untitled


European	Journal	of	Chemistry	3	(2)	(2012)	252‐257	

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

DOI:10.5155/eurjchem.3.2.252‐257.527	

	
	

	

	

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

	 	 	

Simple	and	straight	forward	synthesis	of	2,4‐disubstituted	quinazolines	in	
aqueous	medium	

Madhav	Bandaru,	Narayana	Murthy	Sabbavarapu,	Anil	Kumar	Bandam	Santosh	Pavan,		
Ashwan	Kumar	Akula	and	Nageswar	Yadavalli	Venkata	Durga*	

Organic	Chemistry	Division‐I,	Indian	Institute	of	Chemical	Technology,	Hyderabad,	500607,	India	

*Corresponding	author	at:	Organic	Chemistry	Division‐I,	Indian	Institute	of	Chemical	Technology,	Hyderabad,	500607,	India.		
Tel.:	+91.40.27160512;	fax:	+91.40.27193198.	E‐mail	address:	dryvdnageswar@gmail.com	(N.Y.V.	Durga).	

	
	

	 	

	 	 	
COMMUNICATION	INFORMATION	 	 ABSTRACT	
Received:	12	September	2011	
Received	in	revised	form:	12	October	2012	
Accepted:	13	October	2011	
Online:	30	June	2012	

KEYWORDS	

	 Efficient	 synthesis	 of	 diverse	 quinazolines	 from	 readily	 available	 starting	 materials	 was
achieved	in	aqueous	medium	via	one‐pot	protocol.	A	number	of	2,4‐disubstituted	quinazolines
were	prepared	 in	moderate	 to	 good	 yields	 under	mild	 and	 catalyst‐free	 conditions.	Neutral
reaction	conditions,	easy	work‐up	procedures	with	wide	substrate	scope	and	atom	economy
are	the	remarkable	features	of	this	method.	

Catalyst	free	
Aqueous	medium	
One‐pot	synthesis	
Ammonium	acetate	
2‐Amino	carbonyl	compounds	
2,4‐Disubstituted	quinazolines	

	
1.	Introduction	
	

Quinazolines	 acquired	 much	 prominence	 among	 N‐
containing	heterocyclic	compounds	because	of	their	wide	range	
of	 pharmacological	 and	 medicinal	 properties	 such	 as	
antibacterial	 [1],	 antidiabetic	 [2],	 antihypertensive	 [3],	
antitumor	 [4,5],	 anti‐inflammatory	 [6],	 anticancer[7‐13],	
antiviral	 [14,15]	 and	 antitubercular	 [16,17].	 In	 addition,	 this	
ubiquitous	structural	motif	is	present	in	potent	tyrosine	kinase	
and	 cellular	 phosphorylation	 inhibitors	 [18‐20],	 and	 also	 has	
found	 applications	 as	 ligand	 for	 benzodiazepine	 and	
neurotransmitter	 gamma‐aminobutyric	 acid	 [GABA]	 receptors	
in	 the	 central	 nervous	 system	 [CNS]	 [21,22]	 and	 as	 DNA	
binders	[23].	

Consequently,	 diverse	 approaches	 have	 been	 explored	 to	
synthesize	various	types	of	quinazolines.	2‐Aminobenzonitriles,	
2‐halophenyl	 precursors,	 2‐nitrobenzoic	 acids	 or	 anthranilic	
acids	as	well	as	N‐arylbenzamides	are	commonly	used	starting	
materials	 among	 those	 methods.	 The	 applicability	 of	 these	
methods	 is	 restricted	 due	 to	 less	 availability	 of	 these	 starting	
materials.	 Bischler	 cyclization,	 Niementowski	 quinazoline	
reaction,	 and	 the	 reaction	 of	 dicarbonyl	 compounds	 with	
diamines	 are	 some	 of	 the	 traditional	 methods	 in	 quinazoline	
synthesis	 [24‐30].	 Bischler	 reaction	 requires	 harsh	 reaction	
conditions	which	are	not	compatible	with	many	functional	and	
protecting	 groups.	 Moreover,	 syntheses	 of	 2,4‐disubstituted	
quinazolines	 from	 anthranilic	 acids	 or	 o‐fluorobenzoyl	
derivatives	have	also	been	investigated	[31].	

However,	 these	 methods	 have	 certain	 limitations	 in	 the	
substrate	 generality,	 availability	 of	 starting	 materials,	 and	
reaction	procedures.	Recently,	Walton	et	al.	 [32]	 reported	 the	
preparation	 of	 quinazolines	 and	 dihydroquinazolines	 from	 2‐
aminoarylalkanone	 O‐phenyl	 oximes	 under	 microwave	

conditions	 at	 160	 0C	 in	 presence	 of	 emimPF6	 in	 toluene	 in	 a	
two‐step	process.	 It	 also	 requires	anhydrous	ZnCl2	 for	 further	
oxidation	 of	 dihydroquinazolines	 to	 quinazolines.	 The	
preparation	 of	 2‐aminoarylalkanone	 O‐phenyl	 oximes	 is	 a	
complicated	 process	 which	 requires	 pyridine	 under	 N2	
atmosphere.	 Taddei	 et	 al.	 [33]	 synthesized	 2,4‐disubstituted	
quinazolines	 starting	 from	 anilides	 under	 microwave	
conditions	 (heating	 at	 1000	 for	 3‐6	min,	 and	maintaining	 the	
internal	pressure	at	150	psi).	Although	this	method	is	efficient,	
it	 has	 limited	 substrate	 scope	 with	 few	 examples.	 Wang	 and	
coworkers	 [34]	 synthesized	 various	 quinazolines	 from															
2‐aminocarbonyl	 compounds	 and	 benzyl	 amines	 as	 starting	
materials	 using	 CuO	 nanoparticles	 supported	 on	 kaolin.	 The	
same	 research	 group	 reported	 quinazoline	 synthesis	 using	
I2/TBHP	as	another	catalytic	system	[35].	Very	recently,	Sarma	
and	 Prajapati	 [36]	 reported	 a	 quinazoline	 synthesis	 using	
urea/AcONH4	 as	 another	 N‐source	 under	 microwave	
conditions.	 Dihydroquinazolines	 were	 obtained	 in	 relatively	
high	 yields	 in	 this	 method.	 Dabiri	 et	 al.	 synthesized	
quinazolines	using	acidic	ionic	liquids	under	aerobic	conditions	
[37].	 The	 same	 authors	 synthesized	 quinazoline	 derivatives	
containing	triazole	ring	systems	using	cu	catalyst	via	a	one‐pot	
four‐component	reaction	[38].		

