A direct green route towards the synthesis of 2-aroyl-3,5-diarylthiophenes from 1,5-diketones

Abstract

The synthesis of 2-aroyl-3,5-diarylthiophenes has been achieved from various 1,5-diketones with elemental sulphur and morpholine under efficient microwave conditions. The reaction follows a green protocol involving solvent-free conditions, short reaction time, and simple work-up avoiding chromatographic purification.

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Introduction

The synthesis of heterocyclic motifs with one or more heteroatoms from acyclic counterparts has traditionally attracted attention.¹ Thiophene is an important class of heterocycle forming the core of several compounds from natural and synthetic sources with widespread biological properties with promising pharmacological characteristics.^2,3 Most of the substituted thiophenes find numerous applications in modern drug design,⁴ biodiagnostics,⁵ electronic and optoelectronic devices,⁶ conductivity-based sensors,⁷ self-assembled superstructures,⁸ and dye chemistry.⁹ Several synthetic methods have been developed to generate trisubstituted thiophenes from functionalized carbonyl systems.¹⁰ The classical strategy for the synthesis of thiophenes involves the reaction of phosphorous sulphides such as Lawesson's reagent or bis-(trimethylsilyl)sulphide with 1,4-dicarbonyl systems.¹¹ Still the methods for constructing of di- or tri-substituted thiophene derivatives are meagre among the existing synthetic strategies.¹² Several transition metal catalyzed cross-couplings as well as C–S bond formation reactions have been employed for the synthesis of trisubstituted thiophenes.¹³ Multicomponent and domino reactions have gained tremendous attention for the construction of numerous complex molecules.¹⁴ In continuation of our efforts in the generation of heterocycles from 1,5-diketones and other functionalised acyclic systems,¹⁵ we planned to synthesize bisthiophenes under Gewald conditions. Interestingly the reaction has resulted in a different product. The Gewald reaction is the most convenient and well established protocol for the synthesis of 2-aminothiophenes¹⁶ and it involves the three-component domino reaction of a ketone with an activated nitrile and elemental sulfur in the presence of a base, this transformation being a remarkable one as the elemental sulphur is incorporated in the ring. 2-Aminothiophenes serve as important intermediates in dye preparation and drug formulations and as the basic framework for a variety of natural products.¹⁷

Results and discussion

The plan of this investigation was to generate bis-thiophene from the Gewald reaction of 1,3,5-triaryl-1,5-diketones and the interesting outcome is described here. The 1,5-diketones are very ideal to Gewald reaction with two different ends being ready to get cyclised. The 1,5-diketones 3 for the present investigation have been prepared by slightly modifying the reported procedure in a greener route.¹⁸ Out of the diketones synthesised, 3a–3e and 3m–3o have not been reported so far. It must be indicated that a preliminary attempt to get the Gewald product from 1,3,5-triphenyl-1,5-diketone was a failure from our group.^15a Now by changing the conditions, the reaction has been revisited. In a typical procedure to generate the bisthiophene, a mixture of 1,5-diketone 3h (R¹, R², R³ = 4-CH₃) (1.0 equiv.), malanonitrile (2.0 equiv.) and stoichiometric amount of sulfur (2.2 equiv.) in the presence of diethylamine (4.0 equiv.) was subjected to microwave irradiation for 20 minutes at 70 °C under solvent free condition. On completion of the reaction, a white solid was obtained upon washing with water and subsequent recrystallization from ethanol.¹⁹ This pure product was expected to be the bisthiophene 4′ by a double-Gewald pathway. But a closer analysis of the spectral data suggested that the desired bisthiophene has not been formed (Scheme 1) and a different product 4h was obtained.

Scheme 1 Attempted synthesis of bisthiophene 4′ and the formation of substituted thiophenes 4.

