Efficient construction of biologically important heterocycles via cycloaddition reaction of activated strained ring with dipolar species

Abstract

Chapter 1: Introduction Heterocycles are the largest division of organic compound that contains at least one or two heteroatoms in a ring. The presence of heteroatom in the heterocyclic compound gives them many significant physical and chemical properties. Heterocycles are ubiquitous in nature and shows excellent importance in human life because of their existence in a wide variety of drugs, most vitamins, many natural products, biomolecules, and biologically active compounds, including antitumor, antibiotic, anti-inflammatory, antidepressant, antimalarial, anti-HIV, antimicrobial, antibacterial, antifungal, antiviral, antidiabetic, herbicidal, fungicidal, and insecticidal agents. Heterocycles are also essential structural subunits of many synthetic pharmaceuticals and agrochemicals. In addition to this, heterocycles also possess important application in material science. Due to the importance of these bioactive molecules organic chemist involved in the development of facile and shortest route for their synthesis. In the beginning section of this chapter, an account of the importance of heterocycles synthesis and also various approaches for designing the heterocycles are discussed by employing the distinct application of strained ring molecule. In this context, three different classes of strained ring viz donor-acceptor cyclopropane (DAC), aziridine, epoxide are used as a synthetic precursor for the synthesis of heterocycles and carbocycles. The structure, bonding and different type of reactivity of DAC, aziridine and epoxides are discussed in details. The utility of these synthetic tool such as DAC, aziridine and epoxides with some selected example in cycloaddition reaction are briefly highlighted in their respective part. Chapter 2: Construction of Isoxazolidines via Formal [3+2] Cycloaddition of in situ Generated Nitrosocarbonyls with Donor-Acceptor Cyclopropanes: Application towards the Synthesis of α-amino γ-butyrolactones Isoxazolidines are one of the important scaffold having potential as intermediate for nitrogen and oxygen conataing heterocycle. Isoxazolidine shows varieties of biological activities such as antiviral, anti-inflammatory, herbicidal, and nucleosides. This scaffold is an important constituent of nucleoside analogue aza-dideoxyfluorouracil (ADF), which is highly potent and induces remarkable levels of apoptosis of lymphoid and monocytoid cells. Isoxazolidine act as synthetic precursor for the construction of α-amino γ-butyrolactones, which constitute the cyclic core structure of many natural product and shows a wide range of biological activities. Scheme 1. [3+2] cycloaddition of DACs and hydroxycarbamates. This chapter reports, a MgI2‐catalyzed cycloaddition reaction of DAC with in situ generated nitrosocarbonyls from hydroxycarbamates to access highly functionalized isoxazolidines. This methodology was examined with varieties of Lewis acids and solvents. It was observed that transformation worked well with MgI2 in (40 mol %) in CH2Cl2 at room temperature. Scope and limitation of this methodology is also studied by varying substrates with respect to both DACs and hydroxycarbamate. Activated DACs that had electron-donating substituents on the phenyl ring favor the good yield of the product. While with electron-poor substrate yield of the desired product. Scheme 2. One –pot Synthesis of aminolactone. was moderate. In addition to this protocol gives one-step access to valuable α-aminoγ- butyrolactones by reductive cleavage of N–O bond, deprotection of N-protecting groups, and subsequent lactonization of an isoxazolidine derivative in a single step. Despite of this, isoxazolidines undergo deprotection of boc group in the presence of TFA to provide Ndeprotected isoxazolidines in excellet yield. Chapter 3: Lewis Acid Catalyzed [3+3] Annulation of Donor-Acceptor Cyclopropanes and Indonyl Alcohols: One Step Synthesis of Substituted Carbazoles with Promising Photophysical Properties Polycylic indole are ubiquitous in nature and prime scaffold in vast number of natural alkaloids, pharmaceuticals, and agrochemicals as well as materials. Carbazole and its hydroderivative, subset of polyclic indole have been isolated from various natural sources. They demonstrated a broad spectrum of biological activities including antimalarial, anticancer, detoxification agents, treatment of skin diseases and efficiency in relieving abdominal pain. Such biological activities compelled us to explore new protocol for the functionalized carbazole and their derivative from readially available starting material. In this section, a new protocol for the one-pot synthesis of substituted carbazole via Lewis acid catalyzed annulation of DACs and indonyl alcohol has been