Hydroamination

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][7][8]

Examples of intramolecular hydroamination

Hydroamination can be used intramolecularly to create heterocycles or intermolecularly with a separate amine and unsaturated compound.[9] The development of catalysts for hydroamination remains an active area, especially for alkenes.

Prototypical intermolecular hydroamination reactions.

History

The first 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.[10] 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.[11] The first non-metallocene chiral catalysts were reported in 2003, and used bisarylamido and aminophenolate ligands to give higher enantioselectivity.[12]

Notable hydroamination catalysts by year of publication

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.[13]

Products

Addition across the unsaturated carbon-carbon bond can be Markovnikov or anti-Markovnikov depending on the catalyst.[14] Interestingly, 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

Catalysts

Many metal-ligand combinations have been reported to catalyze hydroamination, including main group elements including alkali metals such as lithium,[13] group 2 metals such as calcium,[15] as well as group 3 metals such as aluminum,[16] indium,[17] and bismuth.[18] 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.[13]

Catalytic cycles

The mechanism of metal-catalyzed hydroamination has been well studied.[19] Particularly well studied is the organolanthanide catalyzed intramolecular hydroamination of alkenes.[20] First, the catalyst is activated by amide exchange, generating the active catalysis (i). Next, the alkene inserts into the Ln-N bond (ii).[21] 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.

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) nucleophilic attack on an alkene alkyne, or allyl ligand and (2) insertion of the alkene into the metal-amide bond.[19] Generic catalytic cycles appear below. Mechanisms are supported by rate studies, isotopic labeling, and trapping of the proposed intermediates.

Common catalytic cycles for hydroamination

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.[22][23] Consequently, catalysts are necessary for this reaction to proceed.[3][19] 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.[24] The other reported system utilized a palladium catalyst at room temperature with a wide range of primary and secondary cyclic and acyclic amines.[25] Both systems produced the desired allyl amines in high yield, which contain an alkene that can be further functionalized through traditional organic reactions.

Possible thermodynamic and kinetic products when utilizing an allene

Base catalyzed hydroamination

Strong bases catalyze hydroamination, an example being the ethylation of piperidine using ethylene:[26]

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

Such base catalyzed reactions proceed well with ethylene 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 Figure 1. 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.

Figure 1. The catalytic hydroamination of aminoallenes to form chiral α-vinyl-pyrrolidine (1) and tetrahydropyridine (2) products. L2 = Cp2 or bis(amide).

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[27] and nitroarenes[28] 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.[29]

Synthesis of cinnarizine via hydroamination

Hydroamination is also promising for the synthesis of alkaloids. An example was the total synthesis of (-)-epimyrtine.[30]

