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1. WO2021038581 - SYNTHÈSE EN UNE ÉTAPE DE BENZO[B]THIOPHÈNES SUBSTITUÉS EN POSITION 2

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

A ONE STEP SYNTHESIS OF 2-SUBSTITUTED BENZO [B] THIOPHENES

FIELD OF INVENTION:

The invention pertains to the chemical synthesis of benzo[b]thiophene derivatives with special reference to a one step environmental friendly and energy efficient process for the synthesis of 2-acylbenzo[b]thiophene derivatives.

BACKGROUND OF THE INVENTION:

Synthesis of 2-substituted benzo[b]thiophene derivatives were earlier from the acylation of benzo[b]thiophene using acyl source like acetyl chloride, acetic anhydride, 2-oxocarboxylic acid, N, N-dimethylacetamide, acetaldehyde and benzoyl chloride. These reactions yielded major amount of 3-substituted and minor amount of 2-substituted benzo[b] thiophenes due to the high reactivity of C-3 than C-2 position of benzo[b]thiophene. Expensive starting materials, handling of butyl lithium, high temperature, inert atmosphere, synthesized beta zeolite to utilize for the industrial scale preparation of 2-substituted benzo[b]thiophene will be very difficult Prior arts show that to get the 2-substituted benzo[b] thiophenes, reaction was conducted through sulfur insertion and cyclization from commercially available 2-chlorobenzaldehyde, phenacyl bromide, elemental sulfur and sodium sulfide in N-methylpyrrolidone or N,N-diethylacetamide medium. The reaction of 2-chlorobenzaldehyde and mercaptoacetic acid ester was also performed and has been carried out in a basic medium. Scaling up and large-scale production was a great problem because of the unpleasant odor and also the step wise addition of the reactants required monitoring of the reaction.

There were other synthesises in which the 1,2-addition of benzo[b]thiophene to carbonyl of 4-chlorobenzaldehyde using butyl lithium followed by oxidation with MnO2 or I2 in the presence of K2CO3 resulted the 2-acylbenzo[b]thiophenes. Furthermore, the 1,2-addition followed by oxidation of benzo[b]thiophen-2-carb aldehyde by aryl iodide in the presence of Pd-thioether imidazolinium carbene catalyst also was performed. The thiosalicylic acid react with Iron 1,3-diketone complex yielded the 2-acylbenzo[b] thiophenes. The 2-fluoro-5-methoxybenzaldehyde also yielded the 2-acyl-5-hydroxybenzo[b]thiophene through

multi step process. Soon after, Suzuki cross coupling protocol was utilized for the preparation of 2- acylbenzo[b]thiophenes from the heteroaryl boronic acids and activated amide in the presence of Pd catalyst. Further, the transmetallation of triarylstibanes and boron trihalides gave aryl boron dihalide followed by cross coupling with aroyl halide in presence of Pd catalyst at 100°C for 3 h gave 2-acylbenzo[b]thiophenes. The reaction of aryl iodide, CO and arene in presence of palladium catalyst furnished benzo[b]thiophen-2-yl(p-tolyl)methanone via aroyl triflate. For all these reactions expensive palladium catalyst is required. The iridium and palladium catalyzed decarboxylative coupling of a-oxocarboxylate amide with aryl halide heated by blue LED light at 25°C for 20 h generated 2-acylbenzo[b]thiophenes. Here expensive iridium, palladium catalyst and blue LED light are required.

Subsequently, the 2-acylbenzo[b]thiophenes were synthesized from 2-halochalcone or 3-(2-fluorophenyl)-l-phenylprop-2-yn-l-ol using potassium ethyl xanthate sulfur source in the presence of Cu catalyst in DMSO medium From 2-nitrochalcone, the synthesis of 2-acylbenzo[b]thiophenes protocol was developed with usage of stoichiometric amount of elemental sulfur with DIPEA activator or EtgN in DMSO. The double thiolation between C(sp2) and C(sp3) of 3-(2-iodophenyl)-l-phenylpropan- 1 -one with K2S in presence of Cu catalyst in a sealed tube at 130°C for

