One-Pot Synthesis of N-Substituted Alkylaminocyclohexanols by the Addition of Electrophiles Formed in situ in the System Н2О2 + HBr (HCl)

Article abstract of DOI:10.1134/S1070363218040072

Highly selective one-pot synthesis of N-substituted aminocyclohexanols has been performed by hydroxyhalogenation of the corresponding cyclohexenes with electrophilic reagents formed in situ in the system Н₂О₂ + HHlg (Hlg = Cl, Br), with subsequent substitution of halogen atoms with amines. Some products were tested as antimicrobial additives to motor oils and cooling lubricants and showed high antibacterial and antifungal activity.

Full text of DOI:10.1134/S1070363218040072

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 4, pp. 650–657. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © О.А. Sadygov, Kh.М. Alimardanov, Sh.I. Ismailova, N.R. Babaev, 2018, published in Zhurnal Obshchei Khimii, 2018, Vol. 88,
No. 4, pp. 566–573.
One-Pot Synthesis of N-Substituted Alkylaminocyclohexanols
by the Addition of Electrophiles Formed in situ
in the System Н О + HBr (HCl)
2
2
a
a
a
a
О. А. Sadygov *, Kh. М. Alimardanov , Sh. I. Ismailova , and N. R. Babaev
a
Mammadaliyev Institute of Petrochemical Processes, Azerbaijan National Academy of Sciences,
Hojaly ave. 30, Baku, AZ 1025 Azerbaijan
*
e-mail: оmar.sadiqov@gmail.com
Received November 2, 2017
Abstract—Highly selective one-pot synthesis of N-substituted aminocyclohexanols has been performed by
hydroxyhalogenation of the corresponding cyclohexenes with electrophilic reagents formed in situ in the
system Н О + HHlg (Hlg = Cl, Br), with subsequent substitution of halogen atoms with amines. Some
2 2
products were tested as antimicrobial additives to motor oils and cooling lubricants and showed high
antibacterial and antifungal activity.
Keywords: hydroxyhalogenation; electrophilic intermediates; aminocyclohexanols; alicyclic aminoalcohols
DOI: 10.1134/S1070363218040072
Acyclic aminoalcohols possess unique properties
and are used as reagents in the synthesis of numerous
analogs of complex natural and biologically active
compounds [1–3]. Monocyclic aminoalcohols of
cyclohexane series and their N- and O-substituted
derivatives are fragments of some synthetic pharma-
ceuticals possessing sedative, antispasmodic, analgesic,
and local anesthetic properties. Thus, a number of
vicinal aminoalcohols containing a piperidine motif
were used for preparation of widely used multifunc-
tional drugs [4–6]. A general method for the synthesis
of cyclic aminoalcohols of a given structure is the
aminolysis of epoxide compounds with nitrogen-
containing nucleophilic reagents [2]. In this case the
synthesis of aminoalcohols is performed by successive
epoxidation of cycloolefins with peroxoacids or organic
hydroperoxides, isolation of the obtained epoxides, and
their reaction with amines in acidic or basic media.
Earlier, we have shown that HCl or HBr solutions
of low concentration in the presence of Н О or NaOCl
2
2
are effective hydroxyhalogenating reagents for vinyl-
and allylacetylene, as well as mono- and bicyclic
unsaturated compounds [7–9]. In particular, it was
established that alkylcyclohexenes under mild condi-
tions (30–50°С) selectively add electrophiles formed
in the system H O (or NaOCl)–НХ (8–15% aqueous
2
2
solution), as shown in Scheme 1.
It is known that the course of the oxirane ring
opening is determined by conformational effects and
the reaction proceeds predominantly in trans-diaxial
manner. The regularities of electrophilic addition were
investigated by the example of the model reaction of
4
1
-methylcyclohexene or 1-(cyclohex-1-en-1-yl)ethan-
-one with a pre-prepared solution of HOX (X = Cl,
Br) [7]. According to IR spectroscopy data [2], the
addition of HOX to the double bond of cycloolefins
occurs to the diaxial trans position. The addition of
electrophilic halogen in this case is apparently con-
trolled by the location of the substituent and by
structural-conformational orientation, similar to the
nucleophilic oxirane ring opening according to the Fürst-
Plattner rule [2].
The present article describes the preparation of
vicinal aminoalcohols by hydrohyhalogenation of cyclo-
hexene derivatives with electrophilic reagents formed
in situ in the system Н О –НХ (X = Cl, Br) with
2
2
subsequent treatment of the formed products with
primary or secondary amines without isolation from
the reaction mixture.
6
50

ONE-POT SYNTHESIS OF N-SUBSTITUTED ALKYLAMINOCYCLOHEXANOLS
651
Scheme 1.
2
HX
X + H O
2
2
H O
+
2
2
HX
+
O
_
_
+
_
_
H
O
O
H
H
O
H X
HO X
_
H O
2
HX
H
R
X+
X+
R
X
R
R
1
a_1c
_
_
O
O
O
H
H
H
R
R
X
OH
+
OH
X
_
_
2d 2f
2
3
a 2c
_
_
3d 3f
а 3c
(а, d), COCH
X= Cl (2), Br (3); R = 1-CH
3
3
(b, e), CH=CH (c, f).
