Direct Synthesis of β,γ-Unsaturated α-Keto Esters from Aldehydes and Pyruvates

Article abstract of DOI:10.1055/s-0037-1612255

Herein, we describe two practical methods to synthesize β,γ-unsaturated α-keto esters directly from aldehydes and pyruvates promoted by BF ₃ ?Et ₂ O in the presence of Ac ₂ O or by Ti(OEt) ₄ under mild condition

Full text of DOI:10.1055/s-0037-1612255

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
en
J. K. Mansaray et al.
Letter
Synlett
Direct Synthesis of β,γ-Unsaturated α-Keto Esters from Aldehydes
and Pyruvates
John Kamanda Mansaray
Jiarui Sun
RCHO
BF3•Et2O (0.5 equiv)
Ac2O (1.5 equiv)
O
Ti(OEt)4 (1.2 equiv)
toluene, 40 °C, 72 h
O
R
CO2R1
+
Shisheng Huang
toluene, 40 °C, 48 h
R
CO2Et
O
R = Ar or i-Pr, Cy
Weijun Yao*
0
0
0
0-0
0
0
1-6
4
6
3-
2
9
3
7
R = Ar or alkyl
11 examples
CO2R1
atom-economic, step-economic, mild conditions
20 examples
Department of chemistry, Zhejiang Sci-Tech University,
Hangzhou 310018, P. R. of China
orgywj@zstu.edu.cn
Received: 08.12.2018
Accepted after revision: 30.01.2019
Published online: 25.02.2019
steps to prepare the ylide from pyruvate. These methods
above lack atom economy13 and step economy.14 Although
Dujardin et al.15 reported that copper(II)triflate catalyzed
the direct synthesis of β,γ-unsaturated α-keto esters from
aldehydes with pyruvate (path d), this method is limited to
aromatic aldehydes, and aliphatic aldehydes are not suit-
able. This seems to be just a simple aldol condensation reac-
tion; however, there are still challenges to synthesize β,γ-
unsaturated α-keto esters directly not only from aromatic
aldehydes but also from aliphatic aldehydes with pyruvate.
DOI: 10.1055/s-0037-1612255; Art ID: st-2018-b0793-l
Abstract Herein, we describe two practical methods to synthesize β,γ-
unsaturated α-keto esters directly from aldehydes and pyruvates pro-
moted by BF3•Et2O in the presence of Ac2O or by Ti(OEt)4 under mild
conditions. A variety of aromatic aldehydes was tolerated to afford the
desired products in moderate to excellent yield. Moreover, aliphatic al-
dehydes and Isatin were also employed to give the γ-alkyl β,γ-unsatu-
rated α-keto esters in moderate yield with use of the Ti(OEt)4 system.
Key words unsaturated α-keto esters, step economy, pyruvates, alde-
hydes, aldol condensation
O
ArCHO
path a
+
COOH
OR1
O
TMSO
Because of their diverse reactivities, β,γ-unsaturated α-
keto esters1 are synthetically useful building blocks, which
have been widely applied in a variety of reactions, such as
reduction,2 Diels–Alder reaction,3 inverse-electron-demand
hetero-Diels–Alder reaction,4 Friedel–Crafts reaction,5 aldol
reaction (or nitro-aldol reaction),6 Michael addition,7 multi-
component reaction,8 and other cascade reactions9 to con-
struct more complex compounds. Generally, β,γ-unsaturat-
ed α-keto esters could be prepared by aldol condensation of
pyruvic acid with aromatic aldehydes under strong caustic
conditions, followed by acidification and esterification
(Scheme 1, path a).10 However, this method needs three
steps with low overall yield and is limited to aromatic alde-
hydes. Sugimura’s group11 developed a Mukayaima-aldol
reaction of 2-(trimethylsiloxy) acrylate with acetal promot-
ed by BF3•Et2O at very low temperature, and subsequent β-
elimination in the presence of silica gel in benzene heated
to reflux (path b). Although versatile aldehydes could be
employed with moderate to good yields in this process, it is
a long journey under harsh conditions. The Wittig reaction
has also been applied to synthesize β,γ-unsaturated α-keto
esters with moderate yield (path c),12 but it takes three
O
+
O
CO2R1
path b
path d
+
R
CO2R1
R
OMe
OMe
ArCHO
path c
O
CO2R1
RCHO
+
Ph3P
Scheme 1 Reported synthesis methods
As a continuation of our studies on exploring the reac-
tivity of β,γ-unsaturated α-keto esters,16 we would like to
establish a direct and practical procedure to prepare β,γ-
unsaturated α-keto esters efficiently. Herein, we document
two direct methods to synthesize β,γ-unsaturated α-keto
esters from aldehydes with pyruvates promoted by BF3•Et2O
in the presence of acetic anhydride or by titanium ethoxide
as dehydrate. As Dujardin reported that the dehydrate
played an important role in improving the yield, we investi-
gated the catalysis of various Lewis acids with acetic anhy-
dride as the dehydrating agent in the cross-condensation
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

