5020
A. Sakakura et al. / Tetrahedron Letters 49 (2008) 5017–5020
applied to a large-scale process. The ester condensation of an equi-
molar mixture of 2-octyldodecanol and myristic acid catalyzed by
CSA (1 mol %) gave the corresponding ester in 97% yield, just after
simple extraction with the minimal use of organic solvents (entry
3).9
esterification method, since it does not require any solvent as well
as additional equipment or additional amounts of materials and
energy for dehydration. Through the present protocols, a large
amount of esters can be synthesized in a rather small apparatus.
For example, 49 g of 2-octyldodecyl palmitate was synthesized in
a 100-mL round-bottomed flask (Table 2, entry 3).
Esters derived from secondary alcohols were also obtained in
good yields (entries 7–16), although the reactivities of secondary
alcohols were lower than those of primary alcohols. Ester conden-
sation of trans-1,2-cyclohexanediol gave the corresponding diester
in high yields (entries 7–9), while Lewis acidic metal salts, such as
HfCl4(THF)2, were not suitable for use with these diols due to tight
chelation with metal ions.3c The reactions catalyzed by TsOH and
CSA gave particularly excellent results (entries 8 and 9), although
the use of H2SO4 led to isomerization of the product (trans:
cis = 93:7) (entry 7). When the reaction of 6-undecanol with 3-
phenylpropionic acid was conducted with a catalytic amount of
H2SO4, a significant amount of 5-undecene was generated (12%)
and the yield of the desired ester was decreased (78%) (entry 10).
In contrast, neither TsOH nor CSA promoted the generation of
5-undecene and the ester was obtained in good yields (entries 11
and 12). Ester condensation of acrylic acid was also successfully
conducted without promoting undesired conjugate addition (en-
tries 13–15). When substrates and/or products were solid, they
were effectively dissolved by the addition of a small amount of
octane. For example, the reaction of b-cholestanol (solid, 2 mmol)
with oleic acid proceeded well in the presence of octane (1 mL),
and gave the corresponding ester (solid) in 98% yield (entry 16).
Tertiary alcohols are generally much less reactive than secondary
alcohols and decompose much more easily to give alkenes under
acidic conditions. In fact, the reaction of 2-methyl-4-phenyl-
2-butanol with 4-phenylbutyric acid resulted in the generation of
alkenes in ca. 85% yields under the present reaction conditions.
In contrast to the ester condensation of aliphatic alcohols, the
reaction of 4-methoxyphenol with methoxyacetic acid gave poor
results (entries 17–19), while bulky ammonium salt-catalyzed
esterification gave the corresponding ester in 99% yield.5 It is con-
ceivable that the hydrophilic nature of sulfonic acids promoted
hydrolysis of the product to decrease its yield without the removal
water.10 Amino acid esters could be prepared through the present
ester condensation by using 1 equiv of an additional sulfonic acid.
Acknowledgments
This project was supported by JSPS.KAKENHI (Grant 20245022),
Tokuyama Science Foundation, the Toray Science Foundation, and
the G-COE in Chemistry, Nagoya.
Supplementary data
Analytical data for new compounds, and 1H and 13C NMR data of
all products. Supplementary data associated with this article can
References and notes
1. Otera, J. Esterification; Wiley-VCH: Weinheim, Germany, 2003.
2. Otera, J. Angew. Chem., Int. Ed. 2001, 40, 2044.
3. For our studies on Hf(IV)- or Zr(IV)-catalyzed ester condensation, see: (a)
Ishihara, K.; Ohara, S.; Yamamoto, H. Science 2000, 390, 1140; (b) Ishihara, K.;
Nakayama, M.; Ohara, S.; Yamamoto, H. Synlett 2001, 1117; (c) Ishihara, K.;
Nakayama, M.; Ohara, S.; Yamamoto, H. Tetrahedron 2002, 58, 8179; (d)
Nakayama, M.; Sato, A.; Ishihara, K.; Yamamoto, H. Adv. Synth. Catal. 2004, 346,
1275; (e) Sato, A.; Nakamura, Y.; Maki, T.; Ishihara, K.; Yamamoto, H. Adv.
Synth. Catal. 2005, 347, 1337; (f) Nakamura, Y.; Maki, T.; Wang, X.; Ishihara, K.;
Yamamoto, H. Adv. Synth. Catal. 2006, 348, 1505.
4. For recent studies on catalytic ester condensation, see: (a) Wakasugi, K.;
Misaki, T.; Yamada, K.; Tanabe, Y. Tetrahedron Lett. 2000, 41, 5249; (b) Manabe,
K.; Sun, X.-M.; Kobayashi, S. J. Am. Chem. Soc. 2001, 123, 10101; (c) Xiang, J.;
Toyoshima, S.; Orita, A.; Otera, J. Angew. Chem., Int. Ed. 2001, 40, 3670; (d)
Gacem, B.; Jenner, G. Tetrahedron Lett. 2003, 44, 1391; (e) Funatomi, T.;
Wakasugi, K.; Misaki, T.; Tanabe, Y. Green Chem. 2006, 8, 1022.
5. (a) Ishihara, K.; Nakagawa, S.; Sakakura, A. J. Am. Chem. Soc. 2005, 127, 4168; (b)
Sakakura, A.; Nakagawa, S.; Ishihara, K. Tetrahedron 2006, 62, 422; (c) Sakakura,
A.; Nakagawa, S.; Ishihara, K. Nat. Protocol. 2007, 2, 1746.
6. Sakakura, A.; Watanabe, H.; Nakagawa, S.; Ishihara, K. Chem. Asian J. 2007, 2,
477.
7. For solvent-free DMAP-catalyzed esterification, see: Sakakura, A.; Kawajiri, K.;
Ohkubo, T.; Kosugi, Y.; Ishihara, K. J. Am. Chem. Soc. 2007, 129, 14775.
8. For the measurement of pKa in CD3CO2D, see: Rode, B. M.; Engelbrecht, A.;
Schantl, J. Z. Physik. Chem. (Leipzig) 1973, 253(1–2), 17.
When L-phenylalanine and benzyl alcohol (2 equiv) were reacted
9. Experimental procedure: A 100-mL round-bottomed flask was charged with
2-octyl-1-dodecanol (100 mmol), myristic acid (100 mmol) and CSA (1 mmol).
The mixture was stirred at 60 °C for 24 h, and then the reaction mixture was
quenched by the addition of NaHCO3 (1 mmol) and water (30 mL). After the
mixture was stirred for 5 min, the resulting aqueous mixture was extracted
with hexane (10 + 20 mL), and the organic layer was concentrated in vacuo to
give the product (49.3 g, 97% yield, 97% purity).
with CSA (1.05 equiv), the corresponding benzyl ester was
obtained in good yield and with complete retention of its chiral
center (entry 20).
In conclusion, we have demonstrated that 1–5 mol % of sulfonic
acids could efficiently catalyze the ester condensation of alcohols
with carboxylic acids (1.0–1.1 equiv) under open-air and solvent-
free conditions. This is a highly practical and atom-economical
10. Offenhauer, R. D. J. Chem. Educ. 1964, 41, 39.