Alkylating agents, alkyl halides epoxides

As alkylating agents may for example be used alkyl halides, dialkyl sulfates, alkyl sulfonates and epoxides. Aryl halides and vinylic halides do not react. 

Alkyl halides, alkyl sulfonates and other alkylating agents have also been subject to scmtiny in spheres other than pharmaceuticals, such as in environmental analysis. Various approaches have included two-step SPE, derivatisation with trifluoroacetic anhydride followed by GC/MS (for cyclophosphamide and its analogues in sewage water) SPE on surface water to isolate the antineoplastic agents carmustine, chlorambucil, cyclophosphamide and melphalan for LC-UV and LC-fluorescence measurements and derivatisation of alkyl halides and epoxides with 4-nitrothiophenol followed by HPLC-UV detection (claimed to be better than NBP derivatisation). A patent exists for a field test kit for mustard gases in military use based on NBP derivatisation. 

N-Alkylation—Secondary Mannich bases can give the corresponding tertiary derivatives by treatment with particular alkylation agents, such as epoxides (affording P-ami-noalcohols) and acrylic derivatives. Tertiary Mannich bases, mostly, are submitted to N-alkylation in order to produce stable quaternary ammonium salts to be subsequently subjected to deamination (Sec. A.2). However, different quaternary ammonium byproducts can be readily given by the reaction. " For instance, a base-catalyzed rearrangement is afforded by allyl ammonium salts 365 (Fig. 144), obtained by N-alkylation of acetylenic Mannich bases with ally] halides. " In the presence of sodium hydride, the compounds 365 yield a wide range of 3-amino-5-hexen-l-yne derivatives 366. 

Suitable cleaving agents include organic halides such as primary alkyl bromides, iodides or sulfo-nates " ° allylic," - allenic and propargylic bromides vinylic or aryl halides with nickel or palladium promoters " alkyl chloroformates epoxides and even cyanogen or cyanogen bromide. Typical examples of such couplings are depicted in equations (55)-(57). 

Compared with other synthetic intermediates, enolates show a decreased reactivity. The differences in reactivity are most striking in reactions with alkylating agents [1] and epoxides [6]. The reactivities of the various types of enolates towards alkyl halides decrease in the order C=C(0 )NR2 (amide-enolate) C=C(0 )0R (ester enolate) C=CO (ketone-enolate). Metallated nitriles, imines, and S,S-acetals are, in general, much better nucleophiles than enolates in alkylations and ft-hydroxyalkylations [1], Furthermore, the alkylation of aldehyde and ketone enolates usually does not stop after the mono-functionalization [12]. The decreased reactivity of (especially) aldehyde and ketone enolates also appears in thiolations with disulfides [2]. A solution of lithiated cyclohexanone in THF does not react at 20°C with CH3SSCH3 [1,2]. 

Aikyiation of Azide ion Foiiowed by Reduction (Section 23.7B) Azides are prepared by treatment of a primary or secondary alkyl halide or an epoxide with KNj and are reduced to primary amines by a variety of reducing agents, including lithium aluminum hydride. 

Several years ago, we reported the synthesis and synthetic utility of lithium aminoborohydrides (LABs) a new class of powerful, safe, and highly selective reducing agents (2, 3). These reagents performed many of the transformations for which lithium aluminum hydride is usually used. Thus, the following reduction reactions were carried out with LABs aldehydes and ketones to alcohols, esters to alcohols, oc,P>unsaturated ketones to allylic alcohols, a,P-unsaturated esters to allylic alcohols, alkyl halides to hydro-carbons, azides to amines, and epoxides to alcohols. These reduction reactions are summarized in Figure 3. 

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