A highly versatile catalytic system for N-arylation of amines with aryl chlorides in water

Article abstract of DOI:10.1002/ejoc.201100458

The C-N coupling between nucleophiles and aryl chlorides, which are less expensive, less reactive, and more abundant than their bromide and iodide counterparts, is challenging but of great interest for industrial applications. An oxalyldihydrazide/hexane-2,5-dione (100-150 mol-%)/CuO system was found to enable the reaction of a wide range of nucleophiles with a variety of aryl chlorides in water for the first time.

Full text of DOI:10.1002/ejoc.201100458

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100458
A Highly Versatile Catalytic System for N-Arylation of Amines with Aryl
Chlorides in Water
[a]
[a]
[a]
[a]
[a]
Manna Huang, Xiaoqin Lin, Xinhai Zhu, Weili Peng, Jianwei Xie, and
Yiqian Wan*[
a]
Keywords: Copper / Cross-coupling / Amination / Water chemistry
The C–N coupling between nucleophiles and aryl chlorides,
which are less expensive, less reactive, and more abundant
than their bromide and iodide counterparts, is challenging
but of great interest for industrial applications. An oxalyldi-
hydrazide/hexane-2,5-dione (100–150 mol-%)/CuO system
was found to enable the reaction of a wide range of nucleo-
philes with a variety of aryl chlorides in water for the first
time.
the aryl chloride as the solvent (51–95% isolated yields);[4a]
with the assistance of microwave heating (10–20 h), aryl
chlorides have been successfully aminated with aqueous
Introduction
Many significant products (drugs, materials, optical de-
vices, etc.), whether commercialized or at the development
ammonia by using a Cu O-catalyzed system in water/NMP
[
1]
2
phase, possess aromatic carbon–nitrogen bonds. Until
[
7]
(
1:1). However, additional studies are strongly needed to
[
1a,2]
[2j,3]
now, Pd-
and Cu-catalyzed
cross-coupling reactions
develop a versatile copper catalytic system that can couple
a broad spectrum of potential amines with aryl chlorides
under mild conditions. Furthermore, protocols avoiding the
use of toxic and/or high-boiling organic solvents have re-
cently attracted much attention to fulfill one or more
requirements of a sustainable chemistry. Hence, Ullmann-
type C–N reactions of aryl bromides and aryl iodides have
successfully been performed in pure water or aqueous me-
have been the most efficient for the construction of aro-
matic C–N bonds both in industrial and academic settings,
although traditional Cu-mediated C–N cross-couplings,
such as the Ullmann and Goldberg-type reactions, have
showed limitations in practical applications due to the
requirement of stoichiometric amounts of copper reagents
and harsh reaction conditions. The study of copper-cata-
lyzed C–N couplings has been reinvigorated because of the
potential attractiveness of copper and Buchwald’s and
[
2h,5g,8]
dia.
ous organic reactions,
As part of our ongoing research interest in aque-
[
8a–8c,8f]
we report herein an oxalyldi-
Taillefer’s pioneering work[
latter judiciously employed selected ligands enabling the
coupling to be performed under mild conditions with a
catalytic amount of copper.
3a,4]
followed by others.
[3e,5]
The
hydrazide/hexane-2,5-dione/CuO system for the amination
of aryl chlorides in water that does not requiring an inert
atmosphere or microwave irradiation.
From general considerations, aryl chlorides are less ex-
pensive and more abundant than their bromide and iodide
counterparts, but they less reactive and of much greater
interest for industrial applications. However, the develop- Results and Discussion
ment of several highly effective classes of catalysts for the
cross-coupling of aryl chlorides with low catalyst loadings,
Previously, we described an oxalyldihydrazide/ketone/
excellent yields, and reasonable scope remains a challeng- CuO system that enabled the amination of aryl halides in
[
2a,6]
ing.
It has rarely been mentioned in the literature that water. In particular, some aryl chlorides were aminated to
[
8a]
Cu-catalyzed C–N coupling reactions of aryl chlorides with afford trace amounts of the desired products.
Hence, it
arylamines are difficult: For example, cyclohexane-1,2-di- is reasonable to develop a versatile catalytic system for the
amine as a ligand facilitates the CuI-catalyzed amination of N-arylation of amines with aryl chlorides in water by ex-
aryl chlorides when performed with an excess amount of tending the reaction time from minutes to hours. To test
this hypothesis, we used the previously described conditions
[
a] School of Chemistry and Chemical Engineering,
for the reaction between 4-bromoanisole and aniline for the
amination of 4-chloroanisole. Thus, we found that 4-chloro-
anisole afforded 4-methoxy-N-phenylaniline in 14% iso-
lated yield upon heating for 8 h in a preheated oil bath
(Scheme 1).
Sun Yat-sen University
Guangzhou 510275, P. R. China
Fax: +86-20-8411-3610
E-mail: ceswyq@mail.sysu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100458.
Eur. J. Org. Chem. 2011, 4523–4527
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4523

