Copper/N,N-dimethylglycine catalyzed Goldberg reactions between aryl bromides and amides, aryl iodides and secondary acyclic amides

Article abstract of DOI:10.3390/molecules190913448

An efficient and general copper-catalyzed Goldberg reaction at 90-110 °C between aryl bromides and amides providing the desired products in good to excellent yields has been developed using N,N-dimethylglycine as the ligand. The reaction is tolerant toward a wide range of amides and a variety of functional group substituted aryl bromides. In addition, hindered, unreactive aromatic and aliphatic secondary acyclic amides, known to be poor nucleophiles, are efficiently coupled with aryl iodides through this simple and cheap copper/N,N-dimethylglycine catalytic system.

Full text of DOI:10.3390/molecules190913448

Molecules 2014, 19, 13448-13460; doi:10.3390/molecules190913448
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Copper/N,N-Dimethylglycine Catalyzed Goldberg Reactions
Between Aryl Bromides and Amides, Aryl Iodides and
Secondary Acyclic Amides
Liqin Jiang
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development,
East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China;
E-Mail: jiangliqin_777@163.com or lqjiang@sat.ecnu.edu.cn;
Tel.: +86-21-6223-2468; Fax: +86-21-5434-1159
Received: 26 June 2014; in revised form: 14 July 2014 / Accepted: 4 August 2014 /
Published: 29 August 2014
Abstract: An efficient and general copper-catalyzed Goldberg reaction at 90–110 °C
between aryl bromides and amides providing the desired products in good to excellent
yields has been developed using N,N-dimethylglycine as the ligand. The reaction is tolerant
toward a wide range of amides and a variety of functional group substituted aryl bromides.
In addition, hindered, unreactive aromatic and aliphatic secondary acyclic amides, known
to be poor nucleophiles, are efficiently coupled with aryl iodides through this simple and
cheap copper/N,N-dimethylglycine catalytic system.
Keywords: N,N-dimethylglycine; Goldberg reaction; aryl bromides; secondary acyclic amides
1. Introduction
N-arylation of amides has received considerable attention over the past decades due to its important
synthetic utility [1–4]. Although Pd-catalyzed arylations of amides have made great progress [2,3,5–10]
the high cost of Pd and the corresponding ligands as well as the difficulty of removing the Pd from
polar products limit their application. The less expensive copper-catalyzed N-arylation of amides,
known as the Goldberg reacton, is still an attractive option. Significant improvements have been
achieved in the Goldberg reaction over the past decade by the introduction of chelating ligands, which
make this transformation work under significantly milder reaction conditions [3]. For instance, in
2002, Buchwald and coworkers reported that several diamine-type ligands could greatly facilitate the
coupling of aryl halides with amides at low temperatures [11,12]. This catalyst system was later

Molecules 2014, 19
13449
extended to other coupling partners such as carbamates [13], iodo-selenophene [14], halo-furans [15],
and oxindoles [16]. However, one of diamine ligands, trans-N,N′-dimethyl-1,2-cyclohexanediamine, is
more expensive than other common ligands. Moreover, even for the coupling of aryl iodides and
hindered, unreactive amide substrates with the diamine-type ligands, significant N-arylation of the
diamine ligand (>5% with respect to the aryl halide) is observed. The resulting N-arylated diamines are
less catalytically active than the starting diamine, a problem which is further exacerbated in the
reactions involving hindered amides [12]. Most of the subsequently reported copper/ligand catalytic
systems for the Goldberg reaction only can be applied to the coupling of aryl iodides and
amides [14,17–22]. To the best of our knowledge, besides diamine ligands, only β-keto ester [23]
and amino acid ligands [24,25] were applicable to the copper catalyzed coupling of aryl bromides
and amides and the amide substrates were restricted to primary amides [24], lactams [23] and
oxazolidinones [25]. A systematical study of the coupling of aryl bromides with diversified amides,
especially with acyclic secondary amides and amino acids as ligands has not been reported yet.
Tertiary amides which could be generated from aryl halides and secondary amides are found in
numerous biologically active compounds [26–30]. Synthesis of tertiary aryl amides through arylation
of the secondary amides would facilitate the generation of analogues for the structure-activity study in
medicinal chemistry and life science by easily changing the aryl component. Secondary amides are
often intermediates in total synthesis and their direct arylation would facilitate more efficient synthetic
routes [30]. Additionally, provided that we sequentially arylated primary amides and N-alkylated the
resulting N-aryl amides to prepare the tertiary aryl amides, dialkylation resulting in quaternary
ammonium salts, or N,O-dialkylation could occur. Only a few reactions involving palladium or copper
as catalysts for N-arylation of secondary acyclic amides have been described [10,22]. Cheap, general,
efficient catalyst systems for N-arylation of secondary amides under mild conditions are still desirable.
As a result of our interest in the ligand-promoted Ullman and Goldberg reactions [31], we found that
CuI/N,N-dimethylglycine is a cheap, efficient and general catalytic system for the coupling of aryl
bromides and amides, affording the corresponding products, including diversified tertiary amides,
in good to excellent yields at 90–110 °C. In addition, one of the advantages of using
N,N-dimethylglycine as a ligand is that it cannot be arylated. This simple and cheap catalytic system
also gave good yields when hindered, unreactive amide substrates were coupled with aryl iodides.
Herein, we report in details our results.
2. Results and Discussion
As indicated in Table 1, a CuI-catalyzed coupling reaction of 1-bromo-4-methoxybenzene (1a) with
N-methylformamide (2a) was chosen as a model reaction to screen suitable ligands. Given that
4-hydroxy-L-proline is an effective ligand for the coupling of N-substituted o-bromobenzamides with
primary amides [24] and effective in other C-N coupling reactions [31,32], we initially carried out the
model reaction with 10 mol% of CuI, 20 mol% of 4-hydroxy-L-proline and 2 equivalents of K2CO3 in
1 mL of DMF at 110 °C. The desired product was isolated in 24% yield after 24 h (Table 1,
entry 1). Increasing the amount of the ligand to 30 mol% led to a negligible change of the yield
(Table 1, entry 2). Increasing the concentration of the reaction by decreasing the amount of DMF to
0.5 mL improved the yield to 61% (Table 1, entry 3). Then other bases, solvents, and copper salts were

