Ligand-assisted rate acceleration in lanthanum

Article abstract of DOI:10.1021/ol102753n

The transesterification of an equimolar mixture of carboxylic esters and primary (1°), secondary (2°), and tertiary (3°) alcohols in hydrocarbon solvents was promoted with high efficiency by a lanthanum(III) complex, which was prepared in situ from lanthanum (III) isopropoxide (1 mol %) and 2-(2-methoxyethoxy)ethanol (2 mol %). The present La(III) catalyst was highly effective for the chemoselective transesterification in the presence of competitive 1°-and 2°-amines. Remarkably, esters were obtained in good to excellent yields as colorless materials without an inconvenient workup procedure.

Full text of DOI:10.1021/ol102753n

ORGANIC
LETTERS
2011
Vol. 13, No. 3
426-429
Ligand-Assisted Rate Acceleration in
Lanthanum(III) Isopropoxide Catalyzed
Transesterification of Carboxylic Esters
Manabu Hatano,† Yoshiro Furuya,† Takumi Shimmura,† Katsuhiko Moriyama,†
Sho Kamiya,† Toshikatsu Maki,† and Kazuaki Ishihara*,†,‡
Graduate School of Engineering, Nagoya UniVersity, Furo-cho, Chikusa,
Nagoya, 464-8603, Japan, and Japan Science and Technology Agency (JST), CREST,
Furo-cho, Chikusa, Nagoya, 464-8603, Japan
ishihara@cc.nagoya-u.ac.jp
Received November 13, 2010
ABSTRACT
The transesterification of an equimolar mixture of carboxylic esters and primary (1°), secondary (2°), and tertiary (3°) alcohols in hydrocarbon solvents
was promoted with high efficiency by a lanthanum(III) complex, which was prepared in situ from lanthanum(III) isopropoxide (1 mol %) and 2-(2-
methoxyethoxy)ethanol (2 mol %). The present La(III) catalyst was highly effective for the chemoselective transesterification in the presence of competitive
1°- and 2°-amines. Remarkably, esters were obtained in good to excellent yields as colorless materials without an inconvenient workup procedure.
Catalytic transesterification of carboxylic esters with alcohols
and dehydrative condensation of carboxylic acids with
alcohols have wide applications in academic as well as
industrial research (eqs 1 and 2).1-3 In particular, transes-
terification is valuable due to good substrate solubility
† Nagoya University.
‡ CREST.
in common organic solvents, while carboxylic acids in
dehydrative condensation often have low solubility and
sometimes large excess amounts of either carboxylic acids
(1) For reviews of (trans)esterifications, see: (a) Otera, J. Esterification;
Wiley-VCH Verlag GmbH: Weinheim, Germany, 2003. (b) Otera, J. Acc.
Chem. Res. 2004, 37, 288. (c) Nahmany, M.; Melman, A. Org. Biomol.
or alcohols that are used for smooth conversion. To date,
several procedures for transesterification catalyzed by a
variety of protic and Lewis acids, organic and inorganic
bases, enzymes, and antibodies have been developed.1
However, an extemely practical catalytic transesterification
of rather reactive carboxylic esters with alcohols has not yet
Chem. 2004, 2, 1563. (d) Grasa, G. A.; Singh, R.; Nolan, S. P. Synthesis
2004, 971. (e) Hoydonckx, H. E.; De Vos, D. E.; Chavan, S. A.; Jacobs,
P. A. Top. Catal. 2004, 27, 83. (f) Enders, D.; Niemeier, O.; Henseler, A.
Chem. ReV. 2007, 107, 5606. (g) Ishihara, K. Tetrahedron 2009, 65, 1085
.
(2) For recent contributions to catalytic transesterifications, see these
selected examples: (a) Bose, D. S.; Satyender, A.; Rudra Das, A. P.;
Mereyala, H. B. Synthesis 2006, 2392. (b) Remme, N.; Koschek, K.;
Schneider, C. Synlett 2007, 491. (c) Kondaiah, G. C. M.; Reddy, L. A.;
Babu, K. S.; Gurav, V. M.; Huge, K. G.; Bandichhor, R.; Reddy, P. P.;
Bhattacharya, A.; Anand, R. V. Tetrahedron Lett. 2008, 49, 106. (d)
Ohshima, T.; Iwasaki, T.; Maegawa, Y.; Yoshiyama, A.; Mashima, K. J. Am.
