Copper-catalyzed direct synthesis of di- and triphenylamines: A dramatic accelerating effect of 2-aminophenols

Article abstract of DOI:10.1002/ejoc.201001113

Utilizing the dramatic accelerating effect of 2-aminophenols, we developed a copper-catalyzed system for the selective synthesis of di- and triphenylamines. In addition, N- and O-arylation could be achieved in coupling reactions between 2-aminophenol and nitroaryl halides. A copper-catalyzed system for the selective synthesis of di- and triphenylamines has been developed. This new protocol provides a direct and efficient way to synthesize o-hydroxy-substituted di- and triphenylamines. Copyright

Full text of DOI:10.1002/ejoc.201001113

FULL PAPER
DOI: 10.1002/ejoc.201001113
Copper-Catalyzed Direct Synthesis of Di- and Triphenylamines: A Dramatic
Accelerating Effect of 2-Aminophenols
Yaming Li,*[a] Huifeng Wang,[a] Linlin Jiang,[a] Fangfang Sun,[a] Xinmei Fu,[a] and
Chunying Duan[a]
Keywords: Copper / Amines / Amino alcohols / N,O ligands / Reaction mechanisms
Utilizing the dramatic accelerating effect of 2-aminophenols,
we developed a copper-catalyzed system for the selective
synthesis of di- and triphenylamines. In addition, N- and O-
arylation could be achieved in coupling reactions between 2-
aminophenol and nitroaryl halides.
wald obtained mainly N-arylation products, together with
3–7% N,N-diarylated products in most cases.
Introduction
Di- and triphenylamines are important building blocks
in pharmaceuticals, natural products, and functional photo-
electric materials.[1] Copper-mediated arylation of amines
(Ullmann condensation) provides some of the most useful
practical methods for the synthesis of these compounds.
However, the synthetic scope of these transformations was
historically restricted because of the often harsh reaction
conditions, range of substrates, and the moderate yields ob-
tained.[2] The discovery of efficient Pd/phosphane-ligand-
catalyzed amination reactions (Buchwald–Hartwig reac-
tion)[3,4] has been a major breakthrough in this field.
Despite these significant improvements, limitations still ex-
ist, such as air- and moisture-sensitivity, functional group
tolerance, and the high cost of palladium. Recently, the
introduction of chelating ligands has led to dramatic im-
provements in copper/ligand systems (post-Ullmann reac-
tions)[5,6] for the formation of C–N bonds, enabling the use
only of catalytic amounts of copper under much milder
conditions. There was still a challenge, however, in the syn-
thesis of triphenylamines containing active hydroxy and
amine groups, which have often been problematic,[7] and
protecting group strategies have always needed to be em-
ployed.[8,9]
2-Aminophenol derivatives should serve as substrates for
the synthesis of di- and triphenylamines bearing hydroxy
groups, and so a set of reaction conditions to enable the
controlled formation of N-monoarylated and N,N-di-
arylated products from chelating 2-aminophenols was de-
veloped. In addition, the wide substrate scope of these reac-
tions was extended and a preliminary mechanism study was
also performed.
Results and Discussion
The reaction conditions for the selective synthesis of the
di- and triphenylamines were optimized with iodobenzene
and 2-aminophenol as a model system and with CuI as cat-
alyst. In the case of the diphenylamine compound, the polar
solvents DMSO, DMF, and CH3CN were more efficient
than the less polar toluene (Table 1, Entries 1–4). After
screening of a variety of bases, K3PO4 was found to give
the best result (Table 1, Entry 8). It should be pointed out
that an excess of 2-aminophenol was necessary (Table 1,
Entries 8–10), because the 2-aminophenol presumably
served as not only raw material but also as ligand to pro-
mote the conversion; in addition, the excess of 2-amino-
phenol could restrain the formation of the triphenylamine
compound. In the case of the triphenylamine compound,
increasing the amount of iodobenzene to 3 equiv. and brief
screening of the conditions (the optimization of conditions
is detailed in the Supporting Information) allowed us to
obtain the triphenylamine compound in 87% isolated yield
(Table 1, Entry 11).
In our previous work the use of 2-aminophenol deriva-
tives as ligands to promote the Cu-catalyzed formation of
C–N bonds was reported.[10] Recently, Buchwald reported
Pd- and Cu-catalyzed systems for the selective O- and N-
arylation of aminophenols.[11] As in our own previous
study,[10] by using 2-aminophenol itself as the ligand, Buch-
[a] State Key Laboratory of Fine Chemicals, College of Chemical
Engineering, Dalian University of Technology,
Dalian 116012, P. R. China
The scope of the N-arylation for the selective synthesis
of diphenylamines was explored with a variety of aryl io-
dides or bromides, containing either electron-donating or
electron-withdrawing groups on their aromatic rings. Gen-
erally, the diphenylamines were obtained in good to excel-
Fax: +86-411-39893900
E-mail: ymli@dlut.edu.cn
yamingli@chem.dlut.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001113.
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FULL PAPER
Table 1. Optimized reaction conditions for the selective synthesis
of the di- and triphenylamines.[a]
Table 2. Scope of N-arylation and N,N-diarylation of 2-amino-
phenols.
Entry
Base
Solvent
A/B
Yield [%]
1
2
3
4
5
6
7
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KOH
DMSO
DMF
CH3CN
C6H5CH3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.2:1
2.0:1
1.0:3
33
46
44
trace
40
25
46
62
40
Et3N
K2CO3
K3PO4
K3PO4
K3PO4
Cs2CO3
9
10
11
95
87[b]
[a] Reaction conditions: 2-aminophenol, iodobenzene (1 mmol),
CuI (0.2 mmol), the base (2 mmol), and the solvent (2 mL) were
allowed to react under argon at 80 °C for 16 h. The yield (HPLC)
was calibrated with diphenylamine as an internal standard. [b] Re-
action conditions: 2-aminophenol (1 mmol), iodobenzene
(3 mmol), CuI (0.2 mmol), and Cs2CO3 (3 mmol) in DMF (2 mL)
were allowed to react at 110 °C for 24 h (isolated yield).
lent yields (Table 2, Entries 1–11). The CuI catalytic system
also displayed great tolerance towards a range of functional
groups such as methyl, methoxy, and acetyl, and in particu-
lar towards free hydroxy and amine groups. In addition,
aryl iodides with ortho-substituents, which usually need rig-
orous conditions, coupled with 2-aminophenol in good
yields (Table 2, Entries 4, 5), showing that steric hindrance
does not have a huge influence on the N-arylation process.
