Cobalt(II)-catalyzed regioselective C-H halogenation of anilides

Article abstract of DOI:10.1039/c8ob01448e

A cobalt-catalyzed regioselective C-H halogenation methodology is reported herein. The highlight of this work is the highly selective C-H functionalization of anilides, which results in high-yielding, versatile, and practical halogenated products. Thereby, brominations, chlorinations and iodinations of many electron-rich and electron-deficient anilides were achieved in a highly selective fashion. Mechanistic studies with respect to the pathway of the reaction are also described.

Full text of DOI:10.1039/c8ob01448e

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Cobalt(II)-Catalyzed Regioselective C–H Halogenation of Anilides
Ze-lin Lia, Kang-kang Suna, and Chun Cai*a
Received 00th January 20xx,
Accepted 00th January 20xx
A cobalt-catalyzed regioselective C-H halogenation methodology is reported herein. The highlight of this work is the highly
selective C-H functionalization of anilides, which results in high-yielding, versatile, and practical halogenated products.
Thereby, brominations, chlorinations and iodinations of many electron-rich and electron-deficient anilides were achieved
in a highly selective fashion. Mechanistic studies with respect to the pathway of the reaction were also describled.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Ir(III)/l-MPAA-catalyzed halogenation of anilides was
established by Nicholls and his workers, featuring an
Introduction
extraordinarily
high
mono-halogenation
Aromatic halides have been an important class of compounds,
due to their role as fundamental structural motifs in a range of
natural product synthesis, material sciences and medicinal
chemistry1. In addition, the use of chloro-, bromo-, and
iodoarenes in cross-coupling reactions has tremendously
increased the importance of these building blocks in organic
synthesis2.
(iodination, bromination, and chlorination) at room
temperature with very low catalyst loadings. Meanwhile, cobalt
catalysis has recently exhibited its great potential in C-H bond
functionalization reactions due to its low-cost and unique catalytic
mode4,8. In 2014, the first example4a of Co(III)-catalyzed C–H
halogenation of amides and 2-arylpyridines using Cp*Co(III)
catalysis was describled by Glorius’s group. Next to it, Pawar and
co-workers4b showed a cobalt-catalyzed C–H halogenation of
biologically important 6-arylpurines under mild conditions with
good functional group tolerance. However, they were generally
limited by their scope, by efficiency, or by being suitable for
only one type of C-X bond formation. On the other hand, no
example concerning cheap transition metal cobalt catalyzed
selective halogenation reaction between ortho- and para-
position in anilides has been described yet.
Over the past decades, a great deal of effort has been made in
the strategy to create carbon-halogen bonds3. Conventional
methods such as the Sandmeyer or electrophilic aromatic
substitution or the directed ortho-lithiation approach are the
most established procedures for the synthesis of aryl halides5.
But the utility of these transformations is limited to the need
for stoichiometric amounts of toxic halogens and harsh
reaction conditions, resulting in low chemo-selectivities.
In recent years, the catalytic systems of the transition metal
including
Pd(II)6a,6e,6f
,
Rh(III)6g,
Ir(III)6d,
and
Pd(II)&Cu(II)6b,6c,6hcatalyzed halogenations of C-H bonds in
Previous work
anilides have been well established. For example, Webster and
H
H
H
N
co-workers reported
a Pd-catalyzed C-H halogenation of
N
R''
N
R''
R''
Pd(II), Pd(II)&Cu(II), Rh(III), Ir(III)
anilides in 20116a. In their procedure, ortho-selective
bromination was achieved by the use of p-toluenesulfonic acid
(PTSA) as an additive, and the reaction can be also performed
under very mild reaction conditions. Then, a Rh(III)-catalyzed
ortho bromination and iodination of anilides was describled,
opening up new possibilities for the synthesis of a panel of
aromatic halides6g. Furthermore, Kapur’s group6c showed the
ortho-selective C-H halogenation of anilides by the
coordination of Pd(OAc)2 and Cu(OTf)2 to assist the
transformation, avoiding the use of protic media or protic
additives. More recently, first example6d of a highly selective
O
O
O
X
X
X=Cl, or Br, or I
This work
HN
O
HN
X
O
O
HN
O
X
Co(acac)2
Ag2O
N
O
X
R
R
R
TFA DCE
60oC 16h
X= Cl, Br, I
regioselective C-H halogenation
cheap transition metal cobalt
tolerating good functional compatibility
relatively mild reaction conditions
Scheme 1. Previous Strategies for C-H Halogenations.
