Heteroatomic coupling electrophilic reactions

GSH may also be coupled to electrophilic reaction intermediates nonenzymatically or by GSH transferase (GST)-catalyzed reactions. Many different types of substrates will undergo GSH conjugation, including epoxides, halogenated compounds, aromatic nitro compounds, and many others. In these reactions, GSH can interact with an electrophilic carbon or heteroatom (O, N, and S) [35]. One such substrate is a reactive metabolite of acetaminophen (APAP), N-acetyl-p-benzoquinonimine (NAPQI), which will readily form a GSH conjugate (Scheme 3.2). Other examples of Phase II bioactivation reactions that lead to toxic endpoints are shown in Table 3.1. 

A very large number of these systems with ring junction heteroatoms exists, and this number is constantly increasing. Only illustrative examples of the preparation of such systems can be given here. The synthetic methods for the formation of this type of heterocycle can be usefully classified as follows (i) various cyclocondensations between the corresponding heterocyclic derivatives and bifunctional units, (ii) intramolecular cyclizations of electrophilic, nucleophilic or (still rare) radical type, (iii) cycloadditions, (iv) intramolecular oxidative coupling, (v) intramolecular insertions, (vi) cyclization of open-chained predecessors, (vii) various reactions (quite often unusual) which are specific for each type of system. Examples given below illustrate all these cases. 

The same transition metal systems which activate alkenes, alkadienes and alkynes to undergo nucleophilic attack by heteroatom nucleophiles also promote the reaction of carbon nucleophiles with these unsaturated compounds, and most of the chemistry in Scheme 1 in Section 3.1.2 of this volume is also applicable in these systems. However two additional problems which seriously limit the synthetic utility of these reactions are encountered with carbon nucleophiles. Most carbanions arc strong reducing agents, while many electrophilic metals such as palladium(II) are readily reduced. Thus, oxidative coupling of the carbanion, with concomitant reduction of the metal, is often encountered when carbon nucleophiles arc studied. In addition, catalytic cycles invariably require reoxidation of the metal used to activate the alkene [usually palladium(II)]. Since carbanions are more readily oxidized than are the metals used, catalysis of alkene, diene and alkyne alkylation has rarely been achieved. Thus, virtually all of the reactions discussed below require stoichiometric quantities of the transition metal, and are practical only when the ease of the transformation or the value of the product overcomes the inherent cost of using large amounts of often expensive transition metals. 

The presence of a heterosubstituent facilitates deprotonation. 4-Methyl-4H-pyran and 1,4-dimethyldihydropyr-idine are regioselectively metallated at the position next to the heteroatom by LIC-KOR or trimethylsilylmethylpotassium.47 The metallation of cyclic vinyl ethers with Schlosser s base has been successfully used in the synthesis of C-glycosides48 50 via metallation of the glucal followed by a reaction with tributyltin chloride to afford the corresponding tin derivative that could be submitted to coupling reactions with various electrophiles.48... 

A cross-coupling reaction can be partially defined by equation (1), where Nu is a carbon (or heteroatom) nucleophile see Nucleophile), R X is an electrophilic substrate, X is a halogen or other appropriate leaving group, and M is a metal or metalloid. At first glance, it would appear that simple nucleophihc substitution reactions should fall under this definition. However, what makes the cross-coupling chemistry special is its ability to perform transformations that cannot be accomplished with simple substitution chemistry. 

The coupling of an allyl or acyl moiety onto carbon atoms is achieved by anodic oxidation of a-heteroatom substituted organostannanes or Oj -acetals in the presence of allylsilanes or silyl enol ethers. The reaction probably involves carbocations as intermediates that undergo electrophilic addition to the double bond [245c]. 

The use of aryl tosylates as electrophiles is attractive, since they can be synthesized from readily available phenols with less expensive reagents than those required for the preparation of the corresponding triflates. More importantly, tosylates are more stable towards hydrolysis than are triflates. However, this greater stability renders tosylates less reactive in transition metal-catalyzed coupling reactions. As a result, protocols for traditional cross-coupling reactions of these electrophiles were only recently developed [1], In contrast, catalytic direct arylations with aryl tosylates were not reported previously. However, a ruthenium complex derived from heteroatom substituted secondary phosphine oxide (HASPO) preligand 72 [81] allowed for direct arylations with both electron-deficient, as well... 

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