Ortholithiation of unprotected benzoic acids: Application for novel 2-chloro-6-substituted benzoic acid syntheses

Article abstract of DOI:10.1081/SCC-200050946

2-Chloro-6-substituted benzoic acids of the type 2a-h were prepared by the tandem metallation sequence from 2-chlorobenzoic acid 1 with the 1:1 complex secbutyllithium/TMEDA in THF at -78°C followed by quenching with electrophiles.

Full text of DOI:10.1081/SCC-200050946

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Ortholithiation of Unprotected Benzoic Acids:
Application for Novel 2‐Chloro‐6‐Substituted
Benzoic Acid Syntheses
Frédéric Gohier a , Anne‐Sophie Castanet a & Jacques Mortier a
a Université du Maine and CNRS, Unité de chimie organique moléculaire
et macromoléculaire (UMR 6011), Faculté des sciences, Le Mans Cedex 9,
France
Version of record first published: 20 Aug 2006.
To cite this article: Frédéric Gohier, Anne‐Sophie Castanet & Jacques Mortier (2005): Ortholithiation of
Unprotected Benzoic Acids: Application for Novel 2‐Chloro‐6‐Substituted Benzoic Acid Syntheses, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:6,
799-806
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Synthetic Communicationsw, 35: 799–806, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200050946
Ortholithiation of Unprotected Benzoic
Acids: Application for Novel 2-Chloro-6-
Substituted Benzoic Acid Syntheses
´ ´
Frederic Gohier, Anne-Sophie Castanet, and Jacques Mortier
´
´ ´
Universite du Maine and CNRS, Unite de chimie organique moleculaire
´ ´
et macromoleculaire, Faculte des sciences,
Le Mans Cedex 9, France
Abstract: 2-Chloro-6-substituted benzoic acids of the type 2a–h were prepared by the
tandem metallation sequence from 2-chlorobenzoic acid 1 with the 1:1 complex sec-
butyllithium/TMEDA in THF at 2788C followed by quenching with electrophiles.
Keywords: Alkyllithiums, benzoic acids, ortholithiation/substitution
2-Chloro-6-substituted benzoic acids have found uses in many areas of pesti-
cidal, pharmaceutical, and materials chemistry as versatile intermediates. For
instance in agrochemistry, 7-chloro-3-alkylphthalides are the key precursors
for the synthesis of (4,6-dimethoxypyrimidine-2-yl)thiosalicylates, which were
recognized to act on the same target site, acetolactate synthase (ALS), as the
well-known classes of the sulfonylureas and the triazolopyrimidines,
inhibiting the biosynthesis of the branched-chain amino acids valine, leucine,
and isoleucine.[1] 7-Chloro-3-alkylphthalides were prepared by lithiation of
2-chloro- N-alkylbenzamides or even the salt of 2-chlorobenzoic acid[1]
followed by quenching with the appropriate ketone or aldehyde.
Received in the U.K. November 1, 2004
Address correspondence to Jacques Mortier, Universite du Maine and CNRS, Unite
´
´
´
´
´
de chimie organique moleculaire et macromoleculaire (UMR 6011), Faculte des
sciences, avenue Olivier Messiaen, 72085 Le Mans Cedex 9, France. Fax: þ33 (0)
243 83 39 02; E-mail: jacques.mortier@univ-lemans.fr

