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
! Hultszschch'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. V.; Hultzsch, K. C.; Hampel, F. J. Am. Chem. Soc. 2006, 128, 3748. Gribkov, D. V.; Hultzsch, K. C. Chem. Commun. 2004, 730. CChhiirraall RRaarree EEaarrtthh MMeettaall CCaattaallyyssttss BBaasseedd oonn NNoonn--CCyyccllooppeennttaaddiieennyyll LLiiggaannddss
!! HHuultltszscschchh's's' s 33 3,,33,3'-'-'b-bbiissi(s(t(trrtirsisiasaarryrylyslslisliyliylly)l)lb)bbinininaaappphhhtthhthooolalalatteete cc acaattaatalylylsystst tcc acaannn aa alllololowww ff ooforr r hh higigighhheeerr r ee ennnaaannnttioitoiosseseelelelecctctivitviivtityiyty
MMee 1 2 R 1 R 2 H R R NH ccaatatalylysst,t, L Lnn = = Y Y Me N NH2 Me NH2 22 ºC 22 ºC 2 Si Me RR2 Si Me 3 >98% cv 1 3 >98% cv RR1 Me2N Me2N H H H OO N N N Ln Me Me Me Ln OO H H H Me2N N N N Me2N Me Me Me Me PPhh Me Me Si Me Me Si Me 2 h, 53% ee 20 h, 83% ee 1.2 h, 65% ee, 1.4:1 dr Me Me 2 h, 53% ee 20 h, 83% ee 1.2 h, 65% ee, 1.4:1 dr Me Me 33 H N Me H Me N Me Ln = Lu Me 14 h, 68% ee 16.5 h, 90% ee
H H H N Me N Me Me N
Ph Ph 0.1 h, 80% ee 0.5 h, 78% ee 21 h, 55% ee
Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. J. Am. Chem. Soc. 2006, 128, 3748. Gribkov, D. V.; Hultzsch, K. C. Chem. Commun. 2004, 730. Chiral Rare Earth Metal Catalysts Based on Non-Cyclopentadienyl Ligands
! Livinghouse reported a bisthiolate yttrium complex showing less substrate dependence
Me
Me R SiMe2Ph R R NHR3 S 5 mol% catalyst n N R2 Y N(SiMe3)2 R 2 C D , 60 ºC N n R 6 6 N S R3 SiMe2Ph Me
Me
Me Me Me Me Me Me Ph Me N Me N Me N N Me N H H H H Me 9h, 87% ee 8h, 81% ee 3h, 80% ee 3h, 82% ee 30h, 69% ee (75 ºC)
Kim, J. Y.; Livinghouse, T. Org. Lett. 2005, 7, 1737. Other Chiral Rare Earth Metal Catalysts for Intramolecular Hydroamination
! There are still more chiral catalysts for intramolecular hydroamination....
S Li(THF)n O O R R Pi-Pr2 Ph Ph N N N N N Y N(SiMe3)2 Ln N Ln N N Ph Ph Pi-Pr2 R R (Me3Si)2N N(SiMe3)2 S
61% ee (Marks) 17-67% ee 60-73% ee (Trifonov) Me t-Bu Ph Ph
(THF)n Me O N N Ln N(SiHMe2)2 Me O Lu (Trifonov) N N Me t-Bu i-Pr i-Pr (Marks) 8-36% ee 9-44% ee
N N N N N N t-Bu Y N(SiMe3)2 Y N(SiMe ) 3 2 t-Bu Y N N N N N N N(SiMe3)2
17% ee 5% ee 11% ee Intermolecular Hydroamination Catalyzed by Rare Earth Metal Catalysts
! Only a very limited number of reports of of rare earth catalyzed intermolecular reactions, both racemically and enantioselectively
Primary Challenge: inefficient competition between strongly binding amines and weakly binding alkenes for vacant coordination sites
rate = k[amine]0[alkene]1[catalyst]1
large excess of alkene is generaly required, contradicting the atom economical aspect of hydroaminations
New Consideration: regioselectivity (Markovnikov vs. anti-Markovnikov)
HN Me H N Me Me H2N Me Me Me Me markovnikov anti-markovnikov Asymmetric Intermolecular Hydroamination Catalyzed by Rare Earth Metals
! In 2010 Hultzsch reports the first (and to date the only) asymmetric intermolecular hydroamination using a chiral binaphtholate yttrium catalyst
SiPh3
2 R Me2N 5 mol% catalyst HN 1 2 R R NH2 O benzene or toluene Y 9 to 15 equiv R1 Me O 150 ºC terminal alkene primary amine Me2N ≥ 85% cv Ph
SiPh3
HN Ph HN Ph HN Ph HN Ph Me Me n Me Me Ph Me
n = 1 70%, 61% ee 59%, 51% ee 72%, 56% ee 25%, --% ee n = 2 54%, 61% ee n = 4 72%, 57% ee
Me Me
HN HN HN HN Ph HN Ph
OMe Me 3 Me Ph Me Ph Me Me 3 Me Me 3 Me
61%, 61% ee 68%, 54% ee 67%, 56% ee 75% cv, 73% de < 20%, --% de
Reznichenko, A. L.; Nguyen, H.N.; Hultszch, K. C. Angew. Chem. Int. Ed. 2010, 49, 8984. Rare Earth Metal Catalyzed Hydroaminations: Summary
! Rare earth metal catalyzed hydroaminations are almost exclusively restricted to intramolecular
PROS No protecting groups CONS Very low functional group tolerance Non-activated alkenes and simple amines Air and moisture sensitive - GLOVEBOX
Me
SiPh3
Me2N Me Si SiMe2Ph Ln X(SiMe3)2 O Y S O N Y N(SiMe3)2 Me2N N S R* Ph SiMe2Ph SiPh3 Me ansa-Metallocene binaphtholate/biphenolate bisthiolate (Marks) (Marks, Hultzsch, Scott) (Livinghouse) Me