2
To optimize the reaction conditions, we have
The obtained results show that for molar ratio
studied the dependence of the yield of compounds 2а–
substrate : НХ : Н О (NaOCl) = 1 : 1–1.5 : 1–5 and
2
2
2
c and 3а–3c on the temperature, concentration of
the use of 8–15% solutions of hydrohalogenic acids
the yields of products 2а–2c and 3а–3c are maximal
reaching 69–80%. For HCl concentration less than
10% products 2а–2c and 3а–3c are not formed.
aqueous solutions of hydrohalogenic acids, molar ratio
of the components, and the rate of stirring of hetero-
geneous reaction mass. The formation of electrophilic
intermediate occur in aqueous phase, while hydroxy-
halogenation of cycloolefins, in organic phase or at the
boundary between the phases. Without vigorous
stirring the transition of electrophilic intermediate from
aqueous to organic phase is hindered, which lowers the
yield of the target products 2а–2c and 3а–3c. There-
fore, all experiments were carried out at vigorous stirring.
Addition of 3–5 wt % of metal chloride MeCl (Ме =
n
Na, K, Co; n = 1, 2) increases the yield of the target
products by 8–12%. The yield of hydroxyhalides
increases when the temperature rises to 30–50°С
reaching 72–80.5% for hydroxychlorides and 64–
75.4% for hydroxybromides. It is not recommended to
increase the temperature above 50°С because of the
increased rate of decomposition of the electrophilic
intermediate with the formation of molecular chlorine
or bromine, and accumulation in the products of the
reaction, along with hydroxyhalogenides, of up to 25–
In the system under investigation the formation of
electrophilic intermediates is reversible, while their
addition to the double bond of the substrate is
irreversible. It is worth noting that no induced
hydroxyhalogenation of cycloolefins occurs in the
absence of Н О or NaOCl, since HX does not add to
3
5% of dichloro(dibromo)derivatives.
Substitution of halogen atoms by primary or
2
2
the double bond of the substrate in a dilute solution.
secondary aminogroups in products 2а–2c and 3а–3c
was performed without isolation from the reaction
mixture to afford the corresponding alkylaminocyclo-
hexanols 4а–4e–6а–6e and their isomers 7а–7e–9а–9e
(Scheme 2).
The role of Н О in this reaction consists in intensifica-
2
2
tion of formation of active electrophilic substrate,
which then irreversibly adds to the double bond of the
substrate until full consumption of the oxidant.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

6
52
SADYGOV et al.
Scheme 2.
H
H
_
_
R1
R1
2
3
a 2f
Δ, OH
NR R3
2
OH
+ HNR2R3
_
+
a 3f
_HX
NR R3
2
OH
H
H
_
4
a_6e
7a 9e
2 5 2 2 2
OH (b), (–CH –) (c), (–CH CH –) O (d);
1
2
3
2
3
R = 1-CH
3
(4, 7), COCH
(e).
3
(5, 8), CH=CH
2
(6, 9); R = R = C
2
H
5
(а), R + R = CH
2
CH
2
2
3
6 5
R = H, R = C H
The main factors affecting the course of the reaction
of hydroxychloro(bromo)derivatives and the yield of
N-substituted cyclohexanols are the temperature of the
reaction and pH of the medium. At 40–50°С after 3–
yields of aminoalcohols of 92.0–96.4% are reached at
рН = 9.8–10.2, the temperature of 50–60°С, and the
reaction time 5–6 h. Lowering the pH to 8.0–8.5
notably decreases the rate of condensation because
amines form ammonium salts with the formed HBr or
HCl.
5
h primary and secondary alkylamines readily enter
the reaction of substitution with hydroxychloro(bromo)
derivatives 2а–2f and 3а–3f with the formation of the
corresponding N-substituted cyclohexanols 4а–4e–6а–
The selectivity and the yield of aminoalcohols is
higher in the reactions of amines with hydroxy-
bromides than with hydroxychlorides.
6
e and 7а–7e–9а–9e. The results of investigation of the
effect of temperature and pH of the medium on the
selectivity of reactions of 2-chloro-1-methylcyclo-
hexan-1-ol 2а and 1-(1-bromo-2-hydroxycyclohexyl)
ethan-1-one 3b with piperidine are summarized in
Table 1. It is clearly seen that the reactions effectively
proceed at 40–60°С and the pH of the medium of 9.8–
We have examined the reaction of aminolysis of
1,3
3-ethenyl-7-oxabicyclo[4.1.0 ]heptane with piperidine
in the temperature range 70–120°С with participation
of MgBr . The highest yield of isomers 4- (6c) and
2
5-ethenyl-2-(piperidin-1-yl)cyclohexan-1-ol (9c) is
reached at the temperature of 110–120°С and рН 5.5–
1
0.2. It is recommended to carry out the reactions of
amines with hydroxyhalogenides with excess of amine
1 : 1.5–2.5), which allows to reach a full conversion
1
6.3 (42.5–47.3%). IR and Н NMR spectra of the
(
synthesized compound practically coincide with those
of the product of condensation of 2-bromo-5-ethenyl-
cyclohexan-1-ol 3c with piperidine.
and simplifies the isolation of the target product.
The course of the reaction strongly depends on the
basicity of the medium. At pH above 10.2 the rate of
dehydrohalogenation of hydroxyhalides to the corres-
ponding oxiranes increases but the yield of amino-
alcohols strongly decreases due to lowering the rate of
aminolysis of the latter under these conditions. High
The oxirane ring opening proceeds regioselectively,
by the Krasusky rule [2], with preferable formation of
isomer 9c, 6c : 9c = (32–35) : (65–68). In contrast to
aminolysis of the aforementioned oxirane, the
condensation of 2-bromo-4-ethenylcyclohexan-1-ol 3c
Table 1. Selectivity and yield of aminoalcohol in the reaction of 2-chloro-2-methylcyclohexan-1-ol (2а) and 1-(1-bromo-2-
a
hydroxycyclohexyl)ethan-1-one (3b) with piperidine
Exp. no.
