Copper-catalyzed amination in the synthesis of polyoxadiamine derivatives of aza-and diazacrown ethers Текст научной статьи по специальности «Химические науки»

Crown Ethers

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Статья

Paper

http://macroheterocycles.isuct.ru

DOI: 10.6060/mhc141035a

Copper-Catalyzed Amination in the Synthesis of Polyoxadiamine Derivatives of Aza- and Diazacrown Ethers

Alexei A. Yakushev,ac Alexei D. Averin,ab@ Maxim V. Anokhin,b Olga A. Maloshitskaya,b Frédéric Lamaty,c and Irina P. Beletskayaab

aA.N. Frumkin Institute of Physical Chemistry and Electrochemistry, 119991 Moscow, Russia hLomonosov Moscow State University, Department of Chemistry, 119991 Moscow, Russia

cInstitut des Biomolécules Max Mousseron (IBMM) UMR 5247, Université Montpellier 2, 34095 Montpellier Cedex, France @Corresponding author E-mail: [email protected]

Cu(I)-Catalyzed amination of N-(iodobenzyl) substituted azacrown ethers with propane-1,3-diamine and several polyoxadiamines was investigated. In the case of diamine excess and the use of CuI/l-proline catalytic system in EtCN the formation of the compounds with one azacrown and one diamine moieties was observed. When taking the excess of N-(iodobenzyl) derivative of azacrown ether and CuI/2-(isobutyryl)cyclohexanone catalytic system in DMF, bis(azacrown) substituted oxadiamine could be obtained. Amination of N,N'-di(iodobenzyl) substituted diazacrown ether was studied under the same conditions. The comparison of Pd(0)- with Cu(I)-mediated amination reactions was done using N-(bromobenzyl) substituted azacrown ethers.

Keywords: Catalysis by Cu(I) complexes, amination, azacrown ethers, diamines.

Медь-катализируемое аминирование в синтезе полиоксадиаминовых производных аза- и диазакраун-эфиров

A. A. Якушев,^ A. Д. Аверин,^ M. В. Анохин,b O. А. Малошицкаяь Ф. Ламати^ И. П. Белецкая^

aИнститут физической химии и электрохимии им. А.Н. Фрумкина, 119991 Москва, Россия

bМосковский государственный университет им. М.В. Ломоносова, Химический факультет, 119991 Москва, Россия cInstitut des Biomolécules Max Mousseron (IBMM) UMR 5247, Университет Монпелье 2, 34095 Монпелье Седекс, Франция

@E-mail: [email protected]

Изучено Cu(I)-катализируемое аминирование N-(иодбензил) замещенных азакраун-эфиров пропан-1,3-диами-ном и некоторыми полиоксадиаминами. При использовании избытка диаминов и каталитической системы CuI/l-пролин в EtCN наблюдалось образование соединений, содержащих один азакраун-эфирный и диаминовый фрагменты. При использовании избытка ^(иодбензил) производных азакраун-эфиров и каталитической системы CuI/2-(изобутирил)циклогексанон в ДМФА могут быть получены бис(азакраун) замещенные оксадиамины. Аминирование Ы,К'-ди(иодбензил) замещенного дизакраун-эфира исследовано в тех же условиях. Проведено сравнение Pd(0)- и Cu(I)-катализируемого аминирования с использованием И-(бромбензил) замещенных азакраун-эфиров.

Ключевые слова: Си(1)-Катализ, аминирование, азакраун-эфиры, диамины.

Introduction

Oxygen- and nitrogen-containing macrocyclic compounds attract researchers' attention due to their unique properties of efficient and selective binding of metal cations, inorganic anions and small polar organic molecules. Introduction of additional donor atoms in the exocyclic substituents of such macrocycles may increase selectivity, binding constants and thus is widely used in coordination and supramolecular chemistry. One of the most important and renowned compounds of such type is ^,^',^",^"'-tetrasubstituted 1,4,7,10-tetraazacyclododecane (DOTA) bearing four carboxylic groups. It has been widely used in the coordination studies with various metal cations including rare earth metals and lanthanides.[1-4] Well-studied are other tetrasubstituted tet-raazamacrocycles like cyclen and cyclam (1,4,8,11-tetraaza-cyclotetradecane) with phosphonate,[5-10] amide,[11] nitrile,[12] primary and tertiary amino groups.[13,14] In many cases additional donor atoms are present in C-substituted macrocycles like cyclam[15,16] or crown ethers.[17] Special interest is paid to substituents bearing several donor atoms (podands), among them oligoethylene oxides are very attractive due to an easy introduction of such podands into macrocycles, possibility to vary the number of donor atoms and their non-ionogenic character. Aza-crown ethers are usually modified with these podands at the nitrogen atom,[18-20] while crown ethers may contain these substituents only at carbon atoms.[21-23] We have developed a simple and efficient approach to macrobicycles and trismacrocycles compounds using Pd(0)-catalyzed mac-rocyclization of ^,^'-di(bromobenzyl) substituted diazac-rown ethers with polyamines and polyoxadiamines,[24,25] also we carried out the synthesis of various bismacrocycles based on V-benzyl substituted azacrown ethers.[26] Recently we have started thourough investigation of Cu(I)-catalyzed arylation and heteroarylation of polyamines and polyoxadiamines[27-29] as well as Cu(I)-mediated amination of steroids.[30] In this connection, the aim of the present research is to apply Cu(I)-catalyzed amination to the synthesis of polyoxadiamine derivatives of aza- and diazacrown ethers and to compare it with the approach which exploits Pd(0) catalysis.

