3 directed ortho metalation

Myers

Directed Ortho Metalation

Chem 115

Reviews:
Snieckus, V. Chem. Rev. 1990, 879.
Clayden, J. In Chemistry of Organolithium Compounds; Rappoport, Z., Marek, I., Eds.; Wiley:
Chichester, 2004; Vol. 1, pp 495–646.
DMG

DMG

RLi

Relative Rates of Directed Metalation:

SO2NR2, CONR, CH2NR2 > OCH3 > CH2CH2NR2, CF3, F, NR2

DMG

E

Li

Slocum, D. W.; Jennings, C. A. J. Org. Chem. 1976, 41, 3653.

E

Gliman, H.; Bebb, R. L. J. Am. Chem. Soc. 1939, 61, 109.

Wittig, G.; Fuhrman, G. Chem. Ber. 1940, 73, 1197.

O
CONR > CONR2 >

N

Ar

CH3
CH3 > SO2NR2, SO2NR, CH2NR, OCH3, Cl

Directed metalation of anisole with n-BuLi was discovered independently in 1939–1940 by
Gilman and Wittig. This led to the discovery of more than 40 directing groups.
Beak, P.; Brown, R. A. J. Org. Chem. 1982, 47, 34.
Beak, P.; Tse, A.; Hawkins, J.; Chen, C.; Mills, S. Tetrahedron 1983, 39, 1983.
O
Ar

O
N
R

N
R

ArO

R

ArN

N

CH3
CH3

Ar

N

O
Ot-Bu

R

O
Ar

R

O

Ar

Ar

N

R

Protective groups that also serve as strong directing groups are especially useful:
OR

N

OR
N
R

Ar

ArOCH2OCH3

Ar

OR

OR

H O
Ar

O

NR2

Ar

N

CH3
CH3

Meta oriented directing groups almost always direct metalation to the position ortho to both
groups.
O
P NR2
ArO NR2

O O
S
t-Bu
Ar

ArCF3

H O
Ar

CH3
CH3

NR2
O

ArOCH2OCH3

ArOCH3

ArO–

N

ArCH2O–

THF, −78 °C
~100%
Cl

ArF

ArCl

ArCH2N(CH3)2

1. 3.0 eq n-BuLi
2. MeI

CH3
CH3
O

N
CH3
Cl

ArN(CH3)2
Pansegrau, P. D.; Rieker, W. F.; Meyers , A. I. J. Am. Chem. Soc. 1988, 110, 7178.

Dionicio Siegel, Jonathan William Medley

1


Myers

Directed Ortho Metalation

Lithiation occurs ortho to the stronger directing group in cases where two lithiation sites
are possible.
O
N

CH3
CH3

H3CO

Ortho tolyl anion formation is facile by directed metalation.
Cl

CH3 O

1. sec-BuLi, TMEDA
2. MeI
THF, −78 °C

Chem 115

N

CH3

H3CO

NR2

CH3

H3CO

H3CO

O

THF, −78 °C

CH3

97%

H3CO

O

s-BuLi, LDA

OCH3

NR2

O
NHR2

THF, −78 °C

CH2Li

Mills, R. J.; Snieckus, V. J. Org. Chem. 1989, 54, 4386.

OCH3
Reitz, D. B.; Massey, S. M. J. Org. Chem. 1990, 55, 1375.

Ethoxyvinyllithium (EVL) with HMPA shows a reversal in selectivity; the proton ortho
to the methoxyl group is removed.

74%

Heterocycle and Vinyl Ether Metalation:
Metalation of vinyl ethers and heterocycles occurs readily at the indicated positions.

OEt
1.

O
N(i-Pr)2

2. MeI

OCH3
N(i-Pr)2

THF, −78 → −30 °C

CH3O

O

HMPA
Li

O

H

H

CH3

Aldehydes can be transiently protected and, at the same time, transformed into a directing
group by amide anion addition.

CHO

N Li
H3C

H
LiO

OCH3

1. t-BuLi, −65 to 0 °C
2. cyclopentanone, −65 °C
THF

O

H3CO
HO

HCl

HO

CH3

88%

98%

CH3

CH3

Baldwin, J. E.; Hofle, G. A.; Lever, O. W., Jr. J. Am. Chem. Soc. 1974, 96, 7125.
1. n-BuLi
2. MeI

Directed lithiation of a tryptamine derivative has been employed in the total synthesis of
(+)-minfiensine.

CHO
CH3

THF, −20 °C

THF, −20 °C
Cl

N

N

H

S

Vinyl ether anions provide an acyl anion equivalent.

Shimano, M.; Meyers, A. I. J. Am. Chem. Soc. 1994, 116, 10815.

