Hofmann degradation rearrangement

The first successful transformation of protoberberines to benzo[c]-phenanthridines was reported by Onda et al. (122,123). Irradiation of the enamines 200 and 195, the Hofmann degradation products of the corresponding protoberberines, in benzene afforded the initial photoproducts 201, which immediately rearranged to the tetrahydrobenzo[c]phenanthridines 202 in 70% yield (Scheme 37). Dehydrogenation of 202 afforded dihydro-chelerythrine (203) and dihydrosanguinarine (204), which were further oxidized with dichlorodicyanobenzoquinone (DDQ) to yield chelerythrine (205) and sanguinarine (206), respectively. 

Scheme 52). The reaction will proceed via the enolate 292 and the quinodimethide 293 as key intermediates. Basic treatment of 291 did not cause the Stevens rearrangement but gave the Hofmann degradation product 295. 

Kano et al. (161,162) also investigated the Stevens rearrangement of tetrahydroprotoberberine metho salts 302 with dimsylsodium and obtained the spirobenzylisoquinolines 303 in high yield (Scheme 56). Similarly C-homoprotoberberine 304 gave the new spiro compound 305, whereas B-homoprotoberberine 306 afforded only the Hofmann degradation product 307. 

Curtins Rearrangement Similar to a Hofmann degradation with an azide replacing the amide. 

Racemic argemonine (5) has been synthesized from the readily available tetrahydro-6,12-methanodibenz[c,/Iazocine (74) (120-122) through a sequence involving a Stevens rearrangement and in an overall yield of 53% from 74 (Scheme 11) (123). Hofmann degradation of 74 furnished the cxo-methylene compound 75 (120,122). An oxidative ring expansion of 75 afforded ketone 76, which was then reduced to secondary alcohol 77. A transannular reaction, effected by acetic acid-acetic anhydride, resulted in the formation of the tetra-... 

Hofmann degradation of benzamide This reaction produces aniline, which contains one less carbon than the starting material (benzamide). The group (phenyl) attached to the carbonyl carbon in the amide (benzamide) is found joined to nitrogen in the product (aniline). This is an example of molecular rearrangement. 

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. 

Rearrangement of N-nitrosoamides. N-Nitrosamides (1), prepared by acetylation of primary amines followed by nitrosation, are known to decompose in nonpolar solvents at 80-100° to form alkyl acetates with elimination of nitrogen.9 The presumed diazoalkane intermediate (a) can be trapped as a rhodium carbene (b), which undergoes rearrangement to an alkene (equation I). The overall result is a mild, nonbasic version of the classical Hofmann degradation of amines. 

Arylfurazancarboxamides on treatment with alkaline hypochlorite undergo Hofmann degradation to the amines likewise carbamates result from Curtius rearrangement of furazanylacyl azides in the presence of alcohols. 

Optically active ochotensanes of structure (117) have been obtained from (+)-and (—)-/S-canadine methochloride (116 R = H) and iV-methylthalictricavine chloride (116 R = Me) by rearrangement with organometallic compounds, other products being the two Hofmann degradation products.122... 

Phenylethylamine has been made by a number of reactions, many of which are unsuitable for preparative purposes. Only the most important methods, from a preparative point of view, are given here. The present method is adapted from that of Adkins,1 which in turn was based upon those of Mignonac,2 von Braun and coworkers,3 and Mailhe.4 Benzyl cyanide has been converted to the amine by catalytic reduction with palladium on charcoal,5 with palladium on barium sulfate,6 and with Adams catalyst 7 by chemical reduction with sodium and alcohol,8 and with zinc dust and mineral acids.9 Hydrocinnamic acid has been converted to the azide and thence by the Curtius rearrangement to /3-phenyl-ethylamine 10 also the Hofmann degradation of hydrocinnamide has been used successfully.11 /3-Nitrostyrene,12 phenylthioaceta-mide,13 and the benzoyl derivative of mandelonitrile 14 all yield /3-phenylethylamine upon reduction. The amine has also been prepared by cleavage of N- (/3-phenylethyl) -phthalimide 15 with hydrazine by the Delepine synthesis from /3-phenylethyl iodide and hexamethylenetetramine 16 by the hydrolysis of the corre-... 

Gates and Malchick utilized the Beckmann rearrangement for their purposes (Scheme 24).217) When the Hofmann degradation of 142 and 143, followed by catalytic dehydrogenation over 5 % palladium on asbestos at 300—310 °C, afforded not 1-vinylpentalene but azulene, the workers concluded that the former was thermodynamically unstable relative to the latter. 

A number of methods involve the rearrangement of carboxylic acid derivatives via nitrenes. The best known of these is the Hofmann degradation of amides. This involves treating an amide with bromine and alkali. The A-bromo compound undergoes an a-elimination in the presence... 

Hofmann degradation, styrene 468 was formed. Epoxidation of 468 with m-chloroperbenzoic acid from the less hindered side and lithium aluminum hydride reduction gave ( )-epicorynoline (469). Moreover, slow addition of the a-methoxystyrene 471 to isoquinolinium salt 470 gave cycloadduct 472 in 90% yield. The adduct was hydrolyzed by acid and the resultant aldehyde oxidized to naphthoic acid by Jones oxidation. Modified Curtius rearrangement of 473 with added benzyl alcohol afforded benzyl urethane 474, which was reduced by lithium aluminum hydride and formylated with chloral to give 0-methylarnottiamide (475) (Scheme 60). 

Conversion of acid derivatives into amines with the loss of the carbonyl group can be done in i.-ious ways. In Chapter 40 we recommended either the Curtius rearrangement or the Hofmann tejradation (p. 1073). The Hofmann degradation is easier starting with an ester. We convert into . imide with ammonia and treat with bromine in basic solution. The N-bromo derivative forms a afcene by a-elimination that rearranges to an isocyanate. 

The strongest support for the mechanism just outlined is the fact that many of the proposed intermediates have been isolated, and that these intermediates have been shown to yield the products of the Hofmann degradation. The mechanism is also supported by the fact that analogous mechanisms account satisfactorily for observations made on a large number of related rearrangements. Furthermore, the actual rearrangement step fits the broad pattern of 1,2-shifts to electron-deficient atoms. 

Problem 28.3 Many years before the Hofmann degradation of optically active a-phenylpropionamide was studied, the following observations were made when the ( ciopentane derivative II, in which the —COOH and —CONH groups are cis to each other, was treated with hypobromite, compound HI was obtained compound 111 could be converted by heat into the amide IV (called a lactam). W t do these results show about the mechanism of the rearrangement Use models.)... 

We should be clear about what the question is here. It is not whether some groups migrate faster than others—there is little doubt about that—but whether the rate of rearrangement affects the overall rate—the measured rate—of the Hofmann degradation. 

It is likely, then, that electron-releasing substituents speed up Hofmann degradation by speeding up rearrangement. Now, under what conditions can this happen Consider the sequence (3) and (4). Loss of bromide ion (3) could be fast... 

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