H3PO4 catalyzed one-pot synthesis of 1,3-diphenyl-1H-pyrazole-4-carbaldehyde to novel 1,3-diphenyl-1H-pyrazole-4-carbonitrile

Article abstract of DOI:10.1007/s12039-021-01939-w

Abstract: One-pot condensation of pyrazole-4-aldehydes and hydroxylamine hydrochloride to form the corresponding oxime using formic acid as a medium and further dehydration of oxime using a catalytic amount of orthophosphoric acid to afford novel pyrazole-4-carbonitrile. This protocol serves as an ortho-phosphoric acid-catalyzed one-pot conversion of aldehyde to nitrile. Most remarkable features of this method are metal-free, cost-effective, atom efficiency with excellent yield (98–99%). This process will serve as a robust and scalable tool for the synthesis of valuable and versatile precursor (nitriles). This precursor will pave the way for the synthesis of various medicinally important valuable compounds. Graphic abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s12039-021-01939-w

J. Chem. Sci. ( 2 0 2 1 ) 1 3 3 : 6 9
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REGULAR ARTICLE
H3PO4 catalyzed one-pot synthesis of 1,3-diphenyl-1H-pyrazole-4-
carbaldehyde to novel 1,3-diphenyl-1H-pyrazole-4-carbonitrile
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T U K A R A M S C H O U D H A R E , D E V E N D R A S W A G A R E , S A G A R E S H IR S A T H a n d
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Abstract. O n e - p o t c o n d e n s a t i o n o f p y r a z o l e - 4 - a l d e h y d e s a n d h y d r o x y l a m i n e h y d r o c h l o r id e t o f o rm t he
c o r r e s p o n d i n g o x i m e u s i n g f o r m i c a c i d a s a m e d i u m a n d f u r t h e r d e h y d r a t i o n o f o x i m e u s i n g a c at a ly t i c
a mo u n t o f o r t h o p h o s p h o r i c a c i d t o a f f o r d n o v e l p y r a z o l e - 4 - c a r b o n i t r i l e . T h i s p r o t o c o l s e r v e s a s a n o rt h o-
p h o s p h o r i c a c i d -c a t a l y z e d o n e - p o t c o n v e r s i o n o f a l d e h y d e t o n i t r i le . M o s t r e m a r k a b le f e a tu r e s o f t h i s m e t h od
a r e m e t a l -f r e e , c o s t - e f f e c t i v e , a t o m e f fi c i e n c y w i t h e x c e ll e n t y i e l d ( 9 8 – 9 9 % ) . T h i s p r o c e s s w i l l s e r ve a s a
r o b u s t a n d s c a l a b l e t o o l f o r t h e s y n t h e s i s o f v a l u a b l e a n d v e r s a ti l e p r e c u r s o r ( n it r i l e s ) . T h i s p r e c u r s o r w i l l
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Keywords. P y r a z o l e - 4 - c a r b a l d e h y d e ; p y r a z o l e - 4 - c a r b o n i t r i l e ; H P O ; f o r m i c a c i d .
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Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s12039-021-
01939-w.

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of nitrile derivatives (B1–B10)
2
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C N M R s p e c t r a l t e c h n i q u e s .
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.
2 . 3 General procedure for the preparation
of nitrile derivatives (D1–10)
A
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m
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Scheme 1. H P O
3
c
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:
1
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.
Scheme 2. T r a n s f o r m a t i o n o f p y r a z o l e c a r b a l d e h y d e s t o n o v e l p y r a z o l e n i t r i le s .

J. Chem. Sci. ( 2 0 2 1 ) 1 3 3 : 6 9
Table 1. S o l v e n t o p t i m i z a t i o n f o r o n e - p o t s y n t h e si s o f n i t r i l e .
P
a
g
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a
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n
t
r
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H P O C a t a l y s t m o l e %
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1 %
1 %
1 %
1 %
1%
A
c
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t
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c
a
c
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d
1 0 0 °C
1 0 0 °C
1 0 0 °C
1 0 0 °C
100 °C
7
9
7
1 2
5
9 0
8 5
8 8
8 8
99
A c e t i c a c i d : F o r m i c a c i d ( 1 : 1 )
A c e t i c a c i d : F o r m i c a c i d ( 2 : 1 )
F o r m i c a c i d : W a te r ( 1 :1 )
Formic acid
a
E x p er im e n ta l c o nd i t i o n s : B e n z a l d e h y d e ( 1 m m o l ) , N H O H . H C l ( 1 m m o l ) , H P O ( 1 m m o l ) .
