This literature review focuses on the thermal rearrangement of O-aryl thiocarbamates to yield the corresponding S-aryl thiocarbamates: the Newman-Kwart rearrangement. The purpose of the review is to highlight the utility of the rearrangement which provides a key step in an efficient route to convert phenols into thiophenols. The scope of the Newman-Kwart rearrangement is illustrated by way of numerous examples of its application to the preparation of Ar-S species ranging from large-scale industrial processes through to the synthesis of complex organic molecules such as ligands and supramolecular structures. The review contains 238 references and covers just over 40 years of the literature, from the first reports of the rearrangement by Edwards and Pianka in 1965 up to mid-2007. 1 Introduction 2 The Newman-Kwart Rearrangement (NKR) 2.1 Background and History 2.2 Preparation of O-Aryl Thiocarbamates for NKR and Subsequent Cleavage 2.3 Mechanism of Rearrangement 2.4 Nonclassical Conditions for Rearrangement 2.5 Allylic and Benzylic Rearrangements 2.
The synthesis and biochemical evaluation of a series of oxadiazole derivatives of imidazobenzodiazepines related to the benzodiazepine antagonist Ro 15-1788 (2a) are reported. Although the oxadiazole ring is seen as an isosteric replacement for the ester linkage, significant differences in structure-activity trends were observed. Specifically, oxadiazoles 9-12 invariably had increased receptor efficacy (as witnessed by measurements of the GABA shift) relative to the corresponding ester. Additionally, and in direct contrast to the classical agonists such as diazepam, affinity for the benzodiazepine receptor was enhanced by a 7- rather than 8-halo substituent. The results are discussed in terms of a six-point receptor-binding model originally based on the X-ray structure of 2a. For comparison, the crystal structures of two representative oxadiazole derivatives, 10h and 12o, having a 6-oxo and 6-phenyl group, respectively, were determined and the data incorporated into a modified binding model to account for the greater efficacy of these compounds. It is concluded that the antagonist behavior of 2a relies upon the hydrogen-bond-acceptor properties of the ester carbonyl oxygen whereas for the oxadiazole series this site is localized at the imidazole nitrogen.
The synthesis and biochemical evaluation of a series of indole oxadiazole 5-HT3 antagonists are described. The key pharmacophoric elements have been defined as a basic nitrogen, a linking group capable of H-bonding interactions, and an aromatic moiety. The steric limitations of the aromatic binding site have been determined by substitution about the indole ring. Variation of the heterocyclic linking group has shown that while two hydrogen-bonding interactions are possible, only one is essential for high affinity. The environment of the basic nitrogen has been investigated and shown to be optimal when constrained within an azabicyclic system. These results have been incorporated into a proposed binding model for the 5-HT3 antagonist binding site, in which the optimum distance between the aromatic binding site and the basic amine is 8.4-8.9 A and the steric limitations are defined by van der Waals difference mapping.
We present here an informed estimate of the millions of parameter settings that might be required to optimise one typical transition-metal-catalysed reaction. We describe briefly how both Design of Experiments (DoE) and Principal Component Analysis (PCA) techniques may be combined to reduce the number of potential reaction settings to a practical number of experiments without losing critical information. A key feature of this approach is the ability to relate discrete or discontinuous parameters to one another. The methodology is presented so that any reaction may be assessed in a similar way. We believe this represents for the first time an informed estimate of the number of potential permutations that are possible for these types of reactions in particular, and therefore the enormity of the task in optimising them. The powerful combination of DoE and PCA applied systematically and in an experimentally directed approach is beneficial for optimising reactions, particularly challenging transition-metal-catalysed reactions. However, this approach is beneficial to all reactions, especially when dealing with discrete parameters, such as solvents for example.
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