Room temperature C(sp2)-H oxidative chlorination: Via photoredox catalysis

Article abstract of DOI:10.1039/c7sc03010j

Photoredox catalysis has been developed to achieve oxidative C-H chlorination of aromatic compounds using NaCl as the chlorine source and Na₂S₂O₈ as the oxidant. The reactions occur at room temperature and exhibit exclusive selectivity for C(sp²)-H bonds over C(sp³)-H bonds. The method has been used for the chlorination of a diverse set of substrates, including the expedited synthesis of key intermediates to bioactive compounds and a drug.

Full text of DOI:10.1039/c7sc03010j

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DOI: 10.1039/C7SC03010J
Photoredox catalysis has been developed to achieve room temperature oxidative C-H
chlorination of aromatic compounds using NaCl as the chlorine source and Na2S2O8 as the
oxidant.

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DOI: 10.1039/C7SC03010J
Journal Name
ARTICLE
Room temperature C(sp2)-H oxidative chlorination via photoredox
catalysis
Lei Zhanga and Xile Hu*a
Received 00th January 20xx,
Accepted 00th January 20xx
Photoredox catalysis has been developed to achieve oxidative C-H chlorination of aromatic compounds using NaCl as the
chlorine source and Na2S2O8 as the oxidant. The reactions occur at room temperature and exhibit exclusive selectivity for
C(sp2)-H bonds over C(sp3)-H bonds. The method has been used for the chlorination of a diverse set of substrates,
DOI: 10.1039/x0xx00000x
www.rsc.org/
including the expedite synthesis of key intermediates to bioactive compounds and
a
drug.
In Nature, halogenases have been evolved to carry out C-H
chlorination using the benign chloride anion in an oxidative
manner.7 Inspired by Nature, synthetic systems for oxidative
chlorination have been developed,8-9 but their scope and
selectivity remain to be improved. Additionally, the majority of
these systems employ H2O2 as the oxidant and operate under
acidic conditions,10 which pose a constraint in functional group
compatibility. Konig, Wolf, and co-workers11 recently reported
an elegant photoredox approach for oxidative chlorination
using dioxygen as the oxidant. Photoexcitation of the organic
dye, riboflavin tetraacetate (RFT), followed by quenching with
O2, generated H2O2 in situ, which oxidized acetic acid to
peracetic acid. The latter in turn oxidized Cl- to OCl-, which was
the active species for electrophilic chlorination of a number of
aromatic substrates. Notwithstanding the novelty of this
approach, at this early stage of its development, 6-10
equivalents of acetic acids, HCl, and p-methoxy benzyl alcohol
(to regenerate the dye) were necessary and the scope were
limited to simple arenes containing a methoxy, amino or
amide group. Zhang and co-workers12 used potassium
persulfate, a convenient inorganic oxidant for oxidative
chlorination. However, a high temperature (95~100 oC) was
needed and a sulphonamide group was essential to improve
efficiency through formation of a proposed N-Cl intermediate.
In several cases C(sp3)-H chlorination was preferred over
C(sp2)-H chlorination.
Chlorinated aromatic compounds exist extensively as natural
products, synthetic pharmaceuticals, pesticides, and materials
(Scheme 1).1 Moreover, they are versatile start materials and
synthetic intermediates in organic synthesis, for example,
through transition-metal-catalysed cross-coupling reactions.
Thus, efficient methods to synthesize chlorinated aromatic
compounds are of significant interest. Direct C(sp2)-H
electrophilic chlorination is an appealing strategy for aryl
chlorination, because no directing or leaving group needs to be
pre-installed on the substrates, leading to wider substrate
availability, lower cost, and better step-economy. However,
traditional electrophilic chlorination methods employ either
toxic, hazardous, and corrosive chlorine gas, or organic
electrophilic
chlorination
reagents,
such
as
N-
Chlorosuccinimide (NCS) and tBuOCl,2-6 which are prepared
from Cl2 and generate significant amounts of organic wastes.
