Efficient synthesis of 2-phenyl-3-substituted furo/thieno[2,3-b]quinoxalines via Sonogashira coupling reaction followed by iodocyclization and subsequent palladium-catalyzed cross-coupling reactions

Abstract

In this paper, we report the successful synthesis of new 2-phenyl-3-substituted furo/thieno[2,3-b]quinoxaline derivatives from 2-chloro-3-methoxyquinoxaline and 2-chloro-3-(methylthio)quinoxaline by a three-step approach. The Sonogashira coupling reaction of the title compounds with terminal alkynes afforded 2-methoxy-3-(phenylethynyl)quinoxaline and 2-(methylthio)-3-(phenylethynyl)quinoxaline in good to excellent yields. The iodocyclization of the resulting compounds using ICl in CH₂Cl₂ afforded 3-iodo-2-phenylfuro[2,3-b]quinoxaline and 3-iodo-2-phenylthieno[2,3-b]quinoxaline. The subsequent palladium-catalyzed Sonogashira, Suzuki, and Heck reactions of the resulting iodo compounds led to the formation of 2,3-disubstituded furo/thieno[2,3-b]quinoxaline in high yields. All compounds were fully characterized by FT-IR, mass, ¹H NMR, and ¹³C NMR spectral data. The synthesized quinoxaline derivatives were also screened against the two bacterial strains Escherichia coli and Micrococcus luteus.

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Introduction

Heterocyclic compounds containing nitrogen atoms often have a wide variety of important biological activities. Furo/thieno[2,3-b]quinoxalines display diverse biological properties (Scheme 1). 2-Substituted thieno[2,3-b]quinoxaline derivatives (I) have been tested for apoptosis, teratogenicity and hepatotoxicity in zebrafish embryos. These compounds were considered as potential inducers of apoptosis.¹ 2-Arylthiopheno[2,3-b]quinoxalines (II) and compound (III) exhibited anti-microbial activity against Gram positive and Gram negative bacterial strains.² 3-Pyrrolylthieno[2,3-b]quinoxaline-2-carbohydrazide (IV) was displayed to have anti-fungal activities.³ Likewise, furo[2,3-b]quinoxaline derivatives showed promising pharmacological properties in vitro and in vivo as the potential inhibitors of sirtuins.⁴ Among them, furo[2,3-b]quinoxalines, compounds having a linear alkyl side chain at C-2 (V), showed significant inhibition in the presence of 5-FOA (5-fluoroorotic acid). The compound (VI) inhibited cell growth significantly against human hepatocellular liver carcinoma (HepG2) and cervical cancer (HeLa) cells.⁴

Scheme 1 Structure drugs based on the furo/thieno[2,3-b]quinoxaline moeity.

Carbon–carbon bond formation is an interesting field of study in organic synthesis.^5–10 The Sonogashira cross-coupling reaction of terminal alkynes with C-sp² halides has established a powerful manner for the creation of aryl- and vinyl-alkynes, which have been applied in the synthesis of natural products^11,12 and in material science.¹³

A few studies have been reported for the synthesis of furo[2,3-b]quinoxaline and thieno[2,3-b]quinoxaline.^{1–4,14–23} Armengol and Joule have reported a three-step synthesis of the thienoquinoxalines involving the Pd/Cu-catalyzed cross-coupling of 2-haloquinoxalines with terminal alkynes, addition of bromine, and cyclization of the thiophene ring using Na₂CS₃.²³ In additon, furo[2,3-b]quinoxalines have been prepared from 2-chloro-3-alkynyl quinoxalines via a one-pot tandem hydrolysis-cyclization strategy.⁴ In continuation of our recent studies on the Pd-catalyzed synthesis of pyrrolo[2,3-b]quinoxalines,^24–26 herein we report the synthesis of a series of new disubstituted furo/thieno[2,3-b]quinoxalines in good to excellent yields by a three-step process, involving coupling/iodocyclization/coupling strategy to generate a library of new quinoxaline derivatives under the mild reaction conditions.

Results and discussion

According to a literature procedure,^27,28 2-chloro-3-methoxyquinoxaline (3a) was prepared by the reaction of 2,3-dichloroquinoxaline with NaOMe in MeOH at room temperature. Treatment of 2,3-dichloroquinoxaline with Na₂S·9H₂O in DMF at room temperature for 3 h, leads to compound 2 in quantitative yield. The compound 2 reacts with methyl iodide to give 2-chloro-3-(methylthio)quinoxaline (3b) in 86% yield (Scheme 2).

Scheme 2 Synthesis of starting materials 3a–b.

A two-step procedure was followed for the synthesis of 3-iodo-2-phenylfuro[2,3-b]quinoxaline involving (i) the Sonogashira coupling of 2-chloro-3-methoxyquinoxaline with phenyl acetylene, and (ii) an electrophilic cyclization by iodine monochloride. To establish the optimal reaction conditions, treatment of 2-chloro-3-methoxyquinoxaline (3a) with phenylacetylene was selected as the model reaction (Table 1). It is evident in Table 1 that the maximum amount of product was observed when DMF was used as the solvent in the presence of triethylamine as the base at room temperature (entry 1). When the reaction was carried out in the absence of CuI, the desired product was obtained in 90% yield (entry 6). Interestingly, when water was employed as the solvent, the reaction proceeded to completion, and it provided the desired product in 92% yield in 10 h at 70 °C (entry 5). To access the generality of this overall approach, the scope of the Sonogashira coupling of 2-chloro-3-methoxyquinoxaline with terminal alkynes was also studied. Treatment of 2-chloro-3-methoxyquinoxaline (3a) with a variety of terminal alkynes such as phenyl acetylene, hex-1-yne, and prop-2-yn-1-ol under the standard Sonogashira coupling conditions [compound 3a (0.5 mmol), an alkyne (0.6–1 mmol), PdCl₂(PPh₃)₂ (3.5 mol%), CuI (7 mol%), Et₃N as the base, and DMF as the solvent] afforded high yields of the desired products (Scheme 3, Table 2). Attempts to cyclize 4a for the synthesis of 3-unsubstituted-2-phenylfuro[2,3-b]quinoxaline or by the one-pot Sonogashira coupling reaction/heteroannulation of 3a with terminal alkynes, was not successful.

