untitled


ISSN	215

A	facile	
analogu

Amr	Moha
Holger	Bu

1	Department	of
2	Institut	für	Org

*	Corresponding
Tel.:	+2.3.56765

	
	

	

ARTICLE	IN

DOI:	10.5155/e

Received:	23	No
Received	in	rev
Accepted:	19	De
Published	onlin
Printed:	31	Mar

KEYWORDS
Azaenamine	
Michael	additio
Cyanoacetylure
4‐Deazatoxoflav
α‐Cyanoacrylam
HMBC	spectros

	
1.	Introduct
	

The	 biol
compounds	
them	 a	 targ
thetic	appro
the	 first	 on
diazomethan
and	the	othe
Alder	 cyclo
functionalize
their	 prevale
expensive	 s
hazard	 reag
synthesize	d
[3+3]	 atom
acrylonitrile	
zines	 [17‐21
makes	 the	 a
enamine‐like

The	 pres
atom	combin
with	various

53‐2249	(Print)	

	

	

	

synthesis
ues	via	[3+

amed	Abdel
utenschön	2	a

f	Chemistry,	Faculty
ganische	Chemie,	L

g	author	at:	Depart
572.	Fax:	+2.3.5727

FORMATION	

	
eurjchem.7.1.73‐80

ovember	2015	
vised	form:	12	Dece
ecember	2015	
ne:	31	March	2016	
rch	2016	

S	

on	
ea	
vin	
mide	
scopy	

tion	

ogical	 importa
as	 antimicrobi
get	 of	 enormou
aches	of	pyrida
e	 (Figure	 1,	 m
ne	derivatives	t
er	method	(Figu
oaddition	 of	
ed	 dienophiles	
ence	 in	 literatu
starting	 mater
gents,	 etc.	 A	
dihydropyridazi
	 combination	
derivatives	 yi

1].	 In	 this	 case,
azomethine	 ca
e	reactivity	take
sent	work	 aims
nation	reaction	
s	α‐cyanoacryla

/	ISSN	2153‐225
ht

Europ

s	of	3‐ami
+3]	atom	

moniem	1,*,	
and	Ismail	A

y	of	Science,	Cairo	U
eibniz	Universität	H

tment	of	Chemistry,
7556.	E‐mail	addres

0.1371	

ember	2015	

nce	 of	 pyridaz
al	 and	 antican
us	 scientific	 eff
azines	 involve	
method	 A)	 is	 t
to	cyclopropene
ure	1,	method	
substituted	 1
[11‐16].	 Both	
ure,	 have	 vario
ials,	 tedious	
third	 relative
ines	(Figure	1,	
of	 arylhydra

ielding	 3‐amino
,	 the	 nitrogen	
arbon	 relatively
es	place	[22,23]
s	 at	 studying	 t
of	azaenamine
mides	as	an	int

European	Journ

Europ
57	(Online)		20
ttp://dx.doi.org

pean	Jo
Journal	web

ino‐2,5‐di
combinat

	Said	Ahmed
Abdelshafy	A

University,	12613	G
Hannover,	Schneide

y,	Faculty	of	Science
ss:	amrmachem@g

	 	

	 	

	 ABSTRACT
	 Michael	 addi
cyanoacrylam
further	 react
4‐deazatoxofl
reacting	azae
Unambiguous

Cite	this:	Eur.

ines	 and	 their	
cer	 agents	 ren
forts	 [1‐5].	 The
two	main	strat
the	 cycloadditi
e	compounds	[
B)	is	the	retro	
1,2,4,5‐tetrazine
methods,	 in	 sp
ous	 disadvantag
experimental	
ly	 new	 metho
method	C)	 imp
azones	 to	 acti
o‐2,5‐dihydropy
lone	 pair	 reso
y	 electron	 rich
].	
the	 potency	 of	
es,	as	Michael	do
teresting	strate

al	of	Chemistry	7

	

pean	Journal	of	C
016	Atlanta	Pub
/10.5155/eurjch

	

ournal	
bpage:	www.

	

ihydropy
tion	

d	Soliman	G
Abdelhamid

Giza,	Egypt	
erberg	1B,	D‐30167

e,	Cairo	University,	
mail.com	(A.	M.	Ab

tion	 reactions	
mides	were	cond
tion	 with	 acetic
lavin	analogue.	A
namine	with	N‐
s	structural	eluci

.	J.	Chem.	2016,	

fused	
ndered	
e	 syn‐
tegies:	
ion	 of	
6‐10],	
Diels‐
es	 to	
pite	 of	
ges	 of	
work,	
od	 to	
plies	a	
ivated	
yrida‐
nance	
h	 and	

[3+3]	
onors,	
egy	for	

the	
exte
[4,5
tiga
	
2.	E
	
2.1.

app
as	p
spe
reco
100
sam
shif
spe
EX	
per

7	(1)	(2016)	73‐

Chemistry	
lishing	House	LL
hem.7.1.73‐80.1

of	Che
.eurjchem.co

yridazines

hozlan	1,		
d	1,2	

7	Hannover,	Germa

12613	Giza,	Egypt.
delmoniem).	

of	 arylhydrazon
ucted	and	yielde
c	 anhydride	 wa
A	one	step	synth
carbamoyl‐2‐cy
idation	was	don

7(1),	73‐80	

synthesis	of	pa
ending	 these	 r
5‐c]pyridazines
ated.	

Experimental

.	Instrumentat
	
Melting	points

paratus	and	are
potassium	brom
ectrophotomete
orded	with	a	V
0	 MHz,	 respect
mples	were	diss
fts	 are	 reporte
ectra	(EI‐MS)	we
mass	spectrom
rformed	at	the	M
	
	
	

‐80	

LC	‐	All	rights	re
1371	

emistry
m	

s	and	4‐de

any	

.		

ne	 derivatives	
ed	new	pyridazi
as	 investigated	
hesis	of	4‐deazat
ano‐3‐phenylacr
e	using	2D‐HMB

artially	unsatur
reactions	 to	 pr
	(4‐deazatoxofl

tion	

s	were	measure
e	uncorrected.	T
mide	pellets	us
er.	 All	 the	 1H	
Varian	Gemini	N
tively,	 using	 TM
solved	in	DMSO
ed	 as	 δ	 in	 pp
ere	measured	o
meter	at	70	eV.	
Microanalytical	

served	‐	Printed

y	

eazatoxof

with	 different	
ine‐4‐carboxami
resulting	 in	 the
toxoflavin	was	a
rylamide	 to	give
BC	spectroscopy.

