untitled


European	Journal	of	Chemistry	8	(4)	(2017)	417‐421	

	

European	Journal	of	Chemistry	
ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2017	Atlanta	Publishing	House	LLC	‐	All	rights	reserved	‐	Printed	in	the	USA	

http://dx.doi.org/10.5155/eurjchem.8.4.417-421.1659 

	
	

	

	

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

	 	 	

Reactions	of	5‐(4‐methoxy‐3‐methylphenyl)‐2(3H)‐furanone		
with	some	electrophilic	and	nucleophilic	reagents	

Mohamed	Helmy	Abd	El‐hamied	Soliman	and	Sahar	Said	Ahmed	El‐Sakka	*	

Chemistry	Department,	Faculty	of	Science,	Suez	University,	Suez,	43527,	Egypt	

*	Corresponding	author	at:	Chemistry	Department,	Faculty	of	Science,	Suez	University,	Suez,	43527,	Egypt.		
Tel.:	+20.100.6054033.	Fax:	+20.62.3707040.	E‐mail	address:	sahar.alsakka@suezuniv.edu.eg	(S.S.A.	El‐Sakka).	

	
	

	 	

	 	 	

ARTICLE	INFORMATION	 	 ABSTRACT	

	
DOI: 10.5155/eurjchem.8.4.417-421.1659	

Received:	11	October	2017	
Received	in	revised	form:	02	November	2017	
Accepted:	05	November	2017	
Published	online:	31	December	2017	
Printed:	31	December	2017

 

	 5‐(4‐Methoxy‐3‐methylphenyl)‐2(3H)‐furanone	 was	 prepared	 and	 reacted	 with	 some
nucleophilic	 and	 electrophilic	 reagents.	 The	 condensation	 of	 furanone	 with	 aromatic
aldehydes	or	phthalic	anhydride	yielded	the	corresponding	3‐arylidenefuranone	derivatives
and	 phthalide,	 respectively.	 While	 the	 treatment	 of	 furanone	 with	 amines	 in	 refluxing
ethanol	 led	 to	 the	 formation	 of	 amides.	 The	 reaction	 of	 the	 amides	 with	 thionyl	 chloride
afforded	 the	corresponding	 isothiazolones.	The	benzimidazole	derivative	was	prepared	via
the	 reaction	 of	 the	 2(3H)‐furanone	with	 o‐phenylenediamine	 in	 boiling	 ethanol.	 However,
hydrazine	 hydrate	 affected	 ring	 opening	 of	 furanone	 to	 give	 the	 corresponding	 acid
hydrazide,	 which	 underwent	 in	 situ	 cyclization	 into	 the	 corresponding	 pyridazinone.	 The
base	catalyzed	ethanolysis	of	furanone	afforded	the	corresponding	ethyl	ester.	

KEYWORDS	
Isothiazolone		
Pyridazinone		
2(3H)‐Furanone	
4‐Oxobutanamide	
o‐Phenylenediamine	
Condensation	reaction	

Cite	this: Eur.	J.	Chem.	2017,	8(4),	417‐421

	
1.	Introduction	
	

The	furanone	ring	system	has	a	wide	range	of	 interesting	
biological	activities	 in	addition	of	being	recognized	as	a	com‐
ponent	 of	 natural	 products.	 Compounds	 incorporating	 such	
heterocycles	 in	 their	 structure	 have	 been	 found	 to	 display	
broad	 spectrum	 of	 biological	 activities	 including	 anti‐inflam‐
matory	[1‐3],	cardiotonic	activity	[4],	analgesic	[5],	anticancer	
[6],	anti‐convulsant	[7],	anti‐microbial	[8]	and	antiviral	active‐
ties	[9].		

It	is	well	known	that	the	hydrogen	atoms	of	the	CH2	group	
in	2(3H)‐furanone	are	reactive	and	by	virtue	of	this	reactivity,	
the	 substance	 so	 readily	 undergoes	 condensation	 with	 alde‐
hydes	and	ketones	[10].	Besides	their	reactivity	towards	alde‐
hydes	and	ketones,	 the	ester	moiety	of	 these	compounds	 is	a	
favorable	unit	for	nucleophilic	attack	that	give	acyclic	products	
which	 on	 recyclization	 can	 afford	 other	 heterocyclic	 systems	
[9,11,12].	

In	continuation	of	our	previous	studies	on	the	application	
of	 keto	 acids	 in	 the	 synthesis	 of	 different	 heterocyclic	 com‐
pounds	[13,14],	the	present	study	describes	the	synthesis	of	5‐
(4‐methoxy‐3‐methylphenyl)‐2(3H)‐furanone	(2)	 (via	 the	 lac‐
tonization	 of	 the	 4‐(4‐methoxy‐3‐methylphenyl)‐4‐oxobuta‐
noic	 acid	 [15]	 and	 its	 reactivity	 towards	 nucleophilic	 and	
electrophilic	 reagents.	 Elemental	 analysis,	 IR,	 1H	 NMR,	 13C	

NMR	 and	 MS	 spectral	 data	 were	 obtained	 to	 determine	 the	
structure	of	the	new	synthesized	compounds.	
	
2.	Experimental	
	
2.1.	Instrumentation	

	
All	 melting	 points	 reported	 are	 uncorrected	 and	

determined	by	the	open	capillary	tube	method	on	a	Buchi	510	
melting	point	 apparatus.	Elemental	 analyses	were	performed	
on	a	 flash	EA‐1112	instrument.	 1H	NMR	spectra	were	measu‐
red	 on	 Bruker	 (300	MHz)	 instrument	 and	 TMS	was	 used	 as	
internal	 standard.	 IR	 spectra	 were	 recorded	 on	 a	 Perking	
Elmer	1430	 ratio	 recording	 infrared	 spectrophotometer	with	
CDS	 data	 station	 using	 KBr	 Wafer	 technique.	 Mass	 spectra	
were	 measured	 on	 a	 GC‐MSQP	 1000EX	 Shimadzu	 at	 Micro‐
Analytical	Laboratory,	Cairo	University,	Cairo,	Egypt.		