M. Huang, X. Lin, X. Zhu, W. Peng, J. Xie, Y. Wan
SHORT COMMUNICATION
Table 1. Optimization of coupling reaction of 4-chloroanisole with
aniline.[
a]
Scheme 1. Model reaction for the amination of aryl chlorides.
Entry [Cu]
Base
(mol-%)
PTC
(mol-%)
Conv. / Yield
(%)
This promising result encouraged us to screen typical re-
action parameters including different copper sources, bases,
ketones as well as different proportions of substrates, cata-
[b]
(mol-%)
1
2
3
4
5
6
7
8
9
none
K
K
K
3
3
3
PO
PO
PO
4
4
4
(2)
(2)
(2)
TBAB (25)
TBAB (25)
TBAB (25)
TBAB (25)
TBAB (25)
TBAB (25)
TBAB (25)
TBAB (25)
TBAB (25)
0/0
CuO (10)
CuO (1)
CuO (5)
CuI (10)
Cu O (10)
2
CuCl (10)
Cu (10)
98/82
54/44
96/73
58/30
26/22
98/76
20/17
21/13
97/73
90/70
31/24
98/77
100/79
12/10
II
lysts, and ligands. A range of different copper sources (Cu
I
and Cu ) were more or less active, but CuO provided the
K PO (2)
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
K
K
K
K
K
K
K
PO
PO
PO
PO
PO
PO
PO
(2)
(2)
(2)
(2)
(2)
highest yields (Table 1). The latter has the advantage of be-
ing inexpensive and air stable. However, the amount of CuO
was much more important to make full conversion (10 mol-
%). The choice of base and ketone was another important
4
CuSO (10)
factor. K PO was found to be the best base, affording ex- 10
CuO (10)
CuO (10)
CuO (10)
CuO (10)
CuO (10)
CuO (10)
CuO (10)
CuO (10)
CuO (10)
CuO (10)
CuO (10)
CuO (10)
CuO (10)
CuO (10)
CuO (10)
CuO (10)
CuO (10)
(1.5) TBAB (25)
3
4
11
12
13
14
(3)
TBAB (25)
TBAB (25)
(2) TBAB (25)
cellent conversion and yield (98% conversion, 82% GC
yield), although Cs CO and K CO also provided high
KOH (2)
Cs CO
CO
2
3
2
3
2
3
conversion. However, KOH (a strong base) afforded a much
K
2
3
(2)
TBAB (25)
none
SDS-Na (25) 66/56
lower conversion and a poor yield. This disparity probably 15
K PO (2)
3
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
4
16
K
K
K
K
K
K
K
K
K
K
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
results from the need to match the rate of deprotonation of
the amine to the rate of C–N bond formation.[3a] With re-
17
TBAB (10)
TBAB (50)
TBAB (25)
TBAB (25)
TBAB (25)
TBAB (25)
TBAB (25)
TBAB (25)
TBAB (25)
TBAB (25)
83/70
94/74
18
19
20
gard to the ketone, we found that hexane-2,5-dione was a
prerequisite for obtaining high activity (98% conversion
[c]
0/0
[d]
52/40
89/66
94/69
92/73
0/0[
32/24
96/79
[
[
[
e]
f]
and 82% GC yield), and other related ketones afforded 21
2
2
2
2
2
3
4
5
much lower conversions and poor yields (data not presented
here). After a brief optimization campaign, it was discov-
ered that employing oxalyldihydrazide/hexane-2,5-dione/
g]
h]
[i]
[
j]
CuO (50:100:10 mol-%) at 120 °C in water gave 98% con- 25
3 4
K PO (2)
version of 4-chloroanisole into 4-methoxy-N-phenylaniline
with 73% isolated yield after 24 h (Scheme 2, 3a). Thus, we (4.0 mmol), catalyst, oxalyldihydrazide (25 mol-%), hexane-2,5-di-
obtained the first effective example for the Cu-catalyzed one (100 mol-%), base, phase-transfer catalyst (PTC),
coupling of nonactivated aryl chlorides in water with no
microwave irradiation. It should be noted that oxalylhydraz-
ide is crucial for the effective copper-catalyzed C–N cou-
[
a] Reaction conditions: 4-chloroanisole (1.0 mmol), aniline
2
H O
(
2.0 mL), 120 °C, 24 h. [b] Calculated GC yield. [c] No oxalyldihyd-
razide was used. [d] Oxalyldihydrazide (10 mol-%). [e] Oxalyldihyd-
razide (20 mol-%). [f] Aniline (2.0 mmol). [g] Aniline (3.0 mmol).
[
h] No hexane-2,5-dione was used. [i] Hexane-2,5-dione (50 mol-
pling in water, although its role is not yet well understood %). [j] Hexane-2,5-dione (200 mol-%).
(Table 1, Entry 19).
In most cases, N-arylation of aniline with most aryl chlo-
rides (electron-rich, electron-neutral, or electron-poor) pro- obtained in good yields (72–80%) without the use of strong
vided the desired products in good isolated yields. As for bases, toxic and expensive metals, or sophisticated ligands.
ortho-substituted aryl chlorides, the reaction was slower and
Azoles and arylazoles play an important role as struc-
less efficient and afforded the corresponding 2-methoxy-N- tural and functional units in many biologically active com-
phenylaniline (Scheme 2, 3d) in only 37% isolated yield af- pounds, natural products, and useful synthons. However,
ter 24 h. This observation was relevant to Cu-catalyzed sys- the preparation of N-arylazoles is severely restricted, be-
tems because of steric hindrance.[
9]
cause nitrogen heterocycles are not good substrates for the
Notably, a much larger excess of benzylamine (6 equiv.) traditional arylation reagents.[11] We were pleased to find
and hexane-2,5-dione (1.5 equiv.) were needed to provide that the arylation reaction also proceeds with pyrazole in
complete conversion of the aryl chlorides due to unexpected good to excellent yields when extending the reaction time
Paal–Knorr side reactions[8a] that consumed the benzyl- to 48 h. However, the reaction between imidazole or 1H-
amine and hexane-2,5-dione, reducing the yield of the de- benzimidazole and aryl chlorides afforded fair to good
sired products.
It is very interesting to apply the procedure for the prepa- conversion of aryl chlorides.
ration of anilines, which are key intermediates in aromatic It should be noted that nitro-substituted aromatic chlo-
Microwave-assisted direct amination of aryl rides were not good substrates for amination under the ex-
yields of the corresponding products due to incomplete
[
10]
processes.
chlorides with ammonia has been reported. In most cases perimental conditions. Although the desired cross coupling
Scheme 3, 3m, 3n, 3o, 3p), the corresponding anilines were products were still obtained in fair yields (Scheme 2, 3e, 3k;
[7]
(
4524
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4523–4527

