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European	Journal	of	Chemistry	8	(2)	(2017)	179‐182	

	

European	Journal	of	Chemistry	
ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2017	Atlanta	Publishing	House	LLC	‐	All	rights	reserved	‐	Printed	in	the	USA	

http://dx.doi.org/10.5155/eurjchem.8.2.179-182.1567 

	
	

	

	

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

	 	 	

Solvent‐free	protocol	for	the	green	synthesis	of	benzamide	analogs	of	
dibenzoazepine	

Maria	Aqeel	Khan,	Farhana	Batool,	Asma	Khatoon,	Rabia	Sadiq,	
Sher	Rahman	and	Fatima	Zehra	Basha	*	

Hussain	Ebrahim	Jamal	Research	Institute	of	Chemistry,	International	Center	for	Chemical	and	Biological	Sciences,	University	of	Karachi,	Karachi‐75270,	Pakistan	

*	Corresponding	author	at:	Hussain	Ebrahim	Jamal	Research	Institute	of	Chemistry,	International	Center	for	Chemical	and	Biological	Sciences,	University	of	
Karachi,	Karachi‐75270,	Pakistan.		
Tel.:	+92.21.99261767.	Fax:	+92.21.4819018.	E‐mail	address:	bashafz@gmail.com	(F.	Z.	Basha).	

	
	

	 	

	 	 	

ARTICLE	INFORMATION	 	 ABSTRACT	

	
DOI: 10.5155/eurjchem.8.2.179-182.1567	

Received:	16	March	2017	
Received	in	revised	form:	14	April	2017	
Accepted:	19	April	2017	
Published	online:	30	June	2017	
Printed:	30	June	2017

 

	 Dibenzoazepine	 represents	 an	 important	 class	 of	 heterocycles,	 exhibiting	 potent
antidepressant	 and	anticonvulsant	 activities.	Beside,	various	modifications	on	 this	nucleus,
amide	 analogs	 at	 N‐5	 position	 showed	 potent	 antidepressant	 activities.	 A	 previously
reported	method	 for	 the	 synthesis	of	benzamide	analogs	 of	 dibenzoazepine	use	hazardous
and	toxic	solvents.	Herein,	we	report	a	new,	efficient	and	solvent‐free	green	method	for	the
synthesis	of	dibenzoazepine	benzamides	(6‐21).	

KEYWORDS	
Amidation	
Benzamides	
Solvent‐free	
Dibenzoazepine	
Benzoyl	chlorides	
Green	methodology	

Cite	this:	Eur.	J.	Chem.	2017,	8(2),	179‐182	

	
1.	Introduction	
	

Dibenzoazepine	 (1)	 (Figure	 1)	 represents	 an	 important	
class	of	nitrogen	containing	benzo	fused	heterocycles	that	are	
particularly	 known	 for	 antidepressant	 and	 anticonvulsant	
therapies	 [1‐3].	 Carbamazpeine	 (2)	 (Figure	 1),	 commonly	
marketed	under	the	trade	name	of	Tegretol®,	is	urea	analog	of	
compound	1	 and	used	 for	 the	 treatment	of	neuropathic	pain,	
seizures,	and	trigeminal	neuralgia	[4,5].	Modification	of	double	
bond	at	C‐10,	 and	C‐11	position	 to	ketone	moiety	 resulted	 in	
oxcarbazepine	 (3)	 (Figure	 1),	 which	 is	 not	 only	 effective	
against	epilepsy,	but	also	used	for	the	treatment	of	Parkinson’s	
disease,	 and	 AIDS‐related	 CNS	 disorders	 [6].	 In	 addition,	 a	
number	of	other	biological	activities	were	also	reported	in	the	
literature	 for	 dibenzazepine	 analogs,	 including	 antileishma‐
nial,	 antioxidant,	 anti‐inflammatory,	 antihistaminic,	 antialler‐
gic,	fungicidal,	cardioselective	anti‐muscarinic,	and	anti‐tumor	
activities,	as	well	as	acts	as	NMDA	channel	blockers,	dopamine	
agonists,	 topoisomerase,	 and	 dihydrofolate	 reductase	 inhi‐
bitors	[7‐13].		

Various	modifications	have	been	done	on	dibenzoazepine	
nucleus,	 but	 urea	 formation	 at	 N‐5	 of	 compound	 1	 showed	
promising	CNS‐related	 activities,	 such	 as	 for	major	marketed	

drugs	2	 and	3	 [4‐6].	 Moreover,	 in	 2009	 Balaure	 et	 al.	 docu‐
mented	 heterocyclic	 analogs	 of	 dibenzoazepine	 urea	 4‐5	
(Figure	1),	which	were	found	to	be	potent	psycologically	active	
compounds	[14].	

	

	
	

Figure	1.	Dibenzoazepine	1	and	its	biologically	potent	analogs	2‐5.	
	
