The use of formamidine protection for the derivatization of aminobenzoic acids

Article abstract of DOI:10.1021/jo8017186

(Chemical Equation Presented) N,N-Dimethylformamidine and novel N,N-diisopropylformamidine protecting groups were used to carry out a one-pot conversion of aminobenzoic acids into the corresponding amides. General conditions for an in situ transformation of aminobenzoic acids and their heterocyclic analogues into the corresponding formamidine-protected acid chlorides were developed. These chlorides were used in reactions with amines, including poorly reactive anilines. The protected amides were then smoothly deprotected by heating with ethylenediamine derivatives, resulting in a general procedure for the one-pot transformation of aminobenzoic acids into their amides. Our one-pot procedure was successfully applied to the preparation of several compounds of pharmaceutical interest.

Full text of DOI:10.1021/jo8017186

The Use of Formamidine Protection for the Derivatization of
Aminobenzoic Acids
Paul E. Zhichkin,* Lisa H. Peterson, Catherine M. Beer, and W. Martin Rennells
Medicinal Chemistry Department, AMRI, 26 Corporate Circle P.O. Box 15098, Albany, New York 12212
paul.zhichkin@amriglobal.com
ReceiVed August 1, 2008
N,N-Dimethylformamidine and novel N,N-diisopropylformamidine protecting groups were used to carry
out a one-pot conversion of aminobenzoic acids into the corresponding amides. General conditions for
an in situ transformation of aminobenzoic acids and their heterocyclic analogues into the corresponding
formamidine-protected acid chlorides were developed. These chlorides were used in reactions with amines,
including poorly reactive anilines. The protected amides were then smoothly deprotected by heating
with ethylenediamine derivatives, resulting in a general procedure for the one-pot transformation of
aminobenzoic acids into their amides. Our one-pot procedure was successfully applied to the preparation
of several compounds of pharmaceutical interest.
Introduction
were found to be potent bradykinin B2 receptor antagonists,5
as well as inhibitors of epidermal growth factor receptor,6 DNA
methyltransferase,7 and cyclooxygenase-1.8 Examples of bio-
logically active 4-aminobenzanilides are the antimitotic agent
DW2282,9 ameltolide and other anticonvulsants,10 antiviral
compounds,11 histone deacetylase inhibitor CI-994,12 adenosine
2A receptor antagonists,13 and vasopressin receptor antagonists
lixivaptan, conivaptan, and mozavaptan.14
There are numerous examples of anilides of 3- and 4-ami-
nobenzoic acids and their heterocyclic analogues serving as key
moieties or precursors to biologically active compounds. Oli-
gomers of 2-aminopyrrole-3-carboxamide, such as netropsin,
distamycin A, tallimustine, and brostallicin, as well as their
aromatic congeners, are DNA minor groove binders and
topoisomerase inhibitors, and they have been extensively studied
as potential treatments for cancer and bacterial and viral
infections.1 The 3-aminobenzanilide suramin has been used
clinically as a sensitizer to cancer chemotherapy and antiparasitic
agent,2 and some of its derivatives were reported to be selective
P2X or P2Y,3 and sirtuin4 inhibitors. Other 3-aminobenzanilides
The aliphatic amides of aminobenzoic acids can be prepared
under typical amide coupling conditions by taking advantage
of the fact that the reactivity of aliphatic amines is much greater
(2) Villalona-Calero, M.; Wientjes, M. G.; Otterson, G. A.; Kanter, S.; Young,
D.; Murgo, A. J.; Fischer, B.; DeHoff, C.; Chen, D.; Yeh, T.-K.; Song, S.; Grever,
M.; Au, J. L.-S. Clin. Cancer Res. 2003, 9, 3303, and references cited therein.
(3) (a) Kassack, M. U.; Braun, K.; Ganso, M.; Ullman, H.; Nickel, P.; Bo¨ing,
B.; Mu¨ller, G.; Lambrecht, G. Eur. J. Med. Chem. 2004, 39, 345. (b) Ullmann,
H.; Meis, S.; Hongwiset, D.; Marzian, C.; Wiese, M.; Nickel, P.; Communi, D.;
Boeynaems, J.-M.; Wolf, C.; Hausmann, R.; Schmalzing, G.; Kassack, M. U.