T, °С
рН
Reaction time, h
Selectivity, %
Yield, %
1
2
3
4
5
6
7
8
40
50
60
70
50
60
70
60
8.5
7.5
7.0
7.0
9.8
9.8
9.8
10.2
10.0
8.5
7.5
7.0
6.0
6.0
6.0
6.5
–
–
–
–
–
–
–
–
97.5/96.0
97.3/97.0
92/90.5
98.0/97.5
93.5/92.6
94.6/95.4
71.4/70.5
96.4/96.6
a
2 3
Molar ratio 1 : (1.1–1.2), 0.05 mol/L (2a), 0.05 mol/L (3b), 50 mL of propan-2-ol, K СО
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

ONE-POT SYNTHESIS OF N-SUBSTITUTED ALKYLAMINOCYCLOHEXANOLS
653
a
Table 2. Antimicrobial properties of the synthesized N-substituted cyclohexanols
Diameter of inhibition zone, cm
Comp. no. Concentration,
Oil М-10
Azerol-5
bacteria mixture
wt %
bacteria mixture
fungi mixture
fungi mixture
6
6
а
1.0
+ +
+ +
+ +
1.4–1.6
1.3–1.5
+ +
1.2–1.2
+ +
1.6–1.8
1.4–1.6
1.0–1.2
0
0
.5
.25
+ +
b
1.0
0.7–0.9
+ +
+ +
1.4–1.2
1.2–1.3
+ +
2.0–2.2
1.4–1.6
1.2–1.2
+ +
+ +
+ +
0
0
.5
.25
6
c
1.0
0.8–0.6
0.6–0.6
+ +
1.6–1.8
+ +
+ +
2.0–2.2
1.8–2.0
1.2–1.4
1.4–1.6
1.2–1.4
1.0–1.0
0
0
.5
.25
6
d
1.0
1.0–0.8
0.8–0.8
+ +
2.0–2.0
1.6–1.8
1.2–1.4
2.2–2.4
2.0–1.8
1.4–1.6
+ +
+ +
+ +
0
0
.5
.25
6
e
1.0
2.0–1.8
1.3–1.7
0.8–0.6
1.8–1.6
1.1–1.3
0.8–0.8
1.4–1.6
1.2–1.4
1.0–0.8
1.2–1.4
1.0–1.2
+ +
0
0
.5
.25
a
(
“+”) full absence of the zone of inhibition of microorganisms growth.
with piperidine leads predominantly to another isomer.
The ratio 6c : 9c = (84–87) : (13–16) practically cor-
responds to the isomeric ratio of the original halohydrine.
and careful rectification of the product. 1-Cyclo-
hexenylethanone was prepared by acylation of
cyclohexene with acetyl chloride [7], 4-vinylcyclo-
hexene, by dimerization of buta-1,3-diene by the
known procedure [10]. Commercially available amines
The synthesized N-alkylderivatives of alkylcyclo-
hexanols were tested as antimicrobial additives to
motor oils М8, М10 and emulsion cooling lubricant
Azerol-5, which are not bioresistant. The obtained
results show that some representatives of this class of
compounds (6а–6e) in concentration of 1.0–0.25%
demonstrate the activity and protecting properties
(
Аlfa Aesar) were used. Hydroxychloro(bromo)alkyl-
cyclohexanes were obtained by the earlier elaborated
procedure [7–9].
From the GC analysis, the products of the reaction
of hydroxyhalogenation of cyclohexene derivatives
and of aminolysis of chloro(bromo)hydroxyhalo-
genides are the corresponding mixtures of two isomers
2а–2c, 2d–2f and 3а–3c, 3d–3f, 4а–6e and 7а–9e. The
isomeric composition was determined by GC analysis.
(
Table 2).
EXPERIMENTAL
IR spectra of the synthesized compounds were
taken on a Fourier spectrometer Alpha in the range 400–
2
-Chloro-1(2)-methylcyclohexan-1-ol (2а, 2d)
–
1
was obtained from 9.6 g (0.1 mol) of 1-methyl-
cyclohex-1-ene (1а). Yield 11 g (74.1%), the ratio of
isomers 2а : 2d = 84 : 16, bp 110–112°С (10 mmHg).
4
000 cm from suspensions in mineral oil or KBr
1
13
pellets. H and C NMR spectra were registered on a
Bruker 300 spectrometer with working frequency
–
1
1
IR spectrum, ν, cm : 3486 (ОН), 2950 (СН
2
), 2870
3
00.18 MHz ( Н) in CDCl , internal reference HMDS.
3
1
(
СН ), 1460 (СН ), 1115 (ОН), 780, 760 (CCl). Н
3
2
Elemental analysis was performed on a TruSpes Micro
Leco Corporation analyzer (USA). GC analysis was
done on a Tsvet-100 chromatograph, detector: katharo-
meter, column 2000×4 mm, 10% poly(ethylene glycol
succinate) on Сhromasorb W, gas-carrier helium, oven
temperature 150°С.