NH2
COOH
H2N
Cl
OMe
H
N
N
O
Cl
Baclofen
Metoclopramide
O
O
N
Cl
N
A key challenge in electrophilic C(sp2)-H chlorination is to
achieve selectivity over competing C(sp3)-H chlorination.
However, literature data show the opposite selectivity for
HO
H
OH
NH2
Cl
S
OH
OH
α
-carbonyl C(sp3)-H
OH
O
O
O
substrates containing weak benzylic and
bonds. For example, acetophenone was exclusively chlorinated
at the
-C(sp3) position under oxidative chlorination conditions
Chlortetracycline
Clopidogrel
α
Scheme 1: Selected examples of pharmaceuticals and natural
products containing an aryl-Cl moiety
using either H2O2 or O2 as oxidant [Eq. (1)].11 Likewise, methyl
4-(chloromethyl)benzoate was only chlorinated at the benzylic
C(sp3) position using K2S2O8 as oxidant at 100oC [Eq. (2)].12 To
further illustrate this issue, toluene, which contains both
C(sp2)-H bonds and benzylic C(sp3)-H bonds, was subjected to
oxidative chlorination conditions at 100 oC using K2S2O8 as
oxidant [Eq. (3)]. The C(sp3)-H chlorination product,
chloromethybenzene, was obtained in 45% yield while the
C(sp2)-H chlorination product was not formed. This undesired
selectivity probably originates from the frequent formation of
a Dr. L. Zhang, and Prof. Xile Hu
Laboratory of Inorganic Synthesis and Catalysis, Institute of Chemical Sciences and
Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), ISCI-LSCI BCH 3305,
1015 Lausanne (Switzerland)
E-mail: xile.hu@epfl.ch
Homepage: http://lsci.epfl.ch
†Electronic Supplementary Information (ESI) available: For ESI and other electronic
format See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Table 1: Optimization of reaction conditions[a]
Cl radical under electrophilic chlorination conditions, which
reacts faster with weaker C(sp3)-H bonds than with the
stronger C(sp2)-H bonds. For the broad applicability of
oxidative C(sp2)-H chlorination, this selectivity problem has to
be resolved. Another challenge is to develop methods that
operate under mild conditions, which are essential to achieve
high functional group compatibility. Here we describe a room-
temperature oxidative chlorination method to selectively
View Article Online
DOI: 10.1039/C7SC03010J
catalyst
8 (y equiv.)
photoredox
Na2S2O
Cl
+
Cl
+
+
NaCl
equiv)
(x
CH CN/H O
(1:1)
RT
2
blue3LED
(20W),
Cl
2a'
1
2a
2a''
Yield
(%)
catalyst
NaCl
Na2S2O
equiv.)
8 (y equiv.)
Entry
photo
(x
2a
2a'
2a''
chlorinate aryl C-H bonds in the presence of benzylic and α-
1
2
3
3.0
1.6
1.6
1.6
1.6
1.6
1.6
0
56%
0%
0%
0%
0%
0%
0%
34%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
mol%)
mol%)
carbonyl C(sp3)-H bonds. Key to achieve this selectivity is the
use of photoredox catalysis,13-16 which is able to generate
efficiently the electrophilic chlorination reagent in situ while
supressing the detrimental Cl radical. The scope, application,
and preliminary mechanistic study are described.
(3
4
3.0
3.0
3.0
3.0
3.0
3.0
(3
5
3
mol%)
mol%)
mol%)
(10
4
6
(10
5[b]
6
3
0
3
(3
O
O
RTF
HOAc, pMBA
HCl
mol%),
(10
Cl
7
mol%)
(3
(1)
Ref
[11]:
[12]:
work:
nm
MeCN, air, 455
-
2+ 2Cl-
+ PF6
F3C
63%
F
tBu
N
N
K2S2O8 4.0
(
equiv.
Cl
)
F
Ref
N
N
N
N
N
(2)
(3)
RuII
N
Ir
CH CN/sat. NaCl
(1:1)
3
MeOOC
MeOOC
100 o
C
N
F
67%
N
tBu
F
K2S2O8 4.0
(
equiv.
