Selectivities in reactions of organolithium reagents with unprotected 2-halobenzoic acids

Article abstract of DOI:10.1021/ol034491e

(Matrix presented) Exposing 2-fluorobenzoic acid (1a) to 2.2 equiv of LTMP at ca. -78°C leads to deprotonation at the 3-position whereas 2-chloro/bromobenzoic acids (1b,c) are lithiated adjacent to the carboxylate. The resulting dianions 3Li-1a and 6Li-1b

Full text of DOI:10.1021/ol034491e

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1919-1922
Selectivities in Reactions of
Organolithium Reagents with
Unprotected 2-Halobenzoic Acids
Fre´de´ric Gohier, Anne-Sophie Castanet, and Jacques Mortier*
UniVersite´ du Maine and CNRS, Unite´ de chimie organique mole´culaire et
macromole´culaire (UMR 6011), Faculte´ des sciences, aVenue OliVier Messiaen,
72085 Le Mans Cedex 9, France
jacques.mortier@uniV-lemans.fr
Received March 21, 2003
ABSTRACT
Exposing 2-fluorobenzoic acid (1a) to 2.2 equiv of LTMP at ca. −78 °C leads to deprotonation at the 3-position whereas 2-chloro/bromobenzoic
acids (1b,c) are lithiated adjacent to the carboxylate. The resulting dianions 3Li-1a and 6Li-1b,c are trapped as such by chlorotrimethylsilane.
In the absence of internal quench, 6Li-1b,c isomerize to the more stable 3Li-1b,c. The latter eliminate lithium halide and set free benzyne-3-
carboxylate (2) that reacts regioselectively with LTMP to give 3-tetramethylpiperidinobenzoic acid (3).
Studies of selectivities of reactions of organolithium reagents
with substrates bearing multiple sites for reaction can be
useful for developing the understanding and use of these
reagents. In the course of our investigation of the extension
of the general ortho-lithiation of the lithium salts of
unprotected benzoic acids,1 we have shown recently that
lithium 3-halo-2-lithiobenzoates (halo ) F, Cl, Br), generated
by the reaction of 3-halobenzoic acids and hindered lithium
2,2,6,6-tetramethylpiperidide (LTMP), react with a variety
of electrophiles to give elaborated benzoic acids, most of
which were unknown.2
the manner in which the products are formed. The benzoic
acid 1a-c in THF was added to 2.2 equiv of base at the
temperature T indicated in the table. The resulting reaction
mixture was either stirred for the time t prior to addition of
an excess (4-10 equiv) of deuterium oxide (D2O) or
immediately trapped by chlorotrimethylsilane (Me3SiCl)
(external quench (EQ) technique). The yields were estimated
by an 1H NMR analysis of the crude reaction mixtures, with
pure sample being isolated and characterized. The isomer
distribution was determined in each case to evaluate the
orienting effect of the substituents on metalation.
We now describe our efforts in adding further to the
synthetic utility of this approach by demonstrating a series
of regioselective reactions derived from the competition of
2-fluoro/chloro/bromobenzoic acids (1a-c) with organo-
lithiums. Results are listed in Table 1. Scheme 1 diagrams
Reaction of 2-fluorobenzoic acid (1a) with LTMP (2.2
equiv) at -50 °C followed by quench with a deuterium
provided 3-tetramethylpiperidinobenzoic acid (3, 22%) plus
a tiny yield of the d3 isotopomer 2-fluoro-3-deuteriobenzoic
acid (3D-1a, 5%, entry 1). Under these conditions, the acid
1a is initially metalated ortho to the halogen. LiF is ejected
from the resulting nucleophilic species 3Li-1a forming the
now electrophilic, unsymmetrical lithium benzyne-3-car-
boxylate (2), which is readily attacked by LTMP furnishing
the cine substitution product 3 as a single isomer after
(1) (a) Mortier, J.; Moyroud, J.; Bennetau, B.; Cain, P. A. J. Org. Chem.
1994, 59, 4042. Reviews: (b) Mortier, J.; Vaultier, M. In Recent Research
DeVelopments in Organic Chemistry; Transworld Research Network:
Trivandrum, India, 1998; Vol. 2, p 269. (c) Mortier, J.; Vaultier, M. C. R.
Acad. Sci. Ser. IIC 1998, 1, 465.
