α-Pinene-based new chiral ionic liquids and their application as phase transfer catalysts in enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.2174/157017809787893073

Amino alcohol functionalized new chiral ionic liquids have been synthesized from (+)-α-pinene, an easily available natural product. The effectiveness of these CILs as phase transfer catalysts (PTC) in enantioselective C-C bond formation has been demonstra

Full text of DOI:10.2174/157017809787893073

Letters in Organic Chemistry, 2009, 6, 264-268
264
ꢀ-Pinene-Based New Chiral Ionic Liquids and their Application as Phase
Transfer Catalysts in Enantioselective Addition of Diethylzinc to Alde-
hydes
Sanjay V. Malhotra*,#, Yun Wang and Vineet Kumar#
Department of Chemistry and Environmental Science, New Jersey Institute of Technology, University Heights, Newark,
NJ 07102, USA
Received September 29, 2008: Revised February 03, 2009: Accepted February 06, 2009
Abstract: Amino alcohol functionalized new chiral ionic liquids have been synthesized from (+)-ꢀ-pinene, an easily
available natural product. The effectiveness of these CILs as phase transfer catalysts (PTC) in enantioselective C-C bond
formation has been demonstrated through the addition of diethylzinc to representative aldehydes, and the corresponding
chiral alcohols with good yields and enantiomeric excess have been obtained.
Keywords: Chiral ionic liquids, amino alcohols, enantioselecivity, diethylzinc.
INTRODUCTION
copper catalyzed enantioselective 1,4-addition of diethylzinc
to get chiral enones with good ee (up to 76%) [13]. Another
study showed the camphor-based CIL employed in presence
of Ti(OPri)4 for asymmetric diethylzinc addition to benzal-
dehyde which resulted in low to moderate ee (39-64%) [14].
Several ammonium based chiral salts have also been ex-
plored for asymmetric induction as phase transfer catalysts
(PTC) which provide mild and safe reaction conditions, op-
erational simplicity and selectivity [15]. However, not much
work has been done on the application of PTC in the addi-
tion of diethylzinc to aldehydes. These studies and our ear-
lier efforts toward development and applications of new
CILs derived from biorenewable resources [13, 16] inspired
us to synthesize amino alcohol functionalized new chiral
ionic liquids derived from ꢀ-pinene and to investigate their
applications as phase transfer catalyst in enantioselective
addition of diethylzinc to different aromatic aldehydes.
Catalytic asymmetric addition reactions are important
tools for enantioselective carbon-carbon bond formation
which forms the backbone of synthetic organic chemistry
[1]. One such methodology involves catalytic addition of
organozinc to carbonyl compounds in presence of chiral
modifiers [2]. Oguni et al. for the first time reported the
enantioselective addition of diethylzinc to aldehydes in pres-
ence of catalytic amount of chiral amino alcohols as effective
chiral ligands to give corresponding alcohols [3]. Later,
Noyori et al. carried out a similar reaction using a terpene
based chiral ligand DAIB (N,N-dimethylamino isoborneol)
in presence of diethyl zinc and obtained the product in re-
markably high enantioselectivity (up to 98%) [4]. Subse-
quently, various chiral amino alcohols derived from terpenes
have been explored as chiral catalyst/promoters/ligands for
these types of reactions [2, 5].
