Iron/copper-cocatalyzed ullmann N,O-arylation using FeCl3, CuO, and rac-1,1′-Binaphthyl-2,2′-diol

Article abstract of DOI:10.1055/s-2008-1078214

We have developed an efficient and inexpensive bimetallic catalyst FeCl₃, CuO, and rac-BINOL that could promote N,O-arylation of aliphatic, arylamines, and phenols. The cross-coupling reaction conditions have high tolerance of various functional groups. This versatile and efficient iron/copper-cocatalyst can widely be used in the synthesis of the compounds containing (aryl)C-N or (aryl)C-O(aryl) bond. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078214

2540
LETTER
Iron/Copper-Cocatalyzed Ullmann N,O-Arylation Using FeCl3, CuO,
and rac-1,1¢-Binaphthyl-2,2¢-diol
I
ron/Copper-Co
h
catalyzedU
l
e
lmann
N
,O-Aryla
W
tion ang,a Hua Fu,*a Yuyang Jiang,a,b Yufen Zhaoa
a
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
Fax +86(10)62781695; E-mail: fuhua@mail.tsinghua.edu.cn
Key Laboratory of Chemical Biology, College of Shenzhen, Tsinghua University, Guangdong Province,
Shenzhen 518057, P. R. of China
b
Received 22 May 2008
alyst FeCl3, CuO, and BINOL to construct C(aryl)–N and
C(aryl)–O bonds from aryl iodides and bromides.
Abstract: We have developed an efficient and inexpensive bime-
tallic catalyst FeCl3, CuO, and rac-BINOL that could promote N,O-
arylation of aliphatic, arylamines, and phenols. The cross-coupling
reaction conditions have high tolerance of various functional
groups. This versatile and efficient iron/copper-cocatalyst can
widely be used in the synthesis of the compounds containing
(aryl)C–N or (aryl)C–O(aryl) bond.
After the optimization process of solvents, ligands, and
catalysts, the following cross-coupling reactions were car-
ried out under our standard conditions – 10 mol% FeCl3
and 10 mol% CuO as the cocatalyst, 20 mol% rac-BINOL
as the ligand relative to aryl halides, DMF as the solvent,
and Cs2CO3 as the base.
Key words: copper, iron, cross-coupling, N-arylation, O-arylation
The iron/copper cocatalyzed N-arylation of aliphatic
amines was explored under our standard conditions.17 As
shown in Table 1, the coupling reactions were performed
well for all the substrates examined, and the desired aryl-
amines were obtained in good yields. Aryl halides con-
taining electron-withdrawing group showed higher
reactivity than those containing electron-donating group.
Although aryl iodides containing electron-donating group
and aryl bromides gave slightly lower reaction yields,
they could provide higher yields when temperature was
raised. For aryl halides, coupling of iodobenzenes con-
taining bromine or chlorine selectively took place on the
C–I bond (entries 15–18) using 1.2 equivalents of aliphat-
ic amines as partners.
Although copper-catalyzed Ullmann reactions have been
developed for more than one hundred years,1 their appli-
cations are limited because of the harsh reaction condi-
tions such as high temperatures, the usual requirement of
stoichiometric amounts of copper catalysts, long reaction
times, and low yields.2 In recent years, copper-catalyzed
Ullmann reactions show renaissance because of the dis-
covery of new copper sources, bases, ligands, and other
additives. Highly efficient ligands for copper-catalyzed
arylations have been reported, including aliphatic di-
amines,3 1,10-phenanthroline and its derivatives,4 ethyl-
ene glycol,5a 1,1,1-tris(hydroxymethyl)ethane,5b diethyl-
salicylamide,5c amino acids,6 oxime-type and Schiff base
ligands,7 thiophene-2-carboxylate,8 bidentate phos-
phines,9a diphosphinidenecyclobutene,9b diazaphos-
pholane,10 cyclic b-diketone,11a b-ketone ester,11b
diphenyl pyrrolidine-2-phosphonate,12a pyrrolidine-2-
phosphonic acid phenyl monoester,12b and BINOL (1.1¢-
binaphthyl-2.2¢-diol)12c–12e for N-arylation of amines and
amides; 1-naphthoic acid,13a 2,2,6,6-tetramethylheptane-
3,5-dione,13b N,N-dimethylglycine,6d 8-hydroxyquino-
