The one-pot four-component eco-friendly synthesis of spirooxindoles in deep eutectic solvent

Article abstract of DOI:10.1007/s12039-019-1730-6

Abstract: An efficient and facile synthesis of spirooxindole derivatives bearing pyrano[2,3-c]pyrazole moiety has been achieved using deep eutectic solvent (DES) promoting a four-component reaction. The protocol avoids the use of costly and toxic catalyst

Full text of DOI:10.1007/s12039-019-1730-6

J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 2 8
Ó I n d ia n A c a d e m y o f S c i en c es
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REGULAR ARTICLE
The one-pot four-component eco-friendly synthesis of spirooxindoles
in deep eutectic solvent
T H O K C H O M J E E T A D E V I , T H O K C H O M P RA S A N T A S IN GH a n d
*
O K R A M M U K H E RJ E E S I N G H
C h em i s t r y D e p a rt m e n t , M a n i p u r U n i v e r s i t y , C a n c h i p u r 7 9 5 0 0 3 , M a n i p u r , I n d ia
E - m a i l : o k _ m u k h e r j e e @ y a h o o . c o . i n
T h o k c h o m J e e t a D e v i a n d T h o k c h o m P r a s a n t a S i n g h h a v e e q u a l c o n t r i b u ti o n .
M S r e c e i v e d 2 5 J u l y 2 01 9 ; r e v i s e d 1 O c t o b e r 2 0 1 9; a c c e p t e d 4 O c t o b e r 2 0 1 9
Abstract. A n e f fi c i e n t a n d f a c i l e s y n t h e s i s o f s p i r o o x i n d o l e d e r iv a ti v e s b e a r i n g p y r a n o [ 2 ,3 - c] p yr a zo l e
m o i et y h a s b e e n a c h i e v e d u s i n g d e e p e u t e c t i c s o l v e n t ( D E S ) p r o m o t i n g a f o u r - c o m p o n e n t r e a c t i on . T he
p r o t o c o l a v o i d s t h e u s e o f c o s t l y a n d t o x i c c a t a l y s t s a n d o r g a n i c s o l v e n t s w h ic h e n c o u n t e r s m a n y s i d e e ff ec t s
o n t h e e n v i r o n me n t a n d h u m a n b e i n g s . T h e s i m p l ic i ty a n d v e r s a t i li t y o f t h i s e c o - f r i e n d l y g r e e n m e th o d i s
d e sc r i b e d .
Keywords. D e e p e u t e c t i c s o l v e n t ; s p ir o o x i n d o le s ; e c o - f r ie n d l y ; h y d r a z i n e ; i s a t in .
1. Introduction
a ct i v i t i e s , s p i r o o x i n d o l e d e r i v a t i v e s h a v e d r a w n c o n -
s i d e ra b l e a t t e n t i o n t o s y n t h e t i c c h e mi s t s f o r t h e i r
9
p r e p a ra t i o n . I n s p i t e o f s e v e r al r e p o r t s o n t h e s y n -
t h es i s o f s p i r o o x i n d o l e d e r i v a t i v e s i n v o l v i n g v a r i o u s
T h e c h e m i s t r y o f i n d o l e i s o n e o f t he m o s t e x c i t i n g a n d
c h a l l e ng i n g fi e l d f o r i nv e s ti ga t iv e w o r k s o f s y n t h e t i c
1
a n d m e d i c i n a l c h e m is ts . T h e s i g ni fi c a n t a p p l i c at i o n o f
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i n d o l e d e r i v a t i v es i n p h a r m a c e u t i c a ls , a g ro c h em i c a l s
a n d o r g a n i c e l e c t ro n i c s c o nt i nu e s t o i ns p i re t h e t i r el es s
e f f o r t s o f s y n t h e t ic o r g a n i c c h e m is t s s i n c e t i me
c l o d ex t r i n ,
p i p e ri d i n e,
L- p r o l i n e ,
C eO - N P s , d o d e c y l -
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s p i r o o x i n do l e d e r i v a t iv e s a l s o o c c u py a s p e c i a l p l ac e
i n o r g a n i c a n d m e di c i n a l c h e m is tr y s i n c e t h e y e x h i b i t
3,4
d i v e r se b i o l o g i c a l a n d p h a r m a c o lo gi c a l a c t iv i t i e s .
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m en t a l l y b e n i g n s y n t h e t i c a p p r o a c h e s t o s p i r o o x i n d o l e
d e r i v a t i v e s b e a ri n g p y r a n o [ 2 , 3 -c] p y r a z o l e s r em ai n s a n
i m m en s e i n t e r es t t o o r g a n i c c h e mi s t s .
T h e c h a l l e n g es i n r e s o u r c es a n d e n v i ro nm e n t a l
s u s t a i n a b i l i t y r eq u i r e m o r e e f fic i e n t a n d b e n i g n s ci -
e n t i fic t e c h n o l o g i e s f o r c h e mi ca l p r o c e s s e s a n d t h e
m an u f ac t u re o f p r o d u c t s . D e ep e u t e c t i c s o l v en t s
( D E S s ) a d d r e s s e s s u c h c h a l l e n g es b y b r i d gi n g a s
e n v i ro n m en t a l l y f r i e n d l y a n d a cc e p t a b l e, d u e t o t h e i r
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s p i r o t r y p r o s t a t i n A a n d B , i s o la te d f ro m t h e f er m e n -
t a ti o n b r o t h o f Aspergillus fumigatus, w e r e f o u n d t o
c o m p l e t e l y i n h i b i t t he G 2 /M p r o gr e s s i o n o f c el l u l a r
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t h e fi e l d o f s y n t h e t ic t he ra p e u t i c a g e n t s , c o m p o u n d s
c o n t a i n in g t h e s pi r o o xi n d ol e c o re , S O I D -8 , a n a l o g u e
o f s p i r o t r y p r o s t a t i n B , h a ve b e e n d e s c ri b e d a s h a v i n g
a n t i c an ce r a c t i v i t y a g a i n s t M e l a n o m a c e l ls , w h i l e
N I T D 6 0 9 i s a p r o m is in g n o v e l d ru g f o r t he t re a t m en t
6
l o w v a p o r p r e s s u r e , n o n - t o x i c p r o p e r t i es , r e u s ab i l i t y ,
2 5 ,2 6
a n d c h e ap n e s s .
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o f m al a r i a ( F i g u re 1 ) . I n l ig h t o f t he ir u n i q u e
s t r u ct u r a l f e a t u r e s a l o ng w i th t he i m p o rt a nt b io l o g i ca l
t w o o r m o r e c o m p o n e n t s , f o r mi n g a e u t e c t i c w i t h a
m el t i n g p o i n t m u c h l o w er t h an t h e s t a r t i n g
* 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/s12039-019-1730-6) contains
supplementary material, which is available to authorized users.

2 8 P a g e 2 o f 1 0
J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 2 8
o p e n c a p il l a r y t u b e s a n d a r e u n c o r r e c te d u s i n g B u c hi
m e l t in g p o i n t a p p a r a t u s .
2 . 1 Preparation of deep eutectic solvent
2 6
A c c o r d i n g t o l it e r a t u r e , 5 0 m m o l c h o l i n e c h l o r i d e a nd t he
r e q u i r e d a m o u n t o f u r e a w e r e m i x e d a s s h o w n i n T a bl e 1 , i n
a r o u n d fl a s k a n d w e r e h e a te d t o o b t a i n a c l e a r l i qu i d a s
D E S c a l l e d u r e a : Ch C l ( F i g u r e 2 ) .
T h e F T - I R s p e c tr a o f f r e s h l y p r e p a r e d u r e a : Ch C L ( 2: 1 )
s t
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a n d t h e 1 a n d 2 r e c y c l e d u r e a : Ch C l ( 2 : 1 ) w e r e r e co r de d
i n F T - I R S p e c t r o p h o t o m e t e r ( P e r k i n E l m e r S p e c t r um - 2) .
F i g u r e 3 d e p ic t s t h e s p e c t r a l a n a l y s i s o f b o n d f r e q u en c i es
f o r u r e a : Ch C l w h ic h i n d i c a t e s a c l o s e r e s e m b l a n c e w i t h t he
3 5
Figure 1. E x a mp l e s o f n a t u ra l p r o d u c t s a n d s y n t h e t i c
t h e r a pe u t i c a g en t s c o n t a i n i n g a s p i r o x i n d o l e c o re .
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b r o a d a b s o r p t i o n b a n d s a t 3 4 2 3 c m -1 a n d 3 3 2 2 c m -1
i n d i c a t e s t h e s t r e t c h i n g m o d e o f – N H (ta s N H a nd ts
c o mp o ne nt s . T h e c o m p o n e n t s o f D E S a r e b i o d e g r ad -
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m a t io n o f h y d r o g e n b o n d i n g b e t w e e n u r e a a n d c ho l i ne
c h l o r i d e . T h e h y d r o g e n b o n d s f o r m e d m a y b e r e p r e s e n te d
a s N - H …N - H , N - H …O - H , H - O …H O a n d O - H …N - H . F u r -
t h e r , t h e p r e s e n c e o f b e n d i n g m o d e o f - N H (ds N H a nd da s
c o mp a re d t o i o n i c l iq u id s . A m o n g t h e D E S s , c h o l i n e
c h l or i d e : u r e a - b a s e d D E S h a s b e e n s u c c e s s f u l l y u s e d
2 7
f o r c a r b o l i ne s y n t h e s i s , c o u m a r i n s y nt h e s i s , l i p a s e -
2 8
2 9
c at a l yz e d t r a ns es t e r i fi c a t i o n s , s y nt h e s e s o f d i h y -
3 0
d r o p y r i m i di n - 2 ( 1H ) -o ne s , e t c .
