A Visible Light-Mediated Regioselective Halogenation of Anilides and Quinolines by Using a Heterogeneous Cu-MnO Catalyst

Article abstract of DOI:10.1002/ejoc.201801097

A simple and practical heterogeneous Cu-MnO catalyzed regioselective halogenation of anilides and quinolines under irradiation with household 40 W incandescent lamp was developed. This method uses a recyclable Cu-MnO catalyst, acetonitrile as an industrially friendly solvent, and economic N-halo succinimides as a halogenating source. The reaction is scalable and well tolerated with a broad range of functional groups.

Full text of DOI:10.1002/ejoc.201801097

A Journal of
Accepted Article
Title: A Visible Light-Mediated Regioselective Halogenation of Anilides
and Quinolines by Heterogeneous Cu-MnO Catalyst
Authors: Subhash Chandra Ghosh, Harshvardhan Singh, Chiranjit
Sen, and Tapan Sahoo
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801097
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801097
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10.1002/ejoc.201801097
European Journal of Organic Chemistry
COMMUNICATION
A Visible Light-Mediated Regioselective Halogenation of Anilides
and Quinolines by Heterogeneous Cu-MnO Catalyst
Harshvardhan Singh, Chiranjit Sen, Tapan Sahoo, Subhash Chandra Ghosh*
Dedication ((optional))
Abstract: A simple and practical heterogeneous Cu-MnO catalyzed
regioselective halogenation of anilides and quinolines under
irradiation with household 40W incandescent lamp was developed.
This method uses recyclable Cu-MnO catalyst, acetonitrile as an
industrially friendly solvent, and economic N-halo succinimides as a
halogenating source. The reaction is scalable and well tolerated with
a broad range of the functional group.
are stringent. Considering the above factors and with the
economical point of view, the development of simple and efficient
recyclable heterogeneous catalyst is highly desirable for easy
separation and reusability. Therefore, the development of an
efficient method for versatile C-H halogenation under the mild
condition is highly desirable.
As part of our ongoing research on aromatic C-H
functionalization[20]
especially
regioselective
C-H
halogenation,[20c-d] we have reported halogenations of arenes with
the non-removable 2-pyridyl directing group and using hazardous
Aromatic halides are important structural motifs because of their
presence in many natural products, agrochemicals, and
pharmaceuticals.[1] They are widely used in organic synthesis as
key building blocks to build complex molecules via transition metal
catalyzed cross-coupling reactions.[2] Also, they are the precursor
for the synthesis of organometallic reagents.[3] Therefore, the
development of an efficient and selective synthetic method for the
synthesis of aryl halides is of great interest. Traditionally, aromatic
halides are synthesized by electrophilic aromatic substitution,
directed ortho lithiation followed by halogen quench and
Sandmeyer reaction.[4] However, these methods face several
limitations on poor site selectivity, tedious and or hazardous
reaction procedures and poor functional group tolerance.
nitrobenzene as a solvent at 125C for 24h, these are the critical
[20a]
drawbacks of our halogenation procedure.
These aspects
motivate us to search for a mild and benign reaction condition with
broad substrate scope. Herein, we report mono-ortho-
halogenations of anilides and quinolines that relies on the readily
removable directing group. This method uses recyclable Cu-MnO
catalyst, acetonitrile as an industrially friendly solvent, and
economic N-halo succinimide as a halogenating source, under
visible light irradiation and possesses high regioselectivity.
At the outset of our studies, we tried to improve the halogenation
reaction conditions in the transformation of 4′-Bromoacetanilide
to 4’-bromo, 2′-chloroacetanilide (Table 1). The reaction was
carried out in water (green solvent) under the irradiation of visible
light (40 W incandescent bulb) in air with, our developed Cu-MnO
as catalyst (Figure S1) and N-chlorosuccinamide (NCS) as
chlorinating agent; to our delight, a 25% of chlorinated product
was obtained after 4h (Table 1, entry 1). After screening of a
series of industrially favorable solvent, such as methanol, tert-
butanol, acetonitrile, toluene and ethyl acetate we are delighted
to found that acetonitrile is the best solvent and reaction
completed in just 2h with almost quantitative yield (entries 2-7).
