BF3OEt2: An efficient catalyst for transesterification of β-ketoesters

Article abstract of DOI:10.1080/00397910903029842

A facile and selective transesterification of β-ketoesters using BF₃OEt₂ as catalyst is described. The emphasis has been placed on the reaction of methyl acetoacetate with a series of alcohols of different structures, leading in all cases to good to excellent yields.

Full text of DOI:10.1080/00397910903029842

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BF3·OEt2: An Efficient Catalyst for
Transesterification of β-Ketoesters
Jinhui Yang a , Congbin Ji a , Yanmin Zhao a , Yunfeng Li a , Shizhi
Jiang a , Zhiwei Zhang b , Yongqiang Ji a b & Wanyi Liu a b
a Key Laboratory of Energy Resources and Engineering, Ningxia
University, Yinchuan, Ningxia, China
b College of Chemistry and Chemical Engineering, Ningxia University,
Yinchuan, Ningxia, China
Version of record first published: 04 Mar 2010.
To cite this article: Jinhui Yang , Congbin Ji , Yanmin Zhao , Yunfeng Li , Shizhi Jiang , Zhiwei
Zhang , Yongqiang Ji & Wanyi Liu (2010): BF3·OEt2: An Efficient Catalyst for Transesterification of β-
Ketoesters, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 40:7, 957-963
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Synthetic Communications1, 40: 957–963, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903029842
BF3 ꢀ OEt2: AN EFFICIENT CATALYST FOR
TRANSESTERIFICATION OF b-KETOESTERS
Jinhui Yang,1 Congbin Ji,1 Yanmin Zhao,1 Yunfeng Li,1
Shizhi Jiang,1 Zhiwei Zhang,2 Yongqiang Ji,1,2 and
Wanyi Liu1,2
1Key Laboratory of Energy Resources and Engineering, Ningxia University,
Yinchuan, Ningxia, China
2College of Chemistry and Chemical Engineering, Ningxia University,
Yinchuan, Ningxia, China
A facile and selective transesterification of b-ketoesters using BF3 ꢀ OEt2 as catalyst is
described. The emphasis has been placed on the reaction of methyl acetoacetate with a
series of alcohols of different structures, leading in all cases to good to excellent yields.
Keywords: b-Ketoesters; Carroll rearrangement; transesterification
b-Ketoesters are important synthons, and they can be transformed into other useful
building blocks in organic synthesis. The electrophilic and nucleophilic sites of
b-ketoesters make them a valuable tool for the synthesis of complex natural
products,[1] such as paclitaxel,[2] podophyllotoxin,[3] serricornine,[4] and trichodiene[5]
(Fig. 1).
Of the many methods reported for the transesterification of b-ketoester with
alcohol, most are catalyzed by a variety of protic or Lewis acids, organic bases,
enzymes, or antibodies. It is well known that traditional homogeneous acidic
catalysts such as sulfuric acid and phosphoric acid can cause several environmental
problems.[6] Moreover, most of the transesterification methods are equilibrium-
driven reactions where the excess of one of the reactants is required to achieve good
yields and an acidic or basic catalyst is required to promote the reaction. Recently,
transesterification has been effected with various catalysts such as S-SnO2,[7]
CuSO4,[8] Montorillonite K-10,[9] B2O3=ZrO2,[10] Nb2O5,[11] ceria-yttria-based Lewis
acid,[12] zeolites,[13] I2,[14] Amberlyst-15,[15] and NH2SO3H=[C3MIm]Cl.[16] Neverthe-
less, some of these catalysts are difficult to prepare or are expensive. Moreover, the
reaction of transesterification failed with aromatic substrates over S-SnO2 catalyst.[7]
In our attempt, we started by investigating the transesterification of methyl
acetoacetate with n-butanol under different catalysts in toluene under reflux
Received December 23, 2008.
Address correspondence to Jinhui Yang, Key Laboratory of Energy Resources and Engineering,
Ningxia University, Yinchuan, Ningxia, China. E-mail: yang_jh@nxu.edu.cn
957

