untitled


European	Journal	of	Chemistry	5	(4)	(2014)	584‐587	

	

European	Journal	of	Chemistry	
ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2014	Eurjchem	Publishing	‐	Printed	in	the	USA	

http://dx.doi.org/10.5155/eurjchem.5.4.584‐587.1093	

	
	

	

	

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

	 	 	

Synthesis	and	study	of	antimicrobial	activity	of	new	tetralone	esters	

Krishna	Mudeenahally	Hucchegowda,	Basavaraju	Yeriyur	Basavaiah	*,	
Umesha	Basavaiah	and	Shivakumar	Santhekasalagere	Basavaiah		

Department	of	Studies	in	Chemistry,	University	of	Mysore,	Manasagangotri,	Mysore‐570	006,	Karnataka,	India	

*Corresponding	author	at:	Department	of	Studies	in	Chemistry,	University	of	Mysore,	Manasagangotri,	Mysore‐570	006,	Karnataka,	India.		
Tel.:	+91.948.0441804.	Fax:	+91.821.2421263.	E‐mail	address:	basavaraju_yb@yahoo.co.in	(Y.B.	Basavaraju).	

	
	

	 	

	 	 	
ARTICLE	INFORMATION	 	 ABSTRACT

	
DOI:	10.5155/eurjchem.5.4.584‐587.1093	

Received:	17	May	2014	
Received	in	revised	form:	28	June	2014	
Accepted:	01	July	2014	
Online:	31	December	2014	

KEYWORDS	

	 Podophyllotoxin	belongs	to	the	class	of	cyclolignan	family	of	natural	products,	which	exhibits
strong	antimitotic,	anti‐AIDS	(HIV),	antitropical	skin	disease,	antimalarial,	virucidal,	fungicidal
and	other	biological	activities.	The	new	tetralone	esters	(9a‐d)	of	podophyllotoxin	analogues
were	 synthesized	 in	 good	 yields	 by	 chalcone	 route	 to	 study	 their	 structure‐activity
relationship.	All	the	products	obtained	were	characterized	by	spectral	and	elemental	analysis
data	 and	 they	were	 screened	 for	 antimicrobial	 activity.	 Compounds	 9b	 and	 9c	were	 shown
significant	antibacterial	and	antifungal	activities.	

Tetralone	esters	
Cyclopropanation	
Antimicrobial	activity	
Friedel‐Crafts	acylation	
Claisen‐Schmidt	reaction	
Ethyl	monochloro	acetate	

	
1.	Introduction	
	

Podophyllotoxin	 (1)	 is	 a	 strong	 antimitotic	 agent	 [1,2].	
Podophyllin	 is	 a	 resinous	 extract	 of	 two	 important	medicinal	
plants	Podophyllum	emodi	and	Podophyllum	peltatum	belonging	
to	the	family	of	Berberidaceae	[3‐6].	It	has	also	been	extracted	
from	 many	 other	 plants	 of	 podophyllum	 species.	 Podophyl‐
lotoxin	 and	 its	 derivatives	 also	 exhibit	 strong	 antiviral	 and	
neoplastic	 activity	 [7].	 The	 use	 of	 podophyllotoxin	 in	 cancer	
chemotherapy	 is	 restricted	 due	 to	 its	 toxic	 side	 effects	 and	
unfavourable	solubility.	

The	 semi‐synthetic	 derivatives	 of	 podophyllotoxin,	
etoposide	 (VP‐16,	 2),	 teniposide	 (VM‐26,	 3)	 are	 used	 in	 the	
treatment	 of	 cancers,	 including	 small‐cell	 lung	 cancer,	 lym‐
phoma,	 testicular	 carcinoma	 and	 Kaposi’s	 sarcoma	 (Figure	 1)	
[8,9].	 Some	 of	 its	 synthetic	 derivatives	 exhibit	 cathartic,	
cytotoxic	 and	 anticancer	 activities	 [10‐12].	 In	 view	 of	 these	
reports,	it	was	decided	to	synthesize	new	tetralone	esters	(9a‐
d)	 to	 study	 their	 structure	 activity	 relationship	 by	modifying	
structures	of	podophyllotoxin.	
	
2.	Experimental	
	
2.1.	Materials	and	methods	
	

All	 reagents	 and	 chemicals	 were	 purchased	 from	 Merck	
chemicals	and	were	used	without	further	purification.	Melting	

points	 were	 determined	 by	 open	 capillary	 method	 and	 are	
uncorrected.	The	 IR	 spectra	were	 recorded	on	a	 FT‐IR	 in	KBr	
disc	 or	 Nujol.	 The	 1H	 NMR	 spectra	 were	 recorded	 on	 Jeol	
300MHz	and	Jeol	GSX‐400	spectrometer	using	CDCl3	or	DMSO‐
d6	 as	 solvent	 and	TMS	as	an	 internal	 reference.	 13C	NMR	(100	
MHz)	 spectra	 were	 recorded	 on	 Bruker	 DRX‐400	 instrument	
with	DMSO‐d6	solvent.	The	chemical	shifts	were	expressed	in	δ	
ppm	 values.	 The	 mass	 spectra	 (ESI‐MS)	 were	 recorded	 by	
Bruker	daltonics	on	ESQUIRE‐3000	instrument.		

	

	
Figure	 1.	 The	 structure	 of	 podophyllotoxin	 (1)	 and	 its	 semi	 synthetic	
derivatives	etoposide	(2)	and	teniposide	(3).	

