Studies towards synthesis and Lewis acid catalysed functionalization of 3-(4′-substitutedphenylthio)-azetidin-2-ones

Article abstract of DOI:10.1007/s12039-020-01836-8

Abstract: Medicinal chemistry of heterocycles especially β-lactams have been an important discovery in today’s mankind. β-Lactam nucleus is structural feature and core of the biological activity of one of most successful classes of therapeutics to date ch

Full text of DOI:10.1007/s12039-020-01836-8

J. Chem. Sci.
(
2
0
2
0
)
1
3
2
:
1
2
9
Ó I n d ia n A c a d e m y o f S c i en c es
h t tp s :/ / d o i . o r g/ 1 0 . 1 0 0 7 / s 1 2 0 3 9 - 0 2 0 - 0 1 8 3 6 - 8 Sadhan
(
0
1
2
3
4
5
6
7
8
9
(
)
.
v
o
l
V
)
F
T
3
]
(
0
1
2
3
4
5
6
(
)
.
v
o
l
V
)
REGULAR ARTICLE
Studies towards synthesis and Lewis acid catalysed functionalization
of 3-(40-substitutedphenylthio)-azetidin-2-ones
a
b
c
S U V I D H A P A N D E Y , A A R T I T H A K U R , R E SH M A , S H A M S H E R S B A RI a n d
a
b ,
*
R E N U T H A P A R
a
D e p a r t m e n t o f C h e m i s t r y , P a n j a b U n i v e r s i ty , C h a n d i g a r h , I n d ia
U n i v e r s i t y I n s t i t u t e o f E n g i n e e r i n g a n d T e c h n o l o g y , P a n j a b U n iv e r s i t y , C h a n d i g a r h , I n d ia
D A V C o l l e g e , S e c t o r 1 0 , C h a n d i g a r h , I n d ia
b
c
E - m a i l : r e n u a r o r a c h e m _ p u @ y a h o o . c o .i n
M S r e c e i v e d 2 9 A u gu s t 2 01 9 ; r e v i s e d 2 9 J u l y 2 0 2 0; a c c e p t e d 2 9 J u l y 2 0 2 0
Abstract. M e d i c i n a l c h e m i s t r y o f h e t e r o c y c l e s e s p e c ia l ly b- l a c t a m s h a v e b e e n a n i m p o r t a n t d i s c o ve r y i n
t o d ay ’ s m a n k i n d . b- L a c t a m n u c l e u s i s s t r u c t u r a l f e a tu r e a n d c o r e o f t h e b i o l o g i c a l a c t i v i t y o f o n e o f m o s t
s u cc e s s f u l c l a s s e s o f t h e r a p e u t i c s t o d a t e c h a r a c t e r i z e d b y a b r o a d s p e c tr u m o f a c t i v i t y a n d l o w t o x i c it y . I t
c on st i t u t e s c l a s s e s o f d r u g s t h a t i n c lu d e s t h e a n t i b i o t i c s l ik e p e n i c i l li n s , c e p h a l o s p o r i n s , c l a v u l a n i c a ci d ,
m o n o b a c t a m s a n d a l s o s h o w s w i d e r a n g e o f i m p o r ta n t b i o l o g i c a l a c t i v i t i e s s u c h a s a n t i - c a n c e r , a nt i - in -
fl a m m a t o r y a n d a n t i -m a l a r i a l . T h e m o n o c y c li c b- l a c t a m s a n d t h e i r h e t e r o - s u b s t i tu t e d c o n j u g a te s a re a ls o
a p pl i e d f o r t h e s y n t h e s i s o f m a n y c l a s s e s o f c o m p o u n d s w h ic h i n c l u d e t a x o l d e r i v a t i v e s , a l k a l o i d s a n d a m i n o
a ci d s . A n t i m i c r o b i a l r e s i s t a n c e i s o n e o f t h e m a j o r a n d g r o w i n g c o n c e r n s i n h o s p it a l a n d c o m m u n i t y a c qu i re d
i n f e ct i o n s a n d n e w a n t i -m i c ro b i a l a g e n t s a r e t h e r e f o r e u r g e n t ly r e q u i r e d . S o n o w , t h e o r g a n i c c h e m i s t s h av e
f o c u s s e d o n t h e m o d i fi c a t i o n o f e x i s ti n g m o l e c u l e s f o r t h e s y n t h e s i s o f n e w c o m p o u n d s h a v in g d iv e r s e
p h ar m a c o l o g i c a l a c t i v i t i e s w i t h b r o a d s p e c tr u m a c t i v i ty . M o n o c y c l i c b- l a c t a m s a r e s t a b l e t o h y d r o l y s i s b y b-
l ac t a m a s e s i n c o m p a r i s o n t o o t h e r b- l a c t a m s a n d t h u s a r e a t t r a c t i v e p l a t f o r m f o r s e a r c h i n g a n t i - b ac t e ri a l
a g en t s . T h e d i s c o v e r y o f d i f fe re n t l y s u b s t i tu te d 3 - a lk y l/ a r y l b- l a c t a m s h a v in g s i g n i fi c a n t a n t i - m i c ro b ia l
a ct i v i t i e s h a v e g i v e n i n s i g h t t h a t s u b s t i tu t i o n a t C - 3 a n d C - 4 o f b- l a c t a m r i n g a f f e c t s t h e b i o l o g i c a l a c t i vi t y o f
t h e r i n g . S o , k e e p i n g t h i s i n m i n d a n d s y n t h e t i c u t i li t y o f b- l a c t a m s h e r e w e h a v e m a d e a n a t t e m p t t o w a r d s t he
f e as i b i l i t y a n d e f fi c i e n c y o f 3 - ( p- s u b s t it u t e d - p h e n y lt h i o ) - b- l a c t a m s t o w a r d s L e w is a c i d f u n c t io n al i za t i on
r e ac t i o n s . I n o u r p r e v i o u s w o r k s , w e h a v e e x p lo r e d t h e s y n t h e t i c u t i li t y o f cis- 3 - c h l o r o - 3 - p h e n y l / b en z y l/
m et h y l t h i o - b- l a c t a m s a s s u i t a b l e s u b s t r a t e f o r t h e L e w i s a c i d c a t a l y s e d n u c l e o p h i li c s u b s t i tu ti o n . T h e c ur r e nt
w o r k i s d e s i g n e d t o e x p l o r e t h e e f f e c t o f e l e c t r o n i c c h a n g e s a t p h e n y l th i o g r o u p a t C - 3 o n t h e p r o d u c t s p ro fi l e
i n t h e L e w i s a c i d c a t a l y s e d n u c l e o p h i l i c s u b s t i tu t i o n r e a c ti o n s .
Keywords. b- L a c t a m ; a z e t i d i n - 2 - o n e ; C - 3 s u b s t i tu ti o n ; L e w i s a c i d ; 3 - ( 4 0- s u b s ti t u t e d p h e n y l t h i o ) - a z e t i di n -2 -
o n es .
1. Introduction
i n cl u d e a n t i b a ct e ri al , a n t i f u n g a l , a n t i - HI V , a n t i c a n c e r
3
a n d a n t i ma l a r i a l a ct i v i t i e s . B es i d e s t h ei r i m p o r t a n c e
H e t e r oc yc l e s h a v e a l w a ys d ra w n t he a t t e n t i o n o f
c h e m i s t s o v e r t h e y e a r s b e c a u s e o f t he ir i nd is p en s ab l e
p r o fi l e o f b i ol o g i c a l p r o pe r t ie s . A m o ng t h e m , t h e f o u r -
m e m b er ed h e t e r o c y c l i c c o m p o u nd a z e t i d i n- 2- o n e ( b-
l a ct a m ) i s e n d o w e d w i t h a u n i q u e r in g s y s t e m a n d
a s t h e k e y s t ru ct u r a l c o m p o n e n t o f b- l a c t a m a n t i b i -
o t i c s , t h es e m o l e c u l e s h a v e b e e n a t t r a c t i n g c o n s i d e r -
a b l e i n t e re s t i n o r g a n i c s y n t h e s i s a s v e r s a t i l e s y n t h e t i c
4
5
i n t e rm e d i at es , L H R a n t a g o n i s t s a n d c h o l e st e r o l
6
a b s o r p t i o n i n h i b i t o r s .
I n r ec e n t y e a rs , t h er e h a s b e e n r eg u l a r a n d w i d e -
1
g r e a t b i ol o g i c a l p o t e n ti a l . T h e a z e t i d i n- 2- o n e s c a ff o l d
c o n s t i t ut e s n u m e r o u s b io l o g i c a l l y a c t iv e m o l e c u l e s
2
a n d n a t u r a l p r o d u c t s . T h e i r b io l o g i c a l p r o p er t i es
s p r e a d u s e o f b- l a c t a m d e r i v e d d r u g s t o fi g h t t h e e v e r -
* F o r c o r re s p o n d e n c e
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-020-01836-8) contains
supplementary material, which is available to authorized users.

1 2 9 P a g e 2 o f 1 1
J. Chem. Sci.
( 2 0 2 0 ) 1 3 2 : 1 2 9
c h l o r o p h e n y l t h i o ) e th a n o i c a c i d 1, 2 a n d a p p r o p r ia t e s c h i f f
b a s e 3a-c. T o a w e l l - s t ir r e d s o l u t io n o f a p p r o p r ia t e s c h i f f
b a s e ( 5 .5 m m o l ) a n d 4 0- s u b s t it u t e d p h e n y l t h i o a ci d
( 8 .2 m m o l ) i n d r y t o l u e n e ( 8 0 m L ) a d d e d t r i e t h y l a m i n e
( 2 2 m m o l ) u n d e r a n i t r o g e n a t m o s p h e r e a n d t h e r ea ct i o n
w a s s u b j e c t e d t o r e fl u x i n g . I t w a s f o ll o w e d b y d r op w i s e
a d d it i o n o f p h o s p h o r o u s o x y c h l o r id e ( 8 .2 m m o l ) u s i n g
p r e s s u r e e q u a li z e r o v e r 3 0 m i n u n d e r r e fl u x i n g c o n d i t io n s .
A f te r 5 h o f r e fl u x in g , a l l o w e d t h e r e a c t io n t o s t ir o ve rn i gh t
a t r o o m t e m p e r a tu r e f o r o v e r n i g h t . T h e c o m p l e t io n o f t he
r e a c t io n w a s c h e c k e d b y T L C ( 1 0 % E t O A c / h e x a n e ) . T he n
e v a p o r a t e d t h e s o l v e n t ( t o l u e n e ) f r o m t h e r e a c t io n m i x t ur e
a n d d i s s o l v e d t h e r e s i d u e i n d i c h l o r o me t h a n e , w a s h ed t he
i n c r ea si ng b a c t e r i a l i nf e c ti o n s o v e r t h e c o u r s e o f t i me .
T h i s i n cr ea se d u s e o f t he s e d ru g s h a s l e d t o t h e
e m e r g en ce o f d r u g- re s i s t a n t p a t ho g e n s w h i c h h a v e
7
d e c r e a s ed t h e e f f e c t iv e n e s s o f b- la c t a m a n t ib i o t i c s .
T h i s h a s m a i n t a i n e d t he i n t e r e s t o f o r g a n i c c h e mi s t s
w o r l d o v e r i n t h e s y nt h e s i s o f n e w a n d e f f e c t i v e b-
l a ct a m a n a l o g ue s w i th a n i m p r o v e d b r o a d s p e c t r u m o f
8
b i o l o g i c a l a c t i v i t y . T h e r e s e a r c h e r s h a v e f o c u s s e d o n
t h e s y n t h e s i s a n d m o d i fi c a t i on o f b- la c t a m r i n g t o
p r e p a r e c o m p ou nd s w i t h d iv e r s e p h a r m a c o l o g i c a l
a ct i v i t i es . T h e d i s c o v e ry o f b i o lo g ic a l a c t iv i ty o f d i f-
6
f e r e n t l y s u b s t i t u t e d 3 - a lk yl /a r y l b- la c t a m s h as l e d t o
o r g a n i c l a y e r w i t h 1 N H C l , f o ll o w e d b y 5 % N a H C O a nd
3
t h e d e v e l o p m en t o f c o n v e n i e nt a p p r o a c h e s f o r t h e
s y n t h e s i s o f b- l a ct a m s b e a r i ng a v a ri e ty o f a p pe n d a g e s
a t C - 3 & C - 4 .
b r in e . D r ie d t h e o r g a n i c l a y e r o v e r a n h y d r o u s N a S O . T he
2
4
c r u d e p r o d u c t w a s p u r i fi e d b y s i li c a g e l c h r o m a t og r a ph y
( 1 0 % E t O A c / h e x a n e ) . T h e s o l i d b- l a c t a m s w e r e c r y s t al l i ze d
f r o m D C M / h e x a n e .
I n c o n n e c t i on w it h o u r c u rr e n t r e s e a r c h i nt e r es t i n
9– 1 4
t h e p r e p a r a t i o n
a
n
d
s
y
n
t
h
e
t
i
c
u
t
i
l
i
t
y
o
f
b
-
l
a
c
t
a
m
s
,
h e r e w e e x a m i n e t he f e a s i b i l it y a n d e f fi c i e n c y o f 3 - ( p-
s u b s t i t u t e d - ph en yl t h i o ) b- la c t a m s t ow a rd s L e w i s a ci d
f u n c t i o na l i z at i o n r e a c t io ns .
2 . 2 a Compound 4a: trans-1-(40-methoxyphenyl)-
3-(40-methylphenylthio)-4-phenylazetidin-2-
one: C o l o u r l e s s c r y s t a l li n e s o l i d ; y i e l d : 5 5 % ( 1 . 13 g );
M . p . 1 1 6 - 1 1 7 °C ; R : 0 . 4 6 ; C H N O S : A n a l. F o u nd : C ,
7 3 . 5 2 ; H , 5 . 5 9 ; N , 3 . 7 9 % C a l c .: C , 7 3 . 5 7 ; H , 5 . 6 3; N ,
f
2
3
2
1
2
2. Experimental
-
1
1
3
.
7
2
%
.
I
R
(
c
m
)
:
m
,
1
7
2
0
;
H
N
M
R
(
d
,
p
p
m
i
n
(
C
=
O
)
C
D
C
l
,
4
0
0
M
H
z
)
:
7
.
3
6
-
7
.
2
1
(
m
,
5
H
,
P
h
)
,
7
.
1
9
-
7
.
0
0
(
m
,
3
2 . 1 General information
3
6 H , P h ) , 6 . 6 6 - 6 . 6 4 ( m , 2 H , P h ) , 4 . 6 7 ( d , J = 2 . 3 , 1 H , C - 3 ),
3
4 . 1 0 ( d , J = 2 . 3 , 1 H , C - 4 ) , 3 . 6 3 ( s , 3 H , O C H ) , 2 . 2 1 ( s , 3 H ,
1
1 3
H N MR a nd C N M R s p e c t r a w e re r e c o r d e d a t 4 0 0 M H z
3
1 3
C
H
)
;
C
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
1
0
0
M
H
z
)
:
1
6
2
.
9
,
3
3
a n d 1 0 0 M H z r e s p e c t i v e l y , i n C D C l s o l u t i o n u s i n g B RU -
3
1 5 6 .2 , 1 3 8 .4 , 1 3 6 .4 , 1 3 3 .0 , 1 3 0 .7 , 1 3 0 .0 , 1 2 9 .2 , 1 28 . 8,
1 2 8 .2 , 1 2 6 .0 , 1 1 8 .6 , 1 1 4 .2 , 7 7 . 3 , 7 7 . 2 , 7 7 . 0 , 7 6 . 7 , 6 3 . 0, 6 1. 9 ,
5 5 . 4 , 2 1 . 1 .