rated	aminopyr
repare	 some	 n
lavin	analogues

ed	with	a	Stuar
The	IR	spectra	
sing	a	FT‐IR	Br
and	 13C	 NMR
NMR	spectrome
MS	 as	 internal	
O‐d6	or	CDCl3	an
m.	 Electron	 io
on	a	Shimadzu	G
The	elemental	
Center,	Cairo	U

d	in	the	USA	

	

	

	

flavin	

functionalized	
ide	compounds.	
e	 formation	 of	
also	carried	out	b
e	deazatoxoflavi
	

ridazines.	Also,
novel	 pyrimido
s)	is	also	inves‐

rt	melting	point
were	recorded
uker‐vector	22
R	 spectra	 were
eter	at	400	and
standard.	 The

nd	the	chemical
onization	 mass
GCMS‐QP‐1000
analyses	were

University.		

α‐
A
a
by
in.

,	
o	
‐

t	
d	
2	
e	
d	
e	
l	
s	
0	
e	



74	 Abdelmoniem	et	al.	/	European	Journal	of	Chemistry	7	(1)	(2016)	73‐80	
	
	

	
	

Figure	1.	General	synthetic	strategies	of	pyridazine	ring	systems.	
	
	
2.2.	Synthesis	
	

Azaenamines	1a,b	were	prepared	in	a	similar	procedure	to	
that	 reported	 by	 Reynolds	 et	 al.	 [24].	 All	 α‐cyanoacrylamide	
derivatives	 (2a‐e	 and	16)	 in	 this	 paper	were	 prepared	 via	 a	
typical	 Knoevenagel	 condensation	 procedure	 [25].	 The	
synthetic	 strategies,	 physical	 data	 and	 spectral	 characteri‐
zation	of	the	newly	synthesized	products	are	stated	below.	
	
2.2.1.	Synthesis	of	6‐acetyl‐3‐amino‐N,2,5‐triphenyl‐2,5‐
dihydropyridazine‐4‐carboxamide	(8a)	
	

A	 mixture	 of	 azaenamine	 1a	 (162	 mg,	 1	 mmol)	 and	
activated	 cyanoacrylamide	 derivative	 2a	 (248	 mg,	 1	 mmol)	
was	 heated	 at	 reflux	 in	 dioxane	 (10	 mL)	 in	 the	 presence	 of	
piperidine	 (0.2	 mL,	 2	 mmol)	 for	 5	 h.	 The	 solvent	 was	
evaporated	 under	 reduced	 pressure	 and	 the	 collected	 solid	
was	 crystallized	 from	 ethanol:dioxane	 mixture	 (5:1,	 v:v,	 10	
mL)	 to	 give	 compound	 8a	 (Scheme	 1).	 Yield:	 375	 mg,	 915	
mmol,	91%.	Color:	Bright	yellow	crystals.	M.p.:	190‐192	°C.	FT‐
IR	(KBr,	ν,	cm‐1):	3360,	3181	(NH)	(br,	CONH	and	NH2),	1673	
(CO)	(COCH3),	1634	(CO)	(CONH).	 1H	NMR	(400	MHz,	DMSO‐
d6,	δ,	ppm):	2.39	(s,	3H,	CH3),	5.72	(s,	1H,	pyridazine‐H),	6.96‐
7.59	(m,	17H,	Ar‐H	and	NH2),	9.05	(br	s,	1H,	NH).	13C	NMR	(100	
MHz,	DMSO‐d6,	 δ,	 ppm):	 25.6	 (CH3),	 33.4	 (CH),	66.6	 (C),	 78.4	
(C),	 121.4	 (CH),	 123.1	 (CH),	 126.2	 (CH),	 127.2	 (CH),	 127.7	
(CH),	 128.1	 (CH),	 128.6	 (CH),	 129.1	 (CH),	 130.0	 (CH),	 140.1	
(C),	143.3	(C),	146.5	(C),	151.2	(C),	167.9	(C),	196.9	(C).	MS	(EI,	
m/z	(%)):	411	[(M+1)+]	(1),	410	[M+]	(2),	366	(1),	333	(8),	318	
(10),	291	(100),	248	(22),	93	(7),	77	(23).	HRMS	(EI)	calcd.	for	
C25H22N4O2:	 410.1743;	 found:	 410.1766.	 Anal.	 calcd.	 for	
C25H22N4O2:	 C,	 73.15;	 H,	 5.40;	 N,	 13.65.	 Found:	 C,	 73.09;	 H,	
5.36;	N,	13.42%.	
	
2.2.2.	Synthesis	of	6‐acetyl‐3‐amino‐2,5‐diphenyl‐N‐(p‐tolyl)	
‐2,5‐dihydropyridazine‐4‐carboxamide	(8b)	
	

Following	 the	 procedure	 given	 for	 compound	 8a,	
azaenamine	 1a	 (162	 mg,	 1	 mmol)	 and	 cyanoacrylamide	
derivative	2b	 (262	mg,	1	mmol)	were	reacted	 in	dioxane	(10	
mL)	in	presence	of	piperidine	(0.2	mL,	2	mmol).	Crystallization	
of	the	isolated	product	from	ethanol:dioxane	mixture	(5:1,	v:v,	
10	mL)	afforded	the	compound	8b	(Scheme	1).	Yield:	382	mg,	
901	mmol,	90%.	Color:	Golden	yellow	crystals.	M.p.:	198‐200	
°C.	IR	(KBr,	ν,	cm‐1):	3392	(NH)	(br,	CONH	and	NH2),	1631	(CO)	
(br,	COCH3	and	CONH).	1H	NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	

2.23	(s,	3H,	CH3),	2.36	(s,	3H,	CH3CO),	5.65	(s,	1H,	pyridazine‐
H),	7.03‐7.56	(m,	16H,	Ar‐H	and	NH2),	8.95	(br	s,	1H,	NH).	13C	
NMR	(100	MHz,	DMSO‐d6,	δ,	ppm):	20.9	(CH3),	25.3	(CH3),	33.4	
(CH),	78.4	(C),	121.4	(CH),	126.1	(CH),	127.2	(CH),	127.7	(CH),	
128.1	 (CH),	 128.9	 (CH),	 129.0	 (CH),	 129.9	 (CH),	 132.0	 (C),	
137.4	 (C),	 140.7	 (C),	 143.3	 (C),	 146.5	 (C),	 150.7	 (C),	 167.9	
(CONH),	 196.5	 (COCH3).	MS	 (EI,	m/z	 (%)):	 424	 [M+]	 (5),	 318	
(10),	290	(100),	248	(15),	214	(4),	106	(5),	77	(21).	HRMS	(EI)	
calcd.	 for	C26H24N4O2:	424.1899;	 found:	424.1876.	Anal.	calcd.	
for	C26H24N4O2:	C,	73.56;	H,	5.70;	N,	13.20.	Found:	C,	73.49;	H,	
5.66;	N,	13.18%.	
	
