Cyclopropenone 1,3-Propanediyl Acetal1

[60935-21-9]  · C6H8O2  · Cyclopropenone 1,3-Propanediyl Acetal  · (MW 112.12)

(cyclopropenone synthesis;4 vinylcarbene formation;1 acceptor of organometallic reagents;13 dienophile15)

Physical Data: bp 30-35 °C/1.25 mmHg.

Solubility: insol H2O.

Form Supplied in: colorless liquid.

Analysis of Reagent Purity: GLC, NMR.

Preparative Methods: the best current preparation of cyclopropenone acetals involves the reaction of 1,3-dichloroacetone 1,3-propanediyl acetal with Sodium Amide in a liq. NH3/Et2O mixture.2 The latter acetal can be prepared in high yield from commercially available 1,3-dichloroacetone and 1,3-propanediol. This method is superior to the previous method which employs the less convenient reagents KNH2 and 1-chloro-3-bromoacetone 1,3-propanediyl acetal.3

Purification: distillation under reduced pressure.

Handling, Storage, and Precautions: cyclopropenone acetals may be stored in a refrigerator.

Cyclopropenone Synthesis.

Alkyl-, aryl-, and vinyl-substituted cyclopropenones have been prepared by the reaction of a metalated cyclopropenone acetal with an electrophile followed by acid hydrolysis of the acetal.4 Deprotonation of the vinylic proton of the cyclopropenone acetal with n-Butyllithium or Sodium Amide afforded the lithium or sodium salt of the cyclopropenone acetals. The lithium salt is treated with 0.5 equiv of Zinc Chloride to obtain the corresponding zinc salt. The sodium and lithium salts are useful for the synthesis of alkyl- and hydroxymethyl-substituted cyclopropenone acetals by their reaction with an alkyl halide or a carbonyl compound, respectively. Acid hydrolysis of the acetal affords the corresponding cyclopropenone in good yield (eq 1). This reaction is effective for the synthesis of biologically active cyclopropenones, e.g. penitricin (R1, R2 = H) and its congeners.5

The zinc salt of cyclopropenone acetal is useful for the synthesis of vinyl- and aryl-substituted cyclopropenones. Thus the reaction of the zinc salt with vinyl iodide, vinyl triflate, and aryl iodide in the presence of a catalytic amount of Tetrakis(triphenylphosphine)palladium(0) affords vinyl- and aryl-substituted cyclopropenones after acid hydrolysis (eq 2).

Disubstituted cyclopropenone acetals are synthesized by repetition of the metalation/alkylation sequence on a monosubstituted cyclopropenone acetal.

Vinylcarbene Precursors.

Thermolysis of cyclopropenone acetal generates a singlet vinylcarbene, which undergoes [2 + 1] and [3 + 2] cycloaddition reactions with electron deficient alkenes. The vinylcarbene, which is generated from the cyclopropenone acetal at 70-120 °C, reacts with an alkene bearing a single electron-withdrawing group in a [2 + 1] manner to afford the cyclopropane derivative.6 The reaction takes place through an endo transition state, and gives predominantly 1,2-cis-substituted cyclopropanes (eq 3). The ketene acetal of the product can be easily hydrolyzed to the corresponding ester with aqueous acid. On the contrary, the reaction of cyclopropenone acetal with an alkene bearing geminal electron-withdrawing groups affords exclusively the cyclopentenone acetal derivative by a single-electron transfer pathway (eq 3).7

In contrast to the thermal reaction, Ni0-catalyzed [1 + 2] cycloaddition of the cyclopropenone dimethyl acetal with methyl acrylate mainly gives thermodynamically stable 1,2-trans-disubstituted cyclopropane derivatives.8 The reaction of the cyclopropenone dimethyl acetal with dimethyl fumarate or maleate in the presence of a catalytic amount of Bis(1,5-cyclooctadiene)nickel(0) affords trans-cyclopropane derivatives with respect to the ester groups (eq 4). The loss of the stereospecificity of this reaction is due to a stepwise cycloaddition of a nickel vinylcarbene complex with an alkane.

