Regioselective Michael addition

A new method of kinetically controlled generation of the more substituted enolate from an unsymmetrical ketone involves precomplexation of the ketone with aluminium tris(2,6-diphenylphenoxide) (ATPH) at —78°C in toluene, followed by deprotonation with diisopropylamide (LDA) highly regioselective alkylations can then be performed.22 ATPH has also been used, through complexation, as a carbonyl protector of y./)-unsaturated carbonyl substrates during regioselective Michael addition of lithium enolates (including dianions of /i-di carbonyl compounds).23... 

In fact, the reaction of (33) with ene-dione (50), in the presence of diaza(l,3) bicyclo[5.4.0]undecane (DBU) as base, proceeds as depicted in Figure 2.15 as a tandem process in which a regioselective Michael addition (yielding 51) is presumably followed by the elimination of nitrous acid, to give the corresponding nitro-enone (52). 

Regioselective Michael addition of imidazole to levoglucosenone 475 is effectively catalyzed by cathodic electrolysis. The electrochemical conditions are milder and provide higher yields as compared to the base-catalyzed reactions (Scheme 110) <1996JOC8786>. 

Regioselective aza-annulation with acrylonitrile met with somewhat limited success. Aza-annulation of 10 with acrylonitrile resulted in the formation of a 75 25 mixture of 11 (eq. I).4 The mixture of 11 was taken on to 12, which was used in the synthesis of optically active 2,2 -bipyridines and 1,10-phenanthrolines. A more selective route to 11a was reported, and this approach started from optically pure (/ )-(+)-pu egone (13, eq. 2).5 In this case, regioselective Michael addition to give 14 was accomplished due to the presence of the isopropylidene moiety of the (/ )-(+)-pulegone. Subsequent rhodium catalyzed deisopropylidenation, nitrile hydration, and cyclization gave lib, which was taken on to (-)-pumiliotoxin C (15). 

Asymmetric induction in the aza-annulation reaction through the use of a chiral auxiliary was pioneered by d Angelo and coworkers in their work with 456. Even though annulation was not accomplished with the use of methyl crotonate, crotonyl cyanide produced an equimolar mixture of 458 and 459 in moderate yield (Scheme 36).112 Both 458 and 459 reflect regioselective Michael addition at the most substituted cx-carbon. The vicinal methyl substituents that resulted from aza-annulation were oriented in a cis relationship. 

Various versions of the acyl anion equivalent (32) are described by Stork etal. (use of Et2NCH2CN), Krief and co-workers (1,3-dithianes in regioselective Michael addition), Gokel et al. (use of sulphur heterocycles with thermal deblocking), Cohen and Weisenfeld" (conversion of acids into vinyl sulphides), Meyers and Campbell " (acetals derived from aryl aldehydes), and Hunig and co-workers (cyanohydrin derivatives of aryl aldehydes). 

Regioselective Michael additions of nitroalkanes to levoglucosenone under cadiodic electrolysis conditions have been reported and can be illustrated by the use of 2-nitropropane to give derivative 26. ... 

The Michael reaction is of central importance here. This reaction is a vinylogous aldol addition, and most facts, which have been discussed in section 1.10, also apply here the reaction is catalyzed by acids and by bases, and it may be made regioselective by the choice of appropriate enol derivatives. Stereoselectivity is also observed in reactions with cyclic educts. An important difference to the aldol addition is, that the Michael addition is usually less prone to sterical hindrance. This is evidenced by the two examples given below, in which cyclic 1,3-diketones add to o, -unsaturated carbonyl compounds (K. Hiroi, 1975 H, Smith, 1964). 

The synthesis of spiro compounds from ketones and methoxyethynyl propenyl ketone exemplifies some regioselectivities of the Michael addition. The electrophilic triple bond is attacked first, next comes the 1-propenyl group. The conjugated keto group is usually least reactive. The ethynyl starting material has been obtained from the addition of the methoxyethynyl anion to the carbonyl group of crotonaldehyde (G. Stork, 1962 B, 1964A). 

Addition of HCN to unsaturated compounds is often the easiest and most economical method of making organonitnles. An early synthesis of acrylonitrile involved the addition of HCN to acetylene. The addition of HCN to aldehydes and ketones is readily accompHshed with simple base catalysis, as is the addition of HCN to activated olefins (Michael addition). However, the addition of HCN to unactivated olefins and the regioselective addition to dienes is best accompHshed with a transition-metal catalyst, as illustrated by DuPont s adiponitrile process (6—9). 

The best method to achieve a high regioselectivity is the use of preformed enolates. A double annulation reaction is possible if, for example, a diketone such as 11 is used as starting material. The product of the Michael addition 12 can undergo two subsequent aldol condensation reactions to yield the tricyclic dienone 13 ... 