! Current Asymmetric State of the Art - Livinghouse's bisthiolate and Hultzsch's binaphtholate catalysts
Me Me 3 HN Ph Me NHR Y-bisthiolate H2N Ph Y-binaphtholate Me 60 ºC Me N Me Me H Me 22 ºC 9 h, 87% ee 72, 61% ee Group 4 Metal-Catalyzed Hydroaminations Group 4 Metal-Catalyzed Hydroamination
! Early studies of group 4 metals as catalysts for hydroamination restricted scope to alkynes and allenes
Me
Me N Me NR Ti Ti Si Ti 2 Ti Me N NH Me N NR Me Me 2 Me Me
NMe2 N t-Bu i-Pr N Ti NMe NMe i-Pr 2 Si NMe2 2 Ti Me O Ti N NEt2 N N NMe Ph Ti 2 NMe2 N Me O 2 NEt2 t-Bu
R H [Ti] NR' NR' Effective for both inter- and intramolecular
R'NH2 R H R H Less air and moisture sensitive markovnikov anti-markovnikov Better functional group tolerance R NR' • [Ti] Many precatalysts commercially available
R'NH2 R Me
Müller, T. E.; Hultzsch, K.C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008,108, 3795. Group 4 Metal-Catalyzed Hydroamination of Alkenes
! Cationic group 4 metal complexes are isoelectronic to lanthanocene complexes so should have similar reactivity
MeB(C6F5)3
La CH(TMS)2 Zr Me
14e–, d0 14e–, d0
! Scope of group 4 metal-catalyzed hydroaminations should be able to include aminoalkenes
Gribkov, D. V.; Hultzsch, K.C. Angew. Chem. Int. Ed. 2004,43, 5452. Knight, P. D.; Munslow, P. N.; O'Shaughnessy, Scott, P. Chem. Commun. 2004, 894. Group 4 Metal-Catalyzed Hydroamination of Alkenes
! Cationic group 4 metal complexes are isoelectronic to lanthanocene complexes so should have similar reactivity ! In 2004 both Hultzsch (racemic) and Scott (enantioselective) reported cationic zirconium catalysts for the intramolecular hydroamination of alkenes using secondary amines
t-Bu
Scott: t-Bu R Me R B(C F ) R R n O 6 5 4 H 10 mol% catalyst Me N N Me Zr N Me N n R 100 ºC O Ph R Me 100% cv t-Bu
t-Bu
Me Me Me Me
Me N Me N Me N Me N Me Me Me Me 64% ee, 4 h 14% ee, 48 h 82% ee, 3 h 20% ee, 3 h
Gribkov, D. V.; Hultzsch, K.C. Angew. Chem. Int. Ed. 2004,43, 5452. Knight, P. D.; Munslow, P. N.; O'Shaughnessy, Scott, P. Chem. Commun. 2004, 894. Mechanism of Cationic Group 4 Metal-Catalyzed Hydroamination
! Hydroamination reactions with cationic group 4 metal complexes proceed through an analogous mechanism to the rare earth metal catalysts
H N [Zr]–CH3 R CH4
H Me N R = H [Zr] N R N [Zr] catalytically R ≠ H inactive H N R
R + R !– N [Zr] N [Zr] !– !+
! Primary aminoalkenes result in no reaction because cationic zirconium amido species are readily deprotonated to yield catalytically inactive zirconium imido species
! Neutral metal imido species operate by a different mechanism and are unreactive towards non- activated alkenes using these catalysts
Gribkov, D. V.; Hultzsch, K.C. Angew. Chem. Int. Ed. 2004,43, 5452. Knight, P. D.; Munslow, P. N.; O'Shaughnessy, Scott, P. Chem. Commun. 2004, 894. Asymmetric Neutral Group 4 Metal-Catalyzed Hydroamination
! In recent years, several groups have developed chiral neutral zirconium catalysts for primary amines
R1 R1 R2 R2 catalyst n NH2 n Me N H
Ar Ar Mes P O O Mes NMe2 N Zr NMe2 O Zr Me N t-Bu Me2N N 2 NMe2 NMe2 Me N O NMe2 Zr 2 Zr N Me N O NMe2 P O N H t-Bu Ar Ar O Mes R = Ph, t-Bu R Ar = 3,5-C6H3Me2
Bergman, 2006 Schafer (Scott), 2007 Scott, 2008 Zi, 2009 33-99%, 33-80% ee 82-98%, 62-93% ee >95%, 14-70% ee 83-100%, 38-72% ee (8 substrates) (7 substrates) (2 substrates) (3 substrates)
substrates require !-geminal substitution generally restricted to pyrrolidines
Watson, D. A.; Chiu, M.; Bergman, R. G. Organometallics 2006, 25, 4731. Bexrud, J. A.; Beard, J. D.; Leitch, D. C.; Schafer, L. L. Angew. Chem. Int. Ed. 2007, 46, 354. Gott, A. L.; Clarke, A. J.; Clarkson, G. J.; Scott, P. Chem. Commun. 2008, 1422. Zi, G.; Liu, X.; Xiang, L.; Song, H. Organometallics 2009, 28, 1127. Asymmetric Neutral Group 4 Metal-Catalyzed Hydroamination
! In recent years, several groups have developed chiral neutral zirconium catalysts for primary amines
R1 R1 R2 R2 catalyst n NH2 n Me N H
