Copper-promoted Chan-Lam coupling between enaminones and aryl boronic acids

Article abstract of DOI:10.1016/j.tetlet.2018.10.030

A novel copper-promoted N-arylation of enaminones with aromatic boronic acids has been developed, which provides an efficient way to synthesize N-aryl enaminones with a broad substrate scope and excellent functional group compatibility. The N-aryl enaminones could be converted into a series of highly valuable building blocks and bioactive compounds. Notably, in comparison with traditional methods, this alternative approach provides accesses to N-aryl enaminones bearing multiple aromatic rings.

Full text of DOI:10.1016/j.tetlet.2018.10.030

Accepted Manuscript
Copper-Promoted Chan−Lam Coupling between Enaminones and Aryl Boronic
Acids
Xiyan Duan, Ning Liu, Kun Liu, Yakun Song, Jia Wang, Xianhua Mao,
Weidong Xu, Shijie Yang, Huixian Li, Junying Ma
PII:
S0040-4039(18)31237-1
https://doi.org/10.1016/j.tetlet.2018.10.030
TETL 50340
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 September 2018
12 October 2018
16 October 2018
Please cite this article as: Duan, X., Liu, N., Liu, K., Song, Y., Wang, J., Mao, X., Xu, W., Yang, S., Li, H., Ma, J.,
Copper-Promoted Chan−Lam Coupling between Enaminones and Aryl Boronic Acids, Tetrahedron Letters (2018),
doi: https://doi.org/10.1016/j.tetlet.2018.10.030
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Graphical Abstract
.
Copper-Promoted Chan−Lam Coupling between
Enaminones and Aryl Boronic Acids
Leave this area blank for abstract info.
Xiyan Duan,*a Ning Liu, a Kun Liu,a Yakun Song,a Jia Wang,a Xianhua Mao,a Weidong Xu,a Shijie Yang,a Huixian Li,a
Junying Ma *a
Ar
O
NH2
R2
O
HN
Cu(OAc)2
R1
R1
R2
ArB(OH)2
Et3N, DCE
air, 50 oC
R1 = aryl, alkyl, OMe
R2 = aryl, alkyl
this work
24 examples
up to 98% yield
effective C-N bond formation
broad scope
Tetrahedron Letters
journal homepage: www.elsevier.com
Copper-Promoted Chan−Lam Coupling between Enaminones and Aryl Boronic Acids
Xiyan Duan* a, Ning Liu a, Kun Liu a, Yakun Song a, Jia Wang a, Xianhua Mao a, Weidong Xu a, Shijie
Yang a, Huixian Li a, Junying Ma* a,
a School of Chemical Engineering & Pharmaceutics, Henan University of Science and Technology, Luoyang 471003, Henan, China;
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel copper-promoted N-arylation of enaminones with aromatic boronic acids has been
developed, which provides an efficient way to synthesize N-aryl enaminones with a broad
substrate scope and excellent functional group compatibility. The N-aryl enaminones could be
converted into a series of highly valuable building blocks and bioactive compounds. Notably, in
comparison with traditional methods, this alternative approach provides accesses to N-aryl
enaminones bearing multiple aromatic rings.
Available online
Keywords:
2013 Elsevier Ltd. All rights reserved.
Copper-promoted
Chan-Lam Coupling
Enamines
Aryl boronic Acids
C-N bond formation
N-aryl enaminones have been recognized as important synthetic intermediates and building blocks in organic chemistry because of
their versatile chemical reactivities.1a-1i For instance, elegant methodologies have been developed for the transformation of N-aryl
enaminones into various N-heterocycles including indole,1b,1h 1,2,3-Triazoles,1f Benzo[b][1,4]oxazins,1i and pyrroles1c. In addition, N-
aryl enaminones derivatives have drawn extensive and enduring attention for their broad range of biological activities and significant
pharmaceutical potentials, such as antiviral, anti-bacterial, anticonvulsant, anti-tussive, and anti-inflammatory activities.2
The most well-known synthetic methods of N-aryl enaminones have utilized the direct condensation of 1,3-dicarbonyl compounds
with amines in a refluxing aromatic solvent in the presence of various catalysts (Scheme 1a).3 Although these methods are in general
well suitable for symmetrical β-diketones and several unsymmetrical β-dicarbonyls (arylalkyldicarbonyls), the reaction of
unsymmetrical β-diketones bearing substituted aromatic ring with aniline gives two isomeric enaminones (Scheme 1b).4a Moreover,