One	of	the	main	principles	of	green	chemistry	is	to	develop	
cost‐effective	 and	 environmentally	 benign	 synthetic	 protocols	
which	have	 become	one	 of	 the	main	 themes	 of	 contemporary	
synthetic	 chemistry.	 Herein,	 we	 report	 a	 mild,	 catalyst‐free	
single‐step	 procedure	 for	 the	 conversion	 of	 readily	 available									
2‐aminocarbonyl	 compounds	 in	 water	 medium	 to	 the	
corresponding	 substituted	 quinazolines,	 as	 a	 part	 of	 our	
ongoing	 research	programme	 in	 the	development	of	new	eco‐
friendly	 protocols	 [39‐45].	 Even	 though,	 different	
methodologies	 are	 reported	 for	 this	 reaction	 under	 various	



Bandaru	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	252‐257	 253	
 

 

conditions,	 to	 the	 best	 of	 our	 knowledge	 this	 catalyst	 free	
reaction	was	not	attempted	in	aqueous	medium.	
	
2.	Experimental	
	
2.1.	Instrumentation	
	

All	 reactions	 were	 carried	 out	 without	 any	 special	
precautions	in	an	atmosphere	of	air.	Chemicals	were	purchased	
from	Fluka	and	S.	D.	Fine	Chemicals	 and	directly	used	 for	 the	
synthesis.	 Analytical	 thin	 layer	 chromatography	 (TLC)	 was	
carried	 out	 using	 silica	 gel	 60	 F254	 pre‐coated	 plates.	
Visualization	 was	 accomplished	 with	 UV	 lamp	 or	 I2	 stain.	 1H	
NMR	 and	 13C	 NMR	 Spectra	 were	 recorded	 on	 Varian	 200,	
Varian	 Inova	500	 or	Avance	 300	 spectrometer	 in	 CDCl3	 using	
TMS	as	the	internal	standard;	δ	in	ppm,	J	 in	Hz.	Melting	points	
were	 determined	 using	 Fischer‐Johns	 and	 Barnstead	
Electrothermal	apparatus	and	are	uncorrected.	MS:	QSTAR	XL,	
LCQ‐Ion	Trap	spectrometer	in	m/z.	
	
2.2.	Synthesis	
	

General	 procedure	 for	 the	 synthesis	 of	 2,4‐Substituted	
quinazolines	 in	 water:	 To	 a	 flask	 containing	 the	 2‐amino	
acetophenone/2‐amino	benzophenones	(1	mmol)	in	water	(20	
mL),	 aldehydes	 (1.25	 equiv.)	 and	 NH4OAc	 (0.77	 g,	 10	 mmol)	
were	added.	The	mixture	was	magnetically	stirred	at	75	oC	until	
reaction	was	complete	(as	monitored	by	TLC).	After	completion	
of	 the	 reaction,	 the	 reaction	mixture	was	extracted	with	ethyl	
acetate	 (25	mL).	 The	 extract	 was	 further	 washed	with	water	
and	saturated	brine	solution,	dried	over	anhydrous	Na2SO4,	and	
evaporated	 under	 reduced	 pressure	 to	 give	 2,4‐substituted	
quinazolines	in	25‐77	%	yields	(Scheme	1	and	2).		

4‐Methyl‐2‐phenylquinazoline	 (Table	 1,	 Entry	 1):	 Brown.	
Yield:	62%.	M.p.:	72‐75	oC.	 1H	NMR	(500	MHz,	CDCl3,	δ,	ppm):	
8.61‐8.59	 (m,	 2H,	 ArH),	 8.02	 (m,	 2H,	 ArH),	 7.53‐7.43	 (m,	 5H,	
ArH),	2.99	(s,	3H,	CH3).	13C	NMR	(75	MHz,	CDCl3,	δ,	ppm):	168.3,	
160.2,	 150.45,	 139.7,	 138.4,	 133.6,	 130.5,	 129.1,	 128.4,	 128.3,	
126.7,	124.5,	123.6,	122.6,	21.8.	MS	(ESI,	m/z):	221	[M+H]+.		

6,7‐Dimethoxy‐4‐methyl‐2‐phenylquinazoline	(Table	1,	Entry	
2):	 Light	 yellow.	 Yield:	 59%.	 M.p.:	 132‐134	 oC.	 1H	 NMR	 (300	
MHz,	CDCl3,	δ,	ppm):	8.55‐8.51	(m,	2H,	ArH),	7.46‐7.43	(m,	3H,	
ArH),	 7.32	 (s,	 1H,	 ArH),	 7.12	 (s,	 1H,	 ArH),	 4.06	 (s,	 3H,	OCH3),	
4.01	(s,	3H,	OCH3),	2.89	(s,	3H,	CH3).	13C	NMR	(75	MHz,	CDCl3,	δ,	
ppm):	 164.4,	 155.3,	 149.7,	 149.4,	 147.8,	 139.0,	 138.4,	 130.2,	
128.7,	 128.3,	 128.1,	 127.9,	 107.4,	 102.1,	 56.1,	 55.9,	 21.8.	 MS	
(ESI,	m/z):	 281	 [M+H]+.	 HR‐MS	 (ESI,	m/z):	 281.1282	 [M+H]+.	
C17H17N2O2+;	calc.	281.1290.		

