Monoalcoholates of 1,3-diols as effective catalysts in the Tishchenko esterification of 1,3-dioxan-4-ols

Article abstract of DOI:10.1016/S0040-4039(01)00277-5

Alkali metal monoalcoholates of 1,3-diols can be used as very effective catalysts in the Tishchenko reaction of 4-hydroxy-1,3-dioxanes to the corresponding monoesters of 1,3-diols. These catalysts are extremely efficient and fast compared to metal hydroxides commonly used. Thus, monoalcoholate catalysts give fast transesterification with the product ester. The loss in yield due to ester interchange can be minimized by using a suitable 1,3-diol moiety in the catalyst.

Full text of DOI:10.1016/S0040-4039(01)00277-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2743–2746
Monoalcoholates of 1,3-diols as effective catalysts in the
Tishchenko esterification of 1,3-dioxan-4-ols
Olli P. To¨rma¨kangas and Ari M. P. Koskinen*
Laboratory of Organic Chemistry, Helsinki University of Technology, PO Box 6100, FIN-02015 HUT, Finland
Received 8 February 2001; revised 9 February 2001; accepted 19 February 2001
Abstract—Alkali metal monoalcoholates of 1,3-diols can be used as very effective catalysts in the Tishchenko reaction of
4-hydroxy-1,3-dioxanes to the corresponding monoesters of 1,3-diols. These catalysts are extremely efficient and fast compared to
metal hydroxides commonly used. Thus, monoalcoholate catalysts give fast transesterification with the product ester. The loss in
yield due to ester interchange can be minimized by using a suitable 1,3-diol moiety in the catalyst. © 2001 Published by Elsevier
Science Ltd.
In the normal Tishchenko reaction two aldehydes are
converted to a monofunctional simple ester in the pres-
ence of a Lewis acid catalyst,1 most commonly with
aluminium alcoholates.2 The reaction has been carried
out with a number of other catalysts such as ruthenium
complexes,3 alkali earth metal oxides,4 boric acid,5
sodium alkoxides6 (with aryl aldehydes), alkali metals,7
zirconocenes,8 and lanthanide (amide) complexes.9 The
mechanism of the Tishchenko reaction involves a
hydride shift.2 Very recently a bidentate bisaluminum
alcoholate has been reported to give an especially fast
Tishchenko reaction with excellent yield.10 One special
case of the Tishchenko reaction is the esterification of
1,3-dioxan-4-ols where an intramolecular hydride shift
is activated in the presence of a base catalyst. These
dioxanols are usually dimers of b-hydroxyaldehydes
(aldol product) or similar hemiacetals formed between
b-hydroxyaldehydes and another aldehyde.11 Merger et
al. have reported the first mechanistic features of the
esterification of such compounds (Scheme 1).12 Esterifi-
cation of 1,3-dioxan-4-ols is usually carried out with
basic catalysts such as alkali metal hydroxides instead
of the aluminium alcoholates used in the traditional
Tishchenko reaction.12
O
H+
O
O
cat.
H
O
HO
O
OH
HO
O
OH
HO
OM
1
2
3
Scheme 1.
O
O
4
O
O
R
H
R
O
R
O
O
H
O
O
O
Li
H
OH
Li
H
Li
4
6
7
5
Scheme 2.
* Corresponding author. Tel.: +358 9 451 2526; fax: +358 9 451 2538; e-mail: ari.koskinen@hut.fi
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00277-5

