Organic Syntheses, CV 8, 556
Submitted by Scott A. Miller and Robert C. Gadwood
1.
Checked by Jeffrey A. McKinney and Leo A. Paquette.
1. Procedure
A.
1-Bromo-1-ethoxycyclopropane.2 A
500-mL, round-bottomed flask equipped with a magnetic stirring bar and a calcium sulfate drying tube is charged with
84.1 g (0.483 mol) of 1-ethoxy-1-trimethylsiloxycyclopropane.
3 Phosphorus tribromide (35.6 mL, 103 g, 0.379 mol) (Note
1) is added at room temperature with brisk stirring, followed by a catalytic amount
(0.5 ml) of 48% aqueous hydrobromic acid (Note
2). The resulting clear, pale-yellow solution is stirred for 6 hr (Note
3). After the stirring bar is removed, the reaction mixture is distilled by
Kugelrohr apparatus at aspirator vacuum (10 mm) from 25 to 70°C to afford crude
1-bromo-1-ethoxycyclopropane (Note
4) and (Note
5). The crude product is dissolved in
300 mL of pentane in a
1-L Erlenmeyer flask and the resulting solution is chilled to −20°C in a
dry ice–ethanol: water (30 : 70) bath. While the temperature of the solution is maintained below 25°C,
300 mL of saturated, aqueous sodium carbonate is carefully added (Note
6). The layers are carefully shaken and separated, and the aqueous phase is extracted with
100-mL of pentane. The organic layer is dried over
magnesium sulfate, filtered, and most of the
pentane is removed by distillation through a
15-cm Vigreux column at atmospheric pressure. The residue is transferred to a smaller distillation flask and distilled through the same column under aspirator vacuum to afford
47.0–57.6 g (
59–72%) of
1-bromo-1-ethoxycyclopropane as a colorless liquid (bp
35–43°C, 10 mm) (Note
7) and (Note
8).
Caution! Because of the relatively large amount of pyrophoric tert-butyllithium involved, the following preparation should be performed in a hood behind a safety shield.
B.
(E)-1-Ethoxy-1-(1-hydroxy-2-butenyl)cyclopropane. A
1-L, three-necked flask is equipped with a gas inlet adapter, a septum, a 250-mL graduated addition funnel capped with a septum, and a magnetic stirring bar (Note
9). The flask is charged with
500 mL of anhydrous diethyl ether (Note
10) and cooled to −78°C under a
nitrogen atmosphere. The addition funnel is charged with
177 mL (19.2 g, 0.30 mol) of tert-butyllithium (Note
11), transferred from the reagent bottle via a stainless-steel cannula under positive
nitrogen pressure. The
tert-butyllithium is added dropwise to the stirred
diethyl ether over approximately 20 min while the
cooling bath is maintained at −78°C. After the addition is complete,
26.4 g (0.16 mol) of freshly prepared 1-bromo-1-ethoxycyclopropane is added to the reaction over about 5 min by syringe. The resulting cloudy, colorless, or light-yellow reaction mixture is stirred for 20–25 min, and a solution of
7.0 g (0.10 mol) of crotonaldehyde (Note
12) in
50 mL of anhydrous diethyl ether (chilled to −78°C) is added via a stainless-steel cannula under positive
nitrogen pressure. The reaction mixture is stirred at −78°C for an additional 10 min, warmed to 0°C in an
ice bath, and carefully quenched with
100 mL of saturated, aqueous ammonium chloride. The layers are shaken and separated and the aqueous phase is extracted with
100 mL of diethyl ether. The combined organic layers are dried over
magnesium sulfate and filtered. After the crude adduct is concentrated on a
rotary evaporator, it is filtered through a
10-cm pad of silica gel (Note
13) in a
sintered-glass funnel with
10% ethyl acetate in hexane. After concentrating again on a
rotary evaporator, the crude adduct is obtained as a pale-yellow oil (
14.2–15.6 g) (Note
14). This material is not further purified, but is used directly in the next reaction.
C.
(E)-2-(1-Propenyl)cyclobutanone. To a
1-L, round-bottomed flask equipped with a magnetic stirring bar is added
15.3 g (0.098 mol) of (E)-1-ethoxy-1-(1-hydroxy-2-butenyl)cyclopropane,
500 mL of reagent-grade diethyl ether, and
6.6 mL (4.3 g, 0.049 mol) of 48% aqueous fluoboric acid (Note
15). After the reaction mixture is stirred for 15 min at room temperature, it is quenched with
60 mL (0.06 mol) of 1 M aqueous sodium carbonate. The layers are carefully shaken and separated, and the organic phase is washed with three 125-mL portions of water (Note
16). The combined aqueous layers are extracted with
100 mL of diethyl ether and the organic phase is dried over
magnesium sulfate and filtered. The filtrate is concentrated on a
rotary evaporator without external heating and the residue is distilled through a
10-cm Vigreux column under aspirator vacuum. The product,
7.2–8.3 g (
66–75% yield from
crotonaldehyde), is obtained as a colorless oil, bp
61–65°C (10 mm) (Note
17).
2. Notes
1.
Phosphorus tribromide was obtained from the Aldrich Chemical Company, Inc. and used without further purification.
3. The course of the reaction is most conveniently followed by
1H NMR analysis of a drop of the reaction mixture in
carbon tetrachloride. The downfield quartet of the starting ketal (3.52 ppm) is replaced by a clean quartet at 3.62 ppm from the product. The checkers have found by this technique that reaction is complete in much less than 6 hr.
5.
Caution! After distillation the Kugelrohr apparatus should first be cooled and then carefully vented to an atmosphere of nitrogen since traces of elemental phosphorus may be present in the pot residue and may ignite if exposed to air while still hot.
