New hydrosoluble perylene and coronene derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.10.040

Several lipophilic perylene and coronene derivatives, employed mainly as liquid crystalline dyes are known and their synthesis has been widely studied. We have applied an analogue strategy using hydrophilic substituents to obtain highly water soluble perylene diimides (4) and a new hydrosoluble coronene derivative (CORON, 6), whose molecular features appear particularly suitable for inducing G-quadruplex DNA structures and inhibiting human telomerase.

Full text of DOI:10.1016/j.tetlet.2004.10.040

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9015–9020
New hydrosoluble perylene and coronene derivatives
*
Marco Franceschin, Antonello Alvino, Giancarlo Ortaggi and Armandodoriano Bianco
Dipartimento di Chimica, Universit a` di Roma ‘‘La Sapienza’’, Piazzale A. Moro 5, 00185 Roma, Italy
Received 26 July 2004;revised 6 October 2004;accepted 8 October 2004
Available online 22 October 2004
Abstract—Several lipophilic perylene and coronene derivatives, employed mainly as liquid crystalline dyes are known and their syn-
thesis has been widely studied. We have applied an analogue strategy using hydrophilic substituents to obtain highly water soluble
perylene diimides (4) and a new hydrosoluble coronene derivative (CORON, 6), whose molecular features appear particularly suit-
able for inducing G-quadruplex DNA structures and inhibiting human telomerase.
Ó 2004 Elsevier Ltd. All rights reserved.
Perylene-3,4:9,10-tetracarboxydiimides with hydrophilic
side chains have been widely studied as G-quadruplex
molecules are able to induce and stabilize G-quadruplex
1
structures in G-rich single-stranded oligonucleotides.
,2
1–3
interactive compounds and telomerase inhibitors. G-
quadruplexes are unusual DNA secondary structures
based on planes of four guanines (G-tetrads) stabilized
This is of great pharmaceutical interest, since the termi-
nal ends of eukaryotic chromosomes (telomeres) are
characterized by the presence of a single-stranded G-rich
overhang that represents the substrate of a reverse tran-
scriptase enzyme, the ribonucleoprotein telomerase,
which is involved in the maintenance of telomere
4
by Hoogsteen G–G pairings and monovalent cations
(
Fig. 1). The central aromatic core of the perylene
diimides is suitable for p–p stacking interactions with
the terminal G-tetrad of DNA G-quadruplex, while
the hydrophilic side chains interact with the DNA groo-
5
length. This enzyme is not active in most somatic cells
but is active in most human tumours, and is therefore
considered a potentially highly selective target for differ-
2
a
ves. By means of these two kinds of interactions, these
6
ent anti-tumour strategies. By means of the stabiliza-
tion and/or induction of G-quadruplex structures,
perylene diimides are able to inhibit human telomerase
in cell-free systems, together with a wide series of other
7
compounds.
The tertiary amines, present in the hydrophilic side
chains of this series of perylene diimides, can be trans-
formed into the respective hydrochlorides, leading to a
moderate water solubility of otherwise highly hydropho-
bic perylene core. Nevertheless, these compounds can
3
undergo extensive Ôself-aggregationÕ. In order to achieve
more water-soluble perylene diimides, as well as to ob-
tain a new water soluble coronene derivative with mole-
cular features designed to improve interactions with
G-quadruplexes, a synthetic strategy already applied in
the synthesis of lipophilic perylene derivatives used as
Figure 1. Schematic representation of a G-tetrad (left) and of a
possible conformation of a monomeric G-quadruplex structure (right).
8
liquid crystalline dyes was used, obtaining the new
compounds reported in Figure 2. Lipophilic perylene
and coronene derivatives have been widely studied as
chromophores in dye chemistry and used for many
applications, such as photovoltaic cells, optical switches
Keywords: Perylene;Coronene;Hydrosoluble;G-quadruplex;Telo-
merase inhibitors.
