Synthesis of N-aryl and N-alkyl anthranilic acids via SNAr reaction of unprotected 2-fluoro- and 2-methoxybenzoic acids by lithioamides

Article abstract of DOI:10.1021/ol1007586

Substitution of the fluoro or methoxy group in unprotected 2-fluoro- and 2-methoxybenzoic acids to afford N-aryl and N-alkyl anthranilic acids occurs upon reaction with lithioamides under mild conditions in the absence of a metal catalyst.

Full text of DOI:10.1021/ol1007586

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2406-2409
Synthesis of N-Aryl and N-Alkyl
Anthranilic Acids via SNAr Reaction of
Unprotected 2-Fluoro- and
2-Methoxybenzoic Acids by Lithioamides
Mickae¨l Belaud-Rotureau,† Tin Thanh Le,†,‡ Thi Huong Thu Phan,†,‡
Thi Huu Nguyen,† Regadia Aissaoui,†,§ Fre´de´ric Gohier,† A¨ıcha Derdour,§
Arnaud Nourry,† Anne-Sophie Castanet,† Kim Phi Phung Nguyen,‡ and
Jacques Mortier*,†
UniVersite´ du Maine and CNRS, Unite´ de Chimie Organique Mole´culaire and
Macromole´culaire (UMR 6011), Faculte´ des Sciences, aVenue OliVier Messiaen,
´
72085 Le Mans Cedex 9, France, UniVersite´ Nationale de Ho-Chi-Minh-Ville, Ecole
des Sciences Naturelles, Laboratoire de Chimie Organique, 283/2 Nguyen Van Cu.
arrondissement 5, Ho Chi Minh Ville, Viet Nam, and UniVersite´ d’Oran Es-Senia,
Laboratoire de Synthe`se Organique Applique´e, Faculte´ des Sciences, BP 1524
Es-Senia, Oran 31000, Algeria
jacques.mortier@uniV-lemans.fr
Received April 1, 2010
ABSTRACT
Substitution of the fluoro or methoxy group in unprotected 2-fluoro- and 2-methoxybenzoic acids to afford N-aryl and N-alkyl anthranilic acids
occurs upon reaction with lithioamides under mild conditions in the absence of a metal catalyst.
N-Aryl and N-alkyl anthranilic acids are very important
synthetic intermediates which have been marketed as anti-
inflammatory agents for the treatment of dysmenorrhea and
rheumatic pain and as candidates for the therapy of neuro-
degenerative and amyloid diseases.1 N-Aryl anthranilic acids
are also synthetic precursors of acridines, which have been
utilized as antimalarial and anticancer drugs.2 Traditionally,
these compounds have been prepared by the copper-mediated
coupling of amines with halobenzoic acids (the Ullmann
reaction).3 The success of this reaction often requires strongly
activated aryl halides and forcing reaction conditions. An-
thranilic acids have also been prepared by Buchwald-Hartwig
amination with alkyl 2-halobenzoates in the presence of base
and palladium catalyst and subsequent ester cleavage.4
Due to potentially toxic contamination of pharmaceutical
products, effective removal of Pd or Cu in active pharma-
ceutical ingredients (API) poses acute problems inasmuch
as the limits set by health authorities are very low. Guidelines
from the European Medicines Agency have set the permitted
† Universite´ du Maine and CNRS.
‡ Universite´ Nationale de Ho-Chi-Minh-Ville.
§ Universite´ d’Oran Es-Senia.
(1) (a) Green, N. S.; Palaninathan, S. K.; Sacchettini, J. C.; Kelly, J. W.
J. Am. Chem. Soc. 2003, 125, 13404–13414. (b) Oza, V. B.; Smith, C.;
Raman, B.; Koepf, E. K.; Lashuel, H. A.; Petrassi, H. M.; Chiang, K. P.;
Powers, E. T.; Sachettinni, J.; Kelly, J. W. J. Med. Chem. 2002, 45, 321–
332.
(2) (a) Sebolt-Leopold, J. S.; Dudley, D. T.; Herrera, R.; Van Becelaere,
K.; Wiland, A.; Gowen, R. C.; Tecle, H.; Barrett, S. D.; Bridges, A.;
Przybranowski, S.; Leopold, W. R.; Saltiel, A. R. Nat. Med. (N. Y., NY,
U. S.) 1999, 5, 810–816. (b) Barrett, S. D.; Kaufman, M. D.; Milbank,
J. B.; Rewcastle, G. W.; Spicer, J. A.; Tecle, H. WO03062191, 2003.
(3) Wolf, C.; Liu, S.; Mei, X.; August, A. T.; Casimir, M. D. J. Org.
