Epoxide opening phenol

ARO reaction with phenols and alcohols as nucleophiles is a logical extension of HKR of epoxides to synthesize libraries of stereochemically defined ring-opened products in high optical purity. To this effect Annis and Jacobsen [69] used their polymer-supported Co(salen) complex 36 as catalyst for kinetic resolution of epoxides with phenols to give l-aiyloxy-2-alcohols in high yield, purity and ee (Scheme 17). Conducting the same reaction in the presence of tris(trifluoromethyl)methanol, a volatile, nonnucleophilic protic acid additive accelerates KR reaction with no compromise with enantioselectivity and yield. Presumably the additive helped in maintaining the Co(III) oxidation state of the catalyst. 

Based on the labeling experiments, a plausible mechanism involving mthenium vinylidene intermediates SS is proposed in Scheme 6.21. Cydization of this vinylidene intermediate leads to the formation of the epoxy carbenium 56, which then undergoes an epoxide opening to form l,4-dien-3-ol 57. A subsequent pinacol rearrangement of this alcohol furnishes ketone 58, providing the required skeleton for the observed phenol product 54. 

MgBr2, Et20, CH2CI2, 70% yield." In this case previous attempts to cleave the phenolic EOM groups (ethoxymethyl ether) with acid all failed because of epoxide opening. 

Aryloxy alcohols. These glycol monoethers are formed by epoxide opening. From meso-epoxides, chiral products are obtained in the presence of the linked BINOL complex. Reaction with simple BINOLs is complicated by erosion of enantioselectivity due to phenolate exchange (i.e., BINOL and phenolate nucleophile). 

It is also possible that epoxide opening is initiated by electron push from the nitrogen atom rather than the phenol, and this will be discussed in a later section. In either case, epoxide opening is the trigger for cycloaromatization, diradical formation and DNA damage [118-120]. 

The HKR of epichlorhydrine (X = Cl, Scheme 141) and 4-hydroxy-l-butene oxide (X = OH, Scheme 141), the dynamic kinetic resolution of epibromhydrin and the enantioselective ring opening of epoxides by phenol were examined. In the first experiment, combination of the crude organic soluble products of the five recycle reactions and concentration led to the (5)-epichlorhydrine in 41% overall yield and > 99% ee and the (/ )-chlorodiol in 93% ee. In the second one, the sum of five experiments provided (iS)-triol in 36% overall yield and 94.4% ee while the enantioselectivity of the epoxide was only 59% ee. 

The dynamic resolution of epibromohydrine provided only the bromodiol in 94% overall yield and 96% ee (sum of the five experiments). Excellent results were also obtained for the ring opening epoxides with phenol, ee could reach more than 99% and yield 98%. 

The ring opening of terminal epoxides by phenols usually requires forcing conditions and the reaction is unsuitable for sensitive substrates. It is, however, catalysed by certain (salen)Co(III) complexes and the reaction has now been applied to the asymmetric synthesis of a-aryloxy alcohols. The (salen)Co(ni)-catalysed ring opening of terminal epoxides is highly enantioselective, so that kinetic resolution of the... 

Likewise, Kollek (1985) used FTIR diffuse reflectance analysis to study the absorption chemistry of epoxide and phenolic resins on aluminum substrates. He observed that both the curing agent and the epoxy resin monomer were adsorbed on the aluminum oxide surface. They found that the dicyandiamide monomer was adsorbed by the oxide layers of the substrate and was attributed to the acid proton of the aluminum oxide reacting with and reducing the observed nitrile peaks. For the epoxide monomer, less adsorption was observed, and it was suggested that this occurred by the opening of the epoxide ring. 

Compounds are prepared by a fairly standard sequence which consists of condensation of an appropriate phenol with epichlorohydrin in the presence of base. Attack of phenoxide can proceed by means of displacement of chlorine to give epoxide (45) directly. Alternatively, opening of the epoxide leads to anion 44 this last, then, displaces halogen on the adjacent carbon to lead to the same epoxide. Reaction of the epoxide with the appropriate amine then completes the synthesis. 

Biernath et al. concluded that phenolic novolac and epoxidized cresol novolac cure reactions using triphenylphosphine as the catalyst had a short initiation period wherein the concentration of phenolate ion increased, followed by a (steady-state) propagation regime where the number of reactive phenolate species was constant.85 The epoxy ring opening was reportedly first order in the steady-state regime. 

To date, effecting the subsequent reaction chemistry (as hypothesized in Fig. 12.9) has not been possible in our laboratories. There have been indications that reaction of the epoxide quinone methide QM24 in chloroform with acetic acid may have opened the epoxide before rearomatizing the quinone methide moiety, but this is not well authenticated. However, all attempts to add phenols to this epoxide, particularly aimed at producing 8-0-4-ethers PI, have been unsuccessful. Similar reactions using QM25 have also failed. 

Alkylations of phenols with epichlorohydrin under PTC conditions and microwave irradiation were described twice in 1998. Subsequently, ring-opening reactions of the epoxide group were also performed using microwaves (Eqs. 20 and 21) [31, 32]. In the first catalytic synthesis of chiral glycerol sulfide ethers was described [31] in the second biologically active amino ethers were prepared [32],... 

Metoprolol Metoprolol, l-(wo-propylamino)-3-[4 (2-methoxyethyl)phenoxy]-2-propanol (12.1.5), is synthesized by reacting 4-(2-methoxyethyl)phenol with epichlorhy-dride in the presence of a base, isolating l,2-epoxy-3-[4 (2-methoxyethyl)phenoxy] propane (12.1.4), the subsequent reaction of which, analogous to that described before, with jio-propylamine, gives an opening of the epoxide ring and leads to the formation of metoprolol (12.1.5) [7,8]. 

A parallel was drawn between stable ion and AMI studies of methylphenanthrenes and solvolytic studies of K-region and non-K-region phenanthrene oxides. The carbocation formed by opening of the 1,2-epoxide closely resembled the 2-methylphenanthrene cation (and 7H ), and the regiochemistry of phenol formation (1-phenanthrol) could be understood. Similarly, phenanthrenium cations derived from the 3-methyl and dimethylated compounds served as models for carbo-cations formed by solvolysis of phenanthrene-3,4-epoxide (formation of 4-phenanthrol following hydride shift). 

Oxidative stress and covalent binding to macromolecules. Oxidation to the epoxide occurs via a tetrahedral intermediate, which can form either an epoxide or a phenol directly (see the scheme below). The epoxide can covalently bind nucleophiles, such as DNA or proteins, to open up the epoxide to a phenol and make toxic covalent adducts. The phenols can be further oxidized to bisphenols, which can in turn form quinones. Quinones can cause serious oxidative damage to cells through radical pathways, or can alkylate N- or S-nucleophiles, such as glutathione and glycine. 

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