Bis(cyclohexanone) oxalyldihydrazone/copper(II) oxide - A novel and efficient catalytic system for ullmann-type C-N coupling in pure water

Article abstract of DOI:10.1055/s-2006-950336

Animations of aryl halides were conducted under fast copper- bis(cyclohexanone) oxalyldihydrazone catalysis in pure water with both temperature-controlled microwave heating and traditional heating. With a reaction time of five minutes under microwave heating at 130 °C or at reflux for 10 hours, both electron-rich and electron-deficient aryl halides reacted with various amines to provide fair to good yields of the corresponding anilines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950336

PAPER
3955
Bis(cyclohexanone) Oxalyldihydrazone/Copper(II) Oxide – A Novel and
Efficient Catalytic System for Ullmann-type C–N Coupling in Pure Water
Ullmann
C
–N Cou
i
pling i
n
School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. of China
Fax +86(20)84112245; E-mail: ceswyq@mail.sysu.edu.cn
Received 16 June 2006; revised 3 August 2006
but there are a number of other successful couplings, for
example Suzuki reactions,13a that have been performed in
water.
Abstract: Aminations of aryl halides were conducted under fast
copper–bis(cyclohexanone) oxalyldihydrazone catalysis in pure
water with both temperature-controlled microwave heating and tra-
ditional heating. With a reaction time of five minutes under micro-
wave heating at 130 °C or at reflux for 10 hours, both electron-rich
and electron-deficient aryl halides reacted with various amines to
provide fair to good yields of the corresponding anilines.
Microwave irradiation often leads to a remarkable de-
crease in reaction time and easier workup, consistent with
green chemistry protocols.14 Considering the high poten-
tial and the versatility of amination of aryl halides, the re-
action would be even more attractive if shorter reaction
times could be used, in particular in a high-throughput
chemistry context.13b
Key words: bis(cyclohexanone) oxalyldihydrazone, aminations,
copper, coupling, catalysis
We herein report that fair to good yields can be achieved
after at most five minutes at 130 °C in the reaction of both
electron-rich and electron-deficient aryl bromides with
amines in pure water. The key to the successful reaction is
utilization of the novel ligand bis(cyclohexanone) ox-
alyldihydrazone (BCO) combined with copper as a cata-
lyst. BCO is a well-documented sensor for determining
the Cu2+ ion in water, but has, to our knowledge, never
been employed as a ligand in C–N coupling reactions.
The presence of the aniline motif in naturally occurring
compounds and synthetic materials, coupled with the
wide application of arylamines both in industry and aca-
demic laboratories, illustrates the need for efficient and
versatile strategies for the construction of molecules con-
taining anilines. The tremendous development of palladi-
um-catalyzed methods of C–N bond formation seemed to
overtake the classical Ullmann chemistry during the last
three decades.1 However, significant progress has been
made in the past few years in Ullmann-type C–N forma-
tion with the discovery of a series of practical ligands, in-
cluding monodentate and bidentate ones,2–8 although
some ligand-free copper-catalyzed Ullmann C–N reac-
tions have been employed, but with high substrate limita-
tion.9
Considering that bromopyridine was successfully con-
verted into aminopyridine in water under catalysis with
Cu2O or CuCl2 in a sealed tube,15 we chose Cu2O and CuO
as the copper source and examined some ligands contain-
ing oxygen, such as amino alcohols, L-proline, 8-hydroxy-
quinoline, ethanolamine, and 2-(dimethylamino)ethanol,
which contain at least one coordinating oxygen atom, to
perform the Ullmann-type C–N bond forming in the mod-
el reaction of 4-bromoanisole with benzylamine as shown
in Scheme 1. However, all of these did not afford N-ben-
zyl-4-methoxyaniline in more than 10% conversion (of 1-
bromo-4-methoxybenzene), the isolated yields of the
product being at most less than 5%. Since Tuong et al. re-
vealed that the hydroxide ion could hamper Ullmann C–N
coupling, perhaps by coordination of the hydroxide ion to
Reactions in aqueous media or in pure water are of great
interest for large-scale industrial processes for economic
and safety reasons. A few very practical applications have
been reported that involve copper-catalyzed C–N bond
forming in water7,10,11 or aqueous media,12 but the meth-
odologies are all substrate-limited; for example, the aryl
halides used need to be ortho-carboxy-substituted.10 Es-
tablishing a general and mild procedure for copper-cata-
lyzed amination of aryl halides has been a long process,
Cu source (10 mol%)
ligand (20 mol%)
KOH (2 equiv)
TBAB (1 equiv)
O
O
Br
+
H2O, MW
130 °C, 5 min
H2N
N
H
Scheme 1 Model reaction for Ullmann-type C–N bond formation (Cu source = CuO, Cu2O)
SYNTHESIS 2006, No. 23, pp 3955–3962
x
x.
