First general, direct, and regioselective synthesis of substituted methoxybenzoic acids by ortho metalation

Article abstract of DOI:10.1021/jo070082a

(Chemical Equation Presented) New general methodology of value in aromatic chemistry based on ortho-metalation sites in o-, m-, and p-anisic acids (1-3) (Scheme 1) is described. The metalation can be selectively directed to either of the ortho positions by varying the base, metalation temperature, and exposure times. Metalation of o-anisic acid (1) with s-BuLi/TMEDA in THF at -78°C occurs exclusively in the position adjacente to the carboxylate. On the other hand, a reversal of regioselectivity is observed with n-BuLi/t-BuOK. With LTMP at 0°C, the two directors of m-anisic acid (2) function in concert to direct introduction of the metal between them while n-BuLi/t-BuOK removes preferentially the proton located ortho to the methoxy and para to the carboxylate (H-4). s-BuLi/TMEDA reacts with p-anisic acid (3) exclusively in the vicinity of the carboxylate. According to these methodologies, routes to very simple methoxybenzoic acids with a variety of functionalities that are not easily accessible by other means have been developed (Table 1).

Full text of DOI:10.1021/jo070082a

First General, Direct, and Regioselective Synthesis of Substituted
Methoxybenzoic Acids by Ortho Metalation
Thi-Huu Nguyen,† Nguyet Trang Thanh Chau,†,‡ Anne-Sophie Castanet,†
Kim Phi Phung Nguyen,‡ 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), and UniVersite´
nationale de Ho-Chi-Minh-Ville, EÄ cole des sciences naturelles, Laboratoire de chimie organique,
283/2 Nguyen Van Cu. arrondissement 5, Ho Chi Minh Ville (Vietnam)
jacques.mortier@uniV-lemans.fr
ReceiVed January 15, 2007
New general methodology of value in aromatic chemistry based on ortho-metalation sites in o-, m-, and
p-anisic acids (1-3) (Scheme 1) is described. The metalation can be selectively directed to either of the
ortho positions by varying the base, metalation temperature, and exposure times. Metalation of o-anisic
acid (1) with s-BuLi/TMEDA in THF at -78 °C occurs exclusively in the position adjacente to the
carboxylate. On the other hand, a reversal of regioselectivity is observed with n-BuLi/t-BuOK. With
LTMP at 0 °C, the two directors of m-anisic acid (2) function in concert to direct introduction of the
metal between them while n-BuLi/t-BuOK removes preferentially the proton located ortho to the methoxy
and para to the carboxylate (H-4). s-BuLi/TMEDA reacts with p-anisic acid (3) exclusively in the vicinity
of the carboxylate. According to these methodologies, routes to very simple methoxybenzoic acids with
a variety of functionalities that are not easily accessible by other means have been developed (Table 1).
Introduction
tance to hydrolysis1,2 and the paucity of methods for their
transformation to other useful functionalities. Comins and
Brown3 and Reitz and Massey4 have addressed the hydrolysis
problem by developing tert-amide DMGs which are readily
converted into secondary amides, the cleavage of which, via
the N-nitrosoamide, has long been known. Snieckus et al.5 have
shown that N-methyl-N-[bis(trimethylsilyl)methyl]benzamides
and their monotrimethylsilyl analogues are ortho-lithiated and
that the derived ortho-substituted products can be transformed,
in two steps, into the corresponding benzyl alcohols or benzal-
dehydes.
The use of â-amino tertiary amides in place of the N,N-
dialkylamide allows for more versatility in manipulating the
directing group after ortho substitution has been effected.3
However, deprotection of the amide group still requires drastic
conditions, typically 6 N HCl hydrolysis or three-step, one-pot
reaction involving methylation, elimination, and treatment with
aqueous acid,4 which are very often not applicable for delicate
There are a number of carboxylic acid derivatives such as
secondary and tertiary amides, esters, R-amino alkoxides,
oxazolines, acetals, imidazolidines, imidazoles, and cyclohexy-
limines which are widely used for directed ortho-metalation
(DoM).1 The advantages of the tertiary amide directing meta-
lation group (DMG), originally introduced by Beak in 1977,2
include ease of preparation, priority over directors during the
metalation step, utility in polysubstituted aromatic systems, and
resistance to nucleophilic attack. The resistance to nucleophilic
attack can be a problem if one wishes to convert the tertiary
amide group into another functionality. In fact, the main
disadvantages of N,N-dialkylamides as DMGs are their resis-
* Corresponding author. Fax: +33 (0) 243 83 39 02.
† Universite´ du Maine and CNRS.
‡ Universite´ nationale de Ho-Chi-Minh-Ville
(1) Reviews: (a) Snieckus, V. Chem. ReV. 1990, 90, 879. (b) Hartung,
C. G.; Snieckus, V. Modern Arene Chemistry; Astruc, D. Ed.; Wiley-
VCH: New York; 2002, p. 330. (c) Schlosser, M. Angew. Chem., Int. Ed.
2005, 44, 376.
(3) Comins, D. L.; Brown, J. D. J. Org. Chem. 1986, 51, 3566.
(4) Reitz, D. B.; Massey, S. M. J. Org. Chem. 1990, 55, 1375.
(5) Snieckus, V. Lect. Heterocycl. Chem. 1984, 95.
(2) Beak, P.; Brown, R. A. J. Org. Chem. 1977, 42, 1823.
10.1021/jo070082a CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/29/2007
J. Org. Chem. 2007, 72, 3419-3429
3419

Nguyen et al.
TABLE 1. Regioselective Preparation of Substituted o-, m-, and p-Anisic Acidsa
starting acid
lithiation conditionb
electrophile
E
product
% (isolated)
mp (°C)
mp (°C, lit.)
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
A
Ac
A
A
A
A
Ad
Ad
Ad
Ad
B
MeI
6-Me
6-Me3Si
6-Cl
6-Br
6-I
6-MeS
6-CHO
6-PhCH(OH)
6-CH2CHdCH2
6-CH2Ph
3-Me
3-Me3Si
3-Cl
3-Br
4a
4b
4c
4d
4e
4f
61
89
58
59
46
47
43
52
45
47
40
40
39
34
27
45
41
50
75
47
60
53
46
27
65
54
59
39
45
20
51
54
54
55
63
50
61
73
80
75
54
71
76
64
69
138.5-139
85.5-87
142.5-144
127-129
129-131
182-184
155-157
136-138
89-91
137-138 4
TMSCl
C2Cl6
C2Br2Cl4
I2
Me2S2
DMF
PhCHO
BrCH2CHdCH2
BrCH2Ph
MeI
TMSCl
C2Cl6
C2Br2Cl4
I2
Me2S2
PhCHO
MeI
TMSCl
C2Cl6
C2Br2Cl4
I2
Me2S2
DMF
PhCHO
O2
-
140-14126
124-12722g
128-13027
184-18528
4ge
4hf
4i
155-15629
139-141.530
9131
4j
148-149.5
81-83
-
5a
5b
5c
5d
5e
5f
5g
6a
6b
6c
6d
6e
6f
83-83.53 2
B
96-98
-
B
114-116
119-121
122-124
77-79
-
Bd
Bd
B
12133
3-I
-
3-MeS
3-PhCH(OH)
2-Me
2-Me3Si
2-Cl
2-Br
2-I
2-MeS
2-CHO
2-PhCH(OH)
2-OH
4-Me
4-Cl
4-Br
4-I
4-MeS
4-PhCH(OH)
6-Me
6-Cl
6-Br
-
Bd
Cd
Cc,g
C
124-126
145-146
91-92
-
146.5-14934
-
-
160-161
154-155
145-146
132-134
154-155
147-148
150-152
210-213
210-212
212-213
210-212
186-187
122-124
151-152
168-169.5
158-160
132.5-134
144-146
177-178.5
134-136.5
111.5-113
-
C
C
C
C
C
C
D
D
D
D
D
D
E
E
E
E
E
155-15635
148-14936
-
6gh
6hi
6i
7a
7b
7c
7d
7e
7f
156-15737
-
15138
MeI
212-21421b
C2Cl6
C2Br2Cl4
I2
Me2S2
PhCHO
MeI
C2Cl6
C2Br2Cl4
I2
-
-
-
-
-
8a
8b
8c
8d
8e
9a
9b
9c
9dj
9e
9f
151-151.539
169-17140
16041
6-I
6-MeS
2-Me
2-Me3Si
2-Cl
2-Br
-
-
MeI
MeI
F
176-17842
Fc
F
TMSCl
C2Cl6
C2Br2Cl4
I2
Me2S2
DMF
-
-
-
-
-
-
-
F
F
F
F
2-I
173-175
118-120
134-136
124-126
2-MeS
2-CHO
2-PhCH(OH)
9gk
9hl
F
PhCHO
a Analytical and spectra data (IR, NMR, MS) data are in accord with the structures of all new compounds. For general procedures, see Experimental
Section. b External quench except otherwise noted. c In situ quench technique. See Experimental Section. d Reverse addition. See ref 50. e Product cyclized
into 3-hydroxy-7-methoxyisobenzofuran-1(3H)-one (11). f Product cyclized into 7-methoxy-3-phenylisobenzofuran-1(3H)-one (12). g 3-Methoxy-2,6-
bis(trimethylsilyl)benzoic acid (10) resulting from the partial deprotonation of lithium salt of the primary product 6b by the excess of base at the carbon C-6
was also isolated (7%). h Product cyclized into 3-hydroxy-4-methoxyisobenzofuran-1(3H)-one (13). i Products cyclized into 4-methoxy-3-phenylisobenzofuran-
1(3H)-one (14). j Two isomers 9d and 20 (9d/20, 48:52) could not be separated by chromatography. k Product cyclized into 3-hydroxy-5-methoxyisobenzofuran-
1(3H)-one (15). l Product cyclized into 5-methoxy-3-phenylisobenzofuran-1(3H)-one (16).
structures. Secondary benzamides, although useful in directed
metalation syntheses usually suffer from problems which arise
from the lack of solubility of the dianion generated.6 Many times
their reactions require the use of a cosolvent (e.g., HMPA) and/
or higher reaction temperatures which sometimes cause un-
wanted side reactions.7,8
aromatic nucleus.10 Herein we detail our investigations on the
synthetic utility of the CO2Li group for the preparation of o-,
m-, and p-anisic acids substituted with a variety of functional-
ities. The CO2Li DMG is of modest strength when compared
to some of the strong ortho-directors, but it is strong enough to
exert a substantial directing influence in the presence of a MeO
group. More importantly, the carboxylic acid group permits a
The best protecting group is the one which can be omitted.
When the carboxylic acid substituent is employed as a DMG,
substantial selectivity toward metalation can be obtained.9 This
group increases the discrimination between ortho positions, and
favors metalation over nucleophilic addition reactions to the
(9) (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.
(10) Conjugate addition of organolithium reagents to unprotected 1- and
2-naphthalenecarboxylic acids (a) Plunian, B.; Mortier, J.; Vaultier, M.;
Toupet, L. J. Org. Chem. 1996, 61, 5206. (b) Plunian, B.; Vaultier, M.;
Mortier, J. J. Chem. Soc. Chem. Commun. 1998, 81. Nucleophilic aromatic
substitutions of 2-fluorobenzoic acid with organolithiums: see ref. 9a.
(6) Puterbaugh, W. H.; Hauser, C. R. J. Org. Chem. 1964, 29, 853.
(7) Narasimhan, N. S.; Bhide, B. H. Tetrahedron 1971, 27, 6171.
(8) See also: Fisher, L. E.; Muchowski, J. M.; Clark, R. D. J. Org. Chem.
1992, 57, 2700.
