Synthesis of Arylidene-β-lactams via exo-Selective Matsuda-Heck Arylation of Methylene-β-lactams

Article abstract of DOI:10.1021/acs.joc.1c00638

exo-Methylene-β-lactams were synthesized in two steps from commercially available 3-bromo-2-(bromomethyl)propionic acid and reacted with arene diazonium salts in a Heck-type arylation in the presence of catalytic amounts of Pd(OAc)2 under ligand-free conditions. The products, arylidene-β-lactams, were obtained in high yields as single isomers. The β-hydride elimination step of the Pd-catalyzed coupling reaction proceeds with high exo-regioselectivity and E-stereoselectivity. With aryl iodides, triflates, or bromides, the coupling products were isolated only in low yields, due to extensive decomposition of the starting material at elevated temperatures. This underlines that arene diazonium salts can be superior arylating reagents in Heck-type reactions and yield coupling products in synthetically useful yields and selectivities when conventional conditions fail.

Full text of DOI:10.1021/acs.joc.1c00638

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Article
Synthesis of Arylidene-β-lactams via exo-Selective Matsuda-Heck
Arylation of Methylene-β-lactams
̈
Nastja Riemer, Martin Riemer, Mandy Kruger, Guy J. Clarkson, Michael Shipman,**
and Bernd Schmidt*
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ABSTRACT: exo-Methylene-β-lactams were synthesized in two
steps from commercially available 3-bromo-2-(bromomethyl)-
propionic acid and reacted with arene diazonium salts in a
Heck-type arylation in the presence of catalytic amounts of
Pd(OAc)2 under ligand-free conditions. The products, arylidene-β-
lactams, were obtained in high yields as single isomers. The β-
hydride elimination step of the Pd-catalyzed coupling reaction
proceeds with high exo-regioselectivity and E-stereoselectivity.
With aryl iodides, triflates, or bromides, the coupling products
were isolated only in low yields, due to extensive decomposition of
the starting material at elevated temperatures. This underlines that
arene diazonium salts can be superior arylating reagents in Heck-
type reactions and yield coupling products in synthetically useful yields and selectivities when conventional conditions fail.
For example, the penem BRL 42715 (1a) was found to
inhibit certain cephalosporinases 104 to 106 times stronger than
clavulanic acid.5,6 A few years later, Buynak et al. started to
investigate pyridyl-alkylidene-substituted penam sulfones,7 e.g.,
SA-1-204 (1b) and LN-1-255 (1c), as inhibitors of β-
lactamases. Compound SA-1-204 (1b) inhibits class A and
class D β-lactamases efficiently,8 and LN-1-255 (1c) combined
with piperacillin was found to be more active against
Escherichia coli-DH10B strains containing extended spectrum
and inhibitor-resistant β-lactamases than the clinically used
combination of piperacillin and tazobactam.9 The mechanism
of action of these β-lactamase inhibitors was elucidated by
crystallographic and spectroscopic studies.10−12 Very recently,
derivatives of LN-1-255 (1c) that are substituted at the
pyridine ring were synthesized and successfully tested against
multidrug-resistant Acinetobacter baumannii in combination
with the β-lactam antibiotic imipenem.13 Biological activities of
arylidene-β-lactams are, however, not limited to β-lactamase
inhibition: several compounds with this structural pattern (e.g.,
1e) are active against the fungal plant pathogen Alternaria
solani Sorauer, the causal agent of early blight. This disease
mainly affects potato and tomato plants and is responsible for
INTRODUCTION
■
Azetidin-2-ones, also referred to as β-lactams, are the
pharmacophore unit of β-lactam antibiotics, such as penicillins,
cephalosporins, carbapenems, and monobactams. They act by
deactivating transpeptidases via an acylation of a serine residue
at the catalytically active site, which hinders the final step of
bacterial cell wall synthesis.1 The main driving force for the
acylation is the relief of ring strain, as the azetidin-2-one ring is
opened in the process. For β-lactam antibiotics, resistance
mainly occurs through the expression of β-lactamases, which
catalyze the hydrolytic ring opening of the antibiotics and thus
deactivate them.1 A strategy to overcome resistance toward β-
lactam antibiotics relies on the coadministration of β-lactamase
inhibitors, such as tazobactam, which is clinically combined
with piperacillin.2 However, some β-lactamases became in turn
resistant against established, clinically used inhibitors. For
instance, some variants of TEM-1 and SHV-1-β-lactamases,
which are commonly produced by Escherichia coli and
Klebsiella pneumoniae (bacteria responsible for infections of
the urinary and respiratory tract and the bloodstream)
developed a resistance against clavulanic acid.3 As a
consequence, tackling antibiotic resistance does involve not
only the constant search for new antibiotics but also the
development of novel β-lactamase inhibitors1,2 and fluorogenic
probes for detecting β-lactamases.4 Apart from diazabicyclooc-
tanes (DBOs) and cyclic boronic acids, substituted β-lactams,
such as the 3-arylidene-azetidin-2-ones (1), have been
intensively investigated as inhibitors of β-lactamases (Figure
1).
Received: March 17, 2021
Published: June 22, 2021
https://doi.org/10.1021/acs.joc.1c00638
© 2021 American Chemical Society
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chloride by heating in thionyl chloride, which was then treated
with anilines 3a−f without prior purification. Apart from the
acetamide-substituted derivative 4c, all amides were isolated in
fair to good yields. The yield of 4c could not be improved by
using a dimethylformamide-catalyzed synthesis of acid
chlorides;31 these conditions led to the formation of several
unidentified byproducts. The resulting amides 4a−f underwent
a base-mediated intramolecular nucleophilic substitution/
elimination to furnish the α-methylene-β-lactams 5a−f in
moderate overall yields upon treatment with NaH (Table 1).
Table 1. Synthesis of α-Methylene-β-lactams 5
yield
b
yield
(%)
a
a
entry
3
R
4
(%)
5
1
2
3
4
5
6
3a
4-(OCH3)C6H4
4a28
4b
4c
4d
4e28
50
52
13
87
74
5a32,33
5b32
5c
92
63
39
62
74
quant.
3b 4-ClC6H4
3c
3d 3-BrC6H4
3e
3f
4-(NHAc)C6H4
5d
3,4-Cl2C6H3
3-(CF3)-4-ClC6H3 4f
5e28
5f
62
a
b
References reporting characterization data. Yield over two steps
Figure 1. Structures of biologically active azetidin-2-ones.
from 2.
severe economic losses.14 Compound 1d is an effective
histamine-3-receptor-(H3R) agonist at nanomolar concen-
trations. Therapeutic potential of H3R agonists for the
treatment of myocardial ischemia has been demonstrated.15,16
From a synthetic point of view, arylidene-substituted β-
lactams with the general formula 1 offer the opportunity to
connect other pharmacophores to the azetidin-2-one core
through a covalent bond, e.g., by conjugate addition. This
concept is known as pharmacophore hybridization and has
been recognized as an emerging strategy for drug discov-
ery.17,18 Following this concept, β-lactams have been combined
with purine nucleobases in search for novel antiviral agents.19
Previously reported syntheses of arylidene-β-lactams 1, as for
example the β-lactamase inhibitors SA-1-204 (1b) or LN-1-
255 (1c), rely on a Wittig olefination of 6-oxo-penicillanic acid
derivatives, which were in turn synthesized from 6-amino-
penicillanic acid in a multistep synthesis.13 Alternative
strategies (as for example used for the synthesis of 1e)
proceed via a late-stage β-lactamization of 2-aminomethyl
cinnamates, which are accessible via a sequence of Baylis-
Hillman reaction, dehydrative bromination, and nucleophilic
substitution.14,20,21
Heck Reaction of α-Methylene-β-lactam 5a with Aryl
Halides and Triflates. Aryl iodides, bromides, and triflates
are the most commonly used electrophilic coupling partners in
Mizoroki-Heck reactions.34 Conditions that have been
successfully used for the arylation of electron-deficient exo-
methylene heterocycles, e.g., α-methylene-γ-butyrolactones,
involve Pd(OAc)2 as a precatalyst, DMF as a solvent, and
heating at elevated temperatures for up to 24 h.35 In particular,
electron-rich aryl halides often react slowly in Heck reactions
and do not give the desired coupling products in acceptable
yields. It has been shown that in these cases the addition of tri-
ortho-tolyl phosphine in a precatalyst-to-ligand ratio of 1:2
reliably accelerates the reaction and that the coupling products
can be obtained in synthetically useful yields.36,37 We first
investigated the coupling of α-methylene-β-lactam 5a with
iodo-4-methoxybenzene (6a) (Table 2).
