Mesityllithium as a reagent for chemoselective halogen-lithium exchange reaction.

Article abstract of DOI:10.1021/ol000253x

[figure: see text] Mesityllithium was found to be an excellent selective lithiating agent to prepare aryllithium compounds having alkoxycarbonyl groups. To extend our studies on chemoselective lithiation, an important precursor for the synthesis of camptothecin was prepared using a halogen-lithium exchange reaction followed by an intramolecular 1,2-addition.

Full text of DOI:10.1021/ol000253x

ORGANIC
LETTERS
2001
Vol. 3, No. 1
13-15
Mesityllithium as a Reagent for
Chemoselective Halogen−Lithium
Exchange Reaction
Yoshinori Kondo,* Miho Asai, Tohru Miura, Masanobu Uchiyama, and
Takao Sakamoto
Graduate School of Pharmaceutical Sciences, Tohoku UniVersity,
Aobayama, Aoba-ku, Sendai 980-8578, Japan
ykondo@mail.pharm.tohoku.ac.jp
Received August 31, 2000
ABSTRACT
Mesityllithium was found to be an excellent selective lithiating agent to prepare aryllithium compounds having alkoxycarbonyl groups. To
extend our studies on chemoselective lithiation, an important precursor for the synthesis of camptothecin was prepared using a halogen−
lithium exchange reaction followed by an intramolecular 1,2-addition.
Halogen-metal exchange reaction is one of the most
powerful methods for preparing various organometallic
compounds among which the preparation of organolithium
compounds has been most extensively studied.1 Organo-
lithium compounds display a strong anionic character that
allows reactions with various electrophiles to take place.
However, compatibility with electrophilic substituents such
as ester groups is limited. To overcome this restriction,2,3
we employed the combination of a sterically hindered
aromatic lithiating agent, such as mesityllithium,4 and bulky
ester groups. An aryllithium with a tert-butoxycarbonyl
group, which was prepared using mesityllithium as the
lithiating agent, was stable enough to react with various
electrophiles at -78 °C, without any self condensation. To
extend the use of mesityllithium for chemoselective lithiation,
an important precursor for the synthesis of camptothecin5a,b
was prepared by a halogen-lithium exchange reaction prior
to a cyclization by an intramolecular 1,2-addition.
First, halogen-lithium exchange reactions involving iodo-
benzoates were investigated using mesityllithium. Ethyl
2-iodobenzoate was treated with mesityllithium in THF at
(1) (a) Gilman, H.; Jacoby, A. L. J. Org. Chem. 1938, 3, 108. (b) Gilman,
H.; Langham, W.; Jacoby, A. L. J. Am. Chem. Soc. 1939, 61, 106. (c)
Wakefield, B. J. The Chemistry of Organolithium Compounds; Pergamon:
Oxford, 1974. (d) Wakefield, B. J. Organolithium Method; Academic
Press: London, 1988. (e) Snieckus, V.; Gray, M.; Tinkl, M. In Compre-
hensiVe Organometallic Chemistry II; Abel, F. G., Stone, F. G. A.,
Wilkinson, G., McKillop, A., Eds.; Pergamon Press: Oxford, 1995; Vol.
1, p 1.
(2) For examples of previous approaches in chemoselective lithiation,
see: (a) Parham, W. E.; Jones, L. D. J. Org. Chem. 1976, 41, 2704. (b)
Parham, W. E.; Jones, L. D.; Sayed, Y. A. J. Org. Chem. 1975, 40, 2394.
(c) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300. (d)
Beak, P.; Musick, T. J.; Liu, C.; Cooper, T.; Gallagher, D. J. J. Org. Chem.
1993, 58, 7330. (e) Gray, M.; Tinkl, M.; Snieckus, V. In ComprehensiVe
Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G.,
Eds.; Elsevier Science Ltd.: Oxford 1995; Vol. 11, pp 1-92 and references
therein.
(3) For recent examples of chemoselective aromatic metalation, see: (a)
Zhu, R.; Wehmeyer, R. M.; Rieke, R. D. J. Org. Chem. 1991, 56, 1445.
(b) Kondo, Y.; Matsudaira, T.; Sato, J.; Murata, N.; Sakamoto, T. Angew.
Chem., Int. Ed. Engl. 1996, 35, 736. (c) Kondo, Y.; Fujinami, M.; Uchiyama,
M.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1997, 799. (d) Kondo,
Y.; Komine, T.; Fujinami, M.; Uchiyama, M.; Sakamoto, T. J. Comb. Chem.
1999, 1, 123. (e) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J.
Am. Chem. Soc. 1999, 121, 3539. (f) Boymond, L.; Rottlaender, M.; Cahiez,
G.; Knochel, P. Angew. Chem., Int. Ed. 1998, 37, 1701.
(4) For an example of hydrogen-lithium exchange reaction using
mesityllithium, see: Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett.
1988, 29, 773.
(5) (a) Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail.
A. T.; Sim, G. A. J. Am. Chem. Soc. 1966, 88, 3888. (b) Comins, D. L.;
Hong, H.; Saha, J. K.; Jianhua, G. J. Org. Chem. 1994, 59, 5120.
10.1021/ol000253x CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/15/2000

