Efficient synthesis of novel 1,2,3-triazole-linked quinoxaline scaffold via copper-catalyzed click reactions

Abstract

In this work, new derivatives of the 1,2,3-triazole-linked quinoxaline ring system are prepared by the reaction of 2-chloro-3-(prop-2-ynyloxy)quinoxaline or 2,3-bis(prop-2-ynyloxy)quinoxaline with aromatic azides via copper-catalyzed azide-alkyne cycloaddition reactions in the presence of the Schiff base ligands. These reaction procedures have the advantages of high-to-excellent yields, short reaction times, mild experimental conditions, and operational simplicity. The synthesized compounds were screened against the three bacterial strains Micrococcus luteus, Pseudomonas aeruginosa, and Bacillus subtilis. The anti-bacterial activity of 6b against P. aeruginosa was better than that for the standard drug (tetracycline).

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Introduction

Click chemistry offers a highly efficient technique for connecting two potential building blocks to other functional groups under mild conditions with high tolerance.^1–3 Click reaction has been widely applied to the synthesis of macromolecules⁴ and functionalization of biomolecules.⁵ 1,2,3-Triazole compounds have an important role not only in organic chemistry but also in medicinal chemistry, drug discovery, agrochemicals, and also as dyes due to their easy synthesis by click chemistry and interesting features as well as multiple biological activities.^6,7 The 1,2,3-triazole framework constitutes the structure of a large variety of bioactive molecules such as the anti-fungal,⁸ anti-bacterial,^9,10 anti-allergic,¹¹ anti-HIV,^12,13 anti-tubercular,^14,15 and anti-inflammatory agents.¹⁶

Quinoxaline and its derivatives display a broad biological activities, and have been used as the anti-cancer,¹⁷ anti-viral,¹⁸ anti-bacterial,¹⁹ and kinase-inhibition agents.²⁰ They have contributed to their usefulness in the combinatorial drug discovery libraries.^21–26 The quinoxaline skeleton is an important part of a number of antibiotics such as echinomycin, actinomycin, and leromycin that are known to inhibit the growth of Gram-positive bacteria, and to be active against various transplantable tumors.^27,28

Binding 1,2,3-triazole moieties to other pharmacophores via copper-catalyzed click reactions is important for the synthesis of biologically-active compounds. A series of 6,7-dichloro-1,4-dihydro-(1H,4H)-quinoxaline-2,3-diones have been prepared, in which the 5-position of the ring in these compounds has been occupied by a heterocyclylmethyl or a 1-(heterocyclyl)-1-propyl group. The most anti-tumor activity potent available in this series is 6,7-dichloro-5-[1-(1,2,4-triazol-4-yl)propyl]-1,4-dihydro-(1H,4H)-quinoxaline-2,3-dione.²⁹ Therefore, the synthesis of 1,2,3-triazole linked to the quinoxaline scaffold has gained prominence in the synthetic organic as well as medicinal chemistry.

Copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions have several priorities over the thermal version³⁰ including selectivity, increased reactivity of deactivated alkynes, and high yields.³¹ In continuation of our studies directed toward the efficient synthesis of biologically-active molecules with a quinoxaline ring,^32–34 we decided to synthesize new derivatives of the 1,2,3-triazole-linked quinoxaline ring system via the copper-catalyzed click reactions.

Results and discussion

Treatment of 2,3-dichloroquinoxaline (1) with prop-2-yn-1-ol (2) in DMF in the presence of t-BuOK, as a base, afforded 2-chloro-3-(prop-2-ynyloxy)quinoxaline (3) in good yield (Scheme 1). The ¹H NMR spectrum of 3 showed a triplet for the CH proton at δ 3.73, a doublet for the CH₂ protons at δ 5.18, and a multiplet for the aromatic protons of the quinoxaline ring at δ 7.55–8.10.

Scheme 1 Synthesis of 2-chloro-3-(prop-2-ynyloxy)quinoxaline by reaction of 2,3-dichloroquinoxaline with prop-2-yn-1-ol.

Similarly, the reaction of 2,3-dichloroquinoxaline (1) with two equivalents of prop-2-yn-1-ol (2) afforded 2,3-bis(prop-2-ynyloxy)quinoxaline (4) under the same experimental conditions (Scheme 2).

Scheme 2 Synthesis of 2,3-bis(prop-2-ynyloxy)quinoxaline by reaction of 2,3-dichloroquinoxaline with 2 eq. of prop-2-yn-1-ol.

