Copper-catalyzed N-arylation of aryl iodides with benzamides or nitrogen heterocycles in the presence of ethylenediamine

Article abstract of DOI:10.1055/s-2002-20457

The copper-catalyzed N-arylation of benzamides or nitrogen heterocycles was carried out with catalytic CuI (10 mol%) in the presence of ethylenediamine (10 mol%) as a ligand and K₃PO₄ or Cs₂CO₃ as a base under mild conditions.

Full text of DOI:10.1055/s-2002-20457

LETTER
427
Copper-catalyzed N-Arylation of Aryl Iodides with Benzamides or Nitrogen
Heterocycles in the Presence of Ethylenediamine
C
opper-Cataly
u
zed
N
-Aryla
k
tion of
A
ryl
-
I
odides Ku Kang,* Doo-Hwan Kim, Joung-Nam Park
Department of Chemistry and Lab for Metal-Catalyzed Reactions, Sungkyunkwan University, Suwon 440-746, Korea
E-mail: skkang@chem.skku.ac.kr
Received 7 December 2001
Table 1 N-Arylation of 2-Iodothiophene (1a) with 2-Pyrrolidinone
(2a)
Abstract: The copper-catalyzed N-arylation of benzamides or ni-
trogen heterocycles was carried out with catalytic CuI (10 mol%) in
the presence of ethylenediamine (10 mol%) as a ligand and K3PO4
or Cs2CO3 as a base under mild conditions.
Entry Lignad
Base
Solvent
Isolated
(10 mol %)
Yield (%)
Key words: copper-catalyst, N-arylation, benzamides, nitrogen
heterocycles
1
2
3
ethylenediamine
ethylenediamine
K3PO4
K3PO4
dioxane
CH3CN
dioxane
95
95
94
1,3-propylenedi- Cs2CO3
amine
Recently Buchwald, Hartwig and others have developed
valuable and new palladium-catalyzed N-arylation of aryl
halides and amines to form arylamines, which supplanted
the classical Ullmann coupling reaction.1 The reactions
can be carried out at a lower temperature under milder
conditions than the copper-mediated classical Ullmann
condensation.2 Ma et al.3 reported the CuI-catalyzed N-
arylation of a certain type of -amino acid with aryl ha-
lides at 90 °C in DMF. Subsequently, copper-catalyzed
amination was achieved by adding 1,10-phenanthroline as
a ligand to conduct coupling at lower temperature than the
classical Ullmann condensation.4 Recently Buchwald et
al.5 demonstrated CuI-catalyzed N-arylation of aryl ha-
lides with nitrogen heterocycles utilizing racemic trans-
1,2-cyclohexanediamine as a ligand under mild condi-
tions. In connection with our programs to utilize CuI cat-
alyzed carbon-carbon bond formations,6 we have
explored the CuI-catalyzed N-arylation of benzamides
and heterolytic amines using ethylenediamine (10 mol%)
as a simple ligand in the presence of CuI (10 mol%). To
find optimum conditions a series of experiments has been
performed with 2-iodothiophene (1a) and pyrrolidinone
(2a) as model compounds (Scheme), which are summa-
rized in Table 1. Of the ligands tested ethylenediamine,
1,3-propylenediamine, TMEDA, and 1,2-benzen- di-
amine, ethylenediamine were the best choice. As a base
K3PO4 or Cs2CO3 was suitable. As a solvent dioxane was
better than other solvents even if sometimes CH3CN was
more suitable.
4
5
TMEDA
Cs2CO3
Cs2CO3
dioxane
dioxane
61
70
1,2-benzenedi-
amine
6
7
8
9
ethylenediamine
ethylenediamine
ethylenediamine
ethylenediamine
Cs2CO3
K3PO4
K3PO4
K3PO4
dioxane
dioxane
NMP
78
47
40
20
toluene
The N-arylation of aryl iodides with benzamides and ni-
trogen heterocycles was very sensitive to the substrates
and reaction conditions and the results were summarized
in Table 2. 2-Iodothiophene (1a) reacted with pyrrolidi-
none (2a) using CuI (10 mol%) ethylenediamine (10
mol%) as a ligand in dioxane at reflux in the presence of
K3PO4 for 24 h to afford the N-arylation product 3a in
95% yield (entry 1 in Table 2). However with oxazolidone
as a nitrogen heterocycles under the same conditions the
N-substituted oxazolidinone 3b7 was obtained in 59%
yield (entry 2).
