Intramolecular reactions of dialkoxycarbenes with a carbonyl group

Article abstract of DOI:10.1139/v02-200

Thermolysis of 5,5-dimethyl-2-methoxy-2-(2-oxocyclohexylmethoxy)-Δ ³-1,3,4-oxadiazoline (3a) in benzene at 110°C generated a carbonyl ylide intermediate that gave, in a minor side reaction, a product of 1,3-dipolar cycloaddition to the carbonyl

Full text of DOI:10.1139/v02-200

598
Intramolecular reactions of dialkoxycarbenes with
a carbonyl group
Ma»gorzata Dawid and John Warkentin
Abstract: Thermolysis of 5,5-dimethyl-2-methoxy-2-(2-oxocyclohexylmethoxy)-∆3–1,3,4-oxadiazoline (3a) in benzene
at 110°C generated a carbonyl ylide intermediate that gave, in a minor side reaction, a product of 1,3-dipolar cyclo-
addition to the carbonyl group. The major fate of the ylide was fragmentation to acetone and a dialkoxycarbene, MeO-
(RCH2O)C:, where R = 2-oxocyclohexyl. The carbene, in turn, underwent overall [2 + 1] cycloaddition to the carbonyl
group, presumably to afford diastereomeric dialkoxyoxiranes that could not be isolated. A product of methanolysis of
the presumed oxiranes was isolated by GC and its structure was determined by means of X-ray diffraction. Methanol is
believed to result from reaction of an intermediate or product with adventitious water. Deliberate hydrolysis of the
product of methanolysis gave a hydroxy lactone, the structure of which was also secured by means of single crystal X-
ray diffraction. Those structures indicated the likely structures of the oxirane precursors. A second, and major, product
from the carbene was a bicyclic ketone. Similar products were obtained from intramolecular reactions of a carbene
tethered to cyclopentanone through a two-carbon or a one-carbon tether. Some compounds that are apparently “dimers”
of the oxiranes were also isolated and identified by means of X-ray diffraction. These dimers are thought to originate
from the reaction of a ring-opened oxirane (a dipole or a cation from electrophilic opening of the oxirane) with a mol-
ecule of the oxirane rather than from bimolecular reaction between two oxirane molecules. The oxiranes open by cleav-
age of the (RO)2C—O bond rather than the oxirane C—C bond, the normally observed sense of thermal ring opening.
The properties of the carbenes and the presumed oxiranes serve to point out the options available to such intermediates
and suggest that some new, synthetically useful reactions may become possible.
Key words: bicyclic ketone, dialkoxycarbene, dialkoxyoxirane, hydroxylactone, “oxirane dimers”.
Résumé : La thermolyse de la 5,5-diméthyl-2-méthoxy-2-(2-oxocyclohexylméthoxy)-∆3-1,3,4-oxadiazoline (3a), dans le
benzène, à 110 °C, génère la formation d’un ylure de carbonyle comme intermédiaire qui réagit, dans une réaction la-
térale mineure, pour former un produit de cycloaddition 1,3-dipolaire sur le groupe carbonyle. La réaction principale de
l’ylure est une fragmentation en acétone et en dialkoxycarbène, MeO(RCH2O)C:, dans lequel R = 2-oxocyclohexyle.
Par la suite, le carbène subit une réaction globale de cycloaddition [2 + 1] sur le groupe carbonyle qui fournit proba-
blement les dialkoxyoxiranes diastéréomères qui n’ont pas été isolés. Faisant appel à la CG, on a toutefois pu en isoler
un produit de méthanolyse et on a déterminé sa structure par diffraction des rayons X. On croit que le méthanol est
issu de la réaction d’un intermédiaire ou d’un produit avec de l’eau présente de façon fortuite. L’hydrolyse délibérée
du produit de méthanolyse conduit à une hydroxylactone dont la structure a été déterminée par diffraction des rayons
X sur un cristal unique. Ces structures suggèrent celles des oxiranes qui leur ont donné naissance. Un deuxième et le
plus important produit provenant du carbène est une cétone bicyclique. Des produits semblables ont été obtenus par le
biais de réactions intramoléculaires d’un carbène auquel on a attaché une cyclopentanone par le biais de rallonges à un
ou deux atomes de carbones. On a aussi isolé des composés qui sont apparemment des dimères d’oxiranes et on les a
identifiés par le biais de la diffraction des rayons X. On croit que ces dimères trouvent leur origine dans la réaction
d’un oxirane à cycle ouvert (un dipôle ou un cation résultant de l’ouverture électrophile de l’oxirane) avec une molé-
cule d’oxirane plutôt par une réaction bimoléculaire entre deux molécules d’oxirane. Les oxiranes s’ouvrent par rupture
de la liaison (RO)2C—O plutôt que par ouverture de la liaison C—C de l’oxirane, le sens d’ouverture normalement ob-
servé dans l’ouverture thermale du cycle. Les propriétés des carbènes et des oxiranes suggérés permettent de préciser
les diverses options ouvertes à ces intermédiaires et de suggérer que de nouvelles réactions utiles en synthèse puissent
se développer.
