Highly Selective Nucleophilic 4-Aryl-2,3-allenylation of Malonates?

Article abstract of DOI:10.1002/cjoc.202000300

Allenes are a class of very important compounds and the development of straightforward, efficient, and highly enantioselective synthetic strategies for allenes have attracted extensive interests. Along this line, it is well known that aryl-substituted allenes may be readily racemized, thus, difficult to prepare in high ee. Herein, an efficient palladium-catalyzed nucleophilic allenylation of malonates with racemic 4-aryl-2,3-butadienyl carbonates has been developed. The selectivity issue of mono- vs. bis-allenylation with 2-non-substituted malonates has been addressed. By utilizing (R)-(–)-DTBM-SEGPHOS (5,5'-bis[di(3,5-di-t-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3-benzodioxole) as a chiral ligand, various aryl-substituted allenes and bisallenes have been prepared with good to excellent yields with high chemoselectivity and enantioselectivity under mild reaction conditions. Au-catalyzed cycloisomerization and APK (allenic Pauson–Khand) reactions affording optically active mono- and bicyclic products have been demonstrated.

Full text of DOI:10.1002/cjoc.202000300

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Highly Selective Nucleophilic 4-Aryl-2,3-allenylation of Malonates
Authors: Shihua Song and Shengming Ma*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000300.
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published online in Early View: http://dx.doi.org/10.1002/cjoc.202000300.
ISSN 1001-604X • CN 31-1547/O6
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Chinese Journal
of Chemistry
Catalytic asymmetric synthesis, Palladium, Optically active aryl allenes,
Optically active bis-allenes, Selectivities
Report
CJC
中
国 化 学 - An International Journal
Highly Selective Nucleophilic 4-Aryl-2,3-allenylation of Malonates
Shihua Songa and Shengming Ma*,a
a Laboratory of Molecular Recognition and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, Zhejiang, People’s Republic of China.
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion Allenes are a class of very important compounds and the development of straightforward, efficient, and
highly enantioselective synthetic strategies for allenes have attracted extensive interests. Along this line, it is well known that aryl-substituted allenes may
be readily racemized, thus, difficult to prepare in high ee. Herein, an efficient palladium-catalyzed nucleophilic allenylation of malonates with racemic 4-
aryl-2,3-butadienyl carbonates has been developed. The selectivity issue of mono- vs. bis-allenylation with 2-non-substituted malonates has been
addressed. By utilizing (R)-(-)-DTBM-SEGPHOS as the chiral ligand, various aryl-substituted allenes and bisallenes have been prepared with good to excellent
yields with high chemoselectivity and enantioselectivity under mild reaction conditions. Au-catalyzed cycloisomerization and APK reaction affording
optically active mono- and bicyclic products have been demonstrated.
allenylation of non-substituted malonates (Scheme 1f). The
protocol also works well with allenylation of sterically bulkier 2-
Background and Originality Content
Allene units present widely in natural products and non-natural
substituted malonates and bisallenylation of 2-non-substituted
products with unique bioactivities.[1] Also, they have been
malonates under mild reaction conditions.
demonstrated as versatile building blocks in organic syntheses,[2]
providing novel methodologies to construct diverse and complex
Scheme 1 Ready racemization of chiral arylallenes and syntheses allenes via
compounds, especially optically active chemicals via chirality
transfer strategy.[3] Thus, design and development of new catalytic
recipes to access functionalized chiral allenes are of high current
interest.[4,5] However, it is well known that aryl-substituted allenes
racemize easily in the presence of metal catalysts, which results
mostly from the interaction of metal catalysts with the conjugate
C=C in the allene parts (Scheme 1a)[6] and highly enantioselective
syntheses of chiral aryl allenes are still challenging. Recently,
catalytic asymmetric allenylation of malonates with 2,3-allenol
derivatives[7] or 1,3-dien-2-yl derivatives[8] sharing the same
intermediacy has been developed as an efficient approach for
enantioselective syntheses of alkyl-substituted allenes (Scheme
1b). We wonder whether such a protocol may be applied to the
syntheses of the thermo-sensitive aryl-allenes (Scheme 1c). The
challenges are as follows: 1) such reactions with 4-aryl-2,3-allenol
derivatives may be too reactive, resulting in the formation of a
mixture of mono- and bis-allenylation products with non-
substituted malonates (for such a report with 1,3-dien-2-yl
derivatives, see: Scheme 1d);[9] 2) the reported enantioselectivity
with 4-phenyl-2,3-allenyl derivatives is low even with the sterically
bulky diethyl 2-acetamidomalonate (Scheme 1e);[7a,8] 3) a more
active catalytic system, which will work at very mild reaction
conditions to avoid the racemization of in situ generated sensitive
aryl-substituted allenes, is required. Herein, we wish to report our
recent realization of Pd-catalyzed highly chemoselective mono-
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differences between this version and the Version of Record. Please cite this article as doi:
10.1002/cjoc.202000300
This article is protected by copyright. All rights reserved.

Song et al.
Report
nucleophilic allenylation of different malonates
with 2aa
r
r
.
