Palladium-catalyzed bisfunctionalization of active alkenes by β-acetonitrile-α-allyl addition: Application to the synthesis of unsymmetric 1,4-di(organo)fullerene derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.12.075

A new, efficient palladium-catalyzed bisfunctionalization of ethylidene malononitriles by addition of acetonitrile and allyl groups is developed for the construction of all-carbon quarternary and tertiary centers simultaneously. This methodology is succes

Full text of DOI:10.1016/j.tetlet.2011.12.075

Tetrahedron Letters 53 (2012) 1210–1213
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Tetrahedron Letters
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Palladium-catalyzed bisfunctionalization of active alkenes by
b-acetonitrile-
a-allyl addition: application to the synthesis of unsymmetric
1,4-di(organo)fullerene derivatives
Shirong Lu a,b, Tienan Jin c, , Ming Bao a, Abdullah M. Asiri d,e, Yoshinori Yamamoto c,
⇑
⇑
a State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116012, China
b Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8548, Japan
c Advanced Institute for Materials Research (WPI-AIMR), Tohoku University, Sendai 980-8577, Japan
d Chemistry Department, Faculty of Science, King Abdulaziz University, PO Box 80203, Jeddah, Saudi Arabia
e Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah, PO Box 80203, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
A new, efficient palladium-catalyzed bisfunctionalization of ethylidene malononitriles by addition of ace-
tonitrile and allyl groups is developed for the construction of all-carbon quarternary and tertiary centers
simultaneously. This methodology is successfully applied to the synthesis of unsymmetric 1,4-disubsti-
Received 27 October 2011
Revised 7 December 2011
Accepted 19 December 2011
Available online 5 January 2012
tuted C60
.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
b-Acetonitrile-a-allyl addition
Bisfunctionalization of active alkenes
All-carbon quarternary center
Unsymmetric 1,4-disubstituted C60
Palladium-catalyzed b-nucleophilic-
olefins through p-allyl-palladium intermediates has emerged as a
mild and efficient multiple bond-forming method for the simulta-
neous construction of all-carbon quaternary and tertiary centers,1,2
which are important structural units in a wide range of bioactive
substances and natural products.3 Over the past decade, we and
other groups have been interested in developing new palladium-
a
-allyl addition of active
of our interest in transition metal catalyzed functionalization of
[60]fullerene (C60),6 we reasoned that if successful, this methodol-
ogy would be applicable to the selective bisfunctionalization of C60
because of its electrophilic nature and specialized alkene compo-
nent. Transition metal catalyzed functionalization of C60 has
emerged as a promising method for preparing functionalized C60
derivatives with high selectivity and high functional group com-
patibility under mild reaction conditions.7 However, investigations
on the synthesis of unsymmetric 1,4-di(organo)fullerenes have
been seldom studied,8 in particular, a one-step catalytic method
has not been reported.
Herein, we report a new Pd-catalyzed bisfunctionalization of
various malononitriles 1 with cyanoacetic acid allyl ester (2), that
affords the b-acetonitrile-a-allyl addition products 3 in good to
high yields (Eq. 1). Moreover, we have successfully applied this
method to the synthesis of unsymmetric 1-acetonitrile-4-allyl-
[60]fullerene 4a in good yield in one step.
catalyzed b-nucleophilic-
alkenes through various
a-allyl addition reactions toward active
p-allyl palladium intermediates, including
heteroatom- and carbon-nucleophile addition/allylation,2e–k bis-
allylation,2a–d acetonation/allylation,2l,m amidoallylation,2n and
iminoallylation (Fig. 1).2o The palladium-catalyzed decarboxylative
reaction for the formation of
p-allyl palladium species is an envi-
ronmentally friendly and economical process1c,4,5; the reaction
proceeds under essentially neutral conditions with high atom
economy. Based on this concept, we envisioned that the bis-
p-
allylpalladium2a analogue acetonitrile-(
p
-allyl)palladium complex
should be formed by the reaction of cyanoacetic acid allyl ester
with a palladium catalyst, which will undergo acetonitrile/allyl
addition to the active alkenes (Fig. 1). Furthermore, in continuation
5 mol% Pd2dba3•CHCl3
CN
CN
CN
20 mol% BINAP
O
CN
+
⇑
Corresponding authors. Tel.: +81 22 217 6177; fax: +81 22 217 6165 (T.J.); tel.:
O
CN
CN
THF, rt
R
+81 22 217 6164; fax: +81 22 217 5979 (Y.Y.).
E-mail addresses: tjin@m.tohoku.ac.jp (T. Jin), yoshi@m.tohoku.ac.jp
(Y. Yamamoto).
R
1
2
3
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.075

