Synthesis of β,β-diaryl propiophenones via palladium-catalyzed domino arylboronation, elimination and enone hydroarylation of enaminones

Article abstract of DOI:10.1039/c6ob01038e

The syntheses of β,β-diaryl aryl propiophenones have been realized via palladium-catalyzed domino reactions of dimethyl amino functionalized enaminones and aryl boronic acids. This is the first example of transition metal-catalyzed enaminone C-N bond conversion for the generation of a new C-C(aryl) structure.

Full text of DOI:10.1039/c6ob01038e

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DOI: 10.1039/C6OB01038E
Synthesis of β, βꢀdiaryl propiophenones via palladiumꢀcatalyzed domino
arylboronation, elimination and enone hydroarylation of enaminones
Shanshan Zhong,a Yu Lu,a Yan Zhang,a Yunyun Liua and JieꢀPing Wana,*
aCollege of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang 330022, China.
Email: wanjieping@jxnu.edu.cn
The first example on the domino reactions involving the enaminone CꢀN
conversionꢀbased arylation has bee realized as efficient new route toward the
synthesis of β,βꢀ diaryl propiophenones.

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ARTICLE
Synthesis of β, β-diaryl propiophenones via palladium-catalyzed
domino arylboronation, elimination and enone hydroarylation of
enaminones
Received 00th January 20xx,
Accepted 00th January 20xx
Shanshan Zhong,a Yu Lu,a Yan Zhang,a Yunyun Liua and Jie-Ping Wana,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The synthesis of β,β-diaryl aryl propiophenones have been Although not an issue of long research history, the strategy of
realized via palladium-catalyzed domino reactions of dimethyl transition metal-catalyzed C-N bond activation has rapidly
amino functionalized enaminones and aryl boronic acids. This is emerged as a powerful tool in a variety of syntheses via the
the first example of transition metal-catalyzed enaminone C-N construction of new chemical bonds through the C-N bond
bond conversion for the generation of new C-C(aryl) structure.
cleavage.5 Under the inspiration of C-N activation protocols
and our longstanding efforts in exploring new synthetic
applications of enaminones,6 we have envisioned that the
conversion of the C-N bond in the enaminones might also be
potentially useful as complementary route of generating new
C-C bond.
Previously, Georg and co-worker have investigated and
revealed that the coupling reactions between cyclic
enaminones and aryl boronic acids could provide either β- or
α-arylated enaminones via the cleavage of C(sp2)-H bond
under the conditions of Pd-catalysis (Scheme 1).7 While there
is presently no example on enaminone C-N bond conversion-
based arylation available, discovering practical new reactions
initiated by such transformation is a crucial issue in both
complementing the known synthetic application of
enaminones and providing efficient synthetic methods for the
synthesis of diverse arylated products. After making extensive
efforts in screening reaction partners and catalytic conditions,
we report herein an unprecedented domino reaction pattern
toward the synthesis of β, β-diaryl propiophenones via key Pd-
As easily available, structurally diverse and highly reactive
building blocks, enaminones have been well known for their
universal application in both target and diversity-oriented
synthesis.1 As one of the commonsense transformations in the
N,N-disubstituted enaminones, the C-N bond conversion
forming new C-heteroatom bonds such as C-N, C-O and C-S
bonds have been frequently employed and contributed
enormously to the synthesis of functional organic molecules.2
On the other hand, unlike the easy occurrence of C-
heteroatom bond formation, the construction of new C-C bond
by conversing the enaminone C-N bond in the presence of a C-
nucleophile is hardly practical. Actually, except in the classical
[2+2+2] enaminone cyclotrimerization,3 no example of other C-
C bond formation via the conversion of the enaminone C-N
bond has been previously known (Fig. 1). In this regard,
searching for practical catalytic approaches which enable the
construction of new C-C bonds by breaking the C-N bond
makes up a main challenge in the present chemistry of
emaninone-based organic synthesis.4
