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Summer Research Fellowship Programme of India's Science Academies

Metal-free regioselective preparation of sulfonylated di- and tri-substituted 1,2,3 triazoles

Ishita Roy

Indian Association for the Cultivation of Science (IACS), Raja S C Mullick Road, Jadavpur, West Bengal, Kolkata 700032

Prof. Tanmaya Pathak

Affiliation- Indian Institute of Technology (IIT) Kharagpur, West Bengal, Kharagpur 721302

Abstract

The substituted 1, 2, 3-triazole moiety has attracted increasing attention in the current research in synthetic chemistry because of its potential utility in bio-conjugation, agriculture, synthetic organic chemistry, medicinal chemistry and supra-molecular chemistry. In general 1, 4- and 1, 5-di-substituted 1, 2, 3-triazoles are obtained as mixtures when terminal alkynes and organic azides react in 1, 3 dipolar cycloaddition fashion under thermal conditions (Huisgen reaction). Recently introduced Copper-catalyzed-alkyne-azide-cycloaddition (CuAAC) afforded only the 1, 4-regioisomer. On the other hand, the ruthenium-catalyzed-alkyne-azide-cycloaddition (RuAAC) afforded the 1, 5-triazoles. Unlike CuAAC conditions RuAAC has limited applications and the catalyst is highly expensive. Vinyl sulfones, known as acetylenic equivalents were introduced for the regioselective synthesis of 1, 2, 3-triazoles which avoided the use of toxic and expensive metal catalysts. In order to synthesize sulfonylated triazoles, propargyl sulfones, known to exist in a mixture with the corresponding allene sulfones, were introduced for the first time. Allene-sulfones are known to exhibit an unique reactivity due to the presence of two cumulative C=C double bonds and three reactive carbon centres. The mixture of propargyl sulfone and allene sulfone, on reactions with organic azides was expected to afford mainly, the 1, 4-disubstituted 1, 2, 3- triazoles. However, we observed that the nature of organic azides influences the outcome of this class of cycloaddition reactions at the elevated temperatures. Thus in addition to the formation of 1, 4-disubstituted 1, 2, 3-triazoles, we have identified the presence of 1, 5-di-substituted 1, 2, 3-triazoles as well as 1, 4, 5-tri-substituted 1, 2, 3-triazoles depending on the selection of organic azides. Initial analytical data revealed the presence of a methyl group at C-4 of the triazole ring of 1, 4, 5-tri-substituted 1, 2, 3-triazoles. Studies are currently underway to rationalize the product distribution of these cycloaddition reactions.

Keywords: Sulfonylated triazole, vinyl sulfone, allene sulfone,propargyl sulfone, methylated 1, 4, 5-tri-substituted 1, 2, 3-triazoles

Abbreviations

Abbreviations
 1, 4-DT1, 4-Disubstituted 1, 2, 3-Triazole 
 1, 5-DT1, 5-Disubstituted 1, 2, 3-Triazole 
13C Carbon-13 isotope 
 CDCl3 Deuterated chloroform 
 CuAAC Copper-catalyzed azide-alkyne cycloaddition  
DCM Dichloromethane 
Et2O Diethyl ether 
 EtOAc Ethyl acetate 
Et3N Triethylamine  
 gGram 
h Hour 
1HHydrogen-1 isotope 
H2O2Hydrogen peroxide 
H2OWater 
Hz Hertz 
 KMnO4Potassium permanganate 
 MeOH Methanol
 MHzMega hertz 
m-CPBAmeta-chloro perbenzoic acid 
 mLmililitre 
 mmolmilimole 
MMPP Magnesium bis(monoperoxyphthalate) hexahydrate 
m-CPBA meta-chloro perbenzoic acid
NaHCO3Sodium hydrogen carbonate 
Na2SO4Sodium sulphate 
 NMRNuclear Magnetic Resonance 
 OxonePotassium peroxymonosulfate 
 ppmParts per million  
 RuAACRuthenium-catalyzed azide-alkyne cycloaddition 
 TLCThin layer Chromatography 