(2) Gohier, F.; Mortier, J. J. Org. Chem. 2003, 68, 2030.
10.1021/ol034491e CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/08/2003

Table 1. Deprotonation of 2-Halobenzoic Acids by Strong Basesa,b
D2Oc
Me3SiCld
entry acid
basee
LTMP
LTMP
LTMP
LTMP
LTMP
s-BuLi/TMEDA
s-BuLi
n-BuLi
t-BuLi
LTMP
LTMP
LTMP
LTMP
s-BuLi/TMEDA
LTMP
LTMP
T (°C) t (h) 1f 6D-1 3D-1
3
4
others 1f
6Si-1
3Si-1
3
4
others
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
-50
-78
-90
-90
-90
-78
-78
-78
-78
-30
-50
-50
-78
-78
-50
-78
1
1
1
4
15
1
0.5 50
1
2
1
1
4
4
0.5
1
41
48
79
61
52
46
0
0
0
0
0
0
0
0
0
5
4
5
0
85*
0
0
5
21
21
38
36
0
0
0
0
0
0
0
0
0
0
0
22*
9
0
0
0
0
0
0
0
20
8
18
0
0
6
0
0
0
0
0
0
0
0
0
0
0
0
0
0
86
41
g
0
0
8
0
0
0
0
0
28
62 (74*)
57
0
0
0
0
0
0
g
0
0
3
4
5
6
0
0
50 [7]
29 [7]
62
53
0
0
0
0
70
78
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
32 [7]
30* [7], 11* [9]
38* [10]
51* [8], 10* [11]
7
8
9
45
9
38 [10] 53
63 [8]
15
0
0
10
11
12
13
14
15
16
50
75
69
95
5
0
0
0
0
0
0
0
0
0
0
0
0
0
84 (74)
76* h
(69)
0
0
0
0
0
0
0
0
0
0
7
7
0
0
0
0
3
52
4
0
53 (74*)
1
a The structures of all products were confirmed by IR, MS, H NMR, and 13C NMR spectroscopy. b NMR yields (%). Isolated yields (recrystallized or
c
chromatographed) are followed by an asterisk (*). See also footnote 9 and Supporting Information. The base was allowed to react with 1a-c at temperature
d
T for t h before D2O was added. External quench (EQ) protocol. The benzoic acid 1a-c was added to the base in THF at temperature T. The resulting
reaction mixture was quenched immediately by Me3SiCl. In parenthesis: in situ quench (ISQ) method. The base and Me3SiCl were premixed prior to
e
f
g
addition of the benzoic acid. 2.2 equiv. Recovered starting benzoic acid. Degradation products. h s-BuLi/TMEDA and 1b were stirred for 30 min at -78
°C prior to addition of Me3SiCl.
hydrolytic quenching. In agreement with other additions to
benzynes containing an electron-withdrawing group,3,4 the
observed regioselectivity is due to a thermodynamic control
in the addition of LTMP in a transition state that leads to
the most stable (less basic) carbanion 2Li-3 (chelation to the
carboxylate) and hence the position of the lithium cation
(Scheme 2).5
(kinetic) products 6 whose formation can be understood in
terms of functional group-reagent preequilibrium complex-
ation, which places the organolithium (RLi) in the proximity
of the ortho carbon, prior to subsequent irreversible and
necessarily intramolecular addition of the R group to the
triple bond (Complex Induced Proximity Effect (CIPE)
Process).7 It seems reasonable to assume that the initial
interaction of LTMP with the CO2Li substituent of the aryne
2 is not strong enough to counterbalance the classical
Meyers has shown6 that alkyllithium addition to the 2,3-
benzyne oxazolidines 5 gives preferentially the 3-lithio
Scheme 1
1920
Org. Lett., Vol. 5, No. 11, 2003

to react slowly with bulky bases such as lithium diisopro-
pylamide (LDA) and LTMP, coexisting with them at low
temperature over hours.10,11 The same is the case with tert-
butyllithium and n-butyllithium as recently shown by Schlo-
sser.12,13
Scheme 2
Whatever the nature of the electrophile, the reaction of
1a with sec-butyllithium alone or chelated to 1 equiv of
N,N,N′,N′-tetramethyl-1,2-ethylenediamine (TMEDA) did not
afford the expected reaction products but the ipso product
7, arising out of substitution of the fluorine atom by the alkyl
group (entries 6 and 7). With Me3SiCl, the ketone 9 was
also detected (11%). In that case, the use of s-butyllithium
does not suppress the reactivity of the carbonyl toward 1,2-
addition.1b,c,14 Nucleophilic addition of n-butyllithium to the
CO2Li functionality provided the butyrophenone 10 after
aqueous workup (entry 8) whereas reaction of tert-butyl-
lithium gave a mixture of 2-tert-butylbenzoic acid (8) and
tert-butyl ketone 11 (entry 9).
resonance, stereoelectronic, inductive, and steric effects that
would cause addition to occur meta to the carboxylate.