x
x
.
2
0
0
6
Advanced online publication: 02.11.2006
DOI: 10.1055/s-2006-950336; Art ID: F09406SS
© Georg Thieme Verlag Stuttgart · New York

3956
X. Zhu et al.
PAPER
Table 2 Effect of Base, Catalyst, Ligand, Temperature, and Time
the catalyst to form a hydroxide-bridged polynuclear cop-
per(I) complex in aqueous media,16 we envisioned that
BCO, oxalic dihydrazide, or EDTA as ligand might pro-
mote the model reaction by preventing the formation of
the copper complex, as all three ligands can form intramo-
lecular binuclear complexes. Fortunately, BCO worked
well with both Cu2O and CuO, to afford the product in the
model reaction in 58 and 72% isolated yields, respective-
ly, whereas EDTA and oxalic dihydrazide gave very poor
conversions (<20%).
on the Coupling Reaction of 4-Bromoanisole with Benzylaminea
Entry Temp
(°C)
Base
CuO
BCO
Yieldc
(mol%)b (mol%)b (%)
1
2
3
80
120
130
KOH
KOH
KOH
25
25
25
50
50
50
45
72
82, 78d
72e, 78,f 71g
4
5
140
130
130
130
130
130
130
130
130
130
130
130
KOH
K2CO3
K3PO4
Cs2CO3
CsF
25
25
25
25
25
25
10
20
10
20
25
25
50
50
50
50
50
50
10
10
20
40
25
50
77
After examination of the ratios between CuO and BCO,
we found that a catalytic system of 25% CuO coupled
with 50% BCO is the most suitable for the model reaction,
giving 82% isolated yield. Thus, BCO was used to inves-
tigate a variety of copper catalyst sources. As indicated in
Table 1, there was no significant difference between the
yields obtained with copper(II) and copper(I) under the
same reaction conditions, but that copper metal was much
less effective, leading to a drop in the yield to about 40%.
59
6
26
7
62
8
35
9
Et3N
0
10
11
12
13
14
15
KOH
KOH
KOH
KOH
KOH
KOH
35
Table 1 Optimization Investigation of Copper Sourcea
37
H2N
Br
72
O
Cu source, KOH, BCO
+
74
TBAB (1 equiv), H2O,
MW, 130 °C, 5 min
N
H
O
66
82, 69h, 80i
Entry
Cu source
Yield
(%)
Entry Cu source
Yield
(%)
a Reagents and conditions: 4-bromoanisole (0.5 mmol), BnNH2 (2.0
mmol), KOH (1.0 mmol), TBAB (0.5 mmol), H2O (1.5 mL), MW
(100 W), 5 min.
1
2
3
4
CuO
82
72
71
69
5
6
7
8
CuI
73
71
72
40
b Relative to 4-bromoanisole.
c Isolated yield.
CuCl2
CuCl
Cu2O
Cu
d After 2 min.
CuSO4
Cu(OAc)2
e With 0.75 mmol KOH.
f With 1.25 mmol KOH.
g With 0.38 mmol TBAB.
a Reagents and conditions: cat. (0.125 mmol), BCO (0.25 mmol), 4-
bromoanisole (0.5 mmol), BnNH2 (2.0 mmol), KOH (1.0 mmol),
TBAB (0.5 mmol), H2O (1.5 mL), MW, 130 °C, 5 min.
h With 1.5 mmol BnNH2.
i With 3.0 mmol BnNH2.