A
mo
6
a
2 5
l
Pd db 3•CHCl3
%
(
)
2
e
OCO2M
mo
an
l% Lig
d
e c
a
en e: r
r
n
a
ea
dy
ace a o
m z n
t
i
o a
r
f
a e es
r
h
T
h
ll
g
i
yl ll
e
A
)
CO2M
me
di thyl
ma ona e
a
x
e
u v
q
i
)
l
t
2
(
+
r
A
r
A
r
A
acem za on
ti
e
R
i
w
e
resence o :
.
CO2
M
-
e
e
ith th
p
f
,
=
r
M
CO2
CO2
e
q
u v
i
a
1
K2CO3 2 0
A
p
F H4
C6
.
,
,
,
u
e c or
∆
t
]
(
)
u
A
Pd
]
C
[
[
[
]
,
,
30 o
o ven
l
t
,
R
R
N2
S
C
14 h
H
-
aa
±)
4
M
-
A
aa
3
±)
(
(
-
-
-
-
-
a
-
-
,
ca a ze as mme r c a en
a
on o non su
f 2
s
u e or su
s
u e ma ona es w
b
)
Pd
ll
t
ly
d
y
t i ll yl ti
b
tit
t
d
2
b
tit
t
d
l
t
ith 4 lkyl 2 3
R1
a eno er va ves
l d
i
ti
-
-
-
aa
3
eco e
v
r
y
±)
CO2R3
.
R
aa:
3
(
±)
±)
LG
n r
E
t y
an
Lig
x
o ven
l
t
*
(
(
d
S
ca
t
/
Pd L
[ ]
,
b
b
R2
R2
%
)
a
1
o
f
CO2R3
(
b
aa
+
4
ase so ven
CO2R3
or a
b
l
t
R1
R1
CO2R3
ee
R2
-
-
-
.
-
c
=
=
:
a
lkyl
±)
±)
±)
THF
THF
THF
THF
THF
1
2
3
4
BINAP
BINAP
BINAP
2 0
68
81 19
H
lkyl
(
-
54 96
%
.
-
-
c
:
3 0
7
1
91 9
(
(
-
-
-
-
,
c
oss e ca a c as mme r c mono ar
a en a on o ma ona es
yl 2 3 ll yl ti f
l
t
P
ibl
t
lyti
y
t i
4
)
.
c
:
93
4 0
63
6
7
r
A
.
LG
.
*
ca
t
CO2R
CO2R
Pd 0
(
L
:
/
)
DPPE
4 0
100 0
7
3
+
?
CO2R
CO2R
r
A
.
-
-
c
ase
b
c
d
5
4 0
61
PPh3
H
-
.
-
c
oxane
Di
:
±)
6
7
8
BINAP
4 0
68
74
100 0
(
(
(
-
ssue o se ec
v
:
ou e a en
a
on com
e
n
w
mono a en
a
on
d
)
I
f
l
ti ity
d
a
bl ll yl ti
p
ti
g
ith
ll yl ti
-
.
-
-
Ph
Ph
c
o uene
T l
:
±)
BINAP
4 0
100 0
Ph
e
e
CO2M
-
.
c
o uene
T l
:
Pd /dpbp
±)
BINAP
2 0
1
00 0
[
]
+
80
78 e
(
e
e
)
CO2
M
e
CO
2M
)2]
+
Ph
N
H
C
[
(
CO2M
r
B
H
CO2M
aThe reaction of Pd2(dba)3·CHCl3 (2.5 mol%), ligand (0.012 mmol), K2CO3 (0.4
mmol), 2a (x equiv)/solvent (1.0 mL), and 1a (0.2 mmol) in solvent (1.0 mL)
was stirred at 30 oC. bData determined by NMR analysis of the crude
reaction mixture. cNot detected. d12 mol% PPh3 was used. eIsolated yield.
:
81 19
-
-
-
,
e
e
or e
s
n
y
es s w
th
en
u a en
os a e
di yl ph ph
t
R
p
t
d
i
ith 4 ph yl 2 3 b
t
)
Ph
t
)
2
,
*
]
OPO OE
Et
O2C
(
Pd /L BSA
[
+
c
NHA
CO2Et
a so e exam
e
pl
)
l
Ph
(
EtO2C
c
A
HN
t
CO2E
,
ee
e
60%
80% yi ld
-
-
-
-
-
,
ca a ze as mme r c s
n
eses o ar a enes v a a en
a
on w
ar
u a en
di yl
f
Pd
t
ly
t
d
y
t i
k
y
th
f
yl ll
i
ll yl ti
ith 4 yl 2 3 b
t
)
-
s wor
:
car ona es
Thi
b
Next, the substrate scope for the synthesis of racemic 1,3-
disubstituted arylallenes was investigated (Table 2). The reaction
of dimethyl malonate (2a) with allenylic carbonates 1a-1f afforded
the monoallenylation products (±)-3aa to (±)-3fa exclusively in 64-
78% yields. As for nucleophilic reagents 2b-2e equipped with useful
functional groups, such as 2-acetamide, 2-allyl, 2-allenyl, and 2-
propargyl, the reaction with different 4-aryl-2,3-allenylic
carbonates 1 containing electron-withdrawing and electron-
donating groups on the aryl ring could all deliver the desired
products with moderate to excellent yields (44-90%), regardless of
the location of the substituents.
e
OCO2M
r
A
r
A
- - -
-
r
A
e
e
1
CO2M
Pd 0 / R
(
DTBM SEGPHOS
CO2R2
) ( ) ( )
,
-
or
+
o uene or
,
5
oC N2
CO2M
K2CO3
T
l
THF
CO2R2
R1
CO2R2
or
20
R1
r
A
4
3
CO2R2
.
