Application of chiral ionic liquids in the copper catalyzed enantioselective 1,4-addition of diethylzinc to enones

Article abstract of DOI:10.1016/j.tetasy.2006.03.030

Copper catalyzed enantioselective addition of diethylzinc to various enones has been achieved in the presence of a new class of chiral ionic liquid (ChirILs) derived from α-pinene. This first study on the application of ChirILs for the title reaction show

Full text of DOI:10.1016/j.tetasy.2006.03.030

Tetrahedron: Asymmetry 17 (2006) 1032–1035
Application of chiral ionic liquids in the copper
catalyzed enantioselective 1,4-addition of diethylzinc to enones
Sanjay V. Malhotra* and Yun Wang
Department of Chemistry and Environmental Science, New Jersey Institute of Technology, University Heights, Newark, NJ 07102, USA
Received 16 March 2006; accepted 30 March 2006
Available online 8 May 2006
Abstract—Copper catalyzed enantioselective addition of diethylzinc to various enones has been achieved in the presence of a new class of
chiral ionic liquid (ChirILs) derived from a-pinene. This first study on the application of ChirILs for the title reaction shows that the
chiral reaction medium has a significant influence on chiral induction.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
mising results seen for such reactions, attention toward
chiral ionic liquids has been very limited. The only reported
applications of ChirILs have been in the study of a Diels–
Alder reaction,16,17 Baylis–Hillman reaction18 or as a
reagent for chiral discrimination.19,20 With earlier success
in the preparation of enantiopure compounds in ionic
liquids,21,22 and our on going investigation of organic
reactions in these new systems, herein, we report the first
synthetic application of a-pinene based chiral ionic liquids
in the copper-catalyzed enantioselective conjugate addition
of diethylzinc to a,b-unsaturated enones.
The enantioselective conjugate additions to a,b-unsatu-
rated carbonyl compounds are among the most useful
transformations for stereoselective C–C bond formation
in organic synthesis.1 Numerous chiral auxiliaries and
reagents have been developed toward this end.2 The conju-
gate 1,4-addition of dialkylzinc to enones is one such reac-
tion, which has gained lot of attention.3–5 Catalytic systems
with different metals have been studied for this reaction,
however, application of copper in the presence of chiral
ligands has gained most attention.6 Also, chiral ligands
such as chiral phosphites,7 phosphoramides,8 bisoxazo-
line,9 diamines,10 and bidentate P,N ligands,11 Schiff-base
ligands,12 have been studied extensively. Though solvents
are known to influence chiral properties,13 the application
of chiral solvents to achieve asymmetric induction has
not been reported for 1,4-conjugate addition.
2. Results and discussion
A large number of a-pinene-based effective reagents have
been developed for various asymmetric organic transfor-
mations.22 Terpene-based catalysts have also been used
for asymmetric addition reactions.23–25 This suggests the
potential of solvents derived from a terpene in achieving
similar results in the absence of any other chiral inducer.
To this end, chiral ionic liquids 1 and 2 (Fig. 1) were
Recently, the study of ionic liquids has been increasing
greatly.14 These liquids have attracted the attention of syn-
thetic chemists for some time owing to their remarkable
properties. Being composed entirely of ions, they possess
negligible vapor pressures, and the possibility of the wide
range of cations and anions means that other solvent prop-
erties can be easily controlled. Currently, there is a great
deal of interest in the use of these materials as solvents
for a wide range of applications in organic, organometallic
and bio-catalytic reactions.15 Surprisingly, even with pro-
O
CH3
N
A
C3H7
A = BF4, 1
PF6, 2
*
Corresponding author. Tel.: +1 973 596 5583; fax: +1 973 596 3586;
e-mail: malhotra@njit.edu
Figure 1. Chiral ionic liquids.
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.03.030

