Generation, electrocyclic ring opening, and unprecedented conversion of a 3-acylaminoazetinone into cis-3,4-disubstituted azetidinones

Article abstract of DOI:10.1139/v01-102

An attempt to synthesize the nucleus of cefaclor by insertion of an appropriately functionalized rhodium carbene into a β-lactam N-H bond leads instead to attack at sulfur, followed by fragmentation into a four-membered thietanone and a four-membered 3-acylaminoazetinone. The azetinone undergoes electrocyclic ring opening, with a calculated half-life of 11 s at 40°C, to a trans-disubstituted vinyl isocyanate, but can be trapped by saturated, unsaturated allylic and benzylic alcohols to form 3,4-disubstituted azetidinones in which the cis- isomer predominates.

Full text of DOI:10.1139/v01-102

1259
Generation, electrocyclic ring opening, and
unprecedented conversion of a 3-
acylaminoazetinone into cis-3,4-disubstituted
azetidinones
Saul Wolfe, Stephen Ro, and Zheng Shi
Abstract: An attempt to synthesize the nucleus of cefaclor by insertion of an appropriately functionalized rhodium
carbene into a β-lactam N—H bond leads instead to attack at sulfur, followed by fragmentation into a four-membered
thietanone and a four-membered 3-acylaminoazetinone. The azetinone undergoes electrocyclic ring opening, with a cal-
culated half-life of 11 s at 40°C, to a trans-disubstituted vinyl isocyanate, but can be trapped by saturated, unsaturated
allylic and benzylic alcohols to form 3,4-disubstituted azetidinones in which the cis- isomer predominates.
Key words: rhodium carbene, torquochemical, azetinone, mercaptoazetidinone.
Résumé : Un essai de synthèse du noyau cefaclor, par insertion d’un carbène de rhodium fonctionnalisé de façon ap-
propriée dans une liaison N—H d’un β-lactame, conduit plutôt à une attaque au niveau du soufre, suivie d’une frag-
mentation en une thiétanone à quatre chaînons et à une 3-acétylaminoazétinone à quatre chaînons. L’azétinone subit
une ouverture de cycle électrocyclique, avec un temps de demi-vie de 11 s à 40°C, qui conduit à un isocyanate de vi-
nyle trans-disubstitué; on peut toutefois la piéger à l’aide d’alcools saturés, insaturés et benzyliques qui avec formation
d’azétidinones 3,4-disubstituées dans lesquelles l’isomère cis prédomine.
Mots clés : carbène de rhodium, torquochimique, azétinone, mercaptoazétidinone.
[Traduit par la Rédaction] Wolfe et al. 1271
Introduction
The thiazoline azetidinone 1 (Cooper’s compound), which
is readily accessible from penicillin V (1), is a useful starting
material for the partial synthesis of unnatural β-lactam-
containing compounds (2). The work reported here began
with the idea that 1 might serve as a precursor of the 3-chloro-
∆3-cephem nucleus (2), which is a desirable synthetic target
(3) because of the orally effective broad-spectrum antibacte-
rial properties of cefaclor (2, R = D-PhCH(NH2)CONH) (4).
It was thought that hydrolysis of 1 to the mercaptoazetid-
inone 3 (5), followed by reaction with a γ-bromoacetoacetate
(4), diazotization of 5 (6), and cyclization of 6 via N—H in-
sertion using rhodium acetate (7), would lead to a 3-
hydroxycephem 7, the precursor of 2. Significantly, although
this plan appeared to have ample precedent in the numerous
reports of carbenoid insertion into β-lactam N—H bonds to
produce carbacephems (8) (8), oxacephems (9) (9),
carbapenems (10) (10), and oxapenems (11) (11), there were
no reported examples of the successful application of this
methodology to syntheses of cephems (12) or penems (13).
A reason for this absence of (published) activity soon be-
came clear.
Received January 29, 2001. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on August 21, 2001.
S. Wolfe,1 S. Ro, and Z. Shi. Department of Chemistry,
Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
1Corresponding author (telephone: (604) 291-5972; fax: (604)
291-5973; e-mail: swolfe@sfu.ca).
Can. J. Chem. 79: 1259–1271 (2001)
© 2001 NRC Canada
DOI: 10.1139/cjc-79-8-1259

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Can. J. Chem. Vol. 79, 2001
Scheme 1.
Scheme 2.
Serendipitous formation and electrocyclic
ring opening of an acylaminoazetinone
1
Fig. 1. The IR and H NMR spectra of 22.
The synthesis of 6 is summarized in Scheme 1.
Bromination of ethyl acetoacetate in acetic acid produced
the γ-bromide 4 (R = Et), which was converted to the α,γ-
dibromide 14 with 1 equiv of pyrrolidone hydrotribromide
(PHT) (12). With 1 and 2 equiv of PHT, ethyl acetoacetate
gave, successively, the α-bromide 15 and the α,α-dibromide
16. Following Osborne (13), who reported that 3 reacts with
ethyl bromoacetate in hexamethylphosphoramide solvent
(HMPA) to give 17 (R = OEt), stirring of 3 with 4 in HMPA
afforded 17 (R = CH2CO2Et) in 53% yield. The same prod-
uct was obtained from the α,γ-dibromide 14. Diazo transfer
to 17 (R = CH2CO2Et) to form 6 (mp 135–137°C) proceeded
reproducibly
in
70–75%
yield
using
p-
carboxybenzenesulfonyl azide and triethylamine in
acetonitrile (14).2
Refluxing of 6 with rhodium acetate in benzene did not
lead to 7. Instead, a compound C11H10N2O3 was isolated as
1
an oil, whose IR and H NMR spectra showed the presence
of PhOCH2- and -CH=CH-, and the absence of a β-lactam
ring. The structure considered initially was N-
phenoxyacetylimidazolone (18), whose formation could be
rationalized in terms of Scheme 2, which proposes attack of
the metallocarbenoid 19 on sulfur to form the neutral sulfon-
ium ylide 20 (16). Fragmentation of 20 into the neutral
acylaminoazetinone 21 (C11H10N2O3) and the neutral
thietanone 22, ring opening of 21 to the cis-vinyl isocyanate
23 (17), and cyclization of 23 would lead to 18 (18).
Support for this mechanistic proposal was sought through
a search for 22 among the products, and by an independent
synthesis of the putative imidazolone 18. Refluxing of 6
with rhodium acetate in methylene chloride afforded, in 32%
yield, a fragrant oil C6H8O3S, identified as 22 on the basis of
1
its IR and H NMR spectra (Fig. 1). In subsequent experi-
ments, conducted in refluxing benzene, both the presumed
imidazolone 18 (68%) and 22 were isolated as products.
The synthesis of 18 is summarized in Scheme 3. Reaction
of aminoacetaldehyde diethyl acetal with potassium cyanate
gave the ureidoacetal 24 (19) which, when refluxed with
phenoxyacetyl chloride in acetonitrile containing 4 Å molec-
ular sieves, underwent acylation and cyclization to 18, a
crystalline compound that melted with decomposition at
82°C and liquefied completely at 89°C. It was immediately
apparent, from the isolation of a crystalline compound and
from the IR and NMR spectra, that 18 was different from
the rhodium acetate product; the latter exhibited, inter alia, a
2 For other diazo transfer reagents and conditions, see ref. 15.
© 2001 NRC Canada

Wolfe et al.
1261
1
Scheme 3.
constant in the H NMR, which is compatible with the pres-
ence of a trans-double bond (21). All of these observations
are consistent with the trans-substituted vinyl isocyanate 25
as the structure of the rhodium acetate product. This corre-
sponds to the less-hindered torquochemical (22) sense of
conrotatory ring opening of the putative azetinone 21.
1
Fig. 2. The IR and H NMR spectra of 25.
There is precedent for such an electrocyclic reaction in the
behaviour of the benzoazetinones 26, which equilibrate with
iminoketenes 27 (23). In related work, Li and Miller (24)
have reported that tosylation of the 1-hydroxy-2-azetidinone
28 leads to the imidazolone 29, possibly via intermediates
30–32. The cyclization 32 → 29 is analogous to 23 → 18
but, in view of ref. 23 and the present findings, it can be pro-
posed that the precursor of 32 is the azetinone 33, whose
preferred mode of electrocyclic ring opening leads to a
trans-relationship between the methyl and acylamino
groups.
The
tert-butyl-
and
adamantyl-substituted
benzoazetinones 26 exhibit carbonyl stretching bands at
1812 and 1825 cm–1, respectively, (23). The calculated
(HF/6-31G*) C=O stretch of the parent azetinone 34 is at
1895 cm–1, and the calculated (6-31G*) C=O stretch of the
acylaminoazetinone 35 is at 1889 cm–1 (see Experimental).
Since no IR peak higher than 1800 cm–1 can be detected
during the reaction of 6 with rhodium acetate, the
acylaminoazetinone 21 is presumed to have an extremely
short lifetime. In retrospect, this is not surprising: 34 has a
half-life of 2.0 ± 0.5 s at 35°C (25), the homologous 1-
pyrrolin-5-one 36 has a half-life of 5.5 ± 0.5 s (25), and at-
carbonyl stretch at 1713 cm–1, while 18 showed peaks at
1732 and 1559 cm–1.