	
2.2.	Synthesis		
	
2.2.1.	Synthesis	of	5‐[4‐methoxy‐3‐methylphenyl]‐2(3H)‐
furanone	(2)	
	

A	 mixture	 of	 4‐[4‐methoxy‐3‐methylphenyl]‐4‐oxo‐
butanoic	acid	(1)	(0.01	mole)	and	acetic	anhydride	(3	mL)	in		



418	 Soliman	and	El‐Sakka	/	European	Journal	of	Chemistry	8	(4)	(2017)	417‐421	
	
	

	
	
Conditions:	(i)	aromatic	aldehydes,	sodium	acetate,	acetic	anhydride;	(ii)	phthalic	anhydride,	sodium	acetate,	acetic	anhydride;	(iii)	amines,	ethanol;	(iv)	thionyl	
chloride,	stirring;	(v)	o‐phenylenediamine,	ethanol;	(vi)	hydrazine	hydrate,	ethanol;	(vii)	sodium	ethoxide,	ethanol.	
	

Scheme	1	
	
	
20	mL	 toluene	was	heated	 under	 reflux	 for	 1	 h,	 the	 reaction	
was	then	cooled,	the	solid	product	obtained	after	cooling	was	
collected	by	 filtration	and	 recrystallized	 from	ethanol	 to	 give	
compound	2	[15].	
	
2.2.2.	Synthesis	of	3‐arylidene‐5‐[4‐methoxy‐3‐methyl	
phenyl]‐2(3H)‐furanone	(3a‐f)	and	phthalal	(4)	
	

To	 a	 solution	 of	 5‐[4‐methoxy‐3‐methylphenyl]‐2(3H)‐
furanone	 (2)	 (0.01	 mole)	 in	 acetic	 anhydride	 (10	 mL),	 we	
added	the	respective	aromatic	aldehyde,	or	phthalic	anhydride	
(0.01	mole)	 and	 anhydrous	 sodium	 acetate	 (0.01	mole).	 The	
reaction	 mixture	 was	 heated	 under	 reflux	 for	 2	 h,	 the	 solid	
product	 that	 separated	 after	 cooling	 was	 filtered	 off	 and	
crystallized	from	the	proper	solvent	to	give	the	title	products	
(Scheme	1).	

3‐Benzylidene‐5‐[4‐methoxy‐3‐methylphenyl]‐2(3H)‐furano	
ne	 (3a):	 Color:	 Yellow.	 Yield:	 68%.	 M.p.:	 171‐173	 °C.	 FT‐IR	
(KBr,	,	 cm‐1):	1754	ν(C=O),	1610	ν(C=C).	 1H	NMR	(300	MHz,	
DMSO‐d6,	δ,	ppm):	2.26	(s,	3H,	CH3Ar),	3.89	(s,	3H,	OCH3),	6.79‐
7.64	(m,	10H,	Ar‐H	and	CH	olefinic).	Anal.	calcd.	 for	C19H16O3:	
C,	78.06;	H,	5.52.	Found:	C,	78.31;	H:	5.27	%.	

3‐(4‐Methoxybenzylidene)‐5‐[4‐methoxy‐3‐methylphenyl]‐2	
(3H)‐furanone	 (3b):	 Color:	 Yellow.	 Yield:	 64%.	M.p.:	 182‐183	
°C.	 FT‐IR	 (KBr,	 ,	 cm‐1):	 1769	 ν(C=O),	 1603	 ν(C=C).	 1H	 NMR	
(300	MHz,	DMSO‐d6,	δ,	ppm):	2.27	(s,	3H,	CH3Ar),	3.88	(s,	3H,	
OCH3),	 3.89	 (s,	 3H,	 OCH3),	 6.77‐7.63	 (m,	 9H,	 Ar‐H	 and	 CH	

olefinic).	Anal.	calcd.	 for	C20H18O4:	C,	74.52;	H,	5.63.	Found:	C,	
74.67;	H,	5.39%.	

3‐(4‐Chlorobenzylidene)‐5‐[4‐methoxy‐3‐methylphenyl]‐2	
(3H)‐furanone	 (3c):	 Color:	 Yellow.	 Yield:	 80%.	M.p.:	 203‐205	
°C.	 FT‐IR	 (KBr,	 ,	 cm‐1):	 1782	 ν(C=O),	 1594	 ν(C=C).	 1H	 NMR	
(300	MHz,	DMSO‐d6,	δ,	ppm):	2.27	(s,	3H,	CH3Ar),	3.90	(s,	3H,	
OCH3),	6.74‐7.60	(m,	9H,	Ar‐H	and	CH	olefinic).	Anal.	calcd.	for	
C19H15ClO3:	C,	69.84;	H,	4.63.	Found:	C,	69.53;	H,	4.76%.	

3‐(4‐Formylbenzylidene)‐5‐[4‐methoxy‐3‐methylphenyl]‐2	
(3H)‐furanone	 (3d):	Color:	Orange.	Yield:	83%.	M.p.:	283‐285	
°C.	 FT‐IR	 (KBr,	 ,	 cm‐1):	 1768	 ν(C=O),	 1694	 ν(C=O).	 1H	NMR	
(300	MHz,	DMSO‐d6,	δ,	ppm):	2.33	(s,	3H,	CH3Ar),	3.91	(s,	3H,	
OCH3),	 6.80‐7.97(m,	 9H,	 Ar‐H	 and	 CH	 olefinic),	 10.06	 (s,	 1H,	
CHO).	 Anal.	 calcd.	 for	 C20H16O4:	 C,	 74.99;	 H,	 5.03.	 Found:	 C,	
74.73;	H,	5.31%.	

