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European	Journal	of	Chemistry	3	(2)	(2012)	172‐178	

European	Journal	of	Chemistry	
ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2012	EURJCHEM	

DOI:10.5155/eurjchem.3.2.172‐178.582	

	
	

	

	

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

	 	 	

An	efficient	cyclocondensation	reactions,	antimicrobial	activity	and	molecular	
orbital	calculations	of	α‐benzopyrone	derivatives	

Hafez	Mohamed	El‐Shaaer*,	Salah	Sayed	Ibrahim,		
Wafaa	Ramzy	Abd‐Elmonem	and	Christine	Gamal	Ibrahim	

Department	of	Chemistry,	Faculty	of	Education,	Ain	Shams	University,	Roxy,	11711,	Cairo,	Egypt	

*Corresponding	author	at:	Department	of	Chemistry,	Faculty	of	Education,	Ain	Shams	University,	Roxy,	11711,	Cairo,	Egypt.		
Tel.:	+2.02.0112627069;	fax:	+2.02.2581243.	E‐mail	address:	elshaaer@hotmail.com		(H.M.	El‐Shaaer).	

	
	

	 	

	 	 	
ARTICLE	INFORMATION	 	 ABSTRACT	
Received:	15	October	2011	
Received	in	revised	form:	11	December	2011	
Accepted:	26	December	2011	
Online:	30	June	2012	

KEYWORDS	

	 An	 efficient	 synthesis	 of	 4,6,8‐trimethyl‐2‐oxo‐2H‐chromene‐3‐carbonitrile	 (2)	 via	 Claisen
condensation	 of	 3,5‐dimethyl‐2‐hydroxyacetophenone	 with	 ethyl	 cyanoacetate	 in	 the
presence	 of	 sodium	 metal	 is	 reported.	 Cyclocondensation	 reactions	 of	 compound	 (2)	 with
ethyl	 acetate	 or	 with	 ethyl	 cyanoacetate	 in	 the	 presence	 of	 ethoxide	 gave	 sodium	 salt	 of
7‐amino‐9‐hydroxy‐2,4‐dimethyl‐6H‐benzo[c]chromen‐6‐one	 derivatives	 (3)	 and	 (4)
respectively,	 which	 upon	 neutralization	 with	 10	 %	 hydrochloric	 acid	 gave	 7‐amino‐9‐
hydroxy‐2,4‐dimethyl‐6H‐benzo[c]chromen‐6‐one	 (5).	 Hydrolysis	 of	 compound	 (2)	 with
ethanolic	 sodium	 hydroxide	 solution	 gave	 4,6,8‐trimethyl‐2‐oxo‐2H‐chromene‐3‐carboxylic
acid	 (6).	 Treatment	 of	 compound	 (2)	 with	 Vilsmier	 reagent	 using	 excess	 POCl3	 gave
4‐(chloro(formyl)methyl‐6,8‐dimethyl‐2‐oxo‐2H‐chromene‐3‐carbonitrile	 (7).	 Also,	 conden‐
sation	 of	 compound	 (2)	with	 DMF‐DMA	 in	 xylene	 or	with	 POCl3/DMF	 in	 pyridine	 gave	 the
same	 product	 4‐((E)‐2‐(dimethylamino)vinyl)‐6,8‐dimethyl‐2‐oxo‐2H‐chromene‐3‐carbo‐
nitrile	 (8).	 The	 cyclocondensation	 reactions	 of	 compound	 (8)	 with	 hydroxylamine
hydrochloride,	 urea,	 and	 with	 hydrazinecarbodithioic	 acid	 gave	 3,4‐dihydro‐3‐hydroxy‐4‐
imino‐7,9‐dimethylchromeno[3,4‐c]pyridin‐5‐one	 (9),	 4‐imino‐7,9‐dimethyl‐5‐oxo‐4H‐chro‐
meno[3,4‐c]pyridine‐3(5H)‐carboxamide	(10)	and	3‐amino‐3,4‐dihydro‐4‐imino‐7,9‐dimethyl
chromeno[3,4‐c]pyridin‐5‐one	(11),	respectively.	Also,	acid	hydrolysis	of	compound	(8)	gave
7,9‐dimethyl‐3H‐chromeno[3,4‐c]pyridine‐4,5‐dione	 (12).	 Structures	 of	 the	 products	 were
established	 on	 the	 basis	 of	 elemental	 analysis,	 IR,	 1H	 and	 13C	NMR,	mass	 spectra	 and	 semi‐
empirical	AM1‐MO	calculations.	The	antimicrobial	activities	of	the	synthesized	products	were
also	studied.	

Synthesis	
α‐Benzopyrone	
Cyclocondensation	
Antimicrobial	Activity	
Chromeno[3,4‐c]pyridinones	
Molecular	orbital	calculations	

	
1.	Introduction	
	

‐Benzopyrone	derivatives	constitute	an	important	class	of	
oxygenated	heterocycles	 [1].	Many	 compounds	 containing	 the	
benzopyrone	 nucleus,	 both	 naturally	 occurring	 and	 synthetic,	
are	 known	 to	 exhibit	 pharmacological	 activity	 such	 as	
antifungal	 [2‐4],	 antibacterial	 [5],	 anti‐mycobacterial	 [6,7],	
anticoagulants	 [8,9],	 inhibitors	 of	 some	 enzymes	 [10,11],	 and	
antitumor	 [12‐14].	 With	 the	 expectations	 to	 find	 biological	
activity,	we	decided	to	investigate	the	synthesis	of	some	novel	
systems	 of	 ‐benzopyrone	 derivatives	 bearing	 fused	 and	
isolated	 moiety.	 Recently,	 the	 synthesis	 [15],	 photochemical	
[16]	 and	 theoretical	 [1,2,17]	 properties	 of	 ‐benzopyrone	
derivatives	were	investigated.	