	



Krishna	et	al.	/	European	Journal	of	Chemistry	5	(4)	(2014)	584‐587	 585	
 

	

	
	

Scheme	1
	
	
The	purity	of	the	compounds	was	checked	by	TLC	on	silica	

gel	 glass	 plates	 in	 benzene:ethyl	 acetate	 mixture	 (7:0.5,	 v:v).	
The	 compounds	 were	 purified	 by	 column	 chromatography	
using	 silica	 gel	 (60‐120	 mesh)	 as	 adsorbent	 and	 benzene	 as	
eluent.	
	
2.2.	Synthesis	
	
2.2.1.	Synthesis	of	acetophenone	(5)	
	

2‐Chloro	toluene	(4)	(10	g,	0.079	mol)	 in	acetic	anhydride	
(50	 mL)	 containing	 fused	 zinc	 chloride	 (10.76	 g,	 0.079	 mol)	
were	stirred	at	room	temperature	for	12	h.	After	usual	workup,	
the	 product	 was	 obtained	 and	 it	 was	 recrystallized	 from	
ethanol	(Scheme	1).	

4'‐Chloro‐3'‐methyl‐acetophenone	 (5):	 Color:	 Colourless	
liquid.	Yield:	93.81%.	B.p.:	104‐105	°C.	 IR	 (KBr,	ν,	 cm‐1):	1673	
(C=O),	1598	(C=C).	1H	NMR	(400	MHz,	CDCl3,	δ,	ppm):	2.32	(s,	
3H,	CH3),	2.49‐2.54	(s,	3H,	COCH3),	7.34‐7.73	(m,	3H,	Ar‐H).	13C	
NMR	 (100	MHz,	 DMSO‐d6,	 δ,	 ppm):	 199.4	 (C‐1),	 138.6	 (C‐4'),	
135.5	 (C‐3'),	 134.7	 (C‐1'),	 130.3	 (C‐2'),	 127.9	 (C‐5'),	 126.8	 (C‐
6'),	28.8	(C‐2),	14.9	(3'‐CH3).	MS	(ESI,	m/z):	168.03	(M+).	Anal.	
calcd.	for	C9H9ClO:	C,	64.11;	H,	5.38.	Found:	C,	64.08;	H,	5.35%.	
	
2.2.2.	General	procedure	for	the	synthesis	of	chalcones	(7a‐
d)	
	

4'‐Chloro‐3'‐methyl‐acetophenone	 (5)	 (5	 g,	 0.0296	 mol)	
and	 substituted	 benzaldehydes	 (6a‐d)	 (0.0296	 mol)	 were	
stirred	 vigorously	 in	 water	 (40	 mL)	 and	 ethanol	 (25	 mL)	
mixture	 in	 the	 presence	 of	 sodium	 hydroxide	 (1.18	 g,	 0.0296	
mol)	 at	 15‐30	 °C	 for	 4h.	 The	 reaction	 mixture	 was	 kept	
overnight	 in	 an	 ice	 bath.	 The	 precipitated	 products	 were	
filtered	and	recrystallized	from	ethanol	(Scheme	1).	

1‐(4'‐Chloro‐3'‐methyl‐phenyl)‐3‐(4''‐methylphenyl)‐prop‐2‐
ene‐1‐one	(7a):	Color:	Pale	yellow	solid.	Yield:	98.6%.	M.p.:	96‐
98	°C.	IR	(KBr,	ν,	cm‐1):	1665	(C=O),	1594	(C=C).	1H	NMR	(400	
MHz,	CDCl3,	δ,	ppm):	2.32	(s,	3H,	CH3),	2.36	(s,	3H,	CH3),	7.04‐
7.62	(m,	8H,	Ar‐H,	α‐CH),	8.02	(d,	1H,	 J=12Hz,	β‐CH).	 13C	NMR	
(100	MHz,	DMSO‐d6,	δ,	ppm):	188.9	(C‐1),	144.7	(C‐3),	139.5	(C‐
4'),	137.1	(C‐4''),	136.3	(C‐3'),	135.2	(C‐1'),	131.8	(C‐1''),	130.7	
(C‐2'),	128.9	(C‐5'),	128.1	(C‐3'',	C‐5''),	127.9	(C‐6'),	126.1	(C‐2'',	
C‐6''),	121.1	(C‐2),	23.8	(4''‐CH3),	14.9	(3'‐CH3).	MS	(ESI,	m/z):	
270.08	(M+).	Anal.	calcd.	for	C17H15ClO:	C,	75.41;	H,	5.58.	Found:	
C,	75.38;	H,	5.54%.	

1‐(4'‐Chloro‐3'‐methyl‐phenyl)‐3‐(4''‐methoxyphenyl)‐prop‐
2‐ene‐1‐one	 (7b):	 Color:	 Yellow	 solid.	 Yield:	 92.3%.	M.p.:	 102‐
104	°C.	IR	(KBr,	ν,	cm‐1):	1662	(C=O),	1591	(C=C).	1H	NMR	(400	
MHz,	DMSO,	δ,	ppm):	2.31	(s,	3H,	CH3),	3.82	(s,	3H,	OCH3),	6.84‐
7.78	(m,	8H,	Ar‐H,	α‐CH),	8.05	(d,	1H,	 J=13Hz,	β‐CH).	 13C	NMR	
(100	MHz,	DMSO‐d6,	 δ,	ppm):	188.8	 (C‐1),	159.2	 (C‐4''),	145.1	
(C‐3),	139.9	(C‐4'),	136.4	(C‐3'),	135.4	(C‐1'),	131.3	(C‐2'),	129.1	
(C‐5'),	128.1	(C‐6'),	127.2	(C‐1''),	127	(C‐2'',	C‐6''),	121.3	(C‐2),	
114.1	 (C‐3'',	 C‐5''),	 55.7	 (OCH3),	 15.1	 (3'‐CH3).	MS	 (ESI,	m/z):	
286.08	 (M+).	 Anal.	 calcd.	 for	 C17H15ClO2:	 C,	 71.20;	 H,	 5.27.	
Found:	C,	71.18;	H,	5.24%.	

