Synthesis of β-ketoesters from renewable resources and Meldrum's acid

Article abstract of DOI:10.1039/c4ra08986c

β-Ketoesters are valuable building blocks for the synthesis of compounds with different biological activities. In this study, a series of fatty β-ketoesters were obtained from fatty acids and Meldrum's acid using N,N-dicyclohexylcarbodiimide and dimethylaminopyridine. In addition, we demonstrate for the first time the synthesis of new fatty β-ketoesters from oleic (cis-C18:1), elaidic (trans-C18:1), ricinoleic (cis-C18:1, 12-OH), linoleic (cis,cis-C18:2), and linolenic (cis,cis,cis-C18:3) acids in good yields.

Full text of DOI:10.1039/c4ra08986c

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Synthesis of b-ketoesters from renewable
resources and Meldrum's acid†
Cite this: RSC Adv., 2014, 4, 49556
Rafael C. Brinkerhoff,a Hernan F. Tarazona,a Patrick M. de Oliveira,a Darlene C. Flores,a
b
b
a
*
Caroline Da R. Montes D'Oca, Dennis Russowsky and Marcelo G. Montes D'Oca
Received 20th August 2014
Accepted 18th September 2014
DOI: 10.1039/c4ra08986c
www.rsc.org/advances
b-Ketoesters are valuable building blocks for the synthesis of condensation reactions of ketene silyl acetals and methyl esters
compounds with different biological activities. In this study, a series of catalysed by sodium hydroxide have also resulted in good yields
fatty b-ketoesters were obtained from fatty acids and Meldrum's acid of various b-ketoesters.14,15
using N,N-dicyclohexylcarbodiimide and dimethylaminopyridine. In
An important route for the synthesis of b-ketoesters is acyl-
addition, we demonstrate for the first time the synthesis of new fatty ation of Meldrum's acid followed by a reaction with an alcohol.
b-ketoesters from oleic (cis-C18:1), elaidic (trans-C18:1), ricinoleic (cis- Oikawa et al.16 showed that the acylation of various acyl chlo-
C18:1, 12-OH), linoleic (cis,cis-C18:2), and linolenic (cis,cis,cis-C18:3) rides with Meldrum's acid yielded the corresponding acyl Mel-
acids in good yields.
drum's acids, which readily underwent alcoholysis with
methanol, ethanol, tert-butyl alcohol, benzyl alcohol, and tri-
chloroethanol to produce various b-ketoesters.
b-Ketoesters are extremely important and versatile organic
compounds with a wide range of applications, including alpha-
halogenation and alpha-azidation,1 synthesis of thiazoles and
thiophenes,2 and use in multicomponent reactions.1–6 Using b-
ketoesters as the building blocks in multicomponent reactions
yields several different structures based on the dihydropyr-
idinone, tetrahydropyridine, or dihydropyridine skeleton,
creating an extensive library of compounds with various bio-
logical activities.4–7
According to the literature, the transesterication process for
the synthesis of b-ketoesters in solvent-free conditions without
the use of catalysis results in high yields when using excess
alcohol at a high temperature.3 Primary, secondary, and tertiary
alcohols have been tested in the presence of molecular sieves,
resulting in good b-ketoester yields.8 The catalysts in the
transesterication reaction vary and include new silica-based
hybrid materials,9 triethylamine,10 boric acid,11 and
triphenylphosphine.12
C-acylation of Meldrum's acid by N-protected amino acids,
using isopropenyl chloroformate (IPCF) or dicyclohexyl-
carbodiimide (DCC) and dimethylaminopyridine (DMAP) as the
condensing agent, has been performed, and d-amino-b-
ketoesters have been obtained in high yields.17
In a continuation of our studies developing new fatty acid
compounds,18–20 we investigated the synthesis of b-ketoesters
through acylation reactions of Meldrum's acid with different
families of saturated and unsaturated carboxylic acids. In
addition, we report for the rst time the synthesis of new fatty b-
ketoesters from oleic (cis-C18:1), elaidic (trans-C18:1), ricinoleic
Claisen condensation is a classic method of b-ketoester
synthesis. The condensation of the acid chlorides and esters
catalysed by titanium tetrachloride and N-methylimidazole
produces various b-ketoesters in good yields.13 Crossed Claisen
a
´
´
ˆ
Universidade Federal do Rio Grande, Laboratorio Kolbe de Sıntese Organica, Rio
Grande-RS, Brazil. E-mail: dqmdoca@furg.br; Tel: +55 5332336964
b
´
´
ˆ
Universidade Federal do Rio Grande do Sul-UFRGS, Laboratorio de Sıntese Organica,
Porto Alegre-RS, Brazil
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra08986c
Scheme 1 Synthesis of fatty b-ketoester 4e from Meldrum's acid (2)
via a fatty acid chloride.
