Design and synthesis of C-2 substituted chiral imidazolium ionic liquids from amino acid derivatives

Article abstract of DOI:10.1021/jo051888i

A series of novel chiral ionic liquids (CILs) has been synthesized and fully characterized. The reaction of 1-methyl-2-imidazolecarboxaldehyde and chiral amino alcohols followed by reduction is key to the design of these new CILs. This is the first time t

Full text of DOI:10.1021/jo051888i

BF4-, PF6-, CF3SO3-, or (CF3SO3)2N-, and cations are
typically imidazolium or pyridium species. One of the
most important properties of RTILs is their extremely
high polarity, which makes them ideal candidates to
dissolve a wide variety of polar reactants and to stabilize
polar reaction intermediates. In addition, by modifying
the structures of these cations or anions, the properties
of RTILs can be fine-tuned to meet specific solvation
requirements in order to influence reaction outcomes. In
recent years, the use of chiral RTILs as reaction media
for asymmetric organic reactions4 and chiral discrimina-
tion, as well as optical resolution of racemic mixtures,5
has dramatically increased. Unfortunately, there are only
a few chiral ionic liquids that are designed, synthesized,
and used as solvents for asymmetric reactions.4,6
Design and Synthesis of C-2 Substituted
Chiral Imidazolium Ionic Liquids from
Amino Acid Derivatives
Bukuo Ni,† Allan D. Headley,*,† and Guigen Li*,‡
Department of Chemistry, Texas A&M
University-Commerce, Commerce, Texas 75429-3011, and
Department of Chemistry and Biochemistry, Texas Tech
University, Lubbock, Texas 79409-1061
allan_headley@tamu-commerce.edu
Received September 8, 2005
A thorough review of the literature reveals that known
chiral RTILs 6 are derived through various modifications
of cations such as ammonium,7 pyridinium,8 oxazolinium,7a
and thiazolium.9 The imidazolium-cation-derived chiral
RTILs (Figure 1) have gained widespread usage due to
their facile preparation, low melting points, and relatively
favorable viscosity.10 As shown in Figure 1, the best
known imidazole-derived chiral RTILs that have been
reported thus far contain the chiral moieties bonded to
one or both of the nitrogen atoms on positions 1 and 3 of
the imidazolium cation (I-VI).11,12 Also, there are several
chiral RTILs in which the chiral moiety is contained in
the anion (VII-IX)4a,13 (Figure 1).
A series of novel chiral ionic liquids (CILs) has been
synthesized and fully characterized. The reaction of 1-meth-
yl-2-imidazolecarboxaldehyde and chiral amino alcohols
followed by reduction is key to the design of these new CILs.
This is the first time that CILs have been synthesized by
introducing chiral scaffolds on the C-2 position of the
imidazolium cation of ILs. The simple and straightforward
procedure resulted in CILs as colorless oils at room tem-
perature in good yields.
For imidazolium-derived ionic liquids, we have previ-
ously found that there is an intimate interaction of the
hydrogen on the C-2 position of the imidazolium cation
of RTILs with the counteranions as compared to the other
Room-temperature ionic liquids (RTILs) have attracted
widespread interest in the chemical community due to
their ability to serve as reaction media for organic
synthesis.1,2 This is mainly a result of their unique
properties, such as recyclability, involatility, and incom-
(4) (a) Earle, M. J.; McCormac, P. B.; Seddon, K. R. Green Chem.
1999, 1, 23. (b) Pe´got, B.; Vo-Thanh, G.; Gori, D.; Loupy, A. Tetrahedron
Lett. 2004, 45, 6425. (c) Wang, Z.; Wang, Q.; Zhang, Y.; Bao, W.
Tetrahedron Lett. 2005, 46, 4657.
(5) Kaoru, N.; Wataru, K.; Yuichi, I. JP Patent 2004277351, 2004.
