An expeditious and green synthesis of new enaminones and study their chemical reactivity toward some different amines and binucleophiles under environmentally friendly conditions

Khadijah M. Al-Zaydi; Ramadan A. Mekheimer; Sameera M. Mousally; Rita M. Borik; Mohamed H. Elnagdi

doi:10.1016/j.arabjc.2013.10.013

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Original article

10 (

2_suppl

); S2697-S2704

doi:

10.1016/j.arabjc.2013.10.013

An expeditious and green synthesis of new enaminones and study their chemical reactivity toward some different amines and binucleophiles under environmentally friendly conditions

Khadijah M. Al-Zaydi^{^a}, Ramadan A. Mekheimer^{^a,^b,⁎}, Sameera M. Mousally^{^a}, Rita M. Borik^{^a}, Mohamed H. Elnagdi^{^c}

a Department of Chemistry, Faculty of Science for Girls, King Abdulaziz University, Jeddah, P.O. Box 50918, Jeddah 21533, Saudi Arabia

b Department of Chemistry, Faculty of Science, El-Minia University, El-Minia 61519, Egypt

c Department of Chemistry, Faculty of Science, Kuwait University, P.O. Box 5969, Safat 13060, Kuwait

⁎Corresponding author at: Department of Chemistry, Faculty of Science, El-Minia University, El-Minia 61519, Egypt. Tel.: +966 568973615. rmekh@yahoo.com (Ramadan A. Mekheimer)

Received: 2012-11-8, Accepted: 2013-10-20, Published: 2013-05-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

The condensation reaction of 3-heteroaromatic-3-oxopropanenitriles 3, 4 and 7 with dimethylformamide–dimethylacetal (DMF–DMA) gave the corresponding enaminones 8, 9 and 10, respectively. Nucleophilic substitution of 8 and 9 with different amines resulted in a new derivatives of enaminones 11–18. The reactivity of enaminones 8 and 9 toward some nitrogen nucleophiles was investigated with a view to synthesize new heterocyclic systems. Thus, treatment of compounds 8 and 9 with phenylhydrazine afforded the pyrazole derivatives 19 and 20, respectively. On the other hand, reacting 8 and 9 with guanidine gave the pyrimidines 21 and 22, respectively. Treatment of compound 9 with hydroxylamine hydrochloride afforded the aminoisoxazoles 23. The foregoing reactions were carried out with conventional heating and under green conditions [ultrasound (US) irradiations or ionic liquids (ILs)] and a comparative study was employed. All the new structures are fully characterized.

Keywords

Green synthesis

Enaminones

Ultrasound irradiations

Ionic liquids

Nucleophilic substitution

Binucleophiles

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1 Introduction

Various indole derivatives have been reported to possess antiinflammatory (Misra et al., 1996; Andreani et al., 1994), anticonvulsant (El-Gendy Adel et al., 1993), cardiovascular (Kumar et al., 1986) and antibacterial activities (Dandia et al., 1993). In addition, the indole nucleus, is an important target in organic synthesis, as this structure is found in a large variety of biologically active synthetic and natural products (Saracoglu, 2007; Suzen, 2007). Furthermore, some of indole derivatives, possessing a heterocyclic moiety at 3-position, have been synthesized and reported to have promising anti-inflammatory and antitumor activities (Verma et al., 1994; Farghaly, 2010). Moreover, meridianins (indole derivatives substituted in the C-3 position by a 2-aminopyrimidine ring) were successfully evaluated for their ability to inhibit various protein kinases and to display antitumor activity (Radwan and El-Sherbiny, 2007; Akue-Gedu et al., 2009). Also, it is observed from the literature that the pyrrole nucleus plays a vital role in many biological activities (El-Gaby et al., 2002; Almerico et al., 1998; Obniska et al., 1998; Reed et al., 1999 ). Encouraged by the above observations, we undertook the synthesis of some new 3-substituted indoles and 2-substituted pyrrole incorporating an extra heterocyclic ring: pyrazole; pyrimidine and isoxazole with the expectation that they would be of potential biological interest because of their resemblance to the above mentioned substances. Previously, we have reported several efficient routes to polyfunctionally substituted heterocycles utilizing enaminones as starting materials (Al-Zaydi et al., 2000a,b, 2007a,b, 2010; Agamy et al., 2001; Alnajjar et al., 2009 ). In continuation to this work and our efforts to develop efficient environmentally benign protocols for the synthesis of various heterocycles of biological interest (Al-Zaydi et al., 2004, 2007a,b, 2010; Mekheimer et al., 2008a,b ), we report in this article the first synthesis of the enaminones 8–10, which are considered to be very important intermediates for the synthesis of various new heterocycles of expected potential biological activity, under environmentally friendly conditions and study their chemical reactivity toward some different amines and binucleophiles under the effect of both ultrasonic (US) irradiations and in ionic liquids (ILs) as well as in the classical conditions.

2 Experimental

2.1

2.1 Measurements

Melting points were measured on a Gallenkamp electrothermal melting point apparatus and are uncorrected. The completion of the reaction was checked by thin-layer chromatography (TLC) on Merck silica gel 60 plates, 0.25 mm thick with F-254 indicator. Visualization was accomplished by UV light. ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) were recorded in deuterated dimethylsulfoxide [DMSO-d₆] on a Bruker DPX spectrometer using tetramethyl-silane (TMS) as an internal reference; chemical shifts (δ) are reported in ppm. IR spectra were recorded with a Nicolet Magna 520FT IR spectrophotometer in KBr disks. Mass spectra were measured on a Shimadzu GCMS-QP 1000 EX mass spectrometer at 70 eV. Ultrasonic irradiation was carried out using a sonics and materials device, 750 W ultrasonic processor VCX 750, solid probe with non-replaceable tip, with processing capability: 10–250 ml, length: 53/8^″ (136 mm), weight: 3/4 lb (340 g), titanium alloy Ti–6Al–4V, with integrated temperature control, allows sample temperature to be monitored up to 100 °C. The shape and the size of reactor dimensions (H × W × D) are 91/4^″ × 71/2^″ × 131/2^″ and 235 × 190 × 340 mm , weight: 15 lb (6.8 kg) with sealed converter piezoelectric lead zirconate titanate crystals (PZT) of diameter: 21/2^″ (63.5 mm), length: 71/4^″ (183 mm), weight: 2 lb (900 g) and all reactions undergo at 300 W power (40%). Microanalyses were performed by the microanalytical data unit at Cairo University, and analytical values obtained were within ±0.4% of the calculated values. All reagents were of commercial quality or were purified before use and the organic solvents were of analytical grade or purified by standard procedures. X-ray crystallography was carried out on a Kappa CCD Enraf Nonius FR 590 diffractometer, National Research Center, Dokki, Cairo, Egypt.

