Communication
ent method can be applied on biologically active small mole-
cules and natural products as well.
Table 2. Screening of solvents for formation of 2a.[a]
In our initial study, we examined the possibility of hydroxyl-
ation of aniline 1, using various oxidants (Table 1) in the pres-
ence of TFA. The reactions with reagents such as oxone,
m-CPBA, H2O2, and K2S2O8 led to interesting observations, and
Entry
Solvent
T [8C]
Yield [%][b]
1
2
3
4
5
6
7
dioxane
THF
DMF
MeCN
MeCN/H2O (1:1)
DMSO
101
66
152
82
reflux
189
65
42
0
0
25
0
30
25
Table 1. Screening of various oxidants for formation of 2a.[a]
MeOH
Entry
Oxidant
Yield [%][b]
[a] All reactions were performed by using oxone as the oxidant and a re-
action time of 12 h. [b] Yields are based on GC-MS analysis.
1
2
3
4
5
6
7
oxone
TBHP
Fe2O3
m-CPBA
DDQ
42
0
0
25
0
30
25
Table 3. Yields of product 2a at various temperatures.[a]
K2S2O8
H2O2
Entry
T [8C]
Yield [%][b]
Side products
3
4
5
[a] All reactions carried out in dioxane at reflux. [b] Yields are based on
GC-MS analysis.
1
2
3
4
5
101
90
70
50
42
64
35
25
18
30
11
10
5
15
16
30
40
68
11
1.2
2
5
5
we could detect the selective formation of ortho-hydroxylated
trifluoroacetanilide 2a as the major product along with side
products nitrobenzene (3), 1,2-diphenyldiazene oxide (4), and
N-trifluoroacylated product 5 (Scheme 2). In case of Fe2O3, tert-
butylhydroperoxide (TBHP), and 2,3-dichloro-5,6-dicyanobenzo-
quinone (DDQ) no product formation was observed. Initially,
we carried out all reactions using dioxane at reflux conditions.
25
5
[a] All reactions performed by using oxone as the oxidant, dioxane as the
reaction solvent, and a reaction time of 12 h. [b] Yields are based on GC-
MS analysis.
tion was continued till 12 h at this temperature. The equiva-
lence study for oxone and trifluoroacetic acid (TFA) was carried
out, wherein the reaction with 1.2 equivalents of oxone and
2.4 equivalents of TFA gave maximum yields.
The acidic nature of TFA was explored on the basis that its
role may be important in hydroxylation. We carried out experi-
ments with various acids. The reaction with TFA without oxone
gave only N-acylated product 5 and reaction with HCl, H2SO4,
and methanesulfonic acid using oxone, led to formation of ni-
trobenzene (3) exclusively. However, acetic acid gave 1,2-di-
phenyldiazene (9) as a major product.
With these optimised conditions, the present reaction offers
wide substrate scope and applicability. To demonstrate this,
several electron-withdrawing as well as electron-donating sub-
strates were explored. In this context, varieties of substrate
were reacted in presence of oxone and TFA and all gave the
ortho-hydroxyl-N-trifluoroacylated aryamine products in good
yields (Tables 4 and 5). However, comparatively low yields were
obtained for substrates bearing electron-donating groups. In
case of 2,6-dimethylaniline, the required transformation was
not observed, which indicates the specificity of the substrates.
However, in case of meta-substituted aryl amines, two prod-
ucts were observed and ortho-hydroxylation towards the steri-
cally hindered side was found to be very low or negligible. The
examples of meta-substituted substrates are presented sepa-
rately in Table 5.
Scheme 2. Reaction of aniline with TFA and oxone.
Considering the importance of ortho-hydroxy amino group
bearing class of pharmacologically active compounds,[11] and
our chance encounter of the potential of “greener”[12] oxone in
this important transformation, we decided to explore this reac-
tion and its application in more detail (Scheme 2). For optimi-
sation of reactions we conducted the solvent screening using
various solvents and dried dioxane was found to give the best
results (Table 2). All future reactions were carried in anhydrous
dioxane under inert conditions.
Based on this early interesting observation and encouraging
results, we intended to improve the yields of 2-hydroxy-N-tri-
fluroacetamide 2a. In this direction, we planned for conduct-
ing the temperature dependent reactions. The reactions at var-
ious temperatures gave varying yields. Amongst all, the reac-
tion conducted at 908C for 1.5 h gave maximum yield of 2a
(Table 3), there was no increase in yields even after the reac-
Furthermore, to see the substrate specificity of the present
reaction, we explored the possibility of ortho-hydroxylations
on different arylamines (Table 6). The reaction of N-arylsulfon-
amide under optimised condition could go easily offering the
desired product 2a (Table 6, entry 1) in good yields. 2-Hydroxy-
&
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Chem. Eur. J. 2014, 20, 1 – 6
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