Indian Journal of Chemistry Vol. 408. October 200 1 . pp. 994-996

Note

A convenient synthesis of 4,8,9-trimethox ybenz[ f ] indenone,

a potential BCD ring intermediate for stealthins and kinamycinst

Dipakranjan Mal *, SUjit Ghorai & Nirmal Hazra

Department of Chemistry. Indian Insti tute of Technology. Kharagpur-72 I 302. India

Receil'ed 26 December 2000: accepted (rel'ised) 23 May 2001

A convenient regiospecitic synthesis of 4. 8. 9-trimethoxybenz! f J i ndenone 6 has been developed which involves Hauser reaction between phthalide sulfone 3 and enone 4. fol lowed by O-methylation of Sa and retro Diels-Alder reaction of 5b.

The chemistry of indenones, I for a long time, was l imited to the preparation of 2, 3-disubsti tuted derivatives because of their potent fungicidal activities. With the structural revision2 of kinamycin antibiotics (e.g., kinamycin D 1) in 1 994 and the isolation) of first benzo[b]fluorenone natural products stealthins 2 (Figure 1) in 1 992, the importance of the chemistry of indenones, specially fused indenones has considerably increased over the last few years.

Recently, we reported a short regiospecific synthesis4 of fused indenones, and the usefulness5 of indenone in anionic cycloaddition for a faci le entry to prekinamycin antibiotics. Hauser and Zhou uti lized the chemistry to accompl ish a regiospecific total synthesis of prekinamycin6. Though we fai led to demonstrate Diels-Alder reactivit/ of indenones, the Ishikawa group recently succeeded in synthesizing a model compound of kinamycins via Diels-Alder reaction of an indenone with a Danishefsky diene8. It appeared from this investigation that the Diels-Alder reaction of the title compound i .e . , 6 would be particularly useful for the total synthesis of kinamycin antibiotics, because it would constitute the entire BCD ring system. Furthermore, the indenone 6 would give an invaluable intermediate for the synthesis of pyranonaphthoquinone antibiotics 9. Consequently, it deemed worthwhile to extend our methodology to the preparation of 6. However, it re-

tDedicated to Prof. U.R. Ghatak on his 70lh birthday

HO

R

1 : Kinamycin 0 2: R=CH20H (steallhin A) R=CHO (stealth in B)

Figure 1 mained elusive for quite sometime apparently due to a trivial problem.

The required phthalide sulfone 3" was prepared in three steps from ethyl 2-methoxy-6-methylbenzoate in good overal l yield and the Michael acceptor 44 in two steps from commercial ly avai lable dicyclopentadiene. When 3 and 4 were submitted to the Hauser reaction lO under typical conditions (l ithium tert-butoxide, THF, -600 C to 25"C) (Scheme I), quinol Sa was expectedly obtained as a yellow solid in excellent yield. Since such a quinol is often susceptible to aerial oxidation, i t was not further purified. Its IH NMR spectrum showed it to be > 95% pure. Attempted derivatization of the quinol Sa to O-trimethyl derivative Sb was a serious problem. Treatment of Sa with dimethyl sulfate in the presence of potassium carbonate in acetone provided, after usual work-up, a mixture of compounds. 'H NMR spectrum of the mixture had several signals in the range of 5 3.9 - 4.2 confirming the presence of more than one product. Since the products were inseparable by column chromatography, they were not characterized. The complexity of the reaction was possibly due to the formation of keto-enol isomers 7 of Sa and their subsequent 0-methylation. Change of reaction medium and temperature had very l ittle effect on the composition of the reaction mixture. Final ly, we found that if the methylation of a dry sample of Sa is carried out with iodomethane in the place of dimethyl sulfate, the desired product Sb is formed in very good yield. The product was ful ly characterized by spectral and analytical data. Flash vacuum pyrolysis of Sb at 400°C/O. I mm furnished 6 in 96% yield. Its spectral data were consistent with the structure. The indenone 6 is fairly unstable and tends to undergo dimerization on standing in CDCI) solution. The utility of 6 was

