Synthesis of Enaminones by a Palladium-Catalyzed Four-Component Carbonylative Addition Reaction

Article abstract of DOI:10.1055/s-0036-1590976

A palladium-catalyzed carbonylative addition reaction of aryl bromides, amines, and alkynes has been developed. The reaction occurs readily in N, N -dimethylformamide with PdCl ₂ (PPh ₃) ₂ as a catalyst to give the corresponding enaminones in medium to excellent yields. Furthermore, a mechanism for the palladium-catalyzed four-component carbonylative addition reaction is proposed.

Full text of DOI:10.1055/s-0036-1590976

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
en
L. Wang et al.
Letter
Synlett
Synthesis of Enaminones by a Palladium-Catalyzed Four-Component
Carbonylative Addition Reaction
Liangguang Wang*a
Juan Maa
Xia Chenb
Xiaoyu Zhou*b
R3
O
N
Br
R4
PdCl2(PPh3)2 (5 mol%)
DMF, Et3N, 120 °C, 20 h
CO
R2
R1
R2
HNR3R4
+
four-component one-pot reaction
operationally simple
mild reaction conditions
broad substrate scope
R1
a College of Chemistry and Chemical Engineering,
Anshun University, Anshun, 561000, P. R. of China
wang825663@163.com
b Department of Chemistry and Chemical Engineering,
Liupanshui Normal University, Liupanshui, 553004,
P. R. of China
26 examples
up to 95% yield
zhouxiaoyu20062006@126.com
Received: 05.06.2017
Accepted after revision: 03.07.2017
Published online: 08.08.2017
tion of the acylpalladium amine intermediate was inter-
rupted by coordination of an alkyne and that a carbonyla-
tive addition reaction of an aryl bromide, CO, an amine, and
an alkyne successfully occurred with PdCl2(PPh3)2 as cata-
lyst at 120 °C in DMF (Scheme 1), thereby providing an effi-
cient and novel strategy for the synthesis of enaminones.9
The method has several prominent advantages over con-
ventional methods, such as mild reaction conditions, high
efficiency, simple starting materials, and straightforward
operations.
DOI: 10.1055/s-0036-1590976; Art ID: st-2017-w0436-l
Abstract A palladium-catalyzed carbonylative addition reaction of aryl
bromides, amines, and alkynes has been developed. The reaction
occurs readily in N,N-dimethylformamide with PdCl2(PPh3)2 as a catalyst
to give the corresponding enaminones in medium to excellent yields.
Furthermore, a mechanism for the palladium-catalyzed four-component
carbonylative addition reaction is proposed.
Key words palladium catalysis, multicomponent reaction, carbonyla-
tive addition, enaminones, aryl bromides, amines
O
R2
Br
PdCl2(PPh3)2
NR3R4
R1
HNR3R4
+
R2
+
CO
+
For economic and environmental reasons, environmen-
tally friendly chemistry has attracted considerable atten-
tion in modern organic synthesis.1 Multicomponent reac-
tions (MCRs)2 can produce target products directly by sim-
ple operations with high efficiency and with reduced waste
generation compared with conventional methods in organ-
ic synthesis.3 Palladium-catalyzed carbonylation is a repre-
sentative MCR4 that has played an important role in the
synthesis of carbonyl compounds because of its high selec-
tivity and mild reaction conditions. In recent years, palladi-
um-catalyzed three-component carbonylative coupling re-
actions of aryl halides with organometallic reagents,
alkenes, alkynes, amines, alcohols, water, or hydrogen have
been studied.5 However, much to our regret, there have
been few reports on palladium-catalyzed four-component
carbonylations.6
Recently, Wu and co-workers reported a palladium-cat-
alyzed four-component carbonylation for the synthesis of
4(3H)-quinazolinones or thiochromenones.7 In 2014, Bao
and co-workers reported the palladium-catalyzed three-
component carbonylative addition reaction using 1,4-
bis(diphenylphosphino)butane (DPPB) as a ligand in DMF.8
In the present study, we found that the reductive elimina-
DMF, Et3N, 120 °C
R1
O
L
L
Pd NR3R4
R2
R1
Scheme 1 Palladium-catalyzed four-component one-pot synthesis of
enaminones
Initially, we began our study by using 1-(4-bromophe-
nyl)ethanone (1a, 0.5 mmol), ethynylbenzene (2a, 0.6
mmol), HNEt2 (3a, 0.75 mmol), and CO (5 atm) as substrates
and PdCl2 (5 mol%) as a catalyst to optimize the reaction
conditions. The expected reaction occurred, and 1-(4-
acetylphenyl)-3-(diethylamino)-3-phenylprop-2-en-1-one
(4a) was obtained in 20, 22, and 45% yields in the presence
of the bidentate ligands DPPB, 1,3-bis(diphenylphosphi-
no)propane (DPPP), and 1,2-bis(diphenylphosphino)ethane
(DPPE) respectively (Table 1, entries 1–3). To our delight,
however, the isolated yield of product 4a improved to 86%
when PPh3 was used as the ligand in DMF solvent (entry 4).
