Copper-catalyzed N-arylation of amides using (S)-N-methylpyrrolidine-2- carboxylate as the ligand

Article abstract of DOI:10.3390/molecules15031154

(S)-N-methylpyrrolidine-2-carboxylate, a derivative of natural L-proline, was found to be an efficient ligand for the copper-catalyzed Goldberg-type N-arylation of amides with aryl halides under mild conditions. A variety of N-arylamides were synthesized in good to high yields.

Full text of DOI:10.3390/molecules15031154

Molecules 2010, 15,1154-1160; doi:10.3390/molecules15031154
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Copper-Catalyzed N-Arylation of Amides Using
(S)-N-Methylpyrrolidine-2-carboxylate as the Ligand
Chaoyu Wang 1, 2, Lijuan Liu 1, Wei Wang 1, Dong-Sheng Ma 1 and Hua Zhang 1,*
1
College of Chemical Engineering and Material, Heilongjiang University, Haerbin 150080, China;
E-Mails: wgyxhz@126.com (C.W.); liulijuan1972@yahoo.com.cn (L.L.); dms_70@163.com
(D.M.); amewangwei@yahoo.cn (W.W.)
2
Mudanjiang Normal University, Mudanjiang 157012, China
∗ Author to whom correspondence should be addressed; E-Mail: byzhanghua@yahoo.com.cn;
Tel.: +86-0451-86609936; Fax: +86-0451-86609936.
Received: 23 January 2010; in revised form: 25 February 2010 / Accepted: 2 March 2010 /
Published: 2 March 2010
Abstract: (S)-N-methylpyrrolidine-2-carboxylate, a derivative of natural L-proline, was
found to be an efficient ligand for the copper-catalyzed Goldberg-type N-arylation of
amides with aryl halides under mild conditions. A variety of N-arylamides were
synthesized in good to high yields.
Keywords: copper; (S)-N-methylpyrrolidine-2-carboxylate; arylations; amides
1. Introduction
N-Arylamides are valuable compounds widely employed in the fields of organic synthesis,
pharmaceutical chemistry, or biology [1–3]. One of the most common synthetic protocols for their
preparation is the copper-catalyzed Ullmann reaction [4] and the related Goldberg reaction
(copper-catalyzed N-arylation of amides) [5]. However, classic Ullmann reactions are usually
conducted under harsh conditions, and therefore their applications would be restricted. In recent years,
some efficient ligands [6–9] have been disclosed for copper-catalyzed N-arylation under mild
conditions including diamines [10–12], diimines [13], amino acids [14,15], β-keto esters [16], and
diols [17]. Some ligand-free Ullmann-type coupling reactions have also been reported [18–22].
However, it is well accepted that some reactions require 10 mol% of copper as a catalyst and long

Molecules 2010, 15
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reaction times for the reaction to proceed accordingly. We now report the use of (S)-N-
methylpyrrolidine-2-carboxylate (Figure 1), a derivative of natural L-proline, as the ligand of 5 mol %
copper catalyst in the N-arylation of amides. Satisfactory results were obtained under mild conditions
and short reaction time.
Figure 1. (S)-N-methylpyrrolidine-2-carboxylate (ligand).
COOCH3
(S)
N
CH3
( L )
Table 1. Optimization of reaction conditions for N-phenylation of 2-pyrrolidone.
CuI(5 mol%),ligand
N
Ph
HN
O
PhX
base,solvent, Ar
O
a
Temperature
(°C)
110
Time
Yield
(%)
10
13
60
61
63
66
76
76
75
62
15
90
90
11
3
Entry
Substrate Ligand
Base
Solvent
(h)
5
1
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhBr
PhCl
L
L
L
L
L
L
L
L
L
L
-
KOt-Bu DMF
2
KOH DMF
Cs2CO3 DMF
K2CO3 DMF
Na2CO3 DMF
110
5
3
110
5
4
110
5
5
110
5
6
Li2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
DMF
110
5
7
DMF
110
5
8
DMF
110
7
9
DMF
120
5
10
11
12
13
14
15
DMF
90
5
DMF
110
5
L
L
L
L
DMSO
DMSO
DMSO
DMSO
110
5
110
7
110
5
110
5
2. Results and Discussion
The ligand (S)-N-methylpyrrolidine-2-carboxylate was synthesized according to the reported
procedure [23]. Initially, we tried to seek the optimal reaction conditions for copper-catalyzed
N-arylation of amides. Aryl halides and 2-pyrrolidone were chosen as the model substrates with
5 mol % of CuI as a catalyst under an argon atmosphere at 110 °C (Table 1). In the presence of
(S)-N-methylpyrrolidine 2-carboxylate as a ligand and DMF as a solvent, K3PO4 was found to be the
most appropriate base, 110 °C to be the most appropriate reaction temperature, and 5 hours to be the
most appropriate reaction time (entries 1–10). Without using the ligand, the yield was greatly
decreased (entry 11). The effect of various aryl halides and solvents was investigated (entries

