Vinyl-β-lactams as efficient synthons. Eco-friendly approaches via microwave assisted reactions

Article abstract of DOI:10.1016/S0040-4020(00)00409-9

Vinyl-β-lactams are efficient synthons for a variety of compounds of biomedical interest - such as isocephalosporins, carbapenem and thienamycin intermediates, and pyrrolidine alkaloids. Convenient methods are described for obtaining both enantiomers of some of these synthons. Microwave-induced Organic Reaction Enhancement (MORE) chemistry techniques allow highly accelerated synthesis of variously substituted vinyl-β-lactams using limited amounts of solvents and with efficient stereocontrol - thus achieving high 'atom economy'. The effect (if any) of microwaves on bond angles and bond lengths and the geometry of transition states are not well understood yet. Nonetheless, reactions under microwave irradiation in open systems are rapid, safe, and cost-effective for synthetic approaches that are much more friendly to the environment than conventional processes. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00409-9

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5587±5601
Vinyl-b-lactams as Ef®cient Synthons. Eco-friendly Approaches
via Microwave Assisted Reactions1
²
Maghar S. Manhas, Bimal K. Banik, Arvind Mathur, John E. Vincent and Ajay K. Bose
³
*
George Barasch Bioorganic Research Laboratory, Department of Chemistry and Chemical Biology, Stevens Institute of Technology,
Hoboken, NJ 07030, USA
Received 11 October 1999; accepted 10 January 2000
AbstractÐVinyl-b-lactams are ef®cient synthons for a variety of compounds of biomedical interestÐsuch as isocephalosporins, carba-
penem and thienamycin intermediates, and pyrrolidine alkaloids. Convenient methods are described for obtaining both enantiomers of some
of these synthons. Microwave-induced Organic Reaction Enhancement (MORE) chemistry techniques allow highly accelerated synthesis of
variously substituted vinyl-b-lactams using limited amounts of solvents and with ef®cient stereocontrolÐthus achieving high `atom
economy'. The effect (if any) of microwaves on bond angles and bond lengths and the geometry of transition states are not well understood
yet. Nonetheless, reactions under microwave irradiation in open systems are rapid, safe, and cost-effective for synthetic approaches that are
much more friendly to the environment than conventional processes. q 2000 Elsevier Science Ltd. All rights reserved.
Synthetic chemists and medicinal chemists have been inter-
ested in b-lactams for more than half a century.2 The agility
with which these four-membered heterocycles can undergo
ring scission and rearrangements has provided easy access
to many other heterocycles and acyclic compounds. In the
course of our ongoing studies on b-lactam synthons or
natural products, various preparative methods for diversely
substituted 2-azetidinones have been developed.
chemistry techniques3 have been employed to reduce pollu-
tion at the source and to increase atom economy.4
3-Vinyl-2-azetidinones
Synthesis of a-vinyl-b-lactams (A)
In 1971, we5 devised a direct synthesis of a-vinyl-b-lactams
(A) by the reaction of an a,b-unsaturated acid chloride (for
example, crotonyl chloride 1) with Schiff bases 2 in the
presence of triethylamine in re¯uxing dichloromethane or
benzene. Exclusive formation of trans-b-lactams 3 in low
yield was observed from trans crotonyl chloride (1) and the
diaryl Schiff bases 2 (entry a, b, f, and g; Scheme 1).
Recently, increasing attention has been paid in our labora-
tory to synthetic approaches that are more environmentally
benign than conventional organic reactions. We wish to
report here on some of our work directed to the preparation
of b-lactams (A, B, C) with a vinyl substituent at various
positions on the ring. The transformation of these hetero-
cycles to compounds of interest via the manipulation of the
vinyl group is also described. In several instances Micro-
wave-induced Organic Reaction Enhancement (MORE)
Zamboni and Just6 used this reaction in 1979, for preparing
a number of trans a-vinyl-b-lactams as potential synthons
for b-lactam antibiotics (Scheme 2). Thus, the reaction of
b,b-dimethylacryloyl chloride 4 and the Schiff base 2 to
give the trans b-lactam 5 (Scheme 2) was reported.
In 1991, Georg et al.7 used crotonic acid and Mukaiyama's
reagent8 (Scheme 3) in place of crotonyl chloride for the
synthesis of trans 3g (R1ˆPh, R2ˆPMP). In a more recent
report, Torii et al.9 have described a novel method for the
synthesis of a-vinyl-b-lactams 3 which involves palladium
catalyzed carbonylation of allyl diethylphosphate 7 in the
presence of imines in an atmosphere of carbon monoxide
under pressure. The stereochemistry of the product depends
on the nature of the substituents R1 and R2 (Scheme 4).
Keywords: annulation; azetidinones; microwave irradiation; nitrogen
heterocycles; stereocontrol; sulfur heterocycles.
* Corresponding author. Fax: 1201-216-8240;
e-mail: mmanhas@stevens-tech.edu
²
Present address: University of Texas, M.D. Anderson Cancer Center,
Houston, TX 77030.
Present address: Pharmaceutical Research Institute, Princeton, NJ 08543.
³
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00409-9

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M. S. Manhas et al. / Tetrahedron 56 (2000) 5587±5601
Scheme 1.
Microwave Assisted Synthesis
In the course of developing MORE10 chemistry techniques,
we11 discovered that a-vinyl-b-lactams could be prepared in
high yield in a few minutes instead of a few hours by
subjecting the reaction mixture to microwave irradiation.
Scheme 2.
Key aspects of MORE chemistry are:
Steric course of cyclization
(a) the use of open systems (thus no danger of explosions
Zamboni and Just6 showed that crotonyl chloride (1) and
dimethylacryloyl chloride (4) behave in the same way
during the formation of a-vinyl-b-lactams 3 and 5, respec-
tively. The Schiff bases 2 (R1ˆPh or furfuryl or styryl)
derived from aniline or p-anisidine lead only to trans
b-lactams. But, the Schiff base from cinnamaldehyde and
aniline gives a mixture of cis and trans b-lactams. At room
temperature the cis isomer predominates but higher
temperature favors the trans product.6 Schiff bases 8
prepared from aliphatic amines give mostly the cis
a-vinyl-b-lactam 9 (Scheme 5).6
Scheme 5.
Scheme 3.
Scheme 4.

