Aza-MBH reaction

In related work, Sasai developed several bifunctional BINOL-derived catalysts for the aza-Morita-Baylis-Hillman (aza-MBH) reaction [111]. In early studies, careful optimization of the catalyst structure regarding the location of the Lewis base unit revealed 41 as an optimal catalyst for the aza-MBH reaction between acyclic a,P-unsaturated ketones and N-tosyl imines. Systematic protection or modification of each basic and acidic moiety of 41 revealed that all four heterofunctionalities were necessary to maintain both chemical and optical yields. As seen in Scheme 5.58, MO calculations suggest that one hydroxyl groups forms a... 

M. Shi and Y.-L. Shi reported the synthesis and application of new bifunctional axially chiral (thio) urea-phosphine organocatalysts in the asymmetric aza-Morita-Baylis-Hillman (MBH) reaction [176, 177] of N-sulfonated imines with methyl vinyl ketone (MVK), phenyl vinyl ketone (PVK), ethyl vinyl ketone (EVK) or acrolein [316]. The design of the catalyst structure is based on axially chiral BINOL-derived phosphines [317, 318] that have already been successfully utilized as bifunctional catalysts in asymmetric aza-MBH reactions. The formal replacement of the hydrogen-bonding phenol group with a (thio)urea functionality led to catalysts 166-168 (Figure 6.51). 

Scheme 6.159 Representative products obtained from the 166-catalyzed asymmetric aza-MBH reaction between N-sulfonated imines a,(i-unsaturated ketones and acrolein.

Scheme 6.160 Mechanistic proposal for the 166-catalyzed aza-MBH reaction using benzoic acid as additive.

S)-3-(A-Isopropyl-A-3-pyridinylaminomethyl)BINOL (4) has been established as an efficient asymmetric bifunctional organocatalyst for the aza-MBH reaction.23 The acid-base functionalities cooperate in substrate activation and fixing of the organocatalyst conformation to promote the reaction with high enantiocontrol. 

While THF or CH2CI2 are the most commonly used solvents, the solubility of the reagents or the catalyst may dictate the use of other solvents. Reactions are usually slow in DMF and in CH3CN when DABCO, DBU or DMAP were used as catalysts. An often-observed byproduct of the aza-MBH reaction is a bridged compound of type 97. This product is the result of a stepwise addition of 95 to 75 via the Mannich reaction, followed by an intramolecular conjugated addition (Michael addition) of the formed anion to the a,/ -unsaturated ketone, and thus due to the elevated basicity of the catalyst (Scheme 5.21) [92]. 

Scheme 5.21 Product and byproducts in the tertiary amine-catalyzed aza-MBH reaction of 95 and 75.

Scheme 5.22 The mechanistic model of the aza-MBH-reaction. EWG = electron-withdrawing group.

As discussed previously for the MBH reaction, the aza-MBH reaction involves rate-limiting proton transfer in the absence of added protic species (Scheme 5.22) [93]. In contrast to the MBH reaction, however, the aza-MBH exhibits no autocatalysis. Bronsted acidic additives lead to substantial rate enhancements through acceleration of the elimination step. It has been shown that phosphine catalysts - either alone or in combination with protic additives - may trigger epimerization of the aza-MBH product by proton exchange at the stereogenic center. This fact indicates that the spatial arrangement of a bifunctional chiral catalyst in this reaction is crucial not only for the stereodifferentiation within the catalytic cycle but also to prevent subsequent epimerization. 

As in the MBH reactions, / -ICD (44) is also an efficient and remarkably general catalyst in aza-MBH reactions [94, 95]. This catalyst promotes the addition a variety of electron-deficient olefins such as acrylates, enones, and enals with activated aromatic aldimines. Of note, the absolute stereochemistry of the product is generally opposite compared to the analogous MBH reaction with / -ICD catalyst imines gives rise to (S)-enriched adducts, in contrast to aldehydes which afford ( -products [94]. Substitution patterns of the olefin may alter or even invert this trend, however. 

Table 5.11 The /MCD-mediated aza-MBH reaction of diphenyl-phosphinoyl imines and HFPA.

Table 5.12 The / -1 CD-mediated aza-MBH reaction of tosyl aldimines and acrylates.

ICD mediated the addition of aryl methylbenzenesulfonamides, such as 105, to ethyl or methyl vinyl ketones in MeCN DMF (1 1) mixtures at a lower temperature (—30 °C) [95a]. The reaction afforded products with (R) absolute configuration (Table 5.13). Of note, this situation was opposite to that observed in the related aza-MBH reaction with acrylonitrile with acryl aldehyde or with acrylates. Related N-mesyl or N-SES-protected imine afforded similar results. 

Table 5.14 The BINOL-dimethylaminopyridine hybrid catalyst-mediated aza-MBH reaction.

Table 5.15 Chiral thioureas 114 and DABCO-mediated aza-MBH reaction.

Scheme 5.24 Bifunctional chiral phosphines as catalysts in the aza-MBH reaction with imines and MVK.

Aza-MBH reactions of alkyl or aryl acrylates, as well as acrolein, required higher reaction temperatures than were required with MVK or EVK. While phenyl- or naphthyl acrylates afforded products in CH2C12 with ee-values up to 69%, the best solvent in the addition of acrolein to activated aldimines proved to be THF (Scheme 5.25) [100]. 

Table 5.16 The 119a-mediated aza-MBH reaction of aryl tosylated imines with MVK and EVK.

Table 5.17 The 119f-mediated aza-MBH reaction with of aldimines with cyclohexenone and cyclopentenone. 

The Hatakeyama group later reported the use of catalyst 103 for the asymmetric aza-MBH reactions of HFIPA with activated aromatic imines [96]. The aza-MBH reactions of four different diphenylphosphinoyl aryl imines (109) with HFIPA were promoted using 10 mol% 103 and afforded the corresponding a-methylene-/ -amino acid derivatives (110) in reasonable yields (42-97%) and moderate -values (54-73% Scheme 6.13). Aliphatic imines were not suitable substrates for the reaction due to imine lability. (For experimental details see Chapter 14.10.3). 

Table 6.34 Bifunctional BINOL-promoted aza-MBH reactions of aldimines.

General Procedure for the / -ICD-Mediated Asymmetric Aza-MBH Reaction ofTosyl Aryl Aldimines and Methyl Acrylate [44] (pp. 177 and 233)... 

Typical Procedure for the Bifunctional BINOL-Promoted Aza-MBH Reactions of Aldimines [45] (pp. 179 and 234)... 

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]. 

Meanwhile, Leitner and coworkers monitored the aza MBH reaction of methyl vinyl ketone (MVK) with N tosylated imine in the presence of P Ph 3 in TH F dg at room temperature by NMR spectroscopy [10]. The rate law was derived by analyzing the initial rates as a function of concentration for the individual components. The broken order of 0.5 in imine indicated that the rate determining step was partially influenced by proton transfer. A variety of Bronsted acidic additives with different p/<., values were examined with 3,5 bis(CF3)phenol at pKa 8 corresponding to a 14 fold rate enhancement as compared to the reaction without additive. Examination of the kinetics in the presence of phenol as prototypical additive revealed that the rate law of the reaction changed in the presence of the Bronsted acid, showing first order dependence on imine. Thus, the elimination step was not involved in the... 

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