Планарно-хиральные макробициклы с фрагментом циклама Текст научной статьи по специальности «Химические науки»

Cyclams

Цикламы

Макрогэтэроцмклы

Статья

Paper

http://macroheterocycles.isuct.ru

DOI: 10.6060/mhc2012.121102a

Planar-Chiral Macrobicycles Comprising Cyclam Moiety

Sergei M. Kobelev,a Alexei D. Averin,ab@ Olga A. Maloshitskaya,a Franck Denat,c Roger Guilard,c and Irina P. Beletskayaab

Dedicated to Academician Asian Yusupovich Tsivadze on the occasion of his 70th Anniversary

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

cInstitut de Chimie Moléculaire de l'Université de Bourgogne (ICMUB), UMR CNRS 5260, 21078 Dijon Cedex, France @Corresponding author E-mail: [email protected]

Macrobicycles derived from 1,8-disubstituted cyclam in principle may be planar-chiral provided that the second chain cannot rotate around the cyclam fragment. Hindered rotation is enabled by the introduction of two additional substituents at nitrogen atoms and by enough short chain which forms the second cycle. N,N',N",N'"-tetrasubstituted cyclams bearing two 3-bromobenzyl and two arylmethyl substituents were synthesized starting from protected bis-formaldehyde-cyclam. These compounds were introduced in the Pd-catalyzed amination reactions with 1,3-diaminopropane, 1,2-diaminoethane and 1,2-diphenyl-1,2-diaminoethane to form corresponding macrobicycles. Various chiral diphosphine ligands were tested in these reactions and asymmetric induction was noted in some cases. The pronounced dependence of the chemical yields and enantiomeric excess on the nature of the starting compounds and chiral phosphine ligand was observed. The highest chemical yields of macrobicycles reached 50 %, the best enantiomeric excess was 13 % when using Josiphos-type ferrocene-based ligand.

Keywords: Macrocycles, palladium-catalized amination, planar chirality, enantioselectivity.

Планарно-хиральные макробициклы с фрагментом циклама

С. А. Кобелев^ А. Д. Аверин,^ О. А. Малошицкая^ Ф. Дена^ Р. Гиляр^ И. П. Белецкая^

Посвящается академику Аслану Юсуповичу Цивадзе по случаю его 70-летнего юбилея

Московский государственный университет им. М.В. Ломоносова, Химический факультет, 119991 Москва, Россия ьИнститут физической химии и электрохимии им. А. Н. Фрумкина, 119991 Москва, Россия cInstitut de Chimie Moléculaire de l'Université de Bourgogne (ICMUB), UMR CNRS 5260, 21078 Дижон, Франция @E-mail: [email protected]

Макробициклы, содержащие в своем составе фрагмент 1,8-дизамещенного циклама, в принципе могут быть планарно-хиральными при условии, что цепь атомов, образующих второй макроцикл, не может свободно прокручиваться вокруг фрагмента циклама. Затрудненное вращение может быть обеспечено двумя дополнительными заместителями при атомах азота при условии небольшой длины цепи второго цикла. N,N',N",N"'-тетразамещенные цикламы, содержащие два 3-бромбензильных и два арилметильных заместителя, были синтезированы из бис-формальдегид-циклама. Данные соединения ввели в реакции палладий-катализируемого аминирования с 1,3-диаминопропаном, 1,2-диаминоэтаном и 1,2-дифенил-1,2-диаминоэтаном, при этом были получены соответствующие макробициклы. В данных реакциях исследовали различные хиральные дифосфиновые лиганды и в некоторых случаях была отмечена асимметрическая

индукция. Наблюдалась сильная зависимость химических выходов и энантиомерных избытков от природы исходных соединений и хиральных лигандов. Наибольшие химические выходы макробициклов составили 40-50 %, а наилучший энантиомерный избыток составил 13 % в реакции с 1,3-диаминопропаном при использовании лиганда типа Josiphos на основе 1,2-дизамещенного ферроцена.

Ключевые слова: Макроциклы, палладий-катализируемое аминирование, планарная хиральность, энантиоселективно сть.

Introduction

In recent years much attention is paid to the design, synthesis and use of various macrocyclic receptors, since their cavity size and shape can be finely tuned. This useful feature led to the development of many applications of these compounds, including catalysis, transport of ions and molecules, development of molecular sensors, molecular machines, and applications in pharmacology.111 Chiral macrocyclic ligands are of special interest because they may be used as host molecules for asymmetric catalysis[2] and chiral recognition.[3] For example, lanthanide complexes, that catalyze asymmetric aldol reactions, were synthesized on the basis of chiral ^,0-macrocycles,[4] they were also used as catalysts in the enantioselective Michael addition reactions. [5] Chiral carbohydrate-based crown ethers were employed as ligands in asymmetric hydrogenation.[6] The catalysts for C-C coupling reactions may contain the complexes of chiral macrocycles with the transition metals.[7] Macrocycles with planar chirality occupy a special position among other chiral macrocycles, and yet no general and convenient synthetic procedures has been developed for their synthesis. The simplest bicyclic compounds based on tetraazamacrocycles are various so-called cross-bridged cyclen and cyclam. [8-10] The introduction of aromatic and heteroaromatic fragments in polymacrocyclic compounds often increases the conformational rigidity of the molecule thus fixing the cavity size. Also, these fragments are crucial in the creation of chemosensors because (hetero)aromatic moieties play the role of chromophores or fluorophores being responsible for the physical response to coordination. Usually macrobicycles possessing cross-bridged cyclen and cyclam moieties do not contain many donor atoms like nitrogen, oxygen or sulfur in the second cycle,[11-15] however, described are macrobicycles with several donor atoms.[16] Our own interest is drawn to the synthesis of macrobicyclic compounds derived from trans-disubstituted cyclen and cyclam and we proposed simple routes to macrobicycles using Pd-catalyzed amination of bis(bromobenzyl) derivatives of tetraazamacrocycles. [17-20] Also we were first to show the possibility to use Pd-catalyzed amination with chiral ligands for the synthesis of planar-chiral macrocycles based on 1,5-disubstituted anthracene and anthraquinone.[21] In this work we decided to combine our approaches to macrobicyclic cryptands with asymmetric induction in the amination reaction in order to try the synthesis of planar-chiral macrobicycles.

