Sustainable transesterification of β-ketoesters catalyzed by amine grafted on silica gel

Article abstract of DOI:10.1055/s-2004-831309

Transesterification of β-ketoesters with various alcohols has been effected by N,N-diethylaminopropylated silica gel (NDEAP) as a catalyst in refluxing xylene. Generality of the reaction was demonstrated by successful transesterification of olefinic alcohols, tertiary alcohols and alcohols having acid- or base-sensitive substituents. The catalyst has been efficiently recycled more than five times without any re-activation.

Full text of DOI:10.1055/s-2004-831309

2188
LETTER
Sustainable Transesterification of b-Ketoesters Catalyzed by Amine Grafted
on Silica Gel
T
a
ransesterification
i
of
b
-K
s
etoesters ahiro Hagiwara,*a Aiko Koseki,b Kohei Isobe,a Ken-ichi Shimizu,b Takashi Hoshi,b Toshio Suzukib
Graduate School of Science and Technology, Niigata University, 8050, 2-Nocho, Ikarashi, Niigata 950-2181, Japan
b
Faculty of Engineering, Niigata University, 8050, 2-Nocho, Ikarashi, Niigata 950-2181, Japan
Fax +81(25)2627368; E-mail: hagiwara@gs.niigata-u.ac.jp
Received 7 June 2004
Silica gel is a better support due to its chemical and me-
chanical stability with wide surface area. By a post-modi-
fication procedure, the aminopropyl residue was grafted
on the surface of silica gel.6
Abstract: Transesterification of b-ketoesters with various alcohols
has been effected by N,N-diethylaminopropylated silica gel
(NDEAP) as a catalyst in refluxing xylene. Generality of the reac-
tion was demonstrated by successful transesterification of olefinic
alcohols, tertiary alcohols and alcohols having acid- or base-sensi-
tive substituents. The catalyst has been efficiently recycled more
than five times without any re-activation.
O
O
O
O
NDEAP-SiO2 (pellet)
Xylene, reflux
OR
Keywords: transesterification, b-ketoester, amine catalyst, silica
gel support
OR'
1
3
+
2
HOR'
OMe
O
O
DEAP-SiO2:
Si
A b-ketoester is a very useful substrate1 for a variety of
synthetic transformations such as alkylation, nucleophilic
condensation, diazotization and others. The synthetic im-
portance of b-ketoesters has prompted considerable ef-
forts for efficient preparation, since the reaction of
diketene with alcohol is not always welcomed due to its
low availability, corrosiveness and difficulty in handling.
Indeed, methyl- or ethyl acetoacetate (1) has been em-
ployed often as a surrogate of diketene. For the transester-
ification of fundamental b-ketoesters 1, a number of
methods have been reported employing homogeneous
catalysts such as tetrabutyl distannoxane, DBU, DMAP,
titanium tetraalkoxide, PTSA and so on.2,3 In the reaction
with the homogeneous catalyst, aqueous work-up is nec-
essary to remove the catalyst. From the environmental as
well as economical points of view, a heterogeneous cata-
lyst is much more desirable. Amberlyst-15, S-SnO2 or nat-
ural clay has been developed recently.2,3 However, a
milder method which is suitable to functionalized sub-
strates having acid- or base-sensitive substituents is yet to
be exploited either under homogeneous or heterogeneous
condition.
NEt2
Equation 1
Optimum reaction conditions were examined employing
methyl acetoacetate (1a) and menthol (2a). Reactions
were carried out with 0.2 equivalents of the heterogeneous
silica gel catalysts at refluxing temperature under nitrogen
atmosphere. The supernatant of the reaction was evaporat-
ed to dryness and subsequent column chromatography of
the residue provided the product 3. No aqueous work-up
is required. The results are shown in Table 1. Among the
catalysts and solvents investigated, N,N-diethylaminopro-
pylated silica gel (NDEAP) in refluxing xylene provided
the highest yield (entry 1, Table 1). Since the reactivity of
NDEAP powder or pellets was the same, the latter was
employed for the further reaction owing to easy work-up
and re-use. An ionic liquid, [bmim]PF6, which was ex-
pected as a recyclable solvent, was not effective due to
low recovery of the product 3 (entries 8 and 9, Table 1),
though substrates 1 and 2 were consumed completely. En-
tries 4 and 5 show that the amino residues on the silica gel
actually play a role of catalyst.
The generality of the optimum reaction conditions7 (entry
1, Table 1) of the present protocol is illustrated in Table 2.
It is worthy of note that the transesterification of the alco-
hol 2 having acid- or base-sensitive substituents provided
the desired b-ketoester 3 in high yields (entries 4–6,
Table 2), which exemplified the mild nature of the present
protocol. This reaction condition was applicable to the
