Highly efficient one-step microwave-assisted synthesis of structurally diverse bis-substituted α-amino acid derived diimides

Article abstract of DOI:10.1039/c8ra05835k

We report herein a facile and widely applicable microwave-assisted protocol for the synthesis of symmetrical diimides based on three structurally distinct aromatic dianhydrides: pyromellitic (PMA), biphenyl-tetracarboxylic acid (BPDA) and benzophenone-tet

Full text of DOI:10.1039/c8ra05835k

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Highly efficient one-step microwave-assisted
synthesis of structurally diverse bis-substituted a-
Cite this: RSC Adv., 2018, 8, 29840
amino acid derived diimides†
ab
Marcin Konopka,‡ab Grzegorz Markiewicz‡ab and Artur R. Stefankiewicz
*
We report herein a facile and widely applicable microwave-assisted protocol for the synthesis of
symmetrical diimides based on three structurally distinct aromatic dianhydrides: pyromellitic (PMA),
biphenyl-tetracarboxylic acid (BPDA) and benzophenone-tetracarboxylic (BTDA) and five natural amino
acids (Phe, Tyr, Ile, Lys, Cys). Fifteen symmetrical diimides with different structural characteristics
containing a variety of functional groups can be produced with high yields and on a large scale.
Received 9th July 2018
Accepted 16th August 2018
DOI: 10.1039/c8ra05835k
rsc.li/rsc-advances
in low yields.17–19 In addition, purication of these molecules is
usually very difficult because of their generally low solubility
Introduction
and tendency to form undened polymeric materials. For these
reasons, the development of an accessible methodology based
on microwave-assisted synthesis of non-NDI/PBI diimides in
short reaction times, with easy work up and in high yields is
greatly desirable from the viewpoints of both synthesis and the
application potential of these molecules.
Here, we describe a one-step process for microwave assisted
synthesis of symmetrical a-amino acid derived diimides based
on three structurally distinct aromatic cores namely, pyro-
mellitic dianhydride (PMA),20 biphenyl-tetracarboxylic acid
dianhydride (BPDA)21 and benzophenone-tetracarboxylic acid
dianhydride (BTDA)22 (Scheme 1). We chose these anhydrides
due to their potential to deliver diimides with properties
different to those of NDIs and PBIs. The PMA little core was
found as an interesting platform for designing n-channel
transistor semiconductors based on pyromellitic diimides.23
BPDA introduces a free rotation axis in the center of diimide
Symmetrical diimides have found a wide spectrum of uses in
the last decade.1 The vast majority of these materials have
structures based on naphthalene diimide (NDI) or perylene
bisimide (PBI) cores.1,2 Both systems have constituted essential
components of numerous non-covalent polymers3,4 and self-
assembled supramolecular architectures,5,6 and have been
used in DNA complexation7–9 and biomolecular recognition.10,11
Currently, there is an increased interest in this class of
compounds, especially those bearing unique functional
substituents and containing alternative central diimide cores,
due to their signicant application potential in materials
chemistry and receptors in supramolecular chemistry.12–14
Despite the widely reported synthetic methodologies for the
preparation of NDI and PBI derivatives, the literature protocols
concerning compounds that are alternatives to them are scant.
It has been previously shown that a-amino acid derived NDIs
can be obtained in high yields by microwave assisted
synthesis.15,16 Although the protocols developed have consider-
ably improved the preparation of these molecules in terms of
time and ease of workup, the studies were devoted to a single
group of diimides only i.e. NDIs, leaving the others to be syn-
thesised by classical synthesis which was found to be dependent
in an ill understood manner on the particular choice of dia-
nhydride and amine. Thus, the synthesis of this important
group of molecules is still associated with time-consuming and
complicated protocols oen leading to contaminated products
a
´
Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan,
Poland. E-mail: ars@amu.edu.pl
bCenter for Advanced Technologies, Adam Mickiewicz University, Umultowska 89c, 61-
´
614 Poznan, Poland
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra.
Scheme 1 General synthetic method for the microwave assisted
preparation of symmetrical diimides from three distinct dianhydrides
and a-amino acids.
See DOI: 10.1039/c8ra05835k
‡ These authors contributed equally to this work.