2
2
N H ) i s a t t r i b u t e d b y t h e v a l u e s a t 1 6 5 3 c m -1 a nd
2
1 6 1 5 c m -1 . I n a d d i t io n , t h e b a n d s a t 1 4 2 8 c m -1 a n d 9 49 c m -1
T h u s , i n c o n t i n u a t i o n o f o u r w o r k i n i n d ol e c h e m-
3 1 – 3 4
c o r r e s p o n d t o qC H a n d tC CO o f C h C l, r e s p e ct i ve l y.
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T h e s e c l e a r l y r e v e a l t h a t t h e s t r u c t u r e o f C h ? i n C h C l i s
n o t d e s t r o y e d i n U r e a : C h C l s y s t e m . O n c o m p a r in g t he
s p e c tr a o f f r e s h l y p r e p a r e d a n d r e c y c l e s , s i m il a r p e ak s a re
o b t a i n e d w h ic h s u p p o r t t h a t t h e r e c y c l e d u r e a : Ch C l c an b e
f u r t h e r u s e d f o r v a r io u s r e a c t io n s y s t e m .
s y nt h es i s o f s p i r o [ in d o l i n e - 3 , 4 ’ - p y ra n o[ 2 , 3 - c] p y r az o l e
d e r i v a t i v es u s i n g D E S -c a t a l y z e d f ou r- c o m p o n en t
r e a c t i o n o f b- k e t o e s t e r s , p h e n y lh y d ra z i ne s , m a l o n o n i -
t r i l e , a n d i s a t i n s ( S c h e m e 1) .
2. Experimental
2 . 2 General procedure for the synthesis
of spirooxindole derivatives (5a–5r)
A l l o f t h e c om m e r c i a l l y a v a i l a b l e r e a g e n t s a n d s o l v e n t s
w e r e u s ed w i t h o u t f u r t h e r p u r i fi c a t i o n . T h e c h r o m a to -
g ra p h i c p u r i fi c a t i o n o f c o m p o u n d s w a s c a rr i e d o u t o n s i li c a
g e l ( 6 0 – 2 0 0 lm ) . T L C a n a l y s i s w a s p e rf o rm e d o n p r e -
c o a t ed ( 0 . 2 5 m m ) g l a s s s u p p o r t e d s i l i c a g e l p l a t e s
A m i x t u r e o f b- k e to e s t e r 1 ( 1 m m o l ) , p h e n y l h y d r a zi n e 2
( 1 m m o l ) , i s a t in 3 ( 1 m m o l ) , a c t i v e m e t h y l e n e c o m po u nd s
4 ( 1 m m o l ) , a n d U r e a : C h C l ( 1 0 m o l %, 5 m L ) w a s s t i rr e d a t
r o o m t e m p e r a t u r e f o r 1 0 m i n o r u n t i l t h e c o m p l e t i on o f
r e a c t io n a s i n d i c a t e d b y T L C . A f te r c o m p l e t i o n o f t he
r e a c t io n , t h e r e a c t io n m i x t u r e w a s p o u r e d t o 2 5 m L w a t er
a n d e x t r a c te d w i t h 5 0 m L o f e t h y l a c e t a t e . T h e s e pa r a te d
o r g a n i c l a y e r w a s d r i e d o v e r a n h y d r o u s N a S O , fi l t e re d
1
1 3
( Ki e s e l g e l 6 0 ) . A l l H N M R a n d C N M R s p e c t r a w e r e
r e c o r d ed o n a B r u k e r - 4 0 0 a n d 1 0 0 . 6 2 M H z , r e s p e c t i v e l y
u s in g C D C l a s t h e s o l v e n t w i t h t e t r a m e t h y l s i l a n e ( TM S) a s
3
a n i n t er n a l s t an d a r d . T h e f o l l o w i n g a b b r e v i a t i o n s a r e u s e d
t o d e s cr ib e p ea k p a t t e r n s : s = s i n g l e t , d = d o u b l e t, t =
t ri p l et q = q u a r t et , m = m u l t i p l e t . A l l c o u p l i n g c o n s t a n t s
( J) a r e g i v en i n H z . F T I R s p e c t r a w e re r e c o r d e d i n F T / I R
4 1 0 s p ec t r o p h o t o m e t e r . M e l t i n g p o i n t s w e r e d e t e r m in e d i n
2
4
a n d e v a p o r a t e d . 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 rf o rm ed
u s i n g 1 0 % E t O A c i n h e x a n e a s e l u e n t t o g e t t h e d es i re d
p r o d u c t s , w h ic h w e r e f u r t h e r r e c r y s t a l l iz e d f r o m w a rm
e t h a n o l t o g e t p u r e c o m p o u n d s .
2 . 3 Spectral data of synthesized compounds
2 . 3 a Entry-5a: 6’-Amino-3’-methyl-2-oxo-1’-phenyl-1’H-
spiro[indoline-3,4’-pyrano[2,3-c]pyrazole]-5’-
carboni-
trile: W h i t e s o l i d ( 8 5 % ) ; M . p . 2 3 4 – 2 3 6 °C ( ex p) ,
2 3 8 – 2 4 0 °C ( r e p ) ; I R ( K Br , m, c m -1 ) : 3 3 6 9 , 3 1 5 4 , 3 03 1,
1 2
Scheme 1. S y n t h e s i s o f s p i r o o x i n d o l e s i n D E S .

J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 2 8
Table 1. O p t i m i z a t i o n o f r e a c t i o n c o n d i ti o n .
P a g e 3 o f 1 0 2 8
a
o
T e m p ( C )
b
Y i e l d ( % )
E n t r y
S o l v e n t
T i m e ( m i n )
1
2
3
4
5
6
7
8
U re a : C h C l ( 2 : 1 )
U re a : C h C l ( 2 : 1 )
U re a : C h C l ( 2 : 1 )
U re a : C h C l ( 2 : 1 )
U re a : C h C l ( 2 : 1 )
U re a : C h C l ( 2 : 1 )
M a l o n i c a c i d : C h C l : ( 1 : 1 )
O x a l i c a c i d : C h C l ( 2 : 1 )
P T S A: C h C l ( 2 : 1 )
G l y c e r i n : C h C l ( 2 : 1 )
N / A
5
r . t .
r . t .
r . t .
5 0
6 0
4
r . t .
r . t .
r . t .
r . t
8 5
9 0
9 0
9 0
9 0
8 0
8 0
7 0
1 0
3 0
1 0
1 0
3 0
1 0
3 0
3 0
3 0
3 6 0
9
1 0
1 1
6 0
7 5
r . t
N
o
r
e
a
c
t
i
o
n
a
R ea c t i o n c o n d i t i o n : m e t h y l a c e t o a c e t a t e 1a ( 1 m m o l ) , p h e n y l h y d r a z i n e 2a ( 1 m m o l ) , i s a t in 3a
( 1 m m o l ) a n d m a l o n i t r i l e 4a ( 1 m m o l) , D E S s ( 5 m L ) .
b
I s o l a t e d y i e l d o f p r o d u c t s .
a
b
O
H
N
H
NH
H
Cl-
O
80oC
Cl-
N+
N+
HO
HO
H2N
NH2
H
NH
H
(100 mmol)
(50 mmol)
N
H
O
Figure 2. ( a) D e e p e u t e c t i c s o l v e n t p r e p a r a t i o n f ro m u r e a a n d C h C l i n 2 : 1 r a t i o . ( b) T h e F T - I R s p e c tr a o f f r e s h l y p re pa r ed
U r e a : C h C l ( 2 : 1 ) a n d t h e 1 s t r e c y c l e d a n d 2 n d r e c y c l e d U r e a : C h C l ( 2 :1 ) .
J = 7 . 2 H z , 1 H ) , 7 . 3 8 – 7 .3 5 ( m , 2 H ) , 7 . 3 4 – 7 .2 1 ( m , 4 H ),
7 . 1 2 – 7 .0 4 ( m , 2 H ) , 6 . 9 2 ( d , J = 8 . 0 H z , 1 H ) , 1 . 6 7 ( s , 3 H );
1
3
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1 1 4 .4 , 1 1 9 .1 , 1 2 2 .6 , 1 2 4 .8 , 1 2 6 .8 , 1 2 7 .6 , 1 2 8 .0 , 1 29 . 4,
1 3 8 .0 , 1 4 2 .5 , 1 4 7 . 1 , 1 5 3 .1 , 1 6 8 .0 , 1 7 7 .6 ; E I M S (m/z) : 3 69
( M ?) ; A n a l. c a l c d f o r C H N O : C , 6 8 . 2 8 ; H , 4 .0 9 ; N ,
2
1
1
5
5
2
1 8 . 9 6 ; O , 8 . 6 6 . F o u n d : C , 6 8 . 2 4 ; H , 4 . 1 2 ; N , 1 8 . 9 1 ; O , 8 .6 3 .
