Synthetic strategies for 5- and 6-membered ring azaheterocycles facilitated by iminyl radicals

The author thanks EaStCHEM for financial support.The totality of chemical space is so immense that only a small fraction can ever be explored. Computational searching has indicated that bioactivity is associated with a comparatively small number of ring-containing structures. Pyrrole, indole, pyridine, quinoline, quinazoline and related 6-membered ring-containing aza-arenes figure prominently. This review focuses on the search for fast, efficient and environmentally friendly preparative methods for these rings with specific emphasis on iminyl radical mediated procedures. Oxime derivatives, particularly oxime esters and oxime ethers, are attractive precursors for these radicals. Their use is described in conventional thermolytic, microwave-assisted and UV-vis based preparative procedures. Photoredox catalyzed protocols involving designer oxime ethers are also covered. Choice can be made amongst these synthetic strategies for a wide variety of 5- and 6-membered ring heterocycles including phenanthridine and related aza-arenes. Applications to selected natural products and bioactive molecules including trispheridine, vasconine, luotonin A and rutaecarpine are included.Publisher PDFPeer reviewe

Cycloadditions to 1-azetines and 1-azetin-4-ones

1-Azetines (1) have until recently been unknown. Prepared for the first time in 1967, they since have met with little interest. The azetine system is a thermolabile one, as to be expected from a strained four-membered ring incorporating a C=N bond.1,3-Dipolar cycloadditions and [4+2] cycloadditions to the C=N bond of 1-azetines would yield bi-cyclic systems of related structure to the beta-lactam nucleus of beta-lactam antibitics.Thus, three 1-azetine systems (2-4) were prepared by alkylation of their precursor azetidinones and thioazetidinones.The ability of these systems to enter into cycloaddition reactions with a variety of 1,3-dipoles and dienes was investigated.Nitrile oxides (5) and nitrile ylides (7) were found to add smoothly to the 1-azetine systems to yield the bicyclic adducts (6) and (8) respectively.Nitrile imines (9) also add to 1-azetines in a similar fashion to yield the bi-cyclic adduct (10). In some cases, however, these adducts were found to undergo a rearrangement reaction to the bi-cyclic triazoles (11).Attempted [4+2] cycloadditions using electron rich and electron deficient dienes to 1-azetines were unsuccesful.In an extension of this work, addition of 1,3-dipoles to l-azetin-4-one (12) was also attempted, in a bid to establish a new route to the highly sought after beta-lactam antibiotics. Unfortunately, azetinone (12) was found to be unreactive towards both nitrile oxides and imines.This lack of reactivity of azetinone (12) is believed to be due to steric hinderance by the geminal ¿-butyl groups. Hence, several attempts were made to synthesise an azetinone species free of these constraints were made. This work remains incomplete, and is expected to attract further research.Finally, some work was done to investigate the effectiveness of aryl iminophosphoranes (13) as precursors to a variety of heterocyclic systems, including 1,3-benzoxazoles, 1,4- benzoxazines, and benzodiazepines

Metal-catalyzed 1,3-dipolar cycloaddition reactions of nitrile oxides

In the present review advances in the metal-catalyzed 1,3-dipolar cycloaddition reactions of nitrile oxides, mainly in the last decade, will be presented and discussed. An overview on the structure, preparation, dimerization and related reactions as well as the relevant aspects in the cycloaddition chemistry of nitrile oxides (including mechanistic aspects) have also been considered

An investigation into reactivity and selectivity in cycloadditions of 1,3-dipoles with formamidines

The objective of this research was to investigate the synthesis of nitrile oxides and to study their reactivity in 1,3-dipolar cycloadditions with formamidines. Chapter one looks at the literature surrounding the 1,3-dipolar cycloaddition reaction. It explores the generation of 1,3-dipoles (mainly nitrile oxides) and dipolarophiles (predominantly amidines). It discusses the potential synthetic uses of the 1,3-dipolar cycloadducts. It examines both and inter- and intra-molecular cycloaddition reactions. It recognises the use of the 1,3-dipolar cycloadditions as a successful method in building natural products and oxadiazolines. The decomposition of oxadiazolines as a route to nitriles is also outlined in this chapter. Chapter two discusses the results of this research candidate. The preparation of nitrile oxide precursors - hydroximoyl halides - is outlined at first. The generation of nitrile oxides is then demonstrated, followed by the preparation of furoxans. Methods for preparing the reference materials (nitriles and ureas), which result from decomposition of oxadiazolines, then follow. The preparation of series of Δ2-1,2,4- oxadiazolines via the 1,3-dipolar cycloaddition reaction is illustrated in this chapter. The selectivity of the addition of nitrile oxides to dipolarophiles was tested by competition reactions, which are also described in this chapter. NMR techniques were used in the study of the kinetics of the 1,3-dipolar cycloadditions used for the preparation of a series of Δ2-1,2,4-oxadiazolines, which is addressed in this chapter. Chapter three charts the experimental procedures followed to gain results which are discussed in chapter two. It also outlines all analytical data produced during the course of this research

Approaches to cyanoisocyanide and related systems

Imperial Users onl

Exploring new synthetic routes towards cyanamides

This thesis describes the development of new routes towards the synthesis of cyanamides. Cyanamides are present in a range of biologically active compounds and are useful functional groups for the synthesis of many interesting compounds such as guanidines, ureas, isoureas and many varieties of heterocycles. A range of methods for the synthesis of cyanamides exist, however the most common technique is utilising cyanogen bromide and amines. The technique is effective and vast arrays of cyanamides can be accessed in one step. However, cyanogen bromide is highly toxic and poses a significant safety risk. In recent times new methods have been developed to avoid cyanogen bromide, however many of these techniques are operationally complex or use other highly toxic compounds. In this work three new methods for the synthesis of cyanamides have been developed. A new method for cyanamide synthesis using trichloroacetonitrile as a less toxic and safer to handle cyano source has been developed. A range of cyanamides can be formed in an operationally simple one-pot two-step procedure. This technique provides complementary selectivity to cyanogen bromide. It has also been applied to the synthesis of a biologically active PDE4 inhibitor. The one-pot deoxycyanamidation of alcohols has been developed using N-cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS) as a sulfonyl transfer reagent and cyano source accessing a range of tertiary cyanamides. An array of tertiary cyanamides were accessed, including aniline type, which could not be accessed with TCAN. This approach exploits the under-developed desulfonylative (N-S bond cleavage) reactivity pathway of NCTS. A novel cyanamide and allenamide moiety, N-allenyl cyanamides have been synthesised. Utilising the deoxycyanamidation process, propargyl alcohol and a range of sulfonamides could be reacted to access an array of aryl substituted N-allenyl cyanamides. In addition, this moiety was investigated as a novel chemical building block accessing a range of otherwise challenging to access bespoke cyanamides by hydroarylation, hydroamination, [4+2] and [2+2] cycloadditions