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molecule and this offers a means to engender of new class of be used for the systems described here but the use of these
symmetrical diimides with greater conformational lability. reagents is associated with certain difficulties. Although DMF is
BTDA has a ketone group in the center of molecule which offers perfectly suited for conducting nucleophilic reactions under
prospects for further modication or provision of an attach- microwave conditions, due to its high dipole moment and low
ment point for coupling of two or more diimide molecules into vapor pressure, as well as its stability under microwave condi-
larger systems.24 Use of well-known reversible reactions like tions, very oen its residues are problematic during reaction
imine formation, reductive amination or formation of hemi- work-up and purication of the products. Et3N, due to its very
thioacetals was seen as a pathway to further variations. All three high volatility, generates high pressures (0.5–1.0 MPa) in the
aromatic platforms were functionalized with ve different closed reaction systems, which limits its application only to
amino acids: L-phenylalanine, L-tyrosine, L-isoleucine, N3-Boc-L- expensive high-pressure reactors with xed volume and
lysine and S-Tr-L-cysteine. These were selected as structurally synthesis scales. To facilitate reaction work-up and be able to
diverse species providing a stringent test of the sensitivity of our carry out reaction on the larger scales at atmospheric pressure,
methods to the presence of several functional groups. We have we therefore investigated modication of this procedure. The
prepared een diimides, nine of them new, in very high yields reaction between PMA and L-phenylalanine was chosen as
independent of the reaction scale, and without evidence of a model for the optimization of the synthetic methodology.
racemization at the chiral centers.
These reagents give the diimide, PMI-Phe, in the form of very
ne powder requiring only a simple water wash during workup.
Two different solvents, N,N-dimethylformamide (DMF) and
acetonitrile (MeCN), and three bases: triethylamine (Et3N), 4-
(dimethylamino)pyridine) (DMAP), and 1,4-diazabicyclo[2.2.2]
octane (DABCO) were selected for the test reactions.
Results and discussion
General synthetic methodology
The enantiomerically pure diimides were synthesized as shown
in Scheme 1. The reactions were conducted in pressure-
resistant glass vessels with a total volume of ꢀ10 mL,
designed for CEM microwave ovens and closed with silicone/
PTFE caps.
The outcomes of the reactions performed under the different
conditions are shown in Table 1. The highest yield (z87%) was
observed when DMF and DMAP were employed as solvent and
base, respectively. Despite the fact that MeCN slightly reduces
the reaction yields (down to z79% and z63% for the DABCO
and DMAP, respectively), it is an interesting alternative for
DMF, especially when fully aliphatic amino acids are used (see
ahead). Complete removal of DMF from the products was
possible through a combination of several water rinses, ultra-
sonic irradiation and pumping in vacuum, but in some cases, it
was a very time-consuming process. The previously proposed
pre-evaporation of the DMF15,16 from the reaction mixtures
seems to be helpful but it does not solve the trace contamina-
tion problem. What we have now found is that the use of
acetonitrile instead of DMF greatly facilitates the work-up, and
signicantly improves the separation and drying processes.
The poorest results were obtained when DMF/DABCO and
MeCN/Et3N pairs were employed. While the rst pair is ineffi-
cient and gives contaminated products, the second generates
high overpressure, which is problematic even for a dedicated
microwave reactor. On the basis of these initial observations, we
decided to synthesize the entire series of symmetrically func-
tionalised diimides using the DMF/DMAP pair, since this gave
the highest yield for the model reaction. As shown in Table 2, all
The optimal scale for these reactions was to use 0.5 mmol of
an anhydride, 1.0 mmol of amino acid, and ꢀ2 mmol of base,
which is equal to less than 1 g of total material load. We found
that higher loadings led to signicant contamination with
thermal decomposition products. The reaction mixtures were
irradiated for 10 min at 140 ꢁC using full microwave power (300
W) for the temperature ramping (ꢀ30 s) followed by short pulses
(20–40 W) to maintain the scheduled conditions. Aer cooling to
room temperature, the reaction mixtures were poured into
hydrochloric acid (1.0 mol ꢂ dmꢃ3), the solid product was
ltered off, washed with deionized water and dried in high
vacuum for 12 h. This procedure turned out to be sufficient to
obtain the desired products with high spectroscopic and analyt-
ical purity (See Experimental section for details).