1‐(4'‐Chloro‐3'‐methyl‐phenyl)‐3‐(4''‐methylthiophenyl)‐
prop‐2‐ene‐1‐one	 (7c):	 Color:	 Yellow	 solid.	 Yield:	 91.6%.	M.p.:	
109‐111	°C.	IR	(KBr,	ν,	cm‐1):	1667	(C=O),	1598	(C=C).	1H	NMR	
(400	MHz,	CDCl3,	δ,	ppm):	2.33	(s,	3H,	CH3),	2.51	(s,	3H,	SCH3),	
7.26‐7.62	 (m,	8H,	Ar‐H,	α‐CH),	 8.04	 (d,	1H,	 J=12Hz,	β‐CH).	 13C	
NMR	 (100	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 189.1	 (C‐1),	 145.1	 (C‐3),	
139.9	 (C‐4'),	136.2	 (C‐3'),	135.8	 (C‐1'),	135.1	 (C‐4''),	131.2	(C‐
1'',	C‐2'),	129.1	(C‐5'),	128.1	(C‐6'),	126.2	(C‐3'',	C‐5''),	125.9	(C‐
2'',	C‐6''),	121.1	(C‐2),	15.1	(3'‐CH3),	14.8	(SCH3).	MS	(ESI,	m/z):	
302.05	 (M+).	 Anal.	 calcd.	 for	 C17H15ClOS:	 C,	 67.43;	 H,	 4.99.	
Found:	C,	67.41;	H,	4.96%.	

1‐(4'‐Chloro‐3'‐methyl‐phenyl)‐3‐(3'',4''‐dimethylphenyl)‐
prop‐2‐ene‐1‐one	 (7d):	 Color:	 Yellow	 solid.	 Yield:	 94.7%.	M.p.:	
121‐123	°C.	IR	(KBr,	ν,	cm‐1):	1665	(C=O),	1597	(C=C).	1H	NMR	
(400	MHz,	CDCl3,	δ,	ppm):	2.34	(s,	3H,	3'‐CH3),	2.34	(s,	3H,	3''‐
CH3),	2.34	(s,	3H,	4''‐CH3),	6.63‐7.95	 (m,	7H,	Ar‐H,	α‐CH),	8.06	
(d,	 1H,	 J=12Hz,	β‐CH).	 13C	NMR	 (100	MHz,	DMSO‐d6,	 δ,	 ppm):	
189.3	(C‐1),	144.8	(C‐3),	140.1	(C‐4'),	136.7	(C‐3''),	136.1	(C‐3'),	
135.8	(C‐4''),	135.2	(C‐1'),	132.1	(C‐1''),	131.5	(C‐2'),	129.2	(C‐
5'),	128.6	(C‐5''),	128.1	(C‐6'),	126.1	(C‐2''),	123.1	(C‐6''),	121.2	
(C‐2),	 18.1	 (3''‐CH3),	 17.3	 (4''‐CH3),	 14.9	 (3'‐CH3).	 MS	 (ESI,	
m/z):	284.10	(M+).	Anal.	calcd.	for	C18H17ClO:	C,	75.92;	H,	6.02.	
Found:	C,	75.89;	H,	6.01%.	
	
2.2.3.	General	procedure	for	the	synthesis	of	cyclopropyl	
keto	esters	(8a‐d)	
	

Chalcones	 (7a‐d)	 (0.0184	 mol),	 freshly	 distilled	 ethyl	
monochloro	acetate	(2.25	g,	0.0184	mol)	and	powdered	sodium	
(0.8	 g,	 0.0368	mol)	were	 stirred	 in	 dry	 benzene	 (120	mL)	 at	
room	temperature	for	30	h.	The	unreacted	sodium	and	its	salts	
were	 filtered	 off.	 The	 filtrate	 was	 washed	 with	 5%	 aqueous	
sodium	hydroxide	solution	(2	×	50	mL),	2%	brine	solution	(2	×	
50	mL)	and	dried	over	anhydrous	sodium	sulphate.	The	solvent	



586	 Krishna	et	al.	/	European	Journal	of	Chemistry	5	(4)	(2014)	584‐587	
	
was	removed	by	distillation	to	give	a	crude	product,	which	was	
purified	 by	 column	 chromatography	 using	 chloroform	 as	
eluent.	The	products	were	recrystallized	from	ethanol	(Scheme	
1).	

