Intermolecular reactions oxygen nucleophiles

Unfortunately, in many cases the reaction is not so straightforward it becomes complicated because of the nature of the activated component. There is another nucleophile in the vicinity that can react with the electrophile namely, the oxygen atom of the carbonyl adjacent to the substituted amino group. This nucleophile competes with the amine nucleophile for the electrophilic center, and when successful, it generates a cyclic compound — the oxazolone. The intermolecular reaction (path A) produces the desired peptide, and the intramolecular reaction (path B) generates the oxazolone. The course of events that follows is dictated by the nature of the atom adjacent to the carbonyl that is implicated in the side reaction. 

A development of the last two decades is the use of Wacker activation for intramolecular attack of nucleophiles to alkenes in the synthesis of organic molecules [9], In most examples, the nucleophilic attack is intramolecular, as the rates of intermolecular reactions are very low. The reaction has been applied in a large variety of organic syntheses and is usually referred to as Wacker (type) activation of alkene (or alkynes). If oxygen is the nucleophile, it is called oxypalladation [10], Figure 15.4 shows an example. During these reactions the palladium catalyst is often also a good isomerisation catalyst, which leads to the formation of several isomers. 

Several types of intramolecular allylic substitution reactions of carbon, nitrogen, and oxygen nucleophiles catalyzed by metalacyclic iridium phosphoramidite complexes have been reported. Intramolecular allylic substitution is much faster than the competing intermolecular process when conducted in the presence of iridium catalysts. Thus, conditions involving high dilution are not required. Intramolecular... 

Intermolecular reactions with O- and A-nucleophiles produce labile adducts of type 65 (equation 42). These adducts can be used for reversible generation of oxyiminium cations in situ. In contrast, reaction of hydroxylamines with S- or 8-lactols results in intramolecular additions of an oxygen nucleophilic group to intermediate oxyiminium cation, thus providing stable cyclic products. Reactions of this type have been extensively used for glycosidation of hydroxylamine derivatives such as 66 (equation 42), resulting in neoglycosides of type 67 . 

Palladium-catalyzed addition of oxygen nucleophiles to alkenes dates back to the Wacker process and acetoxylation of ethylene (Sects. 1 and 2). In contrast, catalytic methods for intermolecular oxidative amination of alkenes (i.e., aza-Wacker reactions) have been identified only recently. Both O2 and BQ have been used as oxidants in these reactions. 

Utilization of an oxygen nucleophile gives similar results (Scheme 8E.35). Whereas modest enantioselectivities (7-54% ee) have been recorded with various ligands [177], the use of 5 results in the efficient cyclization of phenol to furnish the nucleus of tocopherol (vitamin E) with 86% ee [178], Extension of this methodology to intermolecular reactions requires control of regiochemistry, a problem that is not present in the corresponding intramolecular... 

In this example the oxygen of the hydroxy group acts as an intramolecular nucleophile. Recall from Section 8.13 that intramolecular reactions are favored by entropy. Therefore, the formation of a cyclic hemiacetal has a larger equilibrium constant than a comparable intermolecular reaction. This reaction is especially important in the area of carbohydrates (sugars) because sugars contain both carbonyl and hydroxy functional... 

The synthesis of oxygen-heterocycles by intermolecular reactions of a-TK with nucleophiles has received only limited attention. However, a-tosyloxy derivatives of several acetophenones have been prepared by brief exposure of neat HTIB/ketone mixtures to microwave (MW) radiation, and employed on mineral oxide surfaces for microwave-assisted syntheses of thiazoles and 2-aroylbenzofurans 40 (Scheme 11) (98JCS(P1)4093, 99JHC1565). 

An intermolecular reaction, again with overall syn Sn substitution, was successfully applied in a synthesis of the carbocyclic nucleoside analog aristeromycin to introduce the nitrogen base stereoselectively (equation 21), although with heteronucleophiles, unlike the case of carbon nucleophiles, a lower propensity for attack distal to oxygen to give the 1,4-product with vinyloxiranes exists. 