Chem. 2006, 71, 3270–3273.
(4) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534–1544.
10.1021/ol1007586  2010 American Chemical Society
Published on Web 04/29/2010

daily exposure of patients to palladium, 100 µg·day-1 for
oral doses and 10 µg·day-1 for parenterally administered
drugs.5 On the basis of these guidelines, the pharmaceutical
industry generally needs to achieve less than 10 and 1 ppm,
for oral and parentral drug substances, respectively. For large
scale synthesis, it is best to avoid the use of Pd during the
last three steps and place Pd-coupling reactions early in the
process in hopes of reducing the amount of metal throughout
the synthesis. On a practical level, when a synthetic scheme
requires the use of a metal such as Pd at the end of a synthesis
and the standards of metal content permitted in the API are
exceeded, it is necessary to find empirically a disposal
method such as nanofiltration or use scavenging agents,
which is costly in time and money.6
The amino substituent was directly introduced in place of
the ortho-fluoro/methoxy group in fair-to-excellent yields
(Table 1).
LiNEt2, LiN(CH2CH2)2NMe, LiNMeBn, and LiNBn2
readily displaced the fluorine of the lithium salt of 2-fluo-
robenzoic acid (1) at -50 °C to give anthranilic acids 3-6
(entries 1-4). Lithium arylamides and diarylamides entered
into the displacement reaction with benzoate 1 under
somewhat forcing conditions (50-60 °C, entries 5 and 6).
This may be attributed to lower pKa values in comparison
to dialkylamines.14 Most striking are those examples using
so-called “nonnucleophilic” bases such as LDA and LiNHt-
Bu, indicating that there are virtually no steric effects to
inhibit fluoro displacement (entries 7 and 9). LDA which is
commonly used as a strong base of scarce nucleophilicity
due to steric congestion reacted with lithium benzoate 1 to
afford the aminated product 9 in appreciable amount.15 In
an attempt to introduce an ortho-NH2 unit, 1 was treated
with a THF solution of LiNH2 (3.5 equiv) (entry 8).
However, the amidation product 11 was the only isolable
product from this reaction. LiNHt-Bu also led to 11 by rapid
degradation of 12 during acidic workup.
In view of the efficiency of lithioamides in this reaction
and the unlikelihood of their ability to proceed by electron
transfer (ET) mechanisms, this reaction presumably proceeds
through an addition-elimination sequence.16,17
The closely related lithium 2,2,6,6-tetramethylpiperidide
(LTMP) exhibited a totally different behavior when exposed
to 1 (entry 10 and Scheme 1). LTMP metalated the position
adjacent to fluorine affording dianion 14 which partly
Conventional wisdom indicates that the nucleophilic
aromatic substitution (SNAr) reaction of benzoic acids
requires steps of protection and deprotection of the carbonyl
which acts as an essential carbon anchor group for subsequent
chemical transformations. Although there have been numbers
of reports using aryloxazolines7 and 2,6-dialkylphenyl aryl-
carboxylates8 to dictate the SNAr reaction course, these
methods have suffered from several limitations, the most
severe being most certainly the difficulty of removal of the
protecting carbonyl group. 2,6-Disubstituted benzamides and
benzoates are especially inert to hydrolysis except in cases
where anchimeric assistance by ortho-introduced electro-
philes is capable of forming five- or six-membered-ring
tetrahedral intermediates, which greatly enhances amide
hydrolytic rates.9,10 Therefore, there is still a need to explore
more efficient and concise methodologies.
While carrying out earlier work involving the coupling
reactions of alkyllithium with unprotected fluoro-substituted
benzoic acids,11 we became aware that surprisingly only very
few studies investigated the fluoro displacement reaction of
2-fluorobenzoic acid derivatives with lithioamides.12,13 Herein
we report that this process is general, affords anthranilic
acids, and does not require the use of a catalyst. It is also
shown that subjecting 2-methoxy benzoic acids to lithioa-
mides results in methoxide displacement.
