A R T I C L E S
Maiti and Buchwald
O-arylated 4-aminophenol could be isolated as the major product
with trans-N,N′-dimethyl-1,2-cyclohexanediamine (CyDMEDA
2, Figure 2),9,32-36 using a variety of solvent and base
combinations. Unfortunately, formation of the reduction product
(ArI f ArH, e.g, 14% GC-yield of m-xylene in entry 3a and
16% GC-yield of anisole in entry 6a, Table 3) and/or traces of
N-arylated product could not be completely prevented in most
of the cases examined. Further optimization indicated that the
combination of butyronitrile as solvent and K2CO3 as base
afforded the highest yield and selectivity for O-arylation.
Increasing the temperature above 70 °C led to increased
reduction of the aryl halide; decreasing the reaction temperature
resulted in slower reaction rates. In a typical protocol, 10 mol
% CuI, 20 mol % 2 and K2CO3, in butyronitrile at 70 °C were
employed along with the aryl iodide and 4-aminophenol (Table
3).
As shown in Table 3, under these conditions the reaction
tolerates a number of different substituents either on the
nucleophile or electrophile. Systematic variation of the substit-
uents on the aryl halide from the para (entry 2a) to the meta
(entries 3a) and ortho positions (entry 4a) provided the corre-
sponding O-arylated products of 4-aminophenol. Functional
groups such as ketones and esters, both on the aminophenol
and on the aryl iodide, were tolerated (Table 3, entries 7a, 8a,
9a and 14a). Heteroaryliodides such as 2-iodopyridines could
be O-arylated in good yield (Table 3, entry 15a). Substituted
4-aminophenols were shown to provide the desired products in
moderate yields (Table 3, entries 5a, 6a, 7a, 8a, 9a, 10a, 11a,
12a, 13a and 14a) as did 4-aminophenols with fluoride or
chloride substituents (Table 3, entry 6a, 8a, 9a, 10a and 11a).
The reaction of 2-methyl-4-aminophenol (entry 5a) gave a low
yield of O-arylated product and produced a significant quantity
of the N-arylated compound (16%). Here an ortho methyl
substituent is problematic, possibly due to reduced binding
efficiency of oxygen to the Cu center owing to steric interactions.
We currently have no explanation for why complete selectivity
is seen with 5-amino-o-cresol (Table 2, entry 10a), but not with
2-methyl-4-aminophenol (Table 3, entry 5a).
Figure 3. Ligand and precatalyst used in these studies for palladium
catalysis.
Pd-Catalyzed N-Arylation of 3-Aminophenol. Recently we
reported that precatalyst 8 based on BrettPhos 7 provides a
highly efficient catalyst for C-N cross-coupling reactions
(Figure 3).29,30 Such catalysts have been shown to allow the
coupling of anilines and aryl halides with short reaction times
and low catalyst loadings. We found that employing 0.2 mol
% 8 with NaOt-Bu in 1,4-dioxane at 90 °C in the reactions of
aryl bromides and chlorides with 3-aminophenols cleanly led
to the N-arylation products. This, combined with our above-
described copper method constitutes an orthogonal set of
catalysts for the selective N-(Pd) or O-(Cu) arylation of
3-aminophenols.
As shown in Table 2, electron-rich, -deficient and -neutral
aryl bromides underwent N-arylation in excellent yields and with
high levels of chemoselectivity using 8 (Table 2, entries 1b,
2c, 3c, 4b and 5c). The selective N-arylation of 3-aminophenol
was also successful with 2-substituted aryl halides (Table 2,
entry 6b). The use of NaOt-Bu precludes the presence of base-
sensitive functional groups, however, the weak base K2CO3 can
be used in t-BuOH with BrettPhos precatalyst 8 at a slightly
higher temperature (110 °C) and with longer reaction times (80
min). A variety of functional groups were tolerated, including
an ester and a nitrile (Table 2, entries 8b and 9b).
An aryl chloride could also be present in either the nucleo-
philic or electrophilic coupling partner (Table 2, entries 7b and
17b). As with O-arylation, substituted aminophenols were
successfully N-arylated (Table 2, entries 10b, 11b, 12b, 13b,
14b, 15b, 16b and 17b), thus complementing the Cu-catalyzed
O-arylation process described above. Heteroaryl bromides
containing pyridines, thiophenes, quinolines and isoquinolines
were all selectively N-arylated in good to excellent yields (Table
2, entry 18b, 19b, 20b and 21b).
As with 3-aminophenol, the use of aryl bromides as coupling
partners (Table 3, entries 2b and 3b) resulted in lower yields of
the desired products.
Pd-Catalyzed N-Arylation of 4-Aminophenol. As is the case
of 3-aminophenols, we found that the use of 0.2 mol % 2 in
combination with 2.5 mmol NaOt-Bu (or K2CO3) in 1,4-dioxane
(or t-BuOH) at 110 °C (Table 3) catalyzed the selective
N-arylation of 4-aminophenols with aryl bromides and chlorides.
In all of the cases examined, aryl chlorides behaved similarly
to aryl bromides in their selective N-arylation with 3-aminophe-
nols under these conditions (Table 2, entries 6c, 8c, 9c, 12c,
13c and 16c). The faster rate of oxidative addition of LPd(0) to
the aryl bromide allowed for the selective amination of
chlorobromo substrates (Table 2, entries 7b and 17b).
(26) Lam, M. S.; Lee, H. W.; Chan, A. S. C.; Kwong, F. Y. Tetrahedron
Lett. 2008, 49, 6192–6194.
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73, 5167–5169.
Cu-Catalyzed O-Arylation of 4-Aminophenol. Following our
success with 3-aminophenol, we set out to find conditions that
would allow analogous transformations of 4-aminophenol. While
the combination of CuI with 1 promotes the O-arylation of
4-aminophenol in 1,4-dioxane with K3PO4 or Cs2CO3, the
reactions proceed in low yield. The use of all the ligands shown
in Table 1 resulted in formation of the N-arylated and N,N-
diarylated products and a trace of the O-arylated products. Next,
a series of ligands previously employed by our group in copper-
catalyzed reactions were examined.27,31 We found that the
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17426 J. AM. CHEM. SOC. VOL. 131, NO. 47, 2009