*
Corresponding author. Tel.: +39 0649913341;fax: +39
649913841;e-mail: marco.franceschin@uniroma1.it
9
0
and lasers. All these compounds have two or four
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.040

9016
M. Franceschin et al. / Tetrahedron Letters 45 (2004) 9015–9020
O
N
N
O
N
O
O
N
O
N
O
O
N
N
N
N
O
N
N
O
O
N
CORON (6)
MORPHO–PIPER (1,6) [4b(II)]
N
N
O
O
O
N
O
N
N
N
O
N
O
N
N
N
O
O
N
N
PIP–PIPER (1,7) [4a(I)]
PIP–PIPER (1,6) [4b(I)]
Figure 2.
lipophilic side chains. We have used the same strategy
8
The twofold bromination of the commercially available
perylene-3,4:9,10-tetracarboxylic dianhydride (1) was
easily carried out with elemental bromine in 96% sulf-
uric acid to give a mixture of the two isomers 2a and
2b in 98% yield (Scheme 1). The dianhydride 1 (9g)
was initially dissolved in 96% sulfuric acid (150ml)
and stirred for 4h at room temperature. Elemental io-
dine (200mg) was subsequently added and the mixture
was heated. When a temperature of 80°C was reached,
elemental bromine (3ml) was added drop wise, achiev-
ing a final excess of 20%. The reaction mixture was stir-
red at 80°C overnight. After cooling, it was added drop
wise to ice and then filtered and washed with a 5% so-
dium metabisulfite solution to provide a red solid, which
described by Mullen and co-workers (bromination of
the bay-area of 3,4,9,10-perylenetetracarboxylic dianhy-
dride 1), combined with the preparation of perylene
1
diimides with hydrophilic side chains, to obtain the
brominated perylene diimide 3 PIPER-Br (Scheme 1),
onto which two other hydrophilic substituents could
be inserted (Scheme 2A and B). When bromine
atoms on the perylene bay-area are substituted by
piperidine or morpholine rings, new highly water-
soluble perylene derivatives (4) are obtained (Scheme
2
1
A). Upon replacement with the piperidine containing
-alkyne 7 a two-step cyclization can occur, leading to
the new hydrophilic coronene derivative 6 CORON
Scheme 2B).
1
0
(
was dried and characterized. The two isomers (2a and
2
a
3a
Br
Br
O
O
O
O
O
O
N
N
O
O
N
N
O
O
O
O
O
O
Br
Br
Br
N
NH2
Br /H SO (96%)
2
2
4
O
+
+
Br
O
80ºC overnight
6 h reflux,
DMA / dioxane
O
O
O
O
N
O
O
O
1
N
O
N
N
O
O
Br
Br
3
b
2
b
Scheme 1.

M. Franceschin et al. / Tetrahedron Letters 45 (2004) 9015–9020
9017
3
3
7
THF / Et N
CuI, Pd(PPh3)4
3
X
N
24 h reflux
3
6 h reflux
N
H
(
under argon)
THF (under argon)
N
X
N
O
O
N
O
N
O
O
N
N
N
O
N
O
N
N
O
N
N
5
X
N
4
a
+
X
2
0 h reflux
under argon)
DBU
Toluene
(
O
N
O
O
N
N
N
N
O
N
O
O
N
X
4
b
N
N
O
N
O
N
6
(A)
(B)
Scheme 2.
2
b) could not be separated and the isomeric mixture was
PER(1,7) and (1,6) respectively] were isolated by col-
umn chromatography on silica gel (CHCl3).
used in the following step, in which the commercially
available 1-(2-aminoethyl)piperidine was added to give
a mixture of the two isomers 3a and 3b (Scheme 1).
Six grams of 2, obtained in the previous reaction and
A
standard commercial silica gel had been previously
washed with 1N HCl, followed by water until the chlo-
rine test was negative, activated at 120°C for 48h and
1
3
3
.6ml of 1-(2-aminoethyl)piperidine were stirred in a
refluxing mixture of N,N-dimethylacetamide (DMA,
0ml) and 1,4-dioxane (60ml) for 6h. After cooling,
water was added and a red solid was separated by filtra-
finally equilibrated with 10% water. In order to obtain
the water soluble hydrochlorides, these compounds were
dissolved in 0.2M HCl and after filtration, the solution
was concentrated under vacuum, adding repeatedly an
equal volume of chloroform until water had been elimi-
nated completely. When repeating the same experimen-
tal conditions using morpholine (X = O in Scheme 2A)
only the isomer 4b(II) [MORPHO-PIPER(1,6)] was iso-
6
1
1
tion (71% yield). This mixture of isomers (3) was used
in the following steps (Schemes 2A and B).
