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European	Journal	of	Chemistry	2	(3)	(2011)	300‐307	

	
European	Journal	of	Chemistry	

ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2011	EURJCHEM	
DOI:10.5155/eurjchem.2.3.300‐307.358	

	
	

	

	

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

	 	 	

Synthesis	of	dihydrooxazoylarylisoxazoles	by	conventional	and	under	
microwave	conditions	

Parikibanda	Venkata	Ramana	and	Annadi	Ram	Reddy*	

Department	of	Chemistry,	University	College	of	Science,	Osmania	University,	Hyderabad,	500007,	India	

*Corresponding	author	at:	Department	of	Chemistry,	University	College	of	Science,	Osmania	University,	Hyderabad,	500007,	India.	Tel.:	+91.40.27203573;		
fax:	+91.40.27090020.	E‐mail	address:	a_ramreddy@yahoo.com	(A.R.	Reddy).	

	
	

	 	

	 	 	
ARTICLE	INFORMATION	 	 ABSTRACT
Received:	02	December	2010	
Received	in	revised	form:	08	January	2011	
Accepted:	27	January	2011	
Online:	30	September	2011	

KEYWORDS	

	 The	synthesis	of	series	of	3‐aryl‐4‐dihydrooxazolyl‐5‐methyl	trisubstituted	isoxazoles	(VI)	is
reported,	both	under	thermal	and	microwave	conditions	starting	from	various	benzaldehydes
(I).	Benzaldehydes	undergo	oximation	with	hydroxylamine	hydrosulphate	to	provide	oximes
that	 upon	 chlorination,	 followed	 by	 condensation	 with	 methylacetoacetate,	 resulted	 in	 the
formation	of	esters.	Hydrolysis	of	the	esters	to	acids	followed	by	treatment	with	PCl5,	resulted
in	 the	 formation	 of	 acid	 chlorides	 (III)	 that	 upon	 reaction	 with	 hydroxyamines,	 gave	N‐β‐
hydoxyalkyl	amides	 (IV).	These	on	 further	 reaction	with	SOCl2,	 followed	by	 cyclization	with
2	N	NaOH	provided	oxazoline	substituted	isoxazoles	(VI)	in	good	yields.	The	conversion	acid
chlorides	(III)	to	isoxazoles	(VI)	was	also	achieved	by	microwave	irradiation	in	moderate	to
excellent	yields,	with	shorter	reaction	times	compared	to	the	conventional	thermal	method.	

Isoxazole	
Ethanolamine	
Microwave	irradiation	
Dihydrooxazoline	
Conventional	
Oximation	

	
1.	Introduction	
	

Several	 compounds	 of	 natural	 and	 synthetic	 isoxazole	
scaffold	 posses	 a	 broad	 spectrum	of	 biological	 properties	 like	
fungicidal	 [1‐3],	 antibacterial	 [4,5],	 anti‐inflammatory	 [6,7],	
antitubercular	 [8],	 antitumor	 [9,10],	 herbicidal	 [11‐13],	
antifeedent	 [14]	 and	 antiviral	 [15‐17]	 activities.	 Ureido	
derivatives	 of	 5‐amino‐3‐methylisoxazole‐4‐carboxylic	 acid	
were	 found	 to	 have	 a	 significant	 antileukemic	 activity	 [18].	
Structure‐activity	 relationship	 (SAR)	 studies	 of	 5‐methyl‐3‐
substituted	phenylisoxazole‐4‐carboxamides	revealed	that	they	
are	potent	antagonists	 for	secretagogue	 receptors	 [19].	 It	was	
also	demonstrated	that	the	C=O	group	at	the	C‐(4)	 is	the	most	
adaptable	 site	 for	 chemical	 change	and	 is	an	area	 that	greatly	
influences	 potency	 spectrum	 and	 safety.	 On	 the	 other	 hand	
oxzoline	 heterocycles	 are	 found	 to	 be	 potential	 anticancer	
[20,21],	 antidepressant	 [22],	 anti‐inflammatory	 [23],	
antioxidant	[24],	LpxC	[25]	and	FAAH	inhibitors	[26].	Some	of	
the	oxazoline	compounds	show	ovicidal	activity	[27].	Oxazoline	
complexes	 are	 useful	 as	 catalysts	 for	 the	 enantioselective	 C‐C	
bond	 formation	 [28,29]	 and	 enantioselective	 terminal	 alkene	
hydrogenation	 [30].	 Isoxazole	 coupled	 oxazolines	 were	
reported	 as	 Ca‐activated	 K	 channel	 openers	 [31]	 and	 also	
reported	 as	 catalysts	 for	 regioselective	 ring	 opening	 of	
propylene	 oxides	 [32].	 The	 importance	 of	 oxazolines	 and	
isoxazoles	 has	 prompted	 the	 design	 and	 synthesis	 of	 various	
oxazoline	 substituted	 isoxazoles	 and	 herein,	 we	 report	 the	
synthesis	 of	 a	 few	 4‐(4,5‐dihydrooxazol‐2‐yl)‐5‐methyl‐3‐aryl	
isoxazole	under	thermal	and	microwave	irradiation.	
	
2.	Experimental	
	
2.1.	Instrumentation	
	

The	 reagents	 and	 solvents	 were	 of	 analytical	 grade	 and	
were	 used	 without	 further	 purification	 unless	 otherwise	
mentioned.	Thin	 layer	 chromatography	 (TLC)	was	 carried	out	
on	aluminum	sheets	coated	with	silica	gel	60	F254	(Merck).	TLC	
plates	 were	 inspected	 under	 UV	 light.	 Micro‐analytical	 data	
were	obtained	by	employing	a	Perkin‐Elmer	240c	analyzer.	 IR	
spectra	 were	 recorded	 with	 a	 Perkin‐Elmer‐1700	 spectro‐
photometer.	1H	NMR	and	13C	NMR	spectra	were	measured	on	a	
Bruker	 Avance	 400	 MHz	 spectrometer.	 The	 following	
abbreviations	 have	 been	 used	 to	 explain	 the	 observed	
multiplicities:	s,	singlet;	d,	doublet;	t,	triplet;	m,	multiplet;	br	s,	
broad	singlet.	Coupling	constants	in	Hz	have	been	assigned	and	
listed	 without	 duplication	 in	 the	 1H	 NMR	 description	 of	 the	
synthesized	 compounds.	 Electron	 spray‐mass	 spectra	 were	
recorded	 on	 an	 LCQ	 system	 (Finnigan	 MAT,	 USA)	 using	
methanol	as	the	mobile	phase.	Melting	points	were	recorded	on	
a	 Polmon	 MP	 96.	 Microwave	 reactions	 performed	 in	 MARS	
240/50,	model	No.	907510.	
	
2.2.	General	procedure	for	the	preparation	of	5‐methyl‐3‐
phenyl/substituted	phenyl‐	isoxazole‐4‐carboxylic	acid	(IIa‐
IId)	
	

To	 a	 solution	 of	 aldehyde	 (Ia‐Id)	 (1	 mol)	 in	 400	 mL	 of	
methanol,	 hydroxylamine	 hydrosulphate	 (1.4	mol)	was	 added	
and	stirred	for	30	min	(Scheme	1).	The	turbid	reaction	mixture	
was	 slowly	 converted	 to	 a	 clear	 solution.	 Later	 the	 pH	 was	
adjusted	 to	 8‐9	 with	 Na2CO3	 and	 refluxed	 for	 30	 min.	
Subsequently,	 it	was	 cooled	 to	0‐5	 °C	 and	was	 chlorinated	by	
passing	Cl2	 gas	over	 a	period	of	1‐2	h.	The	excess	Cl2	 gas	was	
removed	by	passing	the	nitrogen	and	the	highly	acidic	pH	was	
adjusted	 to	 1‐2	 by	 using	 Na2CO3	 at	 0	 °C	 (Ia3	 to	 Id3)	 (mild	
effervescence	of	CO2	observed	in	the	beginning).		

	



Ramana	and	Reddy	/	European	Journal	of	Chemistry	2	(3)	(2011)	300‐307	 301	
 

 
 

 

 
	

Reagents	 and	 conditions:	 a	 =	 hydroxylamine	 hydrosulfate,	 MeOH,	 Na2CO3,	 reflux,	 30	 min;	 b	 =	 Cl2	 gas,	 0‐5	 °C,	 1‐2	 h;	 c	 =	
methylacetoacetate,	MeOH,	NaOH,	rt,	1	h;	d	=	aq.	NaOH	(25%),	reflux,	1	h.	

	
Scheme	1	

	
	
In	 another	 flask	 sodium	 salt	 of	 methylaceto	 acetate	 was	

prepared	 by	 the	 addition	 of	 1.4	mol	 of	NaOH	 to	 a	 solution	 of	
methyl	acetoacetate	(1.4	mol)	in	400	mL	of	methanol	at	0‐5	°C	
and	 stirred	 for	 30	 min	 by	 maintaining	 the	 pH	 at	 10.	 The	
precipitate,	 sodium	salt	 of	methylaceto	 acetate	 formed	during	
the	 course	 of	 reaction	 in	 methanol	 was	 added	 to	 the	 chloro	
compound	 (Ia3	 to	 Id3)	 during	 a	 period	 of	 1	 h	 at	 0‐5	 °C	 and	
subsequently	 stirred	 for	 1	 h	 at	 room	 temperature	 by	
maintaining	the	pH	=	9	with	NaOH.	Later	the	pH	was	adjusted	
to	 11‐13	 with	 aq.	 25%	 NaOH	 and	 the	 reaction	 mixture	 was	
refluxed	 for	 1	 h.	 The	 methanol	 was	 distilled,	 suspended	 the	
residue	in	5	times	of	water	and	adjusted	the	pH	to	2.0‐2.5	with	
20%	H2SO4.	The	compound	was	filtered,	washed	with	hot	water	
and	 recrystallized	 in	 methanol	 to	 afford	 a	 pure	 product	
(Scheme	1).	

5‐Methyl‐3‐phenyl‐isoxazole‐4‐carboxylic	 acid	 (IIa):	 Color:	
white.	 Yield:	 82%.	M.p.:	 189‐190	 °C.	 IR	 (KBr,	 ):	 3075,	 3020,	
2878,	2689,	 2613,	 1689,	 1598,	 1471,	 1424,	 1338,	 1162,	1122	
cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	2.72	(s,	3H),	7.45	(m,	
3H),	7.63	(d,	 J	=	6.8	Hz,	2H)	13.12	(br	S,	1H).	 13C	NMR	(CDCl3,	
100	MHz,	δ,	ppm):	13.5,	107.5,	127.8,	128.1,	129.4,	129.8,	163.2,	
167.1,	 175.2.	 MS	 (ES,	 m/z):	 204	 [M+H]+.	 Anal.	 Calcd.	 for	
C11H9NO3:	C,	65.02;	H,	4.46;	N,	6.89.	Found:	C,	64.88;	H,	4.32;	N,	
6.95%.	

3‐(2‐Chlorophenyl)‐5‐methyl‐isoxazole‐4‐carboxylic	 acid	
(IIb):	 Color:	 white.	 Yield:	 85%.	M.p.:	 193‐196	 °C.	 IR	 (KBr,	 ):	
3017,	2881,	2686,	2607,	1690,	1603,	1574,	1456,	1405,	1317,	
1250,	1162,	1104	cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	2.75	
(s,	 3H),	 7.42	 (m,	 4H),	 12.52	 (br	 s,	 1H).	 13C	 NMR	 (CDCl3,	 100	
MHz,	 δ,	 ppm):	 13.0,	 110.2,	 126.3,	 128.8,	 129.2,	 130.4,	 130.9,	
133.9,	 160.9,	 162.9,	 174.9.	 MS	 (ES,	 m/z):	 238	 [M+H]+.	 Anal.	
Calcd.	 for	 C11H8ClNO3:	 C,	 55.60;	 H,	 3.39;	 N,	 5.89.	 Found:	 C,	
55.48;	H,	3.32;	N,	5.99%.	