12 h yielded 91% 2-acylbenzo[b]thiophenes and CO2 catalyzed oxidation of benzo[b]thiophen-2-yl(phenyl)methanol by DMSO in presence of K3PO4 at 90°C for 48 h yielded 97% of 2-acylbenzo[b]thiophenes. The 3-methoxythiophenol and phenacyl bromide condensed product underwent Friedel Craft acylation using benzoyl chloride in presence of anh. aluminium chloride gave the expected 2-benzoylbenzo[b] thiophene derivatives. In the Cu catalyzed reaction, either we have to use high temperature, hazardous solvent or smelling stoichiometric sulfur source and base are not convenient for industrial process. Earlier studies revealed multistep procedure for the synthesis of 2-acylbenzo[b]thiophenes to utilize for the selective estrogen receptor down regulator for drug preparation. In these multi step procedure, some steps need high temperature, low temperature, argon atmosphere.

Hence, the need of industrial production of 2-substituted benzo[b]thiophenes from inexpensive commercially available starting materials with easy handling, environment friendly, energy efficient and odorless protocol becomes an urgent goal due to their wide applications in medicinal, material and natural product synthesis.

OBJECT OF THE INVENTION;

An object of the invention is for the one step synthesis of 2-subsituted benzo[b]thiophenes which is environmentally benign process and is useful for the industrial production of 2-acylbenzo[b]thiophene derivatives in an aqueous medium.

DRAWINGS AND FIGURES:

Figure 1 is a schematic representation of the synthesis of the compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION:

The invention is illustrated by the following disclosures and various examples which are not meant to limit the scope of the invention in any manner. All the embodiments that may be obvious to a skilled person in view of the disclosure would fall within the scope of the present invention.

Accordingly, the invention is for the one step synthesis of 2-subsituted benzo[b]thiophenes which is environmentally benign process and is useful for the industrial production of 2-acylbenzo[b]thiophene derivatives in an aqueous medium.

In an aspect of the invention the reaction is in water medium with starting materials selected from one of, 2-iodobenzaldehyde, 2-iodo-5-methylbenzaldehyde, 5-bromo-2-iodobenzaldehyde, 2-iodobenzophenone, or 2-iodochalcones and selected from one of phenacyl bromide, acetyl bromide, 2-bromocycloalkanone, 2-bromotetralone or 2-bromoindanone, a sulphur source, a catalyst and a phase transfer catalyst at temperature in the range of 25°C-30°C in atmospheric air.

In one embodiment of the invention the reaction is in water medium with preferred starting material 2-iodobenzaldehyde, phenacyl bromide, a sulphur source, a catalyst and a phase transfer catalyst at temperature in the range of 25°C-30°C in atmospheric air.

In another aspect of the invention the reaction is in water medium with starting material 2-iodobenzaldehyde, phenacyl bromide and potassium ethyl xanthate as sulfur source, a catalyst and a phase transfer catalyst at temperature in the range of 25°C-30°C in atmospheric air.

In another aspect of the invention the reaction is in water medium with starting material 2-iodobenzaldehyde, phenacyl bromide and potassium ethyl xanthate as sulfur source, and a catalyst is selected from one of Cu, Fe, Zn, Co or Ni, and a phase transfer catalyst at temperature in the range of 25°C-30°C in atmospheric air.

In another aspect of the invention the reaction is in water medium with starting material 2-iodobenzaldehyde, phenacyl bromide and potassium ethyl xanthate as sulfur source, with a preferred catalyst as Cu and a phase transfer catalyst at temperature in the range of 25°C-30°C in atmospheric air. The Cu is in the form of copper acetate.

In another aspect of the invention the reaction is in water medium with starting material 2-iodobenzaldehyde, phenacyl bromide and potassium ethyl xanthate as sulfur source, with a preferred catalyst as Cu and a phase transfer catalyst selected from one of tetrabutylammonium chloride (TBAC), benzyltriethylammonium chloride, tetrabutylammonium bromide, tetraoctylammonium bromide or tetramethylammonium chloride and at temperature in the range of 25°C-30°C in atmospheric air.

