Studies with β-oxoalkanonitriles: Simple novel synthesis of 3-[2,6-diaryl-4- pyridyl]-3-oxopropanenitriles

Article abstract of DOI:10.3390/molecules13123140

Heteroaromatization of ethyl 2-cyano-4-oxo-2-(2-oxo-2-arylethyl)-4- arylbutanoates 3a,b with ammonium acetate gave ethyl 2,6-diarylisonicotinates 4a,b. Treatment of the latter with acetonitrile afforded novel β-oxoalkanonitriles 6a,b. Reactions of 6a,b wi

Full text of DOI:10.3390/molecules13123140

Molecules 2008, 13, 3140-3148; DOI: 10.3390/molecules13123140
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Studies with β-Oxoalkanonitriles: Simple Novel Synthesis of
3-[2,6-Diaryl-4- pyridyl]-3-oxopropanenitriles
Sayed M. Riyadh 1,2, Hamad M. Al-Matar 2,* and Mohamed H. Elnagdi 2
1
Department of Chemistry, Faculty of Science, Cairo University, Giza-12613- Egypt. E-mail:
riyadh1993@hotmail.com (S-M. R.)
2
Department of Chemistry, Faculty of Science, Kuwait University, Safat 13060 Kuwait, P.O. Box
5969. E-mail: shelmy1941@yahoo.com (M-H. E.)
* Author to whom correspondence should be addressed; E-mail: almatarc60@hotmail.com.
Received: 5 September 2008; in revised form; 27 September 2008 / Accepted: 5 November 2008 /
Published: 15 December 2008
Abstract: Heteroaromatization of ethyl 2-cyano-4-oxo-2-(2-oxo-2-arylethyl)-4-aryl-
butanoates 3a,b with ammonium acetate gave ethyl 2,6-diarylisonicotinates 4a,b.
Treatment of the latter with acetonitrile afforded novel β-oxoalkanonitriles 6a,b. Reactions
of 6a,b with phenyl hydrazine and hydroxylamine gave the corresponding pyridyl
aminopyrazoles 8a,b and pyridyl aminoisoxazoles 10a,b, respectively.
Keywords: β-Oxoalkanonitriles; 3-Pyrazolylamine; 3-Isoxazolylamine; Phenacyl
bromide; Ethyl cyanoacetate.
Introduction
β-Oxoalkanonitriles are versatile reagents and their chemistry has received in the past [1] and
continues to receive considerable attention [2-9]. In conjunction with our interest in utilizing
oxoalkanonitriles to prepare azolylazines [10-13] a route to 3-(4-pyridyl)-3-oxopropanenitrile was
needed. 4-Pyridyl derivatives possess many pharmacological activities [14], and they can also be used
as N-donor ligands in complexation with metal ions with superior cytotoxicity towards bacteria [15].

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Results and Discussion
β-Oxoalkanonitriles are generally prepared via: i) acylation of active nitriles in the presence of
suitable basic catalysts [16-18]; ii) reacting α-haloketones with cyanide ion [19], and iii) hydrolysis of
β-enaminonitriles [7]. We decided to develop our synthesis via reaction of acetonitrile with ethyl 2,6-
diarylisonicotinate. Although the parent ethyl 2,6-diphenylisonicotinate (3a) is a known compound,
[20] the 2,6-diarylsubsubstituted derivatives have not, to our knowledge, been previously reported.
Consequently, a method for their synthesis was developed. Reaction of phenacyl bromide (1a) with
ethyl cyanoacetate (2) afforded the dialkylated derivative 3a [21]. Similarly, 3b was obtained by
reacting 1b with ethyl cyanoacetate. Refluxing 3a,b in acetic acid in the presence of ammonium
acetate afforded the target pyridines 4a,b (Scheme 1).
Scheme 1. Synthetic pathway for preparation of compounds 4a,b.
EtO2C
CN
O
O
O
CN
2
+
Br
R
R
R
COOEt
3a,b
1a,b
2
COOEt
NH4OAc
AcOH
1a, 3a, 4a; R = Ph,
1b, 3b, 4b; R = 2-thienyl
R
N
R
4a,b
Attempts to condense acetonitrile in an aqueous protic solvent with pyridines 4a,b under different
conditions afforded only the carboxylic acid derivatives 5a,b [22]. However, the target β-oxo-
alkanonitriles 6a,b were obtained by reacting 4a,b with acetonitrile in dry benzene in the presence of
sodium hydride (Scheme 2).
Scheme 2. Synthetic pathway for preparation of compounds 5a,b and 6a,b.
COOEt
COCH2CN
COOH
CH3CN / NaH
Or KOH /EtOH
CH3CN / NaH
benzene
R
N
4a,b
R
R
N
R
R
N
R
6a,b
5a,b
4a-6a; R = Ph,
4b-6b; R = 2-thienyl
As would be expected, β-oxoalkanonitriles 6a,b reacted with phenyl hydrazine hydrochloride to
yield the corresponding 5-aminopyrazoles 7a,b or 3-aminopyrazoles 8a,b. Despite literature reports

