Electrophiles, bifunctional/unsaturated

Phosphoric acid 25a was successfully employed for mediating enantioselective synthesis of 1,3-disubstituted isoindolines from electrophilic bifunctional substrates (containing an imine and a Michael acceptor site) and indoles [33]. Catalyst 7a was used effectively in an organocatalytic asymmetric F-C alkylation/cyclization cascade reaction between 1-naphthols and a,(i-unsaturated aldehydes to give chro-manes in good yields and select vities (Scheme 3 5.18) [ 10]. Furthermore, 2-naphthols and p,y-unsaturated a-keto ester also reacted in a F-C alkylation/dehydration sequence, in the presence of a thiourea catalyst and a catalytic amount of concentrated sulfuric acid, affording optically active naphthopyran derivatives [54]. 

Some of the components shown in these examples have two electrophilic centres and some have a nucleophilic and an electrophilic centre in other situations components with two nucleophilic centres are required. In general, components in which the two reacting centres are either 1,2- or 1,3-related are utilised most often in heterocyclic synthesis, but 1,4- ( e.g. HX-C-C-YH) (X and Y are hetero atoms) and 1,5-related ( e.g. 0=C-(C)3-C=0) bifunctional components, and also reactants which provide one-carbon units (formate, or a synthon for carbonic acid - phosgene, Cl2C=0, or a safer equivalent) are also important. Amongst many examples of 1,2-difunctionalised compounds are 1,2-dicarbonyl compounds, enols (which first react in a nucleophilic sense at carbon and then provide an electrophilic centre (the carbonyl carbon), Hal-C-C=0, and systems with HX-YH units. Amongst often used 1,3-difunctionalised compounds are the doubly electrophilic 1,3-dicarbonyl compounds and a,P-unsaturated carbonyl compounds (C=C-C=0), doubly nucleophilic HX-C-YH (amidines and ureas are examples), and a-amino- or a-hydroxycar-bonyl compounds (HX-C-C=0), which have an electrophilic and a nucleophilic centre. 

Catalytic enantioselective iodoetherification of l-aryl-P,Y-unsaturated ketoximes such as 41 was accomplished using N-iodosuccinimide (MS) as electrophilic iodine source, catalytic I2, and the bifunctional oi anocatalyst 42. The corresponding 3-aryl A -isoxazohnes containing a quaternary stereocenter at C-5 were obtained with high yield and enantioselectivity (13AGE8450). 

The detailed mechanistic explanation pictures the initial weak interaction among the bifunctional thiourea catalyst 158, the malonic ester 157 as nucleophile, and the nitroalkane 140 as electrophile that should promote the first chemo- and stereoselective Michael addition. The resulting adduct A would be poised to participate directly in the second catalytic cycle by acting as donor in a regioselective ititro-Michael reaction with the a,p-unsaturated aldehyde 95, here activated as iminium ion by the secondary amine catalyst (5)-76. The new inteimediate B, with its aldehyde and malonate moiety suitably spatial disposed, would undergo a base-promoted aldol cychzation to efficiently generate the planned cyclohexanol 159 in moderate yield (up to 87%) and marvelous enantioselectivity (up to >99% ee). 

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