A facile and efficient oxalyldihydrazide/ketone-promoted copper-catalyzed amination of aryl halides in water

Article abstract of DOI:10.1002/ejoc.200800940

A novel three-component catalyst CuO/oxalyldihydrazide/hexane-2,5-dione was a very convenient, economic, and effective catalytic system for the Ullmann-type C-N coupling reaction in water. Both aryl bromides and aryl iodides could be aminated by a variety of amines even at room temperature or with heating to afford very good isolated yields.

Full text of DOI:10.1002/ejoc.200800940

FULL PAPER
DOI: 10.1002/ejoc.200800940
A Facile and Efficient Oxalyldihydrazide/Ketone-Promoted Copper-Catalyzed
Amination of Aryl Halides in Water
[
a]
[a]
[a]
[a]
[a]
[a]
Xinhai Zhu, Li Su, Liye Huang, Gong Chen, Jinlong Wang, Huacan Song, and
Yiqian Wan*[
a]
Keywords: Amination / Cross-coupling / Copper / Water chemistry / Sustainable chemistry
A novel three-component catalyst CuO/oxalyldihydrazide/
hexane-2,5-dione was a very convenient, economic, and ef-
fective catalytic system for the Ullmann-type C–N coupling
reaction in water. Both aryl bromides and aryl iodides could
be aminated by a variety of amines even at room temperature
or with heating to afford very good isolated yields.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
lides in water or aqueous media, desirable for reasons of
[
18]
economy and safety,
especially for large-scale industrial
Many significant products (drugs, materials, optical de-
vices, etc.), commercialized or in the development phase,
possess aromatic carbon–nitrogen bonds that can be as-
sembled by transition metal (palladium and copper) cata-
lyzed C–N bond-formation reactions.[ Significant im-
provements have been made in palladium-catalyzed C–N
bond-forming processes through the development of more
active catalysts in recent years.[ However, in comparison
with the use of costly palladium and toxic phosphane-con-
taining ligands, C–N bond formation with the use of inex-
pensive copper catalysts in aqueous media or even in pure
water would be a most attractive improvement. The copper-
catalyzed Ullmann-type N-arylation of amines predates pal-
ladium-catalyzed amination methodology by many decades,
and applications of the methodology in academic and in-
dustrial laboratories are well documented. A landmark im-
provement was the work of Buchwald and coworkers on the
processes, has hitherto remained elusive. Moreover, other
advantages, such as different selectivity from that observed
[
18a]
in organic media, may occur in aqueous media.
To the
best of our knowledge, the methodologies are all substrate-
1]
limited; for example, only aryl halides containing ortho-car-
[
19]
[15b,20]
boxy substituents or water-soluble amines
could be
aminated smoothly and effectively in aqueous solution.
We previously reported a typical Ullmann C–N coupling
in water with utilization of bis(cyclohexanone) oxalyldihyd-
2]
[
21]
razone (“BCO”)/copper oxide as a catalyst. However, the
correspondingly harsh conditions (130 °C) and the scope
limitation of substrates (for example, aniline and imidazole)
for N-arylation, as well as our curiosity about the mecha-
nism of the reaction, prompted us to investigate further.
Fortunately, we found that a three-component catalyst sys-
tem, CuO/oxalyldihydrazide/ketone, facilitated various car-
bon–nitrogen coupling reactions in water. Herein, we wish
to detail the investigation of various promoters in the cop-
per-catalyzed amination of aryl halides and report that,
promoted by oxalyldihydrazide and hexane-2,5-dione (or
cyclohexanone, for benzylamine), aryl bromides or aryl io-
dides could successfully couple with a variety of amines and
imidazoles under relatively mild conditions, and even at
room temperature.
[
3]
use of catalytic copper in the presence of diamino ligands.