6‐Chloro‐2‐phenylquinazoline	 (Table	 1,	 Entry	 3):	 Light	
yellows.	Yield:	60%.	M.p.:	200‐204	oC.	1H	NMR	(300	MHz,	CDCl3,	
δ,	ppm):	9.36	(s,	1H,	ArH),	8.61‐8.57	(m,	2H,	ArH),	8.0	(m,	1H,	
ArH),	7.88	(m,	1H,	ArH),	7.83‐7.79	(m,	1H,	ArH),	7.52‐7.47	(m,	
3H,	ArH).	13C	NMR	(75	MHz,	CDCl3,	δ,	ppm):	159.8,	149.2,	137.5,	
135.0,	 132.7,	 130.8,	 130.4,	 128.64,	 128.60,	 125.7,	 123.9.	 MS	
(ESI):	m/z	241	[M+H]+.	

8‐Methyl‐6‐phenyl‐[1,	3]	dioxolo	 [4,	5‐g]	quinazoline	 (Table	
1,	Entry	4):	Brown.	Yield:	61%.	M.p.:	133‐136	oC.	1H	NMR	(500	
MHz,	CDCl3,	δ,	ppm):	8.51	(m,	1H,	ArH),	7.49‐7.44	(m,	4H,	ArH),	
7.29	(s,	1H,	ArH),	7.22	(s,	1H,	ArH),	6.08	(s,	2H,	OCH2O),	2.84	(s,	
3H,	CH3).	13C	NMR	(75	MHz,	CDCl3,	δ,	ppm):	165.1,	159.2,	153.4,	
149.7,	 147.8,	 138.3,	 129.9,	 129.9,	 128.4,	 128.2,	 128.1,	 119.5,	
105.3,	101.9,	100.1,	22.10.	MS	(ESI,	m/z):265	[M+H]+.		

2,4‐Diphenylquinazoline	 (Table	 1,	 Entry	 5):	 Yellow.	 Yield:	
63%.	M.p.:	117‐119	oC.	1H	NMR	(500	MHz,	CDCl3,	δ,	ppm):	8.73	
(m,	2H,	ArH),	8.15‐8.16	 (m,	 2H,	ArH),	 7.90‐7.86	 (m,	3H,	ArH),	
7.60‐7.48	 (m,	 7H,	 ArH).	 13C	 NMR	 (75	 MHz,	 CDCl3,	 δ,	 ppm):	
168.0,	 160.0,	 152.2,	 138.2,	 137.7,	 133.3,	 130.5,	 130.2,	 129.7,	
129.1,	128.8,	128.2,	126.9,	121.7.	MS	(ESI,	m/z):	283	[M+H]+.	

	
	

6‐Chloro‐2,4‐diphenylquinazoline	(Table	1,	Entry	6):	Yellow.	
Yield:	67%.	M.p.:	201‐204	oC.	1H	NMR	(500	MHz,	CDCl3,	δ,	ppm):	
8.68‐8.64	 (m,	 2H,	 ArH),	 8.09‐8.06	 (m,	 2H,	 ArH),	 7.87‐7.77	 (m,	
3H,	 ArH),	 7.62‐7.58	 (m,	 3H,	 ArH)	 7.50‐7.47	 (m,	 3H,	 ArH).	 13C	
NMR	(75	MHz,	CDCl3,	δ,	ppm):	167.6,	160.9,	151.5,	138.2,	137.8,	
134.7,	133.0,	131.6,	131.2,	130.6,	129.3,	129.2,	129.0,	126.2.	MS	
(ESI,	m/z):	317	[M+H]+.	

6‐Chloro‐4‐(2‐chlorophenyl)‐2‐phenylquinazoline	 (Table	 1,	
Entry	7):	Grey.	Yield:	65%.	M.p.:	210‐212	oC.	1H	NMR	(500	MHz,	
CDCl3,	δ,	ppm):	8.64‐8.61	(m,	2H,	ArH),	8.06	(m,	1H,	ArH),	7.78‐
7.81	 (m,	1H,	ArH),	7.62‐7.46	 (m,	8H,	ArH).	 13C	NMR	 (75	MHz,	
CDCl3,	δ,	ppm):	167.7,	160.5,	151.2,	138.0,	137.9,	134.5,	133.1,	
131.5,	131.4,	130.5,	129.5,	129.1,	128.7,	126.0.	MS	 (ESI,	m/z):	
351	[M+H]+.	

7‐Bromo‐2,4‐diphenylquinazoline	(Table	1,	Entry	8):	Yellow.	
Yield:	62%.	M.p.:	136‐139	oC.	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	
8.64‐8.67	 (m,	 2H,	ArH),	 8.14	 (m,	1H,	ArH),	8.04	 (m,	1H,	ArH),	
7.86‐7.88	 (m,	 1H,	 ArH),	 7.70‐7.77	 (m,	 4H,	 ArH),	 7.47‐7.55	 (m,	
4H,	ArH).	13C	NMR	(75	MHz,	CDCl3,	δ,	ppm):	167.2,	160.4,	152.3,	
138.0,	 136.8,	 133.7,	 131.9,	 130.8,	 129.5,	 128.7,	 127.4,	 126.6,	
124.8,	121.5.	MS	(ESI,	m/z):	361	[M+H]+.		

