S. Jung et al. / Tetrahedron Letters 54 (2013) 5718–5720
5719
Table 1
Effect of the quantity of 4-chloroaniline (2a), ethyl chloroformate and triethylamine on the amidation of 3-phenylpropanoic acid (1)a
O
O
O
1) ClCO2Et, Et3N, THF, 0 oC, 30 min
Ph
N
H
Cl EtO
+
N
H
Cl
Ph
OH
2)
, H2O, 0 oC, 1.5 h
1
Cl
NH2
3a
4a
2a
Entry
ClCO2Et (equiv)
Aniline (equiv)
Et3N (equiv)
Yield of 3ab (%)
Yield of 4ab (%)
1
2
3
4
5
6
7
1.4
1.1
1.1
1.05
1.05
1.0
1.1
1.1
1.1
1.1
1.05
1.05
1.0
1.1
1.5
1.1
1.1
1.1
1.1
1.1
57
83
88
77
74
79
83
34
2
13
9
11
5
4
1.0
a
All reactions were carried out with 1.0 mmol of 1 in 20 mL of THF. After stirring for 30 min at 0 °C, 1.5 mL of water and 2a were added at 0 °C
to the reaction mixture.
b
Isolated yield.
Table 3
Reaction of 3-phenylpropanoic acid (1) with aniline derivatives 2a
Table 2
Effect of solvent on the amidation of 3-phenylpropanoic acid (1)a
O
O
O
1) ClCO2Et, Et3N, MeCN, 0 oC, 30 min
R3
Ph
N
H
+
O
O
Ph
OH
EtO
4
N
H
, H2O, 0 oC, 24 h
O
1) ClCO2Et, Et3N, solvent, 0 oC, 30 min
2)
R3
R3
1
3
NH2
Ph
N
H
Cl EtO
+
N
H
Cl
Ph
OH
2)
, H2O, 0 oC, 24 h
2
1
Cl
NH2
3a
4a
2a
Entry
R3
2
Yield of 3b (%)
Yield of 4b (%)
Entry
Solvent
Yield of 3ab (%)
Yield of 4ab (%)
1
2
3
4
5
6
7
8
9
4-Cl
4-F
2,3,4,5,6-F5
4-EtO2C
4-O2N
3,5-(O2N)2
2,4-(O2N)2
H
4-Me
4-HO
2-EtO
4-EtO
2a
2b
2c
2d
2e
2f
2g
2h
2i
96
97
67
70
65
30
0
94
95
92
89
98
Trace
0
34
0
0
0
0
Trace
1
3
Trace
2
1
2
3
4
5
6
THF
92
19
89
96
50
13
4
8
3
1,4-Dioxane
Acetone
MeCN
EtOH
MeOH
Trace
35
70
a
All reactions were carried out with 1.0 mmol of 1, 1.1 mmol of Et3N and
1.1 mmol of ClCO2Et in 20 mL of solvent. After stirring for 30 min at 0 °C, 1.5 mL of
water and 1.1 mmol of 2a were added at 0 °C to the reaction mixture.
10
11
12
2j
2k
2l
b
Isolated yield.
a
All reactions were carried out with 1.0 mmol of 1, 1.1 mmol of Et3N and
1.1 mmol of ClCO2Et in 20 mL of MeCN. After stirring for 30 min at 0 °C, 1.5 mL of
water and 1.1 mmol of 2 were added at 0 °C to the reaction mixture.
Then, the amidations of 1 with several kinds of aniline deriva-
tives 2a–2l via the corresponding mixed carbonic carboxylic anhy-
dride were carried out in aqueous MeCN, and the results are
showed in Table 3. 3-Phenylpropanoic acid (1) was reacted with
4-fluoroaniline (2b) containing an electron-withdrawing group to
afford the corresponding amide 3b in 97% yield (entry 2). The reac-
tions of 1 with pentafluoroaniline (2c), ethyl 4-aminobenzoate
(2d), 4-nitroaniline (2e), and 3,5-dinitroaniline (2f) containing an
even stronger electron-withdrawing group afforded the corre-
sponding amides 3c, 3d, 3e and 3f in 67%, 70%, 65% and 30% yields,
respectively (entries 3–6). In the case of 2,4-dinitroaniline (2g), the
reaction did not proceed as indicated in entry 7. The reaction of 1
with aniline (2h) easily proceeded to afford N-phenyl-3-phenyl-
propanamide (3h) in 94% yield, which was similar to the case of
2a. 4-Methylaniline (2i), 4-aminophenol (2j), 2-ethoxyaniline
(2k) and 4-ethoxyaniline (2l) containing an electron-donating
group reacted to afford the corresponding amides 3i–3l in excel-
lent yields (entries 9–12).
b
Isolated yield.
afforded Cbz-L-Phe-NHC6H4-4-OEt, Cbz-L-Phe-NHC6H4-2-OEt and
Cbz- -Phe-NHC6H4-4-OH in good to excellent yields (79–91%,
L
entries 1, 3 and 5) as single enantiomers, respectively, by high-
pressure liquid chromatography (HPLC) analysis using Chiralcel
OD in all cases.5 Cbz-
D
-Phe-OH (5aD) reacted with 2l, 2k and 2j
in the similar conditions to afford Cbz- -Phe-NHC6H4-4-OEt,
Cbz- -Phe-NHC6H4-2-OEt and Cbz- -Phe-NHC6H4-4-OH in good
to excellent yields (77–91%, entries 2, 4 and 7) as -form enantio-
mers, respectively. Various N-protected -amino acids were
conveniently converted to their corresponding acetaminophen
analogues of -amino acids in 82–99% yields without racemization
D
D
D
D
a
a
as indicated in entries 8–19.
Finally, the reactions of fatty acids 7a–7f with 4-ethoxyaniline
(2l) were carried out, and the results are summarized in Table 5.
In all cases, the reactions were easily proceeded in aqueous MeCN
to afford the corresponding acetaminophen analogues 8a–8f of
fatty acids in excellent yields.
Furthermore, the amidations of N-protected
a-amino acids
5aL–5gL and 5aD–5gD with 4-ethoxyaniline (2l), 2-ethoxyaniline
(2k) and 4-aminophenol (2j) were carried out in aqueous MeCN,
and the results are collected in Table 4. The reactions of
In conclusion, we have found that acetaminophen analogues 3,
6 and 8 were prepared in 65–99% yields from the corresponding
Cbz-L-Phe-OH (5aL) with 2l, 2k and 2j using ClCO2Et and Et3N