Carbenes epoxides

The synthon will be, in a lower valeney state - if X is C then it will be a carbene or the synthetic equivalent of a carbene. Let s see how this disconnection works out for epoxides. Taking X = O first we have... 

More definitive evidence for the formation of an oxirene intermediate or transition state was presented recently by Cormier 80TL2021), in an extension of his earlier work on diazo ketones 77TL2231). This approach was based on the realization that, in principle, the oxirene (87) could be generated from the diazo ketones (88) or (89) via the oxocarbenes 90 or 91) or from the alkyne (92 Scheme 91). If the carbenes (90) (from 88) and (91) (from 89) equilibrate through the oxirene (87), and if (87) is also the initial product of epoxidation of (92), then essentially the same mixture of products (hexenones and ketene-derived products) should be formed on decomposition of the diazo ketones and on oxidation of the alkyne this was the case. 

Although most of the examples of [3S+2C] cycloaddition reactions with carbene complexes are referred to as 1,3-dipolar processes, we should include in this section another kind of non-dipolar transformation dealing with the reaction of pentacarbonyl(methoxymethylcarbene)chromium with a base followed by treatment with an epoxide in the presence of boron trifluoride. This reaction gives cyclic carbene complexes in a process that can be considered a [3S+2C] cycloaddition [44] (Scheme 14). 

The radical versus electrophilic character of triplet and singlet carbenes also shows up in relative reactivity patterns given in Table 10.1. The relative reactivity of singlet dibromocarbene toward alkenes is more similar to electrophiles (bromination, epoxidation) than to radicals ( CCl,). 

The outstanding chemoselectivity of Cp2TiCT was amply demonstrated by Merlic [50,51] and by Dotz [52] who employed a, /3-unsaluraled tungsten and chromium carbenes as radical traps for C - C bond formation. In the latter contribution the very acid sensitive glycal epoxides were used with good success. An example is shown in Scheme 8. 

Azibenzil, in the presence of 02 and Pd(OAc)2 or PdCl2 2 PhCN, forms an intermediate metal-oxygen-carbene complex which is able to epoxidize aliphatic and alicyclic olefins azibenzil itself is transformed into benzil75). 

The enantioseiective hydrogenation of a-amino ketones has been applied extensively to the synthesis of chiral drugs such as the / -agonist SR 58611 (Sanofi Cie). m-Chlorstyreneoxide was obtained via carbene-induced ring closure of the amino alcohol. Epoxide-opening by a chiral amine obtained via a ruthenium-catalyzed hydrogenation of an enamide has led to the desired compound where... 

An alternative to the synthesis of epoxides is the reaction of sulfur ylide with aldehydes and ketones.107 This is a carbon-carbon bond formation reaction and may offer a method complementary to the oxidative processes described thus far. The formation of sulfur ylide involves a chiral sulfide and a carbene or carbenoid, and the general reaction procedure for epoxidation of aldehydes may involve the application of a sulfide, an aldehyde, or a carbene precursor as well as a copper salt. This reaction may also be considered as a thiol acetal-mediated carbene addition to carbonyl groups in the aldehyde. 

Titanium enolates.1 This Fischer carbene converts epoxides into titanium enolates. In the case of cyclohexene oxide, the product is a titanium enolate of cyclohexanone. But the enolates formed by reaction with 1,2-epoxybutane (equation I) or 2,3-epoxy butane differ from those formed from 2-butanone (Equation II). Apparently the reaction with epoxides does not involve rearrangement to the ketone but complexation of the epoxide oxygen to the metal and transfer of hydrogen from the substrate to the methylene group. 

To date, the most frequently used ligand for combinatorial approaches to catalyst development have been imine-type ligands. From a synthetic point of view this is logical, since imines are readily accessible from the reaction of aldehydes with primary or secondary amines. Since there are large numbers of aldehydes and amines that are commercially available the synthesis of a variety of imine ligands with different electronic and steric properties is easily achieved. Additionally, catalysts based on imine ligands are useful in a number of different catalytic processes. Libraries of imine ligands have been used in catalysts of the Strecker reaction, the aza-Diels-Alder reaction, diethylzinc addition, epoxidation, carbene insertions, and alkene polymerizations. 

Metal oxides were also chirally modified and few of them showed a significant or at least useful e.s. Thus, while Al203/alkaloid [80] showed no enantiodifferentiation, Zn, Cu, and Cd tartrate salts were quite selective for a carbene addition (45% e.e.) [81] and for the nucleophilic ring opening of epoxides (up to 85% e.e.) [82], Recently, it was claimed that /(-zeolite, partially enriched in the chiral polymorph A, catalyzed the ring opening of an epoxide with low but significant e.s. (5% e.e.) [83], All these catalysts are notyet practically important but rather demonstrate that amorphous metal oxides can be modified successfully. 