2.2

2.2 General procedure for the synthesis of 3-heteroaromatic substituted-3-oxopropane nitriles 3, 4 and 7

Method I (US): to a solution of cyanoacetic acid (0.1 mol) in acetic anhydride (50 mL), compound 1 or 2 or 5 (0.1 mol) was added. The reaction mixture was exposed to US irradiation at 70 °C for 20–60 min and then left to cool to room temperature. The solid product so-formed was filtered off, dried and recrystallized from ethanol.

Method II (Δ) for compound 7: a solution of cyanoacetic acid (0.1 mol) in acetic anhydride (20 mL) was added to a well mixed powder of compound 6 (0.1 mol) and anhyd. AlCl₃ (0.15 mol) dropwise. Then, the reaction mixture was refluxed under stirring for 2.5 h. After cooling to room temperature, it was poured into cold water. The resulting solid product was collected by filtration, washed well with H₂O, dried and recrystallized from dioxane.

2.2.1

2.2.1 3-Oxo-3-(1H-pyrrol-2-yl)-propionitrile 3

Brown crystals, mp: 80–81 °C [Lit. (Walker, 1987) mp: 79–81 °C].

2.2.2

2.2.2 3-(1H-Indol-3-yl)-3-oxo-propionitrile 4

Yellowish crystals, mp: 239–240 °C [Lit. (Kreher and Wagner, 1980) mp: 240 °C].

2.2.3

2.2.3 N-(1-(2-Cyanoacetyl)-4-oxo-4H-thieno[3,4-c]chromen-3-yl)acetamide 7

Buff crystals; mp: 220–221 °C; IR (ν_max, cm⁻¹): 3250 (NH), 3091 (Ar, CH), 2229 (CN), 1685 (C⚌O), 1640 (amide CO). ¹H NMR (400 MHz, DMSO-d₆), δ_H 2.33 (3H, s, CH₃), 3.97 (2H, s, CH₂CN), 7.30 (2H, m, Ar-H), 7.43 (1H, d, J = 7.2 Hz, Ar-H), 7.99 (1H, d, J = 7.2 Hz, Ar-H), 10.81 (1H, br s, NH). MS, m/z = 326 (M⁺, 3). Anal. Calcd. for C₁₆H₁₀N₂O₄S (326.33): C, 58.89; H, 3.09; N, 8.58; S, 9.83%, Found: C, 58.74; H, 3.16; N, 8.69; S, 9.94%.

2.3

2.3 General procedure for the synthesis of enaminones 8–10

Method I (Δ): to a solution of compound 3 or 4 or 7 (0.1 mol) in dry toluene (20 mL), DMF-DMA (0.1 mol) was added. The reaction mixture was heated at reflux for 8 h. The precipitated solid product was collected by filtration and dried.

Method II (US): to a solution of compound 3 or 4 or 7 (0.1 mol) in dry toluene (50 mL), DMF-DMA (0.1 mol) was added. The reaction mixture was exposed to ultrasound irradiation at 70 °C for 2.5 h and then left to cool to room temperature. The solid product so-formed was filtered off, dried and recrystallized from ethanol.

2.3.1

2.3.1 3-Dimethylamino-2-(1H-pyrrole-2-carbonyl)acrylonitrile 8

Buff crystals, mp: 200–201 °C; IR (ν_max, cm⁻¹): 3261 (NH), 2200 (CN), 1648 (C⚌O). ¹H NMR (400 MHz, DMSO-d₆), δ_H 3.27 (3H, s, NCH₃), 3.35 (3H, s, NCH₃), 6.16 (1H, m, pyrrole H-4), 7.0 (1H, m, pyrrole H-3), 7.19 (1H, m, pyrrole H-5), 8.0 (1H, s, olefinic CH), 11.63 (1H, br s, NH). ¹³C NMR (100 MHz, DMSO-d₆), δ_c 40.4 (NMe₂), 76.3 (C–CN), 109.9 (pyrrole C-4), 115.6 (CN), 121.7 (pyrrole C-3), 124.3 (pyrrole C-5), 130.7 (pyrrole C-2), 159.3 (C-NMe₂), 176.5 (C⚌O). MS, m/z = 189 (M⁺, 57). Anal. Calcd. for C₁₀H₁₁N₃O (189.21): C, 63.48; H, 5.86; N, 22.21%, Found: C, 63.65; H, 5.95; N, 22.16%.

2.3.2

2.3.2 3-Dimethylamino-2-(1H-indole-3-carbonyl)acrylonitrile 9

Yellowish crystals, mp: 185–186 °C [Lit. (Slätt et al., 2005) mp: 187–188 °C].

2.3.3

2.3.3 N-(1-(2-Cyano-3-(dimethylamino)acryloyl)-4-oxo-4H-thieno[3,4-c]chromen-3-yl)-acetamide 10

Buff crystals, mp: 236–238 °C; IR (ν_max, cm⁻¹): 3300 (NH), 3090 (Ar, CH), 2220 (CN) 1680 (C⚌O), 1644 (amide CO). ¹H NMR (400 MHz, DMSO-d₆), δ_H 2.34 (3H, s, CH₃), 3.31 (6H, br s, NMe₂), 7.33 (2H, m, Ar-H), 7.43 (1H, d, J = 7.5 Hz, Ar-H), 7.70 (1H, s, olefinic CH), 8.04 (1H, d, J = 7.5 Hz, Ar-H), 10.20 (1H, br s, NH). MS, m/z = 381 (M⁺, 22). Anal. Calcd. for C₁₉H₁₅N₃O₄S (381.41): C, 59.83; H, 3.96; N,11.02; S, 8.41%, Found: C, 59.90; H, 3.79; N, 11.12; S, 8.23%.

2.4

2.4 General procedure for the synthesis of 3-(phenylamino)-2-(1H-pyrrole-2-carbonyl)- acrylonitrile 11, 2-(1H-Indole-3-carbonyl)-3-(phenylamino)acrylonitrile 13 and 3-(benzo-[d]thiazol-2-ylamino)-2-(1H-pyrrole-2-carbonyl)acrylonitrile 14

Method I (Δ): to a solution of 8 or 9 (0.1 mol) in ethanol (20 mL), aniline (0.1 mol) was added. The reaction mixture was heated to reflux for 4 h and was allowed to cool to room temperature. Then, the resulting solid product was collected by filtration and dried to give compounds 11 and 13, respectively. Similarly, a solution of 8 (0.1 mol) in ethanol (20 mL) was reacted with 2-aminobenzothiazole (0.1 mol), under the same reaction conditions, to give compound 14.

