J. McNulty et al. / Tetrahedron Letters 46 (2005) 3641–3644
3643
O
O
O
NO2
S
ionic liquid, 80oC, 3h
+
O2N
COOH
N
O
+
O
Scheme 2. Alkylative esterification with (2S)-2-hexyl tosylate.
tion:inversion). The reaction was slower at 50 ꢁC but
gave complete (>99%) inversion of configuration. These
results are consistent with the involvement of essentially
an SN2-type process with some ionization (and racemi-
zation) occurring at higher temperatures. This result is
in agreement with earlier work carried out in conven-
tional solvents.10
References and notes
1. (a) Smith, M. B.; March, J. Advanced Organic Chemistry,
5th ed.; Wiley: New York, 2001, pp 484–490; (b) Larock,
R. C. Comprehensive Organic Transformations, 2nd ed.;
Wiley-VCH: New York, 1999.
2. Palermo, A.; Webb, C. Green Chem. 2004, 6, G22.
3. Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis;
Wiley-VCH: Weinheim, 2003.
Finally, while the use of ionic liquid solvents offers many
advantages over conventional solvents, one drawback is
that often a volatile organic solvent is employed in the
work-up or product isolation,15 partially defeating the
original purpose.16 Having demonstrated the wide scope
of the alkylative esterification method, we next investi-
gated the possibility of a solvent-free product isolation
and IL recycling protocol based on the low volatility
of phosphonium salt ILs. To this end, the synthesis of
the widely used commodity ester butyl acetate was
investigated. The reaction of acetic acid (1.10 equiv)
and potassium carbonate (1.10 equiv) with butyl
bromide (1.0 equiv) was conducted in the phosphonium
salt IL under slightly modified conditions.17b Thin-layer
chromatography indicated clean conversion to the ester
which was isolated in 74% yield by direct distillation
from the reaction mixture. The ionic liquid phase was
washed with water, dried and a second esterification
cycle conducted. Butyl acetate was isolated in 85% yield
after the second cycle.
4. (a) For recent IL reviews see Welton, T. Chem. Rev. 1999,
99, 2071; (b) Sheldon, R. Chem. Commun. 2001, 2399; (c)
Gordon, C. M. Appl. Catal. A 2001, 101; (d) Zhao, D.;
Wu, M.; Kou, Y.; Min, E. Catal. Today 2002, 1; (e) Zhao,
H.; Malhotra, S. V. Aldrichim. Acta 2002, 35, 75.
5. (a) We have recently demonstrated the recyclability of
phosphonium salt ionic liquids in both Pd-mediated
Suzuki and Heck cross-coupling reactions, see McNulty,
J.; Capretta, A.; Wilson, J.; Dyck, J.; Adjabeng, G.;
Robertson, A. J. Chem. Commun. 2002, 1986; (b) Ger-
ritsma, D. A.; Robertson, A. J.; McNulty, J.; Capretta, A.
Tetrahedron Lett. 2004, 45, 7629.
6. (a) Yoshino, T.; Togo, H. Synlett 2004, 1604; (b) Deng,
Y.; Shi, F.; Beng, J.; Qiao, K. J. Mol. Catal. A, Chem.
2001, 165, 33; (c) Brinchi, L.; Germani, R.; Savelli, G.
Tetrahedron Lett. 2003, 44, 2027; (d) Brinchi, L.; Germani,
R.; Savelli, G. Tetrahedron Lett. 2003, 44, 6583.
7. (a) Mehta, G. Synthesis 1972, 262; (b) Pfeffer, P. E.;
Foglia, T. A.; Barr, P. A.; Schmeltz, I.; Silbert, L. S.
Tetrahedron Lett. 1972, 4063.
8. Alvarez, F. S.; Watt, A. N. J. Org. Chem. 1968, 33, 2143.
9. Raphael, R. A.; Taylor, E. C.; Wynberg, H. In Advances in
Organic Chemistry; Interscience: New York, 1965; Vol. 5,
p 37.
The high stereochemical inversion and generality dem-
onstrated by this carboxylate alkylation process in the
phosphonium salt IL using primary, secondary and ter-
tiary bromides or primary and secondary tosylates with
a large variety of hindered, electron rich or electron defi-
cient acids makes this process attractive from the struc-
tural viewpoint. No elimination from the electrophile or
a-alkylation of any acid/ester has been observed in any
of the cases described. The product ester can be readily
isolated from these phosphonium salt ILs using either a
standard extraction protocol,15 or by direct, solvent-free
distillation allowing IL re-use. Finally, the reaction
takes place at a relatively low temperature in compari-
son to other processes reported in ILÕs.6 Given these
desirable features, we believe that this esterification
protocol is a prime candidate for the development of
economically viable, benign industrial processes for both
HPV ester synthesis as well as lower volume, high-value
targets. Applications toward the synthesis of biologi-
cally important targets is under active investigation in
our laboratories.
10. (a) Kruizinga, W. H.; Strijtveen, B.; Kellogg, R. M.
J. Org. Chem. 1981, 46, 4323; (b) Torisawa, Y.; Okabe, H.;
Ikegami, S. Chem. Lett. 1984, 1555.
11. Chevallet, P.; Garrouste, P.; Malawska, B.; Martinez, J.
Tetrahedron Lett. 1993, 34, 7409.
12. This and related phosphonium salt ionic liquids are
available from Cytec (CYPHOSꢂ IL 109) and Strem
Chemicals.
13. Shaw, J. E.; Kunerth, D. C.; Sherry, J. J. Tetrahedron Lett.
1973, 689.
14. Moore, G. G.; Foglia, T. A.; McGahan, T. J. J. Org.
Chem. 1979, 44, 2425.
15. McNulty, J.; Capretta, A.; Cheekoori, S.; Clyburne, J. A.
C.; Robertson, A. J. Chemica Oggi 2004, 22(11/12), 13.
16. Reetz, M. T.; Wiesenhofer, W. Chem. Commun. 2004,
2750.
17. (a) Sample procedure: (a) Table 1 entry 5: 4-nitrobenzoic
acid (40 mg, 0.24 mmol), HunigÕs base (0.48 mmol) and
ionic liquid (0.50 g) were stirred at 30 ꢁC under Ar for
10 min whereupon bromoethane (0.48 mmol) was added.
After TLC indicated the reaction to be complete (in all
cases within 12 h), the reaction mixture was poured into a
methanol/water (3:2) solution (5 mL) and extracted with
n-hexane (3 · 5 mL). The hexane fractions were dried
over anhydrous sodium sulfate, diluted with 5% v/v ethyl
acetate and the solution filtered through a plug of silica
gel. Concentration of the filtrate gave the ester product in
95% yield. All compounds reported were characterized by
Acknowledgements
We thank NSERC and McMaster University for finan-
cial support of this work.