Para -Selective copper-catalyzed C(sp2)-H amidation/dimerization of anilides via a radical pathway

Article abstract of DOI:10.1039/c9cc09824k

Copper-catalyzed amidation/dimerization of anilides via regioselective C(sp²)-H functionalization is achieved. The para-selective amidation is accomplished on the anilide aromatic ring via a radical pathway leading to C-N bond formation in the presence of ammonium persulfate as a radical source/oxidant for the copper catalyst. The developed protocol tolerates a wide range of anilide substrates. The regioselectivity is confirmed by single-crystal X-ray studies.

Full text of DOI:10.1039/c9cc09824k

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DOI: 10.1039/C9CC09824K
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para-Selective Copper-Catalyzed C(sp2)─H Amidation/
Dimerization of Anilides via a Radical Pathway
Amol B. Viveki,†,‡ Dnyaneshwar N. Garad,†,‡ Rajesh G. Gonnade‡,§ and Santosh B. Mhaske*,†,‡
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Copper-catalyzed amidation/dimerization of anilides via functionalization of quinazolinones as well as acrylamides
regioselective C(sp2)─H functionalization is achieved. The using ruthenium catalysis for alkenylation and cascade
para-selective amidation is accomplished on the anilide annulation respectively.6
aromatic ring via a radical pathway leading to C─N bond
Amide is one of the potential functional group as well as
formation in the presence of ammonium persulfate as a directing group, which has been utilized enormously in
radical source/oxidant for the copper catalyst. The developed chelation controlled functionalization using transition-metal
protocol tolerates a wide range of anilide substrates. The catalysis.7 In continuation of our interest in developing new
regioselectivity is confirmed by single-crystal X-ray.
methods utilizing amide as an inherent directing group for the
C─H activation, we were exploring the functionalization of
Transition-metal-catalyzed C─H bond functionalization has anilide derivatives. Interestingly, during the course of our
emerged as a prominent synthetic tool in organic chemistry investigation, we observed self-dimerization of anilide under
over the past few decades.1 It avoids the need for one of our Cu-catalyzed reaction condition. After careful
prefunctionalization of substrates and offers straightforward observation and characterization of the obtained product, we
access to the desired scaffold in high atom and step-economy. have confirmed the C─N bond formation at the para-position
Regioselective C─H functionalization to furnish C─C and C─X (X to the nitrogen of the electron-rich anilide ring. Interestingly,
= O, N, S, etc.) bond formation is generally achieved either by literature survey revealed that Masui et al. observed
using
a
directing-group or steric/electronic factors. The dimerization of benzanilides during anodic oxidation,8
metal-catalyzed para-selective amidation/
functionalization of arenes ortho to the directing-groups can however,
be realized easily since the metal can reach readily to the dimerization of anilides through C─N bond formation
desired site. Whereas, selectively reaching meta or para specifically on aniline aromatic ring as observed here is not
position is difficult because of many other factors.2 The
pioneering work in the field of meta and para-selective C─H
functionalization has been reported by Yu3 and Maiti4 groups
respectively, employing molecular template to direct a metal
catalyst to a specific position. Despite of the many advantages
of template-assisted site-selective C─H functionalization over
the traditional methods, sometimes the template is larger than
the substrate and additional steps are required to install or
remove them, which makes the process lengthy, tedious and
economically unviable. Hence, the process wherein the
functional group of the molecule itself acts as an inherent
directing group is preferred over the earlier.5 We have
previously utilized amide as an inherent directing group for the
Scheme 1 Selected metal-catalyzed aminations and our work
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reported until now. Nevertheless, C(sp2)─H amidation/
imidation/sulfonamidation or amination at ortho/meta/para-
position of various functional/directing groups have been
reported using transition-metal catalysis (Scheme 1, eq 1-4)9 or
transition metal-free methods.10 Copper catalysts are the most
desired transition-metal catalysts for this purpose as they are
robust, cost-effective, and provide practical alternative over
the other expensive transition-metal catalysts such as [Pd],
[Ru], [Ir] etc.9b,h,11 Hence, we aimed at optimizing the protocol
using a copper catalyst. In this context, reported herein is a
protocol for the para-selective amidation/dimerization of
anilides using a copper catalyst and inexpensive ammonium
persulfate (APS) as an oxidant/radical source (Scheme 1, eq 5).
