CuBr/H2O2-mediated oxidative coupling of N,N-dialkylarylamines in water: A practical synthesis of benzidine derivatives

Article abstract of DOI:10.1055/s-2005-868490

CuBr/H₂O₂ was deployed into mediating the oxidative coupling reaction of N,N-dialkylarylamines in water, which gave benzidine derivatives in an economically and environmentally satisfying manner. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-868490

LETTER
1381
CuBr/H2O2-Mediated Oxidative Coupling of N,N-Dialkylarylamines in
Water: A Practical Synthesis of Benzidine Derivatives
S
ynthesis of Benzi
a
dine
D
eriva
n
tives feng Jiang, Chanjuan Xi,* Xianghua Yang
Key Laboratory for Bioorganic Phosphorus Chemistry of Ministry of Education, Department of Chemistry, Tsinghua University, Beijing
100084, P. R. China
Fax +86(10)62618239; E-mail: cjxi@tsinghua.edu.cn
Received 22 March 2005
Copper derivatives have been known to mediate the oxi-
Abstract: CuBr/H2O2 was deployed into mediating the oxidative
dative coupling of aryls to obtain biaryls.15–20 In this broad
context, copper(II) reagent was the mainly used oxidant
coupling reaction of N,N-dialkylarylamines in water, which gave
benzidine derivatives in an economically and environmentally
for the coupling reaction of substrates with low oxidative
potential, such as naphthols and naphthylamines.21–26
Cu(I)-catalyzed aerobic oxidative coupling of 2-naphthol
derivatives has also been reported.27 However, in the case
of oxidative coupling of aniline derivatives, all these cop-
per reagents have never been involved, most probably due
to their relatively lower oxidative activities. Seeking for a
more active copper oxidant is challenge. We have found
that anilines could be oxidized with CuBr in the presence
of H2O2 in water to give benzidine derivatives in high
yields. Water as solvent clearly has both economical and
environmental advantages.13,14
satisfying manner.
Key words: oxidative coupling, aqueous reaction, N,N-dialkylaryl-
amine, CuBr, H2O2
Benzidine derivatives have received growing interest for
manufacturing materials due to a tunable electric conduc-
tivity, which admitted to diverse applications such as or-
ganic light-emitting diodes,1,2 organic field-effect
transistors,3 organic solar cells,4 and organic photocon-
ductors.5 A number of methods for the coupling reaction
have been reported.6–11 Among them, oxidative coupling
To begin our study, various copper salts such as CuCl2,
Cu(OAc)2, CuCl/H2O2, CuBr/H2O2, CuI/H2O2 and CuCl2/
H2O2 were examined for the desired reaction (Table 1).
All the Cu(II) salts were inefficient and CuBr/H2O2 was
proved to be the best one. CuCl/H2O2 showed lower
activity and CuI/H2O2 appeared to be inert in this reaction.
of aniline derivatives provided an efficient access to
10
benzidine derivatives. Recently, TiCl4
and 1,8-
bis(diphenylmethylium)naphthalenediyl dications11 were
both reported to be effective oxidants for such coupling
reactions, although the large excess of anilines (in the
former) and the relatively hard-to-obtain dications (in the
latter) retarded their acceptance as practical approaches.
Very recently, our group reported a more practical and en-
vironmentally friendly method using cerium ammonium
nitrate (CAN)12 to mediate such reactions in water. How-
ever, this approach was not suitable for some solid-state
substrates that were difficult to dissolve in water. On the
consideration of current attention in the development of
more efficient, environmentally friendly and general
methods for chemical synthesis,13,14 it could be highly de-
sirable to develop a transition metal-mediated oxidative
coupling reaction of tertiary aromatic amines in water.
Herein we would like to report the coupling reaction of
N,N-dialkylanilines in the presence of CuBr and H2O2 in
water gave corresponding N,N,N¢,N¢- tetraalkylbenzidines
(Scheme 1).
Table 1 Various Copper Salts for the Coupling Reaction of 2aa
Entry
Salts (1 equiv) H2O2 (equiv)
Yield (%)b
1
2
CuCl2
Cu(OAc)2
CuCl
CuCl
CuCl
CuBr
CuBr
CuBr
CuI
–
–
0
0
3
1
5
8
4
23
34
58
72
55
Trace
Trace
0
5
10
5
6
7
10
20
5
8
1 equiv CuBr
10 equiv H2O2
R1
R2
R1
N
R1
R2
9
N
N
R2
H2O, 0 to r.t., 10 h
R
R
R
10
11
CuI
10
10
Scheme 1
CuCl2
a Conditions: N,N-diethylaniline (1 mmol), H2O (3 mL), 30% H2O2
was added at 0 °C in H2O and the reaction was kept at 0–25 °C for
SYNLETT 2005, No. 9, pp 1381–1384
Advanced online publication: 25.04.2005
0
1.
0
6.
2
0
0
5
10 h.
b Isolated yield.
DOI: 10.1055/s-2005-868490; Art ID: U07805ST
© Georg Thieme Verlag Stuttgart · New York

