Spiroheterocycles via regioselective cycloaddition reactions of nitrile oxides with 5-methylene-1H-pyrrol-2(5H)-ones

Article abstract of DOI:10.1071/CH09479

Substituted 5-methylene-1H-pyrrol-2(5H)-ones underwent a 1,3-dipolar cycloaddition reaction with nitrile oxides to give the corresponding spiro heterocycles. Critical to this reaction was the development of a biphasic system for base-induced dehydrohaloge

Full text of DOI:10.1071/CH09479

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2010, 63, 445–451
Spiroheterocycles via Regioselective Cycloaddition
Reactions of Nitrile Oxides with 5-Methylene-
1H-pyrrol-2(5H)-ones
Nicola J. Beattie,A Craig L. Francis,A Andris J. Liepa,A 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 5-methylene-1H-pyrrol-2(5H)-ones underwent a 1,3-dipolar cycloaddition reaction with nitrile oxides to give
the corresponding spiro heterocycles. Critical to this reaction was the development of a biphasic system for base-induced
dehydrohalogenation of hydroximoyl chlorides, to give nitrile oxides, in the presence of a base-sensitive dipolarophile. A
substituted N-tolyl 5-methylene-1H-pyrrol-2(5H)-one exhibited atropisomerism, which in turn led to a 4:1 facial selectivity
during cycloaddition.
Manuscript received: 9 September 2009.
Manuscript accepted: 21 October 2009.
R2
R2
OH
EWG
Introduction
EWG
O
EWG
O
O
O
R2
Base
Acid
Despite their seemingly simple structure, 5-methylene-1H-
pyrrol-2(5H)-ones 2 are quite uncommon in the literature. They
have been patented as remedies for diseases caused by protein
dephosphorylase,[1] and as non-steroidal ligands for modulat-
ing ecdysone receptors.[2] Pattenden and coworkers prepared
5-ylidenene-1H-pyrrol-2(5H)-ones by direct Wittig-type reac-
tions of substituted maleimides with stabilized phosphoranes
under forcing conditions.[3] Demir and coworkers reported a
synthesis of 5-methylene-1H-pyrrol-2(5H)-ones in two steps
via initial singlet oxygen oxidation of 2-methylpyrroles to give
5-hydroxy-γ-lactams 1, which eliminated water under acid con-
ditions to give 2.[4] This method is limited by side reactions and
over-oxidation.
ϩ
O
N
R1
N
R1
1
NH
R1
CH3
2
Scheme 1. EWG, electron withdrawing group.
Ar
Ar
HO
N
N
O
ArCNO
X
X
NR
O
O
O
3a X ϭ O
4a X ϭ O
4b X ϭ NR
5
3b X ϭ NR
More recently, Liepa and coworkers reported a conve-
nient base-catalyzed condensation of 1,2-diketones with acti-
vated acetamides to give substituted 5-hydroxy-γ-lactams 1.
Subsequent acid-catalyzed elimination of water from 1 gave
5-methylene-1H-pyrrol-2(5H)-ones 2 (Scheme 1).[5]
Scheme 2.
activity as herbicides and plant growth regulators.[22] The spiro
adducts 4b were sometimes accompanied by minor amounts of
E and Z oximes 5. The low solvent effects on reaction rates
and product distribution led the authors to speculate that the
oximes 5 were formed by a competitive stepwise biradical mech-
anism along with the 1,3-dipolar cycloaddition leading to spiro
adducts 4b.
Recently, the reaction mechanism for this cycloaddition and
side reaction has been studied using density functional theory
at the (U)B3LYP/6–31G* level.[23] The latter analysis led to the
conclusion that 1,3-dipolar cycloaddition reactions of benzo-
nitrile oxides with 3-methyleneisoindolinones take place along
concerted but highly asynchronous reaction pathways, while
the formation of oximes occurs through a stepwise mechanism
involving zwitterionic intermediates.
The 1,3-dipolar cycloaddition reaction[6] of nitrile oxides
with carbon dipolarophiles has continued to attract attention as
a versatile method to prepare ꢀ2-isoxazolines and isoxazoles.[7]
We have been interested in controlling the stereochemistry and
regiochemistry of cycloaddition,[8,9] inhibiting the competing
side reaction of nitrile oxide dimerization,[10,11] novel methods
of ring-opening isoxazole cycloaddition products,[12–14] and
subsequent reactions of the ring-opened products.[15] In partic-
ular, we have investigated nitrile oxide cycloaddition reactions
with exocyclic methylene compounds, which lead to novel spiro
heterocyclic systems.[16–19]
The reactivity of 5-methylene-1H-pyrrol-2(5H)-ones towards
nitrile oxides has not been reported. The related
3-methyleneisobenzofuranone3a and3-methyleneisoindolinone
3b react readily with aromatic nitrile oxides to give the
corresponding spiroheterocycles 4a and 4b, respectively
(Scheme 2).[20,21] The spiro adducts 4a were found to possess
We now describe the nitrile oxide cycloaddition of
some 5-methylene-1H-pyrrol-2(5H)-ones to generate 1-oxa-2,6-
diazaspiro[4.4]nona-2,8-dien-7-one systems.
© CSIRO 2010
10.1071/CH09479
0004-9425/10/030445

446
N. J. Beattie et al.
R1
O
O
O
CH3
CH3
CH3
OH
CH3
CH3
R1
R1
OH
NaHCO3
ϩ
Ϫ
N
R3
C
N
O
DBU
TFA
ϩ
Water/EtOAc
R1
CH3
R3 Cl
NH
R2
O
O
N
R2
N
R2
8
O
N
O
N
R1
R3
CH3
R2
6
7a–d
9a–j
O
N
R1
R2
Entry
R2
7a–d
a
b
c
d
–CN
–CN
–CN
4-Chlorophenyl
2,4-Dichlorophenyl
2-Methylphenyl
3-Chlorophenyl
Scheme 4.
with nitrile oxide dimerization products. The most convenient
and effective method for cycloaddition was found to be in situ
nitrile oxide generation in a biphasic reaction mixture. Thus,
the 5-methylene-1H-pyrrol-2(5H)-one 7 was dissolved in ethyl
acetate and mixed with an aqueous solution of sodium bicar-
bonate. Benzohydroximoyl chloride was added slowly to this
two-phase system and moderate stirring allowed enough con-
tact between the hydroximoyl chloride and the carbonate to
achieve dehydrohalogenation to the nitrile oxide 8. Cycloaddi-
tion then took place with the 5-methylene-1H-pyrrol-2(5H)-ones
to afford spiro isoxazolines 9 without the associated complica-
tion of base-induced decomposition. Dichloromethane could be
used as solvent in place of ethyl acetate with essentially the same
results.