In another aspect of the invention the reaction is in water medium with starting material 2-iodobenzaldehyde, phenacyl bromide and potassium ethyl xanthate as

sulfur source, a Cu catalyst, with a preferred phase transfer catalyst tetrabutylammonium chloride and at temperature in the range of 25°C-30°C in atmospheric air.

In another aspect of the invention the reaction is in water medium with starting material 2-iodobenzaldehyde, phenacyl bromide and potassium ethyl xanthate as sulfur source, a Cu catalyst, with a preferred phase transfer catalyst (PTC) tetrabutylammonium chloride and at temperature in the range of 25°C-30°C in atmospheric air, with or without base and the base is selected from one of NaOAc, tBuOK, KOAc, K2CO3, or triethylamine.

In an aspect of the invention, the ratio of the reactants is of 1:1:1 :3:0.1 of 2- iodobenzaldehyde, phenacyl bromide, PTC, potassium ethyl xanthate and Cu catalyst in water medium at temperature in the range of 25°C-30°C in atmospheric air.

The yield of 2-substituted benzo[b]thiophenes obtained by the invention is 95%. The yield obtained by the methods in the prior art is provided below in the table 1 as a comparison. It is seen that the method of synthesis of the invention is environmentally benign process and is useful for the industrial production of 2- acylbenzo[b]thiophene derivatives in an aqueous medium with high yield.

Table 1

The present invention is for the synthesis of 2-substituted benzo[b]thiophenes (I) from the copper acetate (VI) catalyzed water (VII) mediated reaction of commercially available starting materials of substituted or unsubstituted 2- halogenobenzaldehyde (II) reacting with potassium ethyl xanthate (III) for sulfur source and substituted or unsubstituted acetyl/phenacyl bromide (IV) in presence of phase transfer catalyst tetrabutylammonium chloride (V) in open air atmosphere at temperature in the range of 25°C-30°C.

EXAMPLES;

Materials:

The synthesis was performed at atmospheric air and at temperature in the range of 25°C-30°C and IKA magnetic stirrer used for gentle stirring. Most of the reactions were conducted using commercially available starting materials and some of the 2-iodobenzaldehyde derivatives were synthesized from 2-iodobenzoic arid and 2-aminobenzoic acid by simple reduction, oxidation and iodination steps. The reactions were monitored through thin-layer chromatography (TLC) using Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence and eluents are ethyl acetate (EtOAc) and hexanes mixtures (5% / 10% EtOAc). Reactant materials such as 2-iodobenzoic acid derivatives, 2-iodobenzaldehyde derivatives, phenacyl bromide derivatives, tetrabutylammonium chloride, copper acetate and potassium ethyl xanthate were purchased from Alfa-Aesar, Sigma-Aldrich Company, Avra Synthesis and Spectrochem Pvt. Ltd. Solvents like hexanes, ethyl acetate, dichloromethane etc., and silica gel 100-200 mesh were purchased from Avra Synthesis Pvt. Ltd. Using Bruker NMR instrument, 1H NMR spectra were recorded

in 400 MHz and 13C NMR spectra were recorded in 100 MHz. All shifts were reported in parts per million (ppm) relative to residual CHC13 peak (7.26 and 77.2 ppm, 1H NMR and 13C NMR, respectively). All coupling constants (J) are reported in hertz (Hz). Abbreviations are: s, singlet; d, doublet; t, triplet; td, triplet of doublet. Melting points were recorded on a Guna capillary melting point apparatus and are corrected with benzoic acid as reference. Infrared spectra were recorded on a FTIR 4000 Series Spectrometer using dry KBr pellet for solid samples and neat condition for liquid samples. The wave numbers of recorded IR signals are quoted in cm-1. High resolution mass spectra (HRMS) were recorded on Q-T of Micro mass spectrometer.

