Copper-Mediated Remote Highly Site-Selective C–H Bond Bromination and Chlorination of Quinolines at the C5 Position that is Geometrically Difficult to Access

Article abstract of DOI:10.1002/ejoc.201601151

A concise, simple, and efficient method for remote C–H bond halogenation (Br and Cl) of 8-aminoquinoline scaffolds at the geometrically difficult-to-access C5 position was explored with diverse substrate combinations in DMF. This protocol made use of inex

Full text of DOI:10.1002/ejoc.201601151

A Journal of
Accepted Article
Title: Copper-mediated remote highly site-selective C-H bond
bromination and chlorination of Quinolines on the C5-Position
that is geometrically difficult to access
Authors: Maheswaran Harihara Sarma, Naidu Sambasiva Rao,
Ganapam Manohar Reddy, and Balasubramanian Sridhar
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601151
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10.1002/ejoc.201601151
European Journal of Organic Chemistry
COMMUNICATION
Copper-mediated remote highly site-selective C-H bond bromination and
chlorination of Quinolines on the C5-Position that is geometrically difficult to
access
Naidu Sambasiva Rao,a Ganapam Manohar Reddy,a B. Sridhar, and Maheswaran Harihara Sarmaa*
halogenation of Quinolines should be developed. In this regard, to
our delight, however, during routine screening studies, we have
Abstract: We report a concise and efficient method for the remote
C-H bond halogenation (Br & Cl) of 8-aminoquinoline scaffolds on
discovered that simple CuX2 (X = Br, Cl) salts without any
the C5 position that is geometrically difficult to access. The
additives promote remote C5 halogenations (Br and Cl) when N-
protocol makes use of inexpensive CuBr2 and CuCl2 as a mediator
(8-quinolinyl)benzamides are used as substrates with a broader
and shows good tolerance toward numerous N-(8-quinolinyl)-
substrate scope. The results from these studies form the focus of
benzamides, giving the corresponding products in good to excellent
this paper.
yield.
Previous work
Cl
R2
R2
eqn(1)
CuCl2 (2 equiv.)
Introduction
R1
R1
N
N
Cu(OAc)2 (2 equiv.)
DCE
Quinoline structural motifs are very common in natural products
and bioactive molecules.[1] In particular, Quinoline, motifs which
were halogenated on their phenyl counterparts, has been frequently
found in many biologically active natural products and
pharmaceuticals.[2-3] Notably, they can also be used as Daugulis-
type bidentate directing groups participating in various kinds of
transition-metal mediated organic reactions involving directed
sp2(C-H)-sp2(C-H) and sp2(C-H)-sp3(C-H) functionalizations.[4]
Even though efficient classical synthetic methods have been
reported for Quinoline derivatives, they are often confined to
functionalization of Quinoline scaffolds mainly on the C2, C3, C4,
and C8 positions which are easily accessible.[5-6] Notably, the
reports involving Quinoline functionalization at the C5 position are
quite rare, and this is mainly due to electron-deficient nature of the
Quinoline ring which makes it difficult to control the
regioselectivity.
NHOAc
NHOAc
X
X
O
N
H
eqn(2)
eqn(3)
PhI(OAc)2 (4 eq)
NaX (4 eq)
N
O
X= Br
N
Cu(OAc)2 (15 mol%)
H
X
N
PivOH (30 mol%)
1,4-dioxane
O
X= I, Br, Cl
N
H
SET pathway
PhI(OAc)2 (2 eq)
NaX (2 eq)
X= Cl very low yield obtained
N
Present work
X
O
O
CuX2
DMF
eqn(4)
N
H
N
H
N
N
X= Br 2eq
X= Cl 3eq
X= Br, Cl
Br yield 71-98
Cl yield 70-93
SET pathway
Scheme 1
Results and Discussion
Therefore, the remote C-H bond halogenations of 8-
aminoquinoline scaffolds on the C5 position are geometrically
difficult to access. However, only very recently, with advances in
catalytic direct C-H activation technologies, some select examples
of remote C5 functionalization using Daugulis-type 8-amino-
quinoline bidentate amide as directing groups under transition-
metal catalyzed conditions has been reported. The reported
examples include sulfonyl moiety (containing alkyl and aryl
groups)[7], nitro group,[8] allyl moiety[9], and chalcogenides (SR &
SeR)[10]. To the best of our knowledge, there are only two
published examples for remote C5 halogenation of Quinoline
scaffolds exist-to-date (Scheme 1)[11a-11d]. These new methods,
nonetheless, have obvious defects such as long reaction times, use
of noble metals, and use of basic additives such as Cu(OAc)2 or
hyper-valent iodine oxidant (PhI(OAc)2) in large amounts to
promote the reaction. Therefore, both eco-friendly and affordable
as well as highly efficient synthesis protocols for remote C5
We have first evaluated the use of CuBr2 (0.4mmol) for a
(0.2mmol) substrate and the relevant findings in the screening
conditions are presented in (Scheme 2). From this Scheme, it clear
that solvents such as DCE and DMSO upon heating gave only
moderate yields for highly site-selective C5 bromination of N-(8-
quinolinyl)benzamide. However, solvent DMF was found to be the
ideal for this reaction as it gave about 90% isolated yield for the C5
brominated product at 130ºC. A decrease in the loading of CuBr2 to
0.2mmol decreased the product yield to 56%. Higher loadings of
CuBr2 (0.8mmol) slightly decreased the yield of the reaction but
we have not observed the formation of non-directed C7
functionalized Quinoline products under our experimental
conditions.