The optimization of the protocol commenced with the
modifications in the previously perceived condition. Selected
modifications are presented in Table 1. Though several
variations in oxidant, catalyst, reaction concentration, time
and temperature were tried, the best yield achieved through
optimization studies was 62% (Table 1, entry 9). However,
0.037 mmol of the starting material was recovered unchanged,
and hence the actual yield based on the recovered starting
material (brsm) was 77%. GC/GC-MS analysis of the crude
reaction mixture, as well as purified product 2a, confirms the
formation of a single regioisomer. The para regioselectivity of
2a was confirmed by X-ray crystallography (CCDC-1954354).
or meta to anilide nitrogen furnished the corresponding
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products 2b and 2c respectively in good yields. Similarly,
DOI: 10.1039/C9CC09824K
anilide with electron-donating methoxy group at the ortho
position also worked smoothly to provide the expected
compound 2d in optimum yield. The fluoro substituted anilides
resulted into the expected products 2e and 2f with
comparatively lower yields. The ortho-substituted anilides (1b
1e) worked better than the corresponding meta-substituted
anilides (1c 1f) probably because of the steric hindrance.
,
,
Following the same trend, iodo-substituted anilide also
provided the dimer 2g in good yield. However, anilide with
electron-withdrawing –NO2 substituent failed to furnish the
expected product 2h under the optimized conditions. We
reasoned that the amide group of the electron-deficient
anilide fails to bind with the metal during the course of the
reaction.
Table 2 A
midation/dimerization of N-arylalkylamidea-c
Table 1 Optimization of Reaction Conditionsa
Obs.
No.
Oxidant
(equiv)
Cu(OAc)2
(mol%)
Concen.
(in M)
Yieldb
(%)
1
APS (1.5)
5
0.15
0.15
0.15
0.15
0.15
0.15
0.30
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
27
2
APS (1.0)
-
-
trace
NR
16
3
5
4
APS (2.0)
APS (1.0)
APS (0.75)
APS (1.0)
APS (1.0)
APS (1.0)
K2S2O8 (1.0)
Na2S2O8 (1.0)
APS (1.0)/O2
(tBuO)2 (1.0)
APS (1.0)
APS (1.0)
5
5
5
41
6
5
32
7
5
21
8
5
49
9
10
10
10
10
10
10
10
62 (77)c
46
aReaction conditions: 1a-l (0.2 mmol), Cu(OAc)2 (10 mol%), APS (0.2 mmol),
DMSO (0.1M) in a screw cap glass tube at 100 OC for 18 h. bIsolated yields.
cYields in parentheses are based on the recovered starting material.
dStarting material recovered unchanged.
10
11
12
13
14d
15e
42
22
At this point, we decided to study the substrate scope by
varying the aliphatic group of anilide 1a. Accordingly, N-
phenylisobutyramide was treated under the optimized
reaction condition, which worked well leading to 2i. N-
phenylacetamide also resulted into the corresponding
dimerized product 2j in moderate yield. The reaction worked
NR
40
52
aReaction conditions: 1a (0.2 mmol), Cu(OAc)2, oxidant-ammonium
persulfate (APS) in DMSO at 100 OC for 18h, bIsolated yield. cYield in the
d
parentheses is based on the recovered starting material. Additive: AcOH (1
equally well with N-phenylpropionamide to obtain 2k
.
equiv), eAdditive: NaOAc (1 equiv).
However, the substrate N-phenylhexanamide having a long
alkyl chain provided the corresponding dimer 2l in relatively
lower yield. Overall, the bulkiness of the aliphatic group had
minimal effect on the yield. The regioselectivity of 2j was
confirmed by its synthesis from known amine (see SI).
After optimizing the reaction condition, our next target was
to generalize the scope of the developed protocol. The study
began with the variation of substituents on the aromatic part
of the anilide 1a. The substrates with methyl substituent ortho
2 | J. Name., 2012, 00, 1-3
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Table 3 Amidation/dimerization of N-arylbenzamidesa-c
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substituted anilides also worked fine to provide the
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corresponding desired products 2v,
2wDaOnId: 120.x10r3e9s/pCe9CctCiv0e98ly24inK
moderate yields.
Overall, the developed protocol is quite general and many
substituents, except highly electron-withdrawing groups, are
well tolerated. The protocol is highly selective for anilides. We
neither observed cross-coupling products between anilides
and aliphatic/aromatic amides/amines nor dimerization of
other amides (see SI). Derivatives of the products 2a-2x are
commonly used in polymer/material chemistry,12 and they
would also be interesting precursors for the synthesis of the
corresponding carbazoles or phenanthridinones via
regioselective C─H activation strategy.