6‐Nitro‐2,	4‐diphenylquinazoline	 (Table	1,	Entry	9):	Brown.	
Yield:	25%.	M.p.:	214‐218	oC.	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	
9.03	 (s,	 1H,	 ArH),	 8.71‐8.73	 (m,	 2H,	 ArH),	 8.23	 (m,	 1H,	 ArH),	
7.90‐7.91	 (m,	 2H,	 ArH)	 7.65‐7.66	 (m,	 3H,	 ArH),	 7.51‐7.52	 (m,	
3H,	ArH),	7.24	(s,	1H,	ArH).	13C	NMR	(75	MHz,	CDCl3,	δ,	ppm):	
124.1,	 126.9,	 167.5,	 160.8,	 150.8,	 132.5,	 131.7,	 131.1,	 130.9,	
130.3,	129.3,	129.1,	128.7.	MS	(ESI,	m/z):	328	[M+H]+.		

4‐Methyl‐2‐p‐tolylquinazoline	 (Table	 2,	 Entry	 1):	 Brown.	
Yield:	60%.	M.p.:	80‐85	 oC.	 1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	
8.51	 (m,	2H,	ArH),	 7.99	 (m,	 2H,	ArH),	 7.83‐7.76	 (m,	 1H,	ArH),	
7.52‐7.46	 (m,	 1H,	 ArH),	 7.29‐7.23	 (m,	 2H,	 ArH),	 2.97	 (s,	 3H,	
CH3),	2.43	(s,	3H,	CH3).	ESI‐MS:	235	[M+H]+.	

4‐Methyl‐2‐(naphthalen‐1‐yl)	quinazoline	(Table	2,	Entry	2):	
Yield:	64%.	M.p.:	92‐95	 oC.	 1H	NMR	(500	MHz,	CDCl3,	δ,	ppm):	
8.78	 (m,	 1H,	 ArH),	 8.09‐7.81	 (m,	 6H,	 ArH),	 7.56‐7.47	 (m,	 4H,	
ArH),	3.03	(s,	3H,	CH3).	13C	NMR	(75	MHz,	CDCl3,	δ,	ppm):	167.5,	
159.8,	 149.5,	 135.1,	 134.2,	 134.0,	 133.0,	 129.0,	 128.8,	 128.6,	
128.4,	 127.6,	 127.4,	 127.2,	 126.4,	 126.3,	 125.6,	 125.1,	 124.5,	
122.6,	 122.3,	 21.6.	 MS	 (ESI,	 m/z):	 271	 [M+H]+.	 HR‐MS	 (ESI,	
m/z):	271.1239	[M+H]+.	C19H15N2;	calc.	271.1235.	

2‐(4‐Chlorophenyl)‐4‐methylquinazoline	 (Table	 2,	 Entry	 3):	
Brown.	Yield:	69%.	M.p.:	64‐67	oC.	1H	NMR	(300	MHz,	CDCl3,	δ,	
ppm):	8.57	(m,	2H,	ArH),	7.94‐7.96	(m,	2H,	ArH),	7.81‐7.78	(m,	
1H,	ArH),	7.49‐7.35	(m,	3H,	ArH),	2.86	(s,	3H,	CH3).	13C	NMR	(75	
MHz,	 CDCl3,	 δ,	 ppm):	 168.1,	 158.8,	 150.0,	 136.5,	 136.3,	 133.4,	
129.7,	 128.9,	 128.5,	 126.8,	 124.8,	 123.9,	 122.7,	 21.7.	MS	 (ESI,	
m/z):	255	[M+H]+.		

4‐Methyl‐2‐(4‐nitrophenyl)quinazoline	 (Table	 2,	 Entry	 4):	
Brown.	Yield:	74%.	M.p.:	151‐153	oC.	1H	NMR	(300	MHz,	CDCl3,	
δ,	ppm):	8.83	(m,	2H,	ArH),	8.34	(m,	2H,	ArH),	8.11‐8.06	(m,	2H,	
ArH),	 7.92‐7.86	 (m,	 1H,	 ArH),	7.68‐7.60	 (m,	1H,	ArH),	 3.03	 (s,	
3H,	CH3).	13C	NMR	(75	MHz,	CDCl3,	δ,	ppm):	133.9,	129.6,	129.4,	
127.8,	125.0,	123.5,	22.0.	MS	(ESI,	m/z):	266	[M+H]+.		

2‐(4‐Methoxyphenyl)‐4‐methylquinazoline	 (Table	 2,	 Entry	
5):	Brown.	Yield:	58%.	M.p.:	67‐71	oC.	1H	NMR	(300	MHz,	CDCl3,	
δ,	 ppm):	8.55	 (m,	 2H,	ArH),	 8.02‐7.96	 (m,	 2H,	ArH),	 7.81‐7.75	
(m,	2H,	ArH),	7.52‐7.45	(m,	1H,	ArH),	6.96	(m,	1H,	ArH),	3.88	(s,	
3H,	OCH3),	2.97	(s,	3H,	CH3).	13C	NMR	(75	MHz,	CDCl3,	δ,	ppm):	
167.4,	 161.7,	 160.1,	 150.6,	 133.0,	 130.9,	 130.3,	 129.3,	 128.9,	
126.0,	 124.8,	 124.3,	 124.0,	 122.6,	 115.4,	 113.7,	 55.1,	 22.0.	MS	
(ESI):	 m/z	 251	 [M+H]+.	 HR‐MS	 (ESI,	m/z):	 251.1174	 [M+H]+.	
C16H15N2O+;	calc.	251.1184.	

