Atropisomerism-induced facial selectivity in nitrile oxide cycloadditions with 5-methylenehydantoins

Article abstract of DOI:10.1021/jo2011818

N-Aryl 5-methylenehydantoins underwent nitrile oxide cycloaddition with benzonitrile oxide to give 5-spiro isoxazoline adducts with complete regioselectivity. Atropisomerism around the N-aryl bond also led to facial selectivity in these cycloadditions. Published 2011 by the American Chemical Society.

Full text of DOI:10.1021/jo2011818

NOTE
pubs.acs.org/joc
Atropisomerism-Induced Facial Selectivity in Nitrile Oxide
Cycloadditions with 5-Methylenehydantoins
Anna M. Said and G. Paul Savage*
CSIRO Materials Science and Engineering, Bag 10, Clayton South MDC, VIC 3169, Australia
S Supporting Information
b
ABSTRACT: N-Aryl 5-methylenehydantoins underwent nitrile oxide
cycloaddition with benzonitrile oxide to give 5-spiro isoxazoline
adducts with complete regioselectivity. Atropisomerism around the
N-aryl bond also led to facial selectivity in these cycloadditions.
he chemistry of hydantoin (imidazolidine-2,4-dione) dates
T
back 150 years to Adolph von Baeyer,1 but interest in this
system has continued unabated. The ongoing interest in hydan-
toin is due in large part to the extensive biological activity
associated with its derivatives.2ꢀ4 Spiro hydantoin derivatives,
such as the herbicidal (+)-hydantocidin from Streptomyces
hygroscopicus5 and the spiro hydantoin aldose reductase inhibitor
Sorbinil,6 have attracted strong interest from pharmaceutical
companies (Figure 1). DielsꢀAlder and 1,3-dipolar cycloaddi-
tion reactions on 5-methylenehydantoins7,8 have been success-
fully employed to access 5-spiro hydantoins.9ꢀ14
Figure 1. Structures of hydantoin, (+)-hydantocidin, and sorbinil.
Scheme 1. Formation of 5-Methylenehydantoins
We have an ongoing interest in the construction of spiro
isoxazolines using nitrile oxide cycloaddition (NOC) reactions
on exocyclic methylene compounds.15ꢀ19 NOC chemistry is
reliable and predictable because the regiochemistry of cycloaddi-
tion is controlled to a great extent by steric influences. The
oxygen of the nitrile oxide almost exclusively adds to the most
hindered end of the dipolarophile, regardless of the polarity of
the dipolarophile.20ꢀ22 This characteristic of NOC reactions can
be used to advantage in controlling the regiochemistry of
cycloaddition to give a desired isomer.23ꢀ26 In addition, subtle
steric effects can control the facial selectivity of cycloaddition.15
Recently we discovered that the exocyclic methylene dipolaro-
phile in N-(2-methylphenyl)-5-methylene-1H-pyrrol-2(5H)-
one underwent nitrile oxide cycloaddition with approximately a
4:1 facial selectivity as governed by atropisomerism along the
arylꢀnitrogen bond.19 Such atroposelective nitrile oxide cy-
cloaddition reactions are rare in the literature,27ꢀ29 generally
show poor selectivity, and are previously unknown for exocyclic
methylene dipolarophiles. Some π-facial selectivity has been
achieved in analogous open-chain systems.30 Atropisomerism is
a largely overlooked source of chirality, with important implica-
tions in the pharmaceutical industry.31
one NOC reaction,14 no such facial selectivity has been de-
scribed. This is because in each reported case the N-substituent
has been symmetrical and so the possibility of an asymmetric
reaction due to atropisomerism has been overlooked. We herein
report the formation of spiro hydantoins via benzonitrile oxide
cycloaddition reactions with 5-methylenehydantoins bearing an
unsymmetrical aryl group on N-1 and the facial selectivity
engendered by atropisomeric control.
