Copper-Catalyzed Site-Selective Oxidative C?C Bond Cleavage of Simple Ketones for the Synthesis of Anilides and Paracetamol

Article abstract of DOI:10.1002/adsc.201801096

A copper-catalyzed approach for the N-acylation of anilines with acetone and acetophenones via C?C bond cleavage is described. Under the developed conditions both CHCl₃ and CH₂Cl₂ were identified as potential C1-source to promote the transformation. The reaction features a site selective C?C bond cleavage to install the amide moieties with high functional-group compatibility and wide substrate scope. The developed method avoids the use of sensitive and narcotic agents. The method also represents an excellent complement to the previous protocols with lower E-factor (13.91 mg/1 mg) than current industrially used method (E-factor 17.54 mg/1 mg). The developed approach has also been extended for the effective preparation of pyridine derivatives and paracetamol in gram scale. The course of the reaction was monitored by ¹H NMR as a preliminary investigation of the reaction mechanism. (Figure presented.).

Full text of DOI:10.1002/adsc.201801096

Title: Copper-Catalyzed Site-Selective Oxidative C–C Bond Cleavage
of Simple Ketones for the Synthesis of Anilides and Paracetamol
Authors: Chandi Malakar, Nagaraju Vodnala, Raghuram Gujjarappa,
Chinmoy Hazra, Dhananjaya Kaldhi, Arup Kabi, and Uwe
Beifuss
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801096
Link to VoR: http://dx.doi.org/10.1002/adsc.201801096

10.1002/adsc.201801096
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper-Catalyzed Site-Selective Oxidative C–C Bond Cleavage
of Simple Ketones for the Synthesis of Anilides and
Paracetamol
Nagaraju Vodnala,[a]† Raghuram Gujjarappa,[a]† Chinmoy K. Hazra,[b] Dhananjaya
Kaldhi,[a] Arup. K. Kabi,[a] Uwe Beifuss,[c] Chandi C. Malakar[a]*
a
Department of Chemistry, National Institute of Technology Manipur, Langol, Imphal - 795004, Manipur, Phone:
(+91) 0385-2058566, Fax: (+91) 0385-2445812, E-Mail: cmalakar@nitmanipur.ac.in
Department of Chemistry, Korea Advanced Institute of Science & Technology (KAIST), Daejeon 305-701, South
b
Korea.
c
Institut für Chemie, Universität Hohenheim, Garbenstr. 30, D-70599 Stuttgart, Germany.
N. V. and R. G. contributed equally to this work.
†
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. A copper-catalyzed approach for the N-acylation (13.91 mg/1 mg) than current industrially used method (E-
of anilines with acetone and acetophenones via C-C bond factor 17.54 mg/1 mg). The developed approach has also
cleavage is described. Under the developed conditions both been extended for the effective preparation of pyridine
CHCl3 and CH2Cl2 were identified as potential C1-source to derivatives and paracetamol in gram scale. The course of
1
promote the transformation. The reaction features a site the reaction was monitored by H NMR as a preliminary
selective C-C bond cleavage to install the amide moieties investigation of the reaction mechanism.
with high functional-group compatibility and wide substrate
scope. The developed method avoids the use of sensitive and
narcotic agents. The method also represents an excellent
complement to the previous protocols with lower E-factor
Keywords: Cu-Catalysis; C-C Bond cleavage; Simple
Ketones; Anilide; Paracetamol
catalysts, and hazardous conditions. Thus, the
development of a practical and convenient method is
a worthwhile challenge. To serve this purpose, very
Introduction
Scalable and economic conversion of an amine group recently the concept of oxidative C(sp3)-C(sp2) bond
into an amide functionality remains an unarguably cleavage of carbonyl compounds has been
important task in organic synthesis.[1] This is due to
their wide occurrence in biological systems and
extensive use of the amide derivatives as synthetic
intermediates.[2] The significance of these motifs can
also be recognized from their presence in natural
products,[3] pharmaceuticals,[4] polymers,[5] and their
advanced application as versatile building blocks in
protein and peptide chemistry.[6,7] Molecules with
anilide moieties are recognized as antipyretic,[8]
antimalarial,[9] antiinflammatory,[10] and antitumor[11]
agents. Recent data gathered by medicinal chemists
disclosed that in modern pharmaceuticals, the most
frequently used methods for N-acylation rely on the
reaction between amines and activated carboxylic
acids.[12] Additionally, their preparation based on acid
amine coupling,[13] cross-coupling reactions,[14]
Beckmann rearrangement,[15] rearrangement of keto
azides,[16] reaction of amines with aldehydes or
Scheme 1
. Approaches for the anilide synthesis
alcohols,[17] using nitrile substrates[18] and using
amino carbonylation methods.[19] However, these
protocols suffer from significant limitations such as
the use of sensitive substrates and reagents, expensive
using C-C bond cleavage of ketones.
introduced.[20-23] However, the previous reported C-C
1
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10.1002/adsc.201801096
Advanced Synthesis & Catalysis
bond cleavage methods hinge on the use of activated
substrates. The synthesis of anilides using the C-C
bond cleavage of non-activated ketones such as
acetones and acetophenones remains so far
unprecedented.
not observed (Entry 11), whereas using CHCl3 alone
as solvent the desired anilide 3a was obtained in 9%
yield (Entry 12). Therefore, it was realized that the
combination of DMSO/CHCl3 as solvent remains
essential, whereas replacing DMSO with other
The processes towards efficient and selective
cleavage of C-C bonds have emerged as an incredibly
demanding topic due to the high strength of the C-C
bond. Thus, the concept is extensively explored in
recent years under the influence of transition-metal
catalysis.[24] At present the most welcome approaches
for the preparation of anilides via C-C bond cleavage
were attempted using α-nitro ketones (Scheme 1a),[21]
Table 1. Screening of the conditions for the reaction
between 1a and 2a.[a]
1,3-diketones (Scheme 1b)[22] and using
a
combination of carbodiimides and carbonyl
derivatives (Scheme 1c)[23] as starting materials.
Although, these methods are benign and well
examined, they are limited by their narrow scope, use
of activated 1,3-diketones as substrates and in few
cases the use of hazardous reagents, radical initiators,
and expensive catalysts. These limitations lead us to
develop of convenient catalytic approach for the
engineering of anilide functionalities using simple
ketones and inexpensive methods. Here we describe
an example of Cu-catalyzed site-selective oxidative
C(sp3)-C(sp2) or C(sp2)-C(sp2) bond cleavage of
acetone and acetophenones to accomplish a facile
approach for the synthesis of anilide derivatives
(Scheme 1d). The developed protocol features high
functional-group compatibility and wide substrate
scope under the influence of CHCl3 or CH2Cl2 as C1-
source.