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. Propane-1,3-diamine, dioxa-and trioxadiamines, aza- and diazacrown ethers, 1-(bromomethyl)-3-bromobenzene, /-proline, 2-isobutyrylcyclohexanone, BINAP, cesium carbonate, potassium carbonate, sodium tert-butoxide, CuI were purchased from Aldrich and used without further purification, Pd(dba)2 was synthesized according to the method described,[31] 1-(bromomethyl)-3-iodobenzene was obtained from commercially available ra-iodotoluene by a standard bromination with NBS in CCl4. Dioxane was distilled over NaOH followed by the distillation over sodium under argon, acetonitrile was distilled over CaH2, DMF, EtCN, dichloromethane and methanol were used freshly distilled.

Typical procedure for the synthesis of aza- and diazacrown derivatives 1-4, 9. A flask equipped with a condenser and magnetic stirrer was charged with corresponding azacrown ether (1 mmol), MeCN (3 ml), 1-(bromomethyl)-3-bromobenzene or 1-(bromomethyl)-3-iodobenzene (1 mmol), potassium carbonate

(2.5 mmol) and stirred under reflux for 15 h. In the case of compound 9 diaza-18-crown-6 ether (1 mmol) was reacted with 1-(bromomethyl)-3-iodobenzene (2 mmol) in the presence of potassium carbonate (4 mmol). After cooling the reaction mixture down to room temperature the reaction mixture was diluted with CH2Cl2 (10 ml), the solution was filtered, evaporated in vacuo, dissolved in CH2Cl2 (10 ml), washed with an equal volume of water and dried over molecular sieves. After evaporating the solvent, target V-halogenobenzyl derivatives of aza- and diazacrown ethers were obtained as viscous yellowish oils.

13-(3-Bromobenzy/)-1,4,7,10-tetraoxa-13-azacyc/openta-decane (1). Obtained from 1-aza-15-crown-5 (2 mmol, 438 mg) and 3-bromobenzyl bromide (2 mmol, 500 mg) in the presence of K2CO3 (5 mmol, 695 mg) in 7 ml MeCN. Yield 728 mg (94 %). (MALDI-TOF) found: 388.1167. C17H27BrNO4 requires 388.1123 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.76 (4H, t, 3J = 5.8 Hz), 3.60-3.64 (10H, m), 3.65-3.69 (8H, m), 7.13 (1H, t, 3J = 7.8 Hz), 7.24 (1H, d, 3J = 7.8 Hz), 7.33 (1H, d, 3J = 7.8 Hz), 7.51 (1H, s). 13C NMR (CDCl3, 298 K) Sc ppm: 54.2 (2C), 60.1 (1C), 69.9 (2C), 70.2 (2C), 70.5 (2C), 70.9 (2C), 122.4 (1C), 127.3 (1C), 129.7 (1C), 129.9 (1C), 131.6 (1C), 142.3 (1C).

16-(3-Bromobenzy/)-1,4,7,10,13-pentaoxa-16-azacyc/oocta-decane (2). Obtained from 1-aza-18-crown-6 (1 mmol, 263 mg) and 3-bromobenzyl bromide (1 mmol, 250 mg) in the presence of K2CO3 (2.5 mmol, 348 mg) in 4 ml MeCN. Yield 415 mg (96 %). (MALDI-TOF) found: 432.1425. C19H31BrNO5 requires 432.1386 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.76 (4H, t, 3J = 5.3 Hz), 3.57-3.62 (8H, m), 3.63-3.69 (14H, m), 7.13 (1H, t, 3J = 7.7 Hz), 7.24 (1H, d, 3J = 8.0 Hz), 7.32 (1H, d, 3J = 7.6 Hz), 7.50 (1H, s). 13C NMR (CDCl3, 298 K) Sc ppm: 53.9 (2C), 59.5 (1C), 69.9 (2C), 70.4 (2C), 70.8 (4C), 70.9 (2C), 122.4 (1C), 127.3 (1C), 129.7 (1C), 129.9 (1C), 131.6 (1C), 142.5 (1C).

13-(3-Iodobenzy/)-1,4,7,10-tetraoxa-13-azacyc/openta-decane (3). Obtained from 1-aza-15-crown-5 (4 mmol, 876 mg) and 3-iodobenzyl bromide (4 mmol, 1188 mg) in the presence of K2CO3 (8 mmol, 1104 mg) in 12 ml MeCN. Yield 1.600 g (92 %). (MALDI-TOF) found: 436.0932. C17H27INO4 requires 436.0985 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.70 (4H, t, 3J = 5.9 Hz), 3.54-3.59 (10H, m), 3.60-3.64 (8H, m), 6.96 (1H, t, 3J = 7.7 Hz), 7.23 (1H, d, 3J = 7.6 Hz), 7.49 (1H, d, 3J = 7.8 Hz), 7.65 (1H, s).

16-(3-Iodobenzy/)-1,4,7,10,13-pentaoxa-16-azacyc/oocta-decane (4). Obtained from 1-aza-18-crown-6 (1 mmol, 263 mg) and 3-iodobenzyl bromide (1 mmol, 297 mg) in the presence of K2CO3 (2.5 mmol, 348 mg) in 4 ml MeCN. Yield 445 mg (93 %). (MALDI-TOF) found: 480.1289. C19H31INO5 requires 480.1247 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.76 (4H, t, 3J = 5.7 Hz), 3.59-3.64 (10H, m), 3.64-3.70 (12H, m), 7.01 (1H, t, 3J = 7.7 Hz), 7.29 (1H, d, 3J = 7.7 Hz), 7.54 (1H, d, 3J = 7.8 Hz), 7.70 (1H, s). 13C NMR (CDCl3, 298 K) Sc ppm: 53.9 (2C), 59.4 (1C), 69.9 (2C), 70.4 (2C), 70.8 (4C), 70.9 (2C), 104.5 (1C), 128.0 (1C), 129.9 (1C), 135.9 (1C), 137.6 (1C), 142.6 (1C).