M. S. Manhas et al. / Tetrahedron 56 (2000) 5587±5601
5589
Scheme 6.
Table 1.
Lengtha of
irradiation
Procedureb
trans:cis
(12:11)c
Temp.d of reaction
mixtures (8C)
Amount of water as
heat sinke (mL)
1 min
2 min
3 min
4 min
5 min
10 min
30 s
1 min
10 min
30 min
6 h
M
M
M
M
M
M
M
M
C
40:60
60:40
70:30
70:30
80:20
80:20
25:75
30:70
80:20
65:35
40:60
78
92
95
105
108
118
55
200
200
200
200
200
200
800
800
±
62
115f
RT-115g
40h
C
C
±
±
a Reaction was complete after 5 min of irradiation.
b M and C indicate microwave and conventional methods, respectively.
c Ratio of trans to cis was based on NMR studies.
d The approximate temperature of the reaction mixture was determined by using a thermometer immediately after the microwave irradiation was stopped.
e A beaker of water was used as a heat sink to control the amount of energy entering the reaction mixture in the microwave oven.
f A preheated oil bath was used.
g The reactants were mixed at room temperature and the temperature was raised.
h Re¯uxing dichloromethane was used as the solvent.
due to rapid rise of pressure as in some sealed system
reactions);
in place of benzene. Improved yields (70±75%) were
obtained at elevated temperatures.
(b) careful control of the microwaves energy input into
the reaction mixture such that the temperature is well
below the boiling point of the mixtureÐtherefore, no
re¯ux condenser is needed;
(c) no solvents needed if one of the reactants is a polar
liquid-molecules with dipole absorb microwave energy
directly while the glass reaction vessel is nearly trans-
parent to microwaves;
Schiff bases from aromatic aldehydes and substituted
anilines gave only trans a-vinyl-b-lactams 3 (Scheme
1).11 But, the Schiff base 10 from benzaldehyde and methyl-
amine produced a mixture of cis and trans b-lactams 11 and
12 in a ratio depending on the temperature of the reaction
mixture (Scheme 6).11
(d) minimal amounts of polar solvents used since it has
been found that a slurry at room temperature is generally
adequate for effective reaction at higher temperatures
under microwave irradiation-less solvent means higher
atom economy;
Higher temperature favored the formation of the trans
b-lactam, which is thermodynamically more stable (Table
1). However, this was not a simple base-catalyzed isomeri-
zation; unchanged cis b-lactam 11 was recovered after
irradiation in the presence of N-methylmorpholine.
(e) simple beakers, conical ¯asks or glass trays are used
as reaction vessels; since the reactants are energized
directly, no stirrers are needed in most cases;
(f) most organic reactions on a molar scale require only a
few minutes of irradiation instead of hours of reaction
time as in conventional set ups;
Interestingly, cis b-lactams 16 and 17 were obtained exclu-
sively from acid chlorides 1 or 4 and Schiff bases 15
(derived from glyoxalic esters 13 or phenyl glyoxal 14)-
irrespective of the temperature of the reaction (Scheme 7).12
(g) very rapid rise of temperature favors some reaction
pathways over others and thus leads to selectivity and
hence cleaner products.
The problem of cis/trans isomerism disappears when an
imine 19 derived from a ketomalonate 18 is used for the
preparation of the vinyl-b-lactam 20.13,14 However, an
isomer 21 is also produced in which the double bond in
the side chain is conjugated with the b-lactam carbonyl
group (Scheme 8).
Further details about MORE chemistry techniques are
provided in later sections.
For microwave assisted synthesis of a-vinyl-b-lactams, a
large beaker with a loose cover was used as the reaction
vessel. Triethylamine as a tertiary base was replaced with
the higher boiling N-methylmorpholine (bp 1168C). Since
benzene absorbs microwave energy very poorly, chloro-
benzene, which has a substantial dipole and a reasonably
high boiling point (1338C), was used as the reaction medium
a-Vinyl-b-lactams as synthons
Synthesis of a-alkyl b-lactams became of interest after the
discovery of PS-5 (28), PS-6 (29), thienamycin, and
asparenomycin. a-Vinyl b-lactams were employed14 in
our laboratory for the synthesis of carbapenem antibiotics

5590
M. S. Manhas et al. / Tetrahedron 56 (2000) 5587±5601
Scheme 7.
Scheme 8.
intermediates; the key steps were a combination of
dealkoxycarbonylation±hydrogenation experiments under
microwave irradiation. First, dealkoxycarbonylation15 of
b-lactams 20a and 21a was conducted under the in¯uence
of lithium chloride in DMF. The products were found to be a
mixture of E and Z isomers 22a and 22b (1:1 ratio). Similar
reactions of the mixtures of 20b and 21b afforded a single
product 23 in good yield (Scheme 9).
Scheme 9.
Scheme 10.

M. S. Manhas et al. / Tetrahedron 56 (2000) 5587±5601
5591
Scheme 11.
Scheme 12.
The mixture of unsaturated compounds 22 and 23 was then
reduced to the saturated compounds 24 and 25, respectively,
by microwave assisted catalytic transfer hydrogenation
method16 (see below for details) developed in our labora-
tory.17,18 Ethylene glycol was used as the solvent, ammo-
nium formate as the hydrogen donor and 10% Pd/C as the
catalyst. The stereochemistry of the products 24 and 25 from
this study was found to be exclusively cis (Scheme 10).
Therefore plans were made to transform the a-vinyl group
of b-lactam 3 to an acetyl group (for example, 32) through
palladium-catalyzed oxidation. However, a b-lactam 33
with an aldehyde-containing side chain was the major
product.21 The yield of the expected a-acetyl-b-lactam 32
was very low. This unusual regioselectivity (anti-Markov-
nikov rule) of the product 33 could be explained by
assuming coordination of palladium with the b-lactam
carbonyl group as well as the double bond of the vinyl
group (Scheme 13).
In previous publications,12 the conversion of 24 and 25 to 26
and 27, respectively, have been described. Kametani et al.19
had prepared the same stereoisomeric mixtures by a
different route and converted them to PS-5 (28) and PS-6
(29). The synthesis of 26 and 27 from 20a and 20b, respec-
tively, can be considered therefore, as a formal synthesis of
these antibiotics (Scheme 11).
A more ef®cient route to the a-hydroxyethyl-b-lactam 35
was developed via the mixture of epoxides 34 obtained on
m-chloroperbenzoic acid oxidation of 3g. The epoxide rings
were opened by reaction with potassium bromide and acetic
acid and the resulting mixture of 2-bromohydrins was
debrominated with tributyltin hydride. The products were
two stereoisomeres of 35, which could be separated by
chromatography (Scheme 14).22
Ozonolysis of 16 produced a cis b-lactam 30 with an
a-acetyl side chain, which could be reduced to a
thienamycin type compound. Epimerization of the C-3
center of 30 was achieved upon treatment with DBN
(1,5-diazabicyclo[4.3.0]non-5-ene); the trans b-lactam 31
was the major product (Scheme 12). Conversion of a
terminal double bond to an acetyl group by palladium cata-
lyzed oxidation in the presence of cuprous chloride and
oxygen is a well-established synthetic methodology.20
The aldehyde 33 of trans stereochemistry was used via its
reduction product 36 for the synthesis of pyrrolidine
derivatives.21 The chloride 37, prepared from the alcohol
36, was heated with sodium cyanide and methanol to induce
a stereospeci®c rearrangement.23 The product obtained in
good yield was the pyrrolidine 38 with the predictable cis
Scheme 13.
Scheme 14.