,
t
,
,
,
,
=
R1
H
llyl ll yl lkyl NHA
a
a
en
a
c
e c
2
-
,
e
o
ee
%
51 91 yi ld 90 t 98
%
Results and Discussion
We commenced our study on the reaction of allenylic
carbonate 1a with the most challenging dimethyl malonate 2a to
address the selectivity issue of monoallenylation over
bisallenylation. As expected, we found that treatment of 1a with
2a catalyzed by Pd2(dba)3·CHCl3 with (±)-BINAP as ligand and K2CO3
as base in THF furnished (±)-3aa smoothly in 68% yield together
with the bisallenylation product (±)-4aa (entry 1, Table 1) in a poor
selectivity of 4:1.[9] Increasing the loading of 2a would slightly
increase the selectivity of monoallenylation product (±)-3aa over
bisallenylation product (±)-4aa (entries 2 and 3, Table 1). The
screening of ligands inferred that (±)-BINAP was still the best choice
(entries 4-5, Table 1). Interestingly, a profound solvent effect was
observed: By using dioxane as solvent the reaction afforded
monoallenylation product (±)-3aa in 68% yield, exclusively (entry 6,
Table 1). A much higher yield with an exclusive chemoselectivity
was observed using toluene as solvent (entry 7, Table 1). In this
solvent, reducing the amount of 2a further increased the yield of
(±)-3aa to 80%, with no formation of bisallenylation product (±)-
4aa.
Table 1 Identifying the optimal reaction conditions for the reaction of 1a
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Chin. J. Chem.
Table 2 The synthesis of racemic 1,3-disubstituted arylallenyl malonatesa
conditionsa
r
A
.
mo
a
2 5
l
Pd db 3•CHCl3
%
mo
a
)
(
)
2
2 5
l
Pd db 3•CHCl3
%
(
e
r
A
OCO2M
-
E
E
r
A
mo
±
e
6
l%
BINAP
m
OCO2
M
o
c a a
2 r
hi l li
g
%
n
d
(
)
.
l
6
+
R
e
e
CO2M
me
d
i
ma ona e
a
2
x
e
q
u v
thyl
l
t
i
)
r
A
e
30 o
u v
i
(
K2CO3 2 0
(
q
E
E
)
+
e
e
CO2M
r
A
,
,
-
o uene
l
CO2M
N2
T
C
-
=
p F H4
C6
±
,
2
3
R
1
u v
i
e
a
1
r
A
(
)
K2CO3
,
y
(
q
,
)
.
CO2M
e
q
u v
i
H
2 0
5 o
C
aa
4
-
-
,
o uene
T l
aa
3
N2
Ra
)
r
A
R
(
a Ra
(
)
e
CO2M
e
CO2M
CO2M
e
e
e
CO2M
CO2
Et
CO2E
NHA
OM
CO2M
e
CO2M
e
e
t
CO2M
O
e
c
CO2M
O
O
a
2
c
2
e
2
2b
O
O
2d
e
M
e
M
r
PPh2
PPh2
PPh2
PPh2
PPh2
PPh2
PA
PA
O
O
O
2
2
NH NH
r
O
PPh2 Ph2
P
O
e
OM
=
Ph
:
r
L5
L1
L2
L3
L4
A
e
e
e
e
e
e
CO2
M
M
O
CO2M
-
-
-
-
-
e
CO2M
,
=
:
r
u
L6
A
3 5 t B 2 4 OM C6H2
(
)
M
CO2M
e
e
CO2
e
H
H
CO2M
H
-
.
-
-
-
ca
±)
3
,
,
3d 21 5 h
4
6
,
,
,
,
-
a
a
±)
(
e
i ld
% y
±)
±)
-
3b
1
h
75
i
ld
1
h
7
i
ld
3
% y
3 6
% y
aa
:
e
o
(
e o
f
(
(
Yi ld
f
Ra
3
E
(
R
)
n r
t y
an
Lig
x
E
d
/y
t
h
-
-
-
,
(
)
c
b
d
aa
aa
3
aa
Ra
( )
a Ra
)
4
%
Ra
(
3
%
( )
)
(
)
r
B
F
.
.
.
-
-
-
1e
2e
3e
4e
5e
6e
7e
8
0/
f
f
L1
2
2 2
10
10
11
e
e
Cl
CO2M
CO2M
e
e
e
e
e
CO2M
CO2M
.
H
:
40
75
84
77
CO2M
e
L2
L3
L4
L5
L6
L6
L6
2 0 2 2
77
74
7
89 11
/
H
7
CO2M
e
H
-
-
,
,
,
a
,
,
,
aa
ea
±)
3
14 h
i
ld
±)
3f 11 h
i ld
% y
8% y
6
5
3
1
h
i
ld
6
66% y
(
(
.
.
.
.
.
.
(
:
2
2
2
2
2
2
0/
0/
0/
0/
0/
2 2
8
4 1
6
.
NC
:
2 2
13
.