substrate having an olefinic moiety (entry 2, Table 2),
which would be sensitive to halogenated reagents, metal
salts or oxidative reagents as catalysts.2,3 Not only methyl
acetoactate (1a) but also tert-butyl acetoacetate (1b) and
methyl 2-benzyl-3-ketobutyrate (1c, entry 9 and 10,
Table 2) exchanged the alkoxy groups successfully. The
As a part of our ongoing efforts on development of the
synthetic potential of the organic molecular catalyst sup-
ported on silica gel, we previously reported a sustainable
1,4-conjugate addition4 and a self-aldol condensation5 of
unmodified aldehydes catalyzed by N-methylaminopro-
pylated silica gel (NMAP). In this paper, we focused on
further effect of the catalytic activity of amine grafted on
silica gel, and disclose herein a mild and sustainable trans-
esterification of b-ketoesters 1 with various alcohols 2
(Equation 1).
SYNLETT 2004, No. 12, pp 2188–2190
0
1
.1
0
.2
0
0
4
Advanced online publication: 26.08.2004
DOI: 10.1055/s-2004-831309; Art ID: U16304ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Transesterification of b-Ketoesters
2189
Table 1 Effect of the Silica Gel-Supported Catalysts in Transester- tained in
ification of Methyl Acetoacetate (1a) with Menthol (2a)
a shorter period of time than the
transesterification of methyl acetoacetate (1a). In entry 3,
2-(4-hydroxyphenyl)ethylalcohol (2b) reacted at the pri-
mary alcohol terminal, which enabled a regioselective
transesterification.
Entrya
Catalyst
NDEAPb
NMAPc
PyrAPd
–
Solvent
Xylene
Xylene
Xylene
Xylene
Xylene
Toluene
Toluene
Time (h) Yield of 3a (%)g
1
2
3
4
5
6
7
8f
9f
7
99
85
76
45
47
93
65
20
18
6.5
9
Table 3 Transesterification of 2-Carbomethoxycyclopentanone
(1d) with Various Alcohols 2
Entry Alcohol 2
Time (h) Yield of 3 (%)a
8
1
2
3
4
5
6
7
8
2-Phenylethylalcohol
7
95
91
99
84
88
85
89
94
Silica gel
NMAP
NAPe
7
cis-3-Hexenol
3.5
3
21
24
2-(4-Hydroxyphenyl)ethylalcohol
6-Acetoxyhexanol
4
NDEAP
–
[bmim]PF6 21
[bmim]PF6
6-t-Butyldimethylsiloxypentanol
2
8
6-Tetrahydropyranyloxypentanol 1.5
a Reaction was carried out with 0.2 equiv of the catalyst at reflux tem-
perature under nitrogen atmosphere.
Cholesterol
Menthol
4.5
3.5
b N,N-3-Diethylaminopropylated silica gel.
c N-3-Methylaminopropylated silica gel.
d 3-(4-Pyridiyl)propylated silica gel.
e 3-Aminopropylated silica gel.
a Yields were for isolated pure products based on alcohol 2 after de-
cantation followed by column chromatography.
f Reaction was carried out at 90 °C.
g Yields were for isolated pure products based on menthol (2a).
The catalyst was re-used intact without re-activation up to
five times as shown in Table 4. The shape of pellets had
not been changed after the recycle use. Moreover, the
amount of the catalyst could be successfully reduced and
the highly efficient and stable nature of the catalyst was
exemplified by a TON of 425 and a TOF of 170 in the re-
action of t-butyl acetoacetate (1b) and menthol (2a). Dis-
tribution of the N,N-diethylamino residue on a wide
surface area on the silica gel might be the origin of such
high TON.
transesterification proceeded also with tertiary alcohol
(entry 12, Table 2), which is another advantageous feature
of the method.
This method was also effective to 2-carbomethoxycyclo-
pentanone (1d, Table 3), in which better yields were ob-
Table 2 Transesterification of Methyl Acetoacetate (1a) with Vari-
ous Alcohols 2
Entry Alcohol 2
Time (h) Yield of 3 (%)a
The transesterification of b-ketoesters 4 or 5 (Figure 1)
with menthol (2a) under the present reaction condition re-
covered all substrates. Similarly, the transesterification of
methyl a-phenylsulfinylacetate and methyl dieth-
1
2
2-Phenylethylalcohol
24
24
56
70
75
84
88
85
89
72
82
76
97
78
cis-3-Hexenol
3
Benzylalcohol
5.5
Table 4 Recycle of NDEAP in Transesterification of Methyl Ace-
toacetate (1a) with Menthol (2a)
4
6-Acetoxypentanol
6-t-Butyldimethylsiloxypentanol
6-Tetrahydropyranyloxypentanol
Cholesterol
4
2
5
Cyclea
Time (h)
Yield (%)b
6
2
1
2
3
4
5
6
7
7
98
99
97
98
97
97
7
24
21
8
Isoborneol
13
9
9b
10c
11
12
Menthol
0.5
Menthol
8.5
6.5
3.5
10
10
2-Adamantanol
Terpineol
a After cycle 1, the catalyst was re-used intact for the subsequent re-
actions.
a Yields were for isolated pure products based on alcohol 2 after de-
cantation followed by column chromatography.
b tert-Butyl acetoacetate (1b) was used.
b Yields were for isolated pure products based on menthol (2a) after
decantation followed by column chromatography.
c Methyl 2-benzyl-3-ketobutyrate (1c) was used.
Synlett 2004, No. 12, 2188–2190 © Thieme Stuttgart · New York

