Copper-catalyzed arenes amination with saccharins

Article abstract of DOI:10.1007/s11426-015-5385-y

A novel copper-catalyzed direct C-N formation reaction of simple arenes with cheap and pharmacological saccharin derivatives under relatively mild conditions was developed with arenes as limiting reagents. This work provided a new method for oxidative cou

Full text of DOI:10.1007/s11426-015-5385-y

SCIENCE CHINA
Chemistry
•
ARTICLES •
doi: 10.1007/s11426-015-5385-y
·
SPECIAL ISSUE · CH bond activation
Copper-catalyzed arenes amination with saccharins
2
1*
1*
Kai Sun , Yan Li & Qian Zhang
1
Department of Chemistry, Northeast Normal University, Changchun 130024, China
2
College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang 455000, China
Received December 6, 2014; accepted December 24, 2014
A novel copper-catalyzed direct C–N formation reaction of simple arenes with cheap and pharmacological saccharin deriva-
tives under relatively mild conditions was developed with arenes as limiting reagents. This work provided a new method for
2
oxidative coupling of aromatic C(sp )–H bonds and N–H bonds.
aromatic amines, C–N bond formation, arenes, saccharins, arenes as limiting reagents
3
1
Introduction
C(sp )–H amination reaction [8], directed aromatic
2
C(sp )–H amination [9], allylic C–H amintion [10], annula-
tion of amidines [11], diamination, aminocynation [12] and
aminofluorination [13] of alkenes, herein, in the presence of
Aromatic amines widely exist in both naturally occurring
and synthetic compounds which demonstrate high levels of
biological activity [1]. Accordingly, various methods for the
construction of C–N bonds were developed and successfully
used in academia [2] and industry [3]. For example, cross
coupling reactions of aromatic halides/pseudohalides with
amines, as well as arenes with various aminating reagents
(e.g., N–Cl, N–Br, N–F, N–O), were commonly applied to
form C–N bonds [4–6]. In both cases, prefunctionalization
of arenes or amines was required. Recently, the direct C–N
formation reaction between C–H and N–H bond [7] became
an additional powerful methodology for the construction of
C–N bonds, which could avoid prefunctionalization of the
substrates and minimize environmental impact. Cho et al.
[
1
7b] (Scheme 1(A-a)) and DeBoef et al. [7d] (Scheme
(A-b)) reported intermolecular imidation reactions be-
tween C–H bonds of arenes and N–H bonds of nitrogen
sources with hypervalent iodine(III) as oxidant based on
Togo’s work [7c]. Under their conditions, arenes were usu-
ally used as solvents to ensure efficient amination. As part
+
of our interest in utilizing F oxidants to perform benzylic
*
Corresponding authors (email: liy078@nenu.edu.cn; zhangq651@nenu.edu.cn)
Scheme 1 Synthesis of aromatic amines.
©
Science China Press and Springer-Verlag Berlin Heidelberg 2015
chem.scichina.com link.springer.com

