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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).

References

1

Tschaen D M, Fuentes L M, Lynch J E, Laswell W L,

Volante R P Shinkai I , Tetrahedron Lett 28, 1988, 2779.

2 Ganboa I Palomo C, Synthesi

s

1986, 52 .

3

Balsamo A, Macchia B, Rossello A Scatena P, 1 Org

Chem 5l 1986 540

4

Guest A W, Milner P H Southgate R, Tetrahedron

Le11.

30 1989, 5791.

5

Bycroft B W, Shute R E Begley M J, 1 Chern Soc Chern

Commun

1988 275.

6

Sakamoto M, Aoyama H Omote Y Tetrahedron Leu 27,

1986, 1335.

7

Roche G, 1 Pharm Clin 7, 1988, 197.

8 Willett M S Absher R K,

1 Pharm Tecllllo

l

4, 1988, 2 13.

9 Branch C L, Pearson M J Smale T C,

1 Chem Soc Perkin

Trans I

1988, 2865.

10 Roth G P Sapino C,

Tetrahedron Let/

32, 1991 4077.

I I Berry P D , Brown A C, Hausan J C, Kaura A C , Milner PH ,

Moorse C

J,

Quick

J

K, Sau ndras R N, Southgate R

Whitta ll , Tetrahedron Le

t/

32, 1991, 2683.

12

13

14

15

16

17

Barton D H R, Buschmann E, Haus ler

J,

Holzapfel C W

Sheradsky T Taylor D A

1 Chem Sor. Perkin Trans I

1977, 07.

Aratani M Hashimoto M,

1 Am Ch

em

Soc

102 , 1980,

6171.

Meslin J C, Reliquet A Reliqu et F, Su lfur l .e 5, 1987,

117

.

Wolfe S Hasan S K, Ch

em Commun

1970, 833.

Lefler M T Calkins A E,

Org Synth

23 , 1943. 52.

Kenney W J Walsh J A Dave ntort D A

1 Am Chem Soc

83, 1961 4019 .