Michael Addition of C-nucleophiles

Only three examples of intramolecular organocatalyzed and enantioselective Michael additions of C-nucleophiles seem to have been reported in the literature. In 1979 Wynberg and ten Hoeve reported the (—)-quinine-catalyzed double Michael addition of the 1,3-diones 74a,b to the 1,5-disubstituted pentadien-3-ones 75a-c (Scheme 4.37) [61]. 

Intermolecular Michael Additions of C-Nucleophiles Catalysed by Proline Derivatives... 

On the other hand, a number of asymmetric Michael additions of C-nucleophiles involving acceptors other than a,p-unsaturated aldehydes and catalysed by a proline derivative have recently been reported. As an example. 

A number of highly efficient asymmetric domino nitro-Michael additions of C-nucleophiles catalysed by organocatalysts were described in 2008. One of the most employed organocatalysts for these types of reactions is diphenylprolinol silyl ether. This catalyst was used by Hong et al. to develop a highly diastereo-and enantioselective domino reaction occurring between 7-oxohept-2-enoate and nitroalkenes (Scheme 1.61). ° The reaction afforded highly functionalised... 

Table 16 Michael addition of C-, N-, 0-, and S-centered nucleophiles to furyl nitroalkene and subsequent IMDAF reaction of...

An attractive method to generate C5-monoalkyl-substituted Meldrum s acids consists of a two-step synthesis (Scheme 10). In the first step, a Knoevenagel reaction between Meldrum s acid (22) and an aldehyde (or sometimes a ketone) yields the C5-alkylidene derivative 23. In the following step, the alkylidene derivative 23 is reduced, to generate the C5-monoalkyl-substituted Meldrum s acid 24.[43 71 104 1051 Alternatively, in the second step, Michael addition of a nucleophile to the conjugated C=C bond in the C5-alkylidene derivative generates a Meldrum s acid 25 monosubstituted on C5 by a more elaborated alkyl.t106 ... 

Resin-bound amines can be converted into imines [710,711] or enamines by reaction with carbonyl compounds (Entries 6 and 7, Table 3.39). Resin-bound enamines have also been prepared by Michael addition of resin-bound secondary amines to acceptor-substituted alkynes [712], by Hg(II)-catalyzed addition of resin-bound secondary amines to unactivated alkynes [713], by addition of C-nucleophiles to resin-bound imino ethers [714], and by chemical modification of other resin-bound enamines [712,713,715], Acceptor-substituted enamines ( push-pull alkenes) are not always susceptible to hydrolytic cleavage by TFA alone and might require aqueous acids to undergo hydrolysis [716]. 

The first examples of asymmetric Michael additions of C-nudeophiles to enones appeared in the middle to late 1970s. In 1975 Wynberg and Helder demonstrated in a preliminary publication that the quinine-catalyzed addition of several acidic, doubly activated Michael donors to methyl vinyl ketone (MVK) proceeds asymmetrically [2, 3], Enantiomeric excesses were determined for addition of a-tosylnitro-ethane to MVK (56%) and for 2-carbomethoxyindanone as the pre-nudeophile (68%). Later Hermann and Wynberg reported in more detail that 2-carbomethoxy-indanone (1, Scheme 4.3) can be added to methyl vinyl ketone with ca 1 mol% quinine (3a) or quinidine (3b) as catalyst to afford the Michael-adduct 2 in excellent yields and with up to 76% ee [2, 4], Because of their relatively low basicity, the amine bases 3a,b do not effect the Michael addition of less acidic pre-nucleophiles such as 4 (Scheme 4.3). However, the corresponding ammonium hydroxides 6a,b do promote the addition of the substrates 4 to methyl vinyl ketone under the same mild conditions, albeit with enantioselectivity not exceeding ca 20% [4],... 

Intermolecular Michael Addition 69 4.1.1.3 Addition of C-nucleophiles to Azodicarboxylates... 

The most important kinds of conjugate addition reactions are Michael reactions, which involve the addition of C nucleophiles to C=C 7r bonds. The nucleophiles are often 1,3-dicarbonyl compounds such as malonates, cyanoacetates, j8-ketoesters, and 1,3-diketones, but simple carbonyl compounds may also be used. Only catalytic amounts of base are usually required. 

To further probe the scope of this chemistry, Somei and coworkers studied the reaction of l-methoxy-3-(2-nitrovinyl)indole (103) with nucleophiles [43]. In this substrate, there are two possible sites for the nucleophile to attack. Dipolar aprotic solvents such as DMF or hexamethylphosphoramide (HMPA) encourage attack of the nucleophile at C-2 with concomitant loss of methoxide to form 104. Use of tetrahydrofuran (THF) results in Michael addition of the nucleophile to the p-carbon of the nitrovinyl side chain to produce 105. 

The Michael addition of a nitrogen-centered nucleophile to nitroalkenes affords compounds that may serve as precursors of vicinal diamines, since the nitro group can be reduced to an amino function by reduction. The very convenient method for the preparation of 1,2-diamines is developed by the addition of C-ethylhydroxylamines to nitroalkenes followed by reduction with H2 in the presence of Pd/C (Eq. 4.24).30... 