3‐(2,6‐Dichlorophenyl)‐5‐methyl‐isoxazole‐4‐carboxylic	 acid	
(IIc):	 Color:	 white.	 Yield:	 79%.	 M.p.:	 225‐226	 °C.	 IR	 (KBr,	 ):	
3060,	2927,	2675,	2606,	1695,	1601,	1560,	1514,	1463,	1383,	
1320,	1262,	1194	cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	2.79	
(s,	 3H),	 7.38	 (m,	 3H),	 12.86	 (br	 s,	 1H).	 13C	 NMR	 (CDCl3,	 100	
MHz,	 δ,	 ppm):	 13.0,	 110.0,	 127.6,	 128.4,	 130.7,	 135.2,	 158.7,	
162.4,	 175.3	 MS	 (ES,	 m/z):	 272	 [M+H]+.	 Anal.	 Calcd.	 for	
C11H7Cl2NO3:	C,	48.56;	H,	2.59;	N,	5.15.	Found:	C,	48.41;	H,	2.45;	
N,	5.15%.	

3‐(2‐Chloro‐6‐flourophenyl)‐5‐methyl‐isoxazole‐4‐carboxylic	
acid	 (IId):	Color:	white.	Yield:	76%.	M.p.:	206‐208	°C.	 IR	(KBr,	
):	 3072,	 2895,	 2686,	 2607,	 1689,	 1605,	 1517,	 1454,	 1379,	
1316,	1250,	1188	1161	cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	
2.75	(s,	3H),	7.12	(t,	1H,	J	=	8.1	Hz	),	7.31(d,	1H,	J	=	7.6	Hz),	7.43	
(m,	 1H),	 12.91	 (br	 s,	 1H).	 13C	NMR	 (CDCl3,	 300	MHz,	δ):	 13.2,	
110.3,	 114.0,	 117.8,	 125.0,	 131.2,	 135.0,	 155.6,	 159.5,	 162.6,	
175.4.	MS	(ES,	m/z):	256	[M+H]+.	Anal.	Calcd.	for	C11H7ClFNO3:	
C,	51.68;	H,	2.76;	N,	5.48.	Found:	C,	51.41;	H,	2.73;	N,	5.61%.	

2.3.	General	procedure	for	the	preparation	of	5‐methyl‐3‐
aryl‐isoxazole‐4‐carboxyl	chloride	(IIIa‐IIId)	
	

To	 the	 compound	 IIa‐IId	 (1	mol)	 in	 neat	 condition	 (with	
out	any	solvent)	was	added	PCl5	(1	mol)	at	room	temperature	
and	heated	to	45	°C	to	become	clear	solution.	It	was	stirred	for	
1h	 and	 the	 by	 product	 POCl3	 was	 distilled	 under	 reduced	
pressure.	To	the	residue	75	mL	of	hexane	was	added	and	set	for	
crystallization.	 The	 crystallized	 acid	 chloride	 was	 filtered	
(Scheme	2).	

5‐Methyl‐3‐phenyl‐isoxazole‐4‐corbonyl	 chloride	 (IIIa):	
Color:	Color	less	liquid.	Yield:	90%.	B.p.:	115‐117°C	(3	Torr).	IR	
(neat,	 ):	 3065,	 3010,	 1741,	 1689,	 1605,	 1462,	 1316,	 1250,	
1157,	 1116	 cm‐1.	 1H	 NMR	 (CDCl3,	 400	MHz,	 δ,	 ppm):	 2.79	 (s,	
3H),	7.45	(m,	3H),	7.62	(d,	J	=	7.6	Hz,	2H).	13C	NMR	(CDCl3,	100	
MHz,	 δ,	 ppm):	 13.6,	 107.5,	 128.0,	 128.1,	 129.3,	 129.8,	 162.6,	
166.3,	 177.4.	 MS	 (ES,	 m/z):	 222	 [M+H]+.	 Anal.	 Calcd.	 for	
C11H8ClNO2:	 C,	 59.61;	 H,	 3.64;	 N,	 6.32%.	 Found:	 C,	 59.58;	 H,	
3.73;	N,	6.31%.	

3‐(2‐Chlorophenyl)‐5‐methyl‐isoxazole‐4‐corbonyl	 chloride	
(IIIb):	 Color:	 white.	 Yield:	 93%.	 M.p.:	 45‐48	 °C.	 IR	 (KBr,	 ):	
3061,	3005,	1732,	 1685,	 1604,	 1458,	 1309,	 1258,	 1141,	 1117	
cm‐1.	 1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	2.79	(s,	3H),	7.39	(m,	
4H).13C	 NMR	 (CDCl3,	 300	 MHz,	 δ):	 13.9,	 114.8,	 126.7,	 127.4,	
129.6,	 131.0,	 131.3,	 134.2,	 158.9,	 160.2,	 176.7.	MS	 (ES,	m/z):	
256	 [M+H]+.	Anal.	 Calcd.	 for	C11H7Cl2NO2:	C,	 51.59;	H,	2.76;	N,	
5.47%.	Found:	C,	51.42;	H,	2.83;	N,	5.47%.	

3‐(2,6‐Dichlorophenyl)‐5‐methyl‐isoxazole‐4‐corbonyl	
chloride	(IIIc):	Color:	white.	Yield:	84%.	M.p.:	88‐89	°C.	IR	(KBr,	
):	 3089,	 3002,	 1757,	 1689,	 1562,	 1498,	 1432,	 1390,	 1290,	
1249,	1195,	1145	cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	2.85	
(s,	3H),	7.38	(m,	3H).	13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	14.2,	
114.0,	 127.0,	 128.0,	 131.7,	 135.6,	 158.1,	 158.6,	 177.7.	MS	 (ES,	
m/z):	 290	 [M+H]+.	 Anal.	 Calcd.	 for	 C11H6Cl3NO2:	 C,	 45.47;	 H,	
2.08;	N,	4.82%.	Found:	C,	45.61;	H,	2.03;	N,	4.90%.	

3‐(2‐Chloro‐6‐flourophenyl)‐5‐methyl‐isoxazole‐4‐corbonyl	
chloride	 (IIId):	 Color:	 white.	 Yield:	 88%.	M.p.:	 181‐184	 °C.	 IR	
(KBr,	 ):	 3054,	 3010,	 1757,	 1693,	 1576	 1514,	 1449,	 1393,	
1290,	 1250,	 1185,	 1162	 cm‐1.	 1H	 NMR	 (CDCl3,	 400	 MHz,	 δ,	
ppm):	2.86	 (s,	3H),	7.14	 (t,	1H,	 J	=	 8.0	Hz),	 7.31(d,	1H,	 J	=	 8.0	
Hz),	 7.44	 (m,	 1H).	 13C	 NMR	 (CDCl3,	 100	 MHz,	 δ,	 ppm):	 14.2,	
109.0,	 113.9,	 116.5,	 125.4,	 132.2,	 135.2,	 155.0,	 158.6,	 162.1,	
177.6.	MS	(ES,	m/z):	274	[M+H]+.	Anal.	Calcd.	for	C11H6Cl2FNO3:	
C,	48.21;	H,	2.21;	N,	5.11%.	Found:	C,	48.10;	H,	2.08;	N,	5.11%.	
	
2.4.	General	procedure	for	the	synthesis	of	N‐(2‐hydroxy‐
ethyl/substituted	ethyl)‐5‐methyl‐3‐arylisoxazole‐4‐
carboxamide	(IVa‐IVd)	
	

To	a	 turbid	 solution	of	12	mmol	 of	 compound	 IIIa‐IIId	 in	
20	mL	 of	 CHCl3	 was	 added	 triethylamine	 (20	mmol)	 at	 10	 °C	
and	obtined	a	clear	solution.		



302	 Ramana	and	Reddy	/	European	Journal	of	Chemistry	2	(3)	(2011)	300‐307	
	

	 	

R'

R
N
O

O

OH

R'

R
N
O

O

N
H

IIa R=H, R'=H
IIb R=H, R'=Cl
IIc R=Cl, R'=Cl
IId R=Cl, R'=F

R'

R
N
O

O

Cl

IIIa
IIIb
IIIc
IIId

R'

R
N
O

O

N
H

a b c

IVa1-3
IVb1-3
IVc1-3
IVd1-3

R''

OH Cl

R''

R'

R
N
O
VIa1-3
VIb1-3
VIc1-3
VId1-3

R'

R
N
O
VIa4
VIb4
VIc4
VId4

O

N

O

N

R''
R'

R
N
O

O

N
H

IVa4
IVb4
IVc4
IVd4

OH

Va1-3
Vb1-3
Vc1-3
Vd1-3

c

R'' = -H/-CH3/ -CH(CH3)2

R'' = -H/-CH3/ -CH(CH3)2

R'' = -H/-CH3/ -CH(CH3)2

d
e

 
 

 
	

Reagents	and	conditions:	a	=	PCl5,	rt,	1	h;	b	=	1/2/3,	TEA,	CHCl3,	10	°C,	rt,	3	h;	c	=	CHCl3,	SOCl2,	0‐5	°C,	rt,	
overnight;	d	=	MeCN,	2N	NaOH,	rt,	overnight;	e	=	4,	TEA,	CHCl3,	10	°C,	rt,	3	h;	

	
	

Scheme	2
	

	
To	 the	 resulting	 mixture	 ethanolamine/substituted	

ethanolamine	 (16	 mmol)	 was	 added	 drop	 wise	 while	
maintaining	 the	 temperature	 at	 10	 °C.	 The	 reaction	 was	 fast	
and	 exothermic.	 The	 resulting	 solution	was	 stirred	 for	 3	 h	 at	
room	 temperature,	 monitored	 by	 TLC.	 The	 reaction	 mixture	
was	extracted	with	CHCl3	 (2	x	30	mL).	The	combined	extracts	
were	dried	over	anhydrous	MgSO4	and	concentrated	 in	vacuo.	
The	residue	was	purified	by	silica	gel	column	chromatography	
with	hexane:	EtOAc	(90:10%)	to	afford	IVa‐IVd.	
	
2.5.	General	procedure	for	the	synthesis	of	N‐(2‐hydroxy‐
ethyl/substituted	ethyl)‐5‐methyl‐3‐aryl‐isoxazole‐4‐carbox‐
amide	(IVa‐IVd)	in	microwave	
	

Compound	 IIIa‐IIId	 (5	 mmol)	 was	 adsorbed	 on	 silicagel	
(200‐400	 mesh)	 and	 added	 ethanolamine/substituted	
ethanolamine	(8	mmol)	 followed	by	 triethyl	amine	(10	mmol)	
in	 to	 a	 microwave	 vial.	 The	 vial	 was	 sealed	 and	 placed	 in	
microwave.	 The	 reaction	was	 run	 at	 50	 °C	 for	 3	min.	 For	 the	
entire	 experiment,	 the	power	 setting	was	 held	 at	 100	W.	 The	
reaction	 mixture	 was	 then	 cooled	 to	 room	 temperature	 and	
purified	 by	 SiO2	 gel	 column	 chromatography	 with	 hexane:	
EtOAc	 (90:10%)	 to	 afford	 IVa‐IVd	 (c	 =	 yield	 of	 conventional	
method;	m	=	yield	of	microwave	method)	(Scheme	2).	

N‐(2‐Hydroxyethyl)‐5‐methyl‐3‐phenylisoxazole‐4‐carbox‐
amide	(IVa1):	Color:	white.	Yield:	88%m	(73%)c.	M.p.:	121‐123	
°C.	 IR	 (KBr,	 ):	 3411,	 3228,	 3068,	 2912,	 1689,	 1609,	 1564,	
1462,	1402,	1368,	1260,	1174,	1124,	1071,	1040	cm‐1.	1H	NMR	
(CDCl3,	400	MHz,	δ,	ppm):	2.69	(s,	3H),	3.38	(q,	J	=	5.6	Hz,	2H),	
3.60	(t,	J	=	5.6	Hz,	2H)	5.89	(br	s,	1H),	7.49	(m,	3H),	7.59	(d,	J	=	
7.1	Hz,	2H).	13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	12.5,	42.1,	61.7,	
111.2,	 128.5,	 128.9,	 130.2,	 160.1,	 162.3,	 173.5.	MS	 (ES,	m/z):	

247	 [M+H]+.	 Anal.	 Calcd.	 for	 C13H14N2O3:	 C,	 63.40;	 H,	 5.73;	 N,	
11.38%.	Found:	C,	63.73;	H,	6.01;	N,	11.03%.	

