Domino reactions in water

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Domino reactions in water: diastereoselective synthesis of densely functionalized indolyldihydrofuran derivatives†

Downloaded by Madurai Kamraj Univeristy on 17 April 2012 Published on 23 January 2012 on http://pubs.rsc.org | doi:10.1039/C2GC16517A

Pethaiah Gunasekaran,a Kamaraj Balamurugan,a Sathiyamoorthi Sivakumar,a Subbu Perumal,*a J. Carlos Menéndez*b and Abdulrahman I. Almansourc Received 25th November 2011, Accepted 27th December 2011 DOI: 10.1039/c2gc16517a

A library of trans-5-aroyl-2-(indol-3-yl)-4-aryl-4,5-dihydrofuran-3-carbonitriles was diastereoselectively synthesized in excellent yields from the reaction of 2-(3-indolylcarbonyl)-3-aryl-2-propenenitriles with (2-aryl-2-oxoethyl)pyridinium bromides in the presence of triethylamine via a simple, user-friendly domino process carried out in water. Extraction and chromatographic steps were avoided, since the final products could be simply filtered from the aqueous reaction medium and recrystallized. This one-pot transformation generates one C–C and one C–O bond and presumably proceeds by a domino sequence involving the generation of a pyridinium ylide, a Michael addition and a final annulation via intramolecular nucleophilic substitution.

Introduction The elimination of hazardous solvents in chemical processes and their replacement by environmentally more benign reaction media is an important goal of modern synthetic chemistry. Water can be considered to be nature’s reaction medium and is a nonflammable, non-toxic, inexpensive solvent that has the additional advantage of being a non-exhaustible resource that is almost freely available even in the least developed countries.1,2 Although some limitations have been pointed out,3 it is generally accepted that these properties mean that in many cases water is close to being the ideal solvent, and preferable to alternatives like ionic liquids.4 Furthermore, the use of water as the reaction medium enhances the rate and selectivities of many organic reactions, besides often enabling the facile separation of the reaction products. The low solubility of non-polar starting materials in water can often be overcome by the use of organic cosolvents or surfactants which disrupt the strong hydrogen-bond network of pure water and facilitate the solubility of the reactants and the reactions. Moreover, several types of reactions of water-insoluble organic compounds (“on-water” processes) occur more rapidly in heterogeneous phase in water than in homogeneous phase in organic solvents.5,6 a

Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India. E-mail: subbu.perum@ gmail.com; Fax: +91-452-2459845 b Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain. E-mail: [email protected]; Fax: +34-91-3941822 c Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia † Electronic supplementary information (ESI) available: Spectra of representative compounds. CCDC reference numbers . For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/ c2gc16517a 750 | Green Chem., 2012, 14, 750–757

One of the most relevant approaches to achieving synthetic efficiency is based on the use of methods that are able to generate several bonds in a single operation,7 including domino reactions.8 These methods offer remarkable advantages from the environmental viewpoint such as operational simplicity, facile automation and minimized waste generation because of the reduction in the number of work-up, extraction and purification stages. The combination of these advantages with those associated to the use of water is relatively unexplored in synthetic methodology, although it would lead to procedures that can be considered close to the ideal reaction from economic and environmental points of view. Against this background, we illustrate in this paper the synthesis of a library of biologically relevant heterocycles by means of a domino reaction carried out in water. This work stems as part of our recent research program on the construction of novel heterocyclic ring systems via multicomponent/domino reaction pathways,9 and their screening for antimycobacterial activities.10 It is pertinent to note that the design of synthetic routes to privileged heterocyclic scaffolds11 of medicinal relevance that combine the synthetic efficiency of domino reactions with the environmental benefits of using water as the reaction medium constitutes a very important challenge that has received relatively little attention. Due to the biological significance of both substructures, our target compounds were designed as dihydrofuran–indole hybrids. Thus, substituted di- and tetrahydrofurans form the core structure of many important families of natural products12 and also serve as valuable intermediates in the syntheses of natural products and pharmaceuticals.13 Some examples are muscarine, the main component of the poisonous mushroom Amanita muscaria, which is the prototype of the muscarinic cholinomimetic agents,14 and the anticancer marine natural product (+)-varitriol (Fig. 1).15 On the other hand, in view of the role of indole as a privileged scaffold in drug development,16 it is not surprising This journal is © The Royal Society of Chemistry 2012


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Fig. 1 Select examples of naturally occurring furans and a dihydrofuran–indole hybrid. Table 1

Solvent and base screen for the model synthesis of 4a

Entry

Base (eq)

Solvent

Time (h)

Yielda (%)

1 2 3 4 5 6 7 8 9 10 11

Et3N (1.0) Et3N (1.0) Et3N (1.0) Et3N (1.0) Et3N (1.0) Et3N (0.25) Et3N (0.50) Et3N (1.0) K2CO3 (1.0) NaOAc (1.0) NH4OAc (3.0)

CH3CN DMF MeOH EtOH Dioxane Water Water Water Water Water Water

5 7 4 4 4 0.5 0.5 0.5 5 5 5

56 35 40 45 55 95 95 94 35 55 68

a

Isolated yield after purification by recrystallization from EtOAc–EtOH.

that many bioactive hybrid heterocycles comprising indole and di-/tetrahydrofuran substructures are known such as indole nucleosides 1, which show potent and selective toxicity against human cytomegalovirus.17 Related hybrid structures are found in natural products such as serotobenine, an alkaloid from the seeds of safflower (Carthamus tinctorius),18 and decursivine, isolated from Rhaphidophora decursiva.19

Results and discussion We describe here the preparation of dihydrofuran derivatives by reaction between chalcone-type compounds containing an indole moiety and phenacylpyridinium salts.20 We initially carried out a solvent optimization study for the reaction between 2-(1H-3indolylcarbonyl)-3-phenyl-2-propenenitrile 2a and 1-(2-oxo-1phenylethyl)pyridinium bromide 3a. Several solvents, such as EtOH, MeOH, dioxane, CH3CN and DMF, and different bases, viz. Et3N, NH4OAc, NaOAc and K2CO3, were assayed (Table 1). The best results, in terms of maximum yield of product 4a and This journal is © The Royal Society of Chemistry 2012

Scheme 1 Synthesis of trans-5-aroyl-2-(1H-indol-3-yl)-4-aryl-4,5dihydrofuran-3-carbonitriles 4.

