Studies with azinylacetonitriles: 2-Pyridylacetonitrile as a precursor to functionally substituted pyridines

Article abstract of DOI:10.3390/molecules14114406

2-Pyridylacetonitrile (1) couples with aromatic diazonium salts to yield arylhydrazones 2a-c, that were shown to exist in the syn-form 2 rather than the anti-form 4. Compounds 2a,c reacted with hydroxylamine in refluxing DMF to yield the interesting 1,2,3-triazolylpyridines 6. Attempts to cyclize 2 to give the corresponding fused pyrazolopyridines 9 failed. On the other hand, compound 1 condensed with dimethylformamide dimethyl acetal to yield enaminonitrile 10 that could be converted into pyrazolylpyridine 11.

Full text of DOI:10.3390/molecules14114406

Molecules 2009, 14, 4406-4413; doi:10.3390/molecules14114406
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Studies with Azinylacetonitriles: 2-Pyridylacetonitrile as a
Precursor to Functionally Substituted Pyridines
2
Mariam Abdullah Al-Sheikh 1,* and Mohamed Hilmy Elnagdi
1
Department of Chemistry, Girls College of Education, Jeddah, P. O. Box 138016, Jeddah 21323,
Kingdom of Saudi Arabia
2
Department of Chemistry, Faculty of Science, Kuwait University, Kuwait
* Author to whom correspondence should be addressed; E-Mail: r1425@hotmail.com.
Received: 7 September 2009; in revised form: 27 October 2009 / Accepted: 28 October 2009 /
Published: 3 November 2009
Abstract: 2-Pyridylacetonitrile (1) couples with aromatic diazonium salts to yield
arylhydrazones 2a-c, that were shown to exist in the syn-form 2 rather than the anti-form 4.
Compounds 2a,c reacted with hydroxylamine in refluxing DMF to yield the interesting
1,2,3-triazolylpyridines 6. Attempts to cyclize 2 to give the corresponding fused
pyrazolopyridines 9 failed. On the other hand, compound 1 condensed with
dimethylformamide dimethyl acetal to yield enaminonitrile 10 that could be converted into
pyrazolylpyridine 11.
Keywords: 2-pyridylacetonitrile; enaminonitrile; arylhydrazones
Introduction
It is well accepted that the methylene moieties in heteroaromatic substituted acetonitriles are
reactive toward electrophiles under mild conditions [1-3]. This reactivity has been utilized for
synthesis of a variety of functionally substituted azoles [4,5] and condensed azoles [6,7]. However,
little has been reported on the utility of azinylacetonitriles for synthesis of functionally substituted
azines [8].

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Results and Discussion
In conjunction with our interest in using aromatic and heteroaromatic substituted acetonitriles as
precursors for the synthesis of heteroaromatics, we report herein the reactivity of 2-pyridylacetonitrile
(1) as a good precursor to several azolylpyridines. Thus, compound 1 coupled with aromatic
diazonium salts to yield arylhydrazones 2a-c. Although a mixture of the two geometrical isomers was
expected based on an earlier report [9], the existence of only the syn-structure 2 could be established,
at least in the solid state, based on X-ray crystal structure determination [10] (cf. Figure 1 and Table 1
for bond angles and bond lengths).
Scheme 1. Syntheses of hydrazones.
CN
CN
N
N
N
N
HN
Ar
N
Ar
H
2 a, Ar= p-Cl-C6H4
b, Ar= p-NO2-C6H4
c, Ar= p-OMe-C6H4
ArN2Cl
3
N
CN
1
CN
N
N
NH
Ar
4
Figure 1. X-ray crystal structure of compound 2a.