Thereafter, a series of novel mono- and bidentate ligands
for Cu-based C–N coupling were discovered, such as or-
[
4]
[5]
ganic phosphanes, N-containing aromatic heterocycles,
[
6]
[7]
[8]
[9]
[10]
diamines, diols, triols, rac-binol, salicylamide,
β-
[
11]
[12]
[13]
[16]
[14]
diketones,
β-keto esters,
imines,
amino acids,
[
15]
amino alcohols,
amino phosphates,
and diazaphos-
[
17]
pholane.
Among them, Buchwald introduced β-dike-
tones as ligands, which made it possible to carry out the
coupling of aryl iodides with aliphatic amines even at room
Results and Discussion
temperature in organic media.[
11a]
However, a general and
mild procedure for copper-catalyzed amination of aryl ha-
Influence of Oxalyldihydrazide and Ketones
[
a] School of Chemistry and Chemical Engineering, Sun Yat-Sen
Substantial amounts of cyclohexanone and 1,2-dicyclo-
hexylidenehydrazine were found in the reaction mixtures of
CuO/BCO-catalyzed C–N coupling reactions by GC–MS
analysis. Considering the possible decomposition of BCO
in aqueous base, on the one hand, we postulated that either
University,
Guangzhou 510275, P. R. China
Fax: +86-20-84112245
E-mail: ceswyq@mail.sysu.edu.cn
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2009, 635–642
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
635

X. Zhu, L. Su, L. Huang, G. Chen, J. Wang, H. Song, Y. Wan
FULL PAPER
a combination of oxalyldihydrazide with cyclohexanone or
a combination of hydrazine with cyclohexanone might be
the actual active species of ligands for copper; on the other
hand, a very significant result reported recently by Buch-
wald, which described a room-temperature coupling proto-
col with β-diketones as ligand in organic media for aryl
iodides with amines,[
11a]
led us to assume that cyclohexan-
one, oxalyldihydrazide, or hydrazine might uniquely act as
the actual active ligand.
To test these hypotheses, we ran our previous reaction of
4-bromoanisole with benzylamine under almost the same
conditions but replaced BCO with cyclohexanone, oxalyl-
dihydrazide, or hydrazine; unfortunately, oxalyldihydrazide
was far less active than BCO, and hydrazine and cyclohexa-
Figure 2. Effect of additives on the coupling reaction of 4-bromo-
anisole with aniline. Reaction conditions: 4-bromoanisole
(
0.5 mmol), aniline (2.0 mmol), CuO (0.125 mmol), oxalyldihydraz-
none definitely afforded little target compound. Even 2-ace- ide (0.25 mmol), ketone (2.0 mmol for monoketones, 1.0 mmol for
diketones) or DMF (0.5 mL) or THF (0.5 mL), KOH (1.0 mmol),
TBAB (0.5 mmol), H O (1.0 mL), 130 °C, 5 min, microwave
2
tylcyclohexanone, which is one of the best ligands discov-
ered by Buchwald, did not work under our aqueous condi-
tions. Replacement of BCO with a combination of hydraz-
ine and cyclohexanone also had a negative impact on the
reaction, but the utilization of an equivalent amount of ox-
alyldihydrazide and cyclohexanone instead of BCO, fortu-
nately, provided the desired product in 77% isolated yield.
Further study showed four equivalents of cyclohexanone to
be enough to convert 4-bromoanisole completely and af-
forded N-benzyl-4-methoxyaniline in 86% isolated yield.
Encouraged by the result, we tried CuO/oxalyldihydrazide/
cyclohexanone in a more challenging model reaction
(
100 W). Conversions and yields were calculated by GC.
As can be seen from Figure 2, when electron-rich mono-
ketones with less steric hindrance (A, B, D, E) were added,
the reaction provided very high conversion of 4-bromoani-
sole, but sometimes with problematic side reactions of de-
bromination and hydrolysis. Adamantanone (H), a steri-
cally hindered ketone, afforded no acceleration, as did some
sort of electron-deficient monoketones (C, F) in compari-
son to pure oxalyldihydrazide as a ligand. Flexible β-dike-
tones (K, L, M) and a highly electron-deficient monoketone
(G) produced some negative effects and resulted in the ab-
solute halt of the reactions. A rigid β-diketone (I) and but-
anedione (J) also provided no acceleration, and hexane-2,5-
dione(N) was the most significant promoter of those
studied, giving an 80% GC yield of the desired product.
