Literature Seminar (D1 part)

070523 (wed)

Wataru Itano (D2)page 1

Directed (Chelated) Catalytic C-H Functionalization
with Pd(ii)/Pd(iv) manifold~ based on Melanie S. Sanford's chemistry ~Pd catalyzed reaction is one of the most important transformation in organic chemistry.
There are many types of Pd catalyzed reactions such as cross-coupling (Stille, Sonogashira,Suzuki-Miyaura, Negishi, Heck etc.), allylation, oxidation (Wacker) or reduction.
In these cases, we (I) usually think Pd(0)/Pd(ii) manifold.
Recently, in the field of catalytic C-H activation, Pd(ii)/Pd(iv) cycle becomes to be realizedusing some strong terminal oxidant such as PhI(OAc)2.
Today I will summarize and talk about this trend.
A. J. Canty. Acc. Chem. Res. 1992, 83.
(Review(with Iiii) : Inorg. Chem. 2007, 46, 1924.)~ main stream of her Chemistry ~Pd(iv) complex is not so rare in organometalic field.
(Pd(ii) + MeI etc)

known as Palladacycle
catalytic application is recent trend

assumed more reactive toward r.e. than Pd(ii) complex
C-X (X = O, Cl, Br, F) forming reductive elim. can occurr
C-O r.e. from Pd(ii) is rare until 1990's (and still problematic)

J. F. Hartwig. Acc. Chem. Res. 1998, 852. (Ar(Csp2)-OR forming only(?), β-hydride elim. of OR)· Melanie Sanford grew up in Providence, RI.
· She received her undergraduate degree in chemistry fromYale University in 1996 where she worked with Professor
Bob Crabtree studying C-F bond functionalization.
· She then moved to Caltech where she worked withProfessor Bob Grubbs investigating the mechanism ofruthenium-catalyzed olefin metathesis reactions.
· After receiving her PhD in 2001, she worked with Professor
Jay Groves at Princeton University as an NIH post-doctoral
fellow studying metalloporphyrin-catalyzed functionalizationof olefins.
· Melanie has been an Assistant Professor of Chemistry at
the University of Michigan since the summer of 2003.

< Contents >1. Directed C-H Activation
1-1. Brief look for C-H activation
1-2. Pd-mediated directed C-H activation (palladacycle)
1-3. Mechanism for palladacycle formation

(p2)
(p3)
(p4-5)

2. Sanford`s work (Pd(ii)/Pd(iv))
2-1. Representative examples for C-O forming reaction
2-2. Mechanistic aspects for C-O forming reductive elimination
2-3. Further development of C-O forming reaction
2-4. Other C-X forming reaction(p6-8)(p9-12)(p13-14)(p15-17)

1. Directed C-H Activation

page 2

1-1. Brief look for C-H activation(review)< merit >M. S. Sanford et al. Tetrahedron 2006, 2439.
D. Sames et al. Science 2006, 312, 67.
Oka-P san`s lit.sem. 2002

no FG for further functionalization
atom economy
structual diversification at later stage< trend >C-H functionalization is somewhat popular in organic rxn. (Ar-H: electrophilic aromatic substitution, ortho lithiation
C(sp3)-H: free radical, dioxirane etc.) --- selectivity, functinal group compatibility, sometimes problematic
mild, general, and selective (transition) metal catalyzed methods
have the potential to fundamentally change retrosynthetic approaches
to complex molecule synthesis. (like metathesis)
The vast majority of transition metal catalyzed C–H activation/functionalization reactions of complex
organic molecules have focused on the transformation of C–H bonds into C–C bonds
Du Bois (Rhii) C-H amination (Tanaka(Y)`s-B4 lit.sem.)Hartwig (Iriii/v, Rhiii/v) C-H borylation (Shibuguchi san`s D3 lit sem.)
Sanford (Pdii/iv) C-H oxygenation< classification >C–H

C–X
organometalic(anionic at C)intermediate

1 Inner-spherestandardtransition metal
less sterically hindered C-H (Ar-H, 1°,2°-C-H)

2 Outer-sphere

mimics biological oxidation reactions catalyzed by enzymes(cytochrome P450, methane monooxygenase (MMO))

weaker C–H (benzylic, allylic
3°, or α to heteroatoms).

radical and/or cationiccharacter at C

metal oxo-, imidocarbene species etc.

