Cu-catalyzed direct ortho-chlorination/-oxygenation of aryls: Switching of oxidant, control the diversity of products

Article abstract of DOI:10.1016/j.tetlet.2018.11.071

Highly regioselective copper catalyzed ortho-chlorination of aryl pyridines was achieved with TBHP as oxidant and 1,2-dichloroethane as chlorinating agent for the first time. Switching the oxidant from TBHP to benzoyl peroxide under identical reaction conditions effects ortho-oxygenation.

Full text of DOI:10.1016/j.tetlet.2018.11.071

Accepted Manuscript
Cu-Catalyzed Direct ortho-Chlorination/-Oxygenation of Aryls: Switching of
Oxidant, Control the Diversity of Products
Vinayak Botla, Ashok Akudari, Chandrasekharam Malapaka
PII:
S0040-4039(18)31425-4
https://doi.org/10.1016/j.tetlet.2018.11.071
TETL 50456
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Reference:
Tetrahedron Letters
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Please cite this article as: Botla, V., Akudari, A., Malapaka, C., Cu-Catalyzed Direct ortho-Chlorination/-
Oxygenation of Aryls: Switching of Oxidant, Control the Diversity of Products, Tetrahedron Letters (2018), doi:
https://doi.org/10.1016/j.tetlet.2018.11.071
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Cu-Catalyzed Direct ortho-Chlorination/-
Oxygenation of Aryls: Switching of Oxidant,
Control the Diversity of Products.
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Vinayak Botlaa, Ashok Akudariab and Chandrasekharam Malapakaab

1
Tetrahedron Letters
Cu-Catalyzed Direct ortho-Chlorination/-Oxygenation of Aryls: Switching of
Oxidant, Control the Diversity of Products.
Vinayak Botlaa, Ashok Akudariab and Chandrasekharam Malapakaab
aP&FM Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, India.
bAcademy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Highly regioselective copper catalyzed ortho-chlorination of aryl pyridines was achieved with
TBHP as oxidant and 1,2-dichloroethane as chlorinating agent for the first time. Switching the
oxidant from TBHP to benzoyl peroxide under identical reaction conditions effects ortho-
oxygenation.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Copper
Directing group
Phenyl pyridine
Chlorination
Benzoxylation
1. Introduction
presence of oxygenated aryls in many natural products and
pharmaceuticals.8 Further benzoxylated aryls have potential
Dense population of C-H bonds is present on the surface of
organic and biomolecules and hence the construction of
regioselective C-C and C-heteroatom bonds is attracting
applications as alternative electrophilic partners in palladium-
free cross couplings and also as latent phenols.9
tremendous importance.1 Control of site selectivity is
a
Scheme 1. ortho-chlorination and -benzoxylation of 2-aryl
challenging task in C-H functionalization of arene derivatives
due to the subtle differences among the C-H bonds present in the
substrate.2 Further formation of diverse products from the same
substrate with site selectivity poses much bigger challenge. In
this direction, several molecular architectures have been realized
with a range of directing group (DG) assisted reactions (transient,
traceless, easily removable, pharmacophorically significant, etc.,)
that override innate reactivity and prevent prefunctinalization of
the substrates.3 However pyridine continues to occupy central
position in these reactions, attributed mainly to its ability to
selectively direct at ortho- or meta-positions depending on the
transition metal/reaction conditions employed.4 Many
investigators reported efficient transition metal catalyzed ortho-
halogenation and -benzoxylation of phenyl pyridines. However a
common and simple reaction protocol that effects either ortho-
chlorination or ortho-oxygenation would be a value added
commodity in chemist’s basket.5 Chlorine is known to be a
function by itself and a versatile functionality by virtue of its
lability towards electrophilic aromatic substitution as well as in
cross coupling reactions.6 Further similar to fluorine and unlike
bromine and iodine, many of the pharmaceutical compounds
enhance their biological activity with the incorporation of
chlorine in the molecule.7 Construction of C-O bond via aryl
benzoxylation is an important synthetic operation owing to the
pyridine.
Noteworthy are the reports by Sanford on the Pd catalysed C-H
chlorination by NCS as terminal oxidant, and electrophilic ortho-
chlorination of phenyl pyridine via C-Cl bond forming reductive
elimination.10Chlorination of phenyl pyridine was also effected
with the combination of CuCl2 and tetrachloroethane solvent,5a
and with Lithium halide in acetic acid.5b However both the
methods produce dichlorinated products in addition to the desired
mono ortho-chlorination product. Pd catalysed aryl chlorinations
with acyl chlorides proceed at 140 °C under inert reaction
conditions.5c Thus most of the reported reactions are plagued
with either one or more of the following limitations 1. expensive
catalyst, 2. high temperature conditions, 3. non-regioselectivity,
4. inert or oxygen atmosphere. We recently reported chlorination
———
 Corresponding author. Tel.: +91-40-27191710; fax: +91-40-27193186; e-mail: csmalapaka@csiriict.in