3
–6
NMR spectrum, δ, ppm: 1.41–1.78 m (8Н, Н ), 1.65
s (3Н, СН , 2а), 1.27 s (3Н, СН , 2d), 4.46 t (1Н,
НССl, J = 7.2 Hz, 2а), 3.46 t (1Н, НСОН, J = 7.1 Hz,
d), 3.62 br.s (1Н, НОССН , 2а), 3.55 br.s (1Н,
НСОН, 2d). С NMR spectrum, δ , ppm: 83.0 (С ),
2.4 (С ), 37.4 (С ), 30.7 (СН ), 28.9 (С ), 23.7 (С ),
3
3
2
3
1
3
1
C
2
3
6
5
7
3
4
1
-Methylcyclohexene was obtained by dehydration
22.4 (С ). Found, % С 56.35; Н 8.86; Cl 23.77.
С Н ClО. Calculated, %: С 56.56; Н 8.75; Cl 23.91.
of 2-methylcyclohexanol-1 at 220–250°С over γ-Al O
2
3
7
13
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

6
54
SADYGOV et al.
–
1
2
-Bromo-1(2)-methylcyclohexan-1-ol (3а, 3d)
ν, cm : 3492, 3350 (ОН), 3050 (СН =), 1645 (C=C),
2
1
was prepared from 9.6 g (0.1 mol) of 1-methyl-
cyclohex-1-ene 1а. Yield 13.6 g (69.9%), the ratio of
isomers 3а : 3d = 82 : 18. bp 100–102.6°С (2 mmHg).
Found, %: С 43.25; Н 6.86; Br 41.21. С Н BrО.
1085 (ОН), 550–610 (CBr). Н NMR spectrum, δ,
ppm: 1.33–2.09 m (6Н, СН ), 2.10 q (1Н, Н , J =
6.4 Hz), 3.48 d (1Н, Н , J = 7.3 Hz), 3.56 d (1Н,
НCOH, J = 7.2 Hz), 3.61 br.s (1Н, HОCН), 4.89 d.d
(1Н, Н Н C=CH, J = 10.2, 2.3 Hz), 4.91 d.d (1Н,
Н H C=CH, J = 16.8, 2.2), 5,77 d.d (1Н, НC=CH , J =
6.7, 10.3 Hz). Found, % : С 47.12; Н 6,43; Br 38.71.
5
2
2
7
13
а
b
Calculated, %: С 43.52; Н 6.74; Br 41.45.
-[2(1)-Chloro-1(2)-hydroxycyclohexyl]ethan-1-
one (2b, 2e) was prepared from 3.1 g (25 mmol) of 1-
cyclohexenyl)ethan-1-one 1b. Yield 3.2 g (72.6% ),
the ratio of isomers 2b : 2e = 75 : 25, mp 73–75°С, bp
b
a
2
1
1
С Н BrО. Calculated, %: С 46.83; Н 6.34; Br 39.02.
8
13
(
General procedure for the synthesis of amino-
–
1
1
(
(
29–131°С (2 mmHg). IR spectrum, ν, cm : 3465
ОН), 2960 (СН ), 2855 (СН ), 1731 (С=О), 1450
alcohols from hydroxychlor(brom)ides. To the mix-
ture of 2.97 g (20 mmol) of compound 2а or 3.86 g
(20 mmol) of 3а 0.1 g KОН and 50–100 mL of
2-propanol was added. The mixture was heated for 1–
.5 h at 60–70°С with constant dropwise addition of
.1 mol of amine. The reaction was monitored by GC
(5–6 h). The formed precipitate was filtered, washed
with 2-propanol, dried and crystallized from the
mixture 2-propanol–water (2.5 : 1).
2
3
1
СН ), 1100 (ОН) 780, 760 (CCl). Н NMR spectrum,
2
δ, ppm: 1.45–1.98 m (8Н, CH ), 2.15 s (3Н, СН С=О),
.68 br.s (1Н, CН), 3.61 d.d (1Н, НCОН, J = 10.8,
.2 Hz); Found, %: С 54.54; Н 7.45; Cl 19.97.
2
3
3
7
1
0
С Н ClО . Calculated, %: С 54.39; Н 7.36; Cl 20.11.
8
13
2
1
-[2(1)-Bromo-1(2)-hydroxycyclohexyl]ethan-1-
one (3b, 3e) was prepared from 3.1 g (25 mmol) of 1-
cyclohexenyl)ethan-1-one 1b. Yield 4.2 g (76%), the
ratio of isomers 3b : 3e = 83 : 17. mp 101–103.6°С, bp
(
2
-(Diethylamino)-1(2)-methylcyclohexan-1-ol
4а, 7а) was prepared from 2.97 g (20 mmol) of the
mixture of isomers 2а and 2d or 3.86 g (20 mmol) 3а
and 3d and 3.3 g (45 mmol) of diethylamine. Yield
.1 g (56.7%, from 2а, 2d), 2.3 g (62.2% from 3а, 3d),
the ratio of isomers 4а : 7а = 83 : 17, mp 59–61°С, bp
27–129°С (2 mmHg). IR spectrum, ν, cm : 3496
ОН), 3340, 3236 (CN), 2960 (СН ), 2855 (СН ),
666, 1658 (NC), 1460 (CH ), 1128, 1110 (ОН). Н
2
NMR spectrum, δ, ppm: 1.13 t [6Н, N(CH CH ) , J =
.2 Hz], 1.23–1.77 m (8Н, СН ), 1.28 s (3H, CH , 4а),
.39 s (3H, CH , 7а), 2.44 d [4Н, N(CH CH ) , J =
.3 Hz], 2.66 d [1Н, НCN, J = 7.2 Hz], 3.37 d (1Н,
НCOH, J = 7.0 Hz), 3.61 br.s (1Н, ОН). Found, %: С
0.86; Н 12.61; N 7.39. С Н NО. Calculated, %: С
1.35; Н 12.43; N 7.57.
