Divergent synthesis of α,α-dihaloamides through α,α-dihalogenation of β-oxo amides by using N-halosuccinimides

Article abstract of DOI:10.1002/ejoc.201300341

An efficient and divergent one-pot synthesis of α,α- dihaloamides from readily available β-oxo amides based on the selection of reaction conditions is reported. α,α-Dihalo-β-oxo amides were produced by treating β-oxo amides with N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) in water at room temperature, whereas α,α-dihaloacetamides were synthesized by subjecting β-oxo amides to NCS or NBS in ethanol under reflux. A divergent synthesis of α,α-dihalo-β-oxo amides and α,α-dihaloacetamides has been developed from readily available β-oxo amides. Upon treatment with N-halosuccinimides in water at room temperature, α,α-dihalo-β- oxo amides were produced, whereas dihaloacetamides were synthesized by treatment of β-oxo amides with N-halosuccinimides in ethanol under reflux. Copyright

Full text of DOI:10.1002/ejoc.201300341

FULL PAPER
DOI: 10.1002/ejoc.201300341
Divergent Synthesis of α,α-Dihaloamides through α,α-Dihalogenation of β-Oxo
Amides by Using N-Halosuccinimides
Jia Wang,[a,b] Hongtao Li,*[a] Dingyuan Zhang,[b] Peng Huang,[b] Zikun Wang,[b]
Rui Zhang,*[b,c] Yongjiu Liang,[b] and Dewen Dong[b,c]
Keywords: Amides / Synthetic methods / Halogenation / Domino reactions
An efficient and divergent one-pot synthesis of α,α-dihaloam- chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) in
ides from readily available β-oxo amides based on the selec-
tion of reaction conditions is reported. α,α-Dihalo-β-oxo
amides were produced by treating β-oxo amides with N-
water at room temperature, whereas α,α-dihaloacetamides
were synthesized by subjecting β-oxo amides to NCS or NBS
in ethanol under reflux.
N-Halosuccinimides are extremely versatile halogenating
reagents owing to their ready availability and easy hand-
ling.[7] The major advantage of the use of N-halosuccin-
imides is that the byproduct succinimide can be easily reco-
vered and converted back to N-halosuccinimides to be re-
used.[8] Classically, N-halosuccinimide halogenation of 1,3-
diketones, β-oxo esters, cyclic ketones, aryl alkyl and dialkyl
ketones proceeds through a radical process promoted by
initiators such as azobis(isobutyronitrile) (AIBN) and di-
benzoyl peroxide (BPO) in CCl4 heated to reflux.[9] Re-
cently, Iskra et al. reported that benzylic brominations of
substituted toluenes with N-bromosuccinimide could be ac-
complished in water with good to excellent yields.[10]
During the course of our studies on the chemistry and
applications of β-oxo amide derivatives,[11] we successfully
developed convenient syntheses of α-oxo ketene S,S-acet-
als,[12a] dihydropyranones,[12b] cyclopropyl amides,[12c] and
isoxazoles[12d] in aqueous media. We also noticed that β-
oxo amides are easily deacylated under appropriate condi-
tions.[13] In light of these studies and the synthetic impor-
tance of functionalized β-oxo amides, we examined the re-
action of β-oxo amides with N-halosuccinimides. As a re-
sult, we developed an efficient and divergent synthesis of
α,α-dihaloamides. Herein, we wish to report our experimen-
tal results.