The	 aim	of	 the	present	paper	 is	 to	 investigate	 an	 efficient	
synthesis	of	coumarin	derivatives	containing	active	methyl	and	
cyano	groups	and	study	their	cyclocondensation	reactions	with	
ethyl	 acetate,	 ethyl	 cyanoacetate,	 hydroxylamine	 hydro‐
chloride,	 urea,	 and	 with	 hydrazine	 carbodithioic	 acid.	 The	
condensations	of	4‐methyl	group	of	coumarin	derivatives	with	
Vilsmier	 reagents	 at	 different	 conditions	 and	 with	 DMF‐DMA	
were	also	studied.		

The	 antimicrobial	 activities	 for	 the	 prepared	 compounds	
were	 investigated.	 Also,	 semi‐empirical	 AM1	 and	 Ab	 Initio	
(STO‐3G)	 molecular	 orbital	 calculations	 for	 the	 new	

compounds	 were	 performed	 and	 compared	 with	 their	
experimental	data.	
	
2.	Experimental	
	
2.1.	Instrumentation	
	

The	uncorrected	melting	point	was	determined	in	an	open	
capillary	tube	on	a	digital	Stuart	SMP‐3	apparatus.	1H	NMR/13C	
NMR	spectra	were	obtained	on	a	300	MHz/75.46	MHz	Varian	
Mercury	 VX‐300	 NMR	 spectrometer	 in	 DMSO‐d6	 with	
tetramethylsilane	 as	 an	 internal	 standard.	 Elemental	 analyses	
were	 performed	 on	 Vario	 El	 Elementar	 apparatus.	 IR	 spectra	
were	recorded	on	FTIR	Nicolet	IS10	spectrophotometer	(cm‐1),	
using	 KBr	 disks.	 Mass	 spectra	 recorded	 on	 a	 Gas	
Chromatographic	GCMSqp	1000	ex	Shimadzu	instrument	at	70	
eV.		

The	 chemicals	 were	 purchased	 from	 the	 suppliers	 as	 the	
highest	purity	grade.	The	theoretical	data	which	were	obtained	
from	 molecular	 mechanical	 calculations	 on	 the	 basis	 of	 the	
semi‐empirical	 AM1	 and	 Ab	 Initio	 (STO‐3G)	 methods	 of	
HyperChem	8.03	computer	program.	
		
	
	



El‐Shaaer	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	172‐178	 173	
 

	

OH

COCH3

O O

CN

+

O

ONa

NH2

O

R

O

O

NH2

ONa

R

O

O

NH2

O O

OH

NH2

O

21

3a R = H
4a R = CN

3b R = H
4b R = CN

dil. HCl
R = H

5b 5a

RCH2CO2C2H5

NCCH2CO2C2H5

EtONa

Na

 
	

Scheme	1
	
	
2.2.	Synthesis	
	
2.2.1.	4,6,8‐Trimethyl‐2‐oxo‐2H‐chromene‐3‐carbonitrile	(2)	
	

Sodium	metal	(2	g,	8.6	mmol)	was	added	in	small	portion	to	
a	solution	of	3,5‐dimethyl‐2‐hydroxyacetophenone	(1)	(4	g,	2.4	
mmol)	 in	 ethyl	 cyanoacetate	 (30	 cm3).	 The	 reaction	 mixture	
was	 heated	 on	 water‐bath	 for	 3	 h,	 and	 then	 cooled	 to	 room	
temperature,	 treated	with	ethanol	(10	cm3)	and	refluxed	for	1	
h.	The	solid	obtained	was	filtered,	and	crystallized	from	ethanol	
to	give	(2)	as	pale	green	crystals	(Scheme	1).	Yield:	62%.	M.p.:	
200‐202	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3072	 (CHarom.),	 2921,	 2953	
(CHaleph.),	 2230	 (CN),	 1721	 (C=O),	 1608	 (C=C).	 1H	 NMR	 (300	
MHz,	DMSO‐d6,	δ,	ppm):	2.26	(s,	3H,	CH3),	2.31	(s,	3H,	CH3),	2.61	
(s,	 3H,	 CH3),	 7.42	 (s,	 1H,	H‐7),	 7.49	 (s,	 1H,	H‐5).	 13C	NMR	 (75	
MHz,	 DMSO‐d6,	 δ,	 ppm):	 24.2,	 27.7,	 29.6,	 109.9,	 123.5,	 126.7,	
133.6,	 134.9,	 143.6,	 146.7,	 158.3,	 165.9,	 172.9.	 MS	 (EI,	 m/z	
(%)):	 212.4	 (M‐1,	 86.9),	 212.8	 (M+,	 100),	 213.8	 (M+1,	 14.5).	
Anal.	calcd.	 for	C13H11NO2:	C,	73.23;	H,	5.20;	N,	6.57.	Found:	C,	
73.10;	H,	5.00;	N,	6.60%.	
	
2.2.2.	Sodium	salt	of	7‐amino‐9‐hydroxy‐2,4‐dimethyl‐6H‐
benzo[c]chromen‐6‐one	derivatives	(3)	and	7‐amino‐9‐
hydroxy‐2,4‐dimethyl‐6H‐benzo[c]chromen‐6‐one	(5)	
	

A	solution	of	compound	(2)	(2.0	g,	0.93	mmol)	in	ethoxide	
(1.0	g	sodium,	40	cm3	absolute	ethanol),	and	then	ethyl	acetate	
(24	 cm3)	was	 added	 and	 the	mixture	was	 refluxed	 on	water‐
bath	for	3	h,	cooled	to	room	temperature,	treated	with	diethyl	
ether	(40	cm3).	The	solid	obtained	was	filtered,	and	crystallized	
from	diethyl	ether	to	give	(3)	as	pall‐yellow	crystals	(Scheme	1	
and	2).	Yield:	89%.	M.p.:	168‐170	°C.	The	compound	(3)	(0.5	g,	
0.18	mmol)	was	acidified	with	10%	HCl	and	the	solid	obtained	
was	 filtered,	 and	 crystallized	 from	 water	 to	 give	 (5)	 as	 pall‐
yellow	crystals	(Scheme	1	and	2).	Yield:	89%.	M.p.:	166‐169	°C.		

