Научная статья на тему 'Pd-сatalyzed amination for the synthesis of macropolycycles comprising cyclen, cyclam and naphthalene moieties'

Pd-сatalyzed amination for the synthesis of macropolycycles comprising cyclen, cyclam and naphthalene moieties Текст научной статьи по специальности «Биологические науки»

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PD-CATALIZED AMINATION / MACROPOLYCYCLES / CYCLEN / CYCLAM

Аннотация научной статьи по биологическим наукам, автор научной работы — Averin A.D., Shukhaev A.V., Vovk A.I., Kukhar V.P., Denat F.

Pd-catalyzed amination reactions were employed for the synthesis of macrobicyclic compounds possessing cyclen or cyclam moieties, naphthylmethyl spacers and polyamine linkers. The results of the macrocyclization reactions involving 1,7-bis(4-bromonaphthyl-1-methyl)cyclen and 1,8-bis(4-bromonaphthyl-1-methyl)cyclam were shown to be dependent on the nature of starting tetraazamacrocycles and polyamines, the better yields being observed in the case of cyclen derivatives. Valuable macrotricyclic compounds were obtained as the second products in the reactions of 1,7-bis(4-bromonaphthyl-1-methyl)cyclen with the majority of polyamines.

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Текст научной работы на тему «Pd-сatalyzed amination for the synthesis of macropolycycles comprising cyclen, cyclam and naphthalene moieties»

Cyclic Polyamines

Циклические полиамины

Макрогэтэроцмклы

http://macroheterocycles.isuct.ru

Paper

Статья

DOI: 10.6060/mhc140502a

Pd-Catalyzed Amination for the Synthesis of Macropolycycles Comprising Cyclen, Cyclam and Naphthalene Moieties

A. D. Averin,a@ A. V. Shukhaev,a A. I. Vovk,b V. P. Kukhar,b F. Denat,c R. Guilard,c and I. P. Beletskayab

Dedicated to Corresponding member of Russian Academy of Sciences Prof. Oscar Koifman

on the occasion of his 70th Anniversary

aLomonosov Moscow State University, Department of Chemistry, 119991 Moscow, Russia bInstitute of Bioorganic Chemistry and Petrol Chemistry of Ukraine NAS, 02660 Kiev, Ukraine cInstitut de Chimie Moléculaire de l'Université de Bourgogne (ICMUB), 21078 Dijon Cedex, France @Corresponding author E-mail: averin@org.chem.msu.ru

Pd-catalyzed amination reactions were employed for the synthesis of macrobicyclic compounds possessing cyclen or cyclam moieties, naphthylmethyl spacers and polyamine linkers. The results of the macrocyclization reactions involving l,7-bis(4-bromonaphthyl-l-methyl)cyclen and l,8-bis(4-bromonaphthyl-l-methyl)cyclam were shown to be dependent on the nature of starting tetraazamacrocycles and polyamines, the better yields being observed in the case of cyclen derivatives. Valuable macrotricyclic compounds were obtained as the second products in the reactions of 1,7-bis(4-bromonaphthyl-1-methyl)cyclen with the majority of polyamines.

Keywords: Pd-Catalized amination, macropolycycles, cyclen, cyclam.

Р^Катализируемое аминирование в синтезе макрополициклических соединений с фрагментами циклена, циклама и нафталина

А. Д. Аверин,^ А. В. Шухаев^ А. И. Вовк,ь В. П. Кухарь Ф. Дена^ Р. Гиляр^ И. П. Белецкаяb

Посвящается Член-корреспонденту РАН профессору Оскару Иосифовичу Койфману

по случаю его 70-летнего юбилея

Московский государственный университет им. М.В. Ломоносова, Химический факультет, 119991 Москва, Россия ьИнститут биоорганической химии и нефтехимии НАН Украины, 02660 Киев, Украина Институт молекулярной химии Университета Бургундии, 21078 Дижон, Франция @E-mail: averin@org.chem.msu.ru

Реакции Pd-катализируемого аминирования использованы для синтеза макробициклических соединений, содержащих фрагменты циклена или циклама, нафтилметильные спейсеры и полиаминовые линкеры. Показано, что результат реакции макроциклизации с участием 1,7-бис(4-бромнафтил-1-метил)циклена и 1,8-бис(4-бромнафтил-1-метил)циклама зависят от природы исходных тетраазамакроциклов и полиаминов, лучшие выходы наблюдались для производных циклена. Ценные макротрициклические соединения получены в качестве вторых продуктов реакций 1,7-бис(4-бромнафтил-1-метил)циклена с большинством полиаминов.

Ключевые слова: Pd-Катализируемое аминирование, макрополициклические соединения, циклен, циклам.

Introduction

The first macrocycles incorporating naphthalene moieties were described in 1930s,[1] and since that time dozens of works appeared in which various macrocyclic compounds bearing this endocyclic fragment were described. Macrocycles containing 2,3-disubstituted naphthalene fragment have been investigated for alkali metals, ammonium and alkylam-monium salts coordination,[2-7] as well as macrocycles possessing two naphthalene and two polyoxa fragments.[8,9] Macrocycles with polyoxa chains were obtained on the basis of 1,51,7- and 1,8-disubstituted naphthalene and their complexing properties towards alkali metals were studied.[5-10] Several works deal with polyoxamacrocycles organized around 2,2'-and 3,3'-disubstituted 1,1'-binaphthalenes,[67] among these compounds there are sophisticated macrotricyclic cryptands bearing two 1,10-diaza-18-crown-6 fragments.[11] Spherands with 2,2'-dioxy-1,1'-binaphthalenes and 2,7-disubstituted 1,8-dihydroxynaphtahlene moieties constitute another class of macrocycles,[10,12] the latter compound was tested in the coordination studies with Mg(II), Fe(II), Co(II), Ni(II) and Zn(II) cations. Various nitrogen-containing macrocycles with naphthalene moieties were reported, among them are cyclic Schiff bases,[13] diamides and diimides,[1415] lactams;[16] naphthalene fragments were also condensed with tetraaza-macrocycles.[17] Naphthalene fragments were combined with calixarenes,[18] catenanes,[19] and porphyrins.[20] Besides coordination with alkali cations, naphthalene-containing macrocycles were used for the formation of anion receptors and molecular rotors.[21,22]

Experimental

NMR spectra were registered using Bruker Avance 400 spectrometer, MALDI-TOF spectra were obtained with Bruker Ultraflex spectrometer using 1,8,9-trihydroxyanthracene as matrix and PEGs as internal standards. 1-Bromo-4-methylnaphthalene, di- and polyamines 7a-j, 2-(dicyclohexylphosphino)-2'-(dimethylamino)-1,1'-biphenyl (DavePhos ligand), sodium tert-butoxide were purchased from Aldrich and Acros and used without further purification. Cis-glyoxal-cyclen 1 and bis-formaldehyde-cyclam 2 were provided by CheMatech Co. 1-Bromo-4-(bromomethyl)naphthalene was synthesized in 90 % yield from 1-bromo-4-methylnaphthalene according to a standard procedure using bromination with Br2 in CCl4. Pd(dba)2 was synthesized according to a known method.[23] Dioxane was distilled over NaOH followed by the distillation over sodium under argon, acetonitrile was distilled over CaH2, dichloromethane and methanol were used freshly distilled.

