Synthesis and applications of novel bis(ammonium) chiral ionic liquids derived from isomannide

Article abstract of DOI:10.1021/ol071390y

Carbohydrate-based novel bis(ammonium) chiral ionic liquids have been synthesized by following a straightforward protocol using isomannide as the substrate. Their applications in chiral discrimination and optical resolution of racemates have been establis

Full text of DOI:10.1021/ol071390y

ORGANIC
LETTERS
2007
Vol. 9, No. 20
3905-3908
Synthesis and Applications of Novel
Bis(ammonium) Chiral Ionic Liquids
Derived from Isomannide
|
Vineet Kumar,†,‡,§ Carl E. Olsen, Susan J. C. Scha
1ffer,
Virinder S. Parmar,*,‡ and Sanjay V. Malhotra*,†,§
Department of Chemistry and EnVironmental Science, New Jersey Institute of
Technology, UniVersity Heights, Newark, New Jersey 07102, Department of Chemistry,
UniVersity of Delhi, Delhi 110007, India, Faculty of Life Sciences, Department of
Natural Sciences, UniVersity of Copenhagen, DK-1871 Frederiksberg C, Denmark, and
Department of Chemistry, Building 207, Technical UniVersity of Denmark,
DK-2800 Lyngby, Denmark
malhotrasa@mail.nih.goV; Virparmar@gmail.com
Received June 12, 2007
ABSTRACT
Carbohydrate-based novel bis(ammonium) chiral ionic liquids have been synthesized by following a straightforward protocol using isomannide
as the substrate. Their applications in chiral discrimination and optical resolution of racemates have been established.
Ionic liquids (ILs) have shown tremendous applications in
modern organic chemistry due to their inimitable physical
and chemical properties, which allow them to enhance the
reaction kinetics and selectivity and to facilitate catalyst
recovery, etc.1 Significant progress along this line has been
made with the development of chiral ionic liquids (CILs).2
Although, CILs are at a premature phase of development,
they have already found promising applications in asym-
metric synthesis,3 stereoselective polymerization,4 chroma-
tography,5 liquid crystals,6 and chiral resolution and as NMR
shift reagents.7 The studies so far reveal the prospective of
such media and further encourage the synthesis of novel CILs
(3) (a) Pegot, B.; Vo-Thanh, G.; Gori, D.; Loupy, A. Tetrahedron Lett.
2004, 45, 6425. (b) Ding, J.; Desikan, V.; Han, X.; Xiao, T. L.; Ding, R.;
Jenks, W. S.; Armstrong, D. W. Org. Lett. 2005, 7, 335. (c) Wang, Z.;
Wang, Q.; Zhang, Y.; Bao, W. Tetrahedron Lett. 2005, 46, 4657. (d)
Howarth, J.; Hanlon, K.; Fayne, D.; McCormac, P. Tetrahedron Lett. 1997,
38, 3097. (e) Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P.
Angew. Chem., Int. Ed. 2006, 45, 3093. (f) Malhotra, S. V.; Wang, Y.
Tetrahedron: Asymmetry 2006, 17, 1032.
(4) (a) Biedron, T.; Kubisa, P. Polym. Int. 2003, 52, 1584. (b) Biedron,
T.; Kubisa, P. J. Polym. Sci. Part A: Polym. Chem. 2005, 43, 3454. (c)
Ma, H.-Y.; Wan, X.-H.; Chen, X.-F.; Zhou, Q.-F. Chin. J. Polym. Sci. 2003,
21, 265.
† New Jersey Institute of Technology.
‡ University of Delhi.
§ Current address: Laboratory of Synthetic Chemistry, SAIC-Frederick,
National Cancer Institute at Frederick, 1050 Boyles Street, Frederick, MD
21702. Fax: +1-301-846-7239. Phone: +1-301-846-5141.
| University of Copenhagen.
Technical University of Denmark.
(5) (a) Ding, J.; Welton, T.; Armstrong, D. W. Anal. Chem. 2004, 76,
6819. (b) Rizvi, S. A. A.; Shamsi, S. A. Anal. Chem. 2006, 78, 7061.
(6) (a) Baudoux, J.; Judeinstein, P.; Cahard, D.; Plaquevent, J.-C.
Tetrahedron Lett. 2005, 46, 1137. (b) Tosoni, M.; Laschat, S.; Baro, A.
HelV. Chim. Acta 2004, 87, 2742.
(7) (a) Wasserscheid, P.; Bosmann, A.; Bolm, C. Chem. Commun. 2002,
200. (b) Clavier, H.; Boulanger, L.; Audic, N.; Toupet, L.; Mauduit, M.;
Guillemin, J.-C. Chem. Commun. 2004, 1224. (c) Levillain, J.; Dubant, G.;
Abrunhosa, I.; Gulea, M.; Gaumont, A.-C. Chem. Commun. 2003, 2914.
(d) Ishida, Y.; Miyauchi, H.; Saigo, K. Chem. Commun. 2002, 2240. (e)
Ishida, Y.; Sasaki, D.; Miyauchi, H.; Saigo, K. Tetrahedron 2004, 45, 9455.
(f) Jurcik, V.; Wilhelm, R. Tetrahedron: Asymmetry 2006, 17, 801.
(1) (a) Sheldon, R. A. Green Chem. 2005, 7, 267. (b) Seddon, K. R. J.
Chem. Technol. Biotechnol. 1997, 68, 351. (c) Welton, T. Chem. ReV. 1999,
99, 2071. (d) Wasserchied, W.; Kim, W. Angew. Chem., Int. Ed. 2000, 39,
3772. (e) Sheldon, R. A. Green Chem. 2001, 2399. (f) Zhao, H.; Malhotra,
S. V. Aldrichimica Acta 2002, 35, 75. (g) Jain, N.; Kumar, A.; Chauhan,
S.; Chauhan, S. M. S. Tetrahedron 2005, 60, 1015.
(2) (a) Baudequin, C.; Baudoux, J.; Levillain, J.; Cahard, D.; Gaumont,
A.-C.; Plaquevent, J.-C. Tetrahedron: Asymmetry 2003, 14, 3081. (b) Ding,
J.; Armstrong, D. W. Chirality 2005, 17, 281. (c) Baudequin, C.; Bregeon,
D.; Levillain, J.; Guillen, F.; Plaquevent, J.-C.; Gaumont, A.-C. Tetrahe-
dron: Asymmetry 2005, 16, 3921.
10.1021/ol071390y CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/29/2007

