Construction of five- and six-membered heterocycles on both Cp rings of the ferrocene moiety of α-oxoketene-S,S-acetal and β-oxodithioester via heteroaromatic annulation

Abstract

1,1′-Bis(1,1-dimethylsulfanyl-3-oxo-1-propene)ferrocene and 1,1′-Bis(methyl-3-hydroxy-prop-2-ene-dithioate)ferrocene have been shown to be useful three-carbon synthons for the efficient synthesis of hitherto unreported and synthetically demanding Fc-heterocycles. Five-membered (pyrazole, isoxazole, and thiophene) and six-membered (pyrimidine, coumarin, and quinoline) heterocycles have been constructed on both Cp rings of the ferrocene matrix via regioselective heteroaromatic annulation.

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Introduction

Since the accidental discovery of ferrocene¹ in 1951 (an isostere of benzene), the fascinating metallocene has experienced a renaissance, and captured the attention of synthetic, materials, as well as medicinal chemists. Ferrocene appended scaffolds are important synthetic targets for both the pharmaceutical industry and academic laboratories, owing to their rich chemistry and numerous applications in organic synthesis,^2,3 asymmetric catalysis,⁴ development of new materials,⁵ non-linear optics,⁶ and in bio-organometallic chemistry.⁷ In particular, ferrocene grafted compounds play a key role as scaffolds for ligands in asymmetric synthesis,⁸ and display a wide range of biological activities, such as anticancer⁹ (ferrocifen I, ferrocenyl acridine II), antimalarial¹⁰ (ferrochloroquine III), anti-proliferative,¹¹ and inhibitors of enzymes¹² (Chart 1). Incorporation of a ferrocene moiety into the skeleton of an organic compound often leads to enhanced activity or unexpected biological properties,¹³ which is due to their different membrane permeation properties and anomalous metabolism.¹⁴ There are many examples in the literature where a phenyl or alkyl group has been replaced by a ferrocene moiety as a drug design strategy.

Chart 1 Some important ferrocene appended scaffolds.

Apart from the above properties, ferrocene based compounds have also been widely utilized as organic conductors¹⁵ (ferrocene-π-extended-dithiafulvalenes IV), redox-active coordination polymers¹⁶ (V), and as ligands in metal-catalyzed cyclopropanation and Diels–Alder reactions¹⁷ (VI) (Chart 1). Furthermore, several mono- and bis-urea substituted ferrocene receptors are synthesized and utilized for anion recognition and sensing.¹⁸ Recently, a ferrocene-functionalized polydiacetylene liposome has been developed,¹⁹ which has the propensity to respond colorimetrically and electrochemically upon binding to a cyclodextrin oligomer. Hence, there has been renewed interest in the synthesis of ferrocene based heterocycles with potential applications.

Functionalized α-oxoketene-S,S-acetals, due to their highly polarized push (MeS)–pull (C=O) interaction on the C=C bond, have been proved to be versatile three-carbon building blocks²⁰ for the construction of various heterocyclic systems, such as pyrazole,^21a,b isoxazole,^21c thiophene,^21d,e pyrimidine,^22a–c coumarin,^22d,e and quinoline^22f,g derivatives. Due to their broad array of applications in biology, materials science, and chemistry, there has been an ever increasing demand for ferrocene appended heterocycles. Recently, few synthetic approaches toward ferrocene-based heterocycles have been developed.²³ The scarcity of resourceful synthetic methods for ferrocene-heterocycles synthesis, and the significant limitations of existing procedures prompted us to develop an efficient and more viable route for the synthesis of ferrocene grafted heterocycles.

To the best of our knowledge, there is no report available for the synthesis of ferrocene derivatives with 5- and 6-membered heterocycles installed on both Cp rings of a ferrocene matrix, utilizing a ferrocene based α-oxoketene-S,S-acetal and β-oxodithioester. As part of our ongoing studies on the chemistry of functionalized α-oxoketene acetals²⁴ and β-oxodithioesters,²⁵ we wish to report herein a highly efficient regioselective heteroannulation of ferrocene based α-oxoketene-S,S-acetal and β-oxodithioester to furnish hitherto unreported ferrocene-heterocycles containing five-/six-membered and fused heterocycles on both Cp rings.

