Efficient organocatalyzed solvent-free selective synthesis of conjugated enones

Article abstract of DOI:10.1016/j.tetlet.2008.12.036

A series of conjugated dienones and enones were synthesized by a reaction of both conjugated and simple aldehydes, respectively, with 1,3-dicarbonyl compounds and aldehydes under solvent-free conditions at room temperature in the presence of 10 mol % of l-proline as catalyst. The selective formation of one isomer was observed exclusively with most of the 1,3-dicarbonyl compounds and aldehydes. The most commonly formed xanthene derivative from the cyclic diketones is inhibited with our protocol, with the exclusive formation of conjugated dienones only.

Full text of DOI:10.1016/j.tetlet.2008.12.036

Tetrahedron Letters 50 (2009) 897–900
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Tetrahedron Letters
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Efficient organocatalyzed solvent-free selective synthesis of conjugated enones
*
Papori Goswami , Babulal Das
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of conjugated dienones and enones were synthesized by a reaction of both conjugated and simple
aldehydes, respectively, with 1,3-dicarbonyl compounds and aldehydes under solvent-free conditions at
room temperature in the presence of 10 mol % of L-proline as catalyst. The selective formation of one iso-
mer was observed exclusively with most of the 1,3-dicarbonyl compounds and aldehydes. The most com-
monly formed xanthene derivative from the cyclic diketones is inhibited with our protocol, with the
exclusive formation of conjugated dienones only.
Received 10 November 2008
Revised 2 December 2008
Accepted 4 December 2008
Available online 13 December 2008
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
1,3-Dicarbonyl compounds
Knoevenagel
Aldehydes
Enones
Solvent free
a,b-Enones are synthetically important organic molecules,
these, L-proline was found to be the best at room temperature
which are generally used as substrates for Morita–Baylis–Hilmann
reactions,1 addition to carbonyl groups and conjugated double
bonds.2 On the other hand, conjugated enones are versatile synt-
hones3 and significant substrates for Diels–Alder reactions and
1,4-addition.4 These compounds are generally synthesized by the
aldol and Knoevenagel condensation,5 the Horner–Wadsworth–
and has a very short reaction time as shown in Scheme 1.
Initially, we screened a variety of amines as well as amino acids
for effective catalytic activity as shown in Table 1. Benzoyl acetone,
an unsymmetric diketone, and cinnamaldehyde were taken as the
model substrates. Among the screened catalysts, 10 mol % of L-pro-
line was found to be the most effective as the reaction was com-
pleted within a very short time.
Emmons reaction,6 and isomerization of
a
,b-ynones,6c among
which the Knoevenagel condensation is of great significant value.
These condensations are generally carried out in the presence of
base,7 acids8 and solvent-free conditions9 under microwave10 or
infra red irradiation.11 However, these methods suffer from numer-
ous limitations such as harsh reaction conditions, use of hazardous
solvents, and requirement of high temperatures, to name a few.
Although the reaction can be carried out under catalyst-free condi-
tions, the yields of the condensed products were low.12
The incapability of the protocol to furnish one pure isomer
selectively in ethanol, forced us to find a suitable solvent system
in order to get the optimum yield of one isomer selectively. Hence,
another set of reactions was performed with cinnamaldehyde and
benzoyl acetone in various solvents in the presence of a catalytic
amount of
L-proline as shown in Table 2. The observations indicate
that one selective isomer was obtained exclusively under the
While the Knoevenagel condensations are generally carried out
with active methylene compounds such as b-ketoesters, cyanoace-
tates, malononitriles, the reaction with b-diketones is less re-
ported.13 This is because the 1,3-diketones have an inherent
tendency to form a stable cyclic enol, which makes it less reactive
than other active methylene compounds. Furthermore, a very re-
cent report14 of 1,3-diketones as the Knoevenagel substrate faces
the drawbacks of much longer times and smaller yields.
