Synthesis of 2-exo-methylenepenam and 3-chloro-Δ3-cephem through a sequential reductive 1,2-elimination/S-S bond fission or chloride ion-addition/cyclization of 3,4-disubstituted 2-butenoates in metal salt/metal combinations

Article abstract of DOI:10.1021/jo970051n

Synthesis of 2-exo-methylenepenam 1 through a sequential reductive 1,2-elimination/S-S bond fission/cyclization of 6 was performed by treatment with a PbBr₂/Al (or a BiCl₃/Al) combination in DMF, while that of 3-chloro-Δ³-cephem 2 through reductive 1,2-elimination/chloride ion-addition/cyclization was attained by use of an AlCl₃/Al combination in N-methylpyrrolidone (NMP). The selective transformation of 6 to the allenecarboxylate 3 was also achieved by treatment with an AlBr₃/Al combination in NMP. Cyclic voltammograms of 3,4-disubstituted 2-[2-oxo-3-(phenylacetamido)-4-[(phenylsulfonyl)thio]azetidin-1-yl]-2- butenoates (6) exhibit two irreversible reduction peaks responsible for reductive 1,2-elimination of the 3,4-disubstituted 2-butenoate moiety (at less negative potential) and for reductive S-S bond fission of the (phenylsulfonyl)thio moiety, suggesting that the reductive 1,2-elimination of 6 leading to allenecarboxylate 3 would occur prior to the reductive S-S bond cleavage.

Full text of DOI:10.1021/jo970051n

3610
J . Org. Chem. 1997, 62, 3610-3617
Syn th esis of 2-exo-Meth ylen ep en a m a n d 3-Ch lor o-∆3-cep h em
th r ou gh a Sequ en tia l Red u ctive 1,2-Elim in a tion /S-S Bon d F ission
or Ch lor id e Ion -Ad d ition /Cycliza tion of 3,4-Disu bstitu ted
2-Bu ten oa tes in Meta l Sa lt/Meta l Com bin a tion s
Hideo Tanaka, Shin-ichi Sumida, Yoichi Nishioka, Noriko Kobayashi, Yoshihisa Tokumaru,
Yutaka Kameyama, and Sigeru Torii*
Department of Applied Chemistry, Faculty of Engineering, Okayama University,
Tsushima-naka 3-1-1 Okayama, 700 J apan
Received J anuary 8, 1997X
Synthesis of 2-exo-methylenepenam 1 through a sequential reductive 1,2-elimination/S-S bond
fission/cyclization of 6 was performed by treatment with a PbBr2/Al (or a BiCl3/Al) combination in
DMF, while that of 3-chloro-∆3-cephem 2 through reductive 1,2-elimination/chloride ion-addition/
cyclization was attained by use of an AlCl3/Al combination in N-methylpyrrolidone (NMP). The
selective transformation of 6 to the allenecarboxylate 3 was also achieved by treatment with an
AlBr3/Al combination in NMP. Cyclic voltammograms of 3,4-disubstituted 2-[2-oxo-3-(phenylac-
etamido)-4-[(phenylsulfonyl)thio]azetidin-1-yl]-2-butenoates (6) exhibit two irreversible reduction
peaks responsible for reductive 1,2-elimination of the 3,4-disubstituted 2-butenoate moiety (at less
negative potential) and for reductive S-S bond fission of the (phenylsulfonyl)thio moiety, suggesting
that the reductive 1,2-elimination of 6 leading to allenecarboxylate 3 would occur prior to the
reductive S-S bond cleavage.
In tr od u ction
disclosed a conceptually new synthetic route to 2 through
a sequential chloride ion-addition/cyclization of the al-
lenecarboxylate 3 (Scheme 1, path b).7
2-exo-Methylenepenam 1 may be regarded as a new
candidate for potent broad spectrum antibiotics in its own
right1 and as a strategic intermediate for the synthesis
of penam and penem families of â-lactam antibiotics
through manipulation of the exo-methylene moiety.2 The
Our methodologies for the synthesis of the 2-exo-
methylenepenam 1 and the 3-chloro-∆3-cephem 2 (vide
supra) are, however, not necessarily satisfactory for
practical use because the key intermediate 3 is not
always easy to handle owing to its lability.8 We, there-
fore, sought a synthetic equivalent to the allenecarboxy-
late 3 that was readily available and stable under
ambient conditions. As a result, we found that 3,4-
disubstituted 2-[2-oxo-3-(phenylacetamido)-4-[(phenylsul-
fonyl)thio]azetidin-1-yl]-2-butenoates 6 (Y ) Cl, OTf, and
OTs) may behave as an alternative precursor of both the
2-exo-methylenepenam 19 and the 3-chloro-∆3-cephem 2.
Herein, we describe the synthesis of the 2-exo-methyl-
enepenam 1 through a sequential reductive 1,2-elimina-
tion/S-S bond fission/cyclization of the 3,4-disubstituted
2-butenoates 6 and the 3-chloro-∆3-cephem 2 through
reductive 1,2-elimination/chloride ion-addition/cyclization
of 6 (Scheme 2), both of which were performed by use of
metal salt/aluminum redox systems.
first synthesis of the 2-exo-methylenepenam 1 (R1
)
PhOCH2CONH, R2 ) p-NO2C6H4CH2) was performed by
Baldwin through decarboxylative Pummerer-type reac-
tion of penicillin-2-carboxylic acid elaborated from peni-
cillin V.3 Recently, we developed an alternative access
to 1 through reductive S-S bond fission of the (phenyl-
sulfonyl)thio moiety of allenecarboxylate 3, derived from
penicillin, with a BiCl3/Zn combination, producing a thiol
(4) which underwent intramolecular Michael addition of
the thiol moiety to the center carbon of the allene moiety
(Scheme 1, path a).2b,4
On the other hand, 3-chloro-∆3-cephem 2 is currently
used as an orally active drug in antibacterial chemo-
therapy.5 Syntheses of the 3-chloro-∆3-cephem 2 explored
so far mainly relied on the displacement of the C(3)-
hydroxy group of 3-hydroxy-∆3-cephem.6 Lately, we
Resu lts a n d Discu ssion
X Abstract published in Advance ACS Abstracts, May 1, 1997.
(1) The 2-exo-methylenepenam’s framework represents a structural
hybrid of those of penicillin and clavulanic acid, which displays a potent
â-lactamase-inhibiting property.
(2) (a) Tanaka, H.; Kameyama, Y.; Sumida, S.; Torii, S. Bioorg. Med.
Chem. Lett. 1993, 3, 2253. (b) Tanaka, H.; Kameyama, Y.; Yamauchi,
T.; Torii, S. J . Chem. Soc., Chem. Commun. 1992, 1793.
(3) Baldwin, J . E.; Forrest, A. K.; Ko, S.; Sheppard, L. N. J . Chem.
Soc., Chem. Commun. 1987, 81.
(4) Tanaka, H.; Kameyama, Y.; Torii, S. Synlett 1992, 878.
(5) Druckhemier, W.; Adam, F.; Fischer, G.; Kirrstetter, R. Advances
in Drug Research; Druckhemier, W. Ed.; Academic Press: New York,
1988; Vol. 17, p 190.
(6) (a) Chauvette, R. R.; Pennington, P. A. J . Am. Chem. Soc. 1974,
96, 4986. (b) Scartazzini, R.; Bickel, H. Helv. Chim. Acta 1974, 57,
1919. (c) Chauvette, R. R.; Pennington, P. A. J . Med. Chem. 1975, 18,
403. (d) Kukolja, S.; Gleissner, M. R.; Ellis, A. I.; Dorman, D. E.;
Paschal, J . W. J . Org. Chem. 1976, 41, 2276. (d) Scartazzini, R.; Bickel,
H. Heterocycles 1977, 7, 1165. (e) Spry, D. O.; Bhala, A. R. Heterocycles
1986, 24, 1653. (f) Farina, V.; Baker, S. R.; Hauck, S. I. J . Org. Chem.
