Michael-intramolecular alkylation reaction

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

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.

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... 

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... 

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. 

The competition between Michael addition of a,(3-unsaturated ketones and Diels-Alder reactions involving furan and 2-methylfuran is affected by the catalyst used. Methyl vinyl ketone gives the alkylation product with furan and 2-methylfuran in the presence of silica gel (88TL175). Bis(alkylated) products have also been obtained in reactions of 2-methylene-1,3-dicarbonyl compounds (90H(31)1699). An intramolecular proton catalyzed alkylation reaction of an a,(3-unsaturated ketone provided a straightforward synthesis of norpinguisone (90TL4343) and in the example shown in Equation (4) the cyclization reaction involved an a,(3-y,8-dienone (94TL4887). 

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. 

Surprisingly, little follow-up work on this idea of small molecule asymmetric catalysis appeared for the next 25 years. In the late 1980s, Agami reported the asymmetric intramolecular aldol reaction of acyclic diketones with (S)-proline as the catalyst. It was not nntil the twenty-first centnry, however, when this notion of organocatalysts became fnlly exploited. List and Barbas ° pioneered enam-ines as catalysts for aldol and Mannich and related reactions. MacMillan has developed a variety of imininm-based catalysts prodncing large asymmetric indnction for Diels-Alder chemistry, Friedel-Crafts alkylations, Mnkaiyama-Michael and cyclopropanation " reactions. 

Easily reduced polyhalides such as CCI4 (—0.75 V) and Cl3CCOOEt (—0.65 V) form anions upon two-electron reduction and cleavage of a halide ion. The anion may add to activated, but less easily reduced, alkenes such as acrylonitrile or alkyl acrylates. With excess alkene and no added proton donor, cyclopropanes are formed via Michael addition followed by intramolecular Sn2 reaction [188] (Scheme 16). 

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. ... 

Hydroacylation of Michael acceptors. The organotetracarbonylferrates obtained by alkylation of disodium tetracarbonylferrate undergo insertion reactions with Michael-type acceptors to give eventually y-keto esters, ketones, and nitriles. The last example shows an interesting synthesis of a cyclopentanone by an intramolecular insertion reaction. ... 

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