)
F
3C
Cl
This
3
4
,
Cl2
,
Ru(bpy)3
Ir[dFppy]2(dtbbpy)PF6
CH CN/sat. NaCl
(1:1)
3
100 o
C
45%
O
CN
OH
We commenced our study using toluene as the model
substrate (Table 1). The selective chlorination of toluene is
relatively challenging compared to other election-rich aromatic
compounds. The methyl group is not a strong election-
donating group and several side products such as
benzaldehyde and chloromethylbenzene might form. We
aimed for an “open-flask” method, so the optimizations were
conducted under air (for details, see table S1, SI). To our
Br
HO
Br
O
O
CN
Br
Br
5
6
9,10-anthracenedicarbonitrile
Eosin
Y,
[a] Reaction conditions: Toluene (0.25 mmol) in CH3CN/H2O (1 mL) at
25 °C. Yields were obtained from the crude reaction mixture by GC
delight, selective C(sp2-H) chlorination could be obtained at relative to mesitylene internal standard. [b] Without light.
.
room temperature using Ru(bpy)3Cl2 6H2O
3 (3 mol%) as
photocatalyst, Na2S2O8 (1.6 equiv.) as oxidant, NaCl (3.0 equiv.)
as the chlorine source, CH3CN/H2O (1:1) as solvent, yielding
56% of 1-chloro-2-methyl-benzene 2a and 34% of 1-chloro-4-
methyl-benzene 2a’ (entry 1). The use of other commonly used
With the optimized conditions in hand, we studied the scope
and limitation of this C-H chlorination method (Table 2). We
first explored monosubstituted aromatic compounds. The
substrates with an electron-donating group (isopropyl, 2b
;
photocatalysts such as Ir[dFppy]2(dtbbpy)PF6
4
(entry 2), Eosin
(entry 4) led
methoxy, 2c) on the phenyl ring were chlorinated in good
yields, and both para- or ortho- chlorinated products were
formed. Substrates bearing functional groups such as –CN (2d),
ester (2e), and halogen (2f and 2g) were all chlorinated in good
yields as well. 1-(3-bromopropyl)-4-chlorobenzene (2g) is an
important building block for the synthesis of Parogrelil
hydrochloride, a medication for the treatment of intermittent
claudication. Previously17 it took four steps to prepare this
compound, whereas using our method 1-(3-bromopropyl)-4-
chlorobenzene (2g, 39%) and its isomer 1-(3-bromopropyl)-4-
chlorobenzene (2g’, 33%) were prepared in one step. The two
isomers were easily separated by column chromatography. In
addition, aromatic compounds containing unprotected tertiary
Y
5
(entry 3) and 9,10-anthracenedicarbonitrile 6
to no yield of chlorination. Control experiments showed that
under identical conditions but in the absence of light (entry 5),
.
Ru(bpy)Cl2 6H2O (entry 6), or Na2S2O8 (entry 7), no chlorination
was obtained. It should be noted that no chlorination of
benzylic C-H bond was observed.
alcohol (2h) and amide groups (2i, 2j) were suitable substrates.
In agreement with the limiation of electrophilic chlorination,
substrates containing only an election-withdrawing group such
as nitrobenzene (2k) and (trifluoromethoxy)benzene (2l) could
not be chlorinated by this method.
However, substrates with election-withdrawing group(s) could
be used if they also contain an election-donating group on the
2 | J. Name., 2012, 00, 1-3
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ARTICLE
aryl ring, for example, an alkoxy group (2m
-
2v, 2y, 2z, 2aa, Table 2. Scope of C(sp2)-H chlorination[a]
View Article Online
DOI: 10.1039/C7SC03010J
Cl2.6H O
2ac, 2ad). Thus, electron-withdrawing functional groups such
as ester (2p 2r), trifluoromethyl (2x), amide (2o), halogen (2t
2aa), and sulfonate (2s) were all comptaible. Even strong
election-withdrawing groups such as cyano (2m) and nitro (2q
or
5 mol%)
(3
Ru(bpy)3
2
,
,
or
Na2S2O
2.0
8 (1.6
equiv.)