The possible function of an EDTA ligand is to protect the nucleophilic oxygen in A from intermolecular reactions although the system operates also without it, even though more slowly (272, 273). 

The second set of examples involves the use of thionium ions as electrophiles in inter- and intramolecular processes to obtain a-substituted sulfides (see 24 25, Scheme 20.7T which is the most common type of Pummerer reaction. Applications of this classical Pummerer rearrangement are exemplified in the synthesis of trans-solamin, the synthesis of indolizidine alkaloids, and the synthesis of the CDE ring of erinacine E. The first exanple fScheme 20.10 uses Pummerer chemistry in the generation of a thionium ion, which reacts in an intermolecular tin-mediated ene reaction the second one fScheme 20.11 uses Pummerer chemistry to introduce a nitrogen-containing heterocycle by intramolecular addition to form the coniceine core and the third example fScheme 20.12 is an intramolecular silicon-induced Pummerer reaction with oxygenated nucleophiles applied to the synthesis of a precursor of erinacine. Details of these Pummerer-based strategies are discussed below. 

Catalytic and stoichiometric additions of oxygen nucleophiles to coordinated dienes are summarized in Equations 11.33 and 11.34. Early studies involved 1,4-additions of two acetoxy or alkoxy groups across a diene. More recently, intermolecular additions of two different nucleophiles have been developed. The stereochemistry for additions across cyclic dienes makes this procedure particularly valuable. Conditions for either cis or trans additions have been developed. Cis addition is typically observed in the presence of added chloride, and trans addition occurs in the absence of chloride. Both intermolecular and intramolecular " 1,4 additions to dienes have been developed, and reactions of nitrogen and carbon nucleophiles have also been reported. More details on these processes are reported in Chapter 16. 

The oxidations of olefins with many oxygen nucleophiles other than water have also been reported. These reactions include the s5mthesis of vinylic and allylic ethers from reactions of olefins with alcohols and phenols, and vinylic and allylic esters from reactions of olefins with carboxylic acids. These reactions have been conducted with both monoenes and 1,3-dienes. Both intermolecular and intramolecular versions of each of these processes have been developed. Some discussion of these reactions was included in Chapter 11 because of their connection to the nucleophilic attack of oxygen nucleophiles on coordinated olefins and dienes. 

C.ii.a. Intramolecular Attack by Oxygen Nucleophiles. The first intramolecular reaction was done with a 1,3-cyclohexadiene having a carboxylate attached to the 5-position.f Just as with the intermolecular additions, it turned out that the amount of LiCl plays a crucial role, in terms of both the stereo- and chemoselectivities (Scheme 9). Without any... 

V. 3.1 The Wacker Oxidation and Related Intermolecular Reactions Involving Oxygen and Other Group 16 Atom Nucleophiles... 

Carbanions are some of the most common nucleophiles through which a new C—C bond can be formed. C—C instead of C—O or C—N bond formation can be achieved with oxygen and nitrogen bidentate nucleophiles in intermolecular reactions. However, in the intramolecular processes, C—O and C—N bonds could be formed. Nucleophiles derived from other heteroatoms react to form a new C-hetCToatom bond. 

This realization led me to study related possible intermolecular electrophilic reactions of saturated hydrocarbons, Not only protolytic reactions but also a broad scope of reactions with varied electrophiles (alkylation, formylation, nitration, halogenation, oxygenation, etc.) were found to be feasible when using snperacidic, low-nucleophilicity reaction conditions. 

Application of an organocatalytic domino Michael addition/intramolecular aldol condensation to the preparation of a series of important heterocycles has recently received much attention [158] with methods being disclosed for the preparation of benzopyrans [159-161], thiochromenes [162-164] and dihydroquinolidines [165, 166]. The reports all use similar conditions and the independent discovery of each of these reactions shows the robust nature of the central concept. A generalised catalytic cycle which defines the principles of these reports is outlined in Fig. 10. Formation of iminium ion 102 is followed by an intermolecular Michael addition of an oxygen, sulfur or nitrogen based nucleophile (103) to give an intermediate... 

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