2.2.3.	Synthesis	of	6‐acetyl‐3‐amino‐N‐(4‐nitrophenyl)‐2,5‐
diphenyl‐2,5‐dihydropyridazine‐4‐carboxamide	(8c)	
	

Following	 the	 procedure	 given	 for	 compound	 8a,	
azaenamine	 1a	 (162	 mg,	 1	 mmol)	 and	 cyanoacrylamide	
derivative	2c	 (293	mg,	1	mmol)	were	 reacted	 in	dioxane	 (10	
mL)	in	presence	of	piperidine	(0.2	mL,	2	mmol).	Crystallization	
of	the	isolated	product	from	ethanol:dioxane	mixture	(5:1,	v:v,	
10	mL)	afforded	the	compound	8c	(Scheme	1).	Yield:	398	mg,	
877	mmol,	88%.	Color:	Orange	solid.	M.p.:	192‐194	°C.	IR	(KBr,	
ν,	cm‐1):	3460	(NH)	(br,	CONH	and	NH2),	1684	(CO)	 (COCH3),	
1644	(CO)	(CONH).	1H	NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	2.37	
(s,	3H,	CH3CO),	5.76	 (s,	1H,	pyridazine‐H),	7.17‐8.16	 (m,	16H,	
Ar‐H	and	NH2),	9.56	(br	s,	1H,	NH).	13C	NMR	(100	MHz,	DMSO‐
d6,	δ,	ppm):	25.3	(CH3),	33.2	(CH),	77.9	(C),	120.0	(CH),	124.9	
(CH),	 126.3	 (CH),	 127.3	 (CH),	 127.6	 (CH),	 128.4	 (CH),	 129.1	
(CH),	 130.1	 (CH),	 140.5	 (C),	 141.7	 (C),	 143.2	 (C),	 147.0	 (C),	
151.9	(C),	168.1	(C),	196.7	(C).	MS	(EI,	m/z	(%)):	455	[M+]	(3),	
409	(9),	318	(12),	290	(100),	248	(13),	92	(27),	77	(30).	HRMS	
(EI)	 calcd.	 for	 C25H21N5O4:	 455.1594;	 found:	 455.1578.	 Anal.	
calcd.	 for	 C25H21N5O4:	 C,	 65.93;	 H,	 4.65;	 N,	 15.38.	 Found:	 C,	
65.88;	H,	4.63;	N,	15.36%.	
	
2.2.4.	Synthesis	of	6‐acetyl‐3‐amino‐2‐(4‐chlorophenyl)‐N,5‐
diphenyl‐2,5‐dihydropyridazine‐4‐carboxamide	(8d)	
	

Following	 the	 procedure	 given	 for	 compound	 8a,	
azaenamine	 1b	 (196	 mg,	 1	 mmol)	 and	 cyanoacrylamide	
derivative	2a	 (248	mg,	1	mmol)	were	reacted	 in	dioxane	(10	
mL)	in	presence	of	piperidine	(0.2	mL,	2	mmol).	Crystallization	
of	the	isolated	product	from	ethanol:dioxane	mixture	(5:1,	v:v,	
10	mL)	afforded	the	compound	8d	(Scheme	1).	Yield:	414	mg,	
932	mmol,	93%.	Color:	Pale	yellow	solid.	M.p.:	194‐196	°C.		

	



Abdelmoniem	et	al.	/	European	Journal	of	Chemistry	7	(1)	(2016)	73‐80	 75	
 

	

Me

O

N
NH

1a, R1 = Ph

b, R1 = C6H4Cl(p)

Me

O

N
N NH2

R1

+

Pathway A

Pathway C

O

N
NH

R1

C
O

Ph

NH2

N
N

R1

HO

Ph

NH2

N
N

R1

3 4(I) 4(II)

N
N

Me

O NH2

Me

O

N
N

R1

C

R1

5 6

Me

O

N
NH

R1

C

R1

7

CN

Pathway B
N

N

N

2a, R2 = Ph

b, R2 = MeC6H4(p)

c, R2 = O2NC6H4(p)

d, R2 = MeOCOC6H4(o)

e, R2 = n-Bu

Ph

Ph Ph

Ph Ph

O
NHR2

NHR2

O

NHR2

O O

NHR2

O

NHR2

O

NHR2

NHR2

O

NHR2

O

Ph

8a, R1 = Ph, R2 = Ph

8b, R1 = Ph, R2 = MeC6H4(p)

8c, R1 = Ph, R2 = O2NC6H4(p)

8d, R1 = C6H4Cl(p), R2 = Ph

8e, R1 = C6H4Cl(p), R2 = MeC6H4(p)

8f, R1 = Ph, R2 = MeOCOC6H4(o)

8g, R1 = Ph, R2 = n-Bu 	
	

Scheme	1
	
	
IR	 (KBr,	 ν,	 cm‐1):	 3321	 (NH)	 (br,	 CONH	 and	 NH2),	 1649	

(CO)	(COCH3),	1625	(CO)	(CONH).	 1H	NMR	(400	MHz,	DMSO‐
d6,	 δ,	 ppm):	 2.36	 (s,	 3H,	 CH3CO),	 5.67	 (s,	 1H,	 pyridazine‐H),	
6.97‐7.58	(m,	16H,	Ar‐H	and	NH2),	9.03	(br	s,	1H,	NH).	MS	(EI,	
m/z	(%)):	447	(1)	[(M+2)+],	446	(1),	445	[M+]	(4),	409	(8),	430	
(12),	368	(23),	318	(34),	290	(100),	186	(14),	77	(53).	HRMS	
(EI)	 calcd.	 for	 C25H21ClN4O2:	 446.1324	 [(M+2)+],	 444.1353	
[M+];	found:	446.1315	[(M+2)+],	444.1346	[M+].	Anal.	calcd.	for	
C25H21ClN4O2:	 C,	 67.49;	H,	 4.76;	N,	 12.59.	 Found:	 C,	 67.47;	H,	
4.73;	N,	12.58%.	
	
