Scientific paper
Synthesis of DDNP Analogs with an Aromatic Ring Attached via an Ethylidene Tether
Alenka @abjek,1 Jorge R. Barrio2 and Andrej Petri~1'*
1 Faculty of Chemistry and Chemical Technology, University of Ljubljana, A{ker~eva 5, 1000 Ljubljana, Slovenia 2 David Geffen School of Medicine at UCLA, Los Angeles, CA, USA * Corresponding author: E-mail: andrej.petric@fkkt.uni-lj.si
Received: 24-11-2008 Dedicated to Professor Blanko Stanovnik on the occasion of his 70'' birthday
Abstract
The parent DDNP molecule was modified in such a manner that an aromatic or heteroaromatic ring was attached through an ethylidene tether. A series of analogs of FDDNP, a molecular probe for protein aggregate deposition in the central nervous system, was obtained. These analogs exhibit similar optical properties as DDNP/FDDNP and thus fulfill the optical requirements for successful application in fluorescence microscopy. The introduced aromatic ring offers an additional opportunity for n-interaction between the molecule and protein aggregates.
Keywords: DDNP, fluorescent probes, synthesis, fluorescence
1. Introduction
Starting from {1-[6-(dimethylamino)naphthalen-2-yl]ethylidene}propanedinitrile (DDNP)1 as the lead compound, (1- { 6- [(2-fluoroethyl)(methyl)amino]naphthalen-2-yl}ethylidene)propanedinitrile (FDDNP) was developed and successfully applied as a molecular probe for in vitro and in vivo assessment of amyloid protein aggregate deposition in the central nervous system (CNS) of patients with Alzheimer's and other neurodegenerative diseases with similar pathogenesis.2-10
To facilitate routine application in medical diagnostics and research, fully automated synthesis of radiolabeled [18F]FDDNP was developed.11 Besides FDDNP, four other compounds: 2-[4-(methylamino)phenyl]-1,3-ben-
zothiazol-6-ol ([^-methyl-11C]PIB), 5-{(E)-2-[6-(2-fluo-roethoxy)-1,3-benzoxazol-2-yl] vinyl} -^,^-dimethyl-1,3-thiazol-2-amine ([11C]BF-227), 4-{(£)-2-[4-(methylami-no)phenyl]vinyl}phenol ([11C]SB-13), and 4-[(E)-2-(4-{2-[2-([18F]2-fluoroethoxy)ethoxy]ethoxy}phenyl)vinyl]-^-methylaniline ([18F]-BAY94-9172) have been recently introduced.12a In this work we investigate the effect of molecular modifications in the parent structure (FDDNP) on the optical properties for their use with fluorescence microscopy of protein aggregation in the CNS.12b Molecules of the DDNP family bind strongly to protein aggregates (<nM) when two conditions are met: hydrophobic stacking of aromatic rings and relatively large dipole moment. The hydrophobic stacking is enhanced if the molecule can attain planar conformation, which also increases the probability of strong dipole moments. Polar interactions between the probe and amino acid residues within the binding site also contribute to stronger binding.
Several FDDNP analogs have already been prepared and characterized. Bifunctional heterocyclic or acyclic amino group were introduced instead of the dimethylami-no group in DDNP thus enabling the preparation of phar-macophore-containing analogs, intended for structural and functional imaging of dopamine-D2 receptors by fluo-
rescence microscopy.13-15 Modifications of DDNP at the acceptor part of the molecule were also introduced utilizing the relatively high reactivity of the ethylidenemalo-nonitrile side-chain resulting in the transformation of DDNP into highly fluorescent 2-hetaryl-6-dimethylami-nonaphthalene derivatives. In contrast to the parent DDNP, functional groups in these compounds allow further synthetic elaboration.16
In this contribution we describe the synthesis of a series of DDNP derivatives with an additional aromatic ring attached via an ethylidene tether to the acceptor side-chain. We intended these derivatives to probe the impact of the additional aromatic ring on optical properties and on binding to protein aggregates.
2. Results and Discussion
The synthetic approach is summarized in Scheme 1. Utilizing relatively high acidity of the methyl group in 1-[6-(dimethylamino)naphthalen-2-yl]ethanone (2) or its 6-methoxy precursor (1) in a Claisen-Schmidt condensation17 with aromatic aldehydes, a,ß-unsaturated ketones 3-15 were formed. The sodium hydroxide catalyzed reactions were run in ethanol at room temperature. Under these conditions the reactions yielded exclusively E'-alkenes. For most compounds this was supported by the measured vicinal coupling constants between the alkene protons in 1H NMR spectra. The coupling constants between 15 and 16.2 Hz were in the normal range for E-arrangement of protons. In some spectra the signals for alkene protons overlapped with other signals and such proof is lacking. In these cases we assumed E-stereochemistry by analogy. Alkenes 10-15 no longer exhibited the fluorescent properties of the precursor, but their intense yellow color indicated absorption red-shift of these derivatives in the vi-
sible region of the spectrum. The C=C bond was selectively reduced using iron pentacarbonyl18 to give substituted naphthyl ethyl ketones 16-27. The saturation of the exocyclic double bond enabled products 22-27 to exhibit similar visible fluorescence as observed in 2. The met-hoxy derivatives 16-21 were prepared from 1 with the intent to serve as substrates for nucleophilic aromatic substitution with lithium salts of a series of secondary amines to yield novel fluorescent compounds with a reactive side chain. Low yields in experiments, in which we tried to prepare dimethylamino compounds 22-27 from their met-hoxy analogs, indicated that this wasn't the best synthetic approach. The yield was acceptable only in the case of transformation of 17 into 23. As a result the introduction of the dimethylamino group at the beginning and performing the Claisen-Schmidt condensation as well as the reduction with this group already in place was the most efficient pathway. However, the methoxy group in 16-21 re-
Scheme 2.
1: OCH3 2: R= NMfi.
.^rllflTIf 1
3: R--4: R= 5: R= 6: R= 7: R= 8: R= 9: R= 10: R= 11: R= 12: R= 13: R= 14: R= R=
OMe; Ar= OMe; Ar= OMe; Ar= OMe; Ar= OMe; Ar= OMe; Ar= OMe; Ar= NMe2; Ar= NMej; Ar= NMe2; Ar= NMe2; Ar= NMe2; Ar= NMe,; Ar=
phenyl
3-hydroxyphenyl
3-nitrophenyl
2,6-dichlorophenyl
biphenyl-4-yl
2-naphthyl
quinolin-3-yl
: phenyl
: 3-hydroxyphenyl : 2,6-dichlorophenyl : biphenyl-4-yl : 2-naphthyl : quinolin-3-vl
16: R 17: R 18: R 19: R 20: R 21: R 22: R= NMG
OMe; Ar= OMe; Ar= OMe; Ar= OMe; Ar= OMe; Ar= OMe; Ar= ; Ar= ; Ar= ; Ar= ; Ar=
■ An
23: R= NMe 24: R= NMe 25: R= NMe 26: R= NMe2, ... 27: R= NMe.: Ar=
phenyl
3-hydroxyphenyl
2,6-dichlorophenyl
biphenyl-4-yl
2-naphthyl
quinolin-3-yl
: phenyl
: 3-hydroxyphenyl : 2,6-dichlorophenyl : biphenyl-4-yl : 2-naphthyl auinolin-3-vl
main a potential reactive site for e.g. demethylation and subsequent further transformations leading to other, reactive site containing, fluorescent analogues.
