Aminolysis of epoxides in ionic liquid 1-ethylpyridinium trifluoroacetate as green and efficient reaction medium

Article abstract of DOI:10.1080/00397910802323056

Aminolysis of epoxides has been carried out using the ionic liquid 1-ethylpyridinium trifluoroacetate ([EtPy][TFA]) as reaction medium. The reactions went smoothly under mild conditions without any catalyst to afford corresponding β-aminoalcohols in high

Full text of DOI:10.1080/00397910802323056

This article was downloaded by: [Pennsylvania State University]
On: 20 August 2013, At: 11:30
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Aminolysis of Epoxides in
Ionic Liquid 1-Ethylpyridinium
Trifluoroacetate as Green and
Efficient Reaction Medium
Sanjay V. Malhotra a , Richard P. Andal a & Vineet
Kumar a
a Department of Chemical and Environmental
Science, New Jersey Institute of Technology,
University Heights, Newark, New Jersey, USA
Published online: 31 Oct 2008.
To cite this article: Sanjay V. Malhotra , Richard P. Andal & Vineet Kumar (2008)
Aminolysis of Epoxides in Ionic Liquid 1-Ethylpyridinium Trifluoroacetate as Green
and Efficient Reaction Medium, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 38:23, 4160-4169, DOI:
10.1080/00397910802323056
To link to this article: http://dx.doi.org/10.1080/00397910802323056
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views

expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communications1, 38: 4160–4169, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802323056
Aminolysis of Epoxides in Ionic Liquid
1-Ethylpyridinium Trifluoroacetate as Green
and Efficient Reaction Medium
Sanjay V. Malhotra, Richard P. Andal, and Vineet Kumar
Department of Chemical and Environmental Science, New Jersey Institute
of Technology, University Heights, Newark, New Jersey, USA
Abstract: Aminolysis of epoxides has been carried out using the ionic liquid
1-ethylpyridinium trifluoroacetate ([EtPy][TFA]) as reaction medium. The reac-
tions went smoothly under mild conditions without any catalyst to afford corres-
ponding b-aminoalcohols in high conversions. Moreover, further enhancement in
the conversions was observed when AlCl3 was used as Lewis acid catalyst.
Keywords: b-Amino alcohols, aminolysis, epoxides, ionic liquids
INTRODUCTION
b-Amino alcohols are important class of organic compounds obtained by
nucleophilic ring opening of epoxides with amines. These compounds are
used as building blocks for the synthesis of large number of medicinally
and pharmaceutically important products[1] including synthetic amino
acids.[2] They have also been used as chiral ligands in asymmetric synth-
esis.[3] The classical methods to synthesize b-amino alcohols require high
temperatures and the use of excess amine.[4] Most often these reactions
are slow and result in incomplete conversions. Also, the high reaction
Received December 31, 2007.
Address correspondence to Sanjay V. Malhotra, Laboratory of Synthetic
Chemistry, SAIC Frederick Inc., National Cancer Institute at Frederick, 1050
Boyles Street, Frederick, MD 21702, USA (current address). E-mail: malhotrasa@
mail.nih.gov
4160