7,16-Bis(3-iodobenzy/)-1,4,10,13-tetraoxa-7,16-diazacyc/o-octadecane (9). Obtained from diaza-18-crown-6 (4 mmol, 1.060 g) and 3-iodobenzyl bromide (8 mmol, 2.376 g) in the presence of Na2CO3 (16 mmol, 1.696 g) in 15 ml MeCN. Yield 2.498 g (90 %). (MALDI-TOF) found: 695.0802. C26H37I2N2O4 requires 695.0843 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 2.76 (8H, t, 3J = 5.3 Hz), 3.52-3.65 (20H, m), 6.98 (2H, t, 3J= "7.7 Hz), 7.26 (2H, d, 3J = 7.7 Hz), 7.51 (2H, d, 3J = 7.7 Hz), 7.67 (2H, s).

Typical procedure for the Cu(I)-cata/yzed amination of compounds 3, 4, 9. A two-necked flask equipped with a condenser and magnetic stirrer was flushed with argon, charged with corresponding azacrown ether derivative 3, 4, 9 (0.5 mmol for the monoamination or diamination or 1 mmol for the diarylation), CuI (10 mol% for the monoamiantion or 20 mol% for the diamination and diarylation), l-proline or 2-isobutyrylcyclohexanone (20 mol% for the monoamination or 40 mol% for the diamination and diarylation), EtCN or DMF (1 ml), corresponding diamine/

oxadiamine (1 mmol for the monoamination, 2 mmol for the diamination, or 0.5 mmol for the diarylation), cesium carbonate (1.5 equiv. for each NH2 group participating in the arylation). The reaction mixture was stirred under reflux (EtCN) or at 140 oC (DMF) for 24 h. After cooling the reaction mixture down to room temperature the reaction mixture was diluted with CH2Cl2 (10 ml), the solution was filtered, evaporated in vacuo, dissolved in CH2Cl2 (10 ml), and additional precipitate was separated. After evaporating the solvent, the residue was chromatographed on silica gel using a sequence of eluents: CH2Cl2, CH2Cl2/MeOH (50:1-3:1), CH2Cl2/ MeOH/NH3aq (100:20:1-10:4:1).

Typical procedure for the Pd(0)-catalyzed synthesis of compounds 7a,b. A two-necked flask equipped with a condenser and magnetic stirrer was flushed with argon, charged with corresponding azacrown ether derivative 1 or 2 (0.5 mmol), Pd(dba)2 (4 mol%, 12 mg), BINAP (4.5 mol%, 14 mg), absolute dioxane (20-20 ml), propane-1,3-diamine (1.5 or 2 mmol, 111 or 148 mg) was added followed by sodium tert-butoxide (0.75 mmol, 72 mg). The reaction mixture was refluxed for 8 h, after cooling the reaction mixture down to room temperature the reaction mixture was diluted with CH2Cl2 (10 ml), the solution was filtered, evaporated in vacuo, dissolved in CH2Cl2 (10 ml), and additional precipitate was separated. After evaporating the solvent, the residue was chromatographed on silica gel using a sequence of eluents: CH2Cl2, CH2Cl2/MeOH (50:1-3:1), CH2Cl2/MeOH/NH3aq (100:20:1-10:4:1) to produce target compounds as viscous yellowish oils or glassy solids.

N1-(3-((1,4,7,10-Tetraoxa-13-azacyclopentadecan-13-yl)-me-thyl)phenyl)propane-l,3-diamine (6a). Obtained from compound 1 (1 mmol, 388 mg), propane-1,3-diamine (5a) (3 mmol, 222 mg), in the presence of Pd(dba)2 (4 mol%, 24 mg), BINAP (4.5 mol%, 28 mg), tBuONa (1.5 mmol, 144 mg) in 20 ml dioxane. Eluent: CH2Cl2/MeOH/NH3aq (100:25:5-100:35:6). Yield 221 mg (58 %). (MALDI-TOF) found: 382.2670. C20H36N3O4 requires 382.2706 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.75 (2H, quintet, 3J = 6.6 Hz), 2.73 (4H, t, 3J = 5.7 Hz), 2.79 (2H, br. t, 3Jobs = 6.2 Hz), 3.14 (2H, t, 3J = 6.6 Hz), 3.56 (2H, s), 3.57-3.65 (16H, in), 6.44 (1H, dd, 3J = 7.8 Hz, 4J = 1.0 Hz), 6.56 (1H, d, 3J = 7.3 Hz), 6.67 (1H, s), 7.04 (1H, t, 3J = 7.7 Hz). (Three NH protons were not assigned). 13C NMR (CDCl3, 298 K) Sc ppm: 32.1 (1C), 39.8 (1C), 41.7 (1C), 54.2 (2C), 60.7 (1C), 69.5 (2C), 69.9 (2C), 70.0 (2C), 70.6 (2C), 110.7 (1C), 113.7 (1C), 117.7 (1C), 128.8 (1C), 140.0 (1C), 148.5 (1C).

