Direct copper(II)-mediated regioselective α-halogenation of N-aryl enaminones

Article abstract of DOI:10.1016/j.tetlet.2016.09.076

A mild copper(II)-mediated α-halogenation of N-aryl enaminones was developed. α-Halogenated N-aryl enaminones were obtained in moderate to good yields using CuX₂in EtOH at 40 °C.

Full text of DOI:10.1016/j.tetlet.2016.09.076

Tetrahedron Letters xxx (2016) xxx–xxx
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Tetrahedron Letters
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Direct copper(II)-mediated regioselective
enaminones
a-halogenation of N-aryl
a,
Hui Xu a, Pan Zhou a, Rong Hang b, Jie Zhou b, Ling-Ling Lu a, Yuehai Shen a, , Fu-Chao Yu
⇑
⇑
a Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650504, PR China
b Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University,
Kunming 650091, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild copper(II)-mediated a-halogenation of N-aryl enaminones was developed. a-Halogenated N-aryl
enaminones were obtained in moderate to good yields using CuX2 in EtOH at 40 °C.
Received 4 August 2016
Revised 21 September 2016
Accepted 23 September 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Halogenation
N-Aryl enaminones
a-Halogenated N-aryl enaminones
Regioselective
Copper(II) halide
Introduction
O
MeO2C
Me
Cl
O
The sp2 C–X units are one of the most important strategic tools
in organic chemistry, which provide easy starting points for the
preparation of functionalized building blocks and intermediates.1
Conventionally, the synthetic methods for sp2 C–X bond formation
are mainly via electrophilic substitution using molecular halogen
or N-X-based reagents.2 However, these methods have some draw-
backs, such as toxic reagents, harsh reaction conditions, low yields,
and poor regioselectivity. Recently, transitional metal–catalyzed
C–H functionalization–halogenation has been studied extensively,3
which offers unique regioselectivities in high yields. But these
methods require the assistance of nitrogen- or oxygen-containing
directing groups, thus limiting their synthetic applications. Nota-
N
H
N
2
Anticonvulsant
Cl
O
O
1 enaminone
i-Pr
N
H
Br
O
OH
NH
MeO
MeO
OMe
N
H
OMe
Cl
3
4
GABAAR modulator
Antiproliferative
Figure 1. Representative bioactive enaminones.
bly, for the direct halogenation of
a,b-unsaturated carbonyl com-
pounds, far fewer synthetic choices are available other than
traditional methods.4 Recent examples in this area include
a-halo-
previous work:
NR1R2
genation of cyclohexenones using oxidant/pyridine hydrohalides,5a
NR1R2
X
NXS
one pot b-halogenation of cyclohexenones via a hydrazone inter-
(a)
(b)
mediate,5b and
a
-halogenation of
a,b-unsaturated amides by Rh
X = Cl, Br, I
ref. 4b
(III)-catalyzed b-C–H activation.5c
O
O
O
this work:
Enaminones (Fig. 1, 1) are well known for their versatile reactiv-
ity, and have been widely used in the synthesis of a variety of
O
H
X
CuX2
Ar1
Ar1
Ar2
Ar2
EtOH, 12 h
X = Cl, Br
6
N
H
5
N
H
⇑
Corresponding authors. Tel.: +86 871 65920747.
E-mail addresses: yuehaishen@gmail.com (Y. Shen), yufuchao05@126.com
(F.-C. Yu).
Scheme 1. a-Halogenation of enaminones.
http://dx.doi.org/10.1016/j.tetlet.2016.09.076
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
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2
H. Xu et al. / Tetrahedron Letters xxx (2016) xxx–xxx
heterocyclic6 and fused heterocyclic compounds.7 In addition,
Table 1
Optimization of reaction conditionsa
enaminone is also a common motif in some biologically active
compounds and potential drug candidates8 (Fig. 1, compounds
2,8a 38d and 48b). As direct halogenation of enaminones could
efficiently increase the structural diversity of target compounds
and provide further chances of modification, developing selective
methods is thus potentially valuable. However, to the best of our
knowledge, although significant progress in halogenation has
been achieved, the halogenation of enaminones is still
surprisingly underdeveloped (Scheme 1a).4b Copper(II) salts has
been demonstrated as effective reagents or catalysts for
halogenation9 as exemplified in the synthesis of aryl halides,3h,10a
2-/3-haloindoles,10b,c and halopyrrolones.10d Inspired by these
studies, we herein report an efficient and highly regioselective
O
H
O
Cl
MCln
solvent, 12 h
N
N
H
H
6a
5a
Entry
Solvent
Catalyst (equiv)
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
DCM
DCM
DCM
DCM
FeCl3 (1.0)
CrCl2 (1.0)
BiCl3 (1.0)
CuCl (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (1.0)
CuCl2 (2.0)
CuCl2 (3.0)
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
40
rt
n.r.
n.r.
n.r.
n.r.
50
27
40
43
45
DCM
Xylene
Toluene
Hexane
Cyclohexane
Acetonitrile
DMF
DMSO
Water
Glycerol
PEG-400
MeOH
EtOH
method for the synthesis of
a-halogenated N-aryl enaminones
9
utilizing CuX2 as the halogenation reagent (Scheme 1b).
10
11
12
13
14
15
16
17
18
19
20
21
35
n.d.c
n.d.c
n.r.d
n.r.d
n.r.d
36
Results and discussion