Figure 1. Construction of new C-heteroatom and C-C bond via enaminone C-N
bond conversion
a.College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang 330022, P.R. China. Email: wanjieping@jxnu.edu.cn
Electronic Supplementary Information (ESI) available: [general experimental
information, procedure for the synthesis of
Scheme 1 Different enaminone C-H arylation reactions
3 and 4,
1H and 13C NMR spectra of all
products and the crystallographic data of 3a]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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catalyzed C-N bond conversion-based arylation (Scheme 1). As led to the observation that the entry in DMF gave better yield
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DOI: 10.1039/C6OB01038E
useful organic molecules, the β, β-diarylated propiophenones of 3a than other investigated solvents (entries 9-13, Table 1).
have been predominantly synthesized by either the In addition, the attempt on using aqueous DMF demonstrated
hydroaryaltion of enones or direct β-C-H arylation of that the mixed DMF/water (v/v = 1 : 4) was even better
propiophenones etc,8 the present method involving the Pd- medium for the reaction (entries 14-16, Table 1). Varying the
catalyzed domino enaminone C=C bond aryl boronation, reaction temperature didn’t afford any improvement on the
elimination and enone hydroarylation represents a brand new product yield (entries 17-18, Table 1). Final examination on
synthetic methodology toward these compounds.
reducing the loading of Pd(OAc)2 and ligand to 5 mol% and 10
Initially, the reaction of enaminone 1a with phenylboronic acid mol% gave identically well result, and further decrease in the
2a was subjected to the condition of Pd-catalysis. It was found catalyst/ligand was not favored (entries 19-20, Table 1).
that the Pd(OAc)2 could catalyze the reaction to provide β, β- The investigation on the application scope of this synthetic
diphenyl ketones 3a in the presence of 2,2’-bipyridine (bpy) method was conducted under the optimal conditions by
o
ligand with 90 C heating (entry 1, Table 1). The employment employing various enaminones
1
and aryl boronic acids
2 for
of different Pd-catalysts indicated that Pd(OAc)2 was a better reaction. The results in providing products
3
were outlined in
catalyst than other palladium catalysts such as Pd(PPh3)4, PdCl2 Table 2,9 according to the acquired results, this protocol is
and Pd/C (entries 2-5, Table 1). Subsequently, control generally tolerable to the reactions of aryl functionalized
experiments using other ligands, such as 1,10-phenanthroline enaminones and aryl boronic acids. Functional groups of
(1,10-phen), PPh3 and
L-proline suggested that bpy was the different properties such as alkyl, alkoxyl, halogen and nitro
most effect ligand (entries 6-8, Table 1). Further optimization etc in both substrates were all well compatible to afford target
on the reaction medium utilizing solvents of different polarity
products with moderate to good yields. And no observable
electronic or steric impact of the substitution to the yield or
related products was observed.
Table 1 Screening of reaction conditionsa
Table 2 Scope for C-N arylation-based synthesis of β, β-diaryl propiophenones
Entry
1
Catalyst
Pd(OAc)2
Pd(PPh3)4
PdCl2
Ligand
bpy
Solvent
NMP
T (oC) Yield(%)b
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
100
80
90
90
40
35
R1
R2
Product
3a
3b
3c
Yield (%)a
75
2
bpy
NMP
H
H
H
3
bpy
NMP
10
4-Me
74
4
Pd/C
bpy
NMP
trace
0
H
4-MeO
72
5
no
bpy
NMP
H
4-F
3d
3e
3f
71
6
Pd(OAc)2 1,10-phen
NMP
10
H
4-Cl
70
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
L-proline
bpy
NMP
37
H
naphth-1-yl
72
8
NMP
trace
30
H
2-MeO
3g
63
9
DMSO
4-Me
4-Cl
H
H
3h
3i
75
10
11
12
13
14
15
16
17
18
19c
20d
bpy
DMF
62
73
bpy
1,4-dioxane
toluene
40
4-MeO
4-CF3
4-NO2
2-NO2
3-NO2
3-Cl
H
3j
70
bpy
45
H
3k
69
bpy
H2O
65
H
3l
71
bpy
DMF/H2O(1/3)
DMF/H2O(1/4)
DMF/H2O(1/5)
DMF/H2O(1/4)
DMF/H2O(1/4)
DMF/H2O(1/4)
DMF/H2O(1/4)
73
H
3m
3n
3o
3p
3q
3r
65
bpy
74
H
68
bpy
70
4-Me
4-Me
H
68
bpy
72
4-Br
69
bpy
71
naphth-2-yl
naphth-2-yl
71
bpy
75
4-Me
71
bpy
63
aYield of isolated product based on 1.
aGeneral conditions: 1a (0.3mmol), 2a (0.75mmol), catalyst (0.03 mmol), ligand
