Palladium-catalyzed regio- And diastereoselective allylic alkylation in ionic liquids

Article abstract of DOI:10.1246/cl.2011.953

Palladium-catalyzed regio- and diastereoselective allylic alkylations using ionic liquids (ILs) as a solvent were demonstrated. The reaction using diethyl(2-methoxyethyl)methylammonium bis(trifluoromethanesulfonyl)amide ([N_221ME][NTf₂]) or ethylhexyldimethylammonium bis(trifluoromethanesulfonyl)- amide ([N₆₂₁₁][NTf₂]) as solvent realized the recyclable use of the palladium catalyst while maintaining excellent regioselectivity and diastereoselectivity.

Full text of DOI:10.1246/cl.2011.953

doi:10.1246/cl.2011.953
Published on the web September 5, 2011
953
Palladium-catalyzed Regio- and Diastereoselective Allylic Alkylation in Ionic Liquids
Motoi Kawatsura,* Hideyuki Nobuto, Shunsuke Hayashi, Takuya Hirakawa, Daiji Ikeda, and Toshiyuki Itoh*
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University,
Koyama, Tottori 680-8552
(Received May 17, 2011; CL-110412; E-mail: kawatsur@chem.tottori-u.ac.jp, titoh@chem.tottori-u.ac.jp)
Palladium-catalyzed regio- and diastereoselective allylic
OAc
Me
alkylations using ionic liquids (ILs) as a solvent were demon-
strated. The reaction using diethyl(2-methoxyethyl)methylam-
monium bis(trifluoromethanesulfonyl)amide ([N221ME][NTf2])
or ethylhexyldimethylammonium bis(trifluoromethanesulfonyl)-
amide ([N6211][NTf2]) as solvent realized the recyclable use of
the palladium catalyst while maintaining excellent regioselec-
tivity and diastereoselectivity.
Me
Me
Me
Me
Ph
Ph
CO2Et
1
5 mol% Pd(OAc)2
10 mol% 2-DPPBA
O
3 (major)
Me
+
NaHMDS
IL (solvent)
60 °C, 12 h
O
Me
Me
CO2Et
Ph
CO2Et
Me
O
2
4
Palladium-catalyzed allylic alkylation is one of the most
widely and frequently used carbon-carbon bond formation
reactions, and stereocontrolled reactions have been developed by
several groups.1 We also reported the palladium-catalyzed regio-
and diastereoselective allylic alkylation of allylic acetates with
dimethyl methylmalonate anion using 2-(diphenylphosphino)-
benzoic acid (2-DPPBA) as a ligand;2 it was found that use of
NaHMDS as a base was an essential factor in attaining high
regio- and diastereoselectivities in the reaction. On the other
hand, in recent years, ionic liquids (ILs) have been widely
recognized as greener solvents, suitable for use in organic
reactions including transition-metal-catalyzed reaction, catalyst
immobilization and recycling.3 We have been interested in the
use of ILs in organic synthesis in both chemical and biochemical
reactions, and have shown successful examples of the recyclable
use of enzymes or iron salt catalysts using these liquids as
reaction media.4 Previously, ILs had been considered inappro-
priate for strong base-mediated reactions. However, several
examples have recently been reported showing the possibility of
using ILs as reaction media for strong base-mediated reactions.5
Although palladium-catalyzed allylic substitutions using IL as a
solvent have been reported,6 there has been no example of regio-
and diastereoselective allylic alkylation of 1,3-disubstituted
unsymmetrical allylic esters using an ionic liquid solvent system
to date. One of the most important benefits of using ILs as
reaction media for transition-metal-catalyzed reaction is that the
system makes it possible to realize the recyclable use of the
transition-metal catalyst. To the best of our knowledge, there is
only a single example of the reuse of palladium catalyst
immobilized in the IL in an allylic amination reaction, although
the catalyst activity decreased significantly after three repetitions
of the reaction.6h The reason for the difficulty in reuse of the
palladium catalyst for allylic alkylation was assumed to be that
the reaction demanded a strong base, while many ILs have acidic
protons in the molecules. Herein, we now report the first success
of recyclable use of palladium catalyst in the allylic alkylation
using an IL as solvent while maintaining excellent regio- and
diastereoselectivities.
