1.2- difunctionalized substrates

Metal-promoted reductive p-elimination reactions in 1,2-difunctionalized substrates have been one of the most important means of generating C=KZ bonds [9]. In the past few years, a number of reductive elimination reactions of 1,2-difunctionalized compounds have been reported under various organometallic reagents, such as Sml2 [10], Zn [11], or In [12], In addition, those low-valent organometallic species exhibit excellent properties for sequential organic reactions and several examples have been described in which a metal-promoted ehmination reaction occurs as a step of a sequential process [13],... 

The catalytic borylation offers unique selectivity when compared to traditional aromatic substitution reactions. Thus, mono- and 1,3-disubstituted (type 32) arenes react predominantly at meta-positions. This high meta-selectivity is a sterically controlled process. In the case of 1,3-difunctionized substrates borylation occurs exclusively at the 5-position even where functionalizations at the... 

The term condensation polymerization was originally used because this form of polymerization involves condensation reactions. Such transformations normally involve combining two functionalized molecules through an addition-elimination process, termed nucleophilic acyl substitution (Sec. 20.1), that results in the loss of a small molecule, H-L, such as water (Eq. 22.4). The aldol condensation (Sec. 18.3) and esterification (Sec. 20.2) are examples of such reactions. In the case of condensation or step-growth polymerization, difunctionalized substrates are required as monomers, as illustrated in Equation 22.5. 

When 1,3-dienes containing a tethered alcohol are subjected to Wacker-type reactions, the initial intramolecular oxypalladation event creates a 7r-allylpalladium species, which can then undergo an additional bond-forming process to effect an overall 1,4-difunctionalization of the diene with either cis- or // -stereochemistry (Scheme 18).399 An array of substrate types has been shown to participate in this reaction to generate both five- and six-membered fused or ro-oxacycles.435-437 Employing chiral benzoquinone ligands, progress toward the development of an asymmetric variant of this reaction has also been recorded, albeit with only modest levels of enantioselectivity (up to 55% ee).438... 

See Chapdelaine, M. J. Huke, M. Tandem Vicinal Difunctionalization / -Addition to a, /MJnsaturated Carbonyl Substrates Followed by a-Functionaliza-tion in Paquette, L. A. ed. Org. React. John Willey Sons, New York, 1990, p. 38. 

G. H. Posner, Conjugate Addition Reactions of Organocopper Reagents, in W. G. Dauben, Ed., Organic Reactions, Vol. 19, Chap. 1, John Wiley Sons, New York, 1972 M. J. Chapdelaine and M. Hulce, Tandem Vicinal Difunctionalization 0-Addition to a,/3-Unsaturated Carbonyl Substrates Followed by cx-Functionalization, in L. A. Paquette, ed., Organic Reactions, Vol. 38, Chap. 

The two distinct bond-forming steps in tandem vicinal difunctionalization have been studied extensively. The first step consists of a nucleophilic addition to a ir-system the nucleophile is almost invariably an organometal. 1,4-Addition to an a, -unsaturated carbonyl substrate concomitantly generates a new cr-bond at the (3-carbon and an enolate ion. The second step constitutes C-functionalization of the enolate intermediate, forming a new o -bond between the nucleophilic a-carbon of the enolate and an electrophilic reagent. 

As with mechanism, the stereochemical outcome of tandem vicinal difunctionalization is dependent upon the individual bond-forming steps in the sequence. The conjugate addition reaction is quite sensitive to the steric environment of the a,(3-unsaturated substrate, so that the bond-forming process at the 3-carbon adheres to steric approach control factors the 5-methoxycarbonyl substituent of (5) directs axial attack of a bis(dimethylphenylsilyl)copperlithium reagent so that only the 3,5-trans adduct is formed... 

Ketones, specifically 2-alkenones and 2-cycloalkenones, have been used extensively as substrates for tandem vicinal difunctionalization, allowing delineation of various reactivity patterns based upon the structural elements present in the enone. Aldehyde substrates have been used less widely comparison... 

Simple substitution at the a-carbon of the enoate substrate also does not appear to have much effect on the course of the reaction methyl acrylate and methyl methacrylate both function well as substrates in the reaction sequence and isolated yields of the products are similar.100 In certain sterically demanding reaction sequences, a-substitution does reduce the chemical yields of the products but the presence of an a-substituent appears to be of greater importance than the particular identity of the substituent.101 As with ketones, enoate substrates are activated towards tandem vicinal difunctionalization when electron-withdrawing a-substituents are present.102-104... 

Enoate 3-substitution and 3-disubstitution cause a decrease in the rate of the initial conjugate addition step of the reaction sequence that is directly related to the steric bulk of the substituent.103,105 Equation (24) provides a representative case in the a-alkylation of enoates by means of conjugate amination-enol-ate alkylation followed by dehydroamination.106 When 3-substitution results in stereoisomeric ( )- and (Z)-alkenoate substrates, tandem difunctionalization typically proceeds with greater facility for ( )-isomers.64103 Obviously, when the double bond of the ester is part of a medium-sized ring, an ( )-alke-noate geometry is mandated in such cases, tandem vicinal difunctionalization proceeds with uniformly excellent results (equation 25).25... 

When alkynic esters are used as substrates in the reaction sequence, activated alkenes of good isomeric purity can be prepared. Initiation of the difunctionalization usually is by means of organocopper-medi-ated 1,4-addition, which proceeds via carbometallation of the alkynyl moiety of the ester to give a vi-nylcopper intermediate, (14). Trapping by an electrophile affords cis-difunctionalized alkenoates... 

Allenic esters react as enoates in tandem difunctionalization reactions using organocopper reagents as Michael donors (J.-y-unsaturated esters result (equation 28).81 These substrates have found application in the synthesis of a variety of heterocyclic systems.114... 

A similar but conceptually distinct approach to difunctionalization of terminal alkynes consists of sequential carboboration-palladium-catalyzed cross-coupling 137 equation (33) illustrates that this method also provides alkenes of high stereochemical purity by net syn Markovnikov addition. Benzyne-contain-ing molecules can act as highly activated substrates for vicinal difunctionalizations initiated by nucleophiles 138-140 thus, nucleophilic addition-electrophilic trapping can serve as an alternative to sequential directed metallation for the production of 1,2-disubstituted and 1,2,3-trisubstituted aromatic systems (equation 34).141... 

A wide range of nucleophilic reagents has been used to initiate tandem vicinal difunctionalizations of a, -un saturated carbonyl-containing substrates. Dominant among these reagents are organocopper (Gil-... 

Organometallic reagents can be used direcdy or with a transition metal catalyst in tandem vicinal difunctionalization reactions. Relatively basic reagents find greater use with substrate molecules that are not enolizable so that competitive a-deprotonation is avoided and with substrates that have been activated towards conjugate addition by an electron-withdrawing a-substituent. 

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