It is notable that high loading of ketones at first led us
unambiguously to check if the ketones had an effect as the
cosolvent or the additive. Interestingly, when DMF and
THF or even acetone was used as cosolvents instead of
ketone additives, the model reaction provided obvious less
conversion.
(
Scheme 1). The yield increased remarkably to 63%, which
[
21]
is an increase of more than 10% over our prior result.
We then examined different mono- and diketones, which
are compiled in Figure 1, as additives for the reaction of 1a
with 2a and found substantial effects on the yields (Fig-
ure 2).
Optimization of the C–N Coupling Condition
Scheme 1. Reaction of 4-bromoanisole with aniline.
Inspired by these results, we decided to focus on hexane-
2,5-dione and altered the reaction conditions to optimize
the Cu sources, bases, time, temperature, phase-transfer cat-
alysts, and the proportions among the starting materials,
Cu sources, ligand, and additives with the reaction of 4-
bromoanisole with aniline as a model reaction (Table 1).
As shown in Table 1, with oxalyldihydrazide as a ligand
and hexane-2,5-dione as an additive, all kinds of copper
sources were effective in promoting the reaction (Table 1,
Entries 5–11) and CuO proved to be the best one. Remarka-
bly, when the catalyst loading was decreased from 25 mol-
%
to 5 mol-%, the reaction proceeded very well (Table 1,
Entries 2, 5, 15), and even down to 1.25 mol-% loading of
CuO, the yield was only slightly decreased (Table 1, En-
try 16). Moreover, several bases with different basicities led
to similar efficiencies of the reaction, and KOH was found
Figure 1. Ketones used for additives.
36
6
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Eur. J. Org. Chem. 2009, 635–642

Amination of Aryl Halides in Water
to be the most appropriate one (Table 1, Entries 5, 12–14). slightly lower isolated yields (Table 2, Entries 5–8) for dif-
However, for the model reaction, more investigation indi- ferent reasons: For the reaction of 1-bromo-4-(trifluoro-
cated that if the loading of oxalyldihydrazide, hexane-2,5- methyl)benzene with aniline (Table 2, Entry 5), the lower
dione, TBAB, or aniline was reduced excessively, the con- yield was due to a large amount of unreacted starting mate-
version of 4-bromoanisole did not change, but the yield of rial, but the reaction of 1-bromo-4-chlorobenzene with ani-
the target product decreased because of the increase of side line (Table 2, Entry 6) provided very high conversion (96%
products resulting from debromination and hydrolysis of 4- by GC analysis) with some side products of debromination
bromoanisole. In addition, the reaction temperature (13% in GC yield) and hydrolysis (14% in GC yield). Aryl
(120 °C) was good enough to realize the reaction (Table 1, iodides are generally accepted as being more reactive than
Entries 1–3).
aryl bromides; hence, under our reaction conditions, the re-
action of iodobenzene with aniline gave a slightly lower
yield than bromobenzene because of some side reactions
(Table 2, Entries 4 and 9).
Table 1. Copper/oxalohydrazide/hexane-2,5-dione catalyzed N-
arylation of 4-bromoanisole with aniline under different condi-
[
a]
tions.
Table 2. Microwave-assisted CuO/oxalyldihydrazide/ketone-cata-
[
a]
lyzed coupling reactions of aryl halides with anilines in water.
