Reductive cross-coupling of 3-substituted Δ3-cephems with alkenyl halides in an Al/PbBr2/NiBr2(bpy) triplemetal redox system. Synthesis of 3-alkenyl-Δ3-cephems

Article abstract of DOI:10.1021/jo001429b

Synthesis of 3-alkenyl-Δ³-cephems was performed successfully by cross-coupling 3-(trifluoromethylsulfonyloxy or chloro)-Δ³-cephem with alkenyl halides, e.g., vihyl bromide, trans-1-bromo-1-propene, and trans-β-bromostyrene in an Al/cat·PbBr₂/cat·NiBr₂(bpy)/NMP (or DMF) system. Reduction of 3-(trifluoromethylsulfonyloxy)-Δ³-cephem into norcephalosporin was also achieved by a similar reaction in the presence of 5 molar equiv of water. Scope and a plausible mechanism of the Al/Pb/Ni triplemetal-redox promoted reactions are discussed.

Full text of DOI:10.1021/jo001429b

570
J . Org. Chem. 2001, 66, 570-577
Red u ctive Cr oss-Cou p lin g of 3-Su bstitu ted ∆3-Cep h em s w ith
Alk en yl Ha lid es in a n Al/P bBr 2/NiBr 2(bp y) Tr ip lem eta l Red ox
System . Syn th esis of 3-Alk en yl-∆3-cep h em s
Hideo Tanaka,* J infeng Zhao, and Hiroshi Kumase
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Tsushima-naka 3-1-1,
Okayama 700-8530, J apan
tanaka95@cc.okayama-u.ac.jp
Received October 2, 2000
Synthesis of 3-alkenyl-∆3-cephems was performed successfully by cross-coupling 3-(trifluorometh-
ylsulfonyloxy or chloro)-∆3-cephem with alkenyl halides, e.g., vinyl bromide, trans-1-bromo-1-
propene, and trans-â-bromostyrene in an Al/cat‚PbBr2/cat‚NiBr2(bpy)/NMP (or DMF) system.
Reduction of 3-(trifluoromethylsulfonyloxy)-∆3-cephem into norcephalosporin was also achieved by
a similar reaction in the presence of 5 molar equiv of water. Scope and a plausible mechanism of
the Al/Pb/Ni triplemetal-redox promoted reactions are discussed.
Sch em e 1
In tr od u ction
â-Lactam antibiotics represent the most widely pre-
scribed drugs in medicine because of their high antibac-
terial activities against many pathogenic bacteria as well
as exceptionally low toxicity toward hosts by exerting
their toxic effects on only peptidoglycan metabolism of a
bacterial cell wall.1 A wide variety of prominent cepha-
losporin antibiotics have been developed by chemical
modification of the (C)3-substituent as well as (C)7-amido
moiety of naturally occurring cephalosporins.2 Among
these, 3-alkenyl-∆3-cephems, e.g., 3-vinyl-∆3-cephem (Ce-
fixime) and 3-(Z)-propenyl-∆3-cephem (Cefprozil), have
met a great success particularly as potent orally active
drugs in antibacterial chemotherapy (Scheme 1).3
Convenient general methodologies for the synthesis of
cephems bearing C(3)-alkenyl substituents are not avail-
able, thereby hindering progress in this medicinally
important area. The hitherto disclosed procedures for
introduction of the C(3)-alkenyl substituents mainly rely
on Wittig reaction of 3-formyl-∆3-cephems with phospho-
ranes (route a) or 3-[(triphenylphosphoranylidene)meth-
yl]-∆3-cephems with aldehydes (route b), which, however,
invariably produces an E/Z mixture.4 Stereoselective
construction of the C(3)-alkenyl moieties has been achieved
by the reaction of 3-(trifluoromethylsulfonyloxy)-∆3-
cephem and its analogues with organotins in the presence
of a palladium catalyst5 and/or with organocuprate6
(route c). The scope of the reaction is rather limited and
the 3-alkenyl-∆3-cephems isolated are often contaminated
with the undesired ∆2-isomers, and we need tedious
(1) (a) Kammer, R. B. In Chemistry and Biology of â-Lactam
Antibiotics; Academic Press: New York, 1982; Vol. 3, p 287. (b)
Duerckheimer, W.; Blumbach, J .; Lattrell, R.; Scheunemann, K. H.
Angew. Chem., Int. Ed. Engl. 1985, 24, 180.
(2) (a) Duerckheimer, W.; Adam, F.; Fisher, G.; Kirrestetter, R. In
Advances in Drug Research; Duerckheimer, W., Ed.; Academic Press:
New York, 1988; Vol. 17, p 190. (b) Caprile, K. A. J . Vet. Pharmacol.
Therap. 1988, 11, 1.
(3) (a) Newall, C. E. In Recent Advances in the Chemistry of
â-Lactam Antibiotics; Bently, P. H., Southgate, R., Eds.; The Royal
Society of Chemistry: London, 1988; Special Publication No. 70, p 365.
(b) Sakagami, K.; Atsumi, K.; Yamamoto, Y.; Tamura, A.; Yoshida, T.;
Nishigata, K.; Fukatsu, A. Chem. Pharm. Bull. 1991, 39, 2433.
operations to prepare the required organotins or the
organocuprates before the reaction. Although other ap-
proaches to 3-alkenyl-∆3-cephems have been reported,7
the methods explored so far are not always satisfactory
in term of selectivity, versatility, yield, operational
simplicity, and manufacturing cost. Indeed, there still
remains a great demand for development of newly
10.1021/jo001429b CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/19/2000

Synthesis of 3-Alkenyl-∆3-cephems
J . Org. Chem., Vol. 66, No. 2, 2001 571
Sch em e 2
devised procedures for the introduction of the C(3)-
alkenyl substituents to fulfill the requirements in the
synthesis of the highly sophisticated cephalosporin an-
tibiotics.
Incidentally, aluminum is an ideal reducing reagent
because it is cheap, easy to handle, and able to release
enough electrons (3e-/atom). However, aluminum is not
frequently used in modern organic chemistry owing to
the lack of efficient electron transfer between aluminum
metal and organic substrates. Recently, various combina-
tions of aluminum metal and a catalytic amount of metal
salts have been developed and used as a powerful
reduction system for various synthetic purposes, wherein
aluminum acts as an electron pool (electron source) and
the metal salts work as an electron-transfer catalyst.8
The chemical behavior of the multimetal redox systems
is highly dependent on the nature of the metal salts
employed. In this connection, we developed an Al/PbBr2/
NiBr2(bpy) triplemetal redox system (bpy: 2,2′-bipyri-
dine) that could efficiently promote homocoupling reac-
tions of alkenyl and aryl halides through disproportiona-
tion of in situ generated alkenyl- and aryl-Ni(II) com-
plexes.9
In our continuing studies on the Al/PbBr2/NiBr2(bpy)
redox system, we found that the cross-coupling reaction
of 3-(trifluoromethylsulfonyloxy or chloro)-∆3-cephem 1
(X ) OTf or Cl) with alkenyl bromides 2 was performed
successfully in the Al/PbBr2/NiBr2(bpy) redox system to
afford the corresponding 3-alkenyl-∆3-cephems 3 (Scheme
2). This procedure could be operated successfully under
ambient conditions without use of any organometal
reagents, offering a new straightforward route to 3-al-
kenyl-∆3-cephems 3. Herein, we describe the new access
to 3-alkenyl-∆3-cephems 3 through alkenylation of 3-sub-
stituted ∆3-cephems 1 with alkenyl bromides 2 in the Al/
PbBr2/NiBr2(bpy) system and several attempts to utilize
the triplemetal redox system to synthesis of the ∆3-
cephems 3 baring carbon-based C(3)-substituents as well
as norcephalosporin 5.