Mots clés : cétone bicyclique, dialkoxycarbène, dialkoxyoxirane, hydroxylactone, dimères d’oxirane.
[Traduit par la Rédaction] Dawid and Warkentin 606
Received 8 August 2002. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 22 May 2003.
Dedicated to Professor Don Arnold, for his exemplary devotion to excellence in chemistry.
M. Dawid and J. Warkentin.1 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: 598–606 (2003)
doi: 10.1139/V02-200
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Dawid and Warkentin
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Introduction
Methods, results, and discussion
The oxadiazoline precursors (3) of dialkoxycarbenes were
prepared from 2-hydroxyalkyl cyclanones (2) and 2-acetoxy-
2-methoxy-5,5-dimethyl-∆3-1,3,4-oxadiazoline (1) by the ex-
change method (19), as illustrated in Scheme 5. The ex-
change had to be done carefully to minimize dehydration of
2a or destruction of 3 subsequent to their formation. Protec-
tion of the carbonyl group of 2a with 1,2-ethane dithiol and
subsequent exchange followed by deprotection was achieved
but that route did not offer any improvement of the yield of
3a. Compounds 3 were isolated by chromatography on silica.
After purification of 3a by chromatography, a benzene so-
lution was heated for 24 h at 110°C in a sealed glass tube.
Products isolated by chromatography on silica included 4
(7%) and 1-methoxy-8-oxa-9-oxobicyclo[4.2.1]nonane (5,
31%), as shown in Scheme 6. Acetal 6 (16%), which had
The nucleophilicity of dialkoxycarbenes was first reported
by Hoffmann’s group, and other examples followed (1). Rel-
ative nucleophilicities of various carbenes have been quanti-
fied by Moss et al. (2). The nucleophilic characteristics of
dialkoxycarbenes are evident from their sluggish reactions
with simple alkenes, such as cyclohexene (1b, 3) and their
greater reactivity toward Michael acceptors such as isocya-
nates and diphenylketene (1d), for example. Donor-atom-
substituted carbenes are also capable of bimolecular nucleo-
philic displacements. Nucleophilic substitution at unsatu-
rated carbon occurs between an imidazolylidene and
2,3,4,5,6-pentafluoropyridine (4) and in reactions of dimeth-
oxycarbene (DMC) with hexachlorocyclopentadiene (5), 1-
fluoro-2,4-dinitrobenzene, and hexafluorobenzene (6), for
example, although the yields can be very low (6).
1
two methoxy signals in the H NMR spectrum and the cor-
A common reaction of nucleophiles with carbonyl com-
pounds is addition, to change the geometry at the carbonyl
carbon from planar to tetrahedral. Diaminocarbenes were
known to attack at the carbonyl carbon atom of aldehydes
(7), and DMC appears to add to the carbonyl group of hexa-
fluoroacetone (Scheme 1) (8), fluorenone (9), and cyclo-
hexanone (10). Recently it was shown that DMC reacts to
effect insertion into the bond between the carbonyl carbon
and the α-oxygen atom of anhydrides (11) and a lactone
(12). Similar apparent insertion into the bond between a car-
bonyl carbon and the α-carbon of strained cyclic ketones
was reported (12) (Scheme 2). Such reactions could be con-
certed or they could involve tetrahedral intermediates with
dipolar or diradical characteristics. Either of those interme-
diates could rearrange by ring enlargement or cyclize to
isolable dialkoxyoxiranes, as in the case of addition of
dimethoxycarbene to cyclohexanone (Scheme 3) (10).
Dimethoxycarbene also reacts with thiocarbonyl compounds
to form dimethoxythiiranes (13). Although imidazolylidenes
are known to form stable dipolar intermediates by forming a
single bond to carbon disulfide (14), carbon dioxide (15), or
sulfur trioxide (16), attack of a less-nucleophilic dialkoxy-
carbene at a carbonyl or thiocarbonyl group could be con-
rect mass for 6–OMe, was isolated by means of GC. Despite
many attempts the material could not be crystallized. Struc-
ture 6 was inferred from the structure of the single product
of hydrolysis of the material (below). In addition, diastere-
omers 7a and 7b, both crystalline solids, were isolated by
means of radial chromatography on silica. Compound 7a
was identified completely by means of single crystal X-ray
diffraction and 7b was assigned on the basis of its NMR
spectra, which closely resembled those of 7a.
The products can be accounted for as follows. Oxadi-
azoline 3a loses N2 in the first step to generate carbonyl
ylide 8 (Scheme 7). Intramolecular cycloaddition of the
ylide to the carbonyl group leads to 4, the stereochemistry of
which was assigned on the basis of the structure of the prod-
uct of acid-catalyzed hydrolysis of 4, hydroxy lactone 9. The
structure of 9 was secured by means of single crystal X-ray
diffraction.