Method optimisation
We found that the procedure originally presented by Panto¸s
et al.15,16 for naphthalene diimides (NDI), which utilizes DMF as
a solvent and triethylamine (Et3N) as a base catalyst, could also
Table 1 Comparison between the reaction yields under different solvent/base conditions for representative reaction between PMA and L-Phe
Entrya
Base
Solvent
Reaction timeb (min)
Temp. (ꢁC)
Yieldc (%)
1
2
3
4
5
6
Et3N
Et3N
DABCO
DABCO
DMAP
DMAP
DMF
MeCN
DMF
MeCN
DMF
MeCN
10
10
10
10
10
10
140
140
140
140
140
140
71–75
72–74
51–56
77–81
85–88
61–65
a
b
Reactions were carried out on 0.5 mmol of dianhydride, 1.0 mmol of amino acid, 2.0 mmol of base and 5 mL of the solvent. Excluding
temperature ramping. c Each reaction was repeated 3-times, giving isolation yields in the ranges shown.
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Table 2 List of synthesized symmetrical diimides with structures and abbreviations
Amino
Entry Dianhydride acid
Reaction
Reaction
Producta
Abbreviation timeb (min) temp. (ꢁC) Yieldc (%)
1
2
PMA
PMA
L-Phe
L-Tyr
PMI-Phe
PMI-Tyr
10
10
140
140
87
87
3
4
PMA
PMA
L-Ile
PMI-Ile
10
10
140
140
72
75
S-Tr-L-Cys
PMI-Cys
5
PMA
N3-Boc-L-Lys
PMI-Lys
10
140
70
6
7
8
9
BPDA
BPDA
BPDA
BPDA
L-Phe
BPDI-Phe
BPDI-Tyr
BPDI-Ile
BPDI-Cys
10
10
10
10
140
140
140
140
84
72
72
90
L-Tyr
L-Ile
S-Tr-L-Cys
10
BPDA
N3-Boc-L-Lys
BPDI-Lys
10
140
75
11
12
BTDA
BTDA
L-Phe
L-Tyr
BTDI-Phe
BTDI-Tyr
10
10
140
140
75
76
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Table 2 (Contd.)
Amino
Entry Dianhydride acid
Reaction
Reaction
Producta
Abbreviation timeb (min) temp. (ꢁC) Yieldc (%)
13
14
BTDA
BTDA
L-Ile
BTDI-Ile
10
10
140
140
79
90
S-Tr-L-Cys
BTDI-Cys
15
BTDA
N3-Boc-L-Lys
BTDI-Lys
10
140
70
a
Reactions were carried out on 0.5 mmol of dianhydride, 1.0 mmol of amino acid and 2.0 mmol of DMAP in 5 mL of DMF. b Excluding temperature
ramping. c Yield of isolated product.
een different diimides were obtained in high yields and conducted at high temperature.25 In the present case, due to the
purities, indicating the broad utility of the procedure and thus presence of two chiral centers, it is possible to generate three
that it should be useful for the synthesis of any desired diimide. products with LL, DD and DL congurations. However, the high
We have not found any marked dependence on the structure of symmetry of signals in the 1H NMR spectra, namely single set of
the substrates used and consider that the minor variations in resonances for a-CH and b-CH2 protons implies that the applied
yield are probably due to differences in solvation. In Fig. 1 we methodology leads to the formation of enantiomerically pure
present the stacked 1H-NMR spectra of molecules PMI-Phe products. The only noticeable but obvious difference between
(blue), BPDI-Phe (green), BTDI-Phe (red) with L-phenylalanine the three spectra is the distribution of aromatic signals from
and three structurally different dianhydrides. Signals due to the central aromatic cores.
a-CH and b-CH2 protons of the amino acid residue appear at
To further conrm this, we performed the test reaction
essentially identical positions (z5.2 and 3.4 ppm, respectively). between PMA dianhydride and racemic tyrosine. Indeed as ex-
Importantly, it was previously found that racemization of pected, the use of the substrate in its racemic form has led to
amino acid may occur when the fusion with anhydride is a mixture of diastereomeric products whose presence was
manifested by the multiplication of all resonances in the 1H
NMR spectrum, in contrast to the fully symmetrical spectrum
observed when chirally pure amino acids were used (Fig. 2).
