Synthesis, structures, and conformations of linked bis-glyoxylamides derived from bis-acylisatins

Article abstract of DOI:10.1071/CH14135

A series of bis-glyoxylamides possessing hydrophobic alkyl chains was successfully synthesised by ring opening of bis-acylisatins with amines or amino acid alkyl esters. The crystal structures revealed the interplay of intra-and intermolecular interactions (NH...O and C=O...C=O interactions) and the conformations of these long molecules.

Full text of DOI:10.1071/CH14135

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2014, 67, 1270–1278
Full Paper
http://dx.doi.org/10.1071/CH14135
Synthesis, Structures, and Conformations of Linked
Bis-Glyoxylamides Derived from Bis-Acylisatins
A B
,
A
C
Venty Suryanti,
Glenn C. Condie, Mohan Bhadbhade,
A
A D
,
A D
,
Roger Bishop, David StC. Black,
and Naresh Kumar
A
School of Chemistry, The University of New South Wales, Sydney, NSW 2052,
Australia.
B
Current address: Department of Chemistry, The University of Sebelas Maret,
Surakarta, Jawa Tengah 57126, Indonesia.
C
Mark Wainwright Analytical Centre, The University of New South Wales, Sydney,
NSW 2052, Australia.
D
Corresponding authors. Email: d.black@unsw.edu.au; n.kumar@unsw.edu.au
A series of bis-glyoxylamides possessing hydrophobic alkyl chains was successfully synthesised by ring opening of
bis-acylisatins with amines or amino acid alkyl esters. The crystal structures revealed the interplay of intra- and
intermolecular interactions (NHꢀꢀꢀO and C¼OꢀꢀꢀC¼O interactions) and the conformations of these long molecules.
Manuscript received: 11 March 2014.
Manuscript accepted: 16 April 2014.
Published online: 19 May 2014.
R1
Introduction
O
Various non-covalent interactions, such as hydrogen bonding,
p–p stacking, and hydrophobic interactions, are involved in the
formation and stabilisation of molecular self-assemblies.[1–8]
Molecules containing more than one hydrogen bond donor/
acceptor group and/or aromatic rings can form multiple types of
such interactions simultaneously.[9] The synthesis of oligomers
containing identical units in one molecule is a strategy that has
been used to facilitate a greater number of non-covalent inter-
actions between chains.[10–14] In particular, the self-assembly of
polyamides and oligoamides has been extensively studied
because of their structural similarity to proteins, where both
intramolecular and intermolecular hydrogen bonding interac-
tions play an important role in determining their secondary and
tertiary structures.[15–20] However, there are no strict rules
governing the rational design of these compounds and predict-
ing the self-organisation processes for different molecules
remains difficult.
O
R2
O
N
H
CH3
N
H
O
NH
O
O
NH
O
O
O
R1 ꢀ H, CH3 or Br
R3
R2 ꢀ alkyl or alkyl ester
R3 ꢀ alkyl
CH3
2
1
R1
R2
O
N
H
R2
O
O
R3
HN
O
N
H
O
HN
O
O
O
NH
H
N
O
NH
H
2
R2
N
R
O
O
3
4
R1
Chart 1.
We have previously demonstrated that mono-glyoxylamides
can undergo different modes of assembly depending on the
nature of cooperative effects between strong and weak non-
covalent interactions. The parent glyoxylamide 1 exhibited
dimeric association,[21] while N-acylglyoxylic amides 2 con-
taining alkyl side chains formed supramolecular assem-
blies.[22,23] As part of our continued interest in glyoxylamides
and their derivatives, we targeted bis-glyoxylamides 3 and 4 as
interesting scaffolds for further investigation into the self-
assembly of this class of molecules (Chart 1). We report herein
the synthesis of novel bis-glyoxylamides derived from oxalyl-
bis-isatins or bis-acylisatins linked through their carbonyl
groups, and analyse the intra- and intermolecular interactions
of these molecules in the solid state.
Results and Discussion
Synthesis of Oxalyl-Bis-Glyoxylamides
The synthesis of some bis-glyoxylamides from N-oxalyl-bis-
isatin has been previously reported by our group and some
analogues showed potent quorum sensing (QS) inhibitor activity
against Gram-positive bacteria.[21] In this study, novel bis-
glyoxylamides were synthesised by nucleophilic ring-opening
reactions of N-oxalyl-bis-isatin with alkyl amines or amino acid
alkyl esters. The oxalyl isatins were in turn prepared using a
modification of the procedure described by Black and Moss.[24]
In the present work, oxalyl-bis-isatins were heated at reflux
for 6 h in dichloromethane with hexylamine, dodecylamine, or
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

Linked Bis-Glyoxylamides
1271
R1
O
R2
O
N
H
O
O
O
N
R1
HN
O
O
R1
O
R2
O
O
O
i
N
R1
ii
O
N
O
H
HN
O
O
N
ꢁ
O
O
H
NH
N
Na
O
O
N
R2
O
NH
O
18
H
N
O
N
O
R2
O
R1
O
19–21
22–26
O
R1
8–17
R1 and R2 ꢀ alkyl
6–7
R1 ꢀ H, CH3
Scheme 2. Reagents and conditions: (i) acyl chlorides, anhydrous ben-
R2 ꢀ alkyl or amino acid alkyl ester
zene, reflux; (ii) amines, CH2Cl2, reflux.
Scheme 1. Reagents and conditions: CH2Cl2, alkylamine, reflux, 4 h or
mono alkyl ester hydrochloride salts, saturated NaHCO3, CH2Cl2–H2O (v/v,
6 : 2), 58C to room temperature, 24 h.
Table 2. Synthesis of bis-glyoxylamides 22–31
Entry
Product
R1
R2
YieldA [%]
Table 1. Synthesis of bis-glyoxylamides 8–17
1
2
3
4
5
6
22
23
24
25
26
30
1,3-phenylene
–(CH2)2–
–(CH2)4–
–(CH2)4–
–(CH2)4–
tartaryl
H
91
62
68
47
60
40
H
Entry
Product
R1
R2
YieldA [%]
–CH3
t-butyl
n-butyl
n-butyl
1
2
8
9
H
hexyl
54
50
59
61
53
56
42
36
38
43
CH3
H
hexyl
3
10
11
12
13
14
15
16
17
dodecyl
AIsolated yield (reaction was not optimised).
4
CH3
H
dodecyl
5
octadecyl
6
CH3
H
octadecyl
H
7
glycine hexyl ester
glycine hexyl ester
alanine hexyl ester
alanine hexyl ester
N
O
O
O
8
CH3
H
O
9
10
CH3
O
N
NH
i
ii
O
O
O
O
O
AIsolated yield (reaction was not optimised).
O
O
O
N
Cl
O
H
O
O
N
O
O
NH
27
O
octadecylamine to give analogues 8–13 in 50–61 % yields
(Scheme 1, Table 1). The bis-glyoxylamide peptidomimetics
were synthesised using the methodology and reaction conditions
previously described.[21] Hence, the oxalyl-bis-isatins were
stirred in dichloromethane for 24 h with amino alkyl ester
hydrochloride salts and sodium hydrogen carbonate at 58C to
room temperature to give the desired products 14–17 in 36–43 %
yields (Scheme 1, Table 1).
O
O
Cl
O
N
H
29
28
30
Scheme 3. Reagents and conditions: (i) pyridine, CH2Cl2, reflux, 3.5 h;
(ii) n-butylamine, CH2Cl2, reflux, 1.5 h.
Synthesis of Linked Bis-Glyoxylamides
tartaryl-bis-glyoxylamide 30 included two NH signals, with a
downfield singlet at 11.80 ppm corresponding to the amide NH
protons and a triplet at 7.34 ppm corresponding to the glyox-
ylamide NH protons.
The targeted bis-glyoxylamides 8–17, 22–26, and 30 were
recrystallised from various solvents by slow evaporation of the
solvent at room temperature. Crystals suitable for X-ray struc-
ture determination were successfully obtained for compounds 9
and 24–26[27–30] from methanol, while the other compounds
yielded only amorphous solids. Single crystal X-ray structure
determinations were carried out on compounds 9 and 24–26.