Chem. Soc. 2008, 130, 2944. (e) Ishihara, K.; Niwa, M.; Kosugi, Y. Org.
Lett. 2008, 10, 2187. (f) Iwasaki, T.; Maegawa, Y.; Hayashi, Y.; Ohshima,
T.; Mashima, K. J. Org. Chem. 2008, 73, 5147. (g) Iwasaki, T.; Maegawa,
(3) Catalytic transesterifications with 2°- and 3°-alcohols have been
limited. (a) Singh, R.; Kissling, R. M.; Letellier, M.-A.; Nolan, S. P. J.
Org. Chem. 2004, 69, 209. (b) Tanaka, K.; Osaka, T.; Noguchi, K.; Hirano,
`
M. Org. Lett. 2007, 9, 1307. (c) Pericas, A.; Shafir, A.; Vallribera, A.
Tetrahedron 2008, 64, 9258. Catalytic tert-butyl ester-interchange reaction:
(d) Stanton, M. G.; Gagne´, M. R. J. Org. Chem. 1997, 62, 8240.
Y.; Hayashi, Y.; Ohshima, T.; Mashima, K. Synlett 2009, 1659
.
10.1021/ol102753n  2011 American Chemical Society
Published on Web 12/22/2010

been well established, because of the inherently low reactivity
of secondary (2°) and tertiary (3°) alcohols rather than
primary (1°) alcohols.3,4 Therefore, a more efficient trans-
esterification procedure with general applicability to 1°-, 2°-,
and even 3°-alcohols involving simple preparations and a
nontoxic catalyst is still desired. In 1995, Okano and co-
workers reported that the transesterification of carboxylic
esters (0.1 mmol scale) was efficiently catalyzed by La(Oi-
Pr)3 (2 mol %) under heating conditions in excess molar
amounts of 1°- and 2°-alcohols (5 mL).5 According to this
pioneering work, the catalytic activity of lanthanoid(III)
decreased in the order La(III) > Nd(III) > Gd(III) > Yb(III)
and was much higher than those of Al(III) and Ti(IV). After
this publication, the La(OMe)(OTf)2-catalyzed methanolysis
of aryl and alkyl esters was reported by Brown and
co-workers.6 They proposed that a methoxy-bridged La(III)
dimer might efficiently catalyze methanolysis through the
corresponding transition-state assembly based on Lewis
acid-Lewis base dual activation7 (Figure 1). Methanol as a
ligands in n-hexane (bp 69 °C) under azeotropic reflux
conditions for 3 h with the removal of methanol using MS
5 Å in a Soxhlet thimble (Table 1).
Table 1. Screening of Catalystsa
entry
ligand (mol %)
yield (%)
1b
2c
3
-
0
33
38
45
-
O(CH2CH2OH)2 4 (1)
4 (2)
4
5
6
7
HO(CH2CH2O)2Me 5 (1)
5 (2)
5 (3)
65
74 [93]d
70
8
O(CH2CH2OMe)2 6 (1)
35
a See the Supporting Information for detailed procedures. Catalysts were
prepared in advance at room temperature for 1 h. b Without La(Oi-Pr)3 and
a ligand. c Without a ligand. d The reaction was conducted as soon as La(Oi-
Pr)3 and a ligand were mixed.
Figure 1. Transition state of the methanolysis of carboxylic esters
At the beginning of the preliminary screening, catalysts
were prepared in advance at room temperature for 1 h. With
regard to the pioneering Okano’s report,5 the transesterifi-
cation catalyzed by La(Oi-Pr)3 proceeded with only a 33%
yield of 5-nonyl benzoate (3a) due to the low reactivity of
a 2°-alcohol and instability of La(Oi-Pr)3 (entry 2), while
the reaction did not occur in the absence of catalyst (entry
1). As a ligand for La(Oi-Pr)3, we found that monomethyl
ether of diethylene glycol (5) (entry 5) was effective (65%
yield), and diethylene glycol (4) (entry 4) and its dimethyl
ether (6) (entry 8) were much less active than 5. The addition
of 2-3 mol % of 5 had a slightly better influence on the
catalytic activity (entries 6 and 7). In order to prevent the
deterioration of the labile catalyst, when the reaction mixture
was heated as soon as La(Oi-Pr)3 (1 mol %) and 5 (2 mol
%) were mixed, compound 3a was ultimately obtained in
93% yield (entry 6, bracket).
