Hydroamination
In
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Prototypical intermolecular hydroamination reactions.
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Examples of intramolecular hydroamination.
History
Hydroamination is well-established technology for generating fragrances from
Reaction scope
Hydroamination has been examined with a variety of amines, unsaturated substrates, and vastly different catalysts. Amines that have been investigated span a wide scope including primary, secondary, cyclic, acyclic, and anilines with diverse steric and electronic substituents. The unsaturated substrates that have been investigated include alkenes, dienes, alkynes, and allenes. For intramolecular hydroamination, various aminoalkenes have been examined.[11]
Products
Addition across the unsaturated carbon-carbon bond can be
Catalysts and catalytic cycle
Hydroamination reactions are
However, hydroamination reactions pose some tough challenges for catalysis: Strong electron repulsion of the nitrogen atom
Catalysts
Many metal-ligand combinations have been reported to catalyze hydroamination, including main group elements including alkali metals such as
Catalytic cycles
The mechanism of metal-catalyzed hydroamination has been well studied.[11] Particularly well studied is the organolanthanide catalyzed intramolecular hydroamination of alkenes.[23] First, the catalyst is activated by amide exchange, generating the active catalyst (i). Next, the alkene inserts into the Ln-N bond (ii).[24] Finally, protonolysis occurs generating the cyclized product while also regenerating the active catalyst (iii). Although this mechanism depicts the use of a lanthanide catalyst, it is the basis for rare-earth, actinide, and alkali metal based catalysts.
Late transition metal hydroamination catalysts have multiple models based on the regioselective determining step. The four main categories are (1) nucleophilic attack on an alkene alkyne, or allyl ligand and (2) insertion of the alkene into the metal-amide bond.[11] Generic catalytic cycles appear below. Mechanisms are supported by rate studies, isotopic labeling, and trapping of the proposed intermediates.
Thermodynamics and kinetics
The hydroamination reaction is approximately thermochemically neutral. The reaction however suffers from a high activation barrier, perhaps owing to the repulsion of the electron-rich substrate and the amine nucleophile. The intermolecular reaction also is accompanied by highly negative changing entropy, making it unfavorable at higher temperatures.
[14][15] Consequently, catalysts are necessary for this reaction to proceed.[3][11] As usual in chemistry, intramolecular processes occur at faster rates than intermolecular versions.
Thermodynamic vs kinetic product
In general, most hydroamination catalysts require elevated temperatures to function efficiently, and as such, only the
Base catalyzed hydroamination
Strong
Such base catalyzed reactions proceed well with ethene but higher alkenes are less reactive.
Hydroamination catalyzed by group (IV) complexes
Certain
Formal hydroamination
The addition of hydrogen and an amino group (NR2) using reagents other than the amine HNR2 is known as a "formal hydroamination" reaction. Although the advantages of atom economy and/or ready available of the nitrogen source are diminished as a result, the greater thermodynamic driving force, as well as ability to tune the aminating reagent are potentially useful. In place of the amine, hydroxylamine esters[28] and nitroarenes[29] have been reported as nitrogen sources.
Applications
Hydroamination could find applications due to the valuable nature of the resulting amine, as well as the greenness of the process. Functionalized allylamines, which can be produced through hydroamination, have extensive pharmaceutical application, although presently such species are not prepared by hydroamination. Hydroamination has been utilized to synthesize the allylamine Cinnarizine in quantitative yield. Cinnarizine treats both vertigo and motion sickness related nausea.[26]
Hydroamination is also promising for the synthesis of alkaloids. An example was the hydroamination step used in the total synthesis of (-)-epimyrtine.[30]
See also
- nitriles
- Hydroboration
- Hydrosilylation
- (Olefin) Hydration
- Hydrofunctionalization
References
This article incorporates text by David Michael Barber available under the CC BY 2.5 license.
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