Although the Sharpless catalyst was extremely useful and efficient for allylic alcohols, the results with ordinary alkenes were very poor. Therefore the search for catalysts that would be enantioselective for non-alcoholic substrates continued. In 1990, the groups of Jacobsen and Katsuki reported on the enantioselective epoxidation of simple alkenes both using catalysts based on chiral manganese salen complexes [8,9], Since then the use of chiral salen complexes has been explored in a large number of reactions, which all utilise the Lewis acid character or the capacity of oxene, nitrene, or carbene transfer of the salen complexes (for a review see [10]). 

The preparation of novel phase transfer catalysts and their application in solving synthetic problems are well documented(l). Compounds such as quaternary ammonium and phosphonium salts, phosphoramides, crown ethers, cryptands, and open-chain polyethers promote a variety of anionic reactions. These include alkylations(2), carbene reactions (3), ylide reactions(4), epoxidations(S), polymerizations(6), reductions(7), oxidations(8), eliminations(9), and displacement reactions(10) to name only a few. The unique activity of a particular catalyst rests in its ability to transport the ion across a phase boundary. This boundary is normally one which separates two immiscible liquids in a biphasic liquid-liquid reaction system. 

Carboxylic acid, aldehyde, ketone, ether, alcohol, ester, ester-R (the chain attached to the oxygen atom being a generic substituent), anhydride, acetal, amide, epoxide, acid halyde, primary amine, primary imine, cyano, secondary amine, secondary imine, tertiary amine, nitro derivative, metal-1, metal-2, carbene, halo derivative. 

The proposed catalytic cycle for this reaction begins with the initial attack of the in situ generated thiazolylidene carbene on the epoxyaldehyde followed by intramolecular proton transfer (Scheme 28, XXXII-XXXIII). Isomerization occurs to open the epoxide forming XXXIV which undergoes a second proton transfer forming XXXV. Diastereoselective protonation provides activated carboxylate intermediate XXXVI. Nucleophilic attack of the activated carboxylate regenerates the catalyst and provides the desired P-hydroxy ester. 

A difference in reaction efficiency was observed depending on the catalyst used. Imidazolium salt 305 provides the highest yield of desired product. When preformed complex 307 is subjected to the reaction conditions, fran -2-ethylcyclohex-anol is detected by gas chromatography in 76% yield (Eq. 30). Alkylation starting with free carbene 306 results in only 28% yield of desired alkylated epoxide. 

On the contrary, a-lithiated epoxides have found wide application in syntheses . The existence of this type of intermediate as well as its carbenoid character became obvious from a transannular reaction of cyclooctene oxide 89 observed by Cope and coworkers. Thus, deuterium-labeling studies revealed that the lithiated epoxide 90 is formed upon treatment of the oxirane 89 with bases like lithium diethylamide. Then, a transannular C—H insertion occurs and the bicyclic carbinol 92 forms after protonation (equation 51). This result can be interpreted as a C—H insertion reaction of the lithium carbenoid 90 itself. On the other hand, this transformation could proceed via the a-alkoxy carbene 91. In both cases, the release of strain due to the opening of the oxirane ring is a significant driving force of the reaction. 

Another carbenoid-typical reaction of a-lithiated epoxides is the 1,2-hydrogen shift, illustrated in Scheme 14. Two mechanistic pathways offer an explanation for the formation of the lithium enolate 94 First, the route via the a-ring opening of the epoxide followed by an 1,2-hydride shift in the carbene 93, and second, the electrocyclic ring opening of an oxiranyl anion 95 to an enolate anion 94. Both mechanisms are in accordance with different experimental... 

The proposed mechanism of this reaction is based on the nucleophilic attack of the alkyllithium compound at the carbenoid carbon atom or at the a-lithiooxy carbene. The dilithium compound 102 gives the alkene 103 by the loss of lithium oxide (equation 56). When an alkoxy residue, which is a better leaving group than U2O, is offered in the a-position of the corresponding dilithium compound, the elimination of lithium alkoxide takes place instead of lithium oxide. This is illustrated by the reaction of epoxide 104 that delivers the allylic alcohol 105 upon treatment with n-butyllithium (equation The... 

As with many polymers, polyisoprene exhibits non-Newtonian flow behavior at shear rates normally used for processing. The double bond can undergo most of the typical reactions such as carbene additions, hydrogenation, epoxidation, ozonolysis, hydrohalogena-tion, and halogenation. As with the case of the other 1,4-diene monomers, many copolymers are derived from polyisoprene or isoprene itself. 

The radical versus electrophilic character of triplet and singlet carbenes also shows up in relative reactivity patterns shown in Table 10.1. The relative reactivity of singlet dibromocarbene toward alkenes is more similar to that of electrophiles (bromination, epoxidation) than to that of radicals ( CC13). Carbene reactivity is strongly affected by substituents.61 Various singlet carbenes have been characterized as nucleophilic, ambi-philic, and electrophilic as shown in Table 10.2. This classification is based on relative reactivity toward a series of different alkenes containing both nucleophilic alkenes, such as tetramethylethylene, and electrophilic ones, such as acrylonitrile. The principal structural feature that determines the reactivity of the carbene is the ability of the substituents to act as electron donors. For example, dimethoxycarbene is devoid of electrophilicity toward... 

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