We further found that this two-phase system could also
be used to conveniently generate the precursor hydrox-
imoyl chlorides from the corresponding aldoximes using
N-chlorosuccinimide, which could then be carried through to
the cycloadducts 9 without any isolation of intermediates.
In each case, the cycloaddition only occurred on the exo-
cyclic methylene group. Cycloaddition on the ring double bond
of the pyrrolone was deemed unlikely as tetrasubstituted double
bonds are known to react sluggishly with nitrile oxides, often to
the point of there being no reaction occurring.[7] NMR analysis
of the products, specifically the total absence of the signals due
to the exocyclic methylene protons, supported this contention.
Furthermore, the cycloaddition was regioselective in orientation
in that the oxygen of the nitrile oxide became attached to the
disubstituted end of the double bond. This was established by
3-Chlorophenylcarbamoyl
Scheme 3.
Results and Discussion
Convenient precursors to nitrile oxides are the correspond-
ing hydroximoyl chlorides, which readily eliminate HCl on
treatment with mild bases such as triethylamine or sodium
carbonate.[24] Thus, benzohydroximoyl chloride can be conve-
niently prepared from benzaldehyde oxime by treatment with
N-chlorosuccinimide.[25] Nitrile oxide generation can be car-
ried out in THF, dichloromethane, diethyl ether, or other aprotic
solvents.
5-Methylene-1H-pyrrol-2(5H)-ones 7a–d were prepared
according to the method of Liepa and coworkers.[5] Hence,
butadione was condensed with N-substituted cyanoacetamide
or N,Nꢀ-disubstituted malonamide in DMF under base cataly-
sis at room temperature. The reaction proved to be sluggish
with the reported use of morpholine or piperidine as base,
and instead a few drops of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) gave superior results. The intermediate hydroxy lac-
tams 6 underwent acid-catalyzed elimination of water when
treated with trifluoroacetic acid at room temperature to yield
5-methylene-1H-pyrrol-2(5H)-ones 7a–d (Scheme 3).
Benzaldehyde oxime was converted to benzohydroximoyl
chloride with N-chlorosuccinimide in DMF, according to the lit-
erature procedure.[25] Benzonitrile oxide was generated in situ
by treating benzohydroximoyl chloride with a slight excess of
triethylamine in either THF or dichloromethane in the pres-
ence of the dipolarophile 5-methylene-1H-pyrrol-2(5H)-ones
7a–d at 0◦C.This standard nitrile oxide cycloaddition procedure
caused the solution to immediately turn black. No cycloaddi-
tion products could be isolated and all of the pyrrolone starting
materials had decomposed. We speculated that the 5-methylene-
1H-pyrrol-2(5H)-ones were unstable to basic conditions and
indeed, treating any these pyrrolones with triethylamine in
organic solvents led to black solutions and extensive decom-
position. Using more hindered bases such as Hünig’s base also
led to decomposition.
Nitrile oxides are usually generated in the presence of
the dipolarophile to minimize the competing side reac-
tion of dimerization.[10] Nevertheless, separate generation of
benzonitrile oxide (by treating benzohydroximoyl chloride
with triethylamine, followed by careful neutralization or even
slight acidification with HCl) and subsequent reaction with
5-methylene-1H-pyrrol-2(5H)-ones did lead to cycloadducts.
The yields were poor and products were inevitably contaminated
1
observing the H chemical shifts for the methylene protons of
the newly formed isoxazoline rings. In each case, the characteris-
tic AB system of these diastereotopic protons fell in the range of
3.2–3.6 ppm, which is indicative of protons on C4 of the isoxazo-
line ring rather than C5 (4.5–5.0 ppm), [17] hence establishing the
regiochemistry of cycloaddition as shown (Scheme 4, Table 1).
In the cases of spiro isoxazolines 9a, 9b, 9d, and 9e, single-
crystal X-ray data were also obtained to confirm the structure
of the cycloaddition adducts. Representative structures for spiro
isoxazolines 9a and 9e are shown in Figs 1 and 2.
In each of the spiro heterocycles 9, the diastereotopic protons
on C4 of the isoxazoline ring appear as an AB quartet at ∼3.0–
3.6 ppm. In the case of 9e, an additional AB quartet could be
observed for isoxazoline protons ∼0.4 ppm downfield (the other
resonances were also duplicated but not so clearly resolved).
The additional isomeric spiro cycloadduct was attributed to
atropisomerism,[26] giving two rotational isomers in a ratio of
4:1. Restricted rotation around the N–tolyl bond makes this a
stereogenic axis, which leads to substantially different magnetic
environments for the isoxazoline protons depending on whether
the tolyl methyl group is above or below the pyrrole plane and

Spiroheterocycles via Regioselective Cycloaddition Reactions
447
Table 1. Yields of spiro adducts 9 (Scheme 4)
R1
R2
R3
Yield [%]
9a
9b
9c
9d
9e
9f
9g
9h
9i
CN
CN
CN
CN
4-Chlorophenyl
2,4-Dichlorophenyl
4-Chlorophenyl
2,4-Dichlorophenyl
2-Methylphenyl
3-Chlorophenyl
3-Chlorophenyl
3-Chlorophenyl
3-Chlorophenyl
3-Chlorophenyl
Ph
Ph
43
49
49
31
79
51
45
76
89
35
CO2Et
CO2Et
CO2Et
Ph
COMe
Thien-2-yl
Pyridin-2-yl
CO2Et
CN
3-Chlorophenylcarbamoyl
3-Chlorophenylcarbamoyl
3-Chlorophenylcarbamoyl
3-Chlorophenylcarbamoyl
3-Chlorophenylcarbamoyl
9j
S
CI(1)
H3C
O
C(11)
N
CH3
C(10)
C(12)
O(1)
10
Scheme 5.
