Synthesis of a new fluorinated fluorescent β-cyclodextrin sensor

Article abstract of DOI:10.1016/j.jfluchem.2005.01.006

The synthesis of a new fluorescent sensor incorporating a fluorinated indolizine unit bound to 6-amino-β-cyclodextrin by two different synthetic ways is described. Its sensing ability toward adamantanol has been demonstrated.

Full text of DOI:10.1016/j.jfluchem.2005.01.006

Journal of Fluorine Chemistry 126 (2005) 385–388
www.elsevier.com/locate/fluor
Synthesis of a new fluorinated fluorescent b-cyclodextrin sensor
a
Neculai Catalin Lungu , Adrien Depret , Franc¸ois Delattre , Georgiana G Surpateanu ,
a
a
b
´
Francine Cazier a, Patrice Woisel a, Pirouz Shirali b, Gheorghe Surpateanu a,
*
a
` ´ ˆ
Laboratoire de Synthese Organique et Environnement, EA 2599 Universite du Littoral Cote d’Opale,
145 Avenue Maurice Schumann, 59140 Dunkerque, France
´ ˆ
Laboratoire de Recherche en Toxicologie Industrielle et Environnementale, Universite du Littoral Cote d’Opale,
b
189A Avenue Maurice Schumann, 59140 Dunkerque, France
Received 17 June 2004; received in revised form 11 January 2005; accepted 17 January 2005
Available online 16 February 2005
Abstract
The synthesis of a new fluorescent sensor incorporating a fluorinated indolizine unit bound to 6-amino-b-cyclodextrin by two different
synthetic ways is described. Its sensing ability toward adamantanol has been demonstrated.
# 2005 Elsevier B.V. All rights reserved.
Keywords: Trifluoroacetyl; Indolizine; 6-Amino-b-cyclodextrin; Sensor
1. Introduction
sensor containing in its structure the trifluoroacetyl
fragment. Our aim is to obtain a more efficient biological
marker and drug carrier.
The attachment of fluorophores to synthetic or natural
receptors has received considerable interest over the last few
years, in endeavours to furnish new fluorescent sensors [1].
Great attention has been devoted to fluorescent cyclodex-
trins and in particular recent articles have been focussed not
only on their synthesis but also on their sensory [2] and
biochemical [3] properties. Such reactive fluorophores are,
for example, widely employed as fluorescent labels in the
study of complex biological systems like DNA hybridisation
[4] and biological markers [5]. Indolizinic derivatives are of
interest also for their pharmacological effects [6].
2. Results and discussion
The N-(6-deoxy-b-cyclodextrin-6-yl)-1-aminocarbonyl-
3-(trifluoroacetyl)-7-pyridin-4-yl indolizine 9 was synthe-
sized by two different synthetic ways a and b (Scheme 1). The
compounds 1 and 2 are commercially available. The
propynoate of 4-nitrophenyl 5 and the propynamido-b-CD
10 have been synthesized by the procedures described
previously [7a,b]. The salt 3 is obtained by quaternization of
bipyridine with very good yield. Thus, the well-known salt
method has been employed [9]. Next that salt, in presence of
triethylamine (TEA) forms the monosubstituted carbanion
ylide 4 ‘‘in situ’’ which undergo a 1,3-dipolar cycloaddition
reaction with the electron-deficient the compound 5 to give
primary cycloadduct 6 which spontaneously furnishes, after
aromatisation, the final indolizine compound 7, in good yield.
Then, the 6-amino-b-cyclodextrin 8 was synthesized via
a three step process involving a preliminary regioselective
tosylation into the primary face of b-CD [10], following by
Considering the well-known fluorescence properties of
indolizines and the inner capture ability of b-cyclodextrin
(b-CD), we synthesized a new class of molecular fluorescent
sensors incorporating a pyridinoindolizine unit and a b-CD
fragment [7]. Taking in account the significant effect
exercised by fluorinated groups on the level of cellular
membranes [8], we describe herein the convenient synthesis
and characterisation of a new fluorescent indolizino-b-CD
* Corresponding author. Tel.: +33 3 28 65 82 54; fax: +33 3 28 23 76 05.
E-mail address: surpatea@univ-littoral.fr (G. Surpateanu).
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.01.006

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N.C. Lungu et al. / Journal of Fluorine Chemistry 126 (2005) 385–388
Scheme 1. Synthesis of N-(6-deoxy-b-cyclodextrin-6-yl)-1-(amino carbonyl)-3-(4-trifluoroacetyl)-7-pyridyn-4-yl indolizine 9.

