Origin of the relative stereoselectivity of the β-lactam formation in the Staudinger reaction

Article abstract of DOI:10.1021/ja056711k

The relative (cis, trans) stereoselectivity of the β-lactam formation is one of the critical issues in the Staudinger reaction. Although many attempts have been made to explain and to predict the stereochemical outcomes, the origin of the stereoselectivit

Full text of DOI:10.1021/ja056711k

Published on Web 04/14/2006
Origin of the Relative Stereoselectivity of the â-Lactam
Formation in the Staudinger Reaction
Lei Jiao, Yong Liang, and Jiaxi Xu*
Contribution from the Key Laboratory of Biooganic Chemistry and Molecular Engineering of
Ministry of Education, College of Chemistry and Molecular Engineering, Peking UniVersity,
Beijing 100871, P. R. China
Received October 8, 2005; E-mail: jxxu@pku.edu.cn
Abstract: The relative (cis, trans) stereoselectivity of the â-lactam formation is one of the critical issues in
the Staudinger reaction. Although many attempts have been made to explain and to predict the
stereochemical outcomes, the origin of the stereoselectivity remains obscure. We are proposing a model
that explains the relative stereoselectivity based on a kinetic analysis of the cis/trans ratios of reaction
products. The results were derived from detailed Hammett analyses. Cyclic imines were employed to
investigate the electronic effect of the ketene substituents, and it was found that the stereoselectivity could
not be simply attributed to the torquoelectronic model. Based on our results, the origin of the relative
stereoselectivity can be described as follows: (1) the stereoselectivity is generated as a result of the
competition between the direct ring closure and the isomerization of the imine moiety in the zwitterionic
intermediate; (2) the ring closure step is most likely an intramolecular nucleophilic addition of the enolate
to the imine moiety, which is obviously affected by the electronic effect of the ketene and imine substituents;
(3) electron-donating ketene substituents and electron-withdrawing imine substituents accelerate the direct
ring closure, leading to a preference for cis-â-lactam formation, while electron-withdrawing ketene
substituents and electron-donating imine substituents slow the direct ring closure, leading to a preference
for trans-â-lactam formation; and (4) the electronic effect of the substituents on the isomerization is a minor
factor in influencing the stereoselectivity.
Introduction
one; (2) the reaction is initiated by the nucleophilic attack of
an imine to a ketene, giving rise to a zwitterionic intermediate;
The Staudinger reaction (the [2 + 2] ketene-imine cycload-
dition reaction) is regarded as one of the most fundamental and
versatile methods for the synthesis of â-lactam (2-azetidinone)
derivatives,1 which are important in both pharmaceutical and
synthetic chemistry.2,3 Many experimental and theoretical
investigations into the Staudinger reaction have been presented
during the past decades,4,5 and the most widely accepted reaction
process is described as follows:6 (1) the ketene-imine cycload-
dition reaction is a stepwise reaction rather than a concerted
(3) a conrotatory electrocyclic ring closure of the zwitterionic
intermediate produces the final â-lactam product. The reaction
of a monosubstituted ketene with an acyclic imine produces
two new stereocenters (C3 and C4 in the â-lactam ring), so the
product might be cis-, trans-, or a mixture of cis- and trans-
â-lactam derivatives. Thus, the relative (cis, trans) stereoselec-
tivity is considered as one of the critical issues in the Staudinger
reaction.6 However, the pathway for the formation of cis- and
trans-â-lactams has not been well understood to date. Many
possible stereochemical processes have been proposed in
previous investigations4d,4f-g,5b-c,5e,6 (Scheme 1), but each of
them only focused on the Staudinger reaction involving a
particular ketene or imine and failed to provide a universal
explanation for the observed complicated stereochemical out-
comes.
(1) For recent reviews on syntheses of â-lactam, see: (a) Van der Steen, F.
H.; van Koten, G. Tetrahedron 1991, 47, 7503-7524. (b) Palomo, C.;
Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Eur. J. Org. Chem. 1999, 3223-
3235. (c) Singh, G. S. Tetrahedron 2003, 59, 7631-7649.
(2) (a) Chemistry and Biology of â-Lactam Antibiotics; Morin, R. B.; Gorman,
M., Eds.; Academic Press: 1982; Vols. 1-3. (b) Southgate, R.; Branch,
C.; Coulton, S.; Hunt, E. In Recent progress in the Chemical Synthesis of
Antibiotics and Related Microbital Products; Luckacs, G., Ed.; Springer-
Verlag: Berlin, 1993; Vol. 2, p 621. (c) Southgate, R. Contemp. Org. Synth.
1994, 1, 417.
(3) For a review, see: The Organic Chemistry of â-Lactams; Georg, G. I.,
Ed.; Verlag Chemie: New York, 1993.
(5) (a) Sordo, J. A.; Gonza´lez, J.; Sordo, T. L. J. Am. Chem. Soc. 1992, 114,
6249-6251. (b) Cossio, F. P.; Ugalde, J. M.; Lopez, X.; Lecea, B.; Palomo,
C. J. Am. Chem. Soc. 1993, 115, 995-1004. (c) Arrieta, A.; Ugalde, J.
M.; Cossio, F. P. Tetrahedron Lett. 1994, 35, 4465-4468. (d) Cossio, F.
P.; Arrieta, A.; Lecea, B.; Ugalde, J. M. J. Am. Chem. Soc. 1994, 116,
2085-2093. (e) Arrieta, A.; Lecea, B.; Cossio, F. P. J. Org. Chem. 1998,
63, 5869-5876. (f) Arrieta, A.; Cossio, F. P.; Fernandez, I.; Gomez-Gallego,
M.; Lecea, B.; Mancheno, M. J.; Sierra, M. A. J. Am. Chem. Soc. 2000,
122, 11509-11510. (g) Venturini, A.; Gonza´lez, J. J. Org. Chem. 2002,
67, 9089-9092.
(4) (a) Moore, H. W.; Hernandez, L., Jr.; Chambers, R. J. Am. Chem. Soc.