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[23,24], the δ value for the pyrazole ring H-4 for both isomers vary over the range between 5.3-6.1
ppm. To substantiate the regioselectivity of the reaction products, NOE difference experiments were
performed, which showed that irradiation of the amino protons at δ 4.45 ppm did not enhance the aryl
protons at δ 7.5 ppm and vice versa, irradiation of the o-aryl protons at δ 7.5 ppm did not enhance the
amino protons. These results allowed us to conclude that the amino and aryl protons are not proximal
(Scheme 3); that is, the compounds have the structures 8a,b. Moreover, the reaction of β-oxoalkano-
nitriles 6a,b with hydroxylamine hydrochloride in the presence of sodium acetate could yield 5-
1
aminoisoxazoles 9a,b or the isomeric 3-aminoisoxazole structures 10a,b. H-NMR revealed a singlet
signal at δ = 7.00 ppm correlated to the isoxazole ring H-4. It was reported that the H-4 of 3-amino-
isoxazole appears at lower field (δ ~ 6.1 ppm) than that of 5-aminoisoxazole (δ ~ 5.5 ppm) [25, 26].
15
Moreover, N, 1H-heteronuclear multiple bond correlation (HMBC) of the product indicated that
amino proton at δ 5.85 ppm has a cross peak at δ 350 ppm (3J coupling). These results indicated that
structures 10a,b are the most probable for the reaction products (cf. Scheme 3). The reaction of 2-
substituted-3-oxoalkanonitriles with hydroxylamine hydrochloride in presence of sodium acetate has
been reported by Elnagdi et al. [27] to yield amidoximes that cyclised into 3-aminoisoxazoles. On the
other hand formation of 5-aminoisoxazoles from the reaction of isonicotinylacetonitriles with
hydroxylamine hydrochloride was reported in the patent literature [28, 29], although there is no
mention of added base in those cases.
Scheme 3. Reactions of β-oxoalkanonitriles 6a,b with nitrogen nucleophiles.
Ph
NH2
NH2
N
O
N
N
COCH2CN
R
N
R
R
N
R
PhNHNH2.HCl
NaOAc
NH2OH.HCl
NaOAc
7a,b
9a,b
NH2
R
N
R
NH2
N
N
6a,b
Ph
N
O
6a-10a; R = Ph,
6b-10b; R = 2-thienyl
R
R
N
R
N
R
8a,b
10a,b