(12) Two recent papers described LiHMDS-promoted coupling of
primary and N-substituted anilines with 2-fluorobenzoic acid (or amide) to
give N-arylanthranilic acids and N-arylanthranilamides: (a) Chen, M. H.;
Beylin, V. G.; Iakovleva, E.; Kesten, S. J.; Magano, J.; Vrieze, D. Synth.
Commun. 2002, 32, 411–417. (b) Davis, E. M.; Nanninga, T. N.; Tjiong,
H. I.; Winkle, D. D. Org. Process Res. DeV. 2005, 9, 843–846.
(13) Nucleophilic displacements of 2-fluorobenzoic acid derivatives are
well known to occur readily in the presence of strong electron-withdrawing
substituents (NO2, CF3, CN, Fx. .). See: Crampton, M. R. Organic Reaction
Mechanisms; A. C. Knipe, W. E. W., Ed.; John Wiley & Sons: UK, 2004;
p 189.
(14) Lithium arylamides have weaker nucleophilic strengths than lithium
dialkylamines but are more stable at higher temperature (50-60 °C).
(15) The synthesis of anthranilic acids using sterically hindered
amines via a three-component coupling with arynes and CO2 has been
reported: Yoshida, H.; Morishita, T.; Ohshita, J. Org. Lett. 2008, 10, 3845–
3847.
(5) Note for guidance on specification limits for residues of metal
catalysts, 2002. The European Agency for the Evaluation of Medicinal
Products Web site. http://www.emea.europa.eu/pdfs/human/swp/444600en.
pdf (accessed April 21, 2010).
(16) Smith, M. B.; March, J. AdVanced Organic Chemistry, 6th ed.;
Wiley- Interscience: New York, 2007; pp 853-864, and references cited
therein. Addition of radical scavengers (tetraphenylhydrazine or 2-methyl-
2-nitrosopropane dimer) to a mixture of 1 and LiNEt2 gave only a slight
decrease of yield of the substitution product 3.
(17) Ifitisassumedthatthesereactionsproceedviaanaddition-elimination
sequence, then the σ complex B allows the carboxylate to orientate itself
in a coplanar fashion with the aromatic ring while Li+ forms a strong
complex with the fluoro/methoxy group and the carboxylate. For the
complex-induced proximity effect, CIPE, see: Whisler, M. N.; MacNeil,
S.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004, 43, 2206–2225.
The transition state leading to B may be envisioned as forming from A,
where the NR1R2 group enters from the side almost perpendicular to the
aromatic ring (to the π cloud). This is consistent with the lack of steric
inhibition to addition by large groups.
(6) See, for instance: (a) Prasad, K.; Repic, O.; Blacklock, T. J. Org.
Process Res. DeV. 2003, 7, 733–742. (b) Pink, C. J.; Wong, H. t.; Ferreira,
F. C.; Livingston, A. G. Org. Process Res. DeV. 2008, 12, 589–595.
(7) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297–2360.
(8) Hattori, T.; Satoh, T.; Miyano, S. Synthesis 1996, 514–518.
(9) Snieckus, V. Chem. ReV. 1990, 90, 879–933
.
(10) Deprotection of 2-aminated aryloxazolines requires acidic conditions
(3 M HCl, 12-24 h, reflux) which are not compatible with delicate
structures. Yields do not exceed 70%, and in many instances the deprotection
only leads to degradation products. See: Meyers, A. I.; Gabel, R. J. Org.
Chem. 1977, 42, 2653–2654
.
(11) The reaction of 2-fluorobenzoic acid with s-BuLi and t-BuLi affords
the the ipso-attack product arising out of substitution of the fluorine atom
by the alkyl group: (a) Gohier, F.; Castanet, A.-S.; Mortier, J. Org. Lett.
2003, 5, 1919–1922. Metalation reactions, recent references: (b) Nguyen,
T. H.; Castanet, A.-S.; Mortier, J. Org. Lett. 2006, 8, 765–768. (c) Nguyen,
T. H.; Chau, N. T. T.; Castanet, A.-S.; Nguyen, K. P. P.; Mortier, J. J.
Org. Chem. 2007, 72, 3419–3429. (d) Tilly, D.; Fu, J.-m.; Zhao, B.-p.;
Alessi, M.; Castanet, A.-S.; Snieckus, V.; Mortier, J. Org. Lett. 2010, 12,
68–71.
