Copper-Catalyzed Asymmetric Oxidation of Sulfides

Copper-catalyzed asymmetric sulfoxidation of aryl benzyl and aryl alkyl sulfides, using aqueous hydrogen peroxide as the oxidant, has been investigated. A relationship between the steric effects of the sulfide substituents and the enantioselectivity of the oxidation has been observed, with up to 93% ee for 2-naphthylmethyl phenyl sulfoxide, in modest yield in this instance (up to 30%). The influence of variation of solvent and ligand structure was examined, and the optimized conditions were then used to oxidize a number of aryl alkyl and aryl benzyl sulfides, producing sulfoxides in excellent yields in most cases (up to 92%), and good enantiopurities in certain cases (up to 84% ee)

Cocrystallization of Nutraceuticals

Cocrystallization has emerged over the past decade as an attractive technique for modification of the physicochemical properties of compounds used as active pharmaceutical ingredients (APIs), complementing more traditional methods such as salt formation. Nutraceuticals, with associated health benefits and/or medicinal properties, are attractive as coformers due to their ready availability, known pharmacological profile, and natural origin, in addition to offering a dual therapy approach. Successful studies of favorably altering the physicochemical properties of APIs through cocrystallization with nutraceuticals are highlighted in this review. Many of the key functional groups commonly seen in nutraceuticals (e.g., acids, phenols) underpin robust supramolecular synthons in crystal engineering. This review assesses the structural data available to date across a diverse range of nutraceuticals, both in pure form and in multicomponent materials, and identifies the persistent supramolecular features present. This insight will ultimately enable predictive and controlled assembly of functional materials incorporating nutraceuticals together with APIs

Crystal Landscape of Primary Aromatic Thioamides

The crystal landscape of a series of primary aromatic thioamides is described, displaying similar characteristic intermolecular hydrogen-bonding interactions in the solid state to those observed in their widely studied amide analogues, including R₂²(8) dimers and C(4) chains. In a number of cases, high <i>Z</i>′ values were observed in the structures. On the basis of the observed solid-state features, the thioamide functional group, which is a strong hydrogen-bond donor and moderate acceptor, offers considerable potential as a key moiety for crystal engineering

Crystal Landscape of Primary Aromatic Thioamides

The crystal landscape of a series of primary aromatic thioamides is described, displaying similar characteristic intermolecular hydrogen-bonding interactions in the solid state to those observed in their widely studied amide analogues, including R₂²(8) dimers and C(4) chains. In a number of cases, high <i>Z</i>′ values were observed in the structures. On the basis of the observed solid-state features, the thioamide functional group, which is a strong hydrogen-bond donor and moderate acceptor, offers considerable potential as a key moiety for crystal engineering

Asymmetric Synthesis of <i>cis</i>-7-Methoxycalamenene via the Intramolecular Buchner Reaction of an α-Diazoketone

The asymmetric synthesis of <i>cis</i>-7-methoxycalamenene <b>1</b> has been accomplished using the intramolecular Buchner reaction of α-diazoketone <b>7</b> as the key step in the synthetic route. Upon reduction of the equilibrating azulenone structure <b>8</b>, the resulting azulenol <b>9</b> rearranges to dihydronaphthalene <b>10</b> containing the 6,6-membered bicyclic ring system characteristic of <b>1</b>, by means of an acid-catalyzed aromatization process. Transformation of <b>10</b> to <b>1</b> is accomplished through a three-step reaction sequence

Diversity in a simple co-crystal: racemic and kryptoracemic behaviour

The crystal structure containing (+/-)-3-methyl-2-phenylbutyramide with salicylic acid is the first example of a kryptoracemate co-crystal. It exhibits the first temperature mediated reversible single-crystal to single-crystal transition between two kryptoracemate forms, in addition to crystallising in another, racemic, form. Theoretical calculations and structural analysis reveal that there are only small differences in both energy and packing arrangements between the three forms. These results suggest that co-crystals can be an opportunity to investigate kryptoracemate behaviour.The crystal structure containing (+/-)-3-methyl-2-phenylbutyramide with salicylic acid is the first example of a kryptoracemate co-crystal. It exhibits the first temperature mediated reversible single-crystal to single-crystal transition between two kryptoracemate forms, in addition to crystallising in another, racemic, form. Theoretical calculations and structural analysis reveal that there are only small differences in both energy and packing arrangements between the three forms. These results suggest that co-crystals can be an opportunity to investigate kryptoracemate behaviour

