Efficient copper-catalyzed direct amination of aryl halides using aqueous ammonia in water

Article abstract of DOI:10.1002/ejoc.201001150

The N²,N²′-diisopropyloxalohydrazide/CuO system efficiently catalyzed the direct amination of aryl bromides andiodides with aqueous ammonia in water at 60 °C in 24 h or at 120 °C in only 20-30 min. Both activated and unactivated aryl and heteroaryl bromides and iodides were readily aminated in good to excellent yields. A highly efficient N ²,N²′-diisopropyloxalohydrazide/CuO system was developed for the direct amination of aryl halides with aqueous ammonia in water at 60 °C for24 h or at 120 °C for 20-30 min. The resulting aromatic primary amines were obtained in good to excellent yields.

Full text of DOI:10.1002/ejoc.201001150

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001150
Efficient Copper-Catalyzed Direct Amination of Aryl Halides Using Aqueous
Ammonia in Water
Fei Meng,[a] Xinhai Zhu,[a] Ying Li,[a] Jianwei Xie,[a] Bo Wang,[a] Junhua Yao,[b] and
Yiqian Wan*[a]
Keywords: Amination / Copper / Amines / Cross-coupling / Water chemistry
The N2,N2Ј-diisopropyloxalohydrazide/CuO system effici-
ently catalyzed the direct amination of aryl bromides and
iodides with aqueous ammonia in water at 60 °C in 24 h or
at 120 °C in only 20–30 min. Both activated and unactivated
aryl and heteroaryl bromides and iodides were readily amin-
ated in good to excellent yields.
catalyst with ammonia in water was pioneered by the group
of Zhou.[6] A wide range of aryl bromides and iodides were
aminated with aqueous ammonia to afford good to excel-
lent yields in 12 h. However, this protocol also has some
drawbacks: harsh conditions (120 °C and 12 h and the use
of the strong base KOH). Hence, a fast or a mild procedure
for the copper-catalyzed direct amination of aryl halides in
water has hitherto remained desirable.
As part of our studies on the copper-catalyzed amination
of aryl halides in water,[7] we herein report that the direct
amination of both activated and unactivated aryl and het-
eroaryl bromides and iodides can be achieved under very
mild conditions (60 °C, K3PO4 as base, without inert atmo-
sphere) and by using N2,N2Ј-diisopropyloxalohydrazide/
CuO as a catalytic system with aqueous ammonia as a ni-
trogen source in water. In addition, our procedure might
provide an alternative route to the high throughput synthe-
sis of primary aromatic amines just by increasing the reac-
tion temperature to 120 °C (with a reaction time of only
20–30 min).
Introduction
Primary aromatic amines are important intermediates for
the synthesis of natural products, pharmaceuticals, agro-
chemicals, and polymers. Hence, their preparation has at-
tracted more and more attention.[1] Traditional methods for
the preparation of primary amines by direct coupling of
aryl halides with ammonia often suffer from high pressure,
high temperature, and long reaction times, which make
those methodologies less practical.[2] Recently, transition-
metal-catalyzed (such as palladium and copper) coupling
reactions of aryl halides with ammonia or ammonia surro-
gates have made big improvements for the preparation of
parent anilines.[3,4] Several palladium-catalyzed methods
have been reported with broad substrate scope and excellent
functional group tolerance.[3] Numerous copper-catalyzed
methods have also been well established under mild reac-
tion conditions in dry or aqueous organic media,[4] particu-
larly by using a series of novel ligands (such as, β-di-
ketones,[4h] -proline and its derivatives,[4d,4k] pyridine-β-
ketones[4m]). During our submission process, two protocols
for the copper-catalyzed synthesis of aminopyridine deriva-
tives were reported in ethylene glycol.[5] Those methodolo-
gies suffered from drawbacks such as the use of high-boil-
ing-point solvents, including, DMF, DMSO, and NMP; the
need for 3–4 bar of ammonia pressure; competition due to
C–O arylation of ethylene glycol or ethanol solvents; and
the use of strong bases.[4,5] Interestingly, direct amination
of aryl halides using a sulfonato-Cu(salen) complex as the
Results and Discussion
For our initial experiments, we chose to study the amina-
tion of 4-bromoanisole with aqueous ammonia in water.
The reaction positively gave 4-methoxyaniline in moderate
yield (63% GC yield; Table 1, Entry 9) at 120 °C for 30 min
when using CuO (5 mol-%)/N2,N2Ј-diisopropyloxalohydraz-
ide (25 mol-%) as the catalytic system and KOH as the base.