Large scale synthesis
The synthesis of symmetrical diimides is usually the rst step in
the synthesis of functionalized monomers used in self-
assembled systems such as dynamers,26 so relatively large
quantities of these precursors are oen required. Therefore, we
investigated whether the method above might be applied in
reaction at a larger scale while maintaining the high yields and
purities obtained in test reactions.
The high scale reactions were performed using 10.0 mmol of
appropriate amino acid, and 5.0 mmol of dianhydride. The non-
pressurized DMF/DMAP system was found to be well suited for
the open vessel conditions. Reactions were conducted in
a standard 100 mL round-bottom ask with an air-cooled
condenser to provide reux. Using the standard reaction
times (10 min) the expected products were obtained in essen-
tially identical yields compared to that observed in low scale
under pressurized conditions. We were able to obtain up to 5 g
Fig. 1 1H NMR (300 MHz, DMSO-d6) spectra of PMI-Phe (blue), BPDI
(green), BTDI-Phe (red). Peaks description: a-CH (2H), b-CH2 (4H) and
Ph-H (10H) stands from L-phenylalanine moieties.
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from Deutero GmbH (Germany). NMR spectra were acquired on
Bruker Fourier 300 spectrometer equipped with 1H/13C 5 mm
probe, at 298 K and were referenced on solvent residual peaks.
Mass spectra were recorded on Bruker Impact HD Q-TOF
spectrometer in negative ion mode. Elemental analyses were
obtained using an Elemental Analyser Vario EL III. Samples
were dried for 12 h under high vacuum prior to analysis. The
microwave assisted reactions were performed on CEM Discover
SP oven.
General method for the synthesis of symmetrical diimides
A representative example is that of the PMA and L-phenylalanine
reaction. L-Phenylalanine (165.2 mg, 1.0 mmol), PMA (109.0 mg,
0.5 mmol) and DMAP (244.0 mg, 2.0 mmol) were placed in
a glass vessel and suspended in 5 mL of dry DMF. The mixture
was sonicated until complete dissolution had occurred. The
vessel was sealed with a silicon cap and placed in a microwave
Fig. 2 1H NMR (300 MHz, DMSO-d6) spectra of the products isolated
after reaction of PMA dianhydride with chirally pure L-tyrosine (top)
and racemic tyrosine (bottom).
of pure diimide in one large-scale batch and use it for further
modication. The MeCN/DABCO system was also found to be
useful in open-vessꢁel reactions but due to the low boiling point
of acetonitrile (82 C), it was necessary to extend the reaction
time up to 20 minutes in order to obtain yields comparable to
that obtained under high pressure. The results of six large scale
syntheses are shown in Table 3.
ꢁ
oven. The mixture was heated at 140 C for 10 min. Aer cool-
ing, the mixture was poured into 50 mL of hydrochloric acid
(1 mol ꢂ dmꢃ3). The precipitate was ltered off and washed
with 200 mL of water to remove residual DMF. The solid residue
was dried under high vacuum. Yield: 223 mg (87%) of PMI-Phe.
By conducting reactions at lower temperature (82 ꢁC, 10 min)
in the MeCN/DABCO mixture we were able to observe reaction
intermediates, among which the most interesting are mono-
substitution products that are essential in the synthesis of
unsymmetrical bis-substituted compounds. Unfortunately,
despite the utilisation of both thermodynamic and stoichio-
metric control, we were not able to isolate them using meth-
odology presented in this work, as their high solubility in all
range of solvents prevents their effective precipitation from
reaction mixtures. Although it was possible to separate the
monosubstituted products by reverse phase HPLC methods, we
believe that easier and more efficient synthetic and isolation
protocols may be developed which will open the way for the
desymmetrisation of the presented diimides in the future.
General method for the large-scale synthesis of symmetrical
diimides
A representative example again is that of the PMA/L-phenylala-
nine reaction. PMA (1.09 g, 5.0 mmol), L-phenylalanine (1.65 g,
10.0 mmol) and DMAP (2.44 g, 20.0 mmol) were placed in
100 mL round-bottom ask and dissolved in 50 mL of dry DMF.
