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222 Chemistry and Biology of Beta-Lactams
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223Solid Support-Mediated Beta-Lactam Synthesis
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7
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Mechanism of Beta-Lactam Synthesis
by Cycloaddition Reaction
Aparna Das1 and Bimal Krishna Banik
1
Department of Mathematics and Natural Sciences, College of Sciences and Human Studies,
Prince Mohammad Bin Fahd University, Al Khobar 31952, Kingdom of Saudi Arabia.
2
Department of Mathematics and Natural Sciences, College of Sciences and
Human Studies, Deanship of Research Development, Prince Mohammad
Bin Fahd University, Al Khobar 31952, Kingdom of Saudi Arabia.
*Corresponding authors: Bimal Krishna Banik, email: bimalbanik10 @gmail .c om;
bbanik @pmu .edu .sa; Aparna Das, email: aparnadasam @gmail . com
2
7.1 Introduction
Staudinger cycloaddition between ketenes and Schiff bases for the synthesis of β-lactams was discovered
in 19 0 7.1 Since then, it has become one of the most attractive methods for an efcient and stereoselective
method for the synthesis of β-lactams.2 This important process generally uses diverse ketene precursors:
acyl chlorides3 and diazo ketones.
In this chapter, a few experimental-computational studies to identify the mechanism of the cycload-
dition reaction for β-lactam synthesis are described. To identify the origin of the stereochemical outcome of this reaction is crucial, but it is a highly complicated process and still it remains a challenging
objective.
The most important aim is that substituted β-lactams can be directly prepared by this method. The
structures of the reactants are very crucial in the formation of the β-lactams. All experimental conditions
are necessary to follow to describe the most probable mechanism successfully.
4
7.2 Re su lts
Staudinger cycloaddition reaction toward β-lactams is an example of low-energy [2+2] thermal cycloaddition process, for which the least motion supra–supra approach is symmetry forbidden.5 Rather, the
reactants avoid the symmetry but demand [pi2s+pi2s] thermal route through a stepwise mechanism.6 This
reaction involves a sequential formation of the N1–C2 and C3–C4 bonds of the β-lactam through a convergent process (Scheme 7.1).
Cossio et al. conducted numerous seminal mechanistic studies on Staudinger cycloaddition reaction.7
They demonstrated that the rst step of the process is a nucleophilic reaction of the nitrogen of the Schiff
base on the sp-hybridized carbon of the ketene (originated from one of the reactants). This was formed
through a rapid reaction, and the transition structure TS1, a specic zwitterionic intermediate INT, was
developed spontaneously (Scheme 7.1). Then cycloadduct (the nal product) was produced through the
unstable intermediate by a conrotatory ring cyclization associated with one of these transition state structures, TS2. In principle, this was similar with an intramolecular Mannich reaction of the enolate species
with an electrophilic iminium component.8 The intramolecular nature of this second step and the participation of the frontier orbital of the intermediate INT were responsible in creating a rapid conrotatory
224
7
DOI: 10.1201/9780367816339-7
12
INT
Ketene
OH
H
R'
H
R'
st
TS3ciscis
OC
OC
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Precursor
225Mechanism of Beta-Lactam Synthesis by Cycloaddition Reaction
4
3
N
2
1
O
3
TS2
+
TS1
N
O
O
SCHEME 7.1 General Staudinger cycloaddition between ketenes and imines.
MeO
R
O
Cr
OH
H
O
OMe
H
C
+
CO
CO
2
endo
R
N
R'
exo
[M]
OH
MeO
O
[M]
OH
H
N
R'
2
H
R
H
N
R'
2
H
MeO
MeO
SCHEME 7. 2 Chromium carbonyl-mediated β-lactam synthesis.
1
N
4
2
[M]
O
TS3tran
OH
2
[M]
O
H
H R
MeO
R
H
N
R'
R
H
N
R'
O
[M]
OH
2
rans
MeO R
H
O
[M]
OH
2
N
N
pathway in the formation of the second transition structure TS2. The latter step underwent torquoelectronic effects, an effective and powerful process that dictated the nal stereochemistry of the products.
The substituents present in the reactive starting materials indicated the stereochemistry of the prod-
9, 10
uct.