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O. P. To¨rma¨kangas, A. M. P. Koskinen / Tetrahedron Letters 42 (2001) 2743–2746
We have recently investigated the preparation and
Tishchenko esterification of 4-hydroxy-1,3-dioxanols.
Based on the literature and partly on our own previous
work, the catalysts used in this case are usually metal
hydroxides or alcoholates of monofunctional alco-
hols.12,13 Metal hydroxides cause rapid and irreversible
hydrolysis of product esters when used in catalytic
amounts. Similarities in the mechanisms of hydrolysis
and transesterification prompted us to use monoalcohol-
ates of 1,3-diols as catalysts.
water. Dioxanols related to HPA 1 are hemiacetal like
dimers of b-hydroxyaldehydes, which can be monomer-
ized in the presence of water and with slight heating.
Thus, the monomerization of 1,3-dioxan-4-ols, due to
the presence of water, can partly interfere with their
Tishchenko esterification to monoesters.
Al(OiPr)3 was found to be inactive as a catalyst. It is
possible that catalytic aluminium coordinates to the
primary hydroxyl group located at the end of the side
chain of 1 instead of forming the transition state related
to 6. Lanthanide oxides (e.g. Nd2O3) also gave negative
results. The reaction proceeds only in the presence of
basic catalysts indicating that deprotonation is an ini-
tial step of the reaction.
We report herein, for the first time to our knowledge,
the use of monoalkalimetal alcoholates of 1,3-diols as
very efficient and simple catalysts in the Tishchenko
esterification of 1,3-dioxan-4-ols. To our surprise, the
reaction was several times faster than with the metal
hydroxides traditionally used. With these new 1,3-diol
based catalysts such as 4 (Scheme 2), the hydrolysis of
the product esters can be completely avoided but they
seemed to give rapid transesterification between the
product and the alcoholate catalyst. This limits the use
of different diols, being case dependent (relative to
structure of the used b-hydroxyaldehyde). The use of
the catalyst was also found to be possible on larger
scales.
In order to avoid hydrolysis we reasoned that use of a
monoalcoholate of the diol as the catalyst might solve
the problem. Additionally, the product from transester-
ification is the same if the 1,3-diol in the catalyst is the
same as in the monoester product after Tishchenko
esterification. Meth-Cohn has reported that lithium
alcoholates give quite fast transesterification with an
ester when THF was used as the solvent.15 To our
surprise such catalysts gave reactions (1“3) several
times faster than the metal hydroxides we had tested
previously. The first diol based catalyst we studied was
monolithium-2,2-dimethyl-1,3-propandiol 4 (later Li-
NPG; neopentyl glycol).16 With catalyst 4 (5 mol%) the
reaction was complete in 25 minutes even at 0°C and
monoester 3 was obtained in 92% isolated yield. The
reaction was quenched with a slight excess of 2 M HCl
in order to avoid the presence of LiOH and hydrolysis
of the product. The efficiency of catalyst 4 is most likely
due to its good solubility in organic solvents which
provides totally homogenous reaction conditions. In
contrast, with metal hydroxides these reactions are
usually two phase systems (especially with higher alde-
hydes) or a totally heterogeneous slurry (Ca(OH)2).
Another reason for the efficiency of the catalyst might
be intramolecular hydrogen bonding in the catalyst 4,
which could lead to an increased cationic nature of the
metal and thus give easier and stronger coordination to
the substrate 1 (Scheme 2). The mechanism has been
discussed very briefly earlier (as presented here in
Scheme 1) by Merger et al.12 We believe that the
catalyst first deprotonates a hydroxyl group of the
dioxanol ring and then coordinates to the hydroxyl
group and the ring oxygen in position 2 of the dioxanol
5. The electron density will be shifted from both oxy-
gens and the carbon between them towards lithium (6
In our catalyst experiments the 5,5-dimethyl-2-(1%,1%-
dimethyl - 2% - hydroxyethyl) - 4 - hydroxy - 1,3 - dioxane 1
(later referred to as dimeric HPA) was used as a test
because of its good stability to storage and easy moni-
toring of the reactions. Compound 1 was prepared by
the aldol reaction of 37% formalin and 2-methyl-
propanal in the presence of Et3N catalyst with 86%
yield.14 The aldol product spontaneously dimerized and
precipitated to give dioxanol 1 as a mixture of
diastereomers with a ratio of 40:60 when cooled to
room temperature. An apolar solvent (i-octane) was
used to facilitate the dimerization. Initially, different
metal hydroxides were used as catalysts in order to
study the effects of the metal on the rate of esterifica-
tion to monoester 3 and hydrolysis. In all experiments 5
mol% of the catalyst was used.
Alkali metal hydroxides gave faster esterification than
alkali earth metal hydroxides, but rapid hydrolysis of 3
was observed in every case. Some results of these
experiments are collected in Table 1. Unfortunately,
metal hydroxides usually require the presence of water
that may require extra investment, e.g. in handling
waste water on an industrial scale. Another problem is
the stability of 1,3-dioxan-4-ols in the presence of
Table 1. Some catalyst tests in the Tishchenko esterification of 1,3-dioxan-4-ol 1 to monoester 3
Entry
Catalyst
Solvent
T (°C)
Reaction time
Yield (%)a
1
2
3
4
5
6
LiOH (4.5 M)
Ca(OH)2 (neat)
Ba(OH)2×8H2O
Al(OiPr)3
Nd2O3
Li-NPG (4)
MTBE
MTBE
MTBE
MTBE
MTBE
THF
+32
+32
+32
+32
+32
0
6 hours
Days
40 min
No reaction
No reaction
25 min
70
65
88
0
0
92
a Isolated yield.

