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ISSN 2522-1841 (Online) ISSN 0005-2531 (Print)
UDC 547.56.563.364
SYNTHESIS OF MANNICH BASES BASED ON NORBORNENYLMETHANOL, CYCLIC AMINES AND BENZALDEHYDE AND THEIR ANTIMICROBIAL ACTIVITY
G.E.Hajiyeva
Institute of Petrochemical Processes of NAS Azerbaijan [email protected] Received 18.04.2019
On the basis of norbornenylmethanol, heterocyclic amines and benzaldehyde, new norbornene-containing Mannich bases were synthesized. The physico-chemical-characteristics of the target products were determined. The composition and structure of the synthesized compounds were confirmed by the methods of elemental analysis, IR spectroscopy, 1H and 13C NMR. The antimicrobial activity of the target products against various microorganisms (Staphylococcus aureus, Pseudomonas aeruginosa, E. coli, Candida fungi) was studied, and the minimum inhibitory concentration and minimum bactericidal concentration of the studied compounds were determined with respect to some of the above microorganisms.
Keywords: dicyclopentadiene, norbornenylmethanol, secondary amines, Mannich bases, antimicrobial activity.
https://doi.org/10.32737/0005-2531-2019-3-68-74
Organic compounds, containing a nitrogen atom are used in fine organic synthesis as synthons, in agriculture, as pesticides, as component of fuels and oils, as antimicrobial and antioxidant additives to oils and fuels, and also as medical drugs [1, 2]. One of the most common methods for producing nitrogen-containing compounds is the Mannich reaction. The classical Mannich reaction is carried out in the presence of formaldehyde, but to expand the range of Mannich bases formed, as well as to obtain compounds with new properties, the reaction is also carried out with other aldehydes [3]. There is a wide range of Mannich bases obtained on the basis of benzaldehyde [4, 5]. It is obvious that the introduction of an additional aromatic nucleus into the molecule of the formed Mannich base affects its properties.
Among the biologically active compounds of the norbornene series, their amine-containing derivatives are distinguished, the value of which is associated with the presence in their molecules of two pharmacophoric fragments - the nitrogen-containing group and the carbon skeleton [6], akin to natural terpenes [7]. The norbornene fragment, as well as the norbornane and adamantane structures, form the basis of many amines, which are medicinal substances. For amines with norbornane skeletons,
antiviral activity is characteristic. The basis of many important natural compounds such as borneol, camphor, etc. is the structure of bicy-clo[2.2.1]-heptane (norbornane). Water-soluble sulfonamides, containing the norbornene fragment in their composition, possess a higher level of analgesic and tranquilizing activity than the well-known metamizole sodium, which is used as an internal standard [8].
Since biologically active compounds, which combine several pharmacophoric fragments, have more effective actions, researchers are trying to expand the range of such compounds and study their physiological active properties [9].
By introducing a norbornene fragment into the composition of the Mannich bases, their biological activity and other useful properties can be enhanced. Norbornenylmethanol has a mobile hydrogen atom and therefore it easily reacts with Mannich as the CH-acid component. Having studied the literature, it is safe to say that aminomethylation reactions with alcohols (there is little information about norbornenyl-methanol) [3], therefore the use of alcohols, in particular norbornenylmethanol, in the Mannich reaction will expand the range of aminometh-oxy derivatives with various applications. Thus, the synthesis and study of the properties of
aminomethoxy derivatives of norbornenyl-methanol, obtained in the presence of benzaldehyde, is a very urgent task and is of both scientific and practical interest.
Discussion of the received results
This paper discusses the production and properties of previously unknown norbornene-containing Mannich bases on the basis of nor-bornenylmethanol and secondary cyclic amines in the presence of benzaldehyde. Dicyclopenta-diene, necessary for obtaining the original nor-bornylmethanol, is isolated from the C5 side fraction of the liquid pyrolysis products [10], which ensures waste-free production and care for the environment.
