Ninhydrin reaction with phenylethylamine: unavoidable by-products

Article abstract of DOI:10.1007/s12039-020-1751-1

Abstract: Ninhydrin and phenylethylamine reacted to form a complex mixture from which four products were isolated: a benzo-fused spiroheterocyclic and a pyrrole product resulting from tricomponent condensation between ninhydrin, phenylethylamine and phenylacetaldehyde produced in situ, a 2-amino-1,3-indandione dimerisation-dehydrogenation product and a Schiff base. This article analyses these compounds’ structure and proposes reaction mechanisms contributing to knowledge regarding ninhydrin and phenylethylamine chemical reactivity. Graphic abstract: Ninhydrin and phenylethylamine reacted to form a benzo-fused spiroheterocyclic, a pyrrole, a 2-amino-1,3-indandione dimerisation-dehydrogenation product and a Schiff base.[Figure not available: see fulltext.].

Full text of DOI:10.1007/s12039-020-1751-1

J. Chem. Sci.
( 2 0 2 0 ) 1 3 2 : 4 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 - 1 7 5 1 - 1 Sadhan
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RAPID COMMUNICATION
Ninhydrin reaction with phenylethylamine: unavoidable by-products
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A N D R E S G O N Z AL E Z - ON A T E a n d R O D O L FO Q U E V E D O
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M S r e c e i v e d 1 0 D e c e m b e r 2 01 9 ; a c c e p t e d 1 9 J a n u a r y 2 0 2 0
Abstract. N i n h y d r i n a n d p h e n y l e t h y l a m i n e r e a c te d t o f o r m a c o m p le x m i x t u r e f r o m w h ic h f o u r p ro d uc t s
w e r e i s o l a t e d : a b e n z o - fu s e d s p i r o h e t e r o c y c l i c a n d a p y r r o l e p r o d u c t r e s u l ti n g f r o m t r i c o m p o n e n t c on de n -
s at i o n b e t w e e n n i n h y d r i n , p h e n y l e t h y l a m i n e a n d p h e n y l a c e t a l d e h y d e p r o d u c e d in situ, a 2 - a m in o- 1 , 3 -i n -
d a nd i o n e d i m e r i s a t i o n -d e h y d ro g e n a t i o n p r o d u c t a n d a S c h i f f b a s e . T h i s a r t i c l e a n a l y s e s t h e s e c o m p ou n ds ’
s t r u c t u r e a n d p r o p o s e s r e a c t i o n m e c h a n i s m s c o n t r i b u ti n g t o k n o w l e d g e r e g a r d in g n i n h y d r i n a nd
p h en y l e t h y l a m i n e c h e m i c a l r e a c t i v i t y .
Keywords. N i n h y d ri n ; p h e n y l e t h y l a m i n e ; p h e n y l a c e t a l d e h y d e ; S c h i f f b a s e .
1. Introduction
f o r ma t i o n c an b e e x p l ai n e d b y m ea n s o f a t r i c o m p o -
n e n t r ea c t i o n b e t w e e n n i n h y d r i n , p h e n y l e t h y l a m i n e
N i n hy dr i n 1 i s a n i nd a n e - de ri v e d t ri c a rb o n y l c o m -
p o u n d ; i t i s h i gh l y e l e c t ro p h i li c d u e t o h a vi n g t h re e
c o n s e cu t i v e c a r b o n y ls . N i n h yd r in u s ua l ly r e a c t s w i t h
a m i n e s , p h e n o l s a n d e n ol i z a b l e c a rb o n y l c o m p o u n d s
y i e l d i n g d i f f e r i n g h e t e r o c y c li c c o m p o u nd s s u c h a s
c y c l o p ha ne s , i s o i n d o l i n o ne s , h y d ro in do le s , i s o q u i n o -
a n d
( Sc h e m e 2 ) .
