) 156.6 (C=N), 154.7 (C=O), 133.7 (ArC),
130.8, 129.6, 128.9, 128.7 (ArCH), 128.2 (ArC), 127.8, 126.4
(ArCH), 103.0 (C5), 83.1 (C8), 36.8 (C4), 25.1 (CH3CH2), and
9.1 (CH3).
5-Methyl-4-methylene-3,5-diphenyloxazolidin-2-one 3g
The minor diastereomer (5S*,9R*)-6b could not be isolated
from the major diastereomer and the NMR spectra were assigned
by subtraction. δH (200 MHz, CDCl3) 7.52–7.20 (10H, m, Ar),
4.53 (1H, dd, J 8.7 and 4.1, C8–H), 3.49 (1H, d, J 18.3, C4–Ha),
3.25 (1H, d, J 18.3, C4–Hb), 2.20–1.90 (2H, m, CH3CH2) and
1.16 (3H, t, J 7.3, CH3CH2). δC (50 MHz, CDCl3) 156.6 (C=N),
154.7 (C=O), 133.7 (ArC), 130.8, 129.5, 128.9, 128.8 (ArCH),
128.3 (ArC), 127.2, 126.4 (ArCH), 101.1 (C5), 85.1 (C8), 40.7
(C4), 21.8 (CH3CH2), and 10.0 (CH3).
Prepared on a 5-mmol scale (reaction stirred at room temper-
ature for 90 h) to return oxazolidinone 3g (1.33 g, 100%) as a
pale yellow solid, which was recrystallized from ethanol, mp
88.8–90.0◦C. (Found: C 76.3, H 5.8, N 5.3, [M+] 265.1103.
C17H15NO2 requires C 77.0, H 5.70, N 5.3%, [M+] 265.1103).
νmax/cm−1 (CHCl3 solution, NaCl disc) 1767, 1658. δH
(400 MHz, CDCl3) 7.61–7.35 (10H, m, Ar), 4.31 (1H, d, J 2.8,
C=CHH), 4.21 (1H, d, J 2.8, C=CHH) and 2.01 (3H, s, CH3).
δC (50 MHz, CDCl3) 154.4 (C=O), 150.7 (C4), 141.3 and 134.3
(ArC), 129.6, 128.7, 128.6, 128.4, 127.1 and 124.9 (ArCH),
84.9 (C5), 84.3 (=CH2) and 27.7 (CH3). Oxazolidinone 3g was
typically used for further reactions without purification.
9,9-Dimethyl-3,6-diphenyl-1,8-dioxa-2,6-
diazaspiro[4.4]non-2-ene-7-one 6c
Prepared on a 5.0-mmol scale and purified by flash column chro-
matography, eluting with 1% diethyl ether in dichloromethane,
gave isoxazoline 6c (1.03 g, 64%) as a colourless solid, which
was recrystallized from ethanol, mp 175.2–176.4◦C. (Found: C
70.7, H5.7, N8.8, [M+]322.1316. C19H18N2O3 requiresC70.8,
H 5.6, N 8.7%, [M+] 322.1317). νmax/cm−1 (CHCl3 solution,
NaCl disc) 1759, 1599, 1498, 1393, 1372, 1119. δH (400 MHz,
CDCl3) 7.48–7.26 (10H, m, Ar), 3.41 (1H, d, J 18.3, C4–Ha),
3.29 (1H, d, J 18.3, C4–Hb), 1.64 (3H, s, CH3) and 1.62 (3H, s,
CH3). δC (100 MHz, CDCl3) 156.1 (C=N), 155.0 (C=O), 134.2
(ArC), 130.8, 129.7, 128.9, 128.7 (ArCH), 128.3 (ArC), 127.8,
126.5 (ArCH), 104.9 (C5), 84.5 (C8), 37.1 (C4), 25.7, and 21.2
(2 × CH3).
General Method for Benzonitrile Oxide Cycloaddition
Reactions
A solution of benzhydroximoyl chloride[17] (389 mg, 2.5 mmol)
in dichloromethane (5 mL) was slowly added dropwise to a
solution of the appropriate oxazolidinone 3a–g (2.5 mmol) and
triethylamine (385 µL, 2.75 mmol) in dichloromethane (2.5 mL)
at 0◦C. The reaction mixture was allowed to warm to room
temperature and stirred for 16 h before being diluted with
dichloromethane (20 mL) and washed with HCl (2 M, 20 mL),
saturated NaHCO3 (20 mL), and saturated NaCl (20 mL). The
combined organics were dried (MgSO4), filtered, and concen-
trated under reduced pressure to return the crude product, which
was purified as stated.
