Catalytic enantioselective Diels-Alder reaction in ionic liquid via a recyclable chiral in(III) complex

Article abstract of DOI:10.1021/ol062481i

(Chemical Equation Presented) A recyclable, air- and moisture-stable chiral indium complex in [hmim][PF₆^-] ionic liquid has been developed. The cycloaddition of a variety of cyclic and open-chained dienes to 2-methacrolein and 2-brom

Full text of DOI:10.1021/ol062481i

ORGANIC
LETTERS
2
006
Vol. 8, No. 26
999-6001
Catalytic Enantioselective Diels
Reaction in Ionic Liquid via a
−Alder
5
Recyclable Chiral In(III) Complex
Fan Fu, Yong-Chua Teo, and Teck-Peng Loh*
School of Physical & Mathematical Sciences, DiVision of Chemistry and Biological
Chemistry, Nanyang Technological UniVersity, 1 Nanyang Walk, Blk 5, LeVel 3,
Singapore 637616
teckpeng@ntu.edu.sg
Received October 9, 2006
ABSTRACT
A recyclable, air- and moisture-stable chiral indium complex in [hmim][PF
6
-] ionic liquid has been developed. The cycloaddition of a variety
of cyclic and open-chained dienes to 2-methacrolein and 2-bromoacrolein resulted in good yields and excellent enantioselectivities (up to 98%
ee). Moreover, the chiral In(III) complex can be reused for seven successive cycles with comparable enantioselectivities and yields without
loss of catalytic activity.
The application of ionic liquids (IL) as potential “green”
alternatives to conventional solvents for a wide range of
organic transformations has sparked an increasing interest
among organic chemists. In particular, they have been
demonstrated to effect large increases in reaction rates in
asymmetric Diels-Alder reactions.
1
2,3
To the best of our knowledge, only two asymmetric
(
1) Some examples of hydrogenation using ionic liquids: (a) Chauvin,
Y.; Mussman, L.; Olivier, H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2698.
b) Suarez, P. A. Z.; Dullins, J. E. L.; Einloft, S.; de Souza, R. F.; Dupont,
catalytic Diels-Alder reactions performed in ionic liquids
4
(
have been reported. However, the application of chiral
J. Polyhedron 1996, 15, 1217. (c) Monteiro, A. L.; Zinn, F. K.; de Souza,
R. F.; Dupont, J. Tetrahedron: Asymmetry 1997, 8, 177. (d) Brown, R. A.;
Pollet, P.; McKoon, E.; Eckert, C. A.; Liotta, C. L.; Jessop, P. G. J. Am.
Chem. Soc. 2001, 123, 1254. (e) Example of enantioselective allylation in
ionic liquids: McCluskey, A.; Garner, J.; Young, D. J.; Caballero, S.
Tetrahedron Lett. 2000, 41, 8147.
(3) For more examples, see: (a) Evans, D. A.; Miller, S. C.; Thomas
von Matt, P. J. Am. Chem. Soc. 1999, 121, 7559. (b) Evans, D. A.; Olhava,
E. J.; Johnson, J. S.; Janey, J. M. Angew. Chem., Int. Ed. 1998, 37, 3372.
(c) Loh, T.-P.; Wang, R. B.; Sim, K. Y. Tetrahedron Lett. 1996, 37, 2989.
(d) Kobayashi, S.; Araki, M.; Hachiya, I. J. Org. Chem. 1994, 59, 3758.
(e) Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 1561. (f)
Ishihara, K.; Gao, Q.-Z.; Yamamoto, H. J. Org. Chem. 1993, 58, 6917. (g)
Evans, D. A.; Miller, S. J.; Lectka, T. J. Am. Chem. Soc. 1993, 115, 6460.
(h) Corey, E. J.; Loh, T.-P.; Toper, T. D.; Azinioara, M. D.; Noe, M. C. J.
Am. Chem. Soc. 1992, 114, 8290. (i) Corey, E. J.; Loh, T.-P. J. Am. Chem.