catalyzed by La(III) dimeric complex proposed by Brown et al.6
solvent greatly stabilizes and solubilizes the active La(III)
dimer without the need to create specially designed ligands
to stabilize the dinuclear core.6 In general, since the driving
force of metal-ion-catalyzed transesterifications should be
controlled by a balance between the Lewis acidity of metal ions
and the nucleophilicity of the alkoxy moiety on metal ions, we
expected that some suitable ligands might more efficiently
accelerate La(III)-catalyzed8 transesterification. In this context,
we report here that a simply tuned La(III) salt, which is prepared
in situ from lanthanum(III) isopropoxide (1 mol %) and 2-(2-
methoxyethoxy)ethanol (2 mol %), is a highly active catalyst
and promotes the transesterification of carboxylic esters (1
equiv) with 1°-, 2°-, and 3°-alcohols (1 equiv) under reflux
conditions in hydrocarbons such as n-hexane with the removal
of methanol.
To explore the scope of the transesterification reaction,
various carboxylic esters 1 with 1°-, 2°-, and 3°-alcohols 2 were
examined in the presence of La(Oi-Pr)3 (1 mol %) and 5 (2
mol %) (Figure 2). Particularly, the development of an efficient
catalytic methodology for the synthesis of 3°-alcohol-derived
carboxylic esters is important since they are valuable photore-
sistant materials.9 As a result, not only 1°- and 2°- but also
less-reactive 3°-alcohols (see 3n, 3o, 3r, and 3s) were efficiently
transformed with aromatic and aliphatic esters to the desired
esters 3 in a colorless state. Broad compatibility was observed
First, the probe transesterification of an equimolar mixture
of methyl benzoate (1a) and 5-nonanol (2a) was conducted
in the presence of La(Oi-Pr)3 (1 mol %) with chelatable
(4) Stoichiometric transesterification with 3°-alcohols: (a) Rossi, R. A.;
Rossi, R. H. J. Org. Chem. 1974, 39, 855. (b) Meth-Cohn, O. J. Chem.
Soc., Chem. Commun. 1986, 695. (c) Zhao, H.; Pendri, A.; Greenwald, R. B.
J. Org. Chem. 1998, 63, 7559. (d) Vasin, V. A.; Razin, V. V. Synlett 2001,
658
.
(5) Okano, T.; Miyamoto, K.; Kiji, J. Chem. Lett. 1995, 246.
(6) (a) Neverov, A. A.; Brown, R. S. Can. J. Chem. 2000, 78, 1247. (b)
Neverov, A. A.; McDonald, T.; Gibson, G.; Brown, R. S. Can. J. Chem.
2001, 79, 1704.
(7) For acid-base combined catalysis, see: (a) Kanai, M.; Kato, N.;
Ichikawa, E.; Shibasaki, M. Synlett 2005, 1491. (b) Ishihara, K.; Sakakura,
A.; Hatano, M. Synlett 2007, 686.
(9) (a) Nozaki, K.; Watanabe, K.; Yano, E.; Kotachi, A.; Takechi, S.;
Hanyu, I. J. Photopolym. Sci. Technol. 1996, 9, 509. (b) Tsuchiya, Y.;
Hattori, T.; Yamanaka, R.; Shiraishi, H. J. Photopolym. Sci. Technol. 1997,
10, 579. (c) Pasini, D.; Low, E.; Fre´chet, J. M. J. AdV. Mater. 2000, 12,
347. (d) Kavitha, A. A.; Singha, N. K. J. Polym. Sci., Part A: Polym. Chem.
2008, 46, 7101.