3
8
2 1
8
.
e
e
t
CO2E
CO2E
e
CO2M
:
11 5
74
69
77
80
2 2
89
11
t
CO2E
CO2E
e
c
t
CO2M
A
HN
.
c
t
A
HN
:
8
5 15
8
4
2 2
1
8
,
,
88% y
3gb b 1
h
i
ld
-
±)
±)
(
3
,
,
90% y
3hb b 1
h
i
ld
,
-
.
8
,
b
,
72
c 1
6
h
i
ld
93
86
(
cc
3
e
:
2
±)
% y
2
0
12
9
8
(
.
.
:
7
0/
2
0
1
3
9
3
e
e
CO2M
.
.
e
e
:
CO2M
e
9g
L
6
2 5/2 0
17
21
36
6
7
7
8
7
100 0
e
M
O
CO2
M
CO2M
10h,i
,
L6
2 5/2 0
3
1
00 0
.
.
CO2M
e
M
CO2
:
89
,
-
±)
,
,
-
.
-
.
,
,
,
,
,
,
b d 15 h 52 yi ld
±)
.
.
11i
L
6
2 5/2 0
80
100 0
±)
%
3d b d 14 5 h 44
e
3b
b d 1 5 h 45
6
i
ld
%
:
e
e
c
3 d
e
l
d
e
y
i
% y
(
j
(
91
(
aThe mixture of Pd2(dba)3·CHCl3 (0.005 mmol), (±)-BINAP (0.012 mmol),
aA mixture of Pd2(dba)3·CHCl3 (2.5 mol%), chiral ligand (0.012 mmol), K2CO3
(y equiv), and dimethyl malonate 2a (x equiv)/toluene (1.5 mL) was stirred
at 25 oC for 30 min. The mixture was stirred at 5 oC for 10 min and then 1a
K2CO3 (0.4 mmol), 2 (0.4 mmol)/toluene (1.0 mL) and 1 (0.2 mmol)/toluene
o
(1.0 mL) were added and the resulting mixture was stirred at 30 C. The
b
c
yields were gained after column chromatographic separation on silica gel.
bTHF was used instead of toluene. cDTBM-SEGPHOS was used instead of (±)-
BINAP. d5 mol% Pd(dmdba)2 was used instead of 2.5 mol% Pd2(dba)3·CHCl3.
(0.2 mmol)/toluene (0.5 mL) was added. Isolated yields. The ees of (Ra)-
d
3aa were determined by chiral HPLC analysis. Data determined by NMR
analysis of the crude product. eTHF was used as solvent instead of toluene.
f(Ra)-3aa was not afforded and 89% of 1a was recovered. gThe reaction was
We went further to develop the asymmetric version of this
transformation by using 4-aryl-2,3-allenylic carbonate 1a and the
much less sterically hindered dimethyl malonate (2a) as the model
substrates. Under the catalysis of Pd2(dba)3·CHCl3, different chiral
ligands were tried (entries 1-6, Table 3) and (R)-(-)-DTBM-SEGPHOS
was found to be the preferred ligand. The results in Table 3 showed
that both the loadings of 2a and base had an obvious effect on the
enantioselectivity of (Ra)-3aa and the selectivity of
monoallenylation product (Ra)-3aa/bisallenylation product (Ra,Ra)-
4aa (entries 6-9, Table 3). With 2.0 equiv each of 2a and K2CO3, the
reaction afforded (Ra)-3aa in 77% yield with an ee of 93% and the
ratio of (Ra)-3aa/(Ra,Ra)-4aa was improved to 92/8 in THF (entry 7,
Table 3). Replacing THF with toluene, the reaction furnished
monoallenylation product (Ra)-3aa overwhelmingly with an ee of
87% (entry 8, Table 3). Further optimization led to the
establishment of the optimal reaction conditions for further scope
study: with 2.5 equiv of 2a, the reaction in toluene at -20 oC yielded
(Ra)-3aa exclusively with an ee of 91% (entry 11, Table 3).
i
conducted at -5 oC. hThe reaction was conducted at -15 oC. 5 mol%
j
Pd(dmdba)2 was used instead of 2.5 mol% Pd2(dba)3·CHCl3. The reaction
was conducted at -20 oC.
With the optimal reaction conditions in hand (entry 11, Table
3), the substrate scope of 2,3-allenylic carbonates with 2-non-
substituted dimethyl malonate 2a was studied (Table 4). Generally
speaking, electronic and steric effects have a very limited impact
on this reaction and the desired products were afforded in good
yields (62-82%) with high ees (90-95%) and selectivity (s = 94:6 to
100:0). Substituents on phenyl rings in allene 1, such as F, Cl, Br,
and OMe, are all compatible. Importantly, the mono-substituted
malonate-type products (Ra)-3aa to (Ra)-3la still possess a handle
for further synthetic elaboration. The absolute configuration of
major enantiomer of 3ca was determined by X-ray single crystal
diffraction study to be R.
Table 4 The substrate scope of allenylic carbonates with dimethyl
Table 3
Identifying the best ligand and optimization of reaction
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

Song et al.
