Reductive Elimination from High-Valent Palladium Kazunori Nagao MacMillan Group Meeting
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
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
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
Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302.
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
Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302.
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
Reductive Elimination
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
Reductive Elimination
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
Nicholas, D. B.; Kampf, J. F.; Sanford M. S. J. Am. Chem. Soc. 2010, 132, 14682.
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
Nicholas, D. B.; Kampf, J. F.; Sanford M. S. J. Am. Chem. Soc. 2010, 132, 14682.
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
He, G.; Lu, G.; Guo, Z.; Liu, P.; Chen, G. Nat. Chem. 2016, 8, 1131.
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%
+
He, G.; Lu, G.; Guo, Z.; Liu, P.; Chen, G. Nat. Chem. 2016, 8, 1131.
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.