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2
Tetrahedron
polar solvent 1,2-dichloroethane also gave the desired aniline in
good yields. From a practical viewpoint, it is advantageous to
conduct the reaction in moderate to low polar solvents because of
the water-immiscibility and the low boiling point, enabling
simple extraction and evaporation processes. The low solubility
of 1a in THF may result in the low yield of 2a (entry 6). In
diethylene glycol no aniline was obtained probably due to the
trap of isocyanate intermediate by hydroxyl group of diethylene
glycol.
Scheme 1. Plausible reaction mechanism for self-propagated
Lossen rearrangement.
To find the optimal reaction conditions, we began to
investigate the rearrangement of 2,6-dimethoxybenzohydroxamic
acid as a model substrate. As shown in Table 1, hydroxamic acid
1a readily underwent rearrangement to amine 2a on treatment
with K2CO3 (1 equiv) at 90 °C for only 5 min, while lowering the
temperature to 50 °C resulted in significantly longer reaction
time to obtain a satisfactory yield (entries 1-3). As expected
above, adding a catalytic amount (0.01 equiv) of phenyl
isocyanate to the reaction mixture moderately facilitated the
rearrangement (entry 4). A twofold larger concentration also
renders the shortening of the reaction time (entry 5). It is
noteworthy that the utilization of well-dried K2CO3, dried under
vacuum with a heating gun, distinctly shortens the time of the
rearrangement (entry 6). The result seems to imply the
retardation of the rearrangement by H2O existing as impurity of
K2CO3 probably due to the trap of isocyanate intermediate.
Indeed, addition of 0.1 equivalent of H2O in the reaction lowered
the yield of aniline 2a (entry 7). Interestingly, the reaction can be
carried out even at 25 °C within a reasonable reaction time using
well-dried K2CO3 (entry 8). K3PO4 is also a useful base for this
reaction (25 °C, 2 h, 86% yield).
Finally several activating agents were evaluated (Table 2,
entries 8-13). Using N,N’-dicyclohexylcarbodiimide (DCC), a
kind of cumulenes such as isocyanates, gave the corresponding
aniline in a low yield (entry 8). When aryl and alkyl sulfonyl
chlorides, which are well known as O-activating agents of
hydroxamic acids,6 were employed, mesyl chloride gave better
yields than tosyl chloride (entries 9 and 11). For tosyl chloride,
the good yield was achieved if the reaction was carried out for 2
h (entry 10). After further trials, it was found that acetic
anhydride gave the best result for the rearrangement (entry 13).
Interestingly, the reactive trifluoroacetic anhydride gave the poor
result (entry 14).
Table 2
The rearrangement of hydroxamic acid 1a with a catalytic
amount of activating agents
Table 1
Base-mediated rearrangement of hydroxamic acid 1a using a
catalytic amount of phenyl isocyanatea
Entry
Additive
PhNCO
PhNCO
PhNCO
PhNCO
PhNCO
PhNCO
PhNCO
Solvent
DMSO
DMF
Yield (%)
1
2
3
4
5
6
7
92
93
85
86
70
14
ND
MeCN
DCE
Entry PhNCO (equiv)
Conditions
90 °C, 5 min
70 °C, 1 h
Yield (%)
1
–
98
96
90
96
88
92
acetone
THF
2
–
3
–
50 °C, 27 h
50 °C, 10 h
50 °C, 5 h
Diethylene
4
0.01
0.01
0.01
0.01
glychol
5b
6b,c
7b,c
8
DCC
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
15
11
81
76
88
93
58
50 °C, 10 min
9
TsCl
10a
11
12
13
14
TsCl
50 °C, 10min, H2O 66
(0.1 equiv)
MsCl
8b,c
25 °C, 2 h
90
0.01
AcCl
a
Reaction conditions: hydroxamic acid (1.2 mmol), K2CO3
(1.2 mmol), PhNCO (12 µmol), DMSO (1 mL).
Ac2O
b
(CF3CO)2O
The reaction was performed in DMSO (0.5 mL) under
otherwise identical conditions.
a The reaction was performed for 2 h.
c
The reaction was performed with anhydrous K2CO3 that is
dried under vacuum with a heating gun.
With the optimized conditions in hand, the scope of substrates
was examined. As shown in Table 3, a variety of o-substituted
aromatic hydroxamic acids gave the desired anilines in high
yields (entries 1-6).7 On the other hand, those attached electron-
donating groups at m- or p-positions, which are usually good
substrates for classical Lossen rearrangement,8 resulted in poor
yields (entries 7 and 8). The reason for these unexpected results
We then turned our attention to examine the scope of solvents,
especially moderate to low polar solvents (Table 2). Fortunately,
the rearrangement smoothly proceeded in acetonitrile,
dichloroethane, and acetone at 50 °C to give aniline 2a in good to
high yields (entries 1-5). It should be noted that the relatively low