In continuation of our work with new synthetic methodolo-
gies,15 we report a mild and environmentally-benign protocol for
the selective synthesis of an E-isomer of the conjugated enones
using a catalytic amount of either amines or amino acids. Among
O
O
O
R2
R1
O
O
O
L-proline
L-proline
R2
R1
+
CHO
R1
R3
R3
O
O
O
R3
R3
O
O
O
L-proline
R5
R4CHO
+
R5
R4
R1 = Me, Ph
R3 = H, Me
R2 = OMe, OEt.....Me, Ph R4 = Ph, 4-ClC6H4, 4-NO2C6H4,Cyclohexyl
* Corresponding author. Tel.: +91 3612583000; fax: +91 3612690762.
E-mail address: papori@iitg.ernet.in (P. Goswami).
Scheme 1. Synthesis of conjugated dienone system.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.036

898
P. Goswami, B. Das / Tetrahedron Letters 50 (2009) 897–900
Table 1
Screening of catalysta
Entry
Catalyst (10 mol %)b
Time (h) [min]
Yieldc (%)
1
2
3
4
5
6
7
8
9
Benzyl amine
Pyridine
Adenine
Pyridine dicarboxylic acid
Lysine
Aniline
10
8
6
5
4
2
3
3
[40]
60
65
75
82
74
80
70
83
90
L
L
L
-Histidine
-Cysteine
-Proline
Figure 1. Single crystal XRD for compound 8bd.
a
Reaction was carried out with cinnamaldehyde (1 mmol) and benzoyl acetone
entries 1c–4c). The two unsaturated aldehydes chosen were cro-
tonaldehyde (a) and cinnamaldehyde (b), respectively. The reac-
tion with b-ketoesters (Table 3, entries 1c–3c), considered the
classical Knoevenagel substrates, and with aldehydes furnished
the desired conjugated enones 1ad–3ad and 1bd–3bd in excellent
yields.16
(1.1 mmol).
b
c
All the reactions were performed in ethanol.
Yields refer to the isolated yield.
Table 2
Screening of solventsa
All the products were obtained selectively as E-isomers with
the exception of allyl acetoacetate (Table 3, entry 4c) which gave
a mixture of both E and Z isomers 4ad–bd with an E-isomer in
the predominant form. Next, we carried out the reaction with a
variety of both acyclic and cyclic 1,3-diketones (Table 3, entries
5c–8c). It is to be noted that the reported Knoevenagel reac-
tion13a with cyclic diketones and b-carbonyl compounds gener-
ally furnishes xanthene derivatives as the reaction further
proceeds after the condensation to give a Michael product. How-
ever, our protocol gave the conjugated dienone 5ad–8ad and
5bd–8bd exclusively in good yields without a further Michael
reaction.
Entry
Solvents (3 ml)
Time (min)
E:Zb
Yieldc (%)
1
2
3
4
5
Dichloromethane
Chloroform
Acetonitrile
Ethanol
35
40
30
40
10
65:35
60:40
71:29
80:20
100:0
90
88
75
88
87
—
a
Reaction was carried out with cinnamaldehyde (1 mmol) and benzoyl acetone
(1.1 mmol).
b
c
The ratio found from NMR.
Yields refer to the isolated yield.
The structure of 8bd was further confirmed by single crystal
XRD as depicted in Figure 1.
solvent-free condition indicating that the solvent assists in the cis–
trans isomerization of the condensed products.
With these results in hand, we tried to explore the reaction of
both aliphatic and aromatic unconjugated aldehydes (Table 4, en-
Upon finding the optimal condition, a set of reactions were car-
ried out with a variety of 1,3-dicarbonyl compounds (Table 3,
Table 3
Reaction of
a
,b-unsaturated aldehydes with 1,3-dicarbonyl compounds
O
O
O
O
R2
R1
L-Proline
L-Proline
R2
R1
+
1c - 6c
CHO
a = Me, b = Ph
1ad - 6ad, 1bd - 6bd
R3 R3
R3
O
R3
O
O
O
7c - 8c
R1
7ad - 8ad, 7bd - 8bd
Entry
1
1,3-Dicarbonyl compounds (c)
R2 = OMe
Products
Time (min)
Yielda,b [E:Z ratio] (%)
1ad
1bd
2ad
2bd
3ad
3bd
4ad
4bd
5ad
5bd
6ad
6bd
7ad
7bd
8ad
8bd
15
15
15
15
15
10
15
15
15
10
15
10
10
10
10
10
80
80
84
91
72
83
2
3
4
5
6
7
8
R2 = OEt
R2 = OCMe3
R2 = OCH2–CH@CH2
74 [60:40]
81 [80:20]
R2 = Me
R2 = Ph
R3 = H
85
90
79
87
85
93c
81
92c
R3 = Me
a
Yields refer to isolated yield.