When reacting 3 with piperidine (X = CH in Scheme
2
2
1
4
A) two isomers [4a(I) and 4b(I)] were separated and
lated from the chromatographic column (5% yield).
With reaction times under 12h, monosubstituted deriv-
atives can be obtained. In particular, it was possible to
1
2
characterized. Two hundred and fifty milligrams of 3
were stirred under argon in a refluxing mixture of tetra-
hydrofuran (THF, 20ml) and piperidine (20ml) for 36h.
After cooling, water was added and the crude product
was extracted with ethyl acetate. The organic layer was
extracted with water until the aqueous layer was neutral.
The two isomers [4a(I) (30%) and 4b(I) (5%), PIP-PI-
1
5
purify and characterize the compound 10 (30% yield)
(Fig. 3).
According to the model of threading intercalation pro-
a
posed by Hurley and co-workers for the perylene
2

9018
M. Franceschin et al. / Tetrahedron Letters 45 (2004) 9015–9020
O
were not possible at this stage, and the entire mixture
was used in the following cyclization step. The mixture
was poured into 50ml of toluene and 0.17ml of 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU) were added. The
reaction mixture was refluxed with stirring under argon
for 20h. After cooling, water was added and the crude
product was extracted with dichloromethane. The or-
ganic layer was extracted with water until the aqueous
layer was neutral. The crude product was purified by
N
O
N
O
O
N
N
N
O
Br
10
Figure 3.
column chromatography on a silica gel (CHCl :MeOH
3
100:0, 98:2, 95:5, 90:10, 80:20) to give 160mg (31% yield)
of compound 6. It was then purified by dissolving in
diimides interacting with a G-quadruplex structure, it is
possible to suppose that a wider aromatic core and four
positively charged side chains should improve the inter-
actions between these ligands and the G-quadruplex,
leading to higher binding constants and consequently
to increased telomerase inhibition. In order to obtain
a new molecule with these two molecular features, the
synthesis of the new hydrosoluble coronene derivative
CORON (6) was carried out. 3 was reacted with the pre-
viously prepared 7 to give the intermediate 5, using the
conditions previously described by Sonogashira
0.2M HCl and precipitating the respective hydrochlor-
1
ide with acetone (64% yield).
8
The absorption spectra of compounds 4a(I), 4b(I) and
4b(II), performed in chloroform and reported in Figure
4A, show a broad band between 500 and 800nm that is
not present in the spectrum of PIPER-Br (3). This is due
to the conjugation of the N atom of the piperidine or
morpholine ring and the aromatic core of perylene, to
which it is directly linked. This leads to an interesting
chromatic change from the typical red colour of PI-
PER-Br (3) (analogous to that of 3,4,9,10-perylenetetra-
carboxylic dianhydride and previously derived perylene
1
6
et al.; 5 was found to be already partially closed to cor-
onene and provided 6 in the following cyclization step
1
–3
(
Scheme 2B). In this case, the minor isomer due to the
diimides ) to the green colour of 4a(I) and the blue
of 4b(I) and 4b(II). It is also interesting to note that
the colour of each compound depends on the relative
positions of the two nitrogen atoms directly linked to
the aromatic core: the (1,7) isomer is green, while the
(1,6) isomers are blue, regardless of the different kind
initial presence of 1,6-dibromoperylene diimide 3b can-
not be separated from the major isomer, which is the
only one reported in Scheme 2B. Compound 7 was pre-
pared from the commercially available 3-butyn-1-ol by a
1
7
mesylate conversion. Two grams of 3 were dissolved in
anhydrous THF (80ml) and triethylamine (80ml), then
CuI (50mg) and Pd(PPh ) (240mg) were added. After
of cyclic ammine. The UV–vis spectrum (CHCl ) of
3
CORON (6) shows the characteristic five bands between
8
350 and 550nm of coronene (Fig. 4B). In the same fig-
ure, the spectrum of the hydrochloride of 6 performed in
water solution is reported: a minor resolution of the
bands and a slight hypochromic effect with respect to
3
4
adding 1.45g of 7, argon was bubbled into the reaction
mixture that was then refluxed with stirring under argon
for 24h. After cooling, 150ml of diluted HCl (HCl:H O
2
1
:3) were added and the product was extracted with
dichloromethane, after neutralization with NaOH 2M.