S. V. Malhotra, Y. Wang / Tetrahedron: Asymmetry 17 (2006) 1032–1035
1033
prepared by alkylation of the corresponding oxazoline with
an alkyl bromide, followed by anion exchange.26 The oxazo-
line was prepared following a simple procedure, that is, by
reaction of 3-aminohydroxypinane with an aliphatic acid,27
while the aminohydroxypinane was prepared from
a-pinene following the literature method.28 Both ChirILs
were obtained as pale brown liquids.
ee was seen on increasing ChirIL 1 from 25 to 35 mol %.
Therefore, the rest of the investigation was carried out with
35 mol % of ChirIL. With lower than a stoichiometric
amount used here, ChirIL could be considered as an ‘addi-
tive’ or an ‘adjuvant’.
Eqs. 1–3 in Figure 2 show the 1,4 addition of diethylzinc in
the presence of 1 and 2 to cyclohexenone, cyclopentenone
and chalcone, respectively. These substrates were chosen
because a wide range of ligands have been tested for their
effect with these enones, enabling a comparison of the effi-
ciency of chiral ionic liquids. For our reaction, ChirIL was
first mixed with Cu(OTf)2 at room temperature. The addi-
tion of diethyl zinc (1 M in hexane) and enone was then
performed at À20 ꢁC. The reaction was stirred for 15 h
and quenched with NH4Cl at the same temperature.
Conversion was measured by gas chromatography using
n-undecane as an internal standard. The enantioselectivities
were obtained through specific rotation measurement of
the pure isolated product. The % ees were also confirmed
by HPLC using Chiralpak WH column. Results are shown
in Table 2.
Having achieved the synthesis of these ChirILs containing
the pinane moiety, as well as an oxazolium ring, we were
interested in testing their potential for asymmetric induc-
tion. It has been reported earlier that the oxazolium ring
of a chiral auxiliary plays an important role in coordina-
tion to copper catalysts.29,30 Therefore, as a model reaction
we studied the copper-catalyzed addition of diethylzinc to
enones in the presence of ChirILs 1 and 2.31 Preliminary
studies aimed at determining the influence of chiral ionic
liquids revealed that the molar concentration of ChirILs
had an effect on the enantioselectivity to a significant
extent. Table 1 shows the results of the reaction between
cyclohex-2-enone with diethylzinc in the presence of a
chiral ionic liquid.32 With only 3 mol % of ChirIL 1
employed (equal to copper trifluoromethanesulfonate),
enantiomeric excess (ee) of the product was only 17%.
When we increased the molar ratio of ChirIL, but kept
the amount of Cu(OTf)2 constant, the enantioselectivity
improved gradually. However, only a small change in %
In the cases of 2-cyclohexenone and 2-cyclopentenone,
high conversions and fairly good enantioselectivities were
obtained with ChirIL 1. At this point, the active species
inducing chirality is not understood. However, we believe
that the induced chirality is due to the coordination of
the Cu metal with the chiral ionic liquid, creating a chiral
pocket which influences the selectivity of ethyl group trans-
fer from diethylzinc to enone.
Table 1. Effect of ChirIL mol % on enatiomeric excess
Entry
ChirIL 1 (%)
% eea
1
2
3
4
5
6
3
5
10
15
25
35
17
23
38
51
74
76
In the case of chalcone, the enantioselectivity of the prod-
uct using ChirIL 1 is moderate. However, it is important to
point out that this selectivity is still better than earlier re-
ports of conjugate addition to chalcone in an ionic liquid
using a chiral phase transfer catalyst.34 Therefore, even
with moderate % ee, our results are very important because
for the first time we have shown that chiral ionic liquid
a ee measurements were confirmed by HPLC analysis with a Chiralpak
WH column.
O
O
Cu(OTf)2, Et2Zn, ChirIL
(Eq. 1)
- 20 oC, 15h
cyclohex-2-enone
(+)-3-ethyl cyclohexanone
O
O
Cu(OTf)2, Et2Zn, ChirIL
(Eq. 2)
- 20 oC, 15h
cyclopent-2-enone
(+)-3-ethyl cyclopentanone
O
O
Cu(OTf)2, Et2Zn, ChirIL
- 20 oC, 15h
(Eq. 3)
Ph
Ph
Ph
Ph
chalcone
(+)-1,3-diphenylpentan-1-one
Figure 2. Copper-catalyzed 1,4-addition of diethylzinc to enones in chiral ionic liquids.