Under conditions that have previously been successfully
applied to Heck reactions of electron-rich aryl iodides and α-
methylene-γ-butyrolactones35 or α-methylenesuccinimides,22
we observed full conversion of 5a but very low yields of
coupling product 7aa (entry 1). Presumably, heating the
reaction mixtures at high temperatures over longer periods of
time causes extensive decomposition of the β-lactam starting
materials due to their high ring strain. We reasoned that
activating ligands would allow a lower reaction temperature to
be used. Therefore, P(o-tol)3 was added, and the reaction was
conducted at ambient temperature, which led to the complete
recovery of unreacted 5a (entry 2). We then tested whether
the addition of P(o-tol)3 would enhance the rate of the Heck
coupling at elevated temperature to such an extent that it could
compete with the decomposition reaction, but the result was
virtually identical to that observed without any activating
ligand (entry 3). An even lower yield was obtained with the
triflate 6b38 (entry 4), and no coupling product at all could be
detected with bromo-4-methoxybenzene (6c) (entry 5). In
In continuation of previous studies from our group22,23 on
Heck reactions of exo-methylene-substituted heterocycles with
arene diazonium salts (often named Matsuda-Heck reac-
tions24−27), we investigated the feasibility of this approach for
the regio- and stereoselective synthesis of arylidene-β-lactams.
The results are disclosed herein.
RESULTS AND DISCUSSION
■
Synthesis of α-Methylene-β-lactam Starting Materi-
als. Six α-methylene-β-lactams 5a−f were synthesized by an
adaptation of a previously published route that starts from
commercially available 3-bromo-2-bromomethyl propionic
acid (2).28−30 Carboxylic acid 2 was converted to its acid
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Table 2. Mizoroki-Heck Coupling of α-Methylene-β-lactam 5a with Aryl Halides
a
entry
6
X
ligand (mol %)
base (equiv)
T (°C)
t (h)
conv. (%)
yield of 7aa (%)
1
2
3
4
5
6a
6a
6a
6b
6c
I
I
I
--
NEt3 (3)
NEt3 (3)
NEt3 (3)
NEt3 (3)
NaOAc (3)
90
20
90
90
140
18
18
18
18
1
>95
<5
>95
>95
>95
13
n.d.
10
10
n.d.
P(o-tol)3 (10)
P(o-tol)3 (10)
P(o-tol)3 (10)
P(o-tol)3 (10)
OTf
Br
b
a
b
n.d. = not determined. No product detected.
Table 3. Optimization of Conditions for the Coupling of 5a and Diazonium Salts 8a,b
entry
8 (equiv)
R
solvent
base (equiv)
--
NaOAc (4.0)
t (h)
conv.
7
yield (%)
a
1
2
3
4
5
6
7
8
9
8a (1.0)
8a (1.0)
8a (1.0)
8a (1.0)
8a (1.2)
8b (1.0)
8b (1.0)
8b (1.0)
8b (1.0)
8b (1.0)
8b (1.2)
8b (1.2)
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
CH3CN
CH3CN
CH3OH
CH3OH
CH3OH
CH3CN
CH3CN
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
3
3
3
16
16
3
3
3
3
3
<5
<5
<5
7aa
7aa
7aa
7aa
7aa
7ab
7ab
7ab
7ab
7ab
7ab
7ab
n.d.
n.d.
n.d.
72
a
a
--
b
NaOAc (4.0)
NaOAc (4.0)
--
NaOAc (4.0)
--
NaOAc (4.0)
--
--
n.d.
c
f
>95
a
94
<5
<5
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
a
cd
,
>95
b
n.d.
>95
>95
>95
e
cd
,
10
cd
,
11
12
H
H
12
16
c
f
NaOAc (4.0)
quant.
a
b
c
1
No product observed in H NMR spectrum of crude reaction mixture. Incomplete conversion; qualitatively observed by TLC. No starting
d
e
material 5a observed by TLC and 1H NMR of crude reaction mixture. Formation of unidentified side products. Reaction mixture cooled to 0 °C.
f
Isolated yields on a 0.25 mmol scale.
both cases, complete consumption of the starting material 5a
was observed.
solvent plays a decisive role. For these reasons, routinely
screening Matsuda-Heck couplings with hitherto unexplored
olefins in acetonitrile and methanol under both basic and base-
free conditions has proved successful for identifying optimized
reaction conditions. We investigated two test reactions: the
coupling of 5a with 4-methoxybenzenediazonium tetrafluor-
oborate (8a) and with 4-hydroxy-benzenediazonium tetra-
fluoroborate (8b). We know from previous investigations that
these diazonium salts often require orthogonal reaction
conditions; for example, the Pd-catalyzed coupling of 8a with
methyl acrylate gives higher yields in the absence of a base,
while the addition of NaOAc is mandatory for phenol
diazonium salt 8b.44 For the coupling of both diazonium
salts, acetonitrile turned out to be an unsuitable solvent,
because neither basic nor base-free conditions led to a notable
conversion of the starting material 5a (entries 1, 2, 6, and 7).
The same result was observed for 8a in methanol under base-
free conditions (entry 3). Upon addition of NaOAc, most of
the starting material 5a was consumed, and the coupling
product 7aa was isolated in 72% yield (entry 4). Quantitative
conversion and isolation of the product 7aa in a nearly
quantitative yield was accomplished by using a slight excess of
the diazonium salt (1.2 equiv, entry 5).
Optimization of Coupling Conditions for Arene
Diazonium Salts 8. In contrast to Heck-type reactions with
aryl halides, the addition of phosphine ligands has normally
detrimental effects when arene diazonium salts are used. It is
therefore generally advisible to avoid such ligands with these
electrophilic coupling partners. However, in recent work, it was
demonstrated that N,N-chelating or pyridine ligands enable
the control of enantioselectivity39−41 or the use of allylic
alcohols as substrates.42 A more contentious issue is the role of
the base in these reactions. Examples for beneficial as well as
deleterious effects of bases in Pd-catalyzed couplings with
arene diazonium salts have been reported. As Felpin et al. state,
there is an apparent correlation between the solvent used and
the effect of added base.25 While in acetonitrile a base is almost
always required to obtain useful conversions,43 it should be
avoided if alcohols are the preferred solvents.22 It is sometimes
difficult to predict whether acetonitrile or methanol is the
solvent of choice for a Matsuda-Heck reaction. This depends
on the structure of the olefin and the diazonium salt, and apart
from stability issues (that take the nucleophilic nature of
methanol and the sensitivity of the diazonium salt into
account), the solubility of the reactants in the respective
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In contrast to the methoxy-substituted diazonium salt 8a
(entry 3), we observed full conversion of the starting material
5a with phenol diazonium salt 8b in methanol under base-free
conditions (entry 8). The NMR spectra of the crude reaction
mixture show that the arylidene β-lactam 7ab is the major
product but that at least one byproduct is formed (ca. 30%, as
estimated from the integrals of the OH protons), which could
not be identified due to similar polarity and overlapping signals
Table 4. Arene Diazonium Salts Used in This Study
No
R1
R2
R3
R4
R5
ref.
1
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
OCH3
OH
OBn
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
45
44
45
46
47
48
49
50
51
52
44
44
22
53
47
in the aromatic and olefinic region of the H NMR spectrum.
Possible side products are the Z-stereoisomer or the endo-
regioisomer of 7ab, but an acid-catalyzed ring opening by trace
amounts of water present in the reaction mixture is also
conceivable, because 1 equiv of HBF4 is formed during the
reaction, which is not neutralized in the absence of a base.
Indeed, no side products were observed if the reaction was run
in the presence of NaOAc, but the conversion was incomplete
with equimolar amounts of reactants (entry 9). Running the
reaction at lower temperature (0 °C, entry 10) or with an
excess of diazonium salt (1.2 equiv, entry 11) again resulted in
full conversion but also in the formation of the same
byproducts as observed under the conditions listed in entry
8. Quantitative conversion and high selectivity were observed
with added NaOAc and a slight excess of diazonium salt.
Under these conditions, the coupling product 7ab was
obtained in quantitative isolated yield (entry 12).
The optimized conditions for the Matsuda-Heck arylation of
α-methylene-β-lactams are similar to those identified earlier for
itaconimides22 or α-methylene-γ- or δ-lactones and lactams.23
However, with these substrates, base-free conditions are
preferred. The reason why α-methylene-β-lactams require
added base is most likely the high tendency of the strained
four-membered rings to undergo hydrolytic ring opening in the
presence of an acid. In contrast to Heck-type arylations with
aryl iodides, the coupling with the corresponding diazonium
salts proceeds at ambient temperature, which is important to
avoid decomposition of either the starting β-lactams or the
products under the reaction conditions.
CN
C(O)CH3
NHAc
NO2
H
H
OH
OH
Cl
OCH3
Cl
CF3
CH3
Br
CO2CH3
H
OCH3
H
OCH3
H
with diazonium salt 8a), we observed the formation of a
mixture of coupling products under standard conditions. The
expected product 7ca was isolated in a low yield of 28%,
whereas the double arylated product 9ca was obtained in a
somewhat higher yield of 41%, even though only 1.2 equiv of
diazonium salt was used. Although geminal Matsuda-Heck
diarylations have occasionally been reported as side reac-
tions,55,56 examples for the intentional double arylation are
scarce and normally require special conditions or catalysts57,58
or at least a 2-fold excess of diazonium salt.22 Currently, it
remains unclear why the double arylated compound 9ca is the
major product in this case.
