Copper-catalyzed synthesis of primary arylamines via cascade reactions of aryl halides with amidine hydrochlorides

Article abstract of DOI:10.1021/jo800818e

(Chemical Equation Presented) We have developed an efficient method for the synthesis of primary arylamines from aryl halides using amidine hydrochlorides as the ammonia surrogates. The protocol uses 10 mol % CuI as the catalyst, 20 mol % L-proline as the ligand, Cs₂CO₃ as the base, and DMF as the solvent and proceeds the sequential coupling of aryl halides with amidine hydrochlorides and hydrolysis of intermediates to give the target products. This is a convenient, inexpensive, and practical approach to primary arylamines.

Full text of DOI:10.1021/jo800818e

TABLE 1. Copper-Catalyzed Synthesis of N-Nitroaniline via
Cascade Reaction of 1-Iodo-3-nitrobenzene with Acetamidine
Hydrochloride: Optimization of the Catalysis Conditionsa
Copper-Catalyzed Synthesis of Primary
Arylamines via Cascade Reactions of Aryl
Halides with Amidine Hydrochlorides
Xiaoting Gao,†,‡ Hua Fu,*,† Renzhong Qiao,*,‡
Yuyang Jiang,†,§ and Yufen Zhao†
Key Laboratory of Bioorganic Phosphorus Chemistry and
Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua UniVersity,
Beijing 100084, P. R. China, Department of Pharmaceutical
Engineering, College of Life Science and Technology,
Beijing UniVersity of Chemical Technology,
b
entry
catalyst
ligand
base
solvent
yield
1
2
3
4
5
6
7
8
9
10
11
12
13
CuI
A
A
A
A
B
C
D
E
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
DMF
DMF
DMF
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
92
83
41
56
43
22
29
7
16
0
88
65
0
CuBr
CuCl2
CuI
CuI
CuI
CuI
CuI
CuI
Beijing 100029, P. R. China, and Key Laboratory of
Chemical Biology (Guangdong ProVince), Graduate School
of Shenzhen, Tsinghua UniVersity,
Shenzhen 518057, P. R. China
fuhua@mail.tsinghua.edu.cn; qiaorz@mail.buct.edu.cn
A
A
A
F
ReceiVed April 12, 2008
CuI
CuI
PdCl2
Cs2CO3
a Reaction conditions: reaction temperature, 110 °C; reaction time,
10 h); aryl iodide (1 mmol), acetamidine hydrochloride (1.2 mmol),
catalyst (0.1 mmol), ligand (0.2 mmol), base (2 mmol), and solvent (2
mL) under N2. b Isolated yield.
perspective. The Buchwald-Hartwig palladium-catalyzed ami-
nation of aryl halides/triflates has emerged in the past decades
as a powerful tool for the synthesis of arylamines,3 a large
variety of amines and nitrogen nucleophiles undergo this
reaction, but the use of ammonia as the coupling partner does
not afford the corresponding primary anilines.4 Several ammonia
surrogates have been used to overcome this issue, and
allylamine,5a benzophenone imine,5b,c tert-butyl carbamate,5d,e
Li[N(SiMe3)2],5f,g Zn[N(SiMe3)2],5h and 2,2,2-trifluoro-
acetamide5i have been found as suitable masked forms of am-
monia in cross-coupling amination reactions. Solid-supported
ammonia surrogates have also been used in Pd(0)-catalyzed
amination reactions showing the advantage of an easy separation
of the primary aniline precursors from the reaction byproducts. The
final arylamines were obtained after the cleavage step with high
purities and reasonable yields.6 Very recently, a fluoroalkyl
We have developed an efficient method for the synthesis of
primary arylamines from aryl halides using amidine hydro-
chlorides as the ammonia surrogates. The protocol uses 10
mol % CuI as the catalyst, 20 mol % L-proline as the ligand,
Cs2CO3 as the base, and DMF as the solvent and proceeds
the sequential coupling of aryl halides with amidine hydro-
chlorides and hydrolysis of intermediates to give the target
products. This is a convenient, inexpensive, and practical
approach to primary arylamines.
The arylamine moiety is a ubiquitous structural element in
natural products and pharmaceutical and medicinal compounds,
as well as in polymers and materials,1 and its synthesis has
attracted much attention. Although transition-metal-catalyzed
synthesis of primary arylamines has been used via reaction of
aryl halides with NH3, high pressure, high temperature, and
sealed reaction vessels were required.2 Therefore, the procedures
might not be operationally simple and safe from the application’s
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† Department of Chemistry, Tsinghua University.
‡ Beijing University of Chemical Technology.
§ Graduate School of Shenzhen, Tsinghua University.
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Suwanprasop, S.; Nhujak, T.; Roengsumran, S.; Petsom, A. Ind. Eng. Chem.
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10.1021/jo800818e CCC: $40.75 2008 American Chemical Society
Published on Web 07/29/2008

