Cross coupling reactions
(basics)
Cross coupling is a metal-catalyzed reaction where 2 different hydrocarbon fragments R1 & R2 are coupled
Mostly Pd(0)-complexes are used as catalysts for cross-coupling
General Mechanism & elementary steps
All transistion metal catalyzed cross coupling rxn follow the same general mechanism:
a moiety R1-X adds to the activated TM complex & increases the oxidation state by 2 (oxidative addition)
The organic part of an organometallic compound Y-R2 is transferred to the catalyst (transmetallation)
2 coordinated organic moieties couple & dissociate from the catalyst —> catalyst is reduced (reductive elimination)
rate of oxidative addition with Pd(0) increases with
rate of oxidative addition with Pd(0) increases with decreasing C-X bond strength
Kumada cross coupling
Coupling of an aryl- or alkenyl-halide with Grignard reagents
Use of Ni or Pd
stereochemistry of cis alkene is retained!
Kumada cross-coupling
coupling of a aryl- or alkenyl-halide with a grignard reagent with Ni or Pd as catalyst
aryl- or alkenyl-halide with Grignard reagent and Ni or Pd as catalyst
reaction of aryl- or alkenyl-halide with grignard reagent and Ni or Pd as catalyst
Kumada cross coupling —> reaction of aryl- or alkenyl-halide with Grignard reagent
—> reaction of aryl- or alkenyl-halide with Grignard reagent:
Kumada cross coupling:
Reaction of Aryl- or Alkenyl-halide with Grignard reagent:
Reaction of aryl- or alkenyl-Halide with Grignard reagents
reaction of Aryl-, Alkenyl-Halide with Grignard reagent
stereospecific
reaction of Grignard reagent with aryl-/alkenylhalide
cross coupling of aryl- or alkenyl-halide with grignard reagent with use of Pd as catalyst.
Stereospecific!
as catalyst:
Grignard + aryl-/Alkenyl-Halide with Ni or Pd catalyst
Grignard + alkenyl-Halide with Ni or Pd catalyst
Grignard + alkenylhalide with Ni / Pd catalyst —> cross coupled product
Reaction of Grignard + alkenylhalide with help of Ni catalyst —> crosscoupled product R1-R2
disadvantage of Kumada cross coupling
Grignard reagents are strong bases and can therefore react with a large variety of functional groups.
Kumada cross coupling is limited to molecules that don’t contain these functional groups.
Negishi coupling
cross coupling between organozinc compounds with halides and use of Pd(0) as catalyst
Negishi cross coupling (RZnX)
reactivity is between Grignard reagents (hard, more reactive) and stannanes (soft, less reactive)
Negishi coupling still limited, as starting material (organozinc species) has to be prepared by transmetallation of Grignard reagents or organolithium compounds
stille coupling
Stille cross couplilng (RSnBu3) describes the palladium-catalyzed coupling of organostannanes (organotin compounds) with aryl-, alkenyl-, & acyl- halides.
mild reaction conditions
high functional group tolerance
stability of organostannanes make it a useful reaction for the build-up of complex molecules
disadvantage of toxicity
disadvantage of possible contamination of the product with Bu3SnX
Butyl ligands are dummy ligands that do not take part in the reaction as they transmetallate very slowly
Stille cross coupling (RSnBu3)
reaction of organotin compounds with aryl, alkenyl, acyl halides
Stille coupling (RSnBu3)
organotin compound with halide
other possibilities:
Kumada coupling (Grignard + halide)
Negishi coupling (organozinc + halide)
coupling between organotin compounds ann halides
other possibilities (as no other functional groups are present (concerning reactivity)):
Stille coupling (RSnBu3 + X)
cross coupling between toluene-SnBu3 with Ph-Br with Pd-catalyst
Stille cross coupling (RSnBu3 + RX)
Stille cross coupling (RSnBu3 + R-X) high functional group tolerance
Stille cross coupling
Stille cross coupling (intramolecular)
Suzuki-Miyaura cross coupling
cross coupling between organoborons and halides
probably most commonly used in industry
inorganic byproducts can be removed more easily
less toxic than tin (Sn) than stille rxn
boronic acid has to be activated by nucleophilic base (NaOH) to promote the formation of boronate (tetracoordinated boron species)
cross coupling of alkyl groups is generally limited due to unwanted beta-hydride elimination.
