Hofmann rearrangement amine synthesis

The intermediates in making amines are isocyanates (0==C==N) just like the Hofmann Rearrangement. The isocyanates are decomposed with water, just like the Hofmann. In fact, there is a lot of similarity between the Hofmann and the Schmidt reactions. Before I detail the synthesis steps, I should note that if you wish to generate the Hydrazoic Acid in the flask by adding Sodium Azide, you might need a powder addition funnel. This bit of equipment is quite pricey and it s likely you won t have one, so the first part of the synthesis details how to make the Hydrazoic Acid separately. 

This procedure permits the synthesis of cyclobutylamine from cyclobutanecarboxylic acid in one step and in high yield. The procedures involving the Hofmann rearrangement require the preparation of the amide from the acid and afford lower yields of the amine. 

The enantioselective total synthesis of (-)-epibatidine was accomplished in the laboratory of D.A. Evans." The key steps in the synthetic sequence included a hetero Diels-Alder reaction and a modified Hofmann rearrangement. The primary carboxamide was subjected to lead tetraacetate in fert-butyl alcohol that brought about the rearrangement and gave the corresponding A/-Boc protected primary amine in good yield. A few more steps from this intermediate led to the completion of the total synthesis. 

During the late stages of the asymmetric total synthesis of capreomycidine IB it was necessary to transform an asparagine residue into a diaminopropanoic acid residue." R.M. Williams et al. employed a chemoselective Hofmann rearrangement, thereby avoiding protection and deprotection steps that would have been necessary had the diaminopropanoic acid been introduced directly. The complex pentapeptide was treated with FIFA and pyridine in the presence of water to afford the primary amine in high yield. 

Several additional amine syntheses are effectively limited to making primary amines. The reduction of azides and nitro compounds and the Gabriel synthesis leave the carbon chain unchanged. Formation and reduction of a nitrile adds one carbon atom and the Hofmann rearrangement eliminates one carbon atom. Show how these amine syntheses can be used... 

The end product is the amine. There is an essential difference between the Curtius rearrangment and the Hofmann rearrangement. Both involve the formation of isocyanates, but only in the Curtius rearrangement is this intermediate isolable. In the Hofinann rearrangement, base is present and the isocpnate cannot survive (Fig. 18.74). This synthesis of amines is not easy to remember because it involves many steps, thus making it a great favorite of problem writers (open-book, of course). 

Hofmann-type rearrangement of primary amides (107) into the corresponding amines (108) using PIFA [79-81] was used for the initial reaction toward the total synthesis of the potent thrombin inhibitor cyclotheonamide A (109) [Eq. (25)]. 

Phenylethylamine has been made by a number of reactions, many of which are unsuitable for preparative purposes. Only the most important methods, from a preparative point of view, are given here. The present method is adapted from that of Adkins,1 which in turn was based upon those of Mignonac,2 von Braun and coworkers,3 and Mailhe.4 Benzyl cyanide has been converted to the amine by catalytic reduction with palladium on charcoal,5 with palladium on barium sulfate,6 and with Adams catalyst 7 by chemical reduction with sodium and alcohol,8 and with zinc dust and mineral acids.9 Hydrocinnamic acid has been converted to the azide and thence by the Curtius rearrangement to /3-phenyl-ethylamine 10 also the Hofmann degradation of hydrocinnamide has been used successfully.11 /3-Nitrostyrene,12 phenylthioaceta-mide,13 and the benzoyl derivative of mandelonitrile 14 all yield /3-phenylethylamine upon reduction. The amine has also been prepared by cleavage of N- (/3-phenylethyl) -phthalimide 15 with hydrazine by the Delepine synthesis from /3-phenylethyl iodide and hexamethylenetetramine 16 by the hydrolysis of the corre-... 

Thermal decomposition of quaternary ammonium salts and bases is most valuable in structural investigations of amines, particularly heterocyclic secondary amines (Hofmann exhaustive methylation). The course of the elimination (A or B) is determined by the nature of the four alkyl groups on the nitrogen atom. The reaction has found little use in the synthesis of pure olefins. The yields are low even when three of the alkyl groups are methyl radicals. Carbon-skeleton rearrangement does not occur. Thus, the only olefin obtained by pyrolysis of pinacolyltri-methylammonium hydroxide, (CHj),CCH(CHj)N(CHj)j OH, is /-butylethylene (50%). ... 

This means the synthesis must employ a reaction that generates an amine of 1 less carbon from succinic anhydride. Such a reaction is the Hofmann degradation of amides. As seen below, the reaction involves the migration of a group from carbonyl carbon to the adjacent nitrogen atom. It is therefore an example of a molecular rearrangement. ... 

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