New and facile approach for the synthesis of (E)-α,β-unsaturated esters and ketones

Article abstract of DOI:10.1002/chem.201000883

A general and practical synthesis of (E)-α,β-unsaturated esters and ketones was achieved by the reaction of carbonyl compounds with ethyl-4,4,4-trifluoroacetoacetate and trifluoro-substituted 1,3-diketones in the presence of piperidine in dichloromethane at raoom temperature (≈40°C) with excellent stereoselectivity (see scheme).

Full text of DOI:10.1002/chem.201000883

DOI: 10.1002/chem.201000883
New and Facile Approach for the Synthesis of (E)-a,b-Unsaturated Esters
and Ketones
Bhimapaka China Raju* and Pathi Suman[a]
Preparation of (E)-a,b-unsaturated esters and ketones is
an important task in organic synthesis.[1] Such esters and ke-
tones are excellent building blocks for the synthesis of a ple-
thora of synthetic and natural products.[2] The most versatile
and widely used methods are the Wittig reaction[3] with alde-
hydes by using alkoxycarbonylmethylene(triphenyl)phos-
phoranes and the Horner–Wadsworth–Emmons[4] procedure
using trialkyl phosphonoacetates with stronger bases. These
methods generate stoichiometric amounts of byproducts,
namely triphenylphosphine oxide and phosphate salts. De-
carboxylative Knoevenagel-type reactions employing malon-
ic acid half esters[5] and the olefination of aldehydes with
ethyl diazoacetate[6] (EDA) are alternative methods report-
ed for the synthesis of (E)-a,b-unsaturated esters. The syn-
thesis of (E)-a,b-unsaturated ketones involves the reaction
of aromatic aldehydes with aromatic ketones, alkynes and
the Grignard reaction of unsaturated aromatic nitriles.[7] The
Knoevenagel condensation is an important reaction for the
synthesis of a,b-unsaturated compounds; aromatic alde-
hydes afforded (E)-a,b-unsaturated esters and salicylalde-
hydes afforded 3-substituted coumarins[8] with b-ketoesters
in the presence of base. Generally, the condensation of car-
bonyl compounds with active methylene substrates contain-
ing trifluoroacetoacetate substituents seldom gives the con-
densation product; however, it has been reported that the
reaction of benzaldehyde with ethyl-4,4,4-trifluoroacetoace-
tate in the presence of piperidine in toluene under reflux
conditions afforded ethyl (E)-3-phenyl-2-(2,2,2-trifluoroace-
tyl)-2-propenoate in low yields.[9]
synthesis of methyl (E)-3-(2-chloro-5-methyl-3-pyridyl)-2-
propenoate[11] by adopting Horner–Wadsworth–Emmons
(HWE) reaction conditions and synthesized new Knoevena-
gel products. Herein, we report a new, general, and practical
method for the synthesis of (E)-a,b-unsaturated esters and
ketones by Aldol-adduct elimination under basic conditions.
Treatment of 2-chloro-5-methylnicotinaldehyde (1q) with
ethyl-4,4,4-trifluoroacetoacetate (2a) in CH2Cl2 in the pres-
ence of piperidine at room temperature for 4–6 h gave the
geometrically selective E product 3qa instead of the con-
densation product (Scheme 1).
Scheme 1. Synthesis of (E)-a,b-unsaturated esters.
The result surprised and encouraged us to search for the
best reaction conditions. The optimization of the reaction
conditions was first examined with the use of mostly basic
catalysts, namely 1,4-diazabicycloACHTUNTRGNEUNG[2.2.2]octane (DABCO), 4-
dimethylaminopyridine (DMAP), imidazole, triethylamine,
NaOMe, pyridine, and picoline, and we found that the reac-
tion did not take place under these basic conditions. Howev-
er, when we studied the use of piperidine with various sol-
vents we found that CH2Cl2 was the solvent of choice in
terms of yield, reaction time, and selectivity for the synthesis
of (E)-a,b-unsaturated esters (Table 1). Regarding the opti-
mum quantity of catalyst, one equivalent of piperidine is
necessary to promote the reaction in an efficient manner.
We propose a possible mechanism for the formation of
the product, which is in line with the Aldol condensation re-
action. The sequence of the reaction was monitored by
LCMS and the formation of the primary Aldol product (A)
was observed. Further attack of piperidine on the trifluoro-
As part of our ongoing efforts in developing approaches
for the synthesis of various heterocyclic compounds with po-
tential biological applications,[10] we recently reported the
[a] Dr. B. China Raju, P. Suman
Organic Chemistry Division-1
Indian Institute of Chemical Technology
Hyderabad 500 607 (India)
Fax : (+91)40-27160512
E-mail: chinarajuiict@yahoo.co.in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000883.
AHCTUNGTREGaNNUN cetyl carbon followed by in situ stereoselective elimination
11840
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Chem. Eur. J. 2010, 16, 11840 – 11842