(8) For a recent review of lanthanide catalyses, see: Shibasaki, M.;
Matsunaga, S.; Kumagai, N. In Acid Catalysis in Modern Organic Synthesis;
Yamamoto, H., Ishihara, K., Eds.; Wiley-VCH Verlag GmbH: Weinheim,
Germany, 2008; Vol. 2, Chapter 13.
Org. Lett., Vol. 13, No. 3, 2011
427

the corresponding product (3k) was obtained in good yield.
Sterically hindered methyl pivalate transformed to the corre-
sponding 2°-ester (3l) smoothly. The transesterification of
methyl methacrylate and methyl propiolate as R,ꢀ-unsaturated
esters proceeded chemoselectively without decomposition (see
3m and 3o). Although ethyl esters were generally less reactive
than methyl esters, ethyl benzoate was also acceptable for the
synthesis of 3a. Thermal transesterification with ethyl acetate
is often difficult because of its low boiling point (77 °C). In
contrast, with La(Oi-Pr)3 and 5, the acetylation of less reactive
2°- and 3°-alcohols with ethyl acetate proceeded in high yields
under reflux conditions in n-hexane (bp 69 °C) or ethyl acetate
(see 3p-s). Esters produced by conventional catalysts, particu-
larly metal salt catalysts such as Ti(Oi-Pr)4, are often colored,
and this is an industrially serious problem. In contrast, the
catalytic transesterification with La(Oi-Pr)3 and 5 gives colorless
esters. La(III) catalysts can be easily removed by filtration after
a drop of water is added to the reaction mixture, and flash
chromatography is effective to obtain the pure products from
the condensed colorless residue of the organic filtrate obtained.
Moreover, as a great advantage in industrial application, the
toxicity of La(III)10 is much lower than that of other metal ion
catalysts such as Hf(IV), Zr(IV), Zn(II), Sn(IV), and Sb(III)
which are well-known as esterification catalysts.1,2,11
Recently, Ohshima and Mashima et al. demonstrated the
enzyme-like selective transesterification of alcohols in the
presence of amines catalyzed by a tetranuclear zinc cluster
[1.25 mol % of Zn4(OCOCF3)6O ) 5 mol % of Zn(II),
reaction time 18-24 h].2d,f,g Comparatively, we investigated
the chemoselectivity of the reactions by using La(Oi-Pr)3
and 5 (Table 2). Fortunately, the highly selective transes-
Table 2. Chemoselective Transesterification
yield (%)
entry
R1
R2OH
BnOH
R3R4NH
BnNH2
t (h)
3
7
1
2
3
4
5
6a
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
2
3
1
3
3
6
1
1
3b, 76
3t, 91
3u, 89
3v, 90
3w, 87
3x, 86
3x, 86
3y, 90
1
<1
2
<1
<1
1
HO(CH2)5NH2
HO(CH2)6NH2
HO(CH2)10NH2
HO(CH2)12NH2
Figure 2. Transesterification of carboxylic esters. Conditions: (a)
c(C6H11)OH
c(C6H11)OH
c(C6H11)OH
BnNH2
piperidine
piperidine
Unless otherwise noted, methyl esters were used as starting material.
(b) Ethyl esters were used as starting material. (c) Powdered MS 5
Å was used in the reaction mixture, and the temperature was 50
°C. (d) La(Oi-Pr)3 (3 mol %) and 5 (6 mol %) were used.
1
<1
a n-Heptane was used as a solvent in place of n-hexane.
when either functionalized alcohols or esters were used. It was
noticed that optically active methyl (S)-mandelate and N-Boc-
L-Phe-OMe were transformed to the corresponding benzyl esters
(3i and 3j) without epimerization at 50 °C in the presence of
powdered MS 5 Å in the reaction mixture. Phenol was
inherently not so reactive due to its weak nucleophilicity, but
terification but not the possible amidation proceeded even
in the presence of primary and secondary amines such as
benzylamine and pyperidine (entries 1, 6-8). R,ω-Aminoal-
cohols were also suitable as substrates (entries 2-5).
(10) Lethal intake of La(Oi-Pr)3: LD50 (oral, rat) ) >10 000 mg/kg.