N‐((S)‐1‐Hydroxypropan‐2‐yl))‐5‐methyl‐3‐phenylisox‐
azole‐4‐carboxamide	(IVa2):	Color:	white.	Yield:	97%m	(82%)c.	
M.p.:	 130‐132	 °C.	 IR	 (KBr,	 ):	 3379,	 3234,	 3076,	 2972,	 1626,	
1562,	1467,	1419,	1338,	1263,	1180,	1143,	1099,	1055	cm‐1.	1H	
NMR	(CDCl3,	400	MHz,	δ,	ppm):	0.97	(d,	J	=	6.8	Hz,	3H),	2.69	(s,	
3H),	3.38	(dd,	J	=	11.2	Hz,	J’	=	3.6	Hz,	1H),	3.54	(dd,	J	=	11.2	Hz,	J’	
=	3.6	Hz,	1H),	4.09	(m,	1H),	5.60	(br	d,	J	=	6.0	Hz,	1H),	7.50	(m,	
3H),	7.61	(d,	J	=	7.8	Hz,	2H).	13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	
12.6,	16.5,	47.7,	66.5,	 111.1,	128.3,	128.9,	129.0,	130.3,	160.1,	
161.8,	 173.7.	 MS	 (ES,	 m/z):	 261	 [M+H]+.	 Anal.	 Calcd.	 for	
C14H16N2O3:	 C,	 64.60;	 H,	 6.20;	 N,	 10.76%.	 Found:	 C,	 64.46;	 H,	
6.18;	N,	11.12%.	

N‐((S)‐1‐Hydroxy‐3‐methylbutan‐2‐yl)‐5‐methyl‐3‐phenyl	
isoxazole‐4‐carboxamide	 (IVa3):	 Color:	 white.	 Yield:	 92%m	
(88%)c.	M.p.:	118‐120	°C.	IR	(KBr,	):	3464,	3270,	3088,	2967,	
1669,	1616,	1567,	1488,	1435,	1378,	1287,	1165,	1017	cm‐1.	1H	
NMR	(CDCl3,	400	MHz,	δ,	ppm):	0.71	(d,	J	=	6.4	Hz,	3H),	0.83	(d,	
J	=	6.4	Hz,	3H),	1.37	(m,	1H),	2.75	(s,	3H),	3.07	(m,	2H).	3.55	(m,	
1H),	6.05	(br	d,	J	=	6.4	Hz,	1H),	7.44	(m,	3H),	7.68	(d,	J	=	6.5	Hz,	
2H).	 13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	12.7,	17.2,	18.3,	29.0,	
56.5,	 62.8,	 108.3,	 127.3,	 128.4,	 128.8,	 162.1,	 162.9,	 175.0.	MS	
(ES,	m/z):	289	[M+H]+.	Anal.	Calcd.	for	C16H20N2O3:	C,	66.65;	H,	
6.99;	N,	9.72%.	Found:	C,	66.78;	H,	7.16;	N,	9.86%.	

N‐(1‐Hydroxy‐2‐methylpropan‐2‐yl)‐5‐methyl‐3‐phenyliso‐
xazole‐4‐carboxamide	(IVa4):	Color:	white.	Yield:	96%m	(71%)c.	
M.p.:	 110‐112	 °C.	 IR	 (KBr,	 ):	 3459,	 3259,	 2982,	 1651,	 1621,	
1557,	1469,	1418,	1363,	1338,	1280,	1235,	1185,	1062	cm‐1.	1H	
NMR	(CDCl3,	400	MHz,	δ,	ppm):	1.08	(s,	6H),	2.69	(s,	3H),	3.49	
(s,	 2H),	 4.63	 (br	 s),	 5.51	 (br	 s,	 1H),	 7.54	 (m,	 5H).	 13C	 NMR	
(CDCl3,	 100	MHz,	 δ,	 ppm):	 12.5,	 24.1,	 56.2,	 70.0,	 111.6,	128.5,	
128.9,	 129.1,	 129.3,	 130.2,	 160.0,	 161.9,	 173.6.	MS	 (ES,	m/z):	



Ramana	and	Reddy	/	European	Journal	of	Chemistry	2	(3)	(2011)	300‐307	 303	
 

 
 

275	 [M+H]+.	 Anal.	 Calcd.	 for	 C15H18N2O3:	 C,	 65.68;	 H,	 6.61;	 N,	
10.21%.	Found:	C,	65.51;	H,	6.58;	N,	10.21%.	

3‐(2‐Chlorophenyl)‐N‐(2‐hydroxyethyl)‐5‐methylisoxazole‐4‐
carboxamide	 (IVb1):	 Color:	 white.	 Yield:	 80%m	 (64%)c.	 M.p.:	
91‐93	 °C.	 IR	 (KBr,	 ):	 3342,	 3273,	 2937,	 1643,	 1597,	 1529,	
1437,	1375,	1265,	1180,	1043	cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	
ppm):	2.72	(s,	3H),	3.31	(q,	 J	=	5.6	Hz,	2H),	3.51	(t,	 J	=	5.6	Hz,	
2H),	5.79	(br	s,	1H),	7.46	(m,	4H).	13C	NMR	(CDCl3,	100	MHz,	δ,	
ppm):	12.7,	41.9,	61.4,	112.0,	127.3,	127.8,	130.2,	131.5,	131.6,	
134.0,	 158.3,	 161.8,	 173.7.	 MS	 (ES,	 m/z):	 281	 [M+H]+.	 Anal.	
Calcd.	 for	C13H13ClN2O3:	C,	 55.62;	H,	4.67;	N,	 9.98%.	Found:	C,	
55.62;	H,	4.42;	N,	10.12%.	

3‐(2‐Chloropheyl)‐N‐((S)‐1‐hydroxypropan‐2‐yl)‐5‐methyl	
isoxazole‐4‐carboxamide	 (IVb2):	 Color:	 white.	 Yield:	 96%m	
(87%)c.	M.p.:	117‐119	°C.	IR	(KBr,	):	3485,	3427,	3249,	3094,	
2979,	2928,	1633,	1607,	1575,	1450,	1422,	1361,	1269,	1169,	
1057	cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	0.96	(d,	J	=	6.8	Hz,	
3H),	2.72	(s,	3H),	3.34	(dd,	J	=	11.0	Hz,	J’	=	4.8	Hz,	1H)	3.42	(dd,	J	
=	11.0	Hz,	J’	=	4.8	Hz,	1H),	4.02	(m,	1H),	5.71	(br	s,	1H),	7.46	(m,	
4H).	13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	12.5,	16.5,	47.2,	65.6,	
112.4,	 127.1,	 127.9,	 129.2,	 130.0,	 131.4,	 133.9,	 158.4,	 160.9,	
172.9.	MS	(ES,	m/z):	295	[M+H]+.	Anal.	Calcd.	for	C14H15ClN2O3:	
C,	57.05;	H,	5.13;	N,	9.50%.	Found:	C,	57.05;	H,	5.34;	N,	9.81%.	

3‐(2‐Chlorophenyl)‐N‐((S)‐1‐hydroxy‐3‐methylbutan‐2yl)‐5‐
methylisoxazole‐carboxamide	(IVb3):	Color:	white.	Yield:	97%m	
(68%)c.	M.p.:	117‐120	°C.	IR	(KBr,	):	3381,	3252,	3079,	2962,	
1638,	1608,	 1557,	 1437,	 1369,	 1328,	 1258,	 1140,	 1088,	1029	
cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	0.54	(d,	J	=	6.8	Hz,	3H),	
0.71	(d,	J	=	6.8	Hz,	3H),	1.64	(m,	1H),	2.76	(s,	3H),	3.47	(dd,	J	=	
11.5	Hz,	J’	=	4.8	Hz,	1H).	3.52	(dd,	J	=	11.5	Hz,	J’	=	4.8	Hz,	1H),	
3.78	(m,	1H),	5.46	(br	d,	J	=	8.0	Hz,	1H),	7.49(m,	4H).	13C	NMR	
(CDCl3,	 100	 MHz,	 δ,	 ppm):	 12.8,	 17.6,	 19.0,	 28.8,	 56.8,	 63.8,	
112.1,	 127.5,	 129.4,	 130.3,	 131.5,	 131.7,	 134.5,	 158.1,	 161.9,	
174.4.	MS	(ES,	m/z):	323	[M+H]+.	Anal.	Calcd.	for	C16H19ClN2O3:	
C,	59.54;	H,	5.93;	N,	8.68%.	Found:	C,	59.21;	H,	5.71;	N,	8.76%.	

3‐(2‐Chlorophenyl)‐N‐(1‐hydroxy‐2‐methylpropan‐2‐yl)‐5‐
methyl	 isoxazole‐4‐carboxamide	 (IVb4):	 Color:	 white.	 Yield:	
87%m	(79%)c.	M.p.:	126‐130	°C.	IR	(KBr,	):	3422,	3290,	2962,	
1642,	1606,	1551,	1430,	1407,	1370,	1320,	1254,	1194,	1172,	
1088	cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	1.10	(s,	6H),	2.78	
(s,	 3H),	 3.48	 (s,	 2H),	 5.22	 (br	 s,	 1H),	 7.51	 (m,	 4H).13C	 NMR	
(CDCl3,	 100	MHz,	 δ,	 ppm):	 12.5,	 23.8,	 56.4,	 70.0,107.2,	 126.5,	
128.6,	 130.3,	 130.9,	 131.5,	 134.3,	 156.0,	 161.4,	 172.3.	MS	 (ES,	
m/z):	 309	 [M+H]+.	 Anal.	 Calcd.	 for	 C15H17ClN2O3:	 C,	 58.35;	 H,	
5.55;	N,	9.07%.	Found:	C,	58.31;	H,	5.69;	N,	9.00%.	

3‐(2,6‐Dichlorophenyl)‐N‐(2‐hydroxyethyl)‐5‐methyliso‐
xazole‐4‐carboxamide	(IVc1):	Color:	white.	Yield:	73%m	(78%)c.	
M.p.:	 160‐164	 °C.	 IR	 (KBr,	 ):	 3327,	 3284,	 3042,	 2918,	 1691,	
1626,	1581,	 1448,	 1417,	 1370,	 1347,	 1234,	 1174,	 1149,	1059	
cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	2.82	(s,	3H),	3.38	(t,	J	=	
5.1	Hz,	2H),	3.58	(t,	J	=	5.1	Hz,	2H),	5.68	(br	s,	1H),	7.45	(m,	1H),	
7.50	 (m,	 2H).	 13C	 NMR	 (CDCl3,	 100	MHz,	 δ,	 ppm):	 12.9,	 41.9,	
61.7,	111.9,	127.7,	128.6,	131.9,	136.1,	156.1,	161.4,	174.3.	MS	
(ES,	m/z):	315	[M+H]+.	Anal.	Calcd.	for	C13H12Cl2N2O3:	C,	49.54;	
H,	3.84;	N,	8.89%.	Found:	C,	49.32;	H,	3.62;	N,	8.56%.	

3‐(2,6‐dichlorophenyl)‐N‐((S)‐1‐hydroxypropan‐2‐yl)‐5‐
methylisoxazol‐4‐carboxamide	(IVc2):	Color:	white.	Yield:	91%m	
(80%)c.	M.p.:	171‐174	°C.	IR	(KBr,	):	3434,	3273,	2990,	1679,	
1621,	1568,	 1461,	 1411,	 1384,	 1319,	 1264,	 1184,	 1130,	1081	
cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	0.95	(d,	J	=	4.9	Hz,	3H),	
2.82	(s,	3H),	3.39	(dd,	J	=	11.0	Hz,	J’	=	4.9	Hz,	1H)	3.53	(dd,	J	=	
11.0	Hz,	J’	=	4.9	Hz,	1H),	4.05	(m,	1H),	5.36	(br	s,	1H),	7.47	(m,	
1H),	 7.51	 (m,	 2H).	 13C	 NMR	 (CDCl3,	 100	 MHz,	 δ,	 ppm):	 12.8,	
16.5,	47.2,	66.3,	111.7,	127.6,	128.4,	131.8,	136.1,	155.9,	160.8,	
174.3.	MS	(ES,	m/z):	329	[M+H]+.	Anal.	Calcd.	for	C14H14Cl2N2O3:	
C,	51.08;	H,	4.29;	N,	8.51%.	Found:	C,	50.72;	H,	4.03;	N,	8.69%.	