A closer examination of the spectra of the rhodium acetate
product (Fig. 2) then revealed a possible isocyanate absorp-
tion at 2268 cm–1 in the IR, previously (and erroneously) as-
signed by us to carbon dioxide, a possible isocyanate carbon
at 123.33 ppm (20) in the 13C NMR, previously interpreted
as an aromatic carbon, and a 12.5 Hz H-C=C-H coupling
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Can. J. Chem. Vol. 79, 2001
Fig. 3. Conrotatory ring opening of a 3-acylaminoazetinone (6-
31G*//6-31G* calculations). Upper: reactant and transition struc-
ture leading to the Z-isomer. Lower: reactant and transition struc-
ture leading to the E-isomer.
Table 1. Reaction of 6 with rhodium acetate in methylene chlo-
ride in the presence of RXH to form 3-phenoxyacetylamino-4-
XR-substituted azetidinones.
Temperature
(°C)
Yield of
cis-isomer
Yield of
trans-isomer
RXH
EtOH
IpOH
PhCH2OH
Me2C=CHCH2OH
HC=CCH2OH
CH2=CHCH2OH
Furfuryl alcohol
PhCH2SH
20
20
40
40
40
40
40
40
15
41
70
69
26
36
50
12
nda
12
22
24
12
14
nd
4
aNot detected.
More complex alcohols, including hydroxyacetone (42),
ethyl γ-hydroxyacetoacetate (43) (33), ethyl α-diazo-γ-
hydroxyacetoacetate (44), benzyl 4-hydroxy-2-propynoate
(45) (34), and 6-hydroxymethyl-1,3-dioxin-4-one (46) (35)
did not react with the azetinone. In the case of 43, the prod-
uct was the 4-ethoxyazetidinone, presumably via prior
lactonization, with liberation of ethanol, under the reaction
conditions. Benzylamine, N-benzylamine, and benzyl
pentadienoate (47) (36) also did not react. Benzyl mercaptan
gave the cis-benzyl sulfide 48 in low yield (Table 1).
tempts to synthesize 1-azetine (37) lead instead to 2-
azabutadiene (26).
Figure 3 shows the transition structures of the two
conrotatory modes of electrocyclic ring opening of the
acylaminoazetidinone 35, calculated at the MP2/6-31G*//6-
31G* level (27). The pathway leading to the trans-substi-
tuted vinyl isocyanate is 10 kcal mol–1 lower in energy.
From the calculated 20.1 kcal mol–1 barrier and the Eyring
equation, the estimated half-life of 35 is 11 s at 40°C.
An unprecedented result — Trapping the
3S-acylaminoazetinone with alcohols leads
to cis-disubstituted azetidinones
Substituted 2-azetin-4-ones (38) are isolable and, in some
cases, crystalline compounds (28). In contrast, with the ex-
ception of the phthalimido compound 39, claimed in the pat-
ent literature (29), 1-azetin-4-ones (40) and 1-azetidinium
cations (41) are known only as the often-proposed but never-
observed intermediates in C-4-substitution reactions of 2-
azetidinones (30). With compounds containing a C-3-
substituent, all previous work involving the generation and
capture of these putative intermediates has led (31) to trans-
Theoretical considerations
The oxidation of penicillins leads to S-sulfoxides 49, in
which the sulfoxide oxygen occupies the concave (β) face,
and is syn to the acylamino side chain (37). The evidence
strongly suggests (37) that the oxidant is delivered to the
more hindered face of the bicyclic system by hydrogen
bonding to the amide N—H.
In the present work, using no more than a two-fold excess
of an alcohol in the relatively nonpolar solvent methylene
chloride, the alcohol is delivered syn to the acylamino group
of the putative 3-acylaminoazetinone. With the earlier oxida-
tion experiments as a precedent, the chair-like hydrogen-
bonded transition state 50 could be proposed to account for
the trapping results. This idea was pursued computationally.
Figure 4 summarizes the results of 3-21G calculations of
the four-centred cis-addition of methanol to the parent
3,4-disubstituted
azetidinones.
In
contrast,
cis-3-
phenoxyacetamido-4-alkoxyazetidinones have now been
found to be produced as the major isomers (32) when satu-
rated, unsaturated, and aromatic alcohols are included in re-
action mixtures containing 6 and rhodium acetate.
Table 1 summarizes the results of these trapping experi-
ments. The yields shown in this table refer to isolated yields
of pure cis- and (or) trans-isomers.
© 2001 NRC Canada

Wolfe et al.
1263
Fig. 5. Transition structures for the four-centered cis-addition of
methanol syn (left) and anti (right) to 3-formylamino-1-azetin-4-one.
Geometries have been optimized at 6-31G*. Relative energies re-
fer to single point MP2/6-31G* calculations at the 6-31G* opti-
mized geometries.
Fig. 4. cis-Addition of methanol to 1-azetin-4-one (3-21G calcu-
lations). Energy differences are in kcal mol–1; bond lengths are
in Å.
Fig. 6. The gauche effect in MeO-CH2CH2-NHCHO (MP2/6-
31G*//6-31G*) calculations. The gauche conformation is 2.6 kcal
mol–1 more stable than the anti.
azetinone. Figure 5, which is more interesting, shows the 6-
31G* transition structures for the four-centred addition of
methanol syn and anti to the acylamino group of an
acylamino-substituted azetinone. The syn structure shows no
evidence of the intramolecular hydrogen bond postulated in
50. Nevertheless, based on single point MP2/6-31G* calcu-
lations, the energy of this structure is 2.03 kcal mol–1 lower
than that of the anti. In addition, the developing C···O bond
is rather short, suggesting a product-like transition state. If
this were the case, the products of the addition might also
show a syn-preference. This is indeed the case; as seen in
Fig. 6, the gauche conformation of MeO-CH2CH2-NHCHO
is significantly more stable than the anti. Finally, the calcu-
lated MP2/6-31G*//6-31G* barrier for the syn addition of
Fig. 5 is 20.6 kcal mol–1, almost the same as that shown in
Fig. 3 for the electrocyclic ring opening (20.1 kcal mol–1).
NMR (DMSO-d6): 166.59 (acetamido C=O), 161.90 (β-
lactam C=O), 157.33, 129.47, 121.46, 114.86 (aromatic),
150.11 (C-3), 124.76 (C-4), 66.35 (PhOCH2). Anal. calcd.
for C11H12N2O3S: C 52.37, H 4.79, N 11.10; found: C 52.24,
H 5.00, N 11.30.
Experimental
Ethyl γ-bromoacetoacetate (4) (39)
A solution of bromine (1.4 mL, 4.34 g, 27.1 mmol) in gla-
cial acetic acid (4 mL) was added dropwise, with stirring at
0°C, to a solution of ethyl acetoacetate (3.2 mL, 3.3 g,
25.1 mmol) in glacial acetic acid (9 mL). After the addition
was complete, the ice bath was removed and stirring was
continued overnight. The yellow solution was then diluted
with ether (30 mL) and washed successively with water (3 ×
30 mL), saturated sodium bicarbonate (4 × 40 mL), water
(40 mL), and saturated sodium chloride (40 mL), dried over
magnesium sulfate, and evaporated to afford the product as a
yellowish-green liquid (3.99 g, 76%). The compound was
characterized spectroscopically, and used directly in the next
step. MS (CI, m/z): 209 (M + 1, for 79Br), 211 (M + 1, for
3-Phenoxyacetamido-4-mercapto-2-azetidinone (3)
A 40% aqueous solution of p-toluenesulfonic acid hydrate
(13 mL) was added to a solution of the thiazoline
azetidinone 1 (5.03 g, 21.5 mmol) in a mixture of dichloro-
methane (100 mL) and acetone (100 mL). The mixture was
stirred for 2 h, and the mercaptoazetidinone was then col-
lected by filtration and dried in vacuo. A second crop was
recovered by evaporation of the filtrate and trituration with a
minimum amount of water (4.93 g, 91%), mp 138–140°C
(lit. (38) 133–135°C). MS (CI, m/z): 219 ((M + 1)-H2S). IR
1
(KBr) (cm–1): 3283, 3210, 1761, 1659. H NMR (DMSO-
d6): 8.93 (1H, d, 9.3 Hz, NH), 8.79 (1H, s, NH), 7.29 (2H, t,
Ar), 6.98 (3H, m, Ar), 5.32 (1H, dd, 4.7, 9.3 Hz, H-3), 5.00
(1H, 4.7, 10.2 Hz, H-4), 4.61 (1H, d, 15.1 Hz, CHH), 4.58
(1H, d, 15.1 Hz, CHH), 3.19 (1H, d, 10.3 Hz, SH). 13C
1
81Br). IR (KBr) (cm–1): 1744, 1726. H NMR (CDCl3): 4.20
(2H, q, 7.1 Hz), 4.05 (2H, s), 3.70 (2H, s), 1.29 (3H, t,
© 2001 NRC Canada

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Can. J. Chem. Vol. 79, 2001
7.1 Hz). 13C NMR (CDCl3): 194.44 (acetyl C=O), 166.52
(ester C=O), 61.73 (ester methylene), 46.05 (C-4), 33.66 (C-
2), 14.03 (methyl).
C=O), 157.22, 129.81, 122.41, 114.92 (aromatic), 67.44
(PhOCH2), 62.03 (C4), 61.93 (CO2CH2CH3), 60.44 (C-3),
32.91 (SCH2CO), 14.05 (CO2CH2CH3).
