where environmental (moisture sensitive, corrosive, or
toxic) concerns are waiting to be addressed. For eco-
friendly chemistry, one should avoid the use of excess
reagents or high catalyst loadings. Recent elegant works
by Yamamoto and co-workers presented group IVB HfCl4
and ZrCl4 and the corresponding alkoxide species for
direct esterification with equimolar amounts (i.e., atom-
efficient) of both substrates.6 For the past three years,
we have identified several water-tolerant vanadyl and
other oxometallic species as recoverable, amphoteric
catalysts for nucleophilic acyl substitutions (NAS) of
anhydrides7a,b and methyl esters7c (including transesteri-
fication) with protic nucleophiles (alcohols, amines, and
thiols) with high functional group compatibility and
chemoselectivity, Scheme 1. In continuation of our related
works in catalysis,8 herein we report a new air and
moisture stable, environmentally benign protocol for the
target atom efficient, direct esterification catalyzed by
the VOX2 and TiOX2 family.
Direct Atom-Efficient Esterification
between Carboxylic Acids and Alcohols
Catalyzed by Amphoteric, Water-Tolerant
TiO(acac)2
Chien-Tien Chen* and Yogesh S. Munot
Department of Chemistry, National Taiwan Normal
University, Taipei, Taiwan 11650
Received June 29, 2005
After extensive survey of various oxometallic species
through the periodic table, several group IVB MOX2 and
VOX2 species were identified to be suitable catalysts for
the atom-efficient direct esterification. A model reaction
between 1-phenylethanol and benzoic acid in refluxed
xylene with removal of water by Dean-Stark apparatus
was further chosen in view of its sensitive character to
oxidation or dehydration. By varying the catalyst load-
ings, we found that 1-3 mol % is optimal for efficiency
comparison. Among six hydrated oxometallic chlorides
and triflates examined, the catalytic efficiency follows the
trend of Zr > Hf > V > Ti9 (entries 1, 2, 4, 6, 8, and 10,
Table 1).10 Notably, the ligands also play a role on the
catalyst activity. Vanadyl THF complexes (entries 9 and
11) are about 1.5-2 times more reactive than the
corresponding hydrate complexes (entries 8 and 10). In
marked contrast, oxohafnium and oxozirconium THF
complexes (entries 5 and 7) are 1.5-1.6 times less
reactive than the corresponding hydrate complexes (en-
tries 4 and 6). Overall, only ZrOCl2-8H2O, HfOCl2-
8H2O, VOCl2-xTHF, and TiO(acac)2 led to satisfactory
conversions (80-97%) in 42 h. Furthermore, TiO(acac)2
A diverse array of oxometallic species were examined as
catalysts for a test direct condensation of benzoic acid and
2-phenylethanol in 1:1 stoichiometry. Besides group IVB
MOCl2-xH2O and TiOX2-xH2O, group VB VOCl2-xTHF
and group IVB TiO(acac)2 were found to be the most efficient
and water-tolerant catalysts for the test reaction. The new
neutral catalytic protocol with the optimal TiO(acac)2 toler-
ates many stereo/electronic structural variations in both (di)-
acid (1°-3° alkyl and aryl) and (di)alcohol (1°, 2° alkyl, and
aryl) components with high chemoselectivity.
The esterification of carboxylic acids with different
functionalized alcohols is one of the most important and
commonly used transformations in organic synthesis.
Several methods have been well documented in the
literature.1 Conventionally, the direct condensation pro-
cess was carried out with excess loading of limited acid-
tolerant reagent classes in the presence of strong acid
activators (e.g., sulfuric acid, boric acid,2 and solid
superacid).3 In addition, several effective Lewis acid
catalysts such as Ti(IV)4 and Sn(IV)5 salts were reported
(6) (a) Ishihara, K.; Ohara, S.; Yamamoto, H. Science 2000, 290,
1140. (b) Ishihara, K.; Nakayama, M.; Ohara, S.; Yamamoto, H.
Tetrahedron 2002, 58, 8179.
* Address correspondence to this author. Phone: +886 2-2930-9095.
Fax: +886 2-2932-4249.
(1) (a) Otera, J. Eserification Methods, Reactions and applications;
Wiley VCH, Verlag Gmbh and KGaA: Weinheim, Germany, 2003. (b)
Larock, R. C. Comprehensive Organic transformations; VCH: New
York, 1989; p 966.
