Download Catalytic Asymmetric Hydroaminations

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:
NH2
OH
R
R
Br
R
R
R
R
R
R
NH2
R
NH2
O
NH2
NO2
R
R
R
R
R
R
R
! Most classical methods require refined starting materials and generate unwanted byproducts
hydroamination reaction:
NR2
R
R
R2N
H
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
R
R
R2N
H
NR2
R
R
R
R
R2N
H
R
R
H
H
alkylamine
vinylamine
H
R
R
NH2
H
H
N
R
H
N
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
R R
R R R NR NH H
2 2
R R
R R
NR2NR2
R R
R R R2NR2NH H
R R
H H
H H
alkylamine
vinylamine
H H
R R
NH2NH2
R R
R R
H H
H H
N N
R R
NH2NH2
H H
N N
R R
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
R R
R R R NR NH H
2 2
R R
R R
NR2NR2
R R
R R R2NR2NH H
R R
H H
H H
alkylamine
vinylamine
H H
R R
NH2NH2
R R
R R
H H
H H
N N
R R
NH2NH2
H H
N N
R R
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
La
X(TMS)2
La
O
H
Sm
O
2
X = CH, N
1-5 mol% catalyst
H2N
H
N
Me
generally produces the exocyclic
hydroamination product
n
n
Me
H
N
Me
H
N
Me
H
N
Me
H
N
Me
H
N
Me
Me
Me
TOF:
(h–1)
13 (25 ºC)
140 (60 ºC)
125 (25 ºC)
5 (60 ºC)
13 (80 ºC)
84 (25 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
Ln
X(TMS)2
R
R
NH2
XH(TMS)2
catalyst activation
!+
Ln
H !–
N
!–
!+
X = CH, N
Ln
H
N
H
N
R
R
olefin insertion
protonolysis
rate-limiting step
"H ~ –13 kcal/mol
R
"H ~ 0 kcal/mol
NH2
HN
Ln
R
For aminoalkynes, aminoallenes,
conjugated aminodienes
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
catalyst
H2N
Me
H
N
Me
Me
Lu
<1
La
Sm CH(TMS)2
CH(TMS)2
0.977 Å
1.079 Å
h–1
h–1
(80 ºC)
48
CH(TMS)2
1.160 Å
95 h–1 (25 ºC)
(60 ºC)
increasing ionic radii / decreased steric encumbrance
increasing reactivity
Lu
CH(TMS)2
<1 h–1 (80 ºC)
Si
Lu
CH(TMS)2
75 h–1 (80 ºC)
Si
Lu
N
CH(TMS)2
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
Si
Ln
Me
Me
R* =
X(SiMe3)2
Cp
Me
R*
Ln = La, Nd, Sm, Y, Lu
X = CH, N
(+)-neomenthyl
Si
Me
Me
Cp
Me
Me
(–)-menthyl
Ph
Me
(–)-phenylmenthyl
Sm N(SiMe3)2
R*
Me
Me
Cp
Me
H
N
R* = (–)-menthyl
H2N
–30 ºC
Me
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
Si
Ln
Me
Me
R* =
X(SiMe3)2
Cp
Me
R*
Ln = La, Nd, Sm, Y, Lu
X = CH, N
Me
(+)-neomenthyl
Cp
Me
Cp
Me
(–)-menthyl
Me
Ph
Me
(–)-phenylmenthyl
Ha
Si
H
N
He
favoured
Ln
Me
H
N
favoured
Si
Ln
N
Ha
R*
He
R*
Ha
Si
Ln
HN
He
disfavoured
Me
H
N
He
disfavoured
Si
Ln
N
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
Si
Ln
X(SiMe3)2
Me
Me
R* =
Cp
Me
R*
Ln = La, Nd, Sm, Y, Lu
X = CH, N
Me
(+)-neomenthyl
Cp
Me
Me
(–)-menthyl
Cp
Me
Ph
Me
(–)-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
Si
Ln
Me
Me
R* =
X(SiMe3)2
Cp
Me
R*
Ln = La, Nd, Sm, Y, Lu
X = CH, N
Me
(+)-neomenthyl
catalyst
Me
H2N
Me
H
N
Si
Cp
(–)-menthyl
Sm N(SiMe3)2
Me
Ph
Me
(–)-phenylmenthyl
(Me3Si)2N
Sm
Si
25 ºC
(–)-menthyl
62% ee (S)
Si
Me
Cp
Sm N(SiMe3)2
(Me3Si)2N
Y
Si
Si
Sm CH(SiMe3)2
(±)
(+)-neomenthyl
55% ee (R)
(+)-neomenthyl
50% ee (R)
(+)-neomenthyl
(–)-menthyl
60% ee (S)
you can obtain 61% ee from a
racemic precatalyst
ee of product is independent
of ee of precatalyst
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
Si
Ln
NHR
Si
NHR
Ln
NH2R
Si
Ln
NHR
R*
NH2R
R*
N(SiMe3)2
NH2R
*R H
But why does racemic catalyst give enantioenriched product?
