Pd(0)-catalyzed amination in the synthesis of bicyclic compounds comprising triazacycloalkane and fluorophore moieties Текст научной статьи по специальности «Химические науки»

Cryptands

Криптанды

Макрогэтэроцмклы

Статья

Paper

http://macroheterocycles.isuct.ru

DOI: 10.6060/mhc171255a

Pd(0)-Catalyzed Amination in the Synthesis of Bicyclic Compounds Comprising Triazacycloalkane and Fluorophore Moieties

Alexei D. Averin,a'b@ Nataliya M. Chernichenko,a Vadim N. Shevchuk,a Olga A. Maloshitskaya,a Franck Denat,c and Irina P. Beletskayaab

aLomonosov Moscow State University, Department of Chemistry, 119991 Moscow, Russia hA.N. Frumkin Institute of Physical Chemistry and Electrochemistry RAS, 119991 Moscow, Russia cICMUB UMR6302, CNRS, Université Bourgogne Franche-Comté, 21000 Dijon, France ®Corresponding author E-mail: alexaveron@yandex.ru

Direct introduction of one dansyl fluorophore group into the molecule of 1,4,7-triazacyclononane (TACN) and 1,5,9-triazacyclododecane (TACD) was shown to be possible followed by the modification of triazacycles with two bromobenzyl substituents. The resulting compounds were used in the Pd(0)-catalyzed macrocyclization reaction with 1,13-diaza-4,7,10-trioxatridecane to provide corresponding cryptands. The synthesis of bicyclic derivatives of TACN bearing naphthyl and acridinyl fluorophore groups was accomplished via an alternative procedure using aminal-protected TACN. The possibility to form tetracyclic compounds starting from N,N',N"-tris(3-bromobenzyl) substituted TACN was demonstrated. Three cryptands bearing dansyl fluorophore were tested as potential fluorescent chemosensors for metal cations and were found to act as molecular fluorescent probes for Cu(II) and Al(III) by total emission quenching in the presence of these cations.

Keywords: Pd Catalysis, triazacycles, amination, cryptands, fluorescence.

Pd(0)-Катализируемое аминирование в синтезе бициклических соединений, содержащих триазациклоалкановые и флуорофорные фрагменты

А. Д. Аверин,a'b@ Н. М. Черниченко,а В. Н. Шевчук,a О. А. Малошицкая,а Ф. Дена,с И. П. Белецкая^

Московский государственный университет им. М.В. Ломоносова, Химический факультет, 119991 Москва, Россия ьИнститут физической химии и электрохимии им. А.Н. Фрумкина РАН, 119071 Москва, Россия Институт молекулярной химии Университета Бургундии и Франш-Конте, 21000 Дижон, Франция @Е-таИ: alexaveron@yandex.ru

Показана возможность прямого введения одной дансильной флуорофорной группы в молекулу 1,4,7-триаза-циклононана (ТАЦН) и 1,5,9-триазациклододекана (ТАЦД) с последующей модификацией триазациклов двумя бромбензильными заместителями. Полученные соединения использованы в Pd(0)-катализируемой макроциклизации с 1,13-диаза-4,7,10-триоксатридеканом с образованием соответствующих криптандов. С использованием альтернативного подхода через ТАЦН с аминальной защитой были синтезированы бициклы, содержащие нафтильный и акридинильный флуорофоры. Продемонстрирована возможность получения тетрациклических соединений различного строения исходя из N,N',N"-трис(3-бромбензил) замещенного ТАЦН. Три криптанда исследованы в качестве флуоресцентных детекторов катионов металлов и показана их возможность выступать в качестве молекулярных проб на катионы Си(11) и А1(Ш) за счет полного тушения флуоресценции в присутствии данных металлов.

Ключевые слова: Pd Катализ, триазациклы, аминирование, криптанды, флуоресценция.

Introduction

One of the important tasks of the modern organic chemistry is the search for new chemosensors able of selective detection of metal cations. Chemosensors exploiting fluorescence for producing analytical response possess many favorable features like higher sensitivity and selectivity compared to colorimetric detectors, possibility to create ratiometric sensors. At present time many examples of the derivatives of crown and azacrown ethers,[1] calix[4] arene,[2] and thiacalix[4]arene,[3] tetraazamacrocycles[4] bearing fluorescent groups have been described in literature. A special interest paid to 1,4,7-triazacyclononane (TACN) and compounds produced on its basis arises from the application of their metal complexes primarily in the synthesis of bifunctional radiopharmaceuticals capable of selective coordination of mIn, 67/68Ga, 64/67Cu, 90Y, and 99mTc cat-ions[5] which often possess additional chelating carboxylate and phosphonate arms.[6] Till now the data on the fluorescent derivatives of TACN used as chemosensors are quite scarce. One can cite the reports on the tridansyl (dansyl=5-dimeth-ylamino-1-sulphonylnaphthalene) substituted triazacyclo-nonane,[7] benzothiazole derivative bearing two additional pyridylmethyl arms,[8] TACN modified with pyrene fluoro-phore.[9] The tridansyl derivative was used as a fluorescent chemosensor for Ag(I) and Cu(II) cations, and the compounds bearing this fluorophore group attached to various ionophores were described for the detection of Hg(I),[10] Cu(II),[11] Pb(II),[12] Tl(I), Cs(I),[13] and Hg(I)[14] cations. No information can be found about the synthesis of bicyclic compounds comprising TACN unit and their application for detecting metal ions though cryptand-like structures are of special interest due to their special character of binding cations. In our previous research we successfully applied Pd(0)-catalyzed amination reaction to the synthesis of mac-rocyclic[15] and polymacrocyclic[16] compounds and began the studies of their coordination abilities towards metal cations. The first examples of the porphyrin-derived conjugates were shown to be promising fluorescent chemosensors for Cu(II) cations.[17] In this work we develop this approach in the synthesis of bicyclic compounds comprising triazacy-cloalkane units and fluorophore groups.

Experimental

NMR spectra were registered using Bruker Avance 400 spectrometer, MALDI-TOF spectra were obtained with Bruker Autoflex II spectrometer using 1,8,9-trihydroxyanthracene as matrix and PEGs as internal standards. UV-Vis spectra were recorded with Agilent Cary 60 spectrophotometer in MeCN, spectra of fluorescence were obtained with Horiba Jobin Yvon Fluoromax 2 spectrofluorometer in acetonitrile (UHPLC grade). 1,4,7-Triazacyclononane (TACN) and 1,5,9-triazacyclododecane (TACD) were provided by CheMatech Co (Dijon, France), 3- and 4-bromobenzyl bromides, trioxadiamine, 1-aza-15-crown-5 ether, tris(2-aminoethyl)amine, benzaldehyde, dansyl chloride (dansyl=5-dimethylamino-1-sulphonylnaphthalene), 2-bromo-and 2-(chloromethyl)naphthalene, 9-(bromomethyl)acridine, rac-BINAP and DavePhos ligands, sodium tert-butoxide, were purchased from Sigma-Aldrich Co and used without further purification, Pd(dba)2 was synthesized according to the method

described.1181 Acetonitrile of UHPLC grade was used without additional purification, dioxane was successively distilled over NaOH and sodium. Chloroform was distilled over P2O5, dichloromethane was distilled over CaH2, methanol was used freshly distilled.

Method for the synthesis of dansyl derivatives of triazacy-cloalkanes 3, 4. A one-neck flask equipped with a magnetic stirrer was charged with TACN (1) or TACD (2) (2-3 mmol) in acetonitrile, potassium carbonate and the diluted solution of dansyl chloride in acetonitrile was added slowly dropwise during ca 4 h. The residue was filtered off, washed with chloroform (in the case of TACN derivatives) or dichloromethane (in the case of TACD derivatives) (5 ml), the combined organic fractions were evaporated in vacuo and chromatographed on silica gel using a sequence of eluents: CHCL,CHCL-MeOH 100:1-2:1, CHCL-MeOH- NH,

3*3 5 3 3aq

100:20:1-100:20:2 (for TACN derivative) or CH2Cl2, CH2Cl2-MeOH 100:1-2:1 (for TACD derivative).

