Synthesis of trismacrocyclic and macrotricyclic compounds possessing structural fragments of aza-and diazacrown ethers, cyclen and cyclam via Pd-catalyzed amination reactions Текст научной статьи по специальности «Биологические науки»

Crown Ethers

Краун-эфиры

Макрогэтэроцмклы

Статья

Paper

http://macroheterocycles.isuct.ru

DOI: 10.6060/mhc140484a

Synthesis of Trismacrocyclic and Macrotricyclic Compounds Possessing Structural Fragments of Aza- and Diazacrown Ethers, Cyclen and Cyclam via Pd-Catalyzed Amination Reactions

Sergei M. Kobelev,a Alexei D. Averin,ab@ Alexei K. Buryak,b Franck Denat,c Roger Guilard,c and Irina P. Beletskayaab

Dedicated to Academician of Russian Academy of Sciences Oleg N. Chupakhin on the occasion of his 80th Anniversary

aM.V. Lomonosov Moscow State University, Department of Chemistry, 119991 Moscow, Russia bA.N. Frumkin Institute of Physical and Electrochemistry of RAS, 119991 Moscow, Russia

cInstitut de Chimie Moléculaire de l'Université de Bourgogne (ICMUB), UMR CNRS 6302, 21078 Dijon Cedex, France @Corresponding author E-mail: averin@org.chem.msu.ru

Synthesis of trismacrocyclic compounds with a central tetraazamacrocyclic moiety and two aza-crown ether fragments was carried out using the Pd-catalyzed amination of trans-bis(bromobenzyl) substituted cyclen and cyclam with 3 equiv. of azacrown ethers. The yields were shown to be dependent on the nature of the starting tetraazamacrocycles and reached 45 % in the best case. Formation of the cylindrically-shaped cryptands was achieved by reacting equimolar amounts of trans-bis(bromobenzyl) substituted cyclen or cyclam and diazacrown ethers. The yields of the target cryptands reached 30 % and a clear dependence of the result of the reaction on the reciprocal position of two bromine atoms and two nitrogen atoms in the reactants was observed.

Keywords: Macrocycles, amination, Pd catalysis.

Синтез трисмакроциклических и макротрициклических соединений, содержащих фрагменты аза- и диазакраун-эфиров, циклена и циклама, с помощью реакций Pd-катализируемого аминирования

С. М. Кобелев^ А. Д. Аверин, a'b@ А. К. Бурякь Ф. Дена^ Р. Гиляр^ И. П. Белецкая3*

Посвящается академику РАН О.Н. Чупахину по случаю его 80-летнего юбилея

aХимический факультет Московского государственного университета им. М.В. Ломоносова, 119991 Москва, Россия ьИнститут физической и электрохимии им. А.Н. Фрумкина РАН, 119991 Москва, Россия cInstitut de Chimie Moléculaire de l'Université de Bourgogne (ICMUB), UMR CNRS 6302, 21078 Дижон, Франция @E-mail: averin@org.chem.msu.ru

Синтез трисмакроциклических соединений с центральным тетраазамакроциклическим и двумя фрагментами азакраун-эфиров осуществлен с помощью Pd-катализируемого аминирования транс-бис(бромбензил)замещен-ных циклена и циклама 3 экв. азакраун-эфиров. Показано, что выходы продуктов зависят от природы исходных соединений и в лучшем случае достигают 45 %. Образование криптандов цилиндрической формы происходит при реакции эквимольных количеств транс-бис(бромбензил)замещенных циклена и циклама и диазакраун-эфиров. Выходы целевых криптандов достигают 30 %, при этом наблюдается четкая зависимость выходов целевых соединений от взаимного расположения атомов брома и аминогрупп в исходных соединениях.

Ключевые слова: Макроциклы, аминирование, Pd катализ.

