Синтез макрополициклов с фрагментами диазакрауна и адамантана с помощью реакции Pd-катализируемого аминирования Текст научной статьи по специальности «Биологические науки»

Crown Ethers

Краун-эфиры

Макрогэтэроцмклы

Статья

Paper

http://macroheterocycles.isuct.ru

DOI: 10.6060/mhc121214a

Synthesis of Macropolycycles Comprising Diazacrown

and Adamantane Moieties via Pd-Catalyzed Amination Reaction

Alexei A. Yakushev,ab Maksim V. Anokhin,a Alexei D. Averin,ab@ Olga A. Maloshitskaya,a Evgenii N. Savelyev,c Gennadii M. Butov,d Boris S. Orlinson,c Ivan A. Novakov,c and Irina P. Beletskayaab

aLomonosov Moscow State University, Department of Chemistry, 119991 Moscow, Russia bA.N. Frumkin Institute of Physical and Electrochemistry, 119991 Moscow, Russia c Volgograd State Technical University, 400131 Volgograd, Russia

dVolzhsky Polytechnical Institute (Branch) of Volgograd State Technical University, 404131 Volzhsky, Russia @Corresponding author E-mail: averin@org.chem.msu.ru

N,N'-bis(bromobenzyl) substituted diazacrown ethers were obtained in the reactions of corresponding free diaza-crowns with two equivalents of bromobenzyl bromides in high yields. These compounds were introduced in the Pd-catalyzed amination reaction with 1,3-bis(aminomethyl) and 1,3-bis(2-aminoethyl)adamantanes to give macrobicyclic products. The yields were shown to be dependent on the nature of starting diazacrown derivatives and diamines. N,N'-bis(3-bromobenzyl) substituted diazacrown ethers provided better yields of the target macrobicycles than N,N'-bis(4-bromobenzyl) derivatives. In the latter case substantial amounts of cyclic oligomers were formed and isolated.

Keywords: Diazacrown ethers, macropolycycles, palladium-catalyzed amination, adamantane.

Синтез макрополициклов с фрагментами диазакрауна и адамантана с помощью реакции Pd-катализируемого аминирования

А. А. Якушев,аЬ М. В. Анохин,а А. Д. Аверин,а'ь@ О. А. Малощицкая,а

Е. Н. Савельев,0 Г. М. Бутов,d Б. С. Орлинсон,с И. А. Новаков,с И. П. Белецкаяа,ь

Московикий государственный университет им. М. В. Ломоносова, Химический факультет, 119991 Москва, Россия ьИнститут физической химии и электрохимии им. А. Н. Фрумкина РАН, 119991 Москва, Россия сВолгоградский государственный технический университет, 400131 Волгоград, Россия

йВолжский политехнический институт (филиал) Волгоградского государственного технического университета, 404131 Волжский, Россия @E-mail: averin@org.chem.msu.ru

Ы,Ы}-бис(бромбензил)замещенные диазакраун-эфиры были получены с высокими выходами по реакции соответствующих диазакраун-эфиров с двумя эквивалентами бромбензилбромидов. Данные соединения были введены в реакции палладий-катализируемого аминирования с 1,3-бис(аминометил)- и 1,3-бис(2-аминоэтил)-адамантанами с образованием макробициклических продуктов. Показано, что выходы зависят от природы производных диазакраун-эфиров и диаминов. Н,Н'-Бис(3-бромбензил)замещенные диазакраун-эфиры обеспечили более высокие выходы целевых макробициклов, чем Ы,Ы}-бис(4-бромбензил) замещенные изомеры. При использовании последних образовались значительные количества циклических олигомеров.

Ключевые слова: Диазакраун-эфиры, макрополициклы, палладий-катализируемое аминирование, адамантан.

Introduction

During last three decades various synthetic approaches were elaborated for the synthesis of polymacrocyclic compounds comprising two or more crown and azacrwon ether moieties. In particular, bis(azacrown) ethers with isolated macrocycles linked via aliphatic bridges were described,111 as well as the molecules with spiro-conjugated macrocycles,[2] and with condensed macro rings possessing saturated and unsaturated cyclic spacers.[3] The majority of known bis(azacrown) ethers possess two macrocyclic units which are symmetrically arranged around the aromatic,[4,5] matallocene,[6] porphyrin,[7] or calixarene[8] spacer. A special attention has been paid to the macrobicycles of the cryptand type derived from azacrown ethers: known are di- and triazapolyoxacryptands,[910] benzocryptands containing fragments of 1,2-, 1,3-, and 1,4-disubstituted benzene,[1112] 2,6-disubstituted pyridine,[13] described are the compounds in which two diazacrown ethers are combined in macrotricyclic systems via aliphatic[14] or benzyl[15] linkers. Reported are so-called cross-bridged tetracyclic compounds containing diazacrown ethers.[16] Convenient and versatile synthetic approaches to bi- and polycyclic compounds of this type, to cryptands and supercryptands, were elaborated in 1990s by Krakowiak and coauthors using simple nucleophilic substitution reactions.[17-19]

A special interest is evoked by the polyazamacrobicycles containing a bulky lipophilic adamanatane backbone which may improve their solubility in non-polar organic solvents and significantly change the geometry of the macrocyclic cavity. Also such macrocycles can be viewed as potentially physiologically active compounds like other adamantane-containing amines and diamines. For example, 1,3-bis(2-aminoethyl)adamantane together with its analogue, 1,3-bis(aminomethyl)adamantane, as well as their dihydrochlorides were tested as antiviral agents.[20] While the first was found to be active against the poultry plague,[21] the latter was patented as an anti-viral agent for home animals.[22,23] Cyclic Schiff bases were synthesized using 1,3-bis(2-aminoethyl)adamantane for biological activity studies.[24] A,A'-dipyridyl derivative of this amine was synthesized by us earlier[25] and showed nootropic effect in mice. Having acquired a good experience in the synthesis of macropolycycles via Pd-catalyzed amination reactions,[26 27] as well as in the arylation of adamantane-containing amines[28,29] and diamines,[30-32] we decided to investigate the applicability of this approach to previously unknown adamantane-containing macrobicycles derived from diazacrown ethers.

Experimental

NMR spectra were registered using BrukerAvance 400 spectrometer, MALDI-TOF spectra were obtained on Bruker Autoflex II spectrometer using 1,8,9-trihydroxyanthracene as matrix and PEGs as internal standards. 3- and 4-bromobenzyl bromide, 1,7-diaza-15-crown-5 and 1,10-diaza-18-crown-6, BINAP and DavePhos ligands, sodium tert-butoxide were purchased from Aldrich and Acros and used without further purification, Pd(dba)2 was synthesized according to the method described.1331 1,3-Bis(aminomethyl)-adamantane and 1,3-bis(2-aminoethyl)adamantane were obtained

according to a method described earlier.[25] Dioxane was distilled over NaOH followed by the distillation over sodium under argon, acetonitrile, dichloromethane and methanol were used freshly distilled.

