DOI:
10.1039/A904289J
(Paper)
New J. Chem., 2000,
24, 39-45
Synthesis of aromatic and heteroaromatic oligoamides on methoxypoly(ethylene glycol) as solubilizing polymer support
Received 17th May 1999, Accepted 15th November 1999
First published on UnassignedUnassigned4th January 2000
Abstract
A protecting-group-free procedure for the synthesis of short carbo- and heteroaromatic oligoamide chains on MeO-PEG as solubilizing support is introduced. Starting from nitrocarboxylic acids, oligoamides of carboxylic acids derived from N-methylpyrrole, N-methylimidazole and aniline are synthesized that contain up to five arene units. The polymer support facilitates work up procedures and markedly improves the otherwise poor solubility of the products. Each coupling step is monitored by 1H-NMR spectroscopy without cleavage of the product from the polymeric support.
Heteroaromatic oligoamides containing N-methylpyrrole (Py)
and N-methylimidazole (Im) amino acids are an essential part
of the structure of DNA-binding natural products, such as
netropsin1 or distamycin.2 Inspired by these compounds and
their properties, Dervan, Wemmer and others have developed
synthetic heteroaromatic oligoamides that bind sequence specifically to DNA.3 The recently reported fascinating results of
highly specific binding at nanomolar concentrations4 and in
vivo gene regulation5 by such compounds makes their future
application in gene therapy or biotechnology very likely.
Baird and Dervan have provided a procedure for the synthesis
of heteroaromatic oligoamides by automated solid phase synthesis, by which even extended oligoamides are available in
almost every desirable combination using Boc-protected heteroaromatic amino acids as building blocks.6We report here the synthesis of short heteroaromatic oligoamides
on a soluble polymer support.7 A protecting-group-free
procedure using methoxypoly(ethylene glycol) (MeO-PEG-OH),
1, with an average molecular weight of 5000 g
mol−1 as an inexpensive support8 provides practical access to
oligoamides for the synthesis of DNA binding agents or other
purposes. Readily available nitrocarboxylic acids are used as
the starting material. They are reduced to the corresponding
amine after being successfully coupled to the support. It is not
intended to provide a competing procedure to the reported
automated solid phase synthesis6 of extended oligoamides:
the well known restrictions of the MeO-PEG support in the
synthesis of large peptides9 and the difficulty of automatization
limit the synthesis to short oligoamides. However,
synthesis on a MeO-PEG-OH solid support does offer some
advantages: the handling and characterization of insoluble
oligoamides is facilitated, commercially or readily available
nitro compounds are employed as starting materials and every
reaction step can be monitored by NMR without cleavage of
the oligoamide from the polymer. This promotes the optimization
of the coupling conditions for each step, which is
usually required because of the significant differences in reactivity of aromatic and heteroaromatic amino acids in amide
bond formation. We provide here general procedures for oligoamide
synthesis on a liquid–solid support and illustrate the
feasibility of the synthetic route by some examples.
Results and discussion
In
the first step 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chloride, 2,10 is quantitatively bound to MeO-PEG-OH (1) via an
ester linkage using standard conditions (Scheme 1). For purification the polymer-bound product 3 is precipitated by addition
of Et2O and collected by filtration (see general procedure
2 in the Experimental section). The excess of acid chloride is
removed by washing with ether. In the next step the nitro
group is reduced with HCOONH4–Pd/C in methanol solution for 1 h at room temperature (see general procedure 1 in
the Experimental section). The catalyst is removed by filtration
over Celite and Et2O is added to precipitate both the
amine and excess HCOONH4. The solid is dissolved in
dichloromethane leaving behind excess HCOONH4 and the
obtained solution is used directly in the next reaction step.
Reaction with 2 leads to the polymer-bound amide 4 with
quantitative loading of the polymer, which is determined by
NMR spectroscopy (vide infra). Repetition of the reduction-coupling
cycle gives diamide 7, but the loading of the polymer
decreases to 55%. A polymer loading of 83% is obtained with
compound 5,10 which illustrates that the ester linkage of the
heteroarene chain to MeO-PEG is not fully stable under the
coupling conditions.11 Introduction of the next pyrrole yields
pure triamide 9, but the loading of the support decreases to
39%. Finally, the oligoamides are cleaved from the polymer
support by treatment with base, which provides 812 and 10 as
carboxylic acids in good yield (see general procedure 4 in the
Experimental section). |
| Scheme 1 | |
Fig. 1 shows part of the 1H-NMR spectra of 3 (top), 4
(middle) and 7 (bottom), making the growth of the oligoamide
chain visible. Resonance signals of N-methyl groups successively
appear, indicating the incorporation of a new pyrrole
ring. Comparison of the integral of each signal with the
methoxy resonance of MeO-PEG (δ=3.37), which is used as
an internal standard, allows the determination of reaction
yields and polymer loading.