Method II (US): to a solution of 8 or 9 (0.1 mol) in ethanol (50 mL), aniline was added. The reaction mixture was exposed to ultrasound irradiation at 70 °C for 2 h and then left to cool to room temperature. The solid product so-formed was filtered off and dried to give compounds 11 and 13, respectively. Similarly, a solution of 8 (0.1 mol) and 2-aminobenzothiazole (0.1 mol) in ethanol (50 mL) was exposed to ultrasound irradiation at 70 °C for 2 h to give compound 14.

Method III (IL): a mixture of pyridinium chloride ([PyH]Cl) (0.4 mol), compound 8 or 9 (0.1 mol) and aniline was heated at 110 °C for 20 min. After cooling to room temperature, the reaction mixture was treated with ethanol. The resulting solid product was collected by filtration, dried and recrystallized from ethanol to give compounds 11 and 13, respectively. In the case of 14, a mixture of pyridinium chloride ([PyH]Cl) (0.4 mol), compound 8 (0.1 mol) and 2-aminobenzothiazole (0.1 mol) was heated at 110 °C for 20 min. and then the reaction mixture was worked up as described above.

2.4.1

2.4.1 3-(Phenylamino)-2-(1H-pyrrole-2-carbonyl)acrylonitrile 11

Yellow crystals, mp: 180–181 °C; IR (ν_max, cm⁻¹): 3257 (NH), 2198 (CN), 1669 (C⚌O).

¹H NMR (400 MHz, DMSO-d₆), δ_H 6.25 (2H, m, pyrrole H-3, H-4), 7.38–7.45 (5H, m, Ph-H), 7.60 (1H, d, J = 2.4 Hz, pyrrole H-5), 8.48 (1H, d, J = 8.4 Hz, olefinic CH), 11.85 (1H, s, pyrrole NH), 12.58 (1H, d, J = 7.0 Hz, NH-Ph). ¹³C NMR (100 MHz, DMSO-d₆), δ_c 82.7 (C–CN), 110.7 (pyrrole C-4), 115.7 (CN), 118.4 (2C, Ar-C), 126.0 (Ar-C), 126.3 (pyrrole C-3), 130.1 (pyrrole C-5), 130.4 (2C, Ar-C), 130.7 (pyrrole C-2), 140.5 (NH-Ph), 153.7 (⚌C—NH), 178.8 (C⚌O). MS, m/z = 237 (M⁺, 80). Anal. Calcd. for C₁₄H₁₁N₃O (237.26): C, 70.87; H, 4.67; N, 17.71%, Found: C, 70.99; H, 4.59; N, 17.90%.

2.4.2

2.4.2 2-(1H-Indole-3-carbonyl)-3-(phenylamino)acrylonitrile 13

Buff crystals, mp: 174–176 °C; IR (ν_max, cm⁻¹): 3253 (NH), 3046 (Ar, CH), 2200 (CN), 1667 (C⚌O). ¹H NMR (400 MHz, DMSO-d₆), δ_H 6.98–7.59 (8H, m, Ar-H), 8.22 (1H, d, J = 7.8 Hz, olefinic CH), 8.35 (1H, d, J = 7.8 Hz, indole H-4), 8.57 (1H, s, indole H-2), 12.10 (1H, s, indole NH), 12.70 (1H, br, NH-Ph). MS, m/z = 287 (M⁺, 49). Anal. Calcd. for C₁₈H₁₃N₃O (287.32): C, 75.25; H, 4.56; N, 14.63%, Found: C, 75.13; H, 4.62; N, 14.79%.

2.4.3

2.4.3 3-(benzo[d]thiazol-2-ylamino)-2-(1H-pyrrole-2-carbonyl)acrylonitrile 14

Brown crystals, mp: 180–181 °C; IR (ν_max, cm⁻¹): 3258 (NH), 2198 (CN), 1670 (C⚌O). ¹H NMR (400 MHz, DMSO-d₆), δ_H 6.27 (1H, t, J = 2.4 Hz, pyrrole H-4), 7.36 (2H, m, Ar-H), 7.49 (1H, d, J = 2.3 Hz, pyrrole H-3), 7.66 (1H, d, J = 2.6 Hz, pyrrole H-5), 8.0 (1H, s, olefinic CH), 8.15 (1H, d, J = 7.6 Hz, Ar-H), 8.35 (1H, d, J = 7.6 Hz, Ar-H), 11.75 (1H, s, pyrrole NH), 12.43 (1H, br, NH). MS, m/z = 294 (M⁺, 51). Anal. Calcd. for C₁₅H₁₀N₄OS (294.33): C, 61.21; H, 3.42; N, 19.04; S, 10.89%, Found: C, 61.13; H, 3.59; N, 19.17; S, 11.04%.

2.5

2.5 General procedure for the synthesis of enaminones 15–18

Method I (Δ): to a solution of compound 8 or 9 (0.1 mol) in ethanol (20 mL), secondary amine (piperidine or morpholine) (0.1 mol) was added. The reaction mixture was heated at reflux temperature for 4 h. After cooling to room temperature, the solid product so-formed was collected by filtration and dried.

Method II (US): to a solution of compound 8 or 9 (0.1 mol) in ethanol (50 mL), secondary amine (piperidine or morpholine) (0.1 mol) was added. The reaction mixture was exposed to ultrasound irradiation at 70 °C for 2 h. After cooling to room temperature, it was poured into ice-cold water. The resulting solid product was collected by filtration and dried.

Method III (IL): a mixture of pyridinium chloride ([PyH]Cl) (0.4 mol), compound 8 or 9 (0.1 mol) and secondary amine (piperidine or morpholine) (0.1 mol) was heated at 110 °C for 20 min and was allowed to cool to room temperature. Then, it was treated with ethanol and the resulting solid product was collected by filtration, dried and recrystallized from ethanol.

2.5.1

2.5.1 3-(Piperidin-1-yl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile 15

Buff crystals, mp: 168–170 °C; IR (ν_max, cm⁻¹): 3258 (NH), 2850 (aliph. CH), 2193 (CN), 1665 (C⚌O). ¹H NMR (400 MHz, DMSO-d₆), δ_H 1.66 (6H, m, 3CH₂), 3.56 (4H, br, 2NCH₂), 6.16 (1H, t, J = 2.1 Hz, pyrrole H-4), 7.07 (1H, d, J = 3.6 Hz, pyrrole H-3), 7.18 (1H, d, J = 2.7 Hz, pyrrole H-5), 8.01 (1H, s, olefinic CH), 11.58 (1H, s, pyrrole NH). ¹³C NMR (100 MHz, DMSO-d₆), δ_c 23.6 (CH₂), 26.0 (CH₂), 27.0 (CH₂), 57.9 (2NCH₂), 75.4 (C⚌C–N), 109.8 (pyrrole C-4), 115.6 (CN), 121.7 (pyrrole C-3), 124.4 (pyrrole C-5), 130.7 (pyrrole C-2), 157.2 (olefinic carbon), 176.7 (C⚌O). MS, m/z = 229 (M⁺, 85). Anal. Calcd. for C₁₃H₁₅N₃O (229.28): C, 68.10; H, 6.59; N, 18.33%, Found: C, 68.06; H, 6.75; N, 18.45%.