Results and discussion

The utility of α-oxoketene acetals^20–22 and β-oxodithioesters^25,26 as versatile intermediates in organic synthesis has been well recognized. The desired ferrocene appended β-oxodithioester 2 and α-oxoketene dithioacetal 3 were not commercially sourced, and prepared in good yields according to reported procedures.²⁷ The methodology involved reaction of the 1,1′-diacetylferrocene 1 with S,S-dimethyltrithiocarbonate in the presence of NaH in a mixture of N,N-dimethylformamide (DMF) and benzene (1 : 10) at reflux temperature to yield 1,1′-bis(methyl-3-hydroxy-prop-2-ene-dithioate)ferrocene 2 in 65% yield. The β-oxodithioester 2 was further treated with methyl iodide, 50% solution of NaOH and tetrabutyl ammonium bromide (TBAB) in benzene to furnish 1,1′-bis(1,1-dimethylsulfanyl-3-oxo-1-propene)ferrocene 3 in 83% yield (Scheme 1).

Scheme 1 The synthesis of ferrocene-based β-oxodithioester 2 and α-oxoketene dithioacetal 3.

Substituted pyrazoles are important synthetic targets for the synthesis of several commercial drugs and functional materials. Recent studies have shown that incorporation of a ferrocenyl group into such structures may improve their biological activities or create new medicinal properties.²⁸ Earlier studies have shown that it is possible to tune the reactivity of these ambident electrophiles toward unsymmetrical heterobinucleophiles by variation of reaction conditions to afford substituted five-/six-membered heterocycles in a highly regiocontrolled fashion.^21–26

Our first attempt was to synthesize five-membered heterocyclic rings over both the Cp rings of ferrocene template via β-oxodithioester 2 and α-oxoketene dithioacetal 3 (Schemes 2–4). Thus, when β-oxodithioester 2 was treated with phenylhydrazine in refluxing ethanol, the corresponding 1,1′-bis(3-methylsulfanyl-1-phenyl-pyrazol-5-yl)ferrocene 4 was obtained in moderate yield (45%). Similarly, treatment of α-oxoketene dithioacetal 3 with hydrazine hydrate in refluxing ethanol furnished 1,1′-bis(3-methylsulfanyl-pyrazol-5-yl)ferrocene 5 in 73% yield. Further, when 3 was treated with phenylhydrazine in the presence of potassium tert-butoxide in refluxing tert-butanol provided 1,1′-bis(5-methylsulfanyl-1-phenyl-pyrazol-3-yl)ferrocene 6 in 63% yield. Only one regioisomeric pyrazole 6 was observed and no trace of the corresponding 1,1′-bis(3-methylsulfanyl-1-phenyl-pyrazol-5-yl)ferrocene 4 could be isolated from the reaction mixture, making the protocol highly regioselective (Scheme 2).

Scheme 2 The synthesis of ferrocene appended pyrazoles.

Scheme 3 The synthesis of ferrocene appended isoxazoles.

Scheme 4 The synthesis of ferrocene appended thiophenes.

The isoxazole ring is widely present in numerous natural products and synthetic pharmaceuticals. With a view to synthesize isoxazole rings over the ferrocene platform, the ketene dithioacetal 3 was next subjected to treatment with hydroxylamine hydrochloride in the presence of barium hydroxide and ethanol under reflux to give the corresponding 1,1′-bis(5-methylsulfanyl-isoxazol-3-yl)ferrocene 7 in 50% yield. Our attempt to prepare 1,1′-bis(5-ethoxy-isoxazol-3-yl)ferrocene 8 by the treatment of ketene dithioacetal 3 with hydroxylamine hydrochloride in the presence of sodium ethoxide under refluxing ethanol yielded a complex inseparable reaction mixture (Scheme 3).

Redox-active molecules containing π-conjugated thiophene fragments have attracted increasing interest in materials science from the viewpoint of the fabrication of organic semi-conducting materials.²⁹ To further add diversity to the ferrocene platform, ketene dithioacetal 3 was subjected to cyclocondensation with ethylthioglycolate in the presence of potassium carbonate in ethanol to afford 1,1′-bis(5-methylsulfanyl-2-carboethoxy-thiophen-3-yl) ferrocene 9 in moderate yield (45%). Similarly, addition of 2-bromo-1-(4-chlorophenyl)ethanone to a stirred solution of β-oxodithioester 2 and potassium carbonate in acetone produced 1,1′-bis(2-(4-chlorobenzoyl)-5-methylsulfanyl-thiophen-3-yl) ferrocene 10 in 41% yield (Scheme 4).

