Hofmann rearrangements

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. 

More than 100 years ago, Hofmaim reported in a series of papers the conversion of primary amides to amines with bromine in aqueous sodium hydroxide. The occasional side reaction leading to nitrile formation was also observed by Hofmann. Another early observed side reaction is the formation of ureas from the combination of isocyanate with unreacted amide. This particular side reaction can be circumvented by employing sodium methoxide in place of sodium hydroxide to afford the corresponding methyl carbamate, which upon distillation from calcium hydroxide affords the corresponding primary amine, as first described by Jeffreys.  

Unlike many name reactions, the HR has evolved into a myriad of variations, some of which have supplanted the original Hofmann method in both importance and utility. 

The aforementioned Jeffreys modification using Br2/NaOMe has been extended by Nagai et al (8— 10) and Radlick (11— 12).  

Another source of bromine in the HR is A-bromosuccinimide (NBS), which was first employed by Jew et al. in combination with mercuric acetate or silver acetate to convert primary amides 13 to carbamates 14 These workers also used l,3-dibromo-5,5-dimethylhydantoin (dibromatin) in place of NBS with comparable success. Similarly, the combination of N- 

Key steps of this rearrangement represent A -bromination, followed by deprotonation of A -bromamide and C to N migration of the alkyl group inside acyl-nitrene with the formation of isocyanate [7, 8]. In aqueous medium, isocyanate is immediately hydrated to unstable carbamic acid, which decarboxylates to primary amine. In alcohols stable carbamate esters are formed. 

Synthetic application of this reaction extends from rearrangements of aliphatic amides to aromatic and heterocyclic amides. Results of the Hofmann rearrangement are primary amines or their A -acyl derivatives. 

Example 8.2 Complete retrosynthetic analysis and proposed synthesis of TM 8.2. 

In the target molecule, the amino group is bound to the ferf-C-atom and conveniently available via Hofmann rearrangement of the corresponding amide. Another possibility for the introduction of this functionality is discussed in Sect.2.5,  

The Kast building block is conveniendy available by hydrogenation of cinnamic acid ester TM 8.2g, a commodity produced on the large scale. An old technology is 

Upon treatment of primary amides with hypohalites, primary amines with one less carbon are obtained via the intermediacy of isocyanate. Also know as the Hofmann degradation reaction. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 127, Springer-Verlag Berlin Heidelberg 2009 

El-Mariah, F. Hosney, M. Deeb, A. Phosphorus, Sulfur Silicon Relat. Elem. 2006, /8/, 2505-2517. 

Gribble, G. W. Hofmann rearrangement. In Name Reactions for Homologations-Part IP, Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2009, pp 164-199. (Review). 

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. 

The first asymmetric total synthesis of the hasubanan alkaloid (+)-cepharamine was completed by A.G. Schultz et al. In order to construct the c/s-fused A/-methylpyrrolidine ring, the advanced tetracyclic lactone was first converted to the primary carboxamide by treatment with sodium amide in liquid ammonia. Next the Hofmann rearrangement was induced with sodium hypobromite in methanol initially affording the isocyanate, which upon reacting with the free secondary alcohol intramolecularly gave the corresponding cyclic carbamate in excellent yield. 

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. 

This method can also be used to synthesize multilayer phanes.  

For the Flofmann rearrangement reaction, a carboxylic amide 1 is treated with hypobromite in aqueous alkaline solution. Initially an iV-bromoamide 4 is formed. With two electron-withdrawing substituents at nitrogen the A -bromoamide shows NFI-acidity, and can be deprotonated by hydroxide to give the anionic species 5. 

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The conversion of an amide into an amine in this way is termed the Hofmann reaction or the Hofmann rearrangement. 

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. 

