DOI: 10.1002/anie.201007302
Oxygen Heterocycles
Transition-Metal-Free Intramolecular Ullmann-Type O-Arylation:
Synthesis of Chromone Derivatives**
Jie Zhao, Yufen Zhao, and Hua Fu*
À
Aromatic C O bond-forming reactions are important in
organic synthesis because these bonds occur in numerous
natural products, biological compounds, pharmaceuticals,
fragrances, cosmetics, and polymers.[1] Traditionally, aryl
ethers have been prepared by copper-mediated Ullmann
coupling reactions of aryl bromides/iodides and phenols, but
the drawbacks include harsh reaction conditions, such as: the
need for a strong base, long reaction times in high polar
solvents, and a stoichiometric amount of copper.[2] Subse-
quently, some significant achievements in the palladium-
catalyzed O-arylation have been made under mild reaction
conditions (Scheme 1a).[3] Recently, copper-catalyzed Ull-
mann-type O-arylations have been developed under milder
reaction conditions (Scheme 1a) using inexpensive copper
salts and readily accessible ligands,[4,5] such as phenanthro-
lines,[5j.5k] N,N-dimethyl glycine,[5l] pyridine derivatives,[5m] b-
diketones,[5n] 1,1,1-tris(hydroxymethyl)ethane,[5o] and pyrroli-
dine-2-phosphonic acid phenyl monoester.[5p] Palladium- or
copper-catalyzed intramolecular O-arylations have attracted
much attention, and some oxygen heterocycles were con-
structed with the Ullmann-type O-arylation strategy,[6] for
example copper-catalyzed synthesis of substituted 4H-1-
benzopyrans (Scheme 1b),[6d] 2,3-dihydro-1,4-benzoxazines
(Scheme 1c),[6e] benzoxazoles (Scheme 1d),[6f] and copper-
[6g,h]
and palladium-catalyzed[3d,e,j] synthesis of five and six-
Scheme 1. a–e) Copper- and palladium-catalyzed Ullmann-type O-aryla-
membered oxygen heterocycles (Scheme 1e). The results
above show that transition-metal catalysts (palladium and
tions (previous research). f) Transition-metal-free intramolecular Ull-
mann-type O-arylation leading to chromones (this work). DMF=N,N’-
dimethylformamide.
copper) seem to be necessary in O-arylations.
Chromone derivatives are ubiquitous to green-plant cells
and are highly diverse; more than 2000 different flavonoids
have been identified, and their number is growing rapidly.
These derivatives show various biological and pharmaceutical
activity,[7] so they are interesting as structural scaffolds and
have been assigned as privileged structures in drug develop-
ment.[8] Although some approaches to the chromone deriv-
atives have been developed, the methods often suffer from
harsh reaction conditions, limited substrate scope, poor
substituent tolerance, and low yields.[9] Several efficient
palladium-catalyzed routes have been developed for the
synthesis of chromone derivatives.[10] The excellent results
from the copper- and palladium-catalyzed O-arylations
above[1-6] prompted us to make chromone derivatives by
using a transition-metal-catalyzed strategy. Thus, considering
the ready availability and low toxicity of copper catalysts, we
first screened copper-catalyzed reaction conditions by using
the intramolecular O-arylation of 1-(2-bromophenyl)-3-p-
tolylpropane-1,3-dione (1a) as the model reaction (Table 1).
Surprisingly, a more highly efficient O-arylation was observed
in the absence of a copper salt (entry 7, Table 1). Herein, we
report the unexpected transition-metal-free intramolecular
Ullmann-type O-arylation leading to chromone derivatives
(Scheme 1 f).
[*] J. Zhao, Prof. Dr. Y. Zhao, Prof. Dr. H. Fu
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry
Tsinghua University, Beijing 100084 (China)
Fax: (+86)10-6278-1695
E-mail: fuhua@mail.tsinghua.edu.cn
1-(2-Bromophenyl)-3-p-tolylpropane-1,3-dione (1a) was
first used as the model substrate to screen the reaction
conditions for the optimization of the catalyst, base, solvent,
temperature, and reaction time under air. As shown in
Table 1, six copper catalysts were tested at 1108C in the
presence of one equivalent of Cs2CO3 (relative to the amount
[**] The authors wish to thank the National Natural Science Foundation
of China (Grant No. 20972083) and the Ministry of Science and
Technology of China (2009ZX09501-004) for financial support.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 3769 –3773
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3769