Introduction

Macropolycycles of cylindrical topology based on tetraazamacrocycles are valuable compounds for supra-molecular chemistry due to their ability to form binuclear complexes with metal cations. The fixed distance between the two cations induces cations interactions leading to unique electronic properties.11,21 Two of us previously described several convenient methods for the synthesis of macrotricycles possessing two cyclen (1,4,7,10-tetraazacyclodode-cane) or cyclam (1,4,8,11-tetraazacyclotetradecane) moieties linked via two xylylene bridges. These 3-step approaches utilize either A1,A8-ditosyl-A4-Boc-cyclam[3] or A-Boc-sub-stituted dioxocyclen and dioxocyclam.[4] So-called bisami-nal strategy exploits protected glyoxal-cyclen and glyoxal-cyclam and the synthetic scheme also comprises three steps with a reduction reaction at the last step,[5] this method was used for the synthesis of macrotricycles with two cross-bridged cyclen fragments.[6] On the basis of these cryp-tands, mono- and bimetallic homonuclear and heteronuclear complexes were obtained with Cu(II) and Ni(II) cations.[7-10] 1,8-Ditosylcyclam, 1,8-diBoccyclam and 2,9-dioxocyclam were applied for the synthesis of macrotricycles and macro-tetracycles comprising cyclam and porphyrin moieties,[11-13] while more sophisticated macropolycles possessing tetraaza-macrocycles were obtained using functionalized porphy-rins.[14,15] Homo- and heterobinuclear metal complexes with Cu(II), Fe(III) and Co(III) were synthesized on the basis of macrotetracycle and studied as cytochrome oxidase model. [12] All reported approaches to cyclen- and cyclam-containing cryptands utilize only non-catalytic pathways with protected tetraazamacrocycles. During our previous investigations we demonstrated the possibility to synthesize macrobicyclic cryptands on the basis of cyclen and cyclam using Pd(0)-cat-alyzed amination of their trans-bis(bromobenzyl) and trans-bis(halopyridinylmethyl) derivatives.[16-19] In this work we decided to elaborate a simple and general one-pot approach to trismacrocyclic compounds using the Pd(0)-mediated reactions of trans-bis(bromobenzyl) substituted cyclen and cyclam with azacrown ethers and to macrotricyclic cylindrical cryptands using catalytic amination of the same substrates with diazacrown ethers.

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-Aza-15-crown-5 (5), 1-aza-18-crown-6 (6), 1,4,10-trioxa-7,13-diazacyclopentadecane (15), 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane (16), 2-(dicyclohexylphosphino)-2' -(dimethylamino)-1,1'-biphenyl (DavePhos ligand), sodium tert-butoxide were purchased from Aldrich and Acros and used without further purification. 1,7-bis(3-bromobenzyl) cyclen (1), 1,7-bis(4-bromobenzyl) cyclen (2), 1,8-bis(3-bromobenzyl) cyclam (3), 1,8-bis(4-bromobenzyl) cyclam (4) were obtained from cyclen or cyclam according to reported procedures,116171 Cyclen and cyclam were provided by CheMatech Co. Pd(dba)2 was synthesized according to the method described.[20] Dioxane was distilled over NaOH followed by the distillation over sodium under argon, dichlorometh-ane and methanol were used freshly distilled.

Typical procedure for the synthesis of trismacrocycles 7-14.

A two-neck flask equipped with a condenser and magnetic stirrer, flushed with dry argon, was charged with trans-bis(bromobenzyl) derivative of cyclen or cyclam 1-4 (0.2 mmol), Pd(dba)2 (18 mg, 0.032 mmol, 16 mol%) and DavePhos (14 mg, 0.036 mmol, 18 mol%), abs. dioxane (2 mL), the mixture was stirred for 2-3 min, then corresponding azacrown ether 5 or 6 (0.6 mmol) and t-BuONa (58 mg, 0.6 mmol) were added, and the reaction mixture was refluxed for 24-30 h. After cooling it down to ambient temperature the reaction mixture was diluted with CH2Cl2, the residue was filtered off, washed with dichloromethane, combined organic solvents were evaporated in vacuo, the residue was dissolved in CH2Cl2 (5 mL), washed with distilled water (3x10 mL), organic layer was dried over molecular sieves 4 A and evaporated in vacuo, the residue chromatographed on silica gel using a sequence of eluents: CH2Cl2, CH2Cl2/MeOH (25:1-3:1), CH2Cl2/MeOH/NH3aq (100:20:1-10:4:1).