Molecules 2009, 14
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Table 1. Crystal data and structure refinement for compound 2a.
Bond lengths
Bond lengths
N3 N4 1.326(4)
Parameter
Empirical Formula
Formula weight
Crystal System
Space group
Unit cell parameters
a [Å]
2a
C13H9N4Cl
256.696
Monoclinic
P21/c
N4 C8
1.320(4)
1.326(5)
1.906(3)
1.449(5)
1.349(4)
1.985(3)
N2 C9
N2 H3
C8 C17
N2 C14
N4 H3
N3 C13
C6 C13
Cl 1 C12
N10 C17
C13 C16
1.412(5)
1.363(5)
1.742(3)
1.143(4)
1.377(4)
8.4969(3)
13.5879(6)
12.8704(6)
90.00
b [Å]
c [Å]
alpha
Bond angles
Bond angles
Bo
12.(18) 1010
90.00
N3 N4 C8
118.6(3) N2 C14 C8 116.9(3)
gamma
C14 C8 C17 118.5(3) N2 H3 N3
N2 C9 C7 124.3(4) N3 H3 N4
C8C17 N10 179.3(4) C8 C14C15 122.1(3)
N3C13 C6 122.2(3) N4 C8 C14 130.4(3)
N4 N3 C13 118.4(3) N3 C13C16 117.6(3)
132.7(2)
35.4(2)
Unit cell volume
Z
Temperature (K)
Radiation type
Dx Mg/m3
F(000)
1228.62(9)
4
298
Mo Ka
1.388
528 loop
Absorption coefficient 0.30
(mm-1)
Parameters
R factor
103
0.061
Inspection of Table 1 indicates that the acetonitrile N4-C8-C14 bond angle is larger than a typical
sp2 bond angle (120o), perhaps to reduce the steric interaction between hydrogen NH, and the pyridyl
ring N3-N4 bond length is more like a double bond. We assume that nitrogen lone pair is delocalized
at the ring nitrogen and that electrostatic attraction between the positively charged hydrazone moiety
and the negatively charged ring nitrogen holds the molecule in the syn-form. It is thus concluded that
charge separation in 2 contributes significantly to the actual structure [10-12].
Compounds 2a,b reacted with hydroxylamine hydrochloride in refluxing DMF and in the presence
of sodium acetate to yield the products of addition and water elimination which can thus be formulated
as 1,2,3-triazoles 6a,b or their isomeric structures 1,2,4-triazoles 7, and are assumed to be formed via
the intermediately formed amidoximes 5a,b that could be isolated (Scheme 2). NOE difference spectra
enabled the assignment of structure 6 for the products as irradiation of the NH2 protons at δ = 6.3 ppm
did not enhance the aryl protons. If the reaction product were 7 enhancement of these aryl protons
should have been observed. The behavior of 2 towards hydroxylamine is thus similar to that of other
hydrazononitriles and differs from that of 2-p-nitrophenyl-2-arylhydrazonoacetonitrile where
rearrangement preceded cyclization affording 1,2,4-triazoles 7. Although 2-arylhydrazono-2-
acetylpyridine 8 has been recently reported to afford 9 when heating in dichlorobenzene at 190 °C, in
our hands, compounds 2a-c have been recovered unaffected under these conditions [13]. It seems that
replacing a methyl by a cyano group affects the HOMO-LUMO energy of the cyclised 6π electron
system as this cyclization is believed to proceed by a pericyclic rule. Next, compound 1 was reacted

Molecules 2009, 14
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with DMFDMA to yield the corresponding enaminonitrile 10, for which exact stereochemistry could
not be established. Reacting 10 with hydrazine hydrate afforded aminopyrazole derivative 11, in good
yield (cf. Scheme 3). The 1H-NMR of compound 11 revealed three singlets at δ = 5.60, 7.90 and 11.76
ppm for the exocyclic NH2, pyrazole CH and pyrazole NH protons, respectively.
Scheme 2. Syntheses of 1,2,3-triazoles.
NH2
OH
abs. EtOH
reflux 3hrs
N
N
N
NH
Ar
5a, Ar= p-Cl-C6H4
b, Ar= p- NO2-C6H4
NH2OH.HCl
AcONa
2a,b
NH2
N
N
N
N
Ar
6a, Ar= p-Cl-C6H4
b, Ar= p- NO2-C6H4
DMF
reflux 8hrs
N
N
N
NH2
N
Ar
7
Ph
N
NHPh
N
N
N
R
N
R
8
9
Scheme 3. Reactions of the enaminonitrile 10.
NH2
N
NH2NH2
DMFDMA
N
CN
CN
N
N
H
N
1
11
N(CH3)2
10
4-Cl-C6H4NH2
12
CN
CN
N
N
N
NH
C6H4-Cl
C6H4-Cl
14
13

