Catalytic Asymmetric Hydroaminations (And Hydroalkoxylations, But Mostly Hydroaminations) Anna Allen MacMillan Group Meeting February 16, 2011 Hydroamination (and Hydroalkoxylation): An Outline Brief Introduction to Hydroaminations Rare Earth Metal-Catalyzed Asymmetric Hydroaminations Intramolecular reactions Intermolecular reactions Group 4 Metal-Catalyzed Asymmetric Hydroaminations Cationic metal catalysts Neutral metal catalysts Late Transition Metal-Catalyzed Asymmetric Hydroaminations Iridium-catalyzed reactions Palladium-catalyzed reactions Gold-catalyzed reactions Rhodium-catalyzed reactions Base-Catalyzed Asymmetric Hydroaminations Brønsted Acid-Catalyzed Asymmetric Hydroaminations Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. Aillaud, I.; Collin, J.; Hannedouche, J.; Schulz, E. Dalton Trans. 2007, 5105. Hultzsch, K. C. Adv. Synth. Catal. 2005, 347, 367. Hydroamination Reactions ! Amines are a valuable and commercially important class of compounds used for bulk chemicals specialty chemicals and pharmaceuticals synthesis of amines: OH NH2 O NH2 R R R R R R R R Br NH2 NO2 NH2 R R R R R R R R ! Most classical methods require refined starting materials and generate unwanted byproducts hydroamination reaction: NR2 R R2N H R R R H direct addition of an amine across a carbon-carbon multiple bond ! Hydroaminations are 100% atom economical and use simple and inexpensive starting materials Hydroamination Reactions hydroamination reaction: direct addition of an amine across a carbon-carbon multiple bond NR2 NR2 R R2N H R R R R2N H R R R R H H alkylamine vinylamine H H H H N N R R R NH2 R NH2 Why are hydroamination reactions not used more? Challenges: thermodynamically feasible (slightly exothermal) but entropically negative high reaction barrier repulsion between the nitrogen lone pair and the olefin/alkyne !-system regioselectivity (markovnikov vs. anti-markovnikov) for intermolecular reactions anti-markovnikov on the "Top 10 Challenges for Catalysis" in 1993 Haggins, J. Chem. Eng. News 1993, 71, 23. Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. Hydroamination Reactions hydroamination reaction: direct addition of an amine across a carbon-carbon multiple bond NR2NR2 NR2NR2 R R R2NR2NH H R R R R R R R2NR2NH H R R R R R R R R H H H H alkylamine vinylamine H H H H H H H H N N N N R R R R R R NH2NH2 R R NH2NH2 Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. Hydroamination Reactions hydroamination reaction: direct addition of an amine across a carbon-carbon multiple bond NR2NR2 NR2NR2 R R R2NR2NH H R R R R R R R2NR2NH H R R R R R R R R H H H H alkylamine vinylamine H H H H H H H H N N N N R R R R R R NH2NH2 R R NH2NH2 this talk focuses on generating enantioenriched amines Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. Rare Earth Metal Catalyzed Hydroaminations Rare Earth Metal-Catalyzed Intramolecular Hydroaminations: Seminal Work ! Seminal work of lanthanide-catalyzed hydroamination reaction was reported in 1989 by Marks using metallocene-based catalysts O La X(TMS) La H 2 Sm O 2 X = CH, N H N 1-5 mol% catalyst Me generally produces the exocyclic H2N n hydroamination product n H H H H N N Me N H Me Me N N Me Me Me Me Me TOF: 13 (25 ºC) 125 (25 ºC) 5 (60 ºC) 13 (80 ºC) 84 (25 ºC) (h–1) 140 (60 ºC) Gagné, M. R.; Marks, T. J. J. Am. Chem. Soc. 1989, 111, 4108. Gagné, M. R.; Nolan, S. P.; Marks, T. J. Organometallics 1990, 9, 1716. Mechanism for Rare Earth Metal-Catalyzed Hydroaminations ! Transformation proceeds through a rare earth metal amido species !+ H !– Ln X(TMS) R 2 R NH2 Ln N !– !+ XH(TMS)2 catalyst activation X = CH, N H N Ln H N R R olefin insertion protonolysis rate-limiting step "H ~ –13 kcal/mol "H ~ 0 kcal/mol R NH2 HN For aminoalkynes, aminoallenes, Ln conjugated aminodienes R olefin insertion: "H ~ –19 to –35 kcal/mol protonolysis: "H ~ 0 to +4 kcal/mol Rare Earth Metal Catalysts for Intramolecular Hydroamination ! Catalytic activity in rare earth metal-catalyzed hydroamination of aminoalkenes generally increase with increased accessibility to the metal center Me Me H catalyst Me N H2N Me Me Lu CH(TMS)2 Sm CH(TMS)2 La CH(TMS)2 0.977 Å 1.079 Å 1.160 Å <1 h–1 (80 ºC) 48 h–1 (60 ºC) 95 h–1 (25 ºC) increasing ionic radii / decreased steric encumbrance increasing reactivity Si Si Lu CH(TMS)2 Lu CH(TMS)2 Lu CH(TMS)2 N <1 h–1 (80 ºC) 