1989, 54, 4962.
P r ep a r a tion of 3,4-Disu bstitu ted 2-Bu ten oa tes.
The 3,4-disubstituted 2-butenoates 6 were easily pre-
pared starting from penicillin (Scheme 3). The transfor-
mation of the penicillin to enol 9 was performed by the
reported procedures involving ene-type chlorination of
azetidinone 7,10 derived from penicillin,11 and subsequent
oxidative cleavage of the terminal double bond of 8.12 The
(7) (a) Tanaka, H.; Kikuchi, R.; Torii, S. Bull. Chem. Soc. J pn. 1996,
69, 1391. (b) Tanaka, H.; Sumida, S.; Kameyama, Y.; Sorajo, K.; Wada,
I.; Torii, S. Bull. Chem. Soc. J pn. 1996, 69, 3651.
(8) The allenecarboxylates 3 can be stored in a refrigerator for
several days without appreciable change but are gradually decomposed
under ambient conditions, particularly in the presence of a trace
amount of acid or base.
(9) Tanaka, H.; Nishioka, Y.; Kameyama, Y.; Sumida, S.; Matsuura,
H.; Torii, S. Chem. Lett. 1995, 709.
S0022-3263(97)00051-0 CCC: $14.00 © 1997 American Chemical Society

2-exo-Methylenepenam and 3-Chloro-∆3-cephem
J . Org. Chem., Vol. 62, No. 11, 1997 3611
Sch em e 1
Sch em e 3
chloride (1.5 molar equiv) and sodium carbonate (3 molar
equiv) in DMF at 0 °C for 2 h. Treatment of 6b with
lithium chloride (10 molar equiv) and aluminum(III)
chloride (3 molar equiv) in N-methylpyrrolidone (NMP)
at room temperature for 4 h gave 3,4-dichloro-2-butenoate
(6a ) (83%). All of the 3,4-disubstituted 2-butenoates 6
(Y ) Cl, OTf, and OTs) obtained thus far are stable
enough to survive under ambient conditions for several
weeks without appreciable change.
Cyclic Voltam m etr y of 3,4-Disu bstitu ted 2-Bu ten o-
a t es. The transformation of the 3,4-disubstituted
2-butenoates 6 to the 2-exo-methylenepenam 1 involves
two two-electron reduction stages via the allene inter-
mediate 3 (Scheme 2, path a). One is reductive 1,2-
elimination of the 3,4-disubstituted 2-butenoate moiety
of 6, affording the allenecarboxylate 3, and the other is
reductive S-S bond fission of (phenylsulfonyl)thio moiety
of 3, leading to the thiol 4, which subsequently undergoes
ring closure to give the final product 1. On the other
hand, the transformation of 6 to the 3-chloro-∆3-cephem
2 consists of the former two-electron reduction leading
to 3, followed by sequential chloride ion-addition and
cyclization (Scheme 2, path b). In order to achieve both
the conversions, the reductive 1,2-elimination of 6 must
occur selectively or prior to the reductive S-S bond
fission. As a preliminary experiment, we investigated
cyclic voltammetry of the 3,4-disubstituted 2-butenoates
6 and the related compound 7 to know the reduction
potentials of the 1,2-elimination and the S-S bond
fission.
The cyclic voltammetry was performed in DMF con-
taining Et4NOTs with a platinum disk as a working
electrode, a platinum wire as an auxiliary electrode, and
an Ag/Ag+ as a reference electrode at the potential sweep
of 100 mV/s. Cyclic voltammograms of the 3,4-dichloro-
2-butenoate 6a , the triflate 6b, and the tosylate 6c
exhibit two irreversible reduction peaks (ER1, ER2), re-
spectively. ER1 values of the 3,4-disubstituted 2-butenoates
6 vary between -1.8 and -2.0 V, depending on the
leaving group (Cl, OTf, or OTs), while all ER2 values are
nearly constant at -2.2 V (Table 1, entries 1-3). On the
other hand, a single reduction peak (ER2) is observed in
the cyclic voltammogram of the azetidinone 7 at -2.2 V
(entry 4), which is identical to those of the second peaks
Sch em e 2
enol 9 was then allowed to react with trifluoromethane-
sulfonic anhydride and triethylamine (1.5 molar equiv
each) in dichloromethane at -78 °C for 1 h to afford
4-chloro-3-[[(trifluoromethyl)sulfonyl]oxy]-2-butenoate 6b
(Y ) OTf) (95%). 4-Chloro-3-[[(p-methylphenyl)sulfonyl]-
oxy]-2-butenoate 6c (Y ) OTs) (98%, E/Z ) 9/1) was
similarly prepared by treatment of the enol 9 with tosyl
(10) Torii, S.; Tanaka, H.; Saitoh, N.; Siroi, T.; Sasaoka, M.; Nokami,
J . Tetrahedron Lett. 1982, 23, 2187. Torii, S.; Tanaka, H.; Tada, N.;
Nagao, S.; Sasaoka, M.; Nokami, J . Chem. Lett. 1984, 877.
(11) (a) Kamiya, T.; Teraji, T.; Saito, Y.; Hashimoto, M.; Nagaguchi,
O.; Oku, T. Tetrahedron Lett. 1973, 32, 3001. (b) Woodward, R. B.;
Bickel, H. Chem. Abstr. 1979, 86, 29852. (c) Tanaka, H.; Taniguchi,
M.; Uto, S.; Shiroi, T.; Sasaoka, M.; Torii, S. Bull. Chem. Soc. J pn.
1991, 64, 1416.
(12) Tanaka, H.; Taniguchi, M.; Kameyama, Y.; Monnin, M.; Torii,
S.; Sasaoka, M.; Shiroi, T.; Nagao, S.; Yamada, T.; Tokumaru, Y. Bull.
Chem. Soc. J pn. 1995, 68, 1385.

3612 J . Org. Chem., Vol. 62, No. 11, 1997
Tanaka et al.
Ta ble 1. Red u ction P oten tia la
redox system for the transformation of the allenecar-
boxylate 3 to the 2-exo-methylenepenam 1,2b,4 gives 1
(43%) (entry 13), suggesting that the BiCl3/Zn combina-
tion does not efficiently work for the reductive 1,2-
elimination of 6a .
Among the metal salt/metal combinations examined
thus far, the PbBr2/Al combination is the best choice for
the conversion of 6a to 1. The yield of 1 was dependent
on the amounts of metal salt and metal (entries 14 and
15). The reaction of 6a with a catalytic amount of lead-
(II) bromide (0.1 molar equiv) and 5 molar equiv of
aluminum afforded 1 in 76% yield (entry 14), while the
increase of amounts of lead(II) bromide and aluminum
to 1.8 and 25 molar equiv resulted in almost quantitative
conversion of 6a to 1 (entry 15).
A proper choice of the solvent was also important
(Table 3). When NMP was employed instead of DMF,
the yield of the desired penam 1 was reduced to 58% and
a small amount of the 3-chloro-∆3-cephem 2 (1%) was
formed (entry 2). In contrast, in methanol, dichlo-
romethane, and THF, the desired reaction did not take
place, resulting in the formation of a complex mixture of
decomposition products (entry 3) or the recovery of most
of the 6a (entries 4 and 5).
The time course of the transformation of 6a into 1 in
the PbBr2/Al redox system (Table 2, entry 15) was
monitored by HPLC, showing that after a short induction
period (2-3 min), the reaction proceeded smoothly and
most of the 6a was converted to 1 in 10 min (Figure 1).
