AZ9RBAYCAN KIMYA JURNALI № 3 2018 ISSN 2522-1841 (Online)
ISSN 0005-2531 (Print)
UDC 547.422:542:551.543:442 SYNTHESIS OF AMINOALCOHOLS BASED ON OXYHALOGENATION PRODUCTS OF ALKYLCYCLOHEXENES AND C3, C4 ALIPHATIC AMINES
O.A.Sadygov, Kh.M.Alimardanov, Sh.LIsmayilova
Y.Mamedaliyev Institute of Petrochemical Processes, NAS of Azerbaijan
omar. sadiqov@gmail. com Received 01.03.2018
Synthesis of aminocyclohexanols through the steps of hydroxychlor(brom)ination of alkyl- and alkenyl-cyclohexenes has been proposed in the system: cycloolefin + oxidant + Hhal. It was demonstrated that the oxidation process is induced by the electrophilic intermediates HOX, (X=C1, Br), which in the "in situ" mode, are added to the multiple bond of substrates by the formation of the corresponding hydroxy -halides. Substitution of halogen atoms for amino groups with the participation of potassium hydroxide leads to the corresponding amino alcohols.
Keywords: aminocyclohexanols, synthesis, alkyl- and alkenylhydroxychloro- (bromo)cyclohexanol.
Introduction
Interest in compounds containing in its composition monocyclic structural fragments with hydroxyl and amine groups have been caused by high biological activity and wide application of them as raw materials in the pharmacological and perfumery industry [1, 2]. In the literature there are information about the use of amino alcohols for the synthesis of synthetic analogues of natural biologically active substances and medicinal preparations for various purposes [2-8]. Optically active representatives of amino alcohols with 1,2-aminoalcohol fragments can be a source of chirality in asymmetric synthesis [9-11]. For example, (R, S)-3(diben-zyl amino)-! -[(R)-/;-tolylsulfonyl]butane-2-ol is used as a synthon for the preparation of oxazol-idin-2-one and vicinal syn-N,N-dialkyloxiranes [12]. The transformation of the latter with the participation of functional compounds under different conditions allows the synthesis of structural analogues of C4-C6 natural heterocyclic amino alcohols [13].
There are also known photo-redox catalytic methods [14-18] for aminohydroxylation of olefinic hydrocarbons of different structure into the corresponding vicinal amino alcohols that are a part of many natural biologically active compounds.
The interaction of chlorohydrins (the main reagent for the preparation of oxiranes), as well as chiral epoxides with nucleophilic reagents,
produced regioselective 1,2-amino alcohols used as an effective agent against hepatitis [19].
Treatment of D-galactose by acetone at room temperature in the presence of (H2SO4 + ZnCh) and alkylation of the reaction product by epichlorohydrin in the presence of 40% NaOH and interfacial agent - tetrabutylammonium bromide (TBAB) leads to a mixture of 6-0-[2,3-epoxypropyl]-l,2- and 3,4-di-O-isopropyli-dene-a-D-galactopyranose. In the interaction of the oxirane ring of this compound with various aliphatic aminoalcohols of oligomeric type, as well as diamines, analogues of natural aminoalcohols with in vitro antibacterial properties were obtained [21].
Data on the production of amino acids from hydroxychlorine(bromine) derivatives of monocyclic hydrocarbons do not practically exist in the literature, which is probably due to the selection of effective oxidants, as well as the conditions for low-temperature generation in the "in situ" mode of electrophilic intermediates HOX (X = CI, Br), then adding to the multiple bond of cycloolefins.
This work has been devoted the results to the preparation of the hydroxychlor(brom)ides of alkylcyclohexenes in the "in situ" mode of addition of electrophilic intermediates HOX in the system containing HX+H202+cycloolefin, followed by nucleophilic substitution chlo-ro(bromo) atom with primary or secondary aliphatic amines.
Results and Discussion
Hydroxychlor(brom)ides of these alkyl-and alkenyl derivatives of cyclohexene have been obtained by our previously developed method
[21, 22]. In this case, the synthesis process is carried out successively in several stages with the formation of hydroxychlorides (2a-c) or hy-droxybromides (3a-c) according to the scheme 1 :
Scheme 1
H9o9+HX ,
H—p— o- H
I
HX
H— ç>— o- H
I I
H
X
+
R
ftxi
Rlx, x
I a-c
h-—-h2o H o—H
T7-
o-
o-I
H
R
1
OH l/\ X
I /\ I
OH
A
2a—c 3a—c
2aj-Cj
3aj-cj
Where: X=C1 (2); Br (3); Ri=4-CH3(a); COCH3(è); 4-CH=CH2(c).
It is seen from the proposed mechanism of the reaction that as a result of the attack of the nucleophilic oxygen atom of the hydrogen peroxide molecule by HX(X=C1, Br), a low-stable intermediate complex is formed, which then generated an oxyhalide intermediate [X+OH"]. The attack of the substrate by this complex leads to an energetically more favorable redistribution of charges and the formation of an intermediate complex [A], The ion X+ rapidly adds to the multiple bonds of the substrate, forming a carbo-cation, stabilized by the hydroxy anion, which is separated from the oxyhalide intermediate. The reaction of hydroxyhalogenation in the "in situ" mode through the stage of generation of the intermediate [X OH"] occurs in the aqueous phase and the attack of the double bond of the substrate by this intermediate - in the organic phase. An increase the rate of mixing of the reaction mass removes the effect of diffusion factors. As a result, the transition of the active oxyhalide intermediate from the aqueous to the organic phase and the attack of a multiple bond have been facilitated. This has a positive effect on the yield of reaction products.