Acyl chlorides, including isophthaloyl chloride, succinyl
chloride, and adipoyl chloride, were reacted with sodium isatide
in anhydrous benzene under reflux to give the corresponding
bis-acylisatins 19–21 in 69–89 % yields. The targeted bis-
acylisatins 19–21 were then reacted with various amines to give
the corresponding bis-glyoxylamides 22–26 in moderate yields
(Scheme 2, Table 2).
Isatin 27 was reacted with 2,3-O-iso-propylidene-L-tartaryl
chloride (28) in the presence of pyridine in dichloromethane to
generate the desired L-tartaryl bis-acylisatin 29 in 35 % yield
(Scheme 3). The tartaryl chloride 28 was prepared according to
the method of Choi et al.[25] from 2,3-O-iso-propylidene-L-
tartrate, which was itself obtained from L-tartaric acid.[26] The
presence of the tartaryl moiety in compound 29 was confirmed
by 1H NMR spectroscopy, where the methine and methyl
protons of the tartaryl group appeared as singlets at 6.06 and
1.58 ppm. The L-tartaryl bis-acylisatin 29 was heated at reflux
with n-butylamine in dichloromethane to afford the tartaryl-
Crystal Structures
The crystal structure of 9 (Fig. 1a) contains two crystallo-
graphically independent molecules, one with an ordered struc-
ture and one with a disordered structure with two alternate
conformations because of the flexibility of the alkyl side chains
(the disordered structure is not shown). The two alkyl side
chains in the ordered structure of 9 are in a trans relationship.
Both molecules have a planar core and form intramolecular
1
bis-glyoxylamide 30 in 40 % yield. The H NMR spectrum of

1272
V. Suryanti et al.
(a)
(a)
C12A
H2A
N2A
O2A
C11A
O3A
O1A
C10A
C6A
H2A
H6A
C5A
C3
C4
C2
C5
H9A1
O2A
H11A
N2A
C1A
C2A
C3A
C8
N1
O1
H6B
C10A
O1B
C9A
C7A
H1A
O3A
H21
C9A
C6B
C9 C7
H9B
C8B
C8A
N1A
C1
C6
N1A
C4A
O3
C10
H6
O3B
C11
C10B
O2
H12F
C12
H11C
N2
H2
(b)
C15
C12
C13
N2
C14
(b)
O2
C10
O3
H3
C11
C2
H1
C7
C3
C9
H9B
C1
N1
C4
C8
N2C
H2C
C1C
C10C
C8C
O1B
C6
O1C
C8B
C5
C12C
H12F
O1
O3C
C5B
H6
O3B
C10B
H2A
N2A
Fig. 1. ORTEP diagrams showing the (a) intramolecular interactions (blue
dotted lines) and (b) the intermolecular interactions (black dotted lines) of
compound 9. The disordered alkyl chains are not shown for clarity.
(c)
C6
C5
C4
C1
O3
N–HꢀꢀꢀO hydrogen bonding interactions. In addition, the oxygen
atoms of the oxalyl group act as acceptors for intramolecular
hydrogen bonding interactions with the aromatic C6–H6 and the
amide N1–H1 protons. These interactions increase the ridigidity
of the molecule and induce planarity of the aromatic head groups
with the amide and the glyoxylamide groups.
C7
C9
N1
C8
C2
C3
H3
H9B
O1
C10
O2
C11
N2
C13
H12B
C12
C15
C14
H2
In terms of intermolecular interactions, two identical strong
N2–H2ꢀꢀꢀO3 hydrogen bonds are formed between the glyoxy-
lamide N–H protons and oxalyl groups of separate molecules of
9, while the planar cores participate in pꢀꢀꢀp stacking inter-
actions (Fig. 1b). Additionally, the carbonyl groups of the oxalyl
moiety form C¼OꢀꢀꢀC¼O intermolecular interactions, in addi-
tion to the intramolecular N–HꢀꢀꢀO hydrogen bonding inter-
actions described above (Fig. 1a, b). Interestingly, these
interactions are very different from those of compounds 24–26
(see below). Details of the intra- and intermolecular interactions
of 9 and a three-dimensional representation of the extended
molecular assembly of the compound are shown in the Supple-
mentary Material (Tables S1 and S2, Fig. S1).
Perspective views of molecules of 24–26 are shown in Fig. 2.
In the two bis-glyoxylamides 25 and 26, each molecule occupies
a crystallographic centre of symmetry coinciding with the
midpoint of the bond C9–C90 (centrosymmetrically related
C9). Meanwhile, compound 24, although similar to the other
two structures, has a pseudo centre of symmetry. Interestingly,
this molecule of 24 crystallises in a chiral space group P21.
Significant conformational differences were observed in
the crystal structures of bis-glyoxylamides 25 and 26, with mole-
cule 26 being more similar in conformation to molecule 24.
Fig. 2. ORTEP figures of (a) 24, (b) 25 and (c) 26 showing the intra-
molecular interactions (dotted lines).
The intramolecular N1–H1ꢀꢀꢀO2 hydrogen bond found in bis-
glyoxylamide 25 is absent in bis-glyoxylamide 26 because of
rotation of the aromatic ring around the N1–C1 bond of the latter
molecule by ,1808. As a result, molecule 25 is almost planar
(except for the protruding t-butyl substituent), whereas mole-
cule 26 is twisted at both ends.
Weak intermolecular C–HꢀꢀꢀO interactions on both sides of
the molecule 25 provide additional support to stabilise the
assembly (Fig. 2).
In molecule 26, weak C–HꢀꢀꢀO and N2–H2ꢀꢀꢀO2 intermole-
cular interactions are observed, complementing C¼OꢀꢀꢀC¼O
dipolar interactions in a cluster of three carbonyl groups
(Fig. 2). These dipolar associations[22,23,31] might influence
the orientation of O2 and O3, as seen in the torsion angles for
O2–C10–C11–O3 (95.2(4) in molecule 25 and ꢁ152.12(13) in
molecule 26) and C7–N1–C1–C6 (ꢁ7.3(5) in molecule 25 and
ꢁ141.99(13) in molecule 26). The geometric parameters of the

Linked Bis-Glyoxylamides
1273
(a)
O2 C10
H1
N1
N2
H2
C9
H9B
O1
C3
(b)
O3
H1
N1
2.007
C13
H13B
C9
H9B
N2
H2
2.388
O1
O2
Fig. 3. Intermolecular interactions (blue dotted lines) present in molecules (a) 25 and (b) 26.
(a)
intramolecular interactions of 24–26 are provided as Supple-
mentary Material (Tables S1 and S2). The formation of intra-
molecular N–HꢀꢀꢀO interactions, either with overall planarity in
the molecule or alternately with a twisted conformation, has
been previously observed in the mono-glyoxylamides.[22,23] It is
significant that the linked bis-glyoxylamides synthesised in this
work are also able to adopt these two conformations.
Once the amide N1–H1 proton is engaged in a strong
intramolecular hydrogen bond, the glyoxylamide N2–H2 proton
makes centrosymmetrically related intermolecular hydrogen
bonds with O1. In molecule 26, both N1–H1 and N2–H2 protons
make centrosymmetric intermolecular interactions with O3 and
O1 respectively from neighbouring molecules on either side
(Fig. 3). In molecule 25, the intermolecular dipolar interaction
(C7¼O1ꢀꢀꢀC10¼O2) exists supporting the N2–H2ꢀꢀꢀO1 bond;
whereas weaker N2–H2ꢀꢀꢀO1 is supported by two centrosym-
metric bifurcated C–HꢀꢀꢀO contacts (C9–H9BꢀꢀꢀO2 and C13–
H13BꢀꢀꢀO2) in molecule 26. Complementarity of the intra- and
intermolecular interactions present in molecules 25 and 26 (and
24) should hold the key to the nucleation process which
produces the two different conformations observed in the solid
state. Pictures of the extended molecular assemblies in three
dimensions are shown in the Supplementary Material.
(b)
Molecules of 24 and 26 pack together to form layers held
together by N–HꢀꢀꢀO hydrogen bonding (Fig. 4). However, the
packing structures differ with respect to the orientation of layers
in the three dimensions. In molecule 24, the next layer has a 21
screw relationship with the first layer, whereas in molecule
26, the third layer is merely a translation of the preceding
layers. The centre of symmetry in molecule 26 coincides with
¯
the crystallographic centre (in P1), while molecule 24 has
a non-crystallographic centre and crystallises in the non-
centrosymmetric space group P21.