Methyl propiolate was treated with methylamine in 50%
aqueous MeOH to form N-methylpropiolamide 1.32 Equimolar
quantities of 1, the appropriate isocyanate, and triethylamine
were then reacted at room temperature, following the procedure
of Coppola and Damon,8 to give the 1-aryl-3-methyl hydantoins
3 (Scheme 1). This reaction presumably proceeds via the urea
intermediate 2, which is not isolated.
The methylenehydantoins 3 underwent NOC reactions with
benzonitrile oxide to give spiro adducts 4, (Table 1). Benzonitrile
On the basis of the above findings, we anticipated that
cycloadditions to N-aryl 5-methylenehydantoins might also show
facial selectivity, controlled by the orientation of the atropi-
somers. However, despite several reports of 1,3-dipolar cycload-
ditions with N-substituted 5-methylenehydantoins, including
Received: June 8, 2011
Published: July 08, 2011
Published 2011 by the American Chemical Society
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dx.doi.org/10.1021/jo2011818 J. Org. Chem. 2011, 76, 6946–6950
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The Journal of Organic Chemistry
NOTE
Table 1. Atroposelectivity of Benzonitrile Oxide Cycloaddi-
tions with Methylenehydantoins 3
Scheme 2. Atropisometric Facial Selectivity in Benzonitrile
Cycloaddition to 5-Methylenehydantoins 3
entry
N-aryl substituent
yield of 4 (%)
anti/syn ratioa
a
b
c
d
e
f
phenyl
80
74
66
71
76
45
61
N/A
2.5:1
2.6:1
4.7:1
>99:1b
30:1
2-methylphenyl
2,5-dimethylphenyl
1-naphthyl
2-nitrophenyl
2-tert-butylphenyl
2-phenylphenyl
g
15:1
a See Scheme 2 b No syn isomer could be detected.
N-arylimides (ΔGq rotational barrier in toluene = 19.3 kcal/
mol)36 and 2-methyl-N-(4-methyl-3-(o-tolyl)thiazol-2(3H)-yli-
dene)aniline (ΔGq rotational barrier in ethanol = 29 kcal/mol). 37
We explored the barrier to rotation of the dipolarophile methy-
lenehydantoins 3a and 3b around the Nꢀaryl torsional angle,
locating energy minima using a Gaussian constrained optimiza-
tion at each point (see Supporting Information). For unsubsti-
tuted phenyl derivative 3a, the barrier to rotation was calculated
to be approximately 4.2 kcal/mol. For the N-(2-methylphenyl)
substituted methylenehydantoins 3b and 3c the barrier to
rotation was calculated to be approximately 17.6 kcal/mol. For
the more highly hindered compounds 3dꢀg the barrier to
rotation would be expected to be higher still. Hence, it is probable
that torsional rotation around the Nꢀaryl bond of the dipolar-
ophiles at 0 °C is highly restricted.
As previously mentioned, nitrile oxide cycloadditions to exo-
cyclic methylene groups are quite sensitive to steric control often
displaying high levels of facial selectivity.20 Cycloaddition to the
atropisomeric dipolarophiles 3 is therefore more likely to occur on
the face opposite to the aryl 20-substituent leading to an uneven
diastereomeric mix of atropisomers 4 (Scheme 2). In the 1H NMR
spectra of the crude cycloadduct products, the isoxazoline protons
of the major isomer appear upfield from the analogous protons in
the minor isomer. This observation is consistent with preferential
cycloaddition on the face opposite the aryl 20-substituent, which
would then result in the isoxazoline methylene protons being
shielded by the 20-substituent in product 4 (major) relative to the
corresponding isoxazoline methylene protonsofthe minorisomer.
In addition, resonances for the diastereomeric protons on the
isoxazoline ringofthemajor isomertended tobefurther apart than
those for the corresponding protons on the minor isomer. Again,
this is consistent with the stereochemistry of addition as shown in
Scheme 2. The magnetic environment of these protons will be
more differentially affected in 4 (major) by the adjacent 20-
substituent of the N-aryl ring, with one of the protons oriented
toward, and the other pointing away from, the 20-substituent. In
the syn-cycloadduct, 4 (minor), both protons are remote from the
20-substituent.
oxide was generated in situ by the action of 5% sodium hypo-
chlorite on benzaldoxime using a water/CH2Cl2 biphasic
system.33 In each case, the cycloaddition was completely regio-
selective, in that the oxygen of the nitrile oxide became attached
to the disubstituted end of the double bond. This regiochemical
orientation was established from the 1H NMR chemical shifts for
the methylene protons of the newly formed isoxazoline rings.