It is necessary to emphasize that in the absence of hydrogen peroxide, hydroxyhalogena-
tion of cycloolefins does not occur, because the initial HX (X=C1, Br) without the participation of the H2O2 cannot generate in the aqueous solution of the active hydroxyhalide intermediate [X+OH"]. In the case of using 11-15% aqueous solutions of HC1, the highest yields of the reaction products are achieved at a molar ratio of the substrate: HX:H202=1:1:1.5-2.0. In the range of 30-60°C the yields of products increase and comprise 62.0-76.5% in the case of 2a-c and 58-71.6%) in the case 3a-c, respectively. It is necessary to emphaseze that an increase in temperature above 60°C is impractical, because the rate of non-productive decomposition of the active oxyhalogenide intermediate increases to form molecular chlorine (or bromine), which also contributes to the accumulation of up to 12-20% of dichloro(dibromo) derivatives of substrates in the reaction products. Moreover, with an increase of temperature above 60°C in the system containing alkylcyclohexenes (ACHE), hydrogen peroxide and hydrohalic acids HX at the molar ratios ACHE:H20:HX=1:(2-4):1 isomerization of the products of the oxyhaloge-nation reaction occurs. The composition and structure of synthesized hydroxychloride(bro-mide) cyclohexanes of raw 2a-c and 3a-c have
been established by GLC, IRS, NMR 1H, 13C spectral methods of analysis. Thus, in the IR spectra of halogenhydrines 2 a, b and 3 a, b, in besides the stretching vibrations -CH, -CH2, -CH3, absorption bands were observed in 3460, 1725, 800-650 cm"1 area, which are characteristic for the O-H, C=0, C-Cl, C-Br bonds, respectively. The absence of the absorption band of C=C stretching vibrations in the 1630-1650 cm"1 area indicates the addition of the active [X+OH"] intermediate in the "in situ" mode to a multiple bond of the substrates. In the spectra NMR JH of compounds (2 a, 2 b and 2 ah 2 ¿>1), signals at 8 = 3.92 ppm are observed for the proton ( >CH-OH) and 8 = 4.33 ppm for the proton (>CHC1) with constant spin-spin corresponding (CSSC) J 7.8, 10.8 Hz. At the same time, for
Scheme 2.
2 a—c\
compounds 2 c and 2 c\, these protons manifest themselves at 8 = 3.92 ppm for (>CHOH, J 10.8 Hz) and 8 = 4.52 ppm for (>CHC1, J 10.9 Hz). Similar results have been observed for the compounds (3 a, 3 b and 3 a\, 3 b\). The results of GLC analysis and spectral data show that the chloro-(bromo)hydrins of alkylcyclohexenes contain approximately equal amounts of hardly separable isomers: /ra/7.s-2-Hlg(c/)-cyclohexane-l -ol (a) and /ra/7.s-2-Hlg(<^-cyclohexane-l -ol (a), differing in the position of the halogen atom and the hydroxyl group.
Based on synthesized hydroxychlorides (2a-c) and hydroxybromides (3a-c) of alkylcy-clohexanes, N-substituted amino alcohols have been prepared according to the scheme 2:
3 a-c J
+ HNR2R3
Д , OH-
-HX
(Aa-d)-(6a—d)
(4а1-й?1)-(6а1-й?1)
where Ri=4-CH3(4a-J), 4-CH=CH2(5a-J), l-COCH3(6a-J); R2=H, R3=[N(C2H5)2](a), HNC3H7(6), HNC4H9(e), /-HNC4Hy(i/).
The direction of conversion of hydroxychloro(bromo) derivatives and the yield of N-substituted alkylcyclohexanols mainly depend on the temperature of the reaction, the pH of the medium, and the polarity of the solvents (Table 1).
Table 1. Influence of the conditions of interaction propan-1-amine (a) with 2-bromo-4-methylcyclohexan-l-ol (h) on the yield of 5-methyl-2-(propylamino)cyclohexane-l-ol_
т, °с Duration, h Solvent Mol. ratio a:b pH Yield % Unidentified substance, mas. % Conversion (b), mas. %
20 12 Without solvent 1.5:1 9.8 - - -
30 10 H20 1.5:1 9.8 23.0 - 23.0
40 8.0 propanol-2/H20 1.5:1 8.2 56.0 1.6 57.6
50 5.0 ethanol/H20 1.5:1 9.8 65.0 6.5 71.5
60 4.0 propanol-2 /H20 1.5:1 10.0 66.0 10.5 76.5
50 5.0 propanol-2 /H20 2:1 10.2 69.0 15.6 84.6
60 3.0 propanol-2/H20 2:1 10.2 75.0 11.2 86.2
50 4.5 propanol-2 /H20 2.5:1 10.2 76.5 13.8 90.3
60 3.5 ethanol/H20 2.5:1 10.2 76.0 10.6 86.6
Experimental part
The IR spectra of the synthesized compounds have been recorded on an IR Fourier spectrometer Alpha in the range 400-4000 cm"1 in the form of suspensions in vaseline oil or in tablets with KBr. NMR 'h and 13C spectra were recorded on a "Bruker BioSpin AG Fourier" spectrometer at a working frequency of 300.18 MHz in CDCI3. The relative content of protons in various structural fragments was determined by integrating the corresponding resonance absorption bands. Elemental analysis was performed on analyzer TruSpes Micro Leco Corporation USA.
