Studies with enaminonitriles: Synthesis and chemical reactivity of 2-phenyl-3-piperidin-1-yl acrylonitrile under microwave heating

Article abstract of DOI:10.1002/jhet.5570450202

(Chemical Equation Presented) Benzyl cyanide reacts with triethylorthoformate and piperidine in DMF solution to yield the title compound 2. This reacted with aromatic amines to yield either aminoacrylonitriles orquinoline depending on reaction conditions and substitution pattern on the aromatic amine. The reaction of compound 2 with hydrazine hydrate could only be effected in the microwave oven and resulted in the formation of aminopyrazole 7. Diazotization of 7 and coupling with an active methylene reagent afforded pyrazolo[5,1-c]-[1,2,4]triazine derivatives.

Full text of DOI:10.1002/jhet.5570450202

Mar-Apr 2008
307
Studies with Enaminonitriles : Synthesis and Chemical Reactivity of
2-Phenyl-3-Piperidin-1-yl Acrylonitrile under Microwave Heating
Abdellatif M. Salaheldin* and Maryana K. Alphy
Department of Chemistry, Faculty of Science, Cairo University, Giza, A. R. Egypt
e-mail: amsalaheldin@yahoo.com
Received October 27, 2006
Ph
Ph
NH2
Ph
CN
N
NH2NH2
MW
N
i) NaNO2/HCl
N
N
N
N
CN
X
ii)
N
N
H
X
NH2
N
7
2a
H2N
CN
CN
Ph
2a,b
MW
NH2
ArNH2
Ph
NC
NH2
CN
Ph
N
N
N
NH
Ar
N
N
Ar
NH2
NH2
Benzyl cyanide reacts with triethylorthoformate and piperidine in DMF solution to yield the title
compound 2. This reacted with aromatic amines to yield either aminoacrylonitriles or quinoline depending
on reaction conditions and substitution pattern on the aromatic amine. The reaction of compound 2 with
hydrazine hydrate could only be effected in the microwave oven and resulted in the formation of
aminopyrazole 7. Diazotization of 7 and coupling with an active methylene reagent afforded pyrazolo[5,1-c]-
[1,2,4]triazine derivatives.
J. Heterocyclic Chem., 45, 307 (2008).
In the present article, we report results of our work
aimed at exploring the synthetic potential of 2. It has been
found that 2a reacts with aniline, when both reagents were
heated in a domestic microwave oven for two minutes in
absence of solvent to yield the aniline derivative 3a. On
the other hand reacting 2a with aniline in refluxing
dioxane for ten hours afforded the aminoquinoline 4 in
good yield. Compound 3a was converted into 4 on long
reflux in dioxane solution. On the other hand 2a reacted
with 4-nitroaniline to yield 3b. Trials to effect cyclization
of the later into a quinoline derivative failed due to the
effect of an electron attracting substituent on aryl moiety
(Scheme 1).
INTRODUCTION
Microwave (MW) heating has been employed for the
rapid synthesis of a wide variety of organic molecules [1-
4] wherein chemical reactions are accelerated because of
selective absorption of MW energy by polar molecules,
non-polar molecules being inert to the MW dielectric loss.
The applications of microwave irradiation with the use of
catalysts or mineral supported reagents, under solvent-free
conditions, provide unique chemical processes with
special attributes such as enhanced reaction rates, higher
yields, greater selectivity and ease of manipulation. This
solventless microwave methodology is exemplified by a
concise synthesis of amino acrylonitriles, aminopyrazoles,
pyrazolo[1,5-a]pyrimidines, and benzimidazoles.
Compound 3b reacted readily with phenylisothio-
cyanate to yield the thiourea derivative 5. Trials to cyclize
the later into pyrimidine 6 failed. When refluxed in acetic
acid compound 5 afforded only 3b.
RESULTS AND DISCUSSION
Compound 2 failed to react with hydrazine hydrate in
refluxing DMF under a variety of conditions. However,
when heated with hydrazine hydrate in presence of acetic
acid in a microwave oven for two minutes the amino
pyrazole 7 was formed in almost quantitative yield.