2.5.2

2.5.2 3-(Morpholin-4-yl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile 16

Buff crystals, mp: 216–217 °C; IR (ν_max, cm⁻¹): 3290 (NH), 3090 (Ar, CH), 2920 (aliph. CH), 2220 (CN), 1665 (C⚌O). ¹H NMR (400 MHz, DMSO-d₆), δ_H 3.22 (4H, m, 2 NCH₂), 3.60 (4H, m, 2 OCH₂), 6.17 (1H, t, J = 2.1 Hz, pyrrole H-4), 6.98 (1H, d, J = 3.6 Hz, pyrrole H-3), 7.81 (1H, d, J = 2.7 Hz, pyrrole H-5), 7.99 (1H, s, olefinic CH), 11.58 (1H, br s, pyrrole NH). ¹³C NMR (100 MHz, DMSO-d₆), δ_c 48.1 (2 NCH₂), 58.6 (2 OCH₂), 76.4 (C⚌C–N), 109.9 (pyrrole C-4), 115.7 (CN), 121.7 (pyrrole C-3), 124.27 (pyrrole C-5), 130.7 (pyrrole C-2), 159.43 (olefinic carbon), 176.52 (C⚌O). MS, m/z = 231 (M⁺, 3). Anal. Calcd. for C₁₂H₁₃N₃O₂ (231.25): C, 62.33; H, 5.67; N, 18.17%, Found: C, 62.25; H, 5.70; N, 18.11%.

2.5.3

2.5.3 2-(1H-Indole-3-carbonyl)-3-(piperidin-1-yl)acrylonitrile 17

Yellow crystals, mp: 233–234 °C; IR (ν_max, cm⁻¹): 3204 (NH), 2856 (aliph. CH), 2198 (CN), 1667 (C⚌O). ¹H NMR (400 MHz, DMSO-d₆), δ_H 1.63 (6H, m, 3CH₂), 3.57 (2H, m, CH₂), 3.97 (2H, m, CH₂), 7.19 (2H, m, Ar-H), 7.48 (1H, d, J = 7.6 Hz, Ar-H), 8.01 (1H, s, olefinic CH), 8.16 (1H, d, J = 7.6 Hz, Ar-H), 8.30 (1H, s, indole H-2), 11.77 (1H, s, indole NH). ¹³C NMR (100 MHz, DMSO-d₆), δ_c 23.6 (CH₂), 26.0 (CH₂), 27.0 (CH₂), 57.7 (2 NCH₂), 77.2 (C⚌C–N), 112.5 (indole C-3), 115.3 (CN), 121.7 (Ar-C), 122.3 (2C, Ar-C), 123.1 (indole C-3a), 127.0 (Ar-C), 133.7 (indole C-2), 136.4 (indole C-7a), 157.2 (C⚌C–N), 182.5 (C⚌O). MS, m/z = 279 (M⁺, 100). Anal. Calcd. for C₁₇H₁₇N₃O (279.34): C, 73.10; H, 6.13; N, 15.04%, Found: C, 73.18; H, 6.29; N, 15.23%.

2.5.4

2.5.4 2-(1H-Indole-3-carbonyl)-3-(morpholin-4-yl)acrylonitrile 18

Yellowish crystals, mp: 187–189 °C; IR (ν_max, cm⁻¹): 3254 (NH), 2928 (aliph. CH), 2189 (CN), 1667 (C⚌O). ¹H NMR (400 MHz, DMSO-d₆), δ_H 3.27 (4H, m, 2 NCH₂), 3.75 (4H, m, 2 OCH₂), 7.14–7.22 (2H, m, Ar-H), 7.48 (1H, d, J = 7.7 Hz, Ar-H), 8.05 (1H, s, olefinic CH), 8.15 (1H, d, J = 7.7 Hz, Ar-H), 8.30 (1H, s, indole H-2), 11.80 (1H, d, J = 9.5 Hz, indole NH). ¹³C NMR (100 MHz, DMSO-d₆), δ_c 48.0 (2 NCH₂), 67.5 (2 OCH₂), 78.0 (C⚌C–N), 112.5 (indole C-3), 115.2 (CN), 121.7 (Ar-C), 122.3 (2C, Ar-C), 123.1 (indole C-3a), 127.1 (Ar-C), 133.7 (indole C-2), 136.4 (indole C-7a), 157.7 (C⚌C–N), 182.3 (C⚌O). MS, m/z = 281 (M⁺, 38). Anal. Calcd. for C₁₆H₁₅N₃O₂ (281.31): C, 68.31; H, 5.37; N, 14.94%, Found: C, 68.14; H, 5.26; N, 14.86%.

2.6

2.6 General procedure for the synthesis of pyrazole derivatives 19 and 20

Method I (Δ): to a solution of compound 8 or 9 (0.1 mol) in ethanol (20 mL), phenyl hydrazine (0.1 mol) was added. The reaction mixture was refluxed for 4 h. After concentration and cooling to room temperature, the solid product so-formed was collected by filtration and dried.

Method II (US): to a solution of 8 or 9 (0.1 mol) in ethanol (50 mL), phenyl hydrazine (0.1 mol) was added. The reaction mixture was subjected to ultrasound irradiation at 70 °C for 2 h and then left to cool to room temperature. The solid product so-formed was filtered off and dried.

Method III (IL): a mixture of pyridinium chloride ([PyH]Cl) (0.4 mol), compound 8 or 9 (0.1 mol) and phenyl hydrazine (0.1 mol) was heated at 110 °C for 20 min. After cooling to room temperature, it was treated with ethanol and the resulting solid product was collected by filtration, dried and recrystallized from ethanol.

2.6.1

2.6.1 (5-Amino-1-phenyl-1H-pyrazol-4-yl)(1H-pyrrol-2-yl)methanone 19

Buff crystals, mp 208–210 °C; IR (ν_max, cm⁻¹): 3400, 3215, 3164 (NH , NH₂), 1665 (C⚌O). ¹H NMR (400 MHz, DMSO-d₆), δ_H 6.23 (1H, m, pyrrole H-4), 6.96 (2H, br, NH₂), 7.05 (1H, m, pyrrole, H-3), 7.11 (1H, d, J = 2.6 Hz, pyrrole H-5), 7.45 (m, 1Ar-H), 7.60 (4H, m, Ar-H), 8.16 (1H, s, pyrazole H-3), 11.58 (1H, br, pyrrole NH). MS, m/z = 252 (M⁺, 16). Anal. Calcd. for C₁₄H₁₂N₄O (252.27): C, 66.65; H, 4.79; N, 22.21%, Found: C, 66.73; H, 4.92; N, 22.02%.