 |
| Fig. 1 Part of the 1H-NMR (400 MHz, CDCl3) spectrum of polymer-bound N-methylpyrrole oligoamides. From top to bottom: compounds 3, 4 and 7. | |
A particular advantage of oligoamide synthesis on a liquid–solid
support is the possibility to control the success of coupling
without cleavage from the polymer. This is illustrated by
the synthesis of N-methylimidazole N-methylpyrrole diamide,
15, in Scheme 2. Though the nitrocarboxylic acid 11 can be
coupled to the preceding amine, the reaction of compound 12,
after reduction, with 6 is not successful. The low reactivity of
the imidazole amine group in amide formation under standard
conditions has been observed previously.6 To obtain 14
the use of 136 in the amide coupling is required, which was
confirmed by the analysis of the polymer-bound reaction products
by NMR.
 |
| Scheme 2 | |
Starting from the corresponding nitrocarboxylic acids new
aromatic or heteroaromatic amino acids, which have not been
used for the synthesis of oligoamides so far, can be introduced.
This is illustrated (Scheme 3) by the reaction of m-nitrobenzoic
acid, 16-OH, which leads to the synthesis of an analog, 19, of
the distamycin amide core in which the central N-methylpyrrole
unit is replaced by a 1,3-disubstituted benzene
ring. Again, the success of amide formation for each step is
monitored by NMR. Compounds in which one amide linkage
is replaced by a urea moiety, such as 23, are obtained from the
reaction (Scheme 4) with nitroisocyanates (20).
 |
| Scheme 3 | |
 |
| Scheme 4 | |
Extended aromatic oligoamides are known for their low
solubility in organic solvents.13 The unique properties of the
MeO-PEG support facilitates the handling and character
ization of such compounds markedly, as shown by the synthesis
of 30, 31 and 35 (see Schemes 5 and 6). With nitrobenzoic
acids as building blocks for oligoamide synthesis we observed
a constant quantitative loading of the polymer support and
complete conversion for all coupling and reduction steps up to
the tetraamide 34. The growth of the aromatic oligoamide
chain is monitored by the 1H-NMR resonances of the amide
signals of compounds 26, 28, 32 and 34 (Fig. 2, from top to
bottom).
 |
| Scheme 5 | |
 |
| Scheme 6 | |
 |
| Fig. 2 Amide proton resonance region of the 1H-NMR spectrum (400 MHz. CDCl3) of polymer-bound aromatic oligoamides. From top to bottom: compounds 26, 28, 32 and 34. * denotes a noise signal. | |
Conclusion
In summary we have presented a simple and affordable procedure
for the synthesis of short heteroaromatic and aromatic
oligoamides. The described synthesis on MeO-PEG as solid
support combines the convenience of solid phase procedures,
such as simplified work up and removal of excess coupling
reagents, with the advantages of solution reactions, such as
short reaction times and the use of heterogeneous catalysts.
Starting from readily available nitrocarboxylic acids, carbo-
and heteroaromatic oligoamides with up to five arene units
were obtained, whereby neither protecting groups, nor expensive
chemicals or special apparatus are necessary. The synthesis
of libraries of oligoamides from nitrocarboxylic acids may
be envisaged. We hope that the reported procedure will make
heteroaromatic and aromatic oligoamides more widely available
and stimulate their application in biotechnology or
separation techniques, such as new stationary chromatography
phases.14Experimental
General
NMR
spectra were recorded at 400 (1H) and 100 (13C) MHz
in [D]-chloroform solutions unless otherwise stated. The
multiplicity of the 13C signals was determined with the DEPT
technique and are denoted as (+) for CH3 or CH, and (Cquat)
for quaternary carbons. Direct inlet EI mass spectra were
recorded at 70 eV on a double focusing sector field instrument
(Finnigan MAT, MS8430). The source temperature was set to
200°C. High resolution experiments were performed at a
resolution of 10000 (10% valley) by peak matching. In some
cases where molecular ion intensities were too low for exact
mass determination characteristic fragment ions (e.g., M+−CO2) were used instead. The percentage of polymer
loading with oligoamide product was determined from comparison
of the integrals of the 1H-NMR resonance of the terminal MeO-PEG methoxy group and a significant signal of
the oligoamide residue. Py and Im indicate pyrrole and imidazole
amino acids, respectively. HOBt·H2O stands for
hydroxybenzotriazole and DIEA for N,N-diisopropylethylamine. mPh and pPh denote 1,3- and 1,4-benzoic amino acid,
respectively.General procedure 1 (GP 1) for the reduction step
The
MeO-PEG-bound nitro compound was dissolved in
methanol (not more than 100 ml). For large-scale reactions a
minimum amount of dichloromethane had to be added until
all of the solid was dissolved. Excess HCOONH4 and 10%
palladium on carbon were added, and the reaction mixture
was stirred for 1 h at room temperature. The start of the reaction
was indicated by the evolution of gas. In cases where this
could not be observed the reaction mixture was heated with a
heat gun for a short period. After 1 h at room temperature the
catalyst was removed by filtration over Celite and Et2O was
added (250–1000 ml depending on the scale of the reaction) to
precipitate the generated MeO-PEG-bound amine and excess
HCOONH4
. The solid was collected by suction and dissolved
in dichloromethane leaving behind excess HCOONH4, which
was filtered off. The obtained solution is directly used in GP 2
or GP 3.General procedure 2 (GP 2) for coupling with acid chlorides
To
the solution obtained from GP 1 or to a solution of MeO-PEG-OH
in dichloromethane, an excess of pyridine and 3–5
equiv. of the appropriate acid chloride were added and the
reaction mixture was stirred for 12 h. The product was precipitated
by addition of Et2O and collected by filtration. The
polymer was redissolved and precipitated twice for purification,
then dried in vacuo.General procedure 3 (GP 3) for the coupling step with activated acids
The
appropriate acid (3–5 equiv.) was activated with DCC
and HOBt·H2O (1.0 equiv. of each, corresponding to the
amount of acid) in DMF (25 ml) for 4 h. To this reaction
mixture the solution obtained from GP 1 was added, followed
by an excess of DIEA. After 12 h stirring at room temperature
the reaction mixture was filtered and the product was precipitated
by addition of Et2O, and collected by filtration. The
polymer was redissolved, precipitated twice and dried in
vacuo.General procedure 4 (GP 4) for the cleavage of oligoamide from the
polymer
The
MeO-PEG-bound oligoamide was dissolved in 10 ml of
aqueous 2 N NaOH and stirred at room temperature for 12 h.
