Ind ian l ourna l of Chemistry Vol. 4 113, April 2002, pp. 858-862

Note

Synthesis of angular furano - or pyrano-fused coumarins from natural scopoletin

K Nagaiah", G L David Kru padanamb & G Sri mannarayanab*

"Organic Chemistry Division-III , l nd ian Institute ofChcmicn l Technology, Hyderabad 500 007, India

bDepartment of Chemistry , Osmania Uni versity, Hyderabad 500 007 , India

Received I I April 2000; accepted (revised) 18 July 2001

Starling frolll natural coumarin, scopoletin, the sy ntheses of 8-Illcthyl-6-lllcth oxy l-2H-furo(2 , 3- 11 )[ Ilbenzopy ran-2-one 4, 10-eli­hydro-9-hydroxy-6- lllelhoxy-2H, 8H-benzo[ I, 2-b; 3, 4-b] dipy­ran-2-one 7, 8-hydroxy-6-melhoxy-2H, 8H-benzo [ I, 2-b;3, 4-bJdipyran-2-one 8 and 6-methoxy-2H, 9H-benzo[ I, 2-b;3, 4-bldipyran-2, 8-c1i one 9 have been reported.

Natural cOllmarins are biosynthesized in pl ants as phy­toalex ins in response to pathogenic attack. I Many pyrano-and furo-collmarins are isolated from natural source and are reported to have a variety of biological ac ti vi ties?' 3 Tri oxsalcn has photodynamic acti vity and used in the treatment of lellcoderma.2 Furocoumarins such as pimpinell in, isopi mpinellin , bergaptene, iso­bergaptene show high insect -ant ifeedant acti vity.4

From the bark of Xeromph is ulig illosa, sy n. Ranclia llliinosa (Rubiaceae), a coumarin di saccharide, 7-0 -(~-D-ap i ofuranosy I( I ~6)~-D-gl ucopyranosy 1)-6-meth­oxycoumarin was isobted in hi gh yield (2.2%) in our laborato ries. 5 Thi s was also earlier reported as xeroboside6

, or hymexelsin .7. 5 After hydrolys is of the disaccharide, the ag lycone was identifi ed as sco­poletin (7-hydroxy-6-methoxycoumarin 2). It was also isolated from the chl oroform ex tract of X. ulig i­nasa in (0.2%) yield .5 It is in te resting to note that sco­poletin is reported to prod uce hypotension.s

In thi s paper we report the sy nthes is of some angu­lar furano-or pyrano-coumarins start ing from the na tural scopoleti n 2. Propargy lation of scopoletin 2 yielded 7-0 -propargylscopoletin 3, wh ich was sub­jected to Claisen rearrangement and subsequent cycli­sati on4 by retl uxing at 2 10°C to yield 8-methyl-6-methoxy-2H-furo (2, 3-h) [I ] benzopyran-2-one 4 (Scheme 1). III IH NMR (COCl]) spectrum furano meth yl group at Cs observed as a broad singlet at 8 2.50 and C5-proton appeared at 8 6.72 as a singlet

(br). A th ree proton singlet at 83 .90 is due to methoxy l. The C3 and C4 protons appeared as a doublets at 8 6.35 and 7.70 (1=10 Hz) respecti vely MS spectrum showed M+ at mlz 230 as a base p The frag ment ions due to M-CH3 (m/z 2 15) and CO (mJz 202) were also found. Sati sfactory mi, analys is and spectral data were obtained.

Scopoletin 2 was allylated with allyl bromid( give correspondi ng 7-0-allylscopo letin 5 in S yield. This compound on Claisen rearrangement il N'-diethylaniline afforded 8-allylscopoletin 6 in S yield. Eq ui molar amount of 8-ally lscopoleti n 6 ane chl oroperoxybenzo ic ac id were dissolved in benzene and refl uxed fo r 6 hr. Work-up of mi xture gave a semi-solid whi ch was chrom graphed over a co lumn of silica gel using pet-eth chloroform (4:6 v/v) to give 9, 10-dihydro-9-hydro 6-methoxy-2H.8H-benzo[ I, 2-b;3, 4-b ]di pyran-2-7. The structure 7 was ass igned on the bas is spectra l data (lR (KBr): 3450(-OH), 1700 (C=O) I) . ]n IH NMR (COCI3) spectrum it showed a sig pattern characteri stic of ·-O-CHTCHOH-CHra~