Conclusion
A series of bis-glyoxylamides possessing hydrophobic
alkyl chains was successfully synthesised by ring opening of
Fig. 4. Packing of (a) 24 and (b) 26.

1274
V. Suryanti et al.
oxalyl-bis-isatins or bis-acylisatins with amines or amino acid
alkyl esters. The crystal structure of oxalyl-bis-glyoxylamide 9
has a planar core, and the carbonyl groups of the oxalyl moiety
participate in both intramolecular N–HꢀꢀꢀO hydrogen bonding
and intermolecular C¼OꢀꢀꢀC¼O (carbonyl–carbonyl) dipolar
interactions.
Crystal structures of bis-glyoxylamides 24–26 with an n-butyl
linkerrevealthatmolecules24and26havesimilarconformations
in the solid state that were significantly different from that of
molecule 25, as a result of the complementarity of the intra- and
intermolecular interactions present in the molecules. Molecules
25 and 26 possess a crystallographic centre of symmetry, while
molecule 24 exhibits a pseudo centre of symmetry. Additionally,
compound 24 crystallises in the chiral space group P21.
(0.12 g, 1.14 mmol) as an off-white solid (0.16 g, 50 %). The
solid, recrystallised from pyridine by slow evaporation of the
solvent at room temperature, yielded crystals suitable for X-ray
crystal structure determination, mp 260–2628C. nmax (KBr)/
cmꢁ1 3265, 3095, 2927, 2855, 1696, 1644, 1580, 1517, 1459,
1408, 1378, 1302, 1248, 1137, 1041, 979, 864, 803, 757. lmax
(THF)/nm (e/Mꢁ1 cmꢁ1) 248 (14 700), 252 (30 100). dH
(300 MHz, CDCl3) 0.85 (t, J 7.0, 6H, 2 ꢂ NHCH2(CH2)4CH3),
1.23–1.35 (m, 12H, 2 ꢂ CH2CH2(CH2)3CH3), 1.45–1.51 (m,
4H, 2 ꢂ NHCH2CH2(CH2)3CH3), 2.34 (s, 6H, 2 ꢂ ArCH3),
3.47–3.49 (m, 4H, 2 ꢂ NHCH2CH2(CH2)3CH3), 7.59 (d, J 8.6,
2H, ArH), 7.63 (s, 2H, 2 ꢂ CONH), 8.51 (d, J 8.5, 2H, ArH),
8.53 (d, J 8.6, 2H, ArH), 12.36 (s, 2H, 2 ꢂ NHCO). dC (75 MHz,
CDCl3) 14.3 (2 ꢂ CH2(CH2)4CH3), 21.0 (2 ꢂ ArCH3), 22.8,
26.8, 29.5, 31.7 (2 ꢂ CH2(CH2)4CH3), 39.9 (2 ꢂ NHCH2),
118.7, 126.2, 140.0 (6 ꢂ ArC), 121.1, 132.5, 137.6 (6 ꢂ ArCH),
163.2, 169.3, 192.6 (6 ꢂ C¼O). m/z 579.3170. HR-ESI Anal.
Calc. for C32H43N4O6 [M þ H]þ: 579.3177. Anal. Calc. for
C32H42N4O6: C 66.41, H 7.32, N 9.68. Found: C 66.42, H 7.28,
N 9.61 %.
Experimental
General
Melting points were measured using a Reichert microscope
(Gallenkamp hot stage apparatus) and are uncorrected. Infrared
spectra were recorded with a Thermo Nicolet 370 FTIR spec-
trometer with the sample prepared as a KBr pellet. UV-Vis
spectra were recorded using a Varian Cary 100 Scan spec-
trometer. NMR data were recorded using a Bruker DPX300
instrument (1H at 300 MHz, 13C at 75.4 MHz) at 258C and
reported as chemical shift (d) relative to SiMe4. Low and high
resolution mass spectrometric analysis was carried out at the
Biomedical Mass Spectrometry Facility, UNSW, and the spec-
tra was recorded on Q-TOF Ultima API (Micromass). Micro-
analyses were performed on a Carlo Erba Elemental Analyzer
EA 1108 at the Campbell Microanalytical Laboratory, Univer-
sity of Otago, New Zealand. Gravity column chromatography
was carried out using Merck 230–400 mesh ASTM silica gel.
N,N0-Bis-(2-(2-(dodecylamino)-2-oxoacetyl)phenyl)
oxalamide (10)
This compound was prepared by the same method as compound
8 from oxalyl bis-isatin 6 (0.15 g, 0.43 mmol) and dodecylamine
(0.16 g, 0.86 mmol) as an off-white solid (0.18 g, 59 %),
mp 244–2468C. nmax (KBr)/cmꢁ1 3315, 3085, 2918, 2850, 1716,
1645, 1600, 1579, 1529, 1452, 1377, 1312, 1277, 1210, 1121,
853, 764. lmax (THF)/nm (e/Mꢁ1 cmꢁ1) 246 (32 800), 343
(17 050). dH (300 MHz, pyridine-d5) 0.82 (t, J 6.5, 6H, 2 ꢂ
CH2CH2(CH2)9CH3), 1.18–1.39 (m, 36H, 2 ꢂ CH2CH2(CH2)9
CH3), 1.64–1.74 (m, 4H, 2 ꢂ NHCH2CH2(CH2)9CH3), 3.56–
3.63 (m, 4H, 2 ꢂ NHCH2(CH2)9CH3), 7.16–7.22 (m, 2H, ArH),
7.53–7.57 (m, 2H, ArH), 8.49 (dd, J 7.9, 1.6, 2H, ArH), 8.89 (d,
J 8.2, 2H, ArH), 9.99 (t, J 5.7, 2H, 2 ꢂ CONH), 12.91 (s, 2H,
2 ꢂ NHCO). dC (75 MHz, pyridine-d5) 14.0 (2 ꢂ CH2(CH2)10
CH3), 22.6, 26.6, 29.1, 29.2, 29.2, 29.4, 29.5, 29.5, 29.5, 31.3
(2 ꢂ CH2(CH2)10CH3), 39.6 (2 ꢂ NHCH2), 118.7, 141.9 (6 ꢂ
ArC), 120.6, 122.5, 134.3, 136.4 (8 ꢂ ArCH), 162.8, 169.2,
192.1 (6 ꢂ C¼O). m/z 719.43. TOF-ESI Anal. Calc. for
C42H63N4O6 [M þ H]þ: 719.47. Anal. Calc. for C42H62N4O6:
C 70.16, H 8.69, N 7.79. Found: C 70.27, H 8.78, N 7.77 %.
N,N0-Bis-(2-(2-(hexylamino)-2-oxoacetyl)phenyl)
oxalamide (8)
A mixture of oxalyl-bis-isatin 6 (0.20 g, 0.57 mmol) and hex-
ylamine (0.12 g, 1.14 mmol) in dichloromethane (30 mL) was
heated at reflux for 6 h. The cooled reaction mixture was con-
centrated under vacuum. The crude product was purified by
column chromatography using silica gel and a mixture of
dichloromethane and hexane as eluent. The title compound was
obtained as an off-white solid (0.17 g, 54 %), mp 264–2658C.
nmax (KBr)/cmꢁ1 3330, 3248, 2929, 2856, 1714, 1645, 1600,
1579, 1526, 1452, 1377, 1324, 1257, 1209, 1121, 837, 764. lmax
(THF)/nm (e/Mꢁ1 cmꢁ1) 246 (51 100), 342 (28 300). dH
(300 MHz, pyridine-d5) 0.75 (t, J 7.0, 6H, 2 ꢂ CH2(CH2)4CH3),
1.12–1.36 (m, 12H, 2 ꢂ CH2CH2(CH2)3CH3), 1.58–1.69 (m,
4H, 2 ꢂ NHCH2CH2(CH2)3CH3), 3.53–3.59 (m, 4H, 2 ꢂ
NHCH2CH2(CH2)3CH3), 7.17–7.22 (m, 2H, ArH), 7.53–7.58
(m, 2H, ArH), 8.47 (dd, J 7.9, 1.4, 2H, ArH), 8.84 (d, J 8.3, 2H,
ArH), 9.98 (t, J 5.6, 2H, 2 ꢂ CONHCH2), 12.92 (s, 2H, 2 ꢂ
NHCO). dC (75 MHz, pyridine-d5) 13.9 (2 ꢂ CH2(CH2)4CH3),
26.6, 29.4, 31.3 (2ꢂ CH2(CH2)4CH3), 39.3 (2 ꢂ NHCH2), 120.8,
149.8 (4ꢂ ArC), 122.5, 123.9, 124.0, 136.4 (8ꢂ ArCH), 158.6,
165.1, 194.6 (6ꢂ C¼O). m/z 551.26. TOF-ESI Anal. Calc. for
C30H39N4O6 [Mþ H]þ: 551.28. Anal. Calc. for C30H38N4O6:
C 65.44, H 6.96, N 10.17. Found: C 65.51, H 6.92, N 10.13 %.