2‐(4‐Ethoxyphenyl)‐4‐methylquinazoline	 (Table	2,	 Entry	6):	
Grey.	 Yield:	 55%.	M.p.:	 75‐79	 oC.	 1H	NMR	 (300	MHz,	 CDCl3,	 δ,	
ppm):	8.53	(m,	2H,	ArH),	7.99	(m,	2H,	ArH),	7.78	(m,	1H,	ArH),	
7.48	(m,	1H,	ArH),	6.93	(m,	2H,	ArH),	4.12	(q,	J	=	6.7,	2H,	CH2),	
2.97	(s,	3H,	CH3),	1.46	(t,	 J	=	6.7,	3H,	CH3).	MS	(ESI,	m/z):	265	
[M+H]+.	

	



254	 Bandaru	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	252‐257	
	

 

	 	

	
	

Scheme	1

 
	

	
	

Scheme	2	
	

Table	1.	Synthesis	of	quinazolines	from	various	2‐aminoarylcarbonyl	compounds.a		
Entry	 2‐Aminocarbonyl	compounds	 Benzaldehyde Product Yield b

1	

NH2

Me

O

1a	

	

	3a	

62	[46]	

2	

NH2

Me

O

OMe

OMe 1b	

CHO

	

N

N

Me

Ph

OMe

OMe 3b	

59*

3	

NH2

H

O

Cl

1c	

CHO

	 N

N

Ph

Cl

	3c	

60 [46]

4	

NH2

Me

O

O

O 1d	

CHO

	

N

N

Me

Ph

O

O 3d	

61 *

5	

NH2

Ph

O

1e	

CHO

	

N

N

Ph

Ph 	3e	

63 [46]

6	

NH2

O

Cl

1f	

CHO

	

N

N

Ph

Ph

Cl

3f	

67	[46]	

7	

NH2

O Cl

Cl

1g	

CHO

	

N

N

Ph

Cl

Cl

3g	

65	*

8	

NH2

O

Br 1h	

CHO

	

N

N

Ph

PhBr 3h	

62	*	

9	

NH2

O

NO2

1i	

CHO

	
N

N

Ph

Ph

NO2

3i	

25	[47]	

a	Reaction	conditions:	Substituted	2‐aminoarylcarbonyl	compounds	(1.00	eq),	benzaldehyde	(1.25	eq),	AcONH4	(10	eq)	in	H2O	at	75	oC.	
b	Yields	in	percentage.	
*	New	compounds.	
	

4‐(4‐Methylquinazolin‐2‐yl)phenol	 (Table	 2,	 Entry	 7):	
Brown.	Yield:	52%.	M.p.:	208‐210	oC.	1H	NMR	(300	MHz,	CDCl3,	
δ,	ppm):	9.41	(s,	1H,	OH),	8.41	(m,	2H,	ArH),	8.05	(m,	1H,	ArH),	
7.93‐7.79	 (m,	 2H,	ArH),	7.52	 (m,	1H,	ArH),	6.84	 (m,	2H,	ArH),	
2.96	(s,	3H,	CH3).	MS	(ESI,	m/z):	237	[M+H]+.	

2‐Methoxy‐5‐(4‐methylquinazolin‐2‐yl)phenol	 (Table	 2,	
Entry	 8):	 Brown.	 Yield:	 58%.	M.p.:	 198‐200	 oC.	 1H	NMR	 (300	
MHz,	CDCl3,	δ,	ppm):	8.23	(m,	1H,	ArH),	8.16	(s,	1H,	OH),	8.00	
(m,	2H,	ArH),	7.83‐7.76	 (m,	 1H,	ArH),	 7.52‐7.46	 (m,	1H,	ArH),	
6.98	 (m,	1H,	ArH),	6.81‐6.76	 (m,	1H,	ArH),	4.07	 (s,	 3H,	OCH3),	
2.98	 (s,	 3H,	 CH3).	 13C	 NMR	 (75	 MHz,	 CDCl3,	 δ,	 ppm):	 134.7,	

133.3,	 130.9,	 129.0,	 127.6,	 126.0,	 122.9,	 121.0,	 117.4,	 115.7,	
114.5,	 110.9,	 56.0,	 21.9.	 MS	 (ESI,	 m/z):	 267	 [M+H]+.	 HR‐MS	
(ESI,	m/z):	267.1135	[M+H]+.	C16H15N2O2+;	calc.	267.1133.	

4‐Methyl‐2‐(3,4,5‐trimethoxyphenyl)quinazoline	 (Table	 2,	
Entry	 9):	 Brown.	 Yield:	 57%.	M.p.:	 140‐142	 oC.	 1H	 NMR	 (300	
MHz,	CDCl3,	δ,	ppm):	8.05‐8.02	(m,	2H,	ArH),	7.90	(s,	2H,	ArH),	
7.85‐7.79	 (m,	 1H,	 ArH),	 7.55‐7.50	 (m,	 1H,	 ArH),	 4.03	 (s,	 6H,	
OCH3),	3.91	(s,	3H,	OCH3),	3.02	(s,	3H,	CH3).	13C	NMR	(75	MHz,	
CDCl3,	δ,	ppm):	153.3,	150.5,	133.3,	129.3,	126.6,	124.9,	105.9,	
60.8,	56.2,	22.0.	MS	(ESI,	m/z):	311	[M+H]+.	HR‐MS	(ESI,	m/z):	
311.1384	[M+H]+.	C18H19N2O3+;	calc.	311.1395.		