As can be seen from (Table 1) that our optimized reaction protocol
is applicable to remote C5 bromination of Quinoline ring under
diverse N-(8-quinolinyl)benzamide substrate combinations. It is
amply clear that our methodology gives good to excellent yields
for benzamide functionalities that contain both electron-donating
and electron-withdrawing groups. Our protocol also tolerates the
presence of halogen atoms such as Cl, Br, and F in the benzamide
substrate and gives excellent yields for the desired products. A
sensitive functional group such as ester containing benzamide
[a]
Dr. H. Maheswaran
Inorganic & Physical Chemistry Division
CSIR-Indian Institute of Chemical Technology
Uppal road, Hyderabad, India
E-mail : maheswaran_dr@yahoo.com
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10.1002/ejoc.201601151
European Journal of Organic Chemistry
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derivative also underwent the reaction with yields as high as 89%
in DMF. More importantly, amides that are derived from
heterocycles such as furan and thiophene also reacted, and
excellent yields were obtained for these substrates. In total, we
have demonstrated the utilization of our optimized protocol for
remote C5 bromination for as many as diverse 16 substrate
combinations.
Precise reason for obtaining only moderate yields for the
regioselective C-5 chlorination reaction of N-(8-quinolinyl)-
benzamides substrates containing electron-withdrawing groups are
unclear at this time. However, a rationale for this experimental
observation could be present in the mechanism of the reaction. For
example, it is likely that Single Electron Transfer (SET)
mechanism proposed by us for our studies (see below) may lead to
reasonably less-reactive cationic radical Cl. intermediates for N-(8-
quinolinyl)benzamides substrates containing electron-withdrawing
groups; there by giving rise to lower yields of the products. It is to
be noted that like C5-bromination reactions, C5-chlorination
reactions described herein are also highly stereoselective because
we did not detect formation of C7-chlorinated side-products under
our reaction conditions.
Scheme 2. Relevant Findings in the Screening of Conditions.
H
Br
H
H
H
O
H
H
O
H
CuBr2
N
H
N
H
DMF, 4 h.
N
N
H3C
H3C
2
1
0.2 mmol
Isolated
yield(%)
T (oC)
Solvent
Entry
CuBr2 (mmol)
Table 1. Remote C5 bromination of the 8-aminoquinoline N-(8-
quinolinyl)benzamide derivatives.
1
120
130
130
RT
130
90
56
90
82
37
62
67
0.2
0.4
DMF
DMF
DMF
DMF
2
H
Br
H
H
H
O
H
H
O
0.8
0.4
0.4
0.4
3
CuBr2 (0.4 mmol)
DMF, 130o C, 4 h.
