Synthesis and thermolysis rate constants of diastereomeric oxadiazoline sources of acetoxy(methoxy)carbene - Reaction of acetoxy(methoxy)carbene with isocyanates

Article abstract of DOI:10.1139/V06-109

Oxidation of the methoxycarbonylhydrazone of p-methoxyacetophenone affords both the cis- and trans-2-acetoxy-2-methoxy-5-(p-methoxyphenyl)-5-methyl- Δ³-1,3,4-oxadiazolines (also known as corresponding 2,5-dihydro-1,3,4-oxadiazoles) as well as m

Full text of DOI:10.1139/V06-109

927
Synthesis and thermolysis rate constants of
diastereomeric oxadiazoline sources of
acetoxy(methoxy)carbene — Reaction of
acetoxy(methoxy)carbene with isocyanates
Wojciech Sokol and John Warkentin
Abstract: Oxidation of the methoxycarbonylhydrazone of p-methoxyacetophenone affords both the cis- and trans-2-
acetoxy-2-methoxy-5-(p-methoxyphenyl)-5-methyl-∆3-1,3,4-oxadiazolines (also known as corresponding 2,5-dihydro-
1,3,4-oxadiazoles) as well as methyl 1-acetoxy-1-(p-methoxyphenylethyl)diazenecarboxylate. The three isomers were
separated and identified by spectroscopic means. Methyl 1-acetoxy-1-(p-methoxyphenylethyl)diazenecarboxylate is the
major product from oxidation in dichloromethane. Oxidation in acetic acid did not afford the oxadiazolines but gave
the diazenecarboxylate and, in addition, 1-(p-methoxyphenyl)ethyl acetate. Attempts to isomerize the diazenecarboxylate to
the oxadiazolines by acid catalysis were not successful. Thermolysis of the oxadiazolines at 50.4 °C occurred with ap-
proximately the same rate constant (ca. 3.6 × 10–5 s–1) to afford acetoxy(methoxy)carbene, which rearranges to methyl
pyruvate by acetyl transfer. The carbene, which reacts with relatively unhindered isocyanates to transfer the methoxy-
carbonyl group to carbon and the acetyl group to nitrogen, can be considered an acyl anion equivalent in that reaction.
Key words: acetoxy(methoxy)carbene, diazene, oxadiazoline, isocyanate, (acetylamino)oxoacetate.
Résumé : L’oxydation de la méthoxycarbonylhydrazone de la p-méthoxyacétophénone conduit à la formation d’un mé-
lange des 2-acétoxy-2-méthoxy-5-(p-méthoxyphényl)-5-méthyl-∆3-1,3,4-oxadiazolines cis et trans (aussi connues sous le
nom des 2,5-dihydro-1,3,4-oxadiazoles correspondantes) accompagné de 1-acétoxy-1-(p-méthoxyphényléthyl)diazènecar-
boxylate de méthyle. On a séparé les trois isomères et on les a identifiés par des méthodes spectroscopiques. Le 1-
acétoxy-1-(p-méthoxyphényléthyl)diazènecarboxylate de méthyle est le produit majeur de l’oxydation dans le dichloro-
méthane. L’oxydation dans l’acide acétique ne fournit pas d’oxadiazolines, mais conduit à la formation du diazènecar-
boxylate ainsi qu’à de l’acétate de 1-(p-méthoxyphényl)éthyle. On n’a pas réussi dans nos tentatives d’isomériser le
diazènecarboxylate en oxadiazolines par catalyse acide. Les constantes de vitesse des thermolyses de chacune des oxa-
diazolines effectuées à 50,4 °C sont approximativement les mêmes, soit environ 3,6 × 10–5 s–1, et elles conduisent tou-
tes les deux à la formation d’acétoxy(méthoxy)carbène qui se réarrange en pyruvate de méthyle par transfert d’un
groupe acétyle. Le carbène, qui réagit avec les isocyanates non encombrées pour conduire à un transfert du groupe mé-
thoxycarbonyle vers le carbone et du groupe acétyle vers l’azote, peut être considéré comme équivalent à un anion
acyle dans cette réaction.
Mots clés : acétoxy(méthoxy)carbène, diazène, oxadiazoline, isocyanate, (acétylamino)oxoacétate.
[Traduit par la Rédaction] Sokol and Warkentin 933
Introduction
(methoxy)carbene (also known as (acetyloxy)methoxy-
methylene), which had been generated earlier at 110 °C (2),
might have interesting properties, similar to those of ace-
toxy(methylthio)carbene that were reported in 2005,
Scheme 1 (2). The diastereomers were separated and identi-
fied. We now report their spectra and rate constants for their
thermolysis to carbonyl ylides that, in turn, fragment rapidly
to acetoxy(methoxy)carbene. The carbene was intercepted
with various isocyanates to afford methyl (acetyla-
mino)oxoacetates.
