Step-economic synthesis of nitrogen heterocycles via annulation of donoracceptor cyclopropanes by metal and and metalfree activation

Abstract

Chapter 1: Nitrogen Heterocycles and Cyclopropanes in Organic Chemistry Nitrogen heterocycles are of particular importance because of their indispensable involvement in the several essential functions of our life and society. Often, they present as a cyclic core structure in biologically relevant natural products, synthesized pharmaceuticals, pigments, dyes, antibiotics, vitamins, hormones, and so forth. Such widespread appearance is mainly caused by N-atoms, which imparts many significant physical and chemical properties in the molecule and thereby making them the most significant heterocycles. Owing to these importances, the development of the versatile strategies to synthesize N-heterocycles has remained a forefront domain in the ground of organic synthesis since the ancient time. Over the centuries, several methods for the construction of N-heterocycles have emerged. Among them, the annulation of donoracceptor cyclopropanes (DACs) received immense popularity in the last few decades. Owing to their inherent reactivity, secure handling, and ease of synthesis, DACs have widely used in the rapid construction of a broad range of carbo and heterocycles. The structure and boding of cyclopropane have been discussed briefly in this chapter. The various modes of reactivity and the influence of the substituent on controlling the reactivity of cyclopropanes are elaborated. Multiple types of cyclopropanes and their use in synthetic organic chemistry have been introduced. Few seminal works on the donor cyclopropane, acceptor cyclopropane, and donor-acceptor cyclopropanes are exhibited. In the last portion of this chapter, the research work carried out in this thesis is chapter wise outlined. Chapter 2: Lewis acid Catalyzed Diastereoselective Annulation of Donor-Acceptor Cyclopropanes and Vinyl Azides: Synthesis of Functionalized Azidocyclopentane and Tetrahydropyridine Derivatives Tetrahydropyridines are the vital class of N-heterocycle because of their presence as the cyclic core structure in numerous alkaloids. Consequently, the development of efficient protocols for the stereoselective synthesis of these molecular scaffolds from easily accessible starting material is of immense interest. In this perspective, the two-step synthesis of tetrahydropyridines from donor-acceptor cyclopropane has been demonstrated in this chapter. The preliminary investigation was initiated by considering the enamine nature of vinyl azide. In the presence of a Lewis acid catalyst, a [3+2]-annulation of DAC and vinyl azide towards the formation of azidocyclopentane was observed. Optimization study disclosed two optimized reaction conditions: (1) in the presence of MgI2 (20 mol %) in DCM (condition A) reaction proceeded with an excellent diastereoselectivity, but it provided moderate yield and slower reaction, whereas (2) with 20 mol % InCl3 in DCM (condition B) reaction proceeded with poor diastereoselectivity, but it gave faster reaction and excellent yield. A thorough evaluation of the substrate scope was executed under both the optimized conditions. Highly activated cyclopropanes were found as effective substrates for this transformation. A range of azidocyclopentane derivatives was synthesized by employing various DACs in the titled annulation. After that, synthesized [3+2]-annulated adducts were subjected to a thermal chemoselective ring expansion reaction. By this process, an array of tetrahydropyridines was constructed. In addition, to show the synthetic potentiality of the developed methodology, the azidocyclopentane was exploited in an azide-alkyne click reaction to synthesize a triazole functionalized cyclopentane derivative, which is an important structural scaffold of various bioactive compounds. A reduction of tetrahydropyridine was also executed. Using NaBH4, the tetrahydropyridine derivative was smoothly transformed into a piperidine derivative in highly diastereoselective fashion. In this operation, an additional stereogenic center was introduced in the product. The stereochemistry of the product was established using NOE studies. Moreover, a chiral cyclopropane derivative was exploited in the designed protocol to evaluate the stereospecificity of the process. In this attempt, an enantioenriched tetrahydropyridine was obtained as a final product. Transfer of the enantiomeric excess from the substrate to the product revelated the stereospecific nature of the reaction. To explain the formation of the products and their observed selectivity, a plausible reaction pathway for both annulation and ring expansion reactions has been depicted in the last portion of this chapter. Chapter 3: Lewis acid Catalyzed Annulation of Cyclopropane Carbaldehydes and Aryl Hydrazines: Construction of Tetrahydropyridazines and Application Towards a One-pot Synthesis of Hexahydropyrrolo[1,2-b]pyridazines This chapter described the synthesis of tetrahydropyridazine and hydropyrrolo[1,2- b]pyridazine derivatives through a Lewis acid catalyzed annulation of DACs and aryl hydrazines. Two different types of DAC have been used for this work. They are 2-aryl cyclopropane carbaldehyde, and 2-aryl cyclopropane 1,1-dicarboxylate, respectively. In the presence of a Lewis acid, cyclopropane carbaldehyde and aryl hydrazine underwent an annulation reaction towards the formation of tetrahydropyridazine as the sole product. The reaction conditions for this annulation was optimized by using a range of commercially available Lewis acid, which established InCl3 as the optimized catalyst. With this optimized catalyst, the substrate scope and limitation of this annulation reaction was probed for a range of cyclopropane carbaldehydes and aryl hydrazines. This substrate scope evaluation disclosed the fact that moderately activated DACs are an ideal substrate for this annulation. A variety of aryl