2.6.2

2.6.2 (5-Amino-1-phenyl-1H-pyrazol-4-yl)(1H-indol-3-yl)methanone 20

Yellowish crystals, mp: 266–268 °C; IR (ν_max, cm⁻¹): 3414, 3267, 3228 (NH, NH₂), 1667 (C⚌O). ¹H NMR (400 MHz, DMSO-d₆), δ_H 6.97 (2H, br, NH₂), 7.19 (2H, m, Ar-H), 7.43–7.64 (6H, m, Ar-H), 8.19 (1H, s, indole H-2), 8.28 (1H, d, J = 7.8 Hz, Ar-H), 8.31 (1H, s, pyrazole H-3), 11.86 (1H, s, indole NH). ¹³C NMR (100 MHz, DMSO-d₆), δ_c 104.89 (pyrazole C-4), 112.5–130.0 (9C, Ar-C + indole C-2 and C-3), 131.8 (indole C-3a), 136.8 (indole C-7a), 138.4 (pyrazole C-3), 141.1 (N-Ph), 151.0 (pyrazole C-5), 183.6 (C⚌O). MS, m/z = 302 (M⁺, 48). Anal. Calcd. for C₁₈H₁₄N₄O (302.33): C, 71.51; H, 4.67; N, 18.53%, Found: C, 71.66; H, 4.86; N, 18.44%.

2.7

2.7 General procedure for the synthesis of pyrimidine derivatives 21 and 22

Method I (Δ): to a solution of compound 8 or 9 (0.1 mol) and guanidine (0.1 mol) in ethanol (30 mL), potassium carbonate (0.12 mol) was added. The reaction mixture was heated to reflux for 10 h. After cooling to room temperature, it was poured into ice-cold water. The precipitated solid product was filtered off, washed well with water and dried.

Method II (US): to a solution of 8 or 9 (0.1 mol) and guanidine (0.1 mol) in ethanol (50 mL), potassium carbonate (0.12 mol) was added. The reaction mixture was exposed to ultrasound irradiation at 70 °C for 5 h. Then, the reaction mixture was poured into ice-cold water. The solid product so-formed was filtered off, washed well with water, dried and recrystallized from ethanol.

2.7.1

2.7.1 2-Amino-4-(1H-pyrrol-2-yl)pyrimidin-5-carbonitrile 21

Buff crystals, mp: 212–214 °C; IR (ν_max, cm⁻¹): 3478, 3407, 3215 (NH, NH₂), 3064 (Ar, CH), 2207 (CN). ¹H NMR (400 MHz, DMSO-d₆), δ_H 6.31 (1H, br, pyrrole H-4), 7.0–7.2 (2H, m, pyrrole H-3 and H-5), 7.31 (2H, br s, NH₂), 8.68 (1H, s, pyrimidine H-6), 11.57 (1H, s, pyrrole NH). MS, m/z = 185 (M⁺, 100). Anal. Calcd. for C₉H₇N₅ (185.19): C, 58.37; H, 3.81; N, 37.82%, Found: C, 58.49; H, 3.66; N, 37.90%.

2.7.2

2.7.2 2-Amino-4-(1H-indol-3-yl)pyrimidin-5-carbonitrile 22

Buff crystals; mp: 256–258 °C [Lit. (Radwan and El-Sherbiny, 2007) mp: 258–259 °C].

2.8

2.8 Synthesis of (5-aminoisoxazol-4-yl)(1H-indol-3-yl)methanone 23

Method I (Δ): to a solution of 9 (0.1 mol) and hydroxylamine hydrochloride (0.1 mol) in ethanol (25 mL), potassium carbonate (0.12 mol) was added. The reaction mixture was heated to reflux for 10 h. After cooling to room temperature, it was poured into ice-cold water. The resulting solid product was collected by filtration, washed well with water and dried.

Method II (US): to a solution of compound 9 (0.1 mol) and hydroxylamine hydrochloride (0.1 mol) in ethanol (50 mL), potassium carbonate (0.12 mol) was added. The reaction mixture was exposed to ultrasound irradiation at 70 °C for 5 h. After cooling to room temperature, it was poured into ice-cold water. The solid product so-formed was filtered off, washed well with water, dried and recrystallized from ethanol to give compound 23 as buff crystals, mp: 241–243 °C; IR (ν_max, cm⁻¹): 3385, 3228, 3119 (NH, NH₂), 1661 (C⚌O). ¹H NMR (400 MHz, DMSO-d₆), δ_H 6.78 (2H, s, NH₂), 7.0–8.10 (4H, m, Ar-H), 8.25 (1H, s, indole H-2), 8.40 (1H, s, isoxazole H-3), 11.1 (1H, s, indole NH). MS, m/z = 225 (M⁺-2, 14). Anal. Calcd. for C₁₂H₉N₃O₂ (227.22): C, 63.43; H, 3.99; N, 18.49%, Found: C, 63.33; H, 4.18; N, 18.62%.

3 Result and discussion

At the onset of the research, we investigated the synthesis of 3-heteroaromatic-3-oxo-propanenitriles 3, 4, and 7 and convert them to the corresponding enaminones 8, 9 and 10, respectively, which were selected as our primary starting materials for this series of reactions. Although, the synthesis of 3-(1H-indol-3-yl)-3-oxopropanenitrile (3) and 3-oxo-3-(1H-pyrrol-2-yl)propanenitrile (4) has been reported (Bergman, 1968; Slätt et al., 2004, 2005; Farag et al., 1996, 1997; Dawood et al., 1999; Gurevich and Yaroshevskya, 2000; Isobe et al., 2003; Al-Awadi et al., 2007 ) to the best of our knowledge, their syntheses by environmentally benign approaches have not been reported so far.

Thus, condensation of cyanoacetic acid with pyrrole or indole in acetic anhydride, under conventional heating, gave 3-heteroaromatic-3-oxopropanenitriles 3 and 4 in 70 and 77% yields, respectively (Al-Awadi et al., 2007). However, when we conducted these condensation reactions under US irradiations, compounds 3 and 4 were formed (see Scheme 1) and the yields are improved over the conventional method (see Table 1).

Table 1 Shows yield as well as reaction times of compounds 3–23 by the three methodologies (thermal (Δ), ultrasound (US) and ionic liquid (IL)).