For preparative chromatography a column of 150 mm in length and 5 mm in diameter has been used and has been filled with silica gel (100-200 mesh), ethyl acetate and its mixture with 2-propanol (1:1) have been used for elution.
4-methylcyclohexene was obtained by dehydration of 4-methylcyclohexanol-l at 220-250°C over Y-AI2O3, and a precise rectification of the catalysate. 1-Cyclohexenylethanone has been synthesized by acylation of cyclohexene by acetic acid chloride [23]. Buta-l,3-diene has been dimerized to 4-vinylcyclohexene by the known method [24]. Primary and secondary amines, H2O2, HC1 and HBr from Alfa Aesar (A.Johnson Malthey Co.) have been used in the experiments.
Hydroxychlorination(bromination) of al-kyl- and alkenylcyclohexenes has been carried out according to the previously developed procedure [21, 22]. Their yields are given in Table 2.
General procedure for the preparation of amino alcohols from alkyl hydroxychlorides(bro-mides)cyclohexan
0.3 g of KOH and 50-100 ml of propan-2-ol (or ethanol) have been added to the mixture of 14.7 g (0.1 mole) of compound (2 a) or 19.1 g of (3 a) isolated from the catalysate. The mixture has been heated for 1-1.5 hours at the temperature of 40-60°C and 0.2-0.25 mol of the primary or secondary amine has been added dropwise during 0.5-1.0 hours. The reaction has been completed within 3-6 hours, after full consumption of hydroxyhalides (control by GLC method). The reaction mass has been dissolved
in water, extracted with ether or toluene (2 xlOO ml), and the desired products have been obtained after distilling off the solvent and cooling. The physicochemical parameters and yields of the synthesized amine nitrates have been given in the corresponding examples.
2-(diethylamino)-5-methylcyclohexan-l-ol (4a) obtained from 3.7 g (25 mmol) 2a or 3.86 g (20 mmol) 3a and 3.3 g (45 mmol) N-ethyl-ethanamine. Yield from compound 2a - 3.2 g (69.2%), but from compound 3a - 2.86 g (77.3%), 7b.P. 127-129°C/0.27 kPa. IR-spectra, v, cm"1: 3496 (v, OH); 3340, 3236 (v, CN); 2960 (vs, CH3); 2855 (vs, CH2); 1666, 1658 (v, NC); 1460 (Sas, CH2); 1128 (5, OH) [25-27]. Spectra NMR 1H, 5, ppm.: 0.94 t (3H, CH3CH, J 6.8 Hs);<1.06 d [6H, N(CH2CH3)2 , J 8.2 Hz]; 1.25-1.63 m (7H, CH, CH2); 2.43 k [4H, N(CH2 CH3)2, J 8.0 Hz]; 2.67 t [1H, HC-N(C2H5)2, J 1.0 Hz]; 3.42 t (1H, >CHOH, 77.1 Hz); 3.61 broad, s (1H, OH). Spectra NMR 13C, 5, ppm: 75.5(C2), 63^), 40.4(C6), 50.2 (C8, C10), 33.7 (C4), 31(C5), 23.5(C3), 21 (C7), 13.7(C9, C11) [28].
Found, %: C 70.68, H 12.11, N 7.36. CnH23NO. Calculated, %: C 71.35, H 12.43, N 7.56.
5-methyl-2-(propylamino)cyclohexan-l-ol (4b) obtained from 3.7 g (25 mmol) 2a or 3.86 g (20 mmol) 3a and 2.95 g (50 mmol) pro-pan-l-amine. Yield from compound 2a - 2.74 g (64.1%)), but from compound 3a - 2.46 g (71.9%), TB.p.133-134°C/0.33 kPa. IR-spectra, v, cm"1: 3496 (v, OH); 3340, 3236 (v, CN); 2960 (vs, CH3); 2855 (vs, CH2); 1666, 1658 (v, NH); 1460 (Sas, CH2); 1128, 1110 (5, OH). Spectra NMR 1H, 5, ppm.: 0.93 t (3H, CH3CH2, J 6.8 Hz); 0.98 d (3H, CH3CH<, J 8.0 Hz); 1.25-1.73 m (9H, CH, 4CH2); 2.0 broad, s (1H, NH); 2.57 t (2H, NCH^Hs, J 7.2 Hz); 2.67 k [1H, HCNCH2 - J 7.0 Hz]; 3.42 k [1H, HC-OH, /7.0 Hz]; 3.61 broad, s (1H,0H). Spectra NMR 13C, 5, ppm.: 76.5(C2), 65.3^), 50.3(C8), 40.1(C6), 33.4(C4), 31(C5), 24(C9), 21.2(C7), 11.6(C10). Found, %>: C 69.72, H 12.14, N 7.96. Ci0H2iNO. Calculated, %: C 70.18, H 12.27, N8.18.