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(Scheme 1).16 However, aer a long reaction time, the fatty
b-ketoester 4e was obtained in a poor yield (43% from 1e).
Therefore, aerward, we examined the use of DMAP and
DCC as a coupling agent to synthesise the fatty b-ketoesters
from Meldrum's acid and the fatty acids.
Experiments were carried out using palmitic acid (1e) as the
model, along with Meldrum's acid (2), DCC, DMAP, and pyri-
dine at room temperature under a nitrogen atmosphere. The
enol derivative 3e was isolated and used without previous
purication. Then, b-ketoester 4e was obtained from a reaction
of the respective enol 3e and methanol in an acid catalyst at
reux for 12 h. The puried product 4e was obtained in a 65%
yield from 1e (Scheme 2).
Scheme 2 Synthesis of fatty b-ketoester 4e from Meldrum's acid (2)
and fatty acid 1e using DMAP and DCC as the coupling agents
(Method A).
(cis-C18:1, 12-OH), linoleic (cis,cis-C18:2), and linolenic
(cis,cis,cis-C18:3) acids.
Initially, experiments using palmitic acid (1e) as a model
with thionyl chloride and pyridine in the presence of Meldrum's
acid (2) were undertaken according to the literature
During the purication of b-ketoester 4e by chromatography,
a signicant amount of methyl palmitate was obtained from
what could only have been an acid-catalysed esterication
Table 1 Synthesis of b-ketoesters 4a–j from fatty acids 1a–j
Yield (%)
Entry
1
Fatty acid
Fatty b-ketoester
Method A
Method B
78
51
2
3
4
52
50
59
78
76
74
5
6
7
8
9
65
69
70
69
70
80
84
81 (ref. 24)
78 (ref. 25)
79 (ref. 26)
10
69
80 (ref. 27)
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reaction of unreacted palmitic acid (1e) from the acylation step
with methanol.
In Method B, the addition of the fatty acid over DCC in the
absence of Meldrum's acid, leading to the consumption of the
To investigate the acylation reaction with various fatty acids complete fatty acid and the nucleophilic attack of Meldrum's
(C6:0, C8:0, C10:0, C12:0, C18:0, cis-C18:1, trans-C18:1, C18:2, acid (2) on the preformed fatty O-acylisourea, appears to have
C18:3), we used the same protocol to obtain a wide range of fatty been crucial for the increased yield (Scheme 3).
b-ketoesters, namely, 4a–d and 4f–j. However, the protocol
Finally, the b-ketoester 4k derivative from ricinoleic acid was
resulted in the b-ketoester derivatives 4a–j with saturated and synthesised (Scheme 4). Ricinoleic acid or 12-hydroxy-9-cis-
unsaturated alkyl chains in moderate yields (Method A, octadecenoic acid is the major constituent (80–90%) of castor
Table 1).
oil (Ricinus communis)23 and is an uncommon fatty acid that
Next we examined a modied methodology that includes a contains a double bond and a hydroxyl group in the chain.
two-step process. First, the effect of adding palmitic acid (1e) Compound 4k was synthesised by Method B at room tempera-
over DCC in the absence of Meldrum's acid (2) was studied. It ture under a nitrogen atmosphere using Meldrum's acid (2) and
has been proposed that the condensation reaction between ricinoleic acid (cis-C18:1, 12-OH, 1k), which was obtained from
DCC and carboxylic acids initially forms the O-acylisourea the castor oil or via castor oil biodiesel hydrolysis. The puried
intermediate.21 Indeed, in our experiments, aer adding fatty product 4k (ref. 28) was obtained in a 75% yield from 1k.
