Reductive elimination, sulfone-based

The first step in the cycle, analogous to the cross-coupling reactions, is the oxidative addition of an aryl (vinyl) halide or sulfonate onto the low oxidation state metal, usually palladium(O). The second step is the coordination of the olefin followed by its insertion into the palladium-carbon bond (carbopalladation). In most cases palladium is preferentially attached to the sterically less hindered end of the carbon-carbon double bond. The product is released from the palladium in a / -hydrogen elimination and the active form of the catalyst is regenerated by the loss of HX in a reductive elimination step. To facilitate the process an equivalent amount of base is usually added to the reaction mixture. 

Another sulfone-based elimination of large applicability was proposed by Julia [418,419], Condensation of a metalled phenyl alkyl sulfone with a carbonyl compound, functionalization of the alkoxide and reductive elimination leads to an olefin. 

The facility of arene reductive elimination underpins numerous C-C, C-O and C-N bond-forming reactions, which may be catalysed by late transition metals, in particular palladium (Figure 4.10). Although there are many variants, the general reaction scheme involves introduction of the aryl in electrophilic form via oxidative addition of an aryl halide (or sulfonate), substitution of the palladium halide by a nucleophile (which may also be carbon based) followed by reductive elimination. It is noteworthy that nucleophilic aromatic substitution in the absence of such catalysts can be difficult. 

Potassium hexamethylsilazide is used as non-nucleophilic base to deprotonate 24 next to the sulfone. In the (Sylvestre) Julia olefmation the resulting C-nucleophile adds to the aldehyde and, in theory, the following steps of the mode of action yield the desired double bond -selectively by reductive elimination. In this case the Z-configured product was obtained as the major isomer. 

Most recently, the immunosuppressive agent FK-S06 (416) has been the target of total synthesis. To date several approaches to the trisubstituted alkene region at C-19 and C-20 have appeared. These preliminary studies allow the comparison between the Warren phosphine oxide approach and the Julia coupling. In the first total synthesis of FK-S06, Jones and coworkers at Merck formed the the alkene deprotonadon of the phosphine oxide (418) and condensation with the aldehyde (417). The hydroxy-phosphine oxides were formed in a ratio of 1 1 in 77% yield. The less polar diastereomer was treat with base to obtain the ( )-alkene (419) in 32% overall yield from the aldehyde (equation 96). Danishefsky utilized the Julia coupling for the formation of the trisubstituted alkene region. The sulfone anion (420) was treated with isobu raldehyde as a model, followed by acetylation and reductive elimination to... 

A three-stage synthesis of allylic alcohols has been devised (Scheme 32)," which consists of (i) alkylation of a sulfone-stabilized allylic carbanion (ii) peroxy acid oxidation of the allylic sulfone to give a 2,3-epoxy sulfone and (iii) reductive elimination of the 2,3-epoxy sulfone to give the allylic alcohol. The overall strategy is similar to that of the Evans-Mislow allylic alcohol synthesis based on the 2,3-sig-matropic rearrangement of allylic sulfoxides. However, there are regiochemical advantages to the sul-... 

Different routes to the total synthesis of natural products that are based on these two reactions (reductive desulfonylation or reductive elimination) as the key connection steps have been reported. Two different total syntheses248,249 of the 24-membered macrolide isolated from a deep-sea bacterium, (—)-macrolactin A, involve as the key step a sulfone-mediated C-C coupling, with subsequent reductive desulfonylation249 or reductive elimination248. 

The Julia Alkenation and Related Reactions. In 1973, Julia and Paris reported a new connective and regioselective alkene synthesis (eq 10) based on the reductive elimination of fi-acyloxy sulfones. The Juha alkenation is now one of the principal methods for fragment linkage in complex natural product synthesis. Mono-, di-, tri-, and tetrasuhstituted alkenes can he prepared in moderate to good yield, depending on the substrate. The three-step sequence, illustrated in eq 11, entails (a) condensation of a metalated sulfone with an aldehyde or ketone, (h) O-functionalization of the adduct as the acetate, henzoate, or mesylate (to prevent retroaldohzation), and (c) reductive elimination using 6% Na(Hg) in THF-MeOH (3 1) at —20 °C. In favorable cases, step (b) can be omitted and the reductive elimination performed on a... 

The 2,2 -bis(phenylthiomethyl) dispiroketal (dispoke) derivative is cleaved by oxidation to the sulfone, followed by treatment with LiN(TMS)2. The related bromo and iodo derivatives are cleaved reductively with LDBB (lithium 4,4 -di- -butylbiphenylide) or by elimination with the P4- -butylphosphazene base and acid hydrolysis of the enol ether. The 2,2-diphenyl dispiroketal is cleaved with FeCl3 (CH2CI2, rt, overnight)." The dimethyl dispiroketal is cleaved with TFA, and the allyl derivative is cleaved by ozonolysis followed by elimination. ... 

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

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