Table 2. Yield of products hydroxychlorination(bromination) of alkyl- and alkenylcyclohexenols
№ of comp. Name of compound Yield, % Гь.р., UC /kPa T °c 1 melt? Bratto-Formula
2 a 2- chloro-5-methylcyclohexan-l-ol 74.5 106-107/ 1.33 C7H13C10
2b 1 -(1 -chloro-2-hydro xycyclohexyl)ethan-l -one 76.5 135-137 /0.33 C8H13C102
2c 2-chloro -5 -ethenylcyclohexan-1 -ol 68.4 120-122/ 1.33 C8H13C10
2 ax 2-chloro -4 -methylcy clohexan-1 -ol 74.2 106-107/0.34 C7H13C10
2 bx 1 -(2-chloro-1 -hydro xycyclohexyl)ethan-l -one 73.1 97-98 C8H13C102
2 c¡ 2-chloro -4 -ethenylcyclohexan-1 -ol 67.6 112-114/0.41 C8H13C10
3 a 2- bromo-5-methylcyclohexan-l-ol 69.5 127-128/0.27 С7Н12ВЮ
3b 1 -(1 - bromo -2-hydroxycyclohexyl)ethan-1 -one 74.8 102-104 с8н13вю2
3c 2- bromo -5 -ethenylcyclohexan-1 -ol 64.9 123-125 /0.53 С8Н13ВЮ
3ai 2- bromo-4-methylcyclohexan-l-ol 67.3 127-128/0.27 C7H13BrO
3bx 1 -(2- bromo -1 -hydroxy cyclohexyl)ethan-1 -one 72.5 101-103 с8н13вю2
3 Ci 2- bromo-4-ethenylcyclohexan-1 -ol 68.0 109-111/0.27 С8Н13ВЮ
5-methyl-2-(butylamino)cyclohexan-l-ol (4c) obtained from 3.7 g (25 mmol) 2a - or 3.86 g (20 mmol) 3a - and 3.65 g (50 mmol) butan-1-amine. Yield from compound 2a - 3.0 g (64.9%), but from compound 3a - 2.76 g (74.6%). 7b.p. 151-153° C/0.33 kPa. IR spectra, v, cm"1: 3496 (v, OH); 3240 (v, CN); 1665 (v, NH); 1460 (5as, CH2); 1450 (5, CH); 1110 (5, OH). Spectra NMR 1H, 5, ppm: 0.911 (3H, CH3CH2CH2N, J 6.8 Hz); 0.98 d (3H, CH3CH J 6.8 Hz); 1.29-1.75 m (9H, CH, 5CH2); 2.1 broad, s (1H, HNCH2-); 2.58 t (2H, NCH2CH2-, J 7.2 Hz); 2.67 d [1H, HCNCH2- , J 7.0 Hz]; 3.43 t [1H, HCOH, J 7.1 Hz]; 3.61 broad, s (1H, OH). Spectra NMR 13C, 5, ppm: 76.5(C2), 65.^C1), 47.8(C8), 40.0 (C6), 33.4(C4), 33.1(C9), 31(C5), 25.6(C3), 21(C7), 20.2(C10), 14(Cn). Found, %: C 71.66, H 12.23, N 7.22. CnH23NO. Calculated, %: C 71.35; H 12.43; N7.56.
5-methyl-2- [(2-methylpropyl)amino] cyc-lohexan-l-ol (4d) obtained from 3.7 g (25 mmol) 2a or 3.86 g (20 mmol) 3a and 3.65 g (50 mmol) 2-methylpropan-l -amine. Yield from compound 3a - 2.86 g (61.8%>), but from compound 4a - 2.66 g (71.9%). ft.P. 142-144°C/0.33 kPa. IR spectra, v, cm"l: 3496 (v, OH); 3240 (v, CN); 2960 (vs, CH3); 1460 (5as, CH2); 1450 (CH2); 1110 (5, OH). Spectra NMR ^ 5, ppm: 0.94 d [6H, (CH^HCNCHz-, J 7.0 Hz]; 0.98 d (3H, CH3CH<, 76.8 Hz); 2.1 broad, s (1H, HNCH2-); 2.35 d [1H, NCHaHb, J 7.1 Hz]; 2.43 d [1H, HCOH, J 7.0 Hz]; 2.61 d [1H, NCHaHb, J 7.0 Hz]; 2.67 d [1H, HC-NCH2CH(CH3)2, J 7.0 Hz]; 3.61 broad, s (1H, HOCH). Found, %: C
70.98, H 12.25, N 7.26. CnH23NO. Calculated, %>: C 71.35, H 12.43, N7.56.
2-(diethylamino)-5-ethenylcyclohexan-l-ol (5a) obtained from 4.02 g (25 mmol) 2c or 4.12 g (20 mmol) 3c and 3.3 g (45 mmol) N-ethylethanamine. Yield from compound 2c -3.1 g (62.9%), but from compound 3c - 2.7 g (68.5%). 7b.p. 140-141°C/0.33 kPa. IR spectra, v, cm"1: 3480 (v, OH); 3320 (v, CN); 3060 (vas, CH2=); 3020 (vs, CH=); 2960 (vs,CH3); 2860-2855 (vs, CH2); 1630 (v, C=C); 1295 (v, NC); 1110 (5, OH). Spectra NMR ^ 5, ppm: 1.05 t [6H, N(CH2CH3)2, J 8.0 Hz]; 1,35-1,74 m (6H, 3CH2); 2.0 broad, s (1H, NCH); 2.15 k (1H, >HC-CH=CH2, J 7.1 Hz); 2.43 k [4H, N(CH2CH3)2, J 7.0 Hz]; 2.67 t [1H, HC-N(C2H5 )2,J7.0 Hz]; 3.42 d [1H,>HC0H, Jl.l Hz]; 4.91 d. d [1H, HbHaC=CH, J 10.1, 2.1 Hz]; 5.01 d. d. [1H, HaHftC=CH, J 16.8, 2.2 Hz]; 5.82 d. d (1H, HC=CHaHfe, J 16.8, 10, 6.3 Hz). Found, %: C 72.96, H 11.32, N 6.98. Ci2H23NO. Calculated, %: C 73.10, H 11.68, N7.1.