Example 1: Synthesis of benzo[b]thiophen-2-yl(phenyl)methanone:


The 2-iodobenzaldehyde (92.8 mg, 0.4 mmol), phenacyl bromide (79.6 mg, 0.4 mmol), potassium ethyl xanthate (192 mg, 1.2 mmol), tetrabutylammonium chloride (111.2 mg, 0.4 mmol), copper acetate (7.24 mg, 0.04 mmol) and water (2 mL) were taken in 15 mL reaction tube and stirred gently at 30°C temperature in open air atmosphere. Completion of the reaction was confirmed by TLC at 16 hrs, then transferred the reaction mixture into the separating funnel and extracted the product using ethyl acetate (3 X 8 mL) and water (15 mL). Then the organic layer was dried with anhydrous sodium sulphate and evaporated the solvent using rotary evaporator. The crude product was purified by silica gel (100-200 mesh) column chromatography using ethyl acetate and hexanes mixture. The furnished benzo[b]thiophen-2-yl(phenyl)methanone was confirmed using melting point, IR, NMR spectroscopy and mass spectrometry.

Analysis data: 95% yield (91mg); yellow liquid; Rf 0.44 (5% ethyl acetate in hexanes); 1H NMR (CDC13, 400 MHz) d 7.41 (t, J = 8.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.53 (t, J = 8.0 Hz, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.85-7.93 (m, 5H); 13C NMR

(CDC13, 100MHz) d 122.9, 125.1, 126.1, 127.5, 128.6, 129.3, 132.3, 132.5, 137.9, 139.1, 142.7, 143.1, 189.7; FTIR (neat) 3060, 2929, 1636, 1510, 1290, 709 cm1; HRMS (m/z): [M+Na]+ calcd for C15H10ONaS: 261.0350; found: 261.0347.

Example 2: Synthesis of benzo[b]thiophen-2-yl(p-tolyl)methanone:

The 2-iodobenzaldehyde (116 mg, 0.5 mmol), 2-bromo- 1 -(p-tolyl)ethan- 1 -one (106.5 mg, 0.5 mmol), potassium ethyl xanthate (240 mg, 1.5 mmol), copper acetate (9.05 mg, 0.05 mmol), tetrabutylammonium chloride (139 mg, 0.5 mmol) and water (2 mL) were taken in the reaction tube and conducted the reaction as per the example 1 procedure. Completion of the reaction was confirmed by TLC at 21 hrs and followed the above procedure to confirm the benzo[b]thiophen-2-yl(p-tolyl)methanone.

Analysis data: 91% yield (115 mg); light yellow solid; mp 90-92°C; R f 0.51 (5% ethyl acetate in hexanes); 1H NMR (CDC13, 400 MHz,) d 2.46 (s, 3H), 7.33 (d, J = 8.0 Hz, 2H), 7.41 (t, J = 8.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.83-7.92 (m, 5H); 13C NMR (CDC13, 100 MHz) d 21.7, 122.9, 125.0, 126.0, 127.3, 129.2, 129.5, 131.8, 135.2, 139.1, 142.6, 143.3(2), 189.3; FTIR (KBr) 3052, 2918, 1623, 1508, 1286, 752 cm 1; HRMS (m/z): [M+Na]+ calcd for C16H12ONaS: 275.0507; found: 275.0503. Table 2 showing the reaction conditions and yield comparison of compound of example 2 with prior arts

Example 3: Synthesis of benzo[b]thiophen-2-yl(4-methoxyphenyl)methanone:

The 2-iodobenzaldehyde (116 mg, 0.5 mmol), 2-bromo-1-(4-methoxyphenyl)ethan- 1-one (114.5 mg, 0.5 mmol), potassium ethyl xanthate (240 mg, 1.5 mmol), copper acetate (9.05 mg, 0.05 mmol), tetrabutylammonium chloride (139 mg, 0.5 mmol) and water (2 mL) were taken in the reaction tube and followed the example 1 procedure. Completion of the reaction was confirmed by TLC at 21 hrs. The furnished benzo[b]thiophen-2-yl(4-methoxyphenyl)methanone was confirmed by these data.

89% yield (119 mg); white solid; mp 121-123°C; Rf 0.33 (5% ethyl acetate in hexanes); 1H NMR (CDC13, 400 MHz) d 3.91 (s, 3H), 7.02 (d, J = 8.0 Hz, 2H), 7.41 (td, J = 7.2 Hz, 1.2 Hz, 1H), 7.47 (td, J = 8.0 Hz, 1.2 Hz, 1H), 7.85 (s, 1H), 7.89 (dd, J = 10.6, 8.0 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H); 13C NMR (CDC13, 100 MHz) d 55.5,

113.8, 122.9, 124.9, 125.9, 127.2, 130.4, 131.2, 131.8, 139.1, 142.4, 143.3, 163.3, 188.2; FTIR (KBr) 3057, 2926, 1610, 1509, 1255,757 cm1; HRMS (m/z): [M+H]+ calcd for C16H13O2S: 269.0636; found: 269.0633.

