Zwitterion-Catalyzed Deacylative Dihalogenation of β-Oxo Amides

Article abstract of DOI:10.1021/acs.orglett.0c02701

α,α-Dihalo-N-arylacetamides are commonly used as intermediates in various organic reactions. In the study described here, a catalytic synthesis of α,α-dihalo-N-arylacetamides from β-oxo amides was developed using zwitterionic catalysts and N-halosuccinimi

Full text of DOI:10.1021/acs.orglett.0c02701

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Zwitterion-Catalyzed Deacylative Dihalogenation of β‑Oxo Amides
Zhihai Ke,* Ying-Pong Lam, Kin-San Chan, and Ying-Yeung Yeung*
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ABSTRACT: α,α-Dihalo-N-arylacetamides are commonly used as intermedi-
ates in various organic reactions. In the study described here, a catalytic
synthesis of α,α-dihalo-N-arylacetamides from β-oxo amides was developed
using zwitterionic catalysts and N-halosuccinimides as the halogen sources. The
corresponding α,α-dihalo-N-arylacetamides were obtained in good to excellent
yields, and no aromatic halogenated side products were detected. The reaction
conditions were mild, and no strong base or acid was required.
inexpensive and easy-to-handle N-halosuccinimide as the
stoichiometric halogen source under mild conditions (Scheme
1).
he deacylative halogenation of β-oxo amides is a useful
Treaction because the α,α-dihaloamide products are the
constitutional elements of many biologically active com-
pounds, for example, the antibiotic drugs florfenicol1 and
chloramphenicol.2 In addition, the halogens in α,α-dihaloa-
mides can be readily manipulated to give various functional
groups such as hydrazine3 and thiourea.4 Applications of α,α-
dihaloamide compounds as organocatalysts5 and herbicide
antidotes6 have also been reported. This type of molecule
cannot be prepared simply by the direct halogenation of
acetamides because overhalogenation to trihalogenated com-
pounds readily occurs.7 Hence the development of efficient
methods to synthesize versatile α,α-dihaloamide intermediates
is of great importance for both industrial and academic
sectors.8
Scheme 1. Deacylative Dihalogenation
In recent years, a number of methods for the synthesis of
α,α-dihaloamides 2 and 3 via the deacylative dihalogenation of
β-oxo amides 1 have been documented.9 For example, using
N-bromosuccinimide (NBS) with acetic acid (at room
temperature) or ethanol (under reflux) was also found to be
viable.9a,c Using CuBr or ZnBr2 as the bromine source together
with PhI(OAc)2 as the oxidant was also documented.9d
However, these reactions involve the use of a stoichiometric
amount of metal salt, acidic media, or high temperature, which
is undesirable. Zwitterionic catalysts, which involve site
isolation of the positively and negatively charged partners in
the same molecules while the overall charge is neutral,10 have
been applied in some important chemical reactions under mild
conditions.11,12 Our group also reported the use of zwitterions
to catalyze some chemical transformations.13 For instance,
zwitterion 4 was found to be highly active in catalyzing the
transesterification of alcohols.13c Herein we describe a novel
and efficient synthesis of α,α-dihaloarylamides 2 and 3 from β-
oxo arylamides 1 using zwitterionic catalyst 4 and the
At the beginning of the investigation, acetoacetanilide (1a)
and NBS were used as the substrate and the halogen source,
respectively (Table 1). The background reaction was found to
be sluggish (entry 1). A significant amount of aromatic
bromination side product was detected when EtOH was used
as the solvent (entry 2). The desired product 2a was obtained
Received: August 13, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02701
© XXXX American Chemical Society
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A