line,13c neocuproine,13d salicylaldoxime (Salox),13e 1,1,1-
tris-(hydroxymethyl)ethane,5b and aminophosphonic acid
derivatives12b,13f for O-arylation of substituted phenols or
alcohols. Iron is one of the most abundant metals on earth,
and consequently one of the most inexpensive and envi-
ronmentally friendly ones.14 Iron-catalyzed arylation has
made great progress,15 but only a few examples for N-
arylation of amines by using iron alone or associated with
copper as the catalysts were reported.16 In this paper, we
have developed an inexpensive and readily available cat-
We also attempted the cross-coupling reactions of aryl ha-
lides with arylamines.17 As shown in Table 2, we found
that FeCl3, CuO, and rac-BINOL could promote the con-
version of the substrates to the corresponding arylamines,
and aryl bromides containing an electron-withdrawing
group on the benzene ring afforded better results. Aryl io-
dides showed higher reactivity than aryl bromides in the
coupling reaction. For example, coupling of 1-bromo-4-
iodobenzene with indole (entry 21) yielded the target
product 5n containing bromine on the benzene ring.
The standard reaction conditions were also suitable for O-
arylation.18 As shown in Table 3, aryl iodides gave good
yields. However, aryl bromides were slightly inferior sub-
strates (entries 11 and 13). Fortunately, addition of two
equivalents of KI in the reaction system could improve the
yields of the target products (entries 12, 14–17). Similar-
ly, aryl halides containing an electron-withdrawing group
showed higher reactivity than those containing an elec-
tron-donating one, and the substituted phenols containing
an electron-rich group gave higher yields than those con-
taining an electron-deficient one.
SYNLETT 2008, No. 16, pp 2540–2546
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x
.x
x
.2
0
0
8
Advanced online publication: 22.08.2008
DOI: 10.1055/s-2008-1078214; Art ID: W08308ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Iron/Copper-Cocatalyzed Ullmann N,O-Arylation
2541
Table 1 Iron/Copper-Cocatalyzed Cross-Coupling of Aryl Halides
Table 1 Iron/Copper-Cocatalyzed Cross-Coupling of Aryl Halides
with Aliphatic Aminesa
with Aliphatic Aminesa (continued)
FeCl3 (10 mol%)
CuO (10 mol%)
R1
FeCl3 (10 mol%)
CuO (10 mol%)
R1
R1
rac-BINOL (20 mol%)
R1
rac-BINOL (20 mol%)
ArX
X = I, Br
1
+
HN
Ar
N
+
ArX
X = I, Br
1
HN
Ar
N
R2
Cs2CO3, DMF
R2
R2
Cs2CO3, DMF
R2
2
3
2
3
En- Aryl halide
try
Product
Temp Time Yield
(°C) (h)
En- Aryl halide
try
Product
Temp Time Yield
(°C) (h)
(%)b
84
(%)b
PhI
1a
NHC5H11
N
O
1
80 12
13 1e
14 1e
100 12
89
3a
3b
3c
3d
O2N
3k
NHC12H25
2
3
4
5
6
7
8
9
1a
1a
1a
1a
90 12
80 12
90 12
90 12
90 12
90 12
100 12
100 12
100 24
90 12
76
89
85
83
73
72
75
76
82
86
NHC12H25
100 24
81
H
N
O2N
3l
4-BrC6H4I
1f
Br
3m
Br
NHC5H11
15
80 12
90 12
90 12
80 12
87
85
88
90
N
N
O
N
16 1f
3n
Cl
3e
H
N
4-ClC6H4I
1g
17
TolI
1b
Me
NHC5H11
3o
Cl
3f
N
O
18 1g
Me
NHC12H25
1b
1b
3p
3g
Me
3h
a Reaction conditions: aryl halide (1.0 mmol), aliphatic amine (1.2
mmol), ligand (0.2 mmol), Cs2CO3 (2 mmol), DMF (2 mL) under N2.
Amount of catalyst relative to aryl halide.
N
O
b Isolated yield.
PhBr
1c
NHC5H11
In summary, we have developed an efficient and inexpen-
sive bimetallic catalyst FeCl3, CuO, and rac-BINOL that
could promote N,O-arylation of aliphatic, arylamines, and
phenols, and the cross-coupling reactions could tolerate
many functional groups. This versatile and efficient iron/
copper-cocatalyst can widely be used in the synthesis of
the compounds containing the (aryl)C–N or (aryl)C–O(aryl)
bond. Other synthetic applications of this catalyst are now
in progress.
3a
N
O
10 1c
3d
4-O2NC6H4Br
1d
O2N
NHC5H11
11
12
3i
H
N
3-O2NC6H4Br
1e
90 12
88
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
O2N
3j
Synlett 2008, No. 16, 2540–2546 © Thieme Stuttgart · New York