(6) Ding, J.; Armstrong, D. W. Chirality 2005, 17, 281 and references
therein.
bustibility.3 RTILs consist of anions and cations coun-
-
terparts; anions normally include halogen anions, AlX4
,
(7) (a) Wasserscheid, P.; Bo¨smann, A.; Bolm, C. Chem. Commun.
2002, 200. (b) Thanh, G. V.; Pegot, B.; Loupy, A. Eur. J. Org. Chem.
2004, 1112. (c) Pernak, J.; Feder-Kubis, J. Chem. Eur. J. 2005, 11,
4441.
(8) (a) Baudequin, C.; Baudoux, J.; Levillian, J.; Cahard, D.;
Gaumont, A. C.; Plaquevent, J. C. Tetrahedron: Asymmetry 2003, 14,
3081. (b) Haramoto, Y.; Miyashita, T.; Nanasawa, M.; Aoki, Y.; Nohira,
H. Liq. Cryst. 2002, 29, 87. (c) Baudoux, J.; Judeinstein. P.; Cahard,
D.; Plaquevent, J.-C. Tetrahedron Lett. 2005, 46, 1137.
(9) Levillain, J.; Dubant, G.; Abrunhosa, I.; Gulea, M.; Gaumont,
A. C. Chem. Commun. 2003, 2914.
(10) (a) Wilkes, J. S.; Zaworotko, M. J. J. Chem. Soc., Chem.
Commun. 1992, 965. (b) Fuller, J.; Carlin, R. T. DeLong, H. C.;
Haworth, D. J. Chem. Soc., Chem. Commun. 1994, 299.
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hedron Lett 1997, 38, 3097. (b) Bao, W.; Wang, Z.; Li, Y. J. Org. Chem.
2003, 68, 591. (c) Jodry, J. J.; Mikami, K. Tetrahedron Lett 2004, 45,
2033. (d) Tosoni, M.; Laschat, S.; Baro, A. Helv. Chim. Acta 2004, 87,
2742. (e) Kim, E. J.; Ko, S. Y.; Dziadulewicz, E. K. Tetrahedron Lett
2005, 46, 631. (f) Ding, J.; Desikan, V.; Han, X.; Xiao, T. L.; Ding, R.;
Jenks, W. S.; Amstrong, D. W. Org. Lett. 2005, 7, 335. (g) Ge´nisson,
Y.; Viguerie, L-de.; Andre, C.; Baltas, M.; Gorrichon, L. Tetrahedron:
Asymmetry 2005, 16, 1017.
† Texas A&M University-Commerce.
‡ Texas Tech University.
(1) For review, see: (a) Welton, T. Chem. Rev. 1999, 99, 2071. (b)
Dupont, J.; de Souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102,
3667. (c) Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis; Wiley-
VCH: Weinheim, Germany, 2003. (d) Rogers, R. D.; Seddon, K. R.;
Volkov, S. Green Industrial Applications of Ionic Liquids; Kluwer
Academic: Dordrecht, 2002. (e) Baudequin, C.; Baudoux, J.; Levillain,
J.; Cahard, D.; Gaumont, A. C.; Plaquevent, J. C. Tetrahedron:
Asymmetry 2003, 14, 3081. (f) Freemantle, M. Chem. Eng. News 2004,
82, 44.
(2) (a) Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39,
3772. (b) Handy, S. T. Chem. Eur. J. 2003, 9, 2938. (c) Sheldon, R.
Chem. Commun. 2001, 2399. (d) Meracz, I.; Oh, T. Tetrahedron Lett.
2003, 44, 6465. (e) Handy, S. T.; OKello, M. Tetrahedron Lett. 2003,
45, 8399. (f) Dzyuba, S. V.; Bartsch, R. A. Tetrahedron Lett. 2002, 43,
4657. (g) Xiao, J.-C.; Shreeve, J. M. J. Org. Chem. 2005, 70, 3072. (h)
Xu, X.; Kotti, S. R. S. S.; Liu, J.; Cannon, J. F.; Headley, A. D.; Li, G.