Org. Lett., Vol. 13, No. 3, 2011
428

Noteworthy, the selective O-acylation completed within 6 h
in the presence of 1 mol % of La(Oi-Pr)3 with 5.
of an equimolar mixture of carboxylic esters and 1°-, 2°-,
and 3°-alcohols in hydrocarbon solvents under azeotropic
reflux conditions.13 The highly active La(III) catalyst can
be easily prepared in situ from commercially available La(Oi-
Pr)3 and 5. This La(III) catalyst was also effective for the
chemoselective transesterification of carboxylic esters with
alcohols in the presence of competitive 1°- and 2°-amines.
As a great advantage in industrial application, the toxicity
of La(III) is much lower than that other metal ion catalysts
such as Hf(IV), Zr(IV), Zn(II), Sn(IV), and Sb(III) which
are well-known as conventional esterification catalysts, and
moreover, colorless esters were obtained without an incon-
venient workup procedure.
Finally, during the investigation of the tolerance of La(Oi-
Pr)3 with 5, the generation of a dinuclear La(III) complex,
[{La{O(CH2CH2O)2Me}(Oi-Pr)}2O·EtOAc] (8), was found
in the mixture of La(Oi-Pr)3 (1 equiv) and 5 (2 equiv) in
ethyl acetate by ESI-MS analysis (m/z ) 739 for [M +
H]+).12 Taking advantage of Brown’s dinuclear La(III)
complex,6 we can propose that a dinuclear La(III)-O-La(III)
salt might efficiently catalyze the transesterification through
TS-9, which should be regarded as a working model, based
on Lewis acid-Lewis base dual activation7 (Figure 3).
Acknowledgment. Financial support for this project was
partially provided by JSPS, KAKENHI (20245022), MEXT,
KAKENHI (21750094, 21200033), NEDO, the Toray Sci-
ence Foundation, and the Global COE Program of MEXT.
Supporting Information Available: Experimental pro-
cedures and spectral data, as well as copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 3. Possible dinuclear La(III) complex 8 and transition-state
assembly (TS) 9.
OL102753N
(13) General procedure for the transesterification: A mixture of La(Oi-
Pr)3 (12.6 mg, 0.04 mmol) and monomethyl ether of diethylene glycol (5)
(9.4 mL, 0.08 mmol) in anhydrous n-hexane (8 mL) was stirred at room
temperature for 1-2 min. As soon as carboxylic ester (1) (4.0 mmol) and
alcohol (2) (4.0 mmol) were added to the solution, the mixture was heated
under azeotropic reflux conditions with the removal of methanol. Methanol
was removed through a pressure-equalized addition funnel containing a
cotton plug and 6.5 g of 5 Å molecular sieves (pellets) and functioning as
a Soxhlet extractor. After heating for 1-24 h at reflux temperature, the
reaction mixture was allowed to cool to ambient temperature. To quench
the catalysts, a drop of water was added, and the mixture was stirred for 5
min. The mixture was dried over MgSO4, the organic phase was concentrated
in vacuo, and the crude product was purified by column chromatography
on silica gel with n-hexane-ethyl acetate as eluents.
In summary, we have developed a facile, rapid, atom-
economical, and chemoselective transesterification reaction
(11) Zr(IV) and Hf(IV): (a) Ishihara, K.; Ohara, S.; Yamamoto, H.
Science 2000, 290, 1140. (b) Ishihara, K.; Nakayama, M.; Ohara, S.;
Yamamoto, H. Tetrahedron 2002, 58, 8179. Ti(IV): (c) Seebach, D.;
Hungerbu¨hler, E.; Naef, R.; Schnurrenberger, P.; Weidmann, B.; Zu¨ger,
M. Synthesis 1982, 138. (d) Krasik, P. Tetrahedron Lett. 1998, 39, 4223.
Sn(IV): (e) Otera, J.; Danoh, N.; Nozaki, H. J. Org. Chem. 1991, 56, 5307.
Sb(III): Chen, J.-W.; Chen, L.-W. J. Polym. Sci., Part A 1999, 37, 1797.
(12) See the Supporting Information for details.
Org. Lett., Vol. 13, No. 3, 2011
429