2190
H. Hagiwara et al.
LETTER
Tetrahedron Lett. 2002, 43, 8583; and earlier references
ylphosphonoacetate also resulted in complete recovery
due to low acidity of the a-protons. These results suggest
that this reaction proceeds via a ketene intermediate.8
Rapid reaction of tert-butyl acetoacetate (1b) with men-
thol (2a) compared to methyl acetoacetate (1a, entry 9,
Table 2) supports the intervention of such intermediate.
cited in these literatures.
(3) Other references which were not cited in ref. 2; see:
(a) Kumar, B.; Kumar, H.; Parmar, A. Ind. J. Chem., Sect. B
1993, 32, 292. (b) Gianotti, M.; Martelli, G.; Spunta, G.;
Campana, E.; Panunzio, M.; Mendozza, M. Synth. Commun.
2000, 30, 1725. (c) Bandgar, B. P.; Sadavarte, V. S.;
Uppalla, L. S. Synth. Commun. 2001, 31, 2063.
(d) Bandgar, B. P.; Sadavarte, V. S.; Uppalla, L. S. Chem.
Lett. 2001, 894. (e) Bandgar, B. P.; Uppalla, L. S.;
Sadavarte, V. S. Synlett 2001, 1715. (f) Jin, T.; Zhang, S.;
Li, T. Green Chem. 2002, 4, 32. (g) Chavan, S. P.; Kale, R.
R.; Shivasankar, K.; Chandake, S. I.; Benjamin, S. B.
Synthesis 2003, 2695.
(4) (a) Shimizu, K.; Suzuki, K.; Hayashi, E.; Kodama, T.;
Tsuchiya, Y.; Hagiwara, H.; Kitayama, Y. Chem. Commun.
2002, 1068. (b) Hagiwara, H.; Tsuji, S.; Okabe, T.; Hoshi,
T.; Suzuki, T.; Suzuki, H.; Shimizu, K.; Kitayama, Y. Green
Chem. 2002, 4, 461. (c) Shimizu, K.; Suzuki, H.; Kodama,
T.; Hagiwara, H.; Kitayama, Y. Stud. Surf. Sci. Catal. 2003,
145, 145.
(5) (a) Shimizu, K.; Hayashi, E.; Inokuchi, T.; Kodama, T.;
Hagiwara, H.; Kitayama, Y. Tetrahedron Lett. 2002, 43,
9073. (b) Hamaya, J.; Suzuki, T.; Hoshi, T.; Shimizu, K.;
Kitayama, Y.; Hagiwara, H. Synlett 2003, 873.
Figure 1
In summary, we have developed a mild, chemoselective
and sustainable transesterification of b-ketoesters em-
ploying N,N-diethylaminopropylated silica gel as a heter-
ogeneous catalyst, which can be recycled several times
without appreciable loss of reactivity. Simplicity of the
operation as well as the mild and environmentally benign
nature of the reaction would enable applications to a wide
variety of functionalized substrates, even to a larger-scale
reaction.
(6) NDEAP was prepared according to the same procedure as
ref.5b, using N,N-diethyl-3-aminopropyl(trimethoxy)silane
and silica gel. Nitrogen loading was 0.72 mmol/g according
to combustion analysis.
(7) Typical Experimental Procedure: To a stirred solution of
menthol (2a, 156 mg, 1 mmol) and methyl acetoacetate (1a,
130 mL, 1.2 mmol) in anhyd xylene (4 mL) was added
NDEAP pellets (279 mg, 0.72 mmol/g, 0.2 mmol) and the
resulting mixture was heated at reflux for 7 h. After removal
of the catalyst by filtration, the filtrate was evaporated to
dryness to give a residue, which was purified by column
chromatography on silica gel to give b-ketoester 3a (238 mg,
99%). The catalyst NDEAP was re-used intact for the
subsequent reaction.
References
(1) Benetti, S.; Ramagnoli, R.; De Risi, C.; Spalluto, G.;
Zanirato, V. Chem. Rev. 1995, 95, 1065.
(2) (a) da Silva, F. C.; Ferreira, V. F.; Riarelli, R. S.; Perreira, W.
C. Tetrahedron Lett. 2002, 43, 1165. (b) Chavan, S. P.;
Shivasankar, K.; Chandake, S. I.; Sivappa, R.; Kale, R. R.
(8) Witzeman, J. S. Tetrahedron Lett. 1990, 31, 1401.
Synlett 2004, No. 12, 2188–2190 © Thieme Stuttgart · New York