minimum reaction time, corresponded to the water–Et3N combination, which was employed for all subsequent experiments. Our results show that the reaction is accelerated in an aqueous environment, although it may not be considered to satisfy all requirements to be regarded “on-water”, since these reactions are normally heterogeneous and ours start from a clear solution although the final products precipitate from the reaction medium. This is of interest in view of the growing interest in this type of processes from the point of view of synthetic and environmental efficiency, and also because of the relatively reduced number of domino reactions that have been performed in aqueous media.1,6 With these results in hand, we studied the scope of our reaction under the optimal conditions previously established, with the results shown in Scheme 1 and Table 2. Typically, a mixture of 2-(1H-3-indolylcarbonyl)-3-aryl-2-propenenitriles 2 (1.0 eq), 1-(2-oxo-1-arylethyl)pyridinium bromides 3 (1.0 eq), and triethylamine (0.25 eq) in water (10 ml) was stirred at ambient temperature for 0.5–3.5 h, which afforded a library of trans-5aroyl-2-(indol-3-yl)-4-aryl-4,5-dihydrofuran-3-carbonitriles 4 in 83–95% yields. This reaction proceeded in excellent yields and tolerated well the presence in the aromatic moieties of substituents having varied steric and electronic properties, but failed for substrates having aliphatic substituents in place of the Ar′ substituent, while we could not assay analogues of 2 having an aliphatic chain instead of the Ar substituent because we were unable to obtain them. The reactions were routinely carried out at a 1 mmol scale, but we found that the yield of the reaction furnishing 4e dropped only slightly (93–87%) when performed at a 10 mmol scale. Most interestingly from the point of view of green chemistry, the final products could be isolated by filtration because of their low solubility in water. Furthermore, their purity was very high, allowing their preparation in analytically pure form by a single recrystallization, thus avoiding extraction steps and chromatographic separations. Therefore, the use of water as the medium of our reaction allowed us to avoid almost completely the use of organic solvents, and also prevented the generation of waste from discarded chromatographic stationary phases. The structure of the final products was elucidated using 1H, 13 C and 2D-NMR spectroscopic data as described in detail for compound 4m (Fig. 2). The 1H NMR spectrum of this compound has two doublets at 4.60 and 6.39 ppm (J = 4.5 Hz), related by a H,H-COSY correlation and assignable to H-4 and Green Chem., 2012, 14, 750–757 | 751

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Table 2 Synthesis of trans-5-aroyl-2-(1H-indol-3-yl)-4-aryl-4,5dihydrofuran-3-carbonitriles 3 (1 mmol scale) Entry

Cmpd.

Ar

Ar′

Time (h)

Yielda (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

4a 4b 4c 4d 4e 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 4r 4s 4t 4u 4v 4w 4x 4y

C6H5 p-MeC6H4 p-iPrC6H4 p-MeOC6H4 p-ClC6H4 p-ClC6H4 o-MeC6H4 2,4-Cl2C6H3 m-FC6H4 m-ClC6H4 m-BrC6H4 m-O2NC6H4 C6H5 p-MeC6H4 p-iPrC6H4 p-MeOC6H4 p-ClC6H4 o-MeC6H4 2,4-Cl2C6H3 m-FC6H4 m-ClC6H4 m-O2NC6H4 p-ClC6H4 p-BrC6H4 C6H5 o-MeC6H4

C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-MeOC6H4 p-MeOC6H4 p-O2NC6H4 p-O2NC6H4

0.5 1.0 1.5 1.5 1.5 1.5 1.5 1.5 1.0 1.5 1.5 0.5 0.5 1.5 0.75 2.0 0.5 0.75 1.5 0.75 1.0 0.75 1.0 0.75 3.5 2.5

88 92 87 92 93 87b 87 93 90 91 91 93 95 89 88 91 83 89 93 91 93 91 89 92 84 89

a b

Isolated yield after purification by recrystallization from EtOAc–EtOH. This reaction was performed at a 10 mmol scale.

Fig. 2 1H- and tative example.

Fig. 3

ORTEP diagram of compound 4i.

C-4 at 50.5 ppm, C-3 at 79.6 ppm, C-1′′ at 139.5 ppm and C-2 at 165.7 ppm. H-2′ appears as a singlet at 8.14 ppm and shows (i) a C,H-COSY correlation with the carbon at 132.7 ppm due to C-2′ and (ii) a HMBC with the carbon at 165.7 ppm due to C-2. The doublet at 7.53 ppm (J = 8.4 Hz) due to H-7′ showed C, H-COSY correlation with the carbon at 112.8 ppm due to C-7′ and HMBCs with C-5′ at 121.4 ppm. Another doublet at 7.86 ppm (J = 8.1 Hz) due to H-4′ showed C,H-COSY correlation with C-4′ at 123.2 ppm and HMBCs with C-5′ at 121.4 ppm and C-7a′ at 136.4 ppm. The H-5′ appears as a triplet at 7.12 ppm (J = 7.8 Hz) and showed a C,H-COSY correlation at 121.4 ppm due to C-5′ and showed HMBC with C-7′ at 112.8 ppm. A single crystal X-ray crystallographic study of 4i confirmed the structural assignment (Fig. 3). A plausible mechanism for the formation of compounds 4 is depicted in Scheme 2. The Michael addition of the pyridinium ylide 5 (generated in situ from 3) to propenenitriles 2 furnishes the zwitterionic enolate 6, which undergoes annulation via chemoselective intramolecular SN2 substitution to give the final 2,3-dihydrofurans 4, exclusively in trans relative configuration. This complete diastereoselectivity is ascribable to an anti mode of addition for the Michael addition step, whereby repulsive interactions between the aryl and aroyl substituents are

13

C-NMR assignment of compound 4m, as a represen-

H-5 respectively, the J values indicating that H-4 and H-5 are trans to each other. H-4 showed (i) C,H-COSY correlation with C-4 at 50.5 ppm, (ii) HMBCs with the carbon signals, C-3 at 79.6 ppm, C-2′′ at 127.8 ppm, C-1′′ at 139.5 ppm, C-2 at 165.7 ppm and carbonyl C-1′′′ at 193.4 ppm. H-5 showed C, H-COSY correlation with C-5 at 89.5 ppm and HMBCs with 752 | Green Chem., 2012, 14, 750–757

Scheme 2 Proposed domino sequence accounting for the formation of compounds 4.

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minimized, and to the fact that the final SN2 reaction requires attack of the enolate from the side opposite to the leaving group.


Conclusions In conclusion, we have developed a method for the diastereoselective construction of indole–dihydrofuran hybrid heterocycles in excellent yields, using water as the reaction medium. The purification of the final products required a minimum amount of organic solvents and involved simple filtration of the solid material separated from the reaction mixture followed by its recrystallization. These reactions probably proceed via a domino sequence comprising ylide generation/Michael addition/ annulation individual steps, generating C–C and C–O bonds in a single synthetic operation.

