Solvent-free copper-catalyzed N-arylation of amino alcohols and diamines with aryl halides

Article abstract of DOI:10.1016/j.tetlet.2011.12.130

A simple and mild method for the coupling of aryl halides with amino alcohols and diamines is described. The reactions can be performed under ligand-free and solvent-free conditions, and generate the products in good yield.

Full text of DOI:10.1016/j.tetlet.2011.12.130

Tetrahedron Letters 53 (2012) 1265–1270
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solvent-free copper-catalyzed N-arylation of amino alcohols and diamines
with aryl halides
Huiqing Yin a, Ming Jin a, Wei Chen a, Chen Chen a, Likang Zheng a, Ping Wei a, Shiqing Han a,b,
⇑
a College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing 210009, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, CAS, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and mild method for the coupling of aryl halides with amino alcohols and diamines is described.
The reactions can be performed under ligand-free and solvent-free conditions, and generate the products
in good yield.
Received 11 October 2011
Revised 22 December 2011
Accepted 30 December 2011
Available online 5 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Copper-catalyzed
N-arylation
Solvent-free
Amino alcohols
Diamines
Transition-metal-catalyzed amination of aryl halides represents
an important method and is widely used in the synthesis of many
substances including drugs, materials, natural products, agrochemi-
cals, and optical devices.1 Typically, C–N bonds are formed by
Ullmann-type coupling processes. However, the classical coupling
reaction generally suffers from several shortcomings including high
reaction temperatures, moderate yields, extended reaction times,
and poor substrate generality.2 A breakthrough by Buchwald and
co-workers discovered that the Cu-catalyzed N-arylation of nitro-
gen-containing heterocycles with aryl halides could be achieved in
good yields under mild conditions in the presence of bidentate N,
N-ligands.3 Following the work of Buchwald, a number of Cu-cata-
lyzed coupling reactions with various ligands have been reported,
such as organic phosphanes,4 N-containing aromatic heterocycles,5
diamines,6 diols,7 triols,8 rac-binols,9 salicylamides,10 b-diketones,11
b-keto esters,12 imines,13 amino acids,14 amino phosphates,15 and
diazaphospholanes.16 Notably, most ligands are hard to synthesize
and the solvent is difficult to remove. Therefore, it is important to de-
velop a simpler and more efficient catalytic system for the amination
of aryl halides.
by the narrow substrate scope. They found the substrate scope
was extended by adding b-keto esters as ligands.19 Twieg reported
that deanol was used as an efficient solvent and ligand for the cop-
per-catalyzed amination reaction.20
We were interested in developing a mild and effective method
for the N-arylation of amine derivatives. Herein, we report the effi-
cient Cu-catalyzed N-arylation of amino alcohols and diamines
with aryl halides under ligand-free and solvent-free conditions.
Table 1
Screening reaction conditions for copper-catalyzed N-arylation of 2-amino-1-butanol
with iodobenzene
catalyst 10 mol%
base 2 equiv
OH
OH
+
N
H
room temp
8 h
NH2
I
Entry
Cu source
Base
Yielda (%)
1
2
3
4
5
6
7
8
CuCl
CuCl
CuCl
CuCl
CuCl
CuBr
Cu2O
CuI
Cs2CO3
K2CO3
K3PO4
NaOH
KOH
KOH
KOH
KOH
30
20
25
61
91
85
80
72
Recently, several ‘ligand-free’ systems have emerged for the
N-arylation of aromatic N-heterocycles and amino acids catalyzed
by copper compounds.17 However, there are few reports covering
amino alcohols and diamines. Buchwald investigated selective
N-aryl and O-aryl reactions of b-amino alcohols as reactants with
different solvents and bases,18 however, this method was limited
9
Cu(OAc)2
CuCl
KOH
KOH
27
Trace
10b
a
⇑
Corresponding author. Tel.: +86 25 83587334.
E-mail address: hanshiqing@njut.edu.cn (S. Han).
Isolated yield.
2 ml DMSO added.
b
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.130

