ijcb 39b(2) 156-159
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Indian Journal of Chemistry
Vol. 39B, February 2000, pp. 156- 59
Note
Studies on fused
~ l a c t a m s :
Synthesis,
stereochemistry and antimicrobial activity of
some new cepham analogues
S D Sharma*, Aarti Saluja Susmita Bhaduri
Department of Chemistry, Pan ab University,
Chandigarh 160 014, India
Received 29 October /998; accepted revised) 28 July 999
~ L a c t a m ring has been conveniently grafted onto 2-phenyl-
5,6-dihydro-1 3 -thiazine
1
by annelating it with in situ prepared
ketenes to furnish cepham analogues 6-9. A variety
of
acids such
as mentho xy acetic acid 2, butylthioacetic acid 3, chloroacetic
acid 4 and benzotriazole acetic acid 5 have been used as mixed
sulphonic acid anhydrides for the cycloaddition reaction . All the
compounds have been screened for their an tibacterial activities.
The versatile use
of t a m s in
bacterial
chemotherapy needs no introduction. In recent years ,
considerable interest has been focussed on the
synthesis and modification of penam and cepham
nucleus to obtain compounds with enhanced activity.
These studies might throw light on structure-activity
relationship
of
~ l a c t a m
antibiotics as
we11
1
.
9
The
discovery
of
non-classical
~ l a c t a m
antibiotics has
attracted medicinal chemists to incorporate diverse
side chains in place
of
the amide side chain
of
penicillins and cephalosporins . The discovery
of
cephamycins paved the way for structural variations
in
the cephalosporin series which are produced by
streptomyces. Since then development of
methodology for the introduction
of
different
substituents on the cepham is always found useful in
the search for biologically active
cephams
.
.
Much
research works have been
done
to design a variety
of
biologically active analogues
of
cepham
by altering
its C-7 position .
4
. Inspired by this, we report herein
the synthesis
of
some new C-7 substituted cephams
through cycloaddition
of in
situ prepared ketenes to
2-phenyl-5,6-dihydro-1,3-thiazine.
The imine, 2-phenyl-5,6-dihydro-1 ,3-thiazine
1
was
prepared by the cyclisation
of
N-3-hydroxypropyl
benzamide [prepared by simple benzoylation
of
propanol amine with benzoyl chloride] with
P2S
5
in
60% yield . Appropriate acids such as menthoxy
acetic acid 2, butylthioacetic acid 3, chloroacetic acid
4 and benzotriazole acetic acid 5 were prepared for
generating ketenes.
A mixture
of
imine
1,
triethyl amine and the
appropriate acids (2-5) were taken in
dichloromethane and treated with benzene sulphonyl
chloride at low temperature to afford the desired
lactams 6-9
in 60-70%
yield
(Scheme 1 . The
structural assignments to compounds 6-9 were based
on their elemental analysis and spectral (IR,
1
H
NMR
) data.
Compounds
8
and
9 were subjected to
desulphurisation using Raney-nickel in acetone to
give 4-phenyl-1-propyl-2-azetidinone 10 and 3-N
benzotriazolyl-4-phenyl-1-propyl-2-azeti dinone
11
respectively . It is interesting to note the concomtant
removal of chlorine and sulphur in compound 8
during
this reaction to give
10.
As Raney-nickel
desulphurisation is a stereospecific reaction
5
,
formation
of
the cis-monocyclic
c t a m
11 from 9
clearly established the indicated cis-orientation
of
groups at C-3 and C-4
in 11
and
in
9 as well
(Scheme II).
Antimicorbial
activity
All the
~ l a c t a m
compounds were screened for
their antibacterial activities
in
vitro
against
Staphylococcus aureus, Bacillus subtili
s
Escherichia
coli. Pseudomonas aeruginosa, Shigella fl exneri and
Salmonela microorganisms by tube dilutio11 method.
Compounds
6, 8
and
particularly 9
were
found to
be
active against Staphylococcus aureus, Bacillus
subtilis, Escherichia coli
and
Pseudomonas
aeruginosa, up to
500
lg/mL. concentration.
Experimental
Section
All melting points and boiling points are
uncorrected . IR spectra were recorded on a Perkin
Elmer Model 430 spectrometer with sodium chloride
optics using thin liquid film
or
a mull
of compound
in
Nujol;
1
H NMR spectra on a Varian EM-390, 90
MHz
instrument in CDCI
3
solution with
TMS
as an
internal standard. Thin-layer chromatography was
performed using
TLC
grade silica gel (G) and was
developed
in
an atmosphere
of
iodine vapours.