C(9)
C(8)
C(7)
N(1)
C(1)
N(3)
C(4)
C(13)
C(2)
C(5)
and Gasteiger Hückel charges, and by the semi-empirical AM1
method (under vacuum) gives two minimum energy conforma-
tions with N–tolyl torsion angles of 66◦ and 75◦ with the tolyl
methyl above or below the pyrrole plane, which is consistent
with the torsional angle of 71◦ observed in the solid-state crys-
tal structure. The energy difference between these minimum
energy conformations was only 2.5 kJ mol−1. A dihedral driver
was used to vary the N–tolyl dihedral angle, while minimizing
the energy using the MM2 force field at each dihedral angle.
Using this method, the barrier to rotation was estimated to be at
least 200 kJ mol−1 with the CH3 eclipsing the pyrrole carbonyl.
The high energy barrier to rotation and the small difference
in the minimum energy conformations make it unlikely that
the 4:1 ratio of atropisomers 9e represents a thermal equilib-
rium. To explore this, we examined the 1H NMR spectra of the
atropisomeric mixture 9e in [D8]toluene at various temperatures
(25◦C, 40◦C, 55◦C, 70◦C, 85◦C, and 100◦C, and then at 25◦C
after cooling). The spectra in [D8]toluene at 25◦C before and
after heating were identical, including the ratio of atropisomers.
As the sample was heated, the signals from the diastereotopic
methylene protons, and the tolyl aromatic and methyl protons
all became broader and the separation between the major and
minor signals decreased. However, they did not coalesce even
at 100◦C, which is consistent with the high calculated barrier to
rotation.
C(16)
C(6)
C(3)
C(17)
C(15)
N(2)
O(2)
C(14)
C(18)
C(20)
C(19)
Fig. 1. Molecular diagram of 6-(4-chlorophenyl)-9-methyl-7-oxo-3-
phenyl-1-oxa-2,6-diazaspiro[4.4]nona-2,8-diene-8-carbonitrile 9a.
N(2)
C(15)
C(14)
C(3)
C(2)
O(2)
N(3)
C(4)
C(1)
O(1)
N(1)
C(7)
C(5)
C(6)
O(4)
C(16)
C(8)
C(9)
C(12)
O(3)
C(13)
C(17)
It is likely that the dipolarophile precursor, 4-methyl-5-
methylene-1-(2-methylphenyl)-2-oxo-2,5-dihydro-1H-pyrrole-
3-carbonitrile 7c also experiences restricted rotation around the
N–tolyl bond, similar to that reported for 3-(2-methylphenyl)-4-
methylthiazolin-2-one10(Scheme5)(ꢀG= = 122 kJ mol−1).[27]
Nitrile oxide cycloadditions to exocyclic methylene groups
are quite sensitive to steric control, often displaying high levels
of facial selectivity.[17,18] Cycloaddition to 7c is therefore more
likely to occur on the face opposite the methyl group, leading to
an uneven diastereomeric mix of 9e atropisomers (Scheme 6).
The crystal structure of 9e (major) is consistent with nitrile
oxide addition to the face of the pyrrole on the opposite side to
C(11)
C(10)
C(18)
Fig. 2. Molecular diagram of ethyl 8-cyano-9-methyl-7-oxo-6-(2-methyl-
phenyl)-1-oxa-2,6-diazaspiro[4.4]nona-2,8-diene-3-carboxylate 9e.
hence adjacent to, or distant from, the isoxazoline C4 protons.
The atropisomers were inseparable by TLC or HPLC under a
variety of conditions.
Examining the structure of 9e by molecular mechanics using
the Sybyl force field with default parameters (under vacuum)
1
the tolyl methyl group. Furthermore, in the H NMR spectra,
the isoxazoline protons of the major isomer resonate upfield

448
N. J. Beattie et al.
H3C
O
CN
H3C
O
CN
Ϫ
O
ϩN
H3C
CN
CH3
N
CN
O
N
N
EtO CCNO
O
O
2
EtO2C
N
N
O
N
EtO2C
EtO2C
CH3
CH3
CH3
CH3
7c
9e (major)
9e (minor)
Scheme 6.
NOESY correlations
9e (major)
9e (minor)
Fig. 3. Nuclear Overhauser effect correlation spectroscopy (NOESY) correlations for major and minor rotational isomers
of ethyl 8-cyano-9-methyl-7-oxo-6-(2-methylphenyl)-1-oxa-2,6-diazaspiro[4.4]nona-2,8-diene-3-carboxylate 9e.
from the minor isomer. This is also consistent with preferential
cycloaddition on the face opposite the tolyl methyl group, which
would find the isoxazoline methylene protons relatively shielded
by the tolyl methyl group in the product 9e (major) in comparison
with the corresponding isoxazoline methylene protons of the
minor isomer.
with complete regioselectivity. Cycloaddition to the atrop-
isomers of 4-methyl-5-methylene-1-(2-methylphenyl)-2-oxo-
2,5-dihydro-1H-pyrrole-3-carbonitrile 7c gave a 4:1 facial
selectivity leading to spiro adduct 9e, which itself exhibited
atropisomerism such that diastereomers could be clearly dis-
1
tinguished in the H NMR spectrum. To our knowledge, this
Nuclear Overhauser effect correlation spectroscopy
(NOESY) experiments were performed with the sample in both
CDCl3 and [D8]toluene. The results were similar for both sol-
vents. The major and minor atropisomers both had correlations
between one of the diastereotopic isoxazoline methylene protons
and the lactam methyl group.The NOESY spectrum of the major
isomer shows a correlation between the other diastereotopic
methylene proton and the tolyl methyl protons, whereas the
minor isomer exhibits a NOESY correlation between the other
diastereotopic methylene proton and the tolyl ortho-aromatic
proton (Fig. 3).