Table 1 Effects of solvent, base, catalyst, additive, and temperature on Sonogashira coupling reaction of 3a with phenylacetylene^a

Entry	Catalyst (mol%)	Additive	Base	Solvent	T (°C)	Yield^d (%)
a All reactions were carried out under argon using 3a (0.2 equiv.), phenylacetylene (0.3 equiv.), Pd catalyst, a base (4 equiv.), and a solvent (3 mL) for 8 h.b Reaction time was 10 h.c Reaction was carried out without CuI.d Isolated yield.
1	PdCl2(PPh3)2/CuI (3.5, 7)	—	Et3N	DMF	rt	96
2	PdCl2(PPh3)2/CuI (3, 7)	—	Et3N	CH3CN	rt	92
3	PdCl2(PPh3)2/CuI (3.5, 7)	—	Et3N	CHCl3	rt	90
4	PdCl2(PPh3)2/CuI (3.5, 7)	—	Et3N	DMF	80	96
5	PdCl2(PPh3)2/CuI (3.5, 7)^b	SDS	K2CO3	H2O	70	92
6	PdCl2(PPh3)2(3.5)^c	—	Et3N	DMF	rt	90
7	Pd(OAc)2 (5)	—	K2CO3	H2O	70	80
8	Pd(OAc)2 (5)	TBAB	K2CO3	DMF	90	85
9	Pd(OAc)2 (5)	PPh3	K2CO3	DMF	90	90
10	Pd(OAc)2/Cu(OAc)2 (5, 10)	PPh3	K2CO3	DMF	90	88
11	% 10 Pd/C–CuI (10)	PPh3	Et3N	DMF	rt	—

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Scheme 3 Sonogashira coupling of 3a with terminal alkynes.

Table 2 Sonogashira coupling of 3a–b and terminal alkynes^a

Entry	Quinoxaline derivatives	R	Product	Yield^b %
a Reaction conditions, 3a–b (0.5 mmol), terminal alkyne (0.4 mmol), catalyst Pd–CuI (3.5, 7 mol%), DMF (3 mL), Et3N (1 mL) at room temperature.b Isolated yields.
1				96
2	3a			75
3				76

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It was found that when the 2-methoxy-3-(phenylethynyl) quinoxaline 4a was treated with I₂ in CH₂Cl₂ at room temperature underwent smoothly cyclization process. On the other hand, reaction of 4a with ICl in CH₂Cl₂ proceeded very well and 3-iodo-2-phenylfuro[2,3-b]quinoxaline 5a was obtained in a high yield (Scheme 4).

Scheme 4 Synthesis of 3-iodo-2-phenylfuro[2,3-b]quinoxaline.

Although the first step for the synthesis of compound 6 from 3b proceeded very well, however, the second step, the electrophilic cyclization of compound 6 with ICl in CH₂Cl₂ caused a lower yield of the product 7 (Scheme 5).

Scheme 5 Synthesis of 3-iodo-2-phenylthieno[2,3-b]quinoxaline.

In continuation of our study, we focused on the further structure elaboration of these iodo compounds via Pd-catalyzed C–C bond formation such as the Sonogashira, Suzuki, and Heck reactions. First we examined the alkynylation of 5a with phenyl acetylene under various experimental conditions. The results summarized in Table 3. The initial coupling reaction was carried out in the presence of PdCl₂(PPh₃)₂–CuI, in DMF, to produce the adduct at room temperature in a high yield (entry 1). The reaction was also carried out in the absence of CuI, which decreased the product yield (entry 2). The Pd/C, as an inexpensive catalyst, was examined for this transformation, providing the desired product in good yields (entry 3).

Table 3 Effect of catalyst on Sonogashira coupling reaction of 5a with phenylacetylene

Entry	Pd-catalyst	Additive	Time (h)		Yield (%)
a Reaction was carried out using 5a (0.2 mmol), phenyl acetylene (0.3 mmol), PdCl2(PPh3)2 (3.5 mol%), CuI (7 mol%), Et3N (0.5 mL), DMF (2 mL) at rt.b Reaction in the absence of CuI.c 5a (0.2 mmol), phenyacetylene (0.3 mmol), % 10 Pd/C (0.0019 mmol), PPh3 (0.0066 mmol), CuI (0.0019 mmol), Et3N (0.5 mL), DMF (2 mL) at rt.
1	PdCl2(PPh3)2^a	CuI	8	95
2	PdCl2(PPh3)2^b	—	10	30
3	% 10 Pd/C^c	CuI–PPh3	12	85

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In order to explore the scope and generality of this protocol, compounds 5a and 7 were reacted with various terminal alkynes in the presence of PdCl₂PPh₃–CuI (3.5, 7 mol%), as the catalyst, and Et₃N, as the base, in DMF, to afford a variety of 3-substituted 2-phenylfuro[2,3-b]quinoxaline and 3-substituted 2-phenylthieno[2,3-b]quinoxaline derivatives in high yields (Table 4).

Table 4 Sonogashira coupling between iodoquinoxalines (5a, 7) and terminal alkynes^a

Entry	Iodo derivatives	R	Product	Yield^b (%)
a Reaction conditions: 5a and 7 (0.2 mmol), terminal alkyne (0.3 mmol), catalyst Pd–CuI (3.5, 7 mol%), DMF (2 mL), at room temperature for 8–10 h.b Isolated yields.
1				95
2	5a			90
3	5a			94
4				90
5	7			88
6	7			92

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Similarly, the Suzuki reaction of the iodo compounds 5a and 7 was carried out using phenylboronic acid in the presence of 5 mol% Pd(OAc)₂ and K₂CO₃ in DMF at 80 °C for 8 h to give the corresponding 2,3-diphenylfuro[2,3-b]quinoxaline (10a) and 2,3-diphenylthieno[2,3-b]quinoxaline (10b) in good yield (Scheme 6).

