Isocyanide-based three component reaction for synthesis of highly cyano substituted furan derivatives

Abstract

A rapid and efficient solvent-free one-pot synthesis of novel alkyl amino aryl furan tricarbonitrile derivatives is described under catalyst-free conditions. This reaction was carried out through a three-component condensation reaction of isocyanides, 2-arylidenemalononitriles and benzoyl cyanide under solvent-free conditions. Neat conditions were established with many advantages, including high yield, environmentally friendliness, and easy and quick isolation of the products. The newly synthesized compounds were systematically characterized by IR, ¹H NMR, ¹³C NMR and elemental analysis.

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1. Introduction

Nowadays, the pace of development of technology is becoming faster each year, especially in chemical fields. In this regard, organic chemists are facing new challenges for producing novel compounds that are structurally more diverse and prepared more efficiently. To achieve this goal, chemistry researchers' main concern is to have more innovative green methods that lead to new and more complex materials without environmental impact.¹ Among synthetic methods, multicomponent reactions (MCRs) are currently attracting attention of organic chemists due to the new synthetic applications in agreement with green chemistry principles.² A wide range of advantages offered by multicomponent reactions. These reactions are used to synthesize target compounds with high degree of convergence and atom economy. They generate structural complexity in a single operation without isolation of intermediates from three or more reactants.³

There is no doubt isocyanides are indispensable constituents of MCRs. In the past decades, they were used in many cycloaddition reactions and proved themselves to be irreplaceable building blocks in modern multi-component chemistry because they are able to react with both nucleophiles and electrophiles at the same carbon.^4,5

In recent years, more sever legislation and restrictions are decreed in order to avoid or at least, reduce of the environmental impact of manmade chemicals. In this regard, the role of solvent as reaction media to provide the requirements of environmental sustainability is inevitable. It has also been said that ‘the best solvent is no solvent’.⁶ Avoiding the use of solvents in synthesis of chemical compounds can reduce environmental contamination and promise to be an essential facet of ‘Green Chemistry’. They can even be more convenient than using solvent-based synthesis. Solvent-free reactions have attracted much interest because of their ease of experimental procedures and workup, low cost and environmentally benign nature.⁷

Without doubt, heterocyclic compounds play important roles in the drug discovery process. Functionalized heterocycles are present in a wide variety of drugs, vitamins, natural products, biomolecules and biologically active compounds. Moreover, they have been frequently found as a key structural unit in synthetic pharmaceuticals and agrochemicals. Furthermore, some of polycyano heterocyclic compounds exhibit a significant solvatochromic and photochromic properties.⁸ Interesting color changing property of dye chromophores with different solvents named solvatochromism effect.⁹ These polycyano heterocycles have attracted much attention due to optical emission properties such as photoluminescence (PL) and electroluminescence (EL), which can be used in the dye lasers^10,11 and sensors.¹² The most favorable photoactive dyes are merocyanines. They enable a convenient investigation of polyene–polymethine transformations in their chromophore because of their chemical structures that consists of both electron-donor and electron-acceptor groups (Fig. 1).^8,13

Fig. 1 Representative electro-optic active molecules.

In most of these dyes, tricyanovinyldihydrofuran derivatives (Fig. 1-2) play important roles as an acceptor part of chromophores.¹⁴

Over a hundred year ago the adduct of active methylene compounds and carbonyl groups was obtained by Emil Knoevenagel.¹⁵ This pioneering work of Knoevenagel have made impressive advances in the synthesis of five and six membered homo and hetero-cyclic compounds.^16,17 Recently, Takahashi¹⁸ and Nair¹⁹ have subsequently reported the formation of dicynocyclopentene derivatives from intermolecular coupling of arylidenemalononitriles, alkynes and isocyanates or isocyanides, respectively. Later, dicyano-2,3-dihydro-1H-indene derivatives were synthesized via three-component reaction of 2-alkynylbenzaldehyde, malononitrile, and indole.²⁰ It has been known from the studies of various groups that the 1,3 zwitterionic intermediate generated by the reaction of alkyl isocynides and dimethyl acetylenedicarboxylate.²¹

The success of these reactions and considering the literature background that was given above, about reactivity of Knoevenagel's adducts and in view of our general interest to isocyanide-based multicomponent reaction,²² provided us with a conceptual framework for designing novel multicomponent reactions (MCRs). So, as part of our ongoing program to develop new, efficient, and more environmentally benign methods for organic synthesis,²³ we herein report a facile, environmentally benign isocyanides based one-pot three-component strategy for the synthesis of novel highly cyano substituted furan derivatives in solvent less condition (Scheme 1).

Scheme 1 Synthesis of novel highly cyano substituted furan derivatives.

