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In organic chemistry, hydroamination is the addition of an N−H bond of an amine across a carbon-carbon multiple bond of an alkene, alkyne, diene, or allene.^[1] In the ideal case, hydroamination is atom economical and green.^[2] Amines are common in fine-chemical, pharmaceutical, and agricultural industries.^[3]^[4]^[5]^[6] Hydroamination can be used intramolecularly to create heterocycles or intermolecularly with a separate amine and unsaturated compound. The development of catalysts for hydroamination remains an active area, especially for alkenes. Although practical hydroamination reactions can be effected for dienes and electrophilic alkenes, the term hydroamination often implies reactions metal-catalyzed processes.

Prototypical intermolecular hydroamination reactions.
Examples of intramolecular hydroamination.

History

Hydroamination is well-established technology for generating fragrances from myrcene. In this conversion, diethylamine adds across the diene substituent, the reaction being catalyzed by lithium diethylamide.^[7] Intramolecular hydroaminations were reported by Tobin J. Marks in 1989 using metallocene derived from rare-earth metals such as lanthanum, lutetium, and samarium. Catalytic rates correlated inversely with the ionic radius of the metal, perhaps as a consequence of steric interference from the ligands.^[8] In 1992, Marks developed the first chiral hydroamination catalysts by using a chiral auxiliary, which were the first hydroamination catalysts to favor only one specific stereoisomer. Chiral auxiliaries on the metallocene ligands were used to dictate the stereochemistry of the product.^[9] The first non-metallocene chiral catalysts were reported in 2003, and used bisarylamido and aminophenolate ligands to give higher enantioselectivity.^[10]

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 Markovnikov or anti-Markovnikov depending on the catalyst.^[12] When considering the possibly of R/S chirality, four products can be obtained: Markovnikov with R or S and anti-Markovnikov addition with R or S. Although there have been many reports of catalytic hydroamination with a wide range of metals, there are far fewer describing enantioselective catalysis to selectively make one of the four possible products. Recently, there have been reports of selectively making the thermodynamic or kinetic product, which can be related to the racemic Markovnikov or anti-Markovnikov structures (see Thermodynamic and Kinetic Product below).

Catalysts and catalytic cycle

Hydroamination reactions are atom-efficient processes that generally use readily available and cheap starting materials, therefore a general catalytic strategy is highly desirable. Also, direct catalytic hydroamination strategies have in principle significant benefits over more classical methods to prepare amine containing compounds, including the reduction in the number of synthetic steps required.

^[13]

However, hydroamination reactions pose some tough challenges for catalysis: Strong electron repulsion of the nitrogen atom lone pair and the electron rich carbon-carbon multiple bond, coupled with hydroamination reactions being entropically disfavoured (particularly the intermolecular version),^[14]^[15] results in a large reaction barrier. Regioselectivity issues also hamper the synthetic utility of the resulting products, with Markovnikov addition of the amine being the most common outcome over the less favoured anti-Markovnikov addition (see figure). As a result, there are now numerous catalysts that can be utilised in the hydroamination of alkene, allene and alkyne substrates, including various metal based heterogeneous catalysts, early-transition metal complexes (e.g. titanium and zirconium), late-transition metal complexes (e.g. ruthenium and palladium), lanthanide and actinide complexes (e.g. samarium and lanthanum), as well as Brønsted acids and bases.^[16]^[17]^[18]

Catalysts

Many metal-ligand combinations have been reported to catalyze hydroamination, including main group elements including alkali metals such as lithium,^[11] group 2 metals such as calcium,^[19] as well as group 3 metals such as aluminum,^[20] indium,^[21] and bismuth.^[22] In addition to these main group examples, extensive research has been conducted on the transition metals with reports of early, mid, and late metals, as well as first, second, and third row elements. Finally the lanthanides have been thoroughly investigated. Zeolites have also shown utility in hydroamination.^[11]

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 thermodynamic product is observed. The isolation and characterization of the rarer and more synthetically valuable kinetic allyl amine product was reported when allenes was used at the unsaturated substrate. One system utilized temperatures of 80 °C with a rhodium catalyst and aniline derivatives as the amine.^[25] The other reported system utilized a palladium catalyst at room temperature with a wide range of primary and secondary cyclic and acyclic amines.^[26] Both systems produced the desired allyl amines in high yield, which contain an alkene that can be further functionalized through traditional organic reactions.

Base catalyzed hydroamination

Strong bases catalyze hydroamination, an example being the ethylation of piperidine using ethene:^[27]

Hydroamination of ethene with piperidine proceeds with no transition metal catalyst, but requires a strong base.

Such base catalyzed reactions proceed well with ethene but higher alkenes are less reactive.

Hydroamination catalyzed by group (IV) complexes

Certain titanium and zirconium complexes catalyze intermolecular hydroamination of alkynes and allenes.^[3] Both stoichiometric and catalytic variants were initially examined with zirconocene bis(amido) complexes. Titanocene amido and sulfonamido complexes catalyze the intra-molecular hydroamination of aminoalkenes via a [2+2] cycloaddition that forms the corresponding azametallacyclobutane, as illustrated in the figure below. Subsequent protonolysis by incoming substrate gives the α-vinyl-pyrrolidine (1) or tetrahydropyridine (2) product. Experimental and theoretical evidence support the proposed imido intermediate and mechanism with neutral group IV catalysts.

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]

References

This article incorporates text by David Michael Barber available under the CC BY 2.5 license.