800
F. Gohier, A.-S. Castanet, and J. Mortier
We have recently described the synthetic utility of the general ortholithia-
tion of the lithium salts of unprotected benzoic acids[2] by demonstrating a
series of regioselective reactions derived from the competition of 2-fluoro/
chloro/bromobenzoic acids with organolithiums.[3] We now report a
general and efficient synthesis of 2-chloro-6-substituted benzoic acids
(2a–h) via regiospecific 6-lithiation of 2-chlorobenzoic acid (1) with the
in situ trapping by electrophiles in a novel procedure.
The efficiency of ortho-lithiation is a function of the reaction solvent,
organolithium, complexing agent, temperature, and order of addition.
General conditions were chosen on the basis of preliminary experiments
with deuterium oxide. Between 250 8C and 230 8C, 2-chlorobenzoic acid
(1) was not metallated efficiently by the hindered lithium 2,2,6,6-tetramethyl-
piperidide (LTMP) and low yields of 6D-1 were obtained (entries 1–3,
Table 1).
Optimum conditions that have been found are slow addition of the acid in
THF to a slight excess (2.2 equiv) of a 1 : 1 sec-butyllithium/N,N,N0,N0-tetra-
methyl-1,2-ethylenediamine complex (s-BuLi/TMEDA) complex in THF at
278 8C (entry 4). After quenching with D2O, 6D-1 was obtained as a sole
regioisomer in 85% yield. The carboxylate is a strong binder of lithium and
a preequilibrium association between the carboxylate group and the organo-
lithium base should be favorable.[4] This interaction is stronger with the alkyl-
lithium base.
In agreement with previous results,[3] intramolecular lithiations between
the unprotected carboxylic acid and fluorine, chlorine, and bromine atoms
in ortho-disubstituted benzenes follow the order F . CO2H . (Cl, Br).
Table 1. Deprotonation of 2-chlorobenzoic acid (1) by strong basesa
Entry
Baseb
LTMP
LTMP
T (8C)
t (h)
3D-1
6D-1
1c
1
2
3
4
230
250
250
278
1
0
0
0
0
5
4
50
75
69
5
1
LTMP
s-BuLi/TMEDA
4
0.5
5
85
aNMR yields (%).
bThe base (2.2 equiv) was allowed to react with 1 at the temperature T for t h before
D2O in excess was added.
cRecovered starting product.

Ortholithiation of Benzoic Acids
801
Lithiation appears to be complete after 30 min, but the bright orange
lithium-2-chloro-6-lithiobenzoate (6Li-1) is stable over hours at 2788C.
The solution of the metallated species was quenched with a series of electro-
philes (EX) in excess at 2788C and the solution was allowed to warm to room
temperature (Table 2). Standard workup and subsequent recrystallization
afforded 2-chloro-6-substituted benzoic acids 2a–h in 52–76% recrystallized
yields.
2-Chloro-6-methylbenzoic acid (2a) was isolated in good yield (65%) by
trapping 6Li-1 with iodomethane (entry 1). Compound 2a is inter alia a
precursor for the synthesis of xanthene 9-spiro-40-piperidines with opiate
activity.[5] In the literature, this acid, although rather simple, is difficult to
prepare. The product purchased from commercial suppliers is quite
expensive (.E70/g). Four known methods for the synthesis of 2a are
reported which are based on (1) the Sandmeyer reaction of 2-chloro-6-
methyl anilines to form the corresponding nitrile, followed by two more
Table 2. Synthesis of 2-chloro-6-substituted benzoic acids 3a–h
Yielda
(%)
Entry
EX/E
MeI/Me
C2Br2Cl4/Br
I2/I
Me2S2/MeS
TMSCl/TMS
DMF/CHO
PhCHO/PhCH(OH)
CO2/CO2H
Product
F (8C)
1
2
3
4
5
6
7
8
2a
2b
2c
65
56
53
69
76
52
60
65
99–101
145–147
147–149
134–136
132–134
182–184
87–89
2d
2e
2fb
2gc
2h
184–186
aRecrystallized yields (heptane/ethylacetate).
bProduct 2f directly cyclized into hydroxyphthalide 3.
cProduct 2g directly cyclized into lactone 4.