A major fate of the carbonyl ylide must be the well-
precedented loss of acetone (1k) to afford carbene intermedi-
ate 10, which attacks the carbonyl group of the cyclohex-
anone to generate intermediate 11 or, possibly, the oxiranes
12 (Scheme 7). The intermediacy of diasteromers 12 is spec-
ulative because many attempts to isolate a sample by gas
chromatography gave material that contained 6 and, possi-
bly, the diastereomers 12. Deliberate hydrolysis of such sam-
ples led to hydroxy lactone 9 only. The structure of 9 means
that both the ylide 8 (precursor of 4) and the carbene 10
(precursor of 11) react from that conformation in which the
side chain is axial, as shown in Scheme 7.
Although the rearrangement of 10 to 5 amounts to an in-
sertion (overall) of the carbene into a C—CO bond of the
carbonyl group, the reaction is not necessarily concerted.
Reactions of cyclic ketones with diazomethane, leading to
products of ring expansion, are believed to be stepwise (20).
Those reactions are reasonable models for ring expansion of
cyclic ketones by reaction with dialkoxycarbenes. It was
shown previously that migration of the more-substituted car-
bon is preferred when α-alkylcyclobutanones react with
dimethoxycarbene to afford corresponding dimethoxycyclo-
pentanones (12). In the case of postulated intermediate 11,
in which migration of the more-substituted carbon would
lead to a four-membered ring (Scheme 7), the less-
substituted α-carbon migrated to expand the ring from six-
certed, leading directly to
dialkoxythiirane.
a
dialkoxyoxirane or
a
The nucleophilic reactivity of dialkoxycarbenes was sug-
gested by the previously demonstrated reactions of vinyl-
ogous dialkoxycarbenes with ketones (17–19). It is not
surprising that vinylogous dialkoxycarbenes are better nucle-
ophiles than saturated analogues because the former
carbenes are presumably more polarizable and can disperse
positive charge better in a stepwise or nonsynchronous con-
certed reaction. The stepwise pathway for vinylogous dialk-
oxycarbenes is illustrated in Scheme 4.
It was of interest to us to explore further the possible
intramolecular reactions of non-vinylogous dialkoxy-
carbenes with a tethered carbonyl group. Previously only
one case of such a process had been reported and that was
for reaction with the carbonyl group of a tethered cyclo-
butanone (12). We now report reactions of a dialkoxycar-
bene with the carbonyl group of a cyclohexanone tethered at
the α-position with a one-carbon tether to the carbene, as
well as reactions of dialkoxycarbenes tethered analogously
to cyclopentanone with a one- or two-carbon tether.
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Scheme 1.
Scheme 2.
Scheme 4.
Scheme 3.
open a second molecule of oxirane. The connectivity of 14
does require that the oxirane intermediates do not open to
carbonyl ylides; the usual sense of thermal ring opening of
oxiranes. Presumably there were other compounds, analo-
gous to 14, that we were unable to isolate.
Heating of a solution of 3b in benzene afforded similar
products. A major product (33%) was 1-methoxy-2-oxa-8-
oxobicyclo[3.3.1]nonane (17). Again there was indirect evi-
dence for isomeric oxirane intermediates, probably 15 and
16 (Scheme 10), although they were too unstable to be iso-
lated. Preparative gas chromatography gave fractions that
changed during the collection process, probably because of
hydrolysis. Two stable compounds (18 and 19) were also
isolated by means of GC and identified by means of single
crystal X-ray diffraction. Compound 18 is probably formed
by the methanolysis of 15 and 16. The source of methanol is
again assumed to be hydrolysis of an intermediate by adven-
titious water.
The hexahydropyranyl ring of 19 is fused trans to the 1,4-
dioxanyl ring and the ring juncture of the hexahydropyranyl
and cyclopentyl rings is cis. It is analogous to compound 11
that was obtained from 3a, and it appears, at first sight, to be
a head-to-tail dimer of the dipolar intermediate that would
result from stepwise addition of the nucleophilic carbene
center to the carbonyl group (Scheme 10). Such a
dimerization is unlikely, of course, because reactive interme-
diates are not expected to accumulate to concentrations that
to seven-membered. A simple model that aids in visualiza-
tion of the transition state charge separation is the enolate
alkylation model (12) shown in Scheme 8. It should perhaps
be emphasized that such structures, with enolate and cation
character, are simply models for actual transition states or
intermediates.
An additional product from thermolysis of 3a was the
complex compound 13, consisting essentially of 3 equiv of
the proposed oxirane intermediate. Its structure was deter-
mined by means of single crystal X-ray diffraction.
Scheme 9 is a rationalization for its formation from reaction
of the ring-opened oxirane with the oxirane. It should be
emphasized that the mechanism, involving intermediates 11
and 13, is speculative. Instead of the dipolar species 11, one
could invoke a cationic intermediate formed by protonation
(by adventitious water) and subsequent ring-opening of an
oxirane 12. That cation could then act as an electrophile to
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Dawid and Warkentin
601
Scheme 5.
