A practical method for the preparation of 4-nitrogen-substituted benzoic acids

Article abstract of DOI:10.1246/cl.2006.1090

An efficient and practical method for the preparation of 4-nitrogen-substituted benzoic acids is described. Our method consists of the aromatic substitution of 2,2,2,4′-tetrafluoroacetophenone with amines, followed by haloform reaction to the benzoic acids. In this method, even though for the less nucleophilic 7-, 8-, and 9-membered amines 1 equiv. was used, corresponding benzoic acids were obtained in moderate to excellent yield. As the experimental procedure including purification is simple, this method is applicable to large-scale syntheses. Copyright

Full text of DOI:10.1246/cl.2006.1090

1090
Chemistry Letters Vol.35, No.10 (2006)
A Practical Method for the Preparation of 4-Nitrogen-substituted Benzoic Acids
Tsuyoshi Shinozuka,ꢀ Akira Nakao, Keiji Saito, and Satoru Naito
Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd.,
1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710
(Received June 30, 2006; CL-060736; E-mail: sinozu@sankyo.co.jp)
Table 1. Structures of 2, and isolated yields (%) of 4a
An efficient and practical method for the preparation of 4-
nitrogen-substituted benzoic acids is described. Our method
consists of the aromatic substitution of 2,2,2,40-tetrafluoroaceto-
phenone with amines, followed by haloform reaction to the
benzoic acids. In this method, even though for the less nucleo-
philic 7-, 8-, and 9-membered amines 1 equiv. was used, corre-
sponding benzoic acids were obtained in moderate to excellent
yield. As the experimental procedure including purification is
simple, this method is applicable to large-scale syntheses.
Entry
HNR1R2 (2)
HNEt2
4
Yield/%b
1
2
3
4
(2a)
4a14
4b15
4c
71
n = 1 (2b)
n = 2 (2c)
n = 3 (2d)
90 (81)c
86
( )n
NH
67
4d
5
P = Boc (2e)
87 (87)d
4e
PN
X
NH
6
7
8
P = Cbz (2f)
X = Of,g (2g)
X = Sf,g (2h)
83 (84)e
77
4f
4-Nitrogen-substituted benzoic acids are utilized as building
blocks for drug research.1 They are also useful precursors of
several heteroaromatic compounds such as oxazoles,2 thiazoles,3
triazoles,4 and thiadiazoles.5 In a research program, we needed
a variety of 4-aminobenzoic acids, which would be derived
from synthetically elaborated amines. One of the conventional
methods for the preparation of 4-nitrogen-substituted benzoic
acids is a nucleophilic aromatic substitution of 4-flurobenzoni-
triles or 4-fluorobenzoates with amines followed by hydrolysis.6
This method requires large amounts of amines and long reaction
times to achieve good yields. Alternatively, a recent develop-
ment of palladium-catalyzed coupling reactions of aryl halides
with amines can be applied to the preparation of 4-nitrogen-
substituted benzoates.7 However, more complicated amines gave
poor results.8 Herein, we wish to report an efficient and practical
2-step reaction for the preparation of 4-nitrogen-substituted
benzoic acids.
4g
4h
NH
77
9
n = 1 (2i)
99
83
4i
4j
HN
NH
( )n
10
O
X
n = 2f,g (2j)
11
12
X = O (2k)
X = S (2l)
99
83
4k
4l
NH
O
13
(2m)
4m16
81
O
NH
14
(2n)h
74i
4n
N
NH
aAll reactions were carried out on a 10-mmol scale unless other-
The details of the 2-step reaction are summarized in
Scheme 1 and Table 1. The reactions were carried out on a
10-mmol scale unless otherwise noted. The first step of this
reaction is the aromatic substitution of 2,2,2,40-tetrafluoroaceto-
phenone (1)9 with amines. The reaction proceeded quantitatively
within 30 min in DMSO at 100 ꢁC to provide substituted trifluo-
roacetophenones 3.10 In this reaction, 1 equivalent each of
amines 2 and Et3N were sufficient for the complete consumption
wise noted. bIsolated yield over 2 steps. c1,4-Dioxane was used
d
e
f
g
as a solvent. 50-mmol scale. 100-mmol scale. HCl salt. 2.0
equivalents of Et3N were used. h2.0 equivalents of 2n were used.
