Free-Wilson Analysis of Comprehensive Data on Phosphoinositide-3-kinase (PI3K) Inhibitors Reveals Importance of N-Methylation for PI3Kδ Activity.

Phosphoinositide-3-kinase δ (PI3Kδ) is a critical regulator of cell growth and transformation and has been explored as a therapeutic target for a range of diseases. Through the exploration of the thienopyrimidine scaffold, we have identified a ligand-efficient methylation that leads to remarkable selectivity for PI3Kδ over the closely related isoforms. Interrogation through the Free-Wilson analysis highlights the innate selectivity the thienopyrimidine scaffold has for PI3Kδ and provides a predictive model for the activity against the PI3K isoforms.

N-Heterocyclic carbene adducts of the heavier group 15 tribromides. Normal to abnormal isomerism and bromide ion abstraction.

The reactivity of the heavier group 15 tribromides, SbBr3 and BiBr3, towards 1,3-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene (IPr) is described. These reactions quantitatively afford Lewis acid-base adducts, (IPr)EBr3 (E = Sb 1; Bi 2), which readily react with AlBr3 yielding cationic species [(IPr)EBr2]+ (E = Sb 3; Bi 4). Under thermal treatment, the N-heterocyclic carbene ligands in 1 and 2 will readily isomerise to afford the abnormally-bonded (or mesoionic) complexes (aIPr)EBr3 (E = Sb 5; Bi 6). As with 1 and 2, bromide abstraction from such compounds readily affords the cationic complexes [(aIPr)EBr2]+ (E = Sb 7; Bi 8). Finally, in an effort to elucidate the isomerisation process which allows for the conversion of 1 and 2 to the abnormally bonded systems (compounds 5 and 6), compound 1 was reacted with a further equivalent of IPr to afford the cationic species [(aIPr)2SbBr2]+ (9). This strongly suggests that the normal to abnormal isomerisation of the N-heterocylic carbene ligands in compounds 1 and 2 is mediated by the presence of free IPr. Compound [9]Br can be used to access the dicationic species [(aIPr)2SbBr]2+ (10), which we have identified spectroscopically. Single crystal X-ray structures and spectroscopic data for all compounds are discussed.

N-heterocyclic carbene induced reductive coupling of phosphorus tribromide. Isolation of a bromine bridged P-P bond and its subsequent reactivity.

The room temperature reaction of a 1 : 1 mixture of phosphorus tribromide (PBr3) and the N-heterocyclic carbene 1,3-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene (IPr) quantitatively affords the Lewis acid-base adduct (IPr)PBr3 (1). Interestingly, when 1 is heated between 55 and 65 °C for a period of several days, dark red crystals slowly begin to form in the reaction vessel accompanied by the release of bromine. The resulting crystalline sample, [P2(IPr)2Br3]Br ([2]Br), results from the reductive coupling of two equivalents of 1, and contains a cationic moiety with a P-P bond that is bridged by a bromine atom. Anion exchange reactions with Na[BArF4] (BArF4 = B(3,5-{CF3}2C6H3)4) afford [2][BArF4]. Abstraction of two equivalents of bromine allows for the isolation of the unprecedented dicationic species [P2(IPr)2Br2]2+ (3) which was isolated and structurally authenticated as two different [BArF4]- salts. Reaction of 2 with mild reductants such as SnBr2 or tetrakis(dimethylamino)ethylene (TDAE) affords [P2(IPr)2Br]+ (4) and the known radical cation [P2(IPr)2]˙+ (5), respectively. These studies show that relatively weak P-Br bonds present in compounds 1-4 can be cleaved in a straightforward manner to afford low oxidation state compounds in high yields.

Alkali metal salts of ditopic carbanionic carbenes as reagents for the synthesis of novel complexes of group 12 and 14 metals.

Reaction of the lithiated N-heterocyclic carbene [:C[N(2,6-(i)Pr2C6H3)]2(CH)CLi]n (LiIPr) with KO(t)Bu in diethylether (Et2O) afforded the novel organo-potassium compound [:C[N(2,6-(i)Pr2C6H3)]2(CH)CK(THF)2] (KIPr·2THF). Both LiIPr and KIPr can be interpreted as ditopic carbanionic carbenes (or alkali metal salts of anionic "dicarbenes") and are interesting precursors for the synthesis of novel metal complexes bearing carbanionic carbenes as ligands. Reaction of KIPr with M[N(SiMe3)2]2 (M = Zn, Sn) afforded salts of the anionic three coordinate complexes [M{C(CH)[N(2,6-(i)Pr2C6H3)]2C:}{N(SiMe3)2}2](-) (M = Zn (1) and Sn (2)). Contrasting reactivity was observed for the other group 14 bis-amide compounds M[N(SiMe3)2]2 (M = Ge, Pb), which initially appear to yield analogous 1 : 1 complexes (M = Ge (3) and Pb (4)), however over time give rise to compounds bearing two ditopic carbanionic carbenes ([M{C(CH)[N(2,6-(i)Pr2C6H3)]2C:}2{N(SiMe3)2}](-); Ge (5) and Pb (6)) and the tris-amide anions ([M{N(SiMe3)3}](-)), presumably via a Schlenk-type equilibrium. Compounds 5 and 6 can be directly synthesized by reacting M[N(SiMe3)2]2 (M = Ge, Pb) with two equivalents of KIPr, respectively.