Oligoanthranilamides. Non-peptide subunits that show formation of specific secondary structure

Article abstract of DOI:10.1021/ja9539857

A family of novel oligomers based on the anthranilamide nucleus has been prepared and shown to form well-defined secondary structural features. ¹H NMR and X-ray crystallographic techniques have demonstrated that intramolecular hydrogen bonds play a key role in stabilizing both linear sheet and helical conformational forms.

Full text of DOI:10.1021/ja9539857

+
+
J. Am. Chem. Soc. 1996, 118, 7529-7541
7529
Oligoanthranilamides. Non-Peptide Subunits That Show
Formation of Specific Secondary Structure
Yoshitomo Hamuro, Steven J. Geib, and Andrew D. Hamilton*
Contribution from the Department of Chemistry, UniVersity of Pittsburgh,
Pittsburgh, PennsylVania 15260
ReceiVed NoVember 27, 1995X
Abstract: A family of novel oligomers based on the anthranilamide nucleus has been prepared and shown to form
well-defined secondary structural features. 1H NMR and X-ray crystallographic techniques have demonstrated that
intramolecular hydrogen bonds play a key role in stabilizing both linear sheet and helical conformational forms.
Introduction
The modular construction and structural diversity of proteins
provides a paradigm for the design of new molecules with
controlled conformations and defined functions. Repeating
R-amino acids subunits form regions of ordered secondary struc-
ture such as R-helices and â-sheets which in turn provide the
scaffolding onto which binding or catalytic groups are linked.1
Intramolecular hydrogen bonds between amide groups in the
peptide backbone play a critical role in stabilizing secondary
structural regions. A key feature of R-amino acids as building
blocks is that small modifications in form and sequence can
lead to shifts in the intramolecular hydrogen bonding pattern
and so generate a wide range of protein tertiary structures.
In the past few years there has considerable interest in the
preparation of new materials based on modular designs and
constructed from families of variable monomers. In some cases
structural integrity of the materials has been maintained by using
rigid components such as the [1,1,1]bicyclopentanes of Michl2
or the [2,2,2]bicyclooctanes of Zimmerman.3 In others inter-
locking rings, as in Stoddart’s catenanes,4 rigidify the super-
structure. A particularly attractive approach for the construction
of molecular scaffolding is to emulate the biological strategy
of using intramolecular hydrogen bonding to control conforma-
tion.5 This has the advantage of allowing a modular approach
with high yielding amide or ester bond forming steps but with
rigidity imposed by directed hydrogen bonds in place of
polycyclic structures.6 Nowick has recently shown that in-
tramolecular hydrogen bonds can be used to control the structure
of oligourea scaffolds,7 as in 1, and Schreiber has demonstrated
the formation of both helical and sheet structures using
vinylogous amino acids,8 2. A series of peptide-derived oligo-
carbamates9 reported by Schultz, and vinylogous sulfonamides10
recently reported by Gennari, may also exploit intramolecular
hydrogen bonds in the formation of folded conformations.
Our interest lay in developing a simple family of molecular
components that could be connected in different ways to give
a range of compact and well-defined secondary structures.
Several factors can be employed to contribute to the relative
stability of these folded conformations including: (a) intramo-
lecular hydrogen bonding between adjacent or distant subunits,
(b) π-stacking between subunits, (c) rigidification, where
possible, of the subunits to minimize conformational freedom
and torsional strain in the folded state, and (d) destabilization
of alternative, unwanted conformations.
We decided initially to investigate the chemistry of â-amino
acids as building blocks for well-defined molecular scaffolding.
These offer several advantages including ease of synthesis11 and
the potential for intramolecular hydrogen bonding both to
adjacent and distant amide groups.12 One of the simplest
â-amino acids is anthranilic acid. This has the possibility as
its diamido derivative to form stable six-membered ring
hydrogen bonds between adjacent amides (as in 3) with the
potential of additional binding to the externally directed CO
and NH groups. These intramolecular interactions together with
the intrinsic rigidity and trans preference of the secondary amide
bond should, when combined with differently shaped compo-
nents, provide oligomers with a controllable and stable second-
ary structure. Moreover, anthranilic acid subunits can be readily
prepared with different substituents in the 4- and 5-positions,
and their coupling can be accomplished using simple carboxyl
activating routes (such as acid chloride, DCC, etc.). The long
X Abstract published in AdVance ACS Abstracts, June 15, 1996.
(1) For a recent text, see: Brandon, C.; Tooze, J. Introduction to Protein
Structure; Garland Publishing Inc.: New York, 1991.
(2) Hassenru¨ck, K.; Murthy, G. S.; Lynch, V.; Michl, J. J. Org. Chem.
1990, 55, 1013-1016.
(3) Zimmerman, H. E.; Goldman, T. D.; Hirzel, T. K.; Schmidt, S. P. J.
Org. Chem. 1980, 45, 3933-3951.
(4) Philp, D.; Stoddart, J. F. Syn. Lett. 1991, 445-458.
(5) For a recent discussion of the role of intramolecular hydrogen bonding
in a family of simple diamides, see: Dado, G. P.; Gellman, S. H. J. Am.
Chem. Soc. 1993, 115, 4228-4245.
(6) Several synthetic receptors contain intramolecular hydrogen bonds
as an integral part of their structure: Dixon, R. P.; Geib, S. J.; Hamilton,
A. D. J. Am. Chem. Soc. 1992, 114, 365-367. Nowick, J. S.; Ballester,
P.; Ebmeyer, F.; Rebek, J. Jr. J. Am. Chem. Soc. 1990, 112, 8902-8906.
Murray, T. J.; Zimmerman, S. C. J. Am. Chem. Soc. 1992, 114, 4010-
4011.
(8) Hagihara, M.; Anthony, N. J.; Stout, T. J.; Clardy, J.; Schreiber, S.
L. J. Am. Chem. Soc. 1992, 114, 6568-6570.
(9) Cho, C. Y.; Moran, E. J.; Cherry, S. R.; Stephans, J. C.; Fodor, S. P.
A.; Adams, C. L.; Sundaram, A.; Jacobs, J. W.; Schultz, P. G. Science
(Washington D.C.) 1993, 261, 1303-1305.
(10) Gennari, C.; Salom, B.; Potenza, D.; Williams, A. 1994, 3, 2067-
2069. Angew. Chem., Int. Ed. Engl. 1994, 33, 2067-2069.
(11) Chu, K. S.; Konopelski, J. P. Tetrahedron 1993, 9183-9190, and
references therein.
(7) Nowick, J. S.; Powell, N. A.; Martinez, E. J.; Smith, E. M.; Noronha,
G. J. Org. Chem. 1992, 57, 3763-3765.
(12) Dado, G. P.; Gellman, S. H. J. Am. Chem. Soc. 1994, 116, 1054-
1062.
S0002-7863(95)03985-0 CCC: $12 00 © 1996 American Chemical Society

+
+
7530 J. Am. Chem. Soc., Vol. 118, No. 32, 1996
Hamuro et al.
Figure 1. X-ray structure of anthranilamide 15 in extended sheet
conformation.
aniline derivatives. All activation methods attempted (acid
chloride, DCC, CDI, EEDQ) failed to form the anilide product
but rather gave azlactone 6, from intramolecular cyclization of
the benzamide oxygen onto the carboxyl derivative.17 A more
successful strategy involved masking the amide as a nitro group
which can be reduced to the required amine after amide bond
formation.18,19 Reaction of 2-nitrobenzoyl chloride with methyl
anthranilate gave, in 77% yield, nitroamide 7 which could then
be hydrogenated over palladized charcoal to amine 8. Further
reaction with 2-nitrobenzoyl chloride gave trimer 9 which was
reduced to amine 10. This could be acetylated with acetyl
chloride to trimer 11 or subjected to another sequence of
acylation, reduction, and acetylation steps, through 12 and 13,
to tetramer 14.
term goal of this work is to develop functionalized molecular
scaffolds of defined structure with catalytic or recognition
properties. These modular structures can potentially be used
in combinatorial synthesis to form a large family of nonpeptide,
biopolymer mimetics.13 In this paper14 we demonstrate the
viability of the approach with the synthesis of two classes of
oligomeric anthranilamides which take up, respectively, linear
sheet and helical conformations.15
The Linear Strand
Simple head-to-tail coupling of anthranilic acid is expected
to lead to an oligomer which takes up an extended sheet
conformation stabilized, in part, by hydrogen bonding between
adjacent amides, as shown in 4. Initial attempts to effect a
stepwise synthesis of these molecules involved carboxyl activa-
tion of N-benzoylanthranilic acid16 5 followed by reaction with
An X-ray structure of the acetylated dimer 15 shows (Figure
1) the expected extended sheet structure with two intramolecular
hydrogen bonds between adjacent amide-amide (N‚‚‚O, 2.75
Å; H‚‚‚O, 2.06 Å) and amide-ester (N‚‚‚O, 2.67 Å; H‚‚‚O,
1.82 Å) groups. The molecule has an almost planar conforma-
tion with only a small deviation of the anthranilamide rings from
the plane of the amide bonds. Support for this conformation
1
in solution comes from H NMR which shows intramolecular
NOEs between the amide-NH and the adjacent anthranilamide-
6H resonances as well as large downfield shifts of both amide-
NH resonances (δ ) 12.05 and 11.16 ppm for, respectively,
anthranilamide and acetamide in CDCl3).
Similar downfield shifts are seen in the amide-NH resonances
of acetylated trimer 11 (δ ) 12.24, 12.17, and 11.23 ppm) and
tetramer 14 (δ ) 12.38, 12.29, 12.19, and 11.23 ppm) in CDCl3.
The effect of intramolecular hydrogen bonding on chemical shift
is illustrated in control 16a (formed by a method analogous to
15) which has a downfield shifted resonance for the hydrogen
bonded anthranilamide-NH (12.05 ppm) compared to that of
the acetamide (9.94 ppm). Further support for the extended
structure in solution comes from variable temperature measure-
ments of the amide-NH resonances. Internally hydrogen bonded
amides are expected to show a much smaller shift with
temperature (<3.0 × 10-3 ppm K-1) compared to those directed
externally and accessible for hydrogen bonding to a polar solvent
(>4.0 × 10-3 ppm K-1).20 Both amide-NH groups in 15 show
small changes with temperature in 20% DMSO-d6/CDCl3 (2.8
and 1.1 × 10-3 ppm K-1) consistent with their involvement in
(16) Steiger, R. E. J. Org. Chem. 1944, 9, 396-399.
(17) Errede, L. A.; Oien, H. T.; Yarian, D. R. J. Org. Chem. 1977, 42,
12-18.
(18) A related approach has been used to prepare cyclic anthranilamide
oligomers: (a) Hoorfar, A.; Ollis, W. D.; Stoddart, J. F. Tetrahedron Lett.
1980, 4211-4214. (b) Hoofar, A.; Ollis, W. D.; Price, J. A.; Stephanatou,
J. S.; Stoddart, J. F. J. Chem. Soc., Perkin Trans. 1 1982, 8, 1649-1699.
(c) Hoofar, A.; Ollis, W. D.; Stoddart, J. F. J. Chem. Soc., Perkin Trans. 1
1982, 8, 1721-1726. (d) Feigel, M.; Lugert, G.; Manero, J.; Bremer, M.
Liebig Ann. Chem. 1989, 1089-1092.
(13) Liskamp, R. M. Angew. Chem., Int. Ed. Engl. 1994, 33, 633-636.
(14) For preliminary communication of part of this work, see: Hamuro,
Y.; Geib, S. J.; Hamilton, A. D. Angew. Chem., Int. Ed. Engl. 1994, 33,
446-448.
(15) Similar intramolecular hydrogen bonds have been seen in a family
of anthranilic acid-amino acid adducts. Feigel, M.; Lugert, G.; Manero,
J.; Bremer, M. Z. Naturforsch. 1989, 44b, 1109-1116. Feigel, M.; Lugert,
G.; Manero, J.; Bremer, M. Z. Natorforsch. 1990, 45b, 258-266.
(19) Sengupta, D.; Anand, N. Indian J. Chem., Sect. B 1985, 24B, 923-
927.
(20) Kessler, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 512-523.