The aryl bromides were able to couple with 2-aminophenol
at 110 °C in the presence of Cs2CO3 as base (Table 2, En-
tries 1b and 2b). We also observed that iodobenzene was
more reactive. Consequently, the coupling reaction showed
an interesting chemoselectivity, proceeding exclusively at
the iodo group, which allowed us to obtain 2-[(4-bro-
mophenyl)amino]phenol selectively with a yield of 84%
(Table 2, Entry 8).
The triphenylamines were next synthesized selectively
and in satisfactory yields by use of the optimal conditions
for N,N-diarylation (Table 2, Entries 12–17). Iodobenzene
gave a higher yield than 1-iodo-4-methylbenzene and 1-
iodo-4-methoxybenzene (Table 2, Entries 12–15), whereas
bromobenzene and 1-(4-bromophenyl)ethanone gave their
corresponding products in 46% and 65% yields, respec-
tively (Table 2, Entries 12b and 16). Steric effects for N,N-
diarylation were significant in relation to those in the case
of N-arylation, probably because of the weak nucleophilici-
ties of the diphenylamine intermediates for the formation
of the triphenylamine systems. Moreover, electronic effects
on the 2-aminophenols also showed some influence. The
[a] Reaction conditions: the 2-aminophenol (2 mmol), the aryl ha-
lide (1 mmol), CuI (0.2 mmol), K3PO4 (2 mmol), and DMF (2 mL)
were allowed to react under argon at 80 °C for 16 h. [b] Reaction
conditions: the 2-aminophenol (1 mmol), the aryl halide (3 mmol),
presence of electron-withdrawing groups, as in 2-amino-4- CuI (0.2 mmol), Cs2CO3 (3 mmol), and DMF (2 mL) were allowed
to react under argon at 110 °C for 24 h. Isolated yield.
chlorophenol, resulted in slightly lower yields than seen in
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Cu-Catalyzed Synthesis of Di- and Triphenylamines
the case of electron-donating groups (Table 2, Entries 17a, aminophenol occurred simultaneously. Because the oxidat-
17b, and 17c).
ive addition of 1-iodo-4-nitrobenzene was fast, primarily N-
When 2-aminophenol was coupled with 1-iodo-4-nitro- arylation was observed. In the case of 1-chloro-4-nitroben-
benzene (lower temperatures were employed to prevent de- zene, because the C–Cl bond is less active, N- and O-aryl-
halogenation), the N-arylation product was obtained in a ation took place equally. Raising the reaction temperature
yield of 70%, but at the same time the O-arylation byprod- to 110 °C made the C–Cl bond active enough for yields of
uct was detected by HPLC (Table 3, Entry 1). A similar re- the O-arylation product to approach those of the N-aryl-
sult was observed with 1-bromo-4-nitrobenzene (Table 3, ation product. The addition of H2O increased the phenox-
Entry 2). Particularly interestingly, with 1-chloro-4-nitro- ide concentration, so the O-arylation product was obtained
benzene, the N-arylation and the O-arylation products were almost exclusively. In the competition experiments, large
obtained in a ratio of 5:4 (Table 3, Entry 3). These results amounts of the diaryl ether were obtained at 110 °C in
prompted us to investigate selective N- and O-arylation fur- DMF because the aniline could not form the chelate.
ther. With use of a mixed solvent system of DMF and H2O,
The N-arylation of aminophenol derivatives was investi-
2-aminophenol was transformed into the O-arylation prod- gated (Table 4). Steric hindrance at the nitrogen atom de-
uct in 74% yield (Table 3, Entry 4). With use of DMF as pressed the chelation of 2-(N-methylamino)phenol with
solvent and an increase in the temperature to 110 °C, the N- copper, leading to a decline in the yield (Table 4, Entry 2).
arylation product could be obtained in 86% yield (Table 3, No N-arylation of 2-methoxybenzenamine took place
Entry 5).
(Table 4, Entry 3). 3-Aminophenol only afforded a 32%
yield of the diaryl ether, quite consistently with the result
of the competition experiments (Table 4, Entry 4). N-Aryl-
ation of 4-aminophenol was also in low yield (Table 4, En-
try 5). All these results indicated that the ortho-hydroxy
group in 2-aminophenol plays an important role through
the formation of the five-membered chelate.
Table 3. Selective N- and O-arylation of 2-aminophenol.[a]
Table 4. N-Arylation of aminophenol derivatives.[a]
Entry
X
I
Br 80
Cl 80
T (°C)
Solvent
Product[b]
N/O[c]
1
2
3
60
DMF
DMF
DMF
70 (N–Ar)
69 (N–Ar)
53 (N–Ar)
42 (O–Ar)
12:1
11:1
5:4
4
5
Cl 80
Cl 110
DMF/H2O (5:1) 74 (O–Ar)
DMF 86 (N–Ar)
1:15
29:1
[a] Reaction conditions: 2-aminophenol (2 mmol), the aryl halide
(1 mmol), CuI (0.2 mmol), the solvent (2 mL), and K3PO4
(2 mmol) were allowed to react under argon for 16 h. [b] Isolated
yield. [c] Calculated by HPLC at 267.5 nm.