Experimental Melting points were measured in open capillary tubes and are uncorrected. The 1H and 13C 2D-NMR spectra were recorded on a Bruker (Avance) 300 MHz NMR instrument using TMS as internal standard and CDCl3 and DMSO-d6 as solvents. Standard Bruker software was used throughout. Chemical shifts are given in parts per million (δ-scale) and the coupling constants are given in hertz. Silica gel-G plates (Merck) were used for TLC analysis with a mixture of petroleum ether (60–80 °C) and ethyl acetate as eluent. Elemental analyses were performed on a Perkin Elmer 2400 Series II Elemental CHNS analyzer. IR spectra were recorded on a JASCO FT IR instrument (KBr pellet method). HRMS measurements were performed by the CAI de Espectrometria de Mass, Universidad Complutense, using an FTMS Bruker APEX QIV instrument. General procedure for synthesis of (±)-trans-5-aroyl-2-(1H-indol3-yl)-4-aryl-4,5-dihydrofuran-3-carbonitrile derivatives (4)

To a stirred mixture of 2-(1H-3-indolylcarbonyl)-3-aryl-2-propenenitriles 2 (1.0 eq) and phenacylpyridinium bromides 3 (1.0 eq) in water (10 ml) was added dropwise triethylamine (0.25 eq) at room temperature. The resulting clear solution, that slowly became turbid, was stirred at room temperature for 0.5–3.5 h until completion of the reaction (TLC). Then the separated free flowing solid was filtered and washed with methanol (3 ml) to afford compounds 4 as pale yellow solids. The product thus obtained was recrystallized from EtOH–EtOAc mixture (1 : 1 ratio v/v, 5 ml) to give pure compounds 4, as white or pale yellow crystals. Their spectroscopic data are given below. (±)-trans-5-Benzoyl-2-(1H-3-indolyl)-4-phenyl-4,5-dihydro-3furan-carbonitrile (4a)

White solid; Yield 88%; mp 248 °C; 1H NMR (300 MHz, DMSO) δH: 4.69 (d, 1H, J = 4.8 Hz, H-4), 6.47 (d, 1H, J = 4.8 Hz, H-5), 7.13 (t, 1H, J = 7.5 Hz, Ar–H), 7.24 (t, 1H, J = 7.5 Hz, Ar–H), 7.37–7.45 (m, 5H, Ar–H), 7.54–7.59 (m, 3H, Ar– H), 7.71 (t, 1H, J = 7.5 Hz, Ar–H), 7.90–7.97 (m, 3H, Ar–H), 8.21 (s, 1H, Ar–H), 12.1 (br s, N–H); 13C NMR (75 MHz, DMSO) δC: 51.0, 78.6, 89.8, 103.9, 112.0, 117.8, 121.1, 121.3, This journal is © The Royal Society of Chemistry 2012

122.6, 124.8, 127.4, 127.9, 128.7, 128.9, 129.0, 133.6, 133.9, 136.1, 140.1, 166.0, 192.8. HRMS Calcd for C26H18N2O2: 390.13683. Found: 390.13448 (M+), 389.13042 (M+ − 1). Anal. Calcd for C26H18N2O2: C, 79.98; H, 4.65; N, 7.17%. Found C, 79.93; H, 4.61; N, 7.14%. (±)-trans-5-Benzoyl-2-(1H-3-indolyl)-4-(4-methylphenyl)-4,5dihydro-3-furanecarbonitrile (4b)

Pale yellow solid; Yield 92%; mp 229 °C; 1H NMR (300 MHz, DMSO) δH: 2.38 (s, 3H, CH3), 4.64 (d, 1H, J = 5.4 Hz, H-4), 5.96 (d, 1H, J = 5.4 Hz, H-5), 7.13 (t, 1H, J = 7.5 Hz, Ar–H), 7.16–7.33 (m, 5H, Ar–H), 7.46–7.55 (m, 3H, Ar–H), 7.67 (t, 1H, J = 7.5 Hz, Ar–H), 7.95–7.99 (m, 3H, Ar–H), 8.21 (s, 1H, Ar–H), 11.45 (s, br, N–H); 13C NMR (75 MHz, DMSO) δC: 25.8, 55.7, 83.6, 94.6, 108.7, 117.0, 122.7, 126.0, 126.2, 127.5, 129.7, 133.2, 133.6, 133.8, 134.6, 138.3, 138.4, 138.9, 140.0, 142.0, 142.4, 170.8, 197.8. HRMS Calcd. for C27H20N2O2: 404.15248. Found: 404.15163 (M+), 403–14 784 (M+–1). Anal. Calcd for C27H20N2O2: C, 80.18; H, 4.98; N, 6.93%. Found C, 80.13; H, 4.94; N, 6.89%. (±)-trans-5-Benzoyl-2-(1H-3-indolyl)-4-(4-isopropylphenyl)-4,5dihydro-3-furanecarbonitrile (4c)

Pale yellow solid; Yield 87%; mp 235 °C. 1H NMR (300 MHz, CDCl3) δH: 1.20 (d, 6H, J = 6.9 Hz, ipr), 2.88–2.92 (m, 1H, CH), 4.59 (d, 1H, J = 4.5 Hz, H-4), 6.39 (d, 1H, J = 4.8 Hz, H-5), 7.11 (t, 1H, J = 7.8 Hz, Ar–H), 7.19–7.28 (m, 5H, Ar–H), 7.85 (d, 1H, J = 7.8 Hz,), 7.92 (d, 1H, J = 7.5 Hz, Ar–H), 8.14 (s, 1H, Ar–H), 12.10 (s, br, N–H); 13C NMR (75 MHz, DMSO) δC: 23.3, 32.6, 49.7, 78.6, 88.8, 102.9, 111.9, 117.4, 120.6, 122.3, 124.1, 126.6, 126.9, 128.2, 128.4, 128.5, 133.1, 133.6, 135.5, 137.2, 147.7, 165.1, 193.5. HRMS Calcd. for C29H24N2O2: 432.18378. Found: 432.18402 (M+), 431.18061 (M+ − 1). Anal. Calcd for C29H24N2O2: C, 80.53; H, 5.59; N, 6.48%. Found C, 80.55; H, 5.54; N, 6.46%. (±)-trans-5-Benzoyl-2-(1H-3-indolyl)-4-(4-methoxyphenyl)-4,5dihydro-3-furanecarbonitrile (4d)

Pale yellow solid; Yield 92%; mp 213 °C; 1H NMR (300 MHz, CDCl3) δH: 3.83 (s, 3H, OCH3), 4.68 (d, 1H, J = 5.4 Hz, H-4), 5.94 (d, 1H, J = 5.4 Hz, H-5), 6.94 (d, 2H, J = 8.7 Hz, Ar-H), 7.12–7.31 (m, 5H, Ar–H), 7.41 (d, 1H, J = 7.8 Hz,), 7.52 (t, 1H, J = 7.5 Hz, Ar–H), 7.66 (t, 1H, J = 7.5 Hz, Ar–H), 7.96–8.03 (m, 3H, Ar–H), 8.19 (s, 1H, Ar–H), 8.92 (s, br, N–H); 13C NMR (75 MHz, CDCl3) δC: 50.8, 55.4, 80.4, 90.4, 105.4, 111.6, 114.8, 117.9, 121.9, 123.5, 124.4, 125.0, 128.3, 128.9, 129.2, 132.2, 133.7, 133.9, 134.2, 135.7, 159.7, 165.6, 193.1. Anal. Calcd for C27H20N2O3: C, 77.13; H, 4.79; N, 6.66%. Found C, 77.10; H, 4.76; N, 6.63%. (±)-trans-5-Benzoyl-2-(1H-3-indolyl)-4-(4-chlorophenyl)-4,5dihydro-3-furanecarbonitrile (4e)

