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ISSN 2522-1841 (Online) AZERBAIJAN CHEMICAL JOURNAL № 3 2022 ISSN 0005-2531 (Print)
UDC 547(.577+.233+.281.01)
AMINOMETHYLATION OF DIHYDROXYACETOPHENONES
M.M.Agamaliyeva, A.M.Pashajanov, *T.M.Ismailov, N.I.Ismailov, G.O.Hasanova
M.Nagiyev Institute of Catalysis and Inorganic Chemistry, NAS of Azerbaijan
*Azerbaijan Medical University
agamaliyevam.32@gmail.com
Received 15.02.2022 Accepted 25.02.2022
Aminomethylation of trifunctional 2.5-dihydroxyacetophenone (2.5-DHA) and 2.4-dihydroxyaceto-phenone (2.4-DHA) by free primary and secondary amines in the presence of formaldehyde has been conducted for the first time. It has been established that 2.5-DHA is aminomethylated with secondary heterocyclic amines - piperidine and morpholine and with aqueous formaldehyde solution in alcohol medium at 500C. The reaction proceeds simultaneously via all three functions forming stable C,O-substitution products - p-amino-2-aminomethoxy-4-aminomethyl-5-hydroxypropiophenones. The ami-nomethylation reaction of 2.4-DHA proceeds by phenolic function only under the action of methylene bis-amines piperidine and morpholine in absolute alcohol at 200C with the formation of 2.4-dihydroxy-3-aminomethylacetophenones. Aminomethylation of 2.4-DHA with primary aromatic amines - n-to-luidine and n-anisidine proceeds in absolute alcohol under the action of formaldehyde in the form of paraform in the presence of catalytic amounts of KOH at 500C. The reaction products are 3.4-dihydro-2H-1.3-benzoxazines. 2.5-DHA does not react with primary aromatic amines and formaldehyde. The composition and structure of compounds synthesized have been established according to the data of elemental and spectral methods of analysis.
Keywords: dihydroxyacetophenones, aminomethylation, Mannich reaction.
doi.org/10.32737/0005-2531-2022-3-81-86 Introduction
Among various compounds capable of undergoing aminomethylation (Mannich reaction), hydroxyaryls and arilalkylketones are the most frequently used objects for this reaction [1-5].
Their aminomethyl derivatives are known as stabilizers of polymeric materials [6], mineral oils [7] and fuels [8], bioactive substances [9] etc. Hydroxyarylmethyl ketones containing both functional groups of above mentioned compounds are bifunctional under Mannich reaction conditions. According to literature data [10, 11] and results of our investigations [12] aminomethylation of such compounds depending on reaction conditions occurs selectively: in acid medium by using secondary amines chlorohydrates - only by ketone function with hydrogen atom substitution of methyl acetyl group. In basic medium using free secondary amines the reaction proceeds only according to phenolic function with substitution of hydrogen atom of benzene (naphthalene) ring mainly in o-position to hydroxyl group by ami-
nomethyl group. In both cases the substitution occurs at the carbon atom, so called C-aminoethylation [1].
However, during aminomethylation of 2-hydroxy-5-halogen acetophenones (2-HHA) with free secondary amines we found an anomalous course of reaction [13]. So, in absence of solvent the reaction proceeded according to phenolic function but aminomethyl group entered not into benzene ring (C-substitution) but substituted hydrogen atom of hydroxyl group with the formation of first observed stable O-substitution products - 2-aminomethoxy-5-halogen-acetophe-nones. In alcohol solution, the reaction proceeded simultaneously according to the ketone function as well with the formation of O-substitution products such as P-amino-2-aminomethoxy-5-halo-gen-propiophenones.
The composition and structure of the compounds obtained have been proved by alternative synthesis in addition to elemental and spectral methods of analysis. 2-HGAs did not react with primary amines like the alkyl-sub-stituted 2-dihydroxyacetophenones and 2-hydr-oxybenzophenones [5, 14, 15] that we studied.
