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European	Journal	of	Chemistry	5	(1)	(2014)	33‐40	

	

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.5.1.33‐40.900	

	
	

	

	

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

	 	 	

Facile	synthesis	of	new	fused	and	non‐fused	heterocyclic	systems	
from	a	γ‐ketoacid	

Marwa	Sayed	Salem	*,	Maher	Abd	El‐Aziz	Mahmoud	El‐Hashash,		
Al‐Shimaa	Omar	Ali	Mahmoud,	and	Hassan	Mohamed	Fawzy	Madkour	

Synthetic	Organic	Chemistry	Laboratory,	Chemistry	Department,	Faculty	of	Science,	Ain	Shams	University,	Abbasiya,	Cairo,	11566,	Egypt	

*Corresponding	author	at:	Synthetic	Organic	Chemistry	Laboratory,	Chemistry	Department,	Faculty	of	Science,	Ain	Shams	University,	Abbasiya,	Cairo,	11566,	Egypt.		
Tel.:	+2.02.24831836.	Fax:	+2.02.24831836.	E‐mail	address:	marwa_k@sci.asu.edu.eg	(M.S.	Salem).	

	
	

	 	

	 	 	
ARTICLE	INFORMATION	 	 ABSTRACT

	
DOI:	10.5155/eurjchem.5.1.33‐40.900	

Received:	30	July	2013	
Received	in	revised	form:	24	August	2013	
Accepted:	30	August	20113	
Online:	31	March	2014	

KEYWORDS	

	 The	 chemical	 reactivity	 of	 4‐(2‐tetryl)‐4‐oxobut‐2‐enoic	 acid	 towards	 carbon,	 nitrogen,
oxygen,	 sulfur	nucleophiles	 and	binucleophiles	namely	o‐phenylenediamine,	o‐aminophenol,
and	o‐aminothiophenol	has	been	studied.	The	investigated	nucleophilic	reactions	result	in	the
formation	 of	 heterocyclic	 compounds	 with	 fused	 and	 non‐fused	 systems	 namely,
pyridazinone,	tetrhydroquinoline,	quinoxalone,	oxazinone,	thiazole	and	benzocoumarin.	

Thiazole	
Quinoxalone	
Pyridazinone	
Benzocoumarin	
Pyrazolothiazole		
Thiazolopyridazine	

	
1.	Introduction	
	

4‐Aryl‐4‐oxobut‐2‐enoic	 acids	 (also	 considered	 as	 β‐
aroylacrylic	 acids),	 their	 derivatives	 represent	 an	 important	
class	of	compounds	with	wide	spectrum	of	biological	activities	
including	 antibacterial	 activity	 [1‐5],	 anti‐ulcer	 and	
cytoprotective	 properties	 [6,7],	 kynurenine‐3‐hydroxylase	 [8]	
and	 antiproliferative	 activity	 toward	Human	 cervix	 carcinoma	
(HeLa)	 [9,10].	 Moreover,	 the	 β‐aroylacrylic	 acids	 have	 been	
attracting	increasing	attention	in	view	of	their	high	reactivity	as	
building	blocks	for	the	synthesis	of	wide	variety	of	compounds	
of	 various	 classes	 due	 to	 their	 selective	 transformations	with	
different	reagents.	

In	continuation	of	our	previous	works	[11‐19],	the	present	
work	 aimed	 at	 utilization	 of	 the	 reactivity	 of	 4‐(2‐tetryl)‐4‐
oxobut‐2‐enoic	acid	(1)	towards	different	nucleophiles	such	as	
carbon,	 nitrogen,	 oxygen,	 sulfur	 nucleophiles	 and	 binucleo‐
philes	 (o‐phenylenediamine,	o‐aminophenol,	 and	o‐aminothio‐
phenol)	 to	 construct	 mixed	 and	 non‐mixed	 heterocyclic	
systems.	 Several	 electrophilic	 centers	 are	 present	 in	 acid	 (1)	
(α,β‐unsaturated‐γ‐ketoacid),	 viz	 atoms	 C(2)	 and	 C(4)	 which	
are	 hopeful	 for	 many	 reaction	 routes	 with	 nucleophilic	
reagents.	

	
	

2.	Experimental	
	
2.1.	Instrumentation	
	

All	melting	points	were	measured	on	a	Gallenkamp	melting	
point	 apparatus	 and	 are	 uncorrected.	 The	 infrared	 spectra	
were	 recorded	 using	 KBr	 disks	 on	 a	 Pye	 Unicam	 SP‐3‐300	
infrared	spectrophotometer.	 1H	NMR	experiments	were	run	at	
300	MHz	on	a	Varian	Mercury	VX‐300	NMR	spectrometer	using	
TMS	as	 internal	standard	 in	deuterated	chloroform	(CDCl3)	or	
deuterated	 dimethylsulphoxide	 (DMSO‐d6).	 Chemical	 shifts	 δ	
are	 quoted.	 The	 mass	 spectra	 were	 recorded	 on	 Shimadzu	
GCMS‐QP‐1000EX	Mass	spectrometers	at	70	eV.	All	the	spectral	
measurements	as	well	as	elemental	analyses	were	carried	out	
at	the	Micro	analytical	Center	of	Cairo	University.	All	the	newly	
synthesized	compounds	gave	satisfactory	elemental	analyses.	

	
2.2.	Synthesis	
	
2.2.1.	Reaction	of	4‐oxo‐4‐(5,6,7,8‐tetrahydronaphthalen‐2‐
yl)‐but‐2‐enoic	acid	(1)	[20]	with	cyclohexanone	and	/	or	
camphor	
	
	
	



34	 Salem	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	33‐40	
	

	 	

Ar

O

COOH

O

Ar1O

COOHAr

(2a,b)

(1) O

(i) Cyclohexanone and/ or Champhor, NaOH, EtOH
(ii) N2H4.H2O (1:1), EtOH
(iii) Excess N2H4.H2O, EtOH
(iv) Ethyl cyanoacetate, malononitrile, and/or cyclohexanone, AcONH4
(v) N2H4.H2O, EtOH

(i)

2a, Ar1 =

2b, Ar1 =

N

COOH

X

YAr

(5a-c)

(iv)

Ar =

(6)

NAr

COOH

CONHNH2

NH2

No. X Y
5a COOEt NH2
5b CN NH2
5c -(CH2)4-

(v)

O

Ar

N
H
N

O

(4a)

N COOH

Ar

H2NHN

H2N

(3a)

O

Ar

N
H
N

O

(3b)

N COOH

Ar

H2NHN

H2N

(4b)

(ii)

(ii)

(iii)

(iii)

5a

 
	

Scheme	1
	
	
A	 mixture	 of	 acid	 1	 (0.01	 mmol,	 2.30	 g),	 cyclohexanone	

and/or	 camphor	 (0.01	 mmol)	 in	 ethanol	 (30	 mL)	 and	 50%	
sodium	hydroxide	(2	mL)	was	stirred	at	reflux	temperature	for	
6	 h.	 The	 precipitated	 solid	 that	 formed	 after	 cooling	 was	
dissolved	 in	 water	 then	 acidified	 with	 hydrochloric	 acid.	 The	
crude	 solid	 product	 that	 deposited	was	 collected	 by	 filtration	
and	 washed	 with	 water,	 dried	 and	 recrystallized	 from	 light	
petroleum	ether	 (80‐100	 C):	 ethanol	 (2:1)	 to	 give	 compound	
2a,b	respectively	(Scheme	1).		

