Hydroamination

Literature Seminar 2016. 5. 14

Akinori Yamaguchi1

Amines in Biologically Amines in Biologically Amines in Biologically Amines in Biologically AAAActive ctive ctive ctive MMMMoleculesoleculesoleculesolecules

2

Strategies for Amine SynthesisStrategies for Amine SynthesisStrategies for Amine SynthesisStrategies for Amine Synthesis

31) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.

The Challenge for The Challenge for The Challenge for The Challenge for HydroaminationHydroaminationHydroaminationHydroamination

41) Brunet, J. J.; Neibecker, D.; Niedercorn, F. J. Mol. Catal. 1989, 49, 235.

Late Transition Metal CatalystsLate Transition Metal CatalystsLate Transition Metal CatalystsLate Transition Metal Catalysts

PdN

R1 R2+ PdH N

R1

R2

H

calatyst deactibationamine catalyst

Calatyst deactibation

With Brønsted acid cocatalyst

coordination

Ar+

Ar Me

RNAr'

HN

Ar' R

H+

25-100 °C

arylamine vinylarene

+ Pd

catalyst

51) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546.

Intermolecular, Markovnikov Intermolecular, Markovnikov Intermolecular, Markovnikov Intermolecular, Markovnikov HydroaminationHydroaminationHydroaminationHydroamination

NHR

X +

Pd(PPh3)4 (2 mol %)TFA (10 mol%)

toluene25 °C, 24 h

RN

X

N

R1 R2H

aliphatic amine

Ar+

Pd(OCOCF3)2 (5 mol %)DPPF (10 mol %)TfOH (20 mol %)

1,4-dioxane120 °C, 24 h Ar Me

NR1R2

Fe

PPh2

PPh2

DPPF =

NHR

X Ar+

Pd(OCOCF3)2 (2 mol %)DPPF (3 mol %)TfOH (20 mol %)

toluene100 °C, 7-12 h Ar Me

RN

X

6

1) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546.

2) Lober, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4366.

3) Pawlas, J.; Nakao, Y.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 3669.

Mechanistic StudyMechanistic StudyMechanistic StudyMechanistic Study

71) Nettekoven, U.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 1166.

Proposed MechanismProposed MechanismProposed MechanismProposed Mechanism

81) Nettekoven, U.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 1166.

Discovery Discovery Discovery Discovery of Antiof Antiof Antiof Anti----Markovnikov Markovnikov Markovnikov Markovnikov HydroaminationHydroaminationHydroaminationHydroamination

91) Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 126, 5608.

Mechanistic StudyMechanistic StudyMechanistic StudyMechanistic Study

RuPh2P PPh2

H

(cod)Ru

Ru(cod)(2-methylallyl)2

DPPPentTfOH

THF, rt

Ph

THF, 80 °C

isolated ( 6-styrene)Ru complex

OTf

RuPh2P PPh2

H

OTf

Stichometric reaction

O

HN

(20 eq.)

+

dioxane-NMP20 °C

RuPh2P PPh2

H

OTf

NO

RuPh2P PPh2

H

OTf

NO

dioxane-NMP100 °C

(40 eq.)

+ Ph RuPh2P PPh2

H

OTf

PhN

O

+

ligand exchange

nucleophilic attack

101) Takaya, J.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 5756.

Proposed Reaction MechanismProposed Reaction MechanismProposed Reaction MechanismProposed Reaction Mechanism

111) Takaya, J.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 5756.

Limitation: Narrow Substrate ScopeLimitation: Narrow Substrate ScopeLimitation: Narrow Substrate ScopeLimitation: Narrow Substrate Scope

121) Hannedouche, J.; Schulz, E. Chem. Eur. J. 2013, 19, 4972.

Initial Discovery of Initial Discovery of Initial Discovery of Initial Discovery of CuHCuHCuHCuH----Catalyzed Catalyzed Catalyzed Catalyzed HydroaminationHydroaminationHydroaminationHydroamination

13

Novel Mechanistic Novel Mechanistic Novel Mechanistic Novel Mechanistic Approach to Approach to Approach to Approach to HydroaminationHydroaminationHydroaminationHydroamination

141) Zhu, S.; NiljianSkul, N.; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135, 15746.

Proposed Reaction MechanismProposed Reaction MechanismProposed Reaction MechanismProposed Reaction Mechanism

151) Zhu, S.; NiljianSkul, N.; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135, 15746.