Report
malonatea
Table 5 Highly enantio- and diastereoselective bis(arylallenylation)a
r
A
mo
m
a
Pd d db
)
2
7
l
%
r
(
A
.
mo
r
A
L6
8 4
a
2
l%
e
.
mo
m
a
Pd d db
)
.
e
e
e
5
l
%
CO2M
OCO2M
(
2
u v
q
i
2 5
e
OCO2
M
(
)
e
e
- - -
-
CO2
M
e
e
+
CO2
M
mo
l
e
e
6
R
(
DTBM
.
E
S G
PH
OS
%
CO2M
) ( )
e
-
u v
i
)
CO2M
K2CO3 2 0
q
+
r
A
(
,
,
N2
20 o
C
r
A
o uene
t
l
v
)
e
q
u
K2CO3 2 5
N2 THF 5 o
i
CO2M
CO2
M
H
)
(
CO2M
-
,
-
1
q
r
A
1
4
Ra Ra
,
,
Ra
(
3
(
)
.
C
e
u v
-
-
,
2 5
i
-
=
,
:
3
a
2
s
se ec
l
v
ti ity
)
4
Ra
Ra Ra
(
(
)
(
)
r
A
4
R
(
a Ra
)
=
r
A
e
e
e
e
e
e
e
M
O
CO2M
CO2M
CO2M
r
B
F
H
-
H
-
H
CO2M
a
CO2M
CO2M
Cl
-
-
a
-
,
,
,
b
-
a
a
Ra 3b
)
aa
4
b
ca
R
a Ra 4b
R
(
a Ra 4f
-
R
(
a Ra
5
,
,
(
)
)
(
Ra
3
Ra 3d
)
(
)
(
)
ea
R
a Ra
4
.
(
)
,
,
,
,
,
,
,
,
,
e
ee
e
ee
e
e
i
e
ee
e
32 h 64% yi ld 94%
34 h 82% yi ld 90%
32 5 h 86 yi ld
%
5 h
ld
3
9
ee
% y
7
,
34 h 62% yi ld 91%
36 h
99%
8
% yi ld
,
e
=
=
s
35 h 86% yi ld
=
s
:
:
,
s
:
100 0
=
r
d 96 4
100 0
=
:
97 3
100 0
>
ee
:
>
=
r
99%
>
ee
r
:
99%
d
d
97 3
,
ee
r
d
=
:
97 3
>
99%
e
Cl
M
O
F
e
e
e
e
CO2M
M
O
CO2M
e
e
CO2M
aThe mixture of Pd(dmdba)2 (0.01 mmol), (R)-(-)-DTBM-SEGPHOS (0.012
mmol), K2CO3 (0.5 mmol), and 2a (0.2 mmol)/THF (1.5 mL) were stirred at
25 oC for 30 min. The mixture was stirred at 5 oC for 10 min and then 1 (0.5
mmol)/THF (0.5 mL) was added. The ee values and drs were determined by
chiral HPLC analysis. b3.0 equiv 1f was used.
e
H
-
H
CO2M
CO2M
H
CO2M
,
-
-
,
aae
ac
ac
d
f
Ra
3
Ra
3
i
Ra
3
(
)
(
)
j
(
)
,
,
,
,
e
ee
,
,
36 h 80% yi ld 91%
e
ee
%
e
ee
16 h 79 yi ld 93
%
64 h 69% yi ld 91%
=
=
s
:
=
100 0
s
:
s
:
94 6
100 0
r
B
e
e
M
C
l
CO2
e
Cl
CO2M
CO2M
e
M
e
H
eac
,
e
CO2
H
H
-
CO2M
CO2M
,
-
,
,
-
f
f
g
f
g
a
Ra
%
3
a
e
Ra 3f
3
l
(
)
Ra
(
(
)
)
,
,
,
e
ee
,
,
42 h 66 yi ld 95
ee
%
e
ee
58 h 77 yi ld 91
%
58 h
73 yi ld 91
%
s
%
%
=
:
100 0
=
:
100 0
s
=
s
:
100 0
Then the scope of 2-substituted malonates for this
enantioselecctive transformation was evaluated (Table 6).
Compared to 2a, 2-substituted malonates (2b-2f) could afford the
arylallenes with relatively higher ees as expected. When diethyl 2-
acetamidomalonate (2b) was exploited as nucleophile, allenylic
carbonates with the aryl group substituted with 4-Me, 4-F, 4-CN,
and 2-naphthyl gave the products with 97-98% ee.[7a,8] In addition,
2-allyl, 2-allenyl, 2-propargyl, and 2-(3-phenylpropargyl)-
substituted malonates all worked smoothly. These synthetically
useful groups combined with the chiral allene unit could afford
e
e
CO2M
H
ca
3
CO2M
-
Ra
(
)
:
794
CCDC 1938
aThe mixture of 7 mol% Pd(dmdba)2, 8.4 mol% L6, K2CO3 (0.4 mmol), and 2a
o
(0.5 mmol)/solvent (1.5 mL) were stirred at 25 C for 30 min. The mixture
other chiral cyclic molecules via different types of [4+2][3f,3g]
[2+2+1][3h] or [2+2][10] cycloaddition reactions.