Obviously the sulfur has been incorporated in the 1,5-diketone motif and the ring formation has occurred in an intramolecular fashion without involving malanonitrile. Interestingly, in the absence of malanonitrile, the reaction has led to the formation of 2-aroyl-3,5-diarylthiophene 4h exclusively. After this serendipity result, it has been tried to get the expected bisthiophene by optimising the reaction conditions. The screening was carried out with different bases such as triethylamine, piperidine, morpholine, pyridine and DABCO and the stoichiometric amount of sulfur (2.2–2.8 equiv.) by varying the temperature under microwave irradiation for different time durations with no solvent. Increasing the reaction time and the base concentration (upto 10 equiv.) has led to no significant change in the formation 4h and no bisthiophene 4′ has been formed. The clean and neat conversion to 4h has been observed with 2.0 equivalent of morpholine and 1.1 equivalent of elemental sulfur at 110 °C within 5 min at microwave irradiation. Lowering the temperature led to a moderate yield of 65%. There is no significant improvement in the product yield at higher temperature. The ¹H NMR spectrum of 4h shows a distinct singlet at 7.37 ppm other than the aryl ring protons of the original substrate. The absence of –NH₂ peak is very much conspicuous. The ¹³C NMR spectrum clearly indicates the presence of a carbonyl group with the signal at 189.4 ppm. The characteristic nitrile carbon peak was not found. In ESI-MS m/z analysis, the mass of the compound 4h has been found to be 383.11. These observations were in agreement with the formation of a 2-aroyl-3,5-diarylthiophene.

Under the optimized conditions (Entry 9, Table 1), a library of thiophenes have been prepared (Table 2) and thus a facile and elegant method to synthesize 3,5-diaryl-2-aroylthiophenes has been revealed in this investigation.

Table 1 Screening of thiophene 4 formation^a

Entry	Base (equiv.)	Malanonitrile (equiv.)	S8 (equiv.)	Temp. (°C)	Time (min)	Yield % 4h
a Reaction carried out under solvent free condition.b Starting material recovered.
1	Diethylamine (4.0)	2.0	2.2	70	20	24
2	Triethylamine (4.0)	2.0	2.8	70	20	Nil^b
3	Pyridine (10.0)	2.8	2.8	110	5	Nil^b
4	Piperidine (4.0)	2.0	2.2	110	30	31
5	Piperidine (8.0)	2.4	2.8	130	30	33
6	Pyrrolidine (4.0)	2.2	2.2	100	25	38
7	Morpholine (4.0)	2.0	2.2	80	20	67
8	Morpholine (4.0)	—	1.1	80	15	65
9	Morpholine (2.0)	—	1.1	110	5	92
10	Morpholine (2.0)	—	1.1	150	5	91
11	DABCO (2.0)	—	1.1	110	20	Nil^b

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Table 2 Synthesis of 2-aroyl thiophenes (4a–4r)^a

a Reaction condition: In a 10 mL quartz vial 1,3,5-triarylpentane-1,5-dione 3 (1.0 equiv.), morpholine (2.0 equiv.) and elemental sulfur (1.1 equiv.) was sealed and subjected to microwave irradiation at 110 °C for 5 min.

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When the optimized condition was applied to symmetrical diketones (3a–3k) with identical substituents (R¹ = R³), the mode of cyclization could be possible at either of the carbonyl carbons resulting in a single product 4a–4k. If the starting diketone is unsymmetrical (3l, 3n and 3o) with different substituents at 1 and 5 positions (R¹≠R³), there is a possibility for the formation of two regioisomeric products. However, the major isomer has been isolated in the pure form in the cases of 4l, 4n and 4o, where the major: minor ratio ranged from 60 : 40 to 80 : 20. However, an inseparable mixture of regioisomers has been obtained with 4p (65 : 35), 4q (1 : 1) and 4r (1 : 1) as revealed by the NMR spectra of the mixtures. It is difficult to ascertain which of the regioisomers has been obtained as the major one by ¹H NMR and ¹³C NMR spectral data. However, the regiochemical arrangement for the major isomers of 4l, 4n and 4o shown in Table 2 can be justified vide infra.

A single crystal X-ray crystallographic study of 4a²⁰ unambiguously (Fig. 1) discloses the structure of the product 4.

Fig. 1 ORTEP diagram of 4a.

