reductive elimination from high-valent palladiumchemlabs.princeton.edu/macmillan/wp-content/... ·...

Reductive Elimination from High-Valent Palladium

Kazunori NagaoMacMillan Group Meeting

Why do people focus on PdIV

PdIVL

L

PdIV complex

Facile reductive elimination

X

C–Hetero C–CF3

CF3

small ring

Challenging Bond Formation

Merging with C–H activation

PdIIDG L

C

oxidantpalladacycle

Oxidative C–H Functionalization

Mononuclear PdIV or Binuclear PdIII?

How do they work?

Origin of Chemoselectivity

Mechanistic Curiousity for Reductive Elimination

C–X Reductive Elimination

PdIIL

L

X

XPd0

L

L

PdIVL

L

X

XZ

Y

PdII

L

L Z

Y

Keq << 1

Carbon–Halogen Reductive Elimination

kinetically slow and thermodynamically unfavored

oxidation

kinetically fast and thermodynamically favored

Keq >> 1

H PdII(OAc)2PdII

L

L

OAc

X+

halogenoxidant

PdIVL

L

OAc

X

Y

X

REC–Hactivation

C–H activation (PdII catalysis) and Oxidative Functionalization (PdIV catalysis)

Hickman, A. J.; Sanford, M. S. Nature 2012, 484, 177.

Regioselective C–H Oxidative Functionalization

cat. Pd(OAc)2

MeCNsolvent, 75–100 oCN

HN

FG

N Cl

O

O

chlorination95%

N Br

O

O

bromination95%

PhI(OAc)2

acetoxylation86%

Proposed PdIV Intermediate

PdIVN L

OAc

FG

Y

Mechanistic Investigation

Isolation of PdIV complex

Study of Reductive Elimination

Dick, A. L.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300.

Isolation of PdIV Complex

PdIIN N

PdIVN

OBzOBz

N

77% isolated

PhI(OBz)2

stable after a week

60 oC, 1 hN

BzO

Possible Mechanism of C–O Reductive Elimination

PdIVN

OBzC

C

OBz

N

– BzO–

+ BzO–PdIV

N

OBzC

CN

N

BzO

PdIVN

OBzC

C

OBz

N

No dependence on solvent polarity

pathway A

pathway C

pathway B

+

No scrambling of additional AcO–

pathway A is not major.

N N

slower REpathway C is major.

Rigid substrate showed slower RE

Dick, A. L.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 12790.

Isolation of PdIV Complex

PdIIN N

PdIVN

ClCl

N

61% (with PhICl2)

oxidant

80 oC, 24 h

PdIVN

Cl

N

67% (with NCS)

NO O

DCM, 25 oC

N

Cl

AcOH

cat. Pd(OAc)2NCS

MeCN, 75–100 oCN

HN

Cl

N

NO

O

N

N

A B

A 49% 7%B 67% 5% <1%

a good model for C–Cl reductive elimination from PdIV

Whitefield, S. R.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 15142.

Bimetallic PdIII Intermediate

PdIIN O

O

PdIIO

ON

Me

Me oxidantX2

PdIIIO

ON

PdIIIN O

O MeMe

X

X

2e–

oxidationBimetallicReductiveElimination

N

X

Ritter suggested Bimetallic PdII/III Mechanism

HOMO LUMO

Molecular Orbital of Bimetallic PdIII Complex

Synergistic effect by two Pd metals may facilitate redox transformation.

Pd–Pd bond corresponds to redox state of Pd

Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302.

Identification of PdIII Dimer and Bimetallic Reductive Elimination

PdIIN O

O

PdIIO

ON

Me

Me

PdIIIO

ON

PdIIIN O

O MeMe

Cl

Cl

Pd–Pdbond formation

BimetallicReductiveElimination

N

Cl

PhICl2DCM, –30 oC

92%stable below –30 oC

96%

23 oC, 2 h

Possible Mechanism of Bimetallic Reductive Elimination

PdIIIO

ON

PdIIIN O

O MeMe

Cl

Cl

PdIIIN

OAc

Cl

dissociation

ΔG298 PdIII to product = 20.5 kcal/molBDE (PdIII–PdIII) = >22 kcal/mol

PdIIIN

OAc

Cl PdIIIO

ON

PdIIIN O

O

Cl

Cl

Me Me

Me Me

K = 1.2 x 105 (to 2AcOH)

Dissociatiaion into PdIII can be excluded.