Bandaru	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	252‐257	 255	
 

 

	 	
Table	2.	Synthesis	of	quinazolines	from	various	benzaldehydes	a.	
Entry	 2‐Aminoaceto		

phenone	
Aldehyde	 Product	 Yieldb	

1	

NH2

Me

O

	

OHC

	
4a	 N

N

Me

Me5a	

60 *

2	

NH2

Me

O

	

OHC

	
4b	 N

N

Me

	5b	

64 *

3	

NH2

Me

O

	

OHC

Cl 	
4c	 N

N

Me

Cl5c		

69	[47]	

4	

NH2

Me

O

	

OHC

NO2 	
4d	 N

N

Me

NO2 5d	

74 [48]

5	

NH2

Me

O

	

OHC

OMe 	
4e	 N

N

Me

OMe5e	

58 *

6	

NH2

Me

O

	

OHC

OEt 	
4f	 N

N

Me

OEt 	5f	

55	*	

7	

NH2

Me

O

	

OHC

OH 	
4g	 N

N

Me

OH 5g	

52 [49]

8	

NH2

Me

O

	

OHC

OMe

OH

	
4h	 N

N

Me

OMe

OH

5h	

58 *

9	

NH2

Me

O

		

OHC

OMe

OMe

OMe 	
4i	

N

N

Me

OMe

OMe

OMe 5i	

	
57*	

10	

NH2

Me

O

	

OHC

	
4j	 N

N

Me

	5j	

60 [50]

a	Reaction	conditions:	2‐aminoacetophenone	(1.0	eq),	substituted	benzaldehyde	(1.25	eq),	AcONH4	(10	eq)	in	H2O	at	75	oC.		
b	Yields	in	percentage,	
*	New	compounds.	
	

	
4‐Methyl‐2‐phenethylquinazoline	 (Table	 2,	 Entry	 10):	

Brown	liquid.	Yield:	60%.	M.p.:	102‐105	oC.	1H	NMR	(300	MHz,	
CDCl3,	δ,	ppm):	7.99	 (m,	1H),	7.91	 (m,	1H),	7.79‐7.77	 (m,	 1H),	
7.52‐7.49	 (m,	 1H),	7.27‐7.20	 (m,	 4H),	 7.13‐7.10	 (m,	 1H),	 3.34‐
3.31	(m,	2H),	3.21‐3.18	(m,	2H),	2.90	(s,	3H).	13C	NMR	(75	MHz,	
CDCl3,	δ,	ppm):	167.8,	165.8,	150.2,	141.7,	133.2,	128.7,	128.5,	
128.3,	126.5,	125.9,	124.8,	41.5,	34.8,	21.6.	MS	(ESI,	m/z):	249	
[M+H]+.		

2‐(Furan‐2‐yl)‐4‐methylquinazoline	 (Table	 3,	 Entry	 1):	
Yield:	72%.	M.p.:	105‐107	oC.	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	
8.07‐8.02	 (m,	1H,	ArH,	Furan	H),	7.84‐7.81	 (m,	1H,	ArH),	7.65	
(m,	 1H,	 Furan	 H),	 7.54‐7.51	 (m,	 1H,	 ArH),	 7.42	 (m,	 1H,	 ArH),	
6.57	 (m,	 1H,	 Furan	 H),	 2.97	 (s,	 3H,	 CH3).	 13C	 NMR	 (75	 MHz,	
CDCl3,	δ,	ppm):	145.2,	133.7,	129.2,	126.8,	124.9,	113.9,	111.9,	
22.1.	MS	 (ESI,	m/z):	211	 [M+H]+.	HR‐MS	 (ESI,	m/z):	 211.0872	
[M+H]+.	C13H11N2O+;	calc.	211.0871.	

	

2‐(5‐Iodofuran‐2‐yl)‐4‐methylquinazoline	(Table	3,	Entry	2):	
Green.	Yield:	68%.	M.p.:	144‐148	oC.	1H	NMR	(300	MHz,	CDCl3,	
δ,	 ppm):	 8.05‐8.00	 (m,	 2H),	 7.85‐7.80	 (m,	 1H),	 7.56‐7.51	 (m,	
1H),	7.29	(d,	J	=	3.4,	1H,	Furan	H),	6.73	(d,	J	=	3.4,	1H,	Furan	H),	
2.96	 (s,	 3H,	 CH3).	 13C	 NMR	 (75	 MHz,	 CDCl3,	 δ,	 ppm):	 168.2,	
157.6,	149.9,	133.7,	129.1,	126.9,	124.9,	122.9,	116.2,	21.8.	MS	
(ESI,	m/z):	 337	 [M+H]+.	 HR‐MS	 (ESI,	m/z):	 336.9838	 [M+H]+.	
C13H10N2OI+;	calc.	336.9837.		

4‐Methyl‐2‐(thiophen‐2‐yl)quinazoline	 (Table	 3,	 Entry	 3):	
Yield:	74%.	M.p.:	98‐101	oC.	1H	NMR	(500	MHz,	CDCl3,	δ,	ppm):	
8.09	 (m,	 1H,	 ArH),	 7.96‐7.93	 (m,	 2H,	 ArH),	 7.77‐7.74	 (m,	 1H,	
ArH),	 7.46‐7.43(m,	 2H,	 Thiophene	 H),	 7.14‐7.12	 (m,	 1H,	
Thiophene	 H),	 2.92	 (s,	 3H,	 CH3).	 13C	 NMR	 (75	MHz,	 CDCl3,	 δ,	
ppm):	 133.3,	 131.9,	 130.1,	 129.4,	 128.9,	 128.6,	 127.9,	 127.3,	
126.2,	 124.7,	 119.3,	 21.6.	 MS	 (ESI,	m/z):	 227	 [M+H]+.	 HR‐MS	
(ESI,	m/z):	227.0635	[M+H]+.	C13H11N2S+;	calc.	227.0642.	