The mechanism for the formation of 3,5-diaryl-2-aroylthiophene 4 has been proposed (Scheme 2) and initially, morpholine polysulfide²¹ 5 has been formed in situ by the activation of elemental sulfur by morpholine. Then this polysulfide removes a proton from the most acidic α-methylene position creating a reactive nucleophilic poly sulphide adduct 6. The anion 6 behaves as a nucleophile attacking the carbonyl carbon forming 7 and the subsequent dehydration results in 8. Upon air oxidation, stable 3,5-diaryl-2-aroylthiophene 4 has been obtained. The formation of Knoevenagel product 1,5-bisarylidene malanonitrile 9 and the traditional Gewald reaction have not occurred even with the higher base concentration.

Scheme 2 Plausible mechanism for the formation of 4.

Regarding the unsymmetrical systems, of the two different ends, that end where a carbanion formation is stabilized will be attacked by the sulphur adduct. If the aroyl group has an electron releasing substituent, then that group will compete for the stabilization of anion and hence the formation of carbanion at that end may be difficult to achieve. This point is well documented in Scheme 3 justifying the proposed structures for the major regioisomers 4l, 4n and 4o. Unfortunately, it was not possible to grow single crystals in these cases to unambiguously ascertain the structures.

Scheme 3 Regiochemical preference in thiophene formation.

We tried this protocol with an aliphatic substituted 1,5-diketone system (3p) as well in the hope of getting fully substituted thiophene. The expected thiophene 4s was not obtained under the optimized conditions. This could be due to the poor regioselectivity among the three acidic centres for the initial anion generation (Scheme 4).

Scheme 4 Investigation with aliphatic system.

Conclusion

In conclusion, we have developed a rapid and experimentally convenient greener tool for the synthesis of thiophene derivatives from various 1,5-diketones with elemental sulfur in excellent yield. Participation of elemental sulfur in the thiophene ring formation similar to Gewald thiophene synthesis is another highlight of this method.

Experimental

General remarks

A CEM Discover microwave synthesizer (Model no. 908010) operating at 180/264 V and 50/60 Hz with microwave power maximum level of 300 W and microwave frequency of 2455 MHz was employed for the microwave-assisted experiments. Nuclear Magnetic Resonance (¹H and ¹³C NMR) spectra were recorded on a 300 MHz spectrometer in CDCl₃ using TMS as an internal standard. Chemical shifts are reported in parts per million (δ), coupling constants (J values) are reported in Hertz (Hz) and spin multiplicities are indicated by the following symbols: s (singlet), d (doublet), t (triplet), p (pentad), m (multiplet). ¹³C NMR spectra were routinely run with broadband decoupling. Pre coated silica gel on aluminium 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. Spectra were recorded in LCQ Fleet spectrometer, Thermo Fisher Instruments Limited, US. Electrospray ionization spectrometry (ESI-MS) analysis was performed in the positive ion and negative ion mode on a liquid chromatography ion trap.

General procedure for the synthesis of 1,3,5-triarylpentan-1,5-diones (3)

A mixture of chalcone 1 (1.0 equiv.), aryl methyl ketone 2 (1.0 equiv.) and powdered sodium hydroxide (2.0 equiv.) was crushed together for twenty minutes using a pestle and mortar. The mixture got solidified and the completion of the reaction was monitored by TLC chromatography using petroleum ether : ethyl acetate mixture (4 : 1) as eluent. After the completion of the reaction, the reaction mass was washed with water to remove the sodium hydroxide to give the corresponding 1,3,5-triarylpentan-1,5-diones. The product was further purified by recrystallization from ethanol to give colorless crystals.

General procedure for the synthesis of 2-aroyl thiophene (4)

A mixture of 1,3,5-triarylpentane-1,5-dione 3 (1.0 equiv.), morpholine (2.0 equiv.) and elemental sulfur (1.1 equiv.) was taken in a 10 mL quartz vial and placed in the microwave oven. The vial was sealed and subjected to microwave irradiation at 110 °C for 5 min. The reaction was monitored by TLC chromatography using petroleum ether : ethyl acetate mixture (4 : 1) as eluent. After the completion of the reaction, the reaction was cooled to room temperature and ice cooled water was added. The precipitate obtained was filtered, dried in vacuum and recrystallized from ethanol to afford 4.