N-Aryl enaminone 5a was first selected as a model substrate to
define the optimal reaction conditions. As shown in Table 1, vari-
ous transitional metal chlorides, solvents, and temperatures were
screened. First, metal chlorides (1.0 equiv) were investigated;
FeCl3, CrCl2, BiCl3, and CuCl could not afford the desired product
6a after reacting in DCM at 80 °C for 12 h (entries 1–4), while CuCl2
delivered 6a in 50% yield (entry 5). Next, the influence of solvents
was studied using CuCl2 as the halogenations reagent. DCM was
found more efficient than non-polar solvent such as xylene,
toluene, hexane, and cyclohexane (entries 6–9). Polar aprotic
62
67
49
72
EtOH
EtOH
EtOH
EtOH
40
40
74
a
b
c
Reagents and conditions: Enaminone 5a (0.3 mmol), solvent (3.0 mL), 12 h.
Isolated yield based on enaminone 5a.
n.d. = no detected.
d
n.r. = no reaction.
Table 2
Scope of enaminonesa,b
O
O
H
X
EtOH, CuX2
40 o
X = Cl, Br
R1
R1
R2
R2
C
N
H
N
H
6
5
O
O
O
O
Cl
Cl
Cl
OMe
Me
Cl
N
H
N
H
N
H
N
H
6d
: 63%
6a
6b
6c: 69%
: 74%
: 65%
Cl
O
O
O
O
O
Cl
OMe
NO2
Cl
NO2
Cl
Me
Cl
Cl
Cl
MeO
N
H
MeO
Me
N
H
MeO
N
H
N
H
c
6e
6f
6g
6h
: n.r.
: 44%
: 55%
O
: 59%
O
O
Cl
OMe
OMe
Cl
Cl
Cl
F
N
H
Me
N
H
MeO
Cl
N
H
MeO
N
H
: 48%
6j: n.r.c
6i
6k: 54%
6l
: 61%
O
O
O
O
Cl
OMe
Cl
OMe
Cl
Cl
F
N
H
N
H
O2N
Me
N
H
F
N
H
6m
6n
6o
6p
: 38%
: 58%
: 55%
O
: 51%
O
O
O
Cl
Cl
OMe
Cl
NO2
Cl
OMe
N
N
S
: 69%
MeO
N
H
N
H
N
H
N
H
c
d
6t: n.d.d
6q
6r
6s
: n.d.
: n.r.
O
O
O
O
Br
F
Br
OMe
Br
F
Br
Cl
N
H
N
H
MeO
O2N
N
H
O2N
N
H
6v
6w
6x
: 40%
6u
: 50%
: 35%
: 41%
a
b
c
Reagents and conditions: Enaminone 5 (0.3 mmol), CuX2 (0.9 mmol), EtOH (3.0 mL), 40 °C, 12 h.
Isolated yield based on enaminones.
n.r. = no reaction.
n.d. = no detected.
d
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H. Xu et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
the Personnel Training Foundation of Kunming University of
Science and Technology (14118841), the Analytical & Testing
Foundation of Kunming University of Science and Technology
(2016T20130137 and 2016M2014718040).
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data and 1H and 13C NMR spectra of the compounds) associ-
ated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2016.09.076.
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Figure 2. ORTEP diagram of 6b; ellipsoids are drawn at the 30% probability level.
solvents, such as acetonitrile, DMF, and DMSO, failed to give any
desired product (entries 10–12). To our delight, EtOH was found
to be a better solvent than DCM (62% yield, entry 17). The reaction
in MeOH gave a decreased yield of 6a (entry 16), whereas water,
glycerol, and PEG-400 were ineffective solvents (entries 13–15).
In order to further improve the yield, the amount of CuCl2, and
temperature were evaluated. We found that the reaction using
3.0 equiv CuCl2 in EtOH at 40 °C for 12 h provided the best results
(74%, entry 21).11
With the optimal reaction conditions in hand, the scope of sub-
strates was then explored. The results are summarized in Table 2.
N-aryl enaminones 5 with various R1 and R2 substituents, including
electron-withdrawing (4-NO2, 4-F and 2/4-Cl phenyl), electron-
neutral (phenyl) and electron-donating (4-OMe and 4-Me phenyl)
groups, were tested. Most of the reactions proceeded smoothly and
afforded the a-chlorinated enaminones in moderate to good yields
utilizing CuCl2 as the chlorinating reagent (6a–6d, 6f–6i and
6k–6q, 74–35%). However, the reactions failed for substrates con-
taining a nitrated N-phenyl group or a pyridyl ketone moiety, pre-
sumably due to their highly electron deficient natures (6e, 6j, 6r,
and 6s). The substrate with N-cyclohexyl group was also unable
to deliver the desired product (6t). In addition, the reactions of
CuBr2 were tested, and found able to give the corresponding
a-brominated products 6u–6x in 35–50% yields. At last, the struc-
ture of the product was further confirmed by the X-ray single-crys-
tal diffraction studies on 6b (Fig. 2, CCDC 1474342).12
In terms of the reaction mechanism, given that the C@C bond in
enaminones is electron rich, and Cu(II) can be reduced to Cu(I), it is
likely that the reaction experiences a single electron transfer (SET)
mechanism. However, further evidences are necessary to disclose
the details.
Conclusion
In summary, we have developed a novel method for the synthe-
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sis of
a-halogenated N-aryl enaminones via a regioselective halo-
genation. Except substrates bearing extremely electron poor
aryls, various N-aryl enaminones gave moderate to good yields in
the presence of copper(II) halides in EtOH. Attempts toward further
understanding of the reaction mechanism and synthetic applica-
tions are underway in our laboratory.
Acknowledgments
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We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (No. 21402070),
Please cite this article in press as: Xu, H.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.09.076