With lower copper loading (2.5wt %) after 6h, the reaction was not
completed, and inferior yield (55%, entry 8) of the desired product
was obtained. Without copper loading on manganese (II) oxide,
almost no reaction was observed (entry 9), this observation
indicates that 5 wt.% copper loading is the optimum for our
reaction. It is important to note that irradiation with 40 W
Regioselective installation of halogen atoms into organic
molecules in an operationally simple manner, which is both cost-
effective and environmentally benign is ever demanding in
industry. Over the past decade, regioselective halogenations of
C-H bonds received a significant achievement for the synthesis of
aromatic halides.[5] Initially, Pd catalyzed C-H bond halogenations
were reported,[6] later on, Rh,[7] Ru,[8] Ir,[9] Co,[10] Au,[11] and more
economic Cu[12] in catalyzing regioselective halogenation has
emerged in recent years. Several pioneering and elegant
strategies of copper-catalyzed ortho-halogenation of anilines
have been reported by Yu, [13] Stahl, [14] Gusevskaya, [15] Shen, [16]
[17]
[18]
Shi
and others.
Homogeneous Cu catalyzed C-5
halogenations of quinolines also reported by several groups.[19]
Despite these substantial developments, the majority of the C-H
halogenations were achieved in homogeneous catalysis, which
has limitations like the use of an expensive catalyst with low
recyclability, specially designed ligands, the presence of metal
contamination (traces) in the product, which is highly undesired in
specialty chemicals, particularly in pharmaceuticals. Currently, all
over the world, pollution control and environmental regulations
incandescent bulb inside
a closed reaction cabinet; the
temperature of the reaction vessel reaches 50-55 C. However,
Control experiment reveals that in the absence of a catalyst (entry
10), at dark condition (entry 11), dark condition with heating at 50
C (entry 12) and under inert (argon) atmosphere (entry 13)
starting material remain unreacted. The role of the light was
checked in details; we have turned off the light after (a) 15 min,
(b) 30 min and (c) 1h during the reaction course, and run the
reaction for total 2h. In all the cases lower yield was observed (a)
35%, (b) 46% and (c) 82% respectively and rest of the starting
material were unreacted (see ESI). All these factors demonstrate
that our halogenation reaction is a photo-induced reaction and
also indicates that catalyst, light, and oxygen from air as a
terminal oxidant all are essential for the chlorination reaction.
[a]
H. Singh, C. Sen, T. Sahoo and Dr. S. C. Ghosh
Natural Products and Green Chemistry Division
CSIR-Central Salt and Marine Chemicals Research Institute
G.B. Marg, Bhavnagar-364002, Gujarat (India)
E-mail: scghosh@csmcri.res.in
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201801097
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COMMUNICATION
Table 2: Substrate scope for chlorination and bromination of anilides
Table 1: Optimization of the reaction condition[a]
Entry
1
Catalyst
Solvent
H2O
Time (h)
Yield %[b]
25
5 % Cu-MnO
5 % Cu-MnO
5 % Cu-MnO
5 % Cu-MnO
5 % Cu-MnO
5 % Cu-MnO
5 % Cu-MnO
2.5% Cu-MnO
MnO
4
4
4
4
4
4
2
4
2
MeOH
86
3
Ethyl acetate
CH3CN
26
4
98
5c
6
tert-butanol
toluene
55
48
7
CH3CN
CH3CN
98
8
55
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
trace
nr
10
11
12
13
-
5% Cu-MnO
5% Cu-MnO
5% Cu-MnO
nr[c]
trace[d]
trace [e]
[a] Standard reaction conditions: anilides (0.25 mmol), NCS (1.1 equiv), solvent
1 ml, catalyst 15 mg, room temperature, 2h, under visible light condition;
[b]isolated yields; without light at rt; [c] dark condition [d] at 50 C, without light, 4h;
[e] reaction under Argon atmosphere.
With the optimization reaction condition in our hand (Table 1,
entry 4), we explore the substrate scope and limitation of our
catalytic system. To evaluate the generality of chlorination of our
developed catalytic system a series of substrates with two readily
available ortho C-H bonds, and functional group at the para
position of the phenyl ring of acetanilide, including electron
withdrawing group, e.g. fluoro (Table 2, entry 3b, 97%), chloro (3c,
97%), trifluoromethyl (3d, 85%), and electron donating group,
methoxy (3e, 95%), methyl (3f, 90%), and isopropyl (3g, 85%)
proceeded in excellent yields of mono-ortho-chlorinated products.