2a,6a-Bis[(4-bromo-1-naphthyl)methyl]decahydro-4a,8a-dioxa-2a,6a-diazoniacyclopenta-[fg]acenaphtene dibromide (3). A flask equipped with a reflux condenser and magnetic stirrer was charged with cis-glyoxal-cyclen 1 (1.00 g, 5.1 mmol), 1-bromo-4-(bromomethyl)naphthalene (3.06 g, 10.2 mmol) and 17 mL of acetonitrile. The mixture was heated at 50-60 oC for 80 h, the white precipitate formed was filtered off, washed with cold acetonitrile (2x15 mL) and dried in vacuo at 100 oC. Yield 3.58 g (88 %). 1H NMR (DMSO-d6, 298 K) SH ppm: 2.91-2.99 (2H, m), 3.57 (2H, t, J = 11.7 Hz), 3.64-3.83 (6H, m), 3.93 (2H, td, J = 11.1 Hz, 3J = 4.5 Hz), 5.57 (2H, s), 5.62 (2H, s), 7.81-7.86 (2H, m), 7.86-7.91 (2H, m), 7.97 (2H, d, 3J = 7.8 Hz), 8.11 (2H, d, 3J = 7.7 Hz), 8.32 (2H, d, 3J = 8.2 Hz), 8.69 (2H, d, 3J = 8.1 Hz) (6 protons in 3.30-3.40 ppm region are overlapped by the signal of H2O of the solvent). 13C

NMR (DMSO-d6, 298 K) Sc ppm: 42.5 (2C), 46.1 (2C), 55.9 (2C), 56.3 (2C), 59.6 (2C), 76.0 (2C), 123.9 (2C), 124.7 (2C), 126.1 (2C), 127.8 (2C), 128.5 (2C), 128.8 (2C) 129.9 (2C), 131.7 (2C), 134.0 (2C), 134.3 (2C).

N1,N7-di((4-bromonaphth-1-yl)methyl)cyclen (5). A flask equipped with a reflux condenser and magnetic stirrer was charged with disalt 3 (3.58 g, 4.45 mmol), KOH (8.1 g, 0.145 mol) and 50 mL of water. The mixture was stirred at 80-90 oC for 72 h, cooled down to ambient temperature, extracted with CH2Cl2 (3x50 mL). The organic phase was dried over Na2SO4, the solvent was evaporated in vacuo, and the product was obtained as a beige crystalline powder. Yield 2.68 g (99 %), m.p. 133-135 oC. (MALDI-TOF) found: 609.1274. C30H35Br2O4 requires 609.1228 [M+H]+. UV (CH2Cl2) Xmax nm (e): 292 (142000). 1H NMR (CDCl3, 298 K) SH ppm: 2.59-2.67 (16H, m), 3.96 (4H, s), 7.22 (2H, d, 3J = 7.6 Hz), 7.43 (2H, t, 3Jobs = 7.6 Hz), 7.55 (2H, t, Jobs = 7.7 Hz), 7.61 (2H, d, 3J = 7.6 Hz), 8.10 (2H, d, 3J = 8.5 Hz), 8^8 (2H, d, 3J = 8.4 Hz) (two NH protons were not assigned). 13C NMR (CDCl3, 298 K) Sc ppm: 45.7 (4C), 52.3 (4C), 58.1 (2C), 122.5 (2C), 123.8 (2C), 126i (2C), 126.9 (2C), 127.6 (2C), 127.9 (2C), 129.4 (2C), 132.0 (2C), 133.4 (2C) 134.5 (2C).

1,8-Bis[(4-bromo-1-naphthyl)methyl]-4,11-diaza-1,8-diazoniatricyclo[9.3.1.148]hexadecane dibromide (4). A flask equipped with a magnetic stirrer was charged with bis-formaldehyde-cyclam 2 (2.5 g, 11.2 mmol), 1-bromo-4-(bromomethyl)naphthalene (6.9 g, 23 mmol) and 75 mL of acetonitrile. The reaction mixture was stirred at room temperature for 24 h, the white precipitate formed was filtered off, washed with cold acetonitrile (3x50 mL) and dried in vacuo at 100 oC. Yield 7.05 g (76 %). The compound is almost insoluble in common solvents like D2O, CD3OD and DMSO-d6, thus NMR spectra were not recorded and the compound was used directly in the second step.

N1,N7-di((4-bromonaphth-1yl)methyl)cyclam (6). A flask equipped with a reflux condenser and magnetic stirrer was charged with disalt 4 (7.05 g, 8.56 mmol), NaOH (14 g, 0.35 mmol) and 100 mL of water. The mixture was stirred at 90 oC for 48 h, cooled down to ambient temperature, extracted with CH2Cl2 (3x50 mL). The organic phase was dried over Na2SO4, the solvent was evaporated in vacuo, and the product was obtained as a yellowish crystalline powder. Yield 3.32 g (61 %), m.p. 137-139 oC. (MALDI-TOF) found: 637.1517. C32H39Br2N4 requires 637.1541 [M+H]+. UV (CH2Cl2) Xmax nm (e): 292 nm (13000). 1H NMR (CDCl3, 298 K) SH ppm: 1.77 (4H, quintet, 3J = 5.4 Hz), 2.53 (4H, t, 3J = 5.4 Hz), 2.57 (4H, t, 3J = 5.7 Hz), 2.61-2.66 (4H, m), 2.68-2.72 (4H, m), 3.91 (4H, s), 7.27 (2H, d, 3J = 7.8 Hz), 7.53-7.61 (6H, m), 8.21-8.25 (2H, m), 8.36-8.40 (2H, m) (two NH protons were not assigned). 13C NMR (CDCl3, 298 K) Sc ppm: 26.3 (2C), 47.8 (2C), 48.5 (2C), 52.7 (2C), 53.7 (2C), 57.0 (2C), 122.4 (2C), 124.6 (2C), 126.6 (2C), 127.0 (2C), 127.5 (2C), 127.8 (2C), 129.2 (2C), 132.0 (2C), 133.4 (2C), 134.7 (2C).

Typical procedure for the synthesis of macrobicycles 8, 9. A two-neck flask equipped with a reflux condenser and magnetic stirrer, flushed with dry argon, was charged with compound 5 or 6 (0.5 mmol), Pd(dba)2 (44 mg, 16 mol%), DavePhos ligand (32 mg, 16 mol%), absolute dioxane (25 mL), the mixture was stirred for 2-3 min, then appropriate polyamine 7 (0.5 mmol) was added followed by t-BuONa (144 mg, 1.5 mmol). The reaction mixture was stirred at reflux for 24 h, cooled down to ambient temperature, the solvent was filtered and the residue washed with CH2Cl2 (3x5 mL), combined organic fractions were evaporated in vacuo and the oily residue chromatographed on silica gel using a sequence of eluents: CH2Cl2, CH2Cl2/MeOH (50:1-3:1), CH2Cl2/MeOH/NH3aq (100:20:1-10:4:1).