Ethyl α,γ-dibromoacetoacetate (14)
Coupling of 3 with 4
A solution of ethyl γ-bromoacetoacetate (12.5 mg,
0.060 mmol) in tetrahydrofuran (0.2 mL) was treated with a
solution of pyrrolidone hydrotribromide (20.5 mg,
0.060 mmol) in tetrahydrofuran (0.7 mL). Stirring was con-
tinued for 3 h, and the solids were then removed by filtra-
tion. The filtrate was diluted with ethyl acetate (5 mL),
washed successively with water (5 mL) and saturated so-
dium chloride, dried over magnesium sulfate, and evaporated
Ethyl γ-bromoacetoacetate (2.01 g, 9.64 mmol) was added
dropwise with stirring during 15 min to a solution of 3
(2.14 g, 8.49 mmol) in hexamethylphosphoric triamide
(30 mL). The pale yellow solution was stirred for 24 h, di-
luted with ethyl acetate (50 mL) and washed successively
with water (3 × 50 mL) and saturated sodium chloride
(50 mL), dried over magnesium sulfate, and evaporated. The
resulting foam (5) crystallized upon trituration with anhy-
drous ether, 1.84 g (57%), mp 106–108°C. [α]2D0 +69.6°
(c 0.115, chloroform). MS (EI, m/z): 380 (M). HR-MS-EI
calcd. for C17H20N2O6S: 380.1042 (M); found: 380.1044. IR
(KBr) (cm–1): 3304, 1762, 1735, 1701, 1675. 1H NMR
(CDCl3): 7.38 (1H, d, 8.7 Hz, NH), 7.32 (2H, t, Ar), 7.04
(1H, t, Ar), 6.96 (2H, d, Ar), 6.66 (1H, s, NH), 5.56 (1H, dd,
4.7, 8.7 Hz, H-3), 5.00 (1H, d, 4.7 Hz, H-4), 4.58 (1H, d,
15.2 Hz, PhOCHH), 4.57 (1H, d, 15.2 Hz, PhOCHH), 4.19
(2H, q, 7.2 Hz, ester CH2), 3.66 (1H, d, 16.0 Hz, SCHH),
3.54 (1H, d, 16.0 Hz, SCHH), 3.48 (1H, d, 15.5 Hz,
COCHHCO), 3.45 (1H, d, 15.5 Hz, COCHHCO), 1.28 (3H,
t, 7.2 Hz, ester CH3). 13C NMR (CDCl3): 198.00 (C=O),
168.85 (acetamido C=O), 166.93 (ester C=O), 165.16 (β-
lactam C=O), 157.20, 129.82, 122.41, 114.97 (aromatic),
67.41 (PhOCH), 61.89 (C-4), 61.59 (CO2CH2CH3), 60.60
(C-3), 47.07 (COCH2CO), 40.46 (SCH2CO), 14.06
(CO2CH2CH3). Anal. calcd. for C17H20N2O6S·0.5H2O: C
52.43, H 5.44l N 7.19; found: C 52.37, H 5.15, N 7.61.
1
to afford the product as a yellow oil (15.8 mg, 91%). H
NMR (CDCl3): 5.17 (1H, s), 4.30 (2H, q, 7.2 Hz), 1.31 (3H,
t, 7.2 Hz). IR (neat) (cm–1): 1748, 1728.
Ethyl α-bromoacetoacetate (15)
A solution of pyrrolidone hydrotribromide (49.5 mg,
0.099 mmol) in tetrahydrofuran (0.8 mL) was added
dropwise to a solution of ethyl acetoacetate (0.012 mL,
12.3 mg, 0.095 mmol) in tetrahydrofuran (0.4 mL). After
30 min, the reaction mixture was diluted with ether (4 mL)
and maintained overnight at –5°C. The mixture was then fil-
tered and the filtrate was evaporated to dryness. The residue
was dissolved in ethyl acetate (5 mL), and this solution was
washed successively with saturated sodium bicarbonate
(5 mL) and water (5 mL), dried over magnesium sulfate, and
evaporated to afford the product as a colourless oil. 1H NMR
(CDCl3): 4.77 (1H, s), 4.30 (2H, q, 7.3 Hz), 2.45 (3H, s),
1.32 (3H, t, 7.3 Hz).
Ethyl α,α-dibromoacetoacetate (16)
p-Carboxybenzenesulfonyl azide
A solution of pyrrolidone hydrotribromide (77.1 mg,
0.158 mmol) in tetrahydrofuran (0.9 mL) was added
dropwise, with stirring, to a solution of ethyl acetoacetate
(0.011 mL, 10.9 mg, 0.084 mmol) in tetrahydrofuran
(0.3 mL). The mixture was stirred for 3 h and the filtrate was
then diluted with ethyl acetate (5 mL), washed successively
with saturated sodium bicarbonate (50 mL), water (50 mL),
and saturated sodium chloride (50 mL), dried over magne-
sium sulfate, and evaporated to give the product (12.2 mg,
A
suspension of the potassium salt of p-
carboxybenzenesulfonic acid (10.00 g, 41.6 mmol) in
chlorosulfonic acid (14.0 mL) was heated for 3 h at 100°C.
The reaction mixture was then cooled to room temperature
and cautiously poured onto ice (40 g). The white precipitate
was collected, air dried, dissolved in acetone (125 mL), and
treated with a solution of sodium azide (3.11 g, 47.8 mmol)
in water (20 mL). After warming at 40°C for 2.5 h, with ad-
dition of water as necessary to maintain one phase, the solu-
tion was immersed in ice, water was added to the cloud
point, and crystallization was allowed to proceed. The crys-
tals were collected, triturated with ether (50 mL), and dried
to give the product (4.89 g, 52%), mp 177–179°C (lit. (40)
mp 180°C (dec)). MS (EI, m/z): 227 (M). IR (KBr) (cm–1):
3100–2554, 2151, 1703, 1377. 1H NMR (CDCl3,
triethylamine salt): 10.06 (1H, br s, NH), 8.23 (2H, d,
8.8 Hz, Ar), 7.91 (2H, d, 8.8 Hz, Ar), 2.61 (6H, q, 7.2 Hz,
CH2), 1.05 (9H, t, 7.2 Hz, CH3). 13C NMR (CDCl3,
triethylamine salt): 170.49 (carboxylate), 143.98, 139.09,
130.49, 126.93 (aromatic), 45.26 (CH3CH2N), 8.71
(CH3CH2N).
1
51%). H NMR (CDCl3): 4.38 (2H, q, 7.2 Hz), 2.60 (3H, s),
1.35 (3H, t, 7.2 Hz).
Coupling of 3 with ethyl bromoacetate
Ethyl bromoacetate (3.4 µL, 5.1 mg, 0.03 mmol) was
added to a solution of 3 (6.5 mg, 0.03 mmol) in
hexamethylphosphoric triamide (0.06 mL). The solution was
stirred for 23 h. Ethyl acetate (10 mL) was then added and
the resulting solution was washed successively with water (2
× 10 mL) and saturated sodium chloride (10 mL), dried over
magnesium sulfate, and evaporated. The residue was crystal-
lized from chloroform–ether to give 2, 5.8 mg (66%) (13).
1H NMR (CDCl3): 7.44 (1H, d, 8.9 Hz, NH), 7.24 (2H, t,
Ar), 7.03 (1H, t, Ar), 6.94 (2H, t, Ar), 6.65 (1H, br s, NH),
5.62 (1H, dd, 4.5, 8.9 Hz, H-3), 5.14 (1H, d, 4.5 Hz, H-4),
4.57 (2H, s, PhOCH2), 4.17 (2H, q, 7.2 Hz, ester CH2), 3.27
(1H, d, 11.5 Hz, SCHH), 3.24 (1H, d, 11.5 Hz, SCHH), 1.27
(3H, t, 7.2 Hz, ester CH3). 13C NMR (CDCl3): 170.32
(acetamido C=O), 168.84 (ester C=O), 165.35 (β-lactam
Diazo transfer to 5
p-Carboxybenzenesulfonyl azide (845 mg, 3.72 mmol)
was added to a solution of the azetidinone (1.29 g,
3.39 mmol) in acetonitrile (28 mL). The suspension was
stirred in an ice bath while triethylamine (1.4 mL, 1.02 g,
10.04 mmol) was added dropwise. The suspension dissolved
© 2001 NRC Canada

Wolfe et al.
1265
initially and, after 10 min, a precipitate reappeared. The ice
bath was removed and the mixture was stirred for 3 h and
then filtered. The filtrate was evaporated and the yellow res-
idue, in dichloromethane (80 mL), was washed with satu-
rated sodium bicarbonate (2 × 80 mL) and water (80 mL),
dried over magnesium sulfate, and evaporated. Trituration
with ethyl acetate – ether (1:5) and cooling overnight at 5°C
afforded 6 as a pale yellow solid (0.98 g, 71%), mp 135–
137°C. [α]2D0 +55.0° (c 0.109, chloroform). MS (CI, m/z):
161, 219. IR (KBr) (cm–1): 3310, 3192, 2145, 1765, 1719,
sium sulfate, and evaporated under reduced pressure at
25°C. The residue was dried under high vacuum (3.6 mg,
68%). HR-MS-CI calcd. for C11H10N2O3: 219.0762 (M + 1);
1
found: 219.0766. IR (CH2Cl2) (cm–1): 3410, 2268, 1713. H
NMR (CDCl3): 7.99 (1H, d, 10.1 Hz, NH), 7.34 (2H, m, Ar),
7.07 (1H, t, Ar), 6.94 (2H, d, Ar), 6.86 (1H, dd, 10.1,
12.5 Hz, =CH-NH), 6.32 (1H, d, 12.5 Hz, CH=CH-NH),
4.55 (2H, s, PhOCH2). 13C NMR (CDCl3) (13C–1H 2D-
COSY): 166.47 (C=O), 157.59, 130.60, 123.33, 115.47 (aro-
matic),
121.55
(NHCHCHN=C=O),
108.06
1
1663, 1645. H NMR (CDCl3): 7.38 (1H, d, 11.9 Hz, NH),
(NHCHCHN=C=O), 67.96 (PhOCH2CONH).
