A simple and efficient synthesis of 2-(N-phenylamino)-benzoic acids

Article abstract of DOI:10.1081/SCC-120002125

A new method for the synthesis of 2-(N-phenylamino)benzoic acids is presented, with 2-fluorobenzoic acids and anilines as starting materials. Several experimental conditions as well as the factors influencing the outcome of the reaction are described.

Full text of DOI:10.1081/SCC-120002125

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A SIMPLE AND EFFICIENT SYNTHESIS OF 2-(N-
PHENYLAMINO)- BENZOIC ACIDS
M. H. Chen a , V. G. Beylin a , E. Iakovleva a , S. J. Kesten a , J. Magano a & D. Vrieze a
a Pfizer Global Research & Development , 2800 Plymouth Road, Ann Arbor, MI, 48105,
U.S.A.
Published online: 16 Aug 2006.
To cite this article: M. H. Chen , V. G. Beylin , E. Iakovleva , S. J. Kesten , J. Magano & D. Vrieze (2002) A SIMPLE AND
EFFICIENT SYNTHESIS OF 2-(N-PHENYLAMINO)- BENZOIC ACIDS, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 32:3, 411-417
To link to this article: http://dx.doi.org/10.1081/SCC-120002125
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SYNTHETIC COMMUNICATIONS, 32(3), 411–417 (2002)
A SIMPLE AND EFFICIENT
SYNTHESIS OF 2-(N-PHENYLAMINO)-
BENZOIC ACIDS
M. H. Chen, V. G. Beylin, E. Iakovleva,
S. J. Kesten, J. Magano,* and D. Vrieze
Pfizer Global Research & Development,
2800 Plymouth Road, Ann Arbor, MI48105
ABSTRACT
A new method for the synthesis of 2-(N-phenylamino)benzoic
acids is presented, with 2-fluorobenzoic acids and anilines as
starting materials. Several experimental conditions as well as
the factors influencing the outcome of the reaction are
described.
The reaction between aliphatic amines and both 2- and 4-fluoro-
benzoic acids to give 2- or 4-aminobenzoic acids has been reported in
the literature.1–8 However, much more scarcely found is the reaction
between 2- and 4-fluorobenzoic acids and anilines.1,9–13 The most likely
reason for this is the less nucleophilic character of the latter. In the
course of a research project undertaken in our laboratories, the need for
the synthesis of variously substituted 2-(N-phenylamino)benzoic acids (1) as
*Corresponding author.
411
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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CHEN ET AL.
important intermediates arose. The yields we found in the literature were, in
many cases, fair to low, and the need for synthesizing large amounts of these
compounds demanded a more efficient method. We report an improved
method which gives good to excellent yields of the desired products. The
general reaction is shown in Scheme 1.
Scheme 1.
The reactions were run using 1 equivalent each of the fluorobenzoic
acid and the aniline with 3 equivalents of lithium hexamethyldisilazide
(LiHMDS), which was found to be the most suitable base for this type of
reaction.
Three different methods to carry out the reaction were tested:
–
Method A, or ‘‘two-pot procedure’’: In a first flask, base (1 eq)
was added to a solution of the acid (1 eq) in tetrahydrofuran
(THF) at À78ꢀC. In a second flask, base (2 eq) was added to
a solution of the aniline (1 eq) in THF at À78ꢀC. The contents
from the first flask were transferred into the second flask and
the resulting mixture was allowed to reach ambient temperature
overnight.
–
–
Method B, or ‘‘one-pot procedure’’: Both the acid and the aniline
were dissolved in THF, the mixture cooled to À78ꢀC, the
base added, and the mixture allowed to warm up to ambient
temperature overnight. In Method B*, the base was added at
À20 to 0ꢀC, and then the mixture was warmed up at 40–50ꢀC
overnight.
Method C is also a ‘‘two-pot procedure’’. The difference with
respect to Method A is that the 3 equivalents of base are added
to the aniline followed by a solution of the acid in THF.
A summary of the results from this study is shown in Table 1.