(
–
1
1
(
(
46–148°С (1.5 mmHg). IR spectrum, ν, cm : 3480
ОН), 2845 (СН ), 2860 (СН ) 1730 (С=О), 1470
3
2
1
СН ), 1345 (СН) 1100 (ОН), 560–610 (CBr). Н
2
2
NMR spectrum, δ, ppm: 1.40–2.0 m (8Н, CH , 3b),
.45–1.76 m (6Н, 3CH , 3e), 2.05–2.31 m (2Н, CH , 3e),
.15 s (3Н, СН С=О), 3.56 br.s (1Н, HОC H COCH ,
e), 3.63 br.s (1Н, HОHC H , 3b), 3.83 t (1Н, НCBr,
J = 7.2 Hz, 3e), 3.71 t (1Н, НC H ОН, J = 7.1 Hz, 3b);
Found, %: С 43.16; Н 5.93; Br 35.84. С Н BrО .
2
1
2
3
–1
2
2
1
3
6
9
3
(
1
3
2
1
6
8
6
8
2
3 2
8
13
2
8
1
8
2 3
Calculated, %: С 43.44; Н 5.88; Br 36.20.
-Chloro-5(4)-ethenylcyclohexan-1-ol (2c, 2f) was
prepared from 2.7 g (25 mmol) of 4-ethenylcyclohex-
3
2
3 2
2
7
7
1
2
-ene 1c. Yield 2.7 g (67.3%), the ratio of isomers 2c :
f = 65 : 34. bp 112–114°С (3 mmHg). IR spectrum, ν,
11 23
–
1
cm : 3485, 3360 (ОН), 3080, 3050 (СН ), 1640
2
2
-[Bis(2-hydroxyethyl)amino]-1(2)-methylcyclo-
hexan-1-ol (4b, 7b) was prepared from 2.97 g
20 mmol) of the mixture of isomers 2а and 2d or
.86 g (20 mmol) 3а and 3d and 4.73 g (45 mmol) of
diethylamine. Yield 2.1 g (48.4%, from 2a, 2d), 2.3 g
55.0%, from 3a, 3d), the ratio of isomers 4b : 7b =
2 : 18, mp 178–180°С. IR spectrum, ν, cm : 3482
ОН), 3360, 3254 (CN), 2965 (СН ), 2855 (СН ),
666, 1558 (СN), 1145, 1085 (ОН). Н NMR
spectrum, δ, ppm: 1.15–1.76 m (8Н, CH ), 1.31 s (3H,
(
С=C), 1460 (CH ), 1125, 1095 (ОН), 780, 760 (CCl).
Н NMR spectrum, δ, ppm: 1.33–1.89 m (6Н, 3СН2),
.14 q (1Н, НС Н СН=СН , J = 6.8 Hz), 3.49 t (1Н,
2
1
(
3
2
6 8 2
НCOH, J = 7.3 Hz), 3.54 d (1Н, НС(Cl)OH, J =
.2 Hz), 3.61 br.s (1Н, HОCН), 4.89 d.d (1Н,
7
(
8
а
b
Н Н C=CH, J = 10.2, 2.3 Hz), 4.91 d.d (1Н,
–1
b
a
Н H C=CH, J = 16.8, 2.2 Hz), 5.77 d.d (1Н, НC=CH ,
2
(
1
3
2
J = 16.7, 10.3 Hz). Found, %: С 59.56; Н 7.9; Cl
2.37. С Н ClО. Calculated, %: С 59.81; Н 8.1; Cl 22.12.
1
2
8 13
2
2
-Bromo-5(4)-ethenylcyclohexan-1-ol (3c, 3f) was
CH C H OH), 2.57 t [4Н, N(CH ) , J = 7.2 Hz], 2.67 t
3
6
9
2 2
prepared from 2.7 g (25 mmol) of 4-ethenylcyclohex-
[1Н, НС H N, J = 7.1 Hz], 3.65 t [4Н, N(CН CH OH) ,
6
8
2
2
2
1
3
-ene 1c. Yield 3.3 g (64.7%), the ratio of isomers 3c :
f = 61 : 39. bp 123–125.5°С (4 mmHg). IR spectrum,
J = 7.2 Hz), 3.68 br.s (3Н, 2CH ОН + CH C Н OH,
4b), 3.59 br.s (CH C Н OH). Found, %: С 60.25; Н
3 6 9
2 3 6 9
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

ONE-POT SYNTHESIS OF N-SUBSTITUTED ALKYLAMINOCYCLOHEXANOLS
655
1
1
0.71; N 6.34. С Н NО . Calculated, %: С 60.83; Н
(20 mmol) of the mixture of isomers 2b and 2d or
4.42 g (20 mmol) of 3b and 3d and 2.9 g (40 mmol) of
diethylamine. Yield 2.6 g (61.0%, from 2b, 2e), 2.7 g
1
1
23
3
0.6; N 6.45.