Compound 1e (see Figure 1 and Introduction), obtained in
93% yield from the coupling of p-chlorophenyl-substituted β-
lactam 5b and p-chlorobenzene diazonium salt 8o, has
previously been synthesized in four steps via the Baylis-Hilman
reaction and intramolecular nucleophilic substitution. In an
antifungal activity assay, 1e was found to be the most active
out of 28 compounds tested for their activity against the plant
pathogen Alternaria solani Sorauer.14 All other coupling
products 7 shown in Table 5 have not been described in the
literature so far.
Structure Elucidation and Assignment of exo-E-
Configuration for the Coupling Products 7. Several 3-
arylidene-azetidin-2-ones with the general structure 1 (Figure
1) have previously been synthesized via one of the routes
mentioned in the Introduction. In almost all cases, an exo-E-
structure was assigned to the reaction products.14,21,59−61 In a
few reports describing the synthesis of 3-arylidene-2-azetidin-2-
ones via intramolecular nucleophilic substitution, the exo-E-
structure was deduced from the double bond configuration of
the acyclic precursors, but evidence for their configurational
assignment was not provided.20,29 Mixtures of E- and Z-
isomers of 3-arylidene-azetidin-2-ones and 3-alkylidene-azeti-
din-2-ones result from olefin cross-metathesis reactions of α-
methylene-β-lactams 5 with styrenes and 1-alkenes, respec-
tively.62 The stereoisomers were separated and individually
characterized by 1D NMR methods, but direct spectroscopic
or other analytical evidence for the assigned stereochemistry
Substrate Scope and Limitations. We applied the
optimized conditions (Table 3, entries 5 and 12) for the
coupling of 5a and diazonium salts 8a,b to other diazonium
salts 8c−o (see Table 4 for an overview of diazonium salts
used in this study) and α-methylene-β-lactams 5b−e (see
Table 1). The results are summarized in Table 5.
In most cases, the desired coupling products were obtained
in good to excellent yields as single isomers, with the following
exceptions: (i) Compound 7ae, resulting from the coupling of
5a and 4-cyanobenzene diazonium salt 8e, was isolated in a
moderate yield of 52%, which can probably be explained by
partial catalyst deactivation due to coordination of the nitrile to
Pd.54 (ii) With 4-acetamido benzenediazonium salt 8g and 3-
(methylcarboxylate) phenol diazonium salt 8l conversions to
7ag and 7al, respectively, remained below 5%. We have
previously obtained high yields for the coupling of both
diazonium salts with methyl acrylate44,49 but only under base-
free conditions, which are not tolerated with α-methylene-β-
lactams 5. (iii) All attempts to couple 5a with the electron-
deficient 4-nitrobenzene diazonium salt 8h resulted in full
conversion of the starting material but led to the formation of a
complex mixture of products. We have previously observed
sluggish couplings with highly electron-deficient diazonium
salts, mainly due to uncontrollable addition of the solvent
methanol to the C=C double bond and hydrodediazonation of
the diazonium cation.44 (iv) In one case (the coupling of 5c
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a b
,
Table 5. Scope of the Matsuda-Heck Arylation of α-Methylene-β-lactams 5
a
The first letter of the compound number 7xy refers to the β-lactam 5, and the second letter refers to the diazonium salt 8 used for its synthesis.
Coupling of 5a and 8a to 7aa was performed on a 1.0 mmol scale.
b
was not given. However, in a related study on the cross-
Proof for the exo-arrangement of the double bond in
compounds 7 are HMBC interactions between H2′ and C5
and C2′ and H5 and HMBC interactions between H4 and C2,
C3, and C5. In all compounds 7, the proton H5 appears as a
triplet with a 4J-value of 1.4 Hz at ∼7 ppm, and the methylene
group H4 appears as a doublet with the same coupling
constant at ∼4.5 to 4.6 ppm. Howell and co-workers reported
very similar values for the E-configured cross-metathesis
products of N-Boc-protected α-methylene-β-lactam and
styrenes and notably lower (ca. 6.5 ppm for H5 and ca. 4.0
ppm for H4) values for the Z-isomer.62 We observed NOE
interactions between the methylene group of the β-lactam ring
(protons H4) and the ortho-protons of both aryl groups
(protons H2′ and H2″). Due to the small chemical shift
differences in the aromatic region, it was difficult to assign the
observed NOEs unambiguously to the relevant ortho-protons
H2′. Gratifyingly, single crystals suitable for X-ray crystallo-
graphic analysis could be obtained from a DMSO solution of
compound 7bb. Single crystal X-ray structure analysis revealed
unambiguously the assigned exo-E-structure. One molecule of
metathesis of substituted α-methylene-β-lactones, the observed
Z-stereochemistry of the products was determined by NOESY
experiments, which may allow to some extent conclusions by
analogy for the β-lactam cross-metathesis products.63 Examples
of ring closing metathesis reactions of α-methylene-β-lactams
leading to Z-isomers have been reported, and the products
have been fully characterized by single crystal X-ray structure
analysis.64 This lack of direct spectroscopic and analytical proof
for the exo-E-structures assigned to 3-arylidene-azetidin-2-ones
prompted us to perform a comprehensive NMR spectroscopic
investigation using 2D methods for two 3-arylidene-azetidin-2-
ones, compounds 7ab and 7bb, and for the double arylated
product 9ca. A combination of H,H-COSY, HSQC, and
HMBC experiments allowed a full signal assignment for
compounds 7ab and 7bb and an assignment of the most
relevant signals of 9ca. The numbering scheme refers to the
signal assignment used in the Experimental Section and in the
discussion (Figure 2).
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starting materials, the Pd-catalyzed coupling with arene
diazonium salts is highly E-stereoselective.
EXPERIMENTAL SECTION
General Methods. All experiments were conducted in dry
reaction vessels under an atmosphere of dry nitrogen. Solvents were
purified by standard procedures. Unless otherwise stated, reaction
■
1
mixtures were heated with silicon oil baths. H NMR spectra were
obtained at 300, 400, or 500 MHz in CDCl3 with CHCl3 (δ = 7.26
ppm) as an internal standard. Coupling constants are given in Hz. 13C
NMR spectra were recorded at 75 MHz, 101 or 125 MHz in CDCl3
with CDCl3 (δ = 77.1 ppm) as an internal standard. 19F NMR spectra
were recorded at 376 MHz. Whenever the solubility of the sample was
insufficient in CDCl3, it was replaced by DMSO-d6 (DMSO-d5 as an
internal standard for 1H NMR spectroscopy, δ = 2.50 ppm, DMSO-d6
as an internal standard for 13C NMR spectroscopy, δ = 39.5 ppm). In
1
all cases where signal assignments are given for H and 13C NMR
data, these are based on 2D NMR spectra such as H,H-COSY,
HSQC, HMBC, and NOESY. IR spectra were recorded as ATR-FTIR
spectra. Wavenumbers (ν) are rounded to 1 cm−1. The peak
intensities are defined as strong (s), medium (m), or weak (w). Low-
and high-resolution mass spectra were obtained by EI-TOF or ESI-
TOF. Although arene diazonium tetrafluoroborates are generally
considered to be thermally very stable and we have never experienced
any cases of violent decomposition, there have been reports of
explosions caused by arene diazonium tetrafluoroborates. We
recommend that these compounds are therefore handled with care
and that safety measures65 are thoroughly obeyed. All arene
diazonium salts used in this work were synthesized following
previously published literature procedures (Table 4).
General Procedure for the Synthesis of 3-Bromo-2-
bromomethylpropionic Acid Anilides 4. 3-Bromo-2-bromome-
thylpropanoic acid (2, 1.24 g, 5.0 mmol) was heated in SOCl2 (2.50
mL, 4.10 g, 34.5 mmol) at 75 °C for 5 h. The mixture was cooled to
ambient temperature, and all volatiles were evaporated in vacuo. The
residue was dissolved in dry and degassed CH2Cl2 and cooled to 0 °C.
A solution of the respective aniline 3 (10.0 mmol) was added
dropwise at 0 °C; the mixture was allowed to warm to ambient
temperature and stirred for 12 h. It was diluted with CH2Cl2 (15 mL)
and washed with HCl (aq.) (2 M, 2·10 mL) and water (10 mL). The
organic layer was dried with MgSO4, filtered, and evaporated until the
product started to precipitate. The solution was stored at −18 °C to
ensure complete crystallization for 12 h. The products were isolated as
colorless crystals by removing the supernatant solution. Alternatively,
the products can be purified by chromatography on silica, using
hexanes/ethyl acetate mixtures of increasing polarity as eluent.