802
F. Gohier, A.-S. Castanet, and J. Mortier
Scheme 1.
steps,[6] (2) ortho-metalation of 2-chlorobenzaldehyde via an a-aminoalkoxide
formation with N,N,N0-trimethylethylenediamine, followed by oxidation,[7]
(3) nucleophilic aromatic substitution of the imine derived from 2-chloro-6-
fluorobenzaldehyde and n-butylamine, followed by acidic hydrolysis and
oxidation,[6] and (4) carbonylation of 3-chloro-2-iodotoluene to give methyl
2-chloro-6-methylbenzoate followed by hydrolysis.[6] Clearly the method
reported in this paper provides a good complement.1
Bromine and iodine derivatives 2b,c were synthesized conveniently
from reactions of 6Li-1 with 1,2-dibromotetrachloroethane and elemental
iodine (Table 2). These compounds are known as starting products for
the synthesis of teraryl carboxylic acids via the Stille reaction.[8,9]
9-Aminoacridine- 4-carboxamides with antitumoral activity were reported
to be prepared from 2- chloro-6-iodobenzoic acid (2c).[10] 2-Bromo-6-chloro-
benzoic acid (2b) has also been synthesized by metallation of 1-bromo-
3-chlorobenzene (5) with LDA followed by quenching with CO2
(Scheme 1).[11] There is a cooperative effect of the 1,3-interrelated directors
in promoting metallation at the common ortho-site. Alternatively, LDA depro-
tonates 2-bromochlorobenzene (6) randomly.[12] The ability of the chlorine
and bromine atoms to promote ortho-metalations is close. Both anions inter-
mediately formed presumably isomerize to the thermodynamically more
stable 2-bromo-6-chlorophenyllithium, which can be trapped by CO2 as the
acid 2b.[13]
Dimethyldisulfide and chlorotrimethylsilane (Me3SiCl) quenches proceeded
smoothly, leading respectively to 2-chloro-6-(methylthio/trimethylsilyl)benzoic
acids 2d and 2e in 69% and 76% yield (Table 2). The yield of 2e was enhanced
up to 84% when LTMP and Me3SiCl were premixed prior to addition of the acid
(in situ quench technique).[14]
12-Chlorobenzoic acid (1) is very cheap (E 30/kg).

Ortholithiation of Benzoic Acids
803
The regioselectivity of the reaction was ascertained with DMF and
benzaldehyde: 2f and 2g underwent cyclization to hydroxyphthalide 3 and
lactone 4 respectively upon acidic workup (Table 2). Lactones of the type 4
are precursors of benzo[c]pyrans, which have been shown to possess a
variety of biological properties.[15] The lactone 4 was prepared by metallation
of the corresponding benzamide followed by quenching with benzaldehyde.
Our work demonstrates that initial protection of the CO2H group prior to
metallation is not necessary. Addition of carbon dioxide to the dilithiated
benzoate 6Li-1 provided 3-chlorobenzene-1,2-dioic acid (2h) (65%, Table 2).
Alternatively, 2h can be prepared by metalation of 3-chlorobenzoic acid
with the 1 : 1 complex s-BuLi/TMEDA followed by trapping with CO2.[16]
EXPERIMENTAL
General
For standard working practice, see recent studies.[17] Reactions were carried
out under argon in oven-dried glassware. 2-Chlorobenzoic acid (1) was recrys-
tallized (ethylacetate/heptane) prior to use. NMR spectra were recorded on a
400 MHz spectrometer. 13C NMR spectra were obtained with broadband
proton decoupling. Chemical shifts are given in ppm relative to the internal
tetramethylsilane (TMS) reference signal. For DMSO-d6 and acetone-d6
used as solvents, chemical shifts are given relative to the solvent signals.
Melting points are uncorrected.
Reactions were performed in oven-dried glassware under an argon atmos-
phere. Tetrahydrofuran (THF) was distilled from deep-blue solutions of
sodium/benzophenone ketyl prior to use. s-BuLi, 1.3 M and 1.4 M in cyclo-
hexane, was titrated periodically against 2,5-dimethoxybenzyl alcohol.
N,N,N0,N0-Tetramethyl-1,2-ethylenediamine (TMEDA) was distilled from
CaH2 before use.
General Procedure
To a stirred solution of the 1:1 complex s-BuLi/TMEDA (2.2 equiv) in dry
THF (10 mL) at 278 8C, was added dropwise 2-chlorobenzoic acid (1)
(0.548 g, 3.5 mmol) in dry THF (5 mL). The mixture was stirred for 30 min
and then quenched with the electrophile (5 equiv, 17.5 mmol) in THF
(5 mL). The solution was allowed to warm to ambient temperature, and
water (15 mL) was added. The aqueous layer was washed with diethyl ether
(15 mL), acidified with aq. HCl 6M, and extracted with diethyl ether
(3 ꢀ 15 mL). The organic layer was dried over MgSO4, filtrated, and concen-
trated in vacuo to yield the crude 2-chloro-6-substituted benzoic acids 2a–h,
which were recrystallized (heptane/ethylacetate).