(2)-Methyl-2-(piperidin-1-yl)cyclohexan-1-ol
4c, 7c) was prepared from 2.97 g (20 mmol) of the
1
(
7
63.4%, from 3b, 3e), the ratio of isomers 5а : 8а =
8 : 28, mp 119–121.5°С. IR spectrum, ν, cm : 3490
(
–
1
mixture of isomers 2а and 2d or 3.86 (20 mmol) of 3а
and 3d and 3.9 g (45 mmol) of piperidine. Yield 2.8 g
(
ОН), 3365, 3320, (СN), 2960 (СН ), 2855 (СН ),
3 2
2
849 (СН), 1750, 1723 (C=O), 1660, 1580 (CN), 1395
(
71.1%, from 2a, 2d), 3.0 g (76.1%, from 3a, 3d), the
1
(
СН), 1120, 1095 (ОН). Н NMR spectrum, δ, ppm:
ratio of isomers 4c : 7c = 75 : 25, mp 84–86°С. IR
spectrum, ν, cm : 3497 (ОН), 3330, 3256 (CN), 2850
–
1
1
2
.05 s [6Н, (CH СН ) N], 1.15–2.23 m (8Н, СН ),
3 2 2 2
1
.15 s (3H, O=CCH , J = 8.1 Hz), 2.43 q [4Н, N
(
СН ), 1560, 1450 (NС), 1115, 1070 (ОН). Н NMR
3
2
(
CH CH ) , J = 8.2 Hz), 3.66 br.s (Н, ОН). Found, %:
spectrum, δ, ppm: 1.13–1.25 m (14Н, CH ), 1.31 s
2 3 2
2
С 67.22; Н 10.43; N 6.25. С Н NО . Calculated, %:
(
3H, CН С Н OH, 7c), 1.39 s (3H, CН С Н OH, 4c),
12 23
2
3
6
8
3
6
8
С 67.61; Н 10.80; N 6.57.
2
.48 t [4Н, N(CH ) , J = 7.2 Hz], 2.67 d [(1Н,
2 2
НС Н N, J = 7.3 Hz, 4c), 3.42 d (1Н, НС Н ОН, J =
6
8
6
8
1
-{2(1)-Bis[(2-hydroxyethyl)amino]-2(1)-hydroxy-
7
1
1
.3 Hz, 7c), 3.60 br.s (1Н, ОН). Found, %: С 72.86; Н
1.88; N 6.93. С Н NО. Calculated, %: С 73.10; Н
cyclohexenyl}ethan-1-one (5b, 8b) was prepared
from 3.53 g of the mixture of isomers 2b and 2e or
.42 g of 3b and 3e and 4.73 g (45 mmol) of
diethanolamine. Yield 2.5 g (51.0%, from 2b, 2e),
2.7 g (55.1%, from 3b, 3e), the ratio of isomers 5b : 8b =
85 : 15, mp 236–238°С. IR spectrum, ν, cm : 3460
(ОН), 3345 (NС), 2960 (СН ), 2855 (СН ), 2849
1
2
23
1.68; N 7.11.
-(Morpholin-4-yl)-1(2)-methylcyclohexan-1-ol
4d, 7d) was prepared from 2.97 g (20 mmol) of the
4
2
(
–
1
mixture of isomers 2а and 2d or 3.86 (20 mmol) 3а
and 3d and 4.35 g (50 mmol) of morpholine. Yield 1.8 g
3
2
(
45.2%, from 2a, 2d), 2.4 g (60.3%, from 3a, d), the
(СН), 1750, 1723 (C=O), 1620, 1596 (NС), 1450
ratio of isomers 4d : 7d = 85 : 15, mp 99–101°С. IR
spectrum, ν, cm : 3493 (ОН), 3375, 3320 (CN), 2950
(СН ), 1110, 1069 (ОН). Found, %: С 57.84; Н 9.56;
2
–
1
N 5.62. С Н NО . Calculated, %: С 58.78; Н 9.39; N
12
23
4
(
1
СН ), 1620, 1596 (СN), 1465 (CH ), 1380 (CH),
240, 1180 (СОС), 1130, 1089 (ОН). Н NMR
5.71.
2
2
1
1
-[1(2)-Hydroxy-2(1)-(piperidin-1-yl)cyclohexyl]-
spectrum, δ, ppm: 1.13–1.25 m (8Н, СН ), 1.31 s (3H,
2
ethan-1-one (5c, 8c) was prepared from 3.53 g of the
mixture of isomers 2b and 2e or 4.42 g 3b and 3eand
CH C H OH, 4d), 1.39 s (3H, CH C H N, 7d), 2.62 t
3
6
9
3
6
9
(
1Н, НC H N, J = 7.1 Hz, 4d), 3.42 t (1H, HC H OH,
6 8 6 8
3
5
2
.8 g (45 mmol) of piperidine. The ratio of isomers
c : 8c = 81 : 19. Yield 2.5 g (55.6%, from 2b, 2e),
J = 7.2 Hz, 7d), 2.69 t [4Н, N(CH ) J = 7.2 Hz], 3.60
2
2
br.s (1Н, ОН), 3.64 t [4Н, О(CH2)2, J = 7.3 Hz],
Found, %: С 65.78; Н 10.76; N 6.83. С Н NО .
.7 g (60.0%, from 3b, 3e), mp 47–49°С. IR spectrum,
1
1
21
2
–1
ν, cm : 3530, 3370 (ОН), 2960 (СН ), 2850 (СН ),
3
2
Calculated, %: С 66.33; Н 10.55; N 7.04.