In the last step DDNP analogs were prepared in the Knoevenagel reaction of ketones 22-27 with malononitri-le. (Scheme 2) Using this approach {1-[6-(dimethylami-no)-2-naphthyl]-3-(3-aryl)propylidene}malononitrile derivatives 28-33 were obtained in moderate yields.
Measured fluorescence excitation and emission spectra of 28-33 (Table 1) revealed that the described structural modifications did not cause significant changes in the fluorophore. This suggests,12 this these derivatives would have analogous binding characteristics to amyloid aggregates than other closer members of the DDNP family. However, it is anticipated that the additional tethered aromatic ring would play an important role in enhancing binding to protein aggregates through n-interactions.
Table 1. Excitation and emission maxima measured in methanol
Cmpd	^exc	^em
DDNP	433	580
28	441	588
29	440	587
30	439	604
31	433	578
32	439	611
33	446	589
3. Conclusions
We have prepared a series of DDNP analogues to probe their optical properties as predictor of their binding to amyloid aggregates. With an aromatic ring tethered to the parent molecule and additional binding point was introduced aiming for possible n-interaction with the protein aggregate. As hypothesized, the new analogs have optical properties resembling the optical properties of DDNP and its analogs described so far, making these compounds good candidates for successful application in fluorescence microscopy. The methoxy intermediates can serve for further synthetic elaboration at the donor part of the molecule, e.g. to introduce radiolabeling.
4. Experimental
NMR spectra were recorded on a Bruker DPX 300 spectrometer at 302 K using CDCl3 as the solvent. 1H chemical shifts are quoted in parts per million (ppm) down-field from TMS as internal standard, 13C NMR spectra are referenced to the middle line of CDCl3 signal (77.0 ppm). Mass spectra were measured at the Jožef Stefan institute using VG-Analytical AutospecQ spectrometer. Fluores-
cence spectra were measured on a Shimadzu RF 1501 spectrofluorimeter. Melting points were determined on a Kofler hot stage apparatus and are uncorrected. Elemental analyses were determined at the Faculty of Chemistry and Chemical Technology of the University of Ljubljana using a Perkin-Elmer 2400 CHN elemental analyzer. IR spectra were recorded on a Perkin Elmer 727B spectrometer. Radial chromatography was performed using Chromatotron (T-Squared Technology, Inc., 903 Sneath Lane, Suite 125 San Bruno, Ca 94066). The rotors were prepared as recommended by the manufacturer using E. Merck Silica Gel (Cat. No. 7749-3) in 1, 2, or 4 mm layer thicknesses.
General procedure for the Claisen-Schmidt condensation of methyl ketones with aromatic aldehydes. An equi-molar solution of a ketone and an aromatic aldehyde (1 mmol) in anhydrous ethanol (approximately 20 mL per one mmol) was cooled on ice, finely powdered NaOH (one tenth of the mass of the ketone) was added and the mixture was stirred on ice for 1 hour, followed by stirring at rt for additional 24 hours. The solid, which has separated was filtered off and chromatographed by radial chromatography to yield the products. In the case of reactions with 3-hydroxybenzal-dehyde heating at 60-65 °C for 24 hours was required and the products were isolated by extraction (dichloromethane, anhydrous Na2SO4) followed by radial chromatography.
(2£)-1-(6-Methoxy-2-naphthyl)-3-phenylprop-2-en-1-one (3). Yield 78%; radial chromatography on a 2 mm thick silicagel layer using 30% petroleum ether in dichlo-romethane as the eluent; mp 124-126 °C (from benzene-petroleum ether), (lit.19125-126 °C); 1H NMR 5 3.96 (s, 3H, OMe); 7.19 (d, 1H, J 2.6 Hz, H-5); 7.22 (dd, 1H, J 2.6 and 8.9 Hz, H-7); 7.42-7.46 (m, 3H, Ph'); 7.67-7.91 (m, 6H, H-4, H-8, 2H Ph', COCH=CH); 8.11 (1H, dd, J 1.6 and 8.7 Hz, H-3); 8.49 (d, 1H, J 1.6 Hz, H-1).
(2£)-3-(3-Hydroxyphenyl)-1-(6-methoxy-2-naphthyl) prop-2-en-1-one (4). Yield 62%; radial chromatography on 2 mm thick silicagel layer using 1% methanol in dich-loromethane as the eluent; mp 197-199 °C (from dichlo-romethanehexane) Anal. Calcd for C20 H1gO3: C 78.93, H 5.30. Found: C 79.28, H 5.27; 1H ISfMI^ 5 3.96 (s, 3H, OMe); 6.89-6.93 (m, 1H, Ph'); 7.18 (d, 1H, J 2.4 Hz, H-5); 7.23 (dd, 1H, J 2.4 and 9.0 Hz, H-7); 7.27-7.38 (m, 3H, Ph'); 7.66 (d, 1H, J 15.0 Hz, COCH=CH); 7.81 (d, 1H, J 15.0 Hz, COCH=CH); 7.82 (d, 1H, J 8.7 Hz; H-4); 7.89 (d, 1H, J 9.0 Hz; H-8); 8.09 (dd, 1H, J 1.8 and 8.7 Hz, H-3); 8.48(d, 1H, J 1.8 Hz, H-1).
(2£)-1-(6-Methoxy-2-naphthyl)-3-(3-nitrophenyl)prop -2-en-1-one (5). Yield 70%; radial chromatography on 2 mm thick silicagel layer using 50% hexane in dichloro-methane as the eluent; mp 183-184 °C (from dichloro-methane-hexane); Anal. Calcd for C20H15NO4: C 72.06, H 4.54, N 4.20. Found C 71.79, H 4.45, NN 4.11; 1H NMR 5
3.97 (s, 3H, OMe); 7.19 (d, 1H, J 2.4 Hz, H-5); 7.25 (dd, 1H, J 2.4 and 8.7 Hz, H-7); 7.63 (m, 1H, Ph'); 7.79-7.97 (m, 5H, H-4, H-8, 1H Ph', COCH=CH); 8.12 (dd, 1H, J 1.5 and 8.7 Hz, H-3); 8.25-8.29 (m, 1H, Ph'); 8.52 (1H, d, J 1.5 Hz, H-1); 8.56-8.58 (m, 1H, Ph').