Introduction
α,α-Dihaloamides have exceptional academic and indus-
trial significance, because this motif is embedded in the
structure of a number of biologically active compounds, in-
cluding antibiotic drugs such as chloramphenicol[1] and
florfenicol,[2] which find a wide range of applications in the
pharmaceutical and agrochemical industry.[3] They are also
widely used as versatile intermediates in organic transfor-
mations.[4] So far, many synthetic methodologies for α,α-
dihaloamides are available, among which the most prevalent
strategy relies heavily upon the ammonolysis of α,α-dihalo-
carboxylic acid derivatives with an amine.[3,5] Other meth-
ods are reported by the direct α,α-dihalogenation of β-oxo
amides with various halogenating systems, such as chlorine/
hv,[6a] SO2Cl2,[6b] N-chlorosuccinimide/NaH,[6c] aqueous
bromine,[6d] and PhI(OAc)2/ZnX2 (X = Cl, Br).[6e] Never-
theless, some of these methods involve hazardous reagents,
harsh reaction conditions, or generation of wastes that not
only reduce process efficiency but also pose environmental
problems. Therefore, to match the increasing scientific and
practical demands, it is still of continued interest and great
importance to develop new approaches for the preparation
of α,α-dihaloamides that use inexpensive and readily avail-
able reagents, mild reaction conditions, cleaner reactions,
and are simple to undertake.
[a] College of Chemical and Life Science, Changchun University
of Technology,
Results and Discussion
Changchun 130012, P. R. China
Synthesis of α,α-Dihalo-β-oxo Amides
[b] Green Chemistry and Process Laboratory, Changchun Institute
of Applied Chemistry, Chinese Academy of Sciences,
Changchun 130022, P. R. China
Initially, the reaction of 3-oxo-N-phenylbutanamide (1a)
with N-chlorosuccinimide (NCS; 2.0 equiv.) was first at-
tempted in N,N-dimethylformamide (DMF) at room tem-
perature for 10 h. The reaction proceeded smoothly as mon-
itored by TLC and furnished a small amount of 2-chloro-
3-oxo-N-phenylbutanamide (2a) and desired 2,2-dichloro-3-
Fax: +86-431-85262740
E-mail: ariel@ciac.jl.cn
Homepage: http://yjsb.ciac.jl.cn/daoshi_read.php?brow=71&lb
[c] Changzhou Institute of Energy Storage Materials & Devices,
Changzhou 213003, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300341.
5376
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5376–5380

Divergent Synthesis of α,α-Dihaloamides
oxo-N-phenylbutanamide (3a1) in 76% yield, as determined Table 2. Synthesis of α,α-dihalo-β-oxo amides 3.[a]
from spectral and analytical data, after workup and purifi-
cation by column chromatography of the resulting mixture
(Table 1, Entry 1).
Table 1. Optimization of the reaction conditions.
Entry
1
R
X
3
Yield[b] [%]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1a
1b
1c
1f
Ph
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
3a1
3b1
3c1
3d1
3e1
3a2
3b2
3c2
3f2
89
82
78
83
86
80
84
75
85
2-MeC6H4
2,4-Me2C6H3
4-MeOC6H4
5-Cl-2-MeOC6H3
Ph
2-MeC6H4
2,4-Me2C6H3
4-ClC6H4
Entry NCS Solvent
[equiv.]
Temp.
[°C]
Time
[h] 2a 3a1 4a1
Yield[a] [%]
1
2
2.0
2.0
2.0
2.0
2.2
2.2
2.2
2.2
3.3
3.3
DMF
EtOH
H2O
room temp.
room temp.
room temp.
room temp.
room temp.
80
10 15 76
0
0
0
0
0
15
15
15
10
10
2
0
4
3
0
0
82
85
82
89
[a] Reagents and conditions:
(2.2 mmol), H2O (20 mL), room temp., 10–12 h. [b] Isolated yield.
1 (1.0 mmol), NCS or NBS
3
4
5
H2O[b]
H2O
6
7
8
9
H2O
25 67
[c]
DMF
EtOH
H2O
80
reflux
80
reflux
–
2
10
2
0
0
0
0
83
23 65
77
10
EtOH
0
[a] Isolated yield. [b] 5% tetra-n-butylammonium bromide was
added. [c] Complex mixture.
Scheme 1. Halogenation of N-isopropyl-3-oxo-N-phenylbutan-
amide.