	



256	 Bandaru	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	252‐257	
	

 

	 	
Table	3.	Synthesis	of	quinazolines	from	heterocyclic	aldehydes	a.	
Entry	 2‐Aminocarbonyl	 	Aldehyde	 	Product	 	Yieldb	
1	 O

NH2

Me

1a	

	 O
CHO

6a	

N

N

Me

O 7a

72	[51]

2	 O

NH2

Me

1a	

O
CHO

I 6b	
N

N

Me

O

I 7b	

68	*	

3	 O

NH2

Me

1a	

	 S
CHO

6c	

N

N

Me

S 7c	

74	[52]	

4	 O

NH2

Me

1a	
	

N
H

CHO

6d	
N

N

Me

HN 7d

65	*	

5	 O

NH2

Me

1a	 	 N

CHO

6e	 N

N

Me

N7e

77	[53]	

6	 O

NH2

Ph

1e	

	 O
CHO

6f	

N

N

Ph

O 7f	

72	[54]

7	 O

NH2

Ph

1e	

		 S
CHO

6g	

N

N

Ph

S 7g

70	[49]

8	 O

NH2

Ph

1e	 N

CHO

6h	 N

N

Ph

N7h	

76	[53]	

	a	Reaction	conditions:	2‐Aminoacetophenone/2‐Aminobenzophenone	(1.00	eq.),	heteroaromatic	aldehyde	(1.25	eq),	AcONH4	(10.00	eq)	in	H2O	at	75	oC.	
	b	Yields	in	percentage.	
	*	New	compounds.	

	
4‐Methyl‐2‐(1H‐pyrrol‐2‐yl)quinazoline	 (Table	 3,	 Entry	 4):	

Brown.	Yield:	65%.	M.p.:	122‐124	oC.	1H	NMR	(300	MHz,	CDCl3,	
δ,	ppm):	9.69	(bs,	1H,	NH),	7.97	(m,	1H,	ArH),	7.83	(m,	1H,	ArH),	
7.77‐7.72	 (m,	 1H,	 ArH),	 7.44‐7.40	 (m,	 1H,	 ArH),	 7.16	 (s,	 1H,	
Pyrrole	H),	6.92	(s,	1H,	Pyrrole	H),	6.31‐6.28	(m,	1H,	Pyrrole	H),	
2.94	 (s,	 3H,	 CH3).	 13C	 NMR	 (75	 MHz,	 CDCl3,	 δ,	 ppm):	 168.3,	
154.6,	 150.2,	 133.6,	 131.2,	 128.4,	 125.8,	 124.9,	 121.3,	 112.1,	
110.9,	 21.9.	 MS	 (ESI,	 m/z):	 210	 [M+H]+.	 HR‐MS	 (ESI,	 m/z):	
210.1027	[M+H]+.	C13H12N3+;	calc.	210.1031.		

4‐Methyl‐2‐(pyridin‐4‐yl)quinazoline	 (Table	 3,	 Entry	 5):	
Brown.	Yield:	77%.	M.p.:	104‐106	oC.	1H	NMR	(300	MHz,	CDCl3,	
δ,	 ppm):	 8.75	 (d,	 J	 =	6.0,	 2H,	Pyridine	H),	 8.47	 (d,	 J	 =	 6.0,	 2H,	
Pyridine	 H),	 8.11‐8.07	 (m,	 2H,	 ArH),	 7.91‐7.86	 (m,	 1H,	 ArH),	
7.65‐7.59	 (m,	 1H,	 ArH),	 3.03	 (s,	 3H,	 CH3).	 13C	 NMR	 (75	MHz,	
CDCl3,	δ,	ppm):	168.4,	158.0,	150.0,	145.4,	134.0,	129.7,	127.8,	
125.0,	 123.6,	 122.4,	 22.0.	 MS	 (ESI,	m/z):	 222	 [M+H]+.	 HR‐MS	
(ESI,	m/z):	222.1030	[M+H]+.	C14H12N3+;	calc.	222.1031.		

2‐(Furan‐2‐yl)‐4‐phenylquinazoline	 (Table	 3,	 Entry	 6):	
Brown.	Yield:	72%.	M.p.:	168‐170	oC.	1H	NMR	(300	MHz,	CDCl3,	
δ,	ppm):	8.12	(m,	1H,	Furan	H),	8.06	(m,	1H,	ArH),	7.87‐7.79	(m,	
3H,	ArH),	7.66	(s,	1H,	Furan	H),	7.56‐7.45	(m,	5H,	ArH),	6.57	(s,	
1H,	Furan	H).	 13C	NMR	(75	MHz,	CDCl3,	δ,	ppm):	153.0,	151.8,	
145.01,	 137.4,	 134.0,	 130.0,	 129.8,	 129.0,	 128.3,	 127.0,	 126.7,	
121.5,	 114.1,	 112.0.	 MS	 (ESI,	m/z):	 273	 [M+H]+.	 HR‐MS	 (ESI,	
m/z):	273.1025	[M+H]+.	C18H13N2O+;	calc.	273.1027.		

4‐Phenyl‐2‐(thiophen‐2‐yl)quinazoline	 (Table	 3,	 Entry	 7):	
Brown.	Yield:	70%.	M.p.:	139‐141	oC.	1H	NMR	(300	MHz,	CDCl3,	
δ,	ppm):	8.14	(m,	1H,	ArH),	8.08	(m,	1H,	ArH),	7.86‐7.77	(m,	3H,	
ArH),	 7.65	 (s,	 1H,	 Thiophene	 H),	 7.56‐7.43	 (m,	 5H,	 ArH,	
Thiophene	 H),	 6.57	 (s,	 1H,	 Thiophene	 H).	 13C	 NMR	 (75	 MHz,	

CDCl3,	δ,	ppm):	151.8,	138.2,	137.3,	133.5,	130.1,	129.9,	129.7,	
129.3,	 128.8,	 128.5,	 128.1,	 127.1,	 126.5.	 MS	 (ESI,	m/z):	 289	
[M+H]+.	HR‐MS	 (ESI,	m/z):	 289.0789	 [M+H]+.	 C18H13N2S+;	 calc.	
289.0799.		