3420 J. Org. Chem., Vol. 72, No. 9, 2007

Methoxybenzoic Acids by Ortho Metalation
SCHEME 1a
a A: (1) s-BuLi/TMEDA (1:1, 2.2 equiv), THF, -78 °C, 2 h; (2) EX, -78 °C; (3) 2 M HCl, rt. B: (1) n-BuLi/t-BuOK (1:1, 4 equiv), THF, -78 °C, 2
h; (2) EX, -78 °C; (3) 2 M HCl, rt. C: (1) LTMP (5 equiv), THF, 0 °C; (2) EX, 0 °C, 40-65 °C; (3) 2 M HCl, rt. D: (1) n-BuLi/t-BuOK (1:1, 4 equiv),
THF, -78 °C f -50 °C; 2) EX, -50 °C; (3) 2 M HCl, rt. E: (1) LTMP (5 equiv), TMSCl, 75% of 6b; (2) s-BuLi/TMEDA (4 equiv), THF, -78 °C f
-30 °C; (3) EX, -30 °C; (4) 6 M HCl, rt. F: (1) s-BuLi/TMEDA, 2.2 equiv, THF, -78 °C, 2 h; (2) Ex, -78 °C; 3) 2 M HCl, rt.
remarkable degree of control of the regioselectivity of metalation
between nonequivalent ortho centers.
Results and Discussion
Metalation regioselectivity is influenced by additives11 and
FIGURE 1. Dianions derived from anisic acids 1-3.
by variation of metalating agent.12 O-anisic acid (1) when treated
with s-BuLi/TMEDA (1:1, 2.2 equiv, THF, -78 °C, 2 h)
complexation might increase the rate of reaction by providing
followed by addition of an electrophile afforded only benzoic
a new mechanism that has a smaller activation energy.16
acids 4 substituted at the position ortho to the carboxylate (route
Lithium 2,2,6,6-tetramethylpiperidide (LTMP)17 metalated 1
A, Scheme 1).13 DoM involving alkyllithiums is a prime
quantitatively in the position C-6 when in situ quench conditions
example of a reaction that requires self-assembly before the
were used (Vide infra). These results strongly suggest that 6Li-1
transition state can be accessed. Since regioisomers 5 arising
is formed under both kinetic and thermodynamic conditions.
out of metalation ortho to the methoxy are not produced, s-BuLi
The trend is reversed by use of preformed LICKOR superbase18
approaches preferentially the benzoate 1 by chelation with the
made of equimolecular amounts of n-BuLi and t-BuOK at
highly electron-rich π-system in the carboxylate (CIPE effect).14
-78 °C, furnishing 3-substituted-2-methoxybenzoic acids 5 via
The resulting complex forces the deprotonation to occur into
the dianion 3M-1 (route B). The use of 4 equiv of base
the ortho position leading to the lithiated species 6Li-1 (see
constitutes the best conditions investigated to date. t-BuOK is
Figure 1) and ultimately the substitution products after reaction
a strong ligand that is able to break up the ordinary tight
with the electrophile. The directing and accelerating effect of
tetrameric aggregates of n-BuLi to dimers or even monomers.
the carboxylate is probably due to the stabilization of both the
The intramolecular solvation is no longer competitive under
initial complex and the transition structure whose geometries
these circumstances and superbases preferentially attack the
could be radically different.15 The coordination becomes stronger
in the transition state than in the initial complex. As a result,
(15) (a) Van Eikema Hommes, N. J. R.; Schleyer, P. v. R. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 755. (b) Bauer, W.; Schleyer, P. v. R. J. Am. Chem.
(11) Mongin, F.; Maggi, R.; Schlosser, M. Chimia 1996, 50, 650.
(12) Beak, P.; Brown, R. A. J. Org. Chem. 1982, 47, 34.
(13) Preliminary report: Nguyen, T. H.; Castanet, A.-S.; Mortier, J. Org.
Lett. 2006, 8, 765.
(14) (a) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356. (b)
Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int.
Ed. 2004, 43, 2206.
Soc. 1989, 111, 7191. (c) Van Eikema Hommes, N. J. R.; Schleyer, P. v.
R. Tetrahedron 1994, 50, 5903.
(16) Nguyen, T. H.; Chau, N. T. T.; Castanet, A.-S.; Nguyen, K. P. P.;
Mortier, J. Org. Lett. 2005, 7, 2445.
(17) Olofson, R. A.; Dougherty, C. M. J. Am. Chem. Soc. 1973, 95, 581.
(18) Reviews: (a) Lochmann, L. Eur. J. Inorg. Chem. 2000, 1115. (b)
Schlosser, M. Eur. J. Org. Chem. 2001, 3975.
J. Org. Chem, Vol. 72, No. 9, 2007 3421

Nguyen et al.
inductively activated aromatic position next to the most elec-
tronegative heteroatom and/or the most acidic position avail-
able.19
BuOK (routes B and D), the metalation is not regiospecific;
however, the major isomer is always readily isolated by
fractional crystallization.
Under conditions of thermodynamic control, LTMP (5 equiv)
deprotonated the isomeric m-anisic acid (2) at the doubly
activated C-2-position (route C), affording lithium 2-lithio-3-
methoxybenzoate (2Li-2) which was found to be indefinitely
stable in the interval of temperature 0-60 °C.16,20 The presence
of a MeO group located meta to the carboxylate imparts a great
deal of stability to this system relative to other benzoates.21 To
react efficiently with weak electrophiles, 2Li-2 has to be heated
up in refluxing THF (65 °C). When subjected to LICKOR (4
equiv), 4M-2 formed preferentially (route D). To prepare the
6-substituted benzoates 8, one had to block the C-2 site of 2 by
introducing a trimethylsilyl group, lithiate again, deliver the
electrophile, and remove the protecting group (route E).
Although s-BuLi/TMEDA (2.2 equiv) reacted with p-anisic acid
(3) exclusively at C-2 to give 2Li-3 (route F), attempts to
metalate the C-3 position failed.
Substituted anisic acids 4-9 are versatile starting materials
for organic synthesis. Examination of ortho isomer 1 was
performed because of the potential utility of regioselective
metalations as routes to series of relatively inaccessible 3- and
6-substituted 2-hydroxybenzenes 4 and 5 which are characteristic
features of many biologically active natural products of polyketide
origin (macrolides, polyene antibiotics, tetracyclines, etc.).22
Consideration of our tactic in the context of 2-, 4-, and
6-substituted-3-hydroxybenzoyl fragments 6-8 is useful in view
of the large number of derived natural products that incorporate
these substitution patterns.23 Published routes reveal that these
substitution patterns are not easily established.24 Most of the
previously known compounds were synthesized by tedious and
largely inefficient classical multistep sequences.25
Several aspects of the data in Table 1 require emphasis.
Methylation led to 4-9a in acceptable purified yields.43
Sequential reaction of 1 with 2.2 equiv of s-BuLi/TMEDA, 4
equiv of MeI, and excess aq. 2 M HCl gave 2-methoxy-6-
methylbenzoic acid (4a) in 61% yield. Narashimhan44 and
Fisher8 have shown that lithiation of N-methyl and N-propenyl-
2-methoxybenzamides with n-BuLi (2 equiv) at -70 °C
followed by reaction with MeI gave complex mixtures of
products. It is also worthy of note that 2-methoxyphenyloxazo-
lines react with organometallics (RLi, RMgX) not by metalation
but by direct substitution of the methoxyl group, furnishing
o-alkyl or o-aryl derivatives.45 The fact that N,N-dialkyl-2-
methoxybenzamides are metalated exclusively at the position
adjacent to the amide illustrates the dominance of the tertiary
(23) Selected examples of uses of 3-methoxy-4-methylbenzoic acid (7a)
as a building block for natural product synthesis: (a) Eickhoff, J. E.;
Hafenbradl, D.; Schwab, W.; Cotton, M.; Klebl, B. M.; Zech, B.; Mu¨ller,
S.; Harris, J.; Savic, V.; Macritchie, J.; Sherborne, B.; Le, J. PCT Int. Appl.
WO 010637, 1996. (b) Majetich, G.; Hicks, R.; Zhang, Y.; Tian, X.;
Feltman, T. L.; Fang, J.; Duncan, S., Jr. J. Org. Chem. 1996, 61, 8169. (c)
Raju, B. G.; Odowd, H.; Gao, H.; Patel, D. V.; Trias, J. PCT Int. Appl.
WO 2004 007444, 2004. (d) Gauuan, P. J. F.; Trova, M. P.; Gregor-Boros,
L.; Bocckino, S. B.; Crapo, J. D.; Day, B. J. Bioorg. Med. Chem. 2002, 10,
3013. 2-Chloro-4-methoxybenzoic acid (9c): (e) Pellon Comdom, R. F.;
Docampo Palacios, M. L. Synth. Commun. 2003, 33, 921. 2-Bromo-4-
methoxybenzoic acid (9d): (f) Bamford, M. J.; Heightman, T. D.; Wilson,
D. M.; Witherington, J. PCT Int. Appl. WO 2005 087746, 2005. (g) Croisy-
Delcey, M.; Croisy, A.; Carrez, D.; Huel, C.; Chiaroni, A.; Ducrot, P.;
Bisagni, E.; Jin, L.; Leclercq, G. Bioorg. Med. Chem. 2000, 8, 2629.
3-Hydroxy-7-methoxyisobenzofuran-1(3H)-one (10). (h) Haack, T.; Kurt-
kaya, S.; Snyder, J. P.; Georg. G. I. Org. Lett. 2003, 5, 5019.
(24) See references in Table 1.
(25) Weiss, U.; Edwards, J. M. The Biosynthesis of Aromatic Compounds;
Wiley: New York, 1980; Chapter 18.
(26) Postmus, C., Jr.; Kaye, I. A.; Craig, C. A.; Matthews, R. S. J. Org.
Chem. 1964, 29, 2693.
(27) Lewis, A.; Stefanuti, I.; Swain, S. A.; Smith, S. A.; Taylor, R. J. K.
Org. Biomol. Chem. 2003, 1, 104.
(28) Cabiddu, S.; Melis, S.; Piras, P. P.; Secci, M. J. Organomet. Chem.
1977, 132, 321.
By employing the optimized conditions described above
(routes A-F), a rich variety of substituted anisic acids 4-9
that are not easily accessible by conventional means were
synthesized (Table 1). Although yields are only fair, they are
usable, since no protection and deprotection steps of the DMG
are needed. After standard workup (see Experimental Section),
benzoic acids 4-9 were purified by recrystallization or chro-
matography for characterization in each case. With n-BuLi/t-
(29) Freskos, J. N.; Morrow, G. W.; Swenton, J. S. J. Org. Chem. 1985,
50, 805.
(30) Harland, P.; Hodge, P. Synthesis 1983, 419.
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Pudleiner, H.; Laatsch, H. Synthesis 1989, 286. (c) Sugaya, T.; Mimura,
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(20) Attempts of crystallization for X-ray structure determination in ether
or THF failed.
(21) (a) For example, if a solution containing lithium o-lithiobenzoate
2-LiC6H4CO2Li prepared by slow addition of 2 mol of n-BuLi to
2-bromobenzoic acid is allowed to warm up to -20 °C and to remain at
the temperature for 5 h, acidification affords the self-condensation product
2-benzoylbenzoic acid in 68% yield. Parham, W. E.; Bradsher, C. K.; Edgar,
K. J. J. Org. Chem. 1981, 46, 1057. (b) The same dianion generated by
metalation of benzoic acid with s-BuLi/TMEDA at -90 °C degrades above
-20 °C: Bennetau, B.; Mortier, J.; Moyroud, J.; Guesnet, J.-L. J. Chem.
Soc., Perkin Trans. 1 1995, 1265.
(36) Stanley, W. M.; McMahon, E.; Roger, A. J. Am. Chem. Soc. 1933,
55, 706.
(22) See, inter alia: (a) Bender, C. L.; Rangaswamy, V.; Loper, J. Annu.
