One-Pot Construction of Diverse β-Lactam Scaffolds via the Green Oxidation of Amines and Its Application to the Diastereoselective Synthesis of β-Amino Acids

Article abstract of DOI:10.1021/acs.joc.1c01128

In this study, a simple one-pot construction of β-lactam scaffolds was successfully achieved via 4,6-dihydroxysalicylic acid-catalyzed organocatalytic oxidation of amines to imines using molecular oxygen. Although some imines are highly unstable and difficult to isolate by conventional methods, the organocatalytic oxidation of amines described herein, followed by their direct reaction with acyl chlorides in the presence of a base, afforded a series of new β-lactam derivatives with excellent cis selectivity, which could not be synthesized and isolated by previously reported methods. Thus, this one-pot protocol will be one of the powerful methods applicable to the synthesis of various potential drug candidates and functional molecules. Furthermore, the subsequent hydrolysis of these β-lactams successfully afforded the corresponding β-amino acids as almost single diastereomers in up to 99% yields.

Full text of DOI:10.1021/acs.joc.1c01128

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Article
One-Pot Construction of Diverse β‑Lactam Scaffolds via the Green
Oxidation of Amines and Its Application to the Diastereoselective
Synthesis of β‑Amino Acids
Yuki Yamamoto, Shintaro Kodama,* Riku Nishimura, Akihiro Nomoto, Michio Ueshima,
and Akiya Ogawa*
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ABSTRACT: In this study, a simple one-pot construction of β-
lactam scaffolds was successfully achieved via 4,6-dihydroxysalicylic
acid-catalyzed organocatalytic oxidation of amines to imines using
molecular oxygen. Although some imines are highly unstable and
difficult to isolate by conventional methods, the organocatalytic
oxidation of amines described herein, followed by their direct
reaction with acyl chlorides in the presence of a base, afforded a
series of new β-lactam derivatives with excellent cis selectivity, which
could not be synthesized and isolated by previously reported
methods. Thus, this one-pot protocol will be one of the powerful
methods applicable to the synthesis of various potential drug candidates and functional molecules. Furthermore, the subsequent
hydrolysis of these β-lactams successfully afforded the corresponding β-amino acids as almost single diastereomers in up to 99%
yields.
method requires highly pure imines, which are generally
susceptible to hydrolysis. Thus, there are few reported
examples of β-lactams with both aromatic and aliphatic
substituents on their rings. To expand the scope of Staudinger
cycloaddition and make it more atom-economical in the view
of the full transformation from amines to β-lactams, the
development of a one-pot method that incorporates the
oxidative formation of imines from amines would be beneficial.
One-pot reactions that generate unstable imines in situ can be
applied to the synthesis of β-lactams with various functional
groups. In addition, since the required purity of materials and
pharmaceuticals has been increasing in recent years, metal
residues in such products have become a serious problem;
thus, synthetic methods using metal catalysts and reagents
should be avoided. Considering this, metal-free synthetic
methods employing mild conditions are in great demand.47
However, there has only ever been one example of a metal-free,
one-pot method involving the oxidative formation of imines
from amines.48 This method required stoichiometric amounts
of the reagents for the successful oxidation of amines, and the
INTRODUCTION
■
β-Lactams are important heterocycles used in the synthesis of
antibiotics like penicillins and carbacephems, as well as the
anticancer drug, paclitaxel (Taxol), and their demand is ever
increasing (Figure 1).1 In addition, β-lactams are important
synthetic intermediates because they can be hydrolyzed to the
corresponding amino acid derivatives.2−11 From the viewpoint
of diversity, it is highly desirable to develop new synthetic
methods for constructing β-lactam derivatives that cannot be
synthesized by conventional methods. In particular, new
synthetic methods that give β-lactam derivatives intended for
drug discovery should allow a wide range of substitution
patterns while maintaining excellent stereoselectivity.12
Although various methods have been reported for the
construction of β-lactam rings (including transition-metal-
catalyzed reactions, carbonylations, and enolate-imine con-
densations),13−45 Staudinger cycloaddition, which is a formal
[2 + 2] cycloaddition of an imine and a ketene, is the most
versatile method for fabricating β-lactam rings (eq 1).46 This
Received: May 13, 2021
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© XXXX American Chemical Society
A

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Figure 1. Examples of β-lactam-centered antibiotics and key intermediates in drug discovery.
a
Table 1. Optimization of Reaction Conditions for β-Lactam Synthesis via the Homocoupling of 1a
entry
x (mmol)
solvent (mL)
time (h)
yield 5a (%)
1
2
3
4
5
6
7
8
9
1.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
CH3CN (5.0)
CH3CN (5.0)
CH3CN (3.0)
CH3CN (1.5)
CH3CN (3.0)
CH3CN (3.0)
toluene (3.0)
CH2Cl2 (3.0)
THF (3.0)
24
24
24
24
18
6
18
18
18
18
16
52
58
53
82 (72)
38
50
51
34
69
10
1,4-dioxane (3.0)
a
1
Yields were determined by H NMR spectroscopy based on 1a (isolated yield).
substrates were limited to commercially available secondary
amines.
corresponding ketene was thus generated in situ by the
dehydrochlorination of 4a. The reaction mixture was then
stirred at 25 °C for 24 h under an inert atmosphere to give the
corresponding β-lactam (5a), which was obtained in a 16%
yield based on the amount of 1a (Table 1, entry 1).
Surprisingly, only the cis isomer was produced in this
reaction.52 This result encouraged us to further optimize the
reaction conditions (Table 1). When the amounts of 4a and
the base were increased from 1.5 mmol to 4.5 mmol, the yield
of 5a increased to 52% (entry 2). The concentration of 4a in
CH3CN was also examined (entries 2−4), and the yield of 5a
was found to be optimal when 3.0 mL of CH3CN was used
(entry 3). The second step of the reaction was conducted for
18 h and 5a was isolated in a 72% yield with excellent cis
selectivity (entry 5). Reducing the reaction time of the second
step to 6 h had no effect on the formation of 5a (entry 6). The
solvent used to dissolve 4a in the second step was also
investigated in detail, where CH3CN was found to be the
optimal solvent for the reaction (entry 5 vs entries 7−10).
