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DOI:10.15227/orgsyn.063.0147

Organic Syntheses, Coll. Vol. 7, p.131 (1990); Vol. 63, p.147 (1985).

CYCLOPROPANONE ETHYL HEMIACETAL FROM ETHYL 3CHLOROPROPANOATE[Cyclopropanol, 1-ethoxy-]

Submitted by J. Salaün and J. Marguerite1.
Checked by Steven D. Young, Syun-ichi Kiyooka, and Clayton H. Heathcock.

1. ProcedureA. 1-Ethoxy-1-(trimethylsilyloxy) cyclopropane. A 1-L, three-necked, round-bottomed flask is fittedwith an efficient mechanical stirrer (Note 1), a reflux condenser provided with a calcium chloride tube,
and a 500-mL pressure-equalizing dropping funnel equipped with a nitrogen inlet at the top. The flask isflushed with dry nitrogen, and 500 mL of anhydrous toluene (Note 2) and 52.9 g (2.3 g-atom) of sodium
cut in small pieces (Note 3) are introduced. The mixture is brought to reflux by means of a heating
mantle and the sodium is finely pulverized by vigorous stirring. Heating and stirring are stopped (Note4), and the mixture is allowed to cool to room temperature. Toluene is removed under nitrogen pressure
by means of a double-ended needle and replaced by 500 mL of anhydrous diethyl ether (Note 5) and(Note 6). At this point, 108.5 g (1 mol) of chlorotrimethylsilane (Note 7) is added to the flask. To themixture, 136.58 g (1 mol) of ethyl 3-chloropropanoate is added dropwise with stirring at a rate sufficientto maintain a gentle reflux over a 3-hr period (Note 8). When about 0.3 mol of chloro ester has been
added, a deep-blue precipitate appears (Note 9). When the addition is over, the reaction mixture isheated at reflux for 30 min. The contents of the flask are cooled and filtered through a sintered-glass
funnel under a stream of dry nitrogen (Note 10). The precipitate is washed twice with 100 mL ofanhydrous diethyl ether.
The colorless filtrate is transferred to a distilling flask and the solvent is distilled through a 25-cm
vacuum-jacketed Vigreux column, and the residue is distilled under reduced pressure. After a small
forerun (1–2 g), 1-ethoxy-1-(trimethylsilyloxy) cyclopropane is obtained at 43–45°C (12 mm) as acolorless liquid, 106 g (61%) (Note 11).
B. Cyclopropanone ethyl hemiacetal. Into a 500-mL Erlenmeyer flask fitted with a magnetic stirring
bar is placed 250 mL of reagent-grade methanol. Freshly distilled 1-ethoxy-1-(trimethylsilyloxy)
cyclopropane (100 g, 0.56 mol) is added all at once to the methanol and the solution is stirred overnight(12 hr) at room temperature (Note 12). An aliquot (50 mL) of the solution is concentrated by slow
evaporation of methanol with a rotary evaporator at room temperature (Note 13) and formation of themethanolysis product is checked by NMR examination of the residue (Note 14). When the reaction iscomplete (Note 15), the solution is concentrated by removal of the methanol (Note 16). Distillation ofthe residue through a 20-cm helix-packed, vacuum-insulated column under reduced pressure gives 52 g(89%) of 1-ethoxycyclopropanol, bp 60°C (20 mm) (Note 14) and (Note 17), which contains trace
amounts of 1-methoxycyclopropanol (Note 18) and (Note 19).

2. Notes
1. An efficient stirrer is used at a spinning rate sufficient to disperse the molten sodium into small beads
of a diameter of approximately 0.1 mm. The checkers found it necessary to use a mechanical stirrer
equipped with a nichrome wire "beater" rather than a Teflon paddle. If the sodium sand particles are toolarge, the final product will be contaminated with starting chloro ester, from which it is very difficult toseparate.
2. Toluene is freshly distilled from phosphorus pentoxide into the reaction flask.