No.	Yield (%)			Time (min)
No.	Δ	US	IL	Δ	US	IL
3	–	88	–	–	20	–
4	–	92	–	–	20	–
7	81	92	–	150	60	–
8	68	86	–	420	150	–
9	57	88	–	420	150	–
10	75	92	–	420	150	–
11	72	91	88	240	120	20
13	70	90	86	240	120	20
14	66	83	74	240	120	20
15	69	85	80	240	120	20
16	51	86	73	240	120	20
17	73	88	83	240	120	20
18	64	86	79	240	120	20
19	66	82	77	240	120	20
20	69	85	80	240	120	20
21	44	85	–	480	300	–
22	46	88	–	480	300	–
23	42	71	–	480	300	–

On the other hand, when N-(4-oxo-4H-thieno[3,4-c]chromen-3-yl)acetamide (6) prepared by acetylation of 3-amino-4H-thieno[3,4-c]chromen-4-one (5) as described in the literature (Al-Awadi et al., 2007) was subjected to react with cyanoacetic acid in acetic anhydride, under conventional heating for a long time, the expected 3-oxoalkanenitrile derivative 7 was not obtained and the starting materials were recovered. In an attempt to synthesis the desired 3-oxoalkanenitriles 7, we repeated the reaction in the presence of Lewis acid, viz. AlCl₃. Thus, the reaction of 6 with cyanoacetic acid in acetic anhydride and in the presence of a catalytic amount of anhydrous AlCl₃ afforded the requested 3-oxoalkanenitriles 7 in 81% yield. Alternatively, compound 7 could also be obtained, in one step, by reacting compound 5 with cyanoacetic acid in acetic anhydride under US irradiations (see Scheme 2).

The preparation of enaminones 8–10 was accomplished very easily via the condensation of 3-oxopropanenitriles 3, 4 and 7 with dimethylformamide dimethylacetal (DMF-DMA) either with conventional heating for a long time or with US for 2.5 h at 70 °C. The structure of 8, for example, was established for the reaction product on the basis of its elemental analysis and spectral data (MS, IR, NMR; see Section 2). Finally, the structure of 8 was unambiguously confirmed based on NOE difference which indicated that the proton at C-3 in pyrrole at δ = 7.0 ppm is sterically proximal to the olefinic proton at δ = 8.0 ppm.

In order to construct new derivatives of the interesting enaminones of the type 8 and 9, we investigated the reactivity of these enaminones 8 and 9 toward some different amines. Thus, treatment of compound 8, as example, with aniline, under different reaction conditions (conventional heating, US and IL), gave a solid product whose structure was assumed to be 11 (keto form) or 12 (enol form) (Scheme 4). The ¹H NMR revealed four signals for two protons at 12.58, 10.78, 8.48 and 7.99 ppm. The doublet signals at 12.58 and 8.48 ppm are assigned for NH and CH proton, respectively in the keto form 11 while the singlet signals at 10.78 and 7.99 ppm are assigned for OH and CH proton, respectively in the enol form 12. From integrals, it could be calculated that the major constituent in this equilibrium mixture is the keto form 11 (80–85%), while the minor constituent is the enol form 12 (10–15%). Also, compound 9 reacted with aniline either via irradiation with US and/or in IL to yield 2-(1H-indole-3-carbonyl)-3-(phenylamino)acrylonitrile (13) (Scheme 4). The structure of product 13 was confirmed by X-ray crystal determination (Fig. 1) (Crystallographic data for the structure). However, reacting compound 8 with 2-aminobenzothiazol, under green conditions, afforded the new 3-(benzo[d]thiazol-2-ylamino)-2-(1H-pyrrol-2-carbonyl)acrylonitrile (14), in excellent yield (see Schemes 3 and 5).

In conjunction with this study, we investigated the behavior of the reaction of enaminones 8 and 9 with secondary amines. Thus, the reaction of compounds 8 and 9 with equimolar amounts of piperidine and morpholine provided the interesting enaminone compounds 15–18. As it has been reported that heterocycles with piperidine sub-structures display important biological activities, such as anti-cancer (El-Subbagh et al., 2000) and cytotoxic (Dimmock et al., 2001), besides being useful as synthons in the construction of alkaloid natural products (Lee et al., 2001). These heterocycles with piperidine sub-structures 15–18 could exhibit important biological properties. Compounds 15–18 were prepared under conventional heating or irradiating under US for 120 min at 70 °C or with heating in [PyH]Cl, as an IL, at 110 °C for 20 min and the data used to characterize them are given in the experimental section.

Attention was next turned to investigate the reactivity of enaminones 8 and 9 with some binucleophiles such as phenylhydrazine, guanidine and hydroxylamine. Thus, treatment of compounds 8 and 9 with phenylhydrazine, under different environmentally friendly conditions (US and IL), afforded the corresponding pyrazole derivatives 19 and 20, respectively, in high yields (77–92%) (Scheme 6). Their structures were established and confirmed for the reaction products on the basis of their elemental analyses and spectral data (MS, IR, ¹H NMR and ¹³C NMR) (see Section 2).

However, treatment of enaminones 8 and 9 with equimolar amount of guanidine under either conventional heating or environmentally benign reaction conditions gave the interesting pyrimidine derivatives 21 and 22, respectively (Scheme 7). The identity of compounds 21 and 22 was supported by correct elemental analyses and mass spectra as well as the IR and NMR spectra which were compatible with the assigned structures (see Section 2). On the other hand, compound 9 was reacted with hydroxylamine hydrochloride in the presence of anhydrous K₂CO₃ either at reflux temperature or under US activation to yield the aminoisoxazole derivative 23. Although, the reaction completion required a long time at reflux temperature, it needed only 5 h (TLC control) for completing the reaction under US irradiation at 70 °C. The structure of 23 was confirmed as the reaction products from its IR, ¹H NMR and correct elemental analysis as well as mass spectrum. Thus, the IR spectrum of 23 revealed the absence of the cyano group and the presence of absorption bands at ν = 3385, 3228 and 3119 cm⁻¹ due to amino functions (NH, NH₂). The ¹H NMR spectrum of 23 displayed the absence of dimethylamino group (NMe₂) and olefinic CH signals at δ = 3.26, 3.36 and 8.0 ppm, respectively, present in the spectrum of 9, and the presence of two singlet signals at δ = 6.78 and 8.40 ppm attributable to NH₂ and isoxazole H-3, respectively, besides signals due to the indole moiety in their expected positions. Additionally, its structure was fully supported by correct mass spectrum, which was compatible with the assigned structure (see Section 2). Analytical data was also in accordance with the proposed structure.