blue LED
R
+
NaX
R
equiv)
(3.0
CH CN/H O
(1:1),
(20W)
3
2
X
=
X
Cl, Br
2
1
)
groups were tolerated. Although mono-substituted substrates
are chlorinated at both ortho and para positions due to the
inate reactivity of Cl+ (see below), complate site selectivity
could be achieved for disubstitued substrates bearing
functional groups at either 1,4 and 1,2 positions. In these cases
the chlorination occured exclusively ortho to the electron-
donating group. It is noted that exlusive C(sp2)-H chlorination
OMe
OMe
Cl
Cl
Cl
Cl
[b], [e]
[b], [e]
2b
2d
2f
2c,
52%
49%
50%
66%
47%
39%
,
,
2b',
2c',
30%
28%
3 CN
3 CN
3OAc
3OAc
Cl
Cl
2d' 42%[c]
Cl
Cl
Cl
2e' 42%[d]
2e
,
,
,
occurred also for substates containing an acyl group (2n
2ac). Previous electrophilic chlorination methods normally
leads to
-carbonyl C(sp3)-H chlorination for acetophenone
substrates.11-12 In addition to alkoxy groups, the amide group
2w and 2x) could be used to promote the chlorination of
electron-poor substrates. Chlorination of mesitylene gave the
monochlorinated product in 76% yield 2ae). The
, 2u,
3 Cl
OH
3
Cl
3 Br
Br
3
Cl
Cl
35%[d]
Cl
,33%[c]
2g
α
,
,
2f'
,
2g'
H
N
H
N
OH
(
O
O
Cl
Cl
Cl
Cl
30%[c]
[c]
2h
2i
58%
N
52%
,
,
2h
2i'
,
,17%
(
NO2
OCF3
photocatalytic oxidative halogenation strategy was also
applicable to bromination. For example, bromination of
O
Cl
67%[b]
0%[b]
0%[b]
2l
,
2j
2k
2n
,
,
anisole
methoxybenzene (2ag, 79%) and N-(4-bromophenyl)acetamide
2ag, 96%), respectively. However, iodination of anisole was
and
N-phenylacetamide
gave
1-bromo-4-
OMe
Cl
82%[b]
OMe
OMe
Et2N
O
Cl
(
NC
Cl
72%[c]
O
O
2o
86%[b]
not successful, possibly due to over-oxidation of iodine.
2m
,
,
,
OMe
OMe
OMe
NO2
2q
Cl
55%[c]
MeOOC
Cl
O
Cl
84%[b]
2p
2r 77%[b]
,
,
,
OMe
OEt
OMe
O
MeO
S
Cl
Cl
79%[b]
,
Cl
Cl
O
2s
O
2u
42%[c]
62%[b]
2t
,
,
H
H
N
OEt
N
O
O
NC
Cl
78%[b]
F3C
Cl
Cl
89%[b]
MeOOC
2w
Cl
88%[b]
2v
2x
,
,
,
OMe
OMe
OMe
Cl
CN
Cl
COOMe
Br
[c]
[b]
91%[c]
2y
2z
2aa
,
,73%
,78%
O
Cl
Cl
O
MeO
MeO
Cl
68%[b]
2ab
2ac' 27%[c]
,
2ac 42%
,
,
Cl
MeO
COOMe
Cl
MeO
COOMe
Cl
2ad 57%
20%[b]
76%[b], [e]
2ae
,
,
2ad'
,
H
OMe
N
O
Br
Br
79%[b]
96%[b]
2ag
,
2af
,
[a] Reaction conditions: Substrate (0.5 mmol) in CH3CN/H2O (2 mL) at
25 oC. Unless otherwise specified, yields shown are isolated yields.
