(R = H)

[504-02-9]  · C6H8O2  · 1,3-Cyclohexanedione  · (MW 112.13) (R = Me)

[1193-55-1]  · C7H10O2  · 2-Methyl-1,3-cyclohexanedione  · (MW 126.16)

(building block for substituted cyclohexane derivatives2 and condensed carbo- and heterocycles3)

Physical Data: 1,3-cyclohexanedione (CHD): mp 103-105 °C; 2-methyl-1,3-cyclohexanedione (MCHD): mp 206-209 °C.

Solubility: CHD easily sol H2O, EtOH, CHCl3, acetone, and boiling benzene; MCHD sol MeOH and sparingly sol H2O and EtOH.

Form Supplied in: CHD and MCHD are colorless solids; both reagents are commercially available.

Preparative Methods: Raney nickel-catalyzed hydrogenation of resorcinol for CHD;4 methylation of CHD5 with MeI or base-promoted cyclization of ethyl 5-oxoheptanoate for MCHD.6

Handling, Storage, and Precautions: CHD is recommended to be stored at 0-5 °C. MCHD can be kept at rt. Both reagents are stable only in pure form. They are reputed to be of low toxicity.

CHD and its 2-monoalkyl homologs are almost completely enolized.1 Many of their reactions are very similar.

Reactions with Nucleophiles at the Carbonyl Group.

The acid-catalyzed reaction of CHD with alcohols affords b-alkoxy enones (1) (eq 1).2 These compounds can be reduced with Lithium Aluminum Hydride to the corresponding 2-cyclohexen-1-ones,7 whereas addition of organometallics affords 3-alkyl-2-cyclohexen-1-ones.2 With N,N-disubstituted hydrazines, CHD forms monohydrazones, which exist as tautomeric enhydrazinones (2) (eq 1).8

Reactions with Electrophiles at the Enolic Hydroxy Group.

Acylation of CHD with alkanoyl chlorides in pyridine gives rise to the enol esters (3), which can be isomerized to the triketones (4) (eq 2).9 Alkyl tosylates1 convert the dione into the corresponding b-alkoxy enones of type (1).

Reactions with Electrophiles at C-2.

The palladium(0)-catalyzed reaction of MCHD with the substituted allyl acetate (5) results in a clean C-alkylation (eq 3).10

The alkylation of CHD with alkyl halides affords mixtures of 3-alkoxy-2-cyclohexen-1-ones (O-alkylation) and 2-mono- and 2,2-dialkylated 1,3-cyclohexanediones (C-alkylation). Allyl Bromide and Benzyl Bromide as well as alkyl bromoacetates give C-alkylation products in better yields.1 In Michael reactions, a,b-unsaturated carbonyl compounds (eq 4),1,11 acetals of a,b-enals,12 nitroalkenes,13 and Mannich bases14 add to C-2 of MCHD. Aldol cyclization of the methyl vinyl ketone adduct affords the octalindione shown (eq 4) in racemic11a or optically active form.11b

In the presence of Boron Trifluoride Etherate, 2 equiv of Formaldehyde condense with CHD forming the 1,3-dioxin (7). With 2 equiv of CHD, formaldehyde leads to the adduct (6) (eq 5).1,15

With DMF dimethyl acetal (see N,N-Dimethylformamide Diethyl Acetal), an a-aminomethylenation takes place at C-2.16 In the presence of BF3, carboxylic anhydrides acylate CHD at C-2.17

Reactions with Electrophiles at C-4 or at C-6.

The enaminone (8) obtained from CHD and Pyrrolidine is alkylated at C-4 by treatment with n-Butyllithium and Iodomethane (eq 6).18

In contrast, the enol ethers derived from CHD or MCHD can be alkylated at C-6 after deprotonation with Lithium Diisopropylamide (eq 7).19

Annulation Reactions.

Many examples are known for the formation of condensed carbo- and heterocycles by reactions of bifunctional compounds with two of the reactive sites of CHD or MCHD.3,19

Ring Cleavage and Contraction.

Hydroxide- or alkoxide-induced retro-Claisen reactions of 2-alkyl- and 2,2-dialkyl-1,3-cyclohexanediones give rise to d-keto acids or esters (eq 8).20 Chlorination of 2-pentynyl-1,3-cyclohexanedione at C-2 followed by heating in the presence of sodium carbonate effects a Favorskii-type ring contraction with decarbonylation to 2-pentynyl-2-cyclopentenone (eq 9), a useful intermediate for the synthesis of jasmone.21

Related Reagents.

1,3-Cyclopentanedione; 2-Methyl-1,3-cyclopentanedione; Methyl Vinyl Ketone; 2,4-Pentanedione; (S)-Proline.

1. Stetter, H. AG 1955, 67, 769.
2. Gannon, W. F.; House, H. O. OSC 1973, 5, 539. (b) Eschenmoser, A.; Schreiber, J. HCA 1953, 36, 482.
3. Strakov, A. Ya.; Gudriniece, E.; Zicane, D. KGS 1974, 1011 (CA 1974, 81, 136 004).
4. Thompson, R. B. OSC 1955, 3, 278.
5. Mekler, A. B.; Ramachandran, S.; Swaminathan, S.; Newman, M. S. OSC 1973, 5, 743.
6. Chattopadhyay, P.; Banerjee, U. K.; Sarma, A. S. SC 1979, 9, 313.
7. Gannon, W. F.; House, H. O. OSC 1973, 5, 294.
8. Enders, D.; Demir, A. S.; Puff, H.; Franken, S. TL 1987, 28, 3795.
9. Akhrem, A. A.; Lakhvich, F. A.; Budai, S. I.; Khlebnicova, T. S.; Petrusevich, I. I. S 1978, 925.
10. Trost, B. M.; Curran, D. P. JACS 1980, 102, 5699.
11. (a) Ramachandran, S.; Newman, M. S. OSC 1973, 5, 486. (b) Buchschacher, P.; Fürst, A.; Gutzwiller, J. OSC 1990, 7, 368.
12. Coates, R. M.; Hobbs, S. J. JOC 1984, 49, 140.
13. Nakashita, Y.; Watanabe, T.; Benkert, E.; Lorenzi-Riatsch, A.; Hesse, M. HCA 1984, 67, 1204.
14. Swaminathan, S.; Newman, M. S. T 1958, 2, 88.
15. Smith, A. B., III; Dorsey, B. D.; Ohba, M.; Lupo, A. T., Jr.; Malamas, M. S. JOC 1988, 53, 4314.
16. LeTourneau, M. E.; Peet, N. P. JOC 1987, 52, 4384.
17. Sakai, T.; Iwata, K.; Utaka, M.; Takeda, A. BCJ 1987, 60, 1161.
18. Yoshimoto, M.; Ishida, N.; Hiraoka, T. TL 1973, 39.
19. (a) Muskopf, J. W.; Coates, R. M. JOC 1985, 50, 69. (b) Stork, G.; Danheiser, R. L.; Ganem, B. JACS 1973, 95, 3414.
20. (a) Stetter, H. In Newer Methods of Preparative Organic Chemistry; Foerster, W., Ed.; Academic: New York, 1963; Vol. 2, pp 51-99. (b) House, H. O. Modern Synthetic Reactions, 2nd ed.; Benjamin: Menlo Park, CA, 1972; pp 518-520, 784-786.
21. Büchi, G.; Egger, B. JOC 1971, 36, 2021.

Hans Schick

Institut für Angewandte Chemie, Berlin-Adlershof, Germany

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