	Previously	 Martinez	 group	 reported	 a	 library	 of	

benzamide	 analogs	 of	 dibenzazepine	 [15],	which	were	 found	
to	exhibit	antidepressant	as	well	as	tranquilizer	activity.		



180	 Khan	et	al.	/	European	Journal	of	Chemistry	8	(2)	(2017)	179‐182	
	

	

	
Martinez	et	al.	Method	[15]	:	NaH,	C6H6,	reflux,	4.25	h,	34‐39%	

Our	Method	:	NEt3,	120	°C,	0.3	h,	40‐98%	
	
	 Compound	 R	 Compound R 	
	 6	 H	 14	 3"‐OMe	 	
	 7	 2"‐F	 15	 4"‐OMe	 	
	 8	 4"‐F	 16	 3"‐NO2	 	
	 9	 2"‐Cl 17 4"‐NO2 	
	 10	 4"‐Cl 18 2",6"‐di‐F 	
	 11	 2"‐Br 19 3"‐NO2‐4"‐Cl 	
	 12	 4"‐Br 20 3"‐NO2‐4"‐Me 	
	 13	 4"‐Me 21 3",4",5"‐tri‐OMe	 	
	

Scheme	1	

	

These	 compounds	 were	 synthesized	 by	 sodium	 hydride	
catalyzed	amidation	of	compound	1	with	different	substituted	
benzoyl	 chlorides	 using	 benzene	 as	 a	 solvent	 (Scheme	 1).	
Disadvantages,	 such	 as	 low	 yields	 and	 tedious	 chemical	
synthesis,	decrease	utility	of	this	method.		

Most	of	organic	reactions	are	carried	out	in	solutions	using	
toxic,	 flammable,	 and	hazardous	 solvents.	 Solvent‐free	proto‐
col	 is	considered	as	one	of	 the	eco‐friendly	alternates	 to	rep‐
lace	hazardous	solvents.	This	method	prompted	us	to	explore	
new	 green	 methodology	 for	 the	 synthesis	 of	 previously	
reported	 antiepileptic	 dibenzoazepine	 benzamides	 under	
solvent‐free	conditions.	
	
2.	Experimental	
	
2.1.	Instrumentation	
	

Dibenzoazepine	 and	 all	 other	 starting	 materials	 were	
purchased	from	Sigma‐Aldrich,	and	used	without	purification.	
The	 progress	 of	 reactions	 was	monitored	 by	 using	 silica	 gel	
pre‐coated	aluminum	TLC	plates	(Kieselgel	60,	254,	E.	Merck,	
Germany).	 The	 chromatograms	 were	 visualized	 under	 ultra‐
violet	 light	 (254	 nm)	 and	 vanillin	 dips.	 The	 silica	 gel	 60,	 E.	
Merck	was	used	for	column	chromatography.	1H	NMR	spectra	
were	obtained	on	Bruker	500	and	600	MHz	spectrometers.	EI‐
MS	was	obtained	on	JEOL	MS	Route	600	H	spectrometer.	HR‐
EIMS	 was	 recorded	 on	 Thermo	 Finnigan	 MAT	 95XP	 instru‐
ment.	

	
2.2.	Synthesis	

	
2.2.1.	Diisopropylethyl	amine	(DIPEA)	catalyzed	amide	
synthesis	of	(5'H‐dibenzo[b,f]azepin‐5'‐yl)(4"‐nitrophenyl)	
methanone	(17)	
	

To	a	solution	of	dibenzoazepine	(1.0	mmol)	 in	tetrahydro	
furan	 (THF),	 p‐nitrobenzoyl	 chloride	 (1.4	 mmol)	 was	 added	
followed	by	slow	addition	of	DIPEA	(1.4	mmol)	at	0	 °C.	After	
that,	 the	 reaction	mixture	was	 refluxed	 for	 4	 h,	 diluted	with	
distilled	 water	 and	 extracted	 with	 ethyl	 acetate	 (2×20	 mL).	
The	 combined	 organic	 layers	 were	 dried	 over	 MgSO4	
(anhydrous),	 filtered,	 concentrated,	 and	 purified	 by	 column	
chromatography	 (10‐20%	 ethyl	 acetate	 in	 hexanes	 as	 an	
eluent)	to	afford	compound	17	in	80%	yield	(Table	1).	