Encouraged by these results, and realizing that CuO
would be the most suitable copper source in combination
with BCO to promote the typical Ullmann-type aryl ami-
nation, we investigated the conditions to optimize the
base, time, temperature, phase-transfer catalyst, and the
proportions among the starting materials, CuO, and BCO
(Table 2).
rich groups reacted with benzylamine to afford the corre-
sponding products in very good isolated yields (Table 3,
entries 1, 9, 11, 21). An interesting significant steric effect
was observed when 2-bromotoluene was employed as a
substrate (Table 3, entry 15), but the slightly elevated
temperature and higher load of CuO afforded the product
in 56% isolated yield. As for electron-neutral aryl halides
(Table 3, entries 13, 22) and electron-poor aryl halides
(Table 3, entries 16, 17, 19,) the reaction also worked
well, and afforded the desired products in good yields.
However, the very strongly electron-poor 1-bromo-4-ni-
trobenzene (Table 3, entry 20) afforded the corresponding
aniline in moderate yield, with unwanted debromination,
which interestingly was avoided in the case of unactivated
halides. In view of the results, we decided to investigate
some other aliphatic amines, both primary and secondary
(Table 3, entries 4, 5, 6, 7, 8), and could aminate the unac-
tivated aryl bromide 4-bromoanisole in moderate to good
To establish the generality of this protocol, a variety of
functionalized aryl halides were aminated under the opti-
mized reaction conditions [CuO (25 mol%), BCO (50
mol%), TBAB (1.0 equiv), KOH (2.0 equiv), H2O, 130
°C] with some modification of time and temperature to
take into account electronic effects. The results are sum-
marized in Table 3.
As can be seen from Table 3, CuO/BCO is a very effective
catalytic system for the Ullmann-type C–N coupling reac-
tion under microwave irradiation in pure water. All aryl
bromides and aryl iodides para-substituted with electron-
Synthesis 2006, No. 23, 3955–3962 © Thieme Stuttgart · New York

PAPER
Ullmann C–N Coupling in Water
3957
yields. In contrast to benzylamine, aniline also aminated To extend the scope of the reactions to proceed under nor-
various aryl halides (Table 3, entries 2, 3, 10, 12, 14, 18, mal heating, which is usually convenient and preferred by
23) in moderate yields, the major unwanted products re- organic chemists, particularly for industrial purposes, we
sulting from hydrolysis of aryl halides. This protocol was conducted the reactions in an oil bath. As summarized in
not very effective with aryl chlorides (Table 3, entries 24, Table 4, the coupling reactions proceeded equally suc-
25), even the ortho-carboxy-substituted chlorobenzene, cessfully at reflux, with the reaction time increasing from
which is very reactive,10b–i affording a 55% isolated yield, minutes to hours.
whereas chlorobenzene only provided 5% of the desired
product in very poor conversion.
Table 3 CuO/BCO-Catalyzed Coupling of Aryl Halides with Amines in Water under Microwave Conditionsa
CuO, BCO
ArX + RNH2
X = Cl, Br, I
ArNHR
KOH, TBAB
H2O, MW
Entry
1
ArX
Amine
Product
Yieldb (%)
82
O
N
NH2
H
O
Br
1
H
N
2
3
4
55
52
73
O
O
O
Br
Br
Br
NH2
O
2
3
H
O
N
NH2
H
N
NH2
O
O
O
4
5
6
H
N
5
6
55
50
O
O
Br
Br
NH2
H
N
NH2
N
N
7
47
O
O
Br
Br
NH
O
O
7
O
8
9
44
74
O
NH
8
9
N
NH2
H
Br
Synthesis 2006, No. 23, 3955–3962 © Thieme Stuttgart · New York