The organic layer was extracted with water until the
aqueous layer was neutral. The crude product was puri-
fied by column chromatography on a silica gel
the CHCl spectrum can be observed.
3
In this paper, the synthesis and characterization of the
highly water soluble perylene derivatives (4) and of the
new hydrosoluble coronene derivative CORON (6) are
reported (Fig. 2). These compounds show very interest-
ing spectroscopic properties, combining their different
(
(
CHCl :MeOH 100:0, 98:2, 95:5, 90:10) to give 510mg
3
22% yield) of intermediate 5, together with a small
amount of 6. Separation and better characterization
4
3
3
2
2
1
1
0
5
0
5
0
5
0
2
2
1
1
5
0
5
0
(
A)
(B)
5
5
0
0
3
50
400
450
500
550
600
3
50
450
550
nm
650
750
nm
Figure 4. UV–vis absorption spectra in CHCl
PIPER(1,7) [4a(I)] ( ) (A). UV–vis absorption spectra in CHCl
B). All the spectra were performed at 300K using a JASCO V-530 spectrophotometer.
3
of PIPER-Br (3) ( ), MORPHO-PIPER(1,6) [4b(II)] ( ), PIP-PIPER(1,6) [4b(I)] (
) and PIP-
3
of CORON (6) ( ) and in aqueous solution of the respective hydrochloride ( )
(

M. Franceschin et al. / Tetrahedron Letters 45 (2004) 9015–9020
9019
hydrophobic chromophores with the possibility of fur-
ther use in aqueous solution. Many useful applications
can thus be envisaged, ranging from dyes for micro-
scopic techniques to the quantization of biological mac-
9. (a) Zollinger, H. Color Chemistry, 2nd ed.;VCH: Wein-
heim, 1991;(b) Schlettwein, D.;Wohrle, D.;Kaarmann,
E.;Melville, U. Chem. Mater. 1994, 6, 3;(c) Gvishi, R.;
Reisfeld, R.;Burshtein, Z. Chem. Phys. Lett. 1993, 213,
338.
1
9
romolecules. We are mainly interested in the ability of
these compounds to induce G-quadruplex DNA struc-
tures and thereby inhibit human telomerase: preliminary
results look promising and a deeper study is being car-
ried out in our group. It is worth noting that the syn-
thetic strategies used to obtain these compounds result
in a great versatility: different side chains can be added
to the new coronene moiety, with the possibility of
achieving selectivity towards different G-quadruplex
structures, as has been shown previously for perylene
1
0. 1,7-Dibromoperylene-3,4:9,10-tetracarboxylic dianhydride
1
(
2a): H NMR (200MHz, D SO ): d 10.42 (d, J = 8Hz,
2
4
2
H, aromatic H), 9.75 (s, 2H, aromatic H), 9.53 (d,
J = 8Hz, 2H, aromatic H). The signals of the minor (1,6)
isomer (2b) are mainly superimposed with those reported
for 2a, a part from the doublet centred at 10.34ppm, that
is sufficiently separated from the other signals to be
integrated, giving a ratio between 2a and 2b of 6:1.
C H O Br : calcd C 52.4, H 1.1;found C 51.6, H 1.1.
24
6
6
2
0
1
1. N,N -Bis[2-(1-piperidino)-ethyl]-1,7-dibromoperylene-3,4:
9,10-tetracarboxylic diimide (PIPER-Br,3a): H NMR
1
1
diimides. Moreover, it is possible to add two different
(
8
300MHz, CDCl
.89 (s, 2H, aromatic H), 8.67 (d, J = 8Hz, 2H, aromatic
H), 4.41 (t, J = 7Hz, 4H, Nimidic–CH), 2.8–2.6 (broad,
3
): d 9.44 (d, J = 8Hz, 2H, aromatic H),
kinds of side chains (one type on the imidic nitrogen
atoms and a different one directly linked to the aromatic
moiety), since they are added in two different steps. This
is very interesting since some G-quadruplex structures
have four identical grooves (where the side chains
mainly interact), while others have grooves of different
1
3
1
2H, Npiperidine–CH), 1.8–1.4 (br, 12H, CHpiperidine);
C
NMR APT (200MHz, CDCl ): d 162.14 (C@O), 161.64
3
(C@O), 137.31 (CHar.), 132.17 (Car.), 132.02 (Car.), 129.29
(CHar.), 128.50 (Car.), 127.78 (CHar.), 126.28 (Car.), 122.55
4
(Car.), 122.12 (Car.), 120.18 (Car.), 55.74, 54.24, 37.41,
dimensions. Finally, by means of intermediate com-
pounds (such as 10), it will be possible to obtain asym-
metric compounds.