7‐Amino‐9‐hydroxy‐2,4‐dimethyl‐6H‐benzo[c]chromen‐6‐one	
derivatives	 (3):	FT‐IR	(KBr,	cm‐1):	3309,	3489	(br.,	NH2),	2921	
(CHaleph.),	1721	(w,	C=Ocoumarin),	1655	(s,	C=Ocyclic	ketone).	1H	NMR	
(300	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 1.63	 (s,	 2H,	 NH2,	 exchangeable	

with	D2O),	2.22	(s,	3H,	CH3),	2.28	(s,	3H,	CH3),	6.23	(s,	1H,	H‐8),	
7.09	(s,	1H,	H‐3),	7.19	(s,	1H,	H‐1),	7.31	(s,	1H,	H‐10).		

7‐Amino‐9‐hydroxy‐2,4‐dimethyl‐6H‐benzo[c]chromen‐6‐one	
(5):	 FT‐IR	 (KBr,	 cm‐1):	 2922,	 3455	 (br.,	 OH,	 NH2),	 1725	 (m,	
C=Ocoumarin),	1666	(s,	C=Ocyclic	 ketone).	 1H	NMR	(300	MHz,	DMSO‐
d6,	δ,	ppm):	2.29	(s,	3H,	CH3),	2.33	(s,	3H,	CH3),	3.83	(s,	2H,	NH2,	
exchangeable	 with	 D2O),	 6.22	 (s,	 1H,	 OH,	 exchangeable	 with	
D2O),	7.21	(s,	1H,	H‐8),	7.26	(s,	1H,	H‐3),	7.28	(s,	1H,	H‐1),	7.37	
(s,	1H,	H‐10).	 13C	NMR	(75	MHz,	DMSO‐d6,	δ,	ppm):	24.5,	25.3,	
27.7,	29.8,	52.5,	53.8,	 123.4,	127.8,	132.1,	132.7,	134.3,	142.7,	
143.3,	143.9,	157.9,	166.8,	175.5.	MS	(EI,	m/z	(%)):	255.7	(M+,	
6.5).	 Anal.	 calcd.	 for	 C15H13NO3:	 C,	 70.58;	 H,	 5.13;	 N,	 5.49.	
Found:	C,	70.30;	H,	4.90;	N,	5.40%.	
	
2.2.3.	Sodium	salt	of	7‐amino‐9‐hydroxy‐2,4‐dimethyl‐6‐oxo‐
6H‐benzo[c]chromene‐8‐carbonitrile	(4)	
	

A	 solution	 of	 compound	 (2)	 (2	 g,	 0.93	mmol)	 in	 ethoxide	
(0.8	 g	 sodium,	 40	 cm3	 absolute	 ethanol),	 and	 then	 ethyl	
cyanoacetate	(9	cm3)	was	added	and	the	mixture	was	refluxed	
on	water‐bath	 for	3	h,	 cooled	 to	 room	 temperature.	The	 solid	
obtained	was	filtered,	and	crystallized	from	ethanol	to	give	(4)	
as	white	crystals	(Scheme	1	and	2).	Yield:	31%.	M.p.:	183‐185	
°C.	 FT‐IR	 (KBr,	 cm‐1):	 3397	 (br.,	 NH2),	 2976	 (CHaleph.),	 2263	
(CN),	1623	(br.,	C=O).	MS	(EI,	m/z	(%)):	301.0	(M‐1,	16.7).	Anal.	
calcd.	 for	 C16H11N2NaO3:	 C,	 63.58;	 H,	 3.67;	 N,	 9.27.	 Found:	 C,	
63.10;	H,	3.20;	N,	9.10%.	
	
2.2.4.	4,6,8‐Trimethyl‐2‐oxo‐2H‐chromene‐3‐carboxylic	acid	
(6)	
	

A	solution	of	compound	(2)	(0.5	g,	0.23	mmol)	in	ethanol	(2	
cm3),	 sodium	hydroxide	 solution	 (0.09	 g	 sodium	hydroxide,	 2	
cm3	water)	 was	 added	 and	 the	mixture	was	 refluxed	 for	 2	 h,	
cooled	 to	 room	 temperature.	 The	 solid	 obtained	was	 filtered,	
and	crystallized	from	ethanol	to	give	(6)	as	dark	brown	crystals	
(Scheme	 3).	 M.p.:	 206‐207	 °C.	 Yield:	 87%.	 FT‐IR	 (KBr,	 cm‐1):	
3081	 (br.,	 OH),	 2920,	 2959	 (CHaleph.),	 1742	 (s,	 C=Oacid),	 1660	
(br.,	C=Ocoumarin).		