The successful use of 1,2-binucleophiles to construct five-membered heterocycles over the ferrocene platform prompted us to use 1,3-heterobinucleophiles with a view to construct six-membered heterocycles on the ferrocene matrix. Substituted pyrimidines not only represent an important class of six-membered heterocycles prevalent in bioactive natural products and pharmaceuticals, but also represent useful intermediates in organic synthesis. Thus, heterocyclization of 3 with guanidine nitrate in presence of sodium tert-butoxide in tert-butanol furnished 1,1′-bis(2-amino-4-methylsulfanyl-pyrimidin-6-yl) ferrocene 11 in 70% yield (Scheme 5). Compound 11 was found to be insoluble in common NMR solvents, such as CDCl₃, CD₂Cl₂, CD₃COCD₃, and DMSO-d₆, so the structure was assigned with the help of IR and LC-HRMS study. The versatility of heteroaromatic annulation was further demonstrated by the synthesis of ferrocene grafted coumarin 12, as shown in Scheme 6. Thus, (4 + 2) cycloaddition of ketene dithioacetal 3 with 5-bromo-2-hydroxybenzaldehyde in presence of InCl₃ at 80 °C under solvent-free conditions produced 1,1′-bis(6-bromochromene-3-carbonyl)ferrocene 12 in 70% yield.

Scheme 5 The synthesis of a ferrocene appended pyrimidine.

Scheme 6 The synthesis of a ferrocene grafted coumarin.

In order to get more insight into this type of annulation chemistry, in an another strategy, we further extended (4 + 2) cyclocondensation studies of ketene dithioacetal 3 for the synthesis of ferrocene appended quinoline derivatives to add further points of diversity. Thus, the annulation of 3 with o-aminobenzophenone/o-aminoacetophenone produced 1,1′-bis(4-phenyl/methyl-2-methylsulfanyl-quinoline-3-carbonyl)ferrocenes 13 in good yields (Scheme 7).

Scheme 7 The synthesis of ferrocene appended quinolines.

In another alternative pathway, 3 was added to lithiated 3,4-dimethoxyaniline (prepared by drop wise addition of n-BuLi to a solution of 3,4-dimethoxyaniline in dry THF at room temperature under an argon atmosphere) at room temperature to produce the respective N,S-acetal 1,1′-bis(1-(3,4-dimethoxyamino)-1-methylsulfanyl-3-oxo-1-propene)ferrocene 14 in 35% yield. The N,S-acetal 14 thus obtained was treated with polyphosphoric acid (PPA) at 90 °C for 6 h to afford 1,1′-bis(6,7-dimethoxy-2-methylsulfanyl-quinoline-4-yl)ferrocene 15 in 70% yield (Scheme 7). The structural determinations of all the new compounds were done by IR, ¹H and ¹³C NMR, and HRMS studies.

In summary, we have developed an efficient and regioselective protocol for the synthesis of ferrocene grafted five- and six-membered heterocycles via heteroaromatic annulation of β-oxodithioester and α-oxoketene acetal. Here, we have efficiently installed the five-/six-membered heterocycles over the ferrocene matrix. The methodology has been further elaborated to the corresponding N,S-acetal, leading to ferrocene appended quinoline, providing a further point of diversity in the newly synthesized heterocyclic frameworks. In view of the broad range of biological activities displayed by ferrocene grafted heterocycles, these newly synthesized compounds will prove useful for preliminary pharmacological screening. Our further efforts to improve the yields of 5-membered heterocycles and optimization of more annulation reactions on 1,1′-bis(1,1-dimethylsulfanyl-3-oxo-1-propene)ferrocene are in progress.

Experimental

General

Commercially available reagents were purchased from Merck, Aldrich, and Fluka, and used as received without further purification. β-Oxodithioester 2 and α-oxoketene acetal 3 were prepared according to the protocol described in the literature²⁶ and displayed in Scheme 1. Solvents were dried before use by standard procedures. ¹H and ¹³C NMR spectra were recorded on a JEOL AL 300 FT-NMR spectrometer operating at 300 and 75 MHz, respectively. Chemical shifts are given as δ values with reference to tetramethylsilane (TMS) as the internal standard. J values are given in Hz. The IR spectra were recorded on a Varian 3100 FT-IR spectrophotometer. Mass spectra were recorded on a micro TOF-Q II 10330, WATERS-Q-Tof Premier-HAB213 and Q-Tof micro (YA-105) instruments. All the reactions were monitored by TLC using precoated sheets of silica gel G/UV-254 of 0.25 mm thickness (Merck 60 F₂₅₄) using UV light (254 nm/365 nm) for visualization. Melting points were determined with a Büchi B-540 melting point apparatus and are uncorrected.

