Acylation of Meldrum's acid with arylacetic acid imidazolides as a convenient method for the synthesis of 4-aryl-3-oxobutanoates

Article abstract of DOI:10.1007/s11172-011-0019-9

C-Acylation of Meldrum's acid by (het)arylacetic acids in ethanol in the presence of 1,1′-carbonyldiimidazole leads to ethyl 4-(het)aryl-3- oxobutanoates in high yields.

Full text of DOI:10.1007/s11172-011-0019-9

Russian Chemical Bulletin, International Edition, Vol. 60, No. 1, pp. 139—142, January, 2011
139
Acylation of Meldrum´s acid with arylacetic acid imidazolides
as a convenient method for the synthesis of 4ꢀarylꢀ3ꢀoxobutanoates
A. A. Shimkin, V. Z. Shirinian, A. K. Mailian, D. V. Lonshakov, V. V. Gorokhov, and M. M. Krayushkin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: shimkin@ioc.ac.ru
CꢀAcylation of Meldrum´s acid by (het)arylacetic acids in ethanol in the presence of
1,1'ꢀcarbonyldiimidazole leads to ethyl 4ꢀ(het)arylꢀ3ꢀoxobutanoates in high yields.
Key words: βꢀketo esters, Meldrum´s acid, imidazolides, arylacetic acids.
Scheme 1
βꢀKeto esters are widely used for the preparation of
various heterocyclic systems, particularly coumarins,1,2
dihydropyridines,3 pyrazolones,4 quinolines,5,6 dihydroꢀ
pyrimidines,7,8 etc. Furthermore, they are starting comꢀ
pounds in the synthesis of βꢀamino acid derivatives,9,10
cyclohexenones11,12 and other practically useful comꢀ
pounds.
Among numerous approaches to the preparation of
βꢀketo esters,13 those based on acylation of monoethyl
malonate14 and Meldrum's acid are the most convenient
and efficient.15,16 The latter allows one to prepare keto
esters with different ester groups and amides of appropriꢀ
ate βꢀketo acids17 without recourse to organometallic reꢀ
agents (the Grignard reagents, nꢀbutyllithium) and low
temperatures, which stimulated us to investigate this reacꢀ
tion in more detail to prepare 4ꢀarylꢀ3ꢀoxobutanoates,
the members of an important class of 1,3ꢀdicarbonyl
compounds.
The classical method for the preparation of keto esters
by this way involves the acylation of Meldrum's acid with
the acid chloride—pyridine system15,18 followed by the
reaction of the acylation product 3 with a primary alcohol
(Scheme 1).
However, in our experiments with arylacetyl chlorides,
keto esters 4a,b were obtained in 30—40% yields, and the
main products according to 1Н NMR were the correspondꢀ
ing arylacetates. In the case of 2,5ꢀdimethylthiophenꢀ3ꢀ
ylacetic acid, under these conditions its esterification takes
place mainly (Table 1, method A). The best results were
obtained by replacing pyridine by N,Nꢀdimethylaminopyꢀ
ridine (DMAP),19,20 but in this case, too, attempts to exꢀ
clude completely the formation of byꢀproducts failed (see
Table 1, method B).
B is base
The results obtained provide evidence that acylation of
Meldrum's acid with arylacetic acid derivatives considerꢀ
ably differs from similar reactions of aliphatic and aroꢀ
Table 1. The yields of keto esters 4 under differrent conditions*
4
Ar
A
B
C
D
a
b
c
Phenyl
1ꢀNaphtyl
41
28
3**
66
72
60
17
40
41
78
83
81
2ꢀDimethylthiophenꢀ3ꢀyl
* Conditions of acylation of Meldrum's acid: A, ArCH2COCl,
Py; B, ArCH2COCl, DMAP; C, ArCH2COOH, DCC;
D, ArCH2COOH, N,N´ꢀcarbonyldiimidazole (CDI).
** Ethyl 2,5ꢀdimethylthiophenꢀ3ꢀylacetate was the major prodꢀ
uct (75%).