174	 El‐Shaaer	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	172‐178	
	

	

	
Scheme	2

	
	

	
Scheme	3

	
	
1H	 NMR	 (300	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 2.19	 (s,	 3H,	 CH3),	

2.25	 (s,	 3H,	 CH3),	 2.31	 (s,	 3H,	 CH3),	 6.17	 (s,	 1H,	 OH,	
exchangeable	with	D2O),	7.18	(s,	1H,	H‐7),	7.28	(s,	1H,	H‐5).	13C	
NMR	(75	MHz,	DMSO‐d6,	δ,	ppm):	24.3,	25.3,	29.8,	127.5,	130.8,	
132.7,	 134.3,	 142.7,	 144.1,	 157.8,	 158.3,	 166.6,	 175.3.	MS	 (EI,	
m/z	 (%)):	 231.0	 (M‐1,	 32.6),	 232.0	 (M+,	 42.7),	 233.0	 (M+1,	
14.6).	 Anal.	 calcd.	 for	 C13H12O4:	 C,	 67.23;	 H,	 5.21.	 Found:	 C,	
67.20;	H,	5.50%.	
	
2.2.5.	4‐(Chloro(formyl)methyl‐6,8‐dimethyl‐2‐oxo‐2H‐
chromene‐3‐carbonitrile	(7)	
	

Phosphorusoxy	 chloride	 (2.4	 cm3)	was	added	dropwise	 to	
DMF	 (6	 cm3)	with	 stirring	 at	 30‐35	 °C,	 after	 the	 addition	was	
completed,	 the	 solution	was	stirred	at	50‐60	 °C	 for	30	min.	A	
solution	of	 compound	 (2)	 (1	g,	0.46	mmol)	 in	dry	pyridine	 (6	
cm3)	was	added	to	the	above	mixture	dropwise	at	30‐35	°C	and	
after	 the	 addition	was	 completed,	 the	mixture	 was	 stirred	 at	
50‐60	°C	for	3	h,	cooled	to	room	temperature.	The	mixture	was	
poured	 over	 cold	 water.	 The	 solid	 obtained	was	 filtered,	 and	
crystallized	from	DMF	to	give	(7)	as	yellow	crystals	(Scheme	3).		
M.p.:	 268‐270	 °C.	 Yield:	 85%.	 FT‐IR	 (KBr,	 cm‐1):	 3422	 (enolic	
OH),	2930,	2958	(CHaleph.),	2722	(CHaldehde),	2224	(CN),	1723	(s,	
C=Oaldehyde),	1661	(w,	C=O	coumarin),	1621	(exocyclic	C=C).	1H	
NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	2.28	(s,	3H,	CH3),	2.32	(s,	3H,	

CH3),	7.14	(s,	1H,	CH‐Cl),	7.44	(s,	1H,	H‐7),	7.69	(s,	1H,	H‐5),	9.01	
(s,	1H,	CHO).	 13C	NMR	(75	MHz,	DMSO‐d6,	δ,	ppm):	24.4,	29.7,	
55.8,	 113.8,	 124.0,	 128.0,	 135.1,	 143.6,	 146.7,	 158.7,	 166.4,	
169.6,	 170.5,	 194.4.	 MS	 (EI,	 m/z	 (%)):	 275.05	 (M‐1,	 0.31),	
276.05	 (M+,	 0.20),	 277.15	 (M+1,	 0.59),	 278.25	 (M+2,	 2.49).	
Anal.	calcd.	for	C14H10ClNO3:	C,	60.99;	H,	3.66;	N,	5.08.	Found:	C,	
60.80;	H,	3.40;	N,	5.30%.	
	
2.2.6.	4‐((E)‐2‐(Dimethylamino)vinyl)‐6,8‐dimethyl‐2‐oxo‐
2H‐chromene‐3‐carbonitrile	(8)	
	

Method	A:	A	solution	of	compound	(2)	(0.5	g,	0.23	mmol)	in	
dry	xylene	(10	cm3),	and	then	DMF‐DMA	(0.35	cm3,	0.29	mmol)	
was	 added	 and	 the	mixture	was	 refluxed	 for	 0.5	 h,	 cooled	 to	
room	 temperature.	 The	 solid	 obtained	 was	 filtered,	 and	
crystallized	from	DMF	to	give	(8)	as	green	crystals	(Scheme	4).		
M.p.:	271‐272	°C.	Yield:	63%.	FT‐IR	(KBr,	cm‐1):	3438	(br.,	OH),	
2935,	 2999	 (CHaleph.),	 2202	 (CN),	 1676	 (C=O),	 1618	 (C=C).	 1H	
NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	2.28	(s,	6H,	CH3),	2.35	(s,	3H,	
CH3),	2.49	(s,	3H,	CH3),	5.71	(d,	J	=	12.6	Hz,	1H,	H‐9),	7.31	(s,	1H,	
H‐7),	7.73	(s,	1H,	H‐5),	8.45	(d,	J	=	12.3	Hz,	1H,	H‐10).	13C	NMR	
(75	MHz,	 DMSO‐d6,	 δ,	 ppm):	 18.4,	 24.8,	 29.8,	 46.7,	 55.3,	 97.6,	
108.8,	126.4,	129.3,	132.3,	135.0,	142.4,	144.8,	164.3,	238.5.		

	
	



El‐Shaaer	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	172‐178	 175	
 

	

O O

CN

2

O O

CN

H

N

H

8

POCl3 / DMF

XylenePyridine

DMF-DMA

	
Scheme	4	

	

 
	

Scheme	5
	
	
MS	(EI,	m/z	(%)):	266.0	(M‐2,	8.3),	267.0	(M‐1,	26.1),	268.0	

(M+,	 100).	 Anal.	 calcd.	 for	 C16H16N2O2:	 C,	 71.62;	 H,	 6.01;	 N,	
10.44.	Found:	C,	71.20;	H,	6.20;	N,	10.50%.	