Using the optimized reaction conditions (Table 1, entry 5),
we then investigated the reaction scope of this β-lactam
synthesis (Table 2).52 A variety of benzylamine derivatives,
such as p-methyl, m-methoxy, and p-methoxy benzylamines
(1c, 1e, and 1f), could be oxidized under these conditions. The
resultant imine derivatives formed in situ were then
successfully reacted with ketenes to produce the corresponding
β-lactams (5c, 5e, and 5f) in good overall yields. Although p-
tert-butyl- and o-methoxy-benzylamines (1b and 1d) were also
oxidized to imines, the corresponding β-lactams (5b and 5d)
were obtained in only moderate yields due to the steric
hinderance of the imines formed. Furthermore, the use of 1-
Recently, we have developed a method for oxidizing amines
to imines using 4,6-dihydroxysalicyclic acid as an organo-
catalyst with molecular oxygen as a co-oxidant.49 This method
can be performed under metal-free and mild conditions, which
promotes its utilization for metal-free/one-pot formations of
functional scaffolds toward pharmaceutical and functional
molecules.50 We have already succeeded in using this catalytic
oxidation of amines to synthesize triarylmethane derivatives,50a
heterocycles,50b dipeptides,50c and 2,4,6-trisubstituted pyridi-
nes.50d In this study, we used this organocatalytic formation of
imines from primary amines to develop a one-pot method for
the synthesis of β-lactam derivatives under metal-free and mild
conditions. Surprisingly, most of the β-lactams synthesized in
this study were new compounds bearing aromatic and aliphatic
groups on their rings. Moreover, the cis isomers of all of the
products were afforded in moderate-to-good yields and with
excellent stereoselectivity. Furthermore, while preserving their
stereochemistry, β-lactams can be hydrolyzed to yield β-amino
acids derivatives, which are important synthetic intermediates
for functional peptides.51 Therefore, we used this method in
the diastereoselective synthesis of β-amino acids (eq 2).
RESULTS AND DISCUSSION
■
The homocoupling of benzylamine 1a using trihydroxybenzoic
acid (2) was conducted according to the method described in
our previous paper.49 After 4A MS (300 mg) was added to the
reaction vessel to prevent the hydrolysis of imine 3a,
methoxyacetyl chloride (4a) in CH3CN (5.0 mL) was added
dropwise to the reaction mixture alongside Et3N. The
B
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a b
,
Table 2. Reaction Scope of β-Lactam Synthesis via the Homocoupling of Benzylamines
a
b
1
Yields were determined by H NMR spectroscopy based on 1 (isolated yields). 1st step: Benzylamine 1a (10 mmol, 1.08 g), 2 (5 mol %),
toluene (3.0 mL), 90 °C, 2 h, O2 (0.1 MPa). 2nd step: 4 (15 mmol), Et3N (15 mmol), 4A MS (1.0 g), CH3CN (10 mL), 0 °C → 25 °C, and 18 h.
naphthylmethylamine (1g) and 2-thiophenemethylamine (1h)
was also examined, and cis-products 5g and 5h were obtained
in moderate overall yields. When acetoxyacetyl chloride (4b)
was used in this reaction, 5i, which bears an additional
carbonyl group on its scaffold, was successfully obtained in a
good yield. When phenoxyacetyl chloride (4c) and p-
chlorophenylacetyl chloride (4d) were used in this reaction,
5j and 5k, respectively, were also obtained in reasonable yields.
This method could be used to synthesize cis-5a and cis-5k in
good yields on a gram scale. Although we have examined some
acyl chlorides such as ones bearing a t-butyl or a phenyl group
as the ketene precursor in this one-pot protocol, the
corresponding β-lactams could not be obtained in a good
yield, and further optimization is necessary. We consider that
the stability of the corresponding ketenes is one of the
important factors in the present one-pot protocol. Overall,
Table 2 shows that this method led to the synthesis of novel β-
lactam derivatives with high stereoselectivity.
organocatalytic oxidative cross-condensation of two different
amines (Table 3). We previously reported the 4,6-dihydrox-
ysalicylic acid-catalyzed oxidative cross-condensation of
benzylamines with other amines, which we applied in this
work.50c In the first step of β-lactam synthesis, benzylamine 1a
and hexylamine (6a) were reacted in the presence of a catalytic
amount of 2 under an O2 atmosphere (0.1 MPa) to produce
unsymmetrical imine 7a in situ. This imine (7a) was reacted
directly with the ketene derived from 4a and Et3N, and the
resultant reaction mixture was stirred for 18 h to produce only
the cis isomer of 8a in a 42% yield (entry 1). Encouraged by
this result, we further optimized the reaction conditions for the
second step. Specifically, we found that increasing the
concentration of 4a resulted in a slight decrease in the yield
of 8a (entry 2). Moreover, the addition of BF3·Et2O (10 mol
%) as a Lewis acid did not improve the reaction (entry 3).
Furthermore, neither changing the amounts of 4a and Et3N
from 4.5 to 7.5 mmol (entry 4) nor extending the reaction time
to 72 h (entry 5) had any effect on the reaction. Surprisingly,
the temperature of the second step was found to be important
To make the method more versatile, we attempted to
synthesize β-lactams with three different substituents via the
C
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Table 3. Optimization of Reaction Conditions for β-Lactam Synthesis via the Oxidative Cross-Condensation of Two Different
a
Amines
entry
solvent (mL)
temp (°C)
yield 8a (%)
1
2
3
4
5
6
7
8
9
CH3CN (3.0)
CH3CN (1.5)
CH3CN (3.0)
CH3CN (3.0)
CH3CN (3.0)
CH3CN (3.0)
1,4-dioxane (3.0)
DMF (3.0)
25
25
25
25
25
42
33
39
44
43
53 (42)
40
41
N. D.
b
c
d
90
100
110
110
DMSO (3.0)
a
b
c
Yields were determined by 1H NMR spectroscopy based on 1a (isolated yield). BF3·Et2O (10 mol %) was added. 4a (7.5 mmol) and Et3N (7.5
d
mmol) were used. Reaction time: 72 h.
a
Table 4. Scope of β-Lactam Synthesis via the Oxidative Cross-Condensation of Two Different Amines
a
1
Yields were determined by H NMR based on 1 (isolated yields).
D
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for the formation of 8a. When the second step was conducted
at 90 °C, 8a was formed in a 53% yield (entry 6). Although
other solvents were examined to increase the reaction
temperature in the second step (entries 6−9), CH3CN was
found to be the optimal solvent for the reaction (entry 6).
Using the optimized conditions (Table 3, entry 6), we next
investigated the scope of the reaction for β-lactam synthesis by
the organocatalytic oxidative cross-condensation of two
different amines (Table 4). o-Methoxy-, m-methoxy-, p-
methoxy-, p-tert-butyl-, and p-trifluoromethyl-benzylamines
(1b−1f), as well as 1-naphthylmethanamine (1g), could be
used to synthesize unsymmetrical imines (7) by oxidative
cross-condensation with 6a. The following reaction of the
unsymmetrical imines (7; formed in situ) with ketenes yielded
the corresponding β-lactams (8a−8g) in moderate-to-good
yields. Compared to the reactions employing aliphatic amines
(6) with shorter chains, the reactions conducted with aliphatic
amines bearing longer chains (6h and 6i) gave more stable
imines that subsequently gave the corresponding β-lactams (8h
and 8i) in greater yields. 2-Ethylhexylamine (6j) and
cyclohexylamine (6k) afforded β-lactams 8j and 8k,
respectively. 3-Phenylpropylamine (6l), whose nitrogen atom
bears a large substituent, could be converted to β-lactam 8l in a
moderate total yield. Several acyl chlorides, such as phenyl-
acetyl chloride (4m) and p-chlorophenylacetyl chloride (4n),
were also examined, and the corresponding desired β-lactams
(8m and 8n) were successfully obtained.
the corresponding imines could be conducted under mild
reaction conditions with excellent reaction selectivity, whereas
aliphatic amines were hardly converted to imines under the
same mild conditions. Therefore, the present reaction enables
the selective formation of symmetrical and unsymmetrical
imines having the aryl groups derived from benzylamines.
