Intermolecular reactions alcohol additions

Although the high reactivity of metal-chalcogen double bonds of isolated heavy ketones is somewhat suppressed by the steric protecting groups, Tbt-substituted heavy ketones allow the examination of their intermolecular reactions with relatively small substrates. The most important feature in the reactivity of a carbonyl functionality is reversibility in reactions across its carbon-oxygen double bond (addition-elimination mechanism via a tetracoordinate intermediate) as is observed, for example, in reactions with water and alcohols. The energetic basis... 

The reaction worked with both internal and terminal alkynes (except silylated alkynes) and in many solvents, even in the neat alcohol added [105]. The mechanism proposed involved two catalytic cycles first, gold catalysis would lead to dihydro-furan by a fast intramolecular reaction then, the subsequent slower intermolecular reaction would be produced by the addition of alcohol to the enol ether to deliver a ketal (Scheme 8.18). 

During our investigation of the reactivity of the 10 % Pd/C catalyst, we found that le reacts with itself forming dimeric compounds (Scheme 32). This problem was solved by slow addition of the silane to a mixture of the alcohol and catalyst in the second alcoholysis step. We proposed that the silyl ether is activated by the catalyst and intramolecular dimerization occurs on the surface of the catalyst (Figure 8). This reaction is faster than the usual intermolecular reaction of the incoming alcohol with the silane, resulting in the dimeric products. 

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

Sc(OTf)3 also catalyzes acetalization reactions [47a,b], acylal formation [47c], /9-selective glycosilation reactions with thioglycosides [48], and acylation reactions of alcohols [49]. Guanidium formation reactions of carbodiimide with benzylamine [50], intermolecular stereoselective radical additions to A/-enoyloxazolidinones [51], and rearrangement of... 

From a synthetic point of view, intermolecular reactions are more interesting, as a wider variety of substrates is available. In 1990, Larock and coworkers reported a palladium-catalyzed heteroannulation of 1,3-dienes with 2-iodophenols and 2-iodoanilines. Dihydrobenzofurans and indolines were isolated in moderate to good yields (Scheme 2.45). In addition to the 2-iodophenols and 2-iodoanilines, 2-iodobenzyl alcohol and 2-iodoben l amine could be applied as substrates as well and gave the corresponding six-membered heterocyclie eompounds as the terminal products. 

Hf(0Tf)4 was also reported to possess unique reactivity characteristics relative to other Lewis acids. Recent reports indicated that it is capable to catalyze hydrolysis reactions even in the presence of excess water [41]. An example is its capacity to catalyze the efficient direct macrolactonization of secondary acids in high yields (Equation (8.20)). Water was the sole by-product of this reaction. In addition to synthesis of macrolactones and benzolactones this catalyst allowed intermolecular direct esterifications of carboxylic acids and alcohols. 

Dehydration to olefins, which sometimes accompanies the reaction of alcohols with DAST [95, 108], is seldom as extensive as with a-fluoroamines (FAR and 1,1,2,3,3,3 hexafluoropropyldiethylamine) but occurs in a few cases to the exclusion of fluonnation, thus, 9a-fluoro-11-hydroxysteroids give 9a fluoro-A -steroids [127, 128] Dehydration accompanied by Wagner-Meerwein rearrangement occurs during the fluonnation of testosterone [129] Intermolecular dehydration to form ethers in addition to fluorides is observed in the reaction of benzhydryl alcohols [104] (Table 6)... 

Intermolecular hydroalkoxylation of 1,1- and 1,3-di-substituted, tri-substituted and tetra-substituted allenes with a range of primary and secondary alcohols, methanol, phenol and propionic acid was catalysed by the system [AuCl(IPr)]/ AgOTf (1 1, 5 mol% each component) at room temperature in toluene, giving excellent conversions to the allylic ethers. Hydroalkoxylation of monosubstituted or trisubstituted allenes led to the selective addition of the alcohol to the less hindered allene terminus and the formation of allylic ethers. A plausible mechanism involves the reaction of the in situ formed cationic (IPr)Au" with the substituted allene to form the tt-allenyl complex 105, which after nucleophilic attack of the alcohol gives the o-alkenyl complex 106, which, in turn, is converted to the product by protonolysis and concomitant regeneration of the cationic active species (IPr)-Au" (Scheme 2.18) [86]. 

Intramolecular oxonium ylide formation is assumed to initialize the copper-catalyzed transformation of a, (3-epoxy diazomethyl ketones 341 to olefins 342 in the presence of an alcohol 333 . The reaction may be described as an intramolecular oxygen transfer from the epoxide ring to the carbenoid carbon atom, yielding a p,y-unsaturated a-ketoaldehyde which is then acetalized. A detailed reaction mechanism has been proposed. In some cases, the oxonium-ylide pathway gives rise to additional products when the reaction is catalyzed by copper powder. If, on the other hand, diazoketones of type 341 are heated in the presence of olefins (e.g. styrene, cyclohexene, cyclopen-tene, but not isopropenyl acetate or 2,3-dimethyl-2-butene) and palladium(II) acetate, intermolecular cyclopropanation rather than oxonium ylide derived chemistry takes place 334 ). 

The mechanism for the addition of singlet carbenes to alcohols has been studied in some detail (Bethell et al, 1971 Kirmse et al, 1981). By and large, the evidence supports two routes. The first, more common, sequence features initial formation of an ylid. Under some circumstances this reaction is reversible (Zupancic et al., 1985 Liu and Subramanian, 1984 Warner and Chu, 1984). Next, proton transfer, either intramolecularly, which may be slowed by symmetry constraints, or by a pair of intermolecular protonation and deprotonation steps, gives the ether. These reactions are outlined in (7). 

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