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Andy BrusoeAlexanian Lab
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2
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Nucleophilicityp y
Acidity and basicity
3Brotzel, F.; Chu, Y.C.; Mayr, H. J. Org. Chem., 2007, 72 3679
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L t t iti t lLate transition metalsGreater functional group tolerance
Enantioinduction must occur concurrent with C-N bond formationNo imine reductions
Focus heavily on most recent chemistry
Most widely studied examples
4
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H d i tiHydroaminationAlkenes, Alkynes, Allenes
Allylic AminationAllylic Amination
Carbene and Nitrene InsertionsCarbene and Nitrene Insertions
5
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ChallengesPoisoning of catalyst with aminesProducts reacting as nucleophilesRegioselectivityRegioselectivitySmall thermodynamic driving forceProduct racemization
6
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7Zhou, J; Hartwig, J. J. Am. Chem. Soc., 2008, 130, 12220
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PNH2ArH Ir NHAr
P
NH2ArHArHN
IrP
NHArP
H
IrP
P
H
NNHArArHN H
Ar
H
8
IrP NHAr
PNHArZhou, J; Hartwig, J. J. Am. Chem. Soc., 2008, 130, 12220
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9Zhou, J; Hartwig, J. J. Am. Chem. Soc., 2008, 130, 12220
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Au(I)Ln*Cl
AgOTf
Au(I)Ln*
R2N H
R2N Au(I)Ln*
H
Au(I)Ln*
2 n
10Zhang, Z; Lee, S.D.; Widenhoefer, R. A. J. Am. Chem. Soc. 2009, 131, 5372NHR2
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N o-tolyl
80%63% ee
H
Ph
11Shen, X.; Buchwald, S.L.; Angew. Chem. Int. Ed. 2010, 49, 564Liu, Z.; Hartwig, J. J. Am. Chem. Soc. 2008, 130, 1570
O PhPCy2
Cy-Mop =
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NfNNf
MeO
93%98% ee
H
Narsireddy, M; Yamamoto, Y. J. Org. Chem. 2008, 73, 9705 12
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NPh HX
Ph
Pd0Ln
XPd(II)HLn
N
NNf
Nf
Pd(0)Ln
NHNf
PhXPd HLn
H PhNf
PhPd Ln
HX
H
XLnPd(II)
Ph
HNH
Nf
Nf
NHNf
XLnPd(II) Ph
13
Yamamoto et al.J. Am. Chem. Soc., 2004, 126, 1622J. Org. Chem. 2006, 71, 4270J. Org. Chem. 2008, 73, 9705
HNNf
Ph
HPd(II)LnX
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HTos n pentylCbz H
N
80%98% ee
TosN n-pentyl
PhPh
86%98% ee 86%6% ee
14LaLonde, R. L.; Sherry, B.D.; Kang, E. J.; Toste, F.D. J. Am. Chem. Soc. 2007, 129, 2452Zhang, Z.; Bender, F. B.; Widenhoefer, R. A. Org. Lett. 2007, 9, 2887
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N
2
R1N
R12.5% BiarylAu2Cl2
5% AgClO4N
R2
Ph Ph Ph
HCbz
H HCbz Cbz
NCbz H
NCbz H
R2R2m-Xylene
rt, 24 hR1
PhPh
PhPh
PhPh
N
i-Pr
PhPh
(Z)63%
(E)31%
N
C6H13
PhPh
(Z)90%
(E)9% 63%
95% ee31%
67% ee90%91% ee
9%9% ee
N
HCbzN Et
Cbz H
N t-BuCbz H
i-Bu
PhPh
(Z)72%
(E)27%
C6H13
(Z)70%
PhPh
(E)16%
PhPh
(E)50%
(Z)2%
15Zhang, Z.; Bender, F. B.; Widenhoefer, R. A. J. Am. Chem. Soc., 2007, 129, 14148
87% ee 54% ee 84% ee 47% ee rac 2% ee
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N
2
R1N
R12.5% BiarylAu2Cl2
5% AgClO4N
R2
Ph Ph Ph
HCbz
H HCbz Cbz
NHCbz NHCbz A LH Cbz Cb
R2R2m-Xylene
rt, 24 hR1
PhPh
PhPh
PhPh
NHCbz
PhPh
•
Et
BiarylAu2Cl2
AgClO4
NHCbz
PhPh
•