benzophenone imine reagent7a–c and N-substituted-FBoc carba-
mate7d have been used as the ammonia surrogates. Recently,
copper-catalyzed Ullmann N-arylation has become an active field,8
and many research groups9–11 and we12 have developed highly
efficient catalyst systems to perform aminations of aryl halides.
However, the direct use of ammonia as the amino source of primary
arylamines is still ineffective in the absence of pressure thus far.2a
Herein, we report a convenient, inexpensive, and efficient copper-
catalyzed method for synthesis of arylamines from aryl halides
using readily available amidine hydrochlorides as the ammonia
surrogates.
TABLE 2. Copper-Catalyzed Synthesis of Primary Arylamine via
Aryl Halides with Amidine Hydrochloridesa
At first, 1-iodo-3-nitrobenzene and acetamidine hydrochloride
were chosen as the model substrates to optimize reaction
conditions including optimization of the catalysts, ligands, bases,
and solvents at 110 °C under nitrogen atmosphere as shown in
Table 1, and 3-nitroaniline was synthesized in various yields.
Copper salts, CuI, CuBr, and CuCl2 (10 mol % amount relative
to 1-iodo-3-nitrobenzene), were tested in DMF (entries 1-3)
using 20 mol % L-proline as the ligand and 2 equiv of Cs2CO3
as the base, and CuI was found to be the most effective catalyst.
We attempted to change solvents to DMSO from DMF (compare
entries 1 and 4), and the results showed that DMF was much
better than DMSO. The effect of ligands was also investigated
(entries 1, 5-8), and L-proline showed the highest activity. Only
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a Reaction conditions: aryl iodide (1 mmol), amidine hydrochloride
(1.2 mmol), catalyst (0.1 mmol), ligand (0.2 mmol), Cs2CO3 (2 mmol),
solvent (2 mL) under N2. b Isolated yield. c Amidine hydrochloride (2
mmol), Cs2CO3 (3 mmol).
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SCHEME 1. Possible Mechanism for Copper-Catalyzed
Formation of Primary Arylamine
J. Org. Chem. Vol. 73, No. 17, 2008 6865