At first, on the basis of dicyclopentadiene and allyl alcohol (II), norbornenylmethanol (III) was obtained. The reaction was carried out in an
autoclave [11] at a ratio of reagents of 1:2.4, temperature of 170-1800C and pressure of 4-5 atm, for 9 hours. Under this conditions dicyclo-pentadiene is monomerized into cyclopentadi-ene (I), and as a result, the reaction proceeds following scheme:
I II III
The yield of the obtained alcohol is 74%. Then, on the basis of the obtained alcohol (III), benzaldehyde and secondary amines [pi-peridine (IV), morpholine (V), azepane (VI)], aminomethoxy derivatives of norbornenyl-methanol (VII-IX) were synthesized. The yield of the target products is 38-48%. Reactions proceed according to the scheme:
where X = CH2 (IV, VII), O (V, V Reactions were carried out in a solution of benzene at 78-800C for 6-7 h at an equimo-lar ratio of reagents. Compounds (VII-IX) are liquids with a characteristic odor, insoluble in water, readily soluble in organic solvents (etha-nol, acetone, benzene, CCl4, CHCl3, etc.). The purity of the starting and prepared compounds was monitored by GLC. The composition and structure of the obtained compounds (III, VII-IX) were confirmed using elemental analysis data, IR, 1H and 13C NMR spectroscopy. In the IR spectrum of 5-(norborn-2-enyl)methanol (III), a wide absorption band in the region of 3500 cm-1, characteristic of the hydroxyl group is observed [12], and in the IR-spectra of ami-nomethoxy derivatives of norborn-5-ene (VII-IX), there is no absorption band. The absorption bands in the region of 1200-1100 cm-1, characteristic for stretching vibrations of the H-N (vH-
), CH2-CH2 (VI, IX).
N) bond, are replaced in the IR spectra of ami-nomethoxy derivatives of norborn-5-ene (VII-IX) by absorption bands in the region of 10701020 cm-1 C-N bonds (vC-N) characteristic for stretching vibrations. Along with this, absorption bands in the regions of 2857-2853 cm-1, characteristic of the C-H bond (vc-H) of the CH2 group, were found. The stretching vibrations of the C-O bond (vC-O) manifest themselves in the region of 1100-1048 cm-1 in the form of an intense absorption band. Below are the IR spectrum of compound IX is presented in the (Figure 1).
The 1H and 13C NMR spectra of the synthesized compounds confirm their indicated
1 13
structure. The H and C NMR spectra of compounds VIII and VII, respectively, are presented in the (Figure 2 and 3).
Fig. 1. IR spectrum of N-{(bicyclo[2.2.1] hept-2-en-5-ylmethoxy)(phenyl)methyl}azepane (IX).
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
Fig. 2. 1H NMR spectrum of N-(bicyclo[2.2.1]-hept-2-en-5-ylmethoxy)(phenyl)methyl}morpholine (VIII).
iJiwT
""I.........I.........I.........I.........I.........I.........I1........1.........1.........1.........1.........1.........1.........1.........1.........1.........1.........1"
170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm Fig. 3. 13C NMR spectrum of N-{(bicyclo[2.2.1]-hept-2-en-5ylmethoxy)(phenyl) methyl}piperidine (VII).
The antimicrobial activity of the synthesized compounds (VII-IX) was studied in comparison with the known bactericidal preparations widely used in medical practice: ethanol, rivanol, furatsilin, carbolic acid, chloramine. The study was conducted by serial dilution. To this end, a 1% alcoholic solution of the test substance was diluted in distilled water to various concentrations. Then, 0.1 ml of a test-culture, containing 900 thousand microbial cells in 1 ml were sown into each tube with the test substance. The following cultures were used as test cultures: gram-positive (Staphylococcus aureus), gram-negative (Pseudomonas aeruginosa, E. coli) bacteria, and also yeast-like fungi of the genus Candida.
Simultaneously, for the synthesized compounds (VII-IX), the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) were determined for certain microorganisms (S. aureus, Pseudomonas bacillus, Candida fungi).
Based on the research results, the synthesized compounds (VII-IX) can be recommended for use as antimicrobial substances.
Experimental part
The IR spectra of the synthesized compounds were recorded on an "SPEKTRUM BX"
and "BRUKER" apparatus of the "ALPHA IR FURYE" company (Germany) in the region of 4000-400 cm-1. The 1H and 13C NMR spectra were recorded on a "BRUKER" AM-300 spectrometer, at a frequency of 300 MHz in a C6D6 solvent, the internal standard is hexamethyl-disiloxane.
The purity of the reaction products was determined by the boiling point, elemental analysis data and gas-liquid chromatography.
Elemental analysis was performed on a "CARLOERBA" model device - EA 1108. GLC analysis was performed on an LHM-8 MD Chromatograph, a steel column (300*3 mm) with 5% PEGS (polyethyleneglycolsuccinate) on dinochrome P, carrier gas - helium (40 cm3/min), catorometer detector, column temperature
1500C, evaporator - 2300C. The refractive index (n 2°) is on the "ABBEMAT" 350/500 refractometer, the density (p 2°) on the DMA instrument is 4500 M.