Typical procedure for the synthesis ofN,N'-bis(bromobenzyl) derivatives of diazacrown ethers 3-6.

A one-neck flask equipped with a condenser and magnetic stirrer was charged with diazacrown ether 1 or 2 (1-4.5 mmol), 3- or 4-bromobenzyl bromide (2-9 mmol), acetonitrile (3-15 ml), sodium or potassium carbonate (8-36 mmol), and the reaction mixture was refluxed for 15 h. The solvent was filtered, residue washed with CH2Cl2 (5-15 ml), combined organic fractions were evaporated in vacuo. Solid or viscous residue was dissolved in CH2Cl2 and washed with water (3x5-10 ml), organic layer was separated, aqueous layer was washed with CH2Cl2 (3x10-20 ml), and combined organic fractions were dried over molecular sieves 4 A. The solvent was evaporated in vacuo, and resulting compounds 3-6 were obtained as crystalline or glassy compounds.

7,13-Bis(3-bromobenzyl)-1,4,10-trioxa-7,13-diazacyclo-pentadecane (3). Obtained from diazacrown ether 1 (4.5 mmol, 1 g). Yield 2.226 g (89 %), yellowish glassy compound. (MALDI-TOF) found: 555.0821. C24H33Br2N2O3 requires 555.0858 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.57 (4H, t, 3J = 5.1 Hz, CH2N), 2.80 (4H, t, 3J = 5.9 Hz, CH2N), 3.60 (8H, t, 3J = 5.3 Hz, CH2O), 3.62 (4H, s, CH2O), 3.63 (4H, s, ArCH2N), 7.14 (2H, t, 3J = 7.8 Hz, H5-Ar), 7.26 (2H, d, 3J = 7.7 Hz, H6-Ar), 7.34 (2H, d, 3J = 7.8 Hz, H4-Ar), 7.55 (2H, br.s, H2-Ar). 13C NMR (CDCl3, 298 K) SC ppm:

54.2 (2C, CH2N), 54.3 (2C, CH2N), 59.9 (2C, ArCH2N), 69.4 (2C, CH2O), 70.3 (2C, CH2O), 70.6 (2C, CH2O), 122.4 (2C, C3-Ar), 127.2 (2C, CH-Ar), 129.7 (2C, CH-Ar), 129.9 (2C, CH-Ar), 131.6 (2C, CH-Ar), 142.3 (2C, C1-Ar).

7,16-Bis(3-bromobenzyl)-1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane (4). Obtained from diazacrown ether 2 (1.5 mmol, 393 mg). Yield 816 mg (91 %), yellowish crystalline powder, m.p. 79-81 oC. (MALDI-TOF) found: 599.1087. C26H37Br2N2O4 requires 599.1120 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.79 (8H, t, 3J = 4.8 Hz, CH2N), 3.58-3.66 (20H, m, CH2O, ArCH2N), 7.13 (2H, t, 3J = 7.6 Hz, H5-Ar), 7.24 (2H, d, 3J = 7.2 Hz, H4-Ar or H6-Ar), 7.33 (2H, d, 3J = 8.0 Hz, H6-Ar or H4-Ar), 7.50 (2H, br.s, H2-Ar). 13C NMR (CDCl3, 298 K) SC ppm: 53.8 (4C, CH2N), 59.3 (2C, ArCH2N), 69.9 (4C, CH2O), 70.6 (4C, CH2O), 122.3 (2C, C3-Ar), 127.2 (2C, CH-Ar), 129.7 (2C, CH-Ar), 129.9 (2C, CH-Ar), 131.5 (2C, CH-Ar), 142.4 (2C, C1-Ar).

7,13-Bis(4-bromobenzyl)-1,4,10-trioxa-7,13-diazacyclo-pentadecane (5). Obtained from diazacrown ether 1 (2.3 mmol, 0.5 g). Yield 1.211 g (95 %), yellowish glassy compound. (MALDI-TOF) found: 555.0873. C24H33Br2N2O3 requires 555.0858 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.72 (4H, t, 3J = 5.1 Hz, CH2N), 2.77 (4H, t, 3J =5.9, CH2N), 3.55-3.62 (16H, m, CH2O, ArCH2N), 7.22 (4H, d, 3J = 8.2 Hz, H2-Ar, H2'-Ar), 7.39 (4H, d, 'J = 8.2 Hz, H3-Ar, H3'-Ar). 13C NMR (CDCl3, 298 K) 5C ppm: 54.2 (2C, CH2N), 54.3 (2C, CH2N), 59.9 (2C, ArCH2N), 69.4 (2C, CH2O),

70.3 (2C, CH2O), 70.6 (2C, CH2O), 120.5 (2C, C4-Ar), 130.4 (4C, C2-Ar, C2'-Ar), 131.2 (4C, C3-Ar, C3'-Ar), 138.8 (2C, C1-Ar).

7,16-Bis(4-bromobenzyl)-1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane (6). Obtained from diazacrown ether 2 (2 mmol, 0.5 g). Yield 568 mg (95 %), yellowish crystalline powder, m.p. 96-98 oC. (MALDI-TOF) found: 599.1161. C26H37Br2N2O4 requires 599.1120 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.77 (8H, br.s, CH2N), 3.55-3.62 (20H, m, CH2O, ArCH2N), 7.20 (4H, d, 3J = 8.0 Hz, H2-Ar, H2'-Ar), 7.39 (4H, d, 3J = 8 Hz, H3-Ar, H3'-Ar). 13C NMR (CDCl3, 298 K) 5C ppm: 53.7 (4C, CH2N), 59.2 (2C, ArCH2N), 69.9 (4C, CH2O), 70.6 (4C, CH2O), 120.5 (2C, C4-Ar), 130.4 (4C, CH-Ar), 131.2 (4C, CH-Ar), 138.7 (2C, C1-Ar).

Typical procedure for the synthesis of macropolycycles 8-16.

A two-neck flask (25 ml) equipped with a condenser and magnetic stirrer, flushed with argon, was charged with corresponding derivative of diazacrown ether 3-6 (0.25 mmol), Pd(dba)2 (12-24

mg, 8-16 mol%), diphosphine ligand BINAP or DavePhos (9-18 mol%), and absolute dioxane (12 ml). The mixture was stirred for several min, then appropriate diamine 7a,b (0.25 mmol) and tBuONa (72 mg, 0.75 mmol) were added, and the reaction mixture was refluxed for 24-30 h. After the reaction was complete, the mixture was cooled, filtered, the residue was washed with CH2Cl2, the combined organic solvents were evaporated in vacuo, the residue was dissolved in CH2Cl2 (5 ml), washed with water (3x10 ml), aqueous phase was washed with CH2Cl2 (3x15 ml). Combined organic phases were dried over molecular sieves 4 A, the solvent evaporated in vacuo, and the residue chromatographed on silica gel using a sequence of eluents: CH2Cl2, CH2Cl2-MeOH 25:1 - 3:1, CH2Cl2-MeOH-NH3(aq) 100:20:1 - 10:4:1.

