L. Chen et al. / Tetrahedron Letters 44 (2003) 2611–2614
2613
Typical procedure: To a stirred solution of imine 1 (2
mmol), Cp2TiCl2 (0.05 g, 0.2 mmol) in THF (8 ml) were
added a-bromoacetate (or 4-bromocrotonate, a-bro-
momethylacrylate) (3 mmol) and Zn powder (2.4
mmol) at room temperature. The solution turned to
green quickly and the Zn powder began to disappear.
After Zn was consumed almost completely, the reaction
mixture was stirred continuously for 5 min or more and
then 5% Na2CO3 aqueous solution (10 ml) was added
to quench the reaction. The mixture was extracted with
ether (4×10 ml). The organic layers were combined and
washed with saturated brine, then dried over Na2SO4.
After removal of the solvent the residue was purified by
flash column chromatography on silica gel (eluted with
petroleum ether/ethyl acetate) to give the product.11
and electron-deficient olefins. We have suggested a
mechanism7b for the one-pot Reformatsky reaction:
Cp2TiCl2 promotes the formation of Reformatsky
reagents through activating the Zn powder, but it is still
necessary to clarify the role that Cp2TiCl2 plays in the
activating process. Three experiments were carried out:
(1) Imine (1, Table 1, R1=R2=Ph) and a-bromopropi-
onate were added to a solution of [Cp2TiCl]2, prepared
from zinc powder and Cp2TiCl2 according to the litera-
ture,9 the green solution quickly turned to red but the
expected reaction did not occur. This means that the
three valent titanium species [Cp2TiCl]2 itself could not
promote the addition of a-bromopropionate to the
imine in the absence of zinc. (2) At room temperature
zinc powder (1.2 molar ratio to imine) was added to a
mixture of a-bromopropionate (1.5 molar ratio to
imine) and Cp2TiCl2 (0.1 molar ratio to imine) in THF,
the solution turned to green, the zinc disappeared
quickly and a brown solution formed. Then the imine
(1, Table 1, R1=p-FC6H4, R2=4-MeOC6H4) was
added and the mixture stirred for a while. After the
usual work-up the b-lactam (cis:trans=85:15) was iso-
lated in a 50% yield, which is close to the result of the
one-pot reaction. (3) In contrast with the negative result
in the first experiment, when a pre-prepared green
solution of [Cp2TiCl]2 was added to the Reformatsky
reaction mixture consisting of imine (1, Table 1, R1=
trans-styryl, R2=4-MeOC6H4): a-bromopropionate:
zinc powder (molar ratio=1:1.5:1.2) in THF at room
temperature, the expected Reformatsky addition reac-
tion occurred, the b-lactam (60% yield, cis:trans=
70:30) and b-amino acid (10% yield, syn:anti>99:1)
were obtained. This result is almost the same as that of
the one-pot reaction (Table 1, entry 8).
References
1. Gilman, H.; Speeter, M. J. J. Am. Chem. Soc. 1943, 65,
2255.
2. For b-lactam syntheses: (a) van der Steen, F. H.; van
Koten, G. Tetrahedron 1991, 47, 7503; (b) Ghosez, L.;
Marchand-Brynaert, S. Formation of Four-membered
Heterocycles. In Comprehensive Organic Synthesis; Trost,
B. M.; Fleming, I., Eds.; Pergamon: Oxford, UK, 1991;
Vol. 5, p. 85; (c) Hart, D. J.; Ha, D. C. Chem. Rev. 1989,
89, 1447; (d) Kawabata, T. Heteroat. Chem. 2000, 22,
33–58; (e) Palomo, C.; Cossio, F. P.; Arrieta, A.; Odrio-
zola, J. M.; Oiarbide, M.; Ontoria, J. M. J. Org. Chem.
1989, 54, 5736.
3. (a) Morin, R. B.; Gorman, M. Chemistry and Biology of
i-Lactam Antibiotics; Academic Press: New York, 1982;
Vols. 1–3; (b) Thirkettle, J. E.; Schofield, C. J.; Walter,
M. W. Amino Acids Pept. Proteins 1997, 28, 281–333.
4. (a) Furstner, A. Synthesis 1989, 571; (b) Furstner, A. In
The Reformatsky Reaction; Knochel, P.; Jones, P., Eds.
Organic Reagents; Oxford University Press: Oxford, UK,
1999; pp. 287–305.
5. Cintas, P. Activated Metals in Organic Synthesis; CRC
Press: Boca Raton, Florida, USA, 1993; pp. 172–183.
6. (a) Orsini, F.; Pelizzoni, F.; Pulici, M. J. Org. Chem.
1994, 59, 1; (b) Ishihara, T.; Kuroboshi, M. Chem. Lett.
1987, 1145; (c) Shen, Y.; Qi, M. J. Fluorine Chem. 1994,
67, 229; (d) Kagoshima, T.; Hashimoto, L.; Oguro, D.;
Saigo, K. J. Org. Chem. 1998, 63, 691; (e) Gabriel, T.;
Wessjohann, L. Tetrahedron Lett. 1997, 38, 1363; (f)
Fukuzawa, S.; Matsuzawa, H.; Yoshimitsu, S. J. Org.
Chem. 2000, 65, 1702.
Based on the above facts we think that a SET mecha-
nism may be involved in the activation process of the
Zn powder by Cp2TiCl2 to promote the formation of
the Reformatsky reagent.
It is well known that Cp2TiCl2 is easily reduced by Zn
to Ti(III), which is a better single electron transfer
reagent than Zn10 itself and, therefore, can donate one
electron to a-bromoacetate to form the alkoxycarbonyl-
methyl radical and bromide anion at room temperature.
The radical reacts with Zn (or Zn+) to form
ZnCHRCOOR% (or +ZnCHRCOOR%) and then
BrZnCHRCOOR% at room temperature. The Refor-
matsky reagent formed in situ is active enough to add
to the imine.
7. (a) Ding, Y.; Zhao, G. J. Chem. Soc., Chem. Commun.
1992, 941; (b) Ding, Y.; Zhao, Z.; Zhou, C. Tetrahedron
1997, 53, 2899; (c) Zhao, Z.; Ding, Y.; Zhao, G. Synth.
Commun. 2001, 31, 2089.
In conclusion, Zn/Cp2TiCl2 (cat.) is a good mediator
system for promoting the formation of the Refor-
matsky reagent, subsequent addition to an imine in
one-pot forms a b-lactam or a g-lactam in good yield
and diastereoselectivity. Compared to the classical
Reformatsky reaction our modification is much easier
due to there being no need for activation of the zinc in
advance, no strict anhydrous pretreatment of the sol-
vent and also due to the very fast reaction rate at room
temperature.
8. Borgi, E.; Bellassoued, M.; Louis, M. J. C. R. Hebd.
Seances Acad. Sci. Ser. II 1988, 307, 1805.
9. Green, M. L. H.; Lucas, C. R. J. Chem. Soc., Dalton
Trans. 1972, 1000.
10. Davis, S. G.; Thomas, S. E. Synthesis 1984, 1027.
11. Data of representative products: 1-(p-Methoxyphenyl)-4-
(4%-fluorophenyl)-3-methyl-2-azetidinone. 1H NMR (300
MHz, CDCl3): l 0.89 (d, 3H, cis, J=7.5 Hz), 1.48 (d, 3H,
trans, J=7.5 Hz), 3.08 (dq, 1H, trans, J=2.4, 7.5 Hz),
3.66 (dq, 1H, cis, J=5.8, 7.5 Hz), 3.77 (s, 3H), 5.15 (d,