Synthesis of Multisubstituted Allenes via Palladium-Catalyzed Cross-Coupling Reaction of Propargyl Acetates with an Organoaluminum Reagent

Article abstract of DOI:10.1055/s-0036-1588389

We describe a convenient method for the synthesis of multisubstituted allenes from cross-coupling of propargyl acetates with -organoaluminum reagent: The reaction of propargyl acetates with 1.2 equivalents of organoaluminum reagent mediated by Pd(PPh₃)₂Cl₂ (1 mol%)/Ph₃P (2 mol%) and K₂CO₃ in THF may produce tri- or tetrasubstituted allenes in good to excellent yields (83-94%) and high regio-selectivities (up to 99%) at 60 °C in 3-4 hours.

Full text of DOI:10.1055/s-0036-1588389

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
Z. Zhang et al.
Letter
Synlett
Synthesis of Multisubstituted Allenes via Palladium-Catalyzed
Cross-Coupling Reaction of Propargyl Acetates with an Organo-
aluminum Reagent
Zhen Zhang
Song Mo
Pd(PPh3)2Cl2 (1 mol%)
Ph3P (2 mol%)
K2CO3 (2.0 equiv)
R3
OAc
R2
Me
R2
R2
•
Me
R3
R3
Gang Zhang
Xuebei Shao
Qinghan Li*
Ying Zhong
THF, 60 °C, 3–4 h
R1
R1
R1
+ AlMe3
83–94% yield
97:3–99:1
College of Chemistry and Environmental Proection Engineering,
Southwest University for Nationalities, Chengdu, 610041,
P. R. of China
lqhchem@163.com
lqhchem@swun.cn
Received: 04.12.2016
Accepted after revision: 05.12.2016
Published online: 10.01.2017
alkyne product 3. Therefore, the development of rapid and
more efficient procedures for the synthesis of multisubsti-
tuted allenes still remains a challenge.
DOI: 10.1055/s-0036-1588389; Art ID: st-2016-w0709-l
R2
Abstract We describe a convenient method for the synthesis of multi-
substituted allenes from cross-coupling of propargyl acetates with
organoaluminum reagent: The reaction of propargyl acetates with
1.2 equivalents of organoaluminum reagent mediated by Pd(PPh3)2Cl2
(1 mol%)/Ph3P (2 mol%) and K2CO3 in THF may produce tri- or tetra-
substituted allenes in good to excellent yields (83–94%) and high regio-
selectivities (up to 99%) at 60 °C in 3–4 hours.
R2
R1
Nu
R1
Nu
2
LnM
SN2'
LnM
R2
X
X
LnM
SN2
R1
R2
R2
Key words allenes, palladium, propargyl acetate, organoaluminum
reagent, cross-coupling
Nu
MLn
Nu
R1
R1
X
3
Scheme 1 SN2′ and SN2 processes of metal-catalyzed coupling reac-
tions of propargyl derivatives with organometallic nucleophiles
Allenes are very useful building blocks and functional
groups that are widely applied for many transformations in
organic synthesis.1,2 Allene moieties have also been found
in many natural products as well as in pharmaceutically re-
lated compounds.3 As a result, the synthesis of allenes has
inspired ample interest in organic and medical chemistry.4
Developing efficient reactions for the synthesis of allenes
from simple and readily available organic compounds is
very important. To date, numerous synthetic methodolo-
gies have been developed to access allenes,5 and synthetic
protocols for substituted allenes include the elimination of
allylic compounds,6 isomerization of alkynes,7 a reaction of
aldehyde and terminal alkynes,8 and metal-catalyzed reac-
tions of propargylic compounds.9,10 Among the hitherto de-
veloped methods, the metal-catalyzed SN2′-type displace-
ment of propargyl alcohol derivatives with organometal
species is one of the most generally useful (Scheme 1).
However, there are two competing possible reaction path-
ways: The successful application of such a substitution re-
action relies on the choice of catalyst and/or organometallic
reagents to selectively produce either allene product 2 or
Our previous studies show that the catalytic system of 1
mol% Pd(OAc)2/2 mol% (o-tolyl)3P worked efficiently for the
cross-coupling of propargyl acetates with organoalumi-
num, producing the trisubstituted allenes in good to excel-
lent yields of up to 94 % in tetrahydrofuranl.5l However, the
reaction of trimethylaluminum (AlMe3) with 2-methyl-4-
phenylbut-3-yn-2-yl acetate, employing the catalyst of 1
mol% Pd(OAc)2/2 mol% (o-tolyl)3P, yielded tetrasubstituted
allene of 1,1,3-trimethyl-3-phenylallene with only 80%
yield and low selectivity (90:10). In order to continue our
effort to develop cross-coupling reactions using reactive or-
ganometallic reagents11 to synthesize tetrasubstituted al-
lenes, we herein report Pd(PhP3)2Cl2 (1 mol%)/Ph3P (2
mol%)/K2CO3(2.0 equiv) catalyzed cross-coupling reactions
of propargyl acetates with organoaluminum reagents at 60
°C in a short reaction time with good yields for the synthe-
sis of tri- and tetrasubstituted allenes. The process was sim-
ple and easily performed, and it provided an efficient meth-
od for the synthesis of multisubstituted allene derivatives.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