3‐Furfurylidene‐5‐[4‐methoxy‐3‐methylphenyl]‐2(3H)‐fura	
none	 (3e):	Color:	Yellow.	Yield:	71%.	M.p.:	 199‐200	 °C.	FT‐IR	
(KBr,	,	 cm‐1):	1774	ν(C=O),	1626	ν(C=C).	 1H	NMR	(300	MHz,	
DMSO‐d6,	δ,	ppm):	2.27	(s,	3H,	CH3Ar),	3.89	(s,	3H,	OCH3),	6.57‐
7.67	 (m,	 8H,	 Ar‐H	 and	 CH	 olefinic).	 MS	 (EI,	m/z	 (%)):	 282	
(58.5%)	 (M+).	 Anal.	 calcd.	 for	 C17H14O4	 (282.29):	 C,	 72.33;	H,	
5.00.	Found:	C,	72.51;	H,	4.85	%.	

3‐Cinnamylidene‐5‐[4‐methoxy‐3‐methylphenyl]‐2(3H)‐fura	
none	 (3f):	Color:	Orange.	Yield:	69%.	M.p.:	 184‐186	 °C.	FT‐IR	
(KBr,	,	 cm‐1):	1767	ν(C=O),	1612	ν(C=C).	 1H	NMR	(300	MHz,	
DMSO‐d6,	δ,	ppm):	2.26	(s,	3H,	CH3Ar),	3.89	(s,	3H,	OCH3),	6.61‐
7.59	 (m,	 12H,	 Ar‐H	 and	 CH	 olefinic).	 MS	 (EI,	m/z	 (%)):	 318	



Soliman	and	El‐Sakka	/	European	Journal	of	Chemistry	8	(4)	(2017)	417‐421	 419	
 

(42.9%,	M+).	Anal.	calcd.	for	C21H18O3:	C,	79.23;	H,	5.70.	Found:	
C,	79.57;	H,	5.49%.		

3‐[5‐(4‐Methoxy‐3‐methylphenyl)‐2‐oxo‐furylidene]phthalal	
(4):	Color:	Red.	Yield:	71%.	M.p.:	270‐272	°C.	FT‐IR	(KBr,	,	cm‐

1):	1772	ν(C=O),	1639	ν(C=C).	1H	NMR	(300	MHz,	DMSO‐d6,	δ,	
ppm):	2.27	(s,	3H,	CH3Ar),	3.90	(s,	3H,	OCH3),	6.76‐7.86	(m,	8H,	
Ar‐H).	 MS	 (EI,	 m/z	 (%)):	 334	 (30.6%,	 M+).	 Anal.	 calcd.	 for	
C20H14O5:	C,	71.85;	H,	4.22.	Found:	C,	71.63;	H,	4.04%.	
	
2.2.3.	Alternative	preparation	of	compound	3a‐f		
	

To	 a	 mixture	 of	 4‐[4‐methoxy‐3‐methylphenyl]‐4‐oxo‐
butanoic	acid	(1)	(0.01	mole)	and	freshly	fused	sodium	acetate	
(0.01	mole),	aromatic	aldehyde	(0.01	mole)	and	3.0	mL	acetic	
anhydride	were	added.	The	reaction	mixture	was	heated	on	a	
hot	plate	whereby	a	clear	solution	was	obtained.	Heating	was	
continued,	on	a	steam‐bath	till	a	solid	separated	out.	The	solid	
obtained	 was	 filtered	 off,	 washed	 with	 hot‐water	 and	 then	
recrystallized	from	the	suitable	solvent.		
	
2.2.4.	General	procedure	for	the	synthesis	of	N‐substituted‐
4‐[4‐methoxy‐3‐methylphenyl]‐4‐oxo‐butanamide	(5a‐g)	
	

To	 a	 solution	 of	 the	 furanone	 (2)	 (0.01	 mole)	 in	 30	 mL	
ethanol,	 amine	 (0.02	 mole)	 was	 added	 dropwise	 with	 occa‐
sional	 shaking	 whereby	 the	 color	 of	 the	 furanone	 gradually	
disappeared	 with	 the	 formation	 of	 a	 colorless	 solid.	 The	
reaction	mixture	was	heated	under	reflux	for	2	h,	during	which	
the	color	of	the	furanone	disappeared	completely.	On	cooling,	
a	 colorless	 solid	 separated	 out	 which	 was	 filtered	 off	 and	
recrystallized	from	the	suitable	solvent	(Scheme	1).	

N‐Benzyl‐4‐[4‐methoxy‐3‐methylphenyl]‐4‐oxo‐butanamide	
(5a):	Color:	White.	Yield:	78%.	M.p.:	134‐135	°C.	FT‐IR	(KBr,	,	
cm‐1):	 3239	 ν(NH),	 1677	 ν(C=O),	 1601	 ν(C=C).	 1H	NMR	 (300	
MHz,	DMSO‐d6,	δ,	ppm):	6.84‐7.88	(m,	8H,	Ar‐H),	6.15	 (b,	1H,	
N‐H),	 4.44‐4.46	 (d,	 2H,	 J	 =	 5.9,	 NH‐CH2),	 3.90	 (s,	 3H,	 OCH3),	
3.34‐3.38	(t,	2H,	J1	=	6.7,	ArCOCH2CH2CO),	2.63‐2.68	(t,	2H,	J1	=	
6.6,	 ArCOCH2CH2CO),	 2.24	 (s,	 3H,	 CH3Ar).	 13C	 NMR	 (75	MHz,	
DMSO‐d6,	 δ,	 ppm):	 197.35,	 171.29,	 161.17,	 139.61,	 130.14,	
129.08,	 128.15,	 127.11,	 126.62,	 125.67,	 109.85,	 55.63,	 42.02,	
32.94,	 29.30,	 15.97.	MS	 (EI,	m/z	 (%)):	 311	 (4.2%,	M+).	 Anal.	
calcd.	for	C19H21NO3:	C,	73.29;	H,	6.80;	N,	4.50.	Found:	C,	73.48;	
H,	6.57;	N,	4.69%.		