The optimization of the reaction conditions, including
reaction temperature, solvents, and the ratio of NCS/1a,
was then investigated. When 1a was treated with NCS
(2.0 equiv.) in EtOH at room temperature, 3a1 could be ob-
tained alone in 82% yield (Table 1, Entry 2). This result en-
couraged us to exploit the feasibility of preparation of α,α-
dihaloamides in water. The use of water as a reaction me-
dium in organic chemistry was rediscovered in the 1980s in
Breslow’s work, which showed that a hydrophobic effect can
strongly enhance the rates of some organic reactions.[14] Or-
ganic reactions in water without the use of any organic sol-
vent can also benefit from the fact that water is an easily
available, cheap, safe, and environmentally benign sol-
vent.[15] After a series of experiments, the optimal reaction
conditions were obtained when the reaction of 1a was per-
formed with NCS (2.2 equiv.) in water at room temperature
for 10 h, whereby the yield of 3a1 reached 89% (Table 1,
Entry 5).
Having established the optimal conditions for the synthe-
sis of α,α-dihalo-β-oxo amides, we intended to determine
its scope with respect to amide and halogen motifs. As
shown in Table 2, when a series of β-oxo amides 1b–1e bear-
ing varied arylamide groups were subjected to NCS under
identical conditions, all the reactions proceeded smoothly
to afford the corresponding α,α-dichloro-β-oxo amides
3b1–3e1 in good to excellent yields (Table 2, Entries 2–5).
The reaction of N-isopropyl-3-oxo-N-phenylbutanamide
(1g) was examined under identical conditions; only 2-
chloro-N-isopropyl-3-oxo-N-phenylbutanamide (2g) was
obtained, which revealed the influence of the steric hin-
drance of β-oxo amides in this halogenation reaction
(Scheme 1).
The versatility of this α,α-dihalogenation reaction was
further evaluated by performing reactions of β-oxo amides
1b–1c and 1f with N-bromosuccinimide (NBS; Table 2, En-
tries 6–8), which furnished the corresponding α,α-dibromo-
β-oxo amides 3b2–3c2 and 3f2 in moderate to good yields.
It is worth noting that, in all cases of Table 2, Entries 1–8,
the succinimide byproduct is soluble in water,[10b,10c]
whereas products 3a1–3f2 are solid and can precipitate
from the reaction system once formed. Pure product 3
could be obtained after the solid was filtered and washed
with water. Therefore, we provided a clean, facile and prac-
tical approach for the synthesis of α,α-dihalo-β-oxo amides
of type 3.
To expand the scope of the reaction, we then examined
the reaction of 1-phenylbutane-1,3-dione (1h) toward NBS
in water at room temperature. The reaction proceeded
smoothly, as indicated by TLC, and furnished expected α,α-
dibrominated 1,3-dicarbonyl compound 3h2 in 84% yield
(Scheme 2). However, when N-phenylacetamide was treated
with NBS (2.2 equiv.) under otherwise identical conditions
for 10 h, no reaction was observed as indicated by TLC.
This result suggested that the 1,3-dicarbonyl group was es-
sential for the α,α-dihalogenation reaction of β-oxo amides.
Scheme 2. α,α-Dibromination reaction of 1-phenylbutane-1,3-di-
one.
Eur. J. Org. Chem. 2013, 5376–5380
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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H. Li, R. Zhang, et al.
FULL PAPER
Synthesis of α,α-Dihaloacetamides
ethanone when 1-phenylbutane-1,3-dione (1h) was sub-
jected to the identical conditions used for β-oxo amides 1b–
1f, which might be owing to the instability of intermediate
2,2-dibromo-1-phenylbutane-1,3-dione (3h2) at high tem-
perature in ethanol.[13] Nevertheless, we provided an alter-
native and practical synthesis of α,α-dihaloacetamides of
type 4.
Next, we were interested in the reaction behavior of β-
oxo amides with N-halosuccinimides at high temperature.