N.C. Lungu et al. / Journal of Fluorine Chemistry 126 (2005) 385–388
387
the displacement of the tosyl leaving group with NaN3 [11]
¨
and the reduction of the azido group using the Staudinger
protocol [12].
The addition of adamantanol leads to an increase of the
maximum of fluorescence emission. The excitation wave-
length of the fluorescence spectra was 370 nm and emission
slits were 4 nm. Since the fluorescent intensity of the
modified cyclodextrin sensor 9 is affected by the presence of
adamantanol as guest molecule, we tested with good results
this product in detection of volatile organic compounds
(benzene, toluene, phenol, cresols and nitrophenols).
The 6-amino-b-cyclodextrin 8 was treated with the
fluorescent indolizine 7, in N-methylpyrrolidone (NMP) at
50 8C to give the corresponding fluorescent b-CD 9.
The same sensor 9 could be obtained by a 1,3-dipolar
cycloaddition reaction of bipyridinium ylide 4 and
propynamido-b-cyclodextrin 10. The primary cycloadduct
11 susquently eliminates dihydrogen to give the crude
indolizine b-CD derivative 9. These reactions must be
carried out without light in order to prevent cleavage of the
Cꢀ–N+ bond. In both synthetic routes a and b the crude
product 9 was isolated by precipitation from acetone and
then successively purified using Sephadex CM-25 and G-15
chromatography. By the yields, to obtain the sensor 9 the
synthetic way a is recommended. It is well known [13] that
all monosubstituted cycloimmonium ylides, like ylide 4
undergo inactivity due to their dimerisation by a 3 + 3
cycloaddition reaction. Thus, the noticed yield difference
could be explain if we consider that ylide 4 reacts faster with
propionate 5 (way a), then with propinamido-b-cyclodextrin
10 (way b).
3. Experimental
1H NMR spectra were recorded on a Bruker AMX 250
spectrometer with tetramethylsilane as internal standard.
Chemical shift values d are reported in ppm and coupling
constants J are in Hz. The abbreviations used are: s (singlet),
d (doublet), t (triplet) and m (multiplet). Mass spectra were
measured using a Platform II Micromass Apparatus. FTIR
spectra were recorded using a Perkin-Elmer 2000 instru-
ment. Melting points were obtained with a digital IA 9000
apparatus.
3.1. 1-(Trifluoroacetonyl)-4-pyridin-4-yl pyridinium
bromide 3
The structures of new compounds were obtained from
1
their spectroscopic data (MS, IR and H NMR). Complete
spectral characterisation of new compounds 3, 7 and 9 is
provided in the experimental section. In all cases, the mass
spectra (MS ES+, H2O/CH3OH 1:1, cone voltage 110 V)
showed a peak consistent with the sodium complexed
In a 100 ml round-bottomed flask, was dissolved
10 mmol (1.56 g) of 4,40-bipyridine in 25 ml of dry acetone.
Next, 10 mmol (1.05 ml) of 3-bromo-1,1,1-trifluoroacetone
dissolved in 35 ml of acetone were added. The reaction
mixture was refluxed for 6 h under magnetic stirring and
then washed with anhydrous ether. The formed solid was
filtered and then washed with anhydrous ether. The salt is
finally purified by recrystallization from ethanol.
Yield 89%, m.p. 178–179 8C.
1
molecule. H NMR spectra of sensor 9 exhibited broad
resonance signals in the regions expected for the glycon
moiety. Dominantly, the assignments of protons have been
achieved by structural analogy which exist between this
product and others similar sensors, previously published [7].
The fluorescent properties of the sensor 9 and its sensing
ability have been investigated by addition of various
concentrations of adamantanol to initial fluorescent sensor
solution (Fig. 1).
IR (KBr, n cmꢀ1): 1639, 1543, 1459, 1411, 1285, 1169,
1099, 987, 795.
1H NMR (DMSO-d6, d ppm): 9.07 (d, 2H, ortho/N+,
J = 6.7 Hz); 8.88 (d, 2H, meta/N, J = 6.7 Hz); 8.69 (d, 2H,
meta/N+, J = 6.7 Hz); 8.11 (d, 2H, meta/N, J = 6.7 Hz);
4.92 (s, 2H, CH2); 19F NMR (DMSO-d6, d ppm): ꢀ78.1 (s).
MS ES+ m/z (%): 267 [M+] (100), 168 (51), 114 (52).
3.2. 3-(Trifluoroacetyl)-7-(pyridin-4-yl)-1-(4-
nitrophenylcarbonyl) indolizine 7
In a 100 ml round-bottomed flask, was dissolved
0.4 mmol (0.08 g) of 4-nitrophenyl propynoate 5, in DMF
(25 ml). Then was added TEA (0.55 mmol, 0.04 ml) with
stirring. On the reaction mixture at 0–5 8C the solid salt 3
(0.4 mmol, 0.14 g) was slowly added, with stirring, over
15 min. Continue the stirring, without light at room
temperature for 2 h. The mixture was poured into acetone
(70 ml) drop wise. The resulting precipitate was collected
and washed with acetone and diethyl ether.
Fig. 1. Fluorescence spectra of 9 (1 ꢁ 10ꢀ4 M) in aqueous phosphate buffer
at pH 7 in the presence of various concentration of 1-adamantanol (1:
0 mol dmꢀ3
,
2: 4 ꢁ 10ꢀ5 mol dmꢀ3
,
3: 1 ꢁ 10ꢀ4 mol dmꢀ3
,
4:
1.5 ꢁ 10ꢀ4 mol dmꢀ3, 5: 2.5 ꢁ 10ꢀ4 mol dmꢀ3, 6: 8.5 ꢁ 10ꢀ4 mol dmꢀ3
,
7: 1.85 ꢁ 10ꢀ3 mol dmꢀ3).
Yield 42%, m.p. > 240 8C.

