A straightforward method for the synthesis of alkylidene and arylidene malonates through proline-catalyzed Knoevenagel condensation

Article abstract of DOI:10.1081/SCC-120018782

A straightforward method for the synthesis of alkylidene/arylidene malonates and arylidene cyanoacetates, utilizing proline as an alternative to traditional catalysts is presented. A large number of unsaturated esters was obtained from the Knoevenagel reaction under very mild conditions and utilizing cheap reagents.

Full text of DOI:10.1081/SCC-120018782

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A Straightforward Method for the Synthesis of
Alkylidene and Arylidene Malonates Through Proline-
Catalyzed Knoevenagel Condensation
Giuliana Cardillo a , Serena Fabbroni a , Luca Gentilucci a , Massimo Gianotti a & Alessandra
Tolomelli a
a Dipartimento di Chimica “G. Ciamician,”, Università di Bologna, Bologna, Italy
Published online: 16 Aug 2006.
To cite this article: Giuliana Cardillo , Serena Fabbroni , Luca Gentilucci , Massimo Gianotti & Alessandra Tolomelli (2003)
A Straightforward Method for the Synthesis of Alkylidene and Arylidene Malonates Through Proline-Catalyzed Knoevenagel
Condensation, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
33:9, 1587-1594, DOI: 10.1081/SCC-120018782
To link to this article: http://dx.doi.org/10.1081/SCC-120018782
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 9, pp. 1587–1594, 2003
A Straightforward Method for the Synthesis of
Alkylidene and Arylidene Malonates Through
Proline-Catalyzed Knoevenagel Condensation
*
Giuliana Cardillo, Serena Fabbroni, Luca Gentilucci,
Massimo Gianotti, and Alessandra Tolomelli
Dipartimento di Chimica ‘‘G. Ciamician,’’
Universita di Bologna, Bologna, Italy
ABSTRACT
A straightforward method for the synthesis of alkylidene/arylidene
malonates and arylidene cyanoacetates, utilizing proline as an
alternative to traditional catalysts is presented. A large number of
unsaturated esters was obtained from the Knoevenagel reaction
under very mild conditions and utilizing cheap reagents.
Key Words: Knoevenagel condensation; Proline; Alkylidene malo-
nate; Arylidene malonate; Arylidene cyanoacetate.
*Correspondence: Giuliana Cardillo, Dipartimento di Chimica ‘‘G. Ciamician,’’
Universita di Bologna, via Selmi 2, 40126 Bologna, Italy; Fax: þ39 051 2099456;
E-mail: cardillo@ciam.unibo.it.
1587
DOI: 10.1081/SCC-120018782
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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1588
Cardillo et al.
INTRODUCTION
In the course of our studies on the conjugate addition of a nucleo-
phile to a Michael acceptor,[1] we required various alkylidene malonates
in good yield and to be prepared under mild conditions.
Knoevenagel condensation of carbonyl compounds on molecules
containing an active methylene group, is one of the most important
methods for the preparation of substituted alkenes.[2] This reaction
has been widely studied under a variety of conditions, solvents, and
catalysts and is generally catalyzed by a base or a Lewis acid. The
use of inorganic solid supports as catalysts[3] and new techniques
exploiting solvent free microwave assisted conditions,[4] have been
reported as well. Recently pressure effects on the Knoevenagel conden-
sation involving sterically hindered ketones have been highlighted.[5]
Two possible mechanisms have been proposed for this reaction. In the
Hann–Lapworth[2,6] hypothesis an intermediate b-hydroxydicarbonyl
compound is assumed, followed by dehydration to the alkene.
The postulated mechanism would involve catalysis of a weak base
and a weak acid. For this reason amino acids and aminophenols have
been used in the condensation of ketones and aldehydes with
cyanoacetates and in the reaction between benzaldehyde and
diethylmalonate.[2,7]
Employing secondary and primary amines as catalysts,
Knoevenagel[2,8] has shown that a condensation of an aldehyde and an
amine takes place to give an iminium salt, which then forms the
alkylidene or arylidene product.
RESULTS AND DISCUSSION
Recently, the use of proline as a catalyst for the direct asymmetric
aldol reaction between acetone and a variety of aldehydes has been pre-
sented.[9] The proline function has been proposed to act like a
‘‘micro-aldolase’’ that facilitates each step of the mechanism, including
the formation of the intermediate imine and the carbon–carbon bond
formation. On the basis of these observations, we report here the use
of (L)-proline as catalyst in the Knoevenagel reaction between dimethyl-
malonate and a variety of aldehydes (Sch. 1). Obviously the chirality of
the catalyst is not necessary for the described procedure, but the cheap-
ness of (L)-proline in comparison with the corresponding racemic amino
acid, makes it the catalyst of choice.