Generation of dimethoxycarbene from 2,2-dimethoxy-5-
(p-methoxyphenyl)-5-methyl-∆3-1,3,4-oxadiazoline was re-
ported recently (1). The p-methoxyphenyl substituent pro-
1
vided an extra methoxy signal in the H NMR spectrum and
it lowered the temperature for generation of the carbene
from about 110 °C (for the 5,5-dimethyl analogue) to about
50 °C. We decided to make the isomeric 2-acetoxy-2-meth-
oxy-5-(p-methoxyphenyl)oxadiazolines because acetoxy-
Received 27 February 2006. Accepted 9 June 2006. Published
on the NRC Research Press Web site at http://canjchem.nrc.ca
on 27 July 2006.
Results and discussion
The isomeric oxadiazolines, 2a and 2b (also known as
corresponding 2,5-dihydro-1,3,4-oxadiazoles), were pre-
pared by oxidative cyclization (3) of a mixture of the (E)-
and (Z)-methoxycarbonylhydrazones (1) of p-methoxy-
W. Sokol and J. Warkentin.1 Department of Chemistry,
McMaster University, Hamilton, ON L8S 4M1, Canada.
1Corresponding author (e-mail: warkent@mcmaster.ca).
Can. J. Chem. 84: 927–933 (2006)
doi:10.1139/V06-109
© 2006 NRC Canada

928
Can. J. Chem. Vol. 84, 2006
Scheme 1.
Scheme 3.
Ar
MeS OAc
O
O
Pb(OAc)4
O
N
110 0C
C6D6
Me
..
MeSCOCMe
Me
N
O
N
H
MeS
MeS
OMe
Me
N
O
O
Me
Ar= p-MeOC6H4
..
MeSCOCMe
Ar
O
Ar
O
+
OMe
SMe
O
Me
O
OCOMe
Me
N
+
+
Me
MeS
Me
MeS
N
4
N N
OMe
O
O
5
HOAc
HOAc
O
O
Me
3
2
Scheme 2.
(instead of cationic intermediates,
there could be intermediates containing lead)
O
Pb(OAc)4
CH2Cl2
OMe
N
N
of an oxadiazoline is a disrotatory process, requiring that cis
substituents at C-2 and C-5 rotate either both inward (endo)
or both outward (exo) (5). Substituents in a trans relation-
ship place one group endo and the other exo. Assuming that
the aryl group has the largest steric requirement at C-5 and
that polar effects are less important, one would predict that
oxadiazoline 2a would form ylide 7b in preference to 7a.
Similarly, 2b should form 7c in preference to 7d
(Scheme 5). There was little hope of trapping those ylides,
whose lifetimes are probably very short (6, 7), with barriers
MeOC6H4
H
Me
1
MeO OAc
OAc
O
N
MeOC6H4
N
O
+
N
N
OMe
Me
OMe
Me
to fragmentation to carbene and ketone of only
a
2a (trans) (20%)
2b
3 (56%)
few kcal mol–1 (1 cal = 4.184 J), but rate constants for
thermolysis of the isomeric precursors could be measured.
Those rate constants are a measure of the difference between
ground-state and transition-state energies.
(cis) (7%)
acetophenone with lead tetraacetate in dichloromethane. The
products isolated were 2a (20%), 2b (7%), and a surpris-
ingly large amount of an acyclic isomer 3 (ca. 56%)
(Scheme 2). Oxidation in dry acetic acid did not produce 2
but gave 3 (28%) as well as 1-(p-methoxyphenyl)ethyl ace-
tate (22%).
The formation of 3 as a major oxidation product
(Scheme 2) suggests that there are cationlike precursors of
the type 4 and 5 (Scheme 3). Exchange of acetoxy for
methoxy, allyloxy (4), or other hydroxyl-containing groups
under conditions of acid catalysis supports the intermediacy
of ions such as 4 under exchange conditions. Probably, ion 4
does not cyclize easily to 5 because the stabilization af-
forded by the p-methoxyphenyl group is lost if the species
cyclizes.
Cyclization in acetic acid was explored in the expectation
that better solvation of cationlike intermediates would lessen
the energy difference between 4 and 5. Oxidation in acetic
acid did not result in any oxadiazolines 2. Attempts to
isomerize 3 into a mixture of the diastereomers 2 by means
of acid catalysis (CF3CO2H–CH3CO2H in CH2Cl2) did not
succeed either. In the latter case, equal amounts of p-
methoxyacetophenone and 1-(p-methoxyphenyl)ethyl acetate
(6) (22%) were obtained. We suggest that those arise
through the reactions shown in Scheme 4.
The ratio in which oxadiazolines 2a and 2b were formed
by oxidation of 1 (Scheme 2) suggested that 2b is more hin-
dered and that it was expected to thermolyse more rapidly
than 2a. Oxadiazolines 2a and 2b are expected to undergo
thermolysis by concerted 1,3-dipolar cycloreversion, to af-
ford carbonyl ylides 7a–7d (Scheme 5). The cycloreversion
It turned out that 2b does thermolyse faster than 2a
–1
–1
(3.74 × 10–5
s
vs. 3.49 × 10–5
s
in benzene at 50.4 °C).
