Michael reaction routes

Both routes are acceptable and both get back to the same three starting materials. Route a uses a Michael reaction with a stable airion so this is preferable. 

Tetrahydropyridines 103 undergo a Michael reaction to afford [ran.s-(2,3)-cis-(2,6)-trisubstituted piperidines 104 (97T9553). The reaction is stereoselective (a single stereoisomer was obtained) and provides a convenient route to the 5,8-disubstituted indolizidine 105 and 1,4-disubstituted quinolizidine system 106 (found in Dendrobates alkaloids) by introduction of various alkyl, alkenyl, or... 

Another interesting example is provided by the phenylethynylcarbene complex 173 and its reactions with five-, six-, and seven-membered cyclic enamines 174 to form bridgehead-substituted five-, six-, and seven-membered cycloalkane-annelated ethoxycyclopentadienes with high regioselectivity under mild reaction conditions (Scheme 38) [119,120]. In these transformations the phenylethynylcarbene complex 173 acts as a C3 building block in a formal [3+2] cycloaddition. Like in the Michael additions (reaction route F in Scheme 4), the cyclic electron-rich enamines 174 as nucleophiles attack the... 

Route (b) offers a short cut since the reaction between (5) and PhCHO under dehydrating conditions needs no control as (3) is the only possible enone from a ketone enolate attacking the more reactive aldehyde (p T 167). The Michael reaction is also better by this route as explained on p T 171, This is the published synthesis. 

Hassner and coworkers have developed a one-pot tandem consecutive 1,4-addition intramolecular cycloaddition strategy for the construction of five- and six-membered heterocycles and carbocycles. Because nitroalkenes are good Michael acceptors for carbon, sulfur, oxygen, and nitrogen nucleophiles (see Section 4.1 on the Michael reaction), subsequent intramolecular silyl nitronate cycloaddition (ISOC) or intramolecular nitrile oxide cycloaddition (INOC) provides one-pot synthesis of fused isoxazolines (Scheme 8.26). The ISOC route is generally better than INOC route regarding stereoselectivity and generality. 

Scheme 7 Two alternative reaction routes for the organocatalytic Michael-addition of acetylacetone to nitrostyrene...

Figure 1.15 Supramolecular catalysts for organocatalysis (a) Route to catalyst libraries (b) asymmetric nitro-Michael reaction.

Since both oxidative splitting of the double bond and aldol condensation represent reliable and general reactions, their sequence serves as an efficient route for the transformation of readily available cyclohexene systems e.g. formed via the Diels-Alder reaction or Robinson annulation) into functionalized cyclopentene derivatives. This standard operational mode is extensively used in total syntheses. One of the numerous examples, the synthesis of helminthosporal 463, the sesquiterpenoid toxin of fungi, is shown in Scheme 2.150. In the initial phases of the synthesis, commercially available (—)-carvomenthone 464 was transformed into 465 via Michael reaction with methyl vinyl ketone to give 466 and subsequent intramolecular aldol condensation. 

A recent modification due to Sworin and Lin is to incorporate an additional functional group into the substrate so that the intermediate enol can cyclize by intramolecular Sn2 or Michael reactions. As shown in equations (78) and (79), this provides a novel route to hydroazulenes. ... 

Gomtsyan, A. Org. Lett. 2000, 2, 11. For a reaction with methyl esters with an excess of vinylmagnesium halide and a copper catalyst to give a 3-butenyl ketone by a similar acyl substitution-Michael addition route, see Hansford, K.A. Dettwiler, J.E. Lubell, W.D. Org. Lett. 2003, 5, 4887. Gomtsyan, A. Koenig, R.J. Lee, C.-H. J. Org. Chem. 2001, 66, 3613. 

Griseofulvin, an antibiotic produced by the mold Penicillium griseofulvum (Dierckx), has been synthesized by a route that employs a twofold Michael reaction as the key step. Propose a mechanism for this transformation. 

Synthetic polymers can be classified as either chain-growth polymers or step-growth polymers. Chain-growth polymers are prepared by chain-reaction polymerization of vinyl monomers in the presence of a radical, an anion, or a cation initiator. Radical polymerization is the most commonly used method, but alkenes such as 2-methylpropene that have electron-donating substituents on the double bond polymerize easily by a cationic route. Similarly, monomers such as methyl a-cyanoacrylate that have electron-withdrawing substituents on the double bond polymerize by an anionic (Michael reaction) pathway. 

Alder reaction route, since the computation data indicate that the transition state model of Diels-Alder reaction is 17.7 and 12.1 kcal/mol higher in free energy (AG) than those of the Michael and aldol reactions, respectively, and they indicated that the Michael-aldol... 

A more general route is that of Cohen80, in which the enone itself is used as the starting material, and the reagents, e. g., 142, shown to take part in Michael reactions. 

A simple route to a bicyclo[2.2.2]octanone system was achieved by Michael reaction under microwave irradiation of a mixture of cyclohexenones and ethyl acetoacetate adsorbed on the surface of solid lithium (5)-( )-prolinate followed by intramolecular aldolization on a column of basic Al2O3 5 (Scheme 5.31). The bicyclo[2.2.2]octane system is the core unit of several biologically active natural products and a useful intermediate for synthetic manipulation. ... 

The synthesis of dialkyl 3-cyanopropylphosphonates by Michael reaction can be effected by two different routes, the phosphorns reagent being the nucleophile or the Michael acceptor. The Michael addition of compounds containing active methylene groups such as cyanomethylphosphonate, ... 

An intramolecular counterpart of the photochemical step used in the formation of (6) has been successfully applied to the synthesis of 12-epi-lycopodine (14). Photolysis of (10) yielded the intermediate (11) which was converted into the diketone (12). The latter compound gave the aldol product (13) which, in four steps, produced 12-epi-lycopodine (14). An amazing simplification of the overall route resulted when it was found that the diketolactam corresponding to the ketal (15) underwent a stereospecific Michael reaction to give (13) directly in 30% yield. 

In addition to the side reactions mentioned above, deamination of Mannich bases can occur, especially at elevated temperature, to give a,p-unsaturated derivatives. This route of decomposition of Mannich bases has been exploited as a means of in situ generation of a,p-unsaturated ketones in the Michael reaction and for the direct synthesis of a,3-unsaturated ketones several reviews of the Mannich reaction have discussed aspects of these applications.Recently, a direct one-pot synthesis of a-methylene ketones has been reported involving condensation of ketones with formaldehyde and A -methylaniline tri-fluoroacetate in aptotic solvents. Also, a less direct method has been described in which Mannich bases prepared from 3-keto esters, formaldehyde and dimethylamine are subjected to quatemarization and thermal fragmentation to yield a-methylene ketones.This method is particularly useful for the regios-pecific synthesis of a-methylene ketones because the aminomethylation reaction always takes place at the most activated position flanked by the ketone and ester groups. 

Compounds with a carbonyl group conjugated to the double bond are conventionally called Michael acceptors. The Michael reaction is a route to a carbon-carbon bond. A nucleophile adds to a Michael acceptor. Together with nucleophilic addition at the carbonyl group, this is the first step of Robinson s cyclization, which is an excellent method for the preparation of medium-sized (and especially six-membered) rings. 

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