The solution was heated in the microwave oven at 180 W for
10 min under open vessel conditions with an air condenser. The
resulting solution was concentrated to a 10 mL volume on
a rotary evaporator before being mixed with 200 mL of hydro-
chloric acid (1 mol ꢂ dmꢃ3). The white precipitate was ltered
off, washed with 500 mL of water and dried under high vacuum.
Yield 2.12 g (83%) of PMI-Phe.
PMI-Phe. 1H NMR (300 MHz, DMSO-d6) d 13.47 (s, 2H), 8.22
(s, 2H), 7.23–7.07 (m, 10H), 5.16 (dd, J ¼ 11.3, 4.8 Hz, 2H), 3.50
(dd, J ¼ 14.1, 4.8 Hz, 2H), 3.39–3.24 (m, 2H). 13C NMR (75 MHz,
DMSO-d6) d 169.61, 165.18, 137.11, 136.24, 128.75, 128.40,
Experimental
General considerations
All chemicals and solvents were purchased from commercial 126.66, 118.51, 53.60, 33.92. ESI-MS: m/z calculated for: [M ꢃ
sources and used as received. NMR solvents were purchased H]ꢃ 511.1147, found: 511.1153. Elemental analysis calcd (%) for
Table 3 Large scale synthesis results
Entry
Producta
Solvent
Base
Reaction timeb (min)
Reaction temp. (ꢁC)
Yielde (%)
1
2
3
4
5
6
PMI-Phe
PMI-Ile
BPDI-Phe
BPDI-Ile
BTDI-Phe
BTDI-Ile
DMF
MeCN
DMF
DMF
DMF
MeCN
DMAP
DABCO
DMAP
DMAP
DMAP
DABCO
10
20
10
10
10
20
145c
82d
88
70
82
71
73
75
145c
145c
145c
82d
a
Reactions were carried out on 5.0 mmol of dianhydride, 10.0 mmol of amino acid and 20.0 mmol of base in 50 mL of given solvent. b At constant
microwave power ¼ 180 W. ꢄ5 ꢁC maintained at constant power. d Boiling point of the solvent. e Yield of isolated product.
c
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C28H20N2O8: C 65.62, H 3.93, N 5.47; found: C 65.75, H 3.82, N 134.09, 132.05, 130.78, 124.19, 122.63, 56.56, 33.94, 16.85,
5.52.
10.87. ESI-MS: m/z calculated for: [M ꢃ H]ꢃ 519.1773, found:
1
PMI-Tyr. H NMR (300 MHz, DMSO-d6) d 13.40 (s, 2H), 9.15 519.1764. Elemental analysis calcd (%) for C28H28N2O8: C 64.61,
(s, 2H), 8.22 (s, 2H), 6.92 (d, J ¼ 8.0 Hz, 4H), 6.53 (d, J ¼ 7.9 Hz, H 5.42, N 5.38; found: C 64.67, H 5.73, N 5.31.
4H), 5.05 (dd, J ¼ 11.6, 4.8 Hz, 2H), 3.43–3.29 (m, 2H), 3.25–3.13
BPDI-Lys. 1H NMR (300 MHz, DMSO-d6) d 13.19 (s, 2H), 8.33
(m, 2H). 13C NMR (75 MHz, DMSO-d6) d 169.69, 165.21, 155.89, (d, J ¼ 7.3 Hz, 4H), 8.04 (d, J ¼ 8.0 Hz, 2H), 6.74 (d, J ¼ 6.2 Hz,
136.26, 129.70, 127.05, 118.48, 115.23, 53.97, 33.07. ESI-MS: m/z 2H), 4.76 (t, J ¼ 7.8 Hz, 2H), 2.86 (q, J ¼ 6.2 Hz, 4H), 2.20–2.02
calculated for: [M ꢃ H]ꢃ 543.1045, found: 543.1048. Elemental (m, 4H), 1.30 (s, 26H). 13C NMR (75 MHz, DMSO) d 170.53,
analysis calcd (%) for C28H20N2O10: C 61.77, H 3.70, N 5.15; 167.04, 155.56, 144.70, 133.98, 132.21, 130.93, 124.15, 122.52,
found: C 61.72, H 3.73, N 5.11.