ReV. Phytopathol. 1999, 37, 175. (b) Tyman, J. H. P. Recent Res. DeV.
Lipids 2001, 5, 125. (c) Katz, L. Chem. ReV. 1997, 97, 2557. (d) Staunton,
J.; Weissman, K. J. Nat. Prod. Rep. 2001, 18, 380. Selected examples of
uses of 2-methoxy-6-methylbenzoic acid (4a) as a building block for natural
product synthesis: (e) Kotsuki, H.; Araki, T.; Miyazaki, A.; Iwasaki, M.;
Datta, P. K. Org. Lett. 1999, 1, 499. (f) Ghosh, A. K.; Bischoff, A.;
Cappiello, J. Org. Lett. 2001, 3, 2677. 2-Bromo-6-methoxybenzoic acid
(4d): (g) Sugaya, T.; Mimura, Y.; Kato, N.; Ikuta, M.; Mimura, T.; Kasai,
M.; Tomioka, S. Synthesis 1994, 73. (h) Mimura, Y.; Shida, Y.; Kasai, M.;
Ashizawa, T.; Gomi, K. European Patent EP0487097A1, 1992. 2-Iodo-6-
methoxybenzoic acid (4e) (i) Martin, N. M. B.; Smith, G. C. M.; White, C.
R.; Newton, R. F.; Douglas, D. G.; Eversley, P. J.; Vile, J. World Patent
WO 0236576 A1, 2002.
(37) Brimble, M. A.; Caprio, V.; Johnston, A. D.; Sidford, M. Synthesis
2001, 855.
(38) Nishioka, H.; Nagasawa, M.; Yoshida, K. Synthesis 2000, 243.
(39) (a) Newman, M. S.; Bayerlein, F. J. Org. Chem. 1963, 28, 2804.
(b) Roberts, J. D.; Yancey, J. A. J. Am. Chem. Soc. 1951, 73, 1011.
(40) Rauhut, M. M.; Bunnet, J. F. J. Org. Chem. 1956, 21, 939.
(41) Merour, J.-Y.; Coadou, J.-Y.; Tatibouet, F. Synthesis 1982, 1053.
(42) Wyrick, S. D.; Smith, F. T.; Kemp, W. E.; Grippo, A. A. J. Med.
Chem. 1987, 30, 1798.
(43) An expedient synthesis of lunularic acid, a growth inhibitor found
in Lunularia cruciata was recently reported from 2-methoxy-6-methylben-
zoic acid (4a) prepared according to this method. See ref 13.
(44) Narashimhan, N. S.; Bhide, B. H. Tetrahedron 1971, 27, 6171.
(45) Meyers, A. I.; Mihelich, E. D. J. Am. Chem. Soc. 1975, 97, 7383.
3422 J. Org. Chem., Vol. 72, No. 9, 2007

Methoxybenzoic Acids by Ortho Metalation
FIGURE 3. Determination of the location of the TMS group of 4b,
8b, and 10 by qualitative homonuclear NOE difference spectroscopy.
FIGURE 2. Structure determination of 4a and 5a by the NOESY
technique.
SCHEME 2
amide groups in determining the position of lithiation;46
however, the 2,6-disubstituted benzamides thus produced are
inert to hydrolysis.1a,47 Furthermore the regioisomers 5 are not
accessible according to these methods.
Whereas 3-methoxyphenyloxazolines on treatment with either
n-BuLi or s-BuLi/TMEDA gave mixtures of both the ortho-
and para-products,48 route C led to 3-methoxy-2-methylbenzoic
acid (6a) as a sole isomer (45%) along with 2-ethyl-3-
methoxybenzoic acid arising out of lateral metalation of 6a
(15%).49 Thus, eVen aboVe 0 °C, iodomethane in excess does
not destroy totally the remaining LTMP which can then further
deprotonate 6a lithium salt. By slow addition of the preformed
anion 2Li-2 to a THF solution of MeI (reverse addition),50 6a
was produced in satisfactory yield (50%) while formation of
2-ethyl-3-methoxybenzoic acid was reduced to <3%.
The different sets of spatial interactions between different
protons indicated by the NOESY technique help to establish
the position of the methyl group of 4a and 5a (Figure 2). The
hydrogen H4 (7.29 ppm) of 4a shows spatial interactions with
H3 (6.81 ppm) as well as with H5 (6.83 ppm). Furthermore, the
methoxy group (3.88 ppm) interacts with H3 and the methyl
group interacts with H5. Therefore the methyl group of 4a is
located at the position adjacent to the carboxylate. The Me group
of 5a shows spatial interactions with H4 (7.43 ppm); there are
also interactions between H4-H5 (7.17 ppm) and H5-H6 (7.91
ppm), what is only possible if the methyl group is located in
the neighborhood to the methoxy group. All compounds 6a-g
obtained as the result of lithiation of 2 at the position C-2, ortho
to both substituents, show a characteristic triplet corresponding
in 75% yield. In another chromatographic fraction, 3-methoxy-
2,6-bis(trimethylsilyl)benzoic acid (10) resulting from the partial
deprotonation of lithium salt of the primary product 6b by the
excess of base at the carbon C-6 was also isolated. Bissilylation
was cleanly achieved if LTMP was used in large excess (5
equiv) at 0 °C under ISQ conditions (51%).
1
to the H-5 proton in the H NMR spectra. The products of
lithiation ortho to the methoxy group and para to the carboxylate
(7a-f) exhibit a characteristic doublet for H-5. The site of
lithiation and subsequent electrophilic addition is also confirmed
by the melting points of the previously known compounds with
the literature values.
The smooth and high-yield reaction of TMSCl affording 4b,
6b, and 9b is indoubtedly related to its in situ compatibility
with LTMP at low temperature.51 Whereas MeI quenches at
-50 °C left 2 unreacted, in situ trapping with TMSCl at
-78 °C provided 2-trimethylsilyl-3-methoxybenzoic acid (6b)
Proof for the location of the TMS group of 4b, 8b, and 10 is
gathered by qualitative homonuclear NOE difference spectros-
copy (Figure 3). Individual irradiations of H3 (H5) for 4b show
an enhancement of the neighboring OMe (9%) (H4 (4%),
respectively). For 8b, irradiation of H3 results in an enhancement
of the methoxy group (4.5%) while irradiation of H5 causes
large enhancement of two signals, namely OMe (7%) and H6
(13%). Irradiation of H4 for 10 results in a 10.5% NOE of the
methoxy group.
A variety of chlorine, bromine, and iodine derivatives were
conveniently obtained from reactions with hexachloroethane,
1,2-dibromotetrachloroethane, and iodine as electrophiles. Reac-
tion of p-anisic (3) with C2Br2Cl4 led to a mixture of 9d and
20 (54%, 48:52, Scheme 2). The lithium (2-carboxylato-5-
methoxyphenyl)lithium component (17) is partly converted into
the thermodynamically more stable lithium (2-bromo-6-car-
boxylato-3-methoxyphenyl)lithium (19), lithium 2,3-dibromo-
4-methoxybenzoate (18) acting as the presumed turntable for
this new example of a halogen migration (“dance”).52 The latter
(46) (a) Mills, R. J.; Taylor, N. J.; Snieckus, V. J. Org. Chem. 1989, 54,
4372. (b) Sibi, M. P.; Miah, M. A. J.; Snieckus, V. J. Org. Chem. 1984,
49, 737. (c) Watanabe, M.; Sahara, M.; Kubo, M.; Furukawa, S.; Billedeau,
R. J.; Snieckus, V. J. Org. Chem. 1984, 49, 742.
(47) Page, M. I. Angew. Chem., Int. Ed. Engl. 1977, 16, 449.
(48) (a) Meyers, A. I.; Avila, W. B. Tetrahedron Lett. 1980, 21, 3335.
(b) Shimano, M.; Meyers, A. I. Tetrahedron Lett. 1997, 38, 5415.
(49) Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 1.
(50) Mortier, J.; Vaultier, M.; Cantegril, R.; Dellis, P. Aldrichim. Acta
1997, 30, 34.
(51) The base and Me3SiCl are premixed prior to addition of the acid.
See: Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105, 6155. (b)
Schlosser, M.; Guio, L.; Leroux, F. J. Am. Chem. Soc. 2001, 123, 3822. (c)
Lipshutz, B. H.; Wood, M. R.; Lindsley, C. W. Tetrahedron Lett. 1995,
36, 4385.
(52) Reviews: (a) Bunnett, J. F. Acc. Chem. Res. 1972, 5, 139. (b)
Que´guiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. AdV. Heterocycl.
Chem. 1991, 52, 187. Recent examples: see ref 9a,b,e.
J. Org. Chem, Vol. 72, No. 9, 2007 3423

Nguyen et al.
Experimental Section
For standard working practice, see ref 57. Reactions were carried
out under argon in oven-dried glassware. Tetrahydrofuran was dried
from sodium benzophenone. Iodomethane, N,N-dimethylformamide,
and benzaldehyde were dried with CaH2 and distilled prior to use.
NMR spectra were recorded on a 200- or 400-MHz spectrometer.
13C NMR spectra were obtained with broadband proton decoupling.
For spectra recorded in CDCl3, chemical shifts were recorded
relative to the internal TMS (tetramethylsilane) reference signal.
For DMSO-d6, chemical shifts are given relative to the solvent
signals. All melting points are uncorrected. n-BuLi (1.6 M in
hexanes) and s-BuLi (1.3 M in cyclohexane-hexanes) were titrated
periodically against 2,5-dimethoxybenzyl alcohol. N,N,N′,N′-Tet-
ramethyl-1,2-ethylenediamine (TMEDA) was distilled from CaH2.
Potassium tert-butylate (t-BuOK) was sublimated.
General Procedure for the Preparation of 6-Substituted
2-Methoxybenzoic Acids (4a-f,i,j). Preparation of 3-Hydroxy-
7-methoxyisobenzofuran-1(3H)-one (11) and 7-Methoxy-3-phe-
nylisobenzofuran-1(3H)-one (12) (route A). To a stirred solution
of a 1:1 s-BuLi/TMEDA complex (11 mmol) in anhydrous THF at
-78 °C was added dropwise under argon o-anisic acid (1) (0.76 g,
5 mmol) dissolved in dry THF (5 mL). After 2 h at this temperature,
the mixture was treated with an excess of the appropriate electro-
phile (20 mmol) dissolved in THF. The resulting solution was then
slowly allowed to warm to ambient temperature, and water was
added. The aqueous layer was washed with diethyl ether (2 × 30
mL), shaken, and acidified with 2 M HCl. The mixture was then
diluted with diethyl ether, and the organic layer was separated and
dried with MgSO4.
2-Methoxy-6-methylbenzoic Acid (4a). According to the general
procedure, the recrystallized o-anisic acid (1, 0.76 g, 5 mmol) in
THF was added dropwise to a stirred solution of s-BuLi/TMEDA
(11 mmol). The solution was quenched by MeI (2.84 g, 20 mmol).
Workup in the usual manner followed by recrystallization (heptane/
ethyl acetate) afforded 4a (0.51 g, 61%) as a white solid: mp
138.5-139.0 °C (lit.4 137-138 °C). 1H NMR (200 MHz, CDCl3)
δ ppm: 2.45 (s, 3H), 3.88 (s, 3H), 6.82 (d, 1H, J ) 8.0 Hz), 6.83
(d, 1H, J ) 8.0 Hz), 7.29 (t, 1H, J ) J ) 8.0 Hz). 13C NMR (100
MHz, CDCl3) δ ppm: 20.6, 56.6, 109.2, 122.1, 123.6, 131.6, 138.7,
157.4, 173.1. IR (neat): 2995, 1692, 1585, 1471, 1267, 1087, 915
cm-1. Anal. Calcd for C9H10O3: C, 65.05; H, 6.07. Found: C,
65.03; H, 6.05.
