Ortho-metalation of unprotected 3-bromo and 3-chlorobenzoic acids with hindered lithium dialkylamides

Article abstract of DOI:10.1021/jo026514t

Upon treatment of 3-chloro/bromobenzoic acids with hindered lithium dialkylamides (LDA or LTMP) at -50 °C, lithium 3-chloro/bromo-2-lithiobenzoates are generated. These dianions can be trapped as such to afford after electrophilic quenching a variety of s

Full text of DOI:10.1021/jo026514t

TABLE 1. Dep r oton a tion of 3-Ch lor o a n d
3-Br om oben zoic Acid s w ith Hin d er ed Lith iu m
Dia lk yla m id esa
or th o-Meta la tion of Un p r otected 3-Br om o
a n d 3-Ch lor oben zoic Acid s w ith Hin d er ed
Lith iu m Dia lk yla m id es
Fre´de´ric Gohier and J acques 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
T
t
2-D yield concn
(%) (%)d (mol/L)
entry reactant base
nb (°C)
(h)c
jacques.mortier@univ-lemans.fr
Received October 3, 2002
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
LDA
LDA
LDA
LTMP 2.2 -50
LTMP 2.2 -50
LTMP
LTMP
LDA
2.2 -78 0.5-8 <30
2.2 -50 0.5-8 <30
e
e
e
0.15
0.15
0.15
0.15
0.05
0.05
0.2
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
4
-50 0.5
37
86
90
93
83
38
42
17
64
72
75
78
78
4
4
4
4
2
2
1
1
4
1
2
1
80
79
62
69
36
39
16
47
52
53
37
37
Abstr a ct: Upon treatment of 3-chloro/bromobenzoic acids
with hindered lithium dialkylamides (LDA or LTMP) at -50
°C, lithium 3-chloro/bromo-2-lithiobenzoates are generated.
These dianions can be trapped as such to afford after
electrophilic quenching a variety of simple 2-substituted-3-
chloro/bromobenzoic acids. The 3-bromo-2-lithiobenzoate is
less stable than the corresponding 3-chloro derivative and
partly eliminates lithium bromide, thus setting free lithium
2,3- and 3,4-dehydrobenzoates that can be intercepted in situ
with the hindered base.
3
3
-50
-60
2.2 -78
2.2 -60
LDA
LTMP 2.2 -78
LTMP 2.2 -60
LTMP 2.2 -60
LTMP 2.2 -50
LTMP 2.2 -50
LTMP
3
-50
a
General procedure. To a stirred solution of LDA or LTMP (n
equiv) in anhydrous THF at T °C was added dropwise under argon
the recrystallized benzoic acid 1 (6.4 mmol) or 2 (5 mmol) dissolved
in dry THF (5 mL). After t hours at T °C, the mixture was treated
with an excess of deuterium oxide (5 equiv). Workup in the usual
manner (see the Experimental Section) followed by recrystalliza-
tion provided the benzoic acids 2D-1 and 2D-2, which were
The deprotonation of arenes usually requires a strong
base such as an alkyllithium and a directing group such
as a secondary or tertiary amide, an oxazoline, an
R-amino alkoxide, or a carbamate.1 The resulting aryl-
lithium can react with a variety of electrophiles including
alkylating agents, aldehydes, ketones, chloroformates,
silylating agents, and trialkylborates. Amides and ox-
azolines can serve as latent carboxylic acids in the
directed metalation; nevertheless, they require harsh
conditions for their hydrolysis.
The best protective group is the one that can be
omitted.2 The directed ortho-metalation of unprotected
benzoic acids can be achieved by treatment with 2.2 equiv
of s-BuLi/TMEDA in THF at -90 °C;3,4 the resulting
dilithiated species easily react with a variety of electro-
philes to give the ortho-substituted products. Alterna-
tively, 2,3-disubstituted benzoic acids are readily avail-
able by lithiating 1,2-disubstituted compounds, metalation
occurring to the more effective directing group-neighbor-
ing position.5,6
1
b
characterized by H and 13C NMR. Calculated from the starting
benzoic acid (1 or 2). c Reaction time of the lithium dialkylamide
d
with the starting acid. Crude yield. e Not determined.
halogen-metal exchange.7 We record here details of our
investigations on the metalation of 3-halobenzoic acids
(halo ) Cl, Br) by hindered lithium dialkylamides.