Pale yellow solid; Yield 93%; mp 221 °C; 1H NMR (300 MHz, CDCl3) δH: 4.77 (d, 1H, J = 5.4 Hz, H-4), 5.89 (d, 1H, J = 5.4 Hz, H-5), 7.16–7.19 (m, 1H, Ar–H), 7.26–7.34 (m, 3H, Ar–H), Green Chem., 2012, 14, 750–757 | 753

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7.38–7.44 (m, 3H, Ar–H), 7.51–7.56 (m, 2H, Ar–H), 7.67 (t, 1H, J = 8.4 Hz, Ar–H), 7.97–7.80 (m, 3H, Ar–H); 8.22 (d, 1H, J = 3 Hz, Ar–H), 8.89 (s, br, N–H); 13C NMR (75 MHz, CDCl3) δC: 50.4, 79.1, 90.1, 104.8, 111.7, 117.7, 121.6, 121.9, 123.4, 124.8, 127.7, 128.6, 128.9, 129.0, 129.2, 129.5, 133.5, 134.1, 134.3, 135.6, 138.6, 166.2, 192.7. HRMS Calcd for C26H17ClN2O2: 424.09786. Found: 424.09271 (M+), 432.08992 (M+ − 1). Anal. Calcd for C26H17ClN2O2: C, 73.50; H, 4.03; N, 6.59%. Found C, 73.47; H, 4.07; N, 6.56%. (±)-trans-5-Benzoyl)-2-(1H-3-indolyl)-4-(2-methylphenyl)-4,5dihydro-3-furanecarbonitrile (4f )

White solid; Yield 87%; mp 204 °C; 1H NMR (300 MHz, DMSO) δH: 2.19 (s, 3H, CH3), 4.95 (d, 1H, J = 4.5 Hz, H-4), 6.40 (d, 1H, J = 4.8 Hz, H-5), 7.08 (t, 1H, J = 7.5 Hz, Ar–H), 7.18–7.38 (m, 5H, Ar–H), 7.50–7.58 (m, 3H, Ar–H), 7.11 (t, 1H, J = 7.5 Hz, Ar–H), 7.78 (d, 1H, J = 8.1 Hz, Ar–H), 7.94 (d, 2H, J = 3 Hz, Ar–H), 8.14 (s, 1H, Ar–H), 12.15 (s, br, N–H); 13 C NMR (75 MHz, DMSO) δC: 18.4, 45.9, 78.4, 88.7, 102.8, 112.0, 117.3, 120.5, 120.6, 122.3, 124.0, 126.6, 127.0, 127.3, 128.3, 128.5, 128.6, 130.2, 133.4, 133.6, 135.2, 135.5, 138.0, 164.8, 193.7. HRMS Calcd for C27H20N2O2: 404.15248. Found: 404.14729 (M+), 403.14441 (M+ − 1). Anal. Calcd for C27H20N2O2: C, 80.18; H, 4.98; N, 6.93%. Found C, 80.15; H, 4.96; N, 6.96%. (±)-trans-5-Benzoyl-2-(1H-3-indolyl)-4-(2,4-dichlorophenyl)-4,5dihydro-3-furanecarbonitrile (4g)

Pale yellow solid; Yield 93%; mp 213 °C; 1H NMR (300 MHz, CDCl3) δH: 5.40 (d, 1H, J = 4.5 Hz, H-4), 5.91 (d, 1H, J = 4.5 Hz, H-5), 7.15 (t, 1H, J = 7.5 Hz, H-6), 7.23–7.26 (m, 2H, Ar– H), 7.33 (d, 1H, J = 8.4 Hz, Ar–H), 7.41–7.46 (m, 2H, Ar–H), 7.51–7.57 (m, 2H, Ar–H), 7.67 (t, 1H, J = 7.2 Hz, Ar–H), 7.87 (d, 1H, J = 8.1 Hz, Ar–H), 8.03 (d, 2H, J = 7.8 Hz, Ar–H), 8.26 (s, 1H, Ar–H), 8.83 (s, br, N–H); 13C NMR (75 MHz, DMSO) δC: 45.6, 76.6, 87.3, 102.5, 111.9, 116.7, 120.2, 120.5, 122.2, 123.9, 127.8, 128.3, 128.6, 128.9, 130.3, 132.8, 132.9, 133.1, 133.6, 135.4, 135.9, 165.6, 192.5. Anal. Calcd for C26H16Cl2N2O: C, 67.99; H, 3.51; N, 6.10%. Found C, 67.96; H, 3.54; N, 6.13%. (±)-trans-5-Benzoyl-2-(1H-3-indolyl)-4-(3-fluorophenyl)-4,5dihydro-3-furanecarbonitrile (4h)

Pale yellow solid; Yield 90%; mp 220 °C; 1H NMR (300 MHz, DMSO) δH: 4.76 (d, 1H, J = 4.5 Hz, H-4), 6.50 (d, 1H, J = 4.8 Hz, H-5), 7.13–7.23 (m, 5H, Ar–H), 7.50–7.59 (m, 4H, Ar–H), 7.73 (d, 1H, J = 6.9 Hz, Ar–H), 7.86 (d, 1H, J = 6.9 Hz, Ar–H), 7.97 (d, 2H, J = 7. 8 Hz, Ar–H), 8.20 (s, 1H, Ar–H), 12.25 (s, br, N–H); 13C NMR (75 MHz, DMSO) δC: 49.4, 78.2, 88.4, 102.8, 112.1, 114.0 (d, 2JC,F = 21.8 Hz), 115.92 (d, 2JC,F = 20.5 Hz), 117.2, 120.6, 120.8, 122.5, 123.3, 124.1, 128.6 (d, 3JC,F = 9.7 Hz), 129.0, 130.8 (d, 3JC,F = 8.4 Hz), 133.1, 133.8, 135.6, 142.7 (d, 4JC,F = 6.8 Hz), 162.1 (d, 1JC,F = 243.15 Hz), 165.5, 193.3. HRMS Calcd for C26H17FN2O2: 408.12741. Found: 408.12838 (M+), 407.12024 (M+ − 1). Anal. Calcd for 754 | Green Chem., 2012, 14, 750–757

