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European	Journal	of	Chemistry	2	(1)	(2011)	117‐119	

	
European	Journal	of	Chemistry	

ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2011	EURJCHEM	
DOI:10.5155/eurjchem.2.1.117‐119.201	

	
	

	

	

European	Journal	of	Chemistry	
Journal	homepage:	www.eurjchem.com	

	 	 	

Synthesis	of	8‐hydroxy‐6‐methoxy‐3‐pentyl‐1H‐isochromen‐1‐one	
from	Tessmannia	densiflora	

Aamer	Saeed	

Department	of	Chemistry,	Quaid‐I‐Azam	University,	Islamabad,	PK‐45320,	Pakistan	

Corresponding	author	at: Department	of	Chemistry,	Quaid‐I‐Azam	University,	Islamabad,	PK‐45320,	Pakistan.	Tel.:	+92.51.90642128;	fax:	+92.51.90642241.	
E‐mail	address:	aamersaeed@yahoo.com	(A.	Saeed).	

	
	

	 	

	 	 	
COMMUNICATION	INFORMATION	 	 ABSTRACT
Received:	08	July	2010	
Received	in	revised	form:	05	September	2010	
Accepted:	18	October	2010	
Online:	31	March	2011	

KEYWORDS	

	 The	 synthesis	 of	 8‐hydroxy‐6‐methoxy‐3‐pentyl‐1H‐isochromen‐1‐one	 (1)	 isolated	 from	 the
stem	and	root	bark	extracts	of	Tessmannia	densiflora	has	been	described.	The	reaction	of	3,5‐
dimethoxyhomophthalic	 anhydride	 (2)	 with	 hexanoyl	 chloride	 in	 the	 presence	 of	 1,1,3,3‐
tetramethylguanidine	 and	 triethylamine	 afforded	 6,8‐dimethoxy‐3‐pentylisocoumarin	 (3).
Regioselective	demethylation	of	the	latter	using	anhydrous	aluminum	chloride	furnished	the
title	isocoumarin	(1).	

Isocoumarin	
Tessmannia	densiflora	
3,5‐Dimethoxyhomophthalic	acid	
Antimalarial	
3,5‐Dimethoxyhomophthalic	anhydride		
Mechanism	

	
1.	Introduction	
	

Isocoumarins	 (1H‐2‐benzopyran‐1‐ones)	 are	 natural	
lactones	that	are	isolated	from	a	wide	range	of	natural	sources	
(microbes,	plant,	and	insects)	and	possess	an	array	of	biological	
activities	 including	 nephratoxic,	 hepatotoxic,	 protease	
inhibitory,	 antifungal,	 cytotoxic,	 immunomodulatory,	
antiallergic,	and	antimalarial	activities	 [1‐6].	 Isocoumarins	are	
isomeric	 to	 coumarins	with	 an	 inverted	 lactone	 ring.	 	Most	of	
the	 natural	 isocoumarins	 posses	 a	 3‐alkyl	 (C1‐C17)	 or	 a	
substituted	 3‐phenyl	 ring	 and	 6,8‐dioxygenation	 due	 to	 their	
typical	biosynthetic	origin	[7].	

During	 investigations	 for	 botanical	 insecticides	 for	 the	
control	of	malaria‐transmitting	Anopheles	gambiae	mosquitoes,	
Nkunya	 and	 coworkers	 [8]	 isolated	 a	 number	 of	 compounds	
from	the	stem	and	root	bark	extracts	of	Tessmannia	densiflora	
Harms	 (family	 Caesalpiniaceae)	 that	 showed	 mosquito	
larvicidal	 activity.	 The	 isolated	 compounds	were	 identified	 as	
nor‐halimane	 diterpenoid	 tessmannic	 acid	 and	 its	 methyl,	 2‐
methylisopropyl	and	1‐methylbutylesters,	5‐pentyl‐3‐methoxy‐
N‐butylaniline,	 and	 two	 unusual	 isocoumarins.	 The	 structures	
of	the	new	isocoumarins	were	established	unambiguously	as	8‐
hydroxy‐6‐methoxy‐3‐pentyl‐1H‐isochromen‐1‐one	 (Figure	 1)	
and	 7‐chloro‐8‐hydroxy‐6‐methoxy‐3‐pentylisocoumarin,	 res‐
pectively,	by	analysis	of	spectroscopic	data	[8].	

