New ligands for copper-catalyzed C-N coupling reactions with aryl halides

Article abstract of DOI:10.1016/j.tetlet.2012.10.083

2-Carbomethoxy-3-hydroxyquinoxaline-di-N-oxide was identified as an efficient novel ligand for the copper-catalyzed coupling reactions of aryl iodides, bromides, and chlorides with aliphatic amines and N-containing heterocycles under mild conditions. The catalytic system showed great functional-group tolerance and excellent chemoselectivity. 7copy; 2012 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.tetlet.2012.10.083

Tetrahedron Letters 53 (2012) 7121–7124
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New ligands for copper-catalyzed C–N coupling reactions with aryl halides
Dong Chen a,b, , Kai Yang b, , Hua Xiang a, , Sheng Jiang b,
⇑
⇑
a Department of Medicinal Chemistry, College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
b Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, CAS, Guangzhou 510530, China
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Carbomethoxy-3-hydroxyquinoxaline-di-N-oxide was identified as an efficient novel ligand for the
copper-catalyzed coupling reactions of aryl iodides, bromides, and chlorides with aliphatic amines and
N-containing heterocycles under mild conditions. The catalytic system showed great functional-group
tolerance and excellent chemoselectivity.
Received 27 August 2012
Revised 15 October 2012
Accepted 18 October 2012
Available online 26 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
C–N coupling reactions
Copper
Cross-coupling
2-Carbomethoxy-3-hydroxyquinoxaline-di-
N-oxide
Ullmann reactions
Since their discovery 100 years ago, Ullmann-type N-arylations,
as important tools for modern organic synthesis, have been in-
volved in a wide variety of natural product syntheses and numer-
ous industrial applications, such as the syntheses of intermediates
and synthetic targets in the life science and polymer industries.1 Li-
gand identification is important in improving reaction efficiency
and generality during the development of copper-catalyzed Ull-
mann coupling reaction. Several classes of coordination ligands,
such as diols,2 bisamines,3 amino acids,4 amino alcohols,5 phos-
phoramidites,6 oxime-phosphine oxides,7 8-hydroxyquinolin-N-
oxide,8 and b-diketones and b-keto esters,9 have been recently re-
ported to promote the copper-catalyzed Ullmann C–N coupling
reaction.10 However, significant challenges remain to be overcome
in this area. For example, the use of aryl chlorides is desirable in
Ullmann C–N coupling reactions to reduce costs, but most ligands
fail to catalyze the reactions involving aryl chloride.
The copper-catalyzed coupling of both aliphatic amines and N-
containing heterocycles with aryl chlorides is quite difficult be-
cause of the need for harsh reaction conditions, limited range of
suitable substrates, low selectivity, and only moderate yields.11
To the best of our knowledge, only one ligand can be used to pro-
mote copper-catalyzed N-arylations with aryl chlorides in cross-
coupling reactions.8 Thus, identification of new and general ligands
for copper-catalyzed cross-coupling reactions of aryl chlorides is
necessary.
We presumed that 2-carbomethoxy-3-hydroxyquinoxaline-di-
N-oxide (L1) might form transitional 6-membered and 5-mem-
bered rings with the Cu ion (Fig. 1). In this study, 2-carbome-
thoxy-3-hydroxyquinoxaline-di-N-oxide (L1) was designed as a
novel potential tetradentate ligand to improve Cu-catalyzed C–N
bond forming reactions of aryl halides with aliphatic amines and
N-heterocyclic substrates.
The reaction of benzylamine with 4-methyl iodobenzene was
initially chosen as a model reaction for the reaction condition opti-
mization, as described in Table 1. 2-Carbomethoxy-3-hydroxyqui-
noxaline-di-N-oxide (L1) can successfully promote the Cu-
catalyzed coupling reaction with high yield (83%). Interestingly,
2-carbomethoxy-3-hydroxyquinoxaline (L2) showed much lower
efficiency due to the absence of two oxygen atoms (entry 1). After
evaluation of the catalytic efficiency of L1 and L2, several bases
were screened using the same model substrates and supporting li-
gand; cesium carbonate (Cs2CO3) exhibited the best result among
O
N
O
O
1
N
N
OCH3
OH
OCH3
OH
2
N
O
3
4
⇑
Corresponding authors. Tel.: +86 20 32015318; fax: +86 20 32290439.