^ Togni, Antionio; Grützmacher, Hansjörg (2001). Catalytic heterofunctionalization: from hydroanimation to hydrozirconation (1. ed.). Weinheim: Wiley-VCH. doi:10.1002/3527600159. ISBN 978-3527302345.
^ Beller, M.; Bolm, C. (2004). Transition metals for organic synthesis : building blocks and fine chemicals (2nd ed.). Weinheim: Wiley-VCH. doi:10.1002/9783527619405. ISBN 9783527306138.
^ ^a ^b ^c Reznichenko, A. L.; Hultszch, K. C. (2015). Hydroamination of Alkenes. Vol. 88. p. 1. doi:10.1002/0471264180.or088.01. ISBN 978-0471264187. {{cite book}}: |journal= ignored (help)
^ Hultzsch, Kai C. (2005). "Catalytic asymmetric hydroamination of non-activated olefins". Org. Biomol. Chem. (Review). 3 (10): 1819–1824. doi:10.1039/b418521h. PMID 15889160.
^ Hartwig, J. F. (2004). "Development of catalysts for the hydroamination of olefins" (PDF). Pure Appl. Chem. 76 (3): 507–516. doi:10.1351/pac200476030507. S2CID 29945266.
^ Pohlki, F.; Doye, S. (2003). "The catalytic hydroamination of alkynes". Chem. Soc. Rev. 32 (2): 104–114. doi:10.1039/b200386b. PMID 12683107.
^ Takabe, K.; Katahiri, T.; Tanaka, J.; Fujita, T.; Watanabe, S.; Suga, K. (1989). "Addition Of Dialkylamines To Myrcene: N,N-diethylgeranylamine". Org. Synth. 67: 44. doi:10.15227/orgsyn.067.0044.
^ Gagné, M.R.; Marks, T.J. (1989). "Organolanthanide-catalyzed hydroamination. Facile, regiospecific cyclization of unprotected amino olefins". J. Am. Chem. Soc. 111 (11): 4108. doi:10.1021/ja00193a056.
^ Gagné, M.R.; Brard, L.; Conticello, V.P.; Giardello, M.A.; Marks, T.J.; Stern, C.L. (1992). "Stereoselection effects in the catalytic hydroamination/cyclization of amino olefins at chiral organolanthanide centers". Organometallics. 11 (6): 2003. doi:10.1021/om00042a012.
^ O'Shaughnessy, P.N.; Scott, P. (2003). "Biaryl amine ligands for lanthanide catalysed enantioselective hydroamination/cyclisation of aminoalkenes". Tetrahedron Asymmetry. 14 (14): 1979. doi:10.1016/s0957-4166(03)00429-4.
^ ^a ^b ^c ^d ^e ^f Müller, Thomas E.; Beller, Matthias (1998). "Metal-Initiated Amination of Alkenes and Alkynes". Chem. Rev. 98 (2): 675–704. doi:10.1021/cr960433d. PMID 11848912.
^ Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. (2004). "Catalytic Markovnikov and anti-Markovnikov Functionalization of Alkenes and Alkynes: Recent Developments and Trends". Angew. Chem. Int. Ed. 43 (26): 3368–3398. doi:10.1002/anie.200300616. PMID 15221826.
^ Salvatore, R.N.; Yoon, C.H.; Jung, K.W. (2001). "Synthesis of secondary amines". Tetrahedron. 57 (37): 7785–7811. doi:10.1016/S0040-4020(01)00722-0.
^ ^a ^b Brunet, J.-J.; Neibecker, D.; Niedercorn, F. (1989). "Functionalisation of alkenes: catalytic amination of monoolefins". J. Mol. Catal. 49 (3): 235–259. doi:10.1016/0304-5102(89)85015-1.
^ ^a ^b Johns, A.M.; Sakai, N.; Ridder, A.; Hartwig, J.F. (2006). "Direct Measurement of the Thermodynamics of Vinylarene Hydroamination". J. Am. Chem. Soc. 128 (29): 9306–9307. doi:10.1021/ja062773e. PMID 16848446.
^ Müller, T.E.; Hultzsch, K.C.; Yus, M.; Foubelo, F.; Tada, M. (2008). "Hydroamination: Direct Addition of Amines to Alkenes and Alkynes". Chem. Rev. 108 (9): 3795–3892. doi:10.1021/cr0306788. ISSN 0009-2665. PMID 18729420.
^ Alonso, F.; Beletskaya, I.P.; Yus, M. (2004). "Transition-Metal-Catalyzed Addition of Heteroatom−Hydrogen Bonds to Alkynes". Chem. Rev. 104 (6): 3079–3160. doi:10.1021/cr0201068. ISSN 0009-2665. PMID 15186189.
^ Aillaud, I.; Collin, J.; Hannedouche, J.; Schulz, E. (2007). "Asymmetric hydroamination of non-activated carbon–carbon multiple bonds". Dalton Trans. (44): 5105–5118. doi:10.1039/b711126f. ISSN 1477-9226. PMID 17985016.
^ Crimmin, M.R.; Casely, I.J.; Hill, M.S. (2005). "Calcium-Mediated Intramolecular Hydroamination Catalysis". J. Am. Chem. Soc. 127 (7): 2042–2043. doi:10.1021/ja043576n. PMID 15713071.
^ Koller, J.; Bergman, R.G. (2010). "Highly Efficient Aluminum-Catalyzed Hydro-amination/-hydrazination of Carbodiimides". Organometallics. 29 (22): 5946–5952. doi:10.1021/om100735q.
^ Sarma, R.; Prajapati, D. (2011). "Indium catalyzed tandem hydroamination/hydroalkylation of terminal alkynes". Chem. Commun. 47 (33): 9525–7. doi:10.1039/c1cc13486h. PMID 21776504.
^ Komeyama, K.; Kouya, Y.; Ohama, Y.; Takaki, K. (2011). "Tandem ene-reaction/hydroamination of amino-olefin and -allene compounds catalyzed by Bi(OTf)₃". Chem. Commun. 47 (17): 5031–5033. doi:10.1039/c0cc05258b. PMID 21423974.
^ Hong, S.; Marks, T.J. (2004). "Organolanthanide-Catalyzed Hydroamination". Acc. Chem. Res. 37 (9): 673–686. doi:10.1021/ar040051r. PMID 15379583.
^ Crabtree, Robert H. (2005). The organometallic chemistry of the transition metals (4th ed.). Hoboken, N.J.: John Wiley. ISBN 978-0-471-66256-3.
^ Cooke, M.L.; Xu, K.; Breit, B. (2012). "Enantioselective Rhodium-Catalyzed Synthesis of Branched Allylic Amines by Intermolecular Hydroamination of Terminal Allenes". Angew. Chem. Int. Ed. 51 (43): 10876–10879. doi:10.1002/anie.201206594. PMID 23011801.
^ ^a ^b Beck, J.F.; Samblanet, D.C.; Schmidt, J.A.R. (2013). "Palladium catalyzed intermolecular hydroamination of 1-substituted allenes: an atom-economical method for the synthesis of N-allylamines". RSC Adv. 3 (43): 20708–20718. Bibcode:2013RSCAd...320708B. doi:10.1039/c3ra43870h.
^ Wollensak, J.; Closson, R.D. (1963). "N-Ethylpiperidine". Org. Synth. 43: 45. doi:10.15227/orgsyn.043.0045.
^ Miki, Y.; Hirano, K.; Satoh, T.; Miura, M. (2013). "Copper-Catalyzed Intermolecular Regioselective Hydroamination of Styrenes with Polymethylhydrosiloxane and Hydroxylamines". Angew. Chem. Int. Ed. 52 (41): 10830–10834. doi:10.1002/anie.201304365. ISSN 1521-3773. PMID 24038866.
^ Gui, J.; Pan, C.-M.; Jin, Y.; Qin, T.; Lo, J.C.; Lee, B.J.; Spergel, S.H.; Mertzman, M.E.; Pitts, W.J. (2015). "Practical olefin hydroamination with nitroarenes". Science. 348 (6237): 886–891. Bibcode:2015Sci...348..886G. doi:10.1126/science.aab0245. ISSN 0036-8075. PMID 25999503.
^ ^a ^b Trinh, T.T.H.; Nguyen, K.H.; Amaral, P. de A.; Gouault, N. (2013). "Total synthesis of (−)-epimyrtine by a gold-catalyzed hydroamination approach". Beilstein J. Org. Chem. 9: 2042–2047. doi:10.3762/bjoc.9.242. PMC 3817515. PMID 24204417.