Competition experiments were carried out with 1-chloro-
4-nitrobenzene and an aniline and phenol mixture (1:1) un-
der different conditions (Scheme 1). The O-arylation prod-
uct was obtained as the main product either at 80 °C in
DMF/H2O (5:1) or at 110 °C in DMF. We reasoned that
N-arylation was directed by chelation with 2-aminophenol,
whereas O-arylation was an SNAr process. When nitroaryl
[a] Reaction conditions: the aniline derivatives (2 mmol), iodo-
benzene (1 mmol), CuI (0.2 mmol) and K3PO4 (2 mmol) in DMF
(2 mL) were allowed to react under argon at 80 °C for 16 h. Iso-
halides were used as substrates, N- and O-arylation of 2- lated yield.
Scheme 1. Competition experiments with phenol/aniline (1:1).
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Y. Li, H. Wang, L. Jiang, F. Sun, X. Fu, C. Duan
FULL PAPER
From these results and previous findings in our group,[10]
we postulated that the reaction proceeded through a mecha-
nism as shown in Scheme 2. In this process, 2-aminophenol
would not only serve as substrate but would also play the
role of ligand. Firstly, with the help of base, two molecules
of 2-aminophenol, losing protons, would combine with cop-
per to provide the five-membered chelate A as shown. Next,
the aryl halides would go through a process of oxidative
addition and reductive elimination to effect N-arylation. At
this point, if the temperature was 80 °C and the 2-amino-
phenol was in excess, the chelate A would be the major
complex and the catalyst cycle would be turned to the right
in the scheme to provide the N-arylated product continu-
ously. If the aryl halide was in excess and at 110 °C, the
chelate B would become the major complex and the catalyst
and concentrated in vacuo. The resulting residue was purified by
column chromatography on silica gel (petroleum ether/acetone) to
provide the desired product. All the physical data for the known
compounds were in agreement with the literature.
General Procedure for N,N-Diarylation of 2-Aminophenols: 2-Ami-
nophenol or a derivative (1.0 mmol), an aryl halide (3.0 mmol),
CuI (0.2 mmol, 38 mg), Cs2CO3 (3.0 mmol, 978 mg), and DMF
(2 mL) were allowed to react under argon at 110 °C for 24 h. The
resulting mixture was acidified with HCl (2 m) to adjust the pH to
4.
2-(Phenylamino)phenol: 2-Aminophenol (218 mg, 2.0 mmol) was
coupled with iodobenzene (204 mg, 1.0 mmol) by the General Pro-
cedure under the standard conditions (Table 2, Entry 1). When bro-
mobenzene was used as substrate, Cs2CO3 was used as the base
and the reaction temperature was 110 °C. The crude product was
purified over a silica gel column with use of acetone/petroleum
cycle would turned to the left to provide the N,N-di- ether (1:20), giving a light yellow solid; yield 172 mg, 93% (Br:
1
133 mg, 72%). CAS: 644-71-3. H NMR (400 MHz, CDCl3): δ =
5.24 (br., 1 H, NH), 5.76 (br., 1 H, OH), 6.77 (d, J = 7.6 Hz, 2 H,
Ar-H), 6.85–6.90 (m, 2 H, Ar-H), 6.98 (d, J = 8.0 Hz, 1 H, Ar-H),
7.09 (t, J = 8.0 Hz, 1 H, Ar-H), 7.16–7.23 (m, 3 H, Ar-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 115.6, 116.1, 120.5, 121.2, 124.6,
126.0, 129.4, 129.6, 145.5, 151.0 ppm. MS (API): m/z = 186.1 [M
+ H]+.
arylation product.
2-(p-Tolylamino)phenol: 2-Aminophenol (218 mg, 2.0 mmol) was
coupled with 1-iodo-4-methylbenzene (218 mg, 1.0 mmol) at 70 °C
by the General Procedure (Table 2, Entry 2). When bromobenzene
was used as substrate, Cs2CO3 was used as the base and the reac-
tion temperature was 110 °C. The crude product was purified over
a silica gel column with use of acetone/petroleum ether (1:20), giv-
ing a beige solid; yield 169 mg, 85% (Br: 139 mg, 70%). CAS:
87671-67-8. 1H NMR (400 MHz, CDCl3): δ = 2.27 (s, 3 H, Me),
5.19 (br., 1 H, NH), 5.83 (br., 1 H, OH), 6.71 (d, J = 7.2 Hz, 2 H,
Ar-H), 6.87 (m, 1 H, Ar-H), 6.97 (m, 1 H, Ar-H), 7.03 (m, 3 H,
Ar-H), 7.14 (d, J = 7.6 Hz, 1 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 20.5, 115.3, 116.4, 121.0, 123.8, 125.4, 129.9, 142.8,
150.5 ppm. MS (API): m/z = 200.1 [M + H]+, 222.1 [M + Na]+.
Scheme 2. Plausible catalytic mechanism for the selective synthesis
of di- and triphenylamines.
2-(4-Methoxyphenylamino)phenol:
2-Aminophenol
(218 mg,
2.0 mmol) was coupled with 1-iodo-4-methoxybenzene (234 mg,
1.0 mmol) at 70 °C by the General Procedure (Table 2, Entry 3).
Conclusions
In conclusion, by utilizing the dramatic self-accelerating The crude product was purified over a silica gel column with use
of acetone/petroleum ether (1:20), giving a white solid; yield
159 mg, 74%. 1H NMR (400 MHz, CDCl3): δ = 3.77 (s, 3 H,
OMe), 5.63 (br., 2 H, OH, NH), 6.81–6.88 (m, 5 H, Ar-H), 6.93
(d, J = 7.6 Hz, 1 H, Ar-H), 6.98–7.00 (m, 1 H, Ar-H), 7.09 (d, J =
7.6 Hz, 1 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.7,
114.8, 115.1, 118.8, 121.1, 122.2, 124.4, 131.0, 138.3, 149.5,
154.4 ppm. MS (API): m/z = 216.1 [M + H]+, 250.1 [M + Cl]–.
effect of 2-aminophenols, we have developed a copper-cata-
lyzed system capable of selective N-arylation and N,N-di-
arylation of 2-aminophenols. In addition, both N- and O-
arylation products of 2-aminophenol could be obtained
when nitroaryl halides were used as substrates. This catalyst
system is likely to find considerable application because it
provides a direct and efficient way to synthesize 2-hydroxy-
substituted di- and triphenylamines.