Ar Ar Mes P O O Mes NMe2 N Zr NMe2 O Zr Me N t-Bu Me2N N 2 NMe2 NMe2 Me N O NMe2 Zr 2 Zr N Me N O NMe2 P O N H t-Bu Ar Ar O Mes R = Ph, t-Bu R Ar = 3,5-C6H3Me2
Bergman, 2006 Schafer (Scott), 2007 Scott, 2008 Zi, 2009 33-99%, 33-80% ee 82-98%, 62-93% ee >95%, 14-70% ee 83-100%, 38-72% ee (8 substrates) (7 substrates) (2 substrates) (3 substrates)
Me Me
Me N Me N Me N Me N H H H H 80%, 93% ee 91%, 88% ee 96%, 82% ee 88%, 74% ee Watson, D. A.; Chiu, M.; Bergman, R. G. Organometallics 2006, 25, 4731. Bexrud, J. A.; Beard, J. D.; Leitch, D. C.; Schafer, L. L. Angew. Chem. Int. Ed. 2007, 46, 354. Gott, A. L.; Clarke, A. J.; Clarkson, G. J.; Scott, P. Chem. Commun. 2008, 1422. Zi, G.; Liu, X.; Xiang, L.; Song, H. Organometallics 2009, 28, 1127. Asymmetric Neutral Group 4 Metal-Catalyzed Hydroamination
! In recent years, several groups have developed chiral neutral zirconium catalysts for primary amines
R1 R1 R2 R2 catalyst n NH2 n Me N H
Ar Ar Mes P O O Mes NMe2 N Zr NMe2 O Zr Me N t-Bu Me2N N 2 NMe2 NMe2 Me N O NMe2 Zr 2 Zr N Me N O NMe2 P O N H t-Bu Ar Ar O Mes R = Ph, t-Bu R Ar = 3,5-C6H3Me2
Bergman, 2006 Schafer (Scott), 2007 Scott, 2008 Zi, 2009 33-99%, 33-80% ee 82-98%, 62-93% ee >95%, 14-70% ee 83-100%, 38-72% ee (8 substrates) (7 substrates) (2 substrates) (3 substrates)
substrates require !-geminal substitution generally restricted to pyrrolidines
Watson, D. A.; Chiu, M.; Bergman, R. G. Organometallics 2006, 25, 4731. Bexrud, J. A.; Beard, J. D.; Leitch, D. C.; Schafer, L. L. Angew. Chem. Int. Ed. 2007, 46, 354. Gott, A. L.; Clarke, A. J.; Clarkson, G. J.; Scott, P. Chem. Commun. 2008, 1422. Zi, G.; Liu, X.; Xiang, L.; Song, H. Organometallics 2009, 28, 1127. Mechanism of Neutral Group 4 Metal-Catalyzed Hydroamination
! Hydroamination reactions with neutral group 4 metal complexes proceed through a [2 + 2] cycloaddition of a metal imido species and the alkene
LnZr NMe2 H2N
HNMe2
H Me N
[Zr] N
[Zr] N [2 + 2] cycloaddition NH protonolysis [Zr] N
Me [Zr] N
H2N
Bexrud, J. A.; Bear, J. D.; Leitch, D. C.; Schafer, L. L. Org. Lett. 2005, 7, 1959. Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. Asymmetric Neutral Group 4 Metal-Catalyzed Hydroamination
! This year (Jan 2011) Sadow reported a highly enantioselective intramolecular hydroamination
R1 1 2 2 R R R Ph B 10 mol% catalyst n Zr NMe2 NH2 N NMe n C D , 25 ºC Me N 2 6 6 N O H O
Ph Me Me Ph Me
Me Me Me Me Me N N N N N H H H H H >95% cv, 93% ee >95% cv, 90% ee 88% cv, 92% ee 89% cv, 89% ee >95% cv, 93, 92% ee, 1:1 dr (98% ee in THF, 5d)
Ph Ph Ph Ph Me Me N N Me N Me N Me H H H 0% cv, --% ee 24% cv, --% ee 65% cv, 46% ee 48% cv, 31% ee
generally restricted to !-geminal substituted pyrrolidines
Manna, K.; Xu, S.; Sadow, A. D. Angew. Chem. Int. Ed. 2011, 50, ASAP. Group 4 Hydroaminations: Summary
! Group 4 metal -coamtaplylezex dc aatsaylymzmede thriycd hroyadmroianmatiinoantsio anrse aarlem eoxsct leuxscivlueslyiv ienltyra imntoralemcoulaerc fuolar ra flkoer naelksenes ! Numerous examples of inter- and intramolecular hydroaminations for alkynes and allenes
PROS No protecting groups CONS Intramolecular only for alkenes (non-strained) Less air and moisture sensitive Scope limited (ie, pyrrolidines with !-substitution) More functional group tolerance (halides, ethers, nitriles)
! Current Asymmetric State of the Art - Sadow's neutral zirconium catalyst for primary aminoalkenes
Ph Ph B Ph Ph Ph Zr NMe 10 mol% catalyst N 2 NH2 NMe2 Me N C6D6, 25 ºC N O H O >95% cv, 93% IY 93% ee Late Transition Metal-Catalyzed Hydroaminations Late Transition Metal-Catalyzed Asymmetric Hydroamination
! Late transition metals are highly attractive and desirable for asymmetric hydroaminations
Higher functional group tolerance Lowest air and moisture sensitivity
28 29 30 Ni Cu Zn
44 45 46 Ru Rh Pd
77 78 79 Ir Pt Au
! Most substrates are restricted to activated substrates, such as strained olefins, styrenes, dienes, alkynes Late Transition Metal-Catalyzed Asymmetric Hydroamination
! Late transition metals are highly attractive and desirable for asymmetric hydroaminations
