Baran Group Meeting

Directed Metalation: A Survival Guide

Overview of topics to be discussed:

Directed ortho-Metalation, Heterocycle Metalation,
Non-aromatic Metalations, Examples in Synthesis

Common DMGs and their relative strength in directing metalation:

Strong DMGs:
O

Relevant Reviews: Chem. Rev. 1990, 90, 879-933.; Current Org. Chem.
2006, 10, 1817-1848.; Acc. Chem. Res. 1986, 19, 356-363.; Acc. Chem.
Res. 1982, 15, 306-312.; Angew. Chem. Int. Ed. 2005, 44, 376-393.; Chem.
Soc. Rev., 2007, 36, 10691084.

R
DMG Li

DMG

DMG
Li

R-Li

E+

Ar

N
R

O
Ar S t-Bu
O

O R
Ar S N
O R

Directed ortho-Metalation
DMG

Paul Krawczuk

O
S

Ar

O
Ar S N
O R

O
Ar

t-Bu

Ar

Ar

The direct metalation group (DMG) is typically a Lewis basic moiety

that interacts with the Lewis acidic lithium cation allowing for deprotonation
by the alkyl-lithium species from the nearest ortho-position on the arene.
As long as deprotonation does not occur by the highly basic lithiated-aryl
ring, it may react with various electrophiles at the lithiated position in an
ipso-substitution.

ortho-Metalation followed by quench with an electrophile is favored over

traditional electrophilic substitutions due to the regioselective preference for
ortho-substitution as opposed to a mixture of ortho- and para-substitution

N
n
R

Ar

Ar

Ar

n=1,2

Ar

Ph

NR2
P NR
2
O

O
Ar S OR
O

O
Ar S O
O

Ar CF3
Ar
Ar F

NR2

Ar

Ar Cl

R
N

Ar

Ar N

Ar OMe
Ar

Nature of the DMG

DMGs do not function alone in determining the site of metalation.

Sterics and other functional groups on the arene also have a great deal
of influence.

Ar

Moderate DMGs:

This reaction was first discovered independently by:

Henry Gilman (JACS 1939, 61, 109-112.)
Georg Wittig (Chem. Ber. 1940, 73, 1197.)

These groups should be able to effectively coordinate the alkyl-lithium

species (making a hetero-atom a necessity) in order to establish a
complex-induced proximity effect (CIPE) and at the same time be poorly
electrophilic so as to not react via nucleophilic attack by the alkyl-lithium.
Inductive effects may also play a role in some cases by lowering the
pKa of the adjacent proton.

Ar

N
Ar

-RH

N
R

Ar

OR
P OR
O
R

N
R

Weak DMGs:
R
N

OR
Ar

OR

Ar O

Ar S

Ar

Ar

Ar Ph

Ar
N
R

N
Ar
N

Directed Metalation: A Survival Guide

Baran Group Meeting

Other Metalation Considerations

Nature of the Base and Solvent

When two DMGs have a 1,3-disposition on the arene they will direct
lithiation to the 2-position between them through a cooperative
coordination of the alkyl-lithium:
DMG

DMG

DMG
Li

RLi

E+

Typically powerful alkyl-lithium bases are needed for these metalations.

MeLi, n-BuLi, sec-BuLi and t-BuLi are the most common. These alkyl lithiums
exists as various aggregates in solution and amine additives serve to break up
these aggregates to allow accelerated reactivity due to increased basicity.
TMEDA, a bidentate amine, is excellent as a ligand and is therefore more
commonly employed.

E
OMe

DMG

DMG

DMG

n-BuLi
PhMe

When two DMGs are 1,4-disposed on the arene the metalation

will be directed ortho to the DMG that is a "stronger" DMG, if
their strengths are similar a mixture may result:
DMGstronger
RLi

DMGstronger
Li

DMGstronger
E

E+

DMGweaker

DMGweaker

Benzylic positions may be metalated more rapidly even in the

presence of a DMG:
OMe
Me

n-BuLi, TMEDA
THF, 0C

Li
N

-TMEDA

N
Li

Li
MeO

Li

Many Electrophiles react with lithiated arenes.