(0.06 mmol) in 2 mL solvent, stirred for 12 h, NMR = N-methyl pyrrolidinone.
bYield of isolatedproduct based on 1a. cCatalyst (0.015 mmol), ligand (0.03 mmol).
dCatalyst (0.009 mmol), ligand (0.0018 mmol).
As attempts in probing the possible reaction mechanism, some
additional control experiments were designed and executed.
2 | J. Name., 2012, 00, 1-3
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Firstly, the reaction using chalcone
4
as starting material to elimination led to the production of chalcone 4. Finally, the
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react with phenyl boronic acid was carried out under standard products
3
is generated by palladium-catDaOlyIz: e10d.1a0d39d/iCti6oOnBo01f0a3r8yEl
reaction conditions, and it was found that product 3a was boronic acid to the chalcone 4
as in known in literature.8
produced with excellent yield (Eq 1). On the other hand,
although the reactions of enaminone with aryl boronic acids
Conclusions
proceed quickly to provide diarylated propiophenones
3, we
managed to acquire chalcone in the reaction of enaminone
1a with phenyl boronic acid 2a by lowering the reaction
temperature and using excess amount of enamione 1a (Eq 2).
4
In summary, by means of pd-catalysis with the assistance of
bpy ligand, the reactions of N,N-disubstituted enaminones and
boronic acid have been successfully accomplished to provide
β,β-diaryl aryl propiophenones. The efficient C-N bond
conversion enabling new C-C bond formation has revealed
new potential of enaminones as versatile building blocks in
organic synthesis.
These results suggested that chalcone
intermediate in the whole reaction process. What’s more, to
investigate the potential interaction of enaminone with Pd(II)
4 was a key
1
catalyst, a control experiment subjecting only enaminone 1a to
the standard reaction was conducted, and no evident
transformation of the enaminone was found. Finally, the
experiment employing vinylogous ester
5 and 2a provided
Experimental section
General procedure for the synthesis of ketones 3 and 5
target product 3a with 60% yied (Eq 3), demonstrating that the
reaction might not be initiated by the interaction of palladium
catalyst and the enaminone.
To a 25 mL round-bottom flask were added enaminone
1 (0.3
mmol), aryl boronic acid (0.75 mmol, or 0.3 + 0.3 mmol for
2
heteroarylation reaction), Pd(OAc)2 (0.015 mol), bpy (0.03
mmol) and DMF/water (0.4 mL/1.6 mL). Then the mixture was
heated up to 90 oC, and stirred at the same temperature for 12
h under (TLC). After cooling down to room temperature, 5 mL
of water was added, and the resulting mixture was extracted
with ethyl acetate (3 × 8 mL). The organic phases were
collected and washed with small amount of water for three
times. After drying with anhydrous Na2SO4, the solid was
filtered and the acquired solution was subjected to reduced
pressure to remove the solvent. The resulting residue was
subjected to flash silica gel column chromatography to provide
pure products with the elution of mixed petroleum ether/ethyl
acetate (v/v = 20:1).
O
O
standard
conditions
(1)
PhB(OH)2
4
3a, 80%
O
standard
conditions
50 oC
PhB(OH)2
N
(2)
(3)
3a
4
30%
28%
2a, 0.3 mmol
1a, 0.9 mmol
standard
conditions
O
3a
60%
Et
PhB(OH)2
O
5
2a
On the basis of the reaction results and related reports on Pd-
catalyzed C-N activation, a reaction mechanism starting from
the palladium catalyst insertion to the boronic acid is
tentatively postulated. As showing in Scheme 3, insertion of
Acknowledgments
This work is financially supported by the National Natural
Science Foundation of China (21562025) and Natural Science
Foundation of Jiangxi Province (20151BAB203008).
Pd(II) catalyst to aryl boronic acid
species . The Michael-type addition of
provides Pd(II) containing adduct
elimination then gave intermediate
2
provides the aryl palladium
to enaminone
and the reductive
The subsequent
6
6
1
7
,
Notes and references
8
.
extrusion of the amino and boron fragment in the fashion of
1
2
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Scheme 3 The proposed reaction mechanism
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CCDC 1474506
(3a
)
contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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