p h en y l a c et al d e h y d e ,
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T h e s p i r o h e t e r o c yc l i c p r o d u ct 4 y i el d e d b y t h e
r ea c t i o n b e t w e e n n i n h y d r i n , p h en y l a c et al d e h y d e a n d
p r i m a r y a mi n e s a n d t h e s p i r o h e t e r o c y c l i c p r o d u c t 7
y i el d e d b y t h e r ea c t i o n b e t w e e n n i n h y d r i n ,
p h en y l e t h y l a m i n e a n d p h en y l a ce t al d e h y d e p r o d u c ed
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m a r y a mi n e s y i e l d s a d a rk b lu e o r p u r pl e c o m p o u n d ,
k n o w n a s R u h em a n n ’s p u r pl e . T h i s c o l ou re d c o m -
p o u n d ’ s f o r m a t i o n h a s b e e n u s e f u l f o r d e v e l o p i n g
q u a l i t a t iv e a n d q u a n t it a t i ve a n a l y ti c a l t e c hn iq u es f o r
in situ h a d a g r e a t s t ru ct u r a l s i mi l a ri t y . T h e y o n l y
d i ff e r ed r e g a rd i n g t h e p o s i t i o n o f n i t r o g e n a n d o x y g e n ;
4 h a d a l a c t o n e a n d a n e n a mi n e w h i l s t 7 h a d a l a c t a m
a n d a n e n o l e t h e r . A l t h o u g h h a v i n g s t ru ct u r a l s i m i -
l a r i t y , t h es e t w o s p i r o h e t e r o c y c le s ’ h a d d i ff e r e n t f o r -
m at i o n m ec h a n i s m s . T h e fi rs t s t ep i n t h e f o r ma t i o n o f
4 i m p l i e d t h e r e ac t i o n o f n i n h y d ri n c ar b o n 2 w i t h
p h e n y la c e ta l d e h y d e c a r b o n a w h i l s t t h e fi rs t s t e p i n t h e
f o r m at i o n o f 7 o c c u r re d t h ro u g h t h e r e ac t i o n o f n i n -
h y d r i n c ar b o n 2 w i t h p h en y l e t h y l a m in e . T h i s p a t t e r n
s h o w s t h at t h e o r d e r o f a d d i n g t h e r e ag en t s a f f ec t ed
t h e c o u r s e o f t h e r e ac t i o n .
C o n t i n u i n g o u r s t u d i e s o r i e n t at ed t o w ar d s u n d e r -
s t an d i n g p h e n y l e t h y l a mi n e s ’ c h e mi ca l b e h a v i o u r
r eg ar d i n g c ar b o n y l c o m p o u n d s , t h i s a r t i c l e d e s c r i b e s a
s t ru ct u r al a n a l y s i s o f t h re e u n av o i d a b l e s u b -p r o d u ct s
r es u l t i n g f r o m n i n h y d r i n ’ s r ea c t i o n w i t h p h en y l e t h y -
l a m i n e a n d p r o p o s e s r ea c t i o n m ec h a n i s m s c o n t r i b u t i n g
2 ,3
a m i n e s .
T h e t r i c o m p on e n t r e a c t io n b e t w e e n n i n h y d ri n 1,
p h e n y l a c e t a l d e h y d e
2
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e q u i m o l a r a m o u n ts y i e ld s fl u or e s c e n t p y r ro le d e r i v a -
t i v e s w h i ch a r e a l s o u s e f u l f o r q u a n t if y i n g p r i m ar y
a m i n e s , i n c l u d i n g p e pt i de s . T h re e s t r u c tu ra ll y r e l a t e d
p r o d u c t s h a v e b e e n i s o la t e d f ro m t hi s r e a c t i o n : a
h e t e r o cy cl i c c o m p o u nd 3, a s p i ro h e te r o c yc l i c c o m -
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R e c en t s t u d i e s h a v e s h o w n t h a t t he r e a c t i o n o f
n i n h y d r i n 1 w i t h p h e n y le th yl a m in e 6 h a s n o t h a d t h e
o v e r a l l b e h a v i o u r d e s c ri b e d f o r a m in e s a n d p r o d u c es a
b e n z o - f u s e d s p i r o he t e ro c y c l i c p r o du c t ( s p i r o [ fu ra n -
2 , 10- i s oi n d o l i n e ] ) 7. T h i s s p i ro he t e ro c yc l i c p ro d u c t ’ s 7
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Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-020-1751-1) contains
supplementary material, which is available to authorized users.

4 9 P a g e 2 o f 6
J. Chem. Sci.
( 2 0 2 0 ) 1 3 2 : 4 9
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Scheme 1. T r i c o m p o n e n t r e a c t i o n b e t w e e n n i n h y d r in 1, p h e n y l a c e t a l d e h y d e 2 a n d p r im a r y a m i n e s .
O
O
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N
O
+
O
NH
2
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7
Scheme 2. R e a c t i o n b e t w e e n n i n h y d r i n 1, p h e n y l e t h y l a m i n e 6 a n d p h e n y l a c e t a l d e h y d e p r o d u c e d in situ.