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Conclusions
A novel route for the synthesis of β-oxoalkanonitriles has been developed. The products from this
synthesis were further reacted with nitrogen nucleophiles to give azoles. The features of the present
method include the ready availability of the starting materials, mild reaction conditions, and the
simplicity of the workup.
Experimental
General
Melting points were recorded on a Gallenkamp apparatus and are uncorrected. Infrared spectra
1
(KBr) were determined on a Perkin-Elmer 2000 FT-IR system. H-NMR spectra were recorded on a
Bruker DPX 600 MHz superconducting spectrometer using DMSO-d6 as solvent and TMS as internal
standard. Mass spectra were measured on MS 30 and MS 9 (AEI) spectrometers, operating at EI 70 ev.
Elemental analyses were measured by means of LECO CHNS-932 Elemental Analyzer.
Synthesis of ethyl 2-cyano-4-oxo-2-(2-oxo-2-arylethyl)-4-arylbutanoates 3a,b
To a stirred solution of α-haloketone (20 mmol) in ethanol (50 mL) containing ethyl cyanoacetate
(10 mmol) was added potassium hydroxide solution (10 mmol, 0.56 g, dissolved in 20 mL H2O). The
mixture was stirred for 30 minutes and acidified. The solid precipitate was collected by filtration and
recrystallized from hexane/EtOAc (3:1).
Ethyl 2-cyano-4-oxo-2-(2-oxo-2-phenylethyl)-4-phenylbutanoate (3a): Yield: 2.79 g (80%); mp 140
oC (lit. [21] mp 141 oC); IR υ = 2250, (CN), 1722 (CO, ester), 1689 (CO, benzoyl) cm-1; 1H-NMR δ =
1.22 (t, 3H, CH3), 3.95 (d, 2H, CH2), 4.03 (d, 2H, CH2), 4.19 (q, 2H, CH2), 7.56-8.01 (m, 10H, Ar-H)
ppm; MS, m/z (%) 349 (M+, 20), 276 (30), 244 (50), 105 (100), 77 (80); Anal. Calcd. for C21H19NO4:
C, 72.19; H, 5.48; N, 4.01. Found: C, 72.44; H, 5.24; N, 4.05.
Ethyl 2-cyano-4-oxo-2-[(2-oxo-2-(2-thienyl)ethyl]-4-(2-thienyl)butanoate (3b): Yield: 2.7 g (75%); mp
o
1
102 C; IR υ = 2251, (CN), 1730 (CO, ester), 1668 (CO, thienoyl) cm-1; H-NMR δ = 1.21 (t, 3H,
CH3), 3.84 (d, 2H, CH2), 3.96 (d, 2H, CH2), 4.17 (q, 2H, CH2), 7.28-8.10 (m, 6H, Ar-H) ppm; MS, m/z
(%) 361 (M+, 55), 288 (70), 250 (60), 126 (80), 111 (100), 83 (30); Anal. Calcd. for C17H15NO4S2: C,
56.49; H, 4.18; N, 3.88; S, 17.74. Found: C, 56.40; H, 4.11; N, 3.95; S, 18.01.
Synthesis of ethyl 2,6-diarylisonicotinates 4a,b
A mixture of ethyl 2-cyano-4-oxo-2-(2-oxo-2-arylethyl)-4-arylbutanoate (10 mmol) and ammonium
acetate (15 mmol) in glacial acetic acid (20 mL) was refluxed for 8 hours and poured into water. The
solid precipitate was collected by filtration and purified by long column chromatography [eluent:
hexane/EtOAc (3:1)].

