Alkyl azides reduction

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. 

There now are available a number of alkyl azide compounds that may be used in click chemistry reactions and the Staudinger ligation processes. It is not recommended, however, to use aryl azide compounds, as these are light sensitive and photoreactive as well as highly susceptible to reduction in the presence of thiols. Unfortunately, at the time of this writing there are fewer choices in aryl phosphine compounds to participate in this reaction, as commercial sources of labeling reagents are limited. 

The reduction of alkyl azides, alkyl cyanides and amides (Expts 5.193 to 5.195). 

THE REDUCTION OF ALKYL AZIDES. ALKYL CYANIDES AND AMIDES... 

The multielectron reduction of alkylazides catalyzed by various [4-Fe]n and [Mo-Fe]m clusters has been achieved by c.p.e. in homogeneous systems and at modified glassy-carbon electrodes [168-169]. Dithionite reduction of alkyl-azide is catalyzed by [Fe4S4( SC6H4-4-n-C8H 7)4 2 [170] and MoFe3S4... 

There is one method of direct alkylation of a nitrogen nucleophile. Preliminary FGI (with reduction in mind again) to an alkyl azide 52 allows C-N disconnection to the alkyl halide and azide ion 54. This interesting species is linear and can slip into crowded molecules like a tiny dart. But there is a drawback all azides are toxic and POTENTIALLY EXPLOSIVE. 

The alkyl azide 50 can be treated with TfOH followed by reduction to give the corresponding benzoindolizine structures (Equation 186) <2000JOC7158>. The major product was isolated in 45% yield while the minor regio-isomer was isolated in 10% yield. Further examples of this strategy were also reported. 

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. 

The alkyl azide produced can be reduced to the primary amine by a number of methods such as catalytic hydrogenation (Chapter 24) or LiAlH4 (Chapter 12). This method has a similar philosophy to the reductive amination discussed in Chapter 14. 

One of the methods for the synthesis of alkyl azides is based on the regioselective addition of mercury(II) azide, generated from mercury(II) acetate and sodium azide, to alkenes in water/te-trahydrofuran (1 1) to afford /i-azidoalkylineiciiry compounds which are then reductively demercurated to alkyl azides5-7. Completely diastereoselective cis addition occurred with norbornene (exo addition)5 and cyclopropenes6. 

The synthesis shown in Scheme 60 exemplifies the first approach <20010L2575, 2004JOC2831>. A rather lengthy series of transformations provides epoxide 311. The epoxide is opened with azide and the resulting alcohol converted to the mesylate. A few additional functional group modifications are then necessary for the synthesis of 312. A standard azide reduction followed by an intramolecular alkylation provides the aziridine 313. This aziridine is then carried on to FR900482 in three additional steps. 

Selective reduction of a halogenated aromatic nitro compound to the corresponding hydroxylamine or amine upon irradiation of Ti02 suspended in degassed alcohol has also been reported, as has the selective photoreduction of / -nitrobenzaldehyde to the corresponding aldehydic aniline (Eq. 30) [170], and alkyl azides can also be reduced to the corresponding amine. 

Interestingly, our previously described studies concerning the in vitro biotransformation of aryl azides in murine microsomes [93] generally parallel the above results observed for the chemical reduction of azides by thiols, with electron-deficient aryl azides also undergoing metabolic reduction much more rapidly than their electron-rich counterparts or alkyl azides. These similarities have led us to speculate that a possible mechanism for the enzyme-catalyzed reduction of aryl azides may entail analogous initial attack by a sulphydryl group at the active site of the appropriate enzyme, although this hypothesis remains to be confirmed. 

Gurtius and co-workers studied the acid-catalysed decomposition of alkyl azides such as benzyl azide. This was decomposed in either warm 1 1 (v/v) sulphuric acid-water or with concentrated hydrochloric acid to give a mixture of products corresponding to hydrogen migration [benzaldiinine (1)], phenyl migration [formaldehyde anil (2)], the azide reduction product [benzylamine (3)], and the solvolysis product [benzyl alcohol (4)]. The first two were obtained as the... 

The total synthesis of the antiviral marine natural product (-)-hennoxazole A was accomplished by F. Yokokawa and co-workers." The mild reduction of a secondary alkyl azide at C9 was carried out using triphenylphosphine in a THF/water mixture at slightly elevated temperature. The corresponding primary amine was obtained in good yield and was subsequently acylated and converted to one of the oxazole rings of the natural product. 

Reduction of aikyi azides (Section 22.10) Alkyl azides, prepared by nucleophilic substitution by azide ion in primary or secondary alkyl halides, are reduced to primary alkylamines by lithium aluminum hydride or by catalytic hydrogenation. 

Synthesis of alkyl azides.1 Terminal alkenes and strained cyclic alkenes react with the reagent to give a mercurial intermediate, which on reduction with sodium borohydride gives an azide. Internal olefins do not react. The method is an extension of the hydroxymercuration reaction of Brown (2,265-267). 

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