2-Acetoxy-2-methoxy-5,5-dimethyl-Δ3-1,3,4-oxadiazoline and acetoxy(methoxy)carbene

Article abstract of DOI:10.1139/v03-126

2-Acetoxy-2-methoxy-5,5-dimethyl-Δ³-1,3,4-oxadiazoline undergoes two competitive 1,3-dipolar cycloreversions at 110°C. It loses N₂, presumably to afford a short-lived carbonyl ylide that fragments to acetone and acetoxy(methoxy)carbene. It also forms 2-diazopropane and the appropriate mixed anhydride. It is the only currently known source of acetoxy(methoxy)carbene.

Full text of DOI:10.1139/v03-126

1438
2-Acetoxy-2-methoxy-5,5-dimethyl-∆3-1,3,4-
oxadiazoline and acetoxy(methoxy)carbene
Wojciech Czardybon, Arkadiusz Klys, John Warkentin, and Nick Henry Werstiuk
Abstract: 2-Acetoxy-2-methoxy-5,5-dimethyl-∆3-1,3,4-oxadiazoline undergoes two competitive 1,3-dipolar cyclorever-
sions at 110 °C. It loses N2, presumably to afford a short-lived carbonyl ylide that fragments to acetone and ace-
toxy(methoxy)carbene. It also forms 2-diazopropane and the appropriate mixed anhydride. It is the only currently
known source of acetoxy(methoxy)carbene.
Key words: acetoxy(methoxy)carbene, 2-diazopropane, 1,3-dipolar cycloreversion.
Résumé : À 110 °C, la 2-acétoxy-2-méthoxy-5,5-diméthyl-∆3-1,3,4-oxadiazoline subit deux réactions de cycloréversion
1,3-dipolaire compétitives. Elle perd du N2, probablement pour fournir un ylure de carbonyle de temps de vie très court
qui se fragmente en acétone et en acétoxy(méthoxy)carbène. Elle forme aussi du diazopropane et l’anhydride mixte ap-
proprié. C’est aussi la seule source actuellement connue d’acétoxy(méthoxy)carbène.
Mots clés : acétoxy(méthoxy)carbène, 2-diazopropane, cycloréversion 1,3-dipolaire.
[Traduit par la Rédaction] Czardybon et al. 1442
Introduction
(4). At 110 °C in benzene, both the carbene and the
diazopropane can be intercepted with chemical trapping
agents.
Although many alkylacetoxycarbenes have been studied
(1–5) and found to rearrange by 1,2-acyl migration in com-
petition with other intramolecular processes, such as 1,2 mi-
gration of H, acyloxy(alkoxy)carbenes appear to be
unknown. They are interesting intermediates, without the
possibility of a 1,2-H migration. They have the potential for
rearrangement by migration of the acyl group to the carbenic
site, as well as the potential for fragmentation to alkoxy-
carbonyl and acyl radicals. The 1,2-acyl migration of known
acetoxy(alkyl)carbenes and the most likely reactions of
acyloxy(alkoxy)carbenes are illustrated in Scheme 1.
Results and discussion
Thermolysis of 1 in benzene was studied in the absence of
potential traps, in the presence of phenol (a carbene trap as
well as a trap for diazo compounds and a hydrogen donor to
radicals), in the presence of benzylidene malononitrile, and
in the presence of TEMPO. TEMPO is a trap for radicals,
and benzylidene malononitrile also can trap radicals, car-
benes, and diazo compounds.
We prepared and purified 2-acetoxy-2-methoxy-5,5-
dimethyl-∆3-1,3,4-oxadiazoline (1) (6), which is a potential
precursor of acetoxy(methoxy)carbene (3). 2,2-Dialkoxy-
5,5-dimethyl-∆3-1,3,4-oxadiazolines undergo 1,3-dipolar
cycloreversion by loss of N2 at 110 °C to afford carbonyl
ylides that fragment primarily to dialkoxycarbenes and ace-
tone (7). There is a minor competitive 1,3-dipolar cyclo-
reversion, in some cases, to 2-diazopropane (4) and dialkyl
carbonate (8). Scheme 2 shows such cycloreversions for the
case of 1, which was expected to produce carbene 3, via car-
bonyl ylide 2, and perhaps 2-diazopropane (4) and the mixed
anhydride 5. Moreover the carbene might undergo a con-
certed rearrangement to methyl pyruvate (6) or a fragmenta-
tion to the methoxycarbonyl–acetyl radical pair that could
couple to afford 6 also, Scheme 3.
Thermolysis of 1 in benzene-d6 containing internal stan-
dard tert-butylbenzene gave a complex mixture of products.
Yields of 4 or of acetone azine from 1 are unreliable for esti-
