Thiourea catalysed reduction of α-keto substituted acrylate compounds using Hantzsch ester as a reducing agent in water

Article abstract of DOI:10.1039/c7ra00995j

The first method for the reduction of α-keto substituted acrylate compounds by Hantzsch ester in water under the catalysis of thiourea has been developed. The products were isolated in moderate to high yields (38-95%). These products are important intermediates in the synthesis of a series of natural products and other biologically active molecules.

Full text of DOI:10.1039/c7ra00995j

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Thiourea catalysed reduction of a-keto substituted
acrylate compounds using Hantzsch ester as
a reducing agent in water†
Cite this: RSC Adv., 2017, 7, 22909
Guanglin Weng,‡a Xiaobo Ma,‡a Dongmei Fang,b Ping Tan,a Lijiao Wang,a Linlin Yang,a
a
a
a
*
*
Yuanyuan Zhang, Shan Qian and Zhouyu Wang
Received 23rd January 2017
Accepted 18th April 2017
The first method for the reduction of a-keto substituted acrylate compounds by Hantzsch ester in water
under the catalysis of thiourea has been developed. The products were isolated in moderate to high
yields (38–95%). These products are important intermediates in the synthesis of a series of natural
products and other biologically active molecules.
DOI: 10.1039/c7ra00995j
rsc.li/rsc-advances
b-Keto esters are important intermediates in organic acetoacetate and their substituted derivatives by halides or
synthesis,1–5 and they have been extensively used in the esters followed by base promoted cleavage of a carbonyl
synthesis of a series of natural products and other biologically group.23,24 Recently, Heck reaction between Baylis–Hillman
active molecules such as coumarin derivatives 1 (ref. 6) (potent adducts and various aryl sources has been developed as a very
TNF-a inhibitors), pyrazolo[1,5-a]pyrimidin-7(4H)-ones 2 (ref. 7) attractive alternative method for syntheses of b-keto esters.25–27
(potent inhibitors of hepatitis C virus polymerase), cambinol In principle, the reduction of Knoevenagel condensation
analogues 3 (ref. 8) (isoenzyme inhibitors of the sirtuin family of adducts could be an efficient method for the preparation of b-
protein deacetylases), and 4 (ref. 9) (potent prostate cancer keto esters. However, it has been barely reported (Scheme 1).
antigen-1 inhibitors) (Fig. 1).
In recent years, Hantzsch esters and their related organic
Many efforts have been made to achieve efficient preparation hydride donors have been widely utilized in the reduction of
of these scaffolds.10–21 Two general syntheses of b-keto esters a variety of compounds containing C]C, C]N and C]O
include (i) acylation of ketones or carboxylic esters by acyl unsaturated groups.28,29 We reported the rst example of cata-
halides or esters22 and (ii) acylation of acetylacetone or ethyl lyst free transfer hydrogenation of C]C with Hantzsch ester in
water.30 A series of alkenes conjugated with strong electron-
withdrawing groups such as nitrile, ester and nitro could be
reduced to the corresponding products in water with excellent
yields. More recently, we reported a base promoted cascade
protocol for the preparation of reduced Knoevenagel conden-
sation products in water.31 However, the a-keto substituted
acrylate compounds could not be reduced for high yield (35%)
Fig. 1 Synthetic applications of b-keto esters.
aDepartment of Chemistry, Xihua University, Chengdu, 610039, China. E-mail:
zhouyuwang77@gmail.com; qians33@163.com; Fax: +86-28-8772-3006; Tel: +86-
28-8772-9463
bChengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra00995j
‡ These authors contributed equally to this work and should be considered
co-rst authors.
Scheme 1 Methods for the preparation of b-keto esters.
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under the existing reaction conditions. Here in, we wish to However, no improvement could be achieved when a series of
report a simple and efficient synthetic method for the reduction acids with different pKa were used in the reaction (Table 1,
of the a-keto substituted acrylate compounds by Hantzsch ester entries 3–4). Fortunately, 56% yield could be obtained when
in water under the catalysis of thiourea catalysts.
20% of thiourea was used in the reaction under the otherwise
Initially, we found acetic acid could be used as catalyst in the identical conditions (Table 1, entry 6). Thus, thiourea deriva-
reaction to get a moderate yield at 100 ꢀC (Table 1, entry 2). tives Cat 1–8 were synthesized. The yield of the reduction
product could be improved to 72% when 20% of Cat 1 was used
(Table 1, entry 7). The Cat 2 has the best performance among
Table 1 Reaction conditions optimizationa
these new catalysts, and 93% yield could be achieved when 20%
of Cat 2 was used (Table 1, entry 8). Its diastereomer Cat 3 and
enantiomer Cat 4 gave lower yield (Table 1, entries 9 and 10).
The hydroxyl and the thiourea parts of Cat 2 seemed very
important for the activity of the catalyst. When the hydroxyl
protected Cat 5 and the sulfonamides Cat 7 and 8 were used in
the reaction, 80%, 62% and 65% yields could be obtained,
respectively (Table 1, entries 11–14).
ꢀ
We next found 100 C is the most suitable temperature for
the reaction, only 75% yield could be obtained when the reac-
tion temperature was decreased to 80 ꢀC (Table 1, entry 15).
Decreasing the equivalent of the catalyst to 10%, the yield