2 . 3 b Entry-5b: 6’-Amino-2-oxo-1’-phenyl-3’-propyl-1’H-
spiro[indoline-3,4’-pyrano[2,3-c]pyrazole]-5’-carbonitrile:
W h it e s o l i d ( 8 3 %) ; M . p . 2 1 3 – 2 1 5 °C ( e x p ) , 2 1 1 – 2 13 °C
1 2
( r e p ) ; I R ( K B r , m, c m -1 ) : 3 5 2 0 , 3 3 5 4 , 3 3 0 5 , 3 1 7 9, 3 06 9,
3 0 3 1 , 2 9 5 2 , 2 9 2 1 , 2 8 6 2 , 2 2 0 1 , 1 7 0 5 , 1 6 5 3 , 1 5 9 5 , 1 52 2,
1 4 6 8 , 1 3 9 4 , 1 2 9 3 , 1 2 1 3 , 1 1 3 1 , 1 0 7 1 , 1 0 2 6 , 9 2 9 ,7 4 1 , 6 81 ;
1
H N M R ( 4 0 0 M H z , C D C l ) : d 1 0 . 7 0 ( s , 1 H ) , 8 . 3 5 ( s , 1 H ),
3
Figure 3. R e c yc l i n g s t u d i e s o f d e e p e u t e c t i c m i x t u r e o f
( ur e a : C h Cl ) i n r e a c t i o n o f e t h y l a c e t o a c e t a t e 1a, p h e n y l
h y d r a z in e 2a, i s at i n 3a a n d m a l o n i t r i l e 4a.
7 . 6 5 ( d , J = 7 . 6 H z , 1 H ) , 7 . 3 9 – 7 .3 5 ( m , 2 H ) , 7 . 3 4 – 7 . 21 ( m ,
4 H ) , 7 . 1 2 – 7 .0 4 ( m , 2 H ) , 6 . 9 3 ( d , J = 7 . 6 H z , 1 H ) , 2 .6 4 ( t ,
1 3
J = 6 . 8 H z , 2 H ) , 1 . 7 2 – 1 .6 7 ( m , 2 H ) , 1 . 0 0 ( t , 3 H ) ; C N M R
( 1 0 0 M H z , C D C l ) : d 1 3 . 8 , 2 2 . 9 , 3 2 . 0 , 4 8 . 7 , 5 8 . 7 , 1 10 . 3,
3
1 1 4 .4 , 1 1 9 .1 , 1 2 2 .0 , 1 2 2 .6 , 1 2 3 .3 , 1 2 6 .8 , 1 2 8 .0 , 1 29 . 4,
1 3 8 .1 , 1 4 2 .4 , 1 5 4 . 9 , 1 5 5 .4 , 1 6 8 .1 , 1 7 6 .7 ; E I M S (m/z) : 3 97
( M ?) ; A n a l. c a l c d f o r C H N O : C , 6 9 . 5 1 ; H , 4 .8 2 ; N ,
2 9 2 7 , 2 8 0 8 , 2 0 9 3 , 1 7 0 1 , 1 6 3 9 , 1 6 1 1 , 1 5 0 3 , 1 4 7 7 , 1 4 0 1 ,
1
1 3 4 0 , 1 3 0 1 , 1 2 1 7 , 1 0 4 5 , 9 2 6 , 8 6 3 , 8 2 1 , 7 6 8 , 6 2 4 ; H N M R
2 3 1 9
5
2
( 40 0 M H z, C D C l ) : d 1 0 . 7 1 ( s , 1 H ) , 7 . 8 9 ( s , 1 H ) , 7 . 6 6 ( d ,
3
1 7 . 6 2 ; O , 8 . 0 5 . F o u n d : C , 6 9 . 5 1 ; H , 4 . 7 6 ; N , 1 7 . 6 5 ; O , 8 .0 1 .

2 8 P a g e 4 o f 1 0
J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 2 8
2 . 3 c Entry-5c: 6’-Amino-3’-isopropyl-2-oxo-1’-phenyl-1’H- 1 . 7 5 ( m , 2 H ) , 1 . 2 3 ( t , J = 8 . 8 H z , 3 H ) , 0 . 9 7 ( t , J = 8 .0 H z ,
1 3
spiro[indoline-3,4’-pyrano[2,3-c]pyrazole]-5’-carbonitrile: 3 H ) ; C N M R ( 1 0 0 M H z , C D C l ) : d 1 2 . 4 , 1 3 . 7 , 2 2 . 6, 2 3. 1 ,
3
W h i t e s o l id ( 8 4 % ) ; M . p . 2 0 0 – 2 1 2 °C ( e x p ), 1 9 8 – 2 0 0 °C 4 9 . 8 , 6 0 . 9 , 8 1 . 4 , 1 1 0 .3 , 1 1 4 .4 , 1 1 9 .1 , 1 2 2 .6 , 1 2 3 .3 , 1 26 . 8,
( re p ) ; I R ( K B r , m, c m -1 ) : 3 3 6 0 , 3 3 1 8 , 3 1 8 5 , 2 9 2 1 , 2 8 9 3 , 1 2 8 .0 , 1 2 9 .4 , 1 3 8 .1 , 1 4 2 .4 , 1 5 3 .3 , 1 5 4 .9 , 1 5 8 .1 , 1 67 . 4,
1 2
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2
8
6
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6
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1 0 . 7 2 ( s , 1 H ) , 8 . 5 5 ( s , 1 H ) , 7 . 6 3 ( d , J = 6 . 8 H z , 1 H ) , 5 . 4 9 ; N , 1 2 . 6 3 ; O , 1 4 . 4 5 .
7 . 3 8 – 7 . 34 ( m , 3 H ) , 7 . 3 3 – 7 . 2 0 ( m , 3 H ) , 7 . 0 9 – 7 . 0 3 ( m , 2 H ) ,
2 . 3 g Entry-5g: 6’-Amino-3’-methyl-2-oxo-1’H-spiro[indo-
6 . 9 2 ( d , J = 8 . 0 H z , 1 H ) , 3 . 3 1 – 3 . 2 3 ( m , 1 H ) , 1 . 3 1 ( d ,
line-3,4’-pyrano[2,3-c]pyrazole]-5’-carbonitrile:L i g h t r ed
9
1
3
J = 7 . 2 H z , 6 H ) ; C N M R ( 1 0 0 M H z , C D C l ) : d 2 1 . 7 ,
3
s
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C
(
r
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)
;
I
R
3 2 . 3 , 4 8 . 8 , 5 8 . 6 , 1 1 0 . 2 , 1 1 4 . 3 , 1 1 9 . 0 , 1 2 2 . 0 , 1 2 2 . 5 , 1 2 3 .2 ,
1 2 7 . 3 , 1 2 8 . 0 , 1 2 9 . 3 , 1 3 8 . 2 , 1 4 2 . 5 , 1 5 4 . 6 , 1 5 6 . 3 , 1 6 8 .1 ,
1 7 7 . 2 ; E I M S ( m/z) : 3 9 7 ( M ?) ; A n a l . c a l c d f o r C H N O :
( K Br , m, c m -1 ) : 3 4 1 8 , 3 3 8 5 , 3 3 3 4 , 3 1 2 4 , 2 6 8 4 , 2 1 8 0, 1 70 8,
1 6 7 8 , 1 6 2 8 , 1 5 2 3 , 1 4 6 4 , 1 3 2 6 , 1 2 6 5 , 1 1 5 0 , 1 0 5 2 , 9 45 , 7 83 ,
2
3
1
9
5
2
1
7
4
6
,
6
8
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,
6
2
7
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1
2
.
2
2
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3
C , 6 9 . 5 1 ; H , 4 . 8 2 ; N , 1 7 . 6 2 ; O , 8 . 0 5 . F o u n d : C , 6 9 . 5 0 ; H ,
4 . 7 8 ; N , 1 7 . 6 6 ; O , 8 . 0 2 .
1 H ) , 1 0 . 7 3 ( s , 1 H ) , 7 . 1 3 – 6 .9 2 ( m , 3 H ) , 6 . 9 1 – 6 .6 7 ( m , 2 H ),
1 3
6
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d
3
1 2 . 5 , 4 7 . 1 , 5 8 . 5 , 1 1 1 .1 , 1 1 2 .5 , 1 1 6 .2 , 1 2 2 .1 , 1 2 5 .9 , 1 27 . 8,
1 4 0 .7 , 1 6 2 .7 , 1 6 7 .2 , 1 7 5 .1 ; E I M S ( m/z) : 2 9 3 ( M ?) ; A n al .
c a l c d f o r C H N O : C , 6 1 . 4 3 ; H , 3 . 7 8 ; N , 2 3 . 88 ; O ,
2 . 3 d Entry-5d: 6’-Amino- 5-chloro-3’-methyl-2-oxo-1’-
phenyl -1’H-spiro[indoline-3,4’-pyrano[2,3-c]pyrazole]-5’-
carbonitrile: L i g h t r e d s o l i d ( 8 2 % ); M . p . 3 0 2 – 3 0 4 °C ( e x p ) ;
I R ( K B r , m, c m -1 ) : 3 3 5 2 , 3 3 1 9 , 3 1 9 5 , 2 2 0 1 , 1 7 2 3 , 1 6 5 8 ,
1
5
1
1
5 2
1 0 . 9 1 . F o u n d : C , 6 1 . 4 6 ; H , 3 . 8 2 ; N , 2 3 . 8 5 ; O , 1 0 . 9 5.