INTRODUCTION

Background/Rationale

Chemistry is the science of synthesis and structural modification of molecules and recent research trends in the chemical science shows chemistry has gradually undertaken the more challenging biology-oriented synthesis to save mankind from upcoming deep-rooted challenges. It develops new “chemistry” in-between laboratory-synthesized molecules and biological systems via a bio-conjugation [1] strategy that links these modified molecules with different substrate. To develop proper and efficient bio-conjugation [1] chemistry, the chemical reactions should be under the shade of bio-orthogonal [2] chemistry that refers to any chemical reaction that can occur inside of living systems without interfering with native bio-chemical processes. The chemical ligation strategy, that fulfils the recruitments of bio-orthogonality [2], includes Huisgen 1, 3-dipolar cycloaddition [3] between alkyne and azide. In general 1, 4-DT and 1, 5-DT are obtained as mixtures when terminal alkynes and organic azides react in 1, 3 dipolar cycloaddition fashion under thermal conditions (Huisgen reaction) [3]. Huisgen’s original reaction received little attention because of its low reaction rate and lack of regioselectivity yielding a mixture of 1, 4- and 1, 5 regioisomer [4].

Copper-catalyzed-alkyne-azide-cycloaddition (CuAAC) [5] afforded only the 1, 4 regioisomer. On the other hand, the ruthenium-catalyzed-alkyne-azide-cycloaddition (RuAAC) [6] afforded the 1, 5-triazoles. The copper-catalyzed-azide-alkyne cycloaddition [5] has been an extremely fast and effective click reaction for bio-conjugation, but it is not suitable for use in live cells due to the toxicity of Cu(I) ions. Toxicity is due to oxidative damage from reactive oxygen species formed by the copper catalysts. Copper complexes have also been found to induce changes in cellular metabolism and are taken up by cells. Ruthenium compounds are encountered relatively rarely by most people. All ruthenium compounds should be regarded as highly toxic and as carcinogenic. Compounds of ruthenium stain the skin very strongly. It seems that ingested ruthenium is retained strongly in bones. Ruthenium oxide, ReO4, is highly toxic and volatile, and to be avoided. RuAAC [6] has limited applications and the catalyst is highly expensive.Unfortunately, the published methods for regioselective triazole ligations, both for the 1, 4- and 1, 5- isomer, using heavy metal salts limit their applications in living cells. Therefore, the development of a metal-free, and thus biocompatible, regioselective triazole ligation method is under active consideration. In this context, our attention was drawn to propargyl sulfone.

 Sulfones display a diverse range of behaviour and possess unique features that make them valuable for numerous types of synthetic applications. As a result of their utility and versatility, sulfones have been described as “pluripotent” by Fuchs and co-workers and as “chemical chameleons” by Trost. Acetylenic [7] [8], allenic [8] and 1, 3-dienyl sulfones have all been the subjects of earlier reviews, while vinyl sulfones [4] and the related species have been similarly scrutinized, including their use as surrogates for acetylenic [7] sulfones when suitably functionalized. Vinyl sulfones [4], known as acetylenic equivalents, were introduced for the regioselective synthesis of 1, 2, 3-triazoles which avoided the use of toxic and expensive metal catalysts. To synthesize sulfonylated triazoles, propargyl sulfones known to exist in a mixture with the corresponding allene sulfones were introduced. Allene-sulfones are known to exhibit a unique reactivity due to the presence of two cumulative C=C double bonds and three reactive carbon centres. The mixture of propargyl sulfone and allene sulfone, on reactions with organic azides, was expected to afford mainly the 1, 4-DT.