Molecules 2010, 15
1156
7,12,14,15). The use of aryl iodides as substrate and DMSO as a solvent led to a best result for this
reaction (entry 12). Based on those results, the effect of Goldberg-type N-arylations of various amides
with various aryl iodides was investigated (entries 1–11, Table 2). Using 4-substituted aryl iodides led
to good yields of the desired products (entries 1–4). Moreover, 2-iodotoluene and 1-iodonaphthalene
also led to good yields (entries 5,6).
Table 2. Copper-catalyzed N-arylations of amides with aryl iodides.
R2
R2
I
N
O
CuI(5 mol%), ligand (10 mol%)
K3PO4 (1equiv),DMSO(1M)
110℃, 5 h
O
HN
R1
R3
1.2equiv
R3
b-n
R1
Entry
Aryl iodide
Amide
Products
Yield (%)a
HN
H3COC
I
Ac
N
O
1
90
b
O
HN
F3C
N
2
3
89
93
F3C
H3C
I
I
O
c
O
HN
H3C
N
O
O
d
HN
4
5
88
89
H3CO
Br
I
H3CO
N
O
O
e
HN
I
Br
N
O
O
f
HN
6
5
85
86
MeOOC
N
O
MeOOC
I
g
O
CH3
HN
I
N
O
CH3
O
h
HN
O
N
6
93
I
O
i
7
8
81
79
N
O
N
I
HN
O
CH3
HN
j
CH3
O
I
H3C
O
k
H3C
Ph
Ph
9
75
I
N
HN
O
O
H3C
NH
H3C
l
H2N
10
76 (10 b)
I
O
O
H3C
H3C
m

Molecules 2010, 15
1157
Table 2. Cont.
H2N
11
NH
Ph
80 (11 b)
I
O
O n
Ph
Note: a Isolated yield, b bisphenylated yield.
The N-phenylation of various amides gave the corresponding products with moderate to good
yields (entries 7–11). In the reaction of acetamide, bisphenylation product was obtained accompanying
the corresponding product (entries 10–11, Table 2).
3. Experimental
3.1. General
All starting compounds were used as received from commercial sources without further
purification. Petroleum ether (PE) used had the boiling range 60–90 °C. Melting points were
determined on a XRC-1 micromelting point apparatus and are uncorrected. Column chromatography
was carried out on silica gel (200–300 mesh, Qingdao Haiyang Chemical Co., Ltd.). NMR spectra were
recorded at 300 MHz (1H) and 75 MHz (13C) in CDCl3 on a Bruker Avance 300 spectrometer with
TMS as internal standard. MS spectra measurements were carried out on a Finnigan LCQDECA mass
spectrometer (ESI-MS) and a BioTOF-Q mass spectrometer (HR-ESI-MS).
3.2. General procedure for copper-catalyzed N-arylations of amides with aryl iodides
Under an atmosphere of Ar, aryl iodide (12 mmol) was added to the mixture of amide (10 mmol),
K3PO4 (10 mmol), ligand (1 mmol), and CuI (0.5 mmol) in DMSO (10 mL) at r.t. The mixture was
stirred at 110 °C. After 5 h, the mixture was cooled to r.t. diluted with EtOAc, and filtered through
Celite, eluting with additional EtOAc. The filtrate was concentrated under reduced pressure, and the
resulting residue was purified by silica gel chromatography using a mixture of hexane and EtOAc as
eluent. All prepared compounds a-n are known and identified by 1H- and 13C-NMR and MS.
1-Phenylpyrrolidin-2-one (a): mp 68–69 °C. 1H-NMR: δ = 2.12 (m, 2H), 2.45 (t, J = 7.5 Hz, 2H), 3.31
13
(t, J = 7.1 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 7.21 (m, 1H), 7.46 (m, 2H). C NMR: δ = 18.1, 32.7,
49.1, 122.1, 125.3, 131.2, 142.5, 175.3. MS (EI): m/z = 161 (100) [M+]. HRMS: m/z calcd for
C10H11NO: 161.2005; found: 161.2013.
1-(4-Acetylphenyl)pyrrolidin-2-one (b): mp 91–93 °C. 1H-NMR: δ = 2.16 (m, 2H), 2.38 (t, J = 6.5 Hz,
2H), 2.56 (s, 3H), 3.45 (t, J = 6.8 Hz, 2H), 7.62 (d, J = 7.6 Hz, 2H), 8.10 (d, J = 8.7 Hz, 2H).
13C- NMR: δ = 17.1, 30.3, 32.5, 48.6, 122.3, 129.8, 133.1, 146.6, 175.2, 197.6. MS (EI): m/z = 203
(100) [M+]. HRMS: m/z calcd for C12H13NO2: 203.2372; found: 203.2365.
1
1-(4-Trifluoromethylphenyl)pyrrolidin-2-one (c): mp 86–88 °C. H-NMR: δ = 2.15 (m, 2H), 2.58 (t,
J = 7.3 Hz, 2H), 3.32 (t, J = 7.6 Hz, 2H), 7.00 (d, J = 7.2 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H). 13C-NMR:
δ = 18.5, 33.6, 48.9, 122.1, 123.5, 125.0, 127.6, 147.5, 175.8. MS (EI): m/z = 229 (100) [M+]. HRMS:
m/z calcd for C11H10F3NO: 229.1984; found: 229.1976.