3. Sodium pieces are washed in dry pentane or toluene to remove oil.
4. It is essential that stirring be discontinued before cooling is begun to prevent the molten sodium fromcoalescing into one gigantic lump.
5. Diethyl ether is dried by molecular sieves and distilled from lithium aluminum hydride.
6. To remove the toluene completely, the finely divided sodium is washed under nitrogen withanhydrous diethyl ether (3 × 50 mL).
7. Chlorotrimethylsilane, obtained from Aldrich Chemical Co. or Prolabo (France), is distilled fromquinoline or calcium hydride.
8. For the acyloin condensation of diesters it has been recommended that the diester andchlorotrimethylsilane be added together to the sodium dispersion;2 no difference has been noted with
our procedure.
9. The deep-blue color seems to be indicative of a satisfactory reduction. When the color is yellow–green, the yield is usually poor.
10. Caution! Because of the pyrophoric nature of finely divided alkali metal residues or production offree acid (HCl) from the chlorosilane, the products are sensitive to moisture. Unreacted sodium isdestroyed by careful addition of ethanol to the residual solid.
11. The yield varies from 60 to 85%, bp 50–52°C (18 mm); 60–62°C (35 mm); 66–68°C (40 mm); theproton magnetic resonance (PMR) spectrum (CCl4 solution, HCCl3 external reference) shows absorptionat δ: 0.08 (s, 9 H), 0.70 (m, 4 H), 1.05 (t, 3 H, J = 7.11) and 3.55 (q, 2 H, J = 7.11); the IR spectrum(CCl4) exhibits absorption at 3090 and 3010 (cyclopropane), 1250, 845, and 758 cm−1 (−Si[CH3]3).
12. After the solution is stirred for 5–10 min, the clear solution becomes slightly turbid for a few
minutes and then turns clear again. When these changes are not observed, methanolysis has notoccurred.
13. If some 1-ethoxy-1-(trimethylsilyloxy) cyclopropane is still present, it will be lost by too rapid
evaporation of methanol.
14. The product has the following spectral properties: IR (CCl4): 3600 and 3400 (hydroxyl), 3010 and3090 cm−1 (cyclopropyl); 1H NMR (CCl4) δ: 0.84 (s, 4 H), 1.18 (t, 3 H, J = 7.11), 3.73 (q, 2 H, J = 7.11)
and 4.75 (m, 1 H).
15. Lack of NMR absorption around δ 0.08 shows that the trimethylsilyloxy group has been completelyremoved.
16. If the reaction is not complete, as shown by the presence of a singlet around δ 0.08, a spatula tip fullof pyridinium p-toluenesulfonate3 is added and the mixture is stirred for 4 hr. Methanol is then removed,
and the residue is dissolved in 200 mL of diethyl ether. The solution is washed with saturated sodium
chloride until neutral, dried over anhydrous sodium sulfate, and concentrated. Addition of a drop of HClor of chlorotrimethylsilane is also effective to complete the reaction. Then, the hydrochloric acid isremoved with methanol. (Thus, it is not necessary to wash with saturated sodium chloride until neutral.)
17. The yield varies from 78 to 95%, bp 51°C (12 mm), 64°C (25 mm), 75°C (46 mm).
18. On standing with methanol at 25°C for 1 week, 65% of 1-ethoxycyclopropanol is converted into 1methoxycyclopropanol; conversion appears to be complete after 15 days.4 The spectral properties of the1-methoxycyclopropanol are: IR (CCl4): 3600 and 3400 (hydroxyl), 3010 and 3090 cm−1 (cyclopropyl);
1H NMR (CCl ) δ: 0.85 (s, 4 H) and 3.40 (s, 3 H).
419. Cyclopropanone hemiacetal can be kept unaltered for several months at 0°C in the refrigerator. On
heating above 100°C or on standing in acidic solvents, it undergoes ring opening to give ethyl
propionate.

3. Discussion
Cyclopropanone ethyl hemiacetal was first synthesized by the reaction of ketene and diazomethanein ether at −78°C in the presence of ethanol.4 The yield is low (43%) and the reaction is hazardous,
especially when a large-scale reaction is required. The method described in this procedure for thepreparation of cyclopropanone ethyl hemiacetal from ethyl 3-chloropropanoate is an adaptation of that
described previously;5 the procedure described for the synthesis of 1-ethoxy-1-(trimethylsilyloxy)
cyclopropane is patterned after the method reported by Rühlmann.6
Cyclopropanone ethyl hemiacetal is a molecule of considerable interest since its reactions appear toinvolve the formation of the labile cyclopropanone.7 It readily undergoes nucleophilic addition of
Grignard reagents,4,5 azides,4 and amines8 to provide 1-substituted cyclopropanols in high yields. It hasbeen reported that upon treatment with an equimolar amount of methylmagnesium iodide, thecyclopropanone ethyl hemiacetal is converted into iodomagnesium 1-ethoxycyclopropylate,9 which canreact with hydrides, organometallic reagents, cyanide carbanion, and phosphorus ylides10 to provide
useful synthons. The preparation of some challenging 2,3-disubstituted cyclopentanones including atotal synthesis of the 11-deoxyprostaglandin has been reported from the cyclopropanone hemiacetal.11
The ready availability of this compound should lead to other synthetic applications. For a recent review
dealing with the chemistry of the cyclopropanone hemiacetals, see 12.
On the other hand, silylated cyclopropanols, such as 1-ethoxy 1-(trimethylsilyloxy) cyclopropane,
work well as homoenolate anion precursors. They undergo ring opening reactions with a variety ofmetal halides (TiCl4, GaCl3, SbCl5, ZnCl2, HgCl2 …). Thus, in the presence of suitable catalysts, thezinc homoenolates of alkyl propionates undergo a variety of carbon-carbon bond forming reactions witha very high degree of chemoselectivity.13
This preparation is referenced from:Org. Syn. Coll. Vol. 8, 277
Org. Syn. Coll. Vol. 8, 556
z Org. Syn. Coll. Vol. 9, 466
zz