1 5 9 1 , 1 5 2 5 , 1 4 4 8 , 1 3 9 5 , 1 2 2 3 , 1 1 2 8 , 1 0 7 4 , 9 6 5 , 9 0 8 , 7 5 7 ;
1
2 . 3 h Entry-5h: Ethyl 6’-Amino-2-oxo-3’-phenyl-1’H-
spiro[indoline-3,4’-pyrano[2,3-c]pyrazole]-5’-carboxylate:
W h it e s o l i d ( 8 2 %) ; M . p . 2 4 0 – 2 4 2 °C ( e x p ) , 2 4 2 –2 4 3 °C
H N M R ( 4 0 0 M H z , C D C l ) : d 1 0 . 7 2 ( s , 1 H ) , 7 . 8 7 ( s , 1 H ) ,
3
7 . 6 1 ( d , J = 7 . 2 H z , 1 H ) , 7 . 3 6 – 7 . 3 2 ( m , 2 H ) , 7 . 3 2 – 7 . 2 0 ( m ,
3 H) , 7 . 1 1 – 7 . 0 5 ( m , 2 H ) , 6 . 9 1 ( d , J = 8 . 0 H z , 1 H ) , 1 . 6 1 ( s ,
9
( r e p ) ; I R ( K Br , m, c m -1 ) : 3 4 8 2 , 3 3 6 4 , 3 2 6 6 , 3 1 7 4 , 3 05 7,
1 3
3
H
)
;
C
N
M
R
(
1
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0
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D
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l
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6
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4
8
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8
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5
8
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8
,
3
2 9 7 8 , 1 7 1 5 , 1 6 6 4 , 1 6 1 5 , 1 4 7 6 , 1 4 0 3 , 1 2 9 2 , 1 1 4 5 , 1 09 4,
1
1 1 0 . 1 , 1 1 7 . 4 , 1 1 9 . 0 , 1 2 2 . 6 , 1 2 5 . 8 , 1 2 6 . 6 , 1 2 7 . 1 , 1 2 9 .0 ,
1 2 9 . 3 , 1 3 0 . 1 , 1 3 8 . 1 , 1 4 2 . 5 , 1 4 7 . 1 , 1 5 3 . 1 , 1 6 8 . 0 ; E I M S ( m/z) :
4 0 3 ( M ?) ; A n a l . c a l c d f o r C H C l N O : C , 6 2 . 4 6 ; H ,
1 0 3 8 , 9 2 8 , 7 5 1 ; H N M R ( 4 0 0 M H z , C D C l ) : d 1 2 . 17 ( s ,
3
1 H ) , 1 0 . 3 3 ( s , 1 H ) , 7 . 4 2 – 7 .3 7 ( m , 2 H ) , 7 . 3 7 – 7 .2 9 ( m , 3 H ),
7 . 1 8 – 7 .0 9 ( m , 3 H ) , 7 . 0 1 – 6 .9 2 ( m , 2 H ) , 6 . 7 3 ( d , J = 7 .6 H z ,
2 1 1 4
5
2
1 3
3 . 4 9 ; C l , 8 . 7 8 ; N , 1 7 . 3 4 ; O , 7 . 9 2 . F o u n d : C , 6 2 . 4 1 ; H , 3 . 5 2 ;
C l , 8 . 7 1 ; N , 1 7 . 3 0 ; O , 7 . 9 5 .
1 H ) , 3 . 6 2 ( q , J = 6 . 6 H z , 2 H ) , 0 . 6 5 ( t , J = 7 . 4 H z , 3 H );
C
N M R ( 1 0 0 M H z , C D C l ) : d 1 3 . 7 , 4 7 . 8 , 6 0 . 5 , 8 1 . 0 , 1 10 . 7,
3
1 1 3 .7 , 1 2 4 .5 , 1 2 5 .3 , 1 2 5 .8 , 1 2 6 .9 , 1 2 7 .2 , 1 2 7 .9 , 1 28 . 3,
1 2 9 .0 , 1 3 0 .3 , 1 3 9 .6 , 1 4 2 .1 , 1 5 7 .4 , 1 6 1 .7 , 1 6 5 .3 , 1 67 . 2,
1 6 7 .9 ; E I M S ( m/z) : 4 0 2 ( M ?) ; A n a l. c a l c d f o r C H N O :
2 . 3 e Entry-5e: Ethyl 6’-Amino-3’-isopropyl-2-oxo-1’-phe-
nyl-1’H-spiro[indoline-3,4’-pyrano[2,3-c
]pyrazole]-5’-
carboxylate: W h i t e s o l i d ( 8 1 % ); M . p . 2 5 4 – 2 5 6 °C ( e x p ) ,
2
2
1
8
4 4
C , 6 5 . 6 6 ; H , 4 . 5 1 ; N , 1 3 . 9 2 ; O , 1 5 . 9 0 . F o u n d : C , 6 5 . 63 ; H ,
4 . 5 5 ; N , 1 3 . 8 9 ; O , 1 5 . 9 4 .
2 5 8 – 2 5 9 °C ( r e p ) ; I R ( KB r, m, c m -1 ) : 3 3 7 9 , 3 2 0 3 , 3 1 9 0 ,
1 2
3 0 2 4 , 2 9 3 8 , 1 6 7 8 , 1 6 2 8 , 1 5 2 3 , 1 4 3 4 , 1 3 7 6 , 1 2 8 5 , 1 1 5 0 ,
1
1 0 7 2 , 9 5 5 , 7 8 3 , 7 4 6 , 6 8 8 , 6 2 7 ; H N M R ( 4 0 0 M H z ,
2 . 3 i Entry-5i: 6’-Amino-2-oxo-3’-phenyl-1’H-spiro[indo-
line-3,4’-pyrano[2,3-c]pyrazole]-5’-carbonitrile:W h i t e
C D C l ) : d 1 0 . 7 1 ( s , 1 H ) , 8 . 1 3 ( s , 1 H ) , 7 . 6 6 ( d , J = 7 . 2 H z ,
3
9
1 H ) , 7 . 3 8 – 7 . 3 2 ( m , 3 H ) , 7 . 3 2 – 7 . 2 0 ( m , 3 H ) , 7 . 1 2 – 7 . 0 7 ( m ,
2 H ) , 6 . 9 3 ( d , J = 8 . 0 H z , 1 H ) , 4 . 1 9 ( q , J = 6 . 4 H z , 2 H ) , 3 . 3 8
s o l i d ( 8 3 %) ; M . p . 2 7 7 – 2 7 9 °C ( e x p ) , 2 8 0 – 2 8 1 °C ( r e p ); I R
( K Br , m, c m -1 ) : 3 3 8 4 , 3 3 1 3 , 3 2 4 1 , 3 1 4 3 , 2 9 0 7 , 2 1 8 7, 1 70 5,
1 6 4 7 , 1 5 9 1 , 1 4 9 6 , 1 4 0 3 , 1 3 2 0 , 1 2 1 1 , 1 0 5 8 , 9 2 3 , 7 47 ; H
1
( m, 1 H ) , 1 . 3 3 ( d , J = 8 . 0 H z , 6 H ) , 1 . 0 4 ( t , J = 7 . 2 H z , 3 H ) ;
1 3
C N M R ( 1 0 0 M H z , C D C l ) : d 1 4 . 0 , 2 2 . 1 , 3 2 . 2 , 5 0 . 0 , 6 2 . 2 ,
N M R ( 4 0 0 M H z , C D C l ) : d 1 2 . 3 9 ( s , 1 H ) , 1 0 . 4 7 ( s , 1 H ),
3
3
8 1 . 0 , 1 1 0 . 2 , 1 1 4 . 4 , 1 1 9 . 1 , 1 2 2 . 6 , 1 2 3 . 3 , 1 2 7 . 3 , 1 2 8 . 0 , 1 2 9 .4 ,
1 3 8 . 0 , 1 4 2 . 4 , 1 5 3 . 0 , 1 5 4 . 5 , 1 5 8 . 0 , 1 6 5 . 9 , 1 6 7 . 1 ; E I M S ( m/z) :
4 4 4 ( M ?) ; A n a l . c a l c d f o r C H N O : C , 6 7 . 5 5 ; H , 5 . 4 4 ;
7 . 4 2 – 7 .2 7 ( m , 2 H ) , 7 . 2 7 – 7 .1 1 ( m , 3 H ) , 7 . 1 3 – 7 .0 5 ( m , 3 H ),
6 . 9 1 – 6 .8 9 ( m , 2 H ) , 6 . 8 2 ( d , J = 7 . 6 H z , 1 H ) ; 13C N M R ( 10 0
M H z , C D C l ) : d 4 8 . 1 , 5 9 . 1 , 8 0 . 9 , 1 1 1 .5 , 1 1 4 .1 , 1 24 . 4,
2
5
2
4
4
4
3
N , 1 2 . 6 0 ; O , 1 4 . 4 0 . F o u n d : C , 6 7 . 5 1 ; H , 5 . 4 8 ; N , 1 2 . 5 6 ; O ,
1 4 . 4 4 .