Me
Me
Bu
–X
Me
Bu
N
N
N
N
IL =
–X
X = BF4: [bmim][BF4]
X = OTf: [bmim][OTf]
X = NTf2: [bmim][NTf2]
X = BF4: [bdmin][BF4]
X = NTf2: [bdmin][NTf2]
Bu
Et
Bu +P Me
Et +N
OMe
–X
Bu
Me
–NTf2
[P4441][NTf2]
X = BF4: [N221ME][BF4]
X = NTf2: [N221ME][NTf2]
Scheme 1.
(2) using 2-(diphenylphosphino)benzoic acid in dioxane sol-
vent,2a,2b we examined the reaction with several types of ILs as
a solvent (Scheme 1). Although [bmim] salts were the most
popular ILs, it was anticipated that [bmim] salt might be
unsuitable for the reaction because the 2-proton of the
imidazolium cation was too acidic to tolerate the strong
NaHMDS base. The screening revealed that the [bmim] salt
ILs indeed inhibited the reaction (Table 1, Entries 1-3), and we
confirmed that the reaction in the [bdmin] salt type IL gave an
alkylated product (Entries 4 and 5). However, we recognized
that both the chemical yield and the regioselectivity depend on
the anionic part of the ILs; bis(trifluoromethanesulfonyl)amide
(NTf2) salt gave a better result than did tetrafluoroborate (BF4)
salt. To our delight, further investigation revealed that changing
the IL from imidazolium salts to an ammonium salt increased
the yield and/or diastereoselectivity, although the diastereo-
selectivity was lower than that in the dioxane solvent (Entries 6
and 7). Especially, when [N221ME][NTf2] was used as a solvent,
the reaction afforded the alkylated product in 80% yield with
83% diastereoselectivity.7 On the basis of this result, we next
examined the reuse of the palladium catalyst in [N221ME][NTf2]
as solvent (Table 2). We thus established that the catalyst was
successfully recycled 9 times while maintaining excellent
reactivity and regioselectivity. Unfortunately, the reaction rate
suddenly dropped significantly at the 10th run, probably due to
Based on our previous results with the palladium-catalyzed
regio- and diastereoselective allylic alkylation of 1-methyl-3-
phenyl-2-propenyl acetate (1) with ethyl 2-methylacetoacetate
Chem. Lett. 2011, 40, 953-955
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

954
Me
Table 1. Palladium-catalyzed regio- and diastereoselective
allylic alkylation of 1 with 2 in ionic liquids
OAc
Ph2C
2.5 mol% [Pd2(dba)3]
N
Ph
Me
Ph
Entry
IL
Yield/%a
3:4b
H
CO2Et
1
6 (major)
10 mol% 2-DPPBA
1
2
3
4
5
6
7
8
[bmim][BF4]
[bmim][OTf]
[bmim][NTf2]
[bdmin][BF4]
[bdmin][NTf2]
[P4441][NTf2]
[N221ME][BF4]
[N221ME][NTf2]
0
0
0
39
68
30
52
80
+
NaHMDS
Me
IL (solvent)
60 °C, 12 h
Ph2C
N
CO2Et
Ph2C N
Ph
80:20
79:21
63:27
88:12
83:17
H
CO2Et
5
7
Et
+
Me N Hex
Me
–NTf2
[N6211][NTf2]
aIsolated yield. bRatio was determined by 1H NMR of the
crude materials.
Scheme 2.
Table 2. Reuse of palladium catalyst in [N221ME][NTf2] for the
allylic alkylation of 1 with 2
Table 3. Palladium-catalyzed regio- and diastereoselective
allylic alkylation of 1 with 5 in ionic liquids
Cycle
Yield/%a
3:4b
Entry
IL
Yield/%a
6:7b
1
2
3
4
5
6
7
8
9
96
85
99
99
93
87
99
80
91
21
82:18
81:19
80:20
81:19
80:20
80:20
81:19
84:16
82:18
86:14
1
2
3
4
[bdmin][NTf2]
[P4441][NTf2]
[N221ME][NTf2]
[N6211][NTf2]
54
0
33
69
88:12
®
64:36
91:9
aIsolated yield. bRatio was determined by 1H NMR of the
crude materials.