1,3,5-Tri-(4-chlorophenyl)-1,5-pentanedioe 3a. Isolated as colorless solid; mp: 110–112 °C; ¹H NMR (300 MHz, CDCl₃) 7.88 (d, J = 8.4 Hz, 4H), 7.42 (d, J = 8.4 Hz, 4H), 7.29–7.22 (m, 4H), 4.03 (p, J = 6.9 Hz, 1H), 3.48 (dd, J = 17.1, 6.9 Hz, 2H), 3.30 (dd, J = 16.8, 6.9 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃) 196.9, 141.9, 140.0, 134.9, 132.5, 130.8, 129.4, 128.9, 128.8, 44.5, 36.4. Anal. calcd for C₂₃H₁₇Cl₃O₂; C, 63.98; H, 3.97%. Found: C, 63.96; H, 4.02%.

1,5-Bis(4-chlorophenyl)-3-(4-flurophenyl)-1,5-pentanedione 3b. Isolated as colorless solid; mp: 113–114 °C; ¹H NMR (300 MHz, CDCl₃) 7.88 (d, J = 8.7 Hz, 4H), 7.42 (d, J = 8.4 Hz, 4H), 7.24–7.05 (m, 4H), 4.06 (p, J = 6.6 Hz, 1H), 3.48 (dd, J = 16.8, 6.9 Hz, 2H), 3.30 (dd, J = 16.8, 6.9 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃) 197.1, 162.5, 142.7, 139.6, 139.0, 135.0, 129.5, 128.9, 115.4, 44.8, 36.4. Anal. calcd for C₂₃H₁₇Cl₂FO₂; C, 66.52; H, 4.13%. Found: C, 66.55; H, 4.18%.

3-(4-Bromophenyl)-1,5-bis(4-chlorophenyl)-1,5-pentanedione 3c. Isolated as colorless solid; mp: 94–95 °C; ¹H NMR (300 MHz, CDCl₃) 7.88 (d, J = 8.5 Hz, 4H), 7.43 (d, J = 8.5 Hz, 4H), 7.37 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 4.00 (p, J = 6.8 Hz, 1H), 3.45 (dd, J = 16.9, 6.8 Hz, 2H), 3.27 (dd, J = 16.8, 7.2 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃) 197.0, 142.6, 139.9, 135.1, 131.9, 129.6, 129.4, 129.1, 120.7, 44.7, 36.6. Anal. calcd for C₂₃H₁₇BrCl₂O₂; C, 58.01; H, 3.60%. Found: C, 58.03; H, 3.58%.

3-(3-Bromophenyl)-1,5-bis(4-chlorophenyl)-1,5-pentanedione 3d. Isolated as colorless solid; mp: 92–94 °C; ¹HNMR (300 MHz, CDCl₃) 7.88 (d, J = 8.4 Hz, 4H), 7.42–7.12 (m, 8H), 4.06 (p, J = 6.9 Hz, 1H), 3.45 (dd, J = 17.0, 6.8 Hz, 2H), 3.28 (dd, J = 16.9, 6.9 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃) 196.8, 145.9, 139.7, 134.9, 130.4, 130.2, 129.9, 129.5, 128.9, 126.3, 122.7, 44.4, 36.6. Anal. calcd for C₂₃H₁₇BrCl₂O₂: C, 58.01; H, 3.60%. Found: C, 58.04; H, 3.64%.

1,5-Bis(4-chlorophenyl)-3-(4-methoxyphenyl)-1,5-pentanedione 3e. Isolated as colorless solid; mp: 108–109 °C; ¹H NMR (300 MHz, CDCl₃) 7.86 (d, J = 8.4 Hz, 4H), 7.38 (d, J = 8.4 Hz, 4H), 7.17 (d, J = 8.7 Hz, 2H), 6.10 (d, J = 8.6 Hz, 2H), 4.11 (p, J = 7.2 Hz, 1H), 3.7 (s, 3H), 3.46 (dd, J = 16.5, 6.6 Hz, 2H), 3.28 (dd, J = 16.5, 6.9). ¹³C NMR (75 MHz, CDCl₃) 197.2, 158.1, 139.3, 135.2, 135.0, 129.4, 128.7, 128.2, 113.9, 54.9, 44.8, 36.3. Anal. calcd for C₂₄H₂₀Cl₂O₃; C, 67.46; H, 4.72%. Found: C, 67.50; H, 4.69%.

