JOURNAL OF CHEMICAL RESEARCH 2015 275
Table 2 Catalyst- and solvent-free synthesis of different α-hydroxyl
salt, and the carboxylate underwent amidation by another
primary amine molecule.
amides
Entry
1
R1
H
Product
3a
Yield/%a
83
M.p./lit./oC
Liquid
Conclusions
In conclusion, we have demonstrated that the solvent- and
catalyst-free amidation of lactic acid is a useful synthetic
method leading to α-hydroxyl amides. The clean atom
economical operation suggests that this method will be useful
as an additional option for the synthesis of these important
amide products.
2
3
4
5
6
7
8
9
10
11
12
13
2-Cl
2-I
3-Cl
3-NO2
4-Me
4-MeO
4-Cl
4-Br
4-NO2
2-OH, 4-Cl
Naphtha-1-yl
Naphtha-2-yl
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
87
79
77
73
89
90
82
80
71
72
79
81
67–69/–
Liquid
Liquid
100–102/–
85–86/84–867
78–79/–
100–102/–
123–125/–
106–108/–
128–130/–
113–116/–
123–125/–
Experimental section
All chemicals were obtained from commercial sources and were used
as-received. The reaction was monitored with TLC (GF2454 silica
1
gel). H and 13C NMR data were obtained with a Bruker Avance 400
spectrometer (400 MHz) using CDCl3 as solvent, and the chemical
shifts are reported in ppm using TMS as an internal standard.
HRMS data were recorded in a Bruker microTOF-QII QTOF mass
spectrometer operated under ESI mode Melting points were obtained
in X-4A apparatus and are uncorrected.
aYield of isolated product based on aniline.
To further demonstrate the utility of the present method,
a larger scale experiment to synthesise product 3k which
contained multiple N- and O-chelating sites was conducted. As
shown in Eqn (5), the experiment on a 10 mmol scale provided
product 3k with 65% yield, which demonstrated the practicality
of this simple synthetic protocol for the production of useful
lactic amides.
Synthesis of α-hydroxyl amides; general procedure
Lactic acid 1 (0.6 mmol), amine 2 (0.5 mmol) were placed in a 10 mL
round bottom flask equipped with stirring bar, and the mixture was
stirred at 70 °C for 8 h (TLC). After cooling to room temperature,
water (5 mL) was added, and the resulting mixture was extracted with
ethyl acetate (3×8 mL). The organic phases were collected and dried
with anhydrous Na2SO4. After filtration and evaporation the solvent
from the solution under reduced pressure, the residue was subjected
to flash silica gel column chromatography to obtain pure products by
elution with petroleum ether/ethyl acetate (v/v = 4 : 1).
l
C
l
C
O
O
7
0
oC
solvent-free
65
( )
5
H
O
N
H2N
H
H
O
H
OH
O
1
2-Hydroxy-N-phenylpropanamide (3a):7 Pale yellow oil; H NMR
%
H
O
1
(12 mmol, 1.08g)
(10 mmol, 1.43g)
2k
.
3k
4
g
1
,
(400 MHz, CDCl3) δ = 8.63 (s, 1 H), 7.52 (d, 2 H, J = 7.6 Hz), 7.30 (t,
2 H, J = 7.6 Hz), 7.11 (t, 1 H, J = 7.2 Hz), 4.31 (q, 1 H, J = 6.4 Hz), 3.09
(brs, 1 H), 1.48 (d, 1 H, J = 6.4 Hz); 13C NMR (100 MHz, CDCl3) δ =
173.5, 137.0, 129.1, 124.8, 120.1, 68.7, 21.0.
In order to probe the mechanism of this amidation process,
we performed a control experiment by heating lactic acid under
standard conditions. However, no reaction to form a reactive
intermediate such as the anhydride was observed (Scheme 2).