4
H. Xu et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Huang, F.; Wu, P.; Wang, L.; Chen, J.; Sun, C.; Yu, Z. Chem. Commun. 2014,
12479.
1311, 1246, 1102, 1028, 832, 796, 744, 691 cmÀ1 1H NMR (500 MHz, CDCl3):
;
d = 6.92 (d, J = 8.0 Hz, 2H, ArH), 7.06–7.10 (m, 1H, ArH), 7.23 (d, J = 13.0 Hz, 1H,
NH), 7.29–7.33 (m, 2H, ArH), 7.45–7.48 (m, 2H, ArH), 7.51–7.54 (m, 1H, ArH),
7.61–7.62 (m, 2H, ArH), 7.85 (d, J = 13.0 Hz, 1H, C@CH); 13C NMR (125 MHz,
CDCl3): d = 109.8, 116.4, 116.4, 124.1, 128.4, 128.4, 128.5, 128.5, 130.0, 130.0,
131.1, 138.8, 139.2, 141.2, 188.1; HRMS (TOF ES+): m/z calcd for C15H12ClNNaO
[(M+Na)+], 280.0500; found, 280.0503.
11. Procedure for the synthesis of compounds 6a: Enaminone 5a (0.3 mmol), EtOH
(3.0 mL) and CuCl2 (0.9 mmol) were added into a 10mL Ace Glass pressure
tubes, and the mixture was stirred at 40 °C for 12 h until enaminone 5a were
completely consumed. The mixture was cooled to room temperature,
concentrated under reduced pressure, and then taken up in EtOAc
(15 mL Â 2). The solution was washed with water (10 mL), dried over
Na2SO4, concentrated, and purified by flash column chromatography to
12. CCDC 1474342 contains the supplementary crystallographic data for
compound 6b. These data can be obtained free of charge from The
Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_
request/cif.
afford
a-halogenated enaminone 6a. 2-chloro-1-phenyl-3-(phenylamino)prop-
2-en-1-one (6a): White solid; mp 163–165 °C; IR (KBr): 3344, 1644, 1507,
Please cite this article in press as: Xu, H.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.09.076