Inspired by these, we herein report the first example of
cobalt(II)-catalyzed regioselective C–H brominations,
chlorinations and iodinations of anilides.
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could proceed well by using TFA as the acid additive and
generate the ortho-bromination product in 57% yield. In
addition, we explored the influence of silver additives on yield.
Delightedly, the ortho-bromination yield was increased
dramatically to 86% by the addition of 20 mol% Ag2O in the
reaction system (entries 11–17). Unfortunately, lower
temperature is not beneficial to the yield of ortho-bromination
Table 1.
Optimization of the reaction conditions[a]
3a(%)[b]
3a’(%)[b]
reaction
(entries
18–19).
Finally,
the
Entry
Cat.
Additives1
Additives2
yields of ortho-bromination product decreased by using N-
1
2
Co(OAc)2
CoCl2
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgOAc
Ag2CO3
AgOPiv
AgNO3
AgCl
PivOH
PivOH
PivOH
PivOH
PivOH
HOAc
PTSA
TFA
12
Trace
Trace
Trace
31
85
62
Table 2. Screening of substrate scope in the ortho-bromination reaction of
substituted anilides.[a]
3
CoCO3
40
4
CoC2O4
46
5
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
48
6
Trace
38
63
7
55
8
57
41
9
PCy3
Dcype
TFA
0
Trace
Trace
13
10
11
12
13
14
15
16
17
18[c]
19[d]
20[e]
0
73
TFA
51
28
TFA
30
53
TFA
Trace
17
45
TFA
34
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Ag2O
TFA
86
7
AgO2CCF3
Ag2O
TFA
45
41
TFA
0
Trace
26
Ag2O
TFA
10
[a]Reaction condition: anilides (0.5 mmol), cat.(10% mmol), NBS (1.2 equiv), Ag2O
(20% mmol), TFA (25% mmol), DCE (1.5 mL), 60oC, 16h.
Ag2O
TFA
59
17
bromophthalimide instead of N-bromosuccinimide (entry 20).
With the optimal reaction conditions in hand, we examined a
series of substituted anilides to establish the scope (Table 2).
For example, substituted substrates with electron-donating
groups, such as Me and OMe, could produce the desired
[a]Reaction condition: 1a (0.5 mmol), cat.(10% mmol), NBS (1.2 equiv), additives1
(20% mmol), additives2 (25% mmol), DCE (1.5 mL), 60oC, 16h. [b]Isolated yield. [c]
RT. [d] 40oC. [e] N-Bromophthalimide instead of N-bromosuccinimide.
products in 85% and 80% yields, respectively
(3b-3c).
Results and discussion
Meanwhile, anilides bearing electron-withdrawing groups,
such as F, Cl, Br, and COOMe could produce the desired
To begin our study, we selected acetanilide (1a) as the model
substrate for the optimization of the reaction conditions, and
the results are summarized in Table 1. Initially, a number of Co
catalysts, including Co(OAc)2, CoCl2, CoCO3, CoC2O4 and
Co(acac)2, were investigated (entries 1–5). The results showed
that Co(acac)2 displayed the highest catalytic activity for the
bromination reaction (entry 5). Next, the choice of acid or base
additives was made (entries 6–10), we found that the reaction
products in good yields (3d-3f, 3m) except NO2. Moreover, we
applied the optimal conditions to a series of ortho-substituted
anilides (3g-3h) and meta-substituted anilides (3i-3j). They
underwent the reaction to give good yields of the
corresponding ortho-bromination products. However, N-(2-
(trifluoromethyl)phenyl)acetamide could not proceed well in
this procedure (3n). Only 40% yield product was obtained
2 | J. Name., 2012, 00, 1-3
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when N-(naphthalen-1-yl)acetamide was subjected to the C-H
activation bromination. Unfortunately, the reaction of 3-oxo-
N-phenylbutanamide was sluggish and only trace amount of
product (3l) was observed.