J. Med. Chem. 2005, 48, 7040. (c) Hausmann, R.; Rettinger, J.; Gerevich, Z.;
Meis, S.; Kassack, M. U.; Illes, P.; Lambrecht, G.; Schmalzing, G. Mol.
Pharmacol. 2006, 69, 2058.
(4) Trapp, J.; Meier, R.; Hongwiset, D.; Kassak, M. U.; Sippl, W.; Jung, M.
ChemMedChem 2007, 2, 1419.
(5) Sawada, Y.; Kayakiri, H.; Abe, Y.; Imai, K.; Mizutani, T.; Inamura, N.;
Asano, M.; Aramori, I.; Hatory, C.; Katayama, A.; Oku, T.; Tanaka, H. J. Med.
Chem. 2004, 47, 1617.
(1) (a) Review: Bailly, C.; Chaires, J. B. Bioconj. Chem. 1998, 9, 513. (b)
Review: Gallmeier, H.-C. Eur. J. Org. Chem. 2003, 3473. (c) Beria, I.; Baraldi,
P. G.; Cozzi, P.; Caldarelli, M.; Geroni, C.; Marchini, S.; Mongelli, N.;
Romagnoli, R. J. Med. Chem. 2004, 47, 2611, and references cited therein. (d)
Markowska, A.; Rozanski, A.; Wolczynski, S.; Midura-Nowaczek, K. Farmaco
2002, 57, 1019. (e) Puckowska, A.; Bielawski, K.; Bielawska, A.; Midura-
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8954 J. Org. Chem. 2008, 73, 8954–8959
10.1021/jo8017186 CCC: $40.75 2008 American Chemical Society
Published on Web 10/17/2008

DeriVatization of Aminobenzoic Acids
SCHEME 1. Literature Preparations of Aminobenzanilides
carboxylic group of the aminobenzoic acid is activated simul-
taneously with the protection of the amine group. Furthermore,
we planned to react the resulting acid chloride with an aromatic
amine and then to remove the labile protecting group in the
same pot. To be useful, we required this procedure to be
applicable to a wide range of both aromatic amines and
aminobenzoic acids.
Results and Discussion
It did not escape our notice that the same conditions, involving
the intermediacy of a Vilsmeier reagent (e.g., DMF/POCl3), are
used in the literature for the conversion of both carboxylic acids
into acid chlorides19 and primary arylamines into N,N-dimeth-
ylformamidines.20 The N,N-dimethylformamidine moiety is a
known protecting group for amines, which can be cleaved under
mild conditions.21 It has been used as an ortho-directing group
in metal-halogen exchange reactions22 as well as for the
protection of amino-groups in heterocycles, particularly nucle-
otides, nucleosides, and their analogues.23
There are scattered references in the early patent literature
to the preparation of N,N-dimethylformamidine-N′-benzoic acids
using the Vilsmeier reagent, for example, from 3-amino-2,4,6-
triiodobenzoic24 or 4-aminobenzoic20f acids. However, in these
publications, the formamidine-substituted benzoic acids were
the final products and were not further derivatized or deprotected.
The reaction of 4-aminobenzoic acid (1a) and 4-methylaniline
(3a) was chosen as a model system (Scheme 2). We found that
adding 1a at room temperature to a suspension of 2 equiv of
the Vilsmeier reagent in CH2Cl2, prepared in situ from DMF
and oxalyl chloride, directly provided the unstable acid chloride
2. When 2 was further treated with 4-methylaniline (3a) and
N,N-diisopropylethylamine (DIPEA), the protected amide 4 was
produced in 76% isolated yield.
