Silver(I)-mediated regioselective oxidative cross-coupling of phenol and aniline derivatives resulting in 2′-aminobiphenyl-2-ols

Article abstract of DOI:10.1016/j.tetlet.2016.02.111

A broad and efficient regioselective aerobic oxidative cross-coupling of phenols and aniline derivatives in the presence of AgNO₃ and H₂O₂ resulting in 2′-aminobiphenyl-2-ols has been developed. This reaction is selective toward the creation of a new C–C bond at the ortho position to both amine and hydroxyl functional groups in the respective starting materials. Although oxidative cross-coupling of phenols and anilines resulting in 2′-aminobiphenyl-2-ol derivatives have been reported, these reactions have been mainly limited to 2-naphthol and 1-naphthol. This is one of the rare reports in which this type of cross-coupling reaction is expanded to simple phenol derivatives.

Full text of DOI:10.1016/j.tetlet.2016.02.111

Accepted Manuscript
Silver(I)-Mediated Regioselective Oxidative Cross-coupling of Phenol and Ani-
line Derivatives Resulting in 2’-Aminobiphenyl-2-ols
Sololiya C. Berkessa, Zachary J.F. Clarke, Jean Fotie, D. Scott Bohle, Casey C.
Grimm
PII:
S0040-4039(16)30220-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.02.111
TETL 47386
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
3 February 2016
26 February 2016
29 February 2016
Please cite this article as: Berkessa, S.C., Clarke, Z.J.F., Fotie, J., Scott Bohle, D., Grimm, C.C., Silver(I)-Mediated
Regioselective Oxidative Cross-coupling of Phenol and Aniline Derivatives Resulting in 2’-Aminobiphenyl-2-ols,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.02.111
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Silver(I)-Mediated Regioselective Oxidative Cross-coupling of Phenol and Aniline
Derivatives Resulting in 2'-Aminobiphenyl-2-ols
†
†
,†
‡
§
Sololiya C. Berkessa, Zachary J. F. Clarke, Jean Fotie,* D. Scott Bohle, and Casey C. Grimm.
†
Department of Chemistry and Physics, Southeastern Louisiana University, SLU 10878, Hammond,
Louisiana 70402-0878, United States
‡
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A
0B8, Canada
§
Food Processing and Sensory Quality Research, United States Department of Agriculture (USDA),
1100 Robert E. Lee Boulevard, Bldg 001 SRRC, New Orleans, LA 70124, United States
ABSTRACT
A broad and efficient regioselective aerobic oxidative cross-coupling of phenols and aniline
derivatives in the presence of AgNO
3
and H
2
2
O resulting in 2'-aminobiphenyl-2-ols has been
developed. This reaction is selective toward the creation of a new C–C bond at the ortho position to
both amine and hydroxyl functional groups in the respective starting materials. Although oxidative
cross-coupling of phenols and anilines resulting in 2'-aminobiphenyl-2-ol derivatives have been
reported, these reactions have been mainly limited to 2-naphthol and 1-naphthol. This is one of the
rare reports in which this type of cross-coupling reaction is expanded to simple phenol derivatives.

Corresponding author. Tel.: +1 985 549 5112; Fax: +1 985 549 5126; e-mail: jean.fotie@selu.edu
1