5-ethenyl-2-(propylamino)cyclohexan-l-ol (5b) obtained from 4.02 g (25 mmol) 2c or 4.12 g (20 mmol) 3c and 2.95 g (50 mmol) pro-pan-l-amine. Yield from compound 2c - 2.98 g (65.1%)), but from compound 3c - 2.68 g (73.2%). 7b.p. 150-151°C/0.40 kPa. IR spectra, v, cm"1: 3456 (v, OH); 3060 (vas, CH2=); 3035 (vs, CH=); 2860-2855 (vs,CH2); 1660 (v, NH); 1630 (v, C=C); 1534 (v, NH). Spectra NMR 1H, 5, ppm: 0.93 t(3H, CH3,J8.1 Hz); 1,34-1,75 m (6H, 3CH2); 2.0 broad, s (1H, HNCH2-); 2.15 k (1H, >HCCH=CH2, J 7.0, 6.2 Hz); 2.57 d [2H,
NCH2CH2 CH3, 77.0 Hz]; 2.66 d (1H,>HCNH, 7 7.1 Hz); 3.43 d (1H, HCOH, J1.0 Hz); 4.92 d. d [1H, HfcHaC=CH, 7 10.1, 2.1 Hz]; 5.01 d. d [1H, HaH^C=CH, 7 16.8, 2.2 Hz]; 5.81 d. d [1H, HC=CHaHft, 7 16.8, 10.6, 6.2 Hz], Found, %: C 71.92, H 11.13, N 7.45. CnH2iNO. Calculated, %: C 72.13, H 11.47, N7.65.
2-(butylamino)-5-ethenylcyclohexan-l-ol (5c) obtained from 4.02 g (25 mmol) 2c or 4.12 g (20 mmol) 3c and 3.65 g (50 mmol) butan-1-amine. Yield from compound 2c - 3.2 g (65.0%), but from compound 3c - 2.86 g (72.6%). Tmeit. 63-65°C. IR spectra, v, cm"1: 3480 (v, OH); 3250 (v, CN); 3060 (vas, CH2=); 3035 (vs, CH=); 2860-2855 (vs, CH2); 1660 (v, NH); 1630 (v, C=C); 1534 (v, NH); 1110 (5, OH). Spectra NMR 1H, 5, ppm: 0.93 t [3H, N(CH2)3CH3, 7 8.0 Hz]; 1,35-1,75 m (10H, 5CH2); 2.0 broad, s (1H, HNCH2-); 2.14 k (1H, >HC- CH=CH2, J 7.0, 6.3 Hz); 2.56 t (2H, NCH2C2H5, 7 7.1 Hz); 2.66 d [1H, > HC-NC3H7, J7.1 Hz]; 3.60 broad, s (1H, OH); 4.95 d.d [1H, HfrHaC=CH, 7 10.1, 2.2 Hz]; 5.02 d.d [1H, HaH^C=CH, 7 16.8, 2.1 Hz]; 5.8 d.d [1H, HC=CHaHft, 7 16.7, 10.1, 6.2 Hz], Found, %: C 72.89; H 11.42; N 6.93. Ci2H23NO. Calculated, %>: C 73.10, H 11.68, N7.11.
5-ethenyl-2- [(2-methylpropyl)amino] cyc-lohexan-l-ol (5d) obtained from 4.02 g (25 mmol) 2c or 4.12 g (20 mmol) 3c and 3.65 r (50 mmol) 2-methylpropan-l -amine. Yield from compound 2c - 3.1 g (62.9%>), but from compound 3c - 2.78 g (70.6%). rmeit. 63-65°C. IR spectra, v, cm"1: 3480 (v, OH); 3250 (v, CN); 3060 (vas, CH2=C); 3035, 3020 (vs, CH=); 2960 (vs, CH3); 2860, 2855 (vs, CH2); 1660 (v, NH); 1630 (v, C=C); 1534 (v, NH); 1450 (5, CH2); 1295 (v, NC); 1110 (5, OH). Spectra NMR 1H, 5, ppm: 0.94 d [6H, HNCH2 CH(CH3)2, 7 6.8 Hz]; 1,34-1,75 m (7H, CH, 3CH2); 2.1 broad, s (1H, HNCH2-); 2.14 k (1H, >CH-CH=CH2, 7 7.1, 6.2 Hz); 2.36 d [1H, NCHaHb-CH(CH3)2, 7 1.0 Hz]; 2.61 d (1H, -NCHaHb-, 7 6.8 Hz); 2.66 t (1H, HC-NCH2-, 7 7.1 Hz); 3.42 d (1H, HC-OH, 7 7.0 Hz); 4.94 d. d (1H, HbHaC=CH, 7 10.1, 2.2 Hz); 5.02 d. d (1H, HbHaC=CH, 7 16.8, 2.1 Hz); 5.78 d. d [1H, HC=CH2, 7 16.8, 6.3 Hz], Found, %: C 72.96,
H 11.32, N 6.95. Ci2H23NO. Calculated, %: C 73.10,H 11.68,N7.11.