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NOTES
157
H
Ph
NEt
3,
BSC
M < ~ : j ] J
Ph
f)
+
R CH
2C 02H
ooc, CH2Ciz
6
2-5
Compd
R
2
Menthoxy
3
Butylthio
4
Chloro
5
Benwtriawle
H
Ph
c ~ J = t )
8
Scheme
I
Raney-
Ni
Acetone
H Ph
:J=t)
7
H
Ph
Cl::tl
0 8
H Ph
: : t t ~
1
Raney- Ni
Acetone
9 11
Scheme
II
2-Phenyl-5 6-dihydro-4H-1 3-thiazine
1 A
mixture of N-3-hydroxypropylbenzamide ( 15.0
g,
83.7
mmoles) (prepared by taking equimolecular quantities
of
3-aminopropanol and benzoyl chloride in the
presence
of
triethyl amine in dichloromethane)
phosphorous pentasulphide (55.7 g, 251.1 mmoles)
and benzene (400 mL) was refluxed in a round
bottom flask with
constant
stirring for 3 hr.
The
benzene layer was
decant
ed
off and
the white residue
was treated with saturated solution
of
sodium
hydroxide and extracted with benzene.
The
extract
was washed with brine and the solvent distilled n
v cuo
to afford as an oil, yield
60 ;
b.p 158-60
lO mm; IR 1620 em (C=N);
1
H NMR (CDCb): 8
1.85 (2H, quintet, C
5
-CH
2
,
3.1
and 3.9 (2H each, t
each, ring methylene), 7.4 and 7.8 (3H, 2H, m, Ar-H).
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15 8
IND IAN J CHEM,
SE
B, FEBRUARY 2000
Menthoxyacetic
acid
2. This was prepared using
chloroacetic acid and menthol in refluxing toluene
according to the method reported in
the
literature
16
,
yie ld 70 ,IR 1723 em-'
(C=O),
1
1--1 NMR (CDCb): 8
0 .75 (3H, d ,
J
= 6.3 Hz) , 0.90 (9 H, overlapped
signals) , 1.20 (2 H, m), 1.60 (2H, m), 2.0
I
H, br.d),
2.20
I
H, m), 3.20
I
H, m) , 3.75 (2 H, dd ,
J
= 16 .5
Hz) , 4.15
21--1,
dd ,
J
= 16 .5 Hz), 8.5 IH, br.s).
Butylthioacetic acid
17
3. To a 200 mL aqueous
so lution of sodium hydroxide (4.0 g, I
00
mmoles),
chl oroacetic acid (5.22 g, 55
mmoles)
was added,
followed by dropwi se addition of butyl thiol (4.5 g,
50 mmoles)
while
stirring. Th e reaction mixture was
refluxed for 2 hr. After acidification with dilute
sulphuric acid ; it was ex trac ted with et her (3 x
40
mL). The e
ther
was evaporated in
the
steam-bath.
After
drying, the title
compound
was
obtained
as an
oil; yield 60 .
Chloroacetic
acid
4. Commercially available
ch loroacetic acid was taken and dri ed over cone.
H2S0
4
prior to use.
Benzotriazole acetic acid 5. To
an aqueous
so lution of NaOH (4. 0 g, I00 mmoles), chloroacetic
ac id (4 .75 g,
50
mmoles) was added with stirring
in
a
round
bottom
flask. To it benzotriazole (5.95 g, 50
mmoles) was added at once. The reaction mixture
was stirred for half an
hour
and then refluxed on a
water-bath for 2 hr. On acidification with dil. H2
S0
4 ,
the titl e compound
5
was obtained as white so lid
w
hi
ch was filtered ; yie ld
90
; m.p 208-9C ; IR 1700
- I
em .
General
procedure for
the synthesis of cepham
analogous
6-9. A so lution of appropriate acid ( I0
mmoles) , 2-phenyl-5 ,6-dihydro-1 ,3-thiaz
in
e ( 1.77 g,
I0 mm oles) and triethylamine (2.02 g, 20 mmoles) in
dichl oro methane was stirred for ha lf an hour at oac.
To thi s, was added benze ne sulphonyl
chloride
( 1.765
g, I0 mmoles) dropwise. The mi xture was stirred for
3 hr
at
room t
empe
rature and rcfluxed for another 2
hr. The
mi
xture was washed with water,
sodium
bicarbonate and with brine solution.
The
organic
layer was se parated and dried with
anhydrous
sodium
sulphate. Removal
of
the solvent afforded the title
cepham compound, which was purified by column
chromatography.
7-Menthoxy-substituted cepham 6.