--- substrate does not interact directly with M but instead reacts with a coordinated ligand

1-2. Pd-mediated directed C-H activation (palladacycle)

page 3@ directed C-H activation is one reliable approach for C-H bond cleavage by transition metal.
thermodynamical stability

for reactivity

C-M + M

kinetically favorable
orientation

L

C-H(~100 kcal/mol)(metallacycle)

high selectivity also expectedwith chelation(first(?) successful catalytic directed Ar-H functionalization)(1 eq)(1.5 eq)(2 mol%)12 examples(66-100%)(S. Murai et al. Nature 1993, 366, 529.)
speculated via
chelation assistedoxidative addition(1,1-disubstituted OKwith 5 eq of alkene)@ In Pd chemistry, this metalation is common (in the preparation of palladacycle)(J. Dupont et al. Chem. Rev. 2005, 2527.)

K2PdCl4
dioxane / H2O< method of direct metallation >@ initial work
(A. C. Cope et al. J. Am. Chem. Soc. 1965, 3272.)

rt, 2 weeks(usually choiced)(?) role of AcOH

(trans cyclopaladation)< examples >cisoidtransoid(pincer)--- applied in cat. rxn.

5~6 membered ring (can vary 3~11 membered)mostly 5,5-system (5,6- or 6,6- reported)@ β-hydrigen (to Pdii) can be compatible in palladacycle
PdCl2(PPh3)2 (100 mol%) gave 5 in 62%

IN· formed in the course of Heck rxn.

H

5
E E

isolated by column (SiO2)
air, moisture stableconfirmed by X-ray (Pd--N 2.187A)· the metal is conformationally locked in 5-membered ring andcannot adopt the cisoid conformation toward β-hydrogen.

(Chem. Commun. 2003, 272.)

1-3. Mechanism for palladacycle formation

page 4@ it is thought as electrophilic pathway (for Ar-H: like electrophilic aromatic substitution)
AcOH
4

(17)
3
4
3

via arenium ?
--- the result of kinetic investigation was explained in scheme 1
cyclometallation mainly occurred fromcoordinately unsaturated 14e complex [Pd(N-CH)(OAc)2] (k1)(direct path)k1 >> k2
(25 ºC)(in AcOH
with NaOAc)(in CHCl3)(in CHCl3)· KIE k1(H)/k1(D) = 2.2 --- C-H breaking is the rate-limiting· ρ = -1.6 (against σm) --- kinetically electrophilic step

(A. D. Ryabov Chem. Rev. 1990, 403.)· The activation parameters of the rate-limiting stepδH* = 11 kJ/mol accord with "early", highly ordered transition state 19,
δS* = -0.254 J/mol" 6-membered TS "(1 cal = 4.1868 J)

But... in AcOH (with NaOAc)· KIE k1(H)/k1(D) = 1.05 Pdii is no longer a "typical electrophile" in AcOH
· ρ = +1.4 (against σp)still unclear@ recent computational (DFT) study supports" 6-membered TS " (without solvent effect)(D. L. Davies et al. J. Am. Chem. Soc. 2005, 13754.)
electrophilic activation of the arene and intramolecular base for the deprotonation ?

displacement of one arm ofthe η2-OAc by one ortho-C-H

an agostic intermediate (Pd-H)
acetate interaction (ortho-H --- O=C)
+ orientation ideally for H-transfer

the H-acceptor acetate
twists away fromthe new Pd-C bondwith a minimal activation barrier

Pd

Pd

Pd
Pd

Pd

· major changes in atomic charges (1a to TS2a-3a) occur only at the activating C-H bond,C-negative-charge increasing by -0.14, H becomes more positive by +0.09· the maximum increase of ring-carbons-positive-charge is only +0.05
arenium (1)Pd-positive-charge only slight decrease (from +0.75 to +0.72)· 4-membered TS (+34.3 kcal/mol), oxidative addition (via 3-centers TS; +25.7 kcal/mol) less accessible