FIGURE 4. Hydroxyphthalides and lactones 11-16.
isomerization can be readily explained if reversibility of the
lithiation is assumed.
Addition of dimethyl disulfide afforded the methylsulfeny-
lated derivatives 4-6f, 7e, and 8e. In cases where DoM occurs
at the position adjacent to the carboxylate group (routes A, C,
and F), the primary products obtained with DMF (4, 6, 9g) and
benzaldehyde (4, 6, 9h) after acidic hydrolysis were directly
transformed into hydroxyphthalides and lactones 11-16 (Figure
4).53 Hydroxyphthalides are intermediates for assembly of
anthracyclinone-type antibiotics.54
Of special interest is the ability of the carboxylate to introduce
an allyl substituent. Reaction of N,N-diisopropylbenzamide or
2-methoxy-N,N-diethylbenzamide with allyl bromide under
standard conditions (s-BuLi-TMEDA complex, -78 °C, THF)
provided the bromides instead of the allylated derivatives.12
Allylation of tertiary benzamides can only be achieved by prior
transformation of the aryllithium to the corresponding softer
ortho cuprate reagents.1a Nevertheless, it should be noted that
significant amounts of byproducts are frequently formed in these
condensations, probably due to the thermal instability of the
lithio-cuprate species.55 The one-pot lithiation/oxygenation
sequence (LTMP; then O2) afforded a moderate yield of
regiospecifically monohydroxylated product 6i.56
Conclusion
2-Methoxy-6-(trimethylsilyl)benzoic Acid (4b) (in situ quench
technique). To a solution of LTMP (9 mmol) in THF (20 mL) at
-78 °C were added successively TMSCl (1.38 mL, 10.5 mmol) in
THF (5 mL) and o-anisic acid (1) (0.46 g, 3 mmol) in THF (3
mL). After being warmed gradually to rt for 4 h, aqueous 2 M
NaOH was added until the pH reached 10. The aqueous layer was
washed with diethyl ether, acidified with aqueous 4 M HCl, and
extracted with diethyl ether. The organic layer was dried over
MgSO4, filtered, and concentrated in Vacuo. The residue was
purified by colum chromatography on silica gel (cyclohexane/
diethyl ether 90:10) to give 4b (0.60 g, 89%) as a white solid (mp
85.5-87.0 °C). 1H NMR (200 MHz, CDCl3) δ ppm: 0.33 (s, 9H),
3.98 (s, 3H), 7.05 (d, 1H, J ) 8.4 Hz), 7.37 (d, 1H, J ) 7.8 Hz),
7.51 (dd, 1H, J ) 8.4 Hz, J ) 7.8 Hz). 13C NMR (100 MHz, CDCl3)
δ ppm: 0.6 (3C), 56.0, 112.1, 124.2, 127.9, 131.8, 144.4, 157.2,
A systematic study has provided conditions for selective ortho
metalation of anisic acids. Synthetic utility has been demon-
strated by the provision of functionalized derivatives 4-9. The
use of the carboxylate group as ortho-metalation directing groups
has several notable advantages over that of the corresponding
secondary or tertiary benzamides. The synthetic potential thereof
would appear to match if not exceed that of tertiary benzamides
as ortho-lithiation directing groups. A discussion of the subtle
effects of base aggregates, complexing abilities of the substit-
uents, and base strengths must await further studies, but it is
clear that predicting sites of metalation in multiply substituted
aromatics is difficult and should be approached with caution.
In view of the number of groups that promote aromatic directed
metalation,1 the results reported herein may have broader
synthetic implications for polysubstituted aromatic and heteroa-
tom ring annelation methodologies.
170.3. IR (neat): 2840, 1681, 1571, 1445, 1243, 1126, 950 cm-1
.
Anal. calcd. for C11H16O3Si: C, 58.89; H, 7.19. Found: C, 58.94;
H, 7.12.
2-Chloro-6-methoxybenzoic Acid (4c). According to the general
procedure, the recrystallized o-anisic acid (1, 0.76 g, 5 mmol) in
THF was added dropwise to a stirred solution of s-BuLi/TMEDA
(11 mmol). The solution was quenched by hexachloroethane (4.73
g, 20 mmol). Workup in the usual manner followed by chroma-
(53) Under conditions B, the reaction leads to degradation products with
DMF, allyl bromide, and benzyl bromide. Acid 2 also leads to degradation
products by reaction with DMF under conditions D.
(54) See Achmatowicz, O.; Szechne, B. J. Org. Chem. 2003, 68, 2398
and references cited therein.
(55) Casas, R.; Cave´, C.; d’Angelo, J. Tetrahedron Lett. 1995, 36, 1039.
(56) Parker, K. A.; Koziski, K. A. J. Org. Chem. 1987, 52, 674.
(57) Schlosser, M. Organometallics in Synthesis. A Manual, 2nd ed.;
Wiley: Chichester, 2002.
3424 J. Org. Chem., Vol. 72, No. 9, 2007

Methoxybenzoic Acids by Ortho Metalation
tography (cyclohexane/ethyl acetate 80:20) afforded 4c (0.54 g,
58%) as a white solid: mp 142.5-144 °C (lit.26 140-141 °C). 1H
NMR (200 MHz, CDCl3) δ ppm: 3.88 (s, 3H), 6.88 (dd, 1H, J )
8.4 Hz, J ) 0.8 Hz), 7.03 (dd, 1H, J ) 8.2 Hz, J ) 0.8 Hz), 7.29
(dd, 1H, J ) 8.4 Hz, J ) 8.2 Hz). 13C NMR (50 MHz, CDCl3) δ
ppm: 56.1, 110.4, 120.9, 124.9, 129.2, 130.9, 156.3, 165.9. IR
(neat): 2839, 2531, 1713, 1589, 1467, 1262, 1029, 924 cm-1. Anal.
Calcd for C8H7ClO3: C, 51.50; H, 3.78. Found: C, 51.81; H, 3.71.
2-Bromo-6-methoxybenzoic Acid (4d). According to the general
procedure, the recrystallized o-anisic acid (1, 0.76 g, 5 mmol) in
THF was added dropwise to a stirred solution of s-BuLi/TMEDA
(11 mmol). The solution was quenched by dibromotetrachloroethane
(6.51 g, 20 mmol). Workup in the usual manner followed by
chromatography (cyclohexane/ethyl acetate 80:20) afforded 4d (0.68
g, 59%) as a white solid: mp 127-129 °C (lit.22g 124-127 °C).
1H NMR (200 MHz, CDCl3) δ ppm: 3.89 (s, 3H), 6.87 (dd, 1H, J
) 8.4 Hz, J ) 0.8 Hz), 7.02 (dd, 1H, J ) 8.1 Hz, J ) 0.8 Hz),
7.32 (dd, 1H, J ) 8.4 Hz, J ) 8.1 Hz). 13C NMR (50 MHz, CDCl3)
δ ppm: 56.3, 109.6, 121.7, 122.7, 131.5, 131.6, 157.3, 171.3. IR
IR (neat): 2985, 1754, 1600, 1486, 1296, 1196, 1027 cm-1. Anal.
Calcd for C15H12O3: C, 74.99; H, 5.03. Found: C, 74.56; H, 5.03.
2-Allyl-6-methoxybenzoic Acid (4i). According to the general
procedure, the recrystallized o-anisic acid (1, 0.76 g, 5 mmol) in
THF was added dropwise to a stirred solution of s-BuLi/TMEDA
(11 mmol). The solution was quenched by allyl bromide (2.42 g,
20 mmol). Workup in the usual manner followed by chromatog-
raphy (cyclohexane/ethyl acetate 85:15) afforded 4i (0.43 g, 45%)
as a white solid: mp 89-91 °C (lit.31 91 °C). 1H NMR (200 MHz,
CDCl3) δ ppm: 3.54 (d, 2H, J ) 6.7 Hz), 3.89 (s, 3H), 5.04-5.15
(m, 2H), 5.97 (m, 1H), 6.85 (d, 1H, J ) 8.2 Hz), 6.91 (d, 1H, J )
7.8 Hz), 7.34 (dd, 1H, J ) 8.2 Hz, J ) 7.8 Hz). 13C NMR (100
MHz, CDCl3) δ ppm: 37.9, 56.1, 109.3, 116.4, 122.1, 122.3, 131.2,
136.4, 139.6, 156.8, 172.9. IR (neat): 2951, 1685, 1581, 1471, 1289,
1061, 918 cm-1
.
2-Benzyl-6-methoxybenzoic Acid (4j). According to the general
procedure, the recrystallized o-anisic acid (1, 0.76 g, 5 mmol) in
THF was added dropwise to a stirred solution of s-BuLi/TMEDA
(11 mmol). The solution was quenched by benzyl bromide
(3.40 g, 20 mmol) (reverse addition). Workup in the usual manner
followed by chromatography (cyclohexane/ethyl acetate 80:20)
afforded 4j (0.57 g, 47%) as a white solid: mp 148-149.5 °C. 1H
NMR (200 MHz, CDCl3) δ ppm: 3.90 (s, 3H), 4.14 (s, 2H), 6.82
(dd, 2H, J ) 7.9 Hz, J ) 9.9 Hz), 7.16-7.34 (m, 6H). 13C NMR
(100 MHz, CDCl3) δ ppm: 39.2, 56.1, 108.9, 109.2, 122.8, 126.3,
128.4 (2C), 129.2 (2C), 131.2, 140.0, 140.8, 156.8, 172.6. IR
(neat): 2841, 1719, 1589, 1469, 1262 cm-1
.
2-Iodo-6-methoxybenzoic Acid (4e). According to the general
procedure, the recrystallized o-anisic (1, 0.76 g, 5 mmol) in THF
was added dropwise to a stirred solution of s-BuLi/TMEDA (11
mmol). The solution was quenched by iodine (5.07 g, 20 mmol).
Workup in the usual manner followed by chromatography (cyclo-
hexane/ethyl acetate 80:20) afforded 4e (0.64 g, 46%) as a brown
solid: mp 129-131 °C (lit.27 128-130 °C). H NMR (200 MHz,
(neat): 2941, 1690, 1597, 1469, 1293, 1080, 932 cm-1
.
1
CDCl3) 3.84 (s, 3H), 6.92 (dd, 1H, J ) 8.4 Hz, J ) 0.9 Hz), 7.10
(dd, 1H, J ) 8.4 Hz, J ) 8.1 Hz), 7.44 (dd, 1H, J ) 8.1 Hz, J )
0.9 Hz). 13C NMR (100 MHz, CDCl3) δ ppm: 56.6, 92.2, 110.9,
129.2, 131.2, 131.9, 156.7, 172.6. IR (neat): 2841, 1719, 1589,
General Procedure for the Preparation of 3-Substituted
2-Methoxybenzoic Acids (5a-g) (route B). o-Anisic acid (1)
(0.46 g, 3 mmol) in THF (5 mL) was added dropwise to a stirred
solution of n-BuLi/t-BuOK (1:1, 12 mmol) in THF (30 mL) at
-78 °C. After being stirred at -78 °C for 2 h, the reaction mixture
was quenched with the electrophile (18 mmol) in THF (5 mL).
Stirring was maintained for 1 h, and the resulting mixture was
allowed to warm to rt and hydrolyzed with water (30 mL). The
aqueous layer was washed with diethyl ether (2 × 30 mL), acidified
with aqueous (2 M) HCl until pH reached 1, and extracted with
diethyl ether (3 × 30 mL). The organic layer was dried over MgSO4,
filtered, and concentrated in Vacuo to give the crude benzoic acids
(5a-g) which were purified by chromatography or fractional
crystallization.
