X. Duan et al. / Tetrahedron Letters 56 (2015) 4634–4637
4635
Table 1
Optimization of the reaction conditionsa
O
O
MeO
MeO
OMe
oxidant
solvent
MeO
MeO
N
H
OMe
1a
2a
Entry
Oxidant (equiv)
Catalyst (equiv)
Solvent
Temp (°C)
Time (h)
Yieldb (%)
c
1
2
3
4
5
6
7
8
DDQ(1.0)
MnO2(1.0)
FeCl3(1.0)
H2O2(1.0)
—
—
—
—
—
—
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
rt
rt
rt
rt
rt
rt
rt
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
3 h
3 h
3 h
3 h
3 h
1d
n.r.d
n.r.d
n.r.d
n.r.d
0
45
60
68
40
34
39
65
65
88
49
67
c
c
c
c
TEMPO(1.0)
m-CPBA(1.0)
m-CPBA(1.0)
m-CPBA(1.0)
m-CPBA(1.0)
m-CPBA(1.0)
m-CPBA(1.0)
m-CPBA(1.0)
m-CPBA(1.0)
m-CPBA(1.0)
m-CPBA(1.0)
m-CPBA(1.0)
c
CuBr2 (0.1)
CuBr2 (0.1)
CuCl(0.1)
Cu(acac)2 (0.1)
Cu(OAc)2 (0.1)
CuBr (0.1)
CuBr2 (0.1)
CuBr2 (0.1)
CuBr2 (0.1)
CuBr2 (0.1)
1d
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
9
10
11
12
13
14
15
16
1,4-dioxane
DCE
CH3CN
a
b
c
Reaction conditions: 1a (1 mmol), oxidant (1 mmol), catalyst (0.1 mmol) in solvent(10 mL) unless otherwise stated.
Isolated yield.
No catalyst.
d
n.r. = no reaction.
path a). (2) Heron rearrangement of N-alkoxyamides substrates by
SN2 azidation of N-alkoxy-N-chloroamides (Scheme 1, path b).8 (3)
Direct conversion of N-Alkoxyamides to carboxylic esters involving
NBS-mediated oxidative procedure for homocoupling and thermal
denitrogenation (Scheme 1, path c).5 Nevertheless, some of these
methods involve toxic reagents, harsh reaction conditions, multi-
step operations or generation of wastes that not only reduce pro-
cess efficiency but also pose environmental problems.8–12
Compared with the late transition metal catalysts, the first-row
transition metals, especially copper13 have received more and
more attention recently, owing to their availability, low cost, low
toxicity, and ease of use. Herein, we report a method for the
synthesis of esters starting from N-alkoxyamides, via Heron
rearrangement processes in the presence of CuBr2 and m-CPBA in
1,4-dioxane (Scheme 1, path d).
Initially we utilized N-methoxybenzamide 1a as a model sub-
strate to investigate different reaction conditions. Selected data
are listed in Table 1. Firstly, various oxidants were screened for
the reaction in CH2Cl2 at room temperature. Unfortunately, with
the use of oxidants such as DDQ, MnO2, or FeCl3, no desired pro-
duct was detected (Table 1, entries 1–3). Therefore, other oxidants
were tested (Table 1, entries 4–5). When m-CPBA was used, the
desired product 2a was obtained in 45% yield (Table 1, entry 6).
Interestingly, we found that the introduction of CuBr2 greatly
improved the product yield at room temperature in 1 day
(Table 1, entry 7). The reaction temperature is crucial for this reac-
tion. A change in the reaction temperature from room temperature
to 70 °C increased the reaction yield and rate. Probably the increase
of reaction temperature will accelerate the coupling reaction and
rearrangement occurs (Table 1, entry 8). An examination of other
copper catalysts revealed that CuCl, Cu(acac)2, Cu(OAc)2, and
CuBr gave decreased yields of 2a (Table 1, entries 9–12).
Screening of a series of other solvents, including THF, 1,4-dioxane,
DCE, and MeCN (Table 1, entries 13–16), showed that the reaction
in 1,4-dioxane afforded the best yield in 81% (Table 1, entry 14).
With the optimized reaction conditions, we proceeded to
explore the substrate scope of this transformation (Table 2). The
protocol proved to be compatible with a broad range of N-alkoxya-
mides and tolerated a wide variety of functional groups. On the
whole, the reaction was benefited by electron donating groups
and hindered by electron withdrawing groups attached to the aro-
matic ring. Aromatic N-alkoxyamides bearing electron donating
groups reacted smoothly under the optimized conditions to form
the corresponding esters in good yields (2a–2c). With electron
withdrawing groups, the yield of the product decreased (2d–2f).
For example, when 4-fluoro-N-methoxybenzamide was used as
substrate only 46% esterification product 2f was obtained at higher
temperature even for a longer reaction time of 12 h. Using of
heteroaromatic N-alkoxyamide, such as N-methoxythiophene-2-
carboxamide as substrate, resulted in product 2g in a moderate
yield of 65%. Besides the aromatic N-alkoxyamides, we found that
N-benzylcinnamamides and N-methoxycinnamamide, also worked
efficiently (2h and 2i). Furthermore, this catalytic reaction worked
well with aliphatic carboxylic amides. It resulted in esters 2j and
2k in 50% and 55% yields, respectively. Finally, when the R2 group
was changed as benzyl, the desired product was also obtained in
87% yield.
Encouraged by these promising results, we further applied the
optimized reaction conditions to examine the substrate scope of
N-tert-butoxy-amides. Aromatic N-tert-butoxy-amides bearing
electron donating groups, such as methoxy, afforded the desired
products in good yields (2m and 2n). Also this catalytic reaction
is nicely tolerant of halo substituents on the aromatic ring of the
N-tert-butoxy benzamides (2o and 2p). Replacing the phenyl ring
with a naphthalene ring in the substrate does not hamper the reac-
tion, and the desired product 2q was obtained in 68% yield. It is
important to note that the substrate with bulky R1 groups, could
also afford the desired product 2r in 45% yield.
From the above results, we believe that the reaction proceeds
via oxidative homocoupling and Heron rearrangement process by
a
radical mechanism. Our hypothesized mechanism for this
transformation is shown in Scheme 2. Firstly, alkoxyamide 1
was converted to radical intermediate A via radical oxidation
in the presence of Cu/m-CPBA.14 Next, the N-centered radical