3958
X. Zhu et al.
PAPER
Table 3 CuO/BCO-Catalyzed Coupling of Aryl Halides with Amines in Water under Microwave Conditionsa (continued)
CuO, BCO
ArX + RNH2
X = Cl, Br, I
ArNHR
KOH, TBAB
H2O, MW
Entry
10
ArX
Amine
Product
Yieldb (%)
H
N
48
70
Br
NH2
10
N
NH2
11
H
Br
Br
11
12
H
N
12
13
14
49
78
49
NH2
N
H
NH2
Br
Br
13
14
H
N
NH2
N
H
NH2
15
16
56c
57
Br
15
F3C
N
H
NH2
NH2
F3C
Br
16
Cl
N
17
18
19
81
43
78
H
Cl
Cl
Br
17
Cl
H
N
Br
NH2
18
N
NH2
NH2
NH2
NH2
H
Br
O
O
19
O2N
N
20
21
22
50
H
O2N
Br
20
O
N
82
H
O
I
1
N
H
78d
I
13
Synthesis 2006, No. 23, 3955–3962 © Thieme Stuttgart · New York

PAPER
Ullmann C–N Coupling in Water
3959
Table 3 CuO/BCO-Catalyzed Coupling of Aryl Halides with Amines in Water under Microwave Conditionsa (continued)
CuO, BCO
ArX + RNH2
X = Cl, Br, I
ArNHR
KOH, TBAB
H2O, MW
Entry
23
ArX
Amine
Product
Yieldb (%)
H
N
57
<5
I
NH2
14
13
N
H
NH2
24
25
Cl
COOH
COOH
Cl
NH2
N
H
55
21
a Reagents and conditions: ArX (0.5 mmol), amine (2.0 mmol), CuO (0.125 mmol), BCO (0.25 mmol), KOH (1.0 mmol), TBAB (0.5 mmol),
H2O (1.5 mL), 130 °C, MW (100 W), 5 min.
b Isolated yield.
c CuO (0.25 mmol), 140 °C.
d 80 °C, 2 min.
Table 4 CuO/BCO-Catalyzed Coupling Reaction of Aryl Halides with Amines in Watera
CuO, BCO
ArX + RNH2
X = Cl, Br, I
ArNHR
KOH, TBAB
H2O, reflux
Entry
1
ArX
Amine
Product
Yieldb (%)
82
O
N
NH2
H
O
Br
Br
1
O
3
H
N
2
3
4
5
6
52
74
48
78
49
NH2
O
N
H
NH2
Br
Br
9
H
N
NH2
10
N
H
NH2
Br
Br
13
14
H
N
NH2
Synthesis 2006, No. 23, 3955–3962 © Thieme Stuttgart · New York

3960
X. Zhu et al.
PAPER
Table 4 CuO/BCO-Catalyzed Coupling Reaction of Aryl Halides with Amines in Watera (continued)
CuO, BCO
ArX + RNH2
X = Cl, Br, I
ArNHR
KOH, TBAB
H2O, reflux
Entry
7
ArX
Amine
Product
Yieldb (%)
56c
Br
NH2
N
H
15
F3C
N
8
9
H
57
50
NH2
NH2
F3C
O2N
Br
Br
16
O2N
N
H
20
a Reagents and conditions: ArX (1.0 mmol), amine (4.0 mmol), CuO (0.25 mmol), BCO (0.5 mmol), KOH (2 mmol), TBAB (1.0 mmol), H2O
(6.0 mL), reflux, 10 h.
b Isolated yield.
c After 6 h.
(214 mg, 2.0 mmol), KOH (56 mg, 1.0 mmol), TBAB (161 mg, 0.5
mmol), H2O (1.5 mL), and a magnetic stirring bar. The vessel was
sealed with a septum and placed into the single-mode microwave
cavity. It took 1 min to increase the reaction temperature from r.t. to
130 °C, and then the mixture was kept at this temperature for 5 min.
After the mixture had been allowed to cool to r.t., it was extracted
with EtOAc (3 × 40 mL). The combined organic phase was washed
with H2O (2 × 30 mL) and brine (30 mL), dried (MgSO4), and con-
centrated in vacuo. The residue was purified by flash column chro-
matography (silica gel, EtOAc–PE, 1:20); this afforded 1 as a pale
yellow solid.
