Organic Syntheses, Vol. 75, 223
Checked by Zehong Wan and Amos B. Smith, III.
1. Procedure
2. Notes
1. All glass apparatus was dried thoroughly under a flow of dry N
2. All ground glass joints were tightly sealed with Teflon tape and then wrapped with Parafilm. All the preparations were performed in an
efficient fume hood while wearing gloves and adequate eye protection.
2.
Benzophenone purchased from Aldrich Chemical Company, Inc. was used as received.
3.
Toluene, dichloromethane, acetic acid, ammonium hydroxide, concentrated H2SO4, 5 N NaOH and 37% HCl were purchased from Mallinckrodt Inc.;
tetrahydrofuran, tert-butyl alcohol, anhydrous Na2SO4, and NaCl were purchased from EM Science;
potassium tert-butoxide was purchased from Aldrich Chemical Company, Inc.;
hexanes was purchased from Baxter, and
dry O2 was purchased from Air Products. All these reagents were used as received.
4.
Quinine (purity 90%) purchased from Aldrich Chemical Company, Inc., was used as received.
5. A mild endotherm was noted: the temperature fell from 22°C to 19°C.
6. The color changed to yellowish brown immediately upon addition of
potassium tert-butoxide and a mild exotherm was noted, as the temperature rose to 29°C.
7. The slurry became very thick as the temperature approached reflux, requiring vigorous stirring. The color of the mixture gradually changed to dark orange and at the end of the reaction the color was fluorescent orange.
8. The material was sufficiently pure as determined by HPLC (
Zorbax C-8 column RX 25 cm; flow rate 2.5 mL/min; mobile phase
acetonitrile/water (1:1); UV detection at 254 nm showed four peaks t
R(min.) at 0.9 (
quinine), 1.3 (
quininone), 4.4 (
toluene), 5.4 (
benzophenone). A part of this material (8.0 g) was dissolved in
250 mL of diethyl ether at room temperature, left in a freezer for 48 hr, and 6.9 g of light yellow solid was obtained upon filtration; mp
102-104°C.
9. The reaction mixture displayed an exotherm from ambient temperature to 35°C.
10.
Quininone was added at a rate to keep the temperature below 25°C; otherwise the yield of this step was much lower.
Oxygen uptake increased upon the addition of
quininone, but slowed as the reaction proceeded (15 min).
11. If three phases result, add the minimum amount of water (100 mL) that affords two phases (some color in the aqueous phase was noted). Additional quantities of water should be avoided because of the high water solubility of the product.
12. The product was concentrated under reduced pressure at room temperature, but concentration at higher temperature resulted in a lower yield (
35-40%).
13. Any attempts to purify the product by distillation resulted in lower yields because of pyrolysis. The undistilled product was sufficiently pure for most purposes. The yield range was
60-75%;
1H NMR (500 MHz, CDCl
3) δ: 1.32-1.63 (m, 11 H), 2.02-2.30 (m, 4 H), 2.63-3.06 (m, 4 H), 4.90-5.18 (m, 2 H), 6.01-6.10 (m, 1 H);
13C NMR (125 MHz, CDCl
3) δ: 28.1, 28.9, 35.7, 39.4, 43.0, 46.1, 51.4, 80.1, 116.6, 137.2, 172.3.
14. Six volumes of CH
2Cl
2 are used to ensure efficient stirring, since a solid separates after the addition of
benzoyl chloride.
15.
Reagent grade pyridine and benzoyl chloride were purchased from Aldrich Chemical Company, Inc., and used as received.
16. The reaction appeared complete by HPLC. R
f for the product=0.54 (by TLC analysis on
silica gel 60 F-254 precoated plates, hexanes:EtOAc, 1:1, freshly prepared).
17. The crude product was sufficiently pure and used as such for the next step (purification by column chromatography using hexanes:EtOAc, 4:6 as an eluant affords a 92-95% yield of the purified product). A part of the crude product (5.0 g) was crystallized from
50 mL of diethyl ether to furnish light yellow needles; mp
62-64°C (lit.