28,31,36-Trioxa-1,8,18,25-tetraazaheptacyclo[23.8.5.137.1 10'14.110'16.112'16.119'23]-tritetraconta-3(43), 4,6,19(39),20,22-hexaene (8a). Obtained from compound 3 (139 mg, 0.25 mmol), diamine 7a (49 mg, 0.25 mmol) in the presence of Pd(dba)2 (23 mg, 16 mol%) and DavePhos (18 mg, 18 mol%). Eluent CH2Cl2-MeOH 10:1 -5:1. Yield 50 mg (34 %), yellow glassy compound. (MALDI-TOF) found: 589.4072. C36H53N4O3 requires 589.4117 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.38-1.57 (8H, m, H-Ad), 1.62-1.68 (4H, m, H-Ad), 2.08 (2H, br.s, H2-Ad), 2.78 (4H, s, CH2NH), 2.84 (8H, br.s, CH2N), 3.55-3.65 (12H, m, CH2O, ArCH2N), 3.65 (4H, t, 3J = 5.5 Hz, CH2O), 6.41 (2H, d, 3J = 7.6 Hz, H4-Ar or H6-Ar), 6.43 (2H, d, 3J = 7.1 Hz, H6-Ar or H4-Ar), 6.97 (2H, br.s, H2-Ar), 7.01 (2H, t, 3J = 7.5 Hz, H5-Ar), NH protons were not assigned. 13C NMR (CDCl3, 298 K) SC ppm: 28.5 (2C, CH-Ad), 35.4 (2C, C-Ad), 36.8 (1C, CH2-Ad), 40.4 (4C, CH2-Ad), 42.3 (1C, CH2-Ad), 53.3 (2C, CH2NAr), 55.2 (2C, CH2N), 55.5 (2C, CH2N), 60.1 (2C, ArCH2N), 68.8 (2C, CH2O), 69.2 (2C, CH2O), 69.9 (2C, CH2O), 110.9 (2C, CH-Ar), 112.-7 (2C, CH-Ar), 116.6 (2C, CH-Ar), 128.7 (2C, C5-Ar), 140.5 (2C, C1-Ar), 149.5 (2C, C3-Ar).

28,31,61,64,69, 79-Hexaoxa-1,8,18,25,34,41,51,58-octaazatridecacyclo-[56.8. 5. 525-34.13-7.11014.11016.112 16.119-23.136-40.143-4 7.143,49.145 49.1 n 56]hexaoctaconta-3(86),4,6,19(82),20,22,36(76),37, 39,52(72),53,55-dodecaene (9a). Obtained as the second product in the synthesis of 8a. Eluent CH^-MeOH-NH/aq) 100:20:1. Yield 24 mg (16 %), yellow glassy compound. (MALDI-TOF) found: 1177.8243. C72H105N8O6 requires 1177.8157 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.34-1.68 (24H, m, H-Ad), 2.09 (4H, br.s, H2-Ad), 2.71-2.85 (24H, m, CH2N), 3.50-3.70 (32H, m, CH2O, ArCH2N), 6.46 (4H, d, 3J = 8.0 Hz, H4-Ar or H6-Ar), 6.59 (4H, br.d, 3Jobs = 6.4 Hz, H6-Ar or H4-Ar), 6.69 (4H, br.s, H2-Ar), 7.04 (4H, t, 3J = 7.6 Hz, H5-Ar), NH protons were not assigned. 13C NMR (CDCl3, 298 K) 5C ppm: 28.4 (4C, CH-Ad), 34.5 (4C, C-Ad), 36.4 (2C, CH2-Ad), 40.2 (8C, CH2-Ad), 43.7 (2C, CH2-Ad), 54.1 (8C, CH2N), 56.0 (4C, CH2NAr), 60.6 (4C, ArCH2N), 69.5 (4C, CH2O), "70.3 (4C, CH2O), "70.4 (4C, CH2O), 110.6 (4C, CH-Ar), 113.4 (4C, CH-Ar), 117.3 (4C, CH-Ar), 128.8 (4C, C5-Ar), 140.6 (4C, C1-Ar), 149.1 (4C, C3-Ar).

30,33,38-Trioxa-1,8,20,27-tetraazaheptacyclo[25.8.5.13 7.111, 15.111,17.11317.12125]-pentatetraconta-3(45),4,6,21(41),22,24-hexaene (8b). Obtained from compound 3 (139 mg, 0.25 mmol), diamine 7b (56 mg, 0.25 mmol) in the presence of Pd(dba)2 (12 mg, 8 mol%) and BINAP (14 mg, 9 mol%). Eluent CH^-MeOH 5:1 - 3:1. Yield 74 mg (48 %), yellow glassy compound. (MALDI-TOF) found: 617.4483. C38H57N4O3 requires 617.4430 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.35 (2H, br.s, H-Ad), 1.40-1.44 (4H, m, AdCH2), 1.54 (8H, br.s, H-Ad), 1.64 (2H, br.s, H-Ad), 2.07 (2H, br.s, H22-Ad), 2.76 (4H, t, 3J = 5.2 Hz, CH2N), 2.82 (4H, t, 3J = 5.2 Hz, CH2N), 3.13-3.17 (4H, m, CH2NAr), 3.53 (4H, t, 3J = 5.5 Hz, CH2O), 3.57 (4H, s, CH2O or ArCH2N), 3.64 (4H, t, 3J = 5.2 Hz, CH2O), 3.65 (4H, s, CH2NAr or CH2O), 6.43 (2H, d, 3J = 7.6 Hz, H4-Ar or H6-Ar), 6.48 (2H, d, 3J = 7.1 Hz, H6-Ar or H4-Ar), 6.82 (2H, br.s, H2-Ar), 7.00 (2H, t, 3J = 7.6 Hz, H5-Ar), NH protons were not assigned. 13C NMR (CDCl3, 298 K) SC ppm: 29.0 (2C, CHAd), 32.8 (2C, C-Ad), 36.6 (1C, CH2-Ad), 38^ (2C, AdCH2), 42.0 (4C, CH2-Ad), 43.3 (2C, CH2NAr), 47.7 (1C, CH2-Ad), 54.1 (2C,

CH2N), 55.4 (2C, CH2N), 61.1 (2C, ArCH2N), 70.4 (2C, CH2O), 70.-7 (4C, CH2O), 111.3 (2C, C6-Ar), 113.3 (2C, C4-Ar), 117.5 (2C, C2-Ar), 128.(5 (2C, C5-Ar), 141.2 (2C, C1-Ar), 148.5 (2C, C3-Ar).

