Organic Letters
Letter
rarely achieved. In this context, we envisage that a cascade
reaction involving iodocyclization, C−C bond cleavage, and
oxidative hydrolysis in the oxidative system of iodine source/
hydrogen peroxide may be feasible (Figure 1c). In this process,
aqueous hydrogen peroxide serves as a green oxidant and
oxygen source.
In this paper, we report a novel, metal-free, and water-
tolerant method for the synthesis of ortho-acylphenols
promoted by the iodine source/hydrogen peroxide system.
This transformation smoothly proceeds through ether
formation, iodocyclization, C−C bond cleavage, and oxidative
hydrolysis in a one-step manner. In addition, control
experiments led to a possible mechanism.
found to be effective for this transformation, and the desired
product was afforded in 42% yield while 0.8 equiv of NIS was
used (Table 1, entry 7). Additionally, tert-butyl hydroperoxide
(∼65% solution in water) took part in this reaction and the
desired product 2a could be obtained in 39% yield (Table 1,
entry 8; see SI for other oxidants). Then, the effects of solvents
on the reaction were evaluated. As revealed in Table 1, entries
9−12, HFIP had the better effect than other solvents, such as
acetonitrile, 1,4-dioxane, and tert-butanol (see SI for other
solvents). Finally, considering that aqueous hydrogen peroxide
played the role of a green oxidant, an oxygen source, and an
aqueous medium in the reaction, further investigation into the
way of adding it to the reaction was attempted. To our delight,
the yield could be increased to 70% with Method A (Table 1,
entry 13) or 67% with Method B (Table 1, entry 15).
The iodine source/hydrogen peroxide catalytic system was
examined for the reaction by selecting propargyl aryl ether 1a
as a model substrate (Table 1). Our preliminary study was
Subsequently, the scope of different phenolic structures was
investigated by using the optimized Method A or B as shown
in Scheme 1. The halogen functionality at the ortho-, meta-, or
a
Table 1. Optimization of the Reaction Conditions
a b
,
Scheme 1. Scope of Different Phenolic Structures
b
entry
iodine source (equiv)
solvent
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
MeCN
1,4-dioxane
tBuOH
DMSO
HFIP
yield (%)
1
2
3
4
0
NaI (0.6)
I2 (0.3)
I2 (0.4)
I2 (0.4)
I2 (0.6)
NIS (0.8)
I2 (0.4)
I2 (0.4)
I2 (0.4)
I2 (0.4)
I2 (0.4)
I2 (0.4)
I2 (0.4)
NIS (1.0)
trace
29
47
trace
46
42
39
38
0
c
5
6
7
8
d
9
10
11
12
13
14
0
0
e
70
64
67
e
MeNO2
HFIP
f
15
a
The reaction was carried out with propargyl aryl ether 1a (0.2
mmol), iodine source, aqueous H2O2 (∼163.4 μL, ∼30%, ∼8.0 equiv)
in solvent (0.5 mL) under air atmosphere at 100 °C for 12 h.
b
c
d
Isolated yields. 80 °C. tert-Butyl hydroperoxide (∼65% solution in
e
water, ∼8.0 equiv). Method A: After 1a (0.2 mmol), iodine (0.4
equiv), and aq. H2O2 (∼40.8 μL, ∼30%, ∼2.0 equiv) in HFIP (0.5
mL) were stirred at 10 °C for 3 h, additional aq. H2O2 (∼122.6 μL,
∼30%, ∼6.0 equiv) was then added and stirred at 100 °C for 12 h.
f
Method B: 1a (0.2 mmol) and NIS (1.0 equiv) in HFIP (0.5 mL)
were stirred at rt for 2 min, and aq. H2O2 (∼81.6 μL, ∼30%, ∼4.0
equiv) was then added and stirred at 100 °C for 12 h.
carried out by varying the iodine source with aqueous H2O2
(∼30%, ∼8.0 equiv) as the oxidant and oxygen source in
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) under an air atmos-
phere at 100 °C for 12 h. As shown in Table 1, no target
product was detected without any iodine source (Table 1,
entry 1). When sodium iodide was used for the reaction, only a
trace of product could be observed (Table 1, entry 2).
Gratifyingly, molecular iodine could provide ortho-acylphenol
2a in a yield of 29% (Table 1, entry 3). Intriguingly, when the
amount of iodine was changed to 0.4 equiv, the yield was
increased to 47% (Table 1, entry 4). However, the yield was
not further improved by increasing the catalytic quantity of
iodine (Table 1, entry 6). N-Iodosuccinimide (NIS) was also
a
b
Reactions were carried out with Method A or B. Yields of the
isolated products are given.
para-positions of phenol proceeded smoothly with Method A,
and the corresponding products 2b−f were afforded in 49%−
70% yields. A variety of substrates 1d−j bearing electron-
donating or weak electron-withdrawing para-substituents such
as Me, OMe, Bu, and CF3 were also suitable for this
transformation, providing the desired products 2d−j in
moderate to good yields. para-Hydroxymandelic acid and
t
6595
Org. Lett. 2021, 23, 6594−6598