Molecules 2014, 19
13450
screened (Table 1, entry 4–7). Using K3PO4 instead of K2CO3 as a base gave almost the same results
(Table 1, entry 4). Cs2CO3 as base led to no product (Table 1, entry 5). Dioxane or DMSO as solvent
decreased the yield (Table 1, entry 6, 7). Other copper salts such as copper(I) oxide and copper(II)
acetylacetone also led to a decrease in the yield (Table 1, entry 8, 9). Then other 2-carboxylic acid
bidentate compounds were examined as ligands for this model reaction under the above optimized
reaction conditons (Table 1, entry 10–16). Only a trace amount of the desired product was detected
with glycine as ligand instead of 4-hydroxy-L-proline, although glycine was reported to be an efficient
ligand in promoting amidation of aryl iodides (Table 1, entry 10) [18]. Proline as a ligand in the
current reaction gave 76% yield after 24 h (Table 1, entry 11). When picolinic acid was tested as a
ligand the reaction proceeded slowly and afforded an 86% yield of the coupling product after 36h
when the starting material 1a was completely consumed (Table 1, entry 12). To our delight,
N,N-dimethylglycine was discovered to be a powerful ligand to accelerate the reaction and an almost
quatitative yield was achieved after 12 h (Table 1, entry 13). Decreasing the amount of
N-methylformamide (2a) from 2 to 1.2 equivalents still gave an almost quantitative yield after 20 h
(Table 1, entry 14).
Bicine was inefficient to this reaction (Table 1, entry 15). Dimethylethanolamine was also an
inefficient ligand to this reaction (Table 1, entry 16), demonstrating the importance of the carboxylic
acid in N,N-dimethylglycine. Control reactions with only copper or N,N-dimethylglycine as catalyst
both gave no desired product (Table 1, entry 17, 18). Thus, 10 mol% of CuI, 20 mol% of
N,N-dimethylglycine and 2 equivilent of K2CO3 as base in DMF was identified as the optimized
reaction condition.
With the optimized conditions in hand, we examined the scope of the Goldberg reaction between
aryl bromides and amides. The results are summarized in Table 2. Generally, the reaction afforded the
corresponding products in good to excellent yields under 90–110 °C. The reaction can be applicable to
a wide range of amides, including primary amides (Table 2, entries 1–5), lactams (Table 2,
entries 6–10) and secondary acyclic amides (Table 2, entries 11–18), as well as an á,â-unsaturated
amide (Table 2, entry 5). Aryl bromides can contain strongly electron-donating para-substituents. For
example, excellent yields were achieved when 1-bromo-4-methoxybenzene was amidated by either
primary or secondary amides (enties 1, 5, 6, and 13). Free amine (entry 2) substitution on aryl
bromides were tolerated, as well as acyl (entry 7, 15), fluoro (entry 12), trifluoromethyl (entries 8, 10).
The bromo group in 4-bromo-1-chlorobenzene can be selectively amidated in the presence of the
chloro substituent (entry 4). The method can also be extended to heteroaryl bromides such as
2-bromopyridine, 3-bromothiophene (entry 11, 17, 18). The latter is a substrate only moderately
tolerant with the Pd-catalyzed methodology [33,34]. Heteroaromatic reagents are challenging because
the heteroatom could ligate the catalyst, leading to catalyst deactivation, and also may be unfavorable
for the catalytic processes [4]. When 1-bromo-2-methylbenzene was coupled with pyrrolidin-2-one the
yield decreased to 76% (Table 2, entry 9). In order to solve this problem, we attempted to purify the
CuI by another reported method [35]. We found that the yield can be improved to 91% using 10 mol%
N,N-dimethylglycine and 10 mol% CuI purified by the dissolution-precipitation process [35].
Examining the model reaction of 1-bromo-4-methoxybenzene with N-methylformamide using 5% of
CuI purified by this method and 10% N,N-dimethylglycine under 110 °C for 24h, a 95% yield was