acid over DCC, fatty O-acylisourea promptly formed. Next,
adding 2.0 equiv. of Meldrum's acid (2) in dichloromethane and
pyridine under the same experimental conditions resulted in
Conclusions
the formation of the enol derivative 3e (Scheme 3). Subse- In conclusion, we used a simple method to develop fatty b-
quently, b-ketoester 4e was obtained from the reaction of enol ketoesters using Meldrum's acid and a wide range of fatty
3e and methanol in an acid catalyst at reux. Therefore, the chains of saturated, unsaturated, and hydroxylated acids. We
modied protocol resulted in an increased yield (74–84%) of the are currently in the process of synthesizing a series of new fatty
b-ketoester derivatives 4a–j (Method B,22 Table 1).
acid dihydropyrimidinones with different structural arrange-
In this context, the moderated yield of fatty b-ketoesters 4a–j ments using Biginelli's multicomponent protocol29 in the
obtained using the one-pot method (Method A) must be presence of the new fatty b-ketoesters from renewable
attributed to the consumption of DCC (the coupling agent) from resources.
the nucleophilic attack of Meldrum's acid (2).
Acknowledgements
˜
The authors would like to thank the Coordenaçao de Aperfei-
´
˜
çoamento de Pessoal de Nıvel Superior (CAPES), Fundaçao de
`
Apoio a Pesquisa do Estado do Rio Grande do Sul (FAPERGS/
PRONEM) and Conselho Nacional de Desenvolvimento
´
´
Cientıco e Tecnologico (CNPq) for nancial support.
Notes and references
1 M. J. Galligan, R. Akula and H. Ibrahim, Org. Lett., 2014, 16,
600.
2 L. C. Luo, L. L. Meng, Q. Sun, Z. M. Ge and R. T. Li,
Tetrahedron Lett., 2014, 55, 259.
3 G. B. D. Rao, B. N. Acharya and M. P. Kaushik, Tetrahedron
Lett., 2013, 54, 6644.
4 L. Liu, R. Sarkisian, Y. M. Deng and H. Wang, J. Org. Chem.,
2013, 78, 5751.
Scheme 3 Synthesis of fatty b-ketoesters 4a–j from Meldrum's acid
(2) and the fatty acids 1a–j (Method B).
5 D. Russowsky, R. F. S. Canto, S. A. A. Sanches,
´
M. G. M. D'Oca, A. Fatima, R. A. Pilli, L. K. Konhn,
ˆ
M. A. Antonio and J. E. Carvalho, Bioorg. Chem., 2006, 34,
173.
6 A. Crespo, A. El Maatougui, P. Biagini, J. Azuaje, A. Coelho,
J. Brea, M. I. Loza, M. I. Cadavid, X. Garcia-Mera,
H. Gutierrez-de-Teran and E. Sotelo, ACS Med. Chem. Lett.,
2013, 4, 1031.
7 D. Bonne, Y. Coquerel, T. Constantieux and J. Rodriguez,
Tetrahedron: Asymmetry, 2010, 21, 1085.
8 L. I. Koval, V. I. Dzyuba, O. L. Ilnitska and V. I. Pekhnyo,
Tetrahedron Lett., 2008, 49, 1645.
Scheme 4 Synthesis of fatty b-ketoester 4k from Meldrum's acid (2)
and ricinoleic acid (1k, Method B).
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9 G. Sathicq, L. Musante, G. Romanelli, G. Pasquale, J. Autino,
H. Thomas and P. Vazquez, Catal. Today, 2008, 133, 455.
10 O. Mhasni and F. Rezgui, Tetrahedron, 2011, 67, 6322.
11 G. C. M. Kondaiah, L. A. Reddy, K. S. Babu, V. M. Gurav,
K. G. Huge, R. Bandichhor, P. P. Reddy, A. Bhattacharya
and R. V. Anand, Tetrahedron Lett., 2008, 49, 106.
758.1. 1H NMR (CDCl3): d (ppm) 0.86 (t, 3H, J ¼ 6.0 Hz,
CH3), 1.26 (m, 20H, CH2), 1.57 (t, 2H, J ¼ 6.0 Hz, CH2 b-
carbonyl), 1.99 (m, 4H, CH2 allylic), 2.51 (t, 2H, J ¼ 6.0 Hz,
CH2 a carbonyl), 3.43 (s, 2H, CH2 bis-a carbonyl), 3.71 (s,
3H, OCH3), 5.32 (m, 2H, 2CH vinylic). 13C NMR (CDCl3) d
(ppm) 14.0, 22.6, 23.4, 24.2, 27.1, 27.2, 28.9, 29.0, 29.2,
29.3, 29.5, 29.6, 29.7, 31.8, 43.0, 48.9, 52.3, 129.6, 129.9,
167.6, 202.8.