The arylacetic acid—dicyclohexylcarbodiimide (DCC)
system21 as the acylation agent led to moderate yields of
keto esters. Furthermore, we observed the formation of
large amount of byꢀproducts (see Table 1, method C).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 134—136, January, 2011.
1066ꢀ5285/11/6001ꢀ139 © 2011 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 60, No. 1, January, 2011
Shimkin et al.
Scheme 2
B is base
Scheme 3
Ar = Ph (a), 1ꢀnaphtyl (b), 2,5ꢀdimethylthiophenꢀ3ꢀyl (c), 3ꢀMeOC6H4 (d), 4ꢀMeOC6H4 (e), 2ꢀmethylꢀ1ꢀbenzothiophenꢀ3ꢀyl (f)
eter. Melting points were measured on a Boetius hot stage and
are uncorrected. The course of the reaction was monitored by
TLC on silica gel 60 F254 Merck. Column chromatography was
carried out on silica gel 0.060—0.200 Merck. Arylacetic acid 1c
was obtained by Wilgerodt—Kindler's reaction from 3ꢀacetylꢀ
2,5ꢀdimethylthiophene,24 and acid 1f was prepared by reduction
of ethyl 2ꢀ(2ꢀmethylbenzothiophenꢀ3ꢀyl)ꢀ2ꢀoxoacetate with triꢀ
ethylsilane.25
matic carboxylic acids. Apparently, under these reaction
conditions they can convert to ketenes 5, due to the presꢀ
ence of active methylene group.22 Ketenes acylate Melꢀ
drum's acid at the oxygen atom, which results in arylaceꢀ
tates 7 (Scheme 2).
We assumed that the use of milder acylation agents,
particularly imidazolides 8,23 which could be produced
in situ by reaction of carboxylic acids with N,N´ꢀcarbonylꢀ
diimidazole (CDI), will promote Cꢀacylation of Meldrum´s
acid. In this case, in the course of reaction, imidazole, the
soft base, is released (Scheme 3).
In fact, when carrying out the acylation in the presꢀ
ence of CDI, the yields of keto esters 4a—c increased to
78—83% (see Table 1, method D). In this case, in the
second step of the process one can use 96% alcohol in
place of anhydrous ethanol. By similar method, we obꢀ
tained keto esters 4d—f in 60—78% yields.
Thus, we developed a convenient method for the prepꢀ
aration of 4ꢀarylꢀ3ꢀoxobutanoates based on the acylation
reaction of Meldrum's acid by the arylacetic acid—CDI
system, which is characterized by high yields and selectivity.
Preparation of keto esters 4 (general procedure). A. To
a suspension of acid 1 (12 mmol) in dry CH2Cl2 (20 mL), thionyl
chloride (2.0 mL, 27 mmol) and two drops of DMF were added.
The mixture was refluxed for 3 h and concentrated in vacuo. The
resulting acid chloride was dissolved in dry CH2Cl2 (20 mL) and
added to a cooled to 0 °С suspension of Meldrum's acid (2.0 g,
14 mmol) and pyridine (2.0 mL, 14 mmol) in dry CH2Cl2 (20 mL).
After keeping for 20 min at this temperature, the mixture was
allowed to warm to room temperature and kept for 16 h. Then
the reaction mixture was poured into 5% HCl (70 mL) and exꢀ
tracted with CH2Cl2 (3×20 mL). The extract was washed with
5% HCl (50 mL) and with water (50 mL) and concentrated
in vacuo. To the residue, ethanol (10 mL) was added and the
resulting mixture was refluxed for 2 h. The obtained solution was
concentrated and 5% NaHCO3 (70 mL) was added to the resiꢀ
due. The obtained mixture was extracted with ethyl acetate
(3×20 mL). The extract was washed with water, filtered through
thin layer of silica gel (2 cm) and concentrated in vacuo.