of aryls11c, iron catalyzed benzoxylation of N,N-dialkylanilines11d
and chelation assisted remote benzoxylation of 8-
amidoquinolines.11j Inspired by recent literature on copper
catalysed C-H functionalization5a,12 and prompted by our interest
on DG assisted iron or copper catalyzed C-H functionalization
reactions, we investigated on the pyridine directed regioselective
aryl C-H functionalisations. We herein report a typical example
of an interesting and efficient transition metal catalysed ortho-
selective mono-chlorination/benzoxylation of phenyl pyridines
wherein switching of oxidant (TBHP/BPO) result in the
divergence of products with inexpensive copper catalyst under
otherwise identical mild and easy to operate reaction conditions
(Scheme 1). DCE, a solvent in the benzoxylation reaction serves
additionally as a new chlorine source in aryl chlorinations, a
hither to unknown reaction. Our reaction protocol has several
advantages such as, 1. inexpensive copper catalyst 2. DCE
playing dual role as novel chlorination agent as well as solvent 3.
highly regioselective mono ortho-chlorination 4. switching
oxidant from TBHP to BPO produces regioselective oxygenated
product 5. mild and easy to operate reaction conditions.
reaction did not progress even when conducted at 60 °C, (Entry
1, 2 Table 1) however further increase of the reaction temperature
to 90 °C resulted in the formation of the desired product 2a, in
71% yield. Increased loading of the oxidant, TBHP (5-6 M in
decane) further improved the yield to 32%. To our delight, 5.0
equiv. of TBHP significantly improved the yield of the desired
product to 71% (Entry 3, Table 1). Other oxidants i.e., aq.
TBHP, DTBP, PhI(OAc)2, K2S2O8, DDQ, Benzoyl peroxide,
oxone and H2O2 were also screened to check the efficacy of the
aryl chlorination reaction (Entries 4-11, Table 1).
Scheme 2. Substrate scope of DG-assisted ortho-chlorination
of 2-aryl pyridines.a
Table 1. Optimization of the ortho-chlorination
S.No
Catalyst
Oxidant
(5.0 equiv)
TBHP
TBHP
TBHP
Aq. TBHP
DTBP
PhI(OAc)2
K2S2O8
DDQ
Temp °C
Yieldb(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Rt
60
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
-
-
71
32
46
36
-
18
Trace
-
20
48
62
26
33
55
-
BP
Oxone
H2O2
CuI
CuI
Cu(OAc)2
CuCl2
CuBr
CuBr2
Cu(OTf)2
FeCl3
FeCl2
Pd(OAc)2
[Ru(p-
cymene)Cl2]2
-
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
-
-
-
aThe reaction was performed with 1a (1.0 equiv), CuI (20 mol %), TBHP (5.0
equiv) in 1,2 DCE(2 mL) the mixture was heated in an oil bath at 90 °C for
24 h in a sealed tubetightly closed with screw cap.
21
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
90
90
90
90
90
90
90
-
22c
23d
24e
25f
26g
27h
CuI
CuI
CuI
CuI
CuI
CuI
59
68
73
69
65
71
We next turned our attention on catalytic activities of various
copper (Entries 12-16, Table 1), iron salts (Entries 17, 18, Table
1), palladium and ruthenium catalysts (Entries 19, 20, Table 1).
The reaction did not proceed in the absence of any catalyst and
CuI proved to be the best when loaded 20 mol% quantity for
the ortho-chlorination reaction. However with 10 mol% and 40
mol% of the catalyst loading, the reaction is not efficient (Entries
22, 23, Table 1). Among various halogen containing solvents
employed, 1,2-DCE proved to be the best, playing a duel role as
chlorine source and also as solvent for this directing group
assisted ortho-chlorination(See ESI for chlorinating solvent
optimization). Further it was found that excess quantity of 1,2-
DCE is required for the reaction to proceed (ESI). In our hands,
tetrachloroethane could not affect the chlorination under standard
reaction conditions (ESI). When dry 1,2-DCE was used, the
product was obtained in 73% yield (Entry 24, Table 1). When
aReaction Conditions: 1a (1.0 equiv), catalyst (20 mol %), oxidant (5.0
equiv), in 2 mL of 1,2-DCE stirred the reaction for 24 h. ball are isolated
yields, cCuI (10 mol %), dCuI (40 mol %) edry 1,2-DCE, funder
N2 atmosphere, gunder O2 atmosphere, hin the presence of additive (4 A°
Molecular Sieves).
Initially, 2-phenyl pyridine 1a was chosen as a model
substrate to examine the ortho-chlorination of aryls with various
catalysts, oxidants and solvents (Table 1). When the substrate 1a
(1.0 equiv.), was stirred at room temperature in presence of the
catalyst CuI (20 mol %) and the oxidant TBHP (2.0 equiv.) in
1,2-DCE, the starting material was recovered unreacted. The