This result encouraged us to further explore the reaction
parameters including common commercially available cop-
per sources, bases, the reaction times, temperature, and the
catalyst loading. It should be noted that all the CuII and
CuI salts smoothly catalyzed the model reaction with mod-
erate yields, whereas Cu0 gave a very low yield of 5%
(Table 1, Entries 2–9); moreover, no reaction took place un-
der copper-free conditions, as expected (Table 1, Entry 1).
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[a] School of Chemistry and Chemical Engineering, Sun Yat-Sen
University,
Guangzhou 510275, P. R. China
Fax: +86-20-84112245
E-mail: ceswyq@mail.sysu.edu.cn
[b] Instrumentation Analysis & Research Center, Sun Yat-sen
University,
Guangzhou 510275, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001150.
wileyonlinelibrary.com
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F. Meng, X. Zhu, Y. Li, J. Xie, B. Wang, J. Yao, Y. Wan
SHORT COMMUNICATION
In addition, decreasing the loading of the catalyst from 5 Table 2. Copper-catalyzed amination of aryl halides in water.[a]
to 3 mol-% led to a slight decrease in conversion, whereas
increasing the loading of catalyst from 5 to 10 mol-% only
led to a small increase in conversion (Table 1, Entries 10,
18, and 19). The higher ratio (4:1) of L/CuO required under
the optimal reaction conditions is still a challenge in our
catalytic system and its potential mechanism is not very
clear yet.
Table 1. Optimization of the amination of 4-bromoanisole with
aqueous ammonia in water.[a]
Entry
[Cu]
(mol-%)
Base
PTC
Time
[min]
Conv.
/ % Yield[b]
1
2
3
4
5
6
7
8
9
10
11
13
14
15
16
17
18
19
20
21
22
23
24
–
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
K3PO4
NaF
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
20
30
30
30
30
0[c]
72/61
76/57
72/59
78/60
69/43
76/54
7/5
71/63
96/89
6/5
61/51
50/44
96/88
94/83
0[c]
86/75
99/89
92/76
88/79[d]
97/89[e]
83/71[f]
97/91[g]
CuCl2 (5)
CuAc2 (5)
Cu(NO3)2 (5)
CuSO4 (5)
Cu2O (5)
CuI (5)
Cu (5)
CuO (5)
CuO (5)
CuO (5)
CuO (5)
CuO (5)
CuO (5)
CuO (5)
CuO (5)
CuO (3)
CuO (10)
CuO (5)
CuO (5)
CuO (5)
CuO (5)
CuO (5)
Cs2CO3 TBAB
K2CO3 TBAB
K3PO4 PEG600
K3PO4 SDS-Na
–
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
[a] Unless otherwise noted, the reactions were carried out with 4-
bromoanisole (1.0 mmol), commercial 25–28% aqueous ammonia
(1.0 mL), [Cu] (5 mol-%), L (25 mol-%), base (2.0 mmol), water
(1 mL), 120 °C, 30 min. [b] Calculated by GC–MS. [c] No product
was detected by TLC. [d] The reaction temperature was 110 °C.
[e] L = 20 mol-%. [f] L = 15 mmol-%. [g] L = 20 mol-%, TBAB =
0.5 mmol.
For the purpose of exploring the scope of the application
of the catalytic system, a variety of functionalized aryl
iodides and bromides animated with aqueous ammonia in
water under the optimized reaction conditions [aryl halides
(1.0 mmol), commercial 25–28% aqueous ammonia
(1.0 mL), CuO (5 mmol-%), ligand (20 mmol-%), K3PO4
(2.0 mmol), TBAB (0.5 mmol), water (1.0 mL), 120 °C] was
investigated. The coupling of aqueous ammonia with most
electron-rich, electron-neutral, and electron-poor aryl bro-
mides afforded the desired products with good to excellent
yields (Table 2, Entries 1–3, 6–9, 14). As expected, aryl
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Cu-Catalyzed Amination of Aryl Halides using Aqueous Ammonia
Table 2. (Continued)
cilitate the application of our very useful protocol in either
an academic or industrial setting.
Experimental Section
Synthesis of the N2,N2Ј-Diisopropyloxalohydrazide Ligand: A mix-
ture of oxalohydrazide (6.0 g, 50.0 mmol), propan-2-one (6.4 g,
110.0 mmol), and glacial acetic acid (0.1 mL) in methanol (80 mL)
was heated at reflux for 3 h. After allowing the mixture to cool to
room temperature, NaBH4 (4.3 g, 110.0 mmol) was carefully added
in an ice bath. Then, the mixture was stirred at room temperature
for 2 h. The reaction mixture was filtered, and the precipitate was
washed with water (3ϫ20 mL), methanol (3ϫ20 mL), and CH2Cl2
(3ϫ20 mL). The solid was collected and dried under vacuum to
afford the target product as a white solid (7.7 g, 75% yield). M.p.