Org. Lett., Vol. 12, No. 10, 2010
2407

Table 1. Amination Reactions of 2-Fluoro- and 2-Methoxybenzoic Acids (1 and 2)
entry
1, 2
LiNR1R2 (equiv)a
LiNEt2 (2.2)
LiN(CH2CH2)2NMe (2.2)
LiNMeBn (2.2)
LiNBn2 (2.2)
LiNMePh (2.2)
LiNPh2 (2.2)
LDA (2.2)
temp (°C)
3-10 %b
others
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
-50
-50
-50
-50
50
60
-50
60
87 (73*) [3]
95 (88*) [4]
95 (85*) [5]
93 (80*) [6]
100 (64*) [7]
72 [8]
33 (28*) [9]
0
60 (36*) [10]
0
97 (93*) [3]
87 (70*) [4]
90 (65*) [5]
5 [5]
50 (45*) [6]
14 [7]
s
s
s
s
s
s
s
LiNH2 (3.5)
LiNHt-Bu (2.2)
LTMP (2.2)
50 (40*) [11]
9
0
30 (15*) [11]c
d
10
11
12
13
14
15
16
17
18
19
-50
-50 f 0
0
-50 f 0
-50 f 0
0 f rt
60
60
0
-50
LiNEt2 (2.2)
s
LiN(CH2CH2)2NMe (2.2)
LiNMeBn (2.2)
LiNMeBn (5)
LiNBn2 (2)
LiNMePh (2.2)
LiNPh2 (2.2)
s
s
95 (51*) [13]e
s
s
s
0
LDA (2.2)
LTMP (2.2)
5 [9]
s
d
0
a The lithioamides LiNR1R2 were prepared in situ by deprotonation of the corresponding amines with n-BuLi. b NMR yields (%). Isolated yields (recrystallized
or chromatographed) are followed by an asterisk (*). All new compounds gave correct analytical data. See Supporting Information. c Deterbutylation of 12
led to amide 11. d See Scheme 1. e See Scheme 2.
eliminated LiF to give the transient lithium benzyne-3-
carboxylate (16). Electrophilic quenching of 14 with D2O
provided 15, whereas reaction of benzyne 16 with the excess
of LTMP followed by quench with D2O gave 17.
To our delight, the methoxy group was also found to be
an efficient leaving group. Reaction of 2-methoxybenzoic
acid (2) with LiNEt2, LiN(CH2CH2)2NMe, and LiNMeBn
gave anthranilic acids 3-5 in good yields (entries 11-13).
Increasing the amount of LiNMeBn to 5 equiv modified
dramatically the course of the reaction (entry 14). The
dioxindole 13 resulted as the main product.19
An attractive rationale for the formation of dioxindole 13 would
involve initial benzylic deprotonation of 5 by the excess of
LiNMeBn leading to 20 as outlined in Scheme 2. In an experiment
to probe this question, 5 was allowed to react with 5 equiv of
LiNMeBn to give a red solution which was hydrolyzed to 13. It
can be assumed that the benzylic lithiation of 5 is followed by an
intramolecular nucleophilic addition of the carbanion to the
carboxylate leading to indolin-3-one 22 by way of the geminal
dilithio dialkoxide 21.20 Deprotonation by the excess of base in
the presence of molecular oxygen contained in the nondegassed
Scheme 1. Reactions of Benzoic Acids 1 and 2 with LTMP
(18) The base and TMSCl were premixed prior to addition of the acid.
The deprotonation which produces a small concentration of the trappable
aryllithium 18 is sufficiently rapid to make the process competitive with reaction
of the hindered base with the in situ electrophile (TMSCl). See ref 11b.
(19) Structure of 13 was confirmed by NOESY and HMBC (see
Supporting Information).
2408
Org. Lett., Vol. 12, No. 10, 2010

Scheme 2
.