N,N0-Bis-(2-(2-(dodecylamino)-2-oxoacetyl)-4-
methylphenyl)oxalamide (11)
This compound was prepared by the same method as compound
8 from oxalyl bis-isatin 7 (0.16 g, 0.43 mmol) and dodecylamine
(0.16 g, 0.86 mmol) as a yellow solid (0.20 g, 61 %), mp
224–2268C. nmax (KBr)/cmꢁ1 3280, 3081, 2919, 2850, 2359,
2340, 1701, 1642, 1578, 1512, 1454, 1406, 1376, 1330, 1300,
1244, 1135, 866, 753. lmax (THF)/nm (e/Mꢁ1 cmꢁ1) 250
(33 800), 347 (13 700). dH (300 MHz, CDCl3) 0.88 (t, J 6.9, 6H,
2 ꢂ CH2(CH2)10CH3), 1.23–1.35 (m, 36H, 2 ꢂ CH2CH2(CH2)9
CH3), 1.55–1.66 (m, 4H, 2 ꢂ NHCH2CH2(CH2)9CH3), 2.39 (s,
6H, 2 ꢂ ArCH3), 3.47–3.49 (m, 4H, 2 ꢂ NHCH2CH2(CH2)9
CH3), 7.06 (t, J 5.6, 2H, 2 ꢂ CONH), 7.49 (dd, J 8.6, 2.1, 2H,
ArH), 8.48 (d, J 1.6, 2H, ArH), 8.71 (d, J 8.5, 2H, ArH), 12.63 (s,
2H, 2 ꢂ NHCO). dC (75 MHz, CDCl3) 14.0 (2 ꢂ CH2(CH2)10
CH3), 20.8 (2 ꢂ ArCH3), 22.6, 26.8, 29.2, 29.3, 29.4, 29.5,
29.5, 31.8 (2 ꢂ CH2(CH2)10CH3), 39.6 (2 ꢂ NHCH2), 120.1,
133.8, 137.5 (6 ꢂ ArC), 120.6, 134.9, 137.0 (6 ꢂ ArCH),
158.3, 161.8, 190.8 (6 ꢂ C¼O). m/z 769.4861. HR-ESI Anal.
Calc. for C44H67N4O6 [M þ Na]þ: 769.4875. Anal. Calc. for
N,N0-Bis-(2-(2-(hexylamino)-2-oxoacetyl)-4-methylphenyl)
oxalamide (9)
This compound was prepared by the same method as compound
8 from oxalyl bis-isatin 7 (0.21 g, 0.57 mmol) and hexylamine

Linked Bis-Glyoxylamides
1275
C44H66N4O6: C 70.74, H 8.91, N 7.50. Found: C 70.80, H 9.07,
N 7.51 %.
nmax (KBr)/cmꢁ1 3282, 3078, 2955, 2931, 2858, 1733, 1714,
1646, 1600, 1578, 1452, 1372, 1310, 1273, 1200, 1169, 1065,
992, 868, 765. lmax (THF)/nm (e/Mꢁ1 cmꢁ1) 234 (15 350), 262
(18 700), 342 (12 700). dH (300 MHz, CDCl3) 0.88 (t, J 6.9, 6H,
2 ꢂ CH2(CH2)4CH3), 1.28–1.46 (m, 12H, 2 ꢂ CH2CH2(CH2)3
CH3), 1.66–1.74 (m, 4H, 2 ꢂ CH2CH2(CH2)3CH3), 4.21–4.26
(m, 8H, 2 ꢂ NHCH2COOCH2(CH2)CH3), 7.28–7.34 (m, 2H,
ArH), 7.57 (t, J 5.3, 2H, 2 ꢂ NHCH2COO), 7.71–7.77 (m, 2H,
ArH), 8.41 (dd, J 8.1, 1.5, 2H, ArH), 8.67 (dd, J 8.5, 1.0, 2H,
ArH), 12.70 (s, 2H, 2 ꢂ NHCO). dC (75 MHz, CDCl3) 14.0
(2 ꢂ CH2(CH2)4CH3), 22.5, 25.5, 28.5, 31.4 (2 ꢂ CH2(CH2)4
CH3), 41.5 (2 ꢂ NHCH2COO), 66.1 (2 ꢂ COOCH2(CH2)4CH3),
120.0, 140.1 (4 ꢂ ArC), 120.9, 124.2, 134.9, 136.6 (8 ꢂ ArCH),
158.4, 162.0, 168.8, 189.9 (8 ꢂ C¼O). m/z 667.2908. HRMS
(ESI) Anal. Calc. for C34H43N4O10 [M þ H]þ: 667.2901.
N,N0-Bis-2-(2-(octadecylamino)-2-oxoacetyl)phenyl)
oxalamide (12)
This compound was prepared by the same method as compound
8 from oxalyl bis-isatin 6 (0.10 g, 0.29 mmol) and octadecyla-
mine (0.16 g, 0.58 mmol) as an off-white solid after purification
by column chromatography (0.14 g, 53 %), mp 220–2228C. nmax
(KBr)/cmꢁ1 3314, 3252, 2918, 2850, 1717, 1646, 1600, 1579,
1529, 1452, 1376, 1313, 1276, 1212, 1167, 839, 763. lmax
(THF)/nm (e/Mꢁ1 cmꢁ1) 246 (26 800), 343 (13 200). dH
(300 MHz, pyridine-d5) 0.82 (t, J 6.8, 6H, 2 ꢂ CH2CH2(CH2)9
CH3), 1.18–1.39 (m, 60H, 2 ꢂ CH2CH2(CH2)15CH3), 1.65–1.78
(m, 4H, 2 ꢂ NHCH2CH2(CH2)15CH3), 3.53–3.66 (m, 4H, 2 ꢂ
NHCH2(CH2)15CH3), 7.15–7.21 (m, 2H, ArH), 7.54–7.52 (m,
2H, ArH), 8.47 (dd, J 7.9, 1.5, 2H, ArH), 8.89 (d, J 8.2, 2H, ArH),
9.98 (t, J 5.6, 2H, 2 ꢂ CONH), 12.94 (s, 2H, 2 ꢂ NHCO). dC
(75 MHz, pyridine-d5) 14.0 (2 ꢂ CH2(CH2)16CH3), 22.6, 26.6,
29.1, 29.2, 29.2, 29.4, 29.5, 29.5, 29.5, 31.2 (2 ꢂ
CH2(CH2)16CH3), 39.6 (2 ꢂ NHCH2), 118.6, 141.9 (4 ꢂ ArC),
120.6, 122.5, 134.3, 136.4 (8 ꢂ ArCH), 161.8, 167.2, 190.1
(6 ꢂ C¼O). m/z 887.6620. HRMS (ESI) Anal. Calc. for
C54H87N4O6 [M þ H]þ: 887.6603.