12 J. S. Yadav, B. V. S. Reddy, A. D. Krishna, C. S. Reddy and
A. V. Narsaiah, J. Mol. Catal. A: Chem., 2007, 261, 93.
13 T. Misaki, R. Nagase, K. Matsumoto and Y. Tanabe, J. Am. 25 For 4h: 78%, colorless oil. FT-IR (NaCl, lm, n ¼ cmꢁ1
)
Chem. Soc., 2005, 127, 2854.
3020.5, 2927.9, 2854.6, 11745.5, 1716.6, 1460.1, 1215.1,
14 A. Iida, K. Takai, T. Okabayashi, T. Misaki and Y. Tanabe,
Chem. Commun., 2005, 3171.
758.0. 1H NMR (CDCl3): d (ppm) 0.88 (t, 3H, J ¼ 6.0 Hz,
CH3), 1.26 (m, 20H, CH2), 1.59 (m, 2H, CH2 b carbonyl),
15 K. Takai, Y. Nawate, T. Okabayashi, H. Nakatsuji, A. Iida and
Y. Tanabe, Tetrahedron, 2009, 65, 5596.
16 Y. Oikawa, K. Sugano and O. Yonemitsu, J. Org. Chem., 1978,
43, 2087.
1.96 (m, 4H, CH2 allylic), 2.53 (t, 2H, J ¼ 6.0 Hz, CH2
a
carbonyl), 3.45 (s, 2H, CH2 bis-a carbonyl), 3.74 (s, 3H,
OCH3), 5.38 (m, 2H, CH vinylic). 13C NMR (CDCl3) d
(ppm) 14.1, 22.6, 23.4, 28.9, 29.0, 29.2 (2C), 29.3, 29.5,
29.6, 29.7, 31.9, 32.5, 32.6, 43.1, 49.0, 52.3, 130.2, 130.5,
167.7, 202.9.
17 B. Li and R. W. Franck, Bioorg. Med. Chem. Lett., 1999, 9,
2629.
18 C. R. M. D'Oca, T. Coelho, T. G. Marinho, C. R. L. Hack, 26 For 4i: 80%, colorless oil. FT-IR (NaCl, lm, n ¼ cmꢁ1),
R. C. Duarte, P. A. da Silva and M. G. M. D'Oca, Bioorg.
Med. Chem. Lett., 2010, 20, 5255.
3014.0, 2927.1, 2856.3, 1747.2, 1716.1, 1462.7, 1438.1,
1215.0 1H NMR (CDCl3): d (ppm) 0.89 (t, 3H, J ¼ 6.0 Hz,
CH3), 1.30 (m, 14H, CH2), 1.59 (m, 2H, CH2 b-carbonyl),
2.05 (q, J ¼ 6.0 Hz, 4H, CH2 allylic), 2.53 (t, 2H, J ¼ 6.0 Hz,
CH2 a-carbonyl), 2.77 (t, 2H, J ¼ 6.0 Hz, CH2 bis-allylic),
3.45 (s, 2H, CH2 bis -a carbonyl), 3.74 (s, 3H, OCH3), 5.34
(m, 4H, CH vinylic). 13C NMR (CDCl3) d (ppm) 14.0, 22.5,
23.3, 25.5, 27.1 (2C), 28.9, 29.0, 29.2, 29.3, 29.5, 31.4, 43.0,
48.9, 52.3, 127.8, 128.0, 129.9, 130.1, 167.6, 202.8.
19 R. C. Duarte, R. Ongaratto, L. A. Piovesan, V. R. de Lima,
V. Soldi, A. A. Merlo and M. G. M. D'Oca, Tetrahedron Lett.,
2012, 53, 2454.
20 M. O. Rodrigues, J. B. Cantos, C. R. M. D'Oca, K. L. Soares,
T. S. Coelho, L. A. Piovesan, D. Russowsky, P. A. Silva and
M. G. M. D'Oca, Bioorg. Med. Chem., 2013, 21, 6910.
21 H. Wiener and C. Gilon, J. Mol. Catal., 1986, 37, 45.
22 General procedure for synthesis of b-ketoesters 4a–k 27 For 4j: 80%, colorless oil. FT-IR (NaCl, lm, n ¼ cmꢁ1),
(Method B): fatty acid 1a–k (1 mmol), DCC (1.1 mmol), and
DMAP (0.3 mmol) were dissolved in dichloromethane (15
mL) and stirred for 30 min. Then, Meldrum's acid (2
mmol) and pyridine (3.6 mmol) were dissolved in
dichloromethane (10 mL) and added dropwise. The
mixture was stirred for 24 h at room temperature. The
solid dicyclohexylurea formed was removed by ltration,
and the ltrated organic layer was washed with an acid
solution (10% HCl, 3 ꢀ 25 mL) and dried over Mg2SO4.
