Reactions of epoxides

The main mode of communication among insects is via the emission and detection of specific chemical substances. These substances are called pheromones. 

The word is from the Creek pherein, to carry, and horman, to excite. Even though they are emitted and detected in exceedingiy smaii amounts, pheromones have profound bio-iogicai effects. One of their main effects is sexual attraction and stimulation, but they are also used as alarm substances to alert members of the same species to danger, as aggregation substances to call together both sexes of a species, and as trail substances to lead members of a species to food. 

Often pheromones are chemically simple compounds— alcohols, esters, aldehydes, ketones, ethers, epoxides, or even hydrocarbons. Two examples are muscalure and bombykol, the sex attractants of the common housefly and the silkworm moth, respectively. 

Their molecular weights are low enough that the substances are volatile, yet not so low that they disperse too rapidly. Also, their molecular structures must be distinctive to make them species-specific survival of the species would not be served by attracting another species. Often this specificity is attained through stereoisomerism (at double bonds and/or at chiral centers), but it can also be achieved by using specific ratios of two or more pheromones for a particular communication purpose. 

Let us consider a specific pheromone, dispar-lure, the sex attractant of the gypsy moth Lymantria dispat). The gypsy moth is a serious despoiler of forest and shade trees as well as fruit orchards. Gypsy moth larvae, which hatch each spring, are voracious eaters and can strip a tree bare of leaves in just a few weeks. 

The primary type of epoxide reaction remains the nucleophilic ring-opening reaction. Research on the development of novel catalysts or catalytic systems for epoxide opening continues to be a highly active area of study. 

Epoxides have been found to cleanly react with acetic anhydride to provide the diacetate under solvent-free conditions 06TL6865 . Treatment of epoxides with ammonium-12-molybdophosphate and a slight excess of acetic anhydride (1.2 equivalents) provides the corresponding diacetate in excellent yields. A number of epoxides were examined and all worked quite well. It was also found that /V-losyl aziridines participate in this reaction providing the corresponding acetoxysulfonamides. 

A polymeric version of Jacobsen s Cr-salen catalyst has also been reported 06TA1638 . This polymeric catalyst worked well with a variety of amines, showed excellent enantio- and diastereoselectivity with an enantiomeric excess of 90-98%. Most importantly the catalyst was reusable with no loss in stereoselectivity of the products. 

The synthesis of a,a-disubstituted amino acids is a difficult task and continues to attract attention. An efficient route that utilizes the ring-opening of an epoxide with azide has been reported 06TL9268 . Treatment of the sulfoxide substituted epoxide 23 with NaN3 provides intermediate azido aldehyde 24. This aldehyde was not isolated but oxidized to the acid and then the azide reduced to provide the a,a-disubstituted amino acid 25. The regioselectivity of this reaction was impressive with only one product reported. 

A Baylis-Hillman type product has been obtained through a ring-opening reaction of an epoxide with an allenoate 06OL2771 . The reaction of MgL, with ethyl propiolate provides the iodo allenoate 32. This nucleophile reacts with an aryl epoxide to provide the homoallylic alcohol 33. The Z iodide is the major product formed. 

The hydrolysis of epoxides is a well-known reaction which can be exploited for various synthetically useful outcomes. Chiral nonracemic epoxides can be prepared from their racemates through the salen-mediated hydrolytic kinetic resolution (HKR). Racemic epichlorohydrin 53 was resolved in the presence of catalyst 52 and a slight excess of water under solvent-free conditions. The catalyst counterion exerts a significant effect on the course of the reaction, presumably due to competitive addition onto the epoxide, an effect which is evident in apparent reaction rates, but not enantioselectivities. Less nucleophilic counterions, such as tosylate, lead to more rapid resolution and lower catalyst loading requirements 04JA1360 . 

Epoxides also suffer nucleophilic attack by amines, forming ethanolamine derivatives. This reaction can take place under a variety of conditions and with the influence of several catalysts. Styrene oxide 61 undergoes ring opening in the absence of catalyst under strictly thermal conditions (90 C in a sealed tube) to give predominantly the amino-alcohol 62, the product of attack at the more substituted (a) position 04SC2393 . The reaction time can be reduced by using a combination of catalytic bismuth(III) trifluoroacetate and brief microwave irradiation, as 