Z. Zhang et al.
Letter
Synlett
In order to optimize reaction conditions, effects of pal-
ladium source, phosphine ligand, solvent, reaction time, the
amount of organoaluminum, and the molar ratio of metal
to ligand on the cross-coupling reaction were investigated
using propargyl acetate 1a (Table 1 and Table 2). In a pre-
liminary study, we only used Pd(OAc)2 as catalyst, the
cross-coupling reaction of propargyl acetate 1a with
trimethylaluminum (AlMe3) to afford both 1-methyl-1,3-di-
phenyl-allene (2a) and 1,3-diphenylbutyne (3a) with only a
12% conversion (Table 1, entry 1). When 2 mol% Ph3P was
used as ligand, the Pd(OAc)2-catalyzed cross-coupling of
propargyl acetate 1a with AlMe3 produced the product 2a
and 3a in 16% conversion (Table 1, entry 2). The product ra-
tio is about 57:43 in favor of the allene 2a. The other phos-
phine ligand was further examined (Table 1, entries 3 and
4). It was found that the Ph3P ligand had the best effect for
both reactivity and selectivity (Table 1, entry 2). Other
phosphine ligands did not provide satisfactory results. To
our delight, when 2.0 equivalents K2CO3 were used as addi-
tive, the Pd(OAc)2/PPh3-catalyzed cross-coupling of propar-
gyl acetate 1a with AlMe3 produced the product 2a and 3a
with 96% conversion and a ratio of 60:40 in favor of the al-
lene 2a (Table 1, entry 5). However, the cross-coupling of
propargyl acetate 1a with AlMe3 produced the product 2a
and 3a with 98% conversion and a ratio of 95:5 in favor of
the allene 2a at 60 °C for three hours (Table 1, entry 6).
Subsequently, the effect of the amount of AlMe3 was
also investigated. When the AlMe3 loading was increased
from 0.5 mmol to 0.6 mmol, the reaction selectivity in-
creased from 95:5 to 98:2 (Table 1, entries 6 and 7). Howev-
er, when the ratio of Pd(OAc)2 and Ph3P was altered to 1:4,
the product conversation and the reaction selectivity re-
mained unchanged (Table 1, entries 7 and 8).
Table 1 Effect of the Ligands, the Loading of AlMe3, and the Additives
on the Cross-Coupling Reactiona
Me
Pd(OAc)2 (1 mol%)
ligand (2 mol%)
OAc
Ph
•
Me
Ph
Ph
THF (1 mL)
3 h, r.t.
Ph
Ph
Ph
1a
2a
3a
+ AlMe3
1.0 equiv
Entry
Ligand (2 mol%) Additives (2.0 equiv) Conv. (%)b
2a/3a (%)c
1
–
–
12
16
10
12
96
98
98
98
1:99
57:43
45:55
1:99
2
Ph3P
PCy3
dppe
Ph3P
Ph3P
Ph3P
Ph3P
–
3
–
4
–
5
K2CO3
K2CO3
K2CO3
K2CO3
60:40
95:5
6d
7 e
8f
98:2
98:2
a 1a/AlMe3/Pd(OAc)2/ligand = 0.5:0.5:0.005:0.01 mmol.
b Conversion of 2a + 3a determined by 1H NMR spectra.
c The ratio of 2a/3a determined by 1HNMR analysis.
d 60 °C.
e AlMe3 = 0.6 mmol, 60 °C.
f 1a/AlMe3/Pd(OAc)2/ligand = 0.5:0.6:0.005:0.02 mmol, 60 °C.
Table 2 Effect of the Palladium Source and Solvent on the Cross-Cou-
pling Reactiona
Pd (1 mol%)
Ph3P (2 mol%)
Me
OAc
Ph
•
Me
K2CO3 (2.0 equiv)
Ph
Ph
THF (1 mL), 3 h, 60 °C
Ph
Ph
Ph
3a
2a
1a
+ AlMe3
1.2 equiv
To further study reactivity and selectivity, the reaction
of 1a with AlMe3 under others conditions was investigated.
