Morita-Baylis-Hillman reaction mechanism

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... 

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... 

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). 

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]. 

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]... 

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. 

Unfortunately this means the research of the mechanism of enantio-selection of many other reactions presented in this book can hardly be considered complete, and this problem has recently been discussed using the Morita-Baylis-Hillman reaction as an example. ... 

The kinetics of the aza-Morita-Baylis-Hillman reaction have been studied for a range of imine substrates in various solvents, using triphenylphosphine as catalyst, and p-nitrophenol as a Brpnsted acid co-catalyst. The effects of varying the phosphineiphenol catalyst ratio on the rate indicate interdependence between them. This and the solvent effects support reversible protonation of zwitterionic intermediates within the mechanism. ip-NMR and quantum calculations also support such a route. 

Another condensation-elimination sequence consists in a modification of the Morita-Baylis-Hillman reaction which provides dienes bearing an electron-withdrawing group (cyano or ester) in the 2-position 137 (Scheme 61) [122], Its mechanism begins as in a classical Morita reaction but a 1,2-proton shift occurs before the elimination of the phosphonium, leading to an intermediate ylide that condenses readily on a second aldehyde molecule. 

As shown in Equation (17), 2-trimethylsilyloxyfuran also participated in a triphenylphosphine-catalyzed substitution reaction with Morita-Baylis-Hillman acetates to provide interesting 7-butenolides regio- and diastereoselec-tively <2004AGE6689>. However, the reaction mechanism (vinylogous Michael vs. Diels-Alder) has not been distinguished. 

Chen and coworkers employed the cinchona alkaloid-derived catalyst 26 to direct Mannich additions of 3-methyloxindole 24 to the A-tosylimine 25 to afford the all-carbon quaternary center of oxindole 27 with good enantioselectivity (84% ee) [22]. The outcome of this Mannich reaction is notable in that it provided very good selectivity for the anti diastereomer (anti/syn 94 6). The mechanism of asymmetric induction has been suggested to involve a hydrogen bonding network between the cinchona alkaloid 26, the oxindole enolate of 24, and the imine electrophile 25 (Scheme 7). Asymmetric allylic alkylation of oxindoles with Morita-Baylis-Hillman carbonates has been reported by the same group [23]. 

This catalyst was involved in the development of a new asymmetric orga-nocatalytic domino reaction of a,p-unsaturated aldehydes and p-keto esters following a Michael addition-Morita-Baylis-Hillman mechanism." As shown in Scheme 1.38, the formed cyclohexenone products were obtained in moderate to good yields and with high stereoselectivities for a wide range of substrates. 

A related approach for the synthesis of spirocyclopenteneoxindoles was developed by Barbas and coworkers. Chiral diphosphines catalyzed the [3+2] cycloaddition between the A-protected methyleneindolin-2-ones 17b and the Morita-Baylis-Hillman (MBH) carbonates 37 [18]. This reaction was initiated by the displacement of the carbonate moiety by the phosphine VI, an addition-elimination mechanism, which was followed by the deprotonation to afford ylide 39. A regioselective nucleophilic addition on 17 by 39, followed by an intramolecular conjugate addition, afforded intermediate 40 that, after elimination of PR3, delivered the corresponding spirocycle 41 (Scheme 10.11). 

A review of the Morita-Baylis-Hillman (MBH) reaction has covered mechanism, activated olefins and electrophiles as substrates, multicomponent and intramolecular reactions, and the use of ionic liquid reaction media. ... 

---