1 2 5 .3 ,1 2 5 . 7 , 1 2 6 .9 , 1 2 7 .1 , 1 2 7 .8 , 1 2 8 .2 , 1 2 9 .0 , 1 3 1 . 3 , 1 40 . 2,
1 4 3 .2 , 1 6 0 .2 , 1 6 4 .2 , 1 6 8 .2 , 1 7 3 .1 ; E I M S ( m/z) : 3 5 5 ( M ?) ;
A n a l. c a l c d f o r C H N O : C , 6 7 . 6 0 ; H , 3 . 6 9 ; N , 1 9 . 71 ; O ,
2
0
1
3
5
2
2 . 3 f Entry-5f: Ethyl 6’-Amino-2-oxo-1’-phenyl-3’-propyl-
1’H-spiro[indoline-3,4’-pyrano[2,3-c]pyrazole]-5’-carboxy-
9 . 0 0 . F o u n d : C , 6 7 . 6 3 ; H , 3 . 7 2 ; N , 1 9 . 7 5 ; O , 9 . 0 3 .
late: W hi t e s o l id ( 8 0 % ) ; M . p . 2 5 2 – 2 5 4 °C ( e x p ) , 2 . 3 j Entry-5j: 3,7,7-Trimethylmethyl-7,8-dihyro-1H-spir-
2 5 6 – 2 5 8 °C ( r e p ) ; I R ( KB r, m, c m -1 ) : 3 3 6 1 , 3 2 5 8 , 3 1 7 4 , o[chromeno[2,3’-c]pyrazole-4,3-indoline]- 2’,5(6H)-dione:
1 2
3
0
7
1
,
3
0
2
9
,
2
9
5
9
,
2
9
2
9
,
2
8
6
9
,
2
8
3
1
,
2
7
3
5
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1
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2
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2
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–
2
2
2
°
C
1 5 1 1 , 1 4 6 7 , 1 3 7 9 , 1 2 8 1 , 1 1 6 5 , 1 1 3 3 , 1 0 7 2 , 1 0 3 9 , 9 3 5 , 7 8 5 , ( r e p ) ; I R ( K B r , m, c m -1 ) : 3 3 7 0 , 3 1 8 0 , 2 9 1 5 , 1 7 1 9, 1 68 9,
1 6
1
7
6
0
,
7
4
7
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2 H ) , 7 . 2 5 – 7 . 11 ( m , 4 H ) , 7 . 0 9 – 7 . 0 4 ( m , 2 H ) , 6 . 9 3 ( d , J = 8 . 0 1 0 . 5 3 ( s , 1 H ) , 7 . 3 8 – 7 .3 7 ( m , 1 H ) , 7 . 3 6 – 7 .2 1 ( m , 2 H ),
H z , 1 H ) , 4 . 0 8 ( q , J = 5 . 2 H z , 2 H ) , 2 . 5 9 ( t , J = 7 . 6 H z , 2 H ) , 7 . 1 2 – 7 .1 0 ( m , 1 H ) , 2 . 5 9 – 2 .2 0 ( m , 2 H ) , 2 . 1 9 – 2 .1 7 ( m , 2 H ),

J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 2 8
P a g e 5 o f 1 0 2 8
1 . 5 3 ( s , 3 H ) , 0 . 9 8 ( s , 6 H ) ; 13C N M R ( 1 0 0 M H z , C D C l ) : d 1 19 .1 , 1 25 .9 , 1 29 .1 , 1 29 .4 , 1 34 .3 , 1 38 .2 , 1 41 .9 , 1 61 .0 , 1 63 .7 ,
1 8 1 4-
3
1 1 . 1 , 2 7 . 8 , 3 4 . 8 , 4 4 . 6 , 4 9 . 7 , 5 1 . 1 , 1 1 0 . 2 , 1 1 4 . 4 , 1 1 9 . 1 , 1 2 2 .6 , 1 68 .1 , 1 98 .9 ; E IM S (m/z) : 3 99 ( M?) ; A na l. c al cd f or C H
1 2 3 . 3 , 1 2 8 . 0 , 1 3 8 . 1 , 1 4 2 . 4 , 1 6 1 . 4 , 1 6 3 . 6 , 1 6 8 . 4 , 2 0 0 .0 ; B rN O : C , 5 4 . 0 2 ; H , 3 . 5 3 ; B r , 1 9 . 9 6 ; N , 1 0 . 5 0 ; O , 1 1 . 9 9 ;
3
3
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6 8 . 7 5 ; H , 5 . 4 8 ; N , 1 2 . 0 3 ; O , 1 3 . 7 4 ; F o u n d : C , 6 8 . 7 1 ; H ,
5 . 4 5 ; N , 1 2 . 0 8 ; O , 1 3 . 7 7 .
2 . 3 o Entry-5o: 3,7,7- trimethyl-1-phenyl-7,8-dihyro-1H-
spiro[chromeno[2,3’ -c]pyrazole-4,3-indoline]-2’,5(6H)-
2
.
3
k
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,
hyro-1H-spiro[chromeno[2,3’-c]pyrazole-4,3-indoline]- 2’, 2 3 8 – 2 4 0 °C ( r e p ) ; I R ( K Br , m, c m -1 ) : 3 1 3 8 , 2 8 8 1 , 1 70 1,
1 7
5(6H)-dione: W hi t e s o l i d ( 7 9 % ) ; M . p . 2 9 8 – 2 9 9 °C ( e x p ) , 1 6 4 1 , 1 6 0 1 , 1 5 8 9 , 1 5 0 8 , 1 4 6 3 , 1 3 2 6 , 1 2 0 1 , 1 1 7 1 , 1 11 5,
1 5
-
1
1
3
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1 7 1 9 , 1 6 5 2 , 1 6 2 9 , 1 6 1 4 , 1 5 8 9 , 1 4 7 1 , 1 3 4 2 , 1 2 7 6 , 1 1 2 5 , C D C l ) : d 1 0 . 6 1 ( s , 1 H ) , 7 . 7 1 – 7 . 5 9 ( m , 3 H ) , 7 . 5 7 – 7 . 4 8 ( m ,
3
1
1 0 3 6 , 9 1 1 , 7 7 2 , 7 3 6 ; H N M R ( 4 0 0 M H z , C D C l ) : d 1 2 . 2 7 2 H ) , 7 . 4 5 – 7 . 3 8 ( m , 4 H ) , 2 . 4 9 – 2 . 4 5 ( m , 2 H ) , 2 . 2 8 – 2 . 19 ( m ,
3
1 3
( s, 1 H ) , 1 0 . 1 9 ( s , 1 H ) , 7 . 4 9 ( s , 1 H ) , 7 . 2 6 ( d , J = 7 . 4 H z , 1 H ) , 2 H ) , 1 . 6 3 ( s , 3 H ) , 1 . 0 7 ( s , 6 H ) ; C N M R ( 1 00 M H z ,
7 . 1 4 ( d , J = 8 . 0 H z , 1 H ) , 2 . 4 4 – 2 . 3 8 ( m , 2 H ) , 2 . 2 0 – 2 . 1 8 ( m , C D C l ) : d 1 2 . 1 , 2 5 . 7 , 2 6 . 8 , 3 1 . 7 , 4 0 . 9 , 4 6 . 4 , 4 9 . 3 , 9 8. 8 ,
3
2 H) , 1 . 6 2 ( s , 3 H ) , 1 . 1 9 ( s , 6 H ) ; 13C N M R ( 1 0 0 M H z , 1 0 7 .5 , 1 1 1 .2 , 1 1 9 .7 , 1 2 1 .3 , 1 2 2 .4 , 1 2 6 .7 , 1 2 7 .9 , 1 28 . 5,
C D C l ) : d 1 0 . 6 , 2 6 . 7 , 3 1 . 4 , 4 3 . 1 , 4 8 . 9 , 5 0 . 9 , 1 0 9 . 4 , 1 1 0 .5 , 1 3 2 .9 , 1 3 5 .6 , 1 4 1 .2 , 1 4 4 .0 , 1 4 3 .7 , 1 6 5 .3 , 1 7 7 .4 , 1 95 . 2,
3
1 1 1 . 5 , 1 1 4 . 2 , 1 2 4 . 2 , 1 2 3 . 4 , 1 2 6 . 6 , 1 3 8 . 0 , 1 3 9 . 7 , 1 6 2 .2 , 1 9 5 .2 , 1 9 6 .0 ; E I M S (m/z) : 4 2 5 ( M ?) ; A n a l . c a l c d f or
1 9 9 . 3 ; E I M S ( m/z) : 4 2 7 ( M ?) ; A n a l . c a l c d f o r C H
B r N O : C , 5 6 . 0 9 ; H , 4 . 2 4 ; B r , 1 8 . 6 6 ; N , 9 . 8 1 ; O , 1 1 . 2 1 ; C , 7 3 . 3 1 ; H , 5 . 4 4 ; N , 9 . 8 5 ; O , 1 1 . 2 2 .
F o u n d : C , 5 6 . 1 2 ; H , 4 . 2 1 ; B r , 1 8 . 6 1 ; N , 9 . 8 5 ; O , 1 1 . 2 6 .