	

2.2.2.	 Triethylamine	 (NEt3)	 catalyzed	 amide	 synthesis	 of	
(5'H‐dibenzo[b,f]azepin‐5'‐yl)(4"‐nitrophenyl)methanone	
(17)	
	

To	 a	 solution	 of	 dibenzoazepine	 (1.0	 mmol)	 in	 dichloro	
methane	 (DCM),	 p‐nitrobenzoyl	 chloride	 (3.4	 mmol)	 was	
added.	At	0	°C,	NEt3	(1.2	mmol)	was	added	dropwise,	and	the	
reaction	 mixture	 was	 allowed	 to	 stir	 for	 1.8	 h	 at	 room	
temperature.	 Upon	 completion,	 the	 reaction	 mixture	 was	
diluted	with	distilled	water,	 and	 extracted	with	 ethyl	 acetate	
(2×20	 mL).	 The	 combined	 organic	 layers	 were	 dried	
(anhydrous	MgSO4),	 filtered,	 and	 evaporated	 to	 dryness.	 The	
crude	 mixture	 was	 purified	 by	 silica	 gel	 column	 chromato‐
graphy	 using	 10‐20%	 ethyl	 acetate	 in	 hexanes	 to	 get	 pure	
benzamide	17	in	93%	yield	(Table	1).	

	
2.2.3.	Sodium	bicarbonate	(NaHCO3)	catalyzed	solvent‐free	
synthesis	of	(5'H‐dibenzo[b,f]azepin‐5'‐yl)(4"‐nitrophenyl)	
methanone	(17)	
	

Round	 bottomed	 flask	 was	 charged	 with	 dibenzoazepine	
(1.0	mmol)	and	NaHCO3	(2.0	mmol),	followed	by	the	addition	
of	 p‐nitrobenzoyl	 chloride	 (1.5	 mmol)	 at	 0	 °C.	 The	 reaction	
mixture	 was	 then	 heated	 at	 140	 °C	 for	 30	min.	 After	 comp‐
letion	 of	 reaction,	 it	 is	 cooled	 to	 room	 temperature,	 diluted	
with	 distilled	 water,	 and	 extracted	 with	 ethyl	 acetate	 (2×20	
mL).	 The	 combined	 organic	 layers	 were	 dried	 over	 MgSO4	
(anhydrous),	 filtered,	 concentrated,	 and	 purified	 by	 column	
chromatography	 (10‐20%	 ethyl	 acetate	 in	 hexanes	 as	 an	
eluent)	to	obtain	compound	17	in	60%	yield	(Table	1).	

	
2.2.4.	NEt3	catalyzed	solvent‐free	synthesis	of	
dibenzoazepine	benzamides	(6‐21)	
	

To	a	suspension	of	dibenzoazepine	(1	mmol)	 in	NEt3	(1.5	
mmol),	substituted	benzoyl	chloride	(1.5	mmol)	was	added	at	
0	 °C,	 and	 heated	 neat	 at	 120	 °C	 for	 20	 min.	 Upon	 complete	
consumption	 of	 starting	 material,	 the	 reaction	 mixture	 was	
cooled	to	room	temperature,	diluted	with	distilled	water,	and	
extracted	 with	 ethyl	 acetate	 (2×20	 mL).	 The	 organic	 layers	
were	 then	 washed	 with	 saturated	 solution	 of	 NaHCO3.	 The	
combined	 organic	 layers	 were	 dried	 (anhydrous	 MgSO4),	
filtered,	 and	 evaporated	 to	 dryness.	 The	 crude	 mixture	 was	
purified	 by	 silica	 gel	 column	 chromatography	 using	 10‐20%	
ethyl	acetate	in	hexanes	to	afford	dibenzoazepine	benzamides	
in	40‐98%	yields	(Scheme	1).	



Khan	et	al.	/	European	Journal	of	Chemistry	8	(2)	(2017)	179‐182	 181	
 

	
Table	1.	Optimization	of	(5'H‐dibenzo[b,f]azepin‐5'‐yl)(4"‐nitrophenyl)methanone	(17).	
Entry	 Base	 Equivalence	of	1:	benzoyl	chloride:	base	 Solvent	 Temp	(°C)	 Time	(h)	 Yield	(%)	
1	 DIPEA	 1:1.4:1.4	 THF 50 4.0	 80	
2	 NEt3	 1:3.4:1.2	 DCM 25 1.8	 93	
3	 NaHCO3	 1:1.5:2	 ‐ 140 0.5	 60	
4	 NEt3	 1:1:1.5	 ‐ 25 24.0	 Traces
5	 NEt3	 1:1:1.5	 ‐	 50	 24.0	 54	
6	 NEt3	 1:1:1.5	 ‐	 100	 2.0	 76	
7	 NEt3	 1:1:1.5	 ‐ 120 0.3	 82	
8	 NEt3	 1:1.5:1.5	 ‐	 120	 0.3	 98	
	
	

(5'H‐Dibenzo[b,	 f]azepin‐5'‐yl)(phenyl)methanone	 (6):	
Color:	Off	white.	Yield:	90%.	FT‐IR	 (KBr,	ν,	 cm‐1):	3024,	1657	
(C=O)	(amide),	1562	(C=C),	1491,	1445	(C=C),	1344	(C‐N).	1H	
NMR	(500	MHz,	DMSO‐d6,	δ,	ppm):	7.70‐7.30	(m,	8H,	H‐1',	H‐
2',	H‐3',	H‐4',	H‐6',	H‐7',	H‐8',	H‐9'),	7.25	(app	t,	1H,	J4",(3",5")	=	7.5	
Hz,	H‐4"),	7.20‐7.18	(m,	4H,	H‐3",	H‐5",	H‐10',	H‐11'),	7.14	(d,	
2H,	 J2",3"/6",5"	=	8.5	Hz,	H‐2",	H‐6").	MS	(EI,	m/z	(%)):	297	(M+,	
46).	 HRMS	 (EI,	 m/z)	 calcd.	 for	 C21H15ON,	 297.1154;	 found	
297.1159.	