3
2
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.
2.4f 3-(4-chloro-phenyl)-1-phenyl-1H-pyrazole-4-carboni-
trile (D3): W h i t e s o l i d , M . p . 1 5 8 – 1 6 1 °C ; I R ( K B r) m:
T
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c m -1 ; 2 2 2 1 , 1 5 9 4 , 1 2 2 9 , 8 3 4 ( c m -1 ) ; H N M R ( 4 00 M H z ,
ll
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1
D M S O - d 6 ) d 7 . 3 7 – 7 .5 2 ( m , 5 H ) , 7 . 5 4 – 7 .5 7 ( d , J = 8 .2 H z ,
2 H ) , 7 . 5 9 – 7 . 9 9 ( d , J = 8 . 0 H z , 2 H ) , 9 . 4 5 ( s , 1 H ) ; M S ( m / z )
2 8 0 .2 5 [ M ?H ] ?, 2 8 2 .3 0 [ M ?2 ] .
w
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b
R
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n
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q
.
2 . 4 Spectroscopic data
3. Result and Discussion
2.4a 4-(dimethyl amino) benzonitrile: (B3): S c a l e ( 1 5 1 . 3
m g , 1 m m ol ) ; e th y l a c e t a t e : p e t r o l e u m e t h e r = 1 : 2 0 ; 9 3 %
I
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y i e l d ( 1 3 5 . 8 m g ) ; o f f - wh i t e c r y s t a l l i n e p o wd e r ; H N M R
w i
( B
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( 50 0 M H z, C D C l ) d 7 . 4 7 ( d , J = 9 . 0 H z , 2 H ) , 6 . 6 4 ( d ,
3
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3
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d 1 5 2 . 5 2 , 1 3 3 . 3 2 , 1 2 0 . 6 0 , 1 1 1 . 4 3 , 9 7 . 4 4 , 3 9 . 8 5 ; H R M S
( E S I ) m / z c al c d. F o r C H N [ M?H ] ?: 1 4 7 . 0 9 2 2 , f o u n d :
1 4 7 . 0 9 2 0 .
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2.4b Methoxybenzonitrile: (B5): P u r i fi c a t i o n b y c h r o -
m a t o g r a ph y o n S i O ( 1 0 % M T B E / h e x a n e s ) p r o v i d e d 7 ( 4 0 0
m g , 7 8 % y i el d ) a s a c o l o rl e s s o i l . 2 1 H N M R ( 4 0 0 M H z ,
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( 10 0 M H z , C D C l ) 1 6 2 . 8 , 1 3 3 . 9 , 1 1 9 . 2 , 1 1 4 . 7 , 1 0 3 .7 , 5 5 . 5 .
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w i t h H P O a t
3 4
2.4c Tetradecanenitrile: (B10):
2
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d i c h l o r o m et h a n e: p e t r o l e u m e t h e r = 1 : 1 0 ; 9 0 % y i e l d
( 18 8 . 2 m g ) ; c o lo u r l e s s o i l ; 1 H N M R ( 4 0 0 M H z , C D C l 3 ) d
2 . 3 3 ( t , J = 7 . 2 H z , 2 H ) , 1 . 6 8 – 1 . 5 7 ( m , 2 H ) , 1 . 4 4 ( s , 2 H ) ,
T
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( 10 0 M H z , C D C l 3 ) d 1 1 9 . 9 4 , 3 2 . 0 3 , 2 9 . 7 4 , 2 9 . 7 0 , 2 9 . 6 1 ,
2 9 . 4 5 , 2 9 . 4 2 , 2 8 . 8 8 , 2 8 . 7 8 , 2 5 . 5 0 , 2 2 . 8 0 , 1 7 . 2 3 , 1 4 .2 1 ; M S
( 70 e V ) : m / z ( % ) 2 0 9 . 2 ( M ?, 1 0 0 )
Table 2. C a t a ly s t o p t i m i z a t i o n f o r o n e - p o t s y n t he s i s o f
n i t r i le .