Macrobicycle 8a. Obtained from compound 5 (304 mg, 0.5 mmol) and diamine 7a (37 mg, 0.5 mmol). Eluent CH2Cl2/MeOH 3:1. Yield 54 mg (20 %), light-beige crystalline powder, m.p. 183-185 oC. (MALDI-TOF) found: 523.3506. C33H43N6 requires 523.3549 [M+H]+. UV (CH2Cl2) I nm (e): 340 (8300). 1H NMR

(CDCl3, 298 K) SH ppm: 2.04 (2H, quintet, 3J = 6.8 Hz), 2.35-2.44 (4H, m), 2.68-2.76 (4H, m), 2.76-2.85 (4H, m), 2.90-2.97 (4H, m), 3.59 (4H, t, 3J = 6.8 Hz), 3.98 (4H, s), 4.83 (2H, br.s), 6.49 (2H, d, 3J = 7.8 Hz), 6.97 (2H, d, 3J = 7.8 Hz), 7.42 (2H, t, 3Jobs = 7.6 Hz), 7.50 (2H, t, 3Jobs = 7.6 Hz), 7.83 (2H, d, 3J = 8.4 Hz), 8.04 (2H, d 3J = 8.4 Hz) (two NH protons were not assigned). 13C NMR (CDCl3, 298 K) Sc ppm: 27.2 (1C), 41.1 (2C), 47.1 (4C), 51.8 (4C), 57.7 (2C), 105.0 (2C), 120.5 (2C), 123.4 (2C), 123.5 (2C), 123.8 (2C), 124.4 (2C), 125.9 (2C), 128.2 (2C), 133.1 (2C), 142.1 (2C).

Cyclodimer 10a. Obtained as the second product in the synthesis of macrobicycle 8a. Eluent CH2Cl2/MeOH/NH3aq 100:20:1. Yield 44 mg (17 %), beige glassy compound. (MALDI-TOF) found: 1045.56. C66H85N12 requires 1045.70 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.96 (4H, quintet, 3J = 6.7 Hz), 2.51-2.70 (32H, m), 3.51 (8H, br.s), 3.88 (8H, s), 4.64 (4H, br.s), 6.44 (4H, d, 3J = 8.0 Hz), 6.97 (4H, d, 3J = 8.0 Hz), 7.35 (4H, t, 3Jobs = 7.9 Hz), 7.47 (4H, t, 3Jobs = 7.6 Hz), 7.77 (4H, d, 3J = 8.7 Hz), 8°04 (4H, d, 3J = 8.7 Hz) (four NH protons were not assigned).

Macrobicycle 8b. Obtained from compound 5 (304 mg, 0.5 mmol) and diamine 7b (44 mg, 0.5 mmol). Eluent CH2Cl2/MeOH 3:1. Yield 19 mg (7 %), beige crystalline powder, m.p. 163-165 oC. (MALDI-TOF) found: 537.3741. C34H45N6 requires 537.3706 [M+H]+. UV (CH2Cl2) Xmax nm (e): 340 (8300). 1H NMR (CDCl3, 298 K) 5H ppm: 1.95 ^H/br.s), 2.21 (4H, br.s), 2.69-2.81 (12H, m),

3.39 (4H, br.s), 3.98 (4H, s), 4.83 (2H, br.s), 6.49 (2H, d, 3J = 7.8 Hz), 6.97 (2H, d, 3J = 7.8 Hz), 7.42 (2H, t, 3Jobs = 7.6 Hz), 7.50 (2H, t, 3Jobs = 7.6 Hz), 7.83 (2H, d, 3J = 8.4 Hz), 8.04 (2H, d, 3J = 8.4 Hz) (two NH protons were not assigned). 13C NMR (CDCl3, 298 K) Sc ppm: 24.6 (2C), 41.8 (2C), 47.1 (4C), 52.5 (4C), 58.7 (2C), 1034 (2C), 120.7 (2C), 122.8 (2C), 123.5 (2C), 124.2 (2C), 124.5 (2C), 125.8 (2C), 128.6 (2C), 133.0 (2C), 142.9 (2C).

Macrobicycle 8c. Obtained from compound 5 (304 mg, 0.5 mmol) and diamine 7c (86 mg, 0.5 mmol). Eluent CH2Cl2/ MeOH 3:1. Yield 53 mg (17 %), yellowish crystalline powder, m.p. 152-154 oC. (MALDI-TOF) found: 621.4618. C40H57N6 requires 621.4645 [M+H]+. UV (CH2Cl2) Xmax nm (e): 340 (11000). 1H NMR (CDCl3, 298 K) SH ppm: 1.40-L48 (8H, m), 1.57 (4H, quintet, 3J = 6.2 Hz), 1.80 (4H, quintet, 3J = 6.8 Hz), 2.55 (8H, br.s), 2.82 (8H, t, 3J = 5.1 Hz), 3.24 (4H, t, 3J = 6.5 Hz), 4.03 (4H, s), 6.32 (2H, d, 3J = 7.8 Hz), 7.17 (2H, d, 3J = 7.8 Hz), 7.42-7.47 (2H, m), 7.46-7.51 (2H, m), 7.81 (2H, d, 3J = 8.5 Hz), 8.14 (2H, d, 3J = 8.5 Hz) (NH protons were not assigned). 13C NMR (CDCl3, 298 K) 5c ppm: 26.8 (2C), 28.0 (2C), 28.2 (2C), 28.6 (2C), 43.8 (2C), 47.0 (4C), 52.6 (4C), 59.1 (2C), 103.8 (2C), 120.2 (2C),

122.8 (2C), 123.6 (2C), 124.3 (2C), 124.4 (2C), 125.9 (2C), 128.3 (2C), 132.9 (2C), 143.3 (2C).

Macrobicycle 8d Obtained from compound 5 (304 mg, 0.5 mmol) and triamine 7d (65 mg, 0.5 mmol). Eluent CH2Cl2/MeOH/ NH3aq 100:20:1. Yield 52 mg (18 %), yellowish crystalline powder, m.p. 158-160 oC. (MALDI-TOF) found: 580.4087. C36H50N7 requires 580.4128 [M+H]+. UV (CH2Cl2) Xmax nm (e): 339 (13000). 1H NMR (CDCl3, 298 K) SH ppm: 1.96 (4Hquintet, 3J = 5.0 Hz),

2.40 (4H, br.s), 2.66 (12H, br.s), 2.91 (4H, t, 3J = 5.0 Hz), 3.21 (4H, t, 3J = 6.4 Hz), 3.89 (4H, s), 5.82 (2H, d, 3J = 7.8 Hz), 6.94 (2H, d, 3J = 7.8 Hz), 7.38 (2H, t, 3Jobs = 7.5 Hz), 7.49 (2H, t, 3 Jobs = 7.6 Hz), 7.88 (2H, d, 3J = 8.5 Hz),¥.10 (2H, d, 3J = 8.5 Hz) (NH protons were not assigned). 13C NMR (CDCl3, 298 K) Sc ppm: 28.6 (2C), 44.6 (2C), 46.4 (4C), 49.3 (2C), 52.7 (4C), 58.9 (2C), 104.0 (2C),

120.9 (2C), 122.7 (2C), 123.7 (2C), 123.9 (2C), 124.2 (2C), 125.7 (2C), 129.1 (2C), 132.7 (2C), 143.6 (2C).

Cyclodimer 10d Obtained as the second product in the synthesis of macrobicycle 8d. Eluent CH2Cl2/MeOH/NH3aq 100:20:2. Yield 55 mg (19 %), beige glassy compound. (MALDI-TOF) found: 1159.67. C72H99N14 requires 1159.82 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.98 (8H, br.s), 2.51-2.69 (32H, m), 2.87 (8H, br.s), 3.34 (8H, br.s), 3.91 (8H, br.s), 6.43 (4H, d, 3J = 7.7 Hz), 7.23 (4H, d, 3J = 7.7 Hz), 7.29-7.46 (8H, m), 7.84 (4H, br.s), 8.09 (4H, br.s) (NH protons were not assigned).

