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14Crown Ethers Краун-эфиры
Шкрогэтароцмклы
http://macroheterocycles.isuct.ru
Paper Статья
DOI: 10.6060/mhc190554a
Transformations of (y-Piperidono)dibenzoaza-14-crown-4 Ethers
Truong H. Hieu,a,e Alexandra I. Komarova,b Alexander N. Levov,b
Anatoly T. Soldatenkov,bf Elena I. Polyakova,b Nguyen V. Tuyen,ad Dang T. T. Anh,ad
Alena N. Kulakova,b Victor N. Khrustalev,b and Le T. Anhc@
aInstitute of Chemistry, Vietnam Academy of Science and Technology (VAST), Hanoi, Vietnam
department of Inorganic Chemistry, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russian Federation
cFaculty of Chemistry, VNU University of Science, Vietnam National University, Hanoi, Vietnam dGraduate University of Science and Technology, VAST, Hanoi, Vietnam
eSaigon Pharmaceutical Science-Technology Centre, University of Medicine and Pharmacy at Ho Chi Minh City, 70000 Ho Chi Minh City, Vietnam
@Corresponding author E-mail: [email protected]
The transformations of dibenzo[(y-piperidono]aza-14-crown-4 ethers were implemented with Li-organic compounds and sodium borohydride under reduction condition. The structures of new compounds were confirmed by 1H NMR, IR, MS analysis. X-Ray single-crystal structure study has exactly determined the structure of the representative compound 2g. According to the PASS program, these obtained new azacrown ethers containing y-piperidol fragment are interested to develop new biologically active agents such as a CYP2H substrate (60-95 %), membrane permeability inhibitor (60-74 %) and spasmolytic agent (60-92 %).
Keywords: Azacrown ether, Li-organic compound, y-piperidol, single-crystal X-ray structure.
Превращения (у-пиперидоно)дибензоаза-14-краун-4-эфиров
Т. Х. Хиеу,3'6 А. И. Комарова,13 А. Н. Левов,11 А. Т. Солдатенков,1 Е. И. Полякова,13 Н. В. Туен,^ Д. Т. Т. Ань,^ А. Н. Кулакова,1 В. Н. Хрусталев,1 Л. Т. Аньс@
аИнститут химии, Вьетнамская академия науки и технологии, Ханой, Вьетнам
ъКафедра неорганической химии, Российский университет дружбы народов, 117198 Москва, Россия
сФакультет химии, Университет науки, Вьетнамский национальный университет, Ханой, Вьетнам
АВысший университет науки и техники, Вьетнамская академия наук и технологии, Ханой, Вьетнам
еСайгонский фармацевтический научно-технологический центр, Университет медицины и фармакологии, 70000
Хошимин, Вьетнам
@Е-таИ: [email protected]
При взаимодействии дибензо[(у-пиперидоно]аза-14-краун-4-эфиров с Li-органическими соединениями и боро-гидридом натрия были получены соответствующие продукты их восстановления, структура которых была подтверждена данными H ЯМР, ИК спектроскопии и масс-спектрометрии. С помощью рентгеноструктур-ного анализа была установлена структура соединения 2g. В соответствии с программой PASS, полученные впервые азакраун-эфиры, содержащие фрагмент у-пиперидола, представляют интерес для разработки новых биологически активных агентов, таких как CYP2H субстрат (60-95 %%), ингибитор проницаемости мембраны (60-74 %) и спазмолитических веществ (60-92 %).
Ключевые слова: Азакраун-эфир, Li-органическое соединение, у-пиперидол, рештенострукгурный анализ.
Transformations of (y-Piperidono)dibenzoazacrown Ethers Introduction
A large number of heterocyclic compounds containing a y-piperidol fragment or its ester derivatives have shown different and high biological activities.[1] Besides, major interest of crown ether concerns the studying their complex-ing ability with metal ions.[2] A presence of nitrogen atom imparts many interesting properties to crown ethers, namely, increasing ability and selectivity for metal-ion complexation and as phase-transfer catalysts. Macrocyclic compounds containing crown ether and y-piperidol group have attracted attention as ligands for metal ions and as high potential bio-activity agents.[3] In this connection, chemistry of functional-ized azacrown ether continues to develop intensively and we obtained a series of new aza-14-crown-4 ethers containing in the macrocycle an embedded y-piperidol fragment.