(2£)-3-(2,6-Dichlorophenyl)-1-(6-methoxy-2-naph-thyl) prop-2-en-1-one (6). Yield 50%; radial chromatography on 2 mm thick silicagel layer using 50% hexane in dichloromethane as the eluent; mp 122-123 °C (from dichloromethane-hexane); Anal. Calcd for C20H14Cl2O2: C 67.24, H 3.95. Found C 67.49, H 3.90; 1H NMR 5 3.93 (s, 3H, OMe); 7.14-7.21 (m, 3H, H-5, H-7, 1H Ph'); 7.37 (m, 2H, Ph'); 7.79 (d, 1H, COCH=CH, J 16.2 Hz); 7.80 (d, 1H, H-4, J 8.7 Hz); 7.84 (d, 1H, H-8, J 9.0 Hz); 7.89 (d, 1H, COCH=CH, J 16.2 Hz); 8.08 (dd, 1H, J 1.5 and 8.7 Hz, H-3); 8.44 (1H, d, J 1.5 Hz, H-1); 13C NMR 5 55.32, 105.77, 119.66, 125.08, 127.28, 127.75, 128.75, 129.65, 130.29, 130.46, 131.13, 132.73, 132.94, 135.09, 137.18, 137.28, 159.81, 189.39.
(2£)-3-Biphenyl-4-yl-1-(6-methoxy-2-naphthyl)prop-2 -en-1-one (7). Yield 70%; radial chromatography on 2 mm thick silicagel layer using 50% hexane in dichloro-methane as the eluent; mp 192-194 °C (from benzene-petroleum ether); Anal. Calcd for C2gH20O2: C 85.69, H 5.53. Found C 85.57, H 5.51; 1H NMR 5 3.94 (s, 3H, OMe); 7.16 (d, 1H, H-5, J 2.64 Hz); 7.21 (dd, 1H, H-7, J 2.64 and 9.03 Hz); 7.34-7.39 (m, 1H, Ph'/Ph''); 7.42-7.48 (m, 2H, Ph'/Ph''); 7.61-7.66 (m, 4H, Ph'/Ph''); 7.71 (d, 1H, CO^=CH, J 15.5 Hz); 7.74 (m, 2H, Ph'/Ph''); 7.81 (d, 1H, H-4, J 8.7 Hz); 7.89 (d, 1H, H-8, J 8.9 Hz); 7.90 (d, 1H, -COCH=CH, J 15.5 Hz); 8.10 (dd, 1H, H-3, J 1.8 and 8.7 Hz); 8.48 (d, 1H, H-1, J 1.8 Hz); 13C NMR 5 55.39, 105.82, 119.69, 121.85, 125.21, 127.03, 127.26, 127.54, 127.84, 127.89, 128.88, 128.94, 129.84, 131.10, 133.61, 134.02, 137.19, 140.15, 143.14, 143.80, 159.73, 189.69.
(2£)-1-(6-Methoxy-2-naphthyl)-3-(2-naphthyl)prop-2-en-1-one (8). Yield 66%; radial chromatography on 4 mm thick silicagel layer using 50% hexane in dichlorometha-ne as the eluent; mp 190-192 °C (from benzene-petroleum ether); Anal. Calcd for C24H18O2: C 85.18, H 5.36. Found C 85.44, H 5.29; 1H NIVIR 5 3.97 (s, 3H, OMe); 7.19 (d, 1H, J 2.4 Hz, H-5); 7.23 (dd, 1H, J 2.4 and 9.0 Hz, H-7); 7.52-7.55 (2H, m, naphthyl'); 7.78-8.05 (m, 9H, H-4, H-8, 5H naphthyl', COCH=CH); 8.13 (dd, 1H, J 1.7 and 8.7 Hz, H-3); 8.53 (d, 1H, J 1.7 Hz, H-1); 13C NMR 5 55.24, 105.87, 119.73, 122.20, 123.79, 125.27, 126.75, 127.31, 127.82, 127.95, 128.65, 128.72, 129.89, 130.54, 131.15, 132.61, 133.43, 133.67, 134.37, 137.24, 144.40, 159.78, 189.79.
(2£)-1-(6-Methoxynaphthalen-2-yl)-3-(quinolin-3-yl) prop-2-en-1-one (9). Yield 76%; radial chromatography
on 2 mm thick silicagel layer using dichloromethane followed by 1% methanol in dichloromethane as the eluent; mp 261-263 °C (from dichloromethane); Anal. Calcd for C23H17NO2: C 81.40, H 5.05, N 4.13. Found C 81.62, H 4.SI8, ^ 4.02; 1H NMR: 3.97 (s, 3H, OMe); 7.19 (d, 1H, J 2.5 Hz, H-5); 7.24 (dd, 1H, J 2.5 and 9.03 Hz, H-7); 7.58-7.64 (m, 1H, quinolinyl); 7.75-7.80 (m, 1H, quino-linyl); 7.84 (d, 1H, J 8.7 Hz, H-4); 7.88-7.94 (m, 3H, COCH=CH, H-8, 1H quinolinyl); 8.02 (d, 1H, J 15.6 Hz, COCH=CH); 8.11-8.16 (m, 2H, H-3 and 1H quinolinyl); 8.38 (d, 1H, J 2.0 Hz, quinolinyl); 8.53 (d, 1H, J 1.1 Hz, H-1); 9.26 (d, 1H, J 2.0, quinolinyl); 13C NMR 5 55.44, 105.88, 119.85, 123.60, 125.14, 127.44, 127.47, 127.76, 127.90, 128.10, 128.37, 129.43, 130.09, 130.65, 131.20, 133.22, 135.64, 137.39, 140.80, 148.59, 149.43, 159.94, 189.11.
(2£)-1-[6-(Dimethylamino)naphthalen-2-yl]-3-phenyl-prop-2-en-1-one (10). Yield 89%; radial chromatography on 2 mm thick silicagel layer using 3% dichloromethane in petroleum ether as the eluent; mp 186-187 °C (from dichloromethane-petroleum ether); Anal. Calcd for C21H19NO: C 83.69, H 6.35, N 4.65. Found C 83.85, H 6.:^7, ^ 4.70; 1H NMR 5 3.06 (s, 6H, NMe2); 6.85 (d, 1H, J 2.4 Hz, H-5); 7.13 (dd, 1H, J 2.4 and 9.2 Hz, H-7); 7.38-7.41 (m, 3H, Ph'); 7.64-7.71 (m, 4H, 1H-4, COCH=CH, 2H Ph'); 7.79 (d, 1H, J 9.2 Hz, H-8); 7.84 (d, 1H, J 15.8 Hz, COCH=CH); 8.01 (dd, 1H, J 1.5 and 8.7 Hz, H-3); 8.39 (d, 1H, J 1.5 Hz, H-1); 13C NMR 5 40.29, 105.2, 116.17, 122.17, 125.03, 126.32, 128.29, 128.82, 130.10, 130.23, 130.67, 131.53, 135.26, 137.60, 143.38, 150.19, 189.25.