The click reaction of 2-chloro-3-(prop-2-ynyloxy)quinoxaline (3) with 1-azido-3-nitrobenzene (5a) in the presence of 5 mol% of CuSO₄ and 10 mol% of sodium ascorbate only yielded 40% of 2-chloro-3-[(1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl]methoxy)quinoxaline (6a), as the desired product (Table 1, entry 1). The effects of various amounts of the catalyst, solvent, and ligand, and also the temperature were studied, and the results obtained were tabulated in Table 1. The reaction most effective in the presence of 10 mol% of CuSO₄ and 20 mol% of sodium ascorbate at 78 °C in ethanol, giving the desired product with an excellent yield (98%) (Table 1, entry 2).

Table 1 Effects of various amounts of catalyst and solvent, and temperature on reaction of 2-chloro-3-(prop-2-ynyloxy)quinoxaline (3) with 1-azido-3-nitrobenzene (5c)^a

Entry	Catalyst (mol%)	Additive	Solvent	T (°C)	t (h)	Yield (%)
a Reaction conditions: 3 (0.5 mmol), 5a (0.5 mmol), copper salt, sodium ascorbate (twice the amount of copper salt) or ligand (equal copper salt), solvent (4 mL), temperature.
1	CuSO4 (5)		EtOH	78	12	40
2	CuSO4 (10)	—	EtOH	78	1	98
3	CuSO4 (10)	—	CH3CN	78	2	85
4	CuSO4 (10)	—	DMF	r.t.	24	50
5	CuSO4 (10)	—	DMF	65	3	73
6	CuSO4 (10)	—	DMF	75	3	88
7	CuSO4 (10)	—	DMF	95	3	91
8	CuSO4 (10)	—	C6H5CH3	80	4	73
9	CuI (10)	—	DMF	r.t.	2	65
10	CuI (10)	—	DMF	65	2	82
11	CuI (10)	—	EtOH	78	1	92
12	CuCl2 (10)	—	DMF	65	2	80
13	CuSO4 (10)	—	H2O/EtOH (1 : 4)	78	12	40
14	CuSO4 (10)	—	H2O/CH3CN (1 : 4)	80	2	60
15	CuSO4 (10)	—	H2O/DMF (1 : 4)	85	4	65
16	Cu(OAc)2 (10)	—	EtOH	78	1	75
17	Cu(OAc)2 (2.5)	L2	DMF	r.t.	3	77
18	Cu(OAc)2 (2.5	L1	DMF	r.t.	4	55
19	Cu(OAc)2 (1.5)	L2	DMF	r.t.	5	44
20	Cu(OAc)2 (2.5)	L3	DMF	r.t.	3	50
21	Cu(OAc)2 (2.5)	L2	EtOH	78	2	95
22	CuI (2.5)	L2	DMF	r.t.	2	80
23	CuI (2.5)	L2	DMF	50	2	85

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A large amount of a heavy metal catalyst is used in the classic copper-catalyzed click reactions, whereas Cu salts are toxic, pollute the biologically relevant compounds, and their complete removal from the reaction products is difficult. This problem inhibits the utilization of the click reactions in the biomedicine science. The nitrogen ligands allow the use of copper catalysts in reduced amounts compared to the original classic catalyst (CuSO₄ and sodium ascorbate), which is still the most commonly utilized catalyst but in much larger quantities that are often even stoichiometric or superior to stoichiometry.³⁵ Ligands can be used to (a) prevent the formation of unreactive polynuclear copper(I) acetylides; (b) facilitate coordination of the azide to the copper center at the ligand exchange step; and (c) increase the solubility of the copper complex to deliver higher solution concentrations of the necessary Cu(I)-species.³⁶ A number of researchers have efficiently decreased the required amount of the copper catalyst for the click reactions by the usage of ligands.³⁷ Recently, Astruc and co-workers have used the dendrimer ligand to decrease the copper catalyst used to the ppm scale in simple click reactions.³⁸ In order to decrease the amount of the copper catalyst, we decided to use the Schiff base ligands salen (L1) and salophen (L2) as additive in the reaction. We also screened metformine (L3) as the ligand. Surprisingly, in the presence of L1 and with 2.5 mol% of Cu(OAc)₂, the reaction proceeded effectively and was completed to afford the desired product in a 95% yield (Table 1, entry 21). Therefore, the optimal reaction conditions were 2.5 mol% of Cu(OAc)₂, 5 mol% of sodium ascorbate and 2.5 mol% of salophen (L2) at 78 °C in ethanol (Table 1, entry 21).

For the synthesis of 2,3-bis[(1-aryl-1H-1,2,3-triazol-4-yl)methoxy]quinoxalines (7) from 2,3-bis(prop-2-ynyloxy)quinoxaline (4) and aromatic azides (5), the optimization was made in the same fashion, and the results obtained were tabulated in Table 2. The best reaction conditions were 5 mol% of CuI and 5 mol% of salen (L1) in DMF at 50 °C (Table 2, entry 22).

