Synthesis of 4-(diethylamino)-3-methylbutan-2-ol under conditions of phase-transfer catalysis

Full text of DOI:10.1134/S1070428016110282

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 11, pp. 1704–1707. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © G.O. Torosyan, A.A. Cherkezyan, A.S. Prazyan, 2016, published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52, No. 11, pp. 1709–
1711.
SHORT
COMMUNICATIONS
To 110 anniversary of A.T. Babayan,
Academician of Armenian Republic Academy of Sciences
Synthesis of 4-(Diethylamino)-3-methylbutan-2-ol
under Conditions of Phase-Transfer Catalysis
G. O. Torosyan,* A. A. Cherkezyan, and A. S. Prazyan
Armenian National Polytechnic University, ul. Teryana 105, Yerevan, 0009 Armenia
*e-mail: gagiktorosyan@seua.am
Received April 8, 2016
DOI: 10.1134/S1070428016110282
Oxo group is reduced in an alcohol group with
alkali metal hydrides [1]. Among the reducers the
practical interest is attracted by sodium tetrahydro-
borate that is more convenient reagent than analogous
derivatives of other alkali and alkaline earth metals
because of its stability, the hydrogenolysis selectivity,
low price, and simple preparation methods [2].
acetic acid [3]. Gangleron and quateron are widely
applied in medical practice and are important products
of the pharmaceutical industry of Armenian Republic.
We are studying the synthesis of organic reagents
under the conditions of the phase-transfer catalysis
(PTC) aimed for implementation in the production
industry [4–6]. A part of these studies are attempts to
use the PTC achievements in organic synthesis by an
example of oxo group hydrogenation with NaBH4
insufficiently examined in such environment [7, 8].
Ketone 1 and NaBH4 are sufficiently different in
solubility [3], therefore the reaction has been
performed in a two-phase catalytic system.
Formerly the reaction of 4-(diethylamino)-3-me-
thylbutan-2-one 1 with NaBH4 in acetic acid was used
to prepare the corresponding aminoalcohol 2 [3].
Me
Me
NaBH4
Et2N
O
Et2N
OH
The reduction of compound 1 proceeds with a good
yield in a two-phase system benzene–water, 1 : 2, at
room temperature in the presence of phase-transfer
catalysts. Due to the strong dissociation of NaBH4 in
water the reaction occurs with BH4– anion which
possesses a high reductive capability [2, 3]. Just this is
the reason of the low yield of the aminoalcohol in
benzene and a high yield in water and in the system
benzene–water.
Me
Me
1
2
The reaction in such system requires initial
dissolution of the aminoketone in acetic acid and then
performing the reduction in an alkaline medium. It was
apparently taken into account in [3] that the reduction
rate depended on the degree of dissociation of
NaBH4 and the increase in the degree of alkalinization
of the environment increased the reductive ability of
NaBH4.
We used as catalysts quaternary ammonium salts
and their hydroxides (Table 1). The best yield of the
target aminopropanol was obtained in the two-phase
system benzene–water (run no. 3). Therefore the effect
of the phase-transfer catalysts was studied in this two-
phase system. Yields of reaction product grow with the
increasing lipophilicity of the quaternary ammonium
salts (runs nos. 4–8). The best yield was obtained with
an efficient catalyst catamine AB [4]. The yield
The aim of our study was the preparation of an
important initial compound for the synthesis of drugs
gangleron and quateron, 4-(diethylamino)-3-methyl-
butan-2-ol 2 in milder conditions than in the already
implemented procedure of its synthesis in an alkaline
solution of NaBH4 with adding it to the solution of
1704