Thus, the reaction of 1a with NCS (2.2 equiv.) was at-
tempted in water at 80 °C. To our surprise, substrate 1a was
consumed within 2 h as monitored by TLC. After workup
and purification by column chromatography, a new product
was observed along with known product 3a1, which was
characterized as 2,2-dichloro-N-phenylacetamide (4a1) on
the basis of its spectral and analytical data (Table 1, En-
try 5). Formation of 4a1 was attributed to further deacyl-
ation of 3a1 at high temperature.[13] Gratifyingly, 4a1 could
be exclusively formed in 83% yield when the reaction was
conducted in ethanol a reflux temperatures for 2 h (Table 1,
Entry 6). In this case, the resulting reaction mixture was
cooled to room temperature, poured into saturated aqueous
NaCl solution, and the precipitated solid was filtered,
washed with water, and dried in vacuo to furnish pure prod-
uct 4a1, whereas the succinimide byproduct remained in the
water.[10b,10c] Thus, the α,α-dihaloacetamide synthesis was
followed by a very simple, non-chromatographic separation
process.
Under the optimal conditions used for 4a1 (Table 1, En-
try 6), a range of reactions of β-oxo amides 1b–1f with N-
halosuccinimides (2.2 equiv.) were carried out in ethanol at
reflux temperatures. As summarized in Table 2, the effi-
ciency and synthetic interest of the tandem dihalogenation/
deacylation reaction were demonstrated with respect to β-
oxo amides 1b–1f bearing various electron-withdrawing and
electron-donating arylamide groups to afford the corre-
sponding α,α-dihaloacetamides 4b1–4f2 (Table 3).
Conclusions
A facile, practical, and divergent synthesis of α,α-dihalo-
β-oxo amides 3 and α,α-dihaloacetamides 4 has been devel-
oped from readily available β-oxo amides 1. Upon treat-
ment with N-halosuccinimides in water at room tempera-
ture, β-oxo amides 1 were converted into α,α-dihalo-β-oxo
amides 3 through an α,α-dihalogenation process, whereas
treatment of β-oxo amides 1 with N-halosuccinimides in
ethanol at reflux temperatures, α,α-dihaloacetamides 4 were
obtained through a tandem α,α-dihalogenation and deacyl-
ation reaction. This protocol is associated with readily avail-
able substrates, mild conditions, high yields, simple execu-
tion, and easy control of the reaction orientation through
selection of the reaction conditions.
Experimental Section
General Information: All reagents were purchased from commercial
sources and used without treatment, unless otherwise indicated.
Products were purified by column chromatography on silica gel. 1H
NMR spectra were recorded at 300, 400, or 500 MHz with TMS
as internal standard at 25 °C. 13C NMR spectra were recorded at
100 or 125 MHz with TMS as internal standard at 25 °C. IR spec-
tra (KBr) were recorded with an FTIR spectrophotometer in the
range 400–4000 cm–1. Elemental analyses were carried out with a
Perkin–Elmer PE-2400 analyzer.
Table 3. Synthesis of α,α-dihaloacetamides 4.[a]
Synthesis of α,α-Dihalo-β-oxo Amides 3
Typical Procedure for the Preparation of 3 (with 3a1 as Example):
To a suspension of 3-oxo-N-phenylbutanamide (1a) (1.0 mmol) in
water (20 mL) at room temperature was added NCS (2.2 mmol) in
one portion whilst stirring. The reaction mixture was stirred at
room temperature for 10 h, and then the precipitated solid was col-
lected by filtration, washed with water (3ϫ 30 mL), and dried in
vacuo to afford product 3a1 (0.218 g) in 89% yield.
Entry
1
R
X
4
Yield [%][b]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1a
1b
1c
1d
1e
1f
Ph
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
4a1
4b1
4c1
4d1
4e1
4f1
4a2
4b2
4c2
4d2
4e2
4f2
83
85
79
83
85
81
82
80
77
86[c]
79
84
2-MeC6H4
2,4-Me2C6H3
4-MeOC6H4
5-Cl-2-MeOC6H3
4-ClC6H4
Physical Data of Compounds 3
Ph
2,2-Dichloro-3-oxo-N-phenylbutanamide (3a1): White solid. M.p.
