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European	Journal	of	Chemistry	4	(3)	(2013)	311‐328	

European	Journal	of	Chemistry	
ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2013	EURJCHEM	

DOI:10.5155/eurjchem.4.3.311‐328.815	

	
	

	

	

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

	 	 	

3‐Formylchromones	as	diverse	building	blocks	in	heterocycles	synthesis	

Magdy	Ahmed	Ibrahim,	Tarik	El‐Sayed	Ali	*,		
Nasser	Mohamed	El‐Gohary,	and	Azza	Mohamed	El‐Kazak	

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.:	+2.01.003730144;	fax:	+2.02.2581243.	E‐mail	address:	tarik_elsayed1975@yahoo.com	(T.E.	Ali).	

	
	

	 	

	 	 	
REVIEW	INFORMATION	 	 ABSTRACT	
Received:	29	April	2013	
Accepted:	03	June	2013	
Online:	30	September	2013	

KEYWORDS	

	 This	 review	 covers	 the	 chemical	 reactivity	 of	 3‐formylchromones	 towards	 condensation
reactions	 with	 a	 variety	 of	 carbon	 and	 nitrogen	 nucleophiles.	 Some	 chromone	 derivatives
linked	 a	 variety	 of	 heterocyclic	 systems	were	 prepared	 from	 the	 direct	 condensation	 of	 3‐
formylchromones	 with	 heterocyclic	 compounds	 containing	 active	 methylene	 groups.	 A
diverse	 number	 of	 fused	 heterocyclic	 systems	 were	 prepared	 from	 the	 reaction	 of	 3‐
formylchromones	 with	 some	 bifunctional	 nucleophiles,	 these	 reactions	 mainly	 proceed	 via
condensation	with	the	aldehydic	function	followed	by	nucleophilic	attack	at	C‐2	position	of	the
chromone	moiety.	

Addition	reactions	
Ring	transformation	
3‐Formylchromones	
γ‐Pyrone	ring	opening		
Condensation	reaction	
Carbon	and	nitrogen	nucleophiles	

	
1.	Introduction	
	

Chromone	 derivatives	 are	 widely	 known	 as	 an	 important	
class	of	biologically	active	compounds.	The	chemical	reactivity	
of	 3‐substituted	 chromones	 is	 widely	 different	 depending	 on	
the	nature	of	the	functional	group	present	at	the	position	3	and	
the	 reaction	 conditions.	 Among	 the	 3‐functionalized	
chromones,	 their	 3‐formyl	 derivatives	 are	 widely	 used	 in	
heterocyclic	 synthesis.	 3‐Formylchromones	are	also	 known	as	
4‐oxo‐4H‐1‐benzopyran‐3‐carboxaldehydes,	 4‐oxo‐4H‐chro‐
mene‐3‐carboxaldehydes	 and	 chromone‐3‐carboxaldehydes.	
Although	 many	 methods	 are	 known	 for	 the	 synthesis	 of	 3‐
formylchromones,	 Vilsmeier‐Haack	 reaction	 on	 substituted	 2‐
hydroxyacetophenones	is	the	most	suitable	among	them	[1‐17].	
In	Vilsmeier‐Haack	reaction,	the	reaction	takes	place	via	double	
formylation	 of	 o‐hydroxyacetophenones	 followed	 by	 cyclo‐
addition	with	concomitant	dehydration	(Scheme	1).	DMF‐POCl3	
plays	a	dual	role	of	a	reagent	as	well	as	a	solvent.	A	variety	of	
substituted	 3‐formylchromones	 1a‐z	 were	 prepared	 under	
traditional	 and	 microwave	 irradiation	 using	 Vilsmeier‐Haack	
reagent	and	are	reported	herein.		
	
2.	Chemical	reactivity	of	3‐formylchromones	
	

3‐Formylchromones,	1a‐z,	 are	a	versatile	synthons	 for	 the	
synthesis	of	a	variety	of	novel	heterocyclic	systems	possessing	
diverse	 biological	 activities.	 From	 a	 synthetic	 view	 point,	 3‐
formylchromones,1a‐z,	 occupy	 an	 important	 position	 in	 the	
synthesis	 of	 various	 heterocyclic	 systems,	 due	 to	 the	
availability	 of	 three	 electron	 deficient	 sites,	 the	 aldehydes	
carbon,	C‐2	carbon,	and	the	C‐4	carbon	of	 the	carbonyl	group.	
Also,	3‐formylchromones	are	able	to	serve	as	a	heterodiene	as	
well	as	a	dienophile	or	a	Michael	acceptor.	Moreover,	a	variety	
of	fused	heterocycles	were	prepared	directly	from	the	reaction	
of	 compounds	 1a‐z	with	 some	 bifunctional	 nucleophiles.	 The	
present	 review	 aims	 to	 study	 the	 chemical	 reactivity	 of	 3‐

formylchromones	 towards	 a	 variety	 of	 carbon	 and	 nitrogen	
nucleophiles	under	different	reaction	conditions.	
	
2.1.	Chemical	reactivity	of	3‐formylchromones	towards	
active	methyl	and	methylene	compounds	
	
2.1.1.	Condensation	reactions	with	active	methyl	compounds	
	

Condensation	 reactions	of	3‐formylchromone	1a‐c,	h	with	
substituted	 acetophenone	 2	 in	 freshly	 distilled	 pyridine	 or	
glacial	 acetic	 acid	 containing	 perchloric	 acid	 afforded	
substituted	3‐(3‐oxo‐3‐arylprop‐1‐enyl)chromones,	3	 (Scheme	
2)	[18‐21].	

4‐Hydroxy‐1‐alkyl‐3‐[3‐(4‐oxo‐4H‐chromen‐3‐yl)]quinolin‐
2(1H)‐ones	 (5)	 were	 smoothly	 obtained	 via	 a	 Knoevenagel	
condensation	 of	 3‐formylchromone	 (1a)	 with	 3‐acetyl‐4‐
hydroxy‐1‐alkylquinolin‐2(1H)‐one	 (4)	 in	 ethanol	 containing	
piperidine	as	basic	catalyst	(Scheme	3)	[22,23].	

Interaction	 of	 equimolar	 amount	 of	 3‐formyl‐6‐
chlorochromone	 (1c)	 with	 4‐acetyl‐5,6‐diphenylpyridazin‐
3(2H)‐one	 (6)	 in	 sodium	 ethoxide	 afforded	 4‐[3‐(6‐chloro‐4‐
oxochromen‐3‐yl)prop‐2‐enoyl]‐5,6‐diphenylpyridazin‐3(2H)‐
one	 (7)	 in	 87%	 yield.	When	 this	 reaction	 was	 carried	 out	 in	
ethanol	 containing	 few	 drops	 of	 piperidine,	 7‐(6‐chloro‐4‐
oxochromen‐3‐yl)‐3,4‐diphenyl‐6,7‐dihydropyrano[2,3‐c]‐
pyraidazin‐5‐one	 (8)	 was	 obtained	 in	 55%	 yield,	 via	
intramolecular	cycloaddition	reaction	in	compound	7	 (Scheme	
4)	[24].	

Treating	 3‐formylchromones	 1a‐c	 with	 5‐acetylbarbituric	
acid	 (9a)	 and	 5‐acetylthiobarbituric	 acid	 (9b),	 in	 ethanol	
containing	 pyridine	 or	 water‐Zn(L‐proline)2,	 gave	 the	
corresponding	α,β‐unsaturated	ketones,	10a,b	(Scheme	5)	[25].	

