Andy BrusoeAlexanian Lab

2

Nucleophilicityp y

Acidity and basicity

3Brotzel, F.; Chu, Y.C.; Mayr, H. J. Org. Chem., 2007, 72 3679

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

H d i tiHydroaminationAlkenes, Alkynes, Allenes

Allylic AminationAllylic Amination

Carbene and Nitrene InsertionsCarbene and Nitrene Insertions

5

ChallengesPoisoning of catalyst with aminesProducts reacting as nucleophilesRegioselectivityRegioselectivitySmall thermodynamic driving forceProduct racemization

6

7Zhou, J; Hartwig, J. J. Am. Chem. Soc., 2008, 130, 12220

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

9Zhou, J; Hartwig, J. J. Am. Chem. Soc., 2008, 130, 12220

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

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 =

NfNNf

MeO

93%98% ee

H

Narsireddy, M; Yamamoto, Y. J. Org. Chem. 2008, 73, 9705 12

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

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

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

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

H d i tiHydroaminationAlkenes, Alkynes, Allenes

Allylic Amination

Carbene and Nitrene Insertions

17

ChallengesPoisoning of catalyst with aminesProduct reacting as nucleophileProduct racemizationProduct racemizationRegioselectivity▪ Most metals give reaction at less substituted terminus

18

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

OP N

Ph

20Ohmura, T.; Hartwig, J. J. Am. Chem. Soc., 2002, 124, 15164

OP N

Ph

Phosphoramidite

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

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

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

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

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

26Madrahimov, S. T.; Markovic, D.; Hartwig, J.F. J. Am. Chem. Soc., 2009, 131, 7228

27Leitner, A.; Shu, C.; Hartwig J. F. Org. Lett., 2005, 7, 1093

28Leitner, A; Shu, C.; Hartwig, J.F. Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5830

29Yamashita, Y.; Gopalarathnam, A.; Hartwig, J. F. J. Am. Chem. Soc., 2007, 129, 7508

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

31

H d i tiHydroaminationAlkynes, Allenes, Alkenes

Allylic AminationAllylic Amination

Carbene and Nitrene Insertions

32

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

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

NHNs

86%

NHNs

82%86%74% ee

82%73% ee

35Reddy, R. P.; Davies, H. Org. Lett., 2006, 8, 5013

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

OORh

O

37Fiori, K.W.; Du Bois, J. J. Am. Chem. Soc., 2007, 129, 562

O Rh

Rh2(esp)2

NORh Rh

PhthN

Rh2(PTPI)422%, 54% ee

120 mV

38Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc., 2008, 130, 9220

N

O

NPh

Ph

39Liu, B.; Zhu, S.; Zhang, W.; Chen, C.; Zhou, Q. J. Am. Chem. Soc., 2007, 129, 5834

O

Ph

Ligand

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

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

E ik Al iErik Alexanian

Alexanian GrouppKayla BloomeLiz ClineBen GiglioBen GiglioJustin GoodwinVal Schmidt

42

43

44

22

45

46

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