It is notable to mention that exclusively mono chlorinated product
was obtained in all the cases. Next, we examine substrate bearing
other anilides, sterically hindered isobutyramide (3h, 3m),
pivalamide (3i), cyclohexanecarboxamide (3k, 3l) and long chain
octanamide (3j, 3n) of para-substituted anilines were equally
effective and gave good to excellent yields of ortho-chlorinated
products. Meta-bromo substituted acetanilide could also be
selectively chlorinated at para-position with excellent yields (98%,
3o). Whereas, di-ortho-substituted anilides do not react, which
may be due to the steric effect of methyl group prevent
coordination of metal with amide. Furthermore, simple acetanilide
reacted in standard condition and afforded the para chlorinated
product (3q) in excellent yield (95%) when 1
T
Condition: Reactions were carried out with anilide (0.5 mmol), NXS (1.1
equiv), Cu-MnO (25 mg) in acetonitrile (1 mL) for 2 h, under irradiation with
light in a screw cap reaction vessel. All reported yields are isolated yields.
[a] 1.0 eq. NCS/NBS was used; [b] 1.5 eq. NCS/NBS was used
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COMMUNICATION
Table 3: Substrate scope for chlorination, bromination and iodination of
quinoline derivativesa
bromination occurs is better than chlorination reaction, and
good yield of corresponding ortho-brominated product was
observed (4u, 58%). We have checked the compatibility of this
reaction with other electron-rich aromatic compounds like 1,3,5
tri methoxy benzene, p-tolyl acetate, and N,N dimethylaniline,
but quite unfortunately in all the cases no reaction takes place,
and the desired halogenated product was not obtained.
The success of the chlorination and bromination of anilides led
us to extend the substrate scope for other aromatic substrates,
8-amido quinoline moiety. The use of halogenated quinoline is
widely explored in organic synthesis, to synthesize various
biologically important molecules. Transition metal catalyzed
chelation controlled remote C-H activation strategy for
quinoline moiety is widely explored. We have recently reported
the C-5 halogenation in metal-free conditions. Here with our
optimized condition for halogenation of acetanilides, we have
explored C-5 selective halogenation (chlorination, bromination,
and iodination) of quinoline moiety with NXS (X = Cl, BR, I)
under identical conditions. These chlorination, bromination,
and iodination prove to be very versatile as summarized in
Table 3. The halogenation with 8-aminoquinoline amides could
tolerate various functional group and processed well with an
aryl amide group and an alkyl amide group. In general,
chlorination (Table 3, 6a-i, 88-97%) and bromination (7a-i, 92-
98%) works slightly better than the iodination (8a-i, 62-85%)
reaction. Benzamides with both electron donating group (6b-c,
7b-c, 8b-c) and electron withdrawing group (6d-e, 7d-e, 8d-e)
were also well tolerated, and good-excellent yields are
obtained for chlorination, bromination, and iodination with
NXS. With alkyl amides such as acetamide (6f-8f),
cyclopenatnecarboxamide (6g-8g), and decanamide (6h-8h)
reaction proceed smoothly. Moreover, the reaction showed
well tolerance with sterically hindered substrates like
adamantyl carboxamide (6i-8i) and afforded excellent yield (6i,
96%; 7i, 97% and 8i, 76%) of corresponding halogenated
aReactions were carried out with 8-amidoquinoline(0.5 mmol), NXS (1.1
equiv), Cu-MnO (25 mg) in acetonitrile (1 mL) for 2 h, under irradiation with
light in a screw cap reaction vessel. All reported yields are isolated yields.
equivalent NCS was used, but by increasing NCS to 1.5
equivalent, a mixture of mono and di chlorinated product was
obtained (3q and 3r). Aryl amides and NHBoc protected aniline
are less reactive (3s, 3t, 5-10%) with our optimized condition.
When N-(pyridin-4-yl)acetamide an heterocyclic anilides used
reaction is sluggish, and lower yield (3u, 40%) was obtained.