1034
S. V. Malhotra, Y. Wang / Tetrahedron: Asymmetry 17 (2006) 1032–1035
Table 2. Results of the 1,4-addition of diethylzinc to enones in the
presence of chiral ionic liquids
2. Penne, J. S. Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; John Wiley & Sons: New York, 1995; 420pp.
3. Soai, K. Enantiomer 1999, 4, 591.
Entry Enone
ChirILa Temperature
Product
4. Knopff, O.; Alexakis, A. Org. Lett. 2002, 4, 3835.
5. Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; De
Vries, A. H. M. Angew. Chem., Int. Ed. 1997, 36, 2620.
6. New Methodologies in Asymmetric Catalysis; Malhotra, S. V.,
Ed.; Oxford Press: New York, 2004; p 43.
7. Alexakis, A.; Vastra, J.; Burton, J.; Benhaim, C.; Mangeney,
P. Tetrahedron Lett. 1998, 39, 7869.
8. Schinnert, M.; Seitz, M.; Kaiser, A.; Reiser, O. Org. Lett.
2001, 3, 4259.
9. Arena, C. G.; Casilli, V.; Faraone, F. Tetrahedron: Asymme-
try 2003, 14, 2127.
10. Hu, X.; Chen, H.; Zhang, X. Angew. Chem., Int. Ed. 1999, 38,
3518.
11. Chataigner, I.; Gennari, C.; Pairulli, U.; Ceccarelli, S. Chem.
Eur. J. 2001, 7, 2628.
(ꢁC)
Yieldb eec
(%)
(%)
1
2
3
4
5
6
7
8
9
Cyclohexenone
1
1
2
2
1
1
2
2
1
1
2
2
À20
0 (23)
À20
0 (23)
À20
0 (23)
À20
0 (23)
À20
0 (23)
À20
0 (23)
90
76
Cyclohexenone
Cyclohexenone
Cyclohexenone
Cyclopentenone
Cyclopentenone
Cyclopentenone
Cyclopentenone
Chalcone
93 (94) 68 (52)
87 35
90 (91) 26 (24)
40 73
39 (46) 55 (50)
48 20
48 (52) 15 (12)
52 61
55 (57) 48 (37)
55 37
57 (58) 28 (23)
10
11
12
Chalcone
Chalcone
Chalcone
12. Shi, M.; Zhang, W. Tetrahedron: Asymmetry 2004, 15,
167.
13. Seebach, D.; Oei, H. A. Angew. Chem., Int. Ed. Engl. 1975,
14, 634.
14. Zhao, H.; Malhotra, S. V. Aldrichim. Acta 2002, 35, 75.
15. Gordon, C. M. Appl. Catal. A: General 2001, 222, 101.
16. Earle, M. J.; McCormac, P. B.; Seddon, K. R. Green Chem.
1999, 1, 23.
a 35 mol % ChirIL mixed with 3 mol % Cu(OTf)2.
b Isolated yield.
c Based on the specific rotation measured using ATUOPOL IV polari-
meter. The ee measurements were also confirmed by HPLC using Chir-
alpak WH column.
can provide the same effect in inducing chirality in a conju-
gate addition, as seen through the combination of an ionic
liquid and a chiral catalyst. Product enantioselectivities
were lower for all three substrates using ChirIL 2. Notice-
able difference between results from 1 and 2 suggests that
the chirality induced by the ‘active species’ is to some
extent, also influenced by the achiral anion. Overall, this
investigation has given us an important insight into the
application of chiral ionic liquids as a source of chiral
induction.
17. Howarth, J.; Hanlon, K.; Fayne, D.; McCormac, P. Tetra-
hedron Lett. 1997, 38, 3097.
18. Pegot, B.; Thanh, G. V.; Gori, D.; Loupy, A. Tetrahedron
Lett. 2004, 45, 6425.
19. Wasserscheid, P.; Bosmann, A.; Bolm, C. Chem. Commun.
2002, 3, 200.
20. Levillain, J.; Dubant, G.; Abrunhosa, I.; Gulea, M.; Gau-
mont, A. C. Chem. Commun. 2003, 23, 2914.
21. Zhao, H.; Luo, R. G.; Malhotra, S. V. Bitechnol. Prog. 2003,
19, 1016.
22. Zhao, H.; Malhotra, S. V. Biotech. Lett. 2002, 24, 1257.
23. Brwon, H. C.; Ramachandran, P. V. J. Organomet. Chem.
1995, 500, 1.
3. Conclusion
24. Blaser, H. U. Chem. Rev. 1992, 92, 935.
25. Chrisman, W.; Camara, J. N.; Marcellini, K.; Singaram, B.;
Goralski, C. T.; Hasha, D. L.; Rudolf, P. R.; Nicholson, L.
W.; Borodychuk, K. Tetrahedron Lett. 2001, 42, 5805.
26. Goldfuss, B.; Steigelmann, M.; Khan, S. I.; Houk, K. N.
J. Org. Chem. 2000, 65, 77–82.
We have demonstrated that chiral ionic liquids could be
‘designed’ from a known chiral auxiliary such as a-pinene.
It has been shown that these chiral ionic liquids can be used
as an additive or a co-solvent to achieve asymmetric induc-
tion. Although, currently the enantioselectivity obtained is
moderate to good, several important parameters have been
studied. The useful insight into the understanding of the
application of chiral ionic liquids has led to ‘design’ of
other ChirILs derived from terpenes, which should afford
higher enenioselectivities. The results of these studies will
be reported in due course.
27. (a) Synthesis of isopinocamphelyl oxazolium tetrafluroborate
1 ([IpcOxa]+[BF4]À): Reacting isopinocamphelyl oxazolium
bromide31 with an aqueous solution of sodium tetrafluro-
borate gave product 1 as a viscous liquid. This was washed
with water and acetone. The organic mass was dissolved in
ether and dried on anhydrous MgSO4. Evaporation of the
solvent gave product 1, yield: 83.7%; 1H NMR d: 0.86 (m,
3H, CH3), 0.90 (s, 3H, CH3), 1.19 (s, 3H, CH3), 1.69 (s, 3H,
CH3), 2.12 (1H, CH2), 3.36 (1H, CH), 3.91 (1H, CH), 5.31
(1H, H), 5.43 (1H, H), 5.82 (1H, H). (b) Synthesis of
isopinocamphelyl oxazolium hexafluoro-phosphate 2 ([Ipc-
Oxa]+[PF6]À): Reaction of isopinocamphelyl oxazolium bro-
mide,31 with an aqueous solution of sodium hexafluoro-
phosphate gave product 2 as a viscous liquid. This was
washed first with water and then acetone. The organic mass
was dissolved in ether, dried on anhydrous MgSO4. Evapo-
ration of the solvent gave product 2, yield: 88%; 1H NMR d:
0.88 (m, 3H, CH3), 0.90 (s, 3H, CH3), 1.19 (s, 3H, CH3), 1.69
(s, 3H, CH3), 2.14 (1H, CH2), 3.38 (1H, CH), 3.91 (1H, CH),
5.36/5.37 (1H, H), 5.48/5.46 (1H, H), 5.84 (1H, H).
28. Kurth, M. J.; Decker, O. H. W.; Hpe, H.; Yanuck, M. D.
J. Am. Chem. Soc. 1985, 107, 443.
Acknowledgements
We would like to thank Richard DeJianne, for the mass
spectrometric and NMR analysis.
References
1. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Compre-
hensive Asymmetric Catalysis; Springer: New York, 1999;
1105pp.