3-(4-Chlorophenyl)-1,5-bis(2-naphthyl)-1,5-pentanedione 3m. Isolated as colorless solid; mp: 119–120 °C; ¹H NMR (300 MHz, CDCl₃) 8.50 (s, 2H), 8.01–7.83 (m, 8H), 7.63–7.51 (m, 4H), 7.30–7.23 (m, 4H), 4.19 (p, J = 6.9 Hz, 1H), 3.67 (dd, J = 16.7, 6.7 Hz, 2H), 3.47 (dd, J = 16.7, 7.2 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃) 197.9, 142.1, 135.4, 133.8, 132.2, 132.1, 129.6, 129.3, 128.7, 128.5, 128.3, 128.2, 127.5, 126.6, 123.5, 44.6, 36.6. Anal. calcd for C₃₁H₂₃ClO₂: C, 80.42; H, 5.01%. Found: C, 80.38; H, 5.06%.

1-(4-Chlorophenyl)-3-(4-methylphenyl)-5-(thiophene-2-yl)-1,5-pentanedione 3n. Isolated as colorless crystal; mp: 88–90 °C; ¹H NMR (300 MHz, CDCl₃) 7.90 (d, J = 6.8 Hz, 2H), 7.76 (dd, J = 3.8, 1.1 Hz, 1H), 7.63 (dd, J = 4.9, 1.1 Hz, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.18–7.08 (m, 5H), 4.04 (p, J = 6.0 Hz, 1H), 3.54 (dd, J = 15.0, 6.0 Hz, 1H), 3.43 (dd, J = 15.0, 6.0 Hz, 1H), 3.33–3.21 (m, 2H) 2.30 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) 197.7, 191.8, 144.6, 140.6, 139.8, 136.7, 135.5, 134.1, 132.5, 129.9, 129.7, 129.2, 128.5, 127.6, 46.0, 45.0, 37.5, 21.3. Anal. calcd for C₂₂H₁₉ClO₂S; C, 69.01; H, 5.00; S, 8.37%. Found: C, 69.06; H, 5.04; S, 8.40%.

1,3-Bis(4-chlorophenyl)-5-(thiophen-2-yl)-1,5-pentanedione 3o. Isolated as colorless solid; mp: 98–99 °C; ¹H NMR (300 MHz, CDCl₃) 7.89 (d, J = 8.6 Hz, 2H), 7.75 (dd, J = 3.8, 1.1 Hz, 1H), 7.65 (dd, J = 5.0, 1.1 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.27–7.23 (m, 4H), 7.14 (dd, J = 4.9, 3.8 Hz, 1H), 4.02 (p, J = 9.0 Hz, 1H), 3.54–3.41 (m, 2H), 3.33–3.21 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) 197.0, 191.4, 144.3, 141.9, 139.8, 135.0, 134.1, 132.6, 132.3, 129.6, 129.1, 128.9, 128.9, 128.3, 45.4, 44.5, 36.9 Anal. calcd for C₂₁H₁₆Cl₂O₂S; C, 62.54; H, 4.00; S, 7.95%. Found: C, 62.59; H, 4.06; S, 7.91%.

(3,5-Bis(4-chlorophenyl)thiophen-2-yl)(4-chlorophenyl)methanone 4a²². Isolated as pale yellow solid; mp: 192–190 °C ¹H NMR (300 MHz, CDCl₃) δ 8.30 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 7.4 Hz, 2H), 7.65 (s, 1H), 7.62 (d, J = 7.4 Hz, 2H), 7.54–7.44 (m, 6H). ¹³C NMR (75 MHz, CDCl₃) δ 187.9, 148.2, 146.5, 138.8, 135.8, 135.7, 135.0, 134.1, 133.7, 131.3, 130.9, 130.3, 129.3, 128.4, 128.2, 127.3, 126.6.

