Michael-intramolecular alkylation

Michael intramolecular alkylation. The reaction of f-butyl lithioacetate (1) with ethyl 6-iodo-2-hexenoate 2 in the presence of potassium t-butoxide in THF at - 78° results in a single trans-1,2-disubstituted cyclopentane (3). Reaction of 2 with f-butyl lithiopropionate (4) under the same conditions results mainly in syn-5, but when HMPT is also present anti-5 is mainly formed. Similar stereoselectivity is observed in reaction of 1 and 4 with ethyl 6-iodo-2-heptenoate in formation of... 

Scheme 11.5 Cu-catalyzed Michael/intramolecular alkylation reaction of 20 [12).

Scheme 2.43 Tandem Michael/intramolecular alkylation sequence between bro-momalonate and nitroalkenes catalysed by a preformed diamine nickel catalyst.

Scheme 7.44 Domino oxidation-Michael-intramolecular alkylation reaction, domino oxidation-Michael-hemiacetalisation reaction, and domino oxidation-oxa-Michael-Michael reaction catalysed by chiral amine catalysis and ruthenium catalysis.

Enamine addition to an unsaturated ester, followed by an intramolecular alkylation, provided a facile synthesis of an adamantane bis-/3-ketoester 674). Michael addition of pyrrolidinocycloheptene to other acrylic esters 668) and of other enamines to acrylic acids 675), a chloroacrylonitrile 676), and an unsaturated cyanocarboxamide (577) were reported. 

Tandem intramolecular Michael addition - intramolecular alkylation can lead to cyclopropanes. Matthew J. Gaunt of the University of Cambridge has shown (Angew. Chem. Int. Ed. 2004,43, 2681) that this intramolecular Michael addition also responds to organocatalysis. In this case, the catalyst, a quinine-derived amine, covalently binds to the substrate, then is released at the end of the reaction. 

For the most part, alkynic and allenic ketones have found limited use in conjugate addition-enolate trapping sequences 69,81-83 their analogous esters have been used with far greater frequency (vide infra). Alkynic ketones, in particular, have found use in development of a new anionic polycyclizadon method consisting of intramolecular Michael addition followed by intramolecular alkylation (equation 15).84... 

A limited number of other anionic species have been employed as Michael donors in tandem vicinal difunctionalizations. In a manner similar to sulfur ylides described above, phosphonium ylides can be used as cyclopropanating reagents by means of a conjugate addition-a-intramolecular alkylation sequence. Phosphonium ylides have been used with greater frequency261-263 than sulfur ylides and display little steric sensitivity.264 Phosphorus-stabilized allylic anions can display regiospecific 7-1,4-addition when used as Michael donors.265... 

Carbocyclization of m-alkcnyl-z-methoxybcnzy I lithiums to form five- or six-membered rings has been studied 101 the five-membered ring is formed with a cis-stereochemical relationship between the methoxy substituent and the adjacent methyl group. Intramolecular carbolithiation of vinyl sulfides at — 105°C in THF has been found to occur non-stereospecifically with regard to the newly formed C—Li centre.102. The stereochemistry of selective tandem Michael addition alkylation reactions of vinylphosphonates has been explored.103... 

The structurally related optically active a-acyl vinyl p-tolyl sulfoxide 269 underwent asymmetric cyclopropanation. Michael addition of the carbanion of bromomalonate to 269 and the subsequent intramolecular alkylation yielded the corresponding optically active a-acyl-cyclopropane 271, with a high degree of diastereoselectivity (Scheme 70).142 It was proposed that the stereochemical outcome of the reaction can be rationalized by transition state 270, in which there is chelation of the oxygen atom of the carbonyl and sulfinyl groups to the metal cation. 

A synthesis of cyclobutane derivative (301), which may be a useful substrate in an approach to podo-phyllotoxin, involves Knoevenagel reaction of an aromatic aldehyde with cyanoacetate to give (300) followed by a Michael addition, demethylcarbonylation, intramolecular alkylation and exchange of a cyano group with acetate. ... 

A sequence of Michael addition, iodination, and intramolecular alkylation is involved in the formation of 2-substituted cyclopropane-1,1-diphosphonate esters from tetraethyl methylenediphosphonate. The reagents are KF-AI2O3 and I2. 

Recently, the Lilly group [122] has reported on a conceptually similar approach (Scheme 46), to synthesize the carbacephem ring system. In such an approach the initial Michael type addition is followed by intramolecular alkylation and subsequent elimination of the phenylsulfinyl moiety to give the carbacephem ring 311 in one step. 

The reaction is possibly initiated by the addition of NHC to Michael acceptor to generate enolate I, followed by proton shift to give the (3-anion II. Intramolecular alkylation affords cyclization intermediate III, followed by (3-elimination to furnish the hnal product and regenerate the NHC (Scheme 7.58). 

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