Reaction time: 24 h.; [b] 3 mol% of Ru(bpy)3Cl2.6H2O, 1.6 equiv of
Na2S2O8; [c] 5 mol% of Ru(bpy)3Cl2.6H2O, 2.0 equiv of Na2S2O8; [d] 5
mol% of Ru(bpy)3Cl2.6H2O, 1.6 equiv of Na2S2O8. [e] Substrate (0.25
mmol) in CD3CN/H2O (1 mL). Yields were determined by 1H NMR
relative to mesitylene internal standard. Reaction time: 15 h.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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benzene 2a and 7% of 1-chloro-4-methyl-benzene 2a’
View ArticlewOnelirnee
To demonstrate the potential utility of this oxidative
chlorination method, it was applied for the expedite synthesis
formed. The yields were much lower than the reaction
DOI: 10.1039/C7SC03010J
conducted under illunination for the whole duration. This
result indicates that a chain reaction based on activation
peroxodisulfate is unlikely.
of some drugs and their key precursors.
Glibenclamide, a medication used to treat type 2 diabetes. This
compound could be obtained directly from in 80% yield [Eq.
8 is the precursor of
7
Ru(bpy)3(ClO4)3 (3.2 equiv.)
(4)]. Clofibrate (10a) is a lipid-lowering agent used for
controlling the high cholesterol and triacylglyceride level in the
blood. This compound could be obtained in one-step using our
+
+
A
NaCl
3.0
CH CN/H O
R.T.
Cl
56%
Cl
(1:1),
3
2
2a
,
2a'
36%
,
equiv.
C-H chlorination method from its precursor
9 in 57% yield,
Na
1.6
equiv.
2S2O8
(
)
Cl
+
+
B
C
NaCl
3.0
together with 28% of the dichlorination product [Eq. (5)].
Chorination of Boc-protected aminobenzene 11 gave 12a
(58%) and 12a’ (12%) [Eq. (6)]. The major product 12a is a
precursor for synthesis of several gastroprokinetic agents
including Metoclopramide, Renzapride, and Cisapride.
Metoclopramide is one of the most widely used medicines for
treating and preventing nausea and vomiting, and it is listed on
the World Health Organization's List of Essential Medicines.
CH CN/H O
(1:1)
3
2
90 o
C
2a''
26%
,
equiv.
dichlorinated
products
+
+
HClO
3.0
CH CN/H O
(1:1)
3
2
Cl
33%
Cl
2a'
R.T.
~22%
2a
,
30%
,
equiv.
Scheme 2. Experiments to probe the actual oxidant and
chlorinating species in the current system
OMe
OMe
Cl2.6H O
2
mol%)
(3
H
Ru(bpy)3
H
N
(4)
N
Na2S2O
Cl
8 (1.6 equiv.)
Oxidative chlorination is proposed to occur via two major
O
CH CN/H O
(1:1)
O
3
2
20-21
pathways.12,
The first pathway (See supporting
blue LED
Precursor of Glibenclamide,
(20W)
,
7
8
80%
information, Scheme S1, Path A) involves oxidation of chloride
anion (Cl-) to chloride cation or its equivalent ("Cl+")22, which
reacted with aromatic compounds to give the chlorination
products. The second pathway (Scheme S1, Path B) involves
oxidation of aromatic compounds to aromatic radicals, which
then react with chloride anion to give the chlorination
O
O
Cl2.6H O mol%)
O
Ru(bpy)3
(3
2
O
O
OEt
OEt
+
Na2S2O
8 (1.6 equiv.)
O
(5)
OEt
Cl
Cl
Cl
Clofibrate
CH CN/H O
(1:1)
3
2
blue LED
(20W)
9
10a 57%
10a'
, 28%
,
3+
Cl
products. According to its oxidative potential, Ru(bpy)3
Cl2.6H O mol%)
BocHN
OMe
BocHN
OMe
Ru(bpy)3
(5
2
(E1/2III/II = +1.29 V vs SCE) is not able to oxidize toluene (+2.28 V
BocHN
OMe
+
(6)
Na2S2O
8 (2.0 equiv.)