Dihexyl 2,20-((2,20-((Oxalylbis(azanediyl))bis(3-methyl-6,1-
phenylene))bis(2-oxoacetyl))bis(azanediyl))diacetate (15)
This compound was prepared by the same method as compound
14 from oxalyl bis-isatin 7 (0.15 g, 0.39 mmol) and glycine
hexyl ester hydrochloride (0.19 g, 0.98 mmol) as a yellow solid
(0.11 g, 38 %), mp 184–1868C. nmax (KBr)/cmꢁ1 3347, 3202,
2927, 2870, 1742, 1682, 1584, 1518, 1460, 1413, 1363, 1310,
1263, 1182, 1135, 1079, 1037, 969, 863, 754. lmax (THF)/nm
(e/Mꢁ1 cmꢁ1) 237 (37 350), 249 (43 150), 348 (21 450). dH
(300 MHz, CDCl3) 0.93 (t, J 6.8, 6H, 2 ꢂ CH2(CH2)4CH3),
1.29–1.45 (m, 12H, 2 ꢂ CH2CH2(CH2)3CH3), 1.66–1.74 (m,
4H, 2 ꢂ CH2CH2(CH2)3CH3), 2.42 (s, 6H, 2 ꢂ ArCH3), 4.22–
4.26 (m, 8H, 2 ꢂ NHCH2COOCH2(CH2)4CH3), 7.51–7.59 (m,
4H, 2 ꢂ ArH and 2 ꢂ NHCH2COO), 8.40 (d, J 1.4, 2H, ArH),
8.74 (d, J 8.6, 2H, ArH), 12.58 (s, 2H, 2 ꢂ NHCO). dC (75 MHz,
CDCl3) 14.0 (2 ꢂ CH2(CH2)4CH3), 20.9 (2 ꢂ ArCH3), 22.5,
25.5, 28.5, 31.4 (2 ꢂ CH2(CH2)4CH3), 41.6 (2 ꢂ NHCH2COO),
66.1 (2 ꢂ COOCH2(CH2)4CH3), 120.0, 133.9, 137.7 (6 ꢂ ArC),
120.8, 134.9, 137.3 (6 ꢂ ArCH), 158.3, 162.2, 168.8, 190.0
(8 ꢂ C¼O). m/z 717.3113. HRMS (ESI) Anal. Calc. for
C36H47N4O10 [M þ H]þ: 717.3106.
N-(4-Methyl-2-(2-(octadecylamino)-2-oxoacetyl)phenyl)-
N0-(4-methyl-6-(2-(octadecylamino)-2-oxoacetyl)
cyclohexa-1,5-dien-1-yl)oxalamide (13)
This compound was prepared by the same method as compound
8 from oxalyl bis-isatin 7 (0.11 g, 0.29 mmol) and octadecyla-
mine (0.16 g, 0.58 mmol) as an off-white solid (0.13 g, 46 %),
mp 228–2308C. nmax (KBr)/cmꢁ1 3302, 2918, 2850, 1712, 1647,
1583, 1523, 1459, 1374, 1303, 1248, 1188, 1160, 819, 788. lmax
(THF)/nm (e/Mꢁ1 cmꢁ1) 250 (24 900), 348 (11 750). dH
(300 MHz, CDCl3) 0.88 (t, J 7.1, 6H, 2 ꢂ CH2(CH2)16CH3),
1.23–1.34 (m, 60H, 2 ꢂ CH2CH2(CH2)15CH3), 1.54–1.65 (m,
4H, 2 ꢂ NHCH2CH2(CH2)15CH3), 2.39 (s, 6H, 2 ꢂ ArCH3),
3.36–3.45 (m, 4H, 2 ꢂ NHCH2CH2(CH2)15CH3), 7.08 (s, 2H,
2 ꢂ CONH), 7.49 (d, J 8.4, 2H, ArH), 8.47 (s, 2H, ArH), 8.71 (d,
J 8.4, 2H, ArH), 12.62 (s, 2H, 2 ꢂ NHCO). dC (75 MHz, CDCl3)
14.0 (2 ꢂ CH2(CH2)16CH3), 20.8 (2 ꢂ ArCH3), 22.6, 26.8, 29.2,
29.3, 29.4, 29.5, 29.6, 31.8 (2 ꢂ CH2(CH2)16CH3), 39.6 (2 ꢂ
NHCH2), 120.1, 133.8, 137.5 (6 ꢂ ArC), 120.6, 134.9, 137.0
(6 ꢂ ArCH), 158.3, 161.9, 190.8 (6 ꢂ C¼O). m/z 939.5958.
HRMS (ESI) Anal. Calc. for C56H92N4O6Na [M þ Na]þ:
939.7017. Anal. Calc. for C56H92N4O6: C 73.48, H 9.91, N, 6.12.
Found: C 73.35, H 10.03, N 6.51 %.
Dihexyl 2,20-((2,20-((Oxalylbis(azanediyl))bis(2,1-
phenylene))bis(2-oxoacetyl))bis(azanediyl))
dipropanoate (16)
This compound was prepared by the same method as compound
14 from oxalyl bis-isatin 6 (0.15 g, 0.43 mmol) and L-alanine
hexyl ester hydrochloride (0.23 g, 1.08 mmol) as a white solid
(0.11 g, 36 %), mp 170–1728C. nmax (KBr)/cmꢁ1 3365, 3250,
2931, 2856, 1755, 1717, 1649, 1601, 1579, 1529, 1453, 1412,
1324, 1299, 1237, 1167, 1052, 937, 769. lmax (THF)/nm
(e/Mꢁ1 cmꢁ1) 236 (22 900), 259 (28 550), 346 (18 900). dH
(300 MHz, CDCl3) 0.92 (t, J 6.6, 6H, 2 ꢂ CH2(CH2)4CH3),
1.31–1.42 (m, 12H, 2 ꢂ (CH2)2(CH2)3CH3), 1.57 (d, J 7.2, 6H,
2 ꢂ NHCHCH3COO), 1.66–1.73 (m, 4H, 2 ꢂ CH2CH2(CH2)3
CH3), 4.20–4.25 (m, 4H, 2 ꢂ COOCH2(CH2)4CH3), 4.65–4.75
(m, 2H, 2 ꢂ NHCHCH2COO), 7.28–7.32 (m, 2H, 2 ꢂ ArH),
7.60 (d, J 7.6, 2H, 2 ꢂ NHCHCH2COO), 7.69–7.75 (m, 2H,
ArH), 8.64 (dd, J 8.1, 1.5, 2H, ArH), 8.86 (dd, J 8.1, 0.9, 2H,
ArH), 12.71 (s, 2H, 2 ꢂ NHCO). dC (75 MHz, CDCl3) 14.0
(2 ꢂ CH2(CH2)4CH3), 18.2 (2 ꢂ NHCHCH3COO), 20.2 (2 ꢂ
ArCH3), 22.5, 25.5, 28.5, 31.4 (2 ꢂ CH2(CH2)4CH3), 48.6
(2 ꢂ NHCHCH3COO), 66.0 (2 ꢂ COOCH2(CH2)4CH3), 120.0,
137.7 (4 ꢂ ArC), 120.8, 133.9, 134.9, 137.2 (8 ꢂ ArCH), 158.4,
161.5, 171.9, 190.1 (8 ꢂ C¼O). m/z 695.3206. HRMS (ESI)
Anal. Calc. for C36H47N4O10 [M þ H]þ: 695.3214.
Dihexyl 2,20-((2,20-((Oxalylbis(azanediyl))bis(2,1-
phenylene))bis(2-oxoacetyl))bis(azanediyl))diacetate (14)
A solution of glycine hexyl ester hydrochloride (0.21 g,
1.08 mmol) containing saturated NaHCO3 was added to a stirred
solution of the oxalyl bis-isatin 6 (0.15 g, 0.43 mmol) in
dichloromethane (25 mL) at 58C. The reaction mixture was
warmed to room temperature and stirred for 24–28 h. The
organic layer was diluted with CH2Cl2 (25 mL) and washed with
aqueous HCl (0.5 M, 15 mL) and water (20 mL). The organic
extract was dried over anhydrous Na2SO4, filtered, and con-
centrated under vacuum. The crude product was purified by
column chromatography using silica gel and a mixture of
dichloromethane and hexane as eluent. The title compound was
obtained as an off-white solid (0.12 g, 42 %), mp 164–1668C.

1276
V. Suryanti et al.
Dihexyl 2,20-((2,20-((Oxalylbis(azanediyl))bis(3-methyl-
6,1-phenylene))bis(2-oxoacetyl))bis(azanediyl))
dipropanoate (17)
1-(6-(2,3-Dioxo-1H-indol-1-yl)-6-oxohexanoyl)-1H-
indole-2,3-dione (21)
A solution of adipoyl chloride (2.44 g, 13.4 mmol) in anhydrous
benzene (30 mL) was added dropwise over 10 min to a stirred
suspension of sodium isatide (5.00 g, 30 mmol) in anhydrous
benzene (150 mL). The reaction mixture was heated at reflux for
2 h. The hot mixture was then filtered, washed with water, and
dried to give a yellow solid (3.91 g, 72 %), mp .2008C (dec.).
nmax (KBr)/cmꢁ1 1775, 1740, 1700, 1605. lmax (THF)/nm
(e/Mꢁ1 cmꢁ1) 237 (38 000), 269 (15 450), 342 (8800). dH
(300 MHz, DMSO-d6) 1.76 (s, 4H, NHCH2(CH2)2CH2NH),
3.07 (s, 4H, NHCH2(CH2)2CH2NH), 7.36 (t, J 7.2, 2H, 2 ꢂ
ArH), 7.76–7.99 (m, 4H, 4 ꢂ ArH), 8.28 (d, J 8.2, 2H, 2 ꢂ ArH).
