Communications
DOI: 10.1002/anie.200903158
Homogeneous Catalysis
Room-Temperature Copper-Catalyzed Carbon–Nitrogen Coupling of
Aryl Iodides and Bromides Promoted by Organic Ionic Bases**
Chu-Ting Yang, Yao Fu,* Yao-Bing Huang, Jun Yi, Qing-Xiang Guo, and Lei Liu*
Transition-metal-catalyzed couplings provide important tools
in modern organic synthesis.[1] The bases commonly employed
for these couplings are salts of alkaline or alkaline-earth
metals (e.g. K3PO4, NaOtBu, and Cs2CO3). They are thought
to facilitate the otherwise slow transmetalation (e.g. in Suzuki
couplings), reductive elimination (e.g. in Heck couplings), or
nucleophile deprotonation/coordination (e.g. in carbon–het-
eroatom couplings). At present, the choice of base remains
empirical. Problems are often encountered for the couplings
in less polar solvents where most inorganic bases are poorly
soluble. To solve these problems we propose the use of
organic ionic bases composed of organic cations and basic
anions.[2] These bases are well soluble in organic solvents.
More importantly, they exhibit novel useful reactivities.
Figure 1 shows the organic ionic bases synthesized in the
Figure 1. Structures of the organic ionic bases in this study.
present study. Most of them are new compounds.[3] They were
prepared mainly through the reaction between an equimolar
quantity of tetraalkylammonium or -phosphonium hydroxide
and the appropriate acid. To demonstrate the advantage of
using organic ionic bases, we report novel room-temperature
(RT) Cu-catalyzed C–N couplings[4] promoted by these bases.
Our work starts with the coupling of aryl iodides with
amines. Recently Buchwald et al. reported the first protocol
for this coupling at room temperature;[5] other research
groups have described related work.[6] In the present study we
have examined different organic ionic bases. We found that
TMAP and TEAP do not mediate the coupling (Figure 2a) at
room temperature (25 Æ 18C), although they are both well
soluble. Significant yields (ca. 40–80%) are obtained when
TBAP is used, indicating the importance of choosing a bulky
cation. When the cation is fixed as NnBu4+, the yield varies
dramatically with different anions. These observations reveal
that solubility alone does not explain the utility of organic
ionic bases.
The best yield (95%) is obtained with TBAA, which is a
carboxylate base. Remarkably, the use of a very simple and
cheap ligand (i.e. l-proline as opposed to 2-isobutyrylcyclo-
hexanone in the previous protocol[5]) is sufficient for the
reaction to proceed in high yields at room temperature. Also,
the current protocol is not sensitive to water (see Scheme 1,
footnote [a]). Application of the optimized protocol to
diverse aryl iodides (Scheme 1) was successful. Both elec-
tron-rich and electron-poor aryl iodides show high to
excellent yields when coupled with aliphatic amines.
Side products may arise from the reaction of the
nucleophile with the tetraalkylammonium cation. However,
GC–MS analysis of the reaction mixtures from the described
coupling reactions shows no such side products (see the
Supporting Information). To further minimize this potential
problem, we examined the organic ionic bases having
tetraalkylphosphonium as the cation; they are known to be
much more stable than tetraalkylammonium salts.[7] Remark-
ably, the phosphonium bases perform even much better than
the ammonium bases. For the coupling of PhI with BnNH2 at
room temperature, TBPE can drive the reaction to comple-
tion within approximately 30 min (Figure 2c) whereas TBAA
requires roughly 24 h. Additional evidence for the extremely
facile C–N coupling is the fact that TBPE can promote the
amination of aryl iodides even at 08C in 5 h (Scheme 2).
The unprecedented facility of the coupling implies that
even aryl bromides may be activated at room temperature.
Indeed TBPE promotes the coupling of PhBr with BnNH2 at
room temperature (70% yield). Further tests of other
phosphonium bases show that TBPM gives the best result
[*] C. Yang, Prof. Y. Fu, Y. Huang, J. Yi, Prof. Q. Guo
Department of Chemistry
University of Science and Technology of China
Hefei 230026 (China)
Fax: (+86)551-360-6689
E-mail: fuyao@ustc.edu.cn
Prof. L. Liu
Department of Chemistry, Tsinghua University
Beijing 100084 (China)
Fax: (+86)10-6277-1149
E-mail: lliu@mail.tsinghua.edu.cn
[**] This work was supported by the 973 Program (2007CB210205), the
NSFC (20832004), and the NCET (080519). We also thank Prof.
Ronald Breslow of Columbia University for insightful discussions.
Supporting information for this article is available on the WWW
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 7398 –7401