2
Sun et al. Sci China Chem June (2015) Vol.58 No.6
Selectfluor, copper-catalyzed facile construction of C–N
bond between simple arenes (used as limiting reagents) and
saccharin derivatives via oxidative coupling of C–H and
N–H bonds was realized (Scheme 1(B)). The saccharin
moiety has been identified as an important molecular com-
ponent in various classes of 5HT1a antagonists [14], human
leukocyte elastase (HLE) inhibitors [15], analgesics [16],
human mast cell tryptase inhibitors [17], 1-a adrenergic
receptor antagonists [18] and aldehyde dehydrogenase in-
hibitors [19]. Therefore, various saccharin derivatives,
which were generally synthesized starting from ortho-
difunctional arenes [20], were chosen as the nitrogen
sources in this study. Our new methodology based on the
6 h, the desired amination product 2a was obtained in 75%
yield (Table 1, Entry 1). The yield of 2a could be increased
to 94% when Selectfluor was employed as the oxidant (En-
try 2). Even in the absence of 1,10-phenanthroline, 2a could
also be obtained in 83% yield (Entry 3). However, F oxi-
dant 1-fluoro-2,4,6-trimethylpyridinium triflate (NFTMPT)
+
was ineffective (Entry 4), neither were other oxidants such
as Ce(SO
ferent copper catalysts like CuBr, CuCl
Cu(OTf) could also promote this amination to provide 2a
4
)
2
2
, K S
2
O
8
and PhI(OCOCF
3
)
2
(Entries 5–7). Dif-
2
, CuF , CuBr and
2
2
2
in 79%, 54%, 59%, 23% and 37% yields, respectively (En-
tries 8–11) and no reaction was observed in the absence of
copper salt (Entry 12). Solvents such as acetonitrile
2
formation of C–N bond directly from C(sp )–H bond of
3
(CH CN) and 1,2-dichloroethane (DCE) could afford the
arenes and N–H bond of saccharins will provide an attract-
ing alternative approach for saccharin derivatives.
desired aminative product but in relatively low yields (En-
tries 13 and 14). Other solvents, such as tetrahydrofuran
(
(
THF), nitrobenzene (PhNO
DMF) were ineffective (Entries 15–17). It should be noted
2
) and N,N-dimethylformamide
2
Experimental
that only stoichiometric arene substrates were used in all
these cases [7b–7d].
2
.1 General experimental section
With the optimized conditions in hand (Table 1, Entry 2),
we next examined the generality of this amination reaction
with respect to substitutions at aromatic rings. As described
in Table 2, benzene (1b) and naphthalene (1c) could
smoothly react with saccharin to afford 2b and 2c in 57%
All reagents were used as received from commercial
sources, unless otherwise specified or prepared as described
in the literature. All reagents were weighed and handled in
air.1
13
H NMR and C NMR spectra were respectively rec-
a)
orded at 500 and 125 MHz, using tetramethylsilane as an
internal reference. Chemical shifts () and coupling con-
stants (J) were expressed in parts per million and hertz, re-
spectively.
Table 1 Optimization of reaction conditions
2
.2 General procedure for the copper-catalyzed C–N
b)
Entry
Catalyst
Oxidant
Solvent
CH NO
CH NO
Yield (%)
formation of saccharins with arenes
1
2
3
4
5
6
7
8
9
9
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuBr
NFSI
3
2
75
Selectfluor
Selectfluor
3
2
94
To a 5 mL screw-capped vial equipped with a 15×10 mm
spinvane triangular-shaped Teflon stirbar, simple arene 1
c)
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
NO
NO
NO
NO
NO
NO
NO
NO
NO
2
83
d)
NFTMPT
Ce(SO
2
0
0
(
K
0.5 mmol), saccharin (1.0 mmol), Selectfluor (1.0 mmol),
CO (1.0 mmol) and CuCl (0.1 mmol) were added in
4
)
2
2
2
2
2
2
2
2
2
3
K
2
S
2
O
8
0
nitromethane (3.0 mL). The mixture was sealed with a
Teflon-lined cap and stirred at 90 °C for 6.0 h (monitored
by TLC), extracted with dichloromethane (5×3 mL), and
PhI(OCOCF
3
)
2
0
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
79
54
59
23
37
0
CuCl
CuF
CuBr
2
2 4
dried over anhydrous Na SO . The solvent was removed
2
under reduced pressure, and the residue was purified by
flash silica gel column chromatography to give aromatic
amine 2. The characterizations of aromatic amines 2 and 4
were listed in the Supporting Information online.
1
0
2
11
12
13
Cu(OTf)2
none
3
CH NO2
CH
CH
3
NO
CN
2
CuCl
3
65
84
5
1
1
4
5
CuCl
DCE
THF
CuCl
3
Results and discussion
16
CuCl
PhNO2
DMF
0
1
7
CuCl
0
a) Reactions were carried out with 1a (0.5 mmol), copper catalyst (10
mol%), 1,10-phenanthroline (0.1 equiv.), Selectfluor (2.0 equiv.), saccharin
2.0 equiv.) and K CO (2.0 equiv.) in CH NO (3 mL) at 90 °C for 6 h; b)
2 3 3 2
yield of the isolated product; c) without 1,10-phenanthroline; d) NFTMPT=
Initially, biphenyl 1a (0.5 mmol) was tested in the presence
of 10 mol% CuCl, 1,10-phenanthroline (0.1 equiv.),
N-fluorobenzenesulfonimide (NFSI, 2.0 equiv.) and saccha-
(
rin (2.0 equiv.) at 90 °C with CH
3
NO
2
as the solvent. After
1-fluoro-2,4,6-trimethylpyridinium triflate.