C H N O : C , 7 3 . 3 5 ; H , 5 . 4 0 ; N , 9 . 8 2 ; O , 1 1 . 2 8 ; F o u nd :
2 6 2 3 3 3
2 0 1 8 -
3
3
2 . 3 p Entry-5p: 5’- bromo-3,7,7-trimethyl-1-phenyl-7,8-di-
2 . 3 l Entry-5l: 5’-chloro-3,7,7- Trimethylmethyl-7,8-dihyrro- hyro-1H-spiro[chromeno[2,3’-c]pyrazole-4,3-indoline]-
1H-spiro[chromeno[2,3’-c]pyrazole-4,3-indoline]-2’,
5(6H)-dione: C r e am s o l i d ( 8 1 % ) ; M . p . 2 1 2 – 2 1 4 °C ( e x p ) , ( e x p ) , 2 7 2 – 2 7 4 °C ( r e p ) ; I R ( K Br , m, c m -1 ) : 3 2 2 9 , 2 91 8,
2’,5(6H)-dione: O f f w h it e s o l i d ( 8 0 % ) ; M . p . 2 6 6 –2 6 8 °C
1 5
2 1 5 – 2 1 7 °C ( r e p ) ; I R ( KB r, m, c m -1 ) : 3 2 0 9 , 3 1 1 2 , 2 9 1 0 , 1 7 1 7 , 1 6 4 1 , 1 6 0 5 , 1 5 9 1 , 1 5 1 8 , 1 4 7 1 , 1 3 4 1 , 1 2 0 5 , 1 17 5,
1 8
1
1 7 0 9 , 1 6 8 9 , 1 6 5 6 , 1 6 1 2 , 1 5 1 0 , 1 4 6 9 , 1 3 3 9 , 1 2 0 8 , 1 1 6 4 , 1 1 1 5 , 1 0 2 8 , 8 2 0 , 7 7 1 , 6 8 3 , 5 1 9 ; H N M R ( 4 0 0 M H z , C D C l ) : d
3
1
1 0 2 8 , 9 0 8 , 7 6 8 , 7 4 6 ; H N M R ( 4 0 0 M H z , C D C l ) : d 1 2 . 3 8 ( s , 1 0 . 7 6 ( s , 1 H ) , 7 . 6 8 ( d , J = 7 . 6 H z , 1 H ) , 7 . 4 3 ( t , J = 7 .4 H z ,
3
1 H ) , 1 0 . 0 6 ( s , 1 H ) , 7 . 7 3 ( s , 1 H ) , 7 . 3 4 ( d , J = 5 . 6 , 1 H ) , 6 . 9 6 ( d , 2 H ) , 7 . 2 9 – 7 .1 2 ( m , 3 H ) , 7 . 0 9 ( s , 1 H ) , 6 . 9 3 ( d , J = 7 .6 H z ,
1 3
J = 7 . 2 , 1 H ) , 2 . 1 1 ( s , 2 H ) , 2 . 0 9 ( s , 2 H ) , 1 . 5 0 ( s , 3 H ) , 1 . 1 5 ( s , 1 H ) , 2 . 4 2 ( s , 2 H ) , 2 . 3 5 ( s , 2 H ) , 1 . 5 3 ( s , 3 H ) , 1 . 1 7 ( s , 6 H ) ;
1 3
C
6 H ) ; C N M R ( 1 0 0 M H z , C D C l ) : d 1 0 . 9 , 2 7 . 1 , 3 1 . 6 , 4 3 . 4 , N M R ( 1 0 0 M H z , C D C l ) : d 1 2 . 0 , 2 5 . 5 , 2 6 . 7 , 3 1 . 7, 4 0. 9 ,
3
3
4 9 . 1 , 5 1 . 0 , 1 1 0 . 3 , 1 1 0 . 5 , 1 1 4 , 4 , 1 2 4 . 9 , 1 2 5 . 9 , 1 2 7 . 3 , 1 3 8 .3 , 4 6 . 4 , 5 0 . 0 , 9 8 . 1 , 1 0 7 .1 , 1 1 0 .7 , 1 1 8 .2 , 1 2 1 .0 , 1 2 1 .9 , 1 26 . 1,
1 4 0 . 0 , 1 6 3 . 7 , 2 0 0 . 0 ; E I M S ( m/z) : 3 8 3 ( M ?) ; A n a l . c a lc d f o r 1 2 7 .6 , 1 2 8 .1 , 1 3 1 . 2 , 1 3 4 .4 , 1 4 0 .1 , 1 4 3 .2 , 1 4 3 . 6 , 1 6 5 .0 , 1 76 . 8,
C H C lN O : C , 6 2 . 5 8 ; H , 4 . 7 3 ; C l , 9 . 2 4 ; N , 1 0 . 9 5 ; O , 1 8 6 .1 , 1 9 4 .9 , 1 9 5 . 7 ; E I M S ( m/z) : 5 0 3 ( M ?) ; A n a l . c a l cd f or
2 0 1 8
3 3
1 2 . 5 0 ; F o u n d : C , 6 2 . 5 2 ; H , 4 . 6 9 ; C l , 9 . 2 1 ; N , 1 0 . 9 9 ; O , 1 2 . 5 3 . C H B r N O : C , 6 1 . 9 1 ; H , 4 . 4 0 ; B r , 1 5 . 8 4 ; N , 8 . 3 6; O ,
2 6 2 2
3
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9
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2 . 3 m
Entry-5m:
3-
methyl-7,8-dihyro-1H-spir-
o[chromeno[2,3’-c]pyrazole-4,3-indoline]-2’,5(6H)-dione:- 2 . 3 q Entry-5q: 3-methyl-1-phenyl-7,8-dihyro-1H-spir-
W h it e s o l id ( 8 2 % ) ; M . p . 2 9 6 – 2 9 8 °C ( e x p ), 3 0 1 – 3 0 2 °C o[chromeno[2,3’-c]pyrazole-4,3-indoline]-2’, 5(6H)-dione:
( re p ) ; I R ( K B r , m, c m -1 ) : 3 3 3 1 , 3 2 3 3 , 2 9 1 7 , 1 7 1 9 , 1 6 4 5 , O f f w h it e s o l i d ( 8 2 % ) ; M . p . 2 9 3 – 2 9 5 °C ( e x p ) , 2 9 6 –2 9 8 °C
1 5
1 6 1 0 , 1 6 0 1 , 1 5 2 0 , 1 4 7 1 , 1 3 4 4 , 1 2 0 5 , 1 1 7 3 , 1 1 1 4 , 1 0 2 8 , 8 1 7 , ( r e p ) ; I R ( K B r , m, c m -1 ) : 3 1 9 3 , 1 7 1 4 , 1 6 7 1 , 1 6 4 3, 1 61 7,
1 5
1
7
7
1
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7
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1
1 0 . 4 9 ( s , 1 H ) , 7 . 6 6 ( s , 1 H ) , 7 . 6 4 – 7 . 2 1 ( m , 3 H ) , 2 . 7 8 – 2 . 6 8 6 1 9 ; H N M R ( 4 0 0 M H z , C D C l ) : d 1 0 . 5 1 ( s , 1 H ),
3
1 3
( m, 2 H ) , 2 . 1 0 – 2 . 0 7 ( m , 5 H ) , 1 . 6 9 – 1 . 6 4 ( m , 2 H ) ; C N M R 7 . 6 3 – 7 .5 1 ( m , 3 H ) , 7 . 3 9 – 7 .1 7 ( m , 4 H ) , 7 . 1 2 – 6 .9 3 ( m , 2 H ),
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1 1 3 . 1 , 1 1 4 . 4 , 1 2 3 . 3 , 1 2 6 . 7 , 1 2 8 . 0 , 1 3 8 . 0 , 1 4 2 . 5 , 1 6 2 .1 , 2 . 1 3 – 2 .0 5 ( m , 5 H ) , 1 . 6 2 – 1 .5 7 ( m , 2 H ) ; C N M R ( 10 0
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7
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1
0
8
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7
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3
C H N O : C , 6 7 . 2 8 ; H , 4 . 7 1 ; N , 1 3 . 0 8 ; O , 1 4 . 9 4 ; F o u n d : 1 1 2 .0 , 1 1 9 .7 , 1 2 0 .6 , 1 2 1 .3 , 1 2 6 .1 , 1 2 7 .1 , 1 2 8 .7 , 1 33 . 7,
C , 6 7 . 2 5 ; H , 4 . 7 4 ; N , 1 3 . 0 3 ; O , 1 4 . 9 8 .
