L. Zhu et al. / Tetrahedron Letters 49 (2008) 2734–2737
2735
O
O
OH
B
Suzuki coupling
R
R
+
OH
Br
X
2
X
1
R'
R'
R' = H
X = NO2
NH2
R' = H
X = NO2
NH2
Scheme 1. The original synthesis of biphenyl anilines 1.
reduction of the benzylic carbonyl group on the other side
of the biphenyl.
from 2a did not react well with 3a in the cross-coupling
reaction. In contrast, boronate generated in situ from 3a
smoothly coupled with 2a to afford biphenyl acetamide
4a in 74% yield (Scheme 2). In the following step, 4a was
treated under strong acidic conditions in order to produce
aniline 1.8 However, 4a was stable in conc. HCl at an
elevated temperature for days: no desired product was
observed. Thus, we examined other amino protecting
groups such as BOC and the formyl group. Although less
popular than BOC, the formyl group is also known as a
choice for amino protection.9 Following a standard one-
pot Suzuki protocol,6 BOC protected 4-iodoaniline pro-
vided an insignificant amount of the desired biphenyl prod-
uct, while the same reaction with formamides afforded
much better results. The formamide derivatives 3b, 3g,
and 3h were prepared in quantitative yields by treating
appropriate anilines in formic acid/acetic anhydride.10
One-pot Suzuki coupling reaction between 3 and bromides
2 occurred smoothly (Scheme 3), and the results are shown
in Table 1. In most cases, biphenyl 4 was cleanly formed
and isolated without chromatography. Specifically, biphen-
yls 4b–f were obtained cleanly in satisfactory yields (64–
70%) after a simple trituration (entries 1–5). Substituted
biphenyl formanilides 4g–i were also prepared in moderate
yields (entries 6–9). Except for 4g where a slower reaction
was observed, hydrolysis of the biphenyl formanilides 4
readily occurred under mild acidic conditions to afford ani-
lines 1 in near quantitative yields (Scheme 4).9a Compared
with the original preparation of 1, savings realized by this
alternative synthesis were significant.11 Notably, biphenyl
anilines 1g–i obtained in this fashion were inaccessible by
Miyaura pioneered the use of arylboronates, more read-
ily accessible than boronic acids, for the cross-coupling
reaction to afford biaryls.5 We recently expanded the use
of this methodology by developing a convenient one-pot
protocol via aryl boronates generated in situ.6 This one-
pot procedure allows coupling reactions between two aryl
halides without the need for boronic acids. In search for
a scaleable and economical synthesis of biphenyl aniline
1, we investigated amino and protected amino phenyl
halides as boronate precursors in the one-pot Suzuki cou-
pling reaction. Although amide aryl halides are known to
cross couple with boronic acids,7 there is very limited liter-
ature precedent of amide aryl boronate in Suzuki coupling
reactions. We started out with 4-iodoaniline, a readily
available and low-cost starting material, in forming its
corresponding aniline boronate. Not surprisingly, we
found the reaction to be difficult presumably due to the
electron-donating amino group. However, we envisioned
that its amide derivatives were considerably less electron-
donating, therefore boronate formation and subsequent
cross-coupling with aryl bromide 2 would be more likely
to occur. In this Letter, we wish to describe a novel and
efficient synthesis of biphenyl aniline moiety 1 from iodo
phenyl formamides via one-pot Suzuki coupling reactions.
We first chose iodo acetamide 3a, readily prepared from
4-iodoaniline with acetyl chloride, as the boronate precur-
sor in the one-pot Suzuki coupling reaction. Although
using aryl bromide 2 as boronate precursor was not the
focus in this study, it is worth noting that boronate formed
O
O
O
O
O
COOMe
B
B
O
COOMe
I
O
One-pot Suzuki
+
O
Me
N
H
74%
Me
Br
N
H
3a
4a
2a
Scheme 2. Synthesis of biphenyl acetamide from 4-iodo phenylacetamide via one-pot Suzuki coupling reaction.
Zhu, Lei