We have embarked on a detailed investigation of the
deprotonations of 3-chlorobenzoic acid (1) and 3-bro-
mobenzoic acid (2), varying the base, metalation tem-
perature, and exposure times (Table 1). Lithium diiso-
propylamide (LDA) is not suitable for the generation of
lithium 2-lithio-3-chloro and 2-lithio-3-bromobenzoates
(2Li-1 and 2Li-2, respectively): deuteriation (deuterium
oxide quench) at the position flanked by both substituents
does not exceed 42% (entries 1-3, 8, and 9).8 Clean
lithiation was achieved with lithium 2,2,6,6-tetrameth-
ylpiperidide (LTMP, 2.2 equiv) in THF at -50 °C for a
concentration of the reactant of 0.15 mol/L (entries 4 and
13). D2O trapping (4-10 equiv/-50 °C f rt/2 h) provided
The use of alkyllithium bases limits group functional-
ity, for example, by not allowing for the presence of a
bromine or iodine atom on the arene due to competing
* Fax: +33 (0) 243 83 39 02.
1
2D-1 and 2D-2 in satisfying yields. The H and 13C NMR
(1) (a) Snieckus, V. Chem. Rev. 1990, 90, 879-933. (b) Que´guiner,
G.; Marsais, F.; Snieckus, V.; Epsztajn, J . Adv. Heterocycl. Chem. 1991,
52, 187-304. (c) Schlosser, M. Organometallics in Synthesis. A Manual,
2nd ed.; Wiley: Chichester, 2002.
(6) Reviews: (a) Mortier, J .; Vaultier, M. In Recent Research
Developments in Organic Chemistry; Transworld Research Network:
Trivandrum, India, 1998; Vol. 2, pp 269-283. (b) Mortier, J .; Vaultier,
M. C. R. Acad. Sci. Se´rie IIC 1998, 1, 465-478. ortho-Metalation
directed by the carboxylate group was recently investigated by Que´-
guiner and Mongin in the pyridine and quinoline series: (c) Mongin,
F.; Tre´court, F.; Que´guiner, G. Tetrahedron Lett. 1999, 40, 5483-5486.
(d) Rebstock, A.-S.; Mongin, F.; Tre´court, F.; Que´guiner, G. Tetrahedron
Lett. 2002, 43, 767-769.
(7) Parham, W. E.; Bradcher, C. K. Acc. Chem. Res. 1982, 15, 300-
305.
(8) LDA deprotonates more effectively 4-bromo-3-fluoro and 4-bromo-
3-chlorobenzoic acids. See ref 3b.
(2) Schlosser, M.; Geneste, H. Tetrahedron 1998, 54, 10119-10124.
(3) (a) Graneto, M. J .; Phillips, W. G.; Van Sant, K. A.; Walker, D.
M.; Wong, S. C. Eur. Pat. 538231, 1992. (b) Bennetau, B.; Cain, P. A.
U.S. Pat. 5334753, 1994. (c) Cantegril, R.; Croisat, D.; Desbordes, P.;
Guigues, F.; Mortier, J .; Peignier, R.; Vors, J .-P. Wo. Pat. 932287, 1993.
(4) (a) Mortier, J .; Moyroud, J .; Bennetau, B.; Cain, P. A. J . Org.
Chem. 1994, 59, 4042-4044. (b) Bennetau, B.; Mortier, J .; Moyroud,
J .; Guesnet J .-L. J . Chem. Soc., Perkin Trans. 1 1995, 1265-1271.
(5) (a) Moyroud, J .; Guesnet, J .-L.; Bennetau, B.; Mortier, J .
Tetrahedron Lett. 1995, 36, 881-884. (b) Mongin, F.; Schlosser, M.
Tetrahedron Lett. 1996, 37, 6551-6554.
10.1021/jo026514t CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/11/2003
2030
J . Org. Chem. 2003, 68, 2030-2033

SCHEME 1
data allow assignment of the correct deuterium regio-
chemistry of the reaction products.9 Lower concentrations
of the reactant or use of an increasing amount of LTMP
did not improve the results (entries 5-7 and 15).
deuterated in these conditions (D2O quench), 2Li-5, 4Li-
5, and/or 3Li-6 are protonated more likely in situ by a
hydrogen donor such as 2,2,6,6-tetramethylpiperidine
(HTMP). 4D-1 and 4D-2 were not isolated presumably
because 4Li-1 and 4Li-2 are less stable than 2Li-1 and
2Li-2, respectively, and rapidly decompose to form ben-
zyne 4. In the case of 2, warming the reaction mixture
to ambient temperature prior to the hydrolysis step led
to 5 and 6 in 34 and 12% yield, respectively. Below -60
°C, the deprotonation rate is slow and yields are poor
(entries 7-12).