Molecules 2014, 19
13451
obtained. Other several reactions of aryl bromides with secondary acyclic amides were conducted
under these conditions, and good to excellent yields were also achieved (entries 12,13,16,17).
Table 1. Optimization of Goldberg reaction conditions a.
O
O
CuI/Ligand
H
O
Br
O
N
+
H
N
H
3a
2a
1a
HO
OH
OH
OH
H2N
N
OH
N
H
H
N
O
O
O
O
L1
L2
L3
L4
OH
OH
HO
HO
OH
N
N
N
O
O
L5
L7
L6
Entry Copper Salt Ligand
Solvent
DMF
Base
Yield b [%]
1
2
CuI
CuI
L1
L1 c
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L5
L6
L7
--
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
K2CO3
24
25
61
60
0
DMF
3
CuI
DMF d
DMF d
DMF d
4
CuI
5
CuI
6
CuI
DMSO d
Dioxane d K2CO3
47
42
8
7
CuI
8
Cu2O
Cu(acac)2
CuI
DMF d
DMF d
DMF d
DMF d
DMF d
DMF d
DMF d
DMF d
DMF d
DMF d
DMF d
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
9
30
trace
76
86 e
96 f
96 g
0
10
11
12
13
14
15
16
17
18
CuI
CuI
CuI
CuI
CuI
CuI
0
CuI
0
--
L5
0
a
Reaction conditions: 10 mol% of CuI, 20 mol% of ligand, 1.0 equiv of 1-bromo-4-
methoxybenzene, 2.0 equiv of N-methylformamide, 2 equiv of base in 1 mL of DMF, 24 h;
g
b Isolated yield; c 30 mmol% of A; d Using 0.5 mL of solvent; e 36 h. f 12 h. 1.2 equiv of
N-methylformamide, 20 h.
Taillefer reported a copper-catalyzed coupling of aryl iodides with secondary acyclic amides under
130 °C using 2,2,6,6-tetramethyl-3,5-heptadione as ligand [22] as well as other procedures to afford
tertiary amides from secondary amides and aryl iodides have been described [36]. Buchwald and
coworkers report that diamine ligands are arylated when hindered, unreactive amide substrates are
used, and the resulting N-arylated diamines are less catalytically active than the starting diamine,

Molecules 2014, 19
13452
further aggravating the reactions involving hindered amides. The structure of N,N-dimethylglycine
determined that it cannot be N-arylated in the coupling reaction. Thus we are interested in investigating
its use in the coupling reaction of hindered, unreactive amide substrates with aryl iodides.
Table 2. CuI/N,N-dimethylglycine catalyzed amidation of aryl bromides a.
O
O
10 mol% CuI, 20 mol% N,N-Dimethylglycine
Ar
Ar-Br
HN
R'
R
N
R
K2CO3, DMF
R'
1
2
3
Entry
Product
3
T (°C) t (h) Yield b (%)
O
1
3b
100
100
100
100
100
90
22
24
16
8
96
92
93
97
90
90
O
N
H
Ph
Ph
O
O
2
3
4
5
6
3c
3d
3e
3f
H2N
F3C
N
H
N
H
Ph
N
O
Cl
NH
O
Ph
20
18
O
NH
O
3g
O
N
O
O
7
8
3h
3i
90
16
16
93
83
N
O
100
F3C
N
O
76
N
9
3g
3k
3l
110
110
110
24
26
24
91 f
O
10
11
F3C
N
91
O
N
95 c
H
S
O
N
93
H
12
13
3m
3n
100
110
19
20
F
93 f
Me
O
95
93 f
H
O
N
Ph
H
O
N
14
3o
90
19
94
Ph

Molecules 2014, 19
13453
Table 2. Cont.
Entry
Product
3
T (°C) t (h) Yield b (%)
O
O
H
15
3p
110
110
27
14
90
N
Ph
O
96
92 f
H
16
17
18
3q
3r
3s
N
Bn
O
71 d
70 f
100
110
18
24
N
N
H
Bn
O
S
74
N
Ph
a
Reaction conditions: 10 mol% of CuI, 20 mol% of N,N-dimethylglycine, 1.0 mmol of aryl bromide,
1.2 mmol of amide, 2 equiv of K2CO3 in 0.5 mL of DMF, 24 h; b Isolated yields; c With 2 equive of K3PO4 as
d
e
base; With 1.3 equive of aryl bromide and 1.0 equiv of amide; With 2 equiv of amide substrates;
f 5 mol% of dissolution-precipitation purified CuI, 10 mol% of N,N-dimethylglycine under 110 °C for 24 h.
Table 3. CuI/N,N-dimethylglycine catalyzed the coupling between hindered, unreactive
amides and aryl iodides a.
O
O
10% CuI, 20% N,N-Dimethylglycine
K2PO3, DMF
Ar
Ar-I
HN
R'
R
N
R
R'
4
2
3
Entry
Product
3
T ( °C) t (h) Yield b (%)
O
1
3t
90
80
24
24
85
81
N
Ph
F
O
2
3u
N
Ph
O
3
4
3v
3v
90
90
24
24
82
82
N
O
H
N
O
5
3q
80
24
92
N
H
Bn
a
Reaction conditions: 10 mol% of CuI, 20 mol% of N,N-dimethylglycine, 1.0 mmol of aryl iodides,
1.2 mmol of amide, 2 equiv of K2PO3 in 0.5 mL of DMF, 24 h. b Isolated yields.
As indicated in Table 3, N-phenylacetamide can be smoothly coupled with electron-donating or
electron-drawing substituted aryl iodides at 80–90 °C under our catalyst system (Table 3, entry 1, 2).
N-methylacetamide can also be arylated with iodobenzene at 90 °C, giving a good yield (Table 3,
enty 3). The coupling reaction of bulky N-cyclohexylformamide with 1-iodobenzene afforded the
corresponding product in 88% yield at 120 °C, which is higher than the reported 63% yield