7.34 (2H, m, Ar), 7.03 (1H, t, Ar), 6.94 (2H, d, Ar), 6.48
(1H, br s, NH), 5.62 (1H, ddd, 1.0, 4.7, 9.1 Hz, H-3), 5.13
(1H, d, 4.7 Hz, H-4), 4.56 (2H, s, PhOCH2), 4.28 (2H, dq,
7.1, 7.2 Hz, nonequivalent protons of ester methylene), 4.02
(1H, d, 14.5 Hz, SCHH), 3.61 (1H, d, 14.5 Hz, SCHH), 1.31
(3H, t, 7.1 Hz, ester CH3). 13C NMR (CDCl3): 188.02
(acetyl C=O), 168.68 (acetamido C=O), 165.39 (β-lactam
C=O), 161.40 (ester, C=O), 157.21, 129.81, 122.40, 114.99
(aromatic), 67.44 (PhOCH2), 61.99 (C4), 61.58
(CO2CH2CH3), 60.35 (C-3), 36.97 (SCH2CO), 14.26
(CO2CH2CH3). Anal. calcd. for C17H18N4O6S·0.5H2O: C
49.15, H 4.61, N 13.49; found: C 48.90, H 4.51, N 12.55.
Ureidoacetaldehyde diethyl acetal (24)
Aminoacetaldehyde diethyl acetal (3.3 mL, 3.02 g,
22.7 mmol) was mixed with 5 g of crushed ice, cooled to
0°C, and 5 N hydrochloric acid (4.5 mL, 0.82 g, 22.5 mmol)
(cooled to –40°C), was added quickly, followed by a solu-
tion of potassium cyanate (2.54 g, 31.3 mmol) in water
(6.0 mL). The mixture was stirred vigorously for 15 min at
0°C and then refluxed for 3 h and cooled. The product crys-
tallized upon scratching with a glass rod (2.8 g, 70%), mp
102–104°C (lit. (19) mp 107 to 108°C). MS (CI, m/z): 177
(M + 1). IR (KBr) (cm–1): 3383, 3210, 1657. 1H NMR
(CDCl3): 5.53 (1H, s, NH), 4.90 (2H, br s, NH2), 4.48 (1H, t,
5.2 Hz, CH), 3.69 (2H, dq, 7.0, 9.3 Hz, ester CHH), 3.54
(2H, dq, 7.0, 9.3 Hz, ester CHH), 3.28 (2H, dd, 5.6, 5.6 Hz,
CH2NH), 1.19 (6H, t, 7.0 Hz, CH3). 13C NMR (CDCl3):
159.10 (NCON), 101.70 (OCHO), 62.98 (methyl), 43.45
(NHCH2), 15.29 (CH2O). Anal. calcd. for C7H16N2O3: C
47.71, H 9.15, N 15.90; found: C 47.59, H 8.90, N 15.73.
Rhodium(II) acetate (41)
A solution of rhodium(III) chloride trihydrate (126.3 mg,
0.48 mmol) and sodium acetate trihydrate (259.1 mg,
1.90 mmol) in absolute ethanol (2.5 mL) and glacial acetic
acid (2.5 mL) was heated at 105°C for 1.5 h. The green re-
action mixture was then cooled and filtered.
Recrystallization from hot methanol and drying at 35°C in
vacuo yielded emerald green crystals (87.1 mg, 33%). IR
(KBr) (cm–1): 1588, 1439, 1433. 1H NMR (acetone-d6): 1.74
(s). Anal. calcd. for Rh2C8H12O8: C 21.74, H 2.74; found: C
21.98, H 2.86.
N-Phenoxyacetylimidazolone (18)
Phenoxyacetyl chloride (0.03 mL, 37 mg, 0.20 mmol) was
added to a solution of ureidoacetaldehyde diethyl acetal
(35 mg, 0.20 mmol) in acetonitrile (2.0 mL), to which acti-
vated 4 Å molecular sieves (10 mg) had been added. The
mixture was stirred at room temperature for 30 min and then
refluxed for 5 h, cooled, and filtered. The filtrate was evapo-
rated and the residue was purified by column chromatogra-
phy using ethyl acetate – hexanes (1:1). Crystallization from
ethyl acetate – hexanes gave material melting at 82–89°C.
MS (EI, m/e): 218 (M). HR-MS-EI calcd. for C11H10N2O3:
218.0686 (M); found: 218.0691. IR (KBr) (cm–1): 1732,
Reaction of 6 with rhodium acetate — Isolation and
characterization of the thietanone 22
Rhodium(II) acetate (5.1 mg, 0.015 mmol) was added to a
solution of 6 (20 mg, 0.049 mmol) in dichloromethane
(2 mL). The solution was stirred for 23 h and then flushed
through a 5-cm column of silica gel, using dichloromethane,
to give unreacted diazoketone (5 mg) and 22 as a colourless,
fragrant film (2.5 mg, 32%). MS (CI, m/z): 161 (M + 1).
HR-MS-CI calcd. for C6H8O3S: 161.0262 (M + 1); found:
161.0267. IR (CH2Cl2) (cm–1): 1792, 1694. 1H NMR
(CDCl3): 5.16 (1H, d, 3.6 Hz, CH), 4.52 (1H, dd, 3.6,
6.2 Hz, CHH), 4.33 (1H, d, 16.2 Hz, CHH), 4.26 (2H, q,
7.1 Hz), 1.31 (3H, t, 7.1 Hz). 13C NMR (CDCl3): 189.40
(ring C=O), 166.35 (ester C=O), 69.76 (ring CH), 62.49 (es-
ter CH2), 54.31 (ring CH2), 14.03 (ester methyl).
1
1694. H NMR (CDCl3): 9.34 (1H, br s, NH, coupled to
=CH at 6.33), 7.29 (2H, m, Ar), 7.00 (3H, m, Ar +
CH=CHNH), 6.44 (1H, dd, 2.4, 3.3 Hz, =CH-NH), 5.32
(2H, s, PhOCH2). 13C NMR (CDCl3): 166.71
(phenoxyacetyl C=O), 158.05 (imidazolone C=O), 152.21,
129.54,
(CONHCHCHN),
121.84,
115.138
111.93
(aromatic),
(CONHCHCHN),
114.83
68.02
(PhOCH2).
Reaction of 6 with rhodium acetate — Isolation and
characterization of 25
Trapping of the azetinone
(i) With ethanol
Rhodium(II) acetate (0.5 mg, 0.001 mmol) was added to a
suspension of 6 (9.8 mg, 0.024 mmol) in benzene (1.1 mL).
The mixture was immediately immersed in an oil bath pre-
heated to 85°C. The red solution was stirred for 2.5 h,
cooled, diluted with water (5.0 mL), and extracted with di-
chloromethane (2 × 5 mL). The organic extract was washed
with saturated sodium chloride (10 mL), dried over magne-
Rhodium(II) acetate (3.0 mg, 0.007 mmol) was added to a
solution of the diazoketone (37.9 mg, 0.09 mmol) and etha-
nol (0.01 mL, 7.9 mg, 0.20 mmol) in dichloromethane
(5 mL). The red solution was stirred for 20 h and then evap-
orated. The residue was chromatographed, using a dichloro-
methane – ethyl acetate elution gradient, to yield the
© 2001 NRC Canada

1266
Can. J. Chem. Vol. 79, 2001
thietanone
and
cis-3-phenoxyacetamido-4-ethoxy-2-
(1H, ddd, 1.4, 3.9, 9.6 Hz, H-3), 5.26 (1H, d, 3.9 Hz, H-4),
4.57 (2H, s, PhOCH2), 4.53 (1H, d, 15.0 Hz, benzyl CHH),
4.50 (1H, d, 15.0 Hz, benzyl CHH). 13C NMR (CDCl3):
168.57 (acetamido C=O), 168.05 (β-lactam C=O), 138.61,
130.44, 129.25, 128.55, 128.51, 122.55, 115.83 (aromatic),
81.61 (C-4), 70.82 (OCH2Ph), 68.13 (PhOCH2), 60.68 (C-3).