Keywords: Dehydrogenative cross-coupling, silver(I) promoted reaction, aniline and phenol
derivatives, 2'-aminobiphenyl-2-ols
INTRODUCTION
Functionalized biaryls are valuable structural motifs in numerous natural products, biologically active
compounds, and in a wide range of molecules that find application as pharmaceuticals, agrochemicals
1
and in the material industries. They are key components in organic conductors or semiconductors,
and are efficient and selective ligands for asymmetric catalysis, especially when atropisomery is
1
possible. 2'-Aminobiphenyl-2-ols are one of the most important subdivisions of functionalized
2
biaryls primarily found in biologically active natural products and pharmaceuticals. Some examples
of bioactive natural products bearing a 2'-aminobiphenyl-2-ol core moiety include ambidalmine
2
f
derivatives that were shown to exhibit protective effects on hypoxic H9C2 cells, the cytotoxic
2
c, 2d
2e, 3
jadomycin
as well as complestatin derivatives which are HIV-1 integrase inhibitors.
As a
result, a continuous development of highly efficient and environmentally friendly methods for
synthesizing these structural units is critical in organic synthesis. Well-known reactions such as the
Mizoroki–Heck and Suzuki–Miyaura have been for decades the preferred methods to access
1
b, 4
biaryls.
However, in recent years, the direct arylation via C–H activation has become a primary
focus in organic synthesis mainly because these alternative methods proceed in fewer steps with a
1
c, 5
high atom economy.
These new strategies have also proven to have a broader scope including the
use of highly electron-rich arenes, highly electron-poor arenes as well as arenes bearing a directing
group with the primary role of coordinating the transition metal catalyst and facilitating a selective C–
6
H activation.
2

7
Although the dehydrogenative-homocoupling of electron-rich arenes such as aniline derivatives and
8
phenols is very well documented, the regioselective cross-coupling of phenols and anilines resulting
in 2'-aminobiphenyl-2-ol derivatives that does not involve a prefunctionalization of either of the
coupling partners is much more challenging due to the potential formation of many competitive side
products. Nevertheless, there are reports of the cross-dehydrogenative coupling (CDC) of either 2-
9
9b, 9c
naphthol or 1-naphthol with aniline derivatives in the chemical literature. In fact, copper
and
9
a, 9d
iron
have been used to catalyze oxidative and regioselective cross-coupling of 2-naphthol or 1-
naphthol with a range of aniline derivatives resulting in the exclusive formation of a carbon-carbon
bond at the ortho position to the hydroxyl and amine functional groups in the respective substrates.
8
b, 10
However, due to the difference in oxidation potentials (naphthol = 1.87 eV, phenol = 2.10 eV),
all
these reactions failed when any phenol derivative other than naphthols was used as a coupling
9
partner. As part of our continuous effort to investigate the effect of silver(I) in the oxidative
1
1
dehydrogenative coupling of arenes resulting in the formation of C–N bonds, we noticed that
silver(I) can mediate the regioselective cross-coupling of phenol and aniline derivatives resulting in
the exclusive formation of 2'-aminobiphenyl-2-ol derivatives, under very mild conditions. To the best
of our knowledge, this is not only the first report that combines silver(I) and H
2
O
2
to achieve this
type of conversion, but it is also one of the rare cases where the scope of the reaction is expanded to
include a wide range of phenol derivatives other than 2-naphthol and 1-naphthol.
3

RESULTS AND DISCUSSION
In a previous study, we reported that silver(I) could effectively catalyzed the C–H/N–H direct
homocoupling of secondary arylamines resulting in the formation of a new intermolecular C–N
1
1
bond. In a process of expanding the scope of this reaction to include cross-couplings, we noticed
that N,N,4-trimethylaniline reacts with 2-naphthol in the presence of Na (1 eqv) and AgNO
10% mol) resulting in a regioselective formation of a carbon-carbon bond at the ortho position to the
2
S
2
O
8
3
(
hydroxyl and amine functional groups in the respective substrates, with a very low yield (Table 1,
enty1). Based on this initial observation, we decided to use both substrates for a further optimization
of the reaction conditions (Table 1).
The optimization results indicated that 1 equivalent of AgNO was needed to drive the reaction till
3
the complete consumption of N,N,4-trimethylaniline (entries 7, 11 and 19), while none of the catalytic
amounts (even up to 50% mol, entry 6) were able to drive the reaction to the same point.
Furthermore, none of the other silver(I) salts tested (AgCl, AgOAc or AgIO
as AgNO . This might have something to do with the low solubility of these silver salts in the
solvents used. Furthermore, a number of oxidizing agents was also evaluated, and among them, H
appeared to be the most effective under these reaction conditions, while (NH was a close
second. The addition of a silver(I) salt appeared to be critical for the reaction to proceed. While
0.7% yield was observed when 1 equivalent of AgNO was used in the total absence of any
3
) were nearly as effective
3
2
O
2
4
)
2
S
2
O
8
3
3
additional oxidizing agent (entry 12), the reaction systematically failed in the total absence of
silver(I), even when 3 equivalents of the oxidizing agent were present (entry 2). As far as solvents
are concerned, toluene was a better solvent in many cases, and although dichloromethane appeared to
produce similar yield (entry 19), it dries out throughout the reaction and had to be added, especially
when the reaction is performed under open atmospheric conditions.
4