Experimental

NMR spectra were registered using Bruker Avance 400 spectrometer, MALDI-TOF spectra were obtained with Bruker

Autoflex II spectrometer using 1,8,9-trihydroxyanthracene as matrix and PEGs as internal standards. Enantiomeric excess was determined by means of HPLC with Bischoff liquid Chromatograph using Chiralcel OD-H, Chiralpak IA, Kromasil 5-TBB, Welk O1 columns and various eluents containing combinations of hexane (heptane), i-PrOH (MeOH), THF, CHCl3, Et3N and HNEt2 (0.7-1 ml/min, 230, 254, 260 nm UV detector), X-ray analysis of the compound 9 was done using CAD-4 Enraf-Nonius apparatus, the structure is deposited at Cambridge Structural Database (http:// www.ccdc.cam.ac.uk), deposit number CCDC 912600. Benzyl bromide, 3-bromobenzyl bromide, 2-(bromomethyl)naphthalene, 4-methylbiphenyl, propane-1,2-diamine, ethane-1,2-diamine, 1,2-diphenylethane-1,2-diamine, rac-BINAP, (R)-BINAP and other ferrocene-based chiral phosphine 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.1221 4-(Bromomethyl)biphenyl was synthesized from 4-methylbiphenyl by a standard procedure using NBS in CCl4 with AIBN as radical initiator. Bis-formaldehide cyclam and 1,8-dibenzyl cyclam were provided by the CheMatech Co, Dijon, France. Dioxane was distilled over NaOH followed by the distillation over sodium under argon, dichloromethane and methanol were used freshly distilled.

Typical procedure for the synthesis of 1,8-bis(arylmethyl) derivatives of cyclam 5, 6.

In a one-neck flask (100 ml) bis-formaldehyde-cyclam (1) (2.50 g, 11.2 mmol) was dissolved in 52 ml CH3CN, corresponding bromomethyl substituted arene (2-(bromomethyl)naphthalene or 4-(bromomethyl)bipehenyl, 22.4 mmol) was added and the reaction mixture was stirred at room temperature for 72 h. The residue was filtered off, washed with CH3CN (3*40 ml) and dried in vacuo to obtain di-salts 2 and 3. The deprotection was carried out as follows: di-salt (2 or 3, 5 mmol) was mixed with the aqueous solution of NaOH (8 g in 60 ml) and stirred at 80-90 oC for 48 h. The resulting compound (5 or 6) was taken with CH2Cl2, dried over anhydrous Na2SO4, the solvent was evaporated in vacuo to give pure product.

1,8-Bis(2-naphthylmethyl)-4,11-diaza-1,8-diazonia-tricyclo[9.3.1.14,8]hexadecane dibromide (2). Yield 5.80 g (78 %), white crystalline powder, m.p. >200 °C. 1H NMR (DMSO-d6, 298 K) SH ppm: 1.72-1.82 (2H, m), 2.32-2.43 (4H, m), 2.84 (2H, d, 2J = 14.7 Hz), 2.92 (2H, d, 2J = 16.4 Hz), 3.17 (2H, br.s), 3.37 (4H, br.s), 3.53 (2H, d, J = 10.0 Hz), 3.70 (2H, t, J = 14.6 Hz), 4.45 (2H, t, J = 13.4 Hz), 4.87 (4H, s), 5.48 (2H, d, 3J = 9.1 Hz), 7.60-7.67 (4H, m),

7.72 (2H, d, 3J = 8.4 Hz), 8.02 (4H, d, 3J = 7.3 Hz), 8.06 (2H, d, 3J = 8.0 Hz), 8.21 (2H, br.s).

1,8-Bis(biphenyl-4-ylmethyl)-4,11-diaza-1,8-diazonia-tricyclo[9.3.1.148]hexadecane dibromide (3). Yield 3.20 g (64 %). white crystalline powder, m.p. >200 °C. 1H NMR (DMSO-d6, 298 K) SH ppm: 1.72-1.82 (2H, m), 2.28-2.42 (4H, m), 2.83 (4H, t, J = 15.7 Hz), 3.17 (2H, br.s), 3.49 (2H, d, 3J = 9.7 Hz), 3.65 (2H, t, J = 13.3 Hz), 4.42 (2H, t, J = 12.6 Hz), 4.72-4.80 (4H, m), 5.43 (2H, d, 3J = 8.6 Hz), 7.42 (2H, t, 3J = 7.0 Hz), 7.51 (4H, t, 3J = 7.0 Hz),

7.73 (8H, d, 3J = 7.2 Hz), 7.83 (4H, d, 3J = 7.7 Hz), four protons are overlapped by the signal of CHD2.

1,8-Bis(2-naphthylmethyl)-1,4,8,11-tetraazacyclo-tetradecane (5). Yield 2.16 g (90 %), white crystalline powder, m.p.

127-129 oC. (MALDI-TOF) found: 481.3367. C32H41N4 requires 481.3331 [M+H]+. 1H NMR (CDCl3, 298 K) 5H ppm: 1.88 (4H, quintet, 3J = 4.3 Hz), 2.58 (4H, t, 3J = 5.5 Hz), 2.65-2.70 (4H, m), 2.72-2.79 (8H, m), 3.87 (4H, s), 7.38-7.46 (4H, m), 7.51 (2H, dd, 3J = 8.3 Hz, 4J = 1.1 Hz), 7.70 (2H, br.s), 7.73-7.79 (6H, m), two NH protons were not assigned. 13C NMR (CDCl3, 298 K) SC ppm: 25.9 (2C), 47.7 (2C), 49.9 (2C), 51.9 (2C), 53.9 (2C), 58.2 (2C), 125.6 (2C), 125.9 (2C), 127.6 (6C), 127.7 (2C), 128.3 (2C), 132.6 (2C), 133.2 (2C), 135.2 (2C).