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Ethyl 2,6-diphenylisonicotinate (4a): Yield: 1.82 g (60%); mp 98 oC (lit. [20] mp 99 oC); IR υ = 1716
1
(CO, ester), 1561 (C=N), 1250 (C-O) cm-1; H-NMR δ = 1.39 (t, 3H, CH3), 4.44 (q, 2H, CH2), 7.52-
8.27 (m, 12H, Ar-H) ppm; MS, m/z (%) 303 (M+, 90), 231 (100), 127 (50), 77 (20); Anal. Calcd. for
C20H17NO2: C, 79.19; H, 5.65; N, 4.62. Found: C, 78.96; H, 5.90; N, 4.66.
o
Ethyl 2,6-di(2-thienyl)isonicotinate (4b): Yield: 1.89 g (60%); mp 113 C; IR υ = 1714 (CO, ester),
1
1565 (C=N), 1250 (C-O) cm-1; H-NMR δ = 1.39 (t, 3H, CH3), 4.42 (q, 2H, CH2), 7.20-8.10 (m, 8H,
Ar-H) ppm; MS, m/z (%) 315 (M+, 100), 243 (20), 133 (25), 89 (15); Anal. Calcd. for C16H13NO2S2: C,
60.93; H, 4.15; N, 4.44; S, 20.33. Found: C, 60.63; H, 4.45; N, 4.74; S, 20.58.
Synthesis of 2,6-diarylisonicotinic acids 5a,b
A solution of ethyl 2,6-diarylisonicotinate (10 mmol) in ethanol (20 mL) was treated with
potassium hydroxide solution (15 mmol in 10 mL water) and refluxed for 4 hours. The reaction
mixture was poured into ice/HCl. The solid precipitate was collected by filtration and recrystallized
from ethanol.
o
o
2,6-Diphenylisonicotinic acid (5a): Yield: 1.92 g (70%); mp 265 C (lit. [22] mp 263 C); IR υ =
3500-2600 (br, OH acid), 1698 (CO, acid), 1555 (C=N), 1279 (C-O) cm-1; 1H-NMR δ = 7.49-8.26 (m,
12H, Ar-H), 13.98 (COOH) ppm; MS, m/z (%) 275 (M+, 100), 231 (40), 127 (10), 77 (10); Anal.
Calcd. for C18H13NO2: C, 78.53; H, 4.76; N, 5.09. Found: C, 78.38; H, 4.68; N, 5.01.
o
2,6-Di(2-thienyl)isonicotinic acid (5b): Yield: 1.72 g (60%); mp 251 C; IR υ = 3500-2500 (br, OH
1
acid), 1700 (CO, acid), 1561 (C=N), 1271 (C-O) cm-1; H-NMR δ = 7.31-8.21 (m, 8H, Ar-H), 13.86
(COOH) ppm; MS, m/z (%) 287 (M+, 100), 242 (40), 83 (10); Anal. Calcd. for C14H9NO2S2: C, 58.52;
H, 3.16; N, 4.87; S, 22.32. Found: C, 58.33; H, 3.11; N, 4.64; S, 22.51.
Synthesis of β-oxoalkanonitriles 6a,b
A mixture of ethyl 2,6-diarylisonicotinate (1 mmol), dry acetonitrile (2 mmol), and sodium hydride
(20 mmol) in dry benzene (20 mL) was refluxed for 4 hours and poured into water, extracted by ethyl
acetate. The solvent was evaporated under vacuum and the residue was purified by long column
chromatography [eluent: hexane/EtOAc (3:1)].
o
3-(2,6-Diphenyl-4-pyridyl)-3-oxopropanenitrile (6a): Yield: 0.149 g (50%); mp 180 C; IR υ = 2217
1
(CN), 1710 (CO), 1594 (C=N) cm-1; H-NMR δ = 4.98 (s, 2H, CH2), 7.36-8.30 (m, 12H, Ar-H) ppm;
MS, m/z (%) 298 (M+, 100), 270 (15), 127 (65), 77 (70); Anal. Calcd. for C20H14N2O: C, 80.52; H,
4.73; N, 9.39. Found: C, 80.38; H, 4.61; N, 9.08.
3-[2,6-Di(2-thienyl)-4-pyridyl]-3-oxopropanenitrile (6b): This compound was obtained in 0.155 g
1
(50%), mp 192 oC; IR (KBr) υ = 2214 (CN), 1703 (CO), 1592 (C=N) cm-1; H NMR (DMSO-d6) δ =
4.41 (s, 2H, CH2), 7.02-8.10 (m, 8H, Ar-H) ppm; MS, m/z (%) 310 (M+, 100), 282 (35), 139 (20), 83