1978, 100, 2245-2247. (b) Pacansky, J.; Chang, J. S.; Brown, D. W.;
Schwarz, W. J. Org. Chem. 1982, 47, 2233-2234. (c) Moore, H. W.;
Hughes, G.; Srinivasachar, K.; Fernandez, M.; Nguyen, N. V.; Schoon,
D.; Tranne, A. J. Org. Chem. 1985, 50, 4231-4238. (d) Brady, W. T.;
Gu, Y. Q. J. Org. Chem. 1989, 54, 2838-2842. (e) Lynch, J. E.; Riseman,
S. M.; Laswell, W. L.; Tschaen, D. M.; Volante, R.; Smith, G. B.; Shinkai,
I. J. Org. Chem. 1989, 54, 3792-3796. (f) Hegedus, L. S.; Montgomery,
J.; Narukawa, Y.; Snustad, D. C. J. Am. Chem. Soc. 1991, 113, 5784-
5791. (g) Georg, G. I.; He, P.; Kant, J.; Wu, Z. J. J. Org. Chem. 1993, 58,
5771-5778.
(6) Georg, G. I.; Ravikumar, V. T. In The Organic Chemistry of â-Lactams;
Georg, G. I., Ed.; Verlag Chemie: New York, 1993; pp 295-368 and
references therein.
9
6060
J. AM. CHEM. SOC. 2006, 128, 6060-6069
10.1021/ja056711k CCC: $33.50 © 2006 American Chemical Society

Relative Stereochemistry of the Staudinger Reaction
A R T I C L E S
Scheme 2. Steric Effect of N-Substituent R3 in the Staudinger
Scheme 1. Pathways for the Formation of cis- and
trans-â-Lactamsa
Reaction
substituents of ketenes and imines (R1, R2, and R3, Scheme 1)
is the crucial factor that determines the relative stereoselectivity
of the Staudinger reaction. However, since the ketenes are
usually generated in situ in the Staudinger reaction, many
different experimental factors,6 such as the temperature, the
solvent,7a the base,7b the chloride anion,4f,5e,7c and the metal4f,5f
could affect the stereochemical outcomes. These factors inter-
fered with the elucidation of the origin of the stereoselectivity.
Thus, to approach the “origin” ketene-imine reaction,8 we
wished to select a clean reaction system for the ketene generation
as a platform to systematically investigate the substituent effects.
Typically, there are mainly three ways to produce ketenes: (1)
the elimination of acyl chlorides or related derivatives in the
presence of a base,4c,9 (2) the photolysis of metal-carbene
complexes,4f,10 and (3) the Wolff rearrangement of R-diazocar-
bonyl compounds.11-14 Compared with methods (1) and (2),
the use of R-diazocarbonyl compounds as precursors of ketenes
has a distinct advantage: it is a clean reaction system without
any additives (nucleophiles such as chloride anion and tertiary
amine) that could affect the cis/trans ratio of the â-lactam
products. We found that S-phenyl 2-diazoethanethioate (1)
efficiently rearranged to phenylthioketene at 80 °C and gave
â-lactam derivatives in good yields in the presence of imines.
Thus, the reaction of 1 with imine was selected as an appropriate
platform to investigate the origin of the stereoselectivity in the
Staudinger reaction.
a Only one enantiomer is drawn.
Moreover, the nature of the relative stereoselectivity in the
Staudinger reaction is still quite obscure. Hegedus and co-
workers4f pointed out that the zwitterionic intermediate can
isomerize and the stereochemistry is determined primarily by
the structure of the imines and the character of the free or bound
ketenes. Cossio et al. conducted computational investigations
and concluded that the stereochemistry was decided by the
configuration (Z or E) of the starting imines5b and the torquo-
electronic effect of the ketene5e or imine substituents.5c Brady
and Gu4d claimed that the stereochemistry was determined by
the main resonance structure of the zwitterionic intermediates.
Georg et al.4g,6 suggested that the stereochemical results can be
correlated well with the steric demands of the ketenes and
classified the ketenes into three groups according to the size of
their substituents. These investigators have suggested different
models to predict the stereoselectivity, but their proposals are
in conflict to some extent. The most pivotal problems regarding
the relative stereoselectivity remain obscure: (1) How are the
â-lactam products with different relative configurations gener-
ated; i.e., what is the most possible pathway for the formation
of cis- and trans-â-lactams. And (2) why do different ketenes
and imines lead to different stereochemical outcomes; especially,
why do the reactions of different ketenes with the same imine
generate distinct stereochemical results. Therefore, we reinves-
tigated the relative stereoselectivity of the Staudinger reaction.
Herein, we present our experimental results to provide a
comprehensive understanding of the origin of the relative
stereoselectivity in the Staudinger reaction.
First, we conducted the reactions of 1 with imines 2a-c at
80 °C in toluene, respectively. It was found that the cis-â-lactam
product increased as the size of the N-substituent R3 increased
(Scheme 2), which is similar to the results of Moore et al.4c
What is more important is that, a mixture of cis and trans
products15 was obtained from the reaction of 1 and 2b. Because
the cis/trans ratio of the â-lactam products carries the stereo-
chemical information of the reaction, we hope to understand
(7) (a) Palomo, C.; Cossio, F. P.; Odriozola, J. M.; Oiarbide, M.; Ontoria, J.
M. Tetrahedron Lett. 1989, 30, 4577-4580. (b) Browne, M.; Burnett, D.
A.; Caplen, M. A.; Chen, L. Y.; Clader, J. W.; Domalski, M.; Dugar, S.;
Pushpavanam, P.; Sher, R.; Vaccaro, W.; Viziano, M.; Zhao, H. Tetrahedron
Lett. 1995, 36, 2555-2558. (c) Bose, A. K.; Spiegelman, G.; Manhas, M.
S. Tetrahedron Lett. 1971, 12, 3167-3170.
(8) Staudinger, H. Justus Liebigs Ann. Chem. 1907, 356, 51-123.
(9) (a) Sheehan, J. C.; Buhle, E. L.; Corey, E. J.; Lanbach, G. D.; Ryan, J. J.
J. Am. Chem. Soc. 1950, 72, 3828-3829. (b) Bose, A. K.; Anjaneyulu, B.;
Bhattacharya, S. K.; Manhas, M. S. Tetrahedron 1967, 23, 4769-4776.
(c) Evans, D. A.; Williams, J. M. Tetrahedron Lett. 1988, 29, 5065-5068.
(10) (a) McGuire, M. A.; Hegedus, L. S. J. Am. Chem. Soc. 1982, 104, 5538-
5540. (b) Hegedus, L. S.; Imwinkelried, R.; Alarid-Sargent, M.; Dvorak,
D.; Satoh, Y. J. Am. Chem. Soc. 1990, 112, 1109-1117. (c) Hegedus, L.