Scheme 6.
could lead to bimolecular reactions between them. We are
therefore led to propose, again, that there is a bimolecular
reaction between a dipolar species, in equilibrium with the
oxirane precursor and the oxirane. Alternatively, a cationic
species, from electrophile-catalyzed ring opening of the
oxirane, reacts with the oxirane to generate 19. Isomers of
19 might be expected, given that isomeric oxiranes such as
15 and 16 could result from the carbene. The GC trace
showed compounds with retention times similar to that of
19, and we assume that isomers of 19 were generated and
that they account for some of material imbalance.
Thermolysis of 3c gave products analogous to those from
3a and 3b (Scheme 11). Compound 22 (2%) can be attrib-
uted to dipolar cycloaddition of the ylide from 3c to the car-
bonyl group, and the carbene from 3c afforded 23 and 24,
because we were able to isolate a product (25) of apparent
methanolysis of 24. Lactone 26 was also obtained as was
bicyclic ketone 28 (28%), possibly from rearrangement of a
dipolar intermediate 23. In the case of 3c, two dimers (29
and 30) of the putative oxirane intermediate could be ob-
tained in crystalline form suitable for single crystal X-ray
diffraction. Compound 27 is apparently the product of hy-
drolysis of a product like 29. In diastereomer 29 the 1,4-
dioxanyl ring is in the chair conformation, and it is fused cis
to the tetrahydrofuranyl rings. In diastereomer 30 the 1,4-
dioxanyl ring is in a boat conformation, and both tetrahydro-
furanyl rings are again fused cis to it. As in cases of 3a and
3b, there were other products with GC retention times simi-
lar to those of 29 and 30. Those products were probably also
dimers, isomers of 29 and 30.
In order to trap a possible intermediate, thermolysis of 3a
was carried out in the presence of dimethyl acetylenedi-
carboxylate (DMAD). The yield of 5 was reduced by a fac-
tor greater than two, and there were formed, instead, two
products isolated in essentially equal amounts, ca. 3% each,
with greater GC retention times. It was possible to isolate
those compounds, by means of semipreparative GC followed
by MPLC, and to determine that they were diastereomers 32
and 33 (Scheme 12). Structure 32 was secured by means of
single crystal X-ray diffraction while 33 was inferred from
its NMR spectrum, which was very similar to that of 32. It is
clear from the connectivity that DMAD had not intercepted
a carbonyl ylide such as 30, which is the intermediate that is
normally obtained from thermal, conrotatory ring opening of
an oxirane, but something like dipole 31 or the cation from
protonation of 31. The cation mechanism appears to fit best
because a cationic intermediate would not be likely to attack
the triple bond but it could coordinate instead to carbonyl
oxygen.
In summary dialkoxycarbenes, tethered alpha to the car-
bonyl group of cyclohexanone or cyclopentanone, react
intramolecularly with the carbonyl group to generate an in-
termediate with a new five- or six-membered ring. Dialkoxy-
oxirane intermediates could not be isolated but they were
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Can. J. Chem. Vol. 81, 2003
Scheme 7.
Scheme 8.
inferred from products of their ring opening by methanol or
water. Some novel oxirane dimers were isolated, as well as,
in each case, a bicyclic ketone.
clic isomer (19), was treated with hydroxy ketone 2a (21)
and trifluoroacetic acid in dichloromethane. After washing
with dilute base, the organic layer was dried and the solvent
was evaporated. Chromatography of the residue (silica gel,
hexane:ethyl acetate:Et3N (85:15:0.5)) gave oxadiazoline 3a
(67% of pure product) as a colourless oil. IR (neat, KBr)
(cm–1): 2989, 2944, 2865, 1711, 1452, 1211, 1167, 1136,
914. 1H NMR (300 MHz, CDCl3, 1:1 mixture of two
diastereoisomers) δ: 4.14 (dd, J = 9.9, 5.1 Hz, 1H, OCHa),
Experimental
Preparation of oxadiazoline 3a
A solution of 2-acetoxy-2-methoxy-5,5-dimethyl-∆3-1,3,4-
oxadiazoline (1) in CH2Cl2, containing about 30% of an acy-
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Dawid and Warkentin
603
Scheme 9.
Scheme 10.
4.04 (dd, J = 9.9, 5.1 Hz, 1H, OCHa), 3.71 (dd, J = 9.9,
7.7 Hz, 1H, OCHb), 3.59 (dd, J = 9.9, 7.7 Hz, 1H, OCHb),
3.45 (s, 6H), 2.65 (m, 2H), 2.34 (m, 6H), 2.03 (m, 2H), 1.90
(m, 2H), 1.67 (m, 4H), 1.54 (s, 12H), 1.44 (m, 2H). 13C
NMR (75 MHz, CDCl3) δ: 210.7, 137.1, 119.3, 63.9, 52.0,
50.4, 42.2, 31.4, 24.7, 24.2, 24.1. EI-MS m/z (%): molecular
ion not observed, 225 ([M – OMe+], 3), 170 (7), 129 (15),
111 (59), 94 (47), 73 (60), 55 (100). CI-MS (NH3) m/z: 274
as a semicrystalline material. A crystal suitable for X-ray
crystallography could not be obtained. Exposure of the sam-
ple to the atmosphere led to its slow hydrolysis to 9.