7. A low-boiling, silicon-containing fraction is also collected below 37°C (28 mm). The presence of a singlet at 0.10 ppm in the
1H NMR of the product indicates contamination by this low-boiling fraction. Small amounts of this impurity do not seem to interfere in subsequent reactions of the
1-bromo-1-ethoxycyclopropane.
8.
1-Bromo-1-ethoxycyclopropane is relatively unstable at room temperature, but can be stored for several months at −20°C with only slight decomposition. Spectral data for
1-bromo-1-ethoxycyclopropane are as follows: IR (neat) cm
−1: 3100 (w), 2985 (s), 2935 (m), 2885 (m), 1445 (m), 1300 (s), 1160 (s), 1060 (s), 795 (s);
1H NMR (CCl
4) δ: 1.17 (m, 7 H), 3.53 (q, 2 H,
J = 8); MS (15 eV),
m/e 164/166 (M
+), 136/138 (base), 85, 57.
9. The glassware was dried in an
oven overnight at 110°C and assembled while hot under
nitrogen flow.
11.
Caution! tert-Butyllithium is extremely pyrophoric and should be handled on a large scale only by experienced personnel. tert-Butyllithium was obtained from the Aldrich Chemical Company, Inc. as a 1.7
M solution in
pentane. In general, this material was used as received without titration.
12.
Crotonaldehyde was obtained from The Matheson Company, Inc., and is also available (≥99% grade) from the Aldrich Chemical Company, Inc.
13. Merck Silica Gel 60 (230–400 mesh) was obtained from the Aldrich Chemical Company, Inc. Filtration through
silica gel removes residual inorganic salts (mostly
lithium chloride), which may interfere in the subsequent rearrangement step.
14. Spectral data for
(E)-1-ethoxy-1-(hydroxy-2-butenyl)cyclopropane are as follows:
1H NMR (CDCl
3) δ: 0.68 (m, 4 H), 1.12 (t, 3 H,
J = 6), 1.64 (d, 3 H,
J = 5), 2.46 (s, 1 H), 3.54 (m, 2 H), 4.15 (d, 1 H,
J = 6), 5.52 (m, 2 H). Occasionally, a minor impurity is formed as a result of the addition of
tert-butyllithium to
crotonaldehyde (singlet at 0.89 ppm in the
1H NMR). This side reaction occurs because of the presence of unreacted
tert-butyllithium and is best avoided by using the indicated ratio of
tert-butyllithium to
1-bromo-1-ethoxycyclopropane. The checkers were unable to remove this impurity by fractional distillation.
15.
Fluoboric acid was obtained as a 48 wt% aqueous solution from the Aldrich Chemical Company, Inc. On the basis of its density, this solution was calculated to be approximately 7.4
M in HBF
4. The checkers used
5.4 mL (0.049 mol) of 60% fluoboric acid.
16. Washing with water helps to remove the
ethanol generated in the course of the rearrangement. For higher-boiling cyclobutanones, where the
ethanol can easily be removed during distillation, this step is unnecessary.
17. Spectral data for
(E)-2-(1-propenyl)cyclobutanone are as follows: IR (CCl
4) cm
−1: 2960 (s), 1780 (s), 1660 (w), 1450 (m);
1H NMR (CCl
4) δ: 1.62 (m, 3 H), 2.17 (m, 2 H), 2.88 (m, 2 H), 3.73 (m, 1 H), 5.37 (m, 2 H). The product was contaminated by an alcoholic impurity to the extent of 6–11%.
3. Discussion
Cyclobutanones have attained a position of considerable synthetic importance in recent years. In addition to being important synthetic targets themselves, they serve as useful precursors of five-,
4 six-,
5 and eight-membered
6 rings, as well as of a variety of highly functionalized acyclic fragments.
7,8
In general, cyclobutanones are synthesized by either ketene cycloadditions or by ring expansions of cyclopropyl precursors. For the synthesis of simple α-substituted monocyclic cyclobutanones, the latter method is usually employed, and a variety of approaches have been used to prepare the required cyclopropyl intermediates.
Vinylcyclopropanols have been prepared by the addition of alkenyl Grignard reagents to a variety of cyclopropanone equivalents.
9 On treatment with acid, the vinylcyclopropanols rearrange to α-substituted cyclobutanones. Alternatively, a variety of α-heteroatom-substituted cyclopropyllithium reagents have been developed. These react with aldehydes and ketones to afford cyclopropylcarbinols that also rearrange to cyclobutanones under acid catalysis.
8,10,11 Finally, vinylcyclopropanols and cyclopropylcarbinols have been prepared by the cyclopropanation of enol silyl ethers and allylic alcohols.
12
As shown in Table I, a wide variety of α-substituted cyclobutanones have been prepared by the general method described here.
14 The time required for rearrangement of the intermediate cyclopropylcarbinols varies from less than 5 min for entry 2 to 48 hr for entry 10. With most enones and enals, only 1,2-addition is observed, but in two cases (entries 3 and 4), a significant amount of the 1,4-adduct was also produced. The increased 1,4-addition seen in entry 3 apparently occurs because of steric factors, whereas that seen in entry 4 presumably occurs because of chelation of the organolithium to the
benzyl ether oxygen.
TABLE I
CYCLOBUTANONE SYNTHESIS VIA 1-BROMO-1-ETHOXYCYCLOPROPANE
|
Entry |
Ketone/aldehyde |
Cyclobutanone |
Yield(%) |
|
1 |
|
|
97 |
2 |
|
|
86 |
3 |
|
|
40 |
4 |
|
|
30 |
5 |
|
|
65 |
6 |
|
|
71 |
7 |
|
|
79 |
8 |
|
|
74 |
9 |
|
|
81 |
10 |
|
|
81 |
|
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