Intramolecular addition carbon nucleophiles

The mechanism of the indolization of aniline 5 with methylthio-2-propanone 6 is illustrated below. Aniline 5 reacts with f-BuOCl to provide A-chloroaniline 9. This chloroaniline 9 reacts with sulfide 6 to yield azasulfonium salt 10. Deprotonation of the carbon atom adjacent to the sulfur provides the ylide 11. Intramolecular attack of the nucleophilic portion of the ylide 11 in a Sommelet-Hauser type rearrangement produces 12. Proton transfer and re-aromatization leads to 13 after which intramolecular addition of the amine to the carbonyl function generates the carbinolamine 14. Dehydration of 14 by prototropic rearrangement eventually furnishes the indole 8. 

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... 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Suitably semi-protected pyranoses can react with soft carbon nucleophiles generating mixtures of alditols that can undergo elimination of water and intramolecular addition of the 8-hydroxy group to the intermediate alkenes.94,95... 

Terminal alkynes readily react with coordinatively unsaturated transition metal complexes to yield vinylidene complexes. If the vinylidene complex is sufficiently electrophilic, nucleophiles such as amides, alcohols or water can add to the a-carbon atom to yield heteroatom-substituted carbene complexes (Figure 2.10) [129 -135]. If the nucleophile is bound to the alkyne, intramolecular addition to the intermediate vinylidene will lead to the formation of heterocyclic carbene complexes [136-141]. Vinylidene complexes can further undergo [2 -i- 2] cycloadditions with imines, forming azetidin-2-ylidene complexes [142,143]. Cycloaddition to azines leads to the formation of pyrazolidin-3-ylidene complexes [143] (Table 2.7). 

Concerning the M=Co, bond, most of the reported examples result from inter- or intramolecular additions of anionic nucleophiles containing at least two reactive heteroatoms. Thus, sodium dimethyldithiocarbamate was found to react with the cationic allenylidene [RuTp(=C=C=CPh2)(PPh3)2] [PFg] (76) to generate the alle-nyl-metallacycle 77 (Scheme 26) as the result of the nucleophilic addition of one of the sulfur atoms at the Cq, carbon and subsequent coordination of the second sulfur to the ruthenium center, with concomitant release of a triphenylphosphine ligand [282]. Complex 77 could also be synthesized by treatment of the neutral derivative... 

The intramolecular addition of carbon nucleophiles to alkenes has received comparatively little attention relative to heterocyclization reactions. The first examples of Pd-catalyzed oxidative carbocyclization reactions were described by Backvall and coworkers [164-166]. Conjugaled dienes with appended al-lyl silane and stabilized carbanion nucleophiles undergo 1,4-carbochlorination (Eq. 36) and carboacetoxylation (Eq. 37), respectively. The former reaction employs BQ as the stoichiometric oxidant, whereas the latter uses O2. The authors do not describe efforts to use molecular oxygen in the reaction with allyl silanes however, BQ was cited as being imsuccessful in the reaction with stabihzed car-banions. Benzoquinone is known to activate Ti-allyl-Pd intermediates toward nucleophilic attack (see below. Sect. 4.4). In the absence of BQ, -hydride eUm-ination occurs to form diene 43 in competition with attack of acetate on the intermediate jr-allyl-Pd" species to form the 1,4-addition product 44. 

Functionalized cyclopropyl derivatives can be prepared via Michael addition of carbon nucleophiles carrying a leaving group at the a-carbon followed by intramolecular substitution as depicted in equation 125. Anion-stabilizing a-substituents in the nucleophiles... 

In contrast to the well documented conjugate addition of carbon nucleophiles to activated alkenes, similar intermolecular attempts with activated alkynes with non-cuprate reactants are typically non-productive due to competing multiple addition processes.87 6 However, protic intramolecular conjugate additions of ketones as shown for the syntheses of griseofulvin and hirsutic acid,222 are successful. Recently, several aprotic intramolecular conjugate additions to activated alkynes have been reported, as... 

Next, we considered the activation of 13 towards hydrolysis by K-complexation of a cationic metal unit to the electron-rich diene system. On the basis of the well-known palladium-mediated addition of nucleophiles to alkenamines, it was anticipated that the enol ether function in 13 would add H2O in the presence of Pd(II).21 Interestingly, exposure of 13 to a slight excess of Pd(OAc)2 led to the isolation of 14 (Scheme 8). This material suggested the exploitation of the existing Pd-C linkage for carbon-carbon bond formation with an appropriate A-side chain. In particular, the intramolecular syn insertion of the allylic double bond in the rrans-butenyl substituent in 15b and subsequent syn (3-hydride elimination would give the desired E-alkene 17. This proposal was examined using alkene 15a as a model system, synthesized in a manner similar to 13. Upon exposure to Pd(OAc)2 under the conditions... 

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