Table 2 Effects of various amounts of catalyst and solvent, and temperature on reaction of 2,3-bis(prop-2-ynyloxy)quinoxaline (4) with 1-azido-3-nitrobenzene (5a)^a

Entry	Catalyst (mol%)	Additive	Solvent	T (°C)	t (h)	Yield (%)
a Reaction conditions: 4 (0.5 mmol), 5a (1 mmol), copper salt, sodium ascorbate (twice the amount of copper salt) or ligand (equal copper salt), solvent (3 mL), temperature.
1	CuSO4 (20)	—	DMF	r.t.	24	61
2	CuSO4 (20)	—	DMF	65	6	75
3	CuSO4 (20)	—	DMF	85	2	96
4	CuSO4 (20)	—	DMF	85	6	55
5	CuSO4 (10)	—	DMF	85	4	70
6	CuSO4 (20)	—	EtOH	78	10	30
7	CuSO4 (20)	—	CH3CN	80	3	83
8	CuSO4 (20)	—	C6H5CH3	80	5	81
9	CuI (20)	—	DMF	r.t.	12	77
10	CuI (20)	—	DMF	85	2	92
11	CuI (20)	—	DMF	95	2	91
12	CuCl2 (20)	—	DMF	85	2.5	81
13	CuSO4 (20)	—	H2O/DMF (1 : 4)	85	3	87
14	CuSO4 (20)	—	H2O/CH3CN (1 : 4)	80	3	76
15	Cu(OAc)2 (20)	—	DMF	85	3	85
16	Cu(OAc)2 (5)	L2	DMF	r.t.	5	35
17	Cu(OAc)2 (10)	L2	DMF	r.t.	5	50
18	Cu(OAc)2 (5)	L1	DMF	r.t.	4	45
19	Cu(OAc)2 (5)	L3	DMF	r.t.	6	30
20	Cu(OAc)2 (3)	L1	DMF	r.t.	6	20
21	CuI (5)	L1	DMF	50	5	75
22	CuI (5)	L1	DMF	50	4	90
23	CuI (5)	L2	DMF	50	4	70
24	CuI (3)	L1	DMF	50	4	80

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In order to explore the scope and generality of these protocol, various aromatic azides were used as the substrates for the synthesis of substituted 2-chloro-3-[(1-(aryl)-1H-1,2,3-triazol-4-yl)methoxy]quinoxalines (6a–e) and 2,3-bis[(1-(aryl)-1H-1,2,3-triazol-4-yl)methoxy]quinoxalines (7a–e) (Schemes 3 and 4). The results obtained were tabulated in Tables 3 and 4.

Scheme 3 Synthesis of 2-chloro-3-[(1-aryl-1H-1,2,3-triazol-4-yl]methoxy]quinoxalines (6) by reaction of 2-chloro-3-(prop-2-ynyloxy)quinoxaline (3) with an aromatic azide (5) via a copper-catalyzed click reaction.

Scheme 4 Synthesis of 2,3-bis[(1-aryl-1H-1,2,3-triazol-4-yl)methoxy]quinoxalines (7) by reaction of 2,3-bis(prop-2-ynyloxy)quinoxaline (4) with 2 eq. of an aromatic azide (5) via a copper-catalyzed click reaction.

Table 3 Synthesis of 2-chloro-3-[(1-(aryl)-1H-1,2,3-triazol-4-yl]methoxy)quinoxalines^a

Entry	Azide	Product	Time (h)	Yield (%)
a Reaction conditions: 3 (0.5 mmol), 5 (0.5 mmol), CuI (2.5 mol%), salophen (2.5 mol%), EtOH (4 mL), 78 °C.
1			2	95
2			2.5	85
3			2.5	92
4			1	87
5			1.5	97

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Table 4 Synthesis of 2,3-bis[(1-(aryl)-1H-1,2,3-triazol-4-yl)methoxy]quinoxalines^a

Entry	Azide	Product	Time (h)	Yield (%)
a Reaction conditions: 3 (0.5 mmol), 5 (1 mmol), CuI (5 mol%), salophen (5 mol%), DMF (3 mL), 50 °C.
1			4	90
2			5	80
3			4	88
4			3	95

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For the synthesis of a variety of 2-chloro-3-(1H-1,2,3-triazol-4-ylmethoxy)quinoxaline derivatives (6), we decided to replace the chlorine atom in the 2-position of the ring in these compounds by amine nucleophiles (Scheme 5). Nucleophilic substitution of the chlorine atom in 6 was performed easily using secondary amines such as dimethyl amine, morpholine, and piperidine to afford 8 in DMF. The results obtained were tabulated in Table 5.

Scheme 5 Nucleophilic substitution of 2-chloro-3-[(1-(aryl)-1H-1,2,3-triazol-4-yl)methoxy]quinoxalines (6) with nucleophiles.