To predict the conguration of the β-lactams seemed impossible as it depends on a number of fac-
tors. The formation of the trans-isomer of a β-lactam was postulated due to the rotation about the N1–C4
bond in the corresponding intermediates.11 In contrast, the cis-product was formed not because of a rotation of this bond. Our group12 demonstrated that polyaromatic imines in some examples produce the corresponding trans-cycloadducts instead of the cis-cycloadducts. Studies on the stereochemistry of these
β-lactams were highly necessary as they are potent anticancer compounds.13 Cossio et al. conducted a
new computational study7 on this method and showed that the kinetic distribution of the cis:trans ratio of
the products can be explained in terms of the E/Z isomerization of the starting imines.
Like acid chlorides, chromium(0)–carbenes were also used as the ketene precursors in this cycloaddi-
13–17
tion.
These chromium complexes acted like ketenes when these are irradiated or reacted with imines
to form the β-lactams. A rearrangement of the carbonyl yielded metallo-zwitterions under the reaction
conditions, which produce the products through a conrotatory ring cyclization. The cis–trans stereochemical feature was originated during the nucleophilic reaction pathway of the nitrogen of the imine to
the oxygen-coordinated ketene portion. It was apparent that there were no differences in the conrotatory
ring closure between the non-metallated and the metallated processes that produce 2-azetidinones in good
yield (Scheme 7.2).
8
226 Chemistry and Biology of Beta-Lactams
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7.2.1 Stereochemical Outcome in the Synthesis of Racemic Monocyclic β-Lactams
To focus on the mechanism of a reaction, it is necessary to know about the reactants, reagents, solvents, and conditions of the process. All of these had a role in the synthesis and mechanism of monocyclic β-lactam formation. For a comparative study, all conditions of the experiments must be described
adequately.
Racemic monocyclic β-lactam synthesis was performed by reacting acid chloride (activated acid)
with 1,2-substituted imine in the presence of triethylamine/(or another tertiary base) at cold conditions
(0–5°C) using a solvent (benzene, toluene, dichloromethane, dichloroethane, and DMF) and then con-
tinuing the reaction at room temperature. Following these conditions, 1,2-diaryl imines with acetoxy,
phenoxy, benzyloxy, and methoxyacetyl chloride gave exclusively cis-β-lactams regardless of the structure of the imines (derived from aromatic or aliphatic compounds).
On the other hand, phenylthioacetyl chloride under the same conditions produced trans-β-lactams.
A mixture of cis- and trans-β-lactams was obtained with 1,2-dialkyl, 1-aryl-2-alkyl, or 1-alkyl-2-aryl
Schiff bases with these acid chlorides. Phthalimidoacetyl chloride also gave a mixture of two β-lactams
under this condition. However, crotonyl chloride and unsaturated acid chloride failed to yield any
β-lactams at room temperature or cold conditions. But at high temperature, the products were obtained
mostly as trans-isomers. A small yield of the cis-isomer was seen with 1-aryl-2-alkyl or 1-alkyl-2-aryl
imines. Interestingly, crotonyl chloride type of acid chloride produced cis-β-lactams with N-alkyl-2carbomethoxy, N-aryl-2-carbomethoxy, N-alkyl-2-methylketone, N-aryl-2-methyl ketone, and conjugated Schiff bases.
All electron-withdrawing groups at the nitrogen of the Schiff bases gave trans-β-lactams. The substituent nature in the acid chloride with chiral features did not have any effects on this reaction, if electronwithdrawing groups were linked to the nitrogen of the imines. Schiff bases derived from polyaromatic
amines and aromatic aldehyde in general gave trans-β-lactams. Moreover, conjugated Schiff bases
derived from conjugated carbonyl systems produced cis-β -lactams regardless of the groups present in
them or in acid chloride. These results conrmed that the groups present at the -C of the Schiff base is
also very important in controlling the conguration of the β-lactams that can be prepared by cycloaddition reaction.
7.2.2 Stereochemical Observations in the Synthesis of Optically Active β-Lactams
Synthesis of chiral β-lactams using different optically active compounds was investigated. These studies established structural requirements on the enantioselectivity and diastereoselectivity of the β-lactam
formation reaction.