28,31,36,39-Tetraoxa-1,8,18,25-tetraazaheptacyclo[23.8.8. 13 7.11014.11216.119 23]hexatetraconta-3(46),4,6,19(22),20,22-hexaene (10a). Obtained from compound 4 (150 mg, 0.25 mmol), diamine 7a (49 mg, 0.25 mmol) in the presence of Pd(dba)2 (23 mg, 16 mol%) and DavePhos (18 mg, 18 mol%). Eluent CH^-MeOH 10:1 -CHp^MeOH-NH/aq) 100:20:2. Yield 46 mg (29 %), yellow glassy compound. (MALDI-TOF) found: 633.4325. C38H57N4O4 requires 633.4380 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.331.67 (12H, m, H-Ad), 2.09 (2H, br.s, H-Ad), 2.76 (8H, br.s, CH2N), 2.86 (4H, s, CH2NAr), 3.55-3.68 (20H, m, CH2O, ArCH2N), (5.43 (4H, d, 3J = 7.3 Hz, H4-Ar, H6-Ar), 6.92 (2H, br.s, H2-Ar), 7.01 (2H, t, 3J = 7.6 Hz, H5-Ar), NH protons were not assigned. 13C NMR (CDCl3, 298 K) SC ppm: 28.5 (2C, CH-Ad), 35.4 (2C, C-Ad), 36.7 (1C, CH2-Ad), 40C (4C, CH2-Ad), 43.2 (1C, CH2-Ad), 54.6 (4C, CH2N), 55.9 (2C, CH2NAr), 60.2 (2C, ArCH^ 70.1 (4C, CH2O), 10.7 (4C, CH2O), 111.2 (2C, CH-Ar), 112.4 (2C, CH-Ar), 116.8 (2C, CH-Ar), 128.7 (2C, C5-Ar), 139.2 (2C, C1-Ar), 149.5 (2C, C3-Ar).

30,33,38,41-Tetraoxa-1,8,20,27-tetraazaheptacyclo[25.8.8 .137.1U,15.1",17.113,17.12125]-octatetraconta-3(48), 4, 6,21(44),22,24-hexaene (10b). Obtained from compound 4 (150 mg, 0.25 mmol), diamine 7b (56 mg, 0.25 mmol) in the presence of Pd(dba)2 (12 mg, 8 mol%) and BINAP (14 mg, 9 mol%). Eluent CH^-MeOH 5:1 - CH^-MeOH-NH/aq) 100:20:1. Yield 89 mg (54 %), yellow glassy compound. (MALDI-TOF) found: 661.4720. C40H61N4O4 requires 661.4693 [M+H]+. 1H NMR (CDCl3, 298 K) 5H ppm1 1.39 (2H, br.s, H-Ad), 1.40-1.44 (4H, m, AdCH2), 1.51 (8H, br.s, H-Ad), 1.63 (2H, br.s, H-Ad), 2.05 (2H, br.s, H2-Ad), 2.81 (8H, br.s, CH2N), 3.12-3.16 (4H, m, CH2NAr), 3.58-3.63 (20H, m, CH2O, ArC^N), 6.44 (2H, dd, 3J = 8.0 Hz, 4J= 1.8 Hz, H6-Ar), 6.54 (2H, br.d, 3Jobs = 6.7 Hz, H4-Ar), 6.75 (2H, br.s, H2-Ar), 7.03 (2H, t, 3J = 7.7 Hz, H5-Ar), NH protons were not assigned. 13C NMR (CDCl3, 298 K) 5C ppm: 29.0 (2C, CH-Ad), 32.8 (2C, C-Ad), 36.6 (1C, CH2-Ad), 38.6 (2C, AdCH2), 42.2 (4C, CH2-Ad), 43.6 (2C, CH)NAr), 47.0 (1C, CH2-Ad), 54.2 (4C, CH2N), 60.3 (2C, ArCH2N), 770.0 (4C, CH2O), 70.7 (4C, CH2O), 112.0 (2C, C4-Ar or C6-Ar), 112,6 (2C, C6-Ar or C4-Ar), 117.52 (2C, C2-Ar), 128.7 (2C, C5-Ar), 141.0 (2C, C1-Ar), 148.5 (2C, C3-Ar).

26,29,34-Trioxa-1,8,16,23-tetraazaheptacyclo[23.8.5.137.1 0,13.19,15.1", 15.117,21]hentetraconta-3(41), 4,6,17(37), 18,20-hexaene (11a). Obtained from compound 5 (139 mg, 0.25 mmol), diamine 7a (49 mg, 0.25 mmol) in the presence of Pd(dba)2 (23 mg, 16 mol%) and DavePhos (18 mg, 18 mol%). Eluent CH^-MeOH-NH/aq) 100:20:3. Yield 18 mg (12 %), yellow glassy compound. (MALDI-TOF) found: 589.4135. C36H53N4O3 requires 589.4117 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.39-1.66 (12H, m, H-Ad), 2.10 (2H, br.s, H2-Ad), 2.70-2.82 (8H, m, CH2N), 2.84 (4H, s, CH2NAr), 3.50 (4H, s, CH2O or ArCH2N), 3.55-3.63 (8H, m, CH2O or CH2O, ArCH2N), 3.69 (4H, t, 3J = 5.1 Hz, CH2O), 6.48 (4H, d, 3J = 8.5 Hz, H3-Ar, H3'-Ar), 7.14 (4H, d, 3J = 8.5 Hz, H2-Ar, H2'-Ar), NH protons were not assigned. 13C NMR (CDCl3, 298 K) 5C ppm: 28.5 (2C, CH-Ad), 35.8 (2C, C-Ad), 37.2 (1C, CH2-Ad), 39.9 (4C, CH2-Ad), 44.3 (1C, CHfAd), 54.5 (2C, CH2N), 55.6 (2C, CH2N), 56.4 (2C, CH2NAr), 60.1 (2C, ArCH2N), 69.6 (2C, CH2O), 70.2 (2C, CH2O), 70.7 (2C, CH2O), 112.1 (4C, C3-Ar, C3'-Ar), 128.8 (2C, C1-Ar), 130.1 (4C, C2-Ar, C2'-Ar), 148.6 (2C, C4-Ar).

