RESUMO
Palladium-catalyzed couplings of silicon enolates with aryl electrophiles are of great synthetic utility, but often limited to expensive bromide substrates. A comparative experimental study confirmed that none of the established ligand systems allows to couple inexpensive aryl chlorides with α-trimethylsilyl alkylnitriles. In contrast, ylide functionalized phosphines (YPhos) led to encouraging results. A statistical model was developed that correlates the reaction yields with ligand features. It was employed to predict catalyst structures with superior performance. With this cheminformatics approach, YPhos ligands were tailored specifically to the demands of Hiyama couplings. The newly synthesized ligands displayed record-setting activities, enabling the elusive coupling of aryl chlorides with α-trimethylsilyl alkyl nitriles. The preparative utility of the catalyst system was demonstrated by the synthesis of pharmaceutically meaningful α-aryl alkylnitriles, α-arylcarbonyls and biaryls.
RESUMO
Ylide-substituted phosphines (YPhos) have been shown to be highly electron-rich and efficient ligands in a variety of palladium catalyzed transformations. Here, the synthesis and characterization of novel YPhos ligands containing a cyclic backbone architecture are reported. The ligands are easily synthesized from a cyclic phosphonium salt and the chlorophosphines Cy2PCl (L1) and Cy(FluMe)PCl (L2, with FluMe = 9-methylfluorenyl) and were characterized in both solution and solid states. The smaller PCy2-substituted ligand, L1, readily formed the biscoordinate L1 2 Pd species when treated with Pd2(dba)3 and showed no activity in palladium-catalyzed amination reactions even when applied as defined palladium(II) η3-allyl, t-Bu-indenyl, or cinnamyl precursors. Bulkier fluorenyl-substituted ligand L2 similarly was inactive, despite its ability to form the stable monophosphine complex L2·Pd(dba). Assessment of the electronic properties by experimental and computational methods revealed that L1 and L2 are considerably less electron-rich than previously synthesized YPhos ligands. This was shown to be the result of the small P-C-S bond angle, which is sterically enforced due to the cyclic nature of the backbone. Density functional theory calculations revealed that the small angle results in an increased s-character of the lone pair at the ylidic carbon atom and leads to a polarization of the C-P bond toward the carbon atom, thus decreasing the electron density at the phosphorus atom. The results demonstrate the tunability of the donor strength of YPhos ligands by modification of the ligand backbone beyond simple changes of the substitution pattern and are thus important for future ligand design, with a careful balance of many factors to be considered to achieve catalytic activity.
RESUMO
The implementation of gold catalysis into large-scale processes suffers from the fact that most reactions still require high catalyst loadings to achieve efficient catalysis thus making upscaling impractical. Here, we report systematic studies on the impact of the substituent in the backbone of ylide-substituted phosphines (YPhos) on the catalytic activity in the hydroamination of alkynes, which allowed us to increase the catalyst performance by orders of magnitude. While electronic changes of the ligand properties by introduction of aryl groups with electron-withdrawing or electron-donating groups had surprisingly little impact on the activity of the gold complexes, the use of bulky aryl groups with ortho-substituents led to a remarkable boost in the catalyst activity. However, this catalyst improvement is not a result of an increased steric demand of the ligand towards the metal center, but due to steric protection of the reactive ylidic carbon centre in the ligand backbone. The gold complex of the thus designed mesityl-substituted YPhos ligand YMesPCy2, which is readily accessible in one step from a simple phosphonium salt, exhibited a high catalyst stability and allowed for turnover numbers up to 20 000 in the hydroamination of a series of different alkynes and amines. Furthermore, the catalyst was also active in more challenging reactions including enyne cyclisation and the formation of 1,2-dihydroquinolines.
RESUMO
The coupling of aryl chlorides with Reformatsky reagents is a desirable strategy for the construction of α-aryl esters but has so far been substantially limited in the substrate scope due to many challenges posed by various possible side reactions. This limitation has now been overcome by the tailoring of ylide-functionalized phosphines to fit the requirements of Negishi couplings. Record-setting activities were achieved in palladium-catalyzed arylations of organozinc reagents with aryl electrophiles using a cyclohexyl-YPhos ligand bearing an ortho-tolyl-substituent in the backbone. This highly electron-rich, bulky ligand enables the use of aryl chlorides in room temperature couplings of Reformatsky reagents. The reaction scope covers diversely functionalized arylacetic and arylpropionic acid derivatives. Aryl bromides and chlorides can be converted selectively over triflate electrophiles, which permits consecutive coupling strategies.