In conclusion, we have, for the first time, established that
BCO/CuO serves as a novel, efficient, practical, and eco-
nomic catalytic system for the typical Ullmann-type C–N
coupling reaction in water both under microwave irradia-
tion and under traditional heating. The key to the success
was utilization of BCO as a ligand, which was demon-
strated to cooperate with a variety of copper sources to
promote the C–N coupling reaction in water. It is note-
worthy that the good performance of BCO in the Ull-
mann-type C–N bond forming in water under relative
mild conditions might be extended to many other kinds of
coupling reactions, such as sp2–sp carbon–carbon bond
formation. Further investigations into the scope and
mechanism of the BCO/CuO catalytic system in water is
in progress in our laboratory.
Yield: 87 mg (82%).
Synthesis of N-Benzyl-4-methoxyaniline (1) by Reflux in an Oil
Bath; Typical Procedure
A 15-mL flask was charged with CuO (20 mg, 0.25 mmol), BCO
(140 mg, 0.5 mmol), 4-bromoanisole (187 mg, 1.0 mmol), BnNH2
(428 mg, 4.0 mmol), KOH (112 mg, 2.0 mmol), TBAB (322 mg, 1.0
mmol), H2O (6.0 mL), and a magnetic stirring bar. The mixture was
refluxed for 10 h, then cooled to r.t., and extracted with EtOAc
(3 × 40 mL). The combined organic phase was washed with H2O (2
× 30 mL) and brine (30 mL), dried (MgSO4), and concentrated in
vacuo. The residue was purified by flash column chromatography
(silica gel, EtOAc–PE, 1:20); this afforded 1 as a pale yellow solid.
All aryl halides and amines were purchased from Sigma and used as
received. All reactions were carried out on a CEM Discover micro-
wave apparatus in glass vessels (capacity 10 mL) sealed with septa
and with stirring as a possibility. Flash column chromatography was
performed on silica gel (300–400 mesh) purchased from Qingdao
Haiyang Chemical Co. Ltd. TLC was carried out on Merck silica gel
60 F254 plates. All yields reported here represent an average of at
least two independent runs. All products were characterized by liq-
uid chromatography MS and 1H NMR data, which were compared
to the previously reported data. 1H NMR spectra were recorded at
room temperature on a Varian Mercury-Plus 300 instrument with
TMS as an internal reference. Liquid chromatography mass spectra
were recorded on a Shimadzu LCMS-2010A instrument, and FAB
mass spectra were obtained on a VGA-ZAB-HS spectrometer.
Yield: 174 mg (82%).
1H NMR (300 MHz, CDCl3): d = 7.36–7.23 (m, 5 H), 6.75 (d,
J = 8.8 Hz, 2 H), 6.58 (d, J = 8.6 Hz, 2 H), 4.27 (s, 2 H), 3.72 (s, 3
H).
ESI-MS: m/z = 214 [M + H]+.
4-Methoxy-N-4-tolylaniline (2)
1H NMR (300 MHz, CDCl3): d = 7.07–6.85 (m, 8 H), 3.82 (s, 3 H),
2.31 (s, 3 H).
Synthesis of N-benzyl-4-methoxyaniline (1) under Microwave
Irradiation; Typical Procedure
ESI-MS: m/z = 214 [M + H]+.
A 10-mL vessel was charged with CuO (10 mg, 0.125 mmol), BCO
(70 mg, 0.25 mmol), 4-bromoanisole (94 mg, 0.5 mmol), BnNH2
Synthesis 2006, No. 23, 3955–3962 © Thieme Stuttgart · New York

PAPER
Ullmann C–N Coupling in Water
3961
4-Methoxy-N-phenylaniline (3)
Diphenylamine (14)
1H NMR (300 MHz, CDCl3): d = 7.23–7.16 (m, 2 H), 7.05 (d,
J = 8.5 Hz, 2 H), 6.89–6.78 (m, 5 H), 5.42 (br s, 1 H), 3.78 (s, 3 H).
1H NMR (300 MHz, CDCl3): d = 7.20–7.15 (m, 4 H), 6.99 (d,
J = 7.6 Hz, 4 H), 6.84 (t, J = 7.3 Hz, 2 H), 5.88 (br s, 1 H).
