MBH reactions

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... 

Figure 6.7 Hydrogen-bonding (thio)ureas screened in the DABCO-promoted MBH reaction between benzaldehyde and methyl acrylate the pseudo-first-order rate constants relative to the uncatalyzed reaction are given in h . ...

Scheme 6.29 Range of products for the DABCO-promoted MBH reaction utilizing urea derivative 16 as hydrogenbonding organocatalyst. The results of the uncatalyzed reference reactions are given in parentheses.

Figure 6.9 Bifunctional 3-amino quinuclidine derivatives 30 and 31 and DABCO probed in the MBH reaction between methyl acrylate and o-chlorobenzaldehyde.

Scheme 6.107 Product range of the 106-catalyzed asymmetric MBH reaction between aldehydes and 2-cyclohexen-l-one.

Scheme 6.108 Proposed mechanistic picture for the 106-catalyzed MBH reaction affording (R)-adducts (A) and monofunctional thiourea 107 displaying low catalytic activity (B).

Figure 6.34 Bis-(thio)ureas 111-114 derived from IPDA and results of the screening in the DABCO-promoted MBH reaction between cyclohexanecarbaldehyde and 2-cyclohexen-1-one under neat conditions at 10°C.

Scheme 6.110 Typical products of the 114-catalyzed MBH reaction between various aldehydes and 2-cyclohexen-l-one as well as 2-cylopenten-l-one.

Scheme 6.151 Range of allylic alcohols prepared from 145-catalyzed MBH reactions of2-cyclohexene-l-one with various aldehydes.

Figure 6.49 Binaphthyl-derived tertiary amine-functionalized bifunctional thiourea derivatives screened in the MBH reaction between 2-cyclohexen-l-one and 3-phenylpropionaldehyde at rt in dichloromethane.

Scheme 6.154 Proposed catalytic cycle for the binaphthyl amine thiourea-promoted MBH reaction of aldehydes with 2-cyclohexen-l-one revealing the bifunctional mode of action of catalyst 148, 149, and 150.

Scheme 6.155 Representative products resulting from enantioselective MBH reactions catalyzed by binaphthyl thiourea 148.

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.

Scheme 6.163 Product range of the asymmetric MBH reaction catalyzed by bisthiourea 176 in the presence of DABCO.

Enones with a pendant aldehyde, RC(=0)-CH=CH-(CH2)2-CH0, have been cyclized via an intramolecular MBH reaction in a study of the influence of Michael acceptor stereochemistry on yield.164 Using triphenylphosphine as catalyst, the Z-isomer consistently gave 2.5-8.5 times higher yield of the product (55), using reaction times of 1-3 days. It is unclear whether this is due to the relative accessibility of the /3-positions of the isomers to the nucleophilic catalyst, or differential stability in the enolate intermediates. 

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. 

The Morita-Baylis-Hillman (MBH) reaction is the formation of a-methylene-/ -hydroxycarbonyl compounds X by addition of aldehydes IX to a,/ -unsaturated carbonyl compounds VIII, for example vinyl ketones, acrylonitriles or acrylic esters (Scheme 6.58) [143-148]. For the reaction to occur the presence of catalytically active nucleophiles ( Nu , Scheme 6.58) is required. It is now commonly accepted that the MBH reaction is initiated by addition of the catalytically active nucleophile to the enone/enoate VIII. The resulting enolate adds to the aldehyde IX, establishing the new stereogenic center at the aldehydic carbonyl carbon atom. Formation of the product X is completed by proton transfer from the a-position of the carbonyl moiety to the alcoholate oxygen atom with concomitant elimination of the nucleophile. Thus Nu is available for the next catalytic cycle. 

The reaction sequence depicted in Scheme 6.58 also illustrates several problems associated with the MBH reaction. Addition to aldehyde IX can be slow, and side-reactions such as base-induced polymerization of the a,//-unsaturated carbonyl compound can occur. Furthermore, generation of diastereomeric (i.e. E/Z) enolates can complicate matters if enantioselective addition to the aldehyde component is desired. In principle, formation of a stereogenic center at the aldehydic carbonyl C-atom can be steered by (i) use of a chiral a,/ -unsaturated carbonyl compound [149, 150] (ii) use of a chiral aldehyde and (iii) use of a chiral nucleophilic cata-... 

In the presence of Lewis acids such as BF3-Et20 thioethers promote the MBH addition to enones also [159]. Goodman et al. synthesized the C2-symmetric chiral thioether 152 and used it in the MBH addition of a variety of aldehydes to MVK (Scheme 6.64) [160]. As summarized in Scheme 6.64, enantiomeric excesses up to 49% were achieved in this MBH reaction. Interestingly, only very short reaction times (30-120 min) were needed, albeit at overstoichiometric catalyst loading. 

Nucleophilic amines or alkyl phosphines can mediate the addition of electron-deficient alkenes to reactive carbonyls such as aldehydes or ketones. This transformation, which affords functionalized allylic alcohols, is generally termed the Morita-Baylis-Hillman (MBH) reaction (Scheme 5.1) [1, 2]. 

Scheme 5.1 The general reaction scheme of the Morita-Baylis-Hillman (MBH) reaction.

Table 5.1 The effect of Bronsted acid co-catalysts on the rate of the MBH reaction.

DMAP) [27], imidazoles [28], guanidine [29], azole [30], and N-methylpiperidine [31] were also used successfully in non-asymmetric MBH reactions. 

The low reaction rates usually associated with the MBH reaction can be increased either by pressure [15a, 22, 34], by the use of ultrasound [35] and micro-wave radiation [14a], or by the addition of co-catalysts. Various intra- or inter-molecular Lewis acid co-catalysts have been tested [26, 36, 37] in particular, mild Bronsted acids such as methanol [36, 57d], formamide [38], diarylureas and thioureas [39] and water [27a, 40] were examined and found to provide an additional acceleration of the MBH reaction rate (Table 5.1). 

Typically, MBH reactions are conducted at or just below room temperature. The rate of product formation can be increased by warming the reaction mixture above room temperature, though the yields are usually not greater than those achieved when the reaction is run at room temperature [41]. At elevated temperatures, polymerization of the acrylate becomes a viable alternative indeed, the formation of this byproduct makes purification of the desired MBH adducts difficult and should, if at all possible, be avoided. 

The influence of solvents was extensively studied [38, 40b, 42], with reactions shown capable of being performed in neat, or, virtually in any polar medium. Whilst high dielectric constant oxygenated solvents such as tetrahydrofuran (THF), 1,4-dioxane, acetone (Et20), dimethyl sulfoxide (DMSO), and dimethyl-formamide (DMF) are used in non-asymmetric MBH reactions, dichloroethane (CH2C12) or acetonitrile are preferred for asymmetric transformations. MBH re-... 

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-... 

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