+
+
Oligoanthranilamides
J. Am. Chem. Soc., Vol. 118, No. 32, 1996 7531
1
Table 1. Selected H NMR Resonances of linear
intramolecular hydrogen bonds in solution. In contrast, those
of 16a show both small (anthranilamide; 3.4 × 10-3 ppm K-1
)
Oligoanthranilamides
and large (acetamide; 5.8 × 10-3 ppm K-1) temperature effects
as would be expected for one internally and one externally
directed proton.
chemical shifts (ppm)
anthranilamide NH’s
compd
solvent
acylamide NH
15
15
16a
11
14
21
22
23
24
CDCl3
DMSO-d6
CDCl3
CDCl3
CDCl3
CDCl3
DMSO-d6
CDCl3
11.16
10.42
9.94
11.23
11.23
11.11
10.35
11.15
11.44
12.05
11.29
12.05
12.17
12.19
12.32
11.27
12.26
12.57
IR experiments also support the intramolecular hydrogen
bonding secondary structure control in solution. IR spectra of
linear strands (15, 11, and 14), functionalized linear strands (21,
23, and 24), and helices (31 and 32) were taken along with a
reference molecule 16b (2 mM in CH2Cl2). For all compounds
broad hydrogen bonded N-H stretch peaks were observed
around 3200-3300 cm-1, but no peaks were observed in free
N-H stretch region (3400-3500 cm-1) except for 16b which
12.24
12.29
12.38
11.37
12.44
12.83
12.38
12.38
11.41
12.44
12.93
CDCl3
had a relatively sharp peak at 3427 cm-1 7,12
.
intramolecular hydrogen bonding interactions are conserved in
these molecules in a similar manner to the simple linear systems.
Functionalized Linear Strands
This strategy can easily be adapted to allow the incorporation
of functionality into the linear strand. The disposition of the
substituents along the chain and, in particular, the face from
which they project can be controlled by the sequence in which
the individual subunits are reacted. For example, 4-(methoxy-
carbonyl)-2-nitrobenzoic acid 17 could be prepared from the
mono esterification (MeOH, H2SO4) of 2-nitroterephthalic acid
in 64% yield and reacted as its acid chloride with hexyl
anthranilate to give the functionalized dimer 18. Application
of the sequential transformations outlined above (including
hydrogenation of 18 over palladized charcoal to 19, reaction
with 2-nitrobenzoyl chloride to 20, further reduction and
acylation with 4-(methoxycarbonyl)-2-nitrobenzoyl chloride
followed by reduction and acylation with hexanoyl chloride)
provided the tetraamide 21. The methyl esters could be
selectively deprotected in 89% yield with LiOH in THF to give
the functionalized tetraanthranilamide 22 in which both car-
boxylic acid groups project from the same face.
The conservation of this conformation in solution suggests the
potential application of this series of molecules as scaffolds.
The Turn
Further development of the anthranilamides as general
scaffolding subunits required a family of components that would
enforce a turn in the molecule and so lead to potentially helical
conformations, as in 25. Several spacers can be envisioned that
would provide a turn unit through which two linear strands can
be attached. Because a key goal of this work is to maintain
structure by intramolecular hydrogen bonding, an interesting
candidate was pyridine-2,6-dicarboxamide N-oxide 26 and its
derivatives. A crystal structure of the corresponding dicar-
boxylic acid21 27 shows two very short, six-membered ring
intramolecular hydrogen bonds between the acidic hydrogens
and the N-oxide (O‚‚‚O; 2.48 and 2.45 Å). Analogous interac-
tions would be expected to stabilize a turn between two an-
thranilamide units (where R ) 2-benzoate) with an approxi-
mately 120° angle between the phenyl-N bonds. Furthermore,
In a related series of steps differentially protected 2-nitro-
terephthalic acid derivatives were incorporated into the synthesis
in a stepwise manner. The result was a tetramer, 23 or 24, in
which different functionality projected on opposite sides of the
linear strand.
Similar downfield shifts of the amide protons, as in simple
linear compounds 15, 11, and 14, were observed in function-
alized linear compounds 21-24 (Table 1). This indicates that
(21) For a crystal structure, see: (a) Rychlewska, U.; Gdaniec, M. Acta
Cryst. 1977, B33, 3555-3558. (b) Brzezinski, B.; Zundel, G.; Kra¨mer, R.
Chem. Phys. Lett. 1986, 124, 395-400. For a synthesis, see: (c) Heywood,
D.; Dunn, J. J. Org. Chem. 1959, 24, 1569-1570.

+
+
7532 J. Am. Chem. Soc., Vol. 118, No. 32, 1996
Hamuro et al.
reaction of the anilide of anthranilic acid with the two pyridine
diacid chlorides to give 36 and 37.
this arrangement would be favored by a destabilization of the
alternative planar conformation 28 in which three electronegative
oxygen atoms are in close proximity. A simple modification
of the approach would involve using pyridine-2,6-dicarboxamide
29 in place of the N-oxide. Several X-ray structures of pyridine-
2-carboxamide or pyridine-2,6-dicarboxamide derivatives22 show
an almost planar arrangement of the pyridine and carboxamide
groups with close positioning of the pyridine-N and amide-H
(N‚‚‚N, 2.73 and 2.74 Å, N‚‚‚H, 2.61 and 2.63 Å), consistent
with formation of two weak hydrogen bonds (as in 29).
However, intramolecular hydrogen bonding may play a minor
role in 29 due to the reduced basicity of the pyridine and the
less favorable five-membered ring.23 As with 28 the repulsive
electrostatic interactions present in the alternative conformation
30 (from 180° rotation of each pyridine-carboxamide bond)
should also lead to an increased population of the desired turn
structure 29. This is further supported by recent computational
studies on pyridine-2,6-dicarboxamide derivatives which show
a preference of conformation 29 over 30 by 112 kcal mol-1 in
the gas phase.24 The five- or six-membered ring intramolecular
hydrogen bonding arrangements in 26 or 29 should allow a
manipulation of the relative orientations of the two anthranil-
amide subunits.
The Helix
Combining the strand and turn subunits discussed above can
lead in a very simple way to structures with a helical conforma-
tion stabilized by a network of intramolecular hydrogen bonds
between the different components. For example, reaction of
amine 8 with pyridine-2,6-dicarbonyl chloride or pyridine-N-
oxide-2,6-dicarbonyl chloride gave tetraamides 31 and 32 in
76% and 69% yield, respectively.25 In both 31 and 32 the key
structural features that will determine the preferred conformation
are the intramolecular hydrogen bonds, the rigidity and trans
requirement of the amide bonds, and the destabilization of
alternative conformations. These all should constrain the
molecule into a geometry that positions the two terminal
anthranilamide rings above and below each other. The resulting
helical structure (shown from the side in 33) can be compared
to the structure of the helicenes,26 but in this case stabilization
derives from hydrogen bonding rather than fused aromatic
rings.27-29 A second series of molecules was formed from the
The X-ray crystal structures of 31 and 32 have been
determined and confirm that both molecules take up a helical
conformation in the solid state. The structure of 31 shows
(Figure 2) a clear helical arrangement of the five rings stabilized
by a network of intramolecular hydrogen bonds (NHa‚‚‚N, 2.20
and 2.21 Å; NHa‚‚‚OC, 1.82 and 2.02 Å; NHb‚‚‚OC, 1.92 and
1.88 Å). As expected, the distance between the pyridine-N atom
(27) Several helical structures stabilized by metal template effects have
been reported: Constable, E. C. Angew. Chem., Int. Ed. Engl. 1991, 30,
1450-1451. Williams, A. F.; Piguet, C.; Bernardinelli, G. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 1490-1492. Koert, U.; Harding, M. M.; Lehn, J.
M. Nature 1990, 346, 339-342. Dietrich-Bucheker, C. O.; Guilhem, J.;
Pascard, C.; Sauvage, J. P. Angew. Chem., Int. Ed. Engl. 1990, 29, 1154-
1156. Constable, E. C.; Ward, M. D.; Tocher, D. A. J. Chem. Soc., Dalton
Trans. 1991, 1675-1683. Evans, D. A.; Woerpel, K. A.; Scott, M. J.
Angew. Chem., Int. Ed. Engl. 1992, 31, 430-432.
(28) For other examples of helical molecules stabilized by covalent
interactions, see: Deshayes, K.; Broene, R. D.; Chao, I.; Knobler, C. B.;
Diederich, F. J. Org. Chem. 1991, 56, 6787-6795, and references therein.
Fritsch, R.; Hartmann, E.; Andert, D.; Mannschreck, A. Chem. Ber. 1992,
125, 849. Gange, D.; Magnus, P.; Bass, L.; Arnold, E. V.; Clardy, J. J.
Am. Chem. Soc. 1980, 102, 2134-2135.
(29) For discussion of helical structures stabilized by intermolecular
hydrogen bonding, see: Bishop, R.; Dance, I. G. Top. Curr. Chem. 1988,
149, 137-188.
(22) (a) Muir, A. K. S.; Codding, P. W. Can. J. Chem. 1984, 62, 1803-
1806. (b) Alcock, N. W.; Moore, P.; Reader, C. J.; Roe, S. M. J. Chem.
Soc., Dalton Trans. 1988, 2959-2963. (c) Pelizzi, C.; Pelizzi, G. Acta
Crystallogr. 1979, B35, 126-128.
(23) Newkome, G. R.; Fronzcek, F. R.; Kohli, D. K. Acta Crystallogr.
1981, B37, 2114-2117.
(24) Hunter, c. A.; Purvis, D. H. Angew. Chem., Int. Ed. Engl. 1992, 31,
792-795.
(25) Kawamoto, T.; Prakash, O.; Ostrander, R.; Rheingold, A. L.;
Borovik, A. S. Inorg. Chem. 1995, 4294-4295.
(26) Meurer, K. P.; Vogtle, F. Top. Curr. Chem. 1985, 127, 1-76.
Vogtle, F. In Fascinating Molecules; Springer Verlag: Berlin, 1993; pp
156-180.

+
+
Oligoanthranilamides
J. Am. Chem. Soc., Vol. 118, No. 32, 1996 7533
Figure 2. Stereo representations of the front and side view of the X-ray structure of helical oligoanthranilamide 31.
Figure 3. Stereo representations of the front and side view of the X-ray structure of helical oligoanthranilamide 32.
and the adjacent amide-NH is relatively long reflecting the poor
hydrogen bond accepting character of the heterocycle. The
molecule forms a tight coil with close contact between the
terminal anthranilamide rings and a distance of 5.41 Å from
one center of the ring to the other, representing a helix with a
relatively small pitch. As a consequence of this conformation
the protons in the 4- and 5-position of the terminal phenyl ring
are positioned close to the face of the first anthranilamide ring
(Pha). Figure 2 shows the right-handed helix; however, the
crystal is racemic with both right- and left-handed forms present
in the unit cell.
network of hydrogen bonds in the turn region is apparent
although in this case the more favored six-membered ring
hydrogen bonding to the N-oxide leads to a shortening of the
H-bonding distance to the pyridine carboxamide-NH (NHa‚‚‚
ON, 1.83 and 1.84 Å) and a lengthening of the first anthranil-
amide interaction (NHa‚‚‚OC, 2.12 and 2.14 Å), with two further
hydrogen bonds (NHb‚‚‚OC, both 1.88 Å) in the terminal
anthranilamide rings. In addition, there is a wider separation
(compared to 31) of the two terminal anthranilamide rings (the
distance of two centers of the rings, 10.91 Å in 32). The
resultant increase in the pitch of the helix is presumably due to
the greater steric bulk of the pyridine N-oxide in the turn region
as well as the formation six- (rather than five-) membered ring
The X-ray structure of 32 (Figure 3) shows the persistence
of the helical motif despite changes in the molecule. The

+
+
7534 J. Am. Chem. Soc., Vol. 118, No. 32, 1996
Hamuro et al.
1
a
Table 2. Selected H NMR Resonances of Oligoanthranilamides in 20% DMSO-d6/80% CDCl3
compd
concn (mM)
NHa
NHb
Pha6
Pha5
Pha4
Pha3
Phb6
Phb5
Phb4
Phb3
15
16a
31
32
34
35
36
37
2
2
10
2
saturtd
2
10
11.08
9.94
12.02
11.99
11.61
11.77
11.21
12.24
9.74
7.88
7.79
7.57
7.86
8.13
7.99
7.78
7.73
7.23
7.79
7.25
7.37
8.13
7.99
7.27
7.31
7.54
7.96
7.65
7.66
8.24
8.36
7.55
7.54
8.58
7.96
8.85
8.58
8.24
8.36
8.38
8.23
8.12
8.10
7.92
7.92
8.13
8.13
6.89
7.17
7.21
7.14
6.92
6.95
7.17
7.25
6.89
6.97
7.66
7.60
6.69
7.29
7.63
7.35
6.89
7.17
8.76
8.87
8.45
8.81
8.54
8.80
7.29
7.73
13.05
13.68
12.10
12.58
12.48
13.15
10
10.08
a Pha and NHa refer to those groups adjacent to the pyridine and Phb and NHb to the terminal anthranilate.
Figure 4. Stereo representations of the front and side view of the X-ray structure of helical oligoanthranilamide 37.
intramolecular hydrogen bonds. This simple expansion in the
helical structure offers potential in the future for subtle
modification of the folded structures.
Further support for the role of intramolecular hydrogen
bonding in stabilizing the helical conformation of 31 comes from
the temperature dependence of the amide-NH resonances in 20%
DMSO-d6/CDCl3. Both NHa and NHb in 31 show a small
variation with temperature (2.9 × 10-3 and 1.1 × 10-3 ppm
K-1, respectively), as expected for intramolecularly H-bonded
amide-NH groups in a polar solvent.13 As a comparison, the
anilide-NH in 36, which is incapable of intramolecular H-
bonding, shows a large upfield shift with increasing temperature
(7.5 × 10-3 ppm K-1), while the NHa resonance undergoes little
change (2.1 × 10-3 ppm K-1).
The key question of whether these helical conformations are
maintained in solution can be investigated by 1H NMR and by
comparisons to controls such as 34 which due to the para
relationship of the substituents is incapable of forming a helix.
The spectrum of 31 in 20% DMSO-d6/80% CDCl3 solution
shows several features consistent with a helical structure, and
some of these resonances are collected with those of other
oligomers in Table 2. In particular, there is a large downfield
shift of the pyridine carboxamide-NHa resonance in 31 compared
to the equivalent resonance in 15 and 34 indicating a bifurcated
intramolecular hydrogen bond from the first anthranilamide-
NHa to both pyridine-N and carbonyl-O. In contrast, the second
amide-NHb as well as the 6-, 5-, 4-, and 3-protons of the terminal
anthranilamide are shifted upfield (0.41, 0.20, 0.29, 0.97, and
0.31 ppm, respectively) compared to 15. This is consistent with
their position in a helical conformation above the ring current
of the opposing aromatic rings, as depicted in 33. The nearly
1 ppm upfield shift of the proton in the 4-position of the terminal
ring appears to correlate well with the crystal structure of 31
which shows it positioned directly above the plane of the first
This helical motif based on the pyridine and pyridine-N-oxide
turn region appears to be a general one. Removing the carboxyl
substituent in the terminal rings,30 as in anilides 36 and 37, leads
to a loss of the structural control imposed by the intramolecular
hydrogen bond and a consequent increase in flexibility around
the phenyl-N bond. Nonetheless, in both molecules the helical
conformation is maintained. The X-ray structure of N-oxide
37 shows a helical arrangement of the six-membered rings
stabilized by two short (NO‚‚‚HN, 1.82 and 1.86 Å) and two
long (NH‚‚‚OC, 2.42 and 2.21 Å) intramolecular hydrogen
bonds (Figure 4). The overall structure is similar to that of 32
with an expanded helix and a terminal ring distance of 8.65 Å.
The major disruption compared to 32 is the requirement for
the anilide-NH to satisfy its hydrogen bonding needs intermo-
lecularly rather than intramolecularly. Each helix forms two
intermolecular hydrogen bonds to a neighboring helix of
opposite handedness (from the anilide-NH to the pyridine-CO
and visa versa). In pyridine 36 the formation of extensive
1
anthranilamide ring. The H NMR spectrum of 32 in 20%
DMSO-d6/80% CDCl3 is similar to that of 31 with large
downfield shifts of the amide-NHa and NHb resonances,
reflecting strong intramolecular hydrogen bonding in solution.
However, the expanded helical structure of 32 which is seen in
the crystal (Figure 3) is also suggested by its 1H NMR spectrum
which shows (Table 2) smaller upfield shifts of Phb-4H and
Phb-5H due to the greater distance between the aromatic rings.
(30) For the synthesis of anthranylaniline, see: Clark, C. R.; Lin, C.
M.; Sansom, R. T. J. Med. Chem. 1986, 29, 1534-1537.