Synthesis of starting materials and final compounds

1,1′-Bis(methyl-3-hydroxy-prop-2-ene-dithioate)ferrocene (2). A solution of 1,1′-diacetylferrocene 1 (1.0 g, 3.7 mmol) in benzene (20 mL) was added dropwise to a stirred suspension of NaH (60%, 0.74 g, 18.5 mmol) and dimethyltrithiocarbonate (1.27 g, 9.2 mmol) in a solution of benzene (40 mL) and DMF (4 mL) at reflux temperature over a period of 40 min. After addition was over, the refluxing was continued for 8 h (monitored by TLC). The reaction mixture was cooled to room temperature and poured into saturated aqueous ammonium chloride solution (40 mL). The organic layer was separated and washed with water (3 × 40 mL) followed by brine (40 mL) and dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and the residue obtained was purified by column chromatography over neutral alumina using n-hexane–ethyl acetate (5 : 1) as eluent to give 2 as a shiny violet solid (1.1 g, 65%). mp 155–156 °C. IR (KBr): 3437, 1668, 1568, 1455, 1233, 1095 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 14.76 (s, 2H, 2 × OH, D₂O exchangeable), 6.41 (s, 2H, 2 × CH), 4.79 (s, 4H, H_Cp), 4.54(s, 4H, H_Cp), 2.60 (s, 6H, 2 × SCH₃). ¹³C NMR (75 MHz, CDCl₃): δ 213.6, 171.5, 107.9, 79.2, 73.3, 69.4, 16.8.

1,1′-Bis(1,1-dimethylsulfanyl-3-oxo-1-propene)ferrocene (3). To a well stirred solution of β-oxodithioester 2 (1.0 g, 2.2 mmol) in benzene (20 mL), methyl iodide (0.68 mL, 11.0 mmol), phase transfer catalyst TBAB (n-Bu₄N⁺Br⁻) (0.35 g, 1.1 mmol), and 50% aq. NaOH (10 mL) were added slowly at 15 °C. On completion of the reaction (monitored by TLC), the organic layer was separated, washed with water (3 × 40 mL) followed by brine (40 mL), and dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography over neutral alumina using n-hexane–ethyl acetate (3 : 1) as eluent to give 3 as red solid (0.9 g, 83%). mp 186–187 °C. IR (KBr): 1608, 1494, 1374, 1250, 1100 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 6.18 (s, 2H, 2 × CH), 4.74 (s, 4H, H_Cp), 4.46 (s, 4H, H_Cp), 2.55 (s, 6H, 2 × SCH₃), 2.50 (s, 6H, 2 × SCH₃). ¹³C NMR (75 MHz, CDCl₃): δ 188.0, 162.9, 110.7, 83.0, 72.7, 70.7, 17.3, 15.0. LC-HRMS [ESI, (M + H)⁺]: C₂₀H₂₂FeO₂S₄, Calcd: 478.9930, Found 478.9925.

1,1′-Bis(3-methylsulfanyl-1-phenyl-pyrazole-5-yl)ferrocene (4). A solution of β-oxodithioester 2 (0.450 g, 1.0 mmol) and phenylhydrazine (0.32 mL, 3.0 mmol) in absolute ethanol (10 mL) was refluxed for 8 h (monitored by TLC). The solvent was evaporated under reduced pressure and the residue obtained was treated with water followed by extraction with EtOAc (2 × 25 mL). The organic layer was washed with water (2 × 30 mL) followed by brine (30 mL) and dried over anhydrous Na₂SO₄. After evaporating the solvent, the crude product was purified over neutral alumina using n-hexane–ethyl acetate (10 : 1) as eluent to give 4 as an orange colored solid (0.253 g, 45%). mp 160–161 °C. IR (KBr): 3059, 2923, 1595, 1499, 1356, 1195 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.38–7.27 (m, 10H, ArH), 6.26 (s, 2H, ArH), 4.09 (s, 4H, H_Cp), 3.97 (s, 4H, H_Cp), 2.58 (s, 6H, 2 × SCH₃). ¹³C NMR (75 MHz, CDCl₃): δ 147.8, 142.0, 139.8, 128.9, 128.1, 128.0, 126.0, 106.2, 75.4, 70.4, 15.7. HRMS [ESI, (M + H)⁺]: C₃₀H₂₆FeN₄S₂, Calcd: 563.1026, Found: 563.1157.