CuHCuHCuHCuH----Catalyzed Catalyzed Catalyzed Catalyzed HydroaminationHydroaminationHydroaminationHydroamination (1)(1)(1)(1)

161) Zhu, S.; NiljianSkul, N.; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135, 15746.

CuHCuHCuHCuH----Catalyzed Catalyzed Catalyzed Catalyzed HydroaminationHydroaminationHydroaminationHydroamination (2)(2)(2)(2)

171) Zhu, S.; NiljianSkul, N.; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135, 15746.

CuHCuHCuHCuH----Catalyzed Catalyzed Catalyzed Catalyzed HydroaminationHydroaminationHydroaminationHydroamination (3)(3)(3)(3)

R1

NR2

OBz

+

Cu(OAc)2 (2 mol %)(R)-DTBM-SEGPHOS

(2.2 mol %)

(EtO)2MeSiH (2 eq.)THF, 40 °C, 36 h

(1 eq.) (1.2 eq.)

88%, 60% ee

R

R'

R

R'

NR2

R1

-chiral amine

BnNBn2

Me

i-PrNBn2

Me

t-BuNBn2

Me

Me2PhSiNBn2

NC

90%, 83% ee 86%, 92% ee 58%, 92% ee

NBn2

MeO

91%, 80% ee

TrON

D

86%, 12:1 d.r.

Ph

OTBS

Me

Bn

NBn2

HMe

H

HH

MeO87%, >50:1 d.r.

estronederivative

(R)-DTBM-SEGPHOS

Ar = 3,5-(t-Bu)2-4-OMeC6H2

O

O

O

O

PAr2

PAr2

181) Zhu, S.; Buchwald, S. L. J. Am. Chem. Soc. 2014, 136, 15913.

Synthesis of Chiral Secondary AminesSynthesis of Chiral Secondary AminesSynthesis of Chiral Secondary AminesSynthesis of Chiral Secondary Amines

191) Niu, D.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 9716.

Unproductive Reduction of NUnproductive Reduction of NUnproductive Reduction of NUnproductive Reduction of N----O BondO BondO BondO Bond

LCuHN O

O

ArR

H

+ N

R

H

H

O

O

Ar

LCu

+

NMR competition experiment

BnN

O

OH

BnN

O

OBn Cu(OAc)2 (5 mol %), PPh3 (11 mol %)(R)-DTBM-SEGPHOS (5.5 mol %)

(EtO)2MeSiH (5 eq.)d8-THF, 40 °C, 1 h

+

(1 eq.) (1 eq.)

>80% redused <5% redused

BnN

O

OH

BnN

O

OH Cu(OAc)2 (5 mol %), PPh3 (11 mol %)(R)-DTBM-SEGPHOS (5.5 mol %)

(EtO)2MeSiH (5 eq.)d8-THF, 40 °C, 1 h

+

(1 eq.) (1 eq.)

~80% redused ~20% redused

H NMe2

reagent

reduction

201) Niu, D.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 9716.

DFT Calculation for the DFT Calculation for the DFT Calculation for the DFT Calculation for the HHHHydrocuprationydrocuprationydrocuprationydrocupration of Olefinsof Olefinsof Olefinsof Olefins

211) Yang, Y.; Shi, S.; Niu, D.; Liu, P.; Buchwald, S. L. Science 2015, 349, 62.

Proposed Catalytic CycleProposed Catalytic CycleProposed Catalytic CycleProposed Catalytic Cycle

221) Yang, Y.; Shi, S.; Niu, D.; Liu, P.; Buchwald, S. L. Science 2015, 349, 62.

HydrocuprationHydrocuprationHydrocuprationHydrocupration of of of of UnactivatedUnactivatedUnactivatedUnactivated Internal Internal Internal Internal OlefonsOlefonsOlefonsOlefons

R4N

O

OR3

(1 eq.)NEt2

RR

(3 eq.)

+

Cu(OAc)2 (5 mol %)(S)-DTBM-SEGPHOS (5.5 mol %)

(MeO)2MeSiH (3 eq.)THF, 45 °C, 36 h

R1 R2

NR4R3

Et Pr

NBnBn

83%, 98% ee

NBnBn

HOOH

61%, 97% ee

Me Et

NBn

76%, 97% ee

N

Me

Me Et

NBn

70%, 97% ee

OMe

Me Et

NBn

85%, 98% ee

OMeMeO

NMeCF3

EtMe

NMeCF3

EtMe

80%, >95:5 d.r.

with (R)-DTBM-SEGPHOS

81%, >95:5 d.r.

with (S)-DTBM-SEGPHOS

derivatization ofCinacalect

(calcimimetic)

231) Yang, Y.; Shi, S.; Niu, D.; Liu, P.; Buchwald, S. L. Science 2015, 349, 62.