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H. Yin et al. / Tetrahedron Letters 53 (2012) 1265–1270
In our initial screening experiments, iodobenzene and 2-amino-
At first, iodobenzene (1 equiv) was treated with 2-amino-1-buta-
nol (3 equiv) and stirred at room temperature for 8 h with CuCl
(0.1 equiv) and Cs2CO3 (2 equiv), and the corresponding N-arylated
2-amino-1-butanol was formed only in a 30% yield (Table 1, entry
1). Replacement of Cs2CO3 with K2CO3 and K3PO4 also gave low yields
(Table 1, entries 2–3), but NaOH gave a good yield (Table 1, entry 4).
1-butanol were used as the prototypical substrates for the discovery
of suitable reaction conditions. The standardized protocol was
performed using iodobenzene (1 equiv), 2-amino-1-butanol (3 equiv),
base (2 equiv), and Cu source (10 mol %) stirred at room temperature
for 8 h. The results are shown in Table 1.
Table 2
Catalyzed N-arylation of amino alcohols with various iodobenzenesa
CuCl 10 mol%
KOH 2 equiv
R2
R1
R1
HN
+
R2
room temp
8h
N
R3
I
R3
Entry
1
Aryl halide
Amine
Product
Yieldb (%)
99
H2N
OH
OH
N
H
I
H2N
H2N
OH
2
3c
4
97
73
82
91
N
H
OH
OH
OH
N
H
OH
OH
H2N
OH
N
H
NH2
OH
5
N
H
Br
H2N
H2N
Br
OH
OH
6
7
92
95
OH
N
I
H
Br
Br
OH
OH
N
H
I
H2N
H2N
OH
8
9
92
90
I
N
H
MeO
Br
MeO
OH
OH
OH
N
H
I
Br
NH2
NH2
10
11
98
64
OH
OH
N
H
I
OH
I
N
H

H. Yin et al. / Tetrahedron Letters 53 (2012) 1265–1270
1267
Table 2 (continued)
Entry
Aryl halide
Amine
Product
Yieldb (%)
H2N
OH
OH
N
N
NH
N
N
12
13
82
N
O
N
I
O
HN
HO
O
N
O
Trace
0
I
I
OH
14
OH
O
a
Reaction and conditions: CuCl (0.1 mmol, 10 mol %), ArI (1.0 mmol), amine (3.0 mmol), and KOH (2.0 mmol) at room temperature under air (no solvent added).
Isolated yield
Reaction time: 12 h
b
c
An extremely good yield of 91% was obtained when only KOH was
Having established an effective catalytic protocol for the cou-
pling reaction, we then examined the scope of the process with
respect to various amino alcohols.21 We noticed that all the amino
alcohols we explored worked well; in particular, ethanolamine and
propanolamine showed high yields (Table 2, entries 1–2). When 4-
aminobutanol was used, a good yield was obtained (Table 2. entry
3). Even simple amino alcohols with substituents provided high
yields (Table 2, entries 4–5). To explore the scope of the process
with respect to aryl halides, a variety of substituted aryl halides
used (Table 1, entry 5). Other copper compounds (CuBr, CuI, Cu2O
and Cu(OAc)2) were also evaluated under KOH conditions but proved
less effective than CuCl. Notably, Cu(OAc)2 gave a product yield of
only 27% (Table 1, entries 6–9).
The solvent usually plays an important role in the coupling reac-
tion. Surprisingly, it was found that DMSO, the reported effective
solvent, had a deleterious effect on the reaction using this catalytic
system (Table 1, entry 10).
Table 3
Catalyzed N-arylation of diamines with iodobenzenesa
CuCl 10 mol%
R2
R2
H2N
KOH 2 equiv
R1
R1
+
0oC
8h
NH
NH2
NH2
I
Entry
1
Aryl Halide
Amine
Product
Yieldb (%)
98
H2N
NH2
NH2
N
H
I
H2N
H2N
NH2
2
3
92
62
15
N
H
NH2
NH2
NH2
N
H
NH2
H2N
H2N
4c
NH2
N
H
NH2
5
41
NH2
I
N
H
(continued on next page)