For the synthesis of the target compounds, the method of reduction of azacrown ether (1) with sodium borohydride in ethyl alcohol and the interaction of the y-piperidone fragment with a-furyllithium, a-thienyllithium, and a-pyridylmethyllithium were studied. From the reaction mixtures, target compounds were isolated by chromatogra-phy or recrystallization and according to spectral analyzes the y-piperidolocrown ethers (2a-d, 2f-h) were described.
Experimental
Reagents were purchased from commercial sources (Sigma-Aldrich) and were used without any additional purification. Melting points were determined in open capillary tubes on a digital Stuart SMP3 apparatus. Elemental analysis was conducted on Euro Vector EA-3000 analyzer. IR spectra were recorded in KBr disks on an Infralum FT-801 spectrometer. 'H NMR and 13C NMR spectra were recorded in CDCl3 solution at 25 °C, using a BRUKER 500 MHz NMR spectrometer; chemical shifts are given in parts per million (5) and referenced to the appropriate solvent residual peak. Mass spectra were obtained on instruments Finnigan MAT 95 XL (EI, ionizing energy 70 eV). X-ray diffraction data were obtained on an automatic three-circle Bruker APEX-II CCD diffractometer. Column chromatography was performed on aluminium oxide 100-160 fim or on silica gel 40-60 fim. Silufol UV-254 was used for thin-layer chromatography, visualization with the iodine vapor.
Dimethyl-23 -oxo-8 , 11,14-trioxa-25-azatetracyclo-[19.3.1.02-7.015-20]pentacosa-2,4,6,15(20),16,18-hexaen-22,24-di-carboxylate (1a). To a mixture of 3.14 g (10 mmol) of 1,5-bis(2-formylphenoxy)-3-oxapentane, 0.77 g of ammonium acetate, 2 ml of CH3COOH and 30 ml of ethanol, 1.47 ml (0.01 mol) dimethyl ether of 3-oxopentane dicarboxylic acid were added dropwise. The mixture was stirred for 8 hours. The precipitated crystals were filtered, washed with ether and recrystallized from ethyl acetate. The reaction product was obtained in the form of white crystals (3-5 %). M.p. 220-221 °C (from ethanol), R/ = 0.46 (ethylacetate:n-hexane = 3:1). Found, %: C 63.75, H 5.81, N 2.80. C25H27NO8. Calculated, %: C 63.96, H 5.80, N 2.98. m/z (Irel, %): 469 [M]+. IR (KBr) vmax cm-1: 3318 (NH), 1750 (O=CO),re 1698 (C=O). 1H NMR (500 MHz, CDCl3, Me4Si) 5H ppm: 3.53 (s, 6H, CH3), 3.83 (m, 2H, H-1, H-21), 4.01 (d, 2H, J = 10.0 Hz, H-22, H-24), 4.10 and 4.32 (both m, 4H each, 0CH2CH20), 4.23 (br.s, 1H, NH), 6.77 (d, 2H, J = 8.0 Hz, H-6, H-16), 6.82 (t, 2H, J = 8.0 Hz, H-4, H-18), 7.17 (m, 4H, Hrom). 13C NMR (125 MHz, CD3CN, Me4Si) 5C ppm: 52.6 (CH3), 63a()m(C-22, C-24), 66.5 (C-1, C-21), 68.3 (C-9, C-13), 70.5 (C-10, C-12), 112.9 (C-6, C-16), 121.9 (C-4, C-18), 127.7 (C-2,
C-20), 131.0 (C-5, C-17), 132.7 (C-3, C-19), 158.4 (C-7, C-15), 170.3 (COO), 202.4 (C-23).