[Togni-2001-1] Togni, Antionio; Grützmacher, Hansjörg (2001). Catalytic heterofunctionalization: from hydroanimation to hydrozirconation (1. ed.). Weinheim: Wiley-VCH. doi:10.1002/3527600159. ISBN 978-3527302345.

[Beller-2004-2] Beller, M.; Bolm, C. (2004). Transition metals for organic synthesis : building blocks and fine chemicals (2nd ed.). Weinheim: Wiley-VCH. doi:10.1002/9783527619405. ISBN 9783527306138.

[jain-3] Reznichenko, A. L.; Hultszch, K. C. (2015). Hydroamination of Alkenes. Vol. 88. p. 1. doi:10.1002/0471264180.or088.01. ISBN 978-0471264187. {{cite book}}: |journal= ignored (help)

[4] Hultzsch, Kai C. (2005). "Catalytic asymmetric hydroamination of non-activated olefins". Org. Biomol. Chem. (Review). 3 (10): 1819–1824. doi:10.1039/b418521h. PMID 15889160.

[5] Hartwig, J. F. (2004). "Development of catalysts for the hydroamination of olefins" (PDF). Pure Appl. Chem. 76 (3): 507–516. doi:10.1351/pac200476030507. S2CID 29945266.

[Pohlki-2003-6] Pohlki, F.; Doye, S. (2003). "The catalytic hydroamination of alkynes". Chem. Soc. Rev. 32 (2): 104–114. doi:10.1039/b200386b. PMID 12683107.

[Takabe-1989-7] Takabe, K.; Katahiri, T.; Tanaka, J.; Fujita, T.; Watanabe, S.; Suga, K. (1989). "Addition Of Dialkylamines To Myrcene: N,N-diethylgeranylamine". Org. Synth. 67: 44. doi:10.15227/orgsyn.067.0044.

[Gagne-1989-8] Gagné, M.R.; Marks, T.J. (1989). "Organolanthanide-catalyzed hydroamination. Facile, regiospecific cyclization of unprotected amino olefins". J. Am. Chem. Soc. 111 (11): 4108. doi:10.1021/ja00193a056.

[Gagne-1992-9] Gagné, M.R.; Brard, L.; Conticello, V.P.; Giardello, M.A.; Marks, T.J.; Stern, C.L. (1992). "Stereoselection effects in the catalytic hydroamination/cyclization of amino olefins at chiral organolanthanide centers". Organometallics. 11 (6): 2003. doi:10.1021/om00042a012.

[OShaughnessy-2003-10] O'Shaughnessy, P.N.; Scott, P. (2003). "Biaryl amine ligands for lanthanide catalysed enantioselective hydroamination/cyclisation of aminoalkenes". Tetrahedron Asymmetry. 14 (14): 1979. doi:10.1016/s0957-4166(03)00429-4.

[Muller-1998-11] ^ ^a ^b ^c ^d ^e ^f Müller, Thomas E.; Beller, Matthias (1998). "Metal-Initiated Amination of Alkenes and Alkynes". Chem. Rev. 98 (2): 675–704. doi:10.1021/cr960433d. PMID 11848912.

[Beller-AngewChemIntEd-2004-12] Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. (2004). "Catalytic Markovnikov and anti-Markovnikov Functionalization of Alkenes and Alkynes: Recent Developments and Trends". Angew. Chem. Int. Ed. 43 (26): 3368–3398. doi:10.1002/anie.200300616. PMID 15221826.

[Salvatore-2001-13] Salvatore, R.N.; Yoon, C.H.; Jung, K.W. (2001). "Synthesis of secondary amines". Tetrahedron. 57 (37): 7785–7811. doi:10.1016/S0040-4020(01)00722-0.

[Brunet-1989-14] Brunet, J.-J.; Neibecker, D.; Niedercorn, F. (1989). "Functionalisation of alkenes: catalytic amination of monoolefins". J. Mol. Catal. 49 (3): 235–259. doi:10.1016/0304-5102(89)85015-1.

[Johns-2006-15] Johns, A.M.; Sakai, N.; Ridder, A.; Hartwig, J.F. (2006). "Direct Measurement of the Thermodynamics of Vinylarene Hydroamination". J. Am. Chem. Soc. 128 (29): 9306–9307. doi:10.1021/ja062773e. PMID 16848446.

[Muller-2008-16] Müller, T.E.; Hultzsch, K.C.; Yus, M.; Foubelo, F.; Tada, M. (2008). "Hydroamination: Direct Addition of Amines to Alkenes and Alkynes". Chem. Rev. 108 (9): 3795–3892. doi:10.1021/cr0306788. ISSN 0009-2665. PMID 18729420.