N‐Phenyl‐4‐[4‐methoxy‐3‐methylphenyl]‐4‐oxo‐butanamide	
(5b):	Color:	White.	Yield:	73%.	M.p.:	152‐154	°C.	FT‐IR	(KBr,	,	
cm‐1):	 3284	 ν(NH),	 1659	 ν(C=O),	 1601	 ν(C=C).	 1H	NMR	 (300	
MHz,	DMSO‐d6,	δ,	ppm):	8.4	(b,	1H,	N‐H),	6.83‐7.89	(m,	8H,	Ar‐
H),	 3.89	 (s,	 3H,	 OCH3),	 3.39‐3.43	 (t,	 2H,	 J	 =	 6.5	 Hz,	
ArCOCH2CH2CO),	2.79‐2.83	(t,	2H,	J	=	6.6	Hz,	ArCOCH2CH2CO),	
2.24	 (s,	 3H,	 CH3Ar).	 13C	 NMR	 (75	 MHz,	 DMSO‐d6,	 δ,	 ppm):	
197.28,	 170.42,	 161.23,	 139.36,	 130.16,	 129.01,	 128.61,	
128.15,	 125.70,	 122.80,	 118.82,	 109.88,	 55.64,	 32.71,	 30.38,	
15.97.	 Anal.	 calcd.	 for	 C18H19NO3:	 C,	 72.71;	 H,	 6.44;	 N,	 4.71.	
Found:	C,	72.49;	H,	6.27;	N,	4.56%.		

N‐(4‐Tolyl)‐4‐[4‐methoxy‐3‐methylphenyl]‐4‐oxo‐butanami	
de	(5c):	Color:	White.	Yield:	75%.	M.p.:	155‐156	°C.	FT‐IR	(KBr,	
,	cm‐1):	3347	ν(NH),	1669	ν(C=O),	1601	ν(C=C).	1H	NMR	(300	
MHz,	DMSO‐d6,	 δ,	 ppm):	 8.40	 (b,	 1H,	N‐H),	 6.84‐7.89	 (m,	 7H,	
Ar‐H),	 3.90	 (s,	 3H,	 OCH3),	 3.38‐3.42	 (t,	 2H,	 J	 =	 6.6	 Hz,	
ArCOCH2CH2CO),	2.77‐2.81	(t,	2H,	J	=	6.6	Hz,	ArCOCH2CH2CO),	
2.24	 (s,	 3H,	 CH3Ar),	 2.30	 (s,	 3H,	 CH3Ar).	 13C	 NMR	 (75	 MHz,	
DMSO‐d6,	 δ,	 ppm):	 197.31,	 170.14,	 161.22,	 136.87,	 131.62,	
130.16,	 129.00,	 128.14,	 125.70,	 118.84,	 109.88,	 55.63,	 32.73,	
30.32,	 20.38,	 15.97.	MS	 (EI,	m/z	 (%)):	 311	 (5.2%,	M+).	 Anal.	
calcd.	for	C19H21NO3:	C,	73.29;	H,	6.80;	N,	4.50.	Found:	C,	73.63;	
H,	6.42;	N,	4.21%.		

N‐Pentyl‐4‐[4‐methoxy‐3‐methylphenyl]‐4‐oxo‐butanamide	
(5d):	 Color:	White.	 Yield:	 77%.	M.p.:	 84‐85	 °C.	 FT‐IR	 (KBr,	,	
cm‐1):	3317	ν(NH),	1678	ν(C=O),	1650	ν(C=O),	1601	ν(C=C).	1H	
NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	7.84‐7.87	(d,	1H,	J	=	8.7	Hz,	
Ar‐H),	7.81	(s,	1H,	Ar‐H),	7.87	(s,	1H,	NH),	6.84‐6.86	(d,	1H,	J	=	

8.1	Hz,	Ar‐H),	3.90	 (s,	3H,	OCH3),	3.69‐3.74	 (t,	2H,	 J	=	6.9	Hz,	
NCH2CH2),	3.33‐3.37	(t,	2H,	J	=	6.8	Hz,	ArCOCH2CH2),	2.65‐2.69	
(t,	2H,	J	=	6.8	Hz,	ArCOCH2CH2),	2.24	(s,	3H,	CH3Ar),	0.86‐1.53	
(m,	9H,	CH3CH2CH2CH2).	13C	NMR	(75	MHz,	DMSO‐d6,	δ,	ppm):	
197.37,	 170.97,	 161.15,	 130.13,	 129.08,	 128.10,	 125.65,	
109.84,	 55.62,	 33.00,	 29.35,	 28.69,	 21.81,	 15.96,	 13.88.	 Anal.	
calcd.	for	C17H25NO3:	C,	70.07;	H,	8.65;	N,	4.81.	Found:	C,	70.34;	
H,	8.49;	N,	4.99%.		

N‐Cyclohexyl‐4‐[4‐methoxy‐3‐methylphenyl]‐4‐oxo‐butana	
mide	 (5e):	 Color:	White.	 Yield:	 75%.	M.p.:	 164‐165	 °C.	 FT‐IR	
(KBr,	,	cm‐1):	3331	ν(NH),	1676	ν(C=O),	1602	ν(C=C).	1H	NMR	
(300	MHz,	DMSO‐d6,	δ,	ppm):	7.83‐7.86	(d,	1H,	J	=	9.0	Hz,	Ar‐
H),	7.78	(s,	1H,	Ar‐H),	7.37	(s,	1H,	NH),	6.81‐6.84	(d,	1H,	J	=	8.4	
Hz,	 Ar‐H),	 3.88	 (s,	 3H,	 OCH3),	 3.19‐3.24	 (t,	 2H,	 J	 =	 6.6	 Hz,	
ArCOCH2CH2CO),	2.90‐2.94	(m,	1H,	N‐CH	of	cyclohexyl	group),	
2.60‐2.64	 (t,	 2H,	 J	 =	 6.3	 Hz,	 ArCOCH2CH2CO),	 2.23	 (s,	 3H,	
CH3Ar),	 1.12‐2.00	 (m,	 10H,	 cyclohexyl	 group).	 13C	 NMR	 (75	
MHz,	 DMSO‐d6,	 δ,	 ppm):	 197.88,	 174.58,	 161.01,	 130.11,	
129.33,	 128.04,	 125.57,	 109.80,	 55.60,	 49.37,	 33.75,	 33.34,	
30.20,	25.03,	24.21,	15.97.	MS	(EI,	m/z	(%)):	303	(0.34%,	M+).	
Anal.	calcd.	for	C18H25NO3:	C,	71.26;	H,	8.31;	N,	4.62.	Found:	C,	
71.54;	H,	8.67;	N,	4.79%.		

