C O M M U N I C A T I O N S
Table 3. Copper-Catalyzed Amination of Aryl Bromidesa
Table 1. Room-Temperature Amination of Aryl Iodidesa
a
Reaction conditions: ArBr (1.0 mmol), amine (1.5 mmol), Cs2CO3 (2.0
mmol), CuI (0.05 mmol, 5 mol %), and L4 (0.2 mmol, 20 mol %) in 0.5
mL of DMF at 20 °C under argon. b Using K3PO4 (2 mmol, 425 mg). At
c
100 °C.
(
1
entry 3). We were pleased to find that raising the temperature to
00 °C allowed for the coupling of an aryl bromide with a cyclic
a
Reaction conditions: ArI (1.0 mmol), amine (15. mmol), Cs2CO3 (2.0
mmol), CuI (0.05 mmol, 5 mol %), and ligand (0.2 mmol, 20 mol %) in
.5 mL of DMF at room temperature under argon; ligand L4 was used
unless otherwise indicated. Isolated yield, average of two runs. L2 was
used. Using 2.6 mmol of Cs2CO3. 6 h at 50 °C.
0
secondary amine (entry 4), a very challenging substrate combina-
tion. When several reactive functional groups were present, the
reaction occurred selectively at the alkylamine (entry 5). This
approach can potentially circumvent the need for protecting group
manipulations in the synthesis of complex molecules.
b
c
8
e
d
Table 2. Amination of Heterocycle-Containing Substratesa
In summary, a general protocol for room-temperature coupling
of aryl iodides with amines has been described. The catalyst is easily
formed in situ by combining CuI with cyclic â-diketone ligand L2
or L4. With the exception of substrates bearing a coordinating group
9
ortho to the halide, the rate acceleration afforded by these catalysts
is unprecedented for Ullmann-type coupling reactions and allows
for a number of substrates to be transformed in as little as 2-4 h
at room temperature. This process nicely complements palladium-
based methods for the selective N-arylation of aliphatic amines.
Acknowledgment. We thank the National Institutes of Health
(
(
GM058160) for funding this work and the National Cancer Institute
NIH/NCI 5-T32-CA09112-30) for postdoctoral support. We thank
Merck, Amgen, and Boehringer-Ingelheim for unrestricted support
and Chemetall for the gift of Cs CO
2
3
.
Supporting Information Available: Detailed experimental pro-
cedures and characterization of products. This material is available free
of charge via the Internet at http://pubs.acs.org.
a
Reaction conditions same as in Table 1. b Using 3.0 mmol of Cs2CO3.
c
Using 0.5 mmol of 1,4-diiodobenzene and 1.5 mmol of amine.
References
(
1) For recent reviews of copper-catalyzed cross-coupling reactions, see: (a)
Scheme 2. Intra- vs Intermolecular Amination
Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400-5449.
(b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428-2439. (c) Belets-
kaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337-2364.
2) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793-796.
3) (a) Ma, D. W.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453-2455. (b)
Cai, Q.; Zhu, W.; Zhang, H.; Zhang, Y. D.; Ma, D. W. Synthesis 2005,
(
(
496-499.
(
(
(
4) (a) Lu, Z. K.; Twieg, R. J.; Huang, S. P. D. Tetrahedron Lett. 2003, 44,
6289-6292. (b) Lu, Z.; Twieg, R. J. Tetrahedron 2005, 61, 903-918.
5) Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R. P.; Reider,
P. J. Org. Lett. 2002, 4, 1623-1626.
6) A limited number of studies on copper-catalyzed C-arylation of malonates
and â-diketones have appeared: (a) Hennessy, E. J.; Buchwald, S. L.
Org. Lett. 2002, 4, 269-272. (b) Cristau, H.-J.; Cellier, P. P.; Spindler,
J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10, 5607-5622. (c) Jiang Y.;
Wu, N.; He, M. Synlett 2005, 2731-2734.
absence of ligand at 60 °C, while addition of L4 allowed the
reaction to take place at this temperature in 10 h. For 2 (X ) Cl),
the course of the reaction could be diverted toward intermolecular
cross-coupling in the presence of an aryl iodide (product 4).
In addition to aryl iodides, aryl bromides could undergo
amination at 90 °C. Less sterically hindered substrates (Table 3,
entries 1, 2) could be coupled in as little as 3-6 h, while 10 h was
required for the more sterically encumbered R-branched amine
(
7) See Supporting Information.
(8) For some earlier examples, see: Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem.
2005, 70, 5164-5173.
(
9) For recent examples, see: (a) Cai, Q.; Zou, B. L.; Ma, D. W. Angew.
Chem., Int. Ed. 2006, 45, 1276-1279. (b) Nicolaou, K. C.; Boddy, C. N.
C. J. Am. Chem. Soc. 2002, 124, 10451-10455.
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J. AM. CHEM. SOC.
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