[Alonso-2004-17] Alonso, F.; Beletskaya, I.P.; Yus, M. (2004). "Transition-Metal-Catalyzed Addition of Heteroatom−Hydrogen Bonds to Alkynes". Chem. Rev. 104 (6): 3079–3160. doi:10.1021/cr0201068. ISSN 0009-2665. PMID 15186189.

[Aillaud-2007-18] Aillaud, I.; Collin, J.; Hannedouche, J.; Schulz, E. (2007). "Asymmetric hydroamination of non-activated carbon–carbon multiple bonds". Dalton Trans. (44): 5105–5118. doi:10.1039/b711126f. ISSN 1477-9226. PMID 17985016.

[Crimmin-2005-19] Crimmin, M.R.; Casely, I.J.; Hill, M.S. (2005). "Calcium-Mediated Intramolecular Hydroamination Catalysis". J. Am. Chem. Soc. 127 (7): 2042–2043. doi:10.1021/ja043576n. PMID 15713071.

[Koller-2010-20] Koller, J.; Bergman, R.G. (2010). "Highly Efficient Aluminum-Catalyzed Hydro-amination/-hydrazination of Carbodiimides". Organometallics. 29 (22): 5946–5952. doi:10.1021/om100735q.

[Sarma-2011-21] Sarma, R.; Prajapati, D. (2011). "Indium catalyzed tandem hydroamination/hydroalkylation of terminal alkynes". Chem. Commun. 47 (33): 9525–7. doi:10.1039/c1cc13486h. PMID 21776504.

[Komeyama-2011-22] Komeyama, K.; Kouya, Y.; Ohama, Y.; Takaki, K. (2011). "Tandem ene-reaction/hydroamination of amino-olefin and -allene compounds catalyzed by Bi(OTf)₃". Chem. Commun. 47 (17): 5031–5033. doi:10.1039/c0cc05258b. PMID 21423974.

[Hong-2004-23] Hong, S.; Marks, T.J. (2004). "Organolanthanide-Catalyzed Hydroamination". Acc. Chem. Res. 37 (9): 673–686. doi:10.1021/ar040051r. PMID 15379583.

[Crabtree-2005-24] Crabtree, Robert H. (2005). The organometallic chemistry of the transition metals (4th ed.). Hoboken, N.J.: John Wiley. ISBN 978-0-471-66256-3.

[Cooke-2012-25] Cooke, M.L.; Xu, K.; Breit, B. (2012). "Enantioselective Rhodium-Catalyzed Synthesis of Branched Allylic Amines by Intermolecular Hydroamination of Terminal Allenes". Angew. Chem. Int. Ed. 51 (43): 10876–10879. doi:10.1002/anie.201206594. PMID 23011801.

[Beck-2003-26] Beck, J.F.; Samblanet, D.C.; Schmidt, J.A.R. (2013). "Palladium catalyzed intermolecular hydroamination of 1-substituted allenes: an atom-economical method for the synthesis of N-allylamines". RSC Adv. 3 (43): 20708–20718. Bibcode:2013RSCAd...320708B. doi:10.1039/c3ra43870h.

[Wollensak-1973-27] Wollensak, J.; Closson, R.D. (1963). "N-Ethylpiperidine". Org. Synth. 43: 45. doi:10.15227/orgsyn.043.0045.

[Miki-2013-28] Miki, Y.; Hirano, K.; Satoh, T.; Miura, M. (2013). "Copper-Catalyzed Intermolecular Regioselective Hydroamination of Styrenes with Polymethylhydrosiloxane and Hydroxylamines". Angew. Chem. Int. Ed. 52 (41): 10830–10834. doi:10.1002/anie.201304365. ISSN 1521-3773. PMID 24038866.

[Gui-2015-29] Gui, J.; Pan, C.-M.; Jin, Y.; Qin, T.; Lo, J.C.; Lee, B.J.; Spergel, S.H.; Mertzman, M.E.; Pitts, W.J. (2015). "Practical olefin hydroamination with nitroarenes". Science. 348 (6237): 886–891. Bibcode:2015Sci...348..886G. doi:10.1126/science.aab0245. ISSN 0036-8075. PMID 25999503.

[Trinh-2013-30] Trinh, T.T.H.; Nguyen, K.H.; Amaral, P. de A.; Gouault, N. (2013). "Total synthesis of (−)-epimyrtine by a gold-catalyzed hydroamination approach". Beilstein J. Org. Chem. 9: 2042–2047. doi:10.3762/bjoc.9.242. PMC 3817515. PMID 24204417.

