Carbinolamine rearrangements

The mechanism of the indolization of aniline 5 with methylthio-2-propanone 6 is illustrated below. Aniline 5 reacts with f-BuOCl to provide A-chloroaniline 9. This chloroaniline 9 reacts with sulfide 6 to yield azasulfonium salt 10. Deprotonation of the carbon atom adjacent to the sulfur provides the ylide 11. Intramolecular attack of the nucleophilic portion of the ylide 11 in a Sommelet-Hauser type rearrangement produces 12. Proton transfer and re-aromatization leads to 13 after which intramolecular addition of the amine to the carbonyl function generates the carbinolamine 14. Dehydration of 14 by prototropic rearrangement eventually furnishes the indole 8. 

Phenylalanine is hydroxylated to tyrosine and then sequentially to 4-hydroxyphenyl-pyruvate and by dioxygenation and rearrangement to 2,5-dihydroxyphenylpyruvate (Figure 3.16) (Arias-Barrau et al. 2004). Hydroxylation involves 6,7-dimethyltetrahydro-biopterin that is converted into the 4a-carbinolamine (Song et al. 1999). Copper is not a component of the active enzyme, although there is some disagreement on whether or not Fe is involved in the reaction for the hydroxylase from Chromobacterium violaceum (Chen and Frey 1998). 

It has been established that in the Dimroth rearrangement of 2-imino-pyrimidines, water plays an essential role (65JCS7071). In water the imine is, in fact, in equilibrium with its hydrate, the carbinolamine 39. That participation of the hydrate is important is shown by the experimental fact that in dry tetrahydrofuran, acetone, dioxane, or ether, the imine is quite stable and is not inclined to undergo rearrangement. However, on addition of a little water, rearrangement occurs its rate is proportional to the concentration of the water (65JCS7071). 

Deamination. Amine groups can be removed oxidatively via a deamination reaction, which may be catalyzed by cytochromes P-450. Other enzymes, such as monoamine oxidases, may also be involved in deamination reactions (see below). The product of deamination of a primary amine is the corresponding ketone. For example, amphetamine is metabolized in the rabbit to phenylacetone (Fig. 4.27). The mechanism probably involves oxidation of the carbon atom to yield a carbinolamine, which can rearrange to the ketone with loss of ammonia. Alternatively, the reaction may proceed via phenylacetoneoxime, which has been isolated as a metabolite and for which there are several possible routes of formation. The phenylacetoneoxime is hydrolyzed to phenylacetone. Also N-hydroxylation of amphetamine may take place and give rise to phenylacetone as a metabolite. This illustrates that there may be several routes to a particular metabolite. 

The secondary base (15) has been shown to react with formaldehyde and hydrochloric acid, with loss of bromine and rearrangement to the carbinolamine... 

The Canadian chemists (135) speculated that delnudine may be bio-genetically derived from hetisine (125) by the concerted rearrangement portrayed by the arrows in structure 125 and by introduction of the carbinolamine moiety. 

The limited amount of experimental work that has been carried out recently on akuammine shows that its behavior is exactly analogous to that of pseudoakuammigine (49). Thus, the UV-spectrum of 0-methyl-akuammine in neutral and in dilute acid solution is typical of an indoline derivative a marked bathochromic shift is observed in concentrated hydrochloric acid, and the spectrum is now characteristic of the 3-H-indolium ion. The recovery of O-methylakuammine from this solution shows that no rearrangement of the molecule has occurred, and suggests further that the readily reformed carbinolamine ether ring is five- or six-membered. 

Hofmann rearrangement (the mechanism is shown in Section 24.6) of an a-hydroxy amide produces a carbinolamine intermediate that expels ammonia to give an aldehyde. 

The delnudine structure (8) represents a new skeletal variant. It was suggested that it arises in the plant by rearrangement of hetisine (150) -> (151) followed by oxidation to the carbinolamine. 

Tert-Amines - sec-amines.1 When a tertiary amine in pyridine is shaken with 2-nitropropane and CuCl under oxygen, it is converted into a nitrosamine (5), which can be isolated in yields of 15-65% and then reduced to a secondary amine. The reaction proceeds through oxidation to an amine oxide (2) with conversion of (1) into 2-nitro-2-propanol (3). This decomposes into acetone and nitrous acid. The nitrous acid traps the secondary amine formed from the amine oxide (2) after rearrangement to the carbinolamine (4). It is noteworthy that even... 

Fawcettimine-type alkaloids possess a CisNi skeleton and are considered to be derived from the lycopodine skeleton (Scheme 2). Initially, the nucleophilic attack of water on C-13 of the lycopodine skeleton, followed by C-13-N bond scission, would occur. Next, the Wagner-Meerwein rearrangement would proceed to form the fawcettimine skeleton. Fawcettimine (11) exists as an equilibrium mixture of the carbinolamine form and the keto-amine form. A number of fawcettimine-type alkaloids derived from each form have been isolated from nature. 

In some cases the stoichiometry is less obvious because of rearrangements of the product (carbinolamines in N-dealkylation) or variations on the general mechanism (desaturations). 

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