+
+
Oligoanthranilamides
J. Am. Chem. Soc., Vol. 118, No. 32, 1996 7535
structural changes into the molecules. We are currently
preparing extended and substituted versions of these scaffolds
to act as structural and functional analogs of protein secondary
structures.
Experimental Section
General Methods. CH2Cl2 was obtained from Fisher and distilled
from P2O5. Et2O and THF were obtained from Fisher and distilled
from sodium benzophenone ketyl. All other reagents, unless otherwise
noted, were obtained from the Aldrich Chemical Company and used
without further purification.
1H NMR and 13C NMR spectra were recorded on a Bruker AM-300
(300 MHz). NMR chemical shifts are reported in ppm downfield from
internal TMS. FT-IR spectra were obtained on Mattson Cygnus 100
instrument. CaF2 IR cell having a path length of 1.0 mm was used.
Mass spectra were determined at the Department of Chemistry,
University of Pittsburgh. EI and FAB mass spectra (MS) were obtained
using a Varian MAT CH-5 or VG 7070 mass spectrometer under the
direction of Dr. Kasi V. Somayajula. Melting points were determined
using an Electrothermal capillary melting point apparatus and are
uncorrected. Elemental analysis was carried out by Atlantic Microlab,
Inc., Norcross, GA.
Analytical thin layer chromatography (TLC) was conducted using
PolyGram 0.25 mm silica gel precoated plates with fluorescent indicator
UV254. Silica gel 60 (particle size 0.063-0.200 mm, 70-230 mesh
ASTM) (EM Science) was used for flash chromatography.
2-Benzoylaminobenzoic Acid (5). This compound was synthesized
according to a literature procedure:16 mp 180-181 °C (lit.16 181-182
Figure 5. Stereo representation of the front and side view of the X-ray
structure of helical oligoanthranilamide 36.
Table 3. 1H NMR Variable Temperature Data (from -40 to 40 °C
in 20% DMSO-d6/80% CDCl3)
compd concn (mM) NHa (10-3 ppm K-1
)
NHb (10-3 ppm K-1
)
1
°C); H NMR (300 MHz, DMSO-d6) δ 13.82 (s, 1H, acid), 12.19 (s,
15
16a
31
32
36
37
2
2
10
2
10
10
-1.1
-5.8
-2.9
-4.0
-2.1
-3.0
-2.8
-3.4
-1.1
-3.4
-7.5
-6.6
1H, amide), 8.71 (d, J ) 8.7 Hz, 1H), 8.05 (d, J ) 7.8 Hz, 1H), 7.95
(d, J ) 7.2 Hz, 2H), 7.62 (m, 4H), 7.20 (t, J ) 7.7 Hz, 1H); 13C NMR
(300 MHz, DMSO-d6) δ 170.1, 164.7, 141.2, 134.5, 134.4, 132.2, 131.3,
129.0, 127.0, 123.0, 119.9, 116.5; HRMS m/e calcd for C14H11NO3
241.0728, found 241.0739. Anal. calcd for C14H11NO3: C, 69.70; H,
4.60; N, 5.81. Found: C, 69.75; H, 4.65; N, 5.79.
2-Phenyl-4H-3,1-benzoxazin-4-one (6). A solution of 5 (121 mg,
0.50 mmol) and oxalyl chloride (72 mg, 0.55 mmol) in dry CH2Cl2 (3
mL) was stirred and cooled in an dry-ice/acetone bath. DMF (0.025
mL) was added to the mixture which was then stirred in an ice bath
for 3 h. Aniline (140 mg, 1.50 mmol) was added to the reaction mixture
which was then stirred for 10 min in the ice bath. After adding CH2-
Cl2 (15 mL), the reaction mixture was washed with 1 N HCl (15 mL),
saturated aqueous NaHCO3 (15 mL), and H2O (15 mL). The organic
layer was evaporated in vacuo to obtain a white powder. This white
powder seemed to be a cyclized compound from the results of NMR
and MS. The same compound was observed when BOP-Cl was used
for the same coupling reaction: mp 118-119 °C (lit.17 122-123 °C);
1H NMR (300 MHz, CDCl3) δ 8.32 (d, J ) 7.8 Hz, 2H), 8.25 (d, J )
7.8 Hz, 1H), 7.84 (t, J ) 7.7 Hz, 1H), 7.70 (d, J ) 8.4 Hz, 1H), 7.55
(m, 4H); 13C NMR (300 MHz, CDCl3) δ 157.1, 147.0, 136.6, 132.6,
130.2, 128.8, 128.6, 128.33, 128.28, 127.3, 119.9, 117.0; HRMS m/e
calcd for C14H9N2O 223.0633, found 223.0631.
2-(2-Nitrobenzoylamino)benzoic Acid Methyl Ester (7). A solu-
tion of 2-nitrobenzoic acid (33.4 g, 200 mmol) and oxalyl chloride
(27.9 g, 220 mmol) in dry CH2Cl2 (200 mL) was stirred and cooled in
an ice bath. DMF (0.78 g, 22 mmol) was added dropwise through a
silica gel filter, and the mixture was stirred at room temperature for 4
h. The reaction mixture was evaporated in vacuo to obtain the acid
chloride as a yellow oil. A solution of methyl anthranilate (30.2 g,
200 mmol) and pyridine (16.6 g, 220 mmol) in dry CH2Cl2 (200 mL)
was cooled in an ice bath with stirring. A solution of 2-nitrobenzoyl
chloride in CH2Cl2 (150 mL) was added dropwise for 15 min to the
reaction mixture, and then pyridine (11.0 g) was added to the mixture.
The mixture was stirred at room temperature for an additional 1 h.
CH2Cl2 (400 mL) was added to the mixture which was then washed
with 1 N HCl (500 mL), saturated aqueous NaHCO3 (200 mL), and
brine (200 mL). The organic layer was dried over MgSO4 and
evaporated in vacuo to give crude product (55.3 g, 92%). The crude
product was recrystallized from AcOEt (450 mL) and hexane (500 mL)
to obtain the desired compound as a pale yellow powder (46.4 g,
77%): mp 158-160 °C (lit.19 146-147 °C); 1H NMR (300 MHz,
Table 4. X-ray Crystal Structure Data
NO‚‚‚HaN
solvent
distance of
system for
compd or N‚‚‚HaN NHa‚‚‚OC NHb‚‚‚OC two ringsa recrystallization
15
31
2.06
2.02
1.82
2.12
2.14
3.71
2.11
2.42
2.21
1.82
1.88
1.92
1.88
1.88
AcOEt/hexane
CHCl3/hexane
2.21
2.20
1.83
1.84
2.20
2.25
1.82
1.86
5.41
10.91
8.32
32
36
37
THF/hexane
DMSO/THF/Et2O
THF/hexane
8.65
a Distance between two terminal rings, the average of the distance
of two Phb2C’s and that of Phb5C’s.
intermolecular contacts causes a larger deviation of the structure
from that in 31 (Figure 5). Each arm of each helix forms two
intermolecular hydrogen bonds to a neighboring helix analogous
to those in 37. In addition one anilide in Figure 5 forms an
edge-to-face interaction with the terminal anilide of second helix.
Despite a disruption of the π-stacking in the terminal rings
(terminal ring distance, 8.32 Å) and the formation of an
unexpected face-to-face π-stacking (the distance between the
terminal ring of the right arm and the anthranilamide ring of
the left arm, 4.34 Å), the pyridine-2,6-dicarboxamide imposes
a helical conformation on the molecule (NHa‚‚‚N, 2.20 and 2.25
Å; NHa‚‚‚OC, 3.71 and 2.11 Å).
In summary, we have shown that a very simple series of
anthranilic acid based subunits can be induced to take up, in
both the solution and solid state, linear and helical secondary
structural features stabilized, in part, by intramolecular hydrogen
bonds. These conformational features are quite general and are
taken up despite introduction of significant substitution or other