O. P. To¨rma¨kangas, A. M. P. Koskinen / Tetrahedron Letters 42 (2001) 2743–2746
2745
Scheme 3.
Scheme 4.
10/11
(30 mol%)
OH
O
OH
OH
O
D
OH
trans-
+
+
1
3
D
O
O
esterification
OH OH
THF
R.T.
14
12
13
Scheme 5.
tion of diester 16 was observed. After a reaction time of
24 hours at room temperature (+25°C), 16 was the
main product. The similar acidity of the primary
hydroxyl groups in 3 and 13 allows lithium exchange
between the catalyst and product ester (Scheme 5) to
produce the alcoholate 15. The preferred formation of
16 is probably due to stabilizing intramolecular hydro-
gen bonding which makes the protons less acidic and
the diester more stable. The formation of 16 was also
observed when pure monoester 3 was treated with the
catalyst 4.
in Scheme 2). This coordination opens the dioxanol
ring and facilitates a hydride shift via a chair like
[6,6]-membered bicyclic transition state 7, in analogy to
a Tishchenko esterification between a b-hydroxyketone
and an aldehyde first reported by Evans et al.17
Transesterification between the catalyst and the product
ester was established using deuterium labelled mono-
lithio-2,2-dimethyl-1,3-propanediol catalysts 10 and 11
(Scheme 4). In order to prepare 9, dimeric HPA 1 was
monomerized by heating in THF at +65°C for 3 hours
under argon and the resulting monomer 7 was reduced
with LiAlD4 to 9 with 70% isolated yield (>99.5%
deuterated) (Scheme 3).18,19 Preparation of catalysts 10
and 11 was carried out with treatment of n-BuLi in
THF at 0°C. The concentration of the catalyst used was
usually 0.1 M in THF.
In conclusion, utilization of monoalcoholates of 1,3-
diols as catalysts allows Tishchenko esterification of
1,3-dioxan-4-ols to be carried out rapidly at low temper-
atures with good to excellent yields. Simultaneously, the
product ester is not lost via hydrolysis (as with metal
hydroxides) or ester interchange (as with alcoholates)
when the proper 1,3-diol is used as the catalyst.
In the Tishchenko esterification of dimeric HPA 1 with
30 mol% of catalysts 10 and 11 the reaction was
complete in less than 30 minutes at 0°C. GC–MS
analysis showed that there were esters 3 and 12/14 in
the ratio of 1:1 (Scheme 4). The reaction rate (1“3)
was the same with both isotopic catalysts 4 and 10. The
product ester 3 rapidly transesterifies with the catalyst
to form deuterated products 12 and 14, as shown by
NMR and MS.
Acknowledgements
Neste Chemicals, TEKES (National Technology
Agency, Finland) and Neste Research Foundation are
gratefully acknowledged for financial support. In addi-
tion Professor Tapio Hase, University of Helsinki, Fin-
land, is gratefully acknowledged for helpful initial
discussions and ideas in the beginning of this particular
work.
If the reaction time of 3 and 1 was extended or an
elevated reaction temperature was utilized, slow forma-

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O. P. To¨rma¨kangas, A. M. P. Koskinen / Tetrahedron Letters 42 (2001) 2743–2746
13. Duke, R. B.; Perry, M. A. Chem. Abstr. 1970, 72,
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