Checked by Jian-Ping Chao and Robert K. Boeckman, Jr..
1. Procedure
A.
Methyl 3,6-dimethyl-3-hydroxy-6-heptenoate (Note
1). An
oven-dried, three-necked, 500-mL, round-bottomed flask, is fitted with an
efficient mechanical stirrer, a
Claisen adapter bearing a
reflux condenser with a
nitrogen inlet and
rubber septum, and a
thermometer. The flask is maintained under a static
nitrogen pressure and charged with
5-methyl-5-hexen-2-one (24.20 g, 0.216 mol) (Note
2),
trimethyl borate (60 mL) (Note
3),
tetrahydrofuran (60 mL) (THF) (Note
4), and freshly activated
20-mesh zinc granules (16.96 g, 0.259 g-atom) (Note
5). The reaction flask is immersed in an
oil bath at 25°C. Stirring is initiated and
methyl bromoacetate (39.65 g, 0.259 mol) (Note
6) is added in a single portion through the septum. After an induction time (Note
7), a white precipitate starts to form and an increase of the internal temperature, up to reflux, is observed (Note
8). The mixture is stirred for 3 hr, after which time starting material is completely consumed (Note
9). The reaction is quenched by the sequential addition of
glycerol (60 mL) and saturated aqueous
ammonium chloride (60 mL), then is transferred to a separatory funnel using
120 mL of diethyl ether. The aqueous layer is separated and extracted again with
diethyl ether (3 × 60 mL). The combined
ether extracts are washed with aqueous
30% ammonium hydroxide solution (3 × 30 mL) and then with saturated
sodium chloride solution (2 × 30 mL). The organic extracts are dried over
magnesium sulfate (MgSO4) and concentrated at reduced pressure with a
rotary evaporator to afford
37.32–38.92 g of crude β-hydroxy ester (
93–97% yield) (Note
10).
C.
1,4-Dimethylbicyclo[3.2.0]hept-3-en-6-one. A three-necked, 500-mL, round-bottomed flask, equipped with a condenser fitted with a
calcium chloride tube, an efficient mechanical stirrer, and an immersion thermometer, is charged with crude
3,6-dimethyl-3-hydroxy-6-heptenoic acid (29.40 g, 0.171 mol),
acetic anhydride (185 mL) (Note
14) and
potassium acetate (40.28 g, 0.410 mol). The reaction mixture is stirred for 2 hr at room temperature. During this time, an exotherm is observed (up to 50°C) followed by a slow return to room temperature, and the suspension becomes thicker. The reaction is brought to reflux (in ca. 20 min) by means of a heating mantle and stirring is continued for another 3.5 hr. A
two-necked, 2-L, round-bottomed flask fitted with a condenser and
magnetic stirrer is charged with crushed ice (400 g) and water (100 g), and the hot mixture is added carefully with good stirring. Light
petroleum ether (500 mL) is added and the mixture is stirred for 12 hr at room temperature. The reaction mixture is transferred into a
2-L separatory funnel and the aqueous layer is separated and extracted with light
petroleum ether (4 × 100 mL). The combined organic layers are washed with saturated
sodium bicarbonate solution (3 × 50 mL) and saturated
sodium chloride solution (2 × 30 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated at ambient pressure to give the crude product as a dark oil. Final purification is achieved by distillation under reduced pressure (Note
15) affording
17.70–18.86 g (
76–81% yield) of a 99% pure mixture (97:3) of the keto olefin isomers as a colorless oil, bp
84–85°C/26–28 mm (Note
16).
2. Notes
1. This procedure is essentially that of Rathke and Lindert.
3
2. The submitters used freshly distilled ketone prepared according to the
Organic Syntheses procedure.
4 5-Methyl-5-hexen-2-one is also available from Aldrich Chemical Company, Inc., and can be used as purchased.
4.
Tetrahydrofuran (reagent grade) was dried by distillation from
sodium/benzophenone ketyl and freshly distilled before use.
5.
Zinc granules (20-mesh, 99.8%, A.C.S. reagent grade, Pb ≤ 0.01%, Fe ≤ 0.01%) obtained from Aldrich Chemical Company, Inc., were activated according to the procedure of Newman and Evans.