1
8
1
5
3
3
1 3 9 .2 , 1 4 1 .1 , 1 4 3 .0 , 1 6 3 .2 , 1 7 5 ,8 , 1 8 3 .5 , 1 9 1 .6 , 1 93 . 7,
1 9 4 .2 ; E I M S ( m/z) : 3 9 7 ( M ?) ; A n a l. c a l c d f o r C H N O :
2
4
1
9
3
3
2 .3 n Entry-5n: 5’- bromo-3-methyl-7,8-dihyro-1H-spir-
o[chromeno[2,3’-c]pyrazole-4,3-indoline]- 2’, 5(6H)-dione:
Y el lo w s ol id ( 83 %) ; M .p . 3 08 –3 10 °C (e xp ); I R ( KBr , m,
C , 7 2 . 5 3 ; H , 4 . 8 2 ; N , 1 0 . 6 0 ; O , 1 2 . 0 8 ; F o u n d : C , 7 2. 5 0; H ,
4 . 8 5 ; N , 1 0 . 6 5 ; O , 1 2 . 0 3 .
c m-1) : 3 30 1, 3 21 3, 2 90 7, 1 71 3, 1 64 1, 1 60 3, 1 59 1, 1 51 1, 1 45 3, 2 . 3 r Entry-5r: 5’- bromo-3-methyl-1-phenyl-7,8-dihyro-1H-
1
1 32 4, 1 20 1, 1 15 3, 1 10 4, 1 01 3, 8 09 , 7 63 , 7 01 ; H NM R ( 40 0 spiro[chromeno[2,3’-c]pyrazole-4,3-indoline]-2’,5(6H)-
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( d, J = 6 .8 H z, 1 H), 6 .8 4 ( d, J = 8 .4 Hz , 1 H) , 2 .6 3 ( t, J = 6 .0 3 0 7 – 3 0 9 °C ( r e p ) ; I R ( K Br , m, c m -1 ) : 3 0 8 1 , 2 9 3 9 , 1 68 8,
H z , 2 H ) , 2 .1 2 – 2. 0 6 ( m , 5 H ) , 1 . 7 8 – 1. 7 2 ( m , 2 H ) ; C N MR ( 10 0 1 6 4 9 , 1 5 9 0 , 1 5 9 2 , 1 5 2 1 , 1 4 6 8 , 1 3 9 8 , 1 2 6 5 , 1 1 1 8 , 7 48 , 6 77 ,
1
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J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 2 8
a
Table 2. O n e p o t s y n t h e s i s o f s p i r o [ i n d o l i n e - 3 , 4 ’ - p y r a n o [ 2 , 3 - c] p y r a z o le ] d e r iv a t i v e s (5a-i) .
85
a
R e a ct i o n c on di t i o n : b-k e t o e s t e r s ( 1 m m o l ) , h y d r a z in e s ( 1 m m o l ) , i s a t i n s ( 1 m m o l ) a n d a c t i v e m e t h y l e n e c o m p ou nd s
( 1 m m o l ) , 5 m L o f D E S ( Ur e a : C h C l i n 2 : 1 r a t i o ) , s t ir r i n g f o r 1 0 m i n .
( m, 3 H ) , 7 . 2 9 – 7 . 15 ( m , 3 H ) , 7 . 0 3 – 6 . 9 5 ( m , 2 H ) , 2 . 7 7 – 2 . 6 4
( t, J = 6 . 4 H z , 2 H ) , 2 . 2 2 – 2 . 1 7 ( m , 5 H ) , 1 . 7 3 – 1 . 6 7 ( m , 2 H ) ;
f r es h l y p r e p a r ed d e e p e u t e c t i c s o l v e n t ( Fi g u r e 2) o f
u r e a : c h o l i n e c h l o ri d e ( 1 0 m o l % , 2 : 1 r at i o o f u r e a : -
c h o l i n e c h l o ri d e ) a t r o o m t e m p e ra t u r e. T o o u r
d e l i g h t , t h e e x p e c t e d p r o d u c t i . e . , s p i r o [ i n d o l i n e - 3 , 4’ -
p y r a n o [ 2 , 3 -c] p y r a z o l e ] d e r i v a t i v e s 5a w a s i so l at ed
w i t h 8 5 % y i el d . T h e o v er a l l r e ac t i o n t i me f o r c o m -
p l et e t r a n s f o r m a t i on t o o k o n l y 5 m i n a s m o n i t o r e d b y
T L C . ( e n t r y 1 , T a b l e 1 ) . T h e n , t o c h e ck t h e o p t i -
m i z ed c o n d i t i o n , w e p e r fo r me d t h e r e ac t i o n i n d i f -
f er e n t c o n d i t i o n s . W e i n cr e a s ed t h e r e ac t i o n d u r at i o n
f r o m 5 m i n t o 1 0 m i n , t h e y i el d o f t h e i s o l a t e d p r o -
d u ct i n cr e a s e s t o 9 0 % ( e n t r y 2 , T a b l e 1) . O n f u r t h e r
i n cr e a s i n g t h e r e ac t i o n d u r a t i o n u p t o 3 0 m i n , t h e
y i el d o f t h e p r o d u c t r e ma i n s c o n s t an t ( e n t r y 3 ,
1
3
C
N
M
R
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6
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2
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3
4 9 . 6 , 9 7 . 1 , 1 1 1 . 0 , 1 1 1 . 4 , 1 1 2 . 5 , 1 1 9 . 7 , 1 2 5 . 4 , 1 2 5 . 9 , 1 2 8 .7 ,
1 3 0 . 3 , 1 3 5 . 8 , 1 3 6 . 5 , 1 4 0 . 7 , 1 4 3 . 9 , 1 4 4 . 6 , 1 6 5 . 5 , 1 7 2 . 3 , 1 8 9 .9 ,
1 9 3 . 3 ; E I MS ( m/z) : 4 7 5 ( M ?) ; A n a l . c a l c d f o r C H
B r N O : C , 6 0 . 5 2 ; H , 3 . 8 1 ; B r , 1 6 . 7 7 , N , 8 . 8 2 ; O , 1 0 . 0 8 ;
F o u n d : C , 6 0 . 5 5 ; H , 3 . 7 7 ; B r , 1 6 . 7 1 , N , 8 . 7 9 ; O , 1 0 . 1 2 .
2
4
1
8
-
3
3
3. Results and Discussion
A t t h e v e r y o n s e t o f t h i s w o r k , w e s t a rt e d t h e o n e - p o t
f o u r -c o mp o n e nt r ea c t io n u si n g e t hy l ac e to ac e t a t e 1a,
p h e n y l h y d r a z i n e 2a, i s a ti n 3a a n d m a lo ni t ri l e 4a i n

J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 2 8
P
a
g
e
7
o
f
1
0
2
8
Table 3. O n e p o t via f o u r c o m p o n e n t s y n t h e s i s o f s p i r o [ c h r o m e n o [ 2 , 3 - c] p y r a z o le - 4 , 3 ’ - i n d o l i n e ] - d i o n e s ( 5j-r) .
4c-d
a
R e a ct i o n c o nd it i on : b-k e t o e s t e r s ( 1 m m o l ), h y d r a z i n e s ( 1 m m o l ) , i s a t in s ( 1 m m o l ) a n d c y c l i c a c t i v e m e t h y l e n e c o m po u nd s
( 1 m m o l ) , 5 m L o f D E S ( Ur e a : C h C l i n 2 : 1 r a t i o ) , s t ir r i n g f o r 1 0 m i n s .
T a b l e 1 ) . A g a i n, t he e f f e c t o f c h a n g e i n t e m p e r a t u r e i n d i c a t e s t h at t h e D E S c o m p o n e n t s p a r t i ci p a t e i n t h e
w a s o b s e r v e d w h e n t h e r e a c t io n t e m p e r a t u r e w a s r e ac t i o n b u t n o t t o t h e e x t e n t a s t h at o f u r e a : C h C l ,
e n h a n c e d t o 5 0 °C a n d 6 0 °C , t he p e rc e n ta g e o f t h e w h i ch b e h a v e s a s a b a s e f o r a b s t ra c t i n g p r o t o n s f r o m
i s o l a t e d p r o d u c t r e m a in s a s u s ua l o f 9 0 % ( e n t r i e s 4 a ct i v e m et h y l en e c o m p o u n d s a n d p a r t i ci p a t e i n s o l -
a n d 5 , T ab l e 1) . A l s o , w e p e rf o r m e d t h e r e a c t i o n i n v a t i n g a l l t h e c o m p o n e n t s a n d i n t e rm e d i at es o f t h i s
i c e- b a t h c o n d i t i o n i . e . , 4 °C , t h e i s o la te d y i e l d w a s p r o c e d u r e e ffi c i e n t l y . L a s t l y , w h e n t h e r ea c t i o n w as
8 0 % a f t er s t i r r i n g f or 3 0 m i n ( e n t r y 6 , T a bl e 1) . T h e p e r f o r me d u n d e r s o l v e n t - f r ee a t r o o m t e m p e ra t u r e f o r
e f fi c i e n c y o f o t h e r D E S s w a s a l s o d e t e r m i n e d u n d er 2 4 h , t h e r e ac t i o n m i x t u r e d i d n o t p r o c e ed a s i n d i -
o p t i mi z ed t e m p e ra t u r e . W h e n t h e r e a c t io n w a s p e r - c at e d i n t h e T L C . T h u s , t h e o p t i m i z e d c o n d i t i o n f o r
f o r m e d u s i n g v a r i o u s f re s h ly p r e p a re d D E S s n a m el y s y n t h e s i s o f s p i r o o x i n d o l e d e r i v a t i v e s t ar t i n g f r o m
m a l o n i c a c i d : C h C l , o x a l i c a c i d : C h C l, P T S A: Ch Cl , e t h y l a ce t o a c e t a t e 1a, p h e n y l h y d ra z i n e 2a, i s a t i n 3a
g l y c e r i n: C h C l ( e n tr ie s 7 – 1 1 , T a bl e 1) , t he r e a ct i o n a n d m al o n i t r i l e 4a r eq u i r e d D E S p r e p a re d f r o m
d i d n o t i m p r o v e t he y i e ld o f t he p r o du ct . T h i s u r e a : Ch Cl ( 2 : 1 r a t i o o f c h o l i n e c h l o ri d e : u r ea ) a s

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t e m p e r a t u r e f o r j u s t 1 0 m i n ( 5a, 8 5 % ) . s i d e r ea c t i o n p r o d u c t s w e r e o b s er v e d . T h e p r o d u c t s
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t u r n e d o u r a t t e nt i on t o f ul l y c h a r a c te r iz e t h e f o u r h y d ra z i n e s 2a-b, i s at i n s 3a-b a n d a ct i v e m e t h y l e n e
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w a s o b s e r v e d a t 4 8 . 8 p p m , o n e c a rb o n y l a n d o n e c o m p o n e n t r e ac t i o n w a s f u r t h er i n v e s t i g a t e d b y
n i t r i l e p e a k s w e r e o b s e r v e d a t 1 7 7 . 6 a n d 1 1 4 . 4 p p m, c h a n g i n g t h e a l i p h a t i c a ct i v e m et h y l en e c o m p o u n d s t o
r e s p e c t i v el y a n d t h e p e a k a t 1 3 . 6 p p m c o rr e s p o n d s t o c y c l i c a ct i v e m et h y l en e c o m p o u n d s . U n d e r t h e s am e
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B a s e d o n t h e o p ti m i z e d r e a c t io n c o n d i ti o n s ( e n t ry 2 , w e re o b t a i n e d i n g o o d y i el d s b y t r e a t i n g b-k e t o e st e r s
T a b l e 1 ) , w e w i s h t o e x t e n d t h e s c o p e o f t h i s r e a ct i o n 1a, p h en y l h y d r az i ne s 2a-b, i s at i n s 3a-b w i t h 5 , 5 -
u s i n g v a r i o u s t y p e s o f s u bs t ra te s o f e a c h o f t h e f o u r d i m e th y l c y c lo h e x a n e - 1 , 3 - d i o n e 4c a n d c y c l o h e x a n e -
c o m p o n e n t s . A s e ri e s o f s p i ro [i n d o l in e - 3 , 4 ’ -p y r- 1 , 3 -d i o n e 4d. F ro m t h e a b o v e o b s er v a t i o n s , i t w as
a n o[ 2 , 3 -c] p y r a z o l e ] d e ri v a t iv e s 5a-I, w e r e o b t a i n e d i n w o r t h y t o m en t i o n t h at D E S f u n c t i o n a s b o t h a p r o -
g o o d y i el d s ( T a b l e 2 ) a n d t he s e r e a c t io ns w e r e f o u n d m o t e r a s w e l l a s a r ea c t i o n m ed i a , w h i ch r e s u l t s i n t h e
Scheme 2. P ro b a b l e m e c h a n i s m o f s p i r o o x i n d o l e d e r i v a ti v e s s y n t h e s i s .