Molecules 2014, 19
13454
using diamine ligand [18] (Table 3, entry 4). When N-benzylformamide was coupled with
1-iodo-4-methylbenzene, an excellent yield was obtained at 80 °C (Table 3, entry 5).
3. Experimental Section
3.1. General Information & Materials
1
13
1
The new compounds were identified by H-NMR, C-NMR and HRMS. All H-NMR (300 MHz)
and 13C-NMR (100 MHz) spectra were recorded on Bruker AMX-300, Varian EM360A spectrometers
in CDCl3. Chemical shifts are reported in ppm relative to tetramethylsilane (δ = 0) or the residual
protonated solvent (CDCl3: δH = 7.26 ppm, δC = 77.16 ppm). The resonance multiplicity is described
as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). Mass spectra (EI-MS) were
recorded on HP-5989A or VGQUATTRO mass spectrometers. High-resolution mass spectrometry
(HRMS) was performed on a Bruker Daltonics FTMS-7 instrument. Melting points were uncorrected.
DMF and DMSO were freshly distilled from CaH2. THF was distilled over sodium. Commercial
available CuI should be washed with THF using a Soxhlet extractor before it was used to ensure the
purity. When some reactions used the CuI purified according the reported method [35] comments and
a note are provided in the paper. The reported compounds were identified by comparing with the
reported analytical data by 1H-NMR and EI-MS.
3.2. General Procedure for Optimization of Amidation of Aryl Bromides with Copper/N,N-Dimethyl-
glycine Catalytic System
A Schlenk tube was charged with 1-bromo-4-methoxybenzene 1a (1 mmol), N-methylformamide
2a (2 mmol or 1.2 mmol), CuI (0.1 mmol), ligand (0.2 mmol), and base (2 mmol). The tube was
evacuated and backfilled with argon at room temperature. The solvent (0.5 mL) was added under argon
via syringe. The Schlenk tube was immersed in a preheated oil bath and the reaction mixture was
stirred at 110 °C for the specified time with complete consumption of the starting material 1a. The
cooled mixture was partitioned between water and ethyl acetate. The organic layer was separated and
the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with
brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (eluting with 1:8 to 1:2 ethyl acetate/petroleum ether) to give the
desired product.
3.3. General Procedure for the Coupling of Aryl Bromides with Amides Using Copper/N,N-Dimethyl-
glycine Catalytic System
A Schlenk tube was charged with amide (1.2 mmol), aryl halide (1 mmol), CuI (0.05 or 0.1 mmol),
N,N-dimethylglycine (0.1 or 0.2 mmol), and potassium carbonate (2 mmol). The tube was evacuated
and backfilled with argon at room temperature. DMF (0.5 mL) was added under argon via syringe. The
Schlenk tube was immersed in a preheated oil bath and the reaction mixture was stirred for the
specified time at the indicated temperature. The cooled mixture was partitioned between water and
ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate.
The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo.