iPurified by reverse phase column chromatography.
of 1, even when less nucleophilic 7-, 8-, and 9-membered amines
were employed. Under the same reaction condition, the reaction
of 4-flurobenzonitrile with 2b provided the product in only 31%
yield and 60% of starting 4-flurobenzonitrile was recovered.
Thus, the use of 2,2,2,40-tetrafluoroacetophenone (1) is more
practical than 4-flurobenzonitrile in terms of the reactivity. This
increase of reactivity can be ascribed to stronger electron defi-
ciency of the aromatic ring in 1 compared to 4-fluorobenzonitrile
and 4-fluorobenzoate. Nevertheless, in the reaction of 1 with
imidazole (2n), 2 equivalents of 2n and a longer reaction time
of 2 h were required to consume the starting 1 because of its
low nucleophilicity.
The second step was haloform reaction.11 Treatment of 3a
with 8 M NaOH in DMF at 100 ꢁC provided 4a in 71% yield
calculated from 1.12 The product precipitated after the addition
of 1 M HCl to the reaction mixture. Similarly, most of the other
carboxylic acids 4 were also isolated by this workup procedure.
2a-n
Et3N, DMSO
F
NR1R2
100 °C
F3C
F3C
O
O
1
3a-n
NR1R2
NaOH, DMF,
H2O, 100 °C
HO2C
4a-n
Scheme 1. Synthesis of 4-nitrogen-substituted benzoic acids.
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.10 (2006)
1091
Azepane 4b was isolated in 90% yield,13 whereas 8-membered
4c and 9-membered 4d were isolated in 86 and 67% yields,
respectively. Then, the conversion of several 7-membered
amines to the corresponding 4-substituted benzoic acids was
examined. N-Boc-diazepane (2e) and N-Cbz-diazepane (2f)
provided desired products 4e and 4f in 87 and 83% yields,
respectively. Oxazepane 4g, thiazepane 4h, and diazepanone
4j were isolated in 77, 77, and 83% yields, respectively. In these
reactions, the starting amines 2g, 2h, and 2j were HCl salts, and
2 equivalents of Et3N were used. Nucleophilic 6-membered
amines gave excellent results, in particular, piperazinone (2i)
and morpholine (2k) provided 4i and 4k, respectively, in quan-
titative yields. Acetal 4m was obtained in 81% yield without the
cleavage of the acetal group by 1 M HCl treatment. Imidazole 4n
was isolated by reverse phase column chromatography as it was
water soluble.
Lier, E. Hansbury, J. Org. Chem. 1959, 24, 1864.
3
4
a) D. L. Garmaise, C. H. Chambers, R. C. McCrae, J. Med.
Chem. 1968, 11, 1205. b) K. Brown, D. P. Cater, J. F. Cavalla,
D. Green, R. A. Newberry, A. B. Wilson, J. Med. Chem. 1974,
17, 1177. c) R. S. Egan, J. Tadanier, D. L. Garmaise, A. P.
Gaunce, J. Org. Chem. 1968, 33, 4422. d) P. Czerney, H.
Hartmann, J. Prakt. Chem. 1983, 325, 551.
a) A. Omodei-Sale, P. Consonni, G. Galliani, J. Med. Chem.
1983, 26, 1187. b) T. L. Graybill, S. Thomas, M. A. Wang,
Tetrahedron Lett. 2002, 43, 5305. c) A. Kakefuda, T. Suzuki,
T. Tobe, A. Tahara, S. Sakamoto, S. Tsukamoto, Bioorg. Med.
Chem. 2002, 10, 1905.
5
6
Y. Takikawa, K. Shimada, K. Sato, S. Sato, S. Takizawa, Bull.
Chem. Soc. Jpn. 1985, 58, 995.
