The first regioselective metalation and functionalization of unprotected 4-halobenzoic acids

Article abstract of DOI:10.1021/jo0483365

(Chemical Equation Presented) By treatment with s-BuLi, s-BuLi/TMEDA, or t-BuLi at ～-78°C, 4-fluoro- and 4-chlorobenzoic acids (1a,b) are metalated preferentially in the position adjacent to the carboxylate. A complete reversal in regioselectivity is observed for 1a when treated with LTMP; a sequential process involving a rapid intraaggregate lithiation through a quasi dianion complex "QUADAC" is postulated to explain the unusual reactivity of Me₂S₂ and I₂.

Full text of DOI:10.1021/jo0483365

SCHEME 1
The First Regioselective Metalation and
Functionalization of Unprotected
4-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 September 20, 2004
By treatment with s-BuLi, s-BuLi/TMEDA, or t-BuLi at
∼-78 °C, 4-fluoro- and 4-chlorobenzoic acids (1a,b) are
metalated preferentially in the position adjacent to the
carboxylate. A complete reversal in regioselectivity is ob-
served for 1a when treated with LTMP; a sequential process
involving a rapid intraaggregate lithiation through a quasi
dianion complex “QUADAC” is postulated to explain the
unusual reactivity of Me2S2 and I2.
uents when treated with s-BuLi/TMEDA,4 n-BuLi, or
LDA.5 These dianions can be trapped as such by electro-
philes to afford a variety of simple 2-substituted-3-
halobenzoic acids. On the other hand, addition of 2-flu-
orobenzoic acid to 2.2 equiv of LTMP at ∼-78 °C leads
to deprotonation ortho to fluorine whereas lithiation of
2-chloro/bromobenzoic acids occurs ortho to the carboxy-
late functionality.6
We report here our first success in regioselective
deprotonations of 4-halobenzoic acids 1a-c (halo: F, Cl,
Br) and describe the preparation of 3-substitued 4-fluo-
robenzoic acids. The most important question to be
addressed was whether the protons of 1 in C-2 and C-3
positions possess sufficient difference in their acidities
to allow regioselective deprotonations via appropriate
bases. Toward this goal (Scheme 1 and Table 1), the acids
1a-c in THF were submitted to a variety of bases in
various (n) equivalents at the temperature T which was
maintained for the time t prior to addition of an excess
(4-10 equiv) of iodomethane (MeI) (normal addition). The
Lithiation ortho to an unprotected carboxylic acid
group in benzenoid systems is a powerful but still
sparingly explored process which does not require protec-
tion and deprotection of the carboxylic acid group.1 The
presence of the carboxylate functionality makes benzoic
acids more reactive and therefore more sensitive than
their amide and oxazoline counterparts, thus requiring
a gentler approach to lithiation. The carboxylate is
susceptible to nucleophilic attack by alkyllithium bases
such as n-butyllithium.2 We have reported recently that
lithium 3-chloro/bromo-2-lithiobenzoates can be gener-
ated upon treatment of 3-chloro/bromobenzoic acids with
hindered lithium 2,2,6,6-tetramethylpiperidide (LTMP)
at -50 °C.3 3-Fluorobenzoic acid also undergoes hydrogen/
metal exchange at the position flanked by both substit-
1
yields were estimated by H NMR analysis of the crude
reaction mixtures, with pure sample being isolated and
characterized.
Metalation of 4-fluoro- and 4-chlorobenzoic acids (1a,b)
with 2.2 equiv of sec-butyllithium (s-BuLi) at -78 °C in
THF occurs preferentially ortho to the CO2Li group
* To whom correspondence should be addressed. Fax: +33 (0) 243
83 39 02.
(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, 1998; Vol. 2, p 269. (c) Mortier, J.; Vaultier,
M. C. R. Acad. Sci. Se´rie IIC 1998, 1, p 465.
(3) Gohier, F.; Mortier, J. J. Org. Chem. 2003, 68, 2030.
(4) Moyroud, J.; Guesnet, J. L.; Bennetau, B.; Mortier, J. Tetrahe-
dron Lett. 1995, 36, 881.