This compound was too insoluble for a 13C NMR spectrum
to be recorded. m/z 719.33. TOF-ESI Anal. Calc. for
C22H19N2O6 [M þ H]þ: 407.12. Anal. Calc. for C22H16N2O6:
C 65.38, H 4.00, N 6.91. Found: C 65.00, H 4.21, N 6.72 %.
This compound was prepared by the same method as compound
14 from oxalyl bis-isatin 7 (0.15 g, 0.39 mmol) and L-alanine
hexyl ester hydrochloride (0.21 g, 0.98 mmol) as a yellow solid
(0.18 g, 43 %), mp 178–1808C. nmax (KBr)/cmꢁ1 3286, 2929,
2859, 1742, 1698, 1649, 1578, 1515, 1547, 1407, 1389, 1303,
1276, 1249, 1233, 1115, 988, 865, 788. lmax (THF)/nm
(e/Mꢁ1 cmꢁ1) 237 (16 550), 249 (22 050), 347 (9700). dH
(300 MHz, CDCl3) 0.92 (t, J 6.0, 6H, 2 ꢂ CH2(CH2)4CH3),
1.28–1.45 (m, 12H, 2 ꢂ (CH2)2(CH2)3CH3), 1.57 (d, J 7.2, 6H,
2 ꢂ NHCHCH3COO), 1.66–1.76 (m, 4H, 2 ꢂ CH2CH2(CH2)3
CH3), 2.43 (s, 6H, 2 ꢂ ArCH3), 4.20–4.25 (m, 4H, 2 ꢂ COOCH2
(CH2)4CH3), 4.65–4.75 (m, 2H, 2 ꢂ NHCHCH3COO), 7.28–
7.32 (dd, J 8.7, 2.2, 2H, ArH), 7.58 (d, J 7.7, 2H, 2 ꢂ
NHCHCH2COO), 8.41 (d, J 1.9, 2H, ArH), 8.75 (d, J 8.2, 2H,
ArH), 12.62 (s, 2H, 2 ꢂ NHCO). dC (75 MHz, CDCl3) 14.0
(2 ꢂ CH2(CH2)4CH3), 18.1 (2 ꢂ NHCHCH3COO), 20.9 (2 ꢂ
ArCH3), 22.5, 25.5, 28.5, 31.4 (2 ꢂ CH2(CH2)4CH3), 48.6
(2 ꢂ NHCHCH3COO), 66.0 (2 ꢂ COOCH2(CH2)4CH3), 120.1,
133.9, 137.7 (6 ꢂ ArC), 120.8, 134.9, 137.2 (6 ꢂ ArCH), 158.4,
161.5, 171.9, 190.1 (8 ꢂ C¼O). m/z 745.3405. HRMS (ESI)
Anal. Calc. for C38H50N4O10Na [M þ Na]þ: 745.3419. Anal.
Calc. for C38H50N4O10: C 63.14, H 6.97, N 7.75. Found:
C 63.40, H 7.09, N 7.58 %.
N,N0-Bis(2-(2-amino-2-oxoacetyl)phenyl)isophthalamide
Hydrate (22)
The title compound was prepared by bubbling gaseous ammonia
through a solution of isophthaloyl bis-isatin 19 (0.51 g,
1.2 mmol) in dimethylformamide. The title compound was
obtained as a colourless powder (0.50 g, 91 %), mp 208–2098C.
nmax (KBr)/cmꢁ1 3410, 3290, 1727, 1690, 1678, 1650, 1611,
1587, 1535, 1315, 1220, 1168, 982, 792, 702. lmax (THF)/nm
(e/Mꢁ1 cmꢁ1) 238 (38 500), 270 (1600), 341 (9000). dH
(300 MHz, DMSO-d6) 7.30–8.57 (m, 16H, 12 ꢂ ArH and 2 ꢂ
ꢁCONH2), 11.64 (s, 2H, 2 ꢂ ArNHCO). dC (75 MHz, DMSO-
d6) 121.78, 122.69, 123.99, 126.85, 129.52, 130.56, 132.51,
134.72, 134.91, 139.40 (ArC and ArCH), 164.56, 165.99,
193.43 (6 ꢂ C¼O). m/z 459.20. TOF-ESI Anal. Calc. for
C24H19N2O6 [M þ H]þ: 459.13. Anal. Calc. for C24H18N4O6.
H2O: C 60.50, H 4.23, N 11.76. Found: C 60.41, H 4.51,
N 12.02 %.
1-(3-(2,3-Dioxo-1H-indole-1-carbonyl)benzoyl)-
1H-indole-2,3-dione (19)
A solution of isophthaloyl chloride (3.03 g, 15 mmol) in anhy-
drous benzene was added dropwise to a stirred suspension of
sodium isatide (5.00 g, 30 mmol) in anhydrous benzene. The
reaction mixture was warmed for 10 min to complete the reac-
tion and then heated under reflux for 5 min and quickly filtered
to remove the salt. The solvent was evaporated under vacuum to
give the title compound as a yellow solid (5.69 g, 89 %), mp
186–1878C. nmax (KBr)/cmꢁ1 1775, 1745, 1725, 1690, 1650,
1600, 1585, 1535, 1340, 1300, 1210, 1165, 1000, 760, 750, 715.
lmax (THF)/nm (e/Mꢁ1 cmꢁ1) 237 (38 100), 267 (15 250), 341
(8550). dH (300 MHz, DMSO-d6) 7.27–8.56 (m, 12H, 12 ꢂ
ArH). This compound was too insoluble for 13C NMR
spectrum to be recorded. m/z Found 427.05. TOF-ESI Anal.
Calc. for C24H15N2O6 [M þ H]þ: 427.09. Anal. Calc. For
C24H14N2O6.H2O: C 64.87, H 3.63, N 6.30. Found: C 65.04,
H 3.60, N 6.21 %.
N,N0-Bis(2-(2-amino-2-oxoacetyl)phenyl)succinamide (23)
The title compound was prepared by treating a suspension of
succinyl bis-isatin 20 (0.57 g, 1.5 mmol) in absolute ethanol with
a solution of aqueous ammonia (30 mL, 2 M). The title com-
pound was collected by filtration, recrystallised from ethanol–
DMF, and obtained as a pale yellow powder (0.38 g, 62 %), mp
223–2248C. nmax (KBr)/cmꢁ1 3410, 3220, 1700, 1670, 1642,
1605, 1584, 1530, 1450, 1318, 1220, 1175, 1160, 1150, 1127,
980, 774. lmax (THF)/nm (e/Mꢁ1 cmꢁ1) 237 (38 050), 267
(15 600), 341 (8900). dH (300 MHz, DMSO-d6) 2.74 (s, 4H,
-COCH2CH2CO), 7.15–8.17 (m, 12H, 8 ꢂ ArH and 2 ꢂ
–CONH2), 10.81 (s, 2H, 2 ꢂ ArNHCO). dC (75 MHz, DMSO-
d6) 121.20, 122.30, 123.28, 132.12, 134.52, 139.21 (ArC and
ArCH), 166.19, 170.67, 192.91 (6 ꢂ C¼O). m/z 411.19. TOF-
ESI Anal. Calc. for C20H19N4O6 [M þ H]þ: 411.13. Anal. Calc.
for C20H18N4O6: C 58.53, H 4.42, N 13.65. Found: C 58.41,
H 4.22, N 13.42 %.