(4) (a) Murphy, C. F.; Webber, J . A. In Cephalosporins and Penicil-
lins; Chemistry and Biology; Flynn, E. H., Ed.; Academic Press: New
York, 1972; p 134. (b) Scartazzini, R. Helv. Chim. Acta 1977, 60, 1510.
(c) Nishimura, S.; Yasuda, N.; Sasaki, H.; Matsumoto, Y.; Sakane, K.;
Takaya, T. J . Antibiot. 1989, 42, 159. (d) Kamachi, H.; Oka, M.; Narita,
Y.; Iimura, S.; Abe, S.; Yamashita, H.; Tomatsu, K. J . Antibiot. 1990,
43, 533. (e) Iwamatsu, K.; Atsumi, K.; Sakagami, K.; Ogino, H.;
Yoshida, T.; Tsuruoka, T.; Shibahara, S. J . Antibiot. 1990, 43, 1450.
(f) Pitlik, J .; Gunda, T. E.; Batta, G.; J eko, J . J . Chem. Soc., Perkin
Trans. 1 1994, 3043. (g) Hara, R.; Sakamoto, K.; Hisamichi, H.;
Nagano, N. J . Antibiot. 1996, 49, 1126. (h) Barendes, N. C. M. E.; Van
der Klein, P. A. M.; Verweij, J .; Witkamp, H. A.; Van Zoest, W. J .; De
Vroom, E. Synthesis 1998, 145. (i) Choi, K. I.; Cha, J . H.; Pae, A. N.;
Cho, Y. S.; Chang, M. H.; Koh, H. Y. J . Antibiot. 1998, 51, 1122.
(5) (a) Farina, V.; Baker, S. R.; Sapino, C. Tetrahedron Lett. 1988,
29, 6043. (b) Cook, G. K.; Hornback, W. J .; J ordan, C. L.; McDonald,
J . H.; Munroe, J . E. J . Org. Chem. 1989, 54, 5828. (c) Farina, V.; Baker,
S. R.; Benigni, D. A.; Hauck, S. I.; Sapino, C. J . Org. Chem. 1990, 55,
5833. (d) Roth, G. P.; Sapino, C. Tetrahedron Lett. 1991, 32, 4073. (e)
Farina, V.; Kant, J . Synlett 1994, 565. (f) Tanaka, H.; Sumida, S.; Torii,
S. Tetrahedron Lett. 1996, 37, 5967. (g) Tanaka, H.; Sumida, S.; Torii,
S. J . Org. Chem. 1997, 62, 3782. (h) Contento, M.; Da Col, M.; Galletti,
P.; Sandri, S.; Umani-Ronchi, A. Tetrahedron Lett. 1998, 39, 8743.
(6) (a) Peter, H.; Rodriguez, H.; Muller, B.; Sibral, W.; Bickel, H.
Helv. Chim. Acta 1974, 57, 2024. (b) Spry, D. O.; Bhala, A. R.
Heterocycles 1985, 23, 1901. (c) Spry, D. O.; Bhala, A. R. Heterocycles
1986, 24, 1799. (d) Kant, J .; Sapino, C.; Baker, S. R. Tetrahedron Lett.
1990, 31, 3389. (e) Kant, J . J . Org. Chem. 1993, 58, 2296.
(7) (a) Naito, T.; Hoshi, H.; Aburaki, S.; Abe, Y.; Okumura, J .;
Tomatsu, K.; Kawaguchi, H. J . Antibiot. 1987, 40, 991. (b) Kant, J .;
Farina, V.; Tetrahedron Lett. 1992, 33, 3563. (c) Tanaka, H.; Kam-
eyama, Y.; Sumida, S.; Torii, S. Tetrahedron Lett. 1992, 33, 7029. (d)
Tanaka, H.; Sumida, S.; Sorajo, K.; Torii, S. J . Chem. Soc., Chem.
Commun. 1994, 1461. (e) Nagano, N.; Itahana, H.; Hisamichi, H.;
Sakamoto, K.; Hara, R. Tetrahedron Lett. 1994, 35, 4577. (f) Kant, J .;
Roth, J . A.; Fuller, C. E.; Walker, D. G.; Benigni, D. A.; Farina, V. J .
Org. Chem. 1994, 59, 4956. (g) Tanaka, H.; Sumida, S.; Sorajo, K.;
Kameyma, Y.; Torii, S. J . Chem. Soc., Perkin. Trans. 1 1997, 637. (h)
Tanaka, H.; Tokumaru, Y.; Torii, S. Synlett 1999, 774. (i) Tanaka, H.;
Tokumaru, Y.; Torii, S. Heterocycles 2000, 52, 633.
Resu lts a n d Discu ssion
P r ep a r a tion of 3-(Tr iflu or om eth ylsu lfon yloxy)-
a n d 3-Ch lor o-∆3-cep h em s. 3-(Trifluoromethylsulfon-
yloxy)-∆3-cephem 1a was prepared by treatment of 3-hy-
droxy-∆3-cephem10 with trifluoromethanesulfonic anhy-
dride in dichloromethane containing diisopropylethyl-
amine at -78 °C for 0.5 h. 3-Chloro-∆3-cephem 1b was
prepared through several steps starting from readily
available penicillin G according to the procedure reported
previously.11 Preparation of 3-chloro-∆3-cephem 1b was
also achieved successfully by treatment of 1a with LiCl
in THF at room temperature for 24 h.
Rea ction of 3-(Tr iflu or om eth ylsu lfon yloxy)-∆3-
cep h em 1a w ith Vin yl Br om id e 2a in a n Al/P bBr 2/
NiBr 2(bp y) System . The cross-coupling reaction of
3-(trifluoromethylsulfonyloxy)-∆3-cephem 1a (X ) OTf)
with vinyl bromide 2a (R3, R4, R5 ) H, 5 molar equiv)
was carried out in N-methyl-2-pyrrolidinone (NMP) in
the presence of aluminum (7.5 molar equiv) and catalytic
(8) (a) Uneyama, K.; Kawakami, N.; Moriya, A.; Torii, S. J . Org.
Chem. 1985, 50, 5396. (b) Tanaka, H.; Yamashita, S.; Katayama, Y.;
Torii, S. Chem. Lett. 1986, 2043. (c) Tanaka, H.; Yamashita, S.;
Ikemoto, Y.; Torii, S. Tetrahedron Lett. 1988, 29, 1721. (d) Tanaka,
H.; Dhimane, H.; Fujita, H.; Torii, S. Tetrahedron lett. 1988, 29, 3811.
(e) Tanaka, H.; Inoue, K.; Pokorski, U.; Taniguchi, M.; Torii, S.