,
was stirred at -20 oC for 10 min and then 1 (0.2 mmol)/solvent (0.5 mL) was
added. The s values were calculated by NMR yields of (Ra)-3 and (Ra,Ra)-4 as
Table 6 The substrate scope of allenylic carbonates with substituted
malonatesa
b
determined by NMR analysis of the crude product. 5 mol% PPh3 and 9.8
c
.
mol% L6 were used as ligands. 2.5 mol% Pd2(dba)3·CHCl3 and 6 mol% L6
mo
a
)
3
l
Pd db •CHCl3
%
(
r
A
2 5
- - -2
-
e
OCO2M
E
E
mo
l%
6
R
(
DTBM SEGPHOS
.
) ( )
+
R
were used. dThe reaction using 2.0 equiv 2a with THF as solvent was
E
E
r
A
e
u v
q
K2CO3 2 0
N2 THF 5 o
i
(
)
,
,
C
R
1
o
e
f
2
3
conducted at 5 C. 5 mol% Pd(dmdba)2 and 6 mol% L6 were used. The
e
u v
i
2
q
g
mixed solvent (Toluene:THF = 30:1) was used. 3.5 mol% Pd2(dba)3·CHCl3
F
N
C
t
Et
Et
Et
Et
CO2E
CO2
CO2
was used.
c
c
c
c
HN
t
CO2E
CO2
CO2
A
HN
A
HN
a
A
-
-
-
Ra 3gb
Ra
)
3
b
(
)
Ra
3
b
(
(
)
,
,
,
,
e
ee
41 h 91 yi ld 98
%
Moreover, bis(arylallenylation) of dimethyl malonate 2a was
also realized in good to excellent yields (86-95%) and excellent
enantio- and diastereoselectivities (>99% ee, 96:4 to 97:3 dr) upon
the molar ratio of 1:2a being adjusted to 2.5:1 (Table 5).
e
ee
%
,
,
40 h 85 yi ld 98
%
%
e
ee
17 h 71 yi ld 98
%
%
e
e
e
CO2
M
CO2M
t
CO2E
e
CO2
M
CO2M
c
A
t
CO2E
HN
-
-
Ra
3
hb
e
b
-
cc
(
)
Ra
%
3
b
c
3 d
e
(
)
.
Ra
%
,
,
(
)
,
,
ee
18 5 h 90 yi ld 97
%
%
e
ee
45 h 65 yi ld 95
%
,
,
ee
%
17 h 51 yi ld 96
e
e
e
e
e
M
M
O
CO2
CO2
CO2M
e
e
CO2M
M
CO2M
Ph
CO2M
-
-
b
b
e
e
,
-
Ra 3d
Ra 3b
c
(
)
Ra 3bfb
(
)
(
)
.
,
,
,
16 5 h 70 yi ld 96
%
,
e
ee
e
ee
%
,
,
34 h 86% yi ld 95%
e
ee
35 h 76% yi ld 96%
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Chin. J. Chem.
aThe mixture of Pd2(dba)3·CHCl3 (0.0125 mmol), (R)-(-)-DTBM-SEGPHOS
(0.03 mmol), K2CO3 (1.0 mmol), and 2 (1.0 mmol)/THF (4.0 mL) was stirred
at 25 oC for 30 min. The mixture was stirred at 5 oC for 10 min and then 1
(0.5 mmol)/THF (1.0 mL) was added. b5 mol% Pd(dmdba)2 was used instead
Scheme 3 A rationale for the formation of product (Ra)-3
O
r
A
'
r
A
'
u-
r
A
N
O
O
P
+
Pd
r
A
P
'
*
r
A
PdL
'
r
A
*
PdL
e
O
OCO2M
c
of 2.5 mol% Pd2(dba)3·CHCl3. 2f was dimethyl 2-(3-phenylprop-2-ynyl)
u-
N
r
A
+
+
malonate.
r
η1 o η3
A
-
A
r
t
1
)
Ra
(
*
PdL
as
t
e
f
M
*
OCO2
r
A
PdL
+
This transformation could be easily conducted on a gram-scale:
The reaction of allenylic carbonate 1c (4.0 mmol) with diethyl 2-
acetamidomalonate (2b) gave (Ra)-3cb (1.08 g) in 75% yield and 97%
ee. Synthetic applications have been demonstrated to highlight the
potential values of this methodology. Treatment of (Ra)-3ba with
HCHO (37%, aq.) in the presence of NaHCO3 gave γ-allenol (Ra)-5ba,
which subsequently produced optically active tetrahydrofuran
derivative (S,E)-6ba with an exclusive E-C=C bond through gold-
catalyzed cycloisomerization.[3e] Reaction of (Ra)-3ba with 3-
phenylpropargyl bromide gave (Ra)-3bf and its subsequent APK
reaction of (Ra)-3bf in the presence of CO co-catalyzed by
[Rh(CO)2Cl]2/AgOTs afforded the optically active bicyclopentenone
compound (R)-7bf with a highly sensitive chiral center via chirality
transfer strategy.[3h]
-
n
I t A
-
3
η
1
)
Sa
(
-
-
-
,
e
1
η
n
1 3 di yl Pd
E
u
N
H
e
OCO2M
*
ase
B
PdL
r
A
*
PdL
r
u
A
N
*
LPd
r
A
e
OCO2M
- - -
DTBM SEGPHOS
) ( )
-
* =
L
R
(
-
u
Ra
3
N
(
)
Conclusions
In summary, we have developed a Pd(0)-catalyzed synthesis of
the easily racemizable aryl-substituted allenes via highly selective
nucleophilic allenylation of 2-non-substituted and 2-substituted
malonates with allenylic carbonates. The highly enantioselective
version of this transformation has been successfully realized with
(R)-(-)-DTBM-SEGPHOS as the chiral ligand. This method features
high efficiency, high selectivity, good substrate scope, and very
mild reaction conditions avoiding racemization. Synthetic
applications have also been demonstrated. We are actively
pursuing other targets in this area.