S. Tetrahedron 1997, 53, 4105-4128.
(11) Kirmse, W. Eur. J. Org. Chem. 2002, 2193-2256.
(12) For photoirradiation-induced Staudinger reaction, see: (a) Podlech, J.;
Linder, M. R. J. Org. Chem. 1997, 62, 5873-5883. (b) Linder, M. R.;
Podlech, J. Org. Lett. 1999, 1, 869-871. (c) Linder, M. R.; Frey, W. U.;
Podlech, J. J. Chem. Soc., Perkin Trans. 1 2001, 2566-2577.
(13) For microwave-assisted Staudinger reaction, see: Linder, M. R.; Podlech,
J. Org. Lett. 2001, 3, 1849-1851.
Results and Discussion
Selection of the Reaction Platform and the Discovery of
a Good Probe. It is unequivocal that the nature of the
(14) Liang, Y.; Jiao, L.; Zhang, S. W.; Xu, J. X. J. Org. Chem. 2005, 70, 334-
337.
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A R T I C L E S
Jiao et al.
mined by the configuration (Z or E) of the starting imines:5b
(E) imines led preferentially to cis-â-lactams (pathway a f e,
Scheme 1) and (Z) imines gave predominantly the corresponding
trans isomers (pathway i f g, Scheme 1). In fact, all the starting
imines 5 were determined to be exclusively E configuration
based on 1H NMR and 1D NOE experiments,17 and most imines
employed in the Staudinger reaction were confirmed to be E
configuration.18 Thus, we can conclude that the stereoselectivity,
in most cases, cannot be explained by the configuration of the
starting imines.
Table 1. Influence of the Electronic Effect of the C-Substituents of
the Imines on the Stereoselectivity
entry
imine
R
product
yielda (%)
cis/transb
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
MeO
Me
H
Cl
CF3
NO2
6a + 7a
6b + 7b
6c + 7c
6d + 7d
6e + 7e
6f + 7f
87
80
92
75
81
79
4:96
7:93
12:88
17:83
42:58
73:27
There are two other possibilities: (a) the stereochemistry is
decided by the different initial approaches of the imine to the
monosubstituted ketene4d (cis-â-lactam, pathway a f e; trans-
â-lactam, pathway b f f, Scheme 1); and (b) the stereochemistry
is decided by the competition between the direct ring closure
(pathway e) and the isomerization of the imine moiety in the
zwitterionic intermediate (pathway c). In this process, the
approach of the imine to the ketene is opposite to R1, and
subsequent ring closure of the zwitterionic intermediate C leads
to cis-â-lactam (pathway a f e, Scheme 1), while the
isomerization of the imine moiety in the zwitterionic intermedi-
ate C leads to the formation of trans-â-lactam4f,6 (pathway a
f c f g, Scheme 1). For possibility (a), the observed variation
of cis/trans ratios could be explained by the electronic effect of
the imine substituent R2 affecting the ratio of different ap-
proaches (pathway a vs pathway b). For possibility (b), the
experimental results could be explained by the electronic effect
of the imine substituent R2 affecting the competition between
the direct ring closure (pathway e) and the isomerization
(pathway c). To distinguish which one is reasonable, the best
way is to replace imines 5 with a series of cyclic imines with
different electronic substituents in the same reactions. Since
cyclic imines cannot undergo the isomerization in the reac-
tion,4f,6,14 the possibilities (a) and (b) could be distinguished by
the relative configuration of the bicyclic â-lactam products.
The reactions of 1 with cyclic imines, 2-substituted dibenzo-
[b,f][1,4]oxazepines 8, were carried out under the same condi-
tions (Scheme 3) as those of its reactions with imines 5. The
trans-â-lactam derivatives 9a-d were exclusively formed in
excellent yields. This indicates that the initial approach occurs
exclusively at the nonsubstituted side of the ketene, and the
electronic nature of the imine substituent R2 does not affect the
direction of the approach (Scheme 4).
a Isolated yield after column chromatography. b Determined by 1H NMR
of the crude products.
Figure 1. Hammett plot of the reactions between the ketene and imines
with different C-substituents.
the origin of the stereoselectivity in the Staudinger reaction by
systematically measuring a series of cis/trans ratios of the
â-lactam products with different substituents. Thus, N-isopropyl
imines are good probes for detecting the stereochemical
information.
Electronic Effect of the Substituent R2. A series of
N-isopropyl imines 5a-f with different para-substituents on the
C-phenyl group were reacted with S-phenyl 2-diazoethanethioate
(1) at 80 °C in toluene (Table 1). It was found that the electronic
effect of the substituents plays an important role in the
stereoselectivity, which obviously alters, even reverses, the
stereochemical outcomes. For imine 5a with a strong electron-
donating group (p-MeO), the product is predominately trans
(Table 1, entry 1), while, for imine 5f with a strong electron-
withdrawing substituent (p-NO2), the product is mainly cis
(Table 1, entry 6). It is notable that the cis/trans ratios of these
reactions correlate well with the Hammett constants (σ) with a
calculated F-value of +1.62 (Figure 1).16
Electronic Effect of the Substituent R1. To understand the
origin of the stereoselectivity in depth, a series of R-diazoaryl-
ethanones 10a-f with different substituents were reacted with
imine 5f at 140 °C in xylenes19 to afford a series of cis- and
trans-â-lactams (Table 2). The results indicate that the electronic
effect of the ketene substituents also plays an important role in
the stereoselectivity. For the ketene with a strong electron-
donating group (p-MeO), the product is mainly cis (Table 2,
entry 1), while, for the ketene with a strong electron-withdrawing
To our best knowledge, the linear free energy relationship
(LFER) of the relative stereoselectivity of the â-lactam formation
in the Staudinger reaction has never been investigated. How to
explain this intriguing result? According to Scheme 1, the
simplest explanation was that the stereochemistry was deter-
(17) Another experiment involving the N-acetyl iminium was also conducted,
which indicated that the isomerizations of the imine itself and N-acetyl
iminium hardly occur under normal conditions. See Supporting Information
for detailed discussion.