Si
Ln
E(SiMe3)2
(+)-neomenthyl
80:20 (R):(S)
Si
Ln
E(SiMe3)2
(–)-menthyl
>95:5 (S):(R)
Si
Ln
E(SiMe3)2
(–)-phenylmenthyl
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
Me
N
Me
N
Ln
t-Bu
t-Bu
t-Bu
N(SiHMe2)2
Me
N
Me
N
t-Bu
t-Bu
La
O
OMe
N(SiHMe2)2
THF
OMe
Me
N
Me
N
O
N(SiHMe2)2
t-Bu
t-Bu
t-Bu
t-Bu
Y 336 h, 50% ee
Sm 168 h, 33% ee
La 168 h, 18% ee
(THF)2
Y
192 h, 21% ee
24 h, 11% ee
t-Bu
t-Bu
Me
Me
NH2
catalyst
60-70 ºC
100% cv
Me
H
N
Me
N
Me
N
O
La
O
N(SiHMe2)2
t-Bu
Me
Me
Complexes were shown to be configurationally
stable under hydroamination conditions
(THF)2
t-Bu
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
! Hultzsch's
Hultsch's 3,3'-bis(trisarylsilyl)binaphtholate
3,3'-bis(trisarylsilyl)binaphtholatecatalyst
catalystcan
canallow
allowfor
forhigher
higherenantioselectivity
enantioselectivity
Me
R1
R2
catalyst, Ln = Y
NH2
H
N
Me
22 ºC
R2
>98% cv
Me 3
Si
R1
Me2N
O
Me
H
N
Me
H
N
Me
H
N
Ph
Me
Si
Me
Me
2 h, 53% ee
Ln
O
Me2N
Me
20 h, 83% ee
1.2 h, 65% ee, 1.4:1 dr
Me
favoured
Me
H
N
disfavoured
Me
3
H
N
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
Chiral Rare
Rare Earth
Earth Metal
Metal Catalysts
Catalysts Based
Based on
on Non-Cyclopentadienyl
Non-Cyclopentadienyl Ligands
Ligands
!
Hultzsch's
3,3'-bis(trisarylsilyl)binaphtholatecatalyst
catalystcan
canallow
allowfor
forhigher
higherenantioselectivity
enantioselectivity
! Hultsch's
Hultsch's 3,3'-bis(trisarylsilyl)binaphtholate
3,3'-bis(trisarylsilyl)binaphtholate
catalyst
can
allow
for
higher
enantioselectivity
Me
Me
RR11
RR22
catalyst,
catalyst,Ln
Ln==YY
NH
NH22
Me
H
N
H
N
Me
Me
Me
2 h, 53%Meee
Me
2 h, 53% ee
HH
NN
Me
Me
22
22ºC
ºC
>98%
>98%cv
cv
Me
Me
H
N
H
N
Me
Me
Me
Me 33
Si
Si
RR22
RR11
Me
Me22NN
OO
Ln
Ln
OO
Me
Me22NN
H
N
H
N
Me
20 h, 83% ee
1.2 h, 65%Me
ee, 1.4:1 dr
20 h, 83% ee
1.2 h, 65% ee, 1.4:1 dr
Ph
Ph
Me
Me
Si
Si
Me
Me
Me
H
N
Me
H
N
Ln = Lu
Me
Me
14 h, 68% ee
16.5 h, 90% ee
H
N
H
N
Me
33
Me
Me
H
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
NHR3
R
R
5 mol% catalyst
R2
n
SiMe2Ph
R
N
n
R2
C6D6, 60 ºC
N
N
R3
S
Y
S
N(SiMe3)2
SiMe2Ph
Me
Me
Me
Me
Me
N
H
9h, 87% ee
Me
Me
Me
Me
Me
Ph
N
H
8h, 81% ee
Me
N
H
N
H
3h, 80% ee
(75 ºC)
3h, 82% ee
Me
N
Me
30h, 69% ee
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....