Entry Catalyst [mol-%][b] Base[equiv][b] T [°C] Conversion [%] /
[c]
Yield [%]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
CuO (25)
CuO (25)
CuO (25)
CuO (25)
CuO (10)
KOH (2)
KOH (2)
KOH (2)
KOH (1.5)
KOH (2)
KOH (2)
KOH (2)
KOH (2)
KOH (2)
KOH (2)
KOH (2)
130
120
110
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100/75
99/76
96/70
87/61
100/75
97/75
99/59
61/35
81/46
95/64
88/59
99/71
95/71
98/66
100/85
98/84
57/40
2
Cu O (10)
CuI (10)
CuSO
CuCl
4
(10)
(10)
2
0
1
2
3
4
5
6
7
2
Cu(OAc) (10)
Cu (10)
CuO (10)
CuO (10)
CuO (10)
CuO (5)
CuO (1.25)
CuO (0.6)
K
K
Cs
2
CO
PO
CO
3
(2)
(2)
(2)
3
4
2
3
KOH (2)
KOH (2)
KOH (2)
[
(
a] Reaction conditions: 4-bromoanisole (0.5 mmol), aniline
2.0 mmol), catalyst, oxalyldihydrazide (0.25 mmol), hexane-2,5-di-
one (0.5 mmol), base, TBAB (0.125 mmol), H O (1.0 mL), micro-
2
wave (100 W), 5 min. [b] Relative to 4-bromoanisole. [c] Calculated
by GC.
Microwave-Assisted Coupling Reactions of Aryl Halides
with Anilines
To establish the generality of this protocol, a variety of
functionalized aryl halides were coupled with anilines under
the optimized condition [CuO (5 mol-%), oxalyldihydrazide
[
(
(
a] Reaction conditions: ArX (0.5 mmol), amine (2.0 mmol), CuO
0.025 mmol), oxalyldihydrazide (0.25 mmol), hexane-2,5-dione
0.5 mmol), KOH (1.0 mmol), TBAB (0.125 mmol), H O (1.0 mL),
2
(
(
50 mol-%),
TBAB
(25 mol-%),
hexane-2,5-dione 120 °C, 5 min, microwave (100 W). [b] Isolated yield.
1.0 equiv.), KOH (2.0 equiv.), H O, 120 °C, 5 min]. Some
2
conclusions could be drawn from Table 2. CuO/oxalyldi-
hydrazide/hexane-2,5-dione is an exceptionally good cata-
lytic system for the reaction of aryl halides with anilines in
water. Both aryl bromides with electron-rich para substitu-
ents and neutral aryl bromides reacted with anilines to af-
ford good isolated yields (Table 2, Entries 1–4). The tradi-
Microwave-Assisted Coupling Reactions of Aryl Halides
with Aliphatic Amines
When the coupling reactions of various aryl halides with
tionally activated aryl bromides reacted with aniline under benzylamine and aliphatic primary amines were examined,
our reaction condition to provide desired products with cyclohexanone was used instead of hexane-2,5-dione to
Eur. J. Org. Chem. 2009, 635–642
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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637

X. Zhu, L. Su, L. Huang, G. Chen, J. Wang, H. Song, Y. Wan
FULL PAPER
Table 3. Microwave-assisted CuO/oxalyldihydrazide/ketone-catalyzed avoid an unexpected Paal–Knorr reaction to consume ben-
coupling reactions of aryl halides with aliphatic amines in water.[
a]
zylamine and hexane-2,5-dione and decrease the yield of
target product (Table 3, Entry 1). These results are summa-
rized in Table 3. All aryl bromides and aryl iodides reacted
with benzylamine to afford good-to-excellent isolated yields
up to 91%, although o-bromotoluene provided a little lower
yield (Table 3, Entry 4) due to steric hindrance, but these
optimized conditions are not effective to aryl chlorides
(Table 3, Entry 11–13). In addition, linear and cyclic ali-
phatic amines were all feasible, but secondary amines gave
slightly lower yields because of problematic debromination
of aryl bromides (Table 3, Entries 16 and 17).
