!"#$%&'()*+ !-./(+*$* "0 12324&5+.6"/($)%$)6+7$.&8&".

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121&%$"9$%+* :$) ; <-=#$6)/$".>?+#+)*+ !/@)/+A-



A short summer project carried out by
Surendra Karwa
Department of Chemistry, IIT- Kharagpur-721302
Under the supervision of
Prof. Johan Van der Eycken
Department of Organic Chemistry
Lab. For Organic and Bioorganic synthesis
Ghent University











Abstract:

Benzodiazepine/ Benzothiadiazepine based heterocycles can be prepared efficiently on solid-support by
employing different approaches. In this summer project, an effort has been made to highlight academic
and industrial examples of combinatorial synthesis for this type of heterocycles published in the last
decade. 1,2,5-Benzothiadiazepin-4-one-1,1-dioxides were synthesized by a simple procedure utilizing
polymer supported amino acids and sulfonyl chloride as building block.Cyclization of common
aminoamide intermediate with concomitant release from the support(resin-bound substrates) furnished the
desired 1,2,5-Benzothiadiazepin-4-one-1,1-dioxides. The products were recovered in moderate yield and
exhibited excellent purities. Further, the most relevant biological properties of these heterocycles have
also been incorporated.

Introduction:
Benzothiazepines are important nitrogen and sulfur containing seven member heterocyclic compounds.
Which are of great interest in the area of drug discovery and development due to their broad spectrum of
Pharmacological activity. Benzothiazepine and its derivatives show a wide spectrum of Pharmacological
activity such as anticonvulsant, antidepressant, CNS stimulant, anticancer, Anti-HIV, antihypertensive,
antiulcer, Calcium channel blocker and antimicrobial agent.


llg. 1 1emplaLes for Llbrary synLhesls



We purpose Lhe synLhesls rouLe for 1,2,3-8enzoLhladlazepln-4-one-1,1-dloxldes uslng solld supporL. 1he
reLro synLhesls of our LemplaLe ls glven below.








Experimental Details


General Reaction Scheme:


Fig. 1 General Reaction Scheme

Herein we report the synthesis of Benzothioazapines (8 & 9) from commercially available
starting materials as shown in Fig. 1 . We get the library synthesis of Benzothioazapines (8 & 9)
by changing the substituent R1, R2 & R
3
on it .

!&;BCDE ;<CF <EG'HCDI ED J;DI ?K!CD
OH O
O
NHFmoc
R
1
1
2
1. Fmoc-AA-OH, DIC, DMAP,
CH
2
Cl
2
, rt, 16h
2. Ac
2
O/DIPEA/CH
2
Cl
2
1/1/3,
rt, 2 x 2h

OH O
O
NH
2
R
1
O
O
H
N
R
1
S
NO
2
O
O
N
H
N
S
O
O
O
R
1
R
2
O
O
N
R
1
S
NH
2
O
O
R
2
Wang resin
O
O
NHFmoc
R
1
FmocHN
R
1
COOH
DIC, DMAP, CH
2
Cl
2
20%
4-Mepiperidine
in DMF
2x 10 min collidine
CH
2
Cl
2
, 2x 1 h
R
2
OH, DIAD
PPh
3
, DCE
2x 1 h
O
O
N
R
1
S
NO
2
O
O
R
2
CrCl
2
DMF/MeOH 9/1
2x 1 h
SO
2
Cl
NO
2
F
F
N N
N
O O
O
O
O
N
R
1
S
NO
2
O
O
R
2
F
80C, MW
1 h
HN O
1M LiOtBu in THF, 4 h
N
N
S
O
O
O
R
1
R
2
N
O
R
3
(i) K
2
CO
3
, DMF
(ii) R
3
-X, DMF
1
2
3
4
5 6 7
8
9


CLnL8AL 8CCLuu8L :
Preswell: The Wang resin 1 (1.50 g, 1.49 mmol, 1 eq) is preswollen first by suspending it in 20 ml of
CH
2
Cl
2
and by shaking it for 20 min. After filtration, this procedure is repeated for a second time.
Preactivation: To a stirring solution of an N
a
-Fmoc-protected amino acid (2.97 mmol, 2 eq) in 20 ml
CH
2
Cl
2
at 0C is added DIC (2.97 mmol, 2 eq). This reaction mixture is stirred for 20 min at 0C.
Coupling: The preactivated reaction mixture is then added to the preswollen Wang resin together with
DMAP (0.30 mmol, 0.2 eq) and shaken for 16 h at room temperature. The resin was subsequently washed
3 times with DMF, MeOH and CH
2
Cl
2
.
Capping of remaining OH: The resin is suspended in a mixture of Ac
2
O/DIPEA/CH
2
Cl
2
1/1/3 (20 mLl)
and the mixture is shaken for 2h. The resin is filtered and washed with CH
2
Cl
2
, after which it is suspended
in Ac
2
O/DIPEA/CH
2
Cl
2
1/1/3 again and shaken for 2h. The resin is filtered and washed consecutively
with CH
2
Cl
2
, DMF, MeOH and CH
2
Cl
2
. The obtained resin 2 is dried under vacuum.
Determination of loading: The loading of the coupled resin was determined by Fmoc UV-quantification
using 4-methylpiperidine/DMF 1/4 (calibration line: A=8.3585c).