N
H
N
H
R
R
4
N
O
N
H
2
1
0.2 mmol
5
6
DMSO
DCE
Br
Br
Br
Br
Br
Br
O
N
O
CH3
N
N
H
H
N
H
N
N
N
N
N
N
N
N
H3C
2a, 90%
2b, 94%
2c, 84%
O
Br
Br
Br
Br
Br
Br
O
N
O
We then evaluated the feasibility of remote C5 chlorination in N-
(8-quinolinyl)benzamide derivatives using CuCl2 in DMF. A
standard screening conditions for this reaction showed the use of
CuCl2 (0.6 mmol) in DMF at 140ºC was necessary to promote the
reaction, and the relevant findings under these conditions are
presented in (Table 2). As can be seen from Table 2, the remote C5
chlorination reaction gives moderate to excellent yields for as
many as eight N-(8-quinolinyl)benzamides. Interestingly, the
substrates containing simple benzamide or those of one containing
electron-donating groups such as -Me and -OMe gave excellent
yields (90-93%). However, unlike C5-bromination reaction,
benzamides that contain electron-withdrawing groups such as o-
CF3, p-CF3, halogens such as p-F, and p-Br as well as heterocyclic
substrates containing thiophene gave only moderate 70-72% yields
under our reaction conditions.
N
H
N
H
H
N
F3C
O
2d, 98%
O
2f, 85%
O
2e, 95%
Br
Br
Br
O
N
CF3
O2N
F3C
N
H
N
H
H
N
2g, 79%
2i, 77%
2h, 93%
CF3
O
F
O
O
Cl
N
N
H
N
H
H
N
F
2k, 86%
2j, 88%
2l, 86%
O
N
O
Br
O
N
H
H
O
O
N
N
N
H
Br
2m, 74%
2n, 89%
N
O
2o, 86%
O
N
H
N
S
2p, 78%
a Reaction conditions: 1 (0.2 mmol), CuBr2 (0.4 mmol), DMF (2.0 mL),
stirred at 130 °C, under air, 4 h, Isolated yields
The C5-brominated compound (2b; Table 1) was crystallized in the
centrosymmetric triclinic achiral space group P-1, while C5-
chlorinated compound (3b; Table 2) crystallized in non-
centrosymmetric
monoclinic
chiral
space
group
P21
(CCDC 1486157). The crystal structures of both the compounds
are depicted in Figure 1 and 2, respectively. In all perspective view,
the bond lengths and bond angles are similar for (2b; Table 1) and
(3b; Table 2). In both the structures, intramolecular N1-H1N…N2
and C10-H10…O1 hydrogen bonds are observed.
Figure.1 : The X-ray structure of (2b), showing the atom-labelling
scheme. Displacement ellipsoids are drawn at the 30% probability
level. The dashed line indicates a hydrogen bond.
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10.1002/ejoc.201601151
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Very interesting features are observed in the crystal packing
arrangements in both C5 brominated and C5 chlorinated
compounds, and the details of those features are discussed below.
In X-ray structure, (3b; Table 2), Van der Waals interactions
stabilize the crystal structure. It was surprising that achiral C5
chlorinated molecule crystallized in a P21 chiral space group
(CCDC 1486158). However, such achiral molecules crystallizing
in non-centrosymmetric chiral space groups are not an unusual one
though because recent studies have shown that about 15.2% of
achiral molecules crystallize in noncentrosymmetric space
groups.[11e] In viewing the crystal packings of (2b) and (3b), the
dimeric molecules of the former are arranged in centrosymmetric
fashion, while the 21-screw-related molecules are arranged in a zig-
zag fashion in the latter. Hence centrosymmetric versus non-
centrosymmetric space group selections in these molecules may be
attributed to differences in hydrogen bonding and molecular
arrangements.
A plausible mechanism for our studies is presented in Scheme 3.
This mechanism is identical to those of one reported by Yu et. al
for site-selective o-chlorination of 2-phenylpyridine using Cu salts
in the presence of chlorinating agents.[11f] As can be seen, first,
CuBr2 reacts with N-(8-quinolinyl)benzamide scaffold to form
copper(II) complex A. This complex, in turn, undergoes
intramolecular single electron transfer (SET) pathway leading to
cationic radical intermediate B.[11f] Then intramolecular halogen
transfer from
B
to remote C5 position of N-(8-
quinolinyl)benzamide scaffold readily occurs to give Cu(I)-
intermediate complex C. Finally, subsequent loss of a proton, and
copper(I)bromide would give final product 2a. In this mechanism,
we are proposing that solvent DMF functions as the base so as to
trap strongly acidic HBr in the mechanism. This proposition is very
reasonable because we work at a reasonable temperature range
(130ºC-140ºC), and under these conditions, it is well-established
that DMF with water impurity gets oxidized to carbamic acid
which further decomposes to CO2 and basic dimethylamine which
could function as proton-trap.[11g-11h] This rationalization may also
partly explain why stoichiometric amounts of basic additives such
as Cu(OAc)2 are not needed for the reaction described herein (also
see Scheme 1; eqn.1).[11c]
Table 2 : Remote C5 chlorination of the 8-aminoquinoline N-
(8-quinolinyl)benzamide derivatives.