K E R A V A N CE I I N M R s p e c t r o m e t e r . C h e m i c a l s h i f t s a r e
g i v en i n p a r t s p e r m i l l i o n r e l a t i v e t o t e t r a m e t h y l s i l a n e a s a n
1
i
n
t
e
r
n
a
l
s
t
a
n
d
a
r
d
(
d
=
0
p
p
m
)
f
o
r
H
N M R a n d
1 3
( d = 7 7 . 0 p p m ) f o r C N M R . T h e c o u p l i n g c o n s t a n t
J v al u e s a r e g i v e n i n H e r t z ( H z ) . W h i l e c i t i n g H N M R
2 . 2 b Compound 4b: trans-1-(40-methoxyphenyl)-3-
(40-chlorophenylthio)-4-phenylazetidin-2-
1
d a t a , f o l l o w i n g a b b r e v i a t i o n s h a v e b e e n u s e d : s - si n g l e t ; b r
s -b r o a d s i n g le t ; d - d o u b l e t ; t - t r i p l e t ; q - q u a r t e t a n d m - m u l t i -
p l e t . I R s p ec t r a w e re t a k e n o n a n F T I R s p e c t r o p h o t o m e t e r
a n d a r e r e p o r t e d i n c m -1 . T h i n - l a y e r c h ro m a t o g r a p h y
( T L C ) w a s p e r f o r m e d u s i n g T L C g r a d e s i l i c a g e l ‘ G ’
( Ac m e S y n t h et i c C h e m i c a l s ) . T h e s p o t s w e re m a d e v i s i b l e
b y e xp os i n g p l at e s t o i o d i n e v a p o u r s . C o l u m n c h r o m a t o g -
r a p h y w a s p e r f o r m e d w i t h s i l i c a g e l ( A c m e S y n t h e t i c
C h e m i c a l s , 6 0 – 1 2 0 m e s h ) a n d e l u t e d w i t h e t h y l a c e t a t e :
h e x a n e s m i x t u r e s u n l e s s o t h e r wi s e s t a t e d . A l l c o m m e r c ia l l y
a v a i l a b l e c om p ou nd s o r r e a g e n t s w e r e u s e d w i t h o u t f u r t h e r
p u ri fi c at i o n . A l l s o l v e n t s u s e d w e r e o f L R g r a d e . W h e r e
n e c e s sa r y , t h e s o l ve n t s w e re d i s t i l l e d a n d d r i e d b e f o r e u s e ,
w h e n t h i s s e em ed n e c e s s a r y b y s t a n d a r d m e t h o d s .
one: C o l o u r l e s s c r y s t a l li n e s o l i d ; y i e l d 5 0 % ( 1. 0 8 g );
M . p . 1 3 2 - 1 3 4 °C ; R : 0 . 3 3 ; C H N O S C l: A n a l. F o u nd :
C , 6 6 . 7 1 ; H , 4 . 6 0 ; N , 3 . 5 1 % C a l c . : C , 6 6 . 7 4 ; H , 4 .5 8 ; N ,
f
2 2 1 8
2
-
1
1
3
.
5
3
%
.
I
R
(
c
m
)
:
m
,
1
7
2
2
;
H
N
M
R
(
d
,
p
p
m
i
n
(
C
=
O
)
C D C l , 4 0 0 M H z ) : 7 . 4 6 - 7 . 3 6 ( m , 4 H , P h ) , 7 . 3 1 - 7 . 14 ( m ,
3
3
7 H , P h ) , 6 . 7 6 - 6 . 7 3 ( m , 2 H , P h ) , 4 . 7 5 ( d , J = 2 . 2 , 1 H , C - 3 ),
3
4 . 2 1 ( d , J = 2 . 2 , 1 H , C - 4 ) , 3 . 7 1 ( s , 3 H , O C H ) ; C N M R
1 3
3
( d, p p m i n C D C l , 1 0 0 M H z ) : 1 6 2 .4 7 , 1 5 6 .4 2 , 1 36 . 18 ,
3
1 3 4 .2 7 , 1 3 3 .5 4 , 1 3 3 .5 4 , 1 3 0 .8 3 , 1 3 0 .5 5 , 1 2 9 . 3 8 , 1 29 . 33 ,
1 2 9 .0 8 , 1 2 6 .0 5 , 1 1 8 .6 6 , 1 1 4 .3 7 , 7 7 . 3 8 , 7 7 . 2 7 , 7 7 . 0 6 , 7 6. 7 5,
6 2 . 9 6 , 6 1 . 3 3 , 5 5 . 4 2 .
2 . 2 c Compound
4c:
trans-1-phenyl-3-(40-
methylphenylthio)-4-phenylazetidin-2-one: W hi t e
s o l i d ; y i e l d 3 9 . 2 % ( 0 .7 4 g ) ; M . p . 1 1 2 - 1 1 3 °C ; R : 0 .5 0 ;
2 2 1 9
f
2 . 2 General procedure for the synthesis
of 3-(40-methyl/chlorophenylthio) b-lactams (4&5)
C H N O S: A n a l. F o u n d : C , 7 6 . 5 2 ; H , 5 . 5 1 ; N , 4 .0 1 %
-
1
C
a
l
c
.
:
C
,
7
6
.
4
9
;
H
,
5
.
5
4
;
N
,
4
.
0
5
%
.
I
R
(
c
m
)
:
m
,
1
7
3
0
;
(
C
=
O
)
1
H
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
4
0
0
M
H
z
)
:
7
.
3
6
-
7
.
3
4
(
m
,
2
H
,
3
T h e s e c om p o u n d s w e re p r e p a r e d b y t h e d e s c r i b e d p r o c e -
1 6
d u re i n t h e c it e d r e f e r e n c e f o r t h e s y n t h e s i s o f 3 - p h e n y l /
P h ) , 7 . 2 6 - 7 . 1 9 ( m , 6 H , P h ) , 7 . 1 2 - 7 . 1 1 ( m , 3 H , P h ) , 7 .0 1 -
6 . 9 3 ( m , 3 H , P h ) , 4 . 7 0 ( d , 3 J = 2 . 4 , 1 H , C - 3 ) , 4 .1 1 ( d,
0
3 J = 2 . 4 , 1 H , C - 4 ) ; 2 . 2 0 ( s , 3 H , C H ) ; C N M R ( d, p p m i n
1 3
b
e
n
z
y
l
t
h
i
o
/
m
e
t
h
y
l
t
h
i
o
-
b
-
l
a
c
t
a
m
s
u
s
i
n
g
2
-
(
4
-
m
e
t
h
y
l
/
3

J. Chem. Sci.
( 2 0 2 0 ) 1 3 2 : 1 2 9
P a g e 3 o f 1 1
1 2 9
?
?
?
C
D
C
l
,
1
0
0
M
H
z
)
:
1
6
3
.
5
9
,
1
3
8
.
5
2
,
1
3
7
.
1
9
,
1
3
6
.
3
7
,
1
3
3
.
1
1
,
[
a
s
s
i
g
n
m
e
n
t
]
)
:
3
6
8
(
2
2
,
[
M
?
2
3
]
)
,
3
4
6
(
1
0
0
,
[
M
]
)
,
2
2
2
3
1 3 0 . 0 5 , 1 2 9 . 2 7 , 1 2 9 . 0 8 , 1 2 8 . 9 1 , 1 2 8 . 0 9 , 1 2 6 . 0 2 , 1 2 4 .2 8 , ( 6 4 , [ C H N O ] ?) , 1 8 2 ( 1 9 , [ C H C H = N C H ] ?) .
1 1 7 . 2 9 , 7 7 . 4 2 , 7 7 . 1 0 , 7 6 . 7 8 , 6 2 . 8 5 , 6 1 . 9 2 , 2 1 . 1 8 .
1 5 1 2
6
5
6 5
2 . 2 h Compound
5d:
cis-1-phenyl-3-(40-
chlorophenylthio)-4-phenylazetidin-2-one: W hi t e
2 . 2 d Compound
4d:
trans-1-phenyl-3-(40-
chlorophenylthio)-4-phenylazetidin-2-one: W h i t e
s
o
l
i
d
;
y
i
e
l
d
1
3
.
4
%
(
0
.
2
7
g
)
;
M
.
p
.
1
8
6
-
1
8
7
°
C
;
R
:
0
.
5
6
;
f
s o li d , y i el d 4 0 . 5 9 % ( 0 . 8 2 g ) ; M . p . 1 2 6 - 1 2 8 °C ; R : 0 . 6 3 ; C H N O SC l : A n a l. F o u n d : C , 6 8 . 3 0 ; H , 4 . 3 5 ; N , 3 .8 5 %
f
2 1 1 6
C H N O S C l: A n a l . F o u n d : C , 6 8 . 7 0 ; H , 4 . 4 2 ; N , 3 . 7 9 % C a l c . : C , 6 8 . 9 ; H , 4 . 4 0 ; N 3 . 8 2 % . I R ( c m -1 ) : m( C = O ) , 1 73 0 ;
2 1 1 6
C a lc . : C , 6 8 . 9 ; H , 4 . 4 0 ; N , 3 . 8 2 % . I R ( c m -1 ) : m( C = O ) , 1 7 2 5 ;
1
H
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
4
0
0
M
H
z
)
:
7
.
3
8
-
7
.
3
5
(
m
,
3
H
,
3
1
H N M R ( d, p p m i n C D C l , 4 0 0 M H z ) : 7 . 4 9 -7 . 4 6 ( m , 2 H , P h ) , 7 . 3 3 - 7 . 2 2 ( m , 8 H , P h ) , 7 . 1 9 - 7 .0 6 ( m , 3 H , P h ) , 5 .3 9 ( d,
3
3
3
1
3
P
h
)
,
7
.
4
2
-
7
.
3
3
(
m
,
5
H
,
P
h
)
,
7
.
3
0
-
7
.
0
6
(
m
,
7
H
,
P
h
)
,
4
.
8
1
(
d
,
J
=
5
.
6
,
1
H
,
C
-
3
)
,
4
.
8
7
(
d
,
J
=
5
.
6
,
1
H
,
C
-
4
)
;
C
N
M
R
3J = 2 . 4 , 1 H , C - 3 ) , 4 . 2 5 ( d , J = 2 . 4 , 1 H , C - 4 ); C N M R ( d, p p m i n C D C l , 1 0 0 M H z ) : 1 3 8 .5 6 , 1 3 7 .9 0 , 1 32 . 85 ,
3
1
3
3
(
d
,
p
p
m
i
n
C
D
C
l
,
1
0
0
M
H
z
)
:
1
6
3
.
4
7
,
1
3
8
.
9
2
,
1
3
7
.
5
4
,
1
2
9
.
7
0
,
1
2
9
.
0
5
,
1
2
8
.
7
2
,
1
2
6
.
5
2
,
1
2
5
.
8
3
,
1
1
8
.
9
0
,
1
1
4
.
5
0
,
3
1 3 5 . 4 5 , 1 3 2 . 1 2 , 1 3 0 . 9 6 , 1 2 9 . 2 7 , 1 2 8 . 9 1 , 1 2 8 . 7 2 , 1 2 8 .2 4 , 7 7 . 5 0 , 7 7 . 4 2 , 7 6 . 0 5 , 6 0 . 5 0 .
1 2 6 . 5 4 , 1 2 4 . 5 2 , 1 1 8 . 3 0 , 7 7 . 5 0 , 7 7 . 2 0 , 7 6 . 9 0 , 6 3 . 8 5 , 6 1 . 8 5 .
2 . 2 e Compound 4e: trans-1-(40-methoxyphenyl)-3-
2 . 3 General procedure for the synthesis of cis-3-
chloro-3-(40-methyl/chlorophenylthio)-b-lactams
(6)
(40-methylphenylthio)-4-(40-methoxyphenyl)azetidin-2-
one: Y e l l o w o i l ; y i e l d 7 5 % ( 1 . 6 7 g ) ; R : 0 . 2 6 ;
f
C H N O S : A n a l . F o u n d : C , 7 1 . 1 7 ; H , 5 . 7 4 ; N , 3 . 4 1 %
2 4 2 3
3
-
1
T h e s e c o m p o u n d s w e r e p r e p a r e d b y t h e p r o c e d ur e a s
1 6
d e s c r i b e d f o r cis- 3 - c h l o r o - 3 - p h e n y l t h i o -b- l a c t a m s . T o a
C
a
l
c
.
:
C
,
7
1
.
1
4
;
H
,
5
.
7
2
;
N
,
3
.
4
5
%
.
I
R
(
c
m
)
:
m
,
1
7
5
5
;
(
C
=
O
)
1
H
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
4
0
0
M
H
z
)
:
7
.
4
1
-
7
.
3
8
(
m
,
2
H
,
3
s o l u t i o n o f trans- b- l a c t a m 4a-d ( 1 .2 m m o l ) i n d r y d ic h l or -
P h ) , 7 . 2 3 - 7 . 0 5 ( m , 6 H , P h ) , 6 . 8 7 -6 . 6 9 ( m , 4 H , P h ) , 4 . 7 1 ( d ,
3
3 J = 2 . 2 , 1 H , C - 3 ) , 4 . 1 6 ( d , J = 2 . 2 , 1 H , C - 4 ) , 3 . 7 5 ( s , 3 H ,
o m e t h a n e ( 3 0 m L ) w a s a d d e d S O C l ( 1 .4 m m o l ) r ap i dl y
2
2
1 3
O C H ) , 3 . 7 0 ( s , 3 H , O C H ) , 2 . 2 7 ( s , 3 H , C H ) ; C N M R
u n d e r n i t r o g e n a t m o s p h e r e a t 0 °C . T h e r e a c ti o n w a s
m o n i t o r e d u s i n g T L C ( 1 0 % E t O A c / h e x a n e ) . C o n fi r m i n g t he
c o m p le t e d i s a p p e a r a n c e o f r e a c t a n t , t h e r e a c ti o n w a s
q u e n c h e d w i t h w a t e r , e x t r a c t e d w i t h d i c h l o r o me th a n e. T he n
w a s h e d t h e o r g a n i c l a y e r w i t h b r in e a n d d r ie d i t o ve r
a n h y d r o u s N a S O . T h e c r u d e p r o d u c t w a s p u r i fi e d w i t h
3
3
3
( d, p p m i n C D C l , 1 0 0 M H z ) : 1 6 3 . 0 1 , 1 6 0 . 0 2 , 1 5 6 .2 4 ,
3
1 3 8 . 2 5 , 13 2 . 8 0 , 1 3 0 . 7 5 , 1 3 0 . 0 1 , 1 2 8 . 4 5 , 1 2 7 . 4 5 , 1 1 8 .7 1 ,
1 1 4 . 6 2 , 1 1 4 . 2 7 , 7 7 . 5 2 , 7 7 . 2 0 , 7 6 . 8 8 , 6 2 . 8 3 , 6 1 . 8 5 , 5 5 . 4 0 ,
5 5 . 3 3 .
2
4
2 . 2 f Compound 4f: trans-1-(40-methoxyphenyl)-3-
(40-chlorolphenylthio)-4-(40-methoxyphenyl)azetidin-
s i li c a g e l c h r o m a t o g r a p h y ( 1 0 % E t O A c / h e x a n e) a nd
r e c r y s t a l l iz e d f r o m D C M / h e x a n e .