1,8-Bis(biphenyl-4-ylmethyl)-1,4,8,11-tetraazacyclo-tetradecane (6). Yield 2.56 g (96 %), white crystalline powder, m.p. 129-131 oC. (MALDI-TOF) found: 533.3627. C36H45N4 requires 533.3644 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.88 (4H, br.s), 2.57 (4H, t, 3J = 5.2 Hz), 2.62-2.67 (4H, m), 2.73-2.80 (8H, m), 3.09 (2H, br.s), 3.79 (4H, s), 7.30 (2H, t, 3J = 7.3 Hz), 7.36-7.42 (8H, m), 7.50-7.56 (8H, m). 13C NMR (CDCl3, 298 K) 5C ppm: 25.8 (2C), 47.6 (2C), 50.0 (2C), 51.6 (2C), 53.9 (2C), 57.5 (2C), 126.9 (4C), 127.0 (4C), 127.0 (2C), 128.6 (4C), 129.9 (4C), 136.4 (2C), 139.9 (2C), 140.8 (2C).

Typical procedure for the synthesis ofN,N'N",N"'-tetrabenzyl derivatives of cyclam 7-9.

A one-neck flask (100 ml) was charged with a solution of trans-disubstituted cyclam (4, 5 or 6) (1 mmol in 10 ml CH2Cl2), then aqueous solution of NaOH was added (160 mg (4 mmol) in 10 ml H2O), and to a stirred mixture the solution of 3-bromobenzyl bromide (500 mg (2 mmol) in 10 ml CH2Cl2) was added dropwise in 1 h. The reaction mixture was stirred for 48 h, organic phase was separated, dried over anhydrous Na2SO4, solvent was evaporated in vacuot and the pure product was obtained.

1,8-Dibenzyl-4,11-bis(3-bromobenzyl)-1,4,8,11-tetraaza-cyclotetradecane (7). Obtained from 380 mg (1 mmol) of trans-dibenzylcyclam (4). Yield 680 mg (95 %), white crystalline powder, m.p. 129-131 oC. (MALDI-TOF) found: 717.2120. C38H47Br2N4 requires 717.2167 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.80 (4H, quintet, 3J = 6.6 Hz), 2.53 (4H, t, 3J = 6.6 Hz), 2.56 (4H, t, 3J = 7.1 Hz), 2.60-2.64 (4H, m), 2.65-2.69 (4H, m), 3.38 (4H, s), 3.49 (4H, s), 7.15 (2H, t, 3J = 7.8 Hz), 7.22-7.33 (12H, m), 7.38 (2H, d, 3J = 8.0 Hz), 7.61 (2H, br.s). 13C NMR (CDCl3, 298 K) SC ppm: 24.3 (2C), 50.2 (2C), 50.6 (2C), 51.2 (2C), 51.(5 (2C), 58.1 (2C), 59.3 (2C), 122.2 (2C), 126.6 (2C), 127.3 (2C), 128.0 (4C), 128.8 (4C), 129.5 (2C), 129.6 (2C), 131.9 (2C), 139.8 (2C), 142.8 (2C).

1,8-Bis(3-bromobenzyl)-4,11-bis(2-naphthylmethyl)-1,4,8,11-tetraazacyclotetradecane (8). Obtained from 480 mg (1 mmol) of compound 5. Yield 326 mg (40 %), yellowish crystalline powder, m.p. 138-140 oC. (MALDI-TOF) found: 817.2425. C46H51Br2N4 requires 817.2480 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.842 (4H, br.s), 2.46 (4H, t 3J = 6.1 Hz), 2.53-2.68 (12H, m), 3.29 (4H, s), 3.59 (4H, s), 7.07 (2H, t, 3J = 7.7 Hz), 7.17 (2H, d, 3J = 7.3 Hz), 7.33 (2H, d, J = 7.7 Hz), 7.38-7.43 (4H, m), 7.46 (2H, d, 3J = 8.2 Hz), 7.60 (2H, br.s), 7.62-7.70 (6H, m), 7.75-7.80 (2H, m). Sc (CDCl3, 298 K) 24.6 (2C), 50.1 (2C), 50.7 (2C), 51.3 (2C), 51.8 (2C), 57.9 (2C), 60.0 (2C), 122.2 (2C), 125.3 (2C), 125.7 (2C), 127.2 (2C), 127.3 (2C), 127.4 (2C), 127.6 (6C), 129.5 (2C), 129.6 (2C), 132.0 (2C), 132.6 (2C), 133.3 (2C), 137.8 (2C), 143.0 (2C).

1,8-Bis(biphenyl-4-ylmethyl)-4,11-bis(3-bromobenzyl)-1,4,8,11-tetraazacyclotetradecane (9). Obtained from 532 mg (1 mmol) of compound 6. Yield 443 mg (51 %), beige crystalline powder, m.p. 128-130 oC. (MALDI-TOF) found: 869.2865. C50H55Br2N4 requires 869.2793 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.79 (4H, br.s), 2.50 (4H, t, 3J = 6.4 Hz), 2.55 (4H, br.s), 2.60-2.68 (8H, m), 3.35 (4H, s), 3.48 (4H, s), 7.11 (2H, t, 3J = 7.8 Hz), 7.20 (2H, d, 3J = 7.6 Hz), 7.29-7.35 (8H, m), 7.42 (4H, t, 3J = 7.6 Hz), 7.46 (4H, d, 3J = 8.1 Hz), 7.53-7.59 (6H, m). 13C NMR (CDCl3, 298 K) SC ppm: 24.4 (2C), 50.3 (2C), 50.7 (2C), 51.3 (2C), 51.8 (2C), 58.2 (2C), 59.0 (2C), 122.2 (2C), 126.8 (4C), 126.9 (4C), 127.0 (2C), 127.3 (2C), 128.7 (4C), 129.3 (4C), 129.5 (2C), 129.7 (2C), 131.9 (2C), 139.1 (2C), 139.6 (2C), 141.0 (2C), 142.9 (2C).