Encouraged by the above results, we investigated the use of
this catalysis system for C-H iodination (Table 3). Gratifyingly,
this transformation showed excellent tolerance for various
anilides derivatives. The anilides, with electron-donating (4b–
4c) or electron-withdrawing (4d–4f) substituents afforded the
desired
83%). Other anilides (4g-4h) also proceeded well. When N-
(naphthalen-1-yl)acetamide (4i) and 3-oxo-N-
products
in
satisfactory
yields
(70–
phenylbutanamide (4j) were applied to the reaction under
standard conditions, ortho-Iodination reaction could not
proceed smoothly. Aniline substrates containing NO2-, CF3- or
COOMe were also tested. Only 4-acetamidophenyl acetate
could couple well under optimal conditions.
Table 3. Screening of substrate scope in the ortho-Iodination reaction of
substituted anilides.[a]
[a]Reaction condition: anilides (0.5 mmol), cat.(10% mmol), NCS (1.2 equiv), Ag2O
(20% mmol), TFA (25% mmol), DCE (1.5 mL), 60oC, 16h.
activation.
As
expected,
most
substituted
anilides underwent the reaction to give good
yields of the corresponding ortho-chlorination products (Table
4).
[a]Reaction condition: anilides (0.5 mmol), cat.(10% mmol), NIS (1.2 equiv), Ag2O
(20% mmol), TFA (25% mmol), DCE (1.5 mL), 60oC, 16h.
The success of the bromination and iodination reactions
encouraged us to extend this procedure to chlorination and
there is yet no report of chlorination through Co-catalyzed C-H
Table 4. Screening of substrate scope in the ortho-chlorination reaction of
substituted anilides.[a]
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Concerted metalation–deprotonation path and the
intermolecular single-electron transfer path were widely used
in Co-catalyzed C-H functionalization9. For example, Li and co-
workers describled a cross-dehydrogenative coupling reaction
between unactivated C(sp2)-H and C(sp3)-H bonds in 2017,
showing an intermolecular single electron transfer (SET)
process via Co(II) precatalysts and the subsequent C(sp2)-H
cleavage via concerted metalation-deprotonation (CMD).
Moreover,
and
a
cobalt-catalyzed cyclization of aliphatic amides
terminal
alkynes with silver-cocatalyst via CMD process and SET process
were also established well by Zhang’ group.
Scheme 2. Control experiments.
To gain more understanding of this reaction, we have
performed some control experiments. As is shown in Scheme
2, when 4 equivalents of TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxyl), BHT( butylated hydroxytoluene) or 1,1-
diphenylethene were added to the ortho-bromination reaction
as a radical scavenger, the coupling process (Scheme 2, A1, A2
and A3) was completely inhibited as expected (determined by
GC-MS), indicating that the bromination might proceed
through a radical pathway. At the same time, when the
reaction was run without Ag additive, less than 20% yield
ortho-product was obtained (Scheme 2, A4). The role of silver
may participate in activation of catalyst. Importantly, no
desired product was detected in the absence of Co(II) catalyst,
suggesting that Co(II) catalyst plays the significant role in the
procedure (Scheme 2, A5). Notably, less than 10% yield ortho-
product was observed without acid additive (Scheme 2, A6),
showing that the procedure is very dependent on the acid
additive TFA. TFA might work as the acid to protonate a
carbonyl group of the N-halosuccinimide (NXS). Finally, when
we replaced 1a with N-methyl-N-phenylacetamide under
optimal conditions, this reaction proceeded well, showing
aniline NH didn’t participate in coordination. Meanwhile, KIE
experiment and H/D exchange experiment have been carried
Scheme 3. KIE experiment and H/D exchange experiment.
out
(Scheme
3).
As
is
depicted,
significant KIE experiments (both parallel reactions and
competition
(The KIE
reactions)
determined
were
by
made
GC-MS by
was
analyzing the ratio of 3b vs [D]3b’, average of 3 runs). The
results showed that ortho C-H bond cleavage might not be
one of the rate-determining steps of this procedure.
4 | J. Name., 2012, 00, 1-3
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5975C Mass Selective Detector, coupled with a 7890A Gas
Chromatograph (Agilent Technologies).