Suzuki rxn can be performed with alkylboranes, which are easily made from hydroboration of the respective alkenes.
drawback:
limited stability of boronic acid: under aqueous conditions, boronic acids are prone to undergo proto-deborylation —> often excess of boronic acid needed
stability problem has been overcome by developement of potassium alkyltrifluoroborates (KR-BF3) —> stable to air and humidity (no excess needed as stable (but stochiometric))
Suzukui rxn
cross coupling of organoboron compounds with halides
Suzuki cross coupling between organoboron compounds with halides and base needed
Suzuki cross coupling
between organoboron and halide with activation through base and Pd as catalyst
organoboron + halide —> coupling product with use of Pd catalyst and base
problem of instability of boron species is solved due to trifluoroborates
halide + organoborane + Pd-cat. + base for activation (no water) —> cross coupled alkyl with halide
suzuku cross coupling with organoboron compounds —> alkyl coupling with halide
Pd-Catalyst
Base for activation of transmetallation
Suzuki rxn
Halide + organoboron + Pd-cat. + Base (activation) —> cross coupled product
halide + organoboron compound with Pd catalyst and Base for acitvation
Hiyama cross coupling
coupling between organosilanes and aryl-, alkenyl, alkyl halides or triflates with Pd as catalyst + activation by base or fluoride anion in order to undergo transmetallation
rate of reaction depends on the substituents of the silicon atom:
only few examples with -SiMe3
Increased reactivity can be achieved by using silanes bearing alkoxy or fluoro substituents (R = -OR, or -F)
reaction between silane and halide with Pd as catalyst and CsF —> Fluor ion for the activation of the transmetallation
reaction between halide and silane with Pd as catalyst and CsF as activation for transmetallation
silane + halide with Pd as catalyst and CsF as activation for transmetallation —> cross coupling
silane + halide with Pd catalyst and CsF as activation for transmetallation —> cross coupling
Sonogashira coupling
coupling between aryl-/vinyl halides/triflates and terminal alkynes
Important differences:
not only Pd(0) required as catalyst but also a Cu(I) salt in most cases
instead of metal-vinyl, metal-aryl species (aryl boronic acid), a terminal alkyne is used
stochiometric amount of base (mostly amine bases like Et2NH) is crucial to deprotonate the activated alkyne
Cu(I) coordinates to terminal aklyne —> more acidic
proton removed by base (Et2NH) and Cu-acetylide formed
Transmetallation: Acetylide transferred to Pd, forming trans-alkynyl- / vinyl- / aryl- Pd(II) complex
Reductive elimination: Product is eliminated from the cis complex —> Pd(0) complex formation
oxidative addition: Pd(0) complex inserts in the sp^2-X bond, completing the catalytic cycle
coupling between halide and terminal alkyne with help of Pd(0) catalyst and Cu(I) for transmetallation
DIPEA
Diisopropylethylamine
halide and terminal alkyne —-> Pd(0) + Cu(I) —> cross coupled product
halide + terminal alkyne with Pd(0) + Cu(I) —> cross coupled product
Sonogashira cross coupling
Buchwald-Hartwig cross coupling
direct Pd-catalyzed C-N, C-O, C-S bond formation between aryl halides/triflates and amines
or between aryl halides/triflates and alcohols
in the presence of stochiometric amount of base.
Strong base (KOtBu, LiHMDS) is used to generate the corresponding metal amide in situ.
application:
TBDPS: protecting group
aryl halide + amine/alcohol —> C-N/C-O formation
Ullmann Biaryl ehter/amine synthesis
Ullmann condensation
harsh conditions
stochiometric amount of Cu
reflux (high temperature)
Last changed25 days ago