l-[l-(diethylamino)-2-hydroxycyclohe-xyl]-ethan-l-one (6a) obtained from 4.41 g (25 mmol) 2b or 4.42 g (20 mmol) 3b and 3.3 g (45 mmol) N-ethylethanamine. Yield from compound 2b - 3.38 g (63.5%>), but from compound 3b - 3.29 g (67.2%). rmeit. 121-22°C IR spectra, v, cm"1: 3530, 3360 (v, OH); 3250 (v, CN); 2855 (vs, CH2); 1750, 1723 (v, C=0); 1110, 1069 (5, OH). Spectra NMR 1H, 5, ppm: 1.04 t [6H, N(CH2CH3)2, 7 8.0 Hz]; 1,45-1,92 m (8H, 4CH2); 2.15 s (3H, 0=CCH3, 7 8.0 Hz); 2.43 k (4H, N(CH2CH3)2, 7 8.0 Hz); 3.57 broad, s (1H, OH); 3.65 t (1H, >CH-OH, 7 7.0 Hz). Found, %>: C 66.98, H 10.58, N 6.25. Ci2H23N02. Calculated, %: C 67.60, H 10.80, N6.57.
> l-[2-hydroxy-(l-propylamino)cyclohe-xane]ethan-l-one (6b) obtained from 4.41 g (25 mmol) 2b or 4.42 g (20 mmol) 3b and 2.95 g (50 mmol) propan-1-amine. Yield from compound 2b -3.3 g (66.3%>), but from compound 3b - 3.19 g (80.6%). rmeit.l30-132°C. IR spectra, v, cm"1: 3530, 3360 (v, OH); 3270 (v, CN); 2860, 2855 (vs, CH2); 1750, 1723 (v, C=0); 1524 (v, NH); 1110 (5, OH). Spectra NMR 1H, 5, ppm: 0.92 t [3H, N(CH2)2CH3, 7 8.0 Hz]; 1,45-1,92 m (10H, 5CH2); 2.0 broad, s (1H, HNC); 2.15 s. (3H, CH3C=0, 7 8.0 Hz); 2.58 t (2H, HNCH2CH3, 7 7.1 Hz); 3.57 broad, s (1H, OH); 3.64 t (1H, ;HC-OH, 7 7.0 Hz). Found, %>: C 66.0, H 10.28, N 6.9. CnH2iN02. Calculated, %: C 66.33, H 10.55, N 7.03.
1- [1 -(butylamino)-2-hydroxycy clohexyl] -ethan-l-one (6c) obtained from 4.41 g (25 mmol) 2b or 4.42 g (20 mmol) 3b and 3.65 g (50 mmol) butan-1 -amine. Yield from compound 2b - 3.0 g (56.3%>), but from compound 3b - 2.95 g (69.3%). rmeit. 140-142°C. IR spectra, v, cm"1: 3530 (v, OH); 3270 (v, CN); 2860 (v, CH2); 1750, 1723 (v, C=0); 1524 (v, NH); 1110 (5, OH). Spectra NMR 1H, 5, ppm: 0.93 t [3H, N(CH2)3CH3, 7 8.0 Hz]; 1.33-1.93 m (12H, 6CH2); 2.0 broad, s (1H, HNC); 2.15 t (3H, CH3C=0, 7 8.0 Hz); 2.58 t (2H, HNCH2CH3, 7 7.1 Hz); 3.57 broad, s (1H, OH); 3.64 t (1H, HCOH, 7 7.0 Hz). Spectra
NMR 13C, 5, ppm: 205.8(C7), 84(C1), 72(C2), 45(C9), 33(C10), 29(CU), 25.3(C8). Found, %: C 67.12, H 10.58, N 6.46. C12H23NO2. Calculated, %: C 67.60, H 10.80, N 6.57.
l-{2-hydroxy-l-[(2-[(2-methylpropyl)-amino]cyclohexyl}ethan-l-one (6d) obtained from 4.41 g (25mmol) 2b or 4.42 g (20 mmol) 3b 11 3.65 g (50 mmol) 2-methylpropan-l-amine. Yield from compound 2b - 2.9 g (54.5%), but from compound 3b - 2.88 g (67.6%). Tmdt 123-124°C. IR spectra, v, cm"1: 3530, 3360 (v, OH); 2959 (vas, CH3); 2868 (vs, CH2); 2860, 2855 (vs, CH2); 1750, 1723 (v, C=0); 1540 (5, NH); 1524 (v, NH); 1110 (5, OH). Spectra NMR 1H, 5, ppm: 0.94 d [6H, HN CH2CH(CH3)2, J 6.8 Hz]; 1,43-1,94 m (9H, CH, 4CH2); 2.41 s [1H, HNCHaH^]; 2.65 [1H, HNCHaHft, J 7.1 Hz] 3.56 broad, s (1H, OH); 3.64 t [1H, >HCOH, J 7.0 Hz], Spectra NMR 13C, 5, ppm: 205.7(C7), 84.3(C1), 72(C1), 53.4(C9), 29.2(C10), 29(C3), 25.4(C6, C8), 24(C4), 22(C5), 20.7(C10, C11). Found, %: C 67.13, H 10.48, N 6.38. Ci2H23N02. Calculated, %: C 67.60, H 10.80, N 6.57.