Ethyl‐2‐(4'‐chloro‐3'‐methyl‐benzoyl)‐3‐(4''‐methylphenyl)‐
cyclopropane‐1‐carboxylate	 (8a):	 Color:	 Brown	 solid.	 Yield:	
86.3%.	M.p.:	 113‐115	 °C.	 IR	 (KBr,	 ν,	 cm‐1):	 1741	 (COO),	 1675	
(C=O),	1597	(C=C).	1H	NMR	(400	MHz,	CDCl3,	δ,	ppm):	1.12‐1.31	
(t,	 3H,	 J=4Hz,	 COOCH2CH3),	 1.94‐2.78	 (m,	 3H,	 cyclopro‐CH),	
2.31	 (s,	 3H,	 3'‐CH3),	 2.34	 (s,	 3H,	 4''‐CH3),	 4.05‐4.13	 (q,	 2H,	
J=4Hz,	 COOCH2CH3),	 6.97‐7.66	 (m,	 7H,	 Ar‐H).	 13C	 NMR	 (100	
MHz,	DMSO‐d6,	δ,	ppm):	192.3	(C‐1),	170.8	(COO),	140.2	(C‐1''),	
138.6	(C‐4'),	135.3	(C‐3'),	134.4	(C‐1',	C‐4''),	130.2	(C‐2'),	128.6	
(C‐5'),	 128.1	 (C‐3'',	 C‐5''),	 127	 (C‐6'),	 124.6	 (C‐2'',	 C‐6''),	 61.5	
(COOCH2CH3),	35.9	(C‐3),	33.2	(C‐4),	31.1	(C‐2),	24.1	(4''‐CH3),	
15.1	 (3''‐CH3),	13.8	 (COOCH2CH3).	MS	 (ESI,	m/z):	356.12	 (M+).	
Anal.	calcd.	for	C21H21ClO3:	C,	70.68;	H,	5.93.	Found:	C,	70.66;	H,	
5.91%.	

Ethyl‐2‐(4'‐chloro‐3'‐methyl‐benzoyl)‐3‐(4''‐methoxyphenyl)‐
cyclopropane‐1‐carboxylate	 (8b):	 Color:	 Brown	 solid.	 Yield:	
82%.	 M.p.:	 103‐105	 °C.	 IR	 (KBr,	 ν,	 cm‐1):	 1735	 (COO),	 1674	
(C=O),	 1595	 (C=C).	 1H	 NMR	 (400	MHz,	 CDCl3,	 δ,	 ppm):	 0.98‐
1.29(t,	3H,	J=4Hz,	COOCH2CH3),	1.95‐2.75(m,	3H,	cyclopro‐CH),	
2.35	 (s,	 3H,	 CH3),	 3.82	 (s,	 3H,	 OCH3),	 4.05‐4.15(q,	 2H,	 J=4Hz,	
COOCH2CH3),	 6.67‐7.68	 (m,	 7H,	 Ar‐H).	 13C	 NMR	 (100	 MHz,	
DMSO‐d6,	δ,	ppm):	191.9	(C‐1),	171.2	(COO),	156.8	(C‐4''),	138.4	
(C‐4'),	 135.2	 (C‐3'),	 134.9	 (C‐1''),	 134.2	 (C‐1'),	 130.2	 (C‐2'),	
128.3	(C‐5'),	126.7	(C‐6'),	125.8	(C‐2'',	C‐6''),	113.3	(C‐3'',	C‐5''),	
61.6	(COOCH2CH3),	55.3	(OCH3),	36.1	(C‐3),	33.2	(C‐4),	29.9	(C‐
2),	 14.8	 (3'‐CH3),	 13.9	 (COOCH2CH3).	 MS	 (ESI,	 m/z):	 372.11	
(M+).	 Anal.	 calcd.	 for	 C21H21ClO4:	 C,	 67.65;	 H,	 5.68.	 Found:	 C,	
67.61;	H,	5.64%.	

Ethyl‐2‐(4'‐chloro‐3'‐methyl‐benzoyl)‐3‐(4''‐meththio	
phenyl)‐cyclopropane‐1‐carboxylate	 (8c):	 Color:	 Brown	 solid.	
Yield:	 84.6%.	M.p.:	 120‐122	 °C.	 IR	 (KBr,	ν,	 cm‐1):	 1740	 (COO),	
1678	(C=O),	1598	(C=C).	1H	NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	
0.99‐1.29	 (t,	 3H,	 J=4Hz,	 COOCH2CH3),	 1.92‐2.74	 (m,	 3H,	
cyclopro‐CH),	2.34	(s,	3H,	CH3),	2.51	(s,	3H,	SCH3),	3.96‐4.16	(q,	
2H,	J=4Hz,	COOCH2CH3),	7.01‐7.66	(m,	7H,	Ar‐H).	13C	NMR	(100	
MHz,	DMSO‐d6,δ,	ppm):	191.7	(C‐1),	170.9	(COO),	139.8	(C‐1''),	
138.2	(C‐4'),	135.4	(C‐3'),	134.2	(C‐1'),	132.2	(C‐4''),	130.1	(C‐
2'),	128.4	(C‐5'),	126.7	(C‐6'),	126	(C‐3'',	C‐5''),	125	(C‐2'',	C‐6''),	
61.4	(COOCH2CH3),	36	(C‐3),	33.1	(C‐4),	30.8	(C‐2),	15	(3'‐CH3),	
14.6	 (SCH3),	 13.7	 (COOCH2CH3).	 MS	 (ESI,	m/z):	 388.09	 (M+).	
Anal.	calcd.	 for	C21H21ClO3S:	C,	64.85;	H,	5.44.	Found:	C,	64.83;	
H,	5.41%.	