5-(1,4,7-Triazacyclononan-1-ylsulfonyl)-N,N-dimethylnaph-thalene-1-amine (3). Obtained from TACN (1) (387 mg, 3 mmol), dansyl chloride (540 mg, 2 mmol) in the presence of potassium carbonate (2070 mg, 15 mmol) in 105 ml acetonitrile. Eluent: CHCl3 -MeOH-NH3aq 100:20:1-100:20:2, yellow viscous oil. Yield 493 mg (68 %). m/z (MALDI-TOF) found: 363.1815. C18H27N4O2S requires 363.1849 [M+H]+. 'H NMR (CDCl3, 298 K) SH ppm: 1.94 (2H, br. s, NH), 2.82 (6H, s, CH3), 2.84 (4H, s, CH2NH), 3.02-3.06 (4H, m, CH2NH), 3.33-3.37 (4H, m, CH2NS), 7.13 (1H, d, 3J=7.6 Hz, H6(Nf)), 7.45 (1H, dd, 3J=8.5 Hz, 3J=7.3 Hz, H3(Nf)), 7.50 (1H, dd, 3J=8.7 Hz, 3J=7.6 Hz, H7(Nf)), 7.49 (1H, dd, 3J=7.3 Hz, 4J=1.0 Hz, H2(Nf)), 8.43 (1H, d, 3J=8.7 Hz, H8(Nf)), 8.47 (1H, d, 3J=8.5 Hz, H4(Nf)). 13C NMR (CDCl3, 298 K) Sc ppm: 45.2 (2C, CH3), 49.2 (2C, CH2NH), 49.3 (2C, CH2NH), 537 (2C, CH2NS), 115.1 (1C, CH(Nf)), 119.6 (1C, CH(Nf)), 122.9 (1C, CH(Nf)), 127.9 (1C, CH(Nf)), 128.0 (1C, CH(Nf)), 129.9 (1C, CH(Nf)), 130.1 (1C, C(Nf)), 130.2 (1C, C(Nf)), 135.5 (1C, C(Nf)), 151.5 (1C, NC(Nf)).

5,5'-(1,4,7-Triazacyclononan-1,4-diylsulfonyl)bis(N,N-dimethylnaphthalene-1-amine) (5). Obtained as the second product in the synthesis of compound 3. Eluent: CHCl3 - MeOH 15:1, yellow viscous oil. Yield 172 mg (29 %). m/z (MALDI-TOF) found: 596.2319. C30H38N5O4S2 requires 596.2360 [M+H]+. 'H NMR (CDCl3, 298 K) SH ppm: 1.83 (1H, br. s, NH), 2.85 (12H, s, CH3), 3.19-3324 (4H, m, CH2NH), 3.41-3.45 (4H, m, CH2NS), 3.67 (4H, s, CH2NS), 7.16 (2H, d, 3J=7.6 Hz, H6(Nf)), 7.48 (2H, dd, 3J=8.5 Hz, 3J=7.5 Hz, H3(Nf)), 7.53 (2H, dd, 3J=8.7 Hz, 3J=7.6 Hz, H7(Nf)), 7.96 (2H, dd, 3J=7.5 Hz, 4J=1.0 Hz, H2(Nf)), 8.41 (2H, d, 3J=8.7 Hz, H8(Nf)), 8.51 (2H, d, 3J=8.5 Hz, H4(Nf)). 13C NMR (CDCl3, 298 K) Sc ppm: 45.3 (4C, CH3), 48.5 (2C, CH2NH), 52.7 (2C, CH2NS), 53.7 (2C, CH2NS), 115.3 (2C, CH(Nf)), 119.4 (2C, CH(Nf)), 120.0 (2C, CH(Nf)), 128.2 (4C, CH(Nf)), 130.2 (4C, C(Nf), CH(Nf)), 130.3 (2C, C(Nf)), 134.2 (2C, C(Nf)), 151.7 (2C, NC(Nf)).

5-((1,5,9-Triazacyclododecan-1-yl)sufonyl)-N,N-dimethylna-phthalene-1-amine (4). Obtained from TACD (2) (342 mg, 2 mmol) and dansyl chloride (378 mg, 1.4 mmol) in the presence of potassium carbonate (1380 mg, 10 mmol) in 70 ml acetonitrile. Eluent: CH2Cl2-MeOH 5:1, yellow viscous oil. Yield 166 mg (28 %). m/z (MA LDI-TOF) found: 405.2357. C21H33N4O2S requires 405.2324 [M+H]+. 'H NMR (CDCl3, 298 K) SH ppm: 1.83 (2H, quintet, 3J=5.2 Hz, CCH2C), 2.06 (4H, quintet, 3J=5.7 Hz, CCH2C), 2.84 (6H, s, CH3), 2.99 (4H, t, 3J=5.4 Hz, CH2N), 3.07 (4H, t, 3J=52 Hz, CH2N), 3.13 (4H, t, 3J=6.1 Hz, CH2N), 7.14 (1H, d, 3J=7.5 Hz, H6(Nf)), 7.47-7.53 (2H, m, H3, H7(Nf)), 8.07 (1H, d, 3J=7.5 Hz, H2(Nf)), 8.47 (1H, d, 3J=8.6 Hz, H8(Nf)), 8.55 (1H, d, 3J=8.5 Hz, H4(Nf)), two NH protons were not unambiguously assigned. 13C NMR (CDCl3, 298 K) Sc ppm: 22.1 (1C, CCH2C), 25.7 (2C, CCH2C), 45.1 (2C, CH2N), 45.3 (2C, CH3), 49.1 (2C, CH2N), 50.0 (2C, CH2N), 115.3 (1C, CH(Nf)), 119.0 (1C, CH(Nf)), 123.0 (1C, CH(Nf)), 128.2 (1C, CH(Nf)), 130.1 (1C, C(Nf)), 130.7 (1C, CH(Nf)), 131.0 (2C, CH(Nf), C(Nf)), 131.2 (1C, C(Nf)), 151.7 (1C, NC(Nf)).

5,5'-(1,5,9-Triazacyclododecane-1,5-diylsulfonyl)bis(N,N-dimethylnaphthalene-1-amine) (6). Obtained as the second product in the synthesis of compound 4. Eluent: CH2Cl2-MeOH 20:1, yellow crystalline powder, m.p. 158-160 °C. Yield 288 mg (65 %). m/z (MALDI-TOF) found: 638.2809. C33H44N5O4S2 requires 638.2835 [M+H]+. 'H NMR (CDCl3, 298 K) SH ppm: L67 (4H, quintet, 3J=5.5 Hz, CCH2C), 1.87 (4H, quintet, 3J=6.9 Hz, CCH2C), 2.61 (2H, t, 3J=5.4 Hz, CH2N), 2.87 (12H, s, CH3), 3.20 (4H, t, 3J=6.9 Hz, CH2N), 3.27 (4H, t, 3J=5.9 Hz, CH2N), 7.16 (2H, d, 3J=7.5 Hz, H6(Nf)), 7.47-7.53 (4H, m, H3, H7(Nf)), 8.14 (2H, dd, 3J=7.3 Hz, 4J=0.8 Hz, H2(Nf)), 8.35 (2H, d, 3J=8.7 Hz, H8(Nf)), 8.52 (2H, d, 3J=8.5 Hz, H4(Nf)), NH proton was not assigned. 13C NMR (CDCl3, 298 K) 5c ppm: 23.8 (1C, CCH2C), 27.8 (2C, CCH2C), 42.9 (2C, CH2N), 454 (6C, CH3, CH2N), 45.8 (2C, CH2N), 115.1 (2C, CH(Nf)), 119.6 (2C, CH(Nf)), 123.1 (2C, CH(Nf)), 127.9 (2C, CH(Nf)), 130.0 (2C, C(Nf)), 130.1 (2C, CH(Nf)), 130.3 (4C, CH(Nf), C(Nf)), 134.0 (2C, C(Nf)), 135.6 (2C, NC(Nf)).

Method for the synthesis of dansyl and bromobenzyl derivatives of triazacycloalkanes 7-9. A one-neck flask equipped with a magnetic stirrer was charged with a corresponding dan-syl derivative of TACN (3) or TACD (4) which was solubilized in 0.3-0.5 ml dichloromethane, then acetonitrile (2-8 ml) was added to make a solution, followed by potassium carbonate, then appropriate bromobenzyl bromide was added in one portion. The reaction mixture was stirred at ambient temperature for 24 h, then the residue was filtered off, washed with dichloromethane (5 ml), the combined organic fractions were evaporated in vacuo and, if necessary, chromatographed on silica gel using a sequence of eluents: CH2Cl2, CH2Cl2-MeOH 100:1-2:1. In the case when chromatographic purification was unnecessary, the reaction mixture was dissolved in 5 ml dichloromethane, washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to dryness.