Common examples:
ArCHO, RCHO, D2O, RX, CO2, (RS)2, TMSCl, B(OR)3, DMF, Bu3SnCl, TsN3,
BnX, HCO2Et, RCOCl, Ac2O, RNCO, RCN, X2, terminal epoxides, S8, Se, ZnCl2

however:
OMOM
Me

N
Li

N
Li

Li

Reactivity of Metalated Arenes

OMe

E+

Me
Ph O
Me
TMEDA
Li
O
Li
Ph
Li
O Ph
Li
Ph O
Me
Me
OMe
N

OMe
DMGweaker

Paul Krawczuk

n-BuLi, TMEDA
0C

E+

OMOM
E

Transmetalation of lithiated arenes allows for transition metal catalyzed

reactions.
Nucleophilic attack should be faster then deprotonation in the case where
the electrophile has an acidic proton.

Directed Metalation: A Survival Guide

Baran Group Meeting

Paul Krawczuk

Reactivity of Metalated Arenes-Examples

O
NEt2

1) sec-BuLi,
TMEDA, THF
-78C

TMS
O

NH2 O

1) sec-BuLi,
TMEDA, THF
2) TMSCl
-78C

NEt2
O

NEt2

2) TsN3
3) NaBH4
82%
O
NEt2
TMS
OMe

1) sec-BuLi,
TMEDA, THF
-78C
2) TsN3
3) NaBH4
82%

NH2 O

NEt2

J. Org. Chem. 1983, 48,1935-1937.

O
O

1) sec-BuLi,
NMe2 TMEDA, THF
N
H
-78C
O
2)

sec-BuLi,
NEt2 TMEDA, THF
OTMS

O
NEt2 Tf2O, Pyr, 0C

-78C-r.t.

Tet. Lett. 2000, 40, 3795-3798.

OMOM

OMOM
A:B
0.5 : 95

2) ethylene iodochloride

2) ethylene iodochloride

OTf
TBAF,MeCN
r.t., 60%

NEt2

Tet. Lett. 1984, 25, 2827-2830.

1) n-BuLi, C6H12, 0C

TMS

1) t-BuLi, Et2O, -78C

NEt2

TMS
OH

NEt2

OH O

NEt2

OMe

68%

OMOM

-78C-r.t.
70%

TMS

Tet. Lett. 1983, 24, 3795-3798.

O

NEt2

NEt2

O
TMS 2:1

sec-BuLi,
TMEDA, THF

NEt2

90 : 10 O

J. Org. Chem. 1982, 47, 2101-2108.

O
B

1) 2 n-BuLi
THF
t-Bu
-20C-0C

H
N

2) EtI
-50C-r.t.
89%

t-Bu
O
Et

J. Org. Chem. 1982, 47, 2804-2806.

Directed Metalation: A Survival Guide

Baran Group Meeting

OMe O
NMe2

3) LDA
4) OHC

Et2N

OH
O
OMe

CONMe2
OH

2)

1)NaOH

2)HCl 32%

BBr3
DCM MeO

R=H, 30%
R=D, 52%

OMe

OMe

O
3) MsOH/DCM, reflux

OBn
OMe

-78C
45%

ZnCl2, Ac2O
>90%
OAc

Et2N
1) sec-BuLi, TMEDA, THF
CONEt2 2)
OMe
MeO
OMe
OHC

J. Org. Chem. 1982, 47, 2120-2125.

OH OMe

CHO
CO2H

OMe
OMe

TsOH

1) Zn/Cu, KOH/pyr
2) TFAA, DCM
3) K2CO3/MeOH/O2

OMe O

>90%

HO

J. Org. Chem. 1984, 49, 742-747.

OMe

Zn/KOH
MeOH
reflux

phyllodulcin

1) sec-BuLi, TMEDA, THF

OBn

OBn

32% overall
HO

OMe

1) sec-BuLi, TMEDA, THF

2) MeI

Paul Krawczuk

CO2tBu

O
Br

MeO

OMe

CN

OMe

OMe O

OMe

B=

N Mg2LiCl
2

Chem. Pharma. Bull. Jpn. 1983, 31, 2662.