75 h–1 (80 ºC) 90 h–1 (25 ºC) ! Trend usually holds for alkenes using metallocene catalysts, but alkynes often show reverse trend Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. Rare Earth Metal-Catalyzed Asymmetric Hydroamination: Seminal Work ! The first chiral lanthanocene catalysts were reported by Marks in 1992 Me Me Me Si Ln X(SiMe3)2 R* = Cp Cp Cp R* Me Me Me Me Me Me Ph Ln = La, Nd, Sm, Y, Lu X = CH, N (+)-neomenthyl (–)-menthyl (–)-phenylmenthyl Si Sm N(SiMe3)2 H N R* Me Me Me R* = (–)-menthyl H2N Me –30 ºC Me 74% ee (S) Gagné, M. R.; Brard, L.; Conticello, V. P.; Giardello, M. A.; Marks, T. J.; Stern, C. L. Organometallics, 1992, 11, 2003. Rare Earth Metal-Catalyzed Asymmetric Hydroamination: Seminal Work ! The first chiral lanthanocene catalysts were reported by Marks in 1992 Me Me Me Si R* = Ln X(SiMe3)2 Cp Cp Cp R* Me Me Me Me Me Me Ph Ln = La, Nd, Sm, Y, Lu X = CH, N (+)-neomenthyl (–)-menthyl (–)-phenylmenthyl Ha H H e H N N Si favoured Me favoured Si Ln Ln N He Ha R* R* Ha H He N HN Me Si Ln disfavoured disfavoured Si Ln N He Ha R* R* Gagné, M. R.; Brard, L.; Conticello, V. P.; Giardello, M. A.; Marks, T. J.; Stern, C. L. Organometallics, 1992, 11, 2003. Rare Earth Metal-Catalyzed Asymmetric Hydroamination: Seminal Work ! The first chiral lanthanocene catalysts were reported by Marks in 1992 Me Me Me Si R* = Ln X(SiMe3)2 Cp Cp Cp R* Me Me Me Me Me Me Ph Ln = La, Nd, Sm, Y, Lu X = CH, N (+)-neomenthyl (–)-menthyl (–)-phenylmenthyl ionic radii of rare earth metal effects the enantioselectivity maximum enantioseletivity observed with samarocene Hultzsch, K.C. Adv. Synth. Catal, 2005, 347, 367. Gagné, M. R.; Brard, L.; Conticello, V. P.; Giardello, M. A.; Marks, T. J.; Stern, C. L. Organometallics, 1992, 11, 2003. Rare Earth Metal-Catalyzed Asymmetric Hydroamination: Seminal Work ! The first chiral lanthanocene catalysts were reported by Marks in 1992 Me Me Me Si Ln X(SiMe3)2 R* = Cp Cp Cp R* Me Me Me Me Me Me Ph Ln = La, Nd, Sm, Y, Lu X = CH, N (+)-neomenthyl (–)-menthyl (–)-phenylmenthyl catalyst H Si Si N Sm N(SiMe3)2 (Me3Si)2N Sm Me H2N 25 ºC (–)-menthyl (–)-menthyl 62% ee (S) 60% ee (S) you can obtain 61% ee from a Si Si Si Sm N(SiMe3)2 (Me3Si)2N Y Sm CH(SiMe3)2 racemic precatalyst (±) ee of product is independent (+)-neomenthyl (+)-neomenthyl (+)-neomenthyl of ee of precatalyst 55% ee (R) 50% ee (R) 61% ee (R) Hong, S.; Marks, T. J.; Acc. Chem. Res. 2004, 37, 673. Gagné, M. R.; Brard, L.; Conticello, V. P.; Giardello, M. A.; Marks, T. J.; Stern, C. L. Organometallics, 1992, 11, 2003. Epimerization of Chiral Lanthanocene Complexes ! Marks' chrial lanthanocene complexes were found to epimerize under hydroamination conditions NHR Si Si Si Ln NHR Ln Ln N(SiMe3)2 NHR NH2R NH2R R* NH2R R* *R H But why does racemic catalyst give enantioenriched product? Si Si Si Ln E(SiMe3)2 Ln E(SiMe3)2 Ln E(SiMe3)2 (+)-neomenthyl (–)-menthyl (–)-phenylmenthyl 80:20 (R):(S) >95:5 (S):(R) 90:10 (S):(R) equilbrium ratio are independent of the epimer ratio of the precatalyst Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673. Chiral Rare Earth Metal Catalysts Based on Non-Cyclopentadienyl Ligands ! In 2003, new chiral hydroamination catalysts based on non-metallocene ligands were reported Chiral Bisarylamido and Aminophenolate Catalysts t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu OMe O Me N (THF)2 Me N N(SiHMe2)2 Me N Ln N(SiHMe2)2 La Y Me N THF Me N Me N N(SiHMe2)2 OMe O t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu Y 336 h, 50% ee 192 h, 21% ee 24 h, 11% ee Sm 168 h, 33% ee t-Bu La 168 h, 18% ee t-Bu O Me Me H Me N (THF)2 catalyst N La NH Me N(SiHMe ) 2 Me N O 2 2 60-70 ºC Me t-Bu 100% cv Me Complexes were shown to be configurationally t-Bu stable under hydroamination conditions 40 h, 61% ee O'Shaughnessy, P. N.; Scott, P. Tetrahedron: Asymmetry 2003, 14, 1979 Chiral Rare Earth Metal Catalysts Based on Non-Cyclopentadienyl Ligands ! Hultzsschch's' s3 3,3,3'-'b-bisi(st(rtirsiasaryrylslislyilyl)lb)bininaapphhththoolalatete c acatatalylsyts tc acann a allolloww f ofor rh higighheer re ennaanntiotioseselelectcivtiivtyity Me R1 R2 H N catalyst, Ln = Y Me NH2 22 ºC 2 R Si Me 3 >98% cv R1 Me2N O Ln O H H H Me N N N N 2 Me Me Me Ph Si Me Me Me Me 2 h, 53% ee 20 h, 83% ee 1.2 h, 65% ee, 1.4:1 dr Me 3 H H N N favoured Me disfavoured Me Gribkov, D.