Hydroamination reactions of alkenes

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Hydroamination reactions of alkenes represent additions of N-H bonds across carbon-carbon double bonds. Viable substrates for these reactions include unactivated alkenes, vinyl arenes, allenes, and strained alkenes. The scope of the nitrogen-containing reactant includes amines, azoles, and N-protected substrates. A variety of catalysts have been employed including alkali metals, alkaline earth metals, transition metals, and lanthanides.[1]

Introduction

As a consequence of the importance of nitrogen-containing compounds in biological and pharmaceutical applications, methods for the construction of carbon-nitrogen bonds have been heavily studied for at least 150 years. Hydroamination, the addition of HNR2 across a carbon-carbon π bond, is in principle one of the most atom-economical methods for the synthesis of this class of compounds. Catalytic hydroaminations of alkenes, allenes, and dienes (which may be inter- or intramolecular) afford amines, imines, and enamines (Eq. 1).

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Hydroamination-Gen.png

The scope of amine substrates includes ammonia, primary and secondary aliphatic and aromatic amines, azoles, hydrazines, and N-protected amines. Transition metal, rare earth, and alkali metal catalysts have been applied successfully, although the appropriate choice of catalyst depends on the unsaturated and amine substrates.

In general, hydroaminations present issues of site selectivity (Markovnikov/anti-Markovnikov) and enantioselectivity. Site selectivity is a function of the unsaturated substrate as well as the catalyst. The scope of enantioselective hydroamination is very broad; however, a particular catalyst system is typically limited to a fairly narrow range of substrates.

Mechanism and Stereochemistry

Prevailing Mechanisms

Mechanisms of alkene hydroaminations depend strongly on the catalyst system employed. Catalysts that include electropositive elements such as alkali, alkaline earth, and rare earth metals typically operate through a metal-amido species that undergoes nucleophilic addition to the alkene (Eq. 2).[2] The site selectivity of this addition depends on the substitution of the alkene: whereas aliphatic alkenes typically undergo Markovnikov addition, aromatic alkenes more commonly engage in anti-Markovnikov addition due to stabilization of the resulting benzylic metal intermediate.

(2)
Hydroamination-Mech-1.png

Hydroaminations of allenes catalyzed by Group 4 metals proceed by a different mechanism involving a metal imido intermediate (Eq. 3).[3] After formation of a bis-amido precursor, α-elimination generates the metal imido species, which engages in [2+2] cycloaddition with the allene substrate. Protonation then generates an enamido complex with an additional amido ligand; α-elimination then regenerates the metal-imido species.

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Hydroamination-Mech-2.png

Mechanisms of hydroaminations catalyzed by late transition metals are not as well understood as the mechanisms discussed above. Nonetheless, it is generally believed that these reactions involve either amine activation via N-H insertion or alkene activation via π-coordination. Intermolecular hydroamination of norbornene catalyzed by an iridium(I) complex provides an example of the former (Eq. 4).[4] Oxidative addition of the amine is followed by insertion of the alkene and reductive elimination.

(4)
Hydroamination-Mech-3.png

Group 9 and 10 metal complexes tend to react via an alkene activation pathway involving coordination of the alkene to the metal center and external attack of the amine on the coordinated alkene (Eq. 5).[5] Product formation may occur either by proton transfer to the metal center followed by reductive elimination or direct protonation of the β-aminoalkyl ligand.

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Hydroamination-Mech-4.png

Scope and Limitations

The scope of alkene hydroaminations is very broad and includes unactivated and activated alkenes as well as primary and secondary alkyl- and arylamines. However, this broad substrate scope is accompanied by an almost equally broad array of potential catalyst systems. Careful consideration must thus be given to the nature of the alkene and amine substrates in choosing the ideal catalyst. For example, late transition metal catalysts are generally incompatible with basic alkylamines and require either N-protected or aniline substrates.

Small unactivated alkenes generally require harsh conditions to undergo intermolecular hydroaminations, particularly when ammonia is used.[6] Catalyst decomposition is often a significant concern in reactions of alkylamines with unactivated alkenes. On the other hand, less basic anilines are more amenable to reaction with unactivated alkenes; for example, a catalyst system based on rhodium trichloride is effective in the reaction of ethylene with anilines (Eq. 6).[7]

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Hydroamination-Scope-1.png

Unactivated alkenes are significantly more reactive in intramolecular hydroaminations and the scope of available catalysts is accordingly much broader. Rare earth metal catalysts are among the most active for intramolecular reactions of amino alkenes (Eq. 7).[8] Exclusive exo selectivity is observed in these reactions and in related reactions employing alkali or alkaline earth metal catalysts.

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Hydroamination-Scope-2.png

Early transition metal catalysts are also effective in intramolecular hydroaminations of amino alkenes (Eq. 8).[9] In this case, cyclization occurs efficiently even in the absence of geminal substituents in the tethering alkyl chain.