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SYNTHESIS OF 2-(N-PHENYLAMINO)BENZOIC ACIDS
413
Table 1.
DISCUSSION
From the results that we have obtained, several conclusions can be
drawn based on different factors that influence the outcome of the reaction:
1. Method employed (Entries 1–2): Method B provides somewhat
lower yields than method A. The reason for this seems unclear at this

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CHEN ET AL.
point. A possible explanation is that having the acid in the presence of a very
large excess of base (much more than what is needed to deprotonate it) may
give rise to further side reactions through a benzyne intermediate.
2. Nature of the base (Entries 6–11): LiHMDS gives the best yields
compared to other bases. For instance, in the reaction between 2,3,4-tri-
fluorobenzoic acid and 4-iodo-2-methylaniline, the yields were 84%
(LiHMDS), 28% (LDA) and no reaction was observed using NaH or
triethylamine. With LDA, replacement of the F atom by a diisopropylamino
group was detected in some cases, possibly occurring via a benzyne inter-
mediate. Lower yields are also observed with bases such as NaHMDS and
KHMDS.
3. Number of equivalents of base (Entries 12–14): Reducing the
number of equivalents from 3 to 2 in the case of LiHMDS decreases the
yield considerably. The most likely reason for this result is that the product
is a diaryl amine which is much more acidic than the aniline. If a third
equivalent of base is not present in the reaction medium to neutralize it, it
may protonate the anilide anion that has not reacted, stopping the reaction.
The use of more than 3 equivalents of base did not have a noticeable effect
on the yield.
4. Position of the fluorine atom with respect to the carboxylic acid
group in the ring (Entries 17–18): Only 2-fluorobenzoic acids react with
anilines. Thus, the reaction between 2-fluorobenzoic acid and p-anisidine
afforded 71% of the desired product under these reaction conditions;
when 4-fluorobenzoic acid was employed, no reaction was observed.
The proximity of the strongly electron-withdrawing carboxylic acid group
plays a fundamental role. Even though its presence should influence
both ortho and para positions, no effect seems to be observed in the
latter. This is confirmed by the fact that when either 5-bromo-2,3,4-
trifluorobenzoic (Entry 1) or 2,3,4-trifluorobenzoic (Entry 6) acids
were used, the product resulting from attack at the 4-position was not
observed.
5. Effect of the substituents on the aniline ring (Entries 17 and 19):
The presence of electron-donating groups, such as methoxy, increases con-
siderably the reactivity of the aniline. If strongly electron-withdrawing
groups coexist on the ring, the reactivity decreases dramatically. This can
be seen in the reaction between 2-fluorobenzoic acid and both p-anisidine
and p-nitroaniline. In the first case, the yield was 71%, while no reaction was
observed in the second one. This is to be expected, since it is well known that
anilines are less nucleophilic than aliphatic amines due to the involvement of
the lone pair on nitrogen in the conjugation with the ring, and additional
deactivating groups make this conjugation even stronger.

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SYNTHESIS OF 2-(N-PHENYLAMINO)BENZOIC ACIDS
415
We are trying to extend the scope of this methodology to fluorinated
substrates with electron-withdrawing groups other than carboxylic acids,
such as nitro, carbonyl (both aldehyde and ketone), ester and nitrile. The
most promising results so far have been obtained with fluorobenzonitriles
and fluoronitrobenzenes, even though, in some cases, the yields still are quite
modest.
CONCLUSION
We have developed a simple way to prepare 2-(N-phenylamino)ben-
zoic acids and determined the best experimental conditions after considering
important factors such as the nature of the base, steric and electronic effects
and the influence of the substituents.
EXPERIMENTAL
A typical procedure for Method A is as follows:
Flask A: Into a three-necked-round bottomed flask equipped with a
magnetic stirrer and a thermometer and under nitrogen atmosphere was
placed 2-fluorobenzoic acid (1.00 g, 7.14 mmol, 1 eq) and dissolved in dry
THF (35 ml). After cooling this solution to ꢀ70ꢁC in a dry ice-acetone bath,
LiHMDS (7.2 ml of a 1 M solution in THF, 7.20 mmol, 1 eq) was added via
syringe over 10 min. The resulting suspension was stirred at this T for
15 min.
Flask B: Into a three-necked-round bottomed flask equipped with a
magnetic stirrer and a thermometer and under nitrogen atmosphere was
placed p-anisidine (0.88 g, 7.14 mmol, 1 eq) and dissolved in dry THF
(35 ml). After cooling this solution to ꢀ70ꢁC in a dry ice–acetone bath,
LiHMDS (14.3 ml of a 1 M solution in THF, 14.30 mmol, 2 eq) was added
via syringe over 15 min. The resulting suspension was stirred at this T for
15 min.
Then, the contents of Flask A were transferred by cannula into Flask
B and the resulting mixture allowed to reach ambient temperature over-
night. The dark brown solution was quenched with 1 N aqueous HCl to
pH ¼ 1 and extracted with diethylether (3 Â50 ml). The combined organic
extracts were washed with brine and dried over MgSO4. Purification of the
solid residue by flash chromatography (hexanes/ethyl acetate/acetic acid)
afforded 1.23 g (71% yield) of the corresponding 2-(N-phenylamino)benzoic
acid as a beige solid, m.p. 170–172ꢁC.