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a
a
Table 1. Conditions Optimization
Scheme 2. Scope of the Deacylative Dihalogenation
Br
yield
(%)
entry source
cat. (mol %)
solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBA
NBP
NCS
none
none
MeOH
EtOH
9
0
28
28
37
49
76
97
c
b
b
b
b
b
b
NaOMe (20)
K2CO3 (20)
DABCO (20)
DMAP (20)
4a (20)
4b (20)
LiNMeTs (20)
N-Methylpyridinium iodide (20)
4b (10)
4b (5)
4b (5)
4b (5)
4b (5)
4b (5)
4b (5)
4b (5)
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
CH2Cl2
CHCl3
PhMe
21
trace
93
89
trace
trace
trace
70
trace
90
MeOH
MeOH
MeOH
a
Reactions were carried out with 1a (0.05 mmol), a Br source (0.105
mmol), and a catalyst in solvent (1 mL) at 25 °C in the absence of
light for 2 h. The yields were measured using NMR with
b
nitromethane as the internal standard. Reaction time was 30 min.
c
11% of aromatic brominated products was observed. DABCO, 1,4-
diazabicyclo[2.2.2]octane; DMAP, 4-dimethylaminopyridine.
in low yield when alkali metal bases (NaOMe, K2CO3) or
amine bases (DABCO, DMAP) were used as the promoters
(entries 3−6). To our delight, zwitterionic catalyst 4a (20 mol
%) effectively promoted the reaction to give 2a in good yield
(76%) with no aromatic bromination (entry 7). The reaction
efficiency was further enhanced when zwitterion 4b was used
as the catalyst (entry 8). LiNMeTs and N-methylpyridinium
iodide were found to be inefficient in catalyzing the reaction
(entries 9 and 10), suggesting that the anionic and cationic
parts of 4b might work synergistically. A comparable yield was
obtained even when the catalyst loading was reduced to 5 mol
% (entries 11 and 12). Other reaction media such as
dichloromethane, chloroform, and toluene were found to be
not suitable (entries 13−15). The performance of NBS was
found to be superior to that of other brominating agents such
as N-bromoacetamide (NBA) and N-bromophthalimide
(NBP) (entries 16 and 17). α,α-Dichloroarylamide 3a was
obtained when N-chlorosuccinimide (NCS) was used as the
halogen source (entry 18).
a
Reactions were carried out with 1 (0.30 mmol), NBS (for product 2)
or NCS (for product 3) (0.63 mmol), and 4b (0.015 mmol) in
MeOH (6 mL) at 25 °C in the absence of light for 2 h. The yields
b
were isolated yields. 10 mol % of 4b was used, and ca. 40% of the
starting material was recovered. Trace amount of product was
detected when the reaction was conducted at 75 °C in EtOH for 12 h
in the absence of catalyst.
c
(5.0 mmol of 1b), and the desired product 2b was obtained in
comparable yield. The catalytic protocol was also found to be
compatible with substrates 1h−k bearing electron-withdrawing
substituents to give 2h−k. For the highly electron-deficient
difluorinated substrates 1l and 1m, the reactions were operated
using 10 mol % of zwitterionic catalyst 4b. Functional groups
including NBoc, ester, and silyl ether were also compatible
with the catalytic protocol, giving 2n−p in good yields. β-Oxo
amide 1q bearing the benzoyl substituent was successfully
dibrominated and deacylated, giving 2a in 62% yield. The N-
alkylated substrate 1r worked well in the reaction to give 2r in
82% yield. After studying the deacylative dibromination, we
turned our attention to the synthesis of α,α-dichloroarylamides
using NCS as the halogen source. To our delight, excellent
After the optimization of reaction conditions, the substrate
scope of the deacylative dibromination reaction was evaluated
(Scheme 2). For substrates 1b−g with electron-donating
substituents (alkyl and methoxy groups) on the phenyl ring,
the reaction smoothly proceeded to give the products 2b−2g
in good to excellent yields. The reaction was readily scalable
B
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yields of the desired products (3b−o) were obtained for
substrates bearing electron-donating or electron-withdrawing
substituents.
Some control experiments were conducted to shed light on
the mechanistic picture. Zwitterion 4b was acidified with 1
equiv of HCl (i.e., 4b-HCl) before being added to the reaction
mixture (Scheme 3, eq 1). Only a trace amount of the desired
Scheme 3. Control Experiments
Figure 1. NMR experiments.
Scheme 4. Proposed Mechanism
product 2a was detected, revealing the importance of the basic
amide of 4b in the catalysis. In literature, 2,2-dibromo-N-
phenyl-3-oxo-butanamide 5 is believed to be the key
intermediate for the deacylative dihalogenation reaction of β-