Similar conditions have been applied to the ring-opening of meso epoxides using amines. Bismuth triflate catalyzes the reaction of cyclohexene oxide 64 with p-bromoaniline under aqueous conditions to provide the P-aminoalcohol 65 in 84% yield. In this particular case, the water solubility of the starting materials required the use of a micellar solution of sodium dodecyl sulfate (SDS) however, more soluble amines eould be employed in water and bismuth triflate alone 04TL49 . A lanthanide variant has also been reported. Thus, treatment of 64 

Chromium(salen) catalysts (e.g., 69) are also useM in desymmetrizing meso epoxides. Thus, c/5-stilbene oxide 70 is converted to the (5 ,iS)-aminoalcohol 71 in the presence of eatalytic quantities of 69 in methylene ehloride solution open to the atmosphere. The addition of small quantities of triethylamine was found to dramatically increase enantioseleetivities (by almost 25%). This catalytic system also promotes an efficient aminolytic kinetie resolution (AKR) of raeemie epoxides with C2-type symmetry 04OL2173 . 

Epoxides can serve as competent electrophiles in the alkylation of a variety of carbanions, as illustrated by the ring opening of cyclohexene oxide (64) with the dianion of phenylacetic acid (77) to produce the y-hydroxy carboxylic acid 78. In this protocol, the dianion is generated using K-butyllithium and a substoichiometric quantity of a secondary amine lithium chloride is also used as a Lewis acid additive to activate the secondary epoxide toward nucleophilic addition. Primary epoxides undergo addition without the use of catalyst—in these cases, the nucleophile attacks at the less substituted position 04EJOC2160 . 

Problem 9.34 Explain why the treatment of anisole with HBr yields phenol and CHsBr, but not bromobenzene. 

This reaction occurs readily with shong nucleophiles, and with acids like HZ, where Z is a nucleophihc atom. 

Problem 9.35 Explain why cyclopropane, which has a strained three-membered ring like an epoxide, does not react readily with nucleophiles. 

15A Opening of Epoxide Rings with Strong Nucleophiles 

Virtually all strong nucleophiles open an epoxide ring by a two-step reaction sequence  

0 The highly strained three-membered ring of epoxides makes them much more reactive toward nucleophilic substitution than other ethers. 

Acid catalysis assists epoxide ring opening by providing a better leaving group (an alcohol) at the carbon atom undergoing nucleophilic attack. This catalysis is especially important if the nucleophile is a weak nucleophile such as water or an alcohol. An example is the acid-catalyzed hydrolysis of an epoxide. 

The acid reacts with the epoxide to produce a protonated epoxide. 

The protonated epoxide reacts with the weak nucleophile (water) to form a protonated 1,2-diol, which then transfers a proton to a molecule of water to form the 1,2-diol and a hydronlum ion. 

Epoxides can also undergo base-catalyzed ring opening. Such reactions do not occur with other ethers, but they are possible with epoxides (because of ring strain), provided that the attacking nucleophile is also a strong base such as an alkoxide ion or hydroxide ion. 

The ring opening of epoxides with thiols provides an efficient route for the formation of (3-hydroxy sulfides. A one-pot method for the direct synthesis of (3-hydroxy sulfoxides has been developed 07JOC4524 . Treatment of an epoxide with PhSH, Ga(O IT)3, and H202 directly provides the sulfoxide with little to no over oxidation. 

The reaction of stilbene oxide with a variety of aniline derivatives in the presence of indium triflate and the chiral bipyridine ligand 22 provided aminoalcohols in generally good yields and enantioselectivity 07SL2136 . 

Another ring forming reaction uses an initial epoxide opening by the amine of an amino alcohol to generate a ring opened product which was subsequently converted to a quinazoline ring system 07JOC1492 . 

Oxazolidines are an important class of compounds commonly prepared by reaction of an amino alcohol with a carbonyl compound. The reaction of an imine with an epoxide has recently been shown to efficiently provide the oxazolidine ring system 07SL646 . The reaction is catalyzed by Yb(OTf)3 and generally provides the product oxazolidine in good yield albeit with poor ( 2 1) diastereoselectivity. 

Common nucleophiles that open epoxide rings include OH, OR, CN, SR, and NH3. With these strong nucleophiles, the reaction occurs via an S 2 mechanism, resulting in two consequences  

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Although the chemical reactions of epoxides will not be covered m detail until the fol lowing chapter we shall introduce their use m the synthesis of alcohols here... 

There is an important difference in the regiochemistry of ring opening reactions of epoxides depending on the reaction conditions Unsymmetncally substituted epoxides tend to react with anionic nucleophiles at the less hindered carbon of the ring Under conditions of acid catalysis however the more highly substituted carbon is attacked... 

