Synthesis of various substituted thiazole (
Abstract
An environmentally friendly, economic synthetic protocol was advanced for synthesis of biologically and pharmacologically vital five- and six-membered heterocycles containing nitrogen, sulphur and oxygen as heteroatom. A series of thiazole derivatives was prepared by the reaction of substituted phenacyl halides and phenyl thiourea in the presence of TiO2 nanoparticles (NPs) as nanocatalyst in DCM. Similarly, another series of six-membered heterocyclic compounds were synthesized by the reaction of phenacyl halides with phenylenediamine, 2-aminophenol, 2-aminobenzenethiol to produce corresponding products (1,4-quinoxaline, benzoxazine, benzothiazine) under catalytic effect of TiO2nanocatalyst. Analytical and spectral (FTIR, 1H and 13C NMR and SEM) techniques were employed for the structural elucidation of the synthesized compounds.
Keywords
- environmentally friendly
- thiazole derivatives
- nanocatalyst
- 1
- 4-quinoxaline
- benzoxazine
- benzothiazine
This chapter is divided into two sections:
Synthesis of five-membered heterocylces from phenacyl halides
Synthesis of six-membered heterocylces from phenacyl halides
1. Synthesis of five-membered heterocylces from phenacyl halides
1.1 Introduction
Cyclic compounds which contain one or more hetero atoms besides carbon are called heterocyclic compounds. Most commonly nitrogen, sulphur and oxygen are present as hetero atoms. Phosphorous, tin, boron, silicon, etc. are other less common hetero atoms. Numerous heterocyclic compounds have three to six atoms in the ring, but only those compounds which have five- or six-membered ring are by far most significant. Heterocyclic compounds are broadly circulated in nature and are predominantly important because of the extensive variety of physiological activities related with this course of substances. Several of the important compounds contain heterocyclic rings, e.g. most of the members of alkaloids, vitamin B complex, chlorophyll, antibiotics, other plants pigments, dyes, amino acids, enzymes, the genetic material, DNA, drugs, etc. These biologically active molecules always drawn the attention of chemist over the years specifically because of their biological significance.
One striking structural article characteristic to heterocycles, which continue to be exploited to great benefit by the drug industry, lies in their capability to manifest substituents around a core scaffolds in sharp three-dimensional representations [1]. In early studies of chemistry, nitrogen and sulphur containing heterocyclic compounds contained predominantly and they were thoroughly associated with the enlargement of organic chemistry which was concerned with the study of materials separated from living sources and are widely used as structural motif in drug discovery [2].
Heterocycles form by far the leading classical splits of organic chemistry and are of enormous prominence in the biological and industrial field. One of the major causes for the extensive use of heterocyclic compounds is their structures that can be precisely manipulated to attain the required alteration in function. Another important feature embraced by heterocycles is the possibility of incorporating functional groups either as substituents or as the part of ring system itself. They are also the integral part of the wide range of drugs, most of the vitamins, biomolecules, many natural products, and biologically active compounds, including antifungal, antitumor, antimicrobial [3], antibiotic, anti-inflammatory, antidepressant, antimalarial [4] antibacterial, antiviral, herbicidal, anti-HIV, antidiabetic, insecticidal and fungicidal agents. Further, most of the heterocycles possess vital applications in materials science such as dyestuff, fluorescent sensor, plastics, information storage, brightening agents, and analytical reagents. In addition, they have applications in polymer and supramolecular chemistry, especially in conjugated polymers. Moreover, they act as organic light-emitting diodes (OLEDs), organic conductors, light harvesting systems, photovoltaic cells, optical data carriers [5], chemically controllable switches, semiconductors, molecular wires, and liquid crystalline compounds. Thus consideration has been given to advanced effective new methods to synthesize heterocycles.
Now, nanotechnologies are broadly considered to have the potential to bring assistances in area as diverse as water contamination, drug development, information and communication technologies and the production of lighter and strong materials. Nanotechnologies include the conception and manipulation of materials at the nanometre scale, either by refining or reducing bulk materials or by scaling up from single groups of atoms. Nanoparticles (1–100 nm size) have a distinctive place in nanoscience and nanotechnology, not only because of their specific properties subsequent from their reduced dimensions, but also because they are auspicious building blocks for more complex nanostructures. Nanoparticles with the diameter of less than 10 nm have created extreme curiosity over the past decade due to their developed potential application in area such as nanoscale electronics, sensors, optics and catalysis. Due to this importance of nanoparticles so many efforts have been devoted to the synthesis of nanoparticles from last few years.
