CC BY
16Crown Ethers_ МаКрОГЭТЭрОЦМКЛЬ!_Communication
Краун-эфиры http://macroheterocycles .isuct .ru Сообщение
DOI: 10.6060/mhc131264h
Unexpected Formation of [(A3-Piperideino)pyrimidino]-14-crown-4 Ethers in a Petrenko-Kritschenko Type Condensation
Truong Hong Hieu,ab@ Le Tuan Anh,a Anatoly T. Soldatenkov,b Vasily G. Vasil'ev(b Vasily E. Kotsuba,b and Victor N. Khrustalevc
^Vietnam National University, 144 Hanoi, Vietnam ^Peoples'Friendship University of Russia, 117198Moscow, Russia cNesmeyanov Institute of Organoelement Compounds, 119991 Moscow, Russia ®Corresponding author E-mail: thh1101@yahoo.com
Two novel aza-14-crown-4 ether derivatives bearing fused (A3-piperideino)[2,3-e]pyrimidine moieties as subunits were unexpectedly obtained as major products of a modified Petrenko-Kritschenko type cascade condensation of 1-benzyl-4-ethoxycarbonylpiperidin-3-one with 1,5-bis(2formylphenoxy)-3-oxapentane and ammonium acetate. X-ray structure study was performed to determine the structure of the compounds.
Keywords: Aza-14-crown-4 ether, multicomponent reaction, Petrenko-Kritschenko condensation, X-ray structure.
Неожиданный синтез [(А3-пиперидеино)пиримидино]-14-краун-4-эфиров в реакции типа Петренко-Критченко
Чыонг Хонг Хиеу,^^ Ле Туан Ань^ А. Т. Солдатенковь В. Г. Васильев^ В. Е. Коцюба^ В. Н. Хрусталёвc
аВьетнамский национальный университет, 144 Ханой, Вьетнам ьРоссийский университет дружбы народов, 117198 Москва, Россия
сИнститут элементорганических соединений имени А. Н. Несмеянова, 119991 Москва, Россия @Е-таИ: thh1101@yahoo.com
Каскадная конденсация 1-бензил-4-этоксикарбонилпиперидин-3-она с 1,5-бис(2-формилфенокси)-3-оксапен-таном и ацетатом аммония в условиях модифицированного метода Петренко-Критченко неожиданно привела к получению двух новых производных аза-14-краун-4-эфира, сочленённого с (А3-пиперидеино)[2,3-е] пиримидиновыми фрагментами. Строение полученных соединений было подтверждено методом РСА.
Ключевые слова: Аза-14-краун-4-эфир, мультикомпонентная реакция, реакция Петренко-Критченко, РСА.
Introduction of heterocyclic subunits into the structure of macrocyclic crown ethers promises to improve their biological activity.[1,2] A particular interest presents modification of crown macrocycles that involves fusing them with small nitrogenous pharmacophore moieties such as derivatives of pyrrole, pyridine, piperidine, etc. Recently we have developed a modified Petrenko-Kritschenko type cascade condensation of 1,5-bis(2-formylphenoxy)-3-oxapentane (1) with dialkylketones and ammonium acetate, which afforded high yields of azacrown ethers
which include a piperidine subunit.[3-6] When we applied this chemistry to N-alkyl substituted piperidin-4-ones as the ketone components, azacrown ethers containing bispidine (3,7-diazabicyclo[3.3.1]nonane) subunit were obtained.[7-9] The initial purpose of the present study was to synthesize a novel azacrown derivative of 2,7-diazabicyclo[3.3.1] nonane (A) using N-benzyl substituted piperidin-3-one (2) as the ketone component in an analogous multicomponent condensation with 1,5-bis(2-formylphenoxy)-3-oxapentane (1) and ammonium acetate as the starting materials.
Scheme 1. Reaction of the podand aldehyde with jV-benzylpiperidone-3.