Table 5 Synthesis of 2-amino-3-[(1-(aryl)-1H-1,2,3-triazol-4-yl)methoxy]quinoxalines^a

Aryl halide	NuH	Product	Time (h)	Yield (%)
a Reaction conditions: 6 (1 mmol), NuH (2.2 mmol), DMF (5 mL), 70 °C.
6a			5	87
6b			3	90
6c			4	89

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The copper-catalyzed click reaction catalytic cycle mechanism comprises the multi-general steps shown in Scheme 6: (a) formation of copper(I) acetylide A; this step occurs through a π-alkyne copper complex intermediate. (b) The azide is then activated by coordination to copper(I), forming intermediate B. (c) The first C–N bond formation affords the six-membered ring copper metallacycle C. (d) Cyclization takes place to yield the copper triazole intermediate D. (e) Proteolysis of the Cu–C bond gives the triazole product, and regenerates the catalyst. Each stage involves a multi-nuclear Cu species.^1c,2b

Scheme 6 Proposed mechanism for the copper catalyzed click reactions.

The synthesized compounds were tested in vitro for their anti-bacterial activity against the microorganisms Micrococcus luteus, Bacillus subtilis (Gram positive) and Pseudomonas aeruginosa (Gram negative) using tetracycline as a standard anti-bacterial agent, and the results obtained were tabulated in Table 6. Their anti-bacterial activities were determined by a well-diffusion method at a concentration of 4000 μg mL⁻¹. According to these results, 6b showed the highest anti-bacterial activity against P. aeruginosa (20) among all of the compounds. In addition, the anti-bacterial activity of this compound was better than the standard drug tetracycline. Moreover, 6b showed a significant inhibition activity against M. luteus (16). Also 4, 6a, 7a, 7b, and 8b possessed higher anti-bacterial activities against P. aeruginosa. Only 4 and 8a showed good anti-bacterial activity against B. subtilis.

Table 6 Anti-bacterial activities of some selected compounds (4000 μg mL⁻¹) as inhibition zone (in mm)

Entry	Compound	M. luteus	B. subtilis	P. aeruginosa
a Negative control.b Positive control.
1	3	—	—	—
2	4	8	9	7
3	6a	9	—	9
4	6b	16	—	20
5	6c	7	—	—
6	6d	—	—	—
7	7a	—	—	7
8	7b	—	—	8
9	7c	7	—	—
10	7d	8	—	—
11	8a	—	8	—
12	8b	—	—	7
13	DMSO^a	—		—
14	Tetracycline^b	41	15	13

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MIC is defined as the lowest concentration of the compound at which the growth is inhibited after 24 h of incubation in a rotatory shaker at 37 °C. All the newly synthesized compounds were evaluated for their anti-microbial activity against Micrococcus luteus using a micro-method for the determination of the minimum inhibitory concentration (MIC). The MIC values for the active compounds are summarized in Table 7. Compound 7c was the most active compound against this strain in the set (MIC = 31.25 mmol L⁻¹), whereas 6c and 6d were only weakly active against this bacterium (MIC = 500 mmol L⁻¹).

Table 7 In vitro anti-microbial activity of all products expressed as MIC (mmol L⁻¹)

Entry	Compound	MIC
1	6a	250
2	6b	62.5
3	6c	500
4	6d	500
5	7a	250
6	7b	125
7	7c	31.25
8	7d	125
9	7e	62.5
10	Tetracycline	31.25

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Conclusion

We developed an efficient procedure for the synthesis of a 1,2,3-triazole-linked quinoxaline ring system in high-to-excellent yields by the reaction of the quinoxaline acetylenic compound 2-chloro-3-(prop-2-ynyloxy)quinoxaline or 2,3-bis(prop-2-ynyloxy)quinoxaline with aromatic azides via the copper-catalyzed click reactions in the presence of Schiff base ligands. Short reaction time, simple operation, and easy workup are some advantages of this protocol. All the new 1,2,3-triazole-linked quinoxaline scaffold formed were screened for their in vitro anti-bacterial activity against Gram-positive and Gram-negative bacteria using a well-diffusion method.

Experimental part

General information

The materials and solvents used were commercially available. Melting points were determined on 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 a Shimadzu IR-470. NMR data were recorded in CDCl₃ and DMSO on a Bruker Avance 400 MHz spectrometer. The mass spectra were measured on a quadru pole 5973 Network Mass Selective Detector. 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).

Anti-bacterial assay

The anti-bacterial activities of the new compounds were evaluated biologically using a well-diffusion method against M. luteus (ATCC 4698), P. aeruginosa (ATCC 27853), and B. subtilis (DSM 6887) 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 period, 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 a sterilized glass tube. Each well-received 30 μL of the test compounds at a concentration of 4000 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 mm. The results obtained were reported as the inhibition zone in mm. The anti-bacterial activity of each compound was compared with that for tetracycline as the standard drug. DMSO was used as the negative control.