Similarly,	 treating	 3‐formylchromones	1a,b	with	 5‐acetyl‐
1,3‐dimethylbarbituric	 acid	 (11)	 under	 the	 same	 reaction	
conditions	 afforded	 1‐(1,3‐dimethyl‐2,4,6‐pyrimidinetrione‐5‐
yl)‐3‐(4‐oxo‐4H‐chromen‐3‐yl)‐2‐propen‐1‐one	(12a)	and		



312	 Ibrahim	et	al.	/	European	Journal	of	Chemistry	4	(3)	(2013)	311‐328	
	
	

	
	
1	 R1	 R2	 R3	 R4	 Yield	(%)	 M.p.(°C)	
a	 H	 H	 H	 H 63 150‐151	
b	 H	 Me	 H	 H 65 174‐175	
c	 H	 Cl	 H	 H 72 166‐168	
d	 H	 Br	 H	 H 57 190‐191	
e	 H	 F	 H	 H	 76	 155‐160	
f	 H	 OH	 H	 H	 55	 210‐212	
g	 H	 NO2	 H	 H	 82	 253‐254	
h	 H	 H	 OH	 H	 41	 269	
i	 H	 H	 OMe H 62 188‐190	
j	 H	 OMe	 H	 H 65 174‐175	
k	 H	 H	 H	 allyl 42 73‐74	
l	 H	 Me	 Me	 H 63 192‐193	
m	 Me	 H	 Me	 H 68 145‐147	
n	 H	 Me	 H	 Me 61 187‐190	
o	 H	 Me	 H	 Cl 69 170‐171	
p	 H	 Me	 Cl	 H	 45	 166‐167	
q	 H	 Cl	 H	 Cl	 46	 169‐174	
r	 H	 Br	 H	 Br 40 177‐178	
s	 H	 Cl	 H	 NO2	 67	 108	
t	 H	 Cl	 H	 Br	 65	 155	
u	 H	 Me	 H	 NO2 69 180	
v	 H	 Me	 H	 Br 66 145	
w	 H	 NO2	 H	 Br 63 81	
x	 H	 OH	 H	 H 68 198	
y	 H	 H	 OH	 NO2 64 162	
z	 H	 H	 OH	 Br 74 210	

	
Scheme	1	

	
	

1‐(1,3‐dimethyl‐2,4,6‐pyrimidinetrione‐5‐yl)‐3‐(6‐methyl‐
4‐oxo‐4H‐chromen‐3‐yl)‐2‐propen‐1‐one	 (12b),	 respectively	
(Scheme	6)	[26].	
	

	

	
	

Scheme	2	
	
	

	
	

Scheme	3	
	
	

	
	

Scheme	4	

	
	

Scheme	5	
	
	

O

O

CHOR

+

N

O

Me

O N

O

O

Me

Me
O

O

N

N

O

Me

O

Me

R=H, Me

EtOH/ pyridine
or water/Zn(L-proline)2

86-92%

1a,b
11 12a,b

O

O

R

	

Scheme	6	
	

Condensation	 of	 3‐formylchromones	 1a‐c	 with	
dehydroacetic	 acid	 (13)	 in	 ethanol	 containing	 pyridine	 or	
water‐Zn(L‐proline)2	 gave	α,β‐unsaturated	ketones	14	 in	high	
yields	(87‐92%)	(Scheme	7)	[26].	
	

	

Scheme	7	
	

Refluxing	 3‐formylchromones	 1a‐c	 with	 3‐acetyl‐4‐
hydroxycoumarin	(17)	in	ethanol	containing	pyridine	as	a	basic	
catalyst	gave	1‐(4‐hydroxychromen‐2‐one‐3‐yl)‐3‐(chromen‐4‐
one‐3‐yl)‐2‐propen‐1‐ones	 (18)	 in	 65‐92%	 yields	 (Scheme8)	
[26,27].	
	



Ibrahim	et	al.	/	European	Journal	of	Chemistry	4	(3)	(2013)	311‐328	 313	
 

Scheme	8	
	

Reaction	 of	 6,8‐dichloro‐3‐formylchromone	 (1q)	 with	 4‐
methyl‐2‐oxo‐2H‐chromone‐3‐carbonitrile	 (19)	 gave	 the	
addition	 product	 20	 as	 recently	 reported	 by	 El‐Shaaer	 [28].	
While	Melikyan	et	al.	[29]	isolate	the	condensation	products	21	
on	the	reaction	of	1a‐d	with	compound	19	in	refluxing	toluene	
(Scheme	9).		
	

	
	

Scheme	9	
	

Condensation	 of	 3‐formylchromone	 (1a)	with	 2‐methyl‐3‐
acetylchromones	22	 in	acetic	anhydride‐potassium	acetate	led	
to	 bis‐chromonylethylene	 23	 (Scheme	 10).	 This	 reaction	
occurred	only	at	2‐methyl	group	[30].	
	

	
	

Scheme	10	
	
2‐(4‐Oxo‐4H‐chromen‐3‐yl)vinylthiazoline	 (24)	 was	

synthesized	by	condensation	of	3‐formylchromone	1a	with	2‐
methylthiazoline	 in	 glacial	 acetic	 acid	 containing	 sodium	
acetate	(Scheme	11)	[31].		

	

	
	

Scheme	11	
	

Condensation	 of	 3‐formylchromone	 (1a)	 with	 4,5,5‐
trimethyl‐2,5‐dihydrofuran‐2‐ones	25	 and	 4,6,6‐trimethyl‐5,6‐
dihydropyran‐2‐ones	 26	 in	 acetic	 anhydride	 yielded	 the	
condensation	 products	 27	 and	 28,	 respectively	 (Scheme	 12)	
[29].	
	

O

O

CHO

O OMe
Me

Me R

O OMe

Me

Me
R

65-75%

O

O

Me
Me

RO

O

O

O

MeMe

R
O

O

1a

25

26

27

28
R=H, Me

R=H, Me

Ac2O

	
	

Scheme	12	

3‐Formylchromones	 1b,c	 reacted	 with	 2‐
methylbenzimidazole	 29a	 and	 2‐methylbenzothiazole	 29b	 in	
dry	DMSO	 and	boric	 acid	 to	 give	 the	 addition	products	30a,b	
when	 the	 reactiontook	 place	 at	 60	 °C,	 but	 when	 the	 reaction	
took	place	at	120	°C	afforded	the	condensation	products	31a,b	
(Scheme	13)	[32].	
	

	
	

Scheme	13	
	

Condensation	 of	 aldehydes	 1a,b	 with	 2‐methylbenzo‐
thiazolium	 halides	 32	 in	 boiling	 acetonitrile	 gave	
chromenylbenzothiazolium	derivatives	33	(Scheme	14)	[33].		
	

	
	

Scheme	14	
	

Treatment	 of	 3‐formylchromone	1a	 with	 3‐aryl‐2‐methyl‐
4(3H)‐quinazolinones	 (34)	 in	 glacial	 acetic	 acid	 containing	
fused	sodium	acetate	led	to	the	condensed	product	35	(Scheme	
15)	[33].	
	

	
	

Scheme	15	
	

As	 a	 result	 of	 the	 above	 reactions,	 a	 variety	 of	 chromone	
derivatives	bearing	various	heterocyclic	systems	were	obtained	
from	the	condensation	of	3‐formylchromones	with	some	active	
methyl	compounds	either	under	acidic	or	basic	conditions.		

	
2.1.2.	Condensation	reactions	with	acyclic	active	methylene	
compounds	
	

3‐Styrylchromone	37,	 which	 is	 associated	with	 important	
biological	 activities,	 was	 obtained	 by	 the	 condensation	 of	 4‐
nitrotoluene	 or	 4‐nitrophenylacetic	 acid	 36	 with	 3‐formyl‐
chromone	1a	in	dry	pyridine	(Scheme	16)	[34,35].	
	

	
	

Scheme	16	
	

Synthesis	 of	 transβ‐(chromon‐3‐yl)acrylic	 acids	 38	 were	
made	 by	 simple	 Knoevenagel	 condensation	 of	 3‐formyl‐



314	 Ibrahim	et	al.	/	European	Journal	of	Chemistry	4	(3)	(2013)	311‐328	
	
chromones	 1a,b,k	 with	 malonic	 acid	 in	 dry	 pyridine	 under	
reflux	(Scheme	17)	[17,36‐38].	
	

	
	

Scheme	17	
	

6,8‐Dimethylcoumarin‐4‐acetic	 acid	 (39)	 gave	 3‐styryl‐
chromones	40	when	reacted	with	3‐formyl‐chromones	1a,b	in	
boiling	pyridine,	via	condensation	followed	by	decarboxylation	
under	the	reaction	conditions	(Scheme	18)	[39].	
	

	
	

Scheme	18	
	

In	the	same	manner,	3‐formylchromones	1a‐c	reacted	with	
benzo[d]isoxazol‐3‐ylacetic	 acid	 (41)	 in	 dry	 pyridine	 under	
reflux	to	give	3‐(2‐benzo[d]isoxazol‐3‐ylvinyl)‐chromon‐4‐ones	
42	in51‐62%	yields	(Scheme	19)	[40].	
	