+
+
7536 J. Am. Chem. Soc., Vol. 118, No. 32, 1996
CDCl3) δ 11.55 (s, 1H, amide), 8.82 (d, J ) 8.4 Hz, 1H), 8.09 (d, J )
Hamuro et al.
MHz, CDCl3) δ 169.1 (2), 167.9 (2), 141.1, 140.4, 139.9, 134.9, 133.2,
8.1 Hz, 1H), 7.70 (m, 4H), 7.18 (t, J ) 7.7 Hz, 1H), 3.98 (s, 3H); 13
C
133.1, 131.2, 127.4, 127.3, 124.1, 123.5, 123.2 (2), 122.0, 121.4, 120.8,
NMR (300 MHz, CDCl3) δ 168.7, 164.4, 146.9, 141.0, 134.8, 133.8,
132.9, 130.9, 128.2, 124.7, 123.4, 120.6, 115.3, 52.5; HRMS m/e
calcd for C15H12N2O5 300.0746, found 300.0742. Anal. calcd for
C15H12N2O5: C, 60.00; H, 4.03; N, 9.33. Found: C, 60.09; H, 4.04;
N, 9.36.
120.5, 115.8; IR (2 mM in CH2Cl2) 3270, 1695, 1660, 1586, 1521 cm-1
;
HRMS m/e calcd for C24H21N3O5 431.1481, found 431.1463. Anal.
calcd for C24H21N3O5: C, 66.81; H, 4.91; N, 9.78. Found: C, 66.77;
H, 4.91; N, 9.76.
2-(2-(2-(2-Nitrobenzoylamino)benzoylamino)benzoylamino)ben-
zoic Acid Methyl Ester (12). To a solution of 10 (2.14 g, 5.5 mmol)
and pyridine (2.05 g, 22 mmol) in DMF (22 mL) was added
2-nitrobenzoyl chloride (4.08 g, 22 mmol), and then the reaction mixture
was stirred at room temperature for an additional 2 h. CH2Cl2 (200
mL) was added to the mixture which was then washed with 1 N HCl
(100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL).
The organic layer was dried over MgSO4 and evaporated in vacuo to
give the crude product as an orange solid (3.56 g). The crude product
was recrystallized from AcOEt (600 mL) and hexane (300 mL) to obtain
the desired compound as a pale brown powder (746 mg, 25%): mp
234-235 °C (lit.18c 226-228 °C); 1H NMR (300 MHz, CDCl3) δ 12.34
(s, 1H, anthranilamide), 12.17 (s, 1H, anthranilamide), 11.89 (s, 1H,
acetamide), 8.83 (m, 2H), 8.60 (d, J ) 8.1 Hz, 1H), 8.09 (m, 2H),
7.96 (d, J ) 6.8 Hz, 2H), 7.72 (m, 2H), 7.62 (m, 4H), 7.29 (m, 2H),
7.19 (t, 1H), 3.97 (s, 3H); 13C NMR (300 MHz, CDCl3) δ 169.1, 167.9,
167.7, 164.4, 147.0, 141.0, 140.2, 139.8, 134.9, 133.8, 133.4, 133.3,
133.2, 131.2, 130.8, 128.6, 127.5 (2), 124.8, 124.2 (2), 123.6, 122.1,
121.9, 121.6, 120.9, 120.7, 115.8, 52.8; HRMS m/e calcd for C29H22N4O7
538.1488 found 538.1468. Anal. calcd for C29H22N4O7: C, 64.68; H,
4.12; N, 10.40. Found: C, 64.56; H, 4.14; N, 10.37.
2-(2-(2-(2-Aminobenzoylamino)benzoylamino)benzoylamino)ben-
zoic Acid Methyl Ester (13). A suspension of the aforementioned
nitro compound 12 (539 mg, 1.0 mmol) and 10% Pd/C (108 mg) in
DMF (20 mL) was prepared in a 100 mL round-bottomed flask provided
with a magnetic stirrer. H2 was introduced after removal of air by an
aspirator and the solution was stirred vigorously for 2 h at room
temperature. The reaction mixture was filtered through a glass filter.
CH2Cl2 (160 mL) was added to the filtrate which was then washed
with brine (50 mL). CH2Cl2 (100 mL) and DMF (40 mL) were added
to the filtered residue which was then washed with brine (50 mL). The
organic layers were combined, dried over MgSO4, and evaporated in
vacuo to obtain the title compound as a yellow solid (522 mg). The
NMR indicated that this product was the mixture of DMF and the
desired compound (1:1 mol ratio). This means the purity of this product
was 87% (weight), and the yield of this reaction was 90%: 1H NMR
(300 MHz, CDCl3) δ 12.28 (s, 1H, amide), 12.16 (s, 1H, amide), 12.01
(s, 1H, amide), 8.76 (m, 3H), 8.11 (d, J ) 7.8 Hz, 1H), 7.95 (d, J )
7.8 Hz, 2H), 7.76 (d, J ) 7.8 Hz, 1H), 7.62 (m, 3H), 7.26 (m, 5H),
6.78 (t, J ) 7.7 Hz, 1H), 6.70 (d, J ) 8.1 Hz, 1H), 5.76 (s, 2H), 3.97
(s, 3H); 13C NMR (300 MHz, CDCl3) δ 169.1, 168.1, 168.0 (2), 149.3,
141.0, 140.6, 140.0, 134.9, 133.3, 133.0, 132.8, 131.2, 128.0, 127.5,
127.4, 124.0, 123.5, 123.3, 122.2, 121.8, 121.4, 120.9 (2), 117.7, 117.4,
116.0, 115.8, 52.8.
2-(2-(2-(2-Acetylaminobenzoylamino)benzoylamino)benzoylami-
no)benzoic Acid Methyl Ester (14). The tetramer 14 was prepared
by a route analogous to trimer 11 using aforementioned amine 13 (261
mg, 0.50 mmol), pyridine (1400 mg, 15 mmol), and acetyl chloride
(1200 mg, 15 mmol). The crude product (397 mg) was recrystallized
from AcOEt (130 mL) and hexane (120 mL) to obtain the desired
compound as a pale brown powder (142 mg, 50%): mp 235-236 °C,
1H NMR (300 MHz, CDCl3) δ 12.38 (s, 1H, amide), 12.29 (s, 1H,
amide), 12.19 (s, 1H, amide), 11.23 (s, 1H, amide), 8.82 (d, J ) 8.7
Hz, 1H), 8.71 (m, 2H), 8.11 (d, J ) 8.1 Hz, 1H), 7.98 (t, J ) 7.7 Hz,
3H), 7.90 (d, J ) 8.1 Hz, 1H), 7.62 (m, 3H), 7.52 (t, 1H), 7.32 (t, J )
7.5 Hz, 1H), 7.22 (m, 2H), 3.97 (s, 3H), 2.22 (s, 3H); 13C NMR (300
MHz, CDCl3) δ 169.1, 168.0, 167.86, 167.82, 167.77, 141.1, 140.4,
139.94, 139.88, 134.9, 133.3, 133.0 (2), 131.2, 127.7, 127.4 (2), 124.2,
124.1, 123.5, 123.2, 122.2, 121.9, 121.5, 121.4, 121.3, 120.8, 120.6,
115.9, 52.8, 25.5; IR (2 mM in CH2Cl2) 3260, 1694, 1655, 1608, 1588,
1516 cm-1; HRMS m/e calcd for C31H26N4O6 550.1852, found
550.1852.
2-(2-Aminobenzoylamino)benzoic Acid Methyl Ester (8).
A
solution of 7 (3.85 g, 12.8 mmol) and 10% Pd/C (0.39 g) in DMF (45
mL) was prepared in a 250-mL round-bottomed flask provided with a
magnetic stirrer. H2 was introduced after removal of air by an aspirator,
and the solution was stirred vigorously for 15 h at room temperature.
The catalyst was removed by filtration through Celite. CH2Cl2 (300
mL) was added to the filtrate which was then washed with saturated
aqueous NaHCO3 (100 mL) and brine (100 mL). The organic layers
were dried over MgSO4 and evaporated in vacuo to give the desired
compound as a red solid (3.34 g, 96%). This compound was used
without further purification in the next step: 1H NMR (300 MHz,
CDCl3) δ 11.83 (s, 1H, amide), 8.82 (d, J ) 8.4 Hz, 1H), 8.07 (d, J )
8.0 Hz, 1H), 7.73 (d, J ) 8.0 Hz, 1H), 7.59 (t, J ) 8.0 Hz, 1H), 7.26
(t, J ) 8.1 Hz, 1H), 7.10 (t, J ) 7.7 Hz, 1H), 6.78 (t, J ) 7.7 Hz, 1H),
6.71 (d, J ) 8.4 Hz, 1H), 5.75 (s, 2H), 3.95 (s, 3H); 13C NMR (300
MHz, CDCl3) δ 169.0, 168.2, 149.6, 141.9, 134.6, 132.6, 131.0, 127.7,
122.4, 120.4, 117.7, 117.1, 115.8, 115.3, 52.5.
2-(2-(2-Nitrobenzoylamino)benzoylamino)benzoic Acid Methyl
Ester (9). The nitro trimer 9 was prepared by a method analogous to
the dimer 7. A solution of the acid chloride from 2-nitrobenzoic acid
(10.0 g, 60 mmol) in CH2Cl2 (50 mL) was added dropwise to a solution
of 8 (8.11 g, 30 mmol) and pyridine (55.8 g, 60 mmol) in DMF (100
mL) and CH2Cl2 (100 mL). The crude product was recrystallized from
AcOEt and hexane three times to obtain the desired compound as pale
yellow thin needles (4.68 g, 37%): mp 156-158 °C (lit.18c 155 °C);
1H NMR (300 MHz, CDCl3) δ 12.14 (s, 1H, amide), 11.74 (s, 1H,
amide), 8.82 (d, J ) 8.4 Hz, 1H), 8.67 (d, J ) 8.4 Hz, 1H), 8.09 (t, J
) 6.8 Hz, 2H), 7.94 (d, J ) 8.1 Hz, 1H), 7.73 (m, 2H), 7.63 (m, 3H),
7.31 (t, 1H), 7.16 (t, 1H), 3.98 (s, 3H); 13C NMR (300 MHz, CDCl3)
δ 169.0, 167.8, 164.4, 147.1, 140.9, 140.1, 134.7, 133.8, 133.5, 133.2,
131.2, 130.8, 128.5, 127.3, 124.8, 124.1, 123.4, 122.0, 120.7 (2), 115.9,
52.8; HRMS m/e calcd for C22H17N3O6 419.1088, found 419.1117. Anal.
calcd for C22H17N3O6: C, 63.01; H, 4.09; N, 10.02. Found: C, 63.13;
H, 4.09; N, 10.00.
2-(2-(2-Aminobenzoylamino)benzoylamino)benzoic Acid Methyl
Ester (10). The amine 10 was prepared by a route analogous to 8
using 9 (3.15 g, 7.5 mmol) and 10% Pd/C (0.32 g) in DMF (30 mL).
The crude product was a mixture of DMF and the desired compound
(3:4 mol ratio), indicating the purity of this product was 88% (weight)
and the yield of this reaction was 91%. The material was used without
further purification in the next step: 1H NMR (300 MHz, CDCl3) δ
12.08 (s, 1H, amide), 11.95 (s, 1H, amide), 8.84 (d, J ) 8.4 Hz, 1H),
8.74 (d, J ) 8.4 Hz, 1H), 8.09 (d, J ) 8.1 Hz, 1H), 7.92 (d, J ) 8.1
Hz, 1H), 7.75 (d, J ) 7.8 Hz, 1H), 7.60 (m, 2H), 7.24 (t, 1H), 7.16 (t,
1H), 6.75 (t, 1H), 6.70 (d, J ) 8.1 Hz, 1H), 5.76 (s, 2H), 3.96 (s, 3H);
13C NMR (300 MHz, CDCl3) δ 169.0, 168.1, 168.0, 149.8, 141.1, 140.7,
134.8, 133.0, 132.8, 131.1, 127.9, 127.3, 123.2, 123.1, 121.8, 121.0,
120.7, 117.5, 117.0, 115.8, 115.6, 52.7; HRMS m/e calcd for C22H19N3O4
389.1376, found 389.1418.
2-(2-(2-Acetylaminobenzoylamino)benzoylamino)benzoic Acid
Methyl Ester (11). To a solution of 10 (389 mg, 1 mmol) and pyridine
(372 mg, 4.0 mmol) in DMF (4 mL) was added acetyl chloride (314
mg, 4.0 mmol) dropwise, and then the mixture was stirred at room
temperature for 3 h. CH2Cl2 (40 mL) was added to the reaction mixture
which was then washed with 1 N HCl (20 mL), saturated aqueous
NaHCO3 (20 mL), and brine (20 mL). The organic layer was dried
over MgSO4 and evaporated in vacuo to give crude product as a pale
yellow solid (363 mg). The crude product was recrystallized from THF
(50 mL) and hexane (60 mL) to obtain the desired compound as a
white powder (306 mg, 71%): mp 233-235 °C; 1H NMR (300 MHz,
CDCl3) δ 12.24 (s, 1H, anthranilamide), 12.17 (s, 1H, anthranilamide),
11.23 (s, 1H, acetamide), 8.81 (d, J ) 8.4 Hz, 1H), 8.72 (d, J ) 9.3
Hz, 2H), 8.10 (d, J ) 8.1 Hz, 1H), 7.96 (d, J ) 8.1 Hz, 1H), 7.90 (d,
J ) 6.6 Hz, 1H), 7.63 (m, 2H), 7.53 (t, J ) 7.2 Hz, 1H), 7.31 (t, J )
7.7 Hz, 1H), 7.19 (m, 2H), 3.97 (s, 3H, 2.23 (s, 3H); 13C NMR (300
2-(2-Acetylaminobenzoylamino)benzoic Acid Methyl Ester (15).
The dimer 15 was synthesized by a route analogous to trimer 11 using
amine 9 (2.70 g, 10 mmol), pyridine (1.86 g, 20 mmol) and acetyl
chloride (1.57 g, 20 mmol). The crude product (3.12 g) was

