INTRODUCTION:

Quinoxalines are nitrogen containing heterocyclic system. Various pharmaceutical activities¹ such as anti-inflammatory activities, antiviral, anticancer, antibiotic, Kinase inhibitory.^2-9 Quinoxalines derivatives also used as dyes,¹⁰organic semiconductors,¹¹ The most common method for the synthesis of quinoxalines is condensation of an aryl 1,2-diamine with a 1,2-dicarbonyl compounds in presence of ethanol/acetic acid at reflux condition.¹²A number of synthetic strategies have been developed for the preparation of quinoxalines.^13-15 Various reports are available for the synthesis of quinoxalines which involves various catalyst such as Pd(OAc)₂ or RuCl₂-(PPh₃)₃-TEMPO,¹⁶ I₂/DMSO,¹⁷ MnO₂,¹⁸ MnO₂ with microwave,¹⁹ PEG-600-H₂O,²⁰ CuSO₄.5H₂O²¹, [bmim]BF₄,²²TiO₂²³, ACOH/reflux²⁴. 2, 3-Disubstituted quinoxalines have also been prepared by Suzuki–Miyaura coupling reaction²⁴. But these methodologies have various disadvantages such as expensive catalyst, toxic solvents, reaction time, tedious work-up procedure and critical reaction conditions.

In recent years, the use of silica supported catalyst such as silica sulfuric acid²⁶, H₃BO₃-SiO₂²⁷, anhydrous SOCl₂-SiO₂²⁸, SiO₂-Cl²⁹, NaHSO₄-SiO₂³⁰, silica bonded S-sulfonic acid³¹ etc. has received considerable importance in organic syntheses because of easier handling, recovery of catalyst, low cost and simple work-up procedure.

By considering above features of solid supported catalyst and movement of research directed towards the development of environmentally benign procedure with heterogeneous and reusable catalyst for the construction of biologically active heterocyclic moieties, here we developed rapid, efficient and an inexpensive procedure for the synthesis of quinoxaline using silica supported ferric chloride as heterogeneous catalyst. This method allows us to obtain excellent yields of required product in shorter reaction times as compared to those of classical methods.

MATERIAL AND METHODS:

General:

All melting points were measured in open capillary tubes and are uncorrected. The progress of the reaction was monitored by thin layer chromatography (TLC) on Merck silica gel 60 F₂₅₄ aluminum sheets and visualized by UV light. IR spectra were recorded on Shimadzu FTIR (KBr)-408 spectrophotometer. The ¹H-NMR spectra were recorded at 400 MHz in CDCl₃/DMSO-d₆ using TMS as internal standard and are given in δ units. The LC-MS spectra were recorded on WATER, Q-TOF Micossmass.

Preparation of silica supported FeCl₃ (SiO₂-FeCl₃):

Silica supported Ferric chloride can easily be prepared from the readily available inexpensive ingredients FeCl₃.6H₂O and silica gel according to the reported procedure. ^32-34

General Procedure for synthesis of quinoxalines at room temperature:

A mixture of o-phenylenediamine (1 mmol), 1, 2-diketones (1 mmol) was taken in 50 ml round bottom flask containing 10 ml ethanol. SiO₂-FeCl₃ (15 wt %) catalysts with respect to 1, 2-dicarbonyl compound was then added to the reaction flask and the content were stirred at room temperature (rt) for appropriate time as mentioned in the Table-4. The completion of reaction was monitored by TLC (solvent system n-hexane-EtOAc, 9:1). After completion of reaction, the reaction mixture was filtered and the heterogeneous catalyst was recovered. The filtrate was treated with cold water, precipitated product was filtered, washed with water and the crude product was subjected to column chromatography using EtOAc/Hexane mobile phase to furnish pure compound. All the products were isolated as solids in very good yields. The synthesized products were characterized by IR, ¹H NMR, mass spectra, melting point and comparison with the data reported in the literature.