a
b
E n t r y H P O C a t a ly s t m o l e % T i m e ( h ) Y i e ld ( % )
4
3
2.4d (4-fluoro-phenyl)-1-phenyl-1H-pyrazole-4-carbonitrile
(D1): W hi t e s o l id , M . p . 1 7 0 – 1 7 3 °C ; I R ( KB r ) m: c m -1
;
1
2
3
4
5
0 . 5 %
1.0%
1 . 5 %
2 . 0 %
2 . 5 %
9
5
3 . 5
2 . 5
2 . 0
8 5
99
9 5
9 5
9 5
2 2 1 7 , 1 6 7 7 , 1 2 2 6 , 8 3 6 ( c m -1 ) ; H N M R ( 4 0 0 M H z , D M S O -
d 6 ) d 7 . 4 – 7 . 6 0 ( m , 5 H ) , 7 . 9 2 – 8 . 0 1 ( d , J = 6 . 5 H z , 2 H ) ,
8 . 0 1 – 8 . 03 ( d , J = 6 . 8 , 2 H ) , 9 . 4 5 ( s , 1 H ) ; M S ( m / z ) 2 6 5 .2 5 .
1
2.4e
1,3-diphenyl-1H-pyrazole-4-carbonitrile
(D2):
a
-
1
E x p e r i m e n t a l c o n d i ti o n s : B e n z a l d e h y d e ( 1 m m o l ) , N H
O H . H C l ( 1 m m o l ) , H P O ( 1 m m o l ) a t 1 0 0 °C .
I s o la t e d y i e l d .
2
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1
3
,
1 5 8 9 , 1 2 1 4 , 8 1 9 ( c m -1 ) ; H N M R ( 4 0 0 M H z , D M S O - d 6 ) d
7 . 3 6 – 7 . 56 ( m , 5 H ) , 7 . 6 0 – 7 . 9 4 ( m , 5 H ) , 9 . 4 2 ( s , 1 H ) ; H R M S
1
3
4
b
c
( E S I ) m / z c al c d. F o r C H N [ M ?H ] ?: 2 4 6 . 2 2 , f o u n d :
3
B o l d s i g n i fi e s t h e o p t i m i z e d a n d s u i t a b l e c a t a l y s t a nd s o l -
v e n t f o r t h e s y n t h e si s o f n i t r i l e s .
1
6
1
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2
4
6
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Table 3. S y n t h e s i s o f n i t r i l e ( B – B ) f ro m a l d e h y d e .
1
1
0
b
Y i e l d ( % )
C
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p
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d
P
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B1
9
8
5
0
–
5
5
B2
9
9
B
o
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l
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n
g
p
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i
n
t
2
0
5
B3
B4
9 8
9 9
72–75
2
3
5
–
2
3
7
B5
B6
9 9
9 7
256–257
2
1
7
.
6
1
1
B7
B8
B9
9 8
9 7
9 9
144–147
1
8
8
–
1
9
1
B10
9
8
a
R e a ct i o n c on di t io n s : a l d e h y d e ( 1 m m o l ) , N H O H . H C l ( 1 m m o l ) , H P O ( 1 .0 m o l %) s o l v e n t f o r m i c a c i d a t 1 0 0 °C .
I so l at ed y i el d .
2
3
4
b
c
B
o
l
d
s
i
g
n
i
fi
e
s
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s
.

J. Chem. Sci. ( 2 0 2 1 ) 1 3 3 : 6 9
P
a
g
e
5
o
f
7
6
9
a
Table 4. S y n t h e s i s o f p y r a z o l e n i t r i le ( D – D ) f r o m p y r a z o l e a l d e h y d e .
1
2
0
b
Y i e l d ( % )
S
l
.
N
o
.
P
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a
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e
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t
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p
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n
t
°
C
D1
9
7
1
7
0
–
1
7
3
D2
9 4
9 9
1 2 0 – 1 2 3
1 5 8 – 1 6 1
D3
D4
9
5
1
6
0
–
1
6
2
D5
9 8
9 7
1 9 8 – 2 0 0
1 9 5 – 1 9 7
D6
D7
9 2
9 1
1 6 4 – 1 6 6
1 7 0 – 1 7 2
D8

6 9 P a g e 6 o f 7
Table 4. (contd)
J. Chem. Sci. ( 2 0 2 1 ) 1 3 3 : 6 9
b
Y i e l d ( % )
S
l
.