The characteristic AB quartet system of these diastereotopic
protons fell in the range of 3.0ꢀ3.5 ppm, which is indicative of
protons on C-4 of the isoxazoline ring rather than C-5 (4.5ꢀ
5.0 ppm),34,35 hence establishing the regiochemistry of cycload-
dition as shown.
For some of the spiro heterocycles 4, the 1H NMR featured a
double set of resonances for all protons, which was consistent
with atropisomeric mixtures. The diastereotopic protons on C-4
of the isoxazoline ring, at around 3.0ꢀ3.6 ppm, were especially
diagnostic as the resonances for the two isomers were usually
separated by approximately 0.4 ppm. The ratios of the atropiso-
meric products were conveniently determined by integrating
these signals, and the ratios are reported in Table 1.
Restricted rotation around the N-aryl bond of 4 leads to
substantially different magnetic environments for the isoxazoline
C-4 protons depending on whether the 20-substituent on the aryl
group is in close proximity to the isoxazoline protons, via anti-
addition, or remote from the isoxazoline protons, via syn-addition
(Scheme 2).
The ratios reported in Table 1 may conceivably represent
either a thermodynamic equilibrium between the atropisomeric
products or the kinetic atroposelectivity for the reaction. We
reasoned that it was unlikely to be a thermodynamic equilibrium
because the barrier to rotation in the products would be quite
high and the reaction was carried out at 0 °C. As supporting
evidence, the 1H NMR spectrum of the atropisomeric mixture of
spiro-adduct 4c remained unchanged upon heating to 100 °C in
toluene-d8. No coalescence of signals was observed at 100 °C,
and after the temperature was held at 100 °C for 24 h, the
atropisomeric ratio remained unchanged.
The atropisomeric cycloadduct mixtures 4bꢀd could not be
separated, but the major diastereomeric atropisomer of the
tert-butyl-substituted cycloadduct 4f and the biphenyl cycload-
duct 4g could be isolated by column chromatography. The
The dipolarophile precursors themselves may also experience
restricted rotation around the N-aryl bond as, for example, the
rotational barrier around the N-aryl single bond in 20-substituted
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NOTE
(100 MHz, CDCl3) δ 162.5, 153.2, 137.1, 137.0, 131.6, 131.5, 129.6,
128.6, 127.4, 95.8, 25.0, 17.6. Anal. Calcd for C12H12N2O2: C, 66.7; H,
5.6; N, 13.0; [M+] 216.0893. Found: C, 66.8; H, 5.6; N, 13.0; [M+]
216.0890.
3-Methyl-1-(2,5-dimethylphenyl)-5-methyleneimidazoli-
dine-2,4-dione (3c). The product was isolated as a pale yellow solid
(1.95 g, 85%) and recrystallized from EtOH/water. Mp 85ꢀ86 °C; 1H
NMR (400 MHz, CDCl3) δ 7.23 (1H, d, J = 7.8, Ar), 7.16 (1H, d, J = 7.9,
Ar), 7.00 (1H, s, Ar), 5.42 (1H, d, J = 2.0, CH2), 4.48 (1H, d, J = 2.0,
CH2), 3.18 (3H, s, NMe), 2.33 (3H, s, Me), 2.13 (3H, s, Me); 13C NMR
(100 MHz, CDCl3) δ 162.5, 153.3, 137.3, 137.1, 133.5, 131.3, 131.2,
130.4, 129.0, 95.7, 24.9, 20.7, 17.1. Anal. Calcd for C13H14N2O2: C, 67.8;
H, 6.1; N, 12.2; [M+] 230.1050. Found: C, 67.9; H, 6.1; N, 12.3; [M+]
230.1061.