3,6-Diphenyl-1,8-dioxa-2,6-diazadispiro[4.3.4.0]tridec-
2-ene-7-one 6d
3,6-Diphenyl-1,8-dioxa-2,6-diazaspiro[4.4]non-2-ene-
Prepared on a 5.0-mmol scale to return the crude product, which
was purified by flash column chromatography, eluting with
1% diethyl ether in dichloromethane to return isoxazoline 6d
(1.10 g, 63%) as a colourless solid, which was recrystallized
from ethanol, mp 175.9–176.4◦C. (Found: C 72.3, H 5.8, N 8.0,
[M+] 348.1469. C21H20N2O3 requires C 72.4, H 5.79, N 8.0%,
[M+] 348.1471). νmax/cm−1 (CHCl3 solution, NaCl disc) 1758,
1641, 1498, 1373. δH (400 MHz, CDCl3) 7.34–7.24 (10H, m,
Ar), 3.42 (1H, d, J 18.3, C4–Ha), 3.32 (1H, d, J 18.3, C4–Hb),
2.40–2.20 (1H, m, cp) and 2.15–1.70 (7H, m, cp). δC (50 MHz,
CDCl3) 156.0 (C=N), 155.1 (C=O), 134.1 (ArC), 130.7, 129.5,
128.9, 128.6 (ArCH), 128.3 (ArC), 127.8, 126.4 (ArCH), 104.5
(C5), 95.0 (C8), 37.3, 37.0, 32.6, 24.5, and 23.3 (C4 and cp).
7-one 6a
Prepared on a 2.5-mmol scale and purified by flash column chro-
matography, eluting with 4:1 → 1:1 petrol/EtOAc gradient to
return isoxazoline 6a (630 mg, 86%) as a colourless solid, which
was recrystallized from ethanol, mp 160.5–161.1◦C. (Found: C
69.2, H4.8, N9.6, [M+]294.1000. C17H14N2O3 requiresC69.4,
H 4.79, N 9.5%, [M+] 294.1004). νmax/cm−1 (CHCl3 solution,
NaCl disc) 1757, 1720, 1500, 1448, 1400, 1219. δH (400 MHz,
CDCl3) 7.48–7.26 (10H, m, Ar), 4.85 (1H, d, J 10.1, C9–Ha),
4.60 (1H, d, J 10.1, C9–Hb), 3.51 (1H, d, J 18.2, C4–Ha) and 3.37
(1H, d, J 18.2, C4–Hb). δC (125 MHz, CDCl3) 156.6 (C=N),
155.1 (C=O), 133.5 (ArC), 130.9, 129.7, 129.0, 128.7 (ArCH),
128.2 (ArC), 127.4, 126.5 (ArCH), 100.0 (C5), 73.9 (C8), and
41.0 (C4).
3,6-Diphenyl-1,8-dioxa-2,6-diazadispiro[4.3.5.0]tetradec-
2-ene-7-one 6e
(5S*,9S*)- and (5S*,9R*)-9-Ethyl-3,6-diphenyl-1,8-dioxa-
2,6-diazaspiro[4.4]non-2-en-7-one 6b
Prepared on a 5.0-mmol scale to return the crude product, which
was purified by flash column chromatography, eluting with 1%
diethyl ether in dichloromethane followed by recrystallization
fromethanoltogiveisoxazoline6e(910 mg, 50%)asacolourless
solid, mp 186.7–187.6◦C. (Found: C 72.8, H 6.2, N 7.8, [M+]
362.1618. C22H22N2O3 requires C 72.9, H 6.12, N 7.7%, [M+]
362.1630). νmax/cm−1 (CHCl3 solution, NaCl disc) 1743, 1708,
Prepared on a 2.5-mmol scale to return the crude product
(diastereomeric ratio (dr) 5:1), which was purified by flash
column chromatography, eluting with 4:1 → 1:1 petrol/EtOAc
gradient to return isoxazoline 6b (600 mg, 75%, dr 4.4:1) as
a colourless solid. Recrystallization from ethanol returned the
major diastereomer (5S*,9S*)-6b, mp 159.6–161.3◦C. (Found:

Reactions of 4-Methylene-2-oxazolidinones with Benzonitrile Oxide
437
1662, 1599, 1391. δH (400 MHz, CDCl3) 7.52–7.20 (10H, m,
Ar), 3.47 (1H, d, J 18.3, C4–Ha), 3.23 (1H, d, J 18.3, C4–Hb),
2.50–2.35 (1H, m, cy), 2.10–1.95 (1H, m, cy), 1.95–1.60 (6H,
m, cy), 1.55–1.40 (1H, m, cy) and 1.40–1.10 (1H, m, cy). δC
(50 MHz, CDCl3) 156.2 (C=N), 155.0 (C=O), 134.1 (ArC),
130.7, 129.5, 128.8, 128.7 (ArCH), 128.3 (ArC), 128.0, 126.4
(ArCH), 105.0 (C5), 85.5 (C8), 37.0, 33.9, 29.3, 24.9, 21.9, and
21.8 (C4 and cy).
Accessory Publication
The supplementary crystallographic data for the present paper
is available from the authors, or until June 2013, the Australian
Journal of Chemistry.
Acknowledgement
The authors wish to thank Craig Forsyth for the X-ray structure determina-
tions, and Karen Jarvis for technical assistance.
References
(5S*,9S*)- and (5S*,9R*)-9-Ethyl-9-methyl-3,6-diphenyl-
1,8-dioxa-2,6-diazaspiro[4.4]non-2-ene-7-one 6f
[1] C. J. Easton, C. M. M. Hughes, G. P. Savage, G. W. Simpson, Adv.
