Regioselective Oxidative Chlorination of Arenols Using NaCl and Oxone

Article abstract of DOI:10.1002/ejoc.201801063

We developed a practical and environmentally benign method for the chlorinative dearomatization of arenols using transient electrophilic chlorinating species generated in situ from inexpensive sodium chloride and Oxone as a Cl source and oxidant, respectively, under mild conditions. Moreover, the regioselective chlorination or chlorinative dearomatization of 1-naphthols was also achieved by changing the reaction conditions.

Full text of DOI:10.1002/ejoc.201801063

A Journal of
Accepted Article
Title: Regioselective Oxidative Chlorination of Arenols Using NaCl and
Oxone
Authors: Muhammet Uyanik, Naoto Sahara, and Kazuaki Ishihara
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801063
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801063
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10.1002/ejoc.201801063
European Journal of Organic Chemistry
COMMUNICATION
Regioselective Oxidative Chlorination of Arenols Using NaCl and
Oxone
Muhammet Uyanik,[a] Naoto Sahara,[a] and Kazuaki Ishihara*[a]
Abstract: We developed a practical and environmentally benign
method for the chlorinative dearomatization of arenols using
transient electrophilic chlorinating species generated in situ from
inexpensive sodium chloride and Oxone as a Cl source and oxidant,
respectively, under mild conditions. Moreover, the regioselective
chlorination or chlorinative dearomatization of 1-naphthols was also
achieved by changing the reaction conditions.
oxidant, respectively, under mild conditions (Scheme 1).
Moreover, the regioselective chlorination or chlorinative
dearomatization of 1-naphthols was achieved depending on the
use of different reaction conditions.
Results and Discussion
Recently, we reported a dearomatizative spirolactonization of
phenols tethered to a carboxylic acid moiety at the ortho-position
using sodium hypochlorite pentahydrate (NaOCl·5H2O) as an
oxidant (Scheme 2a).[6] Compared to conventional aqueous
NaOCl solution (ca. 10 wt%, pH ~13), this solid oxidant offers
several advantages, including higher chlorine content (ca. 42%),
lower pH upon dissolution (pH ~11) and high stability at lower
temperatures.[7] We envisioned that NaOCl·5H2O could be
Introduction
The dearomatization of arenols has emerged as a promising tool
for the synthesis of various natural products and biologically
active compounds.[1]
Planar achiral substrates can be
transformed into chiral three-dimensional structures through an
sp2-to-sp3 change in geometry on one of the sp2-hybridized
carbon centers. Several different compounds can be generated
depending on the nature of the reagents used.[1] In this context,
the halogenative, especially the chlorinative, dearomatization of
arenols has been developed using electrophilic halogenating
reagents.[2] In 1883, Benedikt and Schmidt first reported the
chlorinative dearomatization of polychlorinated phenols using
toxic chlorine gas.[3] Since the 1950s, various electrophilic
chlorinating systems including isocyanuric chloride, N-
chlorosuccinimide (NCS), SO2Cl2, tBuOCl, NaOCl, SbCl5, SbF5-
CH2Cl2 and hypervalent iodine compounds have been
developed for the chlorinative dearomatization of phenols.[4]
Recently, the enantioselective chlorinative dearomatization of
naphthols has also been developed using 1,3-dichloro-5,5-
dimethylhydantoin (DCDMH).[5] The development of an efficient
method for the chlorinative dearomatization of arenols using
less-toxic and inexpensive chlorinating reagents is still needed.
applied as
a
chlorinating agent to the chlorinative
dearomatization of arenols in the absence of an intramolecular
nucleophilic moiety at an appropriate position (Scheme 2b).
