Organic Letters
Letter
the yield. However, the yield nearly halved with a nonprotected
hydroxyl group of the epoxide, suggesting that the protection of
the hydroxyl is needed for the reaction to proceed well.
Replacing the methoxy group with hydrogen, chlorine, and a
propyl group caused only a small decrease in the yield. In
contrast, the reaction was suppressed significantly with a phenyl
group at position 1 of the epoxide. Having an ester group
instead at the same position led to a 68% yield. A few other
aliphatic and branched alcohols were tested and all gave
comparable alcoholysis yields. However, the epoxide-mediated
hydrolysis of amide 1a in water failed to give the desired acid
product, instead, the ring opening of epoxide by water was
observed as the major side product. Unfortunately, the
racemization of 3a was observed under current alcoholysis
conditions.
Scheme 2. Proposed Strategy for the Alcoholysis of the
Acidic Amide
a
Table 1. Optimization of Reaction Conditions
Having optimized the condition, we proceeded to test it on
other amide substrates. As shown in Scheme 3, it is clear that
b
entry
base
epoxide
alcohol
yield (%)
1
K2CO3
KHCO3
K3PO4
K2HPO4
KH2PO4
KF
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
iPrOH
iBuOH
iAmylOH
EtOH
EtOH
22
74
33
27
trace
36
31
93
95
87
90
0
2
Scheme 3. Scope of Different Amides
3
4
5
6
7
KCl
8
KOAc
KOTFA
NaOAc
LiOAc
NH4OAc
Cu(OAc)2
Mn(OAc)2
TEA
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
trace
0
72
9
DIPEA
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
N/A
92
47
69
89
87
21
68
91
95
92
87
trace
trace
2g
2h
2a
2a
2a
2a
N/A
2a
only acidic amides bearing electron-withdrawing groups can be
cleaved to give ethyl esters. Nonacidic amides remained intact
throughout the reaction, presumably due to (A) their reduced
electrophilicity; (B) bad leaving groups; and (C) the N-
alkylation not happening, as the substrates failed to be
deprotonated by KOAc.
In order to test the generality of this method, we also
examined structurally different substrates bearing the acidic
amide auxiliary prior to C−H activation. α-Hydrogen
containing substrates, including α-amino acid, cyclic, and
acyclic acids, reacted smoothly, giving the corresponding
ethyl esters in excellent yields (3a, 3b, 3f, 3g). In addition,
the method was similarly successful for bulkier α-quaternary
substrates and α, β-unsaturated substrate (3c, 3d, 3e, 3h).
However, the alcoholysis was less efficient for benzamide
derivative, where only a moderate yield was obtained (Scheme
4). Next, we started to investigate the scope of C−H
functionalized compounds. First, the method was applied to
arylated products of acyclic aliphatic acid substrates. The
corresponding esters were obtained in excellent yields (3j−3o).
For cyclic acid substrates, the C(sp3)−H arylation products
underwent facile alcoholysis in good-to-excellent yields (3p−
3w). Notably, the heteroarylated product was also compatible
with this method (3l). Similarly, other C−H functionalized
a
Reaction conditions: 1a (0.2 mmol), epoxide (0.6 mmol), base (0.2
b
mmol), EtOH (2.0 mL), N2, 90 °C, 35 h. Isolated yields.
Then we found that basic potassium phosphates (K3PO4 and
K2HPO4) gave much lower yields. The reaction was shut down
when weakly acidic KH2PO4 was used. Potassium halides, such
as KF and KCl, provided modest yields. Fortunately, KOAc and
KOTFA were found effective and gave excellent yields.
Considering the cost, KOAc was selected as the better choice.
With acetate as the optimal anion, we also compared different
cations and the results indicated that potassium ion was the
best cation. Interestingly, organic base like triethylamine (TEA)
could deliver the product in 72% yield. However, bulkier
diisopropylethylamine (DIPEA) led to much worse reactivity.
Having the best base in hand, we set out to probe different
structures of epoxides. Changing the protecting group from
methyl to benzyl resulted in an almost unnoticeable decrease in
B
Org. Lett. XXXX, XXX, XXX−XXX