13,13'-[1,4,7,10-Tetraazacyclododecane-1,7-diylbis-(methylene-3,1-phenylene)]bis-1,4,7,10-tetraoxa-13-azacyclo-pentadecane (7). Obtained from compound 1 (102 mg, 0.2 mmol) and azacrown ether 5 (131 mg, 0.6 mmol). Eluent CH2Cl2/MeOH 10:1. Yield 48 mg (31 %), yellowish glassy compound. (MALDI-TOF) found: 787.5419. C42H71N6O8 requires 787.5333 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.65-2.72 (8H, m), 2.73-2.77 (8H, m), 3.50 (8H, t, 3J = 5.9 Hz), 3.54-3.63 (28H, m), 3.66 (8H, t, 3J = 5.9 Hz), 6.46 (2H, br.s), 6.48 (2H, d, 3J = 8.4 Hz), 6.64 (2H, d, 3J = 7.2 Hz), 7.11 (2H, t, 3J =7.8 Hz), NH protons were not assigned. 13C NMR (CDCl3, 298 K) Sc ppm: 47.2 (4C), 51.3 (4C), 52.1 (4C), 61.8 (2C), 68.2 (4C), 69.7 (4C), 69.8 (4C), 70.9 (4C), 111.0 (2C), 111.8 (2C), 115.8 (2C), 129.1 (2C), 139.6 (2C), 147.4 (2C).

13,13 '-[1,4,8,11-Tetraazacyclotetradecane-1,8-diylbis-(methylene-3,1-phenylene)]bis-1,4,7,10-tetraoxa-13-azacyclo-pentadecane (8). Obtained from compound 3 (108 mg, 0.2 mmol) and azacrown ether 5 (131 mg, 0.6 mmol). Eluent CH2Cl2/MeOH/ NH3aq 100:20:3. Yield 34 mg (21 %), yellowish glassy compound. (MALDI-TOF) found: 815.5693. C44H75N6O8 requires 815.5646 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.80 (4H, br.s), 2.50 (4H, br.s), 2.57 (4H, br.s), 2.67 (4H, br.s), 2.72 (4H, br.s), 3.55 (8H, t, 3J = 5.5 Hz), 3.58-3.66 (28H, m), 3.71 (8H, t, 'J = 5.5 Hz), 6.49 (2H, d, 3J = 8.0 Hz), 6.50 (2H, br.s), 6.63 (2H, d, 3J =7.1 Hz), 7.10 (2H, t, 3J = 7.5 Hz), NH protons were not assigned. 13C NMR (CDCl3, 298 K) 5c ppm: 25.8 (2C, br., Av1/2 = 10 Hz), 47.7 (2C), 49.4 (2C, br., Av1/2 = 20c Hz), 50.7 (2C), 52.4 (-4C), 53.8 (2C, br., Av1/2 = 20 Hz), 58.22 (2C), 68.5 (4C), 70.1 (8C), 71.2 (4C), 109.9 (2C), 112.6 (2C), 117.0 (2C), 129.0 (2C), 138.3 (2C), 147.3 (2C).

16,16'-[1,4,7,10-Tetraazacyclododecane-1, 7-diylbis-(methylene-3,1-phenylene)]bis-1,4,7,10,13-pentaoxa-16-azacyclo-octadecane (9). Obtained from compound 1 (102 mg, 0.2 mmol) and azacrown ether 6 (158 mg, 0.6 mmol). Eluent CH2Cl2/MeOH 10:1. Yield 54 mg (31 %), yellowish glassy compound. (MALDI-TOF) found: 875.5791. C46H79N6O10 requires 875.5858 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.(50-2.67 (8H, m), 2.68-2.73 (8H, m), 3.47-3.55 (44H, m), 3.57 (8H, t, 3J = 6.0 Hz), 6.43-6.50 (4H, m), 6.61 (2H, d, 3J = 7.0 Hz), 7.07 (2H, t, 3J = 7.7 Hz), NH protons were not assigned. 13C NMR (CDCl3, 298 K) 5c ppm: 46.9 (4C), 50.8 (4C), 51.1 (4C), 61.5 (2C), 68.3 (4C), 70.1 (4C), 70.2 (12C, br.), 110.3 (2C), 112.2 (2C), 116.1 (2C), 128.9 (2C), 139.3 (2C), 147.6 (2C).