4 Conclusion

In summary, we have disclosed the green methodologies (US and IL) for the synthesis of new heterocyclic systems containing indole or pyrrole moiety starting from 3-cyanoacetyl indole and 2-cyanoacetyl pyrrole. In these methodologies, cyanoacetyl group at the 3-position of indole or 2-position of pyrrole is used as a good precursor to construct the appropriately pyrazole, pyrimidine and isoxazole derivatives. The significant advantages of these green methodologies are high yields with lesser reaction time, clean, a simple work-up procedures and no chromatographic separation is necessary to get pure compounds. In addition, the recovered IL could be directly reused after drying without any significant loss of activity. The compounds prepared are expected to be of pharmacological interest. Further application of these green approaches to the synthesis of other new heterocycles is currently ongoing in our laboratory and will be reported in due course.

References

Agamy S.M., Abdel-Khalik M.M., Mohamed M.H., Elnagdi M.H., . Z. Naturforsch.. 2001;56b:1074.
Akue-Gedu R., Debiton E., Ferandin Y., Meijer L., Prudhomme M., Anizon F., Moreau P., . Bioorg. Med. Chem.. 2009;17:4420.
Al-Awadi N.A., Abdelkhik M.M., Abdelhamid I.A., Elnagdi M.H., . Synlett. 2007;19:2979.
Almerico A., Diana P., Barraja P., Dattolo G., Mingoia F., Loi A., Scintu F., Milia C., Puddu L., Lacolla P., . Farmaco. 1998;53:33.
Alnajjar A.-A., Abdelkhalik M.M., Al-Enezi A., Elnagdi M.H., . Molecules. 2009;14:68.
Al-Zaydi K.M., Borik R.M., Elnagdi M.H., . Molecules. 2007;12:2061.
Al-Zaydi K.M., Al-Shiekh M.A.A., Hafez E.A.-A., . J. Chem. Res.. 2000;13
Al-Zaydi K.M., Borik R.M., Elnagdi M.H., . J. Heterocycl. Chem.. 2007;44:1.
Al-Zaydi K.M., Borik R.M., Elnagdi M.H., . Molecules. 2004;9:910.
Al-Zaydi K.M., Borik R.M., Mekheimer R.A., Elnagdi M.H., . Ultrason. Sonochem.. 2010;17:909.
Al-Zaydi K.M., Hafez E.A.-A., Elnagdi M.H., . J. Chem. Res.. 2000;154
Andreani A., Rambaldi M., Locatelli A., Pifferi G., . Eur. J. Med. Chem.. 1994;29:903.
Bergman J., . Acta Chem. Scand.. 1968;22:1063.
Crystallographic data for the structure reported in this paper have been deposited with the Cambridge crystallographic data centre as supplementary publications nos. CCDC 690079. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).
Dandia A., Sehgal V., Singh P., . Indian J. Chem.. 1993;32B:1288.
Dawood K.M., Farag A.M., Kandeel Z.E., . J. Chem. Res.. 1999;88
Dimmock J.R., Padmanilayam M.P., Puthucode R.N., Nazarali A.J., Motaganahalli N.L., Zello G.A., Quail J.W., Oloo E.O., Kraatz H.B., Prisciak J.S., Allen T.M., Santos C.L., Balzarini J., De Clercq E., Manavathu E.K., . J. Med. Chem.. 2001;44:586.
El-Gaby M.S.A., Gaber A.M., Atalla A.A., Abd Al-Wahab K.A., . IL Farmaco. 2002;57:613.
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El-Subbagh H.I., Abu-Zaid S.M., Mahran M.A., Badria F.A., Al-Obaid A.M., . J. Med. Chem.. 2000;43:2915.
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Farag A.M., Dawood K.M., Kandeel Z.E., . Tetrahedron. 1997;53:161.
Farghaly A., . Arkivoc. 2010;xi:177.
Gurevich P.A., Yaroshevskya V., . Chem. Heterocycl. Compd.(Engl. Transl.). 2000;36:1361.
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[Google Scholar]

Introduction

Experimental

Measurements
General procedure for the synthesis of 3-heteroaromatic substituted-3-oxopropane nitriles 3, 4 and 7
General procedure for the synthesis of enaminones 8–10
General procedure for the synthesis of 3-(phenylamino)-2-(1H-pyrrole-2-carbonyl)- acrylonitrile 11, 2-(1H-Indole-3-carbonyl)-3-(phenylamino)acrylonitrile 13 and 3-(benzo-[d]thiazol-2-ylamino)-2-(1H-pyrrole-2-carbonyl)acrylonitrile 14
General procedure for the synthesis of enaminones 15–18
General procedure for the synthesis of pyrazole derivatives 19 and 20
General procedure for the synthesis of pyrimidine derivatives 21 and 22
Synthesis of (5-aminoisoxazol-4-yl)(1H-indol-3-yl)methanone 23

Result and discussion

Conclusion

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[1] Agamy S.M., Abdel-Khalik M.M., Mohamed M.H., Elnagdi M.H., . Z. Naturforsch.. 2001;56b:1074.

[2] Akue-Gedu R., Debiton E., Ferandin Y., Meijer L., Prudhomme M., Anizon F., Moreau P., . Bioorg. Med. Chem.. 2009;17:4420.

[3] Al-Awadi N.A., Abdelkhik M.M., Abdelhamid I.A., Elnagdi M.H., . Synlett. 2007;19:2979.

[4] Almerico A., Diana P., Barraja P., Dattolo G., Mingoia F., Loi A., Scintu F., Milia C., Puddu L., Lacolla P., . Farmaco. 1998;53:33.

[5] Alnajjar A.-A., Abdelkhalik M.M., Al-Enezi A., Elnagdi M.H., . Molecules. 2009;14:68.

[6] Al-Zaydi K.M., Borik R.M., Elnagdi M.H., . Molecules. 2007;12:2061.

[7] Al-Zaydi K.M., Al-Shiekh M.A.A., Hafez E.A.-A., . J. Chem. Res.. 2000;13

[8] Al-Zaydi K.M., Borik R.M., Elnagdi M.H., . J. Heterocycl. Chem.. 2007;44:1.

[9] Al-Zaydi K.M., Borik R.M., Elnagdi M.H., . Molecules. 2004;9:910.

[10] Al-Zaydi K.M., Borik R.M., Mekheimer R.A., Elnagdi M.H., . Ultrason. Sonochem.. 2010;17:909.

[11] Al-Zaydi K.M., Hafez E.A.-A., Elnagdi M.H., . J. Chem. Res.. 2000;154

[12] Andreani A., Rambaldi M., Locatelli A., Pifferi G., . Eur. J. Med. Chem.. 1994;29:903.

[13] Bergman J., . Acta Chem. Scand.. 1968;22:1063.

[14] Crystallographic data for the structure reported in this paper have been deposited with the Cambridge crystallographic data centre as supplementary publications nos. CCDC 690079. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).

[15] Dandia A., Sehgal V., Singh P., . Indian J. Chem.. 1993;32B:1288.