Synthesis of 2-chloro-3-(prop-2-ynyloxy)quinoxaline (3). Prop-2-yn-1-ol 2 (2.1 mmol) was added slowly to a stirring mixture of 1,2-dichloro quinoxaline 1 (2 mmol) and t-BuOK (2.1 mmol) in dry DMF (4 mL) at room temperature. The reaction mixture was warmed to 70 °C, and stirring was continued until the disappearance of compound 1 (monitored by TLC). The solvent was evaporated to dryness, the crude product was washed with H₂O, and the precipitate formed was purified by recrystallization from ethanol.

Mp, 120 °C; ¹H NMR (400 MHz, [D6] DMSO): δ = 3.70 (t, J = 2.4 Hz, 1H, 5-H), 5.22 (d, J = 2.4 Hz, 2H, 6-H), 7.70 (td, J = 7.6 Hz, J = 1.6 Hz, 1H, 2-H), 7.80 (td, J = 7.7 Hz, J = 1.4 Hz, 1H, 3-H), 7.87 (dd, J = 8.2 Hz, J = 1.2 Hz, 1H, 4-H), 7.95 (dd, J = 8.2 Hz, J = 1.2 Hz, 1H, 1-H) ppm; ¹³C NMR (400 MHz, [D6] DMSO): δ = 55.7, 78.6, 79.1, 127.0, 128.1, 128.6, 131.3, 138.3, 138.7, 139.0, 151.9 ppm; IR (KBr): [small nu, Greek, tilde] = 3290, 2960, 2100, 1560, 1480, 1323 cm⁻¹.

Synthesis of 2,3-bis(prop-2-ynyloxy)quinoxaline (4). Prop-2-yn-1-ol (2) (4.2 mmol) was added slowly to a stirring mixture of 1,2-dichloro quinoxaline (1) (2 mmol) and t-BuOK (4.2 mmol) in dry DMF (4 mL) at room temperature. The reaction mixture was warmed to 70 °C, and stirring was continued until the disappearance of compound 1 (monitored by TLC). The solvent was evaporated to dryness, the crude product was washed with H₂O, and the precipitate formed was purified by recrystallization from CH₃CN.

Mp, 180–181 °C; ¹H NMR (400 MHz, [D6] DMSO): δ = 3.66 (t, J = 2.4 Hz, 2H, 3-H), 5.19 (d, J = 2.4 Hz, 4H, 4-H), 7.59–7.61 (m, 2H, 1-H), 7.78–7.81 (m, 2H, 2-H) ppm; ¹³C NMR (400 MHz, [D6] DMSO): δ = 54.7, 78.8, 79.0, 126.7, 127.8, 136.8, 148.3 ppm; IR (KBr): [small nu, Greek, tilde] = 3298, 2965, 2110, 1564, 1480, 1320 cm⁻¹.

General procedure for synthesis of 2-chloro-3-[(1-(aryl)-1H-1,2,3-triazol-4-yl)methoxy]quinoxaline

To a mixture of 3 (0.5 mmol) and an aromatic azide (5) (0.5 mmol) in ethanol (4 mL), were added CuI (2.5 mol%) and salophen (2.5 mol%). The resulting mixture was stirred at 78 °C until the disappearance of compound 3 (monitored by TLC). Upon completion of the reaction, the solvent was evaporated to dryness, the crude product was washed with a (1 : 1) mixture of H₂O and conc. NH₃ to remove the catalyst. The precipitate formed was collected, dried, and finally purified by recrystallization from CH₃CN to give 6.

2-Chloro-3-[(1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy]quinoxaline (6a). Mp, 219–220 °C; ¹H NMR (400 MHz, [D6] DMSO): δ = 5.80 (s, 2H, 6-H), 7.74 (td, J = 7.6 Hz, J = 1.4 Hz, 1H, 2-H), 7.85 (td, J = 7.6 Hz, J = 1.4 Hz, 1H, 3-H), 7.93 (t, J = 8.2 Hz, 1H, 2′-H), 7.99–8.03 (m, 2H, 1′, 3′-H), 8.36 (ddd, J = 8.2 Hz, J = 2.2 Hz, J = 0.8 Hz, 1H, 4-H) 8.44 (ddd, J = 8.4 Hz, J = 1.6 Hz, J = 0.8 Hz, 1H, 1-H), 8.76 (t, J = 2.2 Hz, 1H, 4′-H), 9.25 (s, 1H, 5-H), ppm; ¹³C NMR (400 MHz, [D6] DMSO): δ = 60.8, 115.5, 123.8, 124.6, 126.8, 127.2, 128.1, 128.5, 131.3, 132.0, 137.5, 138.4, 139.0, 139.3, 143.6, 149.0, 152.5 ppm; IR (KBr): [small nu, Greek, tilde] = 3090, 2980, 1561, 1520, 1480, 1340 cm⁻¹. MS (m/z): 382 M⁺.