6-membered TS is the most accessible and proceeds via an agostic C-H intermediate rather than arenium
Pd acetate --- electrophilic activation of a C-H bond (agostic), an intramolecular base for the deprotonation

page 5
Palladacycle have been utilized as catalyst precursor

key intermediate in total synthesis(D. Sames et al. J. Am. Chem. Soc. 2002, 11856.)(Ru, Rh: many)@ Application of palladacycle in Pd0/ii catalytic cycle is also achieved coupled with C-C forming reactionoxidant is always speculated to reoxidize Pd(0)Pd(ii)
classified as C-H directed version of oxidative coupling· Acetoanilide + Heck

(J. G. de Vries et al. J. Am. Chem. Soc. 2002, 1586.)(1 eq)

HN(2 mol%)(1.1 eq)(1 eq)

6 O
Pd

L

X

intactTol / AcOH 2 / 1
TsOH (0.5 eq)
20 °C· TsOH --- activate palladacycle for insertion ?
< others (representative) >· Ar-N-alkyl-amines + carbonylation· oxazoline + R4Sn

(K. Orito et al. J. Am. Chem. Soc. 2004, 14342.)(J-Q. Yu et al J. Am. Chem. Soc. 2006, 78.)

· Pyridine + RB(OR)2 (J-Q. Yu et al J. Am. Chem. Soc. 2006, 12634.)· Carboxylic acid + RB(OR)2 (J-Q. Yu et al J. Am. Chem. Soc. 2007, 3510.)(30-38%)Ar-I also utilized (y. higher (45-70%) although di-Ar products obtained)· Acetoanilide + ArSi(OR)3(Z. Shi et al. J. Am. Chem. Soc. 2007, ASAP.)

directing group? -- sp2 or sp3 C-H? -- coupling partner? -- oxidant?
But analogous catalytic approaches for C-X (-O) forming are rarecf) · C-N forming, but intramolecular (S. L. Buchward et al. J. Am. Chem. Soc. 2005, 14560.)

2. Sanford`s work (Pd(ii)/Pd(iv))
2-1. Representative Examples for C-O forming

page 6(For Ar-H)a single C-H for directed C-H activation
well-known to undergo cyclopalladation· Benzo[h]quinoline 1@ extraordinarily high selectivity for C10@ regioisomeric oxidized products
not observed(3a/3b 11/1) --- 3b formed via hydrolysis
from 3a
simple modification !
in situ generation of PhI(OR)2 ?
excess LiX + PhI(OAc)2 ~ trace
palladacycle 2 also catalysed rxn.
· high regioselectivity· high catalytic activity of the isolated palladacycle 2
X

Pdii

I

Ph

X
X
I

if mecha. is similar
to oxi. with ArIiiiX2

Ph-I

external orinternal ?

N
C

Ph

Pdiv
(a)

X

Pdiv

· benzoquinone or Cu(OAc)2· palladacycle 2

major drawback
no products formed

solv, heat
· Pd(II)/Pd(IV) cycles have been implicated in related benzene acetoxylation reactions(R. H. Crabtree et al. J. Mol. Cat. A 1996, 35.)

2 mol%+ biphenyl
10 eq

1 eq
100 ºC, 20 h

75%

~3%

*without oxidant, biphenyl obtained (~trace)*acetoxylation was initial productby time course exam.

PhI(OAc)2

two products formedby distinctive pathways
Ph-Hpage 7

sp3-C-H OK
no over-oxidationeven at benzylic(steric hindrance)(in AcOH)(in MeOH)
2,2-di-OAc 26%

8-Me selective
cf)(in AcOH)
complexmixture>2eq PhI(OAc)2Me
2,2- and 2,5-di-OAc ~15%

not directed by aldehyde

2,2-di-OAc ~25%
SM ~25%@ exclusion of air/moisture not required--- rxn. performed in a 20ml vial with a Teflon lined cap
They said...

"exceedingly practical method for functional group-directed oxidation of arene C-H bonds""attractive alternative to ortho-lithiation/ electrophilic addition procedures"< PhI(OAc)2 ? >Ph(X)I- hyper leaving group< preparation>

page 8

(sp3 C-H)(Highlighted in Chemical and Engineering News: 2004, 82(31), 35. and Lett. Org. Chem. News and Views Section, 2005, 2(5), 207.)< initial >Pd(OAc)2 (5 mol%)
PhI(OAc)2 (X eq)

1

100 °C, 5.5 h(X = 1.1)

3a-c mixture(X = 4.5)

3c 59%(without Pd)

no rxn.