Macrobicycle 8e. Obtained from compound 5 (304 mg, 0.5 mmol) and tetraamine 7e (80 mg, 0.5 mmol). Eluent CH2Cl2/MeOH/ NH3aq 100:20:2. Yield 28 mg (9 %), yellowish glassy compound. (MALDI-TOF) found: 609.4367. C37H53N8 requires 609.4393 [M+H]+. UV (CH2Cl2) Xmax nm (e): 339 (10000). 1H NMR (CDCl3, 298 K) SH ppm: 1.82 (2H,br.s), 2.47 (4H, br.s), 2.68-2.95 (20H, m), 3.17 (4H, br.s), 3.92 (4H, s), 5.81 (2H, d, 3J = 7.7 Hz), 6.97 (2H, d, 3J = 7.7 Hz), 7.39-7.44 (2H, m), 7.50-7.55 (2H, m), 7.92 (2H, d, 3J = 8.2 Hz), 8.08 (2H, d, 3J = 8.2 Hz) (NH protons were not assigned). 13C NMR (CDCl3, 298 K) Sc ppm: 31.8 (1C), 41.7 (2C), 43.9 (2C),

47.3 (4C), 51.8 (4C), 53.5 (2C), 58.7 (2C), 104.4 (2C), 120.8 (2C), 122.9 (2C), 123.4 (2C), 123.8 (2C), 124.4 (2C), 126.0 (2C), 129.2 (2C), 133.0 (2C), 143.3 (2C).

Cyclodimer 10e. Obtained as the second product in the synthesis of macrobicycle 8e. Eluent CH2Cl2/MeOH/NH3aq 100:20:2. Yield 37 mg (12 %), yellowish glassy compound. (MALDI-TOF) found: 1217.91. C^H^N^ requires 1217.87 [M+H]+. UV (CH2Cl2) ^ nm (e): 339 (20000). 1H NMR (CDCl3, 298 K) SH ppm: 1.75 (4H, quintet, 3J = 5.6 Hz), 2.45-2.71 (32H, m), 2.87 (8H, t, 3J = 5.5 Hz), 3.02 (8H, t, 3J = 5.8 Hz), 3.24 (8H, t, 3J = 5.4 Hz), 3.90 (8H, s), 4.76 (4H, br.s), 6.03 (4H, d, 3J = 7.8 Hz), 7.05 (4H, d, 3J = 7.8 Hz), 7.40 (4H, t, 3Jobs = 7.5 Hz), 7.48 (4H, t, 3Jobs = 7.8 Hz), 7.89 (4H, d, 3J = 8.0 Hz), 8.12 (4H, d, 3J = 8.4 Hz) (fi^r NH protons were not assigned). 13C NMR (CDCl3, 298 K) Sc ppm: 28.9 (2C), 43.8 (4C), 45.9 (8C), 48.8 (4C), 49.4 (4C), 53.2 (8C), 59.3 (4C), 104.6 (4C), 120.6 (4C), 123.5 (4C), 123.9 (4C), 124.1 (4C), 124.4 (4C), 125.8 (4C), 128.4 (4C), 132.8 (4C), 143.1 (4C).

Macrobicycle 8f. Obtained from compound 5 (304 mg, 0.5 mmol) and tetraamine 7f (87 mg, 0.5 mmol). Eluent CH2Cl2/MeOH/ NH3aq 100:20:1. Yield 40 mg (13 %), beige glassy compound. (MALDI-TOF) found: 622.4504. C38H55N8 requires 623.4550 [M+H]+. UV (CH2Cl2) Xmax nm (e): 340 (10000). 1H NMR (CDCl3, 298 K) SH ppm:1.95 ^Hquintet, 3J = 5.6 Hz), 2.45-2.80 (16H, m^ 2.85 (4H, t, 3J = 5.2 Hz), 3.04 (4H, s), 3.34 (4H, t, 3J = 6.3 Hz), 3.95 (4H, s), 6.24 (2H, d, 3J = 7.8 Hz), 7.15 (2H, d, 3J = 7.8 Hz), 7.49 (2H, t, 3Jbbs = 7.8 Hz), 7.56 (2H, t, 3Jobs = 8.1 Hz), 7.95 (2H, d, 3J = 8.5 Hz), 8.s14 (2H, d, 3J = 8.9 Hz) (NH protons were not assigned). 13C NMR (CDCl3, 298 K) 5c ppm: 28.7 (2C), 44.3 (2C), 46.2 (4C),

49.4 (2C), 50.1 (2C), 52.1 (4C), 59.6 (2C), 103.5 (2C), 120.8 (2C), 122.4 (2C), 123.7 (2C), 124.0 (2C), 124.3 (2C), 125.7 (2C), 128.1 (2C), 133.1 (2C), 143.7 (2C).

Cyclodimer 10f. Obtained as the second product in the synthesis of macrobicycle 8f. Eluent CH2Cl2/MeOH/NH3aq 100:20:1. Yield 19 mg (6 %), yellowish glassy compound. (MALDI-TOF) found: 1245.74. C76H109N16 requires 1245.90 [M+H]+. UV (CH2Cl2) ^ nm (e): 340 (20000). 1H NMR (CDCl3, 298 K) 5H ppm: 1.93 (8H, quintet, 3J = 5.6 Hz), 2.45-2.75 (32H, m), 2.88 (8H, s), 2.91 (8H, t, 3J = 5.6 Hz), 3.32 (8H, t, 3J = 6.3 Hz), 3.91 (8H, s), 6.29 (4H, d, 3J = 7.8 Hz), 7.19 (4H, d, 3J = 7.8 Hz), 7.35-7.44 (8H, m), 7.86 (4H, d, 3J = 7.9 Hz), 8.11 (4H, d, 3J = 9.1 Hz) (NH protons were not assigned). 13C NMR (CDCl3, 298 K) Sc ppm: 27.1 (4C), 44.3 (4C), 46.3 (8C),

50.3 (4C), 51.9 (4C), 52.7 (8C), 59.5 (4C), 103.6 (4C), 121.1 (4C), 123.8 (4C), 124.0 (4C), 124.1 (4C), 124.3 (4C), 125.8 (4C), 128.7 (4C), 132.8 (4C), 144.1 (4C).

Macrobicycle 8g. Obtained from compound 5 (304 mg, 0.5 mmol) and tetraamine 7g (94 mg, 0.5 mmol). Eluent CH2Cl2/MeOH/ NH3aq 100:20:2. Yield 55 mg (17 %), beige glassy compound. (MALDI-TOF) found: 637.4753. C39H57N8 requires 637.4706 [M+H]+. UV (CH2Cl2) Xmax nm (e): 340 (122000). 1H NMR (CDCl3, 298 K) SH ppm: 1.84 (4H,quintet, 3J = 6.8 Hz), 1.96 (2H, quintet, 3J = 6.5 Hz), 2.45-2.90 (20H, m), 2.94 (4H, t, 3J = 6.5 Hz), 3.32 (4H, t, 3J = 6.2 Hz), 3.92 (4H, s), 6.09 (2H, d, 3J = 7.8 Hz), 7.06 (2H, d, 3J = 7.8 Hz), 7.39-7.46 (4H, m), 7.88 (2H, d, 3J = 8.3 Hz), 8.13 (2H, d, 3J = 7.9 Hz) (NH protons were not assigned). 13C NMR (CDCl3, 298 K) Sc ppm: 25.1 (1C), 30.4 (2C), 44.6 (2C), 46.2 (4C), 53.1 (4C),

55.4 c(2C), 57.6 (2C), 59.8 (2C), 104.0 (2C), 121.5 (2C), 123.4 (2C), 123.8 (2C), 124.1 (2C), 124.2 (2C), 126.0 (2C), 128.6 (2C), 133.1 (2C), 143.9 (2C).

