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Table 3: Evaluation of the scope for Cu/L1-catalyzed arylation of phenols
bromide and the amide nitrogen (2m and 2n). However, the
reaction with 2-bromobenzamide was slow, afforded moder-
ate yield of the product, and gave an appreciable amount of
hydrodehalogenation product (2o). Aryl bromides containing
secondary and tertiary amides (2p and 2q) also gave high
yields of the products without formation of byproducts, and
the aryl bromide containing a secondary amine formed
moderate yields of the corresponding ether product (2r).
Reactions with aryl halides containing ester functionality at
the p-position gave high yield of the ether product without
any detectable hydrolysis of the ester (2s), and the acetyl
group -COMe (2t) was well tolerated, despite the enolizable
hydrogens, giving the product in high yield with a TON of
1800. A boronic ester (2u) was also tolerated without
competing formation of a biaryl product. Even an aryl halide
containing a secondary alcohol reacted to full conversion to
afford high yield of the biaryl ether product with a TON of
910 (2v).
with (hetero)aryl bromides.[a]
The functional-group tolerance also was evaluated for the
coupling of electron-rich and electron-poor phenols. The
arylation of 4-methoxyphenol with aryl halides containing an
ester group at the o-position (2w) and primary amines at the
o- and p-positions (2x and 2y) gave good to moderate yields
of the biaryl ether products without formation of side
products. The yield of the products in the presence of varying
functional groups at the o-position of the bromoarenes (2w
and 2x) were lower than those of other bromoarenes, due to
incomplete conversion of the starting aryl bromides, again,
consistent with known steric effects on copper-catalyzed
coupling reactions. The electron-rich 4-methoxyphenol cou-
pled with 5-bromobenzo-1,3-dioxole to give high yield of the
corresponding biaryl ether, although a slightly higher loading
of the catalyst was required to achieve complete conversion
(2z). The coupling of a moderately electron-poor aryl
bromide having a -Cl group at the p-position coupled with
a highly deactivated phenol containing a -CN group at the p-
position to give 68% yield of the biaryl ether product
corresponding to a TON of 1360 (2aa). Coupling at a vinyl
bromide (2ab) also gave high yield of the corresponding
product with a TON of 308.
The scope of this method was further evaluated for
a series of heteroaryl bromides (4a–k, Table 3). Most of the
reactions in the presence of heteroaromatic substrates
occurred in moderate to good yields with TONs ranging
between 500 and 2000. A few noteworthy examples demon-
strate the coupling of an electron-rich phenol with a sterically
hindered pyridine affording high yield of the corresponding
product (4b) and the tolerance of a primary amine and an
ester group on a pyridine ring (4c and 4d). One of the least
reactive of the heteroaryl bromides was 8-bromo-2-methyl-
quinoline. Reaction of this bromide required an electron-rich
phenol as coupling partner and a high loading of the catalyst
to afford good yield of the product (4 f and 4i).
[a] Reaction conditions: CuBr (0.1 mol%) and L1 (0.2 mol%) were
mixed in the presence of K3PO4 (1.5 mmol) in DMSO at RT for 1 h
followed by the addition of 3 (1 mmol) and the respective phenol
(1.5 equiv). The reaction mixture was then heated at 1208C. [b] CuBr
(0.05 mol%) and L1 (0.1 mol%) were used. [c] CuBr (0.5 mol%) and L1
(1 mol%) were used. [d] Reaction temperature was 1008C. [e] CuBr
(1 mol%) and L1 (2 mol%) were used.
chlorides all reacted under the standard conditions. This
activity is higher than that reported for reactions catalyzed by
CuBr and oxalamide L22, which were conducted with 5–
10 mol% catalyst.[15a]
The system comprising CuBr and L1 also catalyzed the
coupling of aryl bromides with benzylic and aliphatic alcohols
to form alkyl aryl ethers (Table 5). The reactions of electron-
rich, electron-poor and electron-neutral aryl bromides with
benzyl alcohol (8a–e) formed a series of aryl alkyl ethers, and
reactions with primary aliphatic alcohols (8 f and 8g) and
cyclic secondary alcohols (8h) also formed the corresponding
ethers in high yields. Under these conditions, the reactions of
aryl chlorides to generate aryl alkyl ethers (not shown)
occurred to low or no conversion.
To evaluate the utility of this catalyst for coupling with
more complex aryl halides, we conducted reactions of phenols
with aryl bromides from Merckꢀs informer library that
evaluates the suitability of a process for reactions with
pharmaceutically relevant structures (Table 6).[20] Three of
the complex aryl halides were chosen to obtain yields of
isolated products, and the coupled products (9b, 10b and 11b)
were obtained in good yields with relatively low catalyst
loadings (CuBr: 2.5 mol%, L1: 5 mol%). In these cases, only
the product and unreacted aryl bromide were observed as the
organic materials at the end of the respective reactions. As
expected, an increase in the loading of the catalyst (CuBr:
5 mol%, L1: 10 mol%) led to high yields of the products, and,
in each case, complete conversion of the starting halides was
observed without any side products. These examples highlight
Reactions with aryl and heteroaryl chlorides also occurred
in the presence of the catalyst generated from L1. A higher
loading of the catalyst (1–5 mol%) was necessary for the
reactions with aryl chlorides, but high yields of the biaryl
ethers were obtained (6a–o, Table 4). A series of electron-rich
and electron-poor aryl chlorides, as well as heteroaromatic
Angew. Chem. Int. Ed. 2021, 60, 8203 –8211
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