B
J. K. Mansaray et al.
Letter
Synlett
Table 1 (continued)
reaction of benzaldehyde with ethyl pyruvate. As shown in
Table 1, several common Lewis acids were examined. ZnCl2,
Cu(OAc)2, and BiCl3 did not work at all (Table 1, entries 1–3),
but FeCl3 or TiCl4 could give the desired product 1a in low
yields (Table 1, entries 4, 5). BF3•Et2O, however, afforded the
product in 30% yield (Table 1, entry 6) at room temperature
in toluene after 72 hours. The yield could be greatly in-
creased to 65% by increasing the reaction temperature to
40 °C (Table 1, entry 7). The yield was reduced to 44% (Table
1, entry 8) when the reaction temperature was raised to
100 °C. Further improvement was realized by increasing the
catalyst loading to 50% (Table 1, entry 9) and 96% yield was
achieved. When one equivalent of BF3•Et2O was used, the
reaction could be shortened to one day with the yield
slightly lowered to 75% (Table 1, entry 10). Control experi-
ments demonstrated that both BF3•Et2O and acetic anhy-
dride played a very important role in the reaction (Table 1,
entries 11, 12). A solvent screening showed that this con-
densation reaction could be carried out in other common
solvents, such as dichloromethane, chloroform, 1,2-dichlo-
roethane, whereas the yield slightly dropped compared
with the reaction in toluene (Table 1, entries 13–15). Nota-
Entry
Lewis acid
Solvent
Temperature Time
Yield
(%)b
(°C)
(h)
48
48
14d
15d
BF3•Et2O (50%)
BF3•Et2O (50%)
CHCl3
40
40
78
87
(CH2Cl)2
a Reaction conditions: Benzaldehyde (1 mmol, 102 μL), ethyl pyruvate (1.2
mmol, 131 μL), and acetic anhydride (1.5 mmol, 142 μL) in solvent (5 mL).
b Isolated yield after column chromatography.
c Without acetic anhydride.
d E/Z ratio > 19:1 from 1H NMR spectrum of the crude product.
Having the optimized reaction conditions in hand, we
applied this method to other substrates. As shown in Table
2,17 other pyruvates were tested and could afford the corre-
sponding products in high yield with high E/Z selectivity
(Table 2, entries 1–3). Furthermore, a variety of substituted
benzaldehydes were investigated. All worked well to give
the target products in good to excellent yield (Table 2, en-
Table 2 Substrate Scopea
1
BF3•Et2O (0.5 equiv)
Ac2O (1.5 equiv)
O
bly, only the E isomer was detected in the H NMR spec-
O
R
CO2R1
trum of the crude product. Finally, the best conditions were
obtained: 50% BF3•Et2O as the catalyst with 1.5 equivalents
of acetic anhydride as the dehydrator in toluene at 40 °C for
48 hours.