3‐(2,6‐dichlorophenyl)‐N‐((S)‐1‐hydroxy‐3‐methylbutan‐2‐
yl)‐5‐methylisoxazole‐4‐carboxamide	(IVc3):	Color:	white.	Yield:	

88%m	(75%)c.	M.p.:	124‐127	°C.	IR	(KBr,	):	3422,	3290,	2962,	
1642,	1606,	1551,	1430,	1407,	1370,	1320,	1254,	1194,	1172,	
1088	cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	0.55	(d,	J	=	6.8	Hz,	
3H),	0.72	(d,	J	=	6.8	Hz,	3H),	1.65	(m,	1H),	2.79	(s,	3H),	3.45	(d,	J	
=	4.8	Hz,	2H),	3.76	(m,	1H),	5.43	(br	d,	J	=	8.1	Hz,	1H),	7.39	(m,	
1H),	 7.43	 (m,	 2H).	 13C	 NMR	 (CDCl3,	 100	 MHz,	 δ,	 ppm):	 12.9,	
17.5,	 19.1,	 28.8,	 56.4,	 63.4,	 111.6,	 127.3,	 128.5,	 132.1,	 136.1,	
155.8,	161.2,	174.5.	MS	(ES,	m/z):	357	[M+H]+.	Anal.	Calcd.	for	
C16H18Cl2N2O3:	C,	53.79;	H,	5.08;	N,	7.84%.	Found:	C,	53.63;	H,	
4.79;	N,	7.89%.	

3‐(2,6‐Dichlorophenyl)‐N‐(1‐hydroy‐2‐methylpropan‐2‐yl)‐5‐
methylisoxazole‐4‐carboxamide	 (IVc4):	 Color:	 white.	 Yield:	
80%m	(80%)c.	M.p.:	120‐124	°C.	IR	(KBr,	):	3391,	3308,	3074,	
2978,	2934,	1651,	1614,	1560,	1520,	1429,	1377,	1315,	1255,	
1195	cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	1.04	(s,	6H),	2.79	
(s,	3H),	3.44	(s,	2H),	5.26	(br	s,	1H),	7.46	(m,	1H),	7.52	(m,	2H).	
13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	12.8,	24.0,	55.9,	69.8,	112.0,	
127.6,	 128.4,	 131.9,	 136.2,	 155.9,	 161.0,	 174.4.	MS	 (ES,	m/z):	
343	[M+H]+.	Anal.	Calcd.	for	C15H16Cl2N2O3:	C,	54.49;	H,	4.70;	N,	
8.16%.	Found:	C,	54.64;	H,	4.52;	N,	8.14%.		

3‐(2‐Chloro‐6‐fluorophenyl)‐N‐(2‐hydroxyethyl)‐5‐methyl	
isoxazole‐4‐carboxamide	 (IVd1):	 Color:	 white.	 Yield:	 86%m	
(78%)c.	M.p.:	126‐128	°C.	IR	(KBr,	):	3385,	3267,	3094,	2945,	
1648,	1599,	1567,	1454,	1417,	1319,	1253,	1189,	1098	cm‐1.	1H	
NMR	(CDCl3,	400	MHz,	δ,	ppm):	2.76	(s,	3H),	3.35	(q,	J	=	5.2	Hz,	
2H),	3.56	(t,	J	=	5.2	Hz,	2H),	5.86	(br	s,	1H),	7.17	(t,	J	=	8.1	Hz,	
1H)	7.35	(d,	J	=	7.6	Hz,	1H),	7.40	(m,	1H).	13C	NMR	(CDCl3,	100	
MHz,	δ,	ppm):	12.8,	41.8,	61.4,	112.3,	114.6,	117.0,	125.8,	132.4,	
135.5,	 153.0,	 161.3,	 162.1,	 173.7.	 MS	 (ES,	 m/z):	 299	 [M+H]+.	
Anal.	 Calcd.	 for	 C13H12ClFN2O3:	 C,	 52.27;	 H,	 4.05;	 N,	 9.38%.	
Found:	C,	52.00;	H,	3.89;	N,	9.09%.	

3‐(2‐Chloro‐6‐fluorophenyl)‐N‐((S)‐1‐hydroxypropan‐2‐yl)‐
5‐methylisoxazol‐4‐carboxamide	 (IVd2):	 Color:	 white.	 Yield:	
88%m	(70%)c.	M.p.:	136‐139	°C.	IR	(KBr,	):	3458,	3301,	2997,	
1684,	1629,	1584,	1479,	1403,	1369,	1321,	1262,	1174,	1112,	
1068	cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	0.97	(d,	J	=	6.8	Hz,	
3H),	2.76	(s,	3H),	3.37	(dd,	J	=	11.2	Hz,	J’	=	3.2	Hz,	1H),	3.51	(dd,	
J	=	11.2	Hz,	J’	=	3.2	Hz,	1H),	4.03	(m,	1H),	5.53	(br	d,	J	=	6.4	Hz,	
1H),	7.12	(t,	J	=	8.0	Hz,	1H)	7.18	(d,	J	=	8.6	Hz,	1H),	7.47	(m,	1H).	
13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	12.7,	16.6,	47.3,	66.1,	112.3,	
114.8,	116.8,	125.8,	132.4,	135.5,	152.9,	160.8,	162.1,	173.9.	MS	
(ES,	m/z):	313	[M+H]+;	Anal.	Calcd.	for	C14H14ClFN2O3:	C,	53.77;	
H,	4.51;	N,	8.96%.	Found:	C,	53.40;	H,	4.50;	N,	9.11%.	

3‐(2‐Chloro‐6‐fluorophenyl)‐N‐((S)‐1‐hydroxy‐3‐methyl	
butan‐2‐yl)‐5‐methylisoxazole‐4‐carboxamide	 (IVd3):	 Color:	
white.	Yield:	89%m	(64%)c.	M.p.:	147‐149	°C.	IR	(KBr,	):	3401,	
3269,	2966,	2931,	1639,	1608,	1557,	1455,	1417,	1324,	1251,	
1167,	1030,	983	cm‐1.	 1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	0.61	
(d,	J	=	6.8	Hz,	3H),	0.76	(d,	J	=	6.8	Hz,	3H),	1.67	(m,	1H),	2.79	(s,	
3H),	3.54	(m,	2H),	3.79	(m,	1H),	5.53	(br	d,	J	=	7.6	Hz,	1H),	7.21	
(t,	J	=	7.6	Hz,	1H)	7.40	(d,	J	=	7.2	Hz,	1H),	7.49	(m,	1H).	13C	NMR	
(CDCl3,	 100	 MHz,	 δ,	 ppm):	 12.7,	 17.7,	 19.0,	 28.9,	 56.6,	 63.6,	
112.2,	 114.8,	 117.2,	 125.8,	 132.4,	 135.7,	 152.6,	 161.3,	 162.3,	
174.4.	 MS	 (ES,	 m/z):	 341	 [M+H]+.	 Anal.	 Calcd.	 for	
C16H18ClFN2O3:	C,	56.39;	H,	5.32;	N,	8.22%.	Found:	C,	56.10;	H,	
5.32;	N,	8.54%.		

3‐(2‐Chloro‐6‐fluorophenyl)‐N‐(1‐hydroy‐2‐methylpropan‐2‐
yl)‐5‐methylisoxazole‐4‐carboxamide	 (IVd4):	 Color:	 white.	
Yield:	80%m	(83%)c.	M.p.:	146‐149	°C.	IR	(KBr,	):	3452,	3274,	
3051,	1684,	1664,	1568,	1458,	1427,	1368,	1309,	1280,	1124,	
1182,	 1068	 cm‐1.	 1H	 NMR	 (CDCl3,	 400	MHz,	 δ,	 ppm):	 1.08	 (s,	
6H),	2.76	(s,	3H),	3.46	(s,	2H),	5.35	(br	s,	1H),	7.21	(t,	J	=	8.2	Hz,	
1H),	7.41	(d,	J	=	8.2	Hz,	1H),	7.50	(m,	1H).	13C	NMR	(CDCl3,	100	
MHz,	δ,	ppm):	12.6,	24.0,	55.9,	69.8,	112.6,	114.8,	117.2,	125.8,	
132.4,	 135.7,	 152.7,	 161.0,	 162.2,	 174.0.	 MS	 (ES,	 m/z):	 327	
[M+H]+.	 Anal.	 Calcd.	 for	 C15H16ClFN2O3:	 C,	 55.14;	 H,	 4.94;	 N,	
8.57%.	Found:	C,	55.39;	H,	4.70;	N,	8.39%.	
	



304	 Ramana	and	Reddy	/	European	Journal	of	Chemistry	2	(3)	(2011)	300‐307	
	
2.6.	General	procedure	for	the	synthesis	of	N‐(2‐chloro‐
ethyl/substituted	ethyl)‐5‐methyl‐3‐aryl‐isoxazole‐4‐carbo‐
xamide	(Va‐Vd)	
	

To	the	solution	of	10	mmol	of	compound	IVa‐IVd	in	20	mL	
of	 CHCl3	 was	 added	 20	 mmol	 of	 SOCl2	 drop	 wise	 while	
maintaining	 the	 temperature	at	 0‐5	 °C.	After	 the	 addition,	 the	
reaction	mixture	was	stirred	over	night	 at	 room	 temperature.	
The	reaction	mixture	was	extracted	with	CHCl3	(2	x	30	mL)	and	
dried	 over	 anhydrous	 MgSO4.	 The	 solvent	 was	 evaporated	
under	reduced	pressure	and	the	residue	was	purified	on	a	silica	
gel	column	with	hexane:	EtOAc	(95:5%)	(Scheme	2).	
	
2.7.	General	procedure	for	the	synthesis	of	N‐(2‐chloro‐
ethyl/substituted	ethyl)‐5‐methyl‐3‐aryl‐isoxazole‐4‐carbox‐
amide	(Va‐Vd)	in	microwave	
	

Compound	 IVa‐IVd	 (5	 mmol)	 was	 dissolved	 in	 25	 mL	 of	
dichloroethane	 in	a	microwave	vial	 to	which	SOCl2	(16	mmol)	
was	added.	The	vial	was	sealed	and	placed	 in	microwave.	The	
reaction	 was	 run	 at	 60	 °C	 for	 3	 min.	 The	 entire	 experiment	
power	 setting	 was	 held	 at	 100	W.	 The	 reaction	mixture	 was	
then	 cooled	 to	 room	 temperature	 and	 purified	 by	 column	
chromatography	with	hexane:	EtOAc	 (95:5%)	 to	afford	Va‐Vd	
(Scheme	2).	

N‐(2‐Chloroethyl)‐5‐methyl‐3‐phenylisoxazole‐4‐carbox‐
amide	(Va1):	Color:	white.	Yield:	91%	m	(72%)c.	M.p.:	158‐161	
°C.	 IR	 (KBr,	 ):	 3212,	 3062,	 2964,	 2924,	 1687,	 1624,	 1584,	
1471,	1361,	 1262,	 1174,	 1091,	 983	 cm‐1.	 1H	NMR	 (CDCl3,	 400	
MHz,	δ,	ppm):	2.72	(s,	3H),	3.55	(m,	4H),	5.84	(br	s,	1H),	7.52	
(m,	3H),	7.58	(d,	 J	=	6.3	Hz,	2H).	 13C	NMR	(CDCl3,	100	MHz,	δ,	
ppm):	12.6,	41.2,	43.1,	110.8,	128.4,	128.9,	129.0,	130.2,	160.0,	
161.5,	 174.0.	 MS	 (ES,	 m/z):	 265	 [M+H]+.	 Anal.	 Calcd.	 for	
C13H13ClN2O2:	C,	58.99;	H,	4.95;	N,	10.58%.	Found:	C,	58.64;	H,	
5.10;	N,	10.54%.	