16% yield of 3-nitroaniline was obtained in the absence of ligand
(entry 9). No target product was observed in the absence of
copper catalyst (entry 10). Several bases, Cs2CO3, K2CO3, and
K3PO4, were also screened, and Cs2CO3 proved to be the best
base (compare entries 1, 11 and 12). We also tried the palladium
catalyst PdCl2 in the presence of ligand PPh3, but no target
product was found (entry 13). After the optimization process
for catalysts, solvents, ligands, and bases, the various primary
arylamines were synthesized under our standard conditions: 10
mol % CuI as the catalyst, 20 mol % L-proline as the ligand, 2
or 3 equiv of Cs2CO3 as the base (relative to aryl halides), and
DMF as the solvent.
Having established a suitable combination of copper catalyst,
ligant, solvent, and base, we explored the scope of this protocol.
Reactions of aryl halides containing electron-withdrawing or
electron-donating groups with acetamidine hydrochloride in the
presence of Cs2CO3 were performed, and the corresponding
primary arylamines were obtained in good to excellent yields
(entries 1-10) as shown in Table 2. Aryl halides containing
electron-donating groups showed reactivities slightly weaker
than those of ones containing electron-withdrawing groups. For
example, aryl iodides containing electron-withdrawing groups
were carried out at 110 °C (entries 1-3, 11-14), but amination
of aryl iodides containing electron-donating groups could not
be performed until the temperature was increased to 120 °C,
and 2 equiv of of amidine hydrochlorides relative to aryl iodides
was required for entries 5-10. We also investigated reactivity
of other amidine hydrochlorides, and reactions of benzamidine
hydrochloride or butyramidine hydrochloride with aryl halides
also provided the corresponding primary arylamines in good
yields (entries 11-14). Compared with acetamidine hydrochlo-
ride, benzamidine and butyramidine hydrochlorides showed
slightly lower reactivity.
The possible formation mechanism of primary arylamines is
proposed in Scheme 1. Reaction of amidine hydrochloride (2)
with base (Cs2CO3) produces free amidine (2′) and water, and
the Ullmann coupling reaction of 2′ with aryl halide gives
N-arylamidine (A). Addition of A with water in base medium
provides intermediate B, and the following removal of amide
C from B yields the target product (3).
In summary, we have developed an efficient method for the
synthesis of arylamines, and this protocol uses inexpensive CuI/
L-proline as the catalyst, various aryl halides as the substrates,
and amidines as the ammonia surrogates, the reactions were
performed under simple and safe experimental conditions.
Acetamidine hydrochloride is a more economical ammonia
surrogate compared with other amidine hydrochlorides. The
method provides an important motif for synthesis of natural
products and pharmaceutical and medicinal compounds, as well
as in polymers and materials.
Experimental Section
General Procedure for Copper-Catalyzed Synthesis of Pri-
mary Arylamines. A flask was charged with CuI (19 mg, 0.1
mmol), L-proline (23 mg, 0.2 mmol), and Cs2CO3 (2 or 3 mmol)
(see Tables 1 and 2) in 2 mL of DMF, and aryl halide (1 mmol)
and amidine hydrochloride (1.2 or 2 mmol) (see Tables 1 and 2)
were added to the flask at room temperature under nitrogen
atmosphere. The mixture was stirred at 110 or 120 °C (see Tables
1 and 2) under nitrogen atmosphere. After the coupling reaction
proceeded for 10 h, the resulting solution was cooled to room
temperature and diluted with 5 mL of CH2Cl2. The solution was
filtered, and the inorganic salts were removed. The filtrate was
concentrated with the aid of a rotary evaporator, and the residue
was purified by column chromatography on silica gel using
petroleum ether/ethyl acetate (10:1 to 1:1) as eluent to provide the
desired product. Two examples are shown as follows.
4-Nitroaniline (3a). 13 Eluent: petroleum ether/ethyl acetate (10:
1). Yield: 127 mg (92%). Yellow solid, mp 113-114 °C. 1H NMR
(300 MHz, DMSO-d6) δ 7.20-7.35 (m, 4H), 5.76 (s, 2H). 13C NMR
(75 MHz, DMSO-d6) δ 150.62, 149.25, 130.39, 120.46, 110.28,
107.56. MS M+ m/z 138.0.
p-Phenylenediamine (3 h).
14
Eluent: petroleum ether/ethyl
acetate (1:1). Yield: 102 mg (94%). Brown solid, mp 143-145 °C
(lit.14 141 °C). H NMR (300 MHz, DMSO-d6) δ 6.34 (s, 4H),
1
4.16 (s, 4H).13C NMR (75 MHz, DMSO-d6) δ 139.4, 116.0. MS
M+ m/z 108.1.
Acknowledgment. This work was supported by the National
Natural Science Foundation of China (Grant Nos. 20672065,
20572008, and 20732004), Chinese 863 Project (Grant No.
2007AA02Z160), Programs for New Century Excellent Talents
in University (NCET-05-0062) and Changjiang Scholars and
Innovative Research Team in University (PCSIRT) (No. IRT0404)
in China and the Key Subject Foundation from Beijing
Department of Education (XK100030514).
Supporting Information Available: General experimental
procedures, characterization data, and 1H and 13C NMR spectra
of these synthesized compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO800818E
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6866 J. Org. Chem. Vol. 73, No. 17, 2008