2-(o-Tolylamino)phenol: 2-Aminophenol (218 mg, 2.0 mmol) was
coupled with 1-iodo-2-methylbenzene (218 mg, 1.0 mmol) under
the standard conditions by the General Procedure (Table 2, En-
try 4). The crude product was purified over a silica gel column with
use of acetone/petroleum ether (1:25), giving a beige solid; yield
183 mg, 92%. CAS: 92028-38-1. 1H NMR (400 MHz, CDCl3): δ =
2.32 (s, 3 H, Me), 5.68 (br., 2 H, OH, NH), 6.64 (d, J = 8.0 Hz, 1
H, Ar-H), 6.83–6.91 (m, 2 H, Ar-H), 6.99 (d, J = 7.8 Hz, 1 H, Ar-
H), 7.06–7.11 (m, 3 H, Ar-H), 7.17 (d, J = 7.2 Hz, 1 H, Ar-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 17.9, 115.2, 115.5, 120.7, 121.2,
124.7, 125.2, 126.0, 127.3, 129.5, 130.9, 143.5, 150.9 ppm. MS
(API): m/z = 200.1 [M + H]+.
Experimental Section
General Procedure for N-Arylation of 2-Aminophenol: A flame-
dried test tube containing a magnetic stirring bar was charged un-
der argon with 2-aminophenol or a derivative (2.0 mmol), an aryl
halide (1.0 mmol), CuI (0.2 mmol, 38 mg), K3PO4 or Cs2CO3
(2.0 mmol), and DMF (2 mL). The mixture was treated at the indi-
cated temperature for 16 h and allowed to cool to room tempera-
ture. The resulting mixture was acidified with HCl (2 m) to adjust
the pH to 6. The aqueous fraction was extracted with ethyl acetate
(3ϫ25 mL). The combined organic layers were dried with Na2SO4
2-(2-Hydroxyphenylamino)phenol:
2-Aminophenol
(218 mg,
2.0 mmol) was coupled with 2-iodophenol (220 mg, 1.0 mmol) un-
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Cu-Catalyzed Synthesis of Di- and Triphenylamines
der the standard conditions by the General Procedure (Table 2, En-
try 5). The crude product was purified over a silica gel column with
4-Methyl-2-(phenylamino)phenol: 2-Amino-4-methylphenol (246 mg,
2.0 mmol) was coupled with iodobenzene (204 mg, 1.0 mmol) un-
der the standard conditions by the General Procedure (Table 2, En-
use of acetone/petroleum ether (1:6), giving a white solid; yield
1
165 mg, 82%. CAS: 2391-71-1. H NMR (400 MHz, CDCl3): δ = try 9b). The crude product was purified over a silica gel column
5.45 (br., 3 H, OH, NH), 6.84–6.85 (m, 4 H, Ar-H), 6.91–6.95 (m, with use of acetone/petroleum ether (1:20), giving a yellow solid;
1
4 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 115.1, 120.6,
121.4, 123.5, 131.5, 148.0 ppm. MS (API): m/z = 202.1 [M + H]+,
224.1 [M + Na]+.
yield 169 mg, 85%. H NMR (400 MHz, [D6]DMSO): δ = 2.16 (s,
3 H, Me), 6.56 (dd, J = 8.0, J = 1.6 Hz, 1 H, Ar-H), 6.72–6.75 (m,
2 H, Ar-H), 6.97–6.99 (m, 3 H, Ar-H), 7.07 (br., 1 H, Ar-H), 7.14–
7.18 (m, 2 H, Ar-H), 9.16 (br., 1 H, Ar-H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 20.4, 115.2, 116.0, 118.6, 119.1, 121.7,
127.6, 128.7, 130.3, 144.4, 145.7 ppm. GC–MS (EI): m/z = 199
[M]+.
2-(4-Aminophenylamino)phenol:
2-Aminophenol
(218 mg,
2.0 mmol) was coupled with 4-iodoaniline (219 mg, 1.0 mmol) un-
der the standard conditions by the General Procedure (Table 2, En-
try 6). The resulting mixture did not add HCl. The crude product
was purified over a silica gel column with use of acetone/petroleum
ether (1:6), giving a brown solid; yield 130 mg, 65%. 1H NMR
(400 MHz, [D6]DMSO): δ = 4.80 (br., 2 H, NH2), 6.38 (br., 1 H,
NH), 6.48–6.53 (m, 3 H, Ar-H), 6.58 (t, J = 7.6 Hz, 1 H, Ar-H),
6.74 (d, J = 8.0 Hz, 1 H, Ar-H), 6.78 (d, J = 8.0 Hz, 1 H, Ar-H),
6.84 (d, J = 8.8 Hz, 2 H, Ar-H), 9.31 (br., 1 H, OH) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 112.4, 114.4, 114.7, 117.6,
119.2, 122.3, 131.9, 134.7, 143.5, 145.0 ppm. MS (API): m/z = 235.1
[M + Cl]–. HR-ESI-MS: m/z calcd. for C12H11N2O [M – H]–:
199.0871; found 199.0868.
4-tert-Butyl-2-(phenylamino)phenol:
2-Amino-4-tert-butylphenol
(330 mg, 2.0 mmol) was coupled with iodobenzene (204 mg,
1.0 mmol) under the standard conditions by the General Procedure
(Table 2, Entry 9c). The crude product was purified over a silica gel
column with use of acetone/petroleum ether (1:20), giving a brown
solid; yield 195 mg, 81%. 1H NMR (400 MHz, [D6]DMSO): δ =
1.20 (s, 9 H, Me), 6.70 (t, J = 7.2 Hz, 1 H, Ar-H), 6.75–6.81 (m, 2
H, Ar-H), 6.93 (d, J = 7.6 Hz, 2 H, Ar-H), 7.13 (d, J = 7.6 Hz, 2
H, Ar-H), 7.17–7.18 (m, 2 H, Ar-H), 9.17 (br., 1 H, OH) ppm. 13
C
NMR (100 MHz, [D6]DMSO): δ = 31.5, 33.8, 115.0, 115.4, 116.6,
118.3, 118.4, 128.9, 129.5, 141.3, 144.9, 146.2 ppm. GC–MS (EI):
m/z = 241 [M]+. HR-ESI-MS: m/z calcd. for C16H18NO [M – H]–:
240.1388; found 240.1382.