T [°C] /
t [h]
S.N
Catalyst
Solvent
DMSO
Yield [%][b]
3a (0%), 4a
(˂5%)
3a (52%),
4a (0%)
3a (0%), 4a
(˂5%)
3a (0%), 4a
(˂5%)
3a (0%), 4a
(˂5%)
3a (0%), 4a
(˂5%)
3a (45%),
4a (0%)
3a (46%),
4a (0%)
3a (86%),
4a (0%)
3a (79%),
4a (0%)
3a (0%), 4a
(˂5%)
3a (9%), 4a
(0%)
1
Co(OAc)2
120 / 16
Co(NO3)2•
6H2O
DMSO/
CHCl3
2[c]
140 / 15
120 / 20
120 / 16
120 / 14
140 / 15
120 / 15
120 / 18
120 / 14
120 / 20
120 / 15
65 / 16
3
Pd(OAc)2
DMSO
DMSO
DMSO
DMA
4
CuCl2
Cu(CF3SO2
5
)
2
Cu(OAc)2•
H2O
Cu(NO3)2•
3H2O
6
DMSO/
CHCl3
DMSO/
CHCl3
7[c]
8[c]
9[c]
10[c]
11
12
CuO
Cu(OAc)2• DMSO/
H2O CHCl3
Cu(OAc)2• DMSO/
H2O
Cu(OAc)2•
H2O
Cu(OAc)2•
H2O
Cu(OAc)2•
H2O/
Results and Discussion
CH2Cl2
Initially, various reaction parameters including metal
catalysts, additives, bases and solvents were
examined extensively to establish the ideal conditions
for the C-C cleavage of acetone (2a). Several
reactions between aniline (1a) and acetone (2a) were
carried out under various conditions using metal-
catalysts such as Co-salts (Table 1, Entries 1-2 and
SI), Pd-source (Table 1, Entry 3), Cu-catalysts (Table
1, Entries 4-15 and SI) and using Zn, Fe as well as
Ni-salts (in SI). Interestingly, the formation of anilide
3a was noticed in 52% yield, when a mixture of
DMSO/CHCl3 (3:1) were introduced as solvent in the
presence of 10 mol% Co(NO3)2•6H2O as catalyst at
140 °C (Entry 2). The same observation holds true
with slightly decreased yields of 3a, when the
reactions between 1a and 2a were performed at
120 °C in presence of Cu(NO3)2•3H2O and CuO as
catalysts (Entries 7, 8). Moreover, the use of
Cu(OAc)2•H2O as catalyst showed highest efficacy in
the reaction between 1a and 2a to furnish the desired
product 3a in 86% yield (Entry 9). It was also
investigated that the choice of solvent is crucial to
drive the transformation towards formation of anilide
3a. A mixture of DMSO/CH2Cl2 was suitable to
deliver similar output (Entry 10).When using DMSO
as the only solvent, formation of the product 3a was
DMSO
CHCl3
DMSO/
CHCl3
3a (79%),
4a (0%)
13[c]
120 / 16
FeCl3•6H2
O[d]
Cu(OAc)2•
H2O/
DMSO/
CHCl3
3a (75%),
4a (0%)
14[c]
15[c]
120 / 15
120 / 12
TBAB[e]
Cu(OAc)2•
H2O/
DMSO/
CHCl3
3a (81%),
4a (0%)
[f]
AgSbF6
[a] All reactions were performed using 1.0 mmol of 1a and
1.3 mmol of 2a; [b] Isolated yield; [c] Solvents were used
in 3:1 ratio; [d] 30 mol% FeCl3•6H2O was used as an
additive; [e] 50 mol% TBAB was used as an additive; [f]
30 mol% AgSbF6 was used as an additive.
solvents delivered lower yields of the product 3a (see
SI). Subsequently, the impact of additives was
examined for the progress of the reaction. It has been
investigated that additives such as FeCl3•6H2O,
2
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10.1002/adsc.201801096
Advanced Synthesis & Catalysis
TBAB and AgSbF6 have no influences on enhancing
the yield of desired product 3a (Entries 13-15).
Cu(OAc)2•H2O as catalyst in DMSO/CHCl3 (3:1) as
solvent at 120 °C for 14 hours. Hence, these reaction
parameters were considered as optimal conditions for
further reactions (Entry 9).
Scheme 4. Facile access towards paracetamol (3p) using
acetone (2a) as acetylating agent (in gram scale)
It was found that a large number of non-activated
ketones 2a-w with simple alkyl and aryl substituents
have experienced selective oxidative cleavage of their
higher-mass substituents under the developed
conditions to deliver the anilide 3a (Scheme 2). The
aryl groups containing both electron donating and
electron withdrawing substituents showed equal
efficiency towards the described Cu-catalyzed C-C
cleavage protocol. However, when the cyclic ketones
2x and 2y were examined, the reactions delivered
complex mixture of unwanted compounds and the
formation of the desired C-C cleavage products 3x
and 3y were not identified. This observation can be
Scheme 2. Scope of the Cu(II)-catalyzed C-C cleavage of
acetone and acetophenones for the preparation of anilide
3a.
Additionally, varying solvent, reaction temperature,
low catalyst loading and reaction under nitrogen
atmosphere did not lead to the successful reaction
Scheme 5. Scope of the 1,3-dicarbonyls 5a-e as acetylating
agent via Cu(II)-catalyzed C-C bond cleavage.
explained in terms of less stability of the intermediate
formed after the carbene addition to the
corresponding enamine intermediate which is
sterically less favored. Furthermore, the coordination
of the copper-center may not be favorable after the
cleavage of bicycle intermediate (Scheme 2).
Next, the influence of substituents at various
position of anilines 1b-p were explored, and it was
found that a diverse range of functional groups
including halogen, alkyl, ether and nitro groups were
compatible under the optimized conditions to afford
the desired products 3b-p in yields ranging from 54-
82%. Notably, the developed process proved to be
general for a diverse range of functional groups on
Scheme 3. Cu(II)-catalyzed syntheses of anilides 3 using
various anilines 1 and acetone (2a) via C-C bond cleavage.
conditions (in SI). However, the identical yield of the
product 3a was obtained when the reaction was
carried out using O2-balloon (in SI). After the
extensive screening exercise (Table 1 and SI) for
finding the ideal reaction conditions, it has been
concluded that the maximum isolated yield of anilide
3a was afforded, when the reaction between 1a and
2a was conducted in the presence of 10 mol%
3
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10.1002/adsc.201801096
Advanced Synthesis & Catalysis
anilines 3 (Scheme 3). To further verify the scope of
the described method, the gram scale synthesis of
paracetamol was attempted using acetone (2a) as
acetylating agent. In this regards, 4-methoxy aniline
(1q) was reacted with acetone (2a) under the optimal
conditions to obtain the anilide 3q in 85% yield,
which is then demethylated using BBr3 to afford the
paracetamol (3r) in 95% yield (Scheme 4). However,
when the reaction was attempted under the optimal
conditions using 4-hydroxy-aniline (1r) and acetone
(2a) as substrates, the conversion towards
paracetamol (3r) remains unsuccessful (Scheme 4).
Interestingly, it is also shown that using the
developed conditions the reactions can be optionally
performed with 1,3-dicarbonyls 5a-e as acetylating
agents to obtain the products 3a in high yields and
selectivity (Scheme 5).