The applications of ionic liquids (ILs) have been growing
at an overwhelming rate especially in organic synthesis, due
to their advantageous and tunable features [6]. Their ability
to dissolve biologically important building blocks like nu-
cleosides and amino acids allow the chemo- and enantiose-
lective reactions on these compounds under milder condi-
tions [7]. Also, significant progress has been made in the
development of chiral ionic liquids (CILs) as chiral-
resolution reagents, chiral solvents, chiral catalysts/additives
and liquid crystals etc [8]. CILs are also found to be effective
in asymmetric inductions as seen in case of photoisomeriza-
tion [9], Diels-Alder reaction [10], Baylis-Hilman reaction
[11] and Michael addition reaction [12]. Earlier we reported
synthesis of ꢀ-pinene-based CILs and their application in the
RESULTS AND DISCUSSION
The pioneering work by Brown has led to a large number
of reagents derived from ꢀ-pinene which have proved it to
be highly efficient chiral auxiliary for various asymmetric
transformations [17]. However, most of these reagents are
required in stoichiometric amounts and there have been few
attempts to employ ꢀ-pinene-based catalysts for asymmetric
induction [18]. These studies coupled with the fact that both
enantiomers of ꢀ-pinene are easily commercially available,
prompted us to synthesize pinene-based chiral ionic liquids
bearing amino alcohol substituent. To achieve this goal
commercially available (+)-ꢀ-pinene (1) was first oxidized
following a literature procedure using KMnO4 followed by
resolution of product mixture to obtain 2-hydroxypinan-3-
one (2) in 95% ee (Scheme 1) [18]. The hydroxyketone 2
was reacted with ethylamine followed by reduction with lith-
ium aluminum hydride to give aminoalcohol 3 [19]. The
aminoalcohol 3 was then N-methylated to give tertiary amine
4 [20] which was quaternized using methyl iodide to afford
iodide salt 5. The anion metathesis reaction with the iodide
*Address correspondence to this author at the Department of Chemistry and
Environmental Science, New Jersey Institute of Technology, University
Heights, Newark, NJ 07102, USA; Tel: +1 301 846 5141; Fax: +1 301 846
5206; E-mail: malhotrasa@mail.nih.gov
#Current Address: Laboratory of Synthetic Chemistry, SAIC-Frederick Inc.,
National Cancer Institute at Frederick, 1050 Boyles Street, Frederick, Mary-
land 21702, USA.
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

ꢀ-Pinene-Based New Chiral Ionic Liquids and their Application
Letters in Organic Chemistry, 2009, Vol. 6, No. 3
265
OH
OH
H
O
KMnO4
resolution
1) CH3CH2NH2
2) LAH
N
3
1
2
CH3I
diisopropylethylamine
acetonitrile, RT
-
I
OH
OH
N
+
CH3I
toluene, RT
OH
AgPF6
N
+
or AgBF4
X-
N
6: X = BF4
7: X = PF6
4
5
Scheme 1. Synthesis of chiral ionic liquids derived from (+)-ꢀ-pinene.
salt 5 using AgBF4 and AgPF6 afforded corresponding chiral
ionic liquids 6 and 7, respectively (Scheme 1).
tion with literature value. On the basis of these results a
plausible mechanism is proposed in Fig. (1), which can be
explained by a tricyclic transition state model given by Noy-
ori [21]. The presence of hydroxyl group in the catalyst is
very important for the activation of diethylzinc. The reaction
proceeds through coordination of diethylzinc to the tertiary
hydroxyl group. Also, perhaps there is an interaction be-
tween Zn (II) and anion of the catalyst to form a six member
transition state. The attack of aldehyde from top face is stere-
rically hindered due to stereochemical disposition of gem
dimethyl groups, tertiary methyl group and the bulkier qua-
ternary amine group of the catalyst. There are two di-
astereomeric anti transition states possible. The anti (R)-TS,
where the aromatic aldehyde attack from ‘re face’ without
suffering any unfavorable steric interactions between aro-
matic ring and Zn-Et group is energetically more favored as
compared to anti (S)-TS Fig. (1).
After successful synthesis of CILs 6 and 7, we studied
their capability as chiral phase transfer catalysts for enanti-
oselective addition of diethylzinc to different aromatic alde-
hydes (Scheme 2). Initial screening for the amount of CIL
required for most effective asymmetric induction was carried
out with benzaldehyde as substrate and toluene as solvent, at
room temperature and under inert atmosphere. In case of
both CILs 6 and 7, the maximum yield and ee were obtained
with 35 mol% of catalyst (with respect to substrate). Thus, in
this case CIL could also be considered as a co-solvent and
catalyst. This reaction protocol was further employed for
reaction of diethylzinc with various substituted aromatic
aldehydes. The reaction progress was monitored by thin
layer and gas chromatography and the ee values were con-
firmed by HPLC using Chiralpak WH column and with
NMR where necessary. The isolated yields and ee values of
products are given in Table 1.