7 .7 3 ( dd , 2 H, J = 5 .6 ; 2 .8 H z) , 7 .8 5 ( dd , 2 H, J = 5 . 6 ; 2 . 8 H z ) .
1 3
t o w ar d s k n o w l e d g e r e g a r d i ng t he s t a rt i ng r e ag en t s ’
c h e m i ca l r e a c t i v i t y .
C N MR ( 10 0 M Hz , C DC l ) d: 3 4. 6, 3 9. 3, 1 23 .2 , 1 26 .6 ,
3
1 28 .6 , 1 28 .9 , 1 32 .1 , 1 33 .9 , 1 38 .1 , 1 68 .2 ; EI -M S: (m/z) 2 63 .9
( 88 %) , 1 33 .1 ( 29 %) , 1 04 .2 ( 10 0% )
6,12-dioxo-6,12-dihydro-diindenopyrazine 9, o r a n g e s o l i d,
2 4 3 m g , y i e l d : 1 9 % , M . p . d i d n o t m e l t u p t o 3 5 0 °C IR
2. Experimental
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N i n h y d r i n r e ac t i o n w i t h p h e n y l e t h y l a m i n e : P h e n y l e t h y -
l a m i n e ( 9 . 0 m m o l , 1 . 0 9 2 g ) w a s a d d e d t o a n in h y d r in
( 9. 0 m m ol , 1 . 4 4 0 g ) i n m e t h a n o l s o l u t i o n . T h e m i x t u r e w a s
s ti r r e d a t r o o m t em p e r a t u r e u n t i l t h e r e a c t a n t s ’ d i s a p p e a r -
a n c e w a s o b s er v e d b y T L C ; t h e s o l v e n t w a s r e m o v e d u n d e r
r e d u c ed p r e s s u r e . T h e r e s i d u e s o o b t a i n e d w a s p u r i fi e d b y
c o l u m n c hr o ma t og r a p h y o n s i l i c a g e l u s i n g t o l u e n e : e t h y l
a c e t at e m i x t u r e s a s t h e m o b i l e p h a s e .
3
( p p m ) : 7 . 6 3 ( t , 2 H , J = 7 . 6 H z ) , 7 . 7 6 ( t , 2 H , J = 7 . 6 H z ), ) :
1 3
7 . 8 7 ( d , 2 H , J = 7 . 2 H z ) , 8 . 0 5 ( d , 2 H , J = 7 . 2 H z ),
C
N M R ( 1 0 0 M H z , C D C l ) d: 1 2 2 .7 , 1 2 4 .7 , 1 3 3 .0 , 1 34 . 9,
3
1 3 6 .0 , 1 3 9 . 7 , 1 4 7 .4 , 1 6 3 .4 , 1 8 9 .2 ; E I - M S : ( m/z) 2 83 . 8
( 7 8 %) , 2 2 7 .9 ( 1 0 0 % ) , 2 0 1 .0 ( 2 0 % ) , 1 0 0 .1 ( 1 8 % ), 7 4. 0
( 1 4 %) .
1-phenethyl-3-phenylindeno[1,2-b]pyrrol-4(1H)-one 12, r ed
s o l i d , 4 4 0 m g , y i e l d : 2 8 % , M . p . 6 9 - 7 0 °C I R ( K B r ) :
20-phenethyl-4-phenyl-3H-spiro[furan-2,10-isoindoline]-
3,30-dione 7, W h i t e s o l i d , 7 8 5 m g , y i e l d : 4 6 % , M . p .