N1-(3-((1,4,7,10,13-Pentaoxa-16-azacyclooctadecan-16-yl)-methyl)phenyl)propane-1,3-diamine (7a). Obtained from compound 2 (0.9 mmol, 389 mg), propane-1,3-diamine (5a) (3.6 mmol, 266 mg), in the presence of Pd(dba)2 (4 mol%, 21 mg), BINAP (4.5 mol%, 25 mg), tBuONa (1.4 mmol, 134 mg) in 9 ml dioxane. Eluent: CH2Cl2/MeOH (3:1). Yield 178 mg (46%). (MALDI-TOF) found: 426.299)5. C22H40N3O5 requires 426.2968 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.79 (2H, quintet, 3J = 6.5 Hz), 2.72 (4H, t, 3J = 5.(5 Hz), 2.87 (2H, t, 3J = 6.6 Hz), 3.14 (2H, t, 3J = 6.4 Hz), 3.52 (2H, s), 3.55-3.65 (20H, m), 6.43 (1H, dd, 3J = 7.8 Hz, 4J = 1.1 Hz), 6.53 (1H, d, 3J = 7.5 Hz), 6.59 (1H, s), 7.01 (1H, t, 3J = 7.8 Hz). (Three NH protons were not assigned). 13C NMR (CDCl3, 298 K) Sc ppm: 31.0 (1C), 39.3 (1C), 41.4 (1C), 54.0 (2C), 59.6 (1C), 69.6 (2C), 70.2 (2C), 70.5 (4C), 70.7 (2C), 110.9 (1C), 113.5 (1C), 117.5 (1C), 128.8 (1C), 140.0 (1C), 148.5 (1C).

N1,N3-bis(3-((1,4,7,10,13-Pentaoxa-16-azacyclooctadecan-16-yl)methyl)phenyl)propane-1,3-diamine (8a) was obtained as the second product in the synthesis of compound 7a from compound 2 (0.92 mmol, 396 mg), propane-1,3-diamine (5a) (2.7 mmol, 200 mg), in the presence of Pd(dba)2 (4 mol%, 21 mg), BINAP (4.5 mol%, 26 mg), tBuONa (1.4 mmol, 134 mg) in 10 ml dioxane. CH2Cl2/MeOH/NH3aq (100:35:6). Yield 30 mg (8 %). (MALDI-TOF) found: 777.483. C41H69N4O10 requires 777.50 [M+H]+. 1H NMR (CDCl3, 298 K) SH ppm: 1.90 (2H, quintet, 3J = 6.7 Hz), 2.75 (8H, t, 3J = 5.6 Hz), 3.22 (4H, t, 3J = 6.6 Hz), 3.55-3.67 (44H, m), 3.90 (2H, br. s), 6.46 (2H, d, 3J = 7.7 Hz), 6.60 (2H, d, 3J = 7.5 Hz), 6.65 (2H, s), 7.06 (2H, t, 3J = 7.5 Hz). 13C NMR (CDCl 298 K) 5 ppm:

29.2 (1C), 41.9 (2C), 54.0 (4C), 60.0 (2C), 69.8 (4C), 70.2 (4C), 70.6 (8C), 70.7 (4C), 110.9 (2C), 113.5 (2C), 117.8 (2C), 128.9 (2C), 140.6 (2C), 148.3 (2C).

3-((1,4,7,10-Tetraoxa-13-azacyclopentadecan-13-yl)methyl)-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-aniline (6b). Obtained from compound 3 (0.15 mmol, 66 mg), dioxadiamine (5b) (0.3 mmol, 44 mg), in the presence of CuI (10 mol%, 3 mg), l-proline (20 mol%, 3.5 mg), Cs2CO3 (0.225 mmol, 73 mg) in 1 ml EtCN. Eluent: CH2Cl2/MeOH (3:1), CH2Cl2/MeOH/NH3aq (100:20:1-100:20:3). Yield 51 mg (75 %). (MALDI-TOF) found: 456.3132. C23H42N3O6 requires 456.3074 [M+H]+. 1H NMR (CDCl3, 298 K) 5H ppm: 3.03 (2H, br. s), 3.19 (4H, bs), 3.35 (2H, t, 3J = 4.8 Hz), 3.59-3.70 (20H, m), 3.74 (2H, t, 3J = 4.8 Hz), 3.82 (4H, t, 3J = 4.7 Hz), 4.02 (1H, bs), 6.56-6.63 (2H, m), 7.14 (1H, t, 3J = 7.7 Hz), 7.22 (1H, bs). (NH2 protons were not assigned). 13C NMR (CDCl3, 298 K) 5c ppm: 39.5 (1C), 43.3 (1C), 53.7 (2C), 56.7 (1C), 66.5 (2C), 68.4-70.1 (10C, m), 112.0 (1C), 116.2 (1C), 119.3 (1C), 129.5 (1C), 136.9 (1C), 149.0 (1C).

3-((1,4,7,10-Tetraoxa-13-azacyclopentadecan-13-yl)methyl)-N-(2-(2-(2-(2-aminoethoxy)ethoxy)-ethoxy)ethyl)aniline (6c). Obtained from compound 3 (0.15 mmol, 66 mg), trioxadiamine (5c) (0.3 mmol, 58 mg), in the presence of CuI (10 mol%, 3 mg), l-proline (20 mol%, 3.5 mg), Cs2CO3 (0.225 mmol, 73 mg) in 1 ml EtCN. Eluent: CHp/MeOH (3:1). Yield 25 mg (33 %). (MALDI-TOF) found: 500.3301. C25H46N3O7 requires 500.3336 [M+H]+. 1H NMR (CDCl3, 298 K) 5H ppm: 2.81 (2H, bs), 2.87 (4H, br. s), 3.25 (2H, t, 3J = 4.7 Hz), 3.55-3.69 (26H, m), 3.71 (2H, t, 3J = 5.1 Hz), 3.78 (2H, t, 3J = 5.1 Hz), 4.12 (1H, bs), 6.53 (2H, d, 3J = 8.0 Hz), 7.09 (1H, t, 3J = 7.7 Hz), 7.09 (1H, s). (NH2 protons were not assigned). 13C NMR (CDCl3, 298 K) 5c ppm: 39.6 (1C), 43.6 (1C), 53.9 (2C), 58.7 (1C), 66.3 (2C), 68i (1C), 68.9-70.4 (11C, m), 111.6 (1C), 116.3 (1C), 119.5 (1C), 129.3 (1C), 136.6 (1C), 149.0 (1C).