As	 a	 continuance	 of	 our	 focusing	 on	 the	 synthesis,	
characterization,	 crystal	 structure,	 and	 bioevaluation	 of	 this	
important	class	of	 secondary	metabolites	 [9‐14],	a	 simple	and	
efficient	 synthesis	of	 the	 title	 compound	was	undertaken.	The	
structural	 simplicity,	 coupled	 with	 the	 bioactivity	 associated	
with	 this	molecule,	makes	 it	an	attractive	 target	 for	synthesis.	
The	synthesis	not	only	confirms	the	structural	assignment	but	
also	 make	 it	 accessible	 for	 comprehensive	 evaluation	 of	 its	
bioactivity.	

 

	
	

Figure	1.	Isocoumarin	(8‐hydroxy‐6‐methoxy‐3‐pentyl‐1H‐isochromen‐1‐
one)	from	Tessmannia	densiflora.	
	
2.	Experimental		
	
2.1.	Instrumentation	
	

Melting	 points	 were	 recorded	 using	 a	 digital	 Gallenkamp	
(SANYO)	model	MPD	BM	3.5	apparatus	and	are	uncorrected.	1H	
NMR	and	13C	NMR	spectra	were	determined	in	CDCl3	solutions	
at	 300	MHz	 and	75	MHz	 respectively	 using	 a	Bruker	AM‐300	
spectrophotometer.	FT‐IR	spectra	were	recorded	using	an	FTS	
3000	MX	spectrophotometer,	Mass	spectra	(EI,	70	eV)	on	a	GC‐
MS	instrument	and	elemental	analyses	with	a	LECO‐183	CHNS	
analyzer.	 All	 compounds	 were	 purified	 by	 thick	 layer	
chromatography	 using	 silica	 gel	 from	 Merck	 (Darmstadt,	
Germany).	
	
2.2.	Synthesis	
	
2.2.1.	6,8‐Dimethoxy‐3‐pentylisocoumarin	(3)	
	

A	solution	of	3,5‐dimethoxyhomophthalic	anhydride	(2,	1.0	
g,	 4.50	mmol)	 in	 acetonitrile	 (30	mL)	was	 added	 slowly	 to	 a	
solution	of	1,1,3,3‐tetramethylguanidine	(TMG)	(0.62	mL,	4.95	
mmol)	 in	 acetonitrile	 (12	mL),	while	maintaining	 the	 internal	
temperature	 ≤0	 °C.	 Triethylamine	 (1.0	 mL,	 9.0	 mmol)	 was	



118	 Saeed	/	European	Journal	of	Chemistry	2	(1)	(2011)	117‐119	
	
added	 in	 a	 single	 portion	 followed	 by	 dropwise	 addition	 of	
hexanoyl	chloride	(1.23	mL,	7.20	mmol).	The	reaction	mixture	
was	further	stirred	for	20	minutes,	allowed	to	warm	to	ambient	
temperature	 and	 then	 quenched	 by	 addition	 of	 1	 M	 HCl	 (15	
mL).	The	organic	 layer	was	 separated,	washed	with	 saturated	
brine	 dried	 and	 concentrated.	 The	 crude	 compound	 was	
purified	 by	 thick	 layer	 chromatography	 followed	 by	
recrystallization	from	methanol	to	yield	isocoumarin	3	(0.42	g,	
1.53	mmol,	74	%)	(Scheme	1).	As	a	colorless	oil;	IR	(KBr,	ν,	cm‐