2-Methoxy-3-methylbenzoic Acid (5a). According to the general
procedure, the recrystallized o-anisic acid (1, 0.46 g, 3 mmol) in
THF was added dropwise to a stirred solution of n-BuLi/t-BuOK
(1:1, 12 mmol). The solution was quenched by MeI (2.55 g, 18
mmol). Workup in the usual manner followed by recrystallization
(cyclohexane/ethyl acetate) afforded 5a (0.199 g, 40%) as a white
solid: mp 81-83 °C (lit.32 83-83.5). 1H NMR (200 MHz, CDCl3)
δ ppm: 2.37 (s, 3H), 3.93 (s, 3H), 7.17 (dd, 1H J ) 7.8 Hz, J )
7.4 Hz), 7.43 (d, 1H, J ) 7.4 Hz), 7.91 (d, 1H, J ) 7.8 Hz). 13C
NMR (100 MHz, CDCl3) δ ppm: 16.0, 62.1, 122.2, 124.8, 130.6,
131.9, 136.9, 158.1, 167.6. IR (neat): 2833, 2575, 1667, 1589, 1468,
1307, 1089, 949 cm-1. HRMS (EI) m/z calcd. for C9H10O3 (M+•):
166.0629. Found: 166.0628.
1469, 1262 cm-1
.
2-Methoxy-6-(methylthio)benzoic Acid (4f). According to the
general procedure, the recrystallized o-anisic acid (1, 0.76 g, 5
mmol) in THF was added dropwise to a stirred solution of s-BuLi/
TMEDA (11 mmol). The solution was quenched by dimethyl
disulfide (1.88 g, 20 mmol). Workup in the usual manner followed
by recrystallization (cyclohexane/ethyl acetate) afforded 4f (0.47
g, 47%) as a white solid: mp 182-184 °C (lit.28 184-185 °C). 1H
NMR (200 MHz, CDCl3) δ ppm: 2.45 (s, 3H), 3.98 (s, 3H), 6.80
(d, 1H, J ) 8.2 Hz), 6.98 (d, 1H, J ) 8.2 Hz), 7.40 (t, 1H, J ) 8.2
Hz). 13C NMR (100 MHz, CDCl3) δ ppm: 17.0, 56.6, 107.6, 107.9,
119.4, 131.9, 142.6, 157.9, 169.1. IR (neat): 2941, 1688, 1578,
1461, 1261, 1040, 927 cm-1. Anal. Calcd for C9H10O3S: C, 54.53;
H, 5.08. Found: C, 54.41; H, 5.01.
3-Hydroxy-7-methoxyisobenzofuran-1(3H)-one (11). Accord-
ing to the general procedure, the recrystallized o-anisic acid (1,
0.76 g, 5 mmol) in THF was added dropwise to a stirred solution
of s-BuLi/TMEDA (11 mmol). The solution was quenched by DMF
(1.46 g, 20 mmol) (reverse addition). Workup in the usual manner
followed by chromatography (cyclohexane/ethyl acetate 70:30)
afforded 11 (0.39 g, 43%) as a white solid: mp 155-157 °C (lit.29
1
155-156 °C). H NMR (200 MHz, CDCl3) δ ppm: 3.99 (s, 3H),
6.53 (s, 1H), 7.01 (d, 1H, J ) 8.4 Hz), 7.18 (d, 1H J ) 7.4 Hz),
7.53 (dd, 1H, J ) 8.4 Hz, J ) 7.4 Hz). 13C NMR (100 MHz, CDCl3)
δ ppm: 55.6, 96.5, 112.3, 115.1, 121.2, 130.6, 133.0, 158.0, 167.3.
2-Methoxy-3-(trimethylsilyl)benzoic Acid (5b). According to
the general procedure, the recrystallized o-anisic acid (1, 0.46 g, 3
mmol) in THF was added dropwise to a stirred solution of n-BuLi/
t-BuOK (1:1, 12 mmol). The solution was quenched by TMSCl
(1.96 g, 18 mmol). Workup in the usual manner followed by
chromatography (cyclohexane/ethyl acetate 90:10) afforded 5b
IR (neat): 2987, 1754, 1601, 1486, 1296, 1197, 1027 cm-1
.
7-Methoxy-3-phenylisobenzofuran-1(3H)-one (12). According
to the general procedure, the recrystallized o-anisic acid (1, 0.76
g, 5 mmol) in THF was added dropwise to a stirred solution of
s-BuLi/TMEDA (11 mmol). The solution was quenched by
benzaldehyde (2.12 g, 20 mmol). Workup in the usual manner
followed by recrystallization (cyclohexane/ethyl acetate 70:30)
afforded 12 (0.624 g, 52%) as a white solid: mp 136-138 °C (lit.30
139-141.5 °C). 1H NMR (200 MHz, CDCl3) δ ppm: 4.02 (s, 3H),
6.31 (s, 1H), 6.84 (d, 1H, J ) 7.6 Hz), 6.94 (d, 1H, J ) 8.4 Hz),
7.25-7.39 (m, 5H), 7.53 (dd, 1H, J ) 7.6 Hz, J ) 8.4 Hz). 13C
NMR (100 MHz, CDCl3) δ ppm: 56.1, 81.6, 110.9, 112.9, 114.5,
126.9, 128.9 (2C), 129.1 (2C), 136.6, 136.7, 152.5, 158.5, 168.6.
1
(0.269 g, 40%) as a white solid: mp 96-98 °C. H NMR (400
MHz, CDCl3) δ ppm: 0.34 (s, 9H), 3.89 (s, 3H), 7.21 (t, 1H, J )
7.3 Hz), 7.64 (dd, 1H, J ) 7.3 Hz, J ) 1.8 Hz), 8.04 (dd, J ) 7.6
Hz, J ) 1.8 Hz). 13C NMR (50 MHz, CDCl3) δ ppm: 0.6 (3C),
63.7, 121.6, 124.2, 134.5, 135.0, 141.2, 166.1, 170.6. IR (neat):
2947, 2651, 1677, 1579, 1452, 1298, 1127, 920 cm-1. HRMS (EI)
m/z calcd. for C11H16O3Si (M+•): 224.0868. Found: 224.0860.
3-Chloro-2-methoxybenzoic Acid (5c). According to the general
procedure, the recrystallized o-anisic acid (1, 0.46 g, 3 mmol) in
J. Org. Chem, Vol. 72, No. 9, 2007 3425

Nguyen et al.
THF was added dropwise to a stirred solution of n-BuLi/t-BuOK
(1:1, 12 mmol). The solution was quenched by hexachloroethane
(4.26 g, 18 mmol). Workup in the usual manner followed by
chromatography (cyclohexane/ethyl acetate 80:20) afforded 5c
(0.218 g, 39%) as a yellow solid: mp 114-116 °C. 1H NMR (200
MHz, CDCl3) δ ppm: 4.06 (s, 3H), 7.21 (t, 1H, J ) 8.0 Hz), 7.62
(dd, 1H, J ) 8.0 Hz, J ) 1.6 Hz), 7.99 (dd, 1H, J ) 8.0 Hz, J )
1.6 Hz). 13C NMR (100 MHz, CDCl3) δ ppm: 62.5, 124.6, 125.3,
129.0, 131.2, 135.7, 155.9, 167.6. IR (neat): 2826, 2558, 1667,
1586, 1463, 1234, 1076, 917 cm-1. HRMS (EI) m/z calcd. for
C8H7O3Cl (M+•): 186.0083. Found: 186.0079.
the aqueous phase was washed with diethyl ether (20 mL), acidified
with aqueous (2 M) HCl, and extracted with diethyl ether. The
organic layer was dried over MgSO4, filtered, and concentrated in
Vacuo to give the crude benzoic acids which were chromatographed
on silica gel or recrystallized.
3-Methoxy-2-methylbenzoic Acid (6a). See general procedure.
The solution was quenched with iodomethane (1.9 mL, 30 mmol).
After being stirred for 30 min at 0 °C, the reaction mixture was
heated for 2 h at 40 °C. Standard workup followed by chromatog-
raphy (cyclohexane/ethyl acetate 80:20, Rf ) 0.29) afforded 6a (0.25
g, 50%) as a white solid (mp 145-146 °C, lit.34 146.5-149.0 °C).
1H NMR (400 MHz, CDCl3) δ: 2.52 (s, 3H), 3.87 (s, 3H), 7.04
(d, 1H, J ) 8.4 Hz), 7.20-7.26 (dd, 1H, J ) 8.4 Hz and J ) 7.8
Hz), 7.61 (d, 1H, J ) 7.8 Hz). 13C NMR (50 MHz, CDCl3) δ:
13.3, 56.3, 114.7, 123.3, 126.5, 130.2, 130.6, 158.5, 174.3. IR
(neat): 2646, 1682, 1583 cm-1. Anal. calcd. for C9H10O3: C, 65.05;
H, 6.07. Found: C, 65.01; H, 6.01.
3-Methoxy-2-(trimethylsilyl)benzoic Acid (6b) (in situ quench
technique). To a solution of LTMP (9 mmol) in THF (20 mL) at
-78 °C were added successively TMSCl (1.38 mL, 10.5 mmol) in
THF (5 mL) and m-anisic acid (2) (0.46 g, 3 mmol) in THF (5
mL). After being warmed gradually to 0 °C for 2 h, the solution
was allowed to warm to ambient temperature. Aqueous (2 M) NaOH
was added until the pH reached 10. The aqueous layer was washed
with diethyl ether, acidified with aqueous (4 M) HCl, and extracted
with diethyl ether. The organic layer was dried over MgSO4, filtered,
and concentrated in Vacuo. The residue was purified by colum
chromatography on silica gel (cyclohexane/ethyl acetate 90:10, Rf
) 0.31) to give 6b (0.51 g, 75%) as a white solid (mp 91-92 °C).
1H NMR (400 MHz, CDCl3) δ: 0.33 (s, 9H), 3.82 (s, 3H), 7.01
(d, 1H, J ) 7.8 Hz), 7.35-7.64 (m, 2H). 13C NMR (50 MHz,
CDCl3) δ: 0.6, 54.1, 112.1, 120.1, 126.9, 129.0, 137.9, 163.7, 175.1.
IR (neat): 2959, 2560, 1673 cm-1. Anal. calcd. for C11H16O3Si:
C, 58.89; H, 7.19. Found: C, 58.91; H, 7.17.
3-Bromo-2-methoxybenzoic Acid (5d). According to the general
procedure, the recrystallized o-anisic acid (1, 0.46 g, 3 mmol) in
THF was added dropwise to a stirred solution of n-BuLi/t-BuOK
(1:1, 12 mmol). The solution was quenched by dibromotetrachlo-
roethane (5.86 g, 18 mmol) (reverse addition). Workup in the usual
manner followed by chromatography (cyclohexane/ethyl acetate 80:
20) afforded 5d (0.235 g, 34%) as a white solid: mp 119-121 °C
(lit.33 121 °C). 1H NMR (200 MHz, CDCl3) δ ppm: 4.07 (s, 3H),
7.22 (t, 1H, J ) 8.0 Hz), 7.63 (dd, 1H, J ) 8.0 Hz, J ) 1.5 Hz),
8.01 (dd, 1H, J ) 8.0 Hz, J ) 1.5 Hz). 13C NMR (100 MHz, CDCl3)
δ ppm: 61.6, 124.9, 125.1, 128.2, 129.5, 133.4, 154.5, 166.4. IR
(neat): 2952, 1669, 1588, 1465, 1222, 1077, 992 cm-1
.
3-Iodo-2-methoxybenzoic Acid (5e). According to the general
procedure, the recrystallized o-anisic acid (1, 0.46 g, 3 mmol) in
THF was added dropwise to a stirred solution of n-BuLi/t-BuOK
(1:1, 12 mmol). The solution was quenched by iodine (4.57 g, 18
mmol) (reverse addition). Workup in the usual manner followed
by chromatography (cyclohexane/ethyl acetate 80:20) afforded 5e
1
(0.225 g, 27%) as a white solid: mp 122-124 °C. H NMR (200
MHz, CDCl3) δ ppm: 3.99 (s, 3H), 7.01 (t, 1H, J ) 7.8 Hz), 8.00-
8.07 (m, 2H). 13C NMR (100 MHz, CDCl3) δ ppm: 62.8, 93.1,
123.9, 126.4, 132.3, 144.9, 159.6, 168.1. IR (neat): 2924, 1673,
1581, 1456, 1402, 1296, 1074, 992 cm-1
.