1
1
6
6
750, 1723 (C=O), 1620, 1596 (NС), 1450 (СН2),
110, 1069 (ОН). Found, %: С 68.76; Н 10.43; N
.16. С Н NО . Calculated, %: С 69.33; Н 10.22; N
2-Anilino-1(2)-methylcyclohexan-1-ol (4e, 7e) was
prepared from 2.97 g (20 mmol) of the mixture of
isomers 2а and 2d or 3.86 (20 mmol) 3а and 3d and
1
3
23
2
.22.
4
.2 g (45 mmol) of aniline. Yield 2.6 g (63.4%, from
1
-[1(2)-Hydroxy-2(1)-(morpholin-4-yl)cyclo-
2
a, 2d), 2.8 g (68.3%, from 3a, 3d), the ratio of
hexyl]ethan-1-one (5d, 8d) was prepared from 3.53 g
of the mixture of isomers 2b and 2e or 4.42 g 3b and
isomers 4d : 7d = 82 : 18, mp 126–128°С. IR
–
1
spectrum, ν, cm : 3486 (ОН), 3370, 3320 (СNН),
890 (СН ), 2849 (СН), 1665, 1580 (NС), 1395, 1350
3
(
e and 3.9 g (45 mmol) of morpholine. Yield 2.4 g
53.4%, from 2b, 2e), 2.7 g (60.1%, from 3b, 3e). The
ratio of isomers 5d : 8d = 80 : 20, mp 160–162°С. IR
2
2
1
(
СН). Н NMR spectrum, δ, ppm: 1.13–1.24 m (8Н,
СН ), 1.31 s (3H, CH C H OH, 4d), 1.53 s (3H,
2
3
6
9
–
1
spectrum, ν, cm : 3510, 3486 (ОН), 3367, 3289 (CN),
CH C H NH, 7d), 2.67 t (1Н, HC H NH, J = 7.2 Hz),
3
6
9
6
8
2
1
950 (СН ), 2855 (СН ), 1750, 1723 (C=O), 1620,
3
4
.42 t (1Н, НC H OH, J = 7.2 Hz), 3.60 br.s (1Н, ОН),
3 2
6
8
596 (NС), 1460 (СН ), 1240, 1120 (СОС) 1115, 1070
.1 br.s (1Н, НN), 6.78–6.85 m (4Н, Ar), 7.25 d (2Н,
2
3
,5
(
ОН). Found, %: С 62.79; Н 9.08; N 5.87. С Н NО .
Н , J = 7.6 Hz). Found, %: С 75.87; Н 9.35; N 6.61.
С Н NО. Calculated, %: С 76.10; Н 9.27; N 6.83.
12 21 3
Calculated, %: С 63.44; Н 9.25; N 6.17.
1
3
19
1
-(1(2)-(Diethylamino)-2(1)-hydrocyclohexenyl)-
1-(2-Anilinohydroxycyclohexyl)ethan-1-one (5e,
ethan-1-one (5а, 8а) was prepared from 3.53 g
8e) was prepared from 3.53 g of the mixture of isomers
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

6
56
SADYGOV et al.
2
b and 2e or 4.42 g of 3b and 3e and 4.21 g (45 mmol)
(45 mmol) of morpholine. Yield 2.2 g (47.4%, from
2c, 2f), 2.5 g (54.5%, from 3c, 3f), the ratio of isomers
6d : 9d = 56 : 44, mp 82–84°С, bp 161–162.5°С
of aniline. Yield 2.2 g (47.6%, from 2b, 2e), 2.5 g
(
53.7%, from 3b, 3e), the ratio of isomers 5e : 8e =
–
1
–1
8
4 : 16, mp 188–190°С. IR spectrum, ν, cm : 3470
(1.5 mmHg). IR spectrum, ν, cm : 3495 (ОН), 3370
(
(
ОН), 3320 (NH), 2867 (СН ), 2680 (NС), 1750, 1723
(CN), 3080, 3050 (CH =), 2850 (СН ), 1645 (C=C),
2
2
2
C=O), 1665 (NС), 1645 (C=С), 1450 (СН ), 1395,
1620, 1596 (СN),1450 (СН ), 1240, 1123 (COC),
2
2
1
5
350 (CH), 1145 (ОН). Found, %: С 71.95; Н 8.25; N
.84. С Н NО . Calculated, %: С 72.10; Н 8.15; N 6.0.
1110, 1082 (ОН). Found, %: С 67.93; Н 10.22; N 6.58.
С Н NО . Calculated, %: С 68.25; Н 9.95; N 6.63.
14
19
2
12 21
2
2
-Diethylamino-5(4)-ethenylcyclohexan-1-ol (6а,
2
-Anilino-5(4)-ethenylcyclohexan-1-ol (6e, 9e)
9
а) was prepared from 3.21 g (20 mmol) of 2c and 2f
or 4.1 g (20 mmol) of 3c and 3f and 2.9 g (40 mmol) of
diethylamine. Yield 2.2 g (56.5%, from 2c, 2f), 2.4 g
was prepared from 3.21 g of the mixture of isomers 2c
and 2f or 4.1 g of 3c and 3f and 4.2 g (45mmol) of
aniline. Yield 3.1 g (71.4%, from 2c, 2f), 2.2 g (50.7%,
from 3c, 3f), the ratio of isomers 6e : 9e = 54 : 46, bp
08–110°С (1.5 mmHg). IR spectrum, ν, cm : 3480
OН), 3350 (NН), 3050 (CH =), 2950 (СН ), 2680,
665 (СN), 1640 (C=C), 1350, 1280 (ArN), 1110
ОН). Found, %: С 77.03; Н 8.93; N 6.37. С Н NО.