H
Cl
H
H
H
O
H
H
O
CuCl2 (0.6 mmol)
DMF, 140o C, 4 h.
N
H
N
H
R
R
N
N
H
3
H
1
0.2 mmol
O
O
O
O
SET
Cl
Cl
Cl
NH
NH(I)
Cl
N
O
CuBr2
O
H
Br (II)N
N
N
Br
Cu
Cu
1a
N
H
N
N
H
B Br
ABr
H
Me
N
N
N
N
N
O
H3C
F3C
3c, 93%
O
3a, 90%
O
3b, 92%
O
H
Cl
Cl
Br
Br
O
O
CF3
CuBr
H
SE
T
N
H
N
H
N
H
N
H
NH(I)
N
N
N
Cu
F
2a
Br
3d, 72%
3e, 70%
3f, 72%
Cl
C
HCONMe2 + H2O
Me2NCOOH + 2H+
Cl
O
O
N
N
H
H
Me2NH + CO2
N
N
S
Br
3g, 70%
3h, 71%
Scheme 3
a Reaction conditions: 1 (0.2 mmol), CuCl2 (0.6 mmol), DMF (2.0 mL),
stirred at 140 °C, under air, 4h Isolated yields
Conclusions
In summary, we have developed a simple, novel, concise and
efficient method for the remote C-H bond halogenation (Br &
Cl) of 8-aminoquinoline scaffolds on the C5 position that is
geometrically difficult to access using 24 different substrate
combinations. The outstanding site-selectivity of the reaction was
reflected by the fact that the lack of formation of undesired C7-
halogenated byproduct originating from high nucleophilic
reactivity of 8-aminoquinoline scaffolds at the C7 position even
when excess CuX2 salts were used.
Acknowledgments
N. S. Rao and G. M. Reddy thank Dr. B. M. Reddy, and
Council of Scientific and Industrial Research (CSIR), New
Delhi, India for Fellowship & Financial support.
Figure. 2 : The X-ray structure of (3b), showing the atom-
labelling scheme. Displacement ellipsoids are drawn at the 30%
probability level. The dashed line indicates a hydrogen bond.
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10.1002/ejoc.201601151
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COMMUNICATION
Keywords: Quinolines; Bromination and Chlorination; Cu(II)
salts.
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X-ray Crystallographic Data: CCDC 1486157 (2b, Table 1);
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[3] Quinolines are used as flurescent probes to detect Zn2+ Fe3+
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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Text for Table of Contents
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here))
Layout 2:
COMMUNICATION
Naidu Sambasiva Rao, Ganapam
Manohar Reddy and H.Maheswaran*
7
C
H
C5
H
H
H
H
X
H
H
O
H
O
O
H
H

Page No. – Page No.
CuX2
DMF
NH
N
Cu
NH
Title
N
N
N
H
X
R
R
R
Copper-mediated remote highly site-
selective C-H bond bromination and
chlorination of Quinolines on the C5-
position that is geometrically difficult to
access
X
24 substrates up to 98% yield
Text
R
f
=
o
H
r
,C
T
Ha3b,OleMe
o
,C
f
F3
C
,F
o
,C
nt
l
,
e
B
nt
s
chelation-induced
X=Br,Cl
Key Topic: Regioselective Direct C5-H Halogenation
A concise, simple and efficient method for the remote C-H bond halogenation (Br & Cl) of
8-aminoquinoline scaffolds on the C5 position that is geometrically difficult to access is presented
with diverse substrate combinationsin DMF. This protocol makes use of inexpensive CuBr2 and
CuCl2 as mediator and shows good to excellent yields for as many as 24 substrate combinations.
The outstanding site-selectivity of the reaction was reflected by the fact that the lack of formation
of undesired C7-halogenated by-product originating from high nucleophilic reactivity of
8-aminoquinoline scaffolds at C7 position even when excess CuX2 salts were used.
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