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CHEN ET AL.
1H-NMR and mass spectrometry data for new compounds:
Product 1: (DMSO, 400 MHz): d 2.37 (S, 3H), 6.80–6.84 (m, 1H),
7.53–7.55 (m, 1H), 7.70 (s, 1H), 8.11–8.13 (m, 1H), 9.17 (s, 1H). Mass
(EI): 390 (Mþ þ 1).
Product 2: (DMSO, 400 MHz): d 4.70 (d, J ¼ 1.6 Hz, 4H), 6.75
(q, J ¼ 2.6 Hz, J ¼ 9.0 Hz, 1H), 6.93 (m, 2H), 7.30–7.35 (m, 2H), 7.39
(d, J ¼ 1.6 Hz, 1H), 7.47–7.55 (m, 3H), 8.03 (q, J ¼ 1.8 Hz, J ¼ 7.8 Hz, 1H),
9.79 (s, 1H), 13.22 (s, 1H). Mass (EI): 387 (Mþ þ 1).
Product 3: (DMSO, 400 MHz): d 4.53 (s, 4H), 6.63 (t, J ¼ 9.2 Hz,
J ¼ 8.0 Hz, 3H), 6.74 (t, J ¼ 7.2 Hz, J ¼ 7.6 Hz, 1H), 7.14 (d, J ¼ 8.0 Hz,
1H), 7.2 (t, J ¼ 7.6 Hz, J ¼ 8.0 Hz, 3H), 7.25 (s, 1H), 7.33–7.37 (m, 2H),
7.87 (d, J ¼ 8.0 Hz, 1H), 9.63 (s, 1H), 13.04 (s, 1H). Mass (EI): 244 (Mþ þ 1).
Product 4: (DMSO, 400 MHz): d 2.99 (t, J ¼ 13.6 Hz, 4H), 6.86 (t,
J ¼ 7.6 Hz, 1H), 7.26 (t, J ¼ 7.8 Hz, 3H), 7.34 (t, J ¼ 8.4 Hz, J ¼ 8.8 Hz,
3H), 7.48 (t, J ¼ 7.6 Hz, 1H), 7.64 (d, J ¼ 8.8 Hz, 2H), 8.00 (d, J ¼ 7.6 Hz,
1H), 9.69 (s, 1H), 13.15 (s, 1H). Mass (EI): 331 (Mþ þ 1).
Product 5: (DMSO, 400 MHz): d 2.25 (s, 3H), 6.63 (q, J ¼ 6.8 Hz,
J ¼ 8.0 Hz, 1H), 7.06 (q, J ¼ 9.2 Hz, J ¼ 16.4 Hz, 1H), 7.42 (q, J ¼ 1.6 Hz,
J ¼ 8.4 Hz, 1H), 7.57 (s, 1H), 7.82 (t, J ¼ 7.2 Hz, 1H), 9.05 (s, 1H). Mass
(EI): 400 (Mþ þ 1).
Product 6: (CDCl3, 400 MHz): d 3.81 (s, 3H), 6.67 (t, J ¼ 7.6 Hz, 1H),
6.89–6.94 (m, 3H), 7.17 (d, J ¼ 8.8 Hz, 2H), 7.24–7.30 (m, 1H), 8.00
(d, J ¼ 8.0 Hz, 1H), 9.11 (s, 1H). Mass (EI): 469 (Mþ þ 1).
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417
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Received in the USA March 19, 2001

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