No abstract

This article outlines the benefits of using 'Design of Experiments' (DoE) optimisation during the development of new synthetic methodology. A particularly important factor in the development of new chemical reactions is the choice of solvent which can often drastically alter the efficiency and selectivity of a process. Whilst solvent optimisation is usually done in a non-systematic way based upon a chemist's intuition and previous laboratory experience, we illustrate how optimisation of the solvent for a reaction can be carried out by using a 'map of solvent space' in a DoE optimisation. A new solvent map has been developed specifically for optimisation of new chemical reactions using principle component analysis (PCA) incorporating 136 solvents with a wide range of properties. The new solvent map has been used to identify safer alternatives to toxic/hazardous solvents, and also in the optimisation of an S(N)Ar reaction.

Herein, we report a novel intramolecular ring-closing reaction of biaryl thioethers that give access to highly functionalized dibenzothiophene sulfonium salts under mild conditions. The resulting precursors react regioselectively with [18F]fluoride to give [18F]fluoroarenes in predictable radiochemical yields. The strategy expands the available radiochemical space and provides superior labeling efficiency for clinically relevant PET tracers.

The present report discloses a modular synthetic route to a new type of anionic N-heterocyclic carbene ligand incorporating an enolate group as a reactive backbone component of its heterocyclic framework. The presence of such a reactive unit facilitates further tailoring of the ligand, even after its complexation to transition metals, with concomitant tuning of the electronic donor properties of the carbene center. Simple acylation of the formamidine Ar-NH-CHdNAr (1a,b) (a: Ar = mesityl (Mes); b: Ar = 2,6-diisopropylphenyl (DIPP)) by chloroacetyl chloride gives an acylated formamidine (2a,b), which undergoes a thermally induced cyclization to afford the 4-hydroxyimidazolium salt 3a,b. Single deprotonation by NEt 3 gives the zwitterionic imidazolium-4-olate 4, whereas double deprotonation by 2 equiv of LiHMDS gives the imidazolin-2-ylidene-4-olate ligand 5 -, which reacts with 0.5 equiv of [RhCl(1,5-COD)] 2 to give, after acidification with HCl, the complex [(5 H )RhCl(COD)] (7), in which the "acidified" carbene ligand noted "5 H " adopts the keto form. By contrast, treatment of 4 with electrophilic reagents E-X (E 1 = tBuCO; E 2 = Me; E 3 = Tf) results in the O-functionalized imidazolium derivatives [4 E1-3 ] þ X -, which can be subsequently complexed under the form of the carbene 5 E1-3 to give [(5 E1-3 )RhCl(COD)] (7 E1-3 ). Alternatively, the carbene ligand 5 can be post-functionalized from its complex [(5 H )RhCl(COD)] ( 7) by a simple sequence involving (i) base-induced deprotonation and (ii) addition of E-X, exemplified by the generation of [(5 E4-5 )RhCl(COD)] (7 E4-5 ) (with E 4 = Ph 2 PO; E 5 = tBuSiMe 2 (TBDMS)). In parallel, C-functionalization of the metal-bound ligand can be achieved from 7 by deprotonation with LiHMDS, leading to [(5 -)RhCl(COD)]Li(thf) n þ followed by a classical aldolization/elimination sequence leading to [(5 CH2 )RhCl(COD)] (8), in which the C5 carbon of the NHC bears a methylene group. Parallel direct transformations can be achieved after ligand complexation to copper, as exemplified by the generation of [(5 H )CuCl] (9) or [(5 E5 )CuCl] (9 E5 ) (E 5 = TBDMS). The donor properties of all the above NHC ligands were evaluated from the standard complexes (NHC)RhCl(CO) 2 against the classical IR ν(CO) scale. The resulting order of nucleophilicities for the modulated carbenes is 5 CH2 < 5 H , 5 E4 < 5 E1 < 5 E2 < 5 E5 , 5 -. The X-ray structures analyses of 7 E2 and 7 E4 are reported.

The 4-hydroxyimidazolium salt, readily prepared in two steps by acylation of a formamidine and quaternization of the second nitrogen, affords, after deprotonation, the anionic imidazol-2-ylidene-4-olate, which can be complexed to a transition metal and still be subsequently functionalized at O or C backbone atom in the outer coordination sphere of the metal.

PEPPSI complexes incorporating chiral N-heterocyclic carbene (NHC) ligands based on 2,2-dimethyl-1-(o-substituted aryl)propan-1-amines were synthesized. Two complexes, with one saturated and one unsaturated NHC ligand, were structurally characterized. The chiral PEPPSI complexes were used in asymmetric Suzuki–Miyaura reactions, giving atropisomeric biaryl products in modest to good enantiomeric ratios

Exceptional organic solvent tolerant ene-reductases mined from a drain metagenome library are highly versatile catalysts for difficult enones.

Herein, we report a silver-free Pd(II)-catalyzed C(sp)-H arylation of saturated bicyclic and tricyclic amine scaffolds. The reaction provides good yields using a range of aryl iodides and aryl bromides including functionalized examples bearing aldehydes, ketones, esters, free phenols, and heterocycles. The methodology has been applied to medicinally relevant scaffolds. Two of the intermediate palladium complexes in the catalytic cycle have been prepared and characterized, and a mechanism is proposed. Removal of the directing group proceeded with good yield under relatively mild conditions.