Synthesis of 4H-Benzo[e][1,3]oxazin-4-ones by a Carbonylation–Cyclization Domino Reaction of ortho-Halophenols and Cyanamide

A mild and convenient one-step preparation of 4H-1,3-benzoxazin-4-ones by a domino carbonylation–cyclization process is developed. Readily available ortho-iodophenols are subjected to palladium-catalyzed carbonylative coupling with Mo(CO)6 and cyanamide, followed by a spontaneous, intramolecular cyclization to afford 4H-1,3-benzoxazin-4-ones in moderate to excellent yields. Furthermore, the scope of the reaction is extended to include challenging ortho-bromophenols. Finally, to highlight the versatility of the developed method, Mo(CO)6 is successfully replaced with a wide array of CO-releasing reagents, such as oxalyl chloride, phenyl formate, 9-methylfluorene-9-carbonyl chloride, and formic acid, making this an appealing strategy for the synthesis of 4H-benzo[e][1,3]oxazin-4-ones

Fragment-oriented synthesis: β-elaboration of cyclic amine fragments using enecarbamates as platform intermediates

A strategy for the β-sp3 functionalisation of cyclic amines is described. Regioselective conversion of protected amines to enecarbamates is achieved through electrochemical oxidation; these intermediates can be derivatised by functionalised alkyl halides under photoredox catalysis. The potential of the methods is highlighted by direct growth of a DCP2B-binding fragment

From Heteroaromatic acids and Imines to Azaspirocycles : Stereoselective Synthesis and 3D Shape Analysis

Heteroaromatic carboxylic acids have been directly coupled with imines using T3P and NEt(i-Pr)2 to form azaspirocycles via intermediate N-acyliminium ions. Spirocyclic indolenines (3H-indoles), azaindolenines, 2H-pyrroles and 3H-pyrroles were all accessed using this metal-free approach. The reactions typically proceed with high diastereoselectivity and 3D shape analysis confirms that the products formed occupy areas of chemical space that are under-represented in existing drugs and high throughput screening libraries

Synthesis of fused indoline-cyclobutanone derivatives via an intramolecular [2+2] cycloaddition

We thank the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT, grant code EP/L016419/1, R.M.N.) for funding. We thank the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013) ERC grant agreement no. 279850 (A.D.S.). A.D.S. thanks the Royal Society for a Wolfson Research Merit Award. We also thank the EPSRC UK National Mass Spectrometry Service at Swansea. The research data supporting this publication can be accessed at https://doi.org/10.17630/00aff760-0732-438f-a9d1-30c7cf3a87a0A serendipitously-discovered process for the synthesis of heterocyclic products containing a novel fused indoline-cyclobutanone ring system is reported. This process is believed to take place through in situ generation of a ketene intermediate, followed by intramolecular [2+2] cycloaddition with a pendant enamide. The formation of a ketene intermediate in this process is significant as the reaction conditions employed are analogous to those commonly used in tertiary amine Lewis base catalysis, where the potential intermediacy of ketenes is an important consideration that is often overlooked.PostprintPeer reviewe

Synthesis of β-Lactams by Palladium(0)-Catalyzed C(sp3)−H Carbamoylation

A general and user-friendly synthesis of beta-lactams is reported that makes use of Pd-0-catalyzed carbamoylation of C(sp(3))-H bonds, and operates under stoichiometric carbon monoxide in a two-chamber reactor. This reaction is compatible with a range of primary, secondary and activated tertiary C-H bonds, in contrast to previous methods based on C(sp(3))-H activation. In addition, the feasibility of an enantio-selective version using a chiral phosphonite ligand is demonstrated. Finally, this method can be employed to synthesize valuable enantiopure free beta-lactams and beta-amino acids

Structural and synthetic insights into pyridine homocouplings mediated by a β-diketiminato magnesium amide complex

Reaction of [(DippNacnac)Mg(TMP)] (1) with 4‐subtituted pyridines proceeds via sequential regioselective metalation and 1,2‐addition to furnish a range of symmetric 4,4'R2‐2,2'‐bipyridines in good yield, representing a new entry into bipyridine synthesis. Interestingly, the reaction with of 1 with 2‐OMe‐pyridine led to formation of asymmetric bipyridine 6, resulting from the C6‐magnesiation of the heterocycle followed by a C‐C coupling step by addition to the C2 position of a second, non‐metallated molecule, and subsequent elimination of [DippNacnacMgOMe]2 (7). Synthesis combined with spectroscopic and structural analysis help rationalise the underlying processes resulting in the observed reactivity, and elucidates the key role of the sterically encumbered β‐diketiminate ligand plays in determining regioselectivity

Strategic Oxidative Dearomatization - Rearomatization Cascades in the Synthesis of Aromatic and Heteroaromatic Synthons

Four new synthetic methods employing an oxidative dearomatization - rearomatization strategy are presented. In Chapter 2, a new oxidative dearomatization - radical cyclization - rearomatization approach to form fused oxygen-containing heterocycles is presented. Origins, design, reaction, and optimizations are discussed. In Chapter 3, meta-selective alkylation of catechol mono-ethers is described employing an oxidative dearomatization - radical addition - rearomatization approach using trialkylboranes as source of alkyl radicals. In Chapter 4, a metal-free method to synthesize fluorinated indoles from aniline starting materials is described. Chapter 5 lays the groundwork for para-selective functionalization of catechol mono-ethers. Chapters 6 and 7 highlight the work related to pharmaceutical drug analyses. Chapter 6 presents the FDA approved drugs organized in Disease Focused Posters. Chapter 7.1 and 7.2 present the drug analysis of Sulfur- and Fluorine-Containing Drugs, and Nitrogen-Heterocycle Containing Drugs, respectively.Release after 01-Jul-201