Tetrahedron Lett. 1990, 31, 3023. (f) Tanaka, H.; Nakahata, S.;
Watanabe, H.; Zhao, J .; Kuroboshi, M.; Torii, S. Inorg. Chim. Acta
1999, 296, 204. (g) Kuroboshi, M.; Tanaka, M.; Kishimoto, S.; Goto,
K.; Tanaka, H.; Torii, S. Tetrahedron Lett. 1999, 40, 2785, and
references therein.
(10) (a) Scartazzini, R.; Bickel, H. Helv. Chim. Acta 1974, 57, 1919.
(b) Tanaka, H.; Taniguchi, M.; Kameyama, Y.; Monnin, M.; Sasaoka,
M.; Shiroi, T.; Nagao, S.; Torii, S. Chem. Lett. 1990, 1867 and references
therein.
(11) Tanaka, H.; Sumida, S.; Nishioka, Y.; Kobayashi, N.; Tokumaru,
Y.; Kameyama, Y.; Torii, S. J . Org. Chem. 1997, 62, 3610.
(9) (a) Tanaka, H.; Kosaka, A.; Yamashita, S.; Morisaki, K.; Torii,
S. Tetrahedron Lett. 1989, 30, 1261. (b) Tanaka, H.; Sumida, S.;
Kobayashi, N.; Komatsu, N.; Torii, S. Inorg. Chim. Acta 1994, 222,
323.

572 J . Org. Chem., Vol. 66, No. 2, 2001
Tanaka et al.
Ta ble 3. Effect of th e Am ou n t of Vin yl Br om id ea
Ta ble 1. Cou p lin g of
3-(Tr iflu or om eth ylsu lfon yloxy)-∆3-cep h em a n d Vin yl
Br om id ea
yieldc (%)
entry
bromide 2a b (equiv)
3a
4
5
yieldb (%)
c
Alc
PbBr2
time
(h) 3a
1
2
3
4
5
6
1
2
3
4
5
8
39
45
60
63
78
75
19
21
17
12
15
16
13
12
10
12
6
entry (equiv) (equiv) NiBr2(bpy) solvent
4
5
1a
1
2
3
4
5
6
7
8
7.5
-
0.1
0.1
-
0.1
0.1
0.1
0.1
0.1
0.3
0.3
0.3
NMP
NMP
NMP
NMP
DMF
THF
0.7 85 10
6
6
6
0.3 78 15
1
1
4
83
80
59
7.5
7.5
7.5
7.5
7.5
7.5
-
6
0.3
0.3
0.3
0.3
6
a
85
78
Carried out with 1a (0.2 mmol), Al (1.5 mmol), PbBr2 (0.02
CH3CN
wet
mmol) and NiBr2(bpy) (0.06 mmol) in DMF (2 mL) at room
b
temperature. Molar equivalents based on 1a . c Determined by
3
2
-
75
DMFd
HPLC.
a
Carried out at room temperature with 1a (0.2 mmol) and 2a
b
Sch em e 3
(1.0 mmol) in the solvent (2 mL) indicated in the table. Deter-
mined by HPLC. c Molar equivalent(s) based on 1a . Containing
d
1 mmol (5 molar equiv) of water.
Ta ble 2. Cou p lin g of
3-(Tr iflu or om eth ylsu lfon yloxy)-∆3-cep h em a n d Vin yl
Br om id e in M/M′Xn /NiBr 2(bp y) System sa
yieldb (%)
metals (entries 6-10); thus, the yield of the desired
coupling product 3a decreased in the order: Al (78%) >
Mn (60%) > Zn (18%) > Pb (15%) > Sn, Mg (-).
entry
M
MXn
time (h)
3a
4
5
1a
1
2
3
4
5
6
7
8
Al
Al
Al
Al
PbBr2
PbCl2
BiCl3
SnCl2
CrCl2
PbBr2
PbBr2
PbBr2
PbBr2
PbBr2
0.3
0.3
1
1
1
0.3
0.3
1
0.1
0.3
78
69
40
16
15
17
20
6
2
20
27
The ratio of the products 3a , 4, and 5 was significantly
changed depending on the ratio of 3-(trifluoromethylsul-
fonyloxy)-∆3-cephem 1a and vinyl bromide 2a (Table 3).
When a mixture of 1a and 2a in a molar ratio of 1 to 1
(entry 1) was allowed to react in an Al/PbBr2/NiBr2(bpy)/
DMF system, a mixture of the cross-coupling product 3a
and homo-coupling product 4 in a ratio of 2:1 was formed
together with a small amount of 5 (13%). The ratio of 3a
to 4 increased up to 5:1 when a 5-fold excess amount of
2a was used (entry 5). Further increase of the amount
of vinyl bromide 2a up to an 8-fold excess resulted in no
significant change of the product ratio (entry 6). The yield
of norcephalosporin 5 was slightly decreased by increas-
ing the amount of vinyl bromide 2a .
51
88
80
5
Al
Sn
Zn
Pb
Mn
Mg
18
15
60
27
11
45
27
22
7
9
10c
a
Carried out with 1a (0.2 mmol) and 2a (1.0 mmol) in DMF (2
mL) in the presence of M (1.5 mmol), MXn (0.02 mmol), and
b
NiBr2(bpy) (0.06 mmol) at room temperature. Determined by
HPLC. c A complex mixture without detectable amounts of 1a , 3a ,
4, and 5 was obtained.
amounts of PbBr2 (0.1 molar equiv) and NiBr2(bpy) (0.3
molar equiv) at room temperature. After the mixture was
stirred for 0.7 h, workup of the mixture afforded 3-vinyl-
∆3-cephem 3a (85%) together with small amounts of
homocoupling product 4 (10%) and norcephalosporin 5
(4%) (Table 1, entry 1). The presence of aluminum, PbBr2
and NiBr2(bpy) is indispensable for the cross-coupling,
since a lack of any component of the combination resulted
in the recovery of 1a (59-83%) without formation of any
detectable amounts of 3a (Table 1, entries 2-4). Proper
choice of the solvent is also important; DMF could be used
without significant change of the products, affording the
desired product 3a (78%) together with 4 (15%) and 5
(6%) (entry 5), while in THF and acetonitrile (entries 6
and 7), no appreciable reaction occurred, resulting in the
recovery of most of 1a (85 and 78%, respectively).
Remarkable change of the products was observed when
the reaction was carried out in DMF containing a small
amount of water (5 molar equiv); thus, after stirring for
3 h, norcephalosporin 5 (75%) was mainly formed (entry
8).