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6 . 6 6 ( s , 1 H ) , 6 . 8 0 ( d , 1 H , J = 7 . 3 H z ) , 7 . 0 5 ( t , 1 H ,
J = 7 . 8 3 ) , 7 . 1 4 ( m , 3 H ) , 7 . 1 7 ( d , 1 H , J = 1 H z ) , 7 .1 9 -7 . 24
( m , 2 H ) , 7 . 2 7 ( d , 2 H , J = 7 . 6 H z ) , 7 . 3 6 ( t , 2 H , J = 7 .7 H z ),
7 . 4 0 ( d , 1 H , J = 7 . 1 H z ) , 7 . 8 9 ( d d , 2 H , J 1 = 8 . 2 1 H z ,
1 4 4 - 1 4 5 °C
2-[(2-phenylethyl)imino]-1H-indene-1,3(2H)-dione 8, y ell ow
s ol id , 1 21 m g, y ie ld : 5 %, M .p . 1 28 -1 30 °C I R ( AT R): ( cm-1
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J 2 = 1 , 1 4 H z ) ; C N M R ( 1 0 0 M H z , C D C l ) d: 3 7 . 6 , 5 0 . 2 ,
b a s e p e a k a t m/z = 1 0 4 . 2 . T h i s i n fo rm a t i o n , t o g e t h e r
w i t h t h e s i mp l i c i t y o f t h e N M R s p e c t r a , l e d t o c o n -
c l u d e t h at t h e c o m p o u n d w a s a S ch i f f b a s e 8, b e i n g a
p r o d u c t o f t h e r ea c t i o n b e t w e e n p h en y l e t h y l a m i n e a n d
c ar b o n 2 f r o m n i n h y d ri n ( Sc h e m e 3 ) . O b t ai n i n g t h i s
c o m p o u n d c o n fi r me d t h at c ar b o n 2 w a s n i n h y d r i n ’s
m o s t e l e c t r o p h i l i c s i t e d u e t o t h e r i n g ’ s e l e c t r o - a t -
t r a c t o r e f fe c t a n d t h at o f t h e t w o a d j a c en t c ar b o n y l s. I t
a l s o s h o w ed t h at t h e r e ac t i o n i n t h e c o n d i t i o n s u s e d i n
t h i s w o r k d i d n o t c o m p l e t e l y f a v o u r p r o d u ct s h a v i n g
g r e a t e r c o m p l e x i t y .
3
1 1 6 . 5 , 1 2 0 . 8 , 1 2 3 . 2 , 1 2 3 . 4 , 1 2 9 . 9 , 1 2 4 . 4 , 1 2 8 . 5 , 1 2 8 .8 ,
1 3 2 . 2 , 1 3 2 . 9 , 1 3 3 . 9 , 1 3 5 , 1 3 6 . 9 , 1 3 9 . 7 , 1 5 0 . 8 , 1 6 8 . 2 , 1 8 5 .8 ;
E I - M S : ( m/z) 3 4 9 . 1 , 2 5 8 . 1 , 2 4 5 . 1 , 2 3 0 . 2 , 2 1 7 . 2 , 2 0 2 .2 ,
1 0 5 . 2 , 9 1 . 2 , 7 7 . 1 ; E SI - M S : ( m/z) 3 5 0 . 1 4 3 , C a l c . 3 5 0 .1 4 4
3. Results and Discussion
A s m en t i o n e d b e f o r e h a n d , t he n i n h y dr i n 1 r e a ct i o n
w i t h p h e n y l e t h yla m in e 6, w h ic h i n v ol v e d u s i n g
m e t h a no l a s s o l v e n t , l e d t o p r o du c i n g 2 0- ph en et h y l -
1 , 4 - ph en yl - 3H- s p i r o[ fu ra n - 2 , 10- is oi n d o li n e ] -3 , 30- d i o n e
7. I n a d d i t i o n t o s p i ro 7, t hr e e m i n o r it y c o m p o u n d s
h a v i n g d i f f e r e n t s t ru c t u r a l c h a r a c t e ri s ti c s w e r e i s o l a t e d
i n h i s w o r k .