General procedure for the synthesis of ortho-bromination
product : To a mixture of acetanilide (0.5 mmol) 1a, Co(acac)2
(10%mmol), additives Ag2O (20% mmol), additives TFA (25%
mmol), and solvent (DCE =1.5ml) in a reaction tube was added
N-bromosuccinimide (NBS) (1.2 equiv.). The reaction mixture
was stirred at 60°C for 16h in air. The reaction mixture was
extracted with ethyl acetate (15 mL × 3). The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel to afford the desired products
The rest products were prepared by a similar procedure.
3.
N-(2-bromophenyl)acetamide (3a): white solid (91.59mg,
1
86%). H NMR (500 MHz, Chloroform-d) δ 8.33 (d, J = 8.0 Hz,
1H), 7.61 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H),
6.97 (t, J = 7.5 Hz, 1H), 2.24 (s, 3H). 13C NMR (126 MHz,
Chloroform-d) δ 167.3, 134.7, 131.2, 127.4, 124.2, 121.0, 112.2,
23.9. GC-MS (EI) m/z: 213.
Scheme 4. Possible mechanism.
On the basis of previous studies7,8,9 and our observations, the
possible mechanism for the reaction are proposed in Scheme 4.
N-(2-bromo-4-methylphenyl)acetamide (3b): white solid
(96.48mg, 85%). 1H NMR (500 MHz, Chloroform-d) δ 8.15 (d, J
= 8.3 Hz, 1H), 7.52 (s, 1H), 7.35 (s, 1H), 7.10 (d, J = 8.3 Hz, 1H),
2.29 (s, 3H), 2.22 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ
167.2, 134.3, 132.2, 131.5, 128.0, 121.0, 112.3, 23.8, 19.6. GC-
MS (EI) m/z: 227.
Initially,
the
active
catalyst
Co(III)Xn
is
generated by the reaction of Co(acac)2 with Ag2O. Then,
chelate-directed C-H activation of the anilides take place to
form a six-membered cyclocobalt (III) intermediate A. Next,
this intermediate may then undergo oxidative addition to
Co(IV) species B. Finally, the reductive elimination of
N-(2-bromo-4-methoxyphenyl)acetamide (3c): white solid
(96.20mg, 80%). 1H NMR (500 MHz, Chloroform-d) δ 8.10 (d, J
= 9.1 Hz, 1H), 7.38 (s, 1H), 7.08 (d, J = 2.7 Hz, 1H), 6.86 (dd, J =
9.0, 2.8 Hz, 1H), 3.77 (s, 3H), 2.21 (s, 3H). 13C NMR (126 MHz,
Chloroform-d) δ 167.2, 155.5, 128.1, 122.6, 116.5, 113.6, 112.9,
54.8, 23.6. GC-MS (EI) m/z: 243.
intermediate
B afforded coupling product.
Conclusions
N-(2-bromo-4-fluorophenyl)acetamide (3d): white solid
(64.68mg, 56%). 1H NMR (500 MHz, Chloroform-d) δ 8.27 (dd, J
= 9.2, 5.6 Hz, 1H), 7.47 (s, 1H), 7.29 (dd, J = 7.8, 2.9 Hz, 1H),
7.05 (ddd, J = 9.1, 7.8, 2.9 Hz, 1H), 2.23 (s, 3H). 13C NMR (126
MHz, Chloroform-d) δ 167.2, 131.2, 122.1, 118.4, 118.2, 114.4,
114.2, 112.4, 23.7. GC-MS (EI) m/z: 231.
In summary, the first example by using the abundant,
inexpensive metal cobalt to achieve regioselective C-H
halogenation in anilides has been established here. This
procedure provides high yielding and selective formation of
valuable and versatile aryl halides (Cl, Br, and I) of significant
interest, breaking the limitation of a single substrate under
relatively mild reaction conditions. Further studies in our
N-(2-bromo-4-chlorophenyl)acetamide (3e): white solid
(97.57mg, 79%). 1H NMR (500 MHz, Chloroform-d) δ 8.30 (d, J
= 8.8 Hz, 1H), 7.55 (s, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.28 (dd, J =
8.9, 2.3 Hz, 1H), 2.23 (s, 3H). 13C NMR (126 MHz, Chloroform-d)
δ 167.2, 133.5, 130.7, 128.4, 127.5, 121.5, 112.3, 23.9. GC-MS
(EI) m/z: 247.