The cross-coupling reaction of 3-(trifluoromethylsulfo-
nyloxy)-∆3-cephem 1a with vinyl bromide 2a was inves-
tigated by use of other combinations of low valent metal,
metal salt, and the Ni-catalyst (Table 2). In place of
PbBr2, PbCl2 could be used with only minor change of
the products yields (entry 2) while BiCl3 and SnCl2 were
less effective (entries 3 and 4) and CrCl2 could not
promote any appreciable reactions (entry 5). Aluminum
is the best choice among so far examined low valent
Although the reaction mechanism is not clear at
present, it is likely that Al(0)/Al(III), Pb(0)/Pb(II), and
Ni(0)/Ni(II) redox system promotes the transformation
of 3-(trifluoromethylsulfonyloxy)-∆3-cephem 1a to 3-vinyl-
∆3-cephem 3a . The Ni(0) complex would be initially
formed and then regenerated in the Al/PbBr2/NiBr2(bpy)
redox system, in which, aluminum would release the
required electrons (2e-) through a Pb(0)/Pb(II) redox
mediatory system as illustrated in Scheme 3.9 Direct
electron transfer from aluminum to Ni(II) complex would
not efficiently occur since no appreciable reaction oc-
curred in the absence of PbBr2 (Table 1, entry 3)
A plausible mechanism of thus-formed Ni(0) complex-
promoted cross-coupling of 3-(trifluoromethyl-sulfonyl-
oxy)-∆3-cephem 1a and vinyl bromide 2a is illustrated
in Scheme 4 (X ) OTf; R3, R4, and R5 ) H). The first
stage of the reaction would involve oxidative addition of
Ni(0) complex with 1a and 2a , affording Ni(II) complexes
6 and 7, respectively. Subsequent reaction of 6 and 7
would afford an intermediate 8 which would, in turn,
undergo reductive elimination to afford the cross-coupling
product 3a . On the other hand, disproportionation of Ni-
(II) complex 6, leading to a symmetrical Ni(II) complex
9, followed by the reductive elimination would afford the
homo-coupling product 4. Disproportionation of Ni(II)
complex 7 would also take place to generate the corre-
sponding homocoupling product (1,3-butadiene).

Synthesis of 3-Alkenyl-∆3-cephems
J . Org. Chem., Vol. 66, No. 2, 2001 573
Sch em e 4
3a was formed together with the homocoupling product
4 and norcephalosporin 5. After 20 min, the yield of
norcephalosporin 5 reached to maximum (25%) and then
gradually decreased. On the other hand, the cross-
coupling product 3a continuously increased throughout
the reaction even after the starting material 1a was
completely consumed (30 min). These facts suggest that
the oxidative addition of Ni(0) with 1a takes place more
efficiently than that with vinyl bromide 2a and a
considerable amount of the Ni(II) complex 6 is ac-
cumulated in the reaction mixture and gradually reacts
with the Ni(II) complex 7, affording the cross-coupling
product 3a . The Ni(II)-complex 6 was detected on HPLC
analysis as norcephalosporin 5 generated by hydrolysis
partly with moisture in the reaction media and mainly
during workup process. Homo-coupling of 6 through
symmetrical Ni(II) complex 9 seems less efficient than
the cross-coupling presumably due to the steric repulsion
between two bulky cephem moieties in 9. Notably, major
part of the homocoupling product 4 was formed at initial
20 min, at which period, the concentration of 6 would be
high enough to promote the homocoupling leading to 4.
Cr oss-Cou p lin g of 3-Ch lor o-∆3-cep h em 1b w ith
Vin yl Br om id e 2a in a n Al/P bBr 2/NiBr 2(bp y) Sys-
tem . As another access to 3-vinyl-∆3-cephem 3a , the
reaction of 3-chloro-∆3-cephem 1b (X ) Cl) with vinyl
bromide 2a was carried out in a manner similar to those
for 3-(trifluoromethylsulfonyloxy)-∆3-cephem 1a (Table 1,
entry 1). A mixture of 3-chloro-∆3-cephem 1b with 5
molar equiv of vinyl bromide 2a in NMP (or DMF) in the
presence of Al (7.5 molar equiv), PbBr2 (0.1 molar equiv),
and NiBr2(bpy) (0.3 molar equiv) was stirred at room
temperature for 1 h (or 0.3 h) to afford only 54% (or 40%)
yield of the desired product 3a together with considerable
amounts of 5 (22 or 15%) and recovered 1b (23 or 14%)
(Table 4, entries 1 and 2). Even when 10-fold excess of
vinyl bromide 2a was used, the yield of 3a was only
slightly increased to 50% (entry 3). It is interesting to
note that the homocoupling product 4 could not be
F igu r e 1. Time course of the cross-coupling of 3-(trifluoro-
methylsulfonyloxy)-∆3-cephem 1a and vinyl bromide 2a under
the same conditions as shown in Table 1, entry 1.
During the course of the reactions, Ni(0), Ni(II)BrX and
Ni(II)X2 (X ) OTf) complexes would be liberated. The Ni-
(0) complex would be used again for the formation of the
Ni(II) complexes 6 and 7 while the liberated Ni(II) salts,
e.g., Ni(II)BrX and Ni(II)X2, would be reduced through
two electron-uptake in the Al/Pb/Ni multiredox system
as described above (Scheme 3) and used for the genera-
tion of Ni(II)-complexes 6 and 7, completing the Ni(0)/
Ni(II) catalytic cycle.
The formation of norcephalosporin 5 is reasonably
understood by assuming hydrolysis of the intermediary
Ni(II) complex 6 with moisture of the reaction media.
Indeed, when the reaction was carried out in wet DMF
(Table 1, entry 8), norcephalosporin 5 was obtained
predominantly.
To obtain more insight of the cross coupling reaction
in the Al/PbBr2/NiBr2(bpy)/NMP system, the time-course
of the reaction was followed by HLPC (Figure 1). At the
initial stage of the reaction, the cross-coupling product

574 J . Org. Chem., Vol. 66, No. 2, 2001
Tanaka et al.
Ta ble 4. Rea ction of 3-Ch lor o-∆3-cep h em w ith Vin yl
Ta ble 5. Cr oss-Cou p lin g of
Br om id ea
3-(Tr iflu or om eth ylsu lfon yloxy)-∆3-cep h em a n d
Br om id esa
yieldb (%)
vinyl bromide
entry
2a (equiv)
solvent time (h) 3a
4
5
1a
1
2
3
4
5
5
5
10
NMP
DMF
DMF
NMP
DMF
1
54
40
50
85
59
22 23
15 14
0.3
0.5
1
17
14
22
7
1.5 × 4d
2 × 4d
1
6
a
Carried out with 1b (o.2 mmol), Al (1.5 mmol), PbBr2 (0.02
mmol), and NiBr2(bpy) (0.06 mmol) in the solvent (2 mL) at room
b
d
temperature. Determined by HPLC. c Recovered 1b. Portion-
wise addition at 10 min interval.
detected in the reactions of 1b. These results are reason-
ably explained by assuming that the oxidative addition
of Ni(0) complex with 3-chloro-∆3-cephem 1b would not
so efficiently occur as in the case of 3-(trifluoromethyl-
sulfonyloxy)-∆3-cephem 1a ; thus, the concentration of the
Ni(II) complex 6 (X ) Cl) seems not high enough for the
formation of an appreciable amount of the homocoupling
product 4, while the oxidative addition Ni(0) complex
with vinyl bromide 2a would take place predominantly
to generate a high concentration of the Ni(II) complex 7,
facilitating the disproportionation of the vinyl-Ni(II)
complex 7 leading to the corresponding homocoupling
product (1,3-butadiene). Consequently, most of the vinyl
bromide 2a would be consumed before the desired cross-
coupling reaction was completed.