1
1 3
H - a n d C N M R s p e c t r a f o r t h e s e c o n d c o m p o u n d
9 g a v e s i g n a l s o n l y c o m i n g f r o m n i n h y d r i n 1. I t w as
t h u s d e d u c e d t h at n e i t h e r p h e n y l e t h y l a mi n e n o r
p h e n y la c e ta l d e h y d e p r o d u c e d in situ w e r e i n v o l v e d i n
t h e f o r ma t i o n o f t h i s p r o d u ct . E l em e n t a l a n a l y si s a n d
t h e m o l e c u l a r i o n a t m / z 2 8 3 . 8 i n E I - M S s p e ct r a
e n a b l e d t h e C H N O m o l e c u l a r f o r mu l a t o b e c a l -
1
T h e H - N M R s p e c t ra f or t he fi r s t o f t h e m r e v e a l e d
t w o s i g n a l s i n t h e a l i ph a t ic r e g io n w h i c h w e r e c h a r-
a ct e r i s t i c f o r t h e e t h y l e n e f ro m p h e n y le th yl a m i n e a n d
a m ul t i p l e t i n t h e a r o m a t ic r e g io n b e t w e e n 7 . 2 a n d
7 . 4 p p m , s u g g e s ti v e o f t he h y d ro g e n s f r o m a
p h e n y l e t h y l a m i ne r in g , a n d t w o d o u b l e t s o f d o u b l e t s a t
7 . 7 a n d 7 . 8 p p m , s u g g e s t iv e o f t he h y d ro g e n o u s f r o m
1 8
8 2 2
c u l a t e d . T h e i n fo r ma t i o n s o o b t a i n e d l e d t o e s t a b l i s h -
i n g t h at c o m p o u n d 9 w a s a 6 , 1 2 - d i o x o - 6 , 1 2 ,
d i h y d r o d i i n d e n o py r a zi n e ( Sc h e m e 3 ) . T h i s c o m p o u n d
h a s b e e n p r e v i o u s l y s y n t h e s i s ed b y p h o t o l y t i c
d i me r i s a t i o n o f 3 - a zi d o - 1 - i n de n o n e a n d b y d i m er i sa -
t i o n o f 1 - n i t r o - 1 , 3 -i n d a n d i o n e i n e t h a n o l ; s u c h
d i me r i s a t i o n o c c u r r ed t h ro u g h i n t e rm e d i ary 2 - a m i n o -
1
3
a n i n h y d r in r i n g . T h e C - N M R s p e c t ra g av e t h e
e x p e c t e d s i g n a l s f o r b o t h t he s e s y s t e m s . T h e E I - M S
s p e c t r a r e v e a l e d a m o le c u la r i o n a t m / z 2 6 3 . 9 a n d a
O
O
N
NH2
+
O
O
8
O
6
1
O
O
O
N
O
H2N
+
2
O
11
10
O
O
O
O
O
O
O
O
HO
O
O
O
N
N
NH
2
O
Ruhemann´s Purple
O
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N
N
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-H2
O
O
9
Scheme 3. T h e m e c h a n i sm p r o p o s e d f o r t h e f o r m a t i o n o f t h e n e w p r o d u c t s ( 9, 10) f r o m t h e n i n h y d r in r e a c t i on w i t h
p h en yl e th y l am i n e.

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f
6
J. Chem. Sci.
( 2 0 2 0 ) 1 3 2 : 4 9
1 H- i n d e n e - 1 , 3 ( 2H) -d io n e 10, a c o m p ou n d w h i c h h a s
b e e n p r o p o s e d a s a n i n t e r m e di a r y i n n in hy d r i n r e ac -
6,7
t i o n w i t h a mi n e s .
137.0
H
T h e t w o c o m p o u nd s s o i s o la t e d 8, 9 c o nfi rm e d t h e
g e n e r a l m ec h a n i s m f o r t h e n i n h y dr i n r e a c t io n w i t h
a m i n e s . T h e fi r s t s t e p i n v ol v e d t he f o r m a t i o n o f k e t i -
m i n e 8 t h r o u g h t h e r e a c t io n b e t w e e n c a rb o n 2 f r o m
n i n h y d r i n 1 a n d p h e n y l e t h y l a m in e 6. K e t i m i n e 8 -
a l di mi n e 11 e q u i l i b ri u m , f ol l ow e d b y h y d ro ly s i s , l e d
t o t h e f o r m a t i on o f p h e n y la c e t a l d e h y d e 2 a n d
2 - a mi n o- 1, 3 - i nd an d io ne 10, a c o m p o u nd w h i ch w a s
i s o l a t e d b y R u h e m a n n d u r in g o n e o f h i s fi r s t s t u d i es
123.9
N
132.9
H
4.20
120.9
150.9
124.4
185.0
135.1
O
12
8
(
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2
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d e n s e d w i t h a n i nh y d ri n m o le c u le t o f or m R u h e -
m a n n ’ s p u r p l e o r d im e ri s e d , f ol l ow e d b y
d e h y d r o g en at i o n , f o r m i n g 6 , 1 2 -d i o x o -6 , 12 , d i h y d r o d i -
i n d e n op yr a z i ne 9. T h e S c hi f f b a s e 8 a n d d im er 9 c an
b e c o n s i d e r e d g e n e r a l p r o du c t s a r i s i n g f ro m n i n h y -
d r i n ’ s r e a c t i o n w i th p r i m a ry a m in e s .
Figure 1. S e l e c t e d H M B C c o r r e l a t i o n s o f 12.