16,16'-[1,4,8,11-Tetraazacyclotetradecane-1,8-diylbis-(methylene-3,1-phenylene)]bis-1,4,7,10,13-pentaoxa-16-azacyclo-octadecane (10). Obtained from compound 3 (108 mg, 0.2 mmol) and azacrown ether 6 (158 mg, 0.6 mmol). Eluent CH2Cl2/MeOH/ NH3aq 100:35:6. Yield 58 mg (32 %), yellowish glassy compound. (MA3 LDI-TOF) found: 903.6026. C48H83N6O10 requires 903.6171 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.81 (4H, br.s), 2.50 (4H, t, 3J = 4.9 Hz), 2.59 (4H, br.s), 2.67-2.75 (8H, m), 3.54-3.69 (52H, m), 6.49-6.54 (4H, m), 6.62 (2H, d, 3J = 7.3 Hz), 7.09 (2H, t, 3J = 8.0 Hz), NH protons were not assigned. 13C NMR (CDCl3, 298 K) 5c ppm: 25.2 (2C), 47.5 (2C), 48.9 (2C, br., Av1/2 = 12 Hz), 50.8

(2C), 51.0 (4C), 52.6 (2C, br., Av1/2 = 15 Hz), 58.8 (2C), 68.7 (4C), 70.5 (4C), 70.6 (8C), 70.7 (4C), 110.3 (2C), 113.0 (2C), 117.0 (2C), 129.1 (2C), 138.4 (2C), 147.8 (2C).

13,13 '-[1,4,7,10-Tetraazacyclododecane-1,7-diylbis-(methylene-4,1-phenylene)]bis-1,4,7,10-tetraoxa-13-azacyclo-pentadecane (11). Obtained from compound 2 (102 mg, 0.2 mmol) and azacrown ether 5 (131 mg, 0.6 mmol). Eluent CH2Cl2/MeOH 10:1. Yield 66 mg (42 %), yellowish glassy compound. (MALDI-TOF) found: 787.5397. C42H71N6O8 requires 787.5333 [M+H]+. 1H NMR SH (CDCl3, 298 K) 2.71 (8H, br.s), 2.75 (8H, br.s), 3.53-3.68 (36H, m), 3.72 (8H, t, 3J = 5.1 Hz), 6.61 (4H, d, 3J = 7.8 Hz), 7.13 (4H, d, 3J = 7.8 Hz), NH protons were not assigned. 13C NMR (CDCl3, 298 K) Sc ppm: 47.4 (4C), 51.3 (4C), 52.5 (4C), 60.8 (2C), 68.5 (4C), 69.9 (4C), 70.1 (4C), 71.2 (4C), 111.2 (4C), 125.6 (2C), 130.1 (4C), 147.0 (2C).

13,13 '-[1,4,8,11-Tetraazacyclotetradecane-1,8-diylbis-(methylene-4,1-phenylene)]bis-1,4,7,10-tetraoxa-13-azacyclo-pentadecane (12). Obtained from compound 4 (108 mg, 0.2 mmol) and azacrown ether 5 (131 mg, 0.6 mmol). Eluent CH2Cl2/MeOH/ NH3aq 100:20:2. Yield 18 mg (11 %), yellowish glassy compound. (MALDI-TOF) found: 815.5602. C44H75N6O8 requires 815.5646 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.79 (4H, br.s), 2.46 (4H, t, 3J = 4.7 Hz), 2.53 (4H, br.s), 2.62-2.72 (8H, m), 3.51 (8H, t, 3J = 5.9 Hz), 3.53-3.64 (28H, m), 3.66 (8H, t, 3J = 5.9 Hz), 6.54 (4H, d, 3J = 8.5 Hz), 7.07 (4H, d, 3J = 8.5 Hz), NH protons were not assigned. 13C NMR (CDCl3, 298 K) Sc ppm: 25.6 (2C), 47.6 (2C), 50.0 (2C, br., Av1/2 = 30 Hz), 51.2 (2C, br., Av1/2 = 10 Hz), 52.4 (4C), 53.3 (2C, br., Av1/2 = 20 Hz), 56.8 (2C), 68.5 (4C), 70.0 (8C), 71.2 (4C), 110.9 (4C), 12/23.9 (2C), 130.7 (4C), 146.5 (2C).