Typical procedure for the synthesis of macrobicycles 11 -13.

A two-neck flask (25 ml) equipped with a condenser, flushed with argon, was charged with corresponding tetrasubstituted cyclam 7-9 (0.1-0.2 mmol), Pd(dba)2 (9-18 mg, 16 mol%), diphosphine ligand (0.036 mmol, 18 mol%), and absolute dioxane (5-10 ml). The mixture was stirred for several min, then appropriate diamine 10a-c (0.1-0.2 mmol) and tBuONa (30-58 mg, 0.6 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, and the residue was 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.

22,28-D ibenzyl-1,8,12,19,22,28-hexaazatetracyclo[17.6.6.13 7.11317]tritriaconta-3(33),4,6,13(32),14,16-hexaene (11a). Obtained from 144 mg (0.20 mmol) of compound 7, 15 mg (0.20 mmol) of propanediamine-1,3 (10a), in the presence of the ligand L4 (18 mol%, 20 mg). Eluent: CH2Cl2:MeOH 10:1. Yield 63 mg (50 %), ee = 11 %, light-beige crystalline powder, m.p. 147-149 °C. (MALDI-TOF) found: 631.4465. C41H55N6 requires 631.4488 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.70 (2H, br.s), 1.85 (4H, quintet, 3J = 5.5 Hz), 2.29-2.50 (6H, m), 2.52-2.72 (8H, m), 3.12 (2H, br.s), 3.21-3.28 (2H, m), 3.32 (4H, t 3J = 5.6 Hz), 3.41-3.48 (2H, m), 3.52 (4H, s), 3.90 (2H, br.s), 6.48 (2H, br.d 3Jobs = 6.6 Hz), 6.52 (2H, d, J = 7.8 Hz), 7.04 (2H, br.s), 7.06 (2H, t, 3J = 7.6 Hz), 7.16-7.27 (10H, m). 13C NMR (CDCl3, 298 K) SC ppm: 24.5 (2C), 28.5 (1C), 42.0 (2C), 52.0 (4C), 52.8 (2C), 53.0 (2C), 59.5 (4C), 111.4 (2C), 113.8 (2C), 118.0 (2C), 126.7 (2C), 128.0 (4C), 128.8 (2C), 129.0 (4C),

139.5 (2C), 141.9 (2C), 148.4 (2C).

22,47,53,61-Tetrabenzyl-1,8,12,19,22,26,33,37,44,47,53,61-

dodecaazaheptacyclo-[42.6.6.61926.13 7.11317.12832.13842]hexaconta-3 (66),4,6,13(65),14,16,28(58),29,31,38(57),39,41-dodecaene (14). Obtained as the second product in the synthesis of macrobicycle 7 using BINAP as a ligand. Eluent: CH2Cl2-MeOH-NH3(aq) 100:20:1. Yield 24 mg (19 %), yellowish solid. (MALDI-TOF) found: 1261.8814. C82H109N12 requires 1261.8898 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 170-1.82 (12H, m), 2.44-2.58 (16H, m), 2.62 (16H, br.s), 3.12 (8H, t, 3J = 6.6 Hz), 3.38 (8H, s), 3.46 (8H, s), 6.44 (4H, d, 3J = 8.6 Hz), 6.59 (4H, br.d 3Jobs = 6.4 Hz), 6.65 (4H, br.s), 7.05 (4H, t, 3J = 7.6 Hz), 7.16-7.36 (20H, m), four NH protons were not assigned. 13C NMR (CDCl3, 298 K) SC ppm: 24.1 (4C), 29.2 (2C), 41.9 (4C), 50.0-51.6 m (16H), 59.3 (4C), 59.6 (4C), 111.3 (4C), 113.1 (4C), 118.0 (4C), 126.6 (4C), 128.0 (8C), 128.8 (4C), 128.9 (8C), 140.1 (4C), 141.3 (4C), 148.2 (4C).

N-(3-{[4,11-dibenzyl-8-(3-bromobenzyl)-1,4,8,11-tetraazacyclotetradecane-1-yl]methyl}phenyl)-propane-1,3-diamine (15) was obtained as the by-product in the synthesis of compound 7 using ligand L7. Yield 53 mg (37 %) yellowish solid. (MALDI-TOF) found: 711.3787. C41H56BrN6 requires 711.3750 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.68-1.79 (6H, m), 2.432.66 (16H, m), 2.80 (2H, br.s), 3.11 (2H, br.s), 3.37 (2H, s), 3.38 (2H, s), 3.44 (2H, s), 3.45 (2H, s), 6.46 (1H, br.d 3Jobs = 7.1 Hz), 6.58-6.63 (2H, m), 7.06 (1H, t, 3J = 7.6 Hz), 7.09 (1H, t, 3J = 7.7 Hz), 7.17-7.36 (12H, m), 7.50 (1H, br.s), three NH protons were not assigned. 13C NMR (CDCl3, 298 K) SC ppm: 23.9 (1C), 24.0 (1C), 32.9 (1C), 40.2 (1C), 42.0 (1C), 50.2-51.5 M (8C), 58.6 (1C), 59.2 (2C), 59.5 (1C), 110.9 (1C), 113.2 (1C), 117.9 (1C), 122.2 (1C),

126.6 (2C), 127.3 (1C), 128.0 (4C), 128.8 (1C), 128.9 (4C), 129.5 (1C), 129.7 (1C), 131.7 (1C), 139.9 (1C), 140.2 (1C), 141.1 (1C), 142.8 (1C), 148.4 (1C).