(5'H‐Dibenzo[b,	 f]azepin‐5'‐yl)(2"‐fluorophenyl)methanone	
(7):	Color:	Light	yellow.	Yield:	90%.	FT‐IR	(KBr,	ν,	cm‐1):	2926,	
2856,	1666	(C=O)	(amide),	1616	(C=C),	1491	(C=C),	1352	(C‐
N).	1H	NMR	(500	MHz,	DMSO‐d6,	δ,	ppm):	7.62	(d,	1H,	J4',3'	=	8.0	
Hz,	H‐4'),	7.55‐7.52	(m,	2H,	H‐1',	H‐9'),	7.59‐7.45	(t,	1H,	J	3',(2',4')	
=	7.5	Hz,	H‐3'),	7.38	 (d,	1H,	 J6',7'	=	7.0	Hz,	H‐6'),	7.28‐7.23	(m,	
2H,	H‐4",	H‐6"),	7.20‐7.01	 (m,	7H,	H‐3",	H‐5",	H‐2',	H‐7',	H‐8',	
H‐10',	H‐11').	MS	(EI,	m/z	(%)):	315	(M+,	27).	HRMS	(EI,	m/z)	
calcd.	for	C21H14FON,	315.1059;	found	315.1061.	

(5'H‐Dibenzo[b,	 f]azepin‐5'‐yl)(4"‐fluorophenyl)methanone	
(8):	Color:	White.	Yield:	71%.	FT‐IR	(KBr,	ν,	cm‐1):	3063,	1657	
(C=O)	(amide),	1601	(C=C),	1497	(C=C),	1342	(C‐N),	1229.	1H	
NMR	(600	MHz,	DMSO‐d6,	δ,	ppm):	7.48‐7.17	(m,	12H,	H‐2",	H‐
6",	 H‐1',	 H‐2',	 H‐3',	 H‐4',	 H‐6',	 H‐7',	 H‐8',	 H‐9',	 H‐10',	 H‐11'),	
7.04	 (t,	 2H,	 J	 3",(2",F)/5",(6",F)	 =	 8.8	 Hz,	 H‐3",	 H‐5").	 MS	 (EI,	m/z	
(%)):	 315	 (M+,	 99).	 HRMS	 (EI,	 m/z)	 calcd.	 for	 C21H14FON,	
315.1059;	found	315.1056.	

(2"‐Chlorophenyl)(5'H‐dibenzo[b,	 f]azepin‐5'‐yl)methanone	
(9):	 Color:	 Off	 white.	 Yield:	 81%.	 FT‐IR	 (KBr,	 ν,	 cm‐1):3022,	
1659	(C=O)	(amide),	1595	 (C=C),	1489	(C=C),	1344	(C‐N).	 1H	
NMR	(500	MHz,	DMSO‐d6,	δ,	ppm):	7.59‐7.54	(m,	3H,	H‐4',	H‐
3",	H‐4"),	7.43	(t,	1H,	J	5'',(4'',6'')	=	8.0	Hz,	H‐5"),	7.38‐7.31	(m,	3H,	
H‐1',	H‐9',	H‐6"),	7.36‐7.09	(m,	7H,	H‐2',	H‐3',	H‐6',	H‐7',	H‐8',	
H‐10',	H‐11').	MS	(EI,	m/z	(%)):	331	(M+,	42).	HRMS	(EI,	m/z)	
calcd.	for	C21H14ClON,	331.0764;	found	331.0773.	

(4"‐Chlorophenyl)(5'H‐dibenzo[b,	 f]azepin‐5'‐yl)methanone	
(10):	 Color:	 Off	white.	 Yield:	 73%.	 FT‐IR	 (KBr,	 ν,	 cm‐1):3434,	
1670	(C=O)	(amide),	1624	 (C=C),	1466	(C=C),	1354	(C‐N).	 1H	
NMR	(500	MHz,	DMSO‐d6,	δ,	ppm):	7.70‐7.30	(m,	8H,	H‐1',	H‐
2',	H‐3',	H‐4',	H‐6',	H‐7',	H‐8',	H‐9'),	7.29	(d,	2H,	J2'',3''/6'',5''	=	8.5	
Hz,	H‐2",	H‐6"),	7.17	(s,	2H,	H‐10',	H‐11'),	7.15	(d,	2H,	J3'',2''/5'',6''	
=	8.5	Hz,	H‐3",	H‐5").	MS	(EI,	m/z	(%)):	331	(M+,	22).	HRMS	(EI,	
m/z)	calcd.	for	C21H14ClON,	331.0764;	found	331.0772.	