1-Ethylpyridinium Trifluoroacetate
4161
temperature is unfavorable to the control of selectivity and also harsh for
certain functional groups. Subsequently, a wide range of methods have
been developed for epoxide ring opening such as the use of enzymes,[5]
alumina,[6] metal amides,[7] metal alkoxides,[8] metal triflates,[9] metal
halides,[10] alkali metal perchlorates,[11] silica,[12] and montmorillonite
clay[13] as catalysts or activators. However, most of these catalysts are
moisture sensitive, difficult to handle, expensive, and required in stoichio-
metric amounts. Furthermore, with these catalysts, deactivated aromatic
amines and some sterically hindered amines fail to open up epoxides
or still require high temperature or pressure. In some cases, rearrange-
ment of the oxiranes to allyl alcohols under the basic conditions[14] or
polymerization in strongly acidic conditions has also been reported as
side reactions.
In the last decade, room-temperature ionic liquids (RTILs) have
emerged as attractive alternatives to conventional organic solvents
because of their advantageous properties (viz., negligible vapor pressure,
nonflammability, recyclability, high thermal stability) and their ability to
dissolve a wide range of organic and inorganic compounds. Most impor-
tant, their properties can be adjusted to the reaction needs by proper
manipulation of cations and anions.[15] Apart from tunable physical
and chemical properties of ionic liquids, their immiscibility with various
organic solvents enables the biphasic separation of the desired products
and recyclability of expensive catalysts.[16] Despite such great properties
and their applications in organic synthesis, there are very few examples
of aminolysis of epoxide in ionic liquid medium. In on such report, tetra-
butylammonium bromide has been utilized as reaction medium for these
reactions, which is solid at room temperature and require high reaction
temperatures.[16] In another report, 1-butyl-4-methyl imidazolium
tetrafluoroborate has been used for synthesis of b-amino alcohols from
epoxides.[17] But there are serious toxicity concern about imidazolium-
based ILs. The studies show that toxicity of ILs increases with the
number of nitrogen atoms in an aromatic cation ring and imidazolium-
based ILs are reported to be more highly toxic than their pyridinium
counterparts.[18] In our recent studies, we have proved that pyridinium-
based ILs are not only nontoxic but also biodegradable.[19] In our
attempts to develop cleaner methodologies for organic synthesis, we have
reported the use of pyridinium-based ILs in a variety of reactions like
Diels–Alder reactions,[20] Friedel–Craft alkylation,[21] Friedel–Craft acy-
lation,[22] and asymmetric reductions of aromatic ketones.[23] Considering
the importance of ionic liquids as an efficient new generation of reaction
media, we report the application of ionic liquid 1-ethylpyridinium tri-
fluoroacetate ([EtPy][TFA]) in the ring opening of epoxides by various
aromatic amines.

4162
S. V. Malhotra, R. P. Andal, and V. Kumar
RESULTS AND DISCUSSION
In a typical reaction, equimolar amounts of epoxide and amine were
stirred with ionic liquid [EtPy][TFA] at 50 ꢀC. It is important to note
that no inert atmosphere was required for this reaction. After comple-
tion of the reaction, the product was extracted by diethyl ether, and ILs
were recycled. Cyclohexenoxide (1a) and cyclopentenoxides (1b) were
used as the epoxide in combination with different amines 2 to give cor-
responding b-amino alcohols 3a–j with very high conversions (Scheme 1,
Table 1). All the products were characterized by comparing their IR
1
and H NMR data with those reported in the literature. When the same
reactions were carried out using 10 mol% of anhydrous AlCl3, a further
increase in conversions was observed in all the reactions. Moreover, in
both the cases (i.e., in presence or absence of AlCl3), the IL
[EtPy][TFA] could easily be recovered and reused up to five cycles with-
out loss of any activity. We also performed the same set of reactions
in bulk using anhydrous AlCl3 without any solvent or IL, but there
was no significant conversion observed. These observations indicate
that IL [EtPy][TFA] has a profound effect on the nucleophillic attack
of amines on the epoxides.
It is well reported in the literature that ILs can increase the nucleo-
philicity of amines,[30] which could be a reason for the reaction in the
absence of any catalyst. With the addition of anhydrous AlCl3, the acid-
ity of the reaction medium further increased and the coordination
of Al(III) with epoxide oxygen can further enhance the reaction, which
is reflected by the higher conversions of b-amino alcohols in the
[EtPy][TFA]-AlCl3 system.
In conclusion, we have synthesized b-amino alcohols using IL liquid
[EtPy][TFA] as reaction medium under mild and simple reaction condi-
tions with easy work up. The IL [EtPy][TFA] is playing here the dual
role of solvent as well as catalyst and could be easily recycled to make
the protocol more economical and green. The conversions of products
were further enhanced by using the [EtPy][TFA]-AlCl3 system.
Scheme 1. Aminolysis of epoxides in ionic liquid.

