Checked by Steven D. Young, Syun-ichi Kiyooka, and Clayton H. Heathcock.
1. Procedure
A.
1-Ethoxy-1-(trimethylsilyloxy) cyclopropane. A
1-L, three-necked, round-bottomed flask is fitted with 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 is flushed 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 (Note
4), 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 the mixture,
136.58 g (1 mol) of ethyl 3-chloropropanoate is added dropwise with stirring at a rate sufficient to 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 is heated 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 of anhydrous 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 a colorless 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 the methanolysis product is checked by NMR examination of the residue (Note
14). When the reaction is complete (Note
15), the solution is concentrated by removal of the
methanol (Note
16). Distillation of the 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 too large, the final product will be contaminated with starting chloro ester, from which it is very difficult to separate.
4. It is essential that stirring be discontinued before cooling is begun to prevent the molten
sodium from coalescing into one gigantic lump.
8. For the acyloin condensation of diesters it has been recommended that the diester and
chlorotrimethylsilane 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 of free acid (HCl) from the chlorosilane, the products are sensitive to moisture. Unreacted sodium is destroyed 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); the proton magnetic resonance (PMR) spectrum (CCl
4 solution, HCCl
3 external reference) shows absorption at 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 (CCl
4) exhibits absorption at 3090 and 3010 (
cyclopropane), 1250, 845, and 758 cm
−1 (−Si[CH
3]
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 not occurred.
14. The product has the following spectral properties: IR (CCl
4): 3600 and 3400 (
hydroxyl), 3010 and 3090 cm
−1 (
cyclopropyl);
1H NMR (CCl
4) 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 completely removed.
17. The yield varies from
78 to 95%, bp
51°C (12 mm),
64°C (25 mm),
75°C (46 mm).
19.
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 is a molecule of considerable interest since its reactions appear to involve the formation of the labile
cyclopropanone.
7 It readily undergoes nucleophilic addition of Grignard reagents,
4,5 azides,
4 and amines
8 to provide
1-substituted cyclopropanols in high yields. It has been reported that upon treatment with an equimolar amount of
methylmagnesium iodide, the
cyclopropanone ethyl hemiacetal is converted into
iodomagnesium 1-ethoxycyclopropylate,
9 which can react with hydrides, organometallic reagents,
cyanide carbanion, and
phosphorus ylides10 to provide useful synthons. The preparation of some challenging
2,3-disubstituted cyclopentanones including a total 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 of metal halides (TiCl
4, GaCl
3, SbCl
5, ZnCl
2, HgCl
2 …). Thus, in the presence of suitable catalysts, the zinc homoenolates of alkyl propionates undergo a variety of carbon-carbon bond forming reactions with a very high degree of chemoselectivity.
13
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