Treatment of Eschenmoser's a-pyrone with the cyclopropenone acetal at 75 °C afforded the [4 + 3] cycloaddition compound as a single product, which is an important synthetic precursor of colchicine (eq 5).9 Participation of the cyclopropenone acetal in a competing [4 + 2] Diels-Alder reaction with the a-pyrone is decelerated by unfavorable steric interactions of the acetal group that hinder the exo as well as the endo transition state required for the [4 + 2] cycloaddition reaction (see below).

The vinylcarbene also reacts with carbonyl compounds to give g-lactone acetals, which hydrolyze to the corresponding g-lactone or furan depending on the substituents (eq 6).10

Substituted cyclopropenone acetals are a good precursor of substituted singlet vinylcarbenes. The substituted vinylcarbenes are formed regio- and stereoselectively, and undergo regioselective [3 + 2] cycloaddition to electron deficient alkanes to give a variety of cyclopentenone acetals.11 Phenylthio and ester groups connected to the alkenic carbon effect highly regioselective vinylcarbene formation below rt, permitting the [3 + 2] cycloaddition to take place under extremely mild conditions (eq 7).

In addition to cycloaddition chemistry, the vinylcarbene undergoes C-H and O-H bond insertion reactions with acidic hydrogens. Thus Methyl Propiolate and methanol react with the vinylcarbene to afford an acetal of a vinyl ethynyl ketone and an orthoester of an a,b-unsaturated ester (eq 8).12

Acceptor of Organometallic Reagents.

Cyclopropenone acetals react with organocopper reagents to produce the copper salt of the cyclopropanone acetal, which serves as a synthetic equivalent of the inaccessible cyclopropanone enolate and reacts with a variety of electrophiles to afford substituted cyclopropanone acetals.13 Addition of vinylcuprate to the cyclopropenone acetal followed by trapping with water, alkyl halide, and vinyl iodide in the presence of Pd0 catalyst affords the corresponding vinyl-substituted cyclopropanone acetals (eq 9). These cyclopropane derivatives can be thermally transformed to cyclopentenone acetal, divinyl ketone acetal, and cycloheptadienone acetal by vinylcyclopropane rearrangement, 1,3-sigmatropic rearrangement, and divinylcyclopropane rearrangement, respectively (eq 9).

Regio- and stereoselective carbocupration of a 2-substituted cyclopropenone acetal derived from a chiral 2,4-pentandiol can be used for the stereoselective synthesis of a quaternary carbon center.14 Thus the addition of dimethylcuprate to the ethyl substituted cyclopropenone acetal followed by trapping of the resulting cyclopropylcuprate with benzoyl chloride in the presence of a Pd0 catalyst affords the cyclopropyl ketone derivative as a single isomer. The ketone is transformed into the g-keto acid by successive treatment with aqueous HCl, PCC, and K2CO3 (eq 10).


A variety of dienes, including electron rich, neutral, and electron deficient ones, react with cyclopropenone acetals under thermal or high pressure conditions.15 The reaction proceeds through a sterically less hindered exo transition state. The utility of this reaction is exemplified by the synthesis of tropone derivatives. The reaction of a cyclopropenone acetal with methyl 4-methoxy-1,3-butadiene-1-carboxylate at rt affords the [4 + 2] cycloaddition adduct as a single stereoisomer that possesses the trans relative configuration. Treatment of the cycloadduct with a strong base (Potassium t-Butoxide, 25 °C) affords the 3-methoxycarbonyltroponone acetal through an elimination of methanol followed by a rearrangement of the norcaradiene intermediate. Hydrolysis of the troponone acetal provides 3-methoxycarbonylcycloheptatrienone in a good overall yield (eq 11).

Oligomerization and Polymerization.

Thermal or Pd0 catalyzed reaction of a cyclopropenone acetal affords a dimer, which is thermally converted to a quinone diacetal derivative (eq 12).

Cyclopropenone acetals undergo ring-opening polymerization under cationic conditions.16 Among a variety of initiators examined, Bromine is found to be a good initiator and gives polymers whose Mn values are in the region of 10 000.

Methylenecyclopropane Formation and [3 + 2] Cycloadditions via Trimethylenemethane.