4‐Oxo‐2‐(2‐oxocyclohexyl)‐4‐(5,6,7,8‐tetrahydronaphthalen‐
2‐yl)butanoic	acid	 (2a):	Color:	Orange.	 Yield:	57	%.	M.p.:	 100‐
102	°C.	FT‐IR	(KBr,	ν,	cm‐1):	2858‐2660	(νOH),	1790	(νC=O,cyclic	
ketone),	 1708	 (νC=O,	 acid),	 1679	 (νC=O,	 ketone),	 1604	 (νC=C).	 1H	
NMR	(300	MHz,	CDCl3,	δ,	ppm):	7.68‐7.11	(m,	3H,	Ar‐H),	3.04‐
2.82	(m,	10H,	tetrahydronaphthalene,	cyclohexanone	moiety,	‐
CH2CH‐COOH),	 2.31‐1.27	 (m,	 10H,	 cyclohexanone	 moiety,	
tetrahydronaphthalene	 moiety).	 MS	 (EI,	 m/z	 (%)):	 330	
([M+2] ,	13.6),	216	(33.3),	159	(100.0),	131	(50.0).		

4‐Oxo‐4‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)‐2‐(4,7,7‐tri	
methyl‐3‐oxobicyclo[2.2.1]heptan‐2‐yl)butanoic	acid	(2b):	Color:	
Yellow.	Yield:	49	%.	M.p.:	173	°C	decomp.	FT‐IR	(KBr,	ν,	cm‐1):	
2858‐2660	 (νOH)	 ,	1791	 (νC=O,	 cyclic	ketone),	1708	 (νC=O,	 acid),	
1678	(νC=O,	ketone).	1H	NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	7.67‐

7.17	 (m,	 3H,	 Ar‐H),	 2.99‐2.77	 (m,	 8H,	 tetrahydronaphthalene	
moiety,	 camphor	 moiety,	 ‐CH2CH‐COOH),	 2.09‐1.75	 (m,	 9H,	
camphor,	 tetrahydronaphthalene	 moiety),	 1.24	 (s,	 3H,	 CH3),	
1.08	 (s,	 3H,	 CH3),	 1.03	 (s,	 3H,	 CH3).	 MS	 (EI,	 m/z	 (%)):	 384	
([M+2] ,	3.7),	356	(4.8),	159	(100.0),	131	(22.7).		
	
2.2.2.	Reaction	of	Michael	adducts	(2a,b)	with	hydrazine	
hydrate	
	

A	mixture	of	Michael	adduct	2a,b	(0.005	mmol,	1.89	g)	and	
hydrazine	hydrate	 (0.005	mmol,	 0.25	mL)	 in	 ethanol	 (20	mL)	
was	 heated	 at	 reflux	 for	 8	 h.	 The	 solid	 product	 which	 was	
separated	 out	 on	 hot	 was	 collected,	 dried	 and	 recrystallized	
from	 n‐butanol	 and/or	 dimethylformamide	 (DMF)	 to	 give	
compounds	3a,b,	respectively	(Scheme	1).	

4‐(2‐Oxo‐2‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)ethyl)‐4,4a,	
5,6,7,8‐hexahydrocinnolin‐3(2H)‐one	(3a):	Color:	Red.	Yield:	32	
%.	 M.p.:	 201‐202	 °C.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 3334	 (νNH),	 1667	
(νC=O).	1H	NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	7.82‐7.01	(m,	3H,	
Ar‐H),	 6.87	 (s,	 1H,	 exchangeable,	 NH),	 3.11‐2.78	 (m,	 7H,	
tetrahdronaphthalene,	pyridazinone	moiety,	‐COCH2),	2.31‐1.27	
(m,	13H,	cyclohexanone	moiety,	tetrahydronaphthalene	moiety,	
pyridazinone	 moiety).MS	 (EI,	m/z	 (%)):	 326	 ([M+2] ,	 0.43),	



Salem	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	33‐40	 35	
 

325	([M+1] ,	0.23),	324	(M ,	00.15),	159	(2.39),	131(3.29),	83	
(18.04),	82	(13.34),	81	(16.37),	80	(100.0).	

6‐[2‐Oxo‐2‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)ethyl]‐1,11,	
11‐trimethyl‐3,4‐diazatricyclo[6.2.1.02,7]undec‐2‐en‐5‐one	 (3b):	
Color:	Red.	Yield:	42	%.	M.p.:	223	°C	decomp.	FT‐IR	(KBr,	ν,	cm‐

1):	 3341	 (νNH),	 1665	 (νC=O),	 1608	 (νC=N).	 1H	 NMR	 (300	 MHz,	
DMSO‐d6,	 δ,	 ppm):	 7.78‐7.02	 (m,	 3H,	 Ar‐H),	 6.93	 (s,	 1H,	
exchangeable,	 NH),	 3.30‐2.57	 (m,	 7H,	 tetrahydronaphthalene,	
pyridazinone	 moiety,	 ‐COCH2),	 2.07‐1.51	 (m,	 10H,	 camphor,	
tetrahydronaphthalene,	 pyridazinone	 moiety),	 1.24	 (s,	 3H,	
CH3),	1.08	(s,	3H,	CH3),	0.83	(s,	3H,	CH3).	MS	(EI,	m/z	(%)):	377	
(M ,	2.73),	227	(100.0),	186	(9.56),	185	(5.19),	184	(2.19),	159	
(21.58),	131	(53.83).		
	
2.2.3.	Reaction	of	Michael	adducts	(2a,b)	with	excessive	
hydrazine	hydrate	
	

A	 mixture	 of	 Michael	 adduct	 2a,	 b	 (1	 g)	 and	 hydrazine	
hydrate	(2	mL)	in	ethanol	(20	mL)	was	heated	at	reflux	for	3	h	
and	 left	 to	 cool.	 Then	 the	 mixture	 was	 poured	 in	 ice	 and	
acidified	with	hydrochloric	 acid.	 The	 crude	 solid	product	 that	
deposited	was	 collected	 by	 filtration	 and	washed	with	water,	
dried	and	recrystallized	from	ethanol	to	afford	compound	4a,b,	
respectively	(Scheme	1).		