21,27-Dibenzyl-1,8,11,18,21,27-hexaazatetracyclo[16.6.6 .6.137.11216]-dotriaconta-3(32),4,6,12(31),13,15-hexaene (11b). Obtained from 144 mg (0.20 mmol) of compound 7, 12 mg (0.20 mmol) of ethanediamine-1,2 (10b) in the presence of the ligand L3 (18 mol%, 20 mg). Eluent: CH2Cl2:MeOH 10:1. Yield 39 mg (32 %), ee = 2 %, slightly beige crystalline powder, m.p. 147-149 oC. (MALDI-TOF) found: 617.4351. C40H53N6 requires 617.4332

[M+H]+. Щ NMR (CDCl3, 328 K) 5H ppm: 1.72 (2Н, br.s), 1.91 (2Н, br.s), 2.43 (4Н, br.s), 2.54-2.81 (12Н, m), 3.37-3.56 (12Н, m), 6.39 (2Н, br.s), 6.47 (2Н, br.d, 3Jobs = 6.6 Hz), 6.92 (2Н, br.s), 7.12 (2Н, br.s), 7.18-7.28 (10Н, m), two NH protons were not assigned. 13C NMR (CDCl3, 328 K) SC ppm: 24.5 (2С, br.s, Av1/2 = 50 Hz), 45.0 (2С, br.s, Av1/2 = 15 Hz), 51.8 (2С, br.s, Av1/2 = 50 Hz), 52.1 (4С), 52.8 (2С, br.s, Av1/2 = 20 Hz), 59.3 (2С, br.s, Av1/2 = 20 Hz), 60.0 (2С), 113.6 (4С, brs, Av1/2 = 30 Hz), 118.7 (2С, br.s, Av1/2 = 15 Hz), 127.4 (2С, br.s, Av1/2 = 122 Hz), 128.3 (4С), 128.7 (2СХ 129.5 (4С), 137.0 (2С), 144.1 (2 С), 149.1 (2С).

22,28-Bis(2-naphthylmethyl)-1,8,12,19,22,28-hexaazatetrac yclo[17,6.6.13 7.11317]-tritriaconta-3(33),4,6,13(32),14,16-hexaene (12a). Obtained from 82 mg (0.10 mmol) of compound 8, 7.5 mg (0.10 mmol) of propanediamine-1,3 (10а) in the presence of ligand L3 (18 mol%, 10 mg). Eluent: CH2Cl2:MeOH 10:1. Yield 19 mg (25 %), ее = 9 %, slightly beige crystalline powder, m.p. 141-143°C. (MALDI-TOF) found: 731.4765. C49H59N6 requires 731.4801 [M+H]+. 1H NMR (CDCl3, 328 K) SH ppm: 1.83 (2Н, quintet, 3J = 5.9 Hz), 1.91 (4Н, br.s), 2.40-2.85 (16Н, m), 3.29 (4Н, t, 3J = 5.9 Hz), 3.39 (4Н, br.s), 3.70 (4Н, br.s), 6.39 (4Н, br.s), 6.94 (2Н, br.s), 7.02 (2Н, br.s), 7.32 (2Н, br.s), 7.44 (4Н, br.s), 7.61 (2Н, br.s), 7.677.82 (6Н, m), two NH protons were not assigned. 13C NMR (CDCl3, 328 K) SC ppm: 24.6 (2С, br.s, Av1/2 = 60 Hz), 29.5 (1С, br.s, Av1/2 = 50 Hz), 42.0 (2С, br.s, Av1/2 = 30 Hz), 52.4 (8С, br.s, Av1/2 = 100 Hz), 59.6 (2С, br.s, Av1/2 = 70 Hz), 60.0 (2С), 112.2 (2С, br.s, Av1/2 = 20 Hz), 114.3 (2С), 118.4 (2С, br.s, Av1/2 = 25 Hz), 125.2 (2С), 126.0 (2С, br.s, Av1/2 = 25 Hz), 127.6 (2С), 127.7 (2С), 127.9 (2С), 128.9 (2С), 133.1 (2С), 133.5 (2С), 142.6 (2С), 148.9 (2С), six quaternary carbon atoms were not assigned.

21.27-Bis(2-naphthylmethyl)-1,8,11,18,21,27-hexa-azatetracyclo-[16.6.6.137.11216]dotriaconta-3(32),4,6,12(31 ),

13.15-hexaene (12b). Obtained from 123 mg (0.15 mmol) of compound 8, 9 mg (0.15 mmol) of ethanediamine-1,2 (10b) in the presence of the ligand L7 (18 mol%, 23 mg). Eluent: CH2Cl2:MeOH 10:1. Yield 20 mg (19 %), ее = 1 %, slightly beige crystalline powder, m.p. 107-109 °C. (MALDI-TOF) found: 717.4687. C48H57N6 requires 717.4645 [M+H]+. 1H NMR (CDCl3, 328 K) SH ppm: 1.80 (2Н, br.s), 1.90 (4Н, br.s), 2.45-2.87 (16Н, m), 3.333.55 (6Н, m), 3.58-3.74 (4Н, m), 6.25-6.50 (4Н, m), 6.85 (2Н, br.s), 6.90-7.17 (2Н, m), 7.37-7.50 (6Н, m), 7.57 (2Н, br.s), 7.66-7.81 (6Н, m), two NH protons were not assigned.