2-one: Y e l lo w o i l ; y i e l d 7 9 % ( 1 . 8 5 g ) ; R : 0 . 1 3 ;
f
2 . 3 a Compound 6a: cis-1-(40-methoxyphenyl)-3-
chloro-3-(40-methylphenylthio)-4-phenyl azetidin-2-
one: W h i t e s o l i d ; y i e l d 9 0 % ( 0 .4 4 g ) ; M . p . 1 5 4 - 1 56 °C ;
R : 0 . 5 0 ; C H N O S C l: A n a l. F o u n d : C , 6 7 . 4 2 ; H , 4 .8 7 ;
C H N O S C l : A n a l . F o u n d : C , 6 4 . 8 9 ; H , 4 . 7 1 ; N ,
3
2 3 2 0
3 . 2 5 % C al c . : C , 6 4 . 8 9 ; H , 4 . 7 1 ; N , 3 . 2 5 % . I R ( c m -1 ) :
1
m( C = O ) , 1 7 5 0 ; H N M R ( d, p p m i n C D C l , 4 0 0 M H z ) : 7 . 4 2 -
3
f
2 3 2 0
2
7
.
4
0
(
m
,
2
H
,
P
h
)
,
7
.
2
5
-
7
.
1
5
(
m
,
6
H
,
P
h
)
,
6
.
8
9
-
6
.
7
2
(
m
,
4
H
,
-
1
3
P h ) , 4 . 7 2 ( d , J = 2 . 2 , 1 H , C - 3 ), 4 . 2 1 ( d , J = 2 . 2 , 1 H ,
3
N
,
3
.
4
6
%
C
a
l
c
.
:
C
,
6
7
.
3
9
;
H
,
4
.
9
1
;
N
,
3
.
4
1
%
.
I
R
(
c
m
)
:
1
1
3
m( C = O ) , 1 7 5 2 ; H N M R ( d, p p m i n C D C l , 4 0 0 M H z) : 7 .3 5 -
3
C
-
4
)
,
3
.
7
7
(
s
,
3
H
,
O
C
H
)
,
3
.
7
0
(
s
,
3
H
,
O
C
H
)
;
C
N
M
R
(
d
,
3
3
7 . 2 7 ( m , 7 H , P h ) , 7 . 1 8 - 7 . 0 1 ( m , 4 H , P h ) , 6 . 7 5 - 6 . 7 2 ( m , 2 H ,
P h ) , 5 . 3 6 ( s , 1 H , C - 4 ) , 3 . 6 8 ( s , 3 H , O C H ) , 2 . 2 6 ( s , 3 H ,
p
p
m
i
n
C
D
C
l
,
1
0
0
M
H
z
)
:
1
6
2
.
5
2
,
1
6
0
.
1
6
,
1
5
6
.
3
6
,
1
3
4
.
0
9
,
3
3
1 3 3 . 2 9 , 1 3 1 . 1 1 , 1 3 0 . 5 8 , 1 2 9 . 3 5 , 1 2 7 . 9 5 , 1 2 7 . 4 5 ,1 1 8 . 7 0 ,
1 1 4 . 7 2 , 1 1 4 . 3 9 , 7 7 . 4 7 , 7 7 . 1 5 , 7 6 . 8 3 , 6 2 . 8 0 , 6 1 . 2 4 , 5 5 . 4 1 ,
5 5 . 3 5 .
1
3
C
H
)
;
C
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
1
0
0
M
H
z
)
:
1
3
7
.
9
0
,
3
3
1 3 6 .5 , 1 3 2 .4 0 , 1 2 9 .8 , 1 2 9 .5 , 1 2 8 . 8 , 1 2 7 .6 , 1 2 7 .2 , 1 26 . 52 ,
1 2 5 .9 , 1 1 8 .8 , 7 7 . 8 , 7 7 . 2 , 7 6 . 5 , 7 1 . 5 , 5 4 . 7 , 2 1 . 5 5 .
2
.
2
g
C
o
m
p
o
u
n
d
5c:
cis-1-phenyl-3-(40-
methylphenylthio)-4-phenylazetidin-2-one: W h i t e
2 . 3 b Compound 6b: cis-1-(40-methoxyphenyl)-3-
chloro-3-(40-chlorophenylthio)-4-phenyl azetidin-2-
one: W h i t e s o l i d ; y i e l d 9 2 % ( 0 .4 7 g ) ; M . p . 1 3 5 - 1 36 °C ;
R : 0 . 3 6 ; C H N O S C l : A n a l . F o u n d : C , 6 1 . 3 8 ; H , 3 .9 2 ;
s
o
l
i
d
;
y
i
e
l
d
1
2
.
6
9
%
(
0
.
2
4
g
)
;
M
.
p
.
1
7
6
-
1
7
7
°
C
;
R
:
0
.
4
3
;
f
C
H
N
O
S
:
A
n
a
l
.
F
o
u
n
d
:
C
,
7
6
.
5
4
;
H
,
5
.
4
9
;
N
,
4
.
0
2
%
2
2
1
9
-
1
f
2
2
1
7
2
2
C
a
l
c
.
:
C
,
7
6
.
4
9
;
H
,
5
.
5
4
;
N
,
4
.
0
5
%
.
I
R
(
c
m
)
:
m
,
1
7
2
5
;
(
C
=
O
)
-
1
1
N
,
3
.
3
0
%
C
a
l
c
.
:
C
,
6
1
.
4
0
;
H
,
3
.
9
8
;
N
,
3
.
2
5
%
.
I
R
(
c
m
)
:
H
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
4
0
0
M
H
z
)
:
7
.
3
2
-
7
.
2
8
(
m
,
3
H
,
3
1
m( C = O ) , 1 7 3 5 ; H N M R ( d, p p m i n C D C l , 4 0 0 M H z) : 7 .4 4 -
3
P h ) , 7 . 2 7 - 7 . 2 0 ( m , 6 H , P h ) , 7 . 1 4 -7 . 1 1 ( m , 2 H , P h ) , 7 . 0 2 -
6 . 9 5 ( m , 3 H , P h ) , 5 . 3 0 ( d , 3J = 5 . 6 , 1 H , C - 3 ) , 4 . 8 0 ( d ,
3 J = 5 . 6 , 1 H , C - 4 ) , 2 . 2 2 ( s , 3 H , C H ) . C N M R ( d, p p m i n
7 . 3 7 ( m , 7 H , P h ) , 7 . 2 7 - 7 . 2 2 ( m , 4 H , P h ) , 6 . 8 3 - 6 . 8 0 ( m , 2 H ,
1 3
1
3
P
h
)
,
5
.
4
4
(
s
,
1
H
,
C
-
4
)
,
3
.
7
6
(
s
,
3
H
,
O
C
H
)
;
C
N
M
R
(
d
,
3
3
p p m i n C D C l , 1 0 0 M H z ) : 1 5 9 .9 6 , 1 5 6 .8 7 , 1 3 6 .7 8 , 1 36 . 01 ,
1 3 1 .5 0 , 1 2 9 .8 5 , 1 2 9 .7 0 , 1 2 8 .9 3 , 1 2 8 .7 0 , 1 2 8 . 1 9 , 1 26 . 64 ,
1 1 9 .2 3 , 1 1 4 .5 2 , 7 9 . 7 1 , 7 7 . 3 4 , 7 7 . 0 2 , 7 6 . 7 0 , 7 1 . 7 1 , 5 5. 4 7.
3
C D C l , 1 0 0 M H z ) : 1 3 7 . 5 7 , 1 3 7 . 2 9 , 1 3 1 . 9 3 , 1 2 9 . 7 1 , 1 2 9 .1 4 ,
1 2 8 . 5 3 , 1 2 7 . 7 3 , 1 2 4 . 3 2 , 1 2 8 . 5 3 , 1 2 7 . 7 3 , 1 2 4 . 3 2 , 1 1 7 .3 7 ,
1 1 4 . 9 2 , 7 7 . 3 9 , 7 7 . 0 3 , 7 6 . 7 1 , 6 0 . 0 2 . E I -M S m / z ( R . I % ,
3

1
2
9
P
a
g
e
4
o
f
1
1
J. Chem. Sci.
(
2
0
2
0
)
1
3
2
:
1
2
9
0
2
.
3
c
C
o
m
p
o
u
n
d
6
c
:
c
i
s
-
1
-
p
h
e
n
y
l
-
3
-
c
h
l
o
r
o
-
3
-
(
4
-
2
.
4
b
C
o
m
p
o
u
n
d
7ca/da:
1-phenyl-3,3-
methylphenylthio)-4-phenylazetidin-2-one: W h i t e
s o li d ; y i el d 9 2 % ( 0 . 4 2 g ) ; M . p . 1 5 0 - 1 5 2 °C ; R : 0 . 5 3 ;
bis(40methoxyphenyl)-4-phenylazetidin-2-
one: C o l o u r l e s s o i l ; y i e l d 4 5 % ( 0 .0 4 2 g ) ; R : 0 .1 6 ;
f
f
C H N O S C l: A n a l . F o u n d : C , 6 9 . 5 9 ; H , 4 . 7 3 ; N , 3 . 7 2 % .
2 2 1 8
C H N O : A n a l . F o u n d : C , 7 9 . 9 2 ; H , 5 . 8 1 ; N , 3 .1 9 %
2 9 2 5
3
-
1
-
1
C
a
l
c
:
C
,
6
9
.
5
5
;
H
,
4
.
7
7
;
N
,
3
.
6
8
%
.
I
R
(
c
m
)
:
m
,
1
7
6
0
;
C
a
l
c
.
:
C
,
7
9
.
9
8
;
H
,
5
.
7
8
;
N
,
3
.
2
1
%
.
I
R
(
c
m
)
:
m
,
1
7
5
2
;
(
C
=
O
)
(
C
=
O
)
1
1
H
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
4
0
0
M
H
z
)
:
7
.
4
2
-
7
.
4
0
(
m
,
5
H
,
H
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
4
0
0
M
H
z
)
:
7
.
5
5
-
7
.
3
8
(
m
,
4
H
,
3
3
P h ) , 7 . 3 8 - 7 . 2 8 ( m , 6 H , P h ) , 7 . 1 1 -7 . 0 9 ( m , 3 H , P h ) , 5 . 4 7 ( s ,
1 3
P h ) , 7 . 2 5 - 6 . 9 1 ( m , 9 H , P h ) , 6 . 8 9 - 5 . 7 2 ( m , 5 H , P h ) , 5 .7 2 ( s ,
1 3
1
H
,
C
-
4
)
,
2
.
3
(
s
,
3
H
,
C
H
)
;
C
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
1 H , C - 4 ) , 3 . 7 7 ( s , 3 H , O C H ) , 3 . 6 3 ( s , 3 H , O C H ) ;
3
C
3
3
3
1 0 0 M H z ) : 1 6 0 . 7 9 , 1 3 9 . 9 6 ; 1 3 6 . 5 7 , 1 3 5 . 9 8 , 1 3 1 . 6 2 , 1 2 9 .7 3 ,
1 2 9 . 5 5 , 1 2 8 . 6 5 , 1 2 8 . 1 9 , 1 2 4 . 9 1 , 1 2 4 . 2 8 , 1 1 7 . 8 8 , 7 7 . 3 4 ,
7 7 . 2 2 , 7 7 . 0 2 , 7 6 . 7 0 , 7 1 . 7 2 , 2 1 . 3 3 .
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
1
0
0
M
H
z
)
:
1
6
7
.
6
8
,
1
5
8
.
8
0
,
3
1 5 8 .1 5 , 1 3 7 .5 8 , 1 3 5 .0 4 , 1 3 3 .1 9 , 1 2 9 .6 1 , 1 2 9 . 5 3 , 1 29 . 05 ,
1 2 8 .4 5 , 1 2 8 .4 1 , 1 2 8 .1 3 , 1 2 7 .5 8 , 1 2 4 .0 8 , 1 1 7 . 5 0 , 1 14 . 15 ,
1 1 3 .2 5 , 7 7 . 4 0 , 7 7 . 2 9 , 7 7 . 0 8 , 7 6 . 7 7 , 7 1 . 2 0 , 6 7 . 4 2 , 5 5. 3 5,
5 5 . 0 9 .
2 . 3 d Compound 6d: cis-1-phenyl-3-chloro-3-(40-
chlorophenylthio)-4-phenylazetidin-2-one: W h i t e
0
2
.
4
c
C
o
m
p
o
u
n
d
8
a
b
:
t
r
a
n
s
-
1
-
(
4
-
m
e
t
h
o
x
y
p
h
e
n
y
l
)
-
3
-
s
o
l
i
d
;
y
i
e
l
d
9
0
%
(
0
.
4
2
g
)
;
M
.
p
.
1
5
0
-
1
5
1
°
C
;
R
:
0
.
6
6
;
(20,50-dimethoxyphenyl)-3-(40-methylphenyl
thio)-4-
f
C
H
N
O
S
C
l
:
A
n
a
l
.
F
o
u
n
d
:
C
,
6
3
.
0
3
;
H
,
3
.
7
2
;
N
,
3
.
5
3
%
2
1
1
5
2
phenylazetidin-2-one: W h i t e c r y s ta l l i n e s o l i d ; y ie l d
4 5 % ( 0 .0 4 5 g ) ; M . p . 1 4 6 - 1 4 7 °C ; R : 0 . 3 3 ; C H N O S :
A n a l. F o u n d : C , 7 2 . 7 2 ; H , 5 . 7 5 ; N , 2 . 7 6 % C a l c . : C , 7 2. 7 7 ;
-
1
C
a
l
c
.
:
C
,
6
3
.
0
0
;
H
,
3
.
7
7
;
N
,
3
.
4
9
%
.
I
R
(
c
m
)
:
m
,
1
7
6
5
;
(
C
=
O
)
1
f
3
1
2
9
4
H
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
4
0
0
M
H
z
)
:
7
.
4
5
-
7
.
3
9
(
m
,
7
H
,
3
1
3
P
h
)
,
7
.
3
0
-
7
.
1
2
(
m
,
7
H
,
P
h
)
,
5
.
4
8
(
s
,
1
H
,
C
-
4
)
;
C
N
M
R
(
d
,
-
1
1
H
,
5
.
7
1
;
N
,
2
.
7
3
%
.
I
R
(
c
m
)
:
m
,
1
7
3
5
;
H
N
M
R
(
d
,
(
C
=
O
)
p p m i n C D C l , 1 0 0 M H z ) : 1 3 6 . 8 7 , 1 3 6 . 4 0 , 1 3 1 . 3 9 , 1 2 9 .8 9 ,
1 2 9 . 3 0 , 1 2 8 . 9 7 , 1 2 8 . 7 4 , 1 2 8 . 1 3 , 1 2 6 . 5 2 , 1 2 5 . 0 9 , 1 1 7 .9 0 ,
7 7 . 3 4 , 7 7 . 2 2 , 7 7 . 0 2 , 7 6 . 7 0 , 7 1 . 6 3 .