laboratory are devoted to
investigation.
a more detailed mechanistic
Experimental
General experimental method
N-(2,4-dibromophenyl)acetamide
(3f):
white
solid
(109.88mg, 75%). 1H NMR (500 MHz, Chloroform-d) δ 8.25 (d, J
= 8.8 Hz, 1H), 7.67 (d, J = 2.1 Hz, 1H), 7.56 (s, 1H), 7.42 (dd, J =
8.9, 2.1 Hz, 1H), 2.23 (s, 3H). 13C NMR (126 MHz, Chloroform-d)
δ 167.2, 134.0, 133.4, 130.5, 121.8, 115.7, 112.5, 23.9. GC-MS
(EI) m/z: 293.
All compounds are characterized by 1H NMR, 13C NMR and MS.
Analytical thin-layer chromatography is performed on glass
plates precoated with silica gel impregnated with a fluorescent
indicator (254 nm), and the plates are visualized by exposure
to ultraviolet light. H NMR and 13C NMR spectra are recorded
1
N-(2-bromo-6-methylphenyl)acetamide (3g): white solid
(91.94mg, 81%). 1H NMR (500 MHz, Chloroform-d) δ 7.44 (d, J
= 8.0 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H),
6.96 (s, 1H), 2.30 (s, 3H), 2.24 (s, 3H). 13C NMR (126 MHz,
Chloroform-d) δ 167.4, 137.5, 133.0, 129.2, 129.0, 127.5, 121.1,
22.4, 18.3. GC-MS (EI) m/z: 227.
on an AVANCE 500 Bruker spectrometer operating at 500 MHz
and 125 MHz in CDCl3, respectively, and chemical shifts are
reported in ppm.GC analyses are performed on an Agilent
7890A instrument (Column: Agilent 19091J-413:30 m × 320 μm
× 0.25 μm, H, FID detection). GC-MS data was recorded on a
N-(2-bromo-6-fluorophenyl)acetamide (3h): white solid
(84.68mg, 73%). 1H NMR (500 MHz, Chloroform-d) δ 7.39 (d, J
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= 6.4 Hz, 1H), 7.11 (q, J = 9.2, 8.4 Hz, 2H), 6.97 (s, 1H), 2.23 (s,
N-(4-bromo-2-iodophenyl)acetamide (4f): white solid
3H). 13C NMR (126 MHz, Chloroform-d) δ 167.2, 158.3,156.3, (115.26mg, 68%). 1H NMR (500 MHz, Chloroform-d) δ 8.12 (d, J
127.8, 127.2, 123.4, 121.2, 114.7, 22.2. GC-MS (EI) m/z: 231.
= 8.8 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.45 (dd, J = 8.8, 2.3 Hz,
N-(2-bromo-5-methylphenyl)acetamide (3i): white solid 1H), 7.39 (s, 1H), 2.24 (s, 3H). 13C NMR (126 MHz, Chloroform-d)
(87.39mg, 77%). 1H NMR (500 MHz, Chloroform-d) δ 7.51 (s, δ 167.2, 139.5, 136.5, 131.3, 121.7, 116.4, 89.0, 23.9. GC-MS
1H), 7.42 (dd, J = 5.6, 3.0 Hz, 2H), 7.19 (dd, J = 8.6, 2.6 Hz, 1H), (EI) m/z: 339.
2.34 (s, 3H), 2.15 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ
167.5, 137.6, 136.1, 131.6, 121.2, 118.5, 117.9, 23.6, 22.1. GC- (75.63mg, 55%). 1H NMR (500 MHz, Chloroform-d) δ 8.04 (s,
MS (EI) m/z: 227. 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.36 (s, 1H), 6.68 (d, J = 8.2 Hz, 1H),
N-(2-iodo-5-methylphenyl)acetamide (4g): white solid
N-(2-bromo-5-methylphenyl)acetamide (3j): white solid 2.32 (s, 3H), 2.23 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ
(80.59mg, 71%). 1H NMR (500 MHz, Chloroform-d) δ 8.24 (dd, J 167.2, 138.7, 137.3, 136.9, 126.1, 121.8, 85.0, 23.9, 20.3. GC-
= 11.2, 2.9 Hz, 1H), 7.64 (s, 1H), 7.46 (dd, J = 8.9, 5.8 Hz, 1H), MS (EI) m/z: 275.