Product 4
1
Yield: 7%, colourless oil. H NMR (300 MHz, CDCl3) δ:
4.12 (dd, J = 8.3, 4.7 Hz, 1H), 3.57 (d, J = 8.3 Hz, 1H), 3.35
(s 3H), 2.20 (m, 1H), 2.03 (m, 1H), 1.44 (s, 6H), 1.4–1.85
(m, 7H). 13C NMR (75 MHz, CDCl3) δ: 126.5, 108.8, 87.6,
71.0, 51.4, 44.6, 32.1, 29.3, 28.1, 28.0, 23.5, 23.0. EI-MS
m/z (%): 229 ([M + 1]+, 4), 213 (55), 154 (45), 153 (48),
111 (41), 93 (100), 81 (66), 55 (84), 43(80). Compound 4 in
CDCl3 was converted rapidly to lactone 9 during storage.
+
([M + NH4 ], 28).
Thermolysis of 3a in benzene
A solution of 3a (0.51 g, 2 mmol) in benzene (20 mL) in
a sealed tube was heated at 110°C for 18 h. Evaporation of
the solvent left a residue that was chromatographed on silica
(hexane:ethyl acetate, 90:10) to afford bicyclic ketone 5
(31%), hydroxy orthoester 6 (16%), 4 (7%), and compounds
7 (<5%).
1-Methoxy-8-oxa-9-oxobicyclo[4.2.1]nonane (5)
Yield: 31%, colourless oil. IR (neat) (cm–1): 2938, 2866,
1
1767, 1456, 1189, 1158, 1075, 998. H NMR (200 MHz,
Semipreparative gas chromatography (OV-17, 5%, helium
at 50 mL min–1; temperature program, 80°C for 5 min, in-
creased at 4°C min–1 to 250°C; retention time 26–29 min)
gave 6, which is probably a product of oxirane methanolysis,
CDCl3) δ: 4.34 (dd, J = 8.8, 5.2 Hz, 1H), 4.07 (d, J = 8.8 Hz,
1H), 3.28 (s, 3H), 2.67 (m, 1H), 1.15–1.90 (m, 8H). 13C
NMR (50 MHz, CDCl3) δ: 216.0, 104.9, 70.3, 51.1, 45.6,
33.0, 31.2, 23.7, 22.6. EI-MS m/z (%): 171 ([M + 1]+, 15),
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Scheme 11.
Scheme 12.
142 (42), 110 (68), 83 (55), 74 (100), 53 (92), 41 (100). CI-
EI-MS m/z (%): 341 ([M + 1]+, 100), 340 ([M]+, 78), 339
(46), 154 (100), 153 (22), 139 (19), 109 (21), 95 (29), 79
(30). The connectivity and stereochemistry of 7a were estab-
lished by means of single crystal X-ray diffraction.
MS (NH3) m/z: 188 ([M + NH4]+, 100).
Product 6
1
Semicrystalline. H NMR (500 MHz, CDCl3) δ: 3.80 (dd,
J = 14.4, J = 2.5 Hz, 2H), 3.39 (s, 3H), 3.35 (s, 3H), 2.43 (d,
J = 1.4, 1H), 2.37 (m, 1H), 1.44–1.90 (m, 6H). EI-MS m/z
(%): 171 ([M – OMe]+, 100), 147 (18), 112 (73), 97 (56), 83
(23), 69 (14). Compound 6 was rapidly converted to lactone
9 during storage.
Product 7b
Colourless crystals, mp 148°C. 1H NMR (200 MHz,
C6D6) δ: 4.21 (t, J = 7.7 Hz, 2H), 3.45 (s, 6H), 3.21 (dd, J =
7.7, 3.3 Hz, 2H), 2.25 (m, 2H), 1.44–1.98 (m, 16H). 13C
NMR (50 MHz, C6D6) δ: 117.6, 80.0, 70.1, 48.1, 43.4, 31.6,
28.6, 23.5, 23.3.
Product 7a
Colourless crystals, mp 118°C. 1H NMR (200 MHz,
C6D6) δ: 4.02 (t, J = 7.8 Hz, 2H), 3.50 (dd, J = 7.8, 4.1 Hz,
2H), 3.45 (s, 6H), 2.68 (m, 2H), 2.13 (m, 2H), 1.94 (m, 2H),
1.69–1.55 (m, 6H) 1.40–1.26 (m, 6H). 13C NMR (50 MHz,
C6D6) δ: 116.7, 79.6, 68.9, 48.7, 42.5, 29.9, 25.2, 22.3, 22.2.