part of ring system. The Cg-ax ial and Cg-equi to protons resonated at 83.82 and 3.98 as two dou doublets, whi ch are further split by the C9-pro (1SH"x.8Hcq= 11 .50 Hz; JgHax.9H=6.50 Hz; J8Heq.9H= Hz).The C9-proton resonated at 8 5.15 as a comp multi plet and the C9-OH resonated as a broad si n ~

at 8 2.26. The C lo-ax ial and CIQ-equitorial prot( resonated 8 3.27 and 8 3.47 as a two double doubl whi ch are further split by the C9-prol (11 0Hax. IOHeq=16.0 Hz; J IOHeq.9H=9.5 Hz; J IOHax.9H=' Hz), The C3 and C4 of coumarin ring sho~

charac teri stic AB doubl ets at 86,25 (1= 10Hz) (J

7.60 (J=I OHz) respectively. One proton singlet a 6.70 i ~ ass igned to C5 proton. A three pro ton si ngle! 8 3.90 is due to C6 methoxy l.

In MS, it showed the mo lecular ion at mlz 248 a base peak. The frag ment ions at mJz 247 due to ]\I

[M-I-I ], 229 (M-I-I -H20 ), 204 (M-C2H40 ), 220 (l CO) and 176(M-CO-C2H40 ) were also fou nd. T fragme nt ion at mJz 229, is a pyrill ium ion, which highly characteristi c.: of hydroxyd ihydropyran ri system. The forma ti on of hydroxydi hydropyran ox idation of 8-a ll yl-7-hydroxy-4-methylcoumarin I11 -CPB A was reported 9 from our laboratories.

NOTES

H

o °XXJO 0 HOXXJO 0

OH I __ a_~ .. _ I H CO h- h-- H CO h-- h-

3 3

1 2

o 2 b °XXJOO c --~ .. - I ------.. ~

I H CO 0 h--t d) 3 3

o

o

4 OH

~ O~OyO

H co ~ -------'~ 3

e HO 0 0 f ..

H3CO h--

o 0

5 6 7

t g

H

0 0 o +

h--H3CO

9 8

a MeOI-l/H2S0./l-Iydrolysis; b == CH2Sr/).=O/K2C03; c N,N'-diethylaniline/2100C;

d ~ Sr i';>= O/K2C03

; e N,N'-diethylanilinel2 lOoC; f mCPBA/Dry C6H6 ;

g DDQ/DryC61-16

Scheme I

859

A solution o f 8-::tllylscopoletin 6 ( I mole) was oxi­dised with 2, 3-dichloro-S, 6-dicyanobenzoquinone (DDQ) (3 moles) and rdluxed for 10 hr. TLC exam i­nation revealed the formation of two products . The crude react ion product ,vas chromalographed over

silica gel. Elution with chloroform: ethyl acetate (7:3 vI,,) afforded one major product (40% yield ) and chloroform : ethyl acetate (6:4v/v) afforded a minor product ( 15 % yie ld). The major compound was as­signed structure 8-hydroxy-6-methoxy-2H, 8H-benzo-

860 INDIAN J. CHEM., SEC B, APRIL 2002

[1, 2-b;3, 4-b ]dipyran-2-one 8, m.p. 214°C, analyzed for CI3HiO0 5, and M+246. The minor compound 6-methoxy-2H, 9H-benzo[l, 2-b;3, 4-b]dipyran-2, 8-dione 9, m.p. 234°C, analyzed for CI3Hg0 5, and M+244.

