Cyclization Michael reaction

Claisen condensation reaction Dieckmann cyclization Michael reaction Michael acceptor... 

The Michael reaction with enamines is exemplified in this procedure. In a second (spontaneous) step of the reaction, an aldol-type condensation occurs resulting in cyclization. Finally, the morpholine enamine of the product forms and is hydrolized by the addition of water to yield a mixture of octalones, which is separated by fractional crystallization. J -Octalone-2 can be reduced by lithium in anhydrous ammonia to the saturated tra/i5-2-decalone (Chapter 3, Section III). 

In this example, the /3-diketone 2-methyJ-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,/3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson anuulation reaction, which leads to the formation of an substituted cyclohexenone. Treatment of a /3-diketone or /3-keto ester with an a,/3-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. 

Aminobenzenethiol undergoes a Michael reaction with methyl 5,5-dimethyl-2-oxo-2,5-dihyd-rofuran-3-carboXylate (4) to give the adduct 5, which cyclizes to the tricyclic benzothiazepinone 6 under the influence of triethylamine hydrochloride.426... 

The yield of the cyclization step under the influence of a metal template can be increased when the corresponding dialdehyde 19 of the tetrapyrrole 16 is used. The reaction sequence is initiated by insertion of palladium(II) or nickel(II) into the tetrapyrrole to give 20 followed by Michael addition of one acrylaldehyde side chain to the other yielding the macrotetracycle 21 from which in a retro-Michael reaction acetaldehyde is eliminated to give 22. 

Anionic domino processes are the most often encountered domino reactions in the chemical literature. The well-known Robinson annulation, double Michael reaction, Pictet-Spengler cyclization, reductive amination, etc., all fall into this category. The primary step in this process is the attack of either an anion (e. g., a carban-ion, an enolate, or an alkoxide) or a pseudo anion as an uncharged nucleophile (e. g., an amine, or an alcohol) onto an electrophilic center. A bond formation takes place with the creation of a new real or pseudo-anionic functionality, which can undergo further transformations. The sequence can then be terminated either by the addition of a proton or by the elimination of an X group. 

The Michael reaction of nitromethane with methyl vinyl ketone and l-decene-3-one followed by reductive cyclization gives two isomeric pyrrolizidines, depending on reduction conditions (Eq. 10.74).117... 

Reaction of phenyl vinyl ketone with cyclopentanone under thermal conditions resulted in a diastereomeric mixture of 1,5,9-triketones 374 via a double Michael reaction. Treatment of this mixture with ammonium formate in polyethyleneglycol-200 under microwave irradiation conditions led to the very fast and efficient formation of a 2 1 diastereomeric mixture of cyclopental flquinolizidines 375 and 376 <2002T2189>. When this reductive amination-cyclization procedure was carried out starting from the purified /ra r-isomer of 374, the result was identical to that obtained from the cis-trans mixture, showing the operation of thermodynamic control (Scheme 86). 

Asymmetric intramolecular Michael cyclization.1 Reaction of the ketone 2 with (R)-( + )-l (1 equiv.) generates an enatnine that adds to the unsaturated ester group to give 3a. The yield and the ee of 3 are markedly improved when 5 A... 

As far as the stereochemistry concerns, when the cyclization occurs through a Michael reaction, the thermodynamic product is generally obtained, but some exceptions have been observed such as that of A-acetyl glucosamine protected as 4,6-benzylidene, the reaction of which with [(ethoxycarbonyl)methylene]triphenylphosphorane afforded the ot-C-glycosyl compound stereoselectively.28... 

The formation of cyclopropanes from 7C-deficient alkenes via an initial Michael-type reaction followed by nucleophilic ring closure of the intermediate anion (Scheme 6.26, see also Section 7.3), is catalysed by the addition of quaternary ammonium phase-transfer catalysts [46,47] which affect the stereochemistry of the ring closure (see Chapter 12). For example, equal amounts of (4) and (5) (X1, X2 = CN) are produced in the presence of benzyltriethylammonium chloride, whereas compound (4) predominates in the absence of the catalyst. In contrast, a,p-unsatu-rated ketones or esters and a-chloroacetic esters [e.g. 48] produce the cyclopropanes (6) (Scheme 6.27) stereoselectively under phase-transfer catalysed conditions and in the absence of the catalyst. Phenyl vinyl sulphone reacts with a-chloroacetonitriles to give the non-cyclized Michael adducts (80%) to the almost complete exclusion of the cyclopropanes. 

Balme G, Bouyssi D, Monteiro N (2006) The Virtue of Michael-Type Addition Processes in the Design of Transition Metal-Promoted Cyclizative Cascade Reactions. 19 115-148 Barluenga J, Rodriguez F, Fanands FJ, Fldrez J (2004) Cycloaddition Reaction of Group 6 Fischer Carbene Complexes. 23 59-121 Basset J-M, see Candy J-P (2005) 16 151-210... 

The Ir(lll) complex also funchoned as a catalyst in a tandem Nazarov cyclization-Michael addition. The reaction of monocyclic a-alkylidene-P-keto-y.b-unsaturated ester with nitroalkene gave bicyclic cyclopentenones which possessed an alkyl side chain, with high yield and diastereoselectivity (Scheme 11.36) [47]. 

Andreana and Santra have investigated the influence of the solvent on the generation of molecular diversity arising from a set of MCR substrates under microwave irradiation [36]. They have found that by using water as solvent, both 2,5-DKPs and 2-azaspiro[4.5]deca-6,9-diene-3,8-diones were obtained through aza-Michael reaction and 5-exo Michael cyclization, respectively. Nevertheless,... 

In contrast, ethyl 3-oxo-4-(triphenylphosphoranylidene)butyrate behaves as a C,0-bis(nucleophile) when reacted with unsaturated 5(4//)-oxazolones 584 with a leaving group at the exocyclic p-carbon. In this case, initial Michael reaction generates 585 that eliminates HX to produce a resonance stabihzed ylide 586. Cyclization of 586 with ring opening leads to the interesting ylide intermediate 587 used for the synthesis of 2//-pyran-2-ones (Scheme 7.185). 

The intramolecular Michael reaction is also a powerful transformation. In the cyclizations reported by Tetsuaki Tanaka of Osaka University (J. Org. Chem. 2004, 69, 6335), the stereochemical outcome is controlled by the chirality of the sulfoxide. Remarkably, subsequent alkylation or aldol condensation leads to one or two additional off-ring stereocenters with high diastereocontrol. Note that the high stereoselectivity in the cyclization is only observed with the (Z)-unsaturated ester. 

Michael reactions of chiral lithioenamines of p-oxo esters with dimethyl alkylidenemalonates were studied.173-176 Especially the a-alkyl-substituted compounds (161) and (163), derived from L-valine t-butyl ester, afford, after hydrolysis, the adducts (162) and (164), respectively, diastereoselectively and with high ee (Scheme 57).175 In the presence of TMS-C1, even weaker acceptors like acrylates or MVK were shown to react.176 A somewhat related diastereoselective 1,4-addition, followed by a Pictet-Spen-gler-type cyclization, allows the preparation of compound (165 Scheme 58),177 a central intermediate for the synthesis of several alkaloids.177-178... 

Scheme 24 illustrates how this notation can be combined with that of Seebach.73 Clive has formed a new ring by sequencing a Michael reaction, a carbonyl addition, and a radical cyclization.79 Phenylsele-noacrylonitrile is the actual reagent that accomplishes the transformation implied by synthon (7). 

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