Sun et al. Sci China Chem June (2015) Vol.58 No.6
3
a, b)
Table 3 Direct amination with various nitrogen sources
and 94% yields, respectively. For substrates 1d–1n with
various electron-withdrawing or electron-donating groups at
aromatic rings, the amination reactions proceeded with high
site-selectivity, forming 2d–2n in 62%–94% yields. The
structure of 2d was further confirmed by X-ray crystallog-
raphy [21]. It should be noted that halogen substituents such
as Cl (2g and 2j) and I (2k) were well tolerated, which
provides the possibility for further transformation. In addi-
tion, hetero-aromatic compounds such as pyrrole (1o), furan
(
1p) and thiophene (1q) proved to be suitable substrates for
this amination reaction, affording the 2-aminative products
2
o, 2p and 2q in 94%, 71% and 84% yields, respectively.
Next, other imide derivatives with substituents at the iso-
thiazol-3(2H)-one 1,1-dioxide were examined (Table 3).
Both 5-(4-chlorophenyl)-4-methylisothiazol-3(2H)-one 1,1-
dioxide (3a) and 4-methyl-5-phenylisothiazol-3(2H)-one
a) Reactions were carried out with 1a (0.5 mmol), CuCl catalyst (10
mol%), 1,10-phenanthroline (0.1 equiv.), Selectfluor (2.0 equiv.), 3 (2.0
equiv.) and K
yield of the isolated product.
2 3 3 2
CO (2.0 equiv.) in CH NO (3 mL) at 90 °C for 12 h; b)
a, b)
Table 2 Direct amination with various arenes
1
,1-dioxide (3b) could undergo direct amination with bi-
phenyl (1a), providing 4a and 4b in 86% and 77% yields,
respectively. Aliphatic disubstituted imides 3c and 3d could
also give the desired products 4c and 4d.
NSacc
SaccN
a, 6 h, 94%
NSacc
SaccN
2b, 12 h, 57%
In order to understand the mechanism of these aromatic
2
C(sp )–H amination reactions, we carried out some control
2
2
c, 12 h, 94%
experiments. In the presence of 1.0 equiv. of 2,2,6,6-
tetramethyl-1-piperidinoxyl (TEMPO) under standard reac-
tion conditions, the yield of 2a drastically decreased from
O
O
9
4
4% to 5%. Moreover, when 1.0 equiv. of 2,6-di-tert-butyl-
-methylphenol (BHT) was added, the reaction was com-
SaccN
O
2
e, 2 h, 94%
pletely suppressed and no 2a was detected. These experi-
mental results suggested a possible radical mechanism. In
addition, no isotope effect (k /k =1.08, Scheme 2, the reac-
tion was performed under the optimal reaction conditions)
was observed, implying the C–H bond cleavage of benzene
was not involved in the rate-limiting step.
2
d, 6 h, 93%
2d X-Ray
F
Cl
O
H
D
SaccN
O
SaccN
SaccN
O
O
2f, 6 h, 93%
2g, 6 h, 80%
2h, 12 h, 76%
Although the detailed mechanism of this amination was
unclear at this moment, based on the experimental results
and the previous research work [5c,6a,7c,8a,12,13], we
presently favor a radical pathway. Initially, in the presence
of copper-catalyst, the oxidation of saccharin with Select-
fluor provides imidyl radical, which performs addition reac-
tion to the aromatic ring to provide a carbon radical inter-
mediate. The subsequent oxidative aromatization affords the
SaccN
SaccN
O
SaccN
O
Cl
O
I
2i, 12 h, 67%
2j, 12 h, 75%
SaccN
2k, 12 h, 93%
SaccN
O
SaccN
O
O
CN
O
O
2l, 12 h, 62%
2m, 12 h, 62%
2n, 2 h, 70%
S
H
O
N
SaccN
SaccN
SaccN
2o, 6 h, 94%
2p, 6 h, 71%
2q, 6 h, 84%
a) Reactions were carried out with 1 (0.5 mmol), CuCl catalyst (10
mol%), 1,10-phenanthroline (0.1 equiv.), Selectfluor (2.0 equiv.), saccharin
(
2.0 equiv.) and K
2
CO
3
(2.0 equiv.) in CH
3
NO
2
(3 mL) at 90 °C; b) yield of
Scheme 2 The kinetic deuterium isotope effect of the reaction between
the isolated product.
benzene and saccharin.

4
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In summary, we have developed a copper-catalyzed inter-
molecular oxidative C–N formation reaction of simple
arenes with cheap and pharmacological saccharins under
relatively mild conditions, in which arene substrates served
as limiting reagents. High yields, wide arene substrate scope
and the useful saccharin moiety made this direct C–H ami-
nation strategy very attractive. Further investigation of de-
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