Soc. 1991, 113, 8966. (j) Narasaka, K.; Tanaka, H.; Kanai, F. Bull. Chem.
Soc. Jpn. 1991, 64, 387. (k) Furuta, K.; Shimizu, S.; Miwa, Y.; Yamamoto,
H. J. Org. Chem. 1989, 54, 1481. (l) Narasaka, K.; Inoue, M.; Yamada, T.;
Sugimori, J.; Iwasawa, N.; Chem. Lett. 1987, 12, 2409. (m) Narasaka, K.;
Inoue, M.; Yamada, T. Chem. Lett. 1986, 11, 1967.
(
2) For representative examples on catalytic enantioselective Diels-
Alder, see: (a) Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004,
26, 4800. (b) Sprott, K. T.; Corey, E. J. Org. Lett. 2003, 5, 2465. (c) Ryu,
1
D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388. (d) Nakano, H.;
Suzuki, Y.; Kabuto, C.; Fujita, R.; Hongo, H. J. Org. Chem. 2002, 67,
011. (e) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
24, 2458. (f) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc.
002, 124, 3808. (g) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem.
Soc. 2002, 124, 9992. (h) Breuning, M.; Corey, E. J. Org. Lett. 2001, 3,
559.
5
1
2
1
1
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© 2006 American Chemical Society
Published on Web 11/24/2006

catalytic systems to the asymmetric Diels-Alder reaction
in ionic liquids using a variety of dienes, in particular, open-
chained dienes, has yet to be explored. In this paper, we
report an efficient asymmetric Diels-Alder reaction of both
cyclic and open-chained dienes to 2-methacrolein and
Table 1. Diels-Alder Reaction of Open-Chained 1,3-Dienes
with 2-Methacrolein and 2-Bromoacrolein Catalyzed by Chiral
S)-BINOL-In(III) Complexa
(
2
-bromoacrolein catalyzed by a chiral (S)-BINOL-In(III)
-
complex in [hmim][PF
6
].
Recently, we have demonstrated an efficient protocol for
the asymmetric Diels-Alder reaction in dichloromethane,
which employs a chiral (S)-BINOL-In(III) as precatalyst
and allyltributylstannane as activator to generate the potent
5
Lewis acid. This method has proven to be practical and
convenient, furnishing a variety of cycloadducts in good
yields and excellent enantioselectivities. However, the cata-
6
lyst was not able to be recycled and reused. In this paper,
we demonstrate that the chiral BINOL-In(III) catalytic
system can be extended to the asymmetric Diels-Alder
reaction using ionic liquids with increased chemical yields
of the cycloadducts. In addition, the chiral catalyst can be
recovered and reused through a simple extraction protocol.
This system in ionic liquid was also found to work using 5
mol % catalyst.
In our initial study, we carried out the catalytic enantio-
selective Diels-Alder reaction using a standardized protocol.
The catalyst was prepared by mixing (S)-BINOL, 4 Å
3
molecular sieve (MS), and InCl in dichloromethane at room
temperature. After 2 h of stirring, allyltributylstannane was
added and stirred for 10 min followed by the addition of
a
-
Unless otherwise specified, the chiral indium(III) catalyst was prepared
[
hmim][PF
6
] to the preformed catalyst. The organic solvent
from (S)-BINOL (22 mol %), InCl3 (20 mol %), and allyltributylstannane
was removed under reduced pressure followed by subsequent
addition of cyclopentadiene and 2-bromoacrolein. This
preliminary study afforded the Diels-Alder adduct in a good
yield of 92% and excellent enantiomeric excess of 98%.