C26H17FN2O2: C, 76.46; H, 4.20; N, 6.86%. Found C, 76.42; H, 4.24; N, 6.81%. (±)-trans-5-Benzoyl-2-(1H-3-indolyl)-4-(2-chlorophenyl)-4,5dihydro-3-furanecarbonitrile (4i)

Pale yellow solid; Yield 91%; mp 202 °C; 1H NMR (300 MHz, DMSO) δH: 4.75 (d, 1H, J = 6.0 Hz, H-4), 6.49 (d, 1H, J = 6.0 Hz, H-5), 7.12 (t, 1H, J = 7.8 Hz, Ar–H), 7.23 (t, 1H, J = 7.8 Hz, Ar–H), 7.35–7.61 (m, 7H, Ar–H), 7.73 (d, 1H, J = 7.8 Hz, Ar–H), 7,84 (s, 1H, Ar–H), 7.96 (d, 2H, J = 8.1 Hz, Ar–H), 8.17 (s, 1H, Ar–H), 12.24 (s, br, N–H); 13C NMR (75 MHz, DMSO) δC: 49.3, 78.1, 88.4, 102.8, 112.1, 117.2, 120.7, 120.8, 122.5, 126.0, 127.1, 127.7, 128.2, 128.6, 129.0, 130.7, 133.1, 133.3, 133.8, 135.6, 142.4, 165.5, 193.3. HRMS Calcd. for C26H17ClN2O2: 424.09786. Found: 424.09379 (M+) and 426.09203 (M+ + 2); 423.09076 (M+ − 1) and 425.08872 (M+ + 1). Anal. Calcd for C26H17ClN2O2: C, 73.50; H, 4.03; N, 6.59%. Found C, 73.53; H, 4.07; N, 6.56%. (±)-trans-5-Benzoyl-2-(1H-3-indolyl)-4-(3-bromophenyl)-4,5dihydro-3-furanecarbonitrile (4j)

Pale yellow solid; Yield 91%; mp 195 °C; 1H NMR (300 MHz, CDCl3) δH: 4.77 (d, 1H, J = 5.4 Hz, H-4), 5.30 (d, 1H, J = 5.4 Hz, H-5), 7.13 (t, 1H, J = 8.1 Hz, H-6), 7.23 (t, 1H, J = 8.1 Hz, H-6), 7.28–7.82 (m, 2H, Ar–H), 7.46–7.57 (m, 5H, Ar–H), 7.69 (t, 1H, J = 7.5 Hz, Ar–H), 7.93 (d, 1H, J = 7.5 Hz, Ar–H), 8.01 (d, 2H, J = 7.5 Hz, Ar–H), 8.25 (s, 1H, Ar–H), 11.42 (s, br, N–H); 13C NMR (75 MHz, DMSO) δC: 49.3, 88.3, 102.8, 111.9, 114.0, 120.6, 120.7, 121.9, 122.4, 122.9, 126.3, 128.4, 128.6, 128.9, 129.9, 130.5, 130.8, 133.2, 133.8, 134.9, 135.5, 136.2, 142.5, 165.7, 193.4. HRMS Anal. Calcd for C26H17BrN2O2: 468.04734. Found: 468.04231 (M+) and 470.04132 (M+ + 2); 467.03972 (M+ − 1) and 469.03814 (M+ + 1). Anal. Calcd for C26H17BrN2O2: C, 66.54; H, 3.65; N, 5.97%. Found: C, 66.51; H, 3.61; N, 5.93%. (±)-trans-5-Benzoyl-2-(1H-3-indolyl)-4-(3-bromophenyl)-4,5dihydro-3-furanecarbonitrile (4k)

Pale yellow solid; Yield 93%; mp 230 °C; 1H NMR (300 MHz, DMSO) δH: 5.07 (d, 1H, J = 5.1 Hz, H-4), 6.57 (d, 1H, J = 5.1 Hz, H-5), 7.13 (t, 1H, J = 7.8 Hz, Ar–H), 7.24 (t, 1H, J = 7.8 Hz, Ar–H), 7.53–7.61 (m, 3H, Ar–H), 7.71–7.89 (m, 2H, Ar– H), 7.84 (d, 1H, J = 7.5 Hz, Ar–H), 7.96 (d, 2H, J = 7.5 Hz, Ar– H), 8.21–8.26 (m, 3H, Ar–H),12.24 (s, 1H, N–H); 13C NMR (75 MHz, DMSO) δC: 49.2, 77.8, 88.4, 102.8, 112.3, 117.3, 120.7, 121.0, 122.1, 122.7, 124.2, 128.7, 128.8, 129.3, 130.5, 133.3, 134.0, 134.2, 135.7, 142.2, 147.9, 165.9, 193.2. HRMS Calcd for C26H17N3O4: 435.12191. Found: 434.11544 (M+ − 1); 435.11821 (M+). Anal. Calcd for C26H17N3O4: C, 71.72; H, 3.94; N, 9.65%. Found C, 71.70; H, 3.91; N, 9.61%. (±)-trans-5-(4-Chlorobenzoyl)-2-(1H-3-indolyl)-4-phenyl-4,5dihydro-3-furanecarbonitrile (4l)

White solid; Yield 95%; mp 261 °C; 1H NMR (300 MHz, CDCl3) δH: 4.71 (d, 1H, J = 5.4 Hz, H-4), 5.97 (d, 1H, J = 5.4 This journal is © The Royal Society of Chemistry 2012

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Hz, H-5), 7.14 (t, 1H, J = 7.5 Hz, Ar–H), 7.22 (t, 1H, J = 7.5 Hz, Ar–H), 7.38–7.52 (m, 8H, Ar–H), 7.59 (s, 1H, Ar–H), 7.94 (d, 2H, J = 8.1 Hz, Ar–H), 8.19 (s, 1H, Ar–H), 11.56 (s, br, N–H); 13C NMR (75 MHz, CDCl3) δC: 49.6, 88.3, 102.4, 111.0, 116.4, 119.9, 120.0, 121.5, 123.5, 126.3, 126.8, 127.8, 127.9, 129.4, 130.9, 134.9, 138.8, 138.9, 164.6, 190.9. HRMS Calcd for C26H17ClN2O2: 424.09786. Found: 424.09400 (M+) and 426.09230 (M+ + 2); 423.09051 (M+ − 1) and 425.08882 (M+ + 1). Anal. Calcd for C26H17ClN2O2: C, 73.50; H, 4.03; N, 6.59%. Found C, 73.47; H, 4.01; N, 6.56%. (±)-trans-5-(4-Chlorobenzoyl)-2-(1H-3-indolyl)-4-(4methylphenyl)-4,5- dihydro-3-furanecarbonitrile (4m)