1
195.0–195.8 °C. H NMR (300 MHz, CDCl3): δ = 3.20–3.12 (m, 2
H, CH), 1.13 (d, J = 6.3 Hz, 12 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 157.9, 51.6, 20.7 ppm. MS (ESI): m/z = 203 [M +
H]+.
[a] Reaction conditions: ArX (1.0 mmol), commercial 25–28%
aqueous ammonia (1.0 mL), CuO (5 mmol-%), L (20 mmol-%),
K3PO4 (2.0 mmol), TBAB (0.5 mmol), H2O (1.0 mL), 120 °C,
30 min. [b] Isolated yield. [c] 120 °C, 20 min. [d] 60 °C, 24 h.
General Procedure for the Synthesis of the Coupling Reaction Com-
pounds Under the Optimized Reaction Conditions: A 10-mL sealed
vial was charged with CuO (0.004 g, 0.05 mmol), the ligand
(0.040 g, 0.20 mmol), 4-bromoanisole (0.186 g, 1.0 mmol), com-
mercial 25–28% aqueous ammonia (1.0 mL), K3PO4 (0.424 g,
2.0 mmol), TBAB (0.161 g, 0.5 mmol), H2O (1.0 mL), and a mag-
netic stir bar. The reaction mixture was stirred in an oil bath pre-
heated to 120 °C for 30 min or 60 °C for 24 h. After allowing the
mixture to cool to room temperature, the reaction mixture was ex-
tracted with ethyl acetate (4ϫ2 mL). The combined organic phase
was washed with brine, dried with anhydrous Na2SO4, and concen-
trated in vacuo. The residue was purified by flash column
chromatography on silica gel (ethyl acetate/petroleum ether, 1:5) to
afford target 2a (120 °C, 0.1 g, 81% yield; 60 °C, 0.092 g, 75%
iodides provided almost the same yields as those of the aryl
bromides (Table 2, Entries 4, 5, 12). More interesting,
heteroaryl halides also coupled with aqueous ammonia to
give the corresponding anilines in satisfactory yields
(Table 2, Entries 16 and 17). However, steric hindrance of
ortho substituents resulted in a lower reactivity of the corre-
sponding aryl halides to afford lower yields (Table 2, En-
tries 11–13). In addition, aryl chlorides could not be amin-
ated under the experimental conditions (Table 2, Entries 18
and 19).
Next we focused our attention on the possibility to carry
out the amination of aryl halides at much lower tempera-
ture, i.e. 60 °C, which is of much greater interest for indus-
trial applications. Our procedure is in this case also compat-
ible with a wide range of substituents (Table 2). Various anil-
ine derivatives were obtained with both activated and unac-
tivated aryl and heteroaryl bromides and iodides (Table 2,
Entries 1–10, 16, 17).
1
yield). H NMR (300 MHz, CDCl3): δ = 6.77 (d, J = 8.7 Hz, 2 H,
ArH), 6.66 (d, J = 9.0 Hz, 2 H, ArH), 3.75 (s, 3 H, OCH3), 3.39
(br. s, 2 H, NH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.5,
139.8, 116.2, 114.6, 55.6 ppm. MS (ESI): m/z = 124 [M + H]+.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, and copies of
1
the H and 13C NMR and mass spectra of all compounds
Acknowledgments
This work was financially supported by grants from the National
Natural Science Foundation of China (20872182, 20802095) and
by the National High Technology Research and Development Pro-
gram of China (863 Program, No. 2006AA09Z446).
Conclusions
In summary, we developed a general, efficient, and prac-
tical protocol for the direct coupling of aryl or heteroaryl
halides with aqueous ammonia in water catalyzed by
N2,N2Ј-diisopropyloxalohydrazide/CuO. The reaction was
not sensitive to either electron-donating or electron-with-
drawing substituents and could be performed at 60 °C for
24 h or at 120 °C for 20–30 min with good to excellent
yields of the products. Moreover, the easy availability of the
ligand (from commercially available acetone and oxalyldi-
hydrazide in two steps), the commercially available cheap
copper source, and the use of a green solvent and aqueous
ammonia as the readily available nitrogen source might fa-
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