than the reactivity of the aromatic amine moiety of aminoben-
zoic acids.15,16 However, the direct formation of aromatic amides
from 3- and 4-aminobenzoic acids has been problematic, due
to the cross-reactivity of their amine functionality.6b,13 These
amides are usually prepared in three steps starting with the
corresponding nitrobenzoic acid. The nitro group is reduced in
the final step (Scheme 1A).5,7,8,10d,13,17 In cases when groups
sensitive to reductive conditions are present, or the correspond-
ing nitrobenzoic acids are not available, a four-step procedure
involving protection and deprotection of the amino group must
be applied (Scheme 1B).1h,6b,7,17b,18
When one has to prepare a series of many anilides of
aminobenzoic acids, the three- and four-step sequences depicted
in Scheme 1, albeit trivial, become inconvenient. Instead, we
envisioned a method to streamline this sequence, in which the
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Using 4, we screened several reagents known to remove
the N,N-dimethylformamidine group (zinc chloride,25 HCl,26
NaOH,23d and ammonium hydroxide23b,27). In addition, we tried
ethylenediamine, which has the advantage of higher nucleo-
philicity28 than sodium hydroxide or ammonia. Although another
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H. J. Am. Chem. Soc. 2003, 125, 13126. (b) Miller, W. H.; Seefeld, M. A.;
Newlander, K. A.; Uzinskas, I. N.; Burgess, W. J.; Heerding, D. A.; Yuan,
C. C. K.; Head, M. S.; Payne, D. J.; Rittenhouse, S. F.; Moore, T. D.; Pearson,
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Rempfer, H. Chem. Ber. 1959, 92, 837. (c) Bredereck, H.; Effenberger, F.; Botsch,
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J. Org. Chem. Vol. 73, No. 22, 2008 8955

Zhichkin et al.
SCHEME 2. Development of Formamidine Protection and
Deprotection
method by varying both the acid (1) and amine (3) components
(Table 2). We placed a particular emphasis on the most
challenging substratessanilines with low nucleophilicitysusing
4-nitroaniline30 and 2,6-dichloroaniline as primary examples.
The method worked equally well for the reactions of
4-aminobenzoic acid with electron-poor 4-nitroaniline (entry 2),
electron-rich 4-methoxyaniline (entry 3), and the aliphatic amine
pyrrolidine (entry 4). High yields were also obtained starting
with 3-aminobenzoic acid (entries 8 and 9). 2,6-Dichloroaniline
afforded somewhat lower but still good yields (entries 5 and
10).
Importantly, the described method was fully applicable to
heterocyclic 6-aminonicotinic acid (entries 11-14). As noted
in the introduction (also compare with Scheme 1B), our
approach brings the greatest benefit when the nitrobenzoic acid
corresponding to the aminobenzoic acid cannot be used. In the
case of 6-aminonicotinic acid, 6-nitronicotinic acid is com-
mercially available but more than ten times more expensive.
Underscoring the advantage over existing procedures, the
following examples demonstrate the use of other aminobenzoic
acids with the price ratio of nitro/amino > 10: 2-aminopyridin-
4-ylcarboxylic (entry 15), 3-amino-1,2,4-triazol-5-ylcarboxylic
(entries 16 and 17), and 4-amino-2-hydroxybenzoic (entry 18)
acids. Even greater benefit is achieved when the corresponding
nitrobenzoic acids are not commercially available as in the case
of 4-amino-3,5-dichlorobenzoic (entries 19 and 20) and 4-amino-
3-chloro-6-methoxybenzoic (entry 21) acids.
TABLE 1. Exploration of Deprotection Conditionsa
entry
reagent
4b (%)
5b (%)
6ab (%)
1
2
3
4
5
ZnCl2
4 M aq HCl
4.5 M aq NaOH
14.8 M aq NH3
ethylenediamine
1
81
30
71
0
53
0
1
21
5
46
15
68
21
94
a 0.5 mmol of in 4 mL of EtOH was heated with 2.25 mmol of the
deprotecting reagent at 80 °C in a sealed tube for 4 h. b Amount in the
reaction mixture was determined by HPLC area method analysis.