(15) The configurations of the â-lactam products can be easily determined by
the coupling constants between the protons on C(3) and C(4) of the â-lactam
ring. For cis-â-lactam products, JH(C3)-H(C4) is 4-6 Hz, and for trans
products, JH(C3)-H(C4) is about 2 Hz. The cis/trans ratios can be obtained
(18) It was reported that imines such as C-9-anthryl imines and C-2,6-
disubstitutedphenyl imines partially exist in Z configuration; however, they
are seldom used in the Staudinger reaction. See: Bjorgo, J.; Boyd, D. R.;
Watson, C. G.; Jennings, W. B.; Jerina, D. M. J. Chem. Soc, Perkin Trans.
2 1974, 1081-1084.
1
by the integral of the corresponding protons in H NMR spectra of crude
reaction mixtures.
(19) The reactions of 10 with imines at 80 °C in toluene cannot proceed because
(16) The Hammett constants (σ) cited are all taken from: Hansch, C.; Leo, A.;
Taft, R. W. Chem. ReV. 1991, 91, 165-195.
compounds 10 cannot undergo the Wolff rearrangement at such a
temperature.
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Relative Stereochemistry of the Staudinger Reaction
A R T I C L E S
Scheme 3. Reaction of 1 and Cyclic Imines 8 with Different
Electronic Substituents
a Isolated yield after chromatography.
Figure 2. Hammett plot of the reactions between the imine and ketenes
with different substituents.
Scheme 4 a
The interesting fact that cis/trans ratio of the â-lactam
products varied with the electronic nature of the ketene
substituents was never reported before. First, it seemed that the
above results could be simply explained by the torquoelectronic
model: in the transition states for the conrotatory ring closure
of the zwitterionic intermediates, the electron-donating groups
(EDGs) in the ketene moiety favor occupying the outward
position at C3 of the â-lactam ring, leading to the formation of
cis-â-lactams (e.g., R1 ) p-MeOPh, Table 2, entry 1); while
the electron-withdrawing groups (EWGs) in the ketene moiety
favor occupying the inward position, leading to the formation
of trans-â-lactams (e.g., R1 ) p-NO2Ph, Table 2, entry 6).
Second, the above results could also be explained by the
competition between the direct ring closure and the isomeriza-
tion (pathway e vs pathway c, Scheme 1).
a Only one enantiomer is drawn.
Table 2. Influence of the Electronic Effect of the Ketene
Substituents on the Stereoselectivity
There have been several literatures concerning the torquo-
electronic model in the Staudinger reaction, which discussed
the inward/outward tendency of the ketene substituents:5e,22 the
O-alkyl, N-alkyl, halo, and alkyl groups on the ketene have a
distinct preference of occupying the outward position in the
transition state, while the boryl group22a on the ketene tends to
occupy the inward position. It is not clear whether the phenyl
groups with different electronic substituents have different
preferences of occupimg inward/outward positions in the
transition state to date.
entry
diazoketone
R
product
yielda (%)
cis/transb
1
2
3
4
5
6
10a
10b
10c
10d
10e
10f
p-MeO
p-Me
H
p-Cl
m-Cl
p-NO2
11a + 12a
11b + 12b
11c + 12c
11d + 12d
11e + 12e
11f + 12f
93
68
52
65
56
60
66:34
55:45
47:53
40:60
38:62
27:73
To examine the above possibility, cyclic imine 8d that has a
similar structural feature to imine 5f was selected to react with
R-diazoarylethanones 10 (Scheme 5) under the same conditions.
The reactions afforded the trans-â-lactam derivatives 13 ex-
a Isolated yield after column chromatography. b Determined by 1H NMR
of the crude products.
1
clusively, and the cis isomer was never observed by H NMR
substituent (p-NO2), the product is mainly trans (Table 2, entry
6). The cis/trans ratios of the products also correlate well with
the Hammett constants (σ) with a F-value of -0.63 (Figure 2).
Since the temperature influences the reaction constant F, to get
comparable data with the previous results obtained at 80 °C,
the reactions were also conducted at 130 °C in xylenes,20 and
the cis/trans ratios of reactions at 80 °C were estimated
according to the Eyring formula,21 which have a good correlation
with the Hammett constants (σ) with a F-value of -1.1 (Figure
2).
of the crude products. This indicates that the substituted phenyl
groups on the ketene, compared with the hydrogen atom, prefer
to occupy the outward position. Thus, the results presented in
Table 2 could not be simply explained by the torquoelectronic
model, and they should relate to the competition between the
direct ring closure and the isomerization.
(21) The detailed calculations were given in the Supporting Information. For
reference, see: Eyring, H. J. Chem. Phys. 1935, 3, 107-115.
(22) (a) Lpez, R.; Sordo, T. L.; Sordo, J. A.; Gonza´lez, J. J. Org. Chem. 1993,
58, 7036-7037. (b) Dumas, S.; Hegedus, L. S. J. Org. Chem. 1994, 59,
4967-4971. (c) Hegedus, L. S.; Moser, W. H. J. Org. Chem. 1994, 59,
7779-7784. (d) Alonso, E.; Lo´pez-Ortiz, F.; del Pozo, C.; Peralta, E.;
Mac´ıas, A.; Gonza´lez, J. J. Org. Chem. 2001, 66, 6333-6338. (e) Mac´ıas,
A.; Alonso, E.; del Pozo, C.; Venturini, A.; Gonza´lez, J. J. Org. Chem.
2004, 69, 7004-7012.
(20) The experimental results at 130 °C were given in the Supporting
Information.
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A R T I C L E S
Jiao et al.
(1)
Scheme 5. Reactions between Cyclic Imine 8d and
Phenylketenes with Different Electronic Substituents
[cis] ) k1 [C] dt
∫
[trans] ) k3 [D] dt ) k [C] dt - [D]
(2)
∫
∫
2
k1 [C] dt
∫
[cis]
)
(3)
[trans]
k2 [C] dt - [D]
∫
Because the cyclization step is very fast, the concentration
of the intermediate D is very low, i.e., [D] f 0. Thus, eq 3
could be simplified to eq 4.
k1
k2
[cis]
)
(4)
[trans]
a Isolated yield after chromatography.
In this way, a simple but significant conclusion is obtained:
the product ratio (cis/trans) only depends on the rate constants
of the direct ring closure (k1) and the isomerization (k2).
Relationship between the Structural Features and the Rate
Constants. According to the Hammett equation, each indepen-
dent rate constant can be correlated to the Hammett constant σ
of the substituent (eqs 5 and 6).