3
p p m i n C D C l , 4 0 0 M H z ) : 7 . 4 0 - 7 .3 2 ( m , 3 H , P h ) , 7 . 0 9- 6 . 98
( m , 9 H , P h ) , 6 . 6 9 - 6 . 3 4 ( m , 4 H , P h ) , 5 . 1 1 ( s , 1 H , C - 4 ), 3 .6 9
( s , 3 H , O C H ) , 3 . 6 7 ( s , 3 H , O C H ) , 3 . 2 5 ( s , 3 H , O C H ) ,
3
3
3
3
1 3
2 . 2 5 ( s , 3 H , C H ) ; C N M R ( d, p p m i n C D C l , 1 0 0 M H z ):
3
3
1 6 4 .6 7 , 1 5 6 . 0 0 , 1 5 2 .7 8 ; 1 5 0 .2 4 , 1 3 9 .5 8 , 1 3 6 . 8 9 , 1 35 . 27 ,
1 3 0 .6 2 , 1 2 9 .2 2 , 1 2 8 .1 0 , 1 2 7 .4 3 , 1 2 6 .8 8 , 1 2 2 . 7 7 , 1 18 . 84 ,
1 1 5 .0 5 , 1 1 4 .8 2 , 1 1 4 .0 3 , 1 1 1 .3 2 , 7 7 . 3 6 , 7 7 . 2 4 , 7 7 . 0 4 , 7 6. 7 2,
6 9 . 1 3 , 6 8 . 1 3 , 5 5 . 8 3 , 5 5 . 3 8 , 5 4 . 8 7 , 2 1 . 2 6 . E I - M S m / z ( R . I % ,
[ a s s i g n m e n t ] ?) : 5 3 4 ( 1 2 , [ M ?2 3 ] ?) , 5 1 3 ( 1 8 , [ M ?1 ]?) ,
5 1 2 ( 3 5 , [ M ] ?) , 3 9 0 ( 6 9 , [ C H N O ] ?) , 3 8 9 ( 10 0 ,
2 . 4 General procedure for the synthesis of C-3
substituted b-lactams (7, 8, 9 & 10)
T h e s e c om p o u n d s w e re p r e p a r e d b y t h e p r o c e d u r e a s
d e s c r i b e d f o r n u cl e o p h i l i c s u b s t i t u t i o n s o f cis- 3 - c h lo r o - 3 -
2
4
2
3
4
9
–
1
2
p
h
e
n
y
l
/
b
e
n
z
y
l
/
m
e
t
h
y
l
t
h
i
o
b
-
l
a
c
t
a
m
s
.
T
o
a
s
o
l
u
t
i
o
n
o
f
?
?
[
C
H
N
O
]
)
,
3
6
0
(
6
9
,
[
C
H
N
O
]
)
.
2
4
2
2
4
2
3
2
2
4
cis- 3 - c h l o r o - b- l a ct a m 6a-d ( 0 . 2 4 m m o l ) a n d n u c l e o p h i l e
( 0. 3 6 m m ol ) i n d r y D C M ( 1 5 m L ) w a s a d d e d L e w is a c i d
2 . 4 d Compound 9ab: cis-1-(40-methoxyphenyl)-3-
(20,50-dimethoxyphenyl)-3-(40-methylphenyl
thio)-4-
T i C l ( 0 . 3 6 m m ol ) r a p i d l y u n d e r n i t r o g e n a t m o s p h e r e a t
4
0 °C . T h e r e ac t i o n w a s m o n i t o r e d b y T L C . W h e n r e a c ti o n
p r ofi l e c h an g e s n o f u rt h e r , t h e r e a c t i o n w a s q u e n c h e d w i t h
w at e r , e x tr ac t ed w i t h D C M , w a s h e d t h e o r g a n i c l a y e r w i t h
5 % N a H C O a nd d r i e d i t o v e r a n h y d r o u s N a S O . T h e
phenylazetidin-2-one: W h i t e c r y s ta l l i n e s o l i d ; y ie l d
4 0 % ( 0 .0 4 0 g ) ; M . p . 1 5 8 - 1 6 0 °C ; R : 0 . 4 0 ; C H N O S :
A n a l. F o u n d : C , 7 2 . 8 0 ; H , 5 . 6 8 ; N , 2 . 7 5 % C a l c . : C , 7 2. 7 7 ;
f
3
1
2
9
4
3
2
4
-
1
1
H
,
5
.
7
1
;
N
,
2
.
7
3
%
.
I
R
(
c
m
)
:
m
,
1
7
3
2
;
H
N
M
R
(
d
,
(
C
=
O
)
c r u d e r e a c t i o n m i x t u re w a s p u r i fi e d w i t h s i l i c a g e l c h r o -
m a t o g r a ph y ( 1 0 % E t O A c / h e x a n e ) a n d s o l i d p r o d u c t s w e r e
r e c r y st a ll i z ed f r o m D C M / h e x a n e .
p p m i n C D C l , 4 0 0 M H z ) : 7 . 6 2 - 7 .2 2 ( m , 7 H , P h ) , 6 . 9 6- 6 . 71
3
( m , 9 H , P h ) , 5 . 5 2 ( s , 1 H , C - 4 ) , 3 . 8 0 ( s , 3 H , O C H ) , 3 .7 2 ( s ,
3
1
3
3 H , O C H ) , 3 . 5 0 ( s , 3 H , O C H ) , 2 . 2 2 ( s , 3 H , C H ) ;
3
C
3
3
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
1
0
0
M
H
z
)
:
1
6
6
.
5
2
,
1
5
6
.
0
2
,
3
0
1 5 2 .7 1 , 1 5 0 .6 5 , 1 3 8 .8 0 , 1 3 7 .2 1 , 1 3 4 .0 0 , 1 3 0 . 7 9 , 1 29 . 35 ,
1 2 8 .8 4 , 1 2 8 .7 1 , 1 2 8 .0 0 , 1 2 6 .6 7 , 1 2 6 .3 0 , 1 1 8 . 8 1 , 1 15 . 37 ,
1 1 4 .2 4 , 1 1 4 .1 9 , 1 1 2 .1 2 , 7 7 . 3 9 , 7 7 . 2 8 , 7 7 . 0 7 , 7 6 . 7 5 , 6 7. 1 5,
6 6 . 4 5 , 5 5 . 6 4 , 5 5 . 5 1 , 5 5 . 4 2 , 2 1 . 1 7 .
2
.
4
a
C
o
m
p
o
u
n
d
7
a
a
/
b
a
:
1
-
(
4
-
m
e
t
h
o
x
y
p
h
e
n
y
l
)
-
3
,
3
-
bis(40methoxyphenyl)-4-phenylazetidin-2-
one: C o l ou r l es s o i l ; y i e l d 6 3 . 6 % ( 0 . 0 7 g ) ; R : 0 . 1 3 ;
f
C H N O : A n a l . F o u n d : C , 7 7 . 4 3 ; H , 5 . 8 1 ; N , 3 . 0 4 %
3 0 2 7
4
-
1
C
a
l
c
.
:
C
,
7
7
.
4
0
;
H
,
5
.
8
4
;
N
,
3
.
0
0
%
.
I
R
(
c
m
)
:
m
,
(
C
=
O
)
2 . 4 e Compound 9ac: cis-1-(40-methoxyphenyl)-3-
allyl-3-(40-methylphenylthio)-4-phenylazetidin-2-
one: W h i t e s o l i d ; y i e l d 8 9 % ( 0 .1 g ) ; M . p . 1 2 6 - 1 29 °C ;
R : 0 . 5 0 ; C H N O S : A n a l . F o u n d : C , 7 5 . 1 9 ; H , 6 . 0 9; N ,
1
1
7
4
5
;
H
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
4
0
0
M
H
z
)
:
7
.
5
4
-
7
.
3
1
3
( m, 4 H , P h ) , 7 . 1 4 - 6 . 9 9 ( m , 7 H , P h ) , 6 . 9 1 -6 . 7 6 ( m , 4 H , P h ) ,
6 . 5 5 - 6 . 5 3 ( m , 2 H , P h ) , 5 . 6 7 ( s , 1 H , C - 4 ), 3 . 7 7 ( s , 3 H ,
1
3
O C H ) , 3 . 7 2 ( s , 3 H , O C H ) , 3 . 6 4 ( s , 3 H , O C H ) ;
3
C
f
2
6
2
5
2
3
3
-
1
3
.
3
1
%
C
a
l
c
.
:
C
,
7
5
.
1
5
;
H
,
6
.
0
6
;
N
,
3
.
3
6
%
.
I
R
(
c
m
)
:
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
1
0
0
M
H
z
)
:
1
6
7
.
2
5
,
1
5
9
.
2
5
,
3
1
m( C = O ) , 1 7 4 0 ; H N M R ( d, p p m i n C D C l , 4 0 0 M H z) : 7 .4 4 -
1 5 8 . 7 5 , 1 3 7 . 2 5 , 1 3 5 . 7 4 , 1 3 3 . 2 0 , 1 2 9 . 7 5 , 1 2 9 . 2 5 , 1 2 9 .0 5 ,
1 2 8 . 7 2 , 1 2 8 . 2 5 , 1 2 7 . 9 5 , 1 2 7 . 4 5 , 1 2 4 . 0 5 , 1 1 7 . 7 5 , 1 1 4 .7 5 ,
1 1 3 . 6 3 , 7 7 . 4 2 , 7 7 . 2 9 , 7 7 . 0 5 , 7 6 . 7 5 , 7 2 . 7 4 , 6 8 . 4 9 , 5 5 . 9 5 ,
5 5 . 2 5 , 5 5 . 0 5 .
3
7 . 2 3 ( m , 9 H , P h ) , 7 . 0 7 - 6 .7 8 ( m , 4 H , P h ) , 5 . 9 8 ( m , 1 H ,
H C = C H ) , 5 . 2 5 ( m , 2 H , H C = C H ) , 5 . 1 0 ( s , 1 H , C - 4 ), 3 .5 4
2
2
1
3
( s , 3 H , O C H ) , 2 . 6 ( m , 2 H , C H ) , 2 . 3 0 ( s , 3 H , C H ) ;
2
C
3
3

J. Chem. Sci.
(
2
0
2
0
)
1
3
2
:
1
2
9
P
a
g
e
5
o
f
1
1
1
2
9
-
1
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
1
0
0
M
H
z
)
:
1
6
6
.
6
1
,
1
5
6
.
2
3
,
C
a
l
c
.
:
C
,
7
7
.
8
8
;
H
,
6
.
0
1
;
N
,
3
.
6
3
%
.
I
R
(
c
m
)
:
m
,
1
7
7
0
;
3
(
C
=
O
)
1
1 3 8 . 8 1 , 1 3 5 . 8 0 , 1 3 3 . 5 9 , 1 3 2 . 6 8 , 1 3 0 . 8 0 , 1 2 9 . 6 0 , 1 2 8 .7 7 ,
1 2 8 . 3 6 , 1 2 8 . 0 2 , 1 2 6 . 3 7 , 1 1 9 . 7 3 , 1 1 8 . 8 4 , 1 1 8 . 7 7 , 1 1 4 .4 0 , P h ) , 7 . 3 9 - 7 . 2 5 ( m , 9 H , P h ) , 7 . 1 1 - 7 . 0 7 ( m , 3 H , P h ) , 6 . 0 0 ( m ,
H
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
4
0
0
M
H
z
)
:
7
.
4
8
-
7
.
4
5
(
m
,
2
H
,
3
7 7 . 4 1 , 7 7 . 3 0 , 7 7 . 1 0 , 7 6 . 7 8 , 6 5 . 9 9 , 6 3 . 5 7 , 5 5 . 5 2 , 3 7 . 9 3 , 1 H , H C = C H ) , 5 . 2 7 ( m , 2 H , H C = C H ) , 5 . 1 7 ( s , 1 H , C - 4 ),
2
2
1 3
2 . 6 6 ( m , 2 H , C H ) , 2 . 3 3 ( s , 3 H , C H ) ; C N M R (d, p pm i n
2 1 . 2 8 .
2
3
C D C l , 1 0 0 M H z ) : 1 6 7 .2 9 , 1 3 8 .9 9 , 1 3 7 .4 2 , 1 3 5 .9 6 , 1 33 . 56 ,
3
1 3 2 .6 8 , 1 2 9 .7 4 , 1 2 9 .2 8 , 1 2 8 .9 1 , 1 2 8 .8 0 , 1 2 8 . 7 5 , 1 28 . 49 ,
1 2 8 .0 9 , 1 2 6 .4 0 , 1 2 4 .3 0 , 1 1 9 .9 4 , 1 1 7 .7 2 , 1 1 7 . 6 8 , 1 17 . 62 ,
7 7 . 5 6 , 7 7 . 4 5 , 7 7 . 2 5 , 7 6 . 9 3 , 6 6 . 0 5 , 6 3 . 6 2 , 3 7 . 9 9 , 2 1 . 4 1.
0
0
2
.
4
f
C
o
m
p
o
u
n
d
9
b
b
:
c
i
s
-
1
-
(
4
-
m
e
t
h
o
x
y
p
h
e
n
y
l
)
-
3
-
(
4
-
chlorophenylthio)-3-(20,50-dimethoxy
phenyl)-4-
c r y s t a l s ; y i e l d
phenylazetidin-2-one: C o l o u r l e s s
(
0
.
0
5
9
g
)
;
M
.
p
.
1
5
2
-
1
5
4
°
C
;
R
:
0
.
2
6
;
C
H
N
O
S
C
l
:
f
3
0
2
6
4
2
.
4
j
C
o
m
p
o
u
n
d
9db:
cis-1-phenyl-3-(40-
A n a l . F o un d : C , 6 7 . 7 6 ; H , 4 . 8 8 ; N , 2 . 6 9 % C a l c . : C ,
1
-
1
chlorophenylthio)-3-(20,50-dimethoxyphenyl)-4-
6
7
.
7
2
;
H
,
4
.
9
2
;
N
,
2
.
6
3
%
.
I
R
(
c
m
)
:
m
,
1
7
3
0
;
H
(
C
=
O
)
phenylazetidin-2-one: Y e l l o w o i l ; y i e l d 6 9 % ( 0. 1 g );
R : 0 . 4 3 ; C H N O S C l: A n a l. F o u n d : C , 6 9 . 4 2 ; H , 4 .8 6 ;
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
4
0
0
M
H
z
)
:
7
.
6
0
-
7
.
4
1
(
m
,
5
H
,
P
h
)
,
3
f
2
9
2
4
3
7 . 2 5 - 6 . 9 5 ( m , 7 H , P h ) , 6 . 8 1 - 6 . 7 3 ( m , 4 H , P h ) , 5 . 5 0 ( s , 1 H ,
C - 4 ) , 3 . 7 9 ( s , 3 H , O C H ) , 3 . 7 2 ( s , 3 H , O C H ) , 3 . 5 5 ( s , 3 H ,
-
1
N
,
2
.
7
3
%
C
a
l
c
.
:
C
,
6
9
.
3
8
;
H
,
4
.
8
1
;
N
,
2
.
7
8
%
.
I
R
(
c
m
)
:
3
3
1
1
3
m( C = O ) , 1 7 5 4 ; H N M R ( d, p p m i n C D C l , 4 0 0 M H z) : 7 .6 1 -
3
O
C
H
)
;
C
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
1
0
0
M
H
z
)
:
1
6
5
.
0
9
,
3
3
7 . 4 2 ( m , 5 H , P h ) , 7 . 3 0 - 7 . 1 8 ( m , 4 H , P h ) , 7 . 0 3 - 6 . 9 6 ( m , 6 H ,
P h ) , 6 . 8 1 - 6 . 7 4 ( m , 2 H , P h ) , 5 . 5 4 ( s , 1 H , C - 4 ) , 3 . 7 9 ( s , 3 H ,
1 5 6 . 1 5 , 1 5 2 . 8 8 , 1 5 0 . 5 9 , 1 3 8 . 2 6 , 1 3 5 . 1 7 , 1 3 3 . 8 0 , 1 3 0 .6 4 ,
1 2 9 . 2 9 , 1 2 8 . 9 5 , 1 2 8 . 9 2 , 1 2 8 . 0 4 , 1 2 5 . 9 3 , 1 1 8 . 8 4 , 1 1 5 .4 3 ,
1 1 4 . 3 6 , 1 1 4 . 2 7 , 1 1 2 . 2 2 , 7 7 . 3 4 , 7 7 . 2 3 , 7 7 . 0 2 , 7 6 . 7 1 , 6 7 . 3 1 ,
6 6 . 5 3 , 5 5 . 7 3 , 5 5 . 4 1 .
1
3
O
C
H
)
,
3
.