The preparation of 4-nitroanilides (entries 2, 9, 12, 16, 19,
22, and 24) and amides of benzoic acids containing both amino-
and nitro-groups (entries 22-25) highlights another important
feature of our methodsits applicability to substrates containing
reduction-sensitive functional groups. For these compounds, the
classical synthesis from nitrobenzoic acids (Scheme 1A) would
require developing chemoselective reduction methods,31 while
our approach avoids this inconvenience.
primary amine, cyclohexylamine, was used in the literature,23b
we chose to utilize ethylenediamine, as we envisioned its
unlimited aqueous solubility to be advantageous during the
workup. As expected, ethylenediamine gave the fastest and the
cleanest deprotection, while significant amounts of unreacted 4
and formamide 5 were present in all other cases (Table 1). We
were pleased to find that after the deprotection with ethylene-
diamine, an 80% isolated yield of 6a was obtained.
While all other amines afforded high yields, the reactions
involving 2,6-dichloroaniline were generally less efficient and
required longer time. The lower yields could be remedied by
using 2 equiv of 2,6-dichloroaniline (see entries 14, 17, and
20, values in parentheses).
With the conditions for the separate steps established, we
moved toward our main goal of carrying out the synthesis in
one pot without isolating intermediate 4. Thus, upon completion
of the formation of 4 as judged by HPLC analysis, we replaced
the CH2Cl2 solvent with ethanol and heated the resulting solution
with ethylenediamine. To our satisfaction, with all three steps
carried out in the same pot, an overall 88% isolated yield of
amide 6a was obtained from 1a (Table 2, entry 1).
Unexpectedly, when we tried to apply the above procedure
to the reaction of 1a with 4-nitroaniline, a mixture of products
was formed. However, the simple replacement of the DIPEA
base with pyridine in the amide bond formation step resulted
in 88% overall yield of the desired product 6b (entry 2). We
speculate that DIPEA, being a strong base, converts 2 to the
free-base form, thus promoting the side reaction of self-acylation
on the amidine nitrogen.29 This competing reaction occurring
in the presence of DIPEA is, probably, much slower than the
amide formation in the case of the rapidly reacting 4-methyla-
niline (entry 1). However, the self-acylation side reaction in
the presence of DIPEA becomes predominant in the case of
deactivated 4-nitroaniline. To avoid this complication, we used
pyridine as the base in all subsequent reactions. After this final
optimization, we set out to explore the substrate scope of the
For the benzoic acids with the deactivated amino group, such
as 6-aminonicotinic and 3,5-dichloro-6-aminobenzoic acids,
addition of pyridine, followed by stirring at room temperature
prior to the addition of the aniline, was necessary for the
protection to be complete. For other acids (e.g., 4-aminoben-
zoic), the order of addition did not matter. In most cases, we
used the more general procedure, in which pyridine was added
first. On the second step, the reaction time required to form the
amide bond varied greatly depending on the reactivity of the
amine, from 1 h for the reactive 4-methylaniline to 2-6 d for
2,6-dichloroaniline, and the addition of DMAP and heating
were necessary for 4-aminopyridine (entry 27). The ease of
the final deprotection step also depended on the individual
reactivity of the substrates. The deprotection of the forma-
midine group positioned off the pyridine ring was complete
within 30 min at reflux with ethylenediamine (entries 11-14),
while the deprotection of dichlorophenyl derivatives (entries
(30) Acylation reactions with 4-nitroaniline, see: Rijkers, T. S.; Adams,
H. P. H. M.; Hemker, H. C.; Tesser, G. T Tetrahedron 1995, 41, 11235, and
references cited therein.
(31) For example, see: Shchel’tsyn, V. K.; Varnikova, G. V.; Makova, E. A.;
Kopylevich, G. M.; Kiperman, S. L. Russ. J. Org. Chem. 1979, 15, 1730.
(28) For comparative nucleophilicity scales, see: Brotzel, F.; Chu, Y. C.;
Mayr, G. J. Org. Chem. 2007, 72, 3679, and references cited therein.