77.27, 51.91, 29.02, 28.97, 28.20, 27.80, 23.16. ESI-MS: m/z
PMI-Ile. 1H NMR (300 MHz, DMSO-d6) d 13.16 (s, 2H), 8.33 (s, calculated for: [M ꢃ H]ꢃ 749.3039, found: 749.3042. Elemental
2H), 4.60 (d, J ¼ 7.8 Hz, 2H), 2.45–2.31 (m, 2H), 1.50 (ddd, J ¼ analysis calcd (%) for C38H46N4O12: C 60.79, H 6.18, N 7.46;
13.4, 7.6, 3.6 Hz, 2H), 1.06 (d, J ¼ 6.7 Hz, 6H), 1.03–0.92 (m, 2H), found: C 60.73, H 6.23, N 7.51.
0.81 (t, J ¼ 7.3 Hz, 6H). 13C NMR (75 MHz, DMSO-d6) d 169.46,
BPDI-Cys. 1H NMR (600 MHz, DMSO-d6) d 8.33 (dd, J ¼ 24.6,
165.80, 136.54, 118.44, 57.02, 34.05, 25.28, 16.66, 10.93. ESI-MS: 16.7 Hz, 4H), 8.04 (d, J ¼ 7.7 Hz, 2H), 7.28–7.20 (m, 30H), 4.56
m/z calculated for: [M ꢃ H]ꢃ 443.1460, found: 443.1461. (dd, J ¼ 11.4, 4.5 Hz, 2H), 3.09 (t, J ¼ 12.9 Hz, 2H), 2.91 (dd, J ¼
Elemental analysis calcd (%) for C22H24N2O8: C 59.46, H 5.44, N 13.1, 4.3 Hz, 2H). 13C NMR (151 MHz, DMSO) d 168.86, 166.50,
6.30; found: C 59.34, H 5.48, N 6.34.
143.97, 143.76, 129.02, 128.32, 128.10, 127.76, 127.50, 126.88,
1
PMI-Lys. H NMR (300 MHz, DMSO-d6) d 13.27 (s, 2H), 8.32 126.22, 66.50, 55.77, 39.52, 30.59. ESI-MS: m/z calculated for: [M
(s, 2H), 6.71 (t, J ¼ 5.7 Hz, 2H), 4.80 (dd, J ¼ 7.7 Hz, 2H), 2.84 (q, J ꢃ H]ꢃ 983.2466, found: 983.2485. Elemental analysis calcd (%)
¼ 6.4 Hz, 4H), 2.14–2.05 (m, 4H), 1.40–1.21 (m, 26H). 13C NMR for C60H44N2O8S2: C 73.15, H 4.50, N 2.84; found: C 73.24, H
(75 MHz, DMSO-d6) d 170.15, 165.66, 155.55, 136.67, 118.31, 4.63, N 2.89.
77.27, 52.34, 28.99, 28.18, 27.71, 23.06. ESI-MS: m/z calculated
BTDI-Phe. 1H NMR (300 MHz, DMSO-d6) d 13.49 (s, 2H),
for: [M ꢃ H]ꢃ 673.2726, found: 673.2737. Elemental analysis 8.24–8.10 (m, 3H), 8.06–7.97 (m, 3H), 7.18 (d, J ¼ 4.2 Hz, 10H),
calcd (%) for C32H42N4O12: C 56.97, H 6.27, N 8.30; found: C 5.18 (dd, J ¼ 11.6, 4.8 Hz, 2H), 3.51 (dd, J ¼ 14.1, 5.0 Hz, 2H),
57.13, H 6.25, N 8.40.
3.35 (dd, J ¼ 14.0, 11.5 Hz, 3H). 13C NMR (75 MHz, DMSO-d6)
PMI-Cys. 1H NMR (600 MHz, DMSO-d6) d 13.66 (s, 2H), 8.38– d 193.05, 169.86, 166.28, 141.85, 137.22, 136.35, 133.59, 130.86,
8.27 (m, 2H), 7.30–7.26 (m, 32H), 4.59 (ddp, J ¼ 14.2, 9.2, 4.8 Hz, 128.73, 128.38, 126.64, 124.05, 123.85, 53.28, 33.94. ESI-MS: m/z
2H), 3.11–3.03 (m, 2H), 3.01–2.94 (m, 2H). 13C NMR (151 MHz, calculated for: [M ꢃ H]ꢃ 615.1409, found: 615.1413. Elemental
DMSO) d 168.52, 165.02, 143.75, 136.42, 129.03, 128.31, 128.12, analysis calcd (%) for C35H24N2O9: C 68.18, H 3.92, N 4.54;
126.22, 66.66, 55.82, 39.52, 30.37. ESI-MS: m/z calculated for: [M found: C 68.33, H 3.83, N 4.61.