Higher functional group tolerance Lowest air and moisture sensitivity
26 28 29 30 Fe Ni Cu Zn
44 45 46 47 Ru Rh Pd Ag
77 78 79 Ir Pt Au
! Most substrates are restricted to activated substrates, such as strained olefins, styrenes, dienes, alkynes Late Transition Metal-Catalyzed Asymmetric Hydroamination
! Late transition metals are highly attractive and desirable for asymmetric hydroaminations
Higher functional group tolerance Lowest air and moisture sensitivity
26 28 29 30 Fe Ni Cu Zn
44 45 46 47 Ru Rh Pd Ag
77 78 79 Ir Pt Au
! Most substrates are restricted to activated substrates, such as strained olefins, styrenes, dienes, alkynes Late Transition Metal-Catalyzed Asymmetric Hydroamination
! Late transition metals are highly attractive and desirable for asymmetric hydroaminations
Higher functional group tolerance Lowest air and moisture sensitivity
26 28 29 30 Fe Ni Cu Zn
44 45 46 47 Ru Rh Pd Ag
77 78 79 Ir Pt Au
! Most substrates are restricted to activated substrates, such as strained olefins, styrenes, dienes, alkynes Iridium-Catalyzed Intermolecular Hydroamination
! The first iridium-catalyzed hydromation was reported in 1989 by Milstein
NH2 Ir(PEt ) (C H ) Cl 3 2 2 4 2 NHPh THF H
Ir(PEt3)2(C2H4)2Cl
– 2 C2H4 NH2 NHPh H Ir(PEt3)2Cl
reductive elimination oxidative addition
H Et3P Ir Ir(PEt3)2(NHPh)(H)Cl Et3P N Cl Ph
H Et3P Ir coordination to exo face Et P NHPh 3 Cl
Casalnuovo, A. L.; Calabrese, J. C.; Milstein, D. J. Am. Chem. Soc. 1989, 110, 6738. Iridium-Catalyzed Intermolecular Hydroamination
! Inspired by Milstein, Togni and coworkers developed an asymmetric version in 1997
NH2 1 mol% [IrCl(PP)] 2 NHPh + – H [N(P(NMe2)3)2] F 75 ºC
Me Cy 2 Ph2 P Cl P Ph 2 Ph2 Ir Ir P Cl P P Cl P Ir Ir Fe Ph2 Cy Fe P 2 P Cl Me Ph2 Ph2
81% IY, 38% ee 22% IY, 95% ee 3.4 h –1 0.15 h –1
Fluoride required for yield and enatioselectivity
Possible roles: acts as a good !-donating ligand on iridium deprotonates aniline to generate anilide
Casalnuovo, A. L.; Calabrese, J. C.; Milstein, D. J. Am. Chem. Soc. 1989, 110, 6738. Iridium-Catalyzed Intermolecular Hydroamination
! In 2008, Hartwig and coworkers improved the iridium catalyzed hydroamination to provide high yields and enantioselectivities for a wider scope of bicyclic alkenes
O 1 mol% [Ir(coe)2Cl]2 Ar NH2 O Ar R 2 mol% (R)-DTBM-Segphos R NHAr P R H O P R 2 mol% KHMDS R Ar 70 ºC Ar O
t-Bu Me H H Ar = N N OMe H H OMe t-Bu H N Me DTBM-Segphos H R 94%, 99% ee 88%, 99% ee
R = t-Bu 85%, 92% ee Br 91%, 96% ee OMe 75%, 98% ee Me Me H CF3 77%, 91% ee H N N H H O N O Me Me Me
90%, 99% ee 84%, 98% ee
Zhou, J.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 12220. Palladium-Catalyzed Asymmetric Intermolecular Hydroamination
! In 2001, Hartwig reported the first enantioselective palladium-catalyzed hydroamination of dienes
O O 5 mol% [Pd(!-allyl)Cl] 2 H NH HN NH2 11 mol% ligand N R R 23 ºC, 120 h P P Ph2 Ph2
ligand
H N H N
LnPd
63%, 92% ee H H PdL N N n
PdLn Me Me PhHN 59%, 90% ee 78%, 86% ee
H H N N NH2 proton shift PdLn
EtO2C F3C 83%, 95% ee 73%, 95% ee PhH2N
Lober, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4366 Palllladium-Catallyzed Asymmetriic Intermollecullar Hydrrooaammiinaattiionn
! IIn 2001,, Harttwiig reportted tthe ffiirstt esnuaccnetisossfeulle pcativllaed piuamlla-dciautmal-yczaetda lhyzyeddro haymdirnoaatmionin aotfi odnie onfe dsienes
O O 5 mol% [Pd(!-allyl)Cl] 2 H NH HN NH2 11 mol% ligand N R R 23 ºC, 120 h P P Ph2 Ph2
ligand
naphthyl units extremely important for enantioselectivity H N
63%, 92% ee O O H H N N NH HN
Me Me P P Ph2 Ph2 59%, 90% ee 78%, 86% ee
H H H N N N
EtO2C F3C 83%, 95% ee 73%, 95% ee 65%, 11% ee
Lober, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4366 Palladium-Catalyzed Asymmetric Intermolecular Hydroamination of Styrenes
! Hydroamination of styrenes is a powerful synthetic transformation for benzylic or homobenzylic amines
Me H NH2 N catalyst N R R R H R R R
markovnikov anti-markovnikov
OMe
Me O N Me N Me N NMe NMe2 2 O O OH Me