A preliminary investigation of the proposed
mechanism suggested the involvement of carbene
insertion and the formation of radical species
(Scheme 6a). Progress of the reaction was monitored
1
by H NMR (details in SI). After 2 hours of the
1
reaction, the H NMR guided us to identify the
corresponding characteristic protons from the desired
product 3a (δ = 2.0 ppm) along with the expected
enamine intermediate 4b (δ = 4.69, 4.04, 2.2, and 1.1
ppm) and the intermediate D (δ = 10.36, 4.04, 3.57,
1.98, 1.12 ppm). Moreover, the appearance of a peak
at δ = 6.52 ppm may indicate the presence of a weak
interaction between an aromatic proton and hydroxyl-
group in intermediate D. The identical scenarios were
observed up to 8 hours after starting the reaction. In
1
addition, the H NMR spectra during 6-10 hours
showed distinguishable peaks at δ = 2.40 and 1.90
ppm that may indicate the presence of intermediate B.
1
The late appearance of the intermediate B on H
NMR can be understood from the efficiency of the
catalytic cycle. It is anticipated that in the beginning
of the reaction, the catalyst is highly active and leads
to the efficient cleavage of the unstable intermediate
B. With the decreasing catalytic activity the cleavage
of the intermediate B become slower, and thus can be
1
1
identified by H NMR. Finally, when the H NMR
spectra were recorded after 10 and 12 hours, the
corresponding signals from anilide 3a (δ = 2.0 ppm)
were observed as the major species. Additionally, the
signals from anticipated byproduct G (δ = 5.75, 4.02,
1
1.17 ppm) were identified in the H NMR spectra
during 6-10 hours.
To explain the observed chemoselectivity, two
plausible mechanisms have been proposed for the Cu-
catalyzed C–C bond cleavage of methyl ketones for
the synthesis of acetanilides 3. In path-A, the reaction
of aniline (1a) and acetophenone (2d) may deliver the
enamine intermediate 4c, which followed by the
carbene insertion into the aliphatic C=C bond resulted
in the formation of unstable cyclopropyl intermediate
B׳. It is assumed that the cleavage of unstable
intermediate B׳ can give the copper complex C׳,
which via successive addition of oxygen may afford
the peroxycopper(III)-species D׳ and E׳. Then, the
homolytic cleavage of intermediate E׳ could result in
the formation of radical species F׳. Furthermore, the
C=C bond cleavage of intermediate F׳ could lead to
benzanilide 5a and side product G׳ along with
generation of [CuII]-OH to continue the catalytic
cycle. However, according to the proposed catalytic
cycle, the product benzanilide 5a should be identified
which does not support the obtained experimental
results (Path-A, in SI). Alternatively, it is also
assumed that the enamine intermediate 4c may
undergo the carbene insertion into an aromatic C=C
bond to deliver the unstable cyclopropyl intermediate
B". The cleavage of intermediate B" could give the
copper complex C", which via addition of aerial
oxygen to the Cu-center may deliver the
peroxycopper(III)-species D" and E". The homolytic
cleavage of intermediate E" could result in the
formation of radical species F". Finally, the C-C bond
Scheme 6. Plausible mechanism for the Cu(II)-catalyzed
C-C bond cleavage.
A plausible mechanistic proposal has been drawn
in Scheme 6a. When the optimized conditions were
employed for the reaction between aniline (1a) and
ketone 5d, the corresponding enamine 4b can be
obtained which followed by carbene A insertion may
form the unstable cyclopropane intermediate B. It is
anticipated that the cleavage of unstable intermediate
B leads to the formation of Cu-complex C, which
could then give the peroxycopper(III)-species D and
E in the presence of dioxygen from air.[24b] The
intermediate E may undergo homolytic cleavage and
deliver the intermediate radical species F. The
intermediate F would then furnish the desired product
3a via C-C bond cleavage and generate [CuII]-OH to
continue the catalytic cycle. A set of experiments
carried out in the presence of radical scavengers
(Scheme 6b) inhibited formation of the desired
product.
4
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10.1002/adsc.201801096
Advanced Synthesis & Catalysis
cleavage of intermediate F" could obtain the expected
product 3a and side product G* along with the
generation of [CuII]-OH to continue the catalytic
cycle (Path-B, Scheme 7).
The observed chemoselectivity was proved by the
mechanistic studies for the reaction between aniline
(1a) and acetophenone (2d).
A
preliminary
investigation of the proposed mechanism suggested
the involvement of carbene insertion into aromatic
C=C double bond. After, 1 hour of the reaction, the
1H NMR guided us to identify the corresponding
characteristic protons from the intermediates B" (δ =
5.88 ppm, 2.91 ppm, 1.99 ppm) and D" (δ = 9.5 ppm,
6.60 ppm, 2.12 ppm, 2.02 ppm) along with the
desired product 3a (δ = 2.15 ppm). The proton at δ =
6.60 ppm indicates the presence of hydrogen bonded
aromatic proton. After 4 hours of the reaction, the
amount of the intermediate B" is diminished, whereas
the intensity of the peak corresponding to
intermediate D" has increased. The same scenario was
observed up to 8 hours of the reaction. After 10 hours,
1H NMR spectra revealed the presence of
intermediates B" and D" along with the expected
products 3a and side product G* (δ = 6.65 ppm, 6.44
ppm, 6.19 ppm, 5.72 ppm, 4.22 ppm). The late
appearance of the intermediate B" on 1H NMR can be
attributed to efficiency of the catalytic cycle. It is
assumed that due to high efficiency of the catalyst
leading to the faster cleavage of the unstable
intermediate B". However, the C-C bond cleavage
becomes slower with the reaction time due to the
decreased catalytic activity. The major evidence for
the proposed catalytic cycle is attributed to the
formation of 1,7-dichlorocyclohepta-1,3,5-triene G*
as the side product which is observed after 10 hours
of the reaction. On the other hand, if the reaction
proceeds via path-A, the side product 1,1-
dichloroethylene G׳ is expected to be formed during
the course of the reaction which was not observed by
Scheme 7. The chemoselectivity of Cu-catalyzed C–C
bond cleavage of methyl ketones.
The present protocol described that the role of
CHCl3 remains crucial for the present transformation,
which proceeds via the carbene insertion into the
1
both mass spectrometry and H NMR spectroscopy.
enamine
intermediates.
The
observed
Hence, the proposed path-A mechanism can be ruled
out for the present transformation (in SI).
chemoselectivity for the reaction between aniline (1a)
and acetophenone (2d) can be understood in terms of
the feasibility of carbene insertion to the aromatic and
non-aromatic C=C bonds. The cyclopropyl
intermediate B' formed by the carbene insertion in the
aliphatic C=C is comparatively less favored than the
cyclopropyl intermediate B" formed via the carbene
insertion into the aromatic ring. Hence, the flexibility
for the formation of cyclopropyl intermediate drives
the chemoselectivity of the reaction between anilines
1 and methyl ketones 2. If aliphatic C=C bond
undergoes towards carbene insertion, the formation of
benzanilide 5a should be identified as the sole
product. On the other hand, the carbene insertion into
aromatic C=C bond may deliver the expected anilide
along with the formation of 1,3,5-cyclohexatriene G*
as side product. On the basis of observed anilide 3a
as the major product, the identification of side
product was crucial to determine the correct
mechanistic cycle and chemoselectivity of the
reaction between aniline (1a) and acetophenone (2d).