5 About
25 g of 20-mesh zinc was covered with
5% hydrochloric acid (30 mL) and stirred vigorously for 3 min. The
zinc was washed by decantation with distilled water (3 × 30 mL), with
acetone (2 × 20 mL), with
diethyl ether (2 × 20 mL), and finally dried and stored in a
vacuum desiccator.
7. Induction times from 15 to 45 min have been observed. In one instance, the reaction did not start even after 1.5 hr, and required the mixture to be heated to 60°C for several minutes until a white precipitate began to form. The checkers observed induction periods of 25–35 min.
8. On some occasions, the exotherm induced a vigorous reflux that was difficult to control. In such cases, stirring had to be stopped occasionally to control the reflux rate. Although the use of 20-mesh
zinc granules reduces the possibility of hard-to-control exotherms, a
cold water bath was kept ready to provide cooling if needed. The checkers did not observe an uncontrollable exotherm, but this type of reaction is well-known to be susceptible to such a problem. The checkers recommend that the mesh size not be reduced further without first testing the procedure on smaller scale. The checkers successfully performed this reaction at twice the reported scale without event and obtained the same yield (
93%).
10. The crude ester so obtained is greater than 97% pure by GLC analysis and is used in the next step without further purification. The checkers determined that the remainder of the material (

3%) is unreacted
methyl bromoacetate. Spectral data for the crude ester are as follows: IR (neat) cm
−1: 3516, 2951, 1735, 1649, 1439, 1216;
1H NMR (200 MHz, CDCl
3) δ: 1.22 (s, 3 H), 1.70 (m, 2 H), 1.75 (s, 3 H), 2.11 (m, 2 H), 2.48 (d, 1 H, J = 17.2), 2.54 (d, 1 H, J = 17.2), 3.52 (s, 1 H, disappears after D
2O exchange), 3.73 (s, 3 H), 4.70 (s, 2 H);
13C NMR (50.3 MHz, CDCl
3) δ: 23.07 (CH
3), 27.04 (CH
3), 32.43 (CH
2), 40.33 (CH
2), 45.16 (CH
2), 52.12 (CH
3), 71.26 (C), 110.2 (CH
2), 146.2 (C), 173.8 (C).
11. The submitters employed a
1 N solution of KOH in methanol and observed the saponification to be complete in 24 hr. The checkers observed that the saponification required

48 hr for completion under these conditions. The checkers employed a
2 N solution of KOH in methanol and observed that saponification was complete in 5 hr.
12. The submitters reported
87–92% yields of the acid. In the hands of the checkers, the yield of this reaction appears to be scale dependent. At one half the reported scale, the yield was reduced by 10–12%. This variation appears to result from losses during the isolation procedure. The acid has a very disagreeable butyric acid-like odor. The checkers recommend that all manipulations of this material be performed in a good
hood, and that all apparatus employed be kept in the hood until base washed.
13. Spectral data for the crude acid are as follows: IR (neat) cm
−1: 3380, 2971, 1707, 1646, 1222, 888;
1H NMR (200 MHz, CDCl
3) δ: 1.30 (s, 3 H), 1.67 (m, 2 H), 1.72 (s, 3 H), 2.10 (m, 2 H), 2.55 (d, 1 H, J = 17.1), 2.60 (d, 1 H, J = 17.1), 4.70 (s, 2 H), 6.61 [s (broad), 2 H];
13C NMR (50.3 MHz, CDCl
3) δ: 23.11 (CH
3), 26.33 (CH
3), 32.40 (CH
2), 40.18 (CH
2), 45.13 (CH
2), 71.84 (C), 110.5 (CH
2), 146.0 (C), 177.9 (C).
15. To control foaming, the submitters recommend the use of a distillation flask larger than usual. In this instance, they used a
250-mL flask fitted with a Claisen adapter.