1-[4-(2-Hydroxyphenylamino)phenyl]ethanone:
2-Aminophenol
(218 mg, 2.0 mmol) was coupled with 4-acetylbromobenzene
(199 mg, 1.0 mmol) under the standard conditions by the General
Procedure (Table 2, Entry 7). The crude product was purified over
a silica gel column with use of acetone/petroleum ether (1:6), giving
a yellow solid; yield 175 mg, 77%. 1H NMR (400 MHz, [D6]-
DMSO): δ = 2.43 (s, 3 H, Me), 6.78–6.82 (m, 1 H, Ar-H), 6.88 (d,
J = 8.4 Hz, 2 H, Ar-H), 6.92–6.98 (m, 2 H, Ar-H), 7.21 (d, J =
7.6 Hz, 1 H, Ar-H), 7.76 (d, J = 8.4 Hz, 2 H, Ar-H), 8.06 (br., 1
H, Ar-H), 9.57 (br., 1 H, Ar-H) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 26.0, 113.1, 116.1, 119.2, 123.1, 124.4, 126.6, 128.0,
130.2, 150.0, 150.3, 195.3 ppm. MS (API): m/z = 226.1 [M – H]–,
4-Chloro-2-(p-tolylamino)phenol: 2-Amino-4-chlorophenol (287 mg,
2.0 mmol) was coupled with 1-iodo-4-methylbenzene (218 mg,
1.0 mmol) under the standard conditions by the General Procedure
(Table 2, Entry 10). The crude product was purified over a silica
gel column with use of acetone/petroleum ether (1:15), giving a
dark purple solid; yield 147 mg, 63%. 1H NMR (400 MHz,
CDCl3): δ = 2.30 (s, 3 H, Me), 5.48 (br., 2 H, Ar-H), 6.81–6.84 (m,
3 H, Ar-H), 6.89 (dd, J = 8.6, J = 2.4 Hz, 2 H, Ar-H), 7.08 (d, J
= 8.0 Hz, 2 H, Ar-H), 7.12 (d, J = 2.4 Hz, 1 H, Ar-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 20.8, 116.3, 118.5, 119.0, 122.2,
125.6, 130.1, 131.3, 132.7, 140.7, 146.4 ppm. GC–MS (EI): m/z =
233 [M]+, 235 [M + 2]+. HR-ESI-MS: m/z calcd. for C13H11ClNO
[M – H]–: 232.0529; found 232.0538.
262.1 [M
+
Cl]–. HR-ESI-MS: m/z calcd. for C14H12NO2
[M – H]–: 226.0868; found 226.0867.
2-(4-Bromophenylamino)phenol:
2-Aminophenol
(218 mg,
2.0 mmol) was coupled with 1-bromo-4-iodobenzene (283 mg,
1.0 mmol) at 60 °C for 16 h by the General Procedure (Table 2,
Entry 8). The crude product was purified over a silica gel column
with use of acetone/petroleum ether (1:20), giving a white solid;
4-Chloro-2-(4-methoxyphenylamino)phenol: 2-Amino-4-chlorophen-
ol (286 mg, 2.0 mmol) was coupled with 1-iodo-4-methoxybenzene
(234 mg, 1.0 mmol) under the standard conditions by the General
Procedure (Table 2, Entry 11a). The crude product was purified
over a silica gel column with use of acetone/petroleum ether (1:15),
giving a dark purple solid; yield 160 mg, 64%. 1H NMR (400 MHz,
[D6]DMSO): δ = 3.73 (s, 3 H, Me), 6.58 (dd, J = 8.4, J = 2.4 Hz,
1 H, Ar-H), 6.76 (d, J = 8.4 Hz, 1 H, Ar-H), 6.80 (d, J = 2.4 Hz,
1 H, Ar-H), 6.88 (d, J = 9.2 Hz, 2 H, Ar-H), 7.08–7.10 (m, 3 H, Ar-
H), 9.72 (br., 1 H, OH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 55.2, 112.0, 114.4, 115.4, 117.4, 121.9, 122.7, 135.1, 135.3, 144.4,
154.4 ppm. GC–MS (EI): m/z = 249 [M]+, 251 [M + 2]+. HR-ESI-
MS: m/z calcd. for C13H11ClNO2 [M – H]–: 248.0478; found
248.0475.
1
yield 222 mg, 84%. H NMR (400 MHz, CDCl3): δ = 5.31 (br., 1
H, NH), 5.63 (br., 1 H, OH), 6.66 (d, J = 8.4 Hz, 2 H), 6.87–6.89
(m, 1 H), 6.97 (d, J = 7.6 Hz, 1 H), 7.07–7.10 (m, 1 H), 7.15 (d, J
= 8.0 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 112.4, 115.7, 117.7, 121.3, 124.4, 126.5,
128.7, 132.4, 144.6, 150.9 ppm. MS (API): m/z = 262.0, 264.0 [M –
H]–, 297.9, 299.9 [M + Cl]–.