+
5.48, 23.81. MS (ESI) m/z: 771.10 [(M + 1) ] (calcd for
2
1
38 34 4 4 2
C H N O Br M = 770.09). In this case, all H NMR
signals of the two isomers are superimposed and it is not
possible to obtain the isomeric ratio.
0
1
2. (a)
N,N -Bis[2-(1-piperidino)-ethyl]-1,7-bis(1-piperid-
[PIP-
Acknowledgements
inyl)perylene-3,4:9,10-tetracarboxylic
PIPER(1,7), 4a(I)]: H NMR (200MHz, CDCl
diimide
1
3
): d 9.46
This work was partially supported by FIRB 2001. MS-
ESI measurements have been performed by Dr. Alessan-
(d, J = 8Hz, 2H, aromatic H), 8.33 (s, 2H, aromatic H),
8.30 (d, J = 8Hz, 2H, aromatic H), 4.32 (t, J = 7Hz, 4H,
1
13
dro Dorio; H and C NMR 300MHz spectra by Mr.
Francesco Piccioni. Thanks are due to Dr. Luigi Ros-
setti and Professor Marcella Guiso for helpful discus-
sions and to Mr. Christoph Schultes of the CRUK-
BSG at the School of Pharmacy, University of London,
for help in the final revision of the manuscript.
N
imidic–CH), 3.38 (m, 4H, Car.–Npiperidine–CH), 2.81 (m,
4
H, Car.–Npiperidine–CH), 2.7–2.4 (br, 12H, Npiperidine
–
1
3
CH), 1.8–1.5 (broad, 24H, CHpiperidine); C NMR APT
(
200MHz, CDCl
50.20 (Car.), 134.90 (Car.), 129.36 (Car.), 127.50 (CHar.),
23.70 (Car.), 123.17 (CHar.), 122.64 (CHar.), 122.34 (Car.),
21.85 (Car.), 120.30 (Car.), 55.87, 54.21, 52.27, 37.15,
5.50, 25.21, 23.88, 23.27. MS (ESI) m/z: 779.41 [(M + 1) ]
3
): d 163.05 (C@O), 162.91 (C@O),
1
1
1
2
+
0
(
piperidino)-ethyl]-1,6-bis(1-piperidinyl)perylene-3,4:9,10-
tetracarboxylic diimide [PIP-PIPER(1,6), 4b(I)]:
calcd. for C48
H
54
N
6
O
4
M = 778.42). (b) N,N -Bis[2-(1-
References and notes
1
H
1
. Rossetti, L.;Franceschin, M.;Bianco, A.;Ortaggi, G.;
Savino, M. Bioorg. Med. Chem. Lett. 2002, 12, 2527.
. (a) Han, H.;Cliff, C. L.;Hurley, L. H. Biochemistry 1999,
NMR (200MHz, CDCl ): d 9.63 (d, J = 8Hz, 2H,
aromatic H), 8.53 (d, J = 8Hz, 2H, aromatic H), 8.31 (s,
3
2
2H, aromatic H), 4.30 (m, 4H, Nimidic–CH), 3.29 (m, 4H,
Car.–Npiperidine–CH), 2.79 (m, 4H, Car.–Npiperidine–CH),
2.7–2.4 (broad, 12H, Npiperidine–CH), 1.9–1.5 (br, 24H,
3
8, 6981;(b) Fedoroff, O. Y.;Salazar, M.;Han, H.;
Chemeris, V. V.;Kerwin, S. M.;Hurley, L. H. Biochem-
istry 1998, 37, 12367.
1
3
CHpiperidine); C NMR (200MHz, CDCl ): d 163.23
3
3
. (a) Kerwin, S. M.;Chen, G.;Kern, J. T.;Thomas, P. W.
