2-Aminoethanols in Transacetalization Reactions

Article abstract of DOI:10.1023/A:1026088624655

Symmetric and mixed nitrogen-containing acetals and enol ethers were synthesized in an overall yield of 46-63% by reactions of N,N- dialkylaminoethanols with diethyl acetals derived from cyclohexanone, cyclopentanone, and acetophenone.

Full text of DOI:10.1023/A:1026088624655

Russian Journal of Organic Chemistry, Vol. 39, No. 5, 2003, pp. 622 624. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 5, 2003,
pp. 668 670.
Original Russian Text Copyright
2003 by Kukharev, Stankevich, Kukhareva.
2-Aminoethanols in Transacetalization Reactions
B. F. Kukharev, V. K. Stankevich, and V. A. Kukhareva
Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
fax: +73952396046; e-mail: admin@irioch.irk.ru
Received May 8, 2002
Abstract Symmetric and mixed nitrogen-containing acetals and enol ethers were synthesized in an overall
yield of 46 63% by reactions of N,N-dialkylaminoethanols with diethyl acetals derived from cyclohexanone,
cyclopentanone, and acetophenone.
Transacetalization is widely used in the synthesis
of various symmetric and mixed acetals [1]. However,
published data on such reactions with amino alcohols
and their derivatives are very limited. Amino alcohols
having a secondary amino group [2] and their N-acyl
derivatives [3, 4] are known to react with acetals,
affording cyclic O,N-acetals (oxazolidines). On the
other hand, acetals possessing amino alcohol moieties
are promising intermediate products in organic syn-
thesis, and some derivatives exhibit versatile bio-
logical activity [1 3].
In the present work we studied reactions of ketone
diethyl acetals with N,N-dialkylaminoethanols with
the goal of establishing the preparative potential of
transacetalization reaction for the synthesis of sym-
metric and mixed nitrogen-containing acetals. We
have found that heating of a mixture of N,N-diethyl-
2-aminoethanol (Ia) and cyclohexanone diethyl acetal
(IIa) (molar reactant ratio 2:1) for 8 h at the boiling
point in the absence of a catalyst and without removal
of ethanol results in partial dealkoxylation of IIa to
cyclohexenyl ethyl ether IIIa, while the expected
nitrogen-containing acetals IVa and Va are formed
only in trace amounts (according to the GLC data).
When the reaction was carried out with simulta-
neous removal of ethanol (by distillation), mixed
(IVa) and symmetric (Va) acetals were isolated in
addition to ether IIIa. If the theoretical amount of
ethanol was distilled off, the overall yield of acetals
IVa and Va was 61.4%, the molar ratio IVa:Va
being 1:2.5. If the amount of distilled ethanol was
a half of the theoretical, the overall yield of acetals
IVa and Va was 43% (molar ratio 3.1:1). The yield
of acetals IVa and Va decreased to 33% when the
Scheme 1.
I, R1 = Et (a), Me (b), CH2CH2OCH2CH2 (c); II, III, R2R3 = (CH2)4 (a), (CH2)3 (b), R2 = Ph, R3 = H (c); IV VI, R1 = Et, R2R3 =
(CH2)4 (a), R1 = Me, R2R3 = (CH2)4 (b), R1 = CH2CH2OCH2CH2, R2R3 = (CH2)4 (c); R1 = Me, R2R3 = (CH2)3 (d), R1 = Me,
R2 = Ph, R3 = H (e).
1070-4280/03/3905-0622$25.00 2003 MAIK Nauka/Interperiodica