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+{{short description|1=Addition of an N–H group across a C=C or C≡C bond}}
-The '''hydroamination reaction''' is the addition an N-H bond across the C=C or C<u>=</u>C of an [[alkene]] or [[alkyne]]. This is a highly [[atom economy|atom economical]] method of preparing substituted amines that are attractive targets for organic synthesis and the pharmaceutical industry.
+In [[organic chemistry]], '''hydroamination''' is the [[Addition reaction|addition]] of an {{chem2|N\sH}} bond of an [[amine]] across a [[Carbon–carbon bond|carbon-carbon multiple bond]] of an [[alkene]], [[alkyne]], [[diene]], or [[allene]].<ref name=Togni-2001>{{cite book |last1=Togni |first1= Antionio |last2=Grützmacher |first2=Hansjörg |title=Catalytic heterofunctionalization: from hydroanimation to hydrozirconation |year=2001 |publisher=Wiley-VCH |location=Weinheim |isbn=978-3527302345 |edition=1. |doi=10.1002/3527600159}}</ref> In the ideal case, hydroamination is [[atom economy|atom economical]] and [[green chemistry|green]].<ref name=Beller-2004>{{cite book |last1=Beller |first1=M. |last2=Bolm |first2=C.|title=Transition metals for organic synthesis : building blocks and fine chemicals |year=2004 |publisher=Wiley-VCH |location=Weinheim |isbn=9783527306138| edition=2nd |doi=10.1002/9783527619405}}</ref> Amines are common in fine-chemical, pharmaceutical, and agricultural industries.<ref name="jain">{{cite book | last1 = Reznichenko | first1 = A. L. | last2 = Hultszch | first2 = K. C. | year = 2015 | title = Hydroamination of Alkenes |journal=[[Org. React.]] | volume = 88 | page = 1 | doi=10.1002/0471264180.or088.01| isbn = 978-0471264187}}</ref><ref>{{cite journal | first = Kai C. | last = Hultzsch | title =Catalytic asymmetric hydroamination of non-activated olefins | type = Review | journal = [[Org. Biomol. Chem.]] | year = 2005 | volume = 3 | pages = 1819–1824 | doi = 10.1039/b418521h | pmid = 15889160 | issue = 10}}</ref><ref>{{cite journal | author = Hartwig, J. F. | author-link = John F. Hartwig | url = http://www.iupac.org/publications/pac/2004/pdf/7603x0507.pdf | title = Development of catalysts for the hydroamination of olefins | journal = [[Pure Appl. Chem.]] | year = 2004 | volume = 76 | pages = 507–516 | doi = 10.1351/pac200476030507 | issue = 3| s2cid = 29945266 }}</ref><ref name=Pohlki-2003>{{cite journal |author1=Pohlki, F. |author2=Doye, S. |title=The catalytic hydroamination of alkynes |journal=[[Chem. Soc. Rev.]] |year=2003 |volume=32 |issue=2 |pages=104–114 |doi=10.1039/b200386b |pmid=12683107}}</ref> Hydroamination can be used [[intramolecular reaction|intramolecularly]] to create [[heterocyclic compounds|heterocycles]] or intermolecularly with a separate amine and [[unsaturated compound]]. The development of [[catalyst]]s for hydroamination remains an active area, especially for alkenes. Although practical hydroamination reactions can be effected for dienes and electrophilic alkenes, the term hydroamination often implies reactions metal-catalyzed processes.
-Despite substantial effort, the development of a general catalytic process for this reaction remains elusive. Progress has been reported on the hydroamination of alkynes and alkenes using [[lanthanide]]s and late [[transition metals]]. Although there have been many reports of the catalytic hydroamination reaction with group IV metals, there are far fewer describing [[enantioselective]] catalysis.
+<gallery heights=270 mode=packed>
-[[Titanium]] and [[zirconium]] complexes catalyze inter-molecular hydroamination of alkynes and allenes.  Both stoichiometric and catalytic variants were initially examined with zirconocene bis(amido) complexes. Titanocene amido and sulfonamido complexes catalyze the intra-molecular hydroamination of aminoalkenes via a [2+2] cycloaddition that forms the corresponding azametallacyclobutane, as illustrated in Figure 1. Subsequent protonolysis by incoming substrate gives the α-vinyl-pyrrolidine (1) or tetrahydropyridine (2) product.  There is substantial experimental and theoretical evidence for the proposed imido intermediate and mechanism with neutral group IV catalysts.
+File:Examples of intermolecular hydroamination.png|alt=Prototypical intermolecular hydroamination reactions.|Prototypical intermolecular hydroamination reactions.
+File:Examples of intramolecular hydroamination (2).png|alt=Examples of intramolecular hydroamination.|Examples of intramolecular hydroamination.
+</gallery>
+==History==
-[[Image:Wiki_fig_1.gif|thumb|center|600px|Figure 1.  The catalytic hydroamination of aminoallenes to form chiral α-vinyl-pyrrolidine (1) and tetrahydropyridine (2) products.  L<sub>2</sub> = Cp<sub>2</sub> or bis(amide).]]
+Hydroamination is well-established technology for generating fragrances from [[myrcene]]. In this conversion, diethylamine adds across the diene substituent, the reaction being catalyzed by lithium diethylamide.<ref name=Takabe-1989>{{cite journal |author1=Takabe, K. |author2=Katahiri, T. |author3=Tanaka, J. |author4=Fujita, T. |author5=Watanabe, S. |author6=Suga, K. |title=Addition Of Dialkylamines To Myrcene: N,N-diethylgeranylamine |journal=[[Org. Synth.]] |year=1989 |volume=67 |page=44 |doi=10.15227/orgsyn.067.0044}}</ref> Intramolecular hydroaminations were reported by [[Tobin J. Marks]] in 1989 using [[metallocene]] derived from [[rare-earth metals]] such as [[lanthanum]], [[lutetium]], and [[samarium]]. [[reaction rate|Catalytic rates]] correlated inversely with the [[ionic radius]] of the metal, perhaps as a consequence of [[steric effects|steric interference]] from the ligands.<ref name=Gagne-1989>{{cite journal | last1 = Gagné |first1=M.R. |last2=Marks |first2=T.J. |year=1989 |title=Organolanthanide-catalyzed hydroamination. Facile, regiospecific cyclization of unprotected amino olefins |journal=[[J. Am. Chem. Soc.]] |volume=111 |issue=11 |page=4108 |doi=10.1021/ja00193a056}}</ref> In 1992, Marks developed the first [[Chirality (chemistry)|chiral]] hydroamination catalysts by using a chiral auxiliary, which were the first hydroamination catalysts to favor only one specific [[stereoisomerism|stereoisomer]]. Chiral auxiliaries on the metallocene ligands were used to dictate the stereochemistry of the product.