(2) (a) Jorgenson, M. J. Org. React. 1970, 18, 1. (b) Ahn, T.; Cohen,
T. Tetrahedron Lett. 1994, 35, 203. (c) Plunian, B.; Mortier, J.; Vaultier,
M.; Toupet, L. J. Org. Chem. 1996, 61, 5206.
(5) Bennetau, B.; Cain, P. A. Continuation-in-Part of co-pending U.S.
Pat. 7850128, filed on March 12, 1992.
(6) Gohier, F.; Castanet, A.-S.; Mortier, J. Org. Lett. 2003, 5, 1919.
10.1021/jo0483365 CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/19/2005
J. Org. Chem. 2005, 70, 1501-1504
1501

TABLE 1. Reactivity of Unprotected 4-Halobenzoic Acids 1a-c toward Strong Basesa,b
entry
acid
base
n (equiv)
T (°C)
t (h)
2Me-1a-c
3Me-1a-c
1a-c
othersc
1
2
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1a
1a
1a
1b
1b
1c
s-BuLi
2.2
2.2
2.2
2.2
2.2
5
2.2
2.2
2.2
2.2
2.2
2.2
6
-78
-100
-78
-78
-90
-90
-78
-100
-78
-90
-78
-50
-50
-78
-50
-78
0.5
0.5
0.5
2
71
56
65
40
32
51
69
64
73
52
0
20
22
12
24
2
0
20
13
17
54
13
9
31
18
37
47
36
10
63
62
57
4 [2]
1 [2]
6 [2]
15 [3]
3 [3]
14 [3]
8 [4]
3 [4]
5 [4]
6 [5]
s-BuLi
3
s-BuLi/ TMEDA
t-BuLi
4
5
t-BuLi
2
6
t-BuLi
2
5
7
s-BuLi
0.5
0.5
0.5
2
8
8
s-BuLi
0
9
s-BuLi/ TMEDA
t-BuLi
0
10
11
12
13d
14
15
16
0
LTMP
4
40
50
86
9
12 [3Et-1a]
LTMP
1
0
9 [3Et-1a]
LTMP
2
0
3 [3Et-1a]
LTMP
2.2
2.2
2.2
4
7
21 [2Et-1b]
LTMP
4
0
3
0
6 [2Et-1b], 8 [7], 6 [8]
22 [2Et-1c], 15 [7], 12 [8]
LTMP
4
12
a The product ratio was determined by 1H NMR after acidification and extraction of the crude reaction mixture with ether. b General
Procedure. To a stirred solution of base (n equiv) in anhydrous THF (15 mL) at T °C was added dropwise under argon the recrystallized
4-halobenzoic acid (3.5 mmol) dissolved in dry THF (7 mL). After being stirred for t h at T °C, the mixture was treated with an excess of
iodomethane (17.5 mmol, 1.1 mL). The resulting solution was allowed to warm to ambient temperature, and water (30 mL) was added.
The aqueous layer was washed with ether (20 mL), shaken, and then acidified with HCl 4 M. The mixture was then diluted with ether,
and the organic layer was separated and dried with MgSO4. Filtration and concentration in vacuo gave the crude benzoic acids. c Purified
yields (chromatography). d Reverse addition.
(entries 1 and 7). Conducting the reaction at -100 °C
led unexpectedly to a loss of regioselectivity in the case
of 1a (71:20 f 56:22, entry 2) while the acid 1b was
exclusively converted to 2Me-1b (64%, entry 8). These
experiments strongly suggest that 2Li-1a,b formation is
the kinetically controlled process for both substrates.
