Development of diverse strategies towards the facile access to biologically important nitrogenous scaffolds

Abstract

Chapter 1: Nitrogen-Containing Molecules: The Privileged Motifs and Their Diverse Synthetic Tactics The nitrogen acyclic and heterocyclic scaffolds are of paramount interest among the total heterocycles not only due to their wide therapeutic profile but also because of the services these structures are delivering to the synthetic organic chemists in the form of catalysts, auxiliaries, additives, etc to realize the unprecedented chemical transformations. Moreover, these molecules form the key structural elements in a plethora of important natural products like alkaloids and also the key components of our diet in the form of vitamins (thiamin, riboflavin, pyridoxol, nicotinamide, etc), proteins, etc. The nitrogenous bases (purines and pyrimidines) compose the DNA nucleotides, which form the basis of life. Owing to these striking features, the synthesis and structural tailoring of nitrogenous molecules have been an alluring prospect to synthetic organic chemists. The field of their synthesis has witnessed interesting developments over time and prosperously mined the diverse catalysis strategies to come up with these structures. Metal catalysis has always been the front runner in this realm; however, cleverly capitalizing on the simple but elegant tools of contemporary organic chemistry like umpolung or polarity reversal, chemo-enzymatic (two-world), and electro-organic or the photo-redox catalysis has revolutionized their synthesis in-terms of the selectivity and sustainability. The flexibility of modifying or controlling the chemo- and/or regioselectivity by just modulating the applied redox potential has presented the organic electro catalysis as a promising strategy for the next generation of organic synthesis. This chapter discusses the diverse catalysis strategies like metal-, organo-, photo- and organic electrocatalysis employed to construct the nitrogen-containing scaffolds. The rationale behind the reactivity of strained rings like DACs and oxetanes and other intermediates like aza-oxyallyl cations which have gained a cardinal position in the synthesis of various carbo- and heterocycles has been discussed in detail. The necessity of redesigning the synthetic routes of commercially important active pharmaceutical ingredients (APIs) and the ideal tools for its accomplishment has been demonstrated in the last section of this chapter. The aim of the thesis and the investigations carried out during the doctoral training are outlined in the form of different chapters as follows. Chapter 2: [3+3] Annulation via Ring Opening/Cyclization of Donor–Acceptor Cyclopropanes with (Un)symmetrical Ureas: Facile Access to Functionalized Tetrahydropyrimidinones Pyrimidinones are biologically important nitrogenous heterocycles exhibiting a wide range of pharmacological properties such as antifungal, antimalarial, antiviral, antibacterial, anti-inflammatory, and anticancer activities. These form the key structural unit in natural products like alkaloids, vitamins (thiamin and riboflavin; folic acid), and nucleic acids (uracil, cytosine). In 1891 Pietro Biginelli disclosed the synthesis of pyrimidinones and pyrimidines by condensing an aldehyde, urea/thiourea, and ß-keto ester. Several alternate methodologies have also been demonstrated. No doubt all the reported methods are attractive routes, however, most are thin in terms of generality and the reaction conditions involved. In line with the importance of these scaffolds and the limitations associated with most of the existing protocols, the synthesis of tetrahydropyrimidinones in an efficient manner is highly desirable. In this chapter, we disclosed the facile synthesis of highly functionalized tetrahydropyrimidones exploiting Lewis acid catalysts to activate donor-acceptor cyclopropanes (DACs) which in the presence of ureas generate uriedo-malonates. The malonates on further treatment with I2-base undergo annulation to furnish the target products. DACs have emerged as the versatile building blocks for the construction of complex organic architecture and this present the first strategy to annulate these three carbonwith ureas to furnish pyrimidinone derivatives. Among the various Lewis acids screened, InCl3 was found to efficiently catalyze the reaction. The protocol displayed wide substrate scope in terms of activated DACs and (un)symmetrical ureas and delivered the products in moderate to excellent yields. However, compromised results were obtained in the case of DACs with deactivating functionalities. In the follow-up chemistry, the tetrahydropyrimidinones were subjected to Krapcho decarboxylation which removes one of the ester groups from the molecule. The elimination of a vicinal N-benzyloxy group followed by imine to enamine rearrangement was also observed in this case. Further, the reductive debenzylation afforded N-hydroximic acid type scaffolds, and such structures are known for their metalloenzyme inhibition activities. Chapter 3: Palladium-Catalyzed Stereo- and