S. Lu et al. / Tetrahedron Letters 53 (2012) 1210–1213
1211
Pd
N
C
CH2
N
O
O
N
Pd Nu
Pd
Pd
Pd
Pd
N
Pd CH2 C
acetonitrile
-allylation
this work
Nu: OR, NR2, CN bis-allylation acetonation amidoallylation iminoallylation
-allylation
Figure 1. Bisfunctionalization of active alkenes with various p-allylpalladium species.
Initially, according to our previous results,1b we focused on
screening transition metal catalysts and ligands for the efficient
formation of bisfunctionalized product 3a via the reaction of mal-
ononitrile 1a and cyanoacetic acid allyl ester (2a) under an Ar
atmosphere at room temperature in THF as the solvent (Table 1).
The use of the typical catalyst, Pd(PPh3)4 (10 mol %), afforded the
corresponding product 3a in 40% isolated yield (entry 1). The use
of Pd2(dba)3ꢀCHCl3 (5 mol %) combined with PPh3 (40 mol %) ligand
gave a slightly increased yield, although without the phosphine
ligand, the reaction did not proceed at all (entries 2 and 3). These
results indicated that the use of a phosphine ligand was crucial,
and implied that a change of phosphine ligand species would in-
crease the efficiency of the present transformation. We investi-
gated various phosphine ligands using Pd2(dba)3ꢀCHCl3 as the
catalyst (5 mol %). The electronic characteristics of monodentate
triarylphosphine ligands (40 mol %), such as PPh2(2-MeO-C6H4)
(63%), PPh2(4-F-C6H4) (47%), and P(4-F-C6H4)3 (50%) did not exhibit
any obvious influence on the catalytic activity (entries 4–6). The
use of the triheteroarylphosphine ligand, P(2-furyl)3 gave only a
trace amount of 3a (entry 7). The bulky monodentate trialkylphos-
phine ligand P(t-Bu)3 showed lower reactivity compared to that of
triarylphosphine ligands (entry 8). Bidentate phosphine ligands,
such as dppf, dppe, and dppp showed comparable catalytic activity
(entries 9–11), and finally racemic BINAP gave 3a in 79% isolated
yield (entry 12). It is noted that the use of a 1:1 Pd-BINAP ratio de-
creased the yield of 3a.5
Various ethylidene malononitriles were examined under the
optimized reaction conditions: 5 mol % Pd2(dba)3ꢀCHCl3, 20 mol %
BINAP, cyanoacetic acid allyl ester (2) (1.2 equiv), and THF (0.2 M)
at room temperature (Table 2). The reactions of 1b–d, substituted
with an electron-donating group on the benzene ring at meta or para
positions, gave the corresponding products in good to high yields
(entries 1–3). In contrast, the use of phenylethylidene malononitrile
1e having an electron-withdrawing group (–Cl) on the benzene ring
decreased the yield of 3e dramatically even after longer reaction
times (6 days) (entry 4). The electronic characteristics of the aro-
matic ring of 1 exert a significant influence on the yields of products
3. Not only naphthyl-substituted alkene 1f, but also the heteroaro-
matic 2-thienyl (1g) substituted alkene afforded the corresponding
b-acetonitrile-a-allyl addition products 3f and 3g in high yields
(entries 5 and 6). The reaction with ethylidene malononitriles bear-
ing an alkyl group at R, such as cyclopropyl (1h) or n-octyl (1i), oc-
curred smoothly, giving the corresponding products 3h and 3i in
75% and 74% yields, respectively (entries 7 and 8). Ethylidenemalon-
onitriles bearing a bulky cyclohexyl (1j) or t-butyl (1k) group at R
showed a lower reactivity, giving the corresponding addition prod-
ucts 3j and 3k in 64% and 40% yields, respectively (entries 9 and 10).
It should be noted that in the case of lower yields of 3 (entries 4, 9,
and 10), the major side-product was the decarboxylative self-
coupling product 2-allylpent-4-enenitrile.4c
Table 1
Screening of the reaction conditions for the formation of 3aa
A plausible reaction mechanism is shown in Scheme 1. Initially,
the reaction of cyanoacetic acid allyl ester (2) with the Pd(0) catalyst
CN
Pd-cat/P-Ln
THF, rt, 3 d
CN
CN
O
CN
+
CN
CN
O
Ph
Table 2
Nucleophilic addition of various activated alkenesa
Ph
1a
2
3a
5 mol% Pd2dba3•CHCl3
CN
CN
CN
20 mol% BINAP
O
Entry
Pd-catalyst/P-ligand (10/40 mol %)
Yieldb (%)
CN
+
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
45 (40)
0
50
63
47
50
Trace
36
57
58
O
CN
CN
THF, rt
R
Pd2(dba)3ꢀCHCl3
R
Pd2(dba)3ꢀCHCl3/PPh3
1
2
3
Pd2(dba)3ꢀCHCl3/PPh2(2-MeO-C6H4)
Pd2(dba)3ꢀCHCl3/PPh2(4-F-C6H4)
Pd2(dba)3ꢀCHCl3/P(4-F-C6H4)3
Pd2(dba)3ꢀCHCl3/P(2-furyl)3
Pd2(dba)3ꢀCHCl3/P(t-Bu)3
Pd2(dba)3ꢀCHCl3/dppf
Entry
R
1
Time (d)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
3-Me-C6H4
4-Me-C6H4
1b
1c
1d
1e
1f
1g
1h
1i
3.5
3.5
4
6
3
4.5
4.5
3
4.5
6
3b
3c
3d
3e
3f
3g
3h
3i
72
76
68
35
83
70
75
74
64
40
3-MeO-C6H4
4-Cl-C6H4
2-Naphthyl
2-Thienyl
Cyclopropyl
n-Octyl
10
11
12
Pd2(dba)3ꢀCHCl3/dppe
Pd2(dba)3ꢀCHCl3/dppp
Pd2(dba)3ꢀCHCl3/BINAP
78
84 (79)
dba = trans, trans-dibenzylideneacetone, t-Bu = tert-butyl, dppf = bis(diphenyl-
phosphino)ferrocene, dppe = bis(diphenylphosphino)ethane, dppp = bis(diphenyl-
phosphino)propane, BINAP = (2,2’-bis(diphenylphosphino)-1,1’-binaphthyl).
Cyclohexyl
t-Butyl
1j
1k
3j
3k
10
a
To a mixture of palladium catalyst (10 mol %), phosphine ligand (40 mol %) and
a
phenylethylidene malononitrile (1a) (0.2 mmol) in THF (0.2 M) was added cyano-
acetic acid allyl ester (2) (0.24 mmol). The mixture was stirred at room temperature
for 3 days.
To a THF (0.2 M) solution of Pd2(dba)3ꢀCHCl3 (5 mol %) and BINAP (20 mol %)
were added ethylidene malononitrile 1 (0.2 mmol) and cyanoacetic acid allyl ester
(2) (0.24 mmol). The mixture was stirred at room temperature under Ar for the time
shown in the table.
1H NMR yields determined by using dichloroethane as an internal standard.
b
b
Isolated yields are shown in parentheses.
Isolated yield.