NOTES 995

S02Ph �o + ?D IBuOLi -OMe 0

3

o 4

� YY-{ OMe OMe 0

7

Zn, AcOH -

OMe OR

Sa: R=H ---, CH I, I( CO 5b: R=Me ..,J 3 ''2 3

! FVP

� YY-{ OMe OMe 0

6 Scheme I

demonstrated by its conversion to indanone 7 in 65% yield by ZnI AcOH reduction. The spectral data of the compound 7 fully matched the literature data9. It may be noted the benz[ f ]indanone 7 was previously prepared by a linear sequence of nine steps from 1 ,5-dihydroxynaphthalene and used in the total synthesis of eleutherin, a pyranonapthoquinone antibiotic9•

In conclusion, we accomplished a concise yet regiospecific preparation of indenone 6, a potential synthetic intermediate for kinamycin antibiotics. Further study on the Diels-Alder reactivity of 6 is underway.

Experimetal Section General experimental details are reported in ref. 12 . 5, 10-Dihydroxy-1, 4-methano-9-methoxy-1, 4,

4a, lla-tetrahydro-llH-benzo[b ]fluoren-ll-one Sa. To a stirred solution of lithium tert-butoxide (790 mg, 9.84 mmole) in THF (40 mL) at -60°C (chloroforrnlliquid N2 bath) under an inert atmosphere was added a solution of sulfone 3 ( 1 g, 3 .28 mmole) in THF (5 mL). The resulting yellowish solution was stirred at - 60°C for 30 min, after which a solution of enone 4 (575 mg, 3.93 mmole) was added to the mixture. The cooling bath was removed after about 3 hr at -60°C and the reaction mixture was brought to room temperature over a period of 1 hr and further stirred for 1 2 hr. The reaction was then quenched with 10% HCI ( 1 5 mL) and the resulting solution was concentrated under reduced pressure. A bright yellow solid appeared which was filtered and washed with 1 : 1 mixture (20 mL) of diethyl ether and petroleum

ether to furnish 9 10 mg (9 1 %) of Sa. This was used in the next step without further purification.

IR (KBr): 1 633 cm-I (H-bonded carbonyl group), 1 6 1 8 cm-I ; IH NMR (d6-DMSO, 200 MHz): 10.46 (s, 1 H, intramolecular H-bonded OH), 7 .74 (dd, I H, 1=0.8, 8 Hz), 7 .39 (t, 1 H, 1=8 Hz), 6.74 (d, 1 H, 1=8 Hz), 5 .86 (dd, 1 H, 1=2.5, 6 Hz), 5 .49 (dd, 1 H, 1=2.5, 6 Hz), 3 .96 (s, 3 H), 3.97-3.85 (m, 1 H), 3 .48-3 .45 (m, 1 H), 3.35-3.30 (m, 1 H), 3.2 1 (dd, 1 H, 1=5, 7 Hz), 1 .73- 1 .60 (m, 2 H); \3C NMR (d6-DMSO, 50 MHz): 8 208.7, 1 59.2, 1 50. 1 , 1 39.9, 1 34.2, 133 . 1 , 1 32.8, 1 3 1 .2, 1 29.6, 1 28.7, 1 20.0, 1 1 5 . 1 , 104.9, 56.2, 53.8, 52.4, 45.5, 44.7, 4 1 .6.