A significant increase of the yield of the desired 3a was
attained by portionwise addition of vinyl bromide 2a
throughout the reaction period. Into a mixture of 1b, Al,
PbBr2, and NiBr2(bpy) (1:7.5:0.1:0.3 mol/mol) in NMP, 1.5
molar equiv of vinyl bromide 2a was added four times at
10 min intervals, affording 85% yields of the desired
product 3a (entry 4). A similar attempt in DMF also
resulted in a considerable increase of the yield of 3a
(entry 5).
Similar reactions with 3-(methylsulfonyloxy)- and 3-(p-
tolylsulfonyloxy)-∆3-cephem 1c (X ) OMs) and 1d (X )
OTs) were also attempted by portionwise addition of vinyl
bromide 2a (2 equiv × 4) in the Al (7.5 molar equiv)/PbBr2
(0.1 molar equiv)/NiBr2(bpy) (0.3 molar equiv)/NMP
system. The desired product 3a was, however, obtained
in only 28% and 2% yields together with recovered 1c
(36%) and 1d (76%), respectively, suggesting that meth-
ylsulfonyloxy and p-tolylsulfonyloxy groups are not reac-
tive enough for the generation of a significant amount of
the corresponding Ni(II) complexes 6.
Rea ction of 3-(Tr iflu or om eth ylsu lfon yloxy)-∆3-
cep h em 1a w ith Alk en yl, Ben zyl, a n d Ar yl Ha lid es
2b-i in a n Al/P bBr 2/NiBr 2(bp y) System . Application
of the Al/PbBr2/NiBr2(bpy)-promoted cross-coupling to
synthesis of various C(3)-alkenyl substituted ∆3-cephems
3 was investigated (Table 5, entries 1-5). The reaction
of the 3-(trifluoromethylsulfonyloxy)-∆3-cephem 1a with
trans-1-bromo-1-propene 2b (5 molar equiv) in the Al (7.5
molar equiv)/PbBr2 (0.1 molar equiv)/NiBr2(bpy) (0.3
molar equiv)/NMP system proceeded smoothly to afford
3-(trans-propeneyl)-∆3-cephem 3b in 74% yield (entry 1).
The cross-coupling of 1a with trans-â-bromostyrene 2c
was similarly performed to afford 3-styryl-∆3-cephem 3c
in 71% yield (entry 2). On the other hand, the reaction
of 1a with cis-1-bromo-1-propene 2d afforded no detect-
able amount of the 3-(cis-propeneyl)-∆3-cephem 3d but
its trans isomer 3b in 75% yield (entry 3). With 1-bromo-
a
Carried out with 1a (0.2 mmol) and 2 (1 mmol), Al (1.5 mmol),
PbBr2 (0.02 mmol), and NiBr2(bpy) (0.06 mmol) in NMP (2 mL)
at room temperature. b Determined by HPLC. c A complex mixture
d
involving a small amount of 5 (22%) was obtained. A complex
mixture involving 4 (28%) and 5 (7%) was obtained. e Carried out
in DMF (2 mL).
2-methylpropene 2e and 2-bromopropene 2f, no corre-
sponding alkenylation products 3e and 3f were obtained.
These failures would be attributed to the steric congestion
in the intermediates 8 owing to either the R- or cis-â-
substituent (CH3) of the alkenyl moieties, which would
severely inhibit the formation and/or the reductive
elimination of 8. The formation of the trans isomer 3b
from cis-1-bromopropene 2d can be explained on a similar
basis; thus, the formation of 8d and/or subsequent
reductive elimination would not be allowed to occur
because of the steric repulsion between the ∆3-cephem
moiety and â-methyl group of cis-propenyl moiety as
illustrated in Scheme 5. Isomerization of cis-propenyl-
Ni(II) complex 7d to the corresponding trans isomer 7b12
followed by the reaction with 6 and reductive elimination
(12) Similar cis/trans isomerization was partly observed in a homo-
coupling reaction of alkenyl halids through alkenyl-Ni(II) complexes:
Takagi, K.; Hayama, N. Chem. Lett. 1983, 637. See also ref 9a.

Synthesis of 3-Alkenyl-∆3-cephems
J . Org. Chem., Vol. 66, No. 2, 2001 575
Ta ble 6. Red u ction of
3-(Tr iflu or om eth ylsu lfon yloxy)-∆3-cep h em in Al/P bBr 2/
NiBr 2(bp y) System sa
Sch em e 5
yieldb (%)
entry NiBr2(bpy) (equiv) H2O (equiv) time (h)
4
5
1a
1
2
3
4
5
0.3
0.3
0.4
0.5
1
2
5
5
5
5
42
9
5
5
5
5
29 43
47 32
69
83
9
a
Carried out with 1a (o.2 mmol), Al (1.5 mmol), and PbBr2 (0.02
b
mmol) in NMP (2 mL) at room temperature. Determined by
HPLC.
Sch em e 6
and a small amount of norcephalosporin 5 (9%) (entry
1). When a similar reaction was carried out in the
presence of 5 molar equiv of water, even after 5 h, only
29% yield of norcephalosporin 5 was formed and, notably,
a significant amount of 1a (43%) was recovered (entry
2). At the stage of hydrolysis of the in situ generated Ni-
(II) complex 6, nickel(II) hydroxide (Ni(OH)OTf) would
be liberated, which seems not efficiently reduced to Ni-
(0) complex in the Al/PbBr2 redox system (Scheme 6);
indeed, increasing the amount of NiBr2(bpy) increased
the yield of 5 significantly (entries 3-5), and almost 1
molar equivalent of NiBr2(bpy) was required to complete
the reaction, affording 83% yield of 5.14 In all experiments
in wet NMP (entries 2-5), no detectable amount of the
homocoupling product 4 was formed, suggesting that
hydrolysis of the in situ generated Ni(II) complex 6 to 5
would smoothly proceed before the disproportionation
leading to 4 through the symmetrical Ni(II) complex 9.
of 8b would afford the trans-isomer 3b. The isomeriza-
tion of 8d to 8b is not completely excluded at present
while isomerization of 3d to 3b is not provable since the
cis isomer 3d , prepared by the reported procedure,5e could
survive (1 h) without cis/trans isomerization in the Al/
PbBr2/NiBr2(bpy) system.
Cross-coupling of the 3-(trifluoromethylsulfonyloxy)-
∆3-cephem 1a with benzyl and aryl bromides 2g-i in the
Al/PbBr2/NiBr2(bpy)/NMP(or DMF) system was briefly
investigated (Table 5, entries 6-8). The cross-coupling
of 1a with benzyl bromide 2g occurred in the Al/PbBr2/
NiBr2(bpy) system to afford 3-benzyl-∆3-cephem 3g (42%)
whereas with p-methoxyphenyl and 3-pyridyl bromides
2h and 2i, no appreciable cross-coupling products 3h and
3i were obtained, affording the homocoupling products
4 in 48 and 26% yield, respectively.
