Heterocycles Synthesis through Reactions of Nucleophiles with Acrylonitriles,

Part 9. A Direct One-Pot Synthesis of Pyranopyrazoles

Fathy Fahim Abdel-Latif
Department o f Chemistry, Faculty o f Science, El-Minia University, El-M inia, A. R. Egypt
Z. Naturforsch. 45b, 16 7 5 - 1678 (1990); received March 6 , 1990
Heterocycles Synthesis, Acrylonitriles. One-Pot Synthesis. Pyranopyrazoles
Several pyrano[2,3-c]pyrazoles were synthesized through a convenient one-pot method in
excellent yields. Structure and reaction pathways are also reported and supported by another
synthetic route.

Pyrazoles and their fused ring systems are versa­ reagent to the ylidenic bond in 5 a or 6 a leading to
tile heterocyclic compounds, some of which have an acyclic intermediate 7a which cyclizes sponta­
considerable biological activity. They have been neously to give the final product (cf. Scheme 1).
used as antipyretic, fungicidal and bacteriostatic A structural p ro o f was obtained through anoth­
agents [1—3]. As a continuation of our work for er route of synthesis by stirring a solution of equi-
the simple synthesis of biologically interesting het­ m olar am ounts o f 5 a and 2 in dioxane/piperidine
erocyclic compounds [4-8], several pyrano[2,3-c]- at room tem perature (c f M ethod B. Experimen­
pyrazoles were successfully prepared by a direct tal).
one-pot synthesis in excellent yields from readily Similarly furfural 1 b and thiophene-2-
available chemicals. Only limited synthetic ap­ carboxaldehyde 1 c submitted to the same reaction
proaches for pyrano[2,3-c]pyrazoles are reported conditions afforded the corresponding pyrano-
[9-11]. [2,3-c]pyrazoles 3 b ,c respectively which also were
Thus it has been found that stirring a solution of synthesized from 5 b ,c (cf. Scheme 1 and Experi­
pyridine-3-carboxaldehyde (la ), malononitrile mental).
and 3-methyl-2-pyrazolin-5-one (2) in dioxane/pi- As an example of aliphatic aldehydes, isobuter-
peridine at room temperature afforded 2-amino- aldehyde (Id) was treated as in the previous cases
3-cyano-4,7-dihydro-5-methyl-4-(3-pyridyl) pyra- to afford the corresponding pyrano[2,3-c]pyrazole
no[2,3-c]pyrazole (3a). Structure 3 a was estab­ derivative (3d) in good yield.
lished for the reaction product based on analytical In order to generalize this one-pot synthesis to
and spectral data (cf. Experimental). Structure 4 the different types of aldehydes, we found that
was excluded as a possible isomer of the reaction substituted benzaldehyde ( l e - k ) undergo the ter­
product since the IR spectrum revealed the pres­ nary condensation procedure yielding the corre­
ence of the characteristic bands for NH-, and C = N sponding pyrano[2,3-c]pyrazoles (3 e -k ).
groups. H N M R spectrum also gives evidence of Also pyrano[2,3-c]pyrazoles (3 e ~ k ) were syn­
such structure showing signals for the amino pro­ thesized from 5 e - k [10] and from 6 e - k [9] respec­
tons at <5 3.5 ppm and for the pyran 4-H at Ö tively (c f M ethod B, Experimental).
4.5 ppm (cf. Experimental). We concluded here that this method provides a
Form ation of 3 a is rationalized in terms of the facile one-pot method for the synthesis of
initial condensation of the aldehyde 1 a with m a­ pyrano[2,3-c]pyrazoles from the different types of
lononitrile or 3-methyl-2-pyrazolin-5-one (2) af­ aldehydes.
fording a-cyano-/i-(3-pyridyl)acrylonitrile (5a) or Acetophenone, cyclohexanone and cyclopen-
4-pyridylidene-2-pyrazolin-5-one (6a) followed by tanone (1 1-n) submitted the same reaction condi­
the Michael addition of the other active methylene tions (M ethod A) afforded the corresponding
pyrano[2,3-c]pyrazoles (3 1-n) respectively; benzo-
phenone did not react.
Verlag der Zeitschrift für Naturforschung, D-7400 Tübingen Structures o f 3 b - n were established on similar
0932-0776/90/1200- 1675/$ 01.00/0 grounds for those of 3 a (cf. Experimental).