(2£)-1-[6-(Dimethylamino)naphthalen-2-yl]-3-(3-hy-droxyphenyl)prop-2-en-1-one (11). Yield 78%; radial chromatography on 2 mm thick silicagel layer using 2% methanol in dichloromethane as the eluent; mp 209-211 °C (from dichloromethane-petroleum ether); Anal. Calcd for C21H19NO2 X 0.5 H2O: C 77.28; H 6.17; N 4.29. Found C 77.11; H 5.77; N 4.25; HRMS Calcd for C21H19NO2: 317.1416, found 317.1427; 1H NMR 5 3.12 (s, 6H, NMe2); 5.33 (s, 1H, OH); 6.89-6.92 (m, 2H, H-5 and 1H Ph'); 7.16-7.21 (m, 2H, J 2.4 and 9.0 Hz, H-7, H-7 and 1H Ph'); 7.27-7.33 (m, 2H, Ph'); 7.66-7.71 (m, 2H, H-4 and COCH=CH); 7.82 (d, 1H, J 15.6 Hz, COCH=CH); 7.85(d 1H, J 9.0 Hz, H-8,); 8.02 (dd, 1H, J 1.8 and 8.7 Hz, H-3); 8.40 (d, 1H, J 1.8 Hz, H-1); 13C NMR 5 104.34, 114.24, 115.52, 117.00, 118.85, 121.14, 124.06, 124.14, 125.55, 129.04, 129.47, 130.55, 135.54, 136.77, 142.78, 149.49, 157.07, 188.10.
(2£)-3-(2,6-Dichlorophenyl)-1-[6-(dimethylamino)-2-naphthyl]prop-2-en-1-one (12). Yield 74.4%; radial chromatography on 2 mm thick silicagel layer using 50% petroleum ether in dichloromethane as the eluent; mp 195-197 °C (from benzene-petroleum ether); Anal. Calcd
for C21H17a2NO: C 68.12; H 4.63; Cl 19.15; N 3.78. Found C (58.38; H 4.45; N 3.84; 1H NMR 5 3.10 (s, 6H, NMe2); 6.88 (d, 1H, H-5, J 2.4 Hz); 7.16-7.24 (m, 2H, H-7 and 1H Ph'); 7.38-7.42 (m, 2H, Ph'); 7.67 (d, 1H, H-4, J 8.7 Hz); 7.80 (d, 1H, H-8, J 9.0 Hz); 7.80(d, 1H, COCH=CH, J 16.0 Hz); 7.88 (1H, d, COCH=CH, J 16.0 Hz); 8.01 (dd, 1H, H-3, J 8.7 Hz), 8.39 (d, 1H, H-1, J 1.7 Hz); 13C NMR 5 40.36, 105.33, 116.20, 125.03, 125.10, 126.37, 128.78, 129.53, 130.79, 130.86, 131.14, 133.12, 135,17 136.47, 137.80, 150.38, 189.06, 217.37.
(2£)-3-Biphenyl-4-yl-1-[6-(dimethylamino)-2-naph-thyl]prop-2-en-1-one (13). Yield 80%; radial chromatography on 2 mm thick silicagel layer using 50% petroleum ether in dichloromethane as the eluent; mp 190-192 °C (from benzene-petroleum ether); Anal. Calcd for C27H23N0: C 85.91; H 6.14; N 3.71. Found C 85.89; H 5.976; IN 3.94; 1H NMR 5 3.09 (6H, s, NMe2); 6.88 (d, 1H, H-5, J 2.6 Hz); 7.17 (dd, 1H, H-7, J 2.^ and 9.0 Hz); 7.34-7.39 (m, 1H, Ph'/Ph''); 7.43-7.48 (m, 2H, Ph'/Ph''); 7.61-7.76 (m, 8H, H-4, COCH=CH, 6H Ph'/Ph''); 7.83 (d, 1H, H-8, J 9.0 Hz); 7.85 (d, 1H, COCH=CH, J 15.8 Hz); 8.04 (dd, 1H, H-3, J 1.7 and 8.7 Hz); 8.43 (d, 1H, H-1, J 1.7 Hz); 13C NMR 5 40.42, 105.42, 116.28, 122.12, 125.17, 126.44, 127.07, 127.55, 127.82, 128.90, 128.91, 130.31, 130.79, 131.72, 134.32, 137.70, 140.27, 142.95, 143.07, 150.31, 189.33.
(2£)-1-[6-(Dimethylamino)-2-naphthyl]-3-(2-naph-
thyl) prop-2-en-1-one (14). Yield 67.8%; radial chroma-tography on 2 mm thick silicagel layer using 50% petroleum ether in dichloromethane as the eluent; mp 264-266 °C (from benzene-petroleum ether); Anal. Calcd for C25H21N0 X 0.2 H20: C 84.57; H 6.08; N 3.95. Found C 84t.50; H 5.91; N 4.21; HRMS Calcd for C25H21NO: 351.1623; found 351.1635; 1H NMR 5 3.1^ (s, 6H, NMe2), 6.91 (d, 1H, H-5, J 2.1 Hz); 7.19 (dd, 1H, J 2.1 and 9.0 Hz, H-7); 7.51-7.54 (m, 2H, naphthyl'); 7.70 (d, 1H, J 8.7 Hz, H-4); 7.80-8.06 (m, 9H, COCH=CH, H-8, H-3, 5H naphthyl'); 8.47 (bd, 1H, H-1); 13C NMR 5 40.44, 105.44, 116.28, 122.43, 123.87, 125.18, 126.43, 126.67, 127.26, 127.79, 128.61, 128.64, 130.28, 130.30, 130.78, 131.76, 132.85, 133.46, 134.27, 137.69, 143.63, 150.31, 153.11, 189.38.
(2£)-1-[6-(Dimethylamino)-2-naphthyl]-3-quinolin-3-ylprop-2-en-1-one (15). Yield 60%; radial chromato-graphy on 2 mm thick silicagel layer using 10% petroleum ether in dichloromethane, followed by pure dichlo-romethane and finally, 1% methanol in dichloromethane as the eluent; mp 237-239 °C (from dichloromethane-methanol); Anal. Calcd for C24H20N2O: C 81.79; H 5.72; N 7.95. Found C 81.76; H 5.59; N 8.03; 1H NMR 5 3.13 (s, 6H, NMe2); 6.90 (d, 1H, H-5, J 2.5 Hz); 7.20 (dd, 1H, H-7, J 2.5 and 9.1 Hz); 7.57-7.6 (m 1H, quinolinyl); 7.71 (d, 1H, H-4, J 8.8 Hz); 7.74-7.81(m, 1H, quinolinyl,);
7.85-7.95 (m, 3H, H-8, 1H quinolinyl, COCH=CH); 8.01 (d, 1H, J 15.7 Hz, COCH=CH); 8.06 (dd, 1H, H-3, J 1.7 and 9.2 Hz); 8.14 (d, 1H, quinolinyl, J 8.5 Hz); 8.38 (d, 1H, quinolinyl, , J 2.1 Hz); 8.47 (d, 1H, J 1.7 Hz, H-1); 9.26 (d, 1H, quinolinyl, J 2.1 Hz); 13C NMR 5 40.41, 105.37, 116.31, 123.85, 125.08, 125.10, 126.55, 127.39, 127.82, 128.36, 129.45, 130.49, 130.54, 130.87, 135.73, 137.85, 139.93, 149.56, 150.43, 188.68.