most of these procedures suffer from drawbacks which include the need for the excess amount of amine reagents, drastic reaction
conditions,4b,4f non-reusability of the catalyst,4c long reaction times,4d-f unsatisfactory yields and low selectivity4f.
Sonogashira cross-coupling of terminal alkynes with aroyl chlorides, followed by the Michael addition of anilines with the resultant
α, β-ynones has been developed as an alternative strategy to build N-aryl enaminones (Scheme 1c),1b,5 especially in the synthesis of N-
aryl enaminones bearing multiple aromatic rings. 1b,1h,1f However, this method generally suffers from drawbacks which include the need
for expensive transition-metal catalysts, harsh reaction conditions, and multistep operations. Therefore, new synthetic methods for N-
aryl enaminones synthesis are still under great demand.
R3
R2
R3NH2
O
O
O
HN
(a)
R1
R2
R1
catalysts
R1, R2 = Ar, alkyl; or R1 = Ar, alkyl; R2 = alkyl
R3NH2
catalysts
R3
R3
O
O
NH
O
O
HN
+
(b)
R1
R2
R1
R2
R1
R2
two isomeric enaminones
unsymmetrical arylaryldicarbonyls
O
R3
R3NH2
O
HN
R1
(c)
base
R2
R1
R2
Ar
O
NH2
R2
O
HN
Cu(OAc)2
R1
R1
R2
this work
(d)
ArB(OH)2
R1 = aryl, alkyl, OMe
R2 = aryl, alkyl
Et3N, DCE
air, 50 o
C
Scheme 1. Synthesis of N-aryl enaminones
Copper-promoted Chan-Lam reactions represent one of the most powerful and straightforward tools to construct C-heteroatom
bonds via cross-coupling reactions of aryl boronic acids and different nucleophiles that possess significantly synthetic utility in
chemical synthesis.6 A wide range of N nucleophiles such as amines, anilines, amides, imides, ureas, carbamates, sulfonamides, cyanate
ion, indazole, aqueous ammonia, and azides have been reported to be utilizable in the Chan-Lam reaction with aryl boronic acids.6a-6o
However, the Chan-Lam reactions have rarely been used in the C-N cross-coupling reactions of enaminones. Herein, we report an easy
and highly efficient copper-promoted method for the synthesis of N-aryl enaminones in air at low temperature (50 °C) without the
addition of a ligand (Scheme 1d).
We commenced our investigation by using (Z)-3-amino-1,3-diphenylprop-2-en-1-one 1a and phenylboronic acid as the model
substrates and examined the reaction parameters to identify optimal conditions (Table 1). Firstly, various copper catalysts were
investigated in an open flask using 1,2-dichloroethane (DCE) as a solvent at 50 °C. Only CuCl and Cu(OAc)2 worked for this reaction
(entry 1 and entry 6). Other copper catalysts including CuBr, CuI, CuCl2, and CuBr2 were also studied, but no desired N-arylated
product 2a was observed in any of the cases (entries 2-5). The dosage of Cu(OAc)2 was decreased from 1 to 0.5 equivalents led to no
substantial change. Different additives were also screened (Table 1, entries 8-10) and it was found that Et3N was the most efficient
(Table 1, entry 10). Decreasing the amount of Cu(OAc)2 led to a decrease in yield and incomplete conversion was observed. For
example, when the amount of Cu(OAc)2 was decreased to 0.1 equiv, the reaction afforded a 45% yield of the product 2a (Table 1, entry
11). To our disappointment, when the reaction was operated at room temperature, the reaction turned out to be sluggish with lower
conversions and yield (Table 1, entry 12).
Table 1. Optimization of Reaction Conditionsa
Catalysts,
Ph
Additives
O
NH2
O
HN
PhB(OH)2
air, Solvent
50 oC, 24 h
1a
2a