S. V. Malhotra, Y. Wang / Tetrahedron: Asymmetry 17 (2006) 1032–1035
1035
29. Markowicz, S. W.; Pokrezeptowicz, K.; Wojciechowska, J.
K.; Czylkowski, R.; Omelanczuk, J.; Sobczak, A. Tetra-
hedron: Asymmetry 2002, 13, 1981.
30. Takemoto, Y.; Kuraoka, S.; Hamaue, N.; Aoe, K.; Hira-
amatsu, H.; Iwata, C. Tetrahedron 1996, 52, 14177.
31. Wang, Y. Master Thesis. New Jersey Institute of Technology,
2003.
32. Representative reaction procedure (Table 1, entry 1): Copper
trifluoromethanesulfonate (55.4 mg, 0.15 mmol, 3.0 mol %)
was weighed in a glove box. This was then mixed with
[IpcOxa][BF4] (ChirIL 1, 0.15 mmol, 3.0 mol %) under helium
atmosphere and stirred for 1 h at room temperature. The
mixture was cooled to À20 ꢁC and 2-cyclohexenone
(480.65 mg, 5 mmol) added, followed by the addition of
Et2Zn (6.5 mL, 1.3 equiv, 1 M in hexane), dropwise within
2 min. After stirring for 15 h at À20 ꢁC, the reaction mixture
was treated with saturated NH4Cl and NH3 (32%) solutions
(10 mL each). n-Undecane (194 mg, 1.2 mmol) was mixed as
an internal standard. The mixture was allowed to warm up to
room temperature. After dilution with water and Et2O (2 mL
each) and stirring for 10 min, an aliquot of the organic phase
was taken, filtered through a pad of cotton and analyzed by
GC (95% yield). The aqueous phase was separated and
extracted with Et2O (3 · 3 mL). The combined organic phase
was dried over MgSO4. The solvent was removed at reduced
pressure and the crude product purified by gradient flash
column chromatography (silica gel, 2 · 15 cm, going from
pentane to pentane/diethyl ether 4:1) to afford 0.57 g (90%) of
3-ethylcyclohexanone as a colorless liquid. [a] = +119.7 (c
1%, chloroform); ee = 76% (compared with [a] = 156.0 in
chloroform).33
33. Posner, G. H.; Frye, L. L. Israel J. Chem. 1984, 24, 89.
34. Dere, R. T.; Pal, R. R.; Patil, P. S.; Salunkhe, M. M.
Tetrahedron Lett. 2003, 44, 5351.