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 impractial. Here, we...
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.
The monoylide-phosphines show a linear correlation between their donor strength and their activity in gold-catalysed hydroaminations, while steric congestions leads to lower activities of the diylide congeners despite their higher donor properties.
The ylide‐functionalized diisopropyl phosphine (prYPhos) promotes Pd‐catalyzed Suzuki‐Miyaura couplings of aryl chlorides and bromides with arylboronic acids. Using Pd2(dba)3/prYPhos as the catalyst and K2CO3 as the base, various (hetero)biaryls were synthesized in 45–98% yields at mild reaction conditions, tolerating sensitive functional groups and steric hindrance. The electron rich, sterically demanding ligand induces a high selectivity for halides versus triflate. Chloroaryl triflates were selectively coupled at the chloride, leaving inherently more reactive triflate groups in place.
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 Cy
2
PCl (
L1
) and Cy(Flu
Me
)PCl (
L2
, with Flu
Me
= 9-methylfluorenyl)
and were characterized in both solution and solid states. The smaller
PCy
2
-substituted ligand,
L1
, readily formed
the biscoordinate
L1
2
Pd
species when treated with Pd
2
(dba)
3
and showed
no activity in palladium-catalyzed amination reactions even when applied
as defined palladium(II) η
3
-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.
Hydrogen donors and acceptors in 5-fluorouracil allow the formation of co-crystalline compounds with nontoxic co-formers of the GRAS list and an alternative target-oriented synthon approach from methanol or ethanol to form II of 5-fluorouracil is presented.
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.
The synthesis of bulky, ortho-substituted triarylamines often represents a synthetic challenge, but is highly desirable due to the use of these compounds in organic electronics. Here, we report on a...
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