3-((1,4,7,10-Tetraoxa-13-azacyclopentadecan-13-yl)methyl)-N-(3-(2-(2-(3-aminopropoxy)ethoxy)-ethoxy)propyl)aniline (6d). Obtained from compound 3 (0.29 mmol, 128 mg), trioxadiamine (5d) (0.58 mmol, 128 mg), in the presence ofCuI (10 mol%, 5.5 mg), l-proline (20 mol%, 6.7 mg), Cs2CO3 (0.435 mmol, 142 mg) in 2 ml EtCN. Eluent: CH^/MeOH (5:1-3:1). Yield 57 mg (37 %). (MALDI-TOF) found2 528.3577. C^H^O, requires 528.3649 [M+H]+. 1H NMR (CD3OD, 298 K) 5H ppm: 1.88 (4H, quintet, 3J = 6.1 Hz), 2.72 (4H, t, 3J = 4.5 Hz), 3.03 (2H, bs), 3.19 (2H, t, 3J = 6.6 Hz), 3.56-3.72 (30H, m), 6.55 (1H, d, 3J = 7.1 Hz), 6.59 (1H, s), 6.60 (1H, d, 3J = 8.0 Hz), 7.11 (1H, t, 3J = 7.5 Hz). (NH protons were not observed). 13C NMR (CD3OD, 298 K) 5c ppm: 28.9 (1C), 29.4 (1C), 38.6 (1C), 40.8 (1C), 53.0 (2C), 57.7c(1C), 66.9 (2C), 68.0 (1C), 68.5-70.1 (9C, m), 111.8 (1C), 114.8 (1C), 118.6 (1C), 129.0 (1C), 136. 2 (1C), 149.1 (1C).

3-((1,4,7,10,13-Pentaoxa-16-azacyclooctadecan-16-yl) methyl)-N-(3-(2-(2-(3-aminopropoxy)ethoxy)-ethoxy)propyl) aniline (7d). Obtained from compound 4 (0.5 mmol, 222 mg), trioxadiamine (5d) (1 mmol, 220 mg), in the presence of CuI (10 mol%, 9.5 mg), l-proline (20 mol%, 10.5 mg), Cs2CO3 (1.5 mmol, 489 mg) in 2 ml EtCN. Eluent: CHp/MeOH/NH^q (100:20:1-100:20:3). Yield 185 mg (65 %). (MALDI-TOF) found: 572.3950. C29H54N3O8 requires 572.3911 [M+H]+. 1H NMR (CDCl3, 328 K) 5H ppm: 1.76 (2H, quintet, 3J = 6.8 Hz), 1.83 (2H, quinte!, 3J = 6.0 Hz), 2.85-2.94 (6H, m), 3.18 (2H, t, 3J = 6.4 Hz), 3.50 (2H, t, 3J = 5.7 Hz), 3.50-3.64 (28H, m), 3.69 (4H, bs), 6.47 (1H, d, 3J = 7.5 Hz), 6.50 (1H, d, 3J = 8.0 Hz), 6.65 (1H, s), 7.02 (1H, t, 3J = 7.7 Hz). (NH protons were not assigned). 13C NMR (CDCl3, 298 K) 5c ppm: 27.9 (1C), 29,2 (1C), 37.7 (1C), 41.6 (1C), 54.2 (2C), 57.0 (1C)c, 66.9 (2C), 68.1 (1C), 69.5-70.5 (13C, m), 112.0 (1C), 114.8 (1C), 118.1 (1C), 129.2 (1C), 149.2 (1C). (One aromatic quaternary carbon was not assigned).

N1,N1'-(3,3'-(1,4,10,13-Tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(methylene)bis(3,1-phenylene))dipropane-1,3-diamine (10a). Obtained from compound 9 (0.15 mmol, 104 mg),

propane-1,3-diamine (5a) (0.6 mmol, 44 mg), in the presence of CuI (20 mol%, 6 mg), /-proline (40 mol%, 7 mg), Cs2CO3 (0.45 mmol, 147 mg) in 1 ml EtCN. Eluent: CH.Cl/MeOH/NH^q (100:35:610:4:1). Yield 52 mg (36 %). (MALDI-TOF) found: 587.4349. C32H55N6O4 requires 587.4285 [M+H]+. 1H NMR (CD3OD, 298 K) S7 ppm: 1.79 (4H, quintet, 3J = 7.0 Hz), 2.71 (8H, t, 3J = 4.9 Hz), 2.81 (4H, t, 3J = 6.5 Hz), 3.17 (4H, t, 3J = 6.5 Hz), 3.51 (4H, s), 3.54 (8H, s), 3.61 (8H, t, 3J = 4.9 Hz), 6.47 (2H, d, 3J = 7.2 Hz), 6.53 (2H, s), 6.54 (2H, d, 3J = 7.6 Hz), 7.06 (2H, t, 3J = 7.7 Hz). (N7 protons were not assigned). 13C NMR (CD3OD, 298 K) Sc ppm: 31.8 (2C), 39.9 (2C), 42.0 (2C), 55.2 (4C), 58.6 (2C), 69.8 (4C), 71.3 (4C), 112.5 (2C), 115.7 (2C), 119.4 (2C), 130.0 (2C), 139.3 (2C), 150.0 (2C).