In this regard, the course of the reaction was
Scheme 8. Control experiment using intermediate 4b.
Moreover, the anilide 3a was obtained in 84%
yield, when a control experiment has been performed
under the developed reaction conditions using
enamine 4b as starting material (Scheme 8).
To verify the reproducibility of the developed
method, a set of reactions were performed between
aniline 1a and acetone 2a under the optimized
conditions. It was observed that in all attempts the
identical yields (ranging from 82-86%) of the
expected anilide 3a can be obtained (Figure 1). These
results indicate the generality of the developed
method for the preparation of anilide derivatives in
high yields.
1
monitored by H NMR which revealed the formation
of 1,3,5-cyclohexatriene G* as side product after 10
hours of the reaction.
5
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10.1002/adsc.201801096
Advanced Synthesis & Catalysis
Next, the green chemistry metrics of the developed
corresponding 2,6-diarylpyridines 6a-b was observed
in high isolated yields. The obtained results revealed
that aliphatic amines may act as the nitrogen-source
during the reaction to give pyridine derivatives via
Cu-catalyzed multicomponent reaction using DMSO
as an one carbon synthon (Scheme 10).
method was evaluated and compared with the green
100
90
80
70
60
50
40
30
20
10
0
86
86
85
85
84
84
84
83
83
82
1
2
3
4
5
6
7
8
9
10
No. of attempts
Figure 1. Reaction reproducibility BAR diagram for the
synthesis of anilide 3a.
chemistry metrics of the currently used industrial
approach (Scheme 9 and in SI). It was found that the
developed protocol reflects lower E-factor (13.91
Scheme 10. Scope of the aliphatic amines towards the Cu-
catalyzed C-C cleavage.
mg/1 mg) than industrial approach including high Conclusion
atom-economy (80.16%), atom-efficiency (68.93%),
A facile protocol for the synthesis of anilides
carbon-efficiency (88.88%), and reaction mass-
efficiency (68.28%).
employing Cu(II)-catalyzed C-C bond cleavage of
acetone and acetophenones is established. The
potential of this method is verified by the gram scale
synthesis of paracetamol using acetone as acylating
agent. The developed method excludes the use of
expensive catalysts, sensitive and narcotic reagents.
The developed approach has been extended to the
preparation of 2,6-diarylpyridines using aliphatic
amines as the starting materials. Evaluations of the
green chemistry metrics of described method has
been presented and confirm the efficiencies of the
current protocol.
Experimental Section
General Methods: All starting materials were purchased
from commercial suppliers (Sigma-Aldrich, Alfa-Aesar,
SD fine chemicals, Merck, HI Media) and were used
without further purification unless otherwise indicated. All
reactions were carried out under an argon atmosphere in
oven-dried glassware with magnetic stirring. The reactions
were performed in pressure tube purchased from Sigma-
Aldrich glassware. Solvents used in extraction and
purification were distilled prior to use. Thin-layer
chromatography (TLC) was performed on TLC plates
purchase from Merck. Compounds were visualized with
UV light (λ = 254 nm) and/or by immersion in KMnO4
staining solution followed by heating. Products were
purified by column chromatography on silica gel,
Scheme 9. Green chemistry matrix of the developed
method.
In addition to anilines, the scope of the developed
method has been extended using aliphatic amines as
substrates. It is anticipated that the dual nature of the
reaction pathway may arise due to the greater
propensity for aliphatic amines to undergo C-N bond
cleavage to deliver the aliphatic carbonyl compounds.
Therefore, the expected selectivity of the reactions
between aliphatic amines 1s-u and acetophenone
derivatives 2d,g could rely on the competition
between cleavages of C-C and C-N bonds. To verify
the selectivity, when the reactions were carried out
between n-propylamine (1s) or iso-propylamine (1t)
or n-butylamine (1u) and acetophenone derivatives
2d,g under the developed conditions, the formation of
1
100 - 200 mesh. H (13C) NMR spectra were recorded at
600 (150) and 400 (100) MHz on a Brucker spectrometer
1
using CDCl3 and DMSO-d6 as a solvent. The H and 13C
chemical shifts were referenced to residual solvent signals
at H/C 7.26 /77.28 (CDCl3) and H/C 2.51 /39.50 (DMSO-
d6) relative to TMS as internal standards. Coupling
constants J [Hz] were directly taken from the spectra and
are not averaged. Splitting patterns are designated as s
6
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10.1002/adsc.201801096
Advanced Synthesis & Catalysis
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet)
and brs (broad singlet).
pale yellow solid. Rf = 0.30 SiO2, Hexane/EtOAc = 7:3);
m.p = 75 - 78 °C (Lit[25c] 74 - 77 °C); 1H NMR (600 MHz,
CDCl3) δ = 2.17 (s, 3H; 1-H), 7.06 (dd, J = 8 Hz, 1H; 7-
3
H), 7.21 (t, 3J = 8 Hz, 1H; 8-H), 7.34 (dd, 3J = 6.8 Hz, 1H;
9-H), 7.45 (s, 1H; NH), 7.63 (s, 1H; 5-H); 13C NMR (150
MHz, CDCl3) δ = 24.6 (C-1), 117.69 (C-9), 119.85 (C-5),
124.27 (C-7), 129.93 (C-8), 134.59 (C-6), 139.02 (C-4),
168.39 (C-2) ppm; HRMS (ESI, [M+H]+) calculated for
C8H9ClNO: 170.0373; found: 170.0377.
General experimental procedure for the synthesis of
anilides 3a-q: A 10 mL round bottom flask was charged
with a mixture of anilines 1a-r (1.0 mmol), ketones 2a-w
or 5a-e (1.30 mmol), Cu(OAc)2•H2O (0.10 mmol) and dry
DMSO (1 mL), CHCl3 (0.3 mL). The reaction flask was
fitted with reflux condenser then the mixture was heated at
120 °C for 14 h. After completion of the reaction (progress
was monitored by TLC; SiO2, hexane / ethyl acetate = 7:3)
the mixture was diluted with hot ethyl acetate (15 mL) and
Synthesis of N-(4-chlorophenyl)acetamide (3c); known
compound[25c]: According to the general procedure,
water (20 mL) and extracted with ethyl acetate (3 × 10 mL). reactions between 4-Chloroaniline 1c (1.0 mmol, 127 mg)
The combined organic layer was washed with brine (3 ×
10 mL) and dried over anhydrous Na2SO4. Solvent was
removed under reduced pressure and the remaining residue
was purified by column chromatography over silica gel
using hexane / ethyl acetate (hexane / ethyl acetate = 7:3)
as an eluent to obtain the desired acetanilides 3a-q in good
yield.
and Acetone 2a (1.0 mmol, 75.4 mg) were performed
using 10 mol% Cu(OAc)2•H2O (19.9 mg) to obtain the
desired product N-(4-chlorophenyl)acetamide 3c in 71%
(121 mg) yield as brown solid. Rf = 0.30 SiO2,
Hexane/EtOAc = 70:30); m.p = 174 - 177 °C (Lit[25c] 175 -
1
178 °C); H NMR (400 MHz, CDCl3) δ = 2.17 (s, 3H; 1-
H), 7.27 (d, 3J = 8 Hz, 2H; 6-H and 8-H), 7.34 (s, 1H; NH),
7.45 (d, 3J = 8 Hz, 2H; 5-H and 9-H); 13C NMR (100 MHz,
CDCl3) δ = 24.56 (C-1), 121.07 (C-5 and C-9), 129.01 (C-
6 and C-8), 129.29 (C-7), 136.42 (C-4), 168.33 (C-2) ppm;
HRMS (ESI, [M+H]+) calculated for C8H9ClNO:
170.0373; found: 170.0377.