2 mp
65-67°C);
1H NMR (500 MHz, CDCl
3) δ: 1.39-1.52 (m, 11 H), 2.08-2.31 (m, 3 H), 2.33-2.65 (m, 1 H), 2.97-3.25 (m, 2 H), 3.65-3.75 (m, 1 H), 4.50-4.74 (m, 1 H), 5.08-5.12 (m, 2 H), 5.79-5.92 (m, 1 H), 7.31-7.41 (m, 5 H);
1H NMR (CD
3SOCD
3, 25°C) δ: 1.39 (m, 11 H ), 2.02-2.55 (m, 4 H), 2.90-3.50 (m, 3 H), 4.21-4.42 (m, 1 H), 4.90-5.12 (m, 2 H), 5.76-5.94 (m, 1 H), 7.31-7.41 (m, 5 H);
1H NMR (CD
3SOCD
3, 90°C) δ: 1.39-1.51 (m, 11 H), 2.04-2.21 (m, 3 H), 2.41-2.49 (m, 1 H), 3.06 (ddd, 1 H, J = 2.7, 3.7 and 10.7), 3.24 (dd, 1 H, J = 3.2 and 13.2), 3.91-4.00 (m, 2 H), 5.02-5.13 (m, 2 H), 5.78-5.87 (m, 1 H), 7.31-7.41 (m, 5 H).;
13C NMR (CDCl
3, 125 MHz) δ: 28.1, 35.8, 38.7, 42.2, 46.0, 47.5, 52.4, 80.4, 118.1, 127.0, 128.3, 129.4, 134.7, 136.2, 170.8, 171.8.
18. The color of the reaction mixture changed from light yellow to dark brown at the end of the reaction with the formation of solid particles. The reaction appeared complete by TLC analysis (silica gel 60 F-254 precoated plates,
hexanes:
ethyl acetate, 2:8, freshly prepared); R
f for benzoyl derivative = 0.74, R
f for enone = 0.25.
19. HPLC of the crude product indicated the presence of only cis isomer; no trans isomer was detected in the crude product;
1H NMR (500 MHz, CDCl
3) δ: 1.52-1.82 (m, 2 H), 2.47-2.56 (m, 3 H), 2.82-2.96 (m, 1 H), 3.21-3.41 (m, 1 H), 3.50 (dd, 1 H, J = 13.5 and 4.1), 3.52-3.72 (m, 1 H), 4.35-4.45 (m, 1 H), 6.09 (d, 1 H, J = 9.7), 6.85-7.05 (m, 1 H), 7.27-7.42 (m, 5 H);
1H NMR (CD
3SOCD
3, 25°C) δ: 1.35-1.70 (m, 2 H), 2.46-2.50 (m, 3 H), 2.82 (m, 1 H), 3.22-4.08 (m, 4 H), 5.98 (m, 1 H), 6.92 (m, 1 H), 7.34-7.44 (m, 5 H);
1H NMR (CD
3SOCD
3, 90°C) δ: 1.46-1.59 (m, 2 H), 2.48-2.50 (m, 2 H), 2.80 (m, 1 H), 3.01 (m, 1 H), 3.22-3.31 (m, 1 H), 3.51 (dd, 1 H, J = 4.2 and 13.4), 3.60-3.64 (m, 1 H), 3.84-3.87 (m, 1 H), 5.9 (dd, 1 H, J = 2.2 and 10.1), 6.77 (dd, 1 H, J = 3.0 and 9.8), 7.33-7.45 (m, 5 H);
13C NMR (125 MHz, CDCl
3) δ: 27.2, 33.8, 37.0, 41.8, 44.9, 46.2, 126.8, 128.6, 129.8, 131.0, 135.8, 150.6, 170.8, 198.1.
20. If there was no crystallization, a few crystals of crude product were added to the flask to initiate crystallization. The mp was
148-150°C (lit.