From the viewpoints of the utilization in pharmaceutical fields,
β-lactam that contains an aryl group on the ring is among the
potentially important compounds. Thus, this method can easily
provide a variety of β-lactams for practical utilization in drug
discovery.
It should be noted that all of the products (Tables 2 and 4)
were obtained with excellent cis selectivity (cis isomers only),
and most of them were synthesized and isolated for the first
time in this work by our developed method.
It is not surprising that the above multistep reaction (Tables
3 and 4) would produce many byproducts, but, in fact, few
byproducts were obtained other than those listed below. The
main byproduct was the amide compounds produced by the
reaction of unreacted amines with ketenes generated from acyl
chlorides and Et3N. In addition, the unsymmetrical imines
produced in situ were susceptible to hydrolysis under the
reaction conditions, and therefore, some of them were
converted into the corresponding aldehydes. However, the
present one-pot protocol does not need the isolation of such
unstable imines and could afford a variety of new β-lactams
with aromatic and aliphatic groups on the rings with excellent
cis selectivity in moderate-to-good total yields. In the 1st step
of the present one-pot protocol, oxidation of benzylamines to
The present one-pot synthesis of β-lactams could also be
conducted using 4,6-dihydroxysalicylic acid supported on a
silica gel as a catalyst. As shown in eq 3, 5 mol % silica gel-
supported catalyst (4.7 wt % 2 on silica gel) was used for the
oxidation of benzylamine 1a (3.0 mmol) under atmospheric
oxygen in the first step.49 Then, in the second step,
methoxyacetyl chloride 4a (4.5 mmol), Et3N (4.5 mmol),
and 4A MS (300 mg) were added, and the reaction mixture
was stirred at 25 °C for 18 h. To our delight, this protocol
successfully afforded the corresponding β-lactam 5a in 65%
yields with excellent cis selectivity. To gain insight into the
reaction pathway, an additional experiment was conducted. In
our previous report, this salicylic acid-catalyzed oxidation
system might involve a radical reaction because the oxidation
Scheme 1. Proposed Reaction Pathways for the Organocatalytic Oxidative Formation of β-Lactams
E
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a
Table 5. Application of the Developed Method to the Diastereoselective Synthesis of β-Amino Acids
a
Isolated yields.
of benzylamine did not proceed smoothly in the presence of
TEMPO as a radical scavenger.49 Similarly, the formation of β-
lactam was completely inhibited by adding 1 equiv of TEMPO.
These results clearly indicate that the present β-lactam
synthesis, especially the organocatalytic oxidative imination
of benzylamines, involves the radical pathway. Based on the
results of previous studies49,50 and the reported mechanisms of
compared it with several other known methods. The results
indicated that the one-pot protocol presented in this study has
a much lower E-factor than those of the known methods. The
E-factor was sufficiently low not only in the case of β-lactam
synthesis via homocoupling of two amines (E-factor = 14.0)
but also in the case of β-lactam synthesis via cross-coupling (E-
factor = 21.5, see Scheme S1 in the Supporting Information).
Furthermore, if the silica gel-supported organocatalyst
described above is used, the E-factor of this system is expected
to further reduce because the organocatalyst can be recycled.
From these insights, the present one-pot method is environ-
mentally friendly and less wasteful for the conversion of amine
to β-lactam.
In this study, various novel β-lactam derivatives could be
synthesized with excellent cis selectivity. Therefore, as a
powerful synthetic application of this method, we next
investigated the diastereoselective synthesis of β-amino acids
by the hydrolysis of these β-lactam derivatives (Table 5). β-
Lactams could be hydrolyzed to the corresponding β-amino
acids while maintaining the stereochemistry of the C2 and C3
positions of the fused rings. Therefore, β-lactams 5a or 8i,
synthesized and isolated in this study, were directly reacted
with 10% HCl aq. (1.0 mL) in CH3CN (1.0 mL) at 100 °C for
24 h. As expected, the corresponding β-amino acids (9a and
9b) were obtained in excellent yields as single diastereomers.
Staudinger cycloadditions using imines and ketenes,53
a
reaction pathway was proposed herein (Scheme 1). The key
catalytic species is the corresponding salt generated from a
salicylic acid catalyst and benzylamine. As to the synthesis of
imines, the salt-forming salicylic acid reacts with oxygen to
generate the corresponding phenoxy radicals, which might
abstract hydrogen from the salt-forming benzylamine to form
phenylmethanimine, which could react with another amine to
give the corresponding symmetrical or unsymmetrical
imines:49,50c Namely, benzylamine (1) reacts with 4,6-
dihydroxysalicylic acid to produce salt A at first, which is
then activated under an O2 atmosphere to form phenoxy
radical B. The radical species (B) abstracts H• from 1 to
generate C, and the concomitantly formed HOO• abstracts H•
from another molecule of 1 to produce the corresponding
imine, together with the regeneration of the salicylic acid
catalyst. The subsequent amino group exchange reaction with
another amine yields the corresponding symmetrical (3) or
unsymmetrical (7) imines. In the second step, the imine
formed in situ reacts with the ketene generated by the
dehydrochlorination of the acyl chloride (4) by the base,
producing zwitterionic intermediates. Subsequent intramolec-
ular cyclization forms the desired β-lactam scaffold (8). The
stereoselectivity of the β-lactams is affected by the structure
and stability of a zwitterion.53−57 When an electron-donating
alkoxy group is substituted on a ketene, the zwitterion becomes
unstable and the cyclization is promoted, resulting in the
selective formation of cis β-lactams based on kinetic control.
Furthermore, we calculated the E-factor for the present one-
pot method for the synthesis of β-lactam from amine and
CONCLUSIONS
■
We have developed a simple, metal-free, one-pot method for
the synthesis of β-lactam derivatives that comprises the 4,6-
dihydroxysalicylic acid-catalyzed oxidative condensation of
primary amines to generate imines. This method does not
include an imine isolation step, making the system environ-
mentally friendly and versatile in its reaction scope. Using this
method, a variety of new β-lactam derivatives were synthesized
with excellent cis selectivity, which could not be synthesized
and isolated by previously reported methods. Thus, this one-
pot protocol will be one of the powerful methods applicable to
F
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(d, J = 8.2 Hz, 1H), 5.05 (d, J = 4.5 Hz, 1H), 4.76 (d, J = 14.5 Hz,
1H), 4.65 (d, J = 4.5 Hz, 1H), 4.09 (d, J = 14.5 Hz, 1H), 3.78 (s, 3H),
3.62 (s, 3H), 3.12 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
167.5, 157.6, 157.5, 130.4, 129.3, 128.9, 128.3, 123.5, 122.8, 120.6,
120.5, 110.23, 110.17, 85.8, 58.3, 56.2, 55.4, 55.0, 39.5; HRMS (ESI)
m/z calcd for C19H21NNaO4 [M + Na]+: 350.1368, found: 350.1366.