3-Methyl-1-(naphthalen-1-yl)-5-methyleneimidazolidine-
2,4-dione (3d). The product was isolated as an off-white solid (1.54 g,
61%). Mp 147.5ꢀ148 °C; 1H NMR (400 MHz, CDCl3) δ 7.80ꢀ7.93
(2H, m, Ar), 7.65ꢀ7.51 (4H, m, Ar), 7.47 (1H, dd, J = 7.3 and 1.1, Ar),
5.46 (1H, d, J = 2.2, CH2), 4.44 (1H, d, J = 2.2, CH2), 3.26 (3H, s, NMe);
13C NMR (100 MHz, CDCl3) δ 162.5, 153.7, 137.7, 134.7, 130.1, 129.1,
128.7, 127.4, 127.0, 126.8, 125.7, 122.3, 96.6, 25.1. Anal. Calcd for
C15H12N2O2: C, 71.4; H, 4.8; N, 11.1; [M+] 252.0893. Found: C, 71.2;
H, 4.9; N, 10.9; [M+] 252.0891.
3-Methyl-5-methylene-1-(2-nitrophenyl)imidazolidine-2,
4-dione (3e). The product was isolated as a yellow solid (1.38 g, 56%).
Mp 110ꢀ111 °C; 1H NMR (400 MHz, CDCl3) δ 8.19 (1H, dd, J = 8.2
and 1.4, Ar), 7.82ꢀ7.76 (1H, m, Ar), 7.68ꢀ7.62 (1H, m, Ar), 7.50 (1H,
dd, J = 7.9 and 1.3, Ar), 5.52 (1H, d, J = 2.6, CH2), 4.68 (1H, d, J = 2.6,
CH2), 3.19 (3H, s, NMe); 13C NMR (100 MHz, CDCl3) δ 161.9, 153.0,
145.8, 136.3, 134.5, 130.8, 130.2, 126.7, 126.3, 95.8, 25.1. Anal. Calcd for
C11H9N3O4: C, 53.4; H, 3.7; N, 17.0. Found: C, 53.4; H, 3.5; N, 17.0.
The sample did not give a molecular ion in the mass spectrum.
3-Methyl-1-(2-tert-butylphenyl)-5-methyleneimidazol-
dine-2,4-dione (3f). The product was isolated as off-white crystals
(2.04 g, 79%). Mp 68ꢀ69 °C; 1H NMR (400 MHz, CDCl3) δ 7.60 (1H,
dd, J = 8.2 and 1.5, Ar), 7.44ꢀ7.39 (1H, m, Ar), 7.33ꢀ7.27 (1H, m, Ar),
6.99 (1H, dd, J = 7.8 and 1.5, Ar), 5.49 (1H, d, J = 2.0, CH2), 4.39 (1H, d,
J = 2.0, CH2), 3.19 (3H, s, NMe), 1.33 (9H, s, tBu); 13C NMR (100
MHz, CDCl3) δ 162.6, 154.3, 149.8, 139.6, 131.2, 131.0, 129.9, 129.0,
127.8, 97.4, 35.6, 31.5, 25.0. Anal. Calcd for C15H18N2O2: C, 69.7; H,
7.0; N, 10.8; [M+] 258.1363. Found: C, 69.9; H, 7.2; N, 11.0; [M+]
258.1360.
Figure 2. Molecular diagram of cycloadduct 4e with 50% thermal
ellipsoids and hydrogen atoms as spheres of arbitrary size.