4-Chloro-2-(phenylamino)phenol: 2-Amino-4-chlorophenol (287 mg,
2.0 mmol) was coupled with iodobenzene (204 mg, 1.0 mmol) un-
der the standard conditions by the General Procedure (Table 2, En-
try 9a). The crude product was purified over a silica gel column
with use of acetone/petroleum ether (1:20), giving a brown solid;
yield 143 mg, 66%. 1H NMR (400 MHz, [D6]DMSO): δ = 6.72 (dd,
4-tert-Butyl-2-(4-methoxyphenylamino)phenol: 2-Amino-4-tert-but-
ylphenol (330 mg, 2.0 mmol) was coupled with 1-iodo-4-methoxy-
benzene (234 mg, 1.0 mmol) under the standard conditions by the
J = 8.4, J = 2.4 Hz, 1 H, Ar-H), 6.81–6.86 (m, 2 H, Ar-H), 7.06– General Procedure (Table 2, Entry 11b). The crude product was
7.08 (m, 3 H, Ar-H), 7.23 (t, J = 8.0 Hz, 2 H, Ar-H), 7.35 (br., 1 purified over a silica gel column with use of acetone/petroleum
H, Ar-H), 9.80 (br., 1 H. OH) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 115.5, 116.0, 117.6, 119.6, 120.1, 122.5, 128.9, 132.9,
142.9, 146.0 ppm. GC–MS (EI): m/z = 219 [M]+, 221 [M + 2]+.
HR-ESI-MS: m/z calcd. for C12H9ClNO [M – H]–: 218.0373; found
218.0379.
ether (1:20), giving a dark purple solid; yield 184 mg, 68%. 1H
NMR (400 MHz, [D6]DMSO): δ = 1.19 (s, 9 H, Me), 3.69 (s, 3 H,
OMe), 6.66 (dd, J = 8.2, J = 2.4 Hz, 1 H, Ar-H), 6.73 (d, J =
8.4 Hz, 1 H, Ar-H), 6.82 (d, J = 8.8 Hz, 2 H, Ar-H), 6.98 (d, J =
8.4 Hz, 2 H, Ar-H), 7.07 (d, J = 2.4 Hz, 1 H, Ar-H), 9.13 (br., 1
Eur. J. Org. Chem. 2010, 6967–6973
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6971

Y. Li, H. Wang, L. Jiang, F. Sun, X. Fu, C. Duan
FULL PAPER
H, OH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 31.4, 33.7,
55.2, 113.0, 114.3, 114.4, 116.3, 118.8, 131.5, 137.3, 141.3, 144.4,
153.0 ppm. GC–MS (EI): m/z = 271 [M]+. HR-ESI-MS: m/z calcd.
for C17H20NO2 [M – H]–: 270.1494; found 270.1483.
120.2, 120.4, 128.8, 129.8, 130.5, 131.1, 150.1, 154.1, 196.0 ppm.
MS (API): m/z = 344.1 [M – H]–, 380.1 [M + Cl]–. HR-ESI-MS:
m/z calcd. for C22H18NO3 [M – H]–: 344.1287; found 344.1282.
4-Chloro-2-(diphenylamino)phenol:
2-Amino-4-chlorophenol
2-(Diphenylamino)phenol: 2-Aminophenol (109 mg, 1.0 mmol) was
coupled with iodobenzene (612 mg, 3.0 mmol) under the standard
conditions by the General Procedure (Table 2, Entry 12). The crude
product was purified over a silica gel column with use of acetone/
petroleum ether (1:40), giving a light yellow solid; yield 227 mg,
87% (Br: 120 mg, 46%). 1H NMR (400 MHz, CDCl3): δ = 5.56
(br., 1 H, OH), 6.95 (td, J = 7.8, J = 1.2 Hz, 1 H, Ar-H), 7.05 (m,
7 H, Ar-H), 7.12 (dd, J = 8.0, J = 1.2 Hz, 1 H, Ar-H), 7.22 (td, J
= 7.8, J = 1.2 Hz, 1 H, Ar-H), 7.17 (m, 4 H, Ar-H) ppm. 13C NMR
(143 mg, 1.0 mmol) was coupled with iodobenzene (612 mg,
3.0 mmol) under the standard conditions by the General Procedure
(Table 2, Entry 17a). The crude product was purified over a silica
gel column with use of acetone/petroleum ether (1:30), giving a
light brown solid; yield 181 mg, 61%. 1H NMR (400 MHz, [D6]-
DMSO): δ = 6.88–6.95 (m, 7 H, Ar-H), 7.03 (d, J = 2.8 Hz, 1 H,
Ar-H), 7.14 (dd, J = 8.8, J = 2.8 Hz, 1 H, Ar-H), 7.23 (t, J =
7.2 Hz, 4 H, Ar-H), 9.75 (br., 1 H, OH) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 118.4, 121.1, 121.6, 122.5, 126.7, 128.9, 129.4,
(100 MHz, CDCl3): δ = 116.7, 121.6, 121.9, 122.9, 127.9, 129.6, 134.1, 146.7, 153.0 ppm. MS (API): m/z = 294.0, 296.0 [M – H]–.
133.3, 146.9 152.5 ppm. MS (API): m/z = 262.1 [M + H]+.
HR-ESI-MS: m/z calcd. for C18H13ClNO [M – H]–: 294.0686;
found 294.0688.
2-[Bis(4-methylphenyl)amino]phenol: 2-Aminophenol (109 mg,
1.0 mmol) was coupled with 1-iodo-2-methylbenzene (654 mg,
3.0 mmol) under the standard conditions by the General Procedure
(Table 2, Entry 13). The crude product was purified over a silica
gel column with use of acetone/petroleum ether (1:40), giving a
light yellow solid; yield 214 mg, 74%. 1H NMR (400 MHz,
CDCl3): δ = 2.19 (s, 6 H, Me), 5.46 (br., 1 H, OH), 6.76–6.82 (m,
5 H, Ar-H), 6.89–6.97 (m, 6 H, Ar-H), 7.04 (t, J = 7.6 Hz, 1 H,
Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.9, 116.5, 117.0,
121.5, 121.9, 129.1, 130.1, 132.3, 133.8, 144.7, 152.3 ppm. MS
(API): m/z = 290.3 [M + H]+, 312.1 [M + Na]+.
