Oxygen nucleophiles intermolecular additions

The vinyl metal intermediate arising from intermolecular nucleophilic addition of an oxygen nucleophile to a metal-alkyne complex has been harnessed for further transformations prior to protonation. An example is the ruthenium-catalyzed benzannulation of 1,5-enedyines that occurs through a tandem sequence involving hydroalk-oxylation, carbometallation, and protonation (Equation (82)).293... 

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. 

At the beginning of our investigations enantioselective intermolecular oxa-Michael additions with removable chirality information in the oxygen-nucleophile had not been reported. Therefore we developed a highly diastereo- and enantiose-... 

A concerted addition of this kind, involving simultaneous intramolecular electrophilic assistance by the magnesium bound to oxygen, and intermolecular nucleophilic attack by... 

Oxygen-based nucleophiles 1.03.3.2.2(1) Intermolecular addition reactions... 

Few further examples exist concerning the intermolecular addition of oxygen nucleophiles to a,P-unsaturated sulfoxides [72,118,119] however, several reports have been made concerning the stereoselective intramolecular conjugate addition of oxygen nucleophiles to a,P-unsaturated sulfoxides [55,56,120-122]. Solladie and Moine [55] reported the highly stereoselective formation of the chromene (150) in 96% yield from the hydroquinone (149) on treatment with sodium methoxide in refluxing methanol (Scheme 5.50). 

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. 

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... 

True catalysis of esterolysis, (as opposed to rapid acyl transfer and formation of a stable intermediate) requires a second rapid step in which the acyl group is transferred to water or to an oxygen nucleophile. This has presented micellar histidines and imidazoles with a second role, in experiments first carried out separately by Tagaki, Moss, and Tonellato. In the simplest experimenta mixture of (49) with myristoylhistidine (72) reacts with p-nitrophenyl acetate first by nucleophilic attack of imidazole and then transfer of the acyl group to (49) in a rapid step. In the bifunctional surfactant (73) this process was shown to be intermolecular (but presumably intramicellar). The acylimidazole can be observed spectroscopically when the substrate is p-nitrophenyl hexanoate. Similar conclusions are recorded in a study by Tonellato, who additionally... 

The monolithium salt of 4-hydroxy-4-(phenylethynyl)-2.5-cyclohexadienone (12), prepared in situ by the addition of lithium acetylide to /7-benzoquinone, was treated with methylmagnesium chloride in l HF-TMEDA or in THF —DMPU. The syn-, 4-addition adduct 13, derived from intramolecular delivery of the carbon nucleophile by the hydroxy oxygen, as well as the <7s-1,4-diol 14, obtained via intermolecular 1,2-addition, were obtained in varying amounts depending on the conditions. The selectivity on 1,4- to 1,2-addition increased by the addition of cation chelating agents such as DMPU, TMEDA, and 15-crown-5. Although the 1,4 to 1,2... 

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... 

Additional evidence for the occurrence of gas-phase intermolecular and intramolecular nucleophilic substitution was obtained in an investigation on the reactivity of mono- and dichlorophenols within the high-pressure mass spectrometer source under conditions of argon-enhanced negative ion mass spectrometry282. It was shown that the reactant anions involved in these processes are derived exclusively from the chlorophenols and not from possible impurities such as residual oxygen, water, etc. Thus, for example, the formation of an abundant [2M - H - Cl]" adduct was attributed to an intermolecular nucleophilic Cl displacement by an [M - H]" chlorophenoxide ion282. 

A mechanism for the piperazine-catalyzed formation of 4//-chromenes is complex cascade of reactions, starting with piperazine acting as a base which activates malononitrile, promoting Knoevenagel condensation, and also formation of an enamine, followed by Michael condensation, proton transfer, intermolecular cycliza-tion via a nucleophilic addition of the enolate oxygen to the nitrile group (hetero-Thorpe-Ziegler), and finally hydrolysis and tautomerization. 

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