5-(4,7-Bis(3-bromobenzyl)-1,4,7-triazacyclononan-1-ylsulfonyl)-N,N-dimethylnaphthalene-1-amine (7). Obtained from compound 3 (405 mg, 1.12 mmol), 3-bromobenzyl bromide (500 mg, 2 mmol) in the presence of potassium carbonate (770 mg, 5.58 mmol) in 6 ml acetonitrile. Yellow glassy solid. Yield 577 mg (83 %). m/z (MALDI-TOF) found: 699.1034. C32H37Br2N4O2S requires 699.1004 [M+H]+. 'H NMR (CDCl3, 2938 K) SH ppm: 2.68 (4H, br. s, CH2N), 2.84 (6H, s, CH3), 3.04 (4H, br. s, CH2N), 3.45 (4H, br. s, CH2NS), 3.60 (4H, s, PhCH2N), 7.13-7.18 (3H, m, H6(Nf), H5(Ph)), 7.23 (2H, br. s, H6(Ph)), 7.35 (2H, d, 3J=7.8 Hz, H4(Ph)), 7.44 (2H, br. s, H2(Ph)), 7.47 (1H, dd, 3J=8.5 Hz, 3J=7.5 Hz, H3(Nf)), 7.53 (1H, dd, 3J=8.7 Hz, 3J=777 Hz, H7(Nf)), 8.01 (1H, dd, 3J=7.5 Hz, 4J=0.9 Hz, H2(Nf)), 8.43 (1H, d, 3J=8.7 Hz, H8(Nf)), 8.49 (1H, d, 3J=8.5 Hz, H4(Nf)). 13C NMR (CDCl3, 298 K) Sc ppm: 45.1 (2C, CH3), 50.2 (2C, CH2N), 54.9 (2C, CH2N), 55.1 (2C,c CH2N), 61.4 (2C, NCH2Ph), 115.0 (1C, CH(Nf)), 119^ (1C, CH(Nf)), 122.1 (2C, C3(Ph)), 122.9 (1C, CH(Nf)), 127.4 (2C, CH(Ph)), 127.8 (1C, CH(Nf)), 128.2 (1C, CH(Nf)), 129.7 (2C, CH(Ph)), 129.8 (1C, CH(Nf)), 130.0 (2CH(Ph), 2C(Nf)), 131.6 (2C, CH(Ph)), 135.0 (1C, C(Nf)), 142.0 (2C, C1(Ph)), 151.4 (1C, C(Nf)).

5-(4,7-Bis(4-bromobenzyl)-1,4,7-triazacyclononan-1--ylsulfonyl)-N,N-dimethylnaphthalene-1-amine (8). Obtained from compound 3 (340 mg, 0.94 mmol), 4-bromobenzyl bromide (350 mg, 1.5 mmol), in the presence of potassium carbonate (400 mg, 2.90 mmol) in 8 ml acetonitrile. Yellow glassy solid, yield 520 mg (99 %). m/z (MALDI-TOF) found: 699.1045. C32H37Br2N4O2S requires 699.1004 [M+H]+. 'H NMR (CDCl3, 298 K) SH ppm: 2.(53 (4H, br. s, CH2N), 2.84 (6H, s, CH3) 3.02 (4H, br. s, CH2N), 3.44 (4H, br. s, CH2NS), 3.57 (2H, s, PhCH2N), 7.15 (4H, d, 3J=8.3 Hz, H2, H2'(Ph)), 7.24 (1H, d, 3J=7.6 Hz, H6(Nf)), 7.39 (4H, d, 3J=8.3 Hz, H3, H3'(Ph)), 7.46 (1H, dd, 3J=8.5 Hz, 3J=7.3 Hz, H3(Nf)), 7.51 (1H, dd, 3J=8.6 Hz, 3J=7.6 Hz, H7(Nf)), 7.99 (1H, d, 3J=7.3 Hz, H2(Nf)), 8.40 (1H, d, 3J=8.6 Hz, H8(Nf)), 8.49 (1H, d, 3J=8.5 Hz, H4(Nf)). 13C NMR (CDCl3, 298 K) Sc ppm: 45.3

(2C, CH3), 50.2 (2C, CH2N), 55.2 (2C, CH2N), 55.4 (2C, CH2N), 61.7 (2C, PhCH2N), 115.2 (1C, CH(Nf)), 119.6 (1C, CH(Nf)), 120.7 (2C, C4(Ph)), 12 3.0 (1C, CH(Nf)), 128.0 (1C, CH(Nf)), 128.4 (1C, CH(Nf)), 129.9 (1C, C(Nf)), 130.2 (1C, C(Nf)), 130.7 (4CH(Ph), CH(Nf)), 131.3 (4C, CH(Ph)), 135.1 (1C, C(Nf)), 138.7 (2C, C1(Ph)),

151.6 (1C, NC(Nf)).

5-((5,9-Bis(3-bromobenzyl)-1,5,9-triazacyclododecan-1-yl)-

sulfonyl)-N,N-dimethylnaphthalene-1-amine (9). Obtained from compound 4 (166 mg, 0.41 mmol), 3-bromobenzyl bromide (200 mg, 0.8 mmol), in the presence of potassium carbonate (500 mg, 3.62 mmol) in 4 ml acetonitrile. Eluent: CH2Cl2-MeOH 100:1, yellow glassy solid. Yield 113 mg (38 %). m/z (MALDI--TOF) found: 741.1449. C35H43Br2N4O2S requires 741.1473 [M+H]+. Щ NMR (CDCl3, 298 1С) SH ppm: 1.57 (4H, br. s, CCH2C), 1.67 (2H, br. quintet, 3Jobs=5.1 Hz, CCH2C), 2.22 (4H, br2. t, 3Jobs=4.9 Hz, CH2N), 2.58 S(4H, br.s, CH2N), 2.86 (6H, s, CH3), 3.57 (4H, t, 3J=7.6 Hz, CH2N), 3.39 (4H, s, PhCH2N), 7.14-7.18 (5H, m, H6(Nf), H(Ph)), 7.34-7.38 (4H, m, H(Ph)), 7.46 (1H, dd, 3J=8.5 Hz, 3J=7.3 Hz, H3(Nf)), 7.51 (1H, dd, 3J=8.7 Hz, 3J=7.6 Hz, H7(Nf)), 8.13 (1H, dd, 3J=7.3 Hz, 4J=0.9 Hz, H2(Nf)), 8.18 (1H, d, 3J=8.7 Hz, H7(Nf)), 8.48 (1H, d, 3J=8.5 Hz, H4(Nf)). 13C NMR (CDCl3, 298 K) 5c ppm: 23.1 (2C, CCH2C), 23.9 (1C, CCH2C), 41.3 (2C, CH2N), 45.4c (2C, CH3), 48.3 (2C, CH2N), 51.0 (2C, CH2N), 57.7 (2C, PhCH2N), 115.0 (1C, CH(Nf)), 11^5 (1C, CH(Nf)), 1222.3 (2C, C3(Ph)), 12 3.1 (1C, CH(Nf)), 127.4 (2C, CH(Ph)), 127.8 (1C, CH(Nf)), 129.5 (1C, CH(Nf)), 129.8 (2C, CH(Ph)), 129.9 (br.s, CH(Nf), 2CH(Ph), 2C(Nf)), 131.8 (2C, CH(Ph)), 135.7 (1C, C(Nf)), 141.8 (2C, C1(Ph)), 151.6 (1C, NC(Nf)).

Method for the synthesis of the cryptands 11-13. A two-neck flask equipped with a magnetic stirrer and reflux condenser, flushed with dry argon, was charged with corresponding triazacycloalkane derivative 7-9, Pd(dba)2 (16 mol%), DavePhos (18 mol%), absolute dioxane. The mixture was stirred for 2-3 min, then trioxadiamine 10 was added followed by tBuONa. The reaction mixture was stirred at reflux for 24 h, cooled down to ambient temperature, the residue was filtered off, washed with dichlo-romethane (5 ml), combined organic fractions were evaporated in vacuo, and the residue was chromatographed on silica gel using a sequence of eluents CH2Cl2, CH2Cl2-MeOH 100:1-2:1, CH2Cl2-MeOH- NH 100:20:1-10:4:1.

