Selenoxide elimination (also called α-selenation)[1] is a method for thechemical synthesis ofalkenes fromselenoxides. It is most commonly used to synthesize α,β-unsaturatedcarbonyl compounds from the corresponding saturated analogues.[2] It is mechanistically related to theCope reaction.
After the development ofsulfoxide elimination as an effective method for generatingcarbon–carbondouble bonds,[3] it was discovered that selenoxides undergo a similar process, albeit much more rapidly. Most selenoxides decompose to the corresponding alkenes at temperatures between −50 and 40 °C. Evidence suggests that the elimination issyn; however,epimerization at both carbon and selenium (both of which arestereogenic) may occur during the reaction. As selenoxides can be readily prepared fromnucleophilic carbonyl derivatives (enols andenolates),[4] selenoxide elimination has grown into a general method for the preparation of α,β-unsaturated carbonyl compounds.
(1)
Elimination of selenoxides takes place through anintramolecular syn elimination pathway. The carbon–hydrogen and carbon–selenium bonds are co-planar in the transition state.[5]
(2)
The reaction is highlytrans-selective whenacyclic α-phenylseleno carbonyl compounds are employed. Formation of conjugated double bonds is favored. Endocyclic double bonds tend to predominate overexocyclic ones, unless nosyn hydrogen is available in the ring. Selenium in these reactions is almost always stereogenic, and the effect of epimerization at selenium (which isacid-catalyzed and occurs readily) on theelimination reaction is nearly unknown. In one example, separation and warming of selenoxides1 and2 revealed that2 decomposes at 0 °C, while1, which presumably has more difficulty accessing the necessarysyn conformation for elimination, is stable to 5 °C.[6]
(3)
Kinetic isotope effect studies have found a ratio of pre-exponential factors ofAH/AD of 0.092 for sulfoxide elimination reactions, indicating that quantum tunneling plays an important role in the hydrogen transfer process.[7][8]
α-Selanylation of carbonyl compounds can be accomplished withelectrophilic ornucleophilic selanylating reagents. Usually, simple phenylseleno compounds are used in elimination reactions; although 2-nitrophenylselenides react more quickly, they are more expensive to prepare, and phenylselenides typically react in minutes. Electrophilic selanylating reagents can be used in conjunction withenols,enolates, orenol ethers. Phenylselanating reagents include:
The most commonoxidizing agent employed ishydrogen peroxide (H2O2).[9] It is sometimes used in excess, to overcome catalytic decomposition of H2O2 by selenium; however, undesiredoxidation of starting material has been observed under these conditions. Oxidation of products (via theBaeyer-Villiger reaction, for instance) has also been observed.[10]
(4)
For substrates whose productolefins are sensitive to oxidation,meta-Chloroperoxybenzoic acid (mCPBA) can be employed as an oxidant. It oxidizes selenides below the temperature at which they decompose to alkenes; thus, all oxidant is consumed before elimination begins.Buffering with anaminebase is necessary before warming to avoid acid-mediated side reactions.[11]
(5)
Ozone, which gives onlydioxygen as a byproduct after oxidation, is used to oxidize selenides when special conditions are required forthermolysis or extreme care is necessary during workup.Quinones can be synthesized from the corresponding cyclicunsaturated carbonyl compounds using this method.[12]
(6)
α-Phenylselenoaldehydes, which are usually prepared from the correspondingenol ethers, are usually oxidized with mCPBA or ozone, as hydrogen peroxide causes over-oxidation. α-Phenylselenoketones can be prepared by kinetically controlled enolate formation and trapping with an electrophilic selanylating reagent such as benzeneselenyl chloride. A second deprotonation, forming a selenium-substituted enolate, allowsalkylation or hydroxyalkylation of these substrates.[13]
(7)
Base-sensitive substrates may be selanylated under acid-catalyzed conditions (as enols) using benzeneselenyl chloride.Hydrochloric acid generated during the selanylation of transient enol catalyzestautomerization.[14]
(8)
The seleno-Pummerer reaction is a significant side reaction that may occur under conditions when acid is present.[15] Protonation of the selenoxide intermediate, followed by elimination ofhydroxide andhydrolysis, leads to α-dicarbonyl compounds. The reaction is not a problem for more electron-rich carbonyls—generally, fewer side reactions are observed in eliminations ofesters andamides.[15]
(9)
A second significant side reaction in reactions of ketones and aldehydes is selanylation of the intermediate selenoxide. This process leads to elimination products retaining a carbon-selenium bond,[16] and is more difficult to prevent than the seleno-Pummerer reaction. Tertiary selenoxides, which are unable to undergo enolization, do not react further with selenium electrophiles.
(10)
Analogous sulfoxide eliminations are generally harder to implement than selenoxide eliminations. Formation of the carbon–sulfur bond is usually accomplished with highly reactivesulfenyl chlorides, which must be prepared for immediate use. However, sulfoxides are more stable than the corresponding selenoxides, and elimination is usually carried out as a distinct operation. This allows thermolysis conditions to be optimized (although the high temperatures required may cause other thermal processes). In addition, sulfoxides may be carried through multiple synthetic steps before elimination is carried out.[17]
(11)
The combination ofsilyl enol ethers withpalladium(II) acetate (Pd(OAc)2), theSaegusa oxidation, givesenones. However, the reaction requiresstoichiometric amounts of Pd(OAc)2 and thus is not amenable to large-scale synthesis.[18] Catalytic variants have been developed.[19]
(12)
For β-dicarbonyl compounds,DDQ can be used as an oxidizing agent in the synthesis of enediones. Additionally, some specialized systems give better yields upon DDQ oxidation.[20]
(13)