4‐Hydrazono‐2‐(2‐hydrazinocyclohex‐1‐enyl)‐4‐(5,6,7,8‐tetra	
hydronaphthalen‐2‐yl)but‐2‐enoic	 acid	 (4a):	 Color:	 Pale	 red.	
Yield:	43	%.	M.p.:	 201‐202	 °C.	FT‐IR	 (KBr,	 ν,	 cm‐1):	 3332	 (νNH,	
νNH2	&	νOH),	1675	(νC=O),	1606	(νC=N).	1H	NMR	(300	MHz,	CDCl3,	δ,	
ppm):	8.85	(s,	2H,	exchangeable,	NH2),	7.77‐7.00	(m,	4H,	Ar‐H,	
CH=C‐C=O),	3.04‐2.70	 (m,	4H,	 tetrahydronaphthalene	moiety),	
2.36‐2.20	(br.	s,	3H,	exchangeable,	‐NH‐NH2),	1.79‐1.62	(m,	4H,	
cyclohexenylhydrazine	 moiety),	 1.44‐1.27	 (m,	 8H,	 tetrahydro	
naphthalene,	cyclohexenylhydrazine	moiety).	MS	(EI,	m/z	(%)):	
354	(M ,	100.0),	247	(61.3),	221	(41.9),	177	(27.4),	149	(14.5),	
129	(12.9),	76	(64.5).	

4‐Hydrazono‐4‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)‐2‐(3‐
hydrazino‐4,7,7‐trimethylbicyclo[2.2.1]hept‐2‐en‐2‐yl)but‐2‐
enoic	 acid	 (4b):	 Color:	 Brown.	 Yield:	 64	%.	M.p.:	 240‐242	 °C.	
FT‐IR	 (KBr,	 ν,	 cm‐1):	 3350	 (br.	 νNH,	 νNH2,	 νOH),	 1677	 (νC=O,	 α,β‐
unsaturated	 acid).	 1H	NMR	 (300	MHz,	CDCl3,	 δ,	ppm):	8.23	 (s,	
2H,	 exchangeable,	 NH2),	 7.78‐6.99	 (m,	 4H,	 Ar‐H,	 CH=C‐C=O),	
3.04‐2.76	 (m,	 5H,	 tetrahydronaphthalene,	 camphor	 moiety),	
2.23	(br.	s,	3H,	exchangeable,	‐NH‐NH2),	1.79	(m,	8H,	tetrahydro	
naphthalene,	 camphor	moiety),	 1.27	 (s,	 3H,	 CH3),	 0.89	 (s,	 3H,	
CH3),	0.87	(s,	3H,	CH3).	MS	(EI,	m/z	(%)):	408	(M ,	18.8),	364	
(12.9),	 227	 (69.4),	 226	 (95.3),	 225	 (100.0),	 174	 (12.9),	 173	
(12.9),	165	(9.4),	160	(17.6),	159	(72.9).		
	
2.2.4.	Reaction	of	acid	1	with	ethyl	cyanoacetate,	
malononitrile	and	/	or	cyclohexanone	in	presence	of	
ammonium	acetate	
	

A	mixture	of	acid	1	(0.01	mmol,	2.30	g),	ethyl	cyanoacetate,	
malononitrile	and	/	or	 cyclohexanone	 (0.01	mmol)	and	5	g	of	
ammonium	acetate	were	fused	in	water	bath	for	3‐5	h.	Then	the	
mixture	 was	 poured	 in	 ice,	 the	 crude	 solid	 product	 that	
deposited	was	 collected	 by	 filtration	 and	washed	with	water,	
dried	 and	 recrystallized	 from	ethanol	 to	 give	 isonicotinic	 acid	
derivative	5a,	recrystallized	from	acetic	acid	to	give	isonicotinic	
acid	derivative	5b	and/or	 recrystallized	 from	benzene	 to	 give	
tetrahydroquinoline	derivative	5c	(Scheme	1).	

2‐Amino‐3‐(ethoxycarbonyl)‐6‐(5,6,7,8‐tetrahydronaphtha‐
len‐2‐yl)isonicotinic	acid	(5a):	Color:	Red.	Yield:	56	%.	M.p.:	200	
°C	 decomp.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 3395(νOH,	 νNH2),	 1713	 (νC=O,	
ester),	1681	(νC=O,	acid),	1604	(νC=C).	1H	NMR	(300	MHz,	DMSO‐
d6,	δ,	ppm):	7.70‐7.15	(m,	4H,	Ar‐H),	4.91	(q,	2H,	‐CH2‐CH3),	3.19	
(s,	2H,	exchangeable,	NH2),	2.73	(m,	4H,	tetrahydronaphthalene	
moiety),	 1.74	 (m,	 4H,	 tetrahydronaphthalene	moiety),	 1.24	 (t,	
3H,	 ‐CH2CH3).	MS	 (EI,	m/z	 (%)):	341	 ([M+1] ,	2.9),	248	 (4.7),	
158	(14.1),	96(27.1),	55	(100.0).	

2‐Amino‐3‐cyano‐6‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)	 iso‐
nicotinic	acid	(5b):	Color:	Pale	green.	Yield:	52	%.	M.p.:	191‐192	
°C.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 3457	 (νOH	 ),	 3345,	 3210	 (νNH2),	 2209	
(νC≡N),	1699	(νC=O,	acid),	1678	(νC=N),	1603	(νC=C).	1H	NMR	(300	
MHz,	DMSO‐d6,	 δ,	 ppm):	 7.78‐7.23	 (m,	 4H,	 Ar‐H),	 3.30	 (s,	 2H,	
exchangeable,	 NH2),	 2.99	 (m,	 4H,	 tetrahdronaphthalene	
moiety),	 1.75	 (m,	 4H,	 tetrahdronaphthalene	 moiety).	 MS	 (EI,	
m/z	 (%)):	 294	 ([M+1] ,	 27.7),	 280	 (35.8),	 226	 (23.6),	 127	
(44.2),	110	(65.5),	76	(78.0),	56	(100.0).	

2‐(5,6,7,8‐Tetrahydronaphthalen‐2‐yl)‐5,6,7,8‐tetrahydro	
quinoline‐4‐carboxylic	acid	(5c):	Color:	Pale	brown.	Yield:	67	%.	
M.p.:	 183‐185	 °C.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 3386	 (νOH	 ),	 1724	 (νC=O	
acid),	 1682	 (νC=N),	 1603	 (νC=C).	 1H	 NMR	 (300	 MHz,	 CDCl3,	 δ,	
ppm):	 7.65‐7.16(m,	 4H,	 Ar‐H),	 2.79	 (m,	 8H,	 tetrahdro	
naphthalene,	 cyclohexane	 moiety),	 1.82	 (m,	 8H,	 cyclohaxane,	
tetrahdronaphthalene	 moiety).	 MS	 (EI,	 m/z	 (%)):	 307	 (M ,	
34.2),	 263	 (34.2),	 230	 (21.1),	 185	 (34.2),	 159	 (100.0),	
131(18.4),	129	(39.5),	91	(73.7).		
	