In conclusion, we have introduced two new chiral ionic
liquids derived from (+)-ꢀ-pinene, a cheap, and readily
available and biorenewable chiral auxiliary. The utility of
these CILs has been demonstrated by successful chiral in-
ductions achieved in the addition of diethylzinc to a host of
aromatic aldehydes. A plausible mechanism has been pro-
posed, which accounts for facial enantioselection due to
sterically rigid and stereochemically fixed transition state.
Further studies using these CILs for other reactions are under
progress in our laboratory.
O
HO
H
CIL (35 mol%)
H
Et2Zn, toluene, RT
20 h
R
R
Scheme 2. Diethylzinc addition to aldehydes in presence of CILs.
These results show that for most aldehydes correspond-
ing chiral secondary alcohols were obtained in good yields
(58-80%) and moderate to good enantioselectivity (up to
80% ee). The only exception is p-chlorobenzaldehyde where
yield was less then 50% with both catalysts, though ee of
62% and 64% were obtained for the product with CIL 6 and
7, respectively. With the exception of benzaldehyde (entry 1,
Table 1) and o-methylbenzaldehyde (entry 5, Table 1); in-
creased enantioselectivity was observed in all cases when
CIL 7 was used as compared to those with CIL 6. This sug-
gests that the asymmetric induction using CILs may also be
affected by the achiral anion associated with it. However,
more work is required to establish this point.
EXPERIMENTAL
All reactions were performed under an inert atmosphere
(nitrogen). The solvents used in each reaction were first puri-
fied and dried using standard procedure. H NMR analysis
was performed on Varian 300 MHz instrument. The enanti-
oselectivities were obtained by measurement of optical rota-
tion using Autopol IV polarimeter from Rudolph.
1
2-Hydroxy, 3-N-ethyl pinano amine (3) was prepared
by following the method reported earlier [19]. H-NMR
(CDCl3, 300MHz): ꢁ0.93 (s, 3H), 0.94 (s, 3H), 1.10 (t, 3H),
1.29 (s, 3H), 1.59 (t, 2H), 1.62 (t, 1H), 1.96 (t, 2H), 2.29 (m,
1H), 2.91 (q, 2H), 3.30 (t, 1H), 3.50 (s, 1H), 3.51(s, 1H).
1
The absolute configuration of all alcohols was found to
be R-(+) as determined by comparison of their specific rota-

266 Letters in Organic Chemistry, 2009, Vol. 6, No. 3
Table 1. Enantioselective Catalytic Addition of Diethylzinc to Aldehydes in Presence of CILs
CIL 6 as Catalyst
Malhotra et al.
CIL 7 as Catalyst
Entry
Aldehydes
%Yielda
eeb
%Yielda
eeb
O
1
77
80
74
73
H
H
H
H
OMe
OH
Cl
O
O
O
O
2
3
4
5
80
75
70
67
73
70
65
64
79
74
66
65
77
75
68
61
CH3
H
CH3
O
H
6
78
46
73
62
77
47
76
64
MeO
CH3
O
H
7
8
Cl
O
61
73
59
63
58
72
60
68
H
N
O
9
H
aisolated yield.
bdetermined by HPLC using Chiralpak WH column.
X
X
N
+
N
Zn
+
Zn
O
H
O
O
Ar
O
Zn
Zn
Ar
anti (R)-TS
H
anti (S)-TS
favoured
OH
unfavoured
OH
Ar
Ar
(S)
(R)
Fig. (1). Proposed transition state.

ꢀ-Pinene-Based New Chiral Ionic Liquids and their Application
Letters in Organic Chemistry, 2009, Vol. 6, No. 3
267
2-Hydroxy, 3-[N-ethyl, N’-methyl] pinano amine (4)
was prepared by following literature procedure [20]. Pinano
tion of pinano ammonium iodide 5. The last excess drop of
AgPF6 solution was neutralized by adding a drop of 0.1M
aqueous pinano ammonium iodide 5 solution. Finally the
AgI precipitate was filtered off and the compound 7 was
obtained after removing the water under vacuum in 87%
amine
3
(9.85g, 50mmol), N,N-diisopropylethylamine
(9.68g, 75mmol), methyl iodide (7.81g, 55mmol) and 100 ml
acetonitrile were placed in a round bottom flask and stirred
at room temperature under an inert atmosphere of nitrogen.