T h e r e ac t i o n b e t w e e n n i n h y d r i n 1, p h en y l e t h y -
l a m i n e 6 a n d p h e n y la c e ta l d e h y d e 2 p r o d u c ed in situ
w o u l d h a v e t o i n v o l v e a d i ff e r en t m ec h a n i s m t o t h a t
d e s c r i b e d a b o v e. I t i s t h u s p r o p o s e d t h at p y r r o l e 12
f o r ma t i o n w o u l d i n v o l v e p h e n y l e t h y l a min e ’ s n u c l e -
o p h i l i c a t t a c k o n c ar b o n 2 f r o m n i n h y d ri n t o f o r m
h e m i a mi n a l 14, f o l l o w e d b y a n u cl eo p h i l i c a t t a ck b y
c ar b o n a f r o m p h e n y l ac e t a l d e h y d e o n c a r b o n 1 f r o m
n i n h y d r i n . T h e i n t r am o l e cu l a r c o n d e n s at i o n b e t w e en
t h e c ar b o n y l f r o m p h e n y l a ce t a l de h y d e a n d t h e a m i n o
g r o u p w o u l d e n a b l e d i h y d r o x y py r r o l e 15 f o r m a t i o n
w h i ch w o u l d f o r m p y rr o l e 12 b y d e o x y g en at i on
( Sc h e m e 5 ) .
O v e r a l l , t h e d i ff e r en ce r eg ar d i n g t h e p r o p o se d
m ec h a n i s m s l i es i n t h e i n i t i al n u cl eo p h i l i c a t t a ck o n
c ar b o n 2 f r o m n i n h y d r i n . T h e f o r m at i o n o f t h e i s o l a t e d
p r o d u c t s r e s u l t i n g f r o m t h e t r i co mp o n e n t r e a c t i o n
b e t w e e n n i n h y d r i n 1, p h en y l e t h y l a m in e 6 a n d p h e n y -
l a c e t a l d e h y d e 2 c an b e e x p l ai n e d b y t h e i n i t i a l a t t a c k
b y p h en y l a c et al d e h y d e , w h o s e e n o l f o r m m u s t p r e -
d o m i n a t e d u e t o t h e p r e s e n c e o f e l e ct r o - a t t ra c t o r
g r o u p s s t ab i l i s i n g i t t h ro u g h t h e e f fe c t o f r e s o n an ce .
H o w e v e r , w h e n t h e r ea c t i o n i n v o l v e s n i n h y d r i n a n d
p h e n y l e t h y l a mi n e , t h e i n i t i al n u c l eo p h i l i c a t t a c k
c o m es f r o m p h e n y l e t h y l a min e a n d , w h e n p h e n y l ac -
e t a l d e h y d e i s p r o d u ce d in situ, i t m ak es n e w n u c l e -
o p h i l i c a t t a c k s l e a d i n g t o t h e f o r ma t i o n o f p y r r o l e 12
a n d s p i r o 7.
I n a d d i t i o n t o 8 a n d 9, a r e d s o l id 12 w a s i s o l a t e d ,
h a v i n g a m o r e c o m p le x s t r u c tu re a s e s t a b li s h e d b y
1
1 3
s p e c t r o s c o p i c I R , N M R ( H a n d C , H M B C a n d
H M Q C ) a n d m a s s s p e c tr o m e t r y t e c h n i q u e s ( E I - M S
a n d E SI - M S) . T h e s i g n a ls h a vi n g t h e g r e a t es t r e l e -
1
v
a
n
c
e
i
n
H
N
M
R
s
p
e
c
t
r
a
r
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v
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l
e
d
t
w
o
t
r
i
p
l
e
t
s
a
t
3
.
1
5
a n d 4 . 2 0 p p m , s u g g e s t i v e o f m e th yl e n e s f ro m a u n i t o f
p h e n y l e t h yl a m i n e , v a r io us s i g n a ls b e t w e e n 6 . 8 a n d
8 p p m , s u g g e s t i v e o f t hr e e a r o m a t i c r in gs , o n e d i s u b -
s t i t u t e d a n d t w o m o n o s u b s t it u te d r in gs a n d a s i n g l et a t
6 . 6 9 p p m . T h e H M B C s p e c tr a c o rr e la ti o n w i t h t h e
t r i p l e t a t 4 . 20 p p m a n d t he s i n g l e t a t 6 . 6 9 p p m p r o -
v i d e d t h e n e c e s s a ry i nf or m a ti o n f or t h e s t r u c t u ra l
e l uc i da t i o n o f a n i nd e n e - fu s e d p y r ro le ( F i g u r e 1) .