Scheme 6 Suzuki reaction of 3-iodo-2-phenylfuro/thieno[2,3-b]quinoxaline 5a and 7 with phenylboronic acid.

The Heck reaction of 5a with ethyl acrylate carried out in the presence of 5% Pd(OAc)₂, K₂CO₃ in DMF at 100 °C produced the desired product in a 86% yield (Scheme 7). The Heck reaction of compound 7 with ethyl acrylate was also carried out and due to the impurity of the reaction mixture, the product could not be separated as a pure compound by column chromatography.

Scheme 7 Heck coupling reaction of 3-iodo-2-phenylfuro[2,3-b]quinoxaline (5a) with ethyl acrylate.

The synthesized quinoxaline derivatives were screened against the two bacterial strains Escherichia coli and Micrococcus luteus. Their anti-bacterial activities were determined by a well-diffusion method at a concentration of 1000 μg mL⁻¹. Most of the synthesized compounds were tested in vitro for their anti-bacterial activity against the microorganisms Micrococcus luteus (Gram positive) and Escherichia coli (Gram negative) using penicillin G as a standard anti-bacterial agent, and the results obtained were tabulated in Table 5. According to these results, 9c had the highest anti-bacterial activity against M. luteus. None of the compounds showed an activity against Escherichia coli.

Table 5 Anti-bacterial activities of selected compounds (1000 μg mL⁻¹) as inhibition zone in mm

Entry	Compound	Micrococcus luteus	Escherichia coli
a Negative control.b Positive control.
1	4a	8	—
2	4b	9	—
3	5a	—	—
4	6	8	—
5	7	9	—
6	8a	—	—
7	8b	9	—
8	8c	10	—
9	9a	8	—
10	9b	8	—
11	9c	12	—
12	10a	—	—
13	10b	11	—
14	11	8	—
15	DMSO^a	—	—
16	Penicillin G^b	49	21

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Experimental part

General information

Copper(I) iodode, PdCl₂(PPh₃)₂ and palladium(II) acetate were purchased from Sigma-Aldrich chemical company, and used without further purification. All reactions were carried out under an argon atmosphere. 3-Chloro-2-methoxyquinoxaline (3a) was synthesized according to the previously reported procedures.^27,28 The solvents MeOH, EtOH, CHCl₃, CH₂Cl₂, n-hexane, and ethyl acetate were distilled before use, and pure DMF was commercially available. Melting points were determined by an Electrothermal 9100 melting point apparatus. Products were characterized by melting point determinations, and IR, ¹H NMR, ¹³C NMR, and mass spectroscopic techniques. IR spectra were obtained on FT-IR Bruker model VECTOR 22. NMR data were recorded in CDCl₃ and DMSO using a Bruker Avance 400 MHz spectrometer. Chemical shifts were reported in ppm with the solvent residual peak used as the internal reference [CDCl₃: 7.29 ppm (¹H), 77.0 ppm (¹³C); [D6] DMSO: 2.52 ppm (¹H), and 39.9 ppm (¹³C)]. Multiplicities were described using the following abbreviations: s = singlet, br. s = broad singlet, d = doublet, t = triplet and m = multiplet. The mass spectra were measured with a MS (EI), 5973 quadrupole Analyzer spectrometer, manufactured by Agilent Technologies Company (HP) and ESI Waters Q-T of Ultima. Thin-layer chromatography was performed on a 0.25 mm film of silica gel that contained a fluorescent indicator UV 254 supported on an aluminum sheet (Sigma-Aldrich). Products were purified by column chromatography on silica gel (Kieselgel 100, 70–230 mesh, E. Merck) using hexane : ethyl acetate as the eluent.

Anti-bacterial assay

The anti-bacterial activities of the new fused-furo/thieno quinoxaline derivatives were evaluated biologically using a well-diffusion method against Micrococcus luteus (ATCC 4698) and Escherichia coli (ATCC 25922), supplied from Iranian biological resource center, Tehran, Iran. First the nutrient agar and nutrient broth cultures were prepared according to the manufactures' instructions, which were then incubated at 37 °C. After incubation for an appropriate time, a suspension of 40 μL of each bacterium was added to the nutrient agar plates. Cups (5 mm in diameter) were cut in the agar using sterilized glass tube. Each well received 30 μL of the test compounds at a concentration of 1000 μg mL⁻¹ in DMSO. Then the plates were incubated at 37 °C for 24 h, after which time, the inhibition zone was measured in millimeters (mm). The results obtained were reported as the inhibition zone in mm. The anti-bacterial activity of each compound was compared with penicillin G as the standard drug. DMSO was used as the negative control.

2-Chloro-3-(methylthio)quinoxaline (3b). A mixture of Na₂S·9H₂O (240 mg, 1 mmol) and 2,3-dichloroquinoxaline (1a; 199 mg, 1 mmol) in DMF (5 mL) was stirred for 3 h at rt. Then MeI (0.12 mL, 1 mmol) was added. After completion of the reaction, the solvent was evaporated, and the resulting residue was washed with H₂O (10 mL). The precipitate was filtered off and dried. Further purification was performed with column chromatography using ethyl acetate/hexane (11 : 1), as the eluent, to give 3b (181 mg, 0.85 mmol, 86%) as a white crystal; mp 99–101 °C; ¹H NMR (400 MHz, CDCl₃): δ = 2.71 (s, 3H, –SMe), 7.66 (td, J = 7.6 Hz, J = 1.2 Hz, 1H, 2-H), 7.73 (td, J = 7.7 Hz, J = 1.6 Hz, 1H, 3-H), 7.95–8.01 (m, 2H, 1,4-H), ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 13.8, 127.4, 128.2, 128.7, 130.2, 139.0, 141.3, 145.2, 155.9 ppm; IR (KBr): [small nu, Greek, tilde] = 2925, 1559, 1525, 1481, 1377, 1341, 1316, 1264, 1236, 1173, 1118, 1017, 998, 959, 746, 650, 430 cm⁻¹.