The reaction§ (Scheme 1) was carried out under mild conditions and proceeded smoothly at room temperature during 72 hours to give a mixture of two compounds with unexpected molecular weights (MW). Two peaks were observed in LC/MS spectrum of the formed precipitate. Mass spectrum corresponding to the first peak indicated the formation of a product with MW 553, while the other
peak corresponded to a product with MW 555. The expected bispidino-crown ether (A) has MW 556. Both the detected components were isolated by column chromatography and single crystals were prepared by slow evaporation. An X-ray diffraction study was performed, which unambiguously defined the structure and geometry of compounds 3 and 4 to be correspondingly [octahydro(pyridino)pyrimidino]-
Figure 1. Structure of azacrown ether 3 according to X-ray study data. 380
T. H. Hieu et al.
azacrown ether and [hexahydro(pyridino)pyrimidino] azacrown ether (Figures 1 and 2). The detailed X-ray data will be published in a separate paper.
The suggested mechanism of formation of compound 3 is presented in Scheme 2. The multicomponent process appears to start with a crotonic-type intermolecular condensation of one aldehyde group of podand 1 with the activated methylene group of 3-piperidone (2). The subsequent step is addition of a molecule of ammonia to the ketone group resulting in its conversion into a hydroxy-amino function, which then reacts with the second aldehyde group of the podand residue, thus forming the intermediate aza-16-crown-4-ether moiety, fused with a piperidine ring. As the formed macrocycle contains an 1,4-azadiene moiety, it undergoes double Mannich-type
cycloaddition of another molecule of ammonia, followed by dehydration to afford the major product 3. Determination of the mechanism of formation of a second double bond, leading to the minor product 4, requires additional research. The driving force of this process is presumably the formation of a conjugated diene further stabilized with nitrogen lone electron pairs.
Acknowledgements. We thank the National Foundation for Science and Technology Development (NAFOSTED), Hanoi, Vietnam (grant No 104.02-2012.44) for the financial support of this work. The authors would like also to thank Chembridge Corp. for the opportunity to use LC/MS analysis.
Scheme 2. Suggested mechanism of the formation of azacrown ether 3.
Notes
§Ethyl 23-benzyl-8,n,14-trioxa-23,28,29-triazapentacyclo[1 9.7.1.02 7.0'5-2".02227]nonacosa-2,4,6,15(20),16,18,26-heptaene-26-carboxylate(3)andethyl23-benzyl-8,11,14-trioxa-23,28,29-triazape ntacyclo[19.7.1.027.01520.02227]nonacosa-2,4,6,15(20),16,18,21,26-octaene-26-carboxylate (4). A solution of ammonium acetate (5.0 g, 65 mmol), 1,5-bis(2-formylphenoxy)-3-oxapentane (1.57 g, 5.0 mmol) and 1-benzyl-4-ethoxycarbonylpiperidin-3-one (1.48 g, 5.0 mmol) in a mixture of ethanol (30 ml) and acetic acid (2 ml) was magnetically stirred at room temperature for 3 days. The formed precipitate was filtered off, washed with ethanol and chromatographically purified on silica gel (eluating with hexane-ethylacetate, 3:1). Compound 3 was obtained as light-beige crystals (1.67 g, 2.55 mmol, 51.0 %). R 0.31. M.p. 179-181 oC. Found: C 71.53; H 6.22; N 7.37. C33H35N3O5 requires: C 71.33; H 6.71; N 7.56 %. m/z (APCI) (%): 555(100) [(M+H)+]. IR (KBr) v cm-1: 3299 m, 3270 m, 1645 s, 1580 s. 1H NMR (CDCL, 300