E-mail addresses: cpuxianghua@sina.com (H. Xiang), jiang_sheng@gibh.ac.cn (S.
L1
L2
Jiang).
These authors contributed equally to the work.
Figure 1. Structures of the designed ligands.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.083

7122
D. Chen et al. / Tetrahedron Letters 53 (2012) 7121–7124
Table 1
a
Designed ligands for the copper-catalyzed C–N coupling reaction
10 mol% CuI
20 mol% Ligand
Base (2.0 equiv)
I
H2N
+
N
H
Ar, Solvent, 65°C,12 h
3a
2a
1a
Entry
Ligand
Base
Solvent
Yield (%)b
1
2
4
5
6
7
L2
L1
L1
L1
L1
L1
Cs2CO3
Cs2CO3
K2CO3
NEt3
K3PO4
Cs2CO3
DMF
DMF
DMF
DMF
DMF
DMSO
52
83
39
7
28
69
a
Compound 1a (1.0 mmol), 2a (1.5 mmol), 10 mol % CuI, 20 mol % ligand, base (2.0 mmol), solvent (2 mL), Ar, 65 °C, 12 h.
Isolated yield.
b
Table 2
CuI-Catalyzed Amination of Aryl Iodides
10 mol% CuI
20 mol% L2
I
NR1R2
+
HNR1R2
R
R
2.0 equiv Cs2CO3
DMF, 65 °C
2
3
1
a
Entry
1
Product
Time (h)
Yieldb (%)
Entry
7
Product
Time (h)
24
Yieldb (%)
HN
N
12
83
80
3g
3a
H
N
N
2
3
4
18
18
10
78
85
92
8
9
25
20
83
97
3b
3h
H
N
N
EtO2C
3c
3i
H
H
N
N
10
11
18
18
94
90
COOH
O2N
O2N
3d
3j
H
N
H
N
5
6
15
18
93
93
HO
3e
COOH
O2N
3k
H
N
HO
3f
a
Reaction conditions: ArI (1.0 mmol), amine (1.5 mmol), CuI (0.10 mmol, 10 mol %), and L2 (0.2 mmol, 20 mol %) in 2.0 mL of DMF at 65 °C under argon.
Isolated yield.
b
the various bases tested (entries 2–5). Thus, the following opti-
mized reaction conditions were used: 10 mol % of Cu(I), 20 mol %
of L1, and 2.0 equiv of Cs2CO3 in 0.5 M DMF (as a solvent) under
an argon atmosphere.

D. Chen et al. / Tetrahedron Letters 53 (2012) 7121–7124
7123
Table 3
CuBr-catalyzed amination of aryl bromidesa
10 mol% CuI
20 mol% L2
Br
NR1R2
+
HNR1R2
R
R
2.0 equiv Cs2CO3
DMF, 90 °C
2
4
5
Entry
1
Product
Time (h)
Yieldb (%)
Entry
6
Product
Time (h)
Yieldb (%)
H
N
N
H
HO
20
90
25
85
5a
OCH3
5f
MeO
N
N
N
H
2
3
21
26
81
88
7
8
25
24
94
59
O2N
5b
5g
H
N
O2N
N
H
5c
OCH3
5h
H
N
N
4
5
25
25
53
75
9
26
28
92
68
H3CO
N
5d
OCH3
5i
H
H
N
N
HO
5e
10
OCH3
5j
a
Reaction conditions: ArBr (1.0 mmol), amine (1.5 mmol), CuI (0.10 mmol, 10 mol %), and L2 (0.2 mmol, 20 mol %) in 2.0 mL of DMF at 90 °C under argon.