+
+
Oligoanthranilamides
J. Am. Chem. Soc., Vol. 118, No. 32, 1996 7537
recrystallized from AcOEt (100 mL) and hexane (150 mL) to obtain
the desired compound as pink crystals (2.72 g, 87%): mp 185-187
°C; 1H NMR (300 MHz, CDCl3) δ 12.05 (s, 1H, anthranilamide), 11.16
(s, 1H, acetamide), 8.77 (d, J ) 8.4 Hz, 1H), 8.67 (d, J ) 8.4 Hz, 1H),
8.10 (d, J ) 8.1 Hz, 1H), 7.86 (d, J ) 8.1 Hz, 1H), 7.63 (t, J ) 8.0
Hz, 1H), 7.53 (t, J ) 7.9 Hz, 1H), 7.20 (m, 2H), 3.96 (s, 3H), 2.23 (s,
3H); 13C NMR (300 MHz, CDCl3) δ 168.9, 168.8, 167.7, 141.0, 140.3,
134.8, 133.0, 131.0, 127.0, 123.1, 123.0, 121.4, 120.4, 120.2, 115.6,
52.6, 25.4; IR (2 mM in CH2Cl2) 3260, 1694, 1653, 1608, 1584, 1512
cm-1; HRMS m/e calcd for C16H16N2O4 312.1087, found 312.1110.
Anal. calcd for C16H16N2O4: C, 65.38; H, 5.16; N, 8.97. Found: C,
65.28; H, 5.21; N, 8.90.
NMR (300 MHz, CDCl3) δ 12.08 (s, 1H, benzamide), 8.87 (d, J ) 8.1
Hz, 1H), 8.40 (s, 1H, acetamide), 8.06 (dd, J ) 8.0, 1.3 Hz, 1H), 7.99
(d, J ) 8.7 Hz, 2H), 7.71 (d, J ) 8.4 Hz, 2H), 7.55 (t, J ) 7.2 Hz,
1H), 7.10 (t, J ) 7.7 Hz, 1H), 4.33 (t, J ) 6.6 Hz, 2H), 2.09 (s, 3H),
1.77 (q, J ) 6.8 Hz, 2H), 1.44 (m, 2H), 1.34 (m, 4H), 0.89 (t, J )
6.8 Hz, 3H); 13C NMR (300 MHz, CDCl3) δ 169.1, 168.7, 165.3,
141.82, 141.76, 134.6, 131.0, 130.0, 128.5, 122.6, 120.4, 119.4, 115.6,
65.8, 31.5, 28.5, 25.7, 24.7, 22.6, 14.1; IR (2 mM in CH2Cl2) 3427,
3306, 3266, 1675, 1608, 1590, 1512 cm-1; HRMS m/e calcd for
C22H26N2O4: 382.1893, found 382.1874.
2-Nitroterephthalic Acid 4-Methyl Ester (17). A solution of
nitroterephthalic acid (21.1 g, 100 mmol) and concentrated H2SO4 (5
mL) in MeOH (100 mL) was refluxed for 75 min. The mixture was
cooled to room temperature, and the solvent was evaporated in vacuo.
The residue was dissolved in aqueous NaHCO3 (300 mL) and washed
with CH2Cl2 (200 mL). The aqueous layer was acidified with
concentrated HCl to pH ) 2 and then extracted with AcOEt (3 × 150
mL). The organic layers were combined, washed with brine (150 mL),
and dried over MgSO4. The organic layer was evaporated in vacuo
and recrystallized from H2O (500 mL) to give the titled product as
2-(4-Nitrobenzoylamino)benzoic Acid Methyl Ester. This nitro
compound was prepared by a route analogous to 7 using 4-nitrobenzoic
acid (16.7 g, 100 mmol), oxalyl chloride (14.0 g, 110 mmol), methyl
anthranilate (15.1 g, 100 mmol), and pyridine (8.71 g, 110 mmol). The
crude product (27.3 g) was recrystallized from THF (950 mL) and
hexane (350 mL) to obtain the desired compound as pale yellow needles
1
(24.9 g, 83%): mp 197-199 °C; H NMR (300 MHz, DMSO-d6) δ
11.56 (s, 1H, amide), 8.42 (m, 3H), 8.18 (d, J ) 8.7 Hz, 2H), 7.99 (d,
J ) 8.1 Hz, 1H), 7.70 (t, J ) 7.7 Hz, 1H), 3.87 (s, 1H); 13C NMR (300
MHz, DMSO-d6) δ 167.8, 149.5, 140.0, 139.2, 134.2, 130.7, 128.8,
124.3, 124.2, 121.8, 118.8, 52.7; HRMS m/e calcd for C15H12N2O5
300.0727, found 300.0746. Anal. calcd for C15H12N2O5: C, 60.00; H,
4.03; N, 9.33. Found: C, 60.10; H, 4.04; N, 9.31.
1
white crystals (16.1 g, 71%): mp 134-135 °C; H NMR (300 MHz,
CDCl3) δ 8.55 (d, J ) 1.4 Hz, 1H), 8.37 (dd, J ) 8.1, 1.3 Hz, 1H),
7.96 (d, 8.1, 1H), 4.02 (s, 3H); 13C NMR (300 MHz, CDCl3) δ 169.2,
164.2, 148.7, 134.5, 133.6, 130.7, 129.5, 125.1, 53.3; HRMS m/e calcd
for C9H7NO6 225.0273, found 225.0265.
2-Nitrobenzoic Acid 1-Hexyl Ester. To a solution of 2-nitrobenzoic
acid (33.4 g, 200 mmol) in 1-hexanol (200 mL) was added toluene
(140 mL) and concentrated H2SO4 (1 mL), and the mixture was refluxed
for 2 h. The mixture was cooled to room temperature and washed
with saturated aqueous NaHCO3 (400 mL) and brine (400 mL). The
organic layer was dried over MgSO4, and the drying reagent was filtered
off. The filtrate was evaporated in vacuo to give the titled product as
an amber oil (42.3 g, 84%): 1H NMR (300 MHz, CDCl3) δ 0.90 (t, J
) 6.6 Hz, 3H), 1.36 (m, 6H), 1.72 (p, J ) 7.0 Hz, 2H), 4.33 (t, J )
6.8 Hz, 2H), 7.63 (td, J ) 7.4, 1.7 Hz, 1H), 7.68 (td, J ) 7.6, 1.5 Hz,
1H), 7.76 (dd, J ) 7.3, 1.8 Hz, 1H), 7.90 (dd, J ) 7.6, 1.7 Hz, 1H);
13C NMR (300 MHz, CDCl3) δ 165.0, 148.1, 132.6, 129.6, 127.3, 123.5,
70.6, 31.4, 31.1, 28.0, 25.2, 22.4, 22.2, 13.7; LRMS (FAB, MNBA)
m/e calcd for C13H18NO4 (M + H+) 252.1, found 252.
2-(4-Aminobenzoylamino)benzoic Acid Methyl Ester. A solution
of 2-(4-nitrobenzoylamino)benzoic acid methyl ester (3.0 g, 10.0 mmol)
and 10% Pd/C (0.30 mg) in DMF (15 mL) was prepared in a 50-mL
round-bottomed flask provided with a magnetic stirrer. H2 was
introduced after removal of air by an aspirator, and the solution was
stirred vigorously overnight at room temperature. The catalyst was
removed by filtration through Celite. The filtrate was evaporated in
vacuo to give desired compound as pale brown crystals (2.62 g, 97%).
This compound was used without further purification in the next step:
1H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1H, amide), 8.66 (d, J )
8.1 Hz, 1H), 8.01 (dd, J ) 7.8, 1.5 Hz, 1H), 7.65 (m, 3H), 7.15 (d, J
) 7.2 Hz, 1H), 6.64 (d, J ) 8.7 Hz, 2H), 5.92 (s, 2H), 3.90 (s, 3H);
13C NMR (300 MHz, DMSO-d6) δ 168.3, 164.6, 152.8, 141.6, 134.4,
130.7, 128.8, 122.1, 120.4, 119.9, 115.2, 113.0, 52.5.
2-Aminobenzoic Acid 1-Hexyl Ester. A solution of 1-hexyl
nitrobenzoate (12.6 g, 50 mmol) and 10% Pd/C (500 mg) in MeOH
(50 mL) was prepared in a 250-mL round-bottomed flask provided
with a magnetic stirrer. H2 was introduced after removal of air by an
aspirator, and the solution was stirred vigorously for 3 h at room
temperature. The catalyst was removed by filtration through Celite.
The filtrate was evaporated in vacuo to give the desired compound as
an orange oil (11.5 g, 100%): 1H NMR (300 MHz, CDCl3) δ 7.87
(dd, J ) 8.6, 1.4 Hz, 1H), 7.26 (td, J ) 7.7, 1.5 Hz, 1H), 6.64 (m,
2H), 4.26 (t, J ) 6.6 Hz, 2H), 1.75 (q, J ) 7.0 Hz, 2H), 1.40 (m, 6H),
0.90 (t, J ) 6.2 Hz, 3H).
General Synthesis of Functionalized Linear Strand (21). The
functionalized linear strand 21 from 1-hexyl anthranilate was synthe-
sized by the sequential transformations analogous to linear strand 14
from methyl anthranilate, couplings with nitro compounds and hydro-
genations.
General Coupling Method for 21. To a solution of nitro compound
(2-nitrobenzoic acid or 17, 10 mmol) and oxalyl chloride (2.40 g, 20
mmol) in dry THF (20 mL) was added DMF (0.1 mL) through a silica
gel filter, and the mixture was stirred at room temperature for 30 min.
The reaction mixture was evaporated in vacuo to obtain the acid
chloride. To a solution of the amine (10 mmol) and pyridine (1.58 g,
20 mmol) in CH2Cl2 was added a solution of the acid chloride in dry
CH2Cl2 (10 mL), and the mixture was stirred at room temperature
overnight. CH2Cl2 (200 mL) was added to the mixture which was then
washed with 1 N HCl (2 × 200 mL), saturated aqueous NaHCO3 (200
mL), and brine (200 mL). The organic layer was dried over MgSO4
and evaporated in vacuo to give the crude material.
General Hydrogenation Method for 21. A solution of nitro
compound (6.0 mmol) and 10% Pd/C (300 mg) in dry CH2Cl2 (40 mL)
was prepared in a 100-mL round-bottomed flask provided with a
magnetic stirrer. H2 was introduced after removal of air by an aspirator,
and the solution was stirred vigorously overnight at room temperature.
2-(4-Acetylaminobenzoylamino)benzoic Acid Methyl Ester (16a).
To a solution of 2-(4-aminobenzoylamino)benzoic acid methyl ester
(512 mg, 2.0 mmol) and pyridine (280 mg, 6.0 mmol) in dry THF (10
mL) was added acetyl chloride (236 mg, 6.0 mmol), and the mixture
was stirred at room temperature for 40 min. Hexane (50 mL) was
added to the mixture, and the precipitate was collected on a glass filter.
The filtered residue was washed wtih 1 N HCl (30 mL), saturated
aqueous NaHCO3 (30 mL), and H2O (2 × 30 mL) on the filter. The
crude product was recrystallized from THF (150 mL) and hexane (150
mL) to obtain the desired compound as white crystals (512 mg, 82%):
mp 252-253 °C; 1H NMR (300 MHz, DMSO-d6) δ 11.54 (s, 1H,
benzamide), 10.29 (s, 1H, acetamide), 8.57 (d, J ) 8.7 Hz, 1H), 8.01
(dd, J ) 7.8, 1.4 Hz, 1H), 7.90 (d, J ) 8.7 Hz, 2H), 7.77 (d, J ) 8.7
Hz, 2H), 7.67 (td, J ) 8.0, 1.5 Hz, 1H), 7.22 (t, J ) 7.7 Hz, 1H), 3.89
(s, 3H), 2.09 (s, 3H); 13C NMR (300 MHz, DMSO-d6) δ 168.9, 168.1,
164.2, 142.9, 140.5, 134.4, 130.7, 128.4, 128.1, 123.1, 120.6, 118.6,
116.7, 52.7, 24.2; HRMS m/e calcd for C17H16N2O4 312.1110, found
312.1118. Anal. calcd for C17H16N2O4: C, 65.38; H, 5.16; N, 8.97.
Found: C, 65.46; H, 5.20; N, 8.90.
2-(4-Acetylaminobenzoylamino)benzoic Acid Hexyl Ester (16b).
A solution of 4-acetamidobenzoic acid (358 mg, 2.0 mmol) and oxalyl
chloride (508 mg, 4.0 mmol) in dry THF (5 mL) was stirred at room
temperature. DMF (0.025 mL) was added through a silica gel filter,
and the mixture was stirred at room temperature for 30 min. The
reaction mixture was evaporated in vacuo to obtain the acid chloride.
A solution of hexyl anthranilate (443 mg, 2.0 mmol) and triethylamine
(405 mg, 4.0 mmol) in dry THF (10 mL) was added to the evaporated
residue. The mixture was stirred at room temperature for 40 min. CH2-
Cl2 (30 mL) was added to the mixture, and then the solution was washed
with 1 N HCl (20 mL), saturated aqueous NaHCO3 (20 mL), and H2O
(20 mL). The organic layer was evaporated and then purified by
column chromatography (silica gel, 1/3 ) AcOEt/CH2Cl2) to obtain
the desired compound as a light brown powder (390 mg, 51%): 1H