Li(THF)n
S
O
Pi-Pr2
N
Y
N
Ph
N(SiMe3)2
O
N
N
R
Ph
N
Ln
Ph
Ph
(Me3Si)2N N(SiMe3)2
Pi-Pr2
R
N
N
Ln
R
N
R
S
(Marks)
61% ee
Me
t-Bu
Me
O
Me
O
17-67% ee
Ph
(THF)n
Me
Ln
N
Y
N(SiMe3)2
N
N
17% ee
Ph
N
N(SiHMe2)2
N
Lu
t-Bu
8-36% ee
N
60-73% ee (Trifonov)
(Trifonov)
N
N
i-Pr
i-Pr
(Marks)
9-44% ee
N
N
Y
N
t-Bu
N(SiMe3)2
t-Bu
N
5% ee
N
N
N
Y
N
N(SiMe3)2
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
H2N
Me
Me
Me
Me
markovnikov
Me
H
N
anti-markovnikov
Me
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
5 mol% catalyst
R1
9 to 15 equiv
R2NH2
terminal alkene
primary amine
HN
benzene or toluene
150 ºC
R1
R2
Me2N
O
Y
O
Me2N
Me
≥ 85% cv
Ph
SiPh3
HN
Me
n
n=1
n=2
n=4
Ph
HN
Me
Ph
HN
Me
70%, 61% ee
54%, 61% ee
72%, 57% ee
Ph
59%, 51% ee
HN
Ph
Ph
Me
Me
72%, 56% ee
25%, --% ee
Me
HN
Me
3
HN
Me
61%, 61% ee
Ph
HN
Me
68%, 54% ee
Ph
HN
Me
67%, 56% ee
OMe
Me
3
Me
Ph
Me
75% cv, 73% de
HN
Me
3
Ph
Me
< 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
No protecting groups
PROS
Very low functional group tolerance
CONS
Non-activated alkenes and simple amines
Air and moisture sensitive - GLOVEBOX
Me
SiPh3
Me
Me2N
Si
Ln
SiMe2Ph
O
X(SiMe3)2
Y
O
Me2N
N
N
S
Y
Ph
R*
N(SiMe3)2
S
SiMe2Ph
Me
SiPh3
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
Me
Me
NHR3
H2N
Y-bisthiolate
60 ºC
Me
N
H
9 h, 87% ee
Me
Ph
HN
Y-binaphtholate
22 ºC
Me
Ph
Me
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
Ti
N
Me
Me
Ti
N
Me
NH
i-Pr
N
Ph
H
[Ti]
R
H
R
NR'
[Ti]
R
Ti
R
NMe2
NMe2
Me
O
Ti
NMe2
NMe2
t-Bu
NR'
markovnikov
R'NH2
Si
N
NR'
R'NH2
•
NMe2
N Me
NEt2
NR2
t-Bu
N
N
Ti
O 2
R
NEt2
Ti
NR2
Me
NMe2
N
Ti
N
Me
Me
Me
Me
i-Pr
Si
Ti
H
anti-markovnikov
Effective for both inter- and intramolecular
Less air and moisture sensitive
Better functional group tolerance
Many precatalysts commercially available
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
14e–, d0
Zr
Me
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
R R
n
n
H
N
10 mol% catalyst
R
100 ºC
Me
Me
R
N
Me
N
Me
N
R
O
B(C6F5)4
O
Ph
Zr
Me
100% cv
t-Bu
t-Bu
Me
Me
Me
N
Me
64% ee, 4 h
Me
N
Me
14% ee, 48 h
Me
Me
Me
N
Me
82% ee, 3 h
Me
N
Me
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
[Zr]–CH3
R
H
N
CH4
Me
H
N
R=H
[Zr]
R
R
N
R≠H
H
N
R
N
[Zr]
+
[Zr]
!–
[Zr]
N
catalytically
inactive
R !–
N
!+
! 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 nonactivated 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
catalyst
n
NH2
n
Ar
N
H
Ar
Mes
P O
N
Zr
N
P
Ar
Me
R2
NMe2
NMe2
O
Ar
Ar = 3,5-C6H3Me2
O
Mes
Me
Me
N
N
O
NMe2
Zr
Me2N
O
Zr
NMe2
O
H
N
O
Mes
R = Ph, t-Bu
Me2N
t-Bu
Zr
N
2
R
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
(2 substrates)
(3 substrates)
(7 substrates)
NMe2
t-Bu
Bergman, 2006
(8 substrates)
NMe2