The solution was acidified with HCl, the precipitated oligoamide
was collected by filtration and dried in vacuo.Syntheses and product characterization
MeO-PEG–Py–NO2
(3).. MeO-PEG-OH (1, 50.0 g, 10.0
mmol) was allowed to react with 2 (5.67 g, 30.0 mmol) following
GP 2 (pyridine: 10 ml) to yield 3 with quantitative loading
of the polymer. 1H-NMR: δ=3.99 (s, 3H), 7.43 (d, 4J=2.0
Hz, 1H), 7.68 (d, 4J=2.0 Hz, 1H).
MeO-PEG–Py–Py–NO2
(4).. Compound 3 (5.0 g, 1.0 mmol)
was reduced using GP 1 (HCOONH4: 1.0 g, 15.9 mmol;
Pd/C: 100 mg) and subsequently allowed to react with 2 (567
mg, 3.0 mmol) following GP 2 (pyridine: 1 ml) to yield 4 with
quantitative loading of the polymer. 1H-NMR: δ=3.90 (s,
3H), 4.03 (s, 3H), 7.05 (d, 4J=2.0 Hz, 1H), 7.45 (d, 4J=2.0
Hz, 1H), 7.60 (d, 4J=2.0 Hz, 1H), 7.68 (d, 4J=2.0 Hz, 1H),
8.98 (s, 1H).
MeO-PEG–Py–Py–Py–NO2
(7).. Compound 3 (1.0 g, 0.2
mmol) was reduced using GP 1 (HCOONH4: 0.5 g, 7.9 mmol;
Pd/C: 120 mg) and subsequently allowed to react with 5 (175
mg, 0.6 mmol) following GP 3 (DCC: 124 mg, 0.6 mmol;
HOBt·H2O: 92 mg, 0.6 mmol; DIEA: 1 ml) to yield 7
with
83% loading of the polymer. 1H-NMR: δ=3.90 (s, 3H), 3.95
(s, 3H), 4.05 (s, 3H), 6.86 (d, 4J=2.0 Hz, 1H), 6.91 (s, 1H), 7.32
(s, 1H), 7.46 (d, 4J=1.5 Hz, 1H), 7.50 (d, 4J=1.5 Hz, 1H),
7.60 (d, 4J=1.5 Hz, 1H), 8.51 (s, 1H), 9.18 (s, 1H).