Isomer 2b should have a higher ground-state energy than
isomer 2a, while the transition states for thermolysis of the
isomers could be more nearly isoenergetic. Of course, the
fact that 2b could place both larger substituents exo (7c,
Scheme 5) should favour its thermolysis additionally, but
there would be a statistical penalty (a factor ≤ 2) involved in
a restriction that favours outward rotation of the larger
groups. The result suggests that the difference between the
steric factors that operate in 2a and 2b is relatively small
and probably partly compensated for by the statistical factor.
The putative carbonyl ylide intermediate shown in
Scheme 5 has never been observed. Computations (7) on the
dimethyl analog (rather than aryl methyl as in Scheme 2) in-
dicate that the ylide is a real intermediate with a barrier to
fragmentation to acetoxy(methoxy)carbene and ketone of
about 2 to 3 kcal mol–1. Although the aryl group of 7 could
change that barrier, a change large enough to make the ylide
trappable by conventional 1,3-dipolarophiles is hard to imag-
ine. In an attempt to trap the ylide, thermolysis was carried
out in neat phenyl isothiocyanate, which has been shown to
1
trap carbonyl ylides (8). The H NMR spectrum of the crude
product showed p-methoxyacetophenone as the major prod-
uct (>85%) with the characteristic pair of doublets at low
field.
Evidence of the intermediacy of acetoxy(methoxy)carbene
(9) (also known as (acetyloxy)methoxymethylene) came
from two sources. First, it is known from both experiment
(9) and theory (6) that the carbene rearranges to methyl
© 2006 NRC Canada

Sokol and Warkentin
929
Scheme 4.
OAc
OAc
+
OAc
+
H+
N
O
N
OH
MeOC6H4
MeOC6H4
N
N
MeOC6H4
HOAc
Me
Me
OMe
OMe
Me
O
HOAc
MeOC6H4
OAc
Me
OAc
OAc
.
N
O
MeOC6H4
MeOC6H4
MeOC6H4
H
N
Me
Me
Me
OMe
6
isocyanate afforded many products (many OMe signals in
the H NMR spectrum), suggestive of extensive rearrange-
Scheme 5.
1
OAc
OMe
MeO OAc
ment of the carbene and subsequent reactions of methyl
pyruvate. Although the isocyanate appeared to be unchanged
MeO
AcO
Me
N
O
O
_
O
+
_
+
+
1
N
Ar
(only one tert-butyl signal in the H NMR spectrum), a low
Ar
Me
Ar
yield of the appropriate 12 (<5%) could not be excluded.
Neat phenyl isothiocyanate mixed 1:1 with 2 also did not af-
ford any of the expected product.
Me
7a
7b
2a
A possible mechanism for the reaction of 9 with iso-
cyanates is shown in Scheme 7. Acetoxy(methoxy)carbene
must be nucleophilic toward isocyanates. Although that carbene
has not been placed on a nucleophilicity scale (11), it is
probably ambiphilic toward alkenes. Trifluoroethoxy(meth-
oxy)carbene is ambiphilic toward alkenes (12) and the
acetoxy is only a little poorer than trifluoroethoxy as an
electron donor (13). However, philicity depends on the part-
ner; for example, acetic acid is acidic towards water and ba-
sic towards sulfuric acid.
MeO OAc
OAc
OMe
O+
MeO
Me
AcO
Ar
N
O
O
_
+
+
_
N
Ar
Me
Ar
7c
Me
2b
7d
(only one of many contributing
structures for the ylides is shown)
1
A nucleophilic singlet carbene is expected to attack an
isocyanate at the carbonyl carbon atom to generate
zwitterion 12 or it could add to either double bond in a con-
certed process. However, the three-membered rings resulting
from the latter process would have to undergo ring opening
and acetyl transfer (2) to arrive at the product. Model α-lac-
tams or iminooxiranes with gem-dialkoxy and carboxylate
functions at the ring carbons, which could help to resolve
the latter aspect, are unknown and there was no evidence for
ring formation in the present case. On the other hand, there
are many precedents for formation of zwitterionic intermedi-
ates in nonpolar solvents (14).
α-Lactams and iminooxiranes that could form by ring clo-
sure of 12 may well be unstable at 50 °C. Lengyel et al. (15)
reported that α-lactams that are thermally unstable and
chemically reactive afford 3-benzylamino products upon re-
action with benzyl amine (Scheme 8). A possible explana-
tion of that result is that such lactams open easily to
zwitterions of the type 12. Such an open form of an α-
lactam was invoked by Ohshiro et al. (16) to account for the
product from a reaction with a vinyl isocyanate (Scheme 9).