( )-cis-3-Methoxy-1-(3-methoxybenzyl)-4-(3-methoxyphenyl)-
azetidin-2-one (5e). Yellow oil, 321.0 mg, 65%; 1H NMR (400 MHz,
CDCl3): δ 7.28 (t, J = 8.0 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 6.90−
6.87 (m, 2H), 6.82−6.79 (m, 2H), 6.71 (d, J = 7.7 Hz, 1H), 6.66 (t, J
= 1.8 Hz, 1H), 4.78 (d, J = 14.5 Hz, 1H), 4.66 (d, J = 4.1 Hz, 1H),
4.56 (d, J = 4.1 Hz, 1H), 3.83 (d, J = 15.0 Hz, 1H), 3.78 (s, 3H), 3.75
(s, 3H), 3.13 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 166.8,
160.0, 159.8, 136.5, 135.2, 129.9, 129.5, 120.9 (overlapped), 114.2,
114.1, 113.9, 113.6, 85.9, 61.2, 58.3, 55.33, 55.29, 44.1; HRMS (ESI)
m/z calcd for C19H21NNaO4 [M + Na]+: 350.1368, found: 350.1366.
( )-cis-3-Methoxy-1-(4-methoxybenzyl)-4-(4-methoxyphenyl)-
the synthesis of various potential drug candidates and
functional molecules. Furthermore, our protocol was extended
to the gram scale and diastereoselective synthesis of β-amino
acids was successfully achieved via hydrolysis of the β-lactam
derivatives constructed by our protocol. The reactions
demonstrated, herein, highlight the importance and conven-
ience of β-lactam derivatives as synthetic intermediates in
chemical and pharmaceutical fields.
EXPERIMENTAL SECTION
■
General Remarks. Unless otherwise stated, all starting materials
and catalysts were purchased from commercial sources and used
without further purification. All solvents were distilled and degassed
with nitrogen before use. The 4.7 wt % 4,6-dihydroxysalicylic acid 2
on a silica gel was synthesized by a previously reported method.49 1H
NMR spectra were recorded on a JEOL JNM-ECS400 (400 MHz)
FT NMR system or a JEOL JNM-ECX400 (400 MHz) FT NMR
system in CDCl3 with Me4Si as an internal standard.13C NMR spectra
were recorded on a JEOL JNM-ECX400 (100 MHz) FT NMR or a
JEOL JNM-ECS400 (100 MHz) FT NMR in CDCl3. High-resolution
mass spectroscopy (HRMS) was conducted on a Bruker micrOTOF
II ESI/TOF analyzer or Waters Synapt G2 HDMS.
1
azetidin-2-one (5f). Colorless oil, 326.2 mg, 66%; H NMR (400
MHz, CDCl3): δ 7.23−7.19 (m, 2H), 7.05-7.02 (m, 2H), 6.92−6.88
(m, 2H), 6.83-6.80 (m, 2H), 4.73 (d, J = 15.0 Hz, 1H), 4.60 (d, J =
4.5 Hz, 1H), 4.49 (d, J = 4.5 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.74
(d, J = 14.5 Hz, 1H), 3.11 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 166.8, 159.9, 159.3, 130.0, 129.8, 127.1, 125.3, 114.2,
113.9, 85.7, 60.4, 58.2, 55.3 (overlapped), 43.2; HRMS (ESI) m/z
calcd for C19H21NNaO4 [M + Na]+: 350.1368, found: 350.1375.
General Procedure for the Synthesis of β-Lactams via
Homocoupling of Amines (Table 2). Benzylamines 1 (3.0 mmol),
2,4,6-trihydroxybenzoic acid monohydrate (28.2 mg, 0.15 mmol, 5
mol %), and toluene (1.5 mL) were added to a 20 mL two-neck flask
equipped with an O2 balloon at room temperature and stirred at 90
°C in an oil bath under an O2 atmosphere for 2 h. Then, the O2
balloon was removed and the reaction mixture was cooled to room
temperature. To the reaction mixture, 4A MS (300 mg) and Et3N
(627 μL, 4.5 mmol, 1.5 equiv) were added, and acyl chloride 4 (4.5
mmol, 1.5 equiv) in CH3CN (3.0 mL) was added dropwise at 0 °C.
The resulting solution was stirred at 25 °C for 18 h under a N2
atmosphere. After the reaction was finished, the resulting mixture was
filtered and the filtrate was extracted with AcOMe (10 mL). The
organic layer was washed with H2O (10 mL × 2) and brine (10 mL)
and dried with anhydrous Na2SO4. The solvent was concentrated
under reduced pressure. Finally, the residue was purified by silica-gel
chromatography (AcOMe/iso-hexane) and gel permeation chroma-
tography (eluent: CH2Cl2) to give product 5.
(
)-cis-3-Methoxy-4-(naphthalen-1-yl)-1-(naphthalen-1-
ylmethyl)azetidin-2-one (5g). Light yellow solid, 206.6 mg, 38%, mp
125.2−126.0 °C; 1H NMR (400 MHz, CDCl3): δ 8.13-8.09 (m, 1H),
7.89-7.84 (m, 3H), 7.76 (d, J = 8.2 Hz, 1H), 7.63 (dd, J = 11.4, 7.8
Hz, 2H), 7.55 (d, J = 7.8 Hz, 1H), 7.52−7.48 (m, 2H), 7.46 (dd, J =
8.0, 1.1 Hz, 1H), 7.41−7.37 (m, 1H), 7.20 (dd, J = 8.1, 7.0 Hz, 1H),
7.07 (d, J = 6.4 Hz, 1H), 5.51 (d, J = 14.7 Hz, 1H), 5.13 (d, J = 4.6
Hz, 1H), 4.72 (d, J = 4.6 Hz, 1H), 4.40 (d, J = 14.7 Hz, 1H), 2.95 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 167.0, 134.0, 133.8,
131.5, 131.4, 130.4, 129.5, 129.2, 129.1, 128.9, 128.8, 128.4, 127.1,
126.4, 126.3, 125.8, 125.44, 125.35, 125.2, 123.6, 122.2, 86.3, 58.9,
57.6, 42.4; HRMS (ESI) m/z calcd for C25H21NNaO2 [M + Na]+:
390.1470, found: 390.1475.