N‐((S)‐1‐Chloropropan‐2‐yl)‐5‐methyl‐3‐phenylisoxazole‐4‐
carboxamide	 (Va2):	 Color:	 white.	 Yield:	 74%m	 (76%)c.	 M.p.:	
141‐143	 °C.	 IR	 (KBr,	):	 3194,	 3075,	2980,	2934,	 2882,	 1675,	
1611,	1571,	1448,	1350,	1234,	1128,	1086,	993	cm‐1.	 1H	NMR	
(CDCl3,	400	MHz,	δ,	ppm):	1.05	(d,	J	=	6.4	Hz,	3H),	2.71	(s,	3H),	
3.44	(dd,	J	=	11.2	Hz,	J’	=	3.6	Hz,	1H),	3.60	(dd,	J	=	11.2	Hz,	J’	=	
3.6	Hz,	1H),	4.37	 (m,	1H),	5.57	(br	d,	 J	=	 5.2	Hz,	1H),	7.50	(m,	
3H),	7.59	(d,	J	=	7.8	Hz,	2H).	13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	
12.7,	17.4,	 45.5,	48.7,	110.9,	128.3,	129.0,	129.1,	130.3,	160.1,	
160.8,	 174.0.	 MS	 (ES,	 m/z):	 279	 [M+H]+.	 Anal.	 Calcd.	 for	
C14H15ClN2O2:	C,	60.33;	H,	5.42;	N,	10.05%.	Found:	C,	60.41;	H,	
5.42;	N,	9.88%.	

N‐((S)‐1‐Chloro‐3‐methylbutan‐2‐yl)‐5‐methyl‐3‐phenyl	
isoxazole‐4‐carboxamide	 (Va3):	 Color:	 white.	 Yield:	 91%m	
(89%)c.	M.p.:	170‐172	°C.	IR	(KBr,	):	3202,	3045,	2968,	1666,	
1581,	1521,	1402,	1369,	1317,	1277,	1218,	1178,	1125,	1070,	
1033	cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	0.66	(d,	J	=	6.8	Hz,	
3H),	0.80	(d,	J	=	6.8	Hz,	3H),	1.63	(m,	1H),	2.66	(s,	3H),	3.50	(m,	
2H),	3.94	(m,	1H),	5.89	(br	s,	1H),	7.35	(m,	3H),	7.59	(d,	J	=	7.9	
Hz,	 2H).	 13C	 NMR	 (CDCl3,	 100	MHz,	 δ,	 ppm):	 12.6,	 17.5,	 18.4,	
28.1,	45.1,	54.6,	108.1,	127.1,	128.1,	128.4,	128.7,	161.9,	162.8,	
174.9.	MS	(ES,	m/z):	307	[M+H]+.	Anal.	Calcd.	for	C16H19ClN2O2:	
C,	62.64;	H,	6.24;	N,	9.13%.	Found:	C,	62.65;	H,	6.11;	N,	9.46%.	

N‐(2‐Chloroethyl)‐3‐(2‐chlorophenyl)‐5‐methylisoxazole‐4‐
carboxamide	 (Vb1):	 Color:	 white.	 Yield:	 73%m	 (85%)c.	 M.p.:	
125‐127	 °C.	 IR	 (KBr,	):	 3283,	 3091,	2970,	1644,	 1596,	 1557,	
1417,	1321,	1300,	1260,	1201,	1181,	1122,	1054,	1035	cm‐1.	1H	
NMR	(CDCl3,	400	MHz,	δ,	ppm):	2.77	(s,	3H),	3.49	(t,	J	=	5.2	Hz,	
2H),	3.56	 (t,	 J	=	 5.2	Hz,	2H),	5.72	 (br	 s,	 1H),	 7.49	 (m,	4H).	 13C	
NMR	 (CDCl3,	 100	MHz,	 δ,	 ppm):	12.8,	41.0,	43.5,	111.6,	127.4,	
127.7,	 130.4,	 131.5,	 134.1,	 158.1,	 161.1,	 174.2.	MS	 (ES,	m/z):	
299	[M+H]+.	Anal.	Calcd.	for	C13H12Cl2N2O2:	C,	52.19;	H,	4.04;	N,	
9.36%.	Found:	C,	52.08;	H,	4.15;	N,	9.69%.	

3‐(2‐Chloropheyl)‐N‐((S)‐1‐chloropropan‐2‐yl)‐5‐methyl	
isoxazole‐4‐carboxamide	 (Vb2):	 Color:	 white.	 Yield:	 79%m	

(78%)c.	M.p.:	119‐121	°C.	IR	(KBr,	):	3262,	3009,	2968,	1671,	
1618,	1562,	1474,	 1420,	 1330,	 1305,	 1249,	 1177,	 1128,	 1042	
cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	1.24	(d,	J	=	7.2	Hz,	3H),	
2.80	(s,	3H),	3.42	(dd,	J	=	11.0	Hz,	J’	=	4.8	Hz,	1H)	3.89	(dd,	J	=	
11.0	Hz,	J’	=	4.8	Hz,	1H),	4.41	(m,	1H),	5.41	(br	s,	1H),	7.53	(m,	
4H).	 13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	12.8,	16.1,	47.5,	66.0,	
111.1,	 127.0,	 127.5,	 129.1,	 129.7,	 131.5,	 134.2,	 158.9,	 161.4,	
173.0.	MS	(ES,	m/z):	313	[M+H]+.	Anal.	Calcd.	for	C14H14Cl2N2O2:	
C,	53.69;	H,	4.51;	N,	8.94%.	Found:	C,	53.39;	H,	4.63;	N,	9.12%.	

N‐((S)‐1‐Chloro‐3‐methylbutan‐2yl)‐3‐(2‐chlorophenyl)‐5‐
methylisoxazole‐4‐N‐((S)‐1‐Chloro‐3‐methylbutan‐2yl)‐3‐(2‐
chlorophenyl)‐5‐methylisoxazole‐4‐carboxamide	 (Vb3):	 Color:	
white.	Yield:	74%m	(61%)c.	M.p.:	127‐131	°C.	IR	(KBr,	):	3212,	
3038,	2951,	1668,	1601,	1574,	1465,	1424,	1359,	1334,	1287,	
1156,	1130,	1041	cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	0.68	
(d,	J	=	6.8	Hz,	3H),	0.82	(d,	J	=	6.8	Hz,	3H),	1.64	(m,	1H),	2.78	(s,	
3H),	3.49	(dd,	J	=	11.6	Hz,	J’	=	4.0	Hz,	1H).	3.56	(dd,	J	=	11.6	Hz,	J’	
=	4.0	Hz,	1H),	3.98	(m,	1H),	5.42	(br	d,	J	=	8.0	Hz,	1H),	7.49(m,	
4H).	 13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	12.8,	17.9,	19.0,	45.8,	
49.1,	54.6,	111.6,	127.4,	129.3,	130.4,	130.6,	130.9,	134.2,	158.0,	
160.7,	 174.4.	 MS	 (ES,	 m/z):	 341	 [M+H]+.	 Anal.	 Calcd.	 for	
C16H18Cl2N2O2:	C,	56.32;	H,	5.32;	N,	8.21%.	Found:	C,	56.09;	H,	
5.67;	N,	8.21%.	

N‐(2‐Chloroethyl)‐3‐(2,6‐dichlorophenyl)‐5‐methylisoxazole‐
4‐carboxamide	 (Vc1):	 Color:	 white.	 Yield:	 78%m	 (73%)c.	 M.p.:	
120‐122	 °C.	 IR	 (KBr):	 	 3262,	 3009,	 2968,	 1671,	 1618,	 1562,	
1474,	1420,	1330,	1305,	1249,	1177,	1128,	1042	cm‐1.	1H	NMR	
(CDCl3,	400	MHz,	δ,	ppm):	2.82	(s,	3H),	3.50	(t,	J	=	4.4	Hz,	2H),	
3.59	(t,	 J	=	4.4	Hz,	2H),	5.69	(br	s,	1H),	7.45	(m,	1H),	7.52	(m,	
2H).	13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	12.9,	40.9,	43.6,	111.4,	
127.4,	 128.6,	 131.9,	 136.1,	 155.9,	 160.6,	 174.5.	MS	 (ES,	m/z):	
333	[M+H]+.	Anal.	Calcd.	for	C13H11Cl3N2O2:	C,	46.80;	H,	3.32;	N,	
8.40%.	Found:	C,	46.44;	H,	3.14;	N,	8.12%.	

3‐(2,6‐dichlorophenyl)‐N‐((S)‐1‐chloropropan‐2‐yl)‐5‐methyl	
isoxazole‐4‐carboxamide	 (Vc2):	 Color:	 white.	 Yield:	 88%m	
(75%)c.	M.p.:	119‐121	°C.	IR	(KBr,	):	3223,	3074,	2941,	1663,	
1623,	1565,	1479,	 1410,	 1335,	 1306,	 1237,	 1170,	 1124,	 1084	
cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	1.05	(d,	J	=	6.8	Hz,	3H),	
2.80	(s,	3H),	3.42	(dd,	J	=	11.2	Hz,	J’	=	3.2	Hz,	1H),	3.55	(dd,	J	=	
11.2	Hz,	J’	=	3.2	Hz,	1H),	4.38	(m,	1H),	5.43	(br	d,	J	=	7.2	Hz,	1H),	
7.45	 (m,	 3H).	 13C	 NMR	 (CDCl3,	 100	MHz,	 δ,	 ppm):	 13.0,	 17.6,	
44.9,	49.4,	111.5,	127.4,	128.8,	132.2,	136.0,	156.0,	160.0,	174.8.	
MS	 (ES,	 m/z):	 347	 [M+H]+.	 Anal.	 Calcd.	 for	 C14H13Cl3N2O2:	 C,	
48.37;	H,	3.77;	N,	8.06%.	Found:	C,	48.35;	H,	3.53;	N,	8.25%.	

N‐((S)‐1‐Chloro‐3‐methylbutan‐2‐yl)‐3‐(2,6‐dichlorophenyl)‐
5‐methylisoxazole‐4‐carboxamide	 (Vc3):	 Color:	 white.	 Yield:	
79%m	 (70%)c.	 M.p.:	 96‐99	 °C.	 IR	 (KBr,	 ):	 3287,	 3065,	 2972,	
1645,	1604,	1545,	1444,	1307,	1178,	1130,	1089	cm‐1.	1H	NMR	
(CDCl3,	400	MHz,	δ,	ppm):	0.70	(d,	J	=	6.4	Hz,	3H),	0.84	(d,	J	=	6.4	
Hz,	3H),	1.59	(m,	1H),	2.81	(s,	3H),	3.49	(dd,	J	=	11.6	Hz,	J’	=	4.3	
Hz,	1H),	3.57	(dd,	J	=	11.6	Hz,	J’	=	4.3	Hz,	1H),	3.97	(m,	1H),	5.38	
(br	d,	J	=	8.0	Hz,	1H),	7.44	(m,	3H).	13C	NMR	(CDCl3,	100	MHz,	δ,	
ppm):	 12.8,	 17.8,	 18.9,	 29.1,	 45.9,	 54.4,	 111.4,	 127.7,	 128.4,	
131.9,	 136.3,	 155.8,	 160.3,	 174.8.	 MS	 (ES,	 m/z):	 375	 [M+H]+.	
Anal.	 Calcd.	 for	 C16H17Cl3N2O2:	 C,	 51.15;	 H,	 4.56;	 N,	 7.46%.	
Found:	C,	50.84;	H,	4.50;	N,	7.11%.	