3aq

5-(10,13,16-Trioxa-6,20-diaza-3(1,4)-triazacyclononane-1,5(1,3)-dibenzenocycloicosaphan-37-ylsulfonyl)-N,N-dimethyl-naphthalenyl-1-amine (11). Obtained from compound 7 (140 mg, 0.2 mmol), trioxadiamine 10 (44 mg, 0.2 mmol), in the presence of Pd(dba)2 (18 mg, 0.032 mmol), DavePhos (14 mg, 0.036 mmol), tBuONa (58 mg, 0.6 mmol) in 10 ml dioxane. Eluent: CH2Cl2-MeOH 3:1, yield 37 mg (24 %), yellow glassy solid. UV-Vis (CH3CN) Xmax (logs) nm: 305 (3.76), 340 (3.48). m/z (MALDI-TOF) found1;1759.4223. C42H59N6O5S requires 759.4268 [M+H]+. Щ NMR (CDCl3, 298 K) SH ppm: 1.85 (4H, br. quintet, 3Jobs=5.7 Hz, CH2C#2CH2), 2.86 (4H, br. s, CH2N), 2.87 (6H, s, CH3) 3*08-4.00 (12H, br. m, CH2N, PhCH2N), 3.24 (4H, br. t, 3Jobs=4.8 Hz, CH2NPh), 3.55-3.60 (8H, br. m, CH2O), 3.61-3.66 °4H, br. m, CH2O), 6.58 (2H, br. s, H(Ph)), 6.60 (2H, br. d, 3Jobs=6.9 Hz, H(Ph)), 6.842 (2H, br. s, H2(Ph)), 7.10 (2H, t, 3J=7.7 Hz, H5(Ph)), 7.15 (1H, d, 3J=7.6 Hz, H6(Nf)), 7.49 (1H, t, 3Job=7.8 Hz, H3(Nf)), 7.53 (1H, t, 3Jobs=8.2 Hz, H7(Nf)), 7.98 (1H, br. s, H2(Nf)), 8.34 (1H, br. d, 3J=7.6 Hz, H8(Nf)), 8.54 (1H, br. d, 3J=8.2 Hz, H4(Nf)), two NH protons were not unambiguously assigned. 13C NMR (CDCl3, 298 K) Sc ppm: 28.7 (2C, CCH2C), 41.4 (2C, CH2NPh), 45.3 (2C, CH3), 47.0-57.0 (6C, br. m, CH2N), 61.7 (2C, br. s, Av1/2=100 Hz, PhCH2N), 69.4 (2C, CH2O), 70.1 (2C, CH2O), 70.5 (2C, CH2O),

112.7 (2C, br. s, A v1/2=60 Hz, CH(Ph)), 114.3 (2C, br. s, A v1/2=30 Hz, (CH(Ph)), 115.4 (1С!, CH(Nf)), 118.1 (2C, CH(Ph)), 119.0 (2C, br. s, A v1/2=30 Hz, CH(Nf)), 123.1 (1C, (CH(Nf)), 128.2-131.0 (br. m, 3CH(Nf), 2C5(Ph), 2C(Nf)), 134.4 (1C, C(Nf)), 137.5 (2C, C1(Ph)), 149.2 (2C, br. s, A v1/2=20 Hz, C3(Ph)), 151.9 (1C, NC(Nf)).

5-(10,13,16-Trioxa-6,20-diaza-3(1,4)-triazacyclononan-1,5(1,4)-dibenzenocycloicosaphan-37-ylsulfonyl)-N,N-dimethylnaphthalene-1-amine (12). Obtained from compound

8 (125 mg, 0.178 mmol), trioxadiamine 10 (39 mg, 0.178 mmol), in the presence of Pd(dba)2 (16 mg, 0.028 mmol), DavePhos (13 mg, 0.032 mmol), tBuONa (51 mg, 0.53 mmol), in 10 ml dioxane. Eluent: CH2Cl2-MeOH 2:1, yield 21 mg (15 %), yellow glassy solid. UV-Vis (CH3CN) Xmax (lge) nm: 305 (3.56), 340 (3.48). m/z (MALDI-TOF) found: 7m59.4223. C42H59N6O5S requires 759.4268 [M+H]+. 'H NMR (CDCl3, 298 K) Sjj ppm: 1.88 (4H, br. quintet, 3Job=5.7 Hz, CCH2C), 2.88 (6H, s, CH3), 3.10-4.00 (16H, br. m, CH2N, PhCH2N), 3.26 (4H, br. t, 3Jobs=5.8 Hz, CH2NPh), 3.58-3.63 (8H, m, CH2O), 3.67-3.71 (4H, m, CH2O), 4.52 (2H, br. s, NH), 6.55 (4H, d, 3Jobs=8.1 Hz, H2, H2'(Ph)), 7.03 (4H, br. s, H3, H3'(Ph)), 7.19 (1H0, d, 3Jobs=7.3 Hz, H6(Nf)), 7.52 (1H, t, 3Jobs=8.0 Hz, H3(Nf)), 7.55 (1H,Y, 3Jobs=7.9 Hz, H7(Nf)), 8.04 (1H,°br. s, H2(Nf)), 8.31 (1H, d, 3Job=8.8 Hz, H8(Nf)), 8.56 (1H, d, 3Job=8.6 Hz, H4(Nf)). 13C NMR (CDCl3, 298 K) 5c ppm: 28.7 (2C,°CCH2C), 42.1 (CH2NHPh), 45.4 (2C, CH3), 47.9-53.5 (6C, br. m, CH2N), 60.6 (2C, br. s, A v1/2= 50 Hz, PhCH2N), 70.1 (2C, CH2O), 70.2 (2C, CH2O), 70.7 (2C, CH2O), 112.9 (4C, CH(Ph)), 115^ (1C, CH(Nf)), 118.7 (1C, CH(Nf)), 123.1 (1C, CH(Nf)), 128.6 (1C, CH(Nf)), 130.1 (1C, C(Nf)), 130.3 (2C, C1(Ph)), 130.7 (1C, C(Nf)), 131.1 (1C, C(Nf)), 131.6 (6C, 4CH(Ph), 2CH(Nf)), 149.0 (2C, C4(Ph)), 152.0 (1C, NC(Nf)).

5-(10,13,16-Trioxa-31,35,39,6,20-pentaaza-3(1,5)-cyclodo-decana-1, 5(1, 3)-dibenzenocycloicosaphan-39-ylsulfonyl)-N,N-dimethylnaphthalene-1-amine (13). Obtained from compound

9 (113 mg, 0.152 mmol), trioxadiamine 10 (33 mg, 0.152 mmol), in the presence of Pd(dba)2 (14 mg, 0.0243 mmol), DavePhos (11 mg, 0.0274 mmol), tBuONa (58 mg, 0.608 mmol), in 10 ml dioxane. Eluent: CH2Cl2-MeOH 10:1, yield 32 mg (26 %), yellow glassy solid. UV-Vis (CH3CN) Xmax (loge) nm: 305 (3.59), 340 (3.43). m/z (MALDI-TOF) found: 8014761. C45H65N6O5S requires 801.4737 [M+H]+. 'H NMR (CDCl3, 298 K) SH ppm 1.50-2.70 (14H, br. m, NCCH2CN, CH2N), 1.87 (4H, quintet, 3J=6.3 Hz, NCCH2CO), 2.88 (6H, s, CH3) 3.10-3.70 (20H, br. m, CH2O, CH2N, PhCH2N), 3.20 (4H, t, 3J=5.'6 Hz, CH2NPh), 6.44 (2H, d, 3J=7.2 Hz, H(Ph)), 6.49 (2H, d, 3J=8.2 Hz, H(P2h)), 6.85 (2H, br. s, H2(Ph)), 7.05 (2H, t, 3J=7.8 Hz, H5(Ph)), 7.19 (1H, d, 3J=7.6 Hz, H6(Nf)), 7.49-7.60 (2H, m, H3, H7(Nf)), 8.07 (1H, d, 3J=7.3 Hz, H2(Nf)), 8.41 (1H, br. d, Jobs=8.3 Hz, H8(Nf)), 8.55 (1H, d, 3J=8.2 Hz, H4(Nf)), two NH protons were not unambiguously assigned. 13C NMR (CDCl3, 298 K) 5c ppm: 25.2 (3C, br. s, A v1/2= 30 Hz, NCCH2CN), 29.1 (2C, NCCH2CO), 41.4 (2C, CH2NPh), 45.3 (2C, CH3), 46.9 (2C, br. s, A v1/2= 30 Hz, CH2N), 47.7 (2C, br. s, A v1/2= 30 Hz, CH2N), 48.5 (2C, br. s, A v1/2= 30 Hz, CH2N), 58.7 (2C, PhCH2N), 69.6 (2C, CH2O), 70.2 (2C, CH2O), 70.6 (2C, CH2O), 112.1 (2C, CH(Ph)), 113^ (2C, CH(Ph)), 115.3 (1C, CH(Nf)), 117.7 (2C, CH(Ph)), 119.3 (1C, CH(Nf)), 123.2 (1C, CH(Nf)), 128.3 (1C, CH(Nf)), 129.4 (2C, CH(Ph)), 129.6 (1C, CH(Nf)), 130.1 (1C, C(Nf)), 130.3 (1C, C(Nf)), 130.7 (1C, CH(Nf)), 133.6 (1C, br. s, C(Nf)), 149.3 (2C, C3(Ph)), 151.9 (1C, NC(Nf)), quaternary carbon atom C1(Ph) was not unambiguously assigned.

