Carbocations synthesis with

Pearson, W. H., Walavalkar, R., Schkeryantz, J. M., Fang, W. K., Blickensdorf, J. D. Intramolecular Schmidt reactions of azides with carbocations synthesis of bridged-bicyclic and fused-bicyclic tertiary amines. J. Am. Chem. Soc. 1993,115,10183-10194. 

The formal carbanions and carbocations used as units in synthesis are called donor synthons and acceptor synthons. They are derived from reagents with functional groups. 

Other, removable cation-stabilizing auxiliaries have been investigated for polyene cyclizations. For example, a sdyl-assisted carbocation cyclization has been used in an efficient total synthesis of lanosterol. The key step, treatment of (257) with methyl aluminum chloride in methylene chloride at —78° C, followed by acylation and chromatographic separation, affords (258) in 55% yield (two steps). When this cyclization was attempted on similar compounds that did not contain the C7P-silicon substituent, no tetracycHc products were observed. Steroid (258) is converted to lanosterol (77) in three additional chemical steps (225). 

In the case of NH2OH with a sharp difference in the nucleophilicity of the two functions, the primary amino group reacts with the carbocation C-1 center. For example, the reaction of l-alkylaminoalk-l-en-3-ynes with hydroxylamine leads to selective synthesis of alkylisoxazoles (69ZOR1179). A preparative value of this method is evident because the use of dicarbonyl compounds as starting materials for the synthesis of alkylisoxazoles results in a mixture of isomers. 

Ethers with a tertiary, benzylic, or allylic group cleave by an S l or FI mechanism because these substrates can produce stable intermediate carbocations. These reactions are often fast and take place at moderate temperatures. fcrf-Butyl ethers, for example, react by an El mechanism on treatment with trifluoroacetic acid at 0 °C. We ll see in Section 26.7 that the reaction is often used in the laboratory synthesis of peptides. 

Addition of a proton occurs to give the more-substituted carbocation, so addition is regioselective and in accord with Markovnikov s rule. A more detailed discussion of the reaction mechanism is given in Section 6.2 of Part A. Owing to the strongly acidic and rather vigorous conditions required to effect hydration of most alkenes, these conditions are applicable only to molecules that have no acid-sensitive functional groups. The reaction is occasionally applied to the synthesis of tertiary alcohols. 

There are, however, serious problems that must be overcome in the application of this reaction to synthesis. The product is a new carbocation that can react further. Repetitive addition to alkene molecules leads to polymerization. Indeed, this is the mechanism of acid-catalyzed polymerization of alkenes. There is also the possibility of rearrangement. A key requirement for adapting the reaction of carbocations with alkenes to the synthesis of small molecules is control of the reactivity of the newly formed carbocation intermediate. Synthetically useful carbocation-alkene reactions require a suitable termination step. We have already encountered one successful strategy in the reaction of alkenyl and allylic silanes and stannanes with electrophilic carbon (see Chapter 9). In those reactions, the silyl or stannyl substituent is eliminated and a stable alkene is formed. The increased reactivity of the silyl- and stannyl-substituted alkenes is also favorable to the synthetic utility of carbocation-alkene reactions because the reactants are more nucleophilic than the product alkenes. 

Chapter 10 considers the role of reactive intermediates—carbocations, carbenes, and radicals—in synthesis. The carbocation reactions covered include the carbonyl-ene reaction, polyolefin cyclization, and carbocation rearrangements. In the carbene section, addition (cyclopropanation) and insertion reactions are emphasized. Recent development of catalysts that provide both selectivity and enantioselectivity are discussed, and both intermolecular and intramolecular (cyclization) addition reactions of radicals are dealt with. The use of atom transfer steps and tandem sequences in synthesis is also illustrated. 

An unusual cationic domino transformation has been observed by Nicolaou and coworkers during their studies on the total synthesis of the natural product azadirachtin (1-105) [30]. Thus, exposure of the substrate 1-106 to sulfuric acid in CHjClj at 0°C led to the smooth production of diketone 1-109 in 80% yield (Scheme 1.27). The reaction is initiated by proto nation of the olefinic bond in 1-106, affording the tertiary carbocation 1-107, which undergoes a 1,5-hydride shift with concomitant disconnection of the oxygen bridge between the two domains of the molecule. Subsequent hydrolysis of the formed oxenium ion 1-108 yielded the diketone 1-109. 

A very impressive multiple cationic domino reaction was used in the enan-tioselective total synthesis of (-)-gilbertine (1-190), described by Blechert and coworkers [50]. When the tertiary alcohol 1-184 is treated with TFA, a carbocation is formed which undergoes a cascade of cyclizations to afford 1-190 in very good yield (61 %) (Scheme 1.44). The cations 1-185 to 1-189 can be assumed as intermediates. 

One very fascinating domino reaction is the fivefold anionic/pericydic sequence developed by Heathcockand coworkers for the total synthesis of alkaloids of the Daphniphyllum family [351], of which one example was presented in the Introduction. Another example is the synthesis of secodaphniphylline (2-692) [352]. As depicted in Scheme 2.154, a twofold condensation of methylamine with the dialdehyde 2-686 led to the formation of the dihydropyridinium ion 2-687 which underwent an intramolecular hetero- Diels-Alder reaction to give the unsaturated iminium ion 2-688. This cydized, providing carbocation 2-689. Subsequent 1,5-hydride shift afforded the iminium ion 2-690 which, upon aqueous work-up, is hydrolyzed to give the final product 2-691 in a remarkable yield of about 75 %. In a similar way, dihydrosqualene dialdehyde was transformed into the corresponding polycyclic compound [353]. 

Cationic polymerization was considered for many years to be the less appropriate polymerization method for the synthesis of polymers with controlled molecular weights and narrow molecular weight distributions. This behavior was attributed to the inherent instability of the carbocations, which are susceptible to chain transfer, isomerization, and termination reactions [48— 52], The most frequent procedure is the elimination of the cation s /1-proton, which is acidic due to the vicinal positive charge. However, during the last twenty years novel initiation systems have been developed to promote the living cationic polymerization of a wide variety of monomers. 

The use of deuterated organosilicon hydrides in conjunction with proton acids permits the synthesis of site-specific deuterium-labeled compounds.59 126 221 Under such conditions, the deuterium atom in the final product is located at the charge center of the ultimate carbocation intermediate (Eq. 62). With the proper choice of a deuterated acid and organosilicon hydride, it may be possible to use ionic hydrogenation in a versatile manner to give products with a single deuterium at either carbon of the original double bond, or with deuterium atoms at both carbon centers.127... 

The methoxy substituents on each azulenyl ring stabilized the carbocation effectively (12). The reaction of 6-methoxyazuiene (13) with 6-methoxyazulene-1-carbaldehyde (12) in acetic acid did not afford the condensation product 14, because of low reactivity of these compounds and lack of stability of product 14 under the reaction conditions. However, a high-pressure reaction (10 kbar) afforded the desired hydro derivative 14 in 6% yield. Synthesis of the cation 15+ was accomplished by hydride abstraction from the hydro derivative 14 (Figure 9). 

Synthesis of novel polyelectrochromic materials with the new structural motif utilizing stabilized carbocations has been demonstrated by several examples. The Wurster type violene-cyanine hybrid systems (22z+ and 232+) exhibit the presumed two color changes. The new cyanine-cyanine hybrid system (24 ) with a cyanine unit at the one terminus exhibits three color changes. 

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