General procedure for the reduction of a,ß-unsatura-ted ketones. To a solution of 3 mmol KOH in 100 mL of ethanol, 1 mmol of Fe(C0)5 was added and the mixture was stirred and gradually heated to boiling under argon. After 2 hours, an ethanolic solution of 1 mmol of the respective a,ß-unsaturated ketone was added and reflux was continued for 2-4 hours. The volume of the reaction mixture was diminished to approximately 30 mL, triturated with water and extracted with diethyl ether. Combined ether extracts were dried and the solvent was removed. From the residue the products were isolated by radial chromatography and purified by recrystallization.
1-(6-Methoxy-2-naphthyl)-3-phenylpropan-1-one (16).
Yield 77%; radial chromatography on 2 mm thick silica-gel layer using 25% petroleum ether in dichloromethane as the eluent; mp 112-113 °C (from benzene-petroleum ether); Anal. Calcd for C2oH18O2: C 82.73, H 6.25. Found C 82.97, H 6.02; 1H NM^ 5 ^.07-3.12 and 3.34-3.39 (m, 4H, C0CH2CH2,); 3.90 (s, 3H,0Me); 7.11 (d, 1H, H-5, J 2.6 Hz); 7.17 (dd, 1H, H-7, J 2.6 and 8.9 Hz); 7.19-7.33 (m, 5H, Ph'); 7.72 (d, 1H, H-4, J 8.6 Hz); 7.78 (d, 1H, H-8, J 8.9 Hz); 7.98 (dd, 1H, H-3, J 1.7 and 8.6 Hz); 8.35 (d, 1H, H-1, J 1.7 Hz); 13C NMR 5 30.29, 40.28, 55.32, 105.69, 119.62, 124.51, 126.05, 127.04, 127.76, 128.39, 128.46, 129.48, 131.02, 132.21, 137.18, 141.40, 159.66, 198.75.
3-(3-Hydroxyphenyl)-1-(6-methoxynaphthalen-2-yl) propan-1-one (17). Yield 33%; radial chromatography on 2 mm thick silicagel layer using 2% methanol in dichloro-methane as the eluent; mp 121-123 °C (from dichloro-methane-petroleum ether); Anal. Calcd for C2qH1803: C 78.41, H 5.92. Found C 78.71, H 5.76; NNMR 5 3.03-3.08 and 3.35-3.40 (m, 4H, COCH2CH2); 3.93 (m, 3H, OMe); 6.69-6.71 (m, 1H, Ph'); 6.78-6.84 (m, 2H, Ph'); 7.12-7.19 (m, 3H, H-5, H-7, 1Ph'), 7.73 (m, 1H, H-4, J 8.6 Hz); 7.79 (m, 1H, H-8, J 9.1 Hz); 7.98 (m, 1H, H-3, J 1.7 and 8.6 Hz); 8.36 (d, 1H, H-1, J 1.7 Hz).
3-(2,6-Dichlorophenyl)-1-(6-methoxynaphthalen-2-yl) propan-1-one (18). Yield 69%; radial chromatography on 4 mm thick silicagel layer using 50% petroleum ether in dich-loromethane as the eluent; mp 93-94 °C (from dich-loromethane-hexane); Anal. Calcd for C2QH15Cl2O2: C 66.87, H 4.49. Found C 67.25, H 4.44; H^^ Calcd for C20H16Cl2O2: 358.0527, found 358.0539; 1H NMR 5
3.31-3.37 and 3.39-3.45 (m, 4H, -COCH2-CH2,); 3.95 (s, 3H, OMe,); 7.08-7.14 (m, 1H, H-4'), 7.15 (d, IH, H-5, J 2.6 Hz); 7.19 (dd, 1H, H-7, J 2.6 and 8.8 Hz); 7.32 (d, 2H, H-3' and H-5'); 7.77 (d, 1H, H-4, J 8.7 Hz); 7.82 (d, 1H, H-8, J 8.8 Hz); 8.04 (dd, 1H, H-3, J 1.7 and 8.7 Hz); 8.42 (d, 1H, H-1, J 1.7 Hz).
3-(Biphenyl-4-yl)-1-(6-methoxynaphthalen-2-yl)pro-pan-1-one (19). Yield 80%; radial chromatography on 4 mm thick silicagel layer using 50% petroleum ether in dichloromethane as the eluent; mp 171-172 °C (from benzene-petroleum ether); Anal. Calcd for C2gH22O2: C 85.22, H 6.05. Found C 85.45, H 6.01; 1H NMR 5 3.13-3.18 and 3.41-3.46 (m, 4H, COCH2CH2,); 3.93 (s, 3H, OMe,); 7.14 (d, 1H, H-5, J 2.5 Hz); 7.19 (dd, 1H, H-7, J 2.5 and 8.9 Hz), 7.29-7.44 (m, 5H, Ph'/Ph''); 7.51-7.59 (m, 4H, Ph'/Ph''); 7.76 (d, 1H, H-4, J 8.7 Hz); 7.81 (d, 1H, H-8, J 8.9 Hz); 8.02 (dd, 1H, H-3, J 1.7 and
8.7	Hz); 8.39 (d, 1H, H-1, J 1.7 Hz); 13C NMR 5 29.98, 40.30, 55.40, 105.77, 119.72, 124.60, 127.01, 127.08,
127.14,	127.27, 127.82, 128.72, 128.90, 129.58, 131.11, 132.29, 137.29, 139.14, 140.58, 141.02, 159.76, 198.80.
1-(6-Methoxynaphthalen-2-yl)-3-(naphthalen-2-yl)pro-pan-1-one (20). Yield 68%; radial chromatography on 1 mm thick silicagel layer using 50% petroleum ether in dichloromethane as the eluent; mp 132-133 °C (from dichloromethane-hexane); Anal. Calcd for C24H20O2: C 84.68, H 5.92. Found C 84.94, H 5.96; 1H NMR 5 3.25-3.30 and 3.46-3.51 (m, 4H, COCH2CH2,); 3.93 (s, 3H, OMe,); 7.14 (d, 1H, H-5, J 2.5 Hz); 7.1^ (dd, 1H, H-7, J 2.5 and 8.9 Hz); 7.39-7.49 (m, 3H, naphthyl'); 7.71-7.82 (m, 6H; H-4, H-8, 4H naphthyl'); 8.02 (dd, 1H, H-3, J 1.7 and 8.7 Hz); 8.39 (1H, H-1, J 1.7 Hz); 13C NMR 5 30.69, 40.29, 55.40, 105.76, 129.72, 124.60, 125.29, 126.01, 126.52, 127.14, 127.22, 127.46, 127.62, 127.85, 128.11, 129.57, 131.11, 132.12, 132.30, 133.68, 137.28, 138.97, 159.76, 198.80.