Postulated Mechanism for the Formation of
Scheme 3. Amination Reactions of Methoxybenzoic Acids 26-28,
Dioxindole 13
2,6-Difluorobenzoic Acid 32, and Naphthoic Acids 36 and 38
THF solution21 provides an organolithium peroxide species 24.22
Reduction by a hydride ion transferred by LiNMeBn23 affords
alkoxide 25 which undergoes subsequent 1,2-phenyl shift24 to
dioxindole 13 after acidic hydrolysis.25
The reaction of LiNBn2 yielded anthranilic acid 6 (45%)
(entry 15). LiNMePh, LiNPh2, and LDA were almost
unreactive toward 2. Whereas 2-methoxybenzoic acid (2) did
not react with LTMP after MeI addition (-50 °C) under
external quench conditions (entry 19), in situ quenching
(ISQ) with LTMP in the presence of TMSCl at -78 °C led
to 19 (via 18) free of any isomers (92%) (Scheme 1).18 It is
well demonstrated that the fluoro group is a better leaving
group and smaller in bulk than the methoxy.7,8
Reaction of commercially available 2,3-dimethoxy, 2,3,4-
trimethoxy, and 2,6-dimethoxybenzoic acids (26-28) with
LiNEt2 led to ortho-substituted derivatives 29-31 (Scheme
3).26 Introduction of LiNEt2 to the 2,6-dimethoxybenzoic acid
28 proceeded with less efficiency presumably due to steric
effects. In an attempt to introduce two substituents ortho to the
acid 32, 5 equiv of NEt2 was used, and a good yield of the
2,6-disubstituted product 33 was obtained (THF, -30 to 0 °C).
In the presence of a weaker nucleophile such as LiNMePh (vide
supra), the monosubstitution product 34 was formed exclusively,
even in refluxing THF. These results suggest that it should be
feasible to introduce two different amino groups. This indeed
proved to be the case by the clean conversion of 34 to 35.
In the literature, examples of direct amination reactions
of a naphthalene are very scarce.7,8 Reaction of 2-methoxy-
1-naphthoic acid (36)27 and 1-methoxy-2-naphthoic acid
(38)28 with LiNEt2 provided the naphthalenes 37 and 39.
We believe that the chemistry reported herein might
become rapidly a preferable alternative to the oxazoline and
BHA-ester systems. The carboxylic acid substituent which is
one of the most reliable resources for introduction of various
functionalities does not require protection/deprotection steps or
the use of metal catalysts. These preliminary results indicate
that the amination of ortho-fluoro- and ortho-methoxybenzoic
acids may provide additional methodology to aromatic substitu-
tion, and further studies in this respect are in progress.29 The
biaryl skeleton can be reached by a process involving unpro-
tected benzoic acid derivatives and aryllithium and aryl Grignard
reagents. This work will be reported soon.
Acknowledgment. Helpful discussions with Dr. Sven Taylor
and Dr. Ge´rard Moine (Hoffmann-La Roche Ltd., Basel) are
gratefully acknowledged. M.B.R., T.T.L., and R.A. are indebted
to the French Ministry of Research and Technologies, the
Algerian Ministry of Research, and Soprema for doctoral
fellowships. We also express appreciation to Patricia Gangnery
(Universite´ du Maine) for technical assistance.
(20) The geminal dimetallo dialkoxide C(OM)2 (M ) Li, K) group is a
good director of ortho-metalation: Tilly, D.; Samanta, S. S.; De, A.; Castanet,
A.-S.; Mortier, J. Org. Lett. 2005, 7, 827–830.
(21) Clayden, J.; Menet, C. J. Tetrahedron Lett. 2003, 44, 3059–3062.
(22) Rappoport, Z. The Chemistry of Peroxides; Wiley-Interscience: New
York, 2006; Vol. 2, part 1.
Supporting Information Available: Details of compound
characterization. This material is available free of charge via
the Internet at http://pubs.acs.org.
(23) Majewski, M.; Gleave, D. M. J. Organomet. Chem. 1994, 470, 1–
16.
(24) Observations of a similar rearrangement, leading to dioxindoles,
have been reported: Kafka, S.; Klasek, A.; Kosmrlj, J. J. Org. Chem. 2001,
66, 6394–6399.
OL1007586
(25) In deoxygenated medium, the reaction of 2 with LiNMeBn (5 equiv)
led to 5 (> 90%). It is assumed that the reduction step leading to 25 is the
first irreversible step in the pathway.
(27) (a) Fuson, R. C. J. Am. Chem. Soc. 1956, 78, 5409–5413. (b) Gant,
T. G.; Meyers, A. I. J. Am. Chem. Soc. 1992, 114, 1010–1015.
(28) Castagnetti, E.; Schlosser, M. Chem.sEur. J. 2002, 8, 799–804.
(29) A patent application was filed: Mortier, J.; Castanet, A.-S.; Belaud-
Rotureau, M. patent pending, filing number FR201051226 (2010).
(26) All new compounds gave correct analytical data. See Supporting
Information.
Org. Lett., Vol. 12, No. 10, 2010
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