CO2tBu
Br

1) B, THF, -30C

CN

2) ZnCl2
3) Pd(dba)2, P(2-furyl)3
p-IC6H2CO2Et

O
member of a class of
antitumor-antibiotics

1) B, THF, -20C
2) I2
71%

OMe
1) mCPBA
2) TsOH

2) DMF, -78C
3) MsOH, 50C

Tet. Lett. 2002, 43, 8347-8350.

MeO

1) sec-BuLi, THF, -78C

70%

Angew. Chem. Int. Ed. 2007, 46, 7681-7684.

CO2Et

Directed Metalation: A Survival Guide

Baran Group Meeting

Metalation of Heterocycles

Paul Krawczuk

Side-chains may be metalated:

Position of lithiation:
N
N
R

Li

Li

Li

Li

N
R

N N
R

Li

2) i-PrCONMe2

Li

1) n-BuLi, THF, -70C

i-Pr

N
enaminate anion

Reactivity of Metalated Heterocycles-Examples

Li

N
R

Li

Li

Many of these heterocycles may be lithiated twice.

1) sec-BuLi, TMEDA,
Et2O, -78C

NEt2

2)

N
n-Bu
Li
Direct lithiation of pyridine is
very useful since alkyllithiums may add into pyridine

sec-BuLi, r.t.

air
N

n-BuLi

NEt2
OH

n-BuLi

Br

Li

J. Am. Chem. Soc. 1980, 102, 1457-1460.

However lithium-halogen exchange

can provide the 2-lithiated pyridine

1) n-BuLi, TMEDA,
hexane, reflux

Things to consider:
In addition to the heteroatom DMGs will influence the metalation site.

Li

1) Te powder
BuTe
Li 2) BnBr
PdCl2, TEA,
MeOH, r.t.

For heterocycles alkyl lithium bases are used as well as lithium amides.

TeBu
90%
OH

Solvent choices for these lithiations are usually ether or THF.

HO

TMEDA or HMPA are often added as ligands to coordinate the metal cation.

Tet. Lett. 2003, 44, 1387-1390.

Heterocycles can sometimes fragment:

Ph

Ph
O

Ph

Ph

RLi
-60C

Li

O
87%

Ph

Ph

CHO

N
OLi

Liebigs Ann. Chem., 1979, 219.

H
N

1) n-BuLi, THF
NMe2 2) 2 n-BuLi
3) MeI

J. Org. Chem. 1987, 52, 104-109.

CHO
O

OH

Directed Metalation: A Survival Guide

Baran Group Meeting

Paul Krawczuk

Reactivity of Metalated Heterocycles-Examples

1) LDA, -78C E
2) E+, -78C

N
1) n-BuLi, THF, hexane
-70C - r.t.
Li
N
CO2Li

2) CO2
3) t-BuLi, THF, pentane
-70C - r.t.

N
H

E+
50-95%

N
H

Ph

Org. Pre. Proced. Int. 1988, 20, 585-590.

Ph 1) base, -78C
2) E+, -78C

O
1) 2.2 equiv. t-BuLi
THF, -78C - r.t.
2) O

N
O

NHt-Bu

58%
N
H

OH

Ph 1) n-BuLi, -78C

2) PhCHO, -78C
Ph

1) n-BuLi, -78C
Ph
2) E+, -78C

E= CO2, PhNCO, Ph2CO,

4-MeC6H4SO2F, or DMF

Ph
N

1) 2 equiv. n-BuLi,
Et2O, r.t.

N
O

100%

N
2) MeI
SO2NMe2 82%

Ph

Ph

Ph base
n-BuLi
LDA
LiNEt
2
E

Li

2) Br(CH2)3CH=CH2,
-78C to r.t.

(or LDA)

Kinetic Site

Tetrahedron, 1983, 39, 2009-2021.

Tetrahedron, 1994, 50, 1129-1134.