General procedure I for synthesis of 2-methoxy-3-alkynyl quinoxalines (4a–c). The mixture of 2-chloro-3-methoxyquinoxaline (3a, 97 mg, 0.5 mmol), PdCl₂(PPh₃)₂ (3.5 mol%), and CuI (7 mol%) in 4 mL of Et₃N/DMF (1/3) was stirred for 5 min at rt under an argon atmosphere. Then a terminal alkyne (0.6–1 mmol) was slowly added to the mixture. The reaction mixture was stirred at rt for 7–10 h. After the reaction was completed (monitored by TLC), the solvent was evaporated, and the residue left was washed with water. The crude product was purified by column chromatography using ethyl acetate/hexane as the eluent.
2-Methoxy-3-(phenylethynyl)quinoxaline (4a). Following general procedure I, 2-chloro-3-methoxyquinoxaline (3a; 97 mg, 0.5 mmol), PdCl₂(PPh₃)₂ (12 mg, 3.5 mol%), CuI (6.6 mg, 7 mol%), Et₃N (1 mL), and phenyl acetylene (0.076 mL, 0.7 mmol) were reacted in DMF (3 mL). The crude product was purified by column chromatography (hexane/ethyl acetate = 9 : 1), which was then washed with cold ethanol (1 mL) to give 4a (125 mg, 0.48 mmol, 96%) as a pale yellow crystal; mp 100–101 °C; ¹H NMR (400 MHz, CDCl₃): δ = 4.21 (s, 3H, –OMe), 7.40–7.47 (m, 3H, 2′,3′-H), 7.6 (td, J = 7.6 Hz, J = 1.6 Hz, 1H, 2-H), 7.69 (td, J = 7.6 Hz, J = 1.6 Hz, 1H, 3-H), 7.72–7.75 (m, 2H, 1′-H), 7.86 (dd, J = 8.4 Hz, J = 1.2 Hz, 1H, 4-H), 8.05 (dd, J = 8.4 Hz, J = 1.2 Hz, 1H, 1-H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 54.4, 84.9, 95.6, 121.7, 126.9, 127.1, 128.4, 128.7, 129.6, 130.5, 132.5, 132.7, 138.7, 139.5, 157.2 ppm; IR (KBr): [small nu, Greek, tilde] = 2970, 2206, 1570, 1553, 1490, 1444, 1394, 1363, 1337, 1224, 1133, 1110, 1002, 758, 686 cm⁻¹; ESI-MS: m/z 260.1 (M⁺). HRMS for C₁₇H₁₃N₂O calculated [MH] 261.1028; found m/z = 261.1029.
3-(3-Methoxyquinoxalin-2-yl)prop-2-yn-1-ol (4b). Following general procedure I, 2-chloro-3-methoxyquinoxaline (3a; 97 mg, 0.5 mmol), PdCl₂(PPh₃)₂ (12 mg, 3.5 mol%), CuI (6.6 mg, 7 mol%), Et₃N (1 mL), and prop-2-yn-1-ol (0.07 mL, 1 mmol) were reacted in DMF (3 mL). The crude product obtained was purified by column chromatography (hexane/ethyl acetate = 6 : 3) to give 4b (80 mg, 0.37 mmol, 75%) as a white solid; mp 169–170 °C. ¹H NMR (400 MHz, [D6] DMSO): δ = 4.08 (s, 3H, –OMe), 4.44 (d, J = 6 Hz, 2H, –CH₂), 5.61 (t, J = 6 Hz, 1H, –OH), 7.67 (td, J = 7.6 Hz, J = 1.6 Hz, 1H, 2-H), 7.78 (td, J = 7.6 Hz, J = 1.6 Hz, 1H, 3-H), 7.86 (ddd, J = 8.2 Hz, J = 1.4 Hz, J = 0.4 Hz, 1H, 4-H), 7.96 (ddd, J = 8.4 Hz, J = 1.4 Hz, J = 0.4 Hz, 1H, 1-H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 49.9, 54.7, 79.9, 96.7, 127.0, 127.8, 128.7, 131.5, 132.3, 138.4, 139.1, 157.1 ppm; IR (KBr): [small nu, Greek, tilde] = 3280, 3008, 2944, 2928, 2240, 1574, 1555, 1452, 1395, 1337, 1228, 1206, 1145, 1033, 1004, 950, 764, 646, 624, 611, 502 cm⁻¹. HRMS for C₁₂H₁₁N₂O₂ calculated [MH] 215.0821; found m/z = 215.0820.
2-(Hex-1-yn-1-yl)-3-methoxyquinoxaline (4c). Following general procedure I, 2-chloro-3-methoxyquinoxaline (3a; 97 mg, 0.5 mmol), PdCl₂(PPh₃)₂ (12 mg, 3.5 mol%), CuI (6.6 mg, 7 mol%), Et₃N (1 mL), and hex-1-yne (0.1 mL, 0.8 mmol) were reacted in DMF (3 mL). The crude product obtained was purified by column chromatography (hexane/ethyl acetate = 9 : 1), and then washed with ethanol (1 mL) to give 4c (84 mg, 0.35 mmol, 70%) as a brown oil. ¹H NMR (400 MHz, CDCl₃): δ = 0.98 (t, J = 7.2 Hz, 3H, –CH₃), 1.50–1.60 (m, 2H, 7-H), 1.71 (qui, J = 7.3 Hz, 2H, 6-H), 2.59 (t, J = 7.2 Hz, 2H, 5-H), 4.15 (s, 3H, –OMe), 7.55 (td, J = 7.6 Hz, J = 1.2 Hz, 1H, 2-H), 7.64 (td, J = 8.2 Hz, J = 1.6 Hz, 1H, 3-H), 7.81 (d, J = 8 Hz, 1H, 4-H), 7.98 (d, J = 8.2 Hz, 1H, 1-H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 13.6, 19.5, 22.1, 30.2, 54.2, 98.3, 126.7, 126.8, 128.5, 130.1, 133.0, 138.5, 139.2, 157.1 ppm; IR (CH₂Cl₂): [small nu, Greek, tilde] = 2948, 2928, 2865, 2228, 1573, 1472, 1450, 1394, 1361, 1335, 1247, 1226, 1209, 1136, 1017, 995, 759, 718, 605, 501 cm⁻¹. HRMS for C₁₅H₁₇N₂O calculated [MH] 241.1341; found m/z = 241.1339.