Microwave-Assisted Coupling Reactions of Aryl Halides
with Imidazoles
However, in comparison with benzylamine, anilines, and
aliphatic amines, it was slightly more difficult for nitrogen-
containing heterocyclic aromatic compounds, such as imid-
azoles, to undergo the N-arylating reactions. So, a general
and mild procedure for copper-catalyzed C–N bond forma-
tion of aryl halides with imidazoles has remained relatively
scarce, not to mention the reaction in water. To extend the
applicability of the CuO/oxalyldihydrazide/ketone catalytic
system, the coupling reaction of imidazole with 4-bromo-
anisole in water was investigated (Table 4). The reaction ran
successfully under the optimized conditions, but with an
increase in the reaction temperature to 140 °C, and the de-
sired product was isolated in 82% yield (Table 4, Entry 2).
Modification with utilization of K PO instead of KOH led
3
4
to the isolation of 1-(4-methoxyphenyl)-1H-imidazole in up
to 89% yield (Table 4, Entry 6).
Table 4. Effects of reaction conditions on the coupling reaction of
-bromoanisole with imidazole.[
a]
4
Entry
Base [equiv.][b]
Temperature [°C]
Yield [%][c]
1
2
3
4
5
6
7
8
KOH (2)
KOH (2)
KOH (2)
130
140
150
140
140
140
140
130
70
82
74
78
78
89
80
77
Cs
2
CO
CO
PO
PO
PO
3
(2)
(2)
(2)
K
K
2
3
3
4
K
K
3
4
(1.5)
(2)
3
4
[
(
a] Reaction conditions: 4-bromoanisole (0.5 mmol), imidazole
2.0 mmol), CuO (0.025 mmol), oxalyldihydrazide (0.25 mmol),
hexane-2,5-dione (0.5 mmol), base, TBAB (0.125 mmol), H
1.0 mL), 5 min microwave (100 W). [b] Relative to 4-bromoanisole.
2
O
(
[
(
0
(
a] Reaction conditions: ArX (0.5 mmol), amine (2.0 mmol), CuO
0.025 mmol), oxalyldihydrazide (0.25 mmol), hexane-2,5-dione (N,
.5 mmol) or cyclohexanone (A, 2 mmol), KOH (1.0 mmol), TBAB
0.125 mmol), H O (1.0 mL), 120 °C, 5 min, microwave (100 W).
[c] Isolated yield.
To establish the generality of this protocol, a variety of
b] Isolated yield. [c] CuO (0.1 mmol). [d] GC yield 64%, debromi- aryl halides with different substituents were aminated with
nation product, 34%.
imidazoles under the optimized condition (Table 5). The re-
2
[
638
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Eur. J. Org. Chem. 2009, 635–642

Amination of Aryl Halides in Water
sults showed that CuO/oxalyldihydrazide/hexane-2,5-dione sealed vial at 120 °C and obtained 75% yield of isolated
is also a very effective catalytic system for the N-arylation product (Table 6, Entry 2). It is interesting to note that
reaction of imidazoles in water. Imidazole and 2-methyl- when we performed the coupling reactions at 90 °C (reflux)
1H-imidazole reacted with aryl halides to afford good-to- in a conventional oil bath, the reactions gave good-to-excel-
excellent yields (Table 5, Entries 1, 2, 4–10), but 1H- lent yields only when the reaction time was increased from
benzo[d]imidazole gave only a fair yield, because a large 5 min to 8 h. These results would benefit organic chemists
amount of starting material was left unreacted (Table 5, En- to develop a C–N coupling reaction in water for industrial
try 3).
purposes.
Table 5. Microwave-assisted CuO/oxalyldihydrazide/hexane-2,5-di-
one-catalyzed coupling reactions of aryl halides with imidazoles in
water.
Table 6. CuO/oxalyldihydrazide/ketone-catalyzed coupling reac-
tions of aryl halides with amines in water under conventional heat-
ing conditions.[
[
a]
a]
[
a] Reaction conditions: ArX (1.0 mmol), amine (4.0 mmol), CuO
0.05 mmol), oxalyldihydrazide (0.5 mmol), cyclohexanone (A,
mmol) or hexane-2,5-dione (N, 1.0 mmol), KOH (2.0 mmol),
TBAB (0.25 mmol), H O (6.0 mL), 90 °C, 8 h. [b] Isolated yield.
c] Sealed vial in oil bath, 120 °C. [d] K PO in place of KOH, re-
flux.