2-MeC6H4
2,4-Me2C6H3
4-MeOC6H4
5-Cl-2-MeOC6H3
4-ClC6H4
1
41–42 °C. H NMR (300 MHz, CDCl3): δ = 2.55 (s, 3 H), 7.22 (t,
J = 7.5 Hz, 1 H), 7.39 (t, J = 8.0 Hz, 2 H), 7.55 (d, J = 8.0 Hz, 2
H), 8.35 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.4,
83.2, 120.3 (2 C), 125.9, 129.2 (2 C), 135.9, 160.8, 191.7 ppm.
C10H9Cl2NO2 (246.09): calcd. C 48.81, H 3.69, N 5.69; found C
48.62, H 3.76, N 5.61.
10
11
12
[a] Reagents and conditions: 1 (1.0 mmol), NXS (2.2 mmol), EtOH
(20 mL), 75 °C, 1.5–2.5 h. [b] Isolated yield. [c] The crude product
was purified by flash chromatography (silica gel; petroleum ether/
diethyl ether, 12:1).
2,2-Dichloro-3-oxo-N-(o-tolyl)butanamide (3b1): Yield 0.213 g,
1
82%. White solid. M.p. 62–65 °C. H NMR (300 MHz, CDCl3): δ
= 2.35 (s, 3 H), 2.58 (s, 3 H), 7.17–7.31 (m, 3 H), 7.80 (d, J =
8.0 Hz, 1 H), 8.35 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 17.4, 24.4, 83.4, 122.8, 126.6, 126.9, 129.9, 130.8, 133.9, 160.9,
191.8 ppm. C11H11Cl2NO2 (260.12): calcd. C 50.79, H 4.26, N 5.38;
It should be noted that in all cases pure products 4 were
obtained by non-chromatographic separation, except 2,2-
dibromo-N-(4-methoxyphenyl)acetamide (4d2). However,
we were unable to obtain anticipated 2,2-dibromo-1-phenyl- found C 50.95, H 4.13, N 5.32.
5378
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Eur. J. Org. Chem. 2013, 5376–5380

Divergent Synthesis of α,α-Dihaloamides
2,2-Dichloro-N-(2,4-dimethylphenyl)-3-oxobutanamide (3c1): Yield
0.214 g, 78%. White solid. M.p. 50–52 °C. 1H NMR (300 MHz,
CDCl3): δ = 2.28 (s, 3 H), 2.32 (s, 3 H), 2.55 (s, 3 H), 7.05 (d, J =
5.0 Hz, 2 H), 7.60 (t, J = 9.0 Hz, 1 H), 8.25 (s, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 17.4, 20.9, 24.4, 83.2, 123.1, 127.5,
130.1, 131.2, 131.4, 136.6, 161.1, 191.8 ppm. C12H13Cl2NO2
(274.15): calcd. C 52.57, H 4.78, N 5.11; found C 52.68, H 4.82, N
5.06.
30 mL), and dried in vacuo to afford product 4a1 (0.169 g) in 83%
yield.
Physical Data of Compounds 4: 4a1–4b1, 4d1, 4a2–4b2 and 4d2–
4f2 are known compounds, and their analytical data are in good
agreement with those reported in the literature.[6e]
2,2-Dichloro-N-(p-tolyl)acetamide (4b1): Yield 0.185 g, 85%.
2,2-Dichloro-N-(2,4-dimethylphenyl)acetamide (4c1): Yield 0.182 g,
79%. White solid. M.p. 156–158 °C. 1H NMR (300 MHz, CDCl3):
δ = 2.28 (s, 3 H), 2.32 (s, 3 H), 6.06 (s, 1 H), 7.05 (d, J = 6.5 Hz,
2 H), 7.59 (d, J = 9.0 Hz, 1 H), 8.00 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 17.3, 20.9, 67.0, 123.1, 127.5, 130.1, 131.3,
131.4, 136.3, 161.9 ppm. C10H11Cl2NO (232.11): calcd. C 51.75, H
4.78, N 6.03; found C 51.89, H 4.71, N 6.12.