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1676 F. F. A b d el-L atif • Heterocycles Synthesis

.C = 0

CN
R CH
CH2 ( C N ) 2 -CN
\ / "
■f
/C .0
,N H
H,C N
r f °
/NH ,0 '
h 3c

-N H
H,C N
2
1 ,3 - 7 R R
S chema 1
a H 3-Pyridyl
b H 2-Furyl
c H 2-Thienyl
d H Isopropyl
e H Phenyl
f H / 7-Tolyl
g H /»-Nitrophenyl
h H o-Anisyl
i H o-Chlorophenyl
j H m-Bromophenyl
k H 2,5-Dim ethoxyphenyl
1 CH, Phenyl
m (C H 2) 5
n (C H 2) 4

Experimental tained, and stirred at room temperature for 5 -1 5

All melting points are uncorrected. IR spectra min. The solid obtained or formed after trituration
were recorded (KBr) on a Shimazu 408 spectro­ of water is collected by filtration and recrystallized
photom eter. H NM R spectra were recorded in from a proper solvent.
DM SO-d6 on a 90 MHz on a Varian Em 390 spec­ M ethod B: A suspension of equimolar am ounts
trom eter with TMS as an internal standard and (0.01 mole) of 5 and/or 6 was treated with
chemical shifts are expressed as S values. Analyti­ 3-methyl-2-pyrazolin-5-one (2) and/or m alononi­
cal data were obtained from the m icroanalytical trile (0.01 mole) in dioxane or ethanol (70 ml) and
data unit at Cairo university. a catalytic am ount of piperidine is warmed if need­
ed till a clear solution was obtained and stirred at
room tem perature for 2 -1 5 min. The solid prod­
Synthesis o f pyranof 2,3-cJpyrazoles (3 a —n) uct was collected and purified as in method A.

General procedure 2- Amino-3-cyano-4,7-dihydro-5-methyl-

M ethod A: A suspension of equimolar am ounts 4-(3-pvridyl)pyrano[2,3-cJpyrazole (3a)
(0.01 mole) of each of aldehyde or ketone ( l a - n ) , Colourless crystals (from dioxane), m.p. 2 1 8 -
m alononitrile, 3-methyl-2-pyrazolin-5-one (2) and 220 °C, yield 85%, IR: 3410-3320 (NH, NH,),
a catalytic am ount of piperidine in dioxane (50 ml) 2170 (C = N ) and 1630-1600 cm 1 (C = C, C = N ,
is warmed if needed untill a clear solution is ob­ <5NH2), H NM R: S = 1.8 (s, 3 H. C H 3), 3.5 (m, 3 H,

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F. F. A bdel-L atif • Heterocycles Synthesis 1677