Spectroscopic data of some compound:

2, 3-Diphenylquinoxaline (3a):

Solid, Yield: 96%; M.p.:127-129°C; IR (KBr)ν: 3056, 1693, 1564, 1337,769 cm^-1

¹HNMR (CDC1₃, 300 MHz) δ (ppm): 8.2(dd, J=3.43,6.30Hz, 2H), 7.79 (dd, J=3.43,6.30Hz, 2H), 7.55 (m, 4H), 7.39 (m, 6H); MS: m/z, 283.2 (m+1)

Acenaphtho[1,2-b]quinoxaline (3c):

Yield- 96%; M.p.: 236-238°C; IR (KBr)ν: 3053, 1614, 1572, 1433, 1300, 1209, 1095, 759 cm^-1; ¹HNMR (CDC1₃, 300 MHz) δ(ppm): 8.44(s, 2H), 8.33(s, 2H), 8.23(s, 2H),7.79 (s, 2H), 7.87 (s, 2H), MS: m/z, 255.22(m+1)

6-Methyl -2, 3-diphenylquinoxaline (3d):

Yield: 97 %; M.p.:116-118°C; IR (KBr)ν: 3055, 1608, 1514, 1342, 1184, 1057, 819, 721 cm^-1; ¹HNMR (CDCl₃, 400MHz) δ(ppm): 1.62( s, 3H), 7.3(d, 6H), 7.5 (d, 4H), 7.6(d, 1H), 7.9(s, 1H), 8.1(d, 1H); MS: m/z, 297.2 (m+1)

6-Chloro -2, 3-diphenylquinoxaline (3g):

Yield: 94 %; M.p.:114-116°C; IR (KBr)ν: 3057, 1606, 1550, 1342, 1192, 1070, 922, 767 cm^-1; ¹HNMR (DMSO-d6, 400MHz) δ(ppm): 7.3(m, 6H), 7.5 (m, 4H), 7.8(dd, 1H), 8.1(d, 1H), 8.1(d, 1H); MS: m/z, 317.2(m+1)

9-chloroacenaphtho[1,2-b]quinoxaline (3i):

Yield: 92 %; M.p.:234-236°C; IR (KBr)ν: 3053, 1616, 1568, 1431, 1300, 1209, 1033, 781 cm^-1; ¹HNMR (CDCl₃, 400MHz) δ(ppm): 7.69(dq, J= 2.36 & 2.4 Hz, 1H), 7.83 (m, 4H), 8.1(m, 3H), 8.17(d,J= 2.28Hz, 1H), 8.38(d, J=4.12Hz, 1H), 8.40(d, J=4.12Hz, 1H).

Phenyl (2,3-dip-tolylquinoxalin-6-yl)methanone (3k):

Yield: 92 %; M.p.:220-222°C; IR (KBr)ν: 3107, 1662, 1342, 1207, 1055, 723 cm^-1

¹HNMR (CDCl₃, 400MHz) δ(ppm): 2.36(s, 3H), 2.38(s, 3H), 7.17(t, J= 7.6 & 7.4 Hz, 4H), 7.42-7.53 (m, 6H), 763(t, J= 7.4 & 7.4Hz, 1H), 7.90(d, J= 7.24 Hz, 2H), 8.2(t, 2H), 8.50(s, 1H)

MS: m/z, 415.40(m+1)

(Acenaphtho[1,2-b]quinoxalin-10-yl)(phenyl)methanone (3l):

Yield: 92 %; M.p.:244-246°C; IR (KBr)ν: 3173, 1649, 1440, 1301, 1101, 713 cm^-1

¹HNMR (CDCl₃, 400MHz) δ(ppm): 7.55(t, 2H), 7.65 (t, 1H), 7.86(q, 2H), 7.94(d, J= 7.2 Hz, 2H), 8.15(t, 2H), 8.23(dq, 1H), 8.29(d, 1H), 8.40(d, 1H), 8.44(d, 1H), 8.57(d, 1H); MS: m/z, 359.32(m+1)

2, 3-diphenylquinoxaline-6-carboxylic acid (3m):