N
SO2NMe2

N
Ts

1) t-BuLi
THF, -78C
2)
O

OH
N
Ts

79%

J. Chem. Soc., Perkin Trans. 1, 1984, 481-486.

Li

F n-BuLi, TMEDA
THF, -40C
N

Ph

ratio
9:91
9:91
99:1

1) n-BuLi, -78C

Thermodynamic Site

n-BuLi, TMEDA
Et2O, -40C

1) n-BuLi, Et2O
-78C

Heterocycles, 2002, 57, 1211-1217.

2) MeI

Synthesis, 1991, 1079-1082.

HO

workup with
3N NaOH

Synlett, 1992, 327-328.

F
N

Ph

Directed Metalation: A Survival Guide

Baran Group Meeting

Cl

Reactivity of Metalated Heterocycles-Examples

1) LDA, THF/Hexane
-75C to -5C
2) MeCHO
N
90%
SO2Ph
HO

Me

Me MnO2
90%
N
OH
SO2Ph

N
O
SO2Ph

3) AcOH

THF, -100C

Cl

OMe

Cl
I
BF3Et2O, TES
Cl
79% overall

N
TIPS

N
Boc
N

OMe
NBoc

MeO

BnO

BnO

OBn

OMe

OMe

N
N

Ph

N
Cl

Cl

N
Clavicipitic
Acid

OH

N 49%

OMe
MeO

OBn

BnO

OH
OBn

Reaction Conditions:
1) LiTMP, THF, -78C
2) PhCHO, -78C-r.t.

O
H

J. Org. Chem. 2001, 66, 4783-4786.

79%
OMe

Ph

N
N

82%

N 98% N
OMe

OMe

OH OMe
95%

Ph

N
N

Ph
HO

OMe
N

OMe

OMe

N
N

HO

Tetrahedron, 1999, 55, 10989-11000.

see also: Heterocycles,1993, 36, 29-33. (first study of C-4 lithiation)

OMe

OMe

Ph

OMe

66% yield,
dr: >30:1
n-BuLi, TMEDA ee: 96%
THF, -78C
(optimized conditions)

OH

OMe
OH

OMe

N
TIPS

Li

BnO

OMe

2)

Cl

Sempervirine
Tetrahedron, 1988, 44, 3195-3202.

1) t-BuLi, Et2O, 0C

OH

1) I2 2) BnO

BnO

48% over 4 steps

aq NaOH
MeOH, reflux
N

Li

N
PhO2S

N
SO2Ph

Cl

Cl

6 steps

1) n-BuLi, THF, -78C

2) BrCH2CHO, THF

BrN

LiTMP (3 equiv.)

Paul Krawczuk

OMe
N

MeO

OMe
N

97%

OMe

J. Org. Chem. 1990, 55, 3410-3412.

Ph

MeO

OMe
N

Directed Metalation: A Survival Guide

Baran Group Meeting

Reactivity of Metalated Heterocycles-Examples

F
NH

Li

LDA, THF, -78C

HO
O

LiO

HN
O
HO

HO

MeO

n-Bu

O
OH

TBSO

N
O

TBSO

N 1) 5 equiv. LiTMP
HMPA, THF, -70C
Li
N 2) TMSCl
TBSO

N
TMS
TBSO

n-Bu3SnCl may
also be used to
give similar results

TBSO

Li
H+

2) ClCONEt2
CONEt2
80%

Cl
N

TMS
TBSO

NH

OH

OTBS

OMe

eupolauramine

Tet. Lett. 1991, 32, 4883-4884.

CONEt2
Br

2 equiv. LDA,
THF, 0C-r.t. N
85%

OMe

TBSO

CONEt2

OTBS

J. Org. Chem. 1997, 62, 6833-6841.

B(OH)2

TMS

83% overall
TBSO

N
3) KMnO4, H2O
4) ClCONEt2/ K2CO3
Br
Br
48% overall

OMe
OTBS

CONEt2

1) LDA, THF, -78C

silyl
Cl migration
OTBS

F
Bioorg. Med. Chem. Lett. 1999, 9, 1341-1346.

1) LDA, THF, -78C

2) DMF

Cl

and
desfluoro
18%

Cl

MeO

NH DCM MeO
-78C

HO

Tet. Lett. 1979, 19, 4755-4758.

