Baylis–Hillman reaction
The product is densely functionalized, joining the alkene at the α-position to a reduced form of the electrophile (e.g. in the case of an aldehyde, an allylic alcohol).
Hill and Isaacs performed the first kinetic experiments in the 1990s, discovering that the reaction rate between acrylonitrile and acetaldehyde was first-order in each reactant and in the DABCO catalyst.
[4] However, Hoffman's mechanism rationalizes neither the product's autocatalysis nor (in the reaction of aryl aldehydes with acrylates) the considerable generation of a dioxanone byproduct.
Moreover, it showed a significant kinetic isotope effect for the acrylate's α-hydrogen (5.2 in DMSO, but ≥2 in all solvents), which would imply that proton abstraction is the rate-determining step.
In support of this contention, Aggarwal and Harvey modeled the two pathways using density functional theory calculations and showed that the computed energy profile matches the experimental kinetic isotope effects and observed rate of reaction.
On the other hand, Coelho and Eberlin et al have obtained electrospray-mass-spectroscopy data that is structural evidence for two different forms of the reaction's proton transfer step.
[14] For example, reaction between sterically hindered t-butyl acrylate and benzaldehyde with catalytic DABCO in the absence of solvent required 4 weeks to give moderate conversion to the final product.
[14] In the sila-MBH reaction, α-silylated vinyl aryl ketones couple to aldehydes in the presence of catalytic TTMPP, a large triarylphosphine reagent.
For example, cyclization of α,β-unsaturated aldehydes can be performed in the presence of proline derivative and acetic acid, affording enantioenriched products.
For example, in the three-component coupling of aldehydes, amines, and activated alkenes, the aldehyde reacts with the amine to produce an imine prior to forming the aza-MBH adduct, as in the reaction of aryl aldehydes, diphenylphosphinamide, and methyl vinyl ketone, in the presence of TiCl4, triphenylphosphine, and triethylamine:[19] Likewise, activated acetylenes can undergo conjugate addition and remain an activated alkene for the MBH reaction, as in the following enantioselective cyclization reaction in which a phenolate nucleophile adds to a functionalized enyne before aza-MBH ring closure catalyzed by a chiral amine base.
When an acrylate substituted with the Oppolzer's sultam reacted with various aldehydes in the presence of DABCO catalyst, optically pure 1,3-dioxan-4-ones were afforded with cleavage of the auxiliary (67-98% yield, >99% ee).
Cyclopentenone and various aromatic and aliphatic aldehydes undergo an asymmetric reaction using Fu's planar chiral DMAP catalyst in isopropanol (54-96% yield, 53-98% ee).
[28] BINOL-derived chiral phosphine catalyst is also effective for an asymmetric aza-MBH reaction of N-tosyl imines with activated alkenes such as methyl vinyl ketone and phenyl acrylate.
[29] In addition, a distinct class of chiral phosphine-squaramide molecules could effectively catalyze an intramolecular asymmetric MBH reaction.
Chiral cationic oxazaborolidinium catalysts were shown to be effective in the three-component coupling of α,β-acetylenic esters, aldehydes, and trimethylsilyl iodide (50-99% yield, 62-94% ee).
La(OTf)3 and camphor-derived chiral ligands could induce enantioselectivity in a DABCO-catalyzed MBH reaction of various aldehydes and acrylates (25-97% yield, 6-95% ee).
[32] La(O-iPr)3 and BINOL-derived ligand system, in conjunction with catalytic DABCO, also works for an asymmetric aza-MBH reaction of various N-diphenylphosphinoyl imines and methyl acrylate.
[38] With (S)-proline and DABCO, α-amido sulfones and α,β-unsaturated aldehydes undergo a highly enantioselective aza-MBH reaction (46-87% yield, E/Z 10:1-19:1, 82-99% ee).