(
4
2
[
3
4
[
a] Reaction conditions: ArX (0.5 mmol), amine (2.0 mmol), CuO
(
(
(
0.025 mmol), oxalyldihydrazide (0.25 mmol), hexane-2,5-dione
0.5 mmol), PO (1.0 mmol), TBAB (0.125 mmol),
1.0 mL), 140 °C, 5 min, microwave (100 W). [b] Isolated yield.
K
3
4
2
H O
Coupling Reactions of Aryl Halides with Amines at Room
Temperature
Coupling Reactions of Aryl Halides with Amines under
Conventional Heating Conditions
We ran our model reaction under almost the same condi-
The scope of the reactions extended to conventional tions, but at room temperature. It is noteworthy that the
heating mode successfully (Table 6). At first, we conducted model reaction proceeded equally well with an increase in
the model reaction (Scheme 1) in a preheated oil bath in a the catalyst loading to 20 mol-% and a prolonged reaction
Eur. J. Org. Chem. 2009, 635–642
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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639

X. Zhu, L. Su, L. Huang, G. Chen, J. Wang, H. Song, Y. Wan
FULL PAPER
time of 96 h. An 86% isolated yield of the desired product component catalyst, CuO/oxalyldihydrazide/hexane-2,5-di-
was obtained, which is slightly higher than those obtained one, for C–N coupling in water at room temperature, which
with heating (Table 7, Entry 1). To prove the applicability can be performed under microwave irradiation or under
of this protocol, several functionalized aryl bromides and conventional heating. A variety of amines including N-con-
aryl iodides were aminated and provided good-to-excellent taining aromatic heterocycles could be N-arylated with aryl
yields (Table 7). It should be noted that the reactions failed halides effectively under corresponding experimental condi-
with cyclohexanone as a promoter at room temperature, tions. In addition, four important discoveries were also pre-
even though cyclohexanone was effective for the N-aryl- liminarily established: (1) The loading of the catalyst could
ation of benzylamine under thermal treatment. Moreover, be very low (down to less than 1.25 mol-%). (2) Unactivated
arylation of imidazole did not work because of the poor aryl halides possess high reactivity. (3) Monoketones and
conversion of the aryl bromide.
diketones, but not β-diketones (e.g. 2-acetylcyclohexanone,
which was one of the best ligands discovered by Buchwald,
Table 7. CuO/oxalyldihydrazide/acetonyl acetone catalyzed coup- did not work in water), promoted the catalytic potential of
ling reaction of aryl halides with amines in water at room tempera-
CuO/oxalyldihydrazide in water. This discovery will benefit
the future study of the mechanical differences between Cu-
ture.[
a]
catalyzed C–N coupling in organic media and in water. (4)
Electron-rich ketones are better than their electron-deficient
counterparts for C–N bond formation in water under our
reaction conditions. These discoveries will benefit the future
design of novel, efficient, and environmentally benign Cu-
based catalysts for C–N cross-coupling reactions.
Experimental Section
General Conditions: All aryl halides and amines were commercially
available and used as received. All reactions were carried out on
the CEM discover system (Model NO. 908010, manufactured by
CEM Company in USA, with vertically-focused IR temperature
control system, maximum microwave power 300 W, frequency @
2.455 GHz) in vials (size: 10 mL) sealed with a septum with a stir-
ring option. Flash column chromatography was performed with
silica gel (200–300 mesh). Thin-layer chromatography was carried
out with Merck silica gel 60F254 plates. All yields reported in the
publication represent an average of at least two independent runs.
1
All products were characterized by MS and H NMR spectroscopy,
1
and this data was compared to the previously reported data.