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
catalyst
NH2
n
Ar
Me
N
H
Ar
Mes
P O
N
Zr
N
P
Ar
R2
n
O
Mes
NMe2
Me
NMe2
O
Me
N
N
O
NMe2
Zr
H
R = Ph, t-Bu
Schafer (Scott), 2007
Bergman, 2006
82-98%, 62-93% ee
33-99%, 33-80% ee
(8 substrates)
Me2N
t-Bu
N
O
Mes
Ar = 3,5-C6H3Me2
O
Zr
NMe2
O
Ar
Me2N
Zr
N
2
NMe2
t-Bu
R
Scott, 2008
Zi, 2009
>95%, 14-70% ee
83-100%, 38-72% ee
(2 substrates)
(3 substrates)
(7 substrates)
NMe2
Me
Me
Me
N
H
80%, 93% ee
Me
Me
N
H
91%, 88% ee
N
H
96%, 82% ee
Me
N
H
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
catalyst
n
NH2
n
Ar
N
H
Ar
Mes
P O
N
Zr
N
P
Ar
Me
R2
NMe2
NMe2
O
Ar
Ar = 3,5-C6H3Me2
O
Mes
Me
Me
N
N
O
NMe2
Zr
Me2N
O
Zr
NMe2
O
H
N
O
Mes
R = Ph, t-Bu
Me2N
t-Bu
Zr
N
2
R
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
(2 substrates)
(3 substrates)
(7 substrates)
NMe2
t-Bu
Bergman, 2006
(8 substrates)
NMe2
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
Me
H
N
[Zr]
N
[Zr]
protonolysis
[Zr]
N
[2 + 2]
cycloaddition
NH
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
R1
R2
10 mol% catalyst
NH2
n
n
Me
C6D6, 25 ºC
R2
Ph
N
N
H
O
Ph
Me
N
H
>95% cv, 93% ee
(98% ee in THF, 5d)
O
Me
N
H
>95% cv, 90% ee
Me
N
H
NMe2
N
Ph
Me
Me
N
H
89% cv, 89% ee
88% cv, 92% ee
NMe2
Zr
Me
Me
Ph
Me
B
N
H
>95% cv, 93, 92% ee, 1:1 dr
Ph
Ph
Ph
Me
Me
N
Me
0% cv, --% ee
N
H
24% cv, --% ee
Me
N
H
65% cv, 46% ee
Me
N
H
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
complex catalyzed
hydroaminations
areare
almost
exclusively
intramolecular
for alkenes
metal-catalyzed
asymmetric
hydroaminations
exclusively
intramolecuar
for alkenes
! Numerous examples of inter- and intramolecular hydroaminations for alkynes and allenes
PROS
No protecting groups
CONS
Less air and moisture sensitive
Intramolecular only for alkenes (non-strained)
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
Ph
NH2
Ph
10 mol% catalyst
C6D6, 25 ºC
Me
N
H
>95% cv, 93% IY
93% ee
Ph
B
N
O
O
N
Zr
NMe2
NMe2
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
Ir
78
79
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
Fe
44
28
29
46
47
78
79
30
Ni Cu Zn
45
Ru Rh Pd Ag
77
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
Fe
44
28
29
46
47
78
79
30
Ni Cu Zn
45
Ru Rh Pd Ag
77
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
Fe
44
28
29
46
47
78
79
30
Ni Cu Zn
45
Ru Rh Pd Ag
77
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(PEt3)2(C2H4)2Cl
NHPh
H
THF
Ir(PEt3)2(C2H4)2Cl
– 2 C2H4
NH2
NHPh
Ir(PEt3)2Cl
H
reductive elimination
oxidative addition
H
Et3P
Et3P
Ir
Cl
Ir(PEt3)2(NHPh)(H)Cl
N
Ph
H
Et3P
Et3P
Ir
Cl
coordination to exo face
NHPh
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
[N(P(NMe2)3)2
NHPh
H
]+F–
75 ºC
Me
Fe
Cy2
P
P
Ph2
Cl
Ir
Ir
Ph2
P
P
Cy2
Cl
81% IY, 38% ee
