Azides, from alkyl halides reduction

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). 

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). 

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. 

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. 

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. 

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. 

Alkylation of Azide Ion and Reduction A much better method for preparing a primary amine from an alkyl halide is first to convert the alkyl halide to an alkyl azide (R — N3) by a nucleophilic substitution reaction, then reduce the azide to a primary amine with lithium aluminum hydride. 

The addition of ozone (O3) to alkenes to give a primary ozonide (molozonide), which rearranges to an ozonide and eventually leads, on reduction, to carbonyl compounds (aldehydes and/or ketones), has already been mentioned and the reaction itself is shown in Scheme 6.11. However, it is important to recognize that this is only one example of a 4th- 2n electrocyclic addition and that orbital overlap for many sets of these reactions dictates their courses as well. Thus, to show the similarity of some of these dipolar 3 -f 2 addition reactions Equations 6.53-6.56 are provided. Although any alkene might be used as an example, (Z)-2-butene is used in each to emphasize that aU of them occur with retention of stereochemistry and, in the first (Equation 6.53), the reaction with ozone to form the primary ozonide (molozonide) is presented again (i.e., see Scheme 6.11). In a similar way, with a suitable azide, R-N3, readily prepared from an alkyl halide (Chapter 7), the same alkene forms a triazoline (Equation 6.54) and with nitrous oxide (N2O) the heterocycle (Chapter 13) cis -4,5-dimethyl-A -l,2,3-oxadiazoline (ds-4,5-dihydro-4,5-dimethyl-l,2,3-oxadiazole) (Equation 6.55). Finally, with a nitrile oxide, such as the oxide derived from ethanenitrile (acetonitrile [CH3ON]), the same alkene yields a different heterocycle, the dihydroisoxazole, 3,4,5-trimethyl-4,5-dihydroisoxazole (Equation 6.56). 

Arylamines are prepared by nitration of an aromatic ring followed by reduction. Alkylamines are prepared by Sn2 reaction of ammonia or an amine with an alkyl halide or by the Gabriel amine synthesis. Amines can also be prepared by a number of reductive methods, including UAIH4 reduction of amides, nitriles, and azides. Also important is the reductive amination reaction in which a ketone or an aldehyde is treated with an amine in the presence of a reducing agent such as NaBH4. In addition, amines result from the Hofmann... 

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