October 20th, 2007 Lit. Seminar

Hidetoshi Noda (M2)

Transition Metal Catalyzed Intermolecular Formationsof Ar-Ar Bond : post-Cross Couplingi) Cross Coupling reaction
Ar-M+Ar'-X(M = Zn, Sn, B,,,)Ar-Ar'

both substrate : activatedwastes derived from M and Xii) Direct Arylation
Ar-H+Ar'-X

Ar-Ar'

one substrate : activatedwastes derived from Xiii) Oxidative Ar coupling
Ar-H
Ar'-H+

Ar-Ar'

Today's Topics
1. Direct Arylation via C-H activation -overview2. Heteroarene Direct Arylation
3. Arene Direct Arylation
4. Other Approaches
5. Catalytic Oxidative Coupling of Ar-H

no preactivationoxidant : latent wastes (?)
aerobic : favorable

1. Direct Arylation via C-H Activation -overviewAr

X

oxidative addition

Ar MtlXAr

H

Ar

several proposedmechanism

orAr

H

Ar

HMtl

Ar

Ar

X

oxidative addition

ArAr

Ar

H

Ar

Mtl
X

General Conditions# Metal : second-row transition metals in low oxidation states(Rh, Ru, Pd,,)# Ligand : depend on Ar-X and system
for Ar-I,Br : PhP3 etc
for Ar-Br,Cl : electron rich and bulky trialkylphosphine, Buchwald's ligand, NHC etc
ligand-free conditions is also reported# Base : most cases inorganic bases such as K2CO3, Cs2CO3, KOAc, tBuOK, CsOPiv,,,,# Solvent : polar, aprotic solvents such as DMF, DMA, CH3CN, NMP, DMSO,,,# temp. : > 100 C# mechanism

Although several mechanisms are proposed, exact ones depend on substrate, cat. system and so on.

most suporrted

few support

limited case

2. Heteroarene Direct Arylation

Rcat. Pd(PPh3)4KOAc

NNN
PG

R+RN

Cl2RN

N
R +DMA, refluxNPG

NPG

PG = H : C2-selective
Ts : C3-selective

NR

Ohta, A. et al. Heterocycles 1985, 23, 2327.
Chem. Pharm. Bull. 1989, 37, 1477.

Reactivity order in SEAr is known to C5>C4>C2,but generally relatively less reactive toward electrophiles.
activated electrophile is needed

Bull. Chem. Soc. Jpn. 1998, 71, 467.

catalytic reaction involves an electrophilic
attack of the arylhalopalladium(II) species.
(10 mol%)
DMF, 140 C, 24 h

C5 selective(2 eq.)

role of basesolubility of base : Cs2CO3>K2CO3>Na2CO3
solubility of salt : KI(1.55), KBr(0.065)
CsBr(0.024), CsI(0.23)

2a = Ph-I
2a' = Ph-Br

Indole produces C2-arylated product, which is "nonelectrophilic" regioselectivity.

Org. Lett. 2004, 6, 2897.
etc...

# consideration of mechanism

J. Am. Chem. Soc. 2005, 127, 8050.

# support for SEAr mechanism

EWG = NRcf) thermodynamically stable C-2 adduct??
LiLiN
Bs

-100 to -20 C

N
Bs

J. Org. Chem. 1982, 47, 757.
H

B(C6F5)3H

N

B(C6F5)3N

8.4 kcal/mol stable (DFT)
Organometallics 2004, 23, 5135.

# chance to C-3 selective reaction (?)

3# realization# strategycf) other examples about regiocontroll

J. Am. Chem. Soc. 2006, 128, 2528.
Angew. Chem. Int. Ed. 2005, 44, 3125.

3. Arene Direct Arylation
arene : lower electron density than heteroarene (lower reactivity as to SEAr)
In order to overcome this problem, use of directing group is major strategy. (many reports)
I+OH(2 eq.)

PdCl2 (5 mol%)
LiCl, K2CO3

OH

Miura, M. et al. Chem. Lett. 1996, 823.

other directing groups are amide, ketone, imine, pyridine, quinoline,,,,# ligand screening
J. Am. Chem. Soc. 2006, 128, 11748.

(3 mol%)(1.5 eq.)bulky and strongly pi-accepting ligand is effective

4# nondirected direct arylation of simple arene
nondirectedshows SEAr process(27 eq.)new mechanistic insights are appered from intramolecular rxn

J. Am. Chem. Soc. 2006, 128, 1066.
J. Am. Chem. Soc. 2007, 129, 6880.(full)# substituent effects on regio# base effectNMe2(5 mol%)10aPPh2base has little role on selectivity.

KIE 5.0
KIE 6.7

reaction proceeds at electron deficient ring.

23.5 vs 13.2 kcal/mol

FFF

43.3 vs 34.5 kcal/mol
Pd
H3PBrPd
H3PBrmodels for DFT calculation (7f)
Authors insisted "Assisted intermolecular pass" is suited.
3.0 kcal/mol = 40:1 at 135 C (25:1, experimental)

17.4 vs 14.4 kcal/mol

J. Am. Chem. Soc. 2006, 128, 8754.

broad substrate scope
EvenF

gives product in 8%.

chance to cat. modification!?

() : calculated
Reactivity parallels relative acidities.
more electron deficient, higher reactivity

5slight modification

KIE = 3.0I, Br, Cl, OTf

Org. Lett. 2006, 8, 5097.

DFT cal. showed C2 is the lowest reaction barrier.
There is no indication of catalyst-fluorine interactions. : nondirectedOMe
PCy2OMe

catalyst modification for neutral arenes

J. Am. Chem. Soc. 2006, 128, 16496.

53 eq.

with hydrodebromination and homocoupling

too bulky
nondirected

53 eq.

53 eq.

53 eq.