3.4 h –1
Me
Ph2
P
Fe
P
Ph2
Cl
Ir
Ir
Cl
Ph2
P
P
Ph2
22% IY, 95% ee
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
Ar
1 mol% [Ir(coe)2Cl]2
NH2
R
2 mol% (R)-DTBM-Segphos
R
R
2 mol% KHMDS
70 ºC
R
NHAr
H
R
O
P
Ar
O
P
Ar
Ar
O
t-Bu
Me
H
N
H
N
H
H
H
N
H
R = t-Bu
Br
OMe
CF3
Ar =
OMe
94%, 99% ee
85%, 92% ee
91%, 96% ee
75%, 98% ee
77%, 91% ee
88%, 99% ee
Me
H
N
H
Me
H
N
O
Me
90%, 99% ee
t-Bu
DTBM-Segphos
Me
R
OMe
H
N
O Me
Me
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
NH2
O
5 mol% [Pd(!-allyl)Cl]2
11 mol% ligand
H
N
R
O
NH
HN
R
23 ºC, 120 h
P
Ph2
P
Ph2
ligand
H
N
H
N
LnPd
63%, 92% ee
H
N
H
N
Me
PdLn
Me
59%, 90% ee
78%, 86% ee
H
N
PdLn
PhHN
H
N
PdLn
proton shift
EtO2C
NH2
F3C
83%, 95% ee
73%, 95% ee
PhH2N
Lober, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4366
Palladium-Catalyzed Asymmetric Intermolecular Hydroamination
successful palladium-catalyzed
hydroamination
of dienes
! In 2001, Hartwig reported the first enantioselective
palladium-catalyzed
hydroamination
of dienes
NH2
O
5 mol% [Pd(!-allyl)Cl]2
H
N
11 mol% ligand
R
O
NH
HN
R
23 ºC, 120 h
P
Ph2
P
Ph2
ligand
naphthyl units extremely
important for enantioselectivity
H
N
63%, 92% ee
H
N
H
N
Me
Me
59%, 90% ee
78%, 86% ee
H
N
EtO2C
O
O
NH
HN
P
Ph2
P
Ph2
H
N
H
N
73%, 95% ee
65%, 11% ee
F3C
83%, 95% 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
NH2
R
catalyst
R
R
H
N
N
H
R
R
markovnikov
R
anti-markovnikov
OMe
Me
O
Me
NMe2
N
Me
N
N
O
NMe2
O
OH
Me
Effexor
(Venlafaxine)
Duragesic
(Fentanyl)
H2N
NH2
Me
Exelon
(Rivastigmine)
HN
OMe
NH2
Me
O
N
H
O
Vyvanse
(Lisdexamfetamine)
Adderall
(Amphetamine &
Dextroamphetamine)
Concerta
(Methylphenidate)
Palladium-Catalyzed Asymmetric Intermolecular Hydroamination
! Several groups have developed hydroaminations of styrenes using aryl amines
Me
NH2
PdL*
R
Me
R
Pd-catalyzed reaction generally gives
markovnikov products
Me
Me
NHPh
N
H
PPh2
NHPh
NHPh
PPh2
MeO2C
F3C
80%, 81% ee
99%, 64% ee
70%, 84% ee
(Hartwig)
(Hartwig)
(Hu, SegPhos)
93%, 70% ee
(Hii)
O
MeO
Cl
t-Bu
NHPh
NHPh
NHPh
SiMe3
Me
Me
Me
Hartwig, Hii, Hu
85%, 72% ee
79%, 59% ee
(Hu, SegPhos)
(Hu, silyl BINAP)
PPh2
O
PPh2
PPh2
O
PPh2
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
Ph
H
N
5 mol% Pd(O2CCF3)2
10 mol% ligand
Me
50 mol% TfOH
dioxane, 50 ºC, 48 h
N
Ph
Me
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
Pd
X–
H
migratory insertion
into Pd-H
P
Ar
Ph
Ar
ArNH2
P
Pd
P
P
X
Pd
P
X
Ar
P
X
Me
Ph
(S)
Pd
P
Pd
N
H
Me
Ph
P
attack at C
inversion
Ar
Ar
Ph NH2
Me
P
Me
X–
Pd
H
NAr
Wacker-type
oxidation
Me
P
NH2Ar
X–
nucleophilic attack of amine
on activated arene
NHPh
(R)
Ph
Me
H
H
P
attack at Pd
retention
NHPh
(S)
Ph
H
Me
Nettekoven, U.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 1166.