Ethyl 23-oxo-8,11,14-trioxa-25-azatetracyclo[19.3.1.027.01520] pentacosa-2,4,6,15(20), 16,18-hexaen-22-carboxylate (1c), ethyl 2-{24-ethyloxycarbonylmethyl-23-oxo-8,11,14-trioxa-25-aza-tetracyclo[19.3.1.027.0152"]pentacosa-2(7),3,5,15,17,19-hexaen-22-yl}-acetate (1d), 22,24-dimethyl-8,11,14-trioxa-25-azatetra-cyclo[19.3.1.027.01520]pentacosa-2,4,6,15(20), 16,18-hexaen-23-on (1e) and22-phenyl-8,11,14-trioxa-25-azatetracyclo[19.3.1.02 7.01520] pentacosa-2,4,6,15(20),16,18-hexaen-23-on (1f) were synthesized by general method.[4] 2-[22,24-Dimethyl-23-oxo-8,11,14-trioxa-25-azatetracyclo[19.3.1.027.01520]pentacosa-2,4,6,15(20),16,18-hexaen-25-yl]acetonitrile (1b) was synthesized by method.[5]
Dimethyl-23-hydroxy-8,11,14-trioxa-25-azatetracy-clo[19.3.1.027.01520]pentacosa-2,4,6,15(20),16,18-hexaen-22,24-di-carboxylate (2a). A mixture of 1.0 g (2.1 mmol) of azacrown ether (1a) in 20 ml of ethanol was added over 10 minutes to 0.08 g (2.1 mmol) of NaBH4 with stirring. The mixture was stirred for 1 hour at 20 °C and then for 30 minutes at 78 °C. The precipitate was filtered off, washed with water and recrystallized from ethyl acetate. White crystals (2a) were obtained with yield of 80 % (0.79 g). M.p. 205-207 °C (from ethyl acetate). R7 = 0.55 (ethylac-etate). Found, %: C 63.51, H 6.02, N 3.10. C25H29NO8. Calculated, %: C 63.68, H 6.20, N 2.97. LCMS, m/z (Irel, %): 472 [M+1]+ (two diastereomers). Mass, m/z (Irel, %): 471 [M]+ (3), 457 (1), 440 (3), 412 (4), 383 (15), 369 (47), 2977 (8), 266 (7), 220(7), 206 (12), 192 (17), 178 (13), 162 (18), 148 (90), 131 (95), 119 (100), 103 (37), 91 (85), 77 (70), 71 (31), 65 (24), 59 (44), 51 (17), 43 (50). IR (KBr) vmax cm-1: 3510, 3429 (OH), 3309 (NH), 1727 (OC=OCH3). 1H NMR (500 MHz, CDCl3, Me4Si) SH ppm: 3.62 (s, 6H, CH3), 3.86 (m, 2H, H-1, H-21), 3.98-4.06 (m, 2H, H-22, H-24), 4.10 and 4.35
(both m, 4H each, OCH2CH2O), 4.24 (br.s, 1H, NH), 6.75-7.13 (m, 8H, H ). 2 2
7 arom7
2-[23-Hydroxy-22,24-dimethyl-8,11,14-trioxa-25-azatetra-cyclo[19.3.1.027.01520]pentacosa-2,4,6,15(20),16,18-hexaen-25-yl] acetonitrile (2b). To 1.0 g (2.4 mmol) of piperidone (1b), dissolved in 20 ml of ethanol, 0.09 g (2.4 mmol) of NaBH4 was added. The reaction mixture was stirred for 1 hour at the boiling point of the solvent, 30 ml of water were added, the crystals were filtered and dried. After recrystallization from alcohol, 0.83 g (83 %) of the product was obtained, white crystals with M.p. 237-239 °C, R/ = 0.67 (ethylacetate). Found, %: C 70.92, H 6.97, N 6.43. CÄNA. Calculated, %: C 71.07, H 7.16, N 6.63. m/z (I ,,
25 30 2 4 5 55 v rel.5
%): 422 [M]+(2), 382 (2), 352 (2), 231 (5), 187 (23), 173 (5), 161 (16), 145 (17), 131 (54), 119 (43), 105 (45), 91 (100), 77 (65), 65 (26), 57 (53), 51 (21), 43 (66). IR (KBr) vmax cm-1: 3320 (NH), 3439 (OH), 2226 (C=N). 1H NMR (500 MHz," CDCl3, Me4Si) SH ppm: 0.73 and 0.77 (two d, 3H each, J = 7.0 and 7.0 Hz, CH3), 2.69 and 2.98 (both m, 1H each, H-22, H-24), 3.01 (d, 2H, J = 1.0 Hz, NCH2CN), 3.12 and 3.61 (both d, 1H each, J = 10.0 Hz, H-1, H-21), 3.78-4.05 (m, 10H, OCH2CH2O, H-23, OH), 6.78-7.32 (m, 8H, Harom).