2-AMINOETHANOLS IN TRANSACETALIZATION REACTIONS
623
Scheme 2.
reaction was performed in the presence of 5 mol % of
p-toluenesulfonic acid with removal of ethanol. In this
case, the major product was ether IIIa.
(2-hydroxyethyl)amine should afford oxazolidine VII.
In fact, the reaction between equimolar amounts of
acetal IIa and bis(2-hydroxyethyl)amine gave 87% of
oxazolidine VII. The product possesses a hydroxy
group; therefore, we expected that the reaction with
excess acetal IIa could afford acetals VIII and IX
(Scheme 2). However, from the reaction of bis(2-hy-
droxyethyl)amine with 4 equiv of acetal IIa we
isolated only 4-[2-(1-cyclohexenyloxy)ethyl]-1-oxa-4-
azaspiro[4.5]decane (X) in 43.2% yield. No expected
acetals VIII and IX were detected in the reaction
mixture by GLC; presumably, these compounds
undergo thermal decomposition during the process.
Taking into account that the best yields of acetals
were obtained in the absence of acid catalyst upon
distillation of the theoretical amount of ethanol, the
reactions between other amino alcohols Ia Ic and
diethyl acetals IIa IIc were carried out under the
same conditions. Apart from the corresponding sym-
metric and mixed acetals, we isolated enol ethers VIb,
VIc, and VIe. GLC analysis of the reaction mixtures
showed that in all cases both kinds of nitrogen-con-
taining acetals IVa IVe and Va Ve and enol ethers
VIa VIe were formed. However, we succeeded in
isolating by fractional distillation only several of these
compounds as pure substances. This is explained by
thermal instability of some compounds, as well as by
formation of azeotropic mixtures.
EXPERIMENTAL
The 1H NMR spectra were recorded on a Jeol
FX 90Q spectrometer (90 MHz) at 30 C using HMDS
as internal reference. The reaction mixtures were
analyzed, and the purity of compounds was checked,
According to published data [2 4], transacetaliza-
tion of cyclohexanone diethyl acetal (IIa) with bis-
Table 1. Yields, boiling points, densities, refractive indices, and elemental analyses of compounds IVa, IVd, Va,
Vb, Vd, Ve, VIb, VIc, VIe, and X
Found, %
H
Calculated, %
H
Comp. Yield,
bp,
(p, mm)
C
d240
n2D0
Formula
no.
%
C
N
C
N
IVa
IVd
Va
Vb
Vd
Ve
VIb
VIc
VIe
X
18
16
44
40
48
32
23
38
35
43
116 118 (5)
0.9301 1.4581 69.18 12.02
5.87
6.43
8.38
C14H29NO2
C11H23NO2
C18H38N2O2 68.74 12.18
C14H30N2O2 65.07 11.70 10.84
C13H28N2O2 63.89 11.55 11.46
C16H28N2O2 68.53 10.06
C10H19NO
C12H21NO2
C12H17NO
C16H27NO2
69.09 12.01
65.63 11.52
5.75
6.96
8.91
120 122 (20) 0.9252 1.4440 65.47 11.71
160 162 (3)
109 110 (2)
102 104 (3)
122 124 (2)
66 70 (2)
146 149 (4)
130 132 (8)
190 191 (5)
0.9361 1.4692 69.02 12.23
0.9366 1.4620 65.40 11.83 10.76
0.9470 1.4570 63.98 11.25 11.02
0.9785 1.4962 68.28 10.46
0.9242 1.4735 70.84 11.53
1.0320 1.4945 67.98 10.07
9.58
8.14
6.99
7.17
5.17
9.99
8.28
6.63
7.32
5.28
70.96 11.31
68.21 10.02
0.9761 1.5205 75.44
8.61
75.35
8.96
1.0469 1.5032 72.83 10.07
72.41 10.25
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 5 2003