5592
M. S. Manhas et al. / Tetrahedron 56 (2000) 5587±5601
Deprotection of the amino group, acylation of the amine to
42 followed by oxidative removal of the dimethoxybenzyl
group provided the a-amido-b-vinyl-b-lactam 43. Perman-
ganate oxidation converted the b-vinyl group to a carboxy
group and led to 44 which is a known intermediate for
various bicyclic b-lactams (Scheme 17).24
Optically active a-amido-b-vinyl-b-lactams of the type 43
were prepared by cycloaddition involving Schiff bases 46
(derived from cinnamaldehyde and d-threonine esters 45)
and azidoacetyl chloride or 39 followed by standard
chemical steps (Scheme 18).25
Scheme 15.
The two cis a-amido-b-lactams 47a and 47b that were
obtained as a mixture could be easily separated by column
chromatography. They are formed in nearly equimolar
quantities. However, when the triphenylsilyl ether of 45
was the starting material instead of 45, the silyl ethers of
47a and 47b were in the proportion of 95:5.26
Scheme 16.
Careful oxidation of 47a with a limited amount of Jones
reagent produced optically active 48 with an enolic side
chain on the b-lactam nitrogen. If an excess of Jones reagent
was used for the oxidation, the product was the N-unsub-
stituted b-lactam 49a in the optically pure form.25 The
absolute con®guration of 49 was determined by X-ray
crystallography and chemical correlation.26 In the same
manner, 47b could be converted to 49b, the mirror image
of 49a. Thus, access to both antipodes of 49, or just 49a
became available depending on whether the starting
material was 45 or its triphenylsilyl ether. Oxidation of
the styryl group in 49a or 49b led to optically pure forms
44 or its antipode.26
relationship between the carboxy group and R1 (Scheme
15).
4-Vinyl-2-azetidinones
Synthesis of b-vinyl-b-lactams (B)
In the course of studies with b-lactam antibiotics a variety
of racemic or homochiral b-vinyl-b-lactams have been
prepared in our laboratory by alternative methods. Selected
examples of members of this family are provided here along
with some experimental data not published before.
Recently, some of the conventional methods have been
redesigned by employing MORE chemistry techniques.
An alternative approach to optically active b-lactams was
also developed in our laboratory. The key reaction was the
annulation of the Schiff base (50) from d-glyceraldehyde
acetonide (or related carbohydrate derivatives) and an aryl-
amine such as p-anisidine. Access was thus obtained to
optically pure cis a-hydroxy or a-amino b-lactams of
predictable absolute con®guration (Scheme 19).27,28 It was
shown that the oxygen bearing chiral center adjacent to the
imino group in the Schiff base was the deciding factor for
the induction of optical activity.
An easy access to b-vinyl-b-lactams is provided by
cycloaddition involving Schiff bases derived from
a,b-unsaturated aldehydes (such as cinnamaldehyde). Low
temperature reactions with various acid chlorides and
triethylamine convert such imino compounds to cis
b-lactams in most cases (Scheme 16).
Thus, the Dane salt 39 from glycine and methyl acetoacetate
was allowed to react with the Schiff base 40 (from cinna-
maldehyde and 3,4-dimethoxybenzylamine) in the presence
of a chloroformate ester and triethylamine at low tempera-
ture when the cis b-lactam 41 was obtained in good yield.24
When the optically pure a-mesyloxy-b-lactam 54 (obtained
by the mesylation of 53) was treated with lithium iodide, a
mixture of 3a- and 3b-iodo-b-lactams 55 was obtained.
Obviously, 3-iodo-2-azetidinones also underwent SN2 type
Scheme 17.

M. S. Manhas et al. / Tetrahedron 56 (2000) 5587±5601
5593
Scheme 18.
reactions with iodide ions. This mixture was dehalogenated
with tributyltin hydride to give a single productÐthe 3-
unsubstituted-2-azetidinone 56 in high yield.
react with lithium iodide and zinc in DMF at 808C for
several hours. The probable diiodo intermediate thus formed
was converted to the b-vinyl-b-lactam 59. Removal of the
p-anisyl group by oxidation with cerium(IV) ammonium
nitrate29 in acetonitrile led to the desired 4-vinyl-2-azetidi-
none 60 (Scheme 20). The optical purity of this compound
The next step involved the cleavage of the isopropylidine
group under mild acid treatment. The diol 57 so obtained
was converted to the dimesylate 58 which was allowed to
1
was established by H NMR studies using a chiral shift
Scheme 19.
Scheme 20.

5594
M. S. Manhas et al. / Tetrahedron 56 (2000) 5587±5601
Scheme 21.
reagent. The b-lactam 60 showed the same properties as
those reported in the literature30 for the corresponding
racemic compound.
The N-vinyl groups could be removed easily by ozonation
followed by mild base treatment. The optically active,
N-unsubstituted b-lactam 66 prepared by this method was
identical with a b-lactam prepared by Miller et al.36 This
compound had served previously as a key intermediate for
optically active nocardicin and analogs (Scheme 21). The
a-amido-b-lactam 64 was converted to a racemic, a-meth-
oxy-a-amido-b-lactam (67), which has a cephamycin type
side chain at 3-position.35
4-Vinyl-azetidinine-2-one (60) is a versatile intermediate
for a variety of heterocycles. It has been used by the
Merck group for the synthesis of thienamycin.31 This
compound has also been used as an intermediate for the
synthesis of Aspartame,32 a sweetening agent.
Schiff bases (46) derived from cinnamaldehyde and d-threo-
nine esters described in an earlier section (Scheme 18) have
been used for preparing monocyclic and bicyclic N-vinyl-b-
lactams. Cycloaddition with azidoacetyl chloride in the
presence of triethylamine converted 46 to a 1:1 mixture of
two optically active cis-a-azido-b-lactams 68 that differed
in the absolute con®guration at C-3 and C-4. These diaster-
omers could be separated with dif®culty on a small scale by
thin layer chromatography. The 1:1 mixture of the two cis-
b-lactams was utilized without separation for the next
synthetic step. Controlled oxidation with Jones reagent led
to an enolic side chain on the b-lactam nitrogen (as in the
formation of 48 in Scheme 18). Treatment with mesyl
chloride and a base provided 69 in which the enol form
could no longer equilibrate with the keto-ester form. In this
process, the two chiral centers on the side chain of 68 were
lost and the racemic form of 69 was obtained (Scheme 22).
1-Vinyl-2-azetidinones
Synthesis of N-vinyl-b-lactams (C)
In the course of our preparation of optically active a-amino-
b-lactams from l-serine derivatives by the Mitsunobu type
reaction,33,34 it was found that the dipeptide (N-Boc)-
serinylphenylserine (63) was a convenient starting material
for the synthesis of N-vinyl-b-lactams.23 The desired dipep-
tide was prepared from t-Boc-l-serine (61) and the methyl
ester of dl-phenylserine (62) under the in¯uence of
dicyclohexylcarbodiimide. The b-hydroxy groups required
no protection. Reaction of 63 with triphenylphosphine and
diethyl azodicarboxylate led in good yield to the b-lactam
64 with an N-vinyl group. After deprotection of the t-Boc
amino group by treatment with formic or tri¯uoroacetic
acid, and acylation with an appropriate group, 65 with a
dipeptide side chain similar to that in the monobactam
sulfazecin was obtained.35
Ozonolysis of 69 followed by reduction with a borane±
tetrahydrofuran complex produced a carbinol side chain at
Scheme 22.

M. S. Manhas et al. / Tetrahedron 56 (2000) 5587±5601
5595
Scheme 23.
C-4. Mesylation of this primary alcohol led to the dimesyl-
ate 70, which proved useful as an intermediate for bicyclic
b-lactams. The crude dimesylate was treated with hydrogen
sul®de±triethylamine following a published procedure to
form a second ring and also to reduce the azido group to
an amino group. Acylation and deesteri®cation led to the
isocephalosporin derivative 71 described earlier by Doyle et
al.37 (Scheme 23).
cation of the C-3 side chain to an amido substituent was
achieved by standard reactions to form 77. Removal of
the thiomethyl group gave the desired b-lactam 78. Trans-
formation of the N-vinyl group via the bromohydrin 79 led
to the N-unsubstituted b-lactam 80 which has been shown to
be an intermediate38 for nocardicin analogs 81 (Scheme 24).
Eco-friendly Synthetic Approaches Under Microwave
Irradiation
The dimesylate 70 was converted to the enamino compound
72 by reaction with an excess of morpholine. A pyridine
solution of 72 was treated with bromine at low temperature
to obtain a bromo compound that was hydrolyzed with
p-toluenesulfonic acid hydrate to the enolic bromo
compound 73. Reaction with an excess of potassium acetate
in DMF converted 73 to an oxa-isocephem derivative that
was changed into an oxa-analog 74 of isocephalosporin by
standard reactions involving the azido group (Scheme 23).
Parallel reactions with 47a (or 47b) would have provided
the homochiral forms of 74.
MORE chemistry techniques
Domestic microwave ovens optimized for heating water are
equipped with inexpensive microwave generators (magne-
trons) that produce 600±1200 W of 2450 MHz microwave
beams directed into the oven area. Microwaves are a non-
ionizing radiation that transfer energy to ions in solution and
other compounds with a dipole. Metals re¯ect microwaves
and thus are not heated. Glass, ceramics and many poly-
meric materials are essentially transparent to microwaves.
Hydrocarbons (e.g. hexane, benzene and cyclohexane) and
symmetrical molecules (therefore without dipole) such as
carbon tetrachloride absorb very little microwave energy.
But, chloroform, N,N-dimethylformamide (DMF), ethylene
A direct access to a C-4 unsubstituted N-vinyl-b-lactam was
established by starting with 75Ða known degradation
product of penicillin G. Cycloaddition with 39 (as in
Scheme 17) converted 75 to the trans b-lactam 76. Modi®-
Scheme 24.