22.28-Bis(biphenyl-4-ylmethyl)-1,8,12,19,22,28-hexa-azatetracyclo-[17,6.6.13,7.113,17]tritriaconta-3(33),4,6,13 (32),

14.16-hexaene (13а). Obtained from 130 mg (0.15 mmol) of compound 9, 11 mg (0.15 mmol) of propanediamine-1,3 (10а) in the presence of the ligand L3 (18 mol%, 15 mg). Eluent: CH2Cl2:MeOH 10:1. Yield 32 mg (27 %), ee = 9 %, slightly beige crystalline powder, m.p. 130-132 oC. (MALDI-TOF) found: 783.5038. C53H63N6 requires 783.5114 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.84 (4Н, quintet, 3J = 5.6 Hz), 1.96 (2Н, br.s), 2.45-3.03 (16Н, m), 3.31 (4Н, t, 3J = 5.6 Hz), 3.42 (4Н, s), 3.59 (4Н, s), 4.62 (2Н, br.s), 6.44 (2Н, br.d 3Jobs = 6.8 Hz), 6.46 (2Н, br.d, Job = 7.8 Hz), 6.97-7.04 (4Н, m), 7.27-7.57 (18Н, m). 13C NMR (CDCl3, 298 K) SC ppm: 24.7 (2С, br.s, Av1/2 = 20 Hz), 29.4 (1С, br.s, Av1/2 = 15 Hz), 42.1 (2С, br.s, Av1/2 = 15 Hz), 52.3 (8С, br.s, Av1/2 = 80 Hz), 58.9 (2С, br.s, Av1/2 = 20 Hz), 59.9 (2С), 112.0 (2С, bris, Av1/2 = 15 Hz), 114.2 (2С, br.s, Av1/2 = 15 Hz), 118.4 (2С), 127.0 (8С), 127.3 (2С), 128.8 (4С), 129.0 (2 С), 130.0 (2С, br.s, Av1/2 = 12 Hz), 132.6 (2С), 140.4 (6С, br.s, Av1/2 = 30 Hz), 140.9 (2С), /148.8 (2С).

21,27-Bis(biphenyl-4-ylmethyl)-1,8,11,18,21,27-hexaaza-tetracyclo-[16.6.6.13 7.1121]dotriaconta-3 (32),4,6,12(31),13,15-hexaene (13b). Obtained from 130 mg (0.15 mmol) of compound 9, 9 mg (0.15 mmol) of ethanediamine-1,2 (10b), in the presence of the ligand L3 (18 mol%, 15 mg). Eluent: CH2Cl2:MeOH 10:1. Yield 22 mg (19 %), ee = 0 %, slightly beige crystalline powder, m.p. 135-137 oC. (MALDI-TOF) found: 783.5038. C52H61N6 requires 769.4958 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.69 (2Н,

br.s), 1.93 (2Н, br.s), 2.40-2.75 (16Н, m), 3.40 (4Н, br.s), 3.47 (8Н, br.s), 6.45 (4Н, br.s), 6.97 (4Н, br.s), 7.34 (4Н, t, 3J = 7.1 Hz), 7.327.38 (10Н, m), 7.59 (4Н, br.d, 3Jobs = 6.8 Hz), two NH protons were not assigned. 13C NMR (CDCl3, 328 K) SC ppm: 24.6 (2С, br.s, Av1/2 = 50 Hz), 44.9 (2С), 51.9 (8С, br.s, Av1/2 = 35 Hz), 59.1 (2С, br.s, Av1/2 = 30 Hz), 60.0 (2С, br.s, Av1/2 = 15 Hz), 113.5 (4С, br.s, Av1/2 = 100 Hz), 118.6 (2С, br.s, Av1/2 = 20 Hz), 125.2 (2С), 127.0 (8С), 127.2 (2С), 128.8 (4С), 129.8 (4С), 132.1 (2С), 135.2 (2С), 140.1 (2С), 141.0 (2С), 149.0 (2С).

21,27-Bis(biphenyl-4-ylmethyl) -9,10-diphenyl-1,8,11,18, 21,27-hexaazatetracyclo-[16.6.6.137.11216]dotriaconta-3(32),4,6, 12(31),13,15-hexaene (13c). Synthesizd from 130 mg (0.15 mmol) of compound 9, 32 mg (0.15 mmol) of the diamine (10c) in the presence of the ligand L3 (18 mol%, 15 mg). Elunet: CH2Cl2:MeOH 10:1. Yield 31 mg (22 %), ее = 5 %, slightly beige crystalline powder, m.p. 145-147 oC. (MALDI-TOF) found: 921.5536. C64H69N6 requires 921.5584 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.78 (4Н, br.s), 2.57 (16Н, br.s), 3.33 (4Н, br.s), 3.48 (4Н, br.s), 4.54 (2Н, br.s), 6.35 (2Н, br.s), 6.49 (2Н, br.s), 6.85-7.65 (32Н, m), two NH protons were not assigned. 13C NMR (CDCl3, 328 K) SC ppm: 24.4 (2С, br.s, Av1/2 = 15 Hz), 51.0 (2С, br.s, Av1/2 = 80 Hz), 51.9 (4С, br.s, Av1/2 = 50 Hz), 52.5 (2С, br.s, Av1/2 = 60 Hz), 58.9 (4С, br.s, Av1/2 = 80 Hz), 64.0 (2С, br.s, Av1/2 = 30 Hz), 113.3 (2С, br.s, Av1/2 = 40 Hz), 115.5 (2С, br.s, Av1/2 = 30 H z), 119.0 (2С, br.s, Av1/2 = 50 Hz), 125.2 (2С), 127.0 (8С), 127.3 (4С), 127.7-128.2 (8С, m), 128.8 (4С), 129.8 (4С, br.s, Av1/2 = 30 Hz), 132.1 (2С), 140.4 (4С, br.s, Av1/2 = 40 Hz), 140.9 (4С, brs, Av1/2 = 30 Hz), 148.2 (2С, br.s, Av1/2 = 70 Hz).