3-Iodo-2-phenylfuro[2,3-b]quinoxaline (5a). To a solution of 4a (80 mg, 0.3 mmol) in CH₂Cl₂ (3 mL) was added iodine monochloride (0.03 mL, 0.6 mmol) at room temperature. The reaction mixture was stirred at room temperature, and the reaction progress was monitored by TLC. After completion of the reaction, the solvent was evaporated. The brownish solid obtained was purified by repeated washings with cold ethanol to give the pure material 5a (109 mg, 0.29 mmol, 98%) in the form of amber powder; mp 194–196 °C; ¹H NMR (400 MHz, [D6] DMSO): δ = 7.66–7.71 (m, 3H, 2′,3′-H), 7.86–7.88 (m, 2H, 2,3-H), 8.12–8.14 (m, 1H, 4-H), 8.26–8.29 (m, 1H, 1-H), 8.32–8.35 (m, 2H, 1′-H) ppm; ¹³C NMR (100 MHz, [D6] DMSO): δ = 65.6, 128.4, 128.7, 128.9, 129.1, 129.2, 129.6, 130.0, 132.0, 139.6, 142.2, 145.8, 153.1, 160.1 ppm; IR (KBr): [small nu, Greek, tilde] = 2961, 2918, 1544, 1480, 1441, 1384, 1326, 1317, 1260, 1182, 1134, 1096, 1046, 1019, 957, 802, 760, 686, 660, 602 cm⁻¹; ESI-MS: m/z 372.1 (M⁺). HRMS for C₁₆H₁₀N₂OI calculated [MH] 372.9838; found m/z = 372.9841.
2-(Methylthio)-3-(phenylethynyl)quinoxaline (6). Following general procedure I, 2-chloro-3-(methylthio)quinoxaline (3b; 105 mg, 0.5 mmol), PdCl₂(PPh₃)₂ (12 mg, 3.5 mol%), CuI (6.6 mg, 7 mol%), Et₃N (1 mL), and phenyl acetylene (0.09 mL, 0.82 mmol) were reacted in DMF (3 mL). The crude product obtained was purified by column chromatography (hexane/ethyl acetate = 11 : 1) to give the product 6 (105 mg, 0.38 mmol, 76%) as a yellow solid; mp 121–123 °C; ¹H NMR (400 MHz, CDCl₃): δ = 2.74 (s, 3H, –SMe), 7.42–7.48 (m, 3H, 2′,3′-H), 7.66 (td, J = 7.5 Hz, J = 1.2 Hz, 1H, 2-H), 7.72 (td, J = 7.7 Hz, J = 1.2 Hz, 1H, 3-H), 7.75–7.78 (m, 2H, 1′-H), 7.98 (dd, J = 8.4 Hz, J = 1.2 Hz, 1H, 4-H), 8.06 (d, J = 8 Hz, 1H, 1-H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 13.2, 85.3, 98.1, 121.4, 127.6, 128.4, 128.5, 128.9, 129.9, 130.5, 132.4, 137.8, 139.0, 141.1, 158.3 ppm; IR (KBr): [small nu, Greek, tilde] = 2212, 1518, 1485, 1441, 1333, 1288, 1262, 1232, 1171, 1120, 1050, 1025, 958, 908, 758, 688, 666, 602 cm⁻¹; ESI-MS: m/z 276.1 (M⁺). HRMS for C₁₇H₁₃N₂S calculated [MH] 277.0799; found m/z = 277.0801.
3-Iodo-2-phenylthieno[2,3-b]quinoxaline (7). It was synthesized according to the general procedure for 5a. To a solution of 6 (55 mg, 0.2 mmol) in CH₂Cl₂ (3 mL) was added iodine monochloride (0.02 mL, 0.4 mmol) at room temperature. The reaction mixture was stirred, and the reaction progress was monitored by TLC. After completion of the reaction, the solvent was evaporated. The brownish solid obtained was purified by repeated washings with cold ethanol to give the pure material 7 (58 mg, 0.15 mmol, 75.3%) in the form of an orange powder; mp 174–176 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.55–7.63 (m, 3H, 2′,3′-H), 7.84–7.91 (m, 4H, 2,3,1′-H), 8.22–8.27 (m, 1H, 4-H), 8.37–8.42 (m, 1H, 1-H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 80.1, 128.2, 128.9, 129.6, 129.73, 129.77, 130.0, 130.3, 134.0, 141.0, 141.9, 149.7, 150.9, 154.5 ppm; IR (KBr): [small nu, Greek, tilde] = 1549, 1515, 1478, 1440, 1327, 1286, 1240, 1214, 1183, 1129, 1091, 1029, 914, 789, 759, 732, 691, 669, 598, 436 cm⁻¹; ESI-MS: m/z 388.2 (M⁺). HRMS for C₁₆H₁₀N₂SI calculated [MH] 388.9609; found m/z = 388.9612.