(29) For the reactions of N-aryl-N′,N′-dimethylformamidines with acyl
chlorides, see: Falk, F. J. Prakt. Chem. 1962, 287, 228.
8956 J. Org. Chem. Vol. 73, No. 22, 2008

DeriVatization of Aminobenzoic Acids
TABLE 2. One-Pot Synthesis of Aminobenzamides
entry
carboxylic acid (1)
4-aminobenzoic
4-aminobenzoic
4-aminobenzoic
4-aminobenzoic
4-aminobenzoic
3-aminobenzoic
3-aminobenzoic
3-aminobenzoic
6-aminonicotinic
6-aminonicotinic
6-aminonicotinic
amine (3)
product
yield (%)
1
2
3
4
5
8
9
4-methylaniline
4-nitroaniline
4-methoxyaniline
pyrrolidine
2,6-dichloroaniline
4-methylaniline
4-nitroaniline
2,6-dichloroaniline
4-methylaniline
4-nitroaniline
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
88a
88
85
91
60
82
89
63
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
91
83
pyrrolidine
84
6-aminonicotinic
2,6-dichloroaniline
2,6-dichloroaniline
4-nitroaniline
2,6-dichloroaniline
3-chloroaniline
4-nitroaniline
2,6-dichloroaniline
2-diethylaminoethylamine
4-nitroaniline
2,6-dichloroaniline
4-nitroaniline
48 (74%)b
2-aminopyridin-4-ylcarboxylic
3-amino-1,2,4-triazol-5-ylcarboxylic (0.5H2O)
3-amino-1,2,4-triazol-5-ylcarboxylic (0.5H2O)
4-amino-2-hydroxybenzoic
4-amino-3,5-dichlorobenzoic
4-amino-3,5-dichlorobenzoic
4-amino-3-chloro-6-methoxybenzoic
5-amino-2-nitrobenzoic
5-amino-2-nitrobenzoic
4-amino-3-nitrobenzoic
4-amino-3-nitrobenzoic
4-amino-3-chlorobenzoic
3-aminobenzoic
29
50c (90)b,c
20c (34)b,c
67
87
33 (72)b
84b
6t
87
61
85
59
6u
6v
6w
6x
6y
6z
2,6-dichloroaniline
2-aminothiazole
4-aminopyridine
3-aminobenzoic acid
42
64d
3-aminobenzoic
87e
a DIPEA used in place of py. b 2 equiv of 3 was used. c 2.5 equiv of DMF/COCl2 was used. d DMAP was added. e No base was used.
SCHEME 3. Formation of Quinazolinone 9
19 and 20) required several hours (see the Supporting
Information for details).
We found our method to be convenient for the synthesis of
several benzamides of pharmaceutical interest. For example, we
used our protocol to obtain a reported potent epidermal growth
factor receptor inhibitor6b (entry 18), adenosine 2A receptor
ligand13 (entry 26), antiemetic metoclopramide (entry 21), and
bradykinin antagonist5 (entry 27) in moderate to good yields.
We also prepared the dimer of 3-aminobenzoic acid 6z (entry
28), a core feature in several DNA-binding agents,1d,f,g,j using
our one-pot procedure, while the classical method required
two steps.32 Interestingly, the use of pyridine in the synthesis
of 6z resulted in the formation of multiple products. The best
yield of 6z was obtained when no base was employed in the
derivatives as intermediates in the synthesis of quinazolines36
warrants the development of other methods.
amide formation step, with DMF itself, possibly, acting as a
base.33
When we tried to apply our approach to the reaction of
2-aminobezoic acid and 4-methylaniline, the intermediate 8
formed in high yield (LC-MS analysis). However, this com-
pound was unstable and cyclized to quinazolinone 9, when the
reaction mixture was left for 16 h at room temperature (Scheme
3). Attempts to deprotect 8 immediately after formation by
heating it with ethylenediamine, other amines, or hydrochloric
acid led to mixtures of 9 and the desired product 10a in various
ratios.
