Morita-Baylis-Hillman-type reaction

A highly enantioselective proline-catalysed intramolecular Morita-Baylis-Hillman reaction of hept-2-enedial (111) has been reported. Addition of imidazole to the mixture resulted in an unusual inversion of enantioselectivity.149 The first example of a TiCU-mediated Morita-Baylis-Hillman-type reaction of cy-acetyl cyclic ketene dithioacetals with arylaldehydes has been described.150... 

Contra-Peterson elimination also occurred in Morita-Baylis-Hillman-type reactions of 1-silylcyclopropene 101. Addition of the nucleophilic catalyst tris(2,4,6-trimethoxyphenyl)phosphine (TTMPP) at the 2-position of the alkene and condensation of the anion with an aldehyde led to 1,3-Brook rearrangement, with expulsion of the catalyst to regenerate the cyclopropene double bond in product 102. ... 

PTA was used as an organic base to catalyze Morita-Baylis-Hillman type reactions (Scheme 7.9) [49-51]. Variously substimted aryl aldehydes ArCHO were reacted with ethyl acrylate in THF/H2O (4 1, v/v) at room temperature in the presence of a catalytic amount of 1 (20 mol %) giving the addition products after 5-19 h in yields ranging from 59 to 93%. 

Of the numerous examples of asymmetric reactions catalyzed by Lewis bases, this chapter focuses mainly on the activation of silicon reagents and related processes. Various other types of Lewis basic (nucleophilic) activation, namely the Morita-Baylis-Hillman (MBH) reaction, acyl transfer, nucleophilic carbenes, and carbonyl reduction, are described in the other chapters of this book. 

A review on ynolates, including the synthesis of p-lactones, has appeared <03S2275>. Morita-Baylis-Hillman-type adducts have been converted into a-alkylidene-p-lactones 65, which on reaction with dimethyltitanocene can be transformed into 3-alkylidene-2-methyleneoxetanes <03OL399>. Lactones 66 have been obtained via the cinchona alkaloid-catalyzed dimerization of monosubstituted ketenes <03OL4745>. The PdCh-promoted synthesis of P-lactones 67 have been achieved via cyclocarbonylation of 2-alkynols <03OL4429>. 

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. 

Another class of reaction for which chiral tertiary amines are privileged catalysts is the Morita-Baylis-Hillman type (477, 478). One of the first applications of Cinchona alkaloids to mediate an asymmetric Morita-Baylis-Hillman reaction in a natural product synthesis was reported by Hatakeyama et al. in 2001 (479). Using a stoichiometric amount of (3-isocupreidine (568), a stereoselective addition of hexafluoroisopropyl acrylate (569) to aldehyde 570 could be carried out in good yield and with excellent selectivity (99% ee) (Scheme 119). The chiral p-hydroxy ester 571 was converted further into the epoxide 572, a known intermediate in the synthesis of epopromycin B (573). Epopromycin B (573) is a plant cell wall... 

A general, one-pot synthesis of substituted tetraethyl 2-aminoethylidene-1,1-bisphosphonates (133) has been developed by Gajda. The direct and efficient conversion of the latter into aza-Moritae-Baylis-Hillman-type adducts (134), via the Horner-Wittig reaction with paraformaldehyde, has been also elaborated (Scheme 44). 

Shibasaki et al. also reported that similar Morita-Baylis-Hillman-type products were obtained via asymmetric aldol reaction of a p,y-unsaturated ester with aldehydes using a chiral barium catalyst system (Table 3) [25]. The desired products formed in good yields with high enantioselectivities after isomerization. Several aromatic- and alphatic aldehydes were tested, and in all cases high a-(E) selectivities and high enantioselectivities were observed. Several aryl, heteroaryl, alkenyl, and alkyl aldehydes can be used as substrates in this reaction. 

Shibasaki et al. also developed chiral barium catalysts prepared from barium alkoxide and optically active BINOL 3 or aryloxide 4 derivatives. These catalysts were applied to asymmetric Mannich reactions of p,y-unsaturated esters (Table 27) [101]. In this reaction, the initially formed Mannich adducts isomerized to afford aza-Morita-Baylis-Hillman-type products in moderate to good yields with good enantioselectivities. For four substrate examples, ayloxide 4 ligand worked well (entries 2—4). 

