Baylis-Hillman reaction mechanism

A fundamentally different approach to the synthesis of 3-pyrrolines is evidenced in the annulation in Eq. 13.50 [58]. Ethyl 2,3-butadienoate 150 reacts with N-sulfony-limine 151 in the presence of triphenylphosphine under very mild conditions to give JV-protected 3-pyrroline 152 in 90% yield. The mechanism that has been postulated is related to that of the Baylis-Hillman reaction. Michael addition of triphenylphosphine to the allenyl ester generates a zwitterion that combines with the imine to give 153 in a non-concerted process. This is followed by ring closure, proton exchange and expulsion of triphenylphosphine to give 152. This annulation is successful only for aromatic or cinnamyl imines [59]. 

In the proposed mechanism (Scheme 9), the rate-determining step is the reaction between aldehyde and enolate. In the absence of a solvent, a major issue with this reaction is the typical low rate and the need for a high concentration of catalyst (usually DABCO). It was reported recently that, under basic conditions, the ionic liquid [BDMIM][PF6] is inert and that the Baylis Hillman reaction in [BDMIMjPFg proceeds smoothly with better yields than in [BMIMjPFg (163). 

A series of A - / - n i trobe nzenesul fony 1 imincs have been reported to undergo asymmetric aza-Morita-Baylis-Hillman reactions with methyl acrylate mediated by DABCO in the presence of chiral thiourea organocatalysts with unprecedented levels of enantioselectivity (87-99% ee), albeit only in modest yields (25 19%). Isolation of a DABCO-acrylate-imine adduct as a key intermediate, kinetic investigation, and isotopic labelling, have been employed to determine the mechanism.177... 

The widely accepted mechanism of amine catalysis of the Baylis-Hillman reaction... 

The mechanism of the Baylis-Hillman reaction has been re-evaluated in terms of implications in asymmetric catalysis.39 These studies have shown that in the absence of added protic species, the initial stage of the Baylis-Hillman involves rate-limiting proton transfer. 

In a different study, based on the reaction rate data collected in aprotic solvents, the Morita-Baylis-Hillman reaction has been found to be second order in aldehyde and first order in DABCO and acrylate. On the basis of these data, a new mechanism has been proposed, involving a hemiacetal intermediate (110). The proposed mechanism is further supported by two different kinetic isotope effect experiments.145... 

According to another NMR study, the mechanism of bifunctional activation in the asymmetric aza-Morita-Baylis-Hillman reaction (Scheme 7) involves rate-limiting proton transfer (116) in the absence of added protic species155 (in consonance with the report summarized in Scheme 5144), but exhibits no autocatalysis. Addition of Brpnsted acids led to substantial rate enhancements through acceleration of the elimination step. Furthermore, it was found that phosphine catalysts, either alone or in combination with protic additives, can cause racemization of the reaction product by proton exchange at the stereogenic centre. This behaviour indicates that the spatial arrangement of a bifunctional chiral catalyst for the asymmetric aza-Morita-Baylis-Hillman reaction is crucial not only for the stereodifferentiation within the catalytic cycle but also for the prevention of subsequent racemization.155... 

Warren and coworkers have reported an interesting synthesis of nonracemic allenes by reaction of vinylphosphine oxides with aldehydes in the presence of chiral lithium [(R)-l-phenylethyl](benzyl)amide to give hydroxyvinylphosphine oxides in 33-87% yields (0-51% ee) [38]. These products underwent a Horner-Wittig elimination reaction to produce nonracemic allenes. A mechanism similar to the Baylis-Hillman reaction was suggested. 

Polyhaloalkyl-substituted chromones and 7-pyrones react with salicylaldehydes in the presence of piperidine to give a variety of fused 277-chromenes in good yields (Scheme 58) <2006JOC4538>. Although it is conceivable that this reaction could proceed through a Baylis-Hillman reaction pathway, studies of this reaction point to the mechanism being a tandem intramolecular oxa-Michael addition and subsequent Mannich condensation. 

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 currently accepted mechanism of the Baylis-Hillman reaction involves a Michael addition of the catalyst (tertiary amine) at the (3-position of the activated alkene to form a zwitterionic enolate. This enolate reacts with the aldehyde to give another zwitterion that is deprotonated, and the catalyst is released. Proton transfer affords the final product. 

Propose a mechanism for the following formation of the aza Morita Baylis Hillman reaction product that is obtained from an a hydroxypropargylsilanc (1) and the N tert butanesulfinyl imine. Provide the structure of intermediate A obtained upon slow addition of n BuLi to ( ) 1. 

This chemistry can be used to initiate sequential (cascade) cyclizations. From a Morita-Baylis-Hillman reaction and protection of the resulting hydroxyl we have prepared the triene 12. Treatment of 12 with a catalytic amount of CpCr(CO)3H under H2 for 6d gave the cyclization product 16 in 23% isolated yield, presumably by the mechanism in Scheme 1.11 [53]. 

