Hydroamination

In organic chemistry, hydroamination is the formal addition of an N−H bond of an amine across an carbon-carbon multiple bond of an alkene, alkyne, diene, or allene.[1] In the ideal case, hydroamination is atom economical and green;[2] and the products see extensive use in fine-chemical, pharmaceutical, and agricultural industries.[3][4][5] Hydroamination reactions occur spontaneously only for electrophilic alkenes and some dienes, but these are known by other names (e.g. Michael addition reaction); "hydroamination" is generally reserved for situations where the reaction requires a catalyst.

Hydroamination can be used intramolecularly to create heterocycles or intermolecularly with a separate amine and unsaturated compound.

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[6] and nitroarenes[7] have been reported as nitrogen sources.

History

Hydroamination was first developed for generating fragrances from myrcene. In this conversion, diethylamine adds across the diene substituent, the reaction being catalyzed by lithium diethylamide.[8] 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.[9] 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.[10] The first non-metallocene chiral catalysts were reported in 2003, and used bisarylamido and aminophenolate ligands to give higher enantioselectivity.[11]

Reaction scope

Hydroamination does not occur spontaneously, but requires catalysis.[12][13] It is, however, approximately thermochemically neutral. The reaction has a large barrier, because the nitrogen atom lone pair and the electron rich carbon-carbon multiple bond repel each other, and hydroamination reactions, being an addition reaction, are inherently entropically disfavoured (except in the intramolecular case).[14][15] Radical amination is not a chain reaction, because hydrogen abstraction from the amine to a carbon atom is thermodynamically disfavored.[16]

Hydroamination reactions have seen extensive academic research, because they are atom-efficient processes that generally use readily available and cheap starting materials. Also, direct hydroamination strategies can in principle substantially shorten many synthesis procedures relative to classical aminations.[17] As a result, many different situations now admit hydroamination with the appropriate catalyst. Amines that have been investigated include primary, secondary, cyclic, acyclic, and anilinic amines with diverse steric and electronic substituents. Unsaturated substrates include alkenes, dienes, alkynes, and allenes. Reactions occur both intra- and intermolecularly.[13] Markovnikov addition is generally favored, but some tools exist to control the regioselectivity of the addition.[18]

Catalysts

Many metal-ligand combinations have been reported to catalyze hydroamination, and can be roughly divided into three categories.

pH extremes

In the simplest case, strong Brønsted acids and bases catalyze hydroamination.[16][19] One example is the ethylation of piperidine using ethene:[20]

Such pH-extremal reactions proceed well with ethene but higher alkenes are less reactive.

Weakly-coordinating metals

Alternatively, weakly-coordinating Lewis acids also catalyze the reaction. These include salts of the alkali,[13] alkaline-earth,[21] rare-earth,[22] and low-valent early transition metals (e.g. titanium and zirconium),[12] as well as bismuth[23] and probably certain actinide complexes. Zeolites have also shown utility in hydroamination.[13]

The mechanism of these hydroaminations has been well studied.[13] First, the catalyst is activated by amide exchange, generating the active catalyst (i). Next, the alkene inserts into the Ln-N bond (ii).[22] Finally, protonolysis occurs generating the cyclized product while also regenerating the active catalyst (iii).[24]

Late transition-metal complexes

The complexes of late transition metals (e.g. ruthenium and palladium)[16][25][19] and group 13 metals such as aluminum[26] and indium[27] offer a great deal of control over the regio- and stereoselectivity of the reaction. For example, a rare and more synthetically valuable kinetic allyl amine product was reported when hydroaminating an allene. One system utilized temperatures of 80 °C with a rhodium catalyst and aniline derivatives as the amine.[28] The other reported system utilized a palladium catalyst at room temperature with a wide range of primary and secondary cyclic and acyclic amines.[29] Both systems produced the desired allyl amines in high yield:

In general, hydroamination with late transition-metal complexes has multiple pathways depending 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.[13] Generic catalytic cycles appear below.

Applications

No industrial applications of hydroamination are known, but hydroamination syntheses of industrial products have been performed in academia.

Hydroamination has been utilized to synthesize the anti-nausea medication cinnarizine in quantitative yield.[29]

Hydroamination is also promising for the synthesis of alkaloids as, in the total synthesis of (-)-epimyrtine.[30]

See also

References

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

  1. ↑ Togni, Antionio; Grützmacher, Hansjörg (2001). Catalytic heterofunctionalization: from hydroanimation to hydrozirconation (1. ed.). Weinheim: Wiley-VCH. doi:10.1002/3527600159. ISBN 978-3527302345.
  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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ Pohlki, F.; Doye, S. (2003). "The catalytic hydroamination of alkynes". Chem. Soc. Rev. 32 (2): 104–114. doi:10.1039/b200386b. PMID 12683107.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ Gagné, M.R.; Marks, T.J. (1989). "Organolanthanide-catalyzed hydroamination. Facile, regiospecific cyclization of unprotected amino olefins". J. Am. Chem. Soc. 111 (11): 4108. Bibcode:1989JAChS.111.4108G. doi:10.1021/ja00193a056.
  10. ↑ 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.
  11. ↑ 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.
  12. 1 2 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)
  13. 1 2 3 4 5 6 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.
  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.
  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. Bibcode:2006JAChS.128.9306J. doi:10.1021/ja062773e. PMID 16848446.
  16. 1 2 3 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.
  17. ↑ 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.
  18. ↑ 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.
  19. 1 2 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.
  20. ↑ Wollensak, J.; Closson, R.D. (1963). "N-Ethylpiperidine". Org. Synth. 43: 45. doi:10.15227/orgsyn.043.0045.
  21. ↑ Crimmin, M.R.; Casely, I.J.; Hill, M.S. (2005). "Calcium-Mediated Intramolecular Hydroamination Catalysis". J. Am. Chem. Soc. 127 (7): 2042–2043. Bibcode:2005JAChS.127.2042C. doi:10.1021/ja043576n. PMID 15713071.
  22. 1 2 Crabtree, Robert H. (2005). The organometallic chemistry of the transition metals (4th ed.). Hoboken, N.J.: John Wiley. ISBN 978-0-471-66256-3.
  23. ↑ 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.
  24. ↑ Hong, S.; Marks, T.J. (2004). "Organolanthanide-Catalyzed Hydroamination". Acc. Chem. Res. 37 (9): 673–686. doi:10.1021/ar040051r. PMID 15379583.
  25. ↑ 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.
  26. ↑ Koller, J.; Bergman, R.G. (2010). "Highly Efficient Aluminum-Catalyzed Hydro-amination/-hydrazination of Carbodiimides". Organometallics. 29 (22): 5946–5952. doi:10.1021/om100735q.
  27. ↑ 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.
  28. ↑ 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.
  29. 1 2 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.
  30. 1 2 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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