There is also good evidence that gem-dialkoxycyclopropanes
undergo thermal ring opening at moderate temperatures (17–
20). In the present case, the negative charge of an intermedi-
ate is dispersed by conjugation, making it more likely that a
three-membered-ring system (not shown in Scheme 7)
would either not be formed or would open easily to 12.
Phenyl isothiocyanate is known to be less reactive, by a
pyruvate (10). That product could be detected by H NMR
spectroscopy during kinetic runs in C6D6, but amounted to
only 5% of the signal from p-methoxyacetophenone at 30%
reaction and only about 2% when essentially all of the
oxadiazoline had fragmented (Scheme 6). The reason for the
low yield lies in the fact that methyl pyruvate is very self-
reactive and does not survive the reaction conditions (10).
Rearrangement of acetoxy(methoxy)carbene to methyl
pyruvate could be suppressed, but not eliminated, by an
isocyanate (11) at high concentration. The pyruvate could al-
ways be detected (≤2%) among the crude reaction products.
Eight isocyanates, with a variety of functional groups rang-
ing from unhindered alkyl to hindered alkyl and from phenyl
to variously substituted phenyls (Scheme 7) at nitrogen were
treated with 2 at 50.4 °C. A liquid isocyanate (1 equiv. or
more) was mixed with the liquid oxadiazolines 2 prior to de-
gassing and heating. Homogeneous solutions resulted. A
solid isocyanate, melting near 50 °C, and 2 gave a homoge-
neous solution immediately after the mixture had been
heated to 50.4 °C. In the cases of aryl or alkyl isocyanates,
except for tert-butyl isocyanate, reaction occurred to yield
methyl (acetylamino)oxoacetates 12 (Scheme 7). Yields, not
optimized, ranged from 48% for isopropyl isocyanate to
76% for phenyl isocyanate, after flash chromatography on
silica. Product 12c was obtained simply by washing the
crude with ethyl acetate – hexane. Compound 12c and other
solid products from column chromatography were
recrystallized from a benzene–hexane mixture. tert-Butyl
© 2006 NRC Canada

930
Can. J. Chem. Vol. 84, 2006
Scheme 6.
MeO OAc
O
O
50 0C
C6D6
..
MeOCOCMe +
N
O
MeO
carbonyl ylide
N
OMe
9
Me
acyl migration
Me
2
MeCOCO2Me
10
products of self reaction
Scheme 7.
OAc
O
MeO
N
50.4 0C, benzene
OMe
O
N
:
AcO(MeO)C + N2
+
MeO
Me
Me
2
9
-
O
O
O
N
R
OMe
O
R
OMe
:
RNCO + AcO(MeO)C
11
N
+
+
O
-
O
9
12
OAc
OAc
a
b
) R= Ph; ) R= o-MeOC6H4; ) R= p-O2NC6H4;
c
O
O
d
e
f
g
) R= p-ClC6H4; ) R = Et; ) R = n-Bu; ) R= i-Pr
R
OMe
N
O
Me
13
Rad FTS 40 spectrometer and mass spectra were run with a
Waters Micromass GCT instrument. Melting points were
measured with a Uni-Melt Thomas Hoover capillary melting
point apparatus. Yields were not optimized.
Scheme 8.
R1 R2
O
H
N
R3
N
R3
+
N
NH2
R1
H
O
R2
2-Acetoxy-2-methoxy-5-(p-methoxyphenyl)-5-methyl-∆3-
1,3,4-oxadiazoline (2)
(a chemically reactive,
thermally unstable species)
Lead tetraacetate (7.49 g, 16.05 mmol, 95% purity) was
dissolved in dichloromethane (50 mL), the solution was
cooled to about 0 °C, and the methoxycarbonylhydrazones
of p-methoxyacetophenone (3.61 g, 16.24 mmol) were
added in the solid state. After 0.5 h the temperature had
risen to 25 °C and the mixture was stirred for an additional
4 h. It was filtered through a bed of Celite to afford a clear
solution. The Celite cake was extracted with dichloro-
methane (2 × 25 mL) and the combined organic solution was
washed twice with aqueous sodium bicarbonate (2 × 25 mL)
and dried over MgSO4. Evaporation of the solvent at room
temperature left 4.84 g of crude product. The 1H NMR spec-
trum of the mixture revealed the ratios of isomers 3:2a:2b as
67.1:24.4:8.5. The products were purified by flash-
chromatography on silica with diethyl ether – hexane
(25:75) as eluent. Isolated were 3 (2.53 g, 9.02 mmol, 56%)
and the diastereomers 2a and 2b (1.10 g, 3.91 mmol,
24.4%). Separation of the oxadiazolines was carried out by
centrifugal chromatography with a Chromatotron® appara-
tus.
factor of 11, than phenyl isocyanate toward dimethoxy-
carbene at 140 °C (21). With a less nucleophilic carbene
(acetoxy(methoxy)carbene) and a lower temperature (50.4
rather than 140 °C), the difference in reactivity between
phenyl isocyanate and phenyl isothiocyanate could well be
larger than 11. A product analogous to 12 (Scheme 7) was
not obtained with phenyl isothiocyanate.