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Compound 10 reacted with p-chloroaniline 12 to give compound 13. Structure 14 was excluded
1
based on H-NMR and 13C-NMR that revealed the absence of signals for a sp3 carbon or protons
linked to such a carbon (Scheme 3). It can thus be concluded that while compound 1 is a versatile
precursor to azolylpyridines, conversion of compound 2 to pyrazolo[4,3-b]pyridine via a route similar
to that reported for converting 8 into 9 could not be effected, at least under the conditions reported in
the published work [13].
Experimental
General
All melting points were measured on Gallenkamp electrothermal melting point apparatus and are
uncorrected. Microwave synthesis were carried out in SJO390W microwave oven. IR spectra were
1
recorded as KBr pellets on a Pye Unicam SP 3-300 spectrophotometer. H-NMR spectra were
recorded in deuterated dimethylsulfoxide (DMSO-d ) at 300 MHz on a Varian Gemini NMR
6
spectrometer using tetramethylsilane (TMS) as an internal reference and results are expressed as δ
values. Mass spectra were performed on a Shimadzu GCMS-QP 1000 Ex mass spectrometer at 70 eV.
Elemental analyses were performed by the Microanalytical Center at Cairo University. The crystal
structure was determined by the X-ray unit at the National Research Center, Dokki, Cairo.
General procedure for the synthesis of arylhydrazones 2a-c
A cold solution of aryldiazonium salt (10 mmol), prepared by adding a solution of sodium nitrite
(10 mmol in 10 mL of water) to a cold solution of arylamine hydrochloride (10 mmol of arylamine in 6
mL of HCl) with stirring, was added to a cold solution of 2-pyridylacetonitrile (1, 10 mmol) in ethanol
(50 mL) containing sodium acetate trihydrate (10 mmol). The mixture was then stirred at room
temperature for 1 h and the resulting solid product was collected by filtration, washed well with water,
dried and recrystallized from ethanol.
[(4-Chlorophenyl)hydrazono]pyridine-2-yl-acetonitrile (2a): Orange crystals (92%); mp.147-148 °C;
1
IR (cm-1): 3258 (NH), 2212 (CN), H-NMR: δ = 7.50-8.10 (m, 4H, pyr-H), 8.58 (d, 2H, J = 7.2 Hz,
Ar-H), 8.70 (d, 2H, J = 7.2 Hz, Ar-H), 15.03 (s, 1H, NH); Anal. Calcd. for C13H9ClN4 (256.69): C,
60.83; H, 3.53; N, 21.83. Found: C, 60.64; H, 3.60; N, 21.64. MS (EI): m/z (%) = 255 (M+-1).
[(4-Nitrophenyl)hydrazono]pyridine-2-yl-acetonitrile (2b): Orange crystals (90%); mp. 217-219 °C;
1
IR (cm-1): 3241 (NH), 2218 (CN); H-NMR: δ = 7.40-8.20 (m, 4H, pyr-H), 8.63 (d, 2H, J = 7.3 Hz,
Ar-H), 8.65 (d, 2H, J = 7.3 Hz, Ar-H), 15.25 (s, 1H, NH); Anal. Calcd. for C13H9N5O2 (267.24): C,
58.43; H, 3.39; N, 26.21. Found: C, 58.27; H, 3.29; N, 25.91. MS (EI): m/z (%) = 267 (M+).
[(4-Methoxyphenyl)hydrazono]pyridine-2-yl-acetonitrile (2c): Yellow crystals (81%); mp.181-182 °C;
IR (cm-1): 3250 (NH), 2216 (CN); 1H-NMR: δ = 3.70 (s, 3H, CH3), 6.90-8.07 (m, 4H, pyr-H), 8.60 (d,
2H, J = 7.0 Hz, Ar-H), 8.70 (d, 2H, J = 7.0 Hz, Ar-H), 15.03 (s, 1H, NH); 13C-NMR: δ = 156.1, 151.9,
150.0, 147.7, 139.1, 136.2, 123.2, 121.1, 119.1 (CN), 116.8, 114.8, 55.3 (OCH3); Anal. Calcd. for