The antimicrobial activity of the compounds obtained (VII-IX) was studied by the method of serial dilutions with respect to various microorganisms. Meat-peptone agar of pH 7.2-7.4 for bacteria and Saburo medium for fungi were used as a nutrient mediums. The incubation period in the thermostat was 18-24 h
at 370C, for fungi 1-10 days at 280C. The degree of dilution of the compounds for bacteria was 1:100, 1:200, 1: 400 and 1:800. Seeding was done after 5, 15, 30, 45, 60 min (exposure time). For comparison, ethanol, rivanol, fu-ratsilin, carbolic acid, and chloramine were studied as standards in the same dilutions.
MIC and MBC of synthesized ami-nomethoxy derivatives of norbornene (VII-IX) were studied against bacteria and fungi (S. aureus, E. coli, C. albicans). Meat-peptone broth was used as a nutrient medium for bacteria, and sweet broth was used for mushrooms. A dilution method was used, the incubation time was 24 h.
The original allyl alcohol was used reactive. Before use, dried over CaCl2 and distilled. The initial dicyclopentadiene was isolated according to the method [10] from the C5 fraction of liquid pyrolysis products, which are obtained at the EP-300 installation in Sumgayit city.
Before use, all three heterocyclic amines were distilled and determined their physico-chemical constants, which coincide with the literature data. Benzaldehyde was used reactive, distilled before use. Benzene was used as a solvent.
5-(Norborn-2-enyl) methanol (III) was
obtained in an autoclave according to the method [11] for 9 hours at a temperature of 170-1800C,' pressure of 4-5 atm. at the ratio of dicy-clopentadiene and allyl alcohol (II) is 1:2.4. The yield of the target product was 74%. The boiling point is 82-830C (10 mm Hg), n 2° -1.4970, p2° - 1.027 g/cm3. IR-spectrum, v, cm-1: 1200-1100 (C-N), 2880-2830 (C-H, CH2), 3500 (OH). NMR-spectrum 1H, 5, ppm: 0.45 d.d. (1H, C6Nex, J=4.1, 13.4 Hz), 1.19 t (1H, C7Hanti, J=7.9 Hz), 1.44 t (1H, C6Nend, J=4.1 Hz), 1.68-1.72 m (1H, C7Hs, J=7.9 Hz), 2.86 k (1H, C5H), 3.21-3.36 t (1H, C4H), 3.36-3.46 m (2H, C8H2), 3.46 d.d.d (1H, C1H, J=4.4, 4.6, 4.8 Hz), 3.92 s (1H, OH), 6.00-6.08 m (2H, C2H, C3H). NMR 13C, 5, ppm: 28.83 (C6), 41.76 (C5), 42.26 (C1), 43.60 (C4), 49.41 (C7), 65.76 (C8), 132.32 (C3), 137.78 (C2) .
Aminomethoxy derivatives of norborn-5-ene (VII-IX). General method. With stir-
ring, 0.1 mole of norbornenylmethanol (III), diluted in 20 ml of benzene was added dropwise to 0.1 moles of benzaldehyde diluted in 40 ml of benzene. Then, continuing the stirring, a solution of 0.1 mol of secondary amine (IV-VI) in 20 ml of benzene was added dropwise. Stirring was continued at 78-800C for 6-7 h. After cooling, the mixture was washed by distilled water until neutral rewtion and dried over CaCl2. Benzene was distilled off, the residue was distilled under vacuum.
N-{(bicyclo[2.2.1]hept-2-en-5-ylmethoxy)-(phenyl)methyl}piperidine (VII) was obtained from 12.4 g (0.1 mol) of norbornenylmethanol (III), 10.6 g (0.1 mol) of benzaldehyde and 8.5 g (0.1 mol) of piperidine (IV). The output is 12 g (41%), b.p. - 179-1810C (4 mm Hg), n2° -1.5629, p2° - 1.0605 g/cm3. IR spectrum, v, cm-1: 30548 (C-H, HC=CHcycl), 3026 (C-Narom); 2932, 2861, 2806 (C-H, CH2, CH3); 1657 (C=Ccycl.); 1612, 1599, 1578 (C=Carom.); 1493, 1448, 1336, 1317 (5 C-H, CH2, CH3); 1274, 1210, 1175, 1111 (C-O-C); 1063, 1030 (C-N); 968-788 (5 C-H, HC=CHcycl); 745, 718, 695 (-C6H5). NMR 1H, 5, ppm: 1.18-1.379 m (2H, C20H2), 1.492-1.514 m (4H, C19H2, C21H2), 1.516-1.74 m (4H, C6H2, C7H2), 1.751.880 m (1H, C5H), 2.181-2.505 m (2H, C1H, C4H), 2.811-2.954 m (4H, C18H2, C22H2), 3.279 d.d (2H, C8H2, J 1.5, 6.6 Hz), 4.906 s (1H, C10H), 5.962-5.990 m (1H, =C2H), 6.124-6.154 m (1H, =C3H), 6.917-7.671 m (5H, C12-16H). NMR 13C, 5, ppm: 24.58 (C20), 26.28 (C21), 26.31 (C19), 28.90 (C6), 41.83 (C7), 42.24 (C5), 43.65 (C1), 44.95 (C4) , 46.68 (C22), 49.52 (C18), 67.02 (C8), 126.52 (C10), 128.03 (C14), 128.45 (C15), 128.64 (C13), 129.49 (C16), 132.33 (C12), 136.69 (C2) 137.23 (C3), 163.91 (C11). Found, %: C 80.37; H 9.44; N 4.76. C20H27NO. Calculated, %: C, 80.76; H 9.15; N 4.71.