It should be noted that some of the ami-nomethylation products of hydroxyarylmethyl ketones synthesized by us had pronounced antioxidant [16] and antimicrobial [17] properties.
Taking into account the above mentioned, the investigation of behaviour of trifunc-tional dihydroxyacetophenones under Man-nich's reaction conditions is of certain theoretical and practical interest.
In order to continue our studies on the aminomethylation of hydroxyacetophenones [12, 14, 15] the aminomethylation of dihydrox-yacetophenones with different positions of the second hydroxyl group has been carried out for the first time.
Experimental part
Reagents. 2,5-DHA - Tmelt. 200-2020C (a) and 2,4-DHA - Tmelt. 143-1440C (b) were synthesized by the methods [18 (a, b)].
Methylene bis-piperidine ng0 1.4848/ 1.4834 [19] and methylene bis-morpholine -ng0 1.4830/1.4816 [19] were synthesized according to technique of [19]. The remaining reagents were reagents of the purity grade.
Equipment. The purity of the synthesized compounds was controlled by vapour phase chromatography on the Silufol UV-254 chromatograph in different solvent systems. The Proton NMR spectra were recorded on the spectrometer Tesla BS-487-B with an operating frequency of 80 MHz; tetramethylsilane and hexamethyldisilane were used as internal standards. The samples were solutions of the test substances in CCl4 and CDCl3.
IR spectra were recorded on a prism spectrophotometer UR-20 and Nicolet 1S10 in the microlayer with the range of 4000-400 cm-1 in the form of suspension in vaseline oil (range 2000-400 cm-1) and in the solution of hexa-chlorobutadiene (range 4000-2000 cm-1).
Techniques of aminomethylation
1. Aminomethylation of 2.5-DHA. 0.035 mol of formaldehyde in the form of 36%-solution is added to the solution of 0.01 mol of 2.5-DHA and 0.035 mol of a secondary amine dissolved in 100 ml of isopropyl alcohol, with cooling
(15-200C). The reaction is carried out at 500C for 3 hours. After removing the excess solvent, the precipitated target product is purified from isopropyl alcohol by recrystallization (I, II).
2. Aminomethylation of 2.4-DHA
a) with secondary amines:
0.01 mol of methylene-bis-amine is added to the solution of 0.01 mol of 2,4-DHA dissolved in 100 ml of isopropyl alcohol, with cooling (150C). The reaction is carried out at room temperature for 2 hours. After removing the excess solvent, the target product is purified from the mixture of isopropanol:water (1:2) by recrystallization (III, IV).
b) with primary aromatic amines:
0.02 mol of paraform and 0.0001 mol of KOH added in 70 ml of dehydrated isopropyl alcohol are boiled until the paraform is completely dissolved, cooled and added to the solution of 0.01 mol of 2.4-DHA and 0.01 mol of amine at 200C dissolved in 80 ml of isopropyl alcohol. The reaction is carried out at 45-500C for 3 hours. By cooling, the targeted product is obtained, which is purified from propyl alcohol by recrystallization (V, VI).
Discussion of the results
The present paper presents the results of aminomethylation with secondary heterocyclic and primary aromatic amines of 2.5-dihydroxy-acetophenone (2.5-DHA) and 2.4-dihydroxy-acetophenone (2.4-DHA).
It was found that during aminomethyla-tion of 2.5-DHA with secondary amines - piper-idine and morpholine - the reaction does not take place in the absence of the solvent, but in an alcohol medium, the reaction is carried out through all three functions with simultaneous formation of C, O-substituted products. The change in the ratio of reagents only affected the yield of aminomethylation products.
The composition and structure of the obtained compounds have been established on the basis of the data of elemental and spectral (IR, Proton NMR) methods of analysis.
In the IR spectra, the position of the stretching vibration bands of the carbonyl group vc=0 in compounds I and II (1672cm-1 (I)
1678cm-1 (II)), as well as in their hydrochlorides (HC) Vc=o 1675 cm-1 (I) and 1680 cm-1(II) indicates the absence of the hydroxyl group in the o-position to the acetyl group. At the same time, in the spectra of HC of I and II in the region of 3450-3310 cm-1, an intense absorption band of the hydroxyl group is observed, which is related to the destruction of the intramolecular hydrogen bond (IHB) like OH.. .N type during the formation of HC.