References
1. Mashkovskii M.D. Lekarstvennye sredstva. Ch. I i II: Meditcina. 2000. 622 s.
2. Palchikov V.A. Morfoliny. Sintez i biologicheskaia aktivnost // Zhurn. org. himii. 2013. T. 49. Vyp. 6. S. 807-831. DOI: 10.1134/S10704 280130 60018.
3. Palchikov V.A., Pridma S.A., Kasian KH.I. Sintez i aminoliz N-(4-khlor-fenil)- i N-(2,4-dikhlorfenilsul-fonil)-N-(glitcidil)bitciclo[2.2.1]-gept-5-en-endo-2-il metilaminov // Zhura org. himii. 2010. T. 46. Vyp. 5. S. 649-654. DOI: 10.1134/S1070428010050088.
4. Lohray V.B., Lohray B.B., SrivastiVa B. Novel anti-infective compounds// Pure Appl. Chem. 2005. V. 77. P. 195-200. DOI: 10.1351/pac20057 7010195.
5. SebaharP.R., Willardsen J.A., Andersen M.B. Anticancer Agents: VTA or VDA// Curr. Bioac. Comp. 2009. V. 5. No 1. P. 79-97 (19). DOI: 10.2174/157340709787580919.
6. Levy O., Erez M., Varon D., Keinan E. A new class of antiarrhythmic-defibrillatory agents // Bioorg. Med. Chem. Lett. 2001. V. 11. P. 2921-2926. DOI: 10.1016/S0960-894X(01)00588-1.
7. Apricio P.M., Terain J.L., Gnecco D., Galindo A. Application of amide-stabilized sulfur ylide reactivity to the stereodivergent synthesis of (R, S)-and (S, R)-reboxetine// Tetrahedron: Asymmetry. 2009. V. 20. Issue 23. P. 2764-2768. DOI: 10.1016/j.tetasy.2009.12.004.
8. Assaf G., Cansell G., Critcher D., Field S., Hayes S., Mathew S., Pettuman A. Application of a process friendly morfoline synthesis to (S, S)-Rebo-xetine// Tetrahedron Lett. 2010. V. 51. Issue 38. P. 5048-5051. DOI: 10.1016/j.-tetlet.2010.07.106.
9. Kislitcyn A.N., Kablukova I.N., Trofimov A.N. O himizme zhidko-faznogo okisleniia a-pinena kislo-rodom vozduha // Himiia rastitelnogo Syria. 2004. Vyp.3. S.109-116.
10. Andres J.M., Pedrosa R., Perez-Encabo A. Synthesis of Enantioenriched 2- and 2,6-Substituted Pi-peridin-3-ols from a-Dibenzylamino Aldehydes// Eur. J. Org. Chem. 2007. P. 1803-1810. DOI: 10.1002/ejoc. 200601009.
11. Raghavan S., Mustata S. N-Cbz sulfilimines as valuable intramolecular nucleophiles for the stereoselective synthesis of (-)-deoxocassine and (+)-desoxo-prosophylline // Tetrahedron. 2008. V. 64. Is. 43. P. 10055-10061. DOI: 10.1016/j.tet.2008.08.031.
12. Pierre-Yves Geant, Erwann Grenet, Jean Martinez, Xavier J. Salom-Roig. Stereoselective divergent synthesis of 1,2-aminoalcohol- containing hetero-cyclens from a common chiral nonracemic building block// Tetrahedron: Asymmetry. 2015. DOI: 10.1016/j.tetasy.2015.11.008.
13. Geant P.-Y., Martinez J., Salom-Roig A Route to "all-cis" 2-Methyl-6-Substituted Piperidin-3-ol Alkaloids from syn-(2R,l'S)-2-(l-Dibenzylamino-methyl)epoxide: Rapid Total Synthesis of (+)-Deoxocassine //Eur. J. Org. Chem. 2012. V. 2012. Is. l.P. 62-65. DOI: 10.1002/ejoc.201101333.
14. Donohoe T.J., Callens C.A.K., Flores A., Lacy A.R., Rathi A.H. Recent Developments in Methodology for the Direct Oxyamination of Olefins // Chem. Eur. J. 2011. V. 17. Is. 1. P. 58-76. DOI: 10.1002/ chem.201002323.
15. Lu D.F., Zhu C.L., Jia Z.X., Xu H. Iron(II)-Catalyzed Intermolecular Amino-Oxygenation of Olefins through the N-0 Bond Cleavage of Function-alized Hydroxylamines//J. Am. Chem. Soc. 2014. V. 136. No 38. P.13186-13189. DOI: 10.1021.
16. Christie S.D.R., Warrington A.D. Osmium and palladium: Comple-mentary metals in alkene activation and exidation// Synthesis. 2008. Iss. 9. P. 1325-1341. DOI: 10.1055/s-2008-1067031.
17. Bruncko M., Schlingloff G., Sharpless K.B. Palladium-Catalyzed Additions of Alkenyl Epoxides to Pronucleophiles: A Synthesis of the Macrolactam Aglycone of Fluviricin B1 // Angew. Chem. Int. Ed. Engl. 1997. V. 36. Iss. 13-14. P. 1483-1486. DOI: 10.1002/anie. 199-714831.
