2011/11/15
H.Mitsunuma (M2)

0. Introduction
HNNSONHbenzeneetc.

aromatic rings
1865: Assignment of the benzene structure (F A. Kekule)
Chemically stable, ubiquitous (aromaticity)
One of the most stable molecule in organic chemistry !!

~Aromatic ring as a synthetic scaffold~
R1

R1
R2
R4Dearomatization
R4

R3

R1
R5R9 * ** R2
R8 *R3* *R4
R6R7R5R2R3R6

Synthetic building block

Complex natural productThe dearomatization of arenes will provide synthetically useful hydrocarbons and alicyclic frameworks !!

Contents
1. Background of Dearomatization Reactions
2. Transition Metal Mediated Dearomatization Reactions
2.1 Dearomatization through 6 coordination
2.2 Dearomatization through 2 coordination
2.3 Multinuclear metal-arene complexes
2.4 Catalytic dearomatization reactions

3. Research Proposal (Toward Catalytic Dearomatization Reaction)

1. Background of Dearomatization Reactions
RR
OH
Birch reduction/
Hydrogenation

EnzymaticOH

R

Thermal/PhotochemicalA
B

R

Hypervalent iodine

OTransition metalNuL

M LL

Nu
and some other types...
1

Enzymatic dearomatization
Oxidation
RORmonooxygenase
eukaryots

RdioxygenaseprokaryotsOHOH

Enantioselective dihydroxylation
Many application to total synthesis (since 1987)
Pseudomonas putida: commercially available from AldrichReduction
OSCoAOSCoAcf) Birch reduction

benzoyl-CoA reductase

Disadvantages:
Advantages:
enantioselective dihydroxylation no C-C bond formation
functional group tolerance
aromatic heterocycles

Thermal/Photochemical dearomatization
Thermal (Diels-Alder type)
NC

CN

CN
anthracene
phenolbenzyne...

NC

heat
weak diene

14% y.

R S. H. Liu JACS. 1968, 90, 215.

Photochemical ([2+2], [2+3], [2+4]...)OOOOhv[2+2]

via

hv
[2+3]
[2+2]: e-rich olefin, G 1~1.5 eV[2+3]: G >1.5 eV

hv
[2+4]
Advantages:
C-C bond formation
atom economical

Disadvantages:
limited substrate scope
position selectivity
harsh condition

Birch reduction/ Hydrogenation
Birch reduction
RHydrogenation
EDG

t-BuOH, Na, liq NH3Advantages:
position selectiveEWG
orDisadvantages:
harsh condition
functional group tolerance
C-H bond formation

H2, [cat]heterogenious2Hypervalent iodine-catalyzed dearomatization
OOH

I(III)cf) Pb(OAc)4

I(I)
Nu[O]

Catalytic asymmetric Kita oxidation
MeMesHNOC

OH
CO2H

MeO

O
CONHMesI (15 mol%)
mCPBA (1.3 eq)

OOO

82%y. 85%ee
K Ishihara et al. ACIE. 2010, 49, 2175.
Organocatalytic desymmetrization of meso dienone obtained through oxidative dearomatization

OHO
H

ArN
Ar
H
OTMS
(10 mol%)
PhI(OAc)2 (100 mol%)
MeOH

OH

O
H

MeO

75%y. 99%ee >20/1 dr

Advantages:
catalyticasymmetricmild condition

M J. Gaunt et al. JACS. 2008, 130, 404.

Disadvantages:
applicable to only phenol derivatives

2. Transition Metal Mediated Dearomatization Reactions
2.1 Dearomatization through6

coordination

Changes in arene reactivity after complexation with metal tricarbonyl
Stabilization of benzylic
carbanions and carbocations

Selective side
chain reactions
RHYX
H

Nucleophilic addition
to ring carbons

M
OCElectron withdrawing
properties

COCO

Increased acidityof ring hydrogens

Steric directing group3

Relative reactivity of arene-metal complexes toward nucleophilic addition

Fe+2

Ru+2

200000000 6000000

Mn+COOCCO

Mn+CO
Ph3P
COFe+

11000

160

1OC

Regioselective addition to arene
chromium tricarbonyl complexes

Cr COCOvery lowReactivity of carboanions in the nucleophilic addition process to benzene
NuH
Cr CO +OCCONuOC

Cr- COCO

unreactive
LiCH(CO2R)2, LiCH2COR, CH3MgBr, (CH3)3CMgBr, (CH3)2CuLi,LiC(OR)(CN)Ph
successful
LiCH2CO2R, LiCH2CN, KCH2COC(CH3)3, LiCH(CN)(OR), LiCH2SPh,
2-Li-1,3-dithianyl, LiCH=CH2, LiPh, LiCCR, LiCH2CH=CH2, tBuLi
metalation
nBuLi, LiCH3, sBuLi
Attack of nucleophiles is reversible.
pKa > 22(kinetic product)
Range of products resulting from the sequential reactions of nucleophiles and electrophiles

I2, Ce(IV), Fe(III), O2...

oxidation: it makes the metal poorer at backbonding.