P r ep a r a tion of Nor cep h a losp or in . Norcephalospor-
in 5 is a potent precursor of an important class of
â-lactam antibiotics.13 The reduction of the 3-(trifluoro-
methylsulfonyloxy)-∆3-cephem 1a may offer a straight-
forward route to 5 and hence we investigated the reaction
of 1a in the Al/PbBr2/NiBr2(bpy)/wet NMP system (Table
6). At first, reaction of 1a with an Al/PbBr2/NiBr2(bpy)
combination (7.5/0.3/0.1 mol/mol) in dry NMP was carried
out at room temperature. After 2 h, most of 1a was
consumed, affording the homocoupling product 4 (42%)
Con clu sion
Cross-coupling of 3-(trifluoromethylsulfonyloxy)-∆3-
cephem 1a with vinyl bromide 2a could be performed
successfully in an Al/PbBr2/NiBr2(bpy) (7.5/0.1/0.3 mol/
mol)/NMP or DMF system to afford 3-vinyl-∆3-cephem
3a (78-85%). A similar cross-coupling of 3-chloro-∆3-
cephem 1b with vinyl bromide 2a was attained by
portionwise addition of vinyl bromide at 10 min interval.
A plausible reaction mechanism involving Ni(0)/Ni(II),
Pb(0)/Pb(II), and Al(0)/Al(III) redox-promoted reactions
(Scheme 4) is proposed, wherein oxidative addition of in
situ generated Ni(0) with 1 and 2a followed by the
(14) In contrast, the reduction of the 3-(trifluoromethylsulfonyloxy)-
∆3-cephem 1a in wet DMF in the presence of excess vinyl bromide 2a
(Table 1, entry 8) was successfuly performed by use of only 0.3 molar
equivalent of NiBr2(bpy). The result can be reasonably understood by
assuming that a significant amount of AlBr3 generated from the homo-
coupling of vinyl-Ni(II) bromide 7 would react with water to give Al-
(OH)3 and HBr. The latter would, in turn, react with the Ni(II) complex
6 to afford 5 and nickel bromide (NiBrOTf) which would be reduced to
the Ni(0) complex in the Al/PbBr2/NiBr2(bpy) system.
(13) (a) Yamanaka, H.; Kawabata, K.; Miyai, K.; Takasugi, H.;
Kamimura, T.; Mine, Y.; Takaya, T. J . Antibiot. 1986, 39, 101. (b)
Hamashima, Y.; Kubota, T.; Minami, K.; Ishikura, K.; Konoike, T.;
Yoshioka, M.; Yoshida, T.; Nakashimizu, H.; Motokawa, K. J . Antibiot.
1987, 40, 1468. (c) Tanaka, H.; Yamaguchi, Y.; Sumida, S.; Torii, S. J .
Chem. Soc., Chem. Commun. 1996, 2705 and references therein.

576 J . Org. Chem., Vol. 66, No. 2, 2001
Tanaka et al.
to afford 3-vinyl-∆3-cephem 3a (75 mg, 73%) together with
homo-coupling product 4 (5 mg, 5%) and norcephalosporin 5
(2 mg, 2%).
reaction of thus formed Ni(II) complexes 6 and 7 leading
to asymmetrical Ni(II) complex 8 and subsequent reduc-
tive elimination afford the cross-coupling product 3a . The
in situ generated Ni(0)-promoted reaction was success-
fully applied to the cross-coupling of 3-(trifluoromethyl-
sulfonyloxy)-∆3-cephem 1a with trans-1-alkenyl bromides
2b and 2c and benzyl bromide 2g but not with aryl
bromides 2h and 2i. Reduction of 3-(trifluoromethylsul-
fonyloxy)-∆3-cephem 1a to norcephalosporin 5 was also
achieved by the reaction in wet NMP in the presence of
Al, PbBr2, and NiBr2(bpy) (7.5/0.1/1 mol/mol).
3-Vin yl-∆3-cep h em 3a :5c IR (KBr) 3283, 3063, 3032, 2956,
1
1774, 1720, 1663, 1526, 1496 cm-1; H NMR (CDCl3) δ 3.48
(d, J ) 18.0 Hz, 1H), 3.59 (d, J ) 18.0 Hz, 1H), 3.63 (d, J )
14.9 Hz, 1H), 3.67 (d, J ) 14.9 Hz, 1H), 4.99 (d, J ) 4.8 Hz,
1H), 5.26 (d, J ) 11.3 Hz, 1H), 5.42 (d, J ) 17.9 Hz, 1H), 5.84
(dd, J ) 4.8, 9.2 Hz, 1H), 6.09 (d, J ) 8.9 Hz, 1H), 6.95 (s,
1H), 6.98 (dd, J ) 11.3, 17.9 Hz, 1H), 7.19-7.37 (m, 15H).
Hom ocou p lin g P r od u ct 4: IR (KBr) 3305, 1728, 1496
cm-1; 1H NMR (200 MHz, CDCl3) δ 3.03 (d, J ) 18.3 Hz, 2H),
3.63 (d, J ) 18.3 Hz, 2H), 3.61 (d, J ) 18.0 Hz, 2H), 3.66 (d,
J ) 18.0 Hz, 2H), 4.18 (d, J ) 5.0 Hz, 2H), 5.71 (dd, J ) 5.0,
9.1 Hz, 2H), 5.91 (d, J ) 9.1 Hz, 2H), 6.70 (s, 2H), 7.19-7.37
(m, 30H). Anal. Calcd for C56H46O8N4S2: C, 69.55; H, 4.79; N,
5.79. Found: C, 69.71; H, 4.93; N, 5.50.
Exp er im en ta l Section
IR spectra were obtained on a J apan Spectroscopic Co., Ltd.
J ASCO FT/IR-VALOR-III spectrometer in wavenumber (cm-1).
1H NMR spectra were recorded with a Varian Gemini 200 (200
MHz). The 1H NMR signals are expressed in ppm downfield
from internal tetramethylsilane (0 ppm). High-performance
liquid chromatography (HPLC) was executed with Shimadzu
HPLC instrument equipped with LC-10AT pump, SPD-6A UV
detector and C-R6A integrator. All HPLC analyses were
performed under the following conditions, column: YMC-Pack
AM-312 ODS-AM AM-312 (6.0 mm Φ × 150 mm); mobile
phase CH3CN/H2O ) 2/1; flow rate: 1.5 mL/min; detection:
UV 290 nm. Elemental analyses were performed on a Perkin-
Elmer 2400 Series II CHNS/O analyzer.
Nor cep h a losp or in 5:5c IR (KBr) 3295, 3065, 1782, 1713,
1
1653, 1534, 1496 cm-1; H NMR δ 3.36 (dd, J ) 6.1, 19.4 Hz,
1H), 3.38 (dd, J ) 2.7, 19.4 Hz, 1H), 3.63 (d, J ) 16.0 Hz, 1H),
3.68 (d, J ) 16.0 Hz, 1H), 4.93 (d, J ) 4.8 Hz, 1H), 5.90 (dd,
J ) 4.8, 9.4 Hz, 1H), 6.08 (d, J ) 9.4 Hz, 1H), 6.62 (dd, J )
2.7, 6.1 Hz, 1H), 6.94 (s, 1H), 7.22-7.46 (m, 15H).