2542
Z. Wang et al.
LETTER
Table 2 Iron/Copper-Cocatalyzed Cross-Coupling of Aryl Halides with Arylaminesa
FeCl3 (10 mol%)
CuO (10 mol%)
R3
R3
R4
rac-BINOL (20 mol%)
Cs2CO3, DMF
ArX
X = I, Br
1
+
HN
Ar
N
R4
4
5
Entry
1
Aryl halide
Product
Temp (°C)
100
Time (h)
24
Yield (%)b
H
N
1a
1a
1a
78
68
85
5a
5b
5c
H
N
2
3
80
12
12
H
N
NO2
100
H
N
4
1a
80
12
81
NO2
5d
H
N
5
6
7
8
9
1a
1a
1a
1b
1b
90
90
80
90
90
12
12
12
12
12
89
85
80
79
82
O2N
5e
5f
H
N
OMe
H
N
MeO
5g
Me
5b
Me
H
N
H
N
MeO
5h
5a
5c
5f
H
N
10
11
12
1c
1c
1c
110
110
110
12
24
24
76
82
81
H
N
NO2
H
N
OMe
H
N
OMe
13
1e
100
12
86
O2N
5i
Synlett 2008, No. 16, 2540–2546 © Thieme Stuttgart · New York

LETTER
Iron/Copper-Cocatalyzed Ullmann N,O-Arylation
2543
Table 2 Iron/Copper-Cocatalyzed Cross-Coupling of Aryl Halides with Arylaminesa (continued)
FeCl3 (10 mol%)
CuO (10 mol%)
R3
R3
R4
rac-BINOL (20 mol%)
Cs2CO3, DMF
ArX
X = I, Br
1
+
HN
Ar
N
R4
4
5
Entry
Aryl halide
Product
Temp (°C)
110
Time (h)
12
Yield (%)b
84
H
N
NO2
14
1e
O2N
5j
Ph
N
15
16
17
18
1a
1a
1c
1c
90
90
12
12
24
24
78
89
75
82
5k
Ph
N
5l
Ph
N
110
110
5k
Ph
N
5l
O2N
I
19
20
100
90
12
12
89
84
N
O2N
1h
5m
Br
N
1f
5n
a Reaction conditions: aryl halide (1.0 mmol), arylamine (1.2 mmol), ligand (0.2 mmol), Cs2CO3 (2 mmol), DMF (2 mL) under N2. Amount of
catalyst relative to aryl halide.
b Isolated yield.
Table 3 Iron/Copper-Cocatalyzed Cross-Coupling of Aryl Halides with Phenolsa
FeCl3 (10 mol%)
CuO (10 mol%)
rac-BINOL (20 mol%)
Ar´OH
+
ArX
ArOAr´
Cs2CO3, DMF
X = I, Br
1
6
7
Entry
1
Aryl halide
Product
Temp (°C)
110
Time (h)
12
Yield (%)b
83
O
O
Cl
1a
1a
1g
7a
OMe
2
3
110
110
12
24
84
87
7b
Cl
O
7a
Synlett 2008, No. 16, 2540–2546 © Thieme Stuttgart · New York

2544
Z. Wang et al.
LETTER
Table 3 Iron/Copper-Cocatalyzed Cross-Coupling of Aryl Halides with Phenolsa (continued)
FeCl3 (10 mol%)
CuO (10 mol%)
rac-BINOL (20 mol%)
Ar´OH
+
ArX
ArOAr´
Cs2CO3, DMF
X = I, Br
1
6
7
Entry
4
Aryl halide
Product
Temp (°C)
110
Time (h)
12
Yield (%)b
78
Cl
7c
Cl
O
1g
1g
O
O
O
O
5
120
24
71
7d
Cl
6
7
1g
1g
110
110
24
12
80
80
7e
Cl
7f
Cl
Cl
8
9
1g
1g
110
100
12
12
84
89
7g
Cl
O
O
NO2
7h
Cl
10
1g
120
12
78
7i
O
O
Cl
Cl
11
12
13
14
1c
1c
1d
1d
120
120
120
120
24
24
24
24
60
7a
79c
63
7a
O2N
O
Cl
Cl
7h
82c
O2N
7h
O
O
O2N
15
1d
120
24
75c
7j
Synlett 2008, No. 16, 2540–2546 © Thieme Stuttgart · New York

LETTER
Iron/Copper-Cocatalyzed Ullmann N,O-Arylation
2545
Table 3 Iron/Copper-Cocatalyzed Cross-Coupling of Aryl Halides with Phenolsa (continued)
FeCl3 (10 mol%)
CuO (10 mol%)
rac-BINOL (20 mol%)
Ar´OH
+
ArX
ArOAr´
Cs2CO3, DMF
X = I, Br
1
6
7
Entry
16
Aryl halide
Product
Temp (°C)
120
Time (h)
24
Yield (%)b
O
1e
83c
74c
O2N
NO2
7k
O
Br
17
120
24
NO2
1i
7l
a Reaction conditions: aryl halide (1.0 mmol), phenol (1.2 mmol), ligand (0.2 mmol), Cs2CO3 (2 mmol), DMF (2 mL) under N2. Amount of
catalyst relative to aryl halide.
b Isolated yield.
c Addition of KI (2.0 mmol).
(7) (a) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M.
Acknowledgment
Eur. J. Org. Chem. 2004, 695. (b) Cristau, H.-J.; Cellier,
P. P.; Spindler, J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10,
5607.
This work was supported by the National Natural Science Founda-
tion of China (Grant No. 20672065), Chinese 863 Project (Grant
No. 2007AA02Z160), Programs for New Century Excellent Talents
in University (NCET-05-0062) and Changjiang Scholars and inno-
vative Research Team in University (PCSIRT) (No. IRT0404) in
China and the Key Subject Foundation from Beijing Department of
Education (XK100030514).
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Synlett 2008, No. 16, 2540–2546 © Thieme Stuttgart · New York

