MBH adducts

At 20mol% loading of 114, with DABCO (20mol%), and under solvent-free conditions the desired MBH adducts 1-6 were obtained in very different yields (22-100%) and enantioselectivities (34—96%) (Scheme 6.110). Generally, ahphatic aldehydes gave higher ee values than aromatic aldehydes independent of the enone. 

Lattanzi screened various amino alcoUiol derived thioureas in the enantioselec-tive Morita-Baylis-HiUman model reaction between cyclohexenecarbaldehyde and 2-cyclohexene-l-one (MBH adduct 1 Scheme 6.151) under solvent-free... 

A new tandem Michael-aldol reaction of a,ft-unsaturated compounds bearing a chalcogenide or thioamide group with electrophiles has been reviewed.163 The product o -(o -hydroxyalkyl)enones - Morita-Baylis-Hillman (MBH) adducts - can be formed with significant stereocontrol when an optically active thione is used. 

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. 

In the past years, only a few reports have dealt with a chiral auxiliary induced diastereoselective aza MBH reaction. In 1994, Kiindig et al. explored the reaction of methyl acrylate and acrylonitrile with enantiopure planar chiral o substituted Cr(CO)3. Under the catalysis of DABCO, the corresponding aza MBH adducts were obtained in good yields. Removal of the metal provided chiral amines in high yields and enantiomeric excesses [12]. Later on, Aggarwal ef al. used enantiopure Nsulfinimines in the aza MBH reaction with methyl acrylate in the presence of 3 hydroxyquinuclidine (3 HQD) and Lewis add. The desired adducts, functionalized P sulfonated amino acid derivatives, were obtained with good diastereoselectivities (Scheme 13.4) [13]. 

The reactions of N arylidenediphenylphosphinamides with hexafluoroisopropyl acrylate (HFIPA) to give the corresponding aza MBH adducts in moderate to excellent yields with good enantiomeric excesses was also reported by Hatakeya ma [20] (Scheme 13.11). In contrast to the corresponding aldehydes, imines show the opposite enantioselectivity, and Hatakeyama and coworkers indicated that H bonding was responsible for the reversal in enantioselectivity. Michael addition... 

Sasai and coworkers reported that a chiral BINOL derived amine 16a catalyzed asymmetric aza MBH reaction of N tosyl imines with acrolein and alkyl vinyl ketones [22]. The corresponding aza MBH adducts were obtained in good to excellent yields with high enantiomeric excesses (Table 13.4). Replacing the tPr group with other substituents in amine 16a provided less effective catalysts regarding yield or enantioselectivity [23]. 

Furthermore, other similar catalysts 26a-26j have also been synthesized and applied to the aza MBH reaction, the corresponding aza MBH adducts were obtained in good yields (75 99%) and sometimes with very good enantiomeric excesses (51 95%) under mild conditions (Scheme 13.22) [35]. 

An efficient deprotection of Np toluenesulfinyl group of ( branched aza MBH adducts has been developed by using Amberlite IR 120 (plus) ion exchange resin in methanol solution at room temperature. No racemization was detected under the mild conditions. This new method provides a simultaneous deprotection/purifica tion, which has the great advantage over the solution phase deprotection technique of simplicity of workup (Scheme 13.29) [44]. 

An oven dried vial was charged with N benzylidene 4 nitrobenzenesulfonamide (1 equiv), catalyst la (10mol%), DABCO (1 equiv), and activated 3 A MS. The vial was evacuated and purged with N2. Precooled, freshly distilled, anhydrous xylenes (0.15 M) and methyl acrylate (8 equiv) were added via syringe at 48 °C, and the mixture was stirred for 36 h. The mixture was diluted with anhydrous MeOH and then quenched immediately with 4N HCl in dioxane. The crude adduct was purified by flash chromatography (100% CH2CI2) to afford the pure aza MBH adduct as a white solid. 

