Asymmetric hydrogenation of methyl α-benzamido cinnamate in ionic liquid solvent

Article abstract of DOI:10.1016/j.tetlet.2005.12.066

The room temperature ionic liquid EMIMOTf was employed as the sole reaction solvent for the asymmetric hydrogenation of methyl α-benzamido cinnamate. Under conditions of 60 psi hydrogen and 50°C for 24 h, near quantitative conversions were observed using

Full text of DOI:10.1016/j.tetlet.2005.12.066

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1311–1313
Asymmetric hydrogenation of methyl a-benzamido cinnamate
in ionic liquid solvent
Katherine L. Boyle, Emily Beth Lipsky and Christopher S. Kalberg*
Department of Chemistry, Wheaton College, Norton, MA 02766, USA
Received 21 November 2005; revised 12 December 2005; accepted 13 December 2005
Available online 28 December 2005
Abstract—The room temperature ionic liquid EMIMOTf was employed as the sole reaction solvent for the asymmetric hydrogena-
tion of methyl a-benzamido cinnamate. Under conditions of 60 psi hydrogen and 50 °C for 24 h, near quantitative conversions were
observed using both the achiral DiPFc–Rh catalyst, and the chiral EtDuPHOS–Rh catalysts. Enantiomeric excess of 89% ee was
observed for hydrogenations carried out with the chiral catalyst.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
as Diels–Alder4 and for numerous catalytic reactions
including hydrogenation, hydroformylation, and Heck
type couplings.5
The use of room temperature ionic liquids (RTILs) as
more environmentally friendly alternatives to conven-
tional organic solvents has exploded over the last dec-
ade.1,2 While there are many classes of ionic liquids
including pyridinium salts and quartenary ammonium
salts, ionic liquids based on the imidazolium cation have
received the most attention as reaction solvents. In par-
ticular, ethyl methyl imidazolium (EMIM) and butyl
methyl imidazolium (BMIM) salts (Fig. 1) with a variety
of anions including tetrafluoroborate (BF4) and trifluo-
romethanesulfonate (OTf) have been used widely. The
imidazolium RTILs act like moderately polar organic
solvents with the ability to dissolve many common
organic solutes, both polar and non-polar. The short
chain imidazolium RTILs, in particular, have limited
miscibility in organic solvents like hexanes, toluene,
and ether.3 This allows for ease of extraction of organic
products from the RTIL. For these reasons, imidazo-
lium ionic liquids have been investigated as reaction
solvents for a variety of stoichiometric reactions such
The DuPHOS–Rh and BINAP–Ru catalyst systems
(Fig. 2) have proven to be versatile and highly effective
at asymmetric induction when used for hydrogenation
of a wide variety of substrates including a-enamide
esters,6a,b enol benzoates,7 b-keto esters,8a,b and a-aryl
enamides.9 In addition, the achiral DiPFc10 is a highly
active catalyst useful for generating the racemic material
necessary for development of the method for analysis of
enantiomeric excess. These reactions are typically car-
ried out in organic solvents such as methanol, 2-propa-
nol, or even the more toxic THF and benzene. More
recently, efforts have been made to use this type of cat-
alyst in more ‘green’ solvents. In fact, the use of EtDu-
PHOS–Rh in supercritical CO2 has been reported to
catalyze the hydrogenation of a-enamide esters to the
corresponding amino acid derivatives with levels of
enantioselectivity that rival, and in some cases exceed
those achieved in methanol and hexane.11
N
N
N
N
OTf-
-
BF4
P(iPr)2
P(iPr)2
PPh2
PPh2
EMIMOTf
BMIMBF4
P
P
Fe
Figure 1. Structures of imidazolium ionic liquids.
Keywords: Asymmetric hydrogenation; Ionic liquids.
Corresponding author. Tel.: +1 508 286 3959; e-mail: ckalberg@
wheatonma.edu
DiPFc
(R,R) BINAP
(R,R) EtDuPHOS
*
Figure 2. Structure of DiPFc, EtDuPHOS, and BINAP ligands.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.066