AMINE DEPROTECTION

O
O
NH
2
R
1
3
20% 4-methylpiperidine
in DMF, rT, 2x10 min
O
O
NHFmoc
R
1
2


CLnL8AL 8CCLuu8L

Deprotection: The resin is suspended in a solution of 20 ml 20% 4-methylpiperidine in DMF and shaken
for 10 min. The resin is subsequently washed with DMF, MeOH and CH
2
Cl
2
and this procedure is
repeated for a second time, delivering the resin-bound deprotected a-amino acid 3.

SULFONYL CHLORIDE BUILDING BLOCK COUPLING
O
O
NH
2
R
1
O
O
H
N
R
1
S
NO
2
O O
3 4
sym-collidine,
CH
2
Cl
2,
rt, 2x1 h
F
NO
2
SO
2
Cl F

GENERAL PROCEDURE
The solid supported a-amino acid 7 (0.500 g, 0.37 mmol, 1 eq) is suspended in 10 ml of CH
2
Cl
2
and
shaken in the presence of sulfonyl chloride building block (0.92 mmol, 2.5 eq) and sym-collidine (1,86
mmol, 5 eq). After 1 h shaking at room temperature, the resin is filtered off and washed subsequently with
DMF, MeOH and CH
2
Cl
2
. This reaction is repeated for a second time, delivering the sulfonamide 4.

MITSUNOBU ALKYLATION

O
O
H
N
R
1
S
NO
2
O O
O
O
N
R
1
S
NO
2
O O
R
2
4 5
R
2
-OH, DIAD, PPh
3
,
DCE, rt, 2x1h
F F


GENERAL PROCEDURE
Resin bound compound 4 (0.37 mmol, 1 eq) is suspended in 10 ml of 1,2-dichloroethane, followed by
addition of respectively an alcohol (3.7 mmol, 10 eq), triphenylphosphine (0.488 g, 1.86 mmol, 5 eq) and
DIAD (0.37 ml, 1.86 mmol, 5 eq). After shaking this yellow mixture for 1 h, the resin is filtered off and
washed consecutively 3 times with DMF, MeOH and CH
2
Cl
2
. This procedure is repeated for a second
time, yielding the desired alkylated compound 5.



ON-RESIN NUCLEOPHILIC AROMATIC SUBSTITUTION
O
O
N
S
NO
2
F
R
2
O
O
O
O
N
S
NO
2
N
R
2
O
O
NMP, 80C
MW, 60 min
5 6
O
morpholine
R
1
R
1

To the fluoro containing resin 5 (0.349 mmol, 1 eq), brought in a microwave tube, is added subsequently
5 ml of NMP and morpholine (6.99 mmol, 20 eq). This suspension is heated for 60 min using microwave
heating with constant cooling (Powermax method), then filtered off and washed 3x with DMF, MeOH
and CH
2
Cl
2
. This readily delivers the aminated compounds 6.
NITRO REDUCTION

O
O
N
R
1
S
NO
2
O O
R
2
6
O
O
N
R
1
S
NH
2
O O
R
2
7
Cr(II)Cl
2
, DMF/MeOH 9/1
RT, 2x 1 h
N N
O O

GENERAL PROCEDURE
To the resin bound compound 9 (0.37 mmol, 1 eq) is added 6 ml of a mixture of DMF/MeOH 9/1 and
chromium(II) chloride (2.96 mmol, 8 eq). This green suspension is shaken for 1 h, followed by filtration
and washing 3 times with DMF, MeOH and CH
2
Cl
2
. The reduction and washing procedure is repeated for
a second time, delivering the desired aniline 10.
RING CLOSURE VIA CYCLIZATION/RELEASE
O
O
N
R
1
S
NH
2
O O
R
2
7
N
H
N
S
O
O
O
R
1
R
2
8
1M LiOtBu in THF
RT, 4 h
N
O


GENERAL PROCEDURE
To resin 7 (0.34 mmol, 1 eq) is added 4 ml of a 1M solution of LiOtBu in THF. This suspension is shaken
for 4 h at room temperature, followed by filtrating off the resin and washing with THF. The filtrate is then
evaporated under reduced pressure, redissolved in 12 ml of EtOAc and washed 2 times with a 5% solution
of NaHCO
3
in water and 1 time with 10 ml brine. The organic phase is then dried over MgSO
4
and
evaporated again to yield a brownish oil. This oil is purified using column chromatography or
recrystallization, yielding the desired 1,2,5-benzothiadiazepin-4-one-1,1-dioxides.