Ethyl 23-hydroxy-8,11,14-trioxa-25-azatetracyclo-
[19.3.1.02 7.01520]pentacosa-2,4,6,15(20),16,18-hexaen-22-car-boxylate (2c). To a solution of 2.13 g (5 mmol) of piperidone 1c in 20 ml of ethyl alcohol 0.19 g (5 mmol) of NaBH4 was added in 10 min with stirring. The mixture was stirred for 1 hour at 20 °C and then for 30 minutes at 78 °C. The precipitate was filtered off, washed with water and recrystallized from ethyl acetate. 1.6 g (75 %) of the product (2c) were obtained in the form of white crystals. M.p. 184-186 °C. R7= 0.38 (ethylacetate). Found, %: C 67.27, H 6.62, N 3.32. C^KNO,. Calculated, %: C 67.43, H 6.84, N
24 29 6
3.28. LCMS, m/z (I, %): 428 [M+1]+ (two diastereomers). IR (KBr) vmax cm-1: 3517, 3397 (OH), 3316 (NH), 1723 (O=C-OEt). 1H NMR (500 MHz, CDCl3, Me4Si) SH ppm: 0.85 (br.s, 3H, CH2CH3), 2.20 (m, 3H, H-23, H-24a, H-24e), 3.21 (br.s, 2H, NH, H-21), 3.91-4.25 (m, 13H, OCH2CH2O, OCH2CH3, H-1, H-22, OH), 6.73-6.92 (m, 4H, H ), 7.11-7.25 (m, 4H,H ).
arom arom
Ethyl 2-{24-ethyloxycarbonylmethyl-23-hydroxy-8,11,14-tri-oxa-25-azatetracyclo[19.3.1.02 7.01520]pentacosa-2(7), 3,5,15,17,19-hexaen-22-yl} acetate (2d) and ethyl 2-{24-oxo-8,11,14,25-tetraoxa-28-azatetracyclo[19.6.1.02,7.015,20. 022,26]octacosa-2,4,6,15(20),16,18-hexaen-27-yl} acetate (2e). To 2 g (3.8 mmol) of piperidone (1c), dissolved in 30 ml of ethanol, 0.07 g (1.9 mmol) of NaBH4 was added. The reaction mixture was stirred for 30 minutes at the boiling point of the solvent. Control of reaction was led by TLC. The alcohol was evaporated under vacuum. 50 ml of water and 1 ml of acetic acid were added to the residue, the reaction products were extracted with chloroform (3x30 ml). The combined extracts were dried with anhydrous MgSO4 and evaporated in vacuo. The residue was separated by column chromatography on silica gel, eluting with ethyl acetate:hexane, 1:1 and affording:
A) 0.1 g (6 %) lactone (2e), white crystals with M.p. 196-198 °C, Rf = 0.41 (ethylacetate). Found, %: C 67.22, H 6.44, N 2.86. C27H31NO7. Calculated, %: C 67.35, H 6.49, N 2.91. m/z (Irel, %): 4251 [M]+ (8), 393 (3), 297 (9), 148 (12), 134 (14), 119 (11), 9f (15), 77 (10), 43 (100). IR (KBr) vmax cm-1: 1735 (-OC=O), 1775 (C=O lacton). 1H NMR (500 MHz, CDCl3, Me4Si) SH ppm: 1.13 (t, 3H, J = 7.0 Hz, CH3), 2.02 (br.s, 1H, NH), 2.09 and 2.16 (both dd, 1H each, 2J = 16.0 and 3J = 5.0 Hz, CH2COO), 2.43, 2.47 and 2.52 (all d, 2H sum, J = 9.5, 8.0 and 7.0 Hz, H-23), 3.10 (m, 2H, H-22, H-27), 3.45 (t, 1H, J = 12.5 and 12.0 Hz, H-1), 3.63 (t, 1H, J = 12.5 and 12.0 Hz, H-21), 3.82-4.10 (m, 10H, OCH2CH2O, OCH2CH3), 4.95 (t, 1H, J = 3.5 Hz, H-26), 6.71 and 6.76 (both d, 1H each, J = 8.0 Hz, H-6, H-16), 6.82 and 6.84 (both t, 1H each, J = 8.0 and 7.5 Hz, H-4, H-18), 7.10-7.19 (m, 4H, H ).