A decreased yield of 4a was obtained when the reaction
medium DMF was replaced by DMSO, MeCN or 1,4-dioxane
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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B
L. Wang et al.
Letter
Synlett
(entries 5–7). Note that no product 4a was produced when
the reaction was performed in toluene (entry 8). The yield
of 4a did not improved significantly when the reaction
temperature was increased to 130 °C (entry 9; yield 87%),
and the yield of 4a decreased to 65% when the reaction
temperature was reduced to 110 °C (entry 10). The optimal
reaction temperature is therefore 120 °C. The yield of 4a de-
creased when K2CO3, K3PO4, Bu3N, or DIPEA was used as an
additive (entries 11–14; yield 28–68%). Furthermore, the
reaction did not proceed in the absence of an additive (en-
try 15). Interestingly, the four-component reaction proceed
smoothly with PdCl2(PPh3)2 as the catalyst to give product
4a in 86% yield (entry 16).
h. Next, we tested the reactivity of various alkynes, aryl
bromides, and amines under these optimized reaction con-
ditions.
We first investigated the reactions of various aryl bro-
mides with ethynylbenzene (2a), HNEt2 (3a), and CO under
the optimized conditions (Scheme 2).1-(4-Bromophe-
nyl)ethanone (1a) and 1-(3-bromophenyl)ethanone (1b)
gave good yields of products 4a (86%) and 4b (78%), respec-
tively. However, when 1-(2-bromophenyl)ethanone (1c)
was used as a substrate, the reaction did not occur. Aryl
bromides with an electron-withdrawing group in the para-
position 1d–h reacted smoothly to give the corresponding
products 4d–h in moderate to good yields (71–86%). On the
other hand, products 4i (58%) and 4j (45%) were produced
in lower yields from bromobenzene (1i) and 1-bromonaph-
thalene (1j), respectively.
Table 1 Reaction Condition Screeninga
O
Ph
NEt2
Br
Br
O
Ph
NEt2
PdCl2/ligand, CO (5 atm)
additive, solvent, 20 h
HNEt2
Ph
+
+
PdCl2(PPh3)2 (5 mol%), CO
Et3N, DMF, 120 °C, 20 h
HNEt2
+
Ph
+
R
COMe
R
COMe
1a
2a
3a
4a
1a–1j
2a
3a
4a–4j
Yieldb (%)
NEt2
O
NEt2
O
Entry
Ligand
Solvent
Additive
1
2
DPPB
DPPP
DPPE
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
–
DMF
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
45
22
20
86
58
45
38
NRc
87
65
28
36
68
62
NRc
86
R
DMF
R
4a, R = 4-COMe, 86%
4b, R = 3-COMe,78%
4c, R = 2-COMe, 0%a
4d, R = CHO, 72%; 4e, R = F, 71%
4f, R = CF3, 86%; 4g, R = CN, 84%
4h, R = COOMe, 83%
3
DMF
4
DMF
5
DMSO
MeCN
O
NEt2
O
NEt2
6
7
1,4-dioxane
Et3N
Et3N
Et3N
Et3N
K2CO3
K3PO4
Bu3N
DIPEA
–
4i, 58%
4j, 45%
8
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Scheme 2 Palladium-catalyzed carbonylative addition reactions of
various aryl bromides. Reagents and conditions: 1a–j (0.5 mmol), 2a
(0.6mmol), 3a (0.75 mmol), CO (5 atm), PdCl2(PPh3) (5mol%), Et3N (1.5
mmol), DMF (4 mL), 120 °C, 20 h. Isolated yields are reported. a The
starting materials were recovered.