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H. Yin et al. / Tetrahedron Letters 53 (2012) 1265–1270
Table 3 (continued)
Entry
Aryl Halide
Amine
Product
Yieldb (%)
65
MeO
MeO
H2N
NH2
NH2
6
N
H
NH2
I
Br
Br
H2N
7
56
N
H
NH2
I
a
Reaction and conditions: CuCl (0.1 mmol, 10 mol %), ArI (1.0 mmol), amine (3.0 mmol), and KOH (2.0 mmol) at 0 °C under air (no solvent added).
Isolated yield.
Reaction time: 24 h.
b
c
Table 4
Catalyzed N-arylation of amino alcohols and diamines with various bromidesa
CuCl 10 mol%
KOH 2 equiv
R2
R3
R1
R1
HN
+
Br
90oC
8h
N
R2
R3
Entry
1
Aryl halide
Amine
Product
Yieldb (%)
99
H2N
OH
OH
OH
Br
N
H
2
3
97
97
Br
N
H
OH
Br
N
H
Cl
H2N
Cl
Cl
Cl
OH
4
99
OH
Br
N
H
H2N
H2N
OH
5
6
72
73
OH
N
H
OH
N
OH
H
7
OH
OH
62
42
24
H2N
H2N
OH
OH
Br
N
H
NH2
8c
N
H
NH2
9d
N
H
NH2
a
b
c
Reaction conditions: CuCl (0.1 mmol, 10 mol %), ArI (1.0 mmol), amine (3.0 mmol), and KOH (2.0 mmol) at 90 °C under air (no solvent added).
Isolated yield.
Reaction temperature: 110 °C.
Reaction time: 24 h.
d

H. Yin et al. / Tetrahedron Letters 53 (2012) 1265–1270
1269
under the optimized reaction conditions were tested. Selecting
ethanolamine as the model amine, the corresponding N-arylation
products were obtained in high yields (Table 2, entries 6–9). When
2-aminobutanol was chosen, significant electronic effects were ob-
served for the electron-poor and electron-rich substituted aryl ha-
lides (Table 2, entries 10–11). Electron-donating substituents
showed lower reactivity than electron-withdrawing substituents.
In addition, we found that more complicated aryl iodides worked
well, affording the amination product in an excellent yield (Table
2, entry 12).
In view of these interesting results, we further investigated the
scope of the reaction using various substrates. When ethylene gly-
col or morpholine was used, no product was observed (Table 2,
entries 13–14). However, when ethylenediamine was used, the de-
sired amination products were obtained in an 82% yield at room
temperature, and a yield of 98% was obtained when the reaction
was performed at 0 °C (Table 3, entry 1).22 Diamines are a special
class of amines that are capable of forming stable chelates with a
metal atom, whereas their use as substrates in reactions normally
fails because the formation of chelates may hinder the catalytic
process. Guilard and co-workers reported a selective, convenient
palladium-catalyzed introduction of aryl moieties into diamines
without using any protecting group.23
With the optimized reaction conditions identified for ethylene-
diamine, the other diamines were examined. A high yield was
observed for 1,3-propanediamine (Table 3, entry 2), and a moder-
ate yield was observed for 1,2-propanediamine (Table 3, entry 3).
1,4-Butanediamine gave a poor yield (Table 3, entry 4). We then
evaluated a variety of aryl halides, in which both electron-with-
drawing and -donating groups were tolerated (Table 3, entries
5–7).
Furthermore, we investigated the coupling reaction of aryl
bromides with amino alcohols and diamines. Almost no desired
product was attained at room temperature, but when the reaction
temperature was increased to 90 °C, bromobenzene and ethanol-
amine gave a 99% yield of the product (Table 4, entry 1). The effi-
cacy of the system for various bromides with ethanolamine was
further evaluated. Both electron-withdrawing and electron-donat-
ing groups worked well (Table 4, entries 2–4). Other amino alco-
hols were then used as substrates, and all of them afforded
moderate to good yields (Table 4, entries 5–7). However, a lower
yield was observed for 2-aminobutanol, even at temperatures as
high as 110 °C (Table 4, entry 8). In addition, chlorides failed to un-
dergo this transformation under the standard reaction conditions,
and the coupling reaction of aryl bromides with diamines afforded
much lower yields even with an extended reaction time of 24 h
(Table 4, entry 9).
reaction of amine substrates with CuCl produced a five- or six-
membered chelator I, and subsequent oxidative addition of the
chelator I with an aryl halide led to the formation of intermediate
II. Treatment of the amine substrates with II in the presence of
KOH provided complex III, and then reductive elimination of III
gave the N-arylation product and the chelator I. The mechanism
not only explains the reactivity order of aryl halides, ArI > Ar-
Br > ArCl, but also the lower reactivity of steric amines. This mech-
anism can also rationalize the failure of morpholine as the
substrate, because it must be in boat conformation in order to form
chelator I with Cu, which however, is disfavored. In addition, rela-
tive lower yield of 4-aminobutanol can be explained with the more
difficulty in the formation of seven-membered chelator I with Cu,
compared to five- or six-membered ring.
In summary, we have developed a simple and facile method for
the C–N cross-coupling of amino alcohols and diamines with aryl
halides using CuCl under ligand-free and solvent-free conditions.
This method is convenient, cost effective, environmentally friendly,
and the work-up is easy. The reactions are efficient, affording the
cross-coupled products in short reaction times with high yields.
Currently, we are exploring substrate scope and the application
of the Cu-catalyzed N-arylation under ligand-free and solvent-free
conditions with regard to the synthesis of pharmaceutical
molecules.
Acknowledgments
We thank to the National Natural Science Foundation of China
for supporting this research (Grant No. 20942006, Grant No.
21072095) and the research grants provided by the open fund of
key laboratory of Synthetic Chemistry of Natural Substance, Shang-
hai Institute of Organic Chemistry, CAS.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.130.
References and notes
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R
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ArNu
(NuH)
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Figure 1. Proposed Mechanism.