RE rate is 16 times slower


Identification of PdIII Dimer and Bimetallic Reductive Elimination

PdIIN O

O

PdIIO

ON

Me

Me

PdIIIO

ON

PdIIIN O

O MeMe

Cl

Cl

Pd–Pdbond formation

BimetallicReductiveElimination

N

Cl

PhICl2DCM, –30 oC

92%stable below –30 oC

96%

23 oC, 2 h

Possible Mechanism of Bimetallic Reductive Elimination

PdIIIO

ON

PdIIIN O

O MeMe

Cl

Cl

PdIVN

O

O

PdIIN

O

O

Cl

Me

Me

Cl

disproportionation

PdIIIO

ON

PdIIIN O

O MeMe

Cl

Cl

RE from cationic PdIII

PdII–PdIV dimer resonance can not surpress the Pd–Pdelectronic communication

The RE rate is independentof Cl– and AcO–Concerted Reductive Elimination


Catalytic C–H Chlorination

PdIIN O

O

PdIIOON

Me

Me

PdIIIOON

PdIIIN O

O MeMe

Cl

Cl

PdIIIOON

PdIIIN O

O

Cl

Cl

Me Me

Me Me

N

H

(25 mol%)

PhICl2 (0.25 eq), DCMPdIII

O

ON

PdIIIN O

O MeMe

Cl

Cl

90% isolatedbased on PdII dimer

PhICl2 (0.75 eq) N

Cl23 oC

97%

Catalysis with PhICl2

N

H

Pd catalyst(5 mol%)

NCSMeCN, 100 oC

N

Cl

85–95%

PdIIN O

O

PdIIOON

Me

MePd(OAc)2Pd catalyst

Catalysis with NCS


Computational Study

PdIIIO

ON

PdIIIN O

O MeMe

PdO

ON

PdN O

O MeMe

Cl Cl

PdO

ON

PdN O

O MeMe

Cl

+

PdIIO

ON

PdIIN O

O MeMe

Cl

Cl

ClClCl Cl

Bimetallic Reductive Elimination

0 kcal/mol 21.8 kcal/mol 11.9 kcal/mol –6.8 kcal/mol

The electron bniding energies of two Pd atoms monotonically decrease

Redox synergy between 2 Pd centers

PdIIIO

ON

PdIIIN O

O MeMe

Cl

Cl

Pd–Pd Cleavage

33.2 kcal/mol (Homolytic)29.5 kcal/mol (Heterolytic) PdIII

O

ON

PdIIIN O

O MeMe

Cl

Cl

Pd–Pd distanceActivation Energy RE

Powers, D. C.; Benitez, D.; Tkatchouk, E.; Goddard III, W. A.; Ritter, T. J. Am. Chem. Soc. 2010, 132, 14092.

Mechanistic Studies for C–H Clorination with NCS

N

HPd(OAc)2 (5 mol%)

NCSMeCN, 100 oC

N

Cl

PdIIIN

N

O

PdIIIONN

O

OCl

OAc

PdN

N

O

PdONN

O

O

OAc

NCl

OO

Turnover-Limiting

N

PdIIN

N

O

PdIIO

N

O

O

Acetate-Assisted Oxidation

BimetallicReductive Elimination

Why chemoselective C–Cl RE?

No acetoxylated product

Schoenebeck suggests ligand scrambling mechasm

PdIIIN

N

OC

PdIIIC O

NN

O

OCl

Cl

PdIIIN

N

OC

PdIIIC O

NN

O

OOAc

OAc

+

NCS + AcO–

fast

C–Cl RE product

Powers, D. C.; Benitez, D.; Tkatchouk, E.; Goddard III, W. A.; Ritter, T. J. Am. Chem. Soc. 2010, 132, 14092.Nielsen, M. C.; Lyngvi, E.; Schoenbeck. F. J. Am. Chem. Soc. 2013, 135, 1978.