9d
10e
11
12
13
14
15
16f
We then studied the reactivity of various alkynes under
the optimal conditions (Scheme 3). When the aromatic
alkynes 2b (R = 4-Tol) and 2c (R = 3-Tol) were subjected in
the reaction, the corresponding products 4k and 4l were
obtained in excellent yields of 93 and 92%, respectively,
whereas 2d (R = 2-Tol) gave only a moderate yield of 4m
(78%). Enaminones 4n–p were produced in excellent yields
of 95, 92, and 94%, respectively, from aromatic alkynes con-
taining electron-donating groups in the para-position;
however, lower yields were obtained when the aromatic
alkynes contained electron-withdrawing groups in the
para-position (4q; 56%: 4r; 53%). Interestingly, for aromatic
alkyne 2j with a vinyl group in the para-position, product
4s (85%) was obtained, showing that the palladium-
catalyzed carbonylative addition is highly selective towards
the C≡C triple bond. More importantly, aliphatic alkynes
ethynylcyclohexane (2k) and oct-1-yne (2l) and the hetero-
Et3N
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), 3a (0.75 mmol), CO
(5 atm), PdCl2 (5 mol%), ligand (10 mol%), additive (1.5 mmol), solvent (4
mL), 120 °C, 20 h.
b Isolated yield.
c No reaction; the starting materials were recovered.
d At 130 °C.
e At 110 °C.
f PdCl2(PPh3)2 (5 mol%) was used instead of PdCl2.
From the optimization of the catalytic system, solvent,
temperature, and additive, the optimal conditions for the
palladium-catalyzed four-component carbonylative addi-
tion reaction were identified as follows: PdCl2(PPh3)2 (5
mol%) as catalyst, Et3N (3.0 equiv) as additive, and DMF (4
mL) as solvent in the presence of CO (5atm) at 120 °C for 20
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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C
L. Wang et al.
Letter
Synlett
(Scheme 4). The secondary amines dimethylamine (3b) and
dibutylamine (3c) gave products 4w (87%) and 4x (91%), re-
spectively, in high yields. Primary amine butylamine (3d)
gave a lower yield of product 4y (46%). However, the reac-
tion did not occur smoothly when aniline (3e) was used.
O
R
Br
PdCl2(PPh3)2 (5 mol%), CO
Et3N, DMF, 120 °C, 20 h
NEt2
+
+
R
HNEt2
COMe
COMe
4k–4v
1a
2b–2m
3a
O
NR1R2
O
NEt2
O
NEt2
Br
CO (5 atm)
PdCl2(PPh3)2 (5 mol%)
Ph
+
Ph
HNR1R2
+
Et3N (3.0 equiv), DMF (4.0 mL)
120 °C, 20 h
MeOC
Me
MeOC
4k 93%
4l 92%
Me
COMe
1a
COMe
4x, R1 = R2
=
nBu, 46%; 4z, R1 = H, R2 = Ph, 0%
O
NEt2
O
NEt2 Me
2a
3b–3e
4w, R1 = R2 = Me, 87%;
4y, R1 = H, R2
=
nBu, 91%
(0.5 mmol) (0.6 mmol) (0.75 mmol)
MeOC
MeOC
NMe2
MeOC
MeOC
4m 78%
4n 95%
Scheme 4 Palladium-catalyzed carbonylative addition reactions of var-
ious amines
O
NEt2
O
NEt2
To explore the mechanism of this reaction, we per-
formed several control experiments (Scheme 5). The reac-
tion of bromide 1a, ethynylbenzene (2a), and CO did not oc-
cur in DMF at 120 °C for 20 h (Scheme 1, eq 1), whereas the
reaction of bromide 1a, diethylamine (3a), and CO did occur
under these conditions to give the corresponding product
5a in 92% yield (Scheme 1, eq 2). These results show that, in
the four-component carbonylative reaction system, the re-
action occurs initially between the aryl bromide, the amine,
and CO, rather than the aryl bromide, the alkyne, and CO.
Finally, a plausible reaction mechanism (Scheme 6) is
proposed based on the control experiments and the report-
ed mechanism of palladium-catalyzed carbonylation.10 Bro-
mide 1a undergoes oxidative addition with Pd(0) to form
the arylpalladium intermediate A. Subsequently, this un-
dergoes CO insertion to produce an acylpalladium interme-
diate B, which react with nucleophile 3a to produce inter-
mediate C in the presence of Et3N. The reductive elimina-
tion of intermediate C is interrupted by the coordination of
2a to give the π-alkyne(acyl)palladium intermediate D.11
Insertion then occurs to form intermediate E, which gives a
Pd(0) species and product 4a through reductive elimina-
tion.