2.2.5.	Synthesis	of	6‐acetyl‐3‐amino‐2‐(4‐chlorophenyl)‐5‐
phenyl‐N‐(p‐tolyl)‐2,5‐dihydropyridazine‐4‐carboxamide	
(8e)	
	

Following	 the	 procedure	 given	 for	 compound	 8a,	
azaenamine	 1b	 (196	 mg,	 1	 mmol)	 and	 cyanoacrylamide	
derivative	2b	 (262	mg,	1	mmol)	were	reacted	 in	dioxane	(10	
mL)	in	presence	of	piperidine	(0.2	mL,	2	mmol).	Crystallization	
of	the	isolated	product	from	ethanol:dioxane	mixture	(5:1,	v:v,	
10	mL)	afforded	the	compound	8e	(Scheme	1).	Yield:	403	mg,	

880	mmol,	88%.	Color:	Beige	solid.	M.p.:	186‐188	°C.	IR	(KBr,	
ν,	cm‐1):	3410	(NH)	(br,	CONH	and	NH2),	1678	(CO)	 (COCH3),	
1662	(CO)	(CONH).	1H	NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	2.22	
(s,	 3H,	 CH3),	 2.36	 (s,	 3H,	 CH3CO),	 5.64	 (s,	 1H,	 pyridazine‐H),	
7.02‐7.58	(m,	15H,	Ar‐H	and	NH2),	8.96	(br	s,	1H,	NH).	MS	(EI,	
m/z	 (%)):	461	(2),	460	(1),	459	[M+]	(5),	444	(17),	424	(23),	
416	(12),	401	(26),	380	(19),	318	(36),	290	(100),	166	(13),	92	
(54),	 77	 (62).	 HRMS	 (EI)	 calcd.	 for	 C26H23ClN4O2:	 460.1480	
[(M+2)+],	458.1510	[M+];	found:	460.1522	[(M+2)+],	458.1502	
[M+].	Anal.	calcd.	 for	C26H23ClN4O2:	C,	68.04;	H,	5.05;	N,	12.21.	
Found:	C,	68.06;	H,	5.02;	N,	12.17%.	
	
2.2.6.	Synthesis	of	methyl	2‐(6‐acetyl‐3‐amino‐2,5‐diphenyl‐
2,5‐dihydropyridazine‐4‐carboxamido)benzoate	(8f)	
	

Following	 the	 procedure	 given	 for	 compound	 8a,	
azaenamine	 1a	 (162	 mg,	 1	 mmol)	 and	 cyanoacrylamide	
derivative	2d	 (306	mg,	1	mmol)	were	reacted	 in	dioxane	(10	
mL)	in	presence	of	piperidine	(0.2	mL,	2	mmol).	Crystallization	
of	the	isolated	product	from	ethanol:dioxane	mixture	(5:1,	v:v,	
10	mL)	afforded	the	compound	8f	(Scheme	1).		



76	 Abdelmoniem	et	al.	/	European	Journal	of	Chemistry	7	(1)	(2016)	73‐80	
	

	

	
	

Scheme	2
	
	
Yield:	 399	 mg,	 853	 mmol,	 85%.	 Color:	 Bright	 yellow	

crystals.	M.p.:	206‐208	°C.	 IR	 (KBr,	ν,	 cm‐1):	3410,	3307	(NH)	
(br,	 CONH	 and	 NH2),	 1685	 (CO)	 (COOCH3),	 1644	 (CO)	 (br,	
COCH3	and	CONH).	1H	NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	2.09	
(s,	3H,	CH3CO),	3.91	 (s,	3H,	COOCH3),	5.47	 (s,	1H,	pyridazine‐
H),	7.06‐8.59	(m,	16H,	Ar‐H	and	NH2),	10.91	(br	s,	1H,	NH).	13C	
NMR	(100	MHz,	DMSO‐d6,	δ,	ppm):	25.3	(CH3),	34.2	(CH),	53.3	
(CH3),	77.9	(C),	115.4	(C),	120.7	(CH),	122.2	(CH),	126.2	(CH),	
127.5	 (CH),	 128.0	 (CH),	 128.3	 (CH),	 129.2	 (CH),	 130.2	 (CH),	
131.2	 (CH),	134.7	 (CH),	140.5	 (C),	142.1	 (C),	142.2	 (C),	146.5	
(C),	151.8	(C),	167.8	(C),	168.5	(C),	196.7	(C).	MS	(EI,	m/z	(%)):	
468	[M+]	(3),	453	(5),	425	(11),	440	(19),	409	(37),	394	(43),	
360	 (22),	 318	 (36),	 290	 (100),	 248	 (22),	 146	 (19),	 77	 (28).	
HRMS	 (EI)	 calcd.	 for	 C27H24N4O4:	 468.1798;	 found:	 468.1778.	
Anal.	calcd.	for	C27H24N4O4:	C,	69.22;	H,	5.16;	N,	11.96.	Found:	
C,	69.18;	H,	5.13;	N,	11.98%.	
	