Ethyl‐2‐(4'‐chloro‐3'‐methyl‐benzoyl)‐3‐(3'',4''‐dimethyl	
phenyl)‐cyclopropane‐1‐carboxylate	 (8d):	 Color:	 Brown	 solid.	
Yield:	 87.3%.	M.p.:	 130‐132	 °C.	 IR	 (KBr,	ν,	 cm‐1):	 1738	 (COO),	
1677	 (C=O),	 1593	 (C=C).	 1H	 NMR	 (400	MHz,	 CDCl3,	 δ,	 ppm):	
0.98‐1.30	 (t,	 3H,	 J=4Hz,	 COOCH2CH3),	 1.92‐2.73	 (m,	 3H,	
cyclopro‐CH),	2.30	(s,	3H,	3'‐CH3),	2.33	(s,	3H,	3''‐CH3),	2.36	(s,	
3H,	 4''‐CH3),	 4.07‐4.12	 (q,	 2H,	 J=4Hz,	 COOCH2CH3),	 6.81‐7.64	
(m,	6H,	Ar‐H).	13C	NMR	(100	MHz,	DMSO‐d6,	δ,	ppm):	191.5	(C‐
1),	170.6	 (COO),	139.5	(C‐1'),	138.3	(C‐4'),	135.8	 (C‐3''),	134.8	
(C‐3'),	 134.4	 (C‐1'),	 133.1	 (C‐4''),	 129.8	 (C‐2'),	 128.2	 (C‐5'),	
127.9	 (C‐5''),	 126.8	 (C‐6'),	 126.1	 (C‐2''),	 121.7	 (C‐6''),	 61.2	
(COOCH2CH3),	36.2	(C‐3),	33.2	(C‐4),	30.6	(C‐2),	18.1	(3''‐CH3),	
17.7	 (4''‐CH3),	 14.6	 (3'‐CH3),	 14	 (COOCH2CH3).	MS	 (ESI,	m/z):	
370.13	 (M+).	 Anal.	 calcd.	 for	 C22H23ClO3:	 C,	 71.25;	 H,	 6.25.	
Found:	C,	71.23;	H,	6.22%.	
	
2.2.4.	General	procedure	for	the	synthesis	of	tetralone	esters	
(9a‐d)	
	

A	solution	of	cyclopropyl	keto	esters	(8a‐d)	(0.0140	mol)	in	
dry	 dichloromethane	 (75	 mL)	 was	 added	 dropwise	 to	 a	
magnetically	 stirred	 solution	 of	 anhydrous	 Stannic	 chloride	
(3.65	g,	0.0140	mol)	and	acetic	anhydride	(2.86	g,	0.0280	mol)	
in	dichloromethane	(75	mL)	for	half	anone	h	at	0	°C	and	further	
stirred	for	6	h.	After	treating	the	reaction	mixture	with	5	N	HCl	

solution	 (50	 mL),	 the	 organic	 layer	 was	 washed	 with	 10%	
NaOH	solution	 (2	×	50	mL)	 and	 finally	with	water.	The	 crude	
product	 was	 purified	 by	 column	 chromatography	 using	
benzene	as	eluent	(Scheme	1).	

3‐Ethylcarboxy‐4‐(4'‐methylphenyl)‐6‐chloro‐7‐methyl‐
1‐tetralone	 (9a):	 Color:	 Reddish	 brown	 semi	 solid.	 Yield:	
87.3%.	IR	(KBr,	ν,	cm‐1):	1745	(COO),	1698	(C=O),	1592	(C=C).	
1H	 NMR	 (400	 MHz,	 CDCl3,	 δ,	 ppm):	 0.98‐1.30	 (t,	 3H,	 J=4Hz,	
COOCH2CH3),	2.31	(s,	3H,	7‐CH3),	2.35	(s,	3H,	4'‐CH3),	2.76‐3.02	
(dd,	2H,	CH2),	3.63	(q,	1H,	J=4Hz,	CH),	4.11‐4.22	(q,	2H,	J=4Hz,	
COOCH2CH3),	4.66	(d,	1H,	J=12Hz,	CH),	7.15‐7.58	(m,	6H,	Ar‐H).	
13C	 NMR	 (100	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 196.7	 (C‐1),	 172.8	
(COO),	 139.9	 (C‐1'),	 138.8	 (C‐6),	 138.3	 (C‐4a),	 135.4	 (C‐4'),	
133.1	(C‐7),	131.6	(C‐8a),	130.7	(C‐8),	129.2	(C‐3',	C‐5'),	127.7	
(C‐2',	C‐6'),	127.6	(C‐5),	61.5	(COOCH2CH3),	45.1	(C‐4),	40.8	(C‐
3),	37.2	(C‐2),	24	(4'‐CH3),	14.8	(7‐CH3),	13.9	(COOCH2CH3).	MS	
(ESI,	m/z):	356.12	(M+).	Anal.	calcd.	for	C21H21ClO3:	C,	70.68;	H,	
5.93.	Found:	C,	70.65;	H,	5.91%.	

3‐Ethylcarboxy‐4‐(4'‐methoxyphenyl)‐6‐chloro‐7‐methyl‐
1‐tetralone	 (9b):	 Color:	 Reddish	 brown	 semi	 solid.	 Yield:	
82.6%.	IR	(KBr,	ν,	cm‐1):	1742	(COO),	1696	(C=O),	1594	(C=C).	
1H	 NMR	 (400	 MHz,	 CDCl3,	 δ,	 ppm):	 1.28	 (t,	 3H,	 J=4Hz,	
COOCH2CH3),	2.33	(s,	3H,	CH3),	2.73‐3.04	(dd,	2H,	CH2),	3.62	(q,	
1H,	 J=3Hz,	 CH),	 3.82	 (s,	 3H,	 OCH3),	 4.19	 (q,	 2H,	 J=4Hz,	
COOCH2CH3),	4.68	(d,	1H,	J=12Hz,	CH),	6.92‐7.57	(m,	6H,	Ar‐H).	
13C	 NMR	 (100	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 196.3	 (C‐1),	 173.1	
(COO),	 157.8	 (C‐4'),	 139.1	 (C‐6),	 138.6	 (C‐4a),	 135.1	 (C‐1'),	
132.9	(C‐7),	131.9	(C‐8a),	130.6	(C‐8),	129	(C‐2',	C‐6'),	127.2	(C‐
5),	114.2	(C‐3',	C‐5'),	61.3	(COOCH2CH3),	55.4	 (OCH3),	45.2	 (C‐
4),	 40.6	 (C‐3),	 37.2	 (C‐2),	 15	 (7‐CH3),	 13.7	 (COOCH2CH3).	 MS	
(ESI,	m/z):	372.11	(M+).	Anal.	calcd.	for	C21H21ClO4:	C,	67.65;	H,	
5.68.	Found:	C,	67.62;	H,	5.66%.	