1270
H. Yin et al. / Tetrahedron Letters 53 (2012) 1265–1270
122, 344–348; (c) Kaddouri, H.; Vicente, V.; Ouali, A.; Ouazzani, F.; Taillefer, M.
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(300 MHz, CDCl3) d 7.05 (m, 1H), 6.54 (d, 1H, J = 7.6 Hz), 6.46 (d, 2H,
J = 7.6 Hz), 3.72 (dd, 1H, J = 4.2 Hz, J = 10.8 Hz), 3.5 (dd, 1H, J = 5.9 Hz,
J = 10.8 Hz), 3.38 (m, 1H), 2.28 (s, 3H), 1.54 (m, 2H), 0.95 (t, 3H, J = 7.5 Hz);
13C NMR (75 MHz, CDCl3) d 129.2, 118.8, 114.5, 110.8, 64.1, 56.7, 29.7, 24.9,
21.6, 10.5; ESI-MS m/z 180.2 [M++H].
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22. General procedure for Cu-catalyzed N-arylation of dimines with iodobenzenes:
CuCl (10 mg, 0.1 mmol), aryl iodide (if solid, 1.0 mmol), and KOH (112 mg,
2.0 mmol) were added to a screw-capped test tube. Aryl iodide (if liquid,
1.0 mmol), and dimine (3 mmol) were added by syringe. The reaction mixture
was stirred at 0 °C for 8 h. The resulting mixture was diluted with water (2 mL)
before extraction with methylene chloride (3 Â 5 mL), and dried over Na2SO4,
the filtrate was concentrated under reduced pressure, and the mixture was
purified by flash chromatography on silica gel to afford the desired product.
Selected spectral data for N-Phenyl-1,2-diaminoethane (Table 3, entry 1): 1H
NMR (300 MHz, CDCl3) d 7.19 (t, 2H, J = 7.8 Hz), 6.72 (t, 1H, J = 7.3 Hz), 6.64 (d,
2H, J = 7.8 Hz), 3.16 (t, 2H, J = 5.7 Hz), 2.91 (t, 2H, J = 5.7 Hz); 13C NMR (75 MHz,
CDCl3) d 148.2, 129.0, 117.1, 112.7, 46.2, 40.9.
21. General procedure for Cu-catalyzed N-arylation of amino alcohols with
iodobenzenes: CuCl (10 mg, 0.1 mmol), Aryl iodide (if solid, 1.0 mmol), and
KOH (112 mg, 2.0 mmol) were added to a screw-capped test tube. Aryl iodide
(if liquid, 1.0 mmol), and amino alcohol (3 mmol) were added by syringe at
room temperature. The reaction mixture was stirred at room temperature for
8–12 h. The resulting mixture was diluted with water (2 mL) before extraction
with ethyl acetate (3 Â 5 mL), and dried over Na2SO4, the filtrate was
concentrated under reduced pressure, and the mixture was purified by flash
chromatography on silica gel to afford the desired product. Selected spectral
data for 2-(3-Tolylamino)butan-1-butanol (Table 2, entry 11): 1H NMR
23. Beletskaya, I. P.; Bessmertnykh, A. G.; Averin, A. D.; Denat, F.; Guilard, R. Eur. J.
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