In principle, this chemistry could be catalytic if arene
exchange occurred af ter nucleophilic attack.

( 6arene)Cr(CO)3 complexes

OCCr COCO

yellow to red
often crystalline compound
stable to air (in solid state), moderately air sensitive (in solution)
they can be stored for long preriods if they are kept away from light.

Preparation
1. Cr(CO)6 + arene (excesss) under Ar (1~4 d)
2. Cr(CO)3L3 + arene (L = CH3CN, Py, NH3)
3. (naphthalene)Cr(CO)3 + arene
4Reaction patterns
1. Nucleophilic addition/Protonation reactions
OMeOMeMe2(CN)CLi

Cr(CO)3(OC)3CrO

OMei) TFA, -78 °C, 1hii) NH4OH (99%y.)HCl, 100°C(70%y.)

CNCNCNO

OMei) TFA, rt, 7.5hii) NH4OH (89%y.)HCl, 100°C(77%y.)

Higher temperatures and longer reaction times give isomerized product.

CNCN
Semmelhack et al. JOC 1979, 44, 3275.
Semmelhack et al. T etrahedron 1981, 37, 3957.

2. Nucleophilic addition/C-electrophile addition reactionsSR': all except for propargyl group

SS

Li

S
R'X, COS

SO
H
R'

Cr(CO)3
Cr(CO)3X

Migratory aptitude of R': ethyl > methyl > benzyl, allyl >>propargyl

50-94%y.

X

X
R'R'LiR''X

Reaction yields higher when carried out under CO or in
the presence of an added ligand (PR3, P(OPh)3, NEt3).

X

X= N

O

R'R'

CyN

R''

R''

R'' = alkyl: carbonylation
allyl: small carbonylation
propargyl: no carbonylation

L(OC)3Cr
Cr(CO)3

Cr(CO)3

L: THF

Highly regioselective

Mechanism
SN2Triple addition

Migratory CO insertion depends very much on the nature of the electrophile and the presence or absence of EWG on thearene ring.
3. Asymmetric version
Chiral auxiliary
R*Planer chiralityi)

R* =N
Cr(CO)3RNNO

Ph
MeO

MeO

good selectivity

OC

MeN
Li

MePh TMSClCr CO ii) recrystalizationCOMeO
TMS CrCOOC
CO
70% y. 99%ee

Schmalz et al. Chem. Eur. J. 1998, 4, 57.
5

External chiral ligand

Chiral ligands at chromiumPhPhi) SO

SSSMeLiNi) RLi, MeOOMeii)BrRTMS
HMPA
Cr(CO)3 iii) H2O

TMS

Cr(CO)2L*

75~93%ee
L* =Kundig et al. JOC. 1996, 61, 2258.

ii) MeI, COO
50% y. 69%ee

PhPONiPrPh
MeKundig et al. Pure. Appl. Chem. 1996, 68, 97.

[( 6arene)Mn(CO)3]+ complexes

OCyellow, stable
Preparation
crystalline compound
Mn(CO)5Br + AgBF4, then arene
more electrophilic than chromium
Nucleophiles: Grignard reagent, ketone enolates, malonates, hydride(LAH...)

Mn COCOReaction patterns
Sequential addition of two nucleophiles
Due to the decreased nucleophilicity of the neutral Mn species, reaction with C-electrophiles are not possible.

Substitution of CO ligand to NO makes the complex moreelectrophilic.

Reaction occurred at CO ligand.

[( 6arene)RuCp]+ complexes
high yielding preparation
functional compatibility of RuCp+RuO
N
MeO
P(OEt)2 i) NaHii) acetaldehyde

Preparation[(MeCN)3RuCp][PF6] + areneONMeO
CuBr (2eq)
MeOH, rt, CO

NMe +70%y.

RuCp

RuCp

OMe

CpRu(CO)2Br
55%y.

61%y.
Pigge et al. JACS. 2006, 128, 3498.
OO

NMe Bu3P, NaH
DME, rt

NMe59%y.
CpRu

CpRu

Pigge et al. Organometallics. 2009, 28, 3869.
6

22.1 Dearomatization throughcoordination

Changes in arene reactivity after complexation with metal tricarbonyl
M = Os, Re, Mo, W
This chemistry can be applicable tohetero aromatic rings.

