2-Methyl-1,3-cyclopentanedione1

[765-69-5]  · C6H8O2  · 2-Methyl-1,3-cyclopentanedione  · (MW 112.14)

(building block for the total synthesis of 19-norsteroids2 and many other naturally occurring cyclopentanoids;1 precursor for 2,2-, 2,4-, and 2,5-dialkylated cyclopentanediones1)

Alternate Name: MCPD.

Physical Data: mp 214-216 °C.

Solubility: sparingly sol cold H2O, MeOH, EtOH; insol cold Et2O, benzene, toluene; sol boiling H2O.

Form Supplied in: colorless solid; commercially available.

Preparative Methods: AlCl3-promoted acylation of succinic acid with propanoyl chloride in nitromethane3 or cyclization of 4-oxohexanoic acid4 or its esters.5

Handling, Storage, and Precautions: the pure reagent is a stable compound, which is reputed to be of low toxicity.

Introduction.

2-Methyl-1,3-cyclopentanedione (1a) is completely enolized and therefore has the structure of 3-hydroxy-2-methyl-2-cyclopenten-1-one (1b).6

Reactions with Nucleophiles at the Carbonyl Group.

With alcohols in the presence of acidic catalysts (1) forms 3-alkoxy-2-methyl-2-cyclopenten-1-ones (enol ethers).7 With primary or secondary amines the corresponding 3-amino-2-methyl-2-cyclopenten-1-ones (enamino ketones) are obtained.8 These derivatives of (1) afford 2,3-dialkylated 2-cyclopenten-1-ones in reactions with organolithium or Grignard reagents (eq 1).1

Reactions with Electrophiles at C-2.

Diketone (1) reacts with the tertiary allyl alcohol (2) to give the secosteroid (3), which represents a key intermediate in the estrone synthesis of Torgov (eq 2).9

Diketone (1) adds in a Michael reaction to a,b-unsaturated carbonyl compounds, acrylonitrile, nitroalkenes, and Mannich bases, forming 2,2-disubstituted 1,3-cyclopentanediones.1,10 The thus available triketone (4) affords the (S)-diketone (5) in a highly enantioselective aldol condensation catalyzed by (S)-proline (eq 3).11,12

The palladium(0)-catalyzed reaction of allyl acetate with (1) affords exclusively the 2-allylated compound (eq 4),13 whereas allyl, propargyl, and benzyl halides, as well as alkyl bromoacetates, react with the potassium or sodium salt of (1) to form mixtures of C- and O-alkylated products. In water as solvent the C-alkylation is favored; in DMF or DMSO the O-alkylation predominates.14 2,2-Disubstituted 1,3-cyclopentanediones are easily cleaved by aqueous sodium hydroxide in a retro aldol reaction to 5-substituted 4-oxoalkanoic acids (eq 4).15

Reactions with Electrophiles at the Enolic Hydroxy Group.

The enolic hydroxy group of (1) is substituted by chloro, sulfonyloxy, diethoxyphosphinyloxy, or trimethylsilyloxy groups by reaction with Oxalyl Chloride, sulfonyl chlorides, Diethyl Phosphorochloridate, and Hexamethyldisilazane, respectively.1 The b-substituted enones obtained serve as intermediates for many further reactions (eq 5).1

Reactions with Electrophiles at C-4 and C-5.

Enol ethers and enamines of (1) are versatile intermediates for further functionalization. Lithium Diisopropylamide deprotonates these compounds at C-5,16,17 whereas Lithium Hexamethyldisilazide removes a proton at C-4.17-19 The monoanions thus obtained can be selectively alkylated in the corresponding positions (eq 6). By repeating the deprotonation and subsequent alkylation, 2,4,5-trialkylated 1,3-cyclopentanedione derivatives are available.18

The reactions reported here for (1) are typical also for its higher alkyl homologs.

Related Reagents.

1,3-Cyclohexanedione; 1,3-Cyclopentanedione.


1. Schick, H.; Eichhorn, I. S 1989, 477.
2. Blickenstaff, R. T.; Ghosh, A. C.; Wolf, G. C. Total Synthesis of Steroids; Academic: New York, 1974.
3. (a) Schick, H.; Lehmann, G.; Hilgetag, G. CB 1969, 102, 3238 (CA 1969, 71, 101 367). (b) Meister, P. G.; Sivik, M. R.; Paquette, L. A. OS 1991, 70, 226.
4. Schick, H.; Lehmann, G.; Hilgetag, G. CB 1967, 100, 2973 (CA 1967, 67, 99 698).
5. Hengartner, U.; Chu, V. OS 1978, 58, 83.
6. Hiraga, K. CPB 1965, 13, 1300.
7. Funk, R. L.; Vollhardt, K. P. C. S 1980, 118.
8. Otto, A.; Schick, H. S 1991, 115.
9. Ananchenko, S. N., Torgov, I. V. TL 1963, 1553.
10. Schick, H.; Roatsch, B.; Schwarz, H.; Hauser, A.; Schwarz, S. LA 1992, 419.
11. Eder, U.; Sauer, G.; Wiechert, R. AG 1971, 83, 492; AG(E) 1971, 10, 496.
12. Hajos, Z. G.; Parrish, D. R. OS 1985, 63, 26.
13. Trost, B. M.; Curran, D. P. JACS 1980, 102, 5699.
14. Schick, H.; Schwarz, H.; Finger, A.; Schwarz, S. T 1982, 38, 1279 (CA 1982, 97, 144 427).
15. Schick, H.; Schwarz, S.; Eberhardt, U. JPR 1977, 319, 213 (CA 1977, 87, 52 700).
16. Parsons, W. H.; Schlessinger, R. H.; Quesada, M. L. JACS 1980, 102, 889.
17. Akhrem, A. A.; Lakhvich, F. A.; Lis, L. G.; Pap, A. A.; Rubinov, D. B. DOK 1983, 269, 1361 (CA 1983, 99, 175 519).
18. Koreeda, M.; Chen, Y. P. L. TL 1981, 22, 15.
19. Lakhvich, F. A.; Lis, L. G.; Pap, A. A. ZOR 1988, 24, 1388 (CA 1989, 110, 114 328).

Hans Schick

Institut für Angewandte Chemie, Berlin-Adlershof, Germany



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