This could be readily diazotized and the resulting
diazonium salt 8 coupled with ethyl cyanoacetate and
with malononitrile to yield the amino pyrazolo[5,1-c]-
triazine 10a,b respectively. Intermediates 9 are postulated
although they could not be isolated (Scheme 2).
Enaminonitriles are versatile reagents and their
chemistry is now receiving considerable attention as
precursors to, otherwise not readily obtainable heteroaro-
matics [5-10]. The synthesis of compounds 2a,b were
achieved via reacting benzyl cyanide or 4-nitrobenzyl
cyanide (1a,b) with triethylorthoformate and piperidine in
refluxing dimethylformamide solution (readily available
starting materials instead of using dimethylformamide
dimethylacetal (DMFDMA) an expensive and carcino-
genic material) (Scheme 1).

308
A. M. Salaheldin and M. K. Alphy
Vol 45
Scheme 1
Scheme 3
H
N
CN
CN
Ph
EtO OEt
Ph
N
NH2
OEt
N
NH2
NH2
H2N
CN
CN
EtO
OEt
N
+
N
7
CN
N
N
N
Ph
NC
NHPh
S
NH2
NH
NC
DMF
CN
Ar
EtONa/EtOH
2 mole
11
12
S
C
1
N
h
MW
P
CN
Ph
PhNCS
Ar = 4-NO2C6H5
2a,b
ArHN
AcOH
2 min
CN
NC
Ar1NH2
MW
Ph
CN
N
Ph
NHCSNHPh
N
N
NH2
NH2
1,2 a, Ar = Ph
b, Ar = 4-NO2C6H4
NO2
Ar
3
N
Ph
HN
N
5
N
N
2
N
Ar
3a, Ar1 = Ph
H
NC
PhNH2
3b, Ar1 = 4-NO2C6H4
14
Ph
NH
N
H
NH2
13
Ph
15
N
S
Ph
N
NH2
N
Ar 1 = Ph
Ph
Ph
H
N
N
N
N
N
Ar
N
Ar
O2N
6
4
NH2
NH
17 a, Ar = C6H5
16
b, Ar = 4-NO2C6H4
Scheme 2
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded
Ph
N
N Cl
Ph
NH2
Ph
CN
N
NH2NH2
MW
NaNO2
N
N
HCl
N
N
1
H
H
in KBr pellets with Satellite 2000 spectrophotometer. H NMR
(300 MHz) and 13C NMR (75.4 MHz) spectra were recorded on
a Bruker AC-300 spectrometer in DMSO-d6 and CDCl3 as
solvents and TMS as internal standard; chemical shifts are
reported in δ units (ppm). Mass spectra were measured at 70 eV
using Shimadzu GCMS-QP 1000 EX spectrometer.
Microanalytical Data were obtained from the Microanalytical
Centre at Cairo University. Microwave experiments were
conducted in a domestic microwave oven SJO 390W.
8
7
CN
2a
X
Ph
Ph
HN
N
N
N
X
NC
N
N
N
H
X
NH2
9
10a, X = CN
b, X = CO2Et
General procedure for preparation of compounds 2a,b. To
a mixture of benzyl cyanide 1a or 4-nitrobenzyl cyanide 1b (0.5
mmoles), triethyl orthoformate (0.6 m moles), and piperidine
(0.5 mmoles) DMF (50 ml) was added and the solution was
refluxed for 72 hours. The reaction mixture was then cooled and
poured onto water. The solid product formed, was collected by
filtration and crystallized from ethanol.
Compound 7 reacts with malononitrile in ethanol
sodium ethoxide to afford product 13 and not 11. The
chemical analysis of compound 13 showed that this
compound is a 2:1 adduct with m/z = 291. Two moles of
malononitrile condensed together to afford malononitrile
dimer (in situ) which reacts with aminopyrazole to yield
intermediate 12 (not isolated) which undergoes
cyclization to the final product 13. To confirm the
formation of 13, malononitrile dimer was first prepared
and then reacted with aminopyrazole to yield the same
product 13 (m.p. mixed m.p. and TLC) (Scheme 3).