Indeed, the rapid reaction of 1-methyl-2-naphthol (1a) with
NaOCl·5H2O (2 equiv.) in a mixed solvent of ethyl acetate and
water
at
room
temperature
afforded
1-chloro-1-
However,
methylnaphthalen-2(1H)-one (2a) in 82% yield.
undesired ortho-quinol 3a[8] was also obtained in 13% yield as a
side product. The reaction of 2a under identical conditions did
not afford 3a and most of the 2a was recovered, which revealed
that 3a might be obtained from the direct oxidation of 1a.[9]
A
brief screening of conditions revealed that the generation of 3a
could be suppressed under acidic conditions in aqueous acetic
acid.[9]
a) Dearomatizative spirolactonization[6]
O
CO2H
O
NaOCl·5H2O (1.1 equiv.)
OH
O
R1
O
Cl
OH
R
R2
NaCl, Oxone
O
EtOAc/H2O, 0 °C, 5 min
or
Room Temperature
99%
R4
b) Chlorinative dearomatization
OH
Cl
[O]
Cl
OH
Cl–
Cl+ transient active species
O
+
O
NaOCl·5H2O (2 equiv.)
in situ
solvent, r.t., 5 min
Scheme 1. Chlorinative dearomatization of naphthols using NaCl and Oxone.
1a
2a
3a
EtOAc/H2O (5:1, v/v)
AcOH/H2O (5:1, v/v)
82%
90%
13%
n.d.
Here, we report a practical and environmentally benign protocol
for the chlorinative dearomatization of naphthols and phenols
with transient chlorinating species generated in situ from
inexpensive sodium chloride and Oxone as a Cl source and
Scheme 2. Oxidative dearomatization of 2-naphthols with NaOCl·5H2O.
We next focused on the in situ generation of electrophilic
chlorinating species from chloride (-1) under oxidative
conditions[10] for the chlorinative dearomatization of 1a (Table 1).
First, conventional oxidants (2 equiv.) were investigated under
similar conditions (i.e., EtOAc/H2O at room temperature) in the
presence of 2 equivalents of sodium chloride (entries 1–5).
Almost no reaction occurred with the use of hydrogen peroxide
or alkyl hydroperoxides (tert-butyl hydroperoxide (TBHP) and
[a]
Prof. Dr. M. Uyanik, N. Sahara, Prof. Dr. K. Ishihara
Graduate School of Engineering, Nagoya University
Furo-cho, Chikusa, Nagoya 464-8603 (Japan)
E-mail: ishihara@cc.nagoya-u.ac.jp
Homepage: http://www.ishihara-lab.net/
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801063
European Journal of Organic Chemistry
COMMUNICATION
cumene hydroperoxide (CHP)) (entries 1–3). On the other hand,
the reaction with meta-chloroperbenzoic acid (mCPBA) as an
oxidant afforded a complex mixture of unidentified products
(entry 4). To our delight, the chlorinative dearomatization of 1a
proceeded efficiently with 1 equivalent of Oxone (as 2 equiv. of
oxidant, KHSO5), an inexpensive triple inorganic salt
(2KHSO5·KHSO4·K2SO4). Notably, undesired quinol 3a was not
detected under these acidic conditions (pH of the aqueous
phase ~1.6)[9] and 2a was obtained in 90% yield as a single
product (entry 5). A brief screening of organic solvents (entries
6–8) revealed that the reaction rate was slightly increased in a
mixed tert-butyl methyl ether/water solvent, and 2a was obtained
in 92% isolated yield (entry 8). Notably, the use of water as a
co-solvent under these biphasic conditions was crucial to
dissolve Oxone and control the selective oxidative reaction,
since 1a was almost recovered in the absence of water (entry 9).
A series of 1-substituted 2-naphthols 1 bearing electron-
donating or -withdrawing groups were examined for the oxidative
chlorinative dearomatization using NaCl and Oxone under
optimized conditions (Scheme 3).