10-Phenyl-1,4,7-triazabicyclo[5.2.1]decane (14).[19] A one-neck flask equipped with a magnetic stirrer was charged with 1,4,7-triazacyclononane (645 mg, 5 mmol), 120 ml of ethanol, freshly distilled benzaldehyde (0.5 ml, 4.9 mmol) was added followed by molecular sieves, the mixture was stirred for 6 h. The residue was filtered off, washed with ethanol (10 ml), combined organic fractions were evaporated in vacuo to give compound 14 as pale-yellow crystals, m.p. 103-104 °C. Yield 910 mg (86 %).

4 - (Naphthalen-2-ylme thyl)-10-phenyl-1,4,7-triazabicyclo[5.2.1]decane (15). A one-neck flask equipped with a magnetic stirrer was charged with compound 14 (217 mg, 1 mmol), dissolved in MeCN (20 ml), 2-(bromomethyl) naphthalene (221 mg, 1 mmol) was added followed by K2CO3

(345 mg, 2.5 mmol), the reaction was stirred for 24 h, the residue was filtered off, washed with CH2Cl2 (10 ml), combined organic fractions were evaporated in vacuo to give compound 15 as a yellow oil. Yield 339 mg (95 %). m/z (MALDI-TOF) found: 358.2256. C24H28N3 requires 358.2283 [M+H]+. 'H NMR (CDCl3, 298 K) SH ppm: 2.74 (2H, dt, 2J=14.9 Hz, 3J=2.7 Hz, CH2N), 2.94 (2H, dt, 2J=14.9 Hz, 3J=2.2 Hz, CH2N), 2.99-3.08 (4H, m, CH2N), 3.14-3.20 (2H, m, CH2N), 3.33-3.42 (2H, m, CH2N), 3.97 (2H, s, CH2Nf), 5.77 (1H, s, CHPh), 7.31 (1H, t, 3J=7.4 Hz, H4(Ph)), 7.34 (2H, t, 3Jobs=7.6 Hz, H3, H3'(Ph)), 7.45-7.49 (2H, m, H(Nf)), 7.51 (1H, d, J=8.1 Hz, H(Nf)), 7.55-7.58 (2H, m, H2, H2'(Ph)), 7.72 (1H, s, H1(Nf)), 7.80-7.85 (3H, m, H(Nf). 13C NMR (CDCl3, 298 K) Sc ppm: 49.2 (2C, CH2N), 54.9 (2C, CH2N), 56.3 (2C, CH 2N), 62.5 (1C, CH2Nf), 87.5 (1C, CHPh), 125.5 (1C, CH(Nf)), 125.9 (1C, CH(Nf)), 1265.4 (3C, CH(Ph), C3, C3'(Ph)), 126.8 (1C, CH(Nf)), 126.9 (1C, CH(Nf)), 127.6 (2C, CH(Nf)), 127.9 (2C, C2, C2'(Ph)), 128.0 (1C, CH(Nf)), 132.7 (1C, C(Nf)), 133.2 (1C, C(Nf)), 137.8 (1C, C2(Nf)), 145.4 (1C, C1(Ph)).

1 -(Naphthalenylmethyl)-1,4, 7-triazacyclononane trihydrochloride (16). Synthesized from compound 15 (357 mg, 1 mmol) by stirring with 15 ml 1M HCl for 4 h. The solution was evaporated in vacuo, the crystalline residue was washed with 10 ml chloroform and dried in vacuo. White crystalline powder, yield 377 mg (94 %). 'H NMR (D2O, 298 K) SH ppm: 2.94-2.98 (4H, m, CH2N), 3.11-3.15 (4H, m, CH2N), 3.57 (4H, s, CH2N), 3.95 (2H, s, CH2Nf), 7.48-7.55 (3H, m, H(Nf)), 7.80 (1H, br.s, H1(Nf)), 7.85-7.90 (3H, s, H(Nf)). 13C NMR (D2O, 298 K) 5c ppm: 42.2 (2C, CH2N), 43.6 (2C, CH2N), 47.7 (2C, CH2N), 59.2 (1c, CH2Nf), 126.6 (1C, CH(Nf)), 126.7 (1C, CH(Nf)), 1272.7 (1C, CH(Nf)), 127.9 (2C, CH(Nf)), 128.4 (1C, CH(Nf)), 129.2 (1C, CH(Nf)), 132.6 (1C, C(Nf)), 132.8 (1C, C(Nf)), 132.9 (1C, C(Nf)).

1-(Naphthalen-2-ylmethyl)-1,4,7-triazacyclononane (17). Synthesized from compound 16 (377 mg, 0.94 mmol) by stirring with NaOH (109 mg, 2.72 mmol) in 5 ml water for 2 min followed by extraction with chloroform (4x50 ml), combined organic fractions were evaporated in vacuo to obtain yellow-brown glassy compound. Yield 216 mg (86 %). m/z (MALDI-TOF) found: 270.1935. C17H24N3 requires 270.1970 [M+H]+. 'H NMR (CDCl3, 298 K) SH ppm: 2.68 (8H, br.s, CH2N), 2.82 (4H, br.s, CH2N), 3.85 (2H, s, CH2Nf), 7.41-7.45 (2H, m, H(Nf)), 7.50 (1H, d, 3J=8.5 Hz, H(Nf)), 7.68 (1H, br.s, H1(Nf)), 7.77-7.82 (3H, m, H(Nf)), two NH protons were not assigned. 13C NMR (CDCl3, 298 K) 5c ppm: 45.9 (2C, CH2N), 46.1 (2C, CH2N), 52.2 (2C, CH2N), 61.7 (1C, CH2Nf), 125.6 (1C, CH(Nf)), 126.0 (1C, CH(Nf)), 127.2 (1C, CH(Nf)), 127.4 (1C, CH(Nf)), 127.6 (2C, CH(Nf)), 128.1 (1C, CH(Nf)), 132.7 (1C, C(Nf)), 133.2 (1C, C(Nf)), 136.8 (1C, C2(Nf)).

1,4-Bis(3-bromobenzyl)-7-(naphthalene-2-ylmethyl)-1,4,7-triazacyclononane (18). A one-neck flask equipped with a magnetic stirrer was charged with compound 17 (200 mg, 0.743 mmol), dissolved in MeCN (4 ml), 3-bromobenzyl bromide (280 mg, 1.1 mmol) was added followed by K2CO3 (345 mg, 2.5 mmol), the reaction was stirred for 24 h, the residue was filtered off, washed with CH2Cl2 (5 ml), combined organic fractions were evaporated in vacuo to give compound 18 as a yellow oil. Yield 301 mg (90 %). m/z (MALDI-TOF) found: 606.1128. C31H34Br2N3 requires 606.1119 [M+H]+. 'H NMR (CDCl3, 298 K) SH ppm: 2.78 (4H, br.s, CH2N), 2.81 (4H, br.s, CH2N), 2.86 (4H, br.s, CH2N), 3.57 (4H, s, NCH2Ph), 3.80 (2H, br.s, CH2Nf), 7.15 (2H, t, 3Job=7.8 Hz, H5(Ph)), 7.23 (2H, d, 3J=7.7 Hz, H6(Ph)), 7.37 (2H, d,°3J=7.8 Hz, H4(Ph)), 7.42-7.47 (2H, m, H(Nf)), 7.49 (2H, br.s, H2(Ph)), 7.55 (1H, d, 3J=8.5 Hz, H(Nf)), 7.69 (1H, br.s, H1(Nf)), 7.78-7.84 (3H, m, H(Nf)). 13C NMR (CDCl3, 298 K) 5c ppm: 55.2 (6C, br, CH2N), 62.2 (2C, PhCH2N), 63.0 (1C, CH2Nf),c 122.3 (2C, C3(Ph)), 125.6 (1C, CH(Nf)), 1225.9 (1C, CH(Nf)), 127.6 (6C, br, CH(Ph), 4CH(Nf)), 127.8 (1C, CH(Nf)), 129.7 (2C, CH(Ph)), 129.9 (2C, CH(Ph)), 131.9 (2C, CH(Ph)), 132.7 (2C, C(Nf)), 133.2 (1C, C(Nf)), 142.6 (2C, C1(Ph)).