Molecules 2014, 19
13455
The residue was purified by column chromatography on silica gel (eluting with 1:8 to 1:2 ethyl
acetate/petroleum ether) to give the the desired N-aryl amides.
3.4. General Procedure for the Coupling of Aryl Iodides with Hindered Amides Using
Copper/N,N-Dimethylglycine Catalytic System
A Schlenk tube was charged with amide (1.2 mmol), aryl iodides (1 mmol), CuI (0.1 mmol),
N,N-dimethylglycine (0.2 mmol), and potassium phosphate (2 mmol). The tube was evacuated and
backfilled with argon at room temperature. DMF (0.5 mL) was added under argon via syringe. The
Schlenk tube was immersed in a preheated oil bath and the reaction mixture was stirred for the
specified time at the indicated temperature. The cooled mixture was partitioned between water and
ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate.
The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (eluting with 1:8 to 1:2 ethyl
acetate/petroleum ether) to give the the desired N-aryl amides.
3.5. Analytical Data of Products
O
N-(4-Methoxyphenyl)-N-methylformamide (3a). 1H-NMR (CDCl3): δ 8.35 (s, 1H), 7.11
H
O
O
N
(d, J = 8.7 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 3.83 (s, 3H), 3.28 (s, 3H); EI-MS m/z 165
(M+), 153, 136, 122, 108, 94, 77, 65, 52.
3a
O
N-(4-Methoxyphenyl)benzamide (3b). 1H-NMR (CDCl3): δ 7.87 (d, J = 7.2 Hz, 1H ),
7.79 (s, 1H), 7.56–7.46 (m, 5H), 6.91 (d, J = 9.3 Hz, 2H), 3.82(s, 3H); EI-MS m/z 227
(M+), 210, 178, 149, 122, 105, 77, 51.
Ph
NH
3b
O
N-(3-Aminophenyl)benzamide (3c). 1H-NMR (CDCl3): δ 7.85 (d, J = 7.2 Hz, 2H), 7.79
(s, 1H), 7.57–7.45 (m, 3H), 7.33 (s, 1H), 7.13 ( t, J = 7.8 Hz, 1H), 6.79 (d, J = 7.8 Hz,
1H), 6.48 (d, J1 = 8.1 Hz, J2 = 1.8 Hz,1H), 3.71 (s, 2H); EI-MS m/z 212 (M+), 184, 167,
135, 121, 105, 77, 51.
Ph
NH
H2N
3c
3d
O
Ph
N-(3-(Trifluoromethyl)phenyl)benzamide (3d). 1H-NMR (CDCl3): δ 8.00–7.85 (m, 5H),
7.57–7.39 (m, 5H); EI-MS m/z 265 (M+), 246, 225, 149, 113, 105, 77, 51.
NH
F3C
O
N-(4-Chlorophenyl)nicotinamide (3e). 1H-NMR (CDCl3): δ 9.08 (s, 1H), 8.78 (dd,
J1 = 4.8 Hz, J2 = 1.5 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 8.04 (s, 1H), 7.62 (d, J = 9.0 Hz,
2H), 7.48–7.44 (m, 1H), 7.36 (d, J = 8.7 Hz, 2H); EI-MS m/z 232 (M+), 127, 106, 78, 51.
Cl
O
NH
N
3e
O
Ph
N-(4-Methoxyphenyl)cinnamamide (3f). 1H-NMR (CDCl3): δ 7.75 (d, J = 15.6 Hz, 1H),
7.54 (m, 4H), 7.38 (m, 3H), 6.90 (d, J = 8.7 Hz, 2H), 6.53 (d, J = 15.3 Hz, 1H), 3.81 (s,
3H); EI-MS m/z 253 (M+), 131, 123, 108, 103, 77, 51.
NH
3f
O
1-(4-Methoxyphenyl)pyrrolidin-2-one (3g). 1H-NMR (CDCl3): δ 7.50 (d, J = 9.0 Hz,
2H), 6.91 (d, J = 9.0 Hz, 2H), 3.86–3.00 (m, 5H), 2.60 (t, J = 8.1 Hz, 2H), 2.16 (m, 2H);
EI-MS m/z 191 (M+), 176, 166, 136, 121, 69, 57.
O
N
3g