a
Table 1. Optimization of the reaction conditions
b
Entry
Silver (eqv)
Oxidant (eqv)
Solvent
time Yield (%)
1
2
3
4
5
6
7
8
9
AgNO
3
(0.1 eqv)
Na
Na
Na
H
H
H
2
2
2
S
S
S
2
2
2
O
O
O
8
8
8
(1 eqv)
(3 eqv)
(3 eqv)
Toluene (open air)
Toluene (open air)
Toluene (open air)
Toluene (open air)
Toluene (open air)
Toluene (open air)
Toluene (open air)
Toluene (open air)
Toluene (open air)
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
18 h
18 h
18 h
18 h
18 h
18 h
9.2
N.R
c
none
AgNO
AgNO
3
(1 eqv)
(0.1 eqv)
44.9
16.7
31.1
54.9d
78.5
65.7
41.2
47.1
75.0
30.7
N.R
N.R
3
2
2
2
O
O
O
2
2
2
(3 eqv)
(3 eqv)
(3 eqv)
(3 eqv)
(2 eqv)
(1 eqv)
(3 eqv)
(3 eqv)
AgNO
AgNO
3
(0.25 eqv)
(0.5 eqv )
3
AgNO
3
(1 eqv)
(1 eqv)
(1 eqv)
(1 eqv)
(1 eqv)
(1 eqv)
(1 eqv)
H
2
O
2
AgNO
AgNO
AgNO
AgNO
AgNO
AgIO
AgCl (1 eqv)
AgOAc (1 eqv)
AgNO
AgNO
AgNO
AgNO
3
3
3
3
3
H
H
H
H
2
2
2
2
O
O
O
O
2
2
2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
Toluene (under N
Toluene (under O
2
)
)
d
2
none
Toluene (open air)
Toluene (open air)
Toluene (open air)
Toluene (open air)
Toluene (open air)
Toluene (open air)
THF (open air)
c
3
H
H
H
2
2
2
O
O
O
2
2
2
(3 eqv)
(3 eqv)
(3 eqv)
c
traces
67.8
30.7
46.8
3
3
3
3
(1 eqv)
(1 eqv)
(1 eqv)
(1 eqv)
(NH
4
)
2
S
2
O
8
(3 eqv)
NaClO
4
(3 eqv)
H
H
H
H
2
2
2
2
O
O
O
O
2
2
2
2
(3 eqv)
(3 eqv)
(3 eqv)
(3 eqv)
d
DCM (open air)
72.3
AgNO
3
(0.25 eqv)
DCM (under N
2
)
45.3
54.7
34.3
62.4
2.7
17.2
3.7
8.8
AgNO
AgNO
AgNO
3
3
3
(1 eqv)
(1 eqv)
(1 eqv)
(1 eqv)
Dioxane (open air)
THF (open air)
Dioxane(open air)
THF (open air)
(NH
(NH
(NH
(NH
(NH
(NH
(NH
(NH
4
4
4
4
4
4
4
4
)
)
)
)
)
)
)
)
2
2
2
2
2
2
2
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
S
2
O
O
O
O
O
O
O
O
8
8
8
8
8
8
8
8
(3 eqv)
(3 eqv)
(3 eqv)
(3 eqv)
(3 eqv)
(3 eqv)
(3 eqv)
(3 eqv)
AgIO
3
AgOAc (1 eqv)
AgIO (1 eqv)
AgOAc (1 eqv)
AgIO (1 eqv)
AgOAc (1 eqv)
THF (open air)
3
Toluene(open air)
Toluene (open air)
Dioxane (open air)
Dioxane (open air)
3
7.6
22.2
a
2
.08 mmol of N,N,4-trimethylaniline was reacted with 2.08 mmol of 2-naphthol in an ice bath. The reaction
b
was then allowed to warm progressively to room temperature. The yield of the reaction was determined by
c
d
GC-MS using 1-bromhexadecane as an internal standard. N.R. = No Reaction. No N,N,4-trimethylaniline
was present in the mixture at the end of the reaction as indicated by GC-MS although some 2-naphthol was
still present.
5