-78 °C for 1 h, and the reaction was quenched with H2O.
The expected ethyl benzoate was not obtained as a result of
side reactions during lithiation. When isopropyl 2-iodo-
benzoate was reacted with mesityllithium, isopropyl benzoate
was obtained with a yield of 21%. On the other hand,
lithiation of tert-butyl 2-iodobenzoate using mesityllithium
proceeded smoothly, and tert-butyl benzoate was obtained
with a yield of 68%. Selective lithiation of tert-butyl
4-iodobenzoate using mesityllithium also proceeded smoothly,
and the protonated product was obtained with a yield of 57%
after treatment with H2O (Table 1).
Scheme 2
Table 1. Halogen-Lithium Exchange Reaction Performed on
Iodobenzoates
tert-Butyl 4-lithiobenzoate was also reacted with trimethyl-
borate, followed by treatment with 1,3-propanediol to give
arylborate 5. The arylborate 5 was subjected to reaction with
iodobenzene in the presence of Pd(PPh3)4 in DMF at 100
°C, to give the biaryl ester 6 (Scheme 2).
Next, the chemoselective lithiation of haloaromatics using
mesityllithium was applied for the synthesis of a campto-
thecin precursor. As a preliminary experiment, lithiation-
cyclization was investigated using iodobenzyl ketoester 7 as
the substrate. The lithiation was carried out using mesityl-
litium in THF at -78 °C for 1 h, accompanied by the
spontaneous intramolecular 1,2-addition to give the hydroxy-
lactone 8 in 70% yield (Scheme 3). The use of other
tert-Butyl 2-lithiobenzoate prepared from the lithiation of
tert-butyl 2-iodobenzoate was reacted with several carbonyl
compounds. Substituted phthalides were obtained directly
with excellent yields (Scheme 1). tert-Butyl 4-lithiobenzoate,
Scheme 3
Scheme 1
organolithium compounds such as n-BuLi, t-BuLi gave the
lactone 8 with low yields (25% and 24%), and no for-
mation of the lactone 8 was observed when phenyllithium
was used.
prepared from tert-butyl 4-iodobenzoate and mesityllithium,
was also reacted with various carbonyl compounds. Substi-
tuted hydroxyesters were obtained with excellent yields
(Scheme 2).
(7) Typical Procedure for Scheme 4. Under an argon atmosphere,
t-BuLi (1.44 M in n-pentane, 2.8 mL, 4.0 mmol) was added to a solution
of mesityl bromide (398 mg, 2.0 mmol) in dry THF (7 mL) at -78 °C and
stirred at -20 °C for 1 h. The mixture was then cooled to -78 °C and a
solution of the iodopyridinylmethyl ketoester 9 (349 mg, 1.0 mmol) in dry
THF (5 mL) was added drop by drop. The mixture was stirred at the same
temperature for 5 h and an aqueous solution saturated with NH4Cl was
added. The resulting mixture was extracted with Et2O (20 mL × 3) and
washed with brine (30 mL). The organic layer was dried over anhydrous
MgSO4 and the solvent was evaporated to give a residue, which was purified
by SiO2 column chromatography using n-hexane/AcOEt (5:1) as the eluent
to give a viscous oil (127 mg, 57%): 1H NMR (CDCl3, 300 MHz) δ 8.24
(d, J ) 5.2 Hz, 1H), 7.38 (d, J ) 5.2 Hz, 1H), 5.05 (d, J ) 17.3 Hz, 1H),
4.84 (d, J ) 17.3 Hz, 1H), 4.01 (s, 3H), 2.90 (s, 1H), 2.12 (q, J ) 7.4 Hz,
1H), 1.89 (q, J ) 7.4 Hz, 1H), 1.01 (t, J ) 7.4 Hz, 1H); HRMS calcd for
C11H13NO4 (M+) 223.0844, found 223.0875.
(6) Typical Procedure for Schemes 1 and 2. Under an argon atmo-
sphere, t-BuLi (1.44 M in n-pentane, 2.8 mL, 4.0 mmol) was added to a
solution of mesityl bromide (398 mg, 2.0 mmol) in dry THF (7 mL) at
-78 °C and stirred at -20 °C for 1 h. The mixture was then cooled to -78
°C and a solution of an alkyl iodobezoate (1.0 mmol) in dry THF (7 mL)
was added drop by drop. The mixture was stirred at the same temperature
for 1 h, treated with an electrophile (3 mmol), and stirred at the same
temperature for 1 h before addition of an aqueous solution saturated with
NH4Cl. The resulting mixture was extracted with Et2O (20 mL × 3) and
washed with brine (30 mL). The organic layer was dried over anhydrous
MgSO4 and the solvent was evaporated to give a residue, which was purified
by column chromatography to obtain a pure compound.
14
Org. Lett., Vol. 3, No. 1, 2001

A similar lithiation-cyclization reaction was conducted
using the iodopyridinylmethyl ketoester 9 as the substrate
for the synthesis of the precursor for camptothecin and the
hydroxylactone 10 was obtained with a yield of 57%
(Scheme 4). The conversion of the lactone 10 to campto-
thecin has been well established by Comins, and is consid-
ered to be straightforward.5b
In summary, a chemoselective lithiation of functionalized
haloaromatics could be achieved using mesityllithium, al-
lowing the preparation of an important precursor for the
synthesis of camptothecin. Further applications of the present
method to the synthesis of biologically active aromatic and
heteroaromatic compounds are in progress.
Scheme 4
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research (12557198) from the
Ministry of Education, Science, Sports and Culture, Japan
and by the Tokuyama Science Foundation.
OL000253X
Org. Lett., Vol. 3, No. 1, 2001
15