Et
AuL N
PhPh
AuL
Et
HH Cbz Cbz
N
PhPh
Et
H
BiarylAu2Cl2AgClO4
H CbzNHCbz
PhPh
•Et
BiarylAu2Cl2
AgClO4
NHCbz
PhPh
•Et
AuLN
PhPh
AuL
EtH
H Cbz CbzN
PhPh
EtH
16Zhang, Z.; Bender, F. B.; Widenhoefer, R. A. J. Am. Chem. Soc., 2007, 129, 14148
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H d i tiHydroaminationAlkenes, Alkynes, Allenes
Allylic Amination
Carbene and Nitrene Insertions
17
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ChallengesPoisoning of catalyst with aminesProduct reacting as nucleophileProduct racemizationProduct racemizationRegioselectivity▪ Most metals give reaction at less substituted terminus
18
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Not cheap, but not rhodium[Ir(COD)Cl]2 1g = $115 [Rh(COD)Cl]2 1g = $255 PdCl2(COD) 1g = $62[Ir(COD)Cl]2 1g $115, [Rh(COD)Cl]2 1g $255, PdCl2(COD) 1g $62
Preferentially gives branched substitution products
Phosphoramidites are most commonly used ligandsReadily available, easily made
OO
P N
Ar
Ar
OO
P Cl HN
Ar
Ar
OHOH
PCl3
19
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OP N
Ph
20Ohmura, T.; Hartwig, J. J. Am. Chem. Soc., 2002, 124, 15164
OP N
Ph
Phosphoramidite
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21
Weinhofen, R.; Tverskoy, O; Helmchen, G. Angew. Chem. Int Ed., 2006, 45, 5546Pouy, M. J.; Leitner, A.; Weix, L. D.; Weix, D. J.; Hartwig, J. F. Org. Lett., 2007, 9, 3949Stanley, L. M.; Hartwig, J. F. J. Am. Chem. Soc., 2009, 131, 8971Stanley, L. M.; Hartwig, J. F. Angew. Chem. Int. Ed., 2009, 7841Welter, C.; Dahnz, A.; Brunner, B.; Streiff, S.; Dubon, P.; Helmchen, G. Org. Lett., 2005, 7, 1239
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NH3Cl3
73%97%97% ee
NH3Cl
57%99% ee
22Pouy, M. J.; Stanley, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 11312
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ConsiderationsNature of [Ir]I
RegioselectivityRegioselectivityStereoselectivityRelative rates of amines as nucleophiles
23Kashio, M; Takeuchi, R. J. Am. Chem. Soc., 1998, 120, 8647Bartels, B.; Garcia-Yebra, C.; Rominger, F.; Helmchen, G. Eur. J. Inorg. Chem., 2002, 2569
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IrClCl
Ir2 eq L1
IrL1Cl
Catalytically inactive
Catalytically active
24Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig, J. F. J. Am. Chem. Soc., 2003, 125, 14272
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ligand conditions yield ratio A/B
P(OPh)3 RT, 3 h 89 96:4
PPh3 reflux, 16 h 6 24:76PPh3 reflux, 16 h 6 24:76
dppe reflux, 16 h 18 39:61
25Kashio, M; Takeuchi, R. J. Am. Chem. Soc., 1998, 120, 8647
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26Madrahimov, S. T.; Markovic, D.; Hartwig, J.F. J. Am. Chem. Soc., 2009, 131, 7228
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27Leitner, A.; Shu, C.; Hartwig J. F. Org. Lett., 2005, 7, 1093
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28Leitner, A; Shu, C.; Hartwig, J.F. Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5830
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29Yamashita, Y.; Gopalarathnam, A.; Hartwig, J. F. J. Am. Chem. Soc., 2007, 129, 7508
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N NH 4 mol% [Ir]N
MeO2CO PhN NH
2 eq
BnNH22 eq
