Facile and metal-free synthesis of phenols from benzaldoxime and diaryliodonium salts

Article abstract of DOI:10.3184/174751917X15064232103119

A metal-free, base-promoted facile synthesis of phenol derivatives utilising diaryliodonium salts as the aryl source and benzaldoxime as the hydroxide surrogate has been developed. The reaction is fast and shows good substrate compatibility, giving the corresponding products in good to excellent yields. A gram-scale synthesis of phenols utilising this protocol has also been achieved.

Full text of DOI:10.3184/174751917X15064232103119

JOURNAL OF CHEMICAL RESEARCH 2017
VOL. 41 OCTOBER, 591–593
RESEARCH PAPER 591
Facile and metal-free synthesis of phenols from benzaldoxime and
diaryliodonium salts
Yongsheng Zhou
School of Petrochemical Engineering, Changzhou University, Changzhou 213164, P.R. China
A metal-free, base-promoted facile synthesis of phenol derivatives utilising diaryliodonium salts as the aryl source and benzaldoxime
as the hydroxide surrogate has been developed. The reaction is fast and shows good substrate compatibility, giving the corresponding
products in good to excellent yields. A gram-scale synthesis of phenols utilising this protocol has also been achieved.
Keywords: phenols, O-arylation, benzaldoxime, diaryliodonium salts, metal-free synthesis
Phenols and their derivatives have been found in numerous
pharmaceutical, agrochemical, and natural products.1 They
also serve as key synthetic intermediates in the preparation of
complex compounds. Conventional methods for the synthesis of
phenols including the transition metal-catalysed hydroxylation
of aryl halides,2–7 and the oxidative hydroxylation of aromatic
boronic acids8–13 (Scheme 1, a and b). Route (a) generally suffers
from drawbacks such as harsh conditions (long reaction time
and high temperature), the incompatibility of the substrates,
as well as the requirement for a metal catalyst (Pd, Cu). In
recent years, the oxidative hydroxylation of aromatic boronic
acids (route b) has attracted attention since aromatic boronic
acids have a low toxicity and are stable and readily available.
However, these procedures still require a catalyst and a large
amount of oxidant. Recently, Fier and co-workers reported a Pd
or Cu-catalysed method to prepare phenols with benzaldehyde
oxime as a hydroxide surrogate (route c).14,15 It was found that
a weak base such as Cs2CO3 would promote the deprotonation
of the oxime ether, thereby providing a new route to access
phenols. However, specific ligands were necessary to promote
this transformation. In the light of their contributions, we now
report a modified base-promoted synthesis of phenols under
mild reaction conditions using diaryliodonium salts as the aryl
source and benzaldoxime as the hydroxide surrogate (route d).
2 equiv. of Cs2CO3 at 80 °C. Since the oxime ether generated
from the benzaldoxime was readily deprotonated in the
14,15
presence of Cs2CO3,
we focused on the optimisation of
O-arylation process (step 1). Initially, benzaldoxime (1) and
diphenyliodonium triflate (2a) were selected as the model
substrates to optimise the reaction conditions (Table 1). As
shown in the table, the base exhibited a significant influence on
this transformation. The reaction did not occur in the absence
of a base. Bases such as K2CO3, Cs2CO3 and KOH gave rather
poor yields of the desired products at 60 °C after 12 h (entries
t
2–4). Pleasingly, switching the base to BuOK and tBuONa
provided the corresponding product 3a in 95% and 90% yields,
respectively, in only 30 minutes (entry 5 and 6). The anion of
diphenyliodonium salt was then examined, and an inferior yield
was obtained (82%, entry 7). Other solvents including DMSO,
toluene, dioxane, tetrahydrofuran and acetonitrile were also
surveyed. However, lower yields were obtained (entries 8–12).
Encouragingly, lowering the reaction temperature to room
temperature affected neither the yield of the desired product
nor the reaction time (entry 13). Decreasing the amounts of
substrate 2a and base to 1.2 or 1.0 equiv. led to a decrease in the
yield (entries 14 and 15).
To evaluate the scope and limitations of the current procedure,
a series of diaryliodonium triflates were investigated under the
optimised reaction conditions. The results are summarised
in Table 2. In general, all the reactions proceeded smoothly
to provide the desired products 3 in good to excellent yields.
Substrates bearing either electron-donating or electron-
withdrawing substituents including –CH3, –CH3O, halogen
Results and discussion
This reaction involved two steps, namely the O-arylation and
deprotonation process. When the first step was finished, the
mixture was further stirred for another 1 h in the presence of
Previous work:
metal catalyst
X= Br, I
Ar-X
Ar-OH
(a)
Cl,
catalyst, oxidant
(b) Ar-B(OH)2
Ar-OH
H
base
benzaldoxime
(c) Ar-X
Ar-OH
O
Ar
N
Ph
work:
This
OH
(1) o-arylation
N
+
I
(d)
Ar-OH
OTf
Ar
Ar
(2) base
Ph
Scheme 1 Different routes for the synthesis of phenols.
* Correspondent. E-mail: yszhoucczu@126.com