At -78 °C, the reaction of 1a with LTMP followed by
trapping with D2O gave 3D-1a in 21% yield along with small
amounts of the side product 3 (entry 2). The removal of the
hydrogen H-3 has been shown to be rate determining in base-
initiated aryne reactions.8 Accordingly, although the dianion
3Li-1a is stable around -90 °C, the yield of 3D-1a decreases
rapidly with the temperature (entries 1-3).9 When quenched
immediately thereafter with Me3SiCl at -78 °C or below,
2-fluoro-3-trimethylsilylbenzoic acid (3Si-1a) was formed
in 62% yield (EQ conditions). The deprotonation, which
produces a small concentration of the trappable aryllithium
3Li-1a, is sufficiently rapid to make this process competitive
in rate with the reaction of the hindered base with the in
situ electrophile. The yield was enhanced when the base and
Me3SiCl were premixed prior to addition of the acid (in situ
quench (ISQ) technique).10 Chlorotrimethylsilane is known
The action of LTMP on 2-chlorobenzoic acid (1b) was
next studied. Since the relative stability of 2-halophenyl-
lithiums toward elimination of LiX normally follows the
order LiBr (-100 °C) < LiCl (-90 °C) < LiF (-60 °C),2,15
it was expected that the carboxylate group would greatly
affect the elimination temperature. Astonishingly, whereas
D2O quenching experiments between -50 and -30 °C
provided 3-tetramethylpiperidinobenzoic acid (3) in low yield
along with small quantities of 2-chloro-6-deuteriobenzoic
acid (6D-1b, entries 10-12), trapping with Me3SiCl at -78
°C led to 6Si-1b free of any isomers in 84% yield (entry
13)! Since the acidity of the proton in the position adjacent
to the chlorine atom is normally weaker than that of the
fluorine,1b,c,16 deprotonation presumably proceeds initially
ortho to the CO2Li functionality leading to 6Li-1b. The latter
isomerizes partly to the less basic dianion 3Li-1b, which
reacts further to give 3 via the benzyne 2. The reaction of
(3) (a) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Academic
Press: New York, 1967. (b) Wickham, P. P.; Hazen, K. H.; Guo, H.; Jones,
G.; Hardee Reuter, K.; Scott, W. J. J. Org. Chem. 1991, 56, 2045.
(4) Tripathy, S.; LeBlanc, R.; Durst, T. Org. Lett. 1999, 1, 1973.
(5) The reaction of sodamide and potassium amide in liquid ammonia
on 2-chloro- and 2-bromobenzoic acids (1b,c) produced mixtures of 2- and
3-aminobenzoic acids: (a) Biehl, E. R.; Li, H.-M. J. Org. Chem. 1966, 31,
602. (b) Biehl, E. R.; Nieh, E.; Li, H.-M.; Hong, C.-I. J. Org. Chem. 1969,
34, 500.
(11) Dimethyldichlorosilane, trimethyl and triisopropyl borates, and
hexafluorocetone are also effective as in situ traps with LTMP: (a) Krizan,
T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105, 6155. (b) Caron, S.;
Hawkins, J. M. J. Org. Chem. 1998, 63, 2054. Dimethyl sulfate and
n-butyllithium are mutually compatible in THF at -78 °C: (c) Nwokogu,
G. C.; Hart, H. Tetrahedron Lett. 1983, 24, 5725.
(6) Pansegrau, P. D.; Rieker, W. F.; Meyers, A. I. J. Am. Chem. Soc.
1988, 110, 7178.
(7) (a) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356. (b) Klump,
G. W. Rec. TraV. Chim. Pays-Bas 1986, 105, 1.
(8) Roberts, J. D.; Semonev, D. A.; Simmons, H. E.; Carlsmith, L. A. J.
