MBH mechanisms

A NHC-catalyzed aza-Morita-Baylis-Hillman reaction (aza-MBH) following a standard nucleophile-mediated MBH mechanism has been disclosed very recently (He et al. 2007). Although combined with a preceding equilibrium for the reversible formation of imine-carbene adducts this reaction has similarities with phosphines and their organo-catalytic reactivity (Methot and Roush 2004). 

The first step of this unprecedented umpolung reaction is identical to the standard MBH mechanism. Only the tautomerization event differentiates between a- (enolate) and -functionalization (homoenolate). 

This new kinetic evidence has stimulated further theoretical studies on the MBH mechanism, conducted initially by Xu and Sunoj. Recently, Aggarwal performed an extensive theoretical study, which supported their own kinetic observations and those of McQuade about the proton transfer step. They proposed that the proton-transfer step can proceed via two pathways (i) addition of a second molecular of aldehyde to form a hemiacetal alkoxide (hemil) followed by rate-limiting proton transfer as proposed by McQuade (non-alcohol-catalyzed pathway) and (ii) an alcohol that acts as a shuttle to transfer a proton from the a-position to the alkoxide of int2 (Scheme 1.4). 

To investigate the MBH mechanism, Coelho and Eberlin et al. have also used electrospray ionization mass spectrometry [ESI-MS/MS)] to characterize key MBH reaction intermediates. Using ESI-MS-(/MS), they also shed light on the co-catalytic role of ionic liquids in MBH reactions. Stimulated by the... 

As it has been pointed out before, the mechanism of the organocatalyzed aldol reaction have been extensively studied. Conversely to this situation, the related MBH mechanism (Scheme 4.43) has been scarcely investigated probably due to the complexity of the reaction sequence. 

There have also been proposed MBH mechanisms in the presence of protic solvents and aprotic additives. For example, Aggarwal has suggested that a proton transfer from an alcohol to intermediate 23 delivers the six-membered transition state 24 which then leads to the protonated species 25. 

A Practical Introduction to Structure, Mechanism, and Data Analysis, VCH Publishers, Inc., New York, 1996 (c) H. Biss-wanger, Enzymkinetik, VCH Verlagsge-sellschaft mbH, Weinheim, 1994 ... 

Blodinger, J. (1982). Formulation of Veterinary Dosage Forms. Marcel Dekker, New York. Borowitz, J.L., Moore, P.F., Yim, G.K.W. and Miya, T.S. (1971). Mechanism of enhanced drug effects produced by dilution of the oral dose. Toxicol. Appl. Pharmacol. 19 164-168. Brandau, R. and Lippold, B.H. (1982). Dermal and Transdermal Absorption. Wissenschaf-tliche, Verlagsgesellschaft mbH, Stuttgart. 

Gremaud, G., Kulik, A., and Sathish, S. (1990). Mechanical properties of surfaces and layers measured with a continuous wave acoustic microscope. In Advanced materials and processes (ed. H. E. Exner and V. Schumacher), pp. 1421-6. DGM Informationsgesellschaft mbH, Oberursel. [23]... 

The mechanism of Morita-Baylis-Hillman (MBH) alkylation has been investigated.22 An MBH intermediate exhibiting unprecedented trans geometry of the phos-phonium salt and acyl group has been isolated for the first time. 

While many of the observed events of the MBH reaction could be included in this scheme, the mechanism failed in some critical cases [47]. First, the mechanism did not provide any clue as to why stereocontrol is so difficult in MBH reactions. Privileged nucleophilic chiral catalysts [48], which in the past have usually allowed good results in related asymmetric transformations, afforded only modest asymmetric induction. This fact was surprising, and pointed to lack of understanding of the basic factors governing the selectivity of the reaction. Other obser-... 

Cyclohexanediamine-derived amine thiourea 70, which provided high enantio-selectivities for the Michael addition [77] and aza-Henry reactions [78], showed poor activity in the MBH reaction. This fact is not surprising when one considers that a chiral urea catalyst functions by fundamentally different stereoinduction mechanisms in the MBH reaction, and in the activation of related imine substrates in Mannich or Streclcer reactions [80]. In contrast, the binaph-thylamine thiourea 71 mediated the addition of dihydrocinnamaldehyde 74 to cyclohexenone 75 in high yield (83%) and enantioselectivity (71% ee) (Table 5.6, entry 2) [79]. The more bulky diethyl analogue 72 displayed similar enantioselectivity (73% ee) while affording a lower yield (56%, entry 3). Catalyst 73 showed only low catalytic activity in the MBH reaction (18%, entry 4). 