In addition to the nitrile and alcohol routes for fatty amine preparation, processes have been described by Unocal and Pennwalt Corporation, using an olefin and secondary amine (14—16) by Texaco Inc., hydrogenation of nitroparaffins (17—20) by Onyx Corporation, reaction of an alkyl haUde with secondary amines (21,22) by Henkel Cie, GmbH, reduction of an ester in the presence of a secondary amine (23) by catalytic hydroammonolysis of carboxyhc acids (24) and by the Hofmann rearrangement (25). 

Nicotinamide [98-92-0] (26) and isonicotinamide [1453-82-3] (32) undergo Hofmann rearrangements to form 3- (33) and 4-aminopyridine (34), respectively (35). This provides an important route for the manufacture of these amines. 

Hofmann rearrangement, 7, 34 Hofmann-Loffler-Freytag reaction, 4, 91 Holomycin... 

Hofmann rearrangement, 4, 804 2-Thenoic acid phenyl ester photolysis, 4, 805 2-Thenoic acid, 5-phenyl-synthesis, 4, 868 2-Thenoyl peroxide thermolysis, 4, 804 Thenyl... 

Most aminothiophenes are prepared by the reduction of nitrothio-phenes. Aminothiophenes or their derivatives have also been obtained through the Hofmann rearrangement of the acid amides, which, however, fails with 2-thenamide, in contrast to the 3-isomer. The Beckmann rearrangement of the oxime of 2-acetylthiophene has been applied successfully to the preparation of 2-acetamidothiophene. The free aminothiophenes are very unstable compounds and it has not been possible to distil 3-aminothiophene. They are best stored as the stannic-chloride double salts and give stable acetyl derivatives. 

The Hofmann and Curtius rearrangements have been applied to 2-thienylacryl amides for the preparation of 2-thiophene acetaldehydes. The Hofmann rearrangement proceeds also with 3-thenamides but fails with 2-thenamide. ... 

Generally yields are good. R can be alkyl or aryl. Modern variants of the Hofmann rearrangement use lead tetraacetate" or iodosobenzene instead of hypo-bromite. 

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. 

By application of the Schmidt reaction, the conversion of a carboxylic acid into an amine that has one carbon atom less than the carboxylic acid, can be achieved in one step. This may be of advantage when compared to the Curtius reaction or the Hofmann rearrangement, however the reaction conditions are more drastic. With long-chain, aliphatic carboxylic acids yields are generally good, while with aryl derivatives yields are often low. 

Carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement and tire Curtius rearrangement. Although the Hofmann rearrangement involves a primary-amide and the Curtius rearrangement involves an acyl azide, both proceed through similar mechanisms. 

Figure 24.5 MECHANISM Mechanism of the Hofmann rearrangement of an amide to an amine. Each step is analogous to a reaction studied previously.

The Curtius rearrangement, like the Hofmann rearrangement, involve migration of an -R group from the G-O carbon atom to the neighboring nitro gen with simultaneous loss of a leaving group. The reaction takes place on heat ing an acyl azide that is itself prepared by nucleophilic acyl substitution of m acid chloride. 

Like the Hofmann rearrangement, the Curtius rearrangement is often used commercially. For example, the antidepressant drug tranylcypromine is made by Curtius rearrangement of 2-phenylcyclopropanecarbonyl chloride. 

Hofmann rearrangement, 933 imide (-CONHCO—), 929 primary amine (RNH2), 916 quaternary ammonium salt, 917 reductive amination, 930 Sandmeyer reaction, 942 secondary amine (R2NH), 917 tertiary amine (R3N), 917... 

When an a-hydroxy amide is treated with Br2 in aqueous NaOH under Hofmann rearrangement conditions, loss of C02 occurs and a chain-shortened aldehyde is formed. Propose a mechanism. 

Isobutylene, polymerization of, 1207 Isocyanate. Hofmann rearrangement and,933-934 Isoelectric point (pJ), 1024 calculation of, 1024 table of, 1018-1019 lsoleucine, metabolism of, 911 molecular model of, 304 structure and properties of, 1018 Isomer, conformational, 93 Isomerase, 1041-1042 Isomers, 81... 

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. 

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