3‐Ethylcarboxy‐4‐(4'‐methylthiophenyl)‐6‐chloro‐7‐methyl‐
1‐tetralone	(9c):	Color:	Reddish	brown	semi	solid.	Yield:	89.4%.	
IR	(KBr,	ν,	cm‐1):	1748	(COO),	1691	(C=O),	1583	(C=C).	1H	NMR	
(400	MHz,	CDCl3,	δ,	ppm):	1.28	(t,	3H,	J=4Hz,	COOCH2CH3),	2.34	
(s,	3H,	CH3),	2.53	(s,	3H,	SCH3),	2.74‐3.03	(dd,	2H,	CH2),	3.60	(q,	
1H,	 J=3Hz,	 CH),	 4.21	 (q,	 2H,	 J=4Hz,	 COOCH2CH3),	 4.67	 (d,	 1H,	
J=4Hz,	CH),	7.13‐7.56	(m,	6H,	Ar‐H).	13C	NMR	(100	MHz,	DMSO‐
d6,	δ,	ppm):	196.5	(C‐1),	172.3	(COO),	138.8	(C‐4'),	139.1	(C‐6),	
138.2	(C‐4a),	133.4	(C‐4'),	133	(C‐7),	131.4	(C‐8a),	130.9	(C‐8),	
128.3	 (C‐2',	 C‐6'),	 127.4	 (C‐5),	 127.1	 (C‐3',	 C‐5'),	 61.5	
(COOCH2CH3),	 45.4	 (C‐4),	 41.2	 (C‐3),	 37.6	 (C‐2),	 14.6	 (7‐CH3),	
13.9(SCH3),	 13.2	 (COOCH2CH3).	 MS	 (ESI,	 m/z):	 388.09	 (M+).	
Anal.	calcd.	 for	C21H21ClO3S:	C,	64.85;	H,	5.44.	Found:	C,	64.83;	
H,	5.41%.	

3‐Ethylcarboxy‐4‐(3',4'‐dimethylphenyl)‐6‐chloro‐7‐methyl‐
1‐tetralone	 (9d):	 Color:	 Reddish	 brown	 semi	 solid.	 Yield:	
79.8%.	IR	(KBr,	ν,	cm‐1):	1744	(COO),	1693	(C=O),	1599	(C=C).	
1H	 NMR	 (400	 MHz,	 CDCl3,	 δ,	 ppm):	 1.15‐1.29	 (t,	 3H,	 J=4Hz,	
COOCH2CH3),	 2.32	 (s,	 3H,	 7‐CH3),	 2.34	 (s,	 3H,	 3'‐CH3),	 2.35	 (s,	
3H,	 4'‐CH3),	 2.71‐3.02	 (dd,	 2H,	 CH2),	 3.62	 (q,	 1H,	 J=3Hz,	 CH),	
4.18‐4.22	 (q,	2H,	 J=4Hz,	COOCH2CH3),	 4.68	 (d,	1H,	 J=4Hz,	CH),	
6.97‐7.57	(m,	5H,	Ar‐H).	13C	NMR	(100	MHz,	DMSO‐d6,	δ,	ppm):	
195.7	(C‐1),	172.1	(COO),	139.3	(C‐1'),	138.5	(C‐6),	138	(C‐4a),	
137.1	(C‐3'),	134.2	(C‐4'),	133.1	(C‐7),	131.6	(C‐8a),	130.9	(C‐8),	
129.3	 (C‐2'),	 128.6	 (C‐5'),	 127.5	 (C‐5),	 125	 (C‐6'),	 61.1	
(COOCH2CH3),	45.8	(C‐4),	41	(C‐3'),	37.4	(C‐2),	18	(3'‐CH3),	17.8	
(4'‐CH3),	15(7‐CH3),	13.9	 (COOCH2CH3).	MS	 (ESI,	m/z):	370.13	
(M+).	 Anal.	 calcd.	 forC22H23ClO3:	 C,	 71.25;	 H,	 6.25.	 Found:	 C,	
71.23;	H,	6.24%.	
	