After completion of the reaction (monitored by TLC) the
solvent from reaction mixture was evaporated under reduced
pressure. The residue was dissolved in 100ml of distilled
water. The aqueous layer was washed with 3 ꢀ 50 ml frac-
tions of CH2Cl2. The collected organic fractions were dried
over MgSO4 and the solvent was removed under reduced
pressure to yield the product 4 (7.91g, 75%). 1H-NMR
(CDCl3, 300MHz): ꢀ 0.92 (s, 3H), 0.94 (s, 3H), 1.03 (t, 3H),
1.29 (s, 3H), 1.59 (t, 2H), 1.60 (t, 1H), 2.14 (t, 2H), 2.27 (m,
1H), 2.32 (s, 3H), 2.54 (t, 2H), 2.69 (s, 1H), 3.18 (s, 1H),
5.82 (s, 1H).
1
yield. H-NMR (CD3CN, 300MHz): ꢀ 0.93 (s, 3H), 1.28 (s,
3H), 1.31 (t, 3H), 1.34 (s, 3H), 1.59 (t, 1H), 1.74 (t, 2H),
1.76 (m, 1H), 2.10 (t, 2H), 3.16 (s, 1H), 3.23 (s, 6H), 3.44
(m, 2H), 4.32 (t, 1H).
Typical experimental procedure for asymmetric addi-
tion of Et2Zn to aldehydes: To a solution of 6 or 7 (0.35
mmol) in toluene (2 mL) was added 2 M Et2Zn toluene solu-
tion (1.0 mL, 2 mmol) under argon at room temperature. The
reaction was allowed to stir for 30 min at room temperature
and then aldehyde (1 mmol) in toluene (2 mL) was added to
it over 2 min. The reaction mixture turned yellow upon addi-
tion of aldehyde and was allowed to stir at room temperature
for 20 h. Reaction was quenched with 2N HCl (4 mL), the
organic layer was separated and the aqueous layer was ex-
tracted with diethyl ether (3 ꢀ 5 mL). The combined organic
extracts were washed with saturated sodium hydrogen car-
bonate (5 mL) followed by water (5 mL) and finally brine (5
mL). Drying over Na2SO4 and evaporation under reduced
pressure yielded a crude alcohol, which was further purified
by flash column chromatography (acetone/pet ether 1:25) to
give the purified alcohols (isolated yields of all reactions
mentioned in Table 1). The enantiomeric excess and absolute
configuration was determined by HPLC using Chiralpak WH
column and by comparison of the specific rotation of the
product with the data in the literature for pure compounds.
2-Hydroxy, 3-[N-ethyl, N’,N’’-dimethyl] pinano am-
monium Iodide (5) A solution of pinano amine 4 (7.39g,
35mmol) and methyl iodide (4.97g, 35mmol) in toluene
(50ml) were stirred for 8 hours under nitrogen atmosphere at
room temperature. The resulting precipitate was collected by
filtration and washed with ethyl acetate (20 ml) to give the
product 5 in 73% yield. 1H-NMR (CD3CN, 300MHz): ꢀ 0.94
(s, 3H), 1.29 (s, 3H), 1.31 (t, 3H), 1.33 (s, 3H), 1.57 (t, 1H),
1.72 (t, 2H), 1.74 (m, 1H), 2.08 (t, 2H), 3.13 (s, 1H), 3.22 (s,
6H), 3.42 (m, 2H), 4.33 (t, 1H).
2-Hydroxy, 3-[N-ethyl, N’,N’’-dimethyl] pinano am-
monium tetrafluroborate (6) Tetrafluoroboric acid (pur-
chased as 48% solution in water) (5.6mmol, 1.0ml) was
mixed with aqueous suspension of silver oxide (695mg,
3mmol) in a conical flask covered with aluminum foil (silver
oxide is light sensitive). The mixture was stirred until the
solution became clear. The aqueous solution of silver tetra-
fluoroborate thus formed was mixed with the aqueous solu-
tion of pinano ammonium iodide 5 (2g, 5.6mmol) and the
reaction mixture was stirred for 30 min. The silver iodide
precipitate was filtered off and 0.1M AgBF4 solution was
added to the filtrate drop wise to ensure the total consump-
tion of pinano ammonium iodide 5. The last excess drop of
AgBF4 solution was neutralized by adding a drop of 0.1M
aqueous pinano ammonium iodide 5 solution. Finally the
AgI precipitate was filtered off and the compound 6 was
obtained after removing the water under vacuum in 85%
ACKNOWLEDGEMENT
We are thankful to Richard DeJianne for help in charac-
terization of chiral ionic liquids.