Method	 B:	 A	 mixture	 of	 DMF	 (5	 cm3),	 phosphorusoxy	
chloride	(0.5	cm3)	and	a	solution	of	compound	(2)	(0.5	g,	0.23	
mmol)	in	dry	pyridine	(6	cm3)	was	stirred	at	70‐80	°C	for	3	h,	
cooled	to	room	temperature.	The	mixture	was	poured	over	cold	
water	 and	 neutralized	 with	 sodium	 carbonate	 solution.	 The	
solid	obtained	was	 filtered,	 and	crystallized	 from	DMF	 to	give	
(8)	as	green	crystals,	M.p.:	272	°C.	Yield:	60%.		
	
2.2.7.	3,4‐Dihydro‐3‐hydroxy‐4‐imino‐7,9‐dimethylchromeno	
[3,4‐c]pyridin‐5‐one	(9)	
	

A	 mixture	 of	 compound	 (8)	 (0.5	 g,	 0.19	 mmol),	
hydroxylamine	 hydrochloride	 (0.13	 g,	 0.19	 mmol),	 absolute	
ethanol	(15	cm3),	and	drops	of	acetic	acid	was	refluxed	for	3	h,	
cooled	 to	 room	 temperature.	 The	 solid	 obtained	was	 filtered,	
and	 crystallized	 from	 DMF	 to	 give	 (9)	 as	 yellow	 crystals	
(Scheme	 5).	 M.p.:	 315‐316	 °C.	 Yield:	 85%.	 FT‐IR	 (KBr,	 cm‐1):	
3414	 (br.,	 OH),	 3223	 (br.,	 NH),	 2920	 (CHaleph.),	 1702	 (C=O),	
1625	 (exocyclic	 C=N).	 1H	 NMR	 (300	MHz,	 DMSO‐d6,	 δ,	 ppm):	
2.34	(s,	3H,	CH3),	2.50	(s,	3H,	CH3),	7.31	(s,	1H,	H‐8),	7.52	(d,	J	=	
7.4	 Hz,	 1H,	 H‐1),	 7.92	 (s,	 1H,	 H‐10),	 8.00	 (s,	 1H,	 NH,	
exchangeable	 with	 D2O),	 8.30	 (s,	 1H,	 OH,	 exchangeable	 with	
D2O),	8.50	((d,	J	=	7.2	Hz,	1H,	H‐2).	MS	(EI,	m/z	(%)):	256.0	(M+,	
4.5),	256.8	 (M+1,	2.7).	Anal.	 calcd.	 for	C14H12N2O3:	C,	65.62;	H,	
4.72;	N,	10.93.	Found:	C,	65.30;	H,	4.60;	N,	11.1%.	
	

2.2.8.	4‐Imino‐7,9‐dimethyl‐5‐oxo‐4H‐chromeno[3,4‐c]	
pyridine‐3(5H)‐carboxamide	(10)	
	

A	mixture	of	compound	(8)	(0.5	g,	0.19	mmol),	urea	(0.11	g,	
0.19	mmol),	and	glacial	acetic	acid	(10	cm3)	was	refluxed	for	3	
h,	cooled	to	room	temperature.	The	solid	obtained	was	filtered,	
and	 crystallized	 from	 DMF	 to	 give	 (10)	 as	 green	 crystals	
(Scheme	5).		M.p.:	>300	°C.	Yield:	47%.	FT‐IR	(KBr,	cm‐1):	3452,	
3161	 (br.,	 NH,	 NH2),	 2919	 (CHaleph.),	 1731	 (C=Ocoumarin),	 1669	
(C=Oamide).	 MS	 (EI,	m/z	 (%)):	 280.0	 (M‐3,	 18.8),	 281.0	 (M‐2,	
2.6).	 Anal.	 calcd.	 for	 C15H13N3O3:	 C,	 63.60;	 H,	 4.63;	 N,	 14.83.	
Found:	C,	63.40;	H,	4.20;	N,	14.60%.	
	
2.2.9.	3‐Amino‐3,4‐dihydro‐4‐imino‐7,9‐dimethylchromeno	
[3,4‐c]pyridin‐5‐one	(11)	
	

A	 mixture	 of	 compound	 (8)	 (0.5	 g,	 0.19	 mmol),	
hydrazinecarbodithioic	 acid	 (0.2	 g,	 0.19	 mmol),	 and	 glacial	
acetic	 acid	 (10	 cm3)	 was	 refluxed	 for	 3	 h,	 cooled	 to	 room	
temperature.	 The	 solid	 obtained	was	 filtered,	 and	 crystallized	
from	 DMF	 to	 give	 (10)	 as	 yellow	 crystals	 (Scheme	 6).	 M.p.:	
>300	 °C.	 Yield:	 73%.	 FT‐IR	 (KBr,	 cm‐1):	 3359,	 3096	 (br.,	 NH,	
NH2),	2970,	2919	(CHaleph.),	1728	(C=Ocoumarin),	1626	(exocyclic	
C=N),	1605	 (C=C).	 1H	NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	2.36	
(s,	 3H,	 CH3),	 2.46	 (s,	 3H,	 CH3),	 4.03	 (s,	 2H,	NH2,	 exchangeable	
with	D2O),	7.35	(br.	S,	1H,	H‐1),	8.00	(s,	1H,	H‐8),	8.06	(s,	1H,	H‐
10),	 9.20	 (br.	 S,	 1H,	H‐2).	MS	 (EI,	m/z	 (%)):	 254.0	 (M‐1,	 1.0),	
255.0	 (M+,	 27.9),	 256.0	 (M+1,	 37.9),	 257.0	 (M+2,	 6.4).	 Anal.	
calcd.	 for	 C14H13N3O2:	 C,	 65.87;	 H,	 5.13;	 N,	 16.46.	 Found:	 C,	
65.60;	H,	5.00;	N,	16.10%.	