2.3.	Antimicrobial	activity	
	

The	newly	 synthesized	 compounds	 (9a‐d)	were	evaluated	
for	their	in	vitro	antibacterial	activity	against	the	gram	positive	
bacteria	Staphylococcus	aureus	and	the	gram	negative	bacteria	
Escherichia	coli	by	disc	diffusion	method	[13].	The	bioassay	was	
carried	 out	 using	 Mueller‐Hinton	 agar	 (Hi‐Media)	 medium.	
Ciprofloxacin	 was	 used	 as	 a	 standard.	 Simillarly	 the	 in	 vitro	
antifungal	 activity	 was	 evaluated	 for	 the	 compounds	 9a‐d	



Krishna	et	al.	/	European	Journal	of	Chemistry	5	(4)	(2014)	584‐587	 587	
 

against	Aspergillis	 niger	 and	 Candida	 albicans	 (recultured)	 by	
disc	diffusion	method	[14]	with	Sabouraud’s	dextrose	agar	(Hi‐
Media).	Clotrimazole	was	used	as	 a	 standard.	Each	 compound	
was	 tested	 at	 a	 concentration	of	 100µg/mL	 in	DMSO	 for	 both	
activities.	The	plates	were	incubated	at	35	°C	for	24	h	and	the	
resulting	zone	of	inhibition	(in	mm)	was	measured.	
	
3.	Results	and	discussion	
	
3.1.	Chemistry	
	

In	 this	 paper,	 the	 chalcone	 route	 has	 been	 followed	 with	
some	 changes	 in	 experimental	 procedure	 to	 synthesize	 new	
tetralone	 esters	 (9a‐d)	 (Scheme	 1)	 [15,16].	 The	 4'‐chloro‐3'‐
methyl‐acetophenone	 (5)	 was	 prepared	 in	 high	 yield	 by	
Friedel‐Crafts	 acylation	 reaction	 of	 2‐chloro	 toluene	 (4)	 with	
acetic	 anhydride	 in	 the	 presence	 of	 fused	 zinc	 chloride	 [17].	
The	 structure	 of	 acetophenone	 was	 confirmed	 by	 IR	 and	 1H	
NMR	spectra.	The	IR	spectra	showed	C=C	stretching	frequency	
at	1598	cm‐1	and	C=O	stretching	frequency	at	1673	cm‐1.	The	1H	
NMR	spectra	signals	corresponding	to	COCH3	appeared	at	2.49‐
2.54	ppm.		

The	chalcones	(7a‐d)	were	prepared	in	excellent	yields	by	
Claisen‐Schmidt	 reaction	 of	 4'‐chloro‐3'‐methyl‐acetophenone	
(5)	 with	 benzaldehydes	 (6a‐d)	 in	 the	 presence	 of	 sodium	
hydroxide	 in	 water‐ethanol	 mixture	 [18].	 The	 structures	 of	
chalcones	were	 confirmed	 by	 IR	 and	 1H	NMR	 spectra.	 The	 IR	
spectra	 of	 chalcones	 showed	 C=C	 stretching	 frequency	 in	 the	
range	of	1591‐1598	 cm‐1	 and	C=O	stretching	 frequency	 in	 the	
range	of	1662‐1667	 cm‐1.	The	 1H	NMR	spectra	 signals	 corres‐
ponding	 to	α‐CH	and	β‐CH	of	chalcones	appeared	at	7.62‐7.95	
ppm	and	8.02‐8.06	ppm	with	coupling	constant	J	=	12	Hz.	

The	cyclopropyl	keto	esters	(8a‐d)	were	prepared	in	good	
yields	 by	 the	 reaction	 of	 chalcones	 (7a‐d)	 with	 ethyl	
monochloro	acetate	in	the	presence	of	powdered	sodium	in	dry	
benzene	[19].	The	IR	spectra	showed	stretching	frequencies	at	
1593‐1598,	 1674‐1678	 and	1735‐1741	 cm‐1	 for	C=C,	 C=O	and	
ester	C=O	of	cyclopropyl	keto	esters	respectively.	The	1H	NMR	
spectra	 signals	 of	 cyclopropyl	 CH	 protons	 appeared	 at	 1.92‐
2.78	ppm.	

The	 tetralone	 esters	 (9a‐d)	were	 prepared	 in	 good	 yields	
by	intramolecular	cyclization	of	cyclopropyl	keto	esters	(8a‐d)	
in	 the	 presence	 of	 anhydrous	 stannic	 chloride	 and	 acetic	
anhydride	 in	 dry	 dichloromethane	 [20,21].	 The	 structures	 of	
tetralone	esters	were	based	on	 IR,	 1H	NMR,	Mass	 spectra	 and	
elemental	 analysis	 data.	 The	 IR	 stretching	 frequencies	 of	
compounds	 (9a‐d)	 showed	 at	 1592‐1599,	 1691‐1698	 and	
1742‐1748	cm‐1	 for	C=C,	C=O	and	ester	C=O,	 respectively.	The	
1H	NMR	 spectra	 signals	 appeared	 at	 0.98‐1.30	ppm	and	4.11‐
4.22	 ppm	 for	 CH2	 and	 CH3	 protons	 of	 tetralone	 esters	with	 a	
coupling	constant	J	=	4	Hz.	

	
3.2.	Antimicrobial	activity	
	
3.2.1.	Antibacterial	activity	
	

The	 synthesized	 compounds	9a‐d	were	 screened	 for	 their	
antibacterial	 activity.	 The	 compound	 9a	 has	 low	 activity	
compared	 to	 standard	 (Ciprofloxacin)	 and	 compounds	 9b‐d	
against	 Escherichia	 colia	 nd	 Staphylococcus	 aureus	 at	 a	
concentration	 of	 100µg/mL.	 Compound	 9d	 has	 moderate	
activity	 and	 compounds	9b	 and	9c	 exhibited	 better	 activities	
compared	 to	 ciprofloxacin	 and	 compounds	 9a	 and	 9d	 at	 the	
same	concentration.	The	bacterial	zones	of	 inhibition	(in	mm)	
values	were	summarized	in	Table	1.	
	