2,2-Dichloro-N-(4-methoxyphenyl)-3-oxobutanamide (3d1): Yield
0.229 g, 83%. White solid. M.p. 42–44 °C. 1H NMR (400 MHz,
CDCl3): δ = 2.54 (s, 3 H), 3.81 (s, 3 H), 6.90 (d, J = 9.0 Hz, 2 H),
7.45 (d, J = 9.0 Hz, 2 H), 8.29 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 24.4, 55.5, 83.3, 114.4 (2 C), 122.1 (2 C), 128.9, 157.6,
160.7, 191.7 ppm. C11H11Cl2NO3 (276.12): calcd. C 47.85, H 4.02,
N 5.07; found C 47.61, H 4.10, N 4.98.
2,2-Dichloro-N-(4-methoxyphenyl)acetamide (4d1): Yield 0.194 g,
83%.
2,2-Dichloro-N-(5-chloro-2-methoxyphenyl)-3-oxobutanamide (3e1):
Yield 0.267 g, 86%. White solid. M.p. 67–70 °C. 1H NMR
(300 MHz, CDCl3): δ = 2.54 (s, 3 H), 3.93 (s, 3 H), 6.84 (d, J =
8.5 Hz, 1 H), 7.10 (dd, J1 = 8.5, J2 = 2.5 Hz, 1 H), 8.34 (d, J =
2.5 Hz, 1 H), 9.14 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 24.3, 56.3, 83.2, 111.0, 119.7, 125.0, 126.2, 126.7, 147.0, 160.6,
191.5 ppm. C11H10Cl3NO3 (310.56): calcd. C 42.54, H 3.25, N 4.51;
found C 42.37, H 3.30, N 4.42.
2,2-Dichloro-N-(2-methoxy-5-methylphenyl)acetamide (4e1): Yield
0.227 g, 85%. Yellow solid. M.p. 108–110 °C. 1H NMR (300 MHz,
CDCl3): δ = 3.93 (s, 3 H), 6.04 (s, 1 H), 6.83 (t, J = 9.0 Hz, 1 H),
7.09 (d, J = 8.5 Hz, 1 H), 8.36 (d, J = 2.5 Hz, 1 H), 8.86 (s, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 56.2, 66.8, 110.9, 119.7,
124.7, 126.2, 126.9, 146.9, 161.4 ppm. C9H8Cl3NO2 (268.53): calcd.
C 40.26, H 3.00, N 5.22; found C 40.38, H 3.06, N 5.13.
2,2-Dibromo-3-oxo-N-phenylbutanamide (3a2): Yield 0.269 g, 80%.
2,2-Dibromo-3-oxo-N-(o-tolyl)butanamide (3b2): Yield 0.267 g,
2,2-Dichloro-N-(4-chlorophenyl)acetamide (4f1): Yield 0.193 g,
81%.
84%. White solid. M.p. 78–79 °C. IR (KBr): ν = 3299, 1668, 1510,
˜
2,2-Dibromo-N-phenylacetamide (4a2): Yield 0.242 g, 82%.
2,2-Dibromo-N-(p-tolyl)acetamide (4b2): Yield 0.245 g, 80%.
1458, 1254, 1161, 752 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.36
(s, 3 H), 2.64 (s, 3 H), 7.14–7.29 (m, 3 H), 7.79 (d, J = 7.0 Hz, 1
H), 8.49 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.5,
24.2, 63.0, 122.7, 126.5, 126.9, 129.9, 130.7, 134.2, 161.6,
191.3 ppm. C11H11Br2NO2 (349.02): calcd. C 37.85, H 3.18, N 4.01;
found C 37.97, H 3.09, N 4.06.
2,2-Dibromo-N-(2,4-dimethylphenyl)acetamide (4c2): Yield 0.247 g,
77%. White solid. M.p. 190–191 °C. 1H NMR (300 MHz, CDCl3):
δ = 2.29 (s, 3 H), 2.32 (s, 3 H), 5.94 (s, 1 H), 7.05 (d, J = 6.5 Hz,
2 H), 7.58 (d, J = 9.0 Hz, 1 H), 8.00 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 17.4, 20.9, 36.9, 123.1, 127.5, 130.2, 131.4,
131.6, 136.3, 162.3 ppm. C10H11Br2NO (321.01): calcd. C 37.42, H
3.45, N 4.36; found C 37.68, H 3.49, N 4.41.