2.2.7.	Synthesis	of	6‐acetyl‐3‐amino‐N‐butyl‐2,5‐diphenyl‐
2,5‐dihydropyridazine‐4‐carboxamide	(8g)	
	

Following	 the	 procedure	 given	 for	 compound	 8a,	
azaenamine	 1a	 (162	 mg,	 1	 mmol)	 and	 cyanoacrylamide	
derivative	2e	 (228	mg,	1	mmol)	were	 reacted	 in	dioxane	(10	
mL)	in	presence	of	piperidine	(0.2	mL,	2	mmol).	Crystallization	
of	the	isolated	product	from	ethanol:dioxane	mixture	(5:1,	v:v,	
10	mL)	afforded	the	compound	8g	(Scheme	1).	Yield:	349	mg,	
895	mmol,	89%.	Color:	Yellowish‐white	crystals.	M.p.:	158‐160	
°C.	 IR	 (KBr,	 ν,	 cm‐1):	 3411,	 3173	 (NH)	 (br,	 CONH	 and	 NH2),	
1678	 (CO)	 (COCH3),	 1632	 (CO)	 (CONH).	 1H	 NMR	 (400	 MHz,	
DMSO‐d6,	 δ,	 ppm):	 0.81	 (t,	 3H,	 CH3CH2),	 1.13	 (m,	 2H,	
CH3CH2CH2),	1.33	(m,	2H,	CH3CH2CH2CH2),	2.34	(s,	3H,	CH3CO),	
3.06	(m,	2H,	CH2CH2NH),	5.28	(s,	1H,	pyridazine‐H),	7.03	(br	s,	
2H	 ,	 NH2),	 7.05‐7.53	 (m,	 11H,	 Ar‐H	 and	 NH).	 13C	 NMR	 (100	
MHz,	 DMSO‐d6,	 δ,	 ppm):	 14.6	 (CH3),	 19.9	 (CH2),	 25.3	 (CH3),	
32.0	 (CH2),	 33.5	 (CH),	38.8	 (CH2),	 78.6	 (C),	126.0	 (CH),	127.1	
(CH),	 127.7	 (CH),	 127.6	 (CH),	 128.8	 (CH),	 129.8	 (CH),	 140.9	
(C),	143.2	(C),	145.8	(C),	149.4	(C),	168.8	(C),	196.6	(C).	MS	(EI,	
m/z	(%)):	390	[M+]	(2);	347	(4),	313	(5),	290	(100),	248	(28),	
231	 (3),	 77	 (26).	HRMS	 (EI)	 calcd.	 for	C23H26N4O2:	 390.2056;	
found:	390.2034.	Anal.	calcd.	for	C23H26N4O2:	C,	70.75;	H,	6.71;	
N,	14.35.	Found:	C,	70.77;	H,	6.68;	N,	14.34%.	
	
2.2.8.	Synthesis	of	3‐acetyl‐7‐methyl‐1,4,6‐triphenyl‐4,6‐
dihydropyrimido[4,5‐c]pyridazin‐5(1H)‐one	(11)	
	

Compound	 8a	 (0.41	 g,	 1	 mmol)	 was	 heated	 at	 reflux	 in	
acetic	anhydride	(10	mL,	106	mmol)	for	5	h.	The	solvent	was	
evaporated	 under	 reduced	 pressure	 and	 the	 residue	 was	

washed	with	 25%	 aq.	 ammonia	 solution	 (10	mL,	 260	mmol)	
then	 filtered	 and	 washed	 with	 distilled	 water	 (20	 mL).	 The	
crude	dry	product	was	crystallized	from	ethanol:dioxane	(5:1,	
v:v,	 10	mL)	 to	 give	 compound	11	 (Scheme	2).	Yield:	 332	mg,	
765	mmol,	76%.	Color:	Deep	yellow	solid.	M.p.:	268‐270	°C.	IR	
(KBr,	ν,	cm‐1):	1664	(CO)	(COCH3),	1638	(CO)	(CONH).	1H	NMR	
(400	MHz,	 DMSO‐d6,	 δ,	 ppm):	 1.65	 (s,	 3H,	 CH3),	 2.42	 (s,	 3H,	
CH3CO),	 5.36	 (s,	 1H,	 pyridazine‐H),	 7.22‐7.64	 (m,	 15H,	Ar‐H).	
13C	NMR	(100	MHz,	DMSO‐d6,	δ,	ppm):	24.5	(CH3),	25.0	(CH3),	
34.0	(CH),	98.0	(C),	125.8	(CH),	127.3	(CH),	127.6	(CH),	127.9	
(CH),	 128.2	 (CH),	 128.7	 (CH),	 129.1	 (CH),	 129.3	 (CH),	 130.0	
(CH),	137.7	(C),	141.7	(C),	141.9	(C),	144.2	(C),	150.2	(C),	158.7	
(C),	161.4	(C),	196.2	(C).	MS	(EI,	m/z	 (%)):	434	[M+]	(6),	420	
(11),	 391	 (35),	 357	 (19),	 318	 (27),	 290	 (100),	 168	 (13),	 91	
(63),	 77	 (72).	 HRMS	 (EI)	 calcd.	 for	 C27H22N4O2:	 434.1743;	
found:	434.1719.	Anal.	calcd.	for	C27H22N4O2:	C,	74.64;	H,	5.10;	
N,	12.89.	Found:	C,	74.61;	H,	5.07;	N,	12.90%.	
	
2.2.9.	Synthesis	of	6‐acetyl‐2,5‐diphenyl‐4,5‐dihydro	
pyridazin‐3(2H)‐one	(15)	
	

Compound	 8a	 (0.41	 g,	 1	 mmol)	 was	 heated	 at	 reflux	 in	
formic	acid	(10	mL,	265	mmol)	for	3	h.	The	excess	solvent	was	
removed	 at	 reduced	 pressure	 and	 the	 crude	 substance	 was	
treated	with	 25%	 aq.	 ammonia	 solution	 (10	mL,	 260	mmol)	
then	 filtered	 and	washed	with	water	 (20	mL).	 The	 dry	 solid	
was	 crystallized	 from	 ethanol	 (10	mL)	 to	 give	 compound	15	
(Scheme	 3).	 Yield:	 212	mg,	 726	mmol,	 63%.	 Color:	 Colorless	
crystals.	 M.p.:	 122‐124	 °C.	 IR	 (KBr,	 ν,	 cm‐1):	 1705	 (CO)	
(COCH3),	 1687	 (CO)	 (CONPh).	 1H	 NMR	 (400	 MHz,	 CDCl3,	 δ,	
ppm):	2.50	(s,	3H,	CH3CO),	3.05	(m,	2H,	CHCH2),	4.71	 (m,	1H,	
CHCH2),	7.22‐7.57	(m,	10H,	Ar‐H).	13C	NMR	(100	MHz,	CDCl3,	δ,	
ppm):	24.8	 (CH3CO),	35.0	 (CHCH2),	35.4	 (CHCH2),	124.8	 (CH),	
126.9	 (CH),	 127.4	 (CH),	 127.9	 (CH),	 128.8	 (CH),	 129.3	 (CH),	
137.5	(C),	140.4	(C),	150.4	(C),	164.8	(CONPh),	196.0	(COCH3).	
MS	(EI,	m/z	(%)):	292	[M+]	(15),	277	(10),	249	(35),	215	(22),	
172	(14),	77	(100).	HRMS	(EI)	calcd.	for	C18H16N2O2:	292.1212;	
found:	292.1123.	Anal.	calcd.	for	C18H16N2O2:	C,	73.95;	H,	5.52;	
N,	9.58.	Found:	C,	73.88;	H,	5.48;	N,	9.63%.		
	