(2"‐Bromophenyl)(5'H‐dibenzo[b,	 f]azepin‐5'‐yl)methanone	
(11):	 Color:	 Brown.	 Yield:	 72%.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 3059,	
3022,	1657	(C=O)	(amide),	1591	(C=C),	1489	(C=C),	1344	(C‐
N).	1H	NMR	(500	MHz,	DMSO‐d6,	δ,	ppm):	7.57‐7.43	(m,	6H,	H‐
1',	H‐4',	H‐9',	H‐4",	H‐5",	H‐6"),	7.39	(d,	1H,	J3'',2''	=	6.5	Hz,	H‐3"),	
7.29	(d,	1H,	J6',5'	=	7.5	Hz,	H‐6'),	7.20‐7.10	(m,	6H,	H‐2',	H‐3',	H‐
7',	H‐8',	H‐10',	H‐11').	MS	(EI,	m/z	 (%)):	377	(M++2,	41),	375	
(M+,	 41).	 HRMS	 (EI,	 m/z)	 calcd.	 for	 C21H14BrON,	 375.0259;	
found	375.0267.	

(4"‐Bromophenyl)(5'H‐dibenzo[b,	 f]azepin‐5'‐yl)methanone	
(12):	 Color:	 Light	 yellow.	 Yield:	 80%.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	
3059,	 3020,	 1659	 (C=O)	 (amide),	 1591	 (C=C),	 1489	 (C=C),	
1344	 (C‐N).	 1H	NMR	 (500	MHz,	DMSO‐d6,	 δ,	 ppm):	 7.77‐7.17	
(m,	12H,	H‐1',	H‐2',	H‐3',	H‐4',	H‐6',	H‐7',	H‐8',	H‐9',	H‐10',	H‐
11',	H‐2",	H‐6"),	7.08	(d,	2H,	J3'',2''/5'',6''	=	8.0	Hz,	H‐3",	H‐5").	MS	
(EI,	m/z	 (%)):	377	 (M++2,	53),	 375	 (M+,	56).	HRMS	 (EI,	m/z)	
calcd.	for	C21H14BrON,	375.0259;	found	375.0263.	

(5'H‐Dibenzo[b,	 f]azepin‐5'‐yl)(p‐tolyl)methanone	(13):	
Color:	 White.	 Yield:	 78%.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 1657	 (C=O)	
(amide),	 1611	 (C=C),	 1491	 (C=C),	 1340	 (C‐N).	 1H	 NMR	 (500	
MHz,	DMSO‐d6,	δ,	ppm):	7.46‐7.20	(m,	8H,	H‐1',	H‐2',	H‐3',	H‐4',	
H‐6',	 H‐7',	 H‐8',	 H‐9'),	 7.17	 (s,	 2H,	 H‐10',	 H‐11'),	 7.03	 (d,	 2H,	
J3'',2''/5'',6''	=	8.1	Hz,	H‐3",	H‐5"),	6.99	(d,	2H,	J2'',3''/6'',5''	=	8.0	Hz,	H‐
2",	 H‐6"),	 2.19	 (s,	 3H,	 CH3).	MS	 (EI,	m/z	 (%)):	 311	 (M+,	 40).	
HRMS	 (EI,	 m/z)	 calcd.	 for	 C22H17ON,	 311.1310;	 found	
311.1320.	

(5'H‐Dibenzo[b,	 f]azepin‐5'‐yl)(3"‐methoxyphenyl)methano	
ne	 (14):	 Color:	White.	 Yield:	 82%.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 1655	
(C=O)	(amide),	1578	(C=C),	1491	(C=C),	1340	(C‐N),	1254	(C‐
O).	1H	NMR	(600	MHz,	DMSO‐d6,	δ,	ppm):	7.70‐7.20	(m,	8H,	H‐
1',	H‐2',	H‐3',	H‐4',	H‐6',	H‐7',	H‐8',	H‐9'),	7.18	(s,	2H,	H‐10',	H‐
11'),	7.10	(t,	1H,	J5'',(4'',6'')	=	7.9	Hz,	H‐5"),	6.80	(dd,	1H,	J4'',3''	=	8.3	
Hz,	J4'',5''	=	2.5	Hz,	H‐4"),	6.72	(d,	1H,	J4'',3''	=	7.7	Hz,	H‐6"),	6.67	
(s,	 1H,	H‐2"),	 3.60	 (s,	 3H,	OCH3).	MS	 (EI,	m/z	 (%)):	 327	 (M+,	
52).	 HRMS	 (EI,	 m/z)	 calcd.	 for	 C22H17O2N,	 327.1259;	 found	
327.1257.	