NH, N H 2), 4.5 (s, 1 H, pyran 4-H) and 6 .4 -8 .4 (m, NH,), 2195 (C = N ) and 1640, 1610, 1600 cm "1
4H , pyridyl protons). (C =C , C = N, <SNH,), H NM R: Ö = 1.7 (s, 3H , to-
C 13H 11N 50 (2 5 3 ) lyl C H 3), 2.3 (s, 3 H, pyrazole C H 3), 4.5 (s, 1 H,
Calcd C 61.66 H 4.30 N 27.66, pyran 4-H), 6.7 (s, 2H , NH-,), 7.0 (s, 4H , phenyl
Found C 61.50 H 4.50 N 27.80. protons) and 11.9 (s, 1H, NH).
C ,,H 14N 40 (2 6 6 )
2-Amino-3-cyano-4,7-dihydro-4-( 2-furyl)- Calcd C 67.67 H 5.26 N 21.05,
5-methylpyrano[2,3-cJpyrazole (3 b) Found C 67.70 H 5.40 N 21.20.
Colourless crystals (from dil. ethanol), m.p.
215-216 :C, yield 85%, IR: 3370, 3300, 3150 2- Amino-3-cyano-4,7-dihydro-5-methyl-
(NH, N H ,), 2195 (C = N ) and 1645, 1610 c n T 1 4- (p-nitrophenyl)pyrano[ 2,3-cJpyrazole (3g)
(C = C, C*=N, <SNH,), H NM R: ö = 2.0 (s, 3H ,
C H 3), 4.7 (s, 1H, pyran 4-H), 6.1 (d, 1 H, furan Colourless crystals (from dil. ethanol), m .p.
5-H), 6.3 (m, 1 H, furan 4-H), 6.8 (s, 2 H, N H ,), 7.3 237-239 °C, yield 80%, IR: 3380, 3260, 3120
(d, 1H, furan 3-H )and 12.0 (s, 1 H, NH). (NH, N H ,), 2205 (C = N ) and 1655, 1620, 1610
cm “1(C = C, C = N,e>NH2).
C 12H 10N 4O, (242)
Calcd' C 59.50 H 4.13 N 23.14, C 14H n N 50 3 (297)
Found C 59.70 H 4.00 N 23.20. Calcd C 56.56 H 3.70 N 23.57,
Found C 56.80 H 3.60 N 23.70.

2-Amino-3-cyano-4,7-dihydro-5-methyl-
4- (2-thienyl)pyrano[ 2,3-cJpyrazole (3 c) 2-Amino-4- ( o-anisyl) -3-cyano-4,7-dihydro-
Colourless crystals (from ethanol), m .p. 229 — 5-methylpyrano J 2,3-c Jpyrazole (3 h)
230 °C, yield 75%, IR: 3380, 3300, 3150 (NH, Colourless crystals (from ethanol), m .p. 241 —
NH,), 2190 (C = N ) and 1650, 1610 c m '1 (C = C, 243 °C, yield 72%, IR: 3400, 3370, 3180 (NH,
C = N,(5NH2). NH,), 2200 (C = N ) and 1640, 1610 cm*1 (C = C,
C p H 10N 4OS (258) C = N,t>NH,).
Calcd C 55.81 H3.87 N21.70 S 12.40, C „ H I4N 40 , (282)
Found C 56.00 H4.00 N 21.70 S 12.50. Calcd“ C 63.83 H 4.96 N 19.86,
Found C 64.00 H 5.00 N 19.70.
2- Amino-3-cyano-4,7-dihydro-4-isopropyl-
5-methylpyrano[2,3-cJpyrazole (3d)
Colourless crystals (from ethanol), m .p. 180 — 2-Amino-4-(o-chlorophenyl)-3-cyano-4,7-dihydro-
182 °C, yield 50%, IR: 3400, 3220, 3160 (NH, 5-methylpyranoJ2,3-cJpyrazole (3i)
NH,), 2900-2850 (CH stretches), 2150 (C = N ) Colourless crystals (from dioxane), m .p. 2 4 7 -
and 1625, 1600 cm 1 (C = C, C = N, d'NH,), H 249 °C, yield 70%.
NM R: <5 = 0.8 (2d, 6H , 2 alkyl CH,), 2.2 (s' 3H ,
pyrazole C H 3), 3.3 (m, 2H , CH and pyran 4-H), C 14H h N 4OC1 (286.5)
6.66 (s, 2 H, NH,) and 11.8 (s, 1 H, NH). Calcd C 58.64 H3.84 N 19.55 Cl 12.39,
Found C 58.60 H3.60 N 19.70 Cl 12.50.
C ,,H 14N 40 (2 1 8 )
Calcd C 60.55 H 6.42 N 25.69,
Found C 60.50 H 6.50 N 25.80. 2-Amino-4-( m-bromophenyl) -3-cyano-4,7-dihydro-
5-methylpyranoJ2,3-cJpyrazole (3j)
2-Amino-3-cyano-4,7-dihydro-5-methyl- Colourless crystals (from ethanol), m .p. 2 3 7 -
4-phenylpyrano[2,3-cJpyrazole (3e) 239 °C, yield 80%, IR: 3400, 3320, 3260 (NH,
Colourless crystals (from dioxane), m .p. 2 4 2 - N H ,), 2195 (C = N ) and 1645, 1610, 1600 cm “1
244 °C, lit. m.p. 242 C [10], yield 90%. (C =C , C = N, <5NH,), H NM R: Ö = 2.3 (s, 3H ,
C H 3), 4.6 (s, 1 H, pyran 4-H), 6.8 (s, 2H , NH,), 7.1
2-Amino-3-cyano-4,7-dihydro-5-methyl- (m, 4 H, phenyl protons) and 11.8 (s, 1 H, NH).
4-(p-tolyl)pyrano[ 2,3-cJpyrazole (3f) C l4H ,,N 4OBr (331)
Colourless crystals (from ethanol), m .p. 198- Calcd C 50.75 H3.32 N 16.92 Br 24.17,
199 C, yield 90%, IR: 3420. 3310, 3200 (NH, Found C 50.70 H3.50 N 17.10 B r24.00.