/7 \ ? ? arom7
B) 0.5 g (25 %) alcohol (2d), white crystals with M.p. 210-212 °C, Rf = 0.24 (silufol, ethyl acetate). Found, %: C 65.96, H 6.98, N 2.54. C29H37NO8. Calculated, %: C 66.02, H 7.07, N 2.65. m/z (Irel, %): 527 [M]+ (9), 482 (7), 398 (10), 282 (20), 232 (10), 220 (10), 192 (10), 178 (10), 159 (21), 148 (42), 134 (89), 121 (100), 119 (76), 111 (71), 105 (45), 91 (84), 77 (69), 55 (52), 45 (58). IR (KBr) vmax cm-1: 1725 and 1721 (shoulder) (C=O), (NH), (OH). 1H NMR (500 MHz, CDCl3, Me4Si) SH ppm: 1.11 (t, 6H, J = 7.0 Hz, CH3), 2.16 and 2.35 (both dd, 2H each, 2J = 16.0 and 3J = 6.00 Hz, CH2COO), 2.54 (br.s, 1H, NH), 2.87 (m, 2H, H-22, H-24), 3.36 (t, 1H, J = 10.5 and 10.0 Hz, H-23), 3.49 (t, 2H, J = 11.0 and 10.5 Hz, H-1, H-21), 3.78-4.12 (m., 13H, OCH2CH2O, OCH2CH3, OH), 6.73 (d, 2H, J = 8.0 Hz, H-6, H-16), 6.80 (t, 2H, J = 7.5 Hz, H-4, H-18), 7.09-7.15 (m, 4H, H ).
arom
22,24-Dimethyl-23-(2-furyl)-8,11,14-trioxa-25-azatetracy-clo[19.3.1.027.01520]pentacosa-2,4,6,15(20),16,18-hexaen-23-ol (2f). 0.8 g (34 %) of the product (2f) was isolated, white crystals with M.p. 268-270 °C, Rf = 0.69 (ethylacetate). Found, %: C 71.92, H 6.92, N 3.01. C27H31NO5. Calculated, %: C 72.14, H 6.95, N 3.12. m/z (Irel, %): 449 [M]+ (22), 382 (1), 326 (100), 297 (27), 282 (97), 192 (3), 163 (4), 148 (20), 134 (30), 119 (30), 105 (18), 95 (42), 77 (19), 55 (11), 44 (33). IR (KBr) vmax cm-1: 3311 (NH), 3607 (OH). 1H NMR (500 MHz, CDCl3, Me4Si)\ ppm: 0.47 (d, 6H, J = 7.0 Hz, CH3), 2.02 (s, 1H, OH), 2.25 (br. s, 1H, NH), 2.95 (m, 2H, J = 10.0 and 7.0 Hz, H-22, H-24), 3.85-4.18 (m, 10H, OCH2CH2O, H-1, H-21), 6.24 (d, 1H, J = 2.5 Hz, Hfural), 6.34 (t, 1H, J = 3.0 and 1.5 Hz, Hfural), 6.75, 6.82, 7.14 and 7.18 (AB CD-system, 8H sum., J = 8.0, 7.5/7.0 and 1.0 Hz, H ), 7.36 (br.s, 1H, H. ,).
' arom7' v ' ' rural7
22,24-Dimethyl-23-(2-thienyl)-8,11,14-trioxa-25-azatetra-cyclo[19.3.1.02 7.01520]pentacosa-2,4,6,15(20),16,18-hexaen-23-ol (2g). Allocate 0.92 g (46 %) of the product, white crystals with M.p. 275-277 °C, Rf = 0.67 (silufol, ethyl acetate). Found, %: C 69.29, H 6.82, N 2.96. C27H31NO4S. Calculated, %: C 69.65, H 6.71, N 3.01. m/z (Irel, %): 465 [M]+ (22), 326 (68), 297 (38), 282 (100), 192 (3), 163 (4), 148 (15), 134 (32), 119 (32), 111 (45), 91 (28), 77 (19), 55 (9), 44 (43). IR (KBr) vmax cm-1: 3310 (NH), 3698 (OH). 1H NMR (500 MHz, CDCl3, Me4Si)xSH ppm: 0.52 (d, 6H, J = 7.0 Hz, CH3), 2.08 (s, 1H, OH), 2.25 (br.s, 1H, NH), 2.90 (m, 2H, J = 10.5 and 7.0 Hz, H-22, H-24), 3.84-4.18 (m, 10H, OCH2CH2O, H-1, H-21), 6.73, 6.83, 7.14 and 7.19 (ABCD-system, 8H sum., J = 8.0,
7.5, 7.0 and 1.0 Hz, H ), 6.95, 6.97 and 7.20 (ABC-system, 3H,
arom
J = 4.5, 3.5 and 2.0 Hz, Hthiofen).