(5'H‐Dibenzo[b,	 f]azepin‐5'‐yl)(4"‐methoxyphenyl)methano	
ne	 (15):	 Color:	White.	 Yield:	 79%.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 1651	
(C=O)	(amide),	1605	(C=C),	1499	(C=C),	1339	(C‐N),	1252	(C‐
O).	1H	NMR	(600	MHz,	DMSO‐d6,	δ,	ppm):	7.48‐7.20	(m,	8H,	H‐
1',	H‐2',	H‐3',	H‐4',	H‐6',	H‐7',	H‐8',	H‐9'),	7.17	(s,	2H,	H‐10',	H‐
11'),	 7.09	 (d,	 2H,	 J3'',2''/5'',6''	 =	 8.7	 Hz,	 H‐3",	 H‐5"),	 6.73	 (d,	 2H,	
J2'',3''/6'',5''	=	8.7	Hz,	H‐2",	H‐6"),	3.68	(s,	3H,	OCH3).	MS	(EI,	m/z	
(%)):	 327	 (M+,	 25).	 HRMS	 (EI,	 m/z)	 calcd.	 for	 C22H17O2N,	
327.1259;	found	327.1255.		

(5'H‐Dibenzo[b,	 f]azepin‐5'‐yl)(3"‐nitrophenyl)methanone	
(16):	 Color:	 White.	 Yield:	 80%.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 1663	
(C=O)	 (amide),	 1601	 (C=C),	 1522	 (N‐O)	 (nitro),	 1491	 (C=C),	
1342	 (C‐N).	 1H	NMR	 (500	MHz,	DMSO‐d6,	 δ,	 ppm):	 8.13‐8.11	
(m,	1H,	H‐4'),	8.01	(s,	1H,	H‐2"),	7.78‐7.10	(m,	12H,	H‐1',	H‐2',	
H‐3',	H‐6',	H‐7',	H‐8',	H‐9',	H‐10',	H‐11',	H‐4",	H‐5",	H‐6").	MS	
(EI,	 m/z	 (%)):	 342	 (M+,	 95).	 HRMS	 (EI,	 m/z)	 calcd.	 for	
C21H14O3N2,	342.1004;	found	342.1000.		

(5'H‐Dibenzo[b,	 f]azepin‐5'‐yl)(4"‐nitrophenyl)methanone	
(17):	 Color:	 Yellow.	 Yield:	 98%.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 1661	
(C=O)	 (amide),	 1601	 (C=C),	 1520	 (N‐O)	 (nitro),	 1491	 (C=C),	
1340	(C‐N).	1H	NMR	(500	MHz,	DMSO‐d6,	δ,	ppm):	8.08	(d,	2H,	
J3'',2''/5'',6''	=	8.7	Hz,	H‐3",	H‐5"),	7.71	(d,	1H,	J4',5'	=	8.0	Hz,	H‐4'),	
7.55	(d,	2H,	J1',2'/9',8'	=	5.0	Hz,	H‐1',	H‐9'),	7.42	(m,	4H,	H‐3',	H‐7',	
H‐2",	H‐6"),	7.67	(m,	5H,	H‐2',	H‐6',	H‐8',	H‐10',	H‐11').	MS	(EI,	
m/z	(%)):	342	(M+,	42).	HRMS	(EI,	m/z)	calcd.	for	C21H14O3N2,	
342.1004;	found	342.1001.		

(5'H‐Dibenzo[b,	 f]azepin‐5'‐yl)(2",6"‐difluorophenyl)metha	
none	(18):	Color:	White.	Yield:	96%.	FT‐IR	(KBr,	ν,	cm‐1):	3024,	
2878,	 1672	 (C=O)	 (amide),	 1624	 (C=C),	 1593,	 1491	 (C=C),	
1466,	1356	(C‐N).	1H	NMR	(500	MHz,	DMSO‐d6,	δ,	ppm):	7.57‐
7.52	(m,	3H,	H‐1',	H‐4',	H‐9'),	7.44	(td,	1H,	J3',(2',4')	=	9.0	Hz,	J3',1'	=	
2.0	Hz,	H‐3'),	7.42	(d,	1H,	J7',6'	=	8.0	Hz,	H‐7'),	7.37‐7.31	(m,	1H,	
H‐6"),	7.26‐7.21	(m,	3H,	H‐2',	H‐10',	H‐11'),	7.15‐7.06	(m,	3H,	
H‐6',	H‐3",	H‐5"),	6.83	(t,	1H,	J8',(7',9')	=	8.5	Hz,	H‐8').	MS	(EI,	m/z	
(%)):	 333	 (M+,	 24).	 HRMS	 (EI,	 m/z)	 calcd.	 for	 C21H13F2ON,	
333.0965;	found	333.0978.		