We next examine the bromination using NBS as a brominating
agent, under identical conditions. Gratifyingly, para-substituted
substrates with both electron withdrawing group (Table 2, 4 a-
d) and electron donating group’s (4 e-g) of acetanilide
proceeds well, and excellent yields (81-98%) of mono ortho-
brominated products were obtained. Similar to chlorination
reaction substrates with other anilides (4h-n) bearing isopropyl,
tert-butyl, hexyl, and cyclohexyl group in amide chain and
chloro, bromo,fluoro, and trifluoromethyl group in phenyl ring,
bromination reaction proceeds well with mostly excellent yields
(82-96%) of mono-brominated product. Meta-bromo
substituted acetanilide also be selectively brominated at para-
position with excellent yields (98%, 4o). Simple acetanilides
also underwent reaction to form the corresponding brominated
products (4q and 4r). Importantly, no desired product is
obtained for ortho-disubstituted anilides (4p), and trace amount
for aromatic anilides (4s, (>10%) and NHBoc protected anilines
(4t, >5%). For heterocycle system, N-(pyridin-4-yl)acetamide,
products. Methyl-substituted at
2 positions of quinoline
derivatives also works well, and similar yield of halogenated
product was obtained (6j, 93% and 7j, 95%).
To evaluate the efficiency and practicality of the reaction, we
scaled up the chlorination reaction (Scheme 1a), at 6 mmol
(1.284 g) reaction scale of compound 1a afforded 97% yield of
the desired mono-ortho-chlorinated product (3a). Further, we
have deprotected the amide group under refluxing in ethanol
with potassium hydroxide (scheme 1B) in almost quantitative
yield.
We have checked the recyclability of the catalyst with our
standard reaction, chlorination of 1a and it showed good
performance 98% in 1st recycle, 96% on 2nd, 93% on 3rd and
91% on 4th recycle as shown in Scheme 1C. The catalytic
activity is slightly decreased after each cycle, it’s not due to the
loss of Cu, but it’s due to the decrease of surface area of the
catalyst after the repeated calcination and also the sintering of
impregnated copper nanoparticles.[20b] The heterogeneity of
the reaction confirmed by the hot filtration test and ICP-AES
analysis of the filtrate, it showed the < 1 ppm Cu leached in the
filtrate. The catalyst was filtered and after washing, calcined at
350 C under 5% H2 in the N2 atmosphere and reused.
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10.1002/ejoc.201801097
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COMMUNICATION
Scheme 2:control experiment for the mechanistic study
Scheme1: Gram Scale synthesis, deprotection of amide and reusability.
To understand the reaction pathway we have carried out
several control experiment. First, we have performed the
radical inhibition experiment, carried out the standard reaction
in the presence of the radical scavenger, (2,2,6,6-
Tetramethylpiperidin-1-yl)oxyl (TEMPO) or 2, 6-Di-tert- butyl-
4-methylphenol (BHT) almost completely inhibited. Also, we
have identified the TEMPO trapped chlorine radical in HRMS
(see ESI). This observation indicates that reaction might
proceed through a radical pathway. Next, we check the
importance of amide NH, when the reaction was carried out
with N-methyl N-phenyl acetamide (Scheme 2, B, i), no
reaction was observed, also when NH replaced by O, i.e., with
ester (Scheme 2, B, ii) starting material remain unreacted.
These observations indicate the free NH proton is required for
coordination with metal. In addition, we have observed with
simple acetanilide (Table 1, 3p, 4p) halogenation occurs
selectively at para-position. On the basis of this observations
and with the seminal report in this field a plausible mechanism
is outlined in Scheme 3. Firstly, coordination of nitrogen with
the Copper takes place, followed by homolytic cleavage of N-
Cu bond with visible light to generate Nitrogen radical (Scheme
3, II), which is resonance stabilized and generated the
intermediate aryl cation radical (III).After that, halide radical
produced from the NCS in the presence of light reacts with this
species and followed by rearomatization afforded the desired
halogenated product (V). The similar reaction pathway is
proposed
Scheme 3: proposed reaction mechanism
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10.1002/ejoc.201801097
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COMMUNICATION
for 8-amido quinoline moiety. The halogen radical
regioselectivity added in the para position to the amide group
as it is most electrophilic position in the ring of an aryl radical
cation species.22 Whereas, in case of anilides system when the
para position is blocked, ortho-position is the most electrophilic
and halogenation takes place regioselectively there, but as
observed for simple acetanilide halogenation prefers at most
electron rich para position.