Summary
Diastereomeric oxadiazoline sources of acetoxy(meth-
oxy)carbene were synthesized, separated, and fully charac-
terized. Their thermolyses in benzene at 50.4 °C occurred
with roughly equal rate constants (ca. 3.6 × 10–5 s–1) and
they afforded acetoxy(methoxy)carbene. The carbene reacted
with various isocyanates to add the methoxycarbonyl group
at carbon and the acetyl group at nitrogen. In its addition at
carbon, the carbene behaved as an acyl anion equivalent.
Experimental
trans-2-Acetoxy-2-methoxy-5-(p-methoxyphenyl)-5-
methyl-∆3-1,3,4-oxadiazoline (2a, major diastereomer)
Pale pink oil. IR (neat, cm–1): 3000, 2955, 2843, 1774,
NMR spectra were taken with Bruker Avance 600 MHz
and Bruker Avance 200 MHz instruments operating at fre-
quencies given in each section. IR spectra came from a Bio
1
1612, 1514, 1446, 1372, 1306, 1253, 1032, 834. H NMR
© 2006 NRC Canada

Sokol and Warkentin
931
Scheme 9.
O
O
O
O
O
BuLi/THF
O
O
N
N
N
O
N
H
Cl
NCO
SMe
N
O
O
N
THF
SMe
(200.2 MHz, CDCl3, ppm) δ: 1.88 (s, 3H, CH3), 2.15 (s, 3H,
COCH3), 3.47 (s, 3H, OCH3), 3.78 (s, 3H, C6H4OCH3), 6.87
(d, J = 8.9 Hz, 2H, CHAr), 7.44 (d, J = 8.9 Hz, 2H, CHAr).
1H NMR (200.2 MHz, C6D6, ppm) δ: 1.53 (s, 3H, CH3),
1.95 (s, 3H, CH3), 3.24 (s, 3H, OCH3), 3.29 (s, 3H, OCH3),
6.70 (d, J = 8.9 Hz, 2H, CHAr), 7.49 (d, J = 8.9 Hz, 2H,
CHAr). 13C NMR (50.3 MHz, CDCl3, ppm) δ: 21.43
(COCH3), 24.95 (CH3), 52.87 (OCH3), 55.23 (C6H4OCH3),
113.87 (CHAr), 124.10 (Cbenzyl), 126.41 (CHAr), 130.41
(CAr), 135.11 (Cring), 159.77 (CAr—O), 166.36 (CO). 13C
NMR (50.3 MHz, C6D6, ppm) δ: 20.69 (CH3), 24.85 (CH3),
52.57 (OCH3), 54.74 (OCH3), 114.16 (CHAr), 124.45
(Cbenzyl), 126.87 (CHAr), 131.34 (CAr), 135.86 (Cring), 160.21
(CAr—O), 166.23 (CO). HRMS (CI, NH3) m/z calcd. for
C13H17N2O5: 281.1137 (MH)+; found: 281.1159.
Assignments of the NMR signals are based on 2D correla-
tion spectra. Gradient HMBC and gradient HSQC spectra
were run in CDCl3 with a Bruker AV 600 instrument. The
relative configurations of substituents at C-2 and C-5 was es-
tablished at the same time on the basis of a selective 1D
NOESY experiment with a pulsed field gradient, with the
pulse delay set at 5.0 s and the NOESY mixing time set at
0.6 s. Irradiation of the signal at 1.88 ppm caused enhance-
ment of the signal at 7.44 ppm. Similarly, irradiation at
3.47 ppm caused strong enhancement at 2.15 and 7.44 ppm
and weak enhancement at 6.87 ppm, while irradiation at
3.78 ppm caused signal enhancement at 6.87 ppm.
iments with a pulsed field gradient, as described previously.
Selective irradiation at 1.82 ppm caused signal enhance-
ments at 3.62 and 7.44 ppm, while irradiation at 2.00 ppm
caused strong enhancement at 7.40 ppm and medium en-
hancement at 3.62 ppm. Irradiation at 3.62 and 3.78 ppm
caused enhancements of signals at 1.82 and 6.87 ppm, re-
spectively.