Having achieved the optimum reaction parameters for the
catalytic process, we extended the asymmetric Diels-Alder
reaction of a selection of cyclic and open-chained dienes to
60 mol %) in the presence of activated 4 Å MS. b Isolated yield. c Refer
(
d
to Supporting Information for enantiomeric excess determination. Reaction
e
carried out using 5 mol % catalyst loading. Diels-Alder adduct contains
f
ca. 23% of its regioisomer. Diels-Alder adduct contains ca. 16% of its
regioisomer.
respectively (entries 4 and 5). In addition, the cycloaddition
of 2,3-dimethyl-1,3-butadiene to 2-methacrolein and 2-bro-
moacrolein catalyzed by the BINOL-In(III) complex also
afforded both adducts with excellent enantioselectivities of
97 and 94%, respectively (entries 6 and 7). It is noteworthy
that the yields obtained for the asymmetric Diels-Alder
adducts in ionic liquid were significantly higher as compared
to that in dichloromethane.
2-methacrolein and 2-bromoacrolein. The results are shown
in Table 1.
The reaction of 2-methacrolein and 2-bromoacrolein with
cyclopentadiene afforded both Diels-Alder adducts in 98%
ee (exo:endo 97:3) and yields of 89 and 92%, respectively.
Moreover, the Diels-Alder adduct of cyclopentadiene with
2-bromoacrolein can also be obtained with an enantiomeric
excess of 92% (exo:endo 96:4) and a yield of 89% with as
low as 5 mol % catalyst loading (entry 3). The reaction of
In conjunction with an interest in the application of this
system to the synthesis of steroids, we also tested the reaction
on the complex open-chain diene, 7-methoxy-4-vinyl-1,2-
dihydronaphthalene (Scheme 1). The cycloadduct was ob-
tained with an enantiomeric excess of 92% and chemical
yield of 89%.
2-methyl-1,3-butadiene with 2-methacrolein and 2-bromo-
acrolein afforded the cycloadducts in 88 and 96% ee,
(
4) Examples of asymmetric catalytic Diels-Alder reactions in ionic
liquids: (a) Doherty, S.; Goodrich, P.; Hardacre, C.; Luo, H.-K.; Rooney,
D.W.; Seddonab, K. R.; Styring, P. Green Chem. 2004, 6, 63. (b) Meracz,
I.; Oh, T. Tetrahedron Lett. 2003, 44, 6465. Other examples of Diels-
Alder reactions in ionic liquids: (c) Jaeger, D. A.; Tucker, C. E. Tetrahedron
Lett. 1989, 30, 1785. (d) Fischer, T.; Sethi, A.; Welton, T.; Woolf, J.
Tetrahedron Lett. 1999, 40, 793. (e) Nobuoka, K.; Kitaoka, S.; Kunimitsu,
K.; Iio, M.; Harran, T.; Wakisaka, A.; Ishikawa, Y. J. Org. Chem. 2005,
The absolute configurations of the Diels-Alder products
shown in Table 1 have been assigned by measurement of
optical rotation and comparison with known substances.5
Next, we continued our study by exploring the recyclability
of the chiral indium complex which is important from the
viewpoint of cost-effectiveness. We carried out the model
70, 10106. (f) Silvero, G.; Arevalo, M. J.; Bravo, J. L.; Avalos, M.; Jimenez,
J. L.; Lopez, I. Tetrahedron 2005, 61, 7105. (g) Xiao, Y.; Malhotra, S. V.
Tetrahedron Lett. 2004, 45, 8339. (h) Abbott, A. P.; Capper, G.; Davies,
D. L.; Rasheed, R. K.; Tambyrajah, V. Green Chem. 2002, 4, 24. (i) Song,
C. E.; Shim, W. H.; Roh, E. J.; Lee, S.-G.; Choi, J. H. Chem. Commun.
study by using the cycloaddition of cyclopentadiene and
-
2
-bromoacrolein in [hmim][PF
6
]. After the reaction was
2
001, 1122.
5) Teo, Y.-C.; Loh, T.-P. Org. Lett. 2005, 7, 2539.
(
(6) Teo, Y.-C.; Goh, E. L.; Loh, T.-P. Tetrahedron Lett. 2005, 46, 4573.