General experimental procedure for the synthesis of
pyridines 6a-b: A 10 mL round bottom flask was charged
with a mixture of amines 1s-u (1.0 mmol), ketones 2d,g
(1.30 mmol), Cu(OAc)2•H2O (0.10 mmol) and dry DMSO
(1 mL), CHCl3 (0.3 mL). The reaction flask was fitted with
reflux condenser then the mixture was heated at 120 °C for
14 h. After completion of the reaction (progress was
monitored by TLC; SiO2, hexane / ethyl acetate = 9:1) the
mixture was diluted with hot ethyl acetate (15 mL) and
Synthesis of N-(3,5-dichlorophenyl)acetamide (3d)[25k]
:
According to the general procedure, reactions between 3,5-
dichloroaniline 1d (1.0 mmol, 161 mg) and Acetone 2a
(1.0 mmol, 75.4 mg) were performed using 10 mol%
water (20 mL) and extracted with ethyl acetate (3 × 10 mL). Cu(OAc)2•H2O (19.9 mg) to obtain the desired product N-
The combined organic layer was washed with brine (3 ×
10 mL) and dried over anhydrous Na2SO4. Solvent was
removed under reduced pressure and the remaining residue
was purified by column chromatography over silica gel
using hexane / ethyl acetate (hexane / ethyl acetate = 9:1)
as an eluent to obtain the desired pyridines 6a-b in good
yield.
(3,5-dichlorophenyl)acetamide 3d in 54% (110 mg) yield
as pale brown solid. Rf = 0.34 SiO2, Hexane/EtOAc = 7:3);
1H NMR (600 MHz, CDCl3) δ = 2.18 (s, 3H; 1-H), 7.47 (s,
2H; 5-H and 9-H), 7.95 (s, 1H; 7-H), 8.40 (s, 1H; NH); 13
C
NMR (150 MHz, CDCl3) δ = 24.34 (C-1), 120.48 (C-5 and
C-9), 125.10 (C-7), 130.74 (C-6 and C-8), 139.43 (C-4),
168.92 (C-2) ppm; HRMS (ESI, [M+H]+) calculated for
C8H8Cl2NO: 203.9983; found: 203.9980.
Synthesis of N-phenylacetamide (Acetanilide) (3a)[25a]
:
According to the general procedure, reactions between
Aniline 1a (1.0 mmol, 93 mg) and Acetone 2a (1.0 mmol,
75.4 mg) were performed using 10 mol% Cu(OAc)2•H2O
(19.9 mg) to obtain the desired product N-phenylacetamide
(Acetanilide) 3a in 86% (115 mg) yield as white solid. Rf
= 0.30 SiO2, Hexane/EtOAc = 7:3); m.p = 111 - 113 °C
Synthesis of N-(2-bromo-4-chlorophenyl)acetamide
(3e)[25d]: According to the general procedure, reactions
between 2-bromo-4-chloroaniline 1e (1.0 mmol, 206 mg)
and Acetone 2a (1.0 mmol, 75.4 mg) were performed
using 10 mol% Cu(OAc)2•H2O (19.9 mg) to obtain the
desired product N-(2-bromo-4-chlorophenyl)acetamide 3e
in 80% (198 mg) yield as colorless solid. Rf = 0.35 SiO2,
Hexane/EtOAc = 7:3); m.p = 104 - 106 °C (Lit[25f]
1
(Lit[25a] 110 - 112 °C); H NMR (600 MHz, CDCl3): δ =
2.16 (s, 3H; 1-H), 7.10 (t, 3J = 9.0 Hz, 1H; 7-H), 7.30 (t, 3J
3
1
= 9.0 Hz, 2H; 6-H and 8-H), 7.50 (d, J = 6.0 Hz, 2H; 5-H
103 °C); H NMR (400 MHz, CDCl3) δ = 2.24 (s, 3H; 1-
and 9-H), 7.53 (brs, 1H; NH); 13C NMR (150 MHz,
CDCl3): δ = 24.56 (C-1), 119.90 (C-7), 124.27 (C-5 and C-
9), 128.95 (C-8 and C-6), 137.90 (C-4), 168.43 ppm (C-2);
MS (APCI): m/z (%) = 136.10 (95%) [M + 1]+; HRMS
(ESI, [M+H]+) calculated for C8H10NO: 136.0762; found:
136.0767.
H), 7.30 (d, J = 8.0 Hz, 1H; 8-H), 7.54 (s, 1H; 6-H), 7.57
3
3
(br s, 1H; NH), 8.30 (d, J = 8.8 Hz, 1H; 9-H); 13C NMR
(100 MHz, CDCl3) δ = 24.84 (C-1), 122.50 (C-5), 128.49
(C-8 and C-9), 131.66 (C-6 and C-7), 134.47 (C-4), 168.23
(C-2) ppm; HRMS (ESI, [M+H]+) calculated for
C8H8BrClNO: 247.9478; found: 247.9472.
Synthesis of N-(3-chlorophenyl)acetamide (3b)[25c]
:
Synthesis of N-(2-bromo-5-methylphenyl)acetamide
(3f)[25d]: According to the general procedure, reactions
between 2-bromo-5-methylaniline 1f (1.0 mmol, 186 mg)
and Acetone 2a (1.0 mmol, 75.4 mg) were performed
using 10 mol% Cu(OAc)2•H2O (19.9 mg) to obtain the
desired product N-(2-bromo-5-methylphenyl)acetamide 3f
According to the general procedure, reactions between 3-
Chloroaniline 1b (1.0 mmol, 127 mg) and Acetone 2a (1.0
mmol, 75.4 mg) were performed using 10 mol%
Cu(OAc)2•H2O (19.9 mg) to obtain the desired product N-
(3-chlorophenyl)acetamide 3b in 74% (125 mg) yield as
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801096
Advanced Synthesis & Catalysis
in 77% (176 mg) yield as pale white solid. Rf = 0.30 SiO2,
Hexane/EtOAc = 7:3); m.p = 97 - 99 °C (Lit[25f] 100 °C);
1H NMR (400 MHz, CDCl3) δ = 2.23 (s, 3H; 1-H), 2.32 (s,
3H; 11-H), 6.80 (d, 3J = 8 Hz, 1H; 7-H), 7.39 (d, 3J = 8 Hz,
1H; 6-H), 7.55 (s, 1H; 9-H), 8.16 (s, 1H; NH); 13C NMR
(100 MHz, CDCl3) δ = 21.34 (C-11), 24.93 (C-1), 122.48
(C-5), 126.10 (C-9), 131.74 (C-7), 135.27 (C-6), 138.67
(C-8), 139.43 (C-4), 168.24 (C-2) ppm; HRMS (ESI,
[M+H]+) calculated for C9H11BrNO: 228.0024; found:
228.0025.