Cyclodimer 10g. Obtained as the second product in the synthesis of macrobicycle 8g. Eluent CH2Cl2/MeOH/NH3aq 100:20:2. Yield 12 mg (4 %), yellowish glassy compound. (MALDI-TOF) found: 1273.81. C78H113N16 requires 1273.93 [M+H]+. UV (CH2Cl2) Xmax nm (e): 339 (23000). 1H NMR (CDCl3, 298 K) 5H ppm: 1.84 (4H, quintet, 3J = 6.8 Hz), 1.91 (8H, quintet, 3J = 5.9 Hz), 2.45-2.72 (32H, m), 2.77 (8H, t, 3J = 6.8 Hz), 2.87 (8H, t, 3J = 5.7 Hz), 3.32 (8H, t, 3J = 6.2 Hz), 3.89 (8H, s), 6.34 (4H, d, 3J =

7.8 Hz), 7.20 (4H, d, 3J = 7.8 Hz), 7.30 (4H, t, 3Jb = 7.6 Hz), 7.37 (4H, t, 3Jbbs = 8.0 Hz), 7.88 (4H, d, 3J = 8.3 Hz),°8.10 (4H, d, 3J = 8.1 Hz) (NH protons were not assigned). 13C NMR (CDCl3, 298 K) 5c ppm: 25.3 (2C), 28.6 (4C), 43.9 (4C), 45.9 (8C), 48.8 (4C), 49.1 (4C), 52.9 (8C), 59.6 (4C), 103.3 (4C), 120.9 (4C), 122.5 (4C),

123.8 (4C), 124.0 (4C), 124.1 (4C), 125.8 (4C), 128.2 (4C), 132.9 (4C), 143.8 (4C).

Macrobicycle 8h. Obtained from compound 5 (304 mg, 0.5 mmol) and dioxadiamine 7h (74 mg, 0.5 mmol). Eluent CH2Cl2/ MeOH 3:1. Yield 32 mg (11 %), beige crystalline powder. (MALDI-TOF) found: 597.3867. C36H49N6O2 requires 597.3917 [M+H]+. UV (CH2Cl2) Xmax nm (e): 337 (12000). 1H NMR (CDCl3, 298 K) SH ppm: 2.53 (8H, br.s), 2.69 (8H, br.s), 3.34 (4H, t, 3J = 5.9 Hz), 3.75 (4H, s), 3.86 (4H, t, 3J = 6.0 Hz), 3.94 (4H, s), 4.66 (2H, br.s), 6.05 (2H, d, 3J = 7.8 Hz), 7.00 (2H, d, 3J = 7.8 Hz), 7.39-7.44 (2H, m), 7.48-7.53 (2H, m), 7.91 (2H, d, 3J = 8.2 Hz), 8.13 (2H, d, 3J = 8.4 Hz) (two NH protons were not assigned). 13C NMR (CDCl3, 298 K) Sc ppm: 43.9 (2C), 46.6 (4C), 52.9 (4C), 59.3 (2C), 69.3 (2C), 70.4 (2C), 104.7 (2C), 120.8 (2C), 123.8 (2C), 124.1 (4C), 124.5 (2C),

125.9 (2C), 128.6 (2C), 132.8 (2C), 143.0 (2C).

Cyclodimer 10h. Obtained as the second product in the synthesis of macrobicycle 8h. Eluent CH2Cl2/MeOH/NH3aq 100:20:1-100:20:2. Yield 18 mg (6 %), yellowish glassy compound. (MALDI-TOF) found: 1193.59. C72H97N12O4 requires 1193.78 [M+H]+. UV (CH2Cl2) Xmax nm (e): 336 (23000). 1H NMR (CDCl3, 298 K) SH ppm: 2.50-2.6T(32H, m), 3.41 (8H, t, 3J = 5.5 Hz), 3.73 (8H, s), 3.85 (8H, t, 3J = 5.5 Hz), 3.92 (8H, s), 4.86 (4H, br.s), 6.40 (4H, d, 3J = 7.8 Hz), 7.20 (4H, d, 3J = 7.8 Hz), 7.31 (4H, t, 3Jobs = 7.9 Hz), 7.34-7.39 (4H, m), 7.83 (4H, d, 3J = 8.3 Hz), 8.06 (4H° d, 3J = 8.0 Hz) (four NH protons were not assigned).

Macrobicycle 8i. Obtained from compound 5 (304 mg, 0.5 mmol) and dioxadiamine 7i (102 mg, 0.5 mmol). Eluent CH2Cl2/ MeOH 3:1. Yield 87 mg (26 %), beige crystalline powder, m.p. 143-145 oC. (MALDI-TOF) found: 653.4507. C40H57N6O2 requires 653.4543 [M+H]+. UV (CH2Cl2) Xmax nm (e): 340(10000). 1H NMR (CDCl3, 298 K) SH ppm: 1.82-1.86(4H, m), 2.06 (4H, quintet, 3J =

5.9 Hz), 2.55 (8H, br.s), 2.67 (8H, br.s), 3.39 (4H, t, 3J = 6.5 Hz), 3.53-3.57 (4H, m), 3.70 (4H, t, 3J = 5.2 Hz), 3.90 (4H, s), 5.09 (2H, br.s), 6.43 (2H, d, 3J = 7.8 Hz), 7.20 (2H, d, 3J = 7.8 Hz), 7.38-7.43 (2H, m), 7.43-7.48 (2H, m), 7.85 (2H, d, 3J = 8.0 Hz), 8.11 (2H, d, 3J = 8.0 Hz) (two NH protons were not assigned). 13C NMR (CDCl3, 298 K) 5c ppm: 27.1 (2C), 29.0 (2C), 43.3 (2C), 48.3 (4C), 52.2 (4C), 60.(0 (2C), 70.8 (2C), 71.5 (2C), 102.7 (2C), 120.7 (2C), 122.0 (2C), 123.5 (2C), 124.2 (2C), 124.3 (2C), 126.0 (2C), 128.6 (2C), 132.8 (2C), 143.8 (2C).

Cyclodimer 10i. Obtained as the second product in the synthesis of macrobicycle 8i. Eluent CH^^/MeOH/NH^q 100:20:1. Yield 53 mg (16 %), beige glassy compound. (MALDI-TOF) found: 1305.66. C80H113N12O4 requires 1305.90 [M+H]+. 1H NMR (CDCl3, 298 K) 8H ppm: 1.73-1.77 (8H, m), 2.01 (8H, quintet, 3J = 5.6 Hz), 2.52-2.70 (32H, m), 3.30 (8H, br.s), 3.45-3.50 (8H, m), 3.61 (8H, t, 3J = 5.4 Hz), 3.88 (8H, s), 5.12 (4H, br.s), 6.41 (4H, d, 3J = 7.8 Hz), 7.22 (4H, d, 3J = 7.8 Hz), 7.34-7.39 (8H, m), 7.89 (4H, d, 3J = 9.0 Hz), 8.06 (4H, d, 3J = 8.9 Hz) (four NH protons were not assigned). 13C NMR (CDCl3, 298 K) 8c ppm: 26.6 (4C), 28.9 (4C), 43.0 (4C), 45.9 (8C), 52.2 (8C), 58.5 c(4C), 70.7 (4C), 71.1 (4C), 103.2 (4C), 120.6 (4C), 122.2 (4C), 123.8 (4C), 124.1 (4C), 124.3 (4C), 125.8 (4C), 128.7 (4C), 133.0 (4C), 143.7 (4C).