Firstly, various solvents were screened under the model re-
action conditions, and the results are summarized in Table
2 (entries 1, 2). Solvents such as toluene and hexane were
unsuitable for this reaction, as they gave lower selectivity
(Table 2, entries 1, 2). In contrast, when THF was used as
solvent, a product ratio of 98:2 and 98% conversion was ob-
tained (Table 1, entry 8). Other palladium sources with Ph3P
were subsequently surveyed. Although PdCl2 and Pd(acac)2
can effectively catalyze the cross-coupling reaction, the
product selectivities and conversions were low (Table 2, en-
tries 3, 4). Gratifyingly, excellent selectivity (2a/3a>99%)
and high conversion (>99%) were obtained using
Pd(PPh3)2Cl2 (Table 2, entry 5). Therefore, the optimal cross-
coupling reaction conditions were 1 mol % Pd(PPh3)2Cl2, 2
mol% Ph3P, 1.0 mmol K2CO3, 0.6 mmol AlMe3, 0.5 mmol
propargyl acetate in THF (1 mL) at 60 °C for three hours.
With the optimized reaction conditions in hand, the
scope of this reaction was studied by using various propar-
gyl acetate and organoaluminum reagent, and the results
Entry
Pd salt
Solvent
Conv. (%)b
2a/3a (%)c
1
2
3
4
5
Pd(OAc)2
Pd(OAc)2
PdCl2
hexane
toluene
THF
92
99
72:28
53:47
91:9
80
Pd(acac)2
Pd(PPh3)2Cl2
THF
97
95:5
THF
>99
>99:1
a 1a/AlMe3/Pd(II)/ Ph3P = 0.5:0.6:0.005:0.01 mmol.
b Conversion of 2a + 3a was determined by 1H NMR spectra.
c The ratio of 2a/3a was determined by 1HNMR analysis.
are summarized in Table 3. The cross-coupling of AlMe3
with propargyl acetates 1a–o proceeded smoothly to pro-
vide the tri- and tetrasubstituted allenes 2a–o in good to
excellent yields (83–94%) with high selectivities (up to
99:1; Table 3, entries 1–15). The reaction was not signifi-
cantly affected by the substituents on the aromatic ring of
the aromatic propargyl acetates. Both electron-rich (Table
3, entries 2, 8) and electron-deficient substituent on the ar-
omatic ring of the aromatic propargyl acetates were effec-
tive (Table 3, entries 3, 4, 9–12, 15). Notably, methyl, chloro,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
Z. Zhang et al.
Letter
Synlett
and fluoro groups are all tolerated under the given reaction
conditions. The reaction also worked well with propargyl
acetates bearing n-pentyl, TMS, and thienyl group (Table 3,
entries 5, 6, 15).
with high selectivities. Cross-coupling reactions of aliphatic
propargyl acetates containing n-pentyl and TMS group pro-
ducing the trisubstituted allenes 2e and 2f with 99% selec-
tivity and 83% and 88% yields, respectively. Coupling reac-
tions of 2-methyl-4-thienylbut-3-yn-2-yl acetate (1o) with
AlMe3 can work smoothly to give the tetrasubstituted al-
lenes product of 2o in 88% yield with 99% selectivity. This
methodology provides a useful procedure for the synthesis
of multisubstituted allenes. Further studies on the applica-
tion of this catalyst to other organoaluminum reagents are
currently in progress.
Table 3 Pd(PPh3)2Cl2/PPh3-Catalyzed Cross-Coupling Reaction of
Propargyl Acetate with Organoaluminum Reagenta
Pd(PPh3)2Cl2 (1 mol%)
R3
OAc
Ph3P (2 mol%)
Me
K2CO3 (2.0 equiv)
R2
•
Me
R3
R3
R2
R2
THF (1 mL), 60 °C
R1
R1
R1
1
3
2
+ AlMe3
Acknowledgment
Entry
1
Time 2/3 (%)b Yield of
2 (%)c
We thank the Sichuan Provincial Department of Science and Technol-
ogy support program (No. 2015NZ0033) and the graduate student in-
novation funds of Southwest University for Nationalities (No.
CX2016SZ052).
R1
R2
R3
1
2
Ph
Ph
H
1a
1b
1c
1d
1e
1f
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
99:1
99:1
99:1
99:1
99:1
99:1
97:3
98:2
99:1
99:1
99:1
99:1
99:1
99:1
99:1
2a 85
2b 83
2c 87
2d 88
2e 83
2f 88
2g 85
2h 89
2i 93
Ph
p-MeC6H4
p-ClC6H4
p-BrC6H4
n-pentyl
Ph
H
3
Ph
H
Supporting Information
4
Ph
H
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588389.