desired product N-(4-methoxy-2-methylphenyl)acetamide
3j in 82% (146 mg) yield as colorless solid. Rf = 0.25 SiO2,
Hexane/EtOAc = 7:3); m.p = 126 - 129 °C (Lit[25a]
128 °C); H NMR (400 MHz, CDCl3) δ = 2.16 (s, 3H; 1-
H), 2.21 (s, 3H; 10-H), 3.76 (s, 3H; 11-H), 6.70 – 6.72
1
(overlapped, 2H; 6-H and 8-H), 7.03 (brs, 1H; NH), 7.40
3
(d, J = 6.8 Hz, 1H; 9-H); 13C NMR (100 MHz, CDCl3) δ
= 18.15 (C-10), 23.84 (C-1), 55.39 (C-11), 111.57 (C-9),
115.92 (C-8), 126.22 (C-6), 128.46 (C-4), 133.08 (C-5),
157.46 (C-7), 168.83 (C-2) ppm; HRMS (ESI, [M+H]+)
calculated for C10H14NO2: 180.1025; found: 334.0175
[M+H+2NH4OAc]+.
Synthesis of N-(4-bromophenyl)acetamide (3g)[25c]
:
According to the general procedure, reactions between 4-
Bromoaniline 1g (1.0 mmol, 186 mg) and Acetone 2a (1.0
mmol, 75.4 mg) were performed using 10 mol%
Cu(OAc)2•H2O (19.9 mg) to obtain the desired product N-
(4-bromophenyl)acetamide 3g in 72% (154 mg) yield as
yellowish brown solid. Rf = 0.30 SiO2, Hexane/EtOAc =
Synthesis of N-(4-methylphenyl)acetamide (3k)[25a]
:
According to the general procedure, reactions between 4-
methylaniline 1k (1.0 mmol, 107 mg) and Acetone 2a (1.0
mmol, 75.4 mg) were performed using 10 mol%
Cu(OAc)2•H2O (19.9 mg) to obtain the desired product N-
(4-methylphenyl)acetamide 3k in 77% (115 mg) yield as
colorless solid. Rf = 0.30 SiO2, Hexane/EtOAc = 7:3); m.p
= 148 - 150 °C (Lit[25a] 147 - 149 °C); 1H NMR (600 MHz,
CDCl3) δ = 2.15 (s, 3H; 1-H), 2.30 (s, 3H; 10-H), 7.10 (d,
3J = 7.0 Hz, 2H; 6-H and 8-H), 7.28 (brs, 1H; NH), 7.36 (d,
3J = 7.0 Hz, 2H; 5-H and 9-H); 13C NMR (150 MHz,
CDCl3) δ = 20.83 (C-10), 24.51 (C-1), 119.98 (C-5 and C-
9), 129.44 (C-6 and C-8), 133.9 (C-4), 135.3 (C-7), 168.19
(C-2) ppm; HRMS (ESI, [M+H]+) calculated for
C9H12NO: 150.0919; found: 150.0921.
1
7:3); m.p = 168 - 171 °C (Lit[25c] 166 - 170 °C); H NMR
(400 MHz, CDCl3) δ = 2.17 (s, 3H; 1-H), 7.33 (s, 1H; NH),
7.39-7.44 (m, 4H; 5-H, 6-H, 8-H and 9-H); 13C NMR (100
MHz, CDCl3) δ = 24.60 (C-1), 116.68 (C-7), 121.38 (C-5
& C-9), 131.96 (C-6 & C-8), 136.93 (C-4), 168.34 (C-2)
ppm; HRMS (ESI, [M+H]+) calculated for C8H9BrNO:
213.9868; found: 213.9870.
Synthesis of N-(4-iodomophenyl)acetamide (3h)[25e]
:
According to the general procedure, reactions between 4-
Iodoaniline 1h (1.0 mmol, 219 mg) and Acetone 2a (1.0
mmol, 75.4 mg) were performed using 10 mol%
Cu(OAc)2•H2O (19.9 mg) to obtain the desired product N-
(4-iodoophenyl)acetamide 3h in 73% (190 mg) yield as
yellow solid. Rf = 0.30 SiO2, Hexane/EtOAc = 7:3); m.p =
Synthesis of N-(4-isopropylphenyl)acetamide (3l)[22c]
:
According to the general procedure, reactions between 4-
isopropylaniline 1l (1.0 mmol, 135 mg) and Acetone 2a
(1.0 mmol, 75.4 mg) were performed using 10 mol%
Cu(OAc)2•H2O (19.9 mg) to obtain the desired product N-
(4-isopropylphenyl)acetamide 3l in 76% (134 mg) yield as
colorless solid. Rf = 0.30 SiO2, Hexane/EtOAc = 7:3); m.p
1
172 - 174 °C (Lit[25d] 174 - 176 °C); H NMR (400 MHz,
CDCl3) δ = 2.16 (s, 3H; 1-H), 7.28 (d, 3J = 8.3 Hz, 2H; 5-H
3
and 9-H), 7.35 (s, 1H; NH), 7.60 (d, J = 8.3 Hz, 2H; 6-H
and 8-H); 13C NMR (100 MHz, CDCl3) δ = 24.66 (C-1),
87.47 (C-7), 121.65 (C-5 and C-9), 137.64 (C-6 and C-8),
137.91 (C-4), 168.39 (C-2) ppm; HRMS (ESI, [M+H]+)
calculated for C8H9INO: 261.9729; found: 261.9732.
= 104 - 106 °C (Lit[25b] 106 °C); H NMR (400 MHz,
1
CDCl3) δ = 1.22 (d, 3J = 7.0 Hz, 6H; 11-H), 2.14 (s, 3H; 1-
H), 2.81-2.92 (m, 1H; 10-H), 7.16 (d, 3J = 8.0 Hz, 2H; 6-H
and 8-H), 7.40 (d, 3J = 8.0 Hz, 2H; 5-H and 9-H), 7.54 (brs,
1H; NH); 13C NMR (100 MHz, CDCl3) δ = 24.02 (C-11),
24.45 (C-1), 33.59 (C-10), 120.21 (C-5 and C-9), 126.84
(C-6 and C-8), 135.57 (C-4), 145.03 (C-7), 168.48 (C-2)
ppm; HRMS (ESI, [M+H]+) calculated for C11H16NO:
178.1232; found: 178.1242.