	
	

Scheme	19	
	
Heating	 equimolar	 quantities	 of	 3‐formylchromones	 1a,b	

and	 phenylacetic	 acids	 43	 in	 acetic	 anhydride	 containing	
catalytic	 amounts	 of	 sodium	 acetate	 or	 potassium	 carbonate	
gave	 methyl	 2‐oxo‐2H,5H‐pyrano[3,2‐c]chromen‐5‐yl	 acetates	
44	in	48‐85%	yields	(Scheme	20),	[41‐43]	while	Shingare	et	al.	
[44]	reported	the	formation	of	compounds	45	in	47‐68%	yields	
in	 acetic	 anhydride	 containing	 piperidine	 as	 a	 catalyst,	 the	
spectral	 data	 showed	 the	 presence	 of	 acetyl	 instead	 of	 the	
carboxy	 group,	 which	 could	 be	 explained	 by	 decarboxylation	
followed	by	acetylation	in	situ	(Scheme	20).	
	

	
	

Scheme	20	
	

Condensation	 of	 3‐formylchromones	 1a‐c,g	 with	 3‐	 or	 4‐
coumarinylacetic	 acids	 in	 acetic	 anhydride	 in	 the	 presence	 of	
potassium	 acetate	 either	 by	 heating	 at	 90‐100	 °C	 or	 by	
microwave	 irradiation	 produced	 compounds	 46	 and	 47,	
respectively	(Scheme	21)	[41].		
	

	
	

Scheme	21	
	

Reactions	 of	 3‐formylchromones	 1a‐c	 with	 4‐substituted	
phenylselenylacetic	 acids	 48	 in	 acetic	 anhydride	 containing	
potassium	 acetate	 yielded	 3‐(phenylselenyl)‐2‐oxo‐2H,5H‐
pyrano[3,2‐c]chromen‐5‐yl	 acetates	 49	 and	 not	 the	 other	
expected	products	50	(Scheme	22)	[45].	
	

O

O

CHOR
+

SeCH2CO2H

R

Ac2O,AcOK

O

O

Se

R

OCOMe

O

R

R= H, Me, Cl

80%

1a-c 48

49

O

O

R Se

R

50

R1 = H, Br

1

1

1

	
	

Scheme	22	
	

Synthesis	 of	 trans‐β‐(4‐oxo‐4H‐chromen‐3‐yl)acrylonitrile	
51	was	 made	 by	 simple	 condensation	 of	 3‐formylchromones	
1a,b	 with	 cyanoacetic	 acid	 in	 dry	 pyridine	 under	 reflux	
(Scheme	23)	[46,47].		
	

	
	

Scheme	23	
	

Condensation	 of	 3‐formylchromones	 1a,b,d	 with	 p‐
nitrobenzyl	 cyanide	 and	 1‐naphthyl‐acetonitrile	 in	 the	
presence	 of	 Ac2O/AcOK	 or	 Ac2O/AcONa	 afforded	 the	
corresponding	condensation	products	52	and	53,	 respectively	
(Scheme	24)	[48].		
	

	
	

Scheme	24	
	
	
	



Ibrahim	et	al.	/	European	Journal	of	Chemistry	4	(3)	(2013)	311‐328	 315	
 

Similarly,	 condensation	 of	 3‐formychromones	 1a,	 with	
tetrazolyl‐p‐nitrotoluene	 (54)	 in	 dry	 pyridine	 gave	 3‐[2‐(4‐
nitrophenyl)‐2‐(1H‐tetrazol‐5‐yl)vinyl)]‐4H‐chromen‐4‐one	
(55)	(Scheme	25)	[49].	
	

	
	

Scheme	25	
	

3‐Formylchromones	 1a‐c	 condensed	 with	 1‐(2,4‐
difluorophenyl‐2‐[1,2,4]triazol‐4‐yl]ethanone	 (56)	 in	 acetic	
anhydride	containing	anhydrous	sodium	acetate	to	afford	3‐[3‐
(2,4‐difluorophenyl)‐3‐oxo‐2‐[1,2,4]triazol‐4‐yl)propenyl]	
chromon‐4‐ones	(57)	(Scheme	26)	[50].		
	

	
	

Scheme	26	
	

Knoevenagel	 condensation	 of	 3‐formyl‐7‐methoxy	
chromone	 1i	 with	 ethyl	 3‐(6‐methoxy‐1,3‐benzodioxol‐5‐yl)	
propanoate	58	gave	ethyl	ester	59	(Scheme	27)	[51].	

	

	
	

Scheme	27	
	
Condensation	of	3‐formylchromones	1a,b,d,j	with	phenacyl	

aryl	 sulfones	60,	 in	 glacial	 acetic	 acid	 and	 acetic	 anhydride	 in	
the	 presence	 of	 benzylamine	 as	 catalyst,	 yielded	 1‐(aroyl)‐1‐
(arylsulfonyl)‐	 2‐[4‐oxo‐4H‐chromen‐3‐yl]ethenes	61	 (Scheme	
28)	[52].	
	

	
	

Scheme	28	
	

When	 3‐formylchromone	 (1a)	 was	 treated	 with	 5‐nitro	
furyl	 trichloromethyl	 sulfone	 (62),	 in	glacial	 acetic	acid	 in	 the	
presence	 of	 ammonium	 acetate	 and	 piperidine,	 gave	 the	
condensation	product	63	(Scheme	29)	[52].	
	

	
	

Scheme	29	
	

Condensation	product	64	was	synthesized	by	reaction	of	3‐
formylchromones	 1a,b,c,g	 and	 2,4‐pentanedione	 in	 acetic	
anhydride	containing	sodium	acetate.	While,	acid	catalyzed	1,4‐
addition	 of	 the	 enol	 form	 of	 2,4‐pentanedione	 to	 3‐formyl	
chromones	1a,b,c,g	 followed	 by	 ring	 opening	 and	 enolization	
afforded	 5‐benzoyl‐2‐hydroxyacetophenones	 65	 (Scheme	 30)	
[53,54].	
	

	
	

Scheme	30	
	

Treatment	 of	 3‐formylchromone	 (1a)	 with	 ethyl	
acetoacetate	 in	 acetic	 anhydride	 containing	 sodium	 acetate	
yielded	 3‐(4‐oxo‐4H‐1‐chromen‐3‐yl)‐2‐(1‐oxoethyl)‐2‐
propenoic	 acid	 ethyl	 ester	 (66)	 in	 62%	yield.	However,	when	
the	reaction	was	carried	out	with	a	(1:2)	excess	of	the	reagent	
using	 piperidine	 in	 ethanol,	 5‐(2‐hydroxybenzoyl)‐2‐
methylbenzene‐1,3‐dicarboxylic	 acid	 diethyl	 ester	 (67)	 was	
isolated	in	80%	yield	(Scheme	31)	[54,55].	
	

 
	

Scheme	31	
	
Knoevenagel	 condensation	 of	 3‐formylchromones	 1a‐c	

with	malononitrile,	cyanoacetic	acid	and	cyanoacetamide	were	
carried	 out	 in	 various	 solvents	 such	 as	 water,	 ethanol,	
methanol,	DMF,	DMSO	and	toluene	(Scheme	32).	Among	these	
solvents,	 water	 was	 found	 to	 be	 the	 best	 solvent	 for	 the	
reaction	to	produce	ylidenenitriles	68	in	excellent	yields	[56].	
	

	
	

Scheme	32	
	

Reaction	 of	 aldehyde	 1a‐c	 with	 chloroacetone	 in	 basic	
medium	 gave	 a	 mixture	 of	 arylidine	 69	 (22‐32%)	 and	 o‐
hydroxyphenyl	furyl	ketone	70	(Scheme	33)	[57].		
	

	
	

Scheme	33	
	



316	 Ibrahim	et	al.	/	European	Journal	of	Chemistry	4	(3)	(2013)	311‐328	
	

Condensation	 of	 3‐formylchromones	 1a‐c	 with	 diethyl	
malonate	 in	 acetic	 anhydride	 containing	 sodium	 acetate	 gave	
diethyl	arylidine	ester	71	in	74‐80%	yield	(Scheme	34)	[58].	
	

	
	

Scheme	34	
	

Treatment	of	3‐formylchromone	(1a)	with	3(4`,5`‐dihydro‐
4`‐oxo‐1`‐phenylpyrazolo[3,4‐d]pyrimidin‐5`‐yl)‐3‐
oxopropionic	 acid	 ethyl	 ester	 (72)	 in	 ethanol	 containing	
piperidine	 afforded	 3‐{(4‐oxo‐4H‐chromen‐3‐yl)‐2‐(4,5‐
dihydro‐4‐oxo‐1‐phenylpyrazolo[3,4‐d]pyrimidine‐5`‐
carbonyl}acrylic	acid	ethyl	ester	(73)	(Scheme	35)	[59].	
	