SYNTHESIS OF 4-(DIETHYLAMINO)-3-METHYLBUTAN-2-OL UNDER CONDITIONS
1705
Table 1. Yield of 4-(diethylamino)-3-methylbutan-2-ol 2 under the conditions of phase-transfer catalysis with quaternary
ammonium salts
Yield, %
Run no.
Catalyst
Solvent
HPLC
52.6
38.4
61.9
72.3
66.1
82.8
82.1
84.0
58.8
90.2
80.5
after distillation
1
2
Without catalyst
Water
48
35
58
67
62
78
78
81
55
85
76
Benzene
3
Benzene–water, 1 : 2
Benzene–water, 1 : 2
Benzene–water, 1 : 2
Benzene–water, 1 : 2
Benzene–water, 1 : 2
Benzene–water, 1 : 2
Benzene
4
Et3BnN+Cl–
Et4N+Cl–
Me2PhC12H25N+Br–
(C8H17)4N+Br–
Katamin AB
5
6
7
8
9
Me3BnN+HO–
10
11
Benzene–water, 1 : 2
Benzene–water, 1 : 2
Table 2. Yield of 4-(diethylamino)-3-methylbutan-2-ol 2 under the conditions of phase-transfer catalysis with crown-ethers
Yield, %
Catalyst
18-Crown-6
Solvent
HPLC
46.3
55.2
68.1
63.6
23.7
28.7
36.2
30.9
21.5
24.6
27.9
24.2
75.7
67.5
64.5
after distillation
Water
Benzene–water, 1 : 2
Benzene
42
51
65
59
20
24
33
26
18
21
24
20
72
64
62
Benzeneа
Dibenzo-18-crown-6
Water
Benzene–water, 1 : 2
Benzene
Benzeneа
Dicyclohexano-18-crown-6
Water
Benzene–water, 1 : 2
Benzene
Benzeneа
18-Crown-6b
Dibenzo-18-crown-6b
Dicyclohexano-18-crown-6b
Benzene–water, 1 : 2
Benzene–water, 1 : 2
Benzene–water, 1 : 2
а
Boiling of the reaction mixture at 75°C.
With the addition of 3.0 g of non ionogenic surfactant OS-20 (of an average molecular mass 1200 Da).
b
increased both at the growing surface activity of the
catalyst and at the application of quaternary
ammonium hydroxide (runs nos. 9, 10) or a quaternary
ammonium salts with a hydroxyethyl group (run no.
11). Probably at the use of quaternary ammonium
hydroxide the alkalinization of the environment grows
(pH 10.5) resulting in a larger yield of the reaction
product [2].
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TOROSYAN et al.
1706
As known, the occurrence of the reaction with the
of emulsions of the type “oil in water” with a critical
concentration of micelle formation 0.2 g/L [11]. The
reaction rate slightly increased (Table 2), but to a
lesser degree than at the use as catalysts of quaternary
ammonium salts (Table 1).
phase-transfer catalysis requires that the reacting anion
(Nu–) should be more lipophilic that the leaving anion
(Х–), or the latter would accumulate in the organic
phase as an ion pair with the catalyst cation (Q+X–)
resulting in the stopping of the reaction due to the
“poisoning” of the catalyst [7, 8]. In such occasions to
reach sufficiently high conversions it is necessary to
use a large excess of reacting nucleophile.
4-(Diethylamino)-3-methylbutan-2-ol (2). а. A
mixture of 80 mL of water, 40 mL of benzene, 3.8 g
(0.1 mol) of NaBH4, 0.005 mol of quaternary
ammonium salt (Table 1) was stirred for 10 min at 0–
5°С. Then within 20 min was added dropwise 15.7 g
(0.1 mol) of reagent 1, and the mixture was stirred for
2 h at 25–30°С. The benzene (upper) layer was
separated in a separatory funnel, the water layer was
extracted with benzene (3 × 20 mL). Combined
benzene solutions were washed with water and dried
with Na2SO4. On distilling off benzene the residue was
distilled in a vacuum to obtain 1,2-dimethyl-3-diethyl-
aminopropanol, bp 105–110°С (30 mm Hg), Rf 0.72.
1H NMR spectrum, δ, ppm: 0.98–1.06 m (~8H), 1.29–
1.57 m (~1.3H), 1.72–1.85 m (~0,3H), 2.11–2.72 m
(6H), 3.38 d.q (0.45H, OCH, J 8.4, 6.1 Hz), 3.45 m
(0.23H, OCH), 3.63 q.d (0.32H, OCH, J 6.5, 3.6 Hz),
4.65 (0.32H, OH), 5.04 (0.23H, OH), 6.22 (0.45H,
OH). Found, %: C 67.91; H 13.19; N 8.78. C9H21NO.
Calculated, %: C 67.92; H 13.20; N 8.80.
A possibility was formerly shown to apply PTC [9],
when the catalyst transferred the reagent dissolved in
the organic layer into the water layer where the
reaction took place. This process was designated as a
reverse phase-transfer catalysis (RPTC).
It is known that the rate of the ketone reduction
with sodium tetrahydridoborate depends not only on
the reactivity of the initial oxo compound, but also on
the degree of solvation and dissociation of the
hydrogenation agent. NaBH4 is dissociated in the water
phase, therefore the arising anion easily reduces the
aminoketone in question into the aminoalcohol [2].
Basing on the data of the industrial regulations [3]
and the results of our studies [10] it may be concluded
that the reduction product forms in water phase,
namely, reverse phase-transfer catalysis occurs. This
process in the benzene–water system may be described
as follows: The initial ketone is present in the organic
phase, and water contains NaBH4 and the phase-
transfer catalyst which transmits the substrate from the
organic into water phase. Since the main reagent
(borohydride anion) is dissolved in water and is
sparingly soluble in the organic phase the obtained
complex of the oxo compound with the catalyst
transits in the water phase where the reaction with the
borohydride anion takes place.
b. The reaction was performed similarly, but
instead of the onium salt 1.8 g (0.005 mol) of crown
ether was added. Yield 10.18 g (64%), bp 105–110°С
(30 mm Hg), Rf 0.72.
TLC was carried out on Silufol UV-254 plates in
the system 1-butanol–ethanol–acetic acid–water, 8 : 2 :
1 : 3, development in iodine vapor. NMR spectra were
registered in DMSO-d6 on a spectrometer Varian
Mercury-300 [300.07 (1H) and 75.46 (13C) МHz]. The
quantitative determination of alcohol 2 was performed
by HPLC on an instrument Shimadzu equipped with a
diode-matrix detector, column Macherey-Nagel
Nucleosil 100-5 C18, 150 × 4.6 mm, grains of sorbent
5 µm. Wavelength of the detector 200 nm, flow rate of
the mobile phase 1 mL/min, column temperature 30°C.
We also examined the catalytic activity in the phase-
transfer catalysis of crown ethers. The obtained results
might be used to confirm the suggested reaction
mechanism, since the simple crown ethers are poorly
soluble in water. It was assumed that any action
resulting in increased dispersion state of the emulsion
(formed in the reaction mixture owing to the crown
ether) should increase the rate of reaction between the
reagents. A series of experiments was carried out
where along with the crown ether a non ionogenic
surfactant OS-20 was used. [The surfactant consists of
polyethylene glycol monoalkyl ethers СnН2n+1О·
(С2Н4О)mН, where n = 14–18, m = 20]. This surfactant
is known as a fairly intensive dispergator and stabilizer
Mobile phase acetonitrile –0.05
dihydrogen phosphate (pH 3.5), 5 : 95.
М
potassium
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SYNTHESIS OF 4-(DIETHYLAMINO)-3-METHYLBUTAN-2-OL UNDER CONDITIONS
1707
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