Org. Lett. 2004, 6, 4881. (i) Kotti, S. R. S. S.; Xu, X.; Wang, Y.; Headley,
A. D.; Li, G. Tetrahedron Lett. 2004, 45, 7209. (j) Kabalka, G. W.;
Venkataiah, B.; Das, B. C. Synlett 2003, 12, 2194. (k) Kabalka, G. W.;
Venkataiah, B.; Dong, G. Tetrahedron Lett. 2003, 44, 4673. (l) Zhao,
H.; Malhotra, S. V. Biotechol. Lett. 2002, 24, 1257. (m) Zhao, H.;
Malhotra, S. V. Aldrichimica Acta 2002, 35, 75. (o) Laali, K. K.;
Gettwert, V. J. J. Org. Chem. 2001, 66, 35. (p) Davis, J. H.; Forrester,
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10.1021/jo051888i CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/10/2005
10600
J. Org. Chem. 2005, 70, 10600-10602

SCHEME 1a
a Reaction conditions: (i) (a) MeOH, 4 Å MS, 70 °C, 24 h, (b)
NaBH4, rt; (ii) bromobutane, toluene, 85-90 °C, 24 h.
B via anion exchange. Precursor B can be prepared by
the reaction of bromobutane and the corresponding
imidazole derivatives, which were synthesized via con-
densation with 1-methyl-2-imidazolecarboxaldehyde and
a chiral amino alcohol.
As shown in Scheme 1, the condensation of 1-methyl-
2-imidazolecarboxaldehyde and (S)-(+)-2-amino-3-meth-
yl-1-butanol (S)-1 in MeOH was accomplished to give the
corresponding Schiff base precursor, which was reduced
with NaBH4 to give the desired imidazole derivative (S)-5
in 80% yield. The condensation of 1-methyl-2-imidazole-
carboxaldehyde with (S)-leucinol and (R)-leucinol re-
sulted in the corresponding imidazole derivatives (S)-6
and (R)-6 in 72% and 75% yield, respectively. Similarly,
the more stericly substituted imidazole derivatives (S)-7
and (S)-8 were obtained in 90% and 92% yields starting
from (S)-tert-leucinol and (S)-3-phenyl-2-amino-propanol.
The alkylation salt formation was carried out by heating
imidazoles (S)-5-(S)-8 with 1 equiv of bromobutane at
85-90 °C in toluene for 24 h to form the imidazolium
bromide salts (S)-9-(S)-12 in 75%-90% yield (Scheme
1).
The next step in the synthesis involves the transfor-
mation of imidazolium bromide salts to ionic liquids (S)-
13a-(S)-16c by anion exchange of (S)-9-(S)-12 with
different anions (BF4-, PF6-, (CF3SO2)2N-). Chiral imi-
dazolium tetrafluoroborates (S)-13a-(S)-16a were pre-
pared by the treatment of their precursors, imidazolium
bromide (S)-9-(S)-12, with potassium tetrafluoroborate
in the mixture solvent of methanol and water at room
temperature for 3 days in 91-95% yields after purifica-
tion. Chiral imidazolium hexafluorophosphates (S)-13b-
(S)-16b were also readily obtained by anion exchange of
imidazolium bromide (S)-9-(S)-12 with potassium
hexafluorophosphate in H2O at room temperature for 1
h in 86-100% yields. Similarly, imidazolium bis(trifluo-
romethylsulfonyl)imides were obtained in 92-98% yields
(Scheme 2).