Ac2O --- prevent hydrolysis< reactivity >· OH oxime --- oxidative cleavage (?) to ketone
ketone --- no rxn.
· no α-C-H oxiation despite its higher aciditycf) in stoichimetric Pd(ii) cases
require fully α-alkylated oxime· no β-hydride elim. !
regidity of palladacycle< selectivity >· 1°-β-C-H selective (ent. 2)strong steric preference (1° over 2°) for
5-membered palladacycle (β vs α / γ)
· siginificantly enhanced by α-branching (ent. 1-3)
required conformation for C-H activation(coplanar between oxime and C-H)
is readily accessedSM

Pd(OAc)2 (5 mol%)
PhI(OAc)2 (X eq)
TM
conditions

generally, di-OAc not obtained(X eq)
1.1 AcOH/Ac2O 80 °C
5.5 h
1/1

deemed unreactive in stoichiometric
cyclopalladation

2

90 °C
9h

1.5

100 °C
1.5 h

1.1

80 °C
5 min

t-Bu locks the 2-Me
into coplanarity with the oxime

100 °C
12 h@ Py also effective directing group(ent. 5-9)

3.2

AcOH

1.5

CH2Cl2(conformational effect)might offer mild and selective approachto the dealkylation of ethers/amines

2.1
1.1

@ 2°-β-C-H also reactive (ent. 9-10)
α to O(electronic)
31

structual rigidity
1.5 AcOH/Ac2O 80 °C
1/1
5.5 h

eq. selective(i) ax.C-H followed by r.e. with inversion? (ii) eq. C-H followed by r.e. with retention ?

page 92-2. Mechanistic aspects for C-O forming reductive elimination(Ar(Csp2)-O)

1. oxidation of Pdii with Iiii-oxidant was confirmed by the rational design and isolation of Pdiv complex@ relatively labilefacile manipulation ofelectronic parameters

PdIV @ alkyl ligand can exchange
between metal centers(A. J. Canty. Acc. Chem. Res. 1992, 83.)(1.0-1.1 eq.)

2a: stored in air in solid state
at rt for a weekremarkably in organomet.Pdiv field
CH2Cl2, rt

43-90%

two rigid cyclometalated aryl
(prevent ligand excahnge
and C-C bond forming)

2

X-ray
(R = H, X = NO2)

2. these Pdiv complexes undergo clean C-O bond forming reductive elimination upon themolysis(5%C6D5N added to trap 3a for facilitating mechanistic studies)--- standard technique for r.e.study

60 ºC
1h

clean first-order kinetics

3. possible mechanisms of C-O bond forming reductive elimination were disscussed
same as Ptiv or(bpy)PdivMe3I case(Organometallics
1988, 1363.)·1)strong dependence of solvent polarity·2)highly negative value of ΔS* (-13 ~ -39 e.u.) ~ solvent ordering about
the charged transition state·3)ρ ~ +1.4 (for ArCO2 )A. (pre-equilibrium (ionic)
external/internal coupling)B. (direct coupling)~rare process for Pdiv,Ptiv

C. (dissociate internal coupling)@ A is not probable pathway

Nitrobenzene

was used as SM

CHCl3
acetone2o(more soluble)
benzene1) no dependence of solvent polarity

MeCN
DMSO

page 102) from Eyling analysis for 2c
ΔS*+4.2±1.4 eu (in d6-DMSO)-1.4±1.9 eu (in CDCl3)(not so charged in transition state ?)3) Electron donor substituents led tomoderate rate accelerations(ρ ~ -1.36±0.04) (for ArCO2)(benzoate acts as a nucleophilic partner ?)(comparable r.e. rate)4) no benzoate
exchange2l2ginternal coupling
plausible

no incorporationof acetate2b@ B or C ?
(only preliminary)

added rigidity of the fused ring system is expected todecrease the rate of nitrogen dissociation

mechanism C
chelate-directed C-O coupling at PdIV proceeds by a significantly different mechanism
than other reductive eliminations from PdIV or PtIV.