2-Methoxy-3-(methylthio)benzoic Acid (5f). According to the
general procedure, the recrystallized o-anisic acid (1, 0.46 g, 3
mmol) in THF was added dropwise to a stirred solution of n-BuLi/
t-BuOK (1:1, 12 mmol). The solution was quenched by dimethyl
disulfide (1.69 g, 18 mmol). Workup in the usual manner followed
by recrystallization (cyclohexane/ethyl acetate) afforded 5f (0.27
3-Methoxy-2,6-bis(trimethylsilyl)benzoic Acid (10). To a
stirred solution of LTMP (15 mmol) in THF (20 mL) at 0 °C were
added successively 2 (0.46 g, 3 mmol) in THF (5 mL) and
chlorotrimethylsilane (1.38 mL, 10.5 mmol). After being stirred
for 2 h at 0 °C, the solution was allowed to warm to ambient
temperature. Aqueous (2 M) NaOH was added up to pH 10, and
the aqueous layer was washed with diethyl ether, acidified with
aqueous (4M) HCl, and extracted with diethyl ether. The organic
layer was dried over MgSO4, filtered, and concentrated in Vacuo.
The crude acid 10 was purified by chromatography (cyclohexane/
ethyl acetate 90:10, Rf ) 0.29) to give a yellow solid (0.45 g, 51%)
1
g, 45%) as a white solid: mp 77-79 °C. H NMR (200 MHz,
CDCl3) δ ppm: 2.49 (s, 3H), 4.03 (s, 3H), 7.25 (t, 1H, J ) 7.8
Hz), 7.42 (dd, 1H, J ) 7.8 Hz, J ) 1.6 Hz), 7.89 (dd, 1H, J ) 7.8
Hz, J ) 1.6 Hz). 13C NMR (100 MHz, CDCl3) δ ppm: 14.8, 61.7,
124.5, 124.9, 128.3, 130.1, 134.2, 156.1, 168.5. HRMS (EI) m/z
calcd. for C9H10O3S (M+•): 198.0350. Found: 198.0339.
1
(mp 142-144 °C). H NMR (400 MHz, CDCl3) δ: 0.31 (s, 9H),
0.33 (s, 9H), 3.82 (s, 3H), 6.91 (d, 1H, J ) 8.4 Hz), 7.58 (d, 1H,
J ) 8.4 Hz). 13C NMR (100 MHz, CDCl3) δ: 0.5, 1.3, 55.2, 111.0,
126.1, 128.8, 137.7, 145.1, 165.3, 178.0. IR (neat): 2940, 1679
3-(Hydroxy(phenyl)methyl)-2-methoxybenzoic Acid (5g). Ac-
cording to the general procedure, the recrystallized o-anisic acid
(1, 0.46 g, 3 mmol) in THF was added dropwise to a stirred solution
of n-BuLi/t-BuOK (1:1, 12 mmol). The solution was quenched by
benzaldehyde (1.91 g, 18 mmol) (reverse addition). Workup in the
usual manner followed by chromatography (cyclohexane/ethyl
acetate 70:30) afforded 5g (0.318 g, 41%) as a white solid: mp
cm-1
.
2-Chloro-3-methoxybenzoic Acid (6c). See general procedure.
The solution was quenched with hexachloroethane (4.27 g, 18
mmol). After being stirred for 30 min at 0 °C, the mixture was
heated at 65 °C for 2 h. Standard workup followed by chromatog-
raphy (cyclohexane/ethyl acetate 80:20, Rf ) 0.13) gave 6c (0.263
1
124-126 °C. H NMR (200 MHz, CDCl3) δ ppm: 3.72 (s, 3H),
6.16 (s, 1H), 7.23-7.30 (m, 3H), 7.31-7.38 (m, 3H), 7.69 (dd,
1H, J ) 7.6 Hz, J ) 1.5 Hz), 7.98 (dd, 1H, J ) 7.8 Hz, J ) 1.5
Hz). 13C NMR (100 MHz, CDCl3) δ ppm: 63.1, 71.0, 124.4, 126.6,
127.7, 128.5, 132.2, 133.4, 138.3, 143.1, 158.0, 171.5. IR (neat):
1
g, 47%) as a white solid (mp 160-161 °C). H NMR (400 MHz,
CDCl3) δ: 3.95 (s, 3H), 7.13 (dd, 1H, J ) 8.4 Hz and J ) 1.5
Hz), 7.32 (dd, 1H, J ) 7.9 Hz and J ) 8.4 Hz), 7.56 (dd, 1H, J )
7.9 Hz and J ) 1.5 Hz). 13C NMR (50 MHz, DMSO-d6) δ: 56.4,
114.6, 119.3, 121.2, 127.7, 133.8, 150.0, 167.1. IR (neat): 2938,
1679, 1574 cm-1. HRMS (EI) m/z calcd. for C8H7O3Cl (M+•):
186.0083. Found: 186.0076.
3427, 2939, 1708, 1590, 1429, 1210, 992, 752 cm-1
.
General Procedure for the Preparation of 2-Substituted
3-Methoxybenzoic Acids (6a-f). Preparation of 3-Hydroxy-4-
methoxyisobenzofuran-1(3H)-one (13) and 4-Methoxy-3-phe-
nylisobenzofuran-1(3H)-one (14) (route C). To a stirred solution
of LTMP (5 equiv) in THF (20 mL) at 0 °C was added dropwise
m-anisic (2) (0.46 g, 3 mmol) in THF (5 mL). After being stirred
2 h at this temperature, the solution was quenched with the
electrophile (6-10 equiv). Stirring was maintained for 30 min, and
the solution was then allowed to warm to ambient temperature or
heated to 40-65 °C for 2 h. After hydrolysis with water (30 mL),
2-Bromo-3-methoxybenzoic Acid (6d). See general procedure.
The solution was quenched with dibromotetrachloroethane (5.87 g
18 mmol). After being stirred for 30 min at 0 °C, the solution was
heated at 65 °C for 2 h. Standard workup followed by chromatog-
raphy (cyclohexane/ethyl acetate 80:20, Rf ) 0.15) afforded 6d
(0.414 g, 60%) as a brown solid (mp 154-155 °C, lit.35 155-
1
156 °C). H NMR (400 MHz, CDCl3) δ: 3.98 (s, 3H), 7.07 (dd,
3426 J. Org. Chem., Vol. 72, No. 9, 2007

Methoxybenzoic Acids by Ortho Metalation
1H, J ) 7.8 Hz and J ) 1.5 Hz), 7.38 (t, 1H, J ) 7.8 Hz), 7.52
(dd, 1H, J ) 7.8 Hz and J ) 1.5 Hz). 13C NMR (50 MHz, DMSO-
d6) δ: 56.7, 109.1, 114.4, 121.4, 129.0, 137.0, 156.1, 168.3. IR
(neat): 2941, 1680, 1570 cm-1. Anal. calcd. for C8H7BrO3: C,
41.59; H, 3.05. Found: C, 41.56; H, 3.11. HRMS (EI) m/z calcd.
for C8H7O379Br (M+•): 229.9578. Found: 229.9577.
concentrated in Vacuo to give the crude benzoic acids (7a-f) which
were purified by chromatography or fractional crystallization.
3-Methoxy-4-methylbenzoic Acid (7a). See general procedure.
The solution was quenched with iodomethane (1.12 mL, 18 mmol).
Standard workup followed by fractional crystallization (cyclohex-
ane/ethyl acetate) led to 7a (0.294 g, 59%) as a white solid (mp
210-213 °C, lit.21b 212-214 °C). 1H NMR (200 MHz, CDCl3) δ:
2.27 (s, 3H), 3.89 (s, 3H), 7.18 (d, 1H, J ) 7.8 Hz), 7.58 (s, 1H),
7.74 (d, 1H, J ) 7.8 Hz). 13C NMR (100 MHz, DMSO-d6) δ: 16.5,
55.6, 110.7, 121.9, 130.0, 130.1, 130.7, 157.4, 167.6. IR (neat):
2960, 1673, 1609 cm-1. HRMS (EI) m/z calcd. for C9H10O3
(M+•): 166.0630. Found: 166.0631.
2-Iodo-3-methoxybenzoic Acid (6e). See general procedure. The
solution was quenched with iodine (4.57 g, 18 mmol). After being
stirred for 30 min at 0 °C, the mixture was heated at 65 °C for
2 h. Standard workup followed by chromatography (cyclohexane/
ethyl acetate 80:20) gave 6e (0.442 g, 53%) as a yellow solid (mp
1
145-146 °C, lit.36 148-149 °C). H NMR (400 MHz, CDCl3) δ:
4-Chloro-3-methoxybenzoic Acid (7b). See general procedure.
The solution was quenched with hexachloroethane (4.26 g, 18
mmol). Standard workup followed by fractional crystallization
(cyclohexane/ethyl acetate) led to 7b (0.217 g, 39%) as a brown
3.94 (s, 3H), 6.99 (dd, 1H, J ) 7.9 Hz and J ) 1.5 Hz), 7.38 (t,
1H, J ) 7.9 Hz), 7.49 (dd, 1H, J ) 7.9 Hz and J ) 1.5 Hz). 13C
NMR (50 MHz, CDCl3) δ: 56.9, 87.5, 114.1, 123.6, 129.3, 136.7,
158.9, 172.5. IR (neat): 2927, 1738, 1609 cm-1. HRMS (EI) m/z
calcd.for C8H7O3I (M+•): 277.9440. Found: 277.9445.
1
solid (mp 210-212 °C). H NMR (200 MHz, CDCl3) δ: 3.98 (s,
3H), 7.48 (d, 1H, J ) 7.8 Hz), 7.62 (s, 1H), 7.69 (dd, 1H, J ) 7.8
Hz and J ) 1.5 Hz). 13C NMR (50 MHz, DMSO-d6) δ: 56.1, 112.7,
122.3, 125.9, 129.9, 130.9, 154.4, 166.5. IR (neat): 2975, 1678
cm-1. HRMS (EI) m/z calcd. for C8H7ClO3 (M+•): 186.00837.
Found: 186.0079.
3-Methoxy-2-methylthiobenzoic Acid (6f). See general proce-
dure. The solution was quenched with dimethyl disulfide (1.6 mL,
18 mmol). Standard workup followed by chromatography (cyclo-
hexane/ethyl acetate 60:40, Rf ) 0.39) afforded 6f (0.273 g, 46%)
as a brown-red solid (mp 132-134 °C). 1H NMR (400 MHz,
CDCl3) δ: 2.44 (s, 3H), 3.96 (s, 3H), 7.09 (dd, 1H, J ) 8.4 Hz),
7.40 (dd, 1H, J ) 8.4 Hz and J ) 7.9 Hz), 7.65 (dd, 1H, J ) 7.9
Hz and J ) 1.0 Hz). 13C NMR (50 MHz, CDCl3) δ: 19.2, 56.7,
114.7, 122.9, 123.9, 129.8, 136.3, 160.5, 171.8. IR (neat): 2926,
1739, 1609 cm-1. Anal. calcd. for C9H10O3S: C, 54.53; H, 5.08.
Found: C, 54.28; H, 5.13.
4-Bromo-3-methoxybenzoic Acid (7c). See general procedure.