Org. Lett., Vol. 8, No. 26, 2006
6000

In conclusion, a highly catalytic In(III) complex was
developed to give enantiomerically enriched Diels-Alder
adducts with high enantiomeric excess in ionic liquid. The
Scheme 1
7
main features of this reaction are as follows: (1) the
procedure is operationally simple, and the catalyst can be
easily prepared from commercially available chemicals; (2)
the cycloaddition of a variety of cyclic and open-chained
dienes to 2-methacrolein and 2-bromoacrolein resulted in
good yields and high enantioselectivities without the need
to recourse to low temperatures; (3) good enantiomeric
excess and yield of cyclopentadiene and 2-bromoacrolein
adduct can be achieved with as low as 5 mol % catalyst
loading in ionic liquid; (4) the catalyst can be recycled up
to seven cycles with comparable yields and enantioselec-
tivities; and (5) stringent anhydrous condition during workup
for recycling the catalyst is not required. This contribution
should provide a convenient and practical synthetic strategy
for the construction of six-membered rings for complex
molecules with medicinal and biological significance.
completed, the reaction mixture was extracted with hexanes
(
10 mL × 5) to afford the cycloadduct. The ionic liquid
residue was then azeotroped with THF to facilitate removal
of solvent remnants prior to subsequent addition of the diene
and dienophile in the next cycle. The results are shown in
Table 2.
Table 2. Recyclability of (S)-BINOL-In(III) Complex in
-
a
hmim[PF
6
]
% yieldb
% eec
Acknowledgment. We would like to thank the Nanyang
no. of cycles
Technological University for their generous financial support.
1
2
3
4
5
6
7
st
92
89
88
89
88
86
87
98
98
92
90
90
90
86
nd
rd
th
th
th
th
Supporting Information Available: Experimental de-
tails, characterization data, and stereochemical proofs. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL062481I
a
Unless otherwise specified, the chiral indium(III) catalyst was prepared
from (S)-BINOL (22 mol %), InCl3 (20 mol %), and allyltributylstannane
60 mol %) in the presence of activated 4 Å MS. Reaction mixture was
stirred at room temperature for 20 h. Isolated yield. Refer to Supporting
Information for enantiomeric excess determination.
(
7) Representative procedure for enantioselective Diels-Alder reac-
(
tion in ionic liquid: preparation of (1R,2R,4R)-2-Bromobicyclo[2.2.1]-
hept-5-ene-2-carbaldehyde. To an oven-dried 10 mL round-bottom flask
equipped with a magnetic stirring bar was added InCl3 (22 mg, 0.1 mmol,
b
c
0
.2 equiv). The solid was azeotropically dried with anhydrous tetrahydro-
furan twice (2 mL × 2) prior to the addition of 1.5 mL of dichloromethane.
S)-BINOL (31 mg, 0.11 mmol, 0.22 equiv) and 4 Å molecular sieves (15
(
It was noteworthy that the chiral In(III) complex can be
reused for seven successive cycles with comparable enan-
tioselectivities and yields without loss of catalytic activity.
Moreover, the extraction process was operationally simple
and convenient to execute, which precludes the need for
stringent anhydrous conditions. This extraction process
further demonstrated the moisture-tolerance and stability of
the chiral indium complex with retention of catalytic activity
throughout the recyclability studies.
mg) were added, and the mixture was stirred under nitrogen at room
temperature for 2 h. Allyltributylstannane (0.093 mL, 0.3 mmol, 0.6 equiv)
was added to the resulting mixture and stirred for 10 min followed by
addition of 1 mL of hmim[PF6 ] to the preformed catalyst. The organic
solvent was removed in vacuo, and subsequent dropwise addition of
-
2
-bromoacrolein (67.5 mg, 0.5 mmol, 1.0 equiv) and cyclopentadiene (0.10
mL, 1.5 mmol, 3.0 equiv) along side of the flask was carried out. The
reaction mixture was stirred at room temperature for 20 h. The mixture
was extracted with ether (10 mL × 3). The combined organic extracts were
washed with brine, dried over anhydrous MgSO4, filtered, and concentrated
in vacuo. The residual crude product was purified via silica gel chroma-
tography to afford the Diels-Alder adduct as a colorless solid (92% yield).
Org. Lett., Vol. 8, No. 26, 2006
6001