176	 El‐Shaaer	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	172‐178	
	
	

8

H2N
N
H

S

SH

O

NH

O

O

O

N

O

N

NH2

H

12 11

O O

CN

H

N

H
HCl

EtOH

 
	

Scheme	6
	
	
2.2.10.	7,9‐Dimethyl‐3H‐chromeno[3,4‐c]pyridine‐4,5‐dione	
(12)	
	

A	mixture	 of	 compound	 (8)	 (0.4	 g,	 0.15	mmol),	 and	 conc.	
hydrochloric	 acid	 (3	 cm3),	 was	 stirred	 at	 60‐70	 °C	 for	 0.5	 h,	
cooled	 to	 room	 temperature	 and	 diluted	with	water	 (5	 cm3).	
The	 solid	 obtained	was	 filtered,	 and	 crystallized	 from	DMF	 to	
give	(12)	as	yellow	crystals	(Scheme	6).	M.p.:	303‐304	°C.	Yield:	
82%.	 FT‐IR	 (KBr,	 cm‐1):	 3166	 (br.,	 NH),	 1732	 (s,	 C=Ocoumarin),	
1667	(w,	C=Oamide),	1620	(C=C).	1H	NMR	(300	MHz,	DMSO‐d6,	δ,	
ppm):	2.29	(s,	3H,	CH3),	2.33	(s,	3H,	CH3),	7.10‐7.20	(m,	2H,	H‐1,	
H‐8),	 7.80	 (s,	 1H,	H‐10),	 9.40	 (S,	 1H,	H‐2).	 MS	 (EI,	m/z	 (%)):	
241.0	(M+,	100),	242.0	(M+1,	21.7).	Anal.	calcd.	 for	C14H11NO3:	
C,	69.70;	H,	4.60;	N,	5.81.	Found:	C,	69.50;	H,	4.50;	N,	5.60%.	
	
3.	Results	and	discussion	
	
3.1.	Chemistry	
	

The	 Claisen	 condensation	 of	 2‐hydroxyacetophenone	
derivatives	with	ethyl	acetate	in	the	presence	of	sodium	metal	
gave	 β‐dicarbonyl	 compound	derivatives	which	were	 cyclized	
under	 the	 effect	 of	 concentrated	 sulfuric	 acid	 to	 give	 2‐
methylchromone	derivatives	[17].	

In	 our	 recent	 work	 [2],	 we	 described	 the	 Claisen	
condensation	 of	 3,5‐dichloro‐2‐hydroxyacetophenone	 and	
unsubstituted	2‐hydroxyacetophenone	with	ethyl	cyanoacetate	
in	 the	presence	of	 sodium	metal	gave	7‐amino‐2,4‐dichloro‐9‐
hydroxy‐6‐oxo‐6H‐benzo[c]chromene‐8‐carbonitrile	 and	 a	
mixture	of	4‐methyl‐2‐oxo‐2H‐chromene‐3‐carbonitrile	 and	7‐
amino‐9‐hydroxy‐6‐oxo‐6H‐benzo[c]chromene‐8‐carbonitrile,	
respectively.	

The	 present	 work	 describes	 the	 Claisen	 condensation	 of	
3,5‐dimethyl‐2‐hydroxyacetophenone	 with	 ethyl	 cyanoacetate	
in	the	presence	of	sodium	metal	to	give	4,6,8‐trimethyl‐2‐oxo‐
2H‐chromene‐3‐carbonitrile	 (2)	 (Scheme	 1).	 The	 presence	 of	
cyano	 group	 in	 a	 position	 3	 activates	 the	 methyl	 group	 in	 a	
position	 4	 of	 compound	 (2)	 which	 facilitates	 the	 cyclo‐
condensation	reactions	with	ester	derivatives	containing	active	
methylene	 group,	 so	 the	 reaction	of	 compound	 (2)	with	 ethyl	
acetate	or	with	ethyl	cyanoacetate	 in	the	presence	of	ethoxide	
gave	 sodium	 salt	 of	 7‐amino‐9‐hydroxy‐2,4‐dimethyl‐6H‐
benzo[c]chromen‐6‐one	 derivatives	 (3)	 and	 (4)	 respectively	
(Scheme	 1).	 When	 the	 sodium	 salt	 of	 compound	 (3)	 was	
neutralized	 with	 10%	 hydrochloric	 acid	 gave	 7‐amino‐9‐
hydroxy‐2,4‐dimethyl‐6H‐benzo[c]chromen‐6‐one	(5)	(Scheme	
1).	

The	formation	of	compounds	3a,	4a	and	5a	proceeded	via	
Claisen	condensation	on	active	methyl	group	of	compound	(2)	
followed	by	nucleophilic	cyclization	(Scheme	2).	

The	hydrolysis	of	cyano	group	of	4,6,8‐trimethyl‐2‐oxo‐2H‐
chromene‐3‐carbonitrile	 (2)	 in	 ethanolic	 sodium	 hydroxide	
solution	 gave	 4,6,8‐trimethyl‐2‐oxo‐2H‐chromene‐3‐carboxylic	
acid	 (6)	 (Scheme	 3).	 Also,	 the	 Vilsmier	 reaction	 of	 compound	
(2)	 in	 excess	 POCl3	 gave	 4‐(chloro(formyl)methyl‐6,8‐
dimethyl‐2‐oxo‐2H‐chromene‐3‐carbonitrile	(7)	(Scheme	3).	