General procedure for synthesis of 2-phenyl-3-alkynylfuro[2,3-b]quinoxaline 8a–c and 9a–c. They were synthesized according to the general procedure for 4a.
2-Phenyl-3-(phenylethynyl)furo[2,3-b]quinoxaline (8a). Following general procedure I, 3-iodo-2-phenylfuro[2,3-b]quinoxaline (5a; 112 mg, 0.3 mmol), PdCl₂(PPh₃)₂ (7.2 mg, 3.5 mol%), CuI (4 mg, 7 mol%), Et₃N (0.5 mL), and phenyl acetylene (0.08 mL, 0.6 mmol) were reacted in DMF (2 mL). The crude product obtained was purified by column chromatography (hexane/ethyl acetate = 9 : 1), and then washed with acetonitrile (2 mL) to give product 8a (98 mg, 0.28 mmol, 95%) as a yellowish solid; mp 210–211 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.48 (m, 3H, 2′′,3′′-H), 7.59–7.65 (m, 3H, 2′,3′-H), 7.74–7.77 (m, 2H, 1′′-H), 7.80–7.84 (m, 2H, 2,3-H), 8.16–8.19 (m, 1H, 4-H), 8.35–8.38 (m, 1H, 1 H), 8.57–8.59 (m, 2H, 1′-H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 78.6, 99.2, 99.4, 122.7, 127.3, 128.5, 128.64, 128.69, 128.7, 129.04, 129.07, 129.2, 129.3, 131.6, 131.9, 139.3, 142.4, 143.8, 153.1, 163.2 ppm; IR (KBr): [small nu, Greek, tilde] = 3447, 3061, 2962, 1555, 1481, 1407, 1306, 1259, 1216, 1180, 1100, 1083, 1067, 1022, 866, 802, 755, 686 cm⁻¹; ESI-MS: m/z 346.2 (M⁺). HRMS for C₂₄H₁₅N₂O calculated [MH] 347.1184; found m/z = 347.1188.
3-(Hex-1-yn-1-yl)-2-phenylfuro[2,3-b]quinoxaline (8b). Following general procedure I, 3-iodo-2-phenylfuro[2,3-b]quinoxaline (5a; 78 mg, 0.2 mmol), PdCl₂(PPh₃)₂ (5 mg, 3.5 mol%), CuI (2.6 mg, 7 mol%), Et₃N (0.5 mL) and hex-1-yne (0.05 mL, 0.4 mmol) were reacted in DMF (2 mL). The crude product was purified by column chromatography (hexane/ethyl acetate = 11 : 1), to give the product 8b (58 mg, 0.17 mmol, 89%) as a pale yellow solid; mp 129–130 °C; ¹H NMR (400 MHz, CDCl₃): δ = 1.05 (t, J = 7.4 Hz, 3H, 9-H), 1.61–1.66 (m, 2H, 8-H), 1.78–1.82 (m, 2H, 7-H), 2.73 (t, J = 7 Hz, 2H, 6-H), 7.57–7.62 (m, 3H, 2′,3′-H), 7.79–7.84 (m, 2H, 1′-H), 8.14–8.17 (m, 1H, 2-H), 8.34–8.37 (m, 1H, 3-H), 8.53–8.55 (m, 2H, 1,4-H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 13.7, 20.0, 22.1, 30.6, 69.7, 99.9, 101.4, 127.0, 128.4, 128.6, 128.8, 129.21, 129.26, 129.5, 131.3, 139.2, 142.3, 144.3, 153.1, 162.8 ppm; IR (KBr): [small nu, Greek, tilde] = 3426, 2954, 2925, 1486, 1464, 1444, 1408, 1383, 1314, 1186, 1130, 1057, 1026, 958, 766, 743, 683, 656 cm⁻¹; ESI-MS: m/z 326.2 (M⁺). HRMS for C₂₂H₁₉N₂O calculated [MH] 327.1497; found m/z = 327.1491.
3-(2-Phenylfuro[2,3-b]quinoxalin-3-yl)prop-2-yn-1-ol (8c). Following general procedure I, 3-iodo-2-phenylfuro[2,3-b]quinoxaline (5a; 65 mg, 0.17 mmol), PdCl₂(PPh₃)₂ (5 mg, 3.5 mol%), CuI (2.3 mg, 7 mol%), Et₃N (0.5 mL), and prop-2-yn-1-ol (0.03 mL, 0.34 mmol) were reacted in DMF (2 mL). The crude product obtained was purified by column chromatography (hexane/ethyl acetate = 6 : 3), and then recrystallized in methanol (2 mL) to give product 8c (48 mg, 0.16 mmol, 94%) as an orange crystal; mp 226–227 °C; ¹H NMR (400 MHz, CDCl₃): δ = 4.56 (d, J = 6 Hz, 2H, –CH₂), 5.65 (t, J = 6 Hz, 1H, –OH), 7.66–7.73 (m, 3H, 2′,3′-H), 7.86–7.91 (m, 2H, 2,3-H), 8.11–8.16 (m, 1H, 4-H), 8.25–8.29 (m, 1H, 1-H), 8.43–8.46 (m, 2H, 1′-H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 50.3, 73.5, 98.9, 100.6, 127.1, 128.4, 128.8, 129.2, 129.3, 129.9, 130.1, 132.5, 139.1, 142.1, 144.2, 153.2, 163.0 ppm; IR (KBr): [small nu, Greek, tilde] = 3315, 1627, 1599, 1556, 1470, 1445, 1408, 1319, 1186, 1161, 1130, 1095, 1062, 1030, 924, 902, 765, 679, 606 cm⁻¹; ESI-MS: m/z 300.1 (M⁺). HRMS for C₁₉H₁₃N₂O₂ calculated [MH] 301.0977; found m/z = 301.0973.
2-Phenyl-3-(phenylethynyl)thieno[2,3-b]quinoxaline (9a). Following general procedure I, 3-iodo-2-phenylthieno[2,3-b]quinoxaline (7; 58 mg, 0.15 mmol), PdCl₂(PPh₃)₂ (3.6 mg, 3.5 mol%), CuI (1.9 mg, 7 mol%), Et₃N (1 mL), and phenyl acetylene (0.03 mL, 0.3 mmol) were reacted in DMF (3 mL). The crude product obtained was purified by column chromatography (hexane/ethyl acetate = 10 : 1), and then washed with ethanol (1 mL) to give 9a (50 mg, 0.13 mmol, 92.5%) as a yellow solid; mp 170–171 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.41–7.47 (m, 3H, 2′′,3′′-H), 7.54–7.63 (m, 3H, 2′,3′-H), 7.70–7.73 (m, 2H, 1′-H), 7.83–7.88 (m, 2H, 2,3-H), 8.19–8.22 (m, 1H, 4-H), 8.24–8.27 (m, 2H, 1′′-H), 8.38–8.40 (m, 1H, 1-H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 82.6, 96.6, 112.4, 123.0, 128.4, 128.7, 128.8, 128.9, 129.5, 129.8, 129.9, 130.5, 131.9, 133.3, 140.8, 141.5, 150.9, 153.1, 154.5 ppm; IR (KBr): [small nu, Greek, tilde] = 3057, 1550, 1480, 1440, 1389, 13.62, 1260, 1210, 1137, 1102, 1076, 1027, 943, 915, 803, 768, 689 cm⁻¹; ESI-MS: m/z 362.3 (M⁺). HRMS for C₂₄H₁₅N₂S calculated [MH] 363.0956; found m/z = 363.0953.
3-(Hex-1-yn-1-yl)-2-phenylthieno[2,3-b]quinoxaline (9b). Following general procedure I, 3-iodo-2-phenylthieno[2,3-b]quinoxaline (7; 77 mg, 0.2 mmol), PdCl₂(PPh₃)₂ (4.8 mg, 3.5 mol%), CuI (2.6 mg, 7 mol%), Et₃N (1 mL), and hex-1-yne (0.05 mL, 0.4 mmol) were reacted in DMF (3 mL). The crude product obtained was purified by column chromatography (hexane/ethyl acetate = 12 : 1), and then washed with ethanol (2 mL) to give product 9b (60 mg, 0.17 mmol, 88%) as a pale yellow solid; mp 95–97 °C; ¹H NMR (400 MHz, CDCl₃): δ = 1.02 (t, J = 7.2 Hz, 3H, –CH₃), 1.55–1.62 (m, 2H, 7-H), 1.71–1.78 (m, 2H, 6-H), 2.69 (t, J = 7 Hz, 2H, 5-H), 7.51–7.59 (m, 3H, 2′,3′-H), 7.79–7.86 (m, 2H, 2,3-H), 8.17–8.22 (m, 3H, 1′,4-H), 8.36–8.39 (m, 1H, 1-H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 13.7, 19.9, 22.1, 30.5, 73.6, 98.7, 113.0, 128.3, 128.6, 128.8, 129.3, 129.6, 129.8, 130.3, 133.3, 140.7, 141.4, 151.3, 152.0, 154.6 ppm; IR (KBr): [small nu, Greek, tilde] = 3059, 2957, 2922, 2861, 1482, 1463, 1385, 1361, 1324, 1259, 1159, 1109, 1024, 917, 802, 760, 686 cm⁻¹; ESI-MS: m/z 342.3 (M⁺). HRMS for C₂₂H₁₉N₂S calculated [MH] 343.1269; found m/z = 343.1269.