Acyclic isomer 3
Lemon yellow oil. IR (neat, cm–1): 2960, 2842, 1770,
1
1611, 1514, 1439, 1371, 1305, 1252, 1110, 1029, 835. H
NMR (200.2 MHz, CDCl3, ppm) δ: 2.00 (s, 3H), 2.13 (s,
3H), 3.76 (s, 3H), 3.94 (s, 3H), 6.88 (d, J = 8.9 Hz, 2H),
1
7.42 (d, J = 8.9 Hz, 2H). H NMR (200.2 MHz, C6D6, ppm)
δ: 1.73 (s, 3H), 2.00 (s, 3H), 3.218 (s, 3H), 3.222 (s, 3H)
(these signals not resolved), 6.72 (d, J = 8.9 Hz, 2H), 7.46
(d, J = 8.9 Hz, 2H). 13C NMR (50.3 MHz, CDCl3, ppm) δ:
21.53, 23.87, 54.75, 55.07, 102.07, 113.84, 126.98, 130.43,
159.59, 161.75, 168.31. 13C NMR (50.3 MHz, C6D6, ppm)
δ: 21.17, 24.29, 54.04, 54.71, 102.28, 114.23, 127.53,
131.42, 160.17, 162.50, 167.81. HRMS (CI, NH3) m/z calcd.
for C13H17N2O5: 281.1137 (MH)+; found: 281.1130.
Thermolysis of oxadiazolines
A solution of 2b (0.1837 mmol) and tert-butylbenzene
(0.1021 mmol) in C6D6 (1 mL), in an NMR tube fitted with
a ground glass joint, was degassed by means of three freeze–
pump–thaw cycles before the tube was sealed and heated at
50.4 °C. Oxadiazoline 2a (0.2498 mmol) and tert-butyl-
benzene (0.1512 mmol) were treated analogously. Every 3 h,
1H NMR spectra were acquired with the tubes still sealed
and with a pulse delay of 6 s to ensure complete relaxation.
For 2b, the signal at 1.41 ppm was integrated and compared
with the signal of tert-butylbenzene at 1.20 ppm. For 2a, the
signal at 1.95 ppm was integrated and compared with the
signal of tert-butylbenzene. Standard first-order treatment of
the data gave k2b= 3.74 × 10–5 s–1 (seven points, R2 =
0.9914) and k2a= 3.49 × 10–5 s–1 (seven points, R2 =
0.9920).
cis-2-Acetoxy-2-methoxy-5-(p-methoxyphenyl)-5-methyl-
∆3-1,3,4-oxadiazoline (2b, minor diastereomer)
Pale yellow oil. IR (neat, cm–1): 2993, 2955, 2843, 1776,
1
1612, 1515, 1445, 1372, 1306, 1253, 1080, 1031, 834. H
NMR (200.2 MHz, CDCl3, ppm) δ: 1.82 (s, 3H, CH3), 2.00
(s, 3H, COCH3), 3.62 (s, 3H, OCH3), 3.78 (s, 3H,
C6H4OCH3), 6.87 (d, J = 8.9 Hz, 2H, CHAr), 7.40 (d, J =
1
8.9 Hz, 2H, CHAr). H NMR (200.2 MHz, C6D6, ppm) δ:
1.41 (s, 3H, CH3), 1.62 (s, 3H, CH3), 3.22 (s, 3H, OCH3),
3.35 (s, 3H, OCH3), 6.70 (d, J = 8.9 Hz, 2H, CHAr), 7.52 (d,
J = 8.9 Hz, 2H, CHAr). 13C NMR (50.3 MHz, CDCl3, ppm)
δ: 21.28 (COCH3), 26.53 (CH3), 52.95 (OCH3), 55.23
(C6H4OCH3), 113.81 (2CHAr), 123.83 (Cbenzyl), 126.32
(2CHAr), 129.67 (CAr), 134.98 (Cring), 159.77 (CAr—O),
166.06 (CO). 13C NMR (50.3 MHz, C6D6, ppm) δ: 20.62
(CH3), 26.68 (CH3), 52.53 (OCH3), 54.7 (OCH3), 114.10
(2CHAr), 123.86 (Cbenzyl), 126.83 (2CHAr), 130.58 (CAr),
135.83 (Cring), 160.21 (CAr—O), 165.42 (CO).
Attempt to cyclize 3
A solution of 3 (0.32 g, 1.14 mmol) and trifluoroacetic
acid (0.012 g, 0.105 mmol, 10 mol%) in acetic acid (25 mL)
was stirred at room temperature for 9 days. The mixture was
diluted with water (25 mL) and extracted with dichloro-
methane (3 × 15 mL). The solution in dichloromethane was
then washed with aqueous sodium bicarbonate to remove ac-
ids and dried over MgSO4. After flash chromatography on
The relative configurations of substituents at C-2 and C-5
were established on the basis of selective 1D NOESY exper-
© 2006 NRC Canada

932
Can. J. Chem. Vol. 84, 2006
silica with diethyl ether – hexane (25:75), p-methoxyaceto-
phenone (0.038 g, 0.25 mmol, 22%), 1-(p-methoxy-
phenyl)ethyl acetate (0.049 g, 0.25 mmol, 22%), and
unreacted 3 (0.178 g, 0.634 mmol, 55%) were obtained.