The reaction also produced a better yield when run under an oxygenated environment, but the
atmospheric oxygen appeared to be enough for the reaction to proceed. Based on all these
observations, the reaction conditions in entry 7 (1 eqv AgNO
3
and 3 eqv H
2
2
O in toluene under open
atmospheric environment for 6 h) were selected for further expansion of the scope of the reaction.
Having identified the optimal reaction conditions, the scope of the reaction was first examined by
treating a series of aniline derivatives with 2-naphthol as well as with 1-naphthol, and the results are
summarized in Scheme 1. Tertiary aniline derivatives with an electron-donating group such as CH or
3
OEt (1a, 1b, 4, 5 and 7) at the para-position produced the envisioned products, with isolated yields
between 52.6% and 70.2%. However, the reaction failed when at the same position, the tertiary
aniline derivative was carrying an electron-withdrawing group (Cl, Br or NO ), and even a hydrogen
2
atom (1c-d). The reaction also failed when the tertiary aniline carries any group at the ortho to the
amine, regardless of whether the group is electron-poor (2a) or electron-rich (2b). In the case of 2b, it
is obvious that steric hindrance prevents the reaction. The same steric hindrance might be responsible
of the fact that aniline derivatives with two bulky groups on the amine, including two ethyl groups,
failed to produce the expected products (6a-b). In each of these cases, the starting materials were
collected. Nevertheless, the reaction appeared to tolerate aniline with one bulky group on the amine
(
benzyl, 4 or but-2-enyl, 5) as long as the other group is a methyl group, and providing that the
aniline derivative is also carrying the much needed electron-rich group at the para-position. The
reaction failed to produce any product when secondary aniline derivatives were used (even with
electron-rich group at the para position 3a), and the starting materials were collected in each of these
cases. On the other hand, primary anilines were quickly oxidized into the the corresponding
azobenzene derivatives, and the reaction thus failed to produced the expected products. The structure
of 1b and 7 were unambiguously confirmed by single crystal X-ray diffraction, and the molecular
structures with ellipsoid representation at 50% probability level are shown in Scheme 1.
6

a
Scheme 1. Survey of the scope the reaction using 2-naphthol and 1-naphthol
7
1
b
7