N
o
.
P
y
r
a
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C
D9
9
4
1
8
2
–
1
8
3
D10
9
9
1
6
5
–
1
6
7
a
R ea c t i o n c o n d i t i o n s : P y r a z o l e a l d e h y d e ( 1 m m o l ) , N H 2 O H . H C l ( 1 m m o l ) , H P O ( 1 .0 m o l %)
3
4
s o l ve n t f o r m i c a c i d a t 1 0 0 °C .
I s o l a t e d y i e l d .
b
c
e
a
x
r
c
A
b
e
l
s
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a
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e
d
i
n
Supplementary Information (SI)
l
l
i
e
T a b l e s S 1 – S 3 , N M R s p e c t r a , I R s p e c t r a , M a s s s p e c t r a a re
a v a il a b l e a t w w w . ia s . a c .i n / c h e m s c i .
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Acknowledgements
i
t
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l
e
I
n
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r CN
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n
s
p
k
q
b
c
s
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1 . M a c Fa u l P A , M o r le y A D a n d C r a w f o r d J J 2 00 9 A
s i m p l e i n v i t r o a s s a y f o r a s s e s s i n g t h e r e a c t i vi t y o f
n i t r i le c o n t a i n i n g c o m p o u n d s Bioorg. Med. Chem. Lett.
19 1 1 3 6
2 . O b a ll a R M , T r u c h o n J F , B a y l y C I , C h a u r e t N , D a y S ,
C r a n e S a n d B e r t h e l e t t e C 2 0 0 7 A g e n e r a l l y a p pl i c a b le
m e t h o d f o r a s s e s s i n g t h e e l e c t r o p h i li c i t y a n d r e a ct i v i ty
o f d i v e r s e n i t r i le - c o n t a i n i n g c o m p o u n d s Bioorg. Med.
Chem. Lett. 17 9 9 8
3 . ( a ) S m it h M B 2 0 0 7 M a r . ’ s A d v a n c e d O r g a n i c C h e m -
i s tr y : R e a c t i o n s , M e c h a n i s m s , a n d S t r u c t u r e Wiley &
Sons. B o o t h ; ( b ) D i a s B L , P r o e n c¸ a A M a n d Z a ki M E
2 0 0 1 T h e r e a c t io n s o f d i a m i n o m a le o n i t r i l e w i th i s o -
c y a n a t e s a n d e i t h e r a l d e h y d e s o r k e t o n e s r e v i s i t ed J.
Org. Chem. 66 8 4 3 6 ; ( c ) O h ts u k a Y 1 9 7 8 C h e m i s t r y o f
4. Conclusions
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d i am i n o m a le o n i t ri l e R e a c t i o n w i t h i s o c y a n a t e : a n o v e l 1 2 . B r a c k m a n W a n d S m i t P J 1 9 6 3 A n e w s y n t he s i s o f
p y r i m i di n e s y n t h e s i s J. Org. Chem. 43 3 2 3 1 n i t r i le s Recl. Trav. Chim. Pays-Bas 82 7 5 7
4 . F a t i ad i A J 1 9 8 3 P re p a r a t i o n a n d s y n t h e t i c a p p l i c a t io n s 1 3 . P a r a m e s w a r a n K N a n d F r i e d m a n O M 1 9 6 5 S y n t he s i s
o f c y an o c o m p o u n d s I n Triple-Bonded Functional o f N i t r i le s f r o m A l d e h y d e s Chem. Ind. 9 8 8
Groups: Supplement C S P a t a i a n d Z R a p p o p o r t 1 4 . B o s e D S a n d N a r s a i a h A V 1 9 9 8 E f fi c i e n t o ne p ot
( E ds . ) ( W i lt s h ir e : W i l e y ) P a r t 2 V o l . 2 p . 1 0 5 7
5 . ( a ) L a r c o k R C 1 9 8 9 Comprehensive Organic Trans-
formations: A Guide to Functional Group Preparations
s y n t h e s i s o f n i t r i le s f r o m a l d e h y d e s i n s o l i d s t a t e u s i n g
p e r o x y m o n o s u l f a t e o n a l u m i n a Tetrahedron Lett. 39
6 5 3 3