0_1.JPG
    Pictorial representation of the project work

    Statement of the Problems

    • To accomplish a better and efficient way for bio-conjugation which satisfies the criterias of bio-orthogonality [2] chemistry under the metal-free condition to avoid metal toxicity and cost effect, this strategy may clinch the attention.
    • The regioselectivity can be introduced using this strategy (the prologue of sulfonylated propargyl) without using any metal catalyst. The strategy differs from the conventional CuAAC Click Chemistry [5] and RuAAC [6].
    • Sulfone chemistry can be used to trigger the regioselective triazole formation. Sulfones render the protons, that are adjacent to the moiety, relatively acidic and stabilize adjacent carbanion. The propargyl sulfone was smoothly isomerised to allyl sulfone in-situ.
    • Now the goal is to generalise that sulfonylated-propargyl strategy by using different substituent and have a conclusion on the limitation and the future scope.
    • The reaction is unsuccessful in case of the benzoxazole. During the oxidation of propargyl sulfide to propargyl sulfone, there is something unusual product recovered than expected product.

    Objectives of the Research

    • By varying the substrate, a piece of general information regarding the outcome of the metal-free Huisgen [3] reaction with sulfonylated species have been tried to demonstrate.
    • Sometimes the oxidation from sulfide to sulfone becomes difficult. Varying oxidizing agent, the reaction will be monitored.

    Scope

    Increased interest in the cycloadditions of acetylenic sulfones with azides has been prompted by the advent of Sharpless “click chemistry” [5] and it's potential for obtaining triazoles of medicinal and other biological interest, including the generation of triazole libraries. Regioselectivity was dependent upon both the electron-withdrawing effect of the sulfone aryl group and the steric bulk of the substituent. Thus the ratio of the product can be tuned by varying substituent.

    LITERATURE REVIEW

    The motto of the work is regioselective preparation of 1, 2, 3- triazole using sulfone as sythetic-auxilary. Huisgen’s 1, 3-dipolar cycloaddition [3] reaction, a well-known organic reaction between organic azides and alkynes is a direct route to prepare 1, 2, 3–triazole. By introducing Cu-catalyst, i.e., using click chemistry [5], 1, 4-DT can be synthesized regioselectively. By introducing Ru-catalyst [6], 1, 5-DT can be synthesised regioselectively. Without using metal catalyst 1, 5 DT can also be synthesized from vinyl sulfones [4]. In the context of metal-free 1, 4-DT preparation, propargyl sulfones draw the spotlight towards them.

    METHODOLOGY

    Concepts

    Science needs evidence and the evidence is furnished by proper instrumentation and then analysis of that instrument-generated datas. In the field of chemical components, the detection of the compound is the foremost evidence. The experimental result can be viewed only through the eye of spectroscopy. The experimental data in this report were generated based on 1H NMR and 13C NMR. For a few reactions, this spectroscopic data was not recorded and for those reactions, the conformation was generated based on TLC analysis. Using the concept of polarity and other atomic properties, the conclusions were drawn for a few reactions.

    Methods

    To generalize the outcome of the metal-free regioselective sulfonylated triazole formation reaction, the reaction was performed using different propargyl sufones. The corresponding sulfide should be prepared first and then it is oxidised to get sulfone derivative. After the formation of sulfonylated-propargyl derivative, 1, 2, 3 triazole preparation can be initiated.

    Scheme 1

    Procedure for the preparation of compound 2: To a well stirred solution of Compound 1 (0.5 g, 3.3 mmol) in Et2O (30 mL), Et3N ( 1 mL, 6.5 mmol) was added to it at 0º C and followed by addition of propargyl bromide (0.3 mL, 3.64mmol). After completion of addition the reaction mixture were stirred at rt for 2 h (TLC). The reaction mixture was poured into water, and the product was extracted with Et2O (3x20 mL). The combined organic layer was dried over anhydrous Na2SO4 and filtered, and the filtrate was evaporated under reduced pressure to get a residue. Then the residue was purified over silica gel column chromatography to afford compound 2 (0.44 g, 70%) as a yellow gum. [Eluent: EtOAc: Hexane (1:9)].  

    Characterisation of compound 2: 1H NMR (400 MHz, CDCl3): δ 2.19 (s, 1H); 3.85 (s, 2H); 6.97-7.41 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 20.7 (CH2); 72.5; 77.4; 110.0; 118.7; 124.1; 124.2; 141.7; 152.0; 163.0.