16. The product is about 99% pure by GLC analysis (Note
9), containing about 1% of an unknown impurity having a retention time of 8.01 min. The ratio of the olefin isomers,
1,4-dimethylbicyclo[3.2.0]hept-3-en-6-one and
1-methyl-4-methylenebicyclo-[3.2.0]heptan-6-one, was determined to be 97:3. Spectral data for the major isomer are as follows: IR (neat) cm
−1: 1770;
1H NMR (200 MHz, CDCl
3) δ: 1.35 (s, 3 H), 1.73 (s, 3 H), 2.55 (m, 2 H), 2.87 (dd, 1 H, J = 17.8, 4.7), 3.03 (dd, 1 H, J = 17.8, 2.9), 3.58 (m, 1 H), 5.45 (m, 1 H);
13C NMR (50.3 MHz, CDCl
3) δ: 15.34 (CH
3), 24.03 (CH
3), 35.35 (C), 47.08 (CH
2), 58.81 (CH
2), 79.94 (CH), 126.8 (CH), 135.2 (C), 207.9 (C).
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Bicyclo[3.2.0]hept-3-en-6-ones are fused ring compounds that offer different functionalities in each ring, and have different ring size. They are suitable for chemo-, regio- and stereo-controlled manipulations and are useful for the assembly of more complex structures in a predictable fashion. The preparation reported here illustrates the simplicity of the procedure and the selectivity by which the thermodynamically more stable isomer can be prepared in high purity and good yield. Both yield and stereoselectivity are superior to those observed in the syntheses of
1,4-dimethylbicyclo[3.2.0]hept-3-en-6-one previously reported in the literature.
6,7 This process involves the generation of an α,β-unsaturated ketene intermediate that undergoes intramolecular [2+2] cyclization to give a bicyclo[3.2.0]hept-3-en-6-one. An equilibrium among the possible isomers of the α,β-unsaturated ketene intermediate could account for the good yield as well as the high selectivity in generating the thermodynamically more stable endo-ene isomer.
8
This foregoing procedure is rather general as demonstrated by the preparation of a number of bicyclo[3.2.0]hept-3-en-6-ones by the bicyclization of a variety of secondary and tertiary 3-hydroxy-6-alkenoic acids (Table). The use of bicyclo[3.2.0]hept-3-en-6-ones as starting materials has been reported in the synthesis of racemic
grandisol,
9 lineatin,
1,2,4 filifolone,
10 and several intermediates
5,11 in Curran's synthesis of linear condensed sesquiterpenes such as
hirsutene,
12,13 δ2-capnellene,
14 hypnophilin15 and
coriolin.
15 The successful use of these intermediates in the previously mentioned applications, and their unusual reactivity,
16 suggest the broad usefulness of the bicyclo[3.2.0]hept-3-en-6-ones made readily available by the present procedure. Some bicyclo[3.2.0]hept-3-en-6-ones have been obtained enantiomerically pure
17 by the oxidation of the enantiomers of bicyclo[3.2.0]hept-3-en-6-endo-ols, resolved using
(−)-(1S,4R)-camphanic acid chloride.
18
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
petroleum ether
sodium/benzophenone ketyl
coriolin
grandisol
lineatin
filifolone
hirsutene
δ2-capnellene
hypnophilin
(−)-(1S,4R)-camphanic acid chloride
hydrochloric acid (7647-01-0)
methanol (67-56-1)
ether,
diethyl ether (60-29-7)
acetic anhydride (108-24-7)
ammonium chloride (12125-02-9)
sodium acetate (127-09-3)
glycerol (56-81-5)
sodium bicarbonate (144-55-8)
sodium chloride (7647-14-5)
sodium sulfate (7757-82-6)
nitrogen (7727-37-9)
acetone (67-64-1)
potassium hydroxide,
KOH (1310-58-3)
zinc (7440-66-6)
ammonium hydroxide (1336-21-6)
magnesium sulfate (7487-88-9)
potassium acetate (127-08-2)
Ethyl bromoacetate (105-36-2)
Tetrahydrofuran (109-99-9)
calcium hydride (7789-78-8)
5-Methyl-5-hexen-2-one (3240-09-3)
trimethyl borate (121-43-7)
methyl bromoacetate (96-32-2)
1,4-Dimethylbicyclo[3.2.0]hept-3-en-6-one (133700-21-7)
3,6-Dimethyl-3-hydroxy-6-heptenoic acid
1-methyl-4-methylidenebicyclo[3.2.0]heptan-6-one,
1-methyl-4-methylenebicyclo-[3.2.0]heptan-6-one
Methyl 3,6-dimethyl-3-hydroxy-6-heptenoate
Bicyclo[3.2.0]hept-3-en-6-one, 1,4-dimethyl-, cis-(±)-
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