Hofmann rearrangement isocyanate intermediate

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. 

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. 

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. 

The Hofmann rearrangement (Section 20.17) Amides are converted to amines by reaction with bromine in basic media. An A/-bromo amide is an intermediate it rearranges to an isocyanate. Hydroiysis of the isocyanate yieids an amine. 

Isocyanates, as intermediates in Hofmann rearrangement, 812—813 Isoelectric point, 1058—1059 Isoelectronic, 47—48 Isolated diene, 372, 391 L-Isoleucine, 1054, 1059... 

The Hofmann Rearrangement (HR), which is often called the Hofmann Reaction or Hofmaim Degradation but should not be confused with the Hofmann Elimination, describes the multistep transformation of a primary carboxamide 1 to a primary amine 3 via an intermediate isocyanate 2 under the action of bromine and sodium hydroxide. " As will be shown, many variations of this rearrangement are known and widely used today. 

Carbamates are also formed by one-stage, two-step processes involving isocyanates as intermediates and precursors. Thus, carbamates are prepared under modified Hofmann rearrangement conditions, using NBS/NaOMe as the reagent [443], by Curtius rearrangement of the acyl azide if the reaction is carried out in alcohol, by the reaction of amides with lead tetraacetate [444], or by the Lossen rearrangement, if the carbamates are not sensitive to the presence of base. 

Amides, of course, can also undergo the Hofmann rearrangement (see, e.g.. Scheme 9.103) so that amines bearing one carbon less than that obtained on simple reduction can be generated (Equation 10.27). The same isocyanate intermediate has also been seen in Thble 9.6 (item 5) and Scheme 9.120, the Schmidt rearrangement. Table 9.7 (item 6), and the Curtins rearrangement, and the same result (i.e., amine formation) was obtained on hydrolysis. 

The Hofmann rearrangement involves the treatment of primary amides (those with an NH2 group) with bromine in basic media. Amides are converted to amines and C02is eliminated (Eq. 11.53). The mechanism involves an IV-bromo amide and an isocyanate, both of which have been isolated as intermediates. 

FIGURE 18.72 The first stages in the Hofmann rearrangement. An isocyanate is an intermediate, but cannot be isolated. 

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). 

This reaction constitutes an acid-catalyzed Hofmann rearrangement [34, 35]. The trifluoroacetic acid formed in the reaction hydrolyzes the intermediate isocyanate and protonates the amine as it forms preventing further reaction. 

We recall that an isocyanate intermediate forms in the Hofmann rearrangement and that it is trapped by reaction with an alcohol to give a urethane (Section 23.9). Isocyanates can also be prepared by other methods. They react quantitatively and rapidly with an alcohol or phenol to give carbamate... 

Preparation from Nitrene Intermediates. A convenient, small-scale method for the conversion of carboxyhc acid derivatives into isocyanates involves electron sextet rearrangements, such as the ones described by Hofmann and Curtius (12). For example, treatment of ben2amide [55-21-0] with halogens leads to an A/-haloamide (2) which, in the presence of base, forms a nitrene intermediate (3). The nitrene intermediate undergoes rapid rearrangement to yield an isocyanate. Ureas can also be formed in the process if water is present (18,19). 

The Wolff rearrangement has a close formal resemblance to the Hofmann and related reactions (p. 122), in which migration takes place to an electron-deficient nitrogen atom to form an isocyanate, RN=C=0, intermediate. 

There are a group of reactions very closely related to that of Hofmann, all of which involve the formation of an isocyanate (61) by rearrangement of an intermediate analogous to (60) ... 

Preparation from Silrene Intermediates. A convenient, small-scale method for the conversion of carboxylic acid derivatives into isocyanates involtcs electron sextet rearrangements, such as the ones described by Hofmann and Cuitius. 

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