6.72 (ddd, J = 8.8, 7.5, 3.0 Hz, 1H), 2.24 (s, 3H). 13C NMR (126
MHz, Chloroform-d) δ 167.3, 162.2, 160.2, 135.9, 131.7, 111.1, (80.91mg, 58%). 1H NMR (500 MHz, Chloroform-d) δ 8.15 (dd, J
108.0, 105.8, 24.0. GC-MS (EI) m/z: 231. = 11.4, 3.0 Hz, 1H), 7.70 (dd, J = 8.8, 6.0 Hz, 1H), 7.47 (s, 1H),
N-(5-fluoro-2-iodophenyl)acetamide (4h): white solid
N-(2-bromonaphthalen-1-yl)acetamide (3k): white solid 6.69 – 6.58 (m, 1H), 2.25 (s, 3H). 13C NMR (126 MHz,
(52.60mg, 40%). 1H NMR (500 MHz, Chloroform-d) δ 7.89 – Chloroform-d) δ 167.3, 163.2, 161.3, 138.5, 138.1, 112.1, 108.1,
7.80 (m, 2H), 7.66 (q, J = 8.8 Hz, 2H), 7.56 – 7.48 (m, 2H), 7.20 80.8, 24.0. GC-MS (EI) m/z: 279.
(s, 1H), 2.36 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 168.3,
130.5, 128.9, 128.3, 128.2, 127.4, 127.2, 126.4, 126.1, 125.6, (113.25mg, 71%). 1H NMR (500 MHz, Chloroform-d) δ 8.24 (d, J
122.8, 22.5. GC-MS (EI) m/z: 263. = 9.0 Hz, 1H), 7.58 (d, J = 2.5 Hz, 1H), 7.41 (s, 1H), 7.14 (dd, J =
4-acetamido-3-iodophenyl acetate (4k): white solid
4-acetamido-3-bromophenyl acetate (3m): white solid 9.0, 2.6 Hz, 1H), 2.31 (s, 3H), 2.27 (s, 3H). 13C NMR (126 MHz,
(104.34mg, 77%). 1H NMR (500 MHz, Chloroform-d) δ 8.38 (d, J Chloroform-d) δ 168.2, 167.2, 145.9, 135.2, 130.6, 121.4, 121.2,
= 9.0 Hz, 1H), 7.58 (s, 1H), 7.37 (d, J = 2.6 Hz, 1H), 7.09 (dd, J = 99.0, 23.6, 20.0. GC-MS (EI) m/z: 319.
9.0, 2.6 Hz, 1H), 2.32 (s, 3H), 2.27 (s, 3H). 13C NMR (126 MHz,
Chloroform-d) δ 168.1, 167.1, 145.5, 132.6, 124.4, 121.2, 120.6, (91.8mg, 60%). 1H NMR (500 MHz, Chloroform-d) δ 8.69 (d, J =
111.9, 23.8, 20.0. GC-MS (EI) m/z: 271. 2.5 Hz, 1H), 8.58 (d, J = 9.1 Hz, 1H), 8.27 (dd, J = 9.2, 2.5 Hz, 1H),
N-(2-iodo-4-nitrophenyl)acetamide (4m): white solid
N-(2-iodophenyl)acetamide (4a): white solid (111.78mg, 7.77 (s, 1H), 2.35 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ
85%). 1H NMR (500 MHz, Chloroform-d) δ 8.20 (d, J = 8.0 Hz, 167.4, 142.8, 142.5, 133.2, 124.0, 118.7, 86.3, 24.2. GC-MS (EI)
1H), 7.77 (d, J = 7.8 Hz, 1H), 7.42 (s, 1H), 7.34 (t, J = 7.7 Hz, 1H), m/z: 306.