22-Phenyl-23-(2-pycolyl)-8,11,14-trioxa-25-azatetracy-clo[19.3.1.02 7.01520]pentacosa-2,4,6,15(20),16,18-hexaen-23-ol (2h). 1.77 g (19 mmol) a-picoline was added dropwise to 1.22 g (19 mmol) of butyl lithium in 50 ml of THF with stirring in a stream of argon. Stirred for 20 minutes and slowly added 2 g (4.7 mmol) of 22-azacrown ether (1f) in 50 ml of absolute THF. The reaction mixture was stirred for 1 hour at room temperature (TLC control). 100 ml of water and 1 ml of acetic acid were added. The THF was distilled off and extracted with chloroform (3x100 ml). The chloroform layer was dried with MgSO4. The chloroform is distilled off, the residue is separated using column chromatography on alumina, eluting with a mixture of ethyl acetate:hexane, 1:3. 0.7 g (29 %) of the product is isolated, white crystals with M.p. 255-257 °C, Rf = 0.56 (ethylacetate). Found, %: C 75.81, H 6.44, N 5.16. C33H34N2O4. Calculated, %: C 75.84, H 6.56, N 5.36. m/z (Irel, %): 520 [M]+. IR (KBr) vmax cm-1: 3298 (NH), 3508 (OH). 1Hl NMR (500 MHz, CDCl3, Me4Si) SH ppm: 1.77 (br.d, 1H, J = 12.0 Hz, H-24), 2.05 (s, 1H, OH), 2.35 (br.t, 1H, J = 12.0 Hz, H-24), 2.53 (br.s, 1H, NH), 2.78 (br. d, 1H, J = 12.5 Hz, H-22), 3.55(d, 2H, J = 15.0 Hz, Pyr-CH2), 3.91-4.52 (m, 9H, OCH2CH2O, H-1), 5.29 (d, 1H, J = 12.5 Hz, H-21), 6.40-7.65 (m, 13H, Hrom and 3H ), 8.36 (d, 1H, J = 5.0 Hz, 1H ).
pyr7' v ' ' ' pyr7
25-Acetyl-23-hydroxy-8,11,14-trioxa-25-azatetracyclo-[19.3.1.027.01520]pentacosa-2,4,6,15(20),16,18-hexaen-22-carbox-ylate (3). To a solution of 0.5 g (1.2 mmol) of piperidol (2c) in 20 ml of toluene, 0.11 ml (1.2 mmol) of acetic anhydride was added. The mixture was boiled for 7 hours with a nozzle Dean-stark. The solvent was evaporated to half of the initial volume and cooled. A precipitate was obtained, then recrystallized from toluene. The reaction product was obtained in the form of white crystals (3). The yield 0.13 g (26 %). M.p. 229-231 °C. Found, %: C 66.45, H 6.42, N 3.08. C^H ,NOT Calculated, %: C 66.51, H 6.65, N 2.98.
26 31 7
LCMS, m/z (Irel, %): 470 [M+1]+. IR (KBr) vmax cm-1: 3435 (OH), 1710 (OC=O), 1646 and 1625 (NC=O). 1H NMR(500 MHz, CDCl3, Me4Si) SH ppm: 1.06 (t, 3H, J = 7.0, CH2CH3), 1.95-2.18 (m, 2H, H-24a, H-24e), 2.35 (s, 3H, OCH3), 2.45-2.82 (m, 3H, OCH2CH3, H-22), 3.45-4.11 (m, 9H, OCH2CH2O, H-1, H-21, H-23), 4.51 (br.s, 1H, OH), 6.78-7.21 (m, 8H, H ).
arom
Supporting information (SI) is available at https://macro-heterocycles.isuct.ru/en/mhc190554a.