3
the reaction was performed under N2 or O2 atmosphere, the yields
were comparable with air atmosphere conditions, indicating that
oxygen does not play significant role to improve the yield
(Entries 25, 26, Table 1). Neither the presence of additive (4 A°
Molecular Sieves) affected the yield of the reaction (Entry 27,
Table 1).
conditions, good yields of the ortho-chlorinated products were
obtained with electron withdrawing group present on para-
position of aryl ring (Scheme 2, 2l 65%). In addition, substrates
with heterocyclic motifs also showed good to moderate reactivity
towards ortho-chlorination under standard reaction conditions
and furnished 72, 74% of yields (Scheme 2, 2m, 2n). Substrates
bearing a pyrazole directing group underwent ortho-chlorination
smoothly with good yields of the products in 65%, 61%
respectively (Scheme 2, 2o, 2p). Quinolone and isoquinoline
directing groups also effected the ortho-chlorination producing
the desired products in good yields 65%, 67% respectively
(Scheme 2, 2q, 2r). The chlorination reaction works for bidentate
directing groups as well. The reaction proceeded smoothly on the
subistituted 8-amidoquinolines under standard reaction
conditions and the chlorination occurred at remote C5-position
with good yields 71%, 65% (scheme 2, 2s and 2t) demonstrating
the efficacy of the chlorination protocol. However other directing
groups i.e., benzamide and 2-aryl benzothiazoles failed to effect
the chlorination under standard reaction conditions (Scheme 3).
Scheme 3. Other DG-assisted ortho-chlorination.
However, interestingly when TBHP is replaced with benzoyl
peroxide as the oxidant, we observed the formation of ortho-
benzoxylation product instead of ortho-chlorination under
otherwise identical conditions. Portion wise addition of 2.5
equiv. (5×0.5 equiv./0.5 h) of benzoyl peroxide was found to be
adequate for the successful benzoxylation in good yields.
Scheme 5. Mechanistic insights.
Scheme 4. Substrate scope of DG-assisted ortho-
benzoxylation of 2-aryl pyridines.a
Interestingly, highly selective mono ortho-benzoxylation of 2-
phenyl pyridine was achieved successfully under the same set of
reaction conditions when benzoyl peroxide was employed instead
of TBHP as an oxidant (Scheme 4). The benzoxylation of phenyl
pyridine produced the desired product in 70% yield (Scheme 4,
3a), while 4-methoxy, 4-chloro, 4-phenyl and 1-naphthyl
substituted aryl pyridines also underwent selective ortho-
benzoxylation and afforded 65%-78% yields of the benzoxylated
products (Scheme 4, 3b-3e) Heteroaryl moieties, benzothiophene
and dibenzothiophene also proved to be suitable substrates for
the selective benzoxylation under standard reaction conditions
producing 69%, 71% yields of the products respectively (Scheme
4, 3f, 3g). However ortho-benzoxylation was not observed with
the substrate bearing a pyrazole directing group (Scheme 4, 3h).
For ortho-oxygenation the detailed mechanistic studies and
plausible mechanism was studied (ESI).
aThe reaction was performed with 1a (1.0 equiv), CuI (20 mol %), Benzoyl
peroxide (2.5equiv) in 1,2 DCE (2 mL) the mixture was heated in an oil bath
at 90 °C for 24 h in a sealed tube tightly closed with screw cap.
With the optimal conditions for chlorination reactions in
hand, the substrate scope of the reaction was investigated
(Scheme 2). A moderate, 71% yield of the ortho-chlorination
product was obtained with the substrate 2a and excellent yields
were often achieved when electron-donating moieties including
4-methyl, 4-methoxy, 3-ethoxy and 4,5-ethylenedioxy groups
were present on the aromatic ring (Scheme 2, 2b–2e, 70-86%).
However o-subistituted, o- and p- disubstituted motifs suffered
from steric crowding which inhibited the desired product
formation (scheme 2, 2f and 2g). The yields were moderate with,
4-fluoro, 4-phenyl, naphthyl, 4-N,N-diphenyl substitutions
(Scheme 2, 2h–2k, 66-69%). Under the optimal reaction
From the observations that, failure to produce the desired
product in the absence of CuI (Table 1; entry17) and also the