N-{(bicyclo[2.2.1]-hept-2-en-5-ylmeth-oxy)(phenyl)methyl}morpholine (VIII) was obtained from 12.4 g (0.1 mol) of norbornenyl-methanol (III), 10.6 g (0.1 mol) of benzaldehyde and 8.7 g (0.1 mol) of morpholine (V). The output is 14.48 g (48%), b.p. - 181-1840C (4 mm Hg), n 2° - 1.5235, p 2° - 1.0453 g/cm3. IR spectrum, v, cm-1: 3057 (C-H, HC=CHcycl);
3026 (C-Harom.); 2957, 2863 (C-H, CH2, CH3); 1643 (C=Ccycl); 1609, 1568 (C=Carom); 1494, 1451, 1337, 1317 (5 C-H, CH2, CH3); 1273, 1250, 1179, 1139, 1111 (C-O-C); 1061, 1031 (C-N); 969-788 (5 C-H, HC=CHcycl.); 752, 717, 707, 695 (-C6H5). NMR spectrum 1H, 5, ppm: 1.138-1.316 m (2H, C6H2), 1.386-1.420 m (2H, C7H2), 1.702-1.811 m (1H, C5H), 2.282.391 m (2H, C1,4H), 2.754-2.855 m (4H, C18H2, C22H2), 3.154 d.d (2H, C8H2, J=5.4, 10.5 Hz), 3.563-3.707 m (4H, C19,21H2), 4.784 s (1H, C10H), 5.875-5.949 m (1H, =C2h), 6.025-6.115 m (1H, =C3H), 7.127-7.413 m (5H, C12-16H). NMR 13C, 5, ppm: 28.85 (C6), 41.48 (c7), 42.17 (C5), 43.58 (C1), 44.88 (C4), 46.00 (C22), 49.46 (C18), 65.96 (C21), 66.92 (C19), 67.61 (C8), 126.98 (C10), 127.76 (C14), 128.29 (C15), 128.77 (C13), 130.80 (C16), 132.24 (C12), 136.66 (C2), 137.19 (C3), 162.21 (C11). Found, %: C 76.72, H 8.69, N 4.53. C19H25NO2. Calculated, %: C 76.22; H 8.42; N 4.68.
N-{(bicyclo[2.2.1]hept-2-en-5-ylmethoxy)-(phenyl)methyl}azepane (IX) was obtained from 12.4 g (0.1 mol) of norbornenylmethanol (III), 10.6 g (0.1 mol) of benzaldehyde and 5.72 g (0.1 mol) of azepane (VI). The output is 11.84 g (38%), b.p. - 142-1450C (6 mm Hg), n2 -1.5819, pf - 1.0355 g/cm3. IR spectrum, v, cm-1: 30(50 (C-H, HC=CHcycl.); 3026 (C-Harom); 2926, 2858 (C-H, CH2, CH3); 1643 (C=CCycl.); 1599, 1579, 1554 (C=Carom.); 1494, 1451, 1376 (5 C-H, CH2, CH3); 1271-1110 (C-O-C); 1070, 1026 (C-N); 963, 911, 831, (5 CH, HC=CHcycl); 751, 719, 693 (-C6H5). NMR spectrum 1H, 5, ppm: 1.154-1.448 m (8H, C19-22H2), 1.45-1.90 m (4H, C6,7H2), 2.179 s (1H, C5H), 2.20-2.48 m (2H, C1,4h), 2.64-2.86 m (4H, C18,23H2), 3.207 d.d (2H, C8H2, J=1.6, 5.7 Hz), 4.885 s (1H, C10H), 5.80-6.25 m (2H, =C2,3H), 6.92-7.69 m (5H, C12-16H). NMR 13C, 5, ppm: 25.35 (C21), 25.61 (C20), 27.04 (C22), 27.11 (C19), 30.43 (C6), 30.74 (C7), 38.03 (C5), 40.95 (C1), 45.82 (C4), 55.46 (C23), 55.50 (C18), 67.27 (C8), 127.74 (C10), 128.66 (c14), 128.69 (C15), 128.78 (C13), 129.49 (C16), 130.86 (C12) 136.23 (C2), 137.39 (C3), 162.08 (C11). Found, %: C 80.48; H 9.76; N 4.54. C21H29NO. Calculated, %: C 80.98; H 9.38; N 4.50.
