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Indian Journal of Chemistry Vol. 38B, April 1999, pp. 463-465

Note

LPDE catalysed rate acceleration of Diels­Alder reaction of electron-deficient dienes

with in situ generated 2-methoxycarbonyl-p­benzoquinone t

S Paul, V Srivastava, S Ray & S N Suryawanshi*

Medicinal Chemistry Division, Central Drug Research Institute, Lucknow 226 001 , India

Received 29 April 1998; accepted 19 February 1999

The Diels-Alder reaction of the electron deficient dienes 1, 2, with 2-ntethoxycarbonyl-p-benzoquinone was carried out in benzene, benzenelCTMS, ether, 2.5 M/5M LPDE solutions. Dramatics rate acceleration is observed for the POE catalysed reactions.

The Diels-Alder reaction, constitUtes, one of the most important methods for regio-, diastereo �d enantioselective synthesis of six membered rmg system of polycyclic natural products. In view of its significance, efforts aimed at improving the rate and selectivity of the [47t+27t) cycloaddition reaction have been the subject of recent researchesl . A few notable methods for cate acceleration are: conducting the reaction in aq. media2a-g, use of chlorotrimethyl silane (CTMSi and lithium perchlorate in diethyl ether (LPDEtH as mild Lewis acid. To the best of our knowledge, however, the results reported so far �e based on the Diels-Alder reaction of electron nch dienes, with electron-deficient dienophiles, and not on electron-deficient dienes which are used in inverse electron demand Diels-Alder reactions. In this communication we report the LPDE catalysed rate acceleration of the Diels-Alder reaction of electron deficient dienes 1, 2, with 2-methoxycarbonyl-p­benzoquinone, which is an electron deficient dienophile.

Dienes 1 and 2 were synthesized from the commercially available 2,4-hexadienoic acid using standard procedures. Cycloaddition reaction of the diene 1 with in situ generated 3 yielded the compound 4 as a pale yellow oil . Reaction of 1 with 3 yielded 36% of the product 4 after 1 68 hr of reaction time in benzene (Table I, entry- I ) whereas in benzene/CTMS (Table I, entry-2), a similar yield of

tCDRI Communication No. 5623

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3 4

5

the product was obtained after 84 hr. In 2.5 M LPDE, however, the reaction yielded 4 1 % of 4 after 36 hr (Table I, entry-4).

Reaction of the diene 2 with in situ generated -3 was investigated under varying conditions (Table I, entry-5- I 0) and yielded the compound 5 as a viscous pale yellow oil . Apart from the rate acceleration slight chiral induction ( 1 5-3 t %) was observed under varying conditions. In benzene (Table I, entry-5), the reaction yielded the product in 1 2% yield, whereas in benzene/CTMS (Table I, entry-6), the product 5 was obtained in 48% yield (d.e= 1 5% i after 90 hr. Encouraged by the effect of CTMS, we decided to perform the cycloaddition reaction of 2 with 3 in polar solvent systems. In ether (Table I, entry-7), the reaction was complete in 48 hr, yielding 4 I % of the

464 . INDIAN J CHEM, SEC B, APRIL 1999

Table I-Synthesis of dienes 1 and 2

Diene Dienophilie Product Solvent Lewis Time Yield acid (hr) (%)

1 3 4 Benzene 1 68 36 1 3 4 BenzenelCTMS CTMS 84 38 1 3 4 Ether 48 35 1 3 4 2.5 M LPDE Li 36 41 2 3 5 Benzene 1 80 1 2 2 3 5 BenzenelCTMS CTMS 90 48 2 3' 5 Ether 2 3 5 Ether, in

Steel ' Bomb Reactor

2 3 5 2�5 M LPDE 2 3 5 5 M LPDE

product 5 (d.e=24%)5. A dramatic rate acceleration was observed when the reaction was effected in LPDE (Table I, entry-9 and 1 0). In 2.5 M LPDE, the reaction was over in 1 4 hr to yield 63% of 5 (d.e= 19%i, whereas in 5 M LPDE, the reaction was over in 1 2 hr and furnished 65% of 5 (d.e.=3 1 %)5 . On crystal lization, one of the dias­tereomers crystallized out as a pale yellow crystall ine

compound [(l]�o = +1 3 .80 (c, 0. 1 8, CHCh). The

above mentioned entries indicate that polar solvent systems not only accelerate the reaction but also induce diastereoselectivity. The stereochemistry of 5 was assigned on the basis of noe studies. Irradiation of the H-9 proton at & 3 .70 ppm gave 'noe for the H- l 0 doublet at 8 3 .80 ppm. Conversely, irradiation of the H- 1 0 doublet gave noe for the H-9 multiplet. The above results confirm that H-9 and H- 1 0 are cis to each other and support the assigned configuration.