804
F. Gohier, A.-S. Castanet, and J. Mortier
2-Chloro-6-deuterobenzoic Acid (6D-1)
White solid, 85% (crude yield). 1H NMR (CDCl3) d: 7.56–7.46 (s, 2H), 7.40–
7.32 (s, 1H). 13C NMR (DMSO-d6) d: 171.0, 134.8, 133.6, 132.2
(t, J ¼ 25 Hz), 131.5, 128.3, 126.6.
2-Chloro-6-methylbenzoic Acid (2a)
White solid, 65%. Mp ¼ 99–1018C [lit. 100–1028C, Ref.[18]]. 1H NMR
(CDCl3) d: 7.68–7.25 (m, 2H, H3 and H4), 7.17–7.12 (m, 1H, H5), 2.45
(s, 3H). 13C NMR (CDCl3) d: 173.2, 137.1, 132.5, 131.6, 130.7, 128.6,
127.0, 19.8.
2-Bromo-6-chlorobenzoic Acid (2b)
1
White solid, 56%. Mp ¼ 145–1478C [lit. 144–1468C, Ref.[18]]. H NMR
(CDCl3) d: 7.65 (dd, 1H, H5, JH4H5 ¼ 7.8 Hz and JH3H5 ¼ 1.3 Hz), 7.52
(t, 1H, H4, JH4H5 ¼ JH3H4 ¼ 7.8 Hz), 7.42 (dd, 1H, H5 JH4H5 ¼ 7.8 Hz and
JH3H5 ¼ 1.3 Hz). 13C NMR (CDCl3) d: 167.2, 138.4, 133.4, 133.1, 132.6,
130.4, 120.7.
2-Chloro-6-iodobenzoic Acid (2c)
1
White solid, 53%. Mp ¼ 147–1498C [lit. 152–1548C, Ref.[19]]. H NMR
(CDCl3) d: 7.76 (d, 1H, H5, JH4H5 ¼ 8.4 Hz), 7.42 (d, 1H, H3,
JH3H4 ¼ 8.1 Hz), 7.08 (dd, 1H, H4, JH4H5 ¼ 8.4 Hz and JH3H4 ¼ 8.1 Hz).
13C NMR (CDCl3) d: 172.0, 138.7, 137.5, 131.8, 130.8, 129.2, 91.5. IR
(KBr): 1704, 1426, 1281, 773 cm21
.
2-Chloro-6-(methylthio)benzoic Acid (2d)
White solid, 69%. Mp ¼ 134–1368C. 1H NMR (CDCl3) d: 7.24–7.35
(m, 3H), 2.50 (s, 3H). 13C NMR (CDCl3) d: 171.7, 138.1, 133.0, 131.2,
130.9, 126.9, 126.6, 17.7. IR (KBr): 1693, 1290, 763 cm21. Anal. calcd. for
C8H7ClSO2: C, 47.41; H, 3.48. Found: C, 47.45; H, 3.57.
2-Chloro-6-trimethylsilylbenzoic Acid (2e)
White solid, 78%. Mp 132–1348C [lit. 129–1318C, Ref.[20]]. 1H NMR
(CDCl3) d: 7.49 (dd, 1H, J ¼ 7.8 and 1.6 Hz), 7.43 (dd, 1H, J ¼ 7.8 and
1.6 Hz), 7.36 (t, 1H, J ¼ 7.8 Hz), 0.35 (s, 9H). 13C NMR (CDCl3) d: 174.8,
140.8, 136.9, 132.8, 131.2, 130.5, 130.2, 20.3. IR (KBr): 2951, 1694, 1287,
850, 756 cm21
.

