Indian Journal of Chemistry

Vol. 39B, February 2000, pp. 156- !59

Note

Studies on fused ~-lactams: Synthesis,

stereochemistry and antimicrobial activity of
some new cepham analogues
S D Sharma*, Aarti Saluja & Susmita Bhaduri
Department of Chemistry, Panjab University,
Chandigarh 160 014, India

Received 29 October /998; accepted (revised) 28 July /999

~-Lactam ring has been conveniently grafted onto 2-phenyl5,6-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 th eir an tibacterial activities.

The versatile use of ~-lac tams 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
19
relationship of ~-lactam antibiotics as we11 . The
discovery of non-classical ~-lactam 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
10 11
the search for biologically active cephams . . Much
research works have been done to design a variety of
biologically active analogues of cepham by altering
12 14
its C-7 position . . 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
1
on their elemental analysis and spectral (IR, 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-Nbenzotriazolyl-4-phenyl-1-propyl-2-azetidinone
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
15
desulphurisation is a stereospecific reaction ,
formation of the cis-monocyclic ~-lactam 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 ~-lactam compounds were screened for
their antibacterial activities in vitro against

Staphylococcus aureus, Bacillus subtilis, Escherichia

coli. Pseudomonas aeruginosa, Shigella flexneri 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 PerkinElmer Model 430 spectrometer with sodium chloride
optics using thin liquid film or a mull of compound in
Nujol; 1H 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.

157

NOTES

H Ph

"f)

Ph

+ R'CH2C02H

NEt3, BSC
ooc, CH2Ciz

M<~':j]J
6

2-5

Compd
2
3
4
5

H Ph

"":J=t)

R'

Menthoxy
Butylthio
Chloro
Benwtriawle

H Ph

Cl::tl)
0

Scheme I

H Ph

H Ph

c~J=t)

::tt-~

Raney- Ni
Acetone

10

Raney- Ni
Acetone
9

11
Scheme II

2-Phenyl-5,6-dihydro-4H-1,3-thiazine

1.

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 decanted 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 in
vacuo to afford 1 as an oil, yield 60%; b.p 158-60 I
lO mm; IR 1620 em' (C=N); 1H 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) .

15 8

INDIAN J CH EM, SEC B, FEBRUARY 2000

Menthoxyacetic acid 2. This was prepared using

c hloroacetic acid and me nthol in refluxing tolue ne
according to the method reported in the literature 16,
1
yie ld 70%, IR 1723 em-' (C=O), 1--1 NMR (CDCb): 8
0 .75 (3 H , d , J = 6.3 Hz) , 0 .90 (9 H, overlapped
signals), 1.20 (2H, 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 ( I H, br.s).
17
Butylthioacetic acid 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. The reac tion mixture was
refluxed for 2 hr. After acidification with dilute
sulphuri c acid ; it was ex tracted with ether (3 x 40
mL). The ether 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, I 00 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 reac tion mixture
was stirred for half an hour and the n refluxed on a
water-bath for 2 hr. On acidification with dil. H 2S04 ,
the titl e compound 5 was obtained as white solid
whi 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-thi azine ( 1.77 g,
I 0 mmoles) and tri eth ylamine (2.02 g, 20 mmol es) in
di c hl oro methan e was stirred for half an hour at oac.
To thi s, was added be nzene sulphonyl chloride ( 1.765
g, I 0 mmoles) dropwise . The mi xture was stirred for
3 hr at room temperature and rcflux ed for another 2
hr. The mi xture was washed with water, sodium
bicarbonate and with brin e solution. The organic
laye r 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
obtained as an oil by the above procedure ; yield 65 % ;
1
IR ( 1750 em-'); 1--l NMR (C DCI 3): 8 0.6-2.30 (m,
21 1--1 ; 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, N0 2S : 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; 11--l ]\fMR (CDCI 3): 8
0.87(31--1, t, CI--1 3), 1.20-2.20 (61--1, m, methylenes), 2.603.30 (m, 41--1, SCH 2, NCH 2), 3.8 ( I 1--1, m), 4 .2 ( I 1--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 21NOS 2 : C,
59.44; 1--1, 6 .50; N, 4.33%).
7-Chloro-substituted cepham 8. Yield 70% ; mp
li0C ; JR: 1765 cm-1; 11--1 NMR (CDCh) : 8 1.90 (21--1,
m, CI--12), 2.8 (2H, m, ring 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
1
60% ; mp 175C ; IR: 1770 c m-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 18H 16N 40S: 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
desulphuri sed was take n in acetone, stirred and
heated under reflux for an hour w ith Raney-nickel
catalyst (20 g). The catalyst was filtered and washed
with acetone. Removal of solvent from the filtrate
gave the required compound which was purified by
co lumn chromatography using hexane : ethyl acetate
as an eluent.
4-Phenyl-1-propyl-2-azetidinone 10. It was
obtained from 7-chloro-substituted cepham 8 by
e mploying the above procedure; y ie ld 48%, mp 92C ;
1
IR : 1740 em'; H NMR (CDCI 3): 8 1.0 (3H, t,
CH 2CH3), 1.65 (2H, m, CH rC H 2CH 3), 3. 1 (2H, m, NCH2), 3.65 (I H, dd , J = 2.5, 15.0 Hz, C,-H), 4 .5 (I H,
dd , J = 4.5, 15 .0 Hz, C r 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-propyl-2-azetidinone 11. It was obtained from 7-chl oro-substituted

cepham 9 by employing the above procedure; yield
51 %, mp 155 cc; IR: 1740 em-'; 'H NMR (CDCI 3): 8
1.0 (3H, t, CH 2CH3), 1.7 (2H, m, CH2CH 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).

159

NOTES

Acknowledgement
We thank the CSIR, New Delhi, India for financial
assistance and award of SRF to one of the author
(SB).

8
9
10
II

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