In conclusion, LPDE as a catalyst not only accelerates the cycloaddition reaction of electron­deficient dienes 1 and 2 with in situ generated 2-methoxycarbonyl-p-benzoquinone 3, but also induces chiral induction.

Experimental Section Melting points are uncorrected. Infrared spectra

(vrnax in cm·l) were recorded on a Perkin-Elmer model- 1 57 spectrometer, IH and I 3C NMR spectra on a Bruker-WM 400 instruments and mass spectra on a Jeol-D-300 mass spectrometer.

Synthesis of 4: A representative procedure--To a stirred solution of 2-methoxycarbonyl-p-benzo­quinone (0.336 g, 2 mmole) and silver oxide (0.928 g,

68 40 36 57

Li 14 62 Li 1 2 65

2 mmole) in dry benzene (30 mL) was added the diene 1 (0.252 g, 2 mmole). The reaction mixture was stirred in the dark for a period of 1 68 hr. The reaction mixture was filtered and the residue washed with ethyl acetate (2x 1 00 mL). The combined filtrate was washed with water (2x50 mL), brine (50 mL), dried (Na2S04) and concentrated in vacuo. The crude product was purified by chromatography over Si02 (60- 1 20 mesh). Elution with ethyl acetate : hexane (20 : 80) yield 4 as a viscous oil (0.2 1 8 g, 36%); IR (Neat, cm·I) : 1 720, 1 690, 1 620; IH NMR (400 MHz, CDCb): & 1 . 1 0 (d, J = 6.00 Hz, 3H), 3 .40 (m, I H), 3 .70 (s, 3H), 3 .75 (m, 1 H), 3 .80 (s, 3H), 3 .85 (d, J= 1 0.00 Hz, 1 H), 5 .60 (m, 1 H), 5 .90 (m, I H), 6.70 (d, J = 1 2 .00 Hz, 1 H), 6 .90 (d, J = 1 2.00 Hz, 1 H); MS (m/z): 290 (M+ -2).

Synthesis of 5: A representative procedure. To a stirred solution of 2-methoxycarbonyl-p-benzo-quinol (0.336 g, 2 mmole) and silver oxide (0.928 g, 4 mmole) in dry benzene was added the diene 2 (0.5 g, 2 mmole). The reaction was stirred for a period of 1 80 hr. The reaction mixture was filtered and the residue washed with ethyl acetate (3x50 mL). The combined organic extract was washed with water (2x50 mL), brine (50 mL), dried (Na2S04) and concentrated in vacuo. The crude product was chromatographed over Si02 (60- 1 20 mesh). Elution with ethyl acetate : hexane ( 1 5 : 85) yielded 5 (0. 1 g, 1 2%). When the reaction was conducted in 5 M

LPDE, one of the diastereomers crystallized out as

fine pale yellow crystals. [(l]�o = + 1 3 .80 (c, 0.78,

CHCb), m.p. 65°C: lR (KBr, cm·I): 2900, 2380, 1 7 1 0, 1 620, 1 460, 1 220; I H NMR (400 MHz, CDCh):

).

NOTES 465

. 0 0.85 (d, J = 6.00 Hz, 3H), 0.90 (d, J = 6.00 Hz, 3H), 0.95 (d, J = 6.00 Hz, 3H), 1 . 10 (d, J= 6.00 Hz, 3H), 1 .45 (m, 3H), 1 .70 (m, 3H), 1 .95 (m, 2H), 2 . 10 (m, I H), 3 .50 (m, IH), 3 .65 (s, 3H), 3 .70 (m, I H), 3 .80 (d, J= 1 0.00 Hz, IH), 4.75 (m, IH), 5 .55 (m, IH), 5 .90 (m, I H), 6.65 (d, J= 1 2.00 Hz, I H), 6.90 (d, J= 12.00 Hz, IH); \3C NMR (400 MHz, CDCh): 0 1 6.25 (q), 1 6.84 (q), 20.66 (q), 2 1 .87 (q), 23 .50 (t), 26. 1 1 (d), 3 1 .30 (d), 3 1 . 1 6 (d), 34.20 (t), 40.43 (t), 42.64 (d), 45 .32 (d)� 47. 14 (d), 53 .48 (q), 65 .43 (s), 75 .08 (d), 1 22.6 1 (d), 133 .34 (d), 138.26 (d), 1 40.60 (d), 1 68.75 (s), 1 7 1 .72 (s), 192.49 (s), 195.48 (s): MS (mlz): 4 1 6 (�).

Acknowledgement Financial aid from DST, New Delhi, is gratefully

acknowledged.

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