16,16'-[1,4,7,10-Tetraazacyclododecane-1, 7-diylbis-(methylene-4,1-phenylene)]bis-1,4,7,10,13-pentaoxa-16-azacyclo-octadecane (13). Obtained from compound 2 (102 mg, 0.2 mmol) and azacrown ether 6 (158 mg, 0.6 mmol). Eluent CH2Cl2/MeOH 3:1. Yield 79 mg (45 %), yellowish glassy compound. (MALDI-TOF) found: 875.5784. C46H79N6O10 requires 875.5858 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.76 (16H, br.s), 3.53-3.66 (52H, m), 6.61 (4H, d 3J = 8.1 Hz), 7.11 (4H, d, 3J = 8.1 Hz), NH protons were not assigned. 13C NMR (CDCl3, 298 K) Sc ppm: 46.9 (4C), 50.9 (4C), 51.2 (4C), 60.3 (2C), 68.6 (4 C), 70.4 (4C), 70.5 (8C), 70.6 (4C), 111.6 (4C), 125.2 (2C), 130.1 (4C), 147.3 (2C).

16,16'-[1,4,8,11-Tetraazacyclotetradecane-1,8-diylbis-(methylene-4,1-phenylene)]bis-1,4,7,10,13-pentaoxa-16-azacyclo-octadecane (14). Obtained from compound 4 (108 mg, 0.2 mmol) and azacrown ether 6 (158 mg, 0.6 mmol). Eluent CH2Cl2/MeOH/ NH3aq 100:35:6. Yield 27 mg (15 %), yellowish glassy compound. (MALDI-TOF) found: 903.6253. C48H83N6O10 requires 903.6171 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.80 (4H, br.s), 2.46 (4H, t, 3J = 4.9 Hz), 2.53 (4H, br.s), 2.63-2.72 (8H, m), 3.51-3.58 (16H, m), 3.59-3.66 (36H, m), 6.57 (4H, d, 3J = 8.7 Hz), 7.08 (4H, d, 3J = 8.7 Hz), NH protons were not assigned. 13C NMR (CDCl3, 298 K) Sc ppm: 25.6 (2C, br., Av1/2 = 15 Hz), 47.7 (2C), 50.0 (2C3, br., Av1/2 = 30 Hz), 51.2 (6C), 53.3 (2C, br., Av1/2 = 50 Hz), 56.9 (2C), 68.7 (4C), 70.6 (4C), 70.7 (4C), 70.8 (8C), 111.2 (4C), 124.1 (2C), 130.8 (4C), 146.9 (2C).

Typical procedure for the synthesis of cryptands 17,18, 20-23.

A two-neck flask equipped with a condenser and magnetic stirrer, flushed with dry argon, was charged with trans-bis(bromobenzyl) derivative of cyclen or cyclam 1-4 (0.15 mmol), Pd(dba)2 (14 mg, 0.024 mmol, 16 mol%) and DavePhos (10.5 mg, 0.027 mmol, 18 mol%), abs. dioxane (8 mL), the mixture was stirred for 2-3 min, then corresponding diazacrown ether 15 or 16 (0.15 mmol) and t-BuONa (44 mg, 0.45 mmol) were added, and the reaction mixture was refluxed for 24-30 h. After cooling it down to ambient temperature the reaction mixture was diluted with CH2Cl2, the residue was filtered off, washed with dichloromethane, combined organic solvents were evaporated in vacuo, the residue was dissolved in CH2Cl2 (5 mL), washed with distilled water (3x10 mL), organic layer was dried over molecular sieves 4 A

and evaporated in vacuo, and the residue was chromatographed on silica gel using a sequence of eluents: CH2Cl2, CH2Cl2/MeOH (25:1-3:1), CH2Cl2/MeOH/NH3aq (100:20:1-10:4:1).

23,26,31-Trioxa-1,8,11,14,21,3 7-hexaazapentacyclo[19.7.5. 5s,i4.i2,6.1i6,2o]tetraconta-2(40),3,5,16(34), 17,19-hexaene (17). Obtained from compound 1 (77 mg, 0.15 mmol) and diazacrown ether 15 (33 mg, 0.15 mmol). Eluent CH2Cl2/MeOH 10:1. Yield 9 mg (10 %), yellow glassy compound. (MALDI-TOF) found: 567.3979. C32H51N6O3 requires 567.4023 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.64-2.93 (16H, m), 3.44-3.52 (8H, m), 3.60 (8H, br.s), 3.62 (4H, br.s), 3.88 (4H, t, 3J = 5.3 Hz), 6.48 (4H, br.s), 7.06 (2H, t, 3J = 8.0 Hz), 7.15 (2H, s), NH protons were not assigned. 13C NMR (CDCl3, 298 K) Sc ppm: 49.4 (4C), 52.0 (6C), 54.3 (2C), 63.0 (2C),

69.6 (2C), 70.2 (2C), 70.4 (2C), 110.4 (2C), 114.0 (2C), 117.8 (2C), 128.6 (2C), 139.9 (2C), 149.2 (2C).