The relative stability of unsubstituted ortho-haloge-
nated phenyllithiums toward elimination of LiX follows
the order LiBr (-100 °C) < LiCl (-90 °C).14 It is highly
dependent on the overall electronic effects induced in the
ring by the substituents. Consistently, only traces of 5
and 6 were obtained when 1 was allowed to react at -50
°C under the same conditions (3 and 2%, respectively).
Benzoates 2Li-1 and 2Li-2 are stabilized in these trans-
formations presumably by chelation of lithium with the
adjacent carboxylate moiety.14 The higher temperature
required to generate the lithium 2-lithio-3-chloroben-
zenecarboxylate aryne precursor as compared to its
bromo counterpart probably reflects the poorer leaving
group ability of chloride ion vs bromide ion.15,16
Potential deprotonation pathways were envisioned as
shown in Scheme 1. The dianion 2Li-1 is presumably
more stable than 2Li-2, which partly decomposed over a
period of 2 h at -50 °C (entry 14 vs entry 13). Benzoic
acids 1 and 2 react regiospecifically to give 2D-1 and 2D-2
where CO2Li and the halogen groups completely control
the deprotonation site. Analysis of the side-products
found in the aqueous layer after acidic workup (HCl, 4
M) was informative. After water removal, appreciable
amounts of the anilinium chlorides 5 and 6 were isolated
from the reaction of 2 (in 20 and 12% yields, respectively).
The two isomers were easily separated by chromatogra-
phy. Formation of anilines from benzynes is well prece-
dented.10,11 Steric encumbrance of the amine was said to
lower yields considerably.12 However, LTMP was recently
reported to be a good trap for benzynes.13 The side-
product 6 most reasonably arises by para-addition of
LTMP to benzyne 4. Formation of 5 proceeds by addition
of LTMP to either 3 or 4. Since 5 and 6 were not
(9) 3-Chloro-2-deuteriobenzoic acid (2D-1). 1H NMR (400 MHz,
CDCl3) δ TMS: 8.00 (dd, J ) 7.9, 1.0 Hz; 1H), 7.59 (dd, J ) 7.9, 1.0
Hz; 1H), 7.43 (t, J ) 7.9 Hz; 1H). 13C NMR (100 MHz, DMSO-d6) δ:
166.0, 133.2, 132.8, 132.6, 130.5, 128.5 (t, J ) 25.8 Hz), 127.8. 3-Bromo-
2-deuteriobenzoic acid (2D-2). 1H NMR (400 MHz, CDCl3) δ TMS: 8.04
(d, J ) 7.9 Hz; 1H), 7.74 (d, J ) 7.9 Hz; 1H), 7.36 (t, J ) 7.9 Hz; 1H).
13C NMR (100 MHz, DMSO-d6) δ: 170.8, 136.8, 132.9 (t, J ) 26 Hz),
131.2, 130.0, 128.8, 122.5.
(10) (a) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Aca-
demic Press: New York, 1967. (b) Wickham, P. P.; Hazen, K. H.; Guo,
H.; J ones, G.; Hardee Reuter, K.; Scott, W. J . J . Org. Chem. 1991, 56,
2045-2050.
(11) (a) Biehl, E. R.; Smith, S. M.; Patrizi, R.; Reeves, P. C. J . Org.
Chem. 1972, 37, 137-138 and references therein. (b) Caube`re, P.;
Derozier, N. Bull. Soc. Chim. Fr. 1969, 581-582. (c) Meyers, A. I.;
Rieker, W. Tetrahedron Lett. 1982, 23, 2091-2094.
(12) (a) Dougherty, C. M.; Olofson, R. A. J . Am. Chem. Soc. 1973,
95, 137-138. (b) Fitzgerald, J . J .; Drysdale, N. E.; Olofson, R. A. J .
Org. Chem. 1992, 57, 7122-7126.
(13) Tripathy, S.; LeBlanc, R.; Durst, T. Org. Lett. 1999, 1, 1973-
1975.