Molecules 2014, 19
13456
1-(4-Acetylphenyl)pyrrolidin-2-one (3h). 1H-NMR (CDCl3): δ 7.98 (d, J = 8.7 Hz, 2H),
O
O
7.76 (d, J = 9.0 Hz, 2H), 3.91 (t, J = 7.2 Hz, 2H), 2.65 (t, J = 7.5 Hz, 2H), 2.59 (s, 3H),
N
2.20 (m, 2H); EI-MS m/z 203 (M+), 188, 160, 148, 132, 120, 105, 90, 77, 69, 63, 51,
3h
43.
O
1-(4-(Trifluoromethyl)phenyl)pyrrolidin-2-one (3i). 1H-NMR (CDCl3): δ 7.77 (d,
J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 3.89 (t, J = 7.2 Hz, 2H), 2.64 (t, J = 7.8 Hz,
2H), 2.21 (m, 2H); EI-MS m/z 229 (M+), 210, 174, 145, 127, 95, 84, 57.
F3C
N
3i
O
1-o-Tolylpyrrolidin-2-one (3j). 1H-NMR (CDCl3): δ 7.27–7.21 (m, 3H), 7.16–7.13 (m,
1H), 3.72 (t, J = 7.2 Hz, 2H), 2.59 (t, J = 8.1 Hz, 2H), 2.28–2.18 (m, 5H), EI-MS m/z
175 (M+), 158, 146, 130, 120, 91, 65, 51.
N
3j
O
1-(3-(Trifluoromethyl)phenyl)piperidin-2-one (3k). 1H-NMR (CDCl3): δ 7.53–7.48 (m,
4H), 3.69–3.66 (m, 2H), 2.60–2.56 (m, 2H), 1.98–1.96 (m, 4H); EI-MS m/z 243 (M+),
224, 214, 187, 174, 149, 145, 120, 108, 91, 70, 55.
F3C
N
3k
H
N-Methyl-N-(thiophen-3-yl)formamide (3l). 1H-NMR (CDCl3): δ 8.52 (s, 1H), 8.23 (s,
0.2H), 7.44–7.42 (m, 0.2H), 7.35–7.30 (m, 1.2 H), 7.25–7.23 (m, 0.2H), 6.99–6.97 (m,
1H), 6.84–6.83 (m, 1H), 3.30 (s, 0.6 H), 3.22 (s, 3H); EI-MS m/z 141 (M+), 112, 98, 85,
80, 72, 68, 58, 54, 45, 42.
N
O
S
3l
O
H
N-(4-Fluorophenyl)-N-methylformamide (3m). 1H-NMR (CDCl3): δ 8.40 (s, 1H),
7.18–7.12 (m, 4H), 3.31 (s, 3H); EI-MS m/z 153 (M+), 124, 112, 95, 83, 77, 75, 57.
F
N
3m
3n
N-(4-Methoxyphenyl)-N-phenylformamide (3n). 1H-NMR (CDCl3): δ 8.62 (d,
J = 30.9 Hz, 1H), 7.38–7.34 (m, 2H), 7.31–7.19 (m, 3H), 7.16–7.11 (m, 2H), 6.92 (d,
J = 9.0 Hz, 2H), 3.81 (d, J = 4.2 Hz, 3H); EI-MS m/z 227 (M+), 199, 184, 167, 154, 129,
124, 121, 103, 93, 77, 66, 51, 43
O
N
H
O
Ph
N-Phenyl-N-m-tolylformamide (3o). 1H-NMR (CDCl3): δ 8.66 (d, J = 6.3 Hz,1H),
7.43–7.38 (m, 2H), 7.33–7.26 (m, 3H), 7.18–7.05 (m, 3H), 6.98 (s, 1H), 2.36–2.35 (d,
J = 3.6 Hz, 3H); EI-MS m/z 211 (M+), 183, 167, 141, 128, 118, 108, 91, 80, 65, 51;
EI-HRMS for C15H13NO2 (M+) requires 211.0997, found 211.0992.
O
N
H
Ph
3o
N-(4-Acetylphenyl)-N-phenylformamide (3p). 1H-NMR (CDCl3): δ 7.86 (d, J = 8.1 Hz,
2H), 7.34 (t, J = 7.5 Hz, 2H), 7.18 (d, J = 7.5 Hz, 2H), 7.08 (t, J = 7.2 Hz, 1H), 6.99 (d,
J = 8.4 Hz, 2H), 6.26 (s, 1H), 2.63 (s, 3H); 13C-NMR (CDCl3): δ 196.3, 148.2, 140.4,
130.5 (2C), 129.4 (2C), 128.9, 123.2, 120.5 (2C), 114.2 (2C), 97.6, 26.0; EI-MS m/z
239 (M+), 211, 196, 167, 139, 115, 98, 84, 77, 63, 51, 43; EI-HRMS for C15H13NO2
(M+) requires 239.0946, found 239.0944.
O
N
O
H
Ph
3p
O
N
N-Benzyl-N-p-tolylformamide (3q). 1H-NMR (CDCl3): δ 8.50 (s, 1H), 7.28–7.21 (m,
5H), 7.13 (d, J = 8.1 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 4.97 (s, 2H), 2.32 (s, 3H);
EI-MS m/z 225 (M+), 196, 181, 165, 133, 118, 91, 77, 65, 51
H
Bn
3q
O
N-Benzyl-N-(pyridin-2-yl)formamide (3r). 1H-NMR (CDCl3): δ 9.50 (s, 1H), 8.39 (d,
J = 5.1 Hz, 1H), 7.62 (t, J = 7.2 Hz, 1H), 7.29–7.22 (m, 5H), 7.08 (m, 1H), 6.93(d,
J = 8.1 Hz, 1H), 5.18 (s, 2H); EI-MS m/z 212 (M+), 183, 168, 154, 106, 91, 78, 65, 51
N
N
H
Bn
3r

Molecules 2014, 19
13457
Ph
N
N-Phenyl-N-(thiophen-3-yl)acetamide (3s). 1H-NMR (CDCl3): δ 7.46–7.18 (m, 7H),
7.18 (6.95, J = 5.7 Hz, 1H), 1.99 (s, 3H); EI-MS m/z 217 (M+), 175, 149, 130, 120, 104,
O
S
84, 77, 51, 43.
3s
O
N-(4-Fluorophenyl)-N-phenylacetamide (3t). 1H-NMR (CDCl3): δ 7.32~7.15 (m, 9H),
N
Ph
2.33 (s, 3H), 2.05 (s, 3H).
3t
F
O
N-(4-Fluorophenyl)-N-phenylacetamide (3u). 1H-NMR (CDCl3): δ 7.40~6.99 (m, 9H),
N
2.06 (s, 3H).
Ph
3u
O
N
N-methyl-N-phenylacetamide (3v). 1H-NMR (CDCl3): δ 7.43 (t, J = 7.2 Hz, 2H), 7.34 (t,
J = 7.2 Hz, 1H), 7.19 (d, J = 4.8 Hz, 2H), 3.27 (s, 3H), 1.87 (s, 3H); EI-MS m/z 149
(M+), 129, 120, 109, 106, 92, 81, 77, 65, 51, 43.
3v
O
N-Cyclohexyl-N-phenylformamide (3w). 1H-NMR (CDCl3): δ 8.42 (s, 0.15H), 8.15 (s,
0.85H), 7.44–7.35 (m, 3H), 7.17–7.13 (m, 2H), 4.44–4.37 (m, 0.85H), 3.65–3.57 (m,
0.15H), 1.92–1.74 (m, 4H), 1.63–1.58 (m, 1H), 1.46–1.23 (m,4H), 1.05–0.95 (m, 1H);
EI-MS m/z 203 (M+), 174, 160, 146, 132, 121, 118, 104, 93, 77, 66, 55, 51, 41.
N
H
3w
4. Conclusions
In conclusion, we have found that CuI/N,N-dimethylglycine is a cheap, efficient and general
catalytic system for the coupling of aryl bromides and amides, allowing for secondary acyclic amides
to serve as substrates, and affording the corresponding products in good to excellent yields at
90–110 °C. A variety of functional groups are tolerated under the reaction conditions. In addition, It
was noteworthy that unreactive, hindered aromatic and aliphatic secondary acyclic amides can also
be efficiently coupled with aryl iodides under the CuI/N,N-dimethylglycine catalyst system. Based
on the advantage of N,N-dimethylglycine which cannot be N-arylated or N-alkylated in the coupling
reaction, the utility of it as a ligand to study other challenging coupling reactions are underway in
our laboratory. (For NMR spectra of Products please see supplementary file).
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/19/9/13448/s1.
Acknowledgments
The author acknowledges support from Dawei Ma’s group and support from the National Science
Foundation of China (21002033). The author acknowledges Dawei Ma permitted Liqin Jiang to
publish this work by herself.
Author Contributions
Liqin Jiang designed and performed experiments and wrote the paper.