Bioorg. Med. Chem. Lett. 2002, 12, 447;(b) Kern, J. T.;
Kerwin, S. M. Bioorg. Med. Chem. Lett. 2002, 12, 3395;(c)
Kern, J. T.;Thomas, P. W.;Kerwin, S. M. Biochemistry
(C@O), 163.10, (C@O), 152.76 (ar.), 135.60 (ar.), 131.24
(ar.), 130.21 (ar.), 128.34 (ar.), 127.51 (ar.), 123.26 (ar.),
122.69 (ar.), 122.61 (ar.), 121.85 (ar.), 120.20 (ar.), 119.68
(ar.), 55.91, 54.22, 52.63, 37.24, 37.06, 25.51, 25.28, 23.84,
+
2
002, 41, 11379.
. Neidle, S.;Parkinson, G. N. Curr. Opin. Struct. Biol. 2003,
3, 275.
23.27. MS (ESI) m/z: 779.43 [(M + 1) ] (calcd for
C H N O M = 778.42).
4
4
8
54
6
4
1
13. Bianco, A.;Cavarischia, C.;Guiso, M. Eur. J. Org. Chem.
2004, 2894.
5
6
. De Lange, T. Nature 2002, 21, 532.
0
. (a) Mergny, J. L.;Helene, C. Nat. Med. 1998, 4, 1366;(b)
Sun, D.;Lopez-Guajardo, C. C.;Quada, J.;Hurley, L. H.;
Von Hoff, D. D. Biochemistry 1999, 38, 4037.
14. N,N -Bis[2-(1-piperidino)-ethyl]-1,6-bis(4-orpholinyl)per-
ylene-3,4:9,10-tetracarboxylic
diimide
[MORPHO-
1
PIPER(1,6), 4b(II)]: H NMR (200MHz, CDCl ): d 9.80
3
7
8
. (a) Incles, C. M.;Schultes, C. M.;Neidle, S. Curr. Opin.
Investig. Drugs 2003, 4, 675;(b) Neidle, S.;Parkinson, G.
Nat. Rev. Drug Discov. 2002, 1, 383.
. (a) Rohr, U.;Schlichting, P.;Bohm, A.;Gross, M.;
Meerholz, K.;Brauchle, C.;Mullen, K. Angew. Chem.,
Int. Ed. 1998, 37, 1434;(b) Rohr, U.;Kohl, C.;Mullen,
K.;van de Craats, A.;Warman, J. J. Mater. Chem. 2001,
(d, J = 8Hz, 2H, aromatic H), 8.55 (d, J = 8Hz, 2H,
aromatic H), 8.32 (s, 2H, aromatic H), 4.31 (m, 4H,
Nimidic–CH), 3.87 (m, 8H, CHmorpholine), 3.19 (m, 4H,
CHmorpholine), 3.03 (m, 4H, CHmorpholine), 2.6–2.4 (br, 12H,
1
3
Npiperidine–CH), 1.6–1.3 (br, 12H, CHpiperidine); C NMR
(200MHz, CDCl ): d 162.45 (C@O), 162.41 (C@O),
3
151.07 (ar.), 134.44 (ar.), 130.81 (ar.), 129.68 (ar.),
127.84 (ar.), 127.29 (ar.), 123.35 (ar.), 122.70 (ar.),
1
1, 1789.

9020
M. Franceschin et al. / Tetrahedron Letters 45 (2004) 9015–9020
1
6): H NMR (300MHz, CDCl
H), 9.02 (s, 2H, aromatic H), 8.25 (s, 2H, aromatic H),
4.61 (t, J = 7Hz, 4H, Nimidic–CH), 3.66 (m, 4H, Car.–CH),
1
5
22.57 (ar.), 120.98 (ar.), 120.54 (ar.), 119.93 (ar.), 65.52,
5.29, 53.70, 50.79, 36.80, 36.57, 24.92, 23.31. MS (ESI) m/
3
): d 9.22 (s, 2H, aromatic
+
z: 783.39 [(M + 1) ] (calcd for C H N O M = 782.38).