2-Chloro-3-[(1-(2-nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy]quinoxaline (6b). Mp, 173–175 °C; ¹H NMR (400 MHz, [D6] DMSO): δ = 5.79 (s, 2H, 6-H), 7.74–8.02 (m, 7H), 8.25 (dd, J = 7.6 Hz, J = 0.8 Hz, 1H, 4′-H), 8.93 (s, 1H, 5-H) ppm; ¹³C NMR (400 MHz, [D6] DMSO): δ = 60.7, 126.0, 127.30, 127.35, 128.1, 128.2, 128.5, 129.4, 131.3, 131.8, 134.9, 138.4, 139.0, 139.2, 142.8, 144.5, 152.5 ppm; IR (KBr): [small nu, Greek, tilde] = 3110, 3050, 2920, 1605, 1545, 1528, 1420, 1360, 1320, 1220, 1060, 740 cm⁻¹. MS (m/z): 382 M⁺.

2-Chloro-3-[(1-(3-chloro-4-nitrophenyl)-1H-1,2,3-triazol-4-yl]methoxy)quinoxaline (6c). Mp, 238 °C; ¹H NMR (400 MHz, [D6] DMSO): δ = 5.79 (s, 2H, 6-H), 7.74 (td, J = 7.7 Hz, J = 1.2 Hz, 1H, 2-H), 7.85 (td, J = 7.7 Hz, J = 1.2 Hz, 1H, 3-H), 7.97–8.06 (m, 3H, 1,4,2′-H), 8.31 (dd, J = 8.8 Hz, J = 2.8 Hz, 1H, 1′-H), 8.72 (d, J = 2.8 Hz, 1H, 3′-H), 9.16 (s, 1H, 5-H) ppm; ¹³C NMR (400 MHz, [D6] DMSO): δ = 59.5, 115.3, 123.6, 124.0, 125.1, 125.7, 126.2, 126.7, 127.2, 132.0, 135.3, 137.5, 138.8, 144.2, 147.4, 148.9, 149.4 ppm; IR (KBr): [small nu, Greek, tilde] = 3100, 2960, 1528, 1440, 1347, 1240 cm⁻¹. MS (m/z): 416 M⁺.

2-Chloro-3-[(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy]quinoxaline (6d). Mp, 245–246 °C; ¹H NMR (400 MHz, CDCl₃): δ = 5.80 (s, 2H, 6-H), 7.74 (td, J = 7.6 Hz, J = 1.2 Hz, 1H, 2-H), 7.85 (td, J = 7.6 Hz, J = 1.6 Hz, 1H, 3-H), 8.00–8.04 (m, 2H, 1,4-H), 8.27 (d, J = 9.2 Hz, 2H, 1′-H), 8.47 (d, J = 10.4 Hz, 2H, 2′-H), 9.22 (s, 1H, 5-H) ppm; IR (KBr): [small nu, Greek, tilde] = 3120, 2966, 1598, 1523, 1475, 1323 cm⁻¹. MS (m/z): 382 M⁺.

2-Chloro-3-[(1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy]quinoxaline (6e). Mp, 198 °C; ¹H NMR (400 MHz, [D6] DMSO): δ = 5.70 (s, 2H, 6-H), 7.56–7.65 (m, 4H, Ar-H), 7.88–7.92 (m, 3H, Ar-H), 8.04 (s, 1H, 4′-H), 9.05 (s, 1H, 5-H) ppm; ¹³C NMR (400 MHz, [D6] DMSO): δ = 59.7, 119.3, 120.5, 124.4, 126.8, 127.6, 129.1, 132.0, 134.6, 137.0, 138.0, 143.5, 149.0 ppm; IR (KBr): [small nu, Greek, tilde] = 3108, 2952, 1597, 1480, 1315, 1200 cm⁻¹. MS (m/z): 371 M⁺.

General procedure for synthesis of 2,3-bis[(1-(aryl)-1H-1,2,3-triazol-4-yl)methoxy]quinoxaline

To a mixture of 4 (0.5 mmol) and an aromatic azide (5) (1 mmol) in DMF (3 mL) were added CuI (5 mol%) and salen (5 mol%). The resulting mixture was stirred at 50 °C until the disappearance of compound 5 (monitored by TLC). Upon completion of the reaction, to the resulting mixture was added a (1 : 1) mixture of H₂O and conc. NH₃, and the precipitate formed was collected, dried, and finally purified by recrystallization from CH₃CN, ethanol or toluene to give 7.