nBu
OMe
CHO
4o 92%
4p 94%
O
NEt2
O
NEt2
MeOC
MeOC
MeOC
F
MeOC
MeOC
MeOC
4q 56%
4r 53%
O
O
NEt2
NEt2
4s, 85%
4t, 84%
O
NEt2
O
NEt2
N
4u, 82%
4v, 91%
Scheme 3 Palladium-catalyzed carbonylative addition reaction of vari-
ous terminal alkynes. Reagents and conditions: 2a (0.5 mmol), 2b–m
(0.6mmol), 3a (0.75 mmol), CO (5 atm), PdCl2(PPh3)2 (5mol%), Et3N
(1.5 mmol), DMF (4 mL), 120 °C, 20 h. Isolated yields are reported.
cyclic alkyne 3-ethynylpyridine (2m) also reacted under the
optimal conditions to give products 4t (84%), 4u (82%), and
4v (91%), respectively, in high yields.
Next, we used several secondary and primary amines in
the palladium-catalyzed carbonylative addition reaction
O
Br
CO (5 atm)
PdCl2(PPh3)2
(5 mol%) x
Et3N (3.0 equiv), DMF
(4 mL) 120 °C, 20 h
(eq 1)
Ph
+
Ph
O
COMe
COMe
1a (0.5 mol)
Br
2a (0.6 mmol)
NEt2
CO (5 atm)
PdCl2(PPh3)2 (5 mol%)
(eq 2)
5a, 92% yield
HNEt2
+
Et3N (3.0 equiv), DMF(4 mL)
120 °C, 20 h
COMe
COMe
1a (0.5 mol) 3a (0.75 mmol)
Scheme 5 Control experiments
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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D
L. Wang et al.
Letter
Synlett
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PdCl2(PPh3)
O
N(Et)2
CO
Pd(0)L2
Br
COMe
Ph
1a
MeOC
L
4a
Pd
L
Br
MeOC
L
Pd
L
N(Et)2
Ph
MeOC
CO
A
E
O
O
O
N(Et)2
L
MeOC
L
L
Pd
L
Pd
L
Br
O
Pd N(Et)2
L
D
Ph
MeOC
B
C
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HN(Et)2
Et3N
Ph
Et3N•HBr
3a
2a
COMe
Scheme 6 Proposed reaction mechanism
In summary, we have developed a new type of palladium-
catalyzed one-pot carbonylative addition reaction of aryl
bromides, alkynes, and amines. The reductive elimination
of an acylpalladium amine intermediate is interrupted by
the coordination of an alkyne, and a carbonylative addition
reaction occurs smoothly to produce enaminones in mod-
erate to excellent yields.12 Fortunately, the present method
has distinct advantages, such as compatibility with many
functional groups, high selectivity, simplicity of the catalyt-
ic system and substrates, and mild reaction conditions. The
principle of the reaction will provide a new strategy for de-
veloping new types of catalytic carbonylative addition reac-
tions of alkenes.
Funding Information
This work was supported by the Foundation of Science and Technolo-
gy Department of Guizhou Province (qiankeheJzi [2015] number
2003) and the Doctoral Foundation of Anshun University
(asubsjj201501).
)(
(10) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Eur. J. 2010, 16, 9750.
(11) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873.
(12) Enaminones 4a–z; General Procedure
Supporting Information
Supporting information for this article is available online at
A mixture of the appropriate aryl bromide 1 (0.5 mmol), alkyne
2 (0.6 mmol), amine 3 (0.75 mmol), PdCl2(PPh3)2 (17.5 mg, 5
mol%), Et3N (209 μL, 1.5 mmol), and DMF (4.0 mL) was placed in
a 25 mL autoclave under N2. The autoclave was filled with CO to
5 atm pressure, and heated to 120 °C for 20 h. The product was
extracted with EtOAc (3 × 5 mL), and the organic layers were
combined, washed with brine (2 × 5 mL), dried (Na2SO4), and
concentrated under reduced pressure. The residue was then
purified by chromatography (silica gel).
1-(4-Acetylphenyl)-3-(diethylamino)-3-phenylprop-2-en-1-
one (4a)
Pale-yellow solid; yield: 138.2 mg (86%,); mp 96−98 °C. IR
(neat): 3474, 3059, 2976, 1683, 1625, 1479, 1461, 1439, 1357,
https://doi.org/10.1055/s-0036-1590976.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
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Chem. Soc. Rev. 2014, 43, 4633. (c) Slobbe, P.; Ruijter, E.; Orru, R.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E