H
NMR spectra were recorded at room temperature with a Mercury-
Plus 300 instrument with TMS as an internal reference. LC–MS
were run with a LCMS-2010A. GC–MS were run with a Voyager
GC–MS instrument with an electron impact (70 eV) mass selective
detector. EI mass spectra were recorded with a Thermo DSQ mass
spectrometer. FAB mass spectra were recorded with a VGA-ZAB-
HS instrument. Elemental analyses were perfomed with a Vario
EL instrument. All compounds have been reported previously and
characterized by comparison with their reported data.
General Procedure for the Microwave-Assisted Coupling Reaction.
Synthesis of 3a: A 10-mL vessel was charged with CuO (2 mg,
[
(
(
a] Reaction conditions: ArX (0.5 mmol), amine (2.0 mmol), CuO
0.1 mmol), oxalyldihydrazide (0.25 mmol), hexane-2,5-dione
0.5 mmol), KOH (1.0 mmol), TBAB (0.125 mmol), H O (1.0 mL),
5 °C. [b] Isolated yield. [c] Cyclohexanone (2.0 mmol) instead of
0
.025 mmol), oxalyldihydrazide (30 mg, 0.25 mmol), hexane-2,5-di-
one (57 mg, 0.5 mmol), 4-bromoanisole (1a; 94 mg, 0.5 mmol), ani-
line (2a; 186 mg, 2 mmol), TBAB (40 mg, 0.125 mmol), H
1.0 mL), and a magnetic stir bar. The vessel was sealed with a
2
2
2
O
hexane-2,5-dione (0.5 mmol) was used.
(
septum and placed into the single-mode microwave cavity. The re-
action temperature was raised from room temperature to 120 °C
over 1 min, and then the reaction mixture was held at this tempera-
ture for 5 min. After allowing the mixture to cool to room tempera-
ture, the reaction mixture was extracted with ethyl acetate
Conclusions
We primarily proved that the BCO/CuO catalytic system
is a precatalyst, in which BCO is decomposed in situ into
(
3ϫ40 mL). The combined organic phase was washed with water
and brine, dried with anhydrous MgSO , and concentrated in
4
oxalyldihydrazide and cyclohexanone. On the basis of this vacuo. The residue was purified by flash column chromatograph
discovery, we, for the first time, established a novel three- on silica gel (ethyl acetate/petroleum ether, 1:20) to afford 3a as a
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Eur. J. Org. Chem. 2009, 635–642

Amination of Aryl Halides in Water
1
white solid (78 mg, 78%). H NMR (300 MHz, CDCl
(
3
): δ = 7.11
Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004; b)
J. F. Hartwig, Palladium-Catalyzed Amination of Aryl Halides
and Related Reactions, John Wiley & Sons, New York, 2002; c)
B. H. Yang, S. L. Buchwald, J. Organomet. Chem. 1999, 576,
t, J = 7.8 Hz, 2 H), 6.98 (d, J = 8.7 Hz, 2 H), 6.83–6.74 (m, 5 H),
.45 (br. s, 1 H), 3.71 (s, 3 H) ppm. MS (ESI+): m/z (%) = 200 [M
H] . C13H13NO (199.25): calcd. C 78.36, H 6.58, N 7.03; found
5
+
+
125–146; d) A. Begouin, S. Hesse, M.-J. R. P. Queiroz, G.
C 78.06, H 6.62, N 6.97.
Kirsch, Synthesis 2006, 2794–2798; e) M. J. Bhanushali, N. S.
Nandurkar, M. D. Bhor, B. M. Bhanage, J. Mol. Catal. A 2006,
259, 46–50; f) D. J. Morris, G. Docherty, G. Woodward, M.
Wills, Tetrahedron Lett. 2007, 48, 949–953; g) A. S. Dallas,
K. V. Gothelf, J. Org. Chem. 2005, 70, 3321–3323; h) J. P.
Wolfe, H. Tomori, J. P. Sadighi, J. Yin, S. L. Buchwald, J. Org.
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S. L. Buchwald, Org. Lett. 2002, 4, 2885–2888; k) M. Thute-
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2006, 71, 6522–6529; m) R. Kuwano, M. Utsunomiya, J. F.