Anal. calcd. for C18H18N2O4·H2O: C 62.78, H 5.85, N 8.13;
found: C 62.25, H 5.41, N 7.92. trans-Isomer: 1H NMR
(CDCl3): 7.36–7.30 (8H, m, Ar + NH), 7.04 (1H, m, Ar),
6.92 (2H, d, Ar), 6.91 (1H, d, 7.1 Hz, NH), 6.83 (1H, br s,
NH), 5.27 (1H, d, 1.0 Hz, H-4), 4.95 (1H, dd, 1.0, 7.1 Hz,
H-3), 4.87 (1H, d, 11.8 Hz, OCHHPh), 4.70 (1H, d, 11.8 Hz,
OCHHPh), 4.67 (1H, d, 14.9 Hz, PhOCHH), 4.63 (1H, d,
14.9 Hz, PhOCHH).
azetidinone as a colourless film (3.7 mg, 15%). [α]2D0 –12.1°
(c 0.165, chloroform). MS (CI, m/z): 265 (M + 1). HR-MS-
CI calcd. for C13H16N2O4: 265.1188 (M + 1); found:
265.1185. IR (CHCl3) (cm–1): 3412, 1790, 1691. H NMR
1
(CDCl3): 7.32 (3H, m, Ar + NH), 7.03 (1H, t, Ar), 6.92 (2H,
d, Ar), 6.54 (1H, br s, NH), 5.52 (1H, ddd, 1.4, 3.9, 9.5 Hz,
H-3), 5.17 (1H, d, 3.9 Hz, H-4), 4.59 (1H, d, 15.1 Hz,
PhOCHH), 4.53 (1H, d, 15.1 Hz, PhOCHH), 3.61 (1H, dq,
7.0, 14.0, OCHH), 3.48 (1H, dq, 7.0, 14.0 Hz, OCHH), 1.17
(3H, t, 7.0 Hz, CH3). 13C NMR (CDCl3): 168.30 (acetamido
C=O). 167.24 (β-lactam C=O), 157.63, 129.80, 122,32,
114.85 (aromatic), 81.09 (C4), 67.47 (PhOCH2), 64.61
(OCH2CH3), 59.76 (C-3), 14.92 (OCH2CH3).
(ii) With isopropanol
(iv) With dimethallyl alcohol
Rhodium(II) acetate (1 mg, 0.002 mmol) was added to a
solution of the diazoketone (14.1 mg, 0.035 mmol) and 2-
propanol (0.003 mL, 2.4 mg, 0.039 mmol) in dichloro-
methane (1 mL). The red solution was stirred overnight un-
der nitrogen and then evaporated. The residue was
chromatographed using dichloromethane to elute the
thietanone and a blue film, which decolourized upon wash-
ing with water to afford a white solid. Fractional crystalliza-
tion from ethyl acetate – pentane afforded the cis-isomer as
white crystals (4.0 mg, 41%), mp 93–95°C, and the trans-
isomer (1.2 mg, 12%). cis-Isomer: [α]2D0 +29.3° (c 0.205,
chloroform. MS (CI, m/z): 279 (M + 1). HR-MS-EI calcd.
for C14H18N2O4: 278.1267 (M); found: 278.1266. IR (KBr)
A solution of the diazoketone (181 mg, 0.45 mmol) and 3-
methyl-2-butenol (0.12 mL, 102 mg, 1.2 mmol) in dichloro-
methane (34 mL) was stirred with rhodium(II) acetate
(20 mg, 0.05 mmol) and placed in a preheated oil bath at
50°C. The red solution was refluxed for 11 h and the solvent
was then removed. The residue was chromatographed, using
dichloromethane (100 mL), to isolate the thietanone, fol-
lowed by dichloromethane – ethyl acetate (1:1) to yield the
cis- and trans-disubstituted azetidinones as blue solids.
These was dissolved in dichloromethane (20 mL), and the
solutions were washed with water (20 mL), dried over mag-
nesium sulfate, and evaporated to give the crystalline cis-
disubstituted azetidinone (94 mg, 69%), mp 79–83°C, and
the trans-disubstituted azetidinone (33 mg, 24%). cis-Iso-
mer: [α]2D0 –8.6° (c 0.116, chloroform). MS (CI, m/z): 305
(M + 1). HR-MS-CI calcd. for C16H20N2O4: 305.1502 (M +
1); found: 305.1504. IR (CH2Cl2) (cm–1): 3412, 1790, 1692.
1H NMR (CDCl3): 7.32 (3H, m, Ar + NH), 7.03 (1H, t, Ar),
6.93 (2H, d, Ar), 6.49 (1H, br s, NH), 5.49 (1H, ddd, 1.2,
3.8, 9.4 Hz, H-3), 5.25 (1H, m, OCH2CH=), 5.18 (1H, d,
3.8 Hz, H-4), 4.57 (1H, d, 15.0 Hz, PhOCHH), 4.52 (1H, d,
15.0 Hz, PhOCHH), 4.06 (1H, dd, 6.9, 11.5 Hz,
OCHHCH=), 4.00 (1H, dd, 6.9, 11.5 Hz, OCHHCH=), 1.76
(3H, s, methyl), 1.64 (3H, s, methyl). 13C NMR (CDCl3):
168.31 (acetamido C=O), 167.20 (β-lactam C=O), 157.25,
129.77, 122.29, 114.91 (aromatic), 138.69 (OCH2CH=C),
119.46 (OCH2CH=C), 80.67 (C4), 67.45 (PhOCH2), 65.63
(OCH2CH=), 59.80 (C3), 25.70 (methyl), 18.03 (methyl).
trans-Isomer: MS (CI, m/z): 305 (M + 1). IR (CH2Cl2) (cm–1):
1786, 1696. 1H NMR (CDCl3): 7.32 (2H, t, Ar), 7.16 (1H, d,
7.6 Hz, NH), 7.04 (1H, t, Ar), 6.91 (2H, d, Ar), 6.54 (1H, br
s, NH), 5.34 (1H, m, OCH2CH=), 5.13 (1H, d, 1.2 Hz, H-4),
4.65 (1H, 1.2, 7.6 Hz, H-3), 4.53 (2H, s, PhOCH2), 4.18
(1H, dd, 7.3, 11.3 Hz, OCHHCH=), 4.11 (1H, dd, 7.3,
11.3 Hz, OCHHCH=), 1.76 (3H, s, methyl), 1.70 (3H, s,
methyl). 13C NMR (CDCl3): 169.01, 165.70, 157.08, 138.69,
129.74, 122.18, 114.73, 119.58, 83.94, 67.12, 65.14, 63.64,
25.71, 18.01. Anal. calcd. for C16H20N2O4: C 63.14, H 6.62,
N 9.20; found: C 63.37, H 6.68, N 8.98.
1
(cm–1): 3410, 1792, 1690. H NMR (CDCl3): 7.38 (1H, d,
9.6 Hz, NH), 7.32 (2H, m, Ar), 7.03 (1H, t, Ar), 6.93 (2H, d,
Ar), 6.60 (1H, br s, NH), 5.54 (1H, ddd, 1.4, 3.9, 9.6 Hz, H-
3), 5.27 (1H, d, 3.9 Hz, H-4), 4.60 (1H, d, 15.1 Hz,
PhOCHH), 4.54 (1H, d, 15.1 Hz, PhOCHH), 3.77 (1H, sep-
tet, 6.2 Hz, CH), 1.19 (3H, d, 6.2 Hz, methyl), 1.12 (3H, d,
6.2 Hz, methyl). 13C NMR (CDCl3): 168.22 (acetamido
C=O), 167.57 (β-lactam C=O), 154.93, 129.81, 122.29,
114.85 (aromatic), 79.76 (C4), 71.90 (isopropyl CH), 67.44
(PhOCH2), 59.89 (C-3), 22.59, 22.25 (isopropyl methyls).
1
trans-Isomer: H NMR (CDCl3) 7.32 (2H, m Ar), 7.09 (1H,
d, 7.6 Hz, NH), 7.04 (1H, t, Ar), 6.92 (2H, d, Ar), 6.33 (1H,
br s, NH), 5.22 (1H, d, 1.2 Hz, H-4), 4.54 (2H, s, PhOCH2),
4.59 (1H, dd, 1.2, 7.6 Hz, H-3), 3.87 (1H, sept, 5.6 Hz, Ip
H), 1.23 (3H, d, 5.6 Hz, Me), 1.21 (3H, d, 5.6 Hz, Me).
(iii) With benzyl alcohol
A solution of the diazoketone (19.7 mg, 0.048 mmol) and
benzyl alcohol (0.011 mL, 11.5 mg, 0.106 mmol) in di-
chloromethane (2.6 mL) was stirred briefly with rhodium
(II) acetate (3.1 mg, 14 mol%), and then immersed in a pre-
heated oil bath at 50°C. The red solution was refluxed for
28 h and evaporated to give a red residue with a fragrant
odour. The residue was chromatographed, using dichloro-
methane (20 mL) to elute the thietanone, followed by di-
chloromethane – ethyl acetate (1:1) to isolate a crystalline
cis-benzyloxyazetidinone (15.9 mg, 70%), mp 128–131°C,
and an oily trans-benzyloxyazetidinone (5 mg, 22%). cis-
Isomer: [α]2D0 +26.7° (c 0.15, chloroform). MS (CI, m/z): 327
(v) With propargyl alcohol
A solution of 6 (20.2 mg, 0.050 mmol) and propargyl al-
cohol (0.006 mL, 5.8 mg, 0.10 mmol), in dichloromethane
(2.4 mL), was stirred with rhodium(II) acetate (2 mg,
0.005 mmol) and placed in a preheated oil bath at 50°C. The
1
(M + 1). IR (CH2Cl2) (cm–1): 3414, 1792, 1692. H NMR
(CDCl3): 7.39 (1H, d, 9.6 Hz, NH), 7.32–7.26 (7H, m, Ar),
7.02 (1H, t, Ar), 6.87 (2H, d, Ar), 6.65 (1H, br s, NH), 5.51
© 2001 NRC Canada

Wolfe et al.