1382
Y. Jiang et al.
LETTER
To improve the yield, H2O2 was added at 0 °C in water in phenyl ring did not proceed under the reaction conditions,
order to minimize the possibility of decomposition of which was suspected to be the result of low electron den-
H2O2.28 Various ratios of N,N-diethylaniline (1a) and sity of phenyl ring.
CuBr as well as H2O2 were checked and the best yield was
The coupling product 2a was also confirmed by X-ray
obtained when the 1a/CuBr/H2O2 ratio was 1:1:10.29 The
crystal structure analysis as shown in Figure 1.33 It was
yield decreased when the amount of CuBr or H2O2 was re-
interesting to note that two configuration structures of 2a
duced. However, when the amount of H2O2 was increased
both existed in the crystal.
to 20 equivalents, the yields of 2a also decreased. It is
In connection with the mechanism of this reaction, two
important to note that the reaction did not proceed in the
key points should be considered: (1) Cu(I)/H2O2 was the
absence of either CuBr or H2O2.
active one instead of Cu(II) salts or Cu(II)/H2O2. In other
Under the optimized conditions, various tertiary aromatic
words, the copper should be more active and highly valent
amines were transformed to corresponding benzidine de-
species generated from Cu(I) and H2O2; (2) coordination
rivatives. Representative results were listed in Table 2.
process of amine to copper species was suspected to be in-
Compared with the coupling reaction mediated by cerium
volved. Accordingly, one possible mechanism is pro-
ammonium nitrate,12 the solubility of substrate was not a
posed in Scheme 2. Firstly, Cu(I) salts were oxidized by
problem in the CuBr/H2O2 system, even solid state 3,5-
H2O2 to give more active Cu(III)=O precursor 3,34 which
dimethyl-N,N-diethylaniline (1h) also gave good yields of
coordinated with tertiary amine leading to complex 4. Due
N,N,N¢,N¢-tetraethyl-3,3¢,5,5¢-tetramethyl-benzidine (2h,
to the high electron-withdrawing ability of Cu(III) spe-
entry 8). The reaction of aniline derivative with electron-
cies, a one-electron transfer process occurred from the ter-
withdrawing substituted group such as chloride on the
tiary amine to the copper, which resulted in radical cation
Table 2 The Coupling Reaction of N,N-Dialkylarylamines in the CuBr/H2O2 Systema
Entry
1
Substrate
Productb
Yield (%)c
72
Et
Et
Et
N
Et
Et
Et
N
N
2a10
Me
N
Me
2b10
Me
N
Et
2c10
Me
N
1a
1b
1c
1d
1e
2
3
4
5
6
51
57
53
62
49
Me
N
Me
Me
N
Me
Me
N
Et
Me
N
Et
Me
N
Bu
Me
N
Bu
Bu
2d30
i-Pr
i-Pr
N
Bu
2e31
Bu
N
i-Pr
N
N
Bu
Bu
Bu
Bu
N
N
N
Bu
2f32
Bu
Bu
1f
7
8
76
74
N
N
1g
2g10
Et
N
Et
Et
Et
Et
Et
N
N
1h
2h11
a Conditions: N,N-dialkylarylamines (1 mmol), CuBr (1 mmol), H2O2 (10 mmol), H2O
(3 mL), initiated at 0 °C and kept at 0–25 °C for10 h.
b The spectra and physical data of known products have been reported in literature.
c Isolated yield.
Synlett 2005, No. 9, 1381–1384 © Thieme Stuttgart · New York