ꢃ H]ꢃ 907.2153, found: 907.2158. Elemental analysis calcd (%)
BTDI-Tyr. 1H NMR (300 MHz, DMSO-d6) d 13.43 (s, 2H), 9.17
for C54H40N2O8S2: C 71.35, H 4.44, N 3.08; found: C 71.44, H (s, 2H), 8.19–8.00 (m, 6H), 6.94 (d, J ¼ 8.2 Hz, 4H), 6.56 (d, J ¼
4.73, N 3.11.
8.5 Hz, 4H), 5.08 (dd, J ¼ 11.5, 4.9 Hz, 2H), 3.38 (dd, J ¼ 14.2,
BPDI-Phe. 1H NMR (300 MHz, DMSO-d6) d 13.38 (s, 2H), 4.9 Hz, 2H), 3.24 (dd, J ¼ 14.2, 11.6 Hz, 2H). 13C NMR (75 MHz,
8.31–8.18 (m, 4H), 7.94 (d, J ¼ 8.2 Hz, 2H), 7.22–7.08 (m, 10H), DMSO-d6) d 193.09, 169.98, 166.34, 155.89, 141.86, 136.39,
5.15 (dd, J ¼ 11.6, 4.8 Hz, 2H), 3.50 (dd, J ¼ 14.1, 4.9 Hz, 2H), 133.67, 130.94, 129.69, 127.16, 124.07, 123.85, 115.23, 53.61,
3.42–3.35 (m, 2H). 13C NMR (75 MHz, DMSO-d6) d 170.04, 33.10. ESI-MS: m/z calculated for: [M ꢃ H]ꢃ 647.1307, found:
166.68, 144.64, 137.30, 134.14, 131.70, 130.46, 128.74, 128.37, 647.1309. Elemental analysis calcd (%) for C35H24N2O11: C
126.61, 124.05, 122.61, 53.11, 33.96. ESI-MS: m/z calculated for: 64.82, H 3.73, N 4.32; found: C 64.87, H 3.93, N 4.26.
[M ꢃ H]ꢃ 587.1460, found: 587.1465. Elemental analysis calcd
BTDI-Ile. 1H NMR (300 MHz, DMSO-d6) d 13.12 (s, 2H), 8.26–
(%) for C34H24N2O8: C 69.38, H 4.11, N 4.76; found: C 69.42, H 8.09 (m, 6H), 4.57 (d, J ¼ 8.0 Hz, 2H), 2.47–2.30 (m, 2H), 1.62–
4.27, N 4.82.
1.38 (m, 2H), 1.07 (d, J ¼ 6.7 Hz, 6H), 1.02–0.86 (m, 2H), 0.81 (t, J
BPDI-Tyr. 1H NMR (300 MHz, DMSO-d6) d 13.32 (s, 2H), 9.15 ¼ 7.3 Hz, 6H). 13C NMR (75 MHz, DMSO-d6) d 193.30, 169.68,
(s, 2H), 8.29–8.16 (m, 4H), 7.97–7.93 (m, 2H), 6.94 (d, J ¼ 8.1 Hz, 166.75, 141.86, 136.24, 134.03, 131.26, 124.13, 123.93, 56.74,
4H), 6.55 (d, J ¼ 8.1 Hz, 4H), 5.05 (dd, J ¼ 11.6, 4.9 Hz, 2H), 3.37 33.99, 25.33, 16.75, 10.91. ESI-MS: m/z calculated for: [M ꢃ H]ꢃ
(dd, J ¼ 14.2, 4.9 Hz, 2H), 3.25 (dd, J ¼ 14.2, 11.7 Hz, 2H). 13C 547.1722, found: 547.1725. Elemental analysis calcd (%) for
NMR (75 MHz, DMSO) d 170.16, 166.77, 155.89, 144.68, 134.14,
C29H28N2O9: C 63.50, H 5.15, N 5.11; found: C 63.57, H 5.25, N
131.77, 130.53, 129.71, 127.27, 124.06, 122.62, 115.23, 53.44, 5.24.