In most cases, the
corresponding 2 were obtained in high to excellent yields as sole
products. Several functional groups such as alkoxycarbonyl (2d,
2f an 2k), cyano (2e), bromo (2j and 2n), alkynyl (2l), alkenyl
(2m) and methoxy (2o and 2p) groups were tolerated under
these mild conditions. Notably, a chemoselective chlorinative
dearomatization of 1p afforded 2p, a Cl-analogue of the natural
product lacinilene C methyl ether,[8,12] in high yield. However,
several unidentified byproducts were also obtained from the
reactions of 2-naphthols 1l and 1m bearing alkynyl and alkenyl
groups, respectively. Chemoselective chlorination of these
challenging substrates could be achieved under slightly modified
conditions that maintained a low concentration of the transient
chlorinating species.
Considering the over-chlorination or
Chlorine (Cl2) or hypochlorous acid (HOCl) might be
generated in situ as an active electrophilic chlorinating species
from NaCl and Oxone under acidic conditions.[10,11] Interestingly,
undesired chlorination at multiple bonds of these substrates,[9]
a
cleaner reaction proceeded by lowering the amount of NaCl (2 to
1 equiv.) used for these reactions, and the corresponding 2 were
obtained in good yields. In sharp contrast, the reactions of these
naphthols using NaOCl·5H2O afforded complex mixtures of
products and desired 2l and 2m were obtained in only low yields
(Scheme 3).
the reaction was completed within
5 minutes, as in the
stoichiometric reaction with NaOCl·5H2O (see Scheme 2), when
NaCl was pre-mixed with Oxone for 1 h to generate active
chlorinating species before the addition of 1a (Table 1, entry 10
versus entry 5). This result suggested that the transient active
species was generated in situ slowly and consumed rapidly, and
therefore the concentration of the highly reactive chlorinating
species could be minimized to induce high chemoselectivity
compared to stoichiometric chlorinating reagents such as NaOCl
(vide infra).
R1
NaCl (2 equiv.)
Oxone (1 equiv.)
R1
Cl
OH
O
R
R
tBuOMe/H2O (1:1, v/v)
Room Temperature, 1–3 h
1
2
Product 2: Yield
Table 1. Investigation of Chlorinative Dearomatization of 1a with NaCl.
Cl
R1 = Et (2b): 84%
O
R1
NaCl (2 equiv.), Oxidant
Cl
Cl
Ph (2c): 98%
O
1a
2a
CO2Me (2d): 94%
Br
solvent, r.t.
Solvent
2n: 99%
2o: 74%
CH2CH2CN (2e): 94%
Cl
Cl
Entry
Oxidant (equiv)
30% H2O2 (2)
TBHP (2)
Time [h]
12
2a, Yield [%][a]
<5 (>95)
<5 (>95)
<5 (>95)
<5 (<5)
CH2CH2CO2Et (2f): 89%
MeO
O
O
R3 = Me (2g): 95%
1
EtOAc/H2O[c]
EtOAc/H2O[c]
EtOAc/H2O[c]
EtOAc/H2O[c]
EtOAc/H2O[c]
CH3CN/H2O[c]
Toluene/H2O[c]
tBuOMe/H2O[c]
tBuOMe
Ph (2h): 99%
2
12
Cl (2i): 95%
O
MeO
Br (2j): 92%
3
CHP (2)
12
R3
CO2Me (2k): 92%
CCPh (2l): 86%[a] (30%)[b]
CH2CH=CH (2m): 76%[a] (29%)[b]
4
mCPBA (2)
Oxone (1)
Oxone (1)
Oxone (1)
Oxone (1)
Oxone (1)
Oxone (1)
12
iPr
2p: 90%
5
1.5
4
90 (<5)
Scheme 3. Oxidative chlorinative dearomatization of 2-naphthols 1 with NaCl
and Oxone. [a] NaCl (1 equiv.) was used. [b] Reactions were performed
under stoichiometric conditions with NaOCl·5H2O in AcOH as in Scheme 2.