    Procedure for the oxidation of compound 2: To a well stirred solution of Compound 2 (0.44 g, 2.28 mmol) in MeOH (10 mL), Oxone (3 g, 9.1 mmol) in water (10 mL) was added to it at 0º C and the reaction mixture was stirred at rt for 12 h (TLC). After that MeOH was evaporated under reduced pressure and the reaction mixture was poured into water and the product was extracted with EtOAc (3x20 mL). The combined organic layer was dried over anhydrous Na2SO4 and filtered, and the filtrate was evaporated under reduced pressure to get a residue. Then the residue was purified over silica gel column chromatography to afford compound 3 (0.33 g, 71%) as a yellow gum. [Eluent: EtOAc: Hexane (1:4)].

    Characterisation of compound 3: 1H NMR (400 MHz, CDCl3): δ 7.13 (m, 4H); 10.14 (bs, 1H).

    Procedure for the oxidation of compound 2: To a well-stirred solution of Compound 2 (0.29 g, 1.54 mmol) in MeOH (10 mL) MMPP (4.0 g, 7.7 mmol) was added at 0 º C, and the mixture was stirred at room temperature for 12 h (TLC). After the completion of the reaction (TLC), the volatile matters were removed under reduced pressure to get a residue and the residue was dissolved in saturated NaHCO3. The compound was extracted with EtOAc (3x20 mL). The combined organic layer was dried over anhydrous Na2SO4 and filtered, and the filtrate was evaporated under reduced pressure to get a residue. Then the residue was purified over silica gel column chromatography to obtain compound 3 (0.21 g, 68%) as a yellow gum. [Eluent : EtOAc: Hexane (1:4)]. 

    Procedure for the oxidation of compound 2: To a well-stirred solution of compound 2 (0.15 g, 0.812 mmol) in glacial acetic acid (4 mL, 69.9mmol), 30% H2O2 (1.6 mL, 52.92 mmol) was added at 0 º C, and the reaction mixture was stirred at room temperature for 3 hour (TLC). After the completion of the reaction (TLC), the volatile matters were removed under reduced pressure to get a residue. The compound was extracted with EtOAc (3x20 mL). The combined organic layer was dried over anhydrous Na2SO4 and filtered, and the filtrate was evaporated under reduced pressure to get a residue. Then the residue was purified over silica gel column chromatography to obtain compound 3 (0.11 g, 69%) as a yellow gum. [Eluent : EtOAc: Hexane (1:4)].

    Procedure for the oxidation of compound 2: To well-stirred solution of compound 2 (0.0612 g, 0.317 mmol) was dissolved in 1mL acetone and 3% KMnO4 (1 mL)was added to the reaction mixture and the new resulting mixture was refluxed for 3 hour. The progress of the reaction was monitored by performing TLC at a certain interval. The compound was extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and filtered, and the filtrate was evaporated under reduced pressure and the crude residue was collected. Then the residue was purified over silica gel column chromatography to obtain compound 3 (0.048 g, 74%) as a yellow gum. [Eluent: EtOAc: Hexane (1:4)].

    Procedure for the oxidation of compound 2: To well-stirred solution of compound 2 (0.180 g, 0.95 mmol) in DCM (30 mL, 69.9mmol), m-CPBA (5 g, 2.87 mmol) and NaHCO3 (2.5 g, 3.79 mmol)was added at 0 º C, and the reaction mixture was stirred at room temperature for 12 hour (TLC). After the completion of the reaction (TLC), the volatile matters were removed under reduced pressure to get a residue and the residue was dissolved in saturated NaHCO3. The compound was extracted with DCM. The combined organic layer was dried over anhydrous Na2SO4 and filtered, and the filtrate was evaporated under reduced pressure and the crude residue was collected. Then the residue was purified over silica gel column chromatography to obtain compound 3 (0.135 g, 71%) as a yellow gum. [Eluent : EtOAc : Hexane (1:4)].