All the compounds were characterized by NMR, mass, and elemental analyses.
The crude products were recrystallized from ethanol and analyzed directly without further purification.
b
c

P. Goswami, B. Das / Tetrahedron Letters 50 (2009) 897–900
899
Table 4
Reaction of aldehydes with 1,3-dicarbonyl compounds
O
O
O
O
L-proline
L-proline
R2
R2
9b - 14b
R1
9c - 14c
R3 R3
R1
CHO
+
R3
a
O
R3
O
O
O
R1
15c - 17c
R1 = Me, Ph R2 = Me, Ph R3 = H, Me
15b - 17b
Entry
Aldehyde (a)
1,3-Dicarbonyl compounds (b)
Time (min)
Yielda,b (%)
9
10
11
12
13
14
15
16
17
R1 = Ph
R1 = p-Br–C6H4
R2 = Me
R2 = Me
R2 = Me
R2 = Ph
R2 = Ph
R2 = Me
R3 = Me
R3 = H
30
20
20
35
30
40
20
20
20
85
89
83
67
72
71
76
85
88
R
1 = p-NO2–C6H4
R1 = p-OMe–C6H4
R1 = Ph
R1 = Cyclohexyl
R1 = Cyclohexyl
R1 = Ph
R1 = p-Br–C6H4
R3 = Me
a
Yields refer to isolated yield.
All the compounds were characterized by NMR, mass, and elemental analyses.
b
2. For reviews, see: (a) Jung, M. E.. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Semmelhack, M. F., Eds.; Pergamon Elsevier: Oxford, 1991; Vol. 4, p
1; (b) Lee, V. J.. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Semmelhack, M. F., Eds.; Pergamon Elsevier: Oxford, 1991; Vol. 4, p 69 and 139;
(c) Kozlowski, J. A.. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Semmelhack, M. F., Eds.; Pergamon Elsevier: Oxford, 1991; Vol. 4, p 169.
3. (a) Patai, S.; Rappoport, Z. The Chemistry of Enones; Wiley: Chichester, 1989; (b)
Foster, C. E.; Mackie, P. R.. In Comprehensive Organic Functional Group
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Wadagaonkar, P. P. Tetrahedron Lett. 2006, 47, 9325.
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Rçder, A. Synthesis 2001, 171;; (b) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem.
2002, 3221; (c) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829; (d) Guo,
H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354; For recent reviews on Diels–
Alder reactions, see: (e) Takao, K.-I.; Munakata, R.; Tadano, K.-I. Chem. Rev.
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F. Tetrahedron 2000, 56, 9357; (b) Sugino, T.; Tanaka, K. Chem. Lett. 2001, 110;
(c) Correa, W. H.; Scott, J. L. Green Chem. 2001, 3, 296; (d) Bogdal, D. J. Chem. Res
(S) 1998, 468.
8. (a) Bose, D. S.; Narsaiah, A. V. J. Chem. Res. (S) 2001, 36; (b) Scott, J. L.; Raston, C.
L. Green Chem. 2000, 2, 245; (c) Khan, R. H.; Mathur, R. K.; Ghosh, A. C. Synth.
Commun. 1996, 264, 683; (d) Rao, P. S.; Venkataratnam, R. V. Tetrahedron Lett.
1991, 32, 5821.
tries 9a–17a) with 1,3-diketones (Table 4, entries 9b–17b). Inter-
estingly, the reactions took a considerably longer time for comple-
tion as compared to the conjugated aldehydes as shown in Table 4.