2. Results and discussion

According to Nair's²¹ and Bazgir's²⁴ reports (Scheme 2A) that their product formation were mechanistically proposed through the initial formation of a 1 : 1 zwitterionic intermediate 1 between isocyanide and DMAD, and due to many other researches^25–27 that in all of these reports the obtained product formation were explained through the involvement of 1,3-dipolar intermediate 2 as shown in the Scheme 2, we initiated our studies with the three-component reaction of 4-nitrobenzaldehyde (1 mmol), 2-benzylidenemalononitrile (1 mmol) and cyclohexyl isocyanide (1 mmol) in dry benzene at 80 °C to afford compound 8 or 8′ (Scheme 2B).

Scheme 2

Unluckily, the desired product 8 or 8′ was not obtained, even under inert atmosphere and after extended reaction time up to 16 h. Examination of the reaction with different aldehydes such as benzaldehyde and p-methoxybenzaldehyde have not improved the reaction. It is known that the solvent plays a crucial factor for organic reactions; so, the reaction was performed in the various solvents but there was no breakthrough in progress of the reaction.

Recently, Teimouri has developed one-pot three component condensation reaction which afforded a diverse array of 9 in the absence of catalyst²⁸ (Scheme 3C).

Scheme 3

So, we investigated the one pot three component condensation reaction of cyclohexyl isocyanide 3a, 2-benzylidenemalononitrile 4a and benzoyl cyanide 5 in dry benzene at 80 °C to for 4 h without any additive. To our delight, it afforded highly cyano substituted 5-(cyclohexylamino)-2,4-diphenylfuran-2,3,3(2H)-tricarbonitrile 6aa in 80% isolated yield (Scheme 3D). Encouraged by this success, we examined this reaction in various mediums and temperatures. The results are listed in Table 1. Only a trace amount of the product was detected in THF, DMF, EtOH and toluene, (entries 1–3 and 7). Although water was proved to be capable of promoting the reaction, a huge improvement was observed in benzene (entry 5). Moreover, in water a gummy solid was obtained which makes the separation of products very difficult. Then we investigated the efficiency of benzene as a solvent in lower temperature. At this condition the reaction proceeded with very low yield (entry 6). Interestingly, the reaction has shown the best result in neat conditions (entry 8) and the purity of the obtained product was very high. At this condition, decreasing the temperature lowered the reaction yield (entry 9).

Table 1 The catalyst-free condensation reaction between cyclohexyl isocyanide (3a, 1 mmol), 2-benzylidenemalononitrile (4a, 1 mmol) and benzoyl cyanide (5, 1 mmol) under various conditions

Entry	Solvent (3 mL)	Temp. (°C)	Time (h)	Yield^a (%)
a Isolated yields.
1	THF	65	24	<15
2	DMF	80	24	<15
3	EtOH	77	24	<15
4	H2O	80	24	67
5	Benzene	80	4	80
6	Benzene	50	12	<15
7	Toluene	80	12	<15
8	—	80	4	90
9	—	60	12	23

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With these results in hand, we screened the substrate scope of the synthesis of 5-(alkylamino)-4-(aryl)-2-phenylfuran-2,3,3(2H)-tricarbonitrile in neat conditions, and the results are listed in Table 2.

Table 2 Catalyst-free one-pot three component synthesis of highly cyano substituted furan derivatives at neat condition and 80 °C

Product	R	X	Yield^a (%)	Mp (°C)
a Isolated yields.
6aa	C6H11	H	90	210–212
6ba	(CH3)3C	H	90	217–219
6ca	4-Me-C6H4-SO2-CH2	H	91	222–224
6ab	C6H11	4-NO2	87	241–243
6bb	(CH3)3C	4-NO2	90	238–240
6cb	4-Me-C6H4-SO2-CH2	4-NO2	92	260–261
6ac	C6H11	4-Cl	84	230–232
6bc	(CH3)3C	4-Cl	82	218–220
6cc	4-Me-C6H4-SO2-CH2	4-Cl	87	235–237
6ad	C6H11	4-MeO	56	226–228
6bd	(CH3)3C	4-MeO	43	216–218
6cd	4-Me-C6H4-SO2-CH2	4-MeO	63	236–238
6ae	C6H11	4 F	27	221–223
6be	(CH3)3C	4 F	25	213–214
6ce	4-Me-C6H4-SO2-CH2	4 F	30	227–229

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As it is shown in Table 2, all reactions proceeded efficiently and the desired products were produced in good yields. 2-(4-Subsituated benzylidene) malononitrile with electron withdrawing groups (Table 2; 6ab–6cc) reacted more efficiently compared with those with electron releasing groups (Table 2; 6ad–6cd). While, our methodology has not been worked properly for fluorine substituted of compound 4 (Table 2; 6ae–6ce) the NMR spectroscopy of the crude products of clearly indicated that there were no products other than 6 were formed. The structures of the products 6aa–6ce were deduced from IR, ¹H and ¹³C NMR, mass spectral data and elemental analysis. The mass spectra of these compounds displayed molecular ion peaks at the appropriate m/z values. The IR spectrum of 6aa showed strong absorption at 3422 related to R–NH side chain of furan moiety and at 2374 due to the cyano groups. The ¹H NMR spectrum of 6aa exhibited three multiplet signals readily recognized as arising from cyclohexyl ring and aromatic protons at δ 1.17–1.87, 3.25 and δ 7.21–7.75 ppm respectively, and R–NH gave rise as a singlet peak at δ 8.48 ppm. The ¹³C NMR spectrum displayed nineteen distinct resonances consistent suggested structure. The characteristic signals due to the three carbons of cyano groups were described at δ 108.29, 108.30 and 117.56 ppm. The carbon of furan ring (C(CN)₂) resonated at δ 36.82 ppm. Partial assignment of these resonances is given in the experimental data.