5596
M. S. Manhas et al. / Tetrahedron 56 (2000) 5587±5601
glycol, chlorobenzene, and other organic compounds with
dipole moment are heated very rapidly.39
Raney nickel catalyst be used, there is rapid reduction of
double bonds without any scission of the b-lactam ring.
The usual reaction vessel is either a large Erlenmeyer ¯ask
with a funnel as a loose top or a tall beaker with a loose
cover. Any small amount of vapor produced by the reaction
is condensed by the unheated glass walls of these vessels.
Milligram scale reactions are conducted conveniently in a
test tube or vial with a septum as a cap. If necessary, two
hypodermic needles are temporarily inserted through the
septum to replace the gas inside the capped vial.
Rapid synthesis of b-lactams
Following a method described by Varma et al.3a it is cus-
tomary in our laboratory now to use a small amount of
Montmorillonite clay to accelerate Schiff base formation
under microwave irradiation. We have found it unnecessary
to remove the clay before proceeding to b-lactam formation
by reaction with an acid chloride and a tertiary amine. If the
aldehyde or the amine is a liquid, no solvent need be added
during the Schiff base formation. However, if the reaction
mixture is a very thick slurry, the addition of a small amount
of ethylene dichloride is helpful. During the next step it is
necessary to add ethylene dichloride or chlorobenzene as the
microwave energy transfer reagent (reaction medium). This
microwave assisted one-pot synthesis of b-lactams is more
eco-friendly and much faster than the conventional method.
The temperature inside a domestic microwave oven is
controlled by an on/off cycle. To ®ne tune the energy
absorbed by the reaction mixture, a beaker of water or
DMF (N,N-dimethylformamide) is placed near the reaction
vessel. This extra polar liquid acts as a heat sink by absorb-
ing a portion of the microwave energy. The quantity of
liquid required in the heat sink can be determined easily
by doing one or two pilot experiments.
DMF, with its high dielectric constant, (eˆ36.7) and high
boiling point (1548C), is an ef®cient microwave energy
transfer agent and a convenient solvent because it is
miscible with water. The reaction temperature can be raised
to ,1408C without signi®cant DMF vaporization. Ethylene
glycol (bp 1968C) and 1,3-propanediol are convenient
replacements for alcohols used in traditional reactions. In
place of the usual aromatic solventsÐbenzene, toluene and
xylene, which absorb microwave energy poorlyÐchloro-
benzene (bp 1328C), 1,2-dichlorobenzene (bp 1808C), and
1,2,4-trichlorobenzene (bp 2148C) can be employed. Ether
and THF (tetrahydrofuran) can be replaced by dioxane (bp
1018C), diglyme (bp 1628C), or triglyme (bp 2168C).
Concluding Remarks
Ecologically friendly processes for preparing chemicals for
research and manufacture are increasingly in demand.
Fortunately, many of the traditional synthetic methods can
be modi®ed to achieve higher `atom economy' (less waste
chemicals) and reduced use of solvents. It is also possible in
many cases to ®nd less toxic substitutes for such widely
used reagents as chromium oxides, osmium tetroxide,
benzene, etc.
In the course of our studies on the chemistry of vinyl-b-
lactams which was started more than a quarter century ago,
attempts have been made to redesign synthetic steps to make
them more friendly to the environment. In particular,
MORE chemistry techniques have been employed success-
fully for this purpose.
It is convenient and economical to use a minimal amount of
solvent because, in many cases, a slurry at room temperature
provides adequate solubility for reactants during the rapid
temperature rise that occurs under microwave irradiation. In
the case of crystalline products, much of the product crystal-
lizes out when the small amount of the reaction medium
cools down. Many reactions can be conducted without a
solvent if one of the reactants is a liquid that absorbs micro-
wave energy ef®ciently. Less solvent used means less
solvent waste, and therefore, reduced pollution.
Environmentally benign syntheses and reduction of pollu-
tion at the source are becoming accepted goals for both
academic and industrial laboratories. There are strong indi-
cations that the newly emerging technology of microwave
assisted chemistry will play a special role in the develop-
ment of eco-friendly synthetic processes.
Catalytic transfer hydrogenation
Experimental
In earlier years, catalytic reduction and hydrogenolysis of
vinyl b-lactams was conducted by using hydrogen under
about 40 psi pressure. A fair amount of hydrogen had to
be wasted to ¯ush out all the air in the hydrogenation
apparatus. Also complete reduction usually required one
or more hours of hydrogenation. Currently, catalytic trans-
fer hydrogenation has become the established eco-friendly
procedure in our laboratory. Ammonium formate is used as
the hydrogen donor. At about 1108C the reduction process
takes only about a few minutes and the yield is nearly
quantitative.
Melting points were determined with a Mel-temp apparatus
and are uncorrected. IR spectra were recorded on a Perkin±
Elmer infrared spectrophotometer and NMR spectra were
recorded on a Bruker AC-20 spectrometer using TMS as an
internal standard. Chemical ionization mass spectra were
recorded on a Biospect Instrument using CH4 as the reagent
gas. Thin layer chromatography was performed with
Whatman plates; the spots were detected by UV. Micro-
analyses were performed by Schwartzkopf Microanalytical
Laboratory, NY.
It was observed that cleavage of the b-lactam ring by the
hydrogenolysis of the N±C-4 bond of 4-aryl-2-azetidinones
takes place readily in presence of 10% Pd/C catalyst. But, if
General procedure for b-lactams
Conventional or microwave assisted syntheses of Schiff