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Hydroamination-Scope-3.png

Conjugation significantly increases the reactivity of the alkene in vinyl arenes, although control of site selectivity can be difficult. For example, sodium metal catalyzes the addition of primary or secondary aliphatic amines to styrene with anti-Markovnikov selectivity (Eq. 9).[10]

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Hydroamination-Scope-4.png

Intramolecular reactions of vinyl arenes proceed similarly to reactions of unactivated amino alkenes described above. Catalysts based on rare earth metals are among the most active and react with exo selectivity (Eq. 10).[11]

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Hydroamination-Scope-5.png

Although 1,3-dienes display comparable reactivity to vinyl arenes in hydroaminations, the possibility of 1,2- or 1,4-addition complicates this class of reactions. Late transition metal catalysts are known to catalyze the 1,4-addition of anilines to acyclic 1,3-dienes (Eq. 11).[12] Related reactions of alkylamines show a lack of site selectivity and issues with diene oligomerization.[13]

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Hydroamination-Scope-6.png

Allenes may undergo hydroamination to give enamines, imines, or allyl amines. Early transition metal catalysts such as the titanium half-sandwich imido complex 1 promote formation of imines exclusively (Eq. 12).[14]

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Hydroamination-Scope-7.png

Late transition metal catalysts are more active in the formation of allyl amines. For example, the gold(I) N-heterocyclic carbene complex 2 catalyzes the addition of N-protected amines to substituted allenes at room temperature (Eq. 13).[15]

(13)
Hydroamination-Scope-8.png

Along with conjugated alkenes and cumulenes, strained alkenes represent a third class of substrates activated toward hydroamination. Like allenes, methylenecyclopropanes may afford imines, enamines, or allyl amines upon hydroamination. For instance, rare earth metal complexes catalyze the hydroamination of methylenecyclopropane to afford imines with ring opening (Eq. 14).[2]

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Hydroamination-Scope-9.png

In analogy to reactions of allenes, late transition metal catalysts react with substituted methylenecyclopropanes to afford allylamines (Eq. 15).[16]

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Hydroamination-Scope-10.png

Enantioselective Hydroaminations

Enantioselective hydroamination reactions are an efficient means for the construction of stereocenters that include carbon-nitrogen bonds. At present, intermolecular enantioselective hydroaminations are considerably more challenging than intramolecular reactions, and the latter have been studied much more thoroughly.

Lanthanocene catalysts are some of the earliest discovered for enantioselective cyclization of amino alkenes; however, poor configurational stability of these catalysts limits their utility. Rare earth complexes such as (R)-3 overcome this limitation and are highly active in enantioselective cyclization of substrates assisted by the Thorpe-Ingold effect (Eq. 16).[11]

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Hydroamination-Stereo-1.png

Combination of a palladium(II) precatalyst with the SEGPHOS derivative 4 yields a catalyst for the enantioselective Markovnikov addition of aniline to vinyl arenes (Eq. 17).[17] Early transition metal catalysts afford anti-Markovnikov products in this context.

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Hydroamination-Stereo-2.png

The rare earth complex (R)-3 also catalyzes the enantioselective cyclization of vinyl arenes (Eq. 18).[18] Early transition metals are generally superior to other catalysts in cyclizations of amino alkenes.

(18)
Hydroamination-Stereo-3.png

Enantioselective cyclizations of amino allenes have been observed in the presence of chiral gold catalysts. Even chiral counterions can contribute to stereoinduction, as evidenced by the cyclization of an N-protected amino allene catalyzed by an achiral gold(I) catalyst and chiral phosphate anion (Eq. 19).[19]

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Hydroamination-Stereo-4.png

Synthetic Applications

Intramolecular hydroamination reactions have been applied in the synthesis of alkaloids, although most of these examples use achiral catalysts and involve racemic or scalemic product mixtures. For example, a neodymium catalyst is employed for intramolecular hydroamination of an amino alkene in a synthesis of the anticonvulsant dizocilpine (Eq. 20).[20] The rigid structure of the starting material enables the reaction to occur at moderate temperature and reaction time.

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Hydroamination-Synth-1.png

Intramolecular hydroaminations of internal amino alkenes often require harsh reaction conditions, but reactions of related amino dienes present an attractive alternative. Hydrogenation of the double bond that appears in the product yields the same product that would have been obtained from hydroamination of an internal alkene. For example, the rare earth complex (S)-5-Sm was used in a synthesis of (S)-(+)-coniine via an amino diene intermediate (Eq. 21).[21]

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Hydroamination-Synth-2.png

Comparison to Other Methods

In cases in which direct hydroamination is not possible, indirect methods involving addition of H-Y followed by substitution of Y for an amino group can be employed. Better control of site selectivity is sometimes possible when employing these indirect methods despite their comparative lack of atom economy. For example, hydroboration/amination represents an alternative to anti-Markovnikov direct hydroamination (Eq. 22).[22] In the sequence shown, catalytic enantioselective hydroboration is followed by alkylation to form the more reactive trialkylborane and amination using an electrophilic chloramine.

