Displacement of halide

There are three methods which are commonly used in the steroid field to replace a halogen atom by deuterium. These methods involve treatment of the halides— generally chloride, bromide or iodide—(a) with lithium aluminum deuteride, (b) with deuterium gas and a surface catalyst or (c) with zinc in O-deuterated acids or alcohols. 

Only one of these methods, namely the reaction of halides with lithium aluminum deuteride, is a true displacement reaction, following the same course as the previously discussed displacement of sulfonate esters (section Vl-A). Thus, lithium aluminum deuteride treatment of 7a- and 7jS-bromo-3 -benzoyloxy-5a-cholestanes (195) and (196) gives the corresponding deuterium labeled cholestanols (197) and (198) respectively.  

Similarly, replacement of the bromine in 19-bromo-3 -acetoxyandrost-5-ene (199) proceeds smoothly to yield 19-djL-androst-5-en-3jS-ol (200) while attempts to displace the corresponding tosylate or mesylate give unsatisfactory results.  

Displacement of an allylic halide is complicated by side reactions involving migration of the double bond. A good example is the reaction of 7a-bromo-3 -acetoxy-A -steroids (201) which gives, besides the expected 

Lithium aluminum deuteride treatment of 3j -benzoyloxy-A -6j -chloro steroids (204) provides another example of double bond migration. This 

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Nucleophilic substitution by ammonia on a-halo acids (Section 19.16) The a-halo acids obtained by halogenation of carboxylic acids under conditions of the Hell-Volhard-Zelinsky reaction are reactive substrates in nucleophilic substitution processes. A standard method for the preparation of a-amino acids is displacement of halide from a-halo acids by nucleophilic substitution using excess aqueous ammonia. 

Grignard reagents are rapidly hydrolysed by water or acid to give the parem hydrcxatbon, RH, but this reacdon is rarely of synthedc importance. Hydrocarbons can also be syndiesized by nucleophilic displacement of halide ion from a reacdve alkyl halide, e.g. 

Another entry into the anti ulcer sweepstakes is etinfidine (50). It is synthesized by displacement of halide from 4-chloromethyl-5-methylimidazole (4 ) with substituted thiol The latter is itself made from thiourea analogue by an addition-elimination reaction with cysteamine 52. °... 

Insertion of a triazole ring in place of an imidazole ring is consistent in some cases with retention of antifungal activity. The synthesis of one such agent, azoconazole (64), proceeds simply by displacement of halide with 1,2,4-triazole. The route to terconazole (65) is rather like that to ketoconazole (34). ... 

Pyridones can also be converted to 2-chloropyridines by exchanging the carbonyl functionality using phosphoroxychloride (POCI3) [72]. A combination of N-halosuccinimides and triphenylphosphine has also been applied to introduce halogens in this position [73]. The carbonyl functionality in 2-pyridones makes these systems reactive towards nucleophiles as well, which add in 1,4-reactions with displacement of halides [74]. The use of transition metal mediated couplings like Heck, and Suzuki have also been successfully applied on halogenated 2-pyridones (d. Scheme 10) [36,75]. 

The usual sulfone synthesis by displacement of halide by sulfmate is assumed to have a nucleophilic 8 2 mechanism However, in special cases of alkyl halides with additional, electron-withdrawing substituents a radical substitution pathway has been observed (equation 32). Correspondingly, substitutions under formation of sulfones take... 

Direct nucleophilic displacement of halide and sulfonate groups from aromatic rings is difficult, although the reaction can be useful in specific cases. These reactions can occur by either addition-elimination (Section 11.2.2) or elimination-addition (Section 11.2.3). Recently, there has been rapid development of metal ion catalysis, and old methods involving copper salts have been greatly improved. Palladium catalysts for nucleophilic substitutions have been developed and have led to better procedures. These reactions are discussed in Section 11.3. 

Use of mild conditions was crucial and the development of diimide reduction of singlet oxygenates, silver-salt-assisted displacement of halide by peroxide nucleophiles, peroxymercuration and demercuration, peroxide transfer from organotin to alkyl triflates, and oxygen trapping of azoalkane-derived diradicals have all played a part in providing the rich harvest of new bicyclic peroxides described herein. 

There are examples of nucleophilic displacement of halide from halo-1,2,5-thiadiazoles by ammonia, primary alkylamines, secondary alkylamines, arylamines, sulfonamides, and phthalimide <1984CHEC(6)513, 1996CHEC-II(4)355>, but the reactions often require high temperatures and excess of the nucleophile. 

Lithium salts of resonance-stabilized organic anions have also found a role in carbon-phosphorus bond formation by displacement at phosphorus. The generation of the lithium salt derived from acetonitrile (or other aliphatic nitriles by reaction with butyl lithium or lithium diisopropylamide) provides for carbon-phosphorus bond formation by displacement of halide from phosphorus (Equation 4.24).68... 

Bimolecular reactions of aniline with /V-acyloxy-/V-alkoxyamides are model Sn2 processes in which reactivity is dictated by a transition state that resembles normal Sn2 processes at carbon. Electronic influences of substituents support a non-synchronous process which has strong charge separation at the transition state and which is subject to steric effects around the reactive centre, at the nucleophile but not on the leaving group. The sp3 character of nitrogen and disconnection between the amino group and the amide carbonyl renders these reactions analogous to the displacement of halides in a-haloketones. 

Indolizine is an electron-rich system and its reactions involve mainly electrophilic substitutions, which occur about as readily as for indole and go preferentially at the C-3 position, but may also take place at the C-l. Consistent with their similarity with pyrroles rather than pyridines, indolizines are not attacked by nucleophiles nor are there examples of nucleophilic displacement of halide-substituted systems. 

Nucleophilic displacement of halide ion from a saturated carbon atom by alkali-metal diphenylphosphide reagents occurs with inversion of configuration at carbon, as is found in normal Sn2 displacements.19 Thus menthyl chloride or bromide gives ... 

Substitution with displacement of halide occurs readily at C-1 and much less readily at C-3 for the same reasons, i.e. the loss of benzene resonance if C-3 is attacked. 1-Isoquinolone exists completely in the... 

These syntheses provide further examples of the efficient nucleophilic displacement of halide from ot-halo boronic esters, even by very hindered strong bases, as well as the functional group compatibility of the synthesis. 

Anhydrides of sugars1723 have also been obtained by intramolecular displacement of halide ions. Thus, for example, treatment of 3,4-di-0-acetyl-2-bromo-2-deoxy-D-xylopyranose (133) with (p-ni-trophenyl)hydrazine affords173 3,4-di-0-acetyl-2,5-anhydro-D-lyxose (p-nitrophenyl)hydrazone (135) and 3,4-di-0-acetyl-2,5-anhydro-D-xylose (p-nitrophenyl)hydrazone (136). The formation of two (p-nitrophenyl)hydrazones can be explained by an initial displacement of the bromine atom at C-2 by 0-5, to give 3,4-di-0-acetyl-2,5-... 

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