(4-Chlorophenyl)(5-(4-chlorophenyl)-3-(4-fluorophenyl)thiophen-2-yl)methanone 4b. Isolated as pale yellow solid; mp: 181–182 °C ¹H NMR (300 MHz, CDCl₃) δ 7.63 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 7.37 (s, 1H), 7.24–7.18 (m, 4H), 6.93–6.87 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 188.2, 162.5, 148.2, 146.7, 138.7, 135.8, 135.7, 135.0, 131.4, 130.9, 130.8, 129.4, 128.2, 127.3, 126.8, 115.4, 115.2. Anal. calcd for C₂₃H₁₃Cl₂FOS: C, 64.65; H, 3.07; S, 7.50%. Found: C, 64.69; H, 3.03; S, 7.52%.

(3-(4-Bromophenyl)-5-(4-chlorophenyl)thiophen-2-yl)(4-chlorophenyl)methanone 4c. Isolated as pale yellow solid; mp: 143–145 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.63–7.57 (m, 4H), 7.41 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.7 Hz, 3H), 7.22 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 187.9, 148.2, 146.5, 138.9, 135.7, 135.6, 135.0, 134.2, 131.3, 131.2, 130.8, 130.5, 129.3, 128.3, 127.3, 126.5, 122.4. Anal. calcd for C₂₃H₁₃BrCl₂OS: C, 56.58; H, 2.68; S, 6.57%. Found: C, 56.54; H, 2.69; S, 6.55%.

(3-(3-Bromophenyl)-5-(4-chlorophenyl)thiophen-2-yl)(4-chlorophenyl)methanone 4d. Isolated as pale yellow solid; mp: 166–168 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.62 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 7.36 (s, 1H), 7.24–7.17 (m, 4H), 6.94–6.86 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 188.2, 148.5, 148.2, 146.7, 146.2, 138.7, 137.2, 135.8, 135.1, 132.1, 130.9, 130.7, 129.4, 128.2, 127.3, 126.8, 122.2, 115.4, 115.1. Anal. calcd for C₂₃H₁₃BrCl₂OS: C, 56.58; H, 2.68; S, 6.57%. Found: C, 56.54; H, 2.66; S, 6.59%.

(4-Chlorophenyl)(5-(4-chlorophenyl)-3-(4-methoxyphenyl)thiophen-2-yl)methanone 4e. Isolated as pale yellow solid; mp: 147–148 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.62 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.42–7.37 (m, 3H), 7.17 (d, J = 3.6 Hz, 2H), 7.13 (d, J = 3.7 Hz, 2H), 6.70 (d, J = 8.7 Hz, 2H), 3.75 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 188.3, 159.4, 147.8, 147.6, 138.1, 135.8, 135.0, 134.7, 131.4, 130.8, 130.3, 129.1, 127.9, 127.6, 127.1, 126.7, 113.5, 55.1. Anal. calcd for C₂₄H₁₆Cl₂O₂S: C, 65.61; H, 3.67; S, 7.30%. Found: C, 65.64; H, 3.65; S, 7.32%.

(4-Chlorophenyl)(5-(4-chlorophenyl)-3-(4-(dimethylamino)phenyl)thiophen-2-yl)methanone 4f. Isolated as pale yellow solid; mp: 136–138 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.62 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.46–7.34 (m, 3H), 7.13 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 6.47 (d, J = 8.7 Hz, 2H), 2.91 (s, 6H). ¹³C NMR (75 MHz, CDCl₃) δ 188.7, 150.2, 148.7, 147.7, 137.9, 136.1, 134.7, 134.2, 131.8, 130.9, 130.2, 129.2, 127.9, 127.3, 126.8, 122.9, 111.7, 40.3. ESI-MS m/z calcd for C₂₅H₁₉Cl₂NOS: [M + H]⁺ 451.06 found: 452.00. Anal. calcd for C₂₅H₁₉Cl₂NOS: C, 66.37; H, 4.23; N, 3.10; S, 7.09%. Found: C, 66.35; H, 4.27; N, 3.13; S, 7.05%.