With benzamide 2c as the substrate the coupling product
3c5 was afforded in only 41% yield (entry 3). Employing
2-nitrobenzamide (2d) as an amide the coupled benza-
mide (3d) was afforded in 52% yield (entry 4). When 3,5-
dimethyliodobenzene (1b) was treated with indole (2e) N-
aryl-substituted indole 3e5 was obtained in 96% yield uti-
lizing Cs2CO3 as a base (entry 5). The pyrrole (2f) was re-
acted under the same conditions with 1b to provide N-
aryl-substituted pyrrole 3f5 in 87% yield (entry 6). For
pyrrolidinone (2a) with 3,5-dimethyliodobenzene (1b)
using Cs2CO3 as a base the arylated product 3g5 was pro-
vided in 68% yield (entry 7). Although the coupling reac-
tion of 3,5-dimthyliodobenzene (1b) with benzamide
gave the coupled product in a very low (20%) yield, it is
notable that 2-nitro-substituted benzamide 2d smoothly
O
O
CuI (10 mol %)
N
HN
+
I
S
S
Ligand (10 mol %)
reflux, 24 h
1a
Scheme
Synlett 2002, No. 3, 04 03 2002. Article Identifier:
2a
3a
1437-2096,E;2002,0,03,0427,0430,ftx,en;Y24201ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

428
S.-K. Kang et al.
LETTER
coupled with 1b to provide 3h in a good (88%) yield (en- were coupled with p-methoxyiodobenzene (1c) afforded
try 8) presumably because of electronic effect. According- 3k9 and 3l10 in 45% and 60% isolated yields, respectively
ly picolinamide (2g) was also coupled with 1b to give 3i (entries 11 and 12). This coupling was applied to 2-ni-
in 50% isolated yield (entry 9). When p-methoxyiodoben- trobenzamide (2d), 4-nitrobenzamide (2h), and picolina-
zene (1c) was employed as a substrate for aryl iodides N- mide (2i), the N-arylated products 3m, 3n, and 3o were
arylation of pyrrolidine afforded 3j8 in 85% yield (entry afforded in moderate yields (entries 13–15).
10). However oxazolidinone (2b) and benzamide (2c)
Table 2 The Copper-catalyzed N-Arylation Iodides with Benzamides and Nitrogen Heterocycles
Entry
1
Ioiodides
Heterocycles or
Benzamides
Base
Products
Isolated Yield (%)
95
K3PO4
O
O
O
I
S
HN
N
N
S
1a
1a
2a
3a
2
3
K3PO4
K3PO4
59
41
O
HN
O
O
S
2b
3b
1a
1a
O
O
O
H2N
N
H
S
2c
3c
4
5
K3PO4
52
96
NO2
NO2
O
N
H2N
H
S
3d
2d
Cs2CO3
I
HN
N
2e
1b
1b
3e
3f
6
7
8
K3PO4
Cs2CO3
K3PO4
87
68
88
HN
N
2f
1b
1b
O
O
HN
N
2a
3g
NO2
NO2
O
O
O
O
H2N
N
H
2d
3h
3i
9
1b
K3PO4
50
N
N
H2N
N
H
2g
Synlett 2002, No. 3, 427–430 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Copper-catalyzed N-Arylation of Aryl Iodides
429
Table 2 The Copper-catalyzed N-Arylation Iodides with Benzamides and Nitrogen Heterocycles (continued)
Entry
10
Ioiodides
Heterocycles or
Benzamides
Base
Products
Isolated Yield (%)
K3PO4
85
O
O
O
MeO
I
HN
MeO
N
N
1c
2a
3j
11
12
1c
1c
K3PO4
K3PO4
45
O
MeO
O
HN
O
2b
3k
60
61
O
O
H2N
MeO
N
H
2c
3l
13
1c
K3PO4
O
NO2
NO2
O
MeO
3m
N
H2N
H
2d
14
15
1c
1c
K3PO4
K3PO4
67
59
O
O
O
H2N
MeO
N
H
NO2
NO2
2h
H2N
2i
3n
O
N
N
MeO
3o
N
H
Typical Procedure:
(2) Lindley, J. Tetrahedron 1984, 40, 1433.