ESI-MS: m/z = 200 [M + H]+.
ESI-MS: m/z = 170 [M + H]+.
N-Cyclohexyl-4-methoxyaniline (4)
N-Benzyl-2-methylaniline (15)
1H NMR (300 MHz, CDCl3): d = 6.78–6.58 (m, 4 H), 3.75 (s, 3 H),
3.22–3.12 (m, 1 H), 2.07–1.07 (m, 11 H, 5 CH2, CH).
1H NMR (300 MHz, CDCl3): d = 7.31–7.15 (m, 5 H), 7.03–6.98 (m,
2 H), 6.61–6.51 (m, 2 H), 4.29 (s, 2 H), 3.78 (s, 1 H), 2.09 (s, 3 H).
ESI-MS: m/z = 206 [M + H]+.
ESI-MS: m/z = 198 [M + H]+.
4-Methoxy-N-propylaniline (5)
N-Benzyl-4-(trifluoromethyl)aniline (16)
1H NMR (300 MHz, CDCl3): d = 6.79 (d, J = 8.8 Hz, 2 H), 6.59 (d,
J = 8.8 Hz, 2 H), 3.76 (s, 3 H), 3.05 (t, J = 7.0 Hz, 2 H), 1.68–1.61
(m, 2 H), 1.01 (t, J = 7.4 Hz, 3 H).
1H NMR (300 MHz, CDCl3): d = 7.38–7.23 (m, 7 H), 6.60 (d,
J = 8.4 Hz, 2 H), 4.35 (br s, 3 H, NH, CH2).
ESI-MS: m/z = 252 [M + H]+.
ESI-MS: m/z = 166 [M + H]+.
N-Benzyl-4-chloroaniline (17)
N-Butyl-4-methoxyaniline (6)
1H NMR (300 MHz, CDCl3): d = 7.33–7.23 (m, 5 H), 7.08 (d,
J = 8.7 Hz, 2 H), 6.52 (d, J = 8.7 Hz, 2 H), 4.29 (s, 2 H), 4.04 (s, 1
H).
1H NMR (300 MHz, CDCl3): d = 6.81–6.76 (m, 2 H), 6.62–6.58 (m,
2 H), 3.76 (s, 3 H), 3.08 (t, J = 7.0 Hz, 2 H), 1.66–1.56 (m, 2 H),
1.50–1.38 (m, 2 H), 0.97 (t, J = 7.2 Hz, 3 H).
ESI-MS: m/z = 218 [M + H]+.
ESI-MS: m/z = 180 [M + H]+.
4-Chloro-N-phenylaniline (18)
1-(4-Methoxyphenyl)piperidine (7)
1H NMR (300 MHz, CDCl3): d = 7.22–7.09 (m, 4 H), 6.97–6.84 (m,
5 H), 5.70 (br s, 1 H).
1H NMR (300 MHz, CDCl3): d = 6.94–6.82 (m, 4 H), 3.78 (s, 3 H),
3.04 (t, J = 5.4 Hz, 4 H), 1.78–1.71 (m, 4 H), 1.60–1.52 (m, 2 H).
ESI-MS: m/z = 204 [M + H]+.
ESI-MS: m/z = 192 [M + H]+.
1-[4-(Benzylamino)phenyl]ethanone (19)
4-(4-Methoxyphenyl)morpholine (8)
1H NMR (300 MHz, CDCl3): d = 7.71 (d, J = 8.8 Hz, 2 H), 7.25–
7.19 (m, 5 H), 6.49 (d, J = 8.8 Hz, 2 H), 4.58 (br s, 1 H), 4.31 (s, 2
H), 2.40 (s, 3 H).
1H NMR (300 MHz, CDCl3): d = 6.92–6.84 (m, 4 H), 3.88 (t, J = 4.7
Hz, 4 H), 3.78 (s, 3 H), 3.07 (t, J = 4.7 Hz, 4 H).
ESI-MS: m/z = 194 [M + H]+.
ESI-MS: m/z = 226 [M + H]+.