2.2.10.	Synthesis	of	3‐Acetyl‐1,4‐diphenyl‐6,8‐dihydro	
pyrimido[4,5‐c]pyridazine‐5,7(1H,4H)‐dione	(19)	
	

Following	 the	 procedure	 given	 for	 compound	 8a,	
azaenamine	1a	(162	mg,	1	mmol)	and	N‐carbamoyl‐2‐cyano‐3‐
phenylacrylamide	 16	 (0.22	 g,	 1.0	 mmol)	 were	 reacted	 in	
dioxane	(10	mL)	in	presence	of	piperidine	(0.2	mL,	2	mmol).		

	



Abdelmoniem	et	al.	/	European	Journal	of	Chemistry	7	(1)	(2016)	73‐80	 77	
 

	

	

Scheme	3	
	
	

 
	

Mechanistic	pathway	for	the	reaction	of	azaenamine	1a	with	(E)‐N‐carbamoyl‐2‐cyano‐3‐phenylacrylamide	2.	
	

Scheme	4
	
	
Crystallization	 of	 the	 isolated	 product	 from	

ethanol:dioxane	 mixture	 (5:1,	 v:v,	 10	 mL)	 afforded	 the	
compound	 19	 (Scheme	 4).	 Yield:	 319	 mg,	 886	 mmol,	 89%.	
Color:	Canary‐yellow	crystals.	M.p.:	290‐292	°C.	IR	(KBr,	ν,	cm‐

1):	1681	(CO)	(COCH3),	1619	(CO)	(br,	CONH	and	NHCONH).	1H	
NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	2.36	(s,	3H,	CH3CO),	5.18	(s,	
1H,	pyridazine‐H),	7.11‐7.53	(m,	12H,	Ar‐H	and	2NH).	13C	NMR	
(100	MHz,	DMSO‐d6,	 δ,	ppm):	25.1	 (CH3),	33.3	 (CH),	85.5	 (C),	
125.8	 (CH),	 126.0	 (CH),	 126.6	 (CH),	 127.7	 (CH),	 128.5	 (CH),	
128.7	(CH),	143.3	(C),	144.3	(C),	144.5	(C),	155.4	(C),	157.9	(C),	
165.4	(C),	196.6	(C).	MS	(EI,	m/z	(%)):	360	[M+]	(13),	345	(24),	
317	 (47),	 290	 (100),	 184	 (16),	 77	 (72).	HRMS	 (EI)	 calcd.	 for	
C20H16N4O3:	 360.1222;	 found:	 360.1188.	 Anal.	 calcd.	 for	
C20H16N4O3:	 C,	 66.66;	 H,	 4.48;	 N,	 15.55.	 Found:	 C,	 66.67;	 H,	
4.50;	N,	15.53%.	
	
3.	Results	and	discussion	
	

As	 a	 part	 of	 sequential	 work	 aimed	 at	 manifesting	 the	
proper	 pattern	 of	 the	 azaenamine	 reactivity	 as	 nucleophilic	

carbon	species	towards	activated	cinnamonitriles	[17‐21],	we	
report	here	the	aza‐Michael	addition	of	azaenamines	1a,b	with	
α‐cyano‐N‐arylacrylamide	derivatives	2a‐e.	The	 reaction	may	
proceed	 through	one	of	 three	 reasonable	pathways	A,	B	 or	C	
(Scheme	1).	Pathway	A,	 involving	 the	Michael	addition	of	 the	
nucleophilic	 acyl	 methyl	 carbon	 to	 activated	 acrylonitrile	
followed	 by	 ring	 closure	 caused	 by	 the	 attack	 of	 azomethine	
carbon	 to	 give	 4	 (I)	 and	 their	 tautomeric	 forms	 4	 (II)	 was	
readily	 excluded	 as	 the	 1H	 NMR	 spectrum	 revealed	 a	
characteristic	peak	at	δ	2.39	ppm	corresponding	to	the	acetyl	
protons	 (Scheme	 1).	 Thus,	 the	 reaction	 can	 take	 place	
according	 to	 either	 pathway	 B,	 that	 comprises	 the	 first	
addition	of	hydrazone	 lone	pair	 to	 the	activated	double	bond	
followed	 by	 azomethine	 carbon	 attack	 forming	 5‐amino‐2,3‐
dihydropyridazines	6,	or	pathway	C,	 that	employs	a	 lone	pair	
resonance	 causing	 the	 azomethine	 carbon	 to	 be	 nucleophilic	
and	consequently,	attack	the	activated	acylonitriles	to	yield	3‐
amino‐2,5‐dihydropyridazines	8.		

	
	



78	
	

	

	
Figure	2.	 The	
parentheses.	 Th
square.	The	cha

	
	
Using	 th

unambiguou
of	 the	 produ
compound	 8
cross	couplin
of	 the	 acetyl
carboxamide
the	usual	 rea
high	yield	(T
prepared	com
spectroscopi
molecular	 io
compound	 8
3181	 cm–1.	 T
assigned	 to	
respectively.
at	δ	2.39	ppm
for	pyridazin
for	17	proton
protons.	In	a
9.05	ppm	for
a	methyl	sign
ppm,	a	signa
and	two	char
carboxamide

	
Table	1.	The	yi
Compound	
8a	
8b	
8c	
8d	
8e	
8f	
8g	
	
	

The	 che
extensively	
c]pyridazine
toxoflavin	 [2
in	 the	 field	
alcohols	 [35
ties	and	imp

HMBC	spectrum	o
he	 correlation	 cro
aracteristic	cross	p

e	 simple	 spect
us	decision	conc
ucts,	 yet	 the	 in
8a	 supported	 t
ng	between	pyr
l	 carbonyl	 carb
e	 carbon	 atom	
action	 conditio
Table	1).	Furthe
mpounds	was	e
ic	 tools.	 The	
on	 peak	 at	m/z
8a	 displayed	 b
The	 two	 bands
the	 ketone	 an
.	The	 1H	NMR	s
m	for	the	acyl	m
ne‐H5.	The	mult
ns	and	was	ass
addition,	the	sp
r	the	amide	pro
nal	at	δ	25.6	pp
al	for	the	carbo
racteristic	signa
e	and	ketonic	ca

ield	percentages	of
R1	
Ph	
Ph	
Ph	
ClC6H4	(p)	
ClC6H4	(p)	
Ph	
Ph	

emistry	 of	 py
investigated	 in
es	 could	 be	 re
29‐34].	 These	 c
of	 the	 auto‐r
‐37].	 Moreover
edes	the	xanthe