According to the optimized conditions noted in Table
1 (entries 4 and 13), benzoic acids 1 and 2 were allowed
to react with a variety of electrophiles to give the
corresponding ortho-substituted benzoic acids 9a -d ,f-i
and 10a -i (Table 2). Reaction with iodomethane gave
the anticipated result of methylation at the site mutually
ortho to both substituents. Yields decreased when iodo-
(14) Caster, K. C.; Keck, C. G.; Walls, R. D. J . Org. Chem. 2001, 66,
2932-2936.
(15) Huisgen, R.; Zirngibl, L. Chem. Ber. 1958, 91, 2375.
(16) Reaction of 2-bromobenzoic acid and 3-bromo-4-methoxy-,
3-bromo-4-methyl-, and 3-bromo-4,5-dimethoxybenzoic acids with ary-
lacetonitriles in the presence of LDA at -70 °C was recently reported
to give predominantly 2-cyanobenzoic acids. The reaction was thought
to proceed through a benzyne-3-carboxylate. See: Wang, A.; Maguire,
J . A.; Biehl, E. J . Org. Chem. 1998, 63, 2451-2455.
J . Org. Chem, Vol. 68, No. 5, 2003 2031

SCHEME 2
TABLE 2. Syn th esis of 2-Su bstitu ted 3-Ch lor o a n d
3-Br om oben zoic Acid s
tion of the dilithio intermediates with DMF followed by
acid-catalyzed cyclization gave hydroxyphthalides 13d
and 14d via ortho-formyl products 9d and 10d . Quench-
ing with electrophiles such as hexachloroethane, 1,2-
dibromotetrachloroethane, and iodine led to the corre-
sponding ortho-halogenated benzoic acids (entries 5, 6,
and 13-15). Reaction of C2Cl6 with 3-bromobenzoic acid
gave 2-chloro-3-bromobenzoic acid (10e), albeit in moder-
ate yield (43%). It is worthy of note that previous
lithiation methods were inefficient for preparing 10e.
Thus, LDA deprotonates ortho-bromochlorobenzene (15)
randomly at the two halogen-adjacent positions (Scheme
2). Both anions presumably isomerize to the less basic
and hence thermodynamically more stable 2-bromo-6-
chlorophenyllithium, which can be trapped as the acid
16.5,18 As established by Schlosser, trace amounts of 1,3-
dibromo-2-chlorobenzene most probably act as a turn-
table for a base-catalyzed “halogen dance”.18 The isomeric
2-bromo-3-chlorobenzoic acid 9f was prepared from acid
1 and C2Br2Cl4 (entry 5).
yield
product (%)a
entry reactant
A
B
EX
MeI
EtI
PhCHO PhCH(OH)
DMF CHO
C2Br2Cl4 Br
I2
Me3SiCl Me3Si
Me2S2
MeI
EtI
PhCHO PhCH(OH)
DMF
C2Cl6
E
1
2
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
7
7
8
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
Me
Et
9a
61
41b
63
63
68
55
75e
69
44
15
46
45
43
43
50
38
42
71
69
53
9b
3
4
5
6
7
8
9
9cc
9d d
9f
I
9g
9h
9i
MeS
Me
Et
10a
10b
10cf
10d g
10e
10f
10g
10h
10i
11a
11h
12a
10
11
12
13
14
15
16
17
18
19
20
CHO
Cl
C2Br2Cl4 Br
I2
Me3SiCl Me3Si
Me2S2
MeI
Reaction of dibromotetrachloroethane with 2Li-2 pro-
vided 2,3-dibromobenzoic acid (10f) (entry 14), a com-
pound that was attained with difficulty in the past, by
demanding, invariably and classically poorly regioselec-
tive electrophilic substitution chemistry.19 The previously
unknown 2-iodo-3-chloro and 2-iodo-3-bromobenzoic acids
(9g and 10g) were synthesized from iodine (entries 6,
15).20 Silylation of such systems was cleanly achieved.
The smooth and high-yield reaction of chlorotrimethyl-
silane with 1 affording 9h is indoubtedly related to the
in situ compatibility of TMSCl with lithium dialkyl
amides.21 The process is less efficient with 2Li-2 possibly
I
MeS
Me
F
F
Me3SiCl Me3Si
MeI Me
a
b
Recrystallized yield except otherwise noted. Crude yield.
c Product 9c cyclized into lactone 13c. Product 9d cyclized into
d
hydroxyphthalide 13d . e LDA was used in this example. f Product
g
10c was directly cyclized into lactone 14c. Product 10d was
directly cyclized into phthalide 14d .
ethane was reacted under the same conditions (entries
2 and 10).17
Clean hydroxyalkylation was achieved with benzalde-
hyde to give 9c and 10c, which were directly transformed
into lactones 13c and 14c (entries 3 and 11). Condensa-
(18) Mongin, F.; Schlosser, M. Tetrahedron Lett. 1997, 38, 1559-
1562 and references therein.