The reactions of carboxyUc acids and anhydrides with epoxy resins have been extensively studied in a variety of investigations, particularly References 27—31. The general reaction of epoxide resins and anhydrides is... 

Group of plastics composed of resins produced by reactions of epoxides or oxiranes with compounds such as amines, phenols, alcohols, carboxylic acids, acid anhydrides and unsaturated compounds. 

Reaction of Epoxides with Boron Trifluoride-Etherate... 

Rearrangement of fluorine with concomitant ring opening takes place in fluorinated epoxides Hexafluoroacetone can be prepared easily from perfluo-ropropylene oxide by isomerization with a fluorinated catalyst like alumina pre treated with hydrogen fluoride [26, 27, 28] In ring-opening reactions of epoxides, the distribution of products, ketone versus acyl fluoride, depends on the catalyst [29] (equation 7) When cesium, potassium, or silver fluoride are used as catalysts, dimenc products also are formed [29]... 

The (3-elimination of epoxides to allylic alcohols on treatment with strong base is a well studied reaction [la]. Metalated epoxides can also rearrange to allylic alcohols via (3-C-H insertion, but this is not a synthetically useful process since it is usually accompanied by competing a-C-H insertion, resulting in ketone enolates. In contrast, aziridine 277 gave allylic amine 279 on treatment with s-BuLi/(-)-spar-teine (Scheme 5.71) [97]. By analogy with what is known about reactions of epoxides with organolithiums, this presumably proceeds via the a-metalated aziridine 278 [101]. 

Although several interesting nitrogen-centered nucleophiles have been developed with ARO reactions of epoxides (vide supra), kinetic resolutions with such reagents are unlikely to be of practical value for the recovery of enantioenriched terminal epoxides. This is due to the fact that these nucleophiles are too valuable to be discarded in a by-product of the resolution, are generally not atom-economical, and, particularly in the case of azide, may represent safety hazards. 

Synthesis of Complex Molecules by Rearrangement Reactions of Epoxides... 

A completely different way of preparing isocyanides involves the reaction of epoxides or oxetanes with trimethylsilyl cyanide and zinc iodide, for example, ... 

By studying the NMR spectra of the products, Jensen and co-workers were able to establish that the alkylation of (the presumed) [Co (DMG)2py] in methanol by cyclohexene oxide and by various substituted cyclohexyl bromides and tosylates occurred primarily with inversion of configuration at carbon i.e., by an 8 2 mechanism. A small amount of a second isomer, which must have been formed by another minor pathway, was observed in one case (95). Both the alkylation of [Co (DMG)2py] by asymmetric epoxides 129, 142) and the reduction of epoxides to alcohols by cobalt cyanide complexes 105, 103) show preferential formation of one isomer. In addition, the ratio of ketone to alcohol obtained in the reaction of epoxides with [Co(CN)5H] increases with pH and this has been ascribed to differing reactions with the hydride (reduction to alcohol) and Co(I) (isomerization to ketone) 103) (see also Section VII,C). 

We have already discussed the regioselectiviLy of Lhe reactions of epoxide with nucleophiles and devised strategies (p 64-5) to achieve Lhe synthesis of compounds (32). 

Based on the above results and previous works [3,9] on the reaction of epoxides and CO2, we tentatively propose the plausible mechanism for the copolymerization of GMA and CO2 (schane 1), Alkyhnethyl imidazolim salt (QX) and epoxide (GMA) r cted to synthesize an active spedes followed by chain propagation involving a < ncerted insertion of th e epoxide. However, more detailed mechanistic studies are needed to clairly understand the polymerization steps. 

The enantioselectivity was significantly influenced by the steric factor of the thiols employed. When p-MeC6H4SH and PhSH were used, the optical yields decreased to 69% and 3%, respectively. Shibasaki et al. have reported that gallium-lithium-bi-naphthoxide (GLB) 51 became a good catalyst for the enantioselective ring opening reaction of epoxide for the production of 52 (Eq. 7.39) [46]. 

Scheme 2.52. Reactions of epoxide 2-221 with 1,3-dicarbonyl dianions.

A general method for the preparation of 2-hydroxyalkyl-l,4,7-triazacyclodecane macrocycles 202, 203, 204 with a single pendant arm < 1999J(P 1)1211 > through reaction of epoxides has been achieved from the ortho amide derivative l,4,7-triazatricyclo[5.2.1.04 10]decane 40 (Scheme 30) <1999J(P1)1211>. 

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