958
J. YANG ET AL.
Figure 1. b-Ketoesters as a valuable tool for the synthesis of complex natural products.
(Scheme 1). Under different conditions, we obtained the desired product with some
common Lewis acids as the catalysts (Table 1). We started searching for greater
yields in the transesterification with easily available and cheap catalysts. To our
delight, the transesterification reaction performed well in the presence of commer-
cially available boron trifluoride diethyl etherate (BF3 ꢀ OEt2) (Table 1, entry 13)
in toluene under reflux (110–115 ꢁC). The desired product was obtained with a com-
plete conversion and an excellent isolated yield. However, no transesterification was
observed when the reaction was carried out in the absence of a catalyst in more than
15 h (Table 1, entry 1), and lower yields were obtained when some other metal salts
such as NiCl2, CuCl2, Bi(NO3)5, and CoCl2 were used as the catalysts (Table 1,
entries 4, 6, 7, and 11).
To further expand the reaction scope of this BF3 ꢀ OEt2-catalyzed transesteri-
fication, a wide variety of inhomogeneous alcohols were select to reacted with methyl
acetoacetate or phenyl acetoacetate using 15 mol% of BF3 ꢀ OEt2 (Table 1, entry 13)
under reflux in toluene. The results are summarized in Table 2.
Under the optimized conditions, we investigated the BF3 ꢀ OEt2-catalyzed reac-
tion of various alcohols and b-ketoesters (methyl acetoacetate or phenyl acetoace-
tate). In all cases, the reactions were completed within 4–7 h in good to excellent
yields. It is apparent from Table 2 that n-butanol alcohol (Table 2, entries 1 and
14), n-octyl alcohol (Table 2, entry 8), and benzyl alcohol (Table 2, entry 10) have
been effectively catalyzed by BF3 ꢀ OEt2, giving products in excellent yields. In the
case of n-butanol alcohol, transesterification of aromatic ester is faster than that
of aliphatic ester (Table 2, entries 1 and 14). A notable feature of this protocol is
that allyl alcohols (Table 2, entry 9) underwent transesterification efficiently with
methyl acetoacetate to provide the corresponding b-ketoesters. It should be noted
that allyl ester is known to be very difficult to prepare because it readily undergoes
Scheme 1. BF3 ꢀ OEt2–catalyzed transesterification reaction.

BF3ꢀOEt2 AS CATALYST
959
Table 1. Transesterification for methyl acetoacetate with n-butanol under
different conditionsa
Entry
Catalysts
Time (h)
Yield (%)b
1
2
—
15
0
80
67
43
57
54
47
55
63
61
51
64
92
91
Fe2(SO4)3 (10 mol%)
ZnCl2 (10 mol%)
NiCl2 (10 mol%)
4.5
6.0
5.0
4.0
7.0
5.0
5.5
4.0
5.5
5.5
6.5
5.0
5.5
3
4
5
CuCl (10 mol%)
CuCl2 (15 mol%)
6
7
Bi(NO3)5 (10 mol%)
(NH4)2Ce(NO3)6 (10 mol%)
CeCl3 ꢀ 7H2O (15 mol%)
(NH4)6Mo7O24 (20 mol%)
CoCl2 (10 mol%)
8
9
10
11
12
13
14
BF3 ꢀ OEt2 (10 mol%)
BF3 ꢀ OEt2 (15 mol%)
BF3 ꢀ OEt2 (20 mol%)
aThe molar ratio of methyl acetoacetate and n-butanol is 1:1.5.
bIsolated yield.
the Carroll rearrangement.[17] Other esters, such as a-ketoester, c-ketoester, unsaturated
ester, and nomal ester, failed to undergo the reaction (Table 2, entries 16–21).
In summary, we have demonstrated an efficient protocol for the transesterifica-
tion of b-ketoesters with inhomogeneous alcohols using BF3 ꢀ OEt2 as a novel
catalyst. This method offers significant advantages such as mild reaction conditions,
faster reaction rates, good yields, ready availability of the catalyst, and cleaner
reaction profiles, which make it an attractive and superior method for synthetically
useful transesterification. The experimental procedure is also very simple and
convenient.
EXPERIMENTAL
1H and 13C NMR spectra were recorded at room temperature on a Bruker
400-MHz spectrometer with CDCl3 as solvent and tetramethylsilane (TMS) as inter-
nal standard. Chemical shifts were reported in units (ppm) by assigning TMS reson-
1
ance in the H spectrum as 0.00 ppm and CDCl3 resonance in the 13C spectrum as
77.0 ppm. All coupling constants (J values) were reported in hertz (Hz). Mass spectra
were recorded on a HP-5688 instrument by direct inlet on a 70-eV mass spec-
trometer. Thin-layer chromatography (TLC) was performed on aluminium-backed
silica-gel plates. Silica gel [(200–300 mesh), Qingdao Ocean, China] was used for
chromatographic separation. Silica gel GF254 (Qingdao Ocean HG=T2354–92,
China) was used for TLC.
General Experimental Procedure for Transesterification
BF3 ꢀ (Et2O (15 mol%) was added to a stirred mixture of b-ketoester (2.0 mmol)
and alcohol (3.0 mmol) in toluene (10 mL). The resulting reaction mixture was

960
J. YANG ET AL.
Table 2. Optimization of reaction conditions for transesterification of b-ketoesters catalyzed by BF3
etheratea
Time Yields
(%)b
Entry
1
b-Ketoesters (a)
Alcohols (b)
Products (c)
(h)
5.0
92[14]
2
3
1a
1a
4.5
6.0
94[14]
72[18]
4
5
6
7
8
1a
1a
1a
1a
1a
5.0
5.5
6.5
6.5
4.5
87[14]
81[10]
80[18]
86
91
9
1a
1a
6.0
4.5
68[11]
10
93[14]
11
12
13
1a
1a
1a
6.0
5.0
5.5
76[13b]
83[10]
75
(Continued )