624
KUKHAREV et al.
Table 2. 1H NMR spectra of compounds IVa, IVd, Va, Vd, Vb, Ve, VIb, VIc, VIe, and X
Comp.
no.
Chemical shifts , ppm (J, Hz)
3
3
IVa
IVd
Va
1.02 t (6H, 2NCH2CH3, J = 7.4), 1.16 t (3H, OCH2CH3, J = 6.9), 1.49 m [10H, (CH2)5], 2.57 m [6H,
CH2N(CH2)2], 3.45 m (4H, 2OCH2)
3
3
1.17 t (3H, OCH2CH3, J = 7.2), 1.69 m [8H, (CH2)4], 2.25 s [6H, N(CH3)2], 2.46 t (2H, NCH2, J = 6.4),
3.48 m (4H, 2OCH2)
3
1.02 t (12H, 4NCH2CH3, J = 7.4), 1.50 m [10H, (CH2)5], 2.58 m (8H, 2CH2NCH2), 3.49 t (4H, 2OCH2,
3J = 6.7)
3
3
Vb
Vd
Ve
1.51 m [10H, (CH2)5], 2.25 s (12H, 4CH3), 2.46 t (4H, 2NCH2, J = 6.2), 3.50 t (4H, 2OCH2, J = 6.2)
3
3
1.70 m [8H, (CH2)4], 2.25 s (12H, 4CH3), 2.47 t (4H, 2NCH2, J = 6.3), 3.53 t (4H, 2OCH2, J = 6.3)
3
1.56 s (3H, CH3), 2.24 s [12H, 2N(CH3)2], 2.51 t (4H, 2NCH2, J = 6.3), 3.47 m (4H, 2OCH2), 7.29-7.51 m
(5H, C6H5)
VIb
VIc
VIe
X
1.58 m (4H, C CHCH2CH2CH2CH2), 2.03 m (4H, C CHCH2CH2CH2CH2), 2.26 s [6H, N(CH3)2], 2.58 t
(2H, NCH2, 3J = 5.6), 3.71 t (2H, OCH2, 3J = 5.6), 4.59 t (1H, C CH, 3J = 3.3)
1.56 m (4H, C CHCH2CH2CH2CH2), 2.00 m (4H, C CHCH2CH2CH2CH2), 2.46 2.60 m [6H,
CH2N(CH2)2], 3.64 m (6H, OCH2, CH2OCH2), 4.54 t (1H, C CH, 3J = 3.3)
3
3
2.34 s [6H, N(CH3)2], 2.76 t (2H, NCH2, J = 5.9), 3.97 t (2H, OCH2, J = 5.9), 4.19 d (1H, OC CH-Z, 2J =
2.5), 4.57 d (1H, OC CH-E, 2J = 2.5), 7.26 7.56 m (5H, C6H5)
1.49 1.62 m [14H, (CH2)5, C CHCH2CH2CH2CH2], 2.03 m (4H, C CHCH2CH2CH2CH2), 2.78 t (2H,
3
3
3
NCH2, J = 6.4), 3.05 t (2H, NCH2, J = 6.9), 3.73 3.86 m (4H, 2OCH2), 4.46 t (1H, C CH, J = 3.4)
by GLC using an LKhM-80 chromatograph equipped
with a thermal conductivity detector; carrier gas
helium; 3000 3-mm steel column packed with 3%
of OV-17 on Inerton Super (0.160 0.200 mm); oven
temperature programming from 30 to 250 C at a rate
of 4 deg/min.
Reaction of amino alcohols Ia Ic with diethyl
acetals IIa IIc (general procedure). A mixture of
1 mol of diethyl acetal and 2 mol of amino alcohol
was heated in a flask equipped with an adapter filled
with ethanol as cooling fluid with continuous removal
of ethanol. When 116.5 ml (2 mol) of ethanol was
distilled off, the mixture was subjected to fractional
vacuum distillation through a Vigreaux column with
an efficiency of 10 theoretical plates. The reaction of
bis(2-hydroxyethyl)amine with cyclohexanone diethyl
acetal was carried out in a similar way, but the amino
alcohol-to-acetal ratio was 1:1 and 1:2.
From 172 g (1 mol) of diethyl acetal IIa and 52.5 g
(0.5 mol) of bis(2-hydroxyethyl)amine we obtained
57.3 g (43.2%) of 4-[2-(1-cyclohexenyloxy)ethyl]-1-
oxa-4-azaspiro[4.5]decane (X).
The yields, physical constants, analytical data, and
1H NMR spectra of the newly synthesized compounds
are given in Tables 1 and 2.
REFERENCES
1. Yanovskaya, L.A., Yufit, S.S., and Kucherov, V.F.,
Khimiya atsetalei (Chemistry of Acetals), Moscow:
Nauka, 1973.
2. Mohrle, H. and Kamper, Ch., Pharmazie, 1983,
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3. Yamanoi, K., Ohfune, Y., Watanabe, K., Li, P.N.,
and Takeuchi, H., Tetrahedron Lett., 1988, vol. 29,
p. 1181.
4. Cardani, S., Poli, G., Scolastico, C., and Villa, R.,
Tetrahedron, 1988, vol. 44, p. 5929; Garner, P. and
Park, J.M., J. Org. Chem., 1987, vol. 52, p. 2361;
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vol. 28, p. 6175.
From 17.2 g (0.1 mol) of diethyl acetal IIa and
10.5 g (0.1 mol) of bis(2-hydroxyethyl)amine we ob-
tained 16.1 g (87%) of 4-(2-hydroxyethyl)-1-oxa-4-
azaspiro[4.5]decane (VII), bp 148 150 C (14 mm),
d240 = 1.0920, n2D0 = 1.4970; published data [5]:
bp 165 167 C (24 mm).
5. Bergmann, E.D., Zimkin, E., and Pinchas, S., Recl.
Trav. Chim. Pays Bas, 1952, vol. 71, p. 237.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 5 2003