Protic acid catalysis

Since the revised Biginelli mechanism was reported in 1997, numerous papers have appeared addressing improvements and variations of this reaction. The improvements include Lewis acid catalysis, protic acid catalysis, non-catalytic conditions, and heterogeneous catalysis. In addition, microwave irradiation (MWI) has been exploited to increase the reaction rates and yields. 

We have previously reported that when the rearrangement of trans-stilbene oxide was carried out with CF3SO3H, the solution turned red and the product diphenylacetaldehyde was less pure than that obtained with bismuth triflate. This observation points to the role of bismuth(III) triflate as a Lewis acid in the rearrangement of epoxides and not to protic acid catalysis by triflic acid released by hydrolysis of bismuth triflate. 

Alko xy ally 1)stannane aldehydes (57) can cyclize either thermally or with Lewis or protic acid catalysis to give cyclic ethers (58).85 The interrelationship of the reactant and product stereochemistries has been investigated, as have the methods used to promote the reaction. For both thermal and proton-promoted reactions, [(Z)-57 gave (cis-58), and [(E)-57] gave trans-58), whereas trans-58) was the predominant or exclusive product of Lewis acid mediation, regardless of the double bond geometry of... 

We have a choice of reagents for the -butyl cation a halide with Lewis acid catalysis, and -butanol or isobutene with protic acid catalysis. The least wasteful is the alkene as nothing is lost. Protonation gives the r-butyl cation and two r-butyl groups are added in one operation.3... 

Except for the metallic impurities present on the walls of poorly washed glassware, no other transition metal catalyst may be assumed to be present in this experiment. Consequently, the transfer of the dimethylamino group from the ortho amide II to I must be taking place under less energy demanding conditions, where protic acid catalysis suffices to activate the triple carbon to carbon bond. ... 

Hydrostannation of carbonyl compounds with tributyltin hydride is promoted by radical initiation and Lewis or protic acid catalysis.The activation of the carbonyl group by the acidic species allows the weakly nucleophilic tin hydride to react via a polar mechanism. Silica gel was a suitable catalyst allowing chemoselective reduction of carbonyl groups under conditions that left many functional groups unchanged. Tributyltin triflate generated in situ from the tin hydride and triflic acid was a particularly efficient catalyst for the reduction of aldehydes and ketones with tributyltin hydride in benzene or 1,2-di-chloromethane at room temperature. Esters and ketals were not affected under these conditions and certain aldehydes were reduced selectively in preference to ketones. 

The stereoselective synthesis of (+)-trichodiene was accomplished by K.E. Harding and co-workers. The synthesis of this natural product posed a challenge, since it contains two adjacent quaternary stereocenters. For this reason, they chose a stereospecific electrocyclic reaction, the Nazarov cyclization, as the key ring-forming step to control the stereochemistry. The cyclization precursor was prepared by the Friedel-Crafts acylation of 1,4-dimethyl-1-cyclohexene with the appropriate acid chloride using SnCU as the catalyst. The Nazarov cyclization was not efficient under protic acid catalysis (e.g., TFA), but in the presence of excess boron trifluoride etherate high yield of the cyclized products was obtained. It is important to note that the mildness of the reaction conditions accounts for the fact that both of the products had an intact stereocenter at C2. Under harsher conditions, the formation of the C2-C3 enone was also observed. 

Stork and Atwal reported an intramolecular Michael addition of 53.1 that proceeds with protic acid catalysis (Scheme 53) (104). After hydrolysis and oxidation of ketal 53.2, a 10 1 mixture of lactones of the general structure 53.3 was produced. Proof that the major isomer is 533 followed from conversion into a compound of known configuration. Use of optically enriched acetals 53.1 resulted in products with no loss of optical purity. 

Many additions to a,p-unsaturated carbonyl compounds, take advantage of coordination to the oxygen by a metal cation or a proton, or even just a hydrogen bond. This is true for hydrides and carbon nucleophiles. In such a situation, the LUMO coefficient is largest at the carbonyl carbon, but not at the p carbon. Thus, even soft nucleophiles can be expected to attack directly at the carbonyl carbon when Lewis or protic acid catalysis is involved. It is likely that the difference in the... 