37-(Naphthalen-2-ylmethyl)-10,13,16-trioxa-6,20-diaza-3(1,4)-triazacyclononane-1,5(1,3)-dibenzenacycloicosaphane (19). Obtained according to a general procedure for macrocyclization from compound 18 (121 mg, 0.2 mmol), trioxadiamine 10 (44 mg, 0.2 mmol) in the presence of Pd(dba)2 (18 mg, 0.032 mmol), DavePhos (14 mg, 0.036 mmol), tBuONa (77 mg, 0.8 mmol) in 10 ml of dioxane. Eluent: CH2Cl2 - MeOH 5:1, yield 7 mg (6 %), yellow glassy solid. m/z (MIALDI-TOF) found: 666.4360. C41H56N5O3 requires 666.4383 [M+H]+. 'H NMR (CDCl3, 298 K) SH ppm: 1.83 (4H, quintet, 3J=5.7 Hz, CCH2C), 2.85 (4H, br.s, CH2N), 3.08 (4H, br.s, CH2N), 3.27 (4H, t, 3J=5.9 Hz, CH2NPh), 3.45-3.75 (18H, m, CH2O, CH2N), 3.82 (2H, br.s, NfCH2N), 6.35-6.82 (4H, m, H(Ph)), 6.62 (2H, d, 3J=8.2 Hz, H(Ph)), 7.15 (2H, t, 3J=7.8 Hz, H5(Ph)), 7.45-7.52 (3H, m, H(Nf)), 7.66 (1H, s, H1(Nf)), 7.79-7.83 (3H, m, H(Nf)), two NH protons were not assigned.

9-((1,4,7-Triazacyclononan-1-yl)methyl)acridine (21). A one-neck flask equipped with a magnetic stirrer was charged with compound 14 (54 mg, 0.25 mmol), dissolved in MeCN (6 ml), 9-(bromomethyl)acridine (68 mg, 0.25 mmol) was added followed by K2CO3 (86 mg, 0.625 mmol), the reaction was stirred for 24 h, the residue was filtered off, washed with CH2Cl2 (5 ml), combined organic fractions were evaporated in vacuo and the residue was chromatographed on silica gel. Eluent: CH2Cl2-MeOH-NH3aq 100:20:2, yield 42 mg (52 %), yellow glassy solid. m/z (MALDI-TOF) found: 321.2135. C20H25N4 requires 321.2079 [M+H]+. 'H NMR (CDCl3, 298 K) SH ppm: 2.54 (4H, t, 3J=5.5 Hz, CH2N), 2.72 (4H, s, CH2N), 2.75 (4H, t, 3J=5.5 Hz, CH2N), 4.34 (2H, br.s, NH), 4.64 (2H, s, AcrCH2N), 7.56-7.60 (2H, m, H(Acr)),

7.70-7.73 (2H, m, H(Acr)), 8.18 (2H, d, 3J=8.7 Hz, H1, H8(Acr)), 8.39 (2H, d, 3J=8.8 Hz, H4, H5(Acr)). 13C NMR (CDCl3, 298 K) Sc ppm: 44.3 (2C, CH2N), 45.3 (2C, CH2N), 51.8 (2C, CH2N), 52.1 (1C, NfCH 2N), 124.2 (2C, CH(Acr)), 125.7 (2C, C(Ar)), 126.4 (2C, CH(Acr)), 129.8 (2C, CH(Acr)), 130.3 (2C, CH(Acr)), 140.4 (1C, C9(Acr)), 148.5 (2C, C(Acr)).

1,4,7-Tris(acridin-9-ylmethyl) -1,4,7-triazacyclononane (23). Obtained as the second product in the synthesis of compound 21. Eluent: CH2Cl2-MeOH 10:1, yield 20 mg (34 %), yellow glassy solid. m/z (MALDI-TOF) found: 703.3588. C48H43N6 requires 703.3549 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.65 (12H, s, CH2N), 4.25 (6H, s, AcrCH2N), 7.44-7.47 (2H, m, H(Acr)),

7.71-7.75 (2H, m, H(Acr)), 8.20 (2H, d, 3J=8.7 Hz, H1, H8(Acr)), 8.30 (2H, d, 3J=8.8 Hz, H4, H5(Acr)). 13C NMR (CDCl3, 298 K) Sc ppm: 53.5 (3C, AcrCH2N), 55.4 (6C, CH2N), 125.1 (2C, CH(Acr)), 125.6 (2C, CH(Acr)), 125.9 (2C, C(Acr)), 129.7 (2C, CH(Acr)), 130.1 (2C, CH(Acr)), 142.0 (1C, C9(Acr)), 148.6 (2C, C(Acr)).

9-((4,7-Bis(3-bromobenzyl)-1,4,7-triazacyclononan-1-yl) methyl)acridine (24). A one-neck flask equipped with a magnetic stirrer was charged with compound 21 (53 mg, 0.166 mmol), dissolved in MeCN (3 ml), 3-bromobenzyl bromide (50 mg, 0.2 mmol) was added followed by K2CO3 (138 mg, 1 mmol), the reaction was stirred for 24 h, the residue was filtered off, washed with CH 2Cl2 (5 ml), combined organic fractions were evaporated in vacuo to give compound 24 as a yellow oil. Yield 79 mg (72 %). m/z (MALDI-TOF) found: 657.1176. C34H35Br2N4 requires 657.1228 [M+H]+. 'H NMR (CDCl3, 298 K) SH ppm: 2.63 (4H, s, CH2N), 2.63-2.68 (4H, m, CH2N), 2.383-2.88 (4HH, m, CH2N), 3.38 (4H2, s, PhCH2N), 4.50 (2H, s, AcrCH2N), 7.10 (4H, d, 3Jobs=5.2 Hz, H4, H6(Ph)), "7.30-7.34 (2H, m, H5(Ph)), 7.37 (2H, br.s, H2(Ph)), 7.52-7.56 (2H, m, H(Acr)), 7.73-7.76 (2H, m, H(Acr)), 8.22 (2H, d, 3J=8.3 Hz, H1, H8(Acr)), 8.47 (2H, d, 3J=8.8 Hz, H4, H5(Acr)). 13C NMR (CDCl3, 298 K) Sc ppm: 53.6 (1C, AcrCH2N), 54.8 (4C, CH2N), 55.8 (2C, CH2N), 62.0 (2C, PhCH2N), 122.2 (2C, (C3(Ph)), 125.1 (2C, CH(Acr)), 12 5.7 (2C, CH(Acr)), 125.9 (2C, C(Acr)), 127.4 (2C, CH(Ph)), 129.7 (4C, CH(Ph)), 129.9 (2C, CH(Acr)), 130.1 (2C, CH(Acr)), 137. 2 (2C, CH(Ph)), 142.0 (1C, C9(Acr)), 142.4 (2C, C1(Ph)), 148.6 (2C, C(Acr)).

37-(Acridin-9-ylmethyl) -10,13,16-trioxa-6,20-diaza-3(1,4) -triazacyclononane-1,5(1,3) -dibenzenacycloicosaphane (25).

Obtained according to a general procedure for macrocyclization from compound 24 (79 mg, 0.12 mmol), trioxadiamine 10 (27 mg, 0.12 mmol) in the presence of Pd(dba)2 (11 mg, 0.0192 mmol), DavePhos (9 mg, 0.0216 mmol), tBuONa (46 mg, 0.48 mmol) in 8 ml dioxane. Eluent: CH2Cl2-MeOH 5:1, yield 8 mg (9 %), yellow glassy solid. m/z (MALDI-TOF) found: 717.4547. C44H57N6O3 requires 717.4492 [M+H]+. Щ NMR (CDCl3, 298 K) SH ppm: 1.82 (4H, quintet, 3J=5.8 Hz, CCH2C), 2.60-3.90 (28H, m, CH2N, CH2O), 3.21 (4H, t, 3J= 5.9 Hz, CH2NNPh), 4.72 s (2H, s, AcrCH2N), 6.30-6.75 (6H, m, H(Ph)), 7.11 (2H, br.s, H5(Ph)), 7.65-7.70 (2H, m, H(Acr)), 7.78-7.83 (2H, m, H(Acr)), 8.26 (2H, d, 3J=8.3 Hz, H1, H8(Acr)), 8.49 (2H, d, 3J=8.1 Hz, H4, H5(Acr)), two NH protons were not assigned.