Molecules 2014, 19
13458
Conflicts of Interest
The author declares no conflict of interest.
References
1. Muci, A.R.; Buchwald, S.L. Practical Palladium Catalysts for C-N and C-O Bond Formation.
Top. Curr. Chem. 2002, 219, 131–209.
2. Hartwig, J.F. Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.I., Ed.;
Wiley-Interscience: New York, NY, USA, 2002; pp. 1051–1096.
3. Evano, G.; Blanchard, N.; Toumi, M. Copper-mediated coupling reactions and their applications
in natural products and designed biomolecules synthesis. Chem. Rev. 2008, 108, 3054–3031.
4. Monnier, F.; Taillefer, M. Catalytic C-C, C-N, and C-O ullmann-type coupling reactions.
Angew. Chem. Int. Ed. 2009, 48, 6954–6971.
5. Yin, J.; Buchwald, S.L. Pd-catalyzed intermolecular amidation of aryl halides: The discovery that
xantphos can be trans-chelating in a palladium complex. J. Am. Chem. Soc. 2002, 124, 6043–6048.
6. Huang, X.; Anderson, K.W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S.L. Expanding
Pd-catalyzed C-N bond-forming processes: The first amidation of aryl sulfonates, aqueous
amination, and complementarity with Cu-catalyzed reactions. J. Am. Chem. Soc. 2003, 125,
6653–6655.
7. Shen, Q.; Shekhar, S.; Stambuli, J.P.; Hartwig, J.F. Highly reactive, general, and long-lived
catalysts for coupling heteroaryl and aryl chlorides with primary nitrogen nucleophiles.
Angew. Chem. Int. Ed. 2005, 44, 1371–1375.
8. Shen, Q.; Hartwig, J.F. Lewis acid acceleration of C-N bond-forming reductive elimination from
heteroarylpalladium complexes and catalytic amidation of heteroaryl bromides. J. Am. Chem. Soc.
2007, 129, 7734–7735.
9. Ikawa, T.; Barder, T.E.; Biscoe, M.R.; Buchwald, S.L. Pd-catalyzed amidations of aryl chlorides
using monodentate biaryl phosphine ligands: A kinetic, computational, and synthetic investigation.
J. Am. Chem. Soc. 2007, 129, 13001–13007.
10. Jacqueline, D.H.; Hyde, A.M.; Cuezva, A.M.; Buchwald, S.L. Pd-catalyzed N-arylation of
secondary acyclic amides: Catalyst development, scope, and computational study. J. Am. Chem. Soc.
2009, 131, 16720–16734.
11. Klapars, A.; Antilla, J.C.; Huang, X.; Buchwald, S.L. A general and efficient copper catalyst for
the amidation of aryl halides and the N-arylation of nitrogen heterocycles. J. Am. Chem. Soc. 2001,
123, 7727–7729.
12. Klapars, A.; Huang, X.; Buchwald, S.L. A general and efficient copper catalyst for the amidation
of aryl halides. J. Am. Chem. Soc. 2002, 124, 7421–7428.
13. Mallesham, B.; Rajesh, B.M.; Reddy, P.R.; Srinivas, D.; Trehan, S. Highly efficient
CuI-catalyzed coupling of aryl bromides with oxazolidinones using Buchwald’s protocol: A short
route to linezolid and toloxatone. Org. Lett. 2003, 5, 963–965.