Abd

of	 compound	8a;	 t
oss	 peaks	 between
peak	is	enclosed	in	

troscopic	 tools	
cerning	the	exac
spection	 of	 the
the	 pathway	 C	
ridazine‐H5	at	δ
bon	 atoms	 at	 δ
at	 δ	 167.9	 ppm

ons	compounds
er	support	of	th
established	on	t
mass	 spectrum
z	 =	 410	 [M+].	
broad	 NH2	 band
s	 at		 =	 1673	 a
nd	 amide	 carb
spectrum	exhib
methyl	group,	a	
tiplet	at	δ	6.96‐
igned	to	aroma
pectrum	showed
ton.	The	13C	NM
pm,	a	pyridazin
nitrile	carbon	a
als	at	δ	167.9	an
arbonyl	carbon	

f	compounds	8a‐g.
R2	
Ph	
MeC6H4	(p)	
O2NC6H4	(p)	
Ph	
MeC6H4	(p)	
MeOCOC6H4	(o)	
n‐Butyl	

rimido[4,5‐c]py
n	 literature	 [26
egarded	 as	 ana
compounds	 are
recycling	 oxida
r,	 toxoflavin	 ha
ene	oxygenase	

elmoniem	et	al.	/

the	number	 refers
n	 the	methyl	proto
a	circle	for	clarity.

we	 cannot	ma
ct	chemical	stru
e	HMBC	 spectr
as	 it	 indicated
δ	5.72	ppm	and
δ	 196.9	 ppm	 an
m	 (Figure	 2).	 U
s	8	were	obtain
he	constitution	
the	basis	of	the	
m	 of	 8a	 show
The	 IR	 spectru
ds	 at	 	 =	 336
and	 1643	 cm–1

bonyl	 carbon	 a
bited	a	 singlet	
singlet	at	δ	5.72
‐7.59	ppm	integ
atic	and	amino	
d	a	broad	signa
MR	spectrum	sh
ne‐C5	signal	at	δ
atom	at	δ	121.4
nd	196.9	ppm	f
atoms,	respect

.	
Yield	(%)
92
90
88
92
87
90
89	

yridazines	 wa
6‐28].	 Pyrimid
alogues	 of	 4‐d
e	 extensively	 ut
ation	 of	 amine
as	 antibiotic	 pr
[38].	In	an	exte

/	European	Journ

s	 to	protons,	 the	 le
ons,	 pyridazine‐H5
.

ake	 an	
ucture	
um	 of	
d	 a	 3J‐
d	each	
nd	 the	
Under	
ned	 in	
of	the	
other	
wed	 a	
um	 of	
0	 and	
	were	
atoms,	
signal	
2	ppm	
grated	
group	
al	at	δ	
howed	
δ	33.4	
4	ppm	
for	the	
tively.	

)

s	 not	
do[4,5‐
deaza‐
tilized	
s	 and	
roper‐
ension	

of	
thro
pyr
yiel
cop
and
1.65
met
NM
ppm
The
carb

oth
une
obt
plac
med
form
pyr
bee
of	tw
Thu
acy
CH2

NM
ppm
sign
164

c]py
phe
acry
pip
disc
con
sho
H4	
ami
pre
givi
elim

nal	of	Chemistry	

etters	denotes	 the
5	and	 amide	proto

the	 program	
ough	 boiling	
rimido[4,5‐c]py
ld	 (Scheme	2).	
pically	 revealing
d	bands.	Thus	 t
5	 ppm	 for	 me
thyl	and	a	sing

MR	spectrum	sh
m.	 It	 also	 featu
e	 signals	 at	 δ
boxamide	and	a
Attempts	 to	 e
er	 targeted	
expectedly	 faile
ained	in	73	%	y
ce	 via	 hydroly
diate	13,	which
m	β‐oxoacid	de
ridazinone	deriv
en	confirmed	by
wo	sp3	carbon	a
us	1H	NMR	spec
yl	methyl	proton
2	 and	 multiplet
MR	 spectrum	 sh
m,	 pyridazine‐C
nal	at	δ	35.4	pp
4.8	and	196.0	pp
In	an	attempt	t
yridazine	 der
enylhydrazone	
ylamide	 16	 in
eridine	 (Schem
cussion,	this	rea
nsti‐tution	 of	 th
owing	3J‐cross	c
at	 δ	 5.18	 ppm
ide	carbonyl	at
sumably	forme
ing	 17,	 which	
mination.		

7	(1)	(2016)	73‐

e	carbon	atoms	an
on	with	 the	differe

to	 prepare	
compound	 8a

yridazine	deriva
Compound	11
g	 the	 disappea
the	 1H	NMR	sp
ethyl,	 a	 singlet	
let	at	δ	5.36	pp
owed	two	meth
red	 signal	 at	 δ
161.3	 and	 19

acetyl	carbonyl
extend	 this	 me
analogue	 12	
ed.	 Instead,	 te
yield.	The	form
sis	 of	 the	 enam
h	undergoes	a	
rivative	14,	wh
vative	15	(Sche
y	spectral	data	
atoms	in	additi
ctrum	exhibited
ns,	a	multiplet	
t	 at	 δ	 4.71	 ppm
howed	 the	 acet
CH2	 signal	 at	
m,	amide	and	a
pm,	respectivel
to	affect	a	one	p
rivatives,	 we	
1a	 with	 N‐

n	 dioxane	 at	
me	 4).	 Simil
action	adopts	P
he	 product	 19
coupling	betwee
m	with	 acetyl	 c
t	δ	165.4	ppm	(
ed	as	a	result	of
then	 cyclized	

