Reduction of alkyl azides

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... 

Reduction of alkyl 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. 

Miscellaneous. The reduction of alkyl azides and biomolecule-containing azides to the corresponding primary amine has been recently accomplished with [Ru(bpy)3]Cl2and visible light using an appropriate reductive quencher in organic as... 

Reduction of alkyl azides can also be accomplished under transfer hydrogenation conditions using cyclohexene and formate (Scheme 32). 

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 synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

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. 

Deprotonation of indoles 128 followed by alkylation with 2-methyloxirane led to the secondary alcohols 129 that were used as starting compounds in the preparation of substituted 2-(l//-indol-l-yl)-l-methylethylamines 130, novel agonists of 5HT2C receptors. Sn2 reaction of the corresponding mesylates with sodium azide and reduction of the azides with either hydrogen or LiAlH4 produced amines 130 in excellent yields (Scheme 28) <1997JME2762>. 

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 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). 

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... 

Cleavage of C-N bonds has been described elsewhere, for example, the reduction of g wj-dinitroalkanes to nitrite ion and nitroalkane anion [181,182] and f-nitroalkanes to nitrite and alkyl radical (Chapter 9) and the reduction of pyridylamines to picoline and ammonia (Chapter 18) [13,14] a rare case of a reductive loss of a nitro group from a benzene ring in l,2,4,5-tetrafluoro-3,6-dinitrobenzene has been reported [183]. Reduction of activated azides yields azide ion phenacyl azide is thus reduced to acetophenone and azide [236]. 

We pointed out in chapter 27 that Schultz s asymmetric Birch reduction can be developed with iodolactonisation to remove the chiral auxiliary and set up new chiral centres. Now we shall see how he applied that method to alkaloid synthesis.1 The first reaction is the same as in chapter 27 but the alkyl halide is now specified this gave diastereomerically pure acetate in 96% yield and hydrolysis gave the alcohol 4. Mitsunobu conversion of OH to azide and enol ether hydrolysis gave 5, the substrate for the iodolactonisation. Iodolactonisation not only introduces two new chiral centres but cleaves the chiral auxiliary, as described in chapter 27. Reduction of the azide 6 to the amine with Ph3P leads to the imine 7 by spontaneous ring closure. 

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). 

Whitesell observed that alkylation at the a-carbon of an amide of a C2-symmetric amine, in which the amine acts as a chiral auxiliary, should result in effective symmetric induction [166]. The C2-symmetric aziridines 519 and 520 are readily accessible from 503 and 514, respectively. Ring opening of either epoxide with sodium azide, mesyl activation of the free hy oxy group, and lithium aluminum hydride reduction of the azide with concomitant ring... 

Reduction of Azides. Reduction of alkyl, aryl, and aroyl-azides to the corresponding primary amine or amide occurs... 

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