Suggested Model for the Relative Stereoselectivity of the
â-Lactam Formation. After systematic investigations into the
electronic effect of both ketene and imine substituents, a model
for the relative stereoselectivity of the â-lactam formation can
be drawn: the initial exo attack of the imine B to the
monosubstituted ketene A generates the intermediate C, and
subsequent direct ring closure of C forms cis-â-lactam (pathway
a f e, Scheme 1); the isomerization of the imine moiety of C
gives rise to the intermediate D, leading to the formation of
trans-â-lactam (pathway a f c f g, Scheme 1). The stereo-
selectivity in the Staudinger reaction should be attributed to the
competition between these two pathways (also see Scheme 6,
in which the ka, kd, k1, k2, k2′, and k3 are the rate constants for
each of the steps).
log k1,Y ) F1σ + log k1,H
log k2,Y ) F2σ + log k2,H
(5)
(6)
k
k1,H
k2,H
log 1,Y ) log k1,Y - log k2,Y ) (F1 - F2)σ + log
)
k2,Y
k1,H
k2,H
F ‚ σ + log
(7)
There are some points worth noting: (1) most of the starting
acyclic imines employed in the Staudinger reaction exist in E
configuration exclusively; (2) for the most frequently used
monosubstituted ketenes, such as O, N, S-alkyl/aryl-, halo-,
alkyl-, and arylketenes, the attack of the imine occurs exclusively
at their exo side, and the ketene substituent R1 always occupies
the outward position in the ring closure transition state according
to the torquoelectronic effect; (3) the imine moiety in the
zwitterionic intermediate C, regardless of the imine substituents,
has the possibility of the isomerization to form intermediate
D;23 (4) the stereoselectivity of the reaction is controlled by
the competition between the direct ring closure and the
isomerization;24 and (5) the possibility of the D to C isomer-
ization (k2′) cannot be excluded. However, from a geometric
viewpoint, intermediate D is sterically more favorable than C,
which facilitates the C to D isomerization (i.e., k2 > k2′). Thus,
in our model, the C to D isomerization is assumed to be
irreversible to facilitate the kinetic treatment.25
Since eq 4 shows that the cis/trans ratio is equal to k1/k2, eq
8 can be derived.
cisY
k
k
log
) log 1,Y ) (F1 - F2)σ + log 1,H ) F ‚ σ +
transY
k2,Y k2,H
cisH
log
(8)
transH
Thus, a clear linear relationship between the logarithms of
the determined cis/trans ratios and the Hammett constants of
the electronic substituents in the ketene or imine moiety
emerges, which is consistent with the experimental results
(Figures 2 and 1). Reviewing the above Hammett analyses, we
found that the slope (F) represented the difference between the
reaction constants of the direct ring closure (F1) and the
isomerization (F2), but F1 and F2 remained combined. Only if
the signs of F1 and F2 are determined can we understand the
relationship between k1 (direct ring closure), k2 (isomerization),
and the electronic effect of the substituents.
Electronic Effect on the Rate Constant of the Direct Ring
Closure k1. It is reasonable to assume that the substituents R2
and R3 of the imine influence both the direct ring closure (k1)
and the isomerization (k2), while the substituent R1 of the ketene
affects the direct ring closure but scarcely influences the
isomerization of the imine moiety. Thus, it is easy to under-
stannd the influence of the electronic effect of the ketene
substituents R1 on the direct ring closure. For the different
According to the suggested model (Scheme 6), the kinetic
derivation of the relative stereoselectivity can be achieved:26
(23) In our opinion, the isomerization occurs during the direct ring closure step.
See Supporting Information for detailed discussion.
(24) The exclusive exo-attack to form the zwitterionic intermediate C does not
affect the cis/trans ratio of the products. If the exclusive exo-attack is the
rate-determining step in the two-step Staudinger reaction, it will determine
the rate of the product generation but not the cis/trans ratio.
(25) If the C to D isomerization is considered reversible, the precise derivation
of the relationship between cis/trans ratio and the rate constants cannot be
approached. Otherwise, no one has proved the applicability of the Curtin-
Hammett rule in such a multistep and complex system as the Staudinger
reaction.
(26) The detailed kinetic treatment is shown in the Supporting Information.
9
6064 J. AM. CHEM. SOC. VOL. 128, NO. 18, 2006

Relative Stereochemistry of the Staudinger Reaction
A R T I C L E S
Scheme 6. Suggested Model for the Relative Stereoselectivity in the Staudinger Reactiona
a Only one enantiomer is drawn.
withdrawing group of the ketene (R1) can decrease the nucleo-
philicity of the enolate, lowering the rate constant of the direct
ring closure k1. Similarly, it could be deduced that the rate
constant k1 could also be increased by the electron-withdrawing
group of the imine (R2 and R3) due to the enhancement of the
electrophilicity of the imine moiety (i.e., the reaction constant
F1 should be positive to σR2 and σR3). Considering the electronic
effect of the substituent R2 of the imine on the stereoselectivity
(F ) +1.62 to σR2), though it can influence both the direct ring
closure (k1) and the isomerization (k2), we can conclude that
the electronic effect of R2 mainly influences the direct ring
closure. However, the influence of the electronic effect of R2
on the isomerization remains unclear.
Figure 3. Two different interpretations of the ring closure step in the
Staudinger reaction.
zwitterionic intermediates with the same imine moiety, the rate
constants of isomerization (k2) are almost the same; i.e., the
reaction constant of the isomerization F2 is about 0. Accordingly,
the reaction constant F1 of the direct ring closure is equal to
the experimentally determined F (F ) F1 - F2 ≈ F1 ) -1.1 at
80 °C, Figure 2). The negative reaction constant F1 indicates
that the electron-donating group of the ketene can accelerate
the direct ring closure (increase k1), while the electron-
withdrawing group can slow the direct ring closure (decrease
k1).