(4-Chlorophenyl)(5-(4-chlorophenyl)-3-(p-tolyl)thiophen-2-yl)methanone 4g. Isolated as pale yellow solid; mp: 174–175 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.62 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 7.42 (s, 1H), 7.39 (d, J = 4.4 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.1 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 2.28 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 188.5, 148.0, 147.9, 138.3, 138.0, 135.8, 135.5, 134.8, 132.4, 131.6, 130.9, 129.3, 129.0, 128.8, 128.0, 127.3, 126.8, 21.1. Anal. calcd for C₂₄H₁₆Cl₂OS: C, 68.09; H, 3.81; S, 7.57%. Found: C, 68.06; H, 3.86; S, 7.59%.

(3,5-Di-p-tolylthiophen-2-yl)(p-tolyl)methanone 4h. Isolated as pale yellow solid; mp: 158–159 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.58 (d, J = 7.7 Hz, 4H), 7.37 (s, 1H), 7.23 (d, J = 7.7 Hz, 2H), 7.17 (d, J = 7.4 Hz, 2H), 7.03–6.98 (m, 4H), 2.39 (s, 3H), 2.30 (s, 3H), 2.27 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 189.4, 148.8, 147.6, 142.7, 138.8, 137.4, 135.3, 134.9, 133.0, 130.5, 129.8, 129.7, 128.9, 128.7, 128.4, 126.1, 125.9, 21.4, 21.2, 21.0. ESI-MS m/z calcd for C₂₆H₂₂OS: [M + H]⁺ 382.14; found: 383.11. Anal. calcd for C₂₆H₂₂OS: C, 81.64; H, 5.80; S, 8.38%. Found: C, 81.68; H, 5.83; S, 8.34%.

(3-(4-Fluorophenyl)-5-(p-tolyl)thiophen-2-yl)(p-tolyl)methanone 4i. Isolated as pale yellow solid; mp: 165–166 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.56 (dd, J = 7.3, 5.4 Hz, 4H), 7.33 (s, 1H), 7.23 (t, J = 7.6 Hz, 4H), 7.01 (d, J = 7.9 Hz, 2H), 6.87 (t, J = 8.7 Hz, 2H), 2.38 (s, 3H), 2.30 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 189.1, 163.8, 160.5, 149.1, 146.3, 142.9, 139.0, 135.2, 135.0, 131.9, 131.9, 130.8, 130.6, 130.2, 129.7, 128.5, 125.9, 125.9, 115.0, 114.8, 21.5, 21.2. Anal. calcd for C₂₅H₁₉FOS: C, 77.69; H, 4.96; S, 8.30%. Found: C, 77.66; H, 4.98; S, 8.32%.

Phenyl(5-phenyl-3-(p-tolyl)thiophen-2-yl)methanone 4j. Isolated as pale yellow solid; mp: 135–136 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.72–7.64 (m, 4H), 7.48–7.32 (m, 5H), 7.22–7.14 (m, 4H), 6.97 (d, J = 7.9 Hz, 2H), 2.26 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 189.8, 149.0, 147.9, 137.7, 137.5, 135.4, 133.2, 132.8, 131.9, 129.6, 129.1, 129.0, 128.8, 128.7, 127.7, 126.7, 126.1, 21.1. ESI-MS m/z calcd for C₂₄H₁₈OS: [M + H]⁺ 354.11; found: 355.06. Anal. calcd for C₂₄H₁₈OS: C, 81.32; H, 5.12; S, 9.05%. Found: C, 81.37; H, 5.15; S, 9.02%.

(4-(4-Chlorophenyl)-[2,2′-bithiophen]-5-yl)(thiophen-2-yl)methanone 4k. Isolated as pale yellow solid; mp: 223–224 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.60 (d, J = 4.5 Hz, 1H), 7.52 (d, J = 3.6 Hz, 1H), 7.40–7.21 (m, 7H), 7.14–7.04 (m, 1H), 7.03–6.91 (m, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 180.6, 146.2, 144.1, 142.1, 136.1, 135.0, 134.7, 134.5, 134.4, 134.0, 130.6, 128.9, 128.7, 128.2, 127.1, 126.8, 125.9. Anal. calcd for C₁₉H₁₁ClOS₃: C, 58.98; H, 2.87; S, 24.86%. Found: C, 58.95; H, 2.89; S, 24.82%.