The result implied that the amine component might also act
as the catalytic species during the reaction process. With this
assumption, a general mechanism was proposed as shown in
Scheme 2. The main step was the formation of ammonium salt
as an intermediate 4 in which the hydrogen bond donated by the
hydroxyl in lactic acid assisted the formation of the ammonium
N-(2-Chlorophenyl)-2-hydroxypropanamide (3b): Pale yellow
o
1
solid; m.p. 67–69 C; H NMR (400 MHz, CDCl3) δ = 9.19 (s, 1 H),
8.20 (d, 1 H, J = 8.0 Hz), 7.22 (d, 1 H, J = 8.0 Hz), 7.11 (t, 1 H, J =
8.0 Hz), 6,91 (t, 1 H, J = 7.6 Hz), 4.59 (brs, 1 H), 4.27 (q, 1 H, J = 6.8
Hz), 1.41 (d, 3 H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ = 173.7,
133.9, 129.2, 127.6, 125.1, 123.6, 121.4, 68.9, 20.9; ESI-HRMS: calcd
for C9H11ClNO2[M+H]+: 200.0473; found: 200.0479.
2-Hydroxy-N-(2-iodophenyl)propanamide (3c): Pale yellow oil;
1H NMR (400 MHz, CDCl3) δ = 9.02 (s, 1 H), 8.18 (d, 1 H, J = 8.4
Hz), 7.75 (d, 1 H, J = 8.0 Hz), 7.30 (t, 1 H, J = 8.0 Hz), 6.82 (t, 1 H, J
=8.0 Hz), 4.38 (q, 1 H, J = 6.8 Hz), 4.17 (brs, 1 H), 1.53 (d, 3 H, J = 6.8
Hz); 13C NMR (100 MHz, CDCl3) δ = 173.6, 139.0, 137.6, 129.2, 126.3,
121.8, 90.2, 69.0, 21.1; ESI-HRMS: calcd for C9H11INO2[M+H]+:
291.9829; found: 291.9818.
N-(3-Chlorophenyl)-2-hydroxypropanamide (3d): Colourless oil;
1H NMR (400 MHz, CDCl3) δ = 9.17 (s, 1 H), 8.41 (d, 1 H, J = 7.6 Hz),
7.39 (d, 1 H, J = 8.0 Hz), 7.28 (t, 1 H, J = 6.8 Hz), 7.07 (t, 1 H, J = 7.6
Hz), 4.43 (q, 1 H, J = 6.8 Hz), 3.32 (brs, 1 H), 1.57 (d, 3 H, J = 7.2
Hz); 13C NMR (100 MHz, CDCl3) δ = 172.9, 134.0, 129.0, 127.6, 125.0,
123.3, 121.3, 69.2, 21.2; ESI-HRMS: calcd for C9H11ClNO2[M+H]+:
200.0473; found: 200.0466.
O
o
7
0 C
no reaction
H
O
solvent-free
H
O
1
1
Ar
NH2
O
H
2-Hydroxy-N-(3-nitrophenyl)propanamide (3e). Yellow solid; m.p.
100–102 oC; 1H NMR (400 MHz, CDCl3) δ = 8.99 (s, 1 H), 8.50 (s, 1
H), 7.96–7.91 (m, 2 H), 7.49 (t, 1 H, J = 7.6 Hz), 4.43 (d, 1 H, J = 5.6 Hz)
3.77 (brs, 1 H), 1,55 (d, 1 H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ
= 173.2, 148.5, 138.5, 129.9, 125.5, 119.1, 114.4, 68.8, 21.1; ESI-HRMS:
calcd for C9H11N2O4[M+H]+:211.0713; found: 211.0721.
Ar
H3
N
Ar
O
NH2
O
4
o
2-Hydroxy-N-p-tolylpropanamide (3f):7 White solid; m.p. 85–86 C
(lit. 84–86 oC); 1H NMR (400 MHz, CDCl3) δ = 8.54 (s, 1 H), 7.39 (d,
2 H, J = 8.4 Hz), 7.10 (d, 2 H, J = 8.4 Hz), 4.30 (q, 1 H, J = 6.8 Hz), 3.83
(brs, 1 H), 2.30 (s, 3 H), 1.48 (d, 3 H, J = 6.8 Hz); 13C NMR (100 MHz,
CDCl3) δ = 172.9, 134.5, 134.3, 129.5, 120.0, 68.8, 21.1 20.9.
+
3
H
2O
Scheme 2 The control experiment and proposed reaction mechanism.