Macrobicycle 8j. Obtained from compound 5 (304 mg, 0.5 mmol) and trioxadiamine 7j (110 mg, 0.5 mmol). Eluent CHCL/

MeOH 3:1. Yield 78 mg (23 %), beige glassy compound. (MALDI-TOF) found: 669.4468. C40H57N6O3 requires 669.4492 [M+H]+. UV (CH2Cl2) Xmax nm (e): 340 (12000). 1H NMR (CDCl3, 298 K) SH ppm: 2.05 (4H, quintet, 3J = 5.8 Hz), 2.56 (8H, br.s), 2.66 (8H, br.s), 3.37 (4H, t, 3J = 6.2 Hz), 3.67-3.70 (4H, m), 3.71 (4H, t, 3J = 5.3 Hz), 3.75-3.78 (4H, m), 3.90 (4H, s), 5.03 (2H, br.s), 6.33 (2H, d, 3J = 7.8 Hz), 7.18 (2H, d, 3J = 7.8 Hz), 7.35-7.40 (2H, m), 7.41-7.46 (2H, m,), 7.88 (2H, d, 3J = 8.3 Hz), 8.11 (2H, d, 3J = 8.2 Hz) (two NH protons were not assigned). 13C NMR (CDCl3, 298 K) Sc ppm: 28.9 (2C), 42.9 (2C), 46.2 (4C), 52.7 (4C), 59.2 (2C), 704 (2C), 70.7 (4C), 103.6 (2C), 120.7 (2C), 122.6 (2C), 123.7 (2C), 124.0 (2C), 124.2 (2C), 125.8 (2C), 128.3 (2C), 132.8 (2C), 143.5 (2C).

Cyclodimer 10j. Obtained as the second product in the synthesis of macrobicycle 8j. Eluent CH2Cl2/MeOH/NH3aq 100:20:1. Yield 19 mg (6 %), yellowish glassy compound. (MALDI-TOF) found: 1337.71. C^N^ requires 1337.89 [M+H]+. UV (CH2Cl2) ^ nm (e): 340 (23000). 1H NMR (CDCl3, 298 K) SH ppm: 1.98 (8H, quintet, 3J = 5.7 Hz), 2.48-2.70 (32H, m), 3.32 (8H, t, 3J = 5.4 Hz), 3.56-3.61 (8H, m), 3.62 (8H, t, 3J = 5.4 Hz), 3.66-3.70 (8H, m), 3.88 (8H, s), 5.07 (4H, br.s), 6.41 (4H, d, 3J = 7.7 Hz), 7.22 (4H, d, 3J = 7.7 Hz), 7.32-7.41 (8H, m), 7.81 (4H, d, 3J = 7.7 Hz), 8.07 (4H, d, 3J = 8.5 Hz) (four NH protons were not assigned). 13C NMR (CDCl3, 298 K) Sc ppm: 28.8 (4C), 42.6 (4C), 45.9 (8C), 52.2 (8C), 58.5 (4C), 70.4 (4C), 70.6 (4C), 70.8 (4C), 103.3 (4C), 120.7 (4C), 122.3 (4C), 123.8 (4C), 124.1 (4C), 124.2 (4C), 125.8 (4C), 128.7 (4C), 133.1 (4C), 143.6 (4C).

Macrobicycle 9a. Obtained from compound 6 (318 mg, 0.5 mmol) and diamine 7a (37 mg, 0.5 mmol). Eluent CH2Cl2/MeOH/ NH3aq 100:20:2. Yield 7 mg (2.5 %), beige crystalline powder, m.p. 192-194 oC. (MALDI-TOF) found: 551.3820. C35H47N6 requires 551.3862 [M+H]+. UV (CH2Cl2) Xmax nm (e): 336 (6300). 1H NMR (CDCl3, 298 K) SH ppm: 2.00 (2H,Tr.s), 2.10 (2H, quintet, 3J = 5.9 Hz), 2.29-2.81 (18H, m), 3.50 (4H, br.s), 3.87 (4H, s), 4.87 (2H, br.s), 6.34 (2H, d, 3J = 7.8 Hz), 6.81 (2H, d, 3J = 7.8 Hz), 7.16-7.21 (2H, m), 7.39-7.44 (2H, m), 7.60 (2H, d, 3J = 8.4 Hz), 7.93 (2H, d, 3J = 8.7 Hz) (two NH protons were not assigned). 13C NMR (CDCl3, 298 K) Sc ppm: 25.5 (2C), 28.3 (1C), 43.0 (2C), 43.8 (2C), 49.1 (2C), 53.3 (2C), 54.2 (2C), 57.8 (2C), 104.6 (2C), 120.4 (2C), 123.4 (2C), 123.6 (2C), 123.7 (2C), 124.1 (2C), 125.4 (2C), 127.7 (2C), 133.9 (2C), 142.7 (2C).

Macrobicycle 9b. Obtained from compound 6 (318 mg, 0.5 mmol) and diamine 7b (44 mg, 0.5 mmol). Eluent CH2Cl2/MeOH/ NH3aq 100:20:3. Yield 11 mg (4 %), beige crystalline powder, m.p. 148-150 oC. (MALDI-TOF) found: 565.3981. C36H49N6 requires 565.4019 [M+H]+. UV (CH2Cl2) Xmax nm (e): 340 (8300). 1H NMR (CDCl3, 298 K) SH ppm: 1.74 ^Hbr.s), 1.99 (4H, br.s), 2.40-2.75 (16H, m), 3.39 (4H, br.s), 3.98 (4H, br.s), 4.45 (2H, br.s), 6.11 (2H, d, 3J = 7.8 Hz), 6.33 (2H, d, 3J = 7.8 Hz), 7.26-7.31 (2H, m,), 7.477.52 (2H, m), 7.68 (2H, d, 3J = 8.6 Hz), 8.18 (2H, d, 3J = 8.2 Hz) (two NH protons were not assigned). 13C NMR (CDCl3, 298 K) 8c ppm: 23.8 (2C), 26.3 (2C), 41.8 (2C), 43.9 (2C), 48.5 (2C), 504 (2C), 55.4 (2C), 58.2 (2C), 104.2 (2C), 120.6 (2C), 122.9 (2C), 123.7 (2C), 124.1 (2C), 124.5 (2C), 125.6 (2C), 129.6 (2C), 133.2 (2C), 142.1 (2C).