Furthermore, the assignment of the proton resonance with the structure of 6aa was also confirmed by a homonuclear correlation spectroscopy (COSY) 2D-NMR spectrum shown in Fig. 2a, which provided ¹H–¹H connectivity of neighboring protons, showing a correlation between H_3a and H_3b. This correlation is in good agreement with the labelled 6aa structure in Fig. 2a. Moreover, the spectrum of J-modulated spin-echo experiment was shown negative amplitudes for C_1a–c and C_2a–c aromatic and C_3a related to cyclohexyl that in compliance with structure 6aa (Fig. 2b).

Fig. 2 Nuclear magnetic resonance spectra (300 MHz, CDCl₃) for 6aa: (a) 2D-homonuclear correlation spectroscopy (COSY) (b) spectrum of J-modulated spin-echo experiment.

The ¹H and ¹³C NMR spectra of 6ab–6ce are similar to 6aa, except for isocyanides, and aryl moiety, and the results are reported in the Experimental section.

Although we have not established the mechanism of the reaction, on the basis of the reaction of isocyanides and adducts of Knoevenagel reaction^25–27 it is reasonable to assume that compound 6 was formed by initial formation of a highly reactive 1 : 1 zwitterionic adduct 10 via nucleophilic attack of isocyanides 3 to arylidine malonitrile 4. Then this intermediate was added to carbonyl group of benzoyl cyanide 5 and dipolar species 11 was formed.

Afterward, cyclization reaction was occurred and follow with hydrogen exchange leads to the alkyl amino aryl furan tricarbonitrile derivatives 6 (Scheme 4). Although we have not concerned the stereochemistry of products, it is worth mentioning that before cyclization the adduct 11 can be rotated around (CN)(ph)C–C(CN)₂ bond and the other conformer 11′ is formed (Scheme 4). Then, each of these two conformer can produce different stereoisomers 6 and 6′ through cyclization and trace with hydrogen exchange.

Scheme 4 Proposed mechanism for the synthesis of the alkylamino aryl furan tricarbonitrile derivatives.

In conclusion, we have developed a clean, efficient and simple one-pot three component reaction of isocyanides, 2-aryl malonate and benzoyl cyanides for the synthesis of highly cyano substituted furan derivatives 6 in solvent less conditions. Moreover, in present method not only does not need to toxic solvent and any additive or activating agent as promoter of reaction but the reaction carries in neutral conditions and no need to any special condition such as inert atmosphere or exclusion of moisture from reaction medium.

3. Experimental

3.1. General

Reagents and solvents were purchased from Merck, Fluka or Aldrich and were used without further purification. Melting points were determined in capillary tubes in an Electrothermal 9100 apparatus and uncorrected. The progress of the reaction and the purity of compounds were monitored by TLC analytical silica gel plates (Merck 60 F250). IR spectra: Perkin-Elmer spectrum RXI. FT-IR apparatus. The ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) were run on a Bruker Avance DPX-250, FT-NMR spectrometer. Chemical shifts are given as δ values against tetramethylsylane as internal standard and J values are given in Hz. Microanalysis was performed on a Perkin-Elmer 240 B microanalyzer.

3.2. General procedure for preparation of 2-arylidenemalononitriles (4)

2-Arylidenemalononitriles were prepared via the method that have been reported previously²⁹ with a little manipulation. For preparation of 4a–e In a round-bottomed flask tetra butyl ammonium bromide (TBAB) (0.08 g, 5 mol%) was added to a solution of aldehyde (5 mmol) and malononitrile (5 mmol) in 5 mL of distilled water. The mixture was stirred at room temperature for 1–2 h until complete disappearance of the aldehyde. Then, allowed to stand overnight. Afterwards, the products 4 were collected by suction filtration, washed with water and petroleum ether, dried at room temperature and the products were recrystallized using hexane to give 2-arylidenemalononitriles. The structure of products were determined by comparison of their physical and spectroscopic data with reported compounds.

3.2.1. Selective data for 4a. White powder, Mp 84–86 °C. IR (KBr) (ν_max, cm⁻¹): 1591 (C=C aromatic), 1617 (C=C), 2223 (C=N), 2361 (CN). ¹H NMR (400 MHz, DMSO-d₆): δ_H 7.20–7.35 (5H, m, CH aromatic), 7.84 (1H, s, CH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C 82.37 (CN–C–CN), 113.31 (C=N), 114.09 (C=N), 129.15, 129.61, 130.72, 131.14 (C aromatic), 160.51 (CH).