3,3'-(1,4,10J3-Tetraoxa-7J6-diazacyclooctadecane-7J6-diy/)bis(methy/ene)bis(N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy) ethy/)ani/ine) (10d). Obtained from compound 9 (0.5 mmol, 347 mg), trioxadiamine (5d) (2 mmol, 440 mg), in the presence of CuI (20 mol%, 20 mg), /-proline (40 mol%, 24 mg), Cs2CO3 (2 mmol, 652 mg) in 1 ml EtCN. Yield in the reaction mixture 76%. (MALDI-TOF) found: 823.58. C42H75N6O10 requires 823.55 [M+H]+. 1H NMR (CDCl3, 298 K) S7 ppm: 1.(33 (4H, bs), 1.79 (4H, quintet, 3J = 6.1 Hz), 2.66 (8H, bs), 2.70 (4H, bs), 3.10 (4H, t, 3J = 6.1 Hz), 3.40-3.56 (32H, m), 6.38 (2H, d, 3J = 7.7 Hz), 6.46 (2H, d, 3J = 6.8 Hz), 6.52 (2H, s), 6.98 (2H, t, 3J = 7.7 Hz). (N7 protons were not assigned).

3-((1,4,7,10-Tetraoxa-13-azacyclopentadecan-13-yl)methyl)-N-(3-(2-(2-(3-(4-((1,4,7,10-tetraoxa-13-azacyc/opentadecan-13-y/)methy/)pheny/amino)propoxy)ethoxy)ethoxy)propy/)ani/ine (11d). Obtained from compound 3 (0.78 mmol, 340 mg), trioxa-diamine (5d) (0.39 mmol, 85 mg), in the presence of CuI (20 mol%, 15 mg), 2-(isobutyryl)cyclohexanone (40 mol%, 26 mg), Cs2CO3 (1.5 mmol, 489 mg) in 1 ml DMF. Eluent: CH2Cl2/MeOH/N73aq (100:20:2). Yield 92 mg (28 %). (MALDI-TOF) found: 835.5380. C44H75N4O11 requires 835.5432 [M+H]+. 1H NMR (CDCl3, 298 K) S7 ppm: 1.86 (4H, quintet, 3J = 6.3 Hz), 2.77 (8H, t, 3J = 5.8 Hz), 3.19 (4H, t, 3J = 6.6 Hz), 6.44 (2H, dd, 3J = 7.8 Hz, 4J = 1.3 Hz), 6.59 (2H, d, 3J = 7.6 Hz), 6.62 (2H, s), 7.05 (2H, t, 3J = 7.8 Hz). (N7 protons were not assigned). 13C NMR (CDCl3, 298 K) Sc ppm: 29.2 (2C), 41.6 (2C), 54.3 (4C), 60.8 (2C), 69.6 (2C), 69.8*" (4C), 70.1 (4C), 70.2 (2C), 70.4 (4C), 70.6 (2C), 70.8 (4C), 111.0 (2C), 113.4 (2C), 117.6 (2C), 128.9 (2C), 140.4 (2C), 148.6 (2C).

N,N'-(3,3'-(2,2'-Oxybis(ethane-2,1-diyl)bis(oxy)) bis(propane-3,1-diyl))bis(3-((16-(3-iodobenzyl)-1,4,10,13-tetraoxa-7,16-diazacyc/ooctadecan-7-y/)methy/)ani/ine) (12d). Obtained from compound 9 (1 mmol, 694 mg), trioxadiamine (5d) (0.5 mmol, 110 mg), in the presence of CuI (20 mol%, 19 mg), 2-(isobutyryl)cyclohexanone (40 mol%, 34 mg), Cs2CO3 (1.5 mmol, 489 mg) in 1 ml DMF. Eluent: CHp/MeOH/NH^q (100:25:1-100:25:2). Yield 120 mg (18 %). (MALDI-TOF) found: 1353.54. C^H^N^ requires 1353.51 [M+H]+. 1H NMR (CDCl3, 298 K) S7 ppm: 1.86 (4H, quintet, 3J = 5.9 Hz), 2.74-2.86 (16H, m), 3.19 (4H, t, 3J = 6.4 Hz), 3.51-3.70 (40H, m), 6.45 (2H, d, 3J = 7.2 Hz), 6.58 (2H, s), 6.62 (2H, d, 3J = 7.3 Hz), 7.00 (2H, t, 3J = 7.6 Hz), 7.06 (2H, t, 3J = 7.5 Hz), 7.29 (2H, d, 3J = 7.3 Hz), 7.53 (2H, d, 3J = 7.3 Hz), 7.69 (2H, s). (N7 protons were not

assigned). 13C NMR (CDCl3, 298 K) Sc ppm: 29.2 (2C), 41.6 (2C), 53.6 (4C), 53.7 (4C), 59.2 (2C), 60.0 c(2C), 69.7 (2C), 69.9 (8C), 70.2 (2C), 70.6 (8C), 94.3 (1C), 111.2 (2C), 113.3 (2C), 117.7 (2C), 127.9 (2C), 128.9 (2C), 129.9 (2C), 135.8 (2C), 137.5 (2C), 141.8 (2C), 142.4 (2C), 148.5 (2C).

Results and Discussion

Initially 1-aza-15-crown-5 and 1-aza-18-crown-6 were modified with 3-bromobenzyl or 3-iodobenzyl substituents using simple nucleophilic substitution reactions with corresponding benzyl bromides (Scheme 1). Target products 1-4 were obtained in high yields (92-96 %) after simple work-up of the reaction mixtures.