Rea ction of 3-(Tr iflu or om eth ylsu lfon yloxy)-∆3-cep h -
em 1a w ith Vin yl Br om id e 2a in a n Al/P bBr 2/NiBr 2(bp y)/
Wet DMF System (Ta ble 1, En tr y 8). To a mixture of
3-(trifluoromethylsulfonyloxy)-∆3-cephem 1a (127 mg, 0.2
mmol), finely cut aluminum foils (41 mg, 1.5 mmol), PbBr2 (7
mg, 0.02 mmol), and NiBr2(bpy) (22 mg, 0.06 mmol) was added
a solution of vinyl bromide 2a (107 mg, 1.0 mmol) in DMF (2
mL) containing water (18 µL, 1.0 mmol) under argon atmo-
sphere. After being stirred for 3 h at room temperature, an
aliquot of the reaction mixture was submitted to HPLC
analysis, showing the presence of 3-vinyl-∆3-cephem 3a (2%)
and norcephalosporin 5 (75%). The mixture was diluted with
EtOAc (ca. 30 mL) and poured into ice cold aqueous 5% HCl
and extracted with EtOAc. The combined extracts were
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was chromatographed (silica
gel; EtOAc/toluene: 1/5) to afford 3-vinyl-∆3-cephem 3a (2 mg,
DMF, NMP, and CH3CN were distilled over calcium hydride
and stored over 4A molecular sieves. THF was distilled over
sodium and benzophenone before use. All other chemicals were
purchased from commercial sources and used without further
purification.
3-(Tr iflu or om eth ylsu lfon yloxy)-∆3-cep h em 1a . To a
mixture of 3-hydroxycephem10 (3.14 g, 6.26 mmol) and diiso-
propylethylamine (1.12 mL, 6.27 mmol) in dichloromethane
(40 mL) was added trifluoromethanesulfonic anhydride (1.27
mL, 7.49 mmol) at -78 °C. After being stirred at -78 °C for
30 min, the mixture was diluted with dichoromethane (300
mL), washed with water, and dried (MgSO4). After evaporation
of the solvents, the residue was triturated with ether to afford
3-(trifluoromethylsulfonyloxy)-∆3-cephem 1a (3.6 g, 91%) as
an amorphous solid whose 1H NMR and IR spectra are
identical with those of authentic sample.15
1
2%) and norcephalosporin 5 (72 mg, 74%) whose H NMR and
IR spectra are identical with those of the authentic samples
obtained above.
Rea ction of 3-Ch lor o-∆3-cep h em 1b w ith Vin yl Br o-
m id e 2a in a n Al/P bBr 2/NiBr 2(bp y)/NMP System (Ta ble
4, En tr y 4). To a mixture of 3-chloro-∆3-cephem 1b (105 mg,
0.2 mmol), finely cut aluminum foils (41 mg 1.5 mmol) PbBr2
(7 mg, 0.02 mmol), and NiBr2(bpy) (22 mg,0.06 mmol) was
added a solution of vinyl bromide 2a (32 mg, 0.3 mmol) in NMP
(2 mL) under argon atmosphere. After stirring for 10 min at
room temperature, a solution of vinyl bromide (32 mg, 0.3
mmol) in NMP (0.5 mL) was added three times at interval of
10 min. After being stirred for additional 30 min, an aliquot
of the reaction mixture was submitted to HPLC analysis
showing the presence of 3-vinyl-∆3-cephem 3a (85%) together
with norcephalosporin 5 (14%). The reaction mixture was
diluted with EtOAc (ca. 30 mL) and poured into ice-cold 5%
HCl aq. and extracted with EtOAc. The combined extracts
were washed with brine, dried (MgSO4) and concentrated
under reduced pressure. The residue was chromatographed
(silica gel; EtOAc/toluene: 1/5) to afford 3-vinyl-∆3-cephem 3a
3-Ch lor o-∆3-cep h em 1b. 3-Chloro-∆3-cephem 1b was pre-
pared according to the previously reported procedure.11 As an
alternative method,15 reaction of 3-(trifluoromethylsulfonyl-
oxy)-∆3-cephem 1a (1.66 g, 2.62 mmol) with LiCl (1.11 g, 26.2
mmol) in dry tetrahydrofuran (25 mL) was also carried out at
room temperature under argon atmosphere. After being stirred
for 24 h at room temperature, the mixture was poured into
water and extracted with EtOAc. The combined extracts were
washed with water and dried (MgSO4). Evaporation of the
solvents followed by trituration with ether afforded 3-chloro-
∆3-cephem 1b (1.29 g, 95%).
Rea ction of 3-(Tr iflu or om eth ylsu lfon yloxy)-∆3-cep h -
em 1a w ith Vin yl Br om id e 2a in a n Al/P bBr 2/NiBr 2(bp y)/
NMP System (Ta ble 1, En tr y 1). To a mixture of 3-(triflu-
oromethylsulfonyloxy)-∆3-cephem 1a (127 mg, 0.2 mmol), finely
cut aluminum foils (41 mg, 1.5 mmol), PbBr2 (7 mg, 0.02
mmol), and NiBr2(bpy) (22 mg, 0.06 mmol) was added a
solution of vinyl bromide (107 mg, 1.0 mmol) in NMP (2 mL)
under argon atmosphere. After being stirred for 20 min at
room temperature, an aliquot of the reaction mixture was
submitted to HPLC analysis, showing the presence of 3-vinyl-
∆3-cephem 3a (85%), homo-coupling product 4 (10%) and
norcephalosporin 5 (4%). The mixture was diluted with EtOAc
and poured into ice cold aqueous 5% HCl and extracted with
EtOAc. The combined extracts were washed with brine, dried
over MgSO4, and concentrated under reduced pressure. The
residue was chromatographed (silica gel; EtOAc/toluene: 1/5)
1
(68 mg, 67%) and norcephalosporin 5 (10 mg, 10%) whose H
NMR and IR spectra are identical with those of the authentic
samples obtained above.
Rea ction of 3-(Tr iflu or om eth ylsu lfon yloxy)-∆3-cep h -
em 1a w ith tr a n s-1-Br om o-1-p r op en e 2b in a n Al/P bBr 2/
NiBr 2(bp y) System (Ta ble 5, En tr y 1). To a mixture of
3-(trifluoromethylsulfonyloxy)-∆3-cephem 1a (127 mg, 0.2
mmol), finely cut aluminum foils (41 mg, 1.5 mmol), PbBr2 (7
mg, 0.02 mmol) and NiBr2(bpy) (22 mg, 0.06 mmol) in NMP
(2 mL) was added trans-1-bromo-1-propene 2b (85 µL, 1.0
mmol) under argon atmosphere. After being stirred for 1 h at
room temperature, an aliquot of the reaction mixture was
submitted to HPLC analysis, showing the presence of 3-(trans-
propenyl)-∆3-cephem 3b (74%) and norcephalosporin 5 (8%).
(15) Farina, V.; Baker, S. R.; Hauck, S. I. J . Org. Chem. 1989, 54,
4962.

Synthesis of 3-Alkenyl-∆3-cephems
J . Org. Chem., Vol. 66, No. 2, 2001 577
The reaction mixture was worked up in a manner similar to
those described above to afford 3-(trans-propenyl)-∆3-cephem
3b (66 mg, 63%) and norcephalosporin 5 (6 mg, 6%).
submitted to HPLC analysis, showing the presence of 3-(trans-
propenyl)-∆3-cephem 3b (75%) and the homocoupling product
4 (6%). The reaction mixture was worked up in a manner
similar to those described above to afford 3-(trans-propenyl)-
∆3-cephem 3b (66 mg, 63%) and homo-coupling product 4 (6
mg, 6%) whose 1H NMR and IR spectra are identical with those
of the authentic samples obtained above.