Hydroxy lactone 9
Yield: 16% (formed during chromatography), colourless
crystals, mp 129°C. IR (neat, KBr) (cm–1): 3420 (br), 2972,
1
2879, 1769, 1439, 1372, 1211, 1161, 1011, 970. H NMR
(200 MHz, CDCl3) δ: 4.40 (dd, J = 8.6, 7.0 Hz, 1H), 4.05
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(dd, J = 8.6, 7.5 Hz, 1H), 2.68 (br s 1H), 2.50 (m 1H), 1.32–
1.93 (m, 8H). 13C NMR (50 MHz, CDCl3) δ: 179.1, 73.2,
69.2, 41.0, 31.6, 23.6, 21.8, 21.0. EI-MS m/z (%): molecular
ion not observed, 154 (13), 112 (42), 97 (57), 83 (78), 55
(100). CI-MS (NH3) m/z: 174 ([M + NH4]+, 100). The con-
nectivity and stereochemistry of 9 were established by
means of single crystal X-ray diffraction.
was evaporated. Chromatography of the residue gave pure
oxadiazoline 3c (60%) as a colorless oil. IR (neat) (cm–1):
1
2959, 2888, 1742, 1458, 1211, 1140, 1104, 917. H NMR
(300 MHz, CDCl3, mixture of two diastereoisomers) δ:
3.81–4.02 (overlapping multiplets, 4H), 3.43 (s, 3H), 3.42 (s,
3H), 1.60–2.42 (m, 14H), 1.54 (s, 6H), 1.53 (s, 3H), 1.52 (s,
3H). 13C NMR (75 MHz, CDCl3) δ: 218.5, 136.9, 119.5,
63.6, 63.5, 52.0, 48.8, 38.7, 27.0, 24,3, 24.1, 20.9. EI-MS
m/z (%): molecular ion not observed, 211 ([M – OMe]+, 9),
173 (38), 139 (11), 129 (10), 97 (100), 84 (26), 69 (100). CI-
MS (NH3) m/z: 260 ([M + NH4]+, 58).
Synthesis of 3b
A
solution in CH2Cl2 of 2-acetoxy-2-methoxy-5,5-
dimethyl-∆3-1,3,4-oxadiazoline (1), containing about 40% of
an acyclic isomer (19), was treated with hydroxy ketone 2b
and trifluoroacetic acid in dichloromethane. After washing
with dilute base, the organic layer was dried and the solvent
was evaporated. Chromatography of the residue gave pure
oxadiazoline 3b (57%) as a colorless oil. IR (neat) (cm–1):
Thermolysis of 3c
A solution of 3c (0.51 g, 2 mmol) in benzene (20 mL) in a
sealed tube was heated at 110°C for 20 h. Evaporation of the
solvent left a residue that was chromatographed on silica
(hexane:ethyl acetate, 90:10) to afford bicyclic ketone 28
(28%), 25 (10% isolated, unstable compound, hydrolysing,
in part, to hydroxylactone 26 during the separation proce-
dure), product 22 (2% isolated, undergoes hydrolyses to α-
hydroxylactone 26), hydroxylactone 26, product 27, some of
which could have hydrolysed to 26 during TLC separation
(5% isolated), and dimers 29 and 30 (about 3% each).
1
2961, 2885, 1744, 1449, 1212, 1136, 1125, 1108, 921. H
NMR (300 MHz, CDCl3, 1:1 mixture of two diastereomers)
δ: 3.70–3.85 (m, 4H, -OCH2), 3.43 (s, 3H, -OCH3), 3.42 (s,
3H, -OCH3), 2.43–1.50 (m, 18H), 1.53 (s, 12H). 13C NMR
(75 MHz, CDCl3) δ: 220.7, 137.1, 119.2, 63.1, 52.0, 46.4,
38.0, 29.8, 29.6, 24.3, 24.2, 20.9. EI-MS m/z (%): molecular
ion not observed, 181, 153 (100), 129, 112, 111, 83 (100).
CI-MS (NH3) m/z: 274 ([M + NH4]+).
Product 22
Colourless oil. 1H NMR (200 MHz, C6D6) δ: 4.09 (dd, J =
9.0 Hz, J = 6.4 Hz, 1H), 3.62 (s, 3H), 3.47 (dd, J = 9.0, J =
2.9 Hz, 1H), 2.57 (m, 1H), 2.32 (m, 1H), 2.0–1.55 (m, 4H),
1.54 (s, 3H), 1.50 (s, 3H), 1.27 (m, 1H). 13C NMR (50 MHz,
C6 D6) δ: 124.8, 109.4, 98.1, 70.9, 51.1, 50.1, 34.2, 31.3,
28.1, 27.7, 25.5. Product 22 hydrolysed easily to 26.
Thermolysis of 3b
A solution of 3b (0.51 g, 2 mmol) in benzene (20 mL) in
a sealed tube was heated at 110°C for 20 h. Evaporation of
the solvent left a residue that was chromatographed on silica
(hexane:ethyl acetate, 90:10) to afford bicyclic ketone 17
(33%), hydroxyorthoester 18 (~10% after thermolysis), and
dimer 19 (ca. 4%).