	
	

Scheme	35	
	

3‐Formylchromone	(1a)	reacted	with	acetamides	74	in	dry	
pyridine	 to	 afford	 a	 mixture	 of	 chromenopyridones	 75	 and	
pyridone	derivatives	76	(Scheme	36)	[60,61].	
	

O

O

CHO

R= CN, COMe, CONH2

O

NH

O

O

R1a

+
R

CONH2 NH

OOH

O

R

+

75 76

74

	
	

Scheme	36	
	

3‐Formylchromone	 1a	 condensed	 with	 alkyl	 acetoacetate	
or	 its	 acid	 in	 the	 presence	 of	 ammonia	 to	 give	 the	 pyridine	
derivatives	77	 (46‐50%).	While,	 aldehyde	1a	 condensed	with	
acetoacetamide	 to	 produce	 the	 2‐pyridone	 derivative	 78	
(Scheme	 37).	 The	 reaction	 involves	 ring	 opening	 of	 pyrone	
moiety	at	C2	[62‐64].		
	

 
	

Scheme	37	
	

When	 3‐formylchromones	 1a‐c,g	 were	 allowed	 to	 react	
with	equimolar	amounts	of	tosylmethyl	isocyanide	(TOSMIC)	in	
THF	 in	 the	 presence	 of	 mild	 base	 as	 1,8‐diazabicyclo[5,4,0]	
undec7‐ene	 (DBU)	 at	 room	 temperature,	 the	 2‐tosyl‐5‐(2‐
hydroxybenzoyl)pyrroles	 79	 were	 isolated	 in	 good	 yields	
(Scheme	38)	[65].	
	

	
	

Scheme	38	
	

Condensation	 of	 3‐formylchromones	 1a‐d	 with	 1H‐
benzimidazole‐2‐acetonitrile	 (80)	 in	 ethanol	 at	 room	
temperature	gave	the	carbonitrile	derivative	81	in	96%.	When	
the	reaction	was	carried	out	with	in	boiling	ethylene	glycol,	4‐
cyano‐2‐(2‐hydroxybenzoyl)pyrido[1,2‐a]benzimidazoles	 82	
were	obtainedin	70‐81%	yields	(Scheme	39)	[66,67]	
	

	
	

Scheme	39	
	

Refluxing	 1a	 with	 pyrazolinyltriazinylacetonitrile	 (83)	 in	
ethanol	 containing	 few	 drops	 of	 piperidine	 gave	 the	
condensation	 product	 84	 in	 95%	 yield,	 as	 antitumor	 agent	
(Scheme	40)	[68].	
	

	
	

Scheme	40	
	

Condensation	 of	 1a	 with	 imidazole	 derivative	 85	 in	
Me3SiCl/DMF	produced	the	imidazo[1,2‐a]	pyridine	86	in	75%	
yield	(Scheme	41)	[69].	
	

	
	

Scheme	41	
	

Oxazolones	87	were	readily	obtained	 from	 the	reaction	of	
3‐formylchromones	1a,b	and	N‐acetyl/	benzoylglycine	in	acetic	
anhydride	containing	freshly	fused	sodium	acetate	(Scheme	42)	
[17,70,71].	
	

	
	

Scheme	42	
	

On	 the	 other	 hand,	 the	 isoxazolone	 derivatives	 88	 were	
obtained	 in	 good	 yields	 (81‐89%)	 from	 the	 Knoevenagel	
condensation	 of	 3‐formylchromones	 1a‐d	 with	 3‐methyl	 (or	



Ibrahim	et	al.	/	European	Journal	of	Chemistry	4	(3)	(2013)	311‐328	 317	
 

phenyl)‐5‐isoxazolone	in	ethanol	at	room	temperature	(Scheme	
43)	[72].		
	

	
	

Scheme	43	
	

3‐Formylchromone	 1a	 reacted	 with	 hetarylmethylamines	
89	in	DMF	under	heating	by	molar	ratio	1:1	in	the	presence	of	4	
molar	equivalents	of	Me3SiCl	(trimethylsilyl	chloride)	to	give	5‐
hetaryl‐[1H‐pyrrol‐3‐yl](2‐hydroxyphenyl)methanones	 90	 in	
68‐91%	yields.	When	the	reaction	carried	out	in	molar	ratio	2:1	
(3‐formylchromone:	 amines),	 the	 fused	 chromonopyrrolyl	
chromones	 91	 were	 obtainedin	 54‐64%	 yields	 (Scheme	 44)	
[73].	
	

	
	

Scheme	44	
	

Cyclocondensation	 of	 3‐formylchromone	 1a	 with	 glycine	
derivatives	 92	 in	 the	 presence	 of	 Me3SiCl	 (4	 equivalents)	
afforded	 pyrrole	 derivatives	 93	 in	 moderated	 yield	 (Scheme	
45)	[73].	
	

	
	

Scheme	45	
	
A	 high	 yield	 of	 the	 novel	 pyrrolo[2,1‐a]isoquinoline	

derivative	 94	 was	 prepared	 from	 the	 reaction	 of	 3‐formyl	
chromone	 1a	 with	 isoquinoline	 and	 phenacyl	 bromide	 in	
aqueous	 medim	 containing	 DBU	 as	 a	 catalyst	 as	 reported	 by	
Naskar	et	al.	(Scheme	46)	[74].	
	

	
	

Scheme	46	
	
Therefore,	condensation	of	3‐formylchromones	with	acyclic	

active	 methylene	 compounds	 produced	 the	 corresponding	
condensation	products	 or	 a	 variety	 of	 products	 depending	 on	
the	reagent	used	and	the	reaction	conditions.	
	

2.1.3.	Condensation	reactions	with	cyclic	active	methylene	
compounds	
	

Condensation	 of	 3‐formylchromones	 1a‐d,g	 with	 1,3‐
indandione	 95	 in	 glacial	 acetic	 acid	 containing	 piperidine	
afforded	 the	 condensation	 products	 96	 in	 61‐92%	 yields	
(Scheme	47)	[75].		
	

	
	

Scheme	47	
	

Treatment	 of	 3‐formylchromone	 1a	 with	 3‐oxo‐2,3‐
dihydrobenzo[b]thiophene‐1,1‐dioxide	 97a	 and	 oxindole	
(indolone)	 97b	 in	 dry	 pyridine	 afforded	 the	 corresponding	
condensation	products	98	(Scheme	48)	[76].		
	

	
	

Scheme	48	
	

Simple	condensation	of	aldehyde	1a	with	indolinone	99a,b	
in	 the	 presence	 of	 sodium	 bicarbonate	 under	 microwave	
irradiationyielded	(1H)‐3‐(4‐oxo‐4H‐chromen‐3‐yl)	methylene]	
indolin‐2‐one	 (100a)	 and	 1‐[(2,6‐dichlorophenyl)‐3‐(4‐oxo‐
4H‐chromen‐3‐yl)methylene]	 indolin‐2‐one	 (100b),	
respectively	(Scheme	49)	[76,77].		
	

	
	

Scheme	49	
	
Condensation	 reaction	 of	 1a	 and	 pyrazolone	 derivatives	

101a,b	 in	 1:1	 molar	 ratio,	 under	 classical	 method	 or	
microwave	 irradiation,	 afforded	 1‐aryl‐3‐methyl‐4‐(4‐oxo‐4H‐
chromen‐3‐yl)methylene]pyrazol‐5(4H)‐ones	(102a,b),	[77,78]	
while	using	1:2	molar	ratio	afforded	the	new	1‐(chromon‐3‐yl)‐
1,1‐bis(4‐hydroxy‐6‐methyl‐2‐oxo‐2H‐pyran‐3‐yl)methane	103	
(Scheme	50)	[79].	
	

	

Scheme	50	
	

Condensation	 of	 3‐formylchromone	 (1a)	 with	 1‐
phenylpyrazolidine‐3,5‐dione	 (104)	 in	 glacial	 acetic	 acid	
containing	 freshly	 fused	 sodium	 acetate,	 gave	 4‐[(4‐oxo‐4H‐



318	 Ibrahim	et	al.	/	European	Journal	of	Chemistry	4	(3)	(2013)	311‐328	
	
chromen‐3‐yl)methylene]‐1‐phenyl‐pyrazolidine‐3,5‐dione	
(105)	(Scheme	51)	[80].		
	