3-Bromo-2-(bromomethyl)-N-(4-methoxyphenyl)propanamide
(4a).28 Following the general procedure, 3a (1.23 g, 10.0 mmol, 2.0
equiv) was converted to 4a (0.89 g, 2.5 mmol, 50%); purification by
chromatography (hexanes/ethyl acetate mixtures 5:1 to 3:1 (v/v)):
colorless solid, mp 166−167 °C; 1H NMR (300 MHz, CDCl3) δ 7.42
(d, J = 9.0 Hz, 2H), 7.36 (s (br.), 1H), 6.88 (d, J = 9.0 Hz, 2H), 3.80
(s, 3H), 3.70 (dd, J = 10.2, 8.1 Hz, 2H), 3.58 (dd, J = 10.3, 5.8 Hz,
2H), 3.09−3.06 (m, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 168.2,
157.3, 130.1, 122.6, 114.4, 55.7, 53.1, 31.1; IR (ATR) ν 3282 (m),
1651 (s), 1600 (m), 1542 (s), 1224 (s), 825 (s); HRMS (EI) m/z
calcd for C11H1379Br2NO2 [M]+ 348.9308, found 348.9302.
Figure 2. Numbering scheme for compounds 7. Full assignment of
1H and 13C NMR signals for compounds 7ab, 7bb, and 9ca and
relevant HMBC and NOE interactions. Molecular structure of 7bb
(single crystal X-ray analysis).
DMSO is incorporated in the unit cell; the oxygen atom of the
DMSO molecule binds to the phenolic OH group of 7bb
through a hydrogen bond (d = 183 pm).
The structure of 9ca is supported by HMBC interactions
between the protons of the β-lactam methylene group (H4)
and quaternary carbons C2, C3, and C5. The signals for the
carbonyl group of the β-lactam (C2) and the acetamide group
can be distinguished by an HMBC interaction between the
signals for the amide proton at 7.31 ppm and the acetamide
carbon at 168.3 ppm.
CONCLUSIONS
■
In summary, we report that 3-arylidene-azetidin-2-ones, which
are relevant substructures in β-lactamase inhibitors and other
bioactive molecules, can be synthesized in high yield and
selectivity from α-methylene-β-lactams and arene diazonium
salts in a Heck-type coupling reaction, using Pd(OAc)2 as a
precatalyst. The coupling proceeds efficiently at ambient
temperature under ligand-free conditions but requires added
base to avoid acid-induced decomposition of the β-lactams.
Notably, conventional Heck-coupling conditions (aryl iodides,
activating ligands, elevated temperatures) fail with α-
methylene-β-lactams due to decomposition of the olefinic
coupling partner at the required reaction temperature. In
contrast to olefin cross-metathesis reactions, which give 3-
arylidene-azetidin-2-ones as E/Z-mixtures from the same
3-Bromo-2-(bromomethyl)-N-(4-chlorophenyl)propanamide
(4b). Following the general procedure, 3b (1.28 g, 10.0 mmol, 2.0
equiv) was converted to 4b (0.92 g, 2.6 mmol, 52%); purification by
chromatography (hexanes/ethyl acetate mixtures 5:1 to 3:1 (v/v)):
1
colorless solid, mp 160−161 °C; H NMR (400 MHz, DMSO-d6) δ
10.39 (s (br.), 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H),
3.73−3.63 (m, 4H), 3.32−3.23 (m, 1H); 13C{1H} NMR (101 MHz,
DMSO-d6) δ 168.4, 137.5, 128.7, 127.3, 120.9, 50.6, 32.0; IR (ATR)
ν 3303 (m), 1656 (s), 1608 (s), 1544 (s), 1489 (s), 1398 (s), 824 (s);
HRMS (ESI) m/z calcd for C10H1179Br235ClNO [M + H]+ 353.8896,
found 353.8904.
N-(4-Acetamidophenyl)-3-bromo-2-(bromomethyl)-
propanamide (4c). Following the general procedure, 3c (1.50 g, 10.0
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mmol, 2.0 equiv) was converted to 4c (0.24 g, 0.6 mmol, 13%);
purification by chromatography (hexanes/ethyl acetate mixtures 5:1
to 3:1 (v/v)): colorless solid, mp 198−200 °C; 1H NMR (400 MHz,
DMSO-d6) δ 10.18 (s (br.), 1H), 9.88 (s (br.), 1H), 7.58−7.43 (m,
4H), 3.72−3.62 (m, 4H), 3.30−3.20 (m, 1H), 2.02 (s, 3H); 13C{1H}
NMR (101 MHz, DMSO-d6) δ 168.0, 167.8, 135.2, 133.8, 119.8,
119.3, 50.5, 32.2, 23.9; IR (ATR) ν 3280 (s), 1652 (s), 1549 (s),
1516 (s), 1371 (s), 1312 (m), 1127 (m), 833 (s), 715 (s); HRMS
(EI) m/z calcd for C12H1479Br2N2O2 [M]+ 375.9417, found 375.9411.
3-Bromo-2-(bromomethyl)-N-(3-bromophenyl)propanamide
(4d). Following the general procedure, 3d (1.72 g, 10.0 mmol, 2.0
equiv) was converted to 4d (1.75 g, 4.4 mmol, 87%); purification by
chromatography (hexanes/ethyl acetate mixtures 5:1 to 3:1 (v/v)):
(s); HRMS (ESI) m/z calcd for for C11H11NNaO2 [M + Na]+
212.0682, found 212.0684.
1-(4-Chlorophenyl)-3-methyleneazetidin-2-one (5b).32 Following
the general procedure, anilide 4b (355 mg, 1.00 mmol) was converted
to 5b (122 mg, 0.63 mmol, 63%); purification by chromatography
(hexanes/ethyl acetate mixtures 10:1 to 5:1 (v/v)): off-white solid,
1
mp 92−93 °C; H NMR (300 MHz, CDCl3) δ 7.37−7.29 (m, 4H),
5.90 (q, J = 1.7 Hz, 1H), 5.37 (q, J = 1.3 Hz, 1H), 4.13 (t, J = 1.5 Hz,
2H); 13C{1H} NMR (126 MHz, CDCl3) δ 160.2, 143.3, 136.9, 129.5,
129.3, 117.7, 112.0, 48.0; IR (ATR) ν 2921 (w), 1725 (s), 1491 (s),
1376 (s), 1131 (m), 826 (s); HRMS (EI) m/z calcd for
C10H835ClNO [M+] 193.0289, found 193.0293.
N-(4-(3-Methylene-2-oxoazetidin-1-yl)phenyl)acetamide (5c).
Following the general procedure, anilide 4c (235 mg, 0.62 mmol)
was converted to 5c (51 mg, 0.24 mmol, 39%); purification by
chromatography (hexanes/ethyl acetate mixtures 10:1 to 5:1 (v/v)):
1
colorless solid, mp 123−125 °C; H NMR (400 MHz, DMSO-d6) δ
10.44 (s (br.), 1H), 7.99−7.96 (m, 1H), 7.50 (ddd, J = 7.0, 2.1, 2.1
Hz, 1H), 7.33−7.24 (m, 2H), 3.73−3.63 (m, 4H), 3.31−3.23 (m,
1H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 168.7, 140.1, 130.8,
126.3, 121.7, 121.6, 118.1, 50.7, 31.9; IR (ATR) ν 3280 (s), 1657 (s),
1589 (s), 1535 (s), 1476 (s), 1403 (m), 1344 (m), 1175 (m), 861
(m); HRMS (EI) m/z calcd for C10H1179Br3NO [M + H]+ 397.8391,
found 397.8376.
1
off-white solid, mp 175−176 °C; H NMR (500 MHz, DMSO-d6) δ
9.96 (s, 1H), 7.59 (d, J = 8.9 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H), 5.76
(s, 1H), 5.45 (s, 1H), 4.19 (s, 2H), 2.02 (s, 3H); 13C{1H} NMR (126
MHz, DMSO-d6) δ 168.1, 159.3, 143.7, 135.5, 133.5, 119.8, 116.6,
111.3, 47.7, 23.9; IR (ATR) ν 3321 (w), 1724 (s), 1677 (m), 1539
(m), 1512 (s), 826 (s); HRMS (ESI) m/z calcd for C12H12N2O2
[M+] 216.0893, found 216.0887.
