Nucleophilic additions multiple bonds activated

The previous sections dealt with reactions in which the new carbon-carbon bond is formed by addition of the nucleophile to a carbonyl group. Another important method for alkylation of carbon nucleophiles involves addition to an electrophilic multiple bond. The electrophilic reaction partner is typically an a,(3-unsaturated ketone, aldehyde, or ester, but other electron-withdrawing substituents such as nitro, cyano, or sulfonyl also activate carbon-carbon double and triple bonds to nucleophilic attack. The reaction is called conjugate addition or the Michael reaction. 

By far the commonest and most extensively studied reactions of sulfinate ions are those in which they act as a nucleophile, either to perform a substitution, or to undergo addition to activated carbon-carbon multiple bonds or carbonyl groups. The detailed literature on the many examples of such reactions has been well reviewed by both Stirling (1971) and Oae (1977). We will attempt here only to summarize some of the conclusions of mechanistic interest. 

Oxidative electrophilic activation of a, f-unsaturated phenylsulfides, carried out in an AcOH/AcONa solution results in products of the addition of a nucleophile to the multiple bonds, a,y3-diacetoxysulfides or, as a result of a further oxidation, that eliminates the PhS group, in a-acetoxy ketones (Scheme 23) [89]. 

The rate-determining step in nucleophilic additions is usually nucleophilic attack on the multiple bond.127 For example, the entropy of activation of a Michael condensation is always a large, negative quantity. This arises from the fact that in the transition state the five atoms, 0=C—C—C=0 of the anion and the four atoms, C=C-—C=0 (or C=C—C=N) of the a,/ -unsaturated carbonyl (or nitrile) system are all restricted to one plane to allow maximum... 

The formal addition of a C-H bond at activated methylenes and methynes (pronucleophiles) to activated alkenes in the presence of a base is well known as the Michael reaction (Scheme 1, Type A) [1]. In modem organic syntheses, the use of transition metal (TM) catalysts enables the C-H addition of activated methylenes and methynes to activated alkenes perfectly under neutral conditions (Scheme 1, Type B) [2]. In general, the nonfunctionalized carbon-carbon multiple bonds (for example, EWG2 = H in Scheme 1) are unreactive toward carbon nucleophiles because of their electron rich Jt-orbitals. The pioneering efforts by various research groups resulted in the development of transition metal-catalyzed addition of a C-H bond at active alkanes to such unactivated C-C multiple bonds. This reaction consists of the formal addition of a C-H bond across the C-C multiple bonds and is called a hydrocarbonation reaction. As a milestone in this hydro-carbonation area, early in the 1970s, Takahashi et al. reported the Pd-catalyzed addition of the C-H bond of pronucleophiles to 1,3-dienes [3], The first Pd-catalyzed reaction of activated methylenes with unsubstituted allenes was apparently reported by Coulson [4]. The synthetic applications of this reaction were very limited. In the last decade, the Pd-catalyzed addition of C-H bonds to various unacti-... 

The Michael reaction involves the addition of a nucleophilic carbon species to an electrophilic multiple bond. The electrophilic partners are typically a,fi-unsaturated ketones, esters or nitriles, but other electron-withdrawing substituents can be used to activate the carbon—carbon double bond to nucleophilic attack. A tandem aldol-Michael reaction has been recently described. Wachter-Jurcsak and coworkers66 reported that the reactions involving 2-pyridinecarboxaldehyde, 71, and 2-quinolinecarboxaldehyde with the enolates of acetophenone, 70, afforded the unexpected symmetric l,5-diphenyl-3-(2-heteroaryl)-1,5-pentanediones (Scheme 24). 

Michael addition is a facile reaction between nucleophiles and activated olefins and alkynes in which the nucleophile adds across a carbon-carbon multiple bond [25], For the preparation of hydrogels, the hydroxyl, thiol or amine functionalities have been reacted with vinyl sulfones [26-28], acrylates [29-31], acrylamides [32], and maleimides [33, 34] (Scheme 2). 

Nucleophilic addition to C=0 or C=X multiple bonds is faeilitated by Lewis acid activation. The extent of activation required is dependent on the electrophilicity of the carbon atom and on the nucleophilicity of the reagent. Copper Lewis acids have found utility in a variety of reactions involving nucleophilic addition. 

Nucleophilic catalytic reactions are usually addition and substitution reactions. A diverse array of Lewis bases (e.g., tertiary phosphines, tertiary amines, pyridines, and imidazoles) have been shown to serve as nucleophilic catalysts. Nucleophilic reactions typically occur at C=X and activated C=C multiple bonds. In a general form for a reaction... 

Owing to its tendency to undergo nucleophilic addition with carbonyl groups and other electrophilic carbon-heteroatom multiple bonds (C=NR, C=N, C=S), n-BuLi is usually not the reagent of choice for the generation of enolate anions or enolate equivalents from active hydrogen conpounds. This is done most conveniently using the less nucleophilic lithium dialkylamides (e.g. Lithium DUsopropylamide (LDA), Lithium 2,2,6,6-Tetra-... 

Nucleophilic additions to alkenes and alkynes are also possible, but these reactions generally require that the substrate have substituents that can stabilize a carbanionic intermediate. Therefore, nucleophilic additions are most likely for compoimds with carbon-heteroatom multiple bonds, such as carbonyl compounds, imines, and cyano compounds. We may distinguish two main types of substituents that activate alkenes and alkynes for nucleophilic attack. The first type consists of those activating groups (labeled AG in equation 9.79) that can stabilize an adjacent carbanion by induction. ... 

An extension of Hashmi s Au(III)-catalyzed phenol synthesis [81] to furan substrates 9 bearing an additional alkyne moiety allowed the preparation of C6-C7-heterofused benzofuran 11 (Scheme 9.3) [82]. According to the proposed mechanism, the Au(III)-catalyzed arene formation reaction generates o-alkynylphenol 10. A subsequent Au(III)-catalyzed cycloisomerization of the latter, following the general mechanism for an intramolecular nucleophilic addition of heteroatom to transition metal-activated carbon-carbon multiple bonds, gives 11 (Scheme 9.3). 

Castro first documented cydoisomerization of ortho-alkynylanilines 96 to give the 2-phenyl indole 97 in the presence of substoidiiometric amounts of Cu(I) catalyst in excellent yield (Scheme 9.35) [77, 111]. Mechanistically, it is believed that 5-exo-dig cydization follows the generally accepted mechanism proposed for an intramolecular addition of various nucleophilic entities to transition metal-activated carbon-carbon multiple bonds. 

The mechanism and stereochemistry of hydrophosphonylation of a-ketoesters by dimethylphosphonate [H-P(=0)(0Me)2l has been studied theoretically by the ONIOM method, for catalysis by cinchona-thioureas. Deprotonation of the phosphonate 0 is rate determining. It is followed by C-P bond formation (the stereo-controlhng step) via nucleophilic addition, and then reprotonation (regenerating the catalyst). Multiple hydrogen bonds activate the substrates, facilitate charge transfer and stabihze transition states. 

In 1963, Huisgen et al. published a systematic study on the concerted 1,3-dipolar cycloaddition, based on previous results from Smith and coworkers about the 1,3-addition of diazoalkanes, ozone and azides, as well as kinetic studies on the mechanism. The addition of a 1,3-dipole 1 (a-b-c), possessing ambivalent electrophilic as well as nucleophilic activity to a multiple bond system like the dipolarophile 2 (d-e), leads to a remarkably wide variety of five-membered heterocyclic compounds. ... 

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