Results and Discussion
In our previous work,[4,5] azacrown ethers containing y-piperidone fragment (1b-d) were easily synthesized by Petrenko-Kristrenko multicomponent condensation reaction. The azacrown ethers (1) were obtained by condensation of ketones with 1,5-bis(2-formylphenoxy)-3-oxa-pentane in the presence of ammonium acetate. The reaction was smoothly proceeded when the mixture of the starting materials was kept without heating (at a temperature of 20 °C) in a solution of ethanol with acetic acid (Scheme 1). In the previous publication,[4] in reflux of solvent, the yield of the known macrocycle 1c was a haft (24 %). Azacrown 1a is a new substance that was isolated in the yield of 35 %. In its high-symmetry 1H NMR spectrum, the protons of two methyl groups give one singlet signal (at 3.53 ppm) of six proton units. Signals from the H-1, H-21 appeared as a multiplet in the region of 3.81 ppm, and other signal of piperidone protons (H-22, H-24) were observed as a doublet at 4.10 ppm. The proton at the nitrogen atom was identified as a broad multiplet signal due to resonance with two protons H-1 and H-21.
H,N—R
AcOH.
C2H5OH
NaBH4
C2H5OH
(la-d)
la, 2a: R=H, R, = R2 = -COOMe; lb, 2b: R= -CH2CN, R,=R2= Me; lc, 2c: R=R!=H, R2= -COOEt; Id: R=H, R, = R2 = -CH2COOEt.
H^ .OH
H. .OH
EtOOCHjC. "XT CH2COOEt EtOOCH,C
Scheme 1. Synthesis of azacrown ethers (1a-d) by Petrenko-Kritchenko reaction and their reduction with NaBH4 in ethyl alcohol.
Then, we developed new y-piperidol crown ether by using the reduction method of compounds (1a-d) with sodium borohydride in ethyl alcohol (Scheme 1). From the reaction mixtures, crown ethers containing y-piperidol (2a-d) were isolated by column chromatography. Their structures were determined by 'H NMR, IR, MS spectrometry. Azacrown ether (2c), which was isolated by a high yield of 75 %, apparently indicates the template effect of the crown ether part coordinating the sodium cation, releasing the BH4-anion for a more effective attack on the carbonyl group. In the case of p,p-disubstituted azacrown (2a), the alcohol yield turned out to be low (only 15 %) due to steric hindrances and electronic repulsion for the BH4- anion approach created by two methoxycarbonyl substituents in the a,a'-positions to the carbonyl group. In the IR spectrum of cyclic amino alcohol (2c), the absorption bands at 3517, 3397 cm1 (OH) and 3316 cm1 (NH) confirmed that the carboxyl group has been reduced to alcohol. In 'H NMR spectrum of (2c), a mixture of diastereomers was identified by broadening and superposition of signals of aliphatic and piperidine protons. These HPLC-MS record the presence of two dia-stereomers with M+ 427 each.
In case of reducing compound (1d), two compounds were isolated: the expected piperidol (2d) and compound (2e) containing lactone structure which was confirmed by spectral data. In 'H NMR spectrum of compound (2e), the signal of methyl group was observed in high field at 5 = 1.13 ppm as a triple with 3H, which confirmed there was lactoniza-tion. In 'H NMR spectrum of compound (2d) signals of six methyl and four methylene protons from ethoxycarbonyl groups were observed. The LC-MS analysis of (2d, 2e) gave their clear [M]+ peaks with m/z = 481 and 527, respectively.
It is known,[6] that during the reduction of cycloali-phatic and heterocyclic ketones with sodium borohydride,
mixtures of alcohols with the R- and ^-configuration of the stereogenic center were always formed. In case of cyclic alcohols, the equatorially located OH groups participated in the acylation or trans-esterification reaction much easier than the axial ones. In our case, apparently, the reaction generated diastereomeric alcohols in which the alcohol with the equatorial hydroxyl group underwent an intramolecular trans-esterification reaction with the formation of lactone 2e, and its antipode 2e remains unchanged.
In the second part of this work, interaction of the y-piperidone fragment of azacrowno-phane (1e,f) with a-furyllithium, a-thienyllithium, and a-pyridylmethyllithium was studied. The reaction was carried out in absolute tetrahydrofuran with a threefold excess of organolithium compound (Scheme 2). Azacrown ethers (2f-h) were isolated by chromatography on Al2O3 with not very high yields (29-46 %), probably due to the ste -ric hindrance of the two methyl groups in the a-position of carbonyl group.