	
	

Scheme	51	
	

Also,	 treatment	 of	 3‐formylchromones	 1a‐c,e	 with	 3‐
(trifluoromethyl)‐1‐phenyl‐1H‐pyrazol‐5(4H)‐one	 (106)	 in	
acetic	acid	yielded	3‐(trifluoromethyl)‐4‐[(6‐substituted	4‐oxo‐
4H‐chromon‐3‐yl)methylene]‐1‐phenyl‐1H‐pyrazol‐5(4H)‐ones	
107	in70%	yield	(Scheme	52)	[81].		
	

	
	

Scheme	52	
	

Condensation	 of	 1a	 with	 pyrazolinone	 108a	 and	
isoxazolinone	 108b	 in	 acetic	 acid	 containing	 fused	 sodium	
acetate	 gave	 5{4‐[(4‐oxo‐4H‐chromen‐3‐yl)methylene‐5‐oxo‐
4,5‐dihydro‐1H‐pyrazol‐3‐yl)]}‐1‐phenylpyrazolo[3,4‐d]	
pyrimidin‐4‐one	 109a	 and	 5‐{4‐[(4‐oxo‐4H‐chromen‐3‐
yl)methylene‐5‐oxo‐4,5‐dihydroisoxazol‐3‐yl)]}‐1‐phenyl	
pyrazolo[3,4‐d]pyrimidin‐4‐one	 109b,	 respectively	 (Scheme	
53)	[59].		
	

	
	

Scheme	53	
	

Similarly,	 condensation	 of	 3‐formylchromone	 (1a)	 with	
pyrazol‐3‐ylquinoline	 derivative	 110	 in	 glacial	 acetic	 acid	
containing	 sodium	 acetate	 afforded	 chromenylpyrazolinone	
111	(Scheme	54)	[82].	
	

	
	

Scheme	54	
	

Also,	condensation	of	1a‐d,f,g	with	creatinine	112	in	DMSO	
using	 boric	 acid	 as	 a	 catalyst	 yielded	 2‐imino‐1‐methyl‐5‐(6‐
substituted	 4‐oxo‐4H‐chromen‐3‐yl)methylidene]imidazolin‐4‐
one	 (113).	 While,	 2‐acetamido‐1‐methyl‐5‐[(6‐substituted	 4‐
oxo‐chromen‐3‐yl)methylidene]‐4,5‐dihydroimidazol‐4‐one	
114	 was	 obtained	 when	 the	 reaction	 took	 place	 in	 acetic	
anhydride	and	potassium	acetate	(Scheme	55)	[83].		

3‐Formylchromones	 1a‐d,f,g	 condensed	 with	
thiohydantion	 115	 in	 acetic	 anhydride	 in	 the	 presence	 of	
potassium	 acetate	 under	 both	 irradiation	 and	 classical	
condition	yielded	2‐thioxo‐5‐[(6‐substituted‐4‐oxo‐chromen‐3‐
yl)methylidene]imidazolidine‐4‐ones	(116)	(Scheme	56)	[83].	

	
	

Scheme	55	
	
	

	
	

Scheme	56	
	

Chromonyl‐2,4‐thiazolidinediones	 118	 were	 prepared	 by	
the	 Knoevenagel	 condensation	 of	 2,4‐TZDs	 (2,4‐thiazolidine	
diones)	 117	 with	 3‐formylchromones	 1a,b,n	 in	 glacial	 acetic	
acid	containing	freshly	fused	sodium	acetate	(Scheme	57)	[84‐
86].		
	

	

Scheme	57	
	

Similarly,	condensation	of	3‐formylchromone	1a‐d,f,g	with	
3‐ethylrhodanine	 119	 in	 acetic	 anhydride/potassium	 acetate	
under	both	irradiation	and	classical	condition,	gave	2‐thioxo‐5‐
[(6‐substituted‐4‐oxo‐4H‐chromen‐3‐yl)methylidene]	 thiazoli‐
din‐4‐ones	120	(Scheme	58)	[83].		
	

	
	

Scheme	58	
	

Condensation	 of	 carboxaldehyde	 1f	 with	 ethyl	 2‐cyano‐2‐
(3‐phenyl‐5‐oxo‐1,3‐thiazolan‐2‐ylidene)	 acetate	 (121)	 gave	
the	corresponding	arylidene	derivative	122	(Scheme	59)	[61].		
	

	
	

Scheme	59	
	

Reaction	of	3‐formylchromone	(1a)	with	[1,3]thiazolo[3,2‐
a]benzimidazol‐3(2H)‐one	 (123)	 in	 glacial	 acetic	 acid	
containing	 fused	 sodium	 acetate	 afforded	 the	 condensation	
product	124	in	high	yield	(60‐97%)	[87].Similarly,	treating	1a	
with	 2‐methyl[1,3]thiazolo[1,2,4]triazol‐5(6H)‐one	 (125)	 in	
acetic	 anhydride/sodium	 acetate	 yielded	 the	 condensation	
product	126	in	68‐91%	yields	(Scheme	60)	[88].	

Knoevenagel	 products	 128	 were	 obtained	 in	 low	 yields	
(15‐43%)	 by	 heating	 3‐formylchromones	 1a‐c	 with	 2H‐1,4‐
benzothiazin‐3(4H)‐one	 (127)	 in	 acetic	 anhydride/potassium	
acetate	medium	 for	 6‐10	 h.	 Using	microwave	 the	 yields	were	
increased	(33‐62%)	in	short	time	(7‐20	min)	(Scheme	61)	[87].		
	



Ibrahim	et	al.	/	European	Journal	of	Chemistry	4	(3)	(2013)	311‐328	 319	
 

	
	

Scheme	60	
	
	

	
	

Scheme	61	
	
	

Reaction	 of	 6‐bromo‐3‐formylchromone	1d	with	 2‐aryl‐4‐
hyrdoxy‐6H‐1,3‐thiazin‐6‐ones	 129a,b	 in	 DMSO	 or	 pyridine	
gave	 8‐bromo‐3,10‐dioxo‐N‐(arylcarbonothioyl)‐4,4a‐dihydro‐
3H,10H‐pyrano[4,3‐b]‐chromene‐4‐carboxamides	 (130a,b)	 in	
60‐70%	yields	(Scheme	62)	[89].		
	

	
	

Scheme	62	
	

Also,	condensation	of	3‐formylchromone	1a	with	dimedone	
(5,5‐dimethylcyclohexane‐1,3‐dione)	 in	 acetic	 anhydride	
containing	 sodium	 acetate	 yielded	 the	 condensation	 products	
131	 in	54‐64%	[87].	When	the	reaction	took	place	in	aqueous	
ethanol	containing	pyridine	or	aqueous	pyridine	by	molar	ratio	
(1:2)	 afforded	 the	 adduct	 132	 which	 dehydrated	 to	
formxanthone	133	in	73%	yield	(Scheme	63)	[60,76,90].	

Meldrum's	 acid	 (2,2‐dimethyl‐1,3‐dioxane‐4,6‐dione)	
undergoes	Knoevenagel	 condensation	with	3‐formylchromone	
1a‐c,e	 producing	 the	 corresponding	 condensation	 product	
derivatives	134	in	90‐95%	yields	(Scheme	64)	[91‐93].	

Reaction	 of	 3‐formylchromones	 1a,c	 with	 4‐chromanone	
135	in	ethanol	containing	triethylamine	gave	benzopyrano‐2,3‐
dihydrobenzopyranones	 136	 in	 67‐80%	 yields	 (Scheme	 65)	
[94].		

Treatment	 of	 3‐formylchromone	 (1a)	with	barbituric	 acid	
137a,	 thiobarbituric	 acids	 137b	 and	 1,3‐dimethylbarbituric	
acid	 138	 gave	 5‐[(4‐oxo‐4H‐chromen‐3‐yl)methylene]	
pyrimidine	derivatives	139	and	140,respectively	(Scheme	66)	
[76,77].	

N‐Methylpyrrole	 reacted	with	3‐formylchromones	1a,c,d,g	
under	 solvent–free	 conditions	 exclusively	 via	 1,4‐addition	
followed	 by	 recyclization	 to	 form	 2‐hydroxy‐3‐(1‐methyl‐
pyrrol‐2‐ylmethylene)chroman‐4‐ones	 141	 in	 good	 yield	
(Scheme	67)	[95].	