6.84 (t, J = 7.4 Hz, 1H), 2.24 (s, 3H). 13C NMR (126 MHz,
Chloroform-d) δ 167.3, 137.8, 137.3, 128.3, 125.0, 121.1, 89.0, 72%). 1H NMR (500 MHz, Chloroform-d) δ 8.33 (d, J = 8.1 Hz,
23.9. GC-MS (EI) m/z: 261. 1H), 7.66 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H),
N-(2-chlorophenyl)acetamide (5a): white solid (60.84mg,
N-(2-iodo-4-methylphenyl)acetamide (4b): white solid 7.02 (t, J = 7.5 Hz, 1H), 2.22 (s, 3H). 13C NMR (126 MHz,
(108.42mg, 79%). 1H NMR (500 MHz, Chloroform-d) δ 8.02 (d, J Chloroform-d) δ 167.3, 133.6, 128.0, 126.7, 123.7, 121.7, 120.8,
= 8.3 Hz, 1H), 7.60 (s, 1H), 7.33 (s, 1H), 7.14 (d, J = 8.1 Hz, 1H), 23.9. GC-MS (EI) m/z: 169.
2.28 (s, 3H), 2.22 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ
167.2, 138.0, 135.1, 134.8, 129.0, 121.1, 89.2, 23.8, 19.4. GC- (59.48mg, 65%).1H NMR (500 MHz, Chloroform-d) δ 8.19 (d, J =
MS (EI) m/z: 275. 8.4 Hz, 1H), 7.52 (s, 1H), 7.18 (s, 1H), 7.07 (d, J = 8.3 Hz, 1H),
N-(2-chloro-4-methylphenyl)acetamide (5b): white solid
N-(2-iodo-4-methoxyphenyl)acetamide (4c): white solid 2.29 (s, 3H), 2.22 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ
(119.31mg, 82%). 1H NMR (500 MHz, Chloroform-d) δ 7.93 (d, J 167.1, 133.8, 131.0, 128.3, 127.4, 121.5, 120.6, 23.8, 19.7. GC-
= 9.0 Hz, 1H), 7.31 (d, J = 2.7 Hz, 1H), 7.20 (s, 1H), 6.91 (dd, J = MS (EI) m/z: 183.
9.0, 2.8 Hz, 1H), 3.77 (s, 3H), 2.21 (s, 3H). 13C NMR (126 MHz,
Chloroform-d) δ 167.2, 155.8, 130.7, 122.8, 122.7, 113.8, 90.5, (58.71mg, 59%). 1H NMR (500 MHz, Chloroform-d) δ 8.14 (d, J
54.7, 23.5. GC-MS (EI) m/z: 291. = 9.1 Hz, 1H), 7.40 (s, 1H), 6.92 (d, J = 2.8 Hz, 1H), 6.82 (dd, J =
N-(2-chloro-4-methoxyphenyl)acetamide (5c): white solid
N-(4-fluoro-2-iodophenyl)acetamide (4d): white solid 9.1, 2.8 Hz, 1H), 3.78 (s, 3H), 2.21 (s, 3H). 13C NMR (126 MHz,
(71.28mg, 51%). 1H NMR (500 MHz, Chloroform-d) δ 8.11 (dd, J Chloroform-d) δ 167.1, 155.3, 126.9, 123.1, 122.4, 113.5, 112.2,
= 9.1, 5.5 Hz, 1H), 7.50 (dd, J = 7.6, 2.9 Hz, 1H), 7.29 (s, 1H), 54.7, 23.6. GC-MS (EI) m/z: 199.
7.09 (ddd, J = 9.1, 7.7, 2.9 Hz, 1H), 2.24 (s, 3H). 13C NMR (126
MHz, Chloroform-d) δ 167.2, 133.8, 124.5, 124.3, 122.2, 122.1, (79.04mg, 64%). 1H NMR (500 MHz, Chloroform-d) δ 8.29 (d, J
115.2, 115.0, 23.7. GC-MS (EI) m/z: 279. = 8.8 Hz, 1H), 7.56 (s, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.38 (dd, J =
N-(4-bromo-2-chlorophenyl)acetamide (5d): white solid
N-(4-chloro-2-iodophenyl)acetamide (4e): white solid 8.9, 2.1 Hz, 1H), 2.24 (s, 3H). 13C NMR (126 MHz, Chloroform-d)
(112.10mg, 76%). 1H NMR (500 MHz, Chloroform-d) δ 8.16 (d, J δ 167.2, 132.9, 130.4, 129.9, 122.2, 121.6, 115.2, 23.9. GC-MS
= 8.7 Hz, 1H), 7.79 – 7.71 (m, 1H), 7.39 (s, 1H), 7.32 (dd, J = 8.8, (EI) m/z: 247.