from easily available sources, especially from biorenewable
sources.
sulfonyl chloride using pyridine as base to give the monotosyl
derivative 2 as the major and ditosyl derivative 3 as the minor
product. Because the two hydroxyl groups and also the two
heterocyclic rings of isomannide are cis-oriented (Scheme
1) formation of the ditosyl derivative is sterically unfavorable
Isosorbide and isomannide are renewable, inexpensive, and
commercially available chiral carbohydrates derived by
dehydration of glucose derivatives sorbitol and mannitol,
respectively, which are major components of corn oil and
obtained as byproducts of the starch industry. Major appli-
cations of these compounds are in the polymer, cosmetic,
and pharmaceutical industries. They are used as monomers
for the synthesis of biodegradable and high Tg polymers8
and as starting materials for pharmaceutically important
compounds including vasodilators9a,b and Xa-inhibitors.9c
Their catalytic utilities as chiral ligands or as phase transfer
catalysts have also been reported in a variety of important
reactions such as alkylations,10 Diels-Alder reactions,11 and
asymmetric hydrogenations,12 etc. Nevertheless, very few
studies have investigated their synthetic utility as valuable
chiral pool compounds.13
Scheme 1. Synthesis of Bis(ammonium) CILs from
Isomannide
Recently, in a continuation of our efforts in the production
and applications of new CILs from readily available natural
chiral auxilaries,3f we have used isomannide for the synthesis
of a series of monoammonium CILs. In that approach, one
of the hydroxyl groups of isomannide was protected as the
ethyl ether and the other hydroxyl was converted to an
ammonium salt in combination with different anions to form
a series of CILs (Figure 1). These CILs were utilized for
Figure 1. Monoammonium CILs derived from isomannide.
and obtained only as a minor product even when using an
excess of p-toulenesulfonyl chloride.
The monotosyl derivative 2 was utilized for the synthesis
of monoammonium CILs. The isomannide ditosylate 3 was
reacted with an excess of benzylamine at 180 °C under an
atmosphere of nitrogen to get the bis-secondary amine 4
(Scheme 1). It is essential to use benzylamine in excess, so
that it is sufficient for the substitution reaction as well as to
trap the tosylate. Also, on the basis of literature reports,11,14
it is important to carry out the reaction above 165 °C to avoid
chances of incomplete substitution and the possibility of
elimination reactions to give unsaturated products. As a result
of SN2 substitution of the ditosylate 3 to bis-secondary amine
4, the inversion in configuration at both centers occurs,
converting the isomannide nucleus to an isoiodide nucleus
where both amino groups are pointing downward. The
quaternization of bis-secondary amine 4 was carried out with
methyl iodide to get the bis(ammonium iodide) 5. The
chiral resolution of racemic Mosher’s acid and showed
remarkable results. This prompted us to synthesize bis-
(ammonium) CILs by functional group interconversion of
both the hydroxyl groups of isomannide to ammonium salts.
D-Isomannide, also known as (1R,4R,5R,8R)-2,6-dioxabicyclo-
[3.3.0]octan-4,8-diol (1) was first tosylated with p-toulene-
(8) (a) Kricheldorf, H. R.; Gomourachvili, Z. Macromol. Chem. Phys.
1997, 198, 3149. (b) Adelman, D. J.; Charbonneau, L. F.; Ung, S. United
States Patent 6656577. (c) Okada, M.; Okada, Y.; Aoi, K. J. Polym. Sci.:
Part A Polym. Chem. 1995, 33, 2813. (d) Okada, M.; Tsunoda, K.;
Tachikawa, K.; Aoi, K. J. Appl. Polym. Sci. 2000, 77, 338.
(9) (a) Bidoggia, H. Curr. Med. Res. Opin. 1987, 10, 601. (b) Walker,
J. M.; Curry, P. V.; Bailey, A. E.; Steare, S. E. Int. J. Cardiol. 1996, 53,
117. (c) Vogler, M.; Koert, U.; Harms, K.; Dorsch, D.; Gleitz, J.; Raddatz,
P. Synthesis 2004, 8, 1211. (d) Osterkamp, F.; Wehlan, H.; Koert, U.;
Wiesner, M.; Raddatz, P.; Goodman, S. L. Tetrahedron 1999, 55, 10713.
(10) Kumar, S.; Ramachandran, U. Tetrahedron 2005, 61, 4141.
(11) De Coster, G.; Vandyck, K.; Van der Eycken, E.; Van der Eycken,
J.; Elseviers, M.; Roperb, H. Tetrahedron: Asymmetry 2002, 13, 1673.
(12) Carcedo, C.; Dervisi, A.; Fallis, I. A.; Ooi, L.; Abdul Malik, K. M.
Chem. Commun. 2004, 1236.
1
structure and stereochemistry of 5 were established by H
and 13C NMR spectroscopy and further confirmed by X-ray
studies (Figure 2). The bis(ammonium iodide) 5 was used
(13) (a) Cera, V.; Mazzini, C.; Paolucci, C.; Pollicino, S.; Fava, A. J.
Org. Chem. 1993, 58, 4567. (b) Chao, Q.; Zhang, J.; Pickering, L.; Jahnke,
T. S.; Nair, V. Tetrahedron 1998, 54, 3113. (c) Loupy, A.; Mountex, D. A.
Tetrahedron 2002, 58, 1541
(14) Cope, A.; Shen, T. Y. J. Am. Chem. Soc. 1956, 78, 3177.
Org. Lett., Vol. 9, No. 20, 2007
3906