Molecules 2009, 14
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C14H12N4O (252.27): C, 66.65; H, 4.79; N, 22.21. Found: C, 66.72; H, 4.82; N, 22.28. MS (EI): m/z
(%) = 252 (M+).
General procedure for the synthesis of compounds 5a,b
To a mixture of arylhydrazononitriles 2a,b (10 mmol) and hydroxylamine hydrochloride (10 mmol)
in absolute ethanol (20 mL), anhydrous sodium acetate (2g) was added and the reaction mixture was
then refluxed for 3 hrs. After cooling to room temperature, the mixture was poured into water and the
resulting precipitate collected by filtration, washed with water, dried and recrystallized from ethanol.
2-[(4-Chlorophenyl)hydrazono]-N-hydroxy-2-yl-acetamidine (5a): Yellow crystals (80%); mp.164-
1
165 °C; IR (cm-1): 3495 (OH), 3390, 3273 (NH2), 3185 (NH); H-NMR: δ = 5.60 (s, 2H, NH2), 7.20-
8.0 (m, 4H, pyr-H), 8.50 (d, 2H, J = 7.1 Hz, Ar-H), 8.70 (d, 2H, J = 7.1 Hz, Ar-H), 10.17 (s, 1H, NH),
12.8 (s, 1H, OH); Anal. Calcd. for C13H12ClN5O (289.73): C, 53.89; H, 4.17; N, 24.17. Found: C,
53.79; H, 3.99; N, 24.20. MS (EI): m/z (%) = 288 (M+-1).
2-[(4-Nitrophenyl)hydrazono]-N-hydroxy-2-yl-acetamidine
(5b):
Orange
crystals
(80%);
mp.284-285 °C; IR (cm-1): 3495 (OH), 3382, 3270 (NH2), 3179 (NH); H-NMR: δ = 5.20 (s, 2H,
NH2), 7.40-8.0 (m, 4H, pyr-H), 8.30 (d, 2H, J = 7.0 Hz, Ar-H), 8.70 (d, 2H, J = 7.0 Hz, Ar-H), 8.90 (s,
1H, NH), 15.2 (s, 1H, OH); Anal. Calcd. for C13H12O3N5 (300.27): C, 52.0; H, 4.03; N, 27.99. Found:
C, 52.10; H, 3.98; N, 28.02. MS (EI): m/z (%) = 300 (M+).
1
General procedure for the synthesis of compounds 6a,b
To a mixture of arylhydrazononitriles 2a,b (10 mmol) and hydroxylamine hydrochloride (10 mmol)
in DMF (20 mL), anhydrous sodium acetate (2 g) was added. Then, the reaction mixture was refluxed
for 8 hrs. The solvent was evaporated under vacuum and the crude product was collected by filtration,
washed with ethanol, dried and recrystallized from ethanol/dioxane.
2-(4-Chlorophenyl)-5-pyridin-2-yl-2H-[1,2,3]triazol-4-ylamine (6a): Yellow crystals (80%);
1
mp.167-169oC; IR (cm-1): 3303, 3155 (NH2); H-NMR: δ = 6.30 (s, 2H, NH2), 7.30-8.0 (m, 4H, pyr-
H), 8.02 (d, 2H, J = 7.2 Hz, Ar-H), 8.6 (d, 2H, J = 7.2 Hz, Ar-H); 13C-NMR: δ = 152.8, 150.7, 148.8,
137.9, 137.2, 132.1, 130.3, 129.4, 122.3, 119.7, 118.7; Anal. Calcd. for C13H10ClN5 (271.70): C, 57.47;
H,3.71; N, 25.78. Found: C, 57.31; H, 3.68; N, 25.89. MS (EI): m/z (%) = 271 (M+).
2-(4-Nitrophenyl)-5-pyridin-2-yl-2H-[1,2,3]triazol-4-ylamine (6b): Orange crystals (79%);
1
mp. 280 °C; IR (cm-1): 3336, 3278 (NH2); H-NMR: δ = 6.50 (s, 2H, NH2),7.30-8.11 (m, 4H, pyr-H),
8.30 (d, 2H, J = 7.3 Hz, Ar-H), 8.68 (d, 2H, J = 7.3 Hz, Ar-H); 13C-NMR: δ =157.1, 150.0, 148.4,
137.7, 135.0, 132.1, 130.0, 129.0, 124.0, 122.0, 119.0, Anal. Calcd. for C13H10N6O2 (282.26): C,
55.32; H, 3.57; N, 29.77. Found: C, 55.20; H, 3.46; N, 29.69. MS (EI): m/z (%) = 282 (M+).
Synthesis of 3-dimethylamino-2-pyridin-2-yl-acrylonitrile (10): A mixture of compound 1 (10 mmol)
and dimethylformamide dimethylacetal (DMFDMA) (10 mmol) was irradiated in a domestic