HO2C–Py–Py–Py–NO2
(8)12.. Compound 7 (400 mg, 0.074
mmol) was treated according to GP 4 and yielded 21 mg (0.05
mmol) of 8 (70%) as a yellow solid. IR(KBr):
=3408, 2953,
1665, 1438 cm−1. UV(CH3CN): λmax (log ε)=240 (4.36), 296
(4.43) nm. 1H-NMR (400 MHz, DMSO-d6): δ=3.82 (s, 3H),
3.86 (s, 3H), 3.96 (s, 3H), 6.85 (d, 4J=1.9 Hz, 1H), 7.05 (d,
4J=1.8 Hz, 1H), 7.26 (d, 4J=1.6 Hz, 1H), 7.42 (d, 4J=1.8
Hz, 1H), 7.59 (d, 4J=1.9 Hz, 1H), 8.18 (d, 4J=1.8 Hz, 1H),
9.94 (s, 1H), 10.28 (s, 1H), 12.16 (s, 1H). 13C-NMR (100 MHz,
DMSO-d6): δ=36.1 (+), 36.2 (+), 37.5 (+), 104.6 (+), 107.6
(+), 108.4 (+), 118.7 (+), 119.6 (Cquat), 120.3 (+), 121.5 (Cquat),
122.6 (Cquat), 122.9 (Cquat), 126.3 (Cquat), 128.3 (+), 133.8 (Cquat),
156.9 (Cquat), 158.3 (Cquat), 162.0 (Cquat). MS (EI) m/z (%)=370
(74) [M−CO2]+, 275 (100). MeO-PEG–Py–Py–Py–Py–NO2
(9).. Compound 7 (620 mg,
0.12 mmol) was reduced using GP 1 (HCOONH4: 0.45 g, 7.1
mmol; Pd/C: 50 mg) and subsequently allowed to react with 6
(63 mg, 0.37 mmol) following GP 3 (DCC: 77 mg, 0.37 mmol;
HOBt·H2O: 57 mg, 0.37 mmol; DIEA: 1 ml) to yield 9 with
39% loading of the polymer. 1H-NMR: δ=3.89 (s, 3H), 3.95
(s, 3H), 3.97 (s, 3H), 4.05 (s, 3H), 6.87 (m, 2H), 6.94 (m, 1H),
7.40 (m, 1H), 7.45 (m, 2H), 7.56 (m, 1H), 7.60 (m, 1H), 8.75 (s,
1H), 9.33 (br s, 2H).
HO2C–Py–Py–Py–Py–NO2
(10).. Compound 9 (754 mg,
0.137 mmol) was treated according to GP 4 and yielded 20 mg
(0.037 mmol) of 10 (82%) as a yellow solid. Mp: 245°C
(decomp.). IR (KBr):
=3427, 1701, 1648 cm−1.
UV(CH3CN): λmax (log ε)=192 (4.49) 240 (4.43), 300 (4.50), nm. 1H-NMR (400 MHz, DMSO-d6): δ=3.82 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), 3.97 (s, 3H), 6.86 (d, 4J=1.8 Hz, 1H), 7.06 (m, 2H), 7.25 (d, 4J=1.5 Hz, 1H), 7.28 (d, 4J=1.5 Hz, 1H), 7.43 (d, 4J=1.8 Hz, 1H), 7.62 (d, 4J=1.9 Hz, 1H), 8.19 (d, 4J=1.7 Hz, 1H), 9.91 (s, 1H), 10.00 (s, 1H), 10.33 (s, 1H). 13C-NMR (100 MHz, DMSO-d6): δ=36.1 (+), 36.1 (+), 36.2 (+), 37.5 (+), 104.6 (+), 104.8 (+), 107.7 (+), 108.4 (+), 118.6
(+), 118.7 (+), 119.5 (Cquat), 120.3 (+), 121.5 (Cquat), 122.2
(Cquat), 122.6 (Cquat), 122.7 (Cquat), 123.0 (Cquat), 126.3 (Cquat), 128.2 (+), 133.8 (Cquat), 156.9 (Cquat), 158.4 (Cquat), 158.5 (Cquat), 162.0 (Cquat). MS (EI) m/z (%)=492 (100) [M−CO2]+, 397 (18), 275 (49), 153 (36). HRMS: C23H24N8O5, [M−CO2]+=492.1865±2 ppm.
MeO-PEG–Py–Im–NO2
(12).. Compound 3 (1.0 g, 0.2
mmol) was reduced using GP 1 (HCOONH4: 0.5 g, 7.9 mmol;
Pd/C: 100 mg) and was afterwards allowed to react with 11
(136 mg, 0.8 mmol) following GP 3 (DCC: 247 mg, 1.2 mmol;
HOBt·H2O: 162 mg, 1.2 mmol; DIEA: 1 ml) to yield 12
with
87% loading of the polymer. 1H-NMR: δ=3.92 (s, 3H), 4.21
(s, 3H), 6.98 (d, 4J=2.0 Hz, 1H), 7.41 (d, 4J=2.0 Hz, 1H),
7.93 (s, 1H), 9.29 (s, 1H).
MeO-PEG–Py–Im–Py–NO2
(14).. Compound 3 (0.5 g, 0.2
mmol) was reduced using GP 1 (HCOONH4: 0.9 g, 14.3
mmol; Pd/C: 50 mg) followed by reaction with 13 (88 mg, 0.3
mmol) according to GP 3 (DCC: 62 mg, 0.3 mmol;
HOBt·H2O: 46 mg, 0.3 mmol; DIEA: 1 ml) to yield 14 with
61% loading of the polymer. 1H-NMR: δ=3.92 (s, 3H), 4.05
(s, 3H), 4.10 (s, 3H), 6.89 (m, 1H), 7.44 (m, 1H), 7.48 (m, 1H),
7.49 (m, 1H), 7.64 (m, 1H), 9.05 (s, 1H), 9.16 (s, 1H).
HO2C–Py–Im–Py–NO2
(15).. Compound 7 (293 mg, 0.054
mmol) was treated according to GP 4 and yielded 10 mg
(0.024 mmol) of 15 (73%) as a yellow solid. Mp: 220°C.