R
CHO
+
CO2R1
toluene, 40 °C, 48 h
1
Entry
R
R1
Et
Product 1
E/Z ratiob
Yield (%)c
1
2
Ph
1a
1b
1c
1d
1e
1f
> 19:1
16:1
95
91
89
78
77
74
58
91
75
81
77
91
92
87
96
53
31
27
trace
35
42
Table 1 Optimization of the Direct Aldol Condensationa
Ph
Ph
Me
i-Pr
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
3
> 19:1
6.5:1
6.4:1
7:1
O
O
CHO
+
4
2-MeC6H4
3-MeC6H4
4-MeC6H4
Ac2O (1.5 equiv)
conditions
CO2Et
CO2Et
(1.2 mmol)
5
1a
(1 mmol)
6
7
4-MeOC6H4
4-FC6H4
2-ClC6H4
3-ClC6H4
2,4-Cl2C6H3
2-BrC6H4
4-BrC6H4
3-NO2C6H4
4- NO2C6H4
1-naphthyl
2-furyl
1g
1h
1i
5.8:1
> 19:1
9:1
Entry
Lewis acid
Solvent
Temperature Time
Yield
(°C)
(h)
(%)b
8
1
2
ZnCl2 (20%)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
rt
rt
rt
rt
rt
rt
72
0
0
9
Cu(OAc)2 (20%)
BiCl3 (20%)
72
72
72
72
72
72
24
48
24
48
48
48
10
11
12
13
14
15
16
17
18
19
20
21
1j
15:1
3
0
1k
1l
> 19:1
> 19:1
> 19:1
> 19:1
> 19:1
> 19:1
> 19:1
> 19:1
-
4
FeCl3 (20%)
8
5
TiCl4 (20%)
12
30
65
44
96
75
0
1m
1n
1o
1p
1q
1r
6
BF3•Et2O (20%)
BF3•Et2O (20%)
BF3•Et2O (20%)
BF3•Et2O (50%)
BF3•Et2O (100%)
–
7
40
8
100
40
40
40
40
40
9d
10d
11
12c
13d
2-thienyl
n-Pr
1s
1t
BF3•Et2O (50%)
BF3•Et2O (50%)
0
i-Pr
> 19:1
> 19:1
88
Cy
1u
a Reaction conditions: aldehyde (2 mmol), pyruvate (2.4 mmol), BF3•Et2O (1
mmol), and acetic anhydride (3 mmol) in toluene (10 mL) at 40 °C for 48 h.
b The E/Z ratio was detected by 1H NMR analysis of the crude product.
c Isolated yield after column chromatography.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

C
J. K. Mansaray et al.
Letter
Synlett
a
tries 4–15), and the benzaldehydes substituted with elec-
tron-donating groups showed lower yields with moderate
selectivity than those with electro-withdrawing groups. 1-
Naphthaldehyde can also be employed in this reaction to af-
ford product 1p in 53% yield (Table 2, entry 16). Because of
their low stability, 2-furyl-substituted 1q and 2-thienyl-
substituted 1r were isolated in 31 and 27% yield, respective-
ly (Table 2, entries 17, 18). Encouraged by the good results
of the aromatic aldehydes, we wanted to apply this method
to aliphatic aldehydes. Unfortunately, the linear butyralde-
hyde only afforded a low amount of product (Table 2, entry
19). However, the branched isobutyraldehyde and cyclo-
hexane carboxaldehyde could be involved in this method to
form the γ-alkyl β,γ-unsaturated α-keto esters 1t and 1u,
respectively, in moderate yields (Table 2, entries 20, 21).
Notably, a large scale reaction of 20 mmol benzaldehyde
was carried out and 3.92 g (96% yield) of 1a could be sepa-
rated (Scheme 2).