Conclusion
1. On the basis of dicyclorentadiene and allilic alcohol by the Diels-Alder reaction in an autoclave at a temperature of 170-1800C and a pressure of 4-5 atm, norbornylmethanol was obtained with a yield of 74%.
2. By a one-pot three-component Mannich reaction basis on the of obtained norbornenyl-methanol, benzaldehyde and heterocyclic secondary amines (piperidine, morpholine, azepane) previously unknown aminomethoxy derivatives of norbornenylmethanol were synthesized. Optimal conditions for obtaining the target products were found. The reaction was carried out at an equimolar ratio of the initial reagents at a temperature of 78-800C in the presence of benzene for 6-7 h, the yield was 38-48%.
3. The physico-chemical constants of the synthesized compounds were determined. The structure of the compounds obtained was confirmed by elemental analysis methods, IR spec-troscopy, 1H and 13C NMR.
4. The antimicrobial activity of the target products was studied in relation to bacteria, such as Staphylococcus aureus, Pseudomonas aeruginosa, E. coli and yeast-like fungi of the genus Candida. Comparing the results of the study with the data of the antimicrobial activity of known bactericidal drugs (ethanol, rivanol, furatsilin, carbolic acid, chloramine), they have concluded that the synthesized compounds have a higher antimicrobial activity and their disastrous effect on microorganisms appears much faster.
5. The minimum inhibitory concentration and the minimum bactericidal concentration for the synthesized compounds with respect to bacteria were determined: Staphylococcus aureus, Pseudomonas aeruginosa, Candida fungi, and it was shown that the obtained compounds respond to microorganisms at very low concentrations.
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NORBORNENILMETANOL, TSIKLIK AMINLOR VO BENZALDEHID OSASINDA MANNIX OSASLARININ SiNTEZi VO ONLARIN MiKROB OLEYHiNO AKTiVLiYi
G.O.Haciyeva
Norbornenilmetanol, heterotsiklik aminlar va benzaldehid asasinda yeni norbornen tarkibli Mannix asaslari sintez edilmi§dir. Alinan maddalarin fiziki-kimyavi xassalari öyranilmi§dir Sintez olunmu§ maddalarin tarkib va qurulu§u element analizi, iQ, :H va 13C NMR spektroskopiya üsullan ila tasdiq edilmi§dir. Ahnmi§ maddalarin müxtalif mikroorqanizmlara (qizili stafilokok, göyya§il irin göplari, bagirsaq göplari, Kandida cinsli göbalaklar) qar§i antimikrob aktivliyi öyranilmi§dir, hamginin tadqiq olunan maddalarin bazi yuxanda geyd olunan mikroorqanizmlara qar§i minimal inhibisiya konsentrasiyasi va minimal mikrobosid konsentrasiyasi tayin edilmi§dir.
Agar sözlar: ditsiklopentadien, norbornenilmetanol, ikili aminlar, Mannix asaslari, antimikrob aktivlik.
СИНТЕЗ ОСНОВАНИЙ МАННИХА НА ОСНОВЕ НОРБОРНЕНИЛМЕТАНОЛА, ЦИКЛИЧЕСКИХ АМИНОВ И БЕНЗАЛЬДЕГИДА И ИХ АНТИМИКРОБНАЯ АКТИВНОСТЬ
Г.Э.Гаджиева
На основе норборненилметанола, гетероциклических аминов и бензальдегида синтезированы новые норборнен-содержащие основания Манниха. Определены физико-химические характеристики целевых продуктов. Состав и строение синтезированных соединений подтверждены методами элементного анализа, ИК спектроскопии методом ЯМР 1Н и 13С. Изучена антимикробная активность целевых продуктов против различных микроорганизмов (золотистый стафилококк, синегнойная палочка, кишечная палочка, грибы рода Кандида), а также определены минимальная ингибирующая концентрация и минимальная бактерицидная концентрация исследуемых соединений по отношению некоторых вышеуказанных микроорганизмов.
Ключевые слова: дициклопентадиен, норборненилметанол, вторичные амины, основания Манниха, антимикробная активность.