Effexor Exelon NH (Venlafaxine) Duragesic 2 (Rivastigmine) (Fentanyl) Me HN H2N OMe NH2 Me O N O H Adderall Vyvanse (Amphetamine & Concerta (Lisdexamfetamine) Dextroamphetamine) (Methylphenidate) Palladium-Catalyzed Asymmetric Intermolecular Hydroamination
! Several groups have developed hydroaminations of styrenes using aryl amines
Me
NH2 Pd-catalyzed reaction generally gives PdL* N markovnikov products R R H
Me Me Me
PPh2 NHPh NHPh NHPh PPh2 MeO2C F3C
80%, 81% ee 99%, 64% ee 70%, 84% ee (Hartwig) (Hartwig) (Hu, SegPhos) Hartwig, Hii, Hu
Me SiMe3 t-Bu Me Me O NHPh NHPh NHPh O PPh2 PPh2 Cl MeO PPh PPh 93%, 70% ee 2 O 2 85%, 72% ee 79%, 59% ee (Hii) (Hu, SegPhos) (Hu, silyl BINAP) O
SiMe3 Hu t-Bu Limited to the addition of aryl amines
Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546. Li, K.; Horton, P. N.; Hursthouse, M. B.; Hii, K. K. J. Organomet. Chem. 2003, 665, 250. Hu, A.; Ogasawara, M.; Sakamoto, T.; Okada, A.; Nakajima, K.; Takahashi, T.; Lin, W. Adv. Synth. Catal. 2006, 348, 2051. Palladium-Catalyzed Asymmetric Intermolecular Hydroamination
! Hartwig reoptimized the reaction to be successful with secondary alkylamines
! Only one asymmetric example was reported with lower yield than the racemic variant
Me 5 mol% Pd(O2CCF3)2 H Ph N 10 mol% ligand N Ph Me 50 mol% TfOH Me dioxane, 50 ºC, 48 h 36%, 63% ee
Et
P Et Fe Et P
Et
Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 14286. Palladium-Catalyzed Hydroamination of Styrenes: Mechanism
– P X H Pd P migratory insertion Ar into Pd-H Ph Ar
ArNH2 X– P Me P P X H Pd Pd Pd P Ar P X P X
Wacker-type NAr PhNH2 oxidation P Me Ar Me Me Pd NH2Ar P – Ph Ar X Ph N nucleophilic attack of amine H on activated arene
NHPh attack at C (R) (S) Me inversion Ph Me H H Pd NHPh P P attack at Pd (S) retention Ph H Me
Nettekoven, U.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 1166. Palladium-Catalyzed Hydroamination of Styrenes: Mechanism
– P X H Pd P migratory insertion Ar into Pd-H Ph Ar
ArNH2 X– P Me P P X H Pd Pd Pd P Ar P X P X
Wacker-type NAr PhNH2 oxidation P Me Ar Me Me Pd NH2Ar P – Ph Ar X Ph N nucleophilic attack of amine H on activated arene
NHPh attack at C (R) (S) Me inversion Ph Me H H Pd NHPh P P attack at Pd (S) retention Ph H Me
Nettekoven, U.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 1166. Palladium-Catalyzed Intramolecular Asymmetric Hydroamination of Alkynes
! Hydroamination of alkynes usually does not introduce a new stereocenter
H N 2 catalyst R N N R H R
! Palladium-catalyzed hydroamination of alkynes proceeds through a different mechanism and creates a stereocenter
PPh NHNf 5-20 mol% Pd(dba)3 2 n 25-100 mol% RENORPHOS N R n PPh2 R 10-40 mol% PhCO2H Nf (R,R)-RENORPHOS
N Ph N N Nf NF NF
OMe CF3 93%, 91% ee 90%, 81% ee 85%, 88% ee
Ph
N Ph NNf Nf 92%, 90% ee 90%, 87% ee
Lutete, L. M.; Kadota, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 1622. Palladium-Catalyzed Intramolecular Asymmetric Hydroamination of Alkynes
! The palladium-catalyzed hydroamination of aminoalkynes proceeds through an allene
PPh NHNf 5-20 mol% Pd(dba)3 2 n 25-100 mol% RENORPHOS N R n PPh2 R 10-40 mol% PhCO2H Nf (R,R)-RENORPHOS
P OBz hydridopalladation Pd !-elimination P NHNf R
R NHNf P P OBz H Pd Pd P • P OBz R NHNf P Pd OBz P hydropalladation N R Nf R NNf
Lutete, L. M.; Kadota, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 1622. Palladium-Catalyzed Intramolecular Asymmetric Hydroalkoxylation of Alkynes
! Yamamoto was able to extend this methodology to the first asymmetric hydroalkoxylation, although with lower yield and selectivity
PPh HO 10 mol% Pd(dba)3 2 n 60 mol% RENORPHOS O R n PPh2 R 20 mol% PhCO2H (R,R)-RENORPHOS
O Ph O O
OMe CF3 52%, 80% ee 48%, 40% ee 60%, 82% ee
Ph
O Ph O 61%, 78% ee 57%, 86% ee
Why do we not see hydroalkoxylation as often as hydroamination? ! diminished nucleophilicity and weaker Lewis base character of oxygen ! high thermodynamic stability of O-H !-bonds (111 kcal vs 93 kcal for N-H)