Oppenlander, T. Photochemical Purification of Water and Air Advanced Oxidation Processes (AOPs) Principles, Reaction Mechanisms, Reactor Concepts, Vch Verlagsgesellschaft Mbh, 2003. 

In accordance with the generally accepted mechanism ofthe MBH reaction, the aza MBH reaction involves, formally, a sequence of Michael addition, Mannich type reaction, and (3 elimination. A commonly accepted mechanism is depicted in Scheme 13.2. A reversible conjugate addition of the nucleophilic catalyst to the Michael acceptor generates an enolate, which can intercept the acylimine to afford the second zvdtterionic intermediate. A proton shift from the a carbon atom to the P amide followed by P elimination then affords the aza M BH adduct with concurrent regeneration of the catalyst [5]. 

B.46 F. Loffler and J. Raasch, Grundlagen der Mechanischen Verfahrenstechnik (Fundamentals of Mechanical Process Engineering), Friedr. Viehweg Sohn Verlagsgesellschaft mbH, Braunschweig/Wiesbaden, Germany (1992). 

Isomerisation studies indicate that the iminium ion formed initially prior to isomerisation as the amount of ( ) product increased over time. Only the (Z) isomer was observed after 10 min. Notably, nonenolisable aldehydes i.e. acrylaldehyde and cinnamaldehyde) were unreactive, indicative of an enamine-type mechanism as opposed to a typical aza-MBH route. Several procedures for the asymmetric, proline-catalysed MBH reaction between methyl vinyl ketone (MVK) and aromatic aldehydes have been developed to date. ... 

The most likely mechanism of the MBH reaction catalyzed by tertiary phosphines is identical to that of the amine-catalyzed reaction except that the initially formed zwitterion 13 can isomerize to phosphorus ylide 14, which can then undergo a Wittig reaction to give olefins 15 (Scheme 1.5). The latter process may require elevated temperatures, since it is not observed in reactions such as the (aza)-MBH reaction involving the more reactive a,p-unsaturated ketones under mild conditions. 

This proposed mechanism has been supported by theoretical studies on the aza-MBH reaction between acrolein and mesyl imine catalyzed by tri-methylamine and trimethylphosphine. The relative energies of the crucial transition states for the PMe3-catalyzed reaction have been found to be lower... 

MBH reaction, it was assumed that a change of mechanism involving direct formation of the anion by abstraction of the a proton had taken place when a stoichiometric amount of butyllithium was employed. 

The iminium salt 199, generated in situ from bis(dimethylamino)methane and acetyl chloride, was found to react with methyl vinyl ketone in the absence of a catalyst to give the a-aminoalkylation product 200 in high yield (Scheme 1.76). ° The mechanism is similar to that of the MBH reaction, with chloride ion or a small amount of bis(dimethylamino)methane acting as the catalyst. 

At almost the same time, Hatakeyama et al. investigated the (3-ICD catalyzed aza-MBH reaction of various aryl diphenylphosphinoyl imines 146 and 1,1,1,3,3,3-hexafluoroisopropyl acrylate (HFIPA), affording the (S)-product 147, in up to 97% yields with high ees, in DMF at low temperature (Scheme 2.70). Notably, the absolute stereochemistry of the aza-MBH adducts is opposite to that of adducts obtained from the analogous MBH reaction. With (3-ICD as catalyst, imines give rise to (5)-enriched adducts, in contrast to aldehydes, which afford (i )-products. A plausible mechanism was proposed. Moreover, the utility... 

On the basis of all these transformations, Kataoka et al. have reinvestigated the products and reaction mechanism of the chalcogeno-MBH reaction. They found that, when purifying the product from the reaction of p-nitrobenzaldehyde with methyl vinyl ketone by column chromatography on silica gel, chloromethyl aldol 251a was obtained in 95% yield as a mixture of... 

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