LETTER
Synthesis of Benzidine Derivatives
1383
R1
N
R1
R2
R1
N
1
R2
Cu(I)
H2O2
Cu(III)=O
R2
N
Cu(II)
O–
Cu(III)
O
3
5
4
R1
N
R2
R1
R1
N
R1
H
R2
N
R2
N
R2
H
Cu(II)
O–
Cu(II)
O–
2 H+, 2 Cu(II)
2
6
Scheme 2
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to give diiminium ion 6, which underwent deprotonation
to afford product 2 after normal work-up.
In conclusion, CuBr/H2O2-mediated oxidative coupling
reaction of N,N-dialkylarylamine in water opened a prac-
tical way for synthesis of benzidines. Compared with oth-
er methods for synthesizing benzidine derivatives, this
approach was highly efficient and low cost. Moreover, the
avoidance of organic solvent accorded with current atten-
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Acknowledgment
This work was supported by the National Natural Science Founda-
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1384
Y. Jiang et al.
LETTER
(28) Strukul, G. Catalytic Oxidations with Hydrogen Peroxide as
Oxidant; Kluwer Academic Publishers: London, 1992.
(29) Representative Procedures.
(30) N,N¢-Dimethyl-N,N¢-dibutylbenzidine (2d): white solid,
53% yield. 1H NMR (CDCl3): d = 7.42 (4 H, d, J = 8.9 Hz),
6.72 (4 H, d, J = 8.9 Hz), 3.30 (4 H, br), 2.93 (6 H, s), 1.52–
1.58 (4 H, m), 1.29–1.38 (4 H, m), 0.94 (6 H, t, J = 7.2 Hz).
13C NMR (CDCl3): d = 147.8, 129.1, 126.9, 112.4, 52.6,
38.4, 28.9, 20.4, 14.0. ESI-MS: m/z = 325 [M + H+].
(31) N,N¢-Diisopropyl-N,N¢-dibutylbenzidine (2e): white solid,
62% yield. 1H NMR (CDCl3): d = 7.40 (4 H, br), 6.75 (4 H,
br), 4.07 (4 H, br), 3.13 (4 H, br), 1.53–1.61 (4 H, m), 1.18
(12 H, d, J = 6.5 Hz), 0.96 (6 H, t, J = 7.2Hz). 13C NMR
(CDCl3): d = 147.1, 129.1, 126.9, 113.3, 48.5, 43.8, 31.6,
20.4, 20.0, 14.0. ESI-MS: m/z = 381 [M + H+].
(32) N,N,N¢,N¢-Tetrabutylbenzidine (2f): white solid, 49%
yield. 1H NMR (CDCl3): d = 7.40 (4 H, br), 6.69 (4 H, br),
3.28 (8 H, br), 1.54–1.62 (8 H, m), 1.30–1.41 (8 H, m), 0.96
(12 H, t, J = 7.2 Hz). 13C NMR (CDCl3): d = 146.5, 128.5,
126.9, 111.9, 50.8, 29.5, 20.4, 14.0. ESI-MS: m/z = 409
[M + H+].
CuBr (144 mg, 1 mmol) and N,N-diethylaniline 1a (159 mL,
1 mmol) was added into H2O (3 mL) at 0 °C under N2. Then,
H2O2 (1 mL, 10 mmol, 30% aq solution) was added dropwise
within 1 min. The reaction mixture was kept at 0 °C for 2 h,
then further stirred at 25 °C for 8 h. The reaction mixture was
quenched by aq K2CO3 solution and the organic residue was
extracted with Et2O (2 × 2 mL). The combined extract was
dried over anhyd MgSO4. The solvent was removed and the
residue was chromatographed on an Al2O3 column.
N,N,N¢,N¢-tetraethylbenzidine(2a) was isolated using 1:50
EtOAc–petroleum ether mixture as eluent (108 mg, 72%).
1H NMR (CDCl3): d = 7.40 (4 H, d, J = 8.6 Hz), 6.71 (4 H,
d, J = 8.6 Hz), 3.35 (8 H, q, J = 7.2 Hz), 1.15 (12 H, t, J = 7.2
Hz). 13C NMR (CDCl3): d = 146.2, 128.8, 127.0, 112.1, 44.4,
12.6. ESI-MS: m/z = 297 [M + H+].
(33) Compound 2a: C20H28N2, crystallized in monoclinic, space
group C2/c with cell parameters: a = 16.0904 (19),
b = 15.7307 (19), c = 13.9754 (17)Å3, a = 90.00, b = 91.843
(2), g = 90.00°, V = 3535.5 (7) Å3, Dc = 1.114 g/cm3, Z = 8.
CCDC 269443.
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1997, 53, 16017.
Synlett 2005, No. 9, 1381–1384 © Thieme Stuttgart · New York