max ' ' ' v 3'
K) 5H ppm: 1.24 (3H, t, 3J=6.8, CH2CH3), 2.16 and 2.71 (1H and 3H, correspondingly, both m, -NCH2CH2-), 3.49 (1H, d, 2J=8.7, NCH2Ar), 3.78, 3.89 and 4.12 (2H, 3H and 8H, correspondingly, all m, -OCH2CH2OCH2CH2O-, CH2CH3, NCH2Ar, H-21 and -22), 4.71 (1H, br. s, NH-29), (5.05 (1H, s, H-1), (5.74 (2H, t, 3J=7.6, H-4 and H-18), 6.81, 7.13, 7.25 and 7.32 (4H, 2H, 3H and 2H, correspondingly, all m, Harom), 8.92 (1H, s, NH-28). Compound 4 was obtained as dark-yellow crystals (0.83 g, 1.5 mmol, 30.0 %). R^ 0.53. M.p. 101-103 oC. Found: C 71.53; H 6.22; N 7.37. C33H35N3O5 requires: C 71.59; H 6.37; N 7.59 %. m/z (APCI) (%): 553(100;) [(M+H)+]. IR (KBr) vmax cm-1: 3453 s, 3374 m, 1644 s, 1599 s. 1H NMR (CDCl3, 300 K) S^ppm: 1.29 (3H, t, 3J = 7.2 and 6.8, CH2CH3), 2.26 and 2.78 (1H and 3H, correspondingly, both m, -NCH2CH2-), 3.50 and 3.85 (1H each, both d, 2J=13.2 each, NCH2Ar), 3.73-4T5 (10H, m, -OCH2CH2OCH2CH2O- and CH2CH3), 4.83 (1H, s, NH-29), 6.05 (1H, s, H-1), 6.73 (2H, dd, 3J=7.7, 4J=1.6, H-6 and H-16), 6.8 (2H, broad t, 3J=8.9, H-4 and H-18), 6.97-7.09 (5H, m, Harom), 7.28 (2H, m, Harom), 7.47 (H, dd, 3J=7.6, 4J=1.6, H-3), 7.87 (H^dd, 3J=7.6,4J=1.2, H-19), 8.61 (1H, s, NH-28).
The 1H NMR spectra were recorded on a Bruker WP-400 spectrometer. The IR spectra were obtained in KBr pellets on
an Infralum FT-801 Fourier spectrophotometer. The elemental analysis was carried out on a Eurovector EA-3000 analyzer. LC/MS analysis was performed using an Agilent 1100 series chromatograph equipped with Agilent 1100 series DAD (wavelength 254±4 nm was used for detection), Sedex 75 ELSD and Agilent LC/MSD VL mass spectrometer (ionization in APCI interface). The X-ray structure study of compounds 3 and 4 was conducted on a Bruker SMART 1000 CCD automated diffractometer, with MoKa-radiation, graphite monochromator, 0-and (»-scan. The crystallographic data can be found in Cambridge Structural Database (CCDC numbers are 931720 and 931721 for compounds 3 and 4, correspondingly).
The following reagents were used in the course of the present study. iV-Benzyl-4-ethoxycarbonylpiperidin-3-one (2), silica gel and ammonium acetate were purchased from Alfa Aesar. All other reagents were used as received. 1,5-Bis(2-formylphenoxy)-3-oxa-pentane (1) was synthesized according to the published procedure.141
References
1. Gokel G.W., Murillo O. Acc. Chem. Res. 1996, 29, 425-432.
2. Bradshow J.S., Izatt R.M. Acc. Chem. Res. 1997, 30, 338-345.
3. Levov A.N., Strokina V.M., Komarova A.I., Anh L.T., Soldatenkov A.T., Khrustalev V.N. Mendeleev Commun. 2006, 16, 35-37.
4. Anh L.T., Levov A.N., Soldatenkov A.T., Gruzdev R.D., Hieu T.H. Russ. J. Org. Chem. 2008, 44, 463-465.
5. Anh L.T., Hieu T.H., Soldatenkov A.T., Kolyadina N.M., Khrustalev V.N. Acta Cryst. 2012, E68, 1588-1589.
6. Anh L.T., Hieu T.H., Soldatenkov A.T., Soldatova S.A., Khrustalev V.N. Acta Cryst. 2012, E68, 1386-1387.
7. Komarova A.I., Levov A.N., Soldatenkov A.T., Soldatova S.A. Chem. Heterocycl. Compd. 2008, 44, 624-625.
8. Hieu T.H., Anh L.T., Soldatenkov A.T., Kolyadina N.M., Khrustalev V.N. Acta Cryst. 2012, E68, 2431-2432.
9. Anh L.T., Hieu T.H., Soldatenkov A.T., Kolyadina N.M., Khrustalev V.N. Acta Cryst. 2012, E68, 2165-2166.
Received 03.12.2013 Accepted 18.12.2013