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Z. Wang et al.
LETTER
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desired product.
1-Phenyl-1H-indole (5l):16a yellow oil, yield 88%. 1H NMR
(300 MHz, CDCl3): d = 7.61 (d, 1 H, J = 7.56 Hz), 7.42–7.51
(m, 5 H), 7.25–7.30 (m, 2 H), 7.13 (dd, 2 H, J = 9.60, 1.74
Hz), 6.61 (t, 1 H, J = 3.45 Hz). 13C NMR (75 MHz, CDCl3):
d = 139.9, 135.9, 129.7, 129.4, 128.1, 126.5, 124.5, 122.5,
121.2, 120.5, 110.6, 103.7. MS (EI): m/z = 193.23 [M+].
(18) General Procedure B: Coupling of Aryl Halides with
Phenols
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J.-H. Tetrahedron Lett. 2007, 48, 7845. (c) Correa, A.;
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Synth. Catal. 2008, 350, 391.
A flask was charged with FeCl3 (16 mg, 0.1 mmol), CuO (8
mg, 0.1 mmol), Cs2CO3 (651 mg, 2 mmol), 1,1¢-binaphthyl-
2,2¢-diol (57 mg, 0.2 mmol), and any remaining solids
(phenol and/or aryl halide). The flask was evacuated and
backfilled with nitrogen (this procedure was repeated five
times). Aryl halide (1 mmol, if liquid), phenol (1.2 mmol, if
liquid), and DMF (2 mL) were added to the flask under
nitrogen atmosphere. The flask mixture was allowed to stir
under nitrogen atmosphere at the shown temperature for the
indicated period of time in the text (see Table 3). After
cooling to r.t., the mixture was diluted with CH2Cl2 (ca. 20
mL), the solution was filtered, and the filter cake was further
washed with CH2Cl2 (ca. 5 mL). The solvent of the filtrate
was removed with the aid of a rotary evaporator, and the
residue was purified by column chromatography on SiO2
using PE or PE–EtOAc (60:1 to 100:1) as eluent to provide
the desired product.
(17) General Procedure A: Coupling of Aryl Halides with
Amines
A flask was charged with FeCl3 (16 mg, 0.1 mmol), CuO (8
mg, 0.1 mmol), Cs2CO3 (651 mg, 2 mmol), BINOL (57 mg,
0.2 mmol), and any remaining solids (amine and/or aryl
halide). The flask was evacuated and backfilled with
nitrogen (this procedure was repeated five times). Aryl
halide (1 mmol, if liquid), amine (1.2 mmol, if liquid), and
DMF (2 mL) were added to the flask under nitrogen
atmosphere. The mixture was allowed to stir under nitrogen
atmosphere at the shown temperature for the indicated
period of time in the text (see Tables 1 and 2). After cooling
to r.t., the mixture was diluted with CH2Cl2 (ca. 20 mL), the
solution was filtered, and the filter cake was further washed
with CH2Cl2 (ca. 5 mL). The filtrate was washed with 1 M
NaOH (ca. 10 mL). The combined aqueous phase was
extracted with CH2Cl2 (2 × 10 mL). Organic layers were
combined and dried over anhyd Na2SO4. The solvent of the
filtrate was removed with the aid of a rotary evaporator, and
the residue was purified by column chromatography on SiO2
using PE–EtOAc (60:1 to 10:1) as eluent to provide the
1-(4-Chlorophenoxy)-3-methylbenzene (7f):6d colorless
oil, yield 79%. 1H NMR (300 MHz, CDCl3): d = 7.25 (dd, 2
H, J = 6.87, 2.07 Hz), 7.18 (d, 1 H, J = 7.53 Hz), 6.91 (dd, 3
H, J = 6.84, 2.04 Hz), 6.78 (s, 2 H), 2.31 (s, 3 H). 13C NMR
(75 MHz, CDCl3): d = 157.0, 156.2, 140.2, 129.8, 129.7,
128.2, 124.6, 120.1, 119.8, 116.1, 21.5. MS (EI): m/z =
218.22 [M+].
Synlett 2008, No. 16, 2540–2546 © Thieme Stuttgart · New York