+
+
7538 J. Am. Chem. Soc., Vol. 118, No. 32, 1996
Hamuro et al.
The catalyst was removed by filtration through Celite. The filtrate was
evaporated in vacuo to give the desired compound.
133.9, 133.3, 131.2, 127.7, 127.6 (2), 125.1, 124.9, 124.4, 124.1, 124.0,
123.8, 123.2, 122.4, 122.0, 121.1, 120.8, 116.2, 66.2, 52.8, 52.5, 38.5,
31.4, 28.5, 25.7, 25.1, 22.6, 22.5, 14.0; IR (2 mM in CH2Cl2) 3259,
1726, 1689, 1659, 1604, 1578, 1519 cm-1; HRMS (FAB, MNBA) m/e
calcd for C44H49N4O10 (M + H+) 793.3449, found 793.3454
2-(2-Nitro-4-methoxycarbonylbenzoylamino)benzoic Acid 1-Hex-
yl Ester (18). The crude product was purified by column chromatog-
raphy (silica gel, CH2Cl2) to obtain the desired product as a yellow
wax (89%): mp 99-100 °C; 1H NMR (300 MHz, CDCl3) δ 11.71 (s,
1H, amide), 8.79 (d, J ) 6.9 Hz, 1H), 8.72 (s, 1H), 8.39 (d, J ) 7.5
Hz, 1H), 8.10 (d, J ) 7.8 Hz, 1H), 7.89 (d, J ) 8.1 Hz, 1H), 7.80 (d,
J ) 8.1 Hz, 1H), 7.64 (t, J ) 8.0 Hz, 1H), 7.20 (t, J ) 8.0 Hz, 1H),
4.28 (t, J ) 6.6 Hz, 2H), 4.01 (s, 3H), 1.73 (q, J ) 7.0 Hz, 2H), 1.38
(m, 6H), 0.90 (t, J ) 6.6 Hz, 3H); 13C NMR (300 MHz, CDCl3) δ
168.5, 164.2, 163.5, 147.0, 140.8, 136.3, 134.8, 134.5, 132.8, 130.9,
128.7, 125.8, 123.6, 120.7, 115.8, 65.8, 53.0, 31.4, 28.4, 25.6, 22.5,
14.0; HRMS m/e calcd for C22H24N2O7: 428.1584, found 428.1587.
2-(2-Amino-4-methoxycarbonylbenzoylamino)benzoic Acid 1-Hex-
yl Ester (19). The filtrate was introduced in the next step directly.
2-(2-(2-Nitrobenzoylamino)-4-methoxycarbonylbenzoylamino)-
benzoic Acid 1-Hexyl Ester (20). Recrystallized from AcOEt and
hexane to obtain the desired product as yellow fine needles (78%):
mp 148-149 °C; 1H NMR (300 MHz, CDCl3) δ 12.33 (s, 1H, amide),
11.72 (s, 1H, amide), 9.40 (s, 1H), 8.66 (d, J ) 8.4 Hz, 1H), 8.10 (td,
J ) 7.1, 1.7 Hz, 2H), 8.00 (m, 2H), 7.74 (m, 2H), 7.65 (m, 1H), 7.58
(td, J ) 8.0, 1.5 Hz, 1H), 7.18 (td, J ) 7.7, 0.6 Hz, 1H), 4.37 (t, J )
6.8 Hz, 2H), 4.00 (s, 3H, methoxy), 1.80 (q, J ) 7.0 Hz, 2H), 1.38 (m,
6H), 0.91 (t, J ) 7.1 Hz, 3H); 13C NMR (300 MHz, CDCl3) δ 168.6,
166.8, 165.9, 164.3, 147.0, 140.6, 140.0, 134.6, 134.2, 133.8, 132.8,
131.1, 131.0, 128.5, 127.3, 124.9, 124.7, 124.1, 123.7, 122.7, 120.6,
116.2, 66.1, 52.6, 31.4, 28.5, 25.7, 22.5, 14.0; HRMS m/e calcd for
C29H29N3O8: 547.1955, found 547.1945.
2-(2-(2-Aminobenzoylamino)-4-methoxycarbonylbenzoylamino)-
benzoic Acid 1-Hexyl Ester: A yellow powder (100%); 1H NMR (300
MHz, CDCl3) δ 12.27 (s, 1H, amide), 11.85 (s, 1H, amide), 9.35 (d, J
) 1.5 Hz, 1H), 8.83 (dd, J ) 8.4, 0.6 Hz, 1H), 8.11 (dd, J ) 8.0, 1.7
Hz, 1H), 7.98 (d, J ) 8.1 Hz, 1H), 7.90 (dd, J ) 8.3, 1.7 Hz, 1H),
7.74 (dd, J ) 8.1, 1.5 Hz, 1H), 7.64 (td, J ) 8.4, 1.5 Hz, 1H), 7.26 (td,
J ) 7.8, 1.5 Hz, 1H), 7.19 (td, J ) 8.0, 0.9 Hz, 1H), 6.78 (td, J ) 8.0,
0.9 Hz, 1H), 6.71 (d, J ) 8.1 Hz, 1H), 4.36 (t, J ) 6.6 Hz, 2H), 3.97
(s, 3H), 1.80 (q, J ) 7.4, 1.40, m Hz, 6H), 0.91 (t, J ) 7.8 Hz, 3H).
2-(2-(2-(2-Nitro-4-methoxycarbonylbenzoylamino)benzoylamino)-
4-methoxycarbonylbenzoylamino)benzoic Acid 1-Hexyl Ester. The
crude product was purified by column chromatography (silica gel,
1/50 ) MeOH/CH2Cl2) to obtain the desired product (62%): mp 206
°C; 1H NMR (300 MHz, CDCl3) δ 12.37 (s, 1H, amide), 12.29 (s, 1H,
amide), 11.95 (s, 1H, amide), 9.18 (d, J ) 1.5 Hz, 1H), 8.82 (d, J )
8.4 Hz, 2H), 8.73 (d, J ) 1.2 Hz, 1H), 8.39 (dd, J ) 7.5, 1.4 Hz, 1H),
8.13 (dd, J ) 7.8, 1.5 Hz, 1H), 7.96 (m, 3H), 7.81 (d, J ) 7.8 Hz, 1H),
7.64 (m, 2H), 7.34 (t, J ) 7.7 Hz, 1H), 7.22 (t, J ) 7.5 Hz, 1H), 4.36
(t, J ) 6.8 Hz, 2H), 4.10 (s, 3H), 3.95 (s, 3H), 1.8 (q, J ) 7.1 Hz, 2H),
1.36 (m, 6H), 0.91 (t, J ) 7.1 Hz, 3H); HRMS m/e calcd for
C38H36N4O11 724.2381, found 724.2366.
2-(2-(2-(2-(1-Hexanoyl)amino-4-hydroxycarbonylbenzoylamino)-
benzoylamino)-4-hydroxycarbonylbenzoylamino)benzoic Acid 1-Hex-
yl Ester (22). To a solution of 21 (935 mg, 1.2 mmol) in THF (48
mL) was added 0.5 N aqueous LiOH (16 mL), and the reaction mixture
was stirred at -8 °C for 54 h. Hexane (200 mL) and 1 N HCl (200
mL) were added. The precipitate was collected on a glass filter and
washed with H2O (40 mL) and then hexane (40 mL). The residue was
purified by column chromatography (silica gel, 7/30/60 ) NH4OH/
MeOH/CH2Cl2) to obtain the desired product (806 mg, 89%): mp 268-
1
270 °C; H NMR (300 MHz, DMSO-d6) δ 13.31 (s, 2H, acid), 11.43
(s, 1H, amide), 11.40 (s, 1H, amide), 11.30 (s, 1H, amide), 10.37 (s,
1H, amide), 8.72 (s, 1H), 8.66 (s, 1H), 8.23 (d, J ) 8.4 Hz, 1H), 8.05
(d, J ) 8.1 Hz, 1H), 7.90 (m, 4H), 7.75 (d, J ) 8.1 Hz, 1H), 7.59 (m,
3H), 7.33 (t, J ) 7.5 Hz, 1H), 7.21 (t, J ) 7.5 Hz, 1H), 4.14 (t, J )
6.5 Hz, 2H), 2.16 (t, J ) 7.2 Hz, 2H), 1.58 (q, J ) 7.2 Hz, 2H), 1.44
(q, J ) 6.9 Hz, 2H), 1.93 (m, 10H), 0.78 (m, 6H); 13C NMR (300
MHz, DMSO-d6) δ 171.3, 167.2, 166.9, 166.5, 166.4, 165.9 (2), 139.1,
137.8, 137.5, 137.0, 134.0 (2), 133.6, 132.3, 130.6, 128.6 (2), 128.4
(2), 127.3, 125.4, 125.0, 124.7, 124.1, 123.8 (2), 123.2, 122.4, 121.9,
118.7, 65.3, 36.7, 30.9, 30.7, 27.9, 25.1, 24.5, 21.9, 13.9; HRMS (FAB,
MNBA) m/e calcd for C42H44N4O10Na (M + Na+) 787.2955, found
787.2944.
2-Nitroterephthalic Acid 4-(2,6-Dimethy-4-heptyl) Ester. 2-Ni-
troterephthalic Acid Bis-(2,6-dimethyl-4-heptyl) Ester. To a solution
of nitroterephthalic acid (21.1 g, 100 mmol) in 2,6-dimethyl-4-heptanol
(200 mL) was added toluene (200 mL) and sulfuric acid (3 g), and the
mixture was refluxed for 7.5 h. The mixture was cooled to room
temperature, and AcOEt (600 mL) was added. The organic phase was
washed with H2O (1000 mL) and brine (500 mL) and dried over
MgSO4. The solvent was evaporated in vacuo to give the crude mixture
of the titled compounds. The crude product was separated by column
chromatography (silica gel, CH2Cl2 and then 1/6 ) MeOH/CH2Cl2) to
give the monoester as a brown oil (19.7 g, 58%) and the diester as a
yellow oil (19.3 g, 42%): 1H NMR (300 MHz, CDCl3) δ 8.51 (d, J )
1.1 Hz, 1H), 8.35 (dd, J ) 8.1, 1.2 Hz, 1H), 7.95 (d, J ) 8.0 Hz, 1H),
7.80 (broad s, 1H, acid), 5.38 (m, 1H), 1.69 (m, 4H), 1.43 (m, 2H),
0.95 (m, 12H); 13C NMR (300 MHz, CDCl3) δ 169.1, 163.5, 148.6,
134.9, 133.6, 130.6, 129.7, 124.9, 74.1, 43.9, 24.8, 23.2, 22.3.
2-Aminoterephthalic Acid Bis-(2,6-dimethy-4-heptyl) Ester. A
solution of 2-nitroterephthalic acid bis-(2,6-dimethy-4-heptyl) ester
(17.4 g, 40 mmol) and 10% Pd/C (700 mg) in dry THF (80 mL) was
prepared in a 250-mL round-bottomed flask provided with a magnetic
stirrer. H2 was introduced after removal of air by an aspirator, and the
solution was stirred vigorously overnight at room temperature. The
catalyst was removed by filtration through Celite. The filtrate was
evaporated in vacuo to give the desired compound as a yellow oil (16.7
g, 95% NMR purity, 91%): 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J
) 8.3 Hz, 1H), 7.34 (s, 1H), 7.25 (dd, J ) 7.5, 1.4 Hz, 1H), 5.78
(broad s, 2H, amine), 5.30 (m, 2H), 1.66 (m, 8H), 1.40 (m, 4H), 0.94
(m, 24H).
2-(2-(2-(2-Amino-4-methoxycarbonylbenzoylamino)benzoylamino)-
4-methoxycarbonylbenzoylamino)benzoic Acid 1-Hexyl Ester. The
filtrate was introduced directly to the next step.
2-(2-(2-(2-(1-Hexanoyl)amino-4-methoxycarbonylbenzoylamino)-
benzoylamino)-4-methoxycarbonylbenzoylamino)benzoic Acid 1-Hex-
yl Ester (21). To a solution of the aforementioned amine (2.0 mmol)
and pyridine (400 mg, 5.0 mmol) in CH2Cl2 was added a solution of
hexanoyl chloride (538 mg, 4.0 mmol) in dry CH2Cl2 (10 mL), and
the mixture was stirred at room temperature for 1 h. CH2Cl2 (50 mL)
was added to the mixture which was then washed with 1 N HCl (2 ×
100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL).
The organic layer was dried over MgSO4, evaporated in vacuo, and
recrystallized from CH2Cl2 (60 mL) and hexane (440 mL) to obtain
the desired product as yellow fine needles (1.31 g, 84%): mp 175 °C;
1H NMR (300 MHz, CDCl3) δ 12.38 (s, 2H, amide), 12.32 (s, 1H,
amide), 11.11 (s, 1H, amide), 9.31 (s, 1H), 9.28 (s, 1H), 8.79 (d, J )
8.4 Hz, 1H), 8.71 (d, J ) 8.4 Hz, 1H), 8.11 (d, J ) 7.8 Hz, 1H), 7.97
(m, 4H), 7.87 (d, J ) 8.1 Hz, 1H), 7.63 (t, J ) 7.8 Hz, 2H), 7.33 (t,
J ) 7.7 Hz, 1H), 7.20 (t, J ) 7.5 Hz, 1H), 4.35 (t, J ) 6.6 Hz, 2H),
4.00 (s, 3H), 3.94 (s, 3H), 2.43 (t, J ) 7.5 Hz, 2H), 1.77 (m, 4H), 1.36
(m, 10H), 0.90 (m, 6H); 13C NMR (300 MHz, CDCl3) δ 172.3, 168.7,
167.7, 167.1 (2), 166.3, 166.0, 140.7, 140.4, 139.9, 139.7, 134.8, 134.2,
General Synthesis of Functionalized Linear Strand (23). The
functionalized linear strand 23 from 2-aminoterephthalic acid bis-(2,6-
dimethy-4-heptyl) ester was synthesized by the sequential transforma-
tions analogous to functionalized linear strand 21. In the synthesis of
23, 2-nitroterephthalic acid 4-(2,6-dimethy-4-heptyl) ester was used for
couplings instead of 2-nitrobenzoic acid.
General Coupling Method for 23. To a solution of 2-nitrotereph-
thalic acid 4-(2,6-dimethy-4-heptyl) ester or 17 (10 mmol) and oxalyl
chloride (2.40 g, 20 mmol) in dry THF (20 mL) was added DMF (0.1
mL) through a silica gel filter, and the mixture was stirred at room
temperature for 30 min. The reaction mixture was evaporated in vacuo
to obtain the acid chloride. To a solution of the amine (10 mmol) and
pyridine (1.58 g, 20 mmol) in CH2Cl2 was added a solution of the acid
chloride in dry CH2Cl2 (10 mL), and the mixture was stirred at room
temperature overnight. CH2Cl2 (200 mL) was added to the mixture
which was then washed with 1 N HCl (2 × 200 mL), saturated aqueous