reported. The reaction was carried out in presence of InCl3 at room temperature in CH2Cl2 as a solvent. Other Lewis acid like Sc(OTf)3, Yb(OTf)3, and In(OTf)3 gave moderate yield of the desired product. InCl3 was found efficient catalyst for the reaction and worked well with all types of substrate employed in this study. Electron donating groups substituted DACs resulted in to the excellent yield of substituted carbazole whereas less activated DACs did not lead to the formation of desired product. Scheme 3. [3+3] annulation of DACs and indonyl alcohol This work also offers an insight into the mechanism of the annulation process. Additionally substituted carbazole undergo aromatization in the presence of LiCl at 160 °C (Krapcho dealkoxycabonylation) gave the compound 9 in moderate yield. This fully conjugated 𝜋- system also showed intense emission band in the visible range and a solvatochromic effect. These fully aromatized carbazole underwent hydrolysis in the presence of alcoholic KOH to give the corresponding monoacid 10 in excellent yield, which is an important structural motif of natural product pityriazole. Scheme 4. Post-functionalization of carbazole Chapter 4. one-pot synthesis of aziridinoxazole from nitrocyclopropane and a terminal alkyne. Reactivity of DACs that are demonstrated in chapter 2 and chapter 3 exhibited the opportunities to make a synthetic design for an array of valuable heterocycles. The reactivity of nitrocyclopropane is different from DACs. In presence of Lewis acid it undergo intramolecular rearrangement to form cyclic nitrone, which can be used as 1,3-dipolar species, which play an important role in the construction of heterocyclic compounds. Out of these heterocycles azridinoisoxazole motifs are an important constituent in a number of biologically active natural products, including the potent anti-tumor alkaloid. Owing to their biological importance, the development of one pot and convenient protocol for the synthesis of functionalized azridinoisoxazole have received significant attention from the organic chemist. In this chapter, one pot synthesis of azridinoisoxazole via domino intramolecular rearrangement/ cycloaddition reaction of nitocycloproane and terminal alkyne in the presence of Lewis acid has been done. The reaction was optimized with various Lewis acids and Yb(OTf)3 was found the effective catalyst for this transformation. Scheme 5. Synthesis azridinoisoxazole. Scope of the transformation was also studied by the varierty of nitrocyclopropene with terminal alkyne and the annulated product was obtained moderated to good yield. Chapter 5. Construction of Thiazines and Oxathianes via [3+3] Annulation of N-Tosylaziridinedicarboxylates and Oxiranes with 1,4-dithiane-2,5-diol : Application Towards the Synthesis of Bioactive Molecules A careful study of DACs with various nucleophiles resulted in to the analogs of bioactive molecule, emerges immense attention to check the possibility of the formation of different other classes of heterocycles. In this regard we were interested to check the reactivity of heteroatom containing strained ring (viz donor-acceptor aziridine and donor-acceptor epoxide) with dipolar species to synthesize two heteroatom containing heterocycles. Two heteroatom containing six membered rings like thiazine and oxathianes are of particular importance, as these scaffolds are important constituent of many natural products and bioactive heterocycles. We envisioned exploring the [3+3] annulation of aziridine and oxiranes with 1,4-dithiane 2,5- diol to provide one step synthesis of thiazine and oxathiane. Scheme 5. [3+3] annulation of aziridine and oxiranes with 1,4-dithiane 2,5-diol. Variety of Lewis acid were examined to optimize the reaction condition and found that 20 mol % of MgI2 in DCM as solvent was the most effective reaction condition for this transformation. Scope of the methodology also assessed by the varieties of substituted D-A aziridine with 1,4- dithiane 2,5-diol. Electron withdrawing group substituted aziridine gave the excellent yield of desired product in short time while electron donating group substituted azirdine gave moderate to good yield of the annulated product. Further, we tested the reactivity of different D-A oxiranes with 1,4- dithiane 2,5-diol and found that the electron releasing D-A oxiranes performed better than electron withdrawing aryl substituted oxiranes. In addition to this, derivatization of thiazine has been demonstrated. In presence of NaH, detosylation of 17 at room temperature has been done to give functionalized imine in excellent yield. Moreover the hydoxy group was protected with Ac2O, which undergo Krapcho decarboxylation accompanied by elimination of acetoxy group gave the monoester 20. The molecule constitute the core structure of biologically active natural product. Sheme 6. Derivatization of thiazine