In the 1H NMR spectra of compounds I and II, the following parameters are sufficient to establish their structure: singlets at 3.9 ppm;
(I), 4.0 ppm (II) and 4.2 ppm (I) and 4.24 ppm
(II) correspond to the methylene protons of two aminomethyl groups Ar-CH?-N and O-CH2-N, respectively; signals of two protons 3H and 6H of the benzene ring in the form of a singlet at 6.47 ppm (I) and 6.35 ppm (II) correspond to two isolated p-protons; the singlet signal of the proton of the hydroxyl group involved in the OH...N type IHB is found in the weak fields at 11.37 ppm (I) and 10.43 ppm (II).
In addition, there is no signal of the acetyl methyl group in the 1H NMR spectra of (I) and (II) and however, there is a multiplet of the methylene group O=CH2-CH2-N in the range of 2.15-2.87 ppm. Taking into account the above data, as well as the results of elemental analysis (see Table), the reaction scheme can be represented as follows:
NR
OH
here, RN = piperidyl (I), morpholyl (II). Scheme 1
Physicochemical properties of compounds I-VI
The highest yields of P-piperidino-2-pipe-ridinomethoxy-4-piperidinomethyl-5-hydroxypro-piophenone (I) - 57% and P-morpholino-2-mor-pholinomethoxy-4-morpholinomethyl-5-hydroxy-propiophenone (II) - 59% are obtained using the 3.5-fold amount of the aminomethylating mixture.
The residual consists of the unreacted 2,5-DHA, and methylene-bis-amines, as well as of traces of resinous substances with undetermined structure.
A comparison of the structures of ami-nomethylation products of 2,5-DHA and 2-HHA shows that the hydroxyl group in position "5" of 2,5-DHA serves simultaneously as a functional group and substituent like halogen atoms.
In aminomethylation with free secondary amines in an alcoholic medium, it is accepted that the aminomethylating agents are adducts of secondary amines with formaldehyde of two types: unstable aminocarbinols (R2N-CH2-OH) and less active stable methylene-bis-amines (R2N-CH2-NR2) [18]. An attempt to ami-nomethylate 2.5-DHA with separately synthesized methylene bis-amines was unsuccessful, which indicates that namely aminocarbinols participate in this case.
It should be noted that 2.5-DHA does not react with primary amines in the presence of formaldehyde regardless of the conditions.
Changing the position of the free hydroxyl group gave other results. Thus, the quantitative formation of the resinous condensation product of 2.4-DHA with formaldehyde is observed during aminomethylation of 2.4-DHA in an alcoholic medium, regardless of the ratio between 2.4-DHA and the ami-nomethylating mixture. The aminomethylation reaction proceeds successfully only when me-thylene-bis-amines are used as aminome-thylating agents.
№ Yield, % Tmelt. ? °C Formula Found/Calculated, %
C H N
I 59 148-150 C26H41N3O3 70.60/70.37 9.53/9.33 9.67/9.47
II 57 154-156 C23H35N3O6 61.65/61.44 8.12/7.86 9.53/9.35
III 78 87-89 C14H19NO3 67.65/67.42 7.92/7.70 5.79/5.62
IV 75 112-114 C13H17NO4 62.32/62.13 7.01/6.87 5.76/5.58
V 65 123-125 CnHnNO3 72.22/72.06 6.27/6.06 5.12/4.94
VI 60 109-111 C17H17NO4 68.00/68.22 5.96/5.69 4.80/4.68
In the Proton NMR spectra of compounds III and IV, singlets at 2.49 ppm (III) and 2.52 ppm (IV), 3.69 ppm (III) and 3.82 ppm (IV) correspond to the signals of the methyl protons of the acetyl group O=C-CH and to the methylene protons of the aminomethyl group Ar-CH-NR, respectively.