a
b
c
These are all isolated yields; N.R = No Reaction (as indicated by GC-MS analysis), For compound 7, 1-
naphthol was used as a substitute for 2-naphthol. The single crystal X-ray data for 1b (CCDC 1442427) and 7
CCDC 1442428) are deposited in the Cambridge database, and copies of these materials can be obtained free
(
of charge from CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, http://www.ccdc.am.ac.uk.
Because these types of cross-dehydrogenative couplings with either 2-naphthol or 1-naphthol have
already been achieved under different reaction conditions, and considering the fact that all these
9
reactions failed when simple phenols (other naphthols) were used as a coupling partner, the primary
focus was directed toward simple phenol derivatives. Scheme 2 summarizes the results obtained
when treating a series of N,N-dimethylaniline derivatives with different types of substituted phenols.
Simple phenols appeared to follow the same reactivity trend observed with 2-naphthol. In fact, 4-
ethoxy-N,N-dimethylaniline reacted with phenol as well as with a wide range of para-substituted
phenols to produce the corresponding 2'-aminobiphenyl-2-ol derivatives (8a-f). The isolated yield for
these reactions ranges from 52.3% for 4-isopropylphenol to 69.8% for 4-methylphenol. The electron-
rich or electron-poor nature of the groups at the para-position of theses phenols does not seem to
have any significant impact on the reactivity of these coupling partners since 4-bromophenol (59.2%)
and 4-chlorophenol (60.3%) produced a yield similar to that found for 4-methoxyphenol (56.7%) or
4-isopropylphenol (52.3%).
To examine whether having substituents at different position of the phenol ring will have any effect
on its reactivity, 3-chlorophenol, 3,4-dichlorophenol, 3,4-dimethylphenol and 2-methoxyphenol were
reacted with 4-ethoxy-N,N-dimethylaniline. Among these reactants, only 2-methoxyphenol failed to
produce the expected product (9d). This result indicates that any group at the ortho-position of either
coupling partners (phenols or aniline derivatives) will create enough steric hindrance to preclude the
reaction from proceeding. On the other hand, 3-chlorophenol, 3,4-dichlorophenol and 3,4-
dimethylphenol produced the expected product, with a very similar yield 9a (57.6%), 9b (53.8%) and
9c (59.4%), respectively. However, the reaction does not tolerate reactive functional groups such as
nitro, nitriles and esters as the reaction systematically failed to produce the expected products when 3-
8

or 4-nitrophenol, methyl 3-hydroxybenzoate, methyl 4-hydroxybenzoate and 4-hydroxybenzonitrile
were used as starting materials. 4-Hydroxyacetophenone produced only traces of the expected
product as indicated by GC-MS analysis. In each of these cases, the post-reaction mixtures appeared
to contain a significant amount of 4-ethoxy-N,N-dimethylaniline used as the coupling partner, while
the phenol derivative was fully (or almost fully) consumed. The side products obtained from these
latter reactions have not yet been fully characterized.
a
Scheme 2. Survey of the scope of the reaction using different types of substituted phenols
a
b
These are all isolated yields; N.R = No Reaction as indicated by GC-MS analysis
Furthermore, to investigate the electronic effect of electron-rich or electron-poor substituents on the
aniline coupling partner, N,N-dimethylaniline, N,N,4-trimethylaniline, 4-bromo-N,N-dimethylaniline
were treated with phenol, 4-methoxyphenol and 4-bromophenol, respectively. As expected, the
9

electronic nature of the substituents appeared to have little effect on the reactivity of phenols.
However, they seem to determine the reactivity of the aniline coupling partners. Any aniline
derivative with either a hydrogen or an electron-withdrawing group (10a-d) failed to produce any
product regardless of the phenol coupling partner, and the starting material was collected in each of
these cases. This indicates that under these conditions, the reaction requires that the aniline derivative
carries a strong electron donating group.
The effect of the size of the groups attached to the nitrogen of the aniline coupling partner (steric
hindrance) was also investigated (see Scheme 3). It turned out that, unlike 2-naphthol that could not
tolerate more than two ethyl groups on the nitrogen of the aniline (6a), phenols appeared to react
easily with 4-ethoxy-N,N-diethylaniline to produce the expected products in acceptable yields as
illustrated by 11a (47.3%) and 11b (45.8%).
Scheme 3: Survey of the steric effects of groups attached to the nitrogen of the aniline on the
a
reaction
1
0

