Alkyl Azides from Amines

Photolysis of the aryl-alkyl azide CH CPhaNa showed that the migratory aptitudes of the methyl and phenyl groups were almost identical and this and the formation of triphenylmethyl amine from irradiation of triphenylmethyl azide in the presence of efficient hydrogen donors were taken to confirm the existence of discrete nitrene intermediates. Although the occurrence of a triplet-sensitized decomposition from alkyl azides and triphenylmethyl azides (the... 

N-Boc amines. Iminophosphoranes derived from alkyl azides are converted to the protected amines by t-BuOCOO-N=C(Ph)CN. 

Unfortunately, these reactions don t stop cleanly after a single alkylation has occurred. Because ammonia and primary amines have similar reactivity, the initially formed monoalkylated substance often undergoes further reaction to yield a mixture of mono-, di-, and trialkylated products. A better method for preparing primary amines from alkyl halides is to use azide ion, N3, as the nucleophile rather than ammonia. The product is an alkyl azide, which is not nucleophilic, so overalkylation can t occur. Subsequent reduction of the alkyl azide with LiAlH4 then leads to the desired primary amine. 

The synthesis and mechanism of formation of a triazene from an arenediazonium ion and an amine with one or two aliphatic substituents (see Scheme 13-1, R = alkyl, R = H or alkyl) will be discussed in Section 13.2. Here we will briefly mention Dimroth s method (1903, 1905 a) for synthesis of wholly aliphatic triazenes (Scheme 13-6, R and R = alkyl). Dimroth obtained these by the action of Grignard reagents on alkyl azides followed by isolation via copper(i) salts. The Grignard method can also be applied for the synthesis of triazenes with an aromatic substituent by using an aryl azide. 

Frankel and co-workers prepared a series of alkyl diazides from the reaction of dihaloalka-nes with sodium azide in DMF at 95 °C, including 1,3-diazidopropane, 1,4-diazidobutane and l,3-diazido-2,2-dimethylpropane. Tris(azidomethyl)amine, an energetic fuel with potential for use in bipropellant propulsion systems, is synthesized from the reaction of tris(chloroethyl)amine with sodium azide." ... 

Primary amines can be prepared from alkyl halides by 0-44, by 0-63, by 0-61 followed by reduction of the azide (9-53), or by the Gabriel synthesis (0-58). 

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. 

Fig. Synthesis of a primary amine from an alkyl halide via an alkyl azide.

The synthesis of secondary amines from azides is efficient in terms of chemos-electivity [57] and has found valuable applications in the preparation of diamines [58,59], m-alkylaminoboronic esters [60], and in Diels-Alder-based amination reactions [61]. A convenient general route to open-chain polyamines, which play major roles in cellular differentiation and proliferation, has also been developed using the reductive alkylation of aliphatic aminoazides by (co-halogenoalk-yi)dichloroboranes as a key step [62] (Scheme 21). 

The reaction of trialkylboranes with A-chloro- or A-(benzoyloxy)alkylamines afforded secondary amines via an anisotropic 1,2-shift of the alkyl group from boron atom to nitrogen in the B-N complex intermediate.519-521 Alkylation of A-chlorodimethylamine with primary trialkylboranes to give A,A-dimethylalkylamines was conducted in the presence of galvinoxyl to avoid the formation of alkyl chlorides via free radical process.522,523 A convenient approach to mixed secondary amines is alkylation of alkyl azides with relatively unhindered trialkylboranes in refluxing xylene followed by hydrolysis with water. The reaction smoothly took place at low temperature when trialkylboranes were replaced by alkyl(dichloro)boranes (Equation (108)).524 Intramolecular amination furnished cyclic amines (Equation (109)).400,525-528... 

Formation and Reduction of Azides Azide ion ( N3) is an excellent nucleophile that displaces leaving groups from unhindered primary and secondary alkyl halides and tosylates. The products are alkyl azides (RN3), which have no tendency to react further. Azides are easily reduced to primary amines, either by LiAlH4 or by catalytic hydrogenation. Alkyl azides can be explosive, so they are reduced without purification. 

An alternative to the azide > nthesis is the Gabriel amine synithesis. which uses a pAfAafi mide alkylation fi>r preparing a primary amine from an alkyl hali do. Iniides < CONHCO I are aimiLar to ethyl acetoaoctate in that... 

The limitations of this approach can be seen in the reaction of a saturated solution of ammonia in 90% ethanol with ethyl bromide in a 16 1 molar ratio, under which conditions the yield of primary amine was 34.2% (at a 1 1 ratio the yield was 11.3%). Alkyl amines can be one type of substrate that does give reasonable yields of primary amine (provided a large excess of NH3 is used) are a-halo acids, which are converted to amino acids. A-Chloromethyl lactams also react with amines to give good yields to the A-aminomethyl lactam. Primary amines can be prepared from alkyl halides by 10-43, followed by reduction of the azide (19-32), or by the Gabriel synthesis (10-41). 

Two reportshave appeared concerning an extension of the Schmidt reaction of aryl aUcyl ketones in which the ketone was treated with an alkyl azide to give benzaldehyde, an aliphatic aldehyde and an amine. The yields of benzaldehyde were claimed to range from... 

A better method for preparing primary amines is to use the azide synthesis, in which azide ion, is used for 8 2 displacement of a halide ion from a primary or secondary alkyl halide to give an alkyl azide, RNj. Since alkyl azides are not nucleophilic, overalkylation can t occur. Reduction of the alkyl azide, either by catalytic hydrogenation over a palladium catalyst or by reaction with LiAlH4, leads to the desired primary amine. Although the method works well, low-molecular-weight alkyl azides are explosive and must be handled carefully. 

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