Undoubtedly, a strong interaction between the highly
electron-rich π-system of the carboxylate and the reagent
places s-BuLi in the proximity of the ortho-carbon
(complex induced proximity effect (CIPE) process).7 This
interaction is capable of counterbalancing totally the
acidifying effect of the chlorine. The acid 1a displays
lower regioselectivity that can be attributed to a stronger
acidifying effect of the fluorine atom in its ortho position.8
The use of alkyllithium bases does not allow for the
presence of a bromine or iodine atom on the arene due
to competing halogen-metal exchange.9
Metalation is influenced by additives10 and by variation
of metalating agent.11 To explore the effect of additive,
1a was treated with s-BuLi/TMEDA (1:1, 2.2 equiv/-78
°C/2 h) followed by MeI quench to afford 2Me-1a and
3Me-1a in a 65:12 ratio (entry 3). Under the same
conditions, 1b was metalated regiospecifically in the
position adjacent to the carboxylate (73%, entry 9). The
deprotonation regioselectivity for 1a-c as a function of
base was tested using tert-butyllithium (t-BuLi) and an
amide base, lithium 2,2,6,6-tetramethylpiperidide (LTMP).
When submitted to t-BuLi metalation-MeI quench con-
ditions (entries 4-6), higher yields of the C-2 isomer 2Me-
1a were reached when 5 equiv of the hindered base was
used at low temperature (-90 °C); however, longer
reaction times were required. t-BuLi deprotonates ex-
clusively the C-2 position of 1b (entry 10). In entries
1-10, small amounts of the undesired ketones 2-5
resulting from the nucleophilic addition of the alkyl-
lithium to the carboxylate were formed.2
By dropwise addition of iodomethane to a solution
containing 3Li-1a formed by treatment of 1a with 2.2
equiv of LTMP in THF at -78 °C (normal addition),
4-fluoro-3-methylbenzoic acid (3Me-1a) was formed as a
sole isomer (40%, entry 11) along with 3-ethyl-4-fluo-
robenzoic acid (3Et-1a) arising out of lateral metalation
of 3Me-1a (12%).12 Iodomethane in excess does not
destroy the remaining LTMP, which can then further
metalate 2Me-1a lithium salt, even in the presence of
iodomethane, to give 3Et-1a.13
At higher temperature (-50 °C), 3Li-1a is stable and
does not decompose to give the benzyne 6 (entry 12).3,14
By slow addition of 3Li-1a (prepared by treatment of 1a
with 6 equiv of LTMP at -50 °C) to MeI in THF (reverse
addition),2c,15 3Me-1a was produced in satisfactory yield
(86%) and formation of 3Et-1a was reduced to 3% (entry
13). The initial interaction of LTMP with the carboxylate
of 1a in the preequibrium complex is presumably too
weak to counterbalance the acidifying effect of the
fluorine atom, and a complete reversal in regioselectivity
is observed (thermodynamic control).6,7 Lithiation via
lithium amides occurs presumably by a single electron
transfer (SET) to initially generate a radical anion.16
While there is electron spin resonance (ESR) evidence
for the SET theory, the overall mechanistic pathway is
still being debated.17
The reaction of 4-chloro- and 4-bromobenzoic acid
(1b,c) with LTMP was next studied (entries 14-16).
(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. (c) Whisler, M.
N.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004,
43, 2206.
(8) (a) Bennetau, B.; Mortier, J.; Moyroud, J.; Guesnet, J.-L. J.
Chem. Soc., Perkin Trans. 1 1995, 1265. (b) Moyroud, J.; Guesnet, J.-
L.; Bennetau, B.; Mortier, J. Bull. Soc. Chim. Fr. 1996, 133, 133.
(9) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300.
(10) Mongin, F.; Maggi, R.; Schlosser, M. Chimia 1996, 50, 650.
(11) Beak, P.; Brown, R. A. J. Org. Chem. 1982, 47, 34.
(12) Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 1.
(13) 3Et-1a-c were prepared in higher yield (respectively 57%, 60%,
and 51%) by treatment of 3Me-1a-c with LTMP (3 equiv, -50 °C/
THF) followed by trapping with iodomethane.
(14) Huisgen, R.; Sauer, J. Angew. Chem. 1960, 72, 91.
(15) Mortier, J.; Vaultier, M.; Cantegril, R.; Dellis, P. Aldrichim.
Acta 1997, 30, 34.