Notably, during the course of the reaction, the allenecar-
boxylate 3 was formed and finally disappeared. The
result can be reasonably understood by assuming a
sequential reaction involving the reductive 1,2-elimina-
tion of the vicinal dichloro group of 6a , leading to 3;
subsequent reductive S-S bond fission of the (phenyl-
sulfonyl)thio moiety of 3, giving the thiol 4; and cycliza-
tion of 4, affording the desired product 1 (Scheme 2, path
a). Although the role of lead(II) bromide and aluminum
is not clear at present, lead(0) species, generated by
reduction of lead(II) bromide with aluminum, probably
works as a reductant for both the reductive 1,2-elimina-
tion and the S-S bond fission. The reaction of 6a with
commercially available lead metal, however, afforded no
detectable amount of 1 (Table 2, entry 16). It is,
therefore, likely that only freshly generated lead(0) on
the aluminum surface could promote the conversion of
6a to 1.
In a similar manner, transformation of the triflate 6b
and the tosylate 6c to the 2-exo-methylenepenam 1 has
been achieved by use of adequate metal salt/metal
combinations (Table 4). The reaction of the triflate 6b
with lead(II) bromide (1 molar equiv) and aluminum (5
molar equiv) in DMF at room temperature for 1 h
afforded 1 in 74% yield (entry 1). Use of a catalytic
amount of lead(II) bromide (0.1 molar equiv) also afforded
1 (73%) without significant change (entry 2), while excess
amounts of lead(II) bromide (2.1 molar equiv) and
aluminum (28.5 molar equiv) gave 1 in a quantitative
yield (entry 3). Other metal salt/metal combinations, e.g.,
BiCl3/Al, SnCl2/Al, and PbBr2/Zn, also afforded the de-
sired product 1 in 50-73% yields (entries 4-6).
entry
sub.
ER1 vs Ag/Ag+, V
ER2 vs Ag/Ag+, V
1
2
3
4
6a
6b
6c
7
-2.0
-1.8
-1.9
-2.1
-2.1
-2.2
-2.2
a
All reactions were carried out in DMF containing Et4NOTs
with a platinum disk as a working electrode and a platinum wire
as an auxilliary electrode at a potential sweep of 100 mV/s.
(ER2) of the 3,4-disubstituted 2-butenoates 6. The com-
mon electroactive functional group of 6 and 7 is the
(phenylsulfonyl)thio moiety. It is, therefore, reasonable
to assume that the second peak (ER2) is the reduction
peak for the S-S bond cleavage of the (phenylsulfonyl)-
thio group and, accordingly, that the ER1 is ascribable to
the reductive 1,2-elimination of the 3,4-disubstituted
2-butenoate moieties.
Above all, the cyclic voltammograms, indicating that
the reductive 1,2-elimination of the 3,4-disubstituted
2-butenoate moiety occurs at less negative potential than
the reductive S-S bond cleavage of the (phenylsulfonyl)-
thio moiety, suggest the reductive 1,2-elimination of 6
leading to 3 takes place prior to the reductive S-S bond
fission. It encouraged us to investigate the direct conver-
sion of the 3,4-disubstituted 2-butenoates 6 to either the
2-exo-methylenepenam 1 or the 3-chloro-∆3-cephem 2.
Red u ctive 1,2-Elim in a tion /S-S Bon d F ission /Cy-
cliza tion of 3,4-Disu bstitu ted 2-Bu ten oa tes to 2-exo-
Met h ylen ep en a m . The transformation of the 3,4-
dichloro-2-butenoate 6a to the 2-exo-methylenepenam 1
has been carried out in various metal salt/metal redox
systems, in which the metal salt would work as an
electron transfer catalyst and the metal would act as an
electron pool (Table 2).13 The reaction of 6a with lead-
(II) bromide (1 molar equiv) and aluminum (5 molar
equiv) in DMF at room temperature for 1 h afforded the
2-exo-methylenepenam 1 (82%) (entry 1). The presence
of both lead(II) bromide and aluminum is indispensable
for the formation of 1, since in the absence of any of the
components, no appreciable amount of 1 was obtained
(entries 2 and 3). Other metal salt/aluminum combina-
tions were also investigated (entries 4-9). Lead(II)
chloride, tin(II) chloride, and bismuth(III) chloride could
similarly effect the desired reaction though the yields of
1 were reduced to 40-65% (entries 4-6). Lead(II)
acetate and titanium(IV) chloride were less effective
(entries 7 and 8), and aluminum(III) chloride did not
work at all (entry 9). In entries 10-12, zinc, tin, and
magnesium were used in place of aluminum. Only zinc
afforded the desired product 1 (59%) (entry 10), while tin
and magnesium did not give 1, resulting in the recovery
of 6a (94%) (entry 11) or the formation of a complex
mixture of decomposition products (entry 12). Notably,
a BiCl3/Zn combination, which is an effective bimetal
(13) (a) Tanaka, H.; Inoue, K.; Pokorski, U.; Taniguchi, M.; Torii,
S. Tetrahedron Lett. 1990, 31, 1721. (b) Tanaka, H.; Yamashita, S.;
Ikemoto, Y.; Torii, S. Tetrahedron Lett. 1988, 29, 1721. (c) Tanaka,
H.; Dhimane, H.; Fujita, H.; Ikemoto, Y.; Torii, S. Tetrahedron Lett.
1988, 29, 3811. (d) Tanaka, H.; Kosaka, A.; Yamashita, S.; Morisaki,
K.; Torii, S. Tetrahedron Lett. 1989, 30, 1261. (e) Tanaka, H.; Sumida,
S.; Kobayashi, N.; Komatsu, N.; Torii, S. Inorg. Chem. Acta 1994, 222,
323.
(14) The formation of 10 can be rationalized by a sequential reaction
involving a two-electron reduction of the chlorine atom of 6 leading to
the corresponding anion and the nucleophilic attack of the terminal
carbanion to the (phenylsulfonyl)thio group. The further reduction of
C(3)-substituent (Z ) OTs) of the cephem 10c with the metal/metal
salt combination would give the 3-norcephem 11.
The reaction of the tosylate 6c with lead(II) bromide
(1 molar equiv) and aluminum (5 molar equiv) proceeded
in a similar fashion to afford 56% yield of 1 together with
a small amount of 3-[[(p-methylphenyl)sulfonyl]oxy]-∆3-
cephem 10c (Y ) OTs) (1%) and 3-norcephem 11 (2%)
(entry 7) (Scheme 4).14 The conversion of the tosylate

2-exo-Methylenepenam and 3-Chloro-∆3-cephem
J . Org. Chem., Vol. 62, No. 11, 1997 3613
Ta ble 2. Red u ctive 1,2-Elim in a tion /S-S Bon d F ission /Cycliza tion of 6a to 2-exo-Meth ylen ep en a m 1a
yield, %b
metal salt
metal
entry
(molar equiv)
(molar equiv)
time, h
1
6a
1
2
3
4
5
6
7
8
9
10
11
12d
13
14
15
16
PbBr2 (1.0)
Al (5.0)
Al (5.0)
1.0
4.2
4.0
1.3
3.6
2.5
8.1
10
3.9
1.5
9.7
1.0
1.3
1.3
1.0
4.0
82
quant
42
PbBr2 (1.0)
PbCl2 (1.0)
SnCl2 (1.0)
BiCl3 (1.0)
Pb(OAc)2‚3H2O (1.0)
TiCl4 (1.0)c
AlCl3 (1.0)
PbBr2 (1.0)
PbBr2 (1.0)
PbBr2 (1.0)
BiCl3 (1.0)
PbBr2 (0.1)
PbBr2 (1.8)
Al (5.0)
Al (5.0)
Al (5.0)
Al (5.0)
Al (5.0)
Al (5.0)
Zn (5.0)
Sn (5.0)
Mg (5.0)
Zn (5.0)
Al (5.0)
Al (25)
65
52
40
25
6
1
5
94
56
59
94
43
76
quant (57)e
Pb (5.0)
43
a
b
All reactions were carried out in DMF at room temperature. Determined by HPLC; HPLC conditions: column, YMC-Pack AMC-312
ODS (6.0 φ × 150 mm); mobile phase, CH3CN/H2O ) 65/35; flow rate, 1.0 mL/min, detection UV at 254 nm. c 1.54 M solution in CH2Cl2
was used. A complex mixture of decomposition products was formed. e Isolated yield after column chromatography (SiO2).