2.2 Hz, 1H), 2.24 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ
167.2, 136.9, 136.1, 128.9, 128.3, 121.4, 88.6, 23.8. GC-MS (EI) (57.65mg, 66%). H NMR (500 MHz, Chloroform-d) δ 7.28 –
N-(2-chloro-6-methylphenyl)acetamide (5e): white solid
1
m/z: 295.
7.24 (m, 1H), 7.17 – 7.08 (m, 2H), 7.03 (s, 1H), 2.27 (s, 3H), 2.23
6 | J. Name., 2012, 00, 1-3
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(s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 167.6, 137.3,
131.7, 130.3, 128.3, 127.0, 126.0, 22.3, 18.0. GC-MS (EI) m/z:
183.
and More, Wiley-VCH, Weinheim, 2013.
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11 2756. (b) F. Kakiuchi, T. Kochi, H. Mutsutani, N.
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N-(2-chloro-6-fluorophenyl)acetamide (5f): white solid
(66.39mg, 71%). 1H NMR (500 MHz, Chloroform-d) δ 8.40 (d, J
= 6.3 Hz, 1H), 7.38 (s, 1H), 7.05 – 6.96 (m, 2H), 2.22 (s, 3H). 13
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NMR (126 MHz, Chloroform-d) δ 167.2, 150.6, 148.6, 128.8,
126.3, 122.9, 120.5, 114.5, 23.7. GC-MS (EI) m/z: 187.
N-(2-chloro-5-methylphenyl)acetamide (5g): white solid
(46.67mg, 51%). 1H NMR (500 MHz, Chloroform-d) δ 8.18 (s,
1H), 7.56 (s, 1H), 7.22 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H),
2.33 (s, 3H), 2.23 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ
167.2, 137.0, 133.2, 127.5, 124.5, 121.1, 118.5, 23.9, 20.4. GC-
MS (EI) m/z: 183.
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N-(2-chloro-5-fluorophenyl)acetamide (5h): white solid
(55.17mg, 59%). 1H NMR (500 MHz, Chloroform-d) δ 8.26 (dd, J
= 11.2, 3.0 Hz, 1H), 7.65 (s, 1H), 7.31 (dd, J = 8.9, 5.5 Hz, 1H),
6.76 (ddd, J = 8.8, 7.4, 3.0 Hz, 1H), 2.25 (s, 3H). 13C NMR (126
MHz, Chloroform-d) δ 167.3, 161.6, 159.6, 134.6, 128.5, 115.9,
110.3, 107.7, 24.0. GC-MS (EI) m/z: 187.
N-(2-bromophenyl)-N-methylacetamide (6a): The crude
product was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate = 4:1) to give 6a as white solid
(81.72mg, 72%). 1H NMR (500 MHz, Chloroform-d) δ 7.97 (dd, J
= 7.9, 1.4 Hz, 1H), 7.46 (td, J = 7.6, 1.4 Hz, 1H), 7.34 – 7.30 (m,
1H), 7.11 (td, J = 7.7, 1.6 Hz, 1H), 3.21 (s, 3H), 1.83 (s, 3H). 13
C
NMR (126 MHz, Chloroform-d) δ 169.3, 145.7, 139.3, 129.0,
128.8, 127.9, 98.5, 34.9, 21.5. GC-MS (EI) m/z: 227.
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Acknowledgements
We gratefully acknowledge the Natural Science Foundation of
Jiangsu Province (BK 20131346, BK 20140776) for financial
support. This work was also supported by the National Natural
Science Foundation of China (21476116, 21402093) and the
Chinese Postdoctoral Science Foundation (2015M571761,
2016T90465).
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Conflicts of interest
There are no conflicts to declare.
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