Macrobicycle 9c. Obtained from compound 6 (318 mg, 0.5 mmol) and diamine 7c (86 mg, 0.5 mmol). Eluent CH2Cl2/MeOH/ NH3aq 100:20:2. Yield 33 mg (10 %), beige glassy compound. (MALDI-TOF) found: 649.4920. C42H61N6 requires 649.4958 [M+H]+. UV (CH2Cl2) Xmax nm (e): 340 (122000). 1H NMR (CDCl3, 298 K) 8H ppm: 1.16-1.38(12H, m), 1.64 (4H, quintet, 3J = 6.8 Hz), 1.77 (4H, br.s), 2.49-2.67 (16H, m), 3.20 (4H, q, 3J = 5.0 Hz), 3.92 (4H, s), 4.33 (2H, br.s), 6.50 (2H, d, 3J = 7.7 Hz), 7.29-7.36 (6H, m), 7.74-7.77 (2H, m), 8.03-8.07 (2H, m) (two NH protons were not assigned). 13C NMR (CDCl3, 298 K) 8c ppm: 25.9 (2C), 26.3 (2C), 28.0 (2C), 28.2 (2C), 29.4 (2C), 43.6c (2C), 44.2 (2C), 48.8 (2C), 53.0 (2C), 53.4 (2C), 56.0 (2C), 103.8 (2C), 120.3 (2C), 122.4 (2C), 123.6 (2C), 124.1 (2C), 124.2 (2C), 125.7 (2C), 128.6 (2C), 133.1 (2C), 142.9 (2C).

Macrobicycle 9d. Obtained from compound 6 (214 mg, 0.34 mmol) and triamine 7d (45 mg, 0.34 mmol). Eluent CH2Cl2/MeOH 3:1. Yield 15 mg (7 %), beige glassy compound. (MALDI-TOF) found: 608.4473. C38H54N7 requires 608.4441 [M+H]+. 1H NMR (CDCl3, 298 K) 8H ppm: 1.95-2.06 (8H, m), 2.40-2.75 (16H, m),

2.97 (4H, t, 3J = 5.8 Hz), 3.31 (4H, t, 3J = 6.3 Hz), 3.97 (4H, s),

5.98 (2H, d, 3J = 7.9 Hz), 6.85 (2H, d, 3J = 7.9 Hz), 7.31-7.51 (4H, m), 7.85 (2H, d, 3J = 8.5 Hz), 8.16 (2H, d, 3J = 8.2 Hz) (NH protons were not assigned).

Macrobicycle 9h. Obtained from compound 6 (214 mg, 0.34 mmol) and dioxadiamine 7h (50 mg, 0.34 mmol). Eluent CH2Cl2/ MeOH 3:1. Yield 10 mg (5 %), yellow glassy compound. UV (CH2Cl2) Xmax nm (e): 339 (11000). (MALDI-TOF) found: 625.4208. C38H53N6Omreqrnres 625.4230 [M+H]+. 1H NMR (CDCl3, 298 K) 8H ppm:1.87 (4H, br.s), 2.49 (4H, br.s), 2.65 (4H, t, 3J = 5.6 Hz), 2.69 (4H, t, 3J = 5.1 Hz), 2.75 (4H, br.s), 3.32 (4H, t, 3J = 5.7 Hz), 3.73 (4H, s), 3.81 (4H, t, 3J = 5.7 Hz), 3.83 (4H, br.s), 6.09 (2H, d, 3J = 7.8 Hz), 6.97 (2H, d, 3J = 7.8 Hz), 7.36-7.41 (2H, m), 7.44-7.49 (2H, m), 7.81 (2H, d, 3J = 8.3 Hz), 8.02 (2H, d, 3J = 8.5 Hz) (NH protons were not assigned). 13C NMR (CDCl3, 298 K) 8c ppm: 24.9 (2C), 43.8 (2C), 48.5 (2C), 49.7 (2C), 52.1 (2C), 54.3c(2C), 57.9 (2C), 69.1 (2C), 70.4 (2C), 104.5 (2C), 121.0 (2C), 122.7 (2C), 123.3 (2C), 123.8 (2C), 124.7 (2C), 126.0 (2C), 128.3 (2C), 132.7 (2C), 143.2 (2C).

Macrobicycle 9i. Obtained from compound 6 (214 mg, 0.34 mmol) and dioxadiamine 7i (69 mg, 0.34 mmol). Eluent CH2Cl2/ MeOH/NH3aq 100:20:2. Yield 23 mg (10 %), yellow glassy compound. UV (CH2Cl2) Xmjx nm (e): 340 (11000). (MALDI-TOF) found: 681.4881. C42H61N6O2"reqmres 681.4856 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.74 (4H, br.s), 1.83 (4H, br.s), 1.96 (4H, br.s), 2.45-2.50 (4H, m), 2.57-2.62 (4H, m), 2.65-2.72 (8H, m), 3.11 (4H, br.s), 3.48 (4H, br.s), 3.58 (4H, t, 3J = 5.0 Hz), 3.81 (4H, s), 5.22 (2H, br.s), 6.21 (2H, d, 3J = 7.8 Hz), 7.13 (2H, d, 3J = 7.4 Hz), 7.16-7.21 (2H, m), 7.23-7.28 (2H, m), 7.73 (2H, d, 3J = 8.3 Hz), 7.87 (2H, d, 3J = 8.5 Hz) (two NH protons were not assigned). 13C NMR (CDCl3, 298 K) 8c ppm: 25.1 (2C), 27.0 (2C), 28.7 (2C), 43.4 (2C), 48.3 (2C), 49.6 (2C), 52.2 (2C), 54.4 (2C), 57.9 (2C), 71.1 (2C), 71.4 (2C), 102.6 (2C), 120.9 (2C), 121.9 (2C), 123.5 (2C), 123.7 (2C), 123.9 (2C), 125.6 (2C), 128.3 (2C), 132.5 (2C), 143.5 (2C).

Macrobicycle 9j. Obtained from compound 6 (318 mg, 0.5 mmol) and trioxadiamine 7i (110 mg, 0.5 mmol). Eluent CH2Cl2/ MeOH/NH3aq 100:20:3. Yield 45 mg (13 %), yellow glassy compound. UV (CH2Cl2) Xmax nm (e): 340 (11000). (MALDI-TOF) found: 697.4841. C42H61N6O* requires 697.4805 [M+H]+. 1H NMR (CDCl3, 298 K) 8H ppm: 1.82 (4H, quintet, 3J = 5.8 Hz), 1.98 (4H, br.s), 2.50-2.60 (4H, m), 2.65-2.75 (4H, m), 2.90 (8H, br.s), 3.48-

3.53 (12H, m), 3.60-3.64 (4H, m), 3.85 (4H, s), 4.89 (2H, br.s), 6.01 (2H, d, 3J = 7.7 Hz), 7.12 (2H, d, 3J = 7.8 Hz), 7.26-7.31 (4H, m), 7.72-7.75 (2H, m), 7.93-7.96 (2H, m) (two NH protons were not assigned). 13C NMR (CDCl3, 298 K) 8c ppm: 26.0 (2C), 28.5 (2C), 43.0 (2C), 48.4 (2C), 49.9 (2C), 54.0 c(2C), 55.0 (2C), 56.3 (2C), 70.3 (2C), 70.4 (2C), 71.3 (2C), 103.0 (2C), 120.9 (2C), 121.7 (2C), 123.5 (2C), 123.7 (2C), 124.1 (2C), 125.3 (2C), 127.5 (2C), 132.7 (2C), 142.9 (2C).