The solution was quenched with dibromotetrachloroethane
(5.87 g, 18 mmol,). Standard workup followed by fractional
crystallization (cyclohexane/ethyl acetate) afforded 7c (0.312 g,
1
45%) as a white solid (mp 212-213 °C). H NMR (400 MHz,
CDCl3) δ: 3.99 (s, 3H), 7.64 (s, 1H), 7.67-7.68 (m, 2H). 13C NMR
(100 MHz, DMSO-d6) δ: 56.1, 112.5, 116.0, 122.3, 130.9, 132.1,
3-Hydroxy-4-methoxyisobenzofuran-1(3H)-one (13). See gen-
eral procedure. The solution was quenched with N,N-dimethylfor-
mamide (1.4 mL, 18 mmol). Usual workup followed by chroma-
tography (cyclohexane/ethyl acetate 60:40, Rf ) 0.24) afforded 13
(0.146 g, 27%) as a white solid (mp 154-155 °C, lit.37 156-
155.4, 166.6. IR (neat): 2970, 1679 cm-1
.
4-Iodo-3-methoxybenzoic Acid (7d). See general procedure. The
solution was quenched with iodine (4.57 g, 18 mmol). Standard
workup followed by fractional crystallization (cyclohexane/ethyl
acetate) afforded 7d (0.167 g, 20%) as a white solid (mp 210-
1
157 °C). H NMR (400 MHz, CDCl3) δ: 3,96 (s, 3H), 6.70 (s,
1
212 °C). H NMR (400 MHz, CDCl3) δ: 4.04 (s, 3H), 7.45 (dd,
1H), 7.17 (d, 1H, J ) 7.9 Hz), 7.47 (d, 1H, J ) 6.9 Hz), 7.57 (dd,
1H, J ) 7.9 Hz, J ) 6.9 Hz). 13C NMR (50 MHz, DMSO-d6) δ:
56.2, 97.5, 116.4, 117.3, 128.7, 133.0, 134.5, 155.5, 168,8.
1H, J ) 8.4 Hz and J ) 1.5 Hz), 7.57 (d, 1H, J ) 1.5 Hz), 8.06
(d, 1H, J ) 8.4 Hz). 13C NMR (50 MHz, DMSO-d6) δ: 56.4, 92.6,
111.2, 123.2, 132.5, 139.3, 157.9, 166.8. IR (neat): 2960, 1673,
4-Methoxy-3-phenylisobenzofuran-1(3H)-one (14). See general
procedure. The solution was quenched with benzaldehyde
(1.84 mL, 18 mmol). Standard workup followed by chromatography
(cyclohexane/ethyl acetate 60:40, Rf ) 0.59) afforded 14 (0.468 g,
1608 cm-1
.
3-Methoxy-4-thiomethylbenzoic Acid (7e). See general pro-
cedure. The solution was quenched with dimethyldisulfide (18
mmol, 1.6 mL). Standard workup followed by fractional crystal-
lization (cyclohexane/ethyl acetate) afforded 7e (0.303 g, 51%) as
a yellow solid (mp 186-187 °C). 1H NMR (400 MHz, CDCl3) δ:
2.48 (s, 3H), 3.97 (s, 3H), 7.16 (d, 1H, J ) 8.4 Hz), 7.51 (d, 1H,
J ) 1.5 Hz), 7.75 (dd, 1H, J ) 8.4 Hz and J ) 1.5 Hz). 13C NMR
(50 MHz, CDCl3) δ: 19.2, 56.7, 114.7, 122.9, 123.9, 129.8, 136.3,
160.5, 171.8. IR (neat): 2970, 1674, 1592 cm-1. HRMS (EI) m/z
calcd. for C9H10O3S (M+•): 198.0351. Found: 198.0361.
1
65%) as a white solid (mp 147-148 °C). H NMR (400 MHz,
CDCl3) δ: 3.74 (s, 3H), 6.40 (s, 1H), 7.08 (dd, 1H, J ) 7.5 Hz
and J ) 1.5 Hz), 7.25-7.28 (m, 1H), 7.33-7.35 (m, 1H), 7.5-
7.56 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 55.6, 81.7, 115.6,
117.1, 127.1, 128.8, 129.0, 131.4, 135.7, 137.2, 154.6, 170.5. IR
(neat): 2926, 1739, 1609 cm-1. Anal. calcd. for C15H12O3: C,
74.99; H, 5.03. Found: C, 74.56; H, 5.05.
2-Hydroxy-3-methoxybenzoic Acid (6i). See general procedure.
O2 was bubbled through the rapidly stirring solution.56 Standard
workup followed by chromatography (cyclohexane/ethyl acetate 80:
20) afforded 6i (0.272 g, 54%) as a white solid (mp 150-152 °C,
4-(Hydroxy(phenyl)methyl)-3-methoxybenzoic Acid (7f). See
general procedure. The solution was quenched with benzaldehyde
(18 mmol, 1.84 mL). Standard workup followed by chromatography
(cyclohexane/ethyl acetate 60:40, Rf ) 0.28) gave 7f (0.389 g, 54%)
as a yellow solid (mp 122-124 °C). 1H NMR (400 MHz, CDCl3)
δ: 3.87 (s, 3H), 6.11 (s, 1H), 7.27-7.42 (m, 5H), 7.47 (d, 1H, J )
7.8 Hz). 7.58 (d, 1H, J ) 1.6 Hz), 7.75 (dd, 1H, J ) 7.8 Hz and
J ) 1.6 Hz). 13C NMR (100 MHz, DMSO-d6) δ: 26.3, 55.5, 67.9,
110.9, 121.9, 126.4, 126.7, 128.0, 130.3, 138.6, 144.6, 155.3, 167.1.
1
lit.38 151 °C). H NMR (400 MHz, CDCl3) δ: 3.93 (s, 3H), 6.89
(d, 1H, J ) 7.9 Hz), 7.11 (d, 1H, J ) 7.9 Hz), 7.54 (t, 1H, J ) 7.9
Hz). 13C NMR (50 MHz, CDCl3) δ: 56.3, 111.8, 117.5, 118.9,
122.0, 148.5, 152.5, 174.5. IR (neat): 3018, 2866, 1618, 1455, 1254
cm-1
.
IR (neat): 3342, 2927, 1677 cm-1
.
General Procedure for the Preparation of 4-Substituted
3-Methoxybenzoic Acids (7a-f) (route C). m-Anisic acid
(2, 0.46 g, 3 mmol) in THF (5 mL) was added dropwise to a stirred
solution of n-BuLi/t-BuOK (1:1, 12 equiv) in THF (30 mL) at
-78 °C. After being stirred for 2 h (-78 °C f -50 °C), the
reaction mixture was quenched with the electrophile (18 mmol).
Stirring was maintained for 30 min at -50 °C, and the resulting
mixture was allowed to warm to rt and hydrolyzed with water
(30 mL). The aqueous layer was washed with diethyl ether (20
mL), acidified with aqueous (2 M) HCl, and extracted with diethyl
ether. The organic layer was dried over MgSO4, filtered, and
General Procedure for the Preparation of 6-Substitued
3-Methoxybenzoic Acids (8a-e) (route E). To a stirred solution
of s-BuLi/TMEDA (4 mmol) in dry THF (5 mL) at -78 °C was
added dropwise 3-methoxy-2-(trimethylsilyl)benzoic acid (6b)
(0.224 g, 1 mmol) in dry THF (5 mL). After being stirred for 2 h
(-78 °C f -30 °C), the reaction mixture was quenched with the
electrophile (6 mmol). Stirring was maintained for 30 min at
-30 °C, and the resulting mixture was allowed to warm to rt and
hydrolyzed with water (20 mL). The aqueous layer was washed
with diethyl ether (2 × 20 mL), acidified with aqueous (2 M) HCl
J. Org. Chem, Vol. 72, No. 9, 2007 3427

Nguyen et al.
until the pH reached 2, and extracted with diethyl ether. The organic
layer was dried over MgSO4, filtered, and concentrated in Vacuo.
The residue was hydrolyzed with aqueous (6 M) HCl to pH 1 to
give the crude 6-substitued 3-methoxybenzoic acids (8a-e) which
were purified by column chromatography or recrystallization.
6-Methyl-3-methoxybenzoic Acid (8a). See general procedure.
After purification by recrystallization (n-heptane/ethyl acetate), the
acid 8a was obtained as a white solid (0.090 g, 54%) (mp 151-
152 °C, lit.39 151-151.5 °C). 1H NMR (200 MHz, CDCl3) δ: 2.59
(s, 3H), 3.83 (s, 3H), 7.02 (dd, 1H, J ) 8.4 Hz and J ) 2.9 Hz),
7.16 (d, 1H, J ) 8.4 Hz), 7.58 (d, 1H, J ) 2.9 Hz). 13C NMR (50
MHz, CDCl3) δ: 20.6, 55.6, 115.2, 117.9, 121.9, 131.0, 132.7,
157.4, 168.9. HRMS (EI) m/z calcd. for C9H10O3 (M+•): 166.0630.
Found: 166.0628.
3H), 3.80 (s, 3H), 6.82 (d, 1H, J ) 8.4 Hz), 6.84 (s, 1H), 7.84 (d,
1H, J ) 8.4 Hz). 13C NMR (100 MHz, DMSO-d6) δ ppm: 22.8,
56.3, 112.2, 118.1, 123.0, 134.5, 144.3, 163.8, 168.9. IR (neat):
2927, 1661, 1566, 1450, 1285, 1158 cm-1
.
4-Methoxy-2-trimethylsilylbenzoic Acid (9b). To a solution of
LTMP (9 mmol) in THF (20 mL) at -78 °C were added
successively TMSCl (1.38 mL, 10.5 mmol) in THF (5 mL) and
p-anisic acid (3) (0.46 g, 3 mmol) in THF (3 mL). After being
warmed gradually to rt for 4 h, the solution was allowed to warm
to rt. Aqueous 2 M NaOH was added until the pH reached 10. The
aqueous layer was washed with diethyl ether, acidified with aqueous
4M HCl, and extracted with diethyl ether. The organic layer was
dried over MgSO4, filtered, and concentrated in Vacuo. The residue
was purified by colum chromatography on silica gel (cyclohexane/
diethyl ether 90:10) to give 9b (0.54 g, 80%) as a white solid: mp
134-136.5 °C. 1H NMR (400 MHz, CDCl3) δ ppm: 0.35 (s, 9H),
3.89 (s, 3H), 6.92 (dd, 1H, J ) 8.6 Hz and J ) 2.6 Hz), 7.23 (d,
1H, J ) 2.6 Hz), 8.19 (d, J ) 8.6 Hz). 13C NMR (100 MHz, CDCl3)
δ ppm: 0.54, 54.9, 112.4, 121.8, 125.9, 133.3, 146.3, 162.4, 172.8.
IR (neat): 2945, 1676, 1584, 1416, 1316, 1235. cm-1. HRMS (EI)
m/z calcd. for C11H16O3Si (M+•): 224.0869. Found: 224.0880.