1,1′-Bis(3-methylsulfanyl-pyrazole-5-yl) ferrocene (5). To a stirred solution of ferrocenyl dithioacetal 3 (0.479 g, 1.0 mmol) in EtOH (15 mL), hydrazine hydrate (0.13 mL, 3.0 mmol) was added and the reaction mixture was refluxed for 12 h (monitored by TLC). The solvent was removed under reduced pressure. The residue was washed with chloroform (2 × 10 mL) to give NMR pure orange solid 5 (0.30 g, 73%). mp decomposes over 250 °C. IR (KBr): 3441, 2924, 2853, 1633, 1384, 1028 cm⁻¹. ¹H NMR (300 MHz, DMSO-d₆): δ 12.72 (s, 2H, 2 × NH, D₂O exchangeable), 6.17 (s, 2H, ArH), 4.55 (s, 4H, H_Cp), 4.18 (s, 4H, H_Cp), 2.50 (s, 6H, 2 × SCH₃). ¹³C NMR (75 MHz, DMSO-d₆): δ 111.0, 82.4, 74.6, 70.3, 70.1, 67.5, 16.5. HRMS [ESI, (M + H)⁺]: C₁₈H₁₈FeN₄S₂, Calcd: 411.0400, Found: 411.0403.

1,1′-Bis(5-methylsulfanyl-1-phenyl-pyrazole-3-yl)ferrocene (6). To a stirred suspension of Bu^tOK (0.448 g, 4.0 mmol) and ferrocenyl dithioacetal 3 (0.479 g, 1.0 mmol) in Bu^tOH, phenylhydrazine (0.32 mL, 3.0 mmol) was added dropwise. The reaction mixture was refluxed for 12 h (monitored by TLC). The solvent was removed under reduced pressure and the residue obtained was treated with saturated aqueous solution of NH₄Cl followed by extraction with EtOAc (2 × 30 mL). The organic layer was washed with water (2 × 30 mL) followed by brine (30 mL) and dried over anhydrous Na₂SO₄. The solvent was evaporated under vacuum, and the residue obtained was purified by column chromatography over neutral alumina using n-hexane–ethyl acetate (19 : 1) as eluent to give 6 as an orange solid (0.349 g, 62%). mp 175–176 °C. IR (KBr): 2922, 2854, 1658, 1595, 1498, 1420, 1364, 1030 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.62 (d, J = 7.5 Hz, 4H, ArH), 7.47–7.35 (m, 6H, ArH), 6.26 (s, 2H, ArH), 4.62 (s, 4H, H_Cp), 4.26 (s, 4H, H_Cp), 2.31 (s, 6H, 2 × SCH₃). ¹³C NMR (75 MHz, CDCl₃): δ 139.6, 138.0, 128.8, 127.4, 124.5, 105.9, 79.0, 69.8, 68.1, 17.9. HRMS [ESI, (M + H)⁺]: C₃₀H₂₆FeN₄S₂, Calcd: 563.1026, Found: 563.1023.

1,1′-Bis(5-methylsulfanyl-isoxazole-3-yl)ferrocene (7). A mixture of Ba(OH)₂ (2.273 g, 12.0 mmol) and NH₂OH.HCl (0.556 g, 8.0 mmol) in EtOH (15 mL) was stirred for 10 min. Ferrocenyl dithioacetal 3 (0.479 g, 1.0 mmol) was added and the reaction mixture was refluxed for 12 h (monitored by TLC). Solvent was evaporated under reduced pressure and the crude product was treated with ice-cold water (30 mL) followed by extraction with ethyl acetate (2 × 30 mL). The combined organic layer was washed with water (3 × 30 mL) followed by brine (30 mL) and dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and the residue obtained was purified by recrystallization to yield 7 as an orange solid (0.206 g, 50%). mp 149–150 °C. IR (KBr): 2924, 2855, 1559, 1436, 1393, 1033 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 5.93 (s, 2H, ArH), 4.65 (s, 4H, H_Cp), 4.35 (s, 4H, H_Cp), 2.61 (s, 6H, 2 × SCH₃). ¹³C NMR (75 MHz, DMSO-d₆): δ 167.2, 161.1, 100.6, 73.9, 71.0, 68.5, 15.2. HRMS [ESI, (M + Na)⁺]: C₁₈H₁₆FeN₂O₂S₂, Calcd: 434.9900, Found 434.9902.