Moreover, a twofold SN -type domino reaction was reported by Krische and coworkers for the synthesis of y-butenolides 2-229 (Scheme 2.53) [128]. Treatment of Morita-Baylis-Hillman acetates 2-226 with trimethylsilyloxyfuran (2-227) in the presence of triphenylphosphane in THF at 0 °C led to 2-229 in yields of up to 94% and diastereoselectivities of >95 5. 

The product of the previous reaction provides a Baylis-Hillman type product via an intermolecular addition of an allenoate to an epoxide. The first example of a true Morita-Baylis-Hillman reaction of an epoxide has recently been reported <06CC2977>. Treatment of enone 34 with Me3P provides a good yield of the epoxide-opened product 35. The reaction must be carried out at low concentrations in order to avoid the generation of a variety of side products. When the terminal end of the epoxide is substituted (e.g. 34) the exo-mode of cyclization is the only product observed. When the terminal end of the epoxide is unsubstituted (e.g. 36), the endo-mode of cyclization predominates providing 37. 

Chen and coworkers published a formal [3 + 3]-type reaction to give highly substituted cyclohexenes 8. This domino process consists of an allylic-allylic alkylation of an a,a-dicyanoalkene derived from 1-indanone and Morita-Baylis-Hillman carbonates, following an intramolecular Michael addition, by employing dual orga-nocatalysis of commercially available modified cinchona alkaloid (DHQD)2AQN If (hydroquinidine (anthraquinone-l,4-diyl) diether) and (S)-BINOL. The cyclic adducts... 

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. 

Abstract The organocatalytic asymmetric Mannich reaction and the related aza-Morita-Baylis-Hillman have been reviewed. The activities in this field have been snbdivided based on the types of catalysts that have been ntilized, which includes catalysis by enamine-forming chiral amines, chiral Br0nsted bases, chiral Brpnsted acids, and phase-transfer catalysts. 

A twofold Sjj type domino organocatalytic reaction for the synthesis of y-butenolides 28 has been reported by Krische and coworkers [19], by treatment of Morita- Baylis- Hillman acetates 26 with trimethylsilyloxyfuran (27) in the presence of triphenylphosphine to afford 28 in yields up to 94% and diastereoselectivities of >95 5 dr (Scheme 4.6). 

Li and co-workers developed a novel asymmetric halo aldol reaction using Evans oxazolidinones as chiral auxiliaries for tandem I-C/C-C bond formations. This reaction provides a practical approach to a variety of halo aldols of a non-Evans type that cannot be easily prepared by other methods. Excellent diastereoselectivity (> 95% de) and yields (80-93%) have been obtained. This reaction can be considered as a Lewis acid (Et2Al-I)-promoted Morita-Baylis-Hillman (MBH) process. 

A novel bis-thiourea-type catalyst (7) was synthesized by Berkessel et al. [83]. The catalyst turned out to be effective in the Morita-Baylis-Hillman reaction (Scheme 2.32). 

The introduction of the activated allylic bromides and Morita-Baylis-Hillman acetates and carbonates pioneered the development of a number of phosphine-catalyzed reactions in subsequent years [45]. Interestingly, the asymmetric variant of this type of transformation only appeared in the literature seven years later. In 2010, Tang, Zhou, and coworkers disclosed a highly enantioselective intramolecular ylide [3-f2] annulation using spirobiindane-based phosphine catalyst 31 (Scheme 20.27). BINAP was found inactive in this reaction even at an elevated temperature (70°C). Notably, both optically active benzobicyclo[4.3.0] compounds 32 and 32 with three continuous stereogenic centers could be obtained as major products in high yields and stereoselectivities just by a choice of an additive [Ti(OPr )4], which can block the isomerization of the double bond [46]. 

Several chalcogenide catalyzed MBH-type reactions are reported [146], Instead of the common ferf-amines or phosphanes, also higher organochalcogenides can act as nucleophilic activator. Such Morita-Baylis-Hillman reactions catalyzed by sub-stoichiometric amounts of sulfides and selenides in the presence of Lewis acid to activate the carbonyl group were described by Kataoka and co-workers [147, 148]. The reaction of p-nitrobenzaldehyde and 2-cyclohexenone has been used for screening a series of chalcogenide catalysts in dichloromethane at room temperature. The best result was found when 10 mol% of chalcogenide where employed with a stoichiometric amount of TiCl in the presence of excess 2-cyclohexenone as Michael acceptor (3 equiv., Table 7.10). 

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