3.3. General procedure for preparation of 5-(cyclohexylamino)-2,4-diphenylfuran-2,3,3(2H)-tricarbonitrile (6aa)

To a magnetically stirred mixture of benzoyl cyanide (0.131 g, 1.0 mmol) and 2-benzylidenemalononitrile (0.154 g, 1.0 mmol) was added slowly cyclohexyl isocyanide (0.109 g, 1.0 mmol) and heating was continued for 4 h. The reaction progress was monitored by TLC (EtOAC : n-hexane 3 : 1). Then after cooling to room temperature, diethyl tether was added to crud mixture and cooled to −5 °C. Afterwards, the product was collected by suction filtration, washed with diethyl ether to afford the pure product 6aa: (0.355 g, 90%) as white powder. Mp 210–212 °C. IR (KBr) (ν_max, cm⁻¹): 1381 (C–O), 2374 (CN), 3422 (NH). ¹H NMR (DMSO-d₆, 400 MHz): δ_H 1.17–1.87, (10H, m, 5CH₂, cyclohexyl), 3.25 (1H, s, CH–N), 7.21–7.75 (10H, m, CH aromatic), 8.48 (1H, s, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C 25.34, 26.04, 32.46, (CH₂, cyclohexyl), 36.82 (C(CN)₂), 52.31 (C–H, cyclohexyl), 82.03 (C–Ar), 87.12 (C–O), 108.29, 108.30, 117.56 (CN), 127.61, 127.85, 128.58, 128.81, 128.99, 129.12, 130.97, 135.18 (C aromatic), 137.40 (O–C–N). Anal. calcd for C₂₅H₂₂N₄O (394.47): C, 76.12; H, 5.62; N, 14.20%. Found: C, 76.19; H, 5.51; N, 14.18%.

3.3.1. 5-(tert-Butylamino)2,4-diphenylfuran-2,3,3(2H)-tricarbonitrile (6ba). White powder (0.332 g, 90%). Mp 217–219 °C. IR (KBr) (ν_max, cm⁻¹): 1347 (C–O), 2361 (CN), 3414 (NH). ¹H NMR (DMSO-d₆, 400 MHz): δ_H 1.40 (9H, s, C(CH₃)₃), 7.30–8.20 (10H, m, CH aromatic), 8.74 (1H, s, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C 30.03 (CH₃), 36.81 (C(CN)₂), 54.05 (CNH), 85.84 (C–Ar), 87.95 (C–O), 108.31, 117.36 (CN), 124, 85, 126.25, 127.52, 128.23, 128.31, 128.66, 132.83, 133.31 (C aromatic), 140.02 (O–C–N), 146.67 (C–N). Anal. calcd for C₂₃H₂₀N₄O (368.43): C, 74.98; H, 5.47; N, 15.21%. Found: C, 75.02; H, 5.39; N, 15.19%.

3.3.2. 2,4-Diphenyl-5-(para-toluene sulfonylmethanamino)furan-2,3,3(2H)-tricarbonitrile (6ca). White powder (0.437 g, 91%). Mp = 222–224 °C. IR (KBr) (ν_max, cm⁻¹): 1345 (C–O), 2360 (CN), 3415 (NH). ¹H NMR (DMSO-d₆, 400 MHz): δ_H 2.42 (3H, s, Me), 4.29 (1H, d, J = 7.65, N–CH₂–S), 4.43 (1H, d, J = 7.65, N–CH₂–S), 7.30–8.17 (14H, m, CH aromatic), 9.29 (1H, s, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C 21.63 (CH₃-ph), 36.82 (C(CN)₂), 61.38 (N–C–S) 80.02 (C–Ar), 87.95 (C–O), 108.30, 117.54 (CN), 124.85, 126.25, 127.51, 128.23, 128.31, 128.43, 128.66, 129.07, 132.83, 133.31, 134.01, (C aromatic), 136.97 (C–S), 137.02 (O–C–N). Anal. calcd for C₂₇H₂₀N₄O₃S (480.54): C, 67.48; H, 4.20; N, 11.66%. Found: C, 67.53; H, 4.19; N, 11.63%.