White solid; 89%; mp 254 °C; 1H NMR (300 MHz, CDCl3) δH: 2.50 (s, 3H, CH3), 4.60 (d, 1H, J = 4.5 Hz, H-4), 6.39 (d, 1H, J = 4.5 Hz, H-5), 7.12 (t, 1H, J = 7.6 Hz, H-6), 7.22–7.25 (m, 5H, H-5, 4Ar–H), 7.53 (d, 1H, J = 8.4 Hz, H-7), 7.65 (d, 2H, J = 8.4 Hz, Ar–H), 7.86 (d, 1H, J = 8.1 Hz, H-4), 7.93 (d, 2H, J = 8.4 Hz, Ar–H), 8.14 (s, 1H, H-2); 13C NMR (75 MHz, CDCl3) δC: 21.0, 50.5, 79.6, 89.5, 103.7, 112.8, 118.1, 121.4, 123.2, 124.9, 127.8, 129.0, 129.4, 129.5, 130.1, 131.2, 132.7, 136.4, 137.6, 137.7, 139.5, 165.7, 193.4. HRMS Calcd for C27H19ClN2O2: 438.11351. Found: 438–11 039 (M+) and 440.10868 (M+ + 2); 437.10702 (M+ − 1) and 440.10868 (M+ + 1). Anal. Calcd for C27H19ClN2O2: C, 73.89; H, 4.36; N, 6.38%. Found C, 73.82; H, 4.31; N, 6.33%. (±)-trans-5-(4-Chlorobenzoyl)-2-(1H-3-indolyl)-4-(4isopropylphenyl)-4,5-dihydro-3-furanecarbonitrile (4n)

Pale yellow solid; Yield 88%; mp 214 °C; 1H NMR (300 MHz, CDCl3) δH: 1.26 (d, 6H, J = 5,4 Hz, ipr), 2.89–2.98(m, 1H, CH), 4.72 (d, 1H, J = 5.4 Hz, H-4), 5.89 (d, 1H, J = 5.4 Hz, H-5), 7.15–7.28 (m, 6H, Ar–H), 7.36 (d, 1H, J = 7.8 Hz, Ar–H), 7.49 (d, 2H, J = 7.2 Hz, Ar–H), 7.92–7.98 (m, 3H, Ar–H), 8.18 (s, 1H, Ar–H), 9.02 (s, br, N–H); 13C NMR (75 MHz, CDCl3) δC: 23.9, 33.8, 50.8, 79.9, 90.2, 105.1, 111.7, 117.9, 121.6, 121.9, 123.5, 124.8, 127.4, 127.5, 128.4, 129.2, 130.6, 132.1, 135.6, 137.1, 140.7, 148.9, 165.7, 191.9. HRMS Calcd for C29H23ClN2O2: 466.14481. Found: 466.14072 (M+) and 468.13851 (M+ + 2); 465.13675 (M+ − 1) and 467.13544 (M+ + 1). Anal. Calcd for C29H23ClN2O2 C, 74.59; H, 4.96; N, 6.00%. Found: C, 74.56; H, 4.93; N, 6.03%.

(±)-trans-5-(4-Chlorobenzoyl)-2-(1H-3-indolyl)-4-(4chlorophenyl)-4,5-dihydro-3-furanecarbonitrile (4p)

White solid; Yield 83%; mp 257 °C; 1H NMR (300 MHz, DMSO) δH: 4.72 (d, 1H, J = 4.8 Hz, H-4), 6.43 (d, 1H, J = 4.8 Hz, H-5), 7.12 (t, 1H, J = 7.5 Hz, Ar–H), 7.23 (t, 1H, J = 7.5 Hz, Ar–H), 7.38 (d, 2H, J = 8.4 Hz, Ar–H), 7.49–7.54 (m, 3H, Ar–H), 7.66 (d, 2H, J = 8.4 Hz, Ar–H), 7.84 (d, 1H, J = 8.4 Hz, Ar–H), 7.94 (d, 2H, J = 8.7 Hz, Ar–H), 8.15 (s, 1H, Ar–H), 12.11 (s, br, N–H); 13C NMR (75 MHz, CDCl3) δC: 49.0, 78.3, 88.3, 102.7, 112.1, 117.2, 120.5, 120.7, 122.5, 124.1, 128.7, 128.9, 129.1, 130.1, 131.8, 132.2, 135.5, 138.8, 165.3, 192.4. HRMS Calcd for C26H16Cl2N2O2: 458.05888. Found: 458.05583 (M+), 460.05328 (M+ + 2) and 462.05234 (M+ + 4); 457.05231 (M+ − 1), 459.0500 (M+ + 1) and 461.04815 (M+ + 3). Anal. Calcd for C26H16Cl2N2O2: C, 67.99; H, 3.51; N, 6.10%. Found C, 67.96; H, 3.54; N, 6.14%.

(±)-trans-5-(4-Chlorobenzoyl)-2-(1H-3-indolyl)-4-(2methylphenyl)-4,5-dihydro-3-furanecarbonitrile (4q)

Pale yellow solid; Yield 89%; mp 226 °C; 1H NMR (300 MHz, CDCl3) δH: 2.34 (s, 3H, CH3), 5.15 (d, 1H, J = 5.4 Hz, H-4), 5.90 (d, 1H, J = 5.4 Hz, H-5), 7.16–7.29 (m, 6H, Ar–H), 7.43(d, 2H, J = 8.4 Hz, Ar–H), 7.48 (d, 2H, J = 8.4 Hz, Ar–H), 8.21 (s, 1H, Ar–H), 8.76 (s, br, N–H); 13C NMR (75 MHz, CDCl3) δC: 19.0, 45.9, 78.5, 89.4, 103.5, 111.7, 117.5, 120.8, 122.4, 124.4, 126.7, 127.0, 127.4, 128.7, 130.1, 130.4, 131.8, 135.4, 135.7, 137.9, 140.1, 165.2, 191.5. HRMS Calcd for C27H19ClN2O2: 438.11351. Found: 438.10995 (M+) and 440.10816 (M+ + 2); 437.10657 (M+ − 1) and 439.10447 (M+ + 1). Anal. Calcd for C27H19ClN2O2: C, 73.89; H, 4.36; N, 6.38%. Found C, 73.85; H, 4.33; N, 6.35%.