3-Bromo-2-(bromomethyl)-N-(3,4-dichlorophenyl)propanamide
(4e).28 Following the general procedure, 3e (1.62 g, 10.0 mmol, 2.0
equiv) was converted to 4e (1.44 g, 3.7 mmol, 74%); purification by
chromatography (hexanes/ethyl acetate mixtures 5:1 to 3:1 (v/v)):
1-(3-Bromophenyl)-3-methyleneazetidin-2-one (5d). Following
the general procedure, anilide 4d (400 mg, 1.00 mmol) was converted
to 5d (148 mg, 0.62 mmol, 62%); purification by chromatography
(hexanes/ethyl acetate mixtures 10:1 to 5:1 (v/v)): colorless solid,
mp 110−112 °C; 1H NMR (600 MHz, CDCl3) δ 7.53−7.48 (m, 1H),
7.36 (dt, J = 7.2, 1.9 Hz, 1H), 7.24 (dt, J = 7.9, 1.7 Hz, 1H), 7.22 (dd,
J = 7.7, 7.4 Hz, 1H), 5.92 (q, J = 1.7 Hz, 1H), 5.39 (q, J = 1.4 Hz,
1H), 4.14 (dd, J = 1.7, 1.4 Hz, 2H); 13C{1H} NMR (151 MHz,
CDCl3) δ 160.3, 143.2, 139.5, 130.8, 127.2, 123.1, 119.4, 115.2, 112.3,
48.1; IR (ATR) ν 1738 (s), 1596 (m), 1482 (m), 923 (s), 769 (s);
HRMS (EI) m/z calcd for C10H879BrNO [M+] 236.9784, found
236.9769.
1
colorless solid, mp 157−160 °C; H NMR (400 MHz, DMSO-d6) δ
10.57 (s (br.), 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H),
7.50 (dd, J = 8.8, 2.4 Hz, 1H), 3.74−3.62 (m, 4H), 3.32−3.22 (m,
1H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 168.9, 138.6, 131.1,
130.8, 125.2, 120.5, 119.5, 50.7, 31.8; IR (ATR) ν 3107 (m), 1661
(s), 1607 (s), 1586 (s), 1531 (s), 1468 (s), 1299 (m), 820 (s); HRMS
(EI) m/z calcd for C10H1079Br235Cl2NO [M + H]+ 387.8506, found
387.8498.
3-Bromo-2-(bromomethyl)-N-[4-chloro-3-(trifluoromethyl)-
phenyl]propanamide (4f). Following the general procedure, 3f (1.96
g, 10.0 mmol, 2.0 equiv) was converted to 4f (1.30 g, 3.1 mmol,
62%); purification by chromatography (hexanes/ethyl acetate
mixtures 5:1 to 3:1 (v/v)): colorless solid, mp 96−99 °C; 1H
NMR (400 MHz, DMSO-d6) δ 10.73 (s (br.), 1H), 8.20 (d, J = 2.8
Hz, 1H), 7.86 (dd, J = 8.8, 2.5 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H),
3.74−3.65 (m, 4H), 3.34−3.24 (m, 1H); 13C{1H} NMR (101 MHz,
DMSO-d6) δ 169.1, 138.0, 132.3, 126.8 (q, J = 30.5 Hz), 124.4 (q, J =
1.8 Hz), 124.1, 122.6 (q, J = 272.8 Hz), 117.9 (q, J = 5.6 Hz), 50.8,
31.8; 19F NMR (377 MHz, DMSO-d6) δ −61.7 ; IR (ATR) ν 1661
(s), 1598 (m), 1543 (s), 1480 (s), 1421 (m), 1319 (s), 1175 (m),
1127 (s), 1111 (s); HRMS (EI) m/z calcd for C11H1079Br235ClF3NO
[M + H]+ 421.8770, found 421.8762.
1-(3,4-Dichlorophenyl)-3-methylideneazetidin-2-one (5e).28 Fol-
lowing the general procedure, anilide 4e (390 mg, 1.00 mmol) was
converted to 5e (169 mg, 0.74 mmol, 74%); purification by
chromatography (hexanes/ethyl acetate mixtures 10:1 to 5:1 (v/
v)): colorless solid, mp 122−124 °C (reported in the literature: mp
128−129 °C);28 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 2.4 Hz,
1H), 7.40 (d, J = 8.7 Hz, 1H), 7.27 (dd, J = 8.7, 2.4 Hz, 1H), 5.92 (q,
J = 1.7 Hz, 1H), 5.40 (q, J = 1.7 Hz, 1H), 4.13 (dd, J = 1.7, 1.4 Hz,
2H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.2, 143.0, 137.7, 133.4,
131.1, 127.4, 118.1, 115.9, 112.7, 48.2; IR (ATR) ν 1745 (s), 1730
(s), 1482 (s), 1394 (s), 1483 (s); HRMS (EI) m/z calcd for
C10H735Cl2NONa [M + Na]+ 249.9797, found 249.9790.
General Procedure for the Synthesis of α-Methylene-β-
lactams 5. The corresponding 3-bromo-2-bromomethyl-propiona-
mide 4 (1.00 mmol) was dissolved in dry and degassed THF (10
mL). NaH (60 wt % dispersion in mineral oil, 80 mg, 2.00 mmol) was
added in small portions at ambient temperature, and the mixture was
stirred for 16 h. The reactions was quenched by addition of saturated
aq. NH4Cl solution (8 mL), and ethyl acetate (30 mL) was added.
The organic layer was separated, and the aqueous layer was extracted
with ethyl acetate (2 × 30 mL). The combined organic layers were
washed with brine (20 mL) and dried with MgSO4, filtered, and
evaporated. The crude product was purified by column chromatog-
raphy on silica, using hexanes/ethyl acetate mixtures of increasing
polarity as eluent, to furnish the α-methylene-β-lactams 5.
1-[4-Chloro-3-(trifluoromethyl)phenyl]-3-methylideneazetidin-2-
one (5f). Following the general procedure, anilide 4f (305 mg, 0.72
mmol) was converted to 5f (188 mg, 0.72 mmol, quant.); purification
by chromatography (hexanes/ethyl acetate mixtures 10:1 to 5:1 (v/
v)): colorless solid, mp 100−102 °C; 1H NMR (400 MHz, CDCl3) δ
7.62−7.56 (m, 2H), 7.47 (d, J = 8.5 Hz, 1H), 5.95 (q, J = 1.8 Hz,
1H), 5.44 (q, J = 1.8 Hz, 1H), 4.18 (t, J = 1.4 Hz, 2H); 13C{1H}
NMR (101 MHz, CDCl3) δ 160.3, 143.0, 137.1, 132.5, 129.3 (q, J =
31.7 Hz), 125.3 (d, J = 280.5 Hz), 121.2, 120.6, 115.2 (q, J = 5.5 Hz),
113.0, 48.2; 19F NMR (377 MHz, CDCl3) δ −62.9; IR (ATR) ν 1731
(s), 1486 (s), 1436 (s), 1367 (s), 1107 (s), 934 (s), 832 (s); HRMS
(ESI) m/z calcd for C11H835ClF3NO [M + H]+ 262.0241, found
262.0241.
Heck Coupling of β-Lactam 5a with 4-Iodoanisol (6a) to
7aa. To a solution of 5a (47 mg, 0.25 mmol) and 4-iodoanisol (6a,
70 mg, 0.30 mmol) in DMF (2.0 mL) were added NEt3 (105 μL, 0.75
mmol), Pd(OAc)2 (2.8 mg, 5 mol %), and optionally P(o-tol)3 (7.6
mg, 10 mol %). The solution was heated to 90 °C for 4 h and then
cooled to ambient temperature. The starting material 5a was fully
consumed, as indicated by TLC. The mixture was diluted with
CH2Cl2 (30 mL) and washed with water (20 mL) and brine (20 mL).
The organic extract was dried with MgSO4, filtered, and evaporated.
The residue was purified by column chromatography on silica, using a
1-(4-Methoxyphenyl)-3-methyleneazetidin-2-one (5a)..32,33 Fol-
lowing the general procedure, anilide 4a (4.50 g, 12.8 mmol) was
converted to 5a (2.23 g, 11.8 mmol, 92%); purification by
chromatography (hexanes/ethyl acetate mixtures 10:1 to 5:1 (v/
v)): off-white solid, mp 112−113 °C (reported in the literature:33 mp
1
108−109 °C); H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 9.1 Hz,
2H), 6.89 (d, J = 9.1 Hz, 2H), 5.83 (q, J = 1.7 Hz, 1H), 5.30 (q, J =
1.3 Hz, 1H), 4.09 (t, J = 1.5 Hz, 2H), 3.79 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 159.8, 156.5, 143.8, 132.2, 117.8, 114.7, 110.6,
55.7, 48.0; IR (ATR) ν 1722 (s), 1512 (m), 1384 (m), 1239 (m), 825
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hexanes/ethyl acetate mixture (10:1 (v/v)) as eluent, to furnish 7aa
(7 mg, 0.02 mmol, 10%). Analytical data are identical to those
obtained for the product of the coupling of 5a and diazonium salt 8a.
General Procedure for the Synthesis of α-Arylidene-β-
lactams 7 by Matsuda-Heck Coupling. To a solution of the
corresponding α-methylene-β-lactam 5 (0.25 mmol) and the
corresponding arene diazonium salt 8 (0.30 mmol) in methanol (4
mL) were added NaOAc (82 mg, 1.00 mmol) and Pd(OAc)2 (2.8 mg,
5 mol %). The mixture was stirred at ambient temperature for 16 h,
dry-loaded on silica (by mixing with silica (1 g) and evaporating all
volatiles), and purified by column chromatography on silica, using
hexanes/ethyl acetate mixtures of increasing polarity as eluents to
furnish the coupling products 7.