The IR spectra of compounds (2f-h) contained the absorption bands due to stretching vibration of the hydroxyl group (OH) (3557-3606 cm1) and the amine group (NH) (in the region of 3290-3347 cm-1). There is no band of stretching vibrations of carbonyl group (C=O) in the region of 1650-1750 cm-1. The molecular structure of compound 2g, its conformational parameters were unambiguously confirmed by X-ray analysis of o single crystal (Figure 1). The bond lengths and valence angles are given in Tables S1 and S2 (see SI). The size of the internal cavity of crown ether 2g, estimated as doubled average distance between the donor atoms and their centroid (the centroid is the center of the quadrilateral N25-O8-O11-O14), is 4.05 A. The conformation of the polyether moiety of the molecule
le, 2f, 2g: R=H, R[ = R2 = Me; If, 2h: R=R!=H, R2= Ph;
Scheme 2. Reaction of organolithium compounds with azacrown ether (1e,f).
Figure 1. Molecular structure of azacrown ether 2g in the representation of atoms by anisotropic displacement ellipsoids (40 % probability); intramolecular hydrogen bonds are shown by dashed and dotted lines.
C7-O8-C9-C10-O11-C12-C13-O14-C15 - t-g(-)-t-t-g(+)-t (t = trans, ± 180°; g = gauche, ± 60°) (Table S3).
Molecule 2g has idealized Cs (m) symmetry, which, however, does not occur in the crystal due to the presence of ethanol and ethyl acetate solvate molecules. The presence in the structure of two intermolecular O23-H...O(s) and N25...H-O(s) hydrogen bonds with the solvate ethanol molecule leads to a slight distortion of the molecule, which
is reflected, in particular, as in the difference in the parameters of the two intramolecular hydrogen bonds N25-H25...O8 [N...O 3.0565(17), H...O 2.537(19) A, angle N-H...O 119.9(15)°] and N25-H25...O14 [N...O 2.9299(17), 2.330(19) A, angle N-H...O 127.2(16)°] (Table S7), and in the asymmetric arrangement of the thiophene cycle (the angles between the planes of the thiophene and benzene cycles are 63.4 and 49.6°). Due to the presence of these intra -molecular hydrogen bonds, the donor atoms of the crown cycle N25, O8, O11, and O14 do not lie in the same plane (the root-mean-square deviation of these atoms from this plane is 0.118 A). The thiophene substituent at the C23 carbon atom occupies the sterically more favorable equatorial position. The angle between the planes of the benzene cycles of the molecule is 78.5°. The piperidine fragment has the conformation of an almost perfect chair [the value of the modules of its torsion angles is 51.24(15)-57.21(16)°]. This compound is a diastereomer with four asymmetric centers - C1, C21, C22, and C24. The molecules in the crystal represent the racemate with the relative configuration of these stereogenic centers - rac-(1R*, 21S*, 22R*, 24S*).
NH-Piperidoloazacrown ether (2c) contained two centers for the electrophilic attack in the acylation. They are both surrounded by bulky substituents, which makes it difficult to predict the accuracy of the acylation sequence. In case of using of acetic anhydride in equimolar amount, a high melting product of mono-acylation 3 at the nitrogen atom was isolated by a yield of 26 %. In IR spectra of compound 3, the absorption bands of the amide group (N-C=O) are observed at 1646 and 1625 cm-1, the band of the ester group (O-C=O) was absent at 1710 cm-1, the absorption band of the unreacted OH group at 3435 cm-1. The structure of azacrown ether 3 was also confirmed by MS spectra ([M+1]+, m/z = 470) and 'H NMR spectra.
он
COOEt
COOEt
(MeCO)2P
2c
Scheme 3. Acylation of azacrown ether (2c).
According to the PASS[7] program (Prediction of Activity Spectra for Substances), compounds 2a-d and 3 containing y-piperidol fragment have the high potential acting as a CYP2H substrate (60-95 %), exhibit membrane permeability inhibitor (60-74 %). In the other side, compounds 2f-h containing 4-aryl-y-piperidol fragment may show high spasmolytic activity (60-92 %).
Conclusions
In summary, several novel macroheterocycles containing NH-y-piperidol fragment were obtained by the transformations of dibenzo[(y-piperidono]aza-14-crown-4 ethers. The NH-y-piperidol derivatives were characterized by IR, 'H NMR, LCMS and X-ray diffraction. These azacrown compounds with the polyfunctional group can be useful building blocks for further synthetic manipulations and drug development.
Acknowledgements. This research was funded by the Vietnam National Foundation for Science and Technology Development (NAFOSTED) under grant number 104.01-2017.318 and the RUDN University Program "5-100".
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Received 29.05.2019 Accepted 02.12.2019
