Meta-selective substitution of phenols with indoles via one-pot oxidative dearomatization-Michael addition-aromatization

Article abstract of DOI:10.1055/s-0030-1259726

An oxidative coupling strategy involving hypervalent organoiodine-induced oxidative dearomatization of 4-substituted phenols, Br?nsted acid catalyzed Michael addition with indoles, and aromatization has been developed. The one-pot reaction provides an eff

Full text of DOI:10.1055/s-0030-1259726

LETTER
923
meta-Selective Substitution of Phenols with Indoles via One-Pot Oxidative
Dearomatization–Michael Addition–Aromatization
m
eta-Selective Sub
a
stitution of
n
Phenols
w
it
g
h Indoles Ye,a Hua Wang,a Renhua Fan*a,b
a
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, P. R. of China
Fax +86(21)65642019; E-mail: rhfan@fudan.edu.cn
b
Shanghai Key Laboratory of Molecular Catalysts and Innovative Materials, Department of Chemistry, Fudan University, 220 Handan
Road, Shanghai 200433, P. R. of China
Received 3 December 2010
Dedicated to Professors Xiyan Lu and Lixin Dai
egy, the first key point was the species of the first
nucleophilic reagent (YH). It should be high reactive to-
ward the oxidative dearomatization of the 4-substituted
phenols and less reactive to the Michael addition of the
Abstract: An oxidative coupling strategy involving hypervalent or-
ganoiodine-induced oxidative dearomatization of 4-substituted
phenols, Brønsted acid catalyzed Michael addition with indoles,
and aromatization has been developed. The one-pot reaction pro-
vides an efficient access to the meta-indole-substituted phenol de- generated cyclohexadienones. Additionally, the Y group
rivatives.
should be a good leaving group to promote the following
aromatization of the resulting Michael adducts. We exam-
ined the oxidation of p-cresol in the presence of various
nucleophiles with (diacetoxyiodo)benzene as the oxidant.
After the optimization of reaction conditions, the methox-
ylation of p-cresol with 1.1 equivalents of PhI(OAc)2 in
methanol gave the best result (Equation 1).7
Key words: aromatic substitution, biaryls, cross-coupling reaction,
oxidation, regioselectivity
Selective substitution on the aryl-ring carbons is the most
commonly used procedure for the preparation of function-
alized aromatic organic compounds.1 As the electron-rich
aromatic systems, phenols and phenol ethers are high re-
active toward electrophilic aromatic substitutions, and the
electron-donating hydroxy and alkoxy groups direct the
electrophilic substitutions to the ortho/para positions.
Compared with the normal ortho/para selectivity, the
meta-selective functionalization of phenols or phenol de-
rivatives remains a challenge and an elusive problem.2
OH
OH
PhIX2, YH, catalyst
+
Nu
H
meta-functionalization
2
Nu
R
1
R
3
PhIX2
YH
oxidative
dearomatization
aromatization
catalyst
Hypervalent organoiodine-induced phenolic oxidation
leads to a variety of synthetically useful compounds.3 Ex-
cept the formation of various benzoquinones from hydro-
quinones, the oxidation of the 4-substituted phenols in the
presence of an appropriate internal or external nucleophile
gives rise to the corresponding cyclohexadienones.4 As
the important intermediates, the resulting cyclohexadi-
enones have found widespread use in the synthesis of nat-
ural and unnatural biologically active compounds.5 Our
planned strategy, based on a formal meta-functionaliza-
tion of 4-substituted phenols, involves the in situ oxida-
tive dearomatization of 4-substituted phenols, the Michael
addition of the generated electrophilic cyclohexadi-
enones, and the aromatization of the resulting Michael ad-
ducts (Scheme 1).
O
O
OH
NuH, catalyst
Michael addition
H
Nu
Nu
R
Y
R
Y
R
Y
Scheme 1 meta-Functionalization of 4-substituted phenols
OH
O
PhI(OAc)2 (1.1 equiv), MeOH, 0 °C
10 min
OMe
4a (83%)
1a
Because of the importance of arylindoles,6 indoles were
chosen as the coupling partners. To begin our study, we
chose p-cresol and indole as the standard substrates to
search for the suitable reaction conditions and the poten-
tial catalysts. To implement this oxidative coupling strat-
Equation 1
Although the obtained 4-methoxy-4-methylcyclohexa-
2,5-dienone (4a) was stable, to simplify the procedure,
one-pot oxidative coupling reaction was investigated. p-
Cresol was treated with 1.1 equivalents of PhI(OAc)2 in
MeOH at 0 °C. After 10 minutes, indole and catalyst were
added. A variety of Lewis acids and Brønsted acids were
examined as catalysts. While no coupling reaction was
SYNLETT 2011, No. 7, pp 0923–0926
x
x.
x
x.
2
0
1
1
Advanced online publication: 10.03.2011
DOI: 10.1055/s-0030-1259726; Art ID: W32410ST
© Georg Thieme Verlag Stuttgart · New York