592 JOURNAL OF CHEMICAL RESEARCH 2017
Table 1 Optimisation of reaction conditionsa
Table 2 Substrate scopea
OH
OH
N
(1) tBuOK, rt, time
(2) Cs2CO3, 80 oC, 1 h
(1) base, temp, time
N
+
I
+
I
X
OTf
Ph-OH
Ar-OH
Ar
Ar
Ph
Ph
2a
(2) Cs2CO3, 80 °C, 1 h
Ph
Ph
2
3
1
3a
1
Temperature Time
Yield
(%)b
0
Trace
Trace
14
95
90
82
89
37
74
60
72
96
85
76
Time
(h)
Yield
Entry X
Base (equiv.)
Solvent
Entry Ar
Product
M.p. (°C)lit.
(°C)
60
60
60
60
60
60
60
60
60
60
60
60
r.t.
r.t.
r.t.
(h)
12
(%)b
1
OTf
–
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
Toluene
Dioxane
THF
CH3CN
DMF
1
C6H5
1
1
6
3
3
1
1
1
1
3
1
2
1
3a
3b
3c
3d
3e
3f
3g
3h
3i
96 40–42 (41–42)17
2
3
4
5
6
7
8
9
10
11
12
13
14
15
OTf
OTf
OTf
OTf
OTf
BF4
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
K2CO3 (1.5)
Cs2CO3 (1.5)
KOH (1.5)
12
12
12
2
3
4
4-CH3C6H4
4-MeOC6H4
4-ClC6H4
86 Yellow oil (yellow oil)18
75 56–58 (57–58)17
90 43–44 (44–45)17
88 58–60 (55–58)19
85 42–45 (43)20
tBuOK (1.5)
tBuONa (1.5)
tBuOK (1.5)
tBuOK (1.5)
tBuOK (1.5)
tBuOK (1.5)
tBuOK (1.5)
tBuOK (1.5)
tBuOK (1.5)
tBuOK (1.2)
tBuOK (1.0)
0.5
5
4-BrC6H4
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
6
7
8
9
10
11
12
13
4-CF3C6H4
4-CHOC6H4
4-NO2C6H4
4-CH3COC6H4
2-BrC6H4
2-CH3C6H4
1-Naphthyl
3-Pyridyl
87 114–116 (113–117)17
84 113-116 (113-114)17
85 108–110 (110)12
84 Yellow oil (colourless oil)21
89 Yellow oil (brown oil)12
91 92–94 (91–93)17
82 125–126 (127)5
3j
3k
3l
3m
a Reaction conditions: 1 (0.5 mmol), 2a/tBuOK (1:1 molar ratio, 1.5 equiv), DMF (5 mL),
r.t., 1h. After step one, the mixture was further stirred for another 1 h in the presence of 2
equiv. of Cs2CO3 at 80 °C. b Isolated yield.
DMF
DMF
1
1
a Reaction conditions: 1 (0.5 mmol), 2a/base (1:1 molar ratio), solvent (5 mL). After step
one, the mixture was stirred for another 1 h in the presence of 2 equiv. of Cs2CO3 at 80 °C.
b Isolated yield.
OH
N
(1) tBuOK, r.t., 1 h
Ph-OH
+
I
OTf
Ph
Ph
2a
(2) Cs2CO3, 80 °C, 1 h
Ph
20 mmol scale
3a
1
(1.69 g, 90%)
Scheme 2 Gram-scale reaction.
spectra were recorded on a Bruker AV300 analyser in chloroform-d
(CDCl3) using TMS as an internal standard. Melting points (m.p.) are
determined with a MPA 100 apparatus and are not corrected. GC–MS
were recorded on an Agilent Technologies 7890A instrument with an
Agilent 5975C mass detector (EI).
(Cl, Br), –CF3, –CHO, –NO2, –C(O)CH3 survived the reaction
conditions well, affording the corresponding products in 75–
96% yields. Among them, electron-rich bis(4-methoxyphenyl)
iodonium triflate afforded the product 3c in 75% yield due
to byproduct formation.16 Moreover, the steric effect was
negligible, with the product 3j and 3k being obtained in 84%
and 89% yields, respectively. Bis(1-naphthyl)iodonium triflate
also showed good reactivity to deliver product 3l in 91% yield.
It was worth noting that bis(3-pyridyl)iodonium triflates was
tolerated well under the reactions, affording 3m in 82% yield.
To further demonstrate the practicality of the protocol which
we have developed, the reaction was scaled-up (20 mmol).
Under the optimised reaction conditions, the reaction proceeded
smoothly to provide the phenol 3a in 90% yield (Scheme 2).
Synthesis of phenols; general procedure
In a sealed tube, benzaldoxime (0.5 mmol), diaryliodonium salt
t
(0.75 mmol), BuOK (0.75 mmol) and DMF (5 mL) were mixed at
room temperature. The reaction mixture was stirred for a given
time. Then, Cs2CO3 (2 equiv.) was added to the tube, and the reaction
mixture was kept stirring for another 1 h at 80 °C. After completion
of the reaction, the mixture was allowed to cool to room temperature,
diluted with water and extracted with ethyl acetate. The organic
layer was dried over anhydrous MgSO4 and then the solvent was
removed under reduced pressure. The residue was further purified by
silica gel chromatography using a mixture of petroleum ether/ethyl
acetate to afford the desired product 3. All of the products are known
compounds, and their characterisation data were compared and found
to be consistent with the reported literature.
Conclusion
In summary, a metal-free and base-promoted facile synthesis of
phenol derivatives has been developed. This protocol utilised
diaryliodonium salts as the aryl source and benzaldoxime as the
hydroxide surrogate. Substrates with different functional groups
survived the reaction conditions to afford the desired products
in good to excellent yields. Importantly, diaryliodonium salts
are readily available and can be prepared from iodobenzene
derivatives, thereby providing a new route to access phenols. A
gram-scale synthesis utilising this protocol could also be achieved.
Received 28 July 2017; accepted 12 September 2017
Paper 1704906
https://doi.org/10.3184/174751917X15064232103119
Published online: 4 October 2017
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