mation of the yield of the former, because diazopropane
would react with the mixed anhydride co-product (5). The
yield of acetone (presumably from the carbenic pathway)
was found to be about 55% by integration of the acetone sig-
nal against those from the phenyl and tert-butyl groups of
the internal standard. The two comparisons were in excellent
agreement. Thus, the yield of acetoxymethoxycarbene was
about 55% and that of 2-diazopropane about 45%. Methyl
pyruvate was a major product (ca. 10%, isolated), but
biacetyl and dimethyl oxalate, which might also be expected
if the pyruvate had arisen by a radical coupling path, could
not be detected by GC, with authentic samples in hand. It
was also possible to detect (by GC) a trace of acetophenone,
in keeping with the expectation that acetyl radicals would at-
We now describe the thermolysis of 1, which does indeed
lead to the formation of both carbene 3 and 2-diazopropane
Received 23 May 2003. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 13 October 2003.
W. Czardybon, A. Klys, J. Warkentin,1 and N.H. Werstiuk. Department of Chemistry, McMaster University, 1280 Main St.
West, Hamilton, ON L8S 4M1, Canada.
1Corresponding author (e-mail: warkent@mcmaster.ca).
Can. J. Chem. 81: 1438–1442 (2003)
doi: 10.1139/V03-126
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Czardybon et al.
1439
Scheme 1.
Scheme 2.
Scheme 3.
tack the benzene solvent. Thermolysis of 1 in the presence
of TEMPO led to the isolation of enough of the known (9)
TEMPO adduct of the acetyl radical (1-acetoxy-2,2,6,6-
tetramethylpiperidine) for an NMR spectrum. However, the
known adduct (10) of TEMPO with the methoxycarbonyl
radical could not be found.
The results listed thus far are accounted for in terms of
Scheme 3, which shows not only parallel 1,3-dipolar cyclo-
reversions but also a radical decomposition of 1. That minor
radical decomposition is assumed to be concerted, leading to
7 and 8. TEMPO would have trapped both 7 and 8 but the
product expected from 7 was not identified. The failure to
find any evidence for the methoxycarbonyl radical indicates
that acetyl and methoxycarbonyl radicals are probably not
formed by fragmentation of carbene 3.
Thermolysis of 1 in benzene containing phenol gave 9
(31%) and 10 (5%) but not 11. Compound 9 probably arises
from a transesterification reaction with 1, while 10 and 11
are expected products from reactions of 4 and 3, respec-
tively, with phenol, Scheme 4. Protonation of 3 and ion-pair
collapse would generate 11, which has never been reported.
Such compounds may be unstable at 110 °C.
Benzylidene malononitrile (12) was very successful in
trapping intermediates from the thermolysis of 1. Dinitrile
12 had been useful in helping to sort out the chemistry of
dibenzyloxycarbene and benzyloxy(methoxy)carbene (11)
because it reacts fast with nucleophilic carbenes, making it
possible to trap some of them before they can fragment to
radical pairs, Scheme 5. Thermolysis of 1 in the presence of
12 did not furnish a carbene adduct. Instead, the methoxy-
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Can. J. Chem. Vol. 81, 2003
Scheme 4.
Scheme 5.
Scheme 6.
carbonyl radical, apparently resulting from carbene frag-
mentation to a radical pair, appeared to be trapped as 13
(30%), Scheme 6. Adduct 20, expected on the basis of pre-
cedent (11) was not found, but 16 (17%) and 17 (12%) were
also isolated.
The finding that 13 was formed from thermolysis of 1 in
the presence of 12 but that 20 could not be found led us to
search the literature for analogues of 20. Such compounds
hydrolyze spontaneously when exposed to the atmosphere
(12), Scheme 6. Thus, the most likely explanation for the
formation of 13 is trapping of a carbene intermediate with
12 to form diastereomers 18 and subsequent ring-opening
fragmentation to diradical 19, followed by fragmentation
and coupling to 20, according to Scheme 6. Subsequent
© 2003 NRC Canada