2-Chloro-4-methoxybenzoic Acid (9c). According to the general
procedure, the recrystallized p-anisic acid (3, 0.76 g, 5 mmol) in
THF was added dropwise to a stirred solution of s-BuLi/TMEDA
(11 mmol). The solution was quenched by hexachloroethane
(4.73 g, 20 mmol). Workup in the usual manner followed by
recrystallization (heptane/ethyl acetate) afforded 9c (0.70 g, 75%)
as a white solid: mp 111.5-112.5 °C. 1H NMR (400 MHz, DMSO-
d6) δ ppm: 3.86 (s, 3H), 6.97 (dd, 1H, J ) 8.8 Hz and J ) 2.5
Hz), 7.09 (d, 1H, J ) 2.5 Hz, 1H), 7.83 (d, 1H, J ) 8.8 Hz). 13C
NMR (100 MHz, DMSO-d6) δ ppm: 56.3, 113.5, 116.5, 122.7,
133.5, 134.5, 162.4, 166.3. IR (neat): 2945, 1661, 1595, 1406, 1272,
1026 cm-1. Anal. calcd. for C8H7ClO3: C, 51.50; H, 3.78. Found:
C, 51.56; H, 3.81
2-Bromo-4-methoxybenzoic Acid (9d) and 3-Bromo-4-meth-
oxybenzoic Acid (20). According to the general procedure, the
recrystallized p-anisic acid (3, 0.76 g, 5 mmol) in THF was added
dropwise to a stirred solution of s-BuLi/TMEDA (11 mmol). The
solution was quenched by dibromotetrachloroethane (6.51 g, 20
mmol). Workup in the usual manner followed by recrystallization
(heptane/ethyl acetate) led to a mixture of 2-bromo-4-methoxy-
benzoic acid (9d) and 3-bromo-4-methoxybenzoic acid (20) (54%)
that could not be separated by chromatography (9d:20 48/52). 9d:
1H NMR (200 MHz, CDCl3) δ ppm: 3.97 (s, 3H), 7.08 (dd, 1H, J
) 8.8 Hz and J ) 2.5 Hz), 7.20 (d, 1H, J ) 8.8 Hz), 7.36 (d, 1H,
J ) 2.5 Hz, 1H). 20:42,58 1H NMR (200 MHz, CDCl3) δ ppm: 3.97
(s, 3H), 7.00 (dd, 1H, J ) 8.9 Hz and J ) 2.5 Hz), 7.92 (d, 1H, J
) 8.8 Hz), 7.94 (d, 1H, J ) 2.5 Hz, 1H).
6-Chloro-3-methoxybenzoic Acid (8b). See general procedure.
After recrystallization (cyclohexane/ethyl acetate), the acid 8b was
obtained as a colorless solid (0.102 g, 55%) (mp 168-169.5 °C,
1
lit.40 169-171 °C). H NMR (200 MHz, CDCl3) δ: 3.85 (s, 3H),
7.02 (dd, 1H, J ) 8.8 Hz and J ) 3.1 Hz), 7.38 (d, 1H, J ) 8.8
Hz), 7.52 (d, 1H, J ) 3.1 Hz). 13C NMR (50 MHz, CDCl3) δ:
55.6, 115.5, 118.3, 122.6, 131.4, 132.2, 157.7, 166.5. IR (neat):
2945, 1672 cm-1. HRMS (EI) m/z calcd. for C8H7O3Cl (M+•):
186.0084. Found: 186.0094.
6-Bromo-3-methoxybenzoic Acid (8c). See general procedure.
After chromatography (cyclohexane/ethyl acetate 80:20, Rf ) 0.15),
the acid 8c was obtained as a colorless solid (0.145 g, 63%) (mp
1
158-160 °C, lit.41 160 °C). H NMR (200 MHz, CDCl3) δ: 3.83
(s, 3H), 6.95 (dd, 1H, J ) 8.8 Hz and J ) 3.1 Hz), 7.54 (d, 1H, J
) 3.1 Hz), 7.59 (d, 1H, J ) 8.8 Hz). 13C NMR (50 MHz, CDCl3)
δ: 55.7, 112.9, 117.1, 120.6, 130.9, 135.6, 158.6, 170.9.
6-Iodo-3-methoxybenzoic Acid (8d). See general procedure.
After chromatography (cyclohexane/ethyl acetate 80:20, Rf ) 0.16),
the acid 8d was obtained as a white solid (0.139 g, 50%) (mp
132.5-134 °C). 1H NMR (200 MHz, CDCl3) δ: 3.84 (s, 3H), 6.81
(dd, 1H, J ) 8.8 Hz and J ) 3.1 Hz), 7.57 (d, 1H, J ) 3.1 Hz),
7.89 (d, 1H, J ) 8.8 Hz). 13C NMR (50 MHz, CDCl3) δ: 55.6,
83.1, 117.2, 120.5, 133.9, 142.5, 159.5, 171.1. IR (neat): 2934,
2559, 1690 cm-1. Anal. calcd. for C8H7IO3: C, 34.56; H, 2.54.
Found: C, 34.37; H, 2.71.
3-Methoxy-6-thiomethylbenzoic Acid (8e). See general pro-
cedure. After recrystallization (n-heptane/ethyl acetate), the acid
8e was obtained was a brown solid (0.121 g, 61%) (mp 144-
1
146 °C). H NMR (200 MHz, CDCl3) δ: 2.48 (s, 3H), 3.89 (s,
3H), 7.09 (dd, 1H, J ) 8.8 Hz and J ) 2.8 Hz), 7.23 (d, 1H, J )
8.8 Hz), 7.65 (d, 1H, J ) 2.8 Hz). 13C NMR (50 MHz, CDCl3) δ:
16.8, 56.0, 116.9, 121.1, 127.3, 127.5, 134.9, 156.9, 171.1. IR
(neat): 2970, 2567, 1673 cm-1. HRMS (EI) m/z calcd. for C9H10O3S
(M+•): 198.0351. Found: 198.0358.
General Procedure for the Preparation of 2-Substituted
4-Methoxybenzoic Acids (9a-f). Preparation of 3-Hydroxy-5-
methoxyisobenzofuran-1(3H)-one (15) and 5-Methoxy-3-phe-
nylisobenzofuran-1(3H)-one (16) (route F). To a stirred solution
of a 1:1 s-BuLi/TMEDA complex (11 mmol) in anhydrous THF at
-78 °C was added dropwise under argon the recrystallized p-anisic
acid (3) (0.76 g, 5 mmol) dissolved in dry THF (5 mL). After 2 h
at this temperature, the mixture was treated with an excess of the
appropriate electrophile (20 mmol) dissolved in THF. The resulting
solution was then slowly allowed to warm to ambient temperature,
and water was added. The aqueous layer was washed with diethyl
ether (2 × 30 mL), shaken, and acidified with 2 M HCl. The
mixture was then diluted with diethyl ether, and the organic layer
was separated and dried with MgSO4.
2-Iodo-4-methoxybenzoic Acid (9e). According to the general
procedure, the recrystallized p-anisic acid (3, 0.76 g, 5 mmol) in
THF was added dropwise to a stirred solution of s-BuLi/TMEDA
(11 mmol). The solution was quenched by iodine (5.07 g, 20 mmol).
Workup in the usual manner followed by recrystallization (chlo-
roform) afforded 9e (0.98 g, 71%) as a brown solid: mp 174-
176 °C. 1H NMR (400 MHz, DMSO-d6) δ ppm: 3.83 (s, 3H), 7.06
(dd, 1H, J ) 8.6 Hz and J ) 2.5 Hz), 7.52 (d, 1H, J ) 2.5 Hz),
7.81 (d, 1H, J ) 8.6 Hz). 13C NMR (100 MHz, DMSO-d6) δ ppm:
55.7, 96.0, 113.7, 127.2, 131.3, 132.1, 161.4, 166.9. IR (neat): 2974,
2646, 1681, 1556, 1406, 1286 cm-1. Anal. calcd. for C8H7IO3: C,
34.56; H, 2.53. Found: C, 34.89; H, 2.51.
4-Methoxy-2-(methylthio)benzoic Acid (9f). According to the
general procedure, the recrystallized p-anisic acid (3, 0.76 g, 5
mmol) in THF was added dropwise to a stirred solution of s-BuLi/
TMEDA (11 mmol). The solution was quenched by dimethyl
disulfide (1.88 g, 20 mmol). Workup in the usual manner followed
by recrystallization (chloroform) afforded 9f (0.76 g, 76%) as a
4-Methoxy-2-methylbenzoic Acid (9a). According to the general
procedure, the recrystallized p-anisic acid (3, 0.76 g, 5 mmol) in
THF was added dropwise to a stirred solution of s-BuLi/TMEDA
(11 mmol). The solution was quenched by MeI (2.84 g, 20 mmol).
Workup followed by recrystallization (heptane/ethyl acetate) af-
forded 9a (0.61 g, 73%) as a white solid: mp 177-178.5 °C (lit.42
1
176-178 °C). H NMR (400 MHz, DMSO-d6) δ ppm: 2.52 (s,
(58) Koo, S.; Ki, E.-h.; Lee, K.-j. Synth. Commun. 2002, 32, 2275.
3428 J. Org. Chem., Vol. 72, No. 9, 2007

Methoxybenzoic Acids by Ortho Metalation
white solid: mp 118-120 °C.59 1H NMR (400 MHz, CDCl3) δ
ppm: 2.38 (s, 3H), 3.85 (s, 3H), 7.76 (m, 2H), 7.90 (d, 1H, J )
9.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ ppm: 14.7, 55.4,
108.6, 109.8, 119.3, 133.3, 145.3, 162.3, 166.8. IR (neat): 3020,
5-Methoxy-3-phenylisobenzofuran-1(3H)-one (16). According
to the general procedure, the recrystallized p-anisic acid (3, 0.76
g, 5 mmol) in THF was added dropwise to a stirred solution of
s-BuLi/TMEDA (11 mmol). The solution was quenched by
benzaldehyde (2.12 g, 20 mmol). Workup in the usual manner
followed by recrystallization (chloroform) afforded 16 (0.830 g,
2565, 1672, 1550, 1483, 1283 cm-1
.
3-Hydroxy-5-methoxyisobenzofuran-1(3H)-one (15). Accord-
ing to the general procedure, the recrystallized p-anisic acid (3,
0.76 g, 5 mmol) in THF was added dropwise to a stirred solution
of s-BuLi/TMEDA (11 mmol). The solution was quenched by DMF
(1.46 g, 20 mmol) (reverse addition). Workup in the usual manner
followed by recrystallization (chloroform) afforded 15 (0.58 g, 64%)
as a white solid: mp 134-136 °C. 1H NMR (200 MHz, CDCl3) δ
ppm: 3.98 (s, 3H), 6.54 (s, 1H), 7.16 (m, 1H), 7.72 (d, 1H, J )
9.2 Hz), 8.12 (d, 1H, J ) 8.0 Hz). 13C NMR (100 MHz, CDCl3) δ
ppm: 55.4, 97.3, 107.6, 117.7, 118.6, 126.1, 150.3, 164.5, 168.0.
IR (neat): 3270, 1727, 1621, 1491, 1294 cm-1. Anal. calcd. for
C9H8O4: C, 60.00; H, 4.48. Found: C, 59.82; H, 4.38.
1
69%) as a white solid: mp 124-126 °C. H NMR (200 MHz,
CDCl3) δ ppm: 3.83 (s, 3H), 6.61 (s, 1H), 6.71 (d, 1H, J ) 1.5
Hz), 7.04 (dd, 1H, J ) 8.9 and J ) 2.5 Hz), 7.25-7.30 (m, 2H),
7.37-7.41 (m, 3H), 7.86 (d, 1H, J ) 8.5 Hz). 13C NMR (100 MHz,
CDCl3) δ ppm: 55.8, 82.5, 106.7, 116.8, 127.1, 129.4, 136.7, 153.0,
165.4, 170.6. IR (neat): 2943, 1749, 1599, 1487, 1293, 1248. cm-1
.
Anal. calcd. for C15H12O3: C, 74.99; H, 5.03. Found: C, 74.66;
H, 5.03.
Acknowledgment. This research was supported by the
CNRS, Universite´ du Maine and Institut universitaire de France.
THN and NTTC are indebted to the French Ministery of
Research and Technologies and the Agence Universitaire de la
Francophonie for doctoral fellowships.
(59) CAS number: 72856-74-7. Robertson, D. W.; Beedle, E. E.;
Krushinski, J. H.; Don Pollock, G.; Wilson, H.; Wyss, V. L.; Hayes, J. S.
J. Med. Chem. 1985, 28, 717. The melting point is not reported.
JO070082A
J. Org. Chem, Vol. 72, No. 9, 2007 3429