MeI4 mol% [Ir]K3PO4 1eq
THF, 50 °C Ph
N
Ph
NHBn
99%26 : 74
N N BnNHMe
5 : 95 26 : 7418 : 82
5 : 95(no K3PO4)
BnNH2 is 20x more nucleophilic BnNH2 is ~3x more nucleophilic
30Stanley, L. M.; Hartwig, J. F. J. Am. Chem. Soc., 2009, 131, 8971
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31
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H d i tiHydroaminationAlkynes, Allenes, Alkenes
Allylic AminationAllylic Amination
Carbene and Nitrene Insertions
32
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Factors that govern site of insertionStrength of bond being brokenSteric environment at center of reactivitySteric environment at center of reactivityStatistics
88 88 98 92 113
33
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R R2
M N - H InsertionHN
R4R3 R R2
NR3 R4
HR R RR R R
RC
R2
H C - H InsertionMN
R3 RC
R2
NR3 H
H H
ChallengesStoichiometric oxidant present with reactive transition metalsOxidation of heteroatoms and ligandOxidation of heteroatoms and ligandLimiting cyclopropanation and aziridination
34
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NHNs
86%
NHNs
82%86%74% ee
82%73% ee
35Reddy, R. P.; Davies, H. Org. Lett., 2006, 8, 5013
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OO
BocN
OS
HN
98%92% ee
SOO
OOO
SHN
51%
OS
HN
OO
48%
36Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc., 2008, 130, 9220
51%54% ee
48%82% ee
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OORh
O
37Fiori, K.W.; Du Bois, J. J. Am. Chem. Soc., 2007, 129, 562
O Rh
Rh2(esp)2
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NORh Rh
PhthN
Rh2(PTPI)422%, 54% ee
120 mV
38Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc., 2008, 130, 9220
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N
O
NPh
Ph
39Liu, B.; Zhu, S.; Zhang, W.; Chen, C.; Zhou, Q. J. Am. Chem. Soc., 2007, 129, 5834
O
Ph
Ligand
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ArO
Ot BuNH2Boc
7% CuBr6% AgSbF68% ( ) bpy* Ar
O
Ot BuN2
Ot-Bu 8% (-)-bpy
DCE, rt
Ot-BuNHBoc
O
Ot-BuNHBoc
71%71%81% ee
OBr
Fe
O
Ot-BuNHBoc
86%
40Lee, E. C.; Fu, G. C. J. Am. Chem. Soc., 2007, 129, 12066(-)-bpy*
NFe
N86%85% ee
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Highly enantio-enriched amines can be synthesized from alkenes, alkynes, allenes, activated allylic alcohols and activated C-H bonds.
F t d l t d d i lk h d i ti d C H b d i tiFuture developments are needed in alkene hydroamination and C-H bond insertions.
41
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E ik Al iErik Alexanian
Alexanian GrouppKayla BloomeLiz ClineBen GiglioBen GiglioJustin GoodwinVal Schmidt
42
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43
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44
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22
45
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46
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OCO Me
2% [Ir(COD)Cl]24% Phosphoramidite
8% TBDTHF rt
HN
N
OCO2Me THF, rt
69%, 99% eeH2N
N
CbzCl, K2CO3CH2Cl2, rt66 - 82%
CbzN CbzN1) HCl, Et2O2) Grubbs II
N
1) TsNHNH2NaOAc96 °C
2) LAH, THFrt
OO
P N
o-anisyl
N N92%N 85%
36% overall99% ee
47Welter, C.; Moreno, R. M.; Streiff, S.; Helmchen, G. Org. Biomol. Chem., 2005, 3, 3266
O
o-anisyl
Phosphoramidite