d
Ta ble 3. Solven t Effecta
was investigated by use of various metal salt/metal redox
yield %b
systems (Table 5). Among the redox systems examined
thus far, an AlCl3/Al combination was the best choice for
the present purpose; thus, the 3,4-dichloro-2-butenoate
6a was allowed to react with aluminum(III) chloride (0.5
molar equiv) and aluminum (10 molar equiv) in NMP at
room temperature for 8.8 h to afford 72% yield of the
3-chloro-∆3-cephem 2 together with a small amount of
the 2-exo-methylenepenam 1 (1%) and monochloro aze-
tidinone 12 (9%) (entry 1). The formation of the monochlo-
ro azetidinone 12 can be reasonably understood by
assuming the protonation of an intermediate (14) gener-
ated from the chloride ion-addition of the allenecarboxy-
late 3 (Scheme 5). The presence of both aluminum(III)
chloride and aluminum is apparently essential for the
formation of 2 since most of the 6a was recovered in the
absence of any of the components (entries 2 and 3). In
entries 4-8, other metal salts were examined with
aluminum. Use of titanium(IV) chloride in combination
with aluminum similarly promoted the reaction to afford
2 (41%) (entry 4). It is of interest to note that an AlBr3/
Al combination gave the allenecarboxylate 3 (91%) (entry
5). The result might be ascribed to the bulkiness of the
bromide ion (or aluminum(III) bromide) which would
suppress the nucleophilic attack to the allenecarboxylate
3. Chromium(III) chloride, iron(III) chloride, and nickel-
(II) chloride could not effect the desired reaction, result-
ing in the recovery of most of the 6a (entries 6-8).
entry
solvent
time, h
1
2
6a
1
DMF
NMP
MeOH
CH2Cl2
THF
1.0
0.5
4.2
8
82
58
2
1
3c
4
2
quant
quant
5
7.8
a
All reactions were carried out with 6a (0.15 mmol), PbBr2 (1.0
molar equiv), and aluminum (5.0 molar equiv) in solvent (2 mL)
b
at room temperature. Determined by HPLC, see footnote b of
Table 2. c A complex mixture of decomposition products was
formed.
The choice of proper solvent is also important; thus,
when DMF was used in place of NMP, the reaction of 6a
with the AlCl3/Al combination did not afford the 3-chloro-
∆3-cephem 2 at all (entry 9). In the presence of excess
lithium chloride (10 molar equiv), the reaction was
accelerated to some extent and completed in 4 h, but the
yield of 2 slightly decreased (63%) (entry 10, cf. entry 1).
Even with an excess amount of lithium chloride, the
PbBr2/Al redox system, however, afforded a mixture of 2
(14%) and the 2-exo-methylenepenam 1 (23%) (entry 11).
The most efficient synthesis of the 3-chloro-∆3-cephem 2
has been attained by the reaction of 6a with the AlCl3/
Al combination in NMP in the presence of 4A molecular
sieves, affording up to 80% yield of 2 (entry 12). Although
the role of the molecular sieves is not clear at present, it
is likely that molecular sieves would trap a trace amount
of water (or hydrogen chloride) in the reaction media to
suppress the formation of 12 (entries 1 and 12).
F igu r e 1. Time course of the transformation of 6a to 1 in a
PbBr2/Al redox system (Table 2, entry 15).
6c into 1 was more efficiently performed by treatment
with a BiCl3/Al combination, affording 1 in 77% yield
(entry 8). Other metal salt/metal combinations, e.g.,
SnCl2/Al, BiCl3/Zn, and BiCl3/Sn, were less effective
(entries 9-11).
Red u ctive 1,2-Elim in a tion /Ch lor id e Ion -Ad d ition /
Cycliza t ion of 3,4-Disu b st it u t ed 2-Bu t en oa t es t o
3-Ch lor o-∆3-cep h em . Next, the direct conversion of the
3,4-dichloro-2-butenoate 6a to the 3-chloro-∆3-cephem 2

3614 J . Org. Chem., Vol. 62, No. 11, 1997
Tanaka et al.
Ta ble 4. Red u ctive 1,2-Elim in a tion /S-S Bon d F ission /Cycliza tion of 6b or 6c to 2-exo-Meth ylen ep en a m 1a
yield, %b
metal salt
metal
entry
sub.
(molar equiv)
(molar equiv)
time, h
1
10
11
3
6
1
2
3
4
5
6
7
8
9
6b
6b
6b
6b
6b
6b
6c
6c
6c
6c
6c
PbBr2 (1.0)
PbBr2 (0.1)
PbBr2 (2.1)
BiCl3 (1.0)
SnCl2 (1.0)
PbBr2 (1.0)
PbBr2 (1.0)
BiCl3 (1.0)
SnCl2 (1.0)
BiCl3 (1.0)
BiCl3 (1.0)
Al (5.0)
Al (5.0)
Al (28.5)
Al (5.0)
Al (5.0)
Zn (5.0)
Al (5.0)
Al (5.0)
Al (5.0)
Zn (5.0)
Sn (5.0)
1.0
2.0
1.2
2.3
3.0
2.1
0.9
1.5
4.0
2.1
5.8
74
73
quant (65)c
68
50
73
56
1
7
1
2
2
1
1
5
77 (47)c
30
2
3
2
7
10
11
58
10
25
a
b
All reactions were carried out in DMF at room temperature. Determined by HPLC; see footnote b of Table 2. c Isolated yield after
column chromatography (SiO2).
Sch em e 4
on sequential reductive 1,2-elimination/S-S bond fission/
cyclization and reductive 1,2-elimination/chloride ion-
addition/cyclization of the 3,4-disubstituted 2-butenoates
6. The direct transformation of 6 to 1 was successfully
achieved in the PbBr2/Al/DMF (or the BiCl3/Al/DMF)
system, while synthesis of 2 was performed by treatment
of 6 with the AlCl3/Al combination in NMP. Stepwise
transformations of 6 to 3, 3 to 1, and 3 to 2 were also
performed by the proper choice of metal salt/metal
combination and solvent (Scheme 6).
The best combination, i.e., AlCl3/Al/4A molecular sieves/
NMP, was applied successfully to the transformation of
the triflate 6b and the tosylate 6c to the 3-chloro-∆3-
cephem 2. The reaction of either the triflate 6b or the
tosylate 6c in the AlCl3/Al/4A molecular sieves system
proceed smoothly to afford the 3-chloro-∆3-cephem 2 in
69 and 76% yields, respectively (entries 13 and 14).
The time course of the transformation of 6a into 2 in
the AlCl3/Al/4A molecular sieves system (Table 5, entry
12) was monitored by HPLC (Figure 2). In the initial
stage of the reaction, the reductive 1,2-elimination of the
dichloro moiety of 6a predominantly occurred and most
of 6a was converted to the allenecarboxylate 3 in 1 h.
The subsequent addition/cyclization reaction of 3 leading
to 2 gradually proceeded and, even after 5 h, ca. 10% of
the intermediate 3 still remained.