Furthermore, the
For several conversions employed in organic and pharmaceutical synthesis, especially,
Thiazole ring containing heterocyclic systems are a significant structural entity for several bioactive molecules [14]. Thiazole has been used in the preparation of imperative drugs essential for antibacterial treatment, inflammation and possesses immunosuppressant activity [15]. It also possesses inhibitor’s activity against antiallergies, enzyme cyclo-independent kinase, antitumor and schizophrenia [16]. Some of the thiazole derivatives prepared as fungicide as well as preventing in vivo growth of
Previously many synthetic methods have been used to synthesize
Here we are reporting a new efficient synthetic procedure for the synthesis of
1.2 Experimental details
All the required chemicals were purchased from Sigma Aldrich, Alpha Aesar and used without further purification. The melting points were checked in open capillary tubes in melting point apparatus and are uncorrected. The completion of the reaction was checked on TLC plates coated with silica gel-G in the n-hexane-EtOAc (v/v = 7:3) and visualised by exposure in UV chamber. The IR spectra were recorded on Shimadzu IR-435 spectrophotometer (νmax in cm−1). 1H NMR, and 13C NMR spectra were recorded using a JEOL RESONANCE Spectrometer at 400.0 and 100.0 MHz respectively (δ in ppm) using TMS (d = 0.0) as an internal standard for 1H NMR, and CDCl3 was used as internal standard (d = 77.0) for 13C NMR. Chemical shifts are reported in parts per million (ppm) as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad). The elemental analysis (C, H and N) were performed using vario-III analyser. The nanoparticles are characterized by FTIR and SEM.
1.2.1 General procedure for the synthesis of TiO2 NPs
TiO2 NPs were prepared by sol-gel method [33], using titanium(IV) isopropoxide. For the synthesis of TiO2 NPs, [Ti{OPri}4] (1.75 g) was taken in round bottom flask with dry isopropanol (~35 ml). 2–3 drops of water-isopropanol mixture (1,1) was added to the above mentioned clear solution and magnetically stirred for 2 h then sol formation occurred immediately. To ensure complete hydrolysis, excess of water ~10 ml {stoichiometric amount (0.22 g)}, in small lots with continuous stirring for ~4 h was added. The mixture was again stirred for 1 h, till a gel is formed. The synthesized gel was dried in an oven (100°C) and then washed properly with acetone then an off-white powder was obtained. This powder was sintered at 600°C for 4 h to yield a white powder, which was characterized by FTIR and SEM as pure TiO2.
1.2.2 Characterization of TiO2 NPs
The TiO2 nanocatalyst was prepared using sol-gel method and characterized by various techniques using FT-IR and Scanning Electron Microscopy (SEM). The FT-IR spectrum of TiO2 NPs is given in Figure 1. The absorbance bands at around 3235–3550 cm−1 were proved to the adsorbed water and hydroxyl group in nano sized TiO2 (Figure 1). The band observed at 720 cm−1 is due to Ti-O-Ti while absorbance bands at 460 cm−1 show stretching vibration due to Ti-O, which is customary with the reported IR spectra for nano TiO2 [33]. The SEM images of this oxide are revealed in Figure 2. The scales that are shown in Figure 2 are of 500 nm come into sight to specify formation of agglomerates granular morphology, constituted by nano-sized crystallites.
1.2.3 General procedure for the synthesis of substituted thiazoles (3a–e )
In a 20 ml round bottom flask phenacyl bromide (
1.3 Spectral data of substituted thiazole (3a–e)
1.3.1 [4-(4-Bromo-phenyl)-thiazole-2-yl]-(4-chloro-phenyl)-amine (3a )
IR (cm−1, KBr): 3315, 1611, 1462, 1370, 762, 644; 1H NMR (CDCl3, 400 MHz): δ 4.03 (s, NH), 7.17 (d, 2H, Ar–H), 7.34 (d, 2H, Ar–H), 7.42 (d, 2H, Ar–H), 7.55 (d, 2H, Ar–H); 13C NMR (CDCl3, 100.4 MHz): δ 106.2, 118.5, 119.5, 128.4, 130.5, 131.0, 131.3, 138.6, 149.4, 175.3; HRMS;
1.3.2 [4-(4-Chloro-phenyl)-thiazole-2-yl]-phenyl-amine (3b )
IR (cm−1, KBr): 3349, 1646, 1434, 1389, 779, 667; 1H NMR (CDCl3, 400 MHz): δ 4.12 (s, NH), 7.18 (d, 2H, Ar–H), 7.42 (d, 2H, Ar–H), 7.45 (d, 2H, Ar–H), 7.57 (d, 2H, Ar–H); 13C NMR (CDCl3, 100.4 MHz): δ 107.3, 119.3, 120.7, 130.3, 131.5, 131.9, 132.3, 140.6, 150.3, 176.9; HRMS;
1.3.3 [4-(4-Methoxy-phenyl)-thiazole-2-yl]-phenyl-amine (3c )
IR (cm−1, KBr): 3317, 1633, 1467, 1379, 767, 648; 1H NMR (CDCl3, 400 MHz): δ 4.07 (s, NH), 7.18 (d, 2H, Ar–H), 7.39 (d, 2H, Ar–H), 7.48 (d, 2H, Ar–H), 7.56(d, 2H, Ar–H); 13C NMR (CDCl3, 100.4 MHz): δ 109.5, 112.5, 120.6, 130.7, 131.8, 131.9, 132.4, 140.6, 150.7, 177.5; HRMS;