( )-cis-3-Methoxy-4-(thiophen-2-yl)-1-(thiophen-2-ylmethyl)-
1
azetidin-2-one (5h). Yellow oil, 51.6 mg, 12%; H NMR (400 MHz,
CDCl3): δ 7.39 (dd, J = 5.0, 0.9 Hz, 1H), 7.24 (dd, J = 5.0, 1.4 Hz,
1H), 7.09−7.07 (m, 1H), 7.05 (dd, J = 5.0, 3.6 Hz, 1H), 6.94 (dd, J =
5.2, 3.4 Hz, 1H), 6.85 (d, J = 3.2 Hz, 1H), 4.96 (d, J = 4.5 Hz, 1H),
4.92 (d, J = 15.4 Hz, 1H), 4.68 (d, J = 4.1 Hz, 1H), 4.10 (d, J = 15.4
Hz, 1H), 3.25 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.8,
137.0, 136.4, 128.1, 127.4, 127.23, 127.18, 126.9, 126.0, 85.8, 58.6,
56.7, 38.0; HRMS (ESI) m/z calcd for C13H13NNaO2S2 [M + Na]+:
302.0285, found: 302.0300.
( )-cis-1-Benzyl-3-methoxy-4-phenylazetidin-2-one (5a).48 Col-
orless oil, 286.5 mg, 72%; 1H NMR (400 MHz, CDCl3) δ 7.39−7.34
(m, 3H), 7.30−7.26 (m, 5H), 7.12 (m, 2H), 4.82 (d, J = 14.7 Hz,
1H), 4.66 (d, J = 4.6 Hz, 1H), 4.56 (d, J = 4.6 Hz, 1H), 3.81 (d, J =
15.1 Hz, 1H), 3.09 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
166.9, 135.0, 133.5, 128.9, 128.70, 128.69, 128.6, 128.5, 127.9, 85.9,
61.1, 58.2, 44.0.
( )-cis-1-Benzyl-2-oxo-4-phenylazetidin-3-yl acetate (5i).58 Col-
orless oil, 242.1 mg, 55%; 1H NMR (400 MHz, CDCl3): δ 7.36−7.34
(m, 3H), 7.31−7.28 (m, 3H), 7.21 (dd, J = 7.1, 3.0 Hz, 2H), 7.14 (dd,
J = 7.1, 2.1 Hz, 2H), 5.77 (d, J = 4.6 Hz, 1H), 4.88 (d, J = 14.7 Hz,
1H), 4.75 (d, J = 4.6 Hz, 1H), 3.91 (d, J = 14.7 Hz, 1H), 1.65 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 169.2, 164.8, 134.5, 132.5,
( )-cis-1-(4-(tert-Butyl)benzyl)-4-(4-(tert-butyl)phenyl)-3-me-
thoxyazetidin-2-one (5b). Yellow oil, 149.1 mg, 26%; 1H NMR (400
MHz, CDCl3): δ 7.40−7.36 (m, 2H), 7.32−7.29 (m, 2H), 7.23−7.20
(m, 2H), 7.08−7.06 (m, 2H), 4.79 (d, J = 14.5 Hz, 1H), 4.64 (d, J =
4.5 Hz, 1H), 4.58 (d, J = 4.5 Hz, 1H), 3.78 (d, J = 15.0 Hz, 1H), 3.12
(s, 3H), 1.33 (s, 9H), 1.30 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3): δ 167.0, 151.6, 150.8, 132.2, 130.4, 128.4, 128.3, 125.7,
125.4, 85.8, 60.8, 58.3, 43.5, 34.7, 34.6, 31.42, 31.41; HRMS (ESI) m/
z calcd for C25H33NNaO2 [M + Na]+: 402.2409, found: 402.2408.
( )-cis-3-Methoxy-1-(4-methylbenzyl)-4-(p-tolyl)azetidin-2-one
129.0, 128.9, 128.6, 128.5, 128.4, 128.2, 77.5, 61.0, 44.6, 19.9.
( )-cis-1-Benzyl-3-phenoxy-4-phenylazetidin-2-one (5j).48 White
solid, 209.0 mg, 42%; 1H NMR (400 MHz, CDCl3): δ 7.33−7.26 (m,
8H), 7.17−7.15 (m, 2H), 7.11−7.06 (m, 2H), 6.86−6.82 (m, 1H),
6.71−6.69 (m, 2H), 5.39 (d, J = 4.6 Hz, 1H), 4.89 (d, J = 14.7 Hz,
1H), 4.75 (d, J = 4.6 Hz, 1H), 3.86 (d, J = 14.7 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3): δ 165.7, 157.0, 134.8, 132.8, 129.3, 129.0,
128.80, 128.77, 128.4, 128.1, 122.1, 115.6, 114.8, 82.2, 61.5, 44.3.
( )-cis-1-Benzyl-3-(4-chlorophenoxy)-4-phenylazetidin-2-one
(5k). White solid, 333.4 mg, 61%, mp 125.8−126.5 °C; 1H NMR (400
MHz, CDCl3): δ 7.33−7.23 (m, 8H), 7.16−7.14 (m, 2H), 7.06−7.02
(m, 2H), 6.66−6.62 (m, 2H), 5.34 (d, J = 4.5 Hz, 1H), 4.89 (d, J =
15.0 Hz, 1H), 4.74 (d, J = 4.5 Hz, 1H), 3.87 (d, J = 15.0 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 165.3, 155.5, 134.7, 132.5,
1
(5c). White solid, 271.4 mg, 61%, mp 63.2−64.0 °C; H NMR (400
MHz, CDCl3): δ 7.18 (s, 4H), 7.10 (d, J = 7.8 Hz, 2H), 7.01 (d, J =
8.2 Hz, 2H), 4.80 (d, J = 14.7 Hz, 1H), 4.61 (d, J = 4.1 Hz, 1H), 4.51
(d, J = 4.6 Hz, 1H), 3.73 (d, J = 14.7 Hz, 1H), 3.11 (s, 3H), 2.37 (s,
3H), 2.32 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 166.9,
138.5, 137.6, 132.0, 130.4, 129.5, 129.3, 128.6, 128.5, 85.8, 60.7, 58.2,
43.5, 21.3, 21.2; HRMS (ESI) m/z calcd for C19H21NNaO2 [M +
Na]+: 318.1470, found: 318.1473.
( )-cis-3-Methoxy-1-(2-methoxybenzyl)-4-(2-methoxyphenyl)-
azetidin-2-one (5d). Yellow solid, 51.3 mg, 10%, mp 98.0−99.0 °C;
1H NMR (400 MHz, CDCl3): δ 7.30−7.22 (m, 3H), 7.14 (dd, J = 7.5,
1.6 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.87 (t, J = 7.2 Hz, 2H), 6.78
129.2, 129.01, 128.95, 128.75, 128.70, 128.5, 128.2, 127.0, 116.9, 82.2,
G
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Article
61.3, 44.3; HRMS (ESI) m/z calcd for C22H18ClNNaO2 [M + Na]+:
386.0924, found: 386.0929.
1.28 (m, 6H), 0.85 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
167.2, 159.9, 129.7, 125.8, 113.9, 85.5, 61.4, 58.1, 55.3, 40.1, 31.4,
27.4, 26.8, 22.6, 14.0; HRMS (ESI) m/z calcd for C17H25NNaO3 [M
+ Na]+: 314.1732, found: 314.1734.