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ton, J. G. Verkade, J. Org. Chem. 2008, 73, 3047–3062.
General Procedure for the Coupling Reaction Heated with an Oil
Bath. Synthesis of 3i: To a 15-mL flask was added CuO (4 mg,
0
.05 mmol), oxalyldihydrazide (59 mg, 0.5 mmol), cyclohexanone
196 mg, 2 mmol), 4-bromoanisole (1a; 187 mg, 1.0 mmol), ben-
zylamine (2c; 428 mg, 4 mmol), KOH (112 mg, 2.0 mmol), TBAB
80 mg, 0.25 mmol), H O (6.0 mL), and a magnetic stir bar. The
(
(
2
reaction mixture was stirred at 90 °C in an oil bath for 8 h. After
allowing the mixture to cool to room temperature, the reaction
mixture was extracted with ethyl acetate (3ϫ40 mL). The com-
bined organic phase was washed with water and brine, dried with
anhydrous MgSO , and concentrated in vacuo. The residue was
4
purified by flash column chromatograph on silica gel (ethyl acetate/
petroleum ether, 1:30) to afford 3i as a white solid (187 mg, 88%).
1
H NMR (300 MHz, CDCl
3
): δ = 7.29–7.14 (m, 5 H), 6.68 (d, J =
[
3] A. Klapars, J. C. Antilla, X. Huang, S. L. Buchwald, J. Am.
9
.0 Hz, 2 H), 6.51 (d, J = 9.0 Hz, 2 H), 4.19 (s, 2 H), 3.65 (s, 3 H)
Chem. Soc. 2001, 123, 7727–7729.
+
ppm. MS (ESI+): m/z (%) = 214 [M + H] . C14H15NO (213.28):
[
4] a) R. Gujadhur, D. Venkataraman, J. T. Kintigh, Tetrahedron
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General Procedure for the Coupling Reaction Performed at Room
Temperature. Synthesis of 3d: To a 10-mL vessel was added CuO
2368.
(
2
8 mg, 0.1 mmol), oxalyldihydrazide (30 mg, 0.25 mmol), hexane-
,5-dione (57 mg, 0.5 mmol), iodobenzene (1h; 102 mg, 0.5 mmol),
aniline (2a; 186 mg, 2 mmol), KOH (56 mg, 1.0 mmol), TBAB
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[
5] a) A. Kiyomori, J.-F. Marcoux, S. L. Buchwald, Tetrahedron
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2
1
0135–10138; c) A. A. Kelkar, N. M. Patil, R. V. Chaudhari,
reaction mixture was stirred at room temperature (25 °C) for 96 h.
The reaction mixture was extracted with ethyl acetate (3ϫ40 mL).
The combined organic phase was washed with water and brine,
dried with anhydrous MgSO , and concentrated in vacuo. The resi-
4
due was purified by flash column chromatograph on silica gel (ethyl
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002, 124, 11684–11688; b) A. Klapars, X. Huang, S. L. Buch-
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acetate/petroleum ether, 1:20) to afford diphenylamine as a pale-
1
yellow solid (78 mg, 92%). H NMR (300 MHz, CDCl
3
): δ = 7.18
(
2
C
t, J = 7.5 Hz, 4 H), 6.98 (d, J = 7.8 Hz, 4 H), 6.84 (t, J = 7.5 Hz,
+
H), 5.66 (br. s, 1 H) ppm. MS (ESI+): m/z (%) = 170 [M + H] .
11N (169.22): calcd. C 85.17, H 6.55, N 8.28; found C 84.92,
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H
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H 6.56, N 8.18.
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Natural Science Foundation (No. 04009718) and the National High
Technology Research and Development Program of China (863
Program), No. 2006AA09Z446. We would like to thank Dr. Mar-
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Received: September 26, 2008
Published Online: December 29, 2008
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Eur. J. Org. Chem. 2009, 635–642