5
4
(
s
,
3
H
,
O
C
H
)
;
C
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
3
3
3
1 0 0 M H z ) : 1 6 5 .7 5 , 1 5 2 .8 7 , 1 5 0 .6 3 , 1 3 8 .8 2 , 1 3 7 . 1 4 , 1 35 . 27 ,
1 3 3 .7 0 , 1 2 9 .2 7 , 1 2 9 .0 7 , 1 2 8 .8 6 , 1 2 8 .1 2 , 1 2 5 . 7 3 , 1 24 . 19 ,
1 1 7 .5 9 , 1 1 5 .4 8 , 1 1 4 .3 6 , 1 1 2 .2 7 , 7 7 . 4 4 , 7 7 . 1 2 , 7 6 . 8 1 , 6 7. 2 5,
6 6 . 4 7 , 5 5 . 7 5 , 5 5 . 4 7 .
2 . 4 g Compound 9bc: cis-1-(40-methoxyphenyl)-3-
allyl-3-(40-chlorophenylthio)-4-phenylazetidin-2-
one: W h i t e s o l i d; y i e l d 9 0 % ( 0 . 0 9 2 g ) ; M . p . 1 0 0 - 1 0 3 °C ;
R : 0 . 3 6 ; C H N O SC l : A n a l . F o u n d : C , 6 8 . 8 1 ; H , 5 . 0 2 ; N ,
2 . 4 k Compound 9dc: cis-1-phenyl-3-allyl-3-(40-
chlorophenylthio)-4-phenylazetidin-2-one: L i gh t
y e l l o w s e m i s o l i d ; y i e l d 9 4 % ( 0 .0 9 1 c g ) ; R : 0 .6 6 ;
f
2
5
2
2
-
1
3
.
2
5
%
C
a
l
c
.
:
C
,
6
8
.
8
7
;
H
,
5
.
0
8
N
,
3
.
2
1
%
.
I
R
(
c
m
)
:
f
1
m( C = O ) , 1 7 2 0 ; H N M R ( d, p p m i n C D C l , 4 0 0 M H z ) : 7 . 5 1 -
3
C H N O SC l : A n a l. F o u n d : C , 7 1 . 0 5 ; H , 4 . 9 2 N , 3 .4 6 %
2 4 2 0
-
1
7 . 3 3 ( m , 5 H , P h ) , 7 . 2 9 -7 . 2 0 ( m , 6 H , P h ) , 6 , 8 3 -6 . 7 9 ( m , 2 H ,
P h ) , 5 . 9 5 ( m , 1 H , H C = C H ) , 5 . 5 0 ( m , 2 H , H C = C H ) , 5 . 1 1
C
a
l
c
.
:
C
,
7
1
.
0
1
;
H
,
4
.
9
6
;
N
,
3
.
4
4
%
.
I
R
(
c
m
)
:
m
,
1
7
6
0
;
(
C
=
O
)
1
2
2
H
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
4
0
0
M
H
z
)
:
7
.
4
0
-
7
.
3
9
(
m
,
2
H
,
3
1
3
( s, 1 H , C - 4 ) , 3 . 7 5 ( s , 3 H , O C H ) , 2 . 6 5 ( m , 2 H , C H ) ;
3
C
2
P h ) , 7 . 3 0 - 7 . 1 2 ( m , 1 0 H , P h ) , 7 . 0 1 - 6 . 9 7 ( m , 2 H , P h ), 5 .8 7
( m , 1 H , H C = C H ) , 5 . 1 7 ( m , 2 H , H C = C H ) , 5 . 0 7 ( s , 1 H ,
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
1
0
0
M
H
z
)
:
1
6
7
.
5
2
,
1
5
8
.
2
3
,
3
2
2
1
3
1 3 7 . 7 5 , 1 3 5 . 2 5 , 1 3 4 . 6 0 , 1 3 2 . 2 5 1 3 1 . 7 5 , 1 3 0 . 5 0 , 1 2 8 .5 0 ,
1 2 8 . 2 5 , 1 2 7 . 5 0 , 1 2 6 . 7 3 , 1 2 0 . 5 0 , 1 1 9 . 7 5 , 1 1 8 . 3 0 , 1 1 6 .2 0 ,
7 7 . 2 5 , 7 7 . 0 5 , 7 6 . 9 0 , 7 6 . 7 5 , 6 5 . 2 5 , 6 3 . 2 5 , 5 5 . 7 5 , 3 9 . 5 2 .
C
-
4
)
,
2
.
7
5
(
m
,
2
H
,
C
H
)
;
C
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
2
3
1 0 0 M H z ) : 1 6 6 .7 6 , 1 3 7 .1 2 , 1 3 7 .0 2 , 1 3 6 .6 6 , 1 3 4 . 9 6 , 1 33 . 17 ,
1 3 2 .0 6 , 1 2 9 .4 6 , 1 2 9 .3 1 , 1 2 9 .1 9 , 1 2 8 .9 7 , 1 2 8 . 8 9 , 1 28 . 80 ,
1 2 8 .6 8 , 1 2 8 .4 2 , 1 2 7 .8 8 , 1 2 4 .3 6 , 1 2 0 .1 1 , 1 1 7 . 7 3 , 1 17 . 51 ,
7 7 . 4 0 , 7 7 . 2 9 , 7 7 . 0 9 , 7 6 . 7 2 , 6 6 . 0 0 , 6 3 . 5 5 , 3 7 . 9 1 .
2
.
4
h
C
o
m
p
o
u
n
d
9cb:
cis-1-phenyl-3-(20,50-
dimethoxyphenyl)-3-(40-methylphenylthio)-4-
2 . 4 l Compound 10aa/ab: 1-(40-methoxyphenyl)-3,3-
bis(40-methylphenylthio)-4-phenylazetidin-2-
phenylazetidin-2-one: W h i t e c r y s t a l l i n e s o l i d ; y i e l d
4 2 . 8 5 ( 0 . 0 6 g ) ; M . p . 1 0 6 - 1 0 8 °C ; R : 0 . 4 0 ; C H N O S :
A n a l . F o un d : C , 7 4 . 8 5 ; H , 5 . 7 1 ; N , 2 . 8 5 % C a l c . : C , 7 4 . 8 2 ;
f
3
0
2
7
3
one: C o l o u r l e s s c r y s ta ls ; y i e l d 3 6 . 3 % ( 0 .0 4 g ) ; M . p .
1 0 8 - 1 1 0 °C ; R : 0 . 5 3 ; C H N O S : A n a l. F o u n d: C ,
7 2 . 3 6 ; H , 5 . 4 9 ; N , 2 . 8 5 % C a l c .: C , 7 2 . 4 0 ; H , 5 . 4 6; N ,
-
1
1
H
,
5
.
6
5
;
N
,
2
.
9
0
%
.
I
R
(
c
m
)
:
m
,
1
7
7
0
;
H
N
M
R
(
d
,
(
C
=
O
)
f
3
0
2
7
2
p p m i n C D C l , 4 0 0 M H z ) : 7 . 6 4 - 7 . 4 1 ( m , 5 H , P h ) , 7 .3 0 - 7 . 1 5
3
-
1
1
( m , 4 H , P h ) , 7 . 0 3 - 6 . 9 3 ( m , 4 H , P h ) , 6 . 8 7 -6 . 7 1 ( m , 4 H , P h ) ,
5 . 5 5 ( s , 1 H , C - 4 ) , 3 . 8 1 ( s , 3 H , O C H ) , 3 . 4 8 ( s , 3 H , O C H ) ,
2
.
8
1
%
.
I
R
(
c
m
)
:
m
,
1
7
3
0
;
H
N
M
R
(
d
,
p
p
m
i
n
(
C
=
O
)
C D C l , 4 0 0 M H z ) : 7 . 5 5 - 7 . 5 3 ( m , 2 H , P h ) , 7 . 3 8 - 7 . 25 ( m ,
5 H , P h ) , 7 . 1 3 - 7 . 0 5 ( m , 8 H , P h ) , 6 . 7 4 - 6 .7 2 ( m , 2 H , P h ) , 5 .1 2
3
3
3
1
3
2
.
2
2
(
s
,
3
H
,
C
H
)
;
C
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
1
0
0
M
H
z
)
:
3
3
1
3
1 6 6 . 1 4 , 1 5 2 . 7 2 , 1 5 0 . 6 9 , 1 3 8 . 8 7 , 1 3 7 . 2 7 , 1 3 7 . 2 2 , 1 3 3 .9 1 ,
1 2 9 . 3 0 , 1 2 9 . 2 2 , 1 2 9 . 0 1 , 1 2 8 . 8 9 , 1 2 8 . 8 1 , 1 2 8 . 7 4 , 1 2 8 .0 4 ,
1 2 6 . 6 0 , 1 2 6 . 1 3 , 1 2 4 . 0 0 , 1 1 7 . 5 5 , 1 1 5 . 4 2 , 1 1 4 . 2 0 , 1 1 2 .2 7 ,
7 7 . 4 0 , 7 7 . 2 9 , 7 7 . 0 8 , 7 6 . 7 6 , 6 7 . 0 8 , 6 6 . 4 0 , 5 5 . 6 4 , 5 5 . 5 5 ,
2 1 . 1 8 .
( s , 1 H , C - 4 ) , 3 . 7 2 ( s , 3 H , O C H ) , 2 . 3 1 ( s , 6 H , C H ) ;
3
C
3
N M R (d, p p m i n C D C l , 1 0 0 M H z ) : 1 6 3 .0 7 , 1 56 . 53 ,
3
1 3 9 .8 4 , 1 3 8 .8 0 , 1 3 5 .8 4 , 1 3 5 .3 6 , 1 3 2 .8 0 , 1 3 0 . 3 0 , 1 29 . 89 ,
1 2 9 .3 3 , 1 2 8 .9 2 , 1 2 8 .2 7 , 1 2 8 .1 6 , 1 2 7 .0 1 , 1 2 6 . 2 7 , 1 18 . 91 ,
1 1 4 .2 4 , 7 7 . 3 6 , 7 7 . 2 5 , 7 7 . 0 4 , 7 6 . 7 2 , 7 2 . 5 3 , 6 6 . 9 2 , 5 5. 4 3,
2 1 . 3 0 .
2 . 4 i Compound 9cc: cis-1-phenyl-3-allyl-3-(40-
methylphenylthio)-4-phenylazetidin-2-one: L i g h t
y e l l o w s em i s o l i d ; y i e l d 9 0 % ( 0 . 0 8 3 g ) ; R : 0 . 5 3 ;
2 . 4 m Compound 10ba/bb: 1-(40-methoxyphenyl)-3,3-
bis(40-chlorophenylthio)-4-phenylazetidin-2-
f
one: W h i t e s o l i d ; y i e l d 5 4 . 1 % ( 0 .0 6 5 g ) ; M . p .
C H N O S : A n a l . F o u n d : C , 7 7 . 8 2 ; H , 6 . 0 5 ; N , 3 . 6 6 %
2 5 2 3

1
2
9
P
a
g
e
6
o
f
1
1
J. Chem. Sci.
(
2
0
2
0
)
1
3
2
:
1
2
9
1
1
8
-
1
2
0
°
C
;
R
:
0
.
4
0
;
C
H
N
O
S
C
l
:
A
n
a
l
.
F
o
u
n
d
:
C
,
F o r t h es e s t u d i e s , p- me t h y l a n d p- ch l o r o t h i o p h e n o l
w e re t a k e n a s t h e s t ar t i n g s u b s t r a t e s w h i ch o n r e a c t i o n
w i t h c h l o ro ac e t i c a ci d g a v e 2 - ( 4 0- me t h y l / c h l o r -
f
2
8
2
1
2
2
2
6 2 . 3 6 ; H , 3 . 8 9 ; N , 2 . 6 4 % C a l c . : C , 6 2 . 4 0 ; H , 3 . 9 3 ; N ,
1
2 . 6 0 % . I R ( c m -1 ) : m( C = O ) , 1 7 3 5 ; H N M R ( d, p p m i n
C D C l , 4 0 0 M H z) : 7 . 5 9 -7 . 5 6 ( m , 2 H , P h ) , 7 . 3 6 -7 . 2 8 ( m ,
1 5
3
o p h en y l t h i o ) e t h an oi c a ci d 1 & 2 r es p e ct i v e l y . F u r -
7 H , P h ) , 7 . 2 0 - 7 . 1 0 ( m , 6 H , P h ) , 6 . 7 7 - 6 . 7 4 ( m , 2 H , P h ) , 5 . 1 3
1 3
t h er r ea c t i o n o f c o m p o u n d 1 & 2 w i t h S ch i f f b a s e 3 i n
t h e p r e s e n c e o f t r i et h y l am i n e a n d p h o s p h o ru s o x y -
c h l o ri d e r es u l t ed i n t h e f o r ma t i o n o f trans- 3 - ( 40-
m et h y l / c h l o r o ph e n y l t h i o ) b- l a c t a ms 4 a s t h e m a j o r
p r o d u c t . H o w e v e r , w i t h S ch i f f b a s e 3b, t h e r e a c t i o n
a l s o g a v e cis- 3 - ( 40- me t h y l / ch lo r o p h e n y l t h i o ) b- l a c t a m
5b a s t h e m i n o r p r o d u ct . T h e s t er e o c h e mi s t r y o f t h e s e
b- l a c t a ms w a s a s s i g n e d b a s e d o n t h e c o u p l i n g c o n s t a n t
v a l u es o f C 3 - H a n d C 4 - H ( J = 2 . 3 6 H z f o r trans &
J = 5 . 6 H z f o r cis i s o m er ) ( Sc h e m e 1 ) . T h e p r e f e r -
e n t i al f o r m at i o n o f trans- b- l a c t a ms i n t h i s r ea c t i o n c a n
(
s
,
1
H
,
C
-
4
)
,
3
.
7
2
(
s
,
3
H
,
O
C
H
)
;
C
N
M
R
(
d
,
p
p
m
i
n
3
C
D
C
l
,
1
0
0
M
H
z
)
:
1
6
4
.
0
5
,
1
5
7
.
7
5
;
1
3
8
.
8
5
,
1
3
8
.
2
5
,
1
3
5
.
2
0
,
3
1 3 4 . 8 9 , 1 3 2 . 9 0 , 1 3 0 . 7 5 , 1 2 9 . 9 0 , 1 2 9 . 2 5 , 1 2 8 . 9 5 , 1 2 8 .2 0 ,
1 2 7 . 9 5 , 1 2 7 . 0 5 , 1 2 6 . 7 5 , 1 1 8 . 9 5 , 1 1 4 . 5 0 , 7 7 . 7 5 , 7 7 . 2 5 , 7 7 . 0 2 ,
7 6 . 7 5 , 7 2 . 2 5 , 6 7 . 8 5 , 5 5 . 5 0 .
2
.
4
n
C
o
m
p
o
u
n
d
10ca/cb:
1-phenyl-3,3-bis(40-
methylphenylthio)-4-phenylazetidin-2-one: W h i t e
s o li d ; y i el d 5 4 % ( 0 . 0 5 1 g ) ; M . p . 9 0 - 9 3 °C ; R : 0 . 5 6 ;
f
C
H
N
O
S
:
A
n
a
l
.
F
o
u
n
d
:
C
,
7
4
.
5
1
;
H
,
5
.
3
2
;
N
,
2
.
9
5
%
2
9
2
5
2
-
1
C
a
l
c
.
:
C
,
7
4
.
4
8
;
H
,
5
.
3
8
;
N
,
2
.
9
9
%
.
I
R
(
c
m
)
:
m
,
1
7
5
0
;
(
C
=
O
)
1
H
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
4
0
0
M
H
z
)
:
7
.
5
5
-
7
.