Results and Discussion

In our previous investigations we successfully synthesized macrobicycles based on cyclen and cyclam central moieties containing benzyl[24-26] and pyridinylmethyl spacers.[27] The yields of the corresponding cryptands were shown to be dependent on the nature of the tetraazamacrocyclic fragment and the spacer used, the better results being obtained for cyclen derivatives, especially those with benzyl spacers. We have also shown the possibility to synthesize macrobicycles based on cyclam possessing two naphthylmethyl substituents on the nitrogen atoms of the cryptand.[28] In this communication we report the synthesis of macrobicyclic derivatives of cyclen and cyclam with naphthylmethyl spacers which can be viewed as a valuable and simple chromophore and fluorophore group useful for the creation of macrocyclic chemosensors for metal cations.

For this purpose we synthesized 1-bromo-4-(bromomethyl)naphthalene in 90 % yield from commercially available 1-bromo-4-methylnaphthalene by its bromination with NBS in CCl4. Protected tetraazamacro-cycles, cis-glyoxal-cyclen 1 and bis-formaldehyde-cyclam 2, were dialkylated in MeCN using this bromide to give disalts 3 and 4 in 88 and 76 % yields respectively, and after a standard deprotection step (heating with NaOH in water) tra«s-bis(4-bromonaphth-1-ylmethyl) substituted cyclen and cyclam 5 and 6 were obtained in overall 87 and 46 % yields (Scheme 1).

Compounds 5 and 6 were introduced in the Pd-catalyzed amination reactions with a series of di- and polyamines 7a-j (Scheme 2). Starting compounds were taken in equimolar

i_i

ffi

N\J1/N 1

ri «

N N 2

6, 46% (overall)

Scheme 1.

amounts, the macrocyclization was catalyzed with Pd(dba)2/ DavePhos catalytic system (DavePhos = 2-(dimethylamino)-2'-(dicyclohexylphosphino)biphenyl) because initial experiments unexpectedly demonstrated low efficiency of a standard BINAP (2,2'-bis(diphenylphosphino)-1,1-binaphthalene) ligand. It was surprising because 1- and 2-bromonaphthalenes are known to be very active substrates in Pd-catalyzed amination reactions.129-311 This fact may be explained by the presence of the tetraazamacrocyclic fragment which competes with the phosphine ligand in the coordination of Pd(0) partially removing it from the catalytic cycle.

Target compounds 8 and 9 were obtained after column chromatography on silica gel, in order to isolate them from mixtures with macrotricyclic cyclodimers which were formed in comparable amounts. The use of the minimal amount of silica gel helped to obtain pure target cryptands. Cyclen-contain-ing macrobicycles 8 were obtained in moderate yields, while the yields of cyclam-containing cryptands 9 were always low (Table 1). Higher yields of the cyclen derivatives compared to cyclam derivatives were observed by us earlier in the majority of cases where macrobicycles were synthesized.1271 The cryptands yields do not notably depend on the chain length of polyamines but rather on the number of nitrogen atoms, it was noted that NHCH2CH2NH and OCH2CH2O fragments present in polyamine structure diminish the yields (Table 1, entries 5, 6, 8). It may be explained by a better coordination of Pd(0) by these fragments which form stable chelates and hinder amination reaction. It is interesting to note that in some cases the decrease in the catalyst loading from 16 to 8 mol% together with the increase in the reagents concentration from 0.02 to 0.04 M and application of 1.5 equiv. of polyamine led

to better yields of the target macrobicycles 8 (entries 9, 12). The formation of cyclic dimers and higher mass oligomers was noted in all reactions, however, macrotricycles 10 were isolated only in the case of cyclen derivatives and in some cases their yields were even higher than those of target cryptands 8 (entries 4, 5, 11). Cyclic oligomers of higher masses have been never isolated as individual compounds, but in some cases corresponding signals were observed in MALDI-TOF spectra of mixtures.

Conclusions

As a result, we elaborated cryptands containing tetraazamacrocycle, two naphthylmethyl and polyamine moieties using Pd-catalyzed macrocyclization of easily avaialable ira«s-V,V-bis(naphthylmethyl) derivatives of cyclen and cyclam. The yields of the target macrobicycles were shown to be dependent on the nature of starting compounds, better yields being observed in the case of cyclen derivatives. Interesting macrotricyclic compounds were obtained as the second products in the reactions of the cyclen derivative with polyamines.

Acknowledgements. This work was carried out in the frame of the International Associated French-Russian Laboratory of Macrocycle Systems and Related Materials (LAMREM) of RAS and CNRS and financially supported by the RFBR grants 12-03-93107, 13-03-00813 and 13-03-90453. Generous provision of cyclen and cyclam derivatives by CheMatech Co is acknowledged.

Table 1. Synthesis of cryptands 8 and 9 (Pd(dba)2/DavePhos, 16/16 mol%, C = 0.02 M).

Entry Tetraazamacrocycle Polyamine 7 Yields of Yields of

derivative macrobicycles cyclodimers

1 5 NH2(CH2)3NH2 7a 8a, 20% 10a, 17%

2 5 NH2(CH2)4NH2 7b 8b, 7%

3 5 NH2(CH2)1oNH2 7c 8c, 17%

4 5 NH2(CH2)3NH(CH2)3NH2 7d 8d, 18% 10d, 19%

5 5 NH2(CH2)2NH(CH2)3NH(CH2)2NH2 7e 8e, 9% 10e, 12%

6 5 NH2(CH2)3NH(CH2)2NH(CH2)3NH2 7f 8f, 13% 10f, 6%

7 5 NH/CH^NH^H^NH^H^NH, 7g 8g, 17% 10g, 4%

8 5 NH2(CH2)2O(CH2)2O(CH2)2NH2 7h 8h, 11% 10h, 6%a)

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9 5 NH2(CH2)2O(CH2)2O(CH2)2NH2 7hb) 8h, 29%

10 5 NH2(CH2)3O(CH2)4O(CH2)3NH2 7i 8i, 13% 10i, 8%

11 5 NH2(CH2)3[O(CH2)J2O(CH2)3NH2 7j 8j, 10% 10j, 13%

12 5 NH2(CH2)3[O(CH2)J2O(CH2)3NH2 7jb) 8j, 28%

13 6 NH2(CH2)3NH2 7a 9a, 2.5%

14 6 NH2(CH2)4NH2 7b 9b, 4%

15 6 N^CH,)^ 7c 9c, 10%

16 6 NH2(CH2)3NH(CH2)3NH2 7d 9d, 7%

17 6 NH2(CH2)2O(CH2)2O(CH2)2NH2 7h 9h, 5%

18 6 NH/CH^O^H^CH^NH, 7i 9i, 10%

19 6 NH2(CH2X[O(CH2)J2O(CH2)3NH2 7j 9j, 13%

a) Cyclodimer 10h was obtained in a mixture with macrobicycle 8h.

b) The reaction was run using 8/9 mol% Pd(dba)2/DavePhos, C = 0.04 M, and polyamine:5 mole ratio

1.5:1.

H- -H

H2N NH2 _IM_^

Pd(dba)2/DavePhos fBuONa, dioxane

H-N N-H

8a-j: n = 1 9a-d,h-j: n = 2

X + H-N N-H <UN

10a,d-j: n = 1

h2n ^^ nh2 h2n"

7a 7b

HoN

7e

HoN

7f

2 HpN

7h

7i

7c

,NHH2N'

H2N --- NH--- NH2

7d

7g

"O ^^ NH2

Scheme 2.

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Received 12.05.2014 Accepted 27.05.2014

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