oxo amide.9 Indeed, a small amount of 5 was detected during
the reaction in MeOH, and it eventually diminished. When
using EtOH as the solvent, the reaction was relatively slow, and
a sufficient amount of 5 was isolated (Scheme 3, eq 2). When 5
was used as the substrate, 2a was obtained quantitatively,
suggesting that 5 might be an intermediate in the reaction
(Scheme 3, eq 3). For the reaction with 1q, methyl benzoate
was detected after the reaction, revealing the deacylation
process by the alcohol (Scheme 3, eq 4).
NMR experiments were conducted to understand the
interaction between β-oxo amide 1b and zwitterion 4b (Figure
1). Instead of CD3OD, CD2Cl2 was employed in all three
spectra as the NMR solvent to prevent the intervention of the
protic solvent. In Figure 1A, the sharp singlet peak at δ 3.6
corresponds to the two α-carbonyl protons Ha in 1b. The
signal disappeared completely upon the addition of 1 equiv of
4b, and a new board signal at δ 4.7 emerged (Figure 1C).
Concurrently, the C−H bonds adjacent to the C−N bonds
(Hb and Hc, Figure 1B) in zwitterion 4b shifted downfield
(Figure 1C). These observations could be attributed to the
interaction between the basic amide in zwitterion 4b and the
acidic proton in 1b.
speculate that the amide of zwitterion 4b might deprotonate
the β-oxo amide 1 to give the enolate species A. NBS might
then react with species A to give the monobrominated species
B, which could be further brominated to give dibromide 5. On
the basis of our previous study on the transesterification
reactions, zwitterion 4b is capable of deprotonating alcohols
while the iminium cation stabilizes the carbonyl oxygen via a
On the basis of the aforementioned results and literature
reports,9,14 a plausible mechanistic picture of the deacylative
dibromination of β-oxo amide is illustrated in Scheme 4. We
C
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nonclassical hydrogen bond interaction.13c Thus we believe
that zwitterion 4b might react with methanol to give
methoxide species C. The carbonyl oxygen of 5 might be
activated by the iminium cation of species C to give species D.
Subsequently, the methoxide might attack the carbonyl carbon
to give species E. The process might be slow with the relatively
bulkier EtOH, which might explain why a significant amount of
5 was detected for the reaction with EtOH (Scheme 3, eq 2).
Finally, retro-Claisen condensation15 by eliminating a molecule
of methyl acetate could furnish the desired α,α-dibromoamide
product 2 together with the regeneration of the zwitterionic
catalyst 4b. Thus, in this reaction, we believe that the
zwitterion might have dual roles: (1) promoting the
halogenation of β-oxo amides to α,α-dihalo-β-oxoamides and
(2) the synergistic activation of MeOH and the carbonyl of
α,α-dihalo-β-oxoamides in the deacylation process.
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https://pubs.acs.org/doi/10.1021/acs.orglett.0c02701.
Experimental procedures and characterization data for
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AUTHOR INFORMATION
Corresponding Authors
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Zhihai Ke − Department of Chemistry and State Key Laboratory
of Synthetic Chemistry, The Chinese University of Hong Kong,
Shatin, Hong Kong; orcid.org/0000-0001-7079-8845;
Email: chmkz@cuhk.edu.hk
Ying-Yeung Yeung − Department of Chemistry and State Key
Laboratory of Synthetic Chemistry, The Chinese University of
Hong Kong, Shatin, Hong Kong; orcid.org/0000-0001-
9881-5758; Email: yyyeung@cuhk.edu.hk
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Authors
Ying-Pong Lam − Department of Chemistry and State Key
Laboratory of Synthetic Chemistry, The Chinese University of
Hong Kong, Shatin, Hong Kong
Kin-San Chan − Department of Chemistry and State Key
Laboratory of Synthetic Chemistry, The Chinese University of
Hong Kong, Shatin, Hong Kong
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02701
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the financial support from the Research
Grants Council of the Hong Kong Special Administration
Region (project no. CUHK14305520), The Chinese Uni-
versity of Hong Kong Direct Grant (project no. 4053394), and
the Innovation and Technology Commission to the State Key
Laboratory of Synthetic Chemistry (GHP/004/16GD).
D
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