N‐(2‐Hydroxyphenyl)‐4‐[4‐methoxy‐3‐methylphenyl]‐4‐oxo‐
butanamide	 (5f):	 Color:	White.	 Yield:	 66%.	M.p.:	 170‐172	 °C.	
FT‐IR	 (KBr,	 ,	 cm‐1):	 3420	 ν(OH),	 3305	 ν(NH),	 1673	 ν(C=O),	
1645	 ν(C=O),	 1599	 ν	 (C=C).	 1H	 NMR	 (300	MHz,	 DMSO‐d6,	 δ,	
ppm):	8.94	 (b,	 1H,	O‐H),	 8.47	 (b,	 1H,	N‐H),	6.82‐7.88	 (m,	 7H,	
Ar‐H),	 3.90	 (s,	 3H,	 OCH3),	 3.42‐3.46	 (t,	 2H,	 J	 =	 6.5	 Hz,	
ArCOCH2CH2CO),	2.87‐2.91	(t,	2H,	J	=	6.4	Hz,	ArCOCH2CH2CO),	
2.24	 (s,	 3H,	 CH3Ar).	 13C	 NMR	 (75	 MHz,	 DMSO‐d6,	 δ,	 ppm):	
197.27,	 171.06,	 161.23,	 147.60,	 130.17,	 129.01,	 128.16,	
126.44,	125.70,	124.40,	121.99,	118.92,	115.80,	109.88,	85.22,	
55.64,	32.90,	30.14,	15.97.	Anal.	calcd.	for	C18H19NO4:	C,	69.00;	
H,	6.11;	N,	4.47.	Found:	C,	69.24;	H,	5.97;	N,	4.73%.		

N‐(2‐Hydroxyethyl)‐4‐[4‐methoxy‐3‐methylphenyl]‐4‐oxo‐
butanamide	 (5g):	 Color:	White.	 Yield:	 64%.	M.p.:	 107‐108	 °C.	
FT‐IR	 (KBr,	 ,	 cm‐1):	 3449	 ν(OH),	 3351	 ν(NH),	 1674	 ν(C=O),	
1631	 ν(C=O),	 1601	 ν(C=C).	 1H	 NMR	 (300	 MHz,	 DMSO‐d6,	 δ,	
ppm):	6.82‐7.86	(m,	4H,	Ar‐H+	NH),	6.53	(b,	1H,	OH),	3.88	(s,	
3H,	OCH3),	3.69‐3.72	(t,	2H,	 J1	=	5.1,	 J2	=	4.5	Hz,	NCH2CH2OH),	
3.40‐3.43	 (m,	 2H,	NCH2CH2OH),	 3.30‐3.35	 (t,	 2H,	 J1	=	6.9,	 J2	=	
6.3	Hz,	ArCOCH2CH2CO),	2.59‐2.63	 (t,	 2H,	 J1	=	6.6,	 J2	=	6.6	Hz,	
ArCOCH2CH2CO),	2.22	(s,	3H,	CH3Ar).	13C	NMR	(75	MHz,	DMSO‐
d6,	 δ,	 ppm):	 197.35,	 171.37,	 161.16,	 130.14,	 129.06,	 128.10,	
125.66,	109.85,	59.89,	55.62,	41.49,	32.98,	29.30,	15.96.	Anal.	
calcd.	for	C14H19NO4:	C,	63.38;	H,	7.22;	N,	5.28.	Found:	C,	63.71;	
H,	6.98;	N,	5.52%.		
	
2.2.5.	Synthesis	of	5‐[4‐methoxy‐3‐methylbenzoyl]‐2‐
(substituted)isothiazol‐3(2H)‐one	(6a‐c)	
	

Thionyl	chloride	(20	mL,	0.17	mole)	was	added	to	(0.001	
mole)	 of	 N‐substituted	 butanamide	 derivatives	 (5a‐c),	 the	
initially	 insoluble	 material	 gradually	 dissolved,	 the	 mixture	
was	 stirred	 at	 room	 temperature	 for	 4	 h.	 The	 excess	 thionyl	
chloride	 was	 then	 evaporated	 under	 vacuum.	 The	 solid	
obtainned	was	collected	by	filtration	and	recrystallized	from	a	
suitable	 solvent	 to	 give	 3(2H)‐isothiazolones	 (6a‐c)	 (Scheme	
1).	

2‐Benzyl‐5‐[4‐methoxy‐3‐methylbenzoyl]‐isothiazol‐3(2H)‐
one	 (6a):	 Color:	 Yellow.	 Yield:	 77%.	 M.p.:	 124‐125	 °C.	 FT‐IR	
(KBr,	,	 cm‐1):	1654	ν(C=O),	1622	ν(C=C).	 1H	NMR	(300	MHz,	
DMSO‐d6,	δ,	ppm):	6.89‐7.83	(m,	8H,	Ar‐H),	6.80	(s,	1H,	vinylic	
proton),	 5.01	 (s,	 2H,	 NCH2),	 3.93	 (s,	 3H,	 OCH3),	 2.26	 (s,	 3H,	
CH3Ar).	Anal.	calcd.	 for	C19H17NO3S:	C,	67.24;	H,	5.05;	N,	4.13.	
Found:	C,	67.51;	H,	5.37;	N,	4.34%.		

2‐Phenyl‐5‐[4‐methoxy‐3‐methylbenzoyl]‐isothiazol‐3(2H)‐
one	 (6b):	 Color:	 Yellow.	 Yield:	 73%.	M.p.:	 211‐213	 °C.	 FT‐IR	
(KBr,	,	 cm‐1):	1647	ν(C=O),	1613	ν(C=C).	 1H	NMR	(300	MHz,	
DMSO‐d6,	δ,	ppm):	6.93‐7.91	(m,	8H,	Ar‐H),	6.83	(s,	1H,	vinylic	
proton),	3.96	(s,	3H,	OCH3),	2.29	(s,	3H,	CH3Ar).	



