Bis(2,4,6-trichlorophenyl) Malonate

(R = H)

[15781-70-1]  · C15H6Cl6O4  · Bis(2,4,6-trichlorophenyl) Malonate  · (MW 462.93) (R = Me)

[15781-71-2]  · C16H8Cl6O4  · Bis(2,4,6-trichlorophenyl) Methylmalonate  · (MW 476.95) (R = Et)

[15781-72-3]  · C17H10Cl6O4  · Bis(2,4,6-trichlorophenyl) Ethylmalonate  · (MW 490.98) (R = i-Pr)

[15897-80-0]  · C18H12Cl6O4  · Bis(2,4,6-trichlorophenyl) Isopropylmalonate  · (MW 505.01) (R = t-Bu)

[-]  · C19H14Cl6O4  · Bis(2,4,6-trichlorophenyl) t-Butylmalonate  · (MW 519.04) (R = Ph)

[15781-73-4]  · C21H10Cl6O4  · Bis(2,4,6-trichlorophenyl) Phenylmalonate  · (MW 539.03) (R = Bn)

[15781-74-5]  · C22H12Cl6O4  · Bis(2,4,6-trichlorophenyl) Benzylmalonate  · (MW 553.05)

(1,3-dielectrophile used mainly for the synthesis of five-, six-, and seven-membered heterocycles functionalized with oxo and hydroxy groups in the 1,3-position)

Alternate Names: active malonates (AMEs); magic malonates.

Physical Data: mp: R = H, 152-153 °C (toluene);1,2 R = Me, 84-85 °C (EtOH);1 R = Et, 101-102 °C (EtOH);1 R = i-Pr, 95-96 °C (EtOH);1 R = t-Bu, 132 °C (n-PrOH);3 R = Ph, 97-98 °C (n-BuOH);1 R = Bn, 106-107 °C (i-PrOH).1 Other analogs: R = n-Pr,4,5 n-Bu,4,6 s-Bu,7 i-Bu,7 4-methoxyphenyl,8 4-chlorobenzene,7 4-methoxybenzyl,7 hexyl,9 and 3-thienyl.9

Preparative Method: from the corresponding malonic acid and 2,4,6-trichlorophenol in the presence of phosphorus oxychloride. The reaction is preferably carried out with an excess of malonic acid (molar ratio 1:1.6). The free malonic acids are readily obtained in about 90% yield by a modified saponification procedure10 from the diethyl malonates (most of them are commercially available).1,5

Handling, Storage, and Precautions: the crude esters are quite unstable and should be used within 2 weeks. Crystallized material can be stored for 6-12 months (depending on the purity).

Reactions.

The vast majority of substrates which have been reacted with active malonic esters (AMEs, magic malonates) represent 1,3-dinucleophiles leading to six-membered heterocycles. Most of these condensations have been carried out thermally, by fusion at 150-250 °C, depending on the reactivity of the substrate. In some cases, bromobenzene, anisole or diphenyl ether have been used as solvents. However, for some substrates (mostly N,N-dinucleophiles) a cold method exists which is useful for compounds which undergo transformations at higher temperature.

The reaction of acyclic and cyclic ketones leads to 4-hydoxy-2-pyrones. Thus the reaction of diethyl ketone with benzyl-AME yields the 3-benzyl-6-ethyl-5-methyl derivative which can be debenzylated with AlCl3 at 150 °C (eq 1).11 This is the starting material for the synthesis of two natural products (edulitin and obtusifolin). This compound cannot be obtained by using the unsubstituted AME, since (as a phenolic compound) it will react with further AME. Also the t-butyl group can be removed with AlCl3; however, the corresponding t-butyl-AME gives lower yields with various substrates, and its preparation requires more steps.3

Phenols react with AMEs to yield 4-hydroxycoumarins.12 The reaction of 3-methoxyphenol with 4-methoxyphenyl-AME (eq 2) affords a coumarin which on cyclodehydrogenation leads directly to coumestrol dimethyl ether.

Enamines or azomethines react to yield 4-hydroxy-2-pyridones (eq 3).13 The reaction temperature is strongly dependent on the structure of the substrate: a b-enamino ester (R1 = CO2Et) will react in refluxing bromobenzene, while acetophenone anil requires 240-250 °C. Cyclic substrates afford bicyclic hydroxypyridones (eq 4).14

Even 2-alkylpyridines react with AMEs to give 2-hydroxy-4-quinolizines (eq 5).1 The presence of an activating group in the side chain (R1 = CO2Et, CN, COR) is helpful, but not necessary. Many five- or six-membered heteroaromatic systems bearing a 2-alkyl side chain react in this way.15

2-Aminopyridine is very reactive and gives pyridopyrimidines even with diethyl malonates if heated to 200 °C. However, in the presence of a substituent in position 6 the reaction requires higher temperatures and leads to formation of naphthyridine derivatives. With AMEs the reaction proceeds at rt to pyridopyrimidines which can then be rearranged quantitatively to naphthyridines (eq 6).16