20-nitro derivative 4e only formed as a single atropisomer during
the NOC reaction as far as we could detect. The greater facial
selectivity in this system, as compared to the 20-tert-butyl system,
presumably reflects some additional electrostatic repulsion be-
tween the nitro group and the approaching nitrile oxide. Such
electrostatic repulsion between nitrile oxides and fluorine has
been postulated by Dolbier38 and Houk39 to explain facial
selectivity in related systems. Crystals of cycloadduct 4e grew
slowly out of ethyl acetate/hexane and a single crystal X-ray
structure was obtained (Figure 2). The molecule crystallized in
the centrosymmetric orthorhombic space group Pbca, with both
enantiomers present in the crystal (Supporting Information). A
single diastereomer, where the cycloaddition had occurred on the
face anti to the 20-nitro substituent of the N-aryl ring, was
observed. This observation is consistent with the NMR and
computational data, and confirms the hypothesis that facial
selectivity in these reactions is controlled by atropisomeric
induction. We are currently examining additional methylene
heterocyclic dipolarophiles to see if this finding holds across
other systems.
3-Methyl-5-methylene-1-(2-phenylphenyl)imidazolidine-
2,4-dione (3g). The product was isolated as a white solid (1.86 g,
’ EXPERIMENTAL SECTION
1
General experimental methods have been previously described.19
General Procedure for the Synthesis of 1-Aryl 3-Methyl-5-
methyleneimidazolidine-2,4-diones (3). Triethylamine (10 mmol)
was cautiously added to an ice-cooled solution of N-methyl propiolamide32
(10 mmol) and the appropriate aryl isocyanate (10 mmol) in anhydrous
THF. The stirred mixture was allowed to warm to room temperature
overnight. The solvent was evaporated, and the residue was recrystallized
from chloroform/hexane unless otherwise stated.
3-Methyl-5-methylene-1-phenylimidazolidine-2,4-dione
(3a). The product was isolated as a fine off-white powder (1.54 g, 76%)
and recrystallized from EtOH. Mp 148ꢀ150 °C (lit.8 153ꢀ156 °C); 1H
NMR (400 MHz, CDCl3) δ 7.53ꢀ7.47 (2H, m, Ar), 7.43ꢀ7.38 (1H, m,
Ar), 7.36ꢀ7.32 (2H, m, Ar), 5.50 (1H, d, J = 2.2, CH2), 4.86 (1H, d, J =
2.2, CH2), 3.19 (3H, s, NMe); 13C NMR (50 MHz, CDCl3) δ 162.3,
153.4, 136.9, 133.0, 129.7, 126.8, 95.8, 24.9.
67%). Mp 118ꢀ119 °C; H NMR (400 MHz, CDCl3) δ 7.57ꢀ7.46
(3H, m, Ar), 7.37ꢀ7.28 (4H, m, Ar), 7.25ꢀ7.22 (2H, m, Ar), 5.29 (1H,
d, J = 2.1, CH2), 4.49 (1H, d, J = 2.1, CH2), 3.05 (3H, s, NMe); 13C
NMR (50 MHz, CDCl3) δ 162.2, 153.4, 141.7, 138.3, 137.2, 131.4,
130.2, 129.8, 129.3, 128.9, 128.5, 127.9, 127.8, 96.0. HRMS-EI calcd for
C17H14N2O2: [M+] 278.1050. Found: [M+] 278.1058.
General Procedure for Benzonitrile Oxide Cycloadditions
with 1-Aryl 3-Methyl-5-methyleneimidazolidine-2,4-diones.
A solution of benzaldehyde oxime (12 mmol) and the appropriate 1-aryl-
3-methyl-5-methyleneimidazolidine-2,4-dione3 (4 mmol) inCH2Cl2 was
cooled to 0 °C and treated with aqueous NaOCl (5%, 24 mmol) added in
portions over 30 min. The vigorously stirred mixture was allowed to warm
to room temperature overnight. The layers were separated, and the
aqueous phase was extracted with CH2Cl2. The solvent was removed
under reduced pressure. The crude reaction mixture was analyzed by 1H
NMR, and the product was purified as stated.
