Hexamethylenetetramine-mediated transesterification of β-keto esters

Article abstract of DOI:10.1055/s-2006-950357

Treatment of methyl or ethyl β-keto esters with primary, secondary, or tertiary alcohols in the presence of a catalytic amount of hexamethylenetetramine results in good to high yields of the corresponding esters. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950357

PAPER
61
Hexamethylenetetramine-Mediated Transesterification of b-Keto Esters
S. Ribeiro,a Rodrigo O. M. A. de Souza,a Mário L. A. A. Vasconcellos,b Bianca L. Oliveira,a
H
examethylenete
o
tramine-Me
d
d
iated
T
ranse
r
sterifica
i
tion of
g
b-Keto Ester
o
s
Leonardo C. Ferreira,a Lúcia C. S. Aguiar*a
a
Núcleo de Pesquisa de Produtos Naturais, Universidade Federal do Rio de Janeiro, CCS, Laboratório H1-29, Rio de Janeiro, 21941-590,
Brasil
Fax +55(21)25626512; E-mail: lcsequeira@nppn.ufrj.br
b
Departamento de Química, Universidade Federal da Paraíba, Campus I, João Pessoa, PB, 58059-900, Brasil
Received 21 August 2006; revised 15 September 2006
methylenetetramine is soluble in water, chloroform, eth-
anol, and some other organic solvents,14 and is employed
in medicine under the name urotropine as a urinary anti-
septic.13 This versatile synthetic reagent has been used in
the preparation of primary amines and N-heterocycles14
and as an efficient catalyst precursor for the microwave-
assisted Knoevenagel reaction.15 Recently, we have dem-
onstrated that hexamethylenetetramine can be used as a
convenient catalyst in the Baylis–Hillman reaction.16
Abstract: Treatment of methyl or ethyl b-keto esters with primary,
secondary, or tertiary alcohols in the presence of a catalytic amount
of hexamethylenetetramine results in good to high yields of the cor-
responding esters.
Key words: transesterification, hexamethylenetetramine, b-keto
esters
The transesterification of b-keto esters has been recog-
nized as one of the most important processes in producing
other b-keto esters, having wide application in academic
and industrial research.1–4 Many useful methods for trans-
esterification of b-keto esters have been reported in the lit-
erature.3–12 Some of the recently developed methods
involve the use of N,N-diethylaminopropylated silica gel
(NDEAP),3 natural clays,4 zinc dust,5 N-bromosuccin-
imide,6 zeolites,7 iodine,8 1,8-diazabicyclo[5.4.0]undec-7-
ene,9 4-(N,N-dimethylamino)pyridine,10 tetrabutyl distan-
noxanes,11 and Amberlyst-15.12 These protocols are nor-
mally efficient; however, most of these methods suffer
from one or more of the following disadvantages: long re-
action times, and the use of toxic and expensive reagents,
and in relatively large amounts. From the environmental
as well as economical points of view, new efficient meth-
ods for transesterification are potentially very useful.
As a model reaction, the transesterification of methyl
acetoacetate (1a) with (–)-menthol (2a) was studied
(Table 1, entries 1–4: methods A, B, or C). The reaction
between 1a (3 mmol) and (–)-menthol (2a; 1 mmol) in the
presence of catalytic amounts of hexamethylenetetramine
(0.3 mmol) in toluene solution at reflux (24 h) gave men-
thyl acetoacetate (3a) in 73% yield (method A, entry 1).
When the transesterification was carried out in refluxing
toluene with a Dean–Stark trap, the yield could be im-
proved to 86% (method B, entry 2), and azeotropic trans-
esterification in cyclohexane10b instead of toluene gave a
yield of 93% (method C, entry 3). Under the same condi-
tions, but in the absence of hexamethylenetetramine, the
yield of this reaction decreased to 53% (entry 4).
This procedure is quite general, as a wide range of struc-
turally varied b-keto esters such as open-chain, cyclic, and
aromatic esters underwent transesterification with various
alcohols (Table 1). The reaction with tert-butyl alcohol,
which is often problematic with other protocols, is also re-
alized with this reagent, but in moderate yields (49–60%;
toluene/Dean–Stark) (Table 1, entries 10, 14). In this case,
an excess of tert-butyl alcohol is necessary to compensate
for its volatility (method D). We have also investigated
the preparation of tert-butyl acetoacetate (3e) under the
same reaction conditions described above (method D), but
without the catalyst17 (entry 15). Although the reaction
can be accomplished without hexamethylenetetramine,
only a low yield of 3e (10%) was obtained. Transesterifi-
cation between an a-substituted acetoacetate 1d and tert-
butyl alcohol also led to a low yield of product (entry 16);
this can be attributed to the bulkiness of the substrate and
hexamethylenetetramine. However, no efforts were made
to optimize the yield of product 3g. The transesterification
of a,a-disubstituted b-keto ester 1e (entries 17, 18) result-
ed in complete recovery of the substrate; this suggests that
this reaction proceeds via a ketene intermediate.3
We wish to report that hexamethylenetetramine (HMT)
acts as an efficient catalyst to effect transesterification of
b-keto esters (Scheme 1).
N
N
N
N
O
O
O
O
HMT
R1OH
+
+
OR1
solvent
R2OH
OR2
1a–f
2a–f
3a–h
Scheme 1
Hexamethylenetetramine is a very inexpensive, nonhy-
groscopic, and stable reagent of low toxicity.13,14 It can be
prepared easily, by allowing a mixture of formalin and
concentrated ammonia solution to evaporate.13 Hexa-
SYNTHESIS 2007, No. 1, pp 0061–0064
x
x
.
x
x
.2
0
0
6
Advanced online publication: 06.11.2006
DOI: 10.1055/s-2006-950357; Art ID: M05306SS
© Georg Thieme Verlag Stuttgart · New York