It
was
ob tained as an oil by the above proce dure ; yield 65 ;
IR ( 1750
em
-');
1
1--l NMR (C DCI
3
): 8
0.6-2.30
(m,
21
;
19H menthoxy group, 21--1 ring methylenes), 3.90
31--1,
s merged
in
m, ring methyl ene and C7-H), 7.2-
7.82 (5H, m, Ar-H) (Found: C, 72. 34; H, 6.27; N,
3.80.
Calcd
for C22H2,N 0
2
S : C, 72 .33; 1--1 , 6 .30; N,
3.84 ).
7-Butylthio-substituted cepham 7. It was obtained
as an oil; yield
60
;
IR:
1760cm-1; 1
1--l
]\fMR (CDCI
3
):
8
0.87 31--1, t,
CI--1
3
,
1.20-2.20
61--1,
m, methylenes), 2.60-
3.30 (m, 41--1, SCH
2
, NCH
2
), 3.8 I 1--1 m), 4 .2 ( I --1 m),
4.5 I H, s, C7-H), 7.2-8.1 (m, 51--1, Ar-H) (Found: C,
59.38; 1--1 6.48; N, 4 .35. Calcd for
C
,H
21
NOS
2
:
C,
59.44;
1--1
, 6 .50; N, 4.33 ).
7-Chloro-s
ubstituted
cepham
8.
Yield 70 ; mp
l i0 C ; JR: 1765
cm
-
1
;
1
1--1
NMR (C DCh) : 8 1.90
21--1,
m, CI--12), 2.8 (2H, m, rin g
methylene)
, 3. 1 and 4 .3 ( I H
each, m), 5.2 I
1--1
, s, C7-H), 7.5 (5H, m, Ar-1--1)
(Found: C,
56.78;
1--1 4 .70 ; N, 5.48. Calcd for
C,2H12NSOCI: C, 56.80; 1--1 , 4 .73 ; N, 5 .52 ).
7-Benzotriazole-substituted cepham
9.
Yield
60 ; mp 175C ; IR: 1770 cm-
1
;
1
1--1
NMR (CDCh): 8
2.0 21--1, m, CH
2
), 2.8 21--1, m ring
methylene)
, 3.4
and
4.45
(lH
each, m) , 6.4 ( IH , s, C7 -H), 7 .05-7.80 (9H,
m, Ar-H) (Found:
C,
64 .30; H,
4.76; N,
16.67.
Calcd
for C
18
H
16
N
4
0S: C, 64 .28; H, 4.76; N 16 .67 ).
General procedure for the
desulphurisation
of 8
and 9.
A solution of compound (3 .0 mmoles) to be
des ulphuri
se
d was taken in acetone, stirred and
heated under reflux for an hour with Raney-nickel
ca talyst (20 g). The
catalyst
was filtered and washed
with acetone. Removal of so lvent from the filtrate
gave the required compound
which
was purified by
co
lumn chromatography using h
exa
ne : ethyl acetate
as an eluent.
4-Phenyl-1-propyl-2-azetidinone
10.
It was
obtained from 7-chloro-substituted
ce
pham 8 by
employing the above proce
dur
e; yie ld 48, mp 92 C ;
IR : 1740 em';
1
H
NMR
(CDCI
3
: 8 1.0 (3H, t,
CH
2
CH
3
,
1.65 (2H, m,
CH
rC
H
2
CH
3
,
3. 1 (2H, m,
N
CH2), 3.65 (I H, dd ,
J
= 2.5, 15.0 Hz, C,-H), 4
.5
(I H,
dd ,
J
= 4.5,
15
.0 Hz, Cr
i--1),
5 .05
(IH,
dd,
J
= 2.5, 4.5
Hz, C
4
-H), 7 .5 (5H, br. s,
Ar-H)
.
3 N Benzotriazolyl-4-phenyl-1-pr
opyl-2-azeti
dinone 11. It was obtained from 7-chloro-substituted
cepham 9 by employing the above procedure; yield
51
, mp 155cc; IR: 1740
em
-';
'H NMR
(CDCI
3
) : 8
1.0 (3H, t, CH 2CH
3
,
1.7 (2H, m, CH
2
CH
3
, 3.05 (3H,
m,
-NCI--1
2
, 5.2 ( I H , d, C
4
_H,
1=4
.5Hz), 6.35 ( I H, d,
CrH, J
= 4.5 Hz) , 6.80-7.85 (9H, m, Ar-H).
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NOTES
159
Acknowledgement
We thank the CSIR, New Delhi, India for financial
assistance and award
of SRF
to one of the author
(SB).
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