Ar–CF3 Reductive Elimination from PdII

PdIIL

L

CF3

Pd0

L

L CF3

Reductive Elimination

Slow

Successful Examples of Ar–CF3 RE from PdII

OMe

PCy2iPriPr

iPr

MeO

Brettphosstoichiometric (80 oC)

catalytic (Et3SiCF3, 80 – 140 oC)

OPPh2 PPh2

Me Me

Xantphosstoichiometric (80 oC)

P PCF3

CF3F3C

F3C

DFMPEstoichiometric (60 – 90 oC)

Nielsen, M. C.; Bonney, K. J.; Schoenebeck, F. Angew. Chem. Int. Ed. 2014, 53, 5903.Glushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128, 12644.

Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.; Buchwald S. L. Science 2010, 328, 1679.

bulkysubstituents large bite angle &

bulky substituents

small bite angle &electronic repulsion

Ar–CF3 Reductive Elimination from PdIV

PdIVL

L

CF3

CF3


Fast?

PdIIN CF3

N

F

tBu

tBu

Me N

Me

Me

F

TfO

DCE, 23 oC

PdIVN CF3

FOTf

N

F

tBu

tBu

53%

NO2Ph80 oC, 3 h

CF3

F

77%

X

Y

PdIIL

L X

Y

N NMe

Me

Me

MeP P

Ph

Ph

Ph

Ph

TMEDA DPPE89% 29%

Stoichiometric CF3 reductive elimination from PdIV

Nicholas, D. B.; Kampf, J. F.; Sanford M. S. J. Am. Chem. Soc. 2011, 133, 7577.

other ligands

Ar–CF3 Reductive Elimination from PdIV

PdIV

L

L

CF3

CF3


Fast?X

Y

PdII

L

L X

Y

Catalytic C–H Trifluoromethylation

N

H

cat. Pd(OAc)2Cu(OAc)2 (1 eq)

CF3+

reagentTFA (10 eq)DCE, 110 oC

N

CF3

SCF3 BF4

86% 11%

TFA (10 eq) is essential for the reactionCu(OAc)2 (1 eq) also improve the yield

What’s the role of these reagents?How does the reaction work?

OICF3

MeMe

Wang. X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3648.

CF3+ reagents

PdIIO

ON

Isolation of CF3–PdIV Intermediate

PdIIN O

O MeMe PdIV

N OH2

OAc

CF3

OAc

PdII dimer CF3–PdIV complex

CF3+ reagent

AcOH, 40 oC

SCF3 BF4

OICF3

OICF3

MeMe

O

SCF3 OTf4

45% 60% 2% 4%

DCE instead of AcOH : <2%DCE / 1 eq AcOH : 48%

DCE / 20 eq AcOH : 65%Additional AcOH is important.

isolated


Reductive Elimination from Isolated CF3–PdIV complex

PdIIN OH2

OAc

CF3

OAc

CF3–PdIV complexisolated

no decomp after 1 month

AcOH or DCE60 oC, 12 h

NF3C

C–CF3 RE product54–56%

<2% C–OAc and C–OH RE

Mechanism for Reductive Elimination

PdIIN OH2

OAc

CF3

OAc

PdIIN OH2

OAc

CF3

PdIIN

OAc

CF3

OAcN

F3C

– H2O

+ H2O

– AcO–

+ AcO–

Increase of [AcO–] significantly slowed C–CF3 REAddition of acidic additive [TFA, TFAA, Yb(OTf)3] accelerated C–CF3 RE

concerted

H2O dissociation

AcO– dissociative RE Pathway

AcO– dissociation

Catalytic Activity of Isolated CF3–PdIV Complex

Pd (10 mol%)Cu(OAc)2 (1 eq)

TFA (10 eq)DCE, 110 oC

SCF3 BF4

NH

NF3C

Pd(OAc)2 : 0.08 x 10–4 M/sCF3–PdIV : 1.40 x 10–4 M/s

18 fold times Initiual rates

The role of Cu(OAc)2 and TFA

PdIIN OH2

OAc

CF3

OAc

CF3–PdIV complex

DCE60 oC, 12 h

NF3C

C–CF3 RE product

additive

none 54%

36%Cu(OAc)2 (10 eq)

89%TFA (100 eq)

94%Cu(OAc)2 (10 eq) + TFA (100 eq)