(E)-3-(4-Methoxybenzylidene)-1-(4-methoxyphenyl)azetidin-2-
one (7aa). Following the general procedure, 5a (189 mg, 1.00 mmol)
and 8a (266 mg, 1.20 mmol) were converted to 7aa (251 mg, 0.85
mmol, 85%). For the optimization study (Table 3) compounds 5a
(47 mg, 0.25 mmol) and 8a (67 mg, 0.30 mmol) were converted to
7aa (69 mg, 0.23 mmol, 94%); purification by chromatography
(hexanes/ethyl acetate mixture 10:1 (v/v)): colorless solid, mp 188−
189 °C; 1H NMR (600 MHz, DMSO-d6) δ 7.47 (d, J = 8.8 Hz, 2H),
7.36 (d, J = 8.8 Hz, 2H), 7.02 (t, J = 1.5 Hz, 1H), 7.01 (d, J = 8.8 Hz,
2H), 6.99 (d, J = 8.8 Hz, 2H), 4.55 (d, J = 1.5 Hz, 2H), 3.80 (s, 3H),
3.74 (s, 3H); 13C{1H} NMR (150 MHz, DMSO-d6) δ 160.4, 160.3,
155.4, 132.7, 132.1, 130.5, 126.6, 124.0, 117.2, 114.6, 114.5, 55.3,
55.3, 48.3; IR (ATR) ν 2926 (w), 1720 (s), 1602 (m), 1508 (s), 1241
(s); HRMS (ESI) m/z calcd for C18H18NO3 [M + H]+ 296.1287,
found 296.1262.
(E)-3-(4-Hydroxybenzylidene)-1-(4-methoxyphenyl)azetidin-2-
one (7ab). Following the general procedure, 5a (47 mg, 0.25 mmol)
and 8b (62 mg, 0.30 mmol) were converted to 7ab (70 mg, 0.25
mmol, quant.); purification by chromatography (hexanes/ethyl
acetate mixture 10:1 (v/v)): yellow solid, mp 223−225 °C; 1H
NMR (400 MHz, DMSO-d6) δ 9.98 (s (br.), 1H, OH), 7.35 (d, J =
8.8 Hz, 2H, H2′), 7.34 (d, J = 9.1 Hz, 2H, H2″), 6.97 (d, J = 9.1 Hz,
2H, H3″), 6.95 (s (br.), 1H, H5), 6.83 (d, J = 8.6 Hz, 2H, H3′), 4.50
(s(br.), 2H, H4), 3.74 (s, 3H, OCH3); 13C{1H} NMR (101 MHz,
DMSO-d6) δ 160.7 (C2), 158.9 (C4′), 155.5 (C4″), 132.3 (C1″),
131.6 (C3), 130.7 (C2′), 125.2 (C1′), 124.4 (C5), 117.2 (C2″),
116.0 (C3′), 114.6 (C3″), 55.4 (OCH3), 48.4 (C4); IR (ATR) ν
3072 (bw), 2923 (w), 1697 (s), 1604 (m), 1581 (m), 1508 (s);
HRMS (ESI) m/z calcd for C17H16NO3 [M + H]+ 282.1130, found
282.1109.
(E)-3-(4-(Benzyloxy)benzylidene)-1-(4-methoxyphenyl)azetidin-
2-one (7ac). Following the general procedure, 5a (47 mg, 0.25 mmol)
and 8c (89 mg, 0.30 mmol) were converted to 7ac (63 mg, 0.17
mmol, 68%); purification by chromatography (hexanes/ethyl acetate
mixture 10:1 (v/v)): off-white solid, mp 209−211 °C; 1H NMR (500
MHz, CDCl3) δ 7.46−7.30 (m, 7H), 7.32 (d, J = 8.9 Hz, 2H), 7.02 (t,
J = 1.4 Hz, 1H), 6.99 (dm, J = 8.8 Hz, 2H), 6.91 (dm, J = 9.0 Hz,
2H), 5.10 (s, 2H), 4.41 (d, J = 1.4 Hz, 2H), 3.80 (s, 3H); 13C{1H}
NMR (126 MHz, CDCl3) δ 161.3, 159.9, 156.1, 136.6, 132.5, 132.4,
130.4, 128.8, 128.3, 127.6, 127.4, 124.7, 117.5, 115.6, 114.7, 70.2,
55.7, 48.7; IR (ATR) ν 1719 (s), 1602 (m), 1508 (s), 1381 (s), 1241
(s); HRMS (EI) m/z calcd for C24H21NO3 [M+] 371.1521, found
371.1526.
(E)-4-((1-(4-Methoxyphenyl)-2-oxoazetidin-3-ylidene)methyl)-
benzonitrile (7ae). Following the general procedure, 5a (47 mg, 0.25
mmol) and 8e (65 mg, 0.30 mmol) were converted to 7ae (38 mg,
0.13 mmol, 52%); purification by chromatography (hexanes/ethyl
1
acetate mixture 10:1 (v/v)): off-white solid, mp 200 °C (dec.); H
NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 8.0 Hz, 2H), 7.70 (d, J =
7.9 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H), 7.18 (s, 1H), 7.00 (d, J = 8.6
Hz, 2H), 4.64 (s, 2H), 3.75 (s, 3H); 13C{1H} NMR (101 MHz,
DMSO-d6) δ 159.9, 156.3, 139.5, 139.2, 133.3, 132.2, 129.8, 123.0,
119.1, 118.0, 115.1, 111.8, 55.8, 49.1; IR (ATR) ν 2223 (m), 1717
(s), 1511 (m), 1242 (m), 1143 (m); HRMS (EI) m/z calcd for
C18H14N2O2 [M+] 290.1050, found 290.1053.
(E)-3-(4-Acetylbenzylidene)-1-(4-methoxyphenyl)azetidin-2-one
(7af). Following the general procedure, 5a (47 mg, 0.25 mmol) and 8f
(70 mg, 0.30 mmol) were converted to 7af (64 mg, 0.21 mmol, 83%);
purification by chromatography (hexanes/ethyl acetate mixture 10:1
(v/v)): yellow solid, mp 207−208 °C; 1H NMR (300 MHz, CDCl3)
δ 7.98 (dm, J = 8.4 Hz, 2H), 7.47 (dm, J = 8.4 Hz, 2H), 7.39 (dm, J =
9.0 Hz, 2H), 7.10 (t, J = 1.5 Hz, 1H), 6.92 (dm, J = 9.0 Hz, 2H), 4.48
(d, J = 1.5 Hz, 2H), 3.81 (s, 3H), 2.62 (s, 3H); 13C{1H} NMR (75
MHz, CDCl3) δ 197.3, 160.3, 156.6, 138.9, 137.7, 137.4, 132.2, 129.1,
128.9, 123.8, 117.8, 114.8, 55.7, 48.9, 26.8; IR (ATR) ν 1720 (s),
1675 (s), 1603 (w), 1511 (s), 1244 (s); HRMS (EI) m/z calcd for
C19H17NO3 [M+] 307.1203, found 307.1205.
(E)-1-(4-Methoxyphenyl)-3-(3-(trifluoromethyl)benzylidene)-
azetidin-2-one (7ai). Following the general procedure, 5a (47 mg,
0.25 mmol) and 8i (78 mg, 0.30 mmol) were converted to 7ai (67
mg, 0.20 mmol, 81%); purification by chromatography (hexanes/ethyl
acetate mixture 10:1 (v/v)): yellow solid, mp 175−177 °C; 1H NMR
(300 MHz, CDCl3): δ 7.65−7.49 (m, 4H), 7.39 (dm, J = 9.0 Hz, 2H),
7.09 (t, J = 1.5 Hz, 1H), 6.92 (dm, J = 9.0 Hz, 2H), 4.47 (d, J = 1.5
Hz, 2H), 3.81 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 160.2,
156.5, 136.9, 135.2, 132.0, 131.8, 131.7 (q, J = 32.0 Hz) 129.7, 125.9
(q, J = 3.6 Hz), 125.1 (q, J = 3.8 Hz), 123.9 (q, J = 273 Hz), 123.4,
117.7, 114.7, 55.6, 48.7; IR (ATR) ν 1721 (m), 1512 (m), 1322 (m),
1123 (s), 695 (m); HRMS (EI) m/z calcd for C18H14F3NO2 [M+]
333.0977, found 333.0969.