Table 3 showing the reaction conditions and yield comparison of compound of example 3 with prior arts

Example 4: Synthesis of benzo[b]thiophen-2-yl(3-methoxyphenyl)methanone:

The 2-iodobenzaldehyde (116 mg, 0.5 mmol), 2-bromo-l -(3-methoxyphenyl)ethan- 1-one (114.5 mg, 0.5 mmol), potassium ethyl xanthate (240 mg, 1.5 mmol), copper acetate (9.05 mg, 0.05 mmol), tetrabutylammonium chloride (139 mg, 0.5 mmol) and water (2 mL) were taken in the reaction tube and followed the example 1 procedure. Completion of the reaction was confirmed by TLC at 21 hrs. The furnished benzo [b] thiophen-2-yl(3-methoxyphenyl)methanone was confirmed by these analysis data. 84% yield (85 mg); yellow liquid; R f 0.42 (5% ethyl acetate in hexanes); 1H NMR (CDC13, 400 MHz) d 3.88 (s, 3H), 7.15-7.18 (m, 1H), 7.39-7.52 (m, 5H), 7.87-7.92 (m, 3H); 13C NMR (CDC13, 100 MHz) d 55.5, 113.9, 118.8, 121.9, 122.9, 125.1, 126.1, 127.5, 129.5, 132.3, 139.0, 139.1, 142.7, 143.0, 159.7, 189.4; FTIR (neat) 3064, 3003, 2935, 2837, 1637, 1587, 1293, 760 cm 1; HRMS (m/z): [M+H]+ calcd for C16H13O2S: 269.0636; found: 269.0638.

Table 4 showing the reaction conditions and yield comparison of compound of example 4 and prior arts

Example 5: Synthesis of benzo[b]thiophen-2-yl(4-bromophenyl)methanone:


The 2-iodobenzaldehyde (92.8 mg, 0.4 mmol), 2-bromo- 1 -(4-bromophenyl)ethan- 1 - one (111.2 mg, 0.4 mmol), potassium ethyl xanthate (192 mg, 1.2 mmol), copper acetate (7.24 mg, 0.04 mmol), tetrabutylammonium chloride (111.2 mg, 0.4 mmol) and water (2 mL) were taken in the reaction tube and followed the example 1 procedure. Completion of the reaction was confirmed by TLC at 22 hrs. The yielded benzo[b]thiophen-2-yl(4-bromophenyl)methanone was confirmed by these data. 86% yield (108 mg); Pale yellow solid; mp 138-140°C; R f 0.71 (10% ethyl acetate in hexanes); 1H NMR (CDC13, 400 MHz) d 7.42 (t, J = 8.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.79 (d, J = 7.6 Hz, 2H), 7.83 (s, 1H), 7.89 (t, J = 8.0 Hz, 2H); 13C NMR (CDC13, 100 MHz) d 122.9, 125.2, 126.1, 127.5, 127.7, 130.8, 131.9, 132.2, 136.6, 139.0, 142.6, 142.8, 188.5; FTIR (KBr) 3074, 3057, 2924, 1626, 1582, 1293,746 cm1; HRMS (m/z): [M+Na]+ calcd for C15H9ONaSBr: 338.9455; found: 338.9453.