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Synthesis of Alkylidene and Arylidene
1589
Scheme 1. Proline-catalyzed Knoevenagel condensation between dimethyl-
malonate and aldehydes.
Table 1. Condensation of aldehydes with dimethylmalonate.
Entry
R
Product
Yielda (%)
1
2
3
4
5
6
7
8
(CH3)2CH
(CH3)2CHCH2
C6H13
1a[10]
1b[11]
1c[12]
1d
72
92
97
82
Ph-(CH2)2
Ph
1e[13]
1f
100
86
4-(CH3)2CH-Ph
2-F-Ph
4-MeO-Ph
1g
1h[11]
89
66
aCalculated on isolated product. The purity of products was
1
verified by GC–MS and H NMR analysis.
The use of proline as catalyst in this reaction allowed us to perform
the condensation under very mild conditions. Indeed, dimethylmalonate,
aldehyde, and 10% of proline were dissolved in DMSO and stirred over-
night at room temperature. The solution was then diluted with ethyl
acetate and washed with water. The reaction proceeded in very good
yields with both aliphatic (Table 1, Entries 1–4) and aromatic aldehydes
(Entries 5–8), furnishing alkylidene and arylidene malonates respectively
in almost pure form. The removal of organic solvent by rotary evapora-
tion, indeed, allowed the elimination of excess dimethyl malonate and
traces of unreacted aldehyde. Purification by flash chromatography on
silica gel was only necessary for aldehydes with a high boiling point or
when the reaction was performed on a large scale. The reaction did not
require any dehydrating agent.
Following the same pathway, we performed the condensation
between benzaldehyde or isobutyladehyde and dimethylmalonate

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1590
Cardillo et al.
Scheme 2. Proline-catalyzed Knoevenagel condensation between ethyl cyanoa-
cetate and aldehydes.
Table 2. Condensation of aldehydes with ethyl cyanoacetate.
Entry
R
Product
Yielda (%)
1
2
3
4
Ph
2a[14]
2b
2c[14]
2d[15]
94
85
98
66
4-(CH3)2CH-Ph
4-MeO-Ph
Cyclohexyl
aCalculated on isolated product. The purity of products was verified by GC–MS
1
and H NMR analysis.
utilizing different amino acids as catalysts. No reaction occurred in the
presence of phenylalanine, isoleucine, or lysine. On the other hand, when
arginine (10%) was used to induce condensation, yields comparable with
obtained in proline-catalyzed reactions were observed.
The condensation in the presence of a catalytic amount of proline
was also performed utilizing ethyl cyanoacetate as a methylene active
reagent (Sch. 2).
The condensation of a stoichiometric amount of ethyl cyanoacetate
on aliphatic aldehydes occurred in very low yields. Furthermore, when an
excess of reagent was used, a large amount of by-products derived from
the polymerization of cyanoacetate was isolated. Only the reaction of
cyclohexylaldehyde furnished the condensation product in good yield
(Table 2, Entry 4) and in (E )/(Z) 96:4 istereomeric ratio. The reaction
performed on aromatic aldehydes occurred in almost quantitative yields
(Entries 1–3) affording compound 2 almost pure as a single stereoisomer.
In conclusion, we have developed a straightforward method for the
synthesis of alkylidene/arylidene malonates and arylidene cyanoacetates,
utilizing amino acids containing a secondary amino function in DMSO
as an alternative to traditional catalysts. The easy access to unsaturated
esters was reached by means of a simple methodology, under very mild
conditions and utilizing cheap and readily available reagents and catalyst.

