Indian Journal of Chemistry

Vol. 428, July 2003 , pp. 1701 - 1705

Preparation of 4-(l-alkyl-benzo[d]imidazole-2-yl)-2-phenyl-2,3-
dihydrobenzo(b)[ 1,4]thiazepines
P K Dubey*, A Naidu , C Ravi Kumar & P V V Prasada Reddy
Dept. of Chemistry, College of Engg. J NT University , Kukatpally , Hyderabad, (AP) - 500 072, India.
Received 19 Novembe r 2001; accepted (revised) 6 January 2003

The syntheses of 4-( I-alkyl-benzo [d] imidazole-2-y l)-2- pheny l-2,3-dihydrobenzo (b)[ I,4Jthi azepi nes 6 in vo lving the
conde nsati on of 2-aminothi opheno l with benzimidazole chalcone 1 using aceti c acid as catalyst in refluxing methanol is re-
ported. Compound 6 is dehydrogenated using suitable reagents to yie ld 4.-(l-alkyl-benzo[d]imidazole-2-y l)-2-
phenylbenzo(b)[1 AJthiazepines 4. The structures of 4 are supported by spec tral and analytica l data.

Benzimidazoles are an important group of heterocycl ic
compounds, several derivatives of which have been
found to possess diverse types of biological activities ' .
The syntheses of 1,5-benzothi azepine deri vati ves 2 such
as diltiazem and thiazesim has attained much signifi -
cance in recent years due to the wide range of pharma-
cological properti es like cardiovascular, psychophar-
macological, sedative and tranquilizing effects associ-
ated with these type of compounds. In continuation of
our earlier work 3 on sy ntheses of new benzimidazoles,
we wish to report our studies on preparation of the title
benzimidazolylbenzothiazepins.
Results and Discussion
Condensation of 4-methoxycinnamoylbenzimida-
zole4.5 la [ i. e., 1, R'= OMe (p)] with 2-amino-
thiophenol usi ng acetic acid as catalyst in refluxing
methanol for 3 hr, followed by processing gave a
clean crystalline product m.p. 130 a C, which has been
characterized as 4-(1H-benzo[d]irnidazole-2-yl)-2-
phenyl-2,3-dihydrobenzo(b)[J,4] thiazepine 2al (i .e.
2, R '=OMe). Its IR (KBr) showed a strong broad band
at == 2950 cm,l ass ignable to imidazo le -NH- stretch -
ing. Its IH NMR (CDC b/TMS) spectrum showed sig-
nals at 8 2.94 (t, IH , -S-CH- ), 3.82 (s, 3 H, -OCH 3 ),
3.96(dd, IH), 5.19(dd , 1H) [due to -CH2 group of
-CH2-C(Hr)=N-], 6.8-7 .9 (Co mplex m, 12H, aromati c
protons), 10.5 (br, s, 1H, -NH-). Its electron impact
mass spectrum showed peaks at mlz (%1): 385
(4,M +), 252 ( 19), 25 1 (63), 134 (99), 119 (13) ,
91(13 ).
The above reaction was found to be a general one
and proceeded smoothly with other substituted 1 g iv-
ing various dih ydrobenzothi azepins 2 (Table I ).
Treatment of 2a. (i.e., 2, R1=OMe) with dimethyl
sulfate gave a product, whi ch was characterized as
4-( 1- methy l-benzo[ d] imidazole-2-y 1)-2-pheny 1-2,3-di-
hydrobenzo(b )[ 1,4 ]thiazepine 6b. (i.e.,6, R=Me,
R1=OMe). Its IR (KBr) spectrum showed the absence
of stron g broadband at == 2950 cm' l assigned earlier to
imidazo le -NH- stretching. Its 'HNMR (CDC bITMS)
spectrum showed signals at 8 2.95 (t, IH, -S-CH-Ar),
3.8 (s, 3H, -OCH 3), 4.2(s, 3H , -NCH 3 ), 4. 1 (dd, IH)
and 5.19 (dd , IH) [due to -CH 2 group of - CHr
C(Hr)=N-], 6.8-7 .9 (co mpl ex m, 12H , aro matic pro-
tons). Its mass spectrum showed peaks at mlz ( %1) :
40 1 (0.5, M+2), 400 (2, M+ I ), 399 (4, M+), 366 (3),
279 (2) 267 (12), 266 (35), 265 (100), 264 (37), 134
(64),131 (13 ), 119 (7), 91 (6).
This reaction of 2a was extended to other alkylat-
ing agents to obtain various substituted 6. The struc-
ture of 6 was assigned on the basis of analytical and
spectral data (Table II).
Treatment of I-methyl-p-methox ycinn amoylbenzi -
midazole 5b. [i.e. , 5, R=Me, R 1=OMe (p)] with 2-
aminothiophenol gave a product, which was found to
be identical in mp, mmp, and co-TLC with 6b. (i.e. , 6,
R=Me, R'=OM e) obtained above. This reacti on has
been found to be general one and has been exte nded
to 5b, 5c and 5d also (Table II).
Treatment of 6b. with chloranil 6 in refluxing chl o-
roform for 2 hr, or with Cu(OAc)/ in acetic ac id at
RT for 1 hr, respectively gave a dehydrogenated
product i.e., 4-(l-methyl-benzo[d]imidazole-2-yl)-2-
phenylbenzo(b)[l,4]thiazepine 4b. (i.e., 4, R=Me,
R I=OMe). Its IR (KBr) spectrum showed the absence
of strong broadband at == 3000 cm,l assigned earli er to
imidazole -NH- stretching. Its 'H NMR (CDCl 3ITMS )
1702 INDIAN 1. CHEM., SEC S , 1UL Y 2003