2.2.5.	2‐Amino‐4‐(carboxy)‐6‐(5,6,7,8‐tetrahydro	
naphthalen‐2‐yl)nicotinohydrazide	(6)	
	

A	mixture	 of	 isonicotinic	 acid	 derivative	5a	 (0.005	mmol,	
1.7	g)	and	hydrazine	hydrate	(0.005	mmol,	0.25	mL)	in	ethanol	
(20	 mL)	 was	 refluxed	 for	 14h,	 left	 to	 cool.	 The	 crude	 solid	
product	that	deposited	after	cooling	was	collected	by	filtration,	
dried	and	recrystallized	from	light	petroleum	ether	(80‐100C):	
ethanol	 (3:1)	 to	 give	 compound	 6	 (Scheme	 1).	 Color:	 Pale	
brown.	 	 Yield:	 52	%.	M.p.:	 260	 C	 decomp.	 FT‐IR	 (KBr,	 cm‐1):	
3401	(νOH),	1713	(νC=O,	acid),	1672	(νC=O,	amide),	1613	(νC=C).	1H	
NMR	 (300	MHz,	DMSO‐d6,	 δ,	 ppm):	 8.30	 (s,	 1H,	 exchangeable,	
NH),	7.72‐7.03	(m,	4H,	Ar‐H),	3.68	(br.s,	4H,	exchangeable,	NH2	
&	 ‐NHNH2),	 2.81(m,	 4H,	 tetrahydronaphthalene	 moiety),	 1.65	
(m,	4H,	tetrahydronaphthalene	moiety).	MS	(EI,	m/z	(%)):	325	
([M‐1] ,	20.0),	226	(57.5),	159	(57.5),	127(57.5),	91	(75.0),	64	
(100.0).	
		
2.2.6.	2‐Amino‐4‐(2‐oxo‐2‐(5,6,7,8‐tetrahydronaphthalen‐2‐
yl)ethyl)thiazol‐5(4H)‐one	(7)	
	

A	mixture	of	acid	1	(0.01	mmol,	2.30	g)	and	thiourea	(0.01	
mmol,	 0.76	 g)	 in	 dry	 ethanol	 (20	mL)	with	 2	 drops	 of	 glacial	
acetic	 acid	 was	 refluxed	 for	 4h,	 left	 to	 cool,	 the	 precipitated	
solid	 was	 collected,	 dried	 and	 recrystallized	 from	 ethanol	 to	
afford	compound	7	(Scheme	2).	Color:	Pale	yellow.	Yield:	83	%.	
M.p.:	192‐193	C.	FT‐IR	 (KBr,	 ν,	 cm‐1):	3381,	3273	 (νNH),	1672	
(νC=O	acid),	1610	(νC=C).	1H	NMR	spectrum	(300	MHz,	DMSO‐d6,	
δ,	 ppm):	 8.95	 (s,	 1H,	NH,	 D2O‐exchangeable),	 8.79	 (s,	 1H,	 NH,	
D2O‐exchangeable),	7.69‐7.19	(m,	3H,	Ar‐H),	7.03	(br.s	2H,	NH2,	
D2O‐exchangeable),	4.39	(dd,	1H,	 jvic,cis	=	10.8	Hz,	Jvic,tr.	=	3.3	Hz,	
Hc),	3.89	(dd,	1H,	Jgem.	=	18.6	Hz,	Jvic,tr	=	3.0	Hz,	Ha)	3.40(dd,	1H,	
Jgem.	 =	 18.6	 Hz,	 Jvic,cis	 =	 10.8	 Hz,	 Hb),	 2.78	 (m,	 4H,	 tetrahydro	
naphthalene	 moiety),	 1.75	 (m,	 4H,	 tetrahydronaphthalene	
moiety).	MS	 (EI,	m/z	 (%)):	 288	 (M ,	 27.3),	 159	 (100.0),	 131	
(30.3),	129	(79.8).	
	
2.2.7.	Reaction	of	acid	1	with	o‐phenylendiamine,	o‐amino	
phenol	and	/or	o‐aminothiophenol	
	

A	 mixture	 of	 acid	 1	 (0.01	 mmol,	 2.30	 g)	 and	 o‐
phenylenediamine,	o‐aminophenol	and	/	or	o‐aminothiophenol	
(0.01	mmol)	in	ethanol	(20	ml)	containing	few	drops	of	glacial	
acetic	 acid,	 was	 heated	 at	 reflux	 for	 4‐7h.	 After	 cooling,	 the	
precipitated	solid	was	collected,	dried	and	recrystallized	 from	
DMF,	ethanol	and/or	benzene:ethanol	(2:1)	to	give	compounds	
8a,b	and	c	(Scheme	2).	

3‐(2‐Oxo‐2‐(5,6,7,8‐tetrahydro‐naphthalen‐2‐yl)ethyl)‐3,4‐
dihydroquinoxalin‐2(1H)‐one	(8a):	Color:	Reddish	brown.	Yield:	
73	%.	M.p.:	>300	C.	FT‐IR	(KBr,	ν,	cm‐1):	3349	(νNH),	1724	(νC=O,	
quinoxalinone),	1676	(νC=O,	ketone),	1603	(νC=C).		



36	 Salem	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	33‐40	
	

	

 
	

Scheme	2	
	
	
1H	 NMR	 (300	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 8.56	 (s,	 1H,	

exchangeable,	 ‐CONH),	 7.68‐6.54	 (m,	 7H,	 Ar‐H),	 4.26	 (s,	 1H,	
exchangeable,	NH),	4.05	(t,	1H,	quinoxalinone	moiety),	3.15	(d,	
2H,	CH2CO),	2.79	(m,	4H,	 tetrahydronaphthalene	moiety),	1.68	
(m,	4H,	tetrahydronaphthalene	moiety).	MS	(EI,	m/z	(%)):	320	
(M ,	 42.9),	 285	 (35.7),	 179(28.6),	 159	 (42.9),	 149	 (50.0),	 55	
(100.0).		

3‐(2‐Oxo‐2‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)ethyl)‐3,4‐
dihydrobenzo[b][1,4]oxazin‐2‐one	 (8b):	 Color:	 Dark	 brown.	
Yield:	 34	%.	M.p.:	 181	 C	 decomp.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 3338	
(νNH),	1713	(νC=O	oxazinone),	1678	(νC=O	ketone),	1603	(νC=C).		1H	
NMR	 (300	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 7.72‐6.65	 (m,	 7H,	 Ar‐H),	
4.32	(s,	1H,	exchangeable,	NH),	4.00	(t,	1H,	oxazinone	moiety),	
3.20	 (d,	 2H,	 ‐CH2CO),	 2.82	 (m,	 4H,	 tetrahydronaphthalene	
moiety),	 1.64	 (m,	 4H,	 tetrahydronaphthalene	moiety).	MS	 (EI,	
m/z	 (%)):	 324	 ([M+3] ,	 23.5),	 303	 (76.5),	 275	 (35.3),	 254	
(23.5),	185(58.8),	159	(88.2),	129(23.5),	91(64.7),	63	(100.0).		