1.3.4 [4-(4-Fluoro-phenyl)-thiazole-2-yl]-phenyl-amine (3d )
IR (cm−1, KBr): 3340, 1623, 1470, 1389, 766, 665; 1H NMR (CDCl3, 400 MHz): δ 4.09 (s, NH), 7.21 (d, 2H, Ar–H), 7.37 (d, 2H, Ar–H), 7.45 (d, 2H, Ar–H), 7.58(d, 2H, Ar–H); 13C NMR (CDCl3, 100.4 MHz): δ 109.8, 121.7, 123.8, 130.6, 131.6, 131.9, 132.1, 139.7, 151.5, 179.8; HRMS;
1.3.5 [4-(2-Chloro-phenyl)-thiazole-2-yl]-phenyl-amine (3e )
IR (cm−1, KBr): 3325, 1632, 1472, 1379, 768, 647; 1H NMR (CDCl3, 400 MHz): δ 4.06 (s, NH), 7.21 (d, 2H, Ar–H), 7.39 (d, 2H, Ar–H), 7.46 (d, 2H, Ar–H), 7.59(d, 2H, Ar–H); 13C NMR (CDCl3, 100.4 MHz): δ 110.5, 119.5, 121.6, 131.6, 131.9, 132.2, 132.5, 141.9, 152.7, 179.3; HRMS;
2. Synthesis of six-membered heterocylces from phenacyl halides: (1,4-quinoxaline, 1,4-benzoxazines, 1,4-benzothiazines)
2.1 Introduction
Quinoxalines are important class of nitrogen containing heterocycles, possessing nitrogen atom at 1,4 position. These heterocycles possess various pharmacological [34, 35, 36, 37, 38] and biological properties such as antibiotic (echinomycin, bleomycin), anticancer [39] anti-viral [40], anti-bacterial, antibiotic, and anti-inflammatory. The compounds of quinoxalines used to develop organic semiconductors [41, 42], dehydroannulenes [43], and also used in dyes [44]. Various methods have been reported in literature for the synthesis of quinoxalines, i.e. condensation of 1,2-diketone with phenylene diamine to yield the desired quinoxaline under reflux condition at ambient temperature with various solvents such as benzene, ethanol [45] with use of different catalyst like molecular iodine, copper(II) sulphate, indium(III) chloride, o-iodoxybenzoic acid, ceric ammonium nitrate, silica gel, gallium(III) triflate phosphorus oxychloride, oxidative coupling of epoxides with ene-1,2-diamines [46], 1,4-addition of 1,2-diamines to diazenylbutenes [47], cyclization-oxidation of phenacyl bromides with 1,2-diamines by HClO4-SiO2 [48] and by using solid phase synthesis [49, 50]. Quinoxaline has also been synthesized by the chemical reaction of phenylene diamine and different substituted phenacyl bromides via solid phase [49, 50], synthesis by using different catalyst like 1,4-diazabicyclo [2,2,2]octane, trimethylsilyl chloride, perchloric acid supported on silica, KF-alumina,
1,4-Benzoxazines are important moiety of heterocyclic compounds having considerable biological [51], pharmaceutical [52] and wide range of synthetic utilities. Therefore, new methods should be developed for an efficient protocol for their synthesis. In addition of above information these compounds also served as precursors for the synthesis of many medicinally important drugs [53]. The skeleton of these type of structures are synthesized by the direct intramolecular reductive cyclization of appropriate nitroketones or by intramolecular annulation of 2-aminophenoxy ketones [54]. Benzoxazines are also prepared by the condensation reaction of 2-aminophenols with substituted phenacyl halides [55]. Although, these reported procedures are not specific and general because involvement of more than one-steps, requirement of high temperature, give low to moderate yields and use of commercially unavailable starting material. Hence the discovery of new protocols which leads to an efficient synthetic procedure for synthesis of 1,4-benzoxazine and their derivatives.
There are many reported methods in literature for the efficient synthesis for multicomponent reactions (
Although, these reported methods suffered from various limitations such as toxic nature of reagents, excess loading of catalyst, need of high temperature, expensive reagents and complicated work-up to complete the reaction. In present era development of green and sustainable protocols attract the attention of scientists because the use of these above reagents causes many allergic diseases. In this connection of research, various researchers have considerable attention on use of non-hazardous reagents like nanoparticles as heterogeneous catalysts for organic transformations. So, keeping in view these facts of green technology we have tried our effort to develop, a new synthetic strategy for the synthesis of 1,4-quinoxaline, 1,4-benzoxazines, 1,4-benzothiazines catalysed by
This method is considered to be environment friendly because of use of solid heterogeneous catalyst that provides many advantages such as, ease of handling, non-corrosiveness, high yield, low cost and reusability of the used nanocatalyst.