(±)-trans-5-(4-Chlorobenzoyl)-2-(1H-3-indolyl)-4-(2,4dichlorophenyl)-4,5-dihydro-3-furanecarbonitrile (4r)

Pale yellow solid; Yield 89%; mp 213 °C; 1H NMR (300 MHz, DMSO) δH: 5.36 (d, 1H, J = 4.5 Hz, H-4), 5.88 (d, 1H, J = 4.5 Hz, H-5), 7.12–7.21 (m, 2H, Ar–H), 7.34–7.52 (m, 6H, Ar–H), 7.80 (s, H, Ar–H), 7.88–8.05 (m, 2H, Ar–H), 8.21 (s, 1H, Ar– H), 11.52 (s, br, N–H). 13C NMR (75 MHz, DMSO) δC: 45.5, 76.7, 87.3, 102.5, 112.1, 116.8, 120.4, 120.7, 122.4, 123.9, 127.9, 128.6, 128.8, 129.1, 130.4, 130.6, 131.9, 133.0, 135.5, 136.0, 138.9, 165.6, 191.6. Anal. Calcd for C26H15Cl3N2O2 C, 63.24; H, 3.06; N, 5.67%. Found C, 63.21; H, 3.03; N, 5.64%.

(±)-trans-5-(4-Chlorobenzoyl)-2-(1H-3-indolyl)-4-(4methoxyphenyl)-4,5-dihydro-3-furanecarbonitrile (4o)

White solid; Yield 91%; mp 213 °C; 1H NMR (300 MHz, CDCl3) δH: 3.83 (s, 3H, OCH3), 4.65 (d, 1H, J = 3.9 Hz, H-4), 5.88 (d, 1H, J = 3.9 Hz, H-5), 6.94 (d, 2H, J = 7.2 Hz, Ar–H), 7.16–7.30 (m, 4H, Ar–H), 7.44–7.52 (m, 4H, Ar–H), 7.91–7.97 (m, 2H, Ar–H), 8.22 (s, 1H, Ar–H), 11.46 (s, br, N–H); 13C NMR (75 MHz, CDCl3) δC: 49.7, 54.4, 78.2, 89.1, 103.1, 111.4, 113.8, 117.0, 120.5, 121.9, 124.1, 127.8, 128.3, 129.7, 131.3, 135.4, 139.5, 158.6, 164.9, 191.2. Anal. Calcd for C27H19ClN2O3: C, 71.29; H, 4.21; N, 6.16%. Found C, 71.26; H, 4.24; N, 6.13%. This journal is © The Royal Society of Chemistry 2012

(±)-trans-5-(4-Chlorobenzoyl)-2-(1H-3-indolyl)-4-(3fluorophenyl)-4,5-dihydro-3-furanecarbonitrile (4s)

Pale yellow solid; Yield 91%; mp 272 °C; 1H NMR (300 MHz, CDCl3) δH: 4.82 (d, 1H, J = 5.4 Hz, H-4), 5.89 (d, 1H, J = 5.4 Hz, H-5), 7.04–7.25 (m, 4H, Ar–H), 7.37–7.54 (m, 5H, Ar–H), 7.90 (d, 1H, J = 8.1 Hz, Ar–H), 7.97 (d, 2H, J = 8.4 Hz, Ar–H), 8.24 (s, 1H, Ar–H), 11.48 (s, br, N–H); 13C NMR (75 MHz, DMSO) δC: 48.1, 77.4, 87.2, 101.6, 110.7, 112.6 (d, 2JC,F = 21.6 Hz), 113.1 (d, 2JC,F = 21.1 Hz), 115.7, 119.4, 121.0, 121.9, 122.9, 127.3, 127.6, 129.2 (d, 3JC,F = 14.4 Hz), 130.6, 134.3, Green Chem., 2012, 14, 750–757 | 755

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137.8, 141.2(d, 4JC,F = 6.2 Hz), 161.0 (d, 1JC,F = 244.2 Hz), 164.0, 190.6. HRMS Calcd for Anal. Calcd for 442.08843. Found: 441.08126 (M+ − 1); 442.08470 (M+) and 444.08316 (M+ + 2); 441.08126 (M+ − 1) and 443.08018 (M+ + 1). C26H16ClFN2O2: C, 70.51; H, 3.64; N, 6.33%. Found C, 70.53; H, 3.61; N, 6.34%.


(±)-trans-5-(4-Chlorobenzoyl)-2-(1H-3-indolyl)-4-(3chlorophenyl)-4,5-dihydro-3-furanecarbonitrile (4t)

Pale yellow solid; Yield 93%; mp 259 °C; 1H NMR (300 MHz, CDCl3) δH: 4.70 (d, 1H, J = 5.1 Hz, H-4), 6.20 (d, 1H, J = 5.1 Hz, H-5), 7.05 (t, 1H, J = 7.5 Hz, Ar–H), 7.16 (t, 1H, J = 7.5 Hz, Ar–H), 7.26–7.41 (m, 4H, Ar–H), 7.45 (d, 1H, J = 7.8 Hz, Ar–H), 7.52 (d, 2H, J = 8.4 Hz, Ar–H), 7.81 (d, 1H, J = 7.8 Hz, Ar–H), 7.93–7.99 (m, 2H, Ar–H), 8.13 (s, 1H, Ar–H), 11.94 (br s, N–H); 13C NMR (75 MHz, CDCl3) δC: 50.1, 89.3, 103.6, 112.5, 117.7, 121.3, 122.9, 124.8, 126.3, 127.7, 128.3, 129.2, 129.5, 130.8, 130.9, 132.3, 134.6, 136.2, 140.2, 142.6, 166.2, 192.1. HRMS Calcd for C26H16Cl2N2O2: 458.05888. Found: 458.05548 (M+); 460.05290 (M+ + 2) and 462.05189 (M+ + 4); 457.05193 (M+ − 1), 459.04961 (M+ + 1) and 461.04765 (M+ + 3). Anal. Calcd for C26H16Cl2N2O2: C, 67.99; H, 3.51; N, 6.10%. Found C, 67.96; H, 3.55; N, 6.13%.

(±)-trans-5-(4-Chlorobenzoyl)-2-(1H-3-indolyl)-4-(3nitrophenyl)-4,5-dihydro-3-furanecarbonitrile (4u)

Pale yellow solid; Yield 91%; mp 223 °C; 1H NMR (300 MHz, CDCl3) δH: 5.02 (d, 1H, J = 5.4 Hz, H-4), 6.10 (d, 1H, J = 5.4 Hz, H-5), 7.13 (t, 1H, J = 7.2 Hz, Ar–H), 7.23 (t, 1H, J = 7.2 Hz, Ar–H), 7.49 (d, 1H, J = 8.1 Hz, Ar–H), 7.55 (d, 2H, J = 8.1 Hz, Ar–H), 7.65–7.70 (m, 2H, Ar–H), 7.80 (d, 1H, J = 8.4 Hz, Ar–H), 7.86 (d, 1H, J = 8.1 Hz, Ar–H), 8.02 (d, 2H, J = 8.4 Hz, Ar–H), 8.21–8.26 (m, 3H, Ar–H), 11.81 (s, br, N–H); 13C NMR (75 MHz, CDCl3) δC: 48.1, 76.3, 87.5, 101.8, 110.9, 115.9, 119.6, 119.8, 121.1, 121.3, 121.4, 123.2, 127.4, 128.0, 129.0, 129.4, 130.8, 132.8, 134.6, 138.5, 140.9, 147.0, 164.8, 190.0. HRMS Calcd for C26H16ClN3O4: 469.08293. Found: 469.08132 (M+) and 470.07320 (M+ + 2); 468.07495 (M+ − 1) and 471.07744 (M+ + 1). Anal. Calcd for C26H16ClN3O4 C, 66.46; H, 3.43; N, 8.94% Found C, 66.43; H, 3.40; N, 8.91%.