It is evident that aluminum(III) chloride plays an
important role in the reductive 1,2-elimination of the 3,4-
disubstituted 2-butenoate moiety of 6, since in the
absence of aluminum(III) chloride, no appreciable reac-
tion occurred (cf. Table 5, entry 3). The fact might be
ascribed to the activation of terminal chlorine atom and/
or the 3-substituent (X) of 6 by coordination with alumi-
num(III) chloride so as to realize the reductive 1,2-
elimination (step 1 in Scheme 5). In the next stage (step
2), thus formed aluminum complex [AlCl3X- (X ) Cl, OTf,
or OTs)] or NMP complex 16, generated from aluminum-
(III) chloride and NMP, would act as a nucleophile (Cl-)
for promoting the subsequent addition reaction. In the
final stage (step 3) of the reaction, the 3-chloro-∆3-cephem
2 was formed together with benzenesulfinate anion,
which would work as a nucleophile (more nucleophilic
than chloride ion), resulting in the formation of 3-(phe-
nylsulfonyl)-∆3-cephem 13. Namely, the reaction of the
benzenesulfinate ion with 3 would afford 13 with regen-
eration of the benzenesulfinate ion, which would again
react with 3, leading to 13.7 Aluminum(III) chloride also
plays an important role in removing the in situ generated
benzenesulfinate anion to suppress the formation of 13.
Exp er im en ta l Section
IR spectra were obtained on a J apan Spectroscopic Co., Ltd.
J ASCO FT/IR-5000 spectrometer. 1H NMR spectra were
recorded with a Varian Gemini 200 (200 MHz) and a Varian
VXR-500 (500 MHz) spectrometer. 13C NMR spectra were
obtained on a Varian Gemini 200 (50 MHz) spectrometer.
HPLC was executed with a Waters HPLC instrument equipped
with a 600 E system controller, a Waters 486 tunable absor-
bance detector, and a Hitachi D-2500 chromatointegrator.
Elemental analyses were performed on a Perkin-Elmer 2400
Series II CHNS/O analyzer. Cyclic voltammetry was carried
out with BAS 100B/W & CV-50W.
DMF and NMP were distilled over calcium hydride under
reduced pressure and stored over 4A molecular sieves. Metha-
nol, dichloromethane, and THF were distilled over magnesium,
phosphorus pentoxide, and sodium/benzophenone ketyl, re-
spectively. All other reagents were purchased from com-
mercial source and used without further purification.
Cyclic Volta m m etr y of 3,4-Dich lor o-2-bu ten oa te 6a . A
typical three-electrode cell fitted with a platinum disk as a
working electrode, a platinum wire as an auxiliary electrode,
and an Ag/Ag+ couple as a reference electrode was used. The
working electrode was polished with alumina before use.
Cyclic voltammetry was carried out in a solution of 6a (10.0
mg, 0.02 mmol) in DMF (4 mL) containing Et4NOTs (12.0 mg,
0.04 mmol). The potential was swept at the rate of 100 mV/s
until the electrode current was limited (+0.4 to -2.5 V).
p-Meth oxyben zyl (E)-3,4-Dich lor o-2-[2-oxo-3-(p h en yl-
a ce t a m id o)-4-[(p h e n ylsu lfon yl)t h io]a ze t id in -1-yl]-2-
bu ten oa te (6a ). A mixture of lithium chloride (2.8 g, 65.52
mmol) and aluminum(III) chloride (2.6 g, 19.66 mmol) in NMP
(100 mL) was stirred for 5 min at room temperature. To the
mixture was added a solution of triflate 6b (5.0 g, 6.55 mmol)
in NMP (25 mL) over a 1 h period at this temperature under
stirring. After being stirred for additional 4 h, the reaction
mixture was poured into ice-cold water and extracted with
ethyl acetate. The combined extracts were washed twice with
water and successively with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was puri-
fied by column chromatography (SiO2, benzene/ethyl acetate
) 5/1) to afford 6a (3.53 g, 83%) as a white solid: IR (KBr)
Con clu sion
3280, 1790, 1680, 1644 cm-1 1H NMR (500 MHz, CDCl3) δ
;
3.51 (s, 2H), 3.68 (s, 3H), 4.20 (d, J ) 12.9 Hz, 1H), 4.59 (d, J
) 12.9 Hz, 1H), 4.64 (dd, J ) 5.5, 7.0 Hz, 1H), 5.01 (d, J )
We developed new synthetic schemes of both the 2-exo-
methylenepenam 1 and the 3-chloro-∆3-cephem 2 based

2-exo-Methylenepenam and 3-Chloro-∆3-cephem
J . Org. Chem., Vol. 62, No. 11, 1997 3615
Ta ble 5. Red u ctive 1,2-Elim in a tion /Ch lor id e Ion -Ad d ition /Cycliza tion of 6 to 3-ch lor o-∆3-cep h em 2a
yield, %b
metal salt
metal
entry
sub.
(molar equiv)
(molar equiv)
additive
time, h
2
3
1
12
13
1
2c
3c
4
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6c
AlCl3 (0.5)
AlCl3 (1.0)
Al (10)
8.8
2.6
6.6
6.5
2.0
4.5
4.5
6.2
3.9
3.9
3.0
7.6
10
72
3
1
9
Al (10)
Al (10)
Al (10)
Al (10)
Al (10)
Al (10)
Al (5.0)
Al (10)
Al (0.5)
Al (10)
Al (10)
Al (10)
TiCl4 (0.5)d
AlBr3 (0.5)
CrCl3 (0.5)
FeCl3 (0.5)
NiCl3 (0.5)
AlCl3 (1.0)
AlCl3 (0.5)
PbBr2 (1.0)
AlCl3 (0.5)
AlCl3 (0.5)
AlCl3 (0.5)
41
4
2
91
3
1
21
2
1
1
5
6c
7c
8c
9e,f
10
11
12
13
14
5
13
LiCl (10 molar equiv)
LiCl (10 molar equiv)
MS-4A (25 mg)
63
14
5
2
1
23
2
1
1
80 (77)g
69
4
6
3
3
20
7
MS-4A (25 mg)
MS-4A (25 mg)
7.6
76
a
b
All reactions were carried out with 6 (100 mg) in NMP at room temperature unless otherwise noted. Determined by HPLC; see
footnote b in Table 2. c Most of the 6a was recovered. 1.54 M solution of CH2Cl2 was used. e 6a was recovered in 56% field. f The reaction
was carried out in DMF. Isolated yield after column chromatography (SiO2).
d
g
Sch em e 5
F igu r e 2. Time course of the transformation of 6a to 2 in an
AlCl3/Al/4A molecular sieves system (Table 5, entry 12).
Sch em e 6
7.63 (m, 12H); 13C NMR (50 MHz, CDCl3) δ 42.8, 44.7, 55.2,
62.5, 68.1, 70.9, 114.1, 121.1, 126.5, 126.6, 127.9, 128.3, 129.3
129.5, 129.5, 130.5, 133.2, 134.3, 144.5, 146.4, 160.0, 160.3,
163.8, 173.3. Anal. Calcd for C29H26Cl2N2O7S2: C, 53.62; H,
4.03; N, 4.31. Found: C, 53.82; H, 4.24; N, 4.07.
p-Meth oxyben zyl (E)-3-Ch lor o-2-[2-oxo-3-(p h en yla ce-
t a m id o)-4-[(p h en ylsu lfon yl)t h io]a zet id in -1-yl]-4-[[(t r i-
flu or om eth yl)su lfon yl]oxy]-2-bu ten oa te (6b). To a solu-
tion of enol 912 (500 mg, 0.79 mmol) in dichloromethane (5 mL)
were successively added triethylamine (166 µL, 1.19 mmol)
and trifluoromethanesulfonic anhydride (200 µL, 1.19 mmol)
at -78 °C. After being stirred for 1 h, the reaction mixture
was poured into ice-cold aqueous 5% HCl and extracted with
dichloromethane. The combined extracts were washed with
water and brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chro-
matography (SiO2, benzene/ethyl acetate ) 8/1) to afford
11.9 Hz, 1H), 5.10 (d, J ) 11.9 Hz, 1H), 5.80 (d, J ) 5.5 Hz,
1H), 6.30 (d, J ) 7.0 Hz, 1H), 6.83 (d, J ) 8.7 Hz, 2H), 7.09-
triflate 6b (574 mg, 95%) as yellow foam: IR (KBr) 3290, 1770,
1685, 1650, 1330, 1140 cm-1 1H NMR (200 MHz, CDCl3) δ
;

3616 J . Org. Chem., Vol. 62, No. 11, 1997
Tanaka et al.