Molecules 2009, 14
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microwave oven for 1 minute at 240 W. The mixture was left standing overnight and the resulting
solid product was collected by filtration, washed with ethanol, dried and recrystallized from ethanol to
1
give compouned 10 as brown crystals (80%), mp.116-118 °C; IR (cm-1): 2221 (CN); H-NMR:
δ = 2.48 (s, 6H, 2CH3), 6.90-8.60 (m, 4H, pyr-H), 8.07 (s, H, olefinic CH); Anal. Calcd. for C10H11N3
(173.21): C, 69.34; H, 6.40; N, 24.26. Found: C, 69.41; H, 6.41; N, 24.17. MS (EI): m/z (%) = 173
(M+).
Synthesis of 4-pyridin-2-yl-2H-pyrazol-3-yl-amine (11): A mixture of compound 10 (10 mmol) and
hydrazine hydrate (80%, 10 mmol) was irradiated in a domestic microwave oven for 2 minutes. The
resulting solid product was collected by filtration, washed with ethanol, dride and recrystallized from
1
ethanol to give compound 11 as brown crystals (75%); mp. 120-121 °C; H-NMR: δ = 5.60 (s, 2H,
NH2), 6.90-8.40 (m, 4H, pyr-H), 7.90 (s, 1H, pyrazole H-5), 11.76 (s, 1H, NH); 13C-NMR: δ = 155.1,
151.1, 148.8, 136.8, 133.4, 119.0, 118.7, 103.0; Anal. Calcd. for C8H8N4 (160.20): C, 59.99; H, 5.03;
N, 34.98. Found: C, 60.01; H, 4.98; N, 34.87. MS (EI): m/z (%) = 160 (M+).
Synthesis of 3-(4-chlorophenylamino)-2-pyridin-2-ylacrylonitrile (13): To a mixture of p-chloroaniline
12 (10 mmol) and compound 10 (10 mmol), a drop of AcOH was added, then the mixture was
irradiated in a domestic microwave oven for 2 minutes at 280 W. The resulting solid product was
collected by filtration, washed with ethanol, dried and recrystallized from ethanol to give compound
1
13 as colourless crystals (86%); mp. 179-180 °C; IR (cm-1): 3387 (NH), 2202 (CN); H-NMR:
δ = 7.1-8.2 (m, 4H, pyr-H), 8.40 (d, 2H, J = 7.2 Hz, Ar-H), 8.50 (s, H, olefinic CH), 8.60 (d, 2H, J =
7.2 Hz, Ar-H), 12.60 (brs, 1H, NH); 13C-NMR: δ = 156.0, 150.0, 149.0, 144.0, 137.0, 130.0, 123.0,
122.0, 121.0, 119.0 (CN), 116.0, 103.0; Anal. Calcd. for C14H10ClN3 (255.7): C, 65.76; H, 3.94;
N,16.43. Found: C, 65.59; H, 3.99; N, 16.52. MS (EI): m/z (%) = 254 (M+-1).
Conclusions
In conclusion, a new simple approach to 2,5-disubstituted-1,2,3-triazole-5-amines from 2-aryl-
hydrazononitriles has been achieved.
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© 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
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Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).