33.14. ESI-MS: m/z calculated for: [M ꢃ H]ꢃ 619.1358, found:
BTDI-Lys. 1H NMR (300 MHz, DMSO-d6) d 13.22 (s, 2H), 8.27–
619.1359. Elemental analysis calcd (%) for C34H24N2O10: C 7.97 (m, 6H), 6.73 (t, J ¼ 5.9 Hz, 2H), 4.77 (t, J ¼ 7.7 Hz, 2H), 2.86
65.81, H, 3.90, N 4.51; found: C 65.77, H 4.03, N 4.62.
(dd, J ¼ 12.5, 6.3 Hz, 4H), 2.09 (t, J ¼ 7.9 Hz, 4H), 1.48–1.11 (m,
BPDI-Ile. H NMR (300 MHz, DMSO-d6) d 13.07 (s, 2H), 8.33 26H). 13C NMR (75 MHz, DMSO-d6) d 193.31, 170.38, 166.66,
(d, J ¼ 8.3 Hz, 4H), 8.05 (d, J ¼ 7.8 Hz, 2H), 4.55 (d, J ¼ 8.1 Hz, 155.57, 141.81, 136.17, 134.20, 131.41, 124.02, 123.92, 77.31,
2H), 2.39 (t, J ¼ 8.3 Hz, 2H), 1.49 (ddd, J ¼ 13.5, 7.5, 3.5 Hz, 2H), 52.10, 29.02, 28.22, 27.80, 27.73, 23.14. ESI-MS: m/z calculated
1.07 (d, J ¼ 6.7 Hz, 6H), 1.04–0.94 (m, 2H), 0.81 (t, J ¼ 7.3 Hz, for: [M ꢃ H]ꢃ 777.2989, found: 777.3006. Elemental analysis
6H). 13C NMR (75 MHz, DMSO-d6) d 169.87, 167.13, 144.77,
1
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calcd (%) for C39H46N4O13: C 60.15, H 5.95, N 7.19; found: C
60.32, H 6.13, N 7.27.
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J. K. Sanders, Angew. Chem., Int. Ed., 2011, 50, 5725–5728.
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BTDI-Cys. 1H NMR (600 MHz, DMSO-d6) d 13.57 (s, 2H), 8.27–
8.20 (m, 3H), 8.17–8.09 (m, 3H), 7.29 (dd, J ¼ 9.2, 5.9 Hz, 30H),
4.62 (dd, J ¼ 11.0, 5.0 Hz, 2H), 3.15–3.08 (m, 2H), 2.98 (dd, J ¼
14.1, 5.0 Hz, 2H). 13C NMR (151 MHz, DMSO) d 193.14, 168.78,
166.10, 143.96, 143.77, 129.07, 129.05, 128.33, 128.13, 127.81,
127.51, 126.92, 126.23, 66.66, 55.85, 30.46. ESI-MS: m/z calcu-
lated for: [M ꢃ H]ꢃ 1011.2415, found: 1011.2435. Elemental
analysis calcd (%) for C61H44N2O9S2: C 72.32, H 4.38, N 2.77;
found: C 72.51, H 4.51, N 2.71.
¨
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Conclusions
In conclusion, the use of microwave heating and an appropriate
choice of solvent/base pair provide an efficient means of
preparing a diverse family of symmetrical diimides based on
three structurally distinct aromatic cores and ve different
amino acids. The developed methodology shows that the
syntheses are equally efficient under pressure (small scale) or in
open vessels (large scale). The reactions proceed without race-
mization at a-centre and led to enantiomerically clean products.
Short reaction times and facile workup make the developed
protocol extremely useful, the present work having provided
a library of functionalised diimides with a variety of possible
applications.
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Conflicts of interest
There are no conicts to declare.
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Acknowledgements
We thank the Polish National Centre for Research and Devel-
opment (LIDER 024/391/L-5/13/NCBR/2014) and Polish
National Science Centre (UMO-2017/25/N/ST5/00451) for
funding.
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29846 | RSC Adv., 2018, 8, 29840–29846
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