Synthesis of thiophenyl thiazole based novel quinoxaline derivatives

A new series of thiophenyl thiazole based novel quinoxaline derivatives 4a - 4t have been synthesized by base catalysed condensation reaction. In which 6-substituted 2,3-dichloroquinoxaline 1a and 4-(thiophen-2-yl)thiazol-2-amine 2b reacted in basic condition to afford intermediate 3c which reacts with various aromatic amine to form final compounds. Easy experimental procedure, high yield, and selectivity are the imperative features of this method. The identity of all the compounds has been established by 1 H NMR, 13 C NMR, FT-IR, and elemental analysis.


INTRODUCTION
A wide variety of pharmacological properties has been associated with quinoxaline derivatives. Quinoxaline also called benzopyrazine is a heterocyclic compound containing a ring complex made up of benzene ring and a pyrazine ring has been considered as a wonderful nucleus. Quinoxalines have extraordinary potential in pharmacological research [1] and practice. These are important components of several pharmacologically active compounds [2][3][4][5][6][7][8] and exhibit special and wider ranges of functions in biologically active compounds [9], electroluminescent materials [10], dyes [11] and anion sensors [12]. Although rarely describe in nature, synthetic quinoxaline derivatives showed variety of pharmaceutical activities encompassed major types of drug target families and effective in many clinical applications such as anti tumor agents [13], kinase inhibitors [14], HIV drugs [15], antibiotics [16], ion channel regulators [17] and anti protozoal agents [18].
Here we report synthesis of novel thiophene thiazole based quinoxaline derivatives by chloro-amine condensation. The constitutions of all the products were confirmed using 1 H NMR, 13 C NMR, FTIR, and elemental analysis.

EXPERIMENTAL
Required all reagents were obtained commercially. Solvents were purified and dried before being used. All melting points were taken in open capillaries and are uncorrected. Thin-layer chromatography (TLC, on aluminium plates precoated with silica gel, 60F 254 , 0.25 mm thickness) (Merck, Darmstadt, Germany) was used for monitoring the progress of all reactions, purity and homogeneity of the synthesized compounds; eluent-hexane:ethyl acetate: (4:6). UV radiation and/or iodine were used as the visualizing agents. Elemental analysis (% C, H, N) was carried out by Perkin-Elmer 2400 series-II elemental analyzer (Perkin-Elmer, USA) and all compounds are within ±0.4% of theory specified. The IR spectra were recorded in KBr on a Perkin-Elmer Spectrum GX FT-IR Spectrophotometer (Perkin-Elmer, USA) and only the characteristic peaks are reported in cm -1 . 1 H NMR and 13 C NMR spectra were recorded in DMSO-d 6 on a Bruker Avance 400F (MHz) spectrometer (Bruker Scientific Corporation Ltd., Switzerland) using solvent peak as internal standard at 400 MHz and 100 MHz respectively. Chemical shifts are reported in parts per million (ppm). Mass spectra were scanned on a Shimadzu LCMS 2010 spectrometer (Shimadzu, Tokyo, Japan).

2.1
Synthesis of the substituted 2,3-dichloroquinoxaline (1a) Substituted benzene-1,2-diamine (5 mmol), diethyl oxalate (5 mmol), piperidine (1 ml), and ethanol (10 ml) were charged in a 100 ml round bottom flask with mechanical stirrer and condenser. The reaction mixture refluxed for 4 h. After the completion of reaction (checked by TLC), the separated substituted quinoxaline-2,3(1H,4H)-dione was filtered and washed with ethanol and dried. Now thionyl chloride (25 mmol) was added to a solution of substituted quinoxaline-2,3(1H,4H)-dione (10gm) in dry DCM (50 mL). Upon the addition of 1-2 drop of DMF a mixture was heated at reflux for 1 h. After the completion of reaction a mixture was washed with water followed by saturated NaHCO 3 solution. The organic phase was dried over anhydrous Na 2 SO 4 and solvent was removed under reduced pressure to afford analytically pure substituted 2,3dichloroquinoxaline.

2.3
General procedure for the synthesis of compounds 4(a-t) Substituted 3-chloro-N-(4-(thiophen-2-yl)thiazol-2-yl)quinoxalin-2-amine 3c (5 mmol) and various aromatic amines (5 mmol) were thoroughly mixed in DMF (10 ml) and then dry K 2 CO 3 (5 mmol) was added to it. The mixture was heated at 100 0 C for 4-5 h. After the completion of reaction (checked by TLC), the solution was cooled to room temperature. The reaction mixture was poured in to chilled water. The separated precipitates were filtered, thoroughly washed well with water, dried, and recrystallized from chloroform to obtain the pure compounds 4a-4t. The physicochemical and spectroscopic characterization data of the synthesized compounds 4a-4t given below.
The structures of all the new synthesized compounds were established by 1 H NMR, 13 C NMR, FTIR, elemental analysis, and molecular weight of some selected compounds were confirmed by mass spectrometry. In 1 H NMR, (DMSO-d6) spectrum of compound 4b two singlet peak at d 10.41 ppm and d 10.62 ppm appeared for two -NH-protons. Aromatic protons of 4b resonate as multiplets at d 6.90-8.00 ppm. A singlet at d 2.80 ppm stands for aromatic methyl protons. 13 C NMR of 4b exhibited a distinctive signal at d 27.12 ppm for aromatic methyl. All the aromatic carbons of 4b showed signals at d 107.25-138.39 ppm in the 13 C NMR spectra. The IR spectrum of compound 4b exhibited characteristic absorption band at 3,318 and 3,226 cm -1 for two -NH-and 3,026 cm -1 for aromatic C-H stretching. Further, the structures of selected compounds 4b, 4c, and 4k were confirmed by its mass spectral studies. The mass spectra detected the expected molecular ion signals corresponding to respective molecular formula of synthesized compounds. Mass spectra of compound 4b gave molecular ion peak at 415.0 (M + 1) corresponding to molecular formula C 22 H 17 N 5 S 2 . All spectroscopic data have been given in spectral data.

CONCLUSION
In this article, we report the synthesis of three structurally correlated heterocyclic candidates, i.e., quinoxaline, thiophene and thiazole derivatives. The engaged synthetic strategy allows the construction of relatively complicated nitrogen and oxygen carrying heterocyclic system as well as the introduction of various aromatic substitutions into 3-position of quinoxaline system.