1, 4-Methano-1, 4, 4a, l la-tetrahydro-5, 9, 10-trimethoxy-llH-benzo[b]fluoren-ll-one 5b. Quinol Sa (9 10 mg , 2.95 mmole) was dissolved in dry acetone (50 mL) under an inert atmosphere. To this solution were added dry K2C03 ( 1 5 mmole) and freshly distilled iodomethane (2.09 g, 14.75 mmole). After 2 hr of reflux, the reaction mixture was cooled, filtered and the filtrate concentrated. The residue was dissolved in ether (50 mL), treated with triethylamine (0.89 g, 8.85 mmole) at r.t. for 30 min. Then the mixture was successively washed with water (20 mL), 5% HCl ( 10 mL) and brine (20 mL), then dried (Na2S04), filtered and evaporated at reduced pressure. Crystallization of the residue from a mixture of ethyl acetate and hexane afforded 720 mg (73%) of 5b as pale yellow crystals, m.p. 203-204°C; IR (KBr): 1 696 cm-I ; IH NMR (CDCh, 200 MHz): 7.63 (d, 1 H, 1 = 7.8), 7.45 (t, 1 H, 1 = 7.8), 6.80 (d, 1 H, 1 = 7.6), 5.95 - 5 .90 (m, 1 H), 5 .56 - 5.5 1 (m, 1 H), 4.0 1 (s, 3 H),

996 INDIAN J. CHEM., SEC. B, OCTOBER 2001

3.98 (s, 3 H), 3.89 (s, 3 H), 3.47 - 3.40 (m, 2 H), 3.23 - 3 . 1 8 (m, 1 H), 1 .80- 1 .69 (m, 2 H); (signals of a bridge-H are buried under the signals of three OMe groups at around 8-4); I 3C NMR (CDCI3, 50 MHz): 204.5 , 1 59.4, 1 53.0, 147.8, 1 39.7, 1 34.9, 1 34. 1 , 1 33.4, 1 29. 1 , 1 28.5, 1 2 1 . 1 , 1 14.2, 1 06.2, 62.7, 6 1 .3 , 59.4, 53.6, 52.3, 45 .9, 45.7, 4 1 .4; MS (mlz): 336, 308, 293, 270, 255, 241 , 2 1 1 , 1 39; Anal. Calcd for C2 ,H2004: C, 74.98; H, 5.99. Found: C, 74.75; H, 6.07%.

4,8,9-TrimethoxybenzUlinden-l-one 6. Compound Sb (200 mg, 0.6 mmole) was submitted to flash vacuum pyrolysis at 400°C/0. l mm with an indigenously built apparatus '2 to furnish 155 mg (96%) of 6 as a yellow solid which was not further purified. 'H NMR spectrum of this material showed no sign of impurity, m.p. 175°C (sublimed); IR (KBr): 1 698, 1590 cm-' ; ' H NMR (CDCh, 200 MHz): 7.87 (d, I H, 1=6 Hz), 7.67 (dd, 1 H, 1=1 , 8 Hz), 7.45 (t, I H, 1=8 Hz), 6.92 (dd, 1 H, 1= 1 , 8 Hz), 6.02 (d, 1 H, 1=6 Hz), 4.06 (s, 3 H), 3.99 (s, 3 H), 3.96 (s, 3 H); DC NMR (CDCI3, 50 MHz): 1 93.8, 1 59.7, 1 53.5, 145.6, 144.9, 1 35.2, 130.4, 1 29.8, 125.8 , 1 22.0, 1 1 8.3, 1 1 6.2, 1 09.7, 62.5, 62.4, 56.5; MS (mlz): 270, 255, 24 1 , 227, 2 1 1 , 1 84, 167, 1 54, 1 39, 1 26.

4,8,9-TrimethoxybenzUlindanone 7. Compound 6 (50 mg, 0. 1 8 mmole) was dissolved in 8 mL of 4: 1 mixture of ethanol and acetic acid. Zn dust (44 mg, 0.7 mmole) was then added. The resulting mixture was stirred at r.t. for 1 5 min, diluted with water (20 mL) and extracted with diethyl ether (3 x 1 5 mL). The

organic layer was washed with water (20 mL), brine (20 mL), dried (Na2S04) and concentrated in vacuo. The crude product was purified by silica gel column chromatography to yield 79 (32 mg, 65%).

Acknowledgement This work was financially supported by CSIR,

New Delhi.

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