Patil, N. T.; Lutete, L. M.; Wu, H.; Pahadi, N. K.; Gridnev, I. D.; Yamamoto, Y. J. Org. Chem. 2006, 71, 4270. Gold-Catalyzed Asymmetric Hydroamination Reactions
! The ability of gold complexes to activate carbon-carbon multiple bonds make them attractive candidates for hydroamination catalysts
! However, to date there are only a few reports of enantioselective hydroamination reactions
Yamamoto's chirality transfer (2006):
H NHPh • H 10 mol% AuBr3 PhNH2 80%, 99% ee C5H11 C H C H C5H11 THF 30 ºC 5 11 5 11
Nishina, N.; Yamamoto, Y. Angew. Chem. Int. Ed. 2006, 45, 3314. Gold(I)-Catalyzed Asymmetric Hydroamination of Aminoallenes
! The first enantioselective gold-catalyzed hydroaminations were by Toste and Widenhoefer in 2007 using dinuclear gold(I)-phosphine complexes with biaryl-based backbone
P Au X PG NHPG R N R • P Au X PG = Ts (Toste, 41-99%, 70-99% ee) R R Cbz (Widenhoefer, 61-99%, 34-91% ee)
Cl O
O MeO PAr2AuCl MeO PPh2AuOPNB PPh2AuOPNB PPh2AuOPNB
MeO PAr2AuCl MeO PPh2AuOPNB PPh2AuOPNB O PPh2AuOPNB
(Widenhoefer) (Toste) (Toste) (Toste) Cl O
! Scope of the reaction is limited to terminal and trisubstituted allenes
Ts Ts N N Me Me Cbz Cbz Cbz N N Et N Me Me Ph Ph Ph Ph Et Ph 98%, 99% ee 70%, 88% ee Ph Ph Ph Toste 97%, 81% ee 83%, 91% ee 91%, 76% ee Ts Ts N N Widenhoefer O LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2452. 88%, 98% ee 79%, 98% ee O Zhang, Z.; Bender, C. F.; Widenhoefer, R. A. Org. Lett. 2007, 9, 2887. Gold(I)-Catalyzed Asymmetric Hydroamination and Hydroalkoxylation
! Widenhoefer's general protocol can be extended to other substrate classes
P Au X OH R 2.5 mol% O MeO PAr2AuCl P Au X R • MeO PAr2AuCl 5 mol% AgOTs
O O Me O O t-Bu
Ph Ph Ph C5H11 Ph Ar = OMe Ph Ph Ph Ph t-Bu 67%, 93% ee 95%, 1:1 E/Z, 93, 95% ee 88%, >20:1 Z/E, >95% ee 96%, 88% ee (from racemic alllene) (from allene at 94% ee)
O O P AuCl Me First intermolecular asymmetric 2.5 mol% Me hydroamination catalyzed by gold(I) RN NH Me P AuCl RN N n n 5 mol% AgOTf substrate scope demonstrated for the simple amine markovnikov asymmetric variant is very limited
O Me O Me O Me Me Me Me MeN 5 PhN 5 t-BuN 5
86%, 76% ee 80%, 71% ee 89%, 78% ee Zhang, Z.; Lee, S. D.; Widenhoefer, R. A. J. Am. Chem. Soc. 2009, 131, 5373. Zhang, Z.; Widenhoefer, R. A. Angew. Chem. Int. Ed. 2007, 46, 283. Gold(I)-Catalyzed Asymmetric Hydroamination and Hydroalkoxylation
! Toste also wanted to expand the scope of the hydroamination protocol, but with poor results
P AuCl PAr2AuCl OH 3 mol% O P AuCl • PAr2AuCl 3 mol% AgX X = BF , 4-(NO )-C H CO 4 2 6 4 2 52-89%, 0-8% ee Chiral Au(I) Catalysts O
O PAr2AuCl
O PAr2AuCl ! Changing to a chiral counterion gave significantly better results ! Employing a chiral counterion gave significantly better results O
OH 3 mol% dppm(AuCl) O • 2 TRIP 5 mol% AgCat O O CH Cl 76%, 65% ee P 2 2 O O THF 83%, 76% ee benzene 90%, 97% ee TRIP Chiral Counterion
Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496. Gold(I)-Catalyzed Asymmetric Hydroamination and Hydroalkoxylation
! Toste also wanteldar tgoe edxisptaanncde the scope of the hydroamination protocol, butl awrgiteh dpisotoanr creesults
P AuCl PAr2AuCl OH 3 mol% O P AuCl PAr AuCl ligand• Au+ substrate ligand Au+ sub2strate 3 mol% AgX X = BF , 4-(NO )-C H CO 4 2 6 4 2 52-89%, 0-8% ee Chiral Au(I) Catalysts O– short Au(I) complexes have linear coordination geometry counterion distance O PAr2AuCl
O PAr2AuCl ! Changing to a chiral counterion gave significantly better results ! Employing a chiral counterion gave significantly better results O
OH 3 mol% dppm(AuCl) O • 2 TRIP 5 mol% AgCat O O CH Cl 76%, 65% ee P 2 2 O O THF 83%, 76% ee benzene 90%, 97% ee TRIP Chiral Counterion
Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496. Gold(I)-Catalyzed Asymmetric Hydroamination and Hydroalkoxylation
! Chiral counterion strategy allows for both hydroamination and hydroalkoxylation with high selectivity
SO2Mes NHSO2Mes R N R • 5 mol% PhMe2PAuCl R 5 mol% AgCat R
SO Mes SO Mes SO Mes 2 2 2 TRIP N N N Me
Me Me O O P Me O O 97%, 96% ee 88%, 98% ee 84%, 99% ee
TRIP Chiral Counterion
