Secondary alcohols, dimerization

There are a number of methods for the oxidation of primary alcohols or ethers to dimeric esters, and secondary alcohols to ketones. We recently also found that quaternary ammonium tribromides, especially BTMA Br3, are useful oxidizing agents for the purpose described above (ref. 31). 

In 2003, Sigman et al. reported the use of a chiral carbene ligand in conjunction with the chiral base (-)-sparteine in the palladium(II) catalyzed oxidative kinetic resolution of secondary alcohols [26]. The dimeric palladium complexes 51a-b used in this reaction were obtained in two steps from N,N -diaryl chiral imidazolinium salts derived from (S, S) or (R,R) diphenylethane diamine (Scheme 28). The carbenes were generated by deprotonation of the salts with t-BuOK in THF and reacted in situ with dimeric palladium al-lyl chloride. The intermediate NHC - Pd(allyl)Cl complexes 52 are air-stable and were isolated in 92-95% yield after silica gel chromatography. Two diaster corners in a ratio of approximately 2 1 are present in solution (CDCI3). 

Depending on the electrode potential, this radical either adds a second electron and a second proton to yield the corresponding secondary alcohol (A), or it dimerizes to the pinacol (B), a dihydric ditertiary alcohol ... 

To access the calphostins, (S)-16 was subjected to Mitsunobu conditions followed by the two-step dimerization protocol (lithiation, FeCl3) resulting in biaryl (R)-17 as the major diastereomer (Scheme 7.2). In this case, the relative stereochemistry matched the stereochemistry of calphostins A and D. Elaboration following the same protocol as for 5 completed the first total synthesis of calphostin D (4d). Calphostin A (4a) was also synthesized via benzoate protection of the secondary alcohols. 

The most characteristic reaction of butadiene catalyzed by palladium catalysts is the dimerization with incorporation of various nucleophiles [Eq. (11)]. The main product of this telomerization reaction is the 8-substituted 1,6-octadiene, 17. Also, 3-substituted 1,7-octadiene, 18, is formed as a minor product. So far, the following nucleophiles are known to react with butadiene to form corresponding telomers water, carboxylic acids, primary and secondary alcohols, phenols, ammonia, primary and secondary amines, enamines, active methylene compounds activated by two electron-attracting groups, and nitroalkanes. Some of these nucleophiles are known to react oxidatively with simple olefins in the presence of Pd2+ salts. Carbon monoxide and hydrosilanes also take part in the telomerization. The telomerization reactions are surveyed based on the classification by the nucleophiles. 

In a mixture of liquid ammonia with alcohol, ketoenols and pinacols are still formed along with secondary alcohols. Process selectivity was enhanced on the basis of mechanistic studies (Rautenstrauch et al. 1981). The initial stages of the reaction include the formation of ketone anion-radicals and their dimerization with a metal cation participation. This dimerization results in pina-col formation as shown in Scheme 7.6. 

Stereospecific ketone reduction was also observed (Giordano et al. 1985) with potassium, rubidium, and cesium (but not with sodium) in tertiary alcohols (but not in secondary or primary alcohols). The undesirable dimerization probably proceeds more readily in the case of sodium. Tertiary alcohols are simply more acidic than primary or secondary alcohols. It is reasonable to point out that the ketone-to-alcohol reduction of 3a-hydroxy-7-oxo-5p-cholic acid by alkali metals is a key step in the industrial synthesis of 3a,7p-dihydroxy-5p-cholic acid. 

An example of a photolabile mask for alcohols and thiols employing o-benzoylbenzoate esters is reported by Porter and co-workers [100], Primary and secondary alcohols as well as thiols can be easily masked via the formation of the corresponding 2-benzoylbenzoate esters and converted back into alcohols/ thiols under PET-reductive conditions. Irradiation in isopropanol/benzene 1 1 leads to 3-phenylphthalide dimers as the coproduct (together with acetone), whereas more potent electron donors (e.g., amines) result in the monomers and the corresponding imine. Yields generally range from 60% to 90% (Scheme 55) [100]. 

DKR of secondary alcohol is achieved by coupling enzyme-catalyzed resolution with metal-catalyzed racemization. For efficient DKR, these catalyhc reactions must be compatible with each other. In the case of DKR of secondary alcohol with the lipase-ruthenium combinahon, the use of a proper acyl donor (required for enzymatic reaction) is parhcularly crucial because metal catalyst can react with the acyl donor or its deacylated form. Popular vinyl acetate is incompatible with all the ruthenium complexes, while isopropenyl acetate can be used with most monomeric ruthenium complexes. p-Chlorophenyl acetate (PCPA) is the best acyl donor for use with dimeric ruthenium complex 1. On the other hand, reaction temperature is another crucial factor. Many enzymes lose their activities at elevated temperatures. Thus, the racemizahon catalyst should show good catalytic efficiency at room temperature to be combined with these enzymes. One representative example is subtilisin. This enzyme rapidly loses catalytic activities at elevated temperatures and gradually even at ambient temperature. It therefore is compatible with the racemization catalysts 6-9, showing good activities at ambient temperature. In case the racemization catalyst requires an elevated temperature, CALB is the best counterpart. 

In addition to converting secondary alcohols into ketones, the platinum catalyst also converts toluene and other benzyl hydrocarbons into dimers. 