1,1′-Bis(5-methylsulfanyl-2-carboethoxy-thiophene-3-yl)ferrocene (9). Ethylthioglycolate (0.20 mL, 2.0 mmol) was added drop wise to a suspension of K₂CO₃ (0.276 g, 2.0 mmol) in EtOH (5 mL) and stirred for 20 min. A solution of ferrocenyl dithioacetal 3 (0.479 g, 1.0 mmol) in EtOH (5 mL) was added to the reaction mixture and the solution was refluxed for 8 h (monitored by TLC). Solvent was evaporated under reduced pressure and the crude residue was treated with water (25 mL) followed by extraction with CHCl₃ (2 × 20 mL). The organic layer was washed with water (2 × 25 mL) followed by brine (30 mL), and dried over anhydrous Na₂SO₄. The solvent was evaporated in vacuo and the residue thus obtained was purified over neutral alumina using n-hexane–EtOAc (9 : 1) as eluent to yield 9 as a red solid (0.264 g, 45%). mp 179–180 °C. IR (KBr): 2924, 2858, 1700, 1507, 1420, 1284, 1090 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 6.85 (s, 2H, ArH), 4.77 (s, 4H, H_Cp), 4.29–4.21 [m, 8H, (4H, H_Cp and 2 × CH₂)], 2.56 (s, 6H, 2 × SCH₃), 1.33 (t, J = 6.9 Hz, 6H, 2 × CH₃). ¹³C NMR (75 MHz, CDCl₃): δ 161.3, 145.0, 143.5, 130.3, 124.4, 80.2, 71.9, 70.2, 60.7, 19.3, 14.2. HRMS [ESI, (M + Na)⁺]: C₂₆H₂₆FeO₄S₄, Calcd: 608.9961, Found: 608.9960.

1,1′-Bis(2-(4-chlorobenzoyl)-5-methylsulfanyl-thiophene-3-yl)ferrocene (10). To a stirred solution of K₂CO₃ (0.278 g, 2.0 mmol) in acetone (4 mL), β-oxodithioester 2 (0.450 g, 1.0 mmol) was added and stirred for 1 h, followed by drop wise addition of 4-chlorophenacylbromide (0.466 g, 2.0 mmol) solution in acetone (6 mL). The reaction mixture was refluxed for 3 h (monitored by TLC). After completion of the reaction, solvent was evaporated under reduced pressure and residue was treated with water (15 mL) followed by extraction with CHCl₃ (2 × 20 mL). Organic layer was washed with water (2 × 20 mL), brine (20 mL) and dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and purified over neutral alumina using n-hexane-EtOAc (49 : 1) as eluent to yield 10 as a red solid (0.294 g, 41%). mp 194–195 °C. IR (KBr): 3094, 2922, 2852, 1670, 1607, 1409, 1284, 1086 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.54 (d, J = 8.4 Hz, 4H, ArH), 7.21 (d, J = 8.4 Hz, 4H, ArH), 6.88 (s, 2H, ArH), 4.20 (s, 4H, H_Cp), 4.03 (s, 4H, H_Cp), 2.60 (s, 6H, 2 × SCH₃). ¹³C NMR (75 MHz, CDCl₃): δ 187.2, 145.7, 143.9, 138.5, 136.5, 134.5, 131.0, 129.5, 128.2, 81.4, 71.0, 70.3, 19.4. HRMS [ESI, (M + H)⁺]: C₃₄H₂₄Cl₂FeO₂S₄, Calcd: 718.9464, Found: 718.9474.