1312
K. L. Boyle et al. / Tetrahedron Letters 47 (2006) 1311–1313
Asymmetric hydrogenations in which RTILs played the
role of solvent or co-solvent for a variety of substrates
have been reported in the literature. The substrates
involved in these reactions include aromatic ketones,12a,b
b-keto esters,13a–c and a-enamide esters.14a–c For exam-
ple, the ionic liquid BMIMPF6 was used in combination
with 2-propanol for the hydrogenation of a-enamide
esters14a and BMIMBF4 was used with the co-solvents
2-propanol or water in a roughly one-to-one ratio for
similar types of reactions.14b In fact, Wolfson et al.
reported no conversion of methyl 2-acetamidoacrylate
under homogenous conditions using EtDuPHOS–Rh in
BMIMPF6 ionic liquid as the only solvent at 5 bar H2
pressure, whereas complete reaction and good enantio-
meric excesses were achieved in a variety of co-solvent
systems in which the ionic liquid was combined with an-
other organic solvent.14c In contrast to that report, our
studies presented here demonstrate near quantitative
conversion of a similar substrate, methyl a-benzamido
cinnamate, to the corresponding protected amino acid
using the ionic liquid EMIMOTf as the sole reaction sol-
vent (Scheme 1).
A change from the BMIMBF4 ionic liquid to the EMI-
MOTf ionic liquid was met with an improvement in con-
version under the same reaction conditions (see Table 1).
The conversion of methyl a-benzamido cinnamate with
the chiral catalysts EtDuPHOS–Rh and BINAP–Ru as
well as the achiral catalyst DiPFc–Rh was increased to
about 15% in all cases. With the EMIMOTf solvent,
dramatic improvement in conversion was observed both
under increased hydrogen pressure of 1000 psi at room
temperature (80% conversion) and under increased reac-
tion temperature of 50 °C at 60 psi (95% conversion).
The product from the high pressure reaction showed a
respectable 62% ee while the product form the 50 °C
reaction showed an outstanding 89% ee. In addition to
increased conversion and excellent stereochemical
induction, the use of EMIMOTf effected easier extrac-
tion of the organic products from the ionic liquid sol-
vent. In our hands, the BMIM was somewhat miscible
with virtually all extraction solvents. Thus, the EMI-
MOTf is the clear choice for ionic liquid as lone solvent
for this type of hydrogenation reaction.
In summary, this study demonstrates that it is possible
to achieve near quantitative conversion and high enan-
tiomeric excesses in the asymmetric hydrogenation of
methyl a-benzamido cinnamate using EMIMOTf RTIL
as sole reaction solvent. With these promising results, we
are in the process of evaluating other substrates such as
benzamido acrylates and acetamido acrylates in an
attempt to determine the scope and limitations of this
solvent for asymmetric hydrogenation reactions.
2. Results and discussion
Initial hydrogenations of methyl a-benzamido cinna-
mate carried out in the BMIMBF4 ionic liquid showed
very low conversion in the case of the DiPFc–Rh cata-
lyst, and no product was observed with the two chiral
catalysts (see Table 1). These results are in agreement
with the recent report by Wolfson et al. in which no
reaction of methyl 2-acetamidoacrylate was found under
homogenous conditions using EtDuPHOS–Rh in either
BMIMPF6 or BMIMBF4 ionic liquid as a single solvent
at 5 bar H2.14c
3. Experimental details
3.1. Typical hydrogenation procedure
The reaction mixture consisting of methyl a-benzamido
cinnamate (0.35 mmol) and the appropriate catalyst
(3 lmol) along with degassed RTIL (4 mL) was added
to an Andrews glass pressure reaction vessel (60 psi) or
a Parr stainless steel reactor (1000 psi) in an inert atmo-
sphere glove box. After removal and three vacuum-
hydrogen flush cycles, the vessel was pressurized to
either 60 psi or 1000 psi. After 24 h, the reaction was
vented and the product extracted using three 5-mL por-
tions of ether (EMIM) or three portions of hexanes
(BMIM). The organic solvent was removed under
reduced pressure and the remaining residue was ana-
lyzed for conversion by NMR and for stereochemistry
by HPLC. The methyl a-benzamido cinnamate and the
RTILs were prepared according to literature
procedures.3,15a,b
CO2CH3
CO2CH3
*
Ph
Ph
Catalyst
HN
Ph
O
HN
Ph
O
RTIL, H2
Scheme 1. Hydrogenation of methyl a-benzamido cinnamate.
Table 1. Results of hydrogenation reactionsa
Catalyst
RTIL
Conversionb (%)
% eec
DiPFc–Rh
BMIMBF4
EMIMOTf
EMIMOTfd
<2
15
—
Racemic
Racemic
100
EtDuPHOS–Rh
BINAP–Ru
BMIMBF4
EMIMOTf
EMIMOTfd
EMIMOTfe
0
15
95
80
—
85
89
62
3.2. Product analyses
BMIMBF4
EMIMOTf
0
16
—
95
Conversion was determined by integration of the methyl
1
ester singlet in the H NMR at d 3.87 for the methyl a-
a Conditions: 1 mol % catalyst, 60 psi H2, 24 h, room temperature,
unless otherwise noted.
benzamido cinnamate and d 3.77 for the hydrogenated
product. Determinations of enantiomeric excess were
made using an Agilent 1100 Series HPLC equipped with
a Chiralcel OD-H column and a flow rate of 1.0 mL/min
of 90/10 hexanes/2-propanol and UV detection at
b Conversion determined by 1H NMR.
c Enantiomeric excess determined by HPLC.
d Reaction carried out at 50 °C for 24 h.
e Reaction carried out at 1000 psi for 24 h.