Czardybon et al.
1441
deacylation of 20 (12), once the sample is exposed to the at-
mosphere, leads to 13.
chromatograph equipped with an HP-5971A mass selective
detector and a DB-1 capillary column (12 m × 0.2 mm).
Other mass spectra were obtained with a VG Analytical
ZAB-E double focusing mass spectrometer.
The concentration of 12 was increased from 0.455 to
2.127 mol·L–1 to improve the chances of trapping carbene 3.
There was little change, suggesting that the lower concentra-
tion was sufficient to trap essentially all of 3. Compounds 16
and 17 can be attributed to reaction of 4 in the expected
sense with 12 to afford 14, which then loses N2, Scheme 6.
The higher concentration of 12 did lead to two very minor
products (not identified) that were detected by GC–MS.
Those compounds, which gave essentially the same mass
spectrum as 16 and 17, might be derived from cycloaddition
of 4 in the alternative sense to form 15, Scheme 6.
Alkylidene malononitriles are known to react with diazo
compounds by cycloaddition, and the resulting 3H-pyra-
zoles, not surprisingly (13), lose N2 at 110 °C to afford
diradicals that rearrange. Both regiochemistries of addition
of diazomethane to a β-phenyl-α,β-unsaturated sulfone have
been reported (14). Although 16 and 17, as well as the minor
products with the same MS, can be accounted for on the ba-
sis of 14 alone, formation and decomposition of some of
compound 15 cannot be excluded.
Synthesis of 1
A solution of the carbomethoxy hydrazone of acetone
(30 g, 0.23 mol) was added slowly to an ice-cooled hetero-
geneous mixture of Pb(OAc)4 (115.3 g, 0.26 mol), acetic
acid (1 mL), and CH2Cl2 (114 mL). The yellow mixture was
stirred under N2, warmed to 25 °C after addition was com-
plete, and stirred for an additional 3 h. The mixture was then
filtered through Celite and washed with 5% Na2CO3 solu-
tion. The water fraction was back-extracted twice with
20 mL of CH2Cl2, and the combined organic fraction was
dried over Na2SO4 before the solvent was evaporated. The
yellow oil that remained weighed 39 g (90%) and consisted
of
1
(ca. 72%) and an acyclic isomer (Me2C-
(OAc)N=NCO2Me) (ca. 28%).
Purification of 1
A yellow mixture of 1 and its acyclic isomer (5 g) was
chromatographed as rapidly as possible on neutral alumina
(35 g) with hexane – ethyl acetate (9:1). The solvents were
evaporated from the combined colourless fractions, and the
residue was distilled under vacuum (2–5 mmHg (1 mmHg =
133.322 Pa)) to afford 2.2 g of pure 1 (61%). IR (neat) (cm–1):
The concerted rearrangement of the carbene and its frag-
mentation to a radical pair were modeled computationally
with Gaussian 98 at the Becke3PW91/6-31+G(d, p) level
(15). Concerted carbene rearrangement from one of the pos-
1
1771. H NMR (200 MHz, CDCl3) δ: 1.52 (s, 3H), 1.63 (s,
3H), 2.11 (s, 3H), 3.59 (s, 3H). 13C NMR (50.3 MHz,
CDCl3) δ: 21.44, 22.59, 24.49, 52.49, 122.15, 133.80,
161.67.
Thermolysis of 1 in benzene-d6
A solution of 1 (0.157 mmol) and tert-butylbenzene
(0.127 mmol) in C6D6 (0.7 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 for
sible sickle conformations (21) has the lowest barrier
(14.6 kcal·mol–1), whereas the lowest barrier to fragmenta-
tion (28.8 kcal·mol–1) is that from a second sickle conforma-
tion (22). Details of the computational work, which includes
the examination of a number of other conceivable pathways,
will be published separately.2
In summary, oxadiazoline 1 undergoes two competing
cycloreversions at 110 °C in benzene, leading to both
carbene 3 and diazopropane 4. A minor, third thermolysis
mechanism, currently regarded as tentative, is a radical pro-
cess that generates the acetyl radical and 7. Carbene 3 does
not fragment to radicals but rearranges to methyl pyruvate
by a 1,2-acyl migration, like other acetoxycarbenes (1–5).
Although thermolysis of 1 is far from ideal, in that it gen-
erates 3 in only about 50% yield and the co-products com-
plicate the thermolysis, it is the only reaction available today
to generate acetoxy(methoxy)carbene.
1
72 h at 110 °C. The H NMR spectrum was acquired with
the tube still sealed and with a pulse delay of 6 s to ensure
complete relaxation of the acetone signal. Integrations of the
acetone signal against those of the tert-butyl and aryl signals
of tert-butyl benzene were in good agreement and gave the
yield of acetone as 55%. Analysis by GC, with the column
compartment cooled alternately to 7, 15, 21, and 32 °C,
showed that methyl pyruvate (ca. 10%) and acetophenone
(trace), both confirmed with authentic samples, were pres-
ent. Biacetyl, dimethyl oxalate, acetaldehyde, and methyl
formate were not detectable, as determined by injection of
authentic samples under the same conditions, but there were
peaks from unidentified volatile components.
Thermolysis of 1 in the presence of phenol
Thermolysis of 1 (1.596 mmol) in C6H6 (7 mL) contain-
ing phenol (3.191 mmol) gave a product mixture that was
analyzed by GC. Major and minor products were phenyl-
acetate (9) (ca. 30%) and isopropyl phenyl ether (10) (ca.
5%). The identities of those products were confirmed by GC
of authentic samples prepared by standard methods. Acetal-
dehyde and methyl formate were not detectable.
Experimental
General
A Bruker AC-200 spectrometer was used to obtain 1H and
13C NMR spectra, with CDCl3 as solvent and with the signal
from residual CHCl3 in CDCl3 set at δ = 7.25. GC–MS mass
spectra were recorded with a Hewlett-Packard 5890 gas
2 W. Czardybon, J. Warkentin, and N.H. Werstiuk. Unpublished results.
© 2003 NRC Canada

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Can. J. Chem. Vol. 81, 2003
Thermolysis of 1 in the presence of 12
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on a 2 mm silica gel plate (Chromatotron apparatus, hexane:
ethyl acetate = 4:1).
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JW and NHW gratefully acknowledge the financial sup-
port of NSERC.
© 2003 NRC Canada