Catalytic System for N-Arylation of Amines in Water
Scheme 2. Products and yields for Cu-catalyzed amination of aryl chloride with different nitrogen sources.
Scheme 3, 3p, 4d, 4m) in most cases, pyrazole coupling to cerning the origin of the broad scope and high activity of
1-chloro-4-nitrobenzene afforded 4-(1H-pyrazol-1-yl)anil- the catalysts featured herein are currently ongoing in our
ine as the main product (70% isolated yield), which was laboratory.
formed during the reduction of the nitro group by the CuO/
oxalyldihydrazide system.
Experimental Section
Conclusions
Representative Procedure: A 10-mL vessel was charged with CuO
10 mg, 0.1 mmol), oxalyldihydrazide (59 mg, 0.5 mmol), hexane-
,5-dione (114 mg, 1.0 mmol), aryl chloride (1.0 mmol), amine
(
2
In conclusion, we have reported a versatile protocol for
the CuO-catalyzed amination of aryl chlorides in water. It (4.0 mmol), K PO ·3H O (532 mg, 2.0 mmol), TBAB (80 mg,
3
4
2
2
obviates the need for microwave irradiation, has a broad 0.25 mmol), H O (2.0 mL) and a magnetic stir bar. The vessel was
substrate scope, which includes various nitrogen sources sealed with a septum and placed into an oil bath, which was pre-
heated to 120 °C. The reaction mixture was held at this temperature
ranging from arylamines to nitrogen-containing aromatic
for 24 h. After allowing the mixture to cool to room temperature,
the reaction mixture was extracted with ethyl acetate (4ϫ30 mL).
The combined organic phase was washed with water and brine,
2 4
dried with anhydrous Na SO , and concentrated in vacuo. The resi-
heterocycles, and includes a range of aryl chlorides (both
activated and unactivated ones). Considering the large vari-
ety and ready availability of the starting materials, as well
as the stability and low price of CuO, in addition to the
operational simplicity of our procedure, a convenient, prac-
tical, and highly efficient catalytic system for C–N cross-
due was purified by flash column chromatograph on silica gel (pe-
troleum ether/ethyl acetate, 20:1) to afford desired product 3a
+
1
(
145 mg, 73%). MS (ESI+): m/z = 200 [M + H] . H NMR
coupling of aryl chlorides was developed for the first time. (300 MHz, CDCl ): δ = 7.25–7.18 (m, 2 H, ArH), 7.08 (d, J =
3
Further investigations to understand the mechanism con- 8.5 Hz, 2 H, ArH), 6.93–6.81 (m, 5 H, ArH), 5.51 (br. s, 1 H, NH),
Eur. J. Org. Chem. 2011, 4523–4527
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4525

M. Huang, X. Lin, X. Zhu, W. Peng, J. Xie, Y. Wan
SHORT COMMUNICATION
Scheme 3. Products and yields for Cu-catalyzed amination of aryl chloride with different nitrogen sources.
3
.82 (s, 3 H, OCH
3
) ppm. 13C NMR (75 MHz, CDCl
3
): δ = 155.4,
Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004; b)
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cle): Experimental procedures, characterization data, and copies of
the H NMR and C NMR spectra of all compounds.
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Published Online: July 11, 2011
Eur. J. Org. Chem. 2011, 4523–4527
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