Scheme 2 Scheme captionGram-scale reaction and synthetic applications
-
a
ram sca e
G
l
)
.
mo
o
T
l
a
)
3
2 5
m
l
Pd db •CHCl
%
(
3
- - - 2
-
e
OCO2M
t
t
CO2E
o
l%
6
R
(
DTBM SEGPHOS
.
) ( )
c
+
t
A
HN
CO2E
o
T
l
e
,
u v
i
K2CO3 2 0
q
CO2E
(
)
.
,
,
c
t
N2 THF 5 o
C
15 5 h
CO2E
A
HN
-
c
c
2
q
Ra
3
( )
b
b
1
.
,
e
1 08 g 75 yi ld
%
.
e
u v
i
mmo
2
4 0
l
ee
97%
Experimental
n
e
c a
ca ons
b
)
Sy th ti ppli ti
Ph
The asymmetric synthesis of (Ra)-3aa (Ssh-07-128): To a dry
Schlenk tube were added K2CO3 (55.4 mg, 0.4 mmol), (R)-(-)-DTBM-
SEGPHOS (14.2 mg, 0.012 mmol) inside a glove box. Then
Pd(dmdba)2 (8.3 mg, 0.01 mmol), and 2a (65.7 mg, 0.5
mmol)/toluene (1.5 mL) were added into this Schlenk tube under
nitrogen atmosphere outside the glove box. After being stirred at
25 oC for 30 min, the resulting mixture was stirred at -20 oC for 10
min. Then 1a (43.3 mg, 0.2 mmol)/toluene (0.5 mL) was added with
stirring. After being stirred for 36 h at -20 oC, the reaction was
complete as monitored by TLC. Filtration through a short column
of silica gel (eluent: ethyl acetate (10 mL × 3)) and evaporation
afforded crude product (Ra)-3aa exclusively ((Ra)-3aa : (Ra,Ra)-4aa
= 100 : 0, which was calculated by NMR yields of (Ra)-3aa and
(Ra,Ra)-4aa as determined by 1H NMR analysis of the crude product).
Column chromatography on silica gel afforded (Ra)-3aa (44.8 mg,
80%) (eluent: petroleum ether (60-90 oC)/ethyl acetate/DCM =
20/1/1) as a liquid: 91% ee (HPLC conditions; Chiralcel OD-H
column, n-hexane/i-PrOH = 90/10, 0.3 mL/min, λ = 214 nm,
tR(major) = 22.7 min, tR(minor) = 23.7 min); [α]D20 = -197.1 (c = 0.63,
Ph
Ph
2
1
e
e
(
)
(
)
CO2M
CO2M
e
e
CO2M
e
CO2
M
O
CO2M
-
H
e
M
,
HO
CO2
a
6b
S E
(
)
-
e
on
o
wo s e
t
ly 93%
s
81% yi ld f t
p
a
-
Ra 5b
,
(
)
a
ee
,
Ra 3b 96%
ee
(
)
E
3
)
(
Ph
Ph
Ph
e
M
e
O2C
4
(
)
e
e
M
O2C
CO2M
O
CO2M
Ph
H
-
,
e
7bf
R
( )
85 yi ld
%
-
,
,
e
ee
Ra 3bf 97 yi ld 96
(
%
%
)
ee
90%
.
.
,
,
,
,
m n
en r
i
th
ro ar
p
=
+
a
e
u v
i
e
u v
m n
;
1
N
HCO3 1 0
q
CH O 4 0
q
i
EtOH/H2O 2/1 0 o
C
;
5
i
10
en
t
24 h
(
2 5
)
.
(
)
(
)
(
)
(
)
)
(
2
-
-
.
-
,
,
,
,
,
AgOT CHCl3 20 oC 8 7 h N2
3
)
3 ph yl p
,
gyl b
id 1 1
mo
l
%
u
os
mo
s
rom
e
A
LB Ph Cl
5
l
%
(
)
(
(
.
,
,
,
,
,
0
oC
5
i
2 h N2
4
)
4
l% RhCl CO
8
+
e
u v
i
a
e
u v
m n
a oon
CO b ll
mo
mo
l%
;
q
N
H
1 1
(
q
i
THF
,
)
)
(
)
(
[
(
)2]2
.
,
,
20 o
o uene
l
,
s
AgOT
T
C
5 h N2
Finally, a rationale was proposed (Scheme 3): SN2’-type
oxidation addition of PdL* with (Ra)-1 or (Sa)-1 from the back side
of the C-OCO2Me bond would generate the same intermediate E-
η1-1,3-dienyl Pd,[11] which would immediately undergo
delocalization to yield intermediate η3-Int A. Subsequently, the
nucleophile would attack from the back side of the terminal carbon
atom to generate the chiral allene 3 in R configuration as shown in
the model on the up right corner.