a
b
These are all isolated yields; N.R = No Reaction as indicated by GC-MS analysis
However, they appeared not to be able to tolerate two substituents with more than 2 carbon-chains on
the nitrogen of the aniline as indicated by 12e-f and 13c-d. Nevertheless, the reaction tolerates one
bulky groups including propyl, isopropyl, isobutyl and even benzyl on the nitrogen of the aniline, as
long as the other group is a methyl or an ethyl (see 12a-c, 13a-b, 14a-c). However, the yield of the
reaction appeared to be significantly affected by the bulkiness of these groups. For example, 8b
obtained by reacting 4-bromophenol with 4-ethoxy-N,N-dimethylaniline produced 59.2% yield, while
reacting the same 4-bromophenol with 4-ethoxy-N,N-diethylaniline, 4-ethoxy-N-methyl-N-
propylaniline, 4-ethoxy-N-ethyl-N-propylaniline, 4-ethoxy-N-isobutyl-N-methylaniline or N-benzyl-
4
2
-ethoxy-N-methylaniline produced only 47.3% (11b), 45.8% (12b), 35.6% (12d), 22.8% (13b) and
5.3% (14c), respectively. Since electron-rich groups on the aniline coupling partner seem to be
having a beneficial effect on the reaction, we thought that adding more electro-donating groups on
aniline will result in the improvement of the yield of the reaction. To examine this hypothesis, 3,4-
dimethoxy-N,N-dimethylaniline was reacted with 4-bromophenol, phenol and 3-chlorophenol,
respectively (see Scheme 4).
1
1

Scheme 4: Survey of the reactivity of 3,4-dimethoxy-N,N-dimethylaniline towards 4-bromophenol,
a
phenol and 3-chlorophenol, respectively
a
b
These are all isolated yields; Traces are as indicated by the GC-MS analysis.
Suprizingly, the yields of these reactions dropped dramatically, with only the reaction with 4-
bromophenol (15a, 12.5%) producing enough product for a full characterization while the two other
reactions produced only traces of the product as indicated by the GC-MS analyses. In this case, it is
probable that 3,4-dimethoxy-N,N-dimethylaniline (0.44 eV) is oxidizing at a much faster rate than
other aniline derivatrives, and thus follows a path that leads mainly to a side-product rather than to
the expected product.
A considerable number of investigations towards elucidating the mechanism of cross-
dehydrogenative coupling of phenols as well as explaning the observed chemoselectivity are reported
in the chemical litterature. In fact, while explaining the chemoselectivity observed during a Cu(II)-
catalyzed naphthol/naphthylamine cross-dehydrogenative coupling, Hovorka and Zavada suggested
that the formation of a binuclear Cu(II)/amine complex comprising metal centers with different redox
1
2
potentials was responsible for the observed selectivity. The same approach was used by
9
a
Chandrasekharam et al, to explain the selectivity observed in their iron(III)-catalyzed cross-
dehydrogenative coupling of aniline derivatives and naphthols. However, based on electrochemical
measurements and frontier molecular orbital theory, Kočovský and coworkers suggested that many of
1
2

these reactions involves the coupling between an electrophilic radical and an anionic acceptor, and
that cross-coupling is favored when the difference in redox potentials between the two coupling
9
b, 13
partners is at least 0.25 V.
In this case, the coupling partner with the lowest redox potential is
selectively oxidized into an electrophilic radical, while the other one plays the role of the nucleophile.
Following a similar approach in our case, one would expect the aniline derivatives, based on their
lower redox potentials when compared to that of the phenol coupling partners, to be oxidized into the
electrophilic radical, leaving the phenols to assume the role of nucleophiles. If this was the case,
electronwithdrawing groups on the aniline derivatives will have a stabilizing effect on the
electrophilic radical and thus improve the yield of the reaction. Instead, electronwithdrawing groups
on the aniline derivatives appeared to preclude the reaction from proceeding, and concomitantly, the
electronic effects of substituents on the phenol coupling partners seem to have little to no effect.
These observations suggest that phenols, rather than the aniline derivatives, are oxidized into the
electrophilic radical intermediate, and the electron-donating groups on the aniline coupling partners
improve their nucleophilicity, resulting in the observed improved yield for the reaction. As a result,
we propose the following tentative mechanism for the silver(I)-mediated cross-coupling reaction. The
reaction starts with the formation of a silver(I)-phenol complex followed by one electron oxidation
resulting in a electrophilic radical intermediate (A). Subsequently, a nucleophilic attack by the aniline
derivative on the electrophilic radical intermediate (A) results in the formation of intermediate B
through the creation of a new C−C bond. Finally, the dehydroaromatization of intermediate B
produces the product as illustrated in Scheme 5. It should be mentioned that a quantitative amount of
metallic silver is produced during the course of the reaction.
1
4
These observation are consistent with the recent report by Libman et al, that showed the critical
importance of the phenol-metal binding during the oxidation step of the reaction that can result in the
selective oxidation of the most available functional group, even if this latter has a much higher
1
3