The presence of two doublets at 6.23 ppm (III) and 6.40 ppm (IV), and 7.40 ppm (III) and 7.50 ppm (IV) is special to aromatic O-H and
shows that the substitution has occurred in position "3". Singlet signals of protons of two hy-droxyl groups appear in weak fields due to the participation of two types in IHB: OH...N (12.22 ppm) - III and (12.07 ppm) - IV; OH...O=C (12.16 ppm) - III and (13.20 ppm) - IV.
From the data of the Proton NMR spectra, it is seen that the reaction proceeds with the formation of 2,4-dihydroxy-3-aminomethyl-acetophenones according to the scheme 2.1:
o ho
hc
rn-ch2-nr
- rnh
2 ch2o+r'nh2
-ho
o
hc
hc
ho
o ho
o
oh iii, iv
n- r' 2
v, vi
here, RN = piperidyl (I), morpholyl (II); R'N = p-tolyl (V), p-anisyl (VI).
Scheme 2 (1,2)
1
The yields of 2.4-dihydroxy-3-piperidino-methylacetophenone (III) and 2.4-dihydroxy-3-morpholinomethylacetophenone (IV) by the action of methylene bis-amines are 78% and 75% respectively (table).
Aminomethylation of 2.4-DHA occurs in the o-position with respect to both hydroxyl groups, that is also special to other dihydroxy-aromatic compounds with a similar arrangement of hydroxyl groups and an acceptor substituent in electrophilic substitution reactions [19].
Unlike 2.5-DHA, 2.4-DHA reacts with primary aromatic amines (p-toluidine and p-ani-sidine) and formaldehyde in an alcoholic medium in the presence of catalytic amounts of KOH.
The Propon NMR spectra of the obtained compounds (V and VI) show the following signals characterizing their structure; singlets: 2.19 ppm CH3-Ar, 2.47 ppm CH3-C=O, 4.47 ppm Ar-CH2-N, 5.25 ppm O-CH2-N, 6.23-7.40 ppm (multiplet) 7H 2Ar; singlet: 12.22 ppm O-H (V), 2.50 ppm CH3-C=O, 3.68 ppm CH3-OAr, 4.57 ppm Ar-CH-N, 5.30 ppm O-CH2-N, 6.35-7.62 ppm (multiplet) 7H 2Ar,
12.24 ppm (singlet) O-H (VI). This shows that the compounds (V and VI) fovmed as result of the reaction are 3.4-dihydro-2H-1.3-benzoxa-zines (scheme 2.2).
Change in the ratio of reagents affects only the yield of 3.4-dihydro-3-(p-tolyl)-5-hydr-oxy-6-acetyl-2H-1,3-benzoxazine (V) and 3.4-dihydro-3 -(p-ani syl)-5-hydroxy-6-acetyl-2H-1,3-benzoxazine (VI).
The residue is a mixture of unreacted 2,4-DHA and adducts of aromatic amines with formaldehyde.
It should be noted that conditions of reaction and structure of its products are identical with those of aminomethylation of 4-hydroxy-acetophenones by primary aromatic amines [15].
From the above data we see that the hy-droxyl group at position "4" of 2,4-DHA acts primarily as a functional group (C-substitution at o-position to form 3,4-dihydro-2H-1,3-benzoxazines) and increases the reactivity of the molecule (interaction with methylene-bis-amines and primary aromatic amines).
Conclusion
1. Aminomethylation of trifunctional di-hydroxyacetophenones with primary and secondary amines and formaldehyde has been carried out for the first time;
2. It has been established that the implementation and direction of the reaction depend mainly on the position of the hydroxyl group that is not involved in IHB, viz:
- anomalous aminomethylation by free secondary amines occurs at position "5" (2.5-DHA) simultaneously at all three functions to form stable products of C,O-substitution - P-amino-2-aminomethoxy-4-aminomethyl-5-hydroxypropiophenones
- at presence of the same hydroxyl group at position "4" (2.4-DHA) aminomethylation proceeds by phenolic function under the action of methylene-bis-amines only with formation of C-substitution products - 2.4-dihydroxy-3-aminomethylacetophenones
- only 2.4-DHA reacts with primary aromatic amines in the presence of formaldehyde via phenolic function to give cyclic 3.4-dihydro-2H-1.3-benzoxazines.