Synthesis of N-(4-(trifluoromethyl)phenyl)acetamide
(3i)[25f]: According to the general procedure, reactions
between 4-(trifluoromethyl)aniline 1i (1.0 mmol, 161 mg)
and Acetone 2a (1.0 mmol, 75.4 mg) were performed
using 10 mol% Cu(OAc)2•H2O (19.9 mg) to obtain the
desired product N-(4-(trifluoromethyl)phenyl)acetamide 3i
in 71% (144 mg) yield as white solid. Rf = 0.30 SiO2,
Hexane/EtOAc = 7:3); m.p = 151 - 154 °C (Lit[25g]
Synthesis of N-(3,4-dimethylphenyl)acetamide (3m)[25j]
:
According to the general procedure, reactions between 3,4-
dimethylaniline 1m (1.0 mmol, 121 mg) and Acetone 2a
(1.0 mmol, 75.4 mg) were performed using 10 mol%
Cu(OAc)2•H2O (19.9 mg) to obtain the desired product N-
(3,4-dimethylphenyl)acetamide 3m in 63% (103 mg) yield
as pale yellow solid. Rf = 0.30 SiO2, Hexane/EtOAc =
1
153 °C); H NMR (400 MHz, CDCl3) δ = 2.21 (s, 3H; 1-
3
3
H), 7.56 (d, J = 8.4 Hz, 2H; 6-H and 8-H), 7.64 (d, J =
8.5 Hz, 2H; 5-H and 9-H), 7.72 (s, 1H; NH); 13C NMR
(100 MHz, CDCl3) δ = 24.65 (C-1), 119.37 (C-5 and C-9),
122.70 (C-10), 126.19 (C-6), 126.22 (C-8), 126.26 (C-7),
140.94 (C-4), 168.80 (C-2) ppm; HRMS (ESI, [M+H]+)
calculated for C9H9F3NO: 204.0636; found: 204.0641.
1
7:3); H NMR (600 MHz, CDCl3) δ = 2.19 (s, 3H; 1-H),
3
2.25 (s, 3H; 11-H), 2.27 (s, 3H; 10-H), 7.12 (d, J = 8 Hz,
3
1H; 8-H), 7.33 (d, J = 8 Hz, 2H; 9-H), 7.45 (s, 1H; 5-H),
8.76 (brs, 1H; NH); 13C NMR (150 MHz, CDCl3) δ = 18.8
(C-10 and C-11), 24.43 (C-1), 118.5 (C-9), 121.07 (C-5),
129.01 (C-8), 132.29 (C-7), 135.42 (C-4 and C-6), 168.9
(C-2) ppm; HRMS (ESI, [M+H]+) calculated for
C10H14NO: 164.1075; found: 164.1072.
Synthesis of N-(4-methoxy-2-methylphenyl)acetamide
(3j)[25a]: According to the general procedure, reactions
between 4-methoxy-2-methylaniline 1j (1.0 mmol, 137
mg) and Acetone 2a (1.0 mmol, 75.4 mg) were performed
using 10 mol% Cu(OAc)2•H2O (19.9 mg) to obtain the
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801096
Advanced Synthesis & Catalysis
Synthesis of N-(4-nitrophenyl)acetamide (3n)[25h]
:
Synthesis of N-(4-hydroxyphenyl)acetamide (3r)[25g]: A
10 mL round bottom flask was charged with N-(4-
methoxyphenyl)acetamide 3q (1.0 mmol, 165 mg), added
Dichloromethane (2 mL) and the reaction mixture was
cooled to 0 °C followed by the slow addition of BBr3 (1.1
mmol, 275 mg). The reaction mixture was stirred at 0 °C
for 1.5h. After completion of the reaction (progress was
monitored by TLC; SiO2, hexane / ethyl acetate = 1:1 the
reaction mixture was quenched with NH4Cl solution
(15 mL) and extracted with hot ethyl acetate (3 x 10 mL).
The combined organic layer was washed with brine (3 ×
10 mL) and dried over anhydrous Na2SO4. Solvent was
removed under reduced pressure and the remaining residue
was purified by column chromatography over silica gel
using hexane / ethyl acetate = 1.5:3.5 as an eluent to obtain
the desired product 3r in 95% (143 mg) yield. Rf = 0.30
SiO2, Hexane/EtOAc = 1:1); m.p = 169- 170 °C (Lit[25j]
168 - 172 °C); 1H NMR (600 MHz, DMSO-d6) δ = 1.98 (s,
3H; 1-H), 6.67 (dd, 3J = 9.0, 4J = 2.5 Hz, 2H; 6-H and 8-H),
7.33 (d, 3J = 7.0 Hz, 2H; 5-H and 9-H), 9.13 (brs, 1H; OH),
9.64 (brs, 1H; NH); 13C NMR (150 MHz, DMSO-d6) δ =
24.2 (C-1), 115.43 (C-6 and C-8), 121.24 (C-5 and C-9),
131.48 (C-4), 153.55 (C-2), 167.94 (C-7) ppm; HRMS
(ESI, [M+H]+) calculated for C8H10NO2: 152.0712; found:
152.0720.
According to the general procedure, reactions between 4-
nitroaniline 1n (1.0 mmol, 138 mg) and Acetone 2a (1.0
mmol, 75.4 mg) were performed using 10 mol%
Cu(OAc)2•H2O (19.9 mg) to obtain the desired product N-
(4-nitrophenyl)acetamide 3n in 73% (131 mg) yield as
yellow solid. Rf = 0.30 SiO2, Hexane/EtOAc = 7:3); m.p =
1
146 - 147 °C (Lit[25e] 145 - 147 °C); H NMR (400 MHz,
3
CDCl3) δ = 2.19 (s, 3H; 1-H), 7.82 (d, J = 8 Hz, 2H; 5-H
and 9-H), 8.20 (d, 3J = 8 Hz, 2H; 6-H and 8-H), 10.35 (brs,
1H; NH); 13C NMR (100 MHz, CDCl3) δ = 24.56 (C-1),
121.07 (C-5 and C-9), 129.01 (C-6 and C-8), 139.29 (C-7),
146.42 (C-4), 168.33 (C-2) ppm; HRMS (ESI, [M+H]+)
calculated for C8H9N2O3: 181.0613; found: 181.0617.
Synthesis of N-(2-nitrophenyl)acetamide (3o)[25b]
:
According to the general procedure, reactions between 2-
nitroaniline 1o (1.0 mmol, 138 mg) and Acetone 2a (1.0
mmol, 75.4 mg) were performed using 10 mol%
Cu(OAc)2•H2O (19.9 mg) to obtain the desired product N-
(2-nitrophenyl)acetamide 3o in 67% (120 mg) yield as
yellow solid. Rf = 0.30 SiO2, Hexane/EtOAc = 7:3); m.p =
1
90 - 92 °C (Lit[25h] 92 - 94 °C); H NMR (400 MHz,
CDCl3) δ = 2.30 (s, 3H; 1-H), 7.18 (td, 3J = 8 Hz, 1H; 7-H),
7.65 (td, 3J = 8 Hz, 1H; 8-H), 8.21 (dd, 3J = 8 Hz, 1H; 6-H),
3
8.76 (dd, J = 8 Hz, 1H; 9-H), 10.34 (s, 1H; NH); 13C
NMR (100 MHz, CDCl3) δ = 25.67 (C-1), 122.18 (C-9),
123.24 (C-7), 125.74 (C-6), 131.19 (C-8), 134.87 (C-4),
136.01 (C-5), 169.07 (C-2) ppm; HRMS (ESI, [M+H]+)
calculated for C8H9N2O3: 181.0613; found: 181.0617.