( )-cis-4-(4-(tert-Butyl)phenyl)-1-hexyl-3-methoxyazetidin-2-
one (8e). Yellow oil, 209.9 mg, 45%; 1H NMR (400 MHz, CDCl3): δ
7.39 (dt, J = 8.5, 1.9 Hz, 2H), 7.25−7.27 (m, 2H), 4.71 (d, J = 4.1 Hz,
1H), 4.66 (d, J = 4.6 Hz, 1H), 3.44 (m, 1H), 3.12 (s, 3H), 2.84−2.91
(m, 1H), 1.41−1.48 (m, 2H), 1.33 (s, 9H), 1.19−1.28 (m, 6H), 0.85
(m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 167.3, 151.6, 130.8,
128.1, 125.4, 85.5, 61.6, 58.2, 40.2, 34.7, 31.4, 27.4, 26.7, 22.5, 14.1;
HRMS (ESI) m/z calcd for C20H31NNaO2 [M + Na]+: 340.2252,
found: 340.2255.
Gram-Scale Synthesis of β-Lactams via Oxidative Coupling
of Benzylamine (Tables 2, 5a). Benzylamine 1a (10.0 mmol, 1.08
g), 2,4,6-trihydroxybenzoic acid monohydrate (5 mol %), and toluene
(3 mL) were added to a 50 mL two-neck flask equipped with an O2
balloon at room temperature and stirred at 90 °C in an oil bath under
an O2 atmosphere for 2 h. Then, the O2 balloon was removed and the
reaction mixture was cooled to room temperature. To the reaction
mixture, 4A MS (1.0 g) and Et3N (15 mmol, 1.5 equiv) were added,
and methoxyacethyl chloride 4a (15 mmol, 1.5 equiv) in CH3CN (10
mL) was added dropwise at 0 °C. The resulting solution was stirred at
25 °C for 18 h under a N2 atmosphere. After the reaction was
finished, the resulting mixture was filtered and the filtrate was
extracted with AcOMe (30 mL). The organic layer was washed with
H2O (30 mL × 2) and brine (30 mL) and dried with anhydrous
Na2SO4. The solvent was concentrated under reduced pressure.
Finally, the residue was purified by silica-gel chromatography
(AcOMe/iso-hexane) to give product 5a (colorless oil, 0.7789 g,
58%).
General Procedure for the Synthesis of β-Lactams via
Cross-Coupling of Amines (8). Benzylamines 1 (1.5 mmol),
amines 2 (3.0 mmol), 2,4,6-trihydroxybenzoic acid monohydrate
(42.3 mg, 0.225 mmol, 15 mol %), and toluene (1.0 mL) were added
to a 20 mL two-neck flask equipped with an O2 balloon at room
temperature and stirred at 90 °C in an oil bath under an O2
atmosphere for 6 h. Then, the O2 balloon was removed and the
reaction mixture was cooled to room temperature. To the reaction
mixture, 4A MS (300 mg) and Et3N (627 μL, 4.5 mmol, 3 equiv)
were added, and acyl chloride 4 (4.5 mmol, 3 equiv) in CH3CN (3.0
mL) was added dropwise at 0 °C. The resulting solution was stirred at
90 °C in an oil bath under a N2 atmosphere for 18 h. After the
reaction was finished, the resulting mixture was filtered and the filtrate
was extracted with AcOMe (10 mL). The organic layer was washed
with H2O (10 mL×2) and brine (10 mL) and dried with anhydrous
Na2SO4. The solvent was concentrated under reduced pressure.
Finally, the residue was purified by silica-gel chromatography
(AcOMe/iso-hexane) and gel permeation chromatography (eluent:
CH2Cl2) to give product 8.
( )-cis-1-Hexyl-3-methoxy-4-(4-(trifluoromethyl)phenyl)-
1
azetidin-2-one (8f). Colorless oil, 134.0 mg, 27%; H NMR (400
MHz, CDCl3): δ 7.66 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H),
4.80 (d, J = 4.1 Hz, 1H), 4.72 (d, J = 4.1 Hz, 1H), 3.42−3.49 (m,
1H), 3.14 (s, 3H), 2.85−2.92 (m, 1H), 1.39−1.50 (m, 2H), 1.18−
1.30 (m, 6H), 0.85 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
167.0, 138.4, 131.0, 128.8, 125.5, 125.4, 85.7, 61.4, 58.4, 40.5, 31.3,
27.4, 26.7, 22.5, 14.0; HRMS (ESI) m/z calcd for C17H22F3NNaO2
[M + Na]+: 352.1500, found: 352.1492.
( )-cis-1-Hexyl-3-methoxy-4-(naphthalen-1-yl)azetidin-2-one
(8g). Yellow oil, 140.8 mg, 30%; 1H NMR (400 MHz, CDCl3): δ 8.02
(d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 7.7 Hz, 1H),
7.50−7.59 (m, 4H), 5.60 (d, J = 4.5 Hz, 1H), 4.91 (d, J = 4.5 Hz,
1H), 3.67 (dt, J = 15.0, 7.0 Hz, 1H), 2.96−3.06 (overlapped: 1H (m)
and 3H (s)), 1.50−1.58 (m, 2H), 1.22−1.32 (m, 7H), 0.85 (t, J = 6.8
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 167.1, 133.5, 131.2,
129.5, 128.9, 128.3, 126.2, 125.5, 125.1, 124.7, 121.8, 85.9, 58.5, 58.0,
40.3, 31.0, 27.0, 26.5, 22.2, 13.7; HRMS (ESI) m/z calcd for
C20H25NNaO2 [M + Na]+: 334.1783, found: 334.1781.
( )-cis-1-Heptyl-3-methoxy-4-phenylazetidin-2-one (8h). Brown
1
oil, 177.9 mg, 43%; H NMR (400 MHz, CDCl3): δ 7.41−7.33 (m,
5H), 4.74 (d, J = 4.5 Hz, 1H), 4.68 (d, J = 4.5 Hz, 1H), 3.48−3.41
(m, 1H), 3.10 (s, 3H), 2.93−2.86 (m, 1H), 1.46−1.43 (m, 2H),
1.27−1.22 (m, 8H), 0.87-0.84 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 167.3, 134.0, 128.7, 128.5, 127.0, 85.5, 61.9, 58.2, 40.3,
31.7, 28.8, 27.4, 27.0, 22.6, 14.1; HRMS (ESI) m/z calcd for
C17H25NNaO2 [M + Na]+: 298.1783, found: 298.1784.
