Nucleophilic aliphatic epoxides

Mechanisms for nucleophilic aliphatic substitution at glycosides, 41, 277 Mechanisms of hydrolysis and rearrangements of epoxides, 40, 247 Mechanisms of oxygenations in zeolites, 42, 225 Mechanisms, nitrosation, 19, 381... 

It was found that the ring opening of phenyl-substituted epoxides, as well as of aliphatic epoxides, can be achieved in high yield in a regio- and stereoselective manner with a mixture of 1 3 of diisopropylamine and hydrogen fluoride (diisopropylamine trishydrofluoride).9 1 m-2,3-Diphenyloxirane. for example, gives pure. >w-2-fluoro-l, 2-diphenylcthanol (1). indicating a nucleophilic reaction mechanism of the SN2 type. 

Although the use of amines in nucleophilic aliphatic substitution is problematic due to the mixtures of products that result, recall from Section 8.4C that amines are excellent nucleophiles for ring opening reactions of epoxides. This is because the inductive effect... 

A heterobimetallic BINOL-Ga/Li complex 53 has been developed for the enantioselective ARO of meso-cpoxides (BINOL = l,T-bi(2-naphthol)).278 Using />-methoxyphenol as the nucleophile, this etherification reaction was observed to take place with a high level of asymmetric induction. An improved catalyst 54 has also been reported that exhibits greater stability under the reaction conditions and delivers higher yields and ee s (Equation (78)).279 A simple catalyst derived from Sc(OTf)3 and the chiral bipyridine ligand 52 has been shown to be effective for the ARO of aryl-substituted /// -epoxides with aliphatic alcohols to give high ee s (Equation (79)).280... 

Wrapping up the nitrogen-based nucleophiles, aromatic amines were also noted to cleave epoxides in the presence of stannic or cupric triflate to form p-amino alcohols such as 86 directly. This protocol appears to be general for aromatic amines, even strongly electron-deficient ones. Aliphatic amines are completely unreactive under the same experimental conditions <99JOC287>. 

Condensations of hydroxylic nucleophiles with ethylene oxides, when considered as a whole, probably constitute the largest single body of epoxide reactions. Included among these nucleophiles are water itself, the aliphatic Alcohols, and the aromatic alcohols or phenols. The present section will be devoted to the reactions of theee substances. 

In mammalian liver microsomes, cytochrome P-450 is not specific and catalyzes a wide variety of oxidative transformations, such as (i) aliphatic C—H hydroxylation occurring at the most nucleophilic C—H bonds (tertiary > secondary > primary) (ii) aromatic hydroxylation at the most nucleophilic positions with a characteristic intramolecular migration and retention of substituents of the aromatic ring, called an NIH shift,74 which indicates the intermediate formation of arene oxides (iii) epoxidation of alkenes and (iv) dealkylation (O, N, S) or oxidation (N, S) of heteroatoms. In mammalian liver these processes are of considerable importance in the elimination of xenobiotics and the metabolism of drugs, and also in the transformation of innocuous molecules into toxic or carcinogenic substances.75 77... 

Diols such as 87 are converted in excellent yields [89] into acetoxy chlorides (88) by treatment with trimethyl orthoacetate and trimethylsilyl chloride [90] or into acetoxybromides (89) with trimethyl orthoacetate and acetyl bromide [91]. These reactions proceed through nucleophilic attack on an intermediate l,3-dioxolan-2-ylium cation [91] with inversion of configuration. In the presence of an aryl substituent as in 87, displacement occurs exclusively at the benzylic position. With aliphatic diols such as 90, the halide is introduced mainly at the less hindered position and acetoxybromides 91 and 92 are formed in a ratio of 7 1. Treatment of the acetoxy halides 88 or 89 under mildly alkaline conditions affords epox.de 93 in 84-87% yield while the mixture of 91 and 92 is converted to epoxide 94 in 94% yield. Because both... 

Following these general examples, we can now analyze the opening of epoxides in more detail. The size of the ring imposes geometric constraint and the SN2 reaction demands colinearity. The approach of the nucleophile should then resemble J7. + which is different from that in displacement of a leaving group on an aliphatic chain, i. e. 19 20. 

Catalysis by acids, which is only rarely effective for aliphatic amines but better suited to the less basic aromatic amines [334], can promote nucleophilic attack at the most strongly polarized C-0 bond of the epoxide (Scheme 4.75) [333, 334, 339]. Vinyl epoxides react with amines in the presence of Pd(0) under mild conditions to yield allylamines [340], If such reactions are performed in the presence of an enantiomerically pure ligand, racemic vinyl epoxides can be converted into enantiomerically enriched products of nucleophilic ring opening (last example, Scheme 4.75). 

Other related reactions are the substitutions of aliphatic sulfonate esters by arenes and the epoxide-opening with benzenes catalyzed by gold. In both cases, the aryl groups are the nucleophiles that attack the gold-coordinated sulfonate esters or epoxides, respectively. 

Conjugated unsaturated ketones are unreactive to peracids because of the depletion of electronic charge in the olefiinic bond, but epoxyketones are readily prepared by using the nucleophilic hydroperoxide ion (H02"") [284], In simple aliphatic compounds the epoxidation follows kinetics first order with respect to hydroperoxide ion and unsaturated ketone [28s]- According to House [286], the reaction should be represented as a reversible addition of hydroperoxide ion, followed by closure of the epoxide ring in a slow step, with expulsion of hydroxide ion. The over-all rate will be determined both by the equilibrium constant in the first step and by the rate constant for the second. 

Reactions with aliphatic and aromatic epoxides. The metabolism of many alkenes and arenes Is known to proceed via epoxides formed by phase I reactions (166). Chemical methods for the preparation of epoxides will not be discussed here but valuable references (or references cited therein) for their synthesis are found In Table VII. The electrophilic character of the epoxides has been utilized In chemical synthesis of several PMAF metabolites. Differences In the reactlvltes of arene oxides are probably less Important In chemical synthesis of their conjugates but may Influence the ratio of positional and dlasteromers formed. The reaction of GSH with a xenobiotic epoxide gives the 1,2-dlhydro--l-hydroxy-2-glutathlonyl-xenoblotlc conjugate and with cysteine and N-acetyl-cystelne the corresponding dlhydro-hydroxy conjugates. The nucleophile (GSH, cysteine or N-acetyl-cystelne)... 

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