7,7'-[1,4,7,10-Tetraazacyclododecane-1,7-diylbis-(methylene-3,1-phenylene)]bis-1,4,10-trioxa-7,13-diazacyclo-pentadecane (19). Obtained as the main product in the synthesis of cryptands 17. Eluent CH2Cl2/MeOH/NH3aq 100:20:3. Yield 13 mg (22 %), yellow glassy compound. (MALDI-TOF) found: 785.58. C42H73N8O6 requires 785.57 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.(55 (16H, br.s), 2.77 (4H, t, 3J = 5.9 Hz), 2.78 (4H, t, 3J = 5.2 Hz), 3.52-3.67 (32H, m), 3.74 (4H, t, 3J = 6.8 Hz), 6.52 (2H, s), 6.56 (2H, d, 3J = 7.6 Hz), 6.71 (2H, d, 3J = 7.5 Hz), 7.18 (2H, t, 3J = 7.7 Hz), NH protons were not assigned. 13C NMR (CDCl3, 298 K) Sc ppm: 45.8 (4C), 48.5 (2C), 48.7 (2C), 51.6 (4C), 52.5 (2C), 52.9 (2C),

60.7 (2C), 68.9 (4C), 69.4 (2C), 70.0 (2C), 70.2 (2C), 71.0 (2C), 110.5 (2C), 112.7 (2C), 116.9 (2C), 129.3 (2C), 139.6 (2C), 147.9 (2C).

22,25,30-Trioxa-1,7,10,13,19,3 7-hexaazapentacyclo[17.8.5. 5713.225.21518]hentetraconta-2,4,15,17,33,40-hexaene (18). Obtained from compound 2 (77 mg, 0.15 mmol) and diazacrown ether 15 (33 mg, 0.15 mmol). Eluent CH2Cl2/MeOH 10:1. Yield 19 mg (22 %), yellow glassy compound. (MALDI-TOF) found: 567.3988. C32H51N6O3 requires 567.4023 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.48 (4Н, br.s), 2.60-2.82 (8Н, m), 2.99-3.11 (4Н, m), 3.163.26 (4Н, m), 3.49 (4Н, br.s), 3.59 (4Н, br.s), 3.66-3.91 (12Н, m), 6.97 (4Н, br.s), 7.25 (4Н, br.s), NH protons were not assigned. 13C NMR (CDCl3, 298 K) Sc ppm: 47.6 (4С), 50.6 (4С), 53.4 (2С), 58.8 (2С), 61.4 (2С), 66.9 (2С), 68.9 (2С), 70.3 (2С), 117.8 (4С), 131.5 (4С), four quaternary carbon atoms were not assigned.

24,2 7,32,35-Tetraoxa-1,8,11,14,21,41-hexaazapentacyclo-[19.8.8.5814.126.11620]tetratetraconta-2(44),3,5,16(38),17,19-hexaene (20). Obtained from compound 1 (77 mg, 0.15 mmol) and diazacrown ether 16 (39 mg, 0.15 mmol). Eluent CH2Cl2/MeOH 3:1. Yield 27 mg (30 %), yellow glassy compound. (MALDI-TOF) found: 611.4261. C34H55N6O4 requires 611.4285 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.77-2.81 (8H, m), 2.83-2.85 (8H, m), 3.543.61 (24H, m), 3.65 (4H, s), 6.52 (2H, d, 3J = 7.3 Hz), 6.57 (2H, dd, 3J = 8.3 Hz, 4J = 1.5 Hz), 6.77 (2H, br.s), 7.07 (2H, t, 3J = 7.7 Hz), NH protons were not assigned. 13C NMR (CDCl3, 298 K) Sc ppm: 48.1 (4C), 51.0 (4C), 51.6 (4C), 62.3 (2C), 68.8 (4C), 70.8c(4C), 112.1 (2C), 113.5 (2C), 117.7 (2C), 129.1 (2C), 139.6 (2C), 148.3 (2C).