The diastereotopic methylene proton closer to the tolyl
methyl group resonates significantly upfield in the major iso-
mer compared with the minor isomer, suggesting shielding of
the methylene proton by the tolyl methyl group. All of these data
are consistent with an atropisomeric mixture of dipolarophile 7c
undergoing nitrile oxide cycloaddition preferentially from the
least hindered face to give rise to a 4:1 diastereomeric mixture
of atropisomers 9e.
is the first reported example of atropisomeric induction of
diastereoselectivity in nitrile oxide cycloadditions.
Experimental
General
Ethyl 2-chloro-2-(hydroxyimino)acetate was purchased from the
Aldrich Chemical Co. Melting points were determined on a
Buchi B-545 instrument and are uncorrected. Analytical TLC
was carried out on Macherey-Nagel Polygram precoated plas-
tic sheets (0.2 mm layer of silica gel with fluorescent indicator
UV254). Developed plates were visualized with either UV
light (254 nm) or a solution of 10% (w/v) phosphomolybdic
acid in ethanol followed by heating. Radial chromatography
was performed on a Harrison Research Chromatotron (Model
7924T) using 1-, 2-, or 4-mm thick silica plates (Merck sil-
1
ica gel 60 PF254 containing gypsum). H NMR spectra were
recorded at room temperature on a Bruker AV400 spectrometer
operating at 400 MHz, using CDCl3 as solvent and internal
reference unless otherwise specified. 13C NMR spectra were
recorded at room temperature on a Bruker AV400 spectrometer
operating at 100.6 MHz, using CDCl3 as solvent and internal
Conclusion
1
Substituted 5-methylene-1H-pyrrol-2(5H)-ones have been
shown to readily undergo 1,3-dipolar cycloaddition reac-
tions with nitrile oxides to give the corresponding 9-
methyl-7-oxo-1-oxa-2,6-diazaspiro[4.4]nona-2,8-dienesystems
reference unless otherwise specified. Variable-temperature H
NMR spectra were recorded on a Bruker DRX500 spectrometer
operating at 500 MHz with [D8]toluene as solvent. Electron-
impact (EI) mass spectra were run on aThermoQuest MAT95XP

Spiroheterocycles via Regioselective Cycloaddition Reactions
449
mass spectrometer using an ionization energy of 70 eV. Accu-
rate mass measurements were obtained on the same instru-
ment with a resolution of 5000–10000 using perfluorokerosene
as the reference compound. Microanalyses were performed
at the Campbell Microanalytical Laboratory, University of
Otago. All other starting materials, reagents, and solvents were
obtained from commercial sources and used as supplied unless
otherwise noted. The Cambridge Crystallographic Data Cen-
tre contains the supplementary crystallographic data for this
paper. Molecular diagrams are shown with 50% thermal ellip-
soids and hydrogen atoms as spheres of arbitrary size. These
data for 6-(4-chlorophenyl)-9-methyl-7-oxo-3-phenyl-1-oxa-
2,6-diazaspiro[4.4]nona-2,8-diene-8-carbonitrile 9a (CCDC
(Found: C 74.5, H 5.5, N 12.6; [M+•] 224.0943. C14H12N2O
requiresC74.9, H5.4, N12.5%;[M+•]224.0944). δH (400 MHz,
CDCl3) 7.37–7.25 (3H, m, Ar), 7.13 (1H, d, 8.5, Ar), 5.21 (1H,
d, 2.7, =CH2), 4.78 (1H, d, 2.7, =CH2), 2.48 (3H, s, CH3),
2.12 (3H, s, CH3). δC (100 MHz, CDCl3) 163.0, 157.5, 145.5,
137.1, 132.1, 131.4, 129.5, 129.0, 127.2, 111.8, 108.0, 100.3,
17.6, 12.4.
N,1-Bis(3-chlorophenyl)-4-methyl-5-methylene-2-oxo-
2,5-dihydro-1H-pyrrole-3-carboxamide 7d
Prepared from N1,N3-bis(4-chlorophenyl)malonamide, isolated
as a yellow powder and recrystallized from methanol to give
pale yellow needles (65%), mp 164–165◦C. (Found: C 60.9,
H 3.6, N 7.3; [M+•] 372.0413. C19H14Cl2N2O2 requires C 61.1,
H 3.8, N 7.5%; [M+•] 372.0427). δH (400 MHz, CDCl3) 10.57
(1H, s, NH), 7.88 (1H, t, 2.0, Ar–H), 7.38–7.48 (3H, m, Ar–H),
7.33 (1H, t, 1.8, Ar–H), 7.20–7.25 (2H, m, Ar–H), 7.07 (1H, m,
Ar–H), 5.39 (1H, d, 2.6, =CH2), 5.15 (1H, d, 2.6, =CH2), 2.70
(3H, s, CH3). δC (100 MHz, CDCl3) 168.3, 160.0, 154.6, 145.9,
139.0, 135.1, 134.63, 134.61, 130.5, 129.9, 128.8, 128.0, 125.9,
124.4, 120.5, 120.1, 117.9, 100.8, 11.5.
746208),
6-(2,4-dichlorophenyl)-9-methyl-7-oxo-3-phenyl-
9b
1-oxa-2,6-diazaspiro[4.4]nona-2,8-diene-8-carbonitrile
(CCDC746209), ethyl8-cyano-6-(2,4-dichlorophenyl)-9-methyl-
7-oxo-1-oxa-2,6-diazaspiro[4.4]nona-2,8-diene-3-carboxylate
9d (CCDC 746210), and ethyl 8-cyano-9-methyl-7-oxo-6-
(2-methylphenyl)-1-oxa-2,6-diazaspiro[4.4]nona-2,8-diene-3-
carboxylate 9e (CCDC 746211) can be obtained free of
charge at www.ccdc.cam.ac.uk/conts/retrieving.html or from
the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44(0)1223–336033; email:
deposit@ccdc.cam.ac.uk.