In summary, 15 novel chiral room-temperature ionic
liquids have been designed and synthesized. These RTILs
were assembled by incorporating chiral side chains on
the C-2 positions of the imidazolium cation rings through
condensation reactions involving 1-methyl-2-imidazole-
carboxaldehyde and chiral amino alcohol followed by
reduction. The synthesis is concise and practical as a
result of the commercial availability of the starting
materials and convenient reaction conditions. The new
ionic liquids avoid the shortcomings of their traditional
counterparts that can participate in deprotonation side
reactions on their C-2 positions. Applications of these new
chiral RTILs as green media for asymmetric synthesis
and catalysis will be investigated in our laboratories.
FIGURE 1. Chiral imidazolium ionic liquids.
FIGURE 2. Retrosynthetic analysis of CILs.
imidazolium hydrogens.14 This results from the fact that
this hydrogen is relatively acidic.15 Consequently, when
they are used as solvents under basic conditions, the
deprotonation of this hydrogen can occur to give unde-
sired side products. For example, Aggarwal and co-
workers have recently encountered this problem during
the study of the Baylis-Hillman reaction when the ionic
liquid butylmethylimidazolium chloride is used as a
solvent.16 To solve this serious problem, the introduction
of a nonprotic substitutent into the C-2 position of the
imidazolium moiety will result in more inert ionic liquids
for reactions that can be carried out under basic condi-
tions or in the presence of anionic intermediates. As a
result, unwanted side reactions can be avoided or mini-
mized when reactions are carried out in such chiral
RTILs. Surprisingly, there have been no reports regard-
ing the synthesis of RTILs with chiral auxiliaries bonded
to the C-2 positions of the imidazolium ring.
In this report we have designed a series of C-2
substituted imidazolium chiral RTILs A (Figure 2). The
present design is concise and practical because of the
ready availability and low cost of the starting materials,
as well the feasible synthesis of the final RTILs under
mild conditions to avoid possible racemization of enan-
tiomerically pure reactants.
The retrosynthetic design of these RTILs is shown in
Figure 2. It was envisioned that synthesis of a variety of
C-2 substituted chiral imidazolium ionic liquids A could
be derived from its precursor imidazolium bromide salts
(14) (a) Headley, A. D.; Jackson, N. M. J. Phys. Org. Chem. 2002,
15, 52. (b) Headley, A. D.; Kotti, S. R. S. S.; Nam, J.; Li, K. J. Phys.
Org. Chem. 2005, 18, 1018.
(15) Handy, S. T.; Okello, M. J. Org. Chem. 2005, 70, 1915.
(16) Aggarwal, V. K.; Emme, I.; Mereu, A. Chem. Commun. 2002,
1612.
J. Org. Chem, Vol. 70, No. 25, 2005 10601

SCHEME 2a
The reaction mixture was then filtered over Celite and concen-
trated to dryness. The residue was dissolved in dichloromethane
and filtered again to give (S)-13a (314 mg, 92%) as a viscous
oil. [R]20D ) -2.4 (c 0.70, EtOH); 1H NMR (300 MHz, DMSO-d6)
δ 7.72 (d, J ) 1.8 Hz, 1H), 7.63 (d, J ) 1.8 Hz, 1H), 4.63-4.54
(m, 1H), 4.24-3.94 (m, 4H), 3.84 (s, 3H), 3.53-3.43 (m, 1H),
3.43-3.24 (br, 2H), 2.30-2.20 (m, 1H), 1.80-1.64 (m, 3H), 1.36-
1.20 (m, 2H), 0.88 (t, J ) 7.5 Hz, 3H), 0.81 (d, J ) 6.6 Hz, 6H);
13C NMR (75 MHz, MeOD-d4) δ 146.6, 124.2, 122.5, 66.3, 63.2,
41.2, 36.0, 33.3, 30.6, 20.7, 19.5, 19.0, 13.9; IR (neat) υ ) 3298,
2956, 1647, 1533, 1470, 1099, 1048 cm-1; HRMS (ESI +) m/z
(%) calcd for [C14H28N3O]+ 254.2232, found 254.2230; HRMS
(ESI -) m/z (%) calcd for [BF4]- 87.0029, found 87.0037.