5
3
(
m
,
2
H
,
b e r a t i o n al i z ed o n t h e b a s i s o f c y c l i z a t i o n o f i s o m e r -
1 6 ,1 7
3
P h ) , 7 . 3 9 - 7 . 2 5 ( m , 5 H , P h ) , 7 . 2 1 -7 . 1 1 ( m , 6 H , P h ) , 7 . 0 7 -
7 . 0 1 ( m , 5 H , P h ) , 5 . 1 7 ( s , 1 H , C - 4 ), 2 . 3 0 ( s , 3 H , C H ) , 2 . 3 1
i
z
e
d
z
w
i
t
t
e
r
i
o
n
i
c
i
n
t
e
r
m
e
d
i
a
t
e
.
H
o
w
e
v
e
r
,
t
h
e
f
o
r
-
3
m at i o n o f m i n o r cis b- l a c t a ms 5c & 5d i n d i c a t e s d i r e c t
r i n g c l o s u r e o f z w i t t er i o n i c i n t e rm e d i at e s u b st i t u t e d
1 6 , 1 7
w i t h s t er i ca l l y l e s s h i n d e r ed s u b s t i t u e n t a t C -4 .
1
3
(
s
,
3
H
,
C
H
)
;
C
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
1
0
0
M
H
z
)
:
3
3
1 6 3 . 3 1 , 1 3 9 . 9 6 , 1 3 8 . 9 1 , 1 3 6 . 8 9 , 1 3 5 . 8 8 , 1 3 5 . 4 3 , 1 3 2 .6 5 ,
1 2 9 . 9 5 , 1 2 9 . 3 9 , 1 2 9 . 0 1 , 1 2 8 . 9 8 , 1 2 8 . 3 3 , 1 2 8 . 0 9 , 1 2 6 .8 8 ,
1 2 6 . 2 2 , 1 2 4 . 3 4 , 1 1 7 . 5 5 , 7 7 . 4 1 , 7 7 . 3 0 , 7 7 . 0 9 , 7 6 . 7 7 , 7 2 . 5 1 ,
6 6 . 8 2 , 2 1 . 3 4 .
T h e f o r m at i o n o f cis b- l a c t a ms w i t h p h en y l / b e n z yl /
m et h y l t h i o s u b s t i t u e n t s a t C -3 h a s n o t b e e n r ep or t ed s o
f ar . S o , t o t h e b e s t o f o u r k n o w l e d g e , t h i s i s t h e fi r st
e x a mp l e w h e r e cis b- l a c t a ms o f t y p e 5 h a v e b e e n
s y n t h e s i s e d . H o w e v e r , a s t h e cis i s o m er w a s a m i n o r
p r o d u c t s o i t c o u l d n o t b e u s e d f o r f u r t h er s t u d i e s . T h e
r es u l t s a r e s u m m ar i ze d i n T a b l e 1.
2
.
4
o
C
o
m
p
o
u
n
d
10da/db:
1-phenyl-3,3-bis(40-
chlorophenylthio)-4-phenylazetidin-2-one: W h i t e
s
o
l
i
d
;
y
i
e
l
d
4
2
.
2
%
(
0
.
0
5
2
g
)
;
M
.
p
.
1
0
1
-
1
0
2
°
C
;
R
:
0
.
7
;
f
C
H
N
O
S
C
l
:
A
n
a
l
.
F
o
u
n
d
:
C
,
6
3
.
7
2
;
H
,
3
.
7
9
;
N
,
2
.
7
2
%
2
7
1
9
2
2
O n l y trans- 3 - ( 40- me t h y l / ch l o ro p h en y l t h i o ) b- l a c -
t a m s 4 w a s s u b j e ct ed t o c h l o ri n a t i o n r e ac t i o n w i t h
s u l f u r y l c h l o ri d e i n d i ch l o r o m e t h a n e a t 0 °C . T h e
r e ac t i o n f u r n i s h e d cis- 3 - c h l o r o - 3 - ( 40- me t h y l / c h l o r -
o p h en y l t h i o ) -b- l a c t a ms 6 i n g o o d y i el d s ( T a b l e 2) .
T h e s t ru ct u r e s o f c o m p o u n d s 6 w e r e c o n fi r me d o n t h e
-
1
C
a
l
c
.
:
C
,
6
3
.
7
7
;
H
,
3
.
7
6
;
N
,
2
.
7
5
%
.
I
R
(
c
m
)
:
m
,
1
7
4
0
;
(
C
=
O
)
1
H
N
M
R
(
d
,
p
p
m
i
n
C
D
C
l
,
4
0
0
M
H
z
)
:
7
.
7
0
-
7
.
6
7
(
m
,
2
H
,
3
P h ) , 7 . 5 9 - 7 . 4 5 ( m , 5 H , P h ) , 7 . 3 1 -7 . 2 5 ( m , 6 H , P h ) , 7 . 1 1 -
1 3
7 . 0 5 ( m , 5 H , P h ) , 5 . 1 7 ( s , 1 H , C - 4 ); C N M R ( d, p p m i n
C D C l , 1 0 0 M H z ) : 1 6 2 . 7 6 , 1 3 2 . 0 2 , 1 3 6 . 6 8 , 1 3 6 . 5 6 , 1 3 6 .1 4 ,
3
1 3 5 . 1 3 , 1 3 2 . 3 9 , 1 3 2 . 1 2 , 1 2 9 . 9 6 , 1 2 9 . 3 9 , 1 2 9 . 3 2 , 1 2 9 .1 8 ,
1 2 8 . 7 8 , 1 2 8 . 6 9 , 1 2 8 . 5 2 , 1 2 8 . 2 5 , 1 2 8 . 0 5 , 1 2 7 . 6 9 , 1 2 5 .1 2 ,
1 2 4 . 1 6 , 1 1 7 . 7 1 , 1 1 7 . 5 5 , 7 7 . 3 6 , 7 7 . 2 5 , 7 7 . 0 5 , 7 6 . 7 3 , 7 2 . 3 5 ,
6 8 . 7 1 , 6 7 . 2 3 .
1
1
3
b a s i s o f F T I R, H N M R a n d C N M R s p e c t r o sc o p i c
a n a l y s i s . T h e s t er e o c h e m i s t ry o f b- l a c t a m s w as
a s s i g n e d o n t h e b a s i s o f c o r r el at i o n o f s p e c t r a l d a t a o f
6 w i t h t h at o f cis- 3 - c h l o r o - 3 - p h en y l th i o -b- l a c t a m s
w h o s e s t er e o c h e mi s t r y h a s a l r e ad y b e e n e s t a b l i s h e d b y
1
6
3. Results and Discussion
X - r ay c ry s t a l l o g r a p h i c a n a l y s i s . T h e s e c o m p o u n d s
w e r e t h en u s e d a s a s u b s t r a t e f o r L e w i s a ci d p r o m o t e d
C -3 f u n c t i o n a l i za t i o n .
O u r p r e v i o u s s t u d i e s h a ve s h o w n t ha t cis- 3 - c h l o r o - 3 -
9 –1 2
p
h
e
n
y
l
/
b
e
n
z
y
l
/
m
e
t
h
y
l
t
h
i
o
b
-
l
a
c
t
a
m
s
a
r
e
s u i t -
a b l e s u b s t r a t e s f o r C - 3 n u c l e o p h i l ic s u bs t it u t i o n i n t h e
I n i t i a l s t u d i es w e re c ar r i e d o u t u s i n g 6a a n d t r e a t i n g
i t w i t h a n i s o l e a s t h e n u c l eo p h i l e i n t h e p r e s e n c e o f
T i Cl i n d i ch l o r o m e t h a ne u n d er n i t r o g e n a t m os p h e r e
p r e s e n ce o f L e w i s a c i d ( T i C l / S n C l ) . H o w e v e r, t h e
4
4
4
r e a c t i o n r e s u l t s i n t h e f or m a t i on o f a m i x tu re o f p r o d u c t s
w h i c h i n c l u d e d m o no s u bs tit ut e d , d is ub s t i tu t ed a s w e l l
a s 3 , 3 –b i s ph en yl t h i o - b- la c t a m s a s t he s i d e p r o d u c t . S o ,
t h e p r e s e n t s t u d i e s w e r e a i m e d t o fi n d i f t h e s u bs t i t u t i o n
o f p h e n y l t hi o g r o u p a t C - 3 b y s o m e e l e c t ro n r e l e as i n g o r
e l ec t r o n - w i t h d ra w i n g g ro u p w i l l c h a n g e t he p r o d u c t
p r o fi l e . F u r t h e r , i t w a s e n vi s a g e d t o s t u dy w h e t h e r t h i s
s u b s t i t u t i o n o n t h e p h e n y l r in g w i l l h a v e a n y e ff e c t o n
t h e s t e r eo ch em i s tr y o f t he p r o du c t f o r m e d .
a t 0 °C . T h e r ea c t i o n w a s d o n e u s i n g o p t i m i s e d c o n -
d i t i o n s f r o m o u r p r e v i o u s w o r k . T h e p r o d u ct p r o fi l e
s h o w ed t h e f o r m at i o n o f t w o c o m p o u n d s w h i c h a f t e r
c h r o m at o g r a p h i c p u r i fic a t i o n w e re f o u n d t o b e 1 - ( 4 0-
m et h o x y p h e n y l ) -3 , 3 -b i s ( 40- me t h o x y p h e n y l )- 4 - ph e n y -
l a z e t i d i n - 2 - o n e 7aa a n d 1 - ( 40- me t h o x y p h e n yl ) - 3 , 3 -
b i s ( 40- me t h y l p h e n y l t h i o ) - 4- p h e n y l a ze t i d i n -2 - o n e 10aa
b a s e d o n t h ei r s p e c t r o s c o p i c c h a r ac t e r i z at i o n . T h e s e
r e s u l t s w e r e s i mi l a r a s r e p o r t e d e ar l i e r f o r cis- 3 -

J. Chem. Sci.
(
2
0
2
0
)
1
3
2
:
1
2
9
P a g e 7 o f 1 1
1
2
9
i) NaOH, H2O, reflux
ii) H+/HCl
RSCH2COOH
ClCH2COOH
R SH
1/2
1: R == C6H4.CH3(4)
2: R == C6H4.Cl(4)
R1
H
Molecular sieves
CH2Cl2, RT
R2NH2
R1CHO
N
R2
3a-c
a: R1 = C6H5,
b: R1 = C6H5,
R2 = C6H4.OCH3(4)
R2 = C6H5
c: R1 = C6H4.OCH3(4), R2 = C6H4.OCH3(4)
H H
N
H H
R1
H
RS
R1
R2
RS
R1
R2
POCl3, Et3N
RSCH2COOH
1/2
N
N
R2
Toluene, reflux
O
O
3a-c
4a-f
5c-d
(Major)
(Minor)
Cl H
H H
N
SO2Cl2, O0C
CH2Cl2
RS
R1
R2
RS
R1
R2
N
O
O
6a-f
4a-f
Scheme 1. S y n t h e s i s o f trans a n d cis- 3 - ( 4 0- m e t h y l/ c h l o r o p h e n y l t h i o ) b- l a c t a m s .
Table 1. S y n t h es i s o f trans a n d cis- 3 - ( 4 0- m e t h y l /c h l o r o p h e n y l t h i o ) b- l a c t a m s (4a-f & 5c-d) f r o m 2 - ( 4 0- m e t h y l / ch l o r-
o p h e ny l t h i o ) e th a n o i c a c i d (1/2) a n d S c h i ff b a s e ( 3a-c) u s i n g P O C l a n d E t N .
3
3
Trans ( % )
(4)
Cis ( % )
(5)
E
n
t
r
y
R
R
R
T
o
t
a
l
y
i
e
l
d
(
%
)
1
2
1
2
3
4
5
6
C H . C H ( 4 )
6
C H
6
C H
6
C H
6
C H
6
C H O C H ( 4 )
6
5 5
5 0
5 2
5 4
7 5
7 9
4a ( 5 5 )
4b ( 5 0 )
4c ( 3 9 .3 )
4d ( 4 0 .6 )
4e ( 7 5 )
4f ( 7 9 )
-
-
4
3
5
5
5
5
4
.
3
C H . C l ( 4 )
4
C H O C H ( 4 )
3
6
6
4
.
C H . C H ( 4 )
6
C H
6
5c ( 12 . 7)
5d ( 13 . 4)
-
-
4
3
5
C H . C l ( 4 )
6
C H
6
4
5
C H . C H ( 4 )
3
C H O C H ( 4 )
4 .
C H O C H ( 4 )
3
6
4
6
3
6
4
.
C H . C l ( 4 )
6 4
C H O C H ( 4 )
3
C H O C H ( 4 )
6 4 . 3
6
4
.
9,1 1
c h l or o - 3 - p h e n yl t h io b- la c t a m s
s t r a t e 6a h a s t h e s a m e r e a c t iv it y .
i nd ic a t i ng t h a t s u b - s p o t s s h o w ed t h e d a t a f o r t h e m o n o s u b s t i t u t e d p r o d u c t .
T h e m ai n d i ff e r en ce w a s i n t h e p o s i t i o n o f C -4 p r o t o n
N e x t , f o r t h e s e r e a c t io n s , 1 , 4- di m e t h o x y b e n z en e w h i ch r es o n a t e d a t d = 5 . 5 2 & 5 . 1 2 p p m . T h e s am e
w a s u s e d a s t h e n u c l e o p h i l e . T h e t re a t m e nt o f c o m - r e ac t i o n w i t h cis- 3 - c h l o r o - 3 - ph e n y l t h i o b- l a c t a m h a d
p o u n d 6a w i t h t h i s n u c l e o p h i le r e s u l t e d i n t h e f o r m a- b e e n r e p o r t e d t o g i v e d i s u b s t i t u t e d p r o d u c t w h i l e
t i o n o f t h r e e n e w s p ot s . A f te r c h r o m a t o g r a p h i c 3 - b e n z y l t h i o g a v e trans m o n o s u b s t i t u t e d p r o d u c t
p u r i fi c at i o n , t h e u p p e r s p ot w a s f o u nd t o b e t h at o f (d = 5 . 1 9 ) w h o s e s t er e o c h e mi s tr y h a d b e e n e st a b -
1 - ( 40- m e t h o x y p h e n y l )- 3, 3 -b is (40- m e t h y l ph e n y l th i o ) -4 - l i s h e d o n t h e b a s i s o f t h ei r s t er e o s p ec i fi c d e s u l f u r i z a -
1
1
p
h
e
n
y
l
a
z
e
t
i
d
i
n
-
2
-
o
n
e
1
0
a
b
a
n
d
b
o
t
h
t
h
e
l
o
w
e
r
t
w
o
t
i
o
n
s
t
u
d
i
e
s
.
T
h
e
3
-
m
e
t
h
y
l
t
h
i
o
-
b
-
l
a
c
t
a
m
s
h
a
d
a

1 2 9 P a g e 8 o f 1 1
J. Chem. Sci.
( 2 0 2 0 ) 1 3 2 : 1 2 9
d i me t h o x y p h e n y l) - 3 - (4 0- me t h y l p h e n y l t h io ) - 4 - p h e n y -
l a z et i d i n - 2 - o n e 8ab (d = 5 . 1 2 ) .
Table 2. S y n t h es i s o f cis- 3 - c h l o r o - 3 - ( 4 0- m e t h y l /c h l o r -
o p h e ny l t h i o ) - b- l a ct a m s ( 6a-d) f ro m trans- 3 - ( 4 0- m e t h y l /
c h l o r o p h e n y l t hi o ) b- l a c t a m s (4a-d) u s i n g S O C l .