IR(KBr):
=3428, 1672, 1572 cm−1. UV(CH3CN): λmax (log
ε)=192 (2.36), 236 (2.21), 292 (2.20) nm. 1H-NMR (400 MHz,
DMSO-d6): δ=3.83 (s, 3H), 3.96 (s, 3H), 3.97 (s, 3H), 6.93 (d,
4J=2.0 Hz, 1H), 7.40 (d, 4J=1.9 Hz, 1H), 7.57 (s, 1H), 7.76
(d, 4J=2.0 Hz, 1H), 8.20 (d, 4J=2.0 Hz, 1H), 10.08 (s, 1H),
10.80 (s, 1H). 13C-NMR (100 MHz, DMSO-d6): δ=36.4 (+),
37.0 (+), 37.6 (+), 107.8 (+), 108.5 (+), 120.0 (Cquat), 120.6
(+), 122.0 (Cquat), 126.3 (Cquat), 126.8 (+), 128.4 (+), 134.0
(Cquat), 135.6 (Cquat), 145.3 (Cquat), 157.1 (Cquat), 159.4 (Cquat),
162.0 (Cquat). MS (EI) m/z
(%)=414 (9) [M−1]+, 399 (100). MeO-PEG–Py–mPh–NO2
(17).. Compound 3 (1.24 g, 0.25
mmol) was reduced using GP 1 (HCOONH4: 0.33 g, 5.2
mmol; Pd/C: 120 mg) followed by reaction with m-nitrobenzoic
acid (16-OH, 567 mg, 3.0 mmol) according to GP
3 (DCC: 155 mg, 0.75 mmol; HOBt·H2O: 115 mg, 0.75
mmol; DIEA: 1 ml) to yield 17 with 86% loading of the
polymer. 1H-NMR: δ=3.93 (s, 3H), 7.02 (d, 4J=2.0 Hz, 1H),
7.59 (d, 4J=2.0 Hz, 1H), 7.67 (t, 3J=8.0 Hz, 1H), 8.35 (m,
1H), 8.42 (m, 1H), 8.90 (m, 1H), 9.48 (s, 1H).
MeO-PEG–Py–mPh–Py–NO2
(18).. Compound 17
(760 mg,
0.15 mmol) was reduced using GP 1 (HCOONH4: 0.45 g, 7.1
mmol; Pd/C: 50 mg) and then allowed to react with 6 (76 mg,
0.45 mmol) following GP 3 (DCC: 93 mg, 0.45 mmol;
HOBt·H2O: 69 mg, 0.45 mmol; DIEA: 1 ml) to yield 18 with
56% loading of the polymer. 1H-NMR: δ=3.92 (s, 3H), 4.07
(s, 3H), 6.90 (d, 4J=2.0 Hz, 1H), 7.44 (t, 3J=7.9 Hz, 1H),
7.57 (d, 4J=1.9 Hz, 1H), 7.65 (m, 2H), 7.70 (m, 1H), 8.09 (m,
1H), 8.15 (m, 1H), 9.01 (s, 1H), 9.14 (s, 1H).
HO2C–Py–mPh–Py–NO2
(19).. Compound 18
(510 mg,
0.094 mmol) was treated according to GP 4 and gave 20 mg
(0.05 mmol) of 19 (92%) as a yellow solid. Mp: 225°C
(decomp). IR(KBr):
=3402, 1677, 1315 cm−1.
UV(CH3CN): λmax (log ε)=276 (4.47), 240 (4.42), 214 (4.44), 192 (4.42) nm. 1H-NMR (400 MHz, DMSO-d6): δ=3.85 (s, 3H), 3.98 (s, 3H), 6.91 (d, 4J=1.4 Hz, 1H), 7.49 (m, 2H), 7.66 (d, 3J=7.6 Hz, 1H), 7.77 (d, 4J=1.6 Hz, 1H), 7.93 (d, 3J=8.0
Hz, 1H), 8.24 (m, 2H), 10.31 (s, 1H), 10.32 (s, 1H), 12.23 (br s, 1H). 13C-NMR (100 MHz, DMSO-d6): δ=36.2 (+), 37.6 (+), 108.6 (+), 108.8 (+), 119.6 (+), 119.8 (Cquat), 120.6 (+), 122.3 (+), 122.6 (Cquat), 122.9 (+), 126.0 (Cquat), 128.7 (+), 128.8 (+), 133.9 (Cquat), 135.2 (Cquat), 138.9 (Cquat), 158.6 (Cquat), 161.9 (Cquat), 163.6 (Cquat). MS (EI) m/z (%)=411
(8) [M]+, 367 (100), 272 (84), 153 (36), 107 (20), 95 (22). HRMS: C19H17N5O6, [M]+=411.1175±2 ppm.
