Epoxides nucleophilic epoxidations

Epoxides provide another useful a -synthon. Nucleophilic ring opening with dianions of carboxylic acids (P.L. Creger, 1972) leads to y-hydroxy carboxylic acids or y-lactones. Addition of imidoester anions to epoxides yields y-hydroxyaldehyde derivatives after reduction (H.W. Adickes, 1969). 

Epoxide opening with nucleophiles occurs at the less substituted carbon atom of the oxlrane ting. Cataiytic hydrogenolysis yields the more substituted alcohol. The scheme below contains also an example for trons-dibromination of a C—C double bond followed by dehy-drobromination with strong base for overall conversion into a conjugated diene. The bicycKc tetraene then isomerizes spontaneously to the aromatic l,6-oxido[l0]annulene (E. Vogel, 1964). 

Silyl ethers serve as preeursors of nucleophiles and liberate a nucleophilic alkoxide by desilylation with a chloride anion generated from CCI4 under the reaction conditions described before[124]. Rapid intramolecular stereoselective reaction of an alcohol with a vinyloxirane has been observed in dichloro-methane when an alkoxide is generated by desilylation of the silyl ether 340 with TBAF. The cis- and tru/u-pyranopyran systems 341 and 342 can be prepared selectively from the trans- and c/.y-epoxides 340, respectively. The reaction is applicable to the preparation of 1,2-diol systems[209]. The method is useful for the enantioselective synthesis of the AB ring fragment of gambier-toxin[210]. Similarly, tributyltin alkoxides as nucleophiles are used for the preparation of allyl alkyl ethers[211]. 

This kind of chemical reactivity of epoxides is rather general Nucleophiles other than Gng nard reagents react with epoxides and epoxides more elaborate than ethylene oxide may be used All these features of epoxide chemistry will be discussed m Sections 16 11-16 13... 

Unlike most ethers epoxides (compounds m which the C—O—C unit forms a three membered ring) are very reactive substances The principles of nucleophilic sub stitution are important m understanding the preparation and properties of epoxides... 

Next in what amounts to an intramolecular Williamson ether synthesis the alkoxide oxygen attacks the carbon that bears the halide leaving group giving an epoxide As m other nucleophilic substitutions the nucleophile approaches carbon from the side oppo site the bond to the leaving group... 

Overall the stereospecificity of this method is the same as that observed m per oxy acid oxidation of alkenes Substituents that are cis to each other m the alkene remain CIS m the epoxide This is because formation of the bromohydrm involves anti addition and the ensuing intramolecular nucleophilic substitution reaction takes place with mver Sion of configuration at the carbon that bears the halide leaving group... 

We saw an example of nucleophilic ring opening of epoxides in Section 15 4 where the reaction of Grignard reagents with ethylene oxide was described as a synthetic route to primary alcohols... 

Nucleophiles other than Gngnard reagents also open epoxide rings These reac tions are carried out in two different ways The first (Section 16 12) involves anionic nucleophiles in neutral or basic solution... 

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... 

Nucleophilic ring opening of epoxides has many of the features of an 8 2 reac tion Inversion of configuration is observed at the carbon at which substitution occurs... 

The experimental observations combine with the principles of nucleophilic substi tution to give the picture of epoxide ring opening shown m Figure 16 5 The nucleophile attacks the less crowded carbon from the side opposite the carbon-oxygen bond Bond... 

As we ve just seen nucleophilic ring opening of ethylene oxide yields 2 substituted derivatives of ethanol Those reactions involved nucleophilic attack on the carbon of the ring under neutral or basic conditions Other nucleophilic ring openings of epoxides like wise give 2 substituted derivatives of ethanol but either involve an acid as a reactant or occur under conditions of acid catalysis... 

The reactivity of epoxides toward nucleophilic ring opening is responsible for one of the biological roles they play Squalene 2 3 epoxide for example is the biological... 

Section 16 12 Anionic nucleophiles usually attack the less substituted carbon of the epoxide m an 8 2 like fashion... 

Predict which carbon undergoes nucleophilic attack on acid catalyzed ring opening of cis 3 3 3 tnfluoro 2 3 epoxybutane Examine the C—O bond distances of the protonated form of the epoxide on Learning By Modeling How do these bond distances compare with your prediction" ... 

Nucleophilic ring opening of epoxides by ammonia (Section 16 12) The strained ring of an epoxide is opened on nucleo philic attack by ammonia and amines to give 3 ammo alcohols Azide ion also re acts with epoxides the products are p azido alcohols... 

Nucleophilic Reactions. The strong electronegativity of fluorine results in the facile reaction of perfluoroepoxides with nucleophiles. These reactions comprise the majority of the reported reactions of this class of compounds. Nucleophilic attack on the epoxide ring takes place at the more highly substituted carbon atom to give ring-opened products. Fluorinated alkoxides are intermediates in these reactions and are in equiUbrium with fluoride ion and a perfluorocarbonyl compound. The process is illustrated by the reaction of methanol and HFPO to form methyl 2,3,3,3-tetrafluoro-2-methoxypropanoate (eq. 4). 

Shown ate glycidyl methacrylate to introduce epoxide fiinctionahty, acetoacetoxyethyl methacrylate to introduce active methylene groups, dimethylaminoethyl methacrylate to introduce amine fiinctionahty, phosphoethyl methacrylate for strong acid fiinctionahty, and isocyanatoethyl methacrylate to introduce isocyanate fiinctionahty, which may then react with a wide variety of nucleophiles. 

Primary cycloaUphatic amines react with phosgene to form isocyanates. Reaction of isocyanates with primary and secondary amines forms ureas. Dehydration of ureas or dehydrosulfuri2ation of thioureas results in carhodiimides. The nucleophilicity that deterrnines rapid amine reactivity with acid chlorides and isocyanates also promotes epoxide ring opening to form hydroxyalkyl- and dihydroxyalkylaniines. Michael addition to acrylonitrile yields stable cyanoethylcycloalkylarnines. 

The reactions are highly exothermic. Under Uquid-phase conditions at about 200°C, the overall heat of reaction is —83.7 to —104.6 kJ/mol (—20 to —25 kcal/mol) ethylene oxide reacting (324). The opening of the oxide ring is considered to occur by an ionic mechanism with a nucleophilic attack on one of the epoxide carbon atoms (325). Both acidic and basic catalysts accelerate the reactions, as does elevated temperature. The reaction kinetics and product distribution have been studied by a number of workers (326,327). 

The dianions derived from furan- and thiophene-carboxylic acids by deprotonation with LDA have been reacted with various electrophiles (Scheme 64). The oxygen dianions reacted efficiently with aldehydes and ketones but not so efficiently with alkyl halides or epoxides. The sulfur dianions reacted with allyl bromide, a reaction which failed in the case of the dianions derived from furancarboxylic acids, and are therefore judged to be the softer nucleophiles (81JCS(Pl)1125,80TL505l). 

---