2.2 General procedure for the synthesis of six-membered heterocycles
2.2.1 General procedure for the synthesis of 1,4-quinoxaline (3a and b )
In a 50 ml round bottom flask we took 1,2-phenylenediamine (
2.2.2 Spectral data of synthesized compounds
2.2.2.1 2-Phenylquinoxaline (3a )
Dark yellow solid; M.P: 75–78.3°C; 1H NMR (400 MHz, CDCl3, TMS = 0 PPM): δ = 7.50–7.58 (m, 3H, ArH), 7.70–7.82 (m, 2H, ArH), 8.14–8.28 (m, 4H, ArH), 9.43 (s, 1H, C3-H) ppm; 13C NMR (100.4 MHz, CDCl3, TMS = 0 PPM): δ = 127.1, 129.19, 129.26, 129.5, 129.6, 130.5, 130.8, 136.4, 141.9, 142.8, 143.6, 152.8 ppm; LCMS (ESI-MS): m/z calcd. for C14H10N2 (M+): 206.24; found: 207.1 (M + H).
2.2.2.2 2-(3-bromophenyl)quinoxaline (3b )
Light brown solid; M.P: 132–133.8°C;1H NMR (400 MHz, CDCl3, TMS = 0 PPM):
2.2.3 General procedure for the synthesis of 1,4-benzoxazines (3c and d )
A catalytic amount of nanoparticles (TiO2) added to the stirring mixture of o-aminophenol (
2.2.3.1 2-Phenyloxazine (3c )
Brown solid; M.P:88–89.5°C; 1H NMR (400 MHz, CDCl3, TMS = 0 PPM): δ = 7.50–7.62 (m, 3H, ArH), 7.76–7.80 (m, 2H, ArH), 8.15–8.29 (m, 4H, ArH), 4.88 (s, 2H, C3-H) ppm; 13C NMR (100.4 MHz, CDCl3, TMS = 77.0 PPM): δ = 127.5, 129.0, 129.2, 129.5, 129.6, 130.1, 130.8, 136.8, 141.5, 142.8, 143.3, 151.8 ppm; LCMS (ESI-MS): m/z calcd for C14H10N2 (M+): 206.24; found: 207.1 (M + H).
2.2.3.2 2-(3-bromophenyl) oxazine (3d )
Light yellow solid, M.P: 142–143.8°C;1H NMR (400 MHz, CDCl3, TMS = 0 PPM):
2.2.4 General procedure for the synthesis of 1,4-benzothiazines (4e and f)
In a round bottom flask the 2-aminobenzenethiol (
2.2.4.1 Phenyl (3-phenyl-3,4-dihydro-4H -benzo[b][1,4]thiazin-2-yl) methanone (4e )
Light yellow solid; M.P.: 124–126°C; 1H NMR (400 MHz, CDCl3):
2.2.4.2 (3-Phenyl-3,4-dihydro-2H -benzo[b][1,4]thiazin-2-yl)(p-tolyl) methanone (4f )
Brown solid; M.P.: 118–120°C; 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 7.5 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.40 (t, J = 7.2 Hz, 2H), 7.26 (t, J = 8.0 Hz, 3H), 7.10–7.04 (m, 4H), 6.68–6.60 (m, 2H), 5.02 (d, J = 5.7, 1H), 4.58 (d, J = 6.3 Hz, 1H), 4.34 (s, 1H), 2.26 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 47.1, 57.6, 113.6, 115.0, 118.2, 127.4, 127.8, 128.2, 128.4, 128.5, 128.6, 128.7, 133.8, 135.2, 142.2, 142.6, 194.2, 21.5 ppm; HRMS (ESI) calcd. for [C22H19NOS + H] + 346.1266, found 346.1260.
3. Results and discussion
In this chapter we have tried to develop an efficient protocol for the synthesis of five-membered disubstituted derivatives (
4. Conclusion
In conclusion, we have developed a green and economic procedure for the synthesis of bioactive five- and six-membered heterocycles. This synthetic methodology allowed us to synthesize products in good to excellent yields, which is irrespective to the functional groups which are present in the starting material. The used protocol is mild and environmental friendly. There are many merits of the used protocol like, low cost of green catalyst, obtaining high yield of products, operational simplicity, and the catalyst can be reused without any significant loss in catalytic property up to four catalytic cycle. These outstanding features of this method make it environmentally friendliness.
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