Checked by Lisa Frey and Ichiro Shinkai.
1. Procedure
A
1000-mL, two-necked, round-bottomed flask (Note
1) is equipped with a
rubber septum,
magnetic stirring bar, and
gas inlet connected to a vacuum/argon line via a Firestone valve. The flask is flame-dried under vacuum, then filled with
argon. Ten cycles of evacuation and
argon fill are carried out. The flask, in which a positive flow of
argon is maintained throughout the entire procedure, is charged with
6.66 mL (75 mmol) of 2-bromopropene (Note
2) dissolved in dry
tetrahydrofuran (250 mL) (Note
3). The solution is cooled to −78°C by a
dry ice/acetone bath, at which point
88 mL of 1.7 M tert-butyllithium in pentane (150 mmol) is introduced dropwise in three roughly equal portions from a
50-mL syringe (Note
4) during 45 min. The colorless reaction mixture is allowed to stir at −78°C for approximately 30 min (Note
5).
A
250 mL, two-necked, round-bottomed flask, equipped with a rubber septum and gas inlet, is flame-dried under vacuum, filled with
argon, and charged with a solution of
diisopropyl squarate (5.94 g, 30 mmol) (Note
6) in dry
tetrahydrofuran (150 mL). The solution is cooled to −78°C and cannulated rapidly into the reaction flask (Note
7). After completion of the addition, the mixture is stirred for 2 hr at 0°C, then for an additional 15 hr at room temperature. Following recooling to 0°C,
180 mL of saturated ammonium chloride solution (Note
8) is added via syringe, the
ice bath is removed, and stirring is continued for an additional 7 hr.
The reaction mixture is poured into a
2000-mL separatory funnel containing water (300 mL) and
ether (300 mL). After thorough mixing, the aqueous layer is separated and extracted with
ether (2 × 200 mL). The combined ethereal solutions are washed with water (300 mL) and
brine (300 mL), dried over
magnesium sulfate, and evaporated under reduced pressure to leave 8.5 g of a pale yellow oil. This material is subjected to flash chromatography on silica gel using
20% ethyl acetate in hexanes as the mobile phase (Note
9). The minor
diquinane (
230 mg, (Note
10)) is eluted first. A mixed fraction of the two isomers follows (570 mg, (Note
11)) in advance of the pure title compound (
6.36 g, (Note
12), (Note
13)).
2. Notes
1. All apparatus was washed with base and oven-dried overnight.
2.
2-Bromopropene was purchased from the Aldrich Chemical Company, Inc., and used as received.
4.
tert-Butyllithium was purchased from the Aldrich Chemical Company, Inc., and titrated before use with
diphenylacetic acid according to an established procedure.
2 The syringe and needle were oven-dried overnight prior to use. The plunger is rotated slowly and continuously throughout the addition to avoid loss of mobility brought on by the adventitious formation of
lithium hydroxide.
This alkyllithium is extremely pyrophoric and must be treated cautiously to avoid exposure to the atmosphere.
5.
tert-Butyllithium forms a yellow complex with
tetrahydrofuran at low temperatures. When all of this reagent is consumed, the yellow color disappears and a colorless solution of the vinyl anion is obtained. If the color continues the remaining
tert-butyllithium can be consumed by the slow addition of a few drops of
2-bromopropene until a colorless solution results.
6.
Diisopropyl squarate, available from the Aldrich Chemical Company, Inc., can be readily prepared from squaric acid according to the procedure reported by Liebeskind.
3
7. An
oven-dried, 18-gauge cannula wrapped with glass wool and aluminum foil was used.
8. This solution was deoxygenated by bubbling
argon through it for a period of 15 min immediately before use.
9. The dimensions of the column were 6.5 cm by 36 cm. The relevant R
f values of the isomers are 0.34 and 0.26.
10. This product, which can be recrystallized from
hexane (colorless crystals, mp
110–111°C), exhibits the following spectral properties: IR (CHCl
3) cm
−1: 3560, 2980, 1650, 1600;
1H NMR (300 MHz, C
6D
6) δ: 0.92–1.12 (m, 1 H), 1.02 (d, 3 H, J = 6.0), 1.03 (d, 3 H, J = 6.0), 1.05 (d, 3 H, J = 6.0), 1.10 (d, 3 H, J = 7.0), 1.15 (d, 3 H, J = 6.0), 1.26 (s, 3 H), 1.25–1.35 (m, 1 H), 1.42–1.50 (m, 1 H), 1.92–2.07 (m, 2 H), 3.08 (s, 1 H), 5.20 (hep, 1 H, J = 6.0), 5.31 (hep, 1 H, J = 6.0);
13C NMR (75 MHz, C
6D
6) δ: 15.3, 19.9, 22.3 (2C), 22.6, 22.8, 30.8, 34.3, 46.6, 52.8, 71.1, 73.4, 83.9, 131.4, 171.9, 199.9.