	
	

Scheme	63	
	
	

	
	

Scheme	64	
	
	

	
	

Scheme	65	
	
	

	
	

Scheme	66	
	
	

	

Scheme	67	
	

A	 similar	 reaction	 of	 6,8‐dibromo‐3‐formylchromone	 (1r)	
with	indole	proceeded	exclusively	via	1,4‐addition	followed	by	
recyclization	to	form	a	mixture	of	E‐isomer	142	(91%)	and	Z‐
isomer	142	(9%)	(Scheme	68)	[95].	
	



320	 Ibrahim	et	al.	/	European	Journal	of	Chemistry	4	(3)	(2013)	311‐328	
	
	

	
	

Scheme	68	
	

	
	

Scheme	69
	

	
Reaction	 of	 3‐formyl‐6‐nitrochromone	 (1g)	 with	 N‐

methylindole	afforded	a	mixture	of	E‐(2‐hydroxy‐6‐nitro‐3‐(1‐
methyindol‐3‐ylmethylene)chroman‐4‐one	 (143)and	 the	 bis‐
adduct	144	(Scheme	69)	[95].	

On	 the	 other	 hand,	 3‐formylchromones	 1a‐c,g,j	 reacted	
without	 solvent	 with	 excess	 indole,	 1‐methyl	 or	 2‐
methylindoles	 (2	 equivalents)	 to	 give	 (chromon‐3‐yl)‐bis‐
(indol‐3‐yl)methanes	145	(Scheme	70)	[95].		
	

	
	

Scheme	70	
	

Also,	 3‐formylchromones	 1a	 reacted	 with	 triacetic	 acid	
lactone	 and	 4‐hydroxycoumarin	 derivatives	 (2	 equivalents),	
under	 conventional	 and	 solvent	 free	 methods,	 to	 give	
(chromon‐3‐yl)‐bis‐(hetaryl)methanes	 146	 and	 147,	
respectively	(Scheme	71)	[79].	
	

	
	

Scheme	71	
	

Condensation	 of	 3‐formylchromones	 1a,b	 with	 alkyl	
isocyanides	 in	 dry	 dichloromethane	 at	 room	 temperature	
afforded	 (1Z)‐3‐(alkylimino)‐1‐[(chromon‐3‐yl)methylene]‐
1,3‐dihydro‐9H‐furo	[3,4‐b]chromen‐9‐ones	148	in	good	yields	
(77‐90%)	(Scheme	72)	[96].		

The	 reaction	 of	 3‐formylchromone	 1a	 with	 3,4‐
dihydroquinoxalin‐2(1H)‐ones	 gave	 2‐(2‐hydroxy‐benzoyl)	
pyrrolo[1,2‐a]quinoxalin‐4(5H)‐ones	 149in	 52‐58%	 yields,	
respectively	(Scheme	73)	[73].		
	

	
	

Scheme	72	
	
	

	
	

Scheme	73	
	
	

Under	 acidic	 conditions,	 p‐cresol	 underwent	 1,2‐addition	
through	 C‐2	 atom	 to	 thealdehyde	 function	 of	 3‐formyl	
chromone	(1a)	to	produce	intermediate	150	which,	converted	
to	 2,14‐dimethyl‐10aH,15aH‐tribenzo[b,e,i][1,6,7]	 trioxaphen‐
alene	(151)	(Scheme	74)	[97]. 
	

	
	

Scheme	74	
	

Treating	 carboxaldehyde	 1a	 with	 β‐ketoacid	 152,	 [98]	 in	
glacial	 acetic	 acid	 containing	 freshly	 fused	 sodium	 acetate,	
yielded	 the	 Knoevenagel	 condensation	 products	 153	 which	
underwent	 dehydration	 by	 stirring	 in	 concentrated	 H2SO4	 at	
room	temperature	to	afford	3‐chromonylmethylenepyrano[3,2‐
c]quinoline	 derivatives	 154.	 Moreover,	 compound	 153	 was	
obtained	 authentically	 from	 condensation	 reaction	 of	 pyrano	
[3,2‐c]quinoline	155	with	1a	(Scheme	75)	[99].	
	



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Scheme	75	
	

Thus,	 a	 large	 number	 of	 chromone	 derivatives	 linked	 a	
variety	of	heterocyclic	systems	were	prepared	 from	the	direct	
condensation	 of	 3‐formylchromones	 with	 heterocyclic	
compounds	containing	active	methylene	groups.	
	
2.2.	Chemical	reactivity	of	3‐formylchromones	towards	
nitrogen	nucleophiles	
	
2.2.1.	Reactions	with	primary	amines	
	

A	large	group	of	3‐(aryl/heteroaryliminomethyl)chromone	
derivatives	156	were	prepared	from	condensation	reactions	of	
3‐formylchromones	 1a‐d	 with	 a	 variety	 of	 aryl/hetaryl‐
aminesin	non	polar	solvents	such	as	benzene,	toluene	or	xylene	
under	 reflux,	 in	 the	 presence	 of	 p‐toluenesulfonic	 acid	 as	 a	
catalyst	(Scheme	76)	[100‐108].	
	

	
	

Scheme	76	
	

On	 the	 other	 hand,	 reaction	 of	 3‐formylchromones	 1a‐c	
with	 equimolar	 ratio	 of	 aryl/hetarylamines	 157	 in	 boiling	
ethanol	 gave	 3‐(aryl/hetarylaminomethylene)‐2‐(ethoxy)	
chromones	 158,	 but	 when	 the	 reaction	 took	 place	 with	 two	
moles	 of	 157	 in	 dry	 toluene,	 the	 1,4‐adducts	 159	 were	
obtained	(Scheme	77)	[105‐115].	
	

	
	

Scheme	77	
	
Reaction	of	3‐formylchromone	1a	with	various	anilines	 in	

the	 presence	 of	 Me3SiCl/DMF	 led	 to	 either	 3‐(2‐
hydroxybenzoyl)quinolines	 160	 or	 7H‐chromeno[3,2‐
c]quinolin‐7‐ones	 161	 (Scheme	 78),	 depending	 on	 the	

structure	 of	 the	 starting	 aniline.	 Substituents	 in	 the	 aniline	
molecule	 that	 withdraw	 electrons	 favored	 the	 formation	 of	
161;	 on	 the	 contrary,	 electron‐rich	 anilines	 gave	 only	 160	
[116,117].	
	

	
	

Scheme	78	
	

Condensation	 of	 3‐formylchromone	 (1a)	 with	 aniline	 and	
6‐amino‐1,4‐benzoxodioxane	 in	 methanol	 gave	 3‐(aniline	
methylene)‐2‐methoxychroman‐4‐one	 (162)	 and	 3‐(1,4‐
benzodioxane‐6‐aminomethylene)‐2‐methoxychroman‐4‐one	
(163),	respectively	(Scheme	79)	[118].	

Also,	 reaction	 of	 6‐substituted	 3‐formylchromone	 1a‐c,j	
with	aromatic	amino	carboxylic	acid	164	in	benzene	or	toluene	
yielded	 only	 3‐(arylaminomethylene)‐2‐hydroxychromon‐4‐
ones	 165	 at	 room	 temperature	 or	 under	 reflux	 (Scheme	 80)	
[113].	

Treatment	 of	 3‐formylchromone	 1a	 with	 ethyl	 2‐amino‐
propanoate	 yielded	 pyrrole	 derivative	 166	 in	 high	 yield	
(Scheme	81)	[119].	
	

	
	

Scheme	79	
	
	

	
	

Scheme	80	
	
	

	
	

Scheme	81	
	

Chromenopyridines	 168	 were	 prepared	 by	 treating	 3‐
formylchromone	1a	 with	 enaminonitriles,	 enaminoketones	 or	
β‐aminoesters	167	(Scheme	82)	[63,64,76,120].	
	

	
	

Scheme	82	



322	 Ibrahim	et	al.	/	European	Journal	of	Chemistry	4	(3)	(2013)	311‐328	
	

	

	
	

Scheme	83
	
	

	
	

Scheme	84	
	
	
Interaction	 of	 3‐formylchromones	 1a‐c,g	 with	 ethyl	

glycinate	in	boiling	toluene	in	the	presence	of	p‐toluenesulfonic	
acid	 gave	 a	 mixture	 of	 ethyl	 4‐(2‐hydroxybenzoyl)‐6‐(4‐oxo‐
chromen‐3‐yl)‐pyridine‐2‐carboxylates	 169	 and	 ethyl	 4‐(2‐
hydroxybenzoyl)pyrrole‐2‐carboxylates	 170	 (Scheme	 83)	
[62,65,76,121].	