(3) Ma, D.; Zhang, Y.; Yao, J.; Wa, S.; Tao, F. J. Am. Chem.
Soc. 1998, 120, 12459.
(4) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron
Lett. 1999, 40, 2657.
(5) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727.
(6) (a) Kang, S.-K.; Yamaguchi, T.; Kim, T.-H.; Ho, P.-S. J.
Org. Chem. 1996, 61, 9082. (b) Kang, S.-K.; Kim, J.-S.;
Choi, S.-C. J. Org. Chem. 1997, 62, 4208. (c) Kang, S.-K.;
Lee, S.-H.; Lee, D. Synthesis 2000, 1022. (d) Kang, S.-K.;
Yoon, S.-K.; Kim, Y.-M. Org. Lett. 2001, 3, 2697.
(7) Selected physical and spectral data are as follows. 3b: mp 88
°C (hexane–ethyl acetate). 1H NMR (500 MHz, CDCl3,
ppm) 6.90 (1 H, dd, J = 5.5 and 1.5 Hz), 6.85 (1 H, dd, J =
5.5 and 3.7 Hz), 6.45 (1 H, dd, J = 3.7 and 1.5 Hz), 4.50 (2
H, m), 4.00 (2 H, m). 13C NMR (125 MHz, CDCl3, ppm)
154.62, 140.33, 124.65, 118.13, 110.93, 62.21, 46.03. IR
(KBr, cm–1): 1726, 1545, 1483, 1035. HRMS: calcd for
C7H7NO2S: 169.0197, found: 169.0194.
To a stirred solution of 2-pyrrolidinone (2a) (102 mg, 1.20 mmol)
and 2-iodothiophene (1a) (210 mg, 1.00 mmol) in 1,4-dioxane (2
mL) under argon atmosphere were added CuI (19 mg, 10 mol%),
and ethylenediamine (6.7 L, 10 mol%) followed by K3PO4 (652
mg, 2.00 mmol) and stirred at 110 °C for 24 h. The reaction mixture
was filtered and the filtrate was concentrated in vacuo. The crude
product was separated on SiO2 column chromatography using
EtOAc and hexane (1: 1) as eluents to afford the coupled product
3a5 (158 mg, 95%) as white needles.
In summary, the CuI (10 mol%) catalyzed N-arylation of some ben-
zamides or nitrogen nucleophiles was carried out in the presence of
ethylenediamine (10 mol%) and base under mild conditions.
Acknowledgement
Generous financial support by NRL program administrated by Mi-
nistry of Science and Technology and KOSEF-CMDS is gratefully
acknowledged. D.-H. Kim and J.-N. Park thank for the financial
supports by BK21 programs.
3d: mp 196 °C (hexane–ethyl acetate). 1H NMR (500 MHz,
CDCl3, ppm) 8.15 (1 H, m), 7.88 (1 H, m), 7.78 (2 H, m),
7.06 (1 H, dd, J = 5.5 and 1.5 Hz), 6.91 (1 H, dd, J = 5.5 and
3.7 Hz), 6.78 (1 H, dd, J = 3.7 and 1.5 Hz). 13C NMR (125
MHz, CDCl3, ppm) 162.83, 147.69, 140.22, 134.88,
132.29, 131.95, 130.30, 125.08, 118.60, 113.18. IR (KBr,
cm–1): 3235, 3118, 2888, 1636, 1574, 1527, 1354. HRMS:
calcd for C11H8N2O3S: 248.0256, found: 248.0254.
3h: mp 162 °C (hexane–ethyl acetate). 1H NMR (500 MHz,
References
(1) Reviews: (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805.
(b) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 853. (c) Yang,
B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125.
Synlett 2002, No. 3, 427–430 ISSN 0936-5214 © Thieme Stuttgart · New York

430
S.-K. Kang et al.
