Electrophiles Other than Alkylating Agents

If the mixture of 3-methyltriazolopyridine and LDA is left at -70°C without adding electrophile two products are formed, one the dimer 173, and the 

the product of a known ring opening reaction (97T8257). Ring opening of compounds of type 173 gives 2,2 -bipyridyls (98T15287) (see Section IV.F). 

Lithiation at methyl groups allows elaboration of side chains, as in the production of compounds 175 (91MIP18880) the 5-methyl group is similarly functionalized (93JMC3321). 

There are no reports of direct electrophilic substitution on system 3. The tria-zololpyridinone 188 is chlorosulfonated on the benzene ring (92GEP4020629) 

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A common route to alkoxy(l-alkynyl)carbene complexes 1 involves addition of a 1-lithio alkyne to a metal carbonyl to give an acyl metallate, which on alkylation affords an alkoxy(l-alkynyl)carbene complex (vide supra). Several transformations of acyl metallates with electrophiles other than alkylation agents have been reported. 

Little is known about the reaction of 3 with electrophiles other than alkylating and acylating agents, but attack of arene (or hetarene) diazonium ions (as Bp4 salts) on N-3 of 3 or its sodium salt, to generate 3-aryl (or 3-hetaryl)azo-3,4-dihydro-l,2,3-benzotriazin-4-ones 94, has been reported <1984J1C65>. 

The insight that zinc ester enolates can be prepared prior to the addition of the electrophile has largely expanded the scope of the Reformatsky reaction.1-3 Substrates such as azomethines that quaternize in the presence of a-halo-esters do react without incident under these two-step conditions.23 The same holds true for acyl halides which readily decompose on exposure to zinc dust, but react properly with preformed zinc ester enolates in the presence of catalytic amounts of Pd(0) complexes.24 Alkylations of Reformatsky reagents are usually difficult to achieve and proceed only with the most reactive agents such as methyl iodide or benzyl halides.25 However, zinc ester enolates can be cross-coupled with aryl- and alkenyl halides or -triflates, respectively, in the presence of transition metal catalysts in a Negishi-type reaction.26 Table 14.2 compiles a few selected examples of Reformatsky reactions with electrophiles other than aldehydes or ketones.27... 

These antitumor agents are compounds that form carbonium ions or other reactive electrophilic groups. Such compounds bind covalently to DNA, and either crosslink the two strands of the helix or otherwise interfere with replication or transcription. Since these processes are more prevalent in rapidly dividing malignant cells than in normal tissues, alkylating agents can control and in some cases even eliminate tumors. However, their selectivity is limited and they have many and serious side effects. 

CN is considered less than lethal or nonlethal because it has a large safety ratio. That is, its effective dose or concentration ECtfo is low compared to its lethal dose or concentration (LCtfo). In the body, CN is converted to an electrophilic metabolite. It is an SN2 alkylating agent that reacts with SH groups and other nucleophilic sites of biomolecules. Alkylation of SH-containing enzymes leads to enzyme inhibition with disruption of cellular processes. CN was found to inhibit human plasma cholinesterase via a non-SH interaction, and some of the toxic effects may be due to alkylation of SH-containing enzymes. 

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