Hofmann elimination procedure

The successful synthesis of furanophane (27) by pyrolysis of the quaternary ammonium hydroxide (28) (60JA1428) has prompted the adaptation of this 1,6-Hofmann elimination procedure to the synthesis of numerous heterophanes (77CRV513,77H(7)81,78T1641). Fluoride anion-induced 1,6-elimination of (29) or (30) gives (27) or (31) and (32), respectively, in good yields (81JOC1043). 

The preparation of an alkene 3 from an amine 1 by application of a /3-elimination reaction is an important method in organic chemistry. A common procedure is the Hofmann elimination where the amine is first converted into a quaternary ammonium salt by exhaustive methylation. Another route for the conversion of amines to alkenes is offered by the Cope elimination. 

Show how styrene can be prepared using the following reactions somewhere in your synthetic procedure, (a) Hofmann elimination, (b) Grignard reaction, (c) Diels-Alder reaction. Compare the atom economies of each process. Identify any issues raised by using this approach to determine the most efficient synthetic route. 

A method for the preparation of olefins from primary amines is shown in equation 120. Treatment of 2-(4-bromophenyl)ethylamine (358) with acetic acid, acetic anhydride and sodium nitrite generates the nitroso amide 359, which decomposes to 4-bromostyrene in the presence of rhodium(II) acetate. The procedure is thus a mild, non-basic alternative to the classical Hofmann elimination of amines396,397. 

In an alternate route designed to improve the yield of argemonine (5), 78 (X = CIO4) was subjected to Hofmann elimination. The resulting compound 80 was quatemized and allowed to react with potassium tcrt-butoxide to generate di-methylamino compound 81. An internal dimethylaminomercuration-demercura-tion procedure followed by N-demethylation then provided ( )-argemonine in 53% yield (123). 

Cyclopropanes via abnormal Hofmann elimination. This procedure provides ethyl 1-benzylcyclopropanecarboxylate in significantly improved yield and is generally applicable to the synthesis of I-substituted cyclopropanecarboxylic esters. 

The total synthesis of the cembranoid diterpene (+)-crassin acetate methyl ether was accomplished by W.G. Dauben et al. In the final stages of the total synthesis, the sensitive a-methylene group was introduced onto the six-membered lactone by using the Eschenmoser methenylation procedure. The lactone was deprotonated with LDA and then treated with Eschenmoser s salt. In the second step, the dimethylamino group was exhaustively methylated and the quaternary ammonium salt underwent a smooth Hofmann elimination upon deprotonation with DBU. 

In the laboratory of D.S. Watt, the enantioselective total synthesis of (+)-picrasin B was achieved from (-)-Wieland-Miescher ketone. At the early stages of the synthetic effort, an exocyclic double bond was introduced in a two-step procedure by first alkylating the bicyclic conjugated TMS end ether with Eschenmoser s salt at the y-position, followed by Hofmann elimination of the dimethylamino group. 

The classical Hofmann elimination reaction (which dates back to 1851) has been adapted to the solid phase in combination with the Michael addition. The REM resin, called this way because the resin tinker is REgenerated after product cleavage and functionalized by means of a Michael addition, has been developed to prepare arrays of tertiary amines. The procedure involves acylation of hydroxy-methylpolystyrene with acrylic chloride to furnish the acrylate on resin. Then, a secondary amine, whose substituents offer two potential sites of diversity, is bound by Michael addition. Quaternization of the amine with an alkyl halide (or reductive animation) introduces another site of diversity and activates the tinker to release the amine by a Hofmann elimination with DIEA (Figure 15.14) [127-129]. Additionally, the use of a second basic resin has been described as a source reagent to promote the elimination [130, 131]. 

In their pioneering work in multilayered cyclophane chemistry, Longone and Chow (97) prepared a mixture of four-layered [2.2]paracyclophanes 82 and 85 by making use of the elegant procedure of Cram, which involves coupling of the p-xylylene intermediate 80 derived by a 1,6-Hofmann elimination of the corresponding quaternary ammonium base. There are available two alternatives for coupling the racemic 80 of C2 symmetry either between enantiomers of opposite chirality or between enantiomers of same chirality. The former should provide meso-82 of C2h symmetry, whereas the latter should yield 85 of D2 symmetry. 

In the procedure of Hofmann elimination, the amine is first completely methylated with excess iodomethane (exhaustive methylation) and then treated with wet silver oxide (a source of HO ) to produce the ammonium hydroxide. Heating degrades this salt to the alkene. When more than one regioisomer is possible, Hofmann elimination, in contrast to most E2 processes, tends to give less substituted alkenes as the major products. Recall that this result adheres to Hofmann s rule (Section 11-6) and appears to be caused by the bulk of the ammonium group, which directs the base to the less hindered protons in the molecule. 

A new synthesis of tropones has been announced which involves cyclocoupling of polybromo-ketones and 1,3-dienes, promoted by iron carbonyl. Stipitatic acid and hinokitiol have been made by a novel procedure involving intermediates (1) and (2) followed by Hofmann elimination of the bridge in (2). 

Elimination of the amino group can also be achieved by the Hofmann procedure, namely, by heating the quaternary ammonium hydroxide.33... 

An alternative bimolecular elimination process involves the thermal decomposition in an atmosphere of nitrogen of a quaternary ammonium hydroxide (Hofmann exhaustive methylation procedure). 

The reaction has been extensively used for the determination of the structure of naturally occurring bases (e.g. the alkaloids). However it has rather limited preparative value, even though the elimination reaction occurs without any rearrangement of the carbon skeleton, and the regioisomer which predominates in the product is the less highly substituted alkene (Hofmann rule contrast the Saytzeff rule). Such alkenes are now more usually prepared by other procedures noted below. 

Modification of this reaction procedure to incorporate a benzene ring in place of one pyridine ring was accomplished by a cross Hofmann-1,6-elimination from an intimate mixture of 67 and 68. Unfortunately, the yield of the desired cyclophane 69 was obtained in only 0.4% yield35). 

In this reaction two different procedures have been used. The first is the classical Hofmann degradation, which prepares the alkene by thermal decomposition of the quaternary ammonium hydroxide. Hofmann orientation is generally observed in acyclic and Zaitsev orientation in cyclohexyl substrates. The second is the treatment of quaternary ammonium halides with very strong bases, e.g. PhLi, KNH2 in liquid NH3. The formation of the alkene proceeds via an 1 mechanism, which means a syn elimination in contrast to the anti elimination which is observed in most of the classical Hofmann degradations. In some cases this type of elimination can also be accomplished by heating the salt with KOH in polyethylene glycol monomethyl ether. 

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