7,7'-[1,4,7,10-Tetraazacyclododecane-1,7-diylbis-(methylene-3,1-phenylene)]bis-1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane (24). Obtained as the second compound in the synthesis of cryptand 20. Eluent CH2Cl2/MeOH/NH3aq 100:20:3. Yield 19 mg (29 %), yellow glassy compound. (MALDI-TOF) found: 873.6095. C46H81N8O8 requires 873.6177 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.64- (16H, br.s), 2.78 (8H, t, 3J = 4.4 Hz), 3.55-3.63 (36H, m), 3.65 (8H, t, 3J = 4.9 Hz), 6.51 (2H, s), 6.55 (2H, d, 3J = 8.1 Hz), 6.69 (2H, d, 3J = 7.5 Hz), 7.18 (2H, t, 3J = 7.8 Hz), NH protons were not assigned. 13C NMR (CDCl3, 298 K) Sc ppm:

45.8 (4C), 49.2 (4C), 50.5 (4C), 51.6 (4C), 60.6 (2C), 687 (4C), 70.4 (8C), 70.5 (4C), 110.2 (2C), 112.5 (2C), 116.6 (2C), 129.3 (2C), 139.7 (2C), 147.9 (2C).

22,25,30,33-Tetraoxa-1,7,10,13,19,4 0-hexaazapentacyclo[17. 8.8.5113.22,5.21518]tetratetraconta-2,4,15,17,36,43-hexaene (21). Obtained from compound 2 (77 mg, 0.15 mmol) and diazacrown

30

Макрогетероциклы /Macroheterocycles 2014 7(1) 28-33

ether 16 (39 mg, 0.15 mmol). Eluent CH2Cl2/MeOH 10:1. Yield 24 mg (27 %), yellow glassy compound. (MALDI-TOF) found: 611.4230. C34H55N6O4 requires 611.4285 [M+H]+. 1H NMR (CDCl3, 298 K) 5H ppm: 2.69-2.71 (12H, m), 2.88 (4H, br.s), 3.28-3.37 (4H, m), 3.46-3.53 (4H, m), 3.55-3.69 (20H, m), 6.73 (4H, d, 3J = 7.8 Hz), 7.16 (4H, d, 3J = 7.8 Hz), NH protons were not assigned. 13C NMR (CDCl3, 298 K) Sc ppm: 47.1 (4C), 50.9 (4C), 52.9 (4C), 61.4 (2C), 68.7 (4C), 71.2 (4C), 115.1 (4C, br., Av1/2 = 25 Hz), 125.0 (2C), 129.2 (4C), 148.0 (2C).

23,26,31,34-Tetraoxa-1,7,10,14,20,41 -hexaazapentacyclo[18. 8.8.67 14.225.216,19]hexatetraconta-2,4,16,18,37,45-hexaene (23). Obtained from compound 4 (81 mg, 0.15 mmol) and diazacrown ether 16 (39 mg, 0.15 mmol). Eluent CH2Cl2/MeOH/NH3aq 100:20:3. Yield 12 mg (12 %), yellow glassy compound. (MALDI-TOF) found: 639.4562. C36H59N6O4 requires 639.4598 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm 1.80 (4H, br.s), 2.42-2.48 (4H, m), 2.53 (4H, br.s), 2.69 (4H, br.s), 2.76 (4H, t, 3J = 4.2 Hz), 3.49-3.65 (28H, m), 6.48 (4H, d, 3J = 8.5 Hz), 7.04 (4H, d, 3J = 8.5 Hz), NH protons were not

assigned. 13C NMR (CDCl3, 298 K) Sc ppm: 25.6 (2C), 48.3 (2C), 49.9 (2C), 50.5 (4C), 51.1 (2C), 53.3 (2C), 58.9 (2C), 68.7 (4C), 70.5 (4C), 112.5 (4C), 124.0 (2C), 129.7 (4C), 146.9 (2C).

Results and Discussion

Initially we synthesized trans-bis(bromobenzyl) substituted cyclen and cyclam 1-4 in high yields via previously described two-step procedure from protected tetraazamacrocycles (Figure 1).[16,17]

These compounds were reacted with three equivalents of azacrown ethers 5 and 6 (Scheme 1). The reactions were run in absolute dioxane and catalyzed with Pd(dba)2/DavePhos system in the presence of sodium tert-butoxide. The use of DavePhos ligand instead of more convenient BINAP was due to the necessity of the azacrown ethers secondary amino

n

,NH N ^N HN

Br

Figure 1. Trans-bis(bromobenzyl) substituted tetraazamacrocycles.