Probing the Electronic Effect on the Isomerization. The
kinetics of the imine isomerization have been investigated in
detail,27 and it was reported that electron-withdrawing groups
on the phenyl groups of aryl-aryl imines promote the isomer-
ization. These isomerizations follow the Hammett equation, and
the F-values are positive for substitution on both the nitrogen
side and the carbon side. The positive F-values indicate that
the low-electron density at the CdN bond facilitates the
isomerization due to the low bond order. It is notable that the
F-value is considerably higher for the substitution on the nitrogen
side (F ) +1.85) than that on the carbon side (F ) +0.41).27
We assume that the isomerization of the CdN bond in the
zwitterionic intermediate would obey the similar rule to the
imine itself. In the case of Figure 1, assuming that the reaction
constant F2 of the isomerization is about +0.4, we can deduce
that the reaction constant F1 of the direct ring closure is about
+2.0 according to eq 7 (F1 ) F + F2, Figure 4A). It is definite
that the electronic effect of the substitution R3 on the nitrogen
side would influence both the direct ring closure (k1) and the
isomerization (k2). We assumed that (1) the influence of the
electronic effects of the substitution on the nitrogen side on the
direct ring closure is at the same level as that on the carbon
side (F1′ is also about +2.0) and (2) the influence of the
electronic effect of the substitution at the nitrogen side on the
isomerization is at the same level as that in the imine itself (F2′
is about +1.8). Thus, the combined influence of electronic
effects on the stereoselectivity can be deduced: the F′ would
be about +0.2 (F′ ) F1′ - F2′, Figure 4B).
It is widely accepted that the ring closure step of the
Staudinger reaction is an electrocyclic process.6 The zwitterionic
intermediate is regarded as a 4π-electron system, and its
conrotatory ring closure is concluded according to the Wood-
ward-Hoffmann rule. However, the observed electronic effect
of the ketene substituent R1 on the direct ring closure is difficult
to explain if the ring closure step is considered as an electro-
cyclic process. Furthermore, our recent research on the photo-
chemical Staudinger reactions showed that the zwitterionic
intermediates cannot undergo the disrotatory ring closure under
ultraviolet irradiation, which is quite different from that of
substituted 1,3-butadienes.14 This reveals the inapplicability of
the Woodward-Hoffmann rule to the photoirradiation induced
Staudinger reaction, suggesting that the ring closure step of the
intermediates is far from a classic electrocyclic process.
Meanwhile, Cossio et al.5b have pointed out that (a) the
electronic structure of the transition state for the ring closure
step of the zwitterionic intermediate differs from those respon-
sible for classic conrotatory electrocyclic processes and (b) the
ring closure step can be alternatively viewed as an intramolecular
nucleophilic addition of the enolate to the imine moiety. Thus,
we prefer to consider the ring closure step as an intramolecular
nucleophilic addition of the enolate to the imine moiety (Figure
3, a), rather than an electrocyclic ring closure (Figure 3, b).
Reviewing the negative F1 obtained from the Hammett
analysis, it is clear that the electron-donating group of the ketene
(R1) can make the enolate more nucleophilic, increasing the rate
constant of the direct ring closure k1, while the electron-
To confirm our prediction, a series of substituted benzylide-
neanilines 14a-f were reacted with S-phenyl 2-diazoethaneth-
(27) Wettermark, G. In The Chemistry of the Carbon-Nitrogen Double Bond;
Patai, S., Ed.; Interscience: London, 1970; pp 565-596.
9
J. AM. CHEM. SOC. VOL. 128, NO. 18, 2006 6065

A R T I C L E S
Jiao et al.
assumption is reasonable. The electron-withdrawing groups R2
and R3 in the imine could lower the electron density of the Cd
N bond, increasing the rate constant of the isomerization k2 (i.e.,
F2 is positive to σR2 and σR3). Furthermore, the electronic effect
of the R3 group, compared with the R2 group, exerts a more
distinct influence on the isomerization.
Relationship between the Relative Stereoselectivity and
the Structural Features. On the basis of the above results and
discussion, a general view of the substituent effects on the rate
constants of the direct ring closure (k1) and isomerization (k2)
is presented (Figure 6).
Figure 4. Electronic effects of the imine moiety on the direct ring closure
(a) and on the isomerization (c). (A) Substitution on the carbon side (R2).
(B) Substitution on the nitrogen side (R3).
The ring closure step of the Staudinger reaction is most likely
to be an intramolecular nucleophilic addition of the enolate to
the imine moiety. The relative stereochemistry is primarily
determined by the rate of the direct ring closure. If the rate
constant k1 is much larger than k2, the â-lactam product is
predominantly cis; on the contrary, if k1 is much smaller than
k2, the product is mainly trans. A mixture of cis and trans
products would be obtained if k1 is close to k2. The electronic
effect of substituent R1 only influences k1, and the electronic
effects of substituents R2 and R3 mainly influence k1. Thus, to
predict the relative stereochemical outcomes of the Staudinger
reaction, much attention should be paid to the rate of the direct
ring closure.
Table 3. Influence of the Electronic Effect of the N-Substituents of
the Imines on the Stereoselectivity
An Overview of the Staudinger Reaction
Rationale of the Experiential Rule. The problem of why
the reactions of different ketenes with the same imine generate
distinctively different stereochemical outcomes is difficult to
explain before the origin of the stereoselectivity is disclosed.
For example, the most widely employed imine, N-benzylide-
neaniline, reacted with methoxyketene to afford cis-â-lactam
predominately, while it reacted with methylketene or chlo-
roketene to give trans-â-lactam exclusively.28 According to the
torquoelectronic model, all these ketene substituents, methoxy,
methyl, and chloro, prefer to occupy the outward position.22a
The above three reactions should have given similar stereo-
chemical outcomes. On the other hand, according to other
viewpoints,4f,6 if attention was only paid to the isomerization
of the imine moiety, the above three reactions should also have
given similar stereochemical outcomes due to the same ability
of the isomerization. The contradiction between the predictions
based on the above models and the experimental results
indicated that these interpretations were incomplete. However,
once the rate of the direct ring closure was taken into
consideration, this problem became clear. Furthermore, the
influence of the electronic effect of the ketene substituents on
the direct ring closure (k1) can be semiquantitatively compared
using eq 4. Two sets of experiments were designed and
performed to semiquantitatively measure the relative rate
constants of the direct ring closure (Table 4).
entry
imine
R
product
yielda (%)
cis/transb
1
2
3
4
5
6
14a
14b
14c
14d
14e
14f
MeO
Me
H
Cl
Ac
15a + 16a
15b + 16b
15c + 16c
15d + 16d
15e + 16e
15f + 16f
75
76
85
72
52
5c
27:73
33:67
34:66
35:65
38:62
48:52
NO2
a Isolated yield after column chromatography. b Determined by 1H NMR
of the crude products. c Yield determined by 1H NMR of the reaction
mixture.