BF3ꢀOEt2 AS CATALYST
Table 2. Continued
961
Time Yields
(%)b
Entry
14
b-Ketoesters (a)
Alcohols (b)
Products (c)
(h)
4.0
92
15
14a
7.0
65
—
16
17
18
19
CH3CH2CH2COOEt
CH3COCH2CH2COOEt
CNCH2COOEt
NRc
NR
NR
NR
8.0
8.0
8.0
8.0
—
—
—
CH3BrCOOEt
20
21
NR
NR
8.0
8.0
—
—
aAll reactions were carried out with 15 mol% of BF3 ꢀ OEt2 in refluxing toluene for the appropriate time.
bIsolated yield. All products were characerized by their 1H NMR, 13C NMR, or mass spectroscopic
data.
refluxed for an appropriate time (Table 2). The progress of the reaction was moni-
tored by TLC. After completion, the reaction mixture was cooled, the contents of
the flask were poured into water to remove the catalyst, and the mixture was
extracted with CH2Cl2. The organic phase was dried with anhydrous Na2SO4, and
the solvent was removed. The resulting crude product was purified by column chro-
matography on silica gel and eluted with ethyl acetate–petroleum ether (60–90 ꢁC) in
a 1:16 ratio to afford the corresponding pure products. The products were character-
ized by comparison of their 1H NMR, 13C NMR, and mass spectrometric data with
authentic samples.
Spectral Data for Selected Products
Butyl 3-oxobutanoate (1c). 1H NMR (400 MHz, CDCl3): d ¼ 0.93 (t,
J ¼ 7.4 Hz, 3H), 1.38 (m, 2H), 1.63 (m, 2H), 2.25 (s, 3H), 3.45 (s, 2H), 4.3 (t,
J ¼ 6.6 Hz, 2H). EIMS: m=z (%): 158 (Mþ 5), 116 (2), 103 (82), 85 (84), 56 (100),
43 (96), 41 (88), 39 (51).
Pentyl 3-oxobutanoate (7c). 1H NMR (400 MHz, CDCl3): d ¼ 0.91
(t, J ¼ 3.8 Hz, 3H), 1.32–1.35 (m, 4H), 1.64–1.67 (m, 2H), 2.27 (s, 3H), 3.46

962
J. YANG ET AL.
(s, 2H), 4.13 (t, 2H, J ¼ 5.4 Hz). EIMS: m=z (%): 172 (Mþ 2), 103 (61), 85 (48),
70 (42), 43 (100).
Octyl 3-oxobutanoate (8c). 1H NMR (400 MHz, CDCl3): d ¼ 0.88 (t,
J ¼ 7.0 Hz, 3H), 1.23–1.36 (m, 10H), 1.60–1.67 (m, 2H), 2.25 (s, 3H), 3.45 (s, 2H),
4.12 (t, J ¼ 6.6 Hz, 2H). EIMS: m=z (%): 214 (Mþ 0.05), 103 (34), 85 (22), 69 (10),
57 (18), 43 (100).
(Tetrahydrofuran-2-yl)methyl
3-oxobutanoate
(13c). 1H
NMR
(400 MHz, CDCl3): d ¼ 1.64 (m, 1H), 1.89–1.95 (m, 3H), 2.27 (s, 3H), 3.51 (s, 2H),
3.76–3.88 (m, 2H). 4.05–4.23 (m, 3H). 13C NMR (100 MHz, CDCl3): d ¼ 200.4,
167.1, 76.3, 68.4, 67.1, 49.9, 30.1, 27.9, 25.7. EIMS: m=z (%): 186 (Mþ 0.06), 84
(17), 71 (98), 43 (100), 41 (21).
Butyl 3-oxo-3-phenylpropanoate (14c). 1H NMR (400 MHz, CDCl3):
d ¼ 0.88 (t, J ¼ 7.4 Hz, 3H), 1.28–1.34 (m, 2H), 1.55–1.60 (m, 2H), 3.99 (s, 2H),
4.14 (t, J ¼ 6.6 Hz, 2H), 7.39–7.94 (m, 5H, ArH). 13C NMR (100 MHz, CDCl3):
d ¼ 192.5, 167.6, 136.1, 133.7, 128.8, 128.5, 128.5, 126.0, 65.3, 46.0, 30.5, 19.0,
13.6. EIMS: m=z (%): 220 (Mþ 2), 147 (5), 105 (100), 51(21), 41 (20).
2-Bromoethyl 3-oxo-3-phenylpropanoate (15c). 1H NMR (400 MHz,
CDCl3): d ¼ 3.94 (t, J ¼ 6.0 Hz, 2H), 4.04 (s, 2H), 4.45 (t, J ¼ 6.2 Hz, 2H),
7.47–7.94 (m, 5H, ArH). 13C NMR (100 MHz, CDCl3): d ¼ 192.1, 167.0, 135.6,
133.9, 128.8, 128.6, 128.5, 126.1, 64.5, 45.6, 28.3. EIMS: m=z (%): 270 (Mþ 1),
146 (3), 105 (100), 77 (47), 51 (31).
ACKNOWLEDGMENTS
The work was supported by the Ministry of National Education (No. 203143),
the National Natural Science Foundation of China (Nos. 20562010, 20962016), the
special pre-inquest of State 973 (No. 2006CB708606), the Key Laboratory of Energy
Resources and Engineering (Ningxia University), and the Province and Ministry of
Education of China.
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