<ref name=Gagne-1992>{{cite journal |last1=Gagné |first1=M.R. |last2=Brard |first2=L. |last3=Conticello |first3=V.P. |last4=Giardello |first4=M.A. |last5=Marks |first5=T.J. |last6=Stern |first6=C.L. |year=1992 |title=Stereoselection effects in the catalytic hydroamination/cyclization of amino olefins at chiral organolanthanide centers |doi=10.1021/om00042a012 |journal=[[Organometallics]] |volume=11 |issue=6 |page=2003}}</ref> The first non-metallocene chiral catalysts were reported in 2003, and used bisarylamido and aminophenolate ligands to give higher [[enantioselective synthesis|enantioselectivity]].<ref name=OShaughnessy-2003>{{cite journal |last1=O'Shaughnessy |first1=P.N. |last2=Scott |first2=P. |year=2003 |title= Biaryl amine ligands for lanthanide catalysed enantioselective hydroamination/cyclisation of aminoalkenes| journal=[[Tetrahedron Asymmetry]] |volume=14 |issue=14 |page=1979 |doi=10.1016/s0957-4166(03)00429-4}}</ref>
+[[File:Notable hydroamination catalysts by year of publication.tif|thumb|center|upright=2.0|Notable hydroamination catalysts by year of publication]]
-==References==
+==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 [[aniline]]s with diverse [[steric effects|steric]] and [[electronic effect|electronic]] substituents. The unsaturated substrates that have been investigated include alkenes, dienes, alkynes, and allenes. For intramolecular hydroamination, various aminoalkenes have been examined.<ref name="Muller-1998"/>
-* Kai C. Hultzsch "Catalytic asymmetric hydroamination of non-activated olefins" (Review) [[Organic & Biomolecular Chemistry]], 2005, 3, 1819-1824. {{doi|10.1039/b418521h}}
-* Hartwig, J. F. [http://www.iupac.org/publications/pac/2004/pdf/7603x0507.pdf Development of catalysts for the hydroamination of olefins]. [[Pure Appl. Chem.]] 2004, 76, 507-516.
-* Odom, A. L. "New C–N and C–C bond forming reactions catalyzed by titanium complexes" Dalton Trans., 2005, (2),225-233. {{DOI|10.1039/b415701j}}
-*Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom, A.L. "Titanium dipyrrolylmethane derivatives: rapid intermolecular alkyne hydroamination" Chem. Commun., 2003, (5),586-587. {{DOI|10.1039/b212423h}}
+===Products===
+Addition across the unsaturated carbon-carbon bond can be [[Markovnikov's Rule|Markovnikov]] or [[Markovnikov's Rule|anti-Markovnikov]] depending on the catalyst.<ref name=Beller-AngewChemIntEd-2004>{{cite journal |author1=Beller, M. |author2=Seayad, J. |author3=Tillack, A. |author4=Jiao, H. |title=Catalytic Markovnikov and anti-Markovnikov Functionalization of Alkenes and Alkynes: Recent Developments and Trends |year=2004 |journal=[[Angew. Chem. Int. Ed.]] |volume=43 |issue=26 |pages=3368–3398 |doi=10.1002/anie.200300616 |pmid=15221826}}</ref> When considering the possibly of R/S chirality, four products can be obtained: Markovnikov with R or S and anti-Markovnikov addition with R or S. Although there have been many reports of catalytic hydroamination with a wide range of metals, there are far fewer describing [[enantioselective]] catalysis to selectively make one of the four possible products. Recently, there have been reports of selectively making the [[Thermodynamic versus kinetic reaction control|thermodynamic or kinetic product]], which can be related to the racemic Markovnikov or anti-Markovnikov structures (see Thermodynamic and Kinetic Product below).
+[[File:Possible regioselective and stereroselective products.tif|thumb|center|upright=2.8|Possible regioselective and stereroselective products]]<!--most chemists would not consider this selectivity to be Markovnikov-->
+==Catalysts and catalytic cycle==
+Hydroamination reactions are [[Atom efficiency|atom-efficient]] processes that generally use readily available and cheap starting materials, therefore a general catalytic strategy is highly desirable. Also, direct catalytic hydroamination strategies have in principle significant benefits over more classical methods to prepare amine containing compounds, including the reduction in the number of synthetic steps required.
+<ref name=Salvatore-2001>{{Cite journal|last1=Salvatore |first1 =R.N. |last2=Yoon |first2=C.H. |last3=Jung |first3=K.W. |year=2001 |title=Synthesis of secondary amines |journal=[[Tetrahedron (journal)|Tetrahedron]] |volume=57 |issue =37 |pages=7785–7811 |doi=10.1016/S0040-4020(01)00722-0}}</ref>
+However, hydroamination reactions pose some tough challenges for catalysis: Strong electron repulsion of the nitrogen atom [[lone pair]] and the electron rich carbon-carbon multiple bond, coupled with hydroamination reactions being [[entropically disfavoured]] (particularly the intermolecular version),<ref name=Brunet-1989 /><ref name=Johns-2006 /> results in a large reaction barrier. [[Regioselectivity]] issues also hamper the synthetic utility of the resulting products, with Markovnikov addition of the amine being the most common outcome over the less favoured anti-Markovnikov addition (see figure). As a result, there are now numerous catalysts that can be utilised in the hydroamination of alkene, allene and alkyne substrates, including various metal based heterogeneous catalysts, early-transition metal complexes (e.g. titanium and zirconium), late-transition metal complexes (e.g. ruthenium and palladium), lanthanide and actinide complexes (e.g. samarium and lanthanum), as well as Brønsted acids and bases.<ref name=Muller-2008>{{cite journal |last1=Müller |first1=T.E. |last2=Hultzsch |first2=K.C. |last3=Yus |first3=M. |last4=Foubelo |first4=F. |last5=Tada |first5=M. |year=2008 |title=Hydroamination: Direct Addition of Amines to Alkenes and Alkynes |journal=[[Chem. Rev.]] |volume=108 |issue=9 |pages=3795–3892 |doi=10.1021/cr0306788 |pmid=18729420 |issn=0009-2665}}</ref><ref name=Alonso-2004>{{cite journal |last1=Alonso |first1=F. |last2=Beletskaya |first2=I.P.|last3=Yus |first3=M. |year=2004 |title=Transition-Metal-Catalyzed Addition of Heteroatom−Hydrogen Bonds to Alkynes |journal=[[Chem. Rev.]] |volume=104 |issue=6 |pages=3079–3160 |doi=10.1021/cr0201068 |pmid=15186189 |issn=0009-2665}}</ref><ref name=Aillaud-2007>{{cite journal |last1=Aillaud |first1=I. |last2=Collin |first2=J. |last3=Hannedouche |first3=J. |last4=Schulz |first4=E. |year=2007|title=Asymmetric hydroamination of non-activated carbon–carbon multiple bonds |journal=[[Dalton Trans.]] |issue=44 |pages=5105–5118 |doi=10.1039/b711126f|pmid=17985016 |issn=1477-9226}}</ref>