MeO-PEG–Py–mNHCONHPh–NO2
(21).. Compound 3
(1.17 g, 0.23 mmol) was reduced using GP 1 (HCOONH4: 0.5
g, 7.9 mmol; Pd/C: 60 mg) and then allowed to react with
3-nitrophenyl isocyanate (20, 192 mg, 1.17 mmol) to yield 21
with 82% loading of the polymer. For purification the product
was precipitated three times with Et2O. 1H-NMR: δ=3.89 (s,
3H), 6.73 (d, 4J=2.0 Hz, 1H), 7.26 (d, 4J=1.8 Hz, 1H), 7.39
(t, 3J=8.1 Hz, 1H), 7.78 (m, 1H), 7.85 (m, 1H), 8.04 (br s, 1H),
8.41 (m, 1H), 8.54 (s, 1H).
MeO-PEG–Py–mNHCONHPh–Py–NO2
(22).. Compound
21 (0.65 g, 0.13 mmol) was reduced using GP 1 (HCOONH4
:
0.5 g, 7.9 mmol; Pd/C: 50 mg) and was afterwards allowed to
react with 6 (66 mg, 0.39 mmol) following GP 3 (DCC: 80 mg,
0.39 mmol; HOBt·H2O: 60 mg, 0.39 mmol; DIEA: 1 ml) to
yield 22 with 62% loading of the polymer. 1H-NMR: δ=3.87
(s, 3H), 4.02 (s, 3H), 6.70 (m, 1H), 7.2–7.3 (m, 3H), 7.42 (m, 1H),
7.53 (d, 4J=1.8 Hz, 1H), 7.61 (m, 1H), 7.68 (m, 1H), 7.74 (m,
1H), 7.92 (s, 1H), 8.72 (s, 1H).
HO2C–Py–mNHCONHPh–Py–NO2
(23).. Compound 22
(285 mg, 0.053 mmol) was treated according to GP 4 and
yielded 12 mg (0.028 mmol) of 23 (86%) as a yellow solid. Mp:
230°C. IR(KBr):
=3408, 1676, 1547, 1314 cm−1.
UV(CH3CN): λmax (log ε)=256 (4.58), 216 (4.38), 192 (4.31)
nm. 1H-NMR (400 MHz, DMSO-d6): δ=3.81 (s, 3H), 3.91 (s,
3H), 6.65 (d, 4J=2.1 Hz, 1H), 7.15–7.25 (m, 3H), 7.29 (m, 1H),
7.73 (d, 4J=2.0 Hz, 1H), 7.93 (m, 1H), 8.22 (d, 4J=1.7 Hz,
1H), 8.30 (s, 1H), 8.66 (s, 1H), 10.09 (s, 1H). 13C-NMR (100
MHz, DMSO-d6): δ=36.1 (+), 37.6 (+), 107.7 (+), 108.5
(+), 109.9 (+), 113.4 (+), 113.5 (+), 119.1 (+), 119.8 (Cquat),
122.7 (Cquat), 126.3 (Cquat), 126.8 (+), 128.8 (+), 133.8 (Cquat),
139.0 (Cquat ), 140.4 (Cquat), 152.3 (Cquat), 158.4 (Cquat), 162.0
(Cquat). MS (FAB−): m/z (%)=425 (4) [M−1]−, 306 (100). MeO-PEG–pPh–NO2
(25). 1. (50.0 g, 10.0 mmol) was
allowed to react with 4-nitrobenzoyl chloride (24, 9.25 g, 50.0
mmol) following GP 2 (pyridine: 5 ml) to yield 25 with quantitative
loading of the polymer. 1H-NMR: δ=8.27 (m, 4H).
MeO-PEG–pPh–pPh–NO2
(26).. Compound 25
(11.5 g, 2.3
mmol) was reduced using GP 1 (HCOONH4: 1.5 g, 23.8
mmol; Pd/C: 100 mg) followed by reaction with 24
(2.13 g,
11.5 mmol) according to GP 2 (pyridine: 1.6 ml) to yield 26
with quantitative loading of the polymer. 1H-NMR: δ=7.93
(d, 3J=8.8 Hz, 2H), 8.05 (d, 3J=8.6 Hz, 2H), 8.31 (m, 4H),
9.69 (s, 1H).
MeO-PEG–pPh–mPh–NO2
(27).. Compound 25
(11.5 g, 2.3
mmol) was reduced using GP 1 (HCOONH4: 1.5 g, 23.8
mmol; Pd/C: 100 mg) and was afterwards allowed to react
with 3-nitrobenzoyl chloride (16-Cl, 2.13 g, 11.5 mmol) following
GP 2 (pyridine: 1.6 ml) to yield 27 with quantitative
loading of the polymer. 1H-NMR: δ=7.70 (t, 3J=8.0 Hz,
1H), 7.97 (d, 3J=8.8 Hz, 2H), 8.05 (d, 3J=8.8 Hz, 2H), 8.38
(m, 1H), 8.50 (m, 1H), 8.99 (m, 1H), 9.74 (s, 1H).