Product 25
Colourless oil. IR (neat) (cm–1): 3510 (br), 2954, 2881,
1449, 1365, 1168, 1135, 1113, 1045, 982. 1H NMR
(500 MHz, CDCl3) δ: 3.92 (t, J = 10.1 Hz, 1H), 3.37 (dd, J =
10.2, J = 5.6 Hz, 1H), 3.34 (s, 3H), 3.31 (s, 3H), 2.88 (br. s,
1H), 2.34 (m, 1H), 1.98–2.10 (m, 2H), 1.72–1.80 (m, 3H),
1.45 (m, 1H). 13C NMR (125 MHz, CDCl3) δ: 118.2, 90.6,
69.6, 51.5, 50.7, 47.9, 35.1, 32.6, 26.1. EI-MS m/z (%): 189
([M + 1]+, 5), 157 ([M – OMe]+, 100), 98 (10), 75 (8).
Product 17
Yield: 33%, colourless oil. IR (neat) (cm–1): 2946, 2861,
1
1740, 1464, 1452, 1164, 1064, 1044. H NMR (300 MHz,
CDCl3) δ: 4.09 (dd, J = 11.8, 6.1 Hz, 1H), 3.60 (d, J = 12.2,
J = 4.4, Hz, 1H), 3.39 (s 3H), 2.86 (m, 1H), 1.51–2.26 (m,
8H). 13C NMR (75 MHz, CDCl3) δ: 212.8, 102.5, 65.0, 50.4,
45.4, 40.5, 35.9, 32.0, 17.9. HR-MS m/z calcd. for C9H14O3:
170.0943; found: 170.0969.
Product 18
Product 26
Colourless oil. IR (neat) (cm–1): 3425 (br), 2962, 2876,
1765, 1446, 1383, 1211, 1156, 1008, 978. 1H NMR
(200 MHz, C6D6) δ: 3.74 (t, J = 9.3 Hz, 1H), 3.04 (dd, J =
9.4, J = 5.8 Hz, 1H), 2.91 (br s, 1H), 2.29 (m, 1H), 2.00–
0.85 (m, 6H). 13C NMR (50 MHz, C6D6) δ: 179.5, 83.6,
71.1, 46.4, 39.0, 31.3, 24.8. EI-MS m/z (%): 143 ([M + 1]+,
41), 112 (10), 98 (94), 97 (100), 83 (19). CI-MS (NH3) m/z:
160 ([M + NH4]+, 100).
Only a few colourless crystals could be obtained for X-ray
diffraction. The compound hydrolysed spontaneously to the
corresponding hydroxylactone.
Product 19
1
Colourless crystals, yield ca. 3%. H NMR (200 MHz,
CDCl3) δ: 3.77 (m, 4H), 3.28 (s, 6H, -OCH3), 2.73 (m, 2H),
2.18–1.32 (m, 16H). 13C NMR (75 MHz, CDCl3) δ: 108.9,
84.9, 61.4, 47.9, 42.6, 33.5, 27.8, 27.2, 20.9. The structure
and stereochemistry were confirmed by means of single
crystal X-ray diffraction.
Product 27
Colourless oil. IR (neat) (cm–1): 3051, 2954, 2875, 1754,
1642, 1441, 1364, 1202, 1074, 1018, 929. 1H NMR
(200 MHz, C6D6) δ: 5.69 (m, 1H), 4.97 (m, 2H), 4.04 (dd,
J = 9.1, J = 6.2 Hz, 1H), 3.69 (s, 3H), 3.43 (dd, J = 9.1, J =
1.6 Hz, 1H), 3.37 (s, 3H), 2.47 (m, 1H), 1.50–2.25 (m, 12H).
13C NMR (125 MHz, C6D6) δ: 171.1, 138.4, 127.1, 115.2,
106.8, 98.7, 71.7, 51.7, 50.1, 36.0, 33.8, 32.7, 31.6, 25.9,
22.1. EI-MS m/z (%): 264 (9), 254 (100), 253 ([M – CO-
Synthesis of 3c
A
solution in CH2Cl2 of 2-acetoxy-2-methoxy-5,5-
dimethyl-∆3-1,3,4-oxadiazoline (1), containing about 40% of
an acyclic isomer (19), was treated with hydroxy ketone 2c
and trifluoroacetic acid in dichloromethane. After washing
with dilute base, the organic layer was dried and the solvent
© 2003 NRC Canada

606
Can. J. Chem. Vol. 81, 2003
(OCH3)]+, 45). HR-MS m/z calcd. for C16H24O6: 312.1573;
found: 312.1555. Compound 27 hydrolysed readily to 26.
acknowledged. We thank Dr. Jim Britten for the X-ray crys-
tallography and Professor Paul Harrison for the use of his
MPLC equipment.