3‐(2‐Oxo‐2‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)ethyl)‐3,4‐
dihydrobenzo[b][1,4]thiazin‐2‐one	 (8c):	 Color:	 Pale	 brown.	
Yield:	32%.	M.p.:	252	decomp.	FT‐IR	(KBr,	ν,	cm‐1):	3375	(νNH),	
1713	(νC=O,	thiazinone),	1678	(νC=O,	ketone),	1608(νC=C).	1H	NMR	
(300	MHz,	DMSO‐d6,	δ,	ppm):	7.59‐6.32	(m,	7H,	Ar‐H),	4.30	(s,	
1H,	exchangeable,	NH),	4.08	(t,	1H,	thiazinone	moiety),	3.21	(d,	
2H,	 ‐CH2CO),	2.80	 (m,	4H,	 tetrahdronaphthalene	moiety),	1.60	
(m,	 4H,	 tetrahdronaphthalene	moiety).	MS	 (EI,	m/z	 (%)):	 337	
(M ,	35.7),	277	(42.9),	262	(64.3),	228	(50.0),	211	(50.0),	191	
(50.0),	 177	 (57.1),	 164	 (64.3),	 155	 (50.0),	 148	 (100.0),	 138	
(57.1),	124	(71.4).	
	
2.2.8.	Reaction	of	acid	1	with	piperidine	and/or	morpholin	
	

A	 mixture	 of	 acid	 1	 (0.01	 mmol,	 2.3	 g)	 and	 piperidine	
and/or	morpholin	(0.01	mmol)	in	ethanol	(20	mL)	was	heated	
at	reflux	temperature	for	14‐19	h,	left	to	cool,	the	precipitated	
solid	 was	 collected,	 dried	 and	 recrystallized	 from	 ethanol	
and/or	 diluted	 dioxane	 to	 give	 compound	 9a,b,	 respectively	
(Scheme	2).	

4‐Oxo‐2‐(piperidin‐1‐yl)‐4‐(5,6,7,8‐tetrahydronaphthalen‐2‐
yl)butanoic	acid	(9a):	Color:	Yellow	crystals.	Yield:	47	%.	M.p.:	
162	 °C	 decomp.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 3400	 (νOH),	 (1730	 (νC=O,	
acid),	 1678	 (νC=O,	 ketone),	 1604	 (νC=C).	 1H	 NMR	 (300	 MHz,	
DMSO‐d6,	δ,	ppm):	7.47‐7.09	(m,	3H,	Ar‐H),	4.12	(t,	1H,	CH2‐CH‐
N‐),	 3.02	 (d,	 2H,	 CH2‐CH‐N‐),	 2.83	 (m,	 4H,	

tetrahydronaphthalene	moiety),	2.20	(t,	4H,	piperidine	moiety),	
1.58	 (m,	10H,	 tetrahydro	naphthalene,	piperidine	moiety).	MS	
(EI,	m/z	(%)):	314	([M‐1] ,	18.5),	290	(44.4),	264	(25.9),	236	
(55.6),	 224	 (37.0),	 215(25.9),	 159	 (66.7),	 144	 (55.6),	 129	
(81.5),	118	(74.1),	64	(100.0).		

2‐Morpholino‐4‐oxo‐4‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)	
butanoic	 acid	 (9b):	 Color:	 Pale	 brown.	 Yield:	 49	 %.	 M.p.:	 >	
300°C.	FT‐IR	(KBr,	ν,	cm‐1):	3424	(νOH),	1707	(νC=O,	acid),	1679	
(νC=O,	 ketone),	 1603	 (νC=C).	 1H	 NMR	 (300	 MHz,	 DMSO‐d6,	 δ,	
ppm):	7.50‐7.10	(m,	3H,	Ar‐H),	4.00	(t,	1H,	CH2‐CH‐N‐),	3.56	(t,	
4H,	morpholine	moiety),	2.98	(d,	2H,	CH2‐CH‐N‐),	2.79	(m,	4H,	
tetrahydronaphthalene	 moiety),	 2.35	 (t,	 4H,	 morpholine	
moiety),	 1.63	 (m,	 4H,	 tetrahydronaphthalene	moiety).	MS	 (EI,	
m/z	 (%)):	317	(M ,	18.2),	185	(45.5),	159	(100.0),	129(54.5),	
91(40.9),	57	(77.3).	
		
2.2.9.	2‐[5‐(acetyloxy)‐2‐amino‐1,3‐thiazol‐4‐yl]‐1‐(5,6,7,8‐
tetrahydronaphthalen‐2‐yl)vinyl	acetate	(10)	
	

A	 solution	 of	 thiazolone	7	 (0.005	mmol,	 1.44	 g)	 in	 acetic	
anhydride	 (10	mL)	was	 refluxed	on	water	bath	 for	10	h,	 then	
poured	 into	 ice/cold	 water	 with	 stirring.	 The	 crude	 solid	
product	that	deposited	was	collected	by	filtration,	washed	with	
water,	 dried	 and	 recrystallized	 from	 aqueous	 dioxane	 to	 give	
compound	10	(Scheme	3).	Color:	Pale	yellow.	Yield:	43	%.	M.p.:	
147	C	decomp.	FT‐IR	 (KBr,	 ν,	 cm‐1):	3244,	3197	 (νNH2),	1764,	
1707	(νC=O	esters).	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	7.66‐7.10	
(m,	3H,	ArH),	6.78	(s,	1H,	CH=C‐OCOCH3),	4.26	(s,	2H,	NH2,	D2O‐
exchangeable),	 3.03‐2.23	 (m,	 4H,	 tetrahydronaphthalene	
moiety),	 1.82	 (s,	 6H,	 ‐2COCH3),	 1.49‐1.33	 (m,	 4H,	 tetrahydro	
naphthalene	moiety).	MS	 (EI,	m/z	 (%)):	 374	 ([M+2] ,	 17.49),	
373	 ([M+1] ,	 13.39),	 372	 ([M] ,	 12.31),	 159	 (16.41),	 131	
(14.25),	129	(17.09),	80	(81.64),	64	(100.0).		
		
2.2.10.	3‐(5,6,7,8‐Tetrahydronaphthalen‐2‐yl)‐1,4‐
dihydrothiazolo[5,4‐c]pyridazin‐6‐amine	(11)	
	 	
A	mixture	of	thiazolone	7	 (0.005	mmol,	1.44	g)	and	hydrazine	
hydrate	(0.005	mmol,	0.25	mL)	in	ethanol	(20	mL)	was	heated	
at	reflux	temperature	for	3	h	left	to	cool	the	solid	product	was	
collected,	dried	and	recrystallized	from	DMF	to	give	compound	
11	 (Scheme	 3).	 Color:	 Red.	 Yield:	 60%.	M.p.:	 238	 C	 decomp.	
FT‐IR	(KBr,	ν,	cm‐1):	3414	&	3310	(νNH2,	νNH)	,1658	(νC=N).	



Salem	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	33‐40	 37	
 

	

 

Scheme	3	
	
	
1H	 NMR	 (300	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 8.01	 (s,	 1H,	 NH,	 D2O‐
exchangeable),	 7.80‐7.08	 (m,	 3H,	 ArH),	 4.20	 (s,	 2H,	NH2,	D2O‐
exchangeable),	 2.82‐2.72	 (m,	 4H,	 tetrahydronaphthalene	
moiety),	 2.44(s,	 2H,	 pyridazine	 moiety),	 1.90‐1.70	 (m,	 4H,	
tetrahydronaphthalene	 moiety).	 MS	 (EI,	m/z	 (%)):	 284	 (M ,	
10.0),	 283	 ([M‐1] ,	 20.0),	 228	 (20.0),	 157	 (23.3),	 131(73.3),	
114	(46.7),	64	(100.0).		
	