[16] Dawood K.M., Farag A.M., Kandeel Z.E., . J. Chem. Res.. 1999;88

[17] Dimmock J.R., Padmanilayam M.P., Puthucode R.N., Nazarali A.J., Motaganahalli N.L., Zello G.A., Quail J.W., Oloo E.O., Kraatz H.B., Prisciak J.S., Allen T.M., Santos C.L., Balzarini J., De Clercq E., Manavathu E.K., . J. Med. Chem.. 2001;44:586.

[18] El-Gaby M.S.A., Gaber A.M., Atalla A.A., Abd Al-Wahab K.A., . IL Farmaco. 2002;57:613.

[19] El-Gendy Adel A., Abdou Naida A., Sarhan El-Taher Z., El-Banna Hosny A., . Alex. J. Pharm. Sci.. 1993;7:99.

[20] El-Subbagh H.I., Abu-Zaid S.M., Mahran M.A., Badria F.A., Al-Obaid A.M., . J. Med. Chem.. 2000;43:2915.

[21] Farag A.M., Dawood K.M., Kandeel Z.E., . Tetrahedron. 1996;52:7893.

[22] Farag A.M., Dawood K.M., Kandeel Z.E., . Tetrahedron. 1997;53:161.

[23] Farghaly A., . Arkivoc. 2010;xi:177.

[24] Gurevich P.A., Yaroshevskya V., . Chem. Heterocycl. Compd.(Engl. Transl.). 2000;36:1361.

[25] Isobe Y., Tobe M., Inoue Y., Isobe Y., Tsuchiya M., Hayashi H., . Biorg. Med. Chem.. 2003;11:4933.

[26] Kreher R., Wagner P.H., . Chem. Ber.. 1980;113:3675.

[27] Kumar A., Saxena K.K., Gurtu S., Sinha J.N., Shanker K., . Indian Drugs. 1986;24:1.

[28] Lee H.K., Chun J.S., Pak C.S., . Tetrahedron Lett.. 2001;42:3483.

[29] Mekheimer R.A., Abdel Hameed A.M., Sadek K.U., . Green Chem.. 2008;10:592.

[30] Mekheimer R.A., Ameen M.A., Sadek K.U., . Chin. Chem. Lett.. 2008;19:788.

[31] Misra U., Hitkari A., Saxena A.K., Gurtu S., Shanker K., . Eur. J. Med. Chem.. 1996;31:629.

[32] Obniska J., Kulig K., Zejc A., . Acta Pol. Pharm.. 1998;55:223.

[33] Radwan M.A.A., El-Sherbiny M., . Bioorg. Med. Chem.. 2007;15:1206.

[34] Reed, L., Farlow, R., Robert, A., Eur. Patent Appl. EP 895, 839 (Cl. B27 K3/34), 10 Feb, 1999, US Application, 907, 761, 8 Aug, 1997 [Chem. Abstr. 1999, 130, 169743h].

[35] Saracoglu N., . Top. Heterocycl. Chem.. 2007;11:1.

[36] Slätt J., Janosik T., Wahlström N., Bergman J., . J. Heterocycl. Chem.. 2005;42:141.

[37] Slätt J., Romero I., Bergman J., . Synthesis 2004:2760.

[38] Suzen S., . Top. Heterocycl. Chem.. 2007;11:145.

[39] Verma M., Tripathi M., Saxena A.K., Shanker K., . Eur. J. Med. Chem.. 1994;29:941.

[40] Walker G.N., . Ciba-Geigy, European Patent 156091, 1984. Chem. Abstr.. 1987;106:156268.
[Google Scholar]

An expeditious and green synthesis of new enaminones and study their chemical reactivity toward some different amines and binucleophiles under environmentally friendly conditions

Abstract

Keywords

Green synthesis

Enaminones

Ultrasound irradiations

Ionic liquids

Nucleophilic substitution

Binucleophiles

1 Introduction

2 Experimental

2.1 Measurements

2.2 General procedure for the synthesis of 3-heteroaromatic substituted-3-oxopropane nitriles 3, 4 and 7

2.2.1 3-Oxo-3-(1H-pyrrol-2-yl)-propionitrile 3

2.2.2 3-(1H-Indol-3-yl)-3-oxo-propionitrile 4

2.2.3 N-(1-(2-Cyanoacetyl)-4-oxo-4H-thieno[3,4-c]chromen-3-yl)acetamide 7

2.3 General procedure for the synthesis of enaminones 8–10

2.3.1 3-Dimethylamino-2-(1H-pyrrole-2-carbonyl)acrylonitrile 8

2.3.2 3-Dimethylamino-2-(1H-indole-3-carbonyl)acrylonitrile 9

2.3.3 N-(1-(2-Cyano-3-(dimethylamino)acryloyl)-4-oxo-4H-thieno[3,4-c]chromen-3-yl)-acetamide 10

2.4 General procedure for the synthesis of 3-(phenylamino)-2-(1H-pyrrole-2-carbonyl)- acrylonitrile 11, 2-(1H-Indole-3-carbonyl)-3-(phenylamino)acrylonitrile 13 and 3-(benzo-[d]thiazol-2-ylamino)-2-(1H-pyrrole-2-carbonyl)acrylonitrile 14

2.4.1 3-(Phenylamino)-2-(1H-pyrrole-2-carbonyl)acrylonitrile 11

2.4.2 2-(1H-Indole-3-carbonyl)-3-(phenylamino)acrylonitrile 13

2.4.3 3-(benzo[d]thiazol-2-ylamino)-2-(1H-pyrrole-2-carbonyl)acrylonitrile 14

2.5 General procedure for the synthesis of enaminones 15–18

2.5.1 3-(Piperidin-1-yl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile 15

2.5.2 3-(Morpholin-4-yl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile 16

2.5.3 2-(1H-Indole-3-carbonyl)-3-(piperidin-1-yl)acrylonitrile 17

2.5.4 2-(1H-Indole-3-carbonyl)-3-(morpholin-4-yl)acrylonitrile 18

2.6 General procedure for the synthesis of pyrazole derivatives 19 and 20

2.6.1 (5-Amino-1-phenyl-1H-pyrazol-4-yl)(1H-pyrrol-2-yl)methanone 19

2.6.2 (5-Amino-1-phenyl-1H-pyrazol-4-yl)(1H-indol-3-yl)methanone 20

2.7 General procedure for the synthesis of pyrimidine derivatives 21 and 22

2.7.1 2-Amino-4-(1H-pyrrol-2-yl)pyrimidin-5-carbonitrile 21

2.7.2 2-Amino-4-(1H-indol-3-yl)pyrimidin-5-carbonitrile 22

2.8 Synthesis of (5-aminoisoxazol-4-yl)(1H-indol-3-yl)methanone 23

3 Result and discussion

4 Conclusion

References

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