3‐(2‐Chloro‐6‐fluorophenyl)‐N‐(2‐Chloroethyl)‐5‐methyl	
isoxazole‐4‐carboxamide	 (Vd1):	 Color:	 white.	 Yield:	 73%m	
(59%)c.	M.p.:	108‐111	°C.	IR	(KBr,	):	3297,	3070,	2924,	1646,	
1606,	1540,	1470,	 1420,	 1353,	 1306,	 1204,	 1175,	 1114,	 1094	
cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	2.79	(s,	3H),	3.51	(q,	J	=	
4.8	Hz,	2H),	3.60	(t,	J	=	4.8	Hz,	2H),	5.81	(br	s,	1H),	7.20	(t,	J	=	6.8	
Hz,	1H),	7.39	(d,	J	=	7.6	Hz,	1H),	7.48	(m,	1H).	13C	NMR	(CDCl3,	
100	MHz,	δ,	ppm):	12.8,	54.6,	66.8,	106.9,	113.9,	118.2,	124.9,	
131.0,	 135.4,	 154.9,	 157.3,	 162.3,	 172.4.	 MS	 (ES,	 m/z):	 317	
[M+H]+.	 Anal.	 Calcd.	 for	 C13H11Cl2FN2O2:	 C,	 49.23;	 H,	 3.50;	 N,	
8.83%.	Found:	C,	49.48;	H,	3.19;	N,	8.96%.	

3‐(2‐Chloro‐6‐fluorophenyl)‐N‐((S)‐1‐chloropropan‐2‐yl)‐5‐
methylisoxazol‐4‐carboxamide	(Vd2):	Color:	white.	Yield:	68%m	
(71%)c.	M.p.:	125‐128	°C.	IR	(KBr,	):	3256,	3067,	2942,	1676,	



Ramana	and	Reddy	/	European	Journal	of	Chemistry	2	(3)	(2011)	300‐307	 305	
 

 
 

1622,	1551,	 1461,	 1413,	 1341,	 1300,	 1222,	 1167,	 1111,	1094	
cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	1.07	(d,	J	=	6.8	Hz,	3H),	
2.78	(s,	3H),	3.44	(dd,	J	=	11.2	Hz,	J’	=	3.2	Hz,	1H),	3.56	(dd,	J	=	
11.2	Hz,	J’	=	3.2	Hz,	1H),	4.39	(m,	1H),	5.49	(br	d,	J	=	6.4	Hz,	1H),	
7.19	(t,	J	=	8.1	Hz,	1H),	7.37	(d,	J	=	6.5	Hz,	1H),	7.49	(m,	1H).	13C	
NMR	 (CDCl3,	 100	MHz,	 δ,	 ppm):	 12.8,	 17.5,	 45.0,	 49.1,	 112.0,	
114.9,	116.9,	125.9,	132.5,	135.6,	152.8,	159.9,	162.1,	174.3.	MS	
(ES,	 m/z):	 331	 [M+H]+;	 Anal.	 Calcd.	 for	 C14H13Cl2FN2O2:	 C,	
50.77;	H,	3.96;	N,	8.46%.	Found:	C,	51.06;	H,	3.96;	N,	8.51%.	

N‐((S)‐1‐Chloro‐3‐methylbutan‐2‐yl)‐3‐(2‐chloro‐6‐fluoro	
phenyl)‐5‐methylisoxazole‐4‐carboxamide	 (Vd3):	 Color:	 white.	
Yield:	88%m	(72%)c.	M.p.:	116‐119	°C.	IR	(KBr,	):	3192,	3071,	
2954,	1668,	1616,	1549,	1443,	1317,	1162,	1128,	1074	cm‐1.	1H	
NMR	(CDCl3,	400	MHz,	δ,	ppm):	0.74	(d,	J	=	7.2	Hz,	3H),	0.86	(d,	
J	=	7.2	Hz,	3H),	1.65	(m,	1H),	2.81	(s,	3H),	3.53	(dd,	J	=	11.6	Hz,	J’	
=	4.3	Hz,	1H),	3.61	(dd,	J	=	11.6	Hz,	J’	=	4.3	Hz,	1H),	4.00	(m,	1H),	
5.46	(br	d,	J	=	8.1	Hz,	1H),	7.21	(t,	J	=	7.6	Hz,	1H),	7.41	(d,	J	=	7.2	
Hz,	1H),	7.50	(m,	1H).	13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	12.8,	
17.9,	 18.9,	 29.2,	 45.9,	 54.5,	 112.0,	 114.9,	 117.3,	 125.9,	 132.4,	
135.7,	 152.6,	 160.3,	 162.3,	 174.5.	 MS	 (ES,	 m/z):	 360	 [M+H]+;	
Anal.	 Calcd.	 for	 C16H17Cl2FN2O2:	 C,	 53.50;	 H,	 4.77;	 N,	 7.80%.	
Found:	C,	53.41;	H,	4.89;	N,	7.39%.	
	
2.8.	General	procedure	for	the	synthesis	of	4‐(4,5‐
dihydrooxazol‐2‐yl)‐5‐methyl‐3‐aryl‐isoxazole	(VIa‐VId)	
	

To	a	solution	of	10	mmol	of	compound	Va‐Vd	 in	10	mL	of	
MeCN	 was	 added	 dropwise	 5	 mL	 of	 2	 N	 NaOH	 at	 rt.	 The	
resulting	solution	was	stirred	over	night	at	rt.	After	completion	
of	 the	 reaction,	 as	 indicated	by	TLC,	 the	 reaction	mixture	was	
extracted	with	 EtOAc	 (2	 x	 20	mL)	 and	 dried	 over	 anhydrous	
MgSO4.	 The	 solvent	 was	 evaporated	 and	 the	 product	 was	
subjected	 to	 column	 chromatography	 with	 hexane:	 EtOAc	
(95:5%)	to	yield	pure	compound	(Scheme	2).	
	
2.9.	General	procedure	for	the	synthesis	of	4‐(4,5‐dihydro	
oxazol‐2‐yl)‐5‐methyl‐3‐aryl‐isoxazole	(VIa‐VId)	in	
microwave	
	

Compounds	 Va‐Vd	 (5	 mmol)	 were	 adsorbed	 on	 silicagel	
(200‐400	mesh)	and	were	suspended	in	MeCN	and	2N	NaOH	(3	
mL)	and	transfered	in	to	a	microwave	vial.	The	vial	was	sealed	
and	placed	 in	microwave.	The	reaction	was	run	at	85	°C	 for	2	
min.	For	 the	entire	experiment,	 the	power	setting	was	held	at	
180	W.	The	reaction	was	then	cooled	to	room	temperature	and	
purified	 by	 SiO2	 gel	 column	 chromatography	 with	 hexane:	
EtOAc	(95:5%)	to	afford	VIa‐Vid	(Scheme	2).	

4‐(4,5‐Dihydrooxazol‐2‐yl)‐5‐methyl‐3‐phenylisoxazole	
(VIa1):	 Color:	 white.	 Yield:	 85%m	 (77%)c.	 M.p.:	 81‐84	 °C.	 IR	
(KBr,	 ):	 3036,	 2974,	 2810,	 1694,	 1623,	 1484,	 1345,	 1221,	
1065,	 1011	 cm‐1.	 1H	 NMR	 (CDCl3,	 400	MHz,	 δ,	 ppm):	 2.68	 (s,	
3H),	3.97	(t,	J	=	9.2	Hz,	2H),	4.26	(t,	J	=	9.2	Hz,	2H),	7.43	(m,	3H),	
7.65	(d,	J	=	6.7	Hz,	2H).	13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	12.7,	
54.7,	66.8,	105.2,	127.8,	129.0,	129.1,	129.4,	158.2,	161.7,	172.6.	
MS	(ES,	m/z):	229	[M+H]+.	Anal.	Calcd.	for	C13H12N2O2:	C,	68.41;	
H,	5.30;	N,	12.27%.	Found:	C,	68.12;	H,	5.16;	N,	12.27%.	

4‐((S)‐4,5‐Dihydro‐4‐methyloxazol‐2‐yl)‐5‐methyl‐3‐phenyl	
isoxazole	 (VIa2):	Color:	white.	 Yield:	88%m	 (70%)c.	M.p.:	 114‐
117	°C.	IR	(KBr,	):	3065,	2966,	2930,	1672,	1612,	1452,	1342,	
1244,	 1147,	 1109,	 1053	 cm‐1.	 1H	 NMR	 (CDCl3,	 400	 MHz,	 δ,	
ppm):	1.32	(d,	J	=	6	Hz,	3H),	2.69	(s,	3H),	3.83	(t,	J	=	6.8	Hz,	1H),	
4.31	 (m,	 2H),	 7.46	 (m,	 3H),	 7.69	 (d,	 J	=	 7.2	Hz,	 2H).	 13C	NMR	
(CDCl3,	 100	MHz,	 δ,	 ppm):	 12.7,	 21.2,	 61.8,	 73.4,	 105.2,	127.9,	
128.8,	 129.0,	 129.5,	 157.1,	 161.6,	 172.6.	 MS	 (ES,	 m/z):	 243	
[M+H]+.	 Anal.	 Calcd.	 for	 C14H14N2O2:	 C,	 69.41;	 H,	 5.82;	 N,	
11.56%.	Found:	C,	69.32;	H,	5.85;	N,	11.69%.	

4‐((S)‐4,5‐Dihydro‐4‐isopropyloxazol‐2‐yl)‐5‐methyl‐3‐
phenylisoxazole	(VIa3):	Color:	white.	Yield:	84%m	(81%)c.	M.p.:	

128‐131	 °C.	 IR	 (KBr,	):	 3039,	 2995,	2876,	1659,	 1620,	 1568,	
1458,	1376,	1221,	1069,	1028	cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	
ppm):	0.90	(d,	J	=	6.8	Hz,	3H),	0.96	(d,	J	=	6.8	Hz,	3H),	1.74	(m,	
1H),	2.65	(s,	3H),	3.97	(m,	2H),	4.22	(m,	1H),	7.39	(m,	3H),	7.71	
(d,	 J	 =	 8.2	 Hz,	 2H).	 13C	 NMR	 (CDCl3,	 100	MHz,	 δ,	 ppm):	 12.6,	
18.3,	 18.4,	 32.8,	 69.7,	 72.7,	 105.4,	 127.7,	 129.0,	 129.1,	 129.3,	
156.9,	161.7,	172.4.	MS	(ES,	m/z):	271	[M+H]+.	Anal.	Calcd.	for	
C16H18N2O2:	 C,	 71.09;	 H,	 6.71;	 N,	 10.36%.	 Found:	 C,	 69.98;	 H,	
6.67;	N,	10.32%.	

4‐(4,5‐Dihydro‐4,4‐dimethyloxazol‐2‐yl)‐5‐methyl‐3‐phenyl	
isoxazole	 (VIa4):	Color:	white.	Yield:	89%m	 (85%)c.	M.p.:	 102‐
105	°C.	IR	(KBr,	):	3063,	2970,	2930,	1728,	1668,	1614,	1454,	
1321,	 1257,	 1190,	 1059	 cm‐1.	 1H	 NMR	 (CDCl3,	 400	 MHz,	 δ,	
ppm):	1.26	(s,	6H),	2.56	(s,	3H),	3.87	(s,	2H),	7.34	(m,	3H),	7.59	
(d,	 J	 =	 6.8	 Hz,	 2H).	 13C	 NMR	 (CDCl3,	 100	MHz,	 δ,	 ppm):	 12.4,	
28.0,	67.6,	78.6,	105.4,	127.9,	128.8,	129.0,	129.4,	155.8,	161.5,	
172.3.	MS	(ES,	m/z):	257	[M+H]+.	Anal.	Calcd.	for	C15H16N2O2:	C,	
70.29;	H,	6.29;	N,	10.93%.	Found:	C,	70.13;	H,	6.29;	N,	11.06%.	

3‐(2‐Chlorophenyl)‐4‐(4,5‐dihydrooxazol‐2‐yl)‐5‐methyl	
isoxazole	 (VIb1):	Color:	white.	Yield:	88%m	 (71%)c.	M.p.:	 113‐
115	°C.	IR	(KBr,	):	2984,	2935,	2885,	1726,	1672,	1610,	1508,	
1454,	1356,	1278,	1232,	1149,	1082	cm‐1.	1H	NMR	(CDCl3,	400	
MHz,	δ,	ppm):	2.73	(s,	3H),	3.82	(t,	J	=	6.9	Hz,	2H),	4.17	(t,	J	=	6.9	
Hz,	2H),	7.38	(m,	4H).	13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	12.8,	
54.7,	66.9,	106.7,	126.3,	128.9,	129.3,	130.5,	131.1,	134.2,	157.9,	
160.3,	 172.1.	 MS	 (ES,	 m/z):	 263	 [M+H]+.	 Anal.	 Calcd.	 for	
C13H11ClN2O2:	C,	59.44;	H,	4.22;	N,	10.66%.	Found:	C,	59.70;	H,	
4.14;	N,	10.79%.	