    01_1.jpg
      Reactions of Scheme 1

       Scheme 2

      Procedure for the synthesis of mixture 4: A mixture of Compound 2 (0.15 g, 0.689 mmol) and cyclohexyl azide [9] (0.172g, 1.38 mmol) were refluxed in toluene for 24 h (TLC). After that the toluene was evaporated to get a 1, 4-DT and 1, 5-DT crude mixture 4 and go to the oxidation step without further purification.

       Procedure for the synthesis of compound 5 : To a well stirred solution of mixture 4 (0.2 g , 0.636 mmol) in MeOH (10 mL), Oxone (0.78 g , 2.54 mmol) in water (10 mL) was added to it at 0º C and the reaction mixture was stirred at room temperature for 12 h (TLC). After that MeOH was evaporated under reduced pressure and the reaction mixture was poured into water and the product was extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and filtered, and the filtrate was evaporated under reduced pressure to get a residue. Then the residue was purified over silica gel column chromatography to afford compound 5 (0.09 g, 71.6%). [Eluent: EtOAc: Hexane (2:3)].

      Characterisation of compound 5: 1H NMR (400 MHz, CDCl3): δ 3.91 (s, 3H); 7.26-7.90 (m, 4H).13C NMR (100 MHz, CDCl3): δ 52.8; 128.6; 129.8; 130.3; 132.0; 133.1; 168.7; 171.9.

      02.jpg
        Reactions of Scheme 2

        Scheme 3

        Procedure for the synthesis of compound 7: To a well stirred solution of compound 6 (0.54 g, 3.73 mmol) in Et2O (20 mL), Et3N (1 mL, 7.46mmol) was added to it at 0º C and followed by addition of propargyl bromide (0.36 mL, 4.10mmol). After completion of addition the reaction mixture were stirred at rt for 2 h (TLC). The reaction mixture was poured into water, and the product was extracted with Et2O (3x20 mL). The combined organic layer was dried over anhydrous Na2SO4 and filtered, and the filtrate was evaporated under reduced pressure to get a residue. Then the residue was purified over silica gel column chromatography to afford compound 7 (0.49 g, 72%). [Eluent : EtOAc: Hexane (1:4)]. 

        Procedure for the synthesis of compound 8: To a well stirred solution of compound 7 (0.46 g, 2.53 mmol) in MeOH (10 mL), Oxone (3 g, 9.7 mmol) in water (10 mL) was added to it at 0º C and the reaction mixture was stirred at rt for 12 h (TLC). After that MeOH was evaporated under reduced pressure and the reaction mixture was poured into water and the product was extracted with EtOAc (3x20 mL). The combined organic layer was dried over anhydrous Na2SO4 and filtered, and the filtrate was evaporated under reduced pressure to get a residue. Then the residue was purified over silica gel column chromatography to afford compound 8 (0.40 g, 74%).

        Characterisation of compound 8: 1H NMR (400 MHz, CDCl3): δ 2.42 (s, 1H); 3.93 (s, 2H); 5.36 (d, J = 6.4 Hz, 2H); 6.19 (m, 1H); 7.34-7.79 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 48.1 (CH2); 84.4 (CH2); 71.7; 76.9; 77.2; 77.6; 129.0; 129.5; 139.7; 140.7; 209.0.

        Procedure for the synthesis of compound 9 and 10: A mixture of compound 8 (0.40 g, 1.86 mmol) and cyclohexyl azide [9] (0.46 g , 3.72 mmol) were refluxed in toluene (15 mL) for 48 h (TLC). After that the toluene was evaporated to get a crude residue. Then the residue was purified over silica gel column chromatography to afford two triazole derivative in pure form compound 9 (0.24 g, 37%) [Eluent: EtOAc: Hexane (1:4)] and compound 10 (0.26 g, 41%) [Eluent: EtOAc: Hexane (3:7)].

        Characterisation of compound 9: 1H NMR (400 MHz, CDCl3): δ 1.24-2.01 (m, 10H); 2.58 (s, 3H); 4.08 (m, 1H); 7.48 (d, J = 8.8 Hz, 2H); 7.98 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 8.4; 24.8 (CH2); 25.3 (CH2); 32.5 (CH2); 58.9; 129.3; 129.5; 134.8; 139.5; 140.3; 143.7.