1-(6-Methoxynaphthalen-2-yl)-3-(quinolin-3-yl)pro-pan-1-one (21). Yield 75%; radial chromatography on 1 mm thick silicagel layer first using dichloromethane and later 1% methanol in dichloromethane as the eluent; mp 135-137 °C; Anal. Calcd for C23H19NO2: C 80.92, H 5.61, N 4.10. Found 80.45, 5.43, ISf 4.33; HRMS Calcd for C23H19NO2: 341.1416, found 341.1427; 1H NMR 5 3.2237-139.32 2and 3.46-3.51 (m, 4H, COCH2CH2); 3.91 (s, OMe); 7.12 (d, 1H, J 2.4 Hz, H-5); 7.18 (dd, 1H, J 2.4 and 9.0 Hz, H-7); 7.47-7.53 (m, 1H, quinolinyl); 7.62-7.67 (m, 1H, quinolinyl); 7.76 (d, 1H, J 8.7 Hz, H-4); 7.78 (m, 1H, quinolinyl); 7.82 (d, 1H, J 9.0 Hz, H-8); 8.01 (dd, 1H, J 1.8 and 8.7 Hz, H-3), 8.05 (d, 1H, J 1.5 Hz, quinolinyl);
8.08	(d, 1H, J 8.7 Hz, quinolinyl); 8.39 (d, 1H, J 1.8 Hz, H-1); 8.90 (d, 1H, J 1.9 Hz, quinolinyl); 13C NMR 5 27.38, l39.56, 55.34, 105.71, 119.73, 124.40, 126.59,
127.15,	127.32, 127.72, 128.04, 128.70, 129.12, 129.49,
130.94, 132.00, 134.04, 134.20, 137.28, 146.89, 151.84, 159.76, 197.94.
1-[6-(Dimethylamino)naphthalen-2-yl]-3-phenylpro-pan-1-one (22). Yield 72%; radial chromatography on 2 mm thick silicagel layer using 50% petroleum ether in dichloromethane as the eluent; mp 125-127 °C (from dichloromethane-petroleum ether); Anal. Calcd for C21H21NO: C 83.13, H 6.98; N 4.62. Found C 83.57, H 7.2010,2 1N 4.67; HRMS Calcd for C21H21NO: 303.1623, found 303.1612; 1H NMR 5 3.13-3;17 (m, 8H, CH2CH2 and NMe2); 3.38-3.43 (m, 2H, CH2-CH2,); 6.89 (d2 1H, H-5, J 2.^ Hz); 7.18 (dd, 1H, H-7, J 2;6 and 9.0 Hz); 7.24-7.34 (m, 5H, Ph'); 7.66 (d, 1H, H-4, J 8.8 Hz); 7.79 (d, 1H, H-8, J 9.0 Hz); 7.96 (dd, 1H, H-3, J 1.8 and 8.8 Hz); 8.34 (d, 1H, H-1, J 1.8 Hz); 13C NMR 5 30.53, 40.20, 40.4, 105.31, 116.26, 124.52, 125.06, 126.03, 126.19, 128.46, 128.49, 129.85, 130.41, 130.68, 137.66, 141.67, 150.24, 198.68.
1-[6-(Dimethylamino)naphthalen-2-yl]-3-(3-hydroxy-phenyl)propan-1-one (23). Yield 52%; radial chromato-graphy on 2 mm thick silicagel layer first using 30% hexa-ne in dichloromethane, then dichloromethane and finally 1% methanol in dichloromethane as the eluent; mp 148-149 °C (from dichloromethane-petroleum ether); Anal. Calcd for C21H21NO2: C 78.97; H 6.63; N 4.39. Found C 78.63; ^ ^.65; N 4.26; HRMS Calcd for C21H21NO2: 319.1573, found 319.1585; 1H NMR 5 3.01-^.07 (m, 8H, NMe2 and CH2-CH2); 3.31-3.36 (m, 2H, CH.-CH,); 5.64 (s2 1H, OH); 6.(59 (m, 1H, Ph'); 6.77-6.84 (m, 3H, H-5 and 2Ph'); 7.11-7.18 (m, 2H, H7, 1Ph'), 7.60 (d, 1H, H-4, J 8.7 Hz); 7.73(d, 1H, H-8, J 9.0 Hz); 7.90 (dd, 1H, H-3, J 1.9 and 8.7 Hz); 8.28 (d, 1H, H-1, J 1.9 Hz); 13C NMR 5 30.41, 40.05, 40.55, 105.30, 113.14, 115.76, 116.27, 120.60, 124.47, 125.01, 126.22, 129.65, 130.08, 130.18, 130.72, 137.71, 143.33, 150.27, 155.98, 199.32.
Alternatively, 23 was prepared by nucleophilic aromatic substitution.1 Dimethylamine was bubbled into a mixture of dry, freshly distilled HMPT (5 mL) and toluene (6 mL) until 1.6 g (35.6 mmol) was dissolved. To the solution, lithium metal (200 mg, 22.8 mmol) in small pieces was added and the mixture was stirred under argon until all the metal has dissolved. Methoxy derivative 17 was added (348 mg, 1.19 mmol) and stirring was continued for 48 hours. The reaction mixture was diluted with brine and extracted with dichloromethane (3 x 20 mL). Combined organic extracts were washed with brine, dried and evaporated. From the residue the compound 23 was isolated as described above in 49% yield.
3-(2,6-Dichlorophenyl)-1-[6-(dimethylamino)naphtha-len-2-yl]propan-1-one (24). Yield 51%; radial chromato-graphy on 4 mm thick silicagel layer using 50% petroleum ether in dichloromethane as the eluent; mp 148-149
°C (from dichloromethane-hexane); Anal. Calcd for C21H19Cl2NO: C 67.75; H 5.14; N 3.76. Found C 67.77; H 5.09; N 3.57; 1H NMR 5 3.096 (s, 6H, NMe2); 3.28-3.34 and 3.38-3.44 (m, 4H, COCH2CH2); 6.86 (d, 1H, H-5, J 2.2 Hz); 7.07-7.17 (m, 2H, H-7 and 1Ph'); 7.31 (m, 2H, Ph'); 7.63 (d, 1H, H-4, J 8.7 Hz); 7.76 (d, 1H, H-8, J 9.0 Hz); 7.95 (dd, 1H, H-3, J 1.9 and 8.7 Hz); 8.34 (d, 1H, H-1; J 1.9 Hz); 13C NMR 5 26.55, 36.42, 40.41, 105.33, 116.47, 124.50, 125.07, 126.22, 127.85, 127.94, 129.99,
130.21,	130.7, 135.46, 137.48, 137.73, 150.47, 198.14.
