Sterically hindered alcohols

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

The ketone is added to a large excess of a strong base at low temperature, usually LDA in THF at -78 °C. The more acidic and less sterically hindered proton is removed in a kineti-cally controlled reaction. The equilibrium with a thermodynamically more stable enolate (generally the one which is more stabilized by substituents) is only reached very slowly (H.O. House, 1977), and the kinetic enolates may be trapped and isolated as silyl enol ethers (J.K. Rasmussen, 1977 H.O. House, 1969). If, on the other hand, a weak acid is added to the solution, e.g. an excess of the non-ionized ketone or a non-nucleophilic alcohol such as cert-butanol, then the tautomeric enolate is preferentially formed (stabilized mostly by hyperconjugation effects). The rate of approach to equilibrium is particularly slow with lithium as the counterion and much faster with potassium or sodium. 

The hydrogenolyaia of cyclopropane rings (C—C bond cleavage) has been described on p, 105. In syntheses of complex molecules reductive cleavage of alcohols, epoxides, and enol ethers of 5-keto esters are the most important examples, and some selectivity rules will be given. Primary alcohols are converted into tosylates much faster than secondary alcohols. The tosylate group is substituted by hydrogen upon treatment with LiAlH (W. Zorbach, 1961). Epoxides are also easily opened by LiAlH. The hydride ion attacks the less hindered carbon atom of the epoxide (H.B. Henhest, 1956). The reduction of sterically hindered enol ethers of 9-keto esters with lithium in ammonia leads to the a,/S-unsaturated ester and subsequently to the saturated ester in reasonable yields (R.M. Coates, 1970). Tributyltin hydride reduces halides to hydrocarbons stereoselectively in a free-radical chain reaction (L.W. Menapace, 1964) and reacts only slowly with C 0 and C—C double bonds (W.T. Brady, 1970 H.G. Kuivila, 1968). 

The alternative synthetic route using the sodium salt of benzyl alcohol and an isopropyl halide would be much less effective because of increased competition from elimination as the alkyl halide becomes more sterically hindered... 

AcCl, NaOH, dioxane, Bu4N HSO, 25°, 30 min, 90% yield. Phase-transfer catalysis with tetra-n-butylammionium hydrogen sulfate effects acylation of sterically hindered phenols and selective acylation of a phenol in the presence of an aliphatic secondary alcohol. 

This reduction is not as suitable for sterically hindered ketones, since in these cases the alcohol is the major product. The reduction of 11- and 12- " keto steroids, for example, is usually very slow. Furthermore, the 11-keto steroid (76) yields only about 10% of the 11,1 l-d2 labeled analog (77), the main product being the 1 IjS-dj-l la-hydroxyl derivative (78). ... 

Other examples of the successful displacement of tosylates are the preparation of 31 -, 16a-,16j - and27- labeled steroids. This displacement reaction fails, however, with certain C-18 and C-19 alcohol derivatives which give mainly O—S instead of C—O bond cleavage. Unsatisfactory results were also obtained with sterically hindered tosylate esters at C-11, C-12 and C-20, which give considerable amounts of olefinic products in addition to O—S bond cleavage. ... 

Sterically hindered amines often tend to form ureas with (BOC)20, because of isocyanate formation. The problem can be avoided by reacting the amine with NaHMDS and then with (BOC)20. The isocyanates can also be converted to the BOC group by heating with r-BuOH. When other alcohols are used, the corresponding carbamate is produced. ... 

X0 to hydroxy compounds. Lower temperatures favor ketone formation and sterically hindered carbonyls, such as 2-thienyl t-butyl ketone, are not reduced. The sensitivity of desulfurization to steric factors is evident by the failure to desulfurize 2,5-di-i-butyl-3-acetylthiophene. The carbonyl groups of both aldehydes and ketones can be protected by acetal formation, as particularly cyclic acetals are stable during desulfurization in methanol at room temperature. " The free aldehydes give primary alcohols on desulfurization. Another method to obtain only keto compounds is to oxidize the mixtures of ketone and secondary alcohol with CrOs after the desulfurization. - Through the desulfurization of 5,5 -diacetyl-2,2, 5, 2"-terthienyl (228), 2,15-hexadecandione (229) has been obtained, which... 

PD—S) to yield phosphates and alcohols, see Scheme 5 reaction a. Sterically hindered aryl phosphites (e.g., AO 14) have an additional chain breaking activity, i.e. they react with peroxyl and alkoxyl radicals during their function as antioxidants (reactions 5b and 5c) [18]. 

There are actually three reactions called by the name Schmidt reaction, involving the addition of hydrazoic acid to carboxylic acids, aldehydes and ketones, and alcohols and alkenes. The most common is the reaction with carboxylic acids, illustrated above.Sulfuric acid is the most common catalyst, but Lewis acids have also been used. Good results are obtained for aliphatic R, especially for long chains. When R is aryl, the yields are variable, being best for sterically hindered compounds like mesi-toic acid. This method has the advantage over 18-13 and 18-14 that it is just one laboratory step from the acid to the amine, but conditions are more drastic. Under the acid conditions employed, the isocyanate is virtually never isolated. 

A Mitsunobu reaction for sterically hindered alcohols Qg% Tsudoda. T. Yamamiya, Y. Kawamura, Y. Ito, S. Tetrahedron Lett., 1995, 36, 2529... 

Although the 0-silylation reaction of the tertiary alcohol 1,1-dimethyl-2-phenylethanol (37) with 27 required a reaction temperature of 120 °C and two equivalents of 27, the 0-silyl ether 38 was still obtained in 86% yield by the simple solvent-free procedure. By contrast, the sterically hindered hydroxyl group of 37 was not silylated at all by heating with 27 in DMF at 120 °C for 5 h [8]. 

The scope of this methodology was extended by these authors to more sterically hindered ketones that provided the corresponding alcohols with enhanced enantioselectivities. As shown in Scheme 9.3, the results demonstrated that the steric and electronic properties of the substrates influenced the reaction course. 

Barium oxide and sodium hydride are more potent catalysts than silver oxide. With barium oxide catalysis, reactions occur more rapidly but O-acetyl migration is promoted. With sodiun hydride, even sterically hindered groups may be quantitatively alkylated but unwanted C-alkylation Instead of, or in addition to, 0-alkylatlon is a possibility. Sodium hydroxide is a suitable catalyst for the alkylation of carboxylic acids and alcohols [497J. 

Recently, however, Sekiguchi et al. reported that the transient disilene ( )- and (Z)-PhMeSi=SiMePh reacted with alcohols in a syn fashion with high diastereoselectivity, the extent of which depended on the concentration and steric bulk of alcohols used.31 These facts suggest that in the reaction with a sterically hindered disilene like (Z)-3, the addition of alcohols might also proceed diastereoselectively under appropriate reaction conditions. 

The lesser acidity of sterically hindered alcohols such as tert-butyl alcohol arises from solvation effects. 

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