80	

	

nd	 the	correlation	
ent	 carbon	 atoms	

4‐deazatoxofla
a	 in	 acetic	 a
ative	11	was	ob
1	was	 character
arance	 of	 NH	 an
ectrum	showed
at	 δ	 2.42	 ppm

pm	for	pyridazi
hyl	signals	at	δ
δ	34.0	ppm	 for	
96.1	 ppm	 wer
.	
ethodology	 to	
using	 formi

etrahydropyrid
mation	of	15	pre
mine	 group	 giv
hydrolytic	anili
hich	then	loses	C
eme	3).	The	ide
which	indicate
on	to	the	acety
d	a	singlet	at	δ	2
at	δ	3.05	ppm	
m	 for	 pyridazin
tyl	 methyl	 sign
δ	 35.0	 ppm,	
acetyl	carbonyls
ly.	
pot	synthesis	of
treated	 pyr

carbamoyl‐2‐cy
reflux	 in	 the

lar	 to	 the	 a
Pathway	C	(Sche
9	 can	 be	 asses
en	pyrimido[4,5
carbonyl	 at	 δ	 1
(Figure	3).	Com
f	Michael	addit
to	 18	 followed

is	 represented	by
are	 enclosed	 in	 a

vin	 analogues
anhydride,	 the
btained	in	good
rized	 spectros‐
nd	NH2	 signals
d	a	 singlet	at	 δ
m	 for	 the	 acyl
ine‐H5.	The	13C
δ	24.4	and	25.0
pyridazine‐C5.
re	 assigned	 to

synthesize	 the
ic	 acid	 have
dazine	 15	 was
esumably	takes
ving	 the	 inter‐
ide	cleavage	to
CO2	to	form	the
entity	of	15	has
ed	the	presence
l	methyl	group.
2.5	ppm	for	the
for	pyridazine‐
ne‐H5.	 The	 13C
nal	 at	 δ	 =	 24.8
pyridazine‐CH
s	appeared	at	δ

f	pyrimido[4,5‐
ruvaldehyde‐1‐
yano‐3‐phenyl‐
e	 presence	 of
aforementioned
eme	1)	and	the
ssed	 by	 HMBC
5‐c]pyridazine‐
196.6	 ppm	 and
mpound	19	was
ion	of	1a	to	16
d	 by	 ammonia

y	
a	

s	
e	
d	
‐
s	
δ	
l	
C	
0	
.	
o	

e	
e	
s	
s	
‐
o	
e	
s	
e	
.	
e	
‐
C	
8	
H	
δ		

‐
‐
‐
f	
d	
e	
C	
‐
d	
s	
6	
a	



	

	
Figure	3.	The	
parentheses.	 Th
square.	The	cha

	
	
Compoun

different	 sp
molecular	 io
indicated	the
stretch	 of	 th
band	at		=	
the	two	amid
signal	at	δ	2
ppm	for	pyri
the	aromatic
deduced	stru
a	pyridazine
157.91	 and	
196.57	ppm.

	
4.	Conclusio

	
Azaenam

candidates	
arylacrylami
yielding	 dif
carboxamide
compounds	
procedure	 i
analogue)	 1
compound	 in
reaction	 o
phenylacryla
	
Acknowledg
	

Ismail	 A
Abdelmoniem
fellowships	b
	
References	
	
[1]. Zeid,	 I.	

Chem.	20

HMBC	spectrum	o
he	 correlation	 cro
aracteristic	cross	p

nd	 19	 was	 als
pectral	 tools:	
on	 peak	 at	 m/
e	presence	of	b
he	 two	 NH	 fun
1681	cm‐1	and	
de	groups.	The
.36	ppm	for	th
idazine‐H4	and
c	and	 two	NH	 p
ucture	involved
e‐CH	signal	at	δ
165.36	 ppm	 a
	

on	

mines	 were	 pro
in	 Michael	
ide	 derivatives
fferent	 N‐Sub
e	 derivatives.	 T
could	 be	 tran
into	 pyrimido
15.	 The	 forma
n	 a	 single	 step
f	 azaenamine
amide	under	th

gements	

Abdelshafy	 A
m	 gratefully
by	the	Alexande

F.;	 Said,	 M.	 M.;	
014,	145,	639‐650

Abdelmoniem	

of	 compound	19;	 t
oss	 peaks	 between
peak	is	enclosed	in	

so	 fully	 charac
the	 mass	 sp
/z	 =	 360	 [M+

road	band	at		
nctional	 group
a	broad	band	
	1H	NMR	spect
e	acetyl	proton
d	a	multiplet	at	
protons.	The	 13
d	acyl	methyl	si
	33.34	ppm,	tw
and	 the	 acetyl	

oven	 to	 be	 sui
addition	 to	
s	 2a‐c	 in	 a	 re
bstituted	 2,5‐d
The	 newly	 syn
nsformed	 by	 a
[4,5‐c]pyridazin
ation	 of	 pyrim
p	 was	 successfu
e	 with	 N‐ca
e	same	conditio

bdelhamid	 an
y	 acknowle
er	von	Humbold

Darwish,	 S.	 A.;	 S
0.	

et	al.	/	European

the	number	refers
n	 the	methyl	proto
a	circle	for	clarity.

cterized	 throug
pectrum	 show
].	 The	 IR	 spe
=	3424	cm‐1	fo

ps,	 acetyl	 absor
at		=	1619	cm
trum	demonstra
ns,	a	singlet	at	δ
δ	7.11‐7.53	pp

3C	NMR	 fits	wit
ignal	at	δ	25.08
wo	amide	signal
carbonyl	 signa

itable	 C‐nucleo
various	 α‐cya
gioselective	 m
dihydropyridaz
nthesized	 pyrid
a	 simple	 acety
ne	 (deazatoxo
mido[4,5‐c]pyrid
ully	 achieved	 b
arbamoyl‐2‐cya
ons.	

nd	 Amr	 Moh
dge	 postdo
dt	foundation	(A

Soliman,	 F.	 M.	 M

n	Journal	of	Chem
 

s	 to	protons, the	 le
ons,	 pyridazine‐H5
.

gh	 the	
wed	 a	
ctrum	
or	N‐H	
rption	
m‐1	 for	
ated	a	
δ	5.18	
pm	for	
th	 the	
8	ppm,	
ls	at	δ	
al	 at	 δ	

ophilic	
ano‐N‐
manner	
ine‐4‐
dazine	
ylation	
oflavin	
dazine	
by	 the	
ano‐3‐

hamed	
octoral	
AvH).	

Monatsh.	

[2].

[3].

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[5].

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