        Characterisation of compound 10: 1H NMR (400 MHz, CDCl3): δ 1.36-2.17 (m, 10H); 4.41 (m, 1H); 4.52 (s, 2H); 7.42 (d, J = 8.4 Hz, 2H); 7.58 (d, J = 8.8 Hz, 2H); 7.73 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 25.0 (CH2); 33.4 (CH2); 54.0 (CH2); 60.3; 122.3; 129.5; 135.3; 140.8.

        03.jpg
          Reactions of Scheme 3

          Scheme 4 

          Procedure for the synthesis of compound 12: To a well stirred solution of compound 11 (0.5 g, 4.02 mmol) in Et2O (20 mL), Et3N (1.2 mL, 8.1 mmol) was added to it at 0º C and followed by addition of propargyl bromide (0.35 mL, 4.43 mmol). After completion of addition the reaction mixture were stirred at room temperature for 2 h (TLC). The reaction mixture was poured into water, and the product was extracted with Et2O (3x20 mL). The combined organic layer was dried over anhydrous Na2SO4 and filtered, and the filtrate was evaporated under reduced pressure to get a residue. Then the residue was purified over silica gel column chromatography to afford compound 12 (0.48 g, 73%). [Eluent :EtOAc: Hexane (1:4)].

          Characterisation of compound 12: 1H NMR (400 MHz, CDCl3): δ 2.25 (s, 1H); 2.36 (s, 3H); 3.57 (s, 2H); 7.16 (d, J = 8 Hz, 2H); 7.40 (d, J = 8 Hz, 2H).

          Procedure for the synthesis of compound 13: To a well stirred solution of compound 12 (0.44 g, 2.71 mmol) in MeOH (10 mL), Oxone (1.6 g , 5.50 mmol) in water (10 mL) was added to it at 0º C and the reaction mixture was stirred at rt for 12 h (TLC). After that MeOH was evaporated under reduced pressure and the reaction mixture was poured into water and the product was extracted with EtOAc (3x20 mL). The combined organic layer was dried over anhydrous Na2SO4 and filtered, and the filtrate was evaporated under reduced pressure to get a residue. Then the residue was purified over silica gel column chromatography to afford compound 13 (0.38 g, 72%).

          Characterisation of compound 13: 1H NMR (400 MHz, CDCl3): δ 2.43 (s, 3H); 3.94 (s, 1H); 5.42 (d, J = 6.4 Hz, 2H); 6.23 (t, 1H); 7.35 (d, J = 6.8 Hz, 2H); 7.78 (d, J = 8 Hz, 2H). 

          Procedure for the synthesis of compound 14 and 15: A mixture of compound 13 (0.38 g, 1.95 mmol) and cyclohexyl azide [9] (0.49 g , 3.91 mmol) were refluxed in toluene (15 mL) for 48 h (TLC). After that the toluene was evaporated to get a crude residue. Then the residue was purified over silica gel column chromatography to afford two triazole derivative in pure form compound 14 (0.24 g, 36%) [Eluent: EtOAc: Hexane (1:4)] and compound 15 (0.25 g, 40%) [Eluent: EtOAc: Hexane (3:7)]

          Characterisation of compound 14: 1H NMR (400 MHz, CDCl3): δ 1.24-2.58 (m, 10H); 2.40 (s, 3H); 2.56 (s, 3H); 4.06 (m, 1H); 7.31 (d, J = 8.4 Hz, 2H); 7.93 (d, J = 8.4 Hz, 2H).13C NMR (100 MHz, CDCl3): δ 8.4; 21.6; 24.8 (CH2); 25.3 (CH2); 32.5(CH2); 58.8; 127.8; 129.8; 134.4; 138.1; 144.3; 144.6.