(4"‐Chloro‐3"‐nitrophenyl)(5'H‐dibenzo[b,	 f]azepin‐5'‐yl)	
methanone	 (19):	 Color:	 Off	 white.	 Yield:	 91%.	 FT‐IR	 (KBr,	 ν,	
cm‐1):	 3026,	 2928,	 2856,	 1662	 (C=O)	 (amide),	 1603	 (C=C),	
1535	(N‐O)	(nitro),	1491	(C=C),	1348	(C‐N).		

	



182	 Khan	et	al.	/	European	Journal	of	Chemistry	8	(2)	(2017)	179‐182	
	

	
Table	2.	Synthesis	of	benzamide	analogs	of	dibenzoazepine	(6‐21).	
Entry	 Compound	 R	 Yield	(%) Entry Compound R Yield	(%)
1	 6	 H	 90	 9 14 3"‐OMe 82	
2	 7	 2"‐F	 72	 10	 15	 4"‐OMe	 79	
3	 8	 4"‐F	 71	 11	 16	 3"‐NO2	 80	
4	 9	 2"‐Cl	 81	 12	 17	 4"‐NO2	 98	
5	 10	 4"‐Cl	 73	 13 18 2",6"‐di‐F 96	
6	 11	 2"‐Br	 72	 14 19 3"‐NO2‐4"‐Cl 91	
7	 12	 4"‐Br	 80	 15 20 3"‐NO2‐4"‐Me 75	
8	 13	 4"‐Me	 78	 16 21 3",4",5"‐tri‐OMe	 40	
	

1H	NMR	(500	MHz,	DMSO‐d6,	 δ,	ppm):	7.89	 (d,	1H,	 J2'',6''	 =	
1.5	Hz,	H‐2"),	7.69	(d,	1H,	J4',5'	=	9.0	Hz,	H‐4'),	7.64	(d,	1H,	J6'',5''	=	
1.5	Hz,	H‐6"),	7.78‐7.39	(m,	4H,	H‐1',	H‐3',	H‐7',	H‐9'),	7.33‐7.29	
(m,	3H,	H‐2',	H‐8',	H‐5"),	7.25‐7.12	(m,	3H,	H‐6',	H‐10',	H‐11').	
MS	 (EI,	 m/z	 (%)):	 376	 (M+,	 10).	 HRMS	 (EI,	 m/z)	 calcd.	 for	
C21H13ClO3N2,	376.0615;	found	376.0624.	

5'H‐Dibenzo[b,	f]azepin‐5'‐yl)(4"‐methyl‐3"‐nitrophenyl)met	
hanone	 (20):	 Color:	 White.	 Yield:	 75%.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	
1657	 (C=O)	 (amide),	 1622	 (C=C),	 1528	 (N‐O)	 (nitro),	 1493	
(C=C),	1344	(C‐N).	1H	NMR	(500	MHz,	DMSO‐d6,	δ,	ppm):	7.78	
(s,	1H,	H‐2"),	7.68‐7.20	(m,	12H,	H‐1',	H‐2',	H‐3',	H‐4',	H‐6',	H‐
7',	H‐8',	H‐9',	H‐10',	H‐11',	H‐5",	H‐6"),	2.42	(s,	3H,	CH3).	MS	(EI,	
m/z	(%)):	356	(M+,	38).	HRMS	(EI,	m/z)	calcd.	for	C22H16O3N2,	
356.1161;	found	356.1146.	

(5'H‐Dibenzo[b,	 f]azepin‐5'‐yl)(3",4",5"‐trimethoxyphenyl)	
methanone	(21):	Color:	Light	yellow.	Yield:	40%.	FT‐IR	(KBr,	ν,	
cm‐1):	 2926,	 2855,	 1657	 (C=O)	 (amide),	 1580	 (C=C),	 1458	
(C=C),	1348	(C‐N),	1238	(C‐O),	1126	(C‐O).	1H	NMR	(500	MHz,	
DMSO‐d6,	δ,	ppm):	7.50‐7.33	(m,	8H,	H‐1',	H‐2',	H‐3',	H‐4',	H‐6',	
H‐7',	H‐8',	H‐9'),	7.21	(s,	2H,	H‐2",	H‐6"),	6.42	(s,	2H,	H‐10',	H‐
11'),	3.57	(s,	6H,	2×OCH3),	3.56	(s,	3H,	OCH3).	MS	(EI,	m/z	(%)):	
387	(M+,	60).	HRMS	(EI,	m/z)	calcd.	 for	C24H21O4N,	387.1471;	
found	387.1456.	
	
3.	Results	and	discussion		

	
Dibenzoazepine	amides	(6‐21)	were	synthesized	in	single	

step	 from	 benzoylation	 of	 dibenzoazepine,	 as	 shown	 in	
Scheme	1.	Previously	dibenzoazepine	amides	(6‐21)	were	pre‐
pared	by	Martinez	et	al.	 [15]	using	sodium	hydride	as	a	base	
and	carcinogenic	benzene	as	 a	 solvent.	Hazardous	 conditions	
used	 in	 this	method	drew	our	attention	to	explore	other	eco‐
friendly	reaction	conditions.	