The biosynthesis of many bis-indole alkaloids has been postulated to proceed by dimerisation of appropriate precursors, and there is now a substantial amount of experimental evidence to support this hypothesis. For example, treatment of the alcohol 1 with acid gives the alkaloid yuehchukene 2, and 1 could arise biogenetically by in vivo prenylation of indole followed by enzymatic oxidation. A study of related 2-prenylated indoles has confirmed the ease with which such molecules can "dimerise". Thus, treatment of the secondary alcohol 3 in benzene with silica gel impregnated with TsOH gave a complex mixture of products from which 4 (5.1%) and 5 (2.1%) were isolated (3 is very sensitive to acid, and is easily decomposed). Treatment of the isomeric tertiary alcohol 6 with a catalytic amount of TFA in anhydrous benzene gave much higher yields of the two "dimeric" products 7 (31%) and 8 (25%). 

Table 2 Use of Pd(II) dimers in oxidative kinetic resolution of secondary alcohols...

A number of systems consist of a palladium salt, typically PdCb or Pd(OAc)2, with abase. For example, PdCb-NaOAc catalyzes the aerobic oxidation of secondary alcohols in ethylene carbonate under nuld conditions. Sheldon has carried out mechanistic investigations on a number of related Pd systems and shown that water-soluble complexes of Pd(II) with phenanthrohnes are stable, recyclable catalysts for the selective aerobic oxidation of a wide range of alcohols to aldehydes, ketones, and carboxylic acids in a biphasic liquid liquid system. The active catalyst is a dihydroxy-bridged palladium dimer. 

As noted above (Section 1.4.2.2) reduction of carbonyl compounds under these conditions proceeds with hydrogen transfer to afford an equimolar mixture of alkoxide and enolate, plus varying quantities of dimeric reduction products. As a consequence, at least in theory, this procedure should afford an equimolar mixture of recovered ketone and reduction product. This appears to be the case if less than one equivalent of metal is used however, with excess metal, camphor, " some 12-keto steroids2 and several 1 -decalones2 afforded 70-99% yields of secondary alcohols. The explanation which has been offered is that the product enolate is protonated by NH3 to regenerate the starting ketone, which is recycled through the reduction process. ... 

All five Group I metals (Li, Na, K, Rb and Cs) and three Group II metals (Ca, Sr, Ba) have been used in NH3 to effect the reduction of ketones to secondary alcohols. " In addition, it has been reported that Yb-NH3 reduction of a,p-unsaturated ketones affords the saturated alcohol as the major product, which presumably arises via reduction of the intermediate saturated ketone.Reduction of (+)-camphor with Yb-NH3 both in the absence and presence of NH4CI affords the same 86 14 ratio of bomeol (2) to iso-bomeol (3). In the presence of NH4CI, the ketone is completely consumed and dimeric reduction products are not observed. Excess Yb-THF-HMPA effects bimolecular reduction of aromatic ketones, but aliphatic ketones are apparently inert to Yb-THF. - ... 

Selective acylation. Acylation of primary alcohols (e.g., with various vinyl esters) while leaving secondary alcohols and phenols untouched can be accomplished by catalysis with BUjSnO and BujSnCl which form a bis(chlorodibutyl)tin oxide dimer. 

This procedure enabled versatile hydrolysis of pyrrohdinones followed by decarboxylation (Scheme 12.191) [347]. It has been disclosed that a neutral organotin dimer [tBu2SnOH(Cl)]2 is an efficient catalyst for deacetylation (Scheme 12.192) [348]. When an MeOH solution of an acetate was heated at 30 °C in fhe presence of a catalytic amount of the organotin dimer deacetylation proceeded quite smoothly to furnish the parent alcohol, in which a variety of acid-labile functional groups remained intact. Acetates of primary alcohols and phenols underwent rapid deacetylation whereas acetates of secondary alcohols reacted only sluggishly. When fhis deacetylation procedure was apphed to acetates derived from tertiary alcohols fhey remained intact, and decomposed under harsher conditions. When nonracemic acetates derived from chiral alcohols and aminoalcohols were treated wifh [tBu2SnOH(Cl)]2 in MeOH, the desired deacetylation proceeded, and no racemization was observed. Exclusive deacetylation of primary alcohols in fhe reaction of peracetates of carbohy-... 

As a mimic of the well-studied galactose oxidase [37], a copper(II) thiophenol complex catalyzes the oxidation of primary alcohols to aldehydes in the presence of (Scheme 12) [38]. The latter also promotes the oxidation of secondary alcohols to diols (Scheme 12). The catalytic cycle starts with the oxidation of copper by O, leading to a biradical species. The intermediate 39 is produced from 38 by coordination of two alkoxide substrates. The rate-limiting step is the formation of 40 from 39 by a hydrogen atom transfer from the secondary alcoholate to the oxygen-centered radicals of the aminophenols ligands. The cycle is then closed by radical dimerization which leads the formation of the diol [39]. 

Scheme 12 Catalytic cycle of Cu(ll)-catalyzed dimerization of secondary alcohols (dashed lines represent hydrogen bonding)...

The reductive power of FAS has been studied in literature. Early works by Nakagawa and Minami [29] on many ketones have led to the proposed reduction mechanism presented in Eigure 13.6, where the reduction proceeds by a one electron transfer followed by radical formation that leads either to a secondary alcohol or a dimer. 

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