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Hydroamination-Alt-1.png

A conceptually related sequence involves hydrometalation followed by electrophilic amination.[23]

The Cope hydroamination reaction does not require catalyst, proceeds with high stereoselectivity, and is applicable to highly substituted alkenes that are challenging substrates in direct hydroamination (Eq. 23).[24] Synthetic applications of this reaction are limited to monosubstituted hydroxylamines, as disubstituted hydroxylamines react reversibly to afford N-oxides. The sensitivity of many hydrazines and hydroxylamines to oxidation also presents a significant limitation.

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Hydroamination-Alt-2.png

Addition of amines to alkenes can be promoted by mercury(II) in aminomercuration reactions. Substitution of mercury for hydrogen is facilitated by a reducing agent such as sodium borohydride (Eq. 24).[25] Markovnikov selectivity is generally observed and the scope of the reaction includes a broad range of unactivated alkenes and amines, including N-protected amines. Despite their apparent utility, the extremely toxic nature of mercury salts is a significant concern in these reactions.

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Hydroamination-Alt-3.png

Experimental Conditions and Procedure

Typical Conditions

The variety of catalyst systems used in hydroaminations precludes significant generalizations about reaction conditions, but inert atmosphere and dry solvents are used universally in reactions involving organometallic species. Solvents should be freshly distilled prior to use.

Example Procedure[17]

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Hydroamination-Ex.png

[(R)-BINAP)]Pd(OTf)2 (103 mg, 0.10 mmol) was suspended in toluene (0.5 mL) in a glovebox. The suspension was placed into a vial, which was sealed with a cap containing a PTFE septum, and the vial was removed from the glovebox. 4-(Trifluoromethyl)styrene (258 mg, 1.50 mmol) and aniline (93 mg, 1.00 mmol) were added to the reaction mixture by syringe which was then stirred at rt for 72 h, adsorbed on silica gel, and the product was isolated by eluting with EtOAc/hexanes (1:9) to give the title compound (212 mg, 80%, er 90.5:9.5 (S)): 1H NMR (CDCl3, 400 MHz) δ 1.44 (d, J = 6.8 Hz, 3H), 3.90–4.05 (br s, 1H), 4.4 (q, J = 6.8 Hz, 1H), 6.39 (d, J = 7.6 Hz, 2H), 6.59 (t, J = 7.6 Hz, 1H), 6.99–7.05 (m, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H); 13C NMR (CDCl3,100 MHz) δ 24.4, 52.6, 112.5, 116.9, 122.2, 124.8, 124.9 (q, J = 4.2 Hz), 125.4, 128.5, 146.1, 148.7. The enantiomeric purity was determined by capillary GLC analysis: tR (S) 48.7 min, tR (R) 49.4 min (permethylated β-Cyclodextrine chiral stationary phase column).

References

  1. ↑ Reznichenko, A. L.; Hultszch, K. C. Org. React. 2015, 88, 1. (link)
  2. ↑ a b Ryu, J.-S.; Li, G. Y.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 12584.
  3. ↑ Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104.
  4. ↑ Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem. 2006, 4555.
  5. ↑ Senn, H. M.; Blöchl, P. E.; Togni, A. J. Am. Chem. Soc. 2000, 122, 4098.
  6. ↑ Deeba, M.; Ford, M. E. Zeolites 1990, 10, 794.
  7. ↑ Baudequin, C.; Brunet, J.-J.; Rodriguez-Zubiri, M. Organometallics 2007, 26, 5264.
  8. ↑ Gagné, M. R.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc. 1992, 114, 275.
  9. ↑ Gribkov, D. V.; Hultzsch, K. C. Angew. Chem., Int. Ed. 2004, 44, 5542.
  10. ↑ Fujita, T.; Suga, K.; Watanabe, S. Aust. J. Chem. 1974, 27, 531.
  11. ↑ a b Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. J. Am. Chem. Soc. 2006, 128, 3748.
  12. ↑ Löber, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4366.
  13. ↑ Takahashi, K.; Miyake, A.; Hata, G. Bull. Chem. Soc. Jpn. 1972, 45, 1183.
  14. ↑ Johnson, J. S.; Bergman, R. G. J. Am. Chem. Soc. 2001, 123, 2923.
  15. ↑ Kinder, R. E.; Zhang, Z.; Widenhoefer, R. A. Org. Lett. 2008, 10, 3157.
  16. ↑ Siriwardana, A. I.; Kamada, M.; Nakamura, I.; Yamamoto, Y. J. Org. Chem. 2005, 70, 5932.
  17. ↑ a b Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546.
  18. ↑ Kim, J. Y.; Livinghouse, T. Org. Lett. 2005, 7, 1737.
  19. ↑ Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496.
  20. ↑ Molander, G. A.; Dowdy, E. D. J. Org. Chem. 1999, 64, 6515.
  21. ↑ Hong, S.; Kawaoka, A. M.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 15878.
  22. ↑ Fernandez, E.; Hooper, M. W.; Knight, F. I.; Brown, J. M. Chem. Commun. 1997, 173.
  23. ↑ Ciganek, E. Org. React. 2008, 72, 1. (link)
  24. ↑ Oppolzer, W.; Spivey, A. C.; Bochet, C. G. J. Am. Chem. Soc. 1994, 116, 3139.
  25. ↑ Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795.
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