2,3-Bis[(1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy]quin oxaline (7a). Mp, 235 °C; ¹H NMR (400 MHz, [D6] DMSO): δ = 5.73 (s, 2H, 6-H), 7.60–7.63 (m, 1H, 1-H), 7.88–7.92 (m, 2H, 2,2′-H), 8.36 (ddd, J = 8.4 Hz, J = 2 Hz, J = 0.8 Hz, 1H, 1′-H), 8.40 (ddd, J = 8 Hz, J = 1.9 Hz, J = 0.8 Hz, 1H, 3′-H), 8.72 (t, J = 2 Hz, 1H, 4′-H), 9.21 (s, 1H, 5-H) ppm; ¹³C NMR (400 MHz, [D6] DMSO): δ = 59.7, 115.5, 123.7, 124.7, 126.8, 127.6, 132.0, 137.0, 137.5, 143.7, 148.9, 149.0 ppm; IR (KBr): [small nu, Greek, tilde] = 3072, 2960, 1522, 1484, 1347 cm⁻¹. MS (m/z): 566 M⁺.

2,3-Bis[(1-(2-nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy]quinoxaline (7b). Mp, 217 °C; ¹H NMR (400 MHz, [D6] DMSO): δ = 5.74 (s, 2H, 6-H), 7.60–7.62 (m, 1H, 1-H), 7.84–7.98 (m, 4H), 8.24 (dd, J = 8.2 Hz, J = 1 Hz, 1H, 4′-H), 8.90 (s, 1H, 5-H) ppm; ¹³C NMR (400 MHz, [D6] DMSO): δ = 59.6, 126.0, 126.8, 127.4, 127.6, 128.2, 129.4, 131.7, 134.9, 137.0, 143.0, 144.5, 149.0 ppm; IR (KBr): [small nu, Greek, tilde] = 3100, 2955, 1600, 1530, 1456, 1350, 1215 cm⁻¹. MS (m/z): 566 M⁺.

2,3-Bis[(1-(3-chloro-4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy]quinoxaline (7c). Mp, 259–260 °C; ¹H NMR (400 MHz, [D6] DMSO): δ = 5.72 (s, 2H, 6-H), 7.59–7.63 (m, 1H, 1-H), 7.86–7.90 (m, 1H, 2-H), 8.02 (d, J = 8.8 Hz, 1H, 2′-H), 8.27 (dd, J = 8.6 Hz, J = 2.6 Hz, 1H, 1′-H), 8.68 (d, J = 2.4 Hz, 1H, 3′-H), 9.12 (s, 1H, 5-H) ppm; ¹³C NMR (400 MHz, [D6] DMSO): δ = 59.6, 117.7, 124.6, 125.1, 125.4, 126.8, 127.6, 133.5, 136.1, 137.0, 143.8, 148.4, 148.9 ppm; IR (KBr): [small nu, Greek, tilde] = 3100, 2960, 1539, 1465, 1360, 1320 cm⁻¹. MS (m/z): 634 M⁺.

2,3-Bis[(1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy]quinoxaline (7d). Mp, 230 °C; ¹H NMR (400 MHz, [D6] DMSO): δ = 5.70 (s, 2H, 6-H), 7.57–7.65 (m, 3H, 1′, 2′, 2-H), 7.88–7.93 (m, 2H, 1, 3′-H), 8.05 (t, J = 2 Hz, 1H, 4′-H), 9.05 (s, 1H, 5-H) ppm; ¹³C NMR (400 MHz, [D6] DMSO): δ = 59.7, 119.4, 120.6, 124.4, 126.8, 127.6, 129.1, 132.0, 134.6, 137.0, 138.0, 143.4, 149.0 ppm; IR (KBr): [small nu, Greek, tilde] = 3100, 2965, 1595, 1460, 1310, 1220 cm⁻¹. MS (m/z): 566 M⁺.

General procedure for synthesis of 2-amino-3-[(1-(aryl)-1H-1,2,3-triazol-4-yl)methoxy]quinoxaline

A mixture of 6 (1 mmol) and a secondary amine (2.2 mmol) in DMF (5 mL) was stirred at 70 °C. After completion of the reaction (monitored by TLC), the solvent was evaporated, the remaining solid was washed with water and dried, and the crude product was purified by recrystallization from ethanol to give 8.