18. Kazuki Miyazawa, Takashi Koike and Munetaka Akita. Regiospecific Intermolecular Aminohy-droxylation of Olefins by Photoredox Catalysis// Chem. Eur. J. 2015. V. 21. P. 11677-11680. DOI: 10.1002/chem. 201501590.
19. Zsolt Szakonyi, Timea Gonda, Sandor Balazs Ot-vos, Ferenc Ftilop. Stereoselective syntheses and
transformations of chiral 1,3-amino-alcohols and 1,3-diols derived from nopinone// Tetrahedron: Asymmetry. 2014. V. 25. P. 1138-1145. DOI: 10.1016/j.tetasy.2014.06.017.
20. Fernandes F.S., Fernandes T.S., Silvers L.S., Caneclii W.. Lorench M.C.S.. Diniz C.G.. de Oliveira P.F., Martins S.P.L., Pereira D.E., Tavares D.C., Le Hyaric M.j de Almeida M.V., Cour M.R.C. Synthesis and evaluation of antibacterial and antitumor activities of new galactopyranosylated amino alcohols // Eur. J. Medicinal" Chem. 2016. V. 108. P. 203-210.
21. Sadygov O. A., Alimardanov Kit. M., Abbasov M. F.. Synthesis of Halohydrines of 5-Alkvlbicy-clo[2.2.1]heptene Series Using the Systems Inducing Electrophilic Reagents // Russian J. General Chem. 2009. V. 79. No 8. P. 1698-1703. DOI: 10.1134/S10-70363209080192.
22. Veliev M.G., Sadygov O.A., Alimardanov Kh.Vl.. Sliatirova M.I. Hypolialogenation of vinyl- and allyl-acetylenes and some chemical transformations of the
products //Russian J. Org. Chem 2007. V. 43. Iss. 11. P. 1604-1611. DOI: 10.1134/S 10-70 428007110036; Hypolialogenation of functionally sybstituted acetylen-ic notbomenes ft Russian J. Org. Chem. 2008. V. 44. Is. 9. P. 1282-1290. D01:10.1134/S1070428008090066.
23. Osokin Iu.G., lablonskii O.P., Lapuka L.F. Os-novnoi organicheskii sintez i neñehimiia: Mezh-vuz. sb. nauch. tr. L.: Izd-vo LTI. 1979. Vyp. 11. S. 55-62.
24. Dobroserdova LB., Anisimov A.B. Praktikiun po nefteliimicheskomu sintezu. M: MGU, 1981. 109 s.
25. Shrainer R.t F lu/on D., Morrill T. ldentifikatciia organicheskikh soedinenii. M.: Mir. 1983. 703 s.
26. Kross A. Vvedenie v prakticheskuiu infrakrasnuiu spektroskopii. \1: Mir. 1967. 279 s.
27. Larkin P.J. Infrared and roman spectroscopy principal and spectral interpretation Stamford. Elsevier. 2011,230 p.
28. Deroum E. Sovremennye metody I AMR dlia hi-micheskikliissledovanii. M.: Mir, 1992. 410 s.
ALKlL- ve ALKENÍLTSÍKLOHEKSENLBRIN OKS I H A LOG EN ЬЭЗ М as í MaHSUL LARl va Cj, C4 ALÍFATÍK AMÍNLaRÍN aSASINDA AMÍNSPÍRTLaRlN SÍNTEZÍ
Ö.a.Sadiqov, H.M.alimardanov, §.l.ismayilova
Alkil va alkcniltsiklolickscnlorin liidroksixlor(brom)idbri osasinda amintsikloheksanollarm sintezi aparilnusdir, Tsik-loolefin + oksidlosdirici + Hlial sistcmindo oksidlosmo prosesi aktiv elektrofil intennediatimn HOX (X = CI, Br) in-duksi\ alasnus "in situ" yaramnasi Иэ bas verir \ э sonraki marhsbda aktiv elektrofil intennediatimn substratin ildqat rabitosino bidosmosindon müvafiq hidroksihalogenidbr этэЬ golir Kalium hidroksidin istiraki ib halogen atomlarimn amin qruplari ib o\o/ edil mos i no ti cos indo müvafiq aminspirtbr alimr.
Agar sözfor amintsikloheksanollar, sintez, alkil- Щ alkenilhidroksixlor(brom)heksanollar.
СИНТЕЗ АМИНОСПИРТОВ НА ОСНОВЕ ПРОДУКТОВ ОКСИГАЛОГЕННРОВАНИЯ АЛКНЛЦИКЛОГЕКСЕНОВ И С3,С4 АЛИФАТИЧЕСКИХ АМИНОВ
О.А.Садыгов, Х.М.Алимарданов, Ш.ИИсмаилова
Предлагается синтез аминоциклогексанолов через стадии гидроксихлор(бром)ирования алкил- и алкенилцикло-гексеиов в системе: ц и к л о о л с ф и н+о к ис л итс л ь+Н lia 1, Показано, что процесс окисления индуцируется электро-фильными интермедиатами НОХ, (Х=С1.Вг), которые в "in situ" режиме присоединяются к кратной связи субстратов образованием соответствующих гидроксигалогенидов. Замещение атомов галогена на аминогруппы с участием гидроксида калия приводит к соответствующим аминоспиртам.
Ключевые слова: аминоциклогексаколы, синтез, алкил- и алкенилгидроксихлор(бром)циклогексанолы.