1,2 – Disubstituted Aromatics:Directed Ortho Metalation

Dennis Hoffart

Nov. 17, 2003

59-636

Outline• Mechanism of DoM Reaction

• Evidence for Proposed Mechanism

• Properties and Hierarchy of DMGs

• Relative Competition of DMGs

• Cooperative Metalation of meta-Substituted Aromatics

• Electrophilic substitution of Lithiated Aromatics

Outline• Successive DoM as a Route to Poly-Substituted Aromatics

•Synthetic Consequences of ortho-Lithiation• Synthesis of Boronic Acids: Reagents for Suzuki Coupling• Synthesis of Stannyl Compounds: Reagents for Stille Coupling

• Further Functionalisation of DoM Products: Towards Liquid Crystals

• Potential Synthesis of Liquid Crystals

Mechanism

DMG DMG

(RLi)n

DMG

Li

DMG

E

n

(RLi)n

-(RH)n E+

Mechanism

Li

MeO+

Li

Li

Li

LiO

O

O

O

Ph

Me

Ph

Me

Ph

MeMe

Ph

TMEDA

Mechanism

Li

LiNN

N N

MeO+

"Free"

- TMEDA

Li

LiNN

Mechanism

Li

LiNN

MeO H- (n-BuH)

irreversible

MeO

H

Mechanism

MeO Li

LiNN

+

E+

MeO E

Reaggregation

Directed Metalation Groups (DMGs)

N

R

O

N

O

O

R

O

N

O

RR

N

O

R

R

N

O

R

NR

OH

NR

R

NR

R

N

O O

Strong

F

FF

Cl

O

NR

R

Moderate

OO

Weak

Relative Competition of DMGs

DMG1

DMG2

b

a

DMG1

DMG2

DMG1

DMG2

DMG1 > DMG2

a >>> b

Cooperative Metalation Effects

• Deprotonation at ‘a’ will be favoured over deprotonation at ‘b’.

• This can be used to our advantage in designing synthetic pathways.

DMG1

DMG2

b

a

Electrophilic Substitution of Ortho-Lithiated Aromatics

MeI CO2

EtI DMF

S8 TsN3 / NaBH4

Br2 R3SiCl

I2 R3SnCl

O2 / H+ B(OMe)3

DMG

E

DMG

Li

E+

E+

Me CO2H

Et CHO

SH NH2

Br SiR3

I SnR3

OH B(OH)2

E

Successive DoM Reactions for Poly-Substituted Aromatics

DMG

DMG2

DMG3

DMG

DMG2

DMG1

DMG2

DMG3

Successive DoM Reactions

DMG

DMG2

DMG3

DMG

DMG2

DMG3

DMG6

DMG4

DMG5

Synthetic Potential 1: Suzuki Reagents

DMG DMG

B(OH)2

1. RLi

2. B(OMe)3

R R

Suzuki Coupling

DMG

R'

RR'

X

DMG

B(OH)2R

Pd0(PPh3)4+

Base

Synthetic Potential 2: Stille Reagents

DMG DMG

SnR3

1. RLi

2. R3SnCl

R R

Stille Coupling

DMG

SnR3

R R'

X

X = Cl, Br, I

Pd0(PPh3)4+

DMG

R'

R

Further Functionalisation of Aromatics: Towards Liquid Crystals

OH

OH

BaseOR'

OR'R

+ 2 R'X

R

O

1. RLi

2. O2 / H+

OH

OHR R

Possible Synthetic Route to a Discotic Liquid Crystal

O

1. RLi

2. O2 / H+

OH

OH

Possible Synthetic Route to a Discotic Liquid Crystal

OH

OH

FeCl3

OH

OH

OH

OH

HO

HO

Possible Synthetic Route to a Discotic Liquid Crystal

RO OR

OR

ORRO

RO

HO OH

OH

OHHO

HO

Base

6 RX

Possible Synthetic Route to a Calamitic Liquid Crystal

CONH2CONH2

B(OH)2

1. RLi

2. B(OMe)3

CONH2CONH2

Possible Synthetic Route to a Calamitic Liquid Crystal

CONH2

CNCONH2

Br

CONH2

B(OH)2

Pd0(PPh3)4+

Base

CNCONH2

Possible Synthetic Route to a Calamitic Liquid Crystal

NBS

AIBN

CONH2

CN

Br

CONH2

CONH2

CNCONH2

Possible Synthetic Route to a Calamitic Liquid Crystal

CONH2

CN

Br

CONH2

CH3(CH2)nOH

Base

CONH2

CN

O

CONH2

n

Conclusions and References

• DoM reaction is an excellent strategy for the (poly-)substitution of aromatic systems.

• Straight forward mechanism with a wide scope.

• Excellent method for the generation of coupling precursors, such as boronic acids and stannyl reagents.

Snieckus, V. Chem. Rev. 1990, 90, 879.

Queguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. Adv. Heterocycl. Chem. 1991, 52, 187.