LETTER
CDCl3, ppm) 8.13 (1 H, d, J = 8.8 Hz), 7.74 (1 H, m), 7.64
(2 H, m), 7.38 (1 H, s), 7.23 (1 H, s), 6.84 (1 H, s), 2.33 (6 H,
s). 13C NMR (125 MHz, DMSO-d6, ppm) 164.85, 147.36,
139.67, 138.68, 134.92, 133.69, 131.74, 130.12, 126.32,
125.09, 118.29, 21.96. IR (KBr, cm–1): 3256, 1657, 1523,
1350, 836. HRMS: calcd for C15H14N2O3: 270.1004, found:
270.1007.
3n: mp 192 °C (hexane–ethyl acetate). 1H NMR (500 MHz,
DMSO-d6, ppm) 10.46 (1 H, s), 8.37 (2 H, d, J = 9.2 Hz),
8.17 (2 H, d, J = 9.2 Hz), 7.68 (2 H, d, J = 9.2 Hz), 6.95 (2
H, d, J = 9.2 Hz), 3.75 (3 H, s). 13C NMR (125 MHz, DMSO-
d6, ppm) 164.23, 156.75, 149.91, 141.57, 132.61, 129.95,
124.38, 122.94, 114.69, 56.05. IR (KBr, cm–1): 3295, 2951,
1648, 1527, 1342. HRMS: calcd for C14H12N2O4: 272.0797,
found: 272.0793.
3i: mp 80 °C (pentane–ether). 1H NMR (500 MHz, CDCl3,
ppm) 9.95 (1 H, s), 8.61 (1 H, m), 8.23 (1 H, m), 7.91 (1 H,
m), 7.48 (1 H, m), 7.44 (2 H, s) 6.80 (1 H, s) 2.34 (6 H, s).
13C NMR (125 MHz, CDCl3, ppm) 162.31, 150.40, 148,36,
139.21, 138.08, 138.00, 126.77, 126.52, 122.78, 117.87,
21.85. IR (KBr, cm–1): 3341, 2913, 1683, 1540, 1458.
HRMS: calcd for C14H14N2O: 226.1106, found: 226.1117.
3m: mp 154 °C (methylene chloride). 1H NMR (500 MHz,
CDCl3, ppm) 10.53 (1 H, s), 8.13 (2 H, d, J = 8.1 Hz), 7.86
(2 H, m), 7.75 (2 H, m), 7.57 (2 H, d, J = 8.8 Hz), 6.94 (2 H,
d, J = 8.8 Hz) 3.74 (3 H, s). 13C NMR (125 MHz, CDCl3,
ppm) 164.49, 156.61, 147.48, 134.84, 133.65, 132.83,
131.72, 130.14, 125.09, 122.11, 114.82, 56.08. IR (KBr,
cm–1): 3263, 1650, 1532, 1350, 1251. HRMS: calcd for
C14H12N2O4: 272.0797, found: 272.0793.
3o: mp 90 °C (hexane–ethyl acetate). 1H NMR (500 MHz,
DMSO-d6, ppm) 10.54 (1 H, s), 8.73 (1 H, m), 8.14 (1 H,
m), 8.01 (1 H, m), 7.81 (2 H, d, J = 8.8 Hz), 7.66 (1 H, m)
6.93 (2 H, d, J = 8.8 Hz), 3.75 (1 H, m). 13C NMR (125 MHz,
DMSO-d6, ppm) 163.09, 156.65, 150.64, 149.32, 138.98,
132.05, 127.68, 123.06, 122.76, 114.72, 56.05. IR (KBr,
cm–1): 3263, 1650, 1532, 1350, 1251. HRMS: calcd for
C13H12N2O2: 228.0899, found: 228.0897.
(8) Duplantier, A. J.; Andresen, C. J.; Cheng, J. B.; Cohan, V.
L.; Decker, C. J. Med. Chem. 1998, 41, 2268.
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Chem. 1971, 36, 3071.
(10) Pai, S. G.; Bajpai, A. R.; Deshpande, A. B.; Samant, S. D.
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Synlett 2002, No. 3, 427–430 ISSN 0936-5214 © Thieme Stuttgart · New York