N,N-Dimethyl-3-[(1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl)meth oxy]quinoxalin-2-amine (8a). Mp, 130–131 °C; ¹H NMR (400 MHz, [D6] DMSO): δ = 3.18 (s, 6H, 7-H), 5.71 (s, 2H, 6-H), 7.37 (td, J = 7.5 Hz, J = 1.4 Hz, 1H, 3-H), 7.45 (td, J = 7.6 Hz, J = 1.4 Hz, 1H, 2-H), 7.61 (dd, J = 8 Hz, J = 1.2 Hz, 1H, 1-H), 7.72 (td, J = 8 Hz, J = 1.2 Hz, 1H, 4-H), 7.91 (t, J = 8.2 Hz, 1H, 2′-H), 8.34 (ddd, J = 8.2 Hz, J = 2.2 Hz J = 0.6 Hz, 1H, 1′-H), 8.43 (ddd, J = 8 Hz, J = 2 Hz J = 0.8 Hz, 1H, 3′-H), 8.75 (d, J = 2.2 Hz, 1H, 4′-H), 9.21 (s, 1H, 5-H) ppm; ¹³C NMR (400 MHz, [D6] DMSO): δ = 31.2, 36.2, 60.7, 117.7, 124.5, 125.1, 125.4, 127.2, 128.1, 128.5, 131.3, 133.6, 136.1, 138.4, 139.0, 139.2, 143.7, 148.5, 152.5 ppm; IR (KBr): [small nu, Greek, tilde] = 3140, 2913, 1523, 1340, 1225, 1020 cm⁻¹. MS (m/z): 391 M⁺.

2-(Morpholin-4-yl)-3-[(1-(2-nitrophenyl)-1H-1,2,3-triazol-4-yl) methoxy]quinoxaline (8b). Mp, 146–147 °C; ¹H NMR (400 MHz, [D6] DMSO): δ = 3.64 (t, J = 4.6 Hz, 4H, 7-H), 3.74 (t, J = 4.6 Hz, 4H, 8-H), 5.73 (s, 2H, 6-H), 7.47–7.54 (m, 2H, 2, 3-H), 7.70 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H, 1-H), 7.78 (dd, J = 7.4 Hz, J = 1.6 Hz, 1H, 4-H), 7.85–7.91 (m, 2H, 1′, 3′-H), 7.99 (td, J = 7.7 Hz, J = 1.2 Hz, 1H, 2′-H), 8.26 (dd, J = 8.2 Hz, J = 1.4 Hz, 1H, 4′-H), 8.88 (s, 1H, 5-H) ppm; ¹³C NMR (400 MHz, [D6] DMSO): δ = 48.3, 59.6, 66.3, 126.0, 126.34, 126.36, 126.47, 126.97, 127.4, 128.3, 129.6, 131.8, 134.9, 136.0, 138.3, 143.4, 144.5, 147.0, 149.8 ppm; IR (KBr): [small nu, Greek, tilde] = 3140, 2900, 1610, 1520, 1460, 1347, 1200 cm⁻¹. MS (m/z): 433 M⁺.

2-[(1-(2-Nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy]-3-(piperidin-1-yl)quinoxaline (8c). Mp, 159–161 °C; ¹H NMR (400 MHz, [D6] DMSO): δ = 1.63 (s, 6H, 8, 9-H), 3.62 (s, 4H, 7-H), 5.71 (s, 2H, 6-H), 7.42 (td, J = 7.6 Hz, J = 1.6 Hz, 1H, 3-H), 7.48 (td, J = 7.6 Hz, J = 1.6 Hz, 1H, 2-H), 7.65 (dd, J = 8 Hz, J = 1.2 Hz, 1H, 1-H), 7.75 (dd, J = 7.8 Hz, J = 1.2 Hz, 1H, 4-H), 7.85–7.91 (m, 2H, 1′, 2′-H), 7.96–8.00 (m, 2H, 3′-H), 8.25 (dd, J = 8 Hz, J = 1.2 Hz, 1H, 4′-H), 8.87 (s, 1H, 5-H) ppm; ¹³C NMR (400 MHz, [D6] DMSO): δ = 24.7, 25.8, 48.8, 59.5, 125.7, 126.0, 126.1, 126.3, 126.8, 127.2, 128.2, 129.5, 131.7, 134.9, 135.8, 138.6, 143.5, 144.5, 147.3, 149.9 ppm; IR (KBr): [small nu, Greek, tilde] = 3140, 2950, 1525, 1485, 1460, 1344, 1310, 1240 cm⁻¹. MS (m/z): 465 M⁺.

Conclusion

An efficient procedure was developed for the synthesis of a 1,2,3-triazole-linked quinoxaline ring system in high-to-excellent yields by the reaction of the quinoxaline acetylenic compound 2-chloro-3-(prop-2-ynyloxy)quinoxaline or 2,3-bis(prop-2-ynyloxy)quinoxaline with aromatic azides via copper-catalyzed click reactions. Short reaction time, simple operation, and easy workup are some advantages of these protocol.

Acknowledgements

We wish to express our thanks to the Research Council of the Shahrood University of Technology for the financial support of this work.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra22603e

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