MVK (0.5 mmol) was added to a solution of N p ethylbenzenesulfonyl)benzal dimine (0.25mmol) and p ICD (0.025mmol) in CH3CN/DMF (1 1, 1.0ml) at 30 °C. The reaction mixture was stirred at 30 °C for 24h. After the reaction completed, the solvent was removed under reduced pressure, and the residue was purified by flash column chromatography (SiO2, EtOAc/petro leum ether = 1 5) to yield the aza MBH adduct as a colorless solid (74% yield, 96% ee). 

Catalytic asymmetric aza MBH reactions and related reactions provide a direct and efficient synthetic approach to a variety of functionalized nonamino acid derived chiral amines under mild conditions. These novel chiral amines can be directly used to prepare many other useful chiral building blocks in organic synthesis. A variety of transformations of the chiral aza MBH adducts were recently demonstrated by Raheem and Jacobsen (Scheme 13.30) [9]. 

Scheme 13.30 Transformations of aza MBH adduct. (Source l.T. Raheem, E.N. Jacobsen, Highly enantioselective aza Baylis Hillman reactions catalyzed by chiral thiourea derivatives. Adv. Synth. Catal. 2005, 347, 1701 1708. Wiley VCH Verlag GmbH. Reproduced with permission.)...

Further synthetic applications ofthe corresponding aza MBH adducts are still being optimized [45]. 

The Pd complexes of (R R,R)-3Sh were found to be highly efficient in the enantiose-lective allylic amination of the esters of racemic Morita-Baylis-Hillman (MBH) adducts with aromatic amines, affording optically active P-arylamino acid esters in high activity (TON up to 4750) with high region- and enantioselectivities (Scheme 53)... 

The allylic alcohol products from Morita-Baylis-Hillman reactions were shown to participate in a DMAP-mediated Tsuji-Trost-type reaction with /3-diketones or /3-ketoesters, forming the C-allylation product without requiring the use of palladium. Previously, it was shown that allylic alcohols combined with /8-ketoesters and DMAP afforded the transesterification products, in which the allylic alcohol displaced the ester substituent. The difference between these diverging reaction pathways is likely due to the electron-withdrawing group on the allylic alcohol in the MBH adducts vs. just alkyl substituents in the latter case. 

Aliphatic aldehydes also react with aryl acrylates more rapidly than with alkyl acrylates, but yield instead the cyclic acetals 25, arising from reaction of the initial MBH adduct 24 with a second molecule of aldehyde, exclusively or in a mixture with the normal adducts 24 (Scheme 1.12). More recently, a-naphthyl acrylates have also been shown to have a significant rate accelaration for the DABCO-catalyzed MBH reactions. Either the normal MBH adduct 26 or l,3-dioxan-4-ones 27 could be obtained by controlling the substrate ratios and reaction time, respectively (Scheme 1.13). ... 

The normal aza-MBH adducts 40 could be formed in moderate yields in the PPhs-catalyzed reaction between methyl 2,3-butadienoate and A -(ethoxy-carbonyl)benzaldimine, while only trace normal aza-MBH adducts 41 were afforded for DABCO-catalyzed reactions of A-tosylated imines with ethyl 2,3-butadienoate (Scheme 1.19). These results show that the reactivities of both imines and catalysts influence the final products using the same starting materials. 

Attempts to add acrolein to aetivated olefins led to polymerization, but methaerolein, crotonaldehyde and cinnamaldehyde reaet normally with acrylates and aerylonitrile (Scheme 1.46). ° Upon treatment of these a,jS-unsaturated aldehydes with methyl vinyl ketone in the presenee of DABCO, the self-eondensation product 3-methylenehepta-2,6-dione was obtained exclusively some MBH adduct was isolated with phosphine catalysis (Scheme 1.46). In addition, crotonaldehyde does not add to phenyl vinyl sulfone. ... 

Acetylenic aldehydes 96 have been utilized as electrophiles in MBH reactions to give allyl propargyl alcohols 97 in moderate to good yields. Aldehydes 98, as a masked formybutadiene, react with activated olefins to give the eorre-sponding MBH adducts 99 via a tandem sequence base-induced elimination-MBH reaction catalyzed by DABCO (Seheme 1.47). ° ... 

In the reaction of aromatic aldehydes with acrylonitrile, complexes 105 containing two molecules of MBH adduct and one molecule of DABCO... 

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