8-Methyl-3,6-diphenyl-1-oxa-2,6,8-triazaspiro[4.4]non-2-
ene-7,9-dione (4a). The product was isolated as a pale yellow solid
(1.03 g, 80%) and recrystallized from isopropyl alcohol. Mp 128ꢀ
129 °C; 1H NMR (400 MHz, CDCl3) δ 7.53ꢀ7.49 (2H, m, Ar),
3-Methyl-5-methylene-1-(2-methylphenyl)imidazolidine-
2,4-dione (3b). The product was isolated as a white solid (1.90 g,
88%). Mp 81ꢀ82 °C; 1H NMR (400 MHz, CDCl3) δ 7.43ꢀ7.29 (3H,
m, Ar) 7.19 (1H, d, J = 7.7, Ar), 5.43 (1H, d, J = 2.0, CH2), 4.49 (1H,
d, J = 2.0, CH2), 3.19 (3H, s, NMe), 2.19 (3H, s, Me); 13C NMR
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NOTE
7.44ꢀ7.33 (7H, m, Ar), 7.33ꢀ7.27 (1H, m, Ar), 3.85 (1H, d, J = 17.8,
C4-Ha), 3.34 (1H, d, J = 17.8, C4-Hb), 3.21 (3H, s, NMe); 13C NMR
(100 MHz, CDCl3) δ 169.1, 156.6, 153.9, 132.9, 130.9, 129.6, 128.8,
128.4, 127.7, 126.8, 126.5, 96.0, 39.4, 25.4. Anal. Calcd for C18H15N3O3:
C, 67.3; H, 4.7; N, 13.1; [M+] 321.1108. Found: C, 67.1; H, 4.7; N, 13.2;
[M+] 321.1098.
168.9, 157.0, 153.3, 134.6, 131.1, 130.2, 129.8, 128.9, 127.4, 126.9, 126.4,
125.6, 96.1, 77.2, 39.6, 25.6. Anal. Calcd for C18H14N4O5: C, 59.0; H, 3.85; N,
15.3; [M+] 366.0959. Found: C, 58.8; H, 3.8; N, 15.2; [M+] 366.0951.
6-(2-tert-Butylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-tri-
azaspiro[4.4]non-2-ene-7,9-dione (4f). The residue was purified
by column chromatography (2% MeOH in CH2Cl2) to give a white
solid (0.68 g, 45%). Mp 157ꢀ159 °C; 1H NMR (400 MHz, CDCl3) δ
[major atropisomer] 7.53ꢀ7.48 (4H, m, Ar), 7.40ꢀ7.30 (4H, m, Ar),
7.23ꢀ7.17 (1H, m, Ar), 3.86 (1H, d, J = 17.5, C4-Ha), 3.38 (1H, d, J =
17.5, C4-Hb), 3.20 (3H, s, NMe), 1.37 (9H, s, tBu); [minor
atropisomer] 7.64ꢀ7.60, (1H, m, Ar), 7.49ꢀ7.47 (2H, m, Ar), 7.42ꢀ
7.28 (4H, m, Ar), 7.22ꢀ7.14 (1H, m, Ar), 6.92 (1H, dd, J = 7.8 and 1.4,
Ar), 3.80 (1H, d, J = 17.6, C4-Ha), 3.69 (1H, d, J = 17.6, C4-Hb), 3.21
(3H, s, NMe), 1.48 (9H, s, tBu); 13C NMR (100 MHz, CDCl3) δ
[major atropisomer] 169.2, 156.0, 155.5, 148.4, 132.3, 130.8, 130.3,
129.8, 128.8, 128.3, 128.0, 127.5, 126.6, 97.1, 36.8, 36.5, 32.5, 25.3;
[minor atropisomer] 170.0, 155.7, 154.8, 151.7, 132.2, 131.3, 130.8,
129.7, 129.1, 128.8, 127.8, 126.7, 126.6, 96.7, 39.9, 36.8, 31.9, 25.4. Anal.
Calcd for C22H23N3O3: C, 70.0; H, 6.1; N, 11.1; [M+] 377.1734. Found:
C, 69.9; H, 6.3; N, 10.85; [M+] 377.1730.