1-(4-(2,3-Dioxo-1H-indol-1-yl)-4-oxobutanoyl)-1H-
indole-2,3-dione (20)
This compound was prepared by the same method as compound
19 from sodium isatide (5.00 g, 30 mmol) and succinyl chloride
2.08 g, 13.4 mmol) as a yellow powder (3.49 g, 69 %), mp 255–
2578C. nmax (KBr)/cmꢁ1 1770, 1740, 1715, 1600, 1590, 1400,
1340, 1300, 1255, 1215, 1175, 1155, 1085, 920, 890, 800, 770,
700. lmax (THF)/nm (e/Mꢁ1 cmꢁ1) 238 (37 750), 270 (15 640),
341 (8600). dH (300 MHz, DMSO-d6) 3.45 (s, 4H, 2 ꢂ
NCOCH2), 7.37–8.32 (m, 8H, 8 ꢂ ArH). This compound was
too insoluble for a 13C NMR spectrum to be recorded. m/z
379.13. TOF-ESI Anal. Calc. for C20H15N2O6 [M þ H]þ:
379.09. Anal. Calc. For C20H14N2O6: C 63.49, H 3.73, N 7.40.
Found: C 63.40, H 3.50, N 7.40 %.
N,N0-Bis(2-(2-(methylamino)-2-oxoacetyl)phenyl)
adipamide (24)
A solution of 1,10-(adipoyl) bis-isatin 21 (0.50 g, 1.24 mmol)
and methylamine (25 % aqueous, 0.8 mL, 6 mmol) in dichloro-
methane (30 mL) was heated at reflux for 3 h. The cooled
solution was washed with dilute hydrochloric acid, dried over
anhydrous magnesium sulfate, and concentrated under vacuum.

Linked Bis-Glyoxylamides
1277
The crude product was purified by suction column chromato-
graphy using dichloromethane as eluent to give the title com-
pound as a white solid (0.40 g, 68 %), mp 194–1968C. nmax
(KBr)/cmꢁ1 3354, 3279, 3254, 1699, 1668, 1608, 1531, 1482,
25.2, 31.7 (6 ꢂ CH2), 38.5 (2ꢂ NHCOCH2), 39.7 (2ꢂ NHCH2),
119.3, 142.4 (4 ꢂ ArC), 121.2, 122.9, 134.8, 136.8 (8 ꢂ ArCH),
163.3, 172.1, 192.6 (6 ꢂ C¼O). m/z 573.28. TOF-ESI Anal.
Calc. for C30H38N4O6 [M þ Na]þ: 573.26. Anal. Calc. for
C30H38N4O6ꢀ0.25H2O C 64.91, H 6.99, N 10.09. Found:
C 64.94, H 7.03, N 10.01 %.
1407, 1302, 1275, 1212, 940, 757. lmax (THF)/nm (e/Mꢁ1 cmꢁ1
)
239 (36 900), 270 (14 600), 345 (8400). dH (300 MHz, DMSO-
d6) 1.63 (s, 4H, COCH2CH2CH2CH2CO), 2.37–2.43 (m, 4H,
COCH2CH2CH2CH2CO), 2.73 (d, J 4.9, 6H, 2 ꢂ NHCH3), 7.22
(d, J 7.9, 2H, ArH), 7.66–7.58 (m, 4H, ArH), 7.88 (d, J 7.9, 2H,
ArH), 8.61 (d, J 4.9, 2H, 2 ꢂ NHCH3), 10.56 (s, 2 H, 2 ꢂ
NHCO). dC (75 MHz, DMSO-d6) 25.8 (2 ꢂ NHCH3), 24.7
(COCH2CH2CH2CH2CO), 36.7 (COCH2CH2CH2CH2CO),
121.8, 123.7, 132.0, 132.4 (8 ꢂ ArCH), 124.1, 138.9 (4 ꢂ ArC),
164.4, 171.7, 191.9 (6 ꢂ C¼O). m/z 467.14. TOF-ESI Anal.
Calc. for C24H27N4O6 [M þ H]þ: 467.19. Anal. Calc. for
C24H26N4O6: C 61.79, H 5.62, N 12.01. Found: C 61.51, H 5.61,
N 11.77 %.
1,10-((4R,5R)-2,2-Dimethyl-1,3-dioxolane-4,5-dicarbonyl)
bis(indoline-2,3-dione) (29)
A
solution of 2,3-O-iso-propylidene-L-tartaryl chloride
(11.97 g, 52.7 mmol) in dichloromethane (50 mL) was added
dropwise to a stirred suspension of isatin (14.73, 100 mmol) and
pyridine (10.3 mL) in dichloromethane (150 mL). The reaction
mixture was heated at reflux for 3.5 h and allowed to cool. The
mixture was washed three times with dilute HCl, twice with
saturated NaHCO3, dried over magnesium sulfate, and the
solvent was evaporated under vacuum. Purification by suction
coloumn chromatography (dichloromethane) gave the title
compound (7.830 g, 35 %). dH (300 MHz, CDCl3) 1.58 (s, 6H,
C(CH3)2), 6.06 (s, 2H, CH), 7.40 (t, 2H, J 7.2, 8.2, ArH),
7.83–776 (m, 4H, ArH), 8.48 (d, 2H, J 8.2, ArH).
N,N0-Bis(2-(2-(tert-butylamino)-2-oxoacetyl)phenyl)
adipamide (25)
A solution containing 1,10-(adipoyl)bis-isatin 21 (0.50 g,
1.24 mmol) and tert-butylamine (1.3 mL, 3 mmol) in dichloro-
methane (30 mL) was heated at reflux for 5 h. The cooled
solution was diluted with dichloromethane, washed with dilute
hydrochloric acid, and then washed with brine and dried over
magnesium sulfate. The solvent was evaporated under vacuum
to give the title compound (0.32 g, 47 %) as a light yellow solid,
mp 193–1958C. nmax (KBr)/cmꢁ1 3312, 1687, 1662, 1609, 1586,
1532, 1449, 1297, 1206, 1161, 759. lmax (THF)/nm (e/Mꢁ1
cmꢁ1) 238 (33 000), 267 (16 000), 344 (8600). dH (300 MHz,
CDCl3) 1.44 (s, 18H, 2 ꢂ C(CH3)4), 1.63–1.86 (m, 4H,
COCH2CH2CH2CH2CO), 2.37–2.48 (m, 4H, COCH2CH2CH2
CH2CO), 6.73 (s, 2H, 2 ꢂ COCONH), 7.10 (t, J 8.3, 2H, ArH),
7.56 (t, J 8.3, 2H, ArH), 8.24 (d, J 8.3, 2H, ArH), 8.63 (d, J 8.3,
2H, ArH), 10.97 (s, 2H, 2 ꢂ NHCO). dC (75 MHz, CDCl3) 28.8
(2 ꢂ C(CH3)4), 25.2 (2 ꢂ COCH2CH2), 38.5 (2 ꢂ COCH2), 52.5
(2 ꢂ C(CH3)4), 119.1, 142.3 (4 ꢂ ArC), 121.1, 122.8, 134.7,
136.6 (8 ꢂ ArCH), 162.8, 172.1, 193.1 (6 ꢂ C¼O). m/z 551.22.
TOF-ESI Anal. Calc. for C30H39N4O6 [M þ H]þ: 551.28. Anal.
Calc. for C30H38N4O6ꢀ0.25H2O: C 64.91, H 6.99, N 10.09.
Found: C 65.24, H 7.21, N 9.68 %.
(4R,5R)-N,N’-Bis(2-(2-(butylamino)-2-oxoacetyl)phenyl)-
2,2-dimethyl-1,3-dioxolane-4,5-dicarboxamide (30)
A solution of 29 (1.00 g, 2.23 mmol) and n-butylamine (0.36 g,
4.9 mmol) in dichloromethane (20 mL) was heated at reflux for
1.5 h. After cooling to room temperature, the solution was
washed twice with dilute HCl, twice with saturated NaHCO3,
dried over magnesium sulfate, and the solvent was evaporated
under vacuum. Purification by gravity coloumn chromatogra-
phy (5 % MeOH/CH2Cl2) gave the title compound (0.54 g,
40 %) as yellow crystals, mp 150–1548C. nmax (KBr)/cmꢁ1
3283, 1703, 1649, 1583, 1520, 1450, 1297, 1213, 756. lmax
(THF)/nm (e/Mꢁ1 cmꢁ1) 239 (40 900), 267 (17 900), 340
(9690). dH (300 MHz, CDCl3) 0.92 (t, 6H, J 6.8, 2 ꢂ CH2CH3),
1.53 (s, 6H, C(CH3)2), 1.38, 1.59, 3.37 (m, each 4H, 2 ꢂ CH2),
4.84 (s, 2H, CHCH), 7.34 (t, 2H, J 6.2, COCONH), 7.07 and 7.42
(t, each 2H, J 7.2, 8.2, ArH), 8.21 and 8.51 (d, each 2H, J 9.2, 8.2,
ArH), 11.80 (s, 2H, NHCO). dC (75 MHz, CDCl3) 13.74 (CH3),
26.51 (C(CH3)2), 20.12, 31.31, 39.39 ((CH2)3CH3), 78.49
(CHCH), 113.93 (C(CH3)2), 120.43, 123.21, 134.40, 136.10
(ArCH), 119.28, 140.59 (ArC), 163.54, 169.70 (CONH), 192.62
(CO). m/z 595.29. TOF-ESI Anal. Calc. for C31H38N4O8
[M þ H]þ: 595.27. Anal. Calc. for C31H38N4O8: C 62.61,
H 6.44, N 9.42. Found: C 62.66, H 6.42, N 9.24 %.