Electrophilic addition f rom
ring carbons

Strong -back-bonding f rom metal[( 2arene)Os(NH3)5]2+ complexes
yellow to red crystalline
thermally stablesensitive to air
coordination to nitrile, aldehyde, some ketones, alkenes and alkyne(not to ester, amide, ether, alcohol, water protonated amine)ammine ligand: powerful -donor, poor -interaction with metal

2+H3N
NH3Os
NH
H3N
NH3 3

Preparation[Os(NH3)5(OTf)][(OTf)2] + arene with Zn0/Hg0
Reaction patterns
1. Electrophilic addition
OOH

MeOH

[Os]2+[Os]2+O

NR3

Py

94%y.

[Os]2+

OH

83%y.

91%y.
MeO

MeO

H2 (1 atm)
Pd/C

[Os]O

Harman et al. JACS. 1994, 116, 6581.

2. Hydrogenation

2+

Me[Os]2+89%y.
Harman et al. JACS. 1988, 110, 7906.

3. Sequential electrophilic/nucleophilic addition
The greatest synthetic potential of this method lies in the ability to stabilize the cationic intermediate.
OMe
OMe
TfOH

[Os]2+OTMS-40°C, 92%y.

[Os]2+[Os]

CO2Me
MeO2C

CO2Mei) MeO C
22+70%y.

R

CO2Me[Os]2+i) TfOH, -40°Cii) hydride reduction[Os]2+[Os]2+[Os]2+OMe

MeO2C

OMe

OMe

OMe

TfOH, -40°C
86%y.

R

CO2Me

DIEA, -40°C
CO2Me

CO2Me

AgOTf

[Os]2+
CO2Me

CO2Me

Harman et al. JACS. 1998, 120, 6199.

7

4. Diels-Alder reactionOMe

5. Electrophilic addition from heterocycles
MeN

OMe

Pyrroles, furanes, thiofenes: same reactivity as above
Me2+O
2+[Os]N[Os]
Me99%y.
[Os]2+NMe
N
MVK2+[Os]MeO
normal styrene as a diene: harsh condition, reactive dienophile
O
Harman et al. JACS. 1998, 120, 2218.
OO

Re, Mo, W complexes (Harman's chemistry)

Harman et al. Organometallics. 2005, 24, 1786.

Alternative system
Problems of osmium system: racemic reaction (use of chiral auxiliary)
ligand tuning is difficult
coordinatively saturated
cost of osmiume-rich metal center to overcome the aromatic stability(but not so e-rich as tofavor C-H insertion)-donating ligand
Dinitrogen IR stretching frequencies and electrochemical dateRe(dien)(PPh3)(CO)

only furan(inactive to novel reaction)

TpRe(PMe3)(CO)
TpRe(MeIm)(CO)Electrophilic addtion ocurred.

8

Reduction potentials of d6 metal complexes as a functionof ligand identity

Mo complexes

W complexes

Resolution of enantiocontrol (using chiral pinene)
These complexes have revealed a vast array of usefulreaction pathway.

2.3 Multinuclear metal-arene complexes
Dinuclear complex(sandwich type)

Dinuclear complex

+M M

M M

32M M
MMM M

There are some - 3: 3-arene dinuclear complexes.
This type of chelation changes the nature of arene.

Trinuclear complex

M

239

Dinuclear Mo-Mo complex

H Masuda et al. Inorg. Chem. 2009, 48, 9069.

Synthesis of dimolybdeum complex
Mo-Mo: 2.1968Å
quadruple bond: 2.0~2.2Å
triple bond: 2.5~2.6Å

Xray

Distortion of benzene ligand !!
Bond order
1.7~1.8
1.2
Mo2

1.1
1.2~1.3

1.1~1.2

Mo

1.6

Reactivity of benzene ligand(excess)Hex, rtDimethylation ocurred !!
Dimethylated product 2 was detected by ESI-MS analysis.
Methylation took place at benzene not diimine ligand.
(C6D6 complex : mass value 2+4)
GC analysis of decomposed products of 2 demonstrates
the generation of xylene. (o/ m/ p = 33/18/49)
Reaction mechanism is unclear (C-H activation path ?).

Dinuclear Pd(I)-Pd(I) complex

T Murahashi et al. JACS. 2011, 133, 14908.

Concept10

Xray

Oxidative addition to arene

58%y.
Bi- 3-allyl structure
Reaction with various arenes
The number of fused rings in polyacenes gave oxdative
dinuclear addition products.
formal [4 +2 ] Diels-Alder reaction

Dinuclear Pt sandwich complex
Synthesis of cationic methyl platinum complexes

Kubas et al. JACS. 2002, 124, 12550.
Synthesis of dinuclear Pt complexes

C-H activation and C-C coupling of arene are occured!!