hydrazines were effortlessly transformed into the desired adduct. However, Longer reaction time and reduced yield of the expected product was observed for the hydrazine derivatives bearing an electronically deactivated aryl ring like 4-chloro, 4-bromo, and 4-cyano phenylhydrazine. To evaluate the practical applicability of the process, this annulation reaction was conducted in a gram-scale under the same optimized conditions. To our delight, the desired annulated adduct was obtained in 68% yield in the gram-scale reaction. Moreover, to know whether both isomers (cis and trans) of cyclopropane carbaldehyde can be used as the efficient substrate for the titled annulation, we carried out a control experiment with cis-2- phenylcyclopropanecarbaldehyde, which yielded the slower reaction and a lower yield of the expected product than that of in trans-2-phenylcyclopropanecarbaldehyde. The annulated adduct tetrahydropyridazine was next employed in a [3+2]-annulation reaction with cyclopropane1,1-dicarboxylate as another type DAC. The optimization study provided the 20 mol % Yb(OTf)3 as the best catalytic system for the said transformation. Several DACs were employed for the construction of various hexahydropyrrolo[1,2- b]pyridazines. To synthesized hexahydropyrrolo[1,2-b]pyridazines in one step, both annulations were conducted in one-pot through in situ formations of the tetrahydropyridazine and then its annulation with DAC. To our delight, the final product was attained in a moderate yield. Furthermore, to display the synthetic potentiality of the developed methodology, we conducted a monodecarboxylation reaction of the hexahydropyrrolo[1,2-b]pyridazine derivatives. In the presence of KOH in alcoholic reflux condition, hexahydropyrrolo[1,2- b]pyridazine was smoothly transformed into the corresponding monoacid derivative in a good yield. A plausible mechanism for both the annulation has been proposed in the last portion of this chapter. Chapter 4: Metal-Free Ring Opening Cyclization of Cyclopropane Carbaldehydes and N-benzyl Anilines: An Eco-friendly Access to Functionalized Benzo[b]azepine Derivatives In general, the reactions of DACs are executed by activating them with a metal catalyst (typically metal-containing Lewis acid or palladium catalyst). Very often, several metalcatalyzed reactions of cyclopropane associated with many disadvantages like hazardous handling, toxicity, high cost, and the trace amount of metal contamination in the final product. In biological and pharmaceutical grounds, the latter issue is a serious practical concern and thereby requires an additional expansive and time-consuming metal removing step. Furthermore, the extreme moisture sensitivity of metal catalysts often mandates to use molecular sieves as an additive in the reaction. Therefore, it is essential to develop the addressed reactions of cyclopropane in metal-free and mild conditions. This chapter disclosed a metal-free substituent-controlled switchable ring opening/ring opening cyclization of cyclopropane carbaldehydes and N-benzyl anilines towards the formation of functionalized 4-amino butanal/2,3- dihydro-1H-benzo[b]azepine derivatives. The optimization study was conducted by employing cyclopropane carbaldehyde and Nbenzyl aniline in the ring opening reaction with the various solvent systems. PTSA in DCM solvent system was found to be the most effective reaction conditions. With developed optimized conditions, the substrate scope of the ring opening reaction was examined, and thereby a broad range of functionalized 4-amino butanal derivatives was synthesized. A chiral (78% ee) 4-amino butanal derivative was synthesized by taking advantage of the stereospecific nature of ring opening. Afterward, efforts have given to employing the ring-opened product in an intramolecular Friedel-crafts acylation towards the cyclization of the formed 4-amino butanal derivative. After successful cyclization, a protocol to conduct both the ring opening and cyclization reaction in one pot was developed. With this one-pot ring opening cyclization strategy, an array of 2,3- dihydro-1H-benzo[b]azepine derivatives were synthesized. By using a fused cyclopropane carbaldehyde, Benzo[b]azepines having a fused [6-7-6] tricyclic skeleton was synthesized in a good yield. The fused [6-7-6] tricycle is a critical Nheterocyclic framework as it presents in the many drug molecules. In addition, 2,3- dihydro-1H-benzo[b]azepine derivative was reduced to the corresponding 2,3,4,5- tetrahydro-1H-benzo[b]azepine derivative by treatment with LAH/FeCl2 mixture. Chapter 5: Summary and Future outlook In pursuit of the step economic synthesis of various Nitrogen heterocycles, several distinct methods have been demonstrated in this thesis. Exhibited works are based on the strain driven activities of donor-acceptor cyclopropane. The combination of inherent ring strain and synergistic push-pull effect of donor and acceptor substituent make donor-acceptor cyclopropane as an ideal three carbon synthon. Under proper kinetic trigger, donor-acceptor cyclopropane transformed into a 1,3-dipole, which participates in annulation reaction with various saturated and unsaturated N-containing reactive partners to fabricate assorted Nheterocycles. The absolute control over the chemo- and regioselectivity disclosed the viability of these annulations. The excellent diastereoselectivity made these annulations attractive in the viewpoint of stereoselective synthesis. The stereospecific nature of these annulations enabled the devolved methods to delivered the products in the optically active form. Moreover, the synthetic applications with annulated adduct under each section manifested the potential of these scaffolds for target molecule synthesis. Eventually, keeping all these achievements in mind, we believe that the methods described in this thesis would serve as elegant strategies towards the step-economic synthesis of diverse Nheterocycles compound in near future.