COMMUNICATION
Table 1. Optimization of reaction conditions.[a]
Table 2. Piperidine catalyzed synthesis of (E)-a,b-unsaturated esters and
ketones.
Entry
Catalyst [equiv]
Solvent
t [h]
Yield [%][b,c]
Entry
R1
2
t [h]
3
Yield [%][a] E[b]
90
1
2
3
4
5
6
7
8
0.1
0.1
0.3
1
1.2
0.1
0.1
0.3
0.3
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
MeOH
MeCN
MeOH
MeCN
MeOH
EtOH
6
24
6
6
8
6
6
6
6
6
6
6
6
20
42
45
95
95
12
10
25
20
60
55
40
45
40
1
2
3
4
5
6
7
8
C6H5
C6H5
2a 6.0
2b 5.0
2a 5.0
2b 4.5
2a 5.0
2b 4.0
2b 4.0
2c 4.0
2a 7.0
2b 5.0
2a 6.5
2a 6.5
2a 4.5
2a 4.0
2a 6.0
2a 5.0
2a 5.0
2a 4.5
2a 5.0
2a 7.5
2a 6.5
2c 6.5
2a 6.0
2b 4.5
2c 4.5
2a 6.5
2a 6.5
2a 5.5
2b 5.0
2c 5.0
3aa
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
–
3ab 91
3ba 92
3bb 92
3ca
3cb
3db 95
3dc
3ea
3eb 89
3 fa
3ga
3ha 90
3ia
3ja
3ka 90
3la 88
3ma 90
3na 67
3oa 71
3pa 62
3pc
3qa 87
3qb 91
3qc
3ra
3sa
3ta
3tb
3tc
3ua 90
3ub 93
3uc
3va
–
4-BrC6H4
4-BrC6H4
4-ClC6H4
4-ClC6H4
4-NO2C6H4
4-NO2C6H4
4-OMeC6H4
4-OMeC6H4
4-MeC6H4
4-EtC6H4
3,5-F2C6H3
3-NO2C6H4
Furyl
91
93
94
84
9
9
10
11
12
13
14
10
11
12
13
14
15
16
17
18
19[c]
20[c]
21[c]
22[c]
23
24
25
26
27
28
29
30
31
32
33
34
35
1
1
1
1
89
88
THF
Benzene
24
95
85
[a] Reaction conditions: 1i (0.2 mmol), 2a (0.2 mmol). [b] Yield of the
isolated product. [c] Reaction was carried out at RT.
2-Pyridyl
3-Pyridyl
4-Pyridyl
AHCTUNGRTEG(NNUN CH3)2CH
n-C5H11
of piperidinium trifluoroacetate gives the (E)-a,b-unsaturat-
ed ester (Scheme 2).
n-C3H7
n-C3H7
74
2-Cl, 5-Me, 3-Pyridyl
2-Cl, 5-Me, 3-Pyridyl
2-Cl, 5-Me, 3-Pyridyl
2-Cl, 5-Et, 3-Pyridyl
2-Cl, 5-Pr, 3-Pyridyl
2-Cl, 5-Ph, 3-Pyridyl
2-Cl, 5-Ph, 3-Pyridyl
2-Cl, 5-Ph, 3-Pyridyl
2-Cl, 6-MeO2C, 3-Pyridyl 2a 5.5
2-Cl, 6-MeO2C, 3-Pyridyl 2b 5.0
2-Cl, 6-MeO2C, 3-Pyridyl 2c 5.0
2-Cl, 3-Quinyl
C6H5COCH3
To evaluate the efficiency of this methodology, various
substituted carbonyl compounds, such as aromatic, aliphatic
and heteroaromatic carbonyl compounds, were subjected to
the reaction conditions and a series of (E)-a,b-unsaturated
esters were obtained in high yields (Table 2). Having suc-
ceeded in the synthesis of a series of (E)-a,b-unsaturated
esters, we extended this protocol for the synthesis of (E)-
a,b-unsaturated ketones and obtained 3aa–3va in very good
yields. Under these conditions the use of acetophenones is
futile. All the products were characterized by their spectral
data (1H NMR and 13C NMR spectroscopy, IR, Mass, and
HRMS), known compounds 3aa, 3ab, 3db, 3cb, 3ia,[3e] 3ea,
3ba, 3ca, 3la,[12a] 3bb, 3eb,[12b] 3dc,[12c] 3 fa, 3ga, 3ka, 3ja,[12d]
3ha,[12e] 3pa, 3na,[12f] 3oa,[12g] 3pc,[12h] and 3va[12i] were com-
pared to literature data and the unknown compounds 3qa–
3uc are documented in the Supporting Information.
92
90
89
90
90
92
92
85
0
2a 6.0
2a 24
1
[a] Yield of the isolated product. [b] Determined by H NMR spectrosco-
py analysis of the crude reaction mixture. [c] The reaction was performed
under nitrogen atmosphere.
In summary, we have established a new, general, and prac-
tical method for the synthesis of (E)-a,b-unsaturated esters
and ketones with high stereoselectivity. The present new
protocol offers several advantages, such as high selectivity
and yields, the use of environmentally benign conditions and
an inexpensive catalyst, shorter reaction times, and a simple
workup procedure, which makes it a useful and alternative
procedure from the existing methods reported.
Scheme 2. The possible mechanism for tandem Aldol-adduct elimination.
Chem. Eur. J. 2010, 16, 11840 – 11842
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11841