Molecules 2008, 13
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(15). Anal. Calcd. for C16H10N2OS2: C, 61.91; H, 3.25; N, 9.03; S, 20.66. Found: C, 61.86; H, 3.14; N,
9.11; S, 20.51.
Reactions of β-oxoalkanonitriles with nitrogen nucleophiles
A mixture of β-oxoalkanonitriles (1 mmol) in dioxane (20 mL) in presence of anhydrous sodium
acetate (2 mmol) and hydroxylamine hydrochloride or phenylhydrazine hydrochloride (1 mmol) was
refluxed for 4 hours. After pouring into water, the solid precipitate was collected by filtration and
recrystallized from hexane/ethyl acetate mixture (3:1).
o
5-(2,6-Diphenyl-4-pyridyl)-1-phenyl-1H-3-pyrazolylamine (8a): Yield: 0.194 g (50%); mp 210 C; IR
1
υ = 3424, 3280 (NH2), 1602 (C=N) cm-1; H-NMR δ = 4.45 (s, 2H, NH2), 6.93 (s, 1H, pyrazole-H),
13
7.34-8.30 (m, 17H, Ar-H) ppm; C-NMR δ = 97.3, 117.8, 118.1, 126.3, 127.1, 127.9, 128.3, 129.1,
130.2, 138.6, 139.3, 144.3, 153.7, 161.5 (Ar-Cs); MS, m/z (%) 388 (M+, 100), 284 (5), 230 (10), 77
(15); Anal. Calcd. for C26H20N4: C, 80.39; H, 5.19; N, 14.42. Found: C, 80.17; H, 5.49; N, 14.51.
o
5-[2,6-Di(2-thienyl)-4-pyridyl)-1-phenyl-1H-3-pyrazolylamine (8b): Yield: 0.20 g (50%); mp 235 C;
IR υ = 3410, 3271 (NH2), 1601 (C=N) cm-1; 1H-NMR δ = 4.43 (s, 2H, NH2), 6.93 (s, 1H, pyrazole-H),
13
7.20-8.30 (m, 13H, Ar-H) ppm; C-NMR δ = 96.8, 117.1, 118.4, 125.7, 126.3, 126.9, 127.1, 128.3,
129.4, 130.2, 134.1, 144.5, 152.7, 161.1 (Ar-Cs); MS, m/z (%) 400 (M+, 40), 296 (100), 241 (40), 77
(15); Anal. Calcd. for C22H16N4S2: C, 65.97; H, 4.03; N, 13.99; S, 16.01. Found: C, 66.13; H, 4.15; N,
13.81; S, 15.91.
o
5-(2,6-Diphenyl-4-pyridyl)-3-isoxazolylamine (10a): Yield: 0.188 g (60%); mp 179 C; IR υ = 3349,
1
3297 (NH2), 1640 (C=N) cm-1; H-NMR δ = 5.85 (s, 2H, NH2), 7.00 (s, 1H, isoxazole-H), 7.48-8.29
(m, 12H, Ar-H) ppm; 13C-NMR δ = 98.3, 124.2, 126.1, 127.3, 128.4, 136.5, 142.6, 148.3, 162.8, 167.2
(Ar-Cs); MS, m/z (%) 314 (M++1, 35), 313 (M+, 30), 275 (100), 127 (25), 77 (15); Anal. Calcd. for
C20H15N3O: C, 76.66; H, 4.82; N, 13.41. Found: C, 76.82; H, 5.05; N, 13.68.
o
5-[2,6-Di(2-thienyl)-4-pyridyl]-3-isoxazolylamine (10b): Yield: 0.195 g (60%); mp 192 C; IR υ =
3342, 3291 (NH2), 1645 (C=N) cm-1; 1H-NMR δ = 5.85 (s, 2H, NH2), 7.21 (s, 1H, isoxazole-H), 7.22-
13
8.10 (m, 8H, Ar-H) ppm; C-NMR δ = 98.8, 125.4, 126.8, 127.5, 128.4, 138.5, 142.2, 149.1, 163.8,
168.1 (Ar-Cs); MS, m/z (%) 325 (M+, 100), 287 (35), 133 (25), 83 (15); Anal. Calcd. for C16H11N3OS2:
C, 59.06; H, 3.41; N, 12.91; S, 19.71. Found: C, 59.13; H, 3.34; N, 12.81; S, 19.51.
Acknowledgements
Support for this work was received from the University of Kuwait through Research Grant SC04/06
and the use of the facilities of Analab/SAF through research grants GC01/01 and GS03/01 is gratefully
acknowledged. The authors also express their gratitude and appreciation to the referees of this
manuscript for their guidance and advice.

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Sample Availability: Not avaliable.

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