2.2.11.	2‐Amino‐4‐(2‐(hydroxyimino)‐2‐(5,6,7,8‐tetrahydro	
naphthalen‐2‐yl)ethyl)thiazol‐5(4H)‐one	(12)	
	

A	 mixture	 of	 thiazolone	 7	 (0.005	 mmol,	 1.44	 g)	 and	
hydroxylamine	hydrochloride	(0.005	mmol,	0.35	g)	and	NaOH	
(0.02	mmol,	0.8	g)	in	ethanol	(20	mL)	was	refluxed	for	8	h.	The	
solid	product	that	deposited	on	hot	was	collected	by	filtration,	
dried	 and	 recrystallized	 with	 DMF	 to	 give	 compound	 12	
(Scheme	3).	Color:	Pale	brown.	Yield:	15	%.	M.p.:	>	300	C.	FT‐
IR	(KBr,	ν,	cm‐1):	3369	(νOH	&	νNH2),	1674	(νC=O),	1599	(νC=N).	1H	
NMR	spectrum	(300	MHz,	DMSO‐d6,	δ,	ppm):	7.77‐7.56	(m,	3H,	
ArH),	 4.36	 (s,	 2H,	 NH2,	 D2O‐exchangeable),	 3.85	 (s,	 2H,	 N=C‐
CH2),	2.85‐2.78	(m,	4H,	tetrahydronaphthalene	moiety),	2.52	(s,	
1H,	CH,	thiazolone	moiety),	2.31	(s,	1H,	OH,	D2O‐exchangeable),	
1.66‐1.54	(m,	4H,	tetrahydronaphthalene	moiety).	MS	(EI,	m/z	
(%)):	 305	 ([M+2] ,	 12.2),	 258	 (14.6),	 199	 (12.2),	 159(100.0),	
144	(24.4),	129	(43.9),	115	(34.1),	98	(43.9).	
		
2.2.12.	2‐Diacetylamino‐4‐(2‐(hydroxyimino)‐2‐(5,6,7,8‐
tetrahydronaphthalen‐2‐yl)ethyl)thiazol‐5‐yl	acetate	(13)	
	

A	mixture	 of	 compound	12	 (0.25	 g)	 and	 acetic	 anhydride	
(10	mL)	was	heated	at	 reflux	 for	2h,	Then	poured	 in	 ice/cold	
water	with	stirring.	The	crude	solid	product	that	deposited	was	
collected	 by	 filtration,	 washed	 with	 water,	 dried	 and	
recrystallized	 from	dioxane	 to	give	compound	13	 (Scheme	3).	
Color:	Black.	 Yield:	 42	%.	M.p.:	 263	 °C	decomp.	 FT‐IR	 (KBr,	 ν,	
cm‐1):	 3438	 (νOH),	 1766	 (νC=O	 ester),	 1716	 (νC=O	 imide),	 1605	
(νC=C).	1H	NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	7.72‐7.23	(m,	3H,	
Ar‐H),	 4.05	 (s,	 2H,	 NOH=C‐CH2),	 2.80‐2.69	 (m,	 4H,	

tetrahydronaphthalene	 moiety),	 2.26	 (s,	 1H,	 OH,	 D2O‐
exchangeable),	2.20	(s,	6H,	‐N(COCH3)2),	1.98	(s,	3H,	CH3COO),	
1.67‐1.60	(m,	4H,	 tetrahydronaphthalene	moiety).	MS	(EI,	m/z	
(%)):	 370	 ([M‐OCOCH3] ,	 31.6),	 233	 (31.6),	 227	 (42.1),	 186	
(36.8),	 162	 (36.8),	 129	 (47.4),	 121	 (68.4),	 105	 (31.6),	 55	
(100.0).		
	
2.2.13.	6‐Imino‐2‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)	
pyrazolo[1,5‐c]thiazol‐4(6H)‐one	(14)	
	

A	 mixture	 of	 thiazolone	 7	 (0.005	 mmol,	 1.44	 g)	 and	
hydroxylamine	hydrochloride	(0.005	mmol,	0.35	g)	in	pyridine	
(15	mL)	was	 refluxed	 for	 6	h.	 Then	 the	 reaction	mixture	was	
poured	 into	 cold	water	 the	 crude	product	 that	 deposited	was	
filtered	 off,	washed	with	water,	 dried	 and	 recrystallized	 from	
ethanol	 to	 give	 compound	 14	 (Scheme	 3).	 Color:	 Pale	 green.	
Yield:	45	%.	M.p.:	193‐195	C.	FT‐IR	(KBr,	ν,	cm‐1):	3285	(νNH),	
1706	(νC=O),	1640	(νC=N),	1607	(νC=C).	1H	NMR	(300	MHz,	DMSO‐
d6,	 δ,	 ppm):	 7.25‐6.99	 (m,	 4H,	 Ar‐H),	 4.50	 (s,	 1H,	 NH,	 D2O‐
exchangeable),	 2.81‐2.72	 (m,	 4H,	 tetrahydronaphthalene	
moiety),	1.65‐1.58	(m,	4H,	tetrahydronaphthalene	moiety).	MS	
(EI,	m/z	 (%)):	 281	 (M‐2] ,	 84.2),	 280	 (68.4),	 265	 (42.1),	 238	
(47.4),	 224	 (36.8),	 210	 (47.4),	 194	 (42.1),	 177	 (26.2),	 128	
(68.4),	112	(42.1),	96	(63.2),	54	(100.0).	
		
2.2.14.	Reaction	of	acid	1	with	benzylamine	and/or																	
p‐toluidine	in	presence	of	carbon	disulphide	
	

To	 a	 solution	 of	 benzylamine	 and/or	 p‐toulidine	 (0.015	
mmol)	in	THF	(20	mL)	and	carbon	disulphide	(0.03	mmol,	2.28	
mL),	 compound	 1	 (0.01	 mmol,	 2.3	 g)	 was	 added	 and	
continuously	 stirred	 at	 room	 temperature	 for	 4h,	 the	 crude	
product	was	filtered	off,	dried	and	recrystallized	from	ethanol,	
to	give	compounds	15a,b,	respectively	(Scheme	4).	

3‐Benzyl‐5‐(2‐oxo‐2‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)	
ethyl)‐2‐thioxothiazolidin‐4‐one	 (15a):	 Color:	 Yellow	 crystals.	
Yield:	43	%.	M.p.:	184‐186	C.	FT‐IR	(KBr,	ν,	cm‐1):	1724	(νC=O,	
thiazolidinone),	1677	(νC=O,	ketone),	1603	(νC=C).		