3.3.3. 5-(Cyclohexylamino)-4-(4-nitrophenyl)-2-phenylfuran-2,3,3(2H)-tricarbonitrile (6ab). Light yellow powder (0.382 g, 87%). Mp 241–243 °C. IR (KBr) (ν_max, cm⁻¹): 1347 (C–O), 2361 (CN), 1345 and 1536 (NO₂), 3414 (NH). ¹H NMR (DMSO-d₆, 400 MHz): δ_H 1.17–1.87 (10H, m, 5CH₂ cyclohexyl), 3.25 (1H, d, J = 7.43, C–N), 7.30–8.21 (9H, m, CH aromatic), 8.73 (1H, s, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C 25.34, 26.03, 32.46 (CH₂, cyclohexyl), 36.81 (C(CN)₂), 52.37 (C–H, cyclohexyl), 82.01 (C–Ar), 87.95 (C–O), 108.31, 117.56 (CN), 124.85, 126.25, 127.52, 128.66, 127.52, 132.83, 133.32 (C aromatic), 130.99 (O–C–N), 147.38 (C–N). Anal. calcd for C₂₅H₂₁N₅O₃ (439.47): C, 68.33; H, 4.82; N, 15.94%. Found: C, 68.31; H, 4.80; N, 15.96%.

3.3.4. 5-(tert-Butylamino)-4-(4-nitrophenyl)-2-phenylfuran-2,3,3(2H)-tricarbonitrile (6bb). Light yellow powder (0.372 g, 90%). Mp 238–240 °C. IR (KBr) (ν_max, cm⁻¹): 1347 (C–O), 1357 and 1522 (NO₂), 2361 (CN), 3414 (NH). ¹H NMR (DMSO-d₆, 400 MHz): δ_H 1.40 (9H, s, C(CH₃)₃), 7.30–8.20 (9H, m, CH aromatic), 8.74 (1H, s, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C 30.03 (C(CH₃)₃), 36.82 (C(CN)₂), 54.05 (CNH), 85.84 (C–Ar), 87.95 (C–O), 108.31, 117.56 (CN), 124.85, 126.25, 127.52, 128.23, 128.66, 132.83, 133.31 (C aromatic), 140.02 (O–C–N), 147.38 (C–N). Anal. calcd for C₂₃H₁₉N₅O₃ (413.43): C, 66.82; H, 4.63; N, 16.94%. Found: C, 66.88; H, 4.53; N, 16.91%.

3.3.5. 4-(4-Nitrophenyl)-2-phenyl-5-(para-toluene sulfonylmethanamino)furan-2,3,3(2H)-tricarbonitrile (6cb). Light yellow powder (0.483 g, 92%). Mp 260–261 °C. IR (KBr) (ν_max, cm⁻¹): 1345 (C–O), 1345 and 1541 (NO₂), 2360 (CN), 3415 (NH). ¹H NMR (DMSO-d₆, 400 MHz): δ_H 2.41 (3H, s, Me), 4.29 (1H, d, J = 7.65, N–CH₂–S), 4.43 (1H, d, J = 7.65, N–CH₂–S), 7.30–8.17 (14H, m, CH aromatic), 9.29 (1H, s, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C 21.63 (CH₃-ph), 36.82 (CH), 61.38 (N–C–S), 80.02, 124.85, 126.25, 127.51, 128.23, 128.43, 128.66, 129.07, 132.83, 133.31, 134.01 (C aromatic), 87.95 (C–O), 108.31, 117.56 (CN), 136.97 (C–S), 137.02 (O–C–N), 147.42 (C–N). Anal. calcd for C₂₇H₁₉N₅O₅S (525.54): C, 61.71; H, 3.64; N, 13.33%. Found: C, 61.65; H, 3.68; N, 13.28%.

3.3.6. 5-(Cyclohexylamino)-4-(4-chlorophenyl)-2-phenylfuran-2,3,3(2H)-tricarbonitrile (6ac). White powder (0.360 g, 84%). Mp 230–232 °C. IR (KBr) (ν_max, cm⁻¹): 680 (C–Cl), 1381 (C–O), 2374 (CN), 3422 (NH). ¹H NMR (DMSO-d₆, 400 MHz): δ_H 1.17–1.87, (10H, m, 5CH₂ cyclohexyl), 2.94 (1H, s, CH–N), 7.21–7.75 (9H, m, CH aromatic), 8.48 (1H, s, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C 25.34, 26.04, 32.46 (CH₂, cyclohexyl), 36.82 (CH, cyclohexyl), 82.01 (C–Ar), 87.98 (C–O), 108.31, 117.56 (CN), 126.25, 128.23, 128.31, 128.66, 128.68, 128.81, 130.04, 133.31 (C aromatic), 130.99 (O–C–N), 135.18 (C–Cl). Anal. calcd for C₂₅H₂₁ClN₄O (428.91): C, 70.01; H, 4.93; N, 13.06%. Found: C, 70.08; H, 4.90; N, 13.01%.