Isolated yield.
b
The CuI/L1 catalyst system was explored under optimum con-
Table 4 shows that the coupling reactions for most of the sub-
strates examined gave 51–82% yields at 115 °C. Optimized reaction
conditions were applied to the coupling of aryl chlorides and pri-
mary amines, achieving good yields (51–81%) in all cases (entries
1–4). The coupling of amino acids, such as valine, with aryl chlo-
rides also achieved excellent yields (71%) (entry 5). The catalyst
system showed high selectivity in the presence of multiple poten-
tially reactive groups, which is highly desirable in the synthesis of
complex molecules (entry 6). The N-arylation of nitrogen contain-
ing heterocycles, such as pyrrole, 1H-benzimidazole, and indole,
also achieved high yields using the CuI/L1 catalyst system (entries
7–10).
In summary, 2-carbomethoxy-3-hydroxyquinoxaline-di-N-
oxide was identified as an efficient ligand for copper-catalyzed C–
N coupling reactions. To the best of our knowledge, the present cat-
alytic system for copper-catalyzed N- and O-arylations with aryl
chlorides in cross-coupling reactions is unprecedented. Our inex-
pensive catalytic system showed great functional group tolerance
and high selectivity in the presence of multiple potentially reactive
groups at moderate temperature. Efforts to extend the application of
this ligand system for other types of copper-catalyzed coupling reac-
tions are currently underway in our laboratory and will be reported
in due course. Moreover, the methodology for designing new li-
gands, as reported in this study, will be applied in other reactions.
ditions. Table 2 shows that the coupling reactions performed well
for most substrates examined, with 78–97% yields at 65 °C. Both
electron-rich and electron-deficient aryl iodides are suitable sub-
strates for this reaction, showing similar reactivities. The reaction
conditions for the coupling of aryl iodides and primary amines
were extended and excellent yields (78–92%) were obtained in
all cases (entries 1–4). The coupling of more hindered cyclic sec-
ondary amines, such as pyrrolidine, piperidine, and morpholine,
also yielded satisfactory yields (80–83%) (entries 7 and 8). The
catalyst system also showed high selectivity in the presence of
multiple potentially reactive groups, which favors its potential
application in the synthesis of complex molecules (entries 5 and
6). The CuI/L1 catalyst system was successfully applied in the
coupling of aryl iodides with indole, with a 97% isolated yield
(entry 9). Moreover, the coupling of aryl iodides with amino acid
was also accomplished with high yields under the same condition
(entries 10 and 11).
Extension of this amination process to aryl bromide substrates
showed promising results. Table 3 shows that all examined aryl
bromides coupled with primary, cyclic secondary amines, or nitro-
gen-containing heterocycles exhibited excellent yields at 90 °C.
The reaction occurred selectively at the alkylamine when several
reactive functional groups were present (entries 5 and 6).

7124
D. Chen et al. / Tetrahedron Letters 53 (2012) 7121–7124
Table 4
Copper-catalyzed amination of aryl chloridesa
10 mol% CuI
20 mol% L1
Cl
NR1R2
+
HNR1R2
R
R
2.0 equiv Cs2CO3
DMF
2
7
6
Entry
1
Product
Time (h)
24
Yieldb (%)
Entry
6
Product
Time (h)
24
Yieldb (%)
H
N
NO2
H
N
71
82
NO2
HO
7f
7a
H
N
N
2
3
24
24
56
81
7
8
22
17
78c
65c
O2N
O2N
7b
7g
H
N
NO2
N
N
NO2
7h
7c
H
N
N
O2N
N
4
5
22
20
51
71
9
19
18
59c
7i
O2N
7d
H
NO2
N
10
57c
N
COOH
N
NO2
7j
7e
a
b
c
Reaction conditions: ArCl (1.0 mmol), amine (1.5 mmol), CuI (0.10 mmol, 10 mol %), and L1 (0.2 mmol, 20 mol %) in 2.0 mL of DMF at 115 °C under argon.
Isolated yield.
130 °C.
4. (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998, 120, 12459;
(b) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164; (c) Ma, D.; Cai, Q.;
Zhang, H. Org. Lett. 2003, 5, 2453; (d) Kim, J.; Chang, S. Chem. Commun. 2008,
3052.