The Nazarov cyclization was the key step in a synthesis of ( )-trichodiene (35) by Harding and co-workers. One significant challenge in the preparation of this natural product is the presence of two adjacent quaternary stereocenters, and Harding and co-workers selected the Nazarov cyclization to tackle this problem. Although the reaction was not efficient under protic acid catalysis, the presence of an excess of boron trifluoride etherate enabled the production of 34a/b in good yield, whereby double bond migration had occurred. These specific reaction conditions were key to the success of this transformation, since under milder conditions or shorter reaction times, the expected a,p-unsaturated ketone was observed. 

The achiral triene chain of (a//-rrans-)-3-demethyl-famesic ester as well as its (6-cis-)-isoiner cyclize in the presence of acids to give the decalol derivative with four chirai centres whose relative configuration is well defined (P.A. Stadler, 1957 A. Escherunoser, 1959 W.S. Johnson, 1968, 1976). A monocyclic diene is formed as an intermediate (G. Stork, 1955). With more complicated 1,5-polyenes, such as squalene, oily mixtures of various cycliz-ation products are obtained. The 18,19-glycol of squalene 2,3-oxide, however, cyclized in modest yield with picric acid catalysis to give a complex tetracyclic natural product with nine chiral centres. Picric acid acts as a protic acid of medium strength whose conjugated base is non-nucleophilic. Such acids activate oxygen functions selectively (K.B. Sharpless, 1970). 

CH2=C(OBn)CH2F, PdCl2(COD), CH3CN, it, 24 h, 89-100% yield. Protic acids can also be used to introduce this group, but the yields are sometimes lower. A primary alcohol can be protected in the presence of a secondary alcohol. This reagent also does not give cyclic acetals of 1,3-diols with palladium catalysis. 

The intervention of mesoionic intermediates is suggested by the facile transformation of steroidal dienones, and by a number of acid-catalyzed nonphotolytic reactions which either parallel the photoisomerizations or correlate photoproducts from reactions in protic and aprotic solvents. The isomerization (175) -> (176) -l- (177) has also beeen achieved in the dark by acetic and formic acid catalysis and clearly involves the conjugate acid of the proposed mesoionic intermediate (199) in the dark reaction. Further,... 

S. Kobayashi, S. Nagayama, T. Busujima, Chiral Lewis Acid Catalysis in Aqueous Media. Catalytic Asymmdric Aldol Readions of Silyl Enol Ethers with Aldehydes in a Protic Solvent Induding Water Chem. Lett. 1999, 71-72. 

The second important solvent effect on Lewis acid-Lewis base equilibria concerns the interactions with the Lewis base. Since water is also a good electron-pair acceptor129, Lewis-type interactions are competitive. This often seriously hampers the efficiency of Lewis acid catalysis in water. Thirdly, the intermolecular association of a solvent affects the Lewis acid-base equilibrium242. Upon complexation, one or more solvent molecules that were initially coordinated to the Lewis acid or the Lewis base are liberated into the bulk liquid phase, which is an entropically favourable process. This effect is more pronounced in aprotic than in protic solvents which usually have higher cohesive energy densities. The unfavourable entropy changes in protic solvents are somewhat counterbalanced by the formation of new hydrogen bonds in the bulk liquid. 

Supplementary studies of the mechanism were conducted. The dependence of the reaction rate on the nature of environment at the cationic carbon has shown that the concurrent formation of the protic acid proceeds, if the substituents can undergo the isomerization (Scheme 61), and thus the carbenium catalysis is utterly negligible. It was shown that the reaction was still catalyzed, even when a base was added in order to rule out a TfOH catalyzed reaction. Obviously, the protonated base was then a catalyst. 

The mechanism of the cycloaddition process was partly clarified on the basis of experiments with acetylenic dithio derivatives 102, which were found to be thermally transformable to allenic isomers 103.149 The latter gave expected 2/7-thiopyrans 104 in 41 to 78% yields under triethylamine catalysis, whereas isomeric thiophenes 105 were formed in the presence of protic acids (Scheme 5). The activation energies for some of the processes were also measured.149... 

Therefore, this ATP-stimulation seems to be attributable to a nonspecific effect as a protic acid (14). Acid catalysis in various redox reactions is well known. 

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