28,31,61,64,69,79-Hexaoxa-1,8,18,25,34,41,51,58-octatridecacyclo [56.8.5.525,34.13 7.1"° 14.110,16.11216.119,23.136 40.143 47. 143,49.14s, 49.1 si 56]hexaconta-3(86),4,6,19(82),20,22,36(76),37,39, 52(72),53,55-dodecaene (12a). Obtained as the second product in the synthesis of compound 11a. Eluent CH^-MeOH-NH/aq) 100:20:3. Yield 18 mg (12 %). Additionally a mixture of 12a with a cyclic trimer 13a was obtained. Eluent CH)Cl)-MeOH-NH3(aq) 100:20:3. Yield 15 mg (10 %). Cyclodimer 12a2: (MALDI-TOF) found: 1177.8090. C72H105N8O6 requires 1177.8157 [M+H]+. 1H

NMR (CDCl3, 298 K) SH ppm: 1.39-1.66 (24H, m, H-Ad), 2.10 (4H, br.s, H2-Ad), 2.70-2.835 (24H, m, CH2N, CH2NAr), 3.54 (8H, s, CH2O or ArCH2N), 3.55-3.63 (24H, m, CH2O, ArC^N), 6.54 (8H, d, 3J = 8.3 Hz, H3-Ar, H3'-Ar), 7.09 (8H, d, 3J = 8.3 Hz, H2-Ar, H2'-Ar), NH protons were not assigned. 13C NMR (CDCl3, 298 k) 5C ppm: 28.5 (4C, CH-Ad), 34.5 (4C, C-Ad), 36.6 (2C, CH2-Ad), 40.2 (8C, CH2-Ad), 43.0 (2C, CH2-Ad), 53.8 (4C, CH2N), 54.1 (4C, CH2N), 60.1 (4C, ArCH2N), 69.4 (4C, CH2O), 70.5 (4C, CH2O), 70.(5 (4C, CH2O), 112.3 (8C, C3-Ar, C3'-Ar), 128.1 (4C, C1-Ar), 130.1 (8C, C2-Ar, C2'-Ar), 148.1 (4C, C4-Ar). Cyclotrimer 13a: (MALDI-TOF) found: 1766.25. C108H157N12O9 requires 1766.2196 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.39-1.63 (36H, m, H-Ad), 2.10 (6H, br.s, H2-Ad), 2.72 (12H, d, 3J = 4.6 Hz, CH2N), 2.78 (12H, br.s, CH2N), 2.81 (8H, s, CH2NAr), 3.51-3.62 (48H, m, CH2O, ArCH2N), 6.54 (12H, d, 3J = 8.0 Hz, H3-Ar, H3'-Ar), 7.08 (12H, d, 3J = 8.0 Hz, H2-Ar, H2'-Ar), NH protons were not assigned. 13C NMR (CDCl3, 298 K) 5C ppm: 28.5 (6C, CH-Ad), 34.5 (6C, C-Ad), 36.6 (3C, CH2-Ad), 40.2 (12C, CH2-Ad), 43.0 (3C, CH2-Ad), 53.7 (12C, CH2N), 56.2 (6C, CH2NAr), 60.0 (6C, ArCH2N), 69.4 (6C, CH2O), 70.5 (6C, CH2O), 70.6 (6C, CH2O), 112.4 (12C, C3-Ar, C3'-Ar), 128.1 (6C, C1-Ar), 130.0 (12C, C2-Ar, C2'-Ar), 148.1 (6C, C4-Ar).

30,33,38-Trioxa-1, 8,20,27-tetraazaheptacyclo[25.8.5.13 7. 111, njn n.pi, 25]pentatetraconta-3(45), 4,6,21 (41), 22,24-hexaene (11b). Obtained from compound 5 (139 mg, 0.25 mmol), diamine 7b (56 mg, 0.25 mmol) in the presence of Pd(dba)2 (12 mg, 8 mol%) and BINAP (14 mg, 9 mol%). Eluent CH^-MeOH 5:1 - CH^^-MeOH-NH3(aq) 100:20:1. Yield 54 mg (35 %), yellow glassy compound. (MALDI-TOF) found: 617.4467. C38H57N4O3 requires 617.4430 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.35-1.41 (4H, m, H-Ad), 1.43 (4H, t, 3J = 7.3 Hz, AdCH2), 1.50-1.59 (6H, m, H-Ad), 1.62-1.68 (2H, m, H-Ad), 2.03 (2H, br.s, H2-Ad), 2.64 (4H, t, 3J = 5.1 Hz, CH2N), 2.71 (4H, t, 3J = 5.6 Hz, CH2N), 3.16 (4H, t, 3J = 7.3 Hz, CH2NAr), 3.51 (4H, s, CH2O or ArCH2N), 3.58 (4H, t, 3J = 5.1 Hz, CH2O), 3.61 (4H, s, ArCHN or CH2O), 3.71 (4H, t, 3J = 5.6 Hz, CH2O), 6.54 (4H, d, 3J = 8.3 Hz, H3-Ar, H3'-Ar), 7.23 (4H, d, 3J = 8.3 Hz, H2-Ar, H2'-Ar), NH protons were not assigned. 13C NMR (CDCl3, 298 K) SC ppm: 29.0 (2C, CH-Ad), 32.9 (2C, C-Ad), 36.8 (1C, CH2-Ad), 39.8 (2C, AdCH2), 42.6 (4C, CH2-Ad), 43.0 (2C, CH2NAr), 45.1 (1C, CH2Ad), 55.0 (2C, CH2N), 55.7 (2C, CH2N), 60.2 (2C, ArCH2N), 69.9 (2C, CH2O), 70.3 (2C, CH2O), 70.8 (2C, CH2O), 112.5 (4C, C3-Ar, C3'-Ar), 128.6 (2C, C1-Ar), 129.7 (4C, C2-Ar, C2'Ar), 147.2 (2C, C4-Ar).

29,32,64, 72,82-Hexaoxa-1,8,19,26,35,42,54,61-octaazatriheptacyclo-[59.8.8.5.525,35.13 7.110,14.11016112,16.120 24.137 41. 145,49j45,51.147,51.155,59.]nonaoctaconta-3(89), 4,6,20(85), 21,23,37 (79),38,40,55(75),56,58-dodecaene (12b). Obtained as the second product in the synthesis of compound 11b. Eluent CH2Cl2-MeOH-NH3(aq) 100:20:2. Yield 15 mg (10 %), yellow glassy compound. (MALDI-TOF) found: 1233.8832. C76H113N8O6 requires 1233.8783 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.32-1.67 (32H, m, H-Ad, AdCH2), 2.05 (4H, br.s, H2-Ad), 2.73 (8H, t, 3J = 4.0 Hz, CH2N), 2.79 (8H, t, 3J = 5.8 Hz, CH2N), 3.09 (8H, t, 3J = 7.0 CH^Ar), 3.51-3.64 (32H, m, CH2O, ArCH2N), 6.52 (8H, d, 3J = 8.3 Hz, H3-Ar, H3'-Ar), 7.10 (8H, d, 3J = 8.3 Hz, H2, H2'-Ar), NH protons were not assigned. 13C NMR (CDCl3, 298 K) SC ppm: 29.0 (4C, CH-Ad), 32.7 (4C, C-Ad), 36.5 (2C, CH2-Ad), 38.8 (4C, AdCH2), 42.0 (8C, CH2-Ad), 43.8 (4C, CH2NAr), 47.9 (2C, CH2-Ad), 53.8 (4C, CH2N), 53.9 (4C, CH2N), 60.1 (4C, ArCH2N), 69.5 (4C, CH2O), 70.6 (8C, CH2O), 112.52 (8C, C3-Ar, C3'-Ar), 127.8 (4C, C1-Ar), 130.0 (8C, C2-Ar, C2'-Ar), 147.5 (4C, C4-Ar).