The	presence	of	 carbonyl	group	 in	a	position	2	and	cyano	
group	 in	 a	 position	 3	 of	 coumarin	 moiety	 facilitate	 the	
condensation	 reactions	of	4‐methyl	group	of	 coumarin,	 so	 the	
reaction	 of	 DMF‐DMA	with	 compound	 (2)	 in	 dry	 xylene	 gave				
4‐((E)‐2‐(dimethylamino)vinyl)‐6,8‐dimethyl‐2‐oxo‐2H‐
chromene‐3‐carbonitrile	 (8).	 Also,	 compound	 (8)	was	 formed	
by	 condensation	 with	 dimethylformamide	 in	 the	 presence	 of	
POCl3	(Scheme	4).	The	compound	(8)	was	formed	in	the	form	of	
E‐isomer	from	1H	NMR	spectra	which	showed	 JCH=CH	=	12.3	Hz	
at		=	5.71	and	8.45	ppm.	

The	 cyclocondensation	 reactions	 of	 4‐((E)‐2‐(dimethyl	
amino)vinyl)‐6,8‐dimethyl‐2‐oxo‐2H‐chromene‐3‐carbonitrile	
(8)	 with	 primary	 amines	 in	 ethanol	 gave	 4‐imino‐7,9‐
dimethylchromeno[3,4‐c]pyridine	 derivatives.	 The	 cyclo	
condensation	 reactions	 of	 compound	 (8)	 with	 hydroxylamine	
hydrochloride,	urea,	and	with	hydrazinecarbodithioic	acid	gave	
3,4‐dihydro‐3‐hydroxy‐4‐imino‐7,9‐dimethylchromeno[3,4‐c]	
pyridin‐5‐one	 (9),	 4‐imino‐7,9‐dimethyl‐5‐oxo‐4H‐chromeno	
[3,4‐c]pyridine‐3(5H)‐carboxamide	 (10)	 (Scheme	 5)	 and										
3‐amino‐3,4‐dihydro‐4‐imino‐7,9‐dimethylchromeno[3,4‐c]	
pyridin‐5‐one	 (11)	 (Scheme	 6)	 respectively.	 Also,	 the	
cyclocondensation	reaction	of	compound	(8)	by	acid	hydrolysis	
of	 cyano	 group,	 followed	 by	 cyclization	 to	 give	 7,9‐dimethyl‐
3H‐chromeno[3,4‐c]pyridine‐4,5‐dione	(12)	(Scheme	6).	

The	 formation	 of	 cyclocondensation	 products	 (9‐11)	
proceeded	 via	 the	 nucleophilic	 replacement	 of	 NH2	 group	 of	
amine	derivatives	to	‐N(CH3)2	group	of	compound	8	to	give	the	
intermediate	 products	 13,	 which	 can	 be	 cyclised	 by	
nucleophilic	addition	of	NH	group	to	C≡N	group	(Scheme	7).	
	
3.2.	Molecular	orbital	calculations		
	

The	 experimental	 IR	 frequencies	 of	 C=O	 groups	 of	
coumarin	 derivatives	 were	 compared	 with	 theoretical	 bond	
lengths	 of	 C=O	 groups	 which	 were	 obtained	 from	 molecular	
mechanical	calculations	on	the	basis	of	the	semi‐empirical	AM1	
and	Ab	 Initio	 (STO‐3G)	methods	of	HyperChem	8.03	computer	
program	 after	 geometrical	 optimization	 of	 the	 structures	 for	
compounds	(2‐12)	(Table	1).	

	



El‐Shaaer	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	172‐178	 177	
 

	

 
	

Scheme	7	
	
	
Table	1.	Calculated	bond	lengths	of	C=O	of	coumarin	derivatives	by	Semi‐empirical	AM1	and	Ab	initio	(STO‐3G)	methods	and	their	experimental	IR	C=O	values	
for	compounds	(2‐12).	

Compound	 Bond	lengths	of	C=O	(Å)	
(by	Semi‐empirical	AM1)	

Bond	lengths	of	C=O	(Å)
[by	Ab	Initio	(STO‐3G)]	 Experimental	C=O	values,	cm‐1	

2	 1.22839	 1.22747 1721
3a	 1.22773a	 1.22604a	 1721	
3b	 1.24427b	 1.23136b	 1655	
4a	 1.23752a	 1.22672a	 1623	
4b	 1.24197b 1.22866b 1623
5b	 1.22443a	 1.22461a 1725
5b	 1.2416b	 1.22477b 1666
6	 1.24879a	 1.21852a 1660
6	 1.22183c	 1.21744c 1742
7	 1.24793a	 1.21722a 1661
7	 1.22641d	 1.22441d	 1723	
8	 1.23984	 1.2181	 1676	
9	 1.22692	 1.22684	 1702	
10	 1.22807a	 1.22699a 1731
10	 1.24126e	 1.21657e	 1669	
11	 1.22723	 1.22662 1728
12	 1.22718a	 1.21812a 1732
12	 1.24092e	 1.22168e 1667
a	COcoumarin	
b	C=Ocyclic	ketone	
c	C=Oacid	
d	C=Oaldehyde	
e	C=Oamide		
	

The	calculated	bond	lengths	of	C=O	groups	(Å)	on	the	basis	
of	 semi‐empirical	 AM1	 method	 are	 linearly	 related	 to	 the	
measured	IR	νC=O	groups	(cm‐1)	for	compounds	(2‐12)	and	from	
the	 linear	 relation	 bond	 length	 (C=O)	 =	 1.699‐2.743	 νC=O,	 r	 =	
0.913	 except	4a,	4b	 (br.	 band	 of	 νC=O),	 where	 r	 is	 regression	
coefficient.	The	negative	slope	reveals	 indirect	proportionality	
of	 the	 calculated	 bond	 lengths	 with	 measured	 νC=O	 values,	
which	 agreement	 with	 Hooke’s	 law	 and	 these	 support	 the	
proposed	structures	for	the	prepared	compounds.	On	the	other	
hand,	 when	 Ab	 initio	 (STO‐3G)	 method	 was	 used,	 the	 linear	
relation	 between	 bond	 length	 (C=O)	 and	 νC=O	 not	 agreement	
which	 is	 less	 efficient	 method	 than	 the	 semi‐empirical	 AM1	
method.	
	
