Table 1. CuI-Catalyzed Coupling Reaction of Various Amines
with Aryl Halidesa
Table 2. CuI-Catalyzed Coupling Reaction of â-Amino Esters
with Aryl Halidesa
temp
(°C)
yield
(%)b
entry
X
H2NR
1
2
3
4
5
6
7
8
9c
10c
Br
Br
Br
Br
Br
Br
I
Cl
Br
Br
3-aminobutanoic acid
3-aminobutanoic acid
(S)-valine
4-aminobutanoic acid
4-aminobutanoic acid
benzylamine
3-aminobutanoic acid
3-aminobutanoic acid
3-aminobutanoic acid
3-aminobutanoic acid ethyl ester
100
90
90
26
14
42
0
90
110
110
90
90
100
100
tr
<4
69
0
64
62
yield
entry
ArX
â-amino ester
product
(%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2a
2b
2c
2d
2e
2f
2g
2h
2j
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3f
4a
4a
4b
4c
4d
4e
74
62
75
83
80
87
c
17
31
72
69
76
74
79
80
c
a Reaction conditions: ArX (1 mmol), amine (1 mmol), CuI (0.1 mmol),
K2CO3 (2.5 mmol), DMF (5 mL), and water (0.1 mL). b Isolated yield.
c Reaction time: 48 h.
at 90 °C, and little conversion was determined at 110 °C
when 4-aminobutanoic acid was used (entries 4 and 5).
Furthermore, it was observed that the reactivity for different
aryl halides was ArI > ArBr > ArCl (compare entries 2, 7
and 8), which was the typical character of the Ullmann
coupling reaction. In addition, similar to 3-aminobutanoic
acid (entry 9), reaction of 3-aminobutanoic acid methyl ester
with bromobenzene also worked to give the coupling product
in 62% yield (entry 10). Obviously, the coupling reagent here
was still a â-amino salt because this ester could be
hydrolyzed in situ under the present reaction conditions. (In
a controlled reaction without addition of CuI and bromoben-
zene, it was found that the â-amino ester was hydrolyzed
completely in less than 30 min.) Since the enantiopure
â-amino esters were conveniently available,3 we could use
it to prepare enantiopure N-aryl â-amino acids.
To explore the scope of the coupling reaction of aryl
halides with â-amino esters, other â-amino esters and aryl
halides were tested under the conditions mentioned above,
and the results are summarized in Table 2. It was found that
electron-deficient aryl iodides gave the best results (entries
4-6), whereas electron-rich aryl halides showed lower yields
or lack of conversion (entries 7-9). Unsubstituted or
electron-deficient aryl bromides were also suitable substrates
(compare entries 2, 10, and 16). In addition, both aliphatic
and aromatic â-amino acids worked well for this reaction.
Thus, this method has proven useful for preparing N-aryl
â-amino acids with considerable diversity in either racemic
or enantiopure form.
4f
4h
4g
4i
4j
4k
4l
2i
2a
2a
2a
2a
2a
2k
4m
3a
a Reaction conditions: aryl halide (1 mmol), â-amino ester (1 mmol),
CuI (0.1 mmol), K2CO3 (2.5 mmol) in 5 mL of DMF and 0.1 mL of water,
stirred at 100 °C for 48 h. b Isolated yield. c No coupling product was
determined.
acid,2 we envisaged that the present coupling reaction might
pass through a mechanism as shown in Scheme 1, in which
a cuprous ion reacted with a â-amino acid salt to form the
chelate A,5 which coordinated with a suitable aryl halide to
provide the π-complex B. Next, intramolecular nucleophilic
substitution occurred at the aromatic ring to give intermediate
C. This step might be the rate-determining step, and the
intramolecular attack would lower the activation energy. With
the increase of distance between the amino and carboxylate
groups, the ring size in the transition state C became larger
and thereby C would be more unstable. This might be the
reason the accelerating effect induced by the structure of
(4) Typical Procedure. To a solution of aryl halide (1 mmol) and
â-amino ester (1 mmol) in 5 mL of DMF were added potassium carbonate
(2.5 mmol), 0.1 mL of water, and CuI (0.1 mmol) under nitrogen. After
the mixture was stirred at 100 °C for 48 h under nitrogen atmosphere, the
cooled solution was concentrated in vacuo. The residue was dissolved in
water, acidified to pH 5, and extracted with ethyl acetate. The combined
organic layers were concentrated and purified by chromatography to afford
the corresponding N-aryl â-amino acid.
On the basis of the proposed mechanism of the Cu(I)-
catalyzed coupling reaction of aryl halides with R-amino
(3) (a) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry, 1991, 2,
183. (b) Davies, S. G.; Ichihara, O.; Walters, I. A. S. J. Chem. Soc., Perkin
Trans. 1 1994, 1141.
(5) Greenstein, J. P.; Winitz, M. Chemistry of the Amino Acids; Wiley:
New York, 1961; Vol. 1; p 569.
2584
Org. Lett., Vol. 3, No. 16, 2001