MeO-PEG–pPh–pPh–pPh–NO2
(28).. Compound 26 (8.25
g, 1.65 mmol) was reduced using GP 1 (HCOONH4: 1.5 g,
23.8 mmol; Pd/C: 100 mg) and was afterwards allowed to
react with 24 (1.53 g, 8.25 mmol) following GP 2 (pyridine: 1.2
ml) to yield 28 with quantitative loading of the polymer. 1H-NMR: δ=8.00 (m, 8H), 8.28 (d, 3J=8.8 Hz, 2H), 8.38 (d,
3J=8.8 Hz, 2H), 9.53 (s, 1H), 10.18 (s, 1H).
MeO-PEG–pPh–mPh–pPh–NO2
(29).. Compound 27 (8.25
g, 1.65 mmol) was reduced using GP 1 (HCOONH4: 1.5 g, 23.8 mmol; Pd/C: 100 mg) and was afterwards allowed to react with 24 (1.53 g, 8.25 mmol) following GP 2 (pyridine: 1.2 ml) to yield 29 with quantitative loading of the polymer. 1H-NMR: δ=7.46 (t, 3J=7.9 Hz, 1H), 7.79 (d, 3J=7.8 Hz, 1H), 7.92 (d, 3J=8.7 Hz, 2H), 8.01 (d, 3J=10.2 Hz, 2H), 8.3–8.4 (m, 6H), 9.44 (s, 1H), 10.04 (s, 1H).
HO2C–pPh–pPh–pPh–NO2
(30).. Compound 28 (4.55 g,
0.84 mmol) was treated according to GP 4 to yield 295 mg
(0.73 mmol) of 30
(86%) as a white solid. Mp: >300°C. IR(KBr): νn=3336, 1524, 1320 cm−1. UV(CH3CN): λmax (log ε)=196 (4.70), 298 (4.52) nm. 1H-NMR (400 MHz, DMSO-d6): δ=8.08 (s, 4H), 8.09 (m, 2H), 8.16 (m, 2H), 8.31 (m, 2H), 8.46 (m, 2H), 10.61 (s, 1H), 10.97 (s, 1H). 13C-NMR (100 MHz, DMSO-d6): δ=119.6 (+), 119.8 (+), 123.7 (+), 126.0 (Cquat), 128.9 (+), 129.4 (+),
130.0 (Cquat), 130.3 (+), 140.4 (Cquat), 142.1 (Cquat), 143.5 (Cquat), 149.4 (Cquat), 164.4 (Cquat), 165.4 (Cquat), 167.3 (Cquat). MS (EI): m/z (%)=405 (8) [M]+, 269 (100), 150 (19), 121 (18), 104 (16), 92 (10), 76 (9). HRMS: C21H15N3O6, [M]+=405.0955±2 ppm. Elem. anal. C21H15N3O6: calcd. C 62.22, H 3.73, N 10.37; found C 62.24, H 3.70, N 10.19%.
HO2C–pPh–mPh–pPh–NO2
(31).. Compound 29 (6.9 g, 1.28
mmol) was treated according to GP 4 to yield 454 mg (1.12
mmol) of 31
(88%) as a white solid. Mp: >300°C. IR(KBr):
=3315, 1645, 1526, 1323 cm−1. UV(CH3CN): λmax (log ε)=194 (4.65), 216 (4.46), 278 (4.47) nm. 1H-NMR (400 MHz, DMSO-d6): δ=7.57 (t, 3J=8.0 Hz, 1H), 7.76 (d, 3J=7.3 Hz, 1H), 7.94 (m, 4H), 8.06 (m, 1H), 8.24 (m, 2H), 8.35 (s, 1H), 8.40 (m, 2H), 10.61 (s, 1H), 10.81 (s, 1H). 13C-NMR (100 MHz, DMSO-d6): δ=119.5 (+), 120.2 (+), 123.3 (+), 123.6 (+), 125.7 (Cquat), 128.9 (+), 129.3 (+), 130.3 (+), 135.4 (Cquat), 139.0 (Cquat), 140.3 (Cquat), 143.3 (Cquat), 149.3 (Cquat), 164.1 (Cquat), 165.9 (Cquat), 167.0 (Cquat). MS (EI): m/z (%)=405 (6) [M]+, 269 (100), 150 (17), 121 (20), 104 (12), 92 (8), 76 (10). HRMS: C21H15N3O6
, [M]+=405.0955±2 ppm. Elem. anal. C21H15N3O6
: calcd. C 62.22, H 3.73, N 10.37; found C 62.01, H 3.71, N 10.07%.
MeO-PEG–pPh–pPh–pPh–mPh–NO2
(32).. Compound 28
(2.65 g, 0.49 mmol) was reduced using GP 1 (HCOONH4: 1.0
g, 15.9 mmol; Pd/C: 100 mg) and was afterwards allowed to react with 16-Cl (454 mg, 2.45 mmol) following GP 2 (pyridine: 1.0 ml) to yield 32 with quantitative loading of the polymer. 1H-NMR: δ=7.68 (t, 3J=8.0 Hz, 1H), 7.96 (d, 3J=8.7
Hz, 2H), 8.1 (m, 10H), 8.31 (m, 1H), 8.74 (d, 3J=7.8 Hz, 1H), 9.04 (m, 1H), 10.05 (s, 1H), 10.19 (s, 1H), 10.81 (s, 1H).