The reaction gave Knoevenagel products 9c–17c exclusively with
the formation of an E-isomer. The aldehydes with both electron-
withdrawing and electron-donating groups underwent the reac-
tion smoothly. However, the yields obtained with electron-donat-
ing aldehydes were smaller and had a longer reaction time. The
aliphatic aldehyde also gave the
and 15c in good yields without undergoing further isomerization17
to b, -unsaturated ones, inspite of the presence of -hydrogens in
aliphatic aldehydes.
a,b-unsaturated products 14c
a
a
In conclusion, we have devised a simple and efficient environ-
mentally-benign protocol for the solvent-free synthesis of conju-
gated dienones with the formation of E-isomer selectively within
a short reaction time at room temperature. The formation of a sin-
gle isomer selectively, without any side products, which is a major
drawback faced with other reported methods, is a major asset of
our protocol. Another notable advantage is the retardation of the
Michael reaction of the synthesized Knoevenagel products from
cyclic diketones. Taking account of these advantages, our clean
protocol should contribute toward the realm of synthetic organic
chemistry.
Acknowledgments
9. (a) Tanaka, K. Solvent-Free Organic Synthesis; Wiley-VCH: Weinheim, 2003.
Chapter 3.2, pp 93–136; (b) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025.
10. (a) Balalaie, S.; Nemati, N. Synth. Commun. 2000, 30, 869; (b) Balalaie, S.;
Nemati, N. Heterocycl. Commun. 2001, 7, 67; (c) Villemin, D.; Labiad, B. Synth.
Commun. 1990, 20, 3333; (d) Sabitha, G.; Reddy, B. V. S.; Satheesh, R. S.; Yadav,
J. S. Chem. Lett. 1998, 773; (e) Bandgar, B. P.; Uppalla, L. S.; Kurule, D. S. Green
Chem. 1999, 1, 243; (f) Loupy, A.; Song, S.; Sohn, S.; Lee, Y.; Known, T. J. Chem.
Soc., Perkin Trans. 1 2001, 1220.
The work was carried out with the financial Grant No. SR/FTP/
CS-15/2007 of DST, New Delhi, India. The Director, IITG is given
special thanks for offering the required research facility to carry
out the work.
11. Obrador, E.; Castro, M.; Tamariz, J.; Zepeda, G.; Miranda, R.; Delgado, F. Synth.
Commun. 1998, 28, 4649.
Supplementary data
12. (a) Maggi, R.; Bigi, F.; Carloni, S.; Mazzoc, A. Green Chem. 2001, 173; (b) Bigi, F.;
Conforti, M. L.; Maggi, R.; Piccinno, A.; Sartori, G. Green Chem. 2000, 173; (c)
Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.; Mazzacani, A.; Sartori, G. Tetrahedron
Lett. 2001, 42, 5203.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.12.036.
13. (a) Kantevari, S.; Bantu, R.; Nagarapu, L. J. Mol. Catal. A: Chem. 2007, 269, 53; (b)
Su, C.; Chen, Z.-C.; Zheng, Q.-G. Synthesis 2003, 555.
14. Bartoli, G.; Bosco, M.; Carlone, A.; Dalpozzo, R.; Galzerano, P.; Melchiorre, P.;
Sambri, L. Tetrahedron Lett. 2008, 49, 2555.
15. (a) Goswami, P.; Ali, S.; Khan, M. M.; Khan, A. T. ARKIVOC 2007, 15, 82; (b)
Goswami, P.; Bharadwaj, S. K. Catal. Lett. 2008, 124, 100; (c) Goswami, P. Green
References and notes
1. (a) Basavaiah, D.; Dharma Rao, P.; Suguna Hyma, R. Tetrahedron 1996, 52, 8001;
(b) Ciganek, E. Org. React. 1997, 51, 201; (c) Basavaiah, D.; Jaganmohan Rao, A.;
Satyanarayana, T. Chem. Rev. 2003, 103, 811.

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P. Goswami, B. Das / Tetrahedron Letters 50 (2009) 897–900
Chem. Lett. Rev. 2008. doi: 10.1080/17518250802403774.; (d) Goswami, P. Syn.
Commun. 2008, in press.