(E)-1-(4-Methoxyphenyl)-3-(3-methylbenzylidene)azetidin-2-one
(7aj). Following the general procedure, 5a (47 mg, 0.25 mmol) and 8j
(62 mg, 0.30 mmol) were converted to 7aj (64 mg, 0.23 mmol, 92%);
purification by chromatography (hexanes/ethyl acetate mixture 10:1
(v/v)): yellow solid, mp 151−152 °C; 1H NMR (600 MHz, DMSO-
d6) δ 7.38 (dm, J = 9.0 Hz, 2H), 7.35−7.30 (m, 3H), 7.22 (dm, J =
7.2 Hz, 1H), 7.02 (t, J = 1.4 Hz, 1H), 6.99 (dm, J = 9.1 Hz, 2H), 4.59
(d, J = 1.4 Hz, 2H), 3.74 (s, 3H), 2.34 (s, 3H); 13C{1H} NMR (151
MHz, DMSO-d6) δ 160.2, 155.6, 138.3, 135.3, 134.1, 132.0, 130.2,
129.4, 129.0, 126.0, 124.3, 117.4, 114.6, 55.4, 48.6, 21.0; IR (ATR) ν
1726 (s), 1583 (w), 1510 (s), 1239 (s), 1142 (s); HRMS (EI) m/z
calcd for C18H17NO2 [M+] 279.1254, found 279.1262.
(E)-3-(3-Bromo-4-hydroxybenzylidene)-1-(4-methoxyphenyl)-
azetidin-2-one (7ak). Following the general procedure, 5a (47 mg,
0.25 mmol) and 8k (86 mg, 0.30 mmol) were converted to 7ak (87
mg, 0.24 mmol, 97%); purification by chromatography (hexanes/ethyl
acetate mixture 10:1 (v/v)): yellow solid, mp 240−242 °C (dec.); 1H
NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.66 (d, J = 1.8 Hz,
1H), 7.38−7.33 (m, 3H), 7.05−6.94 (m, 4H), 4.55 (s, 2H), 3.74 (s,
3H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 160.2, 155.5, 155.3,
133.5, 133.2, 132.1, 129.3, 126.8, 123.0, 117.2, 116.7, 114.6, 109.9,
55.3, 48.2; IR (ATR) ν 3158 (bw), 1704 (s), 1602 (m), 1510 (s),
1250 (s), 819 (s); HRMS (EI) m/z calcd for C17H1479BrNO3 [M+]
359.0152, found 359.0141.
(E)-3-(4-Fluorobenzylidene)-1-(4-methoxyphenyl)azetidin-2-one
(7ad). Following the general procedure, 5a (47 mg, 0.25 mmol) and
8d (63 mg, 0.30 mmol) were converted to 7ad (61 mg, 0.22 mmol,
86%); purification by chromatography (hexanes/ethyl acetate mixture
1
10:1 (v/v)): off-white solid, mp 147−148 °C; H NMR (300 MHz,
(E)-3-(2,4-Dichlorobenzylidene)-1-(4-methoxyphenyl)azetidin-2-
one (7am). Following the general procedure, 5a (47 mg, 0.25 mmol)
and 8m (78 mg, 0.30 mmol) were converted to 7am (78 mg, 0.23
mmol, 93%); purification by chromatography (hexanes/ethyl acetate
mixture 10:1 (v/v)): off-white solid, mp 217−218 °C; 1H NMR (500
MHz, CDCl3) δ 7.49 (d, J = 2.1 Hz, 1H), 7.45 (t, J = 1.4 Hz, 1H),
7.39 (dm, J = 9.0 Hz, 2H), 7.35 (d, J = 8.4 Hz, 1H), 7.28 (dd, J = 8.4,
2.1 Hz, 1H), 6.93 (dm, J = 9.0 Hz, 2H), 4.42 (d, J = 1.5 Hz, 2H), 3.82
(s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 160.1, 156.5, 137.6,
CDCl3) δ 7.41−7.33 (m, 4H), 7.10 (dd, J = 8.6, 8.6 Hz, 2H), 7.04 (t,
J = 1.5 Hz, 1H), 6.92 (dm, J = 9.0 Hz, 2H), 4.43 (d, J = 1.5 Hz, 2H),
3.81 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 163.4 (d, J = 250.9
Hz), 160.8, 156.4, 134.6 (d, J = 2.5 Hz), 132.4, 130.7 (d, J = 3.4 Hz),
130.6 (d, J = 8.5 Hz), 123.9, 117.7, 116.4 (d, J = 21.9 Hz), 114.8,
55.7, 48.7; IR (ATR) ν 1727 (m), 1598 (w), 1505 (m), 1135 (m),
831 (s); HRMS (EI) m/z calcd for C17H14FNO2 [M+] 283.1009,
found 283.1002.
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Article
135.9, 135.7, 132.1, 131.0, 130.4, 128.8, 127.6, 120.3, 117.8, 114.7,
55.7, 48.6; IR (ATR) ν 2923 (w), 1725 (s), 1709 (s), 1511 (s), 1245
(s), 808 (s); HRMS (EI) m/z calcd for C17H1335Cl2NO2 [M+]
333.0323, found 333.0335.
OCH3), 48.0 (C4), 24.6 (C(O)CH3); IR (ATR) ν 3307 (bw), 1712
(w), 1667 (w), 1603 (m), 1506 (s), 1246 (s), 828 (s); HRMS (EI)
m/z calcd for C26H24N2O4 [M+] 428.1736, found 428.1735.
(E)-1-(3-Bromophenyl)-3-(3-methylbenzylidene)azetidin-2-one
(7dj). Following the general procedure, 5d (60 mg, 0.25 mmol) and 8j
(62 mg, 0.30 mmol) were converted to 7dj (79 mg, 0.24 mmol, 96%);
purification by chromatography (hexanes/ethyl acetate mixture 10:1
(v/v)): off-white solid, mp 146−147 °C; 1H NMR (300 MHz,
CDCl3) δ 7.56−7.52 (m, 1H), 7.45−7.37 (m, 1H), 7.35−7.27 (m,
1H), 7.24−7.16 (m, 5H), 7.10 (t, J = 1.4 Hz, 1H), 4.47 (d, J = 1.5 Hz,
2H), 2.39 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 161.5, 139.9,
139.0, 134.0, 134.0, 130.8, 130.8, 129.8, 129.2, 126.9, 126.8, 126.1,
123.2, 119.1, 115.1, 48.9, 21.6; IR (ATR) ν 1726 (s), 1590 (s), 1568
(m), 1480 (s), 1371 (s), 773 (s); HRMS (EI) m/z calcd for
C17H1479BrNO [M+] 327.0259, found 327.0255.
(E)-1-(4-Methoxyphenyl)-3-(3,4,5-trimethoxybenzylidene)-
azetidin-2-one (7an). Following the general procedure, 5a (47 mg,
0.25 mmol) and 8n (85 mg, 0.30 mmol) were converted to 7an (84
mg, 0.24 mmol, 95%); purification by chromatography (hexanes/ethyl
1
acetate mixture 10:1 (v/v)): off-white solid, mp 150−152 °C; H
NMR (300 MHz, CDCl3) δ 7.36 (dm, J = 9.1 Hz, 2H), 6.95 (t, J = 1.4
Hz, 1H), 6.88 (dm, J = 9.1 Hz, 2H), 6.57 (s, 2H), 4.41 (d, J = 1.4 Hz,
2H), 3.89 (s, 6H), 3.88 (s, 3H), 3.78 (s, 3H); 13C{1H} NMR (75
MHz, CDCl3) δ 160.8, 156.3, 153.7, 139.8, 134.1, 132.3, 129.9, 125.1,
117.6, 114.7, 106.3, 61.1, 56.4, 55.6, 48.5; IR (ATR) ν 2948 (m),
1718 (s), 1583 (m), 1505 (s), 1120 (s), 726 (s); HRMS (EI) m/z
calcd for C20H21NO5 [M+] 355.1420, found 355.1430.
(E)-1-(3,4-Dichlorophenyl)-3-(4-hydroxybenzylidene)azetidin-2-
one (7eb). Following the general procedure, 5e (57 mg, 0.25 mmol)
and 8b (62 mg, 0.30 mmol) were converted to 7eb (79 mg, 0.25
mmol, quant.); purification by chromatography (hexanes/ethyl
(E)-1-(4-Chlorophenyl)-3-(4-hydroxybenzylidene)azetidin-2-one
(7bb). Following the general procedure, 5b (48 mg, 0.25 mmol) and
8b (62 mg, 0.30 mmol) were converted to 7bb (68 mg, 0.24 mmol,
95%); purification by chromatography (hexanes/ethyl acetate mixture
1
acetate mixture 10:1 (v/v)): off-white solid, mp 216 °C (dec.); H
1
NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 7.64 (d, J = 8.7 Hz,
1H), 7.59 (s, 1H), 7.45−7.31 (m, 3H), 7.07 (s, 1H), 6.84 (d, J = 8.0
Hz, 2H), 4.59 (s, 2H); 13C{1H} NMR (101 MHz, DMSO-d6) δ
161.8, 159.8, 138.9, 132.2, 131.7, 131.4, 131.2, 126.7, 125.2, 125.1,
117.7, 116.6, 116.5, 49.3; IR (ATR) ν 3356 (bw), 1743 (s), 1727 (s),
1705 (s), 1592 (m), 1479 (s), 1134 (s), 812 (s); HRMS (EI) m/z
calcd for C16H1135Cl2NO2 [M+] 319.0161, found 319.0162.