6
91 (<5)
7
1.5
1
90 (<5)
8
92[d] (<5)
<5 (>90)
92 (<5)
Next, we examined the chlorination of 1-naphthol 4a (Table
2). The reaction of 4a using NaCl and Oxone (Method A) under
conditions similar to those for 2-naphthols afforded the para-
chlorinated product 5a and dearomatized para-dichloro product
6a as major products, which were produced via chlorination at
9
12
10[b]
EtOAc/H2O[c]
0.08
[a] Determined by 1H NMR analysis. Yields of recovered 1a are shown in
parentheses. [b] NaCl and Oxone were pre-mixed for 1 h before the addition
of 1a. [c] Organic solvent/H2O (1:1, v/v). [d] Isolated yield. TBHP, tert-butyl
hydroperoxide; CHP, cumene hydroperoxide, n.d., not detected.
the most nucleophilic 4-position of 4a (entry 1).
ortho-
Chlorinative dearomatized product 7a was a minor component,
and, as in 2-naphthols, ortho-quinol 8a was not detected under
these acidic conditions. A para-selective reaction proceeded
exclusively in an ethyl acetate/water mixed solvent (entry 2). To
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10.1002/ejoc.201801063
European Journal of Organic Chemistry
COMMUNICATION
our delight, both 5a and 6a could be obtained selectively in high
yield by controlling the amount of reagents used (entries 3 and
4). We next examined NaOCl·5H2O as a chlorinating agent for
the same reaction (Method B). Similarly, only para-chlorinated
products 5a and 6a were obtained under acidic conditions using
2 equivalents of KHSO4 as an additive (pH of the aqueous
phase ~3.4)[9] or aqueous acetic acid as a solvent (entries 5 and
6). On the other hand, ortho-chlorinative dearomatized product
7a was obtained in 62% isolated yield as a major product under
basic conditions (pH of the aqueous phase ~10.1[9]) in an ethyl
acetate/water mixed solvent (entry 7). As expected, ortho-quinol
8a[8] was also obtained under these basic conditions. Notably,
slightly higher chemo- and regioselectivities were obtained with
NaOCl·5H2O compared to conventional 10% aqueous NaOCl
(entry 7 versus entry 8).
para-position of methyl ethers 9 or 10 compared to 1-naphthols
4a or 5a.[14] In sharp contrast, no reaction occurred and 9 was
recovered under basic conditions using NaOCl·5H2O (Scheme
4c). These results suggested that the para-chlorinated products
5a or 10 might be generated via electrophilic aromatic
substitution with in situ-generated electrophilic chlorinating
species at the most nucleophilic para-position of 4a or 9 under
acidic conditions (Scheme 4d).[15]
Similarly, subsequent
chlorinative dearomatization of 5a would also proceed at the 4-
position to give 6a in the presence of excess Cl source. On the
other hand, 1-naphthoxide 11 would be generated first under
basic conditions and react with the chlorinating agent to afford
naphthyl hypochlorite 12 followed by a 1,3-shift to give ortho-
chlorinated product 5a (Scheme 4d).[15]
a)
OH
O
Table 2. Regio- and Chemoselective Chlorination of 1-Naphthol 4a.
NaCl (2 equiv.)
Oxone (1 equiv.)
Cl
CO2Me
CO2Me
OH
OH
O
CO2Me
CO2Me
tBuOMe/H2O (1:1, v/v)
r.t., 6 h
(7a: ~90% recovered)
CO2Me
Method
r.t.
+
Cl
5a, n.d.
7a
4a
5a
6a
Cl
Cl
Cl
O
b)
OMe
Method A:
NaCl (x equiv.), Oxone (y equiv.)
OMe
NaCl (2 equiv.)
Oxone (1 equiv.)
+
+
O
CO2Me
6a and 7a
n.d.
CO2Me
Cl
OH
CO2Me
CO2Me
Method B:
NaOCl·5H2O (2 equiv.)
EtOAc/H2O (1:1, v/v)
+
r.t., 7 h
Cl
10, 79%
7a
8a
9
Yield [%][a]
Method
A (x, y) or B
Time
[h]
c)
d)
NaOCl·5H2O
(2 equiv.)