Table 3 Aldol Condensation Promoted by Ti(OEt)4
O
O
Ti(OEt)4 (1.2 equiv)
R
CO2Et
R
CHO
+
CO2Et
toluene, 40 °C, 3 d
1
Entry
R
Product 1
E/Z ratiob
Yield (%)c
1
2
n-Pr
1s
> 19:1
> 19:1
> 19:1
> 19:1
> 19:1
6.3:1
36
32
39
51
86
51
84
63
47
29
68
PhCH2CH2
i-Pr
1v
1t
3
4
Cy
1u
1a
1g
1h
1o
1q
1r
5
Ph
6
4-MeOC6H4
4-FC6H4
4- NO2C6H4
2-furyl
2-thienyl
styryl
7
> 19:1
> 19:1
> 19:1
> 19:1
> 19:1
8
9
10
11
O
1w
BF3•Et2O (0.5 equiv)
O
CHO
+
a Reaction conditions: aldehyde (2 mmol), ethyl pyruvate (2.4 mmol),
Ti(OEt)4 (2.4 mmol) in toluene (10 mL) at 40 °C for 3 d.
b The E/Z ratio was detected by 1H NMR analysis of the crude product.
c Isolated yield after column chromatography.
Ac2O (1.5 equiv)
CO2Et
CO2Et
toluene, 40 °C, 48 h
1a
(3.92 g, 96% yield)
(20 mmol, 2.04 mL)
Scheme 2 Gram-scale synthesis of 1a
What’s more, activated ketone N-benzyl isatin was cho-
sen to expand the application of these two methods. To our
delight, the target product 1x was obtained in 33% yield
with the Ti(OEt)4 system (Scheme 3). In the previous report,
it was prepared only by Wittig reaction in a similar yield.20
In summary, we have developed two practical methods
to synthesize β,γ-unsaturated α-keto esters directly from
aldehydes and pyruvates through aldol condensation pro-
moted by BF3•Et2O in the presence of Ac2O or by Ti(OEt)4
under mild conditions. Both methods could be applied in
most of aromatic aldehydes to afford the target products in
moderate to excellent yields. Moreover, aliphatic aldehydes
also were employed in this process to give γ-alkyl β,γ-un-
saturated α-keto esters in moderate yield with use of the
Ti(OEt)4 system.
So far, the direct synthesis of γ-alkyl substituent β,γ-un-
saturated α-keto esters still remained a challenge. To ad-
dress this problem, a lot of conditions were investigated
and Ti(OEt)4 was found to be a good choice, working as a
Lewis acid and dehydrating agent.18 After simple optimiza-
tion, 1s from butyraldehyde was obtained in 36% yield in
the presence of 1.2 equiv of Ti(OEt)4 in toluene at 40 °C after
three days (Table 3, entry 1).19 3-Phenylpropionaldehyde
could also be employed in this system to achieve the de-
sired product 1v in 32% yield. The yields of 1t and 1u ob-
tained from branched aldehydes were slightly increased
compared with those obtained with the method employing
BF3•Et2O. Aromatic aldehydes performed well in this
Ti(OEt)4 process. Even cinnamaldehyde tolerated those con-
ditions to provide the target compound 1w in 68% yield (Ta-
ble 3, entry 11).
CO2Et
CO2Et
O
BF3•Et2O (0.5 equiv)
O
O
Ti(OEt)4 (1.2 equiv)
toluene, 40 °C, 3 d
Ac2O (1.5 equiv)
O
O
O
toluene, rt, 3 d
N
N
N
Bn
16% yield
Bn
1x
Bn
1x
33% yield
Scheme 3 Application of our method to N-benzyl Isatin
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

D
J. K. Mansaray et al.
Letter
Synlett
Funding Information
(11) Sugimura, H.; Yoshida, K. Bull. Chem. Soc. Jpn. 1992, 65, 3209–
3211.
We are grateful to the National Natural Science Foundation of China
(Grant No. 21702185) and the Science Foundation of Zhejiang Sci-
(12) Meijer, L. H.; Pandit, U. K. Tetrahedron 1985, 41, 467–472.
(13) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259–281.
(14) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem.
Res. 2008, 41, 40–49.
Tech University (Grant No. 16062189-Y).
N
ati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
7
0
2
1
8
5)
(15) Dujardin, G.; Leconte, S.; Bénard, A.; Brown, E. Synlett 2001,
147–149.