Table I - Characterization data for compounds 2

SI Starting mate- Reagent used Product Yield m.p. IHNMR

No. ri al obtained (%) (0C) (8, ppm)

I. la( 2- 2a l 65 110 Data given in tex t

aminothiophenol (R'=OMe)
2. la2 -do- 2a2 64 140 2.95 (t, IH , -S-CH-), 4.0 (dd, IH) & 5.2 (dd, IH , -CHz-),
(R' =H) 7.15-7.8 (complex m, 13H, Ar-H ) 10.4 (broad singlet,
IH, -NH-)
3. 1a3 -do- 2a3 69 108 2.90(t, IH, -S-CH-), 4.1 (dd, IH) & S.18 (dd, IH, -CH z-),
(R'=CI) 7 .15-8.1 (complex m, 12H, Ar-H) 10.37 (broad singlet,
IH, -NH-)

4. la~ -do- 2a4 67 112-1 5 2.91(t, IH , -S-CH-), 4.1 (dd, IH) & 5. 19 (dd, IH, -CHz- ),
(R'= NOJ 7.15-8.12 (complex m, 12H, Ar-H) 10.32 (broad singlet,
IH, -NH-)

Table II - Characterization data for compounds 6

SI Starting Reagent used Product obtained Yie ld m.p. IHNMR

No. material (%) (0C) (8, ppm)

I. 2a( OMS 6b( 65 110 Data given in text

Sb( 2-aminothiophenol (R=Me,R' =OMe)
2. 2a2 OMS 6b 2 67 132 2.85 (t, I H, -S-CH-), 4.05 (dd, I H) & 5.2 (dd, I H.
Sbl 2-aminothiophenol (R=M e, R'=H ) -CHz-C- (Hr)=N-), 4 .25 (s, 3H, -N-CH ), 7.05-8.2
(complex m, 13H, Ar-H)
3. 2a3 OMS 6b 3 66 108 2.80 (t, I H, -S-CH- ), 4.02 (dd, I H) & 5.2 (dd, I H,
Sb) 2-aminothiophenol (R=M e, R ' =CI) -CHz-C(Hr)=N-) , 4.20 (s, 3H, -N-CH}), 7.05-8.0
(complex m, 12H, Ar-H)
4. 2a( DES 6c( 69 130- 1.2 (t, 3H, -NCHz-CH}), 2.8S (t, I H, -CH-S-), 3.7
Sc( 2-ami nothiophenol (R=Et,R '=OMe) 32 (q, 2H, -NCH z-), 3.72 (s, 3H , -OCH}), 4.0 (dd, IH )
& 5.IS (dd, IH, -CHz-C(Hr)=N-), 7.1-7.65 (com-
plex m, 12H, ArH)
5. 2az DES 6cz 67 135- 1.2 (t, 3H, -NCHz-CH), 2.87 (t, IH , -CH-S-), 3.7
SCz 2-aminothiophenol (R=EtR'=H) 40 (q, 2H, -NCH z-), 4.0(dd, IH) 5.25 (dd, IH, -CHz-
C(Hr)=N-, 7.1 -7.85 (complex m, 13H, ArH)
6. 2a( ,PhCHzCI 6d( 62 120- 2.9 (t, IH , -CH -S-), 3.75 (s, 3H, -OCH), 4.1
Sd( 2-aminothiophenol (R=CHzPh,R ' =Ome) 23 (dd, I H) & 5. 15(dd, I H, due to -C Hr group of-
CH2-C(Hr)=N-), 6.1 (dd, 2H, -CH 2-Ph), 6.75-7.95
(complex m, 17H, ArH)
7. 2a( PhCH 2C1 6d z 66 140- 2.9(t, IH,-CH-S-), 4.2(dd,IH) &5.21 (dd, IH ,
Sd z 2-aminothiophenol (R= CHzPh,R' =H) 42 due to -CHz-group of -CH2-C(Hr)=N-), 6.0 (dd,
2H, -CHz- Ph ), 6.72-8.08 (comp lex Ill , 18H, ArH)