3-(2-Phenylthieno[2,3-b]quinoxalin-3-yl)prop-2-yn-1-ol (9c). Following general procedure I, 3-iodo-2-phenylthieno[2,3-b]quinoxaline (7; 77 mg, 0.2 mmol), PdCl₂(PPh₃)₂ (4.8 mg mL, 2.560 mmol), CuI (2.6 mg, 2.560 mmol), Et₃N (1 mL), and prop-2-yn-1-ol (0.02 ml. 0.4 mmol) were reacted in DMF (3 mL). The crude product obtained was purified by column chromatography (hexane/ethyl acetate = 6 : 3), and then washed with methanol (2 mL) to give the product 9c (58 mg, 0.18 mmol, 92%) as a yellow solid; mp 199–200 °C; ¹H NMR (400 MHz, CDCl₃): δ = 2.34 (br. s, 1H, –OH), 4.72 (s, 2H, –CH₂), 7.51–7.57 (m, 3H, 2′,3′-H), 7.80–7.84 (m, 2H, 2,3-H), 8.09–8.12 (m, 2H, 1′-H), 8.14–8.18 (m, 1H, 4-H), 8.32–8.34 (m, 1H, 1-H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 51.9, 72.9, 128.5, 128.6, 129.0, 129.2, 129.9, 130.8, 132.8, 140.8, 150.7, 154.2, 154.5 ppm; IR (KBr): [small nu, Greek, tilde] = 3405, 2921, 1638, 1596, 1481, 1441, 1389, 1356, 1243, 1160, 1114, 1064, 1012, 959, 908, 757, 736, 681; ESI-MS: m/z 316.2 (M⁺). HRMS for C₁₉H₁₃N₂OS calculated [MH] 317.0749; found m/z = 317.0748.
2,3-Piphenylfuro[2,3-b]quinoxaline (10a). To a solution of compound 5a (65 mg, 0.17 mmol) in DMF (2 mL) were added Pd(OAc)₂ (4 mg, 5 mol%) and K₂CO₃ (50 mg, 0.36 mmol) under an argon atmosphere, and the mixture was stirred for 10 min at room temperature. To this solution was added phenyl boronic acid (32 mg, 0.26 mmol), and the mixture was allowed to stir at 80 °C for 8 h. After completion of the reaction, the mixture was cooled to room temperature, the solvent was evaporated, and the residue obtained was wished with water. The crude compound was purified by column chromatography on silica gel using hexane/ethyl acetate (10 : 1) to afford compound 10a (50 mg, 0.15 mmol, 92.5%); mp 210–212 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.41–7.59 (m, 6H, 2′,3′,2′′,3′′-H), 7.73–7.80 (m, 4H, 2,3,1′′-H), 7.87–7.91 (m, 2H, 1′-H), 8.15–8.20 (m, 1H, 4-H), 8.23–8.27 (m, 1H, 1-H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 116.5, 128.1, 128.6, 128.8, 128.9, 129.13, 129.15, 129.2, 129.8, 129.9, 130.7, 139.0, 142.4, 144.3, 153.6, 158 ppm; IR (KBr): [small nu, Greek, tilde] = 2962, 2931, 1742, 1466, 1445, 1403, 1308, 1284, 1261, 1179, 1152, 1096, 863, 799, 757, 694 cm⁻¹; ESI-MS: m/z 321.2 (M⁺). HRMS for C₂₂H₁₅N₂O calculated [MH] 323.1184; found m/z = 323.1183.
2,3-Diphenylthieno[2,3-b]quinoxaline (10b). Following the procedure for 10a, 3-iodo-2-phenylthieno[2,3-b]quinoxaline (7; 65 mg, 0.17 mmol), Pd(OAc)₂ (4 mg, 5 mol%), K₂CO₃ (50 mg, 0.36 mmol), and phenyl boronic acid (32 mg, 0.26 mmol) were reacted in DMF (2 mL). The crude product obtained was purified by column chromatography (hexane/ethyl acetate = 12 : 1), and then washed with ethanol (2 mL) to give the product 10b (51 mg, 0.15 mmol, 89%) as a yellow solid, mp 214–216 °C; ¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.42 (m, 3H, 2′′,3′′-H), 7.44–7.50 (m, 5H, 1′′,2′,3′-H), 7.56–7.59 (m, 2H, 1′-H), 7.76–7.84 (m, 2H, 2,3-H), 8.19–8.24 (m, 2H, 1,4-H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 128.0, 128.3, 128.5, 128.7, 128.9, 129.3, 129.4, 129.7, 129.9, 130.5, 130.9, 133.1, 133.7, 140.3, 141.4, 147.3, 150.7, 156.1 ppm; IR (KBr): [small nu, Greek, tilde] = 3054, 1479, 1440, 1385, 1356, 1261, 1240, 1178, 1124, 1091, 1071, 1027, 864, 802, 760, 693, 643 cm⁻¹; ESI-MS: m/z 337.2 (M⁺). HRMS for C₂₂H₁₅N₂S calculated [MH] 339.0956; found m/z = 339.0958.
(E)-Ethyl-3-(2-phenylfuro[2,3-b]quinoxalin-3-yl)acrylate (11). To a solution of 3-iodo-2-phenylfuro[2,3-b]quinoxaline (5a, 55 mg, 0.15 mmol), and K₂CO₃ (82 mg, 0.6 mmol) in DMF (5 mL) were added Pd(OAc)₂ (2.1 mg, 3 mol%) and ethyl acrylate (0.07 mL, 0.6 mmol). The reaction was stirred at 80 °C for 10 h, and cooled to room temperature. After evaporation of the solvent, the crude compound left was washed with water. The residue was purified by column chromatography on silica gel using hexane/ethyl acetate (12 : 1) to afford compound 11 (45 mg, 0.13 mmol, 86.5%) as a yellow solid; mp 180–181 °C; ¹H NMR (400 MHz, CDCl₃): δ = 1.43 (t, J = 7 Hz, 3H, –CH₃), 4.37 (q, J = 7.2 Hz, 2H, –CH₂), 7.63–7.67 (m, 3H, 2′,3′-H), 7.81–7.85 (m, 2H. 2,3-H), 7.88 (d, J = 15.6 Hz, 1H, 7-H), 8–8.02 (m, 2H, 1′-H), 8.08 (d, J = 15.6 Hz, 1H, 6-H), 8.16–8.19 (m, 1H, 4-H), 8.34–8.36 (m, 1H, 1-H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 14.4, 60.7, 111.7, 123.6, 128.53, 128.58, 128.6, 129, 129.3, 129.4, 129.5, 131.6, 132.1, 138.9, 142.2, 142.7, 153.5, 163.1, 167.4 ppm; IR (KBr): [small nu, Greek, tilde] = 2964, 1743, 1699, 1632, 1416, 1310, 1266, 1219, 1199, 1172, 1128, 1096, 1059, 801, 771, 753, 689 cm⁻¹; ESI-MS: m/z 344.3 (M⁺). HRMS for C₂₁H₁₇N₂O₃ calculated [MH] 345.1239; found m/z = 345.1246.