A Baylis-Hillman reaction was used for the construction of novel arylfuran scaffolds. In a typical example, when phenanthrene-9,10-dione (1.0 mM) was treated with methyl vinyl ketone (3.0 mM) in the presence of titanium tetrachloride (1.0 mM) in dichloromethane at room temperature, 2-methylphenanthro[9,10-i>]furan-3-carboxaldehyde was obtained. A mechanism for the formation of these compounds is discussed in the article <01TL1147>. 

This reaction is very closely related to the Baylis-Hillman Reaction, and is also related to Stetter Reaction and Benzoin Condensation in mechanism. 

The Morita-Baylis-Hillman reaction is, in general, a carbon-carbon bondforming reaction of an a,(3-unsaturated compound with an aldehyde mediated by an organic nucleophilic base resulting in the formation of an allylic alcohol. Morita reported the use of a phosphine as catalyst and Baylis and Hillman used a tertiary amine. Variation of the electrophile to electron-deficient alkenes in a Michael-Michael elimination sequence leads to homo- and heterodimerisation and is known as the Rauhut-Currier reaction. The electrophilic aldehyde could be substituted by an imine or derivative in the aza-Morita-Baylis-Hillman reaction. Recently, there has been an increase in the use of this reaction for the construction of many different targets using many different amine derived catalysts. Scheme 2.2 shows a general view of this reaction and the accepted mechanism. ... 

Scheme 2.2 Proposed mechanism for the Morita-Baylis-Hillman reaction.

The Wang group also realized enantioselective oxidative cross-coupling reactions between tertiary amines and the activated olefins by merging Cu(OTf)2 with quinine as the best cooperative catalysts/ A Morita-Baylis-Hillman-type mechanism is in operation. It was notable that molecular oxygen was employed as the sole oxidant. As shown in Scheme 2.12, the reactions between Ai-aryl THIQs and the a,p-unsaturated aldehydes or ketones 30 proceeded smoothly to afford the a-functionalized products 31 in up to 81% yield and 99% ee. 

Plata, R. E., Singleton, D. A. (2015). A Case Study of the Mechanism of Alcohol-Mediated Morita Baylis-Hillman Reactions. The Importance of Experimental Observations. Journal of the American Chemical Society, 137(11), 3811-3826. 

Reaction of zwitterion 21 with the aldehyde produces another zwitterion, 24, which after proton transfer and loss of the platinum moiety generates the product 25. This mechanism is very similar to the Morita Baylis-Hillman reaction of classic organic chemistry, which is the condensation of an aldehyde... 

ESI Study of mechanism of aza-Morita-Baylis-Hillman reaction Regiani et al. [31 7]... 

Santos, L.S., Pavam, C.H., Almeida, W.P, Coelho, F., Eberlin, M.N. (2004) Probing the Mechanism of the Baylis-Hillman Reaction by Electrospray Ionization Mass and Tandem Mass Spectrometry. Angew. Chem. Int. Ed. 43 4330-4333. 

Carrasco-Sanchez, V, Simirgiotis, M.J., Santos, L.S. (2009) The Morita-Baylis-Hillman Reaction Insights into Asymmetry and Reaction Mechanisms by Electrospray Ionization Mass Spectrometry. Molecules 14 3989-4021. 

Gilman reaction dimethyl cuprate undergoes C-C bond coupling with methyliodide in the Gas Phase the preferred mechanism for Cu involves the formation of a T-shaped Cu transition state. Heck reaction key ionic intermediates of the Heck reaction of arene diazonium salts were intercepted and structurally characterized. Baylis-Hillman reaction protonated intermediates in the catalytic cyde of the Baylis-Hillman reaction between an activated alkene and an electrophile were intercepted and characterized, providing dired evidence for the currently accepted mechanism. 

Probing the mechanisms of nonmetal-catalyzed reactions by ESI-MS/MS have also been carried out by chemists. Eberlin and coworkers have described the use of ESI-MS for the interception and characterization of the organocatalytic intermediates in the DABCO-catalyzed Baylis-Hillman reaction (Scheme 4.5) [19]. Through the ESI-MS study, most proposed intermediates were successfully intercepted and characterized as protonated species, which provided strong evidence for the currently accepted catalytic cycle. In addition, the Baylis-Hillman reaction catalyzed by Lewis adds [20] and dissolved in ionic liquids [21] has also been investigated by Eberlin and coworkers. 

Scheme 4.5 ESI-MS study of the mechanism of Baylis-Hillman reaction catalyzed by DABCO.

Scheme 5.22 Mechanism of Baylis-Hillman reaction of methyl ac late and aldehydes catalyzed by DABCO. The protonated species expected to be intercepted and strurturally characterized by ESI + )-MS/MS, with their respective m/z ratios.

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