Hofmann-type

The preparation of cyclobutylamine from cyclobutanecar-boxylic acid and hydra2oic acid has been reported previously.2,3 Cyclobutylamine has also been prepared by the Hofmann-type rearrangement of cyclobutanecarboxamide.4-7... 

As would be expected in a substrate with a poor leaving group the predominant elimination process is of the Hofmann type. However, the authors did find some unexpected reactions. For example, the p-nitrophenyl sulphone was completely consumed within six hours of heating with the glycolate system, yet alkenes formed only a minor part of the products, the major part not being clearly identified. The p-dimethylaminophenyl sulphone was three to six times more reactive than the other sulphones, but it also underwent elimination at a significant rate with either solvent, even in the absence of alkoxides. The reasons for this are obscure. 

Direct oxidation of amides can also lead to Hofmann-type rearrangement with formation of amines or carbamates. One reagent that is used is Pb(02CCH3)4. 

The elimination of hydrogen halide from organic halides under basic conditions generates alkenes and is a fundamental reaction in organic chemistry. It is sometimes carried out with a base in aqueous media.14 In contrast, the corresponding Hofmann-type eliminations of quaternary ammonium hydroxides are frequently carried out in aqueous media,15 which will be covered in Chapter 11. 

This arrangement of subgroups is due to the hypothetical biosynthetic sequence. It assumes that precursors for these alkaloids are the Af-methylphth-alideisoquinolinium salts, whose presence in plants is well documented. Enol lactones may be the initial degradation products formed in a Hofmann-type jft-elimination process. They could be hydrated to the keto acids and in the next step oxidated in air to the diketo acids. Diketo adds may undergo further oxidative cleavage to yield simple alkaloids of the fumariflorine (87) type 85,86), which seem to be the final products of the metabolism of phthalideiso-quinoline alkaloids. 

Enol lactones are assumed to form from iV-methylisoquinolinium salts as a result of a Hofmann-type degradation process. This P elimination is a highly stereospecific reaction in which Z isomers are produced from precursors of erythro configuration and isomers from threo diastereomers(5,97). This fact seems to suggest that syn rather than the more usual anti elimination takes place. Examination of models indicates, however, that there is a preferred conformation in which the C-8 hydrogen is in the syn and coplanar position to the quaternary nitrogen. This hypothesis was proved correct in experiments carried out in vitro (5,14,15,91-94). 

Investigations of cyanides and cyano complexes of Cd and Hg have augmented tremendously since about 1990, after detection of inclusion compounds of Cd(CN)2. A thorough review on transition-metal cyanides especially emphasizes the chemistry of inclusion compounds of both the Hofmann type (frameworks dominated by planar Ni(CN)4 building blocks) and the cyanocad-mate type (frameworks with tetrahedral Cd(CN)4 units).87 The structures of these inclusion compounds, but also of cyanides themselves, often topologically resemble the structures of minerals this aspect ( mineralomimetic chemistry ) is dealt with in a simultaneous survey.88 A more generic review of framework structures, with a section on cyanide inclusion compounds, is also to be mentioned.90... 

Hofmann reaction, 76 320. See also Hoffman reaction Hofmann rearrangement, 77 741 Hofmann-type inclusion compounds, 74 171-172... 

Another method, which generated in most cases good yields of N-protected gem-diaminoalkyl compounds, involves N-protected peptidyl or aminoacyl carboxamide derivatives. These are subjected to a Hofmann-type rearrangement with the mild oxidizing reagent iodobenzene bis(trifluoroacetate) (IBTFA). 83 IBTFA is also known as phenyl iodosyl... 

Methylpyridazine-4,5-dicarboxamide (189) gives a mixture of the two products (190) and (191), along with an unidentified product, when reacted with potassium hydroxide in a Hofmann type reaction (68JHC523). 

Most pyrimido[4,5-d]pyridazines are prepared from 4,5-disubstituted pyridazine precursors. The versatile intermediate pyrimido[4,5-cf]pyridazine-2,4-dione (85) can readily be formed in high yield from pyridazine-4,5-dicarboxamide (196) by reaction with sodium hypobromite in a Hofmann type reaction (68JHC53). 

Hofmann- and Werner-Type Inclusion Compounds. There is a wide range of clathrates having as the host component inorganic coordination compounds represented by the general formulae M(NH3)2 M (CN)4 and M" X2Y4. The first formula is typical of Hofmann-type clathrates... 

A useful property of hyper valent iodine reagents is their ability to react first as an electrophile and then to be transformed into an excellent leaving group. This particular aspect has been used in different rearrangements for the construction of highly functionalized molecules. Various iodine(III) reagents have been employed in Hofmann-type rearrangements [136-139]. The presence of a nucleophile in the ortho position of aromatic amides of type 72 can lead to direct cyclizations and to the formation of heterocyclic compounds 73 as shown in Scheme 33 [140]. 

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)]. 

With some exceptions, BTI is considered to be the best choice for the Hofmann type degradation of carboxamides to primary amines. Generally, treatment of an aliphatic primary carboxamide with BTI in aqueous acetonitrile (at an acidic pH 1-3), followed by addition of hydrochloric acid delivers the corresponding amine hydrochloride in excellent yield. 

A reaction of considerable interest is the Hofmann type degradation of primary carboxamides to amines. Several examples have been reported of such efficient conversions, notably with the system IOB in formic acid (in water of acetonitrile), which forms in situ PhI(OOCH)2 [44], Other hypervalent iodine reagents have also been used extensively for these transformations (Sections 4.4.1 and 7.4.1). Yields may vary widely as illustrated for three similar amines obtained from the corresponding carboxamides with IOB-formic acid and with [hydroxy-(tosyloxy)iodo]benzene [45] ... 

---