(16) Newkome, G.; Hagar, D. J. Org. Chem. 1982, 47, 599.
1502 J. Org. Chem., Vol. 70, No. 4, 2005

TABLE 2. Synthesis of 3-Substituted 4-Fluorobenzoic
Acidsa,b
SCHEME 2
entry
Add
EX/E
products (%)
1
2
N
R
N
R
N
N
R
R
R
R
I2/I
I2/I
Me2S2/MeS
Me2S2/MeS
D2O/Dc
CO2/CO2H
C2Cl6/Cl
C2Br2Cl4/Br
PhCHO/PhCH(OH)
Me3SiCl/Me3Sid
39 [9], 47 (20*) [17]
83 (56*) [9], 13 [17]
41 [10], 42 (10*) [18]
89 (56*) [10], 8 [18]
86 [11]
3
4
5
6
68* [12]
7
80* [13]
8
65* [14]
9
59* [15]
10
25 (10*) [16]
a Isolated yields (recrystallized or chromatographed) are fol-
lowed by an asterisk (*). b Characterization was done by 1H and
13C NMR and IR spectroscopy and by matching melting points with
those of authentic samples. See the Supporting Information. c The
extent of deuteration was determined by 1H NMR. d In situ quench
technique. LTMP (2.2 equiv) and Me3SiCl (3 equiv) were premixed
prior to addition of 4-fluorobenzoic acid (1a).
addition, entries 2 and 4),15 we hoped to minimize
formation of the species 17 and 18. Indeed, we discovered
that their formation was reduced to 13% and 8%,
respectively, under these conditions.
Compared to 1a, the acidity of the protons adjacent to
chlorine and bromine is weaker. The deprotonation
requires temperatures (∼-50 °C) for which the dianions
3Li-1b and 3Li-1c are not stable.18 LiX is rapidly ejected
forming the transient lithium benzyne-4-carboxylate (6)
which is readily attacked by tetramethylpiperidine
(HTMP) both in the C-3 and C-4 position affording the
anilinium chlorides 7 and 8.3 Compounds 7 and 8 were
isolated from the aqueous layer by chromatography after
acidic workup (HCl, 4 M) (entries 15 and 16). From the
fact that both amino acids 7 and 8 arise from the dianions
3Li-1b,c, it can be deduced that the lithiation of 1b,c is
not site selective.
The established thermodynamic metalation conditions
found in run 13 (Table 1) led to the development of a
synthetically useful reaction. As summarized in Table 2,
treatment of 1a using 6 equiv of LTMP at -50 °C
followed by addition of a variety of electrophiles provided
a direct access to the acids 9-16. Elemental iodine and
dimethyl disulfide quenches (6 equiv) proceeded smoothly,
leading, respectively, to 4-fluoro-3-(iodo/methylthio)ben-
zoic acids 9 and 10 in 39% and 41% yield (entries 1 and
3), along with 4-fluoro-3,5-bis(iodo/methylthio)benzoic
acids 17 (47%) and 18 (42%).
Next we attempted deuteration (D2O) and carboxyla-
tion (CO2) of 1a. In the event, this resulted in the
formation of only the d3 isotopomer 3-deuterio-4-fluo-
robenzoic acid (11) and 4-fluorobenzene-1,3-dioic acid (12)
with no detectable 3,5-bisdeutero-4-fluorobenzoic acid
and 2-fluorobenzene-1,3,5-tricarboxylic acid (entries 5
and 6, normal addition). Likewise, reaction with hexachlo-
roethane, dibromotetrachloroethane, and benzaldehyde
afforded the monosubstituted products 13-15 exclusively
in good recrystallized yields by reverse addition (entries
7-9). The in situ quench technique,21 in which 4-fluo-
robenzoic acid (1a) was added to a solution containing
LTMP (2.2 equiv) and chlorotrimethylsilane (3 equiv),
gave 4-fluoro-3-(trimethylsilyl)benzoic acid (16) in low
yield. The accompanying degradation products presum-
ably arise from deprotonation of the trimethylsilyl group
of 16 by LTMP.22
The seeming incompatibility of the results obtained can
be resolved through a sequential mechanism involving,
in the case of I2 and Me2S2, the intermediate species 9
and 10, Li salts (Scheme 2). The mechanism would
require that (1) just prior to the addition of I2/Me2S2, the
reaction mixture contains 3Li-1a and four addition
These results suggest the formation of 3Li-1a and 3Li,-
5Li-1a as intermediates (Scheme 2). Unlike aliphatic
dimetalation which has been used extensively in organic
synthesis,19 dimetalation of aromatic compounds has
remained relatively understudied and underutilized.20 By
changing the mode of deprotonation to addition of the
mixture (formed by treatment of 1a with LTMP at -50
°C) to a THF solution of the electrophile (reverse, R,
(19) Review: Thompson, C. M. Dianion Chemistry in Organic
Synthesis; CRC Press: Boca Raton, 1994.