Cyclotrimer 13b. Obtained as the third product in the synthesis of compound 11b. Eluent CH^-MeOH-NH/aq) 100:20:2. Yield 15 mg (10 %), yellow glassy compound. (MALDI-TOF) found: 1850.26. C114H169N12O9 requires 1850.3135 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.32 (6H, br.s, H-Ad), 1.39-1.43 (12H, m, AdCH2), 1.43-1.67 (30H, m, H-Ad), 2.04 (6H, br.s, H2-Ad), 2.73 (12H, t, 3J = 4.9 Hz, CH2N), 2.78 (12H, t, 3J = 5.6 Hz, CH2N), 3.07-

3.10 (12H, m, CH2NAr), 3.52-3.64 (48H, m, CH2O, ArCH2N), 6.52 (12H, d, 3J = 8.1 Hz, H3-Ar, H3'-Ar), 7.10 (12H, d, 3J = 8.1 Hz, H2-Ar, H2'-Ar), NH protons were not assigned. 13C NMR (CDCl3, 298 K) 5C ppm: 29.0 (6C, CH-Ad), 32.7 (6C, C-Ad), 36.5 (3C, CH2-Ad), 38.8 (6C, AdCH2), 42.0 (12C, CH2-Ad), 43.8 (6C, CH2NAr), 47,9 (3C, CH2-Ad), 53.7 (12C, CH2N), 60.1 (6C, ArCH2N), 69.5 (6C, CH2O), 70.5 (6C, CH2O), 70.6 (6C, CH2O), 112.5 (12C, C3-Ar, C3'-Ar), 127.8 (6C, C1-Ar), 130.1 (12C, C2-Ar, C2'-Ar), 147.5 (6C, C4-Ar).

28,31,36,39-Tetraoxa-1,8,18,25-tetraazaheptacyclo[23.8.8. 13.7.11".14.11".16.112.16.119.23-hexatetraconta-3(46), 4, 6,19(42), 20,22-hexaene (14a). Obtained from compound 6 (150 mg, 0.25 mmol), diamine 7a (49 mg, 0.25 mmol) in the presence of Pd(dba)2 (23 mg, 16 mol%) and DavePhos (18 mg, 18 mol%). Eluent CH^-MeOH-NH3(aq) 100:20:3. Yield 22 mg (14 %), yellow glassy compound. (MALDI-TOF) found: 633.4410. C38H57N4O4 requires 633.4380 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.34 (4H, d, 3J = 10.9 Hz, H-Ad), 1.41 (2H, s, H-Ad), 1.57 (4H, d, 3J = 11.7 Hz, H-Ad), 1.66 (2H, br.s, H-Ad), 2.09 (2H, br.s, H-Ad), 2.75 (8H, t, 3J = 5.4 Hz, CH2N), 2.82 (4H, s, CH2NAr), 3.60 (12H, s, CH2O, ArCH2N), 3.62 (8H, t, 3J = 5.6 Hz, CH2O), 6.48 (4H, d, 3J = 8.5 Hz, H3-Ar, H3'-Ar), 7.10 (4H, d, 3J = 8.5 Hz, H2-Ar, H2'-Ar), NH protons were not assigned. 13C NMR (CDCl3, 298 K) SC ppm: 28.5 (2C, CH-Ad), 35.7 (2C, C-Ad), 37.1 (1C, CH2-Ad), 40.1 (4C, CH2-Ad), 44.0 (1C, CH2-Ad), 54.3 (4C, CH2N), 56.3 (2C, CH2NAr), 59.3 (2C, ArCH2N), 70.1 (4C, CH2O), 70.9 (4C, CH2O), 112.6 (4C, C3-Ar, C3'-Ar), 128.2 (2C, C1-Ar), 129.8 (4C, C2-Ar, C2'-Ar), 148.5 (2C, C4-Ar).

Cyclodimer 15a. Obtained as the second product in the synthesis of compound 14a. Eluent CH^-MeOH-NH^aq) 100:20:3. Yield 30 mg (19 %). Additionally a mixture of 15a with a cyclic trimer 16a was obtained. Eluent CH^^-MeOH-NH^aq) 100:20:3. Yield 40 mg (25 %). Cyclodimer 15a: (MALDI-TOF) found: 1265.89. C76H113N8O8 requires 1265.87 [M+H]+. 1H NMR (CDCl3, 298 K) 5H ]ppm: 1.37-1.64 (24H, m, H-Ad), 2.09 (4H, br.s, H2-Ad), 2.77 (16H, t, 3J = 5.8 Hz, CH2N), 2.81 (8H, s, CH2NAr), 3.54 (8H, s, ArCH2N), 3.57-3.62 (32H, m, CH2O), 6.54 (8H, d, 3J = 8.5 Hz, H3-Ar, H3'-Ar), 7.07 (8H, d, 3J = 8.5 Hz, H2-Ar, H2'-Ar), NH protons were not assigned. 13C NMR (CDCl3, 298 K) SC ppm: 28.5 (4C, CH-Ad), 34.5 (4C, C-Ad), 36.6 (2C, CH2-Ad), 40.4 (8C, CH2-Ad), 43.8 (2C, CH2-Ar), 53.4 (8C, CH2N), 56.2 (4C, CH2NAr), 59.44 (4C, ArCH2N), 70.0 (8C, CH2O), 70.6 (8C, CH2O), 112.3 (8C, C3-Ar, C3'-Ar), 128.1 (4C, C1-Ar), 130.0 (8C, C2-Ar, C2'-Ar), 148.1 (4C, C2-Ar, C2'-Ar). Cyclotrimer 16a: (MALDI-TOF) found: 1898.23. C114H169N12O12 requires 1898.30 [M+H]+. 1H NMR (CDCl3, 298 K) 5H ppm: 1.39-1.64 (36H, m, H-Ad), 2.10 (6H, br.s, H2-Ad), 2.77 (24H, t, 3J = 5.6 Hz, CH2N), 2.81 (12H, s, CH2NAr), 3.54 (12H, s, ArCH2N), 3.56-3.62 (48H, m, CH2O), 6.54 (12H, d, 3J = 8.3 Hz, H3-Ar, H3'-Ar), 7.07 (12H, d, 3J = 8.3 Hz, H2-Ar, H2'-Ar), NH protons were not assigned. 13C NMR (CDCl3, 298 K) SC ppm: 28.4 (6C, CH-Ad), 34.5 (6C, C-Ad), 36.6 (3C, CH2-Ad), 40.2 (12C, CH2-Ad), 43.7 (3C, CH2-Ad), 53.4 (12C, CH2N), 56.1 (6C, CH2NAr), 59.3 (6C, ArCH2N), 69.9 (12C, CH2O), 70.6 (12C, CH2O), 112.3 (12C, C3-Ar, C3'-Ar), 128.1 (6C, C1-Ar), 130.0 (12C, C2-Ar, C2'-Ar), 148.1 (6C, C4-Ar).