1267
red solution was refluxed for 15 h, and the solvent was then
evaporated. The red residue was chromatographed, using di-
chloromethane, to isolate the thietanone, followed by di-
chloromethane – ethyl acetate (1:1) to give the products as
blue solids. These were dissolved in dichloromethane (10
mL) and washed successively with water (10 mL) and satu-
rated sodium chloride (10 mL), dried over magnesium sul-
fate, and evaporated to give the cis-isomer (4.3 mg, 26%)
and the trans-isomer (2 mg, 12%). cis-Isomer: [α]2D0 –29.4°
(c 0.340, chloroform). MS (CI, m/z): 275 (M + 1). HR-MS-
CI calcd. for C14H14N2O4: 275.1032 (M + 1); found:
275.1035. IR (CHCl3) (cm–1): 3420, 3306, 2402, 1790,
(1H, d, 1.2 Hz, H-4), 4.67 (1H, dd, 1.2, 7.4 Hz, H-3), 4.53
(2H, s, PhOCH2), 4.22 (1H, ddt, 1.4, 5.4, 12.7 Hz,
OCHHCH=CH2), 4.12 (1H, ddt, 1.4, 6.1, 12.7 Hz,
OCHHCH=CH2).
(vii) With furfuryl alcohol
A solution of 6 (31 mg, 0.076 mmol) and furfuryl alcohol
(0.014 mL, 0.162 mmol) in dichloromethane (4 mL) was
heated to reflux under nitrogen and rhodium(II) acetate
(5 mg, 0.01 mmol) was added. Refluxing was continued for
14 h, and the solvent was then removed. The residue was
chromatographed on silica gel; elution with 7:3 ethyl ace-
tate:hexanes gave 12.1 mg (50%) of the cis-product. 1H
NMR (CDCl3): 7.39–7.29 (4H, m, Ph + furfuryl + NH), 7.03
(1H, t, Ph), 6.92 (2H, d, Ph), 6.34 (2H, d, 1.4 Hz, furfuryl),
6.32 (1H, br s, NH), 5.51 (1H, ddd, 1.3, 3.9, 9.6 Hz, H-3),
5.28 (1H, d, 3.9 Hz, H-4), 4.57 (1H, d, 13.2 Hz, OCHH),
4.54 (1H, d, 14.9 Hz, PhOCHH), 4.52 (1H, d, 13.2 Hz,
OCHH), 4.50 (1H, d, 14.9 Hz, PhOCHH).
1
1690. H NMR (CDCl3): 7.32 (3H, m, Ar + NH), 7.03 (1H,
t, Ar), 6.93 (2H, m, Ar), 6.79 (1H, br s, NH), 5.55 (1H, ddd,
1.4, 4.0, 9.6 Hz, H-3), 5.36 (1H, d, 4.0 Hz, H-4), 4.56 (1H,
d, 15.1 Hz, PhOCHH), 4.53 (1H, d, 15.1 Hz, PhOCHH),
4.23 (1H, dd, 2.4, 16.2 Hz, OCHH), 4.18 (1H, dd, 2.4,
16.2 Hz, OCHH), 2.50 (1H, t, 2.4 Hz, (C=C-H). 13C NMR
(CDCl3): 168.45 (acetamido C=O), 166.94 (β-lactam C=O),
157.21, 129.78, 122.34, 114.95 (aromatic), 81.02 (C-4),
78.35 (OCH2C=CH), 75.93 (OCH2C=CH), 67.44 (PhOCH2),
With hydroxyacetone (42)
1
59.96 (C-3), 56.50 (OCH2C=CH). trans-Isomer: H NMR
To bromoacetone (2.06 g, 15.1 mmol), in
dimethylformamide (80 mL), was added sodium formate
(2.11 g, 31.00 mmol). The solution was stirred for 6 h, di-
luted with ethyl acetate (100 mL), washed successively with
water (2 × 100 mL) and saturated sodium chloride
(100 mL), dried over magnesium sulfate, and evaporated at
room temperature to give the formate ester (900 mg, 59%).
(CDCl3): 7.35–7.30 (3H, m, Ar + NH), 7.05 (1H, t, Ar), 6.93
(2H, d, Ar), 6.50 (1H, br s, NH), 5.31 (1H, d, 1.1 Hz, H-4),
4.66 (1H, dd, 1.1, 7.2 Hz, H-3), 4.54 (2H, s, PhOCH2), 4.37
(1H, dd, 1.2, 2.4 Hz, OCHHC=CH), 4.36 (1H, dd, 1.2,
2.4 Hz, OCHHC=CH), 2.49 (1H, t, 2.4 Hz, OCH2C=CH).
1
IR (neat) (cm–1): 1726, 1678. H NMR (100 MHz, CDCl3):
(vi) With allyl alcohol
8.16 (1H, s, aldehyde CHO), 4.76 (2H, s, OCH2), 2.20 (3H,
s, CH3).
To 6 (14.7 mg, 0.036 mmol) and allyl alcohol (0.006 mL,
5.1 mg, 0.81 mmol), in dichloromethane (2.6 mL) was
added rhodium(II) acetate (2 mg, 0.005 mmol). The mixture
was immersed in a preheated oil bath at 50°C and refluxed
for 11 h. The solvent was then removed and the red residue
chromatographed using dichloromethane, to elute the
thietanone, followed by dichloromethane – ethyl acetate
(1:1) to give the products as blue films. These were dis-
solved in dichloromethane (10 mL) and the solutions were
washed successively with water (10 mL) and saturated so-
dium chloride (10 mL), dried over magnesium sulfate, and
evaporated to give the cis-isomer (3.6 mg, 36%) and the
trans-isomer (1.4 mg, 14%) as colourless oils. cis-Isomer:
[α]2D0 –14.3° (c 0.070, CHCl3). MS (CI, m/z): 277 (M + 1).
HR-MS-CI calcd. for C14H16N2O4: 277.1188 (M + 1);
The formate ester (900 mg, 8.82 mmol), in absolute etha-
nol (10 mL), was stirred for 72 h with p-toluenesulfonic acid
hydrate (5 mg, 0.03 mmol). The solution was evaporated at
room temperature and the residue was chromatographed, us-
ing dichloromethane–ether (3:7), to give 42 as a pale yellow
oil. MS (EI, m/z): 73 (M – 1), 74 (M). HR-MS-EI calcd. for
C3H6O2: 74.0368 (M); found: 74.0369. IR (neat) (cm–1):
1
3424, 1724. H NMR (CDCl3): 4.25 (2H, s), 3.12 (1H, br s),
2.18 (3H, s). 13C NMR (CDCl3): 206.91 (C=O), 68.67
(CH2), 25.18 (CH3).
Hydroxyacetone (6.9 mg, 0.093 mmol) was dried
azeotropically with chloroform, and added to a solution of 6
(20.5 mg, 0.051 mmol) in dichloromethane (3 mL). The so-
lution was stirred, rhodium(II) acetate (2.0 mg, 0.005 mmol)
was added, and the mixture was refluxed for 16 h with con-
tinuous monitoring by TLC. Although 22 was produced, no
β-lactam-containing product was detected. The same result
was obtained when the reaction was repeated at room tem-
perature.
1
found: 277.1189. IR (CHCl3) (cm–1): 3418, 1788, 1692. H
NMR (CDCl3): 7.37 (3H, m, Ar + NH), 7.03 (1H, m, Ar),
6.92 (2H, m, Ar), 6.55 (1H, br s, NH), 5.87 (1H, ddt, 5.6,
10.4, 17.2 Hz, =CH), 5.53 (1H, ddd, 1.4, 3.9, 9.6 Hz, H-3),
5.33 (1H, dq, 1.4, 17.2 Hz, =CHH), 5.22 (1H, dq, 1.4,
10.4 Hz, =CHH), 5.21 (1H, d, 3.9 Hz, H-4), 4.58 (1H, d,
15.1 Hz, PhOCHH), 4.53 (1H, d, 15.1 Hz, PhOCHH), 4.22
(1H, ddt, 1.4, 5.6, 12.7 Hz, OCHH), 4.13 (1H, ddt, 1.4, 5.6,
12.7 Hz, OCHH). 13C NMR (CDCl3): 168.90 (acetamido
C=O), 168.40 (β-lactam C=O), 157.25, 129.87, 122.33,
115.00 (aromatic), 133.19 (OCH2CH=CH2), 118.28
(OCH2CH=CH2), 81.01 (C-4), 70.06 (OCH2CH=CH2),
67.46 (PhOCH2), 59.88 (C-3). trans-Isomer: 1H NMR
(CDCl3): 7.33 (2H, t, Ar), 7.12 (1H, d, 7.0 Hz, NH), 7.04
(1H, t, Ar), 6.91 (2H, d, Ar), 6.47 (1H, br s, NH), 5.93 (1H,
m, OCH2CH=CH), 5.33 (1H, dq, 1.4, 3.0, 16.7 Hz,
CH=CHH), 5.25 (1H, dq, 1.4, 2.6, 10.4 Hz, CH=CHH), 5.16
With ethyl γ-hydroxyacetoacetate (43)
Sodium formate (2.82 g, 41.5 mmol) was added to a solu-
tion of ethyl γ-bromoacetoacetate (4) (4.33 g, 20.7 mmol) in
dimethylformamide (80 mL). The solution was stirred rap-
idly for 2 h and then diluted with ethyl acetate (200 mL),
washed successively with water (2 × 200 mL), and saturated
sodium chloride (200 mL), dried over magnesium sulfate,
and evaporated to afford the formate ester as a bright yellow
1
oil (2.83 g, 78%). H NMR (100 MHz, CDCl3): 8.16 (1H, s,
aldehyde CHO), 4.91 (2H, s, OCH2CO), 4.26 (2H, q, 7.1 Hz,
© 2001 NRC Canada

1268
Can. J. Chem. Vol. 79, 2001
ester CH2), 3.53 (2H, s, COCH2CO), 1.30 (3H, t, 7.1 Hz, es-
ter CH3). This oil was dissolved in absolute ethanol (100
mL) and stirred for 20 h with p-toluenesulfonic acid hydrate
(232.3 mg, 1.2 mmol). The solvent was evaporated and the
residue, in ethyl acetate (50 mL), was washed successively
with water (50 mL) and saturated sodium chloride (50 mL),
dried over magnesium sulfate, and evaporated. Purification
of the product by column chromatography using ethyl ace-
tate – hexanes (3:7) gave 43 as a yellow oil (1.14 g, 48%).