(20) (a) Wilson, W. D.; Tanious, F. A.; Watson, R. A.; Baron, H. J.;
Strekowska, A.; Harden, D. B.; Srekowski, L. Biochemistry 1989, 28,
1984. (b) Feringa, B. L.; Hulst, R.; Rikers, R.; Brandsma, L. Synthesis
1988, 316. (c) Cabiddu, S.; Contini, L.; Fattuoni, C.; Floris, C.; Gelli,
G. Tetrahedron 1991, 47, 9279. (d) Liu, W.; Wise, D. S.; Townsend, L.
B. J. Org. Chem. 2001, 66, 4783. (e) Barchrach, S. M.; Chamberlin, A.
C. J. Org. Chem. 2004, 69, 2111.
(21) (a) Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105,
6155. (b) Marsais, F.; Laperdrix, B.; Gu¨ngo¨r, T.; Mallet, M.; Que´guiner,
G. J. Chem. Res., Miniprint 1982, 2863. (c) Wada, A.; Kanatomo, S.;
Nagai, S. Chem. Pharm. Bull. 1985, 33, 1016.
(22) (a) Brought, P. A.; Fisher, S.; Zhao, B.; Thomas, R. C.; Snieckus,
V. Tetrahedron Lett. 1996, 37, 2915. (b) Macdonald, J. E.; Poindexter,
G. S. Tetrahedron Lett. 1987, 28, 1851.
(17) (a) Eberson, L. Acta Chem. Scand. 1984, B38, 439. (b) Feeder,
N.; Lawson, Y. G.; Raithby, P. R.; Rawson, J. M.; Steiner, A.; Wood, J.
A.; Woods, A. D.; Wright, D. S. Angew. Chem., Int. Ed. 2000, 39, 4145.
(18) Caster, K. C.; Keck, C. G.; Walls, R. D. J. Org. Chem. 2001, 66,
2932.
J. Org. Chem, Vol. 70, No. 4, 2005 1503

SCHEME 3
tions. By analogy, in this work, QUADAC A, which could
be apparented to a “preequilibrium complex” of the CIPE
theory,7 might be selectively substituted to give the
ArCO2Li‚LiNR2 complex B, which in turn could be
converted by an intramolecular proton shift (Me2S2 or I2
compete with the complexed carboxylate for the base
LiNR2) to the possibly dimeric mono “anion” C; a further
alkylation of the latter then would give 17,18.28,29
The results reported in this paper corroborate the
recent concept of how to achieve regiocontrol in hydrogen/
metal exchange processes through mechanism-based
matching of substituents and reagents.30 Although the
CO2Li group does activate neighboring positions toward
metalation, its effect remains fairly weak. This enables
regioflexibility as most other electronegative substituents
outperform a competing carboxylate group by their
superior ortho-directing power.