30, 33, 38, 41-Tetraoxa-1, 8, 20, 27-tetraazaheptacyclo[25.8. 8.13,7.1»,15.1",17 .I1317.12', 25]octatetraconta-3(48), 4,6,21(44),22,24-hexaene (14b). Obtained from compound 6 (150 mg, 0.25 mmol), diamine 7b (56 mg, 0.25 mmol) in the presence of Pd(dba)2 (12 mg, 8 mol%) and BINAP (14 mg, 9 mol%). Eluent CH)Cl)- CHp^ MeOH-NH3(aq) 100:20:3. Yield 26 mg (16 %), yellow glassy compound. (MALDI-TOF) found: 661.4671. C40H61N4O4 requires 661.4693 [M+H]+. 1H NMR (CDCl3, 298 K) SH pppn4: 1.36-1.40 (4H, m, H-Ad), 1.42 (4H, t, 3J = 7.2 Hz, AdCH2), 1.49-1.55 (6H, m, H-Ad), 1.63 (2H, br.s, H-Ad), 2.03 (2H, br.s, H-Ad), 2.71 (8H, t, 3J = 4.9 Hz, CH2N), 3.14 (4H, t, 3J = 7.2 Hz, CH2NAr), 3.56 (4H, s, ArCH2N), 3.61 (8H, t, 3J = 5.4 Hz, CH2O), 3.63 (8H, s, CH2O), 6.53 (4H, d, 3J = 8.1 Hz, H3-Ar, H3'-Ar), 7.17 (4H, d, 3J = 8.1 Hz,

H2-Ar, H2'-Ar), NH protons were not assigned. 13C NMR (CDCl3, 298 K) 5C ppm: 29.0 (2C, CH-Ad), 32.8 (2C, C-Ad), 36.7 (1C, CH2-Ad), 39.0 (2C, AdCH2), 42.6 (4C, CH2-Ad), 43.1 (2C, CH2NAr), 45.2 (1C, CH2-Ad), 54.5 (4C, CH2N), 59.6 (2C, ArCH2N), 69.9 (4C, CH2O), 70.8 (4C, CH2O), 112.6 (4C, C3-Ar, C3'-Ar), 128.0 (2C, C1-Ar), 129.8 (4C, C2-Ar, C2'-Ar), 147.4 (2C, C4-Ar).

Cyclodimer 15b. Obtained as the second product in the synthesis of compound 14b. Eluent CH2Cl2-MeOH-NH3(aq) 100:25:5. Yield 26 mg (16 %). Additionally a mixture of 15b with a cyclic trimer 16b was obtained. Eluent CH2Cl2-MeOH-NH3(aq) 100:25:5. Yield 37 mg (22 %). Cyclodimer 151): (MALDI-TOF) found: 1321.91. C80H121N8O8 requires 1321.93 [M+H]+. 1H NMR (CDCl3, 298 K) 5H ppm: 1.32 (4H, br.s, H-Ar), 1.39-1.43 (8H, m, AdCH2), 1.43-1.63 (20H, m, H-Ad), 2.03 (4H, br.s, H2-Ad), 2.78 (16H, t 3J = 5.6 Hz, CH2N), 3.07-3.10 (8H, m, CH2NAr), 3.55 (8H, s, ArCH2N), 3.57-3.63 (32H, m, CH2O), 6.52 (8H, d, 3J = 8.1 Hz, H3-Ar, H3'-Ar), 7.09 (8H, d, 3J = 8.1 Hz, H2-Ar, H2'-Ar), NH protons were not assigned. 13C NMR (CDCl3, 298 K) SC ppm: 28.9 (4C, CHAd), 32.7 (4C, C-Ad), 36.4 (2C, CH2-Ad), 38.8 (4C, AdCH2), 42.0 (8C, CH2-Ad), 43.8 (4C, CH2NAr), 47.9 (2C, CH2-Ad), 53.4 (8C, CH2N), 59.4 (4C, ArCH2N), 70.0 (8C, CH2O), 70.7 (8C, CH2O), 112.5 (8C, C3-Ar, C3'-Ar), 128.0 (4C, Cl-Ar), 130.0 (8C, C2-Ar, C2'-Ar), 147.5 (4C, C4-Ar). Cyclotrimer 16b. (MALDI-TOF) found: 1982.34. C^H^N^O^ requires 1982.39 [M+H]+. 1H NMR (CDCl3, 298 K) 5H ppm: 1.31 (6H, br.s, H-Ar), 1.39-1.42 (12H, m, AdCH2), 1.43-1.61 (30H, m, H-Ad), 2.04 (6H, br.s, H2-Ad), 2.78 (24H, t, 3J = 5.4 Hz, CH2N), 3.06-3.10 (12H, m, CH2NAr), 3.55 (12H, s, ArCH2N), 3.57-3.63 (48H, m, CH2O), 6.52 (12H, d, 3J = 8.3 Hz, H3-Ar, H3'-Ar), 7.09 (12H, d, 3J = 8.3 Hz, H2-Ar, H2'-Ar), NH protons were not assigned. 13C NMR (CDCl3, 298 K) SC ppm: 28.9 (6C, CH-Ad), 32.7 (6C, C-Ad), 36.4 (3C, CH2-Ad), 387 (6C,

AdCH2), 41.9 (12C, CH2-Ad), 43.7 (6C, CH2NAr), 47.9 (3C, CH2-Ad), 53.4 (12C, CH2N), 59.4 (6C, ArC^N), 69.9 (12C, CH2O), 70.6 (12C, CH2O), 112.4 (12C, C3-Ar, C3'-Ar), 127.6 (6C, C1-Ar), 130.0 (12C, C2-Ar, C2'-Ar), 147.5 (6C, C4-Ar).

