Additions, protic-acid-catalyzed

The second major modification was developed by Mukaiyama and coworkers (4) and Hosomi and Sakurai (5). These workers found that weakly nucleophilic silyl enol ethers and allylsilanes add to a,/ -unsaturated ketones that have been precomplexed with a Lewis acid. This process formally mimics the protic-acid-catalyzed Michael addition but allows for regiocontrol over enol generation. 

Protic-acid-catalyzed Michael additions (59) are subject to most of the limitations of base-catalyzed Michael additions (regioselectivity and stereoselectivity of enol generation, polyaddition, etc.), and hence, the stereochemistry has been little studied (60). At low temperatures silyl and stannyl enol ethers,+ ketene acetals, and allyl species are unreactive to all but the most reactive activated olefins. However, it was discovered by Mukaiyama and co-workers that enol ethers and ketene acetals react with a,/f-unsaturated carbonyl compounds in the presence of certain Lewis acids (4,61,62). Sakurai, Hosomi, and co-workers found that allylsilanes behave similarly (5,63,64). 

As with protic-acid-catalyzed additions, the Lewis-acid-promoted additions are believed to occur by attack of an enol species on a Lewis acid complex (protonated) form of the acceptor. Complexation of the acceptor with the Lewis acid serves to lower the energy of the acceptor LUMO and polarize the 71-system. Neutral or anionic nucleophilic species with high HOMOs will then combine with the acceptor-Lewis acid complex to yield products. 

In the context of preparing potential inhibitors of dihydrofolate reductase (DHFR), the group of Organ has developed a rapid microwave-assisted method for the preparation of biguanide libraries (Scheme 6.174) [330]. Initial optimization work was centered around the acid-catalyzed addition of amines to dicyandiamide. It was discovered that 150 °C was the optimum temperature for reaction rate and product recovery, as heating beyond this point led to decomposition. While the use of hydrochloric acid as catalyst led to varying yields of product, evaluation of trimethylsilyl chloride in acetonitrile as solvent led to improved results. As compared to the protic... 

In the Diels-Alder reaction between Danishefsky s diene and N-aryl imines derived from o-hydroxyaniline catalyzed by Ih, Akiyama observed substantial increases in chemical yield and enantioselectivty by the addition of stoichiometric amounts of acetic acid (Scheme 5.14) [27]. The authors concede that the role of the protic acid is unclear. 

In addition to small amounts of methane, acetaldehyde or acetic anhydride can be generated in substantial quantities depending on conditions. However, they are not present simultaneously in any appreciable quantity. Acetic anhydride and acetaldehyde must be competitively formed (equation 6), and subsequently react with each other to form EDA (step C). This reaction (step C) is generally catalyzed by protic acids (2-4). The reaction solution for reductive carbonylation is quite acidic HI is an intermediate generated under reaction conditions of high alkyl iodide concentration and hydrogen pressure. The thermodynamic equilibrium of this condensation is quite favorable for diester formation existence of an abundance of either anhydride or aldehyde in the presence of the other is not found. Yields of stoichiometric preparations are in excess of 95%... 

Selectivity for each product formation may also be controlled by an effective catalyst system. After the discovery of the reaction by Heck, Stille applied the reaction to organic synthesis, as he observed the preferential formation of [3-methoxy esters under neutral conditions and 1,2-diesters in the presence of a base. As Bianchini reported in 2001, selective formation of a,/3-unsaturated ester product is established by an addition of protic acid such as y)-TsOH in bis-phosphine/Pd-catalyzed oxidative alkoxycarbonylation. ... 

Although a seldom used laboratory method, the addition of carboxylic acids to alkenes provides carboxylic esters. The addition is catalyzed by protic acids or Lewis acids and obeys Markovnikov s rule (equation 273).456-458... 