3.3.	Antimicrobial	activity	
	

The	newly	 synthesized	 compounds	were	 screened	 against	
Gram‐positive	 bacteria:	 Staphylococcus	 aureus	 (ATCC 25923)	
and	 Bacillus	 subtilis	 (ATCC 6635),	 Gram‐negative	 bacteria:	
Salmonella	 typhimurium	 (ATCC	 14028)	 and	 Escherichia	 coli	
(ATCC	 25922),	 Yeast:	 Candida	 albicans	 (ATCC	 10231)	 and	
Fungus:	 Aspergillus	 fumigatus.	 The	 standardized	 disc‐agar	

diffusion	method	[18]	was	followed	to	determine	the	activity	of	
the	synthesized	compounds	against the	tested	microorganisms.	

The	 tested	 compounds	 were	 dissolved	 in	 dimethyl	
formamide	(DMF)	solvent	and	prepared	in	two	concentrations	
2	 and	 1	 mg/mL.	 The	 antibiotic	 chloramphencol	 was	 used	 as	
standard	 reference	 in	 the	 case	 of	 Gram‐negative	 bacteria,	
Cephalothin	 was	 used	 as	 standard	 reference	 in	 the	 case	 of	
Gram‐positive	 bacteria	 and	 cycloheximide	 was	 used	 as	
standard	reference	in	the	case	of	yeasts	and	fungi.	Compound	9	
showed	 high	 activities	 against	 Aspergillus	 fumigates	 at	
concentration	of	2	mg	and	1	mg,	while	it	showed	intermediate	
activities	 against	Bacillus	 subtilis,	Escherichia	 coli	 and	Candida	
albicans	(Table	2).	
	
Acknowledgements	

	
I	 am	 particularly	 gratitude	 to	 Dr.	 Ibrahim	 Hassan,	

Department	 of	 Plant	 Protection,	 Faculty	 of	 Agriculture,	 Al‐
Azhar	University,	 for	 his	 kind	 cooperation	 in	 carrying	out	 the	
antimicrobial	screening	throughout	this	work.	
	
	
	



178	 El‐Shaaer	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	172‐178	
	
	
Table	2.	Antimicrobial	activities	data	of	compounds	(2‐12).	

Sample	

Gram‐positive	bacteria	 Gram‐negative	bacteria	 Yeastsb	
Staphylococcus	aureus	

(ATCC	25923)	
Bacillus	subtilis	
(ATCC	6635)	

Salmonella	typhimurium
(ATCC	14028)

Escherichia	coli
(ATCC	25922)

Candida	albicans	
(ATCC	10231)	

Aspergillus	fumigatus

Concentrationg	 Concentrationg	 Concentrationg Concentrationg Concentrationg	 Concentrationg
2	 1	 2	 1	 2	 1	 2	 1	 2	 1	 2	 1	

Mean	of	zone	diametera,	mm
2	 ‐c	 ‐	 ‐	 ‐	 ‐	 ‐	 ‐	 ‐	 ‐	 ‐	 ‐	 ‐	
3	 3	Ld	 ‐	 2	L	 ‐	 2	L	 ‐	 2	L	 ‐	 3	L	 ‐	 ‐	 ‐	
4	 4	L	 ‐	 2	L	 ‐	 5	L 3	L 2	L ‐ ‐ ‐	 2	L	 ‐
5	 ‐	 ‐	 3	L	 ‐	 ‐ ‐ ‐ ‐ 2	L ‐	 5	L	 2	L
6	 4	L	 ‐	 6	L	 3	L	 4	L 2	L 5	L 2	L 3	L ‐	 ‐	 ‐
7	 2	L	 ‐	 4	L	 2	L	 3	L ‐ ‐ ‐ 4	L ‐	 ‐	 ‐
8	 2	L	 ‐	 3	L	 ‐	 ‐ ‐ ‐ ‐ ‐ ‐	 ‐	 ‐
9	 8	L	 4	L	 15	Ie	 11	L	 6	L ‐ 18	I 14	I 20	I 17	I	 29	Hf	 21	H
10	 ‐	 ‐	 3	L	 ‐	 ‐	 ‐	 3	L	 ‐	 2	L	 ‐	 2	L	 ‐	
11	 2	L	 ‐	 ‐	 ‐	 ‐	 ‐	 ‐	 ‐	 4	L	 ‐	 ‐	 ‐	
12	 ‐	 ‐	 2	L	 ‐	 ‐	 ‐	 ‐	 ‐	 ‐	 ‐	 ‐	 ‐	
Controlh	 42	 28	 38	 30	 36 25 38 30 40 28	 40	 31
a	Calculate	from	3	values.	
b	Identified	on	the	basis	of	routine	cultural,	morphological	and	microscopical	characteristics. 
c	‐ :	No	effect.	  
d L:	Low	activity	=	Mean	of	zone	diameter	≤	1/3	of	mean	zone	diameter	of	control.	
e I:	Intermediate	activity	=	Mean	of	zone	diameter	≤	2/3	of	mean	zone	diameter	of control.	
f H:	High	activity	=	Mean	of	zone	diameter	>	2/3	of	mean	zone	diameter	of	control.	
g	Concentration,	mg/mL. 
h	Chloramphencol	in	the	case	of	Gram‐positive	bacteria,	Cephalothin in	the	case	of Gram-negative	bacteria	and	cycloheximide	in	the	case	of	fungi.	
	
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