M. S. Manhas et al. / Tetrahedron 56 (2000) 5587±5601
5597
bases and various b-lactams are described in our previous
publications.10b Also see the section above on `Rapid
Synthesis of b-Lactams'.
base formation was achieved in near 100% yield in about
5 min.
After allowing the reaction mixture to cool to room
temperature, a small amount of ethylene dichloride, croto-
nyl chloride (1) and N-methylmorpholine (in place of
triethylamine) were added. Microwave irradiation for a
few minutes resulted in the formation of 3g in about 50%
overall yield based on benzaldehyde. This yield has not been
optimized; indications are that the use of higher boiling
chlorobenzene instead of ethylene dichloride will allow a
higher temperature of the reaction mixture and an improved
yield. The clay was removed by ®ltration only after
completing the one-pot synthesis of 3g.
Stereoselectivity of a-vinyl-b-lactam formation under
microwave irradiation: In an Erlenmeyer ¯ask (capacity
250 mL), Schiff base 10 (2 g, 16.80 mmol) was placed in
chlorobenzene solution (10 mL). N-methylmorpholine
(5.09 g, 50.4 mmol) and crotonyl chloride (2.09 g,
20 mmol) were added to it and the mixture was shaken
well. A beaker (500 mL capacity) containing water
(200 mL) was placed in the microwave oven as a heat
sink. The reaction mixture was irradiated at low power
setting for 5 min after which TLC indicated disappearance
of the starting material. Ethyl acetate (50 mL) was added
and the organic phase was washed successively with dilute
hydrochloric acid (10%, 2£10 mL), brine (2£10 mL), dried
with sodium sulfate and evaporated. The crude product
showed the presence of 11 and 12 in the ratio of 20:80.
This was chromatographed over silica gel using ethyl
acetate and hexane (10:90) as the eluent.
The preparation of the previously known 5310b (Scheme 19)
provides another illustration of the application of MORE
chemistry techniques. The cyclization reaction to obtain a
cis b-lactam from 50 and benzoyloxyacetyl chloride gave
70% yield of 52 after about 3 min of irradiation. Microwave
assisted catalytic transfer hydrogenation with ammonium
formate in presence of 10% Pd/C catalyst at about 1308C
led to 90% yield of the hydrogenolysis product 53 in about
2 min.
1
11: yield, 15%, oil; IR (CH2Cl2): 1740, 1630 cm21, H
NMR (200 MHz, CDCl3) d: 7.64±6.94 (m, 5H), 5.29±
5.16 (m, 2H), 5.08±4.94 (m, 1H), 4.73 (d, Jˆ5.4 Hz, 1H),
4.28±4.10 (m, 1H), 2.81 (s, 3H); CIMS (CH4 reagent gas):
m/e 188 (M1H)1; Anal. calcd for C12H13NO: C, 76.97; H,
6.99; N, 7.48. Found: C, 76.69; H, 6.81; N, 7.09.
(3R,4S)-cis-1-(p-Anisyl)-3-mesyloxy-4-[(S)30,30-dimethyl-
20,40-dioxalanyl]azetidin-2-one (54). To a mixture of the
hydroxy b-lactam 53 (2.93 g, 10 mmol), triethylamine
(4.04 g, 40 mmol) and 4-dimethyl-aminopyridine (310 mg,
2.5 mmol) in dry methylene chloride (10 mL) at 08C was
added methanesulfonyl chloride dropwise with stirring
under a nitrogen atmosphere. The reaction mixture was
allowed to warm to room temperature and stirred overnight.
It was washed with dilute hydrochloric acid (2£50 mL) and
brine (1£50 mL), dried (Na2SO4), ®ltered and evaporated to
give the crude mesylate (54) which was puri®ed by ¯ash
column chromatography (silica gel, 230±400 mesh,
hexane±ethyl acetate 7:3). Yield, 3.5 g (95%). mp 1338C;
[a]D26ˆ197.48 (cˆ0.3, MeOH); IR and NMR spectra were
satisfactory. CIMS (NH3 reagent gas) m/z 389 (M1NH4)1;
Anal. calcd for C16H21NO7S: C, 51.75, H, 5.66, N, 3.77, S,
8.63. Found: C, 51.06, H, 5.36, N, 3.72, S, 8.69.
12: yield 55%, oil; IR (CH2Cl2): 1740, 1630 cm21; 1H NMR
(200 MHz, CDCl3) d: 7.46±7.28 (m, 5H), 6.09 (m, 1H),
5.39±5.22 (m, 2H), 4.35 (d, Jˆ2.12 Hz, 1H), 3.59 (brs,
1H), 2.79 (s, 3H); CIMS (CH4 reagent gas): m/e 188
(M1H)1; Anal. calcd for C12H13NO: C, 76.97; H, 6.99;
N, 7.48. Found: C, 76.69; H, 6.84; N, 7.51.
Catalytic transfer hydrogenation
Experimental details about the general procedure are
provided in our recent publications.18 An unmodi®ed
domestic microwave oven placed in a hood was used;
1,3-propanediol is environmentally more acceptable than
ethylene glycol as a reaction medium. The catalyst used
was 10% Pd/C, ammonium formate was the hydrogen
donor. To prevent risk of ®re, the catalyst was ®rst placed
in an Erlenmeyer ¯ask under a layer of glycol; the
compound to be reduced was added next; ®nally ammonium
formate was added. Under microwave irradiation a tempera-
ture of 110±1308C was reached in 3±5 min; reduction and/
or hydrogenolysis was usually complete in less than 10 min.
(3R,4S)-cis-1-(p-Anisyl)-3-iodo-4[(S)20,20-dimethyl-1,30-
dioxalan-40-yl]-azetidin-2-one and (3S,4S)-trans-1-(p-
anisyl)-3-iodo-4-[(S)20,20-dimethyl-10,30-dioxalan-40-yll-
azetidin-2-one (55). Lithium iodide (3.2 g, 24 mmol) was
added to a solution of 54, (3 g, 8.0 mmol, 21) in dry N,N-
dimethylformamide (50 mL) under anhydrous conditions
and the resultant mixture was heated at 808C with con-
tinuous stirring. When TLC indicated the absence of the
starting material, it was poured into water (150 mL) and
extracted (6£75 mL) with methylene chloride±diethyl
ether (1:5). The combined organic extracts were washed
with water (5£100 mL), dried (Na2SO4), and evaporated
to give a crude mixture of the title compounds 55. Puri®-
cation by ¯ash chromatography (silica gel, 230±400 mesh,
hexane±ethyl acetate, 1:1) yielded the pure mixture (2.38 g,
74%) as colorless oil. IR and NMR spectra were satis-
factory. CIMS (NH3) reagent gas) m/z 421 (M1NH4)1.
Microwave assisted synthesis of b-lactams
Microwave assisted synthesis of 3g (Scheme 1), previously
described,21 illustrates the application of MORE (Micro-
wave induced Organic Reaction Enhancement) chemistry
techniques. The Schiff base 2 (R1ˆPh, R2ˆPMP) was
prepared by subjecting a mixture of benzaldehyde, p-anisi-
dine and Montmorillonite clay and a minimal amount of
ethylene dichloride to medium power microwave irradiation
in a domestic microwave oven. Monitoring by TLC showed
that on 2±5 g scale of the aldehyde and the amine, Schiff
1-(p-Anisyl)-4-[(S)-20,20-dimethyl-1,30-dioxalan-40-yl]-
azetidin-2-one (56). To a solution of the pure mixture