Base-catalyzed isomerization of an alkyl-substituted cyclopropenone acetal gives the alkylidenecyclopropanone acetal, which is utilized for [3 + 2] cycloaddition reactions through a trimethylenemethane intermediate.17 Upon thermolysis, the alkylidenecyclopropanone acetal generates a dipolar trimethylenemethane, which reacts with an electron-deficient alkene or a carbonyl compound to afford five-membered carbo- and heterocycles (eq 13). This reaction is also useful for the preparation of functionalized buckminsterfullerenes (C60).18

1. Boger, D. L.; Brotherton-Pleiss, C. E. Advances in Cycloaddition; Jai: Greenwich, CT, 1990; Vol. 2.
2. Isaka, M.; Ando, R.; Morinaka, Y.; Nakamura, E. TL 1991, 32, 1339.
3. (a) Boger, D. L.; Brotherton, C. E.; Georg, G. I. OS 1987, 65, 32. (b) Breslow, R.; Pecorato, J.; Sugimoto, T. OSC 1988, 6, 361.
4. (a) Isaka, M.; Matsuzawa, S.; Yamago, S.; Ejiri, S.; Miyachi, Y.; Nakamura, E. JOC 1989, 54, 4727. (b) Isaka, M.; Ejiri, S.; Nakamura, E. T 1992, 48, 2045.
5. (a) Tokuyama, H.; Isaka, M.; Nakamura, E.; Ando, R.; Morinaka, Y. J. Antibiot. 1992, 1148. (b) Ando, R.; Morinaka, Y.; Tokuyama, H.; Isaka, M.; Nakamura, E. JACS 1993, 115, 1174.
6. Boger, D. L.; Brotherton, C. E. TL 1984, 25, 5611.
7. (a) Boger, D. L.; Brotherton, C. E. JACS 1984, 106, 805. (b) Boger, D. L.; Brotherton, C. E. JACS 1986, 108, 6695. (c) Boger, D. L.; Wysocki, Jr., R. J. JOC 53, 3408.
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9. (a) Boger, D. L.; Brotherton, C. E. JOC 1985, 50, 3425. (b) Boger, D. L.; Brotherton, C. E. JACS 1986, 108, 6713.
10. Boger, D. L.; Brotherton, C. E. TL 1984, 25, 5615.
11. Tokuyama, H.; Isaka, M.; Nakamura, E. JACS 1992, 114, 5523.
12. (a) Baucom, K. B.; Butler, G. B. JOC 1977, 42, 674. (b) Butler, G. B.; Herring, K. H.; Lewis, P. L.; Sharpe, III, V. V.; Verzey, R. L. JOC 1977, 42, 679. (c) Ref. 9a.
13. (a) Nakamura, E.; Isaka, M.; Matsuzawa, S. JACS 1988, 1297. (b) Nakamura, E.; Kubota, K.; Isaka, M. JOC 1992, 57, 5809.
14. Isaka, M.; Nakamura, E. JACS 1990, 112, 7428.
15. (a) Albert, R. M.; Butler, G. B. JOC 1977, 42, 674. (b) Boger, D. L.; Brotherton, C. E. T 1986, 42, 2777.
16. (a) Cook, G. A.; Butler, G. B. J. Macromol. Sci.-Chem. 1985, A22, 483. (b) Cook, G. A.; Butler, G. B. J. Macromol. Sci.-Chem. 1985, A22, 507.
17. (a) Yamago, S.; Nakamura, E. JACS 1989, 111, 7285. (b) Ejiri, S.; Yamago, S.; Nakamura, E. JACS 1992, 114, 8708. (c) Yamago, S.; Nakamura, E. JOC 1990, 55, 5553.
18. Prato, M.; Suzuki, T.; Foroudian, H.; Li, Q.; Khemani, K.; Wudl, F.; Leonetti, J.; Little, R. D.; White, T.; Rickborn, B.; Yamago, S.; Nakamura, E. JACS 1993, 115, 1594.

Shigeru Yamago & Eiichi Nakamura

Tokyo Institute of Technology, Japan

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