420	 Soliman	and	El‐Sakka	/	European	Journal	of	Chemistry	8	(4)	(2017)	417‐421	
	

	

	
	

Figure	1.	The	cyclization	reaction	of	amides	with	thionyl	chloride.
	
	
13C	 NMR	 (75	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 185.03,	 166.10,	

162.68,	 153.82,	 136.23,	 131.69,	 130.49,	 129.49,	 127.65,	
126.84,	 124.43,	 119.67,	 110.51,	 55.96,	 15.85.	 Anal.	 calcd.	 for	
C18H15NO3S:	C,	66.44;	H,	4.65;	N,	4.30.	Found:	C,	66.50;	H,	429;	
N,	4.59%.		

2‐(4‐Tolyl)‐5‐[4‐methoxy‐3‐methylbenzoyl]‐isothiazol‐3	
(2H)‐one	(6c):	Color:	Yellow.	Yield:	78%.	M.p.:	187‐189	°C.	FT‐
IR	 (KBr,	 ,	 cm‐1):	 1652	 ν(C=O),	 1592	 ν(C=C).	 1H	 NMR	 (300	
MHz,	DMSO‐d6,	 δ,	 ppm):	6.93‐7.90	 (m,	7H,	Ar‐H),	 6.83	 (s,	 1H,	
vinylic	proton),	3.96	(s,	3H,	OCH3),	2.29	(s,	3H,	CH3Ar),	2.40	(s,	
3H,	 CH3Ar).	 13C	 NMR	 (75	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 166.07,	
162.66,	 137.33,	 133.65,	 131.67,	 130.47,	 129.87,	 126.79,	
124.42,	 119.67,	 110.51,	 55.95,	 20.59,	 15.85.	 Anal.	 calcd.	 for	
C19H17NO3S:	C,	67.24;	H,	5.05;	N,	4.13.	Found:	C,	67.34;	H,	5.29;	
N,	3.91%.		
	
2.2.6.	Reaction	of	5‐[4‐methoxy‐3‐methylphenyl]‐2(3H)‐
furanone	(2)	with	o‐phenylenediamine	
	

To	a	solution	of	the	furanone	(0.01	mole)	in	30	mL	ethanol,	
amine	 (0.01	 mole)	 was	 added	 with	 occasional	 shaking.	 The	
reaction	mixture	was	heated	under	reflux	for	4	h.	On	cooling,	a	
colorless	 solid	 separated	 out	 which	 was	 filtered	 off	 and	
recrystallized	 from	ethanol	 to	 give	2‐[2‐(4‐methoxy‐3‐methyl	
benzoyl)ethyl]benzimidazol	 (7)	 (Scheme	 1).	 Color:	 White.	
Yield:	71%.	M.p.:	192‐194	°C.	FT‐IR	(KBr,	,	cm‐1):	3303	ν(NH),	
1674	 ν(C=O),	 1624	 ν(C=C).	 1H	 NMR	 (300	 MHz,	 DMSO‐d6,	 δ,	
ppm):	 6.73‐7.87	 (m,	 8H,	 Ar‐H	 and	 NH),	 3.89	 (s,	 3H,	 OCH3),	
3.40‐3.44	(t,	2H,	J	=	6.6	Hz,	COCH2CH2CO),	2.76‐2.80	(t,	2H,	J	=	
6.9	Hz,	COCH2CH2CO),	2.24	 (s,	3H,	CH3Ar).	 13C	NMR	 (75	MHz,	
DMSO‐d6,	 δ,	 ppm):	 197.56,	 170.43,	 161.23,	 142.17,	 130.16,	
129.03,	 128.17,	 126.28,	 125.33,	 123.31,	 115.93,	 115.55,	
109.88,	55.64,	33.08,	29.81,	15.97.	Anal.	calcd.	for	C18H18N2O2:	
C,	73.45;	H,	6.16;	N,	9.52.	Found:	C,	73.68;	H,	6.35;	N,	9.34%.		
	
2.2.7.	Hydrazinolysis	of	5‐[4‐methoxy‐3‐methylphenyl]‐2	
(3H)‐furanone		
	

To	 a	 solution	 of	 furanone	 (2)	 (0.01	mole)	 in	 ethanol	 (20	
mL),	 hydrazine	 hydrate	 (0.012	 mole)	 was	 added	 and	 the	
reaction	 mixture	 was	 heated	 under	 reflux	 for	 4	 h.	 The	
precipitate	 that	 formed	after	 cooling	was	 filtered	off,	washed	
with	cooled	ethanol	and	crystallized	from	ethanol	to	give	6‐[4‐
methoxy‐3‐methylphenyl]‐4,	 5‐dihydro‐3(2H)‐pyridazinone	
(8)	(Scheme	1).	Color:	White.	Yield:	67%.	M.p.:	152‐153	°C.	FT‐
IR	 (KBr,	 ,	 cm‐1):	 3200	 ν(NH),	 2923	 ν(CH,	 aliphatic),	 1659	
ν(C=O).	 1H	NMR	(300	MHz,	CDCl3,	 δ,	 ppm):	6.78‐7.59	 (m,	4H,	
Ar‐H	and	NH),	3.89	(s,	3H,	CH3O),	2.86‐2.88	(t,	2H,	J	=	6.6	Hz,	H‐
4	pyridazine),	2.47‐2.54	(t,	2H,	J	=	6.6	Hz,	H‐5	pyridazine),	2.15	
(s,	 3H,	 CH3).	 Anal.	 calcd.	 for	 C12H14N2O2:	 C,	 66.04;	H,	 6.47;	N,	
12.84.	Found:	C,	66.15;	H,	6.41;	N,	12.79%.	
	