2-Phenyl-3-piperidin-1-yl-acrylonitrile (2a). This compound
was obtained as yellowish white needles in 70% yield (EtOH-
H2O), mp 115-116°; ir (potassium bromide): 2190 (CN), 1616
1
(C=C) cm-1; H nmr (CDCl3): δ 1.75 (m, 6H, 3CH2), 3.75 (m,
4H, 2CH2), 6.95 (s, 1H olefinic-H), 7.20-7.45 (m, 5 H, Ar-H).
13C nmr (deuteriochloroform): δ 149.2, 137.2, 129.1, 125.5,
124.4, 121.5, 75.4, 51.9, 26.4, 24.3; ms: m/z 212 (M+). Anal.
Calcd. for C14H16N2 (212.29): C, 79.21; H, 7.60; N, 13.20.
Found: C, 79.29; H, 7.67; N,13.17.
2-(4-Nitrophenyl)-3-piperidin-1-yl-acrylonitrile (2b). This
compound was obtained as pale yellow needles in 70% yield;
mp 130-131°; ir (potassium bromide): 2206, (CN), 1618
(C=C), 1595, 1330 (NO2) cm-1; 1H nmr (deuterio-
chloroform): δ 1.75 (m, 6H, 3CH2); 3.70 (m, 4H, 2CH2); 7.10
(s, 1H, olefinic-H); 7.45 (d, 2H, J = 10 Hz, Ar-H), 8.08 (d,
2H, J = 10 Hz, Ar-H); ms: m/z 257 (M+). Anal. Calcd. for
C14H15N3O2 (257.29): C, 65.35; H, 5.88; N, 16.33.Found : C,
65.15 ; H, 5.70; N, 16.44.
In recent years, urea and thiourea [11-13] have emerged
as structurally novel anticonvulsant agents. Thus
compound 7 reacted with phenylisothiocyanate to yield
the thiourea 14. Finally the enaminonitriles 2a,b were
reacted with amniopyrazole 7, in the microwave oven for
two minutes, to produced pyrazolo[1,5-a]pyrimidine
derivatives 17a,b in excellent yields (Scheme 3).

Mar-Apr 2008
Studies with Enaminonitriles : Synthesis and Chemical Reactivity of
2-Phenyl-3-Piperidin-1-yl Acrylonitrile under Microwave Heating
309
General procedure for preparation of 2-phenyl-3-
(substituted amino) acrylonitrile 3a,b. A mixture of 2a (0.2
mmoles) and aniline or 4-nitro aniline (0.1 mmole), were heated
in a domestic microwave oven for three minutes, in absence of
solvent, the resulting product treated with ethanol, and the solid
collected by filtration, then crystallized from ethanol, to afford
3a,b.
diazonium chloride was prepared by adding a solution of sodium
nitrite (10 mmoles in a small amount of water) to a cold solution
of aminopyrazole (7) in hydrochloric acid with stirring .The
resulting solution was added slowly into a cold solution of
malononitrile or ethyl cyanoacetate in ethanol (40 ml)/sodium
acetate (5g). The mixture was stirred at r.t for 1 hr, the semisolid
so formed, was washed with cold water then dissolved in acetic
acid (15 ml), and refluxed for three hours, The mixture was
allowed to cool, then it was poured onto ice-cold water, the solid
so formed was collected by filtration, and crystallized from
ethanol to afford 10a,b respectively.
4-Amino-8-phenylpyrazolo[5,1-c][1,2,4]triazine-3-carbo-
nitrile (10a). This compound was obtained as yellow solid in
70% yield; mp 290°; ir (potassium bromide): 2227 (CN); 3310
(NH2).cm-1; ms: m/z =235 (M+, 100%); (M+1, 81%). Anal. Calcd.