Am. Chem. Soc. 1956, 22, 601.
(9) 3D-1a was prepared in higher yield (50%) from 2-fluoro-3-bro-
mobenzoic acid (preparation: Moyroud, J.; Guesnet, J.-L.; Bennetau, B.;
Mortier, J. Bull. Soc. Chim. Fr. 1996, 133, 133) by treatment with
n-butyllithium (2.2 equiv) in THF at -78 °C followed by quench with D2O.
See Supporting Information.
(10) (a) Marsais, F.; Laperdrix, B.; Gu¨ngo¨r, T.; Mallet, M.; Que´guiner,
G. J. Chem. Res., Miniprint 1982, 2863. (b) Krizan, T. D.; Martin, J. C. J.
Am. Chem. Soc. 1983, 105, 6155. (c) Lipshutz, B. H.; Wood, M. R.;
Lindsley, C. W. Tetrahedron Lett. 1995, 36, 4385.
(12) Schlosser, M.; Guio, L.; Leroux, F. J. Am. Chem. Soc. 2001, 123,
3822.
(13) Nevertheless, Me3SiCl does not survive in the presence of s-BuLi
or s-BuLi: TMEDA at -85 °C in THF. See Supporting Information.
(14) Depending on the nature of the base and the reaction conditions,
treatment of a lithium benzoate with an additional equivalent of an
organolithium reagent can lead to addition rather than metalation, providing
useful ketone syntheses: (a) Jorgenson, M. J. Org. React. 1970, 18, 1. (b)
Ahn, T.; Cohen, T. Tetrahedron Lett. 1994, 35, 203. See also: (c) Plunian,
B.; Mortier, J.; Vaultier, M.; Toupet, L. J. Org. Chem. 1996, 61, 5206.
(15) Caster, K. C.; Keck, C. G.; Walls, R. D. J. Org. Chem. 2001, 66,
2932.
(16) (a) Mongin, F.; Schlosser, M. Tetrahedron Lett. 1997, 38, 1559.
(b) Moyroud, J.; Guesnet, J.-L.; Bennetau, B.; Mortier, J. Tetrahedron Lett.
1995, 36, 881.
Org. Lett., Vol. 5, No. 11, 2003
1921

6Li-1b with Me3SiCl is comparatively faster and the system
balances to form 6Si-1b exclusively.17
donation, the formation of 4 is thought to proceed via a single
electron-transfer process (SET). Me3SiCl trapping makes it
possible to reduce dramatically the formation of 4. Com-
pound 6Si-1c was prepared in satisfying yield under these
conditions (53%, EQ protocol).20,21 The yield of 6Si-1c was
enhanced (up to 74%) when the base and Me3SiCl were
premixed prior to addition of 1c (ISQ conditions).
Treatment of 1b with 2.2 equiv of a 1:1 s-BuLi/TMEDA
complex at -78 °C in THF provided 6D-1b (85%) and 6Si-
1b (76%) (entry 14). The regiochemistry observed can be
explained in terms of a CIPE process in which kinetic
domination over the resonance and inductive effects is
operative (Scheme 3).7 Thus, the organolithium approaches
From the fact that 2-chloro- and 2-bromobenzoic acids
(1b,c) do not lead to the ipso substitution products 7 and 8
when treated with either s-BuLi or t-BuLi whereas 3Li-1b,c
are expected to be less stable than the corresponding fluoro
derivative 3Li-1a toward LiX-elimination, we deduce that
the formation of 7 and 8 arises from an addition-elimination
sequence (SNAr mechanism) rather than from a reaction
proceeding through an aryne intermediate. While n-butyl-
lithium displays a strong nucleophilic character and a low
Scheme 3
complexing ability toward the carboxylate (entry 8),2
a
critical transition-state geometry must be achieved between
s-BuLi/t-BuLi, and the substrate in a preequilibrium complex
for direct, rate-determining nucleophilic addition of RLi
followed by nucleofugal elimination of the fluoride enhanced
by strong chelation of the lithium cation (Scheme 4).22 Most
the benzoate 1b by chelation with the highly electron-rich
π-system in the carboxylate, and this complex forces the
deprotonation to occur into the ortho position of the benzoate
leading to 6Li-1b and ultimately the products 6D-1b and
6Si-1b. Since 6Li-1b isomerizes to 3Li-1b when LTMP is
the base (vide supra), it is conceivable that the interaction
between 6Li-1b and the TMEDA molecule stabilizes the
chelate 6Li-1b:TMEDA.