Palladium-Catalyzed Hydroamination of Styrenes: Mechanism
P
Pd
X–
H
migratory insertion
into Pd-H
P
Ar
Ph
Ar
ArNH2
P
Pd
P
P
X
Pd
P
X
Ar
P
X
Me
Ph
(S)
Pd
P
Pd
N
H
Me
Ph
P
attack at C
inversion
Ar
Ar
Ph NH2
Me
P
Me
X–
Pd
H
NAr
Wacker-type
oxidation
Me
P
NH2Ar
X–
nucleophilic attack of amine
on activated arene
NHPh
(R)
Ph
Me
H
H
P
attack at Pd
retention
NHPh
(S)
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
H2N
R
catalyst
N
H
R
N
R
! Palladium-catalyzed hydroamination of alkynes proceeds through a different mechanism and creates a
stereocenter
PPh2
5-20 mol% Pd(dba)3
NHNf
n
25-100 mol% RENORPHOS
n
R
10-40 mol% PhCO2H
N
Nf
R
PPh2
(R,R)-RENORPHOS
N
Nf
Ph
N
NF
N
NF
OMe
93%, 91% ee
90%, 81% ee
85%, 88% ee
CF3
Ph
N
Nf
92%, 90% ee
Ph
NNf
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
PPh2
5-20 mol% Pd(dba)3
NHNf
n
25-100 mol% RENORPHOS
n
R
N
Nf
10-40 mol% PhCO2H
R
PPh2
(R,R)-RENORPHOS
P
hydridopalladation
Pd
OBz
!-elimination
P
NHNf
R
NHNf
R
P
P
Pd
P
Pd
H
P
OBz
OBz
•
R
NHNf
P
Pd
OBz
P
N
Nf
hydropalladation
R
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
PPh2
10 mol% Pd(dba)3
HO
n
60 mol% RENORPHOS
n
R
20 mol% PhCO2H
R
O
PPh2
(R,R)-RENORPHOS
Ph
O
O
O
OMe
52%, 80% ee
48%, 40% ee
60%, 82% ee
CF3
Ph
Ph
O
61%, 78% ee
O
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
•
PhNH2
C5H11
H
C5H11
NHPh
10 mol% AuBr3
THF 30 ºC
80%, 99% ee
C5H11
C5H11
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
R
NHPG
•
P
Au
X
P
Au
X
PG
N
R
R
R
PG = Ts (Toste, 41-99%, 70-99% ee)
Cbz (Widenhoefer, 61-99%, 34-91% ee)
Cl
O
MeO
PAr2AuCl
MeO
PPh2AuOPNB
PPh2AuOPNB
O
PPh2AuOPNB
MeO
PAr2AuCl
MeO
PPh2AuOPNB
PPh2AuOPNB
O
PPh2AuOPNB
O
(Toste)
(Widenhoefer)
(Toste)
(Toste)
Cl
! Scope of the reaction is limited to terminal and trisubstituted allenes
Ts
N
Ts
N
Me
Me
Me
Me
Ph
Ph
98%, 99% ee
Ph
97%, 81% ee
Ts
N
Cbz
N
Et
Et
Ph
Ph
70%, 88% ee
Toste
Ts
N
Cbz
N
Cbz
N
Ph
83%, 91% ee
Ph
Ph
91%, 76% ee
Widenhoefer
O
88%, 98% ee
79%, 98% ee
O
LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2452.