3.3.7. 5-(tert-Butylamino)-4-(4-chlorophenyl)-2-phenylfuran-2,3,3(2H)-tricarbonitrile (6bc). White powder (0.329 g, 82%). Mp 218–220 °C. IR (KBr) (ν_max, cm⁻¹): 680 (C–Cl), 1347 (C–O), 2361 (CN), 3414 (NH). ¹H NMR (DMSO-d₆, 400 MHz): δ_H 1.40 (9H, s, C(CH₃)₃), 7.30–8.20 (9H, m, CH aromatic), 8.74 (1H, s, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C 30.03 (3CH₃), 36.82 (C(CN)₂), 54.11 (CNH), 85.91 (C–O), 87.95 (C–O), 108.31, 117.56 (CN), 124.85, 126.25, 127.52, 128.23, 128.66, 132.83, 133.31 (C aromatic), 135.18 (C–Cl), 140.02 (O–C–N). Anal. calcd for C₂₃H₁₉ClN₄O (402.88): C, 68.57; H, 4.75; N, 13.91%. Found: C, 68.51; H, 4.79; N, 13.94%.

3.3.8. 4-(4-Chlorophenyl)-2-phenyl-5-(para-toluene sulfonylmethanamino)furan-2,3,3(2H)-tricarbonitrile (6cc). White powder (0.448 g, 87%). Mp 235–237 °C. IR (KBr) (ν_max, cm⁻¹): 680 (C–Cl), 1345 (C–O), 2360 (CN), 3415 (NH). ¹H NMR (DMSO-d₆, 400 MHz): δ_H 2.42 (3H, s, Me), 4.27 (1H, d, J = 7.65, N–CH₂–S), 4.41 (1H, d, J = 7.65, N–CH₂–S), 7.30–8.17 (14H, m, CH aromatic), 9.29 (1H, s, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C 21.63 (CH₃-ph), 36.82 (C(CN)₂), 61.39 (N–C–S), 80.02 (C–Ar), 87.97 (C–O), 108.31, 117.56 (CN), 124.85, 126.25, 127.51, 128.23, 128.43, 128.66, 129.07, 132.83, 133.31, 134.01 (C aromatic), 135.80 (C–Cl), 136.97 (C–S), 137.02 (O–C–N). Anal. calcd for C₂₇H₁₉ClN₄O₃S (514.98): C, 62.97; H, 3.72; N, 10.88%. Found: C, 62.95; H, 3.76; N, 10.85%.

3.3.9. 5-(Cyclohexylamino)-4-(4-methoxyphenyl)-2-phenylfuran-2,3,3(2H)-tricarbonitrile (6ad). White powder (0.238 g, 56%). Mp 226–228 °C. (KBr) (ν_max, cm⁻¹): 1347 (C–O), 2361 (CN), 3414 (NH). ¹H NMR (DMSO-d₆, 400 MHz): δ_H 1.49–1.64 (10H, m, 5CH₂ cyclohexyl), 2.94 (1H, s, CH–N), 3.80 (3H, s, CH₃–O) 6.89–7.22 (9H, m, CH aromatic), 8.31 (1H, s, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C 25.34, 26.03, 32.46 (CH₂, cyclohexyl), 36.81 (C(CN)₂), 52.37 (CH–N), 55.35 (CH₃ methoxy), 82.01 (C–Ar), 87.95 (C–O), 108.31, 117.56 (CN), 114.74, 126.25, 126.62, 128.23, 128.66, 129.32, 133.32 (C aromatic), 130.99 (O–C–N), 160.01 (C–O). Anal. calcd for C₂₆H₂₄N₄O₂ (424.49): C, 73.56; H, 5.70; N, 13.20%. Found: C, 73.58; H, 5.65; N, 13.23%.

3.3.10. 5-(tert-Butylamino)-4-(4-methoxyphenyl)-2-phenylfuran-2,3,3(2H)-tricarbonitrile (6bd). White powder (0.172 g, 43%). Mp 216–218 °C. IR (KBr) (ν_max, cm⁻¹): 1347 (C–O), 2361 (CN), 3414 (NH). ¹H NMR (DMSO-d₆, 400 MHz): δ_H 1.40 (9H, m, C(CH₃)₃), 3.80 (3H, s, CH₃–O), 6.89–7.22 (9H, m, CH aromatic), 8.47 (1H, s, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C 30.03 (3CH₃, tert-butyl), 36.81 (C(CN)₂), 52.37 (C–N), 55.35 (CH₃ methoxy), 82.01 (C–Ar), 87.95 (C–O), 108.31, 117.56 (CN), 114.74, 126.25, 126.62, 128.23, 128.66, 129.32, 133.32 (C aromatic), 130.99 (O–C–N), 160.01 (C–O), Anal. calcd for C₂₄H₂₂N₄O₂ (398.46): C, 72.34; H, 5.57; N, 14.06%. Found: C, 72.30; H, 5.61; N, 14.09%.