+[[File:General scheme of a catalysed alkyne hydroamination.svg|none]]
+===Catalysts===
+Many metal-ligand combinations have been reported to catalyze hydroamination, including main group elements including alkali metals such as [[lithium]],<ref name=Muller-1998>{{cite journal|last=Müller|first=Thomas E.|author2=Beller, Matthias|title=Metal-Initiated Amination of Alkenes and Alkynes |journal=[[Chem. Rev.]] |year=1998 |volume=98 |issue=2 |pages=675–704 |doi=10.1021/cr960433d |pmid=11848912}}</ref> group 2 metals such as [[calcium]],<ref name=Crimmin-2005>{{cite journal|last=Crimmin |first=M.R. |author2=Casely, I.J. |author3=Hill, M.S. |title=Calcium-Mediated Intramolecular Hydroamination Catalysis |journal=[[J. Am. Chem. Soc.]] |year=2005 |volume=127 |issue=7 |pages=2042–2043 |doi=10.1021/ja043576n |pmid=15713071}}</ref> as well as group 3 metals such as [[aluminum]],<ref name=Koller-2010>{{cite journal |last=Koller |first=J. |author2=Bergman, R.G. |title=Highly Efficient Aluminum-Catalyzed Hydro-amination/-hydrazination of Carbodiimides |journal=[[Organometallics]] |year=2010 |volume=29 |issue=22 |pages=5946–5952 |doi=10.1021/om100735q}}</ref> [[indium]],<ref name=Sarma-2011>{{cite journal |last1=Sarma |first1=R. |author2=Prajapati, D. |title=Indium catalyzed tandem hydroamination/hydroalkylation of terminal alkynes |journal=[[Chem. Commun.]] |year=2011 |volume=47 |issue=33 |pages=9525–7 |doi=10.1039/c1cc13486h |pmid=21776504}}</ref> and [[bismuth]].<ref name=Komeyama-2011>{{cite journal |last1=Komeyama |first1=K. |author2=Kouya, Y. |author3=Ohama, Y. |author4= Takaki, K. |title=Tandem ene-reaction/hydroamination of amino-olefin and -allene compounds catalyzed by Bi(OTf)<sub>3</sub> |journal=[[Chem. Commun.]] |year=2011 |volume=47 |issue=17 |pages=5031–5033 |doi=10.1039/c0cc05258b |pmid=21423974}}</ref>  In addition to these main group examples, extensive research has been conducted on the transition metals with reports of early, mid, and late metals, as well as first, second, and third row elements. Finally the lanthanides have been thoroughly investigated. [[Zeolites]] have also shown utility in hydroamination.<ref name="Muller-1998"/>
+===Catalytic cycles===
+The [[reaction mechanism|mechanism]] of metal-catalyzed hydroamination has been well studied.<ref name=Muller-1998 /> Particularly well studied is the organolanthanide catalyzed intramolecular hydroamination of alkenes.<ref name=Hong-2004>{{cite journal |last=Hong |first=S. |author2=Marks, T.J. |title=Organolanthanide-Catalyzed Hydroamination |journal=[[Acc. Chem. Res.]] |year=2004 |volume=37 |issue=9 |pages=673–686 |doi=10.1021/ar040051r |pmid=15379583}}</ref> First, the catalyst is activated by amide exchange, generating the active catalyst (i). Next, the alkene inserts into the Ln-N bond (ii).<ref name=Crabtree-2005>{{cite book |last=Crabtree |first=Robert H. |title=The organometallic chemistry of the transition metals |url=https://archive.org/details/The_Organometallic_Chemistry_Of_Transition_Metals |year=2005 |publisher=John Wiley |location=Hoboken, N.J. |isbn=978-0-471-66256-3 |edition=4th}}</ref>   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.
+[[File:Proposed catalytic cycle for intramolecular hydroamination.tif|thumb|center|upright=1.5|Proposed catalytic cycle for intramolecular hydroamination]]
+Late transition metal hydroamination catalysts have multiple models based on the regioselective determining step. The four main categories are (1) [[nucleophile|nucleophilic attack]] on an alkene alkyne, or allyl ligand and (2) insertion of the alkene into the metal-amide bond.<ref name=Muller-1998/> Generic catalytic cycles appear below. Mechanisms are supported by [[chemical kinetics|rate studies]], [[kinetic isotope effect|isotopic labeling]], and [[Chemical trap|trapping]] of the proposed intermediates.
+[[File:Three of the four most common catalytic cycles for hydroamination.tif|thumb|center|upright=4.0|Common catalytic cycles for hydroamination]]
+==Thermodynamics and kinetics==
+The hydroamination reaction is approximately thermochemically neutral.  The reaction however suffers from a high [[activation energy|activation barrier]], perhaps owing to the repulsion of the electron-rich [[Substrate (chemistry)|substrate]] and the amine [[nucleophile]]. The intermolecular reaction also is accompanied by highly negative changing [[entropy]], making it [[endergonic reaction|unfavorable]] at higher temperatures.