/—\ - HN-

r TO

v? rh

V-r I J

3,n = 1 5m = im \ ^ 7, n = 0, m = 1,31 %

6 m = 2 m 8, n = 1, m = 1,21%

3 equiv. 9, n = 0, m = 2, 31%

---- 10, n = 1,m = 2, 32%

Pd(dba)2/DavePhos fBuONa, dioxane

\_L/ I m

PCy2

11, n = 0, m = 1,42%

12, n = 1, m = 1, 11%

DavePhos = I VLV ) m 13, n = 0, m = 2 45%

z ^^ ^ 14, n = 1, m = 2 15%

Scheme 1.

-N'

Br 1, m-Br 2, p- Br

15

Pd(dba)2/DavePhos fBuONa, dioxane C = 0.02M

+

r

r\ . .. /

? HN 19, 22%

Pd(dba)2/DavePhos iBuONa, dioxane C = 0.02M

22, traces

NH N

^N HN

Af

L

HN

c

o-

o

HN

3

24, 29%

23, 12%

Scheme 2.

groups arylation which is more difficult and demands more electron-rich phosphine ligands.

Trismacrocycles 7-14 were isolated as individual compounds by column chromatography on silica gel. In the majority of cases the yields of the target trismacrocyclic compounds were higher when cyclen derivatives 1 or 3 were reacted (31-45 %), while cyclam derivatives 2 and 4 provided 11-32 % yields. This may be due to a stronger coordination of Pd(0) by cyclam which removes it from the catalytic cycle. In our previous studies similar lower reactivity of cyclam derivatives was noted.[17,18] Almost in all reactions we observed the formation of bismacrocyclic byproducts comprising one cyclen or cyclam and one azacrown moiety. Their formation was due to the catalytic reduction of one C-Br bond which is a typical by-process especially in the case of secondary amines arylation. However, these bismacrocycles were not isolated in individual state but rather as mixtures with the target trismacrocyclic compounds and were analyzed by NMR and MALDI-TOF spectra. A characteristic feature of 13C NMR spectra of cyclam-based compounds 8, 10, 12, 14 is a notable broadening (up to 50 Hz) of the signals of some aliphatic carbons which is due to hindered conformational changes in cyclam.

A one-pot synthesis of cylindrically shaped macro-tricyclic cryptands employed the reactions of equimolar amounts of tetraazamacrocycles 1-4 and diazacrown ethers 15, 16 (Scheme 2). They were also catalyzed with Pd(dba)2/ DavePhos system but lower concentrations of starting compounds (C=0.02 M) were applied to promote cyclization and limit formation of oligomers. Cyclen derivatives 1 and 2 afforded target cryptands 17, 18, 20 and 21 in 10-30 % yields, while only in one case the reaction of cyclam derivative (compound 4 with diazacrown ether 16) was successful. In two reactions we managed to isolate trismacrocyclic byproducts 19 and 24 which were formed due to a competition between macrocyclization and oligomerization processes. The difference in the yields of macrotricycles can be explained by strong geometric demands for the reciprocal position of two bromine atoms and two nitrogen atoms in the reactants.

Conclusions

To sum up, we elaborated a straightforward approach to trismacrocyclic and macrotricyclic compounds possessing cyclen or cyclam central fragment and azacrown or diazacrown moieties using Pd(0)-mediated amination of trans-bis(bromobenzyl) derivatives of tetraazamacrocycles. The yields of trismacrocycles reached 45 % while macrotricyclic cryptands were obtained in yields up to 30 %. Cyclen derivatives were shown to be more reactive affording better yields of the target polymacrocyclic compounds. As novel cylindrically shaped cryptands possess two secondary

amino groups, they can be easily modified with two identical fluorophores and further tested as fluorescent chemosensors or molecular probes for metal cations.

Acknowledgements. This work was financially supported by the RFBR grants 12-03-93107, 13-03-00813 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". Generous provision of cyclen and cyclam by CheMatech Co is acknowledged.

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Received 10.04.2014 Accepted 14.04.2014