General Method for Nitrile Oxide Cycloadditions
A solution of sodium hydrogen carbonate (0.67 g, 7.9 mmol)
in water (10 mL) was added to a solution of the appropriate
5-methylene-1H-pyrrol-2(5H)-one 7 (1.1 mmol) in ethyl acetate
(10 mL) at room temperature.The two-phase mixture was cooled
to 0◦C and the appropriate hydroximoyl chloride (2.5 mmol)
was added portionwise over 15 min with stirring. The mixture
was stirred for 3 h and allowed to warm to room temperature.
The organic phase was washed with water (3 × 20 mL), dried
(MgSO4), and evaporated using reduced pressure. The residue
was triturated with Et2O, collected by filtration, and the crude
product was recrystallized from the solvent stated.
General Procedure for the Preparation of
5-Methylene-1H-pyrrol-2(5H)-ones 7
Butadione (0.81 g, 10 mmol) was added to a solution of the
appropriate cyanoacetamide (10 mmol) in DMF (6 mL) at room
temperature. A few drops of DBU were added and this initiated
a rise in temperature. The reaction was stirred overnight at room
temperature and then diluted with water (50 mL). The mixture
was extracted with dichloromethane (3 × 40 mL), and the com-
bined extracts were dried (MgSO4) and concentrated to ∼20 mL.
The resulting dichloromethane solution of hydroxy lactam 6 was
treated with trifluoroacetic acid (2 mL), left to stand for 24 h,
and then evaporated to dryness. The residue was recrystallized
as stated to give 5-methylene-1H-pyrrol-2(5H)-ones 7.
6-(4-Chlorophenyl)-9-methyl-7-oxo-3-phenyl-1-oxa-
2,6-diazaspiro[4.4]nona-2,8-diene-8-carbonitrile 9a
1-(4-Chlorophenyl)-4-methyl-5-methylene-2-oxo-
2,5-dihydro-1H-pyrrole-3-carbonitrile 7a
Prepared on a 1.6-mmol scale to give the spiro heterocycle 9a
(0.25 g, 43%) as a white fluffy solid, mp 179–180◦C. (Found: C
65.8, H 3.7, N 11.5; [M+•] 363.0759. C20H14ClN3O2 requires C
66.0, H 3.9, N 11.5%; [M+•] 363.0769). δH (400 MHz, CDCl3)
7.54–7.35 (9H, m, Ar), 3.59 (1H, d, 18.4, H4), 3.37 (1H, d, 18.4,
H4), 2.37 (3H, s, CH3). δC (100 MHz, CDCl3) 168.0, 161.9,
157.4, 134.2, 131.9, 131.4, 129.9, 129.1, 128.0, 127.3, 126.7,
110.8, 110.7, 102.0, 39.6, 12.7.
Prepared from N-(4-chlorophenyl)-2-cyanoacetamide, isolated
as a pale yellow powder and recrystallized from acetic acid to
give pale yellow plates in 77% yield over two steps, mp 182–
184◦C (lit.[5] 182–184◦C).
1-(2,4-Dichlorophenyl)-4-methyl-5-methylene-2-oxo-
2,5-dihydro-1H-pyrrole-3-carbonitrile 7b
Prepared from N-(2,4-dichlorophenyl)-2-cyanoacetamide, iso-
lated as a fawn powder (75%), mp 176–177◦C. (Found: C 55.6,
H 2.7, N 9.8; [M+•] 278.0006. C13H8Cl2N2O requires C 55.9,
H 2.9, N 10.0%; [M+•] 278.0008). δH (400 MHz, CDCl3) 7.58
(1H, d, 2.0, Ar–H), 7.39 (1H, d, 8.5, Ar), 7.25 (1H, dd, 8.5 and
2.2, Ar), 5.24 (1H, d, 2.6, =CH2), 4.77 (1H, d, 2.6, =CH2), 2.48
(3H, s, CH3). δC (100 MHz, CDCl3) 162.9, 158.1, 144.3, 136.3,
134.6, 131.7, 130.8, 129.7, 128.5, 111.4, 108.2, 100.4, 12.5.
6-(2,4-Dichlorophenyl)-9-methyl-7-oxo-3-phenyl-1-oxa-
2,6-diazaspiro[4.4]nona-2,8-diene-8-carbonitrile 9b
Prepared on a 1.4-mmol scale to give spiro heterocycle 9b
(0.28 g, 49%) as a pale orange solid, which was purified by
recrystallization from isopropanol to give a pale yellow solid,
mp 211–213◦C. (Found: C 60.3, H 3.3, N 10.4; [M+•] 397.0374.
C20H13Cl2N3O2 requires C 60.3, H 3.3, N 10.6%; [M+•
]
397.0379). δH (400 MHz, CDCl3) 7.48 (3H, dd, 6.7 and 1.3,
Ar), 7.43 (2H, dd, 5.7 and 2.5, Ar), 7.39 (1H, dd, 5.8 and 1.3,
Ar), 7.30 (1H, d, 2.2, Ar), 7.28 (1H, d, 2.2, Ar), 3.60 (1H, d, 18.4,
H4), 3.44 (1H, d, 18.4, H4), 2.39 (3H, s, CH3). δC (100 MHz,
CDCl3) 168.2, 161.1, 157.1, 136.5, 134.5, 132.6, 131.4, 130.4,
129.1, 128.8, 127.3, 126.7, 110.9, 110.6, 101.6, 38.7, 12.9.
4-Methyl-5-methylene-1-(2-methylphenyl)-2-oxo-
2,5-dihydro-1H-pyrrole-3-carbonitrile 7c
Prepared from N-(2-methylphenyl)-2-cyanoacetamide, isolated
as a dark green-grey solid, which was recrystallized from iso-
propanol to give pale olive crystals (72%), mp 154–159◦C.