2
2
T h e o t h e r s u b s t r a t e t r i ed f o r t h es e s t u d i e s w as 6b
h a v i n g e l e c t r o n - w i t h d r a w i n g c h l o ro g r o u p a t p h e -
n y l t h i o s u b s t i t u e n t a t C -3 . I t w a s e n v i s a g e d t h a t t h i s
d i ff e r en t s u b s t i t u t i o n m ay h a v e a d i ff e r en t e f f ec t o n
r e ac t i o n r e s u l t s . H o w e v e r , h e r e a l s o t h e r e a c t i o n
s h o w ed t h e s a m e r ea c t i v i t y p r o fi l e a s s e e n i n t h e c a se
o f 6a. W i t h 1 , 4 -d i m et h o x y b e n z e n e a s t h e n u c l e -
o p h i l e, f o r t h es e c o m p o u n d s a g a i n cis m o n o s u b s t i -
t u t e d p r o d u ct w a s o b t a i n e d p r e fe r a b l y ( T a b l e 3) .
F u r t h e r t o s t u d y t h e e ff e c t o f t h e s t o i c h i o m e t r y o f
n u cl eo p h i l e a n d t e m p e ra t u r e o n p r o d u ct d i s t r i b u t i o n ,
t h e s t u d i e s w e re d o n e a n d t h e r es u l t s a re s u m m a r i z e d
i n T a b l e 3 .
E
n
t
r
y
S u b s t r a t e
P
r
o
d
u
c
t
y
i
e
l
d
(
%
)
1
2
3
4
4a
4b
4c
4d
6a ( 9 0 )
6b ( 9 2 )
6c ( 9 1 )
6d ( 8 9 )
p r e f e r e n c e f o r cis m o no s u bs ti tut e d p r o d u ct s
(d = 5 . 2 1) o v e r trans i s o m e r (d = 4 . 97 ), w h o s e
s t er e oc h e m i st r y w a s a s s i g n e d o n t he b a s i s o f s i n g l e-
1 2
c
r
y
s
t
a
l
X
-
r
a
y
s
t
r
u
c
t
u
r
e
a
n
a
l
y
s
i
s
.
B
a
s
e
d
o
n
t
h
e
s
e
I t w a s c o n c l u d ed f r o m t h e s t u d i e s t h at t h e 1 : 1 . 5
( s u b s t r a t e : n u c l eo p h i l e ) a t 0 °C w a s t h e b e s t r e a ct i o n
c o n d i t i o n s ( E n t ry 3 a n d 1 0 , T a b l e 3 ) . I t h a s a l s o b e e n
o b s er v e d t h at h i g h e r t e m p e ra t u r e g a v e a n u n i d en t i fi e d
m i x t u r e a n d h i g h e r n u cl eo p h i l e c o n c e n t r a t i o n h a s n o
s i g n i fic a n t e ff e c t o n p r o d u c t r a t i o .
c o r r e l a t i o n s t u d i e s t ha t trans i s o m e r r e s o n a t e s a t l o w er
v a l u e a n d o t he r s p e c t r o s c o p i c d a t a , t h e u p p e r c o m -
p o u n d w a s i d e n t i fi e d t o b e cis- 1 - (40- m e t h o x y p h e n y l ) -
3 - ( 20, 5 0- d i me t h o xy p h e n y l)- 3 - (40- m e t h y l ph e n y l th i o ) -4 -
p h e n y l a z et i d i n - 2 -o n e 9ab (d = 5 . 5 2 ) a n d l o w e r a s
trans- 1 - ( 40- m e t h o x y p h e n yl )- 3 - ( 20, 5 0-
Table 3. S t u d y o f t h e e f f e c t o f s t o i c h i o m e t r y a n d t e m p e r a t u r e o n L e w i s a c i d - c a t a l y z e d r e a c ti o n s o f cis- 3 - ( 4 0- m et h y l/
c h l o r o p h e n y l t hi o ) b- l a c t a m s .
E n t r y S u b s t r a te
N
u
c
l
e
o
p
h
i
l
e
(
e
q
u
i
v
a
l
e
n
t
s
)
T e m p . ( °C ) 7 ( % ) 8 ( % ) 9 ( % ) 10 ( % ) U n r e a c t e d r e a ct a n t ( % )
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6b
6b
6b
6b
6a
6a
6a
6a
6b
6b
6b
A n i s o l e ( 1 . 0 )
A n i s o l e ( 1 . 0 )
A n i s o l e ( 1 . 5 )
A n i s o l e ( 2 . 0 )
A n i s o l e ( 1 . 0 )
A n i s o l e ( 1 . 0 )
A n i s o l e ( 1 . 5 )
A n i s o l e ( 2 . 0 )
1 , 4 - D i m e t h o x y b e n z e n e ( 1 . 0 )
1 , 4 - D i m e t h o x y b e n z e n e ( 1 . 5 )
1 , 4 - D i m e t h o x y b e n z e n e ( 1 . 5 )
1 , 4 - D i m e t h o x y b e n z e n e ( 2 . 0 )
1 , 4 - D i m e t h o x y b e n z e n e ( 1 . 5 )
1 , 4 - D i m e t h o x y b e n z e n e ( 2 . 0 )
1 , 4 - D i m e t h o x y b e n z e n e ( 2 . 0 )
0
2 5
0
0
0
2 5
0
0
0
0
2 5
0
0
0
2 5
5 7 . 4
5 0 . 4
6 3 . 6
6 3
3 6 . 8
3 3 . 2
4 5 . 8
4 6 . 2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
2 4 . 6
2 1 . 6
3 6 . 3
3 7
4 3 . 2
3 8 . 8
5 4 . 1
5 3 . 8
1 2
1 5
1 3
1 5
5 1 . 3
5 1
4 8
1 8
1 6
-
-
2 0
1 5
-
-
1 0
-
-
-
-
-
9
4 1
4 5
4 2 . 2
4 4 . 5
-
3 7
4 0
3 6 . 8
4 0 . 5
4 8 . 7
4 9
4 3
1 0
1 1
1 2
1 3
1 4
1 5
-
-
-
Cl H
NuH
NuH
N
NuH
SRH
RS
O
RS
O
RS
O
RS
O
TiCl4, 0oC
R1
R2
R1
R2
R1
R2
R1
R2
R1
R2
Nu
N
6
N
N
N
Nucleophile
O
9
10
8
7
(formed from 6a only)
Nucleophile = Anisole, 1,4-dimethoxybenzene, allylsilane
Scheme 2. L e w i s a c i d - c a t a l y z e d r e a c t io n s cis- 3 - ( 4 0- m e t h y l/ c h l o r o p h e n y l t h i o ) b- l a c t a m s .

J. Chem. Sci.
(
2
0
2
0
)
1
3
2
:
1
2
9
P
a
g
e
9
o
f
1
1
1
2
9
Table 4. R e s u l ts o f L e w i s a c i d c a t a l y z e d r e a c t i o n s o f cis- 3 - c h l o r o - 3 - ( 4 0- m e t h y l/ c h l o r o p h e n y l t h i o ) - b- l a c t a m s (6a-d) w i t h
n
u
c
l
e
o
p
h
i
l
e
s
u
s
i
n
g
T
i
C
l
a
t
0
°
C
.
4
E n t r y
S u bs t r a t e ( 6)
N
u
c
l
e
o
p
h
i
l
e
7 ( % y i e l d )
8 ( % y i e l d )
9 ( % y i e l d )
10 ( % y ie l d )
1
2
3
4
5
6
7
8
6a
6a
6a
6b
6b
6b
6c
6c
6c
6d
6d
6d
A
n
i
s
o
l
e
7aa ( 6 3 .6 )
-
-
7ba ( 4 5 .8 )
-
8ab ( 4 5 )
-
10aa ( 36 . 3)
10ab ( 15 )
-
10ba ( 54 . 1)
10bb ( 51 . 3)
-
10ca ( 54 )
10cb ( 57 )
-
10da ( 42 . 2)
10db ( 31 )
-
1 , 4 - d i m e t h o x y b e n z e n e
A l l y l s i l a n e
A n i s o l e
1 , 4 - d i m e t h o x y b e n z e n e
A l l y l s i l a n e
A n i s o l e
1 , 4 - d i m e t h o x y b e n z e n e
A l l y l s i l a n e
A n i s o l e
1 , 4 - d i m e t h o x y b e n z e n e
A l l y l s i l a n e
9ab ( 4 0 )
9ac ( 8 9 )
-
9bb ( 4 8 .7 )
9bc ( 9 0 )
-
9cb ( 4 2 .8 )
9 cc ( 9 0 )
-
9db ( 6 9 )
9dc ( 9 4 )
-
-
-
-
-
-
-
-
-
-
-
-
7ca ( 4 5 )
-
-
7da ( 5 7 .7 )
-
-
9
1 0
1 1
1 2
9, 1 1
Cl H
p r o d u ct s .
m ar i ze d i n S ch em e 2 a n d T a b l e 4.
T h e r e s u l t s o f t h es e s t u d i e s a r e s u m -
RS
O
R1
R2
N
T h e s t ru ct u r e s o f a l l n e w c o m p o u n d s 7-9 w er e
c o n fi r me d b y s p e c t r o s c o p i c a n a l y s i s s u c h a s F T I R ,
N M R a n d e l e me n t al a n a l y s i s .
T h e s e r es u l t s i n d i c a t e t h e l o w r e ac t i v i t y o f s u b -
s t ra t e s o f t y p e 6a-d t o w ar d s t h es e r ea c t i o n s . A l s o , t h e
s u b s t a n t i al f o r ma t i o n o f 3 , 3 -b i s t h i o b- l a c t a ms s u p p o r t s
t h i s f ac t . T h e s e s u b s t r a t e s g i v e s t er e o s e l e c t i v e cis-
m o n o s u b s t i t u t e d p r o d u ct s . A l l t h es e f ac t s s u p p o rt t h e
i n t e r me d i a c y o f s t ab i l i ze d c ar b o ca t i o n w h i ch g i v e s
p r e fe r a b l y cis p r o d u ct i f i t i s m o n o s u b s t i t u t e d . H o w-
e v e r, t h e o v e r a l l o u t c o m e m ay b e c o m b i n ed e f f e ct o f
s t ab i l i za t i o n b y s u b s t i t u e n t s a t C -3 a n d s t er i c h i n -
d r a n c e p o s ed b y s u b s t i t u e n t s a t C -4 & N . T h e r e a ct i o n
a l s o g i v e s d i s u b s t i t u t e d a n d b i s t h i o p r o d u c t s d u e t o t h e
a mb i p h i l i c b e h a v i o r o f - SP h g r o u p . T h e p o s si b l e
m ec h a n i s m f o r t h e r e ac t i o n i s g i v e n i n S ch em e 3.
[MCl5]
[MCl5] Nu
H
H
RS
RS
R1
R1
N
N
O
R2
O
R2
(Carbocation)
Nu
RS
SRH
NuH
NuH
NuH
RS
O
R1
R2
RS
R1
R2
R1
R2
RS
R1
R2
Nu
Nu
SR
+
N
N
8
N
7
N
9
O
O
O
10
Scheme 3. M e c h a n i s m s h o w i n g C - 3 s u b s t i t u t i o n .
4. Conclusions
T o s u m m ar i z e , w e h a v e i n v e s t i g at ed t h e s y n t h et i c
u t i l i t y o f 3 - s u b s t i t u t ed p h en y l t h i o a ze t i d i n e - 2 - o n e s
t o w ar d s C -3 f u n c t i o n a l i za t i o n . T h e s u b s t i t u t i o n o f
T
h
e
s
i
m
i
l
a
r
r
e
a
c
t
i
o
n
s
w
e
r
e
t
e
s
t
e
d
w
i
t
h
s
u
b
s
t
r
a
t
e
6
c
a n d 6d w h i ch s t e re o s pe c i fi c a l ly g a v e cis m o n o s u b - p h e n y l t h i o g r o u p a t C -3 b y e i t h er e l e c t r o n r e l e a si n g o r
s t i t u t e d p r o d u c t 9. T h e r e a c t io n u s i n g a l l y l s i l a n e a s
n u c l e o p h i l e f u r n i s h e d t h e s a m e p r o du c t a s o b t a i n ed p r o fi l e . H o w e v e r , i n s o m e c as es , i t r es u l t s i n t h e f o r -
f r o m e a r l i e r s t u d i e s . I t w a s c h a r a c t e ri z e d b y s p e c -
t r o s c op i c d a t a a n d b a s e d o n t ha t i t c a n b e i n f e rr e d s t i t u en t a t C -4 a n d n i t r o g e n w h i ch o t h e rw i s e c a n n o t b e
w i t h d r a w i n g d o es n o t h a v e m u c h e f fe c t o n t h e p r o d u c t
m
a
t
i
o
n
o
f
s
t
a
r
t
i
n
g
c
i
s
b
-
l
a
c
t
a
m
s
w
i
t
h
p
h
e
n
y
l
s
u
b
-
t h a t f o r t h i s p r o d u c t t h e s t e re o c h e m i s t ry i s n o t a l t e r e d
b y t h e t y p e o f s u bs t it u e n t a t C - 3 o f t h e s t ar t i n g
p r e p a re d u s i n g u n s u b s t i t u t e d t h i o g r o u p s . A l s o, t h e s e
s u b s t i t u t ed cis- 3 - c h l o r o b- l a c t a ms g a v e s t er e o s e l e ct i v e
1
1
,
1
2
s
u
b
s
t
r
a
t
e
.
H
o
w
e
v
e
r
,
t
h
e
s
u
b
s
t
r
a
t
e
w
a
s
f
o
u
n
d
t
o
b
e
c
i
s
-
3
-
m
o
n
o
s
u
b
s
t
i
t
u
t
e
d
p
r
o
d
u
c
t
s
w
i
t
h
s
o
m
e
n
u
c
l
e
-
u n r e ac t i v e t o w a r d s m a ny n u c l e o p h i le s l ik e t o l u e n e ,
p h e n ol , t h i o p h e n e , p y r ro le , b r o m o b e n z e ne w h i ch s u b s t i t u t ed p h e n y l t h i ob- l a c t a ms a n d f ai l e d t o g i v e
o t h e r w i s e h a d b e e n r e p o r te d t o g iv e 3 -s u b s t i t u t ed
o
p
h
i
l
e
s
a
l
t
h
o
u
g
h
t
h
e
s
e
a
r
e
n
o
t
a
s
r
e
a
c
t
i
v
e
a
s
3
-
u
n
-
s
u
b
s
t
i
t
u
t
i
o
n
w
i
t
h
m
a
n
y
n
u
c
l
e
o
p
h
i
l
e
s
.

1 2 9 P a g e 1 0 o f 1 1
J. Chem. Sci.
(
2
0
2
0
)
1
3
2
:
1
2
9
3 0 8 6 ; ( e ) B a n i k B K , B a n i k I a n d B e c k e r F F 2 01 0
A s y mm e t r i c s y n t h e s i s o f a n t i c a n c e r b- l a c t a m s v ia
s t a u d i n g e r r e a c t io n : u t i li z a t io n o f c h i r a l k e t e n e f ro m
c a r b o h y d r a t e Eur. J. Med. Chem. 45 8 4 6 ; ( f ) O ’B o y le
N M , C a r r M , G r e e n e L M , B e r g i n O , N a t h w a ni S M ,
M c C a b e T , L l y o d D G , Z i s te r e r D M a n d M e e g an M J
2 0 1 0 S y n t h e s i s a n d e v a l u a t i o n o f a z e t i d i n o n e a n a l ou g es
o f c o m b r e t a s t i n A - 4 a s t u b u l i n t a r g e ti n g a g e n t s J. Med.