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
2.5 mol%
R
OH
•
P
Au
X
P
Au
X
O
R
MeO
PAr2AuCl
MeO
PAr2AuCl
5 mol% AgOTs
O
O
Ph
Ph
Ph
95%, 1:1 E/Z, 93, 95% ee
(from racemic alllene)
2.5 mol%
Me
NH
n
AuCl
P
AuCl
O
RN
MeN
Me
N
Me
n
markovnikov
O
Me
Me
5
86%, 76% ee
PhN
First intermolecular asymmetric
hydroamination catalyzed by gold(I)
substrate scope demonstrated for the
asymmetric variant is very limited
O
Me
Me
5
80%, 71% ee
OMe
t-Bu
96%, 88% ee
5 mol% AgOTf
simple amine
O
Ar =
Ph
88%, >20:1 Z/E, >95% ee
(from allene at 94% ee)
P
t-Bu
Ph
Ph
O
RN
C5H11
Ph
Ph
67%, 93% ee
O
O
Me
t-BuN
Me
Me
5
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
3 mol%
OH
•
P
P
AuCl
AuCl
PAr2AuCl
O
PAr2AuCl
3 mol% AgX
X = BF4, 4-(NO2)-C6H4CO2
52-89%, 0-8% ee
O
! Changing to a chiral counterion gave significantly better results
! Employing a chiral counterion gave significantly better results
OH
•
3 mol% dppm(AuCl)2
Chiral Au(I)
Catalysts
O
PAr2AuCl
O
PAr2AuCl
O
O
TRIP
5 mol% AgCat
CH2Cl2 76%, 65% ee
THF 83%, 76% ee
benzene 90%, 97% ee
O
O
O
P
O
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 wanted
to expand
withdistance
poor results
large
distance the scope of the hydroamination protocol, butlarge
3 mol%
OH
ligand•
Au+
P
P
AuCl
AuCl
PAr2AuCl
O
substrate
3 mol% AgX
X = BF4, 4-(NO2)-C6H4CO2
ligand
52-89%, 0-8% ee
O–
counterion
Au(I) complexes have linear coordination geometry
! Changing to a chiral counterion gave significantly better results
! Employing a chiral counterion gave significantly better results
OH
•
3 mol% dppm(AuCl)2
PAr AuCl
2
substrate
Au+
Chiral Au(I)
Catalysts
short
distance
O
PAr2AuCl
O
PAr2AuCl
O
O
TRIP
5 mol% AgCat
CH2Cl2 76%, 65% ee
THF 83%, 76% ee
benzene 90%, 97% ee
O
O
O
P
O
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
NHSO2Mes
•
R
R
SO2Mes
N
SO2Mes
N
5 mol% PhMe2PAuCl
5 mol% AgCat
R
R
SO2Mes
N
SO2Mes
N
Me
Me
Me
97%, 96% ee
88%, 98% ee
TRIP
Me
O
O
O
P
O
84%, 99% ee
TRIP
Chiral Counterion
R
OH
•
R
O
2.5 mol% dppm(AuCl)2
R
5 mol% AgCat
R
O
Me
Me
90%, 97% ee
O
91%, 95% ee
Me
O
Me
Me
O
Me
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
RN
NH
2.5 mol%
P
AuCl
P
AuCl
5 mol% AgOTf
Me
n
xylenes, 100 ºC
Widenhoefer, 2009
O
RN
Me
N
Me
n
H
N
?
H2N
R
R
R
R
What about the benchmark reaction?
Me
Rhodium-Catalyzed Asymmetric Hydroamination of Aminoalkenes
! In 2010, Buchwald introduced the first rhodium enantioselective hydroamination of aminoalkenes
Ar
Ar
N
H
N
5 mol% [Rh(cod)2]BF4
R
6 mol% ligand
R
OCHPh2
Me
PCy2
R
R
Ligand
Ph
Ph
Me
N
N
Me
H
N
Me
[Rh]+
Ph
Ph
R
L
L = cod or solvent
90%, 83% ee
Ph
Ph
48%, 90% ee
H
N
N
H
R
R
o-Tol
[RhH+]
o-Tol
N
Me
N
[Rh]+
Ph
Me
R
Ph
H
N
OCHPh2
[Rh]
Me
Me
75%, 62% ee
N
intramolecular
proton transfer
80%, 63% ee
Ph
Ph
[Rh] =
P 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
R
O
R
R
hydroamination and hydroalkoxylation
O
O
O
P
TRIP
O
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
NH3
CH2
NH2
Me
200 ºC, 1000 atm
Me
N
H
Me
Me
N
Me
70%
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"
R
slow
M
R
N
H
R'
N
M
R
M
N
R"
R
R'
R
H
fast
H
R"
R
R
N
N
R
R
H
R
Deprotonation of the amine
enables nucleophilic attack
on non-activated alkenes
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
Br
Tf2O, toluene
30% K3PO4
HO
BF3K
Br
Pd(PPh3)4, Cs2CO3
NEt3, EtOH, 45 ºC
92%
TfO
87%
Me
N
H
Br
Br
1.2 equiv
1.5 equiv
n-BuLi, THF, –15 ºC
65%
Br
Me
N
N
1.