3.66 (s, 2H), 3.80 (s, 3H), 4.35 (d, J ) 14.1 Hz, 1H), 4.74 (d, J
) 14.1 Hz, 1H), 4.83 (dd, J ) 5.5, 7.1 Hz, 1H), 5.17 (d, J )
11.7 Hz, 1H), 5.22 (d, J ) 11.7 Hz, 1H), 5.96 (d, J ) 7.1 Hz,
1H), 6.00 (d, J ) 5.5 Hz, 1H), 6.90 (d, J ) 8.7 Hz, 2H) 7.21-
7.77 (m, 12H); 13C NMR (50 MHz, CDCl3) δ 39.8, 43.4, 55.9,
63.7, 69.4, 70.5, 114.6, 119.8, 126.6, 127.5, 128.6, 128.9, 130.0,
130.2, 131.8, 133.7, 134.9, 144.7, 152.1, 160.2, 160.7, 163.5,
163.6, 173.9. Anal. Calcd for C30H26ClF3N2O10S3: C, 47.21;
H, 3.43; N, 3.67. Found: C, 47.47; H, 3.49; N, 3.63.
p-Meth oxyben zyl 3-Ch lor o-4-[[(p-m eth ylp h en yl)su lfo-
n yl]oxy]-2-[2-oxo-3-(ph en ylacetam ido)-4-((ph en ylsu lfon yl)-
th io)a zetid in -1-yl]-2-bu ten oa te (6c). A mixture of enol 912
(500 mg, 0.79 mmol), tosyl chloride (227 mg, 1.19 mmol), and
sodium carbonate (252 mg, 2.34 mmol) in DMF (5 mL) was
stirred at 0 °C for 2 h. The reaction mixture was poured into
ice-cold aqueous 5% HCl and extracted with ethyl acetate. The
combined extracts were washed with brine, dried over Na2-
SO4, and concentrated under reduced pressure. The residue
was purified by column chromatography (SiO2, benzene/ethyl
acetate ) 15/1) to afford tosylates E-6c (554 mg, 89%) and Z-6c
(54 mg, 9%) as yellow foam.
3.71 mmol) in DMF (2 mL) was stirred for 3 min at room
temperature. To the mixture was added triflate 6b (100 mg,
0.13 mmol) under stirring. After being stirred for 1 h at room
temperature, the reaction mixture, whose HPLC (conditions:
column, YMC-Pack AM-312 ODS (6.0 φ × 150 mm); mobile
phase, CH3CN/H2O ) 65/35; flow rate, 1.0 mL/min) analysis
showed the formation of 1 (quantitative) based on an external
reference, was poured into ice-cold aqueous 5% HCl and
extracted with ethyl acetate. The combined extracts were
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chro-
matography (SiO2, benzene/ethyl acetate ) 5/1) to afford 1
(37.4 mg, 65%) as a white solid.
p-Meth oxyben zyl 7-(P h en yla ceta m id o)-3-[[(tr iflu or o-
m eth yl)su lfon yl]oxy]-∆3-cep h em -4-ca r boxyla te (10b): IR
(KBr) 3300, 1770, 1725, 1657, 1300 cm-1; 1H NMR (200 MHz,
CDCl3) δ 3.31 (d, J ) 18.5 Hz, 1H), 3.59 (d, J ) 18.5 Hz, 1H),
3.54 (s, 2H), 3.73 (s, 3H), 4.90 (d, J ) 5.1 Hz, 1H), 5.08 (d, J
) 11.7 Hz, 1H), 5.26 (d, J ) 11.7 Hz, 1H), 5.80 (dd, J ) 5.1,
9.1 Hz, 1H), 6.41 (d, J ) 9.1 Hz, 1H), 6.81 (d, J ) 8.8 Hz, 2H),
7.15-7.33 (m, 7H); 13C NMR (50 MHz, CDCl3) δ 25.30, 42.48,
54.60, 56.94, 58.14, 68.05, 113.28, 120.71, 122.52, 125.33,
127.05, 128.46, 128.66, 130.34, 132.96, 138.67, 157.95, 159.41,
164.56, 170.58.
Red u ctive 1,2-Elim in a tion /S-S Bon d F ission /Cycliza -
tion of Tosyla te 9c to 2-exo-Meth ylen ep en a m 1 by Use
of BiCl3/Al Red ox System (Ta ble 4, en tr y 8). A mixture
of bismuth(III) chloride (40.2 mg, 0.13 mmol) and aluminum
(17.2 mg, 0.64 mmol) in DMF (2 mL) was stirred for 3 min at
room temperature. To the mixture was added tosylate 6c (a
mixture of E- and Z-isomer, 100 mg, 0.13 mmol) with stirring.
After being stirred for 1.5 h at room temperature, the reaction
mixture, whose HPLC (conditions: column, YMC-Pack AM-
312 ODS (6.0 φ × 150 mm); mobile phase, CH3CN/H2O ) 65/
35; flow rate, 1.0 mL/min) analysis showed the formation of 1
(77%), 12 (2%), and recovered 6c (1%) based on external
references, was poured into ice-cold aqueous 5% HCl and
extracted with ethyl acetate. The combined extracts were
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chro-
matography (SiO2, benzene/ethyl acetate ) 5/1) to afford 1
(26.2 mg, 47%) as a white solid.
E-6c: IR (KBr) 3295, 1770, 1680, 1645, 1325 cm-1; 1H NMR
(200 MHz, CDCl3) δ 2.48 (s, 3H), 3.53 (s, 2H), 3.83 (s, 3H),
4.41 (d, J ) 13.1 Hz, 1H), 4.73 (d, J ) 13.1 Hz, 1H), 5.19 (s,
2H), 5.40 (dd, J ) 4.8, 9.1 Hz, 1H), 5.81 (d, J ) 4.8 Hz, 1H),
6.07 (d, J ) 9.1 Hz, 1H), 6.89 (d, J ) 8.7 Hz, 2H), 7.15-7.81
(m, 16H); 13C NMR (50 MHz, CDCl3) δ 21.7, 26.8, 42.9, 55.2,
57.5, 58.4, 67.9, 113.8, 121.9, 126.3, 127.3, 128.3, 128.8, 129.0,
129.2, 129.3, 130.0, 130.2, 130.3, 131.9, 133.9, 139.2, 146.1,
159.1, 159.7, 165.5, 171.2. Anal. Calcd for C36H33ClN2O10S3:
C, 55.06; H, 4.24; N, 3.57. Found: C, 54.95; H, 4.48; N, 3.38.
Z-6c: IR (KBr) 3300, 1770, 1680, 1640, 1325 cm-1; 1H NMR
(200 MHz, CDCl3) δ 2.43 (s, 3H), 3.63 (d, J ) 9.2 Hz, 1H),
3.65 (d, J ) 9.2 Hz, 1H), 3.81 (s, 3H), 3.93 (d, J ) 13.3 Hz,
1H), 4.54 (d, J ) 13.3 Hz, 1H), 4.84 (dd, J ) 5.5, 7.0 Hz, 1H),
5.02 (s, 2H), 5.90 (d, J ) 5.5 Hz, 1H), 5.98 (d, J ) 7.0 Hz, 1H),
6.92 (d, J ) 8.7 Hz, 2H), 7.29-7.81 (m, 16H); 13C NMR (50
MHz, CDCl3) δ 21.7, 26.8, 42.9, 55.2, 57.5, 58.4, 67.9, 113.8,
121.9, 126.3, 127.3, 128.3, 128.8, 129.0, 129.2, 129.3, 130.0,
130.2, 130.3, 131.9, 133.9, 139.2, 146.1, 159.1, 159.7, 165.5,
171.2. Anal. Calcd for C36H33ClN2O10S3: C, 55.06; H, 4.24;
N, 3.57. Found: C, 55.00; H, 4.53; N, 3.50.