F i g u r e 1 s h o w s t h e H M B C s p e c tr a , h i g h l i g h ti n g s o m e
c o r r el a t i on s w i t h f o u r b o n d s w h ic h w e r e e x t r em e l y
u s e f ul f o r s t r u c t u r a l e l u c i d a ti o n ; t h i s t yp e o f s p e c t r o -
s co p i c p a t t e r n h a s b e e n o b s e rv e d p re v i o u s l y f o r s i mi -
8
–
1
0
l a r u n s a t u r a t e d c o m p o u nd s .
S t r u ct u r a l a n a l y s i s o f t he t hr e e c o m p o u nd s p r e v i -
o u s l y i s o l a t e d b y t ri c o m p o n e n t r e a c t io n b e t w e e n n i n -
h y d r i n, p h e n y l a c e t a l d e h y d e a n d p ri m a r y a m in e s l e d t o
p r o p o s i ng t h at t h e i ni t i a l n u c l e o p h i l ic a t t a c k w o u l d
o c c u r o n c a r b o n 2 f ro m n i n h y dr i n a n d t h a t c a r b o n a
f r o m p h e n y l a c e t a l de h y d e ( in i ts e n o l f or m ) w o u l d a ct
a s a n u c l e o p h i l e ( S c h e m e 4) . T h e s u bs e q u e n t a mi n o
g r o u p ’ s n u c l e o p h i l i c a t t a c k o n c a rb o n 1 f ro m n i n h y -
d r i n a n d t h e c a r b o n y l c a rb o n f ro m p h e n y la c e t a l d e hy d e
w o u l d l e a d t o t h e f or m a t i on o f d i h y d ro x y p y rr o l e 13.
C o m p o u n d 3 w o u l d t hu s h a v e b e e n f or m e d b y a w a t e r
m o l e c u l e ’ s n u c l e o p h i li c a t t a c k o n c a rb o n 3 , f o l l o w e d
b y o xi d a t i v e r u p t u r e o f t h e c y c l e . T h i s c o m p o u n d w a s
t h e p r e c u r s o r o f a n o t h e r t w o p ro d u c t s i s o la te d i n t h i s
w o r k 4, 5 ( S c h e m e 4 ) .
4. Conclusions
I t c an t h u s b e c o n c l u d ed t h at t h e r ea c t i o n b e t w e en
n i n h y d ri n a n d p h e n y l e t h y l a min e p r o d u ce d a c o m p l e x
m i x t u r e f r o m w h i ch i t h a s b e e n p o s s i b l e t o i s o l a t e f o u r
p r o d u c t s t o d a t e . T h e p r e v i o u s l y r e p o r t e d b e n z o - f u s ed
s p i r o h e t e r o c y c li c p r o d u ct 7 a n d p y rr o l e 12 w er e

J. Chem. Sci.
(2 0 2 0 ) 1 3 2 : 4 9
P a g e 5 o f 6
4 9
H
O
O
O
O
O
O
OH
OH
O
O
NH
HO
NH2
O
R
R
H2O
O
O
OH
OH
OH
O
H
H
H
O
HO
N
HO
N
OH
R
R
HO
N
13
R
O
OH
HO
O
N
R
3
Scheme 4. T h e m e c h a n i sm p r o p o s e d f o r e x p l a i n i n g t h e t r i c o m p o n e n t r e a c t io n b e t w e e n n i n h y d r i n 1, p h e n y l a c e t a l d eh y d e 2
a n d p r i m ar y a mi n e s .
O
O
14
NH
OH
NH
O
OH
H
O
HO
N
O
O
O
8
O
O
O
OH
N
OH
N
deoxigenation
N
HO
HO
OH
12
H
15
Scheme 5. T h e r e a c t i o n m e c h a n i s m p r o p o s e d f o r p y r r o l e 12 f o r m a t i o n .
f o r m e d b y a t r i c o m p o n e n t r e a c t io n b e t w e e n n i n h y d ri n , d i me r i s a t i o n p r o d u c t a n d s u b s e q u e n t d e h y d ro ge n a t i on
p h e n y l e t h y l am i n e a nd p he n yl a ce t al d e hyd e p r o d u ce d o f 2 - a mi n o - 1 , 3 -i n d a n d i on e 10 a n d t h e S ch i f f b a s e 8
in situ. T h e f o l l ow i n g w e r e a l s o i s o la t ed : t h e p r o d u ce d
b y
n i n h y d ri n
c o n d e n s at i o n
w i t h

4 9 P a g e 6 o f 6
J. Chem. Sci.
( 2 0 2 0 ) 1 3 2 : 4 9
O
O
NH2
O
+
6
1
O
O
O
O
N
N
N
N
O
N
+
+
+
O
12
O
8
O
9
7
Scheme 6. R e a c t i o n o f n i n h y d r in 1 a n d p h e n y l e th y l a m i n e 6.
d o s a g e f o r m s a n d h u m a n p l a s m a t h r o u g h c o n d en s a t i on
w i t h n i n h y d r i n a n d p h e n y l a c e t a l d e h y d e Spectrochim.