Acknowledgment. This work was supported by the
CNRS, Universite´ du Maine, and Institut Universitaire
de France.
equivalents of LTMP; (2) 3Li-1a is quenched by some of
the added electrophile to give 9 and 10, Li salts; (3)
contrary to the other electrophiles, I2 and Me2S2 do not
destroy the remaining LTMP, which can then further
metalate 9/10, Li salts even in the presence of electro-
phile, to give 5Li-9 and 5Li-10; (4) 5Li-9 and 5Li-10, like
3Li-1a, are captured by the electrophile to give 17 and
18, Li salts, before they eliminate lithium fluoride to form
arynes; and (5) Due to steric hindrance of attack by the
third electrophile or to steric inhibition of the third
lithiation, 17 and 18, Li salts are not further metalated
under the reaction conditions, so that no 4-fluoro-2,3,5-
triiodo/trimethylthiobenzoic acid is formed. It is worthy
of note that the second lithiation occurs at C-5 and not
at the C-2 position.23
A sequential process involving a rapid intraaggregate
lithiation through a transient QUAsi DiAnion Complex
“QUADAC” A is postulated to explain the unusual
reactivity of Me2S2 and I2 in these transformations
(Scheme 3). QUADACs have been sought in order to
explain the fact that, while (supposed) dilithiation of
PhCH2CN24 or other products25 by a base R′Li followed
by treatment with electrophiles R′′X or D2O often leads
successfully to disubstituted products, the envisaged
dilithium species PhCLi2CN (if it exists) has proved
difficult to isolate. The existence of QUADAC A′,24b RCN‚
LiR′ complex of the type B′26 and the dimeric “anion” C′27
was demonstrated by means of X-ray crystal determina-
Supporting Information Available: Details of compound
characterization. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO0483365
(24) (a) Boche, G. Angew. Chem., Int. Ed. Engl. 1989, 28, 277. (b)
Zarges, W.; Marsch, M.; Harms, K.; Boche, G. Angew. Chem., Int. Ed.
Engl. 1989, 28, 1392. (c) Ball, S. C.; Cragg-Hine, I.; Davidson, M. G.;
Davies, R. P.; Edwards, A. J.; Lopez-Solera, I.; Raithby, P. R.; Snaith,
R. Angew. Chem., Int. Ed. Engl. 1995, 34, 921. (d) Davies, R. P.;
Raithby, P. R.; Snaith, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 1215.
(25) Maercker, A.; Bo¨s, B.; Hajgholipour, M. T. J. Organomet. Chem.
1998, 566, 413 and references therein.
(26) Boche, G.; Langlotz, I.; Marsch, M.; Harms, K.; Frenking, G.
Angew. Chem., Int. Ed. Engl. 1993, 32, 1171.
(27) Boche, G.; Marsch, M.; Harms, K. Angew. Chem., Int. Ed. Engl.
1986, 25, 373.
(28) While 1a is not dilithiated when CO2 is the electrophile (entry
6 of Table 2), reaction of dibenzodioxin with 2 molar equiv of t-BuLi
at -30 °C followed by quench with CO2 and esterification affords a
symmetrical 1,9-diester. The initially formed 1-carboxylate is able to
direct a second deprotonation of the 9-position during the quench. The
intermediacy of a Quadac is clearly dependent on the nature of the
electrophile and the substrate to be metalated. See: Palmer, B. D.;
Boyd, M.; Denny, W. A. J. Org. Chem. 1990, 55, 438.
(29) Disilylation of aromatic compounds under basic conditions could
be interpreted similarly: (a) Schlosser, M.; Guio, L.; Leroux, F. J. Am.
Chem. Soc. 2001, 123, 3822. See also: (b) Taylor, R. Tetrahedron Lett.
1975, 16, 435. (c) Nwokogu, G. C.; Hart, H. Tetrahedron Lett. 1983,
24, 5725.
(30) Schlosser, M. Eur. J. Org. Chem. 2001, 3975 and references
therein.
(23) Polyiodinated pyrazines formed by treatment of fluoropyrazine
with LTMP followed by quench with elemental iodine were reported
to arise from an halogen-dance involving a iodine-lithium exchange
reaction and not from a polylithiated intermediate: Toudic, F.; Ple´,
N.; Turck, A.; Que´guiner, G. Tetrahedron 2002, 58, 283.
1504 J. Org. Chem., Vol. 70, No. 4, 2005