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1678 F. F. A b d el-L atif • Heterocycles Synthesis

2- Amino-3-cy ano-4,7-dihydro-4- ( 2,5-dimethoxy- 2-Amino-3-cyano-7 H-5-methylspiro[ cyclohexane-

phenyl) -5-methylpyrano[2,3-cJpyrazole (3k) I ,4-pyrano[2,3-c]pyrazole] (3 m)
Yellow crystals (from ethanol), m .p. 2 1 0 - Colourless crystals (from ethanol), m.p. 140—
212 °C, yield 80%. 142 °C, yield 92%, IR: 3450, 3320, 3170 (NH,
N H ,), 2930-2850 (CH stretches), 2195 (C = N )
C 16H 16N 40 3 (312)
and 1640, 1620 cm -' (C = C, C = N , <5NH2).
Calcd C 61.54 H 5.13 N 17.95,
Found C 61.50 H 4.90 N 18.00. C 13H 16N 40 (2 4 4 )
Calcd C 63.93 H 4.09 N 22.95,
2-Amino-3-cyano-4,5-dimethvl-7 H-4-phenyl- Found C 63.80 H 4.20 N 23.10.
pyrano[2,3-c]pyrazole (31)
Colourless crystals (from dil. ethanol), m .p. 2-Amino-3-cyano-7 H-5-methylspiro[ cyclopentane-
204-206 °C, yield 60%, IR: 3400, 3300, 3150 1,4-pyrano[2,3-c]pyrazole] (3 n)
(NH, NH-,), 2950 (CH stretches), 2190 (C = N ) and Colourless crystals (from dil. ethanol), m.p.
1625, 160Ö cm -1 (C = C, C = N, <5NH,), H NM R: 148-150 °C, yield 50%, IR: 3430, 3320, 3200
8 = 2.0 (2s, 6H , 2C H 3), 6.7 (s, 2H . NH,), 7.1 (m, (NH , N H ,), 2920, 2850 (CH stretches), 2200
5 H, phenyl protons) and 11.8 (s, 1 H, NH). (C = N ) and 1650, 1630 c n T 1(C =C , C = N , <5NH,).
C „ H I4N 40 (2 6 6 ) C ,,H 14N 40 (230)
Calcd C 67.67 H 5.26 N 21.05, Calcd C 62.61 H 6.09 N 24.35,
Found C 67.40 H 5.40 N 21.20. Found C 62.60 H 5.90 N 24.20.

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