+<ref name=Brunet-1989>{{cite journal |last1=Brunet |first1=J.-J. |author2=Neibecker, D. |author3=Niedercorn, F. |title=Functionalisation of alkenes: catalytic amination of monoolefins |journal=[[J. Mol. Catal.]] |year=1989 |volume=49 |issue=3 |pages=235–259|doi=10.1016/0304-5102(89)85015-1}}</ref><ref name=Johns-2006>{{cite journal|last=Johns |first=A.M.|author2=Sakai, N. |author3=Ridder, A. |author4= Hartwig, J.F. |title=Direct Measurement of the Thermodynamics of Vinylarene Hydroamination|journal=[[J. Am. Chem. Soc.]] |year=2006 |volume=128 |issue=29 |pages=9306–9307 |doi=10.1021/ja062773e |pmid=16848446}}</ref>   Consequently, catalysts are necessary for this reaction to proceed.<ref name="jain"/><ref name=Muller-1998/>  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 [[Thermodynamic versus kinetic reaction control|thermodynamic product]] is observed. The isolation and characterization of the rarer and more synthetically valuable [[Thermodynamic versus kinetic reaction control|kinetic]] [[allyl]] amine product was reported when [[allenes]] was used at the unsaturated substrate. One system utilized temperatures of 80&nbsp;°C with a [[rhodium]] catalyst and [[aniline]] derivatives as the amine.<ref name=Cooke-2012>{{cite journal |last=Cooke |first=M.L.|author2=Xu, K. |author3=Breit, B. |title=Enantioselective Rhodium-Catalyzed Synthesis of Branched Allylic Amines by Intermolecular Hydroamination of Terminal Allenes |journal=[[Angew. Chem. Int. Ed.]] |year=2012 |volume=51 |issue=43 |pages=10876–10879 |doi=10.1002/anie.201206594 |pmid=23011801}}</ref> The other reported system utilized a [[palladium]] catalyst at room temperature with a wide range of primary and secondary cyclic and acyclic amines.<ref name=Beck-2003>{{cite journal |last=Beck |first=J.F. |author2=Samblanet, D.C. |author3=Schmidt, J.A.R. |title=Palladium catalyzed intermolecular hydroamination of 1-substituted allenes: an atom-economical method for the synthesis of N-allylamines |journal=[[RSC Adv.]] |year=2013 |volume=3 |issue=43 |pages=20708–20718 |doi=10.1039/c3ra43870h|bibcode=2013RSCAd...320708B }}</ref> Both systems produced the desired allyl amines in high yield, which contain an alkene that can be further functionalized through traditional organic reactions.
+[[File:Possible thermodynamic and kinetic products when utilizing an allene2.tif|thumb|center|upright=2.7|Possible thermodynamic and kinetic products when utilizing an allene]]
+==Base catalyzed hydroamination==
+Strong [[base (chemistry)|bases]] catalyze hydroamination, an example being the [[ethyl group|ethylation]] of [[piperidine]] using [[ethene]]:<ref name=Wollensak-1973>{{cite journal |author1=Wollensak, J. |author2=Closson, R.D. |title=N-Ethylpiperidine |journal=[[Org. Synth.]] |year=1963 |volume=43 |pages=45 |doi=10.15227/orgsyn.043.0045}}</ref>
+[[File:C2H4+piperidine.png|thumb|center|upright=1.75|Hydroamination of ethene with [[piperidine]] proceeds with no transition metal catalyst, but requires a strong base.]]
+Such base catalyzed reactions proceed well with ethene but higher alkenes are less reactive.
+==Hydroamination catalyzed by group (IV) complexes==
+Certain [[titanium]] and [[zirconium]] [[coordination complex|complexes]] catalyze intermolecular hydroamination of alkynes and allenes.<ref name="jain"/> Both [[stoichiometry|stoichiometric]] and catalytic variants were initially examined with [[Organozirconium chemistry|zirconocene]] bis(amido) complexes. Titanocene amido and sulfonamido complexes catalyze the intra-molecular hydroamination of aminoalkenes via a [[2+2 Photocycloaddition|[2+2] cycloaddition]] that forms the corresponding azametallacyclobutane, as illustrated in the figure below. Subsequent protonolysis by incoming substrate gives the α-vinyl-pyrrolidine ('''1''') or tetrahydropyridine ('''2''') product. Experimental and theoretical evidence support the proposed imido intermediate and mechanism with neutral group IV catalysts.
+[[File:Hydroamination of aminoallenes.png|thumb|center|700px|The catalytic hydroamination of aminoallenes to form chiral α-vinyl-pyrrolidine ('''1''') and tetrahydropyridine ('''2''') products.]]
+== Formal hydroamination ==
+The addition of hydrogen and an amino group (NR<sub>2</sub>) using reagents other than the amine HNR<sub>2</sub> 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<ref name=Miki-2013>{{cite journal |last1=Miki |first1=Y. |last2=Hirano |first2=K. |last3=Satoh |first3=T. |last4=Miura |first4=M. |year=2013 |title=Copper-Catalyzed Intermolecular Regioselective Hydroamination of Styrenes with Polymethylhydrosiloxane and Hydroxylamines |journal=[[Angew. Chem. Int. Ed.]] |volume=52 |issue=41 |pages=10830–10834 |doi=10.1002/anie.201304365 |issn=1521-3773 |pmid=24038866}}</ref> and nitroarenes<ref name=Gui-2015>{{cite journal |last1=Gui |first1=J. |last2=Pan |first2=C.-M. |last3=Jin |first3=Y. |last4=Qin |first4=T. |last5=Lo |first5=J.C. |last6=Lee |first6=B.J. |last7=Spergel |first7=S.H. |last8=Mertzman |first8=M.E. |last9=Pitts |first9=W.J. |year=2015 |title=Practical olefin hydroamination with nitroarenes |journal=[[Science (journal)|Science]] |volume=348 |issue=6237 |pages=886–891 |doi=10.1126/science.aab0245 |issn=0036-8075 |pmid=25999503 |bibcode=2015Sci...348..886G |doi-access=free}}</ref> 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 [[allylamine]]s, 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]].<ref name=Beck-2003 />
+[[File:Cinnarizine synthesis via hydroamination.png|thumb|center|500px|Synthesis of cinnarizine via hydroamination.]]
+Hydroamination is also promising for the synthesis of [[alkaloid]]s. An example was the hydroamination step used in the  total synthesis of (-)-epimyrtine.<ref name=Trinh-2013>{{cite journal |author1=Trinh, T.T.H. |author2=Nguyen, K.H. |author3=Amaral, P. de A. |author4=Gouault, N. |journal=[[Beilstein J. Org. Chem.]] |title=Total synthesis of (−)-epimyrtine by a gold-catalyzed hydroamination approach |year=2013 |volume=9 |pages=2042–2047 |doi=10.3762/bjoc.9.242|pmid=24204417 |pmc=3817515 }}</ref>
+[[File:Hydroamination in total synthesis of epimyrtine.png|thumb|center|700px|Gold-catalyzed hydroamination used for the total synthesis of (-)-epimyrtine.<ref name=Trinh-2013/>]]
+== See also ==
+* [[Ammoxidation]] - reaction of ammonia with alkenes to give [[nitriles]]
+* [[Hydroboration]]
+* [[Hydrosilylation]]
+* (Olefin) [[Hydration reaction|Hydration]]
+* [[Hydrofunctionalization]]
+==References==
+{{CC-notice|cc=by2.5|url=https://ora.ox.ac.uk/objects/uuid:18e7c533-3789-4800-9813-1d5c7bb4e4ea|author= David Michael Barber}}
+{{reflist|30em}}
-[[Category:Inorganic chemistry]]
+[[Category:Addition reactions]]
-[[Category:Catalysts]]
 [[Category:Organometallic chemistry]]
 [[Category:Homogeneous catalysis]]
+[[Category:Catalysis]]