1):	2913,	2849,	1722,	1605,	1575,	1510,	860,	835,	810.	1H	NMR	
(CDCl3,	,	ppm):	0.88	(t,	J=7.12	Hz,	3H,	H‐5’),	1.30	(m,	2H,	H‐4’),	
1.35	 (quin,	 J=3.5	Hz,	2H,	H‐3’),	1.67	 (quin,	 J=3.5	Hz,	2H,	H‐2’),	
2.47	(2H,	t,	J=7.1	Hz,	H‐1’),	3.85	(s,	3H,	MeO),	3.95	(s,	3H,	MeO),	
6.09	(s,	1H,	H	4),	6.39	(d,	J=2.2	Hz,	1H,	H‐7),	6.47	(d,	J=2.1	Hz,	
1H,	 H‐5).	 13C	 NMR	 (CDCl3,	 ,	 ppm):	 168.1	 (C=O),	 167.3	 (C6),	
163.7	 (C8),	 159.6	 (C3),	 141.8	 (C9),	 103.4	 (C4),	 102.2	 (	 C5),	
100.9	 (	 C7),	 99.9	 (	 C10),	 55.3	 (MeO),	 56.6	 (MeO),	 33.3	 (C1'),	
31.1	(C3'),	26.4	(C2'),	22.3	(C4'),	14.1	(C5').	MS	(m/z):	276	(16),	
219	 (18),	 206	 (52),	 191	 (15),	 177	 (27),	 165	 (14),	 164	 (98).	
Anal.	Calcd.	 for	C16H20O4:	C,	69.54;	H,	7.30.	Found:	C,	69.71;	H,	
7.15.	

	

	
Scheme	1	

	
2.2.2.	6‐Methoxy‐8‐hydroxy‐3‐pentylisocoumarin	(1)	
	

Aluminum	 chloride	 (0.83	 g,	 6.24	 mmol)	 was	 added	 to	 a	
stirred	solution	of	3	(0.35	g,	1.26	mmol)	in	freshly	distilled	dry	
nitrobenzene	(10	mL).	The	reaction	mixture	was	stirred	at	50‐
60	°C	for	6	h,	then	poured	into	ice	water	and	acidified	with	0.5	
N	 HCl.	 The	 acidic	 solution	 was	 extracted	 with	 diethyl	 ether	
(3x50	mL)	 and	 stirred	 for	 10	min.	 The	 layers	were	 separated	
and	 the	 aqueous	 layer	 extracted	with	 dichloromethane	 (2x50	
mL)	and	then	the	combined	organic	extracts	washed	with	2.5	M	
NaOH	(2x60	mL).	The	basic	solution	was	extracted	with	diethyl	
ether,	acidified	and	again	extracted	with	diethyl	ether.	The	last	
extract	 was	 evaporated	 and	 residue	 purified	 by	 thick	 layer	
chromatography	(petroleum	ether:ethyl	acetate	(8:2))	to	afford	
(1)	(0.20	g,	0.8	mmol,	62%).	M.p.:	76‐78	°C	(Lit.	[8]:	79‐80	°C).	
1H	NMR	(CDCl3,	,	ppm):	0.89	(t,	J=7.12	Hz,	3H,	H‐5’),	1.31	(m,	
2H,	H‐4’),	1.39	 (quin,	 J=3.5	Hz,	2H,	H‐3’),	1.68	 (quin,	 J=3.5	Hz,	
2H,	H‐2’),	2.49	(t,	J=7.61	Hz,	3H,	H‐1’),	3.85	(s,	3H,	MeO),	6.18	(s,	
1H,	H	4),		6.39	(d,	J=2.2	Hz,	1H,	H	7),	6.47	(d,	J=2.2	Hz,	1H,	H5),	
11.2	(1H,	br	s,	OH).	13C	NMR	(CDCl3,	,	ppm):	164.4	(C=O),	163.7	
(C8),	163.3	(C6),	159.7	(C3),	142.4	(C9),	103.1	(C4),	102.9	(C5),	
100.3	(C7),	98.7	(C10),	56.3	(MeO),	33.3	(C1'),	31.1	(C3'),	26.4	
(C2'),	22.3	(C4'),	13.9	(C5').	MS	(m/z):	262	(37),	206	(52),	191	
(15),	177	(27),	164	(100),	149	(29).	Anal.	Calcd.	for	C15H18O4:	C,	
68.68;	H,	6.92;	found	C,	68.12;	H,	7.01.	
	