Supporting Information
(16) (a) Yao, W.; Dou, X.; Lu, Y. J. Am. Chem. Soc. 2015, 137, 54–57.
(b) Yao, W.; Pan, L.; Wu, Y.; Ma, C. Org. Lett. 2010, 12, 2422–
2425. (c) Yao, W.; Wu, Y.; Wang, G.; Zhang, Y.; Ma, C. Angew.
Chem. Int. Ed. 2009, 48, 9713–9716.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1612255.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
(17) β,γ-Unsaturated α-Keto Esters (1a–u); General Procedure A
To the solution of aldehyde (2 mmol) and pyruvate (2.4 mmol)
in toluene (10 mL) were added BF3•Et2O (1 mmol) and Ac2O (3
mmol). After stirring for 48 h at 40 °C, the mixture was poured
into saturated NaHCO3 (aq) solution (20 mL). The separated
aqueous phase was extracted with ethyl acetate (20 mL) and the
combined organic phases were washed by brine (20 mL), dried
with Na2SO4, filtered, and concentrated in vacuum. The residue
was filtered through a short pad of silica gel with petroleum
ether/ethyl acetate (10:1) as the eluent to obtain a crude prod-
uct, which was analyzed by 1H NMR spectroscopy to calculate
the E/Z ratio. Further purification was carried out by column
chromatography on silica gel with petroleum ether/ethyl
acetate (20:1) as the eluent to afford the products 1.
Ethyl (E)-4-Cyclohexyl-2-oxobut-3-enoate (1t)
References and Notes
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Pale yellow oil; yield: 176 mg (42%). 1H NMR spectrum of the
crude product shows an E/Z ratio of >19:1. 1H NMR (400 MHz
CDCl3): δ = 7.09 (dd, J = 16.0, 6.8 Hz, 1 H), 6.57 (dd, J = 16.0, 1.1
Hz, 1 H), 4.31 (q, J = 7.1 Hz, 2 H), 2.29–2.13 (m, 1 H), 1.78–1.64
(m, 5 H), 1.35 (t, J = 7.1 Hz, 3 H), 1.31–1.08 (m, 5 H). 13C NMR
(101 MHz, CDCl3): δ = 183.8, 162.5, 159.6, 122.7, 62.2, 41.2,
31.4, 25.8, 25.6, 14.0.
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(19) Ti(OEt)4 System; General Procedure B
To the solution of aldehyde (2 mmol) and pyruvate (2.4 mmol)
in toluene (10 mL) was added Ti(OEt)4 (2.4 mmol). After stirring
for 72 h at 40 °C, the mixture was diluted with ethyl acetate (40
mL) and quenched with water (1 mL). After stirring for 0.5 h at
rt, the mixture was dried with Na2SO4, filtered, and concen-
trated in vacuum. The residue was filtered through a short pad
of silica gel with petroleum ether/ethyl acetate (10:1) as the
eluent to obtain a crude product, which was analyzed by 1H
NMR spectroscopy to calculate the E/Z ratio. Further purifica-
tion was carried out by column chromatography on silica gel
with petroleum ether/ethyl acetate (20:1) as the eluent to afford
the products 1.
Ethyl (E)-2-Oxohept-3-enoate (1s)
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Pale yellow oil; yield: 122 mg (36%). 1H NMR spectrum of the
1
crude product shows an E/Z ratio of >19:1. H NMR (400 MHz,
CDCl3): δ = 7.18 (dt, J = 15.8, 6.9 Hz, 1 H), 6.64 (d, J = 15.9 Hz, 1
H), 6.64 (d, J = 15.9 Hz, 1 H), 4.34 (q, J = 7.1 Hz, 2 H), 2.29 (td, J =
8.0, 1.0 Hz, 2 H), 1.59–1.47 (m, 2 H), 1.37 (t, J = 7.1 Hz, 3 H), 0.95
(t, J = 7.4 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 183.5, 162.4,
154.9, 125.3, 62.30, 35.1, 21.1, 14.0, 13.7.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D