HO2C–pPh–pPh–pPh–mPh–NO2
(33).. Compound 32 (920
mg, 0.167 mmol) was treated according to GP 4 to yield 60
mg (0.115 mmol) of 33 (69%) as a white solid. Mp: >300°C. IR(KBr):
=3325, 1650, 1519, 1321 cm−1. UV(CH3CN): λmax (log ε)=192 (4.39), 216 (4.33), 306 (4.37) nm. 1H-NMR (400 MHz, DMSO-d6): δ=7.88 (t, 3J=8.0 Hz, 1H), 7.9–8.1 (m, 12H), 8.46 (m,
2H), 8.84 (m, 1H), 10.45 (s, 1H), 10.48 (s, 1H), 10.87 (s, 1H).
13C-NMR (100 MHz, DMSO-d6): δ=119.3 (+), 119.7 (+), 122.5 (+), 125.3 (Cquat), 126.3 (+), 128.58 (+), 128.63 (+), 129.0 (Cquat), 129.6 (Cquat), 130.1 (+), 130.2 (+), 134.2 (+), 135.9 (Cquat ), 141.9 (Cquat), 142.5 (Cquat), 143.3 (Cquat), 147.7 (Cquat), 163.6 (Cquat), 165.1 (Cquat), 165.2 (Cquat), 166.9 (Cquat). MS (EI): m/z
(%)=524 (2) [M]+, 507 (2), 480 (4), 388 (72), 286 (36), 269 (60), 150 (100), 120 (51), 104 (41), 76 (38). HRMS: C27H20N4O5
, [M−CO2]+=480.1429±5
ppm. Elem. anal. C28H20N4O7(H2O): calcd. C 61.99, H 4.09, N 10.33; found C 62.23, H 3.98, N 9.80%.
MeO-PEG–pPh–pPh–pPh–mPh–pPh–NO2
(34).. Compound
32 (1.9 g, 0.35 mmol) was reduced using GP 1
(HCOONH4: 1.0 g, 15.9 mmol; Pd/C: 100 mg) and then allowed
to react with 24 (320 mg, 1.73 mmol) following GP 2 (pyridine: 1.0 ml) to yield 34 with quantitative loading of the
polymer. 1H-NMR: δ=7.80 (d, 3J=7.5 Hz, 1H), 7.92 (d, 3J=8.1 Hz, 1H), 7.97 (d, 3J=8.6 Hz, 2H), 8.1 (m, 11H), 8.25 (m, 3H), 8.43 (d, 3J=8.6 Hz, 2H), 9.89 (s, 1H), 9.91 (s, 1H), 10.12 (s, 1H), 10.55 (s, 1H).
HO2C–pPh–pPh–pPh–mPh–pPh–NO2
(35).. Compound 34
(1160 mg, 0.207 mmol) was treated according to GP 4 to yield
100 mg (0.156 mmol) of 35 (75%) as a brownish solid. Mp: >300°C. IR(KBr):
3307, 1648, 1518, 1321 cm−1. UV(CH3CN): λmax (log ε)=194 (4.60), 252 (4.38) nm. 1H-NMR (400 MHz, DMSO-d6): δ=7.59 (t, 3J=7.9 Hz, 1H), 7.79 (d, 3J=7.9 Hz, 1H), 7.9–8.1 (m, 13H), 8.24 (m, 2H), 8.40 (m, 3H), 10.45 (s, 1H), 10.46 (s, 1H), 10.61 (s, 1H), 10.81 (s, 1H), 12.74 (br
s, 1H). 13C-NMR (100 MHz, DMSO-d6): δ=119.3 (+), 119.4 (+), 120.1 (+), 123.2 (+), 123.5 (+), 123.6 (+), 125.2 (Cquat), 128.6 (+), 128.8 (+), 129.0 (Cquat), 129.2 (+), 130.1 (+), 135.3 (Cquat
), 138.9 (Cquat), 140.2 (Cquat), 142.4 (Cquat), 142.5 (Cquat), 143.4 (Cquat), 149.2 (Cquat), 164.0 (Cquat), 165.1 (Cquat), 165.2 (Cquat), 165.7 (Cquat), 166.9 (Cquat). MS (EI): m/z
(%)=599 (0.1) [M−CO2]+, 507 (2), 286 (18), 269 (16), 167 (21), 150 (35), 120 (100). Elem. anal. C35H25N5O8(H2O): calcd. C 63.54, H 4.11, N 10.59; found C 63.46, H 4.04, N 10.08%. Acknowledgements
This
work was supported by the Fonds der Chemischen
Industrie. M.R. thanks the Land Niedersachsen, Germany, for
a graduate fellowship.References
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