Few control experiments were performed for preliminary
understanding of the mechanism of our protocol. The radical
nature of the reaction was determined by performing the
reaction of anilide 1m under the standard reaction condition in
the presence of radical scavengers such as TEMPO and BHT
(Scheme 2, eq 1 and 2). Complete inhibition of reactions was
observed in both cases. Interestingly, adduct
3 (Scheme 2, eq
2) was observed in HRMS of the crude reaction mixture, which
confirms the radical pathway of the reaction. The formation of
brominated product
4 instead of dimer 2a in the presence of
NBS also confirms the radical pathway (Scheme 2, eq 3). The
reaction of anilide 1y showed very less conversion and
complex reaction mixture by TLC (Scheme 2, eq 4). The anilide
substrate 1z having bulky isopropyl substituent on both ortho-
aReaction conditions: 1m
-x (0.2 mmol), Cu(OAc)2 (10 mol%), APS (0.2 positions did not react under the standard reaction conditions
b
mmol), DMSO (0.1M) in a screw cap glass tube at 100 OC for 18 h. Isolated
c
yields. Yields in parentheses are based on the recovered starting material.
dStarting material recovered unchanged.
The successful completion of the substrate scope study of
N-arylalkylamides prompted us to demonstrate the generality
of the protocol with varyingly substituted N-arylbenzamides.
The developed protocol was first applied on N-
phenylbenzamide, and gratifyingly the product 2m was
obtained in a good yield. The regioselectivity of the product
2m was also confirmed by single-crystal X-ray (CCDC-1954355).
Initially, we studied the effect of substituents present on the
electron-rich anilide aromatic ring. Two anilide substrates with
electronically unbiased methyl substituent at ortho and meta
position of the electron-rich aromatic ring worked well to
provide 2n and 2o, respectively. The anilide substrate with
electron-donating methoxy group furnished 2p in moderate
yield. The ortho-fluoro and meta-bromo-substituted anilides
worked fine to provide the corresponding dimers 2q and 2r
,
respectively. However, as observed before, anilide having
strong electron-withdrawing group failed to give the expected
product 2s under the developed protocol.
Scheme 2 Control Experiments
though the para-position was available for the reaction. This
observation indicates that probably the approach of copper
catalyst to the amide –NH is blocked due to the steric
hindrance of isopropyl group leading to the failure of the
reaction (Scheme 2, eq 5). We believe that the developed
After the study of variation in the substituents present on
the electron-rich aromatic ring of anilide, we targeted to study
the effect of variation on electron-deficient aromatic ring of N-
arylbenzamides. The substrate with methyl group at the para-
position of the amide carbonyl did not affect the yield and 2t
was obtained in comparable yield with 2m. Electron-donating
methoxy group substituted anilide also worked well to furnish
protocol works via
a radical mechanism involving the
formation of a para-quinone type of intermediate on aniline
part of the anilide, which makes it highly regioselective. A
dimer 2u
.
meta-Fluoro,
para-chloro, and meta-iodo
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J. Name., 2013, 00, 1-3 | 3
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and D. Morton, J. Org. Chem., 2016, 81, 343. (Vci)ewXA. rCtichleeOnn,linKe.
tentative proof for our hypothesis of para-quinone type
intermediate was realized when the substrate 1ja (a structural
isomer of 1j) lacking the aniline part of the aromatic ring was
subjected to our protocol (Scheme 2, eq 6). The reaction did
not work because para-quinone type intermediate is not
possible on benzamide aromatic ring.
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Scheme 3 Plausible Mechanism
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experiments (Scheme 2), a plausible mechanism via a radical
7
pathway has been depicted in Scheme 3. Anilide
1 first
chelates with a copper catalyst to form complex [I], which
converts to amidyl radical intermediate [II] in the presence of
APS. The amidyl radical intermediate transforms to a stable
para-quinone type imine radical intermediate [III]. A radical
coupling between intermediates [II] and [III] provides the
intermediate [IV], which on aromatization furnish the desired
8
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In conclusion, we have developed a unique process for
para-selective C─H functionalization leading to amidation
/dimerization of anilide derivatives. The developed protocol is
highly selective as the dimerization through C─N bond
formation occurs specifically on aniline part of the anilide.
Preliminary mechanistic investigation demonstrates that the
reaction follows a radical pathway. A broad substrate scope
has been demonstrated utilizing an inexpensive copper
catalyst. The obtained products are potential precursors for
the synthesis of bioactive heterocyclic scaffolds. Currently, we
are exploring the protocol for C─H functionalization of anilide
derivatives with other reacting partners leading to C─C as well
as C─X bond formation.
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A.B.V. thanks CSIR-New Delhi, and D.N.G. thanks UGC-New
Delhi, for the research fellowship. S.B.M. gratefully
acknowledges generous financial support from DST-SERB, New
Delhi.
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Conflicts of interest
There are no conflicts to declare.
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Notes and references
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Ackermann, Chem. Rev., 2019, 119, 2192. (b) H. M. L. Davies
4 | J. Name., 2012, 00, 1-3
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