selective lithiation and electrophilic substitution of

SELECTIVE LITHIATION AND ELECTROPHILIC SUBSTITUTION
OF BIPHENYL 2-CARBOXYLIC ACID
Subhendu S. Samanta and Jacques Mortier
Université du Maine and CNRS, Unité de chimie organique moléculaire et macromoléculaire
(UMR 6011), Faculté des sciences, avenue Olivier Messiaen, 72085 Le Mans Cedex 9
Remote metalation of biaryl amides with t-BuLi or LDA constitutes a convenient route to the
fluorenone and azafluorenone skeleton which is found in significant classes of alkaloids, physiologically
active agents, and environmental pollutants.1,2 Faigl and Schlosser have reported that N-phenylpyrrole
gives a mixture of ortho-mono carboxylic acid, ortho,α-dicarboxylic acid and α-mono carboxylic acid
upon treatment with n-BuLi in presence of TMEDA and reaction with dry ice. 3 On the other hand, the
biaryl unit is present in many natural products, pharmaceuticals, and ligands for homogeneous catalysis.
In addition, biphenyls are of interest as building blocks of host-guest complexes. Although there are some
existing methods for the preparation of substituted biphenyls, preparation of substituted biaryl carboxylic
acids via lithiation method is very rare.
As we have demonstrated previously, the directed ortho-metalation of unprotected benzoic acid can
be achieved by treatment with 2.2 equiv of s-BuLi/TMEDA in THF at low temperature (–90 °C).4 α,βUnsaturated carboxylic acids undergo predominantly conjugate addition with organolithium reagents at
low temperature (–78 °C) in THF and lead to various substituted alkanoic acids after quenching with
electrophiles.5 We wondered how biphenyl 2-carboxylic acid (1) would behave toward strong bases.
Acid (1) was found to react smoothly with 2.2 equiv of s-BuLi at –78°C in THF. Quenching the
intermediate ortho-dilithiocarboxylate with iodomethane as electrophile led to product 2a (80 %
recrystallized yield). A number of 3-substituted biphenyl 2-carboxylic acids were prepared according to
the optimized conditions found for MeI. Selected examples indicate the scope of this reaction:
chlorination, bromination, and methylsulfenylation of biphenyl 2-carboxylic acid (1) gave 2b-d in
excellent yields. The Me 3 Si group was introduced with ease as well as the chlorotributyl tin group. The
regioselectivity of the reaction was ascertained by reaction with DMF: 3g undergoes cyclization to
hydroxyphthalide upon workup.
O
E
n-BuLi/t-BuOK
CO 2H
C 6H 6, 60 °C
CO 2H
2- Electrophile "E+", –78 °C
(70 %)
3
1- s-BuLi, THF, –78 °C
3- H 3O
1
+
2a:
b:
c:
d:
e:
f:
g:
h:
E = Me (80 %)
E = Cl (86 %)
E = Br (90 %)
E = SMe (93 %)
E = SiMe3 (98 %)
E = Sn-Bu3 (95 %)
E = CHO (67 %)
E = PhCH(OH) (74 %)
In benzene at 60 °C, with 3.5 equivalents of the "superbasic" mixture n-butyllithium/potassium,
remote lithiation was observed. The resulting dianion was too unstable to be quenched by electrophiles
and directly cyclized to fluorenone 3 (70 %).
References and Notes
1
(a) Sharp, M. J.; Cheng, W.; Snieckus, V. Tetrahedron Lett. 1987, 28, 5093. (b) Cheng, W.; Snieckus, V. Tetrahedron Lett.
1987, 28, 5097.
2
Fu, J.-m.; Zhao, B.-p.; Sharp, M. J.; Snieckus, V. J. Org. Chem. 1991, 56, 1683-1685 and references cited therein.
3
Faigl, F.; Schlosser, M. Tetrahedron 1993, 10271-10278.
4
(a) Mortier, J.; Moyroud, J.; Bennetau, B.; Cain, P. A. J. Org. Chem. 1994, 59, 4042. (b) Bennetau, B.; Mortier, J.;
Moyroud, J.; Guesnet J.-L. J. Chem. Soc., Perkin Trans. 1 1995, 1265.
5
(a) Plunian, B.; Mortier, J.; Vaultier, M.; Toupet, L. J. Org. Chem. 1996, 61, 5206. (b) Plunian, B.; Vaultier, M.; Mortier, J.
J. Chem. Soc., Chem. Commun. 1998, 81. (c) Mortier, J.; Vaultier, M.; Plunian, B.; Sinbandhit, S. Can. J. Chem. 1999, 77,
98.