Heterocycl. Chem. 1994, 60, 261.
Prepared on a 2.5-mmol scale to return the crude product (dr
5:1), which was purified by flash column chromatography,
eluting with 4:1 → 1:1 petrol:EtOAc gradient to return isox-
azoline 6f as a colourless solid (980 mg, 58% as a mixture
of diastereomers). Recrystallization from ethanol returned the
major diastereomer (5S*,9S*)-6f as colourless crystals, mp
135.8–137.8◦C. (Found: C 71.2, H 6.0, N 8.4, [M+] 336.1467.
C20H20N2O3 requires C 71.4, H 6.0, N 8.3%, [M+] 336.1474).
νmax/cm−1 (CHCl3 solution, NaCl disc) 1757, 1599, 1498, 1371.
δH (200 MHz, CDCl3) 7.50–7.20 (10H, m, Ar), 3.45 (1H, d, J
18.2, C4–Ha), 3.24 (1H, d, J 18.2, C4–Hb), 1.95–1.73 (2H, m,
CH3CH2), 1.58 (3H, s, CH3) and 1.15 (3H, t, J 7.3, CH3CH2).
δC (50 MHz, CDCl3) 156.2 (C=N), 155.0 (C=O), 134.0, 130.6,
129.5, 128.8, 128.5, 128.3, 127.6, 126.3 (Ar), 104.6 (C5), 86.5
(C8), 37.8(C4), 31.2(CH3), 18.8(CH2CH3), and8.0(CH2CH3).
The minor diastereomer (5S*,9R*)-6f could not be isolated
from the major diastereomer and the NMR spectra were assigned
by subtraction. δH (200 MHz, CDCl3) 7.50–7.20 (10H, m, Ar),
4.16 (1H, d, J 2.8, C4–Ha), 4.00 (1H, d, J 2.8, C4–Hb), 2.20–
2.00 (2H, m, CH3CH2), 1.56 (3H, s, CH3) and 1.03 (3H, t, J 7.3,
CH3CH2). δC (50 MHz, CDCl3) 156.1 (C=N), 155.0 (C=O),
134.0, 130.7, 129.5, 128.9, 128.6, 128.2, 127.8, 126.4(Ar), 104.1
(C5), 86.5 (C8), 37.8 (C4), 27.3 (CH3), 22.0 (CH2CH3), and 8.1
(CH2CH3).
[2] C. J. Easton, C. M. M. Hughes, E. R. T. Tiekink, G. P. Savage,
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[3] C. J. Easton, C. M. M. Hughes, E. R. T. Tiekink, C. E. Lubin,
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[10] C. K.Y. Lee, C. J. Easton, G. P. Savage, G. W. Simpson, Arkivoc 2006,
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(5S*,9S*)- and (5S*,9R*)-9-Methyl-3,6,9-triphenyl-1,8-
dioxa-2,6-diazaspiro[4.4]non-2-ene-7-one 6g
Prepared on a 5.0-mmol scale to return the crude product,
which was purified by flash column chromatography, eluting
with 1% diethyl ether in dichloromethane to return isoxazoline
6g (1.01 g, 53%, dr 5:1) as a colourless solid. Recrystalliza-
tion from ethanol gave the major diastereomer (5S*,9S*)-6g, mp
161.5–162.7◦C. (Found: C 74.8, H 5.3, N 7.4, [M+] 322.1314.
C24H20N2O3 requires C 75.0, H 5.2, N 7.3%, [M+] 322.1317).
νmax/cm−1 (CHCl3 solution, NaCl disc) 1767, 1497, 1369, 1236.
δH (200 MHz, CDCl3) 7.55–7.20 (15H, m, Ar), 3.04 (1H, d, J
18.8, C4–Ha), 2.83 (1H, d, J 18.8, C4–Hb) and 2.05 (3H, s, CH3).
δC (50 MHz, CDCl3) 156.8 (C=N), 155.2 (C=O), 140.0, 133.8
(ArC), 130.7, 129.5, 129.2, 129.0, 128.8, 128.7 (ArCH), 128.0
(ArC), 127.8, 126.4, 125.2 (ArCH), 105.3 (C5), 87.2 (C8), 38.7
(C4), and 21.6 (CH3).
The minor diastereomer (5S*,9R*)-6g could not be isolated
from the major diastereomer and the NMR spectra were assigned
by subtraction. δH (200 MHz, CDCl3) 7.55–7.20 (15H, m, Ar),
3.75 (1H, d, J 18.8, C4–Ha), 3.44 (1H, d, J 18.8, C4–Hb) and 2.00
(3H, s, CH3). δC (50 MHz, CDCl3) 156.7 (C=N), 155.2 (C=O),
140.0, 133.8, 130.7, 129.6, 129.1, 129.0, 128.8, 128.6, 128.4,
127.7, 126.3, 124.9 (Ar), 105.1 (C5), 87.4 (C8), 37.7 (C4), and
25.9 (CH3).
[26] H. Martin, G. Pissiotas, O. Rohr, US Patent 3 800 037 1974.