But there are no conclusion about transition state...
Anyway, from Pdiv complex...
@ for Ar(Csp2)-O bond forming r.e. might be internal ~ concerted
three-centered@ for C(sp3)-O bond forming r.e. ?
SN2 mechanism was suggested from recent reports(inversion of stereochemistry)< oxidative functionalization
after palladation >* aminoacetoxylation, intramolecular(Stahl et al.
J. Am. Chem. Soc. 2006, 128, 7180.)

must be faster than competing β-hydride elimination(Sorensen et al. J. Am. Chem. Soc. 2005, 127, 7691.)*carbamate not essential
sulfoneamide

retention(threecentered?)prevent
cat. poison
N-oxi.

transaminopalladation

irreversible* w/o Pd, no rxn.
* Cu(OAc)2 (2.0 equiv) was ineffective.

stereoselective trans alkene difunctionalization(net N,O-anti-addition)trans-aminopalladation;r.e. with retention

* aminoacetoxylation, intermoleculartrans alkene difunctionalization(Stahl et al. J. Am. Chem. Soc. 2006, 128, 7180.)
exquisite regioselectivity(chelation of allylic oxygen)analysis of β-hydride elimination

page 11

Pd-black retarted rxn.

(from trans-15)~trace rxn.

only (allylic)
oxygen containing
external olefin(like Sorensen's work)

cis-aminopalladation; r.e. with inversion* diamination, intramolecular (Muniz et al. J. Am. Chem. Soc. 2005, 127, 14586.)

Fujimori's lit. sem. (M1 part)

only the hypervalent iodine reagent PhI(OAc)2 was highly efficient
stoichiometric base accelerates rxn.

syn alkene difunctionalization

C-N forming r.e.
(via Pdiv ?)trans-

trans-aminopalladation;r.e. with inversion

Recent two reports suggests r.e. with inversion (SN2)(J. Am. Chem. Soc. 2007, 129, 5836.)(concept)

Pdii/0(initial)*bipy --- sometime effective

page 12(stereochem)with 1,2disubstituted-olefin

+

11%

+

8%

+

4%

+

8%

19%

+

25%

59%

+

8%

clean inversion of olefin geometry(Z-5)(mecha)trans-acetoxypalladation
SN2-type attack by
the electron-rich tethered olefin

Me Ph
H

Pdii
OAc

insertion of Pdii
retention of olefin geometry(from Z-5) predominatly one diastereomer, but stereochem could not be established.

(another group also suggests SN2 from stereochemistry of this type product)(J. Am. Chem. Soc. 2007, 129, 4906.)(quite similar substrate)
to inhibit
cyclopropane forming

cat. Pd(OAc)2
PhI(OAc)284%

r.e. with inversion
They suggested C-O r. e. from the alkyl-Pd(IV) species proceeds by an SN2 mechanism

2-3. Further development of C-O forming reaction

page 13(About regiochemistry (for Ar(Csp2)-H))(M. S. Sanford et al. Org. Lett. 2005, 7, 4149.)
ON
also havesame regioselectivity@ tolerate a diverse array of electron-donating and electron-withdrawing meta-substituents@ 6 :1(X = F) ~ >20 : 1 selectivity for oxygenation of less sterically hindered ortho-C-H bondeven when X is secondary chelating group to Li or Ru0(= OMe, OMOM, F, Cl)or reported L-type ligands for Pdii (= ketone, oxime)
can differentiate two directing group (Py > ketone or oxime)@ to invert this regioselectivity
Pd(OAc)2 (5 mol%)
PhI(OAc)2 (1.5 eq)tight chelation required to achieve selectivity prevents catalyst turnover.
(only one substrate can chenge this selectivity)
Pd(OAc)2 (5 mol%)
PhI(OAc)2 (1.2 eq)

cyclic nature of the ether moiety
decreases the effective size andmay render the oxygen lone pair more available

benzene
60 °C, 10 h
29% (2:1)"complemantaly to ortho-lithiation" in terms of regioselectivity(Can omit Iiii oxidant ?)(M. S. Sanford et al. Org. Lett. 2006, 8, 1141.)(concept)cf) same strategy was reported
in Ptiv chemistry

this
work

external -OAc source
possible ?