First bromobenzyl derivatives of azacrown ethers 1 and 2 were employed in the Pd(0)-catalyzed reactions with 3 equiv. of propane-1,3-diamine 5a to check the selectivity of the V-monoarylation vs N,^'-diarylation and to elaborate the conditions for the chromatographic isolation of the target products. Standard conditions for these processes were applied: Pd(dba)2/BINAP catalytic system (4/4.5 mol%), 1.5 equiv. tBuONa as a base. The amination of compound 1 using 0.02 M solution of 1 led to 85 % yield of the monoarylation product 6a, and after column chromatography it was isolated in 43 % yield, whereas the same reaction in a more concentrated solution (C = 0.05 M) led to 87 % yield of the target compound 6a in the reaction mixture and 58 % yield after chromatography. In the case of compound 2 the similar reaction led to 77 % yield of the product of monoarylation 7a and 23 % yield of the diarylated diamine 8a. After column chromatography their yields were 30 and 8 % respectively (Scheme 2). The application of 4 equiv. of propane-1,3-diamine in the reaction with compound 2 resulted in 88 % yield of the target compound 7a in the reaction mixture, thus it can be used in situ for some further transformations. The yield after chromatography in this case also increased to 46 %. Amination reactions were also conducted with iodobenzyl derivative 4 using either CuI/L1 (10/20 mol%) catalytic system (L1 = l-proline), 1.5 equiv. Cs2CO3 in boiling EtCN (C = 0.5 M), or CuI/L2 (10/20 mol%) catalytic system (L2 = 2-isobutyrylcyclohexanone), 1.5 equiv. Cs2CO3 in DMF (140 oC). The first reaction afforded 80 % yield of the compound 7a in the reaction mixture and 22 % after chromatographic isolation, the second reaction produced 17 % of the same compound after chromatography. No product of diarylation 8a was noted in both cases. For this reason we chose CuI/L1/EtCN for further syntheses of monoaryl derivatives of polyoxadiamines. It should be noted that as the excess of propane-1,3-diamine can easily be removed in high vacuum and only 2 equiv. of this diamine

c ™>

^o_o-7

n = 1, 2

K2C03/MeCN Hlg = Br, I

1: n = 1, Hlg = Br, 94% 2: n = 2, Hlg = Br, 96% 3: n = 1, Hlg = I, 92% 4: n = 2, Hlg = I, 93%

Scheme 1.

c

V 1,

Scheme 2.

are needed to form the monoarylated derivative 7a, in the case of further transformations of this compound one does not need its chromatographic purification and may use it in situ.

Further Cu(I)-catalyzed reactions were conducted using iodobenzyl derivatives 3 and 4 and a number of di- and trioxadiamines 5b-c taken in two-fold excess (Scheme 3). These reactions were catalyzed by CuI/L1 (10/20 mol%) in the presence of Cs2CO3 in EtCN and the products were isolated by column chromatography. Dioxadiamine 5b afforded 75 % yield of the target compound 6b, while the reactions with trioxadiamines 5c,d gave lower yields of corresponding derivatives 6c,d (33 and 37 %). The amination of compound 4 with trioxadiamine 5d was much more successful and the product 7d was obtained in 65 % yield. No products of N,N'-diarylation of polyoxadiamiens were isolated in all cases. This fact is in a good correspondence with our previous results of the Cu-catalyzed arylation of polyoxadiamines.[27] In this research we did not use polyamines as substrates though they were found to participate better than oxadi-amines in the copper-catalyzed arylation and heteroarylation reactions.[27,28] This was done in view of a practical impos-

sibility of the isolation of their pure monoaryl derivatives bearing azacrown moiety from the reaction mixture with the excess of polyamine.

Next we investigated the possibility to introduce diazacrown ethers in the reactions with propane-1,3-diamine and oxadiamines. N,N'-di(3-iodobenzyl) derivative of diaza-18-crown-6 9 was synthesized in 90 % yield, and it was introduced in the reaction with 4 equiv. of propane-1,3-diamine catalyzed by CuI/L1 (20/40 mol%) (Scheme 4). The yield of the target compound 10a exceeded 80 % in the reaction mixture, and after column chromatography it was 36 %. The same reaction with trioxadiamine 5d afforded 76 % yield of the bis(trioxadiamine) derivative 10d in the reaction mixture.

According to our previous investigations, the copper-catalyzed N,N'-diarylation of diamines and oxadiamines turned to be a challenging task. We carried out the diarylation of trioxadiamine 5d using 2 equiv. of iodobenzyl substituted azacrown 3 (Scheme 5). In this case the catalytic system CuI/ L2 in DMF (140 oC) was employed because we had shown it to promote N,N'-diarylation of oxadiamines with simple aryl

-J 2,4

H2N- ^ -NH2

Hlg 5a

Pd(0) or Cu(l)

^o /n O N

^•O O

6a: n = 1 7a: n = 2

8a

3,4

H2N X 5b-d

NH,

Cul/L1/EtCN

6b: n = 1, X = 0CH2CH20, 75%

6c: n = 1, X = 0CH2CH20CH2CH20, 33%

6d: n = 1, X = CH2OCH2CH2OCH2CH2OCH2, 37%

7d: n = 2, X = CH2OCH2CH2OCH2CH2OCH2, 65%

« „ ~ ~ x , "NH

w W }

X X

( ) 9,90% NH2 H2N

10a: X = CH2, 36% 10d: X = CH2OCH2CH2OCH2CH2OCH2, 76% (m situ)

Scheme 4.

cr

О N

С

о о

3

о о

Cul/L2 or L1/DMF

Г

h2n

N

н

н

„N.

"О

.О N

С

H2N X NH2 О_о

5d,e 0.5 equiv.

ООО NH HN

11d, 28%

гл о о

3

N О

г«'.......] о

о о ^ о о

5е

NH HN

.0 О О ) (^N^

С°

о о

12d, 18%

Scheme 5.

iodides.[27] The target product 11d was isolated in 28 % yield. The same reaction with tetraamine 5e catalyzed by CuI/L1 in DMF gave a complex mixture of the products of arylation among which the target compound was detected by NMR and MALDI-TOF spectroscopy, however, the pure product could not be isolated by column chromatography, probably due to the formation of isomers with close Rf Similarly, the reaction of N,N'-di(3-iodobenzyl) substituted diazacrown 9 produced corresponding bisazacrown derivative of trioxadiamine 12d, but the reaction with tetraamine 5e gave only an inseparable mixture of unidentified compounds.