450
N. J. Beattie et al.
Ethyl 6-(4-Chlorophenyl)-8-cyano-9-methyl-7-oxo-1-oxa-
2,6-diazaspiro[4.4]nona-2,8-diene-3-carboxylate 9c
purified by recrystallization from dichloromethane/ethanol to
give colourless microcrystals, mp 206–207◦C. (Found: C 57.6,
H 3.8, N 9.3; [M+•] 457.0584. C22H17Cl2N3O4 requires C 57.7,
H 3.7, N 9.2%; [M+•] 457.0591). δH (400 MHz, CDCl3) 10.43
(1H, s, NH), 7.83 (2H, s, Ar), 7.41–7.32 (3H, m, Ar), 7.28–7.22
(3H, m, Ar), 3.48 (1H, d, 19.8, H4), 3.12 (1H, d, 19.8, H4), 2.51
(3H, s, CH3), 2.44 (3H, s, CH3). δC (100 MHz, CDCl3) 191.3,
167.8, 163.7, 158.5, 158.3, 138.5, 135.4, 134.7, 134.2, 130.7,
130.0, 129.2, 127.5, 125.2, 124.8, 122.9, 120.3, 118.1, 103.7,
36.5, 26.6, 11.9.
Prepared on a 2.1-mmol scale to give carboxylate 9c (0.37 g,
49%) as a pale orange solid, which was purified by recrystalliza-
tionfromisopropanoltogivecolourlessneedles, mp184–185◦C.
(Found: C 56.9, H 3.8, N 11.5; [M+•] 359.0660. C17H14ClN3O4
requiresC56.8, H3.9, N11.7%;[M+•]359.0667). δH (400 MHz,
CDCl3) 7.41 (2H, dd, 6.6 and 2.0, Ar), 7.25 (2H, dd, 6.6 and 2.0,
Ar), 4.32 (2H, q, 7.1, CH3CH2O), 3.41 (1H, d, 19.5, H4), 3.21
(1H, d, 19.5, H4), 2.34 (3H, s, CH3), 1.35 (3H, t, 7.1, CH3CH2O).
δC (100 MHz, CDCl3) 166.5, 161.7, 158.6, 152.0, 134.9, 131.2,
131.1, 128.5, 111.3, 110.3, 103.3, 63.0, 37.8, 13.9, 12.6.
N,6-Bis(3-chlorophenyl)-9-methyl-7-oxo-3-(thiophen-2-yl)-
1-oxa-2,6-diazaspiro[4.4]nona-2,8-diene-8-carboxamide 9h
Ethyl 8-Cyano-6-(2,4-dichlorophenyl)-9-methyl-7-oxo-1-
A solution of thiophene 2-aldoxime (0.42 g, 33 mmol) in
dichloromethane (6 mL) containing one drop of concen-
trated hydrochloric acid was cooled to 0◦C and treated with
N-chlorosuccinimide (0.44 g, 33 mmol) added in portions over
15 min, and then stirred for 1.5 h. Dichloromethane (10 mL)
followed by water (10 mL), N,1-bis(3-chlorophenyl)-4-methyl-
5-methylene-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide 7e
(0.6 g, 1.6 mmol), and sodium bicarbonate (0.6 g, 71 mmol) were
added and the whole stirred at 0◦C for 4 h, then at room tem-
perature for 3 h. The precipitate was collected by filtration and
washed with a little dichloromethane and water to give the
spiro heterocycle 9h (0.62 g, 76%). A portion was crystallized
from dichloromethane/isopropanol to give colourless micro-
oxa-2,6-diazaspiro[4.4]nona-2,8-diene-3-carboxylate 9d
Prepared on a 1.3-mmol scale to give spiro heterocycle 9d
(0.17 g, 31%) as a green-grey solid, which was recrystallized
from isopropanol to an off-white solid, mp 185–186◦C. (Found:
C52.0, H3.5, N10.4;[M+•]393.0293. C17H13Cl2N3O4 requires
C 51.8, H 3.3, N 10.7%; [M+•] 393.0278). δH (400 MHz, CDCl3)
7.56 (1H, d, 2.2, Ar), 7.38 (1H, d, 8.5, Ar), 7.33 (1H, dd, 8.5
and 2.2, Ar), 4.30 (2H, q, 7.1, CH3CH2O), 3.43 (1H, d, 19.7,
H4), 3.25 (1H, d, 19.7, H4), 2.35 (3H, s, CH3), 1.33 (3H, t, 7.1,
CH3CH2O). δC (100 MHz, CDCl3) 166.9, 160.8, 158.5, 151.8,
136.8, 134.7, 132.3, 130.6, 129.0, 128.5, 111.1, 110.2, 103.1,
62.9, 36.9, 13.9, 12.8.
needles, mp 252–253◦C. (Found: C 57.5, H 3.3, N 8.3; [M+•
]
Ethyl 8-Cyano-9-methyl-7-oxo-6-(2-methylphenyl)-1-oxa-
2,6-diazaspiro[4.4]nona-2,8-diene-3-carboxylate 9e
497.0360. C24H17Cl2N3O3S requires C 57.8, H 3.4, N 8.4%;
[M+•] 497.0362). δH (400 MHz, CDCl3) 10.58 (1H, s, NH), 7.64
(2H, m, Ar), 7.49–7.06 (9H, m, Ar), 3.78 (1H, d, 21.5, H4), 3.49
(1H, d, 21.5, H4), 2.61 (3H, s, CH3). δC (100 MHz, CDCl3)
168.8, 167.7, 161.8, 161.5, 154.0, 136.5, 136.0, 135.3, 133.1,
130.6, 128.3, 128.0, 127.3, 126.1, 122.6, 122.55, 120.5, 118.7,
115.9, 113.1, 110.2, 102.1, 40.9, 12.6.