Entry
Catalysts
(equiv)
Additives
(equiv)
Yield
(%)b
47
NR
NR
NR
NR
58
57
60
95
98
With the optimized conditions in hand, we first investigated the scope of the
Cu-promoted Chan−Lam coupling with respect to various enaminones. As shown
in Table 2, most of enaminones employed under the optimized conditions
furnished moderate-to-excellent yields within 24 h at 50 °C. It was found that
enaminones bearing either electron-donating or electron-withdrawing groups on
the benzene ring 1b-i could perform the Chan-Lam coupling with phenylboronic
acid to give the desired N-aryl enaminones 2b-i in moderate to good yields. The
method was shown to be also well applicable to the enaminone substrates with R1
being 3, 4-dimethoxy phenyl group (2j). For the enaminone substrate with two
substituted aryl group, the reaction also conveniently afforded the desired product
2k in excellent yield. For substrates where the phenyl group was replaced by a
pyridine group, product 2l was produced in 72% yield. Replacing the phenyl ring
with a naphthyl ring in the substrate does not hamper the reaction, and the desired
product 2m could be obtained in good yield. Moreover, when the benzene ring of
the substrates was changed to ester group, the reactions successfully provided the
N-aryl enaminone product 2n in moderate yield. For substrate when the benzene
group of the substrate (R1) was changed to a more sterically hindered tert-butyl
group, product 2o was produced in 65% yield. Further experiments showed that
this method worked equally well for enaminones when the benzene group of the
1
2
3
4
5
6
CuCl (1)
CuBr (1)
CuI (1)
CuCl2 (1)
CuBr2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (0.5)
Cu(OAc)2 (0.5)
-
-
-
-
-
-
-
7 c
8c
9 c
10 c
11
12 d
KOtBu (0.5)
Cu(OAc)2 (0.5) Pyridine(0.5)
Cu(OAc)2 (0.5)
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.5)
Et3N (0.5)
Et3N (0.5)
Et3N (0.5)
45
60
a Reaction conditions: catalysts (0.2 mmol), enaminone 1a
(0.2 mmol), phenylboronic acid (0.4 mmol), DCE (5 mL), 50
°C, under air, 24 h. b Determined by 1H NMR using 1,3,5-
Trimethoxybenzene as an internal standard. c Reaction
conditions: catalysts (0.1 mmol), additives (0.1 mmol),
enaminone 1a (0.2 mmol), phenylboronic acid (0.4 mmol),
DCE (5 mL), 50 °C, under air, 24 h. d. room temperature
substrate (R2) was changed to the alkyl group (2p-q).
Table 2. Scope of the enaminones a, b
Ph
O
NH2
R2
Cu(OAc)2
O
HN
+
PhB(OH)2
R1
R1
R2
Et3N
DCE, air
50 oC
O
HN
O
HN
O
HN
R
R
2a,
98%
, 2f
R= Me , 81%;
2b
R = MeO, , 81%
, 2g
R= F
, 66%;
, 2h
2c
R= Me,
, 80%;
R= Cl
, 67%;
2i
2d
R= F, , 92% ;
2e
R= Br, , 85%;
R= Cl, , 56%;
O
HN
O
HN
O
HN
MeO
MeO
N
MeO
Cl MeO
2l
, 72%
2k
, 90%
2j
, 93%
O
HN
O
HN
O
HN
MeO
2o,
65%
2n
, 75%
2m
, 83%
HN
O
O
HN
2p,
2q,
92%
47%
aReaction conditions: Cu(OAc)2 (0.5 mmol), Et3N (0.5 mmol), enaminone 1a (1 mmol), phenylboronic acid (2 mmol), DCE, 50 °C, under air，24 h. bIsolated
yields.
To further explore the scope of the reaction, various aromatic boronic acids were examined under the standard reaction conditions
(Table 3). In general, the aromatic boronic acids containing either electron-donating (Me− and MeO−) groups or electron-withdrawing
(F−, Cl−, and Br−) groups at the para or meta position gave the corresponding N-aryl enaminones product in good to excellent yields
(2r-2w). Gratifyingly, naphthyl enaminone also efficiently reacted with 4-methylphenylboronic acid, giving product 2x in 68% yield.
Table 3. Scope of the aryl boronic acids a, b