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Synthesis of Alkylidene and Arylidene
EXPERIMENTAL
1591
Unless stated otherwise, chemicals were obtained from commercial
sources and used without further purification. Flash chromatog-
raphy was performed on Merck silica gel 60 (230–400 mesh). NMR
Spectra were recorded with a Gemini Varian spectrometer 200 or
with a INOVA Varian 300 spectrometer. Chemical shift values are
reported as ꢀ values relative to the solvent peak of CDCl3 set at
ꢀ ¼ 7.27 (1H NMR) or ꢀ ¼ 77.0 (13C NMR). Infrared spectra were
recorded with an FT–IR Nicolet 205 spectrometer. Mass spectra were
recorded with aGC HP 5890 series II-MS HP5971 mass selective detector
coupled system.
Representative Procedure for the Knoevenagel Condensation
of Aldehydes with Dimethylmalonate
A solution of isovaleraldehyde (2.58 g, 3.2 mL, 30 mmol) in dry
DMSO (10 mL) with 10% of proline (345 mg) was stirred for 5 min.
Then dimethylmalonate (7.92 g, 6.86 mL, 60 mmol) was added and the
mixture was stirred at room temperature overnight. The reaction was
diluted with AcOEt (30 mL) and washed twice with water (30 mL). The
organic layer was dried over Na2SO4 and the solvent was removed under
vacuum to afford 2-(3-methylbutylidene)malonic acid dimethyl ester 1b
(5.52 g, 92% yield). Compound 1b was determined to be >98% pure by
1H NMR, 13C NMR, and GC–MS.
2-(3-Methyl-butylidene)malonic acid dimethyl ester 1b: IR (film) 2965,
2866, 1746, 1646, 1434 cmꢀ1
.
1H NMR (CDCl3): ꢀ 0.94 (d, 6H,
J ¼ 6.9 Hz), 1.77–1.86 (m, 1H), 2.19 (dd, 2H, J ¼ 6.9, 7.8 Hz), 3.79
(s, 3H), 3.83 (s, 3H), 7.06 (t, 1H, J ¼ 7.8 Hz). 13C NMR (CDCl3): ꢀ 22.2
(2C), 28.0, 38.5, 52.0, 52.1, 128.4, 149.1, 164.1, 165.7; MS m/z 200 (2), 169
(14), 158 (13), 136 (58), 126 (100), 113 (33), 98 (47), 68 (40), 59 (24). Anal.
Calcd. for: C, 59.98; H, 8.05. Found C, 59.95; H, 8.08.
2-(3-Phenyl-propylidene)malonic acid dimethyl ester 1d: 1H NMR
(CDCl3): ꢀ 2.60–2.72 (m, 2H), 2.75–2.87 (m, 2H), 3.80 (s, 3H), 3.82 (s,
3H), 7.10 (m, 1H), 7.20–7.40 (m, 5H). MS m/z 248 (3), 217 (7), 184 (41),
156 (14), 128 (28), 91 (100).
1
2-(4-Isopropyl-benzylidene)malonic acid dimethyl ester 1f: H NMR
(CDCl3): ꢀ 1.26 (d, 6H, J ¼ 9.9 Hz), 2.95 (m, 1H), 3.86 (s, 3H), 3.89 (s,
3H), 7.25 (d, 2H, J ¼ 12.6 Hz), 7.38 (d, 2H, J ¼ 12.6 Hz), 7.76 (s, 1H), MS
m/z 262 (68), 247 (76), 231 (24), 202 (57), 187 (100), 157 (54), 128 (55), 115
(24).

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Cardillo et al.
2-(2-Fluoro-benzylidene)malonic acid dimethyl ester 1g: 1H NMR
(CDCl3): ꢀ 3.84 (s, 3H), 3.89 (s, 3H), 7.05–7.60 (m, 4H), 7.98 (s, 1H).
MS m/z 238 (35), 207 (52), 178 (48), 139 (100), 120 (67), 109 (20).
Representative Procedure for the Knoevenagel Condensation
of Aldehydes with Ethyl Cyanoacetate
A solution of cyclohexanaldehyde (3.36 g, 3.63 mL, 30 mmol) in dry
DMSO (10 mL) with 10% of proline (345 mg) was stirred for 5 min. Then
ethyl cyanoacetate (3.72 g, 3.51 mL, 33 mmol) was added and the mixture
was stirred at room temperature overnight. The reaction was diluted with
AcOEt and washed twice with water. The organic layer was dried
over Na2SO4 and the solvent was removed under vacuum to afford 2-
cyano-3-cyclohexylacrilic acid ethyl ester 2d (4.49 g, 66% yield).
Compound 2d was determined to be >98% pure by 1H NMR,
13C NMR, and GC–MS.
2-Cyano-3-cyclohexylacrilic acid ethyl ester 2d: IR (film) 2984, 2254,
1727, 1608, 1450 cmꢀ1. 1H NMR (CDCl3): ꢀ 1.19–1.37 (m, 9H), 1.72–1.81
(m, 4H), 2.71 (m, 1H), 4.31 (q, 2H, J ¼ 7.5 Hz), 7.46 (d, 1H, J ¼ 10.5 Hz).
13C NMR (CDCl3): ꢀ 13.9, 24.7 (2C), 25.2, 30.9 (2C), 40.9, 62.2, 107.4,
113.6, 161.4, 167.6. Anal. Calcd. for C, 69.54; H, 8.27; N, 6.76. Found: C,
69.49; H, 8.29; N, 6.77.
2-Cyano-3-(4-isopropyl-phenyl)acrilic acid ethyl ester 2b: 1H NMR
(CDCl3): ꢀ 1.38 (m, 6H), 1.41 (t, 3H, J ¼ 6.9 Hz), 1.60 (m, 1H), 4.41 (q, 2H,
J ¼ 6.9 Hz), 7.55 (d, 2H, J ¼ 8.4 Hz), 7.97 (d, 2H, J ¼ 8.4 Hz), 8.26 (s, 1H).
MS m/z 243 (100), 215 (4), 196 (21), 169 (9), 156 (4), 129 (5), 91 (2).
ACKNOWLEDGMENT
We thank MURST (Cofin 2000, FIRB project, and 60%) and the
University of Bologna (funds for selected topics) for financial support.
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Synthesis of Alkylidene and Arylidene
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