MS (CI, m/z): 147 (M + 1). IR (neat) (cm–1): 3472, 1732,
With benzyl 4-hydroxyprop-2-ynoate (45)
A solution of 3,4-dihydro-2H-pyran (28.0 mL, 25.82 g,
0.307 mol) in dichloromethane (100 mL) was cautiously
added, at 0°C, to a solution of propargyl alcohol (16.5 mL,
15.90 g, 0.283 mol) and p-toluenesulfonic acid hydrate
(159 mg, 0.089 mmol) in dichloromethane (80 mL). The so-
lution was stirred for 2 h at 25° and then washed succes-
sively with water (100 mL), saturated sodium bicarbonate
(100 mL), and saturated sodium chloride (100 mL), dried
over magnesium sulfate, and evaporated. Purification by vac-
uum distillation afforded tetrahydro-2-(2-propynyloxy)pyran
as a colourless oil (32.9 g, 83%), bp 63–65°C/9 torr (1 torr =
133.322 Pa). MS (CI, m/z): 141 (M + 1). IR (cm–1): 3293,
1
1626. H NMR (CDCl3): 4.38 (2H, d, 5.0 Hz, HOCH2CO),
4.20 (2H, q, 7.2 Hz, ester CH2), 3.49 (2H, s, COCH2CO),
3.01 (1H, br. t, 5.0 Hz, HOCH2), 1.28 (3H, t, 7.2 Hz, ester
CH3). 13C NMR (CDCl3): 202.29 (hydroxyacetyl C=O),
166.33 (acetate C=O), 68.49 (HOCH2COCH2), 61.74
(CO2CH2CH3), 45.38 (HOCH2COCH2CO2CH2CH3), 13.98
(CH2CO2CH2CH3). Anal. calcd. for C6H10O4: C 49.31, H
6.90; found: C 49.21, H 6.81.
To a solution of 6 (18.4 mg, 0.045 mmol), in dichloro-
methane (4.0 mL), were added ethyl γ-hydroxyacetoacetate
(14.5 mg, 0.099 mmol) (dried azeotropically with chloro-
form (3×)), and rhodium(II) acetate (3 mg, 0.007 mmol).
The solution was refluxed for 7 h and then evaporated. The
residue was subjected to chromatography using a dichloro-
methane – ethyl acetate gradient to yield 22 and a white
solid identical to the product from trapping with ethanol.
1
2118. H NMR (CDCl3): 4.80 (1H, t, 3.3 Hz, OCHO), 4.27
(1H, dd, 2.4, 15.7 Hz, OCHHC=CH), 4.21 (1H, d, 2.4,
15.7 Hz, OCHHC=CH), 3.82 (1H, m, CH2HHCHO), 3.49
(1H, m, CH2CHHOCHO), 2.40 (1H, t, 2.4 Hz, C=C-H),
1.84–1.72 (6H, m, OCH2CH2CH2CH2CH). 13C NMR
(CDCl3): 96.85 (OCHO), 79.81 (OCH2C=CH), 73.90
(OCH2C=CH), 61.97 (OCH2CH2CH2CH2CH), 53.97
(OCH2C=CH), 30.22 (OCH2CH2CH2CH2CH), 25.35
(OCH2CH2CH2CH2CH), 19.00 (OCH2CH2CH2CH2CH).
A solution of the tetrahydropyranyl ether (2.06 g,
14.73 mmol) in tetrahydrofuran (15 mL), was treated, at
−78°C, with a 2.5 M solution of n-butyllithium in hexane
(5.9 mL, 0.94 g, 14.75 mmol). The resulting yellow solution
was stirred for 1.5 h at –78°, and benzyl chloroformate
(2.0 mL, 2.39 g, 14.01 mmol), in a solution of tetrahydro-
furan (2.0 mL) and hexamethylphosphoramide (3.5 mL),
was then added dropwise. The reaction mixture was warmed
to –65° for 2 h and then to room temperature during 7.0 h,
cooled to 0°, and treated with water (30 mL). The mixture
was diluted with ether (60 mL) and the organic phase was
separated and washed successively with water (60 mL) and
saturated sodium chloride (60 mL), dried over magnesium
sulfate, and evaporated. Purification by column chromatog-
raphy using ethyl acetate – hexanes (1:9) afforded the
With ethyl γ-hydroxy-α-diazoacetoacetate (44)
To ethyl γ-hydroxyacetoacetate (0.59 g, 4.04 mmol), in
acetonitrile (10 mL), was added p-carboxybenzenesulfonyl
azide (1.04 g, 4.57 mmol) followed, during 10 min at 0°C,
by triethylamine (1.7 mL, 1.2 g, 2.20 mmol). The pale yel-
low solution was stirred at 0° for an additional 15 min and
DBU (0.6 mL, 0.61 g, 4.01 mmol) was added to precipitate a
yellow solid. After an additional 3 h of stirring at 0°, the
mixture was filtered and the filtrate was evaporated. The res-
idue was dissolved in ethyl acetate (50 mL) and the solution
was washed successively with water (2 × 50 mL), saturated
sodium bicarbonate (50 mL) and saturated sodium chloride
(50 mL), dried over magnesium sulfate, and evaporated to
give a red oil (309 mg). Purification by column chromatog-
raphy, using ethyl acetate – hexanes (2:3), gave 44 as a yel-
low oil (178.5 mg, 26%). MS (CI, m/z): 173 (M + 1). IR
(neat) (cm–1): 3488, 2986–2911, 2145, 1721, 1659. 1H NMR
(CDCl3): 4.61 (2H, d, 5.1 Hz, HOCH2), 4.28 (2H, q, 7.1 Hz,
ester CH2), 3.40 (1H, 5.1 Hz, OH), 1.33 (3H, t, 7.1 Hz, ester
CH3). 13C NMR (CDCl3): 191.79 (hydroxyacetyl C=O),
160.82 (acetate C=O), 66.97 (HOCH2CO), 61.97
(CO2CH2CH3), 14.31 (CO2CH2CH3). Anal. calcd. for
C6H8N2O4: C 41.87, H 4.68, N 16.27; found: C 42.51, H
4.88, N 15.83.
1
tetrahydropyranyl ether of 45 as a colourless oil. H NMR
(100 MHz, CDCl3): 7.39 (5H, s, Ar), 5.32 (1H, s, OCHO),
5.17 (2H, s, benzyl CH2), 4.82 (2H, s, OCH2C=CH), 3.93–
3.47 (2H, m, OCHOCH2CH2), 1.73 (6H, m,
OCH2CH2CH2CH2). A portion of this oil (50 mg, 0.18 mmol),
in dry methanol (3.8 mL), was treated with trifluoroacetic
acid (0.07 mL, 104 mg, 0.91 mmol). The solvent was evapo-
rated after 30 min, and the product was purified by column
chromatography using ethyl acetate – hexanes (1:4) to yield
45 as white crystals (12 mg, 35%), mp 102–104°C. MS (CI,
m/z): 191 (M + 1). IR (KBr) (cm–1): 3468, 1742. H NMR
1
(100 MHz, CDCl3): 7.41 (5H, s, Ar), 5.21 (1H, br s, OH),
5.09 (2H, s, benzyl CH2), 4.70 (2H, s, HOCH2). 13C NMR
(CDCl3): 178.86 (ester C=O), 173.15 (HOCH2C=CCO2CH2Ph),
133.83, 129.19, 128.93, 128.01 (aromatic), 89.87 (HOCH2C=C),
74.57 (HOCH2C=C), 67.88 (CO2CH2Ph). Anal. calcd. for
C11H10O3·0.25H2O: C 67.86, H 5.44; found: C 67.83, H
5.28.
