Aromatic methyl aldol reaction

Crossed aldol condensations, where both aldehydes (or other suitable carbonyl compounds) have a-H atoms, are not normally of any preparative value as a mixture of four different products can result. Crossed aldol reactions can be of synthetic utility, where one aldehyde has no a-H, however, and can thus act only as a carbanion acceptor. An example is the Claisen-Schmidt condensation of aromatic aldehydes (98) with simple aliphatic aldehydes or (usually methyl) ketones in the presence of 10% aqueous KOH (dehydration always takes place subsequent to the initial carbanion addition under these conditions) ... 

Several attempts to take advantage of the intermediate boron enolate to achieve tandem conjugate addition-aldol reaction have been proposed [71]. Recently, Chandrasekhar [72] reported the addition of triethylborane to methyl vinyl ketone followed by the in situ trapping of the enolate by aromatic aldehyde (Scheme 26). 

In the reactions with the propionate derivatives, which provide synthetically useful a-methyl-/3-hydroxy ester derivatives, a combination of Sn(OTf)2, (5)-l-methyl-2-[(A(-l-naphthylamino)methyl]pyrrolidine, and Bu3Sn(OAc)2 gives better results (Eq. 20) [33,35]. The asymmetric aldol reactions proceed with higher enantioselectivity and, in addition, the reactions proceed faster with Bu3Sn(OAc)2 as an additive than with BusSnE A wide variety of aldehydes including aliphatic, aromatic, and a,/3-unsatu-rated aldehydes can be used in this reaction, and the aldol adducts are always obtained in high yields with perfect syn selectivity the enantiomeric excesses of these syn adducts are > 98 %. 

Asymmetric synthesis of 1,2-diol derivatives based on asymmetric aldol reactions of a-alkoxy silyl enol ethers with aldehydes has been developed. The reaction of (Z)-2-benzyloxy-l-(5)-ethyl-l-trimethylsiloxyethene with benzaldehyde was conducted in dichloromethane at -78 °C with a chiral promoter consisting of Sn(OTf)2, (5)-l-ethyl-2-[(piperidin-l-yl)methyl]pyrrolidine, and Bu2Sn(OAc)2, to afford the corresponding aldol adduct in 83 % yield with 99 % anti preference. The enantiomeric excess of anti aldol is 96 % [38a]. In the aldol reaction of several kinds of aldehydes, e.g. aromatic,... 

The Mukaiyama aldol reaction involves the addition reaction of a TMS-enol ether to an aldehyde. Loh et al. have investigated the reaction of l-methoxy-2-methyl-l-trimethylsiloxypropene with aliphatic and aromatic aldehydes in chloride, [BF4] and [PFg] ionic liquids. The yields varied considerably and it was found that the chloride ionic liquids gave the best yields (50-74%) [230]. Ruthenium complexes have been used in the addition of aUyl alcohols to aldehydes and imines in [BMIM][Pp6] [231] (and later in a very similar paper [232]). The addition of a cootalyst such as indium(iii) acetate was found to dramatically improve the yields in some cases and it was foimd that the ionic Uquid/catalyst combination could be recycled. Examples of these reactions are shown in Scheme 5.2-100. 

Retrosynthetically, spiroketal precursor 8 would be accessed via a diaster-eoselective aldol reaction between chiral aldehyde 9 and a-chiral (3-arylated methyl ketone 10 (Scheme 3). Aldehyde 9 would be readily accessible from commercially available ethyl (S)-hydroxybutyrate, while methyl ketone 10 would be constmcted by the Suzuki cross-coupling of trifluoroboratoamide 11 and rotationally symmetric aryl halides 12/13. The use of Br or I in place of Cl in halides 12/13 was intended to increase the reactivity of 12/13 toward oxidative insertion and overcome the steric hindrance imparted by the ortho-disubstituted aromatic framework. The required functionalization of the aromatic ring to install the phthalide motif was envisioned to be possible via iridium-catalyzed CH-borylation either before or after formation of the spiroketal core. Our group already had experience with this remarkable transformation in the context of naphthalene chemistry. 

Aldol reaction between a silyl enol ether and an aromatic or aliphatic aldehyde can be catalysed by tetrabutylammonium fluoride ketones and epoxides are not attacked by the enolates derived in this manner. Directed cross-aldol reactions have now been carried out by conversion of a methyl ketone into the intermediate (15) using 9-trifluoromethylsulphonyl-9-borabicyclo[3,3,l]nonane and t-amine prior to reaction with the second carbonyl compound. ... 

In 2008 Brimble and coworkers examined the effect of a-substitution in proline-based catalysts for the asymmetric aldol addition of acetone to aromatic aldehydes. In the benchmark aldol reaction between acetone and p-nitro-benzaldehyde they observed a remarkable improvement of stereoselectivity using (5 )-a-methyl-tetrazole 9, albeit with longer reaction times caused by the a-geminal disubstitution. Surprisingly 7a afforded a completely racemic product (Scheme 11.7). Using 9 the scope of this reaction was extended efficiently to several other aromatic aldehydes with excellent enantioselectivities (enantiomeric excess — 70-91%). 

Scheme 19.54 Enantioselective aldol reaction of trifluoroacetaldehyde methyl hemiacetal with aromatic ketones.

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