8-Methyl-6-(2-methylphenyl)-3-phenyl-1-oxa-2,6,8-triazas-
piro[4.4]non-2-ene-7,9-dione (4b). The residue was purified by
columnchromatography (4% MeOH in CH2Cl2) to give an off-white solid
(0.99 g, 74%). Mp 73ꢀ74 °C; 1H NMR (400 MHz, CDCl3) δ [major
atropisomer] 7.53 (1H, d, J = 7.6, Ar), 7.49ꢀ7.43 (2H, m, Ar), 7.42ꢀ7.30
(3H, m, Ar), 7.29ꢀ7.12 (3H, m, Ar), 3.84 (1H, d, J = 17.6, C4-Ha), 3.21
(3H, s, NMe), 3.11 (1H, d, J = 17.6, C4-Hb), 2.24 (3H, s, Me); [minor
atropisomer] 7.49ꢀ7.43 (2H, m, Ar), 7.42ꢀ7.30 (4H, m, Ar), 7.29ꢀ7.12
(2H, m, Ar), 7.08 (1H, d, J = 7.3, Ar), 3.94 (1H, d, J = 17.6, C4-Ha), 3.65
(1H, d, J = 17.6, C4-Hb), 3.22 (3H, s, NMe), 2.43 (3H, s, Me); 13C NMR
(100 MHz, CDCl3) δ [major atropisomer] 169.5, 156.1, 153.4, 139.5,
136.6, 132.2, 130.8, 129.6, 129.3, 128.8, 127.9, 127.8, 127.6, 96.1, 38.5, 25.3,
18.2; [minor atropisomer] 169.5, 155.8, 154.1, 139.5, 136.6, 132.2, 131.0,
129.8, 129.2, 128.8, 127.7, 127.6, 126.8, 96.4, 40.0, 25.4. Anal. Calcd for
C19H17N3O3: C, 68.05; H, 5.1; N, 12.5; [M+] 335.1264. Found: C, 68.8;
H, 5.2; N, 12.0; [M+] 335.1253.
6-([1,10-Biphenyl]-2-yl)-8-methyl-3-phenyl-1-oxa-2,6,8-
triazaspiro[4.4]non-2-ene-7,9-dione (4g). The residue was
purified by column chromatography (2% MeOH in CH2Cl2) to give
a white powder (0.97 g, 61%). Mp 163ꢀ165 °C; 1H NMR (400 MHz,
CDCl3) δ [major atropisomer] 7.56ꢀ7.50 (1H, m, Ar), 7.48ꢀ7.27
(13H, m, Ar), 3.38 (1H, d, J = 17.8, C4-Ha), 3.18 (3H, s, NMe), 2.68
(1H, d, J = 17.8, C4-Hb); [minor atropisomer] 7.48ꢀ7.27 (12H, m,
Ar), 7.20 (2H, d, J = 7.7, Ar), 3.81 (1H, d, J = 17.7, C4-Ha), 3.51 (1H,
d, J = 17.7, C4-Hb), 3.11 (3H, s, NMe); 13C NMR (100 MHz, CDCl3)
δ 169.1, 156.0, 155.6, 141.9, 139.1, 131.9, 131.0, 129.6, 129.1, 128.7,
128.1, 127.6, 126.7, 96.1, 38.5, 25.5. Anal. Calcd for C24H19N3O3: C,
72.5; H, 4.8; N, 10.6; [M+] 397.1426. Found: C, 72.7; H, 4.9; N, 10.3;
[M+] 397.1415.