References and Notes
1. Laboratoire des Carbocycles, ERA n° 316, Bat. 420, Université de Paris-Sud, 91405 Orsay,France.
2. Bloomfield, J. J.; Owsley, D. C.; Nelke, J. M. Org. React. 1976, 23, 306; Bloomfield, J. J.;
Nelke, J. M. Org. Synth., Coll. Vol. VI 1988, 167.
3. Miyashita, M.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977, 42, 3772.
4. Wasserman, H. H.; Clagett, D. C. J. Am. Chem. Soc. 1966, 88, 5368; Wasserman, H. H.; Cochoy,R. E.; Baird, M. S. J. Am. Chem. Soc. 1969, 91, 2375.
5. Salaün, J. J. Org. Chem. 1976, 41, 1237; 1977, 42, 28.
6. Rühlmann, K. Synthesis 1971, 236.
7. Turro, N. J. Acc. Chem. Res. 1969, 2, 25; Shaafsma, S. E.; Steinberg, H.; de Boer, T. J. Recl.
Trav. Chim. Pays-Bas 1966, 85, 1170.
8. Wasserman, H. H.; Adickes, H. W.; de Ochoa, D. Espejo J. Am. Chem. Soc. 1971, 93, 5586.
9. Brown, H. C.; Rao, C. G. J. Org. Chem. 1978, 43, 3602.
10. Salaün, J.; Fadel, A. Tetrahedron Lett. 1979, 4375; Salaün, J.; Bennani, F.; Compain, J. C.;
Fadel, A.; Ollivier, J. J. Org. Chem. 1980, 45, 4129.
11. Salaün, J.; Ollivier, J. Nouv. J. Chim. 1981, 5, 587.
12. Salaün, J. Chem. Rev. 1983, 83, 619; Salaün, J. Top. Curr. Chem. 1988, 144, 1.
13. Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.; Kuwajima, I. J. Am. Chem. Soc. 1987, 109, 8056
and references cited therein.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);(Registry Number)chloro ester
1-substituted cyclopropanols
cyanide carbanion

phosphorus ylides
2,3-disubstituted cyclopentanones
11-deoxyprostaglandin
silylated cyclopropanols
ethanol (64-17-5)hydrochloric acid (7647-01-0)
methanol (67-56-1)
ether,diethyl ether (60-29-7)
sodium chloride (7647-14-5)
sodium sulfate (7757-82-6)
nitrogen (7727-37-9)
toluene (108-88-3)
sodium (13966-32-0)hydroxyl (3352-57-6)
methylmagnesium iodide (917-64-6)
Quinoline (91-22-5)
Pentane (109-66-0)
Ketene (463-51-4)
cyclopropane (75-19-4)
Diazomethane (334-88-3)
ethyl propionate (105-37-3)
lithium aluminum hydride (16853-85-3)
calcium hydride (7789-78-8)
ETHYL 3-CHLOROPROPANOATE (623-71-2)
cyclopropyl (2417-82-5)

CHLOROTRIMETHYLSILANE (75-77-4)
chlorosilane (13465-78-6)
CYCLOPROPANONE (5009-27-8)
Cyclopropanone ethyl hemiacetal,
Cyclopropanol, 1-ethoxy-,1-ethoxycyclopropanol (13837-45-1)
1-ethoxy-1-(trimethylsilyloxy) cyclopropane,
1-ethoxy 1-(trimethylsilyloxy) cyclopropane (27374-25-0)
1-methoxycyclopropanol
Cyclopropanone hemiacetal
iodomagnesium 1-ethoxycyclopropylate
phosphorus pentoxide (1314-56-3)
pyridinium p-toluenesulfonate
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