Lead tetraacetate reaction with alcohols

The reaction of lead tetraacetate (LTA) with monohydric alcohols produces functionalization at a remote site yielding derivatives of tetrahydrofuran (THF) 12). An example is the reaction of 1-pentanol with LTA in nonpolar solvents which produces 30% THF. The reaction, which is believed to proceed through free-radical intermediates, gives a variable distribution of oxidation products depending on solvent polarity, temperature, reaction time, reagent ratios, and potential angle strain in the product. 

Since in the reaction of 20a- and 200-alcohols with lead tetraacetate somewhat similar relative reactivity has been reoorded (L. Velluz, G. Muller, R. Bardoneschi, and A. Poittevin, Cornpt. Rend., 1960, 725), this strongly suggests that the conformational requirements in the transition state of the lead tetraacetate reaction are comparable with those of the Barton reaction. Also see ref. 6 and G. Cainelli, B. Kamber, J. Keller, M. Lj. Mihailovic, D. Arigoni, and O. Jeger, Helv. Chim. Acta, 44, 518 (1961). 

The benzyl group has been widely used for the protection of hydroxyl functions in carbohydrate and nucleotide chemistry (C.M. McCloskey, 1957 C.B. Reese, 1965 B.E. Griffin, 1966). A common benzylation procedure involves heating with neat benzyl chloride and strong bases. A milder procedure is the reaction in DMF solution at room temperatiue with the aid of silver oxide (E. Reinefeld, 1971). Benzyl ethers are not affected by hydroxides and are stable towards oxidants (e.g. periodate, lead tetraacetate), LiAIH, amd weak acids. They are, however, readily cleaved in neutral solution at room temperature by palladium-catalyzed bydrogenolysis (S. Tejima, 1963) or by sodium in liquid ammonia or alcohols (E.J. Rcist, 1964). 

If homolytic reaction conditions (heat and nonpolar solvents) can be avoided and if the reaction is conducted in the presence of a weak base, lead tetraacetate is an efficient oxidant for the conversion of primary and secondary alcohols to aldehydes and ketones. The yield of product is in many cases better than that obtained by oxidation with chromium trioxide. The reaction in pyridine is moderately slow the intial red pyridine complex turns to a yellow solution as the reaction progresses, the color change thus serving as an indicator. The method is surprisingly mild and free of side reactions. Thus 17a-ethinyl-17jS-hydroxy steroids are not attacked and 5a-hydroxy-3-ket-ones are not dehydrated. 

The radical X is formed by homolysis of the X—R bond either thermally or photolytically. In the reactions of alcohols with lead tetraacetate evidence suggests that the X—R bond (X = 0, R = Pb(OAc)3) has ionic character. In this case the oxy radical is formed by a one electron transfer (thermally or photochemically induced) from oxygen to lead. 

The oxidation of alcohols with lead tetraacetate was the first reaction used for oxygenation of an angular methyl group in steroids. It is a simple and efficient method and produces tetrahydrofuran derivatives directly from alcohols. 

Although such alkoxides have never been isolated it is assumed that with bulky alcohols such as steroidal alcohols, the main contributing structure in such an equilibrium (especially when excess lead tetraacetate is present) is the one in which n = 1. An advantage of this procedure held in common with the hypoiodite reaction is the fact that the alcohol derivative is formed in situ. Intermolecular hydrogen abstraction e.g., reaction with solvent)... 

The pyridine-catalysed lead tetraacetate oxidation of benzyl alcohols shows a first-order dependence in Pb(OAc)4, pyridine and benzyl alcohol concentration. An even larger primary hydrogen kinetic isotope effect of 5.26 and a Hammett p value of —1.7 led Baneijee and Shanker187 to propose that benzaldehyde is formed by the two concurrent pathways shown in Schemes 40 and 41. Scheme 40 describes the hydride transfer mechanism consistent with the negative p value. In the slow step of the reaction, labilization of the Pb—O bond resulting from the coordination of pyridine occurs as the Ca—H bond is broken. The loss of Pb(OAc)2 completes the reaction with transfer of +OAc to an anion. 

For the substitution of the angular methyl groups in steroids five methods are known (a) homolysis of N-chloramines [Loffier-Freytag reaction (only C-18)] (b) oxidation of alcohols with lead tetraacetate (c) photolysis of nitrite esters (d) homolysis of hypochlorites (e) the hypoiodite reaction. ... 

A similar reaction can be effected by the treatment of amides with lead tetraacetate.2 4 In this case the initial isocyanate and the amine formed from it react with the acetic acid liberated from the lead tetraacetate to give, respectively, ureas and amides. If the reaction is carried out in the presence of an alcohol, carbamates are formed (6-8). 

The 40-alcohols of the type 2159 with lead tetraacetate and iodine gave, after oxidation of the photolysis mixture, the corresponding lactones (22) as the major product. As illustrated in structure 23, the steric locations of the 40-oxygen atom and the iodomethyl group in this molecule are similar to those in the case of 200-alcohols thus favoring an intramolecular hydrogen abstraction (conversion 11 — 13) over the cycli-zation reaction (conversion 11 —> 12). 

The Diels-Alder reaction of 3-methoxyfuran with octyl vinyl ketone took place at room temperature in quantitative yield to afford exclusively the endo cycloadduct (27) (81CC221). Reduction of the carbonyl group with lithium tri-r-butoxyaluminum hydride produced a single alcohol (28). Ozonolysis of the double bond followed by Jones oxidation yielded the lactone ester (29). Hydrolysis of the ester and lead tetraacetate oxidation gave the lactone acetate. This was converted by further hydrolysis and Jones oxidation to the bis-lactone (30), a known intermediate in the synthesis of ( )-isoavenaciolide (Scheme 6). 

Pinocarveol has been prepared by the autoxidation of a-pinene,5 by the oxidation of /S-pinene with lead tetraacetate,6 and by isomerization of a-pinene oxide with diisobutylalumi-num,7 lithium aluminum hydride,8 activated alumina,9 potassium ferf-butoxide in dimethylsulfoxide,10 and lithium diethylamide.11 The present method is preferred for the preparation of pinocarveol, since the others give mixtures of products. It also illustrates a general method for converting 1-methylcy-cloalkene oxides into the corresponding exocyclic methylene alcohols.11 The reaction is easy to perform, and the yields are generally high. 

The diterpenoid 1 from the heartwood of Callitris macleayana is the Diels-Alder dimer of the dienone 2a. The acetate 2b of the alcohol 2a is readily available by oxidation of 5-isopropyl-2-methylphenol with lead tetraacetate, but all attempts to hydrolyse 2b to 2a failed. "Dimeric indans" were obtained under acidic conditions, while use of potassium hydroxide in methanol at room temperature for 15 minutes followed by acidification with 1M hydrochloric acid, extraction and repeated chromatography over silica gave the three products 3, 4 and 5 in the relative distribution 11.7, 63.7 and 24.7%. The same products were formed in similar proportions when the reaction temperature was varied from 0°C to 64°C treatment of any of the products 3, 4 or 5 with potassium hydroxide in methanol also gave a mixture of 3,4 and 5. 

This reaction pathway is suitable for cis as well as tram diols. In principle, the oxidative cleavage is achieved by lead tetraacetate as well. However, these reagents are complementary, since periodic acid compounds are best used in water and lead tetraacetate in organic solvents. The last step is the reduction of the aldehyde with three equivalents of sodium borohydride to provide alcohol 5. 

---