(5-(4-Bromophenyl)-3-(p-tolyl)thiophen-2-yl)(4-chlorophenyl)methanone 4l. Isolated as pale yellow solid; mp: 164–165 °C ¹H NMR (300 MHz, CDCl₃) δ 7.62 (d, J = 8.5 Hz, 1H), 7.58–7.50 (m, 3H), 7.46 (d, J = 8.5 Hz, 1H), 7.39 (dd, J = 7.0, 5.8 Hz, 2H), 7.30 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 7.12–7.07 (m, 2H), 6.98 (d, J = 8.0 Hz, 2H), 2.28 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 214.59, 188.46, 166.69, 164.29, 159.96, 148.09, 147.94, 138.40, 138.07, 136.33, 135.87, 135.53, 134.89, 132.26, 131.59, 130.98, 129.31, 129.03, 128.87, 128.05, 127.56, 127.31, 126.88, 123.02, 21.12. Anal. calcd for C₂₄H₁₆BrClOS: C, 61.62; H, 3.45; S, 6.85%. Found: C, 61.65; H, 3.42; S, 6.83%.

(3-(4-Chlorophenyl)-5-(naphthalen-2-yl)thiophen-2-yl)(naphthalen-2-yl)methanone 4m. Isolated as pale yellow solid; mp: 213–215 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.22 (d, J = 13.0 Hz, 2H), 7.92–7.77 (m, 8H), 7.60–7.48 (m, 5H), 7.30 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 189.6, 149.8, 147.1, 136.5, 135.5, 135.4, 135.3, 134.7, 134.2, 133.8, 132.4, 132.1, 130.7, 129.6, 129.4, 128.7, 128.5, 128.2, 128.1, 127.3, 127.2, 127.1, 127.0, 125.6, 124.3. Anal. calcd for C₃₁H₁₉ClOS: C, 78.39; H, 4.03; S, 6.75%. Found: C, 78.36; H, 4.08; S, 6.76%.

(4-Chlorophenyl)(4-(p-tolyl)-[2,2′-bithiophen]-5-yl)methanone 4n. Isolated as pale yellow solid; mp: 207–208 °C ¹H NMR (300 MHz, CDCl₃) δ 7.58–7.49 (m, 2H), 7.35 (s, 2H), 7.11 (m, 6H), 6.99 (s, 2H), 2.28 (s, 3H). ¹³C NMR (75 MHz, CDCl₃)* δ 188.3, 148.0, 142.7, 138.2, 138.0, 135.9, 134.5, 132.3, 130.8, 129.0, 128.8, 128.2, 127.9, 126.9, 126.4, 125.5, 21.0. ESI-MS m/z calcd for C₂₂H₁₅ClOS₂: [M + H]⁺ 394.03; found: 394.99. Anal. calcd for C₂₂H₁₅ClOS₂: C, 66.91; H, 3.83; S, 16.24%. Found: C, 66.94; H, 3.88; S, 16.22%. (*one quartnary carbon not picked up).

(3,5-Bis(4-chlorophenyl)thiophen-2-yl)(thiophen-2-yl)methanone 4o. Isolated as pale yellow solid; mp: 179–180 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.65–7.59 (m, 2H), 7.59–7.54 (m, 2H), 7.42 (d, J = 8.6 Hz, 1H), 7.37–7.35 (m, 2H), 7.25–7.22 (m, 2H), 7.20–7.18 (m, 3H), 7.09 (dd, J = 4.9, 3.9 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 187.8, 146.5, 138.7, 135.9, 134.2, 133.7, 130.8, 130.3, 130.1, 129.3, 128.5, 128.4, 128.3, 128.2, 127.3, 126.6, 125.7. Anal. calcd for C₂₁H₁₂Cl₂OS₂: C, 60.73; H, 2.91; S, 15.44%. Found: C, 60.76; H, 2.93; S, 15.48%.

Acknowledgements

We thank the University Grant commission for financial support under the scheme of Minor Research project F. No MRP-5176/14 (SERO/UGC) and K. R gratefully acknowledges the award of a Junior Research Fellowship and financial support from CSIR, New Delhi Grant No. 02 (0061)/12/EMR-II. The authors thank DST, New Delhi for assistance under the IRHPA program for the NMR facility.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1062366. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra17829k

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