5598
M. S. Manhas et al. / Tetrahedron 56 (2000) 5587±5601
obtained from 55, (1 g, 2.48 mmol) in benzene (40 mL),
containing azo-bis-(isobutyronitrile) (AIBN), (catalytic
amount), under nitrogen was added tributyl tin hydride
(0.722 g, 0.66 mL, 2.48 mmol) dropwise at room tempera-
ture. The reaction was monitored by TLC and at the dis-
appearance of the starting material, it was evaporated to
dryness, redissolved in methylene chloride (50 mL) and
washed with water (6£30 mL), brine (1£30 mL) and dried
(Na2SO4). The organic layer was then evaporated and puri-
®ed by silica column chromatography to yield pure 56
(0.54 g, 78.6%). mp 108±1098C; [a]D26ˆ172.848. IR and
NMR spectra were satisfactory; CIMS (NH3 reagent gas)
m/z 295 (M1NH4)1. Anal. calcd for C15H19NO4: C, 64.97,
H, 6.91, N, 5.05. Found: C, 64.78, H, 6.97, N, 4.97.
(1.61 g, 2.96 mmol) dropwise over a 5 min period. The
reaction was stirred at 08C for 30 min and diluted with
10 mL of water. The mixture was extracted with ethyl
acetate (2£10 mL). The organic extracts were combined
and washed with 10% sodium bicarbonate solution and
the aqueous washes were back extracted with ethyl acetate
(2£5 mL). The combined organic extracts were washed
with 10% sodium bisul®te (until the aqueous phase
remained colorless), 10% sodium bicarbonate solution and
brine. The organic phase was dried over anhydrous sodium
sulfate and evaporated under reduced pressure to give the
crude 60 which was puri®ed by silica gel ¯ash column
chromatography using 40% ethyl acetate in hexane as
elutant to afford a colorless liquid (0.070 g, 73%). IR and
NMR spectra were satisfactory; CIMS (NH3 reagent gas)
m/z 115 (M1NH4)1.
1-(p-Anisyl)-4-[10,20-dihydroxy ethyl] azetidin-2-one (57).
To a stirred solution of the b-lactam 56 (9 g, 32±49 mmol)
in tetrahydrofuran:water (75 mL, 3:1), was added p-toluene
sulfonic acid (1.62 g, 8.51 mmol) and the mixture re¯uxed
for 3 h. It was cooled to room temperature and solid sodium
bicarbonate was added until the solution was neutral. It was
extracted with EtOAc (4£30 mL), dried (Na2SO4) and the
organic solvent upon evaporation yielded the crude
b-lactam 57, which was puri®ed by ¯ash column chroma-
tography to yield a white solid (5.65 g, 74%). mp 118±
1208C; [a]D26ˆ199.98 (cˆ1.796, MeOH); IR and NMR
spectra were satisfactory; CIMS (NH3 reagent gas) m/z
255 (M1NH4)1. Anal. calcd for C12H15NO4, C, 60.75, H,
6.37, N, 5.90. Found: C, 61.08, H, 6.42, N, 5.78.
cis-1-(10-p-Nitrobenzyloxycarbonyl-20-mesyloxypropenyl)-
3-azido-4-styryl-azetidin-2-one (^69). To a stirred solu-
tion of the known compound 6825 (16.62 g, 36.85 mmol) in
acetone (1000 mL) at room temperature was added 16.6 mL
of Jones Reagent, prepared by dissolving CrO3 (26.72 g) in
concentrated sulfuric acid (23 mL) and diluting the solution
to a volume of 100 mL with water. Vigorous stirring was
maintained for 1 h, after which time the mixture was ®ltered
to remove the chromous salts, the ®ltrate (acetone solution)
evaporated, and the residue taken up in chloroform
(600 mL). This solution was washed with 5% NaHCO3
(2£300 mL), dried (Na2SO4), and evaporated to yield
15.95 g of a crude oil. Chromatography on 300 g of silica
gel (100±200 mesh), with an eluent of chloroform±ethyl
acetate (10:1) afforded the enol cis-1-(10-p-nitrobezyloxy-
carbonyl-20-hydroxypropenyl)-3-azido-4-styryl-azetidin-
2-one (12.86 g, 77.7%), mp 98±1018C. IR (neat): 2950±
1-(p-Anisyl)-4-[(S)-10,20-dimesyloxy ethane] azetidin-2-
one (58). Mesyl chloride (1.14 mL, 14.76 mmol) was
added dropwise to a stirred solution of the b-lactam 57,
(1 g, 4.22 mmol), and triethylamine (2.65 mL, 19 mmol)
in methylene chloride (50 mL) at 08C under a nitrogen
atmosphere. The reaction was allowed to warm to room
temperature overnight. It was washed with saturated sodium
bicarbonate solution (2£30 mL), water (1£30 mL), brine
(1£30 mL) and dried (Na2SO4). Removal of the solvent
yielded the crude b-lactam 58 which was puri®ed by silica
gel ¯ash column chromatography to yield a white solid
(1.51 g, 91%). mp 115±1178C; [a]D26ˆ167.888 (cˆ1.787,
CH2Cl2); IR and NMR spectra were satisfactory; CIMS
(NH3 reagent m/z 411 (M1NH4)1. Anal. calcd for
C14H19NO8S2, C, 42.74, H, 4.87, N, 3.56, S, 16.30. Found
C, 42.81, H, 4.76, N, 3.42, S, 16.70.
2825, 2100, 1762, 1745, 1650, 1605 cm21 1H NMR
,
(CDCl3) d: (2.13 (s, 3H), 4.55 (dd, 1H, Jˆ5.5, 9.0 Hz),
4.90 (d, 1H, Jˆ5.5 Hz), 5.33 (s, 2H), 6.20 (dd, 1H, Jˆ9.0,
16.0 Hz), 6.70 (d, 1H, Jˆ16.0 Hz), 7.43 (s, 5H), 7.55 (d, 2H,
Jˆ9.0 Hz), 8.25 (d, 2H, Jˆ9.0 Hz), 12.30 (s, 1H).
To a solution of this enol (6.56 g, 14.6 mmol) in anhydrous
methylene chloride (190 mL) was added triethylamine
(1.62 g, 16.1 mmol). The solution was cooled to 08C, and
freshly distilled methanesulfonyl chloride (1.84 g,
16.1 mmol) in anhydrous methylene chloride (10 mL) was
added dropwise with stirring over 20 min. After an
additional hour, the solution was washed with brine
(2£100 mL), dried (Na2SO4), and evaporated to yield
8.80 g of a crude oil which was chromatographed on
300 g of silica gel (100±200 mesh) with an eluent of chloro-
form±ethyl acetate (10:1) to afford the enol mesylate 69
(6.10 g, 79.2%) as an oil. IR (neat): 2110, 1760, 1723,
1-(p-Anisyl)-4-(R)-vinyl-azetidin-2-one (59). To a solution
of the b-lactam 58, (2 g, 5.1 mmol) in dry DMF (100 mL)
was added LiI (6.8 g, 51 mmol) and metallic zinc (3.32 g,
51 mmol). The mixture was heated under a nitrogen atmos-
phere at 808C for 8 h at the end of which it was cooled to
room temperature and poured into water (200 mL). It was
then extracted (3£100 mL) with ether: CH2Cl2 (5:1) and the
combined organic layers washed with water (3£100 mL),
brine (1£100 mL) and dried (Na2SO4). Evaporation of the
solvent yielded the pure b-lactam 59, (1.03 g, 95%) as a
light yellow oil. IR and NMR spectra were satisfactory;
CIMS (NH3 reagent gas) m/z 221 (M1NH4)1.
1
1520, 1360 cm21; H NMR (CHCl3) d: 2.60 (s, 3H), 3.28
(s, 3H), 4.90 (m, 2H), 5.32 (s, 2H), 6.25 (m, 1H), 6.62 (d,
1H, Jˆ16.0 Hz), 7.35 (s, 5H), 7.50 (d, 2H, Jˆ8.0 Hz), 8.20
(d, 2H, Jˆ8.0 Hz).
cis-1-(10-p-Nitrobenzyloxycarbonyl-20-mesyloxypropenyl)-
3-azido-4-mesyloxymethyl-azetidin-2-one (70). A stream
of ozone was passed through a cooled (2788C) solution of
69 (527 mg, 1 mmol) in anhydrous methylene chloride
(60 mL) for 3 min. The blue color was dissipated by
¯ushing the system with oxygen for 1 min. Dimethyl sul®de
4(R)-Vinyl-azetidin-2-one (60). To a solution of the
b-lactam 59, (0.2 g, 0.985 mmol) in 3 mL of acetonitrile
at 08C was added a solution of ceric ammonium nitrate