1,4,7-Tris(3-bromobenzyl)-1,4,7-triazacyclononane (26). A one-neck flask equipped with a magnetic stirrer was charged with TACN (129 mg, 1 mmol), dissolved in MeCN (8 ml), 3-bromobenzyl bromide (750 mg, 3 mmol) was added followed by K 2CO3 (690 mg, 5 mmol), the reaction was stirred for 24 h, the residue was filtered off, washed with CH2Cl2 (10 ml), combined organic fractions were evaporated in vacuo to give compound 26 as a colourless oil. Yield 623 mg (98 %). m/z (MALDI-TOF) found: 634.0124. C27H31Br3N3 requires 634.0068 [M+H]+. Щ NMR (CDCl3, 298 K) SH ppm: 2.77 (12H, s, CH2N), 3.56 (6H, s, PhCH2N), 7.16 (3H, t, 3J=7.7 Hz, H5(Ph)), 7.242 (3H, d, 3J=7.6 Hz, H6(Ph)), 7.35 (3H, d, 3J=7.8 Hz, H4(Ph)), 7.48 (3H, br.s, H2(Ph)). 13C NMR (CDCl3, 298 K) Sc ppm: 55.3 (6C, CH2N), 62.3 (3C, PhCH2N), 122.3 (3C3, C3(Ph)),c127.5 (3C, CH(Ph)), 129.7 (3C, CH(Ph)), 129.9 (3C, CH(Ph)), 131.8 (3C, CH(Ph)), 142.7 (3C, C1(Ph)).

1,4,7-Tris(3-(1,4,7,10-tetraoxa-13-azacyclopentadecan-13-yl)benzyl)-1,4,7-triazacyclononane (28). A two-necked flask flushed with argon was charged with compound 26 (127 mg, 0.2 mmol), 1-aza-15-crown-5 ether (27) (131 mg, 0.6 mmol), Pd(dba)2 (28 mg, 0.048 mmol), DavePhos (21 mg, 0.054 mmol), dioxane (1 ml) was added followed by tBuONa (86 mg, 0.9 mmol). The reaction mixture was stirred at reflux for 24 h, then cooled down to ambient temperature, diluted with 5 ml dichloromethane, the residue was filtered off, washed with 5 ml dichloromethane, the combined organic fractions were evaporated in vacuo and the residue was chromatographed on silica gel. Eluent: CH2Cl2-MeOH-NH3aq 100:20:3, yield 25 mg (12 %), pale-yellow glassy solid. m/z (MAlDI-TOF) found: 1051.6774. C57H91N6O12 requires 1051.6695 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.87 (12H, br.s, CH2N), 3.57 (12H, t, 3J=6.1 Hz, CH2NPh), 3.58-3.67 (42H, m, CH2O, PhCH2N), 3.72 (12H, t, 3J=6.1 Hz, CH2O), 6.55 (6H, br.d, 3Jobs=7.2 Hz, H4, H6(Ph)), 6.69 (3H, br.s, H2(Ph)), 7.12 (3H, t, 3J=7.8 Hz, H5(Ph)). 13C NMR (CDCl3, 298 K) 5c ppm: 52.5 (6C, CH2NPh), 54.5 (6С, br, Au1/2=200 Hz, CH2N), 62.8 (3C, br, au1/2=60 Hz, PhCH2N), 68.6 (6C, CH2O), 70.0 (6C, CH2O), 70.1 (6C, CH2O), 71.2 (6C, CH2O), 110.5 (3C, CH(Ph)), 112.3 (3C, CH(Ph)), 116.6 (3C, CH(Ph)), 129.2 (3C, C5(Ph)), 147.8 (3C, C3(Ph)). Quaternary carbon atoms C1(Ph) were not assigned.

1,4,11,14,17,24,33-Heptaazahexacyclo[12.12.9.24-24.. 1610. 118-22. 128 32]tetraconta-6(40),7,9,18(39),19,21,28(36), 29,31-nonane (30). Obtained according to a general procedure for macrocyclization from compound 26 (127 mg, 0.2 mmol), tris(2-aminoethyl)amine (29) (27 mg, 0.12 mmol) in the presence of Pd(dba)2 (28 mg, 0.048 mmol), DavePhos (21 mg, 0.054 mmol), tBuONa (86 mg, 0.9 mmol) in 10 ml of dioxane. Eluent: CH2Cl2-MeOH 2:1, yield 15 mg (14 %), yellow oil. m/z (MALDI-TOF) found: 540.3854. C33H46N7. requires 540.3815 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.935 (12H, br.s, CH2N), 3.16 (12H, br.s, CH2N), 3.54 (6H, s, PhCH2N), 4.97 (3H, br.s, NH), 6.07 (3H, br.s, H2(Ph)), 6.54 (3H, d, 3J=7.7 Hz, H(Ph)), 6.59 (3H, d, 3J=7.3 Hz, H(Ph)), 7.18 (3H, t, 3J=7.7 Hz, H5(Ph)). 13C NMR (CDCl3, 298 K) Sc ppm: 40.9 (3C, CH2NPh), 48.5 (6С, CH2N), 50.0 (3C, CH2N), 60.6 (3C, PhCH2N), 110.2 (3C, CH(Ph)), 116.1 (3С, CH(Ph)), 12 0.6 (3C, CH(Ph)), 12 9.9 (3C, C5(Ph)), 135.2 (3C, C1(Ph)), 148.1 (3C, C3(Ph)).

The investigations of the spectral properties of the bicycles 11-13 in the presence of 20 metal salts were carried out in a following manner: 3 ml of the solution of the corresponding bicycle (C=21.9 ^M for 11, 21.1 ^M for 12, 15.9 ^M for 13) in MeCN were placed in a spectrofluorimetric cuvette, solutions of appropriate metal salts (Li(I), Na(I), K(I), Mg(II), Ca(II), Ba(II), Al(III), Fe(II), Mn(II), Co(II), Ni(II), Cr(III), Cu(II), Zn(II), Cd(II), Pb(II), Hg(II) perchlorates and Ga(III), In(III), Y(III) nitrates) in MeCN (C=0.01 M) were added sequentially (1, 2, 5, 10 equiv.) and after each addition UV-Vis and fluorescence spectra were recorded.

Results and Discussion

For the synthesis of bicyclic derivatives of triazacycloalkanes we intended to modify them with one fluorophore group at the first step and with two bromobenzyl groupsatthesecondstepfortheaccomplishmentofthecatalytic macrocyclization at the final step. Our investigation started from the synthesis of ^-dansyl substituted TACN and TACD. For this purpose starting free triazacycloalkanes 1 and 2 were reacted with dansyl chloride in MeCN at room temperature in the presence of K 2CO3 (Scheme 1). To ensure a sufficient yield of the monodansylated products 3 and 4 the following precautions are to be taken into consideration: 1) the application of no more than 0.7-0.75 equiv. of dansyl chloride is important to diminish the formation of di-and tridansyl substituted by-products; 2) enough diluted solution of dansyl chloride (C=0.01 M) should be added very slowly during several hours to a solution of compounds 1 or 2 to prevent an easy formation of indicated by-products; 3) only extra-pure MeCN should be used to exclude the traces of acrylonitrile which readily reacts with TACN and TACD under reaction conditions diminishing the yields of the target products; 4) only chloroform can be used for chromatographic isolation of compound 3 as it readily reacts with dichloromethane forming bicyclic aminal.

In the case of TACN the yield of compound 3 was 68 % while the A,A'-didansyl derivative 5 was isolated in 29 % yield. However, TACD was prone for polysubstitution even in the presence of 0.7 equiv. of dansyl chloride, thus the yield of the target product was only 28 % and the second product 6 was obtained in 65 % yield. All compounds were isolated

by column chromatography on silica gel. Further reactions of compound 3 with 3- and 4-bromobenzyl bromides proceeded smoothly affording corresponding £is(bromobenzyl) substituted TACN 7 and 8 in high yields, but the reaction of TACD derivative 4 with 3-bromobenzyl bromide was complicated with the formation of mono- and triben-zylated by-products what led to a necessity of chromato-graphic separation and gave the desired compound in 38 % yield.

