Myers Directed Ortho Metalation Chem 115

Reviews:
Snieckus, V. Chem. Rev. 1990, 879. Relative Rates of Directed Metalation:
Clayden, J. In Chemistry of Organolithium Compounds; Rappoport, Z., Marek, I., Eds.; Wiley:
Chichester, 2004; Vol. 1, pp 495–646.
SO2NR2, CONR, CH2NR2 > OCH3 > CH2CH2NR2, CF3, F, NR2

DMG DMG E DMG

RLi

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

Gliman, H.; Bebb, R. L. J. Am. Chem. Soc. 1939, 61, 109. O CH3
Wittig, G.; Fuhrman, G. Chem. Ber. 1940, 73, 1197. CONR > CONR2 >
N CH3 > SO2NR2, SO2NR, CH2NR, OCH3, Cl
Ar
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 O O O
R R R
Ar N ArO N ArN Ot-Bu Ar N
Protective groups that also serve as strong directing groups are especially useful:
R R

R OR H O O CH3
O N OR ArOCH2OCH3
CH3 Ar OR N CH3
Ar NR2 Ar
Ar N CH3 Ar N Ar OR
Ar N
R
Meta oriented directing groups almost always direct metalation to the position ortho to both
groups.
O O O H O
P NR2 S ArCF3
ArO NR2 Ar t-Bu Ar NR2 CH3 CH3
CH3 CH3
1. 3.0 eq n-BuLi
O N 2. MeI O N
ArOCH2OCH3 ArOCH3 ArO– ArCH2O–
THF, −78 °C CH3
~100%
Cl Cl
ArF ArCl ArCH2N(CH3)2 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 Chem 115
Lithiation occurs ortho to the stronger directing group in cases where two lithiation sites Ortho tolyl anion formation is facile by directed metalation.
are possible. Cl

O 1. sec-BuLi, TMEDA CH3 O

2. MeI H3CO O H3CO O H3CO O
N CH3 N CH3 OCH3
THF, −78 °C NR2 s-BuLi, LDA NR2 NHR2
H3CO CH3 H3CO CH3
CH3 THF, −78 °C CH2Li THF, −78 °C
97%

Mills, R. J.; Snieckus, V. J. Org. Chem. 1989, 54, 4386. OCH3

Reitz, D. B.; Massey, S. M. J. Org. Chem. 1990, 55, 1375. 74%
Ethoxyvinyllithium (EVL) with HMPA shows a reversal in selectivity; the proton ortho
to the methoxyl group is removed. Heterocycle and Vinyl Ether Metalation:

Metalation of vinyl ethers and heterocycles occurs readily at the indicated positions.
OEt
1. HMPA O OCH3
O
Li H
2. MeI N(i-Pr)2 O H N S H
N(i-Pr)2 H O H
CH3
CH3O
CH3O THF, −78 → −30 °C
CH3
Vinyl ether anions provide an acyl anion equivalent.
93%

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

H3CO O
1. t-BuLi, −65 to 0 °C HO CH3
2. cyclopentanone, −65 °C HO HCl
Aldehydes can be transiently protected and, at the same time, transformed into a directing OCH3
group by amide anion addition. THF
88% 98%

H3C CH3
CH3 N
Baldwin, J. E.; Hofle, G. A.; Lever, O. W., Jr. J. Am. Chem. Soc. 1974, 96, 7125.
H3C N
H Directed lithiation of a tryptamine derivative has been employed in the total synthesis of
N Li N
CHO LiO CH3 1. n-BuLi CHO (+)-minfiensine.
H3C 2. MeI CH3
THF, −20 °C n-BuLi (4 equiv) OH
THF, −20 °C NHBoc 1,2-DME NHBoc
N
Cl Cl Cl 80% −78 → 23 °C; CHO
N N N
DMF H
PMB PMB H3C
78% (+)-minfiensine

Jones, S. B.; Simmons, B. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 13606.
Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078.
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 H3C CH H3C CH

3 3
into the pyridine ring. i-PrMgCl•LiCl
NH N MgCl•LiCl
THF, 0 °C
H3C CH3 H3C CH3 TMPMgCl•LiCl
ca.1.2 M in THF
BuLi
H
N N Bu R R TMPMgCl•LiCl R R I2 R R
Li
−25 °C, 30 min 88%
Br THF Br MgCl•LiCl Br I
R = CO2Et

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 TMPMgCl•LiCl OEt

0 °C, 6 h CN
1. sec-BuLi, TMEDA
I THF; TsCN
2. I2 Cl Cl
76%
N OCONEt2 THF, −78 °C N OCONEt2
Lin, W.; Baron, O.; Knochel, P. Org. Lett. 2006, 8, 5673.

This metallation technology has been employed iteratively in the synthesis of a fully
substituted pyrimidine derivative.
SnMe3
1. sec-BuLi, TMEDA
OCONEt2 2. Me3SnCl OCONEt2
N Br TMPMgCl•LiCl H3CS N Br
N THF, −78 °C N N −55 °C, 1.5 h, THF; N
CH3SSO2CH3 TMPMgCl•LiCl
20 °C, 5 min, THF;
81%
FCl2CCClF2
76%
H3CS N Br TMPMgCl•LiCl H3CS N Br

Ph N 20 °C, 20 min, THF; N

CuCN•2LiCl; PhCOCl
Miah, M. A.; Snieckus, V. J. Org. Chem. 1985, 50, 5436 O Cl Cl
81%

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 CH3
N
2. H3C
CH3
CH3
H3C N Li N
1. 3 eq (n-BuLi-KOt-Bu) N CHO
H3C 2. Bu3SnCl H3C H
CH3 OLi
Cl N OCH3
H3CO O O THF, −78 °C H3CO O O SnBu3 3. n-BuLi, −23 °C Cl N OCH3
H H
CH3 CH3 THF
~100%
I2

1. 1 eq n-BuLi
−78 → 0 °C Et O
H3C HO I
OTBS THF
OTBDPS O CHO
H3CO O O N
H 2. CH3
CH3 CH3 N Cl N OCH3
70% OTBDPS
Br O
OTBS 78%

HMPA (S)-camptothecin
0 → 23 oC
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.
H3C CH3
Carbamate directing groups can rearrange upon warming after lithiation. The resulting
H3C amide can be used for a second metalation reaction
O
H O
CH3
O
O 1. sec-BuLi, TMEDA
NH OCONEt2 TBSO O
2. warm to 23 °C
N
O 3. TBSCl, imidazole O NEt2
HO2C NHCH3 O O

Calcimycin 50%

OH O 1. sec-BuLi, TMEDA
O NH TBSO O 2. DMF
THF, −78 °C
O OH O NEt2
Note that treatment with t-BuLi alone failed to provide the desired anion. Trapping the anion H
under LICKOR conditions with tin provided a substrate that could be readily converted to the HO OH O CHO
corresponding organolithium reagent. OH 70%

Pancratistatin
Boeckman, R. K., Jr.; Charette, A. B.; Asberom, T.; Johnston, B. H. J. Am. Chem. Soc. 1987,
109, 7553. Danishefsky, S.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111, 4829.
Dionicio Siegel, Jonathan William Medley