M. S. Manhas et al. / Tetrahedron 56 (2000) 5587±5601
5599
(0.5 mL) was added at 2788C and the solution allowed to
warm to room temperature. This solution was washed with
brine (30 mL), dried (Na2SO4), and evaporated to yield
560 mg of a crude oil. This procedure was repeated ®ve
more times, and the combined preparations resulted in
3.30 g of a crude oil which upon chromatography on
150 g of silica gel (100±200 mesh), chloroform-ethyl
acetate (10:3) as eluent, yielded an aldehyde cis-1-(1-p-
nitrobenzyloxycarbonyl-20-mesyloxypropenyl)-3-azido-
4-formyl-azetidin-2-one (2.10 g, 77.3%) as an oil. IR
washed with brine (5 mL), dried (Na2SO4), and evaporated
to yield a crude oil which, after preparative thick layer
chromatography, afforded the amide p-nitrobenzyl-3-
methyl-7-(phenoxyacetamido)-(2-isocephem)-4-carboxyl-
ate (52 mg, 26.5%) as an amorphous solid. IR (neat): 3310,
1755, 1710, 1680, 1600±1580, 1520 cm21
;
1H NMR
(CDCl3) d: 2.23 (s, 3H), 2.72 (dd, 1H, Jˆ4.5, 12.0 Hz),
3.00 (m, 1H), 3.92 (d, 1H, Jˆ5.0, 10.0 Hz), 4.44 (s, 2H),
5.23 (d, 2H, Jˆ4.0 Hz), 5.46 (dd, 1H, Jˆ5.0, 7.0 Hz), 6.70±
7.45 (m, 6H), 7.52 (d, 2H, Jˆ8.5 Hz), 8.13 (d, 2H,
Jˆ8.5 Hz). Analysis: C23H21N3O7S requires: C 57.14; H
4.38; N 8.69; found: C 57.31; H 4.49; N 8.35.
(neat): 3250±3200, 2110, 1760, 1723, 1515 cm21 1H
;
NMR (CDCl3) d: 2.58 (s, 3H), 3.30 (s, 3H), 4.85 (m, 1H),
5.10 (d, 1H, Jˆ6.0 Hz), 5.32 (s, 2H), 7.55 (d, 2H,
Jˆ7.5 Hz), 8.25 (d, 2H, Jˆ7.5 Hz), 9.70 (d, 1H, Jˆ3.0 Hz).
This isocephem ester (40 mg, 0.0828 mmol) was dissolved
in 1,4-dioxane (1.2 mL) and methanol (0.6 mL) containing
10% palladium-on-charcoal (20 mg) and the mixture hydro-
generated on a Parr shaker at room temperature and 50 psi
for 3 h. The catalyst was ®ltered off and the solution evapo-
rated to dryness in vacuo. The residue was dissolved in ethyl
acetate (10 mL) and washed with 10% HC1 (3£5 mL), and
with brine (5 mL). The combined organic layers were
treated with charcoal and evaporated under reduced
pressure to a solid. The solid was dissolved in very dilute
NaHCO3 containing slightly more than one equivalent of
base. The aqueous solution was washed with ethyl acetate,
acidi®ed to pH 2 with 10% HC1, and extracted twice with
ethyl acetate. The combined organic solutions were dried
(Na2SO4) and evaporated in vacuo to yield the acid 71
(19 mg, 65.9%) as an off-white solid. The product was
recrystallized from ethyl acetate, mp 219±2208C, (lit. mp
219±2208C)35. IR (nujol mull): 3340, 1755, 1745, 1705,
To a stirred solution of this aldehyde (420 mg, 0.927 mmol)
in anhydrous tetrahydrofuran (4.2 mL) at room temperature
was added 3.71 mL of a borane-tetrahydrofuran complex
solution (1 M in tetrahydrofuran) under anhydrous con-
ditions. The reaction mixture was stirred at room tempera-
ture for 8 h, after which time it was quenched with brine
(10 mL). It was then diluted with methylene chloride
(25 mL) and the organic layer separated. The residual
aqueous phase was extracted once more with methylene
chloride (25 mL). The combined organic extracts were
dried (Na2SO4) and evaporated to yield a crude oil which
upon chromatography on 50 g of silica gel (100±200 mesh),
chloroform±ethylacetate (10:3) as eluent, yielded the
alcohol
cis-l-(10-p-nitrobenzyloxycarbonyl-3-azido-4-
hydroxymethyl-2(mesyloxypropenyl)-azetidin-2-one (185
mg, 43.9%) as an oil with some unreacted aldehyde
(160 mg, 38.1%).
1
1660, 1590 cm21; H NMR (DMSO-d6) d: 2.12 (s, 3H),
2.73 (dd, 1H, Jˆ4.0, 12.0 Hz), 3.26 (dd, 1H, Jˆ9.5,
12.0 Hz), 3.70 (m, 1H), 4.50 (s, 2H), 5.45 (dd, 1H, Jˆ5.0,
8.0 Hz), 6.60±7.50 (m, 5H), 8.65 (d, 1H, Jˆ8.0 Hz).
To a solution of this alcohol (53 mg, 0.12 mmol) in anhy-
drous methylene chloride (1.0 mL) was added methane-
sulfonic anhydride (101 mg, 0.58 mmol). The solution was
allowed to stir at room temperature under a nitrogen atmos-
phere for 24 h. The solution was then washed with brine
(1 mL), dried (Na2SO4), and evaporated to yield 60 mg of
a crude oil which, after preparative thick layer chroma-
tography, afforded the dimesylate 70 (40 mg, 64.4%) as an
oil and some unreacted alcohol (15 mg, 28.3%). IR (neat):
7b(2-Thienylacetamido)-3-acetoxymethyl-O-2-isocepham-
4-carboxylic acid (74). To a stirred solution of dimesylate
70 (533 mg, 1.0 mmol) in anhydrous methylene chloride
(25 mL) at room temperature was added morpholine
(209 mg, 2.4 mmol). After 2 h, TLC analysis indicated
virtually complete reaction of 70. The solution was worked
up as usual and on concentration yielded an enamine 72
(520 mg, 100%) as an oil, suf®ciently pure for the further
use. IR (Neat): 3300±2900, 2110, 1770, 1725, 1650, 1620,
2110, 1770, 1725, 1630±1600, 1520 cm21
;
1H NMR
(CHCl3) d: 2.58 (s, 3H), 3.03 (s, 3H), 3.30 (s, 3H), 4.46
(m, 3H), 4.94 (d, 1H, Jˆ5.0 Hz), 5.36 (s, 2H), 7.59 (d,
2H, Jˆ8.5 Hz), 8.28 (d, 2H, Jˆ8.5 Hz).
1520 cm21
.
cis-3-Methyl-7-(phenoxyacetamido)
(2-isocephem)-4-
The enamine 72 (520 mg, 1.0 mmol) and pyridine (158 mg,
2.0 mmol) were dissolved in anhydrous methylene chloride
(15 mL) and the solution cooled to 208C. Bromine (80 mg,
1.0 mmol) in anhydrous methylene chloride (1 mL) was
then slowly added dropwise with stirring. The reaction
mixture was maintained at 2208C and then analyzed by
TLC after 30 min, which showed incomplete bromination.
With an excess of bromine, an excellent yield of the
bromide was obtained. The solution was worked up and
on concentration afforded 610 mg of a crude bromide with
small residual traces of pyridine. IR (Neat): 3300±2900,
carboxylic acid (71). A crude sample of 70 (220 mg) was
dissolved in anhydrous methylene chloride (4.5 mL), and
the solution was cooled to 08C. Hydrogen sul®de was passed
through the reaction mixture for 15 min, after which time
triethylamine (123 mg, 1.20 mmol) in anhydrous, methyl-
ene chloride (2.5 mL) was added dropwise with stirring over
5 min. The solution was allowed to warm to room tempera-
ture over the next 1.5 h. The solution was then washed with
brine (5 mL), dried (Na2SO4), and evaporated to yield the
crude 7-amino-isocephem. This was dissolved in anhydrous
methylene chloride (5 mL), to which was added triethyl-
amine (41 mg, 0.41 mmol). The solution was cooled to
08C and phenoxyacetyl chloride (69 mg, 0.41 mmol) was
added. The reaction mixture was allowed to stir with warm-
ing to room temperature over 2 h after which time it was
2110, 1775, 1725, 1650, 1620, 1515 cm21
.
The unpuri®ed bromide (610 mg) was then dissolved in 1,4-
dioxane (20 mL) to which p-toluenesulfonic acid mono-
hydrate (456 mg, 2.4 mmol) was added. The reaction was

