Isocyanate, Hofmann rearrangement

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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. 

Acyl azides may loose N2 on heating and rearrange to isocyanates (Curtius rearrangement), which may be solvolyzed. Some of the possibilities of classical carboxyl conversions are exemplified in the schemes below, which are taken from a triquinacene synthesis (R. Russo, 1971 C. Merder, 1973) and the ergotamine synthesis of A. Hofmann (1963). 

In the Lossen reaction a hydroxamic acid derivative (usually an 0-acyl derivative) is deprotonated by base, and rearranges via migration of the group R to give an isocyanate 2. Under the usual reaction conditions—i.e. aqueous alkaline solution—the isocyanate reacts further to yield the amine 3. The Lossen reaction is closely related to the Hofmann rearrangement and the Curtins reaction. 

Another reaction that can be used for conversion of carboxylic acids to the corresponding amines with loss of carbon dioxide is the Hofmann rearrangement. The classic reagent is hypobromite ion, which reacts to form an A-bromoamide intermediate. Like the Curtius reaction, this rearrangement is believed to be a concerted process and proceeds through an isocyanate intermediate. 

Section B shows some Hofmann rearrangements. Entry 9, using basic conditions with bromine, provided an inexpensive route to an intermediate for a commercial synthesis of an herbicide. Entry 10, which uses the Pb(OAc)4 conditions (see p. 949), was utilized in an enantiospecific synthesis of the naturally occurring analagesic (-)-epibatidine. Entry 11 uses phenyliodonium diacetate as the reagent. The product is the result of cyclization of the intermediate isocyanate and was used in an enantioselective synthesis of the antianxiety drug (tf)-fluoxetine. 

The amides undergo a rearrangement resembling Hofmann rearrangement and give isocyanate. 

Treatment of amides with bromine in alkaline medium promotes the Hofmann rearrangement, which may or may not involve a free nitrene intermediate." The oxidation of primary amides with lead tetraacetate and the resulting Lossen rearrangement also produces isocyanates, with the possible intervention of an acylni-... 

In 1882 Hofmann discovered that when amides are treated with bromine in basic solution, they are converted to amines with one carbon less than the starting amide.180 He also isolated the N-bromo amine (114) and the isocyanate (115) as intermediates on the reaction path. The mechanism in Equation 6.56 accounts for the products and the intermediates. This reaction (or the analogous rearrangement of the N-chloro amine) is now known as the Hofmann rearrangement or, because of its synthetic usefulness in eliminating a carbon atom, the Hofmann degradation. 

Another method for producing a chiral 3-carbon fragment, this time directly as a protected 5-hydroxymethyl-3-oxazolidin-2-one, is illustrated in scheme 9 (77). In this case, the amide 20 is converted to the 4-trityl ether 24. This undergoes very facile Hofmann rearrangement to give the 5-trityloxymethyl-3-oxazolidin-2-one 26 via the intermediate isocyanate 25. The oxazolidinone 26 is a protected version of 3-amino-1,2-dihydroxypropane. 

The 2-aminonicotinamides 67 react with [fe(trifluoroacetoxy)iodo]ben-zene (BTIB) in aqueous DMF to give the pyrazolopyridines 68 under the same conditions, the amidopyridones 69 are converted to the isoxazolopyridines 70 (97SC2217). These results are somewhat suprising, since BTIB, DAIB, and HTIB are useful reagents for the Hofmann rearrangement (Section III.A.6), and the formation of 71 and 72 from isocyanate intermediates might have been expected. 

Overall, then, the Curtius rearrangement converts an acid chloride to an amine with loss of a car- tk>n atom—very useful. Also useful is the related Hofmann rearrangement, which turns an amide ito an amine with loss of a carbon atom. This time we start with a primary amide and make a trene by treatment with base and bromine. Notice how close this nitrene-forming reaction is to the tarbene-forming reactions we talked about on p. 1072. The nitrene rearranges just as in the Curtius reaction, giving an isocyanate that can be hydrolysed to the amine. 

Hofmann rearrangements Primary amides are converted into amines in high yield by reaction with this owdant at room temperature in aqueous acetonitrile (equation I). The reaction is rslated to a recent method using lead tetraacetate (6, 316) however, the intermet iate isocyanate in this case is not trapped as the carbamate, but is hydrolyzed alirectly to the amine. 

The acyl azide undergoes a rearrangement similar to the Hofmann rearrangement (method 446) and to the Lossen rearrangement (method 448). This step is carried out in inert solvents like benzene and chloroform to give the isocyanate directly or in solvents like alcohol and water which will react with the isocyanate to form urethanes and ureas. 

A variation of the Hofmann rearrangement treated a p-hydroxy primary amide with PhI(02CCF3)2 in aqueous acetonitrile, giving an isocyanate via -CON-I, which reacts with the hydroxyl group intramolecularly to give a cyclic carbamate. Note that carbamates are converted to isocyanates by heating with Montmorillonite KIO. ... 

The rearrangement has a mechanism similar to those of the Hofmann rearrangement of amides, the Lossen rearrangement of acylhydroxamic esters, the Schmidt rearrangement of carbonyl compounds and the Wolff rearrangement of diazoketones. Evidence concerning the mechanism of one can often be applied to the others, and the whole family has been reviewed briefly . Sometimes the distinction is made that the conversion of an acyl azide into an isocyanate or urethane is the Curtius rearrangement whereas the overall sequence is the Curtius reaction, but usually the former name is used for both processes. 

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