D.-K. Kim, J. Y. Lee, J.-S. Kim, J.-H. Ryu, J.-Y. Choi, J. W.
Lee, G.-J. Im, T.-K. Kim, J. W. Seo, H.-J. Park, J. Yoo, J.-H.
Park, T.-Y. Kim, Y.-J. Bang, J. Med. Chem. 2003, 46, 5745.
a) M. H. Ali, S. L. Buchwald, J. Org. Chem. 2001, 66, 2560. b)
J. P. Wolfe, S. L. Buchwald, Tetrahedron Lett. 1997, 38, 6359.
c) C. J. Smith, T. R. Early, A. B. Holmes, R. E. Shute, Chem.
Commun. 2004, 1976. d) C. Meyers, B. U. W. Maes, K. T. J.
7
Preparation of 4e and 4f was also carried out on a larger
scale, and the products were obtained in as good yields as the
reactions on a 10-mmol scale.
`
As described above, DMSO was a suitable solvent in the
aromatic substitution reaction, and DMF was preferred in the
haloform reaction. To avoid the aqueous workup after the
aromatic substitution, one-pot reaction was examined in the
reaction with azepane 2b. Neither DMSO nor DMF gave a sat-
isfactory result, but 1,4-dioxane gave a tolerable result. In 1,4-di-
oxane, a reaction time of 2 days was required for the nucleophil-
ic aromatic substitution reaction, but the subsequent haloform
reaction completed within 1 h to provide 4b in 81% yield.
In summary, an efficient and practical method for the
preparation of 4-nitrogen-substituted benzoic acids was estab-
lished. 2,2,2,40-Tetrafluoroacetophenone (1) reacted with vari-
ous amines including less nucleophilic amines. The adduct 3
was treated with NaOH to afford 4-nitrogen-substituted benzoic
acids 4 in moderate to excellent yields. This method is superior
to the conventional method, especially in the case where the
amine being introduced is precious, as one equivalent of amine
is sufficient in most reactions. In addition, the experimental pro-
cedure including purification is simple; therefore, this method
would be suitable for large-scale syntheses.
Loones, G. Bal, G. L. F. Lemiere, R. A. Dommisse, J. Org.
Chem. 2004, 69, 6010. e) S. Urgaonkar, J.-H. Xu, J. G. Verkade,
J. Org. Chem. 2003, 68, 8416. f) J. P. Stambuli, R. Kuwano, J. F.
Hartwig, Angew. Chem., Int. Ed. 2002, 41, 4746.
Kung and co-workers reported the palladium-catalyzed
amination of complicated amines in moderate yields; See:
P.-P. Kung, M. D. Casper, K. L. Cook, L. Wilson-Lingardo,
L. M. Risen, T. A. Vickers, R. Ranken, L. B. Blyn, J. R. Wyatt,
P. D. Cook, D. J. Ecker, J. Med. Chem. 1999, 42, 4705.
2,2,2,40-Tetrafluoroacetophenone is commercially available:
Aldrich 402478.
8
9
10 For the reaction of 1 with amines, see: a) D. J. McNamara, E. M.
Berman, D. W. Fry, L. M. Werbel, J. Med. Chem. 1990, 33,
2045. b) A. Gangjee, Y. Zhu, S. F. Queener, P. Francom,
A. D. Broom, J. Med. Chem. 1996, 39, 1836. c) T. R. Jones,
M. D. Varney, S. E. Webber, K. K. Lewis, G. P. Marzoni,
C. L. Palmer, V. Kathardekar, K. M. Welsh, S. Webber, D. A.
Matthews, K. Appelt, W. W. Smith, C. A. Janson, J. E.
Villafranca, R. J. Bacquet, E. F. Howland, C. L. Booth, S. M.
Herrmann, R. W. Ward, J. White, E. W. Moomaw, C. A.
Bartlett, C. A. Morse, J. Med. Chem. 1996, 39, 904.