4‐Phenyl‐2‐(pyridin‐4‐yl)quinazoline	 (Table	 3,	 Entry	 8):	
White.	Yield:	76%.	M.p.:	148‐150	oC.	1H	NMR	(300	MHz,	CDCl3,	
δ,	 ppm):	 8.76	 (d,	 J	 =	 5.2,	 2H,	 Pyridine	H),	 8.51	 (d,	 J	 =	 6.0,	 2H,	
Pyridine	H),	 8.15	 (m,	 2H,	 ArH),	 7.94‐7.84	 (m,	 3H,	 ArH),	 7.62‐
7.58	 (m,	 4H,	 ArH).	 13C	 NMR	 (75	 MHz,	 CDCl3,	 δ,	 ppm):	 157.8,	
151.8,	 150.3,	 145.2,	 137.3,	 133.6,	 130.1,	 130.0,	 129.5,	 128.5,	
127.8,	 127.0,	 122.3.	 MS	 (ESI,	m/z):	 284	 [M+H]+.	 HR‐MS	 (ESI,	
m/z):	284.1178	[M+H]+.	C19H14N3+;	calc.	284.1187.	
	
3.	Results	and	discussion		

	
While	 developing	 a	 new	 and	 catalyst‐free	 method	 for	

quinazoline	 derivatives,	 a	 model	 reaction	 was	 carried	 out	 in	
aqueous	 medium	 between	 2‐aminoacetophenone	 (1),	
benzaldehyde	 (2)	 and	 AcONH4	 as	 substrates	 (Scheme	 1).	
Initially,	 the	 desired	 quinazoline	 was	 obtained	 in	 62%	 yield,	
after	heating	the	reaction	mixture	for	15	h	at	100	oC.	Reaction	
time	and	temperature	were	optimized	at	4	h	and	75	oC.	In	the	
investigative	 studies,	 reactions	 were	 conducted	 varying	 the	
molar	 quantities	of	 aldehydes	 (1.0‐1.5	 eq.)	 as	well	 as	AcONH4	
(2.5	 to10.0	eq.).	The	experiments	 indicated	 that	10.0	equiv.	of	
AcONH4	 resulted	 in	 favorable	 completion	of	 the	 reaction	with	
1.25	equiv.	of	aldehyde.	

In	 order	 to	 assess	 the	 solvent	 efficacy	 the	 reactions	were	
conducted	in	different	organic	solvents	such	as	AcOEt,	toluene,	
MeCN,	 MeOH,	 (Me)2CHOH,	 CH2Cl2	 and	 DMSO.	 However,	 H2O	



Bandaru	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	252‐257	 257	
 

 

appeared	 to	be	 the	best	 choice	among	 the	 solvents	 examined,	
whereas	 no	 product	 formation	 was	 observed	 in	 toluene.	
Reactions	conducted	in	MeCN,	(Me)2CHOH	and	MeOH	resulted	
in	 trace	 amounts	 of	 quinazoline	 with	 so	 many	 byproducts.	
Lower	yields	were	obtained	in	case	of	AcOEt,	CH2Cl2	and	DMSO.	
Therefore	 all	 the	 reactions	 were	 carried	 out	 in	 H2O	 at	 75	 oC	
under	optimized	conditions.	

Further,	the	substrate	scope	was	expanded	with	a	variety	of	
2‐amino	carbonyl	compounds	(Scheme	1).	Under	the	optimized	
reaction	 conditions,	 a	 range	of	 functional	 group	 tolerance	 can	
be	 observed	 (Table	 1)	 among	 substituted	 2‐aminocarbonyls.	
The	 investigation	 was	 also	 extended	 to	 diversely	 substituted	
aldehydes.	When	electron‐withdrawing	groups,	such	as	Cl	and	
NO2	 were	 introduced	 to	 the	 phenyl	 ring	 of	 benzaldehyde,	
reactions	resulted	in	good	yields	(Table	2,	entries	3‐4),	whereas	
the	introduction	of	electron‐donating	groups,	such	as	MeO,	EtO	
as	well	as	OH	to	the	phenyl	ring	of	benzaldehyde,	decreased	the	
yields	(	Table	2,	entries	5‐9).	

Heterocylic	 aldehydes	 (Table	 3,	 entries	 1‐8)	 were	 also	
compatible	 in	 this	methodology	 to	 find	wider	 applicability	 in	
synthetic	 as	 well	 as	medicinal	 chemistry.	 Aliphatic	 aldehydes	
such	 as	 propanal,	 butanal,	 hexanal,	 octanal	 and	 cyclohexane	
carboxaldehyde	were	also	examined	for	their	reactivity	in	this	
protocol.	 Hexanal,	 cyclohexane	 carboxaldehyde	 resulted	 in	
corresponding	 dihydro	 quinazolines	 as	 products.	 Rest	 of	 the	
aliphatic	 aldehydes	 remained	 inactive	 in	 the	 present	 reaction	
conditions.	 All	 the	products	were	 identified	by	 comparison	 of	
Mass,	1H	and	13C	NMR	spectra.		
	
4.	Conclusion	
	

In	summary,	a	simple,	eco‐friendly	one‐pot	protocol	for	the	
synthesis	 of	 various	2,	 4	 substituted	quinazolines	 is	 reported.	
The	 ready	 availability	 of	 the	 starting	 materials	 and	 easy	
reaction	 conditions	 add	 to	 the	 utility	 of	 this	 convenient	
methodology.	
		
Acknowledgements	
	

We	 are	 grateful	 to	 Council	 of	 Scientific	 and	 Industrial	
Research	 (CSIR),	 New	 Delhi,	 for	 the	 research	 fellowships	 to	
Madhav	Bandaru,	 Narayana	Murthy	 Sabbavarapu,	 Anil	 Kumar	
Bandam	Santosh	Pavan,	Ashwan	Kumar	Akula.	
	
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