           Characterisation of compound 15: 1H NMR (400 MHz, CDCl3): δ 1.23-2.11 (m, 10H); 2.41 (s, 3H); 4.39 (m, 1H); 4.49 (s, 2H); 7.24 (d, J = 8 Hz, 2H); 7.53 (d, J = 8.4 Hz, 2H); 7.72 (s, 1H). 13C-NMR (100 MHz, CDCl3): δ 21.6; 25.0 (CH2); 25.4 (CH2); 33.4 (CH2); 54.0 (CH2); 60.3; 122.1; 128.4, 130.1; 134.9; 145.0; 145.8.

          04.jpg
            Reactions of Scheme 4

            RESULTS AND DISCUSSION

            Purpose

            • Results and Discussion: The conversion of compound 1 to compound 2 was quiet natural but the problem arises during the oxidation step i.e., during the conversion of sulfide to sulfone. Ordinary oxidising agents failed to oxidise the sulphide. Several oxidising agents were taken in this context. All the reagents congregate at the same point by giving the same product but not the sulfone.To find the origin of the failure of the oxidation reaction, a new strategy was designed. The mixture 1, 4-DT and 1, 5-DT was prepared by Huisgen [3]reaction and then oxidation was carried out. The result is again quiet unsatisfactory as there was formation of unexpected product again. Use of p-chlorophenyl thiol and p-methylphenyl thiol serves the purpose pretty well and tri-substituted 1, 2, 3-triazole was formed along with the one of the traditional di-substituted 1, 2, 3 triazole.

            Statement of the result:

            From scheme 1, it can be concluded that the oxidation of compound 2 turned out to be difficult. Various oxidising agents were used to achieve the oxidised component but all the strategies converge to the same result. Thus, another strategy was designed to attain desired product.

            Monitoring table for the oxidation of compound 2 
            Reagent Reaction Condition Reaction time Reaction Medium Yield (%)
            Oxone Room Temperature 12 hour MeOH : H2O (1:1) 70
            MMPP Room Temperature 12 hour MeOH 68
            30% H2O2 Room Temperature 3 hour Glacial Acetic Acid 69
            3% KMnO4 Room Temperature 3 hour Acetone 74
            m-CPBA + NaHCO3 Room Temperature 12 hour DCM 71

            From scheme 2, it was clear that after triazole formation, the oxidation stage becomes more unpredictable and unexpected product was there. Now the time has come when the spotlight should be reallocated towards another thiol.

            From scheme 3 and scheme 4, it can be demonstrated that there is regioselective formation of 1, 4-DT and another methylated tri-substituted-triazole.

            The plausible mechanism, that suggests the formation of methylayed tri-substituted triazole, passes through allenic sulfone. Due to the presence of sulfone moiety the proton, adjacent to the sulfone moiety becomes more acidic and finally giving rise to allene sulfone in-situ.

            05.jpg
              Plausible mechanism for the methylated triazole
              • Spectral Data:
              1_2.JPG
                1H-NMR (400MHz), CDCl3 (Compound 2)

                2_1.JPG
                  13 C-NMR (100 MHz) - CDCl3 (Compound 2)

                  3.JPG
                    13 C-NMR (100 MHz) - DEPT 135 CDCl3 (Compound 2)

                    4_1.JPG
                      1H-NMR (400MHz), CDCl3 (Compound 3)

                      Capture.JPG
                        1H-NMR (400MHz), CDCl3 (Compound 5)

                        6.JPG
                          13 C-NMR (100 MHz) - CDCl3 (Compound 5)

                          7.JPG
                            13 C-NMR (100 MHz) - DEPT 135 CDCl3 (Compound 5)

                            8.JPG
                              1H-NMR (400MHz), CDCl3 (Compound 8)

                              9.JPG
                                13 C-NMR (100 MHz) - CDCl3 (Compound 8)

                                10_1.JPG
                                  13 C-NMR (100 MHz) - DEPT 135 CDCl3 (Compound 8)

                                  11_2.JPG
                                    1H-NMR (400MHz), CDCl3 (Compound 9)

                                    12_1.JPG
                                      13 C-NMR (100 MHz) - CDCl3 (Compound 9)