Catalytic macrocyclization reactions of compound 7 was first carried out with linear trioxadiamine 10 using a standard protocol in the presence of a traditional Pd(dba)2/ BINAP (dba=dibenzylideneacetone, BINAP=2,2'-£is(di-phenylphosphino)-1,1'-binaphthalene) system (Scheme 2). The yield of the macrocycle 11 was 30 % in the reaction mixture and after column chromatography it was isolated in 16 % yield. The change of BINAP for a more electron-rich phosphine ligand, i.e. DavePhos (2-(dicyclohexylphosphino)-2'-dimethylaminobiphenyl) did not notably increased the yield in the reaction mixture (32 %) but helped to improve the result after chromatographic isolation (24 %) probably due to a change in the composition of by-products which affect the efficacy of chromatography. The reaction of the same trioxadiamine with 6is(4-bromobenzyl) derivative 8 catalyzed by Pd(dba)i/DavePhos system provided 27 % yield of compound 12 in the reaction mixture and 15 % yield after its separation. Supposedly, the macrocyclization processes involving di(3-bromobenzyl) substituted precursors are generally more successful than those with isomeric di(4-bromobenzyl) derivatives, probably due to a longer intramolecular distance between two reaction centers in the latter case. This fact was earlier observed in our works.[20] Macrocyclization with TACD derivative 9 was the most successful as it provided 26 % yield of the macrobicycle 13 after isolation.

'H NMR spectra of compounds 11, 12 registered in CDCl3 at 298 K possess a very broad multiplet in 3.0-4.0 ppm region which is associated with CH2 protons in triazacyclononane ring and in benzyl groups. Signals of some other aromatic protons in benzyl spacers are also notably broadened contrary to aromatic protons in dansyl fluorophore. Analogously, in 13C NMR spectra the signals of corresponding carbon atoms are also more or less

A

NH HN

vUV

1 (n = 0) 2(n = 1)

MeCN/K2C03

Me,N

MeCN/K2C03

7 (n = 0), 3-Br, 83%

8 (n = 0), 4-Br, 99%

9 (n = 1), 3-Br, 38%

5 (n = 0), 29%

6 (n = 1), 65%

Scheme 1.

broadened. The attempt to sharpen the signals by a change of CDCl3 for DMSO-^6 leads to even more broadening of all signals at 298 K, but at 363 K some of them become narrow, however it is insufficient to obtain fully resolved signals for all protons. These facts can be explained by high-energy conformational transitions in these bicyclic compounds which were not observed for previously obtained macrobicycles based on dibenzyl substituted diazacrown ethers,[21] cyclen or cyclam[22] but were noted for the derivatives of tetrabenzyl substituted cyclen and cyclam.[23]

The approach which was found to be useful for the introduction of one dansyl group in TACN molecule could not be applied for the modification of this triazacycle with other fluorophore groups like naphthalene and acridine. The reactions of TACN with various amounts of 2-(bromomethyl)-and 2-(chloromethyl)naphthalene (0.5-1 equiv.) yielded inseparable mixtures of mono-, di- and trisubstituted TACN. To overcome this difficulty, we tried the method of TACN functionalization using the aminal protecting group.[19] According to a described method a bicyclic compound 14 was obtained in a high yield by reacting free TACN with benzaldehyde (Scheme 3). The reaction of compound 14

with 1 equiv. 2-(bromomethyl)naphthalene under standard conditions gave compound 15 in 95 % yield. After treatment by HCl in water to remove the aminal protection and washing with chloroform, trihydrochloride form 16 was obtained in 94 % yield. Its neutralization with KOH and extraction with chloroform provided 86 % yield of the monosubstitued TACN 17. Its reaction with 2 equiv. 3-bromobenzyl bromide proceeded smoothly affording trisubstituted TACN 18 (90 % yield), and the macrocyclization was carried out using trioxadiamine 10 in the presence of Pd(dba)2/DavePhos system. The yield of the target bicycle 19 after preparative chromatography was however quite poor (6 %).

The possibility to carry out a multistep synthesis of the macrobicycle containing a fluorophore group which cannot be introduced directly gave grounds for the synthesis of the relative compound possessing another fluorophore, i.e. acridine. The reaction of bicyclic aminal 14 with 9-(bromo-methyl)acridine unexpectedly resulted in the formation of a mixture of deprotected mono-, di- and trisubstituted derivatives 21, 22 and 23 in which compounds 21 and 23 prevailed (Scheme 4). Surprisingly, the expected monoac-ridinyl derivative with the aminal protection 20 was observed

Scheme 2.

Scheme 3.

in the reaction mixture only in trace amounts (by m/z=409 [M+H]+ in the MALDI-TOF spectrum and by a characteristic singlet at 5.65 ppm in the 'H NMR spectrum which corresponds to CHN2 proton). Chromatographic separation of the reaction mixture afforded compounds 21 and 23 in 52 and 34 % yields, respectively. The reaction of 21 with 2 equiv. 3-bromobenzyl bromide gave trisubstituted TACN derivative 24 in 72 % yield. The macrocyclization reaction of this compound with trioxadiamine 10 catalyzed by Pd(dba)2/ DavePhos system gave rise to the target macrocycle 25 in 9 %, however, it contained some admixtures which could not be separated by chromatography.

The ability of TACN to easily form trialkyl derivatives was employed in the synthesis of its tris(3-bromobenzyl)

derivative 26 which was obtained in nearly quantitative yield (Scheme 5). The compound 26 was introduced in the Pd(0)-catalyzed amination with 3 equiv. 1-aza-15-crown-5 (27) in the presence of Pd(dba)2/DavePhos system (8 mol% catalyst per each amino group), and desired tetramacrocyclic compound 28 was isolated in 12 % yield. The majority of starting compound was converted into bi-and tricyclic derivatives due to C-Br bond catalytic reduction. The compound 26 was shown to participate in the catalytic "end-capping" reaction with tris(2-aminoethyl)amine (29) which allowed the synthesis of a tetracyclic cryptand 30 in 14 % yield (Scheme 5).

The dansyl fluorophore group present in bicycles 11-13 is responsible for the absorption band at 340 nm

Scheme 4.

c:

HN

Br

Br

PdfdbaVDavePhos, 24/27 mol% (BuONa, dioxane

26, 98%

nr>

С

27, 3 equiv.

Pd(dba)2/DavePhos, 24/27 mol% fBuONa, dioxane

-NH,

\„ о

nh2

29,1 equiv.

J

С

с.

w-

28, 12%

30, 14%

Scheme 5.

and intensive fluorescence at ca 520 nm. We investigated the possibilities of these compounds to work as fluorescent chemosensors for metal cations. In the course of investigation UV-Vis and fluorescent spectra of these compounds were recorded in MeCN in the presence of 1, 2, 5 equiv. of corresponding metal perchlorates or nitrates: Li(I), Na(I), K(I), Mg(II), Ca(II), Ba(II), Al(III), Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), Ag(I), Pb(II) (perchlorates) and Ga(III), In(III), Y(III) (nitrates). The addition of 5 equiv. of corresponding cations to the cryptand 11 did not result in notable changes in the emission intensity except for Cu(II) and Al(III) which totally quenched fluorescence (Figure S1). These changes in fluorescence were accompanied with substantial changes in its UV-Vis spectra (Figure S2) as the addition of both metals led to disappearance of the absorption maximum at 305 nm and gave rise to a new maximum at 290 nm in the case of Al(III). Macrobicycles 12 and 13 were found to respond in a similar manner to the addition of 20 above mentioned metals (Figures S3 and S4) with almost total emission quenching in the presence of Al(III) and Cu(II). In the case of these cryptands we also noted 40-50 % reduction of the fluorescence intensity in the presence of 5 equiv. Ga(III) and In(III), as well as a slight emission enhancement in the presence of K(I) together with a small bathochromic shift of the maximum (from 520 to 513 nm). One may conclude that the emission quenching in the presence of Al(III) and Cu(II) is caused by the coordination with the dansyl fluorophore groups, probably via dimethylamino groups. There are literature data on a similar quenching of emission in dansylated aza-crown ethers by Cu(II), Al(III) and Pb(II) cations.[24] We suppose that in the present case Pb(II) did not led to equal diminishing in fluorescence intensity due to a different coordination mode with N and O atoms of the bicyclic structures.

Conclusions

To sum up, we developed the synthetic approach to previously unknown bicyclic derivatives of 1,4,7-triaza-cyclononane (TACN) and 1,5,9-triazacyclododecane (TACD) bearing dansyl, naphthalene and acridine fluoro-phore groups using Pd(0)-catalyzed amination reactions, demonstrated the possibility to use unprotected TACN and TACD in the synthesis of dansyl-substituted bicycles, obtained tetracyclic derivatives of TACN using its tris(3-bromobenzyl) derivative, and showed the possibility to use dansylated bicycles as fluorescent molecular probes for detecting Cu(II) and Al(III) cations.

Acknowledgements. This work was financially supported by the RFBR grant N 17-53-16012.

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Received 04.12.2017 Accepted 28.01.2018