K. L. Boyle et al. / Tetrahedron Letters 47 (2006) 1311–1313
1313
7. Burk, M. J.; Kalberg, C. S.; Pizzano, A. J. Am. Chem. Soc.
1998, 120, 4345–4353.
215 nm. Retention times of 11.5 and 14.8 min repre-
sented the two enantiomers of the hydrogenated
product.
8. (a) Burk, M. J.; Harper, T. G. P.; Kalberg, C. S. J. Am.
Chem. Soc. 1995, 117, 4423–4424; (b) Mashima, K.;
Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki, K.;
Kumobayasi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Aku-
tagawa, S.; Takaya, H. J. Org. Chem. 1994, 59, 3064–3076.
9. Burk, M. J.; Wang, Y. M.; Lee, J. R. J. Am. Chem. Soc.
1996, 118, 5142–5143.
10. Burk, M. J.; Harper, T. G. P.; Lee, J. R.; Kalberg, C.
Tetrahedron Lett. 1994, 35, 4963–4966.
11. Burk, M. J.; Feng, S.; Gross, M. F.; Tumas, W. J. Am.
Chem. Soc. 1995, 117, 8277–8288.
Acknowledgements
C.K. and E.B.L. would like to acknowledge the Mars
Summer Fellowship program at Wheaton College for
financial support of this project. C.K. would also like
to thank Professor Elita Pastra-Landis for helpful dis-
cussions during preparation of this manuscript.
12. (a) Xiong, W.; Lin, Q.; Ma, H.; Zheng, H.; Chen, H.; Li,
X. Tetrahedron: Asymmetry 2005, 16, 1959–1962; (b)
Yinghuai, Z.; Carpenter, K.; Bun, C. C.; Bahnmueller, S.;
Ke, C. P.; Srid, V. S.; Kee, L. W.; Hawthorne, M. F.
Angew. Chem., Int. Ed. 2003, 42, 3792–3795.
References and notes
1. Welton, T. Chem. Rev. 1999, 99, 2071–2083.
2. Earle, M.; Forestier, A.; Oiver-Bourbigou, H.; Wasser-
scheid, P. In Ionic Liquids in Synthesis; Wasserscheid, P.,
Welton, T., Eds.; Organic Synthesis; Wiley-VCH: Wein-
heim, 2003; pp 174–288.
13. (a) Berthod, M.; Joerger, J.-M.; Mignani, G.; Vaultier, M.;
Lemaire, M. Tetrahedron: Asymmetry 2004, 15, 2219–
2221; (b) Hu, A.; Ngo, H. L.; Lin, W. Angew. Chem., Int.
Ed. 2004, 43, 2501–2504; (c) Ngo, H. L.; Hu, A.; Lin, W.
Chem. Commun. 2003, 1912–1913.
3. Bonhote, P.; Dias, A.-P.; Papageorgiou, N.; Kalyanasun-
daram, K.; Gratzel, M. Inorg. Chem. 1996, 35, 1168–1178.
4. Meracz, I.; Oh, T. Tetrahedron Lett. 2003, 44, 6465–6468.
5. Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000,
39, 3772–3789.
6. (a) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R.
L. J. Am. Chem. Soc. 1993, 115, 10125–10138; (b)
Miyashita, A.; Takaya, H.; Souchi, T.; Noyori, R.
Tetrahedron 1984, 40, 1245–1253.
14. (a) Guernik, S.; Wolfson, A.; Herskowitz, M.; Green-
spoon, N.; Geresh, S. Chem. Commun. 2001, 2314–2315;
(b) Pugin, B.; Studer, M.; Kuesters, E.; Sedelmeier, G.;
Feng, X. Adv. Synth. Catal. 2004, 346, 1481–1486; (c)
Wolfson, A.; Vankelecom, I. F. J.; Jacobs, P. A. J.
Organomet. Chem. 2005, 690, 3558–3566.
15. (a) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984,
53–60; (b) Zoller, U.; Ben-Ishai, D. Tetrahedron 1975, 31,
863–866.