( )-cis-1-Hexyl-3-methoxy-4-phenylazetidin-2-one (8a). Yellow
1
( )-cis-1-Octyl-3-methoxy-4-phenylazetidin-2-one (8i). Brown
solid, 252.3 mg, 58%, mp 31.0−32.0 °C; 1H NMR (400 MHz,
CDCl3): δ 7.38−7.36 (m, 5H), 4.74 (d, J = 3.6 Hz, 1H), 4.69 (d, J =
3.6 Hz, 1H), 4.06-4.06 (m, 1H), 3.47-3.43 (m, 2H), 3.10 (s, 3H),
2.93−2.86 (m, 1H), 1.44−1.44 (m, 1H), 1.22−1.22 (m, 9H), 0.88−
0.85 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 167.4, 133.9,
128.7, 128.5, 128.3, 85.4, 61.9, 58.2, 40.3, 31.8, 29.2, 29.1, 27.4, 27.1,
22.7, 14.1; HRMS (ESI) m/z calcd for C18H27NNaO2 [M + Na]+:
312.1939, found: 312.1935.
oil, 164.4 mg. 42%; H NMR (400 MHz, CDCl3): δ 7.41−7.33 (m,
5H), 4.73 (d, J = 4.6 Hz, 1H), 4.68 (d, J = 4.1 Hz, 1H), 3.48-3.41 (m,
1H), 3.10 (s, 3H), 2.92−2.85 (m, 1H), 1.49−1.41 (m, 2H), 1.28−
1.23 (m, 6H), 0.87−0.83 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 167.2, 134.0, 128.7, 128.5 (overlapped), 85.6, 61.9, 58.2,
40.3, 31.4, 27.4, 26.8, 22.5, 14.0; HRMS (ESI) m/z calcd for
C16H23NNaO2 [M + Na]+: 284.1626, found: 284.1624.
( )-cis-1-Hexyl-3-methoxy-4-(2-methoxyphenyl)azetidin-2-one
1
(8b). Yellow oil, 188.5 mg, 43%; H NMR (400 MHz, CDCl3): δ
( )-cis-1-(2-Ethylhexyl)-3-methoxy-4-phenylazetidin-2-one (8j).
7.34−7.26 (m, 2H), 7.01 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H),
5.22 (d, J = 4.5 Hz, 1H), 4.69 (d, J = 4.5 Hz, 1H), 3.86 (s, 3H), 3.57−
3.49 (m, 1H), 3.13 (s, 3H), 2.93−2.86 (m, 1H), 1.54−1.43 (m, 2H),
1.31−1.22 (m, 6H), 0.89−0.82 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 167.6, 157.6, 129.2, 128.4, 122.5, 120.6, 110.3, 85.6, 58.3,
55.7, 55.5, 40.3, 31.4, 27.3, 26.7, 22.6, 14.1; HRMS (ESI) m/z calcd
for C17H25NNaO3 [M + Na]+: 314.1732, found: 314.1733.
( )-cis-1-Hexyl-3-methoxy-4-(3-methoxyphenyl)azetidin-2-one
(8c). Yellow oil, 165.6 mg, 38%; 1H NMR (400 MHz, CDCl3):δ
7.28−7.32 (m, 1H), 6.87−6.94 (m, 3H), 4.70 (d, J = 4.5 Hz, 1H),
4.67 (d, J = 4.5 Hz, 1H), 3.82 (s, 3H), 3.41−3.49 (m, 1H), 3.13 (s,
3H), 2.91 (m, 1H), 1.42−1.50 (m, 2H), 1.20−1.29 (m, 6H), 0.85 (m,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 167.1, 159.7, 135.7,
129.5, 120.8, 114.1, 113.9, 85.6, 61.8, 58.3, 55.4, 40.3, 31.4, 27.4, 26.8,
22.6, 14.0; HRMS (ESI) m/z calcd for C17H25NNaO3 [M + Na]+:
314.1732, found: 314.1731.
1
Yellow oil, 111.0 mg, 26%; H NMR (400 MHz, CDCl3): δ 7.32−
7.42 (m, 5H), 4.73−4.70 (2H, overlapped: δ 4.72 (d, J = 4.4 Hz, 1H),
4.71 (d, J = 5.2 Hz, 1H)), 3.47−3.37 (1H), 3.11 (s, 3H), 2.77−2.68
(1H), 1.41−1.50 (m, 1H), 1.11−1.33 (m, 7H), 0.77−0.92 (m, 7H);
13C{1H} NMR (100 MHz, CDCl3): δ 167.7, 133.8, 128.7, 128.5,
128.5, 85.5, 62.9, 62.8 (d, J = 22.9 Hz), 43.3 (d, J = 4.8 Hz), 38.0 (d, J
= 24.8 Hz), 31.0 (d, J = 22.9 Hz), 28.6, 24.4 (d, J = 9.5 Hz), 23.0 (d, J
= 7.6 Hz), 14.1, 10.6 (d, J = 20.0 Hz); HRMS (ESI) m/z calcd for
C18H27NNaO2 [M + Na]+: 312.1939, found: 312.1932.
( )-cis-1-Cyclohexyl-3-methoxy-4-phenylazetidin-2-one (8k).
White solid, 118.9 mg, 31%, mp 95.0−95.6 °C; 1H NMR (400
MHz, CDCl3): δ 7.35−7.41 (m, 5H), 4.75 (d, J = 4.5 Hz, 1H), 4.59
(d, J = 4.5 Hz, 1H), 3.46 (m, 1H), 3.05 (s, 3H), 1.94 (m, 1H), 1.69−
1.78 (m, 2H), 1.48−1.64 (m, 3H), 0.97−1.28 (m, 4H); 13C{1H}
NMR (100 MHz, CDCl3): δ 166.8, 135.3, 128.6, 128.6, 128.3, 84.7,
60.9, 58.1, 52.5, 31.6, 30.5, 25.1; HRMS (ESI) m/z calcd for
C16H21NNaO2 [M + Na]+: 282.1470, found: 282.1480.
( )-cis-1-Hexyl-3-methoxy-4-(4-methoxyphenyl)azetidin-2-one
(8d). Yellow oil, 158.7 mg, 36%; 1H NMR (400 MHz, CDCl3):δ 7.27
(td, J = 5.8, 3.4 Hz, 2H), 6.92 (dt, J = 9.2, 2.4 Hz, 2H), 4.68 (d, J =
4.1 Hz, 1H), 4.64 (d, J = 4.1 Hz, 1H), 3.82 (s, 3H), 3.37−3.47 (m,
1H), 3.11 (s, 3H), 2.83−2.93 (m, 1H), 1.38−1.48 (m, 2H), 1.18−
( )-cis-3-Methoxy-4-phenyl-1-(3-phenylpropyl)azetidin-2-one
1
(8l). White solid, 120.3 mg, 27%, mp 52.0−53.0 °C; H NMR (400
MHz, CDCl3): δ 7.32−7.41 (m, 5H), 7.24−7.27 (m, 2H), 7.15−7.19
H
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Article
(m, 1H), 7.10−7.12 (m, 2H), 4.66 (d, J = 4.5 Hz, 1H), 4.61 (d, J =
4.1 Hz, 1H), 3.44−3.52 (m, 1H), 3.09 (s, 3H), 2.93−3.00 (m, 1H),
2.53−2.64 (m, 2H), 1.71−1.86 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3): δ 167.3, 141.0, 133.9, 128.8, 128.5, 128.5, 128.4, 126.2, 85.5,
62.0, 58.2, 40.1, 33.5, 29.0; HRMS (ESI) m/z calcd for
C19H21NNaO2 [M + Na]+: 318.1470, found: 318.1471.