B. To a suspension of acid 1 (12 mmol) in dry CH2Cl2
(20 mL), thionyl chloride (2.0 mL, 27 mmol) and two drops of
DMF were added. The mixture was refluxed for 3 h and concenꢀ
trated in vacuo. The resulting acid chloride was dissolved in dry
CH2Cl2 (20 mL) and added to a suspension of Meldrum´s acid
Experimental
1
H NMR spectra were recorded on a Bruker AMꢀ300
spectrometer. Mass spectra were acquired using the Kratos inꢀ
strument (direct inlet probe, ionizing energy 70 eV). High resoꢀ
lution mass spectra were recorded on a Bruker maXis spectromꢀ

4ꢀArylꢀ3ꢀoxobutanoates
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 1, January, 2011
141
(2.0 g, 14 mmol) and DMAP (3.2 g, 26 mmol) in dry CH2Cl2
(20 mL) cooled to 0 °С. After keeping for 20 min at this temperꢀ
ature, the mixture was allowed to warm to room temperature
and kept for 16 h. The reaction mixture was worked up analoꢀ
gously to method A.
C. To a suspension of acid 1 (12 mmol) in dry CH2Cl2
(20 mL), DCC (3.0 g, 14 mmol), DMAP (0.17 g, 1.4 mmol) and
Meldrum's acid (1.9 g, 13 mmol) were added. The resulting
mixture was kept for 16 h at room temperature. The precipitate
of dicyclohexylurea was filtered off, the mother liquor was conꢀ
centrated in vacuo. Ethanol (10 mL) was added to the residue
and the mixture was refluxed for 2 h. The resulting solution was
poured onto ice (200 g), extracted with ethyl acetate (3×20 mL),
the extract was concentrated in vacuo. The product 4 was isolatꢀ
ed by column chromatography on silica gel eluting with light
petroleum—ethyl acetate (8:1).
D. To a suspension of acid 1 (12 mmol) in dry CH2Cl2
(20 mL), CDI (2.1 g, 13 mmol) was added. After stirring for 0.5 h,
Meldrum's acid (1.86 g, 13 mmol) was added and stirred for
additional 12 h. The reaction mixture was worked up analogousꢀ
ly to method A.
Ethyl 4ꢀphenylꢀ3ꢀoxobutanoate (4a). Yellowish liquid.16,26
1H NMR (CDCl3), δ: 1.27 (t, 3 Н, СН2СН3, J = 7.0 Hz); 3.45
(s, 2 Н, СН2); 3.84 (s, 2 Н, СН2); 4.18 (q, 2 Н, СН2СН3,
J = 7.0 Hz); 7.19—7.39 (m, 5 Н, Нarom). Mass spectrum (EI,
70 eV), m/z (Irel (%)): 206 [M]+ (52), 161 [M – EtO]+ (29), 118
[M – CH3COOEt]+ (50), 91 [PhCH2]+ (100).
Ethyl 4ꢀ(4ꢀmethylꢀ1ꢀbenzothiophenꢀ3ꢀyl)ꢀ3ꢀoxobutanoate
(4f). Yield 78%, yellow oil. 1H NMR (CDCl3), δ: 1.24 (t, 3 Н,
СН2СН3, J = 7.0 Hz); 2.54 (s, 3 Н, СН3); 3.40 (s, 2 Н, СН2);
3.99 (s, 2 Н, СН2); 4.14 (q, 2 Н, СН2СН3, J = 7.0 Hz);
7.25—7.40 (m, 2 Н, Нarom); 7.57 (d, 1 Н, Нarom, J = 7.7 Hz);
7.77 (d, 1 Н, Нarom, J = 7.7 Hz). Mass spectrum (EI, 70 eV),
m/z (Irel (%)): 276 [M]+ (42), 188 [M – CH3COOEt]+ (24), 161
[M – COCH2COOEt]+ (100). Found: m/z 299.0712 [M + Na]+.
C15H16NaO3S. Calculated: M + Na = 299.0712.
This work was financially supported by the Council on
Grants at the President of the Russian Federation (State
Support Program for Young scientists and Leading Scienꢀ
tific Schools, Grant MKꢀ269.2009.3).
References
1. J. A. Seijas, M. P. VázquezꢀTato, R. CarballidoꢀReboredo,
J. Org. Chem., 2005, 70, 2855.
2. H. Cui, P. Li, Z. Chai, C. Zheng, G. Zhao, S. Zhu, J. Org.
Chem., 2009, 74, 1400.