Molecules 2010, 15
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1
1-(4-Methylphenyl)pyrrolidin-2-one (d): mp 73.5–75.1 °C. H-NMR: δ = 2.13 (m, 2H), 2.38 (s, 3H),
2.56 (t, J = 7.0 Hz, 2H), 3.21 (t, J = 6.3 Hz, 2H), 6.89 (d, J = 7.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H).
13C-NMR: δ = 17.6, 24.9, 33.1, 49.2, 122.1, 130.5, 134.7, 139.2, 175.8. MS (EI): m/z = 175 (100)
[M+]. HRMS: m/z calcd for C11H13NO: 175.2271; found: 175.2262.
1
1-(4-Methoxyphenyl)pyrrolidin-2-one (e): mp 89.5–91.0 °C. H-NMR: δ = 2.15 (m, 2H), 2.55 (t,
J = 7.6 Hz, 2H), 3.23 (t, J = 7.3 Hz, 2H), 3.71 (s, 3H), 3.806.80 (d, J = 7.6 Hz, 2H), 7.05 (d, J = 8.2
13
Hz, 2H). C-NMR: δ = 17.5, 32.6, 48.7, 56.2, 114.8, 122.1, 135.6, 156.9, 175.2. MS (EI): m/z = 191
(100) [M+]. HRMS: m/z calcd for C11H13NO2: 191.2265; found: 191.2261.
1
1-(4-Bromophenyl)pyrrolidin-2-one (f): mp 99.5–101.0 °C. H-NMR: δ = 2.20 (m, 2H), 2.50 (t,
J = 7.2 Hz, 2H), 3.34 (t, J = 7.4 Hz, 2H), 6.83 (d, J = 7.5 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H). 13C-NMR:
δ = 17.6, 33.2, 48.0, 118.1, 124.1, 132.4, 142.9, 175.0. MS (EI): m/z = 239 (100) [M+]. HRMS: m/z
calcd for C10H10BrNO: 238.9912; found: 238, 9908.
1
Methyl 4-(2-oxopyrrolidin-1-yl)benzoate (g): mp 80.5–82.0 °C. H-NMR: δ = 2.21 (m, 2H), 2.61 (t,
J = 7.0 Hz, 2H), 3.38 (t, J = 7.5 Hz, 2H), 3.91 (s, 3H), 6.83 (d, J = 7.6 Hz, 2H), 7.76 (d, J = 8.0 Hz,
2H). 13C-NMR: δ = 17.0, 33.2, 49.2, 52.3, 122.8, 126.2, 131.1, 147.2, 167.2, 175.3. MS (EI): m/z = 219
(100) [M+]. HRMS: m/z calcd for C12H13NO2: 219.0915; found: 219.0906.
1
1-(2-Methylphenyl)pyrrolidin-2-one (h): mp 74–75.2 °C. H-NMR: δ = 2.12 (m, 2H), 2.31 (t, J = 7.6
Hz, 2H), 2.38 (s, 3H), 3.42 (t, J = 7.4 Hz, 2H), 6.90 (d, J = 7.2 Hz, 1H), 7.00-7.21 (m, 3H). 13C-NMR:
δ =14.8, 17.3, 33.5, 48.0, 122.3, 124.5, 126.3, 131.7, 134.0, 139.7, 175.2. MS (EI): m/z = 175 (100)
[M+]. HRMS: m/z calcd for C11H13NO: 175.2271; found: 175.2265.
1
1-(Naphthalen-1-yl)pyrrolidin-2-one (i): mp 87.5–89.0 °C. H-NMR: δ = 2.05 (m, 2H), 2.34 (t,
13
J = 7.5 Hz, 2H), 2.71 (t, J = 7.6 Hz, 2H), 6.50 (d, J = 6.8 Hz, 1H), 7.10–7.66 (m, 6H). C-NMR:
δ =17.6, 33.5, 49.6, 110.2, 119.3, 121.6, 124.0, 124.9, 126.1, 126.9, 129.0, 135.1, 143.2, 176.2.
MS (EI): m/z = 211 (100) [M+]. HRMS: m/z calcd for C14H13NO: 211.2592; found: 211.2590.
1
1-Phenylpiperidin-2-one (j): mp 71.3–72.1 °C. H-NMR: δ = 1.47 (m, 2H), 1.72 (m, 2H), 2.67 (t,
13
J = 7.6 Hz, 2H), 3.36 (t, J = 7.2 Hz, 2H), 7.12 (d, J = 7.4 Hz, 2H), 7.22–7.40 (m, 3H). C-NMR:
δ = 23.1, 27.1, 34.2, 49.1, 122.3, 123.8, 129.6, 142.5, 170.2. MS (EI): m/z = 175 (100) [M+]. HRMS:
m/z calcd for C11H13NO: 175.2271; found: 175.2272.
1
N-Methyl-N-phenylacetamide (k): mp 100–101 °C. H-NMR: δ = 2.36 (s, 3H), 2.83 (s, 3H) 7.11 (d,
13
J = 7.3 Hz, 2H), 7.26–7.38 (m, 3H). C-NMR: δ =21.2, 33.0, 122.6, 124.8, 129.8, 142.5, 171.3. MS
(EI): m/z = 149 (100) [M+]. HRMS: m/z calcd for C9H11NO: 149.1898; found: 149.1893.
1
N, N-Diphenylacetamide (l): mp 101–103 °C. H-NMR: δ = 2.43 (s, 3H), 7.01–7.32 (m, 6H) 7.69 (d,
J = 7.2 Hz, 4H). 13C-NMR: δ =21.2, 118.8, 119.6, 130.1, 141.3, 173.4. MS (EI): m/z = 211 (100) [M+].
HRMS: m/z calcd for C14H13NO: 211.2592; found: 211.2597.