Encouraged by the above results we decided to expand the
scope of our method to 2-aminobenzoic acid. Although several
direct methods for the preparation of 2-aminobenzanilides are
known, for example, via isatoic anhydride34 or from the acid
itself utilizing thionyl chloride,35 the importance of these
(32) Bredereck, H.; Schuh, H. Chem. Ber. 1948, 81, 215.
(33) DMF forms strong complexes with HCl having the composition
DMF ·HCl and DMF ·2HCl, in both neat and 1,1,2,2-tetrachloroethane solutions: (a)
Kislina, I. S.; Librovich, N. B.; Maiorov, V. D. Russ. Chem. Bull. 1994, 43,
1505. (b) Kislina, I. S.; Maiorov, V. D.; Sysoeva, S. G. Russ. Chem. Bull. 1997,
46, 916.
We envisioned that the most straightforward way to prevent
the unwanted cyclization to 9 would be to create a steric
(34) For example, see: (a) Manhas, M. S.; Amin, S. G.; Rao, V. V. Synthesis
1977, 309. (b) Kornet, M. J. Heterocycl. Chem. 1992, 29, 103.
(35) For example, see: (a) Garin, J.; Merino, P.; Orduna, J.; Tejero, T.; Uriel,
S. Tetrahedron Lett. 1991, 27, 3263, and references cited therein. (b) Tani, J.;
Yamada, Y.; Oine, T.; Ochiai, T.; Ishida, R.; Inoue, I. J. Med. Chem. 1979, 22,
95.
(36) (a) Armanego, W. L. F. The Chemistry of Heterocyclic Compounds.
Vol. 24. Fused Pyrimidines. Part I. Quinazolines; Weissberger, A., Ed.; Wiley
Interscience: New York, 1967, p. 87. (b) Brown, D. J. The Chemistry of
Heterocyclic Compounds. Vol. 55. Quinazolines, Suppl. I; Taylor, E. C., Ed.;
Wiley Interscience: New York, 1996, p. 31.
J. Org. Chem. Vol. 73, No. 22, 2008 8957

Zhichkin et al.
SCHEME 4. Preparation of Anthranylamides 10
0 °C, and the mixture was stirred at rt for 1 h. [A small sample of
2 was filtered under nitrogen and characterized by 1H NMR: (300
MHz, CD3CN) δ 13.06 (br s, 1H), 8.28 (d, J ) 12.3 Hz, 1H), 8.18
(d, J ) 8.9 Hz, 2H), 7.85 (d, J ) 8.8 Hz, 2H), 3.56 (s, 3H), 3.73
(s, 3H).] To the resulting suspension of 2 was added a solution of
3a (1.07 g, 10.0 mmol) in CH2Cl2 (10 mL), followed by the
dropwise addition of DIPEA (5.16 g, 40.0 mmol) with cooling to
keep the reaction temperature below 20 °C. After 1 h at rt, 10% aq
K2CO3 (20 mL) was added, and the aq layer was separated and
extracted with CH2Cl2 (20 mL). The combined organic layers were
dried over Na2SO4 and concentrated, and the resulting residue was
triturated with EtOAc (10 mL) to afford a 76% yield (2.14 g) of 4
as an off-white solid: mp 138-140 °C; 1H NMR (300 MHz,
DMSO-d6) δ 9.93 (s, 1H), 7.86 (s, 1H), 7.85 (d, J ) 8.4 Hz, 2H),
7.65 (d, J ) 8.4 Hz, 2H), 7.13 (d, J ) 8.3 Hz, 2H), 7.01 (d, J )
8.6 Hz, 2H), 3.04 (s, 3H), 2.95 (s, 3H), 2.27 (s, 3H); 13C NMR (75
MHz, DMSO-d6) δ 164.9, 155.0, 154.1, 136.9, 132.0, 128.8, 128.6,
127.5, 120.21, 120.19, 33.9, 20.4. Anal. Calcd for C17H19N3O: C,
72.57; H, 6.81; N, 14.94. Found: C, 72.29; H, 6.91; N, 14.76.