Figure 2. X-ray structure of the cationic part of compound 5.
for anion exchange reactions in an aqueous medium to obtain
other chiral salts with different anions. The solubility of
iodide salt 5 is low in water at room temperature, and the
reactions were, therefore, carried out at 80 °C. Thus, the
desired bis(ammonium) CILs 5-10 have been synthesized
following a simple protocol involving functional group
interconversions followed by anion exchange (Scheme 1).
The melting point comparison of all these bis(ammonium)
CILs is mentioned in Table 1. As reported in the literature,15
Figure 3. 19F NMR (282.4 MHz) signals of CF3 of salt A (a) and
salt A in the presence of 1 equiv of CIL 6 (b).
enhanced [Figure 3, spectrum (b)]. Similar experiments were
carried out in the presence of 4 equiv of each of the CILs,
and the results are summarized in Table 2. As expected, the
Table 2. Enhanced ∆δ Values of CF3 Signals of Racemic
Mosher’s Carboxylate of Salt A in the Presence of 4 equiv of
CILs
Table 1. Melting Points of Bis(ammonium) CILs
entry
CILs
CIL anions
∆δ (Hz)a
entry
CIL
anion
mp (°C)
1
2
3
4
5
6
5
6
7
8
9
[I]
9
23
21
8
17
15
1
2
3
4
5
6
5
6
7
8
9
[I]
190
60
251
65
240
75
[Tf2N]
[PF6]
[TFA]
[BF4]
[TfO]
[Tf2N]
[PF6]
[TFA]
[BF4]
[TfO]
10
10
a
Recorded by 19F NMR at 282.4 MHz.
the nature of the anions was found to have a profound effect
on the melting points. The CILs with [Tf2N], [TFA], and
[TfO] anions have low melting points due to delocalization
of charge through the S-N-S, O-C-O, and O-SO2 core,
respectively. This delocalization results in a decreased
Coulombic interaction between the cation and the anion
compared to the salts with more localized anion charges,
such as the [I], [PF6], and [BF4].
anions of CILs were found to have a profound effect on the
chiral discrimination ability as indicated by the enhancement
in the chemical shift dispersion (Table 2).
After their successful synthesis, the chiral recognition
ability of these new CILs was tested by investigating the
diastereomeric interaction between the CILs and racemic
Mosher’s acid silver salt. The iodide salt 5 was mixed with
racemic Mosher’s acid silver salt in CD3CN, and the resulting
solution containing Mosher’s acid chiral ammonium salt A
was measured by 19F NMR spectroscopy. High splitting of
the CF3 signal [Figure 3, spectrum (a)] shows an excellent
diastereomeric interaction between Mosher’s carboxylate and
the bis(ammonium) cation. When the same NMR solution
was mixed with 1 equiv of CIL 6, the splitting was further
Figure 4. Concentration effect of CIL 6 on the chemical shift of
the CF3 signal (19F NMR, 282.4 MHz) of racemic Mosher’s
carboxylate.
(15) (a) Kim, K.; Lang, C. M.; Kohl, P. A. J. Electrochem. Soc. 2005,
152, E56. (b) Pringle, J. M.; Golding, J.; Baranyai, K.; Forsyth, C. M.;
Deacon, G. B.; Scotta, J. L.; MacFarlanea, D. R. New J. Chem. 2003, 27,
1504.
Org. Lett., Vol. 9, No. 20, 2007
3907