Results and Discussion

To synthesize macrobicyclic compounds comprising diazacrown units, first we synthesized A,A'-bis(bromo-benzyl) derivatives of diazacrwon ethers 3-6 (Scheme 1). The reactions were carried out using exactly two equivalents of bromobenzyl bromides, in boiling acetonitrile, K2CO3 was used as base in the case of a smaller macrocycle 1 whereas Na2CO3 was employed in the reaction with a larger diazacrown ether 2 in order to minimize the coordination of the cation. However, the work-up of the reaction mixtures included a meticulous washing of the resulting compounds 3-6 with water to avoid coordinated salts. As a result, the target compounds were obtained in high yields 89-95 %.

Diazacrown derivatives 3-6 were introduced in the palladium-catalyzed reactions with adamantane-containing diamines 7a,b (Scheme 2). We employed Pd(dba)/BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthalene) (8 mol%) catalytic system for the reactions with 1,3-bis(2-aminoethyl)-adamantane 7b, while the cyclization with 1,3-bis(amino-methyl)adamantane 7a was catalyzed in the presence of Pd(dba)2/DavePhos (2-dicyclohexylphosphino-2'-dimethyl-aminobiphenyl) (16 mol%). The choice of the catalytic

n = 1: 5,95% n = 2: 6, 95%

Br

a *

M2C03, CH3CN

M = K, n = 1 M = Na, n = 2

c

NH 0

n/ HN

n =1: 1 n =2: 2

Br

M2C03, CH3CN

M = K, n = 1 M = Na, n = 2

n= 1:3,89% n = 2:4,91 %

Scheme 1.

n = 1, m-Br 3 n = 2, m-Br 4 n = 1, p-Br: 5 n = 2, p-Br: 6

H,N

NH,

H2N X NH2 7a,b

Pd(dba)2/L Br (8-16/9-18 mol%)

(BuONa, dioxane L = BINAP, DavePhos

n = 1, m-: 8a,b n = 2, m-: 10a,b n = 1,p-: 11a,b NH n = 2, p-: 14a,b

n = 1, m = 1, m-: 9a n = 1, m = 1,p-: 12a,b n = 1, m =2,p-: 13a,b n = 2, m = 1,p-: 15a,b n = 2, m = 2, p-: 16a,b

m

7a

7b

Scheme 2.

Table 1.

Entry Diazacrown ether derivative Diamine Ligand Pd(dba)/L, mol% Product, yield, % By-product, yield, % '

1 3 7a DavePhos 16/18 8a, 34 9a, 16

2 3 7b BINAP 8/9 8b, 48

3 4 7a DavePhos 16/18 10a, 29

4 4 7b BINAP 8/9 10b, 54

5 5 7a DavePhos 16/18 11a, 12 12a, 12a)

6 5 7b BINAP 8/9 11b, 35 12b, 10b)

7 6 7a DavePhos 16/18 14a, 14 15a, 19c)

8 6 7b BINAP 8/9 14b,16 15b, 16d)

9 6 7b BINAP 16/18 14b,15 15b,19

a) Additionally a mixture of 12a and 13a was isolated (10 %).

b) Cyclotrimer 13b was isolated (10 %).

c) Additionally a mixture of 15a and 16a was isolated (25 %).

d) Additionally a mixture of 15b and 16b was isolated (22 %).

system was based on our previous research of the Pd-catalyzed arylation of these diamines with dihalobenzenes. [32] The results of the cyclization reactions are presented in Table 1.

The yields of the target macrobicycles were dramatically dependent on the nature of starting diazacrown derivatives and diamines. For the majority of cases, the reactions with the diamine 7b gave better results than with the diamine 7a, the best yields being 48 and 54 % (entries 2, 4). Probably it was due to the fact that amino groups in the diamine 7a are more sterically hindered by a closer adamantane core. Also the diamine 7a is more rigid compared to the diamine 7b, thus the geometric demands for a successful cyclization with this diamine are stricter. Derivatives of the 3-bromobenzyl substituted diazacrown ethers 3 and 4 provided higher yields of the macrobicycles 8 and 10 (entries 1-4) if compared with 4-bromobenzyl substituted diazacrowns 5 and 6 (entries 5-8). This fact might be also explained by a better adjustment of two bromine atoms to the nitrogen atoms of diamines in the diazacrown ethers with meta-bromobenzyl substituents. On the other hand, we did not observe a pronounced dependence of the reaction result on the size of the diazacrown moiety, thus the different ability of the starting compounds 3-6 to coordinate sodium cation was not important. As the yield of the macrobicycle 14b was low (16 %, entry 8), we tried the application of the twofold amount of the catalyst (entry 9) but obtained almost the same result. It means that 8 mol% of the Pd(dba)2/BINAP system is quite sufficient for the reaction with the diamine 7b while 7a demands greater catalyst loading.

In many cases we obtained not only the target macro-bicyclic compounds but also macrotricyclic cyclodimers and even macrotetracyclic cyclotrimers. These compounds were formed primarily with para-bromobenzyl derivatives 5 and 6 and their yields were comparable with those of macrobicycles (entries 5, 7, 8). This fact can be also explained by the higher sterical demands of bis(4-bromobenzyl) substituted diazacrown ethers which hindered the intramolecular di-amination and decreased the yields of macrobicycles 11, 14 simultaneously boosting the formation of cyclic oligomers.

Conclusions

To sum up, we elaborated a convenient synthesis of the macrobicycles containing diazacrown ether and adamantane moieties using the Pd-catalzyed amination reaction, demonstrated the dependence of the macrobicycles yields on the nature of starting compounds. The reactions with 1,3-bis(2-amonoethyl)adamantane were catalyzed with Pd(dba)2/BINAP whereas 1,3-bis(aminomethyl) adamantane needed the application of Pd(dba)2/DavePhos catalytic system. A,A'-bis(3-bromobenzyl) substituted diazacrown ethers were shown to provide better yields of the target macrobicycles (up to 54 %), whereas the reactions with their 4-bromo-benzyl-containing isomers gave reasonable amounts of cyclic oligomers, i.e. macrotricycles and macrotetracycles.

Acknowledgements. This work was carried out in the frame of the International Associated French-Russian Laboratory of Macrocycle Systems and Related Materials (LAMREM) of the Centre National de la Recherche Scientifique (CNRS). It was financially supported by CNRS, RFBR grants 1203-93107, 10-03-01108, 12-03-00796, and by the Russian Academy of Sciences program P-8 "Development of the methods for the synthesis of new chemicals and creation of new materials".

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Received 13.12.2012 Accepted 10.02.2013