2,2-Dibromo-N-(2,4-dimethylphenyl)-3-oxobutanamide (3c2): Yield
0.272 g, 75%. White solid. M.p. 73–75 °C. IR (KBr): ν = 3379,
˜
1
3356, 1744, 1670, 1529, 1501, 1167, 818, 598, 549 cm–1. H NMR
(300 MHz, CDCl3): δ = 2.32 (s, 6 H), 2.62 (s, 3 H), 7.06 (d, J =
6.0 Hz, 2 H), 7.61 (d, J = 8.5 Hz, 1 H), 8.41 (s, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 17.5, 20.9, 24.2, 63.1, 122.9, 127.5,
130.1, 131.4, 131.5, 136.5, 161.7, 191.2 ppm. C12H13Br2NO2
(363.05): calcd. C 39.70, H 3.61, N 3.86; found C 39.57, H 3.55, N
3.91.
2,2-Dibromo-N-(4-methoxyphenyl)acetamide (4d2): Yield 0.277 g,
86%.
2,2-Dibromo-N-(2-methoxy-5-methylphenyl)acetamide (4e2): Yield
0.282 g, 79%. Yellowish solid. M.p. 145–147 °C. 1H NMR
(500 MHz, CDCl3): δ = 3.94 (s, 3 H), 5.94 (s, 1 H), 6.83 (d, J =
8.0 Hz, 1 H), 7.09 (t, J = 7.5 Hz, 1 H), 8.33 (s, 1 H), 8.85 (s, 1 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 36.6, 56.3, 110.9, 119.4,
124.5, 126.1, 127.1, 146.9, 161.7 ppm. C9H8Br2ClNO2 (357.43):
calcd. C 30.24, H 2.26, N 3.92; found C 30.37, H 2.18, N 3.97.
2,2-Dibromo-N-(4-chlorophenyl)-3-oxobutanamide
(3f2):
Yield
0.314 g, 85%. White solid. M.p. 108–110 °C. IR (KBr): ν = 3325,
˜
1688, 1531, 1491, 1402, 1238, 1171, 831, 507 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 2.64 (s, 3 H), 7.35 (d, J = 8.5 Hz, 2 H),
7.51 (d, J = 8.5 Hz, 2 H), 8.54 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 24.3, 62.3, 121.6 (2 C), 129.2 (2 C), 131.1, 134.8, 161.5,
191.4 ppm. C10H8Br2ClNO2 (369.44): calcd. C 32.51, H 2.18, N
3.79; found C 32.66, H 2.15, N 3.82.
2,2-Dibromo-N-(4-chlorophenyl)acetamide (4f2): Yield 0.274 g,
84%.
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic data for all new compounds.
2,2-Dibromo-1-phenylbutane-1,3-dione (3h2): Yield 0.269 g, 84%.
3h2 is a known compound, and its analytical data are in good
agreement with those reported in the literature.[16]
Acknowledgments
Synthesis of α,α-Dihaloacetamides 4
Financial support of this research by the National Natural Science
Foundation of China (21172211 and 51073150), the Department
of Science and Technology of Jilin Province (201205027) and the
Science and Technology of Changzhou (CJ20125008) is greatly ac-
knowledged.
Typical Procedure for the Preparation of 4 (with 4a1 as Example):
To a solution of 3-oxo-N-phenylbutanamide (1a) (1.0 mmol) in
EtOH (20 mL) at room temperature was added NCS (2.2 mmol).
The resulting mixture was stirred at reflux temperatures for 2 h.
After 1a had been consumed (monitored by TLC), the resulting
mixture was cooled to room temperature, poured into saturated
aqueous NaCl solution (50 mL), filtered, washed with water (3ϫ
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Received: March 7, 2013
Published Online: July 12, 2013
5380
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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