Table 5 showing the reaction conditions and yield comparison of compound of example 5 and prior arts

Example 6: Synthesis of benzo[b]thiophen-2-yl(4-chlorophenyl)methanone:

The 2-iodobenzaldehyde (116 mg, 0.5 mmol), 2-bromo- 1 -(4-chlorophenyl)ethan- 1 - one (116.5 mg, 0.5 mmol), potassium ethyl xanthate (240 mg, 1.5 mmol), copper acetate (9.05 mg, 0.05 mmol), tetrabutylammonium chloride (139 mg, 0.5 mmol) and water (2 mL) were taken in the reaction tube and followed the example 1 procedure. Completion of the reaction was confirmed by TLC at 19 hrs. The yielded benzo[b]thiophen-2-yl(4-chlorophenyl)methanone was confirmed by these data. 97% yield (132 mg); white solid; mp 134-136°C; Rf 0.56 (5% ethyl acetate in hexanes);

1 H NMR (CDC13, 400 MHz) d 7.43 (t, J = 7.6 Hz, 1H), 7.48-7.53 (m, 3H), 7.84 (s, 1H), 7.86-7.93 (m, 4H); 13C NMR (CDC13, 100 MHz) d 122.9, 125.2, 126.1, 127.6, 128.9, 130.7, 132.2 , 136.1, 139.0 (2), 142.7, 142.8, 188.4; FTIR (KBr) 3085, 3057,

2923, 2849, 1627, 1509, 1294, 748 cm 1; HRMS (m/z): [M+Na]+ calcd for C15H9ONaSC1: 294.9960; found: 294.9956.

Table 6 showing the reaction conditions and yield comparison of compound of example 6 and prior arts

Example 7: Synthesis of benzo[b]thiophen-2-yl(4-fluorophenyl)methanone:


The 2-iodobenzaldehyde (92.8 mg, 0.4 mmol), 2-bromo- 1 -(4-fluorophenyl)ethan- 1 - one (86.8 mg, 0.4 mmol), potassium ethyl xanthate (192 mg, 1.2 mmol), copper acetate (7.24 mg, 0.04 mmol), tetrabutylammonium chloride (111.2 mg, 0.4 mmol) and water (2 mL) were taken in reaction tube and followed the example 1 procedure. Completion of the reaction was confirmed by TLC at 16 hrs. The yielded benzo[b]thiophen-2-yl(4-fluorophenyl)methanone was confirmed by these data. 83% yield (85 mg); pale yellow solid; mp 86-88°C; Rf 0.56 (5% ethyl acetate in hexanes);

1 H NMR (CDC13, 400 MHz) d 7.21 (t, J= 8.4 Hz, 2H), 7.42 (t, J= 8.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.9 (t, J = 8.0 Hz, 2H), 7.94-7.98 (m, 2H); 13C NMR (CDC13, 100 MHz) d 115.7 (d, J = 21.7 Hz), 122.9, 125.1, 126.1, 127.5, 131.8, 131.9, 132.0, 134.1 (d, J = 3.3 Hz), 139.0, 142.7 (d, J = 12.7 Hz), 165.4 (d, J = 252.8 Hz), 188.1; FTIR (KBr) 3067, 2923, 1628, 1503, 1292, 752 cm 1; HRMS (m/z): [M+H]+ calcd for C15H10OFS: 257.0436; found: 257.0437.

Table 7 showing the reaction conditions and yield comparison of compound of example 7 with the prior arts

Example 8: Synthesis of benzo[b]thiophen-2-yl(3,4-dichlorophenyl)methanone:


The 2-iodobenzaldehyde (92.8 mg, 0.4 mmol), 2-bromo-1-(3,4- dichlorophenyl)ethan-1-one (107.2 mg, 0.4 mmol), potassium ethyl xanthate (192 mg, 1.2 mmol), copper acetate (7.24 mg, 0.04 mmol), tetrabutylammonium chloride (111.2 mg, 0.4 mmol) and water (2 mL) were taken in the reaction tube and followed the example 1 procedure. Completion of the reaction was confirmed by TLC at 12 hrs. The yielded benzo[b]thiophen-2-yl(3,4-dichlorophenyl)methanone was confirmed by these data. 85% yield (104 mg); light yellow solid; mp 126-128°C; R f 0.55 (5% ethyl acetate in hexanes); 1H NMR (CDC13, 400 MHz) d 7.44 (td, J = 8.0 Hz, 0.8 Hz, 1H), 7.51 (td, J = 8.0 Hz, 1.2 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.76 (dd, J = 8.0 Hz, 2 Hz, 1H), 7.85 (s, 1H), 7.9-7.93 (m, 2H), 8.0 (d, J = 2.0 Hz, 1H); 13C NMR (CDC13, 100 MHz) d 123.0, 125.3, 126.3, 127.9, 128.3, 130.7, 131.1, 132.4,

133.2, 137.1, 137.4, 138.9, 142.1, 142.9, 187.1; FTIR (KBr) 3085, 2922, 2852, 1625, 1506, 1291, 740 cm 1; HRMS (m/z): [M+H]+ calcd for C15H9C12OS: 306.9751; found: 306.9750.