3. M. Sharma, N. Agarwal, D. S. Rawat, J. Heterocyclic Chem.,
2008, 45, 737.
4. Y.ꢀY. Huang, H.ꢀC. Lin, K.ꢀM. Cheng, W.ꢀN. Su, K.ꢀC.
Sung, T.ꢀP. Lin, J.ꢀJ. Huang, S.ꢀK. Lin, F. F. Wong, Tetraꢀ
hedron, 2009, 65, 9592.
Ethyl 4ꢀ(1ꢀnaphtyl)ꢀ3ꢀoxobutanoate (4b). Yellowish liquid.16
1H NMR (CDCl3), δ: 1.24 (t, 3 Н, СН2СН3, J = 7.0 Hz);
3.42 (s, 2 Н, СН2); 4.15 (q, 2 Н, СН2СН3, J = 7.0 Hz); 4.28
(s, 2 Н, СН2); 7.40 (d, 1 Н, Нarom, J = 6.6 Hz); 7.45 (d, 1 Н,
5. A. L. Zografos, C. A. Mitsos, O. IgglessiꢀMarkopoulou,
J. Org. Chem., 2001, 66, 4413.
6. P. Senthilkumar, M. Dinakaran, P. Yogeeswari, D. Sriram,
A. China, V. Nagaraja, Eur. J. Med. Chem. 2009, 44, 345.
7. H. R. Shaterian, A. Hosseinian, M. Ghashang, Phosphorus,
Sulfur, Silicon, 2009, 184, 197.
8. X. Wang, Z. Quan, F. Wang, M. Wang, Z. Zhang, Z. Li,
Synth. Commun., 2006, 36, 451.
9. Y. Hsiao, N. R. Rivera, T. Rosner, S. W. Krska, E. Njolito,
F. Wang, Y. Sun, J. D. Armstrong, III, E. J. J. Grabowski,
R. D. Tillyer, F. Spindler, C. Malan, J. Am. Chem. Soc.,
2004, 126, 9918.
10. Y. Zhao, J. Zhao, Y. Zhou, Z. Lei, L. Li, H. Zhang, New J.
Chem., 2005, 29, 769.
11. B.ꢀD. Chong, Y.ꢀI. Ji, S.ꢀS. Oh, J.ꢀD. Yang, W. Baik, S. Koo,
J. Org. Chem., 1997, 62, 9323.
12. D. B. Ramachary, K. Ramakumar, V. V. Narayana, J. Org.
Chem., 2007, 72, 1458.
13. S. Benetti, R. Romagnoli, C. De Risi, G. Spalluto, V. Zaꢀ
nirato, Chem. Rev., 1995, 95, 1065.
Н
Н
arom, J = 8.1 Hz); 7.48—7.57 (m, 2 Н, Нarom); 7.83 (d, 1 Н,
arom, J = 7.7 Hz); 7.86—7.93 (m, 2 Н, Нarom). Mass specꢀ
trum (EI, 70 eV), m/z (Irel (%)): 256 [M]+ (83), 210 [M –
– EtOH]+ (25), 206 (34), 168 [M – CH3COOEt]+ (64), 141
[C10H7CH2]+ (100).
Ethyl 4ꢀ(2,5ꢀdimethylthiophenꢀ3ꢀyl)ꢀ3ꢀoxobutanoate (4с).
Yellow oil. 1H NMR (CDCl3), δ: 1.27 (t, 3 Н, СН2СН3,
J = 7.0 Hz); 2.29 (s, 3 Н, СН3); 2.38 (s, 3 Н, СН3); 3.41 (s, 2 Н,
СН2); 3.65 (s, 2 Н, СН2); 4.18 (q, 2 Н, СН2СН3, J = 7.0 Hz);
6.46 (s, 1 Н, Нthioph). Mass spectrum (EI, 70 eV), m/z (Irel (%)):
240 [M]+ (47), 152 [M – CH3COOEt]+ (54), 125 [M –
–COCH2COOEt]+ (100). Found: m/z 263.0696 [M + Na]+.