decreased to 82% (Table 1, entry 16). Shorten the reaction time
to 12 hours, the yield dropped to 71% (Table 1, entry 17). Water
was found to be the best solvent for the current reduction
system since only trace or small amounts of products could be
isolated when the reactions were set up in organic solvents such
as toluene, dichloromethane, acetonitrile and tetrahydrofuran
(Table 1, entries 18–22). Solvent-free made the reaction proceed
poorly (Table 1, entry 23). As a result, the best reaction condi-
tions in which the reduction is performed are using 20 mol% of
ꢀ
Cat 2, Hantzsch ester (1.0 equiv.) in water at 100 C for 24 h.
Unfortunately, the products are almost racemate with the
catalysis of chiral catalysts Cat 2–5 and Cat 7–8. Two reasons
maybe responsible for the results. One is that the b-keto esters
are easy to racemize. The other is the high reaction temperature.
With the optimized reaction conditions in hand, the scope of
the thiourea catalyst catalysed reduction was next investigated.
A variety of a-keto arylacrylate compounds could be reduced to
the corresponding products. When the R2 in 5 were p-
substituted phenyls, all the tested substrates could be reduced
to the desired products with 76–94% yields. The substrates with
an electron withdrawn group on the para position of the phenyl
rings comparing with the substrates with an electron donating
groups were easier to be reduced and a higher yield could be
obtained (Fig. 2, 6a–g). When the R2 in 5 were o/m-substituted
phenyls, the substrates could be reduced equally at the existing
reaction conditions, and almost identical yields were obtained
(Fig. 2, 6h and 6i). When the R2 in 5 were bulky groups such as 2-
naphthyl, the substrate could also be reduced with a 93% yield
(Fig. 2, 6j). The 2-furanyl and 2-thiophenyl could also be used as
R2 in the substrate 5, 88% and 77% yields were obtained when
these substrates were used, respectively (Fig. 2, 6k and 6l). The
R1 in 5 could be the para electron donating and withdrawn
groups substituted phenyl rings, 82–95% yields were obtained
when these substrates were reduced under the existing condi-
tions (Fig. 2, 6m–q). The o/m-choro substituted phenyls could
also be used as R1 in 5, and they could be reduced with 83% and
85% yields, respectively (Fig. 2, 6r–s). The relatively bulky rings
Entry Solvent Catalyst
Cat. (eq.) Temp (C) ee (%) Yieldb (%)
1
2
3
4
5
6
7
8
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
PhMe
DCM
EtOH
—
—
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
—
—
—
—
—
—
—
<5
<5
<5
<5
—
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
35
60
40
38
40
56
72
93
82
90
80
85
62
65
75
82
71
48
13
59
12
18
25
CH3COOH 0.2
CF3COOH 0.2
CF3SO3H
Urea
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
Thiourea
Cat 1
Cat 2
Cat 3
Cat 4
Cat 5
Cat 6
Cat 7
Cat 8
Cat 2
Cat 2
Cat 2
Cat 2
Cat 2
Cat 2
9
10
11
12
13
14
15
16
17c
18
19
20
21
22
23
100
100
100
40
78
84
MeCN Cat 2
THF
—
Cat 2
Cat 2
70
100
a
Unless specied otherwise, reactions were carried out with 1.0 mmol
b
of 5a and 1.0 mmol of Hantzsch ester for 24 hours. Isolated yield.
c
The reaction time is 12 hours.
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Scheme
2
A
gram-scale synthesis of ethyl 2-benzyl-3-oxo-3-
phenylpropanoate.
dissolved in water at 100 ꢀC. Both the two carbonyl groups of the
substrate 5 and hydrogen of the Hantzsch ester could be acti-
vated by the two NH of the thiourea and the OH of catalyst Cat 2,
respectively, under the solvent affection of water.
Conclusions
In summary, we have developed a novel method for the reduc-
tion of a-keto arylacrylate and alkylacrylate compounds by
Hantzsch ester in water under the catalysis of thiourea catalysts.
A series of a-alkyl-b-ketoesters were isolated with moderate to
high yields. Although the chiral products were fail to obtained,
the obvious advantages of this method are high chemo-
selectivity, water tolerance and mild experimental conditions
over the traditional methods such as hydrogenation. Especially,
functional groups such as keto, ester, nitro, uoro, chloro,
bromo, furanyl and thienyl are all tolerated by the reaction
conditions employed. We believe that this simple, green cata-
lytic protocol provides an alternative way to prepare a-alkyl-b-
ketoesters.
Acknowledgements
We are grateful for the nancial supports from the Spring Plan
of Ministry of Education (Z2016162), the founds of Sichuan
Province (2017JQ0023, 2017NZ0048), the founds of Chengdu
City (2015-HM01-00366-SF), the Undergraduate Scientic and
Technological Innovation Project, the National Undergraduate
Innovation and Entrepreneurship Training Programs of China
and The Innovation Fund Of Postgraduate, Xihua University.
Fig. 2 Substrate scope of the thiourea Cat 2 catalysed reduction.
and the hetero aromatic ring were tolerated also when they were
used as R1 in 5, and the corresponding products could be iso-
lated with 75–88% yields (Fig. 2, 6t–u). Besides Et, other groups
such as Me, i-Pr, and Bn could also be used as R3 in 5. 85–89%
yields could be obtained when these substrates were reduced
under the existing reaction conditions (Fig. 2, 6x–aa). What's
more, the a-keto alkylacrylate was also can be reduced in the
protocol and the ethyl 2-benzoylpentanoate was obtained with
62% yield (Fig. 2, 6w). However, alkyl group used as R1 in 5 leads
to only 38% yield of the desired product 6v.
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