Deprotection of 4 to 4-Amino-N-(4-tolyl)benzamide (6a). 4
(140 mg, 0.50 mmol) was mixed with ethanol (3 mL) and
ethylenediamine (135 mg, 2.25 mmol), and the mixture was heated
at reflux overnight. The cooled mixture was evaporated to dryness,
and the residue was triturated with water (10 mL) to afford 6a in
80% yield (90 mg) as a white solid: 1H NMR (300 MHz, DMSO-
d6) δ 9.67 (s, 1H), 7.70 (d, J ) 8.6 Hz, 2H), 7.62 (d, J ) 8.4 Hz,
2H), 7.10 (d, J ) 8.3 Hz, 2H), 6.59 (d, J ) 8.6 Hz, 2H), 5.73 (s,
hindrance around the amidine carbon by using a larger dialky-
lamino group. Using our general conditions, but replacing DMF
in the protection-activation reaction with N,N-diisopropylfor-
mamide (Scheme 4), we obtained the N,N-diisopropylforma-
midine protected amide 11a (LC-MS analysis). As expected,
11a was stable and not prone to cyclization. However, the
enhanced stability of 11a was such that our standard deprotection
method of heating with ethylenediamine in refluxing ethanol
failed to remove the protecting group. Nevertheless, heating at
a higher temperature with the more nucleophilic N,N′-dimeth-
ylethylenediamine accomplished the deprotection smoothly,
affording 10a in 82% isolated yield. To our satisfaction, this
reaction also could be extended to poorly reactive 4-nitro- and
2,6-dichloroanilines to provide the corresponding amides 10b
and 10c. In a manner similar to some other examples mentioned
above, 2 equiv of 2,6-dichloroaniline was necessary to afford
10c in a satisfactory yield (56%). We note that this yield was
double the one reported in the literature (28%) for the
conventional procedure depicted in Scheme 1A.37 To the best
of our knowledge, the described procedure is the first example
of the use of N,N-diisopropylformamidine as a protecting group.
In summary, a method for the simultaneous protection and
activation of aminobenzoic acids for amide formation has been
developed. The transformation was effected by the reaction of
aminobenzoic acids with excess Vilsmeier reagent, affording
N,N-dimethylformamidine protected acid chlorides. These acid
chlorides were used in situ for direct coupling reactions with
amines, particularly, with weakly nucleophilic anilines to form
the corresponding anilides. A novel method for the deprotection
of the N,N-dimethylformamidine group with ethylenediamine
was developed and applied to the resulting amides. The
combination of the above steps resulted in a convenient one-
pot synthesis of amides of aminobenzoic acids. For many
substrates, we find this protocol to be superior to the classical
3-4 step methods in terms of speed, materials availability, and
generality. The procedure was also successfully applied to
several targets of pharmaceutical interest. A novel N,N-
diisopropylformamidine protecting group was developed along
the way, allowing the extension of the one-pot protocol to the
preparation of amides of 2-aminobenzoic acid.
1
2H), 2.26 (s, 3H). The H NMR spectrum of this product was
consistent with literature data.8
General One-Pot Procedure for the Preparation of 3- and
4-Aminobenzanilides: 6-Amino-N-(4-nitrophenyl)nicotinamide
(6j). 6-Aminonicotinic acid (1.38 g, 10.0 mmol) was added at 0
°C to Vilsmeier reagent (20.0 mmol) in CH2Cl2 (20 mL) prepared
as described above, then the mixture was stirred at rt for 1 h. CH2Cl2
(10 mL) was added, followed by pyridine (2.45 g, 31.0 mmol) at
0 °C, then the mixture was stirred for 30 min at rt. 4-Nitroaniline
(1.38 g, 10.0 mmol) was added, and the reaction was stirred for a
further 1.5 h. It was then concentrated to dryness, and the residue
was heated at reflux in ethanol (25 mL) with ethylenediamine (2.70
g, 45.0 mmol) for 30 min. The resulting mixture was evaporated
to dryness, stirred with water (50 mL), and filtered. The filter cake
was triturated with methanol (6 mL) to afford 6j as a yellow solid
1
(2.14 g, 83%): mp 275-277 °C; H NMR (300 MHz, DMSO-d6)
δ 10.46 (s, 1H), 8.65 (d, J ) 2.2 Hz, 1H), 8.24 (d, J ) 9.3 Hz,
2H), 8.04 (d, J ) 9.3 Hz, 2H), 7.96 (dd, J ) 8.8, 2.4 Hz, 1H), 6.78
(s, 2H), 6.52 (d, J ) 8.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6)
