Bond formation synthesis Substitution reactions

Pyrimidines can be formed in reactions involving multiple bond formations, and the reactions of this subgroup have a long history <1994HC(52)1>. A recent example is the synthesis of a 6-substituted uracil derivative 740 (Scheme 9), where an a,/3-unsaturated ester 737, A,0-bis(trimethylsilyl)hydroxylamine, phenyl chloroformate, and ammonia supplied the four components of C(4)-C(5)-C(6), N-1, C-2, and N-3, respectively <2000TL4307> ... 

Y. Yamamoto, Formation of C— C Bonds by Reactions Involving Olefinic Double Bonds, Vi-nylogous Substitution Reactions, in Methoden Org. Chem. (Houben-Weyl) 4th ed. 1952-, Stereoselective Synthesis (G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann, Eds.), Vol. E21b, 2011, Georg Thieme Verlag, Stuttgart, 1995. 

The acid-promoted Prins reaction between a homoaUyhc alcohol and an aldehyde is a weU-estabhshed synthesis of tetrahydropyrans (Scheme 4) [ 14,15]. While substituted tetrahydropyrans are often assembled by cyclizations forming a C - O bond, the Prins reaction undergoes cyclization by C - C bond formation. The Prins reaction of the silyl-modified substrates [16], which can be regarded as the intramolecular Hosomi-Sakurai reaction, is effectively activated by the allylsilane unit. The stereochemistry of the 2,6-cfs-form produced in the case of the exo-allylsilane unit is elucidated by the 6-membered transition state model, hi the cyclization of the ewdo-aUylsilane substrates, since the silyl group would be fixed on the axial position of the 6-membered transition states, the tetrahydropyrans with both 2,6-cis and fraws-forms can be synthesized (Panek Sect. 3.3.9). This type of cychzation was also... 

The problem of the synthesis of highly substituted olefins from ketones according to this principle was solved by D.H.R. Barton. The ketones are first connected to azines by hydrazine and secondly treated with hydrogen sulfide to yield 1,3,4-thiadiazolidines. In this heterocycle the substituents of the prospective olefin are too far from each other to produce problems. Mild oxidation of the hydrazine nitrogens produces d -l,3,4-thiadiazolines. The decisive step of carbon-carbon bond formation is achieved in a thermal reaction a nitrogen molecule is cleaved off and the biradical formed recombines immediately since its two reactive centers are hold together by the sulfur atom. The thiirane (episulfide) can be finally desulfurized by phosphines or phosphites, and the desired olefin is formed. With very large substituents the 1,3,4-thiadiazolidines do not form with hydrazine. In such cases, however, direct thiadiazoline formation from thiones and diazo compounds is often possible, or a thermal reaction between alkylideneazinophosphoranes and thiones may be successful (D.H.R. Barton, 1972, 1974, 1975). 

In the second major method of peptide synthesis the carboxyl group is activated by converting it to an active ester, usually a p-nitrophenyl ester. Recall from Section 20.12 that esters react with ammonia and amines to give fflnides. p-Nitrophenyl esters are much more reactive than methyl and ethyl esters in these reactions because p-nitrophenoxide is a better (less basic) leaving group than methoxide and ethoxide. Simply allowing the active ester and a C-protected amino acid to stand in a suitable solvent is sufficient to bring about peptide bond formation by nucleophilic acyl substitution. 

From the foregoing it can be seen that the nitro group can be activated for C C bond formation in various ways. Classically the nitro group facilitates the Henry reaction, Michael addition, and Diels-Alder reaction. Kornblum and Russell have introduced a new substitution reaction, which proceeds via a one electron-transfer process (SrnI). The SrnI reactions have recently been recognized as useful tools in organic synthesis. All these reactions can be used for the preparation of alkenes as described in this chapter. 

While the alkoxymetallation process has typically been affected by highly electrophilic metal salts, high-valent metal species generated by an oxidative addition have also been used to activate alkynes through the formation of 7r-complexes. In such cases, the metal-carbon emerging from the attack of an oxygen nucleophile may enter a reaction manifold that leads to an additional C-G bond formation rather than a simple protic quench. This approach, pioneered by Arcadi and Cacci, has proved to be a powerful strategy for the synthesis of structurally diverse substituted... 

On the basis of these results we embarked on a systematic study on the synthesis of vinyl cations by intramolecular addition of transient silylium ions to C=C-triple bonds using alkynyl substituted disila alkanes 6 as precursors.(35-37) In a hydride transfer reaction with trityl cation the alkynes 6 are transformed into the reactive silylium ions 7. Under essentially nonHnucleophilic reaction conditions, i.e. in the presence of only weakly coordinating anions and using aromatic hydrocarbons as solvents, the preferred reaction channel for cations 7 is the intramolecular addition of the positively charged silicon atom to the C=C triple bond which results in the formation of vinyl cations 8-10 (Scheme 1). 

Furthermore, the copper-mediated SN2 substitution reaction is not restricted to carbon-carbon bond formation, as can be seen form the synthesis of silylallenes [15], stannylallenes [16] and bromoallenes [17] using propargylic electrophiles and the corresponding heterocuprates. The resulting allenes are often used as intermediates in target-oriented synthesis, e.g. in cyclization and reduction reactions [15-17]. 

The synthesis of polyhalide salts, R4NX , used in electrophilic substitution reactions, are described in Chapter 2 and H-bonded complexed salts with the free acid, R4NHX2, which are used for example in acid-catalysed cleavage reactions and in electrophilic addition reactions with alkenes, are often produced in situ [33], although the fluorides are obtained by modification of method I.I.I.B. [19, 34], The in situ formation of such salts can inhibit normal nucleophilic reactions [35, 36]. Quaternary ammonium chlorometallates have been synthesized from quaternary ammonium chlorides and transition metal chlorides, such as IrClj and PtCl4, and are highly efficient catalysts for phase-transfer reactions and for metal complex promoted reactions [37]. 

The formation of C-O, C-S, C-N and C-C bonds by nucleophilic substitution is described in subsequent chapters. In this section the synthesis of haloalkanes by halogen-halogen exchange and related reactions are presented. 

Dicarbonyl compounds are widely used in organic synthesis as activated nucleophiles. Because of the relatively high acidity of the methylenic C—H of 1,3-dicarbonyl compounds, most reactions involving 1,3-dicarbonyl compounds are considered to be nucleophilic additions or substitutions of enolates. However, some experimental evidence showed that 1,3-dicarbonyl compounds could react via C—H activations. Although this concept is still controversial, it opens a novel idea to consider the reactions of activated C H bonds. The chiral bifunctional Ru catalysts were used in enantioselective C C bonds formation by Michael addition of 1,3-dicarbonyl compounds with high yields and enantiomeric excesses. ... 

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