2.2.8.	Base	catalyzed	ethanolysis	of	5‐[4‐methoxy‐3‐methyl	
phenyl]‐2(3H)‐furanone	
	

A	mixture	of	2.0	g	of	 the	furanone	(2)	and	20	mL	sodium	
ethoxide	 (prepared	 from	 0.3	 g	 sodium	 and	 20	 mL	 absolute	
ethanol)	 was	 heated	 under	 reflux	 for	 3	 h.	 After	 cooling,	 the	

reaction	mixture	was	neutralized	with	10%	HCl	to	give	a	white	
precipitate.	 The	 product	 obtained	 was	 crystallized	 from	
ethanol	 to	 give	 ethyl	 4‐[4‐methoxy‐3‐methylphenyl]‐4‐oxo‐
butanoate	(9)	(Scheme	1).	Color:	White.	Yield:	63%.	M.p.:	110‐
111	°C.	FT‐IR	(KBr,	,	cm‐1):	1723	ν(C=O),	1669	ν(C=O),	1600	
ν(C=C).	 1H	 NMR	 (300	MHz,	 DMSO‐d6,	 δ,	 ppm):	 6.84‐7.87	 (m,	
3H,	 Ar‐H),	 4.13‐4.20	 (q,	 2H,	 J	=	 7.2	 Hz,	 CH2CH3),	 3.89	 (s,	 3H,	
OCH3),	3.24‐3.29	(t,	2H,	J	=	6.9	Hz,	COCH2CH2CO),	2.71‐2.76	(t,	
2H,	J	=	6.9	Hz,	COCH2CH2CO),	2.25	(s,	3H,	CH3Ar),	1.24‐1.29	(t,	
3H,	 J	=	7.2	Hz,	CH2CH3).	Anal.	 calcd.	 for	C14H18O4:	C,	 67.18;	H,	
7.25.	Found:	C,	66.94;	H,	7.45	%.		
	
3.	Results	and	discussion		

	
The	 starting	 compound	 2(3H)‐furanone	 (2)	 has	 been	

synthesized	 via	 the	 lactonization	 of	 the	 4‐(4‐methoxy‐3‐
methylphenyl)‐4‐oxobutanoic	 acid	 (1)	 with	 acetic	 anhydride.	
The	reactivity	of	the	methylene	unit	of	2(3H)‐furanone	(2)	has	
been	 studied	 for	 various	 condensation	 reactions	 (Scheme	 1).	
Thus,	 the	 condensation	 of	 furanone	 (2)	 with	 aromatic	 alde‐
hydes	 in	 acetic	 anhydride	 in	 the	 presence	 of	 sodium	 acetate,	
using	different	procedures,	afforded	the	corresponding	3‐aryli	
dene‐5‐(4‐methoxy‐3‐methylphenyl)‐2(3H)‐furanones	 (3)	 in	
good	 yields.	 The	 proposed	 structures	 of	 these	 compounds	
were	 supported	 by	 the	 identity	 of	 their	 melting	 points	 with	
that	 of	 authentic	 samples	 prepared	 from	 the	 reaction	 of	 the	
corresponding	 4‐(4‐methoxy‐3‐methylphenyl)‐4‐oxo‐butanoic	
acid	 (1)	with	aromatic	aldehydes	and	acetic	anhydride	 in	 the	
presence	 of	 anhydrous	 sodium	 acetate.	 The	 structures	 of	
compounds	3a‐f	were	confirmed	from	their	spectral	analyses,	
where	 IR	 spectra	 revealed	 strong	 absorption	 bands	 in	 the	
region	1754‐1782	cm‐1	corresponding	to	the	carbonyl	groups	
of	 the	 2(3H)‐furanone	 rings	 (e.g.	 νC=O	 of	 α,‐unsaturated	
lactones).	It	was	found	that	there	is	no	difference	in	the	yield	
and	 the	purity	of	 the	3‐arylidene	derivatives	prepared	by	the	
different	 methods	 used.	 Attempts	 to	 synthesize	 bis‐ylidene	
compound	 from	 the	reaction	of	 two	or	more	moles	of	2(3H)‐
furanone	(2)	with	terphthaladehyde	were	not	successful.		

The	 condensation	 of	 2(3H)‐furanone	 (2)	 with	 phthalic	
anhydride	in	acetic	anhydride	in	the	presence	of	fused	sodium	
acetate	 under	 similar	 conditions	 afforded	 the	 corresponding	
phthalide	 (4).	 The	 aminolysis	 of	 2(3H)‐furanone	 (2)	 with	
primary	amines	(aliphatic	or	aromatic)	was	proceeded	readily	
and	stopped	at	the	stage	of	the	formation	of	the	N‐substituted	
butanamides	 (5a‐g),	 which	 were	 isolated	 with	 quantitative	
yields.	 The	 1H	 NMR	 spectroscopy	 has	 been	 used	 in	 order	 to	
establish	 the	 open	 chain	 structure	 of	 propionamides	 which	
were	 characterized	 by	 the	 [‐CH2CH2‐]	 methylene	 proton	
signals,	which	appear	as	two	distinct	triplets	at	approximately	
δ	2.59‐2.91	and	3.19‐3.46	ppm.	

The	 treatment	 of	 butanamide	 (5a‐c)	 with	 an	 excess	 of	
thionyl	 chloride	at	 room	temperature	has	been	 found	 to	give	
the	 corresponding	 isothiazolones	 (6a‐c)	 [16,17].	 The	 cycliza‐
tion	 reaction	 of	 amides	 with	 thionyl	 chloride	 has	 been	
suggested	to	precede	 through	 intermediate	sulfinyl	chlorides,	
resulting	from	the	oxidation	of	 the	methylene	group	adjacent	
to	the	aroylcarbonyl	(Figure	1).	



Soliman	and	El‐Sakka	/	European	Journal	of	Chemistry	8	(4)	(2017)	417‐421	 421	
 

The	 furanone	 (2)	 was	 converted	 to	 the	 corresponding	
benzimidazole	(5)	by	the	reaction	with	o‐phenylenediamine	in	
refluxing	 ethanol.	 Apparently,	 the	 reaction	 of	 furanone	 (2)	
with	o‐phenylenediamine	causes	the	opening	of	the	furan	ring	
with	the	formation	of	the	corresponding	amide,	which	under‐
goes	 in	situ	cyclization	 into	 the	corresponding	benzimidazole	
(7).	