5. (a) Lu, Z.; Twieg, R. J.; Huang, S. D. Tetrahedron Lett. 2003, 44, 6289; (b) Lu, Z.;
Twieg, R. J. Tetrahedron 2005, 61, 903.
6. Zhang, Z.; Mao, J.; Zhu, D.; Wu, F.; Chen, H.; Wan, B. Tetrahedron 2006, 62, 4435.
7. (a) Xu, L.; Mao, J.; Zhu, D.; Wu, F.; Wang, R.; Wan, B. Tetrahedron 2006, 61, 6553;
(b) Zhu, D.; Xu, L.; Wu, F.; Wan, B. Tetrahedron Lett. 2006, 47, 5781.
8. (a) Yang, K.; Qiu, Y.; Li, Z.; Wang, Z.; Jiang, S. J. Org. Chem. 2011, 76, 3151; (b)
Yang, K.; Li, Z.; Wang, Z.; Yao, Z.; Jiang, S. Org. Lett. 2011, 13, 4340; (c) Qiu, Y.;
Liu, Y.; Yang, K.; Hong, W.; Li, Z.; Wang, Z.; Yao, Z.; Jiang, S. Org. Lett. 2011, 13,
3556.
Acknowledgment
We gratefully acknowledge the National Natural Science Foun-
dation (Grant Nos. 20972160 and 21172220), the National Basic
Research Program of China (Grant No. 2009CB940900), and the
CSA-Guangdong Joint Foundation (Grant No. 2011B090300069)
for their financial support.
Supplementary data
9. (a) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742; (b) de Lange, B.;
Lambers-Verstappen, M. H.; de Vondervoort, L. S.; Sereinig, N.; de Rijk, R.; de
Vries, A. H. M.; de Vries, J. G. Synlett 2006, 3105; (c) Shafir, A.; Lichtor, P. A.;
Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3490; (d) Xia, N.; Taillefer, M. Angew.
Chem., Int. Ed. 2009, 48, 337.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
10.083.
10. For other ligands on Cu-catalyzed C–N coupling, see: (a) Gujadhur, R.;
Venkataraman, D.; Kintigh, J. T. Tetrahedron Lett. 2001, 42, 4791; (b) Gajare,
A. S.; Toyota, K.; Yoshifuji, M.; Ozawa, F. Chem. Commun. 1994, 2004; (c) Jiang,
D.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2007, 72, 672; (d) Rao, H.; Jin, Y.; Fu,
H.; Jiang, Y.; Zhao, Y. Chem.-Eur. J. 2006, 12, 3636; (e) Wang, H.; Li, Y.; Sun, F.;
Feng, Y.; Jin, K.; Wang, X. J. Org. Chem. 2008, 73, 8639; (f) Suresh, P.;
Pitchumani, K. J. Org. Chem. 2008, 73, 9121; (g) Jones, K. L.; Porzelle, A.; Hall, A.;
Woodrow, M. D.; Tomkinson, N. C. O. Org. Lett. 2008, 10, 797; (h) Ntaganda, R.;
Dhudshia, B.; Macdonald, C. L. B.; Thadani, A. N. Chem. Commun. 2008, 6200; (i)
Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem.-Eur. J. 2004, 10,
5607.
References and notes
1. For recent reviews see: (a) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.;
Lemaire, M. Chem. Rev. 2002, 102, 1359; (b) Thomas, A. W.; Ley, S. V. Angew.
Chem., Int. Ed. 2003, 42, 5400–5449; (c) Evano, G.; Blanchard, N.; Toumi, M.
Chem. Rev. 2008, 108, 3054–3131; (d) Evano, G.; Toumib, M.; Costea, A. Chem.
Commun. 2009, 4166.
2. (a) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581; (b) Job, G. E.;
Buchwald, S. L. Org. Lett. 2002, 4, 3703.
3. (a) Antila, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69,
5578; (b) Klapars, A.; Antila, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 7727; (c) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 7421.
11. (a) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2008, 47, 3096–3099; (b)
Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954.