7.2.3 Stereochemical Observations in the Synthesis of Chiral
β-Lactams Derived from Chiral Aldehydes
Optically active Schiff bases derived from chiral aldehydes and amines (aromatic, aliphatic, alkenyl,
alkynyl) produced cis-β-lactams. The absolute conguration of the β-lactams was controlled by the
asymmetry of the rst carbon of the aldehyde (or the carbonyl compound). The other optically active
centers present in the aldehydes or carbonyl compounds had no effects on the absolute conguration of
the product β-lactams. Chiral aldehydes in some cases failed to yield β-lactams even in low yield.
7.2.4 Stereochemical Observations in the Synthesis of Optically
Active β-Lactams Derived from Chiral Amines
Reaction of Schiff bases derived from chiral amines and racemic carbonyl molecules gave a mixture
of cis- and trans-β-lactams in different proportions. Sterically crowded chiral amines were found to be
superior in terms of enantioselectivity of the process. These types of amines gave a cis-isomer preferentially at cold conditions or at room temperature.
227Mechanism of Beta-Lactam Synthesis by Cycloaddition Reaction
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7.2.5 Stereochemical Observations in the Synthesis of Chiral
β-Lactams Derived from Chiral Ketenes
Optically active Schiff bases obtained from chiral ketenes and racemic imines gave unpredictable results
when synthesis of β-lactams was considered. A single or a mixture of cis- and trans-β-lactams was
obtained depending upon the nature of the chiral acid chloride (equivalent). It appeared that the rst
asymmetric carbon next to the chiral ketene has an inuence on the production of the chiral compounds.
7.2.6 Stereochemical Observations in the Synthesis of Chiral β-Lactams
Derived from Chiral Aldehydes and Chiral Amines
These types of methods gave a mixture of chiral cis-β-lactams in varying proportions. It was difcult to
predict the isomer ratios since the reaction was dependent on the asymmetric nature of both the aldehyde
and amine components. It was not possible to determine the predominant part.
7.2.7 Stereochemical Observations in the Synthesis of Optically Active
β-Lactams Derived from Chiral Aldehydes and Chiral Ketenes
These reactions gave a mixture of chiral cis-β-lactams with 2-hydroxy acid chlorides. In some instances,
a mixture of cis- and trans-products was obtained. To predict the isomeric ratios of the β-lactams was not
possible since the reaction depends on the conguration of both chiral compounds. In a few examples,
the method gave isomeric mixtures.
7.2.8 Stereochemical Observations in the Synthesis of Optically Active β-Lactams
Derived from Chiral Aldehydes, Chiral Amines, and Chiral Ketenes
These reactions gave a mixture of chiral cis- and trans-β-lactams in varying proportions if all reactants
are chiral. It was not possible to determine the main factors that are responsible for the stereochemical
preference.
7.2.9 Conditions of the β-Lactam Synthesis: Experimental Procedure
The reactions described above to prepare racemic and optically active β-lactams were conducted at cold
or room temperature. In general, acid chloride solution (in dichloromethane, dichloroethane, benzene,
toluene, THF, and DMF) was added to a solution of the Schiff base containing triethylamine (or any
other tertiary amine). The variation of the conditions of the reactions affected the yields and stereoselectivity of the products. In particular, the temperature of the process, heating pattern, heating source,
nature of the solvent, order of addition of the reagents, and rate of addition affected the yield and stereochemistry of the β-lactams.
7.3 Mechanism of Staudinger Reaction
Staudinger cycloaddition for the synthesis of β-lactams has been known for the past more than hundred
years. As stated before, the mechanism and the stereochemical outcome of this reaction remained complicated as these are highly specic. A generalization on this subject was difcult to do. Research on this
subject had resulted in numerous publications. Considering many factors and based upon the results, a
proposal on a two-step zwitterionic mechanism was advanced. It appeared that this two-step mechanism
is accepted by majority of the scientists. Nevertheless, there were no generalizations.
Importantly, the mechanism on zwitterionic intermediate formation was supported by spectroscopic
studies and trapping experiments. The zwitterion intermediate was speculated from a ketene that is generated during the process.