(4) General Procedure for the Synthesis of (S)-13b. To
a solution of imidazolium bromide (S)-9 (250 mg, 0.75 mmol) in
water (2 mL) was added potassium hexafluorophosphate (152
mg, 1.1 mmol), and the mixture was stirred for 1 h at room
temperature. The reaction mixture was extracted with CH2Cl2
(15 mL), and the organic phase was washed with water (5 × 5
mL), then concentrated, and dried in a vacuum to give (S)-13b
a Reaction conditions: (i) KBF4, MeOH-H2O, rt, 3 d; (ii) KPF6
or (CF3SO2)2NLi, H2O, rt, 1 h.
Experimental Section
General Procedure for the Synthesis of Compound (S)-
5. To a solution of 1-methyl-2-imidazolecarboxaldehyde (1.32 g,
12 mmol) in methanol (30 mL) was added (S)-(+)-2-amino-3-
methyl-1-butanol (1.24 g, 12 mmol) and 4 Å molecular sieves
(2.4 g). The reaction mixture was stirred under reflux for 24 h
with exclusion of moisture and then cooled to room temperature.
To the resulting solution of Schiff base was added NaBH4 (0.46
g, 12 mmol), and the mixture was stirred for 2 h at room
temperature. The reduction was quenched by slow and dropwise
addition of concentrated HCl (0.6 mL) to the mixture and
subsequent neutralization with solid Na2CO3 (2.0 g, 19 mmol).
Then, the solid in the mixture was filtered out, the filtrate was
evaporated to dryness, and the resultant product was further
purified by flash column chromatography on silica gel (CH2Cl2/
(257 mg, 86%) as a colorless oil. [R]20 ) -2.4 (c 0.37, EtOH);
D
1H NMR (300 MHz, DMSO-d6) δ 7.68 (d, J ) 2.1 Hz, 1H), 7.63
(d, J ) 2.1 Hz, 1H), 4.57 (t, J ) 4.8 Hz, 1H), 4.19 (t, J ) 7.5 Hz,
2H), 4.14-3.94 (m, 2H), 3.83 (s, 3H), 3.53-3.33 (m, 2H), 2.30-
2.18 (br, 2H), 1.80-1.64 (m, 3H), 1.36-1.20 (m, 2H), 0.89 (t, J
) 7.5 Hz, 3H), 0.82 (d, J ) 6.6 Hz, 6H); 13C NMR (75 MHz,
MeOD-d4) δ 146.3, 124.1, 122.5, 65.1, 58.4, 42.0, 39.8, 35.6, 33.2,
25.9, 23.4, 22.8, 20.6, 13.9; IR (neat) υ ) 3602, 3375, 2963, 1536,
1468, 1044, 843 cm-1; HRMS (ESI +) m/z (%) calcd for
[C14H28N3O]+ 254.2232, found 254.2226; HRMS (ESI -) m/z (%)
calcd for [PF6]- 144.9642, found 144.9647.
(Synthesis of (S)-13c. Imidazolium bromide (S)-9 (250 mg,
0.75 mmol) reacted with lithium bis(trifluoromethanesulfonyl)-
imide (215 mg, 0.75 mmol) according to the procedure described
for the preparation of (S)-13b to give (S)-13c (379 mg, 95%) as
a colorless oil. [R]20D ) -1.5 (c 1.05, EtOH); 1H NMR (300 MHz,
CDCl3) δ 7.23 (d, J ) 2.1 Hz, 1H), 7.21(d, J ) 2.1 Hz, 1H), 4.28-
4.08 (m, 4H), 3.93 (s, 3H), 3.77 (dd, J ) 11.1 and 3.3 Hz, 1 H),
3.52 (dd, J ) 11.1 and 7.5 Hz, 1H), 2.70-2.10 (br, 2H), 2.48-
2.38 (m, 1H), 1.88-1.68 (m, 3H), 1.46-1.30 (m, 2H), 0.96 (t, J
) 7.5 Hz, 3H), 0.92 (d, J ) 6.9 Hz, 3H), 0.89 (d, J ) 6.9 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 144.5, 123.0, 121.1, 119.6 (q, J )
319.4 Hz), 64.9, 62.4, 48.4, 40.1, 35.4, 31.9, 29.2, 19.4, 18.6, 18.5,
13.2; IR (neat) υ ) 3556, 1536, 1352, 1196, 1058 cm-1; HRMS
(ESI +) m/z (%) calcd for [C14H28N3O]+ 254.2232, found 254.2224;
HRMS (ESI -) m/z (%) calcd for [N(SO2CF3)2]- 279.9173, found
279.9179.