1212
S. Lu et al. / Tetrahedron Letters 53 (2012) 1210–1213
functional groups in one step. Further extension of this method
to the synthesis of various functionalized fullerenes and applica-
tion to photovoltaic cells are in progress.
Pd(0)
O
CN
3a
O
2
Acknowledgments
CO2
This work was supported by World Premier International Re-
search Center Initiative (WPI), MEXT, Japan. S.L. acknowledges the
support of the China Scholarship Council (CSC).
H2C
CN
C
N
C
Pd
A'
CH2
P
CN
P
P
N
P
P
Pd
Pd
Ph
CN
B
P
Supplementary data
A
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.075.
CN
CN
References and notes
Ph
1a
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Scheme 1. A plausible reaction mechanism.
forms
with
gas. The b-nucleophilic addition of acetonitrile to ethylidene malon-
onitrile 1a gives the ion-paired ( -allyl)palladium intermediate B.
p
r
-allylpalladium complex A0, which should be in equilibrium
-allylpalladium complex A, along with the exclusion of CO2
p
Reductive elimination of B produces the b-acetonitrile-
a-allyl
adduct 3a.
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regioselective synthesis of a 1,4-di(organo)fullerene which has
attracted much attention as potentially useful n-type materials in
organic photovoltaic applications.9 Unfortunately, the reaction of
C60 with cyanoacetic acid allyl ester (2) in the presence of the
Pd2(dba)3ꢀCHCl3/BINAP catalyst system in ortho-dichlorobenzene
(ODCB) afforded only a trace amount of the corresponding prod-
ucts 4a and 4b, and C60 was recovered mainly. After a brief optimi-
zation of the palladium catalyst, we found that the reaction
proceeded smoothly in the presence of Pd(PPh3)4 (1 mol %) to give
an 87:13 mixture of the 1,4-disubstituted product 4a and 1,2-
disubstituted product 4b in 31% yield along with the recovery of
C60 in 40% yield (4a was obtained as the major product) (Eq. 2).
It should be noted that in contrast to the present acetonitrile/ally-
lation, our previously reported acetonation/allylation method2l
was not applicable for the functionalization of C60: Under similar
conditions to Eq. 2, the reaction of C60 with allyl acetoacetate gave
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a mixture of multi-adducts and a small amount of recovered C60
In conclusion, we have developed a novel palladium-catalyzed
b-acetonitrile- -allyl addition reaction of active alkenes with
.
a
cyanoacetic acid allyl ester. This method has provided a new ap-
proach for the construction of an all-carbon quarternary carbon
adjacent to a tertiary carbon. The present methodology was
successfully applied to the unsymmetric bisfunctionalization of
C60 through the selective 1,4-addition of two different organic
CN
+
CN
1 mol% Pd(PPh3)4
ODCB, 90 °C, 3 h
O
C60
CN
+
O
2
4a:4b
= 87:13
31%;
recovery of C60
40%
4a
4b
1,4-adduct
1,2-adduct

S. Lu et al. / Tetrahedron Letters 53 (2012) 1210–1213
1213
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