N

BBr3

F
1) 6N HCl, Zn, 2) TsOH, PhMe
r.t.
reflux
60%
MeO
BH3, THF
reflux
NH
NH 23% MeO

O
HO

NO2
CONHt-Bu

NO2

3) TEA, MeOH, r.t.

31%

n-BuBr 60%
O
HN
O
HO
N
O
TFA
n-Bu
83%

MeO

O
O

NLi

MeO

1) 2 equiv. n-BuLi, -78C

NHt-Bu 2)
MeO

Paul Krawczuk

Pd(PPh3)4, DME
aq. Na2CO3
91%
CONEt2
CONEt2
OMe

Directed Metalation: A Survival Guide

Baran Group Meeting

Non-aromatic Metalations

THF, -78C
O

Li

OCONEt2

OCONEt2 1) sec-BuLi, TMEDA

A few general examples:

R
O

Paul Krawczuk

Li

Li

OCONEt2
OH

OCONEt2 Ph-CHO

OR

THF, -78C

Li

These metalations are possible due to directing groups present in the

substrate and are moderated by combination of factors such as:
resonance, stereoelectronic, inductive, steric and the complex-induced
proximity effect (CIPE).
CIPE is a non-classical way of describing the pre-lithiation complex that
forms between a Lewis basic heteroatom on the directing group and the
alkyl-lithium. By the establishment of this complex the lithiating species is
brought in close proximity to the relatively acidic proton of the substrate
and thus accounting for the observed regioselectivity

THF, -78C
66%

OH O

O
OCONEt2

Ph
minor

1) BF3OEt2O
2)
OCONEt2
O
Li

Li

Ph
30%

Ph
60%

OCONEt2
MeMgBr, NiCl2(dpp)
PhH, reflux
(JOC, 49, 4895)

HO
Br

Non-aromatic Metalations-Examples
O 1) t-BuLi, THF,
-60C-0C
E+:

2) E+, -65C

HCl (dil. aq.)

Li
Vinyl Ether Product:

E
Hydrolysis Product:

OH

OH

Ph-CHO

O 78%

Ph

OH LiTMP
(2.2equiv)

O
O

Ph-CN
Ph

O
O

70%

77%

Ph
O

CH3(CH2)6CH2I

cyclohexanone

H3C(H2C)6H2C
OH
OMe

n.d.

H3C(H2C)6H2C

n.d.

J. Am. Chem. Soc. 1974, 96, 7125-7127.

OH
O

MeO

J. Org. Chem. 1990, 55, 5680-5683.

91%

Ph

MeO
ZnBr2, Pd(PPh3)4
THF, reflux
71%

Li

HO

OCONEt2

OCONEt2
O

OCONEt2

Ph

N
CO2Me

Li

O
N

THF, -78C
MeO

Br

Li

(5 equiv.)
48%

OH
80%

90%

OH

Cl

Cl
N
CO2Me

4.2 equiv. MeLi

THF, 0C
91%

Supinidine

J. Org. Chem. 1983, 48, 1129-1131.

Directed Metalation: A Survival Guide

Baran Group Meeting

Non-aromatic Metalations-Examples
O

O
1) sec-BuLi

Ph

2) PhCHO
69%

OH
HO
O

Ph

1) sec-BuLi

N
2) PhCHO
Ph 78%
J. Am. Chem. Soc. 1984, 106, 1010-1018.
O

Me

N
Boc

1) sec-BuLi,
TMEDA, Et2O
2) MeI
74%

Me

Ph

N
Me
Boc

5% TFA/DCM 92%
O

OH
NaBH4
Me

N
Boc

MeOH
Me 92%

Me

N
Me
Boc

J. Org. Chem. 1990, 55, 2578-2580., J. Org. Chem. 1993, 58, 1109-1117.
1) sec-BuLi
(-)-sparteine
N
Boc 2) CuCN-2LiCl
3) H
CO2Et

CO2Et
N
Boc 56%, 44% ee

1) sec-BuLi
(-)-sparteine
N
Boc 2) CuCN-2LiCl
O
3) I

O
N
Boc
79%, 60% ee

J. Org. Chem. 2004, 69, 3076-3086.

Paul Krawczuk