Azidation reactions alkyl halides

Preparation of alkyl azides The azide ion (N3 ), a good nucleophile, can displace leaving groups from 1° and 2° alkyl halides. Alkyl azides are easily prepared from sodium or potassium azides and alkyl halides. The reaction mechanism resemhles the formation of nitrile. 

The acceleration of substitution reactions with azides using ultrasound techniques (Scheme 31) has not yet been investigated in detail. Activated primary halides react with trimethylsilyl azide (TMS-A) under particularly mild and absolutely neutral conditions (Scheme 31). Secondary and tertiary cyclic halides were treated with TMS-A/SnCU in CH2CI2 or CHCI3 to yield the corresponding azido compounds." Very impressive results with yields of about 90% were in this case reported in the adamantane and diamantane series." High solubility in organic solvents is also noticed with acetyl azide, which, prepared in situ, has also been used for azide syntheses. The scope of this reaction has still to be determined, however." Hassner noticed nearly quantitative yields of azides when alkyl halides (or tosyl-ates) were treated with polymeric quaternary ammonium azides. 

Reaction of sodium azide with alcohols using DEAD/PPhs, PPhs, BF3-Et20, or Zeolites can be used to form azides. Similarly, alkyl halides in ionic liquids or under other conditions, " " chlorocyclodextrin, and certain amines can be reacted with sodium azide to form organic azides as outlined in eqs 35-40. 

Nucleophilic substitution by azide ion on an alkyl halide (Sections 8 1 8 13) Azide ion IS a very good nucleophile and reacts with primary and secondary alkyl halides to give alkyl azides Phase transfer cata lysts accelerate the rate of reaction... 

A better method for preparing primary amines is to use the azide synthesis, in which azjde ion, N3, is used for SN2 reaction with a primary or secondary alkyl halide to give an alkyl azide, RN3. Because alkyl azides are not nucleophilic, overalkylation can t occur. Subsequent reduction of the alkyl azide, either by catalytic hydrogenation over a palladium catalyst or by reaction with LiAlK4. then leads to the desired primary amine. Although the method works well, low-molecular-weight alkyl azides are explosive and must be handled carefully. 

Azide synthesis (Section 24.6) A method for preparing amines by S 2 reaction of an alkyl halide with azide ion, followed by reduction. 

A microwave-assisted three-component reaction has been used to prepare a series of 1,4-disubstituted-1,2,3-triazoles with complete control of regiose-lectivity by click chemistry , a fast and efficient approach to novel functionalized compounds using near perfect reactions [76]. In this user-friendly procedure for the copper(l) catalyzed 1,3-dipolar cycloaddition of azides and alkynes, irradiation of an alkyl halide, sodium azide, an alkyne and the Cu(l) catalyst, produced by the comproportionation of Cu(0) and Cu(ll), at 125 °C for 10-15 min, or at 75 °C for certain substrates, generated the organic azide in situ and gave the 1,4-disubstituted regioisomer 43 in 81-93% yield, with no contamination by the 1,5-regioisomer (Scheme 18). 

Mg or Ca in MeOH, " baker s yeast, Sm/l2, LiMe2NBH3, and tin complexes prepared from SnCl2 or Sn(SR)2. This reaction, combined with RX —+ RN3 (10-65), is an important way of converting alkyl halides RX to primary amines RNH2 in some cases the two procedures have been combined into one laboratory step. Sulfonyl azides (RSO2N3) have been reduced to sulfonamides (RSO2NH2) by irradiation in isopropyl alcohol and with NaH. ... 

We have recently developed a general method of preparation of the heretofore relatively unknown trialkyltriazenes ( ). These substances are readily prepared by reaction of a Grignard reagent or an alkyllithium with an alkyl azide, followed by the reaction of the Intermediate dlalkyltrlazene with base, and alkylation of the resulting trlazenyl anion with an alkyl halide. 

Alkyl azides are conveniently prepared from the reaction of alkali metal azides with an alkyl halide, tosylate, mesylate, nitrate ester or any other alkyl derivative containing a good leaving group. Reactions usually work well for primary and secondary alkyl substrates and are best conducted in polar aprotic solvents like DMF and DMSO. The synthesis and chemistry of azido compounds is the subject of a functional group series. ... 

Alkyl halides undergo Sn2 reactions with a variety of nucleophiles, e.g. metal hydroxides (NaOH or KOH), metal alkoxides (NaOR or KOR) or metal cyanides (NaCN or KCN), to produce alcohols, ethers or nitriles, respectively. They react with metal amides (NaNH2) or NH3, 1° amines and 2° amines to give 1°, 2° or 3° amines, respectively. Alkyl halides react with metal acetylides (R C=CNa), metal azides (NaN3) and metal carboxylate (R C02Na) to produce internal alkynes, azides and esters, respectively. Most of these transformations are limited to primary alkyl halides (see Section 5.5.2). Higher alkyl halides tend to react via elimination. 

An improved method of preparing alkyl azides has been reported wherein Carbitols are used as solvents for the interaction of an alkyl halide and commercial sodium azide [10]. The use of activated sodium azide [34] is not necessary. Sealed-tube reactions for alkyl azides are hazardous a violent explosion has been reported in an attempt to seal such a tube [35]. No reactions reported in this chapter involve sealed tubes. Table II describes the conditions and azides prepared using the Carbitol solvents. 

Organic azides can be prepared from hydrazines and nitrous acid (Section 24-7A) and by the reaction of sodium azide with acyl halides or with alkyl halides having good SN2 reactivity ... 

A one-pot PTC reaction procedure for the overall conversion of an alkyl halide into a primary amine via an azide is particularly illustrative.204 Thus the reduction of the azide is effected by the addition of sodium borohydride to a reaction mixture arising from the PTC displacement reaction of an alkyl halide with sodium azide (the preparation of 1-octylamine, Expt 5.193). The reaction appears to be applicable to primary and secondary alkyl halides, alkyl methane-sulphonates and benzylic halides. 

Reaction of alkyl halides with dimethvl hydrazine184 and by initial formation of azides followed by reaction with borohydride185 also gives routes for their interconversion into amines. 

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