to prevent OAc hydrolysis@ (table 1) oxidants screening@ (scheme 2) scalability OK(Kugelrohr distilation)comparable
slightly good y.
for C(sp3)-Hcf) Oxone
consists of 2KHSO5, KHSO4, K2SO4;
its active component is KHSO5
cheap, (formation of dioxirane etc.)

page 14@ (table 2)@ nearly identical regioselectivities
with PhI(OAc)2(less hindered o-C-H)(w/o Ac2O)
improved functionalgroup tolerance

1°-β-C-H selective
free radical pathways are negligible(well-precedented with K2S2O8)<merit>(c K2S2O8 used as the oxidant)<demerit>
comparable or moderately lower yields than with PhI(OAc)2
N-oxidation of some basic nitrogen containing directing group (pyrazine)

Py-type failed ?
therefore oxime selected ?

@ (table 3) MeOH also utilized as external source
might be genarated

2-4. Other C-X forming reaction

page 15(Org. Lett. 2006, 8, 2523.)
M. S. Sanford et al.

< C-(Cl, Br, I) forming >(Tetrahedron. 2006, 62, 11483.)*C-halogen forming r. e. is thermodynamically disfavored relative to o. a. at most metal centers.
(Keq for r. e. of Ar-X from PdII : ~10-5(for Ar-I), ~10-2(for Ar-Cl))@ NXS was used instead of PhIX2 (instability under rxn conditions)background occurrs
3 days@ So far, good selectivity seems to be only for Ar(sp2)-H@ C(sp3)-I forming achieved
H
N
R1

R

2

J-Q Yu et al. (Angew. Chem. Int. Ed. 2005, 44, 2112.)
I

tBu

N
R1

O

5a-7a

R2

O

tBu

5b-7b

5a

Pd(OAc)2(1 eq)

I2(1 eq)

60%

PhI(OAc)2
I2(unreactive)

PdI2

Pd(OAc)2(reactive)5b

< C-F forming >M. S. Sanford et al. (J. Am. Chem. Soc. 2006, 128, 7134.)* microwave accelerates rxn dramatically.
* No Pd, no fluorinated product.
* formation of 1b is not Pd-catalyzed reaction.

page 16* 3 was optimal F+ source for phenylpyridine type.
(ent 4-12)* Ar-Br is often not tolerated under Pd0/ii (ent 3)

54%
seems via electrophilic pathway< C-C forming >M. S. Sanford et al. (J. Am. Chem. Soc. 2005, 127, 7330.)cf) Pd0/ii approach (see page 5)*Ph-I or Ph-OTf<1%* + catalyst poison unaffectedor free-radical inhibitor*Ph-I or Ph-OTf<1%* [Ph2I]BF4

good.

not involve Pd0 ?

page 17
<diverse Ar group>(i) oxidation to PdIV by [Ph2I]BF4 then C-C forming r. e.
(ii) direct electrophilic cleavage of the PdII-C by [Ph2I]BF4(without a change of oxidation state at the metal).
· negative for Pdiv

@ Mechanism

still unclear

Iiii [iodonium] reagents have been used as highly reactive coupling partoner for Pd0/ii catalyzed reaction

more electron-rich Ar is generally transferred selectively· positive for Pdiv

(1 : 1)A. J. Canty et al.
(Organometallics 2004, 23, 3466.)-50 ºC, 1H NMR
5 mol% Pd(OAc)2
AcOH, 100-120 ºC
12 h

·?

more electron-defficient favor1< other reports for C-C forming >(for oxiditive coupling between two C-H )(for 2-Ar of indole)< Summary >(J. Am. Chem. Soc. 2006, 128, 14047.)(J. Am. Chem. Soc. 2006, 128, 4972.)

What is the key for Sanford's success ?
combined Palladacycle and Pdiv chemistry

extended to many type of C-X forming(X = OR, OAc, Cl, Br, I, F, C, N)< Future >@ asymmetric variant (monodentate ?, trinuclear-Pd ?)@ futher functionalities (N, S, CF3 ?)@ toward more complex molecule