Cu(OAc)2
Et3N
Ar
O
NH2
O
HN
+
ArB(OH)2
Ar
Ph
DCE, air
Ar
Ph
50 o
C
R
Me
Cl
O
HN
O
HN
O
HN
,2r,
R= OMe
R= Me
, 2t
R= Cl
80%;
2x
, 68%
, 2s
, 95%;
2w
, 73%
R= F , 83%;
, 2u
, 88%;
2v
R= Br, , 93%;
a Reaction conditions: Cu(OAc)2 (0.5 mmol), Et3N (0.5 mmol), enaminone 1a (1 mmol), aryl boronic acid (2 mmol), DCE, 50 °C, under air，24 h. b Isolated
yields.
The practical utility of this methodology was also investigated, and a gram-scale reaction of 1a and phenylboronic acid under
standard conditions yielded the desired product 2a in 94% yield (Scheme 2a). The N-aryl enaminones products could be easily
converted into diverse building blocks for biological interesting molecules.1 For example, I2/CuI-mediated intramolecular direct C-H
functionalization of N-aryl enaminone 2a gave indole 3a in excellent yield (Scheme 2b).1h Deacylative diazo transfer/cyclization
reaction of N-aryl enaminone 2a and sulfonyl azides gave 1,5-disubstituted 1,2,3-triazoles 4a in moderate yield (Scheme 2c).1f
Ph
O
NH2
Ph
Cu(OAc)2
O
HN
+
PhB(OH)2
(a)
Ph
Et3N
DCE, air
50 oC
Ph
Ph
1a
Gram-scale
2a
, 94%
Ph
O
Ph
Ph
I2
O
HN
(b)
(c)
CuI, Cs2CO3
Ph
Ph
N
H
2a
3a
, 92%
Ph
Ph
Ph
TsN3
N
N
O
HN
N
LiOtBu
Ph
Ph
4a
, 62%
2a
Scheme 2. Gram-scale reaction and synthetic applications
Our control experiment showed that the addition of radical scavenger TEMPO did not retard the reaction, which indicated that this
reaction may not involve a radical pathway (Scheme 3). Further experiment was conducted in order to gain insight into the mechanism
of the reaction. When the reaction was carried out under N2 atmosphere, the reaction afforded a 46% yield of the product 2a with the
recovery of substrate 1a in 35% yield.
Ph
Ph
O
NH2
Ph
TEMPO (2 eq)
O
HN
+ PhB(OH)2
Ph
standard conditions
Ph
1a
2a
, 95%
HN
Ph
Ph
O
NH2
Ph
Cu(OAc)2
O
+ PhB(OH)2
Ph
Et3N
Ph
1a
DCE, N2
2a
, 46%
50 o
C
Scheme 3. Control experiment.
6n, 6p, 7
On the basis of the above results and previous reports,
we propose a possible mechanism for the coupling reaction between
enaminones and aryl boronic acids. Initially, the enaminones can coordinate to the Cu(ӀӀ) salt forming intermediate A, which
subsequently undergoes transmetalation with aryl boronic acid to give intermediate B. The resulting intermediate B is oxidized by one
equivalent of Cu(II) or air to yield the corresponding higher oxidation-state Cu(ӀӀӀ) intermediate C, which can undergo reductive
elimination to afford the product 2.

O
NHCu(II)Ar
R2
1/2 O2 +2 H+
transmetalation
ArB(OH)2
R1
B
H2O
oxidation
Cu(I)OAc
Cu(II)(OAc)2
O
NHCu(II)(OAc)
O
NHCu(III)Ar
R2
R1
R2
R1
A
C
reductive
elimination
Ar
O
HN
O
NH2
R2
R1
R2
Cu(I)OAc
Cu(II)(OAc)2
R1
2
1
1/2 O2 +2 H+
oxidation
H2O
Scheme 4. Proposed reaction mechanism.
In summary, Cu-promoted Chan-Lam coupling reaction of enaminones with aryl boronic acids has been developed. This novel
method provides an efficient access to N-aryl enaminones. Various substituted N-aryl enaminones were synthesized in moderate to high
yields with a good functional group tolerance. This work not only provides an effective approach to access N-aryl enaminones, but also
contributes new knowledge to Chan-Lam coupling reaction.
Acknowledgments
X. Duan acknowledges the Science and Technology Foundation of Henan Province (182102310106). Students research training
program of Henan University of Science and Technology.
Supplementary data
1
Supplementary data (list of new compounds along with their yield and copies of H NMR and 13C NMR spectra are included)
associated with this article can be found, in the online version, at http://.
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•Chan−Lam coupling between enaminones and aryl boronic acids.
•Our approach provides accesses to N-aryl enaminones bearing multiple aromatic rings.
• The reaction can be conducted on gram scale.
Copper-Promoted Chan−Lam
Coupling between Enaminones
and Aryl Boronic Acids
Xiyan Duan,*a Ning Liu, a Kun Liu,a Yakun Song,a Jia Wang,a Xianhua Mao,a Weidong Xu,a Shijie Yang,a Huixian Li,a
Junying Ma *a
Graphical abstract
Ar
O
NH2
R2
O
HN
Cu(OAc)2
R1
R1
R2
ArB(OH)2
Et3N, DCE
air, 50 oC
R1 = aryl, alkyl, OMe
R2 = aryl, alkyl
this work
24 examples
up to 98% yield
effective C-N bond formation
broad scope