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... 

Treatment of 71a with phosphorus oxychloride readily afforded the dichloro derivative 79 in 95% yield. Michael addition with methyl acrylate in the presence of Triton B led to the regioselective formation of 80 (Scheme 3)... 

Gold-catalyzed direct C-H functionalizations enable the formation of polyalkylated arenes under mild conditions. In many cases, branched products are obtained. Two mechanisms are thought to operate with electron-rich arenes, an S si2-type mechanism via Au(lll) leads to the linear product. The branched product is obtained via a Friedel-Craft-type alkylation. A silver salt is often added and is believed to generate a more electrophilic Au(m) species. Often regioselectivities are poor and symmetric arenes are employed. Intramolecular variants as well as Michael additions are also known (Equations (72)-(74)).71,71a,71b... 

In contrast to these transformations, Michael additions of simple enolates to acceptor-substituted dienes often yield mixtures of 1,4- and 1,6-addition products27-30. For example, a 70 30 mixture of 1,4- and 1,6-adducts was isolated from the reaction of the lithium enolate of methyl propionate with methyl sorbate30. This problem can be solved by using the corresponding silyl ketene acetal in the presence of clay montmorillonite as acidic promoter under these conditions, almost exclusive formation of the 1,4-addition product (syn/anti mixture) was observed (equation ll)30. Highly regioselective 1,4-additions... 

The regioselectivity of Michael additions of thiolates to 2,4-dienones can be altered drastically by variation of the reaction conditions and addition of Lewis acids to the reaction mixture. Lawton and coworkers examined the reaction of 2-mercaptoethanol with l-(3-nitrophenyl)-2,4-pentadien-l-one and observed a high regioselectivity in favor of the 1,6-addition product at 45 °C (equation 42)123,124. Lowering of the reaction temperature caused an increase in the amount of 1,4-adduct, and at —40°C, a product ratio of 40 60 was found. These events suggest that kinetic control favors the 1,4-addition product whereas the 1,6-adduct is thermodynamically more stable. If, however, the reaction was carried out with a complex of the dienone and titanium tetrachloride, only the 1,4-adduct was isolated after hydrolytic workup123. Obviously, this product is trapped as a metal chelate which prevents formation of the 1,6-adduct by retro-Michael/Michael addition. In the absence of the chelating Lewis acid, the 1,4-addition product can indeed be converted... 

The first 1,6-addition reactions of thiolates to steroid dienones were examined well before the discovery of the antiestrogenic properties of 7o -substituted steroids. Ralls and coworkers129 and Djerassi and coworkers130 studied thiol additions to A3,5-steroids for example, the reaction of 3,5-cholestadien-7-one with ethanethiol was reported to proceed with high 1,6-regioselectivity and -stereoselectivity (equation 47)129. In a series of papers, Brueggemeier and coworkers131-137 described the synthesis and biochemical evaluation of numerous 7at-sul fur-substituted steroids which were prepared by Michael addition to steroid dienones. Thus, 4,6-androsta-3,17-dienone was treated with various... 

Vitamin Bi2-catalyzed intramolecular cathodic coupling leads to a regioselective 1,4-addition with formation of a spirocom-pound (Eq. 2) [95]. This chain reaction is initiated by the reduction of Co(III) to a Co(I) species, which reacts in an oxidative addition with the alkyl bromide. The resulting alkyl-Co(III)-Br species is then reduced to an alkyl anion that undergoes a Michael addition and yields Co(I) for the next cycle. 

It should be noted here that a regioselective control may also be exerted by just controlling the experimental conditions. Thus, working under strictly kinetic conditions (low temperature, absence of oxygen and slow addition of the ketone to an excess of a solution of an aprotic base) the less substituted enolate of carvomenthone can also be selectively generated and may be then submitted to different kind of reactions. However, reversible reactions like the Michael addition would equilibrate the reaction mixture to the thermodynamically more stable enolate. 

Thanks to their ambident character, acceptor-substituted dienes can provide several isomeric products in copper-mediated Michael additions, therefore making it particular important to control not only the regioselectivity but also the stereoselectivity of these transformations (Scheme 4.1). 

The first example of a cuprate addition to an acceptor-substituted diene was reported by Naf et al. [9], who used lithium di-(Z)-l-heptenylcuprate in a Michael addition to dienoate 1 (Eq. 4.2). The reaction proceeded highly regioselectively, furnishing a 1 1 mixture of the two isomeric 1,6-adducts 2, which were converted into the Bartlett pear constituent ethyl (2 ,6Z)-2,6-dodecadienoate (3) by basic isomerization. 

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