3.	Results	and	discussion	
	

3,5‐Dimethoxyhomophthalic	 acid	 [15]	 was	 efficiently	
converted	 into	corresponding	anhydride	 (2)	by	refluxing	with	
acetic	anhydride	in	dry	toluene.	The	anhydride	2	in	acetonitrile	
was	added	to	a	solution	of	1,1,3,3‐tetramethyl	guanidine	(TMG)	
in	 the	 same	 solvent	 at	 0	 °C	 followed	 by	 addition	 of	
triethylamine	 [16].	 Treatment	 of	 the	 reaction	 mixture	 with	

hexanoyl	 chloride	 furnished	 the	 6,8‐dimethoxy‐3‐pentyl‐
isocoumarin	 (3)	 in	 74%	 yield.	 Isocoumarin	 3	 exhibited	 the	
characteristic	 singlet	 for	 H‐4	 olefinic	 proton	 at	 6.09	 ppm,	 the	
triplet	for	H‐1’	at	2.46	ppm	(J=7.1	Hz)	and	the	carbon	signals	at	
103.5	 (C‐4)	 and	 159.3	 (C‐3)	 and	 168.1	 (C=O)	 ppm.	 The	 δ‐
lactonic	 carbonyl	 stretching	 in	 the	 IR	 spectrum	 appeared	 at	
1725	 cm‐1.	 The	 construction	 of	 isocoumarin	 3	 from	 the	
anhydride	2	may	be	visualized	by	the	loss	of	a	benzylic	proton	
to	 base	 to	 afford	 the	 resonance	 stabilized	 anionic	 species	 (2a	
and	 2b),	 which	 attacks	 the	 hexanoyl	 chloride	 to	 give	 the	 4‐
hexanoyl‐6,8‐dimethoxyisochroman‐1,3‐dione	 intermediate	 I.	
Loss	of	proton	to	the	base	affords	the	species	II	a,	b,	which	upon	
intramolecular	O‐acylation	 furnishes	 the	 tricyclic	 intermediate	
III,	 which	 under	 basic	 influence	 undergoes	 ring	 opening	 to	
afford	 IV.	 Decarboxylation	 followed	 by	 isomerization	 of	 the	
latter	provided	the	isocoumarin	3	(Scheme	2).	

	

 
	

Scheme	2	
		
The	 C‐8	 methoxyl	 in	 6,8‐dimethoxy‐3‐methylisocoumarin	

(3)	 was	 regioselectively	 demethylated	 using	 anhydrous	
aluminum	 chloride	 in	 dry	 nitrobenzene	 [17‐18],	 due	 to	
hydrogen	bonding	of	the	resulting	hydroxyl	with	the	periplanar	
lactonic	 carbonyl	 to	 yield	 the	 8‐hydroxy‐6‐methoxy‐3‐
pentylisocoumarin	(1).	In	addition	to	the	disappearance	of	the	
C‐8	methoxy	group	at	3.95	ppm,	 the	downfield	shift	of	 singlet	
for	H‐4	and	the	triplet	for	H‐1’	to	6.15	and	2.48	ppm	(J=7.6	Hz),	
respectively,	 was	 detected.	 A	 similar	 shift	 for	 C‐4	 and	 C‐3	
(104.0	 and	 156.2	 ppm,	 respectively)	 was	 also	 noted.	 The	
lactonic	carbonyl	absorption	was	also	lowered	to	1685	cm‐1	due	
to	chelation	with	C‐8	hydroxyl	which	appeared	at	11.2	ppm.	

	
4.	Conclusion	
	

An	 efficient	 synthesis	 of	 a	 natural	 isocoumarin	 has	 been	
achieved.	A	likely	pathway	for	formation	of	isocoumarin	3	from	
anhydride	2	has	also	been	proposed.	
	
Acknowledgement	
	

The	author	gratefully	acknowledges	a	research	grant	 from	
the	Higher	Education	Commission	of	Pakistan	under	project	No.	
20‐Miscel/R&D/00/3834.	
	
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