The IR (KEr) spectrum of major compound 8 showed carbonyl at 1720 cm·1 and newly formed al­coholic-OH at 3375 cm·l. Its IH NMR (CDCI3: I drop DMSO-d6; 200 MHz) spectrum showed the presence of a new structural segment H-C-CH=CH- as a part of a fused ring. The doublet at 8 7.35 (JiOH .9H= 10Hz) is due to olefinic proton at CIO. The double doublet at 8 6.07 (J9H.loH=10 Hz; J9H.gH=3Hz) is due to all ylic Cg-proton. The singlet at 8 3.55 is due to the allylic alco­holic OH. The AB doublet at 8 6.32 (J=10Hz) and 7.64 (J=lOHz) are due to C3 and C4 protons respec­tively. The singlet at 8 6.86 is due to the C5H. The three proton singlet at 8 3.95 is due to C6-OCH3. Its MS showed mlz 246 (M+) and 218 (M-CO). Thus the spectral data established the structure as 8.

The minor compound 9 in its IR spectrum (KBr) showed two carbonyl peaks at 1725 and 1720 cm·1

both characteristic of coumarin carbonyls. Its IH NMR (CDClf 1 drop DMSO-d6; 200 MHz) spectrum showed the absence of allyl group, but revealed one pair of AB doublets at 87.25 (C4-H or CiO-H, J=10Hz) and 6.90 (C3-H or C9-H) (J=lOHz) another pair of AB doublet as at 87.65 (Cw-H or C4-H, J=IOHz) and 86.28 (C9-H or C3-H) (J=lOHz) integrating one proton each. The three proton singlet at 83.98 is due to C6-

OCH3. The singlet at 87.35 is due to the C5-H. Its MS showed 244 (M+), 216 (M-CO) and 186 (M-CO-CO). Thus from analytical and spectral data, the structure of the compound was assigned as 9. Earlier from our laboratory, the formation of coumarin ring system was reported by ox idative cyclisation of 2-allylphenols by DDQ.lo. II

The compounds 1 to 9 (1000 ppm in acetone) were tested for insect-antifeedant act ivity for 8 hI', prestarved larva of IV instal' Spodoptera filura F, on fresh castor leaf disc, by non-choice test method. 12

The percentage of insect antifeedant activity was cal­cu lated by the formula of Singh and Panth. 13 The compounds 1 and 2 showed moderate antifeedant ac­tivity (75 to 50%) and 3 to 9 showed high insect­antifeedant activ ity (82 to 99%). Generally the com­pounds that exhibit above 75 % antifeedant activity are considered to have high insect-antifeedant activity with potential to control agricultural pests while those with 75 to 50% antifeedant activity are considered to

have moderate activity and below 50% poor an­tifeedant activity respectively.

Experimental Section

General. Melting points were taken in open capil· lary on sulph uri c acid bath and are uncorrected . IH NMR spectra (200 or 300 MHz) were recorded on Varian Gemini 200 and R.c. Bruker AM 300 MH2 spectrometer in DMSO-d6 and or CDCI3. Chemical shifts are reported in 8 (ppm) relative to TMS as in· ternal standard, coupling constants(J) were expressec in Hertz. IR spectra were recorded on Perkin-ElmeJ Infrared model 337 in KEr pellet and UV spectrum ir methanol on a Shimadzu UV -VIS 200 spectrometer Mass spectra were taken on a Finnigan Mat-121C double focussing spectrometer. Purification of com pounds were done by si li ca gel (ACME, 200 mesh: column.

Scopoletin (7 -hydroxy-6-methoxycoumarin) 2 7 -O-(P-D-Apiofuranosyl( 1-76)P-D-gI ucopyranosyl )· 6-methoxycoumarin5 1 (lOg) was hydrolysed b) methanolic sulphuric acid (500 mL) to yield sco poletin (5.4 g) as reported in the literature.5

7-0-Propargylscopoletin (7 -propargyloxy-6-meth oxycoumarin) 3. A mixture scopoletin 2 (1.86 g, 0.0 J

mole), propargyl bromide (l.30 g, 0.011 mole) ane K2C03 (20g) in acetone (100mL) was refluxed or steam bath for 6 hr. The acetone was removed unde reduced pressure and then crushed ice was added te the residue. The solution was fi ltered and distilled The crude product was recrystallised from dry chloro form to give 7-0-propargylscopoletin 3 as light yel low crystals. m.p. 210-12°C. (2.16g, yield 98%); IF (KBr): 2130,1710 cm· l; IH NMR (CDCI3, 200 MHz) 82 .. 49 (t, J=2.5 Hz, I H, =CH), 4.70 (d, 1=2.5 Hz -CH2), 6.29(d, J=9 .5 Hz, C3-H), 7.93(d, J=9.5 Hz, C4