MeOH ) 7:1) to give product (S)-5 (1.87 g, 80%) as a colorless
1
oil. [R]20 ) -8.9 (c 0.79, EtOH); H NMR (300 MHz, CDCl3) δ
D
6.91 (d, J ) 1.5 Hz, 1H), 6.82 (d, J ) 1.5 Hz, 1H), 3.89 (AB, ∆ν
) 42.0 Hz and JAB ) 15.0 Hz, 2H), 3.67 (dd, J ) 11.1 and 3.9
Hz, 1 H), 3.63 (s, 3H), 3.50-2.80 (br, 2H), 3.44 (dd, J ) 11.1
and 7.2 Hz, 1H), 2.52-2.42 (m, 1H), 1.86-1.72 (m, 1H), 0.97 (d,
J ) 7.2 Hz, 3H), 0.91 (d, J ) 6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 147.0, 126.3, 121.0, 64.5, 61.0, 43.5, 32.4, 29.3, 19.1,
18.6; IR (neat) υ ) 3328, 2957, 2872, 1659, 1502, 1467, 1043
cm-1; HRMS (ESI) m/z (%) calcd for C10H20N3O (MH+) 198.1601,
found 198.1599.
General Procedure for the Synthesis of Compound (S)-
9. A solution of imidazole (S)-5 (860 mg, 4.36 mmol) and
bromobutane (603 mg, 4.36 mmol) in toluene (2 mL) was stirred
at 85-90 °C for 24 h. The reaction mixture was then cooled to
room temperature, the toluene was removed, and the residue
was purified by flash column chromatography on silica gel (CH2-
Cl2/MeOH ) 7:1 to 5:1) to give product (S)-9 (1.2 g, 82%) as a
viscous oil. 1H NMR (300 MHz, D2O) δ 7.27 (d, J ) 2.1 Hz, 1H),
7.22 (d, J ) 2.1 Hz, 1H), 4.04 (t, J ) 7.2 Hz, 2H), 3.99 (s, 2H),
3.72 (s, 3H), 3.55 (dd, J ) 11.7 and 4.5 Hz, 1 H), 3.36 (dd, J )
14.4 and 6.9 Hz, 1H), 2.35-2.26 (m, 1H), 1.75-1.58 (m, 3H),
1.24-1.08 (m, 2H), 0.80-0.68 (m, 9H). This compound was used
for the next step directly without further characterization.
General Procedure for the Synthesis of (S)-13a. A
solution of imidazolium bromide (S)-9 (334 mg, 1.0 mmol) in
MeOH/H2O (2 mL, 5:1) containing potassium tetrafluoroborate
(152 mg, 1.2 mmol) was stirred at room temperature for 3 days.
Acknowledgment. This work was supported by the
Robert A. Welch Foundation (T-1460). We are grateful
to Professor William Whaley, Cody Timmons, Aadi
Kattuboina, and Sri Kotti for their assistance.
Supporting Information Available: Analytical data for
compounds (S)-6-(S)-8, (S)-10-(S)-12, and (S)-14a-(S)-16c
and 1H and 13C NMR spectra of those compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO051888I
10602 J. Org. Chem., Vol. 70, No. 25, 2005