The solvent was removed by reduced pressure and the
3455.0, 2931.0, 2857.0, 1746.0, 1709.0, 1435.0, 1312.0,
1258.0, 1161.0, 1075.0, 971.0. 1H NMR (CDCl3): d (ppm)
0.90 (t, 3H, J ¼ 7.5 Hz, CH3), 1.22 (m, 8H, CH2), 1.51 (m,
2H, CH2 b-carbonyl), 1.98 (m, 4H, CH2 allylic), 2.46 (t, 2H,
J ¼ 7.5 Hz, CH2 a-carbonyl), 2.73 (t, 4H, J ¼ 6.0 Hz, CH2
bis-allylic), 3.38 (s, 2H, CH2 bis-a carbonyl), 3.66 (s, 3H,
OCH3), 5.28 (m, 6H, CH vinylic). 13C NMR (CDCl3) d (ppm)
14.2, 20.4, 23.3, 25.4, 25.5, 27.1, 28.9, 29.0, 29.2, 29.5, 42.9,
48.9, 52.2, 127.0, 127.6, 128.1, 128.2, 130.1, 131.8, 167.7,
202.8.
respective enol 3a–k was obtained. The crude product was 28 For 4k: 75%, colorless oil. FT-IR (NaCl, lm, n ¼ cmꢁ1),
dissolved in methanol (25 mL), and 5 drops H2SO4 were
added to the mixture, which was reuxed for 12 h. The
solvent was removed by reduced pressure, the residue was
dissolved in dichloromethane (25 mL), and the organic
layer was washed with distilled H2O (3 ꢀ 25 mL) and dried
over Mg2SO4. The solvent was removed by reduced
pressure and the residue obtained was puried by ash
column chromatography on silica gel, eluent, and either
hexane/diethyl ether (97 : 3) to afford b-ketoesters 4a–j or
hexane/ethyl acetate (8 : 2) to obtain b-ketoester 4k.
3489.2, 3018.6, 2929.8, 2856.5, 1737.8, 1714.7, 1438.9,
1215.1. 1H NMR (CDCl3): d (ppm) 0.81 (t, 3H, J ¼ 6.0 Hz,
CH3), 1.22 (m, 16H, CH2), 1.40 (m, 2H, CH2-a-OH), 1.52
(m, 2H, CH2 b-carbonyl), 1.97 (q, 2H, J ¼ 6.0 Hz, CH2
allylic), 2.14 (t, 2H, J ¼ 6.0 Hz, CH2 allylic-a-OH), 2.46 (t,
2H, J ¼ 6.0 Hz, CH2 a-carbonyl), 3.38 (s, 2H, CH2 bis-a-
carbonyl), 3.54 (q, 1H, J ¼ 6.0 Hz, CH carbinolic), 3.67 (s,
3H, OCH3), 5.33 (m, 1H, CH vinylic), 5.48 (m, 1H, CH
vinylic). 13C NMR (CDCl3) d (ppm) 13.0, 21.6, 22.3, 24.7,
26.3, 27.9, 28.0, 28.1, 28.3, 28.5, 30.8, 34.3, 35.8, 42.0, 48.0,
51.3, 70.4, 124.2, 132.3, 166.7, 201.8.
23 G. Lakshminarayana, M. M. Paulose and N. B. Kumari, J. Am.
Oil Chem. Soc., 1984, 61, 1871.
29 D. Russowsky, F. A. Lopes, V. S. S. da Silva, K. F. S. Canto,
M. G. M. D'Oca and M. N. Godoi, J. Braz. Chem. Soc., 2004,
15, 165.
24 For 4g: 81%, colorless oil. FT-IR (NaCl, lm, n ¼ cmꢁ1
)
3008.9, 2926.0, 2854.6, 1747.5, 1716.6, 1460.1, 1217.1,
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