Synthesis of 2,6-diphenylpyridine (6a)[26]: According to
the general procedure, reactions between n-propylamine 1s
(1.0 mmol, 59 mg) and acetophenone 2d (1.0 mmol, 120
mg) were performed using 10 mol% Cu(OAc)2•H2O (19.9
mg) to obtain the desired product 2,6-diphenylpyridine 6a
in 73% (169 mg) yield as white solid. Rf = 0.65 (SiO2,
Hexane/EtOAc = 9:1); m.p = 77 - 79 °C (Lit[26] 79 -
80 °C); 1H NMR (400 MHz, CDCl3): δ = 8.16 (dd, 3J = 7.6
Hz, 4H; 8-H), 7.82 (t, 3J = 7.8 Hz, 1H; 4-H), 7.70 (dd, 3J =
Synthesis
of
N-(4-chloro-2-nitrophenyl)acetamide
(3p)[25i]: According to the general procedure, reactions
between 4-chloro-2-nitroaniline 1p (1.0 mmol, 172 mg)
and Acetone 2a (1.0 mmol, 75.4 mg) were performed
using 10 mol% Cu(OAc)2•H2O (19.9 mg) to obtain the
desired product N-(4-chloro-2-nitrophenyl)acetamide 3p in
69% (148 mg) yield as yellow solid. Rf = 0.35 SiO2,
Hexane/EtOAc = 7:3); m.p = 97 - 99 °C (Lit[25i] 99 -
3
7.8 Hz, 2H; 3-H and 5-H), 7.50 (t, J = 7.6 Hz, 4H; 9-H),
7.43 (t, 3J = 7.8 Hz, 2H; 10-H) ppm; 13C NMR (100 MHz,
CDCl3) δ = 156.82 (C-2 and C-6), 139.48 (C-4), 137.44
(C-7), 128.94 (C-9), 128.65 (C-8), 126.97 (C-10), 118.60
(C-3 and C-5) ppm; HRMS (QTOF, [M + H]+): calculated
for C17H14N: 232.1125; found: 232.1132.
1
100 °C); H NMR (400 MHz, CDCl3) δ = 2.30 (s, 3H; 1-
3
3
H), 7.60 (dd, J = 8 Hz, 1H; 8-H), 8.21 (d, J = 8 Hz, 1H;
4
9-H), 8.78 (d, J = 3.6 Hz, 1H; 6-H), 9.35 (brs, 1H; NH);
13C NMR (100 MHz, CDCl3) δ = 25.77 (C-1), 123.5 (C-9),
125.4 (C-6), 128.5 (C-7), 133.7 (C-4), 136.1 (C-8), 136.5
(C-5), 169.1 (C-2) ppm; HRMS (ESI, [M+H]+) calculated
for C8H8ClN2O3: 215.0223; found: 215.0228.
Synthesis of 2,6-di-p-tolylpyridine (6b)[26]: According to
the general procedure, reactions between i-propylamine 1t
(1.0 mmol, 59 mg) or n-butylamine 1u (1.0 mmol, 73 mg)
and p-methylacetophenone 2g (1.0 mmol, 134 mg) were
performed using 10 mol% Cu(OAc)2•H2O (19.9 mg) to
obtain the desired product 2,6-di-p-tolylpyridine 6b in 78%
(202 mg) or 76% (197 mg) yield respectively as pale white
solid. Rf = 0.65 (SiO2, Hexane/EtOAc = 9:1); m.p = 162 -
165 °C (Lit[26] 163 - 165 °C); 1H NMR (400 MHz, CDCl3):
δ = 8.05 (d, 3J = 8.2 Hz, 4H; 8-H), 7.77 (t, 3J = 7.8 Hz, 1H;
Synthesis of N-(4-methoxyphenyl)acetamide (3q)[25a]
:
According to the general procedure, reactions between 4-
methoxyaniline 1q (1.0 mmol, 123 mg) and Acetone 2a
(1.0 mmol, 75.4 mg) were performed using 10 mol%
Cu(OAc)2•H2O (19.9 mg) to obtain the desired product N-
(4-methoxyphenyl)acetamide 3q in 85% (140 mg) yield as
colorless solid. Rf = 0.30 SiO2, Hexane/EtOAc = 7:3); m.p
3
3
4-H), 7.64 (d, J = 7.8 Hz, 2H; 3-H and 5-H), 7.30 (d, J =
8.3 Hz, 4H; 9-H), 2.42 (s, 6H; 11-H) ppm; 13C NMR (100
MHz, CDCl3) δ = 156.76 (C-2 and C-6), 138.88 (C-4),
137.36 (C-7), 136.77 (C-10), 129.38 (C-9), 126.88 (C-8),
118.07 (C-3 and C-5), 21.29 (C-11) ppm; HRMS (QTOF,
[M + H]+): calculated for C19H18N: 260.1434; found:
260.1438.
1
= 127 - 129 °C (Lit[25a] 128 °C); H NMR (400 MHz,
CDCl3) δ = 2.14 (s, 3H; 1-H), 3.78 (s, 3H; 10-H), 6.84 (dd,
3J = 9.0, 4J = 2.5 Hz, 2H; 6-H and 8-H), 7.27 (brs, 1H; NH)
3
7.38 (d, J = 7.0 Hz, 2H; 5-H and 9-H); 13C NMR (100
MHz, CDCl3) δ = 24.36 (C-1), 55.48 (C-10), 114.13 (C-6
and C-8), 121.95 (C-5 and C-9), 130.93 (C-4), 156.45 (C-
7), 168.28 (C-2) ppm; HRMS (ESI, [M+H]+) calculated
for C9H12NO2: 166.0868; found: 166.0873.
Acknowledgements
9
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10.1002/adsc.201801096
Advanced Synthesis & Catalysis
CCM appreciate Science and Engineering Research Board
(SERB), New Delhi and NIT Manipur for financial support in the
form of research grant (ECR/2016/000337). We acknowledge Mr.
M. Wolf (Institut für Chemie, Universität Hohenheim) and the
central instrumentation fecilities Indian Institute of Technology,
Guwahati for recording NMR and Mass spectra. We sincerely
thank Prof. T. Punniyamurthy, V. Satheesh and R. Bag from
Department of Chemistry, Indian Institute of Technology,
Guwahati for sample analysis and research support. We also
thank Prof. Anil Kumar and S. Dhiman from Department of
Chemistry, BITS PILANI for sample analysis. NV, RG, DK and
AKK grateful to Ministry of Human Resource and Development
(MHRD), New Delhi for fellowship support.
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FULL PAPER
Copper-Catalyzed Site-Selective Oxidative C–C
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