Conclusions

To sum up, we investigated the possibility to modify azacrown ethers with propane-1,3-diamine and polyoxadiamine podands using Cu(I)-catalyzed amination and found out that this approach is quite applicable. The reactions mediated by Cu(I) and Pd(0) were shown to produce the target arylation products in comparable yields. Moderate yields of the target compounds were due to their

difficult isolation using column chromatography, and in the case of propane-1,3-diamine its excess can be removed in vacuo, and the product was shown to be enough pure for further transformations. Cu(I)-catalyzed diamination of the diazacrown derivative was also demonstrated as well as N,N'-diarylation of trioxadiamine with iodobenzyl derivatives of aza- and diazacrown ethers. Only diamines and polyoxadiamines but not polyamines can be employed in these reactions.

Acknowledgements. This work was financially supported by the RFBR grants 12-03-00796, 12-03-93113, 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".

References

1. Caceris W.P., Nickle S.K., Sherry A.D. Inorg. Chem. 1987, 26, 958-960.

2. Hama H., Takamoto S. Nippon Kagaku Kaishi 1975, 1182-1185.

3. Stetter H., Frank W. Angew. Chem., Int. Ed. Engl. 1976, 15, 686-686.

4. Brucher E., Laurenczy G., Makra Z.S. Inorg. Chim. Acta 1987, 139, 141-142.

5. Medved T.Ya., Kabachnik M.I., Belskii F.I., Pisareva S.A. Izv. Akad. Nauk SSSR, Ser. Khim. 1988, 2103-2107 (in Russ.).

6. Polikarpov Yu.M., Belskii F.I., Pisareva S.A., Kabachnik M.I. Izv. Akad. Nauk SSSR, Ser. Khim. 1989, 2112-2116 (in Russ.).

7. Kabachnik M.I., Medved T.Ya., Belskii F.I., Pisareva S.A. Izv. Akad. Nauk SSSR, Ser. Khim. 1984, 844-849 (in Russ.).

8. Delgado R., Siegfried L.C., Kaden T.A. Helv. Chim.Acta 1990, 73, 140-148.

9. Kabachnik M.I., Polikarpov Yu.M. J. Gen. Chem. USSR (Engl. Transl.) 1988, 58, 1729-1750.

10. Pisareva S.A., Belskii F.I., Medved T.Ya., Kabachnik M.I. Izv. Akad. Nauk SSSR, Ser. Khim. 1987, 413-417 (in Russ.).

11. Kataky R., Matthes K.E., Nicholson P.E., Parker D., Buschmann H.J. J. Chem. Soc, Perkin Trans. 2 1990, 1425-1432.

12. Izatt R.M., Pawlak K., Bradshaw J.S. Chem. Rev. 1991, 91, 1721-2085.

13. Basak A.K., Kaden T.A. Helv. Chim. Acta 1983, 66, 20862092.

14. Evers A., Hancock R.D., Murase I. Inorg. Chem. 1986, 25, 2160-2163.

15. Kimura E., Machida R., Kodama M. J. Am. Chem. Soc. 1984, 106, 5497-5505.

16. Fujioka H., Kimura E., Kodama M. Chem. Lett. 1982, 737740.

17. Ikeda I., Katayama T., Okahara M., Shono T. Tetrahedron Lett. 1981, 22, 3615-3616.

18. White B.D.,Dishong D.M., Minganti C., Arnold K.A., Goli D.M., Gokel G.W. Tetrahedron Lett. 1985, 26, 151-154.

19. Zavada J., Koudelka J., Holy P., Belohradsky M., Stibor I. Coll. Czech. Chem. Commun. 1989, 54, 1043-1054.

20. Schultz R.A., White B.D., Dishong D.M., Arnold K.A., Gokel G.W. J. Am. Chem. Soc. 1985, 107, 6659-6668.

21. Dishong D.M., Diamond C.J., Cinoman M.I., Gokel G.W. J. Am. Chem. Soc. 1983, 105, 586-593.

22. Goli D.M., Dishong D.M., Diamond C.J., Gokel G.W. Tetrahedron Lett. 1982, 23, 5243-5246.

23. Nakatsuji Y., Nakamura T., Okahara M., Dishong D.M., Gokel G.W. J. Org. Chem. 1983, 48, 1237-1242.

24. Yakushev A.A., Chernichenko N.M., Anokhin M.V., Averin A.D., Buryak A.K., Denat F., Beletskaya I.P. Molecules 2014, 19, 940-965.

25. Kobelev S.M., Averin A.D., Buryak A.K., Denat F., Guilard R., Beletskaya I.P. Macroheterocycles 2014, 7, 28-33.

26. Anokhin M.V., Averin A.D., Buryak A.K., Beletskaya I.P. Mendeleev Commun. 2011, 21, 132-133.

27. Anokhin M.V., Averin A.D., Beletskaya I.P. Eur. J. Org. Chem. 2011, 6240-6253.

28. Anokhin M.V., Averin A.D., Panchenko S.P., Maloshits-kaya O.A., Beletskaya I.P. Russ. J. Org. Chem. 2014, 50, 923-927.

29. Anokhin M.V., Averin A.D., Panchenko S.P., Maloshits-kaya O.A., Buryak A.K., Beletskaya I.P. Helv. Chim. Acta 2015, 98, 47-59.

30. Kotovshchikov Yu.N., Latyshev G.V., Lukashev N.V., Beletskaya I.P. Eur. J. Org. Chem. 2013, 7823-7832.

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

Received 24.10.2014 Accepted 26.11.2014