4
6
50
6
6
0
1
5. N,N -Bis[2-(1-piperidino)-ethyl]-1-bromo-7-(4-morpholin-
3.1–2.5 (broad, 24H, Npiperidine–CH), 1.9–1.4 (br, 24H,
1
13
yl)perylene-3,4:9,10-tetracarboxylic diimide (10): H NMR
200MHz, CDCl ): d 9.61 (d, J = 8Hz, 1H, aromatic H),
.30 (d, J = 8Hz, 1H, aromatic H), 8.73 (s, 1H, aromatic
H), 8.51 (d, J = 8Hz, 1H, aromatic H), 8.44 (d, J = 8Hz,
H, aromatic H), 8.39 (s, 1H, aromatic H), 4.31 (m, 4H,
3
CHpiperidine). C NMR (300MHz, CDCl ): d 163.66
(
9
3
(C@O), 163.50 (C@O), 138.63 (ar.), 130.77 (ar.), 128.70
(ar.), 127.98 (ar.), 127.72 (ar.), 127.40 (ar.), 124.75 (ar.),
121.26 (ar.), 120.80 (ar.), 120.35 (ar.), 120.12 (ar.), 118.62
(ar.), 60.23, 56.55, 54.92, 54.81, 38.20, 30.86, 26.24, 24.57.
1
1
Nimidic–CH), 3.86 (m, 4H, CHmorpholine), 3.28 (m, 2H,
CHmorpholine), 3.10 (m, 2H, CHmorpholine), 2.7–2.4 (broad,
Aromatic H NMR singlets due to the minor (5,10) isomer
can be detected at 9.28 and 8.92ppm. Integration of the
signals shows that the ratio of the two isomers is about
5:1. It is worth noting that the strong ring-current effect of
the coronene system leads to unusually high deshielding of
about 1–2ppm, in comparison with a benzenic system,
both of the aromatic and benzilic-like protons. H NMR
3
(300MHz, CF COOD, hydrochloride): d 10.74 (s, 2H,
12H, Npiperidine–CH), 1.6–1.3 (broad, 12H, CHpiperidine).
+
MS (ESI) m/z: 776.31 [(M + 1) ] (calcd for C42
M = 775.24).
42 5 5
H N O Br
1
1
6. Sonogashira, K.;Tohda, Y.;Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467.
7. 3-Butyn-1-ol was converted into its mesylate, 1g of
which, without purification, was stirred with piperidine
1
2
0
aromatic H), 10.51 (s, 2H, aromatic H), 9.64 (s, 2H,
aromatic H), 5.38 (m, 2H, Nimidic–CH), 4.88 (m, 2H,
(
1.35ml) in refluxing absolute ethanol overnight under
nitrogen. After cooling, solvent was evaporated under
vacuum, then dichloromethane was added and the organic
layer was repeatedly washed with saturated NaCl solution.
Finally the organic layer was dried under vacuum to give
N
3.7–3.4 (br, 12H, Npiperidine–CH), 2.6–1.9 (br, 24H,
imidic–CH), 4.5–4.1 (br, 16H, Npiperidine–CH + Car.–CH),
1
3
CHpiperidine); C NMR (300MHz, CF3 COOD, hydro-
chloride): d 163.51 (C@O), 163.07 (C@O), 131.35 (ar.),
128.94 (ar.), 127.27 (ar.), 126.84 (ar.), 125.55 (ar.), 123.87
(ar.), 121.48 (ar.), 120.39 (ar.), 119.42 (ar.), 118.03 (ar.),
116.95 (ar.), 116.71 (ar.), 54.53, 52.73, 51.47, 51.21, 32.35,
3
90mg of liquid 7 (42% yield). 1-(3-butynyl)-piperidine
1
(7): H NMR (200MHz, CDCl ): d 2.49 (m, 2H, „C–
3
CH), 2.4–2.2 (br, 6H, N–CH), 1.90 (t, J = 3Hz, 1H,
C„C–H), 1.53 (m, 4H, CHpiperidine), 1.37 (m, 2H,
+
24.37, 19.35, 19.22, 17.14. MS (ESI) m/z: 883.49 [(M + 1) ]
1
3
CHpiperidine);
C NMR (200MHz, CDCl
3
): d 82.50
62 6 4
(calcd for C56H N O M = 882.48).
(
„C), 68.30 („CH), 57.29, 53.64, 25.36, 23.74, 16.10.
19. Liu, Z. R.;Rill, R. L. Anal. Biochem. 1996, 236, 139.
20. Crossland, R. K.;Servis, K. L. J. Org. Chem. 1970, 35,
3195.
0
1
8. N,N -Bis[2-(1-piperidino)-ethyl]-5,11-bis[2-(1-piperidino)-
ethyl]-coronene-2,3:8,9-tetracarboxylic diimide (CORON,