1,1′-Bis(2-amino-4-methylsulfanyl-pyrimidine-6-yl)ferrocene (11). Guanidine nitrate (0.269 mg, 2.2 mmol) was added to a stirred solution of Bu^tONa (4.4 mmol, prepared in situ from 102 mg of Na metal in 4 mL of Bu^tOH) in Bu^tOH (8 mL) at room temperature and stirred for 15 min. Ketene dithioacetal 3 (0.479 mg, 1.0 mmol) was added and the reaction mixture was refluxed for 8 h (monitored by TLC). The solvent was evaporated under reduced pressure. The residue was treated with water (20 mL), the solid obtained was filtered and washed with water (20 mL) followed by chloroform (2 × 15 mL) to give a dark brown solid (0.325 g, 70%). mp > 275 °C (decomp.). IR (KBr): 3421, 2926, 1424, 1025, 872 cm⁻¹. ¹H and ¹³C NMR could not be recorded due to insolubility in common NMR solvents like CDCl₃, CD₂Cl₂, CD₃COCD₃, and DMSO-d₆. LC-HRMS [ESI, (M + H)⁺]: C₂₀H₂₀FeN₆S₂, Calcd: 465.0618, Found: 465.0613.

1,1′-Bis(6-bromochromene-3-carbonyl)ferrocene (12). A mixture of ferrocenoyl dithioacetal 3 (0.479 g, 1 mmol), 5-bromo-2-hydroxybezaldehyde (0.402 g, 2 mmol), and InCl₃ (0.044 g, 20 mol %) was heated in an oil bath at 80 °C for 2 h (monitored by TLC). Reaction mixture was dissolved in EtOAc (30 mL), washed with water (2 × 20 mL), brine (20 mL) and dried over anhydrous Na₂SO₄. The crude product thus obtained was purified by recrystallization with EtOH to yield 12 as a dark brown solid (0.481 g, 70%). mp > 250 °C (decomp.). IR (KBr): 2922, 2852, 1725, 1645, 1556, 1451, 1288, 1170, 1022 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.96 (s, 2H, ArH), 7.76–7.69 (m, 4H, ArH), 7.22 (s, 2H, ArH), 4.94 (s, 4H, H_Cp), 4.73 (s, 4H, H_Cp). ¹³C NMR (75 MHz, DMSO-d₆): δ 192.4, 156.8, 152.4, 141.4, 135.2, 131.2, 126.9, 119.6, 118.1, 115.9, 78.3, 74.8, 72.0. HRMS [ESI, (M + Na)⁺]: C₃₀H₁₆Br₂FeO₆, Calcd: 708.8560, Found: 708.8669.

General procedure for the synthesis of 13

A mixture of 2-aminoaryl/alkyl ketone (2.0 mmol) and α-oxoketene dithioacetal 3 (1.0 mmol) was heated at 80 °C in the presence of InCl₃ (20 mol %, 0.2 mmol, 44 mg) for the stipulated period of time (1.5–2.0 h) until the completion of the reaction (monitored by TLC). The mixture was treated with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extract was washed with water (2 × 20 mL) followed by brine (15 mL) and dried over anhydrous Na₂SO₄. The solvent was evaporated under vacuum. The crude product thus obtained was purified by column chromatography on silica gel (ethyl acetate/n-hexane, 1 : 19).

1,1′-Bis(2-methylsulfanyl-4-phenyl-quinoline-3-carbonyl)ferrocene (13a). Orange solid (0.533 g, 72%): mp 242–243 °C. IR (KBr): 2923, 1651, 1537, 1450, 1249, 1070 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 8.03 (d, J = 8.1 Hz, 2H, ArH), 7.69 (t, J = 8.1 Hz, 2H, ArH), 7.56 (d, J = 8.4 Hz, 2H, ArH), 7.36 (t, J = 7.8 Hz, 2H, ArH), 7.21–7.19 (m, 10H, ArH), 4.37 (s, 4H, H_Cp), 4.32 (s, 4H, H_Cp), 2.55 (s, 6H, 2 × SCH₃). ¹³C NMR (75 MHz, CDCl₃): δ 200.2, 156.2, 148.0, 144.9, 134.8, 131.0, 130.6, 130.3, 128.4, 128.3, 127.9, 126.5, 125.7, 124.1, 80.8, 74.3, 71.8, 13.3. HRMS [ESI, (M + Na)⁺]: C₄₄H₃₂FeN₂O₂S₂, Calcd: 763.1152, Found: 763.1161.