Acknowledgments
CSIR-CSMCRI Communication No. 060/2018. We are thankful to
the SERB, DST, India (EMR/2016/002427), for financial support
for this work. The authors thank Dr. A. B. Panda for the catalyst
characterization. The authors also acknowledge the Analytical
and Environmental Science Division and Centralized Instrument
Facility of CSIR-CSMCRI for all characterization. HS, CS, and TS
thanks to UGC, CSIR, and DST for their fellowship respectively.
In conclusion, we have developed a simple and practical visible
light induced regioselective halogenation of anilides and
quinoline moiety via copper catalyzed chelation controlled C-H
activation strategy. This halogenation provides a wide variety
of synthetically useful selectively chlorinated, brominated and
iodinated arenes and heteroarenes. This methodology is
scalable, well tolerate with a broad range of functional groups,
and proceed well with electron rich, electron poor and sterically
hindered substrates. Our developed heterogeneous catalyst
can be easily separated from the reaction mixture by filtration
and reused for several times.
Keywords: Halogenation • heterogeneous catalysis • visible
light • Cu-MnO• acetanilide
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Experimental Section
Synthesis of Cu-MnO catalyst:
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Cu-MnO catalyst was prepared according to our reported procedure.21 Cu
supported MnO (Cu-MnO) were synthesized by the impregnation method,
impregnating Cu2+ on the surface of Lotus shaped γ-MnO2 followed by
calcination at 350 C under 5% H2 and 95% N2 condition.
Representative Procedure for halogenation of acetanilide:
In a 10 mL screw cap reaction tube, 4-bromo-acetanilide (1a, 107 mg, 0.5
mmol) was taken, catalyst 5 wt% Cu-MnO (25 mg) was added over it
followed by N-cholorosuccinimide (NCS, 73 mg, 1.1 eq), 1 mL acetonitrile
as a solvent was added. Then the reaction tube was screw capped and
irradiated under the 40W incandescent lamp (visible light) for 2h. After the
completion of the reaction, the crude reaction mixture was filtered and
washed with ethyl acetate (25 mL). The organic portion was washed with
water and brine solution and dried over Na2SO4, then concentrated under
reduced pressure. The resulting residue was purified by flash
chromatography on silica gel (n-hexane/EtOAc=10:1) to afford the desired
product 4-bromo-2-chloro-acetanilide (3a, 121 mg, 98%) as a white solid.
For bromination only NBS was used instead of NCS, rest of the procedure
is same.
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Representative Procedure for halogenation of 8-amido-quinoline:
In a 10 mL screw cap reaction tube, N-(quinolin-8-yl)benzamide (5a, 124
mg, 0.5 mmol) was taken, catalyst 5 wt% Cu-MnO (25 mg) was added over
it followed by N-cholorosuccinimide (NCS, 73 mg, 1.1 eq), 1 mL acetonitrile
as a solvent was added. Then the reaction tube was screw capped and
irradiated under the 40W incandescent lamp (visible light) for 2h. After the
completion of the reaction, the crude reaction mixture was filtered and
washed with ethyl acetate (25 mL). The organic portion was washed with
water and brine solution and dried over Na2SO4, then concentrated under
reduced pressure. The resulting residue was purified by flash
chromatography on silica gel (n-hexane/EtOAc=10:1) to afford the desired
product N-(5-chloroquinolin-8-yl)benzamide (6a, 135 mg, 96%) as a white
solid. For bromination and Iodination, only NBS or NIS was used instead
of NCS, rest of the procedure is same.
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COMMUNICATION
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10.1002/ejoc.201801097
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
A
simple and practical method for
Harshvardhan Singh, Chiranjit Sen,
Tapan Sahoo, Subhash Chandra
Ghosh*
regioselective halogenation of anilides
and quinolines with heterogeneous Cu-
MnO catalyst and under irradiation with
household 40W incandescent lamp was
developed. The catalyst is recyclable,
acetonitrile as an industrially friendly






63 examples
up to 98% yield
Recyclable catalyst
Regioselective
Mild condition
Scalable
Page No. – Page No.
A
Visible
Regioselective Halogenation of
Anilides and Quinolines by
Heterogeneous Cu-MnO Catalyst
Light
Mediated
solvent,
and
economic
N-halo
succinimides as a halogenating source.
The reaction is scalable and well
tolerated with a broad range of the
functional group.
This article is protected by copyright. All rights reserved.