For C12H8N6 (236.24) C, 61.01; H, 3.41; N, 35.57. Found. C,
61.35; H, 3.54; N, 35.70.
2-Phenyl-3-(phenylamino)acrylonitrile (3a). This compound
was obtained as pale yellow needles in 85% yield; mp 165-166°;
1
ir (potassium bromide): 2210 (CN); 3360 (NH) cm-1; Hnmr
(dimethylsulfoxide-d6): δ 6.96-7.30 (m, 10H, Ar-H); 6.50 (s,
1H, NH); 7.40 (s, 1H, olefinic-H); ms: m/z 220 (M+). Anal.
Calcd. for C15H12N2 (220.28) C, 81.79; H, 5.49; N, 12.72.
Found: C, 81.88; H, 5.51; N, 12.80.
3-(4-nitrophenyl amino)-2-phenyl acrylonitrile (3b). This
compound was obtained as yellow needles in 80% yield; mp
160°; ir (potassium bromide): 2190 (CN); 3330 (NH), 1590,
1
1320 (NO2) cm-1; H nmr (dimethylsulfoxide-d6): δ 6.40 (s, 1H,
Ethyl 4-amino-8-phenyl pyrazolo[5,1-c][1,2,4]triazine-3-
carboxylate (10b). This compound was obtained in yellow solid
70%yield; mp 220°; ir (potassium bromide): 1675 (C=O); 3391,
NH); 6.90-7.30 (m, 5H, Ar-H); 7.45 (s, 1H, olefinic-H); 7.85 (d,
2H, J = 10Hz, Ar-H); 8.25 (d, 2H, J = 10Hz, Ar-H); ms: m/z =
265 (M+) Anal. Calcd. for C15H11N3O2 (265.27) C, 67.92; H,
4.18; N, 15.84; Found C, 69.74; H, 4.88; N, 16.04.
1
3264, (NH2) cm-1; H nmr (dimethylsulfoxide-d6): δ = 1.38 (t,
3H, J = 7.5 Hz, CH3); 4.44 (q, 2H, CH2); 7.29-7.51 (m, 5H, Ar-
H); 8.24 (s, 2H, NH2); 8.92 (s, 1H, H-6), ms: m/z 283 (M+).
Anal. Calcd. For C14H13N5O2 (283.29): C, 59.36; H, 4.63; N,
24.72. Found. C, 59.52; H, 5.05; N, 25.09.
3-Phenyl quinoline-4-amine (4). A solution of (2a, 1 mmole)
and the aniline (1 mmole) in dioxane (30 ml) was refluxed for
10 hrs. A similar solution with compound 3a (1 mmole) in the
place of aniline was refluxed for 8 hours. The solvent was
reduced under vacuum. The solid formed was collected by
filtration and crystallized from ethanol. This compound was
obtained as yellow solid in 85% yield; mp 135-136°; ir
(potassium bromide): 3360-3290 (NH2) cm-1; 1H nmr
(dimethylsulfoxide-d6): δ 6.14 (s, 2H, NH2); 7.10-7.80 (m, 9H,
Ar-H); 8.33 (s, 1H, quinoline-H-2); ms: m/z 220 (M+). Anal.
Calcd. for C15H12N2 (220.28) C, 81.79; H, 5.49; N, 12.72. Found:
C, 81.95; H, 5.44; N, 12.65.
3-Phenylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-5,6,8-tri-
amine (13). To a solution of aminopyrazole (7, 1 mmol) and
malononitrile (0.5 mmol) in DMF (25 ml) piperidine (1 ml) was
added and then the mixture was refluxed for three hours, the
reaction mixture was allowed to cool, then poured onto ice. The
solid so formed, was collected by filtration and crystallized from
ethanol to afford (13). This compound was obtained as brown
solid in 70% yield mp 226°C; ir (potassium bromide): 1610
(C=C); 3450, 3320 (NH2) cm-1; 1H nmr (dimethylsulfoxide-d6): δ
7.18-7.44 (m, 6H, Ar-H, H-7), 7.55, (s, 2H, NH2), 7.89, (s, 2H,
NH2), 8.16 (s, 2H, NH2), 8.68 (s, 1H, pyrazole–H-2), ms: m/z
291 (M+, 100%). Anal. Calcd. For C15H13N7 (291.28) C, 61.84;
H, 4.50; N, 33.66. Found C, 61.50; H, 4.39; N, 33.30.