Regioselective Synthesis of Allyl Ureas/Carbamates: Facile Access to Imidazolidinones and Oxazepinones Allylic amines are featured as versatile building blocks for the construction of complex structures in synthetic organic chemistry. These are usually synthesized by the trivial substitution reactions at allylic positions, amination of alkenes, and C−H bond activation/functionalizations. No doubt, the synthesis of these molecules from simple precursors has recently witnessed significant progress. But their construction especially in the stereo-defined fashion with tri- or tetra substitutions at the olefin center is highly challenging. These demand the use of stoichiometric sensitive metals and additives as reagents or stereo predefined precursors. These are therefore suffering from limitations of waste generation and poor atom economy. Urea and its derivatives hold a cardinal position in synthetic and medicinal chemistry owing to its hydrogen bond donor and acceptor properties. The N-allyl ureas in particular have been exploited in various transformations, but their stereo-controlled access lags far behind the N-allyl amines. Based on these considerations, the synthesis of N-allyl ureas in a stereospecific fashion from the modular starting materials is highly desirable. Vinyl ethylene carbonates (VECs) have been reported to generate the six-membered palladacycle intermediate upon palladium-mediated decarboxylation. This intermediate can further undergo nucleophilic substitutions to afford regio- and stereoselective allylic scaffolds. Based on these reports and our experience with dibenzyloxyureas, we envisioned a substitution of the palladacycle by urea towards the direct synthesis of stereodefined N-allyl ureas. This chapter demonstrates the formation of Z-selective N-allylureas/N-allylcarbamates from VECs and dibenzyloxyureas/carbamates in the presence of palladium precatalyst and an appropriate ligand. The optimization studies identified Pd2(dba)3-rac-BINAP as the efficient catalyst-ligand combination to carry out the transformation efficiently. The products were delivered in moderate to excellent yield under mild reaction conditions. The screening of the generality of the protocol revealed that a variety of VECs and ureas with different electronics and sterics are compatible with the protocol. The free nitrogen center and the allylic alcohol in the products further paved the way to do further tailoring with these structures. A base-mediated intramolecular allylic substitution by the nitrogen center of N-allylureas furnished functionalized vinyl imidazolidinones. A similar treatment of N-allyl carbamates delivered seven-membered oxazepinones under mild conditions. Further, in the follow-up chemistry, the vinylic double bond could be easily regioselectively halogenated to generate the halohydrins. These halohydrins readily undergo dehydrohalogenation in the presence of a base to furnish oxiranes (styrene epoxide or imidazolidinone epoxide) which in turn are promising building blocks in synthetic organic chemistry. Chapter 4: Aza-Oxyallyl Cation Driven 3-Amido Oxetane Rearrangement to 2-Oxazolines: Access to Oxazoline Amide Ethers The work in this chapter presented aza-oxyallyl cation, a transient electrophilic species as an activating agent for the strained ring oxetane. This adds a new dimension to the reactivity profile of these cationic intermediates. The formation of these cationic intermediates was first hypothesized by Sheehan and Lengyl in the 1960s during the hydrolysis of α–lactams. But the following decades did not witness any significant progress in this direction because of the lack of any experimental evidence regarding their existence. Kikugawa’s solvolysis experiments provided some further insight into these intermediates and classified them into stabilized and non-stabilized aza-oxyallyl cation intermediates. After that things started moving in this direction and finally Jeffery et al. in 2011 successfully trapped these transient intermediates in [3+n] cycloaddition reaction with furans and other reactive partners. After this groundbreaking discovery, the cycloaddition facet of its reactivity observed a sudden bloom and just in one decade, this reactivity becomes well established in organic chemistry. This intermediate finds its use in the facile synthesis of numerous nitrogen heterocycles of structural and biological importance. In addition to it, a few alkylations of aza-oxyallyl cations have also been reported. It has presented itself as an ideal candidate to deliver congested N-(hetero)aryl amines under mild conditions. These structures are of notable significance in the medicinal chemistry and drug discovery; however their synthesis encounters many challenges. The idea behind this work was that since these aza-oxyallyl cations are transient electrophilic species, these should interact with the nucleophilic centers (N, O, S, etc) in other molecules. Such types of interactions (e.g, with the Lewis acids) are widely exploited to activate various ring systems (ethers, aziridines, etc) in synthetic organic