( )-cis-1-Hexyl-3-phenoxy-4-phenylazetidin-2-one (8m). Light
brown solid, 88.7 mg, 18%, mp 88.0−89.0 °C; 1H NMR (400
MHz, CDCl3): δ 7.27−7.34 (m, 5H), 7.09−7.14 (m, 2H), 6.86 (t, J =
7.2 Hz, 1H), 6.72 (d, J = 7.7 Hz, 2H), 5.43 (d, J = 4.1 Hz, 1H), 4.93
(d, J = 4.5 Hz, 1H), 3.48−3.55 (m, 1H), 2.92−2.99 (m, 1H), 1.46−
1.53 (m, 2H), 1.23−1.31 (m, 6H), 0.86 (m, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 166.1, 157.0, 133.3, 129.2, 128.7, 128.3, 122.0,
115.7, 114.8, 81.9, 62.3, 40.6, 31.4, 27.4, 26.8, 22.6, 14.1; HRMS
(ESI) m/z calcd for C21H25NNaO2 [M + Na]+: 346.1783, found:
346.1791.
31.5, 28.7, 28.7, 26.2, 25.3, 22.3, 13.1; HRMS (ESI) m/z calcd for
+
C18H30NO3 [M]+: 308.2220, found: 308.2225.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01128.
1H NMR and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Shintaro Kodama − Department of Applied Chemistry,
Graduate School of Engineering, Osaka Prefecture University,
Osaka 599-8531, Japan; orcid.org/0000-0003-4190-
9539; Email: skodama@chem.osakafu-u.ac.jp
Akiya Ogawa − Department of Applied Chemistry, Graduate
School of Engineering, Osaka Prefecture University, Osaka
599-8531, Japan; orcid.org/0000-0002-8543-2560;
Email: ogawa@chem.osakafu-u.ac.jp
( )-cis-3-(4-Chlorophenoxy)-1-hexyl-4-phenylazetidin-2-one
1
(8n). White solid, 111.1 mg, 21%, mp 108.5−109.5 °C; H NMR
(400 MHz, CDCl3): δ 7.30 (s, 5H), 7.06 (d, J = 9.1 Hz, 2H), 6.66 (d,
J = 8.6 Hz, 2H), 5.37 (d, J = 4.1 Hz, 1H), 4.92 (d, J = 4.5 Hz, 1H),
3.47−3.55 (m, 1H), 2.92−2.99 (m, 1H), 1.49 (m, 2H), 1.25−1.29
(m, 6H), 0.86 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.6,
155.6, 133.0, 129.2, 128.9, 128.6, 128.40, 127.0, 117.0, 81.9, 62.1,
40.6, 31.4, 27.9, 26.8, 22.6, 14.1; HRMS (ESI) m/z calcd for
C21H24ClNNaO2 [M + Na]+: 380.1393, found: 380.1398.
Authors
Yuki Yamamoto − Department of Applied Chemistry,
Graduate School of Engineering, Osaka Prefecture University,
Osaka 599-8531, Japan
Riku Nishimura − Department of Applied Chemistry,
Graduate School of Engineering, Osaka Prefecture University,
Osaka 599-8531, Japan
Akihiro Nomoto − Department of Applied Chemistry,
Graduate School of Engineering, Osaka Prefecture University,
Osaka 599-8531, Japan
Michio Ueshima − Department of Applied Chemistry,
Graduate School of Engineering, Osaka Prefecture University,
Osaka 599-8531, Japan
One-Pot Synthesis of β-Lactam 5a Using Silica-Supported
4,6-Dihydroxysalicylic Acid as the Catalyst for Oxidation of
Benzylamine 1a (eq 3). Benzylamine 1a (321.5 mg, 3.0 mmol), 4.7
wt % 2 on a silica gel (0.15 mmol, 5 mol %), and toluene (1.5 mL)
were added to a 20 mL two-neck flask equipped with an O2 balloon at
room temperature and stirred at 90 °C in an oil bath under an O2
atmosphere for 2 h. Then, the O2 balloon was removed and the
reaction mixture was cooled to room temperature. To the reaction
mixture, 4A MS (300 mg) and Et3N (627 μL, 4.5 mmol, 1.5 equiv)
were added, and methoxyacetyl chloride 4a (488.3 mg, 4.5 mmol, 1.5
equiv) in CH3CN (3.0 mL) was added dropwise at 0 °C. The
resulting solution was stirred at 25 °C for 18 h under a N2
atmosphere. After the reaction was finished, the resulting mixture
was filtered and the filtrate was extracted with AcOMe (10 mL). The
organic layer was washed with H2O (10 mL × 2) and brine (10 mL)
and dried with anhydrous Na2SO4. The solvent was concentrated
under reduced pressure. The yield of β-lactam 5a was confirmed by
1H NMR spectroscopy using 1,3,5-trioxane as an internal standard.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01128
Notes
The authors declare no competing financial interest.
Hydrolysis of the β-Lactams to Diastereoselective Synthesis
of β-Amino Acids (Table 5). β-Lactam (5 or 8, synthesized by this
reported method, 0.3 mmol) was dissolved in CH3CN (1.0 mL) in a
10 mL test tube, and 10% HCl aq. (1.0 mL) was added to the reaction
vessel. The mixture was heated at 100 °C in an oil bath for 24 h. After
the reaction was completed, the solvent was removed under the
reduced pressure, and then recrystallization using CH2Cl2 and iso-
hexane was conducted. The resulting solid was washed with iso-
hexane (10 mL × 2) and then dissolved in EtOH (10 mL). The
solution was filtered over cotton and concentrated under reduced
pressure to give corresponding pure β-amino acids 9.
ACKNOWLEDGMENTS
■
This work was supported by Grant-in-Aid for Scientific
Research on Scientific Research (19H02756, 19H02791)
from The Japan Society for the Promotion of Science (JSPS)
and the Nagoya Institute of Technology Nanotechnology
Platform Program of MEXT, Grant Number JPMXP09
2021008. The authors also acknowledge the editor and
reviewers for their suggestions.
DEDICATION
■
N-Benzyl-2-carboxy-2-methoxy-1-phenylethan-1-aminium
1
This work is dedicated to Emeritus Professor Noboru Sonoda
(Osaka University) on the occasion of his 88th birthday.
chloride (9a). White solid, 95.6 mg, 99%, mp 205.0−206.0 °C; H
NMR (400 MHz, CD3OD): δ 7.55−7.49 (m, 5H), 7.43−7.40 (m,
3H), 7.39−7.36 (m, 2H), 4.43 (dd, J = 22.4, 8.7 Hz, 2H), 4.07 (dd, J
= 33.0, 13.3 Hz, 2H), 3.56 (s, 3H); 13C{1H} NMR (100 MHz,
CD3OD): δ 170.1, 130.5, 130.4, 130.2, 129.9, 129.4, 129.3, 129.2,
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