Outlook Outlook Outlook Outlook

Ph Me

krel 6.6 x 105 1.2 x 102 1.1 x 102 1

more challenginghydrocupration

>1 >>1

Tri- and tertasubstituted alkenes

Aminating agents to transfer aromatic amines or ammonia

N OR

R

N OR

H

H

or

?

aromatic amine ammonia

241) Pirnot, M. T.; Wang, Y.; Buchwald, S. L. Angew. Chem. Int. Ed. 2016, 55, 48.

SummarySummarySummarySummary

25

AppendixAppendixAppendixAppendix

26

Classification of Classification of Classification of Classification of HydroaminationHydroaminationHydroaminationHydroamination: : : : RRRRegiochemicalegiochemicalegiochemicalegiochemical outcomeoutcomeoutcomeoutcome

271) Yang, Y.; Shi, S.; Niu, D.; Liu, P.; Buchwald, S. L. Science 2015, 349, 62.

28

1) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546.

PdPdPdPd----CatalizedCatalizedCatalizedCatalized Markovnikov Markovnikov Markovnikov Markovnikov HydroaminationHydroaminationHydroaminationHydroamination

291) Lober, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4366.

PdPdPdPd----CatalizedCatalizedCatalizedCatalized Markovnikov Markovnikov Markovnikov Markovnikov HydroaminationHydroaminationHydroaminationHydroamination

30

1) Pawlas, J.; Nakao, Y.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 3669.

PdPdPdPd----CatalizedCatalizedCatalizedCatalized Markovnikov Markovnikov Markovnikov Markovnikov HydroaminationHydroaminationHydroaminationHydroamination

Competition ExperimentCompetition ExperimentCompetition ExperimentCompetition Experiment

311) Nettekoven, U.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 1166.

O

HN

+

5 mol%

[Rh(cod)(DPEphos)]BF4

toluene (1 M)70 °C, 48 h

(1 eq.) (4 eq.)

N

O

N

O

53%

18%

DPEphos =O

PPh2PPh2

cod =

RhodiumRhodiumRhodiumRhodium----Catalyzed AntiCatalyzed AntiCatalyzed AntiCatalyzed Anti----Markovnikov Markovnikov Markovnikov Markovnikov HydroaminationHydroaminationHydroaminationHydroamination

32

33

RuRuRuRu----CatalizedCatalizedCatalizedCatalized AntiAntiAntiAnti----Markovnikov Markovnikov Markovnikov Markovnikov HydroaminationHydroaminationHydroaminationHydroamination

1) Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc.

2003, 126, 5608.

34

RuRuRuRu----CatalizedCatalizedCatalizedCatalized AntiAntiAntiAnti----Markovnikov Markovnikov Markovnikov Markovnikov HydroaminationHydroaminationHydroaminationHydroamination

1) Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 126, 5608.

35

Synthesis of Amine Transfer Reagents Synthesis of Amine Transfer Reagents Synthesis of Amine Transfer Reagents Synthesis of Amine Transfer Reagents

1) Niu, D.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 9716.

CuHCuHCuHCuH----Catalyzed Catalyzed Catalyzed Catalyzed HydroaminationHydroaminationHydroaminationHydroamination by Miura et al. by Miura et al. by Miura et al. by Miura et al.

36

1) Miki, Y.; Hirano, K.; Sato, T.; Miura, M. Angew. Chem. Int. Ed. 2013, 52, 10830.

371) Zhu, S.; NiljianSkul, N.; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135, 15746.

CuHCuHCuHCuH----Catalyzed Catalyzed Catalyzed Catalyzed HydroaminationHydroaminationHydroaminationHydroamination

38

HydroaminationHydroaminationHydroaminationHydroamination Using Using Using Using MMMModified odified odified odified AAAAmine Transfer Reagents mine Transfer Reagents mine Transfer Reagents mine Transfer Reagents

1) Niu, D.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 9716.

39

Unproductive Reduction of NUnproductive Reduction of NUnproductive Reduction of NUnproductive Reduction of N----O BondO BondO BondO Bond

1) Niu, D.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 9716.

TransitionTransitionTransitionTransition----State Structures of the State Structures of the State Structures of the State Structures of the HydrocuprationHydrocuprationHydrocuprationHydrocupration

401) Yang, Y.; Shi, S.; Niu, D.; Liu, P.; Buchwald, S. L. Science 2015, 349, 62.