4163

4164

1-Ethylpyridinium Trifluoroacetate
EXPERIMENTAL
4165
The IL [EtPy][TFA] was synthesized following the procedure reported in
the literature.[31] All other chemicals and reagents were of analytical
grade and were used as obtained commercially.
General Procedure for Aminolysis of Epoxides in [EtPy][TFA] and
Recovery of Ionic Liquid
The epoxide (2 mmol) was dissolved in the IL [EtPy][TFA] (2 ml) in a
round-bottomed flask followed by the addition of aromatic amine
(2.2 mmol). The reaction mixture was stirred for 12 h and the conver-
sion was monitored by high performance liquid chromatography
(HPLC) using C 18 column and isopropanol-hexane solvent mixure.
After completion, the product was extracted with diethyl ether
(3 Â 15 ml) and further purified with silica-gel column chromatogra-
phy using ethyl acetate=hexanes as solvent system. The ionic
liquid left after product extraction was further washed with diethyl
ether, dried in a vacuum oven at 60 ꢀC for 8–12 h and used further
for the same reaction. Some of the compounds synthesized are
already known in literature and were characterized by matching
their IR and 1H NMR spectral data with those reported in the
literature.
General Procedure for Aminolysis of Epoxides in [EtPy][TFA]-AlC3 and
Recovery of Ionic Liquid
The epoxide (2 mmol) was dissolved in the mixture of IL
[EtPy][TFA] (2 ml) and anhydrous AlCl3 (0.2 mmol) in a round-
bottomed flask followed by addition of aromatic amine (2.2 mmol).
The reaction mixture was stirred for 12 h, and the conversion was
monitored by HPLC. After completion, the product was extracted
with diethyl ether (3 Â 15 ml) and further purified with silica-gel col-
umn chromatography using ethyl acetate=hexanes as solvent system.
The viscous liquid left after product extraction was washed with
diethyl ether, dissolved in 20 ml of dichloromethane, and passed
through a silica-gel column to get the recovered IL, which was dried
in a vacuum oven at 60 ꢀC for 8–12 h and used further for the same
reaction. 1H and 13C NMR spectra of new compounds are given
here.

4166
S. V. Malhotra, R. P. Andal, and V. Kumar
Data
Compound 3d
1H (300 MHz, CDCl3) d7.09 (m, 1H), 6.43–6.73 (m, 2H), 4.84 (m, 1H),
3.70 (brs, 2H), 2.84 (m, 1H), 2.30 (s, 3H), 1.53–1.59 (m, 4H), 1.39 (m,
2H), 1.27 (m, 2H); 13C (75.5 MHz, CDCl3) d145.96, 129.85, 127.65,
127.15, 116.88, 74.74, 61.71, 32.50, 28.10, 24.40, 20.90, 17.80.
Compound 3g
1H (300 MHz, CDCl3) d6.82 (m, 1H), 6.02–6.35 (m, 3H), 4.54 (m, 1H),
4.27 (brs, 2H), 3.37 (m, 1H), 2.09 (m, 1H), 1.76 (m, 1H), 1.42–1.62 (m,
4H), 1.40 (s, 3H); 13C (75.5 MHz, CDCl3) d160.96, 147.25, 129.22,
107.51, 106.41, 105.36, 76.99, 60.54, 32.67, 29.38, 20.19, 14.77.
Compound 3i
1H (300 MHz, CDCl3) d7.09 (m, 1H), 6.44–6.73 (m, 2H), 4.53 (m, 1H),
3.62 (brs, 2H), 3.40 (m, 1H), 2.30 (s, 3H), 2.11 (m, 1H), 1.77 (m, 1H),
1.62 (m, 2H), 1.50 (m, 2H); 13C (75.5 MHz, CDCl3) d145.96, 129.86,
129.22, 127.65, 127.15, 116.89, 76.99, 62.09, 32.67, 29.38, 20.19, 17.80.
Compound 3j
1H (300 MHz, CDCl3) d7.18 (m, 3H), 6.52 (m, 1H), 4.53 (m, 1H), 3.36 (m,
1H), 2.93 (brs, 2H), 2.11 (m, 1H), 1.77 (m, 1H), 1.62 (m, 2H), 1.50 (m,
2H); 13C (75.5 MHz, CDCl3) d148.60, 126.81, 124.57, 118.91, 117.58,
112.53, 76.99, 60.54, 32.67, 29.38, 20.19.
ACKNOWLEDGMENT
R. P. A. acknowledges Bristol-Myers Squibb, Lawrenceville, N. J. USA,
for summer undergraduate research support.
REFERENCES
1. (a) Corey, E. J.; Zhang, F.-Y. Re- and Si-face-selective nitroaldol reactions
catalyzed by a rigid chiral quaternary ammonium salt: A highly stereoselec-
tive synthesis of the HIV protease inhibitor amprenavir (Vertex 478). Angew.
Chem., Int. Ed. 1999, 38, 1931; (b) Chng, B. L.; Ganesan, A. Solution-phase
synthesis of a b-amino alcohol combinatorial library. Bioorg. Med. Chem.
Lett. 1997, 7, 1511.