53 eq.

reactivity compatible to proton-abstraction pathway
A pivalate anion results in a decrease in transition stateenergy of 1.3 kcal/mol compared to a bicarbonate anion. (DFT)64. Other Approaches

Chem. Commun. 2004, 1926.

# radical pathway ?

reported ratio involved in Ph radical : 54/26/20
R = 4-NH2, 4-NO2, 4-CF3 : noTM
R = Me, OMe, 1-Napht
yield : 20-70%

I

CP*Ir(III)without BHT : 70%with BHT : 10%
CP*Ir(II)aryl iodide radical

aryl radicalAngew. Chem. Int. Ed. 2007, 46, 3135.

cf) effective catalyst for Suzuki-couplingof Ar-Cl

X-ray+ Ar-I
(10 eq.) 70 C, 24 h

3 : [(PN)2Rh][B{C6H3(CF3)2}4]
4 : [NEt4][Rh(cod)Cl2]
Angew. Chem. Int. Ed. 2002, 41, 1521.

TONs(yield)
(78)
(45)

(31)

(40)

(32)

(13)

bimetallic Rh : essential# mechanism

matched??
ρ = 1.33±0.02
typical value for radical reaction (?)
reported ratio involved in Ph radical : 54/26/20
Authors insisted reaction proceeded via radical intermediates.

7

Angew. Chem. Int. Ed. 2007, 46, 6495.

# concept
cross-coupling# reaction of 1Ar+ and 3Ar+

resemblancestrongly exothermic
if Ar+ is obtained directly from ArX,,,# generation of 3Ar+

triplet Ar cation can react selectively
pi-component in polar solvent(some Nu)

I, Br : homolytic (not applicable)

Ar-X with EDG in polar solvent gives triplet Ar cation under hv.
polar solvent : stabilize ionic components

Et3N (0.05M)

20 eq.

Et3N : 2eq.
to prevent de-Si

5. Catalytic Oxidative Coupling of Ar-H

Organometallics 2006, 25, 5973.

conc. of TFA is important for selectivity
choice of Naphthalene : more electron rich than benzene
SEAr is occured to alpha-position (??)
to prevent homocoupling : ratio higher about EWG-aromatic (entry9)
lower about EDG-aromatic (entry8)

# KIE experiment8# proposed reaction pathway

fast

choice of TFA : Pd(OAc)2 to more reactive Pd(TFA)2 (??)
why conc. of TFA is critical??
no KIE

KIEOrg. Lett. 2007, 9, 3137.

(3/2)
0.08M

EDG seems to promote rxn rapidly (entry8), but things are not so simple...

(1 atm)anisole(1 atm)

benzene(3 atm) HPMV = H4PMo11VO40

anisole itself involves in catalyst ??

Science. 2007, 316, 1172.

N-H indole : NR
N-Me indole : dimerization
PivOH~30 eq.

3-nitropyridien : stabilize Pd(0)CsOPiv : not clear

9

generally EDG promote and EWG retard, but entry 2 vs 5 dosen't follow this rule

J. Am. Chem. Soc. 2007, 129, 12072.

in situ metalation of indole to Cu(II) or Ag : denied
conc . of Pd : high to C-3 selective (entry6~9)
existance of OAc : C-2 selective (entry 4,5,10), but Cu(OAc)2...

Author's proposal

PdclusterCu(OAc)2

CsOAc
orAgOAc

Pd Pd
PdPd(monomeric Pd)

this type of approach ?

mixed Pd-Cu
cluster

EWG on indole : not big effect on yield (entry 3,6)
Substituent on benzene : significant effectencounting cat. with arene-H is rds ?? (like organometallics 2006)

6. Trends and Perspectives

10# Heteroarene of Direct Arylation
rxn of many types of heteroaromatic ringalmost used up??
rxn under milder conditionsex) extremly mild condition

M. S. Sanford et al. J. Am. Chem. Soc. 2006, 128, 4972.

realization of real alternative synthetic strategy to cross-couplingex) Merck group
ClN

F3C

N+N

F3C

CNN

90 C, 8 hFFNNArOrg. Proc. Res. Dev. 2006, 10, 398.

# Arene of Direct Arylation
regioselectivity, reactivity problem for nondirected system
妄想 : use of pi-arene complex for arenen activation
MLnOMeXAr Pd +H

pKa : lowproton abstraction mechanism??

regio : m-selective??

cf) Ru-pi-arene complex in catalytic cycle for hydroamination
5 mol% Ru(cod)(methylallyl)2
7 mol% DPPent / 10 mol% TfOH
dioxane, 100 C, 24 h+ R'RNH

ArRNArvia
R'J. F. Hartwig et al. J. Am. Chem. Soc. 2004, 126, 2702.
J. Am. Chem. Soc. 2005, 127, 5756.

removable directing group (but need environmentaly benign)ex) Benzoic acid as directing group
CO2H+RXR

CO2HPd(OAc)2RRX

CO2HY

heteroarene

RJ. Am. Chem. Soc. 2007, 129, 9879.

cf) carboxylic acid as coupling partner

o-Coodinating group
for Cu is needed

RScience 2006, 313, 662.
+ArBrXPd[PtBu3]2

Ar

Y

J. Am. Chem. Soc. 2006, 128, 11350.

# Other Approaches
regioselectivity problem, but maybe difficult to overcome in radicalic or cationic pathway
reactivity problem# Oxidative Couplingobtain some information and understand mechanism
etc...
Keith Fagnou
Current Position: Assistant Professor, Department of Chemistry, University of Ottawa
Education: Ph.D. University of Toronto, 2002;
M.Sc. University of Toronto, 2000,
B.Ed. University of Saskatchewan, 1995.
K. Fagnou' group : http://www.science.uottawa.ca/~kfagn061/