C12H16NaO3S. Calculated: M + Na = 263.0712.
Ethyl 4ꢀ(3ꢀmethoxyphenyl)ꢀ3ꢀoxobutanoate (4d). Yield 64%,
Yellow oil.27 1H NMR (CDCl3), δ: 1.25 (t, 3 Н, СН2СН3
J = 7.0 Hz); 3.44 (s, 2 Н, СН2); 3.78 (s, 5 Н, CH3 + СН2);
4.16 (q, 2 Н, СН2СН3, J = 7.0 Hz); 6.71—6.86 (m, 3 Н,
14. W. Wierenga, H. I. Skulnick, J. Org. Chem., 1979, 44, 310.
15. Y. Oikawa, K. Sugano, O. Yonemitsu, J. Org. Chem., 1978,
43, 2087.
16. G. Capozzi, S. Roelens, S. Talami, J. Org. Chem., 1993,
58, 7932.
Н
arom); 7.24 (t, 1 Н, Нarom, J = 8.1 Hz). Mass spectrum
(EI, 70 eV), m/z (Irel (%)): 236 [M]+ (62), 190 [M –
– EtOH]+ (30), 148 [M –CH3COOEt]+ (74), 121 [M –
– COCH2COOEt]+ (100).
Ethyl 4ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀoxobutanoate (4e). Yield 60%,
yellow oil.16,26 1H NMR (CDCl3), δ: 1.24 (t, 3 Н, СН2СН3,
J = 7.0 Hz); 3.42 (s, 2 Н, СН2); 3.74 (s, 2 Н, СН2); 3.76
(s, 3 Н, СН3); 4.15 (q, 2 Н, СН2СН3, J = 7.0 Hz); 6.85 (d, 2 Н,
17. A. S. Ivanov, Chem. Soc. Rev., 2008, 37, 789.
18. A.ꢀH. Li, S. Moro, N. Forsyth, N. Melman, X. Ji, K. A.
Jacobson, J. Med. Chem., 1999, 42, 706.
19. H. Emtenдs, L. Alderin, F. Almqvist, J. Org. Chem., 2001,
66, 6756.
Н
arom, J = 8.4 Hz); 7.11 (d, 2 Н, Нarom, J = 8.4 Hz).
Mass spectrum (EI, 70 eV), m/z (Irel (%)): 236 [M]+ (68), 190
[M – EtOH]+ (40), 148 [M – CH3COOEt]+ (64), 121 [M –
– COCH2COOEt]+ (100).
20. B. Lu, D. Ma, Org. Lett., 2006, 8, 6115.
21. H. Tabuchi, T. Hamamoto, S. Miki, T. Tejima, A. Ichihara,
J. Org. Chem., 1994, 59, 4749.

142
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 1, January, 2011
Shimkin et al.
22. V. De Matteis, F. L. van Delft, J. Tiebes, F. P. J. T. Rutjes,
Synlett, 2008, 351.
23. S. Hamilakis, D. Kontonassios, C. Sandris, J. Heterocyclic
Chem., 1996, 33, 825.
26. T. Terai, K. Kikuchi, S. Iwasawa, T. Kawabe, Y. Hirata,
Y. Urano, T. Nagano, J. Am. Chem. Soc., 2006, 128, 8699.
27. G. Sun, C. J. Fecko, R. B. Nicewonger, W. W. Webb, T. P.
Begley, Org. Lett., 2006, 8, 681.
24. E. V. Brown, J. A. Blanchette, J. Am. Chem. Soc., 1950,
72, 3414.
25. M. Anzini, L. Canullo, C. Braile, A. Cappelli, A. Gallelli,
S. Vomero, M. C. Menziani, P. G. De Benedetti, M. Rizzo,
S. Collina, O. Azzolina, M. Sbacchi, C. Ghelardini, N. Gaꢀ
leotti, J. Med. Chem., 2003, 46, 3853.
Received May 31, 2010;
in revised form September21, 2010