spectrum showed signals at 8 3.85 (t, 3H,-OCH 3) 4.22
(t, 3H, -NCH 3) , 7.2-8 . 15 (Complex m, 12 H, aromatic
protons), and 7.9 (s, IH, -C-CH=C-) .
The above reaction involving dehydrogenation of
6b 1 to 4b. using chloranil and Cu(OAch has been
extended to other 6 and the dehydrogenated products
obtained have all been assigned the structure 4 by
analogy and on the basis of ana lytical and spectral
data (Table III) .
Treatment of 2a. with chloranil 6 in refluxing chlo-
roform for 2 hr, or with Cu(OAc)/ in acetic acid at
RT for 1.5 hr, respectively yielded the dehydroge-
nated analogue i.e., 4-(lH-benzo[d]irn idazole-2-yl)-2-
phenylbenzo(b)[I,4]thiazepine 3a. (i.e. , 3a,
R l=OMe). Its IR (KBr) spectrum ~. howed a strong
broad band at == 2926 em'l assignab le to imjdazole
-NH- stretching. Its lHNMR (CDCbffMS) spectrum
showed signals at 8 3.85 (t, 3H, -OCH 3), 7.2-8.15
(Complex m, 12H, aromatic protons), 7.9 (s, IH, -C-
CH=C-), 8.55 (s, IH, -NH).
This reaction of 2a was extended to other
substituted dihydrothiazepins 2 and the products
 DUBEY et al.: SYNTHESIS OF BENZIMIDAZOLYLBENZOTHIAZEPINES 1703

Table III - Characterization data for compounds 4

SI Starting Reagent used Product obtained Yield m.p. IHNMR

No. material (%) (0C) (8, ppm)

I. 6b 1 Cu(OAc)2/Chloranil 4b 1 45 245 Data given in text

3al DMS (R=Me, R' =OMe) 51
2. 6b 2 -do- 4b 2 52 220 4.25 (s, 3H, -NCH 3), 6.99-8.8 (compl ex
3a2 (R=Me, R '=H) 55 m, 14H, one vinylic proton and 13 Ar-H)
3. 6bJ -do- 4b 3 46 228 4.22 (s, 3H , -NCH 3), 6.7-8.6 (complex m,
3a3 (R=Me,R'=CI) 48 13H, one vinylic proton and 12 Ar-H)
4. 6d 1 Cu(OAch/Chloranil 4d 1 51 250 3.82 (s, 3H, -OCH3 ), 6.98-8.7 (co mpl ex
331 PhCH 2Cl (R=CH 2Ph,R'= OMe) m, 20H, one vinylic, two benzylic protons
and 17 Ar-H)

CC~
R 0 H

CC
N
Alkylation IPTC

H
• 1# j
R' I'l R'
(1) (5 )

HSX)
H2N #

~
R R'
N H H

CC~#
N N
rH H

S
R'
Alkylation IPTC
• I CC >"'-/
#
N N
7
S
~
H
h

o
"'-/
(2)
0 (6 )

Cu(OAch Cu(OAch
or or
Chloranil Chloranil

~
H ~
R' R R'
H

CC >7
H N

CC >"'-/ h
N
~ h ~ ~
I # 7
~ Alkylation IPTC I #
N N S • N N S
"'-/
0 (3 )
0 (4 )

Scheme I
1704 INDI AN J. C HEM., SEC B, J ULY 2003

Table IV - C haracte ri zat ion data fo r compou nds 3

SI Starting mate- Reage nt used Prod uct ob- Yi eld m.p. ' H NMR
No. ri al tai ned (%) (0C) (0, ppm )

I. 2a1 CU(OAC)2 3al 55 190 Data g iven in tex t

C hloranil (R' =OMe) 51
2. 2a2 -do- 3a2 53 2 10 7.2-8. 15 (complex Ill, 13H, Ar- H), 7.9 (s, IH ,-C-
(R' =H ) 50 C H=C-) , 8.55 (s, I H, -NH-).
3. 2a3 -do- 3a3 48 208 7 .1 -8.25 (co mpl ex m, 12 H, Ar-H), 7.87(s, I H,-C-
(R'=C I) 43 C H=C-), 8.52 (s, IH , -NH -).