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.26-7.17 (m, 2 H, ArH), 7.03-
6.93 (m, 2 H, ArH), 6.22-6.12 (m, 1 H, =CH), 5.62 (q, J = 6.0 Hz, 1 H,
=CH), 3.73 (s, 3 H, OCH3), 3.64-3.52 (m, 4 H, CH + OCH3), 2.85-2.62
(m, 2 H, CH2); 13C NMR (75 MHz, CDCl3) δ 204.9 (d, J = 2.0 Hz), 169.2,
169.0, 162.0 (d, J = 244.9 Hz), 130.0 (d, J = 3.1 Hz), 128.2 (d, J = 7.4
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

Song et al.
Report
Hz), 115.5 (d, J = 21.3 Hz), 95.5, 92.0, 52.6, 52.5, 50.9, 27.8; 19F NMR
(282 MHz, CDCl3) -115.6 (s, 1 F); IR (neat, cm-1) 3002, 2955, 2847,
1951, 1753, 1737, 1602, 1508, 1436, 1342, 1226, 1157, 1094, 1039;
MS (EI, 70 eV) m/z (%) 279 (M+ + 1, 5.38), 278 (M+, 31.41), 146 (100);
HRMS calcd. for C15H15O4F [M+]: 278.0954, found: 278.0952.
42, 8434-8466; (b) Neff, R. K.; Frantz, D. E. Recent applications of chiral
allenes in axial-to-central chirality transfer reactions. Tetrahedron 2015, 71,
7-18; (c) Alonso, J. M.; M. Quirós, T.; Muñoz, M. P. Chirality transfer in
metal-catalysed intermolecular addition reactions involving allenes. Org.
Chem. Front. 2016, 3, 1186-1204; (d) Amako, Y.; Arai, S.; Nishida, A.
Transfer of axial chirality through the nickel-catalysed hydrocyanation of
chiral allenes. Org. Biomol. Chem. 2017, 15, 1612-1617; (e) Zhou, J.; Fu, C.;
Ma, S. Gold-catalyzed stereoselective cycloisomerization of allenoic acids
for two types of common natural γ-butyrolactones. Nat. Commun. 2018, 9,
1654-1663; (f) Han, Y.; Ma, S. Rhodium-catalyzed highly diastereoselective
intramolecular [4+2] cycloaddition of 1,3-disubstituted allene-1,3-dienes.
Org. Chem. Front. 2018, 5, 2680-2684; (g) Han, Y.; Qin, A.; Ma, S. One stone
for three birds-rhodium-catalyzed highly diastereoselective intramolecular
[4+2] cycloaddition of optically active allene-1,3-dienes. Chin. J. Chem.
2019, 37, 486-496; (h) Han, Y.; Zhao, Y.; Ma, S. Rhodium-catalyzed Pauson-
Khand-type cyclization of 1,5-allene-alkynes: a chirality transfer strategy
for optically active bicyclic ketones. Chem. Eur. J. 2019, 25, 9529-9533.
[4] For selected reviews of the synthesis of allenes: (a) Krause, N.; Hoffmann-
Röder, A. Synthesis of allenes with organometallic reagents. Tetrahedron
2004, 60, 11671-11694; (b) Brummond, K. M., DeForrest, J. E. Synthesizing
allenes today (1982–2006). Synthesis 2007, 6, 795-818; (c) Ogasawara, M.
Catalytic enantioselective synthesis of axially chiral allenes. Tetrahedron:
asymmetry 2009, 20, 259-271; (d) Yu, S.; Ma, S. How easy are the syntheses
of allenes? Chem. Commun. 2011, 47, 5384-5418; (e) Neff, R. K.; Frants, D.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement
Financial support from the National Natural Science
Foundation of China (21690063 and 21572202) is greatly
appreciated. We thank Mr. Jie Lin in this group for reproducing the
preparation of
(Ra)-3cb and (Ra, Ra)-4ea. Shengming Ma is a Qiu
Shi Adjunct Professor at Zhejiang University.
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
Chin. J. Chem. 2019, 37, XXX－XXX
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Entry for the Table of Contents
Page No.
Ar
Ar
Highly Selective Nucleophilic 4-Aryl-2,3-
allenylation of Malonates
Me
OCO2
Ar
/L*
[Pd]
Me
Me
CO2
Ar
or
+
Me
Me
CO2
CO2
R2
R2
CO2
CO2
R1
R1
CO2
*
enantioselective
*
diastereoselective
R1
Highly
* Broad substrate
Highly
* Mild reaction conditions
=
or
H
substituent
scope
A Pd(0)-catalyzed synthesis of the easily racemizable aryl-substituted allenes via highly selective
nucleophilic allenylation of 2-non-substituted and 2-substituted malonates with allenylic carbonates
has been developed.
Shihua Song, Shengming Ma*
a
Laboratory of Molecular Recognition and Synthesis, Department of
Chemistry, Zhejiang University, Hangzhou 310027, Zhejiang, People’s
Republic of China.
E-mail:masm@sioc.ac.cn
Chin. J. Chem. 2018, template© 2018 SIOC, CAS, Shanghai,
&
WILEY-VCH Verlag GmbH
&
Co. KGaA,
Weinheim
This article is protected by copyright. All rights reserved.