+
+
Oligoanthranilamides
J. Am. Chem. Soc., Vol. 118, No. 32, 1996 7539
NaHCO3 (200 mL), and brine (200 mL). The organic layer was dried
over MgSO4 and evaporated in vacuo to give the crude material.
2-(2-(2-(2-(1-Hexanoyl)amino-4-methoxycarbonylbenzoylamino)-
4-(2,6-dimethy-4-heptyl)benzoylamino)-4-methoxycarbonylbenzoyl-
amino)terephthalic Acid Bis-(2,6-dimethy-4-heptyl) Ester (23). To
a solution of tetraanthranilamide (5.22 g, 4.8 mmol) and pyridine (949
mg, 12 mmol) in CH2Cl2 (20 mL) was added a solution of 1-hexanoyl
chloride (1.35 g, 10 mmol) in dry CH2Cl2 (20 mL), and the mixture
was stirred at room temperature for 3 h. CH2Cl2 (250 mL) was added
to the mixture which was then washed with 1 N HCl (200 mL),
saturated aqueous NaHCO3 (200 mL), and brine (200 mL). The organic
layer was dried over MgSO4 and evaporated in vacuo to give the crude
product (6.22 g). The crude product was purified by column chroma-
tography (silica gel, 1/5 ) diisopropyl ether/toluene) to give the desired
General Hydrogenation Method for 23. A solution of nitro
compound (20 mmol) and 10% Pd/C (450 mg) in dry THF (50 mL)
was prepared in a 100-mL round-bottomed flask provided with a
magnetic stirrer. H2 was introduced after removal of air by an aspirator,
and the solution was stirred vigorously overnight at room temperature.
The catalyst was removed by filtration through Celite. The filtrate was
evaporated in vacuo to give the desired compound.
2-(2-Nitro-4-methoxycarbonylbenzoylamino)terephthalic Acid
Bis-(2,6-dimethy-4-heptyl) Ester. The crude product was purified by
column chromatography (silica gel, CH2Cl2) to obtain the desired
product as a yellow oil (89%): 1H NMR (300 MHz, CDCl3) δ 11.67
(s, 1H, amide), 9.37 (s, 1H), 8.75 (d, J ) 1.2 Hz, 1H), 8.41 (dd, J )
7.8, 1.5 Hz, 1H), 8.13 (d, J ) 8.4 Hz, 1H), 7.83 (m, 2H), 5.32 (m,
2H), 4.02 (s, 3H), 1.66 (m, 8H), 1.41 (m, 4H), 0.93 (m, 24H); 13C
NMR (300 MHz, CDCl3) δ 167.4, 165.1, 164.2, 163.6, 146.9, 140.9,
136.3, 134.6, 132.9, 130.8, 128.9, 125.9, 124.3, 121.8, 119.2, 73.7,
73.0, 53.0, 43.9, 24.8, 23.1, 22.4; HRMS m/e calcd for C35H48N2O9
640.3360, found 640.3347.
1
product as a yellow foam (3.86 g, 69%): mp 159-161 °C; H NMR
(300 MHz, CDCl3) δ 12.44 (s, 2H, amide), 12.26 (s, 1H, amide), 11.15
(s, 1H, amide), 9.41 (d, J ) 1.2 Hz, 1H), 9.37 (d, J ) 1.2 Hz, 1H),
9.33 (d, J ) 1.5 Hz, 1H), 9.31 (s, 1H), 8.17 (d, J ) 8.4 Hz, 1H), 8.00
(m, 5H), 7.84 (m, 2H), 5.37 (m, 3H), 4.01 (s, 3H), 3.94 (s, 3H), 2.45
(t, J ) 7.7 Hz, 2H), 1.73 (m, 14H), 1.42 (m, 10H), 0.97 (m, 39H); 13
C
NMR (300 MHz, CDCl3) δ 172.4, 167.7, 167.1, 167.0, 166.3, 165.9,
165.1, 140.7, 140.6, 139.9, 139.7, 136.2, 135.1, 134.4, 134.1, 131.1,
127.7, 127.5, 125.4, 124.9, 124.7, 124.3, 124.0, 123.6, 123.3, 122.5,
121.8, 119.5, 74.1, 72.9, 52.8, 43.8, 38.5, 31.4, 24.9, 23.2, 22.5; IR (2
mM in CH2Cl2) 3258, 1722, 1689, 1659, 1576, 1522 cm-1; HRMS
(FAB, MNBA) m/e calcd for C67H90N4O14Na (M + Na+) 1197.6351,
found 1197.6397.
2-(2-Amino-4-methoxycarbonylbenzoylamino)terephthalic Acid
Bis-(2,6-dimethy-4-heptyl) Ester: a yellow oil (99%); 1H NMR (300
MHz, CDCl3) δ 11.99 (s, 1H, amide), 9.43 (d, J ) 1.5 Hz, 1H), 8.12
(d, J ) 8.1 Hz, 1H), 7.77 (m, 2H), 7.43 (m, 2H), 6.08 (broad s, 2H,
amine), 5.35 (m, 2H), 3.93 (s, 3H), 1.69 (m, 8H), 1.44 (m, 4H), 0.95
(m, 24H).
2-(2-(2-(2-(1-Hexanoyl)amino-4-hydroxycarbonylbenzoylamino)-
4-(2,6-dimethy-4-heptyl)-benzoylamino)-4-hydroxycarbonylbenzoyl-
amino)terephthalic Acid Bis-(2,6-dimethy-4-heptyl) Ester (24). To
a solution of the dimethyl ester 23 (1.90 g, 1.61 mmol) in THF (100
mL) was added 0.5 N aqueous LiOH (50 mL), and the reaction mixture
was stirred at room temperature overnight. The solvent was removed
in vacuo. CH2Cl2 (500 mL) added to the residue which was then
washed with 1 N HCl (300 mL) and brine (300 mL). The organic
layer was dried over sodium sulfate and evaporated in vacuo to give
the crude product (1.80 g). The crude product was purified by column
chromatography (silica gel, 1/10/20 ) NH4OH/MeOH/CH2Cl2) to give
the desired product as a yellow foam (813 mg, 44%): mp 246-248
°C; 1H NMR (300 MHz, CDCl3) δ 12.94 (s, 1H, amide), 12.84 (s, 1H,
amide), 12.58 (s, 1H, amide), 11.45 (s, 1H, amide), 9.78 (s, 1H), 9.58
(s, 1H), 9.55 (s, 1H), 9.48 (s, 1H), 8.21 (dd, J ) 8.4, 1.8 Hz, 2H), 8.13
(m, 4H), 8.00 (d, J ) 8.1 Hz, 1H), 7.88 (dd, J ) 5.4, 1.2 Hz, 1H), 5.41
(m, 3H), 2.52 (t, J ) 7.5 Hz, 2H), 1.76 (m, 12H), 1.43 (m, 12H), 0.99
(m, 39H); 13C NMR (300 MHz, CDCl3) δ 172.5, 172.0, 171.7, 167.8,
167.2, 166.9, 165.2, 141.0, 140.8, 140.2, 136.2, 135.2, 133.9, 133.2,
131.2, 128.9, 127.7, 127.6, 125.8, 124.7, 124.5, 124.0, 123.4, 123.1,
122.8, 121.9, 119.6, 74.2, 73.3, 73.0, 44.0, 38.6, 31.5, 29.8, 24.9, 23.3,
2-(2-(2-Nitro-4-(2,6-dimethy-4-heptyl)benzoylamino)-4-methoxy-
carbonylbenzoylamino)terephthalic Acid Bis-(2,6-dimethy-4-heptyl)
Ester. The crude product was purified by column chromatography
(silica gel, 1/3 ) diethyl ether/hexane) to give the desired product as
a yellow foam (54%): mp 63 °C; 1H NMR (300 MHz, CDCl3) δ 12.41
(s, 1H, amide), 11.91 (s, 1H, amide), 9.43 (s, 1H), 9.32 (s, 1H), 8.73
(s, 1H), 8.42 (d, J ) 7.8 Hz, 1H), 8.15 (d, J ) 8.1 Hz, 1H), 8.01 (s,
2H), 7.81 (m, 2H), 5.41 (m, 2H), 5.29 (m, 1H), 3.99 (s, 3H), 1.70 (m,
12H), 1.42 (m, 6H), 0.96 (m, 36H); 13C NMR (300 MHz, CDCl3) δ
167.7, 166.8, 165.9, 165.1, 163.8, 163.5, 147.0, 140.8, 140.1, 136.1,
136.0, 134.7, 134.5, 133.6, 131.0, 128.8, 127.4, 125.8, 125.2, 124.1,
123.7, 122.8, 121.8, 119.5, 74.0, 73.6, 73.1, 52.6, 43.8, 24.8, 23.1, 22.3;
LRMS (FAB, MNBA) m/e calcd for C52H71N3O12Na (M + Na+) 952.5,
found 952.7.
2-(2-(2-Amino-4-(2,6-dimethy-4-heptyl)benzoylamino)-4-meth-
oxycarbonylbenzoylamino)terephthalic Acid Bis-(2,6-dimethy-4-
heptyl) Ester: a yellow foam (100%); 1H NMR (300 MHz, CDCl3) δ
12.33 (s, 1H, amide), 12.04 (s, 1H, amide), 9.42 (s, 1H), 9.36 (s, 1H),
8.16 (d, J ) 8.4 Hz, 1H), 7.97 (m, 2H), 7.82 (d, J ) 9.0 Hz, 2H), 7.46
(m, 2H), 5.35 (m, 3H), 3.99 (s, 3H), 1.70 (m, 12H), 1.40 (m, 6H), 0.95
(m, 36H).
22.6, 14.1; IR (2 mM in CH2Cl2) 3199, 1704, 1657, 1575, 1525 cm-1
;
HRMS (FAB, MNBA) m/e calcd for C65H86N4O14Na (M + Na+)
2-(2-(2-(2-Nitro-4-methoxycarbonylbenzoylamino)-4-(2,6-dimethy-
4-heptyl)benzoylamino)-4-methoxycarbonylbenzoylamino)tereph-
thalic Acid Bis-(2,6-dimethy-4-heptyl) Ester. The crude product was
crystallized from trace CH2Cl2, diethyl ether, and hexane in a freezer
to obtain the desired product (60%): mp 148-150 °C; 1H NMR (300
MHz, CDCl3) δ 12.44 (s, 1H, amide), 12.42 (s, 1H, amide), 11.80 (s,
1H, amide), 9.42 (d, J ) 1.2 Hz, 1H), 9.40 (s, 1H), 9.20 (s, 1H), 8.75
(d, J ) 1.5 Hz, 1H), 8.40 (dd, J ) 8.0, 1.4 Hz, 1H), 8.17 (d, J ) 8.4
Hz, 1H), 8.00 (m, 4H), 7.83 (m, 2H), 5.39 (m, 3H), 4.02 (s, 3H), 3.96
(s, 3H), 1.66 (m, 12H), 1.44 (m, 6H), 0.96 (m, 36H); 13C NMR (300
MHz, CDCl3) δ 167.7, 167.0, 166.9, 165.8, 165.1, 165.0, 164.3, 163.6,
146.8, 140.7, 140.0, 139.6, 136.4, 136.2, 135.3, 134.7, 134.2, 132.8,
131.1, 129.0, 127.6, 127.5, 125.9, 125.2, 124.7, 124.4, 123.6, 123.1,
121.8, 119.5, 74.0, 73.2, 72.8, 53.0, 43.9, 24.8, 23.2, 22.4; LRMS (FAB,
MNBA) m/e calcd for C61H78N4O15Na (M + Na+) 1129.5, found
1130.
1169.6038, found 1169.6029.
2,6-Bis-(2-(2-methoxycarbonylphenylcarbamoyl)phenylcarbam-
oyl)pyridine (31). To a solution of 2,6-pyridinecarboxylic acid (167
mg, 1.0 mmol) and oxalyl chloride (380 mg, 3.0 mmol) in dry THF (5
mL) was added DMF (0.025 mL) through a silica gel filter, and the
reaction mixture was stirred at room temperature for 20 min. The
mixture was evaporated in vacuo to obtain the acid chloride. To a
solution of 8 (541 mg, 2.0 mmol) and pyridine (237 mg, 3.0 mmol) in
dry THF (5 mL) was added the acid chloride in dry THF (5 mL), and
the resulting mixture was stirred at room temperature for 2 h. The
reaction mixture was added to chloroform (40 mL) and washed with 1
N HCl (2 × 20 mL), saturated aqueous NaHCO3 (2 × 20 mL), and
H2O (2 × 20 mL). The organic layer was dried over MgSO4 and
evaporated in vacuo to give the crude product. The crude product was
recrystallized from CHCl3 (30 mL) and hexane (80 mL) to obtain the
desired compound as brown needles (508 mg, 76%): mp 241-242
°C; 1H NMR (300 MHz, CDCl3) δ 13.08 (s, 2H, pyridinedicarboxam-
ide), 11.60 (s, 2H, anthranilamide), 8.88 (d, J ) 8.1 Hz, 2H), 8.48 (m,
4H), 8.13 (t, J ) 7.8 Hz, 1H), 7.90 (dd, J ) 8.1, 1.5 Hz, 2H), 7.62 (m,
4H), 7.22 (t, J ) 7.7 Hz, 2H), 6.75 (t, J ) 6.2 Hz, 2H), 6.70 (t, J )
8.0 Hz, 3H), 3.78 (s, 6H); 13C NMR (300 MHz, CDCl3) δ 168.3, 166.5,
162.1, 149.5, 141.1, 139.2 (2), 134.3, 132.6, 130.5, 127.5, 124.9, 123.6,
122.6, 122.2, 121.8, 120.0, 114.3, 52.2; IR (2 mM in CH2Cl2) 3270,
1693, 1608, 1585, 1532 cm-1; HRMS m/e calcd for C37H29N5O8
2-(2-(2-(2-Amino-4-methoxycarbonylbenzoylamino)-4-(2,6-di-
methy-4-heptyl)benzoylamino)-4-methoxycarbonylbenzoylamino)-
terephthalic Acid Bis-(2,6-dimethy-4-heptyl) Ester: a yellow foam
(100%); 1H NMR (300 MHz, CDCl3) δ 12.42 (s, 1H, amide), 12.36 (s,
1H, amide), 12.03 (s, 1H, amide), 9.41 (s, 1H), 9.37 (s, 1H), 9.32 (s,
1H), 8.17 (d, J ) 8.4 Hz, 1H), 8.01 (m, 4H), 7.84 (d, J ) 9.0 Hz, 2H),
7.51 (s, 1H), 5.37 (m, 3H), 4.02 (s, 3H), 3.93 (s, 3H), 1.72 (m, 12H),
1.44 (m, 6H), 0.96 (m, 36H).