Chem. 53 8 5 6 9 ; ( g ) J a r r a h p o u r A , E b r a h i m i E , K h al i f eh
R , S h a r g h i H , S a h r a e i M , S i n o u V a n d B r u n e l J M 2 01 2
S y n t h e s i s o f n o v e l b- l a c t a m s b e a r i n g a n a n t h r a q ui n o ne
m o i e t y a n d e v a l u a t i o n o f t h e i r a n t i m a l a r i a l a c ti v i t i es
Tetrahedron 68 4 7 4 0 ; ( h ) R o s a M D , V i g l i o t t a G , P a l m a
G , S a t u r i n o C a n d S o r i e n t e A 2 0 1 5 N o v e l p en i ci l l i n
t y p e a n a lo g u e s b e a r i n g a v a r ia b le s u b s t i tu te d 2 - az e ti d i -
n o n e r i n g a t p o s i t io n 6 : s y n t h e s i s a n d b i o lo g i c al
e v a lu a t i o n Molecules 20 2 2 0 4 4
Supplementary Information (SI)
A
l
l
a
d
d
i
t
i
o
n
a
l
i
n
f
o
r
m
a
t
i
o
n
a
b
o
u
t
t
h
e
c
h
a
r
a
c
t
e
r
i
z
a
t
i
o
n
o
f
1
1
3
c o m p o u n d s ( 4-10) u s i n g H N M R , C N M R a n d H R - M S
t e c h n iq u e ( F i g u r e s S 1 - S 5 6 ) a r e g i v e n i n t h e s u p p o r t in g
i n fo r m a ti o n . S u p p l e m e n t a r y I n f o r m a t i o n i s a v a i l a b l e a t
w w w . i a s . a c. in / c h em s c i .
Acknowledgements
F in a n c ia l s u p p o r t f o r t h i s w o r k f ro m T E Q I P -I I ( U I E T , P U ,
C h a n d i g a r h ) a nd P U R S E – I I ( D S T ) i s a c k n o w l e d g e d .
References
4 . ( a ) O j i m a I , C h e n H - J C a n d N a k a h a sh i K 1 9 8 7 J. Am.
Chem. Soc. 110 2 7 8 ; ( b ) H a t a n a k a N , A b e R a n d O j i m a
I 1 9 8 1 b- l a c t a m a s s y n t h e t i c i n t e r m e d i a t e : s y n t h es i s o f
l e u c i n e - e n k e p h a li n Chem. Lett. 10 1 2 9 7 ; ( c ) O j i m a I
1 9 9 5 R e c e n t a d v a n c e s i n t h e . b e t a . - L a c t a m S y n t ho n
M e t h o d Acc. Chem. Res. 28 3 8 3 ; ( d ) O j i m a I 1 99 5 In
Advances in Asymmetric Synthesis A H a s s n e r ( Ed . )
( G r e e n w i c h : J A I ) p . 9 5 ; ( e ) O j i m a I a n d D e l al o ge F
1 9 9 7 A s y m m e t r i c s y n t h e s i s o f b u i l d i n g b l o ck s f or
p e p ti d e s a n d p e p t i d o m i m e t ic s b y m e a n s o f t h e b- l ac t a m
s y n t h o n m e t h o d Chem. Soc. Rev. 26 3 7 7 ; ( f ) D e s h m u kh
A R , B h a w a l B M , K r is h n a s w a m y D , G o v a n d e V V ,
S h i n k r e B A a n d J a y a n t h i A 2 0 0 4 A z e ti d i n -2 - on es ,
s y n t h o n s f o r b i o l o g i c a l l y i m p o r ta n t c o m p o u n d s Curr.
Med. Chem. 11 1 8 8 9 ; ( g ) P a l o m o C , A i z p u r u a J M ,
G a n b o a I a n d O i a r d id e M 2 0 0 4 A s y m m e t r i c s y nt h es i s
o f b- l a c t a m s t h r o u g h t h e S t a u d i n g e r r e a c t io n a n d t he i r
u s e a s b u i l d i n g b l o c k s o f n a t u r a l a n d n o n na t u ra l
p r o d u c t s Curr. Med. Chem. 11 1 8 3 7 ; ( h ) O j i m a I ,
K u z n e t s o v a L , U n g u r e a n u I M , P e p e A , Z a n a rd i I a nd
C h e n J 2 0 0 5 I n Fluorine-Containing Synthons S o lo s h o -
n o k V ( E d .) A C S S y m p o s i u m S e r i e s ( W a s h i n gt o n:
A m e r ic a n C h e m i c a l S o c i e t y / O x f o r d U n iv e r s i ty P r e s s )
p . 5 4 4
1 . ( a ) F l e mi n g A 1 9 2 9 O n t h e a n t i b a c t e ri a l a c t i o n o f
c u lt u r es o f a p en i c i l l i u m , w i t h s p e c i a l r e f e re n c e t o t h e i r
u s e i n i s o l at i o n o f B . i n fl u e n z e a Brit. J. Exp. Pathol. 10
2 2 6 ; ( b ) K a h a n J S , K a h a n F M , G o e g e l ma n R , C u r r ie S
A , J a ck s o n M , S t a p l e y E O , M i l l e r T W , M i l l e r A K ,
H e n d li n D , M o c h a l e s S , H e r n a n d e z S , W o o d r u f f H B
a n d B ir n b a u m J 1 9 7 9 T h i e n a m y c i n , a n e w b- l a c t a m
a n ti b i o ti c I . D i s c o v e r y , t a x o n o m y , i s o l a t i o n a n d p h y s -
i ca l p r o p e r t i e s J. Antibiot. 32 1 ; ( c ) I m a d a A , K i t a n o K ,
K i n t a ka K , M u r o i M a n d A sa i M 1 9 8 1 S u l fa z e c i n a n d
i s o su lf az e c in , n o v e l b- l a c t a m a n t i b i o t i c s o f b a c t e r i a l
o r i g i n Nature 289 5 9 0
2 . ( a ) T s u j i N , N a g a s h i m a K , K o b a y a sh i M , T e r u i Y ,
M at s u m o t o K a n d K o n d o E 1 9 8 2 T h e s t r u c t u r e o f
p l u r a ci d o m y ci n s , a n e w c a rb a p e n e m a n t i b i o t i c s J.
Antibiot. 35 5 3 6 ; ( b ) P C C h e r r y , C E N e w a l l a n d M
G o r m a n ( E ds . ) 1 9 8 0 Chemistry and Biology of b-
Lactam Antibiotics ( Ne w Y o r k : A c a d e m i c P r e s s ) ;
( c ) S y ke s R B , C i m a r u s t i C M , B o n n e r D P , F l o y d D
M , G e o r g o p a p a d a k a o u N H , K o s t e r W H , L i u W C ,
B u sh K H , T r e j o W H a n d W e l l s J S 1 9 8 1 M o n o c y c l i c
b- l a ct a m a nt i b i o t i c s p r o d u c e d b y b a c t e ri a Nature 291
4 8 ; ( d ) A l c ai d e B a n d A l m e n d r o s P 2 0 0 4 b- l a c t a m a s
v e r s at i l e s y n t h e t i c i n t e rm e d i a t e s f o r t h e p r e p a r a ti o n o f
h e te r o c y c le s o f b i o l o g i c a l i n t e re st Curr. Med. Chem. 11
1 9 2 1 ; ( e ) K a h a n J S , K a h a n F M , G o e g e l m a n , R ,
S t a p le y E O a n d H e r n a n d e z S 1 9 7 7 T h i e n a m y c i n
P r o d u c t i o n U S P a t e n t 3 9 5 0 3 5 7
5 . G u il l o n C D , K o p p e l G A , B r o w n s t e i n M J , C h a n ey M
O , F e r r is C F , L u S - F , F a b i o K M , M i l le r M J , H e i nd el
N D , H u n d e n D C , C o o p e r R D G , K a l d o x S W , S k e l to n
J J , D r e s s m a n B A , C la y M P , S t e in b e r g M I a n d B r u ns
R F 2 0 0 7 A z e ti d i n o n e s a s v a s o p r e s s i n v i a a n t ag on i s t s
Bioorg. Med. Chem. 15 2 0 5 4
3 . ( a ) K o u Q , W a n g T , Z o u F , Z h a n g S a n d C h e n Q 2 0 1 8
D e s ig n , s y n t he s i s a n d b i o l o g i c a l e v a l u a t i o n o f C ( 4 )
s u b s ti t ut e d m o n o b a c t u m s a s a n t i b a c t e r i a l a g e n t s a g a i n s t
m u l ti d r u g - r e s i s t a n t g r a m n e g a t i v e b a c t e ri a Eur. J. Med.
Chem. 151 9 8 ; ( b ) J a r r a h p o u r A , R e z a e i S , S i n o u V ,
L a t o ur C a nd B r u n e l J M 2 0 1 7 S y n t h e si s o f s o m e n o v e l
3 - s p i r o m o n o c y c l i c b- l a c t a m s a n d t h e i r a n t i b a c t e r i a l
a n d a nt i f u n g a l i n v e st i g a t i o n s Iran. J. Sci. Technol.
Trans. A Sci. 41 3 3 7 ; ( c ) A m e r i R a d J , J a r ra h p o u r A ,
L a t o ur C , S i n o u V , B r u n e l J M , Z g o u H , M a b k h o t Y ,
B en H a d d a T a n d T u ro s T 2 0 1 7 S y n t h e s i s o f a n t i m i -
c r o b i al / a n t i ma l a r i a l a c t i v i t i e s o f n o v e l n a p h t h a l i m id o
trans- b- l a ct a m d e ri v a t i v e s Med. Chem. Res. 26 2 2 3 5 ;
6 . B u r n e tt D 2 0 0 4 b- L a c ta m c h o l e s t e r o l a b s o r p ti o n
i n h i b i to r s Curr. Med. Chem. 11 1 8 7 3
7 . ( a ) F i s c h e r J F , M e r o u h S O a n d M o b a s h e r y S 2 00 5
B a c t e r i a l r e s i s t a n c e t o b- l a c t a m a n t i b i o t i c s : c o m p e ll i n g
o p p o r t u n i s m , c o m p e l l in g o p p o r t u n i t y Chem. Rev. 105
3 9 5 ; ( b ) R it t e r T K a n d E o n g C - H 2 0 0 1 C a r b oh y dr at e -
b a s e d a n t i b i o t i c s : a n e w a p p r o a c h t o t a c k l i n g t he
p r o b l e m o f r e s i s t a n c e Angew. Chem. Int. Ed. 40 3 50 8
8 . ( a ) P h i ll i p s O A , R e d d y A V N , S e t ti E L e t a l. 2 00 3
S y n t h e s i s a n d b i o l o g i c a l e v a lu a t i o n o f p e n a m s u l f on es
a s i n h i b i t o r s o f b- l a c t a m a s e s Bioorg. Med. Chem. 13
2 8 4 7 ; ( b ) W a ll a c e K M - P, B e t h e l C R a n d G o o t z T D
e t a l . 2 0 1 2 I n a c t iv a t io n o f a c l a s s A a n d a c l as s C b-
l a c t a m a s e b y 6 b- ( h y d r o x y m e t h y l ) p e n i c i l la n i c a ci d
s u l f o n e Biochem. Pharmacol. 83 4 6 2
¨
´
( d ) S p e r k a T , P i t l i k J , B a g o s s i P a n d T O z s e r J 2 0 0 5 B e t a
l ac t a m c o mp o un d s a s a p p a r e n t l y u n c o m p e t i t i v e i n h i b i -
t o r s o f H I V - 1 p r o t e a s e Bioorg. Med. Chem. Lett. 15

J. Chem. Sci.
(
2
0
2
0
)
1
3
2
:
1
2
9
P
a
g
e
1
1
o
f
1
1
1 2 9
9 . M ad a n S , A r o r a ( T h a p a r ) R , V e n u g o p a l a n P a n d B a r i S
S 2 0 0 0 A n e w s y n t h e t i c a p p r o a c h f o r n o v e l C - 3
s u b s ti t ut e d b- l a c t a m s Tetrahedron Lett. 41 5 5 7 7
1 0 . B ar i S S , V e n u g o p a l a n P a n d A ro r a (T h a p a r) R 2 0 0 3 A
f a ci l e L e w i s a ci d p r o mo t e d a l l y l a t i o n o f a z e t i d i n - 2 - o n e s
Tetrahedron Lett. 44 8 9 5
1 1 . B h al l a A , M ad a n S , V e n u g o p a l a n P a n d B a r i S S 2 0 0 6
C - 3 b- l a c ta m c a r b o c a t i o n e q u i v a l e n t s : v e rs a t i l e s y n -
t h o n s f o r C - 3 s u b s t i t u t e d b- l a c t a m s Tetrahedron 62
5 0 5 4
h a v in g s u l f e n y l , s u l fi n y l a n d s u l f o n y l m o i e t y J. Chem.
Sci. 127 1 9 5 7
1 5 . Z a r e i M a n d M o h a m a d z a d e h M 2 0 1 1 3 - T h i o la t ed - 2-
a z e t i d i n o n e s : s y n t h e s i s a n d i n v i t r o a n t i b a c t e r ia l a nd
a n t i f u n g a l a c t i v i ti e s Tetrahedron 67 5 8 3 2
1 6 . ( a ) B a r i S S , V e n u g o p a la n P , A r o r a ( T h a p a r ) R , M o di G
a n d M a d a n S 2 0 0 6 A n u n u s u a l L e w is a c i d p ro m o te d
i s o m e r i z a t i o n o f t r a n s 3 - H a l o - 3 - p h e n y l th i o b- L ac t am s
Heterocycles 68 7 4 9 ; ( b ) V e e n J M V , B a r i S S ,
K r is h n a n L , M a n h a s M S a n d B o s e A K 1 9 8 9 S y n t he s i s
o f A z e ti d i n - 2 ,3 - d i o n e s ( a- K e t o b- L a c t a m s ) v i a 3 -( P h e -
n y l t h i o ) - 2 - a z e ti d i n o n e s J. Org. Chem. 54 5 7 5 8
1 2 . B ar i S S , R e s h m a , B h a l l a A a n d H u n d a l G 2 0 0 9
S t e r e o s e l ec t i ve s y n t h e s i s a n d L e w i s a c i d m e d i a t e d
f u n c ti o n al i z a ti o n o f n o v e l 3 - m e t h y l t h i o - b- l a c t a m s Te- 1 7 . B h a l la A , N a g p a l Y , B e r r y S , N a r u l a D , B a r i S S ,
trahedron 65 1 0 0 6 0
B h a s i n K K a n d K u ma r R 2 0 1 8 S t e r e o s e l e c t iv e s y n t he -
s i s , s p e c tr o s c o p ic a n d X - r a y c r y s t a l lo g r a p h i c c h ar a ct e r-
i z a t io n o f n o v e l trans- a n d cis- 3 - m e t hy l s e l e no
s u b s t i tu t e d m o n o c y c li c b- l a c t a m s : p o t e n ti a l s y nt h on s
f o r C - 3 f u n c t io n a l i z e d / b i c y c l ic /h a l o s p i r o s e l e n o- b- l ac -
t a m s o f m e d i c i n a l i n t e r e s t Inorg. Chim. Acta 477 1 7 2
1 3 . T h a p a r R , R es h m a a n d B a ri S S 2 0 1 6 S t u d i e s t o w a r d s
C - 3 f u n c t io n al i z a t i o n o f b- l a c t a m s u s i n g s u b s t i t u t e d
a ll y l s il a n e s J. Chem. Sci. 128 1 7 4 5
1 4 . R es h m a , A r o r a ( T h a p a r ) R , H u n d a l G , B h a l l a A a n d B a r i
S S 2 0 1 5 A n e f fi c i e n t s y n t h e s i s o f s p i r o - b- l a c t a m s