H), 7.26 (s, IH , C5-H), 7.78(s, IH, Cs-H), 3.78(s , 3H -OCH3); MS: mlz (%) 230(100), 215(5),19 1(60),16: (58), 135 (45) . Anal. Calcd for C 13H IO0 4: C, 67, 84 H, 4.38; Found: C, 67. 82, H, 4.37%.

8-Methyl-6-methoxy-2H -furo[2, 3-11 ][l]benzopy ran-2-one 4. 7-0-Propargyl scopoletin 3 (2.0 g 0.01 mole) was dissolved in N, N/ -diethy lani lin, (25 mL) was refluxed for 5 hr at 210 °C in oil bath The crude product was chromatographed over silic gel (ACME 200 mesh) and eluted with pet.ether benzene(2:8) to give 4, m.p. 169°C (0.80 g, yielt 68%); UY (MeOH) (log E) : 340nm (3.77), 304 (3 .99; 251(4.52),219 (4.54); IR (KBr): 1715 cm·l; IH NMf (CDCI3, 300 MHz): 82.58 (s, I H, =Cg-H), 6.72 (b ~

NOTES 861

IH, Cs-H), 6.35(d, J=IO.O Hz, C3-H), 7.70(d, J=IO.0 Hz, 3.90(s, 3H, -OCH3), MS mlz (%) 230(100), 202(35), 159(38). Anal. Calcd for CI3H 1004: C, 67.84, H, 4.38; Found: C, 67.83, H, 4.36%.

7 -Allyloxyscopoletin (7 -allyloxy-6-methoxycou­marin) 5. Scopoletin 2 (2.52 g, 0.01 mole) and allyl bromide (2.64 g, 0.001 mole) were dissolved in dry acetone (150 mL) and retluxed over anhyd. potassium carbonate (15g) for 6 hr on steam bath. The comple­tion of the reaction was monitored by TLC. The ace­tone from the sol ution was removed under reduced pressure and crushed ice was added to the residue. The resulting product 7-0-allylscopoletin that sepa­rated was filtered, washed thoroughly with water, dried and recrystallised from benzene as colorless needles as 5, m.p. 128°C. (3.24 g, yield 98%); UY (MeOH) (log E): 210 nm (4.50), 248 (4.48), 255(4 .36),325 (3.76); IR (KBr): 3075, 1715 cm"; 'H

NMR (CDCI3, 200 MHz): 83.65 (dd, J' ·,H.2·,H=5 .7 Hz and J '·,HY,H=1.55 Hz, 2H), 5.10 (m, CrH, IH), 6.29(d, J=9 .5 Hz, C)-H), 7.60(d, J=9.5 Hz, C4-H) , 7.79 (s, IH, Cs-H), 6.79(s, IH, Cs-H), 3.98 (s, 3H, C6-

OCH3), Anal. Calcd for C'3H'204: C, 67.24, H, 5.21. Found: C, 67.26, H, 5.18%.

Oxidative cyc1ization of 8-allylscopoletin with m-CPBA: Formation of 9, 10-dihydro-9-hydroxy-6-methoxy-2H, 8H-benzo[l, 2-b;3, 4-b]dipyran-2-one 7. Equimolar amount 8-allylscopoletin 6 (0.56g, 0.002 mole) and m-chloroperoxybenzoic acid (0.36 g, 0.220 mole) were dissolved in dry benzene and re­fluxed for 9 hI'. Work-up of the reaction mixture gave a semi-solid, which was chromatographed over a col­umn of silica gel (ACME, 200 mesh) using pet.ether : ch loroform(l : I v/v) to give 7 . m.p. 194 °C (0.40 g, yield 75 %); UY (MeOH) (log E): 206 nm (3.15), 233 (3.86), 267(3.41); IR (KBr): 3450, 1700 cm" ; 'H NMR (CDC I), 200 MHz): 83.82 and 3.98 (2xdd, 2H , JSHax.sHeq=II.50 Hz, ; J SHax.9H=6 .50 Hz (JSHeq.9 H=3 .0 Hz, C-8ax; Cs-eq) 5.15(m, I H, C9-H), 2 .26(bs, I H,