+
+
7540 J. Am. Chem. Soc., Vol. 118, No. 32, 1996
Hamuro et al.
671.2016, found 671.2107. Anal. calcd for C37H29N5O8: C, 66.16; H,
4.35; N, 10.43. Found: C, 65.87; H, 4.36; N, 10.29.
temperature for 1.5 h. Hexane (30 mL) was added to the reaction
mixture, and the precipitate was collected on a glass filter. The solid
was washed with 1 N HCl (30 mL), saturated aqueous NaHCO3 (30
mL), and H2O (2 × 30 mL). The crude product was recrystallized
from DMSO (60 mL) and MeOH (20 mL) to obtain the desired
compound as a white solid (518 mg, 75%): mp 299-300 °C; 1H NMR
(300 MHz, DMSO-d6) δ 12.51 (s, 2H, pyidinedicarboxamide), 11.58
(s, 2H, benzamide), 8.56 (d, J ) 8.7 Hz, 2H), 8.33 (d, J ) 7.8 Hz,
2H), 8.03 (m, 6H), 7.87 (t, 1H), 7.69 (t, J ) 7.5 Hz, 2H), 7.24 (t, J )
7.7 Hz, 2H); HRMS (FAB, MNBA) m/e calcd for C37H30N5O9 (M +
H+) 688.2044, found 688.2036.
2,6-Pyridinedicarboxylic Acid N-Oxide (26). 2,6-Pyridinedicar-
boxylic acid (8.81 g) was dissolved in H2O2 (50 mL) and AcOH (20
mL), and the mixture was stirred at 100 °C for 6 h. The reaction
mixture was evaporated and solidified from THF (100 mL) and hexane
(150 mL). The solid was collected and washed with hexane (2 × 30
mL) to obtain the desired compound as a white solid (5.46 g, 60%):
1
mp 155-157 °C (lit.21c 155-157 °C); H NMR (300 MHz, DMSO-
d6) δ 8.23 (d, J ) 7.8 Hz, 2H), 7.94 (t, J ) 8.0 Hz, 1H); 13C NMR
(300 MHz, DMSO-d6) δ 161.0, 139.4, 132.4, 129.0; HRMS m/e calcd
for C7H5NO5 183.0168, found 183.0171. Anal. calcd for C7H5NO5:
C, 45.91; H, 2.75; N, 7.65. Found: C, 46.00; H, 2.73; N, 7.70.
2,6-Bis-(2-(2-methoxycarbonylphenylcarbamoyl)phenylcarbam-
oyl)pyridine N-Oxide (32). To a solution of 26 (101 mg, 0.55 mmol)
and oxalyl chloride (190 mg, 1.5 mmol) in dry THF (3 mL) was added
DMF (0.025 mL) through a silica gel filter, and the reaction mixture
was stirred at room temperature for 10 min. The mixture was
evaporated in vacuo to obtain the acid chloride as a yellow oil. To a
solution of 8 (270 mg, 1 mmol) and pyridine (119 mg, 1.5 mmol) in
dry THF (3 mL) was added the acid chloride in dry THF (5 mL)
dropwise, and the resulting mixture was stirred at room temperature
overnight. 1 N HCl (50 mL) was added to the mixture which was
then extracted with AcOEt (50 mL). The organic layer was washed
with saturated aqueous NaHCO3 (50 mL). The precipitation was
collected on a glass filter, and the organic layer was washed with brine.
The filtered residue and the organic layer were combined and
evaporated. The evaporated residue was dissolved in CHCl3, washed
with brine, dried over MgSO4, and evaporated in vacuo to give the
crude product. The crude product was recrystallized from CHCl3 (15
mL) and hexane (50 mL). The second recrystallization was performed
from CHCl3 (20 mL) and hexane (50 mL) to obtain the desired
compound as white crystals (238 mg, 69%): mp 247-249 °C; 1H NMR
(300 MHz, CDCl3) δ 13.80 (s, 2H, pyridinedicarboxamide), 11.78 (s,
2H, anthranilamide), 8.88 (d, J ) 8.4 Hz, 2H), 8.60 (m, 4H), 7.88 (m,
4H), 7.58 (m, 2H), 7.32 (m, 4H), 4.92. t (7.5, 2H), 3.89 (s, 6H, methyl);
13C NMR (300 MHz, CDCl3) δ 168.9, 166.2, 158.0, 142.4, 141.5, 137.4,
134.7, 132.1, 131.4, 130.6, 127.5, 127.0, 126.1, 125.0, 124.1, 122.5,
121.0, 115.1, 52.5; IR (2 mM in CH2Cl2) 3295, 3270, 1676, 1606, 1584,
1527 cm-1; HRMS (FAB, MNBA) m/e calcd for C37H30N5O9 (M +
H+) 688.2044, found 688.2037.
2-Nitrobenzoylanilide. A solution of 2-nitrobenzoic acid (16.7 g,
100 mmol) and oxalyl chloride (14.0 g, 110 mmol) in dry CH2Cl2 (30
mL) was stirred and cooled in an ice bath. DMF (0.31 g, 4.0 mmol)
was added dropwise through a silica gel filter, and then the reaction
mixture was stirred at room temperature for 2 h. The mixture was
evaporated in vacuo to obtain the acid chloride as a yellow oil (18.9 g,
102%). A solution of aniline (27.9 g, 300 mmol) in dry CH2Cl2 (50
mL) was stirred and cooled in a water bath. A solution of the acid
chloride in dry CH2Cl2 (50 mL) was added dropwise, and the mixture
was stirred at room temperature for 2 h. CH2Cl2 (350 mL) was added
to the mixture which was then washed with 1 N HCl (150 mL),
saturated aqueous NaHCO3 (150 mL), and brine (150 mL). The organic
layer was dried over MgSO4 and evaporated in vacuo to give crude
product (11.6 g). The crude product was recrystallized from AcOEt
(170 mL) and hexane (340 mL) to obtain the desired compound as
pale yellow plates (9.39 g, 39%). Through the aqueous washing, a
substantial amount of undissolved material was separated and collected
with a glass filter. This solid showed the same TLC behavior as the
organic layer, and recrystallization from AcOEt (170 mL) and hexane
(340 mL) gave the desired compound as pale yellow needles (12.3 g,
51%; the total yield, 21.7 g, 90%): mp 156-157 °C (lit.30 152-153
1
°C); H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H, amide), 8.14 (d,
J ) 8.1 Hz, 1H), 7.87 (t, J ) 6.3 Hz, 1H), 7.77 (m, 2H), 7.66 (d, J )
8.4 Hz, 2H), 7.36 (t, J ) 8.0 Hz, 2H), 7.11 (t, J ) 7.8 Hz, 1H); 13C
NMR (300 MHz, DMSO-d6) δ 164.1, 146.5, 138.9, 134.1, 132.7, 131.0,
129.3, 128.8, 124.3, 124.0, 119.7; HRMS m/e calcd for C13H10N2O3
242.0691, found 242.0692. Anal. calcd for C13H10N2O3: C, 64.46; H,
4.16; N, 11.56. Found: C, 64.55; H, 4.20; N, 11.60.
2-Aminobenzoylanilide. A solution of 2-nitrobenzoylanilide (4.85
g, 20 mmol) and 10% Pd/C (0.97 g) in dry THF (30 mL) was prepared
in a 100-mL round-bottomed flask provided with a magnetic stirrer.
H2 was introduced after removal of air by an aspirator, and the solution
was stirred vigorously for 8 h at room temperature. The catalyst was
removed by filtration through Celite. The filtrate was evaporated in
vacuo to give the desired compound as a pale yellow wax (4.21 g,
99%): 1H NMR (300 MHz, CDCl3) δ 7.75 (s, 1H, amide), 7.56 (d, J
) 7.8 Hz, 1H), 7.48 (d, 1H), 7.37 (t, J ) 7.8 Hz, 2H), 7.26 (t, J ) 7.8
Hz, 1H), 7.14 (t, J ) 7.4 Hz, 1H), 6.70 (m, 2H), 5.50 (s broad, 2H);
13C NMR (300 MHz, DMSO-d6) δ 167.9, 149.8, 139.3, 132.1, 128.8,
128.6, 123.4, 120.5, 116.4, 115.3, 114.7.
2,6-Bis-(4-(2-methoxycarbonylphenylcarbamoyl)phenylcarbam-
oyl)pyridine (34). To a solution of 2,6-pyridinedicarboxylic acid (167
mg, 1.0 mmol) and oxalyl chloride (381 mg, 3.0 mmol) in dry THF (5
mL) was added DMF (0.025 mL) through a silica gel filter, and the
reaction mixture was stirred at room temperature for 30 min. The
mixture was evaporated in vacuo to obtain the acid chloride. To a
solution of methyl 4-aminobenzoylanthranilate (541 mg, 2.0 mmol)
and pyridine (237 mg, 3.0 mmol) in dry THF (10 mL) was added the
acid chloride in dry THF (5 mL) dropwise, and the resulting mixture
was stirred at room temperature for 1 h. Hexane (40 mL) was added
to the reaction mixture, and the precipitation was collected on a glass
filter. The solid was washed with 1 N HCl (2 × 20 mL), saturated
aqueous NaHCO3 (2 × 20 mL), and H2O (2 × 20 mL). The crude
product was solidified from DMSO (100 mL), MeOH (100 mL), and
H2O (50 mL) to obtain the desired compound as a pale yellow green
powder (600 mg, 89%): mp 326-327 °C; 1H NMR (300 MHz, DMSO-
d6) δ 11.62 (s, 2H, amide), 11.31 (s, 2H, amide), 8.60 (d, J ) 8.4 Hz,
2H), 8.47 (d, J ) 7.5 Hz, 2H), 8.36 (t, J ) 8.1 Hz, 1H), 8.21 (d, J )
8.4 Hz, 4H), 8.05 (m, 6H), 7.70 (t, J ) 8.1 Hz, 2H), 7.25 (t, J ) 7.5
Hz, 2H), 3.93 (s, 3H); LRMS (FAB, MNBA) m/e calcd for C37H30N5O8
(M + H+) 672.2094, found 672.2066.
2,6-Bis-(4-(2-methoxycarbonylphenyl)carbamoyl)phenylcarbam-
oyl)pyridine N-Oxide (35). To a solution of 2,6-pyridinedicarboxylic
acid N-oxide (181 mg, 1.0 mmol) and oxalyl chloride (381 mg, 3.0
mmol) in dry THF (5 mL) was added DMF (0.025 mL) through a silica
gel filter, and the reaction mixture was stirred at room temperature for
30 min. The mixture was evaporated in vacuo to obtain the acid
chloride as a yellow solid. To a solution of methyl 4-aminobenzoyl-
anthranilate (541 mg, 2.0 mmol) and pyridine (237 mg, 3.0 mmol) in
dry THF (5 mL) was added a solution of the acid chloride in dry THF
(5 mL) dropwise, and the resulting mixture was stirred at room
2,6-Bis-(2-phenylcarbamoylphenylcarbamoyl)pyridine (36). To
a solution of 2,6-pyridinedicarboxylic acid (0.84 g, 5.0 mmol) and
oxalyl chloride (1.90 g, 15 mmol) in dry CH2Cl2 (20 mL) was added
DMF (0.25 mL) dropwise through a silica gel filter, and the reaction
mixture was stirred at room temperature for 4 h. The mixture was
evaporated in vacuo to obtain the acid chloride as a yellow oil. To a
solution of anthranylanilide (2.13 g, 10 mmol) and pyridine (1.19 g,
15 mmol) in dry CH2Cl2 (20 mL) was added the acid chloride (1.02 g,
5.0 mmol) in dry CH2Cl2 (20 mL) dropwise and the mixture was stirred
at room temperature overnight. Saturated aqueous NaHCO3 (50 mL)
was added to the mixture, and the precipitation was collected. The
residue was washed with H2O (2 × 20 mL) and CH2Cl2 (2 × 20 mL).
The crude product was dissolved in trace DMSO and recrystallized
from THF (300 mL) and hexane (400 mL) to obtain the desired
1
compound as white thin needles (2.55 g, 92%): mp 300-302 °C; H
NMR (300 MHz, DMSO-d6) δ 12.36 (s, 2H, amide), 10.33 (s, 2H,
anilide), 8.34 (m, 5H), 7.83 (d, J ) 7.8 Hz, 2H), 7.65 (t, J ) 7.8 Hz,
2H), 7.45 (m, 4H), 7.34 (t, J ) 7.5 Hz, 2H), 6.87 (s, 6H); 13C NMR
(300 MHz, DMSO-d6) δ 166.2, 161.1, 148.4, 140.7, 138.5, 137.2, 131.8,
129.1, 124.9, 123.9, 121.9, 120.5; HRMS (FAB, MNBA) m/e calcd
for C33H26N5O4 (M + H+) 556.1985, found 555.2010.

+
+
Oligoanthranilamides
J. Am. Chem. Soc., Vol. 118, No. 32, 1996 7541
2,6-Bis-(2-phenylcarbamoylphenylcarbamoyl)pyridine N-Oxide
(37). To a solution of 26 (0.55 g, 3.0 mmol) and oxalyl chloride (1.14
g, 9.0 mmol) in dry CH2Cl2 (10 mL) was added DMF (0.025 mL)
through a silica gel filter, and the reaction mixture was stirred at room
temperature for 5 min. The mixture was evaporated in vacuo to obtain
the acid chloride (0.81 g) as a yellow oil. To a solution of
anthranylaniline (1.27 g, 6.0 mmol) and pyridine (1.42 g, 18 mmol) in
dry CH2Cl2 (20 mL) was added the acid chloride (0.81 g) in dry CH2-
Cl2 (10 mL), and the mixture was stirred at room temperature overnight.
1 N HCl (30 mL) was added to the mixture, and the precipitate was
collected on a glass filter. The residue was washed with saturated
aqueous NaHCO3 (2 × 15 mL), H2O (2 × 15 mL), and CH2Cl2 (2 ×
15 mL). The crude product was recrystallized from DMSO (8 mL),
THF (80 mL), and hexane (80 mL) to obtain the desired compound as
white crystals (0.90 g, 53%; first crop). The filtrate was evaporated
and recrystallized from DMSO and H2O as pale yellow thin needles
(0.60 g, 35%; second crop): mp 243-245°; 1H NMR (300 MHz,
DMSO-d6) δ 12.75 (s, 2H, amide), 10.49 (s, 2H, anilide), 8.3 (d, J )
7.8 Hz, 2H), 8.20 (d, 8.1H), 7.70 (m, 7H), 7.61 (t, J ) 7.8 Hz, 2H),
7.36 (t, 7.5Hz, 2H), 7.21 (t, J ) 7.6 Hz, 4H), 7.01 (t, J ) 7.4 Hz, 2H);
13C NMR (300 MHz, DMSO-d6) δ 165.9, 157.9, 141.9, 138.9, 135.5,
131.1, 130.1, 128.6, 128.5, 128.2, 127.8, 124.8, 123.8, 123.5, 120.5;
HRMS (FAB, MNBA) m/e calcd for C33H26N5O5 (M + H+) 572.1934,
found 572.1913.
Acknowledgment. We thank the National Science Founda-
tion (CHE 9213937) for support of this work. We also thank
the Kureha Chemical Industry for a fellowship to Y.H.
Supporting Information Available: Crystallographic details
for oligoanthranilamides 15, 31, 32, 36, and 37 (Figures 1-5)
including tables of atomic coordinates, thermal parameters, bond
angles, and bond lengths (40 pages). Ordering information is
given on any current masthead page.
JA9539857