Results and Discussion

Macrobicycles comprising the cyclam fragments can be planar-chiral provided that the chain that forms the second cycle does not rotate around the cyclam moiety. We established that the derivatives of the trans-dibenzylcyclam which do not contain additional substituents at two other nitrogen atoms cannot be planar-chiral because even a short diaminotrimeth-ylene chain easily rotates around the cyclam moiety at room temperature. In this connection we synthesized a series of ^A^A^A^'-tetrasubstitued cyclams bearing two bromine atoms in aromatic substituents, in which additional groups could hinder the rotation of the chain around the cyclam moiety. The reaction of bis-formaldehyde-cyclam (1) with bromomethylar-enes (2 equiv.) in CH3CN led to corresponding di-salts 2 and 3 which were deprotected using aqueous solutions of NaOH at 80-90 oC. As a result, trans-disubstituted cyclams 5 and 6 were obtained in good overall yields (70 % for the compound 5 bearing two naphthylmethyl substituents and 61 % for the compound 6 containing two biphenylmethyl substitutents). The compounds 4-6 were modified with two m-bromobenzyl substituents using 2 equiv. of m-bromobenzyl bromide in a two-phase H2O-CH2Cl2 system with NaOH as a base to give tetrasubstituted derivatives 7-9 in yields 40-95 % (Scheme 1). It is noteworthy that the application of other solvents like CH3CN and other bases like K2CO3 as well as the attempts to introduce first m-bromobenzyl substituents followed by the introduction of arylmethyl groups were all unsuccessful due to the formation of numerous by-products caused by the quater-nization of the nitrogen atoms of cyclam.

We obtained monocrystals of the compound 9 and its molecular structure was studied by X-ray analysis (Figure 1). In the crystalline form two bromine atoms are oriented in the opposite directions but in the solution due to easy rotations around C(sp2)-C(sp3) and C(sp3)-N bonds these bromine

Br

ri

ra

N N

k/J 1

ArCH2Br

CH3CN

ra2Br~

,N^N Ar

C©/x .J

NaOH 80oC

3CN Arv ,N N

k/J

2, 78%, Ar =

3, 64%, Ar = <л л

rra _,

NH N Ar ^ Br j 2 yêâ.

Ar N HN

CH2Cl2/NaOH/H2O

4, R = Ph б, 90%, Ar

6, 96%, Ar =

Br

7, 95%, R = Ph S, 40%, Ar =

S, 51%, Ar = <\ /)-<\ h

Scheme 1.

atoms can be oriented in the same direction to favor the formation of the second macrocycle; this was further verified experimentally.

We studied the Pd-catalyzed amination of the compounds 7-9 with diamines 10a-c using racemic BINAP in order to check the possibility of the macrocyclization reactions leading to the formation of macrobicycles 1113, and then a series of different chiral ligands ((R)- and (5")-BINAP, L1-L8) were tested to study the asymmetric induction (Scheme 2). The results are given in the Table 1. Enantiomeric excess was determined using HPLC with a chiral stationary phase. At first the reactions of tetrabenzyl substituted cyclam 7 were studied. The best chemical yields of macrobicycle 11a (40-50 %) were achieved using ligands L1, L2, L4, L6, L7 (entries 3, 4, 6, 8, 9), while traditional BINAP provided 22-28 % yields (entries 1, 2). As for enantiomeric excess, only ligands L3, L4, L7 were to some extent efficient providing 9, 11 and 13 % ee, respectively (entries 5, 6, 9). For the synthesis of 11b, ligand L3 was

isP t

J/л -,

Figure 1. Molecular structure of the cyclam derivative 9.

better than BINAP considering its chemical yield (entries 11 and 12), however, the asymmetric induction was too small though the chain of the corresponding amine was shorter (4 atoms in 10b vs 5 atoms in 10a). Ligand L3 afforded equal

ra

7, Ar = Ph S, Ar= Nf S: Ar = Biph

ra

NH2 NH2 H2N

1Oa

10b

H2N NH2 10c

11, Ar = Ph 12 , Ar = Nf 1З: Ar = Biph

c^rPPh2 ^tpcV2 ^rat-Bu)2 ^cP(t

*M^PCy2 ^¡¡e^PCy. ^^PPh2 ^M^PCy-

L = rac-BINAP (R)-BINAP

Bu)2

Fe

Fe

PCy2

Fe

Fe

PCy2

L1

L2

L3

L4

^ ^ ^ ra

L5 L6 L7

Fe >i

P(3,5-xylyl)2

LS

Isolated by-products:

ra

ra

CF3'2

2

Scheme 2.

Table 1. Pd-catalyzed amination of tetrasubstituted cyclams 7-9.

Entry Substitutent in cyclam Diamine Ligand Yield of macrobicycle, % ee, % Yield of byproducts, %