Acta Part A 136 1 7 6 0
p h e n y l e t hy l a m i n e ( S c h e m e 6 ) . T h i s w o r k i n v ol v e d t h e
s t r u c t u r a l a n a l y si s o f t h e i s o la te d c o m p ou n d s ( 8, 9 a n d
12) a n d a r e a c t i on m e c h a n is m h a s b e e n p r o p o s ed
e n a b l i n g t h e f o r m a t i o n o f e a c h o n e t o b e r a t io n al i s e d .
4 . W e ig e l e M , B lo u n t J F , T e n g i J P , C z a j k o w s k i R C a nd
L e i m g r u b e r W 1 9 7 2 F l u o r o g e n i c n i n h y d r i n r ea ct i o n.
S t r u c t u r e o f t h e fl u o r e s c e n t p r i n c i p l e J. Am. Chem. Soc.
94 4 0 5 2
Supplementary Information (SI)
´
5 . Q u e v e d o - A c o s ta Y , P e r e z - R e d o n d o A a n d Q u ev e do R
G e n er a l r e a ct i o n p r o c e d u r e a n d N M R d a t a o f t h e c o m -
p o u n d s a r e a va i l a bl e a t w ww . i a s . a c . i n / c h e m s c i .
2 0 1 5 A n u n e x p e c t e d r o u t e f o r t h e s y n t h e si s o f a n ew
s p i r o h e t e r o c y c li c s y s t e m f r o m n i n h y d r i n Tetrahedron
Lett. 56 5 3 0 9
6 . S a r k a r S , O s i s i o m a O , K a r n e y W , A b e M a nd
G u d m u n d s d o t t ir D 2 0 1 6 U s i n g m o l e c u l a r a r c h i t ec t ur e
t o c o n t r o l t h e r e a c ti v i t y o f a t r i p l e t v i n y l n i t r e n e J. Am.
Chem. Soc. 138 1 4 9 0 5
7 . W i t tm a n n H , M u¨ l le r A a n d Z i e g l e r E 1 9 7 0 N e w
r e a g e n t s f o r t h e d e t e c t i o n o f a m i n o a c i d s b y p ap er
c h r o m a t o g r a p h y , V I C o n c e r n i n g t h e ‘‘ N in h y d r i n r ea c-
t io n ’’ Monatsh. fu¨r Chem. 101 1 3 8 8
Acknowledgements
W e w o u l d l i k e t o t h a n k t h e U n i v e r s i d a d N a c i o n a l d e
C o l om b i a ( D I B R es e a r c h P ro j e c t N o . 3 7 3 9 8 ) f o r p r o v i d i n g
fi n a n c i a l s u p p or t . O n b e h a l f o f a l l a u t h o r s , t h e c o rr e s p o n d -
i n g a ut h o r s t at e s t h a t t h e r e i s n o c o n fl i c t o f i n t e re s t.
8 . S o n g H N , L e e H J , K i m H R , R y u E K a n d K i m J N
1 9 9 9 F r i e d e l – C r a f ts t y p e r e a c t io n s o f s o m e a ct i va t ed
c y c li c k e t o n e s w i t h p h e n o l d e r iv a t i v e s Synth. Commun.
29 3 3 0 3
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H M BC s p e c t r a Nat. Prod. Commun. 3 4 4 5
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Rev. 60 3 9
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r e l a t i o n i n t h e p r e s e n c e o f m o d e st h o m o n u c le a r c ou -
p l i n g A p p li c a t i o n t o d i s t a m y c i n A J. Magn. Reson. 82
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3 . O m a r M A , H a m m a d M A , N a g y D M a n d A l y A A
2 0 1 5 D e v e lo p m e n t o f s p e c t r o fl u o r i m e t r i c m e t h o d f o r
d e te r m i n a ti o n o f c e rt a i n a m i n o g l y c o s i d e d r u g s i n