OH R 2.5 mol% dppm(AuCl) O R • 2 R 5 mol% AgCat R
O O Me Me O O Me Me Me Me
90%, 97% ee 91%, 95% ee 79%, 99% ee 81%, 90% ee
Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496. Rhodium-Catalyzed Asymmetric Hydroamination of Aminoalkenes
! Late-transition metal catalyzed asymmetric hydroaminations generally require activated substrates (allenes, strained alkenes, dienes, styrenes) or alkynes
NHR R • RHN R
C=C !-bond of an allene is ~ 10 kcal/mol less stable than the C=C !-bond of a simple alkene
! We've only seen one example of a simple alkene participating in a late transition metal-catalyzed hydroamination
O P AuCl 2.5 mol% O Me H RN NH N P AuCl Me ? Me H N RN N n 2 5 mol% AgOTf R R Me R n xylenes, 100 ºC R
Widenhoefer, 2009 What about the benchmark reaction? Rhodium-Catalyzed Asymmetric Hydroamination of Aminoalkenes
! In 2010, Buchwald introduced the first rhodium enantioselective hydroamination of aminoalkenes
Ar
N 5 mol% [Rh(cod)2]BF4 Me OCHPh2 Ar N H 6 mol% ligand PCy2 R R R R
Ligand
Ph Ph H Me N H N N N Me Me R [Rh]+ L Ph Ph L = cod or solvent Ph R N 90%, 83% ee 48%, 90% ee Ph H R N [Rh]+ + o-Tol o-Tol [RhH ] Ph N N R H Me Me Ph N OCHPh [Rh] 2 Me Me intramolecular Ph proton transfer Ph P Rh 75%, 62% ee 80%, 63% ee [Rh] = Cy2 L
Shen, X.; Buchwald, S. L. Angew. Chem. Int. Ed. 2010, 49, 564. Late Transition Metal-Catalyzed Hydroaminations: Summary
! Late transition metal-catalyzed hydroaminations (and hydroalkoxylations) are almost exclusively with activated alkenes and alkynes ! Enantioselective reactions have been developed using Ir, Pd, Au, Rh
PROS Good functional group tolerance CONS Limited examples for simple alkenes Least air and moisture sensitive Both inter- and intramolecular examples Higher enantioselectivities
! Current Asymmetric State of the Art - Toste's asymmetric counterion
TRIP
SO2Mes N R O R O O P O O R R hydroamination and hydroalkoxylation TRIP Base-Catalyzed Hydroaminations Main Group Metals: Base-Catalyzed Asymmetric Hydroamination
! Recent interest has focued on early and late transition metal catalysts but alkali metals have been known catalysts for over 50 years
Na or Li H2C CH2 NH3 Me NH Me N Me 200 ºC, 1000 atm 2 Me N Me 70% H Me
Howk, B. W.; Little, E. L.; Scott, S. L.; Whitman, G. M. J. Am. Chem. Soc. 1954, 76, 1899.
! Reaction proceeds through the highly nucleophilic alkali metal amide
R" slow
R R M R Deprotonation of the amine N H R' M N M N enables nucleophilic attack R R R" R on non-activated alkenes
R' H fast
H R R N H N R" R R Main Group Metals: Base-Catalyzed Asymmetric Hydroamination
! A base-catalyzed hydroamination has been used by Abbott Laboratories for a scalable synthesis of a histamine-3-inhibior
BF3K Br Br Br Tf2O, toluene 1.2 equiv 30% K PO HO 3 4 TfO Pd(PPh3)4, Cs2CO3 87% NEt3, EtOH, 45 ºC 92%
N Me Br H Br 1.5 equiv Me n-BuLi, THF, –15 ºC N 65%
N 1. HN
bis-citrate salt N O Br Cu, CuI, 8-HO-quinoline N Me Me 140 ºC, 84% O N N 2. citric acid, EtOH, 83% 36% overall yield 4 steps (+ salt formation) former synthesis: 8 steps
Ku, Y.-Y.; Grieme, T.; Pu, Y.-M.; Bhatia, A. V. Adv. Synth. Catal. 2009, 351, 2024. Main Group Metals: Base-Catalyzed Asymmetric Hydroamination
! Despite being known for over 50 years, there is very limited reports of asymmetric variants
Hultzsch, 2006:
N NH Me 2 equiv n-BuLi NH Me N
! Cyclization proceeds with high yields and moderate selectivity
H R R N 2.5-10 mol% Li-Cat Me NH2 R R
H H H N N N Me Me Ph R Me Me R Me R = Me 96%, 68% ee Ph 97%, 31% ee -(CH2)4- 98%, 74% ee 98%, 17% ee 98%, 1.2:1 dr, 64, 72% ee
Horrillo Martinez, P.; Hultzsch, K. C.; Hampel, F. Chem. Commun. 2006, 2221. Main Group Metals: Base-Catalyzed Asymmetric Hydroamination
! Despite being known for over 50 years, there is very limited reports of asymmetric variants
Hultzsch, 2006:
N NH Me 2 equiv n-BuLi NH Me N
! Cyclization proceeds with high yields and moderate selectivity close proximity of the lithium atoms H is essential for catalyst performance R R N 2.5-10 mol% Li-Cat Me NH2