1-Ethylpyridinium Trifluoroacetate
4167
2. (a) O’Brien, P. Sharpless asymmetric aminohydroxylation: Scope, limitations,
and use in synthesis. Angew. Chem., Int. Ed. 1999, 38, 326; (b) Li, G.; Chang,
H.-T.; Sharpless, K. B. Catalytic asymmetric aminohydroxylation (AA) of
olefins. Angew. Chem., Int. Ed. 1996, 35, 451.
3. Ager, D. J.; Prakash, I.; Schaad, D. R. 1,2-Amino alcohols and their hetero-
cyclic derivatives as chiral auxiliaries in asymmetric synthesis. Chem. Rev.
1996, 96, 835.
4. (a) Deyrup, J. A.; Moyer, C. L. 1,2,3-Oxathiazolidines: Heterocyclic system.
J. Org. Chem. 1969, 34, 175; (b) Freifelder, M.; Stone, G. R. Effect of nuclear
substitution on the reaction of aromatic amines with ethylene oxide. J. Org.
Chem. 1961, 26, 1477; (c) Lutz, R. E.; Freek, J. A.; Murphy, R. S. Agents
causing necrosis in tumors, I: Secondary and tertiary amino ketones and
alcohols derived from desoxybenzoin and 1,2-diphenylethanol: Ring-chain
tautomerism of the a-(2-hydroxyethylamino) ketones. J. Am. Chem. Soc.
1948, 70, 2015.
5. Kamal, A.; Damayanthi, Y.; Rao, M. V. Stereoselective synthesis of (S)-
propanol amines: Lipase catalyzed opening of epoxides with 2-propylamine.
Tetrahedron: Asymmetry 1992, 3, 1361.
6. Posner, G. H.; Rogers, D. Z. Organic reactions at alumina surfaces: Mild and
selective opening of epoxides by alcohols, thiols, benzeneselenol, amines, and
acetic acid. J. Am. Chem. Soc. 1977, 99, 8208.
7. (a) Yamammoto, Y.; Asao, N.; Meguro, M.; Tsukade, N.; Nemoto, H.;
Adayari, N.; Wilson, J. G.; Nakamura, H. Regio- and stereoselective ring
opening of epoxides with amide cuprate reagents. J. Chem. Soc., Chem. Com-
mun. 1993, 1201; (b) Yamada, J.-I.; Yumoto, M.; Yamomoto, Y. Aminolead
compounds as a new reagent for regioselective ring opening of epoxides. Tet-
rahedron Lett. 1989, 30, 4255; (c) Carre, M. C.; Houmounou, J. P.; Caubere,
P. A convenient preparation of b-amino alcohols from epoxides and halo-
magnesium alkylamides. Tetrahedron Lett. 1985, 26, 3107.
8. (a) Sagawa, S.; Abe, H.; Hase, Y.; Inaba, T. Catalytic asymmetric
aminolysis of 3,5,8-trioxabicyclo[5.1.0]octane providing an optically pure
2-amino-1,3,4-butanetriol equivalent. J. Org. Chem. 1999, 64, 4962;
(b) Rampalli, S.; Chaudhari, S. S.; Akamanchi, K. G. Diisopropoxyalu-
minium trifluoroacetate: A new promoter for aminolysis of epoxides.
Synthesis 2000, 78.
9. (a) Sekar, G.; Singh, V. K. An efficient method for cleavage of epoxides with
aromatic amines. J. Org. Chem. 1999, 64, 287; (b) Auge, J.; Leroy, F. Lithium
trifluoromethanesulfonate-catalysed aminolysis of oxiranes. Tetrahedron
Lett. 1996, 37, 7715; (c) Fujiwara, M.; Imada, M.; Bab, A.; Matsuda, H.
Tetraphenylstibonium triflate as a regio- and chemoselective catalyst in
the reaction of oxiranes with amines. Tetrahedron Lett. 1989, 30, 739; (d)
Schneider, C.; Sreekanth, A. R.; Mai, E. Scandium-bipyridine-catalyzed
enantioselective addition of alcohols and amines to meso-epoxides. Angew.
Chem., Int. Ed. 2004, 43, 5691.
10. (a) Iqbal, J.; Pandey, A. An unusual chemoselectivity in cobalt(II) chloride
catalysed cleavage of oxiranes with anilines: A highly regioselective synthesis