2-(Diphenylamino)-4-methylphenol:
2-Amino-4-methylphenol
(123 mg, 1.0 mmol) was coupled with iodobenzene (612 mg,
3.0 mmol) under the standard conditions by the General Procedure
(Table 2, Entry 17b). The crude product was purified over a silica
gel column with use of acetone/petroleum ether (1:40), giving a
light yellow solid; yield 193 mg, 70%. 1H NMR (400 MHz, [D6]-
DMSO): δ = 2.15 (s, 3 H, Me), 6.82–6.92 (m, 9 H, Ar-H), 7.19 (t,
J = 7.8 Hz, 4 H, Ar-H), 9.13 (br., 1 H, OH) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 20.2, 116.9, 120.7, 120.9, 127.9, 128.7,
128.9, 130.6, 132.3, 147.1, 151.8 ppm. MS (API): m/z = 274.1 [M –
H]–, 549.2 [2M – H]–. HR-ESI-MS: m/z calcd. for C19H16NO [M –
H]–: 274.1232; found 274.1233.
2-[Bis(4-methoxyphenyl)amino]phenol: 2-Aminophenol (109 mg,
1.0 mmol) was coupled with 1-iodo-4-methoxybenzene (702 mg,
3.0 mmol) under the standard conditions by the General Procedure
(Table 2, Entry 14). The crude product was purified over a silica
gel column with use of acetone/petroleum ether (1:40), giving a
light yellow solid; yield 238 mg, 74%. 1H NMR (400 MHz,
4-tert-Butyl-2-(diphenylamino)phenol: 2-Amino-4-tert-butylphenol
(165 mg, 1.0 mmol) was coupled with iodobenzene (612 mg,
3.0 mmol) under the standard conditions by the General Procedure
(Table 2, Entry 17c). The crude product was purified over a silica
CDCl3): δ = 2.24 (s, 6 H, OMe), 5.58 (br., 1 H, OH), 6.83 (t, J = gel column with use of acetone/petroleum ether (1:40), giving a
7.8 Hz, 1 H, Ar-H), 6.88 (d, J = 8.4 Hz, 4 H, Ar-H), 6.96–7.03 (m,
light brown solid; yield 278 mg, 87%. 1H NMR (400 MHz, [D6]-
6 H, Ar-H), 7.09 (t, J = 7.6 Hz, 1 H, Ar-H) ppm. 13C NMR DMSO): δ = 1.19 (s, 9 H, Me), 6.85–6.90 (m, 7 H, Ar-H), 7.06 (d,
(100 MHz, CDCl3): δ = 55.5, 115.1, 124.4, 125.9, 128.3, 129.1, J = 2.4 Hz, 1 H, Ar-H), 7.14 (dd, J = 8.4, J = 2.4 Hz, 1 H, Ar-H),
135.6, 138.8, 160.0 ppm. MS (API): m/z = 322.1 [M + H]+, 344.0
7.18–7.22 (m, 4 H, Ar-H), 9.19 (br., 1 H, OH) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 31.3, 33.7, 116.6, 120.7, 120.9, 124.1,
127.0, 128.9, 131.8, 142.4, 147.1, 151.8 ppm. MS (API): m/z = 316.1
[M – H]–. HR-ESI-MS: m/z calcd. for C22H22NO [M – H]–:
316.1701; found 316.1716.
[M + Na]+.
2-(Di-o-tolylamino)phenol: 2-Aminophenol (109 mg, 1.0 mmol) was
coupled with 1-iodo-2-methylbenzene (654 mg, 3.0 mmol) under
the standard conditions by the General Procedure (Table 2, En-
try 15). The crude product was purified over a silica gel column
with use of acetone/petroleum ether (1:40), giving a light yellow
solid; yield 225 mg, 78%. 1H NMR (400 MHz, CDCl3): δ = 1.94
(s, 6 H, Me), 5.16 (br., 1 H, OH), 6.76 (dd, J = 7.6, J = 1.2 Hz, 2
2-(4-Nitrophenoxy)benzenamine:
2-Aminophenol
(218 mg,
2.0 mmol) was coupled with 1-chloro-4-nitrobenzene (157 mg,
1.0 mmol) in DMF/H2O (5:1) at 80 °C for 24 h by the General
Procedure (Table 3, Entry 4). The crude product was purified over
H, Ar-H), 6.81 (td, J = 7.6, J = 1.2 Hz, 2 H, Ar-H), 6.94 (d, J = a silica gel column with use of acetone/petroleum ether (1:8), giving
8.0 Hz, 1 H, Ar-H), 7.05–7.10 (m, 5 H, Ar-H), 7.17 (d, J = 7.2 Hz,
2 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.7, 116.4,
121.0, 124.8, 126.1, 126.3, 126.9, 127.1, 127.3, 132.1, 133.0, 135.0,
150.5 ppm. MS (API): m/z = 290.1 [M + H]+, 312.1 [M + Na]+.
HR-ESI-MS: m/z calcd. for C20H18NO [M – H]–: 288.1388; found
288.1385.
a yellow solid; yield 170 mg, 74%. CAS: 18226-25-0. 1H NMR
(400 MHz, [D6]DMSO): δ = 5.05 (br., 2 H, NH2), 6.61 (td, J = 7.4,
J = 1.6 Hz, 1 H, Ar-H), 6.85 (dd, J = 8.0, J = 1.6 Hz, 1 H, Ar-H),
6.93 (dd, J = 8.0, J = 1.2 Hz, 1 H, Ar-H), 7.00–7.04 (m, 3 H, Ar-
H), 8.23 (d, J = 8.0 Hz, 2 H, Ar-H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 116.2, 116.3, 116.5, 121.5, 125.9, 126.5, 139.4,
140.8, 141.7, 163.1 ppm. MS (API): m/z = 231.3 [M + H]+, 253.3
[M + Na]+.