3‐(2‐Chlorophenyl)‐4‐((S)‐4,5‐dihydro‐4‐methyloxazol‐2yl)‐
5‐methylisoxazole	 (VIb2):	 Color:	 white.	 Yield:	 90%m	 (79%)c.	
M.p.:	 147‐150	 °C.	 	 IR	 (KBr,	):	 3012,	2974,	2896,	 1726,	 1658,	
1621,	1432,	1368,	1249,	1112,	1059	cm‐1.	1H	NMR	(CDCl3,	400	
MHz,	δ,	ppm):	1.23	(d,	J	=	3.2	Hz,	3H),	2.73	(s,	3H),	3.71	(m,	1H),	
4.22	(m,	2H),	7.38	(m,	4H).	13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	
12.7,	21.1,	61.7,	73.4,	 106.8,	126.3,	128.9,	129.3,	130.5,	131.1,	
134.2,	 156.8,	 160.3,	 172.0.	 MS	 (ES,	 m/z):	 277	 [M+H]+.	 Anal.	
Calcd.	for	C14H13ClN2O2:	C,	60.77;	H,	4.74;	N,	10.12%.	Found:	C,	
60.36;	H,	4.82;	N,	10.36%.	

3‐(2‐Chlorophenyl)‐4‐((S)‐4,5‐dihydro‐4‐isopropyloxazol‐2‐
yl)‐5‐methylisoxazole	(VIb3):	Color:	white.	Yield:	95%m	(85%)c.	
M.p.:	94‐97	°C.	IR	(KBr,	):	3064,	2954,	2867,	1680,	1601,	1456,	
1384,	 1239,	 1084,	 1061	 cm‐1.	 1H	 NMR	 (CDCl3,	 400	 MHz,	 δ,	
ppm):	0.70	(d,	J	=	6.8	Hz,	3H),	0.84	(d,	J	=	6.8	Hz,	3H),	1.67	(m,	
1H),	2.72	(s,	3H),	3.88	(m,	2H),	4.15	(m,	1H),	7.38(m,	4H).	 13C	
NMR	(CDCl3,	100	MHz,	δ,	ppm):	12.6,	18.3,	18.4,	32.8,	69.8,	72.6,	
106.8,	 126.1,	 129.2,	 130.3,	 131.2,	 131.5,	 134.3,	 156.5,	 160.4,	
171.8.	MS	(ES,	m/z):	305	[M+H]+.	Anal.	Calcd.	for	C16H17ClN2O2:	
C,	63.05;	H,	5.62;	N,	9.19%.	Found:	C,	62.85;	H,	5.42;	N,	9.42%.	

3‐(2‐Chlorophenyl)‐4‐(4,5‐dihydro‐4,4‐dimethyloxazol‐2‐yl)‐
5‐methylisoxazole	 (VIb4):	 Color:	 white.	 Yield:	 79%m	 (73%)c.	
M.p.:	 135‐138	 °C.	 IR	 (KBr,	 ):	 3011,	 2973,	 2923,	 1730,	 1632,	
1602,	1579,	1463,	1321,	1287,	1161,	1012	cm‐1.	1H	NMR	(CDCl3,	
400	MHz,	δ,	ppm):	1.29	(s,	6H),	2.74	(s,	3H),	3.86	(s,	2H),	7.42	
(m,	 4H).	 13C	 NMR	 (CDCl3,	 100	MHz,	 δ,	 ppm):	 12.5,	 28.0,	 67.4,	
78.6,	 107.0,	 126.2,	 129.0,	 129.2,	 130.3,	 131.2,	 134.2,	 155.4,	
160.3,	171.8.	IR	(KBr):	υ	2991,	2942,	28874,	1732,	1652,	1610,	
1501,	1464,	1354,	1271,	1228,	1168,	1087	cm‐1.	MS	(ES,	m/z):	
291	[M+H]+.	Anal.	Calcd.	 for	C15H15ClN2O2:	C,	61.97;	H,	5.20;	N,	
9.64%.	Found:	C,	61.76;	H,	5.29;	N,	9.72%.	

3‐(2,6‐Dichlorophenyl)‐4‐(4,5‐dihydrooxazol‐2‐yl)‐5‐methyl	
isoxazole	 (VIc1):	 Color:	white.	 Yield:	 86%m	 (81%)c.	M.p.:	 141‐
144	°C.	IR	(KBr,	):	3054,	2989,	2926,	1742,	1675,	1609,	1584,	
1460,	 1297,1156,	 1045	 cm‐1.	 1H	 NMR	 (CDCl3,	 400	 MHz,	 δ,	
ppm):	2.80	(s,	3H),	3.89	(t,	J	=	10.8	Hz,	2H),	4.18	(t,	J	=	10.8	Hz,	
2H),	7.34	(m,	1H),	7.40	(m,	2H).	 13C	NMR	(CDCl3,	100	MHz,	δ,	
ppm):	12.8,	54.7,	66.8,	106.6,	127.5,	128.7,	130.5,	135.7,	157.3,	
158.0,	172.3.	IR	(KBr):	υ	cm‐1;	MS	(ES,	m/z):	297	[M+H]+.	Anal.	



306	 Ramana	and	Reddy	/	European	Journal	of	Chemistry	2	(3)	(2011)	300‐307	
	
Calcd.	for	C13H10Cl2N2O2:	C,	52.55;	H,	3.39;	N,	9.43%.	Found:	C,	
52.36;	H,	3.01;	N,	9.65%.	

3‐(2,6‐Dichlorophenyl)‐4‐((S)‐4,5‐dihydro‐4‐methyloxazol‐2‐
yl)‐5‐methylisoxazole	(VIc2):	Color:	white.	Yield:	94%m	(92%)c.	
M.p.:	 106‐108	 °C.	 IR	 (KBr,	 ):	 3029,	 2971,	 2901,	 1732,	 1656,	
1611,	1578,	1463,	1284,1172,	1050	cm‐1.	 1H	NMR	(CDCl3,	400	
MHz,	δ,	ppm):	1.12	(d,	J	=	6.8	Hz,	3H),	2.79	(s,	3H),	3.71	(m,	1H),	
4.18	(m,	2H),	7.33	(m,	3H).	13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	
13.1,	21.3,	 61.6,	73.4,	106.6,	127.6,	128.3,	130.8,	135.5,	156.2,	
158.1,	 172.6.	 MS	 (ES,	 m/z):	 311	 [M+H]+.	 Anal.	 Calcd.	 for	
C14H12Cl2N2O2:	C,	54.04;	H,	3.89;	N,	9.00%.	Found:	C,	53.79;	H,	
3.62;	N,	9.00%.	

3‐(2,6‐Dichlorophenyl)‐4‐((S)‐4,5‐dihydro‐4‐isopropyloxazol‐
2‐yl)‐5‐methylisoxazole	 (VIc3):	 Color:	 white.	 Yield:	 83%m	
(83%)c.	M.p.:	152‐154	°C.	IR	(KBr,	):	3067,	2959,	2914,	1728,	
1680,	1614,	1556,	1431,	1226,1195,	1084	cm‐1.	1H	NMR	(CDCl3,	
400	MHz,	δ,	ppm):	0.81	(d,	 J	=	6.8	Hz,	3H),	0.83	(d,	 J	=	6.8	Hz,	
3H),	1.63	(m,	1H),	2.77	(s,	3H),	3.89	(m,	2H),	4.15	(m,	1H),	7.36	
(m,	 3H).	 13C	NMR	 (CDCl3,	 100	MHz,	 δ,	 ppm):	 12.7,	 18.2,	 32.8,	
69.8,	72.3,	106.7,	127.4,	128.8,	130.4,	135.7,	155.8,	158.2,	171.9.	
MS	 (ES,	 m/z):	 339	 [M+H]+;	 Anal.	 Calcd.	 for	 C16H16Cl2N2O2:	 C,	
56.65;	H,	4.75;	N,	8.26%.	Found:	C,	56.91;	H,	4.34;	N,	8.05%.	

3‐(2,6‐Dichlorophenyl)‐4‐(4,5‐dihydro‐4,4‐dimethyloxazol‐2‐
yl)‐5‐methylisoxazole	(VIc4):	Color:	white.	Yield:	81%m	(78%)c.	
M.p.:	 104‐106	 °C.	 IR	 (KBr,	 ):	 2976,	 2876,	 1724,	 1676,	 1606,	
1562,	1450,	1313,	1249,	1194,	1078	cm‐1.	1H	NMR	(CDCl3,	400	
MHz,	δ,	ppm):	1.24	(s,	6H),	2.78	 (s,	3H),	3.81	(s,	2H),	7.37	(m,	
1H),	 7.41	 (m,	 2H).	 13C	 NMR	 (CDCl3,	 100	 MHz,	 δ,	 ppm):	 12.7,	
28.0,	67.3,	78.5,	106.9,	127.5,	128.4,	130.4,	135.5,	154.7,	158.0,	
172.0.	MS	(ES,	m/z):	325	[M+H]+.	Anal.	Calcd.	for	C15H14Cl2N2O2:	
C,	55.40;	H,	4.34;	N,	8.61%.	Found:	C,	55.24;	H,	4.34;	N,	8.88%.	

3‐(2‐Chloro‐6‐fluorophenyl)‐4‐(4,5‐dihydrooxazol‐2‐yl)‐5‐
methylisoxazole	(VId1):	Color:	white.	Yield:	95%m	(88%)c.	M.p.:	
109‐111	 °C.	 IR	 (KBr,	):	 3055,	 2945,	2939,	1728,	 1635,	 1614,	
1525,	1460,	1323,	1251,	1192,	1074	cm‐1.	1H	NMR	(CDCl3,	400	
MHz,	δ,	ppm):	2.76	(s,	3H),	3.88	(t,	J	=	9.2	Hz,	2H),	4.17	(t,	J	=	9.2	
Hz,	2H),	7.08	(t,	J	=	7.2	Hz,	1H)	7.26	(d,	J	=	7.6	Hz,	1H),	7.38	(m,	
1H).	13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	12.8,	40.9,	43.6,	112.0,	
114.7,	116.7,	126.0,	132.4,	135.5,	152.9,	160.7,	162.1,	174.2.	MS	
(ES,	m/z):	281	[M+H]+.	Anal.	Calcd.	for	C13H10ClFN2O2:	C,	55.63;	
H,	3.59;	N,	9.98%.	Found:	C,	55.45;	H,	3.57;	N,	10.16%.	

3‐(2‐Chloro‐6‐fluorophenyl)‐4‐((S)‐4,5‐dihydro‐4‐methyl	
oxazol‐2‐yl)‐5‐methylisoxazole	 (VId2):	 Color:	 white.	 Yield:	
79%m	 (75%)c.	 M.p.:	 60‐62	 °C.	 IR	 (KBr,	 ):	 2974,	 2908,	 1726,	
1668,	1614,	1570,	1514,	1454,	1342,	1307,	1251,	1182,	1143,	
1107,	1053	cm‐1.	1H	NMR	(CDCl3,	400	MHz,	δ,	ppm):	1.20	(d,	J	=	
4.8	Hz,	3H),	2.76	(s,	3H),	3.72	(m,	1H),	4.21	(m,	2H),	7.08	(t,	J	=	
7.2	 Hz,	 1H),	 7.27	 (d,	 J	 =	 7.2	 Hz,	 1H),	 7.38	 (m,	 1H).	 13C	 NMR	
(CDCl3,	100	MHz,	δ,	ppm):	12.6,	21.0,	61.7,	73.4,	107.0,	113.8,	
118.0,	124.9,	130.9,	135.4,	154.9,	156.1,	162.2,	172..2.	MS	(ES,	
m/z):	295	 [M+H]+.	Anal.	 Calcd.	 for	C14H12ClFN2O2:	 C,	 57.06;	H,	
4.10;	N,	9.51%.	Found:	C,	56.82;	H,	3.85;	N,	9.83%.	