Red u ctive 1,2-Elim in a tion /S-S Bon d F ission /Cycliza -
tion of 3,4-Dich lor o-2-bu ten oa te 6a to 2-exo-Meth yl-
en ep en a m 1 by Use of th e P bBr 2/Al Red ox System (Ta ble
2, en tr y 15). A mixture of lead(II) bromide (100 mg, 0.27
mmol) and aluminum (100 mg, 3.71 mmol) in DMF (2 mL)
was stirred for 3 min at room temperature. To the mixture
was added 3,4-dichloro-2-butenoate 6a (100 mg, 0.15 mmol)
under stirring. After being stirred for 1 h at room tempera-
ture, the reaction mixture, whose HPLC (conditions: column,
YMC-Pack AM-312 ODS (6.0 φ × 150 mm); mobile phase, CH3-
CN/H2O ) 65/35; flow rate, 1.0 mL/min) analysis showed the
formation of 1 (quantitative) based on an external reference,
was poured into ice-cold aqueous 5% HCl and extracted with
ethyl acetate. The combined extracts were washed with brine,
dried over Na2SO4, and concentrated under reduced pressure.
The residue was purified by column chromatography (SiO2,
benzene/ethyl acetate ) 5/1) to afford 1 (38.5 mg, 57%) as a
white solid.
p-Meth oxyben zyl 3-[[(p-m eth ylp h en yl)su lfon yl]oxy]-
7-(p h en yla ceta m id o)-∆3-cep h em -4-ca r boxyla te (10c): IR
(KBr) 3350, 1776, 1675, 1650, 1325 cm-1; 1H NMR (200 MHz,
CDCl3) δ 2.46 (s, 3H), 3.31 (d, J ) 18.7 Hz, 1H), 3.51 (d, J )
18.7 Hz, 1H), 3.57 (s, 2H), 3.78 (s, 3H), 4.95 (d, J ) 4.9 Hz,
1H), 5.00 (s, 2H), 5.79 (dd, J ) 4.9, 9.1 Hz, 1H), 6.00 (d, J )
9.1 Hz, 1H), 6.84 (d, J ) 8.7 Hz, 2H), 7.19-7.36 (m, 9H), 7.73
(d, J ) 8.4 Hz, 2H); 13C NMR (50 MHz, CDCl3) δ 21.1, 26.3,
42.5, 54.6, 56.9, 57.9, 67.3, 113.2, 121.3, 125.7, 126.9, 127.8,
128.4, 128.7, 129.4, 129.8, 131.3, 133.1, 138.4, 145.6, 158.5,
159.2, 164.6, 170.5. Anal. Calcd for C30H28N2O8S2: C, 59.20;
H, 4.64; N, 4.60. Found: C, 59.15; H, 4.62; N, 4.54.
p-Met h oxyb en zyl 7-(p h en yla cet a m id o)-∆3-cep h em -4-
1
ca r boxyla te (11): IR (KBr) 3250, 1776, 1731, 1657 cm-1; H
NMR (200 MHz, CDCl3) δ 3.33 (dd, J ) 6.2, 19.3 Hz, 1H), 3.55
(dd, J ) 2.6, 19.3 Hz, 1H), 3.64 (d, J ) 16.2 Hz, 1H), 3.67 (d,
J ) 16.2 Hz, 1H), 3.80 (s, 3H), 4.91 (d, J ) 4.9 Hz, 1H), 5.18
(d, J ) 12.0 Hz, 1H), 5.21 (d, J ) 12.0 Hz, 1H), 5.87 (dd, J )
4.9, 9.2 Hz, 1H), 6.07 (d, J ) 9.2 Hz, 1H), 6.50 (dd, J ) 2.6,
6.2 Hz, 1H), 6.88 (d, J ) 8.7 Hz, 2H), 7.22-7.41 (m, 7H); 13C
NMR (50 MHz, CDCl3) δ 24.7, 43.9, 55.9, 57.5, 60.2, 68.2,
114.6, 120.4, 127.7, 128.3, 128.6, 129.8, 130.1, 131.0, 134.3,
160.1, 162.0, 165.0, 171.8; Anal. Calcd for C23H22N2O5S: C,
63.00; H, 5.06; N, 6.39. Found: C, 62.81; H, 4.99; N, 6.29%.
Red u ctive 1,2-Elim in a tion /Ch lor id e Ion -Ad d ition /Cy-
cliza tion of 3,4-Dich lor o-2-bu ten oa te 6a in to 3-Ch lor o-
∆3-cep h em 2 by Use of AlCl3/Al Red ox System (Ta ble 5,
en tr y 12). In a 10 mL two-necked flask fitted with a three-
way stopcock were placed aluminum(III) chloride (10.3 mg,
0.08 mmol), aluminum (41.5 mg, 1.54 mmol), and 4A molecular
sieves (25 mg). The flask was purged with argon and to the
mixture was added NMP (0.5 mL) under stirring. After being
stirred for 15 min at room temperature, a solution of the 3,4-
dichloro-2-butenoate 6a (100 mg, 0.15 mmol) in NMP (1.5 mL)
p-Meth oxyben zyl 2-exo-m eth ylen e-6-(p h en yla ceta m i-
d o)p en a m -3-ca r boxyla te (1): IR (KBr) 3309, 1801, 1743,
1
1666, 1627, 1531 cm-1; H NMR (200 MHz, CDCl3) δ 3.63 (s,
2H), 3.82 (s, 3H), 5.12 (s, 2H), 5.18 (dd, J ) 1.5, 1.7 Hz, 1H),
5.24 (dd, J ) 1.5, 2.2 Hz, 1H), 5.35 (dd, J ) 1.7, 2.2 Hz, 1H),
5.59 (d, J ) 4.0 Hz, 1H), 5.75 (dd, J ) 4.0, 9.3 Hz, 1H), 6.13
(d, J ) 9.3 Hz, 1H), 6.89 (d, J ) 8.7 Hz, 2H), 7.21-7.41 (m,
7H); 13C NMR (50 MHz, CDCl3) δ 43.3, 55.3, 60.0, 64.5, 67.8,
69.5, 108.0, 114.1, 126.8, 127.7, 129.1, 129.4, 130.2, 133.6,
146.1, 159.9, 166.9, 170.4, 172.4. Anal. Calcd for
C23H22N2O5S: C, 63.00; H, 5.06; N, 6.39. Found: C, 63.08; H,
4.94; N, 6.32.
Red u ctive 1,2-Elim in a tion /S-S Bon d F ission /Cycliza -
tion of Tr ifla te 6b to 2-exo-Meth ylen ep en a m 1 by Use of
P bBr 2/Al Red ox System (Ta ble 4, en tr y 3). A mixture of
lead(II) bromide (100 mg, 0.27 mmol) and aluminum (100 mg,

2-exo-Methylenepenam and 3-Chloro-∆3-cephem
J . Org. Chem., Vol. 62, No. 11, 1997 3617
was added under stirring. After being stirred for additional
7.6 h at room temperature, HPLC (conditions: column, YMC-
Pack AM-312 ODS (6.0 φ × 150 mm); mobile phase, CH3CN/
H2O ) 65/35; flow rate, 1.0 mL/min) analysis of the reaction
mixture showed the formation of 2 (80%), 3 (4%), 1 (2%), 12
(3%), and 13 (1%) based on external references. The mixture
was poured into ice-cold aqueous 5% HCl and extracted with
ethyl acetate. The combined extracts were washed with brine,
dried over Na2SO4, and concentrated under reduced pressure.
