Oxidation of Amines The Cope Elimination

Primary amines are oxidized in the body by monoamine oxidase (MAO). MAO converts the amine to an imine, which is hydrolyzed to yield an aldehyde and ammonia. One function of MAO is to regulate the levels of the neurotransmitters serotonin and norepinephrine. Monoamine oxidase inhibitors prevent the oxidation (and inactivation) of these neurotransmitters. thereby elevating mood. MAO inhibitors were the first antidepressants, but they are used sparingly now because of numerous side effects. 

Amines are notoriously easy to oxidize, and oxidation is often a side reaction in amine syntheses. Amines also oxidize during storage in contact with the air. Preventing air oxidation is one of the reasons for converting amines to their salts for storage or use as medicines. 

The following partial structures show some of the bonding and oxidation states of amines  

Depending on their specific structures, these states are generally more oxidized as you go from left to right. (Note the increasing number of bonds to oxygen.) 

Secondary amines are easily oxidized to hydroxylamines. Side products are often formed, however, and the yields may be low. The mechanisms of amine oxidations are not well characterized, partly because many reaction paths (especially those involving free radicals) are available. 

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Amines as Leaving Groups The Hofmann Elimination 904 Mechanism 19-4 Hofmann Elimination 904 19-15 Oxidation of Amines The Cope Elimination 907... 

Amine oxides 2, which can be prepared by oxidation of amines 1, react upon heating to yield an olefin 3 and a hydroxylamine 4. This reaction is called the Cope elimination reaction,and as a synthetic method is a valuable alternative to the Hofmann degradation reaction of quaternary ammonium salts. 

The second step involves a syi elimination similar to the Cope elimination of amine oxides. 

J. K. Crandall, M. Apparu, Base-Promoted Isomerizations of Epoxides, Org. React. 1983, 29, 345—443. A. C. Cope, E. R. Trumbull, Olefins from Amines The Hofmann Elimination Reaction and Amine Oxide Pyrolysis, Org. React. 1960, 11, 317-493. 

Mechanism 19-5 The Cope Elimination of an Amine Oxide 908 19-16 Reactions of Amines with Nitrous Acid 910... 

Sinee the Cope elimination reaetion of amine oxides proeeeds with intramoleeular proton abstraction by the A -oxide group aeeording to Eq. (5-122), it is not surprising that with dimethyl sulfoxide as solvent the reaetion oeeurs at room temperature [328, 331]. Pro tie solvents require temperatures of 120 to 150 °C beeause hydrogen bonding of the oxygen terminal makes the reaetion more diffieult. 

Pyrolysis of Amine Oxides The Cope Elimination Reaction ... 

Amine oxides are derived from oxidation of ieri-amines with peroxyacids or hydrogen peroxide. In the Cope elimination, the negatively charged oxygen acts as a base in accepting a (3-hydrogen atom via a syn transition state. 

The Cope elimination has been used to synthesize a variety of acyclic alkenes. 1,2-Disubstituted acyclic alkenes are usually obtained with the ( )-stereochemistry because of steric hindrance to (Z)-alkene formation. The stereochemistry of trisubstituted alkenes is determined by the configuration of the starting amine oxide and is not usually affected by subsequent isomerization. ... 

Normally the Cope elimination is carried out by thermolysis of the amine oxide under reduced pressure with removal of the alkene as it is formed. However, if carried out in a closed system, secondary products can be formed by oxidation of the /V,/V-dialkylhydroxylamine by unchanged amine oxide to form a nitrone, which then adds to the alkene (Scheme 1). ... 

In their search for conformationally biased mimics of mannopyranosylamines, A. Vasella and co-workers planned to synthesize compounds that would inhibit p-mannosidases. In order to construct the bicyclo[3.1.0]hexane framework, a five-membered 0-silylated A/,A/-dimethyl-amino alcohol was synthesized. Oxidation of the tertiary amine with mCPBA yielded 83% of the A/-oxide, which was subsequently subjected to the Cope elimination to give 69% of the desired benzyl enol ether. Cyclopropanation of this enol ether gave rise to the highly functionalized bicyclic skeleton. 

In the Cope elimination, thirty percent hydrogen peroxide, H202, is used to produce an amine oxide, which upon heating undergoes elimination. This is a syn-elimination process. Figure 13-45 illustrates the general reaction, while Figure 13-46 shows the mechanism of the syn-elimination step. 

Pyrolysis of the oxide of tertiary amine 1 yields olefin 2 and hydroxylamine 3. This olefination method is known as the Cope elimination reaction.1-3... 

As an alternative to an olefination method, the Cope elimination can be used as a preparative method for unsymmetrical hydroxylamines. Addition of unsymmetrical secondary amine 41 to a,p-unsaturated compounds gave access to compound 42, which underwent oxidation and Cope elimination to yield the unsymmetrical hydroxylamine product 44.16... 

The initial product 2 loses N2 in a retro-DiELS-Alder reaction forming the 3,4-dihydropyridine 3, which aromatizes giving the pyridine derivative 4 by elimination of amine or alcohol. The geometry of the transition state of this [4+2] cycloaddition with inverse electron demand follows from the reaction of 3- or 6-phenyl-1,2,4-triazine 5 or 8 with enamines of cyclopentanone. It is apparently influenced by the secondary orbital interaction between the amino and phenyl groups. 3-Phenyl-1,2,4-triazine 5 favours the transition state 11. It leads first to the 3,4-dihydropyridine 6 which, on oxidation followed by a Cope elimination, affords the 2-phenyldihydrocyclopenta[c]pyridine 7. However, 6-phenyl-1,2,4-triazine 8 favours the transition state 12 leading to 3,4-dihydropyridine 9. Elimination of amine yields 5 -phenyldihydrocyclopenta[c]pyridine 10 ... 

Pyrolysis of tertiary amine oxides (the Cope elimination reaction) also offers relatively mild reaction conditions (100-200 °C). Oxidation of the tertiary amine... 

The oxidation of a range of /3-cyanoethyl tertiary amines with m-CPBA gives the corresponding (V-oxides which can undergo Cope-elimination to give secondary hydroxylamines in high yields (eq 54).i 4... 

This conclusion was supported by the observation that pyrolysis of 3-butenol has a AS of —8.8 eu, which is similar to the activation entropy values reported for pyrolysis of ethyl formate and for 3-butenoic acid, and the activation energies for all three pyrolyses are also similar (about 40 kcal/mol). Another well-known concerted syn elimination is the Cope elimination, which involves the thermal elimination of an alkene from an amine oxide (Figure 10.53). Unlike the reactions discussed above, all of which have... 

Di-7V-substituted hydroxylamines may be prepared from tertiary amine oxides using the Cope elimination, provided one of the iV-substituents has a p-hydrogen. 

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