ALKYLATION OF N5-POSITION IN SOLUTION

N
N
S
O
O
O
R
1
R
2
9
(i) K
2
CO
3,
DMF
N
O
N
H
N
S
O
O
O
R
1
R
2
8
N
O
R
3
(ii) R
3
-X, DMF


GENERAL PROCEDURE
SubsLance 8 (0.34 mmol, 1eq.) ls dlssolved ln uMl and k
2
CC
3
ls added Lo Lhls soluLlon. now a soluLlon of
8
3
-x (0.34 mmol, 1eq) ln uMl ls added Lo above prepared soluLlon of subsLance 8 . 8eacLlon mlxLure ls
sLlrred for 2 h aL room LemperaLure. uMl ls evaporaLed and compound 9 ls redlssolved ln 8 ml of LLoAC
and washed wlLh a 5% solution of NaHCO
3
in water and 1 time with 10 ml brine. 1he organlc phase ls
Lhen evaporaLed and flnal producL 9 ls column purlfled.
Result:
During my summer internship , I have synthesized library of 12 (twelve) Benzothiadiazepine
compound. List of synthesized compound is given below with yield and crude purity .










NMR spectra :
1.


500 MHz.7108.001.1r.esp
16 14 12 10 8 6 4 2 0 -2 -4
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
N
o
r
m
a
l
i
z
e
d

I
n
t
e
n
s
i
t
y
2.82 1.11 4.20 1.12 4.23 1.04 0.01 1.00 1.07 0.80 5.30 0.66
H2O
CDCl3
7
.
9
0
7
.
3
3
7
.
2
7
7
.
2
6
7
.
0
2
6
.
8
9
6
.
8
7
4
.
6
7
4
.
6
53
.
8
7
3
.
8
6
3
.
8
5
3
.
1
9
3
.
1
8
3
.
1
7
3
.
1
3
3
.
1
1
1
.
5
7
1
.
5
4


2.


300 MHz.7151.001.1r.esp
9 8 7 6 5 4 3 2 1
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
N
o
r
m
a
l
i
z
e
d

I
n
t
e
n
s
i
t
y
2.39 3.98 1.13 1.10 4.10 0.36 1.00 0.00 2.02 1.18 5.32 0.84
CDCL3
8
.
7
8
7
.
3
9
7
.
3
9
7
.
3
6
7
.
3
3
7
.
2
7
7
.
2
5
7
.
0
06
.
9
9
6
.
9
6
4
.
4
7
4
.
4
5
4
.
4
4
4
.
4
2
4
.
1
4
4
.
1
2
3
.
8
83
.
8
6
3
.
8
5
3
.
6
7
3
.
6
5
3
.
3
5
3
.
2
0
3
.
1
8
3
.
1
8
3
.
1
7
3
.
0
7
3
.
0
5
2
.
9
4
2
.
9
1
2
.
8
9
2
.
0
5
1
.
3
7
1
.
3
3
1
.
2
7
1
.
2
4
0
.
8
7
0
.
8
5
0
.
8
2





3.





10 9 8 7 6 5 4 3 2 1 0 -1
Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
I
n
t
e
n
s
i
t
y
8.23 4.15 4.09 1.01 1.00
DMSO-d6
H2O
4.


300 MHz.7125.001.1r.esp
16 14 12 10 8 6 4 2 0 -2 -4
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
N
o
r
m
a
l
i
z
e
d

I
n
t
e
n
s
i
t
y
6.88 4.82 4.41 4.48 1.08 2.26 1.26 1.00
H2O
CDCL3
8
.
4
9
7
.
3
4
7
.
3
3
7
.
2
7
6
.
9
7
6
.
9
4
4
.
6
6
4
.
6
3
4
.
6
1
3
.
8
83
.
8
6
3
.
8
5
3
.
4
9
3
.
1
9
2
.
8
0
1
.
9
0
1
.
8
8
1
.
8
7
1
.
8
5
1
.
0
4
1
.
0
1
0
.
9
9





5.


300 MHz.7161.001.1r.esp
10 9 8 7 6 5 4 3 2
Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
N
o
r
m
a
l
i
z
e
d

I
n
t
e
n
s
i
t
y
3.04 4.08 4.04 2.10 3.08 1.00
DMSO
H2O
1
0
.
3
67
.
2
6
7
.
2
6
7
.
1
3
4
.
1
4
3
.
7
5
3
.
7
3
3
.
7
1
3
.
3
4
3
.
1
3
3
.
1
1
3
.
1
0
2
.
6
9
2
.
5
1
2
.
5
0
2
.
4
9
2
.
4
9


6.