4168
S. V. Malhotra, R. P. Andal, and V. Kumar
of b-amino alcohols. Tetrahedron Lett. 1990, 31, 575; (b) Chandrasekhar, S.;
Ramchander, T.; Prakash, S. J. TaCl5-catalyzed cleavage of epoxides with
aromatic amines. Synthesis 2000, 1817; (c) Ollevier, T.; Lavie-Compin, G.
An efficient method for the ring opening of epoxides with aromatic amines
catalyzed by bismuth trichloride. Tetrahedron Lett. 2002, 43, 7891;
(d) Chakraborti, A. K.; Kondaskar, A. ZrCl4 as a new and efficient
catalyst for the opening of epoxide rings by amines. Tetrahedron Lett.
2003, 44, 8315.
11. Chini, M.; Crotti, P.; Macchia, F. Metal salts as new catalysts for mild and
efficient aminolysis of oxiranes. Tetrahedron Lett. 1990, 31, 4661.
12. (a) Kotsuki, H.; Shimanouchi, T.; Teraguchi, M.; Kataoka, M.; Tatsukawa,
A.; Nishizawa, H. High-pressure organic chemistry, 18: High-pressure pro-
moted and silica gel catalyzed aminolysis of epoxides with glycine esters.
Chem. Lett. 1994, 2159; (b) Kotsuki, H.; Hayashida, K.; Shimanouchi, T.;
Nishizawa, H. High-pressure organic chemistry, 19: High-pressure-promoted,
silica gel–
catalyzed reaction of epoxides with nitrogen heterocycles. J. Org. Chem.
1996, 61, 984.
13. Mojtahedi, M. M.; Saidi, M. R.; Bolourtchain, M. Microwave-assisted ami-
nolysis of epoxides under solvent-free conditions catalyzed by montmorillo-
nite clay. J. Chem. Res., Synop. 1999, 128.
14. (a) Crandall, J. K.; Apparu, M. Base-promoted isomerization of epoxides.
Org. React. 1983, 39, 345; (b) Kissel, C. L.; Rickborn, B. Base-induced rear-
rangement of epoxides, IV: Reaction of cyclohexene oxide with various
lithium alkylamides. J. Org. Chem. 1972, 37, 2060.
15. (a) Welton, T. Room-temperature ionic liquids: Solvents for synthesis and
catalysis. Chem. Rev. 1999, 99, 2071; (b) Zhao, H.; Malhotra, S. V. Applica-
tion of ionic liquids in organic synthesis. Aldrichimica Acta 2002, 35, 75; (c)
Jain, N.; Kumar, A.; Chauhan, S.; Chauhan, S. M. S. Chemical and biochem-
ical transformations in ionic liquids. Tetrahedron 2005, 61, 1015.
16. Khodaei, M. M.; Khosropour, A. R.; Ghozati, K. A powerful, practical,
and chemoselective synthesis of 2-anilinoalkanols catalyzed by Bi(TFA)3
or Bi(OTf)3 in the presence of molten TBAB. Tetrahedron Lett. 2004, 45,
3525.
17. Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V. [Bmim]BF4 ionic
liquid: A novel reaction medium for the synthesis of b-amino alcohols. Tetra-
hedron Lett. 2003, 44, 1047.
18. Couling, D. J.; Bernot, R. J.; Docherty, K. M.; Dixon, N. K.; Maginn, E. J.
Assessing the factors responsible for ionic liquid toxicity to aquatic organisms
via quantitative structure–activity relationship modeling. Green Chem. 2006,
8, 82.
19. Zhang, C. Interactions of ionic liquids with uranium and its implications
on biotransformation. PhD thesis, New Jersey Institute of Technology,
2006.
20. Xiao, Y.; Malhotra, S. V. Diels–Alder reactions in pyridinium based ionic
liquids. Tetrahedron Lett. 2004, 45, 8339.