HN
bis-citrate salt
O
Br
Me
Cu, CuI, 8-HO-quinoline
140 ºC, 84%
N
N
Me
N
2. citric acid, EtOH, 83%
N
O
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
Me
Me
N
NH
NH
2 equiv n-BuLi
! Cyclization proceeds with high yields and moderate selectivity
R
R
NH2
H
N
2.5-10 mol% Li-Cat
Me
R
R
H
N
H
N
Me
H
N
Me
Ph
R
R
Me 96%, 68% ee
Ph 97%, 31% ee
-(CH2)4- 98%, 74% ee
Me
Me
Me
R=
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
Me
Me
N
NH
NH
2 equiv n-BuLi
! Cyclization proceeds with high yields and moderate selectivity
R
R
NH2
H
N
2.5-10 mol% Li-Cat
close proximity of the lithium atoms
is essential for catalyst performance
Me
R
Li
N
R
H
N
H
N
Me
H
N
N
Me
Me
Ph
R
R
Me 96%, 68% ee
Ph 97%, 31% ee
-(CH2)4- 98%, 74% ee
Me
Me
H
N
Me
Me
Me
R=
98%, 17% ee
Me
56%, 2% 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:
Me
Ph
Me
O
Me
O
N
N
Me
O
N
H
O
N
H
Me
N
H
99%, 84% ee
89%, 19% ee
99%, 79% ee
99%, 76% ee
99%, 71% ee
Me
Me
99%, 66% ee
Me
Me
Me
Me
98%, 91% ee
Me
Me
O
N
H
Me
Me
O
R
Me
R = i-Pr
t-Bu
CH2i-Pr
CH2Cy
CH2t-Bu
Ph
20 mol% HNi-Pr2
toluene, –60 ºC
Me
O
R
NMe
Me
O
N
NHMe
40 mol% catalyst
20 mol% n-BuLi
Me
Me
N
Me
Me
98%, 86% 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
toluene
Me
70%
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:
H
amine is more basic than the !-system of
the alkene/alkyne
TfOH
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
TsNH2
5 mol% TfOH
Me
toluene
70%
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
X*
N
H
N
R'
R
X*
R'
Me
X*
H
H
Me
R
chiral bronsted acid
hydrogen bonding anchors chiral
information close to the electrophile and
contributes to molecular organization
Electrostatic forces can hold conjugate base
in proximity to the carbocation but will lack
rigidity and poor enantiotopic discrimination
Non-Metal Catalysts: Acid-Catalyzed Asymmetric Hydroamination
! Recently (February 2011) Toste reported the first asymmetric acid-catalyzed hydroamination
NHTs
Me
Me
NHTs
or
•
Me
Me
Me
Me
Ts
N
Me
acid-catalyst
PhF, 23 ºC
Me
Me
Me
Me
67-99%, 80-99% ee
Ar
O
S
NHTs
Me
Me
Me
O
P
O
S
NHTs
SH
Me
Me
O
P O
S
O
S
P
SH
Ar
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
Me
Me
NHTs
or
•
Me
Me
Me
Me
Ts
N
Me
acid-catalyst
PhF, 23 ºC
Me
Me
Me
Me
67-99%, 80-99% ee
via dienes:
Ts
N
Me
Ts
N
Ts
N
Ar
Me
Me
Me
Me
98%, 96% ee
70%, 94% ee
Ts
N
Me
Ts
N
Me
Me
Me
3
TBSO
91%, 3.6:1 dr, 99, 80% ee
O
Me
Me
O
Me
Me
99%, 96% ee
91%, 97% ee
70%, 90% ee
Me
Ts
N
O
Me
SH
Ar
Ts
N
Me
Ts
N
S
P
90%, 4.7:1 dr, 95, 90% ee
Me
via allenes
Me
Me
Me
Me
t-Bu
O
t-Bu
Me
Me
Me
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
Si
Ln
B
N
X(SiMe3)2
O
O
N
Zr
NMe2
NMe2
R*
Late Transition Metal Catalysis
Base Catalysis
Acid Catalysis
intermolecular strained alkenes,
styrenes, conjugated dienes
intramolecular aminoalkenes
intramolecular aminodienes/allenes
intramolecular aminoalkene,
aminoallene, aminoalkyne
Ar
O
Ir
Pd
PPh2
Au Rh
PPh2
O
Ar
S
P
SH