Table 4. Reuse of palladium catalyst in [N6211][NTf2] for the
allylic alkylation of 1 with 5
10
aIsolated yield. bRatio was determined by 1H NMR of the
crude materials.
Cycle
Yield/%a
6:7b
1
2
3
4
5
6
7
8
9
69
81
67
61
56
83
36
60
39
0
91:9
89:11
91:9
90:10
90:10
89:11
91:9
90:10
92:8
®
the increased viscosity of the ionic liquid solution through the
accumulation of by-products, and the product was obtained in
poor yield.8,9 However, it should be emphasized that the present
system realized 9 repetitions of the reaction without any addition
of the catalyst with excellent yield and good regioselectivity:
[N221ME][NTf2] is indeed an effective solvent and allows reuse
of the palladium catalyst for the regio- and diastereoselective
allylic alkylation of 1 with 2.
10
aIsolated yield. bRatio was determined by 1H NMR of the
crude materials.
We next demonstrated the regio- and diastereoselective
allylic alkylation of 1 with the ethyl N-(diphenylmethylidene)-
glycinate (5)2c in ILs (Scheme 2). As shown in Table 3,
[N221ME][NTf2] was this time not a suitable solvent for the
reaction of 1 with 5 (Entry 3). We found however, that switching
the solvent to ethylhexyldimethylammonium bis(trifluorometh-
anesulfonyl)amide ([N6211][NTf2]) afforded the desired product
6 in an acceptable yield (69%) with excellent regio- and
diastereoselectivity (91%) (Entry 4). Based on this result, we
again demonstrated the reuse of the palladium catalyst, which
was immobilized in [N6211][NTf2]8 (Table 4). As expected, the
desired reaction successfully proceeded without any addition
of the catalyst, and the desired product 6 was obtained in
acceptable yield while excellent diastereoselectivity was main-
tained even with repetition. However, the yield was again
decreased after the 7th run, and no reaction was observed at the
10th run.
allylic alkylation of 1 with ethyl 2-methylacetoacetate or the
ethyl N-(diphenylmethylidene)glycinate using an ionic liquid as
solvent. The reaction with the ammonium salt ILs effectively
produced the desired alkylated product with perfect regioselec-
tivity and high diastereoselectivity. Further investigation of the
scope and limitation of this reaction will make it even more
valuable.
This work was partly supported by a Grant-in-Aid for
Scientific Research in a Priority Area, “Science of Ionic
Liquids,” from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
This paper is in celebration of the 2010 Nobel Prize
awarded to Professors Richard F. Heck, Akira Suzuki, and
Ei-ichi Negishi.
In summary, we demonstrated the first example of recycla-
ble use of palladium catalyst in the regio- and diastereoselective
Chem. Lett. 2011, 40, 953-955
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

955
References and Notes
Toma, Green Chem. 2002, 4, 103. f) J. Ross, J. Xiao,
Chem.®Eur. J. 2003, 9, 4900. g) L. Leclercq, I. Suisse, G.
Nowogrocki, F. Agbossou-Niedercorn, Green Chem. 2007,
9, 1097. h) S. E. Lyubimov, V. A. Davankov, K. N. Gavrilov,
Tetrahedron Lett. 2006, 47, 2721. i) J. Baudoux, K.
Perrigaud, P.-J. Madec, A.-C. Gaumont, I. Dez, Green
Chem. 2007, 9, 1346. j) R. Šebesta, F. Bilčík, Tetrahedron:
Asymmetry 2009, 20, 1892. k) M. V. Escárcega-Bobadilla, E.
Teuma, A. M. Masdeu-Bultó, M. Gómez, Tetrahedron 2011,
67, 421.
Representative procedure for the allylic alkylation of 1 with
2 in ionic liquid, and reuse of the palladium catalyst
immobilized in IL. To a solution of Pd(OAc)2 (5.8 mg,
0.026 mmol), 2-(diphenylphosphino)benzoic acid (L1) (15.9
mg, 0.052 mmol) in [N221ME][NTf2] (1.0 mL) was added
(R)-1-methyl-3-phenyl-2-propenyl acetate (1) (50 mg, 0.26
mmol), ethyl 2-methylacetoacetate (2) (56 mg, 0.39 mmol).