concentration results in a gradual decrease in CF3 signal
splitting (Figure 4).
Due to its high chiral discrimination ability, CIL 6 was
then utilized in determination of the ee values of three
different enantiomerically enriched mixtures of Mosher’s
carboxylate with approximately R/S ) 1:6 (Figure 5a), 1:3
(Figure 5b), and 1:2 (Figure 5c), which were prepared by
mixing the silver salt of racemic Mosher’s acid and (S)-
Mosher’s acid. The exact amount of enantiomers can easily
be calculated by integration of the CF3 signal of each
enantiomer of Mosher’s carboxylate.
In conclusion, we have synthesized a new class of
isomannide-based CILs. The diastereomeric interactions
between these CILs and racemic substrates during NMR
spectroscopy prove their excellent chiral recognition ability.
The high chemical shift dispersion induced by CILs indicate
their potential applications in optical resolution of racemates,
as chiral shift reagents, and in determining the enantiomeric
excess of enantiomerically enriched carboxylates by NMR
spectroscopy. Further research into applications of these CILs
as reaction media and as a phase transfer catalyst in
asymmetric synthesis is in progress in our laboratory.
Acknowledgment. This work was supported by a US
Department of Energy Laboratory Directed Research and
Development Program at Brookhaven National Laboratory.
The authors would like to thank EMD Chemicals, Inc., for
the generous gift of chemicals for chromatography.
Figure 5. Determination of ee values of Mosher’s carboxylate with
(R/S) ) 1:6 (a); 1:3 (b); and 1:2 (c) using CIL 6.
Supporting Information Available: Detailed experi-
mental procecures, 1H (300 MHz), 13C (75.5 MHz), and 19
F
The concentration effect of CIL 6 on the chemical shift
difference of two diastereomeric -CF3 groups was also
studied (as indicated by the ∆δ values) and is demonstrated
in Figure 4. Interestingly, the increase in the ∆δ values with
increased CIL concentration reaches a saturation point with
2 equiv (0.076 mol/L) of 6. Further increase in CIL 6
NMR (282.4 MHz) data, and X-ray data. This material is
available free of charge via the Internet at http://pubs.acs.org.
The X-ray data of compound 5 can be accessed from http://
www.ccdc.cam.ac.uk (deposition number CCDC 656175).
OL071390Y
3908
Org. Lett., Vol. 9, No. 20, 2007