Entry
Solvent
OMe
5a
51
45
6a
24
43
<5
87[f]
25
29
10
15
7a
13
<5
<5
<5
<5
<5
62[f]
58
8a
CO2Me
CO2Me
no reaction
1
2
3
4
5
6
7
8
A (2, 1)
A (2, 1)
A (1, 1)
A (3, 1.5)
B
tBuOMe/H2O[d]
EtOAc/H2O[d]
EtOAc/H2O[d]
EtOAc/H2O[d]
AcOH/H2O[e]
EtOAc/H2O[e]
EtOAc/H2O[e]
EtOAc/H2O[e]
3
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
10
EtOAc/H2O (5:1, v/v)
r.t., 7 h
9
3
4
85[f]
<5
62
67
<5
10
OR
Cl2 or ClOH
Cl2 or ClOH
5a, 10
6a
2
(for 5a)
0.5
0.5
3
R = H (4a), Me (9)
B[b]
Base (NaOH or NaOCl)
(R = H)
B
Cl
O– Na+
CO2Me
O
B[c]
3
12
CO2Me
[1,3]
Cl2 or ClOH
7a
[a] Determined by 1H NMR analysis. [b] KHSO4 (2 equiv.) was added as an
additive. [c] NaOCl (10% aq.) was used instead of NaOCl·5H2O. [d] Organic
solvent/H2O (1:1, v/v). [e] Organic solvent/H2O (5:1, v/v). [f] Isolated yield.
11
12
Scheme 4. Control experiments for the regioselective chlorination of 4a.
To understand the ortho-/para-selectivity observed for the
chlorination of 1-naphthol 4a, several control experiments were
conducted. First, no isomerization was observed from isolated
ortho-product 7a to para-product 5a under our acidic conditions
(Scheme 4a).[4e,13] Moreover, the reaction of the methyl ether 9
under acidic conditions using NaCl and Oxone afforded the
corresponding para-chlorinated product 10 selectively in 79%
yield (Scheme 4b). Notably, a lower reaction rate was observed
In contrast to the chlorination of 2-naphthols, which
proceeded exclusively at the 1-position under acidic or basic
conditions, the regioselectivity of the reaction of 1-naphthols and
phenols depended on the reaction conditions and/or steric and
electronic effects of the substituents at the ortho- and para-
positions. A series of 1-naphthols 4 and phenols 13 were
examined under acidic and basic conditions using NaCl/Oxone
(Method A) or NaOCl·5H2O (Method B), respectively (Scheme
5).[16] 2-Methyl-1-naphthol 4b afforded the para-chlorinated
product 5b or ortho-chlorinated product 7b selectively under
for
9
under identical conditions compared to 4a, and
dearomatized product 6a was not observed even in the
presence of 2 equivalents of NaCl (for comparison, see: Table 2,
entry 2). This might be due to lower local nucleophilicity at the
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10.1002/ejoc.201801063
European Journal of Organic Chemistry
COMMUNICATION
acidic or basic conditions, respectively. Similarly, 4d bearing
ester and methyl substituents at the ortho- and para-positions,
respectively, afforded the corresponding 5d and 7d selectively
depending on the conditions used. On the other hand, since the
electrophilic aromatic substitution reaction proceeded at less-
hindered 2-postions of 4-methyl-1-naphthol (4c) and 4e, a 4-
phenyl analogue of 4d, only ortho-chlorinated products 7c and
7e were obtained selectively under both acidic and basic
conditions.
On the other hand, the chlorinative dearomatization of
phenols 13a and 13b under acidic conditions using NaCl and
Oxone proceeded efficiently at the most nucleophilic and less-
hindered para- or ortho-positions to afford the corresponding
para- (14a) or ortho-product (15b), respectively, in good yields.