Acceleration of RESurpressing decomp pathway

CF3–PdIV complex is a kinetically compete catalyst


Binuclear PdIII or Mononuclear PdIV

PdIIN O

O

PdIIN O

O MeMe

Kinetic study and DFT calculation suggests Reducctive elimination from PdIV

OICF3

MeMe

AcOH, DCM PdIIIN O

O

PdIIIN O

O MeMe

CF3

not detected

PdIVN OH2

OAc

CF3

OAc

Bimetallic Oxidation / Pd–Pd Cleavage

rate = k [PdII dimer][Togni I][AcOH]

OAc

ΔG = 13.7kcal/mol

ΔG = 18.9kcal/mol

fast

PdIIIN O

O

PdIIIN O

O MeMe

CF3

TS REC–CF3

OAc

PdIIN O

O

PdIVN O

O MeMe

CF3

OAc

Why is Pd–Pd cleavage so fast?

CF3 is relatively stronger σ-donor than Cl and AcO

PdIV–PdII structure is a more dominant contributor

Powers, D. C.; Lee, E.; Ariafard, A.; Sanford M. S.; Yates, B. F.; Canty, A. J.; Ritter, T. J. Am. Chem. Soc. 2012, 134, 12002.

Small Ring Formation

NHTf

H

cat. Pd(OAc)2

oxidant

DMF, DCM100 oC

NTf

NHTf

X

PhI(OAc)2

AcOOtBu

NCS

NIS

15

13

0

0

45 (OAc)

50 (OAc)

20 (Cl)

35 (I)

PdIVTfN L

OAc

X

Y

Proposed PdIV intermediate

Problematic RE partner

PdIVTfN L

OAc

FY

N

Me

Me

F

Me

75% 0OTf

C–F is relatively intert for RE

Formation of 5-membered ring

How about 4-membered ring?

Mei, T.-Q.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 10806.

Small Ring Formation

NHTf

H

cat. Pd(OAc)2

oxidant

DMF, DCM100 oC

NTf

NHTf

X

PhI(OAc)2

AcOOtBu

NCS

NIS

15

13

0

0

45 (OAc)

50 (OAc)

20 (Cl)

35 (I)

PdIVTfN L

OAc

X

Y

Proposed PdIV intermediate

Problematic RE partner

Formation of 5-membered ring

Mei, T.-Q.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 10806.

NHTf

H

cat. Pd(OTf)2

oxidant

NMP, DCE120 oC

NHTf

F

F

NTfN

Me

Me

F

Me

OTf

oxidant84%0%

Construction of Azetidine

H

MeCO2Me

NH

O

N

Pd(OAc)2

PhI(OAc)2, AcOHtoluene, 110 oC

picolinamide (PA)

NPA CO2Me

Me

88%

AcO

CO2Me

NH

O

NX

10% (X = H or OAc)C–N RE C–O RE

H

CO2Me

NH

PAMeMe

C–N RE (91%)C–O RE (0%)

H

CO2Me

NH

PA

C–N RE (25%)C–O RE (70%)

H

NH

PA

C–N RE (70%)C–O RE (8%)

AcO

Me Pd

OAc

OAc

NN

O

H

H

R1

R2

H

When R2 is smaller,tortional strain would favor C–O RE.

He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012, 134, 3.

γ-C(sp3)–H

αβ

γ

CO2Me

NH

O

N

αβ

γ

MeH

δNHPA

Hidentical

conditions

δ-C(sp3)–H C(sp2)–H

N

CO2Me

Me

PA

NPA

82% d.r. 8:1 90%

Construction of Benzazetidine

NH

Benzazetidine

A lack of practical synthesis due to ring strain

2.0 kcal/mol stable

NH

aza-o-xyleneunderexplored N-heterocycle

NN

NPh 450W UV

NPh

50%

via NPh

NH

OMe

Br

MeLitBuLi

AcCl NAc

21%

via NLi

OMe

Li

Previous Synthesis

Synthesis of Benzazetidine

Pd(OAc)2

PhI(OAc)2toluene, 100 oC

OMe

NH

O

NH

N

OMe

PA

7%

OMe

NHPA

OAc

89%

PdIVN N

HOAc

OAc

O

O

Me

O

Favoured C–O RE5-memberd TS

PdIVN N

HOAc

O

O

OO

O

Spacer’s strain overcome C–O RE? Design of PhI(OR)2

C–N RE C–O RE

Idea to C–N Selective Reductive Elimination

I

O

O

O

O

Ph

He, G.; Lu, G.; Guo, Z.; Liu, P.; Chen, G. Nat. Chem. 2016, 8, 1131.

