1,2 – disubstituted aromatics: directed ortho metalation
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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.
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