At	 first,	 optimization	 of	 the	 reaction	 was	 done	 using	 p‐
nitrobenzoyl	 chloride	 with	 different	 combination	 of	 solvents	
and	bases	(Table	1).	Results	revealed	that	refluxing	DIPEA	as	a	
base	in	THF	for	4	h	gave	benzamide	17	in	80%	yield.	However,	
switching	 DIPEA	 to	 NEt3	 in	 DCM	 increased	 yield	 up	 to	 93%.	
Although	 excellent	 yield	was	 obtained,	 this	method	 required	
excess	 benzoyl	 chloride	 for	 the	 complete	 consumption	 of	
starting	 material	 and	 used	 hazardous	 DCM	 as	 the	 solvent.	
Therefore,	in	order	to	switch	our	finding	into	“green	process”	
we	explored	different	solvent‐free	conditions	for	the	synthesis	
of	compound	17.	NaHCO3	and	NEt3	were	screened	as	base	for	
this	 reaction,	 and	best	 results	were	obtained	using	NEt3	 as	 a	
base.	 To	 investigate	 optimum	 temperature,	 benzoylation	was	
carried	out	at	25,	50,	100	and	120	°C.	Results	revealed	that	at	
room	 temperature	 there	 was	 negligible	 consumption	 of	
starting	material;	however,	increasing	temperature	up	to	50	°C	
gave	 appreciable	 amount	 of	 product	 (54%).	 The	 impact	 of	
temperature	was	further	studied	by	raising	temperature	up	to	
100	°C	and	120	°C.	Results	showed	that	at	100	°C,	reaction	is	
completed	in	2	h	and	gave	76%	yield,	while	at	120	°C	reaction	
takes	only	20	min	 for	 completion	and	gave	82%	yield.	These	
results	 showed	 that	 raising	 temperature	 not	 only	 gave	
excellent	 yield,	 but	 also	 reduced	 reaction	 time;	 which	
suggested	 that	 high	 temperature	 is	 important	 to	 accelerate	
benzoylation	reaction.	Further	screening	was	done	to	explore	
optimal	 equivalence	 of	 p‐nitrobenzoyl	 chloride.	 Accordingly,	
the	 ideal	 conditions	 were	 achieved	 by	 using	 p‐nitrobenzoyl	

chloride	 up	 to	 1.5	 equivalence	 using	 NEt3	 as	 base.	 As	 this	
reaction	 procedure	 takes	 only	 a	 couple	 of	 minutes	 for	
complete	consumption	of	starting	material	and	did	not	require	
any	 hazardous	 solvent,	 this	 protocol	 is	 an	 efficient	 and	
environmentally	friendly	method.	

With	these	optimized	conditions,	the	scope	of	reaction	was	
investigated	 by	 treating	 compound	 1	 with	 different	 substi‐
tuted	 benzoyl	 chlorides.	 A	 variety	 of	 benzamide	 analogs	 of	
dibenzoazepine	 (6‐21)	 were	 smoothly	 prepared	 in	 40‐98%	
yield	 (Table	 2).	 Dibenzoazepine	 benzamides	 (17‐19)	 with	
electron	 withdrawing	 group	 give	 excellent	 yields.	 However,	
compound	 21	 with	 three	 electron	 donating	methoxy	 groups	
gave	 low	 yield	 (40%).	 Comparison	 between	 disubstituted	
compounds	 19	 and	 20	 also	 revealed	 that	 replacing	 the	
electron	withdrawing	chloro	group	with	the	electron	donating	
methyl	group	at	position‐4"	resulted	in	lowering	of	yield	from	
91	to	75%,	keeping	nitro	group	fixed	at	C‐3".	
	
4.	Conclusion	

	
In	summary,	we	have	developed	an	efficient	and	solvent‐

free	 green	 method	 for	 the	 synthesis	 of	 previously	 reported	
antidepressant	 benzamide	 analogs	 of	 dibenzoazepine.	 A	
library	 of	 dibenzazepine	 benzamides	 with	 varying	 substitu‐
tions	 was	 prepared.	 Most	 yields	 were	 excellent	 with	 one	
exception	 for	 highly	 electron	 rich	 compound	 21.	 These	
methodologies	for	amidation	could	be	widely	applicable.	
	
Acknowledgements	
	

The	authors	are	thankful	to	Higher	Education	Commission	
(HEC),	 Pakistan	 and	 H.	 E.	 J.	 Research	 Institute	 of	 Chemistry,	
International	 Centre	 for	 Chemical	 and	 Biological	 Sciences,	
University	 of	 Karachi,	 Karachi‐75270,	 Pakistan	 for	 providing	
financial	support.	
	
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