Cyclopropanone1

[5009-27-8]  · C3H4O  · Cyclopropanone  · (MW 56.06)

(very reactive three-carbon building block;1 synthesis of geminally functionalized cyclopropanes1 and methylenecyclopropanes; ring expansion to b-lactams;2,3 ring opening to propionic acid derivatives)

Solubility: sol ether, dichloromethane; nucleophilic solvents, e.g. alcohols and water, afford the corresponding adducts (e.g. hemiacetals, hydrates).

Form Supplied in: not commercially available; prepared at low temperature (-50 to -78 °C) in solution (see below) and preferably used directly for further elaboration.

Analysis of Reagent Purity: 1H NMR.

Preparative Methods: special apparatus is required to perform the reaction of ketene with diazomethane (eq 1).4 A solution of Diazomethane in diethyl ether is added to a solution of Ketene in dichloromethane at -78 °C at such a rate that the temperature does not rise above -60 °C. The reaction mixture is kept at -50 °C for 35 min. The reaction mixture thus obtained is a solution of cyclopropanone in dichloromethane/diethyl ether (yield 75%). This solution is suitable for further elaboration, viz. addition of nucleophiles. As an example, the addition of glacial acetic acid (1.04 equiv) in dichloromethane, at -50 °C, to the solution of cyclopropanone affords, after evaporation of the solvents at 0 °C, a residual liquid which is distilled in vacuo to give 1-acetoxycyclopropanol (bp 26-28 °C/0.5 mmHg) (eq 2) as a storable source of cyclopropanone.2

Handling, Storage, and Precautions: in situ preparation in solution at -78 °C as above, using dry solvents (inert atmosphere); the presence of any nucleophilic reagent is incompatible with this preparation; the storage lifetime of the solution of cyclopropanone at -78 °C is very limited as polymerization occurs under the influence of traces of water;5 inhibition of polymerization occurs with moisture scavengers.6 This reagent should be handled in a fume hood.

Adduct Formation.

The majority of reactions performed with cyclopropanones originate from the use of cyclopropanone adducts which are in equilibrium with cyclopropanone (eq 3). Such adducts include 1-Ethoxycyclopropanol (1)7 and 1-acetoxycyclopropanol (2)8 (eq 4). Also the magnesium salt of (1), i.e. adduct (3),9 and 1-piperidino-1-trimethylsilyloxycyclopropane (4) and its free alcohol (5)10,11 have been reported as cyclopropanone sources.

Addition of water,1 methanol,1 ethanol,1 acetic acid,4,6,8 hydrogen chloride,6 and hydrogen cyanide12 to in situ prepared cyclopropanone affords the corresponding hydrate (eq 5), hemiacetal (eq 6), hemiacylal (eq 2), chlorohydrate (eq 7), and cyanohydrin (eq 8), respectively.

The addition of amines to cyclopropanone is more complex and is dependent upon the type of amine and the number of molar equivalents of the amine used. The reaction of cyclopropanone with 0.5 equiv ammonia afforded the bis(cyclopropyl)amine derivative as the major product, in addition to the tris(cyclopropyl)amine derivative as a minor product (eq 9).4 Monoadducts with primary amines were obtained at -78 °C (eq 10),13 while the same reaction at -30 °C with methylamine produced the bis(cyclopropyl) derivative, which cyclocondensed with cyclopropanone hydrate to form tris-spiro adducts (eq 11).13 Aniline reacted with cyclopropanone to give mono- and bisadducts,13 while N,N-Dimethylhydrazine at elevated temperature afforded the monoadduct which could be dehydrated to cyclopropanone N,N-dimethylhydrazone (eq 12).14 Secondary amines,15,16 such as dimethylamine, produced cyclopropanone monoadducts provided that an inverse addition of cyclopropanone was performed (eq 13).4 Further addition of the secondary amine produced the corresponding aminals.15,16

Sulfur nucleophiles, such as hydrogen sulfide, behave like amines in that they afford bis(cyclopropyl) sulfides which serve as a source of methylenethiirane via flash pyrolysis of a bis-spiro carbonate (eq 14).17 Thiols added smoothly to cyclopropanone to give the monoadducts (eq 15).18

Synthesis of b-Lactams.

Sodium Azide in acetone converted cyclopropanone into 1-azidocyclopropanol, which suffered spontaneous rearrangement to azetidin-2-one in variable yields (eq 16).19,20 A similar rearrangement is observed with the cyclopropanone adduct of N-t-butyl-O-benzoylhydroxylamine to form 1-t-butylazetidin-2-one (eq 17).2 A more general approach to 1-substituted azetidin-2-ones consisted of the addition of primary amines to cyclopropanone at -78 °C, resulting in the monoadducts which were N-chlorinated using t-Butyl Hypochlorite and subsequently rearranged under the influence of Silver(I) Nitrate to give the ring expanded azetidine derivatives (eq 18).2 Aliphatic as well as a-amino carboxylic esters have been converted in this way into a wide range of azetidin-2-ones.2,21-23

Addition of Carbon Nucleophiles.