Rhodium(II) acetate (1 mg, 0.002 mmol) was added to a
solution of 6 (12.0 mg, 0.030 mmol) and 45 (8.5 mg,
0.045 mmol) (dried azeotropically with chloroform (3×)), in
dichloromethane (2.5 mL). The red solution was refluxed for
10 h while being monitored by TLC. Purification by column
chromatography, using a dichloromethane – ethyl acetate
To a solution of 6 (17.8 mg, 0.044 mmol) in dichloro-
methane (2.8 mL), was added ethyl γ-hydroxy-α-
diazoacetoacetate (14.8 mg, 0.086 mmol) (dried
azeotropically with chloroform (3×)). The solution was
stirred, rhodium(II) acetate (3 mg, 0.007 mmol) was added,
and the mixture was refluxed for 10 h. Although the
thietanone 22 was detected, no β-lactam-containing product
was found. The same result was obtained when the reaction
was repeated at room temperature.
© 2001 NRC Canada

Wolfe et al.
1269
elution gradient, afforded 22 and unreacted 45. The same re-
sult was obtained when the reaction was repeated at room
temperature.
5 min period. Additional dimethylformamide (5.0 mL) was
added after 3 h, and the solution was stirred for 18 h, diluted
with ethyl acetate (20 mL), and washed successively with
water (4 × 20 mL) and saturated sodium chloride (20 mL),
dried over magnesium sulfate, and evaporated to give a yel-
low oil (30.5 mg). Purification by column chromatography
using ethyl acetate – hexanes (1:7) gave 47 as a colourless
oil (13.8 mg, 18%). MS (CI, m/z): 189 (M + 1). HR-MS-CI
calcd. for C5H6O2: 189.0915 (M + 1); found: 189.0921. IR
With 6-hydroxymethyl-2,2-dimethyl-4H-1,3-dioxin-4-one
(46)
To 2,2,6-trimethyl-4H-1,3-dioxin-4-one (0.93 mL, 1.01 g,
7.12 mmol) in carbon tetrachloride (25 mL), were added N-
bromosuccinimide (1.26 g, 7.08 mmol) and benzoyl perox-
ide (3 mg, 0.012 mmol). The mixture was heated to reflux
with a heat gun and irradiated for 60 min with a 500 W
Photoflood No. 2 bulb mounted beside the flask. The mix-
ture was then cooled to 0°, filtered, and the filtrate was evap-
orated. The residue, in hexanes (20 mL), was washed
successively with water (20 mL), saturated sodium bicarbon-
ate (20 mL), water (20 mL), and saturated sodium chloride
(20 mL), dried over magnesium sulfate, and evaporated to
1
(neat) (cm–1): 1716, 1642, 1600. H NMR (CDCl3): 7.40–
7.26 (6H, m, Ar + H-3), 6.46 (1H, ddt, 0.6, 7.0, 10.0 Hz, H-
4), 5.96 (1H, dd, 0.6, 15.4 Hz, H-2), 5.62 (1H, dt, 0.6,
17.0 Hz, =CHH), 5.50 (1H, dt, 0.6, 10.0 Hz, =CHH), 5.20
(2H, s, benzyl CH2). 13C NMR (CDCl3): 166.57 (ester
C=O), 145.10 (CH2=CH-CH), 136.18, 128.56, 128.40),
125.57 (CH2=CH-CH), 121.97 (CH2=CH-CH-CH), 66.23
(CH-CH-CO2CH2Ph).
The ester (11.1 mg, 0.059 mmol) was dried azeotropically
with chloroform and added to a solution of 6 (17.2 mg,
0.042 mmol) in dichloromethane (5.0 mL). The solution was
stirred, rhodium(II) acetate (3 mg, 0.007 mmol) was added,
and the mixture was refluxed for 4.5 h. Other than the
thietanone 22 and unreacted 47, isolated after chromatogra-
phy using dichloromethane followed by dichloromethane –
ethyl acetate (1:1), no β-lactam-containing product was de-
tected. The same result was obtained when the reaction was
repeated at room temperature.
give
6-bromomethyl-2,2-dimethyl-4H-1,3-dioxin-4-one
1
(300 mg, 19%) as a pale yellow oil. H NMR (100 MHz,
CDCl3): 5.55 (1H, s, =CH), 3.90 (2H, s, BrCH2), 1.74 (6H,
s, CH3).
A
solution of this bromide in dimethylformamide
(3.5 mL) was treated with sodium formate (206.5 mg,
3.04 mmol). The solution was stirred for 5 h and was then
diluted with ether (25 mL), washed successively with water
(25 mL) and saturated sodium chloride (25 mL), dried over
magnesium sulfate, and evaporated to give the formate ester
as a yellow oil. A solution of this compound in dry methanol
(9.0 mL) was cooled to 0°, and a solution of anhydrous po-
tassium carbonate (198.5 mg, 1.44 mmol) in water (2.3 mL)
was added during 10 min. The solvent was evaporated after
an additional 30 min of stirring. The residue, in dichloro-
methane (20 mL), was washed successively with 0.2 M hy-
drochloric acid (20 mL), water (20 mL), and saturated
sodium chloride (20 mL), dried over magnesium sulfate, and
evaporated. The product was purified by column chromatog-
raphy using ethyl acetate – hexanes (3:7) to yield 46 as a
yellow oil (37.9 mg). MS (CI, m/z): 159 (M + 1). IR (neat)
With benzyl mercaptan
To a solution of 6 (48.9 mg, 0.12 mmol) and benzyl
mercaptan (0.025 mL, 26.5 mg, 0.213 mmol), in dichloro-
methane (3 mL), was added rhodium acetate (6.3 mg,
0.014 mmol). The mixture was heated to reflux for 9 h,
cooled to room temperature, diluted with dichloromethane
(10 mL), and washed with water (2 × 13 mL). The dichloro-
methane layer was dried over sodium sulfate, evaporated,
and purified by column chromatography using ethyl acetate –
hexanes (2:1) to give the cis-benzyl sulfide (5.0 mg, 12%)
1
and the trans-benzyl sulfide (1.5 mg, 4%). cis-Isomer: H
(cm–1): 3418, 1713. H NMR (CDCl3): 5.56 (1H, t, 1.2 Hz,
1
NMR (CDCl3): 7.41–7.27 (8H, m, Ar + NH), 7.03 (1H, t,
Ar), 6.94 (2H, d, Ar), 6.60 (1H, br s, NH), 5.58 (1H, dd, 4.6,
9.1 Hz, H-3), 4.91 (1H, d, 4.6 Hz, H-4), 4.55 (1H, d,
15.0 Hz, PhOCHH), 4.51 (1H, d, 15.0, PhOCHH), 3.72 (1H,
d, 13.7 Hz, SCHHPh), 3.69 (1H, d, 13.7 Hz, SCHHPh).
trans-Isomer: 1H NMR (CDCl3): 7.35–7.27 (7H, m, Ar),
7.03 (1H, t, Ar), 7.01 (1H, d, 7.7 Hz, NH), 6.90 (2H, d, Ar),
5.59 (1H, br s, NH), 4.82 (1H, d, 2.3 Hz, H-4), 4.60 (1H, dd,
2.3, 7.7 Hz, H-3), 4.50 (2H, s, PhOCH2), 3.90 (1H, d,
13.8 Hz, SCHHPh), 3.89 (1H, d, 13.8 Hz, SCHHPh).
=CH), 4.19 (2H, d, 1.2 Hz, HOCH2), 2.35 (1H, br s, OH),
1.70 (6H, s, CH3). 13C NMR (CDCl3): 169.85 (C=O), 161.02
(COCH=C), 107.06 (H3CCCH3), 92.37 (HOCH2CCH),
60.99 (HOCH2C), 25.01 (CH3). Anal. calcd. for
C7H10O4·0.5H2O: C 50.30, H 6.63; found: C 50.71, H 6.49.
To a solution of 6 (10.1 mg, 0.025 mmol) in dichloro-
methane (2.3 mL) was added 46 (11.1 mg, 0.059 mmol),
which had been dried azeotropically with chloroform (3×).
The resulting solution was stirred, rhodium(II) acetate
(2 mg, 0.005 mmol) was added, and the mixture was
refluxed for 9 h while being monitored by TLC. Although
the thietanone 22 was formed, no β-lactam-containing prod-
uct was isolated after evaporation of the solvent and chroma-
tography of the residue. The same result was obtained when
the reaction was repeated at room temperature.
Theoretical
Calculations were performed using Gaussian 98 (42). Sta-
tionary points were optimized fully at the level indicated,
and characterized by frequency analysis. For the calculations
of C=O stretching frequencies of azetinones, calculated fre-
quencies were scaled by 0.89 (43).
With benzyl trans-2,4-pentadienoate (47)
To finely ground trans-2,4-pentadienoic acid (39.8 mg,
0.41 mmol), in dry dimethylformamide (6.0 mL), was added
anhydrous potassium carbonate (56.3 mg, 0.41 mmol). The
mixture was stirred for 10 min, and benzyl bromide (0.05 mL,
71.9 g, 0.42 mmol) was then added, with stirring, over a
Acknowledgements
This research was supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC). The au-
© 2001 NRC Canada

1270
Can. J. Chem. Vol. 79, 2001
Davies and L.V.T. Crisco. Tetrahedron Lett. 28, 371 (1987);
C.J. Moody and R.J. Taylor. Tetrahedron Lett. 29, 6005
(1988); A. Padwa and M.D. Weingarten. Chem. Rev. 96, 223
(1996); S. Sengupta and S. Mondal. Tetrahedron Lett. 41,
2965 (2000).
thors thank Marie-Claire Wilson for valuable experimental
assistance.
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