Synthesis of 2-Propargylaminoethanols from α,β-acetylenic aldimines

Article abstract of DOI:10.1134/S1070363207050143

A method of synthesis of 2-propargylaminoethanols, perspective synthons for a one-pot synthetic technology excluding isolation of unstable prop-2-ynylideneaminoethanols is developed. A number of 2-propargylaminoethanol hydrochloride derivatives are synthesized, and their ¹H and ¹³C NMR spectra were discussed. Nauka/Interperiodica 2007.

Full text of DOI:10.1134/S1070363207050143

ISSN 1070-3632, Russian Journal of General Chemistry, 2007, Vol. 77, No. 5, pp. 899 904.
Original Russian Text M.V. Karpov, A.V. Khramchikhin, I.V. Suvorova, Yu.L. Piterskaya, M.D. Stadnichuk, 2007, published in Zhurnal Obshchei
Khimii, 2007, Vol. 77, No. 5, pp. 803 808.
Pleiades Publishing, Ltd., 2007.
Synthesis of 2-Propargylaminoethanols
from , -Acetylenic Aldimines
M. V. Karpov, A. V. Khramchikhin, I. V. Suvorova,
Yu. L. Piterskaya, and M. D. Stadnichuk
St. Petersburg Institute of Technology,
Moskovskii pr. 26, St. Petersburg, 198013 Russia
Received January 16, 2007
Abstract A method of synthesis of 2-propargylaminoethanols, perspective synthons for a one-pot synthetic
technology excluding isolation of unstable prop-2-ynylideneaminoethanols is developed. A number of
1
2-propargylaminoethanol hydrochloride derivatives are synthesized, and their H and 13C NMR spectra were
discussed.
DOI: 10.1134/S1070363207050143
Some 2-propargylaminoethanols are known to be
interesting because of their biological activity [1 3] or
due to the possibility of their application as inter-
mediate compounds in fine organic synthesis [4 11].
In the present communication we report on the results
of developing new routes to 2-propargylmonoamino-
ethanols by hydrogenation of , -acetylenic aldimines
prepared from accessible 2-aminoethanols and ace-
tylenic aldehydes (Scheme 1).
magnesium sulfate, and the solvent was then distilled
off at reduced pressure. Thus isolated 1-aza-1-en-3-
ynes, as a rule, were used without additional purifica-
tion.
Our attempts to prepare azomethines III by this
procedure were unsuccessful. After removal of the
solvent removal, the reaction mixtures, as follows
1
from its H NMR spectra, contained a polymeric sub-
1
stance only. However, the H NMR spectra of freshly
Earlier [12] azomethines were prepared by mixing
equimolar amounts of prop-2-ynal and primary ali-
phatic amines in low-polarity aprotic solvents (ether
or methylene chloride) at room temperature. The reac-
tion mixture was additionally dried with anhydrous
prepared reaction mixtures contained characteristic
singlets in the region of
7.3 7.8 ppm, which, ac-
cording to published data,Hcould be assigned to the
methine protons of the E and Z isomers of expected
azomethines IIIa IIIj. We presumed that such readily
Scheme 1.
R4
R
R
R4
R3
R2
MeOH
H2O
H
OH
R3
H
N
+ H N
O
R
2
OH
R2
II
I
IIIa IIij
R4
R
R4
R3
R2
R3
R2
H
HCl
H
OH
NaBH4
Cl
H2N
HN
OH
IVa IVg
Va Vj
Va (R1 = Ph, R2 = R3 = R4 = H); Vb (R1 = Ph, R2 = R3 = H, R4 = Me); Vc (R1 = Ph, R2 = R3 = Me, R4 = H); Vd (R1 =
Ph, R2 = Et, R3 = R4 = H); Ve (R1 = Ph, R2 = R3 = H, R4 = Ph); Vf (R1 = Ph, R2 = H, R3 = Me, R4 = Ph); Vg (R1 = t-Bu,
R2 = R3 = Me, R4 = H); Vh (R1 = t-Bu, R2 = R3 = H, R4 = Ph); Vi (R1 = t-Bu, R2 = H, R3 = Me, R4 = Ph); Vj (R1 = H,
R2 = H, R3 = Me, R4 = Ph).
899