Molecules 2010, 15
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1
N-Phenylacetamide (m): mp 155–156 °C. H-NMR: δ = 2.33 (s, 3H), 7.11–7.32 (m, 3H) 7.66 (d,
J = 7.4 Hz, 4H), 9.12 (s, 1H). 13C-NMR: δ =23.1, 122.3, 124.7, 130.2, 140.0, 168.2. MS (EI):
m/z = 135 (100) [M+]. HRMS: m/z calcd for C8H9NO: 135.1632; found: 135.1621.
N-Phenylbenzamide (n): mp 163–164.5 °C. 1H-NMR: δ = 6.92–7.30 (m, 3H), 7.40–7.58 (m, 3H), 7.70
13
(d, J = 7.2 Hz, 2H), 7.91 (d, J = 7.4 Hz, 2H). 9.01 (s, 1H). C-NMR: δ = 120.5, 123.2, 127.5, 129.1,
132.8, 134.6, 135.2, 166.5. MS (EI): m/z = 197 (100) [M+]. HRMS: m/z calcd for C13H11NO:
197.08646; found: 197.0841.
4. Conclusions
In summary, we have developed a simple and highly efficient ligand, (S)-N-methylpyrrolidine-2-
carboxylate, that can promote the copper-catalyzed Goldberg-type N-arylation of amides with aryl
iodides. Further work is in progress to examine its catalytic activity in other copper-catalyzed organic
transformations.
Acknowledgments
This work was supported by grants from Youth Fund of Education Department of Heilongjiang
Province (11531279), Youth Fund of Science and Technology Department of Heilongjiang
Province (QC07C65), and Technological Innovation Fund of Harbin Municipal Science and
Technology Bureau (2008RFQXS106).
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Sample Availability: Samples of the compounds are available from the authors.
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