Prepared on a 1.6-mmol scale to give spiro heterocycle 9e
(0.43 g, 79%) as an off-white solid, which was recrystallized
from isopropanol to give white needles, mp 159–160◦C. (Found:
C 63.8, H 5.2, N 12.4; [M+•] 339.1210. C18H17N3O4 requires
C 63.7, H 5.1, N 12.4%; [M+•] 339.1214). Major atropisomer:
δH (400 MHz, CDCl3) 7.34–7.25 (4H, m, Ar), 4.30 (2H, q, 7.1,
CH3CH2O), 3.37 (1H, d, 19.5, H4), 3.04 (1H, d, 19.5, H4), 2.35
(3H, s, lactam CH3), 2.16 (3H, s, tolyl CH3), 1.31 (3H, t, 7.1,
CH3CH2O). δC (100 MHz, CDCl3) 166.6, 159.7, 157.6, 151.5,
136.9, 131.4, 129.8, 129.2, 127.7, 127.0, 111.1, 110.5, 103.5,
62.8, 36.5, 18.2, 12.9, 12.8. Minor atropisomer: δH (400 MHz,
CDCl3) 7.4–7.3 (3H, m,Ar), 7.01 (1H, d, 7.7, tolyl H6), 4.3–4.25
(2H, m, CH3CH2O), 3.65 (1H, d, 19.2, H4), 3.46 (1H, d, 19.2,
H4), 2.35 (3H s, lactam CH3), 2.29 (3H, s, tolyl CH3), 1.30 (3H,
t, 7.1, CH3CH2O).
N,6-Bis(3-chlorophenyl)-9-methyl-7-oxo-3-(pyridin-2-yl)-1-
oxa-2,6-diazaspiro[4.4]nona-2,8-diene-8-carboxamide 9i
One drop of concentrated hydrochloric acid was added to
a mixture of picolinaldehyde oxime (0.61 g, 5 mmol) and
N-chlorosuccinimide (0.67 g, 5 mmol) in dichloromethane
(8 mL) and the whole was stirred overnight. N,1-bis
(3-chlorophenyl)-4-methyl-5-methylene-2-oxo-2,5-dihydro-1H-
pyrrole-3-carboxamide 7e (0.93 g, 2.5 mmol) and water (5 mL)
were added followed by sodium bicarbonate (1 g), which was
added in four portions over 30 min. After 3 h, benzene (10 mL)
andwater(20 mL)wereaddedandthemixturewasstirredfor1 h,
and then filtered to give the product (0.74 g) as fine, colourless
needles. The organic phase from the filtrate was evaporated and
the residue was briefly boiled with isopropanol (10 mL). Cooling
to room temperature followed by filtration afforded an additional
0.27 g of spiro heterocycle 9i (combined weight 1.01 g, 89%).
A portion was crystallized from dichloromethane/isopropanol
to give colourless woolly needles, mp 224–225◦C. (Found: C
60.8, H 3.8, N 11.4; [M+•] 492.0750. C25H18Cl2N4O3 requires
C 60.9, H 3.7, N 11.4%; [M+•] 492.0750). δH (400 MHz, CDCl3)
10.57 (1H, s, NH), 8.53 (1H, m, Py-H6), 7.97–7.87 (2H, m, Ar),
7.76–7.68 (1H, m, Ar), 7.48–7.05 (8H, m, Ar), 3.81 (1H, d, 19.6,
H4), 3.53 (1H, d, 19.6, H4), 2.61 (3H, s, CH3). δC (100 MHz,
CDCl3) 168.0, 165.2, 159.3, 159.0, 149.5, 147.5, 138.7, 136.7,
135.1, 134.7, 130.5, 130.0, 128.7, 127.3, 125.1, 125.0, 124.6,
122.4, 121.7, 120.3, 118.1, 102.2, 38.3, 12.0.
N,6-Bis(3-chlorophenyl)-9-methyl-7-oxo-3-phenyl-1-oxa-
2,6-diazaspiro[4.4]nona-2,8-diene-8-carboxamide 9f
Prepared on a 1.1-mmol scale to give spiro heterocycle 9f as a
white fluffy solid, which was purified by recrystallization from
isopropanol (0.275 g, 51%), mp 247–248.5◦C. (Found: C 63.1,
H 3.9, N 8.5; [M+•] 491.0792. C26H19Cl2N3O3 requires C 63.4,
H 3.9, N 8.5%; [M+•] 491.0798). δH (400 MHz, CDCl3) 10.56
(1H, s, NH), 7.88 (1H, m, Ar), 7.54–7.25 (11H, m, Ar), 7.13
(1H, m, Ar), 3.64 (1H, d, 18.3, H4), 3.37 (1H, d, 18.3, H4), 2.62
(3H, s, CH3). δC (100 MHz, CDCl3) 167.8, 165.2, 158.9, 157.3,
138.6, 135.1, 134.7, 131.2, 130.5, 129.9, 129.0, 128.7, 127.6,
127.1, 126.7, 124.7, 122.5, 120.2, 118.0, 101.8, 39.6, 11.9.
3-Acetyl-N,6-bis(3-chlorophenyl)-9-methyl-7-oxo-1-oxa-
2,6-diazaspiro[4.4]nona-2,8-diene-8-carboxamide 9g
Prepared on a 1.3-mmol scale using pyruvohydroximoyl
chloride[28] to give carboxamide 9g (0.276 g, 45%), which was

Spiroheterocycles via Regioselective Cycloaddition Reactions
451
Ethyl 6-(3-Chlorophenyl)-8-(3-chlorophenylcarbamoyl)-
9-methyl-7-oxo-1-oxa-2,6-diazaspiro[4.4]nona-
2,8-diene-3-carboxylate 9j
[9] C. J. Easton, C. M. M. Hughes, E. R. T. Tiekink, C. E. Lubin,
G. P. Savage, G. W. Simpson, Tetrahedron Lett. 1994, 35, 3589.
doi:10.1016/S0040-4039(00)73248-5
[10] G. P. Savage, G. T. Wernert, Aust. J. Chem. 2005, 58, 877.
doi:10.1071/CH05189
[11] S. J. Barrow, C. J. Easton, G. P. Savage, G. W. Simpson, Tetrahedron
Lett. 1997, 38, 2175. doi:10.1016/S0040-4039(97)00275-X
[12] C. J. Easton, G.A. Heath, C. M. M. Hughes, C. K.Y. Lee, G. P. Savage,
G.W. Simpson, E. R.T.Tiekink, G. J.Vuckovic, R. D.Webster, J. Chem.