REFERENCES
[1]
In Asymmetric Catalysis in Organic Synthesis; Noyori, R., Ed.,
John Wiley & Sons: New York, NY, 1995.
[2]
[3]
Pu, L.; Yu, H. –B. Chem. Rev., 2001, 101, 757.
(a) Oguni, N.; Omi, T.; Yamamoto, Y.; Nakamura, A. Chem. Lett.,
1983, (6), 841; (b) Oguni, N.; Omi, T. Tetrahedron Lett., 1984, 25,
2823.
[4]
[5]
Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc.,
1986, 108, 6071.
1
yield. H-NMR (CD3CN, 300MHz): ꢀ 0.94 (s, 3H), 1.30 (s,
(a) Blaser, H.–U. Chem. Rev., 1992, 92, 935; (b) Hanyu, N.; Mino,
T.; Sakamoto, M.; Fujita, T. Tetrahedron Lett., 2007, 41, 4587; (c)
Hanyu, N.; Aoki, T.; Mino, T.; Sakamoto, M.; Fujita, T. Tetrahed-
ron Asymmetry, 2000, 11, 2971; (d) Maritinez, A.G.; Vilar, E.T.;
Fraile, A.G.; de la Moya Cereo, S.; Martinez-Ruiz, P.; Villas, P.C.
Tetrahedron Asymmetry, 2002, 13, 1; (e) Suzuki, Y.; Ogata, Y.; Hi-
roi, K. Tetrahedron Asymmetry, 1999, 10, 1219.
3H), 1.35 (t, 3H), 1.37 (s, 3H), 1.60 (t, 1H), 1.75 (t, 2H),
1.78 (m, 1H), 2.11 (t, 2H), 3.15 (s, 1H), 3.24 (s, 6H), 3.45
(m, 2H), 4.36 (t, 1H).
2-Hydroxy, 3-[N-ethyl, N’,N’’-dimethyl] pinano am-
monium hexafluorophosphate (7) Hexafluorophosphoric
acid (purchased as 60% solution in water) (5.6mmol, 1.4ml)
was mixed with aqueous suspension of silver oxide (695mg,
3mmol) in a conical flask covered with aluminum foil (silver
oxide is light sensitive). The mixture was stirred until the
solution became clear. The aqueous solution of silver tetra-
fluoroborate thus formed was mixed with the aqueous solu-
tion of pinano ammonium iodide 5 (2g, 5.6mmol) and the
reaction mixture was stirred for 30 min. The silver iodide
precipitate was filtered off and 0.1M AgPF6 solution was
added to the filtrate drop wise to ensure the total consump-
[6]
[7]
[8]
(a) Sheldon, R.A. Green Chem., 2005, 7(5), 267; (b) Dupont, J.; de
Souza, R.F.; Suarez, P.A.Z. Chem. Rev., 2002, 102, 3667; (c) Wel-
ton, T.; Chem. Rev., 1999, 99, 2071; (d) Wasserchied, P.; Kim, W.
Angew. Chem. Int. Ed. Engl., 2000, 39, 3772; (e) Zhao, H.; Mal-
hotra, S.V. Aldrichimica Acta, 2002, 35, 75; (f) Jain, N.; Kumar,
A.; Chauhan, S.; Chauhan, S.M.S. Tetrahedron, 2005, 60, 1015.