Reaction of 2 with p-nitrophenyl isocyanate
Heating 2 with 1.50 equiv. of p-nitrophenyl isocyanate
gave a crude product that was not chromatographed, but was
washed with ethyl acetate – hexane (35:65) to afford yellow
crystals of 12c (mp 107.0–110.0 °C) in 72% yield. IR
(NaCl, cm–1): 3118, 3082, 2955, 1752, 1732, 1710, 1597,
1530, 1352, 1271, 1236, 1141, 855, 750, 699. 1H NMR
(200.2 MHz, CDCl3, ppm) δ: 2.08 (s, 3H), 3.90 (s, 3H), 7.45
(d, J = 9.08 Hz, 2H), 8.37 (d, J = 9.08 Hz, 2H). 13C NMR
(50.3 MHz, CDCl3, ppm) δ: 24.54, 53.18, 125.36, 129.93,
141.22, 148.42, 161.04, 162.11, 170.97. HRMS (CI, NH3)
m/z calcd. for C11H11N2O6: 267.0617 (MH)+; found:
267.0609.
1-(p-Methoxyphenyl)ethyl acetate
Colourless oil. IR (neat, cm–1): 2983, 2938, 2839, 1735,
1614, 1516, 1372, 1242, 1063, 1035, 832. 1H NMR
(200.2 MHz, CDCl3, ppm) δ: 1.50 (d, J = 6.5 Hz, 3H), 2.03
(s, 3H), 3.78 (s, 3H), 5.83 (q, J = 6.5 Hz, 1H), 6.86 (d, J =
8.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H). 13C NMR (50.3 MHz,
CDCl3, ppm) δ: 21.33, 21.87, 55.17, 71.93, 113.74, 127.53,
133.64, 159.18, 170.32.
Reaction of 2 with p-chlorophenyl isocyanate
Heating 2 with 1.08 equiv. of the isocyanate gave, after
flash chromatography and recrystallization from benzene–
hexane (50:50), 57% of 12d as white crystals melting at
115.5–117.5 °C. IR (NaCl, cm–1): 3098, 3076, 2956, 1752,
1727, 1706, 1341, 1275, 1237, 1145, 1095, 1041, 832, 770,
Thermolysis of oxadiazolines in the presence of
isocyanates
All isocyanates except 11c and 11d are liquids at room
temperature. The liquids except isopropyl isocyanate were
freshly distilled before use. The isopropyl compound was
used as received from Sigma-Aldrich. p-Chlorophenyl
isocyanate and p-nitrophenyl isocyanate melted at 28–30.5
and 56–60 °C, respectively.
A mixture of 2 (1.00 mmol) and isocyanate (0.96–
1.63 mmol), placed in an ampoule, was degassed by means
of three freeze–pump–thaw cycles before the ampoule was
sealed and heated at 50.4 °C for 41 h. A large excess of
isocyanate was avoided after initial experiments with a two-
fold excess indicated that a considerable amount of residual
isocyanate hindered isolation of 12. The crude reaction mix-
ture was analysed by 1H NMR spectroscopy before pure
products were isolated as described.
1
720, 675, 635. H NMR (200.2 MHz, CDCl3, ppm) δ: 2.03
(s, 3H), 3.90 (s, 3H), 7.17 (d, J = 8.75 Hz, 2H), 7.47 (d, J =
8.75 Hz, 2H). 13C NMR (50.3 MHz, CDCl3, ppm) δ: 24.44,
53.03, 129.86, 130.41, 134.17, 136.09, 161.49, 162.41,
171.98. HRMS (CI, NH3) m/z calcd. for C11H11NO4Cl:
256.0377 (MH)+; found: 256.0339.
Reaction of 2 with ethyl isocyanate
Heating 2 with 1.37 equiv. of the isocyanate gave, after
flash chromatography on silica with ethyl acetate – hexane
(35:65) as eluent, product 12e as a pale yellow oil in 55%
yield. IR (neat, cm–1): 2986, 2960, 1752, 1720, 1695, 1438,
1380, 1350, 1260, 1217, 1142, 1071, 1009, 781, 735, 635.
1H NMR (200.2 MHz, CDCl3, ppm) δ: 1.20 (t, J = 7.1 Hz,
3H), 2.30 (s, 3H), 3.69 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H). 13
C
Reaction of 2 with phenyl isocyanate
NMR (50.3 MHz, CDCl3, ppm) δ: 13.66, 23.16, 39.02,
52.63, 161.93, 162.60, 172.47. HRMS (CI, NH3) m/z calcd.
for C7H12NO4: 174.0766 (MH)+; found: 174.0768.
Heating 2 with 1.28 equiv. of p-chlorophenyl isocyanate
gave 12a, which was isolated by means of flash chromatog-
raphy on silica with ethyl acetate – hexane (20:80) as eluent.