H3C

H
N
CH3

H

CH3O

93%

CH3
H3C N

O

Cl

NHBoc
Cl

80%

N
PMB

n-BuLi (4 equiv)
1,2-DME
−78 → 23 °C;
DMF
78%

Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078.

OH

NHBoc
CHO
N

PMB

N
N
H

H3C

(+)-minfiensine

Jones, S. B.; Simmons, B. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 13606.
Dionicio Siegel, Jonathan William Medley

2


Myers

Directed Ortho Metalation

Chem 115

The highly hindered amide base TMPMgCl•LiCl has been shown to effect efficient directed
metallation of electron-poor heteroarenes and arenes containing sensitive functional groups.
Metalation of pyridine is complicated by 1,2-addition of the organometallic
into the pyridine ring.

H3C CH
3
NH

H3C CH
3

i-PrMgCl•LiCl

N MgCl•LiCl

THF, 0 °C
H3C CH3

H3C CH3

BuLi
H
Bu

N
Li

N

R

R

Br
R = CO2Et

TMPMgCl•LiCl

R

−25 °C, 30 min
THF

Br

R

TMPMgCl•LiCl
ca.1.2 M in THF

I2
88%

MgCl•LiCl

R

R

Br

I

Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 2958.
With appropriate directing groups, lithiation of the pyridine ring can be efficient.
O

O
OEt

1. sec-BuLi, TMEDA
2. I2
N

OCONEt2

THF, −78 °C

I
N

TMPMgCl•LiCl

OEt

0 °C, 6 h
THF; TsCN

Cl

CN
Cl

76%

OCONEt2

Lin, W.; Baron, O.; Knochel, P. Org. Lett. 2006, 8, 5673.

OCONEt2
N

1. sec-BuLi, TMEDA
2. Me3SnCl
THF, −78 °C

SnMe3
OCONEt2

This metallation technology has been employed iteratively in the synthesis of a fully
substituted pyrimidine derivative.
N

N

TMPMgCl•LiCl

Br

H3CS

N

−55 °C, 1.5 h, THF;
CH3SSO2CH3

N

Br
N

TMPMgCl•LiCl
20 °C, 5 min, THF;
FCl2CCClF2
76%

81%

H3CS

N

Ph
Miah, M. A.; Snieckus, V. J. Org. Chem. 1985, 50, 5436

Br
N

O

Cl

TMPMgCl•LiCl

H3CS

20 °C, 20 min, THF;

CuCN•2LiCl; PhCOCl
81%

N

Br
N

Cl

Mosrin, M.; Knochel, P. Org. Lett. 2008, 10, 2497.
Dionicio Siegel, Jonathan William Medley

3


Myers

Directed Ortho Metalation

Chem 115

Examples of Directed Ortho Metalation in Synthesis:
1. t-BuLi, −78 °C
2.
H3C
H3CO

O

H3C

1. 3 eq (n-BuLi-KOt-Bu)
2. Bu3SnCl

H
CH3

O

H3C
H3CO

THF, −78 °C

O

H
CH3

O

N

Cl

SnBu3

H3C

CH3
N

N

CH3
N
Li

CHO

N

H
OLi

CH3

OCH3

N

Cl

3. n-BuLi, −23 °C
THF

~100%

CH3

OCH3

I2

H3C
H3CO

O

OTBS

H
CH3

70%

1. 1 eq n-BuLi
−78 → 0 °C
THF

CH3

2.

CHO

N

CH3

N

OTBDPS

Br

I

O

OTBDPS

O

O

Et
HO

N

Cl

78%

OTBS
HMPA
0 → 23 oC

H3C
H
O

O

O

(S)-camptothecin
Lithiation adjacent to the methoxyl group followed by trapping with the formamide shown
provides an α-amino alkoxide to direct a second metalation reaction.
Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10971.

CH3

H3C

Carbamate directing groups can rearrange upon warming after lithiation. The resulting
amide can be used for a second metalation reaction
CH3
O

NH

OCH3

O

OCONEt2

N
HO2C

O
NHCH3

1. sec-BuLi, TMEDA
2. warm to 23 °C
3. TBSCl, imidazole

TBSO
O

O

50%
OH O
O

Boeckman, R. K., Jr.; Charette, A. B.; Asberom, T.; Johnston, B. H. J. Am. Chem. Soc. 1987,
109, 7553.

NEt2

O

Calcimycin

Note that treatment with t-BuLi alone failed to provide the desired anion. Trapping the anion
under LICKOR conditions with tin provided a substrate that could be readily converted to the

corresponding organolithium reagent.

O

O

TBSO

NH
H
HO

OH

O

OH

O

OH

O
NEt2

1. sec-BuLi, TMEDA
2. DMF
THF, −78 °C

CHO

70%

Pancratistatin
Danishefsky, S.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111, 4829.
Dionicio Siegel, Jonathan William Medley
4