3.3.11. 4-(4-Methoxyphenyl)-2-phenyl-5-(para-toluene sulfonylmethanamino)furan-2,3,3(2H)-tricarbonitrile (6cd). White powder (0.322 g, 63%). Mp 236–238 °C. IR (KBr) (ν_max, cm⁻¹): 1345 (C–O), 1521 (N=O), 2360 (CN), 3415 (NH). ¹H NMR (DMSO-d₆, 400 MHz): δ_H 2.40 (3H, s, Me), 3.80 (s, CH₃–O), 4.22 (1H, d, J = 7.65, N–CH₂–S), 4.67 (1H, d, J = 7.65, N–CH₂–S), 7.30–8.17 (14H, m, CH aromatic), 8.94 (1H, s, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C 21.62 (CH₃-ph), 36.82 (C(CN)₂), 57.35 (CH₃ methoxy), 61.38 (N–CH₂–S), 80.02 (C–Ar), 87.95 (C–O), 108.31, 117.56 (CN), 124.85, 126.25, 127.51, 128.23, 128.43, 128.66, 129.07, 132.83, 133.31, 134.01 (C aromatic), 136.97 (C–S), 137.02 (O–C–N). Anal. calcd for C₂₈H₂₂N₄O₄S (510.56): C, 65.87; H, 4.34; N, 10.97%. Found: C, 65.81; H, 4.37; N, 10.95%.

3.3.12. 5-(Cyclohexylamino)-4-(4-fluorophenyl)-2-phenylfuran-2,3,3(2H)-tricarbonitrile (6ae). White powder (0.112 g, 27%). Mp 221–223 °C. IR: (KBr) (ν_max, cm⁻¹): 1220 (C–F), 1381 (C–O), 2374 (CN), 3422 (NH). ¹H NMR (DMSO-d₆, 400 MHz): δ_H 1.17–1.87, (10H, m, 5CH₂ cyclohexyl) 3.25 (1H, s, CH–N), 7.21–7.75 (9H, m, CH aromatic), 8.48 (1H, s, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C 25.34, 26.04, 32.46 (CH₂, cyclohexyl), 36.82 (C(CN)₂), 52.35 (C–H, cyclohexyl), 82.01 (C–Ar), 87.95 (C–O), 108.31 (CN), 126.25, 128.23, 128.31, 128.66, 128.68, 128.81, 130.04, 133.31 (C aromatic), 130.99 (O–C–N), 163.15 (C–F). Anal. calcd for C₂₅H₂₁FN₄O (412.46): C, 72.80; H, 5.13; N, 13.58%. Found: C, 72.80; H, 5.09; N, 13.54%.

3.3.13. 5-(tert-Butylamino)-4-(4-fluorophenyl)-2-phenylfuran-2,3,3(2H)-tricarbonitrile (6be). White powder (0.097 g, 25%) Mp 213–214 °C, IR (KBr) (ν_max, cm⁻¹): 1234 (C–F), 1347 (C–O), 2361 (CN), 3414 (NH). ¹H NMR (DMSO-d₆, 400 MHz): δ_H 1.40 (9H, s, C(CH₃)₃), 7.30–8.20 (9H, m, CH aromatic), 8.74 (1H, s, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C 30.03 (CH₃), 36.82 (C(CN)₂), 54.04 (CNH), 85.84 (C–Ar), 87.95 (C–O), 108.31, 117.56 (CN), 124.85, 126.25, 127.52, 128.23, 128.66, 132.83, 133.31 (C aromatic), 140.02 (O–C–N), 163.15 (C–F). Anal. calcd for C₂₃H₁₉FN₄O (386.42): C, 71.49; H, 4.96; N, 14.50%. Found: C, 71.42; H, 5.01; N, 14.54%.

3.3.14. 4-(4-Fluorophenyl)-2-phenyl-5-(para-toluene sulfonylmethanamino)furan-2,3,3(2H)-tricarbonitrile (6ce). White powder (0.150 g, 30%). Mp 227–229 °C. IR (KBr) (ν_max, cm⁻¹): 1242 (C–F), 1345 (C–O), 2360 (CN), 3415 (NH). ¹H NMR (DMSO-d₆, 400 MHz): δ_H 2.42 (3H, s, Me), 4.29 (1H, d, J = 7.65, N–C–S), 4.43 (1H, d, J = 7.65, N–C–S), 7.30–8.17 (14H, m, CH aromatic), 9.29 (1H, s, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ_C 21.64 (CH₃-ph), 36.82 (C(CN)₂), 61.38 (N–C–S), 80.01 (C–Ar), 87.95 (C–O), 108.31, 117.56 (CN), 124.85, 126.25, 127.51, 128.23, 128.43, 128.66, 129.07, 132.83, 133.31, 134.01 (C aromatic), 136.97 (C–S), 137.02 (O–C–N), 163.15 (C–F). Anal. calcd for C₂₇H₁₉FN₄O₃S (498.53): C, 65.05; H, 3.84; N, 11.24%. Found: C, 65.15; H, 3.81; N, 11.26%.

Acknowledgements

The authors are gratefully acknowledge to the Research Council of Islamic Azad University, Shiraz branch for partial financial supporting of this work. The authors also thank Dr Hamid Reza Khavasi, faculty member of chemistry department of Shahid Beheshti University and his research group for his useful advice.