300 MHz.7146.001.1r.esp
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
N
o
r
m
a
l
i
z
e
d

I
n
t
e
n
s
i
t
y
4.43 4.98 5.03 1.24 2.51 1.32 0.00 1.00
H2O
H2O
CDCL3
8
.
7
17
.
3
4
7
.
3
3
7
.
2
7
7
.
0
7
7
.
0
4
7
.
0
2
6
.
9
9
4
.
6
5
4
.
6
44
.
6
3
4
.
6
0
4
.
5
8
3
.
8
8
3
.
8
6
3
.
8
5
3
.
2
0
3
.
1
9
3
.
1
7
2
.
8
1
2
.
0
5
1
.
6
7
1
.
5
8
1
.
5
6




7.




300 MHz.7141.001.1r.esp
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
N
o
r
m
a
l
i
z
e
d

I
n
t
e
n
s
i
t
y
9.30 2.88 4.02 0.63 1.01 3.86 0.48 0.96 1.95 0.77 1.99 1.94 0.93 0.60
H2O
CDCL3
8
.
6
7
8
.
1
5
8
.
1
2
7
.
6
8
7
.
6
0
7
.
3
2
7
.
2
7
7
.
2
5
7
.
2
5
7
.
0
3
6
.
9
6
6
.
9
3
6
.
9
2
4
.
8
5
4
.
8
4
4
.
8
3
4
.
8
3
4
.
8
2
4
.
8
1
4
.
8
0
4
.
1
4
4
.
1
2
4
.
1
0
3
.
8
8
3
.
8
6
3
.
8
4
3
.
7
0
3
.
6
7
3
.
2
5
3
.
2
2
3
.
2
0
3
.
1
9
3
.
1
7
3
.
0
5
2
.
8
2
2
.
7
9
2
.
7
7
2
.
4
1
2
.
1
8
2
.
0
5
1
.
8
8
1
.
7
1
1
.
6
7
1
.
3
9
1
.
2
9
1
.
2
7

8.



300 MHz.7163.001.1r.esp
10 9 8 7 6 5 4 3 2 1
Chemical Shift (ppm)
0
0.05
0.10
0.15
N
o
r
m
a
l
i
z
e
d

I
n
t
e
n
s
i
t
y
9.33 3.09 1.07 3.71 1.03 3.70 0.91 6.76 0.90
DMSO H2O
1
0
.
1
6
7
.
1
5
7
.
1
2
7
.
1
1
7
.
0
9
7
.
0
6
6
.
9
4
6
.
7
7
6
.
7
5
4
.
4
5
4
.
4
4
4
.
4
2
4
.
4
0
3
.
6
2
3
.
6
0
3
.
5
9
3
.
2
3
3
.
2
0
2
.
9
92
.
9
7
2
.
9
6
2
.
8
5
2
.
8
2
2
.
5
0
2
.
3
9
2
.
3
8
2
.
3
7
1
.
9
7
1
.
8
7
1
.
2
5
1
.
1
5
1
.
0
6


9.


300 MHz.7165.001.1r.esp
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0
Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
N
o
r
m
a
l
i
z
e
d

I
n
t
e
n
s
i
t
y
3.00 3.99 1.06 1.03 4.01 0.91 1.00 4.19 0.10 2.03 0.05 1.04 0.86 0.84
H2O
CDCL3
8
.
6
6
8
.
1
7
7
.
6
7
7
.
6
5
7
.
3
5
7
.
3
2
7
.
3
1
7
.
2
7
7
.
1
0
6
.
9
8
6
.
9
6
6
.
9
3
4
.
7
9
4
.
7
7
4
.
7
7
4
.
7
5
4
.
1
7
4
.
1
5
4
.
1
2
4
.
1
0
3
.
8
7
3
.
8
5
3
.
8
4
3
.
7
3
3
.
7
1
3
.
3
2
3
.
3
0
3
.
1
8
3
.
1
7
3
.
1
5
2
.
7
8
2
.
3
2
2
.
0
6
1
.
7
2
1
.
2
9
1
.
2
7
1
.
2
5



Conclusions:
! Cyclization/release strategy is successfully developed.
! Model library is synthesized.
! Synthesized high purity of crude cyclization products
! large diversity possible: a- and !-amino acids
! N4-alkyl derivatives: steric effects are important for amide formation: practically limited
to cis- and trans-aminocyclohexanecarboxylic acids
! Application to further libraries is under investigation
Acknowledgments:
I am thankful to Ghent University and Prof. Johan Van der Eycken group for providing
financial support during my summer internship.
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