N,N-Disubstituted amidines (and similar substrates which bear only one removable hydrogen atom) condense with AMEs to give cross-conjugated mesomeric betaines (eq 7).17 The reaction has been extended to cyclic amidines (e.g. 2-alkylaminopyridines), leading to bicyclic compounds (1) and (2).18 The reaction with five-membered 2-amino heterocycles has been studied extensively by Glennon et al.5,7,19,20 Because of the biological activity found in this series, about 150 derivatives have been synthesized since 1973,19 including those bearing a sugar moiety (R1) at the nitrogen.20

Alternatives.

a-Carbonyl acid chlorides (ketene carbonyl chlorides) represent an effective alternative to AMEs; however, the number of described derivatives is limited. One of their advantages is their much lower molecular weight. On the other hand, the liberation of HCl sometimes brings problems. Bis(pentachlorophenyl) malonates have been proposed as an alternative.21 However, they are less reactive, and very insoluble, and the liberated pentachlorophenol is more difficult to remove. Attempts to prepare mixed anhydrides from malonic acids, ethyl chloroformate, and triethylamine result in the formation of diethyl malonates.22 An explanation for this unusual reaction has been described.23

Related Reagents.

Bis(trimethylsilyl) Malonate; Carbon Suboxide; (Chlorocarbonyl)ethylketene; Diethyl Malonate; 2,2-Dimethyl-1,3-dioxane-4,6-dione; Malonic Acid; Malonyl Chloride.


1. Kappe, T. M 1967, 98, 874.
2. Ziegler, E.; Maier, H. M 1958, 89, 150.
3. Mayrhofer, A. Diploma Thesis, University of Graz, 1993.
4. Frühwirth, F. Ph.D. Thesis, University of Graz, 1978.
5. Glennon, R. A.; Rogers, M. E.; El-Said, M. K. JHC 1980, 17, 337.
6. Soliman, F. S. G.; Stadlbauer, W.; Kappe, T. ZN(B) 1981, 36b, 252.
7. Glennon, R. A.; Rogers, M. E.; Smith, J. D.; El-Said M. K. JMC 1981, 24, 658.
8. Kappe, T.; Brandner, A. ZN(B) 1974, 29b, 292.
9. Koch, A.-C. Ph.D. Thesis, University of Kiel, 1991.
10. Lapachev, V. V.; Stadlbauer, W.; Kappe, T. M 1988, 119, 97.
11. (a) Kappe, T.; Schmidt, H. TL 1970, 5101. (b) Chirazi, A. M.; Brandner, A.; Kappe, T. ZN(B) 1977, 32b, 1189. (c) Kappe, T.; Schmidt, H. CB 1979, 112, 2756.
12. (a) Kappe, T.; Brandner, A. ZN(B) 1974, 29b, 292. (b) Kappe, T. TL 1968, 5327. (c) Nöhammer, G.; Kappe, T. M 1976, 107, 859. (d) Soliman, F. S. G. M 1982, 113, 475.
13. (a) Kappe, T.; Chirazi A. M.; Stelzel, H. P.; Ziegler, E. M 1972, 103, 586. (b) Kappe, T.; Baxevanidis, G.; Ziegler, E. M 1971, 102, 1392. (c) Kappe, T.; Ajili, S.; Stadlbauer, W. JHC 1988, 25, 463. (d) Bonsignore, L.; Cocco, M. T.; Loy, G.; Onnis, V. JHC 1992, 29, 237.
14. (a) Célérier, J. P.; Eskénazi, C.; Lhommet, G.; Maitte, P. JHC 1979, 16, 953. (b) Dannhardt, G.; Meindl, W.; Gussmann, S.; Ajili, S.; Kappe, T. Eur. J. Med. Chem. 1987, 22, 505.
15. (a) Kappe, T. M 1967, 98, 2149. (b) Kappe, T.; Linnau, Y. M 1969, 100, 1726. (c) Kappe, T.; Chirazi, M. A. A.; Ziegler, E. M 1972, 103, 234. (d) Rida, S. M.; Soliman, F. S. G.; Badawey, E.-S. A. M.; El-Ghazzawi, E.; Kader, O. JHC 1988, 25, 1087.
16. (a) Schober, B.; Kappe, T. JHC 1988, 25, 1231. (b) Labouta, I. M.; Soliman, F. S. G.; Kassem, M. G. Pharmazie 1986, 41, 812.
17. (a) Kappe, T.; Lube, W. M 1971, 102, 781. (b) Kappe, T.; Korchid-Zadeh, R. S 1975, 247. (c) Friedrichsen, W.; Schmidt, R.; Van Hummel, G. J.; Van den Ham, D. M. W. LA 1981, 521.
18. (a) Gotthardt, H.; Blum, J. CB 1985, 118, 2079. (b) Kappe, C. O.; Kappe, T. AP 1990, 324, 863.
19. Coburn, R. A.; Glennon, R. A. JHC 1973, 10, 487.
20. Glennon, R. A.; Tejani-Butt, S. M. The Chemistry of Nucleosides and Nucleotides; Townsend, L. B., Ed., Plenum: New York, 1991; Vol. 2, pp 1-25.
21. Dvortsak, P.; Resofski, G.; Huhn, M.; Zalantai, L. T 1976, 32, 3117.
22. Badawey, E.-S. unpublished results, 1992.
23. Gutman, A. L.; Boltanski, A. TL 1985, 26, 1573.

Thomas Kappe

Karl-Franzens University, Graz, Austria



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