N-Benzyl-4-methylaniline (9)
N-Benzyl-4-nitroaniline (20)
1H NMR (300 MHz, CDCl3): d = 7.35–7.21 (m, 5 H), 6.96 (d,
J = 8.1 Hz, 2 H), 6.54 (d, J = 8.2 Hz, 2 H), 4.28 (s, 2 H), 2.22 (s, 3
H).
1H NMR (300 MHz, CDCl3): d = 8.07 (d, J = 9.1 Hz, 2 H), 7.39–
7.31 (m, 5 H), 6.56 (d, J = 9.1 Hz, 2 H), 4.85 (br s, 1 H), 4.42 (s, 2
H).
ESI-MS: m/z = 198 [M + H]+.
MS–FAB: m/z = 229 [M + H]+.
4-Methyl-N-phenylaniline (10)
2-(Benzylamino)benzoic Acid (21)
1H NMR (300 MHz, CDCl3): d = 7.24–7.18 (m, 2 H), 7.07–6.96 (m,
6 H), 6.85 (t, J = 7.3 Hz, 1 H), 5.57 (br s, 1 H), 2.29 (s, 3 H).
1H NMR (300 MHz, CD3OD): d = 7.86–7.83 (m, 1 H), 7.32–7.16
(m, 6 H), 6.61 (d, J = 8.4 Hz, 1 H), 6.54–6.48 (m, 1 H), 4.40 (s, 2 H).
ESI-MS: m/z = 184 [M + H]+.
ESI-MS: m/z = 228 [M + H]+.
N-Benzyl-4-ethylaniline (11)
1H NMR (300 MHz, CDCl3): d = 7.32–7.23 (m, 5 H), 6.98 (d,
J = 8.0 Hz, 2 H), 6.55 (d, J = 8.1 Hz, 2 H), 4.27 (s, 2 H), 3.51 (br s,
1 H), 2.52 (q, J = 7.5 Hz, 2 H), 1.17 (t, J = 7.5 Hz, 3 H).
Acknowledgment
We acknowledge the Guangdong Provincial Natural Science Foun-
dation (No. 04009718) for financial support of this work. We also
thank the CEM Corporation for providing the microwave Discover.
ESI-MS: m/z = 212 [M + H]+.
4-Ethyl-N-phenylaniline (12)
1H NMR (300 MHz, CDCl3): d = 7.24–7.19 (m, 2 H), 7.09 (d,
J = 8.3 Hz, 2 H), 7.00 (d, J = 8.4 Hz, 4 H), 6.86 (t, J = 7.26 Hz, 1
H), 5.62 (br s, 1 H), 2.60 (q, J = 7.5 Hz, 2 H), 1.22 (t, J = 7.6 Hz, 3
H).
References
(1) (a) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046.
(b) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805. (c) Yang, B. H.; Buchwald,
S. L. J. Organomet. Chem. 1999, 576, 125. (d) Hartwig, J.
F. Acc. Chem. Res. 1998, 31, 852.
(2) (a) Kunz, K.; Schloz, U.; Ganzer, D. Synlett 2003, 2428.
(b) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003,
42, 5400. (c) Beletskaya, I. P.; Cheprakov, A. V. Coord.
Chem. Rev. 2004, 248, 2337. (d) Blaser, H. U.; Indolese, A.;
Naud, F.; Nettekoven, U. Adv. Synth. Catal. 2004, 346,
1583.
ESI-MS: m/z = 198 [M + H]+.
N-Benzylaniline (13)
1H NMR (300 MHz, CDCl3): d = 7.36–7.22 (m, 5 H), 7.15 (t, J = 7.8
Hz, 2 H), 6.69 (t, J = 7.3 Hz, 1 H), 6.61 (d, J = 7.7 Hz, 2 H), 4.31 (s,
2 H), 4.00 (br s, 1 H).
ESI-MS: m/z = 184 [M + H]+.
Synthesis 2006, No. 23, 3955–3962 © Thieme Stuttgart · New York

3962
X. Zhu et al.
PAPER
(11) Narayan, S.; Seelhammer, T.; Gawley, R. E. Tetrahedron
(3) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M.