N,N’-Bis(2-(2-(butylamino)-2-oxoacetyl)phenyl)
adipamide (26)
A solution of 1,10-(adipoyl)bis-isatin 21 (0.50 g, 1.24 mmol) and
n-butylamine (0.3 mL, 3 mmol) in dichloromethane (150 mL)
was heated at reflux for 3 h. The cooled solution was washed
with dilute hydrochloric acid three times, and then twice with
saturated sodium bicarbonate and dried over magnesium sulfate.
The solvent was evaporated under vacuum. Recrystallisation
from dichloromethane/hexane gave the title compound as a light
apricot coloured solid (0.41 g, 60 %), mp 170–1738C, nmax
(KBr)/cmꢁ1 3360, 3291, 3257, 1693, 1674, 1655, 1607, 1531,
1482, 1290, 1270, 1226, 1175, 1152, 951, 761. lmax (THF)/nm
(e/Mꢁ1 cmꢁ1) 239 (37 900), 269 (15 400), 343 (8500). dH
(300 MHz, CDCl3) 0.95 (t, J 7.1, 6H, 2 ꢂ CH2CH3), 1.31–1.39
(m, 4H, 2 ꢂ CH2CH3), 1.52–1.58 (m, 4H, 2 ꢂ CH2CH2CH3),
1.63–1.86 (m, 4H, COCH2CH2CH2CH2CO), 2.37–2.48 (m, 4H,
COCH2CH2CH2CH2CO), 3.18–3.38 (m, 4H, 2 ꢂ NHCH2), 6.93
(s, 2H, 2 ꢂ COCONH), 7.12 (t, J 8.3, 2H, ArH), 7.58 (t, J 8.3,
2H, ArH), 8.35 (d, J 8.3, 2H, ArH) 8.64 (d, J 8.3, 2H, ArH), 11.01
(s, 2H, 2 ꢂ NHCO). dC (75 MHz, CDCl3) 17.0 (NHCH3), 20.4,
Structure Determination
Suitable single crystals of 9, 25, and 26 selected under a polar-
ising microscope (Leica M165Z) were picked up on a Micro-
Mount (MiTeGen, USA) consisting of a thin polymer tip with a
wicking aperture. The X-ray diffraction measurements were
carried out on a Bruker KAPPA APEX II CCD diffractometer
at 150 K by using graphite-monochromated MoKa radiation
˚
(l 0.710723 A). The single crystals, mounted on the goniometer
using cryo loops for intensity measurements, were coated with
paraffin oil and then quickly transferred to the cold stream using
an Oxford Cryo stream attachment. Symmetry related absorp-
tion corrections using the program SADABS[32] were applied and
the data were corrected for Lorentz and polarisation effects
using Bruker APEX2 software.[33] All structures were solved by
direct methods and the full-matrix least-squares refinements
were carried out using SHELXL.[34] The non-hydrogen atoms

1278
V. Suryanti et al.
were refined anisotropically. The molecular graphics were
generated using Mercury.[35]
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3219. doi:10.1021/CR000045I
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460. doi:10.1021/JA00157A077
The X-ray diffraction measurements for 9 and 24 were
carried out at MX1 and MX2 beamlines at the Australian
Synchrotron Facility, Melbourne. The procedure for diffraction
intensity measurements on both beamlines was similar. The
crystal was mounted on the goniometer using a cryo loop for
diffraction measurements, was coated with paraffin oil, and then
quickly transferred to the cold stream using a Cryo stream
attachment. Data were collected using Si ,111. monochro-
[20] J. F. Malone, C. M. Murray, M. Nieuwenhuyzen, G. Stewart, R.
Docherty, A. J. Lavery, Chem. Mater. 1997, 9, 334. doi:10.1021/
CM960380G
˚
mated synchrotron X-ray radiation (l 0.71023 A) at 100(2) K
and were corrected for Lorentz and polarisation effects using the
XDS software.[36] The structure was solved by direct methods
and the full-matrix least-squares refinements were carried out
using SHELXL.[34]
[21] W. C. Cheah, K. Wood, D. StC. Black, N. Kumar, Tetrahedron 2011,
67, 7603. doi:10.1016/J.TET.2011.07.036
[22] V. Suryanti, M. Bhadbhade, R. Bishop, D. StC. Black, N. Kumar,
CrystEngComm 2012, 14, 7345. doi:10.1039/C2CE25994J
[23] V. Suryanti, M. Bhadbhade, R. Bishop, D. StC. Black, N. Kumar,
Tetrahedron 2013, 69, 8446. doi:10.1016/J.TET.2013.07.052
[24] D. StC. Black, G. I. Moss, Aust. J. Chem. 1987, 40, 143. doi:10.1071/
CH9870143
[25] H. J. Choi, M. O. Kwak, H. Song, Synth. Commun. 1997, 27, 1273.
doi:10.1080/00397919708003365
[26] E. A. Mash, K. A. Nelso, S. V. Deusen, S. B. Hemperly, Org. Synth.
1989, 68, 92.
Supplementary Material
The geometric parameters of the intramolecular interactions,
intermolecular interaction distances and angles, and molecular
assemblies of 9, 24–26 as well as the 1H and 13C NMR spectra of
compounds 13–17 are available on the Journal’s website.
Acknowledgements
[27] Crystals of
9 were obtained from methanol. Crystal data:
The authors thank the Directorate General of Higher Education, Ministry of
National Education, Indonesia through the University of Sebelas Maret,
Indonesia for a Ph.D. scholarship to Venty Suryanti. They also thank Dr Tom
Caradoc-Davies, Principal Scientist, Australian Synchrotron, for his help in
data acquisition.
C
32H40.67N4O6, MW 577.35, Monoclinic, P21/c. Cell dimensions: a
˚
9.1920 (18), b 23.833 (5), c 21.695 (4) A and b 98.59 (38), Z 6, T 100 K.
Dcalcd 1.224 Mg mꢁ3. Data/restraints/parameters 8258:48:612. Final R
indices, R[F2 . 2s(F2)] ¼ 0.090, wR(F2) ¼ 0.252. CCDC 958544.
[28] Crystals of 24 were obtained from methanol. Crystal data:
C
24H26N4O6, MW 466.49, Monoclinic, P21. Cell dimensions: a
References
˚
9.1500 (18), b 14.679 (3), c 9.3670 (19) A and b 114.43 (3)8, Z 2,
T 100 K. Dcalcd 1.353 Mg mꢁ3. Data/restraints/parameters 3311:1:310.
Final R indices, R[F2 . 2s(F2)] ¼ 0.042, wR(F2) ¼ 0.113. CCDC
957127.
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C30H38N4O6, MW 550.64, Monoclinic, P21/c. Cell dimensions: a
˚
8.9927 (18), b 9.941 (2), c 16.474 (3) A and b 102.128 (11)8, Z 4,
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¯
30H38N4O6, MW 550.64, Triclinic, P1. Cell dimensions: a 8.9717
C
˚
(4), b 9.1948 (4), c 9.6574 (4) A and a 64.779 (2)8, b 81.225 (2)8,
g 89.513 (2)8, Z ¼ 1, T ¼ 150 K. Dcalcd 1.286 Mg mꢁ3. Data/restraints/
parameters 2462:0:182. Final R indices, R[F2 . 2s(F2)] ¼ 0.035,
wR(F2) ¼ 0.096. Crystallographic data excluding structure factors
have been deposited with the Cambridge Crystallographic Data
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