                                      13.JPG
                                        13 C-NMR (100 MHz) - DEPT 135 CDCl3 (Compound 9)

                                        14.JPG
                                          1H-NMR (400MHz), CDCl3 (Compound 10)

                                          15.JPG
                                            13 C-NMR (100 MHz) - CDCl3 (Compound 10)

                                            16.JPG
                                              13 C-NMR (100 MHz) - DEPT 135 CDCl3 (Compound 10)

                                              17.JPG
                                                1H-NMR (400MHz), CDCl3 (Compound 13)

                                                18.JPG
                                                  1H-NMR (400MHz), CDCl3 (Compound 14)

                                                  19.JPG
                                                    13 C-NMR (100 MHz) - CDCl3 (Compound 14)

                                                    20.JPG
                                                      13 C-NMR (100 MHz) - DEPT 135 CDCl3 (Compound 14)

                                                      21.JPG
                                                        1H-NMR (400MHz), CDCl3 (Compound 15)

                                                        Capture1.JPG
                                                          13 C-NMR (100 MHz) - CDCl3 (Compound 15)

                                                          23.JPG
                                                            13 C-NMR (100 MHz) - DEPT 135 CDCl3 (Compound 15)

                                                            CONCLUSION AND RECOMMENDATIONS

                                                            • Conclusions: The conversion of compound 1 to compound 2 was quiet natural but the problem arises during the oxidation step i.e., during the conversion of sulphide to sulfone. Several oxidising agents were taken in this context. All the reagents congregate at the same point by giving the same product but not the sulfone (Scheme 1). A new strategy was then adopted. To check this problem, the mixture 1, 4-DT and 1, 5-DT was prepared by Huisgen [3] reaction first and then oxidation was carried out. The result is again quiet unsatisfactory as there was formation of unexpected product again (Scheme 2). Now it is the time to swift the attention from this benzoxazole to another thiol. The p-methylphenylthiol (Scheme 3) and p-chlorophenylthiol (Scheme 4) mainly affords 1,4-DT along with the tri-substituted 1, 2, 3-triazole.
                                                            • Recomandation:

                                                            Metal-free regioselective preparation of 1, 4-DT was done using sulfone as synthetic-auxilary. In this context, the centre of attraction is propargyl sulfone moiety which is converted to allene sulfone in-situ and finally affords 1, 4-DT and methylated 1, 4, 5-tri-substituted 1, 2, 3-triazole.

                                                            The future scope of this report may include the furthur study of the unsuccessful oxidation of 2-mercapto benzoxazole propargyl sulfide.

                                                            The shortcoming of the report is, the unexpected chemistry and chemical reactions of 2-mercapto benzoxazole moiety cannot be traced successfully during this short span of time.

                                                            In the bio-conjugation, there is wide spread application of 1, 4-DT. 1, 4- di-substituted- 1, 2, 3-triazoles can be considered as isosteres of the trans-amide bond. This method suggests a transition metal catalyst free, more economical strategy for regioselective preparation of 1, 4-DT using sulfone moeity as sythetic-auxilary.

                                                            ACKNOWLEDGEMENTS

                                                            It is an excellent opportunity to express my deepest sense of gratitude, respect and sincere indebtedness to my project supervisor Prof. Tanmaya Pathak, Indian Institute of Technology Kharagpur, Kharagpur-721302, for his valuable and affectionate guidance throughout the “Summer Research Fellowship Programme 2019” conducted by Indian Academy of Science (IASc), without which the project work could not have been successfully completed. His valuable suggestions and constant encouragement, at every stage of the work, have always been a source of great inspiration to me. I would like to acknowledge and show my gratitute to Indian Academy of Science (IASc) for conducting the “Summer Research Fellowship Programme 2019”.

                                                            I remain indebted to Mr. Rajesh Maiti and am also grateful to all my lab seniors for supporting me in every possible way to complete this project work. During this time span, I have been an integral part of this laboratory.

                                                            Finally, I would like to acknowledge my parents for their constant help and support.

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