1 Bn NH/CH^N^ 10a rac-BINAP 11a, 28 _ 14, 19

2 Bn NH2(CH2)3NH2 10a (S)-BINAP 11a, 22 0 _

3 Bn NH2(CH2)3NH2 10a L1 11a, 46 1 _

4 Bn NH2(CH2)3NH2 10a L2 11a, 40 2 14, 33

5 Bn NH2(CH2)3NH2 10a L3 11a, 16 9 14, 16

6 Bn NH2(CH2)3NH2 10a L4 11a, 50 11 14, 42

7 Bn NH2(CH2)3NH2 10a L5 11a, 32 5 15, 30

8 Bn NH2(CH2)3NH2 10a L6 11a, 44 2 14, 51

9 Bn NH2(CH2)3NH2 10a L7 11a, 41 13 15, 37

10 Bn NH/CH^N^ 10a L8 11a, 18 6 _

11 Bn NH/CH^N^ 10b rac-BINAP 11b, 18 _

12 Bn NH/CH^N^ 10b L3 11b, 32 2

13 Nf NH/CH^N^ 10a rac-BINAP 12a, 15 _

14 Nf NH/CH^N^ 10a (tf)-BINAP 12a, 25 1

15 Nf NH/CH^N^ 10a L3 12a, 25 9

16 Nf NH/CH^N^ 10a rac-BINAP 12b, 17 _

17 Nf NH^CH^NH, 10b L7 12b, 19 1

18 Biph NH2(CH2)3NH2 10a rac-BINAP 13a, 21 _

19 Biph NH2(CH2)3NH2 10a L3 13a, 27 9

20 Biph NH^CH^NH, 10b rac-BINAP 13b, 23 _

21 Biph NH^CH^NH, 10b L3 13b, 19 0

22 Biph NH^H^CH^hN^ 10c rac-BINAP 13c, 29 _

23 Biph N^CH^CH^N^ 10c L3 13c, 22 5

enantiomeric excess (9 %) in the reactions of bisnaphthyl and bisbiphenyl derivatives 8 and 9 with diamine 10a (entries 15, 19), and it was again inefficient in the reaction with 1,2-ethanediamine (10b) (entry 21). The use of a more sterically hindered 1,2-diphenyl-1,2-ethanediamine (10c) provided a better result regarding chemical yield of the corresponding macrobicycle 13c and the possibility of asymmetric induction (entries 22, 23). The general feature of all studied reactions was the fact that enantiomeric induction was better for a longer diamine 10a and almost was not dependent on the nature of arylmethyl substitutents introduced in the cyclam moiety to ensure planar chirality.

The formation of macrotricyclic by-product 14 was observed in some reactions of compound 7 with diamine 10a (entries 1, 4-6, 8). The yields reached 50 % and were comparable with those of the target macrobicycle 11a. In two cases (entries 7, 9) the product of monoamination 15 was isolated. NMR spectra of many macrobicycles (11b, 12a,b, 13a-c) are characterized by the signal broadening due to hindered conformational dynamics resulting from the presence of bulky substitutents and short linkers. In many cases satisfactory 13C NMR spectra could be recorded only at elevated temperature (328 K), though many signals were still enough broad (Av1/2 up to 100 Hz).

Conclusions

To sum up, we investigated the synthesis of the planar-chiral macrobicycles using Pd-catalyzed amination

of tetrasubstituted cyclams, bearing two 3-bromobenzyl and two arylmethyl substituents, in the presence of various chiral diphosphine ligands, target macrobicyclic compounds were obtained in yields up to 50 %, we demonstrated the possibility of enantiomeric induction up to 13 % ee and found out that the best enantiomeric excess was achieved with propanediamine-1,3 notwithstanding the bulkiness of the substituents.

Acknowledgements. This work was supported by RFBR grants 09-03-00735, 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". Authors are indebted to the CheMatech Co for a generous supply of cyclam.

References

1. Llinares J.M., Powell D., Bowman-James K. Coord. Chem. Rev. 2003, 240, 57-75.

2. Chen G., Xing Y., Zhang H., Gao J.-X. J. Mol. Cat. A: Chem. 2007, 273, 284-288.

3. Zhang X.X., Bradshaw J.S., Izatt R.M. Chem. Rev.1997, 97, 3313-3362.

4. Kobayashi S., Hamada T., Nagayama S., Manabe K. Org. Lett. 2001, 2, 165-167.

5. Mako A., Bako P., Szollosy A., Bako T., Peltz C., Keglevicha P. ARKIVOC 2009, vii, 165-179.

6. Faltin F., Fehring V., Kadyrov R., Arrieta A., Schareina T., Selke R., Miethchen R. Synthesis 2001, 4, 638-646.

7. Kellogg R.M. Angew. Chem. In. Ed. 1984, 23, 782-794.

8. Weisman G.R., Rogers M.E., Wong E.W., Jasinski J.P., Paight E.S. J. Am. Chem. Soc. 1990, 112, 8604.

9. Weisman G.R., Ho S.C.H., Johnson V. Tetrahedron Lett. 1980, 21, 335.

10. Weisman G.R., Wong E.H., Hill D.C., Rogers M.E., Reed D.P., Calabrese J.C. J. Chem. Soc., Chem. Commun. 1996, 947.

11. Springborg J., Kofod P., Olsen C.E., Toftlund H., Sotofte I. Acta Chem. Scand. 1995, 49, 547.

12. Dapporto P., Formica M., Fusi V., Giorgi L., Micheloni M., Pontellini R., Paoli P., Rossi P. Eur. J. Inorg. Chem. 2001, 1763.

13. Helps I.M., Parker D., Chapman J., Ferguson G. J. Chem. Soc., Chem. Commun. 1988, 1094.

14. Meyer M., Fremond L., Espinosa E., Guilard R., Ou Z., Kadish K.M. Inorg. Chem. 2004, 43, 5572.

15. Chaux F., Denat F., Espinosa E., Guilard R. Chem. Commun. 2006, 5054.

16. Ambrosi G., Formica M., Fusi V., Giorgi L., Guerri A., Micheloni M., Paoli P., Pontellini R., Rossi P. Chem. Eur. J. 2007, 13, 702.

17. Averin A.D., Shukhaev A.V., Buryak A.K., Denat F., Guilard R., Beletskaya I.P. Tetrahedron Lett. 2008, 49, 3950-3954.

18. Kobelev S.M., Averin A.D., Buryak A.K., Denat F., Guilard R., Beletskaya I.P. Heterocycles 2011, 82, 1447-1476.

19. Kobelev S.M., Averin A.D., Buryak A.K., Savelyev E.N., Orlinson B.S., Butov G.M., Novakov I.A., Denat F., Guilard R., Beletskaya I.P. ARKIVOC 2012, vii, 196 - 209.

20. Averin A.D., Tyutenov K.S., Shukhaev A.V., Kobelev S.M., Buryak A.K., Denat F., Guilard R., Beletskaya I.P. Heterocycles 2012. DOI: 10.3987/C0M-12-S(N)88.

21. Ranyuk E.R., Averin A.D., Beletskaya I.P. Adv. Synth. Catal. 2010, 352, 2299-2305.

22. Ukai T., Kawazura H., Ishii Y., Bonnet J.J., Ibers J.A. J. Organomet. Chem. 1974, 65, 253-266.

Received 23.11.2012 Accepted 11.12.2012