Also,	 the	 reaction	 of	 3‐formylchromone	 (1a)	 with	
equimolar	amount	of	aminopyrazoles	171	 in	absolute	ethanol	
afforded	 6‐(2‐hydroxybenzoyl)pyrazolo[1,5‐a]pyrimidines	
172,	via	iminomethyl	derivative	(Scheme	84)	[122].	

Treatment	 of	 3‐formylchromones	 1a,b,e	 with	 5‐amino	
pyrazoles	173	 in	 boiling	 ethanol	 containing	 p‐toluenesulfonic	
acid	 gave	 2‐hydroxybenzoylpyrazolo[3,4‐b]pyridines	 174.	
While,	when	this	reaction	was	carried	out	at	lower	temperature	
(‐10	 °C),	 the	 enamine‐adducts	 175	 were	 isolated.	 Enamine‐
adducts	 rearrange	 into	 pyrazolo[3,4‐b]pyridines	 174	 after	
prolonged	refluxing	(Scheme	85)	[123].	
	

O

O

CHOR

N

N
H2N

Me

p-TsOH

reflux

-10 oC

NN
Me

O

O

R

OEt

N
H

R=H, Me, F
90%

R1=Me, C6H5, 4-NO2C6H4

1a,b,e
173

175

+ reflux

N
N N

O OH

R

174

EtOH

R1

R1

R1

	
	

Scheme	85	
	

Reaction	 of	 3‐formylchromone	 1a	 with	 ethyl	 2‐
aminopyrimidine	carboxylates	176	 in	ethanol	gave	ethyl	7‐(2‐
hydroxybenzoyl)‐2H‐(4H)pyrimido[1,2‐a]pyrimidine‐3‐
carboxylate	177	(Scheme	86)	[124].	

On	 the	 other	 hand,	 aminopyrimidones	 178	 reacted	 with	
aldehyde	 1a	 in	 refluxing	 ethanol	 to	 afford	 the	 unexpected	
pyrido[2,3‐d]pyrimidines	 179	 but	 not	 the	 predicted	
pyridopyrimidines	180	(Scheme	87)	[125].	

Acetic	acid	catalyzed	condensation	of	aldehyde	1a	with	1‐
(2‐aminophenyl)pyrrole	 (181)	 led	 to	 the	 pyrrolo[1,2‐a]	
quinoxaline	derivative	182	(Scheme	88)	[126].	

2‐(4H‐4‐Chromen‐3‐yl)‐3‐aryl‐1,2‐dihydroquinazolin‐
4(3H)‐ones	 184	 are	 the	 final	 products	 from	 the	 reaction	 of	

carboxaldehyde	 1a	 and	 amino	 amides	 183	 in	 both	 ethanolic	
and	nonpolar	medium	(Scheme	89)	[127].	
	

	
	

Scheme	86	
	
	

	
	

Scheme	87	
	
	

	
	

Scheme	88	
	

	
	

Scheme	89	



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Scheme	90
	
	
Reaction	 of	 3‐formylchromone	 1a	 with	 enamine	

derivatives	 185‐189	 in	 pyridine	 or	 glacial	 acetic	 acid	 led	 to	
fused	 pyridine	 derivatives	 190‐194	 in	 one	 step,	 respectively	
(46‐82%	yields)	(Scheme	90)	[76].	

Reaction	 of	 3‐formylchromone	 1a	 with	 4‐amino‐3‐
mercapto‐5‐phenyl‐1,2,4‐triazole	 (195)	 under	 phase	 transfer	
condition	yielded	ring‐opened	 thiadiazepine	196	(Scheme	91)	
[128].	

Condensation	 of	 1a‐c	 with	 4‐phenyl‐1H‐imidazole‐1‐
amines	197	in	the	presence	of	Me3SiCl/DMF	gave	imidazo[1,5‐
b]pyridazines	198	in	81‐96%	yields	(Scheme	92)	[129].	
	

	
	

Scheme	91	
	
	

	
	

Scheme	92	
	

Diaminomethane	 reacted	 with	 3‐formylchromone	 1a	 to	
yield	 pyrimidine	 derivative	 199.	 The	 reaction	 initially	 takes	
place	on	the	formyl	group	and	is	followed	by	an	intramolecular	
attack	 of	 the	 second	 amine	 function	 on	 the	 C‐2	 atom	 of	 the	
pyrone	ring	followed	by	the	ring	opening	(Scheme	93)	[130].	
 

	
	

Scheme	93	
	

Condensation	 of	 equimolar	 amountsof	 1a‐c	 with	
ethylenediamine	 in	 benzene	 gave	 the	 1,2‐bis[(chromon‐3‐
yl)methyleneamino]ethane	 200,	 using	 excess	 of	 ethylene‐
diamine	 afforded	 poor	 yield	 of	 1:1	 condensation	 product	
(Scheme	94)	[130].	
	

	
	

Scheme	94	
	

Reaction	 of	 aldehyde	 1a	 with	 o‐phenylenediamine	 in	
boiling	 ethanol	 gave	 7,16‐bis(2‐hydroxybenzoyl)‐5,14‐
dihydrodibenzo[b‐i][1,4,8,11]tetraazacyclotetradecine	 (201),	
which	 then	 oxidized	 to	 3‐(2‐benzimidazolyl)chromone	 202,	
while	 in	 boiling	 benzene,	 benzodiazepino	 chromone	204	was	
obtained	 during	 dehydrogenation	 ofthe	 initially	 formed	
dihydro	 analogous	 203,	 through	 air	 oxidation	 or	 boiling	 in	
nitrobenzene	(Scheme	95)	[130‐141].	

On	 the	 other	 hand,	 cyclocondensation	 of	 6‐chloro‐3‐
formylchromone	(1c)	with	diaminopyridone	derivative	205	 in	
DMF	under	reflux	containing	 few	drops	of	piperidine	afforded	
the	 1,2,3,5‐tetrahydro[1,2,4]triazolo[1,5‐a]pyridine	 derivative	
206	(Scheme	96)	[142].	

Condensation	 reaction	of	6‐chloro‐3‐formylchromone	 (1c)	
with	 p‐phenylenediamine	 in	 dry	 benzene	 containing	 p‐
toluenesulfonic	 acid	 in	 1:1	 and	 2:1	 molar	 ratio	 gave	 3‐[(4‐
aminophenylimino)methyl]‐6‐chloro‐4‐oxo‐4H‐chromene	
(207)	 and	 the	 bis	 compound	 208,	 respectively	 (Scheme	 97)	
[143].		

On	 the	 other	 hand,	 condensation	 reaction	 of	 3‐formyl	
chromone	(1a)	with	2‐aminophenol	and	2‐aminothiophenol	in	
ethanol	afforded	compound	209	via	the	formation	of	the	simple	
condensation	 product	 followed	 by	 1,4‐addition	 of	 ethanol	
molecules	(Scheme	98)	[132].		

Consequently,	the	products	obtained	from	the	reaction	of	3‐
formylchromones	with	primary	 amines	depend	mainly	 on	 the	
type	of	amine,	molar	ratio	and	the	solvent	used.	Also,	a	diverse	
number	 of	 heterocyclic	 systems	 were	 obtained	 from	 the	
condensation	 of	 3‐formylchromones	 with	 bifunctional	
nucleophiles.	



324	 Ibrahim	et	al.	/	European	Journal	of	Chemistry	4	(3)	(2013)	311‐328	
	
	

	
	

Scheme	95
	
	

	
	

Scheme	96	
	
	
	

O

Cl

O

CHO
H2N NH2

benzene, p-TsOH

O

O

N

NH2

Cl

1c

207
208

O

Cl
N

O

O

N
Cl

61%

+

	
	

Scheme	97	
	
	

	
	

Scheme	98	
	
2.2.2.	Reactions	with	secondary	amines		
	

When	3‐formylchromone	1a	treated	with	secondary	amine	
like	 piperidine,	 an	 unstable	 1,4‐adduct	 210	 is	 formed,	 this	
adduct	 undergoes	 base	 catalyst	 deformylation	 to	 give	 the	

enaminoketone	 211	 in	 55%	 yield	 [151].	 Further,	 3‐
formylchromones	1a	when	heated	with	N‐methylpiperazine	in	
ethanol	 furnished	 1‐(2‐hydroxyphenyl)‐3‐(4‐methylpiperazin‐
1‐yl)propenone	 (212)	 [41].Similarly,	 1‐(2‐hydroxyaryl)‐3‐
(pyrrolidin‐1‐yl)prop‐2‐en‐1‐one	(213)	was	synthesized	by	the	
reaction	 of	 3‐formlylchromones	 1a	 with	 pyrrolidine	 in	 dry	
ethanol	(Scheme	99)	[145,146].	