Yield: 90 %; M.p.:284-286°C; IR (KBr)ν: 3080, 2928, 1689, 1618, 1444, 1346, 1207, 1057, 694 cm^-1; ¹HNMR (DMSO-d6, 400MHz) δ(ppm): 7.35(m, 6H), 7.42 (d, 4H), 8.1(d, 1H), 8.23(dd, 1H), 8.5(d, 1H), 13.45(br. S, 1H); MS: m/z, 327.28(m+1)

2, 3-dip-tolylquinoxaline-6-carboxylic acid (3n):

Yield: 92 %; M. p.: >300°C;IR (KBr)ν: 299, 1691, 1612, 1429, 1340,1201, 1055, 769 cm^-1; ¹HNMR (DMSO-d6, 400MHz) δ(ppm): 2.23(s, 6H), 7.1(s, 4H), 7.4(s, 4H), 8.1(d, 1H), 8.2(d, 1H), 8.6(s, 1H), 11.23(br. S, 1H); MS: m/z, 355.32(m+1)

RESULT AND DISCUSSION:

To establish the suitable experimental conditions we first tried the reaction of benzil and o-phenylenediamine as a model reaction (scheme 1). The reaction was carried out using SiO₂-FeCl₃ (Table 4, entry 1). It was observed that SiO₂-FeCl₃was found to be the effective catalyst for the two component reaction of benzil and o-phenylenediamine affording a very good yield of the desired products. Thus this catalyst was chosen for optimizing the reaction condition.

To investigate the effect of amount catalyst, the reaction was carried out using different weight % of the catalysts, which provided the desired product. An increase in the amount of catalyst to 15 wt % resulted in an increase in the yield of the desired product (Table 1).

Further increases in weight % not affect the yield. It is noteworthy that, in the absence of catalyst no significant product formation was observed under similar reaction condition. The reaction was carried out at room temperatures. It was observed that at room temperature (25^oC), the reaction take place smoothly with significant yield of the desired product was obtained.

Table 1: Reaction of o-phenylene diamine, and benzil in diverse catalytic conditions.

Entry	Catalyst	Wt %	Time Min.	Yield^a %
1	--	--	60	--
2	FeCl₃		60	20
3	SiO₂-FeCl₃	5	60	70
4	SiO₂-FeCl₃	10	60	85
5	SiO₂-FeCl₃	15	20	96
6	SiO₂-FeCl₃	20	20	96

^a Isolated yield

The effect of various solvents such as polar protic, aprotic and non polar solvents was investigated on the two component reaction of benzil and o-phenylenediamine(scheme 1). Reaction was also experimented under solvent free conditions but the reaction did not take place even after prolonged reaction time (Table 2).

Table 2: Preparation of quinoxaline in the presence of SiO₂-FeCl₃ in different solvents.

Entry	Solvent^a	Time Min.	Yield^b %
1	--	100	--
2	n-hexane	60	--
3	1,4-dioxane	60	30
4	H₂O	60	40
5	Acetonitrile	60	70
6	THF	60	85
7	DMF	20	85
8	Methanol	20	92
9	Ethanol	20	96

^aUsing SiO₂-FeCl₃,^bIsolated yield

In non polar solvents such as n-hexane, 1,4-dioxane the reaction did not take place, whereas in case of polar solvents such as acetonitrile, THF and DMF, methanol and ethanol the yield of the reaction was found to be significant (70-95 %, Table 2, Entry 5-9 ).

In case of polar protic solvents such as methanol and ethanol (Table 2, Entry 8-9), the yield of the desire product was excellent (96%). This observation revealed that, the present reaction required highly polar protic organic solvent system, thus we chose ethanol as a solvent for this two component reaction.

The recovered catalyst from the experiment was washed by acetone (3 × 5mL). Then, it was dried in an oven at 100^◦C and used in the synthesis of quinoxaline. Then the catalyst was recycled for four times (Table 3).

Table 3: The catalyst reusability for the synthesis of quinoxaline ^a.

Entry	Cycle	Yield %
1	Fresh	96
2	1	90
3	2	85
4	3	80

^a Reaction condition: o-phenylene diamine(1mmol), Benzil (1mmol), SiO₂-FeCl₃(15wt%), 10ml ethanol, room temperature.