18
228 Chemistry and Biology of Beta-Lactams
'
R''
O
R' H
O
H
H
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It was believed that the least unoccupied molecular orbital (LUMO) of the ketene carbonyl intermediate is attacked by the highest occupied molecular orbital (HOMO) of the Schiff base through an orthogonal approach method. This was in the plane perpendicular to the groups of the ketene, which resulted in
the formation of the zwitterionic structure. This explanation was supported and realized by semiempirical molecular orbital calculation studies (MNDO) of the activated unstable intermediate in the reaction
of methyl ketene and N-methyl-2-methylimine.
This mechanistic route suggested that the attack of the Schiff base takes place from the less hindered
side of the ketene, and this resulted in the formation of the zwitterion. A subsequent rotation of the Schiff
base moiety into the plane of the unstable ketene and a conrotatory ring closure method produced the
thermodynamically less stable β-lactams. The conrotatory ring annulation was successful in the clockwise direction entirely because a ring closure process in anticlockwise direction was not possible. For
this process to occur, this would require the imine and ketene substituents to pass through each other.
These stereochemical origins explained the conguration of the products that are formed from acyclic
imines and ketenes (Scheme 7.3).
It seemed that the substituent R′ on the sp2 carbon center is able to stabilize a positive charge. An isomerization of the zwitterionic species was feasible from the more stable imine to the syn-imine structure
before cyclization process. This operation produced the thermodynamically more stable trans-β-lactam
as the product.19 This happened experimentally with imidates and thioamides. Benzaldimines gave similar results with additional requirements and restrictions. If a large amino R′ substituent was present, this
isomerization is prevented. An isomerization of the zwitterionic species was possible by the addition of
nucleophile followed by a rotation and elimination route. The rate of these processes was able to determine the stereoselectivity of the reaction. With cyclic Schiff base, a trans-β-lactam was the main product
because the substituent in imines is located in syn-geometry (Scheme 7.4).
R
H
N
C
SCHEME 7. 3 Conrotatory cyclization toward β-lactams.
H
R
C
R''
..
R'
R
N
O
H
R
N
O
X
H
N
Nu
R''
H
a
-
Nu
H
H
R'
R
O
H
R'
R
O
R
O
H
N
H
N
R''
(I)
R' =Ph, OMe,SMe
H
R'
H
N
R''
X
H
R
O
R
O
HH
R
O
HH
R'
N
R'
R'
N
R''
X
N
SCHEME 7. 4 Cycloaddition with a cyclic imine that has a heteroatom.
229Mechanism of Beta-Lactam Synthesis by Cycloaddition Reaction
R
H H
trans --lactam
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The origin of stereoselectivity in the Staudinger cycloaddition was focused, and the kinetic origin
of the cis:trans ratio of β-lactam formation was analyzed. Accordingly, the experimental observations
indicated an intramolecular nucleophilic addition pathway but not an electrocyclic route in the cyclization operation. The electron distribution power and the delocalization power of the substituents were the
main components in the stereoselectivity of the reaction. Therefore, the electron-donating ketenes and
the electron-withdrawing imines favored the ring closure (increase k1), leading to cis-β-lactams. Certain
groups in the ketenes and imines made them electron donating or electron withdrawing. On the other
hand, electron-withdrawing ketene substituents and electron-donating imine substituents favored the
ring closure (decrease k1), leading to trans-β-lactams (Scheme 7.5).
The relative stereoselectivity of the process was really composed of a competition between the ring
closure (k1) and the isomerization of the imine (k2) in the intermediates. The actual ratio of k1/k2 was able
to determine the cis:trans ratio of β-lactams. The electronic effect was a key part in the stereoselectivity
of the reaction (Scheme 7.6).
Fernando et al.20 investigated the mechanism of cycloaddition reaction using density functional theory (DFT) extensively. All the precise calculations reported below were performed following DFT.21
The hybrid three-parameter model was denoted as B3LYP.22 The 6-31G* and 6-31+G* basis sets23 as
2
1
R
R
O
R
N
O
cis --lactam
H
1
R
H
N
3
R
D
3
R
2
H H
1
R
k
3
O
2
R
N
3
R
direct
ring-closure
2
R
1
1
C
O
A
R2H
H
N
R
B
k
a
k
3
d
R
N
O
R
C
3
isomerization
k
1
H
H
,
k
2
k
2
SCHEME 7. 5 Direct ring closure and isomerization route toward β-lactams.