1-(2-Cyano-2-phenylvinyl)-1-(4-nitrophenyl)-3-phenyl
thiourea (5). A solution of (0.2 mmoles) (3b) and phenyl
isothiocyanate (0.1 mmole) was dissolved in dry acetone (20 ml)
was refluxed for 3 hours. The reaction mixture was allowed to
cool and the solid so formed was collected by filtration and
crystallized from ethanol/DMF (2:1) to afford (5). This
compound was obtained as a dark yellow solid in 70% yield; mp
250°C; ir (potassium bromide): 1681 (C=S); 2208 (CN); 3301,
1-Phenyl-3-(4-phenyl-1H-pyrazol-5-yl)thiourea (14).
A
solution of aminopyrazole (7, 1 mmol) and phenylisothiocyante
(0.5 mmol) in dry acetone (25 ml) was refluxed for three hours
and the reaction mixture was allowed to cool. A solid formed
was collected by filtration and crystallized from ethanol to
afford (14). This compound was obtained as pale yellow needles
in 75% yield; mp 142-143°; ir (potassium bromide): 1675,
1
3251,(NH) cm-1; H nmr (dimethylsulfoxide-d6 ): δ 7.25-7.37
(m, 10H, Ar-H); 7.52 (d, 2H, J = 10 Hz, Ar-H); 8.17 (d, 2H, J =
10 Hz, Ar-H); 8.23 (s, 1H, CH); 10.25 (s, 1H, NH), ms: m/z 400
(M+, 70%). Anal. Calcd. For C22H16N4O2S (400.46). C, 65.99; H,
4.03; N, 13.99; S, 8.01. Found. C, 66.10; H, 3.86; N, 14.14; S,
8.21.
3-Amino-4-phenyl-1H-pyrazole (7). A mixture of (2a, 1
mmole), hydrazine hydrate (0.5 mmoles) and a few drops from
acetic acid were heated in a domestic microwave oven at full
power for two minutes. A solid formed, which was treated with
ethanol, collected by filtration, was crystallized from ethanol.
This compound was obtained as pale yellow needles in 95%
yield; mp 175-176° (lit. mp 173-173.5°) [14]; ir (potassium
bromide): 3340 (NH2) cm-1; 1H nmr (dimethylsulfoxide-d6): 6.10
(s, 2H, NH2); 7.05 (s, 1H, pyrazole-H), 7.20-7.50 (m, 5H, Ar-
H), 7.65 (s, 1H, NH), ms: m/z 159 (M+). Anal. Calcd. For
C9H9N3 (159.19): C, 67,90; H, 5.70; N, 26.40. Found. C, 67.80;
H, 5.82; N, 26.50.
1
(C=S), 3310, 3256, (NH)cm-1; H nmr (dimethylsulfoxide-d6): δ
7.32-7.53 (m, 10H, Ar-H), 7.90 (s, 1H NH), 8.20 (s, 1H NH),
8.56 (s, 1H, pyrazole-H); 9.42 (s, 1H NH), ms: m/z 294 (M+,
100%). Anal. Calcd. For C16H14N4S (294.37) C, 65.28; H, 4.79;
N, 19.03; S, 10.89. Found. C, 65.42; H, 5.04; N, 19.25; S, 10.68.
General procedure for preparation of pyrazolo[1,5-a]-
pyrimidine derivative (17a,b). A mixture of aminopyrazole (7,
1 mmol) and enaminonitrile (2a, b, 1.3 mmol) was heated in a
domestic microwave oven for two minutes. The resulting
products were treated with ethanol and the solids were collected
by filtration, crystallized from ethanol and identified as 17a,b,
respectively.