References and notes

1. (a) R. A. Sheldon, Pure Appl. Chem., 2000, 72, 1233; (b) B. M. Trost, Angew. Chem., Int. Ed. Engl., 1995, 34, 259; (c) B. M. Trost, Science, 1991, 254, 1471.
2. P. Tundo and P. T. Anastas, Green Chemistry: Challenging Perspectives, Oxford University Press, Oxford, 1999.
3. I. Akritopoulou-Zanze and S. W. Djuric, Top. Heterocycl. Chem., 2010, 25, 231.
4. J. R. Sundberg, The Chemistry of Indoles, Academic, New York, 1996.
5. M. J. F. Da-Silva, J. S. Garden and C. A. Pinto, J. Braz. Chem. Soc., 2001, 12, 273.
6. R. A. Sheldon, Green Chem., 2005, 7, 267.
7. A. Lazuen Garay, A. Pichon and S. L. James, Chem. Soc. Rev., 2007, 36, 846.
8. S. Lindbæk Broman, M. Jevric, B. D. Andrew and M. Brøndsted Nielsen, J. Org. Chem., 2014, 79, 41.
9. Y. A. Son, S. Y. Gwon, S. Y. Lee and S. H. Kim, Spectrochim. Acta, Part A, 2010, 75, 225.
10. M. Fukuda, K. Kodama, H. Yamamoto and K. Mito, Dyes Pigm., 2004, 63, 115.
11. C. C. Lee and A. T. Hu, Dyes Pigm., 2003, 59, 63.
12. D. H. Lee, K. H. Lee and J. I. Hong, Org. Lett., 2001, 3, 5.
13. A. A. Ishchenko, A. V. Kulinich, S. L. Bondarev and V. N. Knyukshto, J. Phys. Chem. A, 2007, 111, 13629.
14. M. He, T. M. Leslie, J. A. Sinicropi, S. M. Garner and L. D. Reed, Chem. Mater., 2002, 14, 4669.
15. E. Knoevenagel, Chem. Ber., 1896, 29, 172.
16. K. Ebitani, Org. Synth., 2014, 2, 571.
17. R. Y. Guo, Z. M. An, L. P. Mo, R. Z. Wang, H. X. Liu, S. X. Wang and Z. H. Zhang, ACS Comb. Sci., 2013, 15, 557.
18. T. Takahashi, Y. Li, F. Y. Tsai and K. Nakajima, Organometallics, 2001, 20, 595.
19. V. Nair, R. S. Menon, P. B. Beneesh, V. Sreekumar and S. Bindu, Org. Lett., 2004, 6, 767.
20. G. Qiu, Q. Ding, Y. Peng and J. Wu, Tetrahedron Lett., 2010, 51, 4391.
21. V. Nair, A. U. Vinod, N. Abhilash, R. S. Menon, V. Santhi, R. L. Varma, S. Viji, S. Mathew and R. Sriniva, Tetrahedron, 2003, 59, 10279.
22. H. R. Safaei, N. Shioukhi and M. Shekouhy, Monatsh. Chem., 2013, 144, 1855.
23. (a) H. R. Safaei, M. Shekouhy, A. Shirinfeshan and S. Rahmanpur, Mol. Diversity, 2012, 16, 669; (b) H. R. Safaei, M. Shekouhy, S. Rahmanpur and A. Shirinfeshan, Green Chem., 2012, 14, 1696; (c) H. R. Safaei, M. Shekouhy, V. Shafiee and M. Davoodi, J. Mol. Liq., 2013, 180, 139; (d) H. R. Safaei, M. Davoodi and M. Shekouhy, Synth. Commun., 2013, 43, 2178; (e) H. R. Safaei, M. Shekouhy, S. Khademi, V. Rahmanian and M. Safaei, J. Ind. Eng. Chem., 2014, 20, 3019; (f) J. A. Gladysz, H. R. Safaei and S. Nouri, Helv. Chim. Acta, 2014, 97, 1539; (g) H. R. Safaei, M. Safaei and M. Shekouhy, RSC Adv., 2015, 5, 6797.
24. H. A. Rouhi Sadabad, A. Bazgir, M. Eskandari and R. Ghahremanzadeh, Monatsh. Chem., 2014, 145, 1851.
25. X. Wang, S.-Y. Wang and S.-J. Ji, Org. Lett., 2013, 15(8), 1954.
26. A. Sagırli, Y. Durust, B. Kariuki and D. W. Knight, Tetrahedron, 2013, 69, 69.
27. X. Wang, X.-P. Xu, S.-Y. Wang, W. Zhou and S.-J. Ji, Org. Lett., 2013, 15(16), 4246.
28. M. B. Teimouri, A. Shaabanib and R. Bazhrang, Tetrahedron, 2006, 62, 1845.
29. F. Bigi, M. L. Conforti, R. Maggi, A. Piccinno and S. Giovanni, Green Chem., 2002, 2, 101.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra22293a

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