11. Assay of this fraction by VPC (SE-30, 70–250°C/min) showed its composition to consist of 8% of the less polar isomer and 92% of the more polar product. The overall yields are consequently 2.5% and 81%, respectively.
12. The title compound was obtained as a colorless oil that slowly crystallized on standing, mp
52–53°C. Its spectral characteristics are as follows: IR (CHCl
3) cm
−1: 3589, 2979, 1697, 1616;
1H NMR (300 MHz, C
6D
6) δ: 0.84–0.98 (m, 1 H), 1.01 (d, 3 H, J = 7.0), 1.07 (d, 3 H, J = 6.0), 1.09 (d, 3 H, J = 6.0), 1.10 (d, 3 H, J = 6.0), 1.11 (d, 3 H, J = 6.0), 1.28 (s, 3 H), 1.23–1.43 (m, 2 H), 1.86–1.94 (m, 1 H), 2.18–2.24 (m, 2 H), 5.24–5.38 (m, 2 H);
13C NMR (75 MHz, C
6D
6) δ: 15.5, 19.6, 22.5, 22.6 (2 C), 22.9, 31.3, 35.0, 46.9, 56.7, 71.2, 73.6, 83.1, 132.5, 165.4, 202.7.
13. The checkers isolated an additional side product
A, not observed by the submitters, in 2% yield; its structure is based upon NMR
1H/
13C correlations and NOE data:
1H NMR (300 MHz, CDCl3) δ: 1.2 [(d, 6 H) (OCH(CH3)2)], 2.08 [(m, 3 H) (CH2=C-CH3)], 2.4 [(s, 3 H) (ar-CH3)], 4.3 [(m, 1 H) (OCH(CH3)2)], 5.08 (m, 2 H, =CH2), 5.2 (s, 1 H, 3-OH), 5.6 (s, 1 H, 2-OH), 6.5 (s, 1 H, ar-H).
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Twofold addition of the same or different vinyl anions to squarate esters leads to polyquinane products.
4 The principal pathway involves trans-1,2-addition of the organometallic reagent to generate a cyclobutene dialkoxide such as
1. Ring strain and electrostatic factors promote the rapid conrotatory opening of
1 in that sense leading to outward splaying of the oxido functional groups.
5 The resultant doubly-charged 1,3,5,7-octatetraenes shown by
2, undergo symmetry-controlled 8π electrocyclization from a coiled conformation, thereby giving rise to cyclooctenyl dienolates
3. In symmetrical examples such as that illustrated, protonation at either available reactive center delivers
4, and sets the stage for intramolecular aldolization via transannular cyclization. In unsymmetrical cases, both aldols are sometimes produced, with steric discrimination occurring.
6 A strong interdependence of the efficiency in this cascade process and vinyl anion substitution has been noted.
6 2-Propenyllithium is particularly conducive to product formation in good yields, presumably because the presence of methyl groups at C-2 and C-7 in
2 favors the adoption of the conformer shown over others less conducive to the conrotatory requirements for the conversion to
3.
The cascade sequence associated with this remarkable series of chemical events is tolerant of structurally varied vinyl anions provided that steric bulk is not excessive. The end result is the potential for establishing many stereogenic centers from a triad of achiral reactants in a single laboratory operation. The very substantial increase in complexity attainable from these tandem stereoregulated chemical events is shown in the Table.
Two minor processes sometimes operate competitively with that illustrated in the scheme. One of these involves 1,4-addition of the second vinyl anion to give a reactive intermediate that differs structurally from
1, but is capable of setting into motion a closely related sequence of chemical events leading to an isomeric diquinane.
4 This is the route followed to produce the minor product characterized here. The other option consists of cis-1,2-addition, an event that is followed by a dianionic oxy-Cope rearrangement via a boat-like transition state.
4 When sufficient substitution is present to allow the installation of multiple stereogenic centers, the adoption of this pathway is easily distinguished from the electrocyclic alternative since a cis relationship between relevant substituents is in place, instead of the trans arrangement required by the electrocyclization cascade.
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