(2) (a) Lawrence W. W., Jr. Tetrahedron. Lett. 1971, 37, 3453. (b)
For a recent application see: Houston, T. A.; Wilkinson, B. L.;
Blanchfield, J. T. Org. Lett. 2004, 6, 679.
(3) (a) Hino, M.; Arata, K. Chem. Lett. 1981, 1671. (b) Olah, G. A.;
Keumi, T.; Meider, D. Synthesis 1978, 929. (c) Tanabe, K.; Hattori,
H.; Ban’I, Y.; Mitsutani, A. Jpn. Patent Appl., No 55-115570, 1980.
(d) Izumi, Y.; Urabe, K. Chem. Lett. 1981, 663. (e) Santacesaria, E.;
Gelosa, D.; Danise, P.; Carra, S. J. Catal. 1983, 80, 427. (f) Chen, Z.;
Iizuka, T.; Tanabe, K. Chem. Lett. 1984, 1085.
(4) (a) Tanabe, K.; Hattori, H.; Ban’I, Y.; Mitsutani, A. Jpn. Kokai
Tokkyo Koho JP 57, 40444, 1982 (b) White, J. F.; Bertrand, J. C. Jpn.
Kokai Tokkyo Koho JP 52, 75684, 1977.
(5) (a) Steliou, K.; Szczygielska-Nowosielska, A.; Favre, A.; Poupart,
M. A.; Hanessian, S. J. Am. Chem. Soc. 1980, 102, 7578. (b) Kumar,
A. K.; Chattopadhyay, T. K. Tetrahedron Lett. 1987, 28, 3713. (c) Otera,
J.; Dan-oh, N.; Nozaki, H. J. Org. Chem. 1991, 56, 5307. (d) See also:
Otera, J. Acc. Chem. Res. 2004, 37, 288 for elegant trnasesterifications
by fluorous distannoxane catalysts.
(7) (a) Chen, C.-T.; Kuo, J.-H.; Li, C.-H.; Barhate, N. B.; Hon, S.-
W.; Li, T.-W.; Chao, S.-D.; Liu, C.-C.; Li, Y.-C.; Chang, I.-H.; Lin, J.-
S.; Lin, C.-J.; Chou, Y.-C. Org. Lett. 2001, 3, 3729. (b) Chen, C.-T.;
Kuo, J.-H.; Pawar, V. D.; Munot, Y. S.; Weng, S.-S.; Ku, C.-H.; Liu,
C.-Y. J. Org. Chem. 2005, 70, 1188. (c) Chen, C.-T.; Kuo, J.-H.; Ku,
C.-H.; Weng, S.-S.; Liu, C.-Y. J. Org. Chem. 2005, 70, 1328.
(8) (a) Chen, C.-T.; Hon, S.-W.; Weng, S.-S. Synlett 1999, 816. (b)
Hon, S.-W.; Li, C.-H.; Kuo, J.-H.; Barhate, N. B.; Liu, Y.-H.; Wang, Y.;
Chen, C.-T. Org. Lett. 2001, 3, 869. (c) Barhate, N. B.; Chen, C.-T.
Org. Lett. 2002, 4, 2529. (d) Chen, C.-T.; Lin, J.-S.; Kuo, J.-H.; Weng,
S.-S.; Cuo, T.-S.; Lin, Y.-W.; Cheng, C.-C.; Huang, Y.-C.; Yu, J.-K.;
Chou, P.-T. Org. Lett. 2004, 6, 4471. (e) See also: Chen, C.-T.; Pawar,
V. D.; Munot, Y. S.; Chen, C.-C.; Hsu, C.-J. Chem. Commun. 2005,
2483. (f) Chen, C.-T.; Weng, S.-S.; Kao, J.-Q.; Lin, C.-C.; Jan, M.-D.
Org. Lett. 2005, 7, 3343.
(9) (a) TiO(OTf)2-xH2O and TiOCl2-xH2O were prepared by mixing
TiO(SO4)-xH2SO4-xH2O with Ba(OTf)2 and BaCl2, respectively, in
MeOH.
(10) (a) The uses of ZrOCl2-8H2O and HfOCl2-8H2O for atom
efficient direct esterification were reported very recently.10b Neverthe-
less, 1-phenylethanol was not studied. (b) Nakayama, M.; Sato, A.;
Ishihara, K.; Yamamoto, H. Adv. Synth., Catal. 2004, 346, 1275.
10.1021/jo051337s CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/20/2005
J. Org. Chem. 2005, 70, 8625-8627
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