Yield of colourless oil: 76%. IR (neat, cm–1): 3064, 3018,
2958, 1750, 1729, 1706, 1597, 1439, 1370, 1343, 1273,
Reaction of 2 with n-butyl isocyanate
1
Flash chromatography on silica with ethyl acetate – hex-
ane (20:80) gave, after heating 2 with 0.96 equiv. of 11f and
55% of 12f as a colourless oil. IR (neat, cm–1): 2963, 2877,
1754, 1724, 1701, 1464, 1437, 1379, 1349, 1282, 1233,
1235, 1140, 1046, 756, 733, 698. H NMR (200.2 MHz,
CDCl3, ppm) δ: 2.01 (s, 3H), 3.90 (s, 3H), 7.19–7.25 (m,
2H), 7.44–7.52 (m, 3H). 13C NMR (50.3 MHz, CDCl3, ppm)
δ: 24.37, 52.90, 128.38, 129.84, 130.08, 135.67, 161.72,
162.52, 172.45. HRMS (CI, NH3) m/z calcd. for C11H12NO4:
222.0766 (MH)+; found: 222.0760.
1
1202, 1145, 1078, 1019, 735, 638. H NMR (200.2 MHz,
CDCl3, ppm) δ: 0.89 (t, J = 7.2 Hz, 3H), 1.22–1.41 (m, 2H),
1.47–1.62 (m, 2H), 2.29 (s, 3H), 3.57–3.64 (m, 2H), 3.81 (s,
3H). 13C NMR (50.3 MHz, CDCl3, ppm) δ: 13.49, 19.84,
23.16, 30.65, 43.73, 52.60, 161.94, 162.81, 172.65. HRMS
(CI, NH3) m/z calcd. for C9H16NO4: 202.1079 (MH)+;
found: 202.1040.
Reaction of 2 with o-methoxyphenyl isocyanate
Heating 2 with 1.63 equiv. of the isocyanate and flash
chromatography of the crude products on silica with ethyl
acetate – hexane (32:68) gave 12b in 74% yield as pale yel-
low crystals, mp 115.5–118.5 °C. IR (NaCl, cm–1): 3018,
2960, 2946, 1755, 1729, 1705, 1600, 1436, 1346, 1283,
Reaction of 2 with isopropyl isocyanate
Heating 2 with 1.08 equiv. of 11g gave 12g by means of
flash chromatography on silica, with ethyl acetate – hexane
(28:72) as eluent. The product was obtained as a pale yellow
oil in 48% yield. IR (neat, cm–1): 3012, 2980, 2957, 1750,
1718, 1696, 1438, 1403, 1368, 1331, 1283, 1212, 1183,
1
1253, 1146, 1023, 754. H NMR (200.2 MHz, CDCl3, ppm)
δ: 1.99 (s, 3H), 3.84 (s, 3H), 3.91 (s, 3H), 7.00–7.09 (m,
2H), 7.16–7.21 (m, 1H), 7.39–7.48 (m, 1H). 13C NMR
(50.3 MHz, CDCl3, ppm) δ: 23.48, 52.81, 55.86, 112.25,
121.36, 124.27, 129.68, 131.44, 155.01, 161.88, 162.34,
172.95. HRMS (CI, NH3) m/z calcd. for C12H14NO5:
252.0872 (MH)+; found: 252.0875.
1
1110, 1055, 1009, 770, 728, 638. H NMR (200.2 MHz,
CDCl3, ppm) δ: 1.42 (d, J = 6.9 Hz, 6H), 2.29 (s, 3H), 3.79
(s, 3H), 4.16 (sept, J = 6.9 Hz, 1H). 13C NMR (50.3 MHz,
© 2006 NRC Canada

Sokol and Warkentin
933
11. (a) R.A. Moss. Acc. Chem. Res. 13, 58 (1980); (b) R.A. Moss.
Acc. Chem. Res. 22, 15 (1989).
12. C.-S. Ge, E.A. Jefferson, and R.A. Moss. Tetrahedron Lett. 34,
7549 (1993).
CDCl3, ppm) δ: 19.65, 23.96, 50.19, 52.55, 161.48, 163.53,
173.41. HRMS (CI, NH3) m/z calcd. for C8H14NO4:
188.0923 (MH)+; found: 188.0922.
13. R.A. Moss, X. Song, and W. Liu. J. Am. Chem. Soc. 116,
1583 (1994).
Acknowledgements
14. (a) V. Nair, A. Deepthi, M. Poonoth, B. Santhamma, S.
Vellalath, B.P. Babu, R. Mohan, and E. Suresh. J. Org. Chem.
71, 2313 (2006); (b) V. Nair, B.P. Beneesh, V. Sreekumar, S.
Bindu, R.S. Menon, and A. Deepthi. Tetrahedron Lett. 46, 201
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Lett. 7. 487 (2005); (e) H. Giera, R. Huisgen, E. Langhals, and
K. Polborn. Helv. Chim. Acta, 85, 1523 (2002).
The authors thank the Natural Sciences and Engineering
Research Council of Canada (NSERC) for continued finan-
cial support and the Department of Chemistry of McMaster
University for office and laboratory space as well as access
to spectroscopy facilities.
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