J. Chem. Sci. ( 2 0 2 0 ) 1 3 2 : 2 8
P a g e 9 o f 1 0 2 8
s u c c e ss iv e c o n d e n s a t i o n f o r m i n g t he d e s i r e d t a r g e t Acknowledgements
p r o d u c t s 5a-r.
F i n a n c i a l s u p p o r t f r o m t h e C S I R [ N o . 0 2 ( 0 2 5 1 ) /1 5 /E M R - I I]
a n d D S T [ N o . E M R / 2 0 1 4 / 0 0 0 3 3 ] , G o v e r n m e n t o f I n d i a, a re
g r a te f u l l y a p p r e c i a t e d .
T h e r e c y c l a b i l it y o f s o l v e n t i s a n i m p o rt a n t f a ct o r
a f f e c t i ng t h e e c o n om ic s o f p ra c t ic a l a p pl i c a t i o n s o f
D E S . T h e m o de l r e a c t io n o f e t h yl a c e t o a c e t a t e 1a,
p h e n y l h y d r a z i n e 2a, i s a ti n 3a a n d m a lo n o n i t r il e 4a
w a s s e l e c t e d t o i n v e s t ig a t e t h i s i s s ue u n d e r t he o p t i m a l
c o n d i t i o n s. A f t e r c o m p le ti o n o f t he r e a c t io n , t h e
r e a c t i o n m i x t u r e , i n c lu di n g D E S a n d p ro d u c t s , w a s
d i s s o l v ed i n w a t e r a n d t he c r u d e p ro d u c t w a s o b t a i n ed
b y e x t r ac t i o n w i t h E t O A c . T h e D E S w a s r e c o v e r ed
f r o m t h e a q u e o u s p h a s e b y e v a p or a t i o n a t 8 0 °C u n d e r
v a c u u m a n d w a s r e c y c l e d f o r t he n e xt r e a c t i o n . A s
d e m o ns t r at e d i n F i gu re 3 , t h e D E S c o ul d b e r ec y c l e d
a n d r e u s e d u p t o f o u r t im e s w i t h o n l y a s l i gh t d ec r e as e
i n c a t a l yt i c a c t i vi t y.
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b e g i n s w i t h t h e a c t iv a t io n o f c a rb o n y l g r o u p o f
e t hy l ac e t oa c e t a t e 1a b y t h e N H g r o up o f D E S
2
( u r e a : c h o l i n e c h l or i d e m i x t u re ), r e s u l t s i n s t ro n g e r
H - b o nd f o r m a t i on w h i c h e n h a n c e s t h e e l e c t r o p h i l i c
c h a r a c t e r o f c a rb o n y l c a rb o n o f c o m p o u n d 1a.
C o m p o u n d 1a u n d e r g o e s a c o n d e n s a t io n r ea c t i o n
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p y r a z o l - 5 -o ne d e r i va ti v e s . A K n o e v e n a g e l c o n d e n -
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i n t r a m o l e cu l a r c y c l is a t io n f ol l ow e d b y t a u to m er i z a -
t i o n t o f o r m t a r ge t p ro d u c t 5a a n d s i m i l a r l y w i t h
c y c l i c c o m p ou nd 4c, t h e p r o du c t 5j w a s o b t a i n e d i n
g o o d y i e l d .
7 . R o t tm a n n M , M c N a m a r a C , Y e u n g B K S , L e e M C S ,
Z o u B , R u s s e l l B , S e i tz P , P l o u f f e D M , D h a r i a N V ,
´
´
T a n J , C o h e n S B , S p e n c e r K R , G o n z a l e z - P a e z G E ,
L a k s h m i n a r a y a n a S B , G o h A , S u e a n a r u s k R , J e g l a T ,
S c h m i t t E K , B e c k H P , B r u n R , N o s t e n F , R e n ia L ,
D a r to is V , K e l l e r T H , F i d o c k D A , W i n z e l e r E A a nd
D i a g a n a T T 2 0 1 0 S p i r o i n d o lo n e s , a p o t e n t c o m p ou nd
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s p i r o i n d o l o n e s : a n e w c l a s s o f a n t i m a l a r i a l s Molecules
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4. Conclusions
I n c o n c l u s i on , a n e f fi c ie n t , c l e a n , a t o m -e c o n o mi c a l
a n d g r e e n m et h o d f o r t he p r e p a ra t i o n o f s p i r o o x i n -
d o l e s u s i n g D E S b a s e d o n c h o l i n e c h l o r id e i s r ep o r t e d .
T h e D E S w a s f o u nd t o p l a y a s a g o o d r e a c t io n m ed -
i u m . T h i s m et h o d o f f e r s s e ve ra l a d v a n t a g e s s u c h a s
o p e r a t i on al s i m p l ic it y , g o o d t o e x c e ll e nt p r o d u ct
y i e l d s , a n d a v o i d s t h e u s e o f e x p e n s i v e o r s e n s i t i v e
c at a l ys t . F u r t h e r , t hi s p r o c e d u r e i s h ig hl y s u s t ai n a b l e
b e c a u s e o f t h e e m pl o y m e n t o f r e a d i ly a v a i l a b l e a n d
b i o d e g r ad a b l e d e e p e u t e c ti c s o l v e n t .
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1 0 . T a y a d e Y A , P a d v i S A , W a g h Y B a n d D a l a l D S 2 01 5
b- c y c l o d e x t r i n a s a s u p r a m o l e c u l a r c a t a l y s t f or t he
s y n t h e s i s o f d i h y d r o p y r a n o [ 2 , 3 - c ] p y r a z o l e a n d s p i r o[ i n-
d o l i n e - 3 , 4 ’ - p y r a n o [ 2 ,3 - c ] p y r a z o l e ] i n a q u e o u s m e d i um
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1 1 . Z o u Y , H u Y , L i u H a n d S h i D 2 0 1 2 R p i d a n d e ffi ci e nt
u l t r a s o u n d - a s s i s t e d m e t h o d f o r t h e c o m b in a t o r i a l s y n -
t h e s i s o f s p i r o [ i n d o l i n e - 3 ,4 ’ - p y r a n o [ 2 , 3 - c ] p yr a zo l e
d e r iv a ti v e s ACS Comb. Sci. 14 3 8
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H N M R a n d C N M R d a t a i s a v a i l a b l e a t w ww . i a s . a c .i n /
c h e m s ci .

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S O H a n d s t u d y o f t h e i r a n t i m ic r o b i a l p r op e r t ie s
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s p i r o c yc l i c[ in do l e - 3 , 4 - p y r a n o [ 2 , 3 - c ] p y ra z o l e
t i v es Tetrahedron Lett. 54 4 4 5 1
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