The addition of thiols to C—C multiple bonds may proceed via an electrophilic pathway involving ionic processes or a free radical chain pathway. The main emphasis in the literature has been on the free radical pathway, and little work exists on electrophilic processes.534-537 The normal mode of addition of the relatively weakly acidic thiols is by the electrophilic pathway in accordance with Markovnikov s rule (equation 299). However, it is established that even the smallest traces of peroxide impurities, oxygen or the presence of light will initiate the free radical mode of addition leading to anti-Markovnikov products. Fortunately, the electrophilic addition of thiols is catalyzed by protic acids, such as sulfuric acid538 and p-toluenesulfonic acid,539 and Lewis acids, such as aluminum chloride,540 boron trifluoride,536 titanium tetrachloride,540 tin(IV) chloride,536 540 zinc chloride536 and sulfur dioxide.541... 

The combination of X2/protic acid (X2=Cl2,Br2> I2) is usually ineffective for reactions of conjugate addition, due to formation of significant amounts of a halogenation product. However, addition of a Lewis acid may alter the course of the reaction. For example, fluorosulfate 44 was isolated in 84% yield in the reaction of HFP with C12/H0S02F catalyzed by SbF5, but in the absence of the catalyst no formation of 44 was observed [82] ... 

The highly reactive semibullvalene structure undergoes facile acid-catalyzed 1,4-addition of protic solvents to one of the vinylcyclopropane units.201 The reaction... 

Let us now examine how substituent effects in reactants influence the rates of nucleophilic additions to carbonyl groups. The most common mechanism for substitution reactions at carbon centers is by an addition-elimination mechanism. The adduct formed by the nucleophilic addition step is tetrahedral and has sp hybridization. This adduct may be the product (as in hydride reduction) or an intermediate (as in nucleophilic substitution). For carboxylic acid derivatives, all of the steps can be reversible, but often one direction will be strongly favored by product stability. The addition step can be acid-catalyzed or base-catalyzed or can occur without specific catalysis. In protic solvents, proton transfer reactions can be an integral part of the mechanism. Solvent molecules, the nucleophile, and the carbonyl compound can interact in a concerted addition reaction that includes proton transfer. The overall rate of reaction depends on the reactivity of the nucleophile and the position of the equilibria involving intermediates. We therefore have to consider how the substituent might affect the energy of the tetrahedral intermediate. 

Often the rates and selectivities of catalytic reactions are enhanced by additional reaction components that are added in small amoimts. These added materials are often called promoters or co-catalysts. Protic acids or Lewis acids are common promoters. As is presented in Chapter 16, triarylboranes are Lewis acid promoters in hydrocyanations catalyzed by transition metal complexes. 

Gold-catalyzed addition of N-H and O-H to a triple bond has proven to be a rich source of protic acid-based multicatalytic systems. The setup for hydrogen transfer from Hantzsch esters has already been discussed other recent examples of Au/protic acid systems include combinations with well-known acid-catalyzed reactions such as the Fischer indole synthesis [114], Povarov reaction [115], and Diels-Alder reaction[116] (Scheme 26.26). 

Although the acid-catalyzed side-reaction of EDOT to EDOT-dimers and -trimers,i induced by toluenesulfonic acid, is no dead end in the reaction route, because these intermediates are also leading to doped PEDOT at the end of the reaction (see Chapter 8), detrimental effects cannot be excluded and may be one of the reasons for improvements by the addition of bases. Additionally, catalytic effects on EDOT polymerization by protic acids— reducing pot life—are suppressed, and premature precipitation of doped PEDOT is diminished. 

Danheiser et al. [133] reported a variety of intramolecular [4 + 2]-cycloadditions of a butenyne subunit with a remote acetylene moiety by thermolysis of the substrates, with the best yields being obtained in the presence of phenolic additives. Two examples are presented in Scheme 6.49. Of particular significance with regard to synthetic utility is the observation that protic and Lewis acids were powerful promoters of these reactions. The intermediacy of 1,2,4-cyclohexatriene derivatives, as shown in Scheme 6.49, is highly likely, at least in the non-catalyzed cases. 

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