11Xray analysis

1

H NMR: phenyl peaks were shifted upfield. (4.74~5.67)-type coordination
bridging dianionic biphenyl ligand
C-C distance in benzene units matched with the allyliccarbons.

Proposed reaction mechanism

The feature of this mechanism is the coupling occurs
without a change in the formal oxidation state of themetal.
cf)

Reactions of bridging biaryl complexes

C-C coupling reaction is proposed to occur via ii .
cf)
C-C coupling in C6D6:
no deuterium incorporationin 3

Hydrolysis similar to Birch reduction:
H+ is reduced to H2, while biphenyl2- ligand is oxidized to free biphenyl.
4a + I2: no o-bitolyl, mixture of m,m'-bitolyl, m,p'-bitolyl and p,p'-bitolyl(due to steric effect?)
This result is against an electrophilic aromatic substitution of C-H bond activation step.

Trinuclear Ru complex

H Suzuki et al. JACS. 1997, 119, 625.
Angew. Chem. Int. Ed. 2006, 45, 7615.

Synthesis of trinuclear Ru arene complex
2 was synthsized through allylic C-H bond activation.

12

Xray analysis of 2

Oxidation of complex 2
1e pathway

2e pathway
Protonation of 2 and successive reductive elimination of H2
Xray analysis of 4

Average coordinated and uncoordinated C-C
distances of benzene are almost equal.
3- 3 coordination
An allyl moiety is coordinated to one of three Ru,
another allyl moiety bridges two Ru.

Trinuclear Ru pyridine complex

1

H NMR suggests that pyridine ligand does not rotate on theNMR time scale.
Nitrogen of pyridine ligand does not coordinate.
Protonation

DBF4: only N-D
direct attack of nitrogen atom (not protonation of metal center)13

2.4 Catalytic dearomatization reactions
Catalytic oxidation of arenes
Catalytic photoinduced charge-transfer osmylation

Mortherwell et al. Angew. Chem. Int. Ed. 1995, 34, 2031.
Chem. Commun. 1997, 1283.

ozone, RuO4: concomitant cleavage of the carbocyclic ringAromatic electron donor-acceptor (EDA) complex
EDA complex

T oward catalytic reaction
Selection of suitable solvent system and oxygen transfer
reagent is important.
J K. Kochi et al. JACS. 1998, 110, 8207.

i) OsO4 (1.3 mol%), hv,
aq.Ba(ClO3)2 (0.22M)ii) Ac2O, Et3N, DMAP

NMP, pyridine, acetone, t-butanol: inhibitors of EDA
complex

OAc
AcO

OAc
OAc

OAc
+36%y.

AcO

OAc

OAc

OAc

OAc
6.2/1

Bio-inspired arene dihydroxylation by a non-haem iron catalyst

L Que, Jr et al. Chem. Commun. 2009, 50.
Proposed reaction mechanism(OTf)2(20 mol%)
H2O2 (10 eq)

OHOH

30%y.

Fe catalyst is the mimic of Riesk dioxygenage (naphthalene 1,2-dioxygenase).

14

3

Catalytic dearomatization via-benzylpalladium intermediate
M Bao, Y Yamamoto et al. JACS. 2001, 123, 759.

ClSnBu3+Pd2(dba)3.CHCl3 (5 mol%),PPh3 (40 mol%), acetone, rt80%y.

Mechanism
Cl
R = Me, Ph, iPr: 71~79%y.
R

The reason of regioselectivity was unclear...
(8 is more stable or reactive than 8' ?)Related works
ClSnBu3+Pd2(dba)3.CHCl3 (5 mol%),PPh3 (20 mol%), DCM, rt84%y.

M Bao, Y Yamamoto et al. Angew. Chem. Int. Ed. 2008, 47, 4366.
PhCl

Ph+ EtO2C

CO2Et

Pd(PPh4)3 (5 mol%),
NaH (2 eq), THF, rt

CO2Et
CO2Et

85%y.
M Bao et al. OL. 2011, 13, 5402.

Summary of chaptor 2
6-arene complex

Advantages

2-arene complex

Multinuclear metalcomplex

Selective coordination Sequential addition
to arene
Asymmetric version
Sequential addition
Heteroaromatic ring
Asymmetric version

Catalytic dearomatization
reactions

Catalytic

Under development

DisadvantagesStoichiometric

Stoichiometric

Narrow substrate
scope

Coordination toseveral FG
15