Moreover, while the related secondary benzamides 2 are
generally thought to be more susceptible to hydrolysis than
tertiary amides,2b acid hydrolysis of 2,6-disubstituted second-
ary benzamides 6 to the corresponding 2,6-disubstituted
benzoic acids 9 still presents quite a challenge. The “built-
in” TMEDA benzamide 3 is a useful director which offers
greater facility in hydrolysis.2b However, the procedure for
deprotection still requires refluxing 7 in 6 N hydrochloric
acid for 7 days in the presence of iodomethane and sodium
ethoxide. Reitz and Massey have addressed the hydrolysis
problem by developing the tert-amide ortho-lithiation direct-
ing group 4 which is converted into secondary amide, the
cleavage of which, via the N-nitrosoamide has long been
known.2c,5
Scheme 1. Site-Selective Deprotonation of 2-Methoxybenzoic
Acid (11) by Strong Bases (See also Table 1)
After considerable experimentation beforehand, we found
that treatment of 11 with the 1:1 complex s-BuLi/TMEDA
(2.2 equiv)6 in THF for 2 h at -78 °C provided the dianion
14 (M ) Li) exclusively. Quenching with an excess of MeI
furnished 2-methoxy-6-methylbenzoic acid (9a) in good yield
(71%) (entry 1). The ketone 12 arising from the nucleophilic
attack of s-BuLi to the CO2Li functionality was also formed
as a byproduct.8,9 At -65 °C with s-BuLi alone (entry 2),
1,2-addition competes with ortho-lithiation, and in minor way
with an addition-elimination sequence leading to 13. We
have shown recently that ortho-lithiation of 2-fluorobenzoic
acid with s-BuLi is hampered by the preferential attack of
the anion to the C-F position.7a
Attempted rationalization of the formation of ortho-
lithiated species 14 turned out to invoke in the initial step a
prelithiation complex PLC (CIPE effect)10 by a strong
coordination of s-BuLi with the electron-rich π-system of
the carboxylate, TMEDA, and the solvent (Scheme 2). The
interaction of the alkyllithium with the p-electrons of the
methoxy group would be comparatively weaker.11 This
coordination is followed by a protophilic attack of the
carbanionic portion of the lithiating agent on the adjacent
hydrogen atom (H6) in the transition state (TS), leading to
the dianion 14.12
The CO2H group which might be thought to be susceptible
to nucleophilic addition by the organolithium bases can retain
its structural integrity and function as an effective director
under suitable conditions. Despite its relatively recent
discovery6 and adequate recognition,7 this director has
received up to now only moderate methodological attention.
In contrast to strong directors such as amides and oxazolines,
the carboxylate group moderately activates neighboring
positions thus conferring maximum regioflexibility in the
aromatic metalation.
Herein we provide a general, short, and regioselective new
method for the construction of simple 3- and 6-substituted
2-methoxybenzoic acids, including the growth inhibitor found
in Lunularia cruciata, lunularic acid (18). All of the
optimization reactions were carried out using commercially
available 2-methoxybenzoic acid (11) under argon and THF
as the solvent (Scheme 1 and Table 1). The intermediates
were trapped with iodomethane or chlorotrimethylsilane. The
product ratio was determined by 1H NMR after acidification
and extraction with ether of the crude reaction mixture. Since
the recovered starting acid 11 and nonacidic products were
also identified in these conditions, the product distribution
represents the selectivity and the efficiency of the metalation
reactions.
In the absence of TMEDA, the competing reaction leading
to 13 follows a SNAr mechanism. A critical transition-state
geometry TS′ must be achieved, presumably via a prelithia-
(8) Jorgenson, M. J. Org. React. 1970, 18, 1.
(9) Attempted lithiation of 11 with n-BuLi alone or chelated to TMEDA
gave exclusively the undesired 1,2-addition product. In the presence of the
tridental ligand N,N,N′,N′,N′′-pentamethyldiethylenetriamine (PMTDA), a
poor yield of 9a was attained (15%).
(10) (a) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356. (b)
Whisler, M. N.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem, Int.
Ed. 2004, 43, 2206.
(11) Katsoulos, G.; Takagishi, S.; Schlosser, M. Synlett. 1991, 731.
(12) In a recent report (ref 7f), we put forward for consideration that the
directing and accelerating effect of the substituents might be due to the
stabilization of both the initial complex and the transition structure. We
also suggested that coordination might be stronger in the transition state
than in the initial complex. As a result, complexation would increase the
reaction rate by providing a new mechanism that has a smaller activation
energy.
(4) Page, M. I. Angew. Chem., Int. Ed. Engl. 1977, 16, 449.
(5) See also: (a) Cuevas, J.-C.; Patil, P.; Snieckus, V. Tetrahedron Lett.
1989, 30, 5841. (b) Fisher, L. E.; Muchowski, J. M.; Clarck, R. D. J. Org.
Chem. 1992, 57, 2700.
(6) Mortier, J.; Moyroud, J.; Bennetau, B.; Cain, P. A. J. Org. Chem.
1994, 59, 4042.
(7) (a) Gohier, F.; Castanet, A.-S.; Mortier, J. Org. Lett. 2003, 5, 1919.
(b) Gohier, F.; Mortier, J. J. Org. Chem. 2003, 68, 2030. (c) Tilly, D.;
Samanta, S. S.; De, A.; Castanet, A.-S.; Mortier, J. Org. Lett. 2005, 7, 827.
(d) Tilly, D.; Castanet, A.-S.; Mortier, J. Chem. Lett. 2005, 34, 446. (e)
Gohier, F.; Castanet, A.-S.; Mortier, J. J. Org. Chem. 2005, 70, 1501. (f)
Nguyen, T. H.; Chau, N. T. T.; Castanet, A.-S.; Nguyen, K. P. P.; Mortier,
J. Org. Lett. 2005, 7, 2445.
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