16. General procedure for the Knoevenagel condensation: A mixture of 1,3-dicarbonyl
compound (1.1 mmol), aldehydes (1 mmol), and -proline (10 mol %) was
J = 6.8 Hz, 2H), 2.63 (t, J = 6.8 Hz, 2H), 2.64 (t, J = 6.8 Hz, 2H), 7.34 (d, J = 15.2 Hz,
1H), 7.38–7.39 (m, 3H), 7.60–7.62 (m, 2H), 7.80 (d, J = 12.0 Hz, 1H), 8.33 (dd,
J = 12.0 Hz, J = 15.2 Hz, 1H). 13C NMR (CDCl3, 100 MHz): d (ppm): 18.35, 38.93,
40.55, 125.88, 129.02(2C), 129.24(2C), 130.74, 131.21, 135.87, 152.14, 153.66,
198.45 199.48. Anal. Calcd for C15H14O2: C, 79.62; H, 6.24. Found: C, 79.50; H,
6.37.2-Acetyl-5-phenyl-penta-2,4-dienoic acid methyl ester (1bd): 1H NMR
(CDCl3, 400 MHz): d (ppm): 2.39 (s, 3H), 3.90 (s, 3H), 7.09 (d, J = 15.2 Hz, 1H),
7.26 (dd, J = 11.6 Hz, J = 15.2 Hz, 1H), 7.34–7.37 (m, 3H), 7.44 (d, J = 11.6 Hz,
1H), 7.49–7.51 (m, 2H). 13C NMR (CDCl3, 100 MHz): d (ppm): 27.83, 52.15,
123.56, 127.91(2C), 128.89(2C), 130.04, 132.09, 135.52, 145.08, 146.01, 166.73,
195.57. Anal. Calcd for C14H14O3: C, 73.03; H, 6.13. Found: C, 73.24; H, 6.24.2-
Acetyl-hexa-2,4-dienoic acid ethyl ester (2ad): 1H NMR (CDCl3, 400 MHz): d
(ppm): 1.34 (t, J = 6.8 Hz, 3H), 1.92 (d, J = 6.8 Hz, 3H), 2.33 (s, 3H), 4.32 (q,
J = 6.8, 2H), 6.39 (pent, J = 6.8 Hz, 1H), 6.54 (dd, J = 11.6 Hz, J = 14.8 Hz, 1H),
7.20 (d, J = 11.6 Hz, 1H). 13C NMR (CDCl3, 100 MHz):d (ppm): 14.37, 19.45,
27.86, 61.39, 127.76, 131.49, 144.78, 145.91, 166.65, 195.81. Anal. Calcd for
C10H14O3: C, 65.91; H, 7.74. Found: C, 66.09; H, 7.88.
L
mixed in a mortar under solvent-free conditions. After the completion of the
reaction as indicated by Thin Layer Chromatography (TLC), ethyl acetate was
added to the crude reaction mixture. The reaction mixture in ethyl acetate was
added to water for the removal of the catalyst. The organic layer was separated,
dried over anhydrous Na2SO4 and evaporated under a vacuum. The crude
products were purified by column chromatography (hexane:ethyl acetate 1:9).
The purified products were analyzed by spectral analyses.Spectroscopic data
for selected compounds:5,5-Dimethyl-2-(3-phenyl-allylidene)-cyclohexane-1,3-
dione (8bd): 1H NMR (CDCl3, 400 MHz): d (ppm):1.07 (s, 6H), 2.53 (s, 2H), 2.54
(s, 2H), 7.34 (d, J = 15.2 Hz, 1H), 7.38–7.39 (m, 3H), 7.59–7.62 (m, 2H), 7.78 (d,
J = 12.0 Hz, 1H), 8.35 (dd, J = 12.0 Hz, J = 15.6 Hz, 1H). 13C NMR (CDCl3,
100 MHz):
d (ppm): 28.70(2C), 30.24, 52.52, 54.22, 125.73, 128.93(2C),
129.16(2C), 131.12(2C), 135.80, 151.43, 153.59, 198.12, 199.17. Anal. Calcd
For C17H18O2: C, 80.28; H, 7.13. Found: C, 80.09, H, 7.28.2-(3-Phenyl-allylidene)-
cyclohexane-1,3-dione (7bd): 1H NMR (CDCl3, 400 MHz): d (ppm): 2.03 (pent,
17. (a) Wilson, B. D. J. Org. Chem 1963, 28, 314; (b) Hiramatsu, H.; Harada, K.;
Kojima, Y.; Fujiwara, K. Nippon Kagaku Kaishi 1989, 4, 714.