The controlled polymerization of (meth)acrylates was achieved by anionic polymerization. However, special bulky initiators and very low temperatures (- 78 °C) must be employed in order to avoid side reactions. An alternative procedure for achieving the same results by conducting the polymerization at room temperature was proposed by Webster and Sogah [84], The technique, called group transfer polymerization, involves a catalyzed silicon-mediated sequential Michael addition of a, /f-unsaluralcd esters using silyl ketene acetals as initiators. Nucleophilic (anionic) or Lewis acid catalysts are necessary for the polymerization. Nucleophilic catalysts activate the initiator and are usually employed for the polymerization of methacrylates, whereas Lewis acids activate the monomer and are more suitable for the polymerization of acrylates [85,86]. 

A diverse group of organic reactions catalyzed by montmorillonite has been described and some reviews on this subject have been published.19 Examples of those transformations include addition reactions, such as Michael addition of thiols to y./bunsatu rated carbonyl compounds 20 electrophilic aromatic substitutions,19c nucleophilic substitution of alcohols,21 acetal synthesis196 22 and deprotection,23 cyclizations,19b c isomerizations, and rearrangements.196 24... 

Intermediates such as 224 resulting from the nudeophilic addition of C,H-acidic compounds to allenyl ketones such as 222 do not only yield simple addition products such as 225 by proton transfer (Scheme 7.34) [259]. If the C,H-acidic compound contains at least one carbonyl group, a ring dosure is also possible to give pyran derivatives such as 226. The reaction of a similar allenyl ketone with dimethyl mal-onate, methyl acetoacetate or methyl cyanoacetate leads to a-pyrones by an analogous route however, the yields are low (20-32%) [260], The formation of oxaphos-pholenes 229 from ketones 227 and trivalent phosphorus compounds 228 can similarly be explained by nucleophilic attack at the central carbon atom of the allene followed by a second attack of the oxygen atom of the ketone at the phosphorus atom [261, 262], Treatment of the allenic ester 230 with copper(I) chloride and tributyltin hydride in N-methylpyrrolidone (NMP) affords the cephalosporin derivative 232 [263], The authors postulated a Michael addition of copper(I) hydride to the electron-... 

Dicarbonyl compounds are widely used in organic synthesis as activated nucleophiles. Because of the relatively high acidity of the methylenic C—H of 1,3-dicarbonyl compounds, most reactions involving 1,3-dicarbonyl compounds are considered to be nucleophilic additions or substitutions of enolates. However, some experimental evidence showed that 1,3-dicarbonyl compounds could react via C—H activations. Although this concept is still controversial, it opens a novel idea to consider the reactions of activated C H bonds. The chiral bifunctional Ru catalysts were used in enantioselective C C bonds formation by Michael addition of 1,3-dicarbonyl compounds with high yields and enantiomeric excesses. ... 

There is no published example of a cyclopropanation of the double bond in chlorocyclopropylideneacetate 1-Me with retention of the chlorine atom. Thus, attempted cyclopropanations under Simmons-Smith [37] or Corey [38] conditions failed [25]. The treatment of the highly reactive methylenecyclopropane derivative 1-Me with dimethoxycarbene generated by thermal decomposition of 2,2-dimethoxy-A -l,3,4-oxadiazoline 26 (1.5 equiv. of 26,PhH, 100 °C,24 h),gave a complex mixture of products (Scheme 7) [39], yet the normal cycloadduct 28 was not detected. The formation of compounds 29 - 33 was rationalized via the initially formed zwitterion 27, resulting from the Michael addition of the highly nucleophilic dimethoxycarbene to the C,C-double bond of 1-Me. The ring closure of 27 to the normal product 28 is probably reversible, and 27 can rearrange or add a second dimethoxycarbene moiety and a molecule of acetone to form 33. 

It is not surprising that chloro esters 1, 2 readily add thiols, catalyzed by sodium thiolates or triethylamine, to give the corresponding 2-(r-organylthiocy-clopropyl)-2-chloroacetates 85,86 (Scheme 22) [15 b, 22b, 27]. This reaction with thiophenol has been used to quantify the Michael reactivity of 1-Me, 2-Me, 3-X in comparison to simple acrylates (see above). With an excess of PhSH, the nucleophilic substitution of the chlorine in 85 a (but not in 85h) proceeded to give the corresponding bis(phenylthio) derivative in 63% yield [15bj. Alkali thiolates (e.g. NaSMe, NaSBn) add smoothly onto 1-Me, 2c-Me and 2p-Me at - 78 °C, because at this temperature subsequent nucleophilic substitution of the chlorine is much slower [7l, 9]. The Michael additions of sodium phenylselenide and sodium arylsulfenates onto 1-Me and their synthetic utility have been discussed above (see Table 1). 

The Michael adducts of nitrogen nucleophiles are among the most important ones for organic synthesis (their synthetic applications will be discussed in the corresponding Sections). The addition of primary amines onto 1 and 2 in methanol was normally complete after a few minutes at - 10°C and gave moderate to good yields of the monoadducts 89 (for example, 67 % for n-butylamine and benzylamine adducts 89a-Me and 89b-fBu [261 ) But later it was found that performing these additions in THF leads to better and well reproducible yields of the adducts 89 (Scheme 25) [11b, 53,561. 

There are three straightforward possibilities of binding a chlorocyclopropyl-ideneacetate molecule onto a polymer resin (Fig. 12) a) binding using an ester functionality as in 267, b) binding by a functionality in a substituent on the three-membered ring as in 268 and c) binding by way of a Michael addition of a polymer-bound nucleophile onto the chloro esters 1,2 as in 269. 

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