~ :O~
H H H H OH

Hr~~r CI ~CI Hr0 Ar + CI ~CI

N S + I I - - - - -•• N S
"-- / CI CI ',- / CI VCI
~ :0: ~ :0:
( 2 or 6 ) Chlora nil

H OH H H
~0 +
H r~ Ar
N
"-- /
S + CI~CI _- - - -
Hrn
N S
Ar
+
CI ¢
I
CI

CI V CI "-- / CI /5: CI

~ OH ~ OH

( 3 or 4 )
Scheme II

obtained have all been ass ig ned th e structure 3a by
analogy and on the bas is of analyti ca l and spectral
data (Table I V).
Treatment of 3 with dimethyl sul fa te/PhCH 2CI in
acetonitri le in the presence of K ZC0 3 and T EBAC
gave the products, whi ch were identi ca l in mp, mmp ,
and co-TLC with 4, obtained from earli er route 1-5-6-
4 (Table III).
All the above reacti ons were summarized in
Scheme I. The mec hani sm of fo rmatio n of 3 or 4
fro m 2 or 6 is g iven in Scheme II
Experimental Section
Spec troscopic data were recorded with J ASC O
FT-IR 5300, VA RIAN 200 (' H NMR , 200MH z),
Hew lett Pac kard (EI-MS 70 eV) in struments. Melt-
in g po ints were determined in open ca pill ary tubes
in sulfuri c acid bath and are un co rrected. TLC
analyses were do ne o n glass pl ates coated with sil-
ica gel-G an d spottin g was do ne us in g iodin e or UV
Li g ht.
Prepa raltion of 2a/6 from 1/5 (General proce-
dure). A mi xture of benzimidazolearylvin ylketone
(1/5) (1 0 mmole) and 2-aminothiopheno l (15 mmole)
in methano l (30 mL) containing gl. acetic acid (2 mL)
was reflu xed fo r 3 hr. On coolin g, a solid produ ct
separated o ut, which was crude 2. T his was filtered,
washed with methanol, dried and recrystalli zed to ob-
tai n pure 2/6 (Table I ).
 DUBEY et af.: SYNTHESIS OF BENZIMIDAZOL YLBENZOTHlAZEPINES
Preparation of 6/4from 2/3 (General procedure).
To a solution of TEBAC (0.2gms) in CH 3CN (20 rnL)
was added K2C0 3 (1.4 gms, 10 mmole) and the mix-
ture stirred at RT. To this mixture, under stirring, was
added a solution of 2/3 (10 mmole) in CH 3CN 00
rnL) followed by the alkylating agent 02 mmole). On
completion of the reaction (3 hr) as shown by TLC
the mixture was filtered and insoluble material was
washed with CH 3CN (2x 5 mL), dried and dissolved in
water. This solution was neutralized with acetic acid,
the product obtained was filtered, washed with water
(2x20 rnL) and dried to obtain first crop of the prod-
uct 6/4. The CH 3CN filtrate was evaporated to dry-
ness. The residue was treated with chloroform,
washed with water (3 x50 rnL) and the chloroform
layer evaporated to dryness to obtain a second resi-
due. The latter on trituration with hexane (2xlO rnL)
gave second crop of 6/4 as insoluble colorless crystal-
line solid (Table II).
Preparation of 4/3 from 6/2 (General procedure)
a) Using chloranil. A mixture of 6/200 mmole) and
chloranil (2.46 g, 10 mmole) in chloroform (40 rnL)
was refluxed for 1 hr. At the end of this period, the
reaction mixture was cooled to RT. The insoluble por-
tion (which is 2,3,5,6-tetrachloro-l A-dihydroquinone)
was filtered, the chloroform solution washed with
10% NaOH (50 rnL). The organic layer separated was
washed with water (2x20 rnL) free of alkali, dried
over anhyd. Na2S04 and the solvent (1 ,2-dichloro-
ethane) was distilled off to obtain residue, which was
crude 4/3. A portion of this solid was recrystallized
from chloroform-hexane to obtain the pure product.
b) Using Cu(OAch (General procedure). A mix-
ture of 6/2 (10 mmole) and cupric acetate (12 mM) in
1705
acetic acid 20 rnL was stirred at RT for 1.5 hr. The
progress of the reaction was monitored on TLC for
the disappearance of 6/2. At the end of this period, the
reaction mixture poured into ice-cold water, the sepa-
rated solid was filtered , washed with water, dried and
recrystallised from chloroform-hexane to obtain pure
4/3 (Table III).
Acknowledgement
The authors were highly indebted to University
Grants Commission, Govt. of India, New Delhi for
financial support of the work done.
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