Reactivity, alkyl halides with

It is also possible to reductively dehalogenate more reactive alkyl halides with either zinc (Zn) dust or a copper-zinc alloy (Cu-Zn) in the presence of an alcohol and protic acid, but this method also suffers from lack of specificity and is also frequently attended by skeletal rearrangement. 

With highly reactive alkyl halides, like allylic, benzylic or phenacyl halides, the ZjA-alkylation can be a serious side-reaction. Because of a SNl-like mechanism in those cases, the effect of enolate concentration on the reaction rate is low, and the resulting monoalkylester 5 may be more acidic than the unsubstituted starting material ... 

Horton, H. R. Koshland, D. E. Jr. Reaction with reactive alkyl halides. Methods Enzymol. 1967, 11, 556-565. 

Solid-liquid phase systems with no added solvent produce esters in high yield [e.g. 2, 3] and are particularly Useful when using less reactive alkyl halides [e.g. 15], for the preparation of sterically hindered esters [16], or where other basic sites within the molecule are susceptible to alkylation, e.g. anthranilic acid is converted into the esters with minimal A-alkylation and pyridine carboxylic acids do no undergo quat-emization [17]. Excellent yields of the esters in very short reaction times (2-7 minutes) are also obtained when the two-phase system is subjected to microwave irradiation [18]. Direct reaction of the carboxylic acids with 1,2-dichloroethane under reflux yields the chloroethyl ester [19], although generally higher yields of the esters are obtained under microwave conditions [20]. 

In some cases, the nature of the electrophile and the type of base used can determine the type of product isolated. For example, after treatment of bis(pyrazol-l-yl)methane (Scheme 34) with ri-BuLi at 25°C, reactive alkyl halides such as methyl iodide or benzyl chloride favor formation of the methylene substituted (kinetic) products, whereas with carbonyl... 

Chlorine or bromine reacts with alkanes in the presence of light (hv) or high temperatures to give alkyl halides. Usually, this method gives mixtures of halogenated compounds containing mono-, di-, tri- and tetra-halides. However, this reaction is an important reaction of alkanes as it is the only way to convert inert alkanes to reactive alkyl halides. The simplest example is the reaction of methane with CI2 to yield a mixture of chlorinated methane derivatives. 

An alternative general approach to 4//-pyrans has been found recently in cathodic alkylation of 2,4,6-triphenylpyrylium perchlorate224 and might be useful, especially where the Grignard reaction (Eq. 9) fails. The salt is electrolyzed (mercury electrode) in the presence of a reactive alkyl halide two-electron reduction generates pyranyl anion 197, which is alkylated with RX to 4//-pyrans 165 (11 to 36%). 

Peptidomimetics in which one amide bond is replaced by a phosphinic acid (R-P(0H)(=0)-R phosphinic peptides ) are of interest as potential protease inhibitors [17-19]. These compounds have been prepared either from orthogonally protected phosphorus-containing monomers [17,18,20], or by forming the phosphorus-containing fragments on solid phase, as sketched in Figure 11.4 [19,21], Phosphinic acids have been prepared on solid phase mainly by reaction of carbon electrophiles with monoalkylphosphinates. As carbon electrophiles, acrylates, aldehydes, reactive alkyl halides, or a, 3-unsaturated ketones can be used. 

Hydroxylamines and hydrazines can be acylated on insoluble supports using the same type of acylating agent as is used for the acylation of amines [146-149]. Because of their higher nucleophilicity, hydroxylamines or hydrazines can be acylated more readily than amines, and unreactive acylating agents such as carboxylic esters can sometimes be successfully employed (Table 13.10). Polystyrene-bound O-alkyl hydroxamic acids can be N-alkylated by treatment with reactive alkyl halides and bases such as DBU (Entry 5, Table 13.10). 

The esterification of support-bound carboxylic acids has not been investigated as thoroughly as the esterification of support-bound alcohols. Resin-bound activated acid derivatives that are well suited to the preparation of esters include O-acylisoureas (formed from acids and carbodiimides), acyl halides [23,226-228], and mixed anhydrides (Table 13.15). A-Acylurea formation does not compete with esterifications as efficiently as it does with the formation of amides from support-bound acids. Esters can also be prepared from carboxylic acids on insoluble supports by acid-catalyzed esterification [152,229]. Alternatively, support-bound carboxylic acids can be esteri-fied by O-alkylation, either with primary or secondary aliphatic alcohols under Mitsu-nobu conditions or with reactive alkyl halides or sulfonates (Table 13.15). 

A further method for preparing hydantoins is the N-alkylation of other hydantoins with reactive alkyl halides in the presence of strong bases [154]. Hydantoinimines have been synthesized from polystyrene-bound isonitriles by an Ugi-type multicomponent condensation (Entry 15, Table 15.13). 

Organometallic compounds which contain a carbon-metal bond are the most reactive carbon nucleophiles. In most cases they are also powerful bases and must be prepared and used under strictly anhydrous and aprotic conditions. A very common way to produce organometallic compounds is to reduce alkyl halides with active metals. Grignard reagents and organolithium compounds are routinely produced in this manner. The transformation is a two-electron reduction of the alkyl halide to a carbanion equivalent the metal is oxidized. 

This reaction allows the alkylation of aryl halides. The more reactive alkyl halide forms an organosodium first, and this reacts as a nucleophile with an aryl halide as the electrophile. Excess alkyl halide and sodium may be used if the symmetric coupled alkanes formed as a side product may be separated readily. 

Alkylpalladium complexes generated by oxidative addition of Pd(0) to alkyl halides with a /3 hydrogen can undergo /3-elimination to yield an alkene and a Pd-hydrido complex (as in the Heck reaction Scheme8.7). Nevertheless, this process is relatively slow compared with transmetalations and reductive eliminations, and simple alkyl halides or tosylates with /3 hydrogen can be cross-coupled with carbon nucleophiles under optimized conditions if the nucleophile is sufficiently reactive [9, 73-75] (Scheme8.6). 

Silver nitrate test The compound to be tested is treated with a few drops of 1% alcoholic silver nitrate. A white precipitate indicates a positive reaction. This could be due to either silver chloride (reaction with a reactive alkyl halide), silver alkynide (reaction with a terminal alkyne), or the silver salt of a carboxylic acid (reaction with a carboxylic acid). 

The acaricide (kills mice and ticks) chlorbenside 43 is disconnected to give an acidic thiophenol 44 and a reactive alkyl halide 25. The synthesis merely combines these two in ethanol with NaOEt as base.6... 

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