3-Biphenyl-4-yl-1-[6-(dimethylamino)-2-naphthyl] propan-1-one (25). Yield 75.4%; radial chromatography on 2 mm thick silicagel layer using 50% petroleum ether in dichloromethane as the eluent; mp 180-183 °C (from dichloromethane-hexane); Anal. Calcd for C27H25NO: C 85.45; H 6.64; N 3.69. Found C 85.4; H 6.64; N 3.56; 1H NMR 5 3.05 (s, 6H, NMe2); 3.11-3.16 and 3.35-3.41 (m, 4H, C0CH2-CH2); 6.83 (1H, d, H-5, J 2.6 Hz); 7.11 (1H, dd, H-7, J 2.6 and 9.0 Hz); 7.28-7.43 (m, 5H, Ph'/Ph''), 7.50-7.58(m, 4H, Ph'/Ph''); 7.61 (1H, d, H-4, J 8.7 Hz); 7.74 (1H, d, H-8, J 9.0 Hz); 7.93 (1H, dd, H-3, J 1.6 and 8.7 Hz), 8.31(d, 1H, H-1, J 1.6 Hz); 13C NMR 5 30.07, 40.04, 40.32, 105.24, 116.22, 124.46, 125.01, 126.17, 126.96, 127.00, 127.17, 128.67, 128.85, 129.84, 130.33, 130.63, 137.63, 138.97, 140.75, 140.99, 150.18, 198.54.
1-[6-(Dimethylamino)-2-naphthyl]-3-(2-naphthyl)pro-pan-1-one (26). Yield 85%; radial chromatography on 4 mm thick silicagel layer using 50% hexane in dichloro-methane as the eluent; mp 167-168 °C (from dichloro-methane-hexane); Anal. Calcd for C25H23NO: C 84.95; H 6.56; N 3.96. Found C 85.02; H 6.54; N 4.16; HRMS Calcd for C25H23NO: 353.1780; found 353.1792; 1H NMR 5 3.02 (s, ^H, NMe2); 3.21-3.26 and 3.38-3.43 (m, 4H, COCH(CH(); 6.81 (d, 1H, H-5, J 2.5 Hz); 7.09 (dd, 1H, J 2.5 and 9.0 Hz, H-7); 7.36-7.45 (m, 3H, naphthyl'); 7.59 (d, 1H, J 8.7 Hz, H-4); 7.68-7.79 (m, 5H, H-8 and 4H naphthyl'); 7.93 (dd, 1H, J 1.5 and 8.7 Hz, H-3); 8.29 (d, 1H, J 1.5 Hz, H-1); 13C NMR 5 30.57, 40.27, 105.18, 116.18, 124.45, 124.98, 125.18, 125.89, 126.15, 126.41,
127.22,	127.41, 127.55, 127.99, 129.81, 130.31, 130.61, 132.03, 133.61, 137.62, 139.13, 150.16, 198.50.
1-[6-(Dimethylamino)-2-naphthyl]-3-quinolin-3-ylpro-pan-1-one (27). Yield 52%; radial chromatography on 2 mm thick silicagel layer first using dichloromethane followed by 1% methanol in dichloromethane as the eluent; mp 155-158 °C (from dichloromethane-hexane); Anal. Calcd for C(4H((N(O x 0.3 H(0 C 80.11; H 6.33; N 7.78. Found C 80.09; H 6.20; N 7.53; HRMS Calcd for C(4H((N(O1: 354.1732; found 354.1745; 1H NMR 5 3.08 (s, 6H, NMe(); 3.27-3.32 and 3.45-3.50 (m, 4H, COCH(CH(); 6.84 (d, 1H, J 2.6 Hz, H-5); 7.14 (dd, 1H, J 2.6 and 9.0 Hz, H-7); 7.48-7.53 (m, 1H, quinolinyl); 7.60-7.67 (m, 2H, H-4, 1H quinolinyl); 7.74-7.77 (m, 2H,
H-8, 1H quinolinyl); 7.92 (dd, 1H, J 1.7 and 9.0 Hz, H-3); 8.02 (d, 1H, J 1.5 Hz, quinolinyl); 8.08 (d, 1H, J= 8.6 Hz, quinolinyl), 8.31 (d, 1H, J 1.7 Hz, H-1); 8.89 (d, 1H, J 2.3 Hz, quinolinyl); 13C NMR 5 27.59, 39.51, 40.34, 105.22, 116.27, 124.37, 124.95, 126.25, 126.57, 127.37, 128.10, 128.66, 129.15, 129.85, 130.13, 130.66, 134.29, 134.46, 137.72, 146.92, 150.27, 151.95, 197.77.
General procedure for the Knoevenagel condensation.
To the solution of a ketone (1 mmol) in pyridine (5 mL) malononitrile (330 mg, 5 mmol) was added and the reaction mixture was heated at 78-80° for 57 hours. Pyridinie was removed under vacuum and from the residue the product was isolated by radial chromatography and re-crystallized.
{1-[6-(Dimethylamino)-2-naphthyl]-3-phenylpropyli-dene}malononitrile (28). Yield 69%; radial chromato-graphy on 2 mm thick silicagel layer first using 30% petroleum ether in dichloromethane followed by 10% petroleum ether in dichloromethane as the eluent; mp 146-147 °C (from dichloromethane-hexane); Anal. Calcd for C(4H(1N3: C 82.02%; H 6.02%; N 11.96%; found C 8^.20"%; H 5.99%; N 11.76%; 1H NMR 5 2.76-2.81 and 3.30-3.35 (m, 4H, COCH(CH(); 3.12 (s, 6H, NMe(); 6.87 (d, 1H, J 2.6 Hz; H-5); 7.10-7.13 (m, 2H, Ph'); 7.18 (dd, 1H, J 2.6 and 9.1 Hz, H-7); 7.25-7.31 (m, 3H, Ph'); 7.46 (dd, 1H, J 1.9 and 8.7 Hz, H-3); 7.69 (d, 1H, J 8.6 Hz, H-4); 7.76 (d, 1H, J 9.1 Hz, H-8); 7.91 (d, 1H, J 1.9 Hz, H-1); 13C NMR 5 34.87, 38.84, 40.36, 105.14, 113.51, 113.89, 116.94, 124.44, 125.19, 126.79, 126.86, 126.98, 128.41, 128.67, 129.31, 130.40, 137.31, 138.90, 150.46, 177.94.