900
KARPOV et al.
Table 1. Yields, melting points, and elemental analyses of compounds IVc and Va Vj
Found, %
Calculated, %
H
Comp.
no.
Yield, %
mp,
C
Formula
C
H
N
C
N
Va
Vb
IVc
Vc
Vd
Ve
Vf
40
40
55
55
45
65
80
65
65
80
25
106
62.11
62.23
63.48
63.58
76.94
77.01
64.87
65.02
64.97
65.15
70.71
70.82
71.69
71.68
60.37
60.28
66.98
67.11
68.22
68.17
62.27
62.37
6.74
6.81
6.98
7.07
8.53
8.49
7.41
7.39
7.68
7.77
6.09
6.30
6.59
6.78
10.23
10.01
8.11
8.09
8.37
8.44
6.53
6.49
6.41
6.51
6.09
6.11
6.77
6.69
5.67
5.74
5.98
5.95
5.01
4.97
4.76
4.77
6.22
6.27
5.37
5.29
5.05
5.07
6.37
6.49
C11H14ClNO
C12H16ClNO
C13H17NO
62.41
63.85
76.81
65.13
65.13
70.95
71.63
60.12
67.28
68.19
62.41
6.67
6.62
6.21
6.89
5.84
5.84
4.87
4.64
6.37
5.23
4.97
6.62
105
71
7.14
8.43
178 180
116 117
178 179
185
C13H18ClNO
C13H18ClNO
C17H18ClNO
C18H20ClNO
C11H22ClNO
C15H22ClNO
C16H24ClNO
C11H14ClNO
7.57
7.57
6.30
6.68
Vg
Vh
Vi
178 180
178 179
185 190
175
10.09
8.28
8.58
Vj
6.67
polymerizable compounds could be introduced to the
reaction without isolation. On this basis we succeeded
in synthesizing target 2-propargylaminoethanols Va
Vj by a one-pot procedure: Immediately after short-
term refluxing of equimolar amounts of the corres-
ponding propynal and monoethanolamine in methanol,
sodium boron hydride (20% molar excess) was added.
ing 2-propargylaminoethanols (bases) were converted
into hydrochlorides (Table 3). The last stage was
necessary because the free bases were mostly viscous
hardly purifiable liquids. In the studied series,
2-methyl-2-(3-phenylprop-2-ynylamino)propan-1-ol
(IVc) was the only compound crystalline both as
hydrochloride and as a free base, and it was isolated
individual in the latter form.
After dilution of the reaction mixture with water
followed by extraction and solvent removal, the result-
1
In accordance with the proposed structure, the H
NMR spectrum of acetylenic aminoalcohol IVc
4
CH3
H
C C C1H2N C CH2OH
2
(Fig. 1, Table 1) showed a signal at
1.02 ppm
H
(6H), corresponding to methyl protons, and a slightly
broadened signal at H 1.60 ppm. corresponding to the
1
CH3
proton at the nitrogen atom. The doublet at
3.20 ppm (2H, JHH 5.09 Hz) and the singlet at
H
3
H
2
3.49 ppm (2H) are assignable to protons of the me-
thylene groups at the oxygen and nitrogen atoms,
respectively. The hydroxyl proton appears as a triplet
3
4
3
at
4.29 ppm (1H, JHH 5.09 Hz), and the phenyl
H
protons, as two ill-resolved multiplets at
(3H) and 7.33 7.38 ppm (2H).
7.28 7.30
H
7
6
5
4
3
2
1
The 13C NMR spectrum of compound IVc is
shown in Fig 2. The quartet at
24.37 ppm (1JCH
, ppm
1
Fig. 1. H NMR spectrum of compound IVc.
C
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 5 2007

SYNTHESIS OF 2-PROPARGYLAMINOETHANOLS
901
Table 2. 1H NMR spectra of acetylenic aminoalcohol hydrochlorides Va Vj [R1 C C CH2 NH+2 CR2R3 CHcR4OH]Cl ,
H, ppm
Comp.
no.
C C CH2
4.08 s
NH+2
OH
R1
Ri
Va
9.88a
5.21a
Ph
(R2 = R3 = H) 3.79 m, R4 = H) 3.13 3.17 m
7.33 7.38 m (3H)
7.46 7.52 m (2H)
Ph
9.83a
5.35a
(R2 = R3 = H) 2.87 3.08 m, R4 = Me) 1.20 d, JHH
3
Vb
4.06 s
7.33 7.38 m (3H) 6.54 Hz, 4.13 m (Hc)
7.46 7.52 m (2H)
IVcb 3.49 s
4.30 t
Ph
(R2 = R3 = Me) 1.1 s, (R4 = H) 3.20 d,
3JHH 5.10 Hz 7.28 7.30 m (3H) JHH 5.10 Hz
3
7.33 7.38 m (2H)
Vc
Vd
4.06 s
9.64a
9.73a
10.10a
5.51a
5.26a
Ph
(R2 = R3 = Me) 1.35 s, R4 = H) 3.54 s
7.35 7.39 m (3H)
7.46 7.50 m (2H)
Ph
4.06 4.18
4.07 4.19
m
m
(R2 = H), (R3 = Et) 3.14 3.26 m (1H