6-(2,5-Dimethylphenyl)-8-methyl-3-phenyl-1-oxa-2,6,8-
triazaspiro[4.4]non-2-ene-7,9-dione (4c). The solid residue was
recrystallized from hexane/ethyl acetate (2:1) to give the product as a
1
white powder (0.92 g, 66%). Mp 123ꢀ124 °C; H NMR (400 MHz,
CDCl3) δ [major atropisomer] 7.51ꢀ7.45 (2H, m, Ar), 7.43ꢀ7.31 (4H,
m, Ar), 7.14 (1H, d, J = 7.8, Ar), 7.06 (1H, d, J = 7.8, Ar), 3.82 (1H, d, J =
17.6, C4-Ha), 3.20 (3H, s, NMe), 3.11 (1H, d, J = 17.6, C4-Hb), 2.26
(3H, s, Me), 2.18 (3H, s, Me); [minor atropisomer] 7.51ꢀ7.45 (2H, m,
Ar), 7.43ꢀ7.31 (3H, m, Ar), 7.18 (1H, d, J = 7.8, Ar), 7.06 (1H, d, J = 7.8,
Ar), 6.88 (1H, s, Ar) 3.91 (1H, d, J = 17.6, C4-Ha), 3.64 (1H, d, J = 17.6,
C4-Hb), 3.21 (3H, s, NMe), 2.37 (3H, s, Me), 2.21 (3H, s, Me); 13C
NMR (100 MHz, CDCl3) δ [major atropisomer] 169.6, 156.1, 130.5,
129.8, 127.9, 96.2, 38.3, 25.4, 20.8, 17.8; [minor atropisomer] 169.5,
155.9, 130.7, 130.5, 129.7, 127.9, 96.5, 39.9, 25.4, 20.7, 17.9; signals that
cannot be assigned to one atropisomer or the other: 153.5, 137.5, 136.5,
136.2, 133.3, 132.0, 130.8, 128.8, 126.7. Anal. Calcd for C20H19N3O3: C,
68.75; H, 5.5; N, 12.0; [M+] 349.1421. Found: C, 68.8; H, 5.45; N, 12.1;
[M+] 349.1411.
’ ASSOCIATED CONTENT
S
Supporting Information. Copies of NMR spectra, X-ray
b
structure data and CIF file, and molecular simulation data. This
material is available free of charge via the Internet at http://pubs.
acs.org.
8-Methyl-6-(1-naphthalenyl)-3-phenyl-1-oxa-2,6,8-triazas-
piro[4.4]non-2-ene-7,9-dione (4d). The crude residue was recrys-
tallized from hexane/ethyl acetate (2:1) to give the product as a white
solid (1.05 g, 71%). Mp 191ꢀ192 °C; 1H NMR (400 MHz, CDCl3) δ
[major atropisomer] 7.92ꢀ7.77 (3H, m, Ar), 7.69ꢀ7.39 (4H, m, Ar),
7.38ꢀ7.27 (4H, m, Ar), 7.25ꢀ7.20 (1H, m, Ar), 3.85 (1H, d, J = 17.8, C4-
Ha), 3.28 (3H, s, NMe), 3.21 (1H, d, J = 17.8, C4-Hb); [minor
atropisomer] 8.20 (1H, d, J = 8.6, Ar), 7.92ꢀ7.77 (2H, m, Ar), 7.69ꢀ
7.39 (4H, m, Ar), 7.38ꢀ7.27 (4H, m, Ar), 7.25ꢀ7.20 (1H, m, Ar), 3.97
(1H, d, J = 17.6, C4-Ha), 3.73 (1H, d, J = 17.6, C4-Hb), 3.28 (3H, s,
NMe); 13C NMR (100 MHz, CDCl3) δ [major atropisomer] 169.5,
156.3, 154.2, 130.7, 127.6, 96.5, 38.7, 25.5; [minor atropisomer] 169.5,
156.3, 154.2, 130.7, 127.6, 96.5, 39.7, 25.5; signals that cannot be assigned
to one atropisomer or the other: 134.4, 131.0, 130.2, 129.0, 128.7, 128.3,
128.2, 128.0, 127.5, 127.0, 126.7, 126.5, 126.0, 124.9, 123.9, 121.7. Anal.
Calcd for C22H17N3O3: C, 71.15; H, 4.6; N, 11.3; [M+] 371.1264. Found:
C, 71.15; H, 4.6; N, 11.3; [M+] 371.1261.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: paul.savage@csiro.au.
’ ACKNOWLEDGMENT
We thank Dr. Leaf Lin and Dr. Michelle Coote of the
Australian National University, Research School of Chemistry
for molecular simulation calculations and Dr. Craig Forsyth of
Monash University for X-ray structure determination.
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