Encouraged by these results, we extended this reaction to a range of 1, 2-diketones and differently substituted o-phenylenediamine (Table 4, Entry 2-14) under optimized reaction conditions to give the corresponding quinoxaline derivatives 4a-o in excellent yields. The results are summarized in a Table 4. It was observed that there was not significant effect of electron donating or withdrawing groups of o-phenylenediamine such as -CH₃, -Cl, -COOH, -COPh and also the simple or cyclic 1, 2-diketones on time of the reaction.

Here, in this SiO₂-FeCl₃ catalyzed one pot two component reaction of 1, 2- diketones and o-phenylenediaminefor the synthesis of quinoxaline using ethanol as a solvent is reported. The present protocol is found to be efficient providing higher yield of the desired product. This procedure offers several advantages including mild reaction conditions, simple work-up procedure, reusability of catalyst, excellent yield, cost effective of products as well as a simple experimental procedure, which makes it an attractive process for the synthesis of quinoxaline and their derivatives.

Table 4: Synthesis of quinoxaline 3a–n by using SiO₂ supported FeCl₃ in ethanol at room temperature.

Entry	R	R₁R₂	M P ^oC		Time (Min)	Yield^b(%)
Entry	R	R₁R₂	Found	Reported	Time (Min)	Yield^b(%)
3a	-H	C₆H₅	127-129	126-127^7f	10	96
3b	-H	p-CH₃ C₆H₄	148-150	149-150⁷ⁱ	15	96
3c	-H	Acenapthaquinone ^c	236-238	238-240^8f	15	96
3d	-CH₃	C₆H₅	116-118	116-117^7f	15	97
3e	-CH₃	p-CH₃ C₆H₄	138-140	137-138^7g	15	95
3f	-CH₃	Acenapthaquinone ^c	232-234	230-232 ^7h	20	95
3g	-Cl	C₆H₅	114-116	115-116^8f	15	94
3h	-Cl	p-CH₃ C₆H₄	160-162	--	15	95
3i	-Cl	Acenapthaquinone ^c	234-236	--	17	92
3j	Ph-CO-	C₆H₅	140-142	137-139^7h	20	90
3k	Ph-CO-	p-CH₃ C₆H₄	220-222	--	20	92
3l	Ph-CO-	Acenapthaquinone ^c	244-246	242-244^7h	20	90
3m	-COOH	C₆H₅	284-286	--	20	90
3n	-COOH	p-CH₃ C₆H₄	>300	--	20	92

Reaction was monitored by TLC.

b Isolated yields.

c Name of diketone used for the synthesis.

CONCLUSIONS:

SiO₂-FeCl₃catalyst is demonstrated as an efficient catalyst for the synthesis of quinoxalines under mild reaction condition with in short reaction time. Quinoxalines were synthesized from various 1, 2-diketones, 1, 2-diamines in and catalytic amount of SiO₂-FeCl₃in ethanol at room temperature. This procedure offers such advantages as shorter reaction times, simple work-up, reusable catalyst, eco friendly approach, excellent yield, cost effective.

ACKNOWLEDGEMENT:

Author is thankful to BCUD, Savitribai Phule Pune University, Pune (Grant No. OSD/BCUD/360/151) for financial assistant and Director, SAIF, Panjab University, Chandigarh for providing spectral analysis facility.

CONFLICT OF INTEREST:

The article entitled “SiO₂-FeCl₃ mediated a simple and efficient procedure for the synthesis of quinoxalines at room temperature” is herewith submitted for publication in Asian Journal of Research in Chemistry. It has not been published before, and it is not under consideration for publication in any other journal (s). I certify that I have obtained written permission for the use of text, tables, and/or illustrations from any copyrighted source(s), and I declare no conflict of interest.

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Received on 11.09.2017 Modified on 22.10.2017

Asian J. Research Chem. 2017; 10(6):827-831.

DOI: 10.5958/0974-4150.2017.00138.9