Angewandte
Communications
Chemie
Cross-Coupling Very Important Paper
CuI/Oxalamide Catalyzed Couplings of (Hetero)aryl Chlorides and
Phenols for Diaryl Ether Formation
Mengyang Fan+, Wei Zhou+, Yongwen Jiang, and Dawei Ma*
Abstract: Couplings between (hetero)aryl chlorides and
phenols can be effectively promoted by CuI in combination
with an N-aryl-N’-alkyl-substituted oxalamide ligand to pro-
ceed smoothly at 1208C. For this process, N-aryl-N’-alkyl-
substituted oxalamides are more effective ligands than bis(N-
aryl)-substituted oxalamides. A wide range of electron-rich and
electron-poor aryl and heteroaryl chlorides gave the corre-
sponding coupling products in good yields. Satisfactory
conversions were achieved with electron-rich phenols as well
as a limited range of electron-poor phenols. Catalyst and ligand
loadings as low as 1.5 mol% are sufficient for the scaled-up
variants of some of these reactions.
were required for complete conversion. Furthermore, the
coupling of pharmaceutically more important (hetero)aryl
chlorides has remained unexplored. Therefore, the discovery
of more powerful ligands for copper-catalyzed couplings of
(hetero)aryl chlorides and phenols is highly warranted.
Building upon our recent success in the development of
effective ligands for copper-catalyzed aryl amination reac-
tions with (hetero)aryl chlorides,[8] we discovered that some
N-aryl-N’-alkyl-substituted oxalamides could promote
copper-catalyzed couplings between (hetero)aryl chlorides
and phenols, leading to the formation of a great variety of
diaryl ethers at 1208C. Herein, we wish to report our results.
As summarized in Table 1, we selected the coupling of
4-chlorotoluene and phenol as a model reaction to optimize
the reaction conditions. Initially, several bis(N-aryl)-substi-
tuted oxalamides that led to excellent yields in the amination
of (hetero)aryl chlorides were examined. It was found that
N,N’-bis(2,4,6-trimethoxyphenyl)oxalamide (BTMPO, L1)
could promote this reaction, but only provided about 44%
conversion at 1208C after 24 hours (entry 1). The use of
oxalamides L2–L4, which are derived from 2-phenoxy- or
2-phenyl-substituted anilines, gave better results, but incom-
plete conversion was still observed (entries 2–4). To our
surprise, improved conversion was observed when N-aryl-N’-
alkyl-substituted oxalamide L5 was used as the ligand
(entry 5), which was inconsistent with the trends observed
in our previous studies on aryl amination.[8a]
We next screened several N-aryl-N’-alkyl-substituted
oxalamides with different substituents at the 4-position of
the aniline moiety. The electronic nature of the aniline group
had limited influence on the reaction efficiency (compare
entries 5–9 and 11). This phenomenon is also inconsistent
with our observations for aryl amination, where the electronic
nature of the aniline part exerted a great influence on its
efficiency.[8a] The best result was achieved when 4-methyl-2-
phenylaniline-derived oxalamide L9 was employed as the
ligand (entry 9). The desired product was isolated in excellent
yield when the loading of both CuI and L9 was reduced to
5 mol% (entry 10). We therefore chose these reaction con-
ditions for further studies.
D
iaryl ethers are frequently found structural motifs of
natural products and synthetic molecules with various bio-
logical functions and properties.[1] The development of useful
methods for preparing diaryl ethers has thus received
continuous attention from the synthetic community.[2–7]
Among the existing methods, metal-catalyzed coupling reac-
tions between aryl halides and phenols represent one of the
most reliable approaches and have been intensively applied in
both academia and industry.[2] Initially, this transformation
required harsh conditions (ca. 2008C) and stoichiometric
amounts of copper reagents, and often gave moderate yields
with a rather narrow reaction scope.[3] This situation was
greatly changed during the past years owing to the discovery
of some effective catalytic systems, such as the combination of
palladium with sterically demanding phosphines[4] and sys-
tems based on copper and bidentate ligands.[5] Although
significant progress has been achieved in this area, there
remain some limitations. For example, although diaryl ether
formation with a Cu/bidentate ligand catalyst system works
well for aryl iodides and bromides,[2,5] the less expensive aryl
chlorides remain difficult substrates. The only successful
example of a Cu/ligand-catalyzed arylation of phenols with
aryl chlorides was reported by Xia and Taillefer;[7] 2,2,6,6-
tetramethyl-3,5-heptanedione was selected as the ligand, and
the reaction took place at 1358C. However, the reaction scope
was limited to electron-rich phenols, and a large amount of
ligand (0.8 equiv) and relatively expensive Cs2CO3 as the base
It seemed that the 2-phenylaniline moiety of the ligands
was important for the high reactivity, as 2-phenoxyaniline-
derived oxalamide L11 gave only 75% conversion (entry 12).
Changing the aliphatic amine moiety of the oxalamides also
altered their efficiency, as evident from the fact that the
cyclohexylamine- and n-hexylamine-derived amides L12 and
L13 led to moderate conversions. Good conversion was
retained when the benzylamine group was replaced with
(2-furanyl)methylamine (compare entries 9 and 15).
[*] M. Fan,[+] W. Zhou,[+] Prof. Dr. Y. Jiang, Prof. Dr. D. Ma
State Key Laboratory of Bioorganic & Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (China)
E-mail: madw@mail.sioc.ac.cn
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
Angew. Chem. Int. Ed. 2016, 55, 6211 –6215
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6211