Reaction with Electrophilic Halogen Sources

In 1943, Reich and Reichstein5 described the oxidation of secondary steroidal alcohols with TV-bromoacetamide (NBA) in aqueous tort-butyl alcohol or acetone. Subsequently, /V-bromoacetamide found ample use in the oxidation of secondary alcohols in the steroid field.6 

In 1952, Kritchevsky et al.1 reported the selective oxidation of a secondary alcohol in the presence of a primary one with /V-bromoacetamide. In 1954, Jones and Kocher highlighted8 the importance of being able to carry out selective oxidations of secondary alcohols with /V-bromoacetamide, which was employed later by other authors for this purpose.9 

In 1980, Stevens et al.10 reported that a plain solution of sodium hypochlorite, which is easily available as swimming pool chlorine , is able to efficiently oxidize secondary alcohols in a solution in acetic acid, while primary alcohols react very slowly. Two years later, this research team published11 a more detailed account on the ability of NaOCl/AcOH to perform the selective oxidation of secondary alcohols in the presence of primary ones. Stevens oxidant became one of the standard reagents for the selective oxidation of secondary alcohols.12 

Other reagents, providing a source of electrophilic halogen, able to selectively oxidize secondary alcohols include molecular chlorine,13 molecular bromine,13c 3-iodopyridine dichloride,13a trichloroisocyanuric acid (TCIA),14 the complex HOF MeCN15 and tetraethylammonium trichloride.16 

General Procedure for Selective Oxidation of Secondary Alcohols in Presence of Primary Alcohol, Using Stevens Protocol (Sodium Hypochlorite in Acetic Acid) 

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Both electrophilic and nucleophilic reactions can generate halogenopur-ines with differences in regioselectivity dependent on substituents and on the nature of the substrate (anion, neutral molecule, or cation). In the neutral molecule nucleophilic displacements occur in the order 2 > 4 > 6 in the anion the imidazole ring may be sufficiently 7r-excessive for attack to occur at C-2, and the nucleophilic substitution order becomes 4 > 6 > 2. Strong electron donors are usually necessary to promote 2-halogenation by electrophilic halogen sources. 

From metalopyridazines by reaction with an electrophilic halogen source... 

Scheme 20 Proposed mechanistic pathways of reaction of an organometallic compound with an electrophilic halogen source (a) Oxidative addition-reductive elimination pathway, (h) Electrophilic Metal-Carbon bond cleavage...

Enzymatic reactions " and electrolysis have also been applied in the stereoselective halogenation but are limited to specific substrates. Generally, these approaches are based on the use of an electrophilic halogen source or an anionic halide nucleophile. For the approaches that use electrophilic halogen sources, the formation of a halonium intermediate is the key to stereochemical control. A subsequent nucleophilic attack of the halonium intermediate typically yields a product with an anti-relationship (Scheme 42.1). 

You have just seen that cyclic halonmm ion intermediates are formed when sources of electrophilic halogen attack a double bond Likewise three membered oxygen containing rings are formed by the reaction of alkenes with sources of electrophilic oxygen... 

Two routes to the electrophilic fluorination of pyrrolo[2,3-3]pyridine A -oxide lead to the 4-fluoro derivative. The Balz-Schiemann reaction route, via a diazonium tetrafluoroborate salt, or a lithium/halogen-exchange reaction followed by quenching with an electrophilic fluorine source, generates the 4-fluoro product in moderate yields <20030L5023>. 

Oxidation of the heterocycles with common reagents such as MCPBA, sodium periodate or hydrogen peroxide cleanly affords the sulfoxides and sulfones, and it is clear that the sulfur atom is the principal centre of reaction for electrophiles. While the sulfone is a quite inert functionality, the sulfoxides may be reduced to the sulfides with phosphorus pen-tasulfide as for the tetrahydro systems (78CJC1423). Positive halogen sources likewise react at sulfur, and the intermediate sulfonium halide rearranges, usually by 1,2-shift to the a-halo product. 

Lithio-heterocycles have proved to be the most useful organometallic derivatives they react with the whole range of electrophiles in a manner exactly comparable to that of aryllithiums and can often be prepared by direct metallation (C-hydrogen deprotonation), as well as by halogen exchange between a halo-heterocycle and an alkyllithium. As well as reaction with carbon electrophiles, Uthiated species are often the most convenient source of heterocyclic derivatives of less electropositive metals, such as zinc, boron, silicon and tin, as will be seen in the following sections. 

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