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fl u or es c en c e o f a z o m e t h i n e d y e s d e ri v e d f ro m d i a m i n o -
m al e o n i t r i l e a n d 2 , 5 - d i a m i n o - 3 , 6 - d i c y a n o p y -
r a z in e Dyes Pigm. 47 1 0 7
e f fi c ie n t m e t h o d f o r t h e c o n v e r s i o n o f a l d e h y de s i nt o
n i t r i le s u s i n g a m m o n i a a n d h y d r o g e n p e r o x i d e Tetra-
hedron Lett. 41 6 7 4 9
1 6 . T a l u k d a r S 2 0 0 1 D i r e c t t r a n s f o r m a ti o n o f a l d e h yd e s t o
n i t r i le s u s i n g i o d i n e i n a m m o n i a w a t e r Tetrahedron
Lett. 42 1 1 0 3
1 7 . B a n d g a r B P a n d M a k o n e S S 2 0 0 6 O r g a n ic r e a c t i on s i n
w a t e r : T r a n s f o r m a t i o n o f a l d e h y d e s t o n i t r i l e s u s i n g
N B S u n d e r m i ld c o n d i ti o n s Synth. Commun. 36 1 34 7
1 8 . A r o t e N D , B h a l e r a o D S a n d K a m a n c h i K G A 2 00 7
D i r e c t o x i d a t iv e c o n v e r s i o n o f a l d e h y d e s t o n i t r i l e s u s i n g
I B X i n a q u e o u s a m m o n ia Tetrahedron Lett. 48 3 65 1
6 . N i e l se n M A , N i e l s e n M K a n d P i t t e l k o w T 2 0 0 4 S c a l e -
u p a n d s af e t y e v a l u a t i o n o f a S a n d m e y e r r e a c t i o n Org.
Proc. Res. Dev. 8 1 0 5 9
7 . P r ad a l A a n d E v a n o G 2 0 1 4 A v i n y l i c R o s e n m u n d – v o n
B r a un r e ac t i o n : p r a c t i c a l s y n t h e s i s o f a c ry l o n i t r i le s
Chem. Commun. 50 1 1 9 0 7
8 . F a n g W Y a n d Q i n H L 2 0 1 9 C a s c a d e p r o c e s s f o r d i r e c t
t r a n sf o r m a t io n o f a l d e h y d e s ( R C H O) t o n i t r i l e s ( R C N )
u s i n g i n o r g an ic r e a g e n t s N H O H/ Na C O / S O F i n 1 9 . T e l v e k a r V N 2 0 0 8 A n o v e l s y s t e m f o r t h e s y n t h es i s o f
2 2
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D M S O J. Org. Chem. 84 5 8 0 3
9 . N o h J H a n d K i m J 2 0 1 5 A e r o b i c o x i d a t i v e c o n v e r s i o n
o f a r o ma t ic a ld e h y d e s t o n i t r i l e s u s i n g a n i t r o x y l /N O x 2 0 . A n X - D a n d Y u S 2 0 1 5 D i r e c t S y n t h e s i s o f N i t r il e s
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c at al ys t s y s t e m J. Org. Chem. 80 1 1 6 2 4 f r o m A l d e h y d e s U s i n g a n O - Be n z o y l H y d r o x yl a m i n e
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m i l d n i ck e l- ca t a l y z e d c y a n a t i o n o f a r y l / h e t e r o a r y l c h l o - 2 1 . Q u in n D J , G r a h a m J H a u n a n d G u s t a v o M o u r a -L e t t s
r i d e s w i t h Z n ( C N ) 2 : k e y r o l e s o f D M A P Org. Lett. 19
2 1 1 8
1 1 . U s h k o v A V a n d G r u s h i n V V 2 0 1 1 R a t i o n a l c a ta l y s i s
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h y d r o x y l a m i n e - O - s u l f o n i c a c i d i n a c i d i c w a t e r Tetra-
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m i d es w i t h N a C N i n r e c y c l a b l e s o l v e n t s J. Am. Chem.
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t io n o f w a s t e w a t e r s c o n ta i n i n g s y n t h e t i c o r g a n i c d ye s
b y e l e c t r o c h e m i c a l m e t h o d s . A n u p d a t e d r e v ie w Appl.
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