3-(tr a n s-P r op en yl)-∆3-cep h em 3b:7a IR (KBr) 3301, 3029,
1
1767, 1723, 1658 cm-1; H NMR (CDCl3) δ 1.76 (dd, J ) 1.6,
6.8 Hz, 3H), 3.35 (d, J ) 17.2 Hz, 1H), 3.49 (d, J ) 17.2 Hz,
1H), 3.58 (d, J ) 17.7 Hz, 1H), 3.68 (d, J ) 17.7 Hz, 1H), 4.96
(d, J ) 4.7 Hz, 1H), 5.77 (dd, J ) 4.7, 8.9 Hz, 1H), 5.93 (dd, J
) 6.8, 15.0 Hz, 1H), 6.35 (d, J ) 8.9 Hz, 1H), 6.81 (dd, J )
15.0, 1.6 Hz, 1H), 6.95 (s, 1H), 7.26-7.45 (m, 15H).
Rea ction of 3-(Tr iflu or om eth ylsu lfon yloxy)-∆3-cep h -
em 1a w ith Ben zyl Br om id e 2g in a n Al/P bBr 2/NiBr 2-
(bp y)/DMF System (Ta ble 5, En tr y 6). To a mixture of
3-(trifluoromethylsulfonyloxy)-∆3-cephem 1a (127 mg, 0.2
mmol), finely cut aluminum foils (41 mg, 1.5 mmol), PbBr2 (7
mg, 0.02 mmol) and NiBr2(bpy) (22 mg, 0.06 mmol) in DMF
(2 mL) was added benzyl bromide 2g (0.12 mL, 1.0 mmol)
under argon atmosphere. After the mixture was stirred for 18
min at room temperature, an aliquot of the reaction mixture
was submitted to HPLC analysis, showing the presence of
3-benzyl-∆3-cephem 3g (42%). The mixture was worked up in
a manner similar to those described above to afford 3-benzyl-
∆3-cephem 3g (44 mg, 38%): IR (KBr) 3281, 3063, 3031, 2964,
Rea ction of 3-(Tr iflu or om eth ylsu lfon yloxy)-∆3-cep h -
em 1a w ith tr a n s-â-Br om ostyr en e 2c in a n Al/P bBr 2/
NiBr 2(bp y)/NMP System (Ta ble 5, En tr y 2). To a mixture
of 3-(trifluoromethylsulfonyloxy)-∆3-cephem 1a (127 mg, 0.2
mmol), finely cut aluminum foils (41 mg, 1.5 mmol), PbBr2 (7
mg, 0.02 mmol), and NiBr2(bpy) (22 mg, 0.06 mmol) in NMP
(2 mL) was added trans-â-bromostyrene 2c (0.13 mL, 1.0
mmol) under argon atmosphere. After stirring for 60 min. at
room temperature, an aliquot of the reaction mixture was
submitted to HPLC analysis, showing the presence of 3-styryl-
∆3-cephem 3c (71%), the homo-coupling product 4 (14%), and
norcephalosporin 5 (8%). The reaction mixture was worked up
in a manner similar to those described above to afford 3-styryl-
∆3-cephem 3c (74 mg, 63%) together with the homo-coupling
product 4 (12 mg, 12%) and norcephalosporin 5 (6 mg, 6%).
3-Styr yl-∆3-cep h em 3c: IR (KBr) 3337, 3031, 1779, 1700,
1
1781, 1723, 1662, 1529, 1495 cm-1; H NMR (CDCl3) δ 3.11
(d, J ) 18.1 Hz, 1H), 3.33 (d, J ) 18.1 Hz, 1H), 3.61 (d, J )
8.0 Hz, 1H), 3.67 (d, J ) 8.0 Hz, 1H), 3.54 (d, J ) 14.7 Hz,
1H), 3.95 (d, J ) 14.7 Hz, 1H), 4.68 (d, J ) 4.7 Hz, 1H), 5.84
(dd, J ) 4.7, 9.0 Hz, 1H), 6.08 (d, J ) 9.0 Hz, 1H), 6.99 (s,
1H), 7.11-7.40 (m, 20H). Anal. Calcd for C35H30N2O4S: C,
73.15; 5.26; N, 4.87. Found: C, 73.37; H, 5.22; N, 4.74.
1
1655, 1531, 1495 cm-1; H NMR (CDCl3) δ 3.52 (d, J ) 17.4
Hz, 1H), 3.65 (d, J ) 17.4 Hz, 1H), 3.63 (d, J ) 8.0 Hz, 1H),
3.68 (d, J ) 8.0 Hz, 1H), 5.02 (d, J ) 4.7 Hz, 1H), 5.81 (dd, J
) 4.7, 9.0 Hz, 1H), 6.39 (d, J ) 9.0 Hz, 1H), 6.67 (d, J ) 16.4
Hz, 1H), 7.02 (s, 1H), 7.14-7.46 (m, 20H), 7.52 (d, J ) 16.4
Hz, 1H). Anal. Calcd for C36H30O4N2S: C, 73.70; H, 5.15; N,
4.77. Found: C, 73.44; H, 4.98; N, 4.65.
Red u ction of 3-(Tr iflu or om eth ylsu lfon yloxy)-∆3-cep h -
em 1a in an Al/P bBr 2/NiBr 2(bpy)/Wet NMP System (Table
6, En tr y 5). A mixture of 3-(trifluoromethylsulfonyloxy)-∆3-
cephem 1a (127 mg, 0.2 mmol), finely cut aluminum foils (41
mg, 1.5 mmol), PbBr2 (7 mg, 0.02 mmol), and NiBr2(bpy) (75
mg, 0.2 mmol) in NMP (2 mL) containing water (18 µL, 1
mmol) was stirred for 5 h at room temperature under argon
atmosphere. An aliquot of the reaction mixture was submitted
to HPLC analysis, showing the presence of norcephalospolin
5 (83%). The analytical sample of 5 was obtained by workup
of the mixture in the manner as described above. 1H NMR and
IR spectra of thus obtained 5 are identical with those of the
authentic sample obtained above.
Rea ction of 3-(Tr iflu or om eth ylsu lfon yloxy)-∆3-cep h -
em 1a w ith cis-1-Br om o-1-P r op en e 2d in a n Al/P bBr 2/
NiBr 2(bp y) System (Ta ble 5, En tr y 3). To a mixture of
3-(trifluoromethylsulfonyloxy)-∆3-cephem 1a (127 mg, 0.2
mmol), finely cut aluminum foils (41 mg, 1.5 mmol), PbBr2 (7
mg, 0.02 mmol), and NiBr2(bpy) (22 mg, 0.06 mmol) in NMP
(2 mL) was added cis-1-bromo-1-propene 2d (85 µL, 1.0 mmol)
under argon atmosphere. After the mixture was stirred for 1
h at room temperature, an aliquot of the reaction mixture was
J O001429B