Figure 5. Hammett plot of the reactions between the ketene and imines
with different N-substituents.
When R1 ) PhS, the relative rate constant of the direct ring
closure is defined to 1 as a reference, and other relative rate
constants are calculated and listed in Table 4. We can divide
the ketene substituents R1 into three groups on the basis of their
relative rate constants (Figure 7): (1) k1,rel > 100 (e.g., R1 )
PhO, k1,rel ) 176), (2) 1 < k1,rel < 100 (e.g., R1 ) PhthN, k1,rel
) 6), and (3) k1,rel < 1 (e.g., R1 ) Ph, k1,rel ) 0.17). The above
ioate (1) at 80 °C in toluene, respectively. It was found that the
electronic effect of the substituents on the N-phenyl group
affected the stereoselectivity (Table 3). The cis/trans ratios of
the products correlate with the Hammett constants (σ) with a
F-value of +0.31 (Figure 5), which is in good agreement with
our prediction. This indicates that the influences of the electronic
effects on the isomerization in the zwitterionic intermediates
are at the same level as those in the imine itself, and our
(28) Bose, A. K.; Chiang, Y. H.; Manhas, M. S. Tetrahedron Lett. 1972, 13,
4091-4094.
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6066 J. AM. CHEM. SOC. VOL. 128, NO. 18, 2006

Relative Stereochemistry of the Staudinger Reaction
A R T I C L E S
Figure 6. Influence of the structural features on the relative stereoselectivity in the Staudinger reaction.
Table 4. Influence of Different Ketene Substituents on the
difference was caused by a significant decrease of the rate of
the direct ring closure.
Stereoselectivity in the Staudinger Reaction
Do Microwave and Photoirradiation Influence the Rela-
tive Stereoselectivity of the Staudinger Reaction? In recent
years, microwave- and photoirradiation-induced Staudinger
reactions, with R-diazoketones (derived from R-amino acids)
as ketene precursors, have been reported.12-14 These reactions
exclusively produced trans-â-lactams, which was considered
uncommon and explained that microwave and photoirradiation
could efficiently promote the isomerization of the imine itself
or the imine moiety of the zwitterionic intermediates. However,
according to our model, the trans selectivity of the above
microwave- and photoirradiation-induced Staudinger reaction
can be well explained by the electronic nature of the ketene
substituents. In the above cases, the R1 groups of the ketenes
are all protected aminoalkyls, which are more electron-poor than
the alkyl group, leading to weaker nucleophilicity of the enolates
in the zwitterionic intermediates. The rate constant of the direct
ring closure (k1) is quite small when R1 is alkyl (Figure 7). So
it can be concluded that the rate constant k1 would be much
smaller when R1 is a protected aminoalkyl. Thus, we prefer to
consider that the low direct ring closure rate k1, rather than the
microwave or photoirradiation, is the real reason for the
exclusive formation of the trans products, even when more
hindered N-tert-butyl imines were used.12c,14
entry
R1
R2
R3
cis/transa
k
1,rel (R1)h
1
2
3
4
5
6
PhOb
PhthNb
PhSc
PhSc
Med
p-MeOPh
p-MeOPh
p-MeOPh
p-NO2Ph
p-NO2Ph
p-NO2Ph
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
17a:17b
18a:18b
6a:7a
88:12f
19:81f
4:96
176
6
1
1
0.20
0.17
6f:7f
19a:19b
11c:12c
73:27
35:65g
32:68
Phe
a Cis:trans ratios obtained at the same temperature (80 °C). b Reaction
performed by adding a solution of acyl chloride to a solution of an imine
and Et3N in toluene at 80 °C. c Taken from Table 1. d Reactions performed
by adding a solution of diazoacetone to a solution of the imine in toluene
at 100 and 110 °C, respectively, and then the mixtures were stirred for 12
h at the corresponding temperatures. e Taken from Figure 2. f Determined
by 1H NMR of the crude reaction mixture. g Derived from the data obtained
at 100 and 110 °C by using the Eyring equation. h Calculated according to
the equation: k1,rel(R1) ) k1(R1)/k1(PhS) ) [k1(R1)/k2(R1)]/[k1(PhS)/k2(PhS)]
) [cis/trans(R1)]/[cis/trans(PhS)].
classification rationalizes the previous experiential classification
by Georg et al.:6 (1) “Bose-Evans ketenes”, possessing strong
electron-donating substituents R1 (such as O-alkyl, O-aryl, and
N-alkylaryl), have a distinct preference for cis-â-lactam forma-
tion due to the large rate constant of the direct ring closure (k1,rel
> 100); (2) “Sheehan ketenes” produce complex stereochemical
outcomes due to the moderate rate constant of the direct ring
closure (1 < k1,rel < 100); and (3) “Moore ketenes” possessing
very weak electron-donating substituents R1 (such as S-alkyl,
S-aryl, alkyl, and aryl) have a strong preference for trans-â-
lactam formation due to the small rate constant of the direct
ring closure (k1,rel < 1).
To verify our opinion, we conducted the microwave- and
photoirradiation-induced reactions of 1 with 2c, respectively.
Cis product 3c was exclusively generated under both conditions,
which is in great accordance with the result of the common
thermal reaction (Scheme 8). This indicates that the microwave
and photoirradiation cannot obviously change the stereoselec-
tivity of the Staudinger reaction.
Another example also proved that the direct ring closure rate
is the critical point in the stereoselectivity. It is generally
considered that the use of N-tert-butyl imines can inhibit the
isomerization of the imine moiety, leading to cis-â-lactam
products. This is suitable for explaining the stereochemical
outcome of the reaction of 1 with 2c (Scheme 2). However,
when another electron-withdrawing group (-CO2Et) was at-
tached to the ketene moiety, the stereoselectivity dramatically
changed.29 Product 21b generated from the isomerized zwitte-
rionic intermediate was obtained predominantly (Scheme 7). The
To further investigate the influence of the photoirradiation
on the stereoselectivity, the reactions of 1 with 5a-f were also
conducted under the ultraviolet irradiation to compare with the
results of the thermal reactions. Interestingly, the results are
similar to those in the common thermal reactions (Table 5),
except for 5f. The results show that, in the common photo-
chemical Staudinger reaction (under a medium-pressure or high-
pressure mercury lamp), the influence of the photoirradiation
is limited, and the stereoselectivity is predominately controlled
by structural features of ketenes and imines, not reaction
conditions.