COOMe
Cl
COOMe
3+
CH CN/H O
(1:1)
3
2
COOMe
vs SCE). To confirm this, the reaction of Ru(bpy)3 with
blue LED
Precursor of
(20W)
Metoclopramide,
11
12a'
12%
,
12a
58%
,
toluene was monitored by UV-Vis spectroscopy. In CH3CN/H2O
(1:1), Ru(bpy)33+ alone slowly decays into Ru(bpy)32+ (Figure S1,
SI). When toluene (20 equiv.) was added to the solution
containing Ru(bpy)33+, the reduction rate remained constant
(Figure S2, SI). When NaCl (60 equiv.) was added to the
solution, the reduction rate of Ru(bpy)33+ became much faster
(Figure S3, SI). These results suggest that Ru(bpy)33+ oxidizes Cl-
rather than the aromatic substrates in the catalysis. Due to the
presence of water, the “Cl+” species might exist in the form of
HClO, which worked as the actual chlorinating species. To test
this hypothesis, HClO was used as the chlorinating reagent for
The mechanism of the reactions was then probed. It is well
established that under light illumination, the excited
2+
2-
3+
·-
*Ru(bpy)3 reacts with S2O8 to give Ru(bpy)3 and SO4 ,
2+
3+
which further reacts with Ru(bpy)3 to give Ru(bpy)3 and
2- 18
·-
SO4
.
Thus, either Ru(bpy)33+ or SO4 or both might be the
actual oxidant in this system. To probe these possibilities,
3+
3+
Ru(bpy)3 was prepared chemically.19 With Ru(bpy)3 (3.2
equiv.; in accord with the loading of Na2S2O8 in the catalytic
system (1.6 equiv.)) as the sole oxidant, the reaction of toluene
(1.0 equiv.) with NaCl (3.0 equiv.) gave 1-chloro-2-methyl-
benzene (2a, 56%) and 1-chloro-4-methyl-benzene (2a’, 36%)
in 30 min at room temperature (Scheme 2, A). The faster rate
of this reaction compared to catalysis reflects the higher
the chlorination of toluene. 1-chloro-2-methyl-benzene (2a
33%), 1-chloro-4-methyl-benzene 2a’ 30%) and some
,
(
,
3+
3+
dichlorinated products (~22%) were detected after 15 h
(Scheme 2, C). The product distribution is similar, although not
exactly the same, as that of the photocatalytic reaction. The
loading of Ru(bpy)3 in the former. Thus, Ru(bpy)3 is a
competent oxidant for the chlorination. Heating a solution of
o
·- 12
Na2S2O8 at 90 C is known to generate SO4 . The reaction of
toluene (1.0 equiv.) with NaCl (3.0 equiv.) was then conducted
in the presence of 1.6 equiv. of Na2S2O8 at 90 oC (Scheme 2, B).
However, no C(sp2)-H chlorination occurred; instead, a small
amount of chloromethylbenzene (2a'', 26%), the C(sp3-H)
chlorination product, was formed (Scheme 2, B). This result
suggests that SO4·- is not the major oxidant to react with the
substrates in our system. To probe whether the chlorination
reaction operates via a chain reaction mechanism after
dichlorinated products might originate from
concentration of HClO in the stoichiometric reaction. Overall,
the result in Scheme suggests HClO as probable
chlorinating species in the photocatalytic reaction.
According to the above results, a tentative catalytic cycle is
a
high
2
a
2+
proposed in Figure 1. Upon photoirradiation of Ru(bpy)3
,
*Ru(bpy)3 was formed 23. Reaction of *Ru(bpy)3 with
2+
2+
3+
·-
2-
Na2S2O8 gives Ru(bpy)3 and SO4 . The latter oxidizes
activation of S2O8 under the photocatalytic conditions, the
3+
Ru(bpy)32+ to give a further equivalent of Ru(bpy)33+. Ru(bpy)3
chlorination of toluene was conducted under illuminated for
40 minutes, and then the light was removed while allowing the then oxidize Cl- to Cl+ or its equivalent (HClO), probably via a Cl