C9-OH) . 8 3.27 and 3.47 (2xdd, 2H, J'OHax., oHcq=16.0 Hz; J((lHeq.911=9 .5 Hz; J 'Ollax.911=7.0 Hz, C,o-ax;CIO-eq), 6.25 (d, J=IO Hz, C)-H), 7.60(d, J=10 Hz, C4-H), 6.70 (s, IH, Cs-H), 3.90(s, 3H, C6-OCH) , MS: mlz(%) 248( I 00), 229(10), 204 (34), 220( I 5), 176(27). Anal. Calcd for C' 3H'20S: C, 62, 90, H 4.87 . Found: C, 62.90, H, 4.83 % .

Oxidative cyc1ization of 8-allylscopoletin with DDQ: Formation of 8-hydroxy-6-methoxy-2H, 8H­benzo[l, 2-b; 3, 4-b ]dipyran-2-one 8 and 6-meth­oxy-2H, 8H-benzo [1, 2-b; 3, 4-b] dipran-2, 8-dione 9. A solution of 8-allylscopoletin 6 (0.300 g, 0.004

mole) in dry benzene and DDQ (2.93g, 0.012 mole) were refluxed for 10 hr on a steam bath. A hydro­quinone that separated was filtered off and benzene solution was washed with saturated NaHS03 solution (3x200 mL) followed by water (3x200 mL), dried over anhydr. Na2S04 and the solvent was removed under reduced pressure. The resulting residue on chromatographic purification over sil ica gel (ACME, 200mesh) by elution with chloroform: ethyl ace­tate(7:3 v/v) afforded 8, m.p. 214 °C (0.08 g, yield 40%) and subsequent elution with chloroform: ethyl acetate (6:4v/v) furnished 9, m.p. 234 °C (0.02 g, yield 15%).

8: UY(MeOH)(log E):216nm (4.99), 223 (3.83), 255(3.59), 347(3.65); IR(KBr):3075, 1715 cm"; 'H

NMR (CDCI3, 200 MHz) : 8 7.35(d, I H, (J IOH.9H= 10Hz,CIO-H), 6.07(dd, IH , J9H . '0I~=10Hz; J 91-1 .S H=3Hz, C9-H), 5.78(d, 1 H, J SH.9H=3 .0Hz, Cs-H), 3.55(s.1 H, C9-OH), 6.32(d, J=1O Hz, C3-H), 7.64(d, J=IO Hz, C4-

H), 6.86 (s, I H, Cs-H), 3.95(s, 3H, C6-OCH) , MS: mlz (%) 246(10), 218(15) Anal. Calcd for C' 3H IOOS: C, 63.42, H, 4.09. Found: C, 63.41, H, 4.06%.

9: UY MeOH (log E): 206 nm (3.66), 273 (3 .66), 344 (4.00), IR (KB r): 1725, 1720 cm"; 'H NMR (CDCI), 200 MHz) : 87 .25(d, IH, J=10Hz, C4-H or Cw-H), 6.90 (d, IH, J=10Hz, C3-H or C9,H) 7.65 (d, IH, J=IOHz, C IO,H or C4,H), 6.28(d, IH, J=IOHz, C9-H or C3-H), 3.98(s, 3H, C6-OCH3); MS: mlz (%) 244(25), 216(18), 186(35), Anal. Calcd for C I3 HS0 5: C, 63.92, H, 3.30. Found: C, 63.93, H, 3.27%.

Acknowledgement We thank Department of Environment and Forests ,

New Delhi and Special Assistance Program, UGC, New Delhi for financial assistance. One of the au­thors, K.N. thanks the Director, nCT, Hyderabad for encouragement.

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862 IND IAN J. CHEM., SEC S, APRIL 2002

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