3‐(2‐Chloro‐6‐fluorophenyl)‐4‐((S)‐4,5‐dihydro‐4‐isopropyl	
oxazol‐2‐yl)‐5‐methylisoxazole	 (VId3):	 Color:	 white.	 Yield:	
96%m	 (87%)c.	 M.p.:	 76‐79	 °C.	 IR	 (KBr,	 ):	 3086,	 2958,	 2892,	
1681,	1612,	1573,	1462,	1444,	1250,	1237,	1088,	982	cm‐1.	1H	
NMR	(CDCl3,	400	MHz,	δ,	ppm):	0.80	(d,	J	=	6.8	Hz,	3H),	0.84	(d,	
J	=	6.8	Hz,	3H),	1.63	(m,	1H),	2.74	(s,	3H),	3.87	(m,	2H),	4.14	(m,	
1H),	7.05	(t,	J	=	8.8	Hz,	1H)	7.25	(d,	J	=	6.8	Hz,	1H),	7.33	(m,	1H).	
13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	12.8,	18.2,	32.8,	69.8,	72.4,	
107.0,	 113.8,	 118.0,	 124.9,	 131.0,	 135.4,	 155.1,	 155.9,	 162.3,	
172.1.	 MS	 (ES,	 m/z):	 323	 [M+H]+.	 Anal.	 Calcd.	 for	
C16H16ClFN2O2:	C,	59.54;	H,	5.00;	N,	8.68%.	Found:	C,	59.11;	H,	
4.78;	N,	8.74%.	

3‐(2‐Chloro‐6‐fluorophenyl)‐4‐(4,5‐dihydro‐4,4‐dimethyl	
oxazol‐2‐yl)‐5‐methylisoxazole	 (VId4):	 Color:	 white.	 Yield:	
91%m	(84%)c.	M.p.:	114‐118	°C.	IR	(KBr,	):	2971,	2919,	1717,	
1656,	1606,	1592,	1524,	1446,	1374,	1316,	1261,	1174,	1134,	
1100,	 1084	 cm‐1.	 1H	NMR	 (CDCl3,	 400	MHz,	 δ,	 ppm):	 1.25	 (s,	
6H),	2.76	(s,	3H),	3.83	(s,	2H),	7.08	(t,	J	=	8.8	Hz,	1H),	7.27	(d,	J	=	

8.4	Hz,	1H),	7.36	(m,	1H).	13C	NMR	(CDCl3,	100	MHz,	δ,	ppm):	
12.7,	27.9,	67.3,	78.5,	 107.1,	113.8,	118.0,	124.9,	130.9,	135.4,	
154.9,	 155.4,	 162.3,	 172.1.	 MS	 (ES,	 m/z):	 309	 [M+H]+.	 Anal.	
Calcd.	for	C15H14ClFN2O2:	C,	58.35;	H,	4.57;	N,	9.07%.	Found:	C,	
58.01;	H,	4.25;	N,	9.08%.	
	
3.	Results	and	discussion	
	

The	focus	of	the	present	investigation	is	on	the	synthesis	of	
a	 few	 4‐(4,5‐dihydrooxazol‐2‐yl)‐5‐methyl‐3‐phenyl/	 substi‐
tuted	 phenyl‐isoxazole	 (VIa‐d)	 from	 substituted	 benzal‐
delhydes.	We	have	simplified	the	procedure	of	Zhi‐Wei	et	al.	for	
the	 preparation	 of	 IIa‐d	 from	 benzaldehyde	 or	 substituted	
benzaldehydes	 [33].	 Oximes	 of	 aromatic	 aldehydes	 (Ia2‐d2)	
were	 prepared	 by	 oximation	 (1	 eq)	 with	 hydroxylamine	
hydrosulfate	(1.7	eq)	in	methanol.	The	resulting	oxime	solution	
(Ia2‐d2)	 was	 treated	 with	 Cl2	 gas	 at	 0	 °C	 to	 form	 chloro	
compound	 (Ia3‐d3).	 Later,	 the	 resulting	mixture	was	added	a	
methanolic	solution	of	the	sodium	salt	of	methylaceto	acetate	at	
0‐5	 °C	 to	 form	 methyl	 5‐methyl‐3‐phenylisoxazole‐4‐
carboxylates	(Ia4‐d4).	Saponification	of	methyl	esters	(Ia4‐d4)	
by	 aq.	 NaOH	 (25%)	 under	 reflux	 condition	 yielded	 the	 key	
intermediates	 IIa‐d.	 All	 these	 reactions,	 i.e.,	 Ia1‐d1	 to	 IIa‐d	
were	 carried	 out	 in	 one	 pot	 experiment	without	 isolating	 the	
intermediate	 molecules,	 as	 depicted	 in	 Scheme	 1.	 The	
formation	of	IIa‐d	was	confirmed	by	a	broad	singlet	signal	at	δ	
12.52‐13.12	 for	 the	 carboxylic	 acid	 proton	 in	 the	 1H	 NMR	
spectrum	and	also	was	 confirmed	by	exchanging	with	D2O.	 In	
the	 13C	 NMR	 spectrum	 of	 IIa‐d,	 C‐(4)	 of	 the	 isoxazole	 ring	
resonated	 at	 up	 field,	 between	 107.5	 and	 114.0	 ppm	 and	 the	
carboxyl	carbon	gave	a	peak	at	around	175	ppm.	In	compound	
IId,	 the	fluorine	containing	aromatic	ipso	carbon	gave	a	signal	
at	 δ	 162.1.	 The	methyl	 group	 at	 C‐(5)	 of	 isoxozole	 resonated	
around	 13	 ppm	 in	 the	 13C	 NMR	 spectrum	 of	 IIa‐d.	 Mass	
spectrum	 of	 IIb	 and	 IId	 exhibited	 molecular	 ion	 peaks	 at	
[M+2]+	(30%)	in	addition	to	the	molecular	ion	peak	due	to	the	
presence	 of	 one	 Cl	 atom.	 Similarly,	 compound	 IIc	 has	 given	
molecular	 ion	peaks	at	 [M]+	 (38%),	 [M+2]+	 (56%)	and	 [M+4]+	
(6%)	 due	 to	 the	 presence	 of	 two	 chlorine	 atoms.	 Compounds	
IIa‐IId	on	reaction	with	PCl5	produced	the	corresponding	acid	
chlorides	 (IIIa‐d),	 The	 formation	 of	 the	 respective	 acid	
chlorides	 was	 confirmed	 by	 the	 disappearance	 of	 carboxylic	
acidic	proton	signal	in	1H	NMR	of	IIIa‐d.	

Compounds	 (IIIa‐IIId)	 upon	 reaction	 with	 ethanolamine	
(1)	 or	 (S)‐2‐methyl	 ethanolamine	 (2)	 or	 2,2‐dimethyl	
ethanolamine	 (3)	 or	 (S)‐2‐isopropyl	 ethanolamine	 (4)	 in	
presence	of	Et3N	yielded	the	respective	β‐hydroxyalkyl	amides	
(IVa‐IVd).	 The	 1H	 NMR	 and	 13C	 NMR	 spectra	 of	 IVa2	
experienced	 a	 different	 electro	 negativity	 effect.	 In	 1H	 NMR	
spectrum,	 the	 proton	 attached	 to	 C‐(2)	 of	 N‐alkyl	 gave	 a	
multiplet	signal	at	4.09	δ,	while	the	diastereotopic	protons	at	C‐
(1)	gave	doublet	of	a	doublet	peaks	at	δ	3.38	and	3.54	(J	=	11.2	
Hz,	 J’	=	3.6	Hz).	However,	 in	 13C	NMR	reversal	 in	 the	chemical	
shifts	was	observed,	i.e.,	C‐(2)	carbon	gave	a	signal	at	up	field	(δ	
47.7)	 compared	 to	 C‐(1)	 (δ	 66.5).	 The	 IR	 spectra	 of	 this	
compound	 exhibited	 a	 new	 absorption	 maximum	 at	 around	
3485	cm‐1	characteristic	of	O‐H	and	3249	cm‐1	characteristic	of	
N‐H	 indicating	 the	 formation	 of	 β‐hydroxyalkylamide.	 The	
signal	corresponding	to	hydroxy	proton	was	not	appeared	in	all	
the	 compounds	 of	 IV	 except	 in	 IVa4.	 The	 amide	 proton	 in	 IV	
appeared	as	broad	signal	 around	δ	 5.22‐6.05.	The	 two	methyl	
groups	 in	 IV3	 are	 expected	 to	 be	 chemically	 equivalent,	
however,	 gave	 two	 signals	between	δ	 0.50	 and	0.80.	 Similarly	
the	non	equivalent	nature	of	 the	 these	 two	methyl	 carbons	of	
the	isopropyl	group	was	also	observed	in	13C	NMR	spectra	and	
gave	two	signals	between	δ	17	and	19.	

These	 β‐hydroxyalkylamides	 (IVa,	 IVb	 and	 IVc)	 upon	
reaction	with	thionyl	chloride	gave	β‐chloroalkylamides	(Va‐c).	
The	 formation	 of	 β‐chloroalkylamides	 was	 confirmed	 by	
spectroscopic	 analysis.	 The	 IR	 spectrum	 of	 V	 reveals	 the	
disappearance	of	O‐H	stretching	frequency	at	3400	cm‐1.	In	the	



Ramana	and	Reddy	/	European	Journal	of	Chemistry	2	(3)	(2011)	300‐307	 307	
 

 
 

13C	NMR	spectrum	of	Va2	halo	group	attached	carbon	shifted	to	
upfield	and	resonated	at	δ	48.7.	

Compound	IVd	resulted	in	formation	of	the	corresponding	
oxazoline	 (VId)	 in	 the	 thionyl	 chloride	 reaction,	 without	
forming	β‐chloro	amide	intermediate.	β‐Chloroalkylamides	(Va,	
Vb	 and	Vc)	 when	 stirred	 in	 the	 basic	medium,	 2	 N	 NaOH	 in	
MeCN,	provided	oxazolines	(VIa,	VIb	and	VIc)	as	presented	in	
Scheme	2.	It	has	been	found	that	the	pseudo	molecular	ions	of	
oxazline	 substituted	 isoxazoles	 [M+H]+	 and	 [M+Na]+	 have	
matched	 with	 their	 respective	 molecular	 weights.	
Diastereotopic	protons	of	C‐(2)	 in	VI2	 and	VI3	are	 showing	a	
multiplet	 signal	 instead	 of	 two	 double	 doublet	 signals	 in	 1H	
NMR.	 The	 imine	 carbon,	 C=N,	 in	 the	 newly	 formed	 oxazoline	
ring	 resonated	 around	 170	 ppm	 in	 13C	 NMR.	 The	 IR	 spectra	
confirmed	the	formation	of	VI	by	showing	the	disappearance	of	
N‐H	 stretching	 frequency	 at	 3200	 cm‐1.	 The	 conversion	 of	
compounds	III	to	VI	via	IV	and	V	under	microwave	irradiation	
is	more	 efficient	 and	 gave	 better	 yields	with	 shorter	 reaction	
times	compared	to	conventional	heating	conditions.	Most	of	the	
newly	synthesized	compounds,	IV,	V	and	VI	melted	between	90	
and	120	°C.	
	
4.	Conclusion	
	

In	 summary,	we	 have	 successfully	 demonstrated	 a	 simple	
and	convenient	route	for	the	synthesis	of	oxazoline	substituted	
isoxazoles	 by	 employing	 conventional	 as	 well	 as	 microwave	
irradiation	 methods.	 In	 addition	 to	 its	 simplicity	 and	 milder	
reaction	 conditions,	 this	 method	 provides	 a	 wide	 range	 of	
oxazoline‐isoxazoles	 in	 moderate	 to	 excellent	 yields.	
Microwave	heating	proved	be	quite	effective	 in	 improving	 the	
yields	and	decreasing	the	reaction	time.	
	
Acknowledgement	

	
One	 of	 the	 authors	 (PVR)	 is	 thankful	 to	 the	 Head,	

Department	 of	 Chemistry,	 Osmania	 University	 and	 Director,	
Central	 Facility	 for	 Research	 and	 Development,	 Osmania	
University,	Hyderabad	for	providing	the	spectral	facility.	
	

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