Heteroatom Conjugate Addition

P-unsaturated carbonyl compounds and related electron-deficient alkenes and alkynes, there exist two electrophilic sites and both are prone to be attacked by nucleophiles. However, the conjugated site is considerably softer compared with the unconjugated site, based on the Frontier Molecular Orbital analysis.Consequently, softer nucleophiles predominantly react with a, P-unsaturated carbonyl compounds through conjugate addition (or Michael addition). Water is a hard solvent. This property of water has two significant implications for conjugate addition reactions (1) Such reactions can tolerate water since the nucleophiles and the electrophiles are softer whereas water is hard and (2) water will not compete with nucleophiles significantly in such 

Thiolates, generated in situ by the action of ammonium tetra-thiomolybdate on alkyl halides, thiocyanates, and disulfides, undergo conjugate addition to a, P-unsaturated esters, nitriles, and ketones in water under neutral conditions (Eq. 10.11). Conjugate addition of thiols was also carried out in a hydrophobic ionic liquid [bmimjPFe/water-solvent system (2 1) in the absence of any acid catalyst to afford the corresponding Michael adducts in high to quantitative yields with excellent 1,4-selectivity under mild and neutral conditions (Eq. 10.12). The use of ionic Mquids helps to avoid the use of either acid or base catalysts 

Addition of azide ion to conjugated systems can be carried out by using NaNs and acetic acid in water (Eq. 10.18). Some reactions were very rapid while others took 1 to 3 days to complete. Lewis base was found to catalyze such conjugate additions of azide ion to cyclic enones 

Highly stabilized phosphorus ylides are prepared from acetylenic esters, a carbon-based nucleophile, and triphenylphosphine in aqueous media. In acetone-water (2 1) solvent, the reaction proceeds via the conjugate addition of triphenylphosphine to dialkyl acetylenedicarboxy-lates the resulting vinyl triphenylphosphonium salts undergo Michael addition reaction with a carbon-nucleophile to give the corresponding highly stabilized phosphoms ylides. 

Delocalized carbanions are soft and can undergo conjugate additions readily with unsaturated carbonyl compounds in water. For nonstabi-lized carbanions, the change of counter-cation can significantly affect 

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Another example of resort to heteroatoms to obtain both oral potency and a split between androgenic and anabolic activities Ls tiomestrone (99). Trienone, 98, prepared in much the same way as 23, undergoes sequential 1,6 and 1,4 conjugate addition of thioacetic acid under either irradiation or free radical catalysis to afford the compound containing two sulfur atoms. 

Conjugate Addition of Heteroatom Nucleophiles and Subsequent Nef Reaction... 

Given the above possible reaction mechanism, it is then intriguing to speculate that another approach to the same stereoselective reduction of a vinyl sulphone could be achieved by the use of a suitably sterically hindered organosilane, as outlined in equation (64). Such a reaction would provide an interesting test for the stereoelectronics of a conjugate addition reaction by a second-row heteroatom to a vinyl sulphone. 

The chemical behavior of heteroatom-substituted vinylcarbene complexes is similar to that of a,(3-unsaturated carbonyl compounds (Figure 2.17) [206]. It is possible to perform Michael additions [217,230], 1,4-addition of cuprates [151], additions of nucleophilic radicals [231], 1,3-dipolar cycloadditions [232,233], inter-[234-241] or intramolecular [220,242] Diels-Alder reactions, as well as Simmons-Smith- [243], sulfur ylide- [244] or diazomethane-mediated [151] cyclopropanati-ons of the vinylcarbene C-C double bond. The treatment of arylcarbene complexes with organolithium reagents ean lead via conjugate addition to substituted 1,4-cyclohexadien-6-ylidene complexes [245]. 

Relatively few examples involving a phosphorous atom in the a-heteroatom-alkylcuprate have appeared [176]. Such cuprates have been treated with allylic and propargylic substrates, but have not been reported to undergo conjugate addition... 

High levels of asymmetric induction can be achieved intramolecularly if the substrate functionality and the heteroatom ligand are contained in the same molecule. Chiral amido(a]kyl)cuprates derived from allylic carbamates [(RCH= CHCH20C(0)NR )CuR undergo intramolecular allylic rearrangements with excellent enantioselectivities (R = Me, n-Bu, Ph 82-95% ee) [216]. Similarly, chiral alkoxy(alkyl)cuprates (R OCuRLi) derived from enoates prepared from the unsaturated acids and trans-l,2-cyclohexanediol undergo intramolecular conjugate additions with excellent diasteroselectivities (90% ds) [217]. 

Conjugate addition reactions of acyclic Michael acceptors possessing heteroatom-substituted stereogenic centers in their y-positions may provide useful levels of diastereoselectivity. A typical example is given with the y-alkoxy-substituted enoate 49 in Scheme 6.8 [17]. High levels of diastereoselectivity in favor of the anti addition product 50 were found in the course of dimethylcuprate addition. 

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