In sharp contrast, the reaction of 13a using NaOCl·5H2O under
basic or acidic[9] conditions gave a complex mixture of many
unidentified products, whereas a sluggish reaction of 14a
afforded the both ortho- and para-products 14b and 15b in low
yield. These results demonstrated again the utility of the
transient generation of chlorinating species instead of
stoichiometric reagents to induce high chemoselectivity.
NaCl (1 equiv.), Oxone (1 equiv.) (Method A)
or NaOCl·5H2O (2 equiv.) (Method B)
4, 13
5 + 7, 14 + 15
EtOAc/H2O, r.t.
OH
OH
O
Conclusions
Cl
A practical and efficient chlorinative dearomatization of arenols
was developed using transient chlorinating species generated in
situ from inexpensive sodium chloride and Oxone as a Cl source
and oxidant, respectively. Chemoselective chlorination could be
achieved under these mild conditions that maintained a low
concentration of the transient chlorinating species. Moreover,
regioselective chlorination or chlorinative dearomatization of 1-
naphthols was also achieved depending on the use of different
reaction conditions.
Cl
4b
5b
7b
n.d.
64%
Method A, 2 h:
Method B, 1 h:
67%
14%
O
OH
OH
Cl
Cl
5c
n.d.
n.d.
4c
7c
64%
52%
Method A, 1 h:
Method B, 1 h:
O
OH
O
Acknowledgements
Cl
CO2Me
CO2Me
CO2Me
tBu
CO2Me
Financial support for this project was partially provided by
JSPS.KAKENHI (15H05755, 15H05484, 18H01973), and the
Program for Leading Graduate Schools: IGER Program in Green
Natural Sciences (MEXT). We are grateful to the Kaneka
Corporation for providing NaOCl·5H2O.
Cl
7d
n.d.
70%
5d
4d
Method A[a], 1 h: 86%
Method B, 3 h:
10%
O
OH
O
Cl
CO2Me
CO2Me
Keywords: chlorination • dearomatization • oxidation • phenol •
chemoselective • regioselective
Ph Cl
Ph
4e
Ph
7e
72%
80%
5e
n.d.
n.d.
[1]
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Method A[a][b], 2 h:
Method B, 3 h:
O
O
OH
Cl
tBu
tBu
tBu
tBu
tBu
Cl
13a
14a
67%
n.d.
14b
n.d.
n.d.
Method A, 3 h:
Method B[c], 12 h:
OH
O
O
Cl
Ac Cl
Ac
13b
Ac
14b
7%
5%
15b
79%
20%
Method A, 3 h:
Method B[d], 12 h:
Scheme 5. Regioselective chlorination of 1-naphthols 4 and phenols 13.
Isolated yields are shown. [a] NaCl (2 equiv.) was used. [b] A tBuOMe/H2O
mixed solvent was used. [c] A messy reaction mixture was obtained. [d] 13b
was recovered in 50% yield.
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10.1002/ejoc.201801063
European Journal of Organic Chemistry
COMMUNICATION
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[16] The reaction of 1-naphthol using NaCl/Oxone afforded both ortho- and
para-chlorinated products in similar yield. The use of NaOCl·5H2O
gave ortho-chlorinated and 2,4-dichlorinated products. On the other
hand, unfortunately, the reactions of 1,1'-bi-2-naphthol and
5,5',6,6',7,7',8,8'-octahydro-1,1'-bi-2-naphthol using both methods gave
a complex reaction mixture. See Supporting Information for details.
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10.1002/ejoc.201801063
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Chlorinative Dearomatization*
Muhammet Uyanik, Naoto Sahara,
Kazuaki Ishihara*
Page No. – Page No.
Regioselective Oxidative Chlorination
of Arenols Using NaCl and Oxone
A practical and efficient chlorination of naphthols and phenols was developed using
transient chlorinating species generated in situ from inexpensive sodium chloride
and Oxone as a Cl source and oxidant, respectively, under mild conditions.
This article is protected by copyright. All rights reserved.