The addition of carbon nucleophiles to cyclopropanone may be accomplished by reactions with 1-ethoxycyclopropanol (1)7,19,20,24-26 or its magnesium salt (3).27 Organolithium9,27-29 as well as organomagnesium reagents7,19,20,24-26 add across the carbonyl function of cyclopropanone to afford the corresponding cyclopropanols (eq 19). Moderate yields of alkylidenecyclopropanes are obtained by condensation of the cyclopropanone precursors with alkylidenephosphoranes (eqs 20,21).27,30

Ring Opening.

Addition of alcohols to cyclopropanone gives hemiacetals which are opened in a Favorskii-like way to afford propionates (eq 22).27

Polymerization.

Polymerization of a solution of cyclopropanone takes place at temperatures above 0 °C and is initiated by traces of water (eq 23).1,5,34 The same polymers are obtained by thermolysis.35

Natural Product Synthesis.

The cyanohydrin of cyclopropanone was converted into cleonine (6) by a sequence of reactions involving protection of the alcohol, aldehyde formation, and Strecker reaction of the latter to give the a-amino acid cleonine (eq 24).31 The ammonia monoadduct of cyclopropanone is stable as its hydrochloride salt, which is further elaborated to coprine (7) (eq 25).32,33

Related Reagents.

Cyclobutanone; Cyclopropenone 1,3-Propanediyl Acetal; 6,6-Dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione; 1-Ethoxycyclopropanol; Methylenecyclopropane; 1-(Tetrahydropyranyloxy)cyclopropanecarbaldehyde.


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2. Wasserman, H. H.; Adickes, H. W.; de Ochoa, O. E. JACS 1971, 93, 5586.
3. Wasserman, H. H.; Glazer, E. A.; Hearn, M. J. TL 1973, 4855.
4. van Tilborg, W. J. M.; Steinberg, H.; de Boer, T. J. SC 1973, 3, 189.
5. Schaafsma, J. E.; Steinberg, H.; de Boer, T. J. RTC 1967, 86, 651.
6. Turro, N. J.; Hammond, W. B. JACS 1967, 89, 1028.
7. Salaün, J. JOC 1977, 42, 28.
8. van Tilborg, W. J. M.; Steinberg, H.; de Boer, T. J. RTC 1974, 93, 287.
9. Brown, H. C.; Rao, C. G. JOC 1978, 43, 3602.
10. Wasserman, H. H.; Dion, R. P. TL 1982, 23, 785.
11. Wasserman, H. H.; Dion, R. P.; Fukuyama, J. T 1989, 45, 3203.
12. van Tilborg, W. J. M.; Schaafsma, S. E.; Steinberg, H.; de Boer, T. J. RTC 1967, 86, 419.
13. van Tilborg, W. J. M.; Steinberg, H.; de Boer, T. J. RTC 1974, 93, 294.
14. Reetz, M. T.; Rheinheimer, J. JOC 1986, 51, 5465.
15. van Tilborg, W. J. M.; Schaafsma, S. E.; Steinberg, H.; de Boer, T. J. RTC 1967, 86, 417.
16. Wasserman, H. H.; Baird, M. S. TL 1970, 1729.
17. Jongejan, E.; Buys, T. S. V.; Steinberg, H.; de Boer, T. J. RTC 1978, 97, 214.
18. Jorritsma, R.; Steinberg, H.; de Boer, T. J. RTC 1981, 100, 184.
19. Wasserman, H. H.; Clagett, D. C. JACS 1966, 88, 5368.
20. Wasserman, H. H.; Cochoy, R. C.; Baird, M. S. JACS 1969, 91, 2375.
21. Wasserman, H. H.; Glazer, E. JOC 1975, 40, 1505.
22. Wasserman, H. H.; Hlasta, D. J.; Tremper, A. W.; Wu J. S. JOC 1981, 46, 2999.
23. Wasserman, H. H.; Hlasta, D. J. JACS 1978, 100, 6780.
24. Wasserman, H. H.; Hearn, M. J.; Cochoy, R. E. JOC 1980, 45, 2874.
25. Liberles, A.; Kang, S.; Greenberg, A. JOC 1973, 38, 1922.
26. Howell, B. A.; Jewett, J. G. JACS 1971, 93, 798.
27. Salaün, J.; Bennani, F.; Compain, J.-C.; Fadel, A.; Ollivier, J. JOC 1980, 45, 4129.
28. Stolle, A.; Salaün, J.; de Meijere, A. TL 1990, 31, 4593.
29. Salaün, J.; Ollivier, J. NJC 1981, 5, 587.
30. Osborne, N. F. JCS(P1) 1982, 1435.
31. Kato, K. TL 1980, 4925.
32. Lindberg, P.; Bergman, R.; Wickberg, B. CC 1975, 946.
33. Lindberg, P.; Bergman, R.; Wickberg, B. JCS(P1) 1977, 684.
34. Schaafsma, S. E.; Steinberg, H.; de Boer, T. J. RTC 1966, 85, 1170.
35. van Tilborg, W. J. M.; Steinberg, H.; de Boer, T. J. RTC 1974, 93, 303.

Norbert De Kimpe

University of Gent, Belgium



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