924
Y. Ye et al.
LETTER
observed in the absence of an acid catalyst, several Brøn-
sted acids proved to be effective in the coupling reaction
(Table 1). 4-Methylbenzenesulfonic acid (TsOH) was the
best catalyst, and 5 mol% TsOH were sufficient to achieve
75% conversion. Interestingly, the isolated product was
not the expected 3-(1H-indol-3-yl)-4-methylphenol (3a),
but 3-(5-methoxy-2-methylphenyl)-1H-indole (5a). As a
control experiment the isolated 4-methoxy-4-methyl-
cyclohexa-2,5-dienone (4a) was treated with indole and
TsOH in DCE under the same conditions. The reaction
gave rise to 3-(1H-indol-3-yl)-4-methylphenol (3a) as the
major product in 77% yield (Equation 2).
Table 1 Conditions Screening for the Oxidative Coupling Reaction
of p-Cresol (1a) with Indolea
OH
OMe
H
catalyst
PhI(OAc)2 (1.1 equiv)
N
+
MeOH, 0–70 °C, 3 h
N
1a
H
5a
Entry
Catalyst (equiv)
MeCOOH (0.1)
PhCOOH (0.1)
Yield of 5a (%)b
1
2
3
4
5
6
7
8
9
0
30
28
32
69
67
76
75
53
OH
O
H
4-MeOC6H4COOH (0.1)
4-O2NC6H4COOH (0.1)
CF3COOH (0.1)
N
TsOH (5 mol%)
DCE, 70 °C
+
OMe
N
4a
H
3a (77%)
CF3SO3H (0.1)
Equation 2
4-MeC6H4SO3H (0.1)
4-MeC6H4SO3H (0.05)
4-MeC6H4SO3H (0.01)
A hypothesized pathway for the formation of 3-(5-meth-
oxy-2-methylphenyl)-1H-indole (5a) is proposed as
shown in Scheme 2. The oxidative dearomatization of p-
cresol with iodobenzene diacetate in the presence of meth-
anol generates 4-methoxy-4-methylcyclohexa-2,5-di-
enone (4a), which is ready to undergo a Brønsted acid
catalyzed Michael addition with indole to form an inter-
mediate I. Because the reaction is carried out in methanol,
the intermediate I is first attacked by methanol to form
intermediate II before the aromatization takes place to
afford 3-(1H-indol-3-yl)-4-methylphenol (3a). After a
Brønsted acid catalyzed aromatization of the resulting
a Reaction conditions: p-cresol (1a, 0.50 mmol), PhI(OAc)2 (0.55
mmol), indole (0.50 mmol), catalyst (as noted), solvent (2.0 mL).
b Isolated yield based on p-cresol (1a).
intermediate, 3-(5-methoxy-2-methylphenyl)-1H-indole
(5a) is yielded as the final product.
The oxidative coupling reaction conditions are compati-
ble with a range of substrates as shown in Scheme 3. The
reaction was found to tolerate a variety of different groups
Ph
I
OH
O
AcO
O
N
H
PhI(OAc)2
AcOH
MeOH
H+
PhI
AcOH
OMe
1a
4a
O
HO OMe
H
HO OMe
H
NH
H
NH
NH
MeOH
H+
H
H+
OMe
OMe
I
II
III
H+
H+
OH
OMe
N
N
H
H
3a
5a
Scheme 2 Possible mechanism for the oxidative coupling reactions of p-cresol (1a) with indole
Synlett 2011, No. 7, 923–926 © Thieme Stuttgart · New York

LETTER
meta-Selective Substitution of Phenols with Indoles
925
OMe
R4
OH
TsOH (5 mol%)
N
R3
PhI(OAc)2 (1.1 equiv)
R3
R2
R2
+
MeOH, 0–70 °C, 3 h
2 (1.0 equiv)
R1
R1
N
R4
1
5
OMe
OMe
OMe
OMe
OMe
OMe
F
Cl
Br
N
N
N
N
H
N
H
N
H
H
H
H
5a (75%)
5b (72%)
5c (78%)
5d (81%)
5e (63%)
5f (76%)
OMe
OMe
OMe
OMe
OMe
OMe
MeO
OMe
NO2
N
N
N
H
N
N
N
H
H
Me
Bn
5k (70%)
5g (65%)
5h (73%)
5i (0%)
5j (64%)
5l (63%)
OMe
OMe
OMe
OMe
OMe
t-Bu
OMe
OMe
Ph
n-Bu
HO
N
N
N
H
N
H
N
H
N
H
H
Ac
5m (0%)
5n (85%)
5o (58%)
5p (67%)
5q (0%)
5r (53%)
Scheme 3 Oxidative coupling reaction of 4-substituted phenols with indoles
with different electronic demands on the indole rings in-
volving electron-donating and electron-withdrawing
groups. N-Alkyl-protected indoles were suitable sub-
strates while no product was detected from the reaction of
N-acetyl indole. 4-Butyl- and 4-phenylphenols were
found to be the effective coupling partners, but the reac-
tion of 4-tert-butylphenol was complicated. When 3,4-
dimethylphenol was employed, the corresponding cou-
pling product 5n was isolated in 85% yield. When 4-hy-
droxyphenethyl acetate was used as the substrate, the
reaction accompanied the oxidative coupling with the
deacetylation to provide 4-(2-hydroxyethyl)-3-(1H-indol-
3-yl)phenol (5r) in 53% yield.
Acknowledgment
Financial support from the National Natural Science Foundation of
China (21072033) and Shanghai Key Laboratory of Molecular Ca-
talysts and Innovative Materials, Department of Chemistry, Fudan
University (2009KF02) are gratefully acknowledged.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2011, No. 7, 923–926 © Thieme Stuttgart · New York

926
Y. Ye et al.
LETTER
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