Chem. Eur. J. 2004, 10, 5607.
Lett. 2004, 45, 757.
(4) Haider, J.; Kunz, K.; Scholz, U. Adv. Synth. Catal. 2004,
346, 717.
(12) (a) Liu, L.; Frohn, M.; Xi, N.; Dominguez, C.; Hungate, R.;
Reider, P. J. J. Org. Chem. 2005, 70, 10135. (b) Job, G. E.;
Buchwald, S. L. Org. Lett. 2002, 4, 3703. (c) Ma, D.; Xia,
C. Org. Lett. 2001, 3, 2583. (d) Saphier, M.; Masarwa, A.;
Cohen, H.; Meyerstein, D. Eur. J. Inorg. Chem. 2002, 1226.
(13) (a) Leadbeater, N. E. Chem. Commun. 2005, 2881.
(b) Wan, Y.; Alterman, M.; Hallberg, A. Synthesis 2002,
1597.
(5) (a) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809.
(b) Wang, Z.; Bao, W.; Jiang, Y. Chem. Commun. 2005,
2849. (c) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70,
5164. (d) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org.
Lett. 2002, 4, 581. (e) Lv, X.; Wang, Z.; Bao, W.
Tetrahedron 2006, 62, 4756.
(6) Choudary, B. M.; Sridhar, C.; Kantam, M. L.; Venkanna, G.
T.; Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 9948.
(7) Lu, Z.; Twieg, R. J. Tetrahedron Lett. 2005, 46, 2997.
(8) Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2005, 70,
8107.
(9) (a) Okano, K.; Tokuyama, H.; Fukuyama, T. Org. Lett.
2003, 5, 4987. (b) Kelkar, A. A.; Patil, N. M.; Chaudhari, R.
V. Tetrahedron Lett. 2002, 43, 7143.
(10) (a) Xu, G.; Wang, Y.-G. Org. Lett. 2004, 6, 985. (b) Robin,
M.; Faure, R.; Perichaud, A.; Galy, J.-P. Synth. Commun.
2002, 32, 981. (c) Cohen, T.; Tirpak, J. G. Tetrahedron Lett.
1975, 16, 143. (d) Glanzel, M.; Bultmann, R.; Starke, K.;
Frahm, A. W. Eur. J. Med. Chem. 2003, 38, 303. (e)Pellon,
R. F.; Mamposo, T.; Carrasco, R.; Rodes, L. Synth.
Commun. 1996, 26, 3877. (f) Carrasco, R.; Pellon, R. Synth.
Commun. 1989, 19, 2077. (g) Hanoun, J.-P.; Galy, J.-P.;
Tenaglia, A. Synth. Commun. 1995, 25, 2443. (h) Palacios,
M. L. D.; Comdom, R. F. P. Synth. Commun. 2003, 33,
1777. (i) Peilon, R. F.; Carrasco, R.; Rodes, L. Synth.
Commun. 1993, 23, 1447.
(14) (a) Microwaves in Organic Synthesis; Loupy, A., Ed.;
Wiley-VCH: Weinheim, 2002. (b) Hayes, B. L. Microwave
Synthesis: Chemistry at the Speed of Light; CEM Publishing:
Matthews NC, 2002. (c) Microwave-Assisted Organic
Synthesis; Tierney, J. P.; Lidström, P., Eds.; Blackwell:
Oxford, 2004. (d) Kappe, C. O. Angew. Chem. Int. Ed. 2004,
43, 6250.
(15) Lang, F. R.; Zewge, D.; Houpis, I. N.; Volante, R. P.
Tetrahedron Lett. 2001, 42, 3251.
(16) (a) Tuong, T. D.; Hida, M. Bull. Chem. Soc. Jpn. 1970, 43,
1763. (b) Tuong, T. D.; Hida, M. Bull. Chem. Soc. Jpn.
1971, 44, 765. (c) Tuong, T. D.; Hida, M. J. Chem. Soc.,
Perkin Trans. 2 1974, 676.
Synthesis 2006, No. 23, 3955–3962 © Thieme Stuttgart · New York