Halogenation, base-induced

Hell-VoLhard-Zelinskii (HVZ) reaction, in which an acid is treated with Bc2 and PBr3. The a-halogenated products can then undergo base-induced E2 elimination to yield a,j6-unsaturated carbonyl compounds. 

The basic OH" ion initially attacks an H atom on the carbon atom adjacent to the halogen-bearing carbon atom in the haloalkane. It forms a bond with this H atom and an HO-H molecule is generated. At the same time, the pair of electrons in the C-H bond moves between the two carbon atoms on the left-hand side of the haloalkane to form a double bond. Finally, the C-Br breaks heterolytically, releasing a Br" ion. You are not required to know this mechanism, but it helps to explain why the elimination reaction is referred to as base-induced. 

The previous discussion of the halogenation of ketones is incomplete in one important respect concerning base-induced halogenation. That is, once an a-halo ketone is formed, the other hydrogens on the same carbon are rendered more acidic by the electron-attracting effect of the halogen and are replaced much more rapidly than the first hydrogen ... 

The alkylation reaction is limited to nitro-substituted arenes and heteroarenes and is highly chemoselec-tive nucleophilic displacement of activated halogens, including fluorine, was not observed. The regio-selectivity is determined by the bulkiness of the silicon reagent. With unhindered silyl derivatives a strong preference for ortho addition was observed, as in the example of equation (6). With bulkier reagents attack took place exclusively at the para position (Scheme 1). The success of this reaction, which could not be reproduced with alkali enolates, was attributed at least in part to the essentially nonbasic reaction conditions under which side processes due to base-induced reactions of nitroarenes can be effectively eliminated.12... 

The increased development of transition metal-catalyzed cross-coupling methods to form C-C bonds has served as an impetus to find methods to synthesize 3-halochromones and 3-haloflavones. The synthesis of 3-halochromones and flavones can be achieved with the addition of halogens across the double bond of the pyrone ring by reaction with a halogenating reagent (e.g., Br2) followed by spontaneous, or base-induced, elimination (Scheme 48). Synthesis of these important compounds has been recently reviewed <2003RCR489>. 

The addition of bromine or iodine to ( )-alkenylboronic acids or esters afforded intermediates, which were converted by base into (Z)-l-halo-l-alkenes.543 On the other hand, ( )-iodo-l-alkenes of high stereochemical purity were prepared by treatment of ( )-l-alkenylboronic acids or esters with sodium hydroxide followed by 1 molar equiv. of iodine.544 Iodine monochloride was used in place of iodine for such a base-induced iodination with retention or inversion of the stereochemistry (Equation (110)).545 Chloramine-T/Nal (Equation (111)),546,547 CuX2 (X = Cl, Br) (Equation (112)),548 and iV-halosuccinimides (Equation (113))549 halogenated the C-B bond with retention of stereochemistry. 

Fig. 40 Concept for the two-step synthesis of enantiomerically pure (S)-epoxides out of aliphatic 1-halogenated 2-ketones. The ketone was reduced by a recombinant whole-cell catalyst bearing alcohol dehydrogenase from Lactobacillus kefir (LKADH) and glucose dehydrogenase (GDH) for regeneration of NADPH. Base-induced cyclization of the enantiomerically pure (5)-(3-halohydrin intermediate gave the desired (S)-epoxides in high yield and enantiomeric purity (>99% ee)...

The nitrogen source for the aziridination of alkenes, a nitrene or nitrenoid, can be generated in various ways (1) oxidation of a primary amine (2) base-induced -elimination of HX from an amine or amide with an electronegative atom X (X = halogen, O) attached to the NH group or by -elimination of metal halides from metal A-arenesulfonyl-A-haloamides (3) metal-catalyzed reaction of [A-(alkane/arenesulfonyl)imino]aryliodanes (4) thermolytic or photolytic decomposition of organyl azides and (5) thermally induced cycloreversion reactions . 

In similar processes, base-induced cleavage of halogenated ketones has been used to prepare cyclopropane derivatives [53] (Figure 6.37). 

Carbonyl compounds are in a rapid equilibrium with their cnols, a process called keto-enol tautomerism. Although enol tautomers arc normally present to only a small extent at equilibrium and can t usually be isolated in pure form, they nevertheless contain a highly nucleophilic double bond and react with electrophiles. P or example, aldehydes and ketones are rapidly halogenated at the a position by reaction with CI2 Br2, or I2 in acetic acid solution. Alpha bromination of carboxylic acids can be similarly accomplished by the Hell-Volhard-Zelinskii (HVZ) reaction, in which an acid is treated with Bt2 and PBrThe a--halogenated inoducts can then undergo base-induced E2 elimination to yield a,/3-un.salurated carbonyl compounds. 

Reductive removal of the halogen atom with either Raney-Ni or with tributyltin hydride in the presence of AIBN (azobisisobutyronitrile) as a free-radical initiator furnishes the halide-free lactone. Halolactonization followed by base-induced anti- im-ination of H-I with DBU (l,8-diazabicyclo[5.4.0]undec-7-ene) produces the unsaturated lactone. 

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