Conclusions

We developed an efficient and successful palladium-catalyzed protocol for the synthesis of a number of 2,3-disubstituted furo/thieno[2,3-b]quinoxalines via sonogashira coupling reaction, followed by iodo cyclization and the subsequent Sonogashira, Suzuki, and Heck reactions. Coupling products were obtained in high to excellent yields in the presence or absence of CuI at room temperature under sonogashira reaction condition. Moreover, we carried out the reactions in water as a green solvent, which generated the desired products in high yields. The iodocyclization of 2-methoxy-3-(phenylethynyl)quinoxalines and their methylthio derivatives led to the formation of 3-iodo-furo/thieno[2,3-b]quinoxalines as the important key intermediates for the reaction with a variety of terminal alkynes, phenyl boronic acid, and ethyl acrylate to produce the new 2,3-disubstituted furo/thieno[2,3-b]quinoxalines. Moreover, all the compounds prepared were tested for their anti-microbial activity; compound 9c was found to be the most active one against M. luteus.

Acknowledgements

The authors gratefully acknowledge the supports by the Research Council of Shahrood University of Technology and the Institute for Advanced Studies in Basic Sciences (IASBS) Research Council under grant no. G2010IASBS120. The authors also thank Mr Haruhiko Fukaya, Tokyo University of Pharmacy and Life Science for its helps carrying out the HRMS analysis.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra15425e

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