3,6-Diphenylpyrazolo[1,5-a]pyrimidine-7-amine (17a).
This compound was obtained as yellow solid in 80% yield; mp
220-222°C; (lit. mp 222-224°C) [15], ir (potassium bromide):
1
General procedure for preparation of pyrazolo[1,5-c]-
[1,2,4]triazine derivatives (10a,b). A cold solution of pyrazole
3340, (NH2).cm-1; H nmr (dimethylsulfoxide-d6): δ 4.50 (brs,
2H, NH2), 6.92 (s, 1H, H-5), 7.13-7.50 (m, 10H, Ar-H), 7.77 (s,

310
A. M. Salaheldin and M. K. Alphy
Vol 45
1H, H-2); 13C nmr (deuteriochloroform): δ 104.4 (C-6), 108.4
(C-3), 124.6, 125.7, 127.4, 128.5, 128.8, 129.2, 133.8, 135.9,
142.3 (C-2), 145.6 (C-3a), 146.2 (C-7), 151.1 (C-5); ms: m/z
286. (M+, 100%). Anal. Calcd. For C18H14N4, (286.34) C, 75.51;
H, 4.93; N, 19.57. Found C, 75.24; H, 5.05; N, 19.71.
Laberge, L.; Rousell, J. Tetrahedron Lett. 1986, 27, 279.
[3] Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet,F.;
Jacquault, P.; Mathe, D. Synthesis 1998, 1213.
[4] Caddick, S. Tetrahedron 1995, 51, 10403.
[5] Elassar, A. A.; El-khair, A. A. Tetrahedron 2003, 59, 8463.
[6] Stanovnik, B. J. Heterocyclic Chem. 1999, 36, 1581.
[7] Davis, K. M.; Carpenter, B. K. J. Org. Chem., 1996, 61,
4617.
6-(4-Nitrophenyl)-3-phenylpyrazolo[1,5-a]pyrimidin-7-
amine (17b). This compound was obtained as yellow solid in
85% yield; mp 196°; ir (potassium bromide): 3360-3290 (NH2),
[8] AL-Shiekh, M. A.; Salah EL-Din, A. M.; Hafez, E. A.;
Elnagdi, M. H. J. Chem. Res (S) 2004, 174.
1
1565, 1360 (NO2) cm-1; H nmr (dimethylsulfoxide-d6): δ 4.60
[9] AL-Shiekh, M. A.; Salah EL-Din, A. M.; Hafez, E. A.;
Elnagdi, M. H. J. Heterocyclic Chem. 2004, 41, 647.
[10] Almazroa, S.; Elnagdi, M. H.; Salah EL-Din, A. M. J.
Heterocyclic. Chem., 2004, 41, 267.
[11] Heinisch, G.; Matuszczak, B.; Rakowitz, D.; Tantisina, B.
Arch. Pharm. (Weinheim) 1997, 330(7), 207.
(bs, 2H, NH2), 6.90 (s, 1H, H-5), 7.08-7.26 (m, 5H, Ar-H), 7.36
(d, 2H, Ar-H); 750 (d, 2H, Ar-H); 7.75 (s, 1H, H-2), ms: m/z
331 (M+). Anal. Calcd. For C18H13N5O2 (331.34) C, 65.25; H,
3.95; N, 21.14. Found: C, 65.50; H, 4.10; N, 21.61.
Acknowledgement. We are grateful to Prof. M. H. Elnagdi
for continued help and critical comments on research progress.
[12] Pandeya, S. N.; Manjula, H.; Stables, J. P. Pharmazie 2001,
56(2), 121.
[13] Dimmock, J. R.; Vashishtha, S. C.; Stables, J. P. Pharmazie,
2000, 55(7), 490.
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C.; Elguero, J. J. Heterocyclic Chem. 1974, 11, 423.
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