(a) Kumar, V.; Parmar, V.S.; Malhotra, S.V. Tetrahedron Lett.,
2007, 48, 809; (b) Prasad, A.K.; Kumar, V.; Malhotra, S.; Raviku-
mar, V.T.; Sanghvi, Y.S.; Parmar, V.S. Bioorg. Med. Chem., 2005,
13, 4467; (c) Zhao, H.; Robert, G.; Wei, D.; Malhotra, S.V. Enan-
tiomer, 2002, 7, 1; (d) Wu, G.; Zhao, H.; Robert, G.; Wei, D.; Mal-
hotra, S.V. Enantiomer, 2001, 6, 343.
(a) Baudequin, C.; Baudoux, J.; Levillain, J.; Cahard, D.; Gaumont,
A.–C.; Plaquevent, J.-C. Tetrahedron Asymmetry, 2003, 14, 3081;

268 Letters in Organic Chemistry, 2009, Vol. 6, No. 3
Malhotra et al.
(b) Ding, J.; Armstrong, D.W. Chirality, 2005, 17, 281; (c) Baud-
equin, C.; Bregeon, D.; Levillain, J.; Guillen, F.; Plaquevent, J.-C.;
Gaumont, A.-C. Tetrahedron Asymmetry, 2005, 16, 3921.
Ding, J.; Desikan, V.; Han, X.; Xiao, T.L.; Ding, R.; Jenks, W.S.;
Armstrong, D.W. Org. Lett., 2005, 7, 335.
(a) Earle, M.J.; McCormac, P.B.; Seddon, K.R. Green Chem.,
1999, 1, 23; (b) Howarth, J.; Hanlon, K.; Fayne, D.; McCormac, P.
Tetrahedron Lett., 1997, 38, 3097.
[16]
[17]
Kumar, V.; Olsen, C.E.; Schäffer, S.C.J.; Parmar, V.S.; Malhotra,
S.V. Org. Lett., 2007, 9, 3905.
(a) Brown, H.C.; Singaram, B. Acc. Chem. Res., 1988, 21, 287; (b)
Brown, H.C.; Ramachandaran, P.V. J. Organometal.Chem., 1995,
500 (1-2), 1; (c) Brown, H.C.; P.V. Ramachandran, In Reductions
in Organic Synthesis; Abdel-Magid, A.F., Ed.; American Chemical
Society: Washington DC, 1996; (d) Malhotra, S.V. Tetrahedron
Asymmetry, 2003, 14, 645.
[9]
[10]
[11]
[12]
Pegot, B.; Vo-Thanh, G.; Gori, D.; Loupy, A. Tetrahedron Lett.,
2004, 45, 6425.
[18]
Markowicz, S.W.; Pokrzeptowicz, K.; Karolak-Wojciechowska, J.;
Czylkowski, R.; Omelanczuk, J.; Sobczak, A. Tetrahedron Asym-
metry, 2002, 13, 1981.
Karolak-Wojciechowska, J.; Kwiatkowski, W.; Markowicz, S.W. J.
Cryst. Spec. Res., 1989, 19, 893.
Moore, J.L.; Taylor, S.M.; Soloshonok, V.A. ARKIVOC, 2005, vi,
287.
(a) Noyori, R.; Kitamura, M. Angew. Chem. Int. Ed. Engl., 1991,
30, 49; (b) Yamakawa, M.; Noyori, R. J. Am. Chem. Soc., 1995,
117, 6327; (c) Yamakawa, M.; Noyori, R. Organometallics, 1999,
18, 128.
(a) Wang, Z.; Wang, Q.; Zhang, Y.; Bao, W. Tetrahedron Lett.,
2005, 46, 4657; (b) Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.;
Cheng, J.-P. Angew. Chem. Int. Ed. Engl., 2006, 45, 3093.
Malhotra, S.V.; Wang, Y. Tetrahedron Asymmetry, 2006, 17, 1032.
(a) Jones, R.A. In Quaternary Ammonium Salts: Their Use in
Phase Transfer Catalyzed Reactions, Academic Press, New York
2001; (b) Lygo, B.; Andrews, B.I. Acc. Chem. Res., 2004, 37, 518;
(c) Maruoka, K.; Ooi, T.; Kano, T. Chem. Commun., 2007, 1487.
Gadenne, B.; Hesemann, P.; Moreau, J.J.E. Tetrahedron Lett.,
2004, 45, 8157.
[19]
[20]
[21]
[13]
[14]
[15]