reaction for 15 further hours. Only 11% of 1-chloro-2-methyl-
radical intermediate. When the chlorination of toluene was
4 | J. Name., 2012, 00, 1-3
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Chemical Science
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Journal Name
ARTICLE
2
S. M. Maddox, C. J. Nalbandian, D. E. Smith, J.VLie.wGAurtsictleafOsnolinne,
DOI: 10.1039/C7SC03010J
T. Hering, B. König, Tetrahedron 2016, 72, 7821.
X. Xiong, Y.-Y. Yeung, Angew. Chem. Int. Ed. 2016, 55, 16101.
Y. Zhang, K. Shibatomi, H. Yamamoto, Synlett 2005, 2837.
G. K. S. Prakash, T. Mathew, D. Hoole, P. M. Esteves, Q.
conducted in the presence of (2,2,6,6-Tetramethylpiperidin-1-
yl)oxyl (TEMPO, 3 equiv), the chlorination was completely
inhibited, supporting the involvement of Cl radical. The further
oxidation of Cl radical must be very fast as no C(sp3-H)
chlorination was observed. Finally, the chlorinating species
reacts with an aromatic compound to effect the C(sp2-H)
chlorination. This step likely occurs via an electrophilic addition
process rather than an aromatic substitution process. To verify
this, a 1:1 mixture of toluene and cyclohexene was subjected
to the chlorination. After 1 h, 2-chlorocyclohexan-1-ol (~20%)
and 1,2-dichlorocyclohexane (2%) were generated while no
chlorination of toluene was observed. This result supports the
electrophilic addition pathway.
Org. Lett. 2015, 17, 1042.
3
4
5
6
Wang, G. Rasul, G. A. Olah, J. Am. Chem. Soc. 2004, 126
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7
8
9
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2013, 355, 1077.
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16 K. L. Skubi, T. R. Blum, T. P. Yoon, Chem. Rev. 2016, 116
2-
S2O8
*RuII
Light
-
2-
+
SO4
SO4
-
2-
SO4
SO4
RuII
RuIII
,
10035.
via Cl
Cl-
"Cl+"
17 C. H. Patel, S. Dhanani, C. P. Owen, S. Ahmed, Bioorg. Med.
Chem. Lett. 2006, 16, 4752.
(HClO)
18 M. Neumann-Spallart, K. Kalyanasundaram, C. Grätzel, M.
Grätzel, Helv. Chim. Acta 1980, 63, 1111.
-H+
19 H. Lv, J. Song, Y. V. Geletii, J. W. Vickers, J. M. Sumliner, D. G.
Musaev, P. Kögerler, P. F. Zhuk, J. Bacsa, G. Zhu, C. L. Hill, J.
Am. Chem. Soc. 2014, 136, 9268.
20 A. Ledwith, P. J. Russell, J. Chem. Soc., Chem. Commun. 1974,
291.
Cl
Cl
H
Figure 1. Proposed mechanism of the photocatalytic oxidative
chlorination reaction
21 A. Ledwith, P. J. Russell, Journal of the Chemical Society,
Perkin Transactions 2 1975, 1503.
22 C. G. Swain, D. R. Crist, J. Am. Chem. Soc. 1972, 94, 3195.
23 A. Company, G. Sabenya, M. González-Béjar, L. Gómez, M.
Clémancey, G. Blondin, A. J. Jasniewski, M. Puri, W. R.
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Conclusions
In conclusion, we have developed a photoredox catalytic
method for C(sp2)-H oxidative chlorination at room
temperature. Our method employs abundant and non-toxic
NaCl as the chlorine source and inexpensive Na2S2O8 as the
oxidant, which offer a practical and convenient alternative to
existing electrophilic chlorination methods. The mild
conditions lead to broad scope and high functional group
compatibility. The synthetic utility of this method is
demonstrated in the chlorination of a diverse set of substrates,
including the expedite synthesis of key intermediates to
bioactive compounds and a drug.
Acknowledgements
This work is supported by the EPFL and the Swiss National
Science Foundation (Grant 200020_152850/1). We thank Dr.
Joel Teuscher and Prof. Jacques-Edouard Moser (EPFL) for
discussion.
Notes and references
1
a) J. Fauvarque, Pure Appl. Chem. 1996, 68, 1713. b) G. W.
Gribble, Acc. Chem. Res. 1998, 31, 141.
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