(29) For more examples and discussion, see: Jiao, L.; Zhang, Q. F.; Liang, Y.;
Zhang, S. W.; Xu, J. X. J. Org. Chem. 2006, 71, 815-818.
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J. AM. CHEM. SOC. VOL. 128, NO. 18, 2006 6067

A R T I C L E S
Jiao et al.
Figure 7. Relationship between the ketene classification and the relative rate constant.
Scheme 7. Effect of the Direct Ring Closure Rate on the
constants of the direct ring closure, we successfully rationalized
the previous experiential rule. In addition, the comparison of
the microwave- and photoirradiation-induced Staudinger reac-
tions with the common thermal ones was also conducted,
indicating that the nature of the substituents, rather than reaction
conditions, predominately controlled the stereoselectivity.
Stereoselectivity in the Staudinger Reaction
On the basis of our results, the origin of the relative
stereoselectivity of the Staudinger reaction is summarized as
follows: (1) the relative stereoselectivity is generated as a result
of the competition of the direct ring closure (k1) and the
isomerization of the imine moiety (k2) in the zwitterionic
intermediates, and the k1/k2 ratio generally determines the cis/
trans ratio of the â-lactam products; and (2) the electronic effect
is a key factor in the stereoselectivity, and the influence of the
electronic effect on the direct ring closure is more distinct than
that on the isomerization of the imine moiety. Thus, much
attention should be paid to the influence of the substituent effects
on the direct ring closure (k1) to predict the relative stereose-
lectivity in the Staudinger reaction.
Scheme 8. Comparison of the Microwave, Photoirradiation, and
Common Thermal Reactions of 1 with 2c
Table 5. Comparison of the Stereoselectivity under Thermal and
Photoirradiation Conditions
Experimental Section
cis/trans
conditions
6a:7a
6b:7b
6c:7c
6d:7d
6e:7e
6f:7f
General Procedure for the Reactions of S-Phenyl 2-Diazoet-
hanethioate (1) with Imines 2, 5, 8, and 14. A flame-dried round-
bottom flask was charged with a solution of imine (1 mmol) in 10 mL
of dry toluene. The flask was immersed in an oil bath and heated to 80
°C. A solution of diazoethanethioate 1 (1.3 mmol) in 5 mL of dry
toluene was then added through a dropping funnel during a period of
30 min. After the addition, the resulting solution was stirred for another
1 h at 80 °C. After removal of the solvent, the residue was directly
submitted to NMR analysis to determine the cis/trans ratio. Column
chromatography of the crude mixture on silica gel afforded the
corresponding cis- and trans-â-lactam products.
General Procedure for the Reactions of r-Diazoacetophenones
10 with Imine 5f and 8d. A flame-dried round-bottom flask was
charged with a solution of imine 5f or 8d (1 mmol) in 10 mL of dry
xylenes. The flask was immersed in an oil bath and heated to the desired
temperature (130 or 140 °C as mentioned). A solution of 10 (1.3 mmol)
in 5 mL of dry xylenes was then added through a dropping funnel
during a period of 30 min. After the addition, the resulting solution
was stirred for another 12 h at the desired temperature. After removal
of the solvent, the residue was purified by flash chromatography to
remove highly polar impurities. The product mixture was then submitted
to NMR or HPLC analysis to determine the cis/trans ratio. Column
chromatography of the crude mixture on silica gel afforded the
corresponding cis- and trans-â-lactam products.
∆
1:24
1:36
1:13
1:11
1:7.3
1:6.7
1:4.9
1:5.0
1:1.4
1:2.6
1:0.37
1:5.4
hVa
a Performed under high-pressure mercury lamp in CH2Cl2 at -20 °C.14
Conclusion
In summary, we have proposed a model for the relative
stereoselectivity in the Staudinger reaction and clearly pointed
out the kinetic origin of the cis/trans ratio of â-lactam products.
The cyclic imines were employed to investigate the electronic
effect of the ketene substituents, and it was found that the
stereoselectivity could not be simply attributed to the torquo-
electronic model. Moreover, the Hammett analysis to the relative
stereoselectivity of the Staudinger reaction was systematically
conducted for the first time. The results indicate that it is
reasonable to consider the ring closure step as an intramolecular
nucleophilic addition process rather than an electrocyclic
process. The electronic effect of the substituent is the key factor
in the stereoselectivity: the electron-donating ketene substituents
and the electron-withdrawing imine substituents accelerate the
direct ring closure (increase k1), leading to a preference for cis-
â-lactam formation, while the electron-withdrawing ketene
substituents and the electron-donating imine substituents lower
the direct ring closure (decrease k1), leading to a preference for
trans-â-lactam formation. The electronic effect of the substit-
uents on the isomerization is a minor factor in the stereoselec-
tivity. Through semiquantitatively measuring the relative rate
General Procedure for the Reactions of Acyl Chlorides with
Imines. A flame-dried round-bottom flask was charged with a solution
of imine (1 mmol) and triethylamine (1.3 mmol) in 10 mL of dry
toluene. The flask was immersed in an oil bath and heated to 80 °C. A
solution of the desired acyl chloride (1.3 mmol) in 5 mL of dry toluene
was then added through a dropping funnel during 30 min. The resulting
9
6068 J. AM. CHEM. SOC. VOL. 128, NO. 18, 2006

Relative Stereochemistry of the Staudinger Reaction
A R T I C L E S
solution was stirred for another 2 h at 80 °C. The reaction mixture was
diluted with chloroform, washed successively with saturated NaHCO3
and brine, and dried over Na2SO4. After removal of the solvent, the
residue was directly submitted to NMR analysis to determine the cis/
trans ratio. Column chromatography of the crude mixture on silica gel
afforded the corresponding cis- and trans-â-lactam products.
Foundation of China (Project Nos. 20272002 and 20472005)
and Peking University (President Grant).
Supporting Information Available: Additional experiments
and discussion, detailed kinetic treatment, experimental details,
representative spectra for determining the cis/trans ratios, and
spectroscopic data and 1H NMR spectra of all â-lactam products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank Prof. D. M. Du for supplying
instrumentation and Prof. K. S. Chan for helpful discussions.
This work was supported in part by the National Natural Science
JA056711K
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J. AM. CHEM. SOC. VOL. 128, NO. 18, 2006 6069