3.2.2.	Antifungal	activity	
	

The	 synthesized	 compounds	9a‐d	were	 screened	 for	 their	
antifungal	 activity.	 Compounds	 9b	 and	 9c	 are	 more	 active	
when	compared	to	standard	(Clotrimazole).	The	compound	9a	

exhibited	 low	 activity	 and	 the	 compound	 9d	 exhibited	
moderate	activity	against	Aspergillis	niger	and	Candida	albicans	
at	a	concentration	of	100µg/mL.	The	fungal	zones	of	inhibition	
(in	mm)	values	were	summarized	in	Table	2.	
	
Table1.	Antibacterial	activity	of	the	synthesized	compounds	9a‐d.	
Compound		 Zone	of	inhibition	in	(mm)	

E.	coli S.	aureus	
9a 9 11	
9b 12 14	
9c 27 28	
9d 29 26	
Ciprofloxacin 21 23	
	
	
Table	2.	Antifungal	activity	of	the	synthesized	compounds	9a‐d.	
Compound Zone	of	inhibition	in	(mm)	

A.	niger C.	albicans	
9a 8 10	
9b 14 15	
9c	 23	 24	
9d	 25	 23	
Clotrimazole 22 20	
	
	
4.	Conclusion	
	

The	 new	 tetralone	 esters	 9a‐d	were	 synthesized	 in	 good	
yields.	They	were	screened	for	their	antimicrobial	activities.	All	
the	compounds	exhibited	better	activities.	
	
Acknowledgement	

	
The	 authors	 are	 thankful	 to	 the	 director,	 Central	 Drug	

Research	 Institute	 (CDRI),	 Lucknow	 and	 Indian	 Institute	 of	
Technology	 (IIT),	 Chennai,	 for	 providing	 NMR,	 Mass	 spectra	
and	elemental	analysis	data	for	our	research	compounds.	
	
References	
	
[1]. Smissman,	E.	E.;	Murray,	R.	J.;	McChesney,	J.	D.	J.	Med.	Chem.	1976,	19,	

148‐153.	
[2]. Jungi,	W.	F.;	Senn,	H.	J.	Cancer	Chemother.	Rep.	1975,	59,	737‐742.	
[3]. Podwyssotzki,	V.	Arch.	Exp.	Pathol.	Pharmakol.	1880,	13,	29‐52.	
[4]. Jackson,	D.	E.;	Dewick,	P.	M.	Phytochemistry	1985,	24,	2407‐2409.	
[5]. Yalamati,	D.;	William,	L.	Curr.	Med.	Chem.	1998,	5,	205‐252.	
[6]. Kelly,	M.	G.;	Hartwell,	J.	L.	J.	Natl.	Cancer	Inst.	1954,	14,	967‐1010.	
[7]. Canel,	C.;	Moraes,	R.	M.;	Dayan,	F.	E.;	Ferreira,	D.	Phytochemistry	2000,	

54,	115‐120.	
[8]. Imbert,	T.	F.	Biochimie	1998,	80(3),	207‐222.	
[9]. Gordaliza,	 M.;	 Garcia,	 P.	 A.;	 Miguel	 del	 Corral,	 J.	 M.;	 Castro,	 M.	 A.;	

Gomez‐Zurita,	M.	A.	Toxicon	2004,	44,	441‐459.	
[10]. Rivera,	G.	Cancer	Chemother.	Rep.	1975,	59,	743‐749.	
[11]. Sathisha,	A.	D.;	Hemakumar,	K.	H.;	Basavaraju,	Y.	B.	Ind.		J.	Heterocycl.	

Chem.	2007,	17,	15‐18.	
[12]. Lee,	C.	T.	L.;	Lin,	V.	C.	K.	Bioorg.	Med.	Chem.	Lett.	1997,	7,	2897‐2902.	
[13]. Bauer,	A.	W.;	Kirby,	W.	M.;	 Sherris,	 J.	 C.	Am.	 J.	Clin.	Pathol.	1966,	39,	

493‐496.	
[14]. Booth,	J.;	Boyland,	E.	Biochem.	J.	1966,	34,	125‐135.	
[15]. Basavaraju,	 Y.	 B.;	 Raju,	 D.;	 Anupama,	 N.	 Int.	 J.	 Pharm.	 Sci.	 Rev.	 Res.	

2013,	21,	305‐309.	
[16]. Umesha,	B.;	Basavaraju,	Y.	B.	Eur.	J.	Chem.	2013,	4(3),	235‐239.	
[17]. Sadashivamurthy,	B.;	Basavaraju,	Y.	B.	 Ind.	 J.	Heterocycl.	Chem.	2006,	

15,	259‐262.	
[18]. Furniss,	 B.	 S.;	Hannaford,	A.	 J.;	 Smith,	P.	W.	G.;	Tatchell,	A.	 R.	Vogels	

text	 book	 of	 practical	 organic	 chemistry,	 5th	 edition,	 ELBS	Longman,	
New	York,	1989.	

[19]. Lokanatha	 Rai,	 K.	 M.;	 Murthy,	 C.	 A.;	 Radhakrishna,	 P.	 M.	 Synth.	
Commun.	1990,	20,	1273‐1277.	

[20]. Vyas,	D.	M.;	 Skonezhy,	M.	P.;	 Jenkins,	T.	A.;	Doyle,	T.	W.	Tetrahedron	
Lett.	1986,	27,	3099‐3102.	

[21]. Sadashivamurthy,	B.;	Basavaraju,	Y.	B.	Bulg.	Chem.	Commun.	2005,	37,	
135‐139.