1
4
oxidation potential. In our case, since the nitrogen atom is fully substituted (tertiary amine), the
correspondent aniline derivatives are less suceptible to a coordination with silver(I), and as result, the
formation of a phenol-silver complex leading to the selective oxidation of the phenols into the
electrophilic radical intermediate (A) is favored. This might explain why the electronic effect of
substituents on the phenol coupling partners has little effect on the reaction. This also explains why
secondary aniline derivative failed to produce any product through this reaction, as they can easily
form a strong complex with silver(I) through a coordination reaction. The formation of such a
complex destroys any nucleophilic tendency for the nitrogen atom involved, and as a result, the
reaction will not proceed, even in a case of the formation of an electrophilic phenol radical
intermediate.
Scheme 5: Tentative mechanistic pathway for the cross-dehydrogenative coupling reaction between
phenols and aniline derivatives
1
4

It is also important to mention that attempts at coupling anisole derivatives with 4-ethoxy-N,N-
dimethylaniline failed to produce the expected product, and the starting material was collected at the
end of the reaction. This is an indication of the critical importance of a free hydroxyl group for this
reaction. However, since aniline derivatives are fully consumed while leftover phenols are
consistantly found in the mixture at the end of each reaction, it is conceivable that these aniline
derivatives are also competitively oxidized under these conditions, and that the resulting
intermediates take a different reaction path leading to the quick consumption of the aniline coupling
partner. All these observations are consistent with the tentative reaction mechanism shown in Scheme
5. Further investigations are currently ongoing in our lab to fully ellucidate the mechanism of this
reaction, and will be reported in due course.
CONCLUSION
A broad-spectrum and regioselective oxidative cross-dehydrogenative coupling reaction between
phenols and aniline derivatives has been developed. This reaction is promoted by AgNO
3
in the
presence of H under mild conditions. The reaction takes place under an opened atmospheric
2
O
2
environment indicating that it is not sensitive to either oxygen or moisture in the air. This reaction is
selective toward the creation of a new C–C bond at the ortho position of both amine and hydroxyl
functional groups in the respective starting materials. Furthermore, although oxidative cross-coupling
of phenols and anilines resulting in 2'-aminobiphenyl-2-ol derivatives have been previously reported,
these reactions have been mainly limited to 2-naphthol and 1-naphthol. This is one of the rare reports
in which the scope of this type of cross-coupling reaction is expanded to include simple phenol
derivatives.
1
5

ASSOCIATED CONTENT
Supporting Information
*
1
13
The preparation and characterization of compounds as well as the H NMR, C NMR and HRESI-
MS spectra for all the reported compounds are provided as supporting information. This material is
available free of charge via the Internet at
ACKNOWLEDGMENTS
JF acknowledges support from the National Science Foundation under grant # MRI-1337372, and the
Louisiana Board of Regents Support Fund: Supervised Undergraduate Research Experiences
(
LEQSF-EPS(2015)-SURE-152). D.S.B. gratefully acknowledges support from NSERC and the
CRC.
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Graphical Abstract
Silver(I)-Mediated Regioselective Oxidative
Cross-coupling of Phenol and Aniline Derivatives
Resulting in 2'-Aminobiphenyl-2-ols
Leave this area blank for abstract info.
†
†
,†
‡
§
Sololiya C. Berkessa, Zachary J. F. Clarke, Jean Fotie,* D. Scott Bohle, and Casey C. Grimm.
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Highlights




Regioselective dehydrogenative oxidative cross-coupling of phenols and anilines
The reaction is silver(I)-promoted in the presence of hydrogen peroxide
The scope of the reaction is expanded to include simple phenol derivatives
o
The reaction takes place at 0 C to rt under an opened atmospheric environment
2
0