{1-[6-(Dimethylamino)-2-naphthyl]-3-(3-hydroxyp-henyl)propylidene}malononitrile (29). Yield 25%; radial chromatography on 2 mm thick silicagel layer first using dichloromethane and later 1% methanol in dichloro-methane as the eluent; mp 179-181 °C (from dichloro-methane-methanol); Anal. Calcd for C(4H(1N3O x 0.5 H(0 C 76.57%; H 5.89%; N 11.16%; found C 76.15%; H 5.53%; N 11.03%; HRMS Calcd for C(4H(1N3O: 367.1685 found 367.1692; 1H NMR 5 2.72-:2.77) and 3.29-3.35 (m, 4H, CH(CH(); 3.13 (s, 6H, NMe(); 6.60-6.61 (m, 1H, Ph'); 6.66-6.71 (m, 2H, Ph'); 6.88 (d, 1H, J 2.6 Hz, H-5); 7.12-7.21 (m, 2H, H-7 and Ph'); 7.47 (dd, 1H, J 2.1 and 8.6 Hz, H-3); 7.69 (d, 1H, J 8.6 Hz, H-4); 7.77 (d, 1H, J 9.0 Hz, H-8); 7.92 (d, 1H, J 2.1 Hz, H-1); 13C NMR 5 34.76, 38.733, 40.42, 81.85, 105.20, 113.60, 113.86, 115.36, 116.79, 120.87, 124.47, 125.24, 126.92, 126.98, 129.36, 129.95, 130.47, 137.17, 140.75, 150.52, 155.82, 177.94.
{3-(2,6-Dichlorophenyl)-1-[6-(dimethylamino)-2-naphthyl]propylidene}malononitrile (30). Yield 76%; radial chromatography on 1 mm thick silicagel layer using
40% petroleum ether in dichloromethane as the eluent; mp 158-161 °C (from dichloromethane-hexane); HRMS Calcd for C2IH19Cl2N3: 419.0956; found 419.0968; 1H NMR 5 3.08^3.1^ (m, ^H, CH2CH2 and NMe2); 3.31-3.36 (m, 2H, CH2CH2); 6.85 (d, 1H, J 2.6 Hz, H-^); 7.02-7.07 (m, 1H, Ph'); 7.15-7.25 (m, 3H, H-7 and Ph'); 7.61 (dd, 1H, J 1.9 and 8.7 Hz, H-3); 7.70 (m, 1H, H-4); 7.78 (m, 1H, H-8); 8.06 (d, 1H, J 1.9 Hz, H-1).
{3-Biphenyl-4-yl-1-[6-(dimethylamino)-2-naphthyl] propylidene}malononitrile (31). Yield 33%; radial chro-matography on 1 mm thick silicagel layer first using 50% petroleum ether in dichloromethane followed by 10% petroleum ether in dichloromethane as the eluent; mp 171-173 °C (from dichloromethane-hexane); HRMS Calcd for C3oH25N3: 427.2048, found 427.2051; 1H NMR 5 2.85-2.90 and 3.38-3.43 (m, 4H, CH2CH2); 3.17 (s, 6H, NMe2); 6.90 (d, 1H, J 2.3 Hz, H-5); 7.19-7.22 (m, 3H, H-7, Ph'/Ph''); 7.35-7.59 (m, 8H, H-3, Ph'/Ph''); 7.72 (d, 1H, J 8.6 Hz, H-4); 7.78 (d, 1H, J 9.4 Hz, H-8); 7.95 (bd, 1H, H-1).
{1-[6-(Dimethylamino)-2-naphthyl]-3-(2-naphthyl) propylidene}malononitrile (32). Yield 40%; radial chro-matography on 1 mm thick silicagel layer using 30% petroleum ether in dichloromethane as the eluent; mp 163-165 °C (from dichloromethane-hexane); Anal. Calcd for C28H23N3 X 0.2H2O: C 83.02%; H 5.82%; N 10.37%; found C ^2.90%; H 5.57%; N 10.02%; HRMS Calcd for C28H23N3: 401.1892; found 401.1905; 1H NMR 5 2.93-2.SI9 and 3.41-3.46 (m, 4H, CH2CH2); 3.13(s, 6H, NMe2); 6.88(d, 1H, J 2.6 Hz, H-5); 7.20(dd, 1H, J 2.6 and 9.0 ^z, H-7); 7.28-7.50 (m, 5H, H-3, naphthyl'); 7.69-7.82 (m, 5H, H-4, H-8, 3H naphthyl'); 7.92(d, 1H, J 1.9 Hz, H-1); 13C NMR 5 35.06, 38.74, 40.42, 105.21, 113.57, 113.85, 116.79, 124.49, 125.25, 125.70, 126.24, 126.68, 126.88, 126.94, 127.05, 127.52, 127.70, 128.477, 129.37, 130.44, 132.37, 136.35, 137.16, 178.01.
{1-[6-(Dimethylamino)-2-naphthyl]-3-quinolin-3-ylpro-pylidene}malononitrile (33). Yield 35%; radial chroma-tography on 2 mm thick silicagel layer first using dichlo-romethane and later 1% methanol in dichloromethane as the eluent; mp 208-210 °C (from dichloromethane-met-hanol); Anal. Calcd for C27H22N4: C 80.57%; H 5.51%; N 13.92%; found C 80.37%; H 5.34%; N 13.65%; HRMS Calcd for C27H22N4: 402.1844; found 402.1857; 1H NMR 5 2.97-3.02 and 3.42-3.48(m, 4H, COCH2CH2); 3.13(s, 6H, NMe2); 6.87(d, 1H, J2.4 Hz, H-5); 7.19 (dd, 1H, J2.4 and 9.1 ^z, H-7); 7.47(dd, 1H, J 1.87 and 8.6, H-3); 7.51-7.56(m, 1H, quinolinyl); 7.66-7.71(m, 2H, H-4, qui-nolinyl); 7.74-7.77 (m, 2H, H-8, quinolinyl); 7.91-7.94 (m, 2H, H-1, quinolinyl); 8.07(d, 1H, J 8.3 Hz, quinolinyl); 8.64(d, 1H, J 2.3 Hz, quinolinyl); 13C NMR 5 32.08, 38.25, 40.39, 105.15, 113.49, 113.68, 116.86, 124.308, 125.21, 126.60, 126.98, 127.12, 127.47, 127.90,
129.27, 129.40, 130.48, 131.53, 134.81, 137.25, 147.25, 150.60, 151.14, 177.04.
5. Acknowledgment
Financial support from the Slovenian Research Agency (P1-0230-0103) is gratefully acknowledged. Special thanks are extended to Dr. B. Kralj and Dr. D. Žigon (Jožef Stefan Institute, Ljubljana, Slovenia) for MS measurements.
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Povzetek
Molekulo spojine vodnice DDNP smo spremenili tako, da smo nanjo preko etilidenske skupine vezali aromatski obroc. Tako smo pripravili serijo analogov FDDNP, spojine, ki služi kot molekularna sonda za opazovanje izločanja proteinskih agregatov v centralnem živčnem sistemu. Sintetizirani analogi kažejo podobne optične lastnosti kot DDNP/FDDNP in tako izpolnjujejo pogoj za uspešno uporabo v fluorescenčni mikroskopiji. Dodatni aromatski obroč nudi dodatno možnost za n-interakcije med molekulo in proteinskimi agregati.