Scheme 4
The behavior of 2-bromobenzoic acid (1c) is of particular
interest. Some rare examples of the literature indicate that
the ortho-acidifying capacity of bromine is comparable with
that of chlorine.16,18 When treated successively with LTMP
(-50 °C) and D2O, 1c gave the parent benzoic acid (4), and
traces of 3 resulting from the decomposition of 3Li-1c.19
Since the LTMP molecule does not have hydrogen atoms
connected to the â-carbons, and is not capable of hydride
striking, the reactivity of the alkyllithiums follows the order
n-Bu < s-Bu < t-Bu hence there are virtually no steric effects
of the alkyl group to inhibit fluorine displacement. The mode
of entry of the alkyllithium would be relatively free of
nonbonded interactions thus allowing bulky alkyl groups easy
access to the sp2 carbon at the ortho position.23 Further studies
of this interesting phenomenon are currently in progress and
will be reported soon.
In conclusion, intramolecular competitive lithiations be-
tween the unprotected carboxylic acid and fluorine, chlorine,
and bromine atoms in ortho-disubstituted benzenes under the
prescribed conditions follow the order (Cl, Br) < CO2H <
F. Development of this metalative approach for synthesis of
contiguously substituted benzoic acids,24 as well as studies
of the underlying structure-stability relationships of other
lithium benzoates, are currently in progress in our labora-
tories.
(17) See also: Graneto, M. J.; Phillips, W. G.; Van Sant, K. A.; Walker,
D. M.; Wong, S. C. European Patent 538231, 1992.
(18) Wang, A.; Maguire, J. A.; Biehl, E. J. Org. Chem. 1998, 63, 2451.
(19) Reduction of aryl halides with lithium amides was observed shortly
after lithium amides were developed as a new class of compounds: (a)
Ziegler, K.; Ohlinger, H. Justus Liebigs Ann. Chem. 1932, 495, 84.
Review: (b) Majewski, M.; Gleave, D. M. J. Organomet. Chem. 1994,
470, 1. See also: (c) Creary, X. J. Org. Chem. 1980, 45, 2419.
(20) The position of the silicon atom in 6Si-1c was confirmed after
subsequent bromination in carbon tetrachloride, which afforded 2,6-
dibromobenzoic acid exclusively (23%). See Supporting Information.
(21) Gilman reported in 1947 the formation and the stability at -78 °C
of lithium 2-lithiobenzoate derived from 2-bromobenzoic acid and n-
butyllithium in diethyl ether: (a) Gilman, H.; Arntzen, C. E. J. Am. Chem.
Soc. 1947, 69, 1537. (b) Parham, W. E.; Bradcher, C. K. Acc. Chem. Res.
1982, 15, 300.
(22) Only a few examples of fluorine displacement reactions have been
explained in terms of a CIPE process: (a) Meyers, A. I.; Reuman, M.;
Gabel, R. A. J. Org. Chem. 1981, 46, 783. (b) Meyers, A. I.; Gabel, R. A.
J. Org. Chem. 1977, 42, 2653. See also: (c) Strekowski, L.; Janda, L.;
Patterson, S. E.; Nguyen, J. Tetrahedron 1996, 52, 3273. (d) Field, L. D.;
Pierens, G. K. Tetrahedron 1990, 46, 7059. (e) Inukai, Y.; Takuma, K.;
Toritani, K.; Sonoda, T.; Kobayashi, H. Bull. Chem. Soc. Jpn. 1984, 57,
225.
Acknowledgment. This research was supported by the
CNRS, Universite´ du Maine, and Institut universitaire de
France.
(23) There also exists the possibility that these displacements are
proceeding via an electron-transfer process.
(24) The reactivity of I2, MeI, PhCHO, C2Br2Cl4, and CO2 as electrophiles
is similar to that observed with D2O. When treated with s-BuLi/TMEDA,
2-chlorobenzoic acid (1b) gives the expected ortho-substituted benzoic acids
in good yield.
Supporting Information Available: Details of compound
characterization. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL034491E
1922
Org. Lett., Vol. 5, No. 11, 2003