5600
M. S. Manhas et al. / Tetrahedron 56 (2000) 5587±5601
Wagle, D. R.; Manhas, M. S.; Bose, A. K. J. Org. Chem. 1999, 64,
5746.
then stirred for 2 h after which time TLC indicated complete
enamine hydrolysis and still an essentially one-component
system. The solution was evaporated to dryness in vacuo,
the residual oil dissolved in chloroform (30 mL), and this
solution washed with brine (2£5 mL), dried (Na2SO4), and
again evaporated to yield 545 mg of the crude bromo-enol
73. IR (neat); 3500±2900, 2115, 1775, 1725, 1655, 1620,
2. For recent reviews, see: (a) Bose, A. K.; Manhas, M. S.; Banik,
B. K.; Srirajan, V. In The Amide Linkage: Selected Structural
Aspects in Chemistry, Biochemistry, and Material Science;
Greenberg, A., Breneman, C. M., Liebman, J. F., Eds.; Wiley-
Interscience: New York, 1999; Chapter 7 (b-Lactams: Cyclic
Amides of Distinction). (b) The Organic Chemistry of b-Lactams;
Georg, G. I., Ed.; VCH: New York, 1992.
1525 cm21
.
3. For recent overviews on microwave assisted chemistry, see: (a)
Varma, R. S. Green Chem. 1999, 43. (b) Bose, A. K.; Banik, B. K.;
Lavlinskaia, N.; Jayaraman, M.; Manhas, M. S. Chemtech. 1997,
27, 18. (c) Caddick, S. Tetrahedron 1995, 51, 10403. (d) Majetich,
G.; Hicks, R. J. Microwave Power Electromagn. Energy 1995, 30,
27. (e) Abramovich, R. A. Org. Prep. Proced. Int. 1991, 23, 683.
4. Trost, B. M. Science 1991, 254, 1471.
The enol 73 (545 mg) and potassium acetate (392 mg,
4.0 mmol) were dissolved in dimethylformamide (5 mL)
to which one drop of water was added. After stirring at
room temperature for 1.5 h, a new major component in
the reaction mixture was detected by TLC. The solution
was then diluted with ethyl acetate (25 mL), and the result-
ing mixture washed with brine (2£15 mL), and dried
(Na2SO4) and evaporated to afford 410 mg of the crude
isocephem as an oil. Preparative thick layer chromatography
of this crude product yielded a pure isocephem (230 mg,
55.0% of dimesylate 70) as an oil. IR (Neat): 3000±2850,
5. Bose, A. K.; Spiegelman, G.; Manhas, M. S. Tetrahedron Lett.
1971, 3167.
6. Zamboni, R.; Just, G. Can. J. Chem. 1979, 57, 1945.
7. Georg, G. I.; Mashava, P. M.; Guan, X. Tetrahedron Lett. 1991,
32, 581.
2110, 1780, 1745, 1720, 1610, 1520 cm21 1H NMR
;
8. Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1979, 18, 707.
9. Torii, S.; Okumoto, H.; Sadakane, M.; Abdul Hai, A. K. M.;
Tanaka, H. Tetrahedron Lett. 1993, 34, 6553.
(CDCl3): d 2.09 (s, 3H), 3.65±4.10 (m, 2H), 4.68 (dd, 1H,
Jˆ3.0, 9.0 Hz), 5.11 (d, 2H, Jˆ3.0 Hz), 5.20 (m, 1H), 5.26
(d, 2H, Jˆ6.0 Hz), 7.67 (d, 2H, Jˆ9.0 Hz), 8.28 (d, 2H,
Jˆ9.0 Hz); MS: M1/eˆ417, [(M1)228]/eˆ389.
10. (a) Bose, A. K.; Manhas, M. S.; Ghosh, M.; Raju, V. S.; Tabei,
K.; Urbanczyk-Lipkowska, Z. Heterocycles 1990, 30, 741. (b)
Banik, B. K.; Manhas, M. S.; Kaluza, Z.; Barakat, K. J.; Bose,
A. K. Tetrahedron Lett. 1992, 33, 3603. (c) Bose, A. K.; Banik,
B. K.; Manhas, M. S. Tetrahedron Lett. 1995, 36, 213. (d) Bose,
A. K.; Jayaraman, M.; Okawa, A.; Bari, S. S.; Robb, E. W.;
Manhas, M. S. Tetrahedron Lett. 1996, 37, 6989. (e) Bose, A. K.;
Banik, B. K.; Lavlinskaia, L.; Jayaraman, M.; Manhas, M. S.
Chemtech. 1997, 27, 18.
Using a known procedure for converting azido-b-lactams to
amido-b-lactams, the isocephem was converted to iso-
cephalosporin 74; mp: 181±28C (dec); lit.40 mp 1828C
(dec); IR (Nujol mull): 3300±2500, 1780, 1750, 1720,
1
1680, 1535 cm21; H NMR (CDCl3±DMSO-D6): d 2.02
(s, 3H), 3.60±4.10 (m, 2H), 3.70 (s, 2H), 4.50 (d, 1H,
Jˆ6.0 Hz), 4.96 (s, 2H), 5.55 (dd, 1H, Jˆ4.5, 8.0 Hz),
6.90±7.30 (m, 3H), 8.75 (d, 1H, Jˆ8.0 Hz), ±COOH not
detected. Analysis: C16H16N2O7S requires: C 50.53; H 4.21;
N 7.37; Found: C 50.69; H 4.17; N 7.31.
11. Bose, A. K.; Manhas, M. S.; Ghosh, M.; Shah, M.; Raju, V. S.;
Bari, S. S.; Newaz, S. N.; Banik, B. K.; Chaudhary, A. G.; Barakat,
K. J. J. Org. Chem. 1991, 56, 6968.
12. Manhas, M. S.; Ghosh, M.; Bose, A. K. J. Org. Chem. 1990,
55, 575.
13. Banik, B. K.; Manhas, M. S.; Newaz, S. N.; Bose, A. K.
Bioorg. Med. Chem. Lett. 1993, 3, 2363.
Acknowledgements
14. Banik, B. K.; Manhas, M. S.; Robb, E. W.; Bose, A. K. Hetero-
cycles 1997, 44, 405.
We are grateful to Stevens Institute of Technology for
research facilities. Thanks are due to the Howard Hughes
Medical Institute for support in the early stages of this
project through a grant to our Chemical Biology Education
Enhancement Program. We are indebted to George Barasch
and the New York Cardiac Center for generous support for
the undergraduate participants in our research projects.
Special thanks go to the many graduate students and post-
doctoral associates whose names appear in our publications
cited in this paper. We wish to thank Ashoke Bhattacharjee
for some data on microwave assisted reactions and Anju
Sharma, Sochanchingwung Rumthao, Unmesh Shah, and
Ronald Suayan for technical help in the preparation of this
manuscript.
15. For a recent example of catalytic transfer hydrogenation, see:
Rajagopal, S.; Spatola, A.F. J. Org. Chem. 1995, 60, 1347.
16. Krapcho, A. P. Synthesis 1982, 805.
17. Bose, A. K.; Banik, B. K.; Barakat, K. J.; Manhas, M. S.
Synlett 1993, 575.
18. Banik, B. K.; Barakat, K. J.; Wagle, D. R.; Manhas, M. S.;
Bose, A. K. J. Org. Chem. 1999, 64, 5746.
19. Kametani, T.; Fukumoto, K.; Ihara, M. Heterocycles 1982, 17,
496.
20. Tsuji, J.; Nagashima, H.; Nemoto, H. Org. Synthesis 1984, 62,
9.
21. Bose, A. K.; Krishnan, L.; Wagle, D. R.; Manhas, M. S.
Tetrahedron Lett. 1986, 27, 5955.
22. Bose, A. K.; Banik, B. K.; Newaz, S. N.; Manhas, M. S. Synlett
1993, 897.
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