The	hydrazinolysis	 of	2(3H)‐furanone	 (2)	with	hydrazine	
hydrate	 in	ethanol	caused	ring	opening	with	the	 formation	of	
the	corresponding	acid	hydrazide	which	also	undergoes	in	situ	
cyclization	into	the	corresponding	pyridazinone	(8).	The	base	
catalyzed	 ethanolysis	 of	 the	 furanone	 (2)	 with	 sodium	
ethoxide	was	conducted	in	refluxing	ethanol	and	afforded	the	
corresponding	 ethyl	 ester	 (9).	 The	 IR	 spectrum	 showed	 two	
strong	carbonyl	absorption	bands	in	the	region	1723	and	1669	
cm‐1	corresponding	to	the	ester	and	keto	groups,	respectively.	
In	the	1H	NMR	spectrum,	the	signal	characteristic	for	the	ethyl	
group	 (CH3CH2O)	 appeared	 as	 triplet	 at	 δ	 1.24‐1.29	 and	
quartet	at	δ	4.13‐4.20,	respectively.		
	
4.	Conclusion	

	
The	present	work	describes	the	synthesize	5‐(4‐methoxy‐

3‐methylphenyl)‐2(3H)‐furanone	 and	 to	 study	 its	 reactivity	
towards	 nucleophilic	 and	 electrophilic	 reagents	 for	 further	
investigations.	 3‐Arylidene‐2(3H)‐furanones	 were	 prepared	
from	 the	 reaction	 of	 2(3H)‐furanone	with	 the	 corresponding	
aromatic	 aldehydes.	 The	 treatment	 of	 furanone	with	 amines	
gave	 the	 corresponding	 butanamides	 which	 afforded	 the	
corresponding	 isothiazolones	 on	 reaction	 with	 thionyl	
chloride.	 The	 chemical	 structures	 of	 these	 compounds	 were	
confirmed	 by	 IR,	 1H	 NMR,	 13C	 NMR,	 mass	 spectroscopy	 and	
elemental	analysis.	
	
References	
	
[1]. Alam,	M.	M.;	 Sarkar,	 D.	 P.;	Husain,	A.;	Marella,	 A.;	 Shaquiquzzaman,	

M.;	 Akhter,	M.;	 Shaharyar,	M.;	 Alam,	O.;	 Azam,	 F.	 J.	Serb.	Chem.	Soc.	
2011,	76(12),	1617‐1626.		

[2]. Khan,	M.;	Husain,	A.	Die	Pharmazie	2002,	57(7),	448‐452.		
[3]. Husain,	A.;	Ajmal,	M.	Acta	Pharma.	2009,	59(2),	223‐233.		
[4]. Leite,	L.;	Jansone,	D.;	Veveris,	M.;	Cirule,	H.;	Popelis,	Y.;	Melikyan,	G.;	

Avetisyan,	A.;	Lukevics,	E.	Eur.	J.	Med.	Chem.	1999,	34(10),	859‐865.		
[5]. Gottesdiener,	K.;	Mehlisch,	D.	R.;	Huntington,	M.;	Yuan,	W.	Y.;	Brown,	

P.;	Gertz,	B.;	Mills,	S.	Clin.	Ther.	1999,	21(8),	1301‐1312.		
[6]. Moosavi‐Movahedi,	A.	A.;	Hakimelahi,	S.;	Chamani,	J.;	Khodarahmi,	G.	

A.;	Hassanzadeh,	F.;	Luo,	F.	T.;	Ly,	T.	W.;	Shia,	K.	S.;	Yen,	C.	F.;	Jain,	M.	
L.	Bioorg.	Med.	Chem.	2003,	11(20),	4303‐4313.		

[7]. Klunk,	W.	K.;	Covey,	D.	F.;	Ferrendelli,	 J.	A.	 J.	Mol.	Pharmacol.	1982,	
22(2),	438‐443.		

[8]. Wu,	H.;	 Song,	 Z.;	Hentzer,	M.;	Andersen,	 J.	B.;	Molin,	S.;	Givskov,	M.;	
Hoiby,	N.	J.	Antimicrob.	Chemother.	2004,	53(6),	1054‐1061.		

[9]. Hashem,	A.	I.;	Youssef,	A.	S.;	Kandeel,	K.	A.;	Abou‐Elmagd,	W.	S.	Eur.	J.	
Med.	Chem.	2007,	42(7),	934‐939.		

[10]. Jefford,	C.	W.;	 Jaggi,	D.;	Boukouvalas,	 J.	 J.	Chem.	Soc.	Chem.	Commun.	
1988,	24,	1595‐1596.		

[11]. Flefel,	E.	M.;	Abdel‐Mageid,	R.	E.;	Tantawy,	W.	A.;	Ali,	M.	A.;	Amr,	A.	E.	
G.	E.	Acta	Pharma.	2012,	62(4),	593‐606.		

[12]. Abou‐Elmagd,	W.	 S.;	 EL‐Ziaty,	 A.	 K.;	 El‐Zahar,	M.	 I.;	 Ramadan,	 S.	 K.;	
Hashem,	A.	I.	,	Synth.	Commun.	2016,	46,	1197‐1208.		

[13]. Soliman,	M.	H.;	El‐Sakka,	S.	S.	J.	Korean	Chem.	Soc.	2011,	55(2),	230‐
234.		

[14]. El‐Sakka,	 S.	 S.;	 Soliman,	 M.	 H.;	 Abdullah,	 R.	 S.	 J.	 Chem.	 Sci.	 2014,	
126(6),	1883‐1891.		

[15]. Shah,	M.	M.;	Phalnikar,	N.	L.	J.	Univ.	Bombay	1944,	13(3),	22‐26.		
[16]. Tsolomitis,	 A.;	 Sandris,	 C.	 J.	Heterocyclic	 Chem.	 1980,	 17(7),	 1645‐

1646.		
[17]. Beer,	R.	J.;	Wright,	D.	Tetrahedron	1981,	37(22),	3867‐3870.