Calculated, %: С 77.42; Н 8.76; N 6.45.
(
8
61.4%, from 3c, 3f), the ratio of isomers 6а : 9а =
4 : 16, bp 130–131.5°С (1.5 mmHg). IR spectrum, ν,
–1
1
(
1
(
–
1
cm : 3530, 3480 (ОН), 3370 (CN), 3050 (СН =),
2
2 2
2
1
960 (СН ), 2855 (СН ), 2849 (СН), 1640 (C=O),
450 (СН ), 1380, 1340 (СН), 1115, 1075 (ОН). Н
NMR spectrum, δ, ppm: 1.11 s [6Н, (CH СН ) N],
.34–1.78 m (6Н, 3СН ), 2.15 d.d (1Н, Н , J = 6.3,
.2 Hz), 2.43 d [2H, N(CH CH ) ], 2.68 q (1H, H , J =
.3 Hz), 3.45 d (1H, H , J = 7.3 Hz), 3.67 br.s (Н,
ОН), 4.91 d.d (1H, H , J = 2.3, 10.4 Hz), 4.96 d.d
1H, H , J = 2.3, 16.5 Hz), 5.78 d.d (1H, H , J = 6.3,
6.7 Hz). Found, %: С 72.84; Н 11.83; N 6.91.
3 2
1
2
14 19
3
2 2
5
1
7
7
2
1
2
3 2
General procedure for testing antimicrobial
activity of aminoalcohols. Antimicrobial activity of
the synthesized compounds 4а–6e was determined by
GOST 9.052-88 and 9.082-77. As test cultures,
bacterial (Mycobacterium lacticolum, Pseudomonas
aeruginosa), fungi (Aspergillus niger, Cladosporium-
resinae) and yeast microorganisms (Candida
tropicalis) were used. The microorganisms were
cultivated at 28±2°С in special thermostat with 90–
100% humidity: fungi for 5–7 days, bacteria for 2–
3 days. As nutrients for bacteria meat-extract agar, for
fungi and yeast cultures wort agar were used. As
reference compounds, 8-oxyquinoline and sodium
pentachlorophenolate were used. The results of tests
are presented in Table 2.
1
8
а
8
b
7
(
1
С Н NО. Calculated, %: С 73.10; Н 11.68; N 7.10.
1
2
23
2
-[Bis(2-hydroxyethyl)amino]-5(4)-ethenylcyclo-
hexan-1-ol (6b, 9b) was prepared from 3.21 g of the
mixture of isomers 2c and 2f or 4.1 g of 3c and 3f and
.9 g (40 mmol) of diethanolamine. Yield 1.9 g
41.5%, from 2c, 2f), 2.1 g (45.8%, from 3c, 3f), the
ratio of isomers 6b : 9b = 56 : 44, mp 160–162.5°С. IR
2
(
–
1
spectrum, ν, cm : 3510, 3493 (ОН), 3370 (CN), 2950
(
1
СН ), 3080, 3050 (CH =), 1645 (C=C), 1560 (СN),
3 2
135, 1100, 1075 (ОН). Found, %: С 62.37; Н 10.23;
N 5.76. С Н NО . Calculated, %: С 62.88; Н 10.04;
1
2
23
3
N 6.11.
(4)-Ethenyl-2-(piperidin-1-yl)cyclohexan-1-ol
6c, 9c) was prepared from 3.21 g of the mixture of
isomers 2c and 2f or 4.1 g of 3c and 3f and 3.9 g
45 mmol) of piperidine. The ratio of isomers 6c : 9c =
4 : 16. Yield 2.2 g (52.6%, from 6c), 2.4 g (57.4%,
REFERENCES
5
1
2
. Mashkovskii, M.D., Lekarstvennye sredstva (Drugs),
Мoscow: Novaya Volna, 2002.
(
. Kas’yan, L.I. and Pal’chikov, V.A., Russ. J. Org.
Chem., 2010, vol. 46, no. 1, p. 1. doi 10.1134/
S107042801001001X
(
8
–
1
from 9c). mp 67–69°С. IR spectrum, ν, cm : 3460
3
4
. Bergmeier, S.C., Tetrahedron, 2000, vol. 56, no. 17,
p. 2561. doi 10.1016/S0040-4020(00)00149-6
(
(
ОН), 3370 (CN), 3080 (CH =), 2850 (СН ), 1645
2 2
C=C), 1560 (CN), 1450 (СH ), 1110, 1069 (ОН).
2
. Inaba, T., Yamada, Y., Abe, H., Sagawa, S., and Cho, H.,
J. Org. Chem., 2000, vol. 65, no. 6, p. 1623. doi
Found, %: С 74.12; Н 10.92; N 6.63. С Н NО.
1
3
23
Calculated, %: С 74.64; Н 11.0; N 6.70.
(4)-Ethenyl-2-(morpholin-4-yl)cyclohexan-1-ol
6d, 9d) was prepared from 3.21 g of the mixture of
isomers 2c and 2f or 4.1 g of 3c and 3f and 3.9 g
1
0.10201/jo991793e
5
5. Cabanel-Duvillard, I., Berier, J.F., Royer, J., and
Husson, H.P., Tetrahedron Lett., 1998, vol. 39, no. 29,
p. 5181. doi 10.1016/S0040-4039(98)01017-X
(
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

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2. Colthup, N.B., Daly, L.H., and Wiberley, S.E.,
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018