Product 28
Colourless oil. IR (neat) (cm–1): 2947, 2888, 1774, 1449,
1
1330, 1178, 1094, 959, 721. H NMR (200 MHz, CDCl3) δ:
References
4.28 (dd, J = 8.4 Hz, J = 4.5 Hz, 1H), 4.21 (t, J = 8.4 Hz,
1H), 3.36 (s, 3H), 2.60 (m, 1H), 1.60–2.15 (m, 6H). 13C
NMR (125 MHz, CDCl3) δ: 211.9, 102.5, 67.8, 52.0, 45.3,
40.8, 34.6, 18.6. EI-MS m/z (%): 157 ([M + 1]+, 5), 128
(58), 113 (10), 97 (32), 84 (20), 74 (100). CI-MS (NH3) m/z:
174 ([M + NH4]+, 100).
1. (a) R.W. Hoffmann and H. Häuser. Tetrahedron, 21, 891
(1965); (b) D.M. Lemal, E.P. Gosselink, and S.D. McGregor.
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13. M. Dawid, G. Mloston, and J. Warkentin. Org. Lett. 3, 2455
(2001).
Product 29
1H NMR (200 MHz, C6D6) δ: 4.22 (t, J = 8.6 Hz, 2H),
3.38 (s, 6H), 3.32 (dd, J = 8.6, J = 5.3 Hz, 2H), 2.87 (m,
2H), 2.27 (m, 2H), 1.45–2.05 (m, 10H). 13C NMR (50 MHz,
C6D6) δ: 115.2, 92.1, 69.6, 49.2, 47.3, 36.4, 31.5, 25.4. EI-
MS m/z (%): 312 ([M]+, 2), 281 ([M – OCH3]+, 9), 141 (81),
140 (100), 139 (63), 112 (62), 111 (42), 79 (27). The struc-
ture and stereochemistry were secured by means of single
crystal X-ray diffraction. The structure of 30, an isomer of
29, was also determined by means of single crystal X-ray
diffraction.
Thermolysis of 3a in the presence of dimethyl acetylene-
dicarboxylate (DMAD)
A solution of 3a (0.26 g, 1 mmol) and DMAD (1.3 mmol)
in benzene (10 mL) in a sealed tube was heated at 110°C for
20 h. Evaporation of the solvent left a residue that was
chromatographed on silica (hexane:ethyl acetate, 90:10) to
afford a mixture of diastereomers 32 and 33. The diastere-
omers were separated with a Merck (LOBAR, MPLC) silica
column, eluent EtOAc–hexane, 10:90).
Product 32
Colourless oil, yield: 3%. IR (neat) (cm–1): 2950, 2860,
1
2248, 1724, 1439, 1254, 1062, 909. H NMR (300 MHz,
CDCl3) δ: 4.28 (dd, J = 8.5, J = 4.6 Hz, 1H), 3.77 (s, 3H),
2.69 (d, J = 8.5 Hz, 1H), 3.34 (s, 3H), 3.55 (s, 3H), 3.47 (s,
3H), 2.3 (br. m, 1H), 2.12 (m, 1H), 1.30–1.85 (m, 8H). 13C
NMR (75 MHz, CDCl3) δ: 153.2, 126.8, 111.5, 90.2, 80.9,
72.8, 71.8, 52.9, 51.8, 51.4, 43.4, 29.8, 27.8, 23.1, 22.6. EI-
MS m/z (%): molecular ion not observed, 281 ([M – CO]+,
32), 229 (13), 140 (35), 111 (100), 93 (64).
14. N. Kuhn, H. Bohnen, and G. Henkel. Z. Naturforsch. 49b,
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427 (1999).
16. N. Kuhn, K. Eichele, and M. Walker. Z. Anorg. Allg. Chem.
627, 2565 (2001).
17. D.L. Boger and C.E. Brotherton. Tetrahedron Lett. 25, 5611
(1984).
18. K. Kassam and J. Warkentin. J. Org. Chem. 59, 5071 (1994).
19. K. Kassam, D.L. Pole, M. El-Saidi, and J. Warkentin. J. Am.
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20. H.N.C. Wong. Houben-Weyl: Methods of organic chemistry.
Vol. E17e. Edited by A. deMeijere. Georg Thieme Verlag,
Stuttgart. 1998. pp. 513–514.
Product 33
Colourless crystals, yield: 3%, mp 68°C. 1H NMR
(300 MHz, CDCl3) δ: 4.19 (dd, J = 8.6, J = 4.3 Hz, 1H),
3.77 (s, 3H), 3.61 (d, J = 8.7 Hz, 1H), 3.56 (s, 3H), 3.40 (s,
3H), 2.25 (br m, 1H), 2.14 (m, 1H), 1.30–1.90 (m, 8H). 13C
NMR (75 MHz, CDCl3) δ: 153.0, 127.0, 112.0, 88.8, 79.5,
72.8, 71.3, 52.9, 52.0, 51.5, 43.8, 30.6, 27.7, 23.1, 22.7. The
structure of 33 (Scheme 12) was determined by means of
single crystal X-ray diffraction.
21. H.E. Zimmerman and J. English. J. Am. Chem. Soc. 76, 2285
(1954).
Acknowledgments
Financial support from the Natural Sciences and Engi-
neering Research Council of Canada (NSERC) is gratefully
© 2003 NRC Canada