B. China Raju and P. Suman
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Experimental Section
Typical procedure for the synthesis of (E)-a,b-unsaturated esters: A mix-
ture of 2-chloro-5-methylnicotinaldehyde (1q, 1.0 mmol) and ethyl-4,4,4-
trifluoroacetoacetate (2a, 1.0 mmol) in dichloromethane (2 mL) was
treated with piperidine (1.0 mmol) slowly dropwise, the contents were
stirred at RT (ꢀ408C) for the indicated time, or until complete con-
sumption of the starting material had occurred, as monitored by TLC.
After the reaction was finished, the solvent was evaporated in a vacuum.
The residue was purified by column chromatography (hexane/ethyl ace-
tate 9:1) to afford the desired product 3qa as a colorless solid in 87%
yield.
Typical procedure for the synthesis of (E)-a,b-unsaturated ketones: A
mixture of 2-chloro-5-methylnicotinaldehyde (1q, 1.0 mmol) and 1,1,1-tri-
fluoro-2,4-pentanedione (2b 1.0 mmol) in dichloromethane (2 mL) was
treated with piperidine (1.0 mmol) slowly dropwise, the contents were
stirred at RT for the indicated time, or until complete consumption of
the starting material had occurred, as monitored by TLC. After the reac-
tion was finished, the solvent was evaporated in a vacuum. The residue
was purified by column chromatography (hexane/ethyl acetate 9:1) to
afford the desired product 3qb as a colorless solid in 91% yield.
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Acknowledgements
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We thank Dr. J. S. Yadav, Director and Dr. J. Madhusudana Rao, Head,
Organic Chemistry Division-I, IICT for constant encouragement and sup-
port of the work. P.S thanks the CSIR, New Delhi for financial assistance.
The authors thank Dr. V. Jayathirtha Rao, Deputy Director, IICT for
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Keywords: esters · ketones · piperidine · stereoselectivity ·
synthetic methods
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Received: April 8, 2010
Published online: September 8, 2010
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Chem. Eur. J. 2010, 16, 11840 – 11842