The solution was cooled to 0 °C, then NaHMDS (0.36 mL,
1.0 M in THF) was added slowly. The resultant mixture was
stirred at 60 °C for 12 h. After completion of the reaction
(TLC), diethyl ether (1 mL © 10) was added for extraction.
The combined ether layers were washed with brine, dried
over anhydrous MgSO4, and evaporated. The regio and
diastereo ratios of the product were determined by 400 MHz
1H NMR of the crude material. The residue was chromato-
graphed on silica gel (EtOAc/hexane = 1/9) to give 58 mg
(80%) of 3 and 4. The separated ionic liquid layer, which
contains the palladium catalyst, was directly reused in the
next reaction.
1
For reviews, see: a) J. Tsuji, Palladium Reagents and
Catalysts: New Perspectives for the 21th Century, Wiley,
Chichester, 2004. b) Z. Lu, S. Ma, Angew. Chem., Int. Ed.
2008, 47, 258.
2
a) J. Uenishi, M. Kawatsura, D. Ikeda, N. Muraoka, Eur. J.
Org. Chem. 2003, 3909. b) M. Kawatsura, D. Ikeda, Y.
Komatsu, K. Mitani, T. Tanaka, J. Uenishi, Tetrahedron
2007, 63, 8815. c) D. Ikeda, M. Kawatsura, J. Uenishi,
Tetrahedron Lett. 2005, 46, 6663. d) M. Kawatsura, D.
Ikeda, T. Ishii, Y. Komatsu, J. Uenishi, Synlett 2006, 2435. e)
M. Kawatsura, S. Wada, S. Hayase, T. Itoh, Synlett 2006,
2483.
7
3
4
For the latest review on ionic liquids, see: H. Olivier-
Bourbigou, L. Magna, D. Morvan, Appl. Catal., A 2010,
373, 1, and references cited therein.
a) T. Itoh, K. Kude, S. Hayase, M. Kawatsura, Tetrahedron
Lett. 2007, 48, 7774. b) Y. Abe, T. Hirakawa, S. Nakajima,
N. Okano, S. Hayase, M. Kawatsura, Y. Hirose, T. Itoh, Adv.
Synth. Catal. 2008, 350, 1954. c) T. Itoh, N. Watanabe, K.
Inada, A. Ishioka, S. Hayase, M. Kawatsura, I. Minami, S.
Mori, Chem. Lett. 2009, 38, 64. d) J. Kobayashi, S. Matsui,
K. Ogiso, S. Hayase, M. Kawatsura, T. Itoh, Tetrahedron
2010, 66, 3917. e) Y. Abe, K. Yoshiyama, Y. Yagi, S.
Hayase, M. Kawatsura, T. Itoh, Green Chem. 2010, 12,
1976.
5
6
a) T. Ramnial, D. D. Ino, J. A. C. Clyburne, Chem. Commun.
2005, 325. b) V. Jurčík, R. Wilhelm, Green Chem. 2005, 7,
844. c) M. C. Law, K.-Y. Wong, T. H. Chan, Chem.
Commun. 2006, 2457. d) S. T. Handy, J. Org. Chem. 2006,
71, 4659.
a) W. Chen, L. Xu, C. Chatterton, J. Xiao, Chem. Commun.
1999, 1247. b) C. de Bellefon, E. Pollet, P. Grenouillet,
J. Mol. Catal. A: Chem. 1999, 145, 121. c) Š. Toma, B.
Gotov, I. Kmentová, E. Solčániová, Green Chem. 2000, 2,
149. d) J. Ross, W. Chen, L. Xu, J. Xiao, Organometallics
2001, 20, 138. e) I. Kmentová, B. Gotov, E. Solcániová, Š.
8
9
[N221ME][NTf2] and [N6211][NTf2] showed hydrophobicity,
and washing by water was effective to remove by-products
in the recycle experiments. However, such a process
decreased the yield of alkylated products.
Diluted reaction conditions or addition of ILs are effective
to prevent viscosity from increasing, but the reaction rate
dropped and needed over 36 h to complete conversion of
allylic acetate.
Chem. Lett. 2011, 40, 953-955
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/