62
R. S. Ribeiro et al.
PAPER
Table 1 HMT-Mediated Transesterification of b-Keto Esters
Entry
1
Ester 1
Alcohol 2
Product 3a
Methodb
Yieldc (%)
O
O
O
O
O
O
O
O
A
73
86
93
53
O
HO
O
O
O
1a
2a
3a
3a
3a
O
O
O
O
2
3
4
B
O
O
O
HO
1a
2a
O
C
HO
1a
2a
O
O
O
Cd
O
HO
1a
2a
3a
3b
3b
OH
O
O
O
O
O
5
6
A
C
70
85
O
O
O
1a
2b
2b
2c
OH
O
O
O
O
O
O
O
1a
O
O
OH
7
8
A
C
78
84
14
O
14
1a
3c
3c
O
O
O
O
OH
O
14
O
14
2c
1a
O
O
O
O
O
O
OH
O
9
C
D
92
60
O
1a
2d
2e
3d
3e
OH
O
O
O
10
O
O
1a
1b
O
O
O
Ce
67
O
11
HO
O
2a
3f
Synthesis 2007, No. 1, 61–64 © Thieme Stuttgart · New York

PAPER
Hexamethylenetetramine-Mediated Transesterification of b-Keto Esters
63
Table 1 HMT-Mediated Transesterification of b-Keto Esters (continued)
Entry
12
Ester 1
Alcohol 2
Product 3a
Methodb
Yieldc (%)
O
O
O
O
B
75
HO
O
O
1c
2a
3a
O
O
O
O
13
C
89
O
HO
O
1c
2a
3a
3e
OH
O
O
O
O
14
15
D
49
10
O
O
1c
2e
OH
O
O
O
O
O
O
O
Dd
O
O
O
O
1c
3e
2e
O
OH
16
17
D
D
8
–
2e
1d
3g
O
O
OH
no reaction
no reaction
O
2e
1e
O
O
18
C
–
O
HO
1e
2a
O
O
O
O
19
20
Ce
B
63
–
OH
OH
O
O
2f
1f
3h
O
O
no reaction
O
O
2f
1g
1g
OH
21
22
no reaction
no reaction
B
B
–
–
2g
Trimyristin
1h
MeOH
2h
a Products were characterized by spectral analysis.
b Reagents and conditions: Method A: ester 1 (3 equiv), alcohol 2 (1 equiv), HMT (0.3 equiv), toluene, reflux; Method B: ester 1 (3 equiv),
alcohol 2 (1 equiv), HMT (0.3 equiv), toluene, reflux, Dean–Stark trap; Method C: ester 1 (3 equiv), alcohol 2 (1 equiv), HMT (0.3 equiv),
cyclohexane, reflux, Dean–Stark trap; Method D: ester 1 (3 equiv), alcohol 2 (excess), HMT (0.3 equiv), toluene, reflux, Dean–Stark trap.
c Yield of analytically pure sample.
d Without catalysis (absence of HMT).
e Ester 1 (1 equiv), alcohol 2 (1.2 equiv).
Synthesis 2007, No. 1, 61–64 © Thieme Stuttgart · New York

64
R. S. Ribeiro et al.
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The yields of products 3f7a and 3h5 (entries 11, 19), ob-
tained from transesterification of b-keto esters 1b and 1f
(1 equiv) with the respective alcohols 2a and 2f (1.2
equiv) were moderate. This may be attributed to the bulk-
iness of the substrates.
References
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failed to undergo the reaction.
In conclusion, we have demonstrated that hexamethylene-
tetramine is an efficient and inexpensive catalyst to effect
transesterification of methyl or ethyl b-keto esters (unsub-
stituted and monosubstituted substrates).
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(–)-Menthyl 3-Oxobutanoate (3a);8 Typical Procedure (Method
C)
A mixture of methyl acetoacetate (1a; 696 mg, 6 mmol), (–)-men-
thol (2a; 312 mg, 2 mmol), and HMT (84 mg, 0.6 mmol) in cyclo-
hexane (13 mL) was heated for 24 h in a flask connected to a Dean–
Stark trap. The mixture was filtered and the filtrate was washed with
5% aq HCl soln (2 × 8 mL) and dried (Na2SO4). Evaporation of the
organic phase was followed by purification by flash chromatogra-
phy (silica gel, 230–400 mesh, 13 × 1.8 cm, EtOAc–hexane, 1:9).
Yield: 446 mg (93%); oil; [a]D20 –69.00 (c 12, benzene).8
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Synthesis 2007, No. 1, 61–64 © Thieme Stuttgart · New York