11 The conversion of aryl trifluoromethyl ketones into the
corresponding carboxylic acids is known. See: A. Delgado, J.
Clardy, Tetrahedron Lett. 1992, 33, 2789.
References and Notes
1
a) J. B. Thomas, X. M. Herault, R. B. Rothman, R. N. Atkinson,
J. P. Burgess, S. W. Mascarella, C. M. Dersch, H. Xu, J. L.
Flippen-Anderson, C. F. George, F. I. Carroll, J. Med. Chem.
2001, 44, 972. b) B. Hu, J. Ellingboe, S. Han, E. Largis, R.
Mulvey, A. Oliphant, F.-W. Sum, J. Tillett, J. Med. Chem.
2001, 44, 1456. c) V. Bavetsias, L. A. Skelton, F. Yafai, F.
Mitchell, S. C. Wilson, B. Allan, A. L. Jackman, J. Med. Chem.
2002, 45, 3692. d) R. J. Steffan, M. A. Ashwell, W. R. Solvibile,
E. Matelan, E. Largis, S. Han, J. Tillet, R. Mulvey, Bioorg. Med.
Chem. Lett. 2002, 12, 2963. e) W. Wang, Q. Li, L. Hasvold,
B. Steiner, D. A. Dickman, H. Ding, A. Clairborne, H.-J. Chen,
D. Frost, R. C. Goldman, K. Marsh, Y.-H. Hui, B. Cox, A.
Nilius, D. Balli, P. Lartey, J. J. Plattner, Y. L. Bennani, Bioorg.
Med. Chem. Lett. 2003, 13, 489. f) K. R. Guertin, C. J. Gardner,
S. I. Klein, A. L. Zulli, M. Czekaj, Y. Gong, A. P. Spada, D. L.
Cheney, S. Maignan, J.-P. Guilloteau, K. D. Brown, D. J.
Colussi, V. Chu, C. L. Heran, S. R. Morgan, R. G. Bentley,
C. T. Dunwiddie, R. J. Leadley, H. W. Pauls, Bioorg. Med.
Chem. Lett. 2002, 12, 1671.
12 General procedure for the preparation of 4: A solution of
2,2,2,40-tetrafluoroacetophenone (1) (1.92 g, 10 mmol), Et3N
(1.39 mL, 10 mmol), and amine 2 (10 mmol) in DMSO (20
mL) was stirred at 100 ꢁC (bath temp.) for 30 min. The reaction
mixture was cooled, diluted with AcOEt (50 mL) and washed
twice with water (50 mL). The organic layer was dried (Na2SO4)
and concentrated. To the residual crude 3 in DMF (20 mL), 8 M
NaOH (5 mL, 40 mmol) was added. The reaction mixture
was stirred at 100 ꢁC (bath temp.) for 2 h. 1 M HCl (60 mL)
was added to the cooled reaction mixture. The resulting solid
was filtered and washed with water to afford 4.
13 The reaction of ethyl 4-iodobenzoate with 2b using Pd catalyst
(Pd2(dba)3, XANTPHOS, and Cs2CO3 in 1,4-dioxane, Et3N,
the reaction condition described in Reference 7a) provided the
product in 54% yield.
14 R. A. Mackie, S. Mhatre, J. M. Tedder, J. Fluorine Chem. 1977,
10, 437.
15 A. H. Khuthier, K. Y. Al-Mallah, S. Y. Hanna, N. A. I. Abdulla,
J. Org. Chem. 1987, 52, 1710.
2
a) D. G. Ott, F. N. Hayes, E. Hansbury, V. N. Kerr, J. Am. Chem.
Soc. 1957, 79, 5448. b) V. N. Kerr, F. N. Hayes, D. G. Ott, R.
16 B. Hu, J. Ellingboe, S. Han, E. Largis, R. Mulvey, A. Oliphant,
F.-W. Sum, J. Tillett, J. Med. Chem. 2001, 44, 1456.
Published on the web (Advance View) August 29, 2006; doi:10.1246/cl.2006.1090