Example 9: Synthesis of benzo[b]thiophen-2-yl(2,4-dichlorophenyl)methanone:

10

The 2-iodobenzaldehyde (92.8 mg, 0.4 mmol), 2-bromo-1-(2,4- dichlorophenyl)ethan-1-one (107.2 mg, 0.4 mmol), potassium ethyl xanthate (192 mg, 1.2 mmol), copper acetate (7.24 mg, 0.04 mmol), tetrabutylammonium chloride (111.2 mg, 0.4 mmol) and water (2 mL) were taken in the reaction tube and followed the example 1 procedure. Completion of the reaction was confirmed by TLC at 9 hrs. The yielded benzo[b]thiophen-2-yl(2,4-dichlorophenyl)methanone was confirmed by these data. 97% yield (118 mg); light yellow solid; mp 92-94°C; Rf 0.42 (5% ethyl acetate in hexanes); 1H NMR (CDC13, 400 MHz) d 7.38-7.54 (m, 5H), 7.62 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.9 (d, J = 8.0 Hz, 1H); 13C NMR (CDC13, 100 MHz) d 123.1, 125.3, 126.4, 127.1, 128.1, 130.0, 130.3, 132.5, 133.7, 136.4, 137.0, 138.9, 142.8, 143.5, 187.7; FTIR (KBr) 3067, 2920, 1643, 1508, 1292, 755 cm 1; HRMS (m/z): [M+H]+ calcd for C15H9C12OS: 306.9751; found: 306.9750.

Example 10: Synthesis of 4-benzo[b]thiophen-2-carbonyl)benzonitrile:


The 2-iodobenzaldehyde (92.8 mg, 0.4 mmol), 4-(2-bromoacetyl)benzonitrile (89.6 mg, 0.4 mmol), potassium ethyl xanthate (192 mg, 1.2 mmol), copper acetate (7.24 mg, 0.04 mmol), tetrabutylammonium chloride (111.2 mg, 0.4 mmol) and water (2 mL) were taken in the reaction tube and followed the example 1 procedure.

Completion of the reaction was confirmed by TLC at 23 hrs. The yielded 4-benzo[b]thiophen-2-carbonyl)benzonitrile was confirmed by these data. 84% yield (88 mg); light yellow solid; mp 144-146°C; R f 0.33 (10% ethyl acetate in hexanes);

1 H NMR (CDC13, 400 MHz) d 7.45 (t, J = 7.6 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.83 (d, J = 4.8 Hz, 2H), 7.85 (s, 1H), 7.88-7.94 (m, 2H), 7.99 (d, J = 8.0 Hz, 2H); 13C

NMR (CDC13, 100 MHz) d 115.8, 117.9, 123.0, 125.4, 126.3, 128.1, 129.6, 132.4, 133.0, 138.9, 141.4, 142.0, 143.0, 188.1; FTIR (KBr) 3085, 3039, 2923, 2222, 1635, 1510, 1287, 755 cm1; HRMS (m/z): [M+Na]+ calcd for C16H9NOSNa: 286.0303; found: 286.0315.

Example 11: Synthesis of benzo[b]thiophen-2-yl(4-nitrophenyl)methanone:


The 2-iodobenzaldehyde (92.8 mg, 0.4 mmol), 2-bromo-1-(4-nitrophenyl)ethan-1-one (97.6 mg, 0.4 mmol), potassium ethyl xanthate (192 mg, 1.2 mmol), copper acetate (7.24 mg, 0.04 mmol), tetrabutylammonium chloride (111.2 mg, 0.4 mmol) and water (2 mL) were taken in the reaction tube and followed the example 1 procedure. Completion of the reaction was confirmed by TLC at 20 hrs. The yielded benzo[b]thiophen-2-yl(4-nitrophenyl)methanone was confirmed by these data. 95% yield (107 mg); Orange solid; mp 188-190°C; R f 0.42 (10% ethyl acetate in hexanes); 1H NMR (CDC13, 400 MHz) d 7.45 (t, J = 8.0 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.92 (dd, J = 14.0 Hz, 8.0 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 8.39 (d, J = 8.4 Hz, 2H); 13C NMR (CDC13, 100 MHz) d 123.0, 123.8, 125.4, 126.4, 128.2, 130.1, 133.1, 138.9, 142.0, 143.0, 143.1, 149.9, 187.9; FTIR (KBr) 3098, 3074, 2923, 2852, 1629, 1594, 1517, 1346, 1285, 706 cm1; HRMS (m/z): [M+H]+ calcd for C15H10NO3S: 284.0381; found: 284.0382.

Table 8 showing the reaction conditions and yield comparison of compound of example 11 with the prior arts

Example 12: Synthesis of (5-methylbenzo[b]thiophen-2-yl)(phenyl)methanone:


The 2-iodo-5-methylbenzaldehyde (98.4 mg, 0.4 mmol), phenacyl bromide (79.6 mg, 0.4 mmol), potassium ethyl xanthate (192 mg, 1.2 mmol), copper acetate (7.24 mg, 0.04 mmol), tetrabutylammonium chloride (111.2 mg, 0.4 mmol) and water (2 mL) were taken in the reaction tube and followed the example 1 procedure. Completion of the reaction was confirmed by TLC at 20 hrs. The yielded (5- methylbenzo[b]thiophen-2-yl)(phenyl)methanone was confirmed by these data. 88% yield (89 mg); light yellow solid; mp 153-155°C; Rf 0.5 (5% ethyl acetate in hexanes); 1H NMR (CDC13, 400 MHz) d 2.48 (s, 3H), 7.32 (d, J = 8.4 Hz, 1H), 7.53 (t, J = 8.0 Hz, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.78-7.80 (m, 2H), 7.91 (d, J = 8.0 Hz, 2H); 13C NMR (CDC13, 100 MHz) d 21.4, 122.5, 125.7, 128.5, 129.3,

129.5, 132.0, 132.4, 134.9, 138.0, 139.4, 140.1, 143.2, 189.7; FTIR (KBr) 3066, 2919, 2855, 1626, 1516, 1295, 707 cm1; HRMS (m/z): [M+H]+ calcd for C16H13OS: 253.0687; found: 253.0690.

Example 13: Synthesis of (5-bromobenzo[b]thiophen-2-yl)(phenyl)methanone:


The 5-bromo-2-iodobenzaldehyde (93.3 mg, 0.3 mmol), phenacyl bromide (59.7 mg, 0.3 mmol), potassium ethyl xanthate (144 mg, 0.9 mmol), copper acetate (5.43 mg, 0.03 mmol), tetrabutylammonium chloride (83.4 mg, 0.3 mmol) and water (2 mL) were taken in the reaction tube and followed the example 1 procedure. Completion of the reaction was confirmed by TLC at 9 hrs. The yielded (5-methylbenzo[b]thiophen- 2-yl)(phenyl)methanone was confirmed by these data. 86% yield (88 mg); light yellow solid; mp 148-150°C; R f 0.53 (5% ethyl acetate in hexanes); 1H NMR (CDC13, 400 MHz) d 7.52-7.57 (m, 3H), 7.64 (t, J = 8.0 Hz, 1H), 7.77 (m, 2H), 7.90 (d, J = 7.6 Hz, 2H), 8 .01 (s, 1H); 13C NMR (CDC13, 100 MHz) d 119.0, 124.3, 128.4, 128.6, 129.3, 130.5, 130.8, 132.8, 137.5, 140.5, 141.1, 144.7, 189.3; FTIR

(KBr) 3062, 2924, 1634, 1504, 1290, 703 cm1; HRMS (m/z): [M+Na]+ calcd for C15H9OBrNaS: 338.9455; found: 338.9451.

Table 9 showing the reaction conditions and yield comparison of compound of example 13 with the prior arts

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