1,1′-Bis(2-methylsulfanyl-4-methyl-quinoline-3-carbonyl)ferrocene (13b). Orange solid (0.395 g, 64%): mp decomposes over 230 °C. IR (KBr): 2961, 2871, 1584, 1476, 1433, 1234, 1094 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ 7.95 (d, J = 8.1 Hz, 2H, ArH), 7.88 (d, J = 8.1 Hz, 2H, ArH), 7.70 (t, J = 7.5 Hz, 2H, ArH), 7.48 (t, J = 7.5 Hz, 2H, ArH), 4.83 (s, 8H, H_Cp), 2.51 (s, 6H, 2 × SCH₃), 2.44 (s, 6H, 2 × ArMe). ¹³C NMR (75 MHz, CDCl₃): δ 200.6, 156.1, 147.2, 140.6, 131.7, 130.2, 128.6, 125.6, 125.2, 124.1, 82.0, 75.0, 72.2, 16.7, 13.3. HRMS (ESI) Calcd for C₃₄H₂₈FeN₂O₂S₂: (M + H)⁺ 617.1019, Found 617.1028 and (M + Na)⁺ 639.0839, Found 639.0849.

Synthesis of 1,1′-bis(6,7-dimethoxy-2-methylsulfanyl-quinoline-4-yl)ferrocene (15). n-BuLi (2 M in cyclohexane, 2.0 mL, 4.0 mmol) was added drop wise to a solution of 3,4-dimethoxyaniline (0.307 g, 2.0 mmol) in THF (5 mL) over a period of 25 min under argon atmosphere at room temperature and stirred for 1 h. Dithioacetal 3 (0.479 g, 1.0 mmol) was added to the reaction mixture. After complete addition, the color of the reaction mixture changed to brown from red. The reaction mixture was further stirred for 6 h. After completion of reaction (monitored by TLC), the mixture was poured in aqueous saturated solution of NH₄Cl and extracted with EtOAc (2 × 20 mL). The extract was washed with water (3 × 25 mL) followed by brine (20 mL). The combined organic extract was dried over anhydrous Na₂SO₄ and evaporated under vacuum to give the crude product. The product was purified over neutral alumina using 20% EtOAc in n-hexane followed by 1% MeOH in DCM to yield 1,1′-bis(1-(3,4-dimethoxyamino)-1-methylsulfanyl-3-oxo-1-propene)ferrocene 14 in 35% yield.

PPA (0.500 g) and N,S-acetal 14 (0.240 g, 0.35 mmol) was mixed well and heated at 90 °C for 6 h. After the completion of reaction (monitored by TLC), the reaction mixture was carefully neutralized by saturated aqueous solution of NaHCO₃ (400 mL). The reaction mixture was extracted with EtOAc (2 × 25 mL), washed with water (3 × 20 mL) followed by brine (20 mL), and dried over anhydrous Na₂SO₄. The crude product was purified over neutral alumina using 20% EtOAc in n-hexane to yield the red colored compound 15 (0.457 g, 70%). mp 197–198 °C. IR (KBr): 2957, 2924, 2853, 1579, 1485, 1464, 1248, 1103, 1006 cm⁻¹. ¹H NMR (300 MHz, DMSO-d₆): δ 8.31 (s, 2H, ArH), 7.56 (s, 2H, ArH), 7.19 (s, 1H, ArH), 7.15 (s, 1H, ArH), 4.97 (s, 4H, H_Cp), 4.54 (s, 4H, H_Cp), 3.90 (s, 6H, 2 × OMe), 3.88 (s, 6H, 2 × OCH₃), 2.54 (s, 6H, 2 × SCH₃). ¹³C NMR (75 MHz, CDCl₃): δ 156.6, 151.9, 148.2, 146.0, 142.5, 119.5, 119.1, 107.8, 103.9, 84.6, 71.7, 71.3, 56.0, 14.1. HRMS [ESI, (M + H)⁺]: C₃₄H₃₂FeN₂O₄S₂, Calcd: 653.1231, Found: 653.1238.

Acknowledgements

We gratefully acknowledge the generous financial support from the Council of Scientific and Industrial Research (CSIR) and the Department of Science and Technology (DST), New Delhi. The authors (G.K.V. & R.K.V.) are thankful to UGC and CSIR, New Delhi for senior research fellowships.

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Footnote

† Electronic Supplementary Information (ESI) available: original ¹H, ¹³C NMR and HRMS spectra of compounds. See DOI: 10.1039/c2ra21744a

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