2-[Bis(4-acetylphenyl)amino]phenol:
2-Aminophenol
(109 mg,
1.0 mmol) was coupled with 4-acetylbromobenzene (594 mg,
3.0 mmol) under the standard conditions by the General Procedure
(Table 2, Entry 16). The crude product was purified over a silica
gel column with use of acetone/petroleum ether (1:40), giving a
light yellow solid; yield 224 mg, 65%. 1H NMR (400 MHz, [D6]-
2-(4-Nitrophenylamino)phenol: 2-Aminophenol (218 mg, 2.0 mmol)
was coupled with 1-iodo-4-nitrobenzene (249 mg, 1.0 mmol) under
the standard conditions by the General Procedure (Table 3, En-
try 5). The crude product was purified over a silica gel column with
DMSO): δ = 2.50 (s, 6 H, Me), 6.90 (t, J = 8.0 Hz, 1 H, Ar-H), use of acetone/petroleum ether (1:6), giving an orange solid; yield
7.02 (m, 5 H, Ar-H), 7.12 (d, J = 8.0 Hz, 1 H, Ar-H), 7.23 (t, J = 198 mg, 86%. CAS: 119707-16-3. 1H NMR (400 MHz, [D6]-
7.6 Hz, 1 H, Ar-H), 7.87 (d, J = 8.4 Hz, 4 H, Ar-H), 9.73 (br., 1 DMSO): δ = 6.80–6.86 (m, 3 H, Ar-H), 6.96 (d, J = 6.8 Hz, 1 H,
H, OH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 26.7, 117.4,
Ar-H), 7.05 (t, J = 7.6 Hz, 1 H, Ar-H), 7.20 (d, J = 6.8 Hz, 1 H,
6972
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6967–6973

Cu-Catalyzed Synthesis of Di- and Triphenylamines
Ar-H), 8.03 (d, J = 9.2 Hz, 2 H, Ar-H), 8.74 (br., 1 H, NH), 9.73
(br., 1 H, OH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 112.7,
116.3, 119.3, 124.8, 125.7, 125.9, 126.6, 137.0, 151.2, 152.3 ppm.
MS (API): m/z = 231.1 [M + H]+, 253.1 [M + Na]+.
Acknowledgments
This work was supported by the National Natural Science Funda-
tion of China (Project No. 20876021) and the Education Depart-
ment of Liaoning Province (2009S021).
2-[Methyl(phenyl)amino]phenol: 2-(Methylamino)phenol (246 mg,
2.0 mmol) was coupled with iodobenzene (204 mg, 1.0 mmol) un-
der the standard conditions by the General Procedure (Table 4, En-
try 2). The crude product was purified over a silica gel column with
use of acetone/petroleum ether (1:20), giving a white solid; yield
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1
103 mg, 52%. H NMR (400 MHz, [D6]DMSO): δ = 3.13 (s, 3 H,
Me), 6.55 (d, J = 8.0 Hz, 2 H, Ar-H), 6.63 (t, J = 7.2 Hz, 1 H, Ar-
H), 6.84 (td, J = 8.0, J = 1.2 Hz, 1 H, Ar-H), 6.98 (dd, J = 8.0, J
= 1.2 Hz, 1 H, Ar-H), 7.06–7.13 (m, 4 H, Ar-H), 9.35 (br., 1 H,
OH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 38.8, 112.9,
116.5, 117.0, 119.9, 127.3, 128.7, 129.0, 134.5, 149.2, 154.0 ppm.
MS (API): m/z = 200.1 [M + H]+, 222.1 [M + Na]+.
3-Phenoxyaniline: 3-Aminophenol (218 mg, 2.0 mmol) was coupled
with iodobenzene (204 mg, 1.0 mmol) under the standard condi-
tions by the General Procedure (Table 4, Entry 4). The crude prod-
uct was purified over a silica gel column with use of acetone/petro-
leum ether (1:20), giving a white solid; yield 59 mg, 32%. CAS:
3586-12-7. 1H NMR (400 MHz, [D6]DMSO): δ = 5.23 (br., 2 H,
NH2), 6.14 (dd, J = 6.8, J = 2.4 Hz, 1 H, Ar-H), 6.19 (d, J =
2.4 Hz, 1 H, Ar-H), 6.33 (d, J = 8.0 Hz, 1 H, Ar-H), 6.97–7.01 (m,
3 H, Ar-H), 7.09 (t, J = 7.2 Hz, 1 H, Ar-H), 7.36 (t, J = 7.6 Hz, 2
H, Ar-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 103.8,
105.9, 109.3, 118.6, 123.0, 129.9, 130.1, 150.5, 157.0, 157.6 ppm.
GC–MS (EI): m/z = 185 [M]+.
[5] For reviews, see: a) S. V. Ley, A. W. Thomas, Angew. Chem. Int.
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4-(Phenylamino)phenol: 4-Aminophenol (218 mg, 2.0 mmol) was
coupled with iodobenzene (204 mg, 1.0 mmol) under the standard
conditions by the General Procedure (Table 4, Entry 5). The crude
product was purified over a silica gel column with use of acetone/
petroleum ether (1:20), giving a white solid; yield 118 mg, 64%.
1
CAS: 112-37-2. H NMR (400 MHz, [D6]DMSO): δ = 6.65 (t, J =
7.2 Hz, 1 H, Ar-H), 6.71 (d, J = 8.8 Hz, 2 H, Ar-H), 6.86 (d, J =
7.6 Hz, 2 H, Ar-H), 6.94 (d, J = 8.8 Hz, 2 H, Ar-H), 7.12 (t, J =
7.6 Hz, 2 H, Ar-H), 7.64 (br., 1 H, NH), 9.01 (br., 1 H, OH) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 114.2, 115.7, 117.6, 121.4,
129.1, 134.3, 145.8, 152.1 ppm. GC–MS (EI): m/z = 185 [M]+.
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Supporting Information (see also the footnote on the first page of
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this article): Experimental procedures, characterization data, and
17429.
1
13
copies of the original H NMR and
C NMR spectra for all
Received: August 9, 2010
compounds.
Published Online: November 5, 2010
Eur. J. Org. Chem. 2010, 6967–6973
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6973