	

O

O

CHO HN

O

O

N

CHO

N

O

OH

55%

OH

O

N

N
Me

NHN Me

212

211
210

1a

N
H

213

OH

O

N

EtOH

EtOH

EtOH

	
	

Scheme	99	
	
Treatment	of	3‐formylchromone	(1a)	with	N‐methylglycine	

in	 boiling	 toluene	 in	 the	 presence	 of	 p‐toluenesulfonic	 acid	



Ibrahim	et	al.	/	European	Journal	of	Chemistry	4	(3)	(2013)	311‐328	 325	
 

produces	 N‐methyl‐3‐salicyloyl	 pyrrole	 214	 in	 high	 yield	
(Scheme	100)	[119].		

Condensation	of	3‐formylchromone	1a	with	N1,N2‐dimethyl	
glycinamide	 (215)	 and	 L‐pyrrolinamide	 216	 afforded	
chromonylimidazolinone	 217	 (79%	 yield)	 and	
pyrroloimidazolinone	 218	 (84%	 yield),	 respectively,	 these	
reactions	 proceed	 via	 [4+1]	 recyclization	 (Scheme	 101)	
[73,147].	

As	 a	 result,	 a	 variety	 of	 products	were	 obtained	 from	 the	
reaction	 of	 3‐formylchromones	 with	 secondary	 amines	
depending	on	the	nucleophile	used.	
	

	
	

Scheme	100	
	
2.2.3.	Reactions	with	tertiary	amines		
	

The	acid‐catalyzed	condensation	of	3‐formylchromone	(1a)	
with	 a	 range	 of	 tertiary	 aromatic	 amines	 gave	 the	 3‐[bis(4‐
aminophenyl)methyl]chromones	 219	 in	 moderate	 yield	
(Scheme	102)	[148].		
	

	
	

Scheme	101	
	

	
	

Scheme	102	
	
2.2.4.	Reactions	with	hydrazines	
	

The	 reaction	 of	 3‐formylchromones	1a‐d	 with	 hydrazines	
gave	initially	hydrazones	220	which	then	reacted	further	at	the	
C‐2	 position	 to	 give	 4‐(2‐hydroxybenzoyl)pyrazoles	 212	
(Scheme	103)	[149‐151].	
	

	
	

Scheme	103	
	
Treatment	 of	 3‐formylchromone	 1a	 with	 substituted	

hydrazines	222a‐c	 in	absolute	ethanol	or	toluene	afforded	the	
corresponding	hydrazones	223a‐c	(Scheme	104)	[152,153].		
	

	
	

Scheme	104	
	
2.2.5.	Reactions	with	hydroxylamine		
	

The	 reaction	 of	 3‐formylchromone	 (1a)	 with	
hydroxylamine	 hydrochloride	 (1:2	 molar	 ratio)	 afforded	 a	
mixture	 of	 pyrazole	 224	 and	 chromone	 225	 (Scheme	 105)	
[154,155].	
	

	
	

Scheme	105	
	

Treatment	 of	 3‐formylchromones	 (1a‐d)	 with	
hydroxylamine	 hydrochloride	 in	 ethanol	 gave	 the	
corresponding	 oximes	 226	 which	 on	 dehydration	 by	 acetic	
anhydride	 gave	 chromone‐3‐carbonitriles	 227.	 When	 the	
reaction	of	1a‐d	with	hydroxylamine	hydrochloride	took	place	
in	 the	 presence	 of	 sodium	 formate	 containing	 HCl,	 the	
carbonitriles	227	were	 obtained	 directly.	 On	 the	 other	 hand,	
Oximination	 of	1a	 and	 its	 oxime	225	 using	 hydroxylamine	 in	
sodium	 hydroxide	 led	 to	 2‐aminochromone‐3‐carboxamide	
(228)	 and	3‐amino‐4H‐chromeno[3,4‐d]	 isoxazol‐4‐one	 (229),	
respectively	(Scheme	106)	[156‐158].	
	

	
	

Scheme	106	
	

Nitrones	 230	 were	 prepared	 from	 the	 reaction	 of	
aldehydes	1a‐c	 with	 hydroxylamine	 in	 ethanol.	 Nitrones	230	
rearranged	 to	 2‐amino‐3‐formylchromones	 231	 in	 ethanol	
containing	 few	 drops	 of	 acetic	 acid	 in	 the	 presence	 of	 zinc	
(Scheme107)	[159,160].	
	

	
	

Scheme	107	
	

Hence,	 hydroxylamine	 on	 reactions	 with	 3‐
formylchromones	gave	diverse	types	of	products	depending	on	
the	reaction	conditions.		
	
	
	
	
	



326	 Ibrahim	et	al.	/	European	Journal	of	Chemistry	4	(3)	(2013)	311‐328	
	
	

	
	

Scheme	108
	
	
2.2.6.	Reactions	with	amidines	
	

Reaction	of	3‐formylchromone	1a	with	formamidine	gave	a	
mixture	 of	 5‐(2‐hydroxybenzoyl)	 pyrimidine	232	 (R=H,	 13%)	
and	 5‐hydroxy‐5H‐chromeno[4,3‐d]pyrimidine	 233	 (R=H,	
31%)	 as	 reported	 by	 Loewe	 [161]	While,	 reaction	 of	1a	with	
several	C‐substituted	formamidines	(R=alkyl,	aryl,	hetaryl,	NH2,	
NHCN,	 SH,	 SMe,	 OH,	 OMe,	 1‐pyrrolidinyl,	 1‐piperidinyl,	 4‐
morpholinyl)	gave	only	chromeno‐pyrimidines	233	 in	26‐90%	
yields	(Scheme108)	[161‐166].	

Thus,	 3‐formylchromones	 are	 a	 good	 precursors	 for	 the	
synthesis	of	pyrimidine	derivatives	via	treatment	with	amidine	
derivatives	as	1,3‐bifunctional	nucleophiles.	
	
2.2.7.	Reactions	with	hyrazides		
	

3‐Formylchromones	1a‐d	 reacted	with	 semicarbazide	 and	
thiosemicarbazide	 in	 ethanol	 to	 give	 the	 corresponding	
semicarbazones	 234a	 (X=O)	 and	 thiosemicarbazone	 234b	
(X=S),	respectively	(Scheme109)	[150,167,168].	

	

	
	

Scheme	109	
	

The	 reaction	 of	 3‐formylchromone	 1a‐d	 with	
aroylhydrazines	 gave	 the	 corresponding	 aroylhydrazone	 235	
(Scheme110)	[169‐172].	
	

	
	

Scheme	110	
	

3‐Formylchromone	1c	 condensed	with	 equimolar	 amount	
of	 hydrazine	 carbodithioic	 acid	 and	 thiocarbohydrazide	 in	
ethanol	 to	 give	 the	 corresponding	 hydrazones	 236	 and	 237,	
respectively.	Also,	 condensation	of	1c	with	 two	equivalents	of	
thiocarbohydrazide	 gave	 bis	 thiocarbohydrazone	 derivative	
238	(Scheme111)	[173].	

Phosphorohydrazone	of	chromone	239	was	obtained	from	
stirring	 3‐formylchromone	 1a	 with	 diethoxythiophosphoryl‐
hydrazide	inethanol	(Scheme112)	[159].		
	

Scheme	111	
	
	

	
	

Scheme	112	
	
	
3.	Conclusion	
	

In	 the	 present	 work,	 the	 chemical	 reactivity	 of	 3‐
formylchromones	was	 evaluated	 and	 summarized	 towards	 all	
types	 of	 carbon	 and	 nitrogen	 nucleophiles	 under	 different	
reaction	conditions.3‐Formylchromones	are	very	active	toward	
the	 nucleophilic	 reagents,	 due	 to	 the	 availability	 of	 three	
electron	deficient	sites,	 the	aldehydes	carbon,	C‐2	carbon,	and	
the	 C‐4	 carbon	 of	 the	 carbonyl	 group.	 A	 variety	 of	 fused	
heterocyclic	systems	were	prepared	directly	from	the	reaction	
of	 3‐formylchromones	 with	 some	 bifunctional	 nucleophiles,	
these	 reactions	 mainly	 proceed	 via	 condensation	 with	 the	
aldehydic	 function	 followed	 by	 nucleophilic	 attack	 at	 C‐2	
position	of	the	chromone	moiety.	
	
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