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DiHiDROKSiASETOFENONLARIN AMiNOMETiLLOSMOSi HAQQINDA
M.M.Agamahyeva, A.M.Pa§acanov, T.M.ismayilov, N.i.ismayilov, G.O.Hasanova
ilk dafa olaraq ügfunksiyali 2.5-dihidroksiasetofenonun (2.5-DHA) va 2.4-dihidroksiasetofenonun (2.4-DHA) sarbast birli va ikili aminlar va formaldehidin i§tiraki ila aminometilla§masi aparilib. Müayyan edilib ki 2.5-DHA ikili heterosiklik aminlar piperidin va morfolin va formaldehidin sulu mahlulu ila spirt mühidinda 50°C-da aminometilla§ir. Reaksiya eyni zamanda har üg funksional qrup üzarinda ba§ verir; naticada C-, O-avazolunmu§ töramalar amala galir -ß-amino-2-aminometoksi-4-aminometil-5-hidroksipropiofenonlar. Fargli olaraq 2,4-DHA yalniz metilen-bis-piperidin (morfolin) tasiri naticasinda susuzla§mi§ spirt mühidinda 200C-da 2,4-dihidroksi-3-aminometilasetofenonlar amala galmasi ila aminometilla§ir. 2,4-DHA birli aromatik aminlar - p-toluidin va p-anizidinla formaldehid isa paraform §aklinda tarkibinda katalitik miqdar KOH olan qurudurmu§ spirt mühidinda 500C-da 3,4-dihidro-2H-1,3-benzoksazin qurulu§lu madda amala gatirir. 2,5-DHA birli aromatik aminlarla va formaldehidla reaksiyaya daxil olmur. Sintez edilmi§ maddalarin tarkibi va qurulu§u element va spektral analiz üsullarinin göstaricilari naticasibda müayyan olunub.
Agar sözlar: dihidroksiasetofenonlar, aminometiÜ3§m3, Mannix reaksiyasi.
ОБ АМИНОМЕТИЛИРОВАНИИ ТРИФУНКЦИОНАЛЬНЫХ ДИГИДРОКСИАЦЕТОФЕНОНОВ
М.М.Агамалиева, А.М.Пашаджанов, Т.М.Исмаилов, Н.И.Исмаилов, Г.О.Гасанова
Впервые проведено аминометилирование трифункциональных в условиях реакции Манниха 2.5-дигидрок-сиацетофенона (2.5-ДГА) и 2.4-дигидроксиацетофенона (2.4-ДГА) свободными первичными и вторичными аминами в присутствии формальдегида. Установлено, что 2.5-ДГА аминометилируется вторичными гетероциклическими аминами - пиперидином и морфолином и водным раствором формальдегида в спиртовой среде при температуре 500С. Реакция протекает одновременно по всем трем функциям с образованием стабильных продуктов С, О-замещения - ß-амино-2-аминометокси-4-аминометил-5-гидроксипропиофенонов. Реакция аминометилирования 2,4-ДГА протекает по фенольной функции только под действием метилен-бис-аминов пиперидина и морфолина в абсолютном спирте при 200С с образованием 2.4-дигидрокси-3-аминометилацетофенонов. Аминометилирование 2.4-ДГА первичными ароматическими аминами - n-толу-идином и n-анизидином протекает в абсолютном спирте при действии формальдегида в виде параформа в присутствии каталитических количеств KOH при 500С. Продуктами реакции являются 3.4-дигидро-2Н-1,3-бензоксазины. 2.5-ДГА первичными аминами не аминометилируется. Состав и строение синтезированных соединений установлены на основании данных элементного и спектральных методов анализа.
Ключевые слова: дигидроксиацетофеноны, аминометилирование, реакция Манниха.
