Vicinal difunctionalization tandem

In this synthesis, a tandem vicinal difunctionalization of enone 18 provides an exceedingly simple solution to the task of synthesizing spirocyclic intermediate 16. When 18 is treated with the or-ganocuprate reagent, t-Bu2Cu(CN)Li2, a smooth 1,4- or Michael ad-... 

Usually, after an enolate ion is generated from an ocP-unsaturated ketone, it is converted to the P-alkylated product as shown above. But it is often possible to have the enolate react with some other electrophile (tandem vicinal difunctionalization), in some cases at the O and in other cases at the C. For example, if an alkyl halide R X is present (R = primary alkyl or allylic), and the solvent is 1,2-dime-thoxyethane, the enolate (66) can be alkylated directly. Thus, by this method, both the a and p positions of a ketone are alkylated in one synthetic operation (see also 15-23). 

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 synthetic implications of this discovery were slow to be exploited. Base-initiated dimerizations of 2-cycloalkenones, known to give crystalline solids,3233 remained puzzling for some time before conjugate additions were suggested to account for some of the possible products 34 indeed, the product of base-catalyzed dimerization of 4,4-dimethyl-2-cyclopentenone, which proceeds via a double Michael addition sequence, was not identified until 1969 (Scheme 2).35 An unanticipated cyclopropanation reaction of acrylaldehyde36 37 using ethyl bromomalonate and proceeding by means of a similar Michael addi-tion-Sw enolate alkylation represents an early synthetic use of tandem vicinal difunctionalization. 

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... 

If the product of a-functionalization has a tertiary a-carbon, equilibration can occur under the conditions of tandem vicinal difunctionalization, as in equation (2). The equilibration process can proceed at... 

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... 

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. 

A limited number of other anionic species have been employed as Michael donors in tandem vicinal difunctionalizations. In a manner similar to sulfur ylides described above, phosphonium ylides can be used as cyclopropanating reagents by means of a conjugate addition-a-intramolecular alkylation sequence. Phosphonium ylides have been used with greater frequency261-263 than sulfur ylides and display little steric sensitivity.264 Phosphorus-stabilized allylic anions can display regiospecific 7-1,4-addition when used as Michael donors.265... 

---