5
Ph
H
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
6
TMS
Ph
H
7
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
1g
1h
1i
References
8
p-MeC6H4
p-BrC6H4
p-FC6H4
m-ClC6H4
m-FC6H4
Ph
Me
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9
Me
10
11
12
13
14
15
Me
1j
2j 94
Me
1k
1l
2k 94
2l 94
Me
Et
1m
1n
1o
2m 83
2n 86
2o 88
m-FC6H4
2-thienyl
Et
Me
a Reaction conditions: 1 (1.0 mmol), AlMe3 (1.2 mmol), Pd(PPh3)2Cl2
(1 mol%), Ph3P (2 mol%), K2CO3 (2.0 equiv), THF (1 mL).
b Ratio of 2/3 determined by 1HNMR analysis.
c Isolated yield.
The cross-coupling of propargyl acetates 1a–f with
AlMe3 gave the trisubstituted allenes 2a–f in 83–88% yield
with 99% selectivity (Table 3, entries 1–6). The cross-cou-
pling reactions of aromatic propargyl acetates 1g–n with
AlMe3 gave tetrasubstituted allenes 2g-n with high selec-
tivity (up to 99:1) and excellent isolated yields (83–94%, Ta-
ble 3, entries 7–14). In particular, the tetrasubstituted al-
lene bearing a thienyl group 2o resulting from propargyl
acetate 1o was obtained with 88% yield and 99% selectivity
(Table 3, entry 15).
In conclusion, a palladium-catalyzed cross-coupling re-
action of propargyl acetates with AlMe3 reagents was re-
ported.12 Cross-coupling reactions of aromatic propargyl
acetates and aliphatic propargyl acetates with AlMe3 afford
tri- and tetrasubstituted allenes in good to excellent yields
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
Z. Zhang et al.
Letter
Synlett
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To a solution of the alkyne (16.5 mmol) in anhydrous THF (25
mL) at –78 °C under nitrogen atmosphere was added n-BuLi 1.6
M (16.5 mmol). The reaction was stirred at this temperature for
20 min then at r.t. for 1 h. After cooling to –78 °C, the aldehyde
or ketone (15.0 mmol) was added, and the reaction was stirred
at r.t. for 1 h. After addition of acetate anhydrous (30.0 mmol) at
0 °C, the reaction mixture was warmed to r.t. and stirred for 2 h
before being quenched with a sat. aq NH4Cl solution. The
mixture was extracted with Et2O (3 × 30 mL). The combined
organic layers were washed with brine, dried over MgSO4, fil-
tered, and evaporated to give the crude products. The crude
product was subjected to flash column chromatography on
silica gel (hexane or EtOAc and hexane) to afford the corre-
sponding propargylic acetate 1.
1,3-Diphenylprop-2-ynyl Acetate (1a)5l
1H NMR (400 MHz, CDCl3): δ = 7.62–7.58 (m, 2 H), 7.50–7.46 (m,
2 H), 7.44–7.37 (m, 3 H), 7.36–7.28 (m, 3 H), 6.70 (s, 1 H), 2.14
(s, 3 H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 169.7, 137.1,
131.8, 128.9, 128.7, 128.6, 128.2, 127.7, 122.0, 87.0, 85.5, 66.0,
21.0 ppm.
General Procedures for the Cross-Coupling Reaction of Prop-
argyl Acetates with Trimethylaluminum
Under a dry nitrogen atmosphere, a mixture of Pd(PPh3)2Cl2
(0.0035 g, 0.005 mmol), Ph3P (0.0026 g, 0.01 mmol), and K2CO3
(0.138 g, 1.0 mmol) in a reaction vessel was added AlMe3 (0.6
mmol) in THF (1 mL) followed by an addition of propargyl
acetate (0.50 mmol). The resulted solution was stirred at 60 °C
for 3–4 h. After completion the reaction, the mixture was
diluted with sat. NH4Cl solution (5 mL) and extracted with
EtOAc (3 × 15 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and evaporated under vacuum. The
residue was subjected to flash column chromatography on silica
gel (hexane or EtOAc and hexane) to afford the corresponding
allene products 2.
1,3-Diphenylbuta-1,2-diene (2a)5l
1
Yellow oil; 0.174 g (85%). H NMR (400 MHz, CDCl3): δ = 7.48–
7.44 (m, 2 H), 7.36–7.28 (m, 6 H), 7.25–7.20 (m, 2 H), 6.48 (q,
J = 2.8 Hz, 1 H), 2.23 (d, J = 2.8 Hz, 3 H) ppm. 13C{1H} NMR (100
MHz, CDCl3): δ = 206.8, 136.3, 134.5, 128.7, 128.5, 127.03,
127.02, 126.9, 125.8, 104.5, 96.6, 16.8 ppm.
(13) Mahrwald, R.; Quint, S. Tetrahedron 2000, 56, 7463.
(14) Kessler, S. N.; Bäckvall, J. E. Angew. Chem. Int. Ed. 2016, 128,
3798.
(12) Experimental Section
1H NMR and 13CNMR spectra were recorded on a Varian 400
MHz spectrometer. The chemical shifts are reported relative to
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D