Soc., Perkin Trans. 1 2001, 1168. doi:10.1039/B008081K
[13] C. J. Easton, C. M. M. Hughes, K. D. Kirby, G. P. Savage,
G. W. Simpson, E. R. T. Tiekink, Chem. Commun. 1994, 2035.
[14] J. Anderson-McKay, G. P. Savage, G. W. Simpson, Aust. J. Chem.
1996, 49, 163.
Prepared on a 1.1-mmol scale to give carboxylate 9j (0.18 g,
35%) as a white fluffy solid, which was purified by recrystal-
lization from isopropanol, mp 219–221◦C. (Found: C 56.9, H
4.1, N 8.6; [M+•] 487.0694. C23H19Cl2N3O5 requires C 56.6,
H 3.9, N 8.6%; [M+•] 487.0696). δH (400 MHz, CDCl3) 10.44
(1H, s, NH), 7.85 (1H, dd, 3.9 and 1.9, Ar), 7.43–7.38 (3H, m,
Ar), 7.28–7.24 (3H, m, Ar), 7.12 (1H, m, Ar), 4.33 (2H, q, 7.1,
CH3CH2O), 3.48 (1H, d, 19.4, CH), 3.24 (1H, d, 19.4, CH),
2.58 (3H, s, CH3), 1.36 (3H, t, 7.1, CH3CH2O). δC (100 MHz,
CDCl3) 167.8, 163.8, 158.8, 158.5, 152.0, 138.5, 135.4, 134.7,
134.1, 130.9, 129.9, 129.2, 127.5, 125.1, 124.8, 122.8, 120.2,
118.0, 103.4, 62.9, 37.8, 13.9, 11.9.
[15] B. M. Kelly-Basetti, I. Krodkiewska, W. H. F. Sasse, G. P. Savage,
G. W. Simpson, Tetrahedron Lett. 1995, 36, 327. doi:10.1016/0040-
4039(94)02242-4
[16] C. K.Y. Lee, C. J. Easton, G. P. Savage, G. W. Simpson, Arkivoc 2006,
3, 175.
[17] B. M. Kelly-Basetti, M. F. Mackay, S. M. Pereira, G. P. Savage,
G. W. Simpson, Heterocycles 1994, 37, 529. doi:10.3987/
COM-93-S49
Acknowledgement
We thank Dr Craig Forsyth (Monash University) for crystallography and
Dr Roger Mulder (CSIRO) for assistance with NMR spectroscopy.
[18] S. M. Pereira, G. P. Savage, G. W. Simpson, R. J. Greenwood,
M. F. Mackay, Aust. J. Chem. 1993, 46, 1401.
[19] R. Newton, G. P. Savage, Aust. J. Chem. 2008, 61, 432. doi:10.1071/
CH08111
[20] K. C. Liu, R. K. Howe, J. Org. Chem. 1983, 48, 4590. doi:10.1021/
JO00172A030
References
[1] A. Koshi, S. Masakazu, World Patent 9732847 1997.
[2] A. J. Liepa, W. M. Johnson, K. A. Turner, World Patent 2008070891
2008.
[3] G. B. Gill, G. D. James, K. V. Oates, G. Pattenden, J. Chem. Soc.,
Perkin Trans. 1 1993, 2567. doi:10.1039/P19930002567
[4] A. S. Demir, F. Aydogan, I. M. Akhmedov, Tetrahedron Asymmetry
2002, 13, 601. doi:10.1016/S0957-4166(02)00140-4
[5] R. Adhikari, D. A. Jones, A. J. Liepa, R. H. Nearn, Aust. J. Chem.
2005, 58, 882. doi:10.1071/CH05286
[21] R. K. Howe, B. R. Shelton, J. Org. Chem. 1990, 55, 4603.
doi:10.1021/JO00302A025
[22] R. K. Howe, K. C. Lui, US Patent 4 364 768 1981.
[23] L. R. Domingo, M. T. Picher, P. Arroyo, J. A. Saez, J. Org. Chem.
2006, 71, 9319. doi:10.1021/JO0613986
[24] A. Werner, H. Buss, Chem. Ber. 1894, 27, 2193.
[25] K.-C. Liu, B. R. Shelton, R. K. Howe, J. Org. Chem. 1980, 45, 3916.
doi:10.1021/JO01307A039
[6] R. Huisgen, Angew. Chem. Int. Ed. Engl. 1963, 2, 565. doi:10.1002/
ANIE.196305651
[7] C. J. Easton, C. M. M. Hughes, G. P. Savage, G. W. Simpson, Adv.
Heterocycl. Chem. 1994, 60, 261. doi:10.1016/S0065-2725(08)
60184-1
[26] G. Bringmann, A. J. Price Mortimer, P. A. Keller, M. J. Gresser,
J. Garner, M. Breuning, Angew. Chem. Int. Ed. 2005, 44, 5384.
doi:10.1002/ANIE.200462661
[8] C. J. Easton, C. M. M. Hughes, E. R. T. Tiekink, G. P. Savage,
G. W. Simpson, Tetrahedron Lett. 1995, 36, 629. doi:10.1016/0040-
4039(94)02321-2
[27] C. Roussel, J.-L. Stein, F. Beauvais, New J. Chem. 1990, 14, 169.
[28] G. Hesse, G. Krehbiel, Chem. Ber. 1955, 88, 130. doi:10.1002/CBER.
19550880121