(±)-trans-5-(4-Methoxybenzoyl)-2-(1H-3-indolyl)-4-(4chlorophenyl)-4,5-dihydro-3-furanecarbonitrile (4v)

Pale yellow solid; Yield 89%; mp 213 °C; 1H NMR (300 MHz, CDCl3 + DMSO) δH: 3.91 (s, 3H, OCH3), 4.75 (d, 1H, J = 5.4 Hz, H-4), 5.87 (d, 1H, J = 5.4 Hz, H-5), 7.01 (d, 2H, J = 7.8 Hz, Ar–H), 7.14 (t, 2H, J = 7.2 Hz, Ar–H), 7.23 (t, 2H, J = 7.2 Hz, Ar–H) 7.32–7.58 (m, 5H, Ar–H), 7.95–7.98 (m, 3H, Ar–H), 8.22 (s, 1H, Ar–H), 11.45 (br s, N–H); 13C NMR (75 MHz, CDCl3 + DMSO) δC: 49.2, 54.4, 88.1, 102.5, 111.1, 112.9, 116.5, 120.0, 120.2, 121.6, 123.6, 125.2, 127.9, 130.2, 132.2, 134.9, 137.8, 163.1, 165.1, 189.9. Anal. Calcd for C28H21ClN2O2: C, 74.25; H, 4.67; N, 6.18%. Found C, 74.35; H, 4.53; N, 6.25%. 756 | Green Chem., 2012, 14, 750–757

(±)-trans-5-(4-Methoxybenzoyl)-2-(1H-3-indolyl)-4-(4bromophenyl)-4,5-dihydro-3-furanecarbonitrile (4w)

Pale yellow solid; Yield 92%; mp 228 °C; 1H NMR (300 MHz, DMSO) δH: 3.91 (s, 3H, OCH3), 4.76 (d, 1H, J = 6.0 Hz, H-4), 5.84 (d, 1H, J = 6.0 Hz, H-5), 6.99 (d, 1H, J = 8.1Hz, Ar–H), 7.12–7.34 (m, 4H, Ar–H), 7.46 (d, 1H, J = 8.1Hz, Ar–H), 7.53–7.55 (m, 3H, Ar–H), 7.96–7.99 (m, 3H, Ar–H), 8.24 (s, 1H, Ar–H), 10.99 (s, br, N–H); 13C NMR (75 MHz, DMSO) δC: 49.4, 54.4, 88.1, 102.6, 111.1, 113.0, 116.5, 120.0, 120.2, 120.5, 121.6, 123.7, 125.2, 128.1, 128.4, 130.3, 130.9, 134.9, 138.4, 163.1, 165.1, 189.9. Anal. Calcd for C28H21BrN2O2: C, 67.61; H, 4.26; N, 5.63%. Found C, 67.70; H, 4.33; N, 5.68%.

(±)-trans-5-(4-Nitrobenzoyl)-2-(1H-3-indolyl)-4-phenyl-4,5dihydro-3-furanecarbonitrile (4x)

White solid; Yield 84%; mp 226 °C; 1H NMR (300 MHz, CDCl3 + DMSO) δH: 4.76 (d, 1H, J = 5.4 Hz, H-4), 6.06 (d, 1H, J = 5.4 Hz, H-5), 7.12 (t, 1H, J = 7.2 Hz, Ar–H), 7.22 (t, 1H, J = 7.2 Hz, Ar–H), 7.40–7.50 (m, 4H, Ar–H), 7.60 (s, 6H, Ar–H), 7.88 (d, 1H, J = 7.8 Hz, Ar–H), 8.19–8.21 (m, 3H, Ar–H), 8.35–8.41 (m, 3H, Ar–H), 11.65 (s, br, N–H); 13C NMR (75 MHz, CDCl3 + DMSO) δC: 49.1, 88.3, 102.7, 110.9, 116.1, 119.7, 121.3, 122.3, 123.3, 126.1, 126.7, 127.8, 129.0, 134.7, 137.3, 138.6, 139.8, 149.1, 164.2, 191.6. Anal. Calcd for C28H21N3O3: C, 75.15; H, 4.73; N, 9.39%. Found C, 75.27; H, 4.83; N, 9.48%.

(±)-trans-5-(4-Nitrobenzoyl)-2-(1H-3-indolyl)-4-(2methylphenyl)-4,5-dihydro-3-furanecarbonitrile (4y)

White solid; Yield 89%; mp 242 °C; 1H NMR (300 MHz, DMSO) δH: 2.37 (s, 3H, CH3), 5.20 (d, 1H, J = 4.8 Hz, H-4), 5.92 (d, 1H, J = 4.8 Hz, H-5), 7.09–7.14 (m, 1H, Ar–H), 7.19–7.42 (m, 6H, Ar–H), 7.82 (d, 1H, J = 7.8Hz, Ar–H), 8.18–8.21 (m, 3H, Ar–H), 8.34–8.56 (m, 3H, Ar–H), 11.23 (s, br, N–H); 13C NMR (75 MHz, CDCl3 + DMSO) δC: 18.3, 45.3, 77.9, 88.8, 102.6, 111.3, 116.6, 120.0, 120.2, 121.7, 122.2, 123.7, 126.1, 126.8, 128.2, 129.4, 134.7, 135.1, 137.1, 137.8, 149.5, 164.3, 191.6. Anal. Calcd for C27H18BrN3O3: C, 63.29; H, 3.54; N, 8.20%. Found C, 63.38; H, 3.62; N, 8.12%.

Acknowledgements S. P. and J. C. M. thank the Department of Science and Technology, New Delhi, and MICINN, Spain, for funding Indo-Spanish collaborative major research projects (grants DST/INT/SPAIN/ 09 and ACI2009–0956). The authors also gratefully acknowledge the Deanship of Scientific Research at King Saud University for funding through research grant RGP-VPP-026. S. P. and J. C. M. also gratefully acknowledge DST for funds under IRHPA program for the purchase of a high resolution NMR spectrometer and MICINN for grant CTQ2009-12320-BQU, respectively. P. G. thanks the Council of Scientific and Industrial Research, New Delhi, for the award of Junior and Senior research fellowships. This journal is © The Royal Society of Chemistry 2012

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