Gold-catalyzed hydroamination used for the total synthesis of (-)-epimyrtine

See also

References

  1. ↑ Grützmacher, ed. by Antonio Togni; Hansjörg (2001). Catalytic heterofunctionalization: from hydroanimation to hydrozirconation (1. ed.). Weinheim [u.a.]: Wiley-VCH. ISBN 3527302344.
  2. ↑ Beller, edited by M.; Bolm, C. (2004). Transition metals for organic synthesis : building blocks and fine chemicals (2nd rev. and enl. ed.). Weinheim ;[Chichester]: Wiley-VCH. ISBN 9783527306138.
  3. 1 2 3 Jain, A. Hydroamination- Direct Addition of Amines to Alkenes and Alkynes
  4. ↑ Kai C. Hultzsch (2005). "Catalytic asymmetric hydroamination of non-activated olefins". Organic & Biomolecular Chemistry (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.
  6. ↑ Shi, Y. H.; Hall, C.; Ciszewski, J. T.; Cao, C. S.; Odom, A. L. (2003). "Titanium dipyrrolylmethane derivatives: rapid intermolecular alkyne hydroamination". Chemical Communications. 5 (5): 586–587. doi:10.1039/b212423h.
  7. ↑ Pohlki, F., Doye, S. (2003). "The catalytic hydroamination of alkynes". Chemical Society Reviews. 32 (2): 104–114. doi:10.1039/b200386b. PMID 12683107.
  8. ↑ Odom, A. L. (2005). "New C–N and C–C bond forming reactions catalyzed by titanium complexes". Dalton Trans. 2 (2): 225–233. doi:10.1039/b415701j. PMID 15616708.
  9. ↑ Chemical Reviews, 2008, Vol. 108, No. 9
  10. ↑ Gagné, M. R.; Marks, T. J. J. Am. Chem. Soc. 1989, 111, 4108 .
  11. ↑ Gagné, M. R.; Brard, L.; Conticello, V. P.; Giardello, M. A.; Marks, T. J.; Stern, C. L. Organometallics, 1992, 11, 2003.
  12. ↑ O'Shaughnessy, P. N.; Scott, P. Tetrahedron: Asymmetry 2003, 14, 1979
  13. 1 2 3 Müller, Thomas E.; Beller, Matthias (1 April 1998). "Metal-Initiated Amination of Alkenes and Alkynes". Chemical Reviews. 98 (2): 675–704. doi:10.1021/cr960433d. PMID 11848912.
  14. ↑ M. Beller; J. Seayad; A. Tillack; H. Jiao (2004). "Catalytic Markovnikov and anti-Markovnikov Functionalization of Alkenes and Alkynes: Recent Developments and Trends". Angewandte Chemie International Edition. 43 (26): 3368–3398. doi:10.1002/anie.200300616. PMID 15221826.
  15. ↑ Crimmin, Mark R.; Casely, Ian J.; Hill, Michael S. (1 February 2005). "Calcium-Mediated Intramolecular Hydroamination Catalysis". Journal of the American Chemical Society. 127 (7): 2042–2043. doi:10.1021/ja043576n.
  16. ↑ Koller, Jürgen; Bergman, Robert G. (22 November 2010). "Highly Efficient Aluminum-Catalyzed Hydro-amination/-hydrazination of Carbodiimides". Organometallics. 29 (22): 5946–5952. doi:10.1021/om100735q.
  17. ↑ Sarma, Rupam; Prajapati, Dipak (1 January 2011). "Indium catalyzed tandem hydroamination/hydroalkylation of terminal alkynes". Chemical Communications. 47 (33): 9525. doi:10.1039/c1cc13486h.
  18. ↑ Komeyama, Kimihiro; Kouya, Yuusuke; Ohama, Yuuki; Takaki, Ken (1 January 2011). "Tandem ene-reaction/hydroamination of amino-olefin and -allene compounds catalyzed by Bi(OTf)3". Chemical Communications. 47 (17): 5031. doi:10.1039/c0cc05258b.
  19. 1 2 3 Müller, T. E. Beller, M. (1998). "Metal-Initiated Amination of Alkenes and Alkynes". Chemical Reviews. 98 (2): 675–704. doi:10.1021/cr960433d. PMID 11848912.
  20. ↑ Hong, Sukwon; Marks, Tobin J. (1 September 2004). "Organolanthanide-Catalyzed Hydroamination". Accounts of Chemical Research. 37 (9): 673–686. doi:10.1021/ar040051r.
  21. ↑ Crabtree, Robert H. (2005). The organometallic chemistry of the transition metals (4th ed.). Hoboken, N.J.: John Wiley. ISBN 0-471-66256-9.
  22. ↑ Brunet, Jean-Jacques; Neibecker, Denis; Niedercorn, Francine (1 February 1989). "Functionalisation of alkenes: catalytic amination of monoolefins". Journal of Molecular Catalysis. 49 (3): 235–259. doi:10.1016/0304-5102(89)85015-1.
  23. ↑ Johns, Adam M.; Sakai, Norio; Ridder, André; Hartwig, John F. (1 July 2006). "Direct Measurement of the Thermodynamics of Vinylarene Hydroamination". Journal of the American Chemical Society. 128 (29): 9306–9307. doi:10.1021/ja062773e.
  24. ↑ Cooke, Michael L.; Xu, Kun; Breit, Bernhard (22 October 2012). "Enantioselective Rhodium-Catalyzed Synthesis of Branched Allylic Amines by Intermolecular Hydroamination of Terminal Allenes". Angewandte Chemie International Edition. 51 (43): 10876–10879. doi:10.1002/anie.201206594.
  25. ↑ Beck, John F.; Samblanet, Danielle C.; Schmidt, Joseph A. R. (1 January 2013). "Palladium catalyzed intermolecular hydroamination of 1-substituted allenes: an atom-economical method for the synthesis of N-allylamines". RSC Advances. 3 (43): 20708–20718. doi:10.1039/c3ra43870h.
  26. ↑ J. Wollensak and R. D. Closson (1973). "N-Methylpiperidine". Org. Synth. 43: 45.; Coll. Vol., 5, p. 575
  27. ↑ Miki, Yuya; Hirano, Koji; Satoh, Tetsuya; Miura, Masahiro (2013-10-04). "Copper-Catalyzed Intermolecular Regioselective Hydroamination of Styrenes with Polymethylhydrosiloxane and Hydroxylamines". Angewandte Chemie International Edition. 52 (41): 10830–10834. doi:10.1002/anie.201304365. ISSN 1521-3773.
  28. ↑ Gui, Jinghan; Pan, Chung-Mao; Jin, Ying; Qin, Tian; Lo, Julian C.; Lee, Bryan J.; Spergel, Steven H.; Mertzman, Michael E.; Pitts, William J. (2015-05-22). "Practical olefin hydroamination with nitroarenes". Science. 348 (6237): 886–891. doi:10.1126/science.aab0245. ISSN 0036-8075. PMID 25999503.
  29. ↑ Beck, John F.; Samblanet, Danielle C.; Schmidt, Joseph A. R. (1 January 2013). "Palladium catalyzed intermolecular hydroamination of 1-substituted allenes: an atom-economical method for the synthesis of N-allylamines". RSC Advances. 3 (43): 20708. doi:10.1039/c3ra43870h.
  30. ↑ Beilstein J. Org. Chem. 2013, 9, 2042–2047
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