(19) Bunnett, J . F.; Rauhut, M. M.; Knutson, D.; Bussell, G. E. J .
Am. Chem. Soc. 1954, 73, 5755-5756.
(20) Fu, J .-M.; Zhao, B.-P.; Sharp, M. J .; Snieckus, V. J . Org. Chem.
1991, 56, 1683-1685.
(17) 2-Ethylated product 10b was prepared in higher yield (76%)
by treatment of 10a with LDA (3 equiv, -50 °C/THF) and trapping
with iodomethane.
(21) (a) Lipshutz, B. H.; Wood, M. R.; Lindsley, C. W. Tetrahedron
Lett. 1995, 36, 4385-4388. (b) Schlosser, M.; Guio, L.; Leroux, F. J .
Am. Chem. Soc. 2001, 123, 3822-3823.
2032 J . Org. Chem., Vol. 68, No. 5, 2003

methylpiperidine (4.7 mL, 28.1 mmol) in anhydrous THF (40
mL) at -20 °C under argon. After the mixture was cooled (-50
°C), 3-chlorobenzoic acid 1 (12.8 mmol) in anhydrous THF (10
mL) was added dropwise and the mixture was stirred for 4 h.
The mixture was then treated with an excess of the appropriate
electrophile (50.4 mmol, 4 equiv). The resulting solution was
allowed to warm to ambient temperature, after which water was
added. The aqueous layer was washed with diethyl ether,
shaken, and then acidified with 4 M HCl. The mixture was
diluted with diethyl ether, and the organic layer was separated
and dried with MgSO4. Filtration and concentration in vacuo
gave the crude benzoic acids, which were purified by recrystal-
lization for characterization in each case.
Syn th esis of 2-Su bstitu ted 3-Br om oben zoic Acid s 10.
Gen er a l P r oced u r e. To a stirred solution LTMP (21.8 mmol)
in anhydrous THF (35 mL) was added dropwise 3-bromobenzoic
acid 2 (9.9 mmol) in THF (10 mL) at -50 °C under argon. The
mixture was stirred for 1 h and then treated with an excess of
the appropriate electrophile (39.6 mmol) in THF (8 mL). Workup
in the usual manner followed by recrystallization provided
benzoic acids 10a -i.
due to its thermal instability. Addition of dimethyl
disulfide to the dilithiated benzoates gave the methyl-
sulfenylated derivatives 9i and 10i (entries 8 and 17). A
fluorine atom located meta to the deprotonation site
shows acidifying effects (entries 18-20). Quenching with
iodomethane and chlorotrimethylsilane led to the corre-
sponding ortho-substituted benzoic acids 11a , 11h , and
12a .
In summary, a general and convenient route to 2-sub-
stituted-3-chloro/bromobenzoic acids has been devised
using the directed ortho-metalation protocol. The fact
that this method gives such simple compounds that were
previously unknown is a testament to its future potential.
The directed ortho-metalation tactic of unprotected ben-
zoic acids should see wide utility in the synthesis of
aromatic compounds by coupling chemistry, among other
things.3,22
Exp er im en ta l Section
Ack n ow led gm en t. This work was supported by the
CNRS, Universite´ du Maine, and Institut universitaire
de France.
For standard working practice, see recent publications (e.g.,
refs 1c and 22).
Syn th esis of 2-Su bstitu ted 3-Ch lor oben zoic Acid s 9.
Gen er a l P r oced u r e. To a stirred solution of n-butyllithium 1.6
M in hexanes (17.5 mL, 28.1 mmol) was added 2,2,6,6-tetra-
Su p p or tin g In for m a tion Ava ila ble: Details of compound
characterization. This material is available free of charge via
the Internet at http://pubs.acs.org.
(22) (a) Cantegril, R.; Mortier, J .; Croisat, D.; Peignier, R. Wo. Pat.
9602138, 1996. (b) Cantegril, R.; Croisat, D.; Desbordes, P.; Guigues,
F.; Mortier, J .; Peignier, R.; Vors, J .-P. U.S. Pat. 5945382, 1999.
J O026514T
J . Org. Chem, Vol. 68, No. 5, 2003 2033