Ortholithiation of Benzoic Acids
805
In situ Quench (ISQ) Protocol
At 278 8C, lithium tetramethylpiperidide (7.7 mmol) in dry THF (10 mL) was
added to a stirred solution of THF (10 mL) containing 2-halobenzoic acid
(3.5 mmol) and chlorotrimethylsilane (10.5 mmol, 1.38 mL). The solution
was stirred for 30 min at 278 8C and then allowed to warm to ambient temp-
erature. Aq. NaOH 2M was added ( ! pH 10), the aqueous layer was washed
with diethyl ether, acidified with aq. HCl 4M, and extracted with diethyl ether.
The organic layer was dried over MgSO4, filtrated, and concentrated in vacuo
to furnish the crude silylated benzoic acid which was purified by chromato-
graphy or recrystallized.
7-Chloro-3-hydroxyisobenzofuran-1(3H)-one (2f)
1
White solid, 52%. Mp ¼ 182–1848C [lit. 174–1768C, Ref.[21]]. H NMR
(CDCl3) d: 7.60–7.82 (m, 3H), 7.10–7.15 (s, 1H), 6.65–6.70 (m, 1H, OH).
13C NMR (CDCl3) d: 165.8, 150.7, 136.4, 132.4, 132.2, 124.3, 123.2, 97.1.
IR (KBr): 1732, 1082, 907, 747 cm21
.
7-Chloro-3-phenylisobenzofuran-1(3H)-one (2g)
1
White solid, 60%. Mp ¼ 87–898C [lit. 888C, Ref.[22]]. H NMR (CDCl3) d:
7.56 (dd, 1H, H4, JH4H5 ¼ 8.0 Hz and JH3H4 ¼ 7.9 Hz), 7.48 (d, 1H, H3,
JH3H4 ¼ 7.9 Hz), 7.42–7.36 (m, 3H), 7.30–7.24 (m, 2H), 7.21 (d, 1H,
J ¼ 7.6 Hz). 6.33 (s, 1H). 13C NMR (CDCl3) d: 167.4, 152.0, 135.9, 135.3,
133.2, 130.7, 129.5, 129.1, 126.9, 122.2, 121.4, 81.3. IR (KBr): 1751, 1464,
1081, 965, 699 cm21
.
3-Chlorobenzene-1,2-dioic Acid (2h)
White solid, 78%. Mp ¼ 184–1868C [lit. 1868C, Ref.[23]]. 1H NMR (acetone-
d6) d: 8.01 (d, 1H, H5, JH4H5 ¼ 8.0 Hz), 7.74 (d, 1H, H3, JH3H4 ¼ 7.8 Hz), 7.58
(dd, 1H, H4, JH4H5 ¼ 8.0 Hz and JH3H4 ¼ 7.8 Hz). 13C NMR (acetone-d6) d:
167.2, 165.9, 136.9, 134.4, 131.6, 131.1, 130.6, 129.6. IR (KBr): 1698,
1293, 922, 763 cm21
.
ACKNOWLEDGMENT
´
This research was supported by the CNRS, Universite du Maine, and Institut
universitaire de France.

806
F. Gohier, A.-S. Castanet, and J. Mortier
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