Investigating CS···I Halogen Bonding for Cocrystallization with Primary Thioamides

Cocrystallization utilizing halogen bonding involving the thiocarbonyl functional group of a series of primary aromatic thioamides has been investigated. The well-known organoiodide 1,4-diiodotetrafluorobenzene was utilized as the halogen bond donor and the CS···I halogen bond was established as a robust supramolecular synthon in these systems. Weak N–H···S hydrogen bonding involving the thioamides influences the overall supramolecular architectures, meaning that there is a diverse range of structural motifs and cocrystal stoichiometries observed. The majority (60%) of the cocrystals obtained have a 2:1 ratio of thioamide/organiodide with the latter present over an inversion center. The higher ratio of organoiodide seen in the other cocrystals is achieved by additional I···I and I···π halogen bonding. The CS···I halogen bond is replaced by N···I halogen bonding in the one cocrystal containing a pyridyl-substituted thioamide. The ability of the thioamides to form cocrystals and the strength of the halogen bond were influenced by the nature of the substituents on the aromatic ring, with derivatives containing electron donating groups most likely to form cocrystals. Calculated molecular electrostatic potential values on the sulfur atom in the thioamides corroborate these experimental results

Design and Synthesis of Ternary Cocrystals Using Carboxyphenols and Two Complementary Acceptor Compounds

A strategy combining a ditopic hydrogen-bond donor with two different hydrogen-bond acceptor molecules is proposed for the assembly of simple trimeric building blocks used in the construction of ternary cocrystals. The crystallization of each of three different low symmetry carboxyphenols (3-hydroxybenzoic acid, 6-hydroxy-2-naphthoic acid, and ferulic acid) with acridine and 2-amino-4,6-dimethylpyrimidine yielded ternary cocrystals where the three components are joined by phenol-pyridine and carboxylic acid-amidine synthons. The use of p<i>K</i>_a values, beta values, and synthon histories in the selection of the acceptor compounds is discussed. Significant challenges to the growth of the desired ternary products from solution were presented by competing crystalline phases, including the individual components, a variety of binary phases, salts, and hydrates. Molecular electrostatic potentials were used to analyze the donating and accepting abilities of the competing synthons

Synthesis of Cyclic α‑Diazo-β-keto Sulfoxides in Batch and Continuous Flow

Diazo transfer to β-keto sulfoxides to form stable isolable α-diazo-β-keto sulfoxides has been achieved for the first time. Both monocyclic and benzofused ketone derived β-keto sulfoxides were successfully explored as substrates for diazo transfer. Use of continuous flow leads to isolation of the desired compounds in enhanced yields relative to standard batch conditions, with short reaction times, increased safety profile, and potential to scale up

Understanding the p-toluenesulfonamide / triphenylphosphine oxide crystal chemistry: a new 1:1 cocrystal and ternary phase diagram

A novel 1:1 cocrystal between p-toluenesulfonamide and triphenylphosphine oxide has been prepared and structurally characterized. This 1:1 cocrystal was observed to form during solid state grinding experiments, with subsequent formation of a known 3:2 cocrystal in the presence of excess sulfonamide. Both cocrystals are stable in the solid state. The ternary phase diagram for the two coformers was constructed in two different solvents: acetonitrile and dichloromethane. Examination of these diagrams clarified solution crystallization of both the newly discovered 1:1 cocrystal and the previously reported 3:2 cocrystal, and identified regions of stability for each cocrystal in each solvent. The choice of solvent was found to have a significant effect on the position of the solid state regions within a cocrystal system