δ 164.8, 162.0, 149.5, 145.9, 142.0, 136.7, 124.7, 119.4, 117.3,
112.3, 106.9. Anal. Calcd for C12H10N4O3: C, 55.81; H, 3.90; N,
21.70. Found: C, 55.56; H, 3.81; N, 21.41.
General One-Pot Procedure for the Preparation of 2-Ami-
nobenzanilides: 2-Amino-N-(4-tolyl)benzamide (10a). The chlo-
rinating-protecting reagent was prepared from N,N-diisopropylfor-
mamide (2.67 g, 20.7 mmol) and oxalyl chloride (2.52 g, 19.8
mmol) in CH2Cl2 (20 mL) following the above procedure for the
preparation of Vilsmeier reagent. 2-Aminobenzoic acid (1.37 g, 10.0
mmol) was added at 0 °C, and the mixture was stirred at rt for 1 h.
A solution of 4-methylaniline (1.07 g, 10.0 mmol) in CH2Cl2 (10
mL), followed by pyridine (2.45 g, 31.0 mmol), was added at 0 °C
and the mixture was stirred at 0 °C for 30 min. After warming to
room temperature, the reaction was evaporated to dryness. A
solution of N,N′-dimethylethylenediamine (3.94 g, 44.7 mmol) in
ethanol (25 mL) was added, and the mixture was heated at reflux,
allowing the solvent to distill until the internal temperature reached
110 °C. The reflux was continued at that temperature for 14 h, at
which point the reaction was complete. Evaporation to dryness,
followed by trituration with water (50 mL) afforded an 82% yield
Experimental Section
Preparation of 4-((Dimethylamino)methyleneamino)-N-4-tolyl-
benzamide (4). The Vilsmeier reagent was prepared by adding
oxalyl chloride (2.52 g, 19.8 mmol) dropwise to a solution of anhyd
DMF (1.50 g, 20.5 mmol) in CH2Cl2 (20 mL) at 0-5 °C (Caution:
Foaming!) with stirring at rt for 30 min. 1a (1.37 g) was added at
1
(1.85 g) of 10a as a white powder: H NMR (300 MHz, DMSO-
d6) δ 9.91 (s, 1H), 7.60 (d, J ) 6.2 Hz, 1H), 7.59 (d, J ) 8.4 Hz,
2H), 7.19 (td, J ) 7.7, 1.2 Hz, 1H), 7.13 (d, J ) 8.3 Hz, 2H), 6.74
(37) Zumstein, F.; Assmann, E.; Koenigsberger, R.; Holzbauer, R.; Zumstein,
F. German Patent 2012094, 1972.
8958 J. Org. Chem. Vol. 73, No. 22, 2008

DeriVatization of Aminobenzoic Acids
(d, J ) 7.9 Hz, 1H), 6.58 (t, J ) 7.4 Hz, 1H), 6.30 (s, 2H), 2.27
(s, 3H). The 1H NMR spectrum of this product was consistent with
literature data.8
Supporting Information Available: Detailed experimental
procedures for all compounds prepared, characterization data,
1
1H and 13C NMR spectra for novel compounds, and H NMR
spectra for literature compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. The authors would like to thank Dr. R.
Jason Herr for the thorough reading and many helpful sugges-
tions to our manuscript.
JO8017186
J. Org. Chem. Vol. 73, No. 22, 2008 8959