Discovery of PhI(DMM)2

diacidic-derived iodonium oxidants

Pd(OAc)2

PhI(OR)2toluene, 100 oC

OMe

NH

O

NH

N

OMe

PA

C–N RE

CO2H

CO2H CO2H

CO2H

CO2H

CO2H

CO2H

CO2HMe

CO2H

CO2HMe

Me

CO2H

CO2H

CO2H

CO2H

<5% 25% 10%

Me OH

O

7%

34% 10% 20%10%DMM


PhI(OAc)2

rt, CHCl3I

O

O O

OMe Me

IPh

OPh

OO

Me Me

O

OI

O

Ph

PhI(DMM)

Substrate Scope

Substrate Scope

Pd(OAc)2

PhI(DMM)Chlorobenzene

110 oC

OMe

NH

O

NH

N

OMe

PA

C–N RE48%

75%(C–O 10%)

54%(C–O 18%)

n.d.(C–O <5%)

72%(C–O 9%)

OMe NHPA

O

C–O RE40%

OMe

Me

N

CF3

PAN

NO2

PAN

I

PA

NPA

61%

NPA

O2N O2N

NPA

18%

+

53%

NPA

NCl NCl

NPA

32%

+


Computational Studies

PdN N

L (HOAc)

O

PdIVN N

OAc

OAc

HOAc

O

F3C

F3C

PdIIIN N

O

OAc

O

F3C

PdIIIN

N

OHOAc

F3C

Me

PhI(OAc)2 PhI(DMM)2

ΔG = 18.9 kcal/mol

ΔG = 0.0 kcal/mol

RE

ΔG = 33.2 kcal/mol

C–N

C–OΔG = 29.4 kcal/mol

RE

ΔG = 14.9 kcal/mol

C–N

C–OΔG = 10.6kcal/molfavored

ΔG = 10.9 kcal/mol

PdIVN

N

OHOAc

ΔG = 0.0 kcal/mol

O

O

F3C

OO

O

Me

Me

PdIIIN N

O

OAc

O

F3C

PdIIIN

N

OHOAc

F3C

O

O

O

Me

Me RE

ΔG = 30.0 kcal/mol

C–O

C–NΔG = 24.3kcal/mol favored

RE

ΔG = 27.1 kcal/mol

ΔG = 26.8kcal/mol

C–OC–N

DFT suggested RE from PdIII dimer

Construction of Aziridine

NHR1

HR2

R3

sec-alkylamine

PdX2

C–H activation

N PdR1

H

R2

R3

4-memberedpalladacycle

oxidant

facile RENR1

R2

R3

aziridine

Pd(OAc)2

ONH

Me Me

Me

H

O

PhI(OAc)2, Ac2Otoluene, 70 oC

ON

MeMe

MeO

74%

ON

Me Me

MeO

PdIICl

PAr3

Ar = 3,5-(CF3)2C6H3

isolated

NO

O

Me

MePdIV

Me

AcO OAc

L

OAc

proposed PdIV intermediate

Chemoselectivity of RE (C–N vs C–O)

RE from PdIII dimer or PdIV

H

no C–O RE

McNally, A.; Haffemayer, B; Collins, B. S.; Gaunt, M. Nature 2014, 510, 129.

Computational Studies

N

OO

PdIVMe

MeMe

OAc

H OO

Me

OO

Me

PdIV intermediate

RE

ΔG = 22.8 kcal/mol

C–N

C–OΔG = 21.9kcal/mol

ΔG = 0.0 kcal/mol

ΔG = 12.7kcal/mol

deprotonation

N

OO

PdIVMe

MeMe

O

OO

O

Me

Me

– AcOH

ΔG = 6.0 kcal/mol

RE

ΔG = 27.3kcal/mol

C–O

C–NΔG = 17.1kcal/mol favored

PdIII dimer is a higher energy intermediate due to steric repulsion between hindered amines.

aminedissosciation

N

OO

PdIVMe

MeMe

O

H OOO

Me

MeO

then SN2Me

O

ΔG = 30.7kcal/mol

unfavored

PdIV mechanism is favored.

Smalley, A. D.; Gaunt, M. J. Am. Chem. Soc. 2015, 137, 10632.

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