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N.C. Lungu et al. / Journal of Fluorine Chemistry 126 (2005) 385–388
(b) C. Chen, H. Wagner, Science 279 (1998) 851–853;
IR (KBr, n cmꢀ1): 1729, 1646, 1523, 1349, 1220, 1168,
(c) A.P. De Silva, H.Q.N. Gunaratne, T. Gunnlaugsson, A.J.M. Hux-
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1515–1566;
1086, 996, 897, 799.
1H NMR (DMSO-d6, d ppm): 9.87 (d, 1H, H-5,
J = 6.1 Hz); 8.84–8.70 (m, 3H, ortho/N and H-8); 8.44–
8.37 (m, 3H, ortho/NO2 and H-2); 8.01 (d, 1H, H-6,
J = 6.1 Hz); 7.91 (d, 2H, meta/N, J = 6.7 Hz); 7.73 (d, 2H,
meta/NO2, J = 7.6 Hz); 19F NMR (DMSO-d6, d ppm):
ꢀ74.0 (s).
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3.3. N-(6-Deoxy-b-cyclodextrin-6-yl)-1-(aminocarbonyl)-
3-(4-trifluoroacetyl)-7-pyridyn-4-yl indolizine 9
(c) R. Corradini, A. Dossena, G. Galaverna, R. Marchelly, A. Paragia,
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(a) A homogeneous mixture of 0.35 mmol (0.40 g)
amino-b-cyclodextrin 6 and 0.35 mmol (0.16 g) fluorescent
indolizine 7 in 40 ml dried DMF, without light, under
stirring and argon was allowed to 608 over 12 h. The reaction
mixture was poured in acetone (100 ml) and resultant
precipitate was dissolved in distilled water. Filter the solid
impurities. After concentration the water solution of
fluorescent product 9 was firstly filtered on Sephadex
CM-25 column and next purified on Sephadex G-15, to give
a pure orange powder.
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Yield 7%.
(b) To a solution of propynamido-b-cyclodextrin 10
(0.45 mmol, 0.54 g) in DMF (1.5 ml) was added the freshly
distilled TEA (0.65 mmol, 0.09 ml) in DMF (1 ml). The
solid salt 3 (0.45 mmol, 0.16 g) is slowly added on mixture,
with stirring, over 15 min at 0–5 8C. The mixture was
maintained under Argon, at room temperature in the absence
of light, for 12 h. Finally, the reaction mixture was poured
into acetone (50 ml) and the resulting precipitate of crude
compound 9 was purified as in previous synthetic way a.
Yield 20%.
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IR (KBr, n cmꢀ1): 1642, 1464, 1426, 1374, 1295, 1144,
1076, 1027, 789.
1H NMR (DMSO-d6, d ppm): 9.82 (d, 1H, H-5,
J= 7.6 Hz); 9.05 (s, 1H, H-8); 8.76 (d, 2H, ortho/N,
J = 6.6 Hz); 8.61–8.36 (m, 3H, H-2 and H-6); 7.91 (d, 2H,
meta/N, J = 6.6 Hz); 6.14–5.40 (m, 14H, OHbCD-2 and
OHbCD-3); 5.14–4.67 (m, 7H, HbCD-1); 4.62–4.22 (m, 6H,
OHbCD-6); 4.06–2.97 (m, 42H, HbCD-2, HbCD-3, HbCD-4,
HbCD-5, HbCD-6); 19F NMR (DMSO-d6, d ppm): ꢀ70.3 (s).
MS ES+ m/z (%): 1472 [M + Na+] (42), 1314 (69), 1156
(100).
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¨
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