10:1 (v/v)): off-white solid, mp 249−251 °C; H NMR (400 MHz,
DMSO-d6) δ 10.03 (s, 1H, OH), 7.45 (d, J = 8.9 Hz, 2H, H3″), 7.39
(d, J = 8.9 Hz, 2H, H2″), 7.37 (d, J = 8.5 Hz, 2H, H2′), 7.04 (s, 1H,
H5), 6.84 (d, J = 8.5 Hz, 2H, H3′), 4.58 (s, 2H, H4); 13C{1H} NMR
(101 MHz, DMSO-d6) δ 161.7 (C2), 159.7 (C4′), 137.9 (C1″),
131.5 (C3), 131.3 (C2′), 129.7 (C3″), 127.3 (C4″), 126.1 (C5),
125.3 (C1′), 117.9 (C2″), 116.5 (C3′), 49.0 (C4); IR (ATR) ν 3116
(bw), 2924 (w), 1705 (s), 1492 (s), 824 (s); HRMS (ESI) m/z calcd
for C16H1335ClNO2 [M + H]+ 286.0635, found 286.0660.
(E)-1-(4-Chloro-3-(triflu or om e th yl) p h en y l )- 3 -( 4 -
hydroxybenzylidene)azetidin-2-one (7fb). Following the general
procedure, 5f (65 mg, 0.25 mmol) and 8b (62 mg, 0.30 mmol) were
converted to 7fb (76 mg, 0.22 mmol, 86%); purification by
chromatography (hexanes/ethyl acetate mixture 10:1 (v/v)): off-
(E)-3-(4-Chlorobenzylidene)-1-(4-chlorophenyl)azetidin-2-one
(1e).14 Following the general procedure, 5b (48 mg, 0.25 mmol) and
8o (68 mg, 0.30 mmol) were converted to 1e (71 mg, 0.24 mmol,
93%); purification by chromatography (hexanes/ethyl acetate mixture
10:1 (v/v)): off-white solid, mp 140−141 °C (reported in the
1
white solid, mp 207−208 °C; H NMR (400 MHz, DMSO-d6) δ
10.04 (s, 1H), 7.76 (s, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 8.9
Hz, 1H), 7.38 (d, J = 7.9 Hz, 2H), 7.10 (s, 1H), 6.84 (d, J = 7.9 Hz,
2H), 4.65 (s, 2H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 161.5,
159.4, 137.8, 132.7, 131.0, 130.6, 127.3 (q, J = 30.9 Hz), 126.5, 124.7,
123.7 (q, J = 2.0 Hz), 122.6 (q, J = 275 Hz), 120.8, 116.0, 114.6 (q, J
= 5.6 Hz), 49.3; 19F NMR (376 MHz, DMSO-d6) δ − 1.6; IR (ATR)
ν 3289 (bw), 1730 (m), 1722 (s), 1605 (m), 1519 (w), 1484 (s),
1108 (s); HRMS (EI) m/z calcd for C17H1135ClF3NO2 [M+]
353.0425, found 353.0418.
literature14 mp 139−142 °C); H NMR (600 MHz, CDCl3) δ 7.39
1
(d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.9 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H),
7.32 (d, J = 8.5 Hz, 2H), 7.08 (t, J = 1.4 Hz, 1H), 4.46 (d, J = 1.5 Hz,
2H); 13C{1H} NMR (126 MHz, CDCl3) δ 161.0, 137.1, 135.9, 134.9,
132.6, 130.1, 129.6, 129.5, 129.2, 125.0, 117.6, 48.7; IR (ATR) ν 1735
(s), 1591 (s), 1492 (m), 1480 (s), 1373 (s), 1123 (m); HRMS (EI)
m/z calcd for C16H1135Cl2NO [M+] 303.0218, found 303.0224. All
analytical data match those reported in the literature.14
(E)-N-(4-(3-(4-Methoxybenzylidene)-2-oxoazetidin-1-yl)phenyl)-
acetamide (7ca) and N-(4-(3-(Bis(4-methoxyphenyl)methylene)-2-
oxoazetidin-1-yl)phenyl)acetamide (9ca). Following the general
procedure, 5c (54 mg, 0.25 mmol) and 8a (67 mg, 0.30 mmol) were
converted to a mixture of 7ca (23 mg, 0.07 mmol, 28%) and 9ca (44
mg, 0.10 mmol, 41%). The reaction products were separated by
column chromatography on silica (hexanes/ethyl acetate mixtures
10:1 to 3:1 (v/v)). Analytical data for 7ca: off-white solid, mp 234 °C
(dec.); 1H NMR (600 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.59 (dm, J =
9.0 Hz, 2H), 7.47 (dm, J = 8.8 Hz, 2H), 7.34 (dm, J = 8.9 Hz, 2H),
7.04 (t, J = 1.4 Hz, 1H), 7.01 (dm, J = 8.8 Hz, 2H), 4.56 (d, J = 1.4
Hz, 2H), 3.80 (s, 3H), 2.02 (s, 3H); 13C{1H} NMR (151 MHz,
DMSO-d6) δ 168.1, 160.6, 160.4, 135.2, 134.0, 132.6, 130.6, 126.7,
124.4, 119.9, 116.3, 114.6, 55.4, 48.3, 24.0; IR (ATR) ν 3310 (bw),
2955 (m), 2913 (m), 1725 (m), 1709 (m), 1600 (m), 1509 (s), 1248
(s), 823 (s); HRMS (EI) m/z calcd for C19H18N2O3 [M+] 322.1317,
found 322.1314. Analytical data for 9ca: off-white solid, mp 239−241
°C; 1H NMR (600 MHz, CDCl3) δ 7.50 (dm, J = 8.9 Hz, 2H, Z- or E-
H3′), 7.46 (dm, J = 8.9 Hz, 2H, H3″), 7.35 (dm, J = 8.9 Hz, 2H,
H2″), 7.31 (s (br.), 1H, NH), 7.23 (dm, J = 8.8 Hz, 2H, Z- or E-H3′),
6.92 (dm, J = 8.9 Hz, 2H, Z- or E-H2′), 6.90 (dm, J = 8.9 Hz, 2H, Z-
or E-H2′), 4.20 (s, 2H, H4), 3.85 (s, 3H, Z- or E-OCH3), 3.83 (s, 3H,
Z- or E-OCH3), 2.14 (s, 3H, C(O)CH3); 13C{1H} NMR (151 MHz,
CDCl3) δ 168.3 (C(O)CH3), 160.4 (C2), 160.3 (Z- or E-C4′), 160.1
(Z- or E-C4′), 142.3 (C3), 135.5 (C1″), 133.8 (C4″), 131.8 (Z- or E-
C3′), 131.5 (C1′), 130.8 (Z- or E-C3′), 129.7 (Z- or E-C1’ or C5),
129.6 (Z- or E-C1′ or C5), 121.0 (C3″), 116.6 (C2″), 114.1 (Z- or E-
C3′), 113.5 (Z- or E-C3′), 55.5 (Z- or E-OCH3), 55.4 (Z- or E-
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00638.
1
Copies of H and 13C NMR spectra for all compounds;
2D NMR spectra for representative compounds (PDF)
Accession Codes
CCDC 2068052 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Bernd Schmidt − Universitaet Potsdam, Institut fur Chemie,
̈
D-14476 Potsdam-Golm, Germany; orcid.org/0000-
0002-0224-6069; Email: bernd.schmidt@uni-potsdam.de
Michael Shipman − Department of Chemistry, University of
Warwick, Coventry CV4 7AL, U.K.; orcid.org/0000-
0002-3349-5594; Email: M.Shipman@warwick.ac.uk
8794
https://doi.org/10.1021/acs.joc.1c00638
J. Org. Chem. 2021, 86, 8786−8796

The Journal of Organic Chemistry
Authors
̈
Nastja Riemer − Universitaet Potsdam, Institut fur Chemie, D-
14476 Potsdam-Golm, Germany; Department of Chemistry,
University of Warwick, Coventry CV4 7AL, U.K.
Martin Riemer − Department of Chemistry, University of
Warwick, Coventry CV4 7AL, U.K.
̈
Mandy Kruger − Universitaet Potsdam, Institut fur Chemie,
̈
D-14476 Potsdam-Golm, Germany
Guy J. Clarkson − Department of Chemistry, University of
Warwick, Coventry CV4 7AL, U.K.
pubs.acs.org/joc
Article
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00638
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank Evonik Oxeno for generous donations of solvents
and Umicore (Hanau, Germany) for generous donations of
catalysts. M.R. was supported by a Marie-Sklodowska-Curie
Individual Fellowship (MSCA-IF-EF-4887, Project 705079).
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