The residue was purified by column chromatography (SiO2,
benzene/ethyl acetate ) 8/1) to afford 2 (56 mg, 77%) as white
solids.
1740, 1682, 1661, 1325, 1151 cm-1; 1H NMR (200 MHz, CDCl3)
δ 3.34 (d, J ) 17.7 Hz, 1H), 3.48 (d, J ) 17.7 Hz, 1H), 3.59 (d,
J ) 15.1 Hz, 1H), 3.62 (d, J ) 15.1 Hz, 1H), 3.82 (s, 3H), 4.92
(d, J ) 5.2 Hz, 1H), 5.35 (s, 2H), 5.86 (dd, J ) 5.2, 9.1 Hz,
1H), 6.01 (d, J ) 9.1 Hz, 1H), 6.91 (d, J ) 8.6 Hz, 2H), 7.19-
7.68 (m, 10H), 7.93 (d, J ) 7.5 Hz, 2H); 13C NMR (50 MHz,
CDCl3) δ 24.2, 43.2, 55.3, 59.1, 60.2, 69.4, 113.9, 114.0, 118.7,
126.1, 127.8, 128.2, 129.1, 129.2, 129.3, 129.4, 130.6, 131.1,
133.3, 133.9, 134.0, 138.6, 160.1, 161.0, 163.9, 171.0. Anal.
Calcd for C29H26N2O7S2: C, 60.19; H, 4.53; N, 4.84. Found:
C, 59.94; H, 4.65; N, 4.72.
Red u ctive S-S Bon d F ission /Cycliza tion of Allen eca r -
boxyla te 3 to 2-exo-Meth ylen ep en a m 1 by Use of Al/
P bBr 2/DMF System . A mixture of lead(II) bromide (26 mg,
0.07 mmol) and aluminum (12.5 mg, 0.46 mmol) in DMF (0.8
mL) was stirred for 3 min at room temperature. To the
mixture was added allenecarboxylate 3 (35 mg, 0.06 mmol)
under stirring. After being stirred for 1.3 h at room temper-
ature, the reaction mixture was poured into ice-cold aqueous
5% HCl and extracted with ethyl acetate. The combined
extracts were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was puri-
fied by column chromatography (SiO2, benzene/ethyl acetate
) 5/1) to afford 1 (10.8 mg, 41%) and 3 (3.4 mg, 10%).
Syn th esis of 3-Ch lor o-∆3-cep h em 2 th r ou gh Ch lor id e
Ion -Ad d ition /Cycliza tion of Allen eca r boxyla te 3 w ith
Lith iu m Ch lor id e in th e P r esen ce of Alu m in u m Ch lo-
r id e. Into a mixture of aluminum(III) chloride (30.7 mg, 0.23
mmol) and lithium chloride (51.5 mg, 1.2 mmol) in NMP (1.0
mL) was added a solution of the allenecarboxylate 3 (66.7 mg,
0.12 mmol) in NMP (1.0 mL) at room temperature. After being
stirred for 2.5 h, the mixture was poured into water and
extracted with ethyl acetate. The extracts were washed with
brine, dried over Na2SO4, and concentrated under reduced
pressure. The crude product was purified by column chroma-
tography (SiO2, benzene/ethyl acetate ) 8/1) to afford 2 (38.7
mg, 71%) and 12 (4.2 mg, 6%).
p -Met h oxyb en zyl 3-ch lor o-7-(p h en yla cet a m id o)-∆3-
cep h em -4-ca r boxyla te (2): IR (KBr) 3352, 1776, 1727, 1665,
1517, 1248, 1223, 1176 cm-1 1H NMR (200 MHz, CDCl3) δ
;
3.45 (d, J ) 18.8 Hz, 1H), 3.70 (d, J ) 18.8 Hz, 1H), 3.60 (s,
2H), 3.78 (s, 3H), 4.94 (d, J ) 4.8 Hz, 1H), 5.20 (s, 2H), 5.81
(dd, J ) 4.8, 9.2 Hz, 1H), 6.62 (d, J ) 9.2 Hz, 1H), 6.87 (d, J
) 8.8 Hz, 2H), 7.20-7.40 (m, 7H); 13C NMR (50 MHz, CDCl3)
δ 31.5, 43.6, 55.8, 57.8, 59.4, 68.7, 114.5, 124.7, 125.7, 127.1,
128.0, 129.5, 129.8, 131.2, 134.5, 160.4, 160.6, 165.3, 172.0.
Anal. Calcd for C23H21ClN2O5S: C, 58.41; H, 4.48; N, 5.92.
Found: C, 58.25; H, 4.50; N, 5.84.
p-Meth oxyben zyl 3-Ch lor o-2-[2-oxo-3-(p h en yla ceta m i-
do)-4-[(ph en ylsu lfon yl)th io]azetidin -1-yl]-2-bu ten oate (12).
1
E-12: IR (CHCl3) 3300, 1786, 1724, 1670 cm-1; H NMR (200
MHz, CDCl3) δ 2.51 (s, 3H), 3.57 (s, 2H), 3.81 (s, 3H), 5.10 (d,
J ) 11.8 Hz, 1H), 5.16 (d, J ) 11.8 Hz, 1H), 5.21 (dd, J ) 5.1,
8.0 Hz, 1H), 5.77 (d, J ) 5.1 Hz, 1H), 5.96 (d, J ) 8.0 Hz, 1H),
6.93 (d, J ) 8.7 Hz, 2H), 7.19-7.79 (m, 12H); 13C NMR (50
MHz, CDCl3) δ 25.2, 43.4, 55.8, 61.5, 68.3, 71.3, 114.7, 121.3,
127.2, 127.3, 128.2, 129.6, 129.8, 130.0, 131.1, 134.1, 134.6,
145.4, 154.1, 160.5, 161.8, 164.0, 172.2. Anal. Calcd for
C29H27ClN2O7S2: C, 56.63; H, 4.42; N, 4.55. Found: C, 56.61;
H, 4.41; N, 4.40.
Z-12: IR (CHCl3) 3300, 1786, 1724, 1670 cm-1; 1H NMR (200
MHz, CDCl3) δ 2.34 (s, 3H), 3.64 (s, 2H), 3.80 (s, 3H), 4.70
(dd, J ) 5.5, 7.2 Hz, 1H), 5.08, (d, J ) 11.8 Hz, 1H), 5.17 (d,
J ) 11.8 Hz, 1H), 5.83 (d, J ) 5.5 Hz, 1H), 5.97 (d, J ) 7.2 Hz,
1H), 6.92 (d, J ) 8.8 Hz, 2H), 7.11-7.71 (m, 12H); 13C NMR
(50 MHz, CDCl3) δ 25.1, 43.4, 55.9, 61.3, 68.2, 71.2, 114.4,
121.3, 127.2, 127.4, 128.2, 129.6, 129.8, 130.0, 131.1, 134.1,
134.6, 145.4, 154.1, 161.0, 161.8, 164.0, 172.3. Anal. Calcd
for C29H27ClN2O7S2: C, 56.63; H, 4.42; N, 4.55. Found: C,
56.52; H, 4.66; N, 4.39.
Ack n ow led gm en t. We acknowledge financial sup-
port by Grants-in-Aid for Scientific Research (06453140
and 05403025) from the Ministry of Education, Science,
Culture, and Sports of J apan. The SC-NMR Laboratory
of Okayama University is thanked for obtaining NMR
spectra.
p-Meth oxyben zyl 7-(p h en yla ceta m id o)-3-(p h en ylsu l-
fon yl)-∆3-cep h em -4-ca r boxyla te (13): IR (KBr) 3310, 1800,
J O970051N