EDGcan
accleratre direct ringclosure(increases k
SCHEME 7. 6 Competitive routes for cis- and trans-β-lactams.
Competitionbetween thedirectring-closureand theisomerization
controls therelativestreoselectivity
EWGcanaccleratre both direct
ring-closure andisomerization
(increases both k
)
1
R
O
Bulkygroup canslow
theisomerization
(decrease k
)
2
2
R
H
1
H
N
3
R
and k2)
1
230 Chemistry and Biology of Beta-Lactams
R
1
1
1
H H
3
t
3
https://t.me/med1917
H
+
2
3
R
R
4
NR
O
1
=
a
:
e
M
R
O
1
=
:
c
b
A
R
O
1
=
aa
:
3
bb
3
e
M
R
O
=
:
c
A
R
1
O
R
O
;
;
a
2
2
b
1
2
R
4
R
2
:
R
4
:
R
2
R
N
=
Ph;R
=
PMP;R
=
Ph;R
=
PMP;R
3
R
4
R
3
=
H;R
2
4
3
=
=
H;R
e
M
,
2
3
=
R
4
=
M
,
3
=
R
O
N
O
e
N
SCHEME 7. 7 Stereoselectivity of β-lactam formation using naphthalenyl and indole systems.
H H
e
M
e
H
M
OC
COC
H
C
:
ransr
t
2
.t.
,
r
l
C
2
2
4
5
%
(
)
a
t
io4
N
a
2
cis
O
l
:
1
N
O
-
aa
cis
3
e
M
O
+
O
t
ran
N
-
aa
s
3
2
b
SCHEME 7. 8 Stereoselectivity of β-lactam formation using naphthalenyl and indole systems.
PMP
c
H
C
60
M
COC
2
,
l
2
%
a
t
e
OC
H
C
:
ransr
t
l
.t.
r
)
:
o
i
2.5
1
H
COC
2
.t.
,
r
l
C
2
2
11
%
(
)
a
o
t
i
A
N
N
H
OC
H
C
2
O
(
:
ransr
cis
t
PMP
N
O
N
cis
H
H
c
A
O
O
cis
l
e
M
.
:
7
2
1
NH
+
O
N
PMP
-
bb
3
H
O
O
cis
NH
O
N
PMP
-
cc
H
c
A
O
O
ran
t
e
M
+
NH
O
N
PMP
-
s
bb
3
H
O
O
ran
NH
O
N
PMP
-
s
cc
231Mechanism of Beta-Lactam Synthesis by Cycloaddition Reaction
https://t.me/med1917
SCHEME 7.9 (A) AND 10 (B) Reaction route between ketenes and Schiff base toward β-lactams. Adapted with permis-
sion from Royal Society Advance 2022, 12, 104 –117.
implemented in the GAUSSIAN 0324 were used. Wiberg index25 Bi was measured using the natural bond
orbital (NBO) method.
Cycloaddition Between Aromatic Imines and Aliphatic Ketenes: This subject was studied with
diverse substrates. The results of this reaction were unique and new as precise mechanistic analysis of
this process seemed unpredictable. The reaction between methoxy and acetoxy ketenes and N-aryl Schiff
bases was investigated. These ketenes were generated in the reaction medium by reacting methoxyacetyl
and acetoxyacetyl chloride with triethylamine. The ratios of the cis- and trans-β-lactams formed were
4:1 (Scheme 7.7).
To explain the conguration of these β-lactams’ formation, computer-assisted calculation was studied.
The stereochemistry of the two products was conrmed by X-ray study (Scheme 7.8).
The potential energy surfaces of all intermediates and transition structures of Staudinger reaction
between the above imines and ketenes were identied. The shape of the scans on the reaction coordinates
with respect to physical parameters, internuclear distances, and dihedral angles is shown (Scheme 7.9
and Scheme 7.10).
A comprehensive analysis of the isomerization pathway of the E-Schiff base was investigated. The
complete geometry of the transition state intermediate TSia, the total energies of the two feasible
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