chemistry. Now if such an interaction is established, the next important thing is that the interaction should be of sufficient strength so that the molecule to be activated gets activated and further participates in a reaction. We anticipated such interaction of it with 3-amido oxetanes. These oxetanes are four-membered cyclic ethers, despite the inherent ring strain these are highly bench stable and need Lewis or Bronsted acids for activation. To our delight, the aza-oxyallyl cation generated under mild conditions simultaneously activated (triggered its rearrangement) and alkylated the 3-amido oxetanes and furnished the corresponding 2-oxazoline amide ethers in good to moderate yields. A series of control experiments were conducted which demonstrated the aza-oxyallyl cation generation and activating nature of the reaction. The generality of the protocol identified a variety of 3-amido oxetanes and 3-haloamides with different electronics and sterics as the viable substrates for this transformation. The dimethyl group at the α–position of the haloamides was found indispensable to the reaction due to its stabilization of the intermediate. Chapter 5: Direct Synthesis of Paracetamol via Site-Selective Electrochemical Ritter-type C–H Amination of Phenol Sustainable synthesis has attracted the attention of the scientific community in view of the severe limitations of the existing protocols towards the environment. Constantly efforts in the form of replacing the corrosive reagents/solvents, decreasing the number of reaction steps, late-stage diversifications, etc are being made to revise the synthetic protocols to make them more environmentally benign. Several new techniques photochemistry, mechanochemistry, etc have emerged over the period time to address these objectives. Among the other techniques, organic electrochemistry has re-emerged as a powerful tool for the making and breaking of bonds under environmentally benign conditions. No doubt electrochemistry can be traced back to 1800; the field remained dormant for decades from the organic electrochemistry point of view. The recent resurgence in this field and its rising popularity could be attributed to the realization of its inherent advantages in the form of innate sustainability, mild reaction conditions, controlling the selectivity by just fine-tuning the potential applied, oxidant-free, employing traceless electrons as the reagents and many others. The ever-growing demand for medicines has made the pharmaceutical industry the front-runners in the generation of hazardous contaminants and waste products in enormous amounts. The multi-step synthetic protocols, usage of metal catalysts in stoichiometric amounts and toxic solvents, and poor atom economy, are some of the limitations associated with the trivial synthesis of important APIs. Therefore, these routes need to be revisited and redesigned with an aim to have their minimal hazardous footprints on the environment. Paracetamol (acetaminophen) is a century-old analgesic and represents the N-aryl amides of medicinal importance. Despite the relative structural simplicity, the conventional routes of this API which are industrially accepted are still based on the multi-step protocols employing stoichiometric amounts of deleterious oxidants. Again, the problem of regioselectivity results in the comparable generation of unwanted ortho-isomer. All these problems with its synthesis and the demand (medicine of every pocket) have put considerable negative pressure on the environment. If we look at the structure of paracetamol, it is phenol with an acetamide group at the para-position. The electrochemical oxidation of phenol is well known. Also, the Ritter-(type) reaction is an elegant tool in organic chemistry to install an acetamide group in a molecule. Taking these considerations in mind, we anticipated the electrochemical acetamidation of phenol at the para-position using acetonitrile (MeCN)as the source for nitrogen. Delightfully, under our electrochemical conditions, the electrolysis of phenol in MeCN selectively acetamidated at the p-C(sp2)-H of phenol and delivered the desired paracetamol in moderate yield under mild conditions. This direct synthesis of paracetamol from phenol using traceless electrons as the reagents mitigates most of the corrosive limitations of the conventional protocols. However, the problem in the conversion of starting material in the scale-up was observed (almost 10-15 % of phenol was remaining unconsumed in the gram scale experiment). We believe that these problems could be addressed by flow electrolysis. The viability of the protocol was further demonstrated on a variety of phenols with different electronics and sterics. Surprisingly, the para-selectivity of the protocol was found so high that the p-methylphenol furnished the dearomatized quinine product instead of the expected ortho-isomer. Moreover, the protocol was found compatible with various sensitive functional groups like aldehydes, ketones, etc. A patent (application number IN202211006501) has been filed for this novel route of paracetamol synthesis.