1-Ethylpyridinium Trifluoroacetate
4169
21. Xiao, Y.; Malhotra, S. V. Friedel–Crafts alkylation reactions in pyridinium-
based ionic liquids. J. Mol. Catal. A: Chem. 2005, 230, 129.
22. Xiao, Y.; Malhotra, S. V. Friedel-Crafts acylation reactions in pyridinium
based ionic liquids. J. Organometall. Chem. 2005, 690, 3609.
23. Xiao, Y.; Malhotra, S. V. Asymmetric reduction of aromatic ketones in
pyridinium-based ionic liquids. Tetrahedron: Asymmetry 2006, 17, 1062.
24. Carree, F.; Gil, R.; Collin, J. Samarium iodides catalyzed meso-epoxides ring
opening by aromatic amines. Tetrahedron Lett. 2004, 45, 7749.
25. Rafiee, E.; Tangestaninejad, S.; Habibi, M. H.; Mirkhani, V. Potassium
dodecatungstocobaltate trihydrate (K5CoW12O40–3H2O) as an efficient
catalyst for aminolysis of epoxides. Synth. Commun. 2004, 34, 3673.
26. Reddy, L. R.; Reddy, M. A.; Bhanumathi, N.; Rao, K. R. An efficient
method for the ring opening of epoxides with aromatic amines catalysed by
indium trichloride. New J. Chem. 2001, 25, 221.
27. Carree, F.; Gil, R.; Collin, J. Enantioselective ring opening of meso-epoxides
by aromatic amines catalyzed by lanthanide iodo binaphtholates. Org. Lett.,
2005, 7, 1023.
28. McCluskey, A.; Leitch, S. K.; Garner, J.; Caden, C. E.; Hill, T. A.; Odell, L. R.;
Stewart, S. G. BiCl3-mediated opening of epoxides, a facile route to
chlorohydrins or amino alcohols: One reagent, two paths. Tetrahedron Lett.
2005, 46, 8229.
29. Singh, M. C.; Peddinti, R. K. Antimony(III) chloride–catalyzed ring opening
of epoxides with anilines. Tetrahedron Lett. 2007, 48, 7354.
30. Crowhurst, L.; Lancaster, N. L.; Arlandis, J. M. P.; Welton, T. Manipulating
solute nucleophilicity with room temperature ionic liquids. J. Am. Chem. Soc.
2004, 126, 11549.
31. Zhao, H.; Malhotra, S. V.; Luo, R. G. Preparation and characterization of
three room-temperature ionic liquids. Phys. Chem. Liquids 2003, 41, 487.