2 mp
150-152°C).
21.
Palladium on activated carbon (10%) was purchased from Aldrich Chemical Company, Inc., and used as received.
22. After 75 min an aliquot was drawn and analyzed by
1H NMR which indicated the presence of enone (< 5%); another
1.0 g of Pd was added and the mixture heated at 50°C/50 psi of H
2 for another 45 min.
23. The
palladium on activated carbon (10%) was not allowed to become completely dry because of its flammable nature.
24. The data for the pure product is: mp
179-181°C (lit.
2 mp
182-183°C);
1H NMR (500 MHz, CDCl
3) δ: 1.49-1.60 (m, 2 H), 2.01-2.13 (m, 2 H), 2.25-2.60 (m, 6 H), 3.03-3.22 (m, 2 H), 3.61-3.81 (m, 1 H), 4.45-4.59 (m, 1 H), 7.28-7.41 (m, 5 H);
1H NMR (CD
3SOCD
3, 25°C) δ: 1.30-1.62 (m, 2 H), 1.82 (m, 2 H), 2.18-2.65 (m, 6 H), 3.04 (m, 1 H), 3.20 (m, 1 H), 3.48 (m, 1 H), 4.22 (m, 1 H), 7.32-7.48 (m, 5 H);
1H NMR (CD
3SOCD
3, 90°C) δ: 1.34-1.52 (m, 2 H), 1.66-1.78 (m, 1 H), 1.80-2.02 (m, 1 H), 2.20-2.31 (m, 2 H), 2.31-2.37 (m, 2 H), 2.48-2.57 (m, 2 H), 3.00-3.12 (m, 1 H), 3.27 (dd, 1 H, J = 3.6 and 13.2), 3.88 (m, 2 H), 7.30-7.50 (m, 5 H);
13C NMR (125 MHz, CDCl
3) δ: 25.5, 26.6, 27.6, 35.0, 37.4, 39.8, 45.9, 47.2, 126.8, 128.5, 129.6, 136.1, 171.0, 210.5
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Cyclization of N-acyl meroquinenes with neat polyphosphoric acid (PPA, thick reaction mixture) required 5 days at ambient temperature and resulted in a 2.4:1 mixture of trans:cis-enones, respectively (55% yield, eq 1).
2 The diastereomeric mixture could easily be separated by column chromatography to provide pure samples of either substance. It was also shown that the pure trans- and cis-enones equilibrated under the PPA cyclization conditions to afford the same 2.4:1 (trans:cis) mixture of enones. Thermodynamic equilibration of either enone also occurred with
p-toluenesulfonic acid (p-TsOH) in THF. Cyclization of N-acyl meroquinenes could be conducted in a mixture of PPA:H
2SO
4 (0°C

20°C) with complete cis-stereocontrol in essentially quantitative yield (30 min) affording only the cis-product. Equilibration of the γ-position occurred at elevated temperatures (> 25°C). It was then determined that concentrated H
2SO
4 could replace the PPA:H
2SO
4 mixture, with identical (cis) product profile.
Trifluoroacetic anhydride (TFAA) also effected the present cyclization albeit with poor efficiency, but alternative acids (H
3PO
4, AlCl
3/CH
2Cl
2, TFAA, HCl, CH
3SO
3H, HOAc, HNO
3) did not.
6 7 8 Either TFAA or mixtures of Ac
2O with catalytic H
2SO
4 have been employed for the cyclization of ω-olefinic acids, although the substrates did not contain stereogenic centers. Polyphosphoric acid has also been used extensively for the acylation of alkenes at high temperatures, usually at 100°C.
9 10 11 12
Furthermore, attempted cyclization of N-carboxymethyl meroquinene ethyl ester failed to afford any of the enone, suggesting that the carboxylic acid was an intermediate. The N-protecting groups, in addition to benzoyl, that are tolerated include CO2Me, pivaloyl, acetyl, toluenesulfonyl, CBz, and alkyl.
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