R Li R N N H H H Me N N N Me Me Ph H N R Me Me Me R Me Me R = Me 96%, 68% ee Me 56%, 2% ee Ph 97%, 31% ee -(CH2)4- 98%, 74% ee 98%, 17% ee 98%, 1.2:1 dr, 64, 72% ee
Horrillo Martinez, P.; Hultzsch, K. C.; Hampel, F. Chem. Commun. 2006, 2221. Main Group Metals: Base-Catalyzed Asymmetric Hydroamination
! Asymmetric intramolecular hydroaminations can be carried out with catalytic n-BuLi and bisoxazolines
Tomioka, 2007:
40 mol% catalyst NHMe 20 mol% n-BuLi NMe
20 mol% HNi-Pr2 Ph toluene, –60 ºC Ph
Me Me Me Me Me Me Me Me Me Me O O O O O O O O Me
N N N N N N N N H H H H R R Me Me Me Me Me Me Me Me Me Me Me R = i-Pr 99%, 84% ee t-Bu 89%, 19% ee 99%, 66% ee 98%, 91% ee 98%, 86% ee CH2i-Pr 99%, 79% ee CH2Cy 99%, 76% ee CH2t-Bu 99%, 71% ee
diisopropylamine acts as an external protonating agent
Ogata, T.; Ujihara, A.; Tsuchida, S.; Shimizu, T.; Kaneshige, A.; Tomioka, K. Tetrahedron Lett. 2007, 48, 6648. Acid-Catalyzed Hydroaminations Non-Metal Catalysts: Acid-Catalyzed Asymmetric Hydroamination
! Brønsted acids have not been used extensively as catalysts in hydroamination reactions
NHTs 5 mol% TfOH TsNH2 Me 70% toluene
markovnikov
Li, Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N. W.; He, C. Org. Lett. 2006, 8, 4175.
! Reaction proceeds through the generation of a carbenium ion followed by attack of the amine
TfO Acid-Catalysis Challenge:
TfOH amine is more basic than the -system of H ! the alkene/alkyne
formation of ammonium salts destroys nucleophilicity and avoids activation of the !-system
NHTs TsNH2 Me Non-Metal Catalysts: Acid-Catalyzed Asymmetric Hydroamination
! Brønsted acids have not been used extensively as catalysts in hydroamination reactions
NHTs 5 mol% TfOH TsNH2 Me 70% toluene
markovnikov
Li, Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N. W.; He, C. Org. Lett. 2006, 8, 4175.
! There is an additional challenge that comes with enantioselective acid-catalyzed hydroaminations:
Proximity and Organization of Chiral Information
R' X* X* N H R' Me N R H Me X* H
R chiral bronsted acid hydrogen bonding anchors chiral Electrostatic forces can hold conjugate base information close to the electrophile and in proximity to the carbocation but will lack contributes to molecular organization rigidity and poor enantiotopic discrimination Non-Metal Catalysts: Acid-Catalyzed Asymmetric Hydroamination
! Recently (February 2011) Toste reported the first asymmetric acid-catalyzed hydroamination
NHTs NHTs Me Ts acid-catalyst Me N or Me Me • Me PhF, 23 ºC Me Me Me Me Me Me 67-99%, 80-99% ee
Ar
O S S S P O SH O P NHTs SH NHTs P O Me O S O Ar Me Me Me Me Me Me
Toste used a chiral Brønsted acid with a nucleophilic conjugate base that forms a covalent bond with the carbocation
Me Me
t-Bu t-Bu Me
Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature 2011, 470, 245. Non-Metal Catalysts: Acid-Catalyzed Asymmetric Hydroamination
! Recently (February 2011) Toste reported the first asymmetric acid-catalyzed hydroamination
NHTs NHTs Me Ts acid-catalyst Me N or Me Me • Me PhF, 23 ºC Me Me Me Me Me Me 67-99%, 80-99% ee via dienes:
Ts Ts Ts Ar Me N N N Me S Me Me Me Me Me O P Me Me Me O SH 98%, 96% ee 70%, 94% ee 90%, 4.7:1 dr, 95, 90% ee
Ts Ts Ts Ar Me N Me N Me N
3 Me Me Me TBSO Me
91%, 3.6:1 dr, 99, 80% ee 99%, 96% ee 91%, 97% ee
Me Me via allenes Ts Ts Me N N t-Bu t-Bu O O Me Me Me Me 70%, 90% ee 67%, 92% ee Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature 2011, 470, 245. Catalytic Asymmetric Hydroamination (and Alkoxylation)
! Five main catalytic pathways for asymmetric hydroamination reactions
Rare Earth Metal Catalysis Group 4 Metal Catalysis
intramolecular aminoalkenes intramolecular aminoalkenes intermolecular simple alkenes
Ph B Zr NMe2 Si Ln X(SiMe ) N 3 2 NMe N 2 O O
R*
Late Transition Metal Catalysis Base Catalysis Acid Catalysis
intermolecular strained alkenes, intramolecular aminoalkenes intramolecular aminodienes/allenes styrenes, conjugated dienes intramolecular aminoalkene, aminoallene, aminoalkyne Ar
O S P Ir Pd PPh2 O SH
Au Rh PPh2 Ar