Molecules 2014, 19
13459
14. Barros, O.S.D.; Nogueira, C.W.; Stangherlin, E.C.; Menezes, P.H.; Zeni, G. Copper-promoted
carbon-nitrogen bond formation with 2-Iodo-selenophene and amides. J. Org. Chem. 2006, 71,
1552–1557.
15. Padwa, A.; Crawford, K.R. Copper-catalyzed amidation of bromo substituted furans and
thiophenes. Tetrahedron Lett. 2002, 43, 7365–7368.
16. Phillips, D.P.; Hudson, A.R.; Nguyen, B.; Lau, T.L.; McNeill, M.H.; Dalgard, J.E.; Chen, J.H.;
Penuliar, R.J.; Miller, T.A.; Zhi, L. Copper-catalyzed N-arylation of oxindoles. Tetrahedron Lett.
2006, 47, 7137–7138.
17. Kang, S.K.; Kim, D.H.; Park, J.N. Copper-catalyzed N-arylation of aryl iodides with benzamides
or nitrogen heterocycles in the presence of ethylenediamine. Synlett 2002, 427–430.
18. Deng, W.; Wang, Y.F.; Zou, Y.; Liu, L.; Guo, Q.X. Amino acie-mediated Goldberg reactions
between amides and aryl iodides. Tetrahedron Lett. 2004, 45, 2311–2315.
19. Chen, Y.J.; Chen, H.H. 1,1,1-Tris(hydroxymethyl)ethane as a new, efficient, and versatile tripod
ligand for copper-catalyzed cross-coupling reactions of aryl iodides with amides, thiols, and
phenols. Org. Lett. 2006, 8, 5609–5612.
20. Cristau, H.J.; Cellier, P.P.; Spindler, J.F.; Taillefer, M. Highly efficient and mild copper-catalyzed
N- and C-arylations with aryl bromides and iodides. Chem. Eur. J. 2004, 10, 5607–5622.
21. Spindler, J.F.; Cellier, P.P.; Cristau, H.J.; Taillefer, M. Process for Formation of a Carbon-Carbon
or Carbon-Heteroatom Bond. French Patent Application 2859205 A1, 4 March 2005.
22. Racine, E.; Monnier, F.; Vors, J.P.; Taillefer, M. A simple copper-catalyzed synthesis of tertiary
acyclic amides. Org. Lett. 2011, 13, 2818–2812.
23. Lv, X.; Bao, W. A β-Keto ester as a novel, efficient, and versatile ligand for copper(I)-catalyzed
C-N, C-O, and C-S coupling reactions. J. Org. Chem. 2007, 72, 3863–3867.
24. Xu, L.; Jiang, Y.; Ma, D. Synthesis of 3-substituted and 2,3-disubstituted quinazolinones via
Cu-catalyzed aryl amidation. Org. Lett. 2012, 14, 1150–1153.
25. Li, J.; Zhang, Y.; Jiang, Y.; Ma, D. CuI/N,N-dimethylglycine-catalyzed synthesis of
N-aryloxazolidinones from aryl bromides. Tetrahedron Lett. 2012, 53, 3981–3983.
26. Hick, J.D.; Hyde, A.M.; Martinez Cuezva, A.; Buchwald, S.L. Pd-Catalyzed N-Arylation of
Secondary Acyclic Amides: Catalyst Development, Scope, and Computational Study. J. Am.
Chem. Soc. 2009, 131, 16720–16734.
27. Wagner, J.; Wagner, M.L.; Hening, W.A. Beyond benzodiazepines: Alternative pharmacologic
agents for the treatment of insomnia. Ann. Pharmacother. 1998, 32, 680–691.
28. VanBever, W.F.M.; Niemegeers, C.J.E.; Janssen, P.A. Synthetic analgesics. Synthesis and
pharmacology of the diastereoisomers of N-(3-methyl-1-(2-phenylethyl)-4-piperidyl)-N-
phenylpropanamide and N-(3-methyl-1-(1-methyl-2-phenylethyl)-4-piperidyl)-N-phenylpropanamide.
J. Med. Chem. 1974, 17, 1047–1051.
29. Anderson, R.; Hokama, T.; Lee, S.F.; Oey, R.; Elich, T.; Breazeale, S. Preparation of Modulators
of Acetyl Coenzyme A Carboxylase as Fungicides and Pharmaceuticals. U.S. Patent 20080200461,
20 February 2008.
30. Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Chemistry, 3rd ed.; John Wiley &
Sons: New York, NY, USA, 1999; pp. 503–564.

Molecules 2014, 19
13460
31. Jiang, L.; Lu, X.; Zhang, H.; Jiang, Y.; Ma, D. CuI/4-hydro-L-proline as a more effective catalytic
system for coupling of aryl bromides with N-Boc hydrazine and aqueous ammonia. J. Org. Chem.
2009, 74, 4542–4546.
32. Xie, X.; Chen, Y.; Ma, D. Enantioselective arylation of 2-methylacetoacetates catalyzed by
CuI/trans-4-hydroxy-L-proline at low reaction temperatures. J. Am. Chem. Soc. 2006, 128,
16050–16051.
33. Watanabe, M.; Yamamoto, T.; Nishiyama, M. Stabilisation of charge-separated states via gain
of aromaticity and planarity of the donor moiety in C60-based dyads. Chem. Commun. 2000,
133–134.
34. Luker, T.J.; Beaton, H.G.; Whiting, M.; Mete, A.; Cheshire, D.R. Palladium catalysed amination
of electron deficient halothiophenes. Tetrahedron Lett. 2000, 41, 7731–7735.
35. Kauffman, G.B.; Fang, L.Y. Purification of copper(I) iodide. Inorg. Synth. 1983, 22, 101–103.
36. Kitching, M.O.; Hurst, T.E.; Snieckus V. Copper-catalyzed cross-coupling interrupted by an
opportunistic smiles rearrangement: An efficient domino approach to dibenzoxazepinones.
Angew. Chem. Int. Ed. 2012, 51, 2925–2929.
Sample Availability: Not available.
© 2014 by the author; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).