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Copper-catalyzed
Directing
group
assisted
highly
regioselective ortho-chlorination and -benzoxylation was
achieved by switching the oxidant under relatively mild
conditions. DCE played dual role as novel chlorination reagent
as well as solvent and TBHP as oxidant for the C-H activation
reaction effecting ortho-chlorination of aryl pyridines. Otho-aryl
C-H oxygenation takes place under the same reaction conditions
with simply switching the oxidant from TBHP to benzoyl
peroxide. The synthesis of divergent products arising from Csp2-
Cl and Csp2-O bond formations by C-H activation reaction on
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Cu-Catalyzed Direct ortho-Chlorination/-
Oxygenation of Aryls: Switching of
Oxidant, Control the Diversity of
Products.
Vinayak Botlaa, Ashok Akudariab and
Chandrasekharam Malapakaab
aP&FM Division, CSIR-Indian Institute of Chemical
Technology, Hyderabad, India. bAcademy of Scientific and
Innovative Research (AcSIR), New Delhi 110025, India.
Copper-catalyzed divergent products via Csp2-
Cl and Csp2-O bond formations, by switching
of oxidant (TBHP/Benzoyl peroxide) is
demonstrated. DCE played dual role as novel
chlorination reagent as well as solvent. The
highly
regioselective
ortho-chlorination/-
oxygenation is affected under easy to operate
reaction conditions
———
 Corresponding author. Tel.: +91-40-27191710;
fax: +91-40-27193186; e-mail:
csmalapaka@csiriict.in

7
Our reaction protocol has several
advantages such as,
 Inexpensive copper catalyst
 DCE playing dual role as novel
chlorination agent as well as solvent
 Highly regioselective mono ortho-
chlorination
 Switching oxidant from TBHP to
BPO
produces
regioselective
oxygenated product
 Mild and easy to operate reaction
conditions.