38	 Salem	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	33‐40	
	

	

 
	

Scheme	4
	
	
1H	NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	7.65‐7.06	(m,	8H,	Ar‐

H),	4.50	(s,	2H,	‐NCH2),	4.02	(dd,	1H,	 jvic,cis=	10.6	Hz,	Jvic,tr.	=	3.0	
Hz,	Hc,	 thioxothiazolidinone	moiety),	 3.67	 (dd,	1H,	 Jgem.	 =	18.8	
Hz,	Jvic,tr	=	3.0	Hz,	Ha,	COCH2),	3.30	(dd,	1H,	Jgem.	=	18.8	Hz,	Jvic,cis	=	
10.6	 Hz,	 Hb,	 COCH2),	 2.82	 (m,	 4H,	 tetrahydronaphthalene	
moiety),	 1.67	 (m,	 4H,	 tetrahydronaphthalene	moiety).	MS	 (EI,	
m/z	(%)):	304	([M‐C6H5‐CH2‐] ,	1.29),	172	(0.99),	159	(45.05),	
131	(13.25),	91	(100.0).		

5‐(2‐Oxo‐2‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)ethyl)‐2‐
thioxo‐3‐p‐tolylthiazolidin‐4‐one	(15b):	Color:	Brownish	yellow.	
Yield:	 64	 %.	 M.p.:	 222	 C	 decomp.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	
1730(νC=O,	 thiazolidinone),	 1677(νC=O,	 ketone),	 1603	 (νC=C).	 1H	
NMR	 (300	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 7.73‐7.00	 (m,	 7H,	 Ar‐H),	
4.05	 (dd,	 1H,	 jvic,cis	=	10.3	Hz,	 Jvic,tr.	 =	 3.1	Hz,	Hc,	 thiazolidinone	
moiety),	3.69	(dd,	Jgem	=	18.4	Hz,	Jvic,tr	=	3.1	Hz,	1H,	Ha,	COCH2),	
3.41	(dd,	Jgem.	=	18.4	Hz,	Jvic,cis	=	10.3	Hz,	1H,	Hb,	COCH2),	2.85	(m,	
4H,	tetrahydronaphthalene	moiety),	2.41	(s,	3H,	CH3),	1.65	(m,	
4H,	tetrahydronaphthalene	moiety).	MS	(EI,	m/z	(%)):	304	([M‐
C6H4CH3	(4)] ,	0.65),	159	(100.0),	131	(17.05),	91	(17.05).		
	
2.2.15.	Reaction	of	acid	1	with	phenol,	α‐	and	/	or	β‐
naphthols	
	

To	a	solution	of	acid	1	(0.005	mmol,	1.15	g)	in	ethanol	(30	
mL),	phenol	α‐	and/or	β‐naphthols	(0.005	mmol)	and	(1	mL)	of	
glacial	 acetic	 acid	 was	 added.	 The	 mixture	 reaction	 was	
refluxed	 for	4	h.	 left	 to	cool	 the	precipitated	solid	was	 filtered	
off,	 dried	 and	 recrystallized	 from	 diluted	 dioxane	 &	 benzene	
and/or	 dioxane	 to	 give	 compounds	 16‐18,	 respectively	
(Scheme	4).		

4‐(1,2,3,4‐Tetrahydronaphthalene‐6‐carbonyl)‐3,4‐dihydro	
chromen‐2‐one	 (16):	 Color:	 Brown.	 Yield:	 42%.	 M.p.:	 152	 C	
decomp.	FT‐IR	(KBr,	ν,	cm‐1):	1730	(νC=O,	coumarin),	1679	(νC=O,	
ketone),	1604	 (νC=C).	 1H	NMR	 (300	MHz,	CDCl3,	δ,	ppm):	7.62‐
7.13	(m,	7H,	Ar‐H),	4.02	(t,	1H,	coumarin	moiety),	2.79	(d,	2H,	
coumarin	 moiety),	 1.80	 (m,	 4H,	 tetrahydronaphthalene	
moiety),	 1.25	 (m,	 4H,	 tetrahydronaphthalene	moiety).	MS	 (EI,	
m/z	 (%)):	 306	 (M ,	 20.98),	 159	 (100.0),	 147	 (20.40),	 131	
(3.74),	119	(6.90).	

4‐(1,2,3,4‐Tetrahydronaphthalene‐7‐carbonyl)‐3,4‐dihydro	
benzo[h]chromen‐2‐one	(17):	Color:	Brownish	yellow.	Yield:	31	
%.	M.p.:	 >	 300	 C.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 1724	 (νC=O	 coumarin),	
1677	 (νC=O	 ketone),	 1603	 (νC=C).	 1H	 NMR	 (300	MHz,	 CDCl3,	 δ,	
ppm):	7.90‐7.22	 (m,	9H,	Ar‐H),	4.32	 (t,	 1H,	 coumarin	moiety),	
2.82	 (d,	 2H,	 coumarin	moiety),	 2.06	 (m,	 4H,	 tetrahydronapht	
halene	 moiety),	 1.58	 (m,	 4H,	 tetrahydronaphthalene	 moiety).	
MS	(EI,	m/z	 (%)):	356	(M ,	23.1),	230	(20.5),	184	(25.1),	159	
(100.0),	131	(42.2),	91	(53.1).		

1‐(1,2,3,4‐Tetrahydronaphthalene‐7‐carbonyl)‐1,2‐di‐hydro	
benzo[f]chromen‐3‐one	 (18):	 Color:	 Pale	 brown.	 Yield:	 30	 %.	
M.p.:	>	300	C.	FT‐IR	(KBr,	ν,	cm‐1):	1738	(νC=O	coumarin),	1679	
(νC=O	 ketone),	 1603	 (νC=C).	 1H	NMR	 (300	MHz,	 CDCl3,	 δ,	 ppm):	
7.85‐7.09	(m,	9H,	ArH),	4.52	(t,	1H,	chromenone	moiety),	2.77	
(d,	 2H,	 chromenone	 moiety),	 2.10	 (m,	 4H,	 tetrahydro	
naphthalene	 moiety),	 1.64	 (m,	 4H,	 tetrahydronaphthalene	
moiety).	 MS	 (EI,	 m/z	 (%)):	 356	 (M ,	 3.1),	 230	 (17.4),	 184	
(15.1),	159	(100.0),	131	(31.8),	91	(33.7).		
	
	
	



Salem	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	33‐40	 39	
 

	

H2N

S

NH2

EtOH

N
H

NH2

O
O

Ar

OH
S

N NH2

O
O

Ar

OH
SH +H+

N NH2

O
O

Ar

+OH2
:SH -H+

-H2O
S

N

O

ArN
NH2

OO

Ar

H2O
+

S

Ar

O

OH

O

NH2

O

7  
	

Scheme	5	
	
	

 
	

Scheme	6	
	
	
3.	Results	and	discussion	
	
3.1.	Chemistry	
	

When	 acid	 1	 was	 submitted	 to	 react	 with	 cyclohexanone	
and/or	camphor	in	the	presence	of	alcoholic	sodium	hydroxide,	
it	 underwent	 carba‐Michael	 addition	 to	 yield	 4‐oxobutanoic	
acid	 derivatives	 2a,b,	 respectively.	 Michael	 adduct	 2a,b	 has	
been	allowed	to	react	with	hydrazine	hydrate	in	1:1	molar	ratio	
in	boiling	ethanol	to	afford	the	pyridazinone	derivatives,	3a,b.	
On	 the	 other	 hand,	 when	 the	 reaction	 was	 conducted	 in	 the	
presence	 of	 excessive	 hydrazine	 hydrate	 it	 yielded	 the	 bis‐
hydrazone	derivative,	followed	by	dehydrogenation	to	yield	the	
more	thermodynamically	stable	products	4a,b.	

As	a	part	of	our	programme	involving	utility	of	4‐(2‐tetryl)‐
4‐oxo‐but‐2‐enoic	acid	(1)	in	the	synthesis	of	some	interesting	
heterocyclic	compounds,	 the	authors	sought	 to	 investigate	 the	
behaviour	of	the	acid	1	with	ethyl	cyanoacetate,	malononitrile	
and/or	cyclohexanone	in	the	presence	of	ammonium	acetate	as	
basic	catalyst.	The	isolated	products	have	been	identified	as	2‐
amino‐3‐ethoxycarbonyl‐6‐(tetryl‐2‐yl)‐pyridine‐4‐carboxy‐lic	
acid	(5a),	2‐amino‐6‐tetryl‐3‐cyano‐4‐carboxylic	acid	(5b)	and	
2‐(2‐tetryl)‐4‐carboxy‐5,6,7,8‐tetrhydroquinoline	(5c),	respect‐
tively.	 When	 the	 enaminoester	 5a	 reacted	 with	 hydrazine	
hydrate	 in	 boiling	 ethanol,	 the	 corresponding	 hydrazide	 6	
(Scheme	1)	was	obtained.	

2‐Amino‐4‐(2‐oxo‐2‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)	
ethyl)thiazol‐5(4H)‐one	 (7)	 was	 obtained	 when	 acid	 1	 was	
allowed	 to	 react	 with	 thiourea,	 as	 nitrogen	 nucleophile,	 in	
boiling	ethanol.	Plausible	mechanism	of	 the	 reaction	 is	 shown	
in	Scheme	5.	

The	 1H	 NMR	 spectrum	 of	 product	 7	 revealed	 that	 it	 is	
present	 in	 solution,	 in	 dynamic	 equilibrium	 of	 two	 forms	 (A)	
and	(B)	with	a	ratio	of	54.65	and	45.35%,	respectively	(Scheme	
6).	

The	very	thorough	study	of	1H	NMR	spectrum	of	compound	
7	showed	a	multiplet	due	to	the	presence	of	two	diastereotopic	
protons	 of	 methylene	 group	 flanked	 between	 the	 carbonyl	

functionality	 of	 the	 tetroyl	 moiety	 and	 the	 methine	 group	 of	
thiazole	nucleus.	Due	to	the	non‐equivalence	of	protons	Ha	and	
Hb,	 they	 undergo	 geminal	 coupling	with	 each	 other	 and	 each	
line	of	the	two	doublets	couples	with	the	stereogenic	proton	Hc	
to	give	the	multiplet.	The	stereogenic	proton	Hc	undergoes	the	
vicinal	coupling	with	the	two	diastereotopic	protons	Ha	and	Hb	
to	give	d	×	d	signal.	

Refluxing	 acid	 1	 with	 bidentate	 nucleophiles	 namely	 o‐
phenylenediamine,	 o‐aminophenol	 and/or	 o‐aminothiophenol	
in	alcohol	afforded	satisfactory	yields	of	quinoxalone	(8a),	3(2‐
tetroylmethyl)3,4‐dihydrobenzo‐1,4‐oxazin‐2‐one	 (8b)	 and	
(8c),	 respectively.	 Acid	 1	 added	 amines	 (piperidine	 and/or	
morpholine,)	to	the	more	reactive	vinylic	carbon	(alpha	carbon	
to	the	carboxyl	group)	to	produce	the	α‐amino‐γ‐ketoacids	9a,b	
(Scheme	2).	

The	 structure	 of	 2‐aminothiazolone	 7	 was	 chemically	
verified	via	acetylating	with	acetic	anhydride	in	which	all	active	
OH	 hydrogens	 have	 been	 acetylated	 to	 afford	 derivative	 10	
(Scheme	 3).	 The	 reaction	 of	 thiazole	 derivative	 7	 with	
hydrazine	 hydrate	 in	 boiling	 ethanol	 resulted	 in	 annulation	
reaction	and	afforded	the	thiazolopyridazine	derivative	11	as	a	
bicyclic	 fused	 heterocyclic	 system.	 Interactions	 of	 thiazole	
derivative	 7	 with	 hydroxyl	 amine	 hydrochloride	 in	 boiling	
ethanol	 in	 the	 presence	 of	 NaOH	 and/or	 in	 boiling	 pyridine	
yield	the	corresponding	oxime	12	and	pyrazolothiazole	14	as	a	
second	bicyclic	 fused	heterocycle.	Acetylation	of	oxime	12	via	
acetic	anhydride	yielded	the	acetoxy	derivative	13	[21‐23].	

Thiazole	 derivatives	 represent	 an	 important	 class	 of	
heterocyclic	 compounds	with	 expected	 biological	 activity	 and	
have	 considerable	 chemical	 and	 pharmacological	 importance.	
Particularly,	 they	 are	 useful	 as	 anticonvulsant	 activity	 [24],	
antimicrobial	 [25,26],	 anticancer	 [27]	 and	 anti‐inflammatory	
[28].	This	prompted	us	 to	synthesize	new	 thiazole	derivatives	
bearing	 a	 tetryl	moiety	with	 the	 aim	of	 decreasing	polarity	 of	
the	 thiazole	 derivatives.	 Thus,	 when	 acid	1	was	 submitted	 to	
react	with	ammonium	benzyldithiocarbamate,	and	4‐tolyldithio	
carbamate	in	tetrahydrofuran,	the	corresponding	2‐thioxo‐1,3‐
thiazolidin‐4‐one	 derivatives	 15a	 and	 15b	 were	 obtained	



40	 Salem	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	33‐40	
	
(Scheme	4).	 The	 present	work	 describes	 the	 reaction	 of	 4‐(2‐
tetryl)‐4‐oxo‐but‐2‐enoic	 acid	 (1)	 with	 phenol,	 α	 and	 /	 or	 β‐
naphthols	 in	 ethanol	 containing	drops	of	 glacial	 acetic	 acid	 to	
give	 4‐tetroyl‐3,4‐dihydrocoumarine	 16,	 4(2‐tetryoyl)‐3,4‐
dihydrobenzocoumarine	derivatives	17	and	18,	respectively.	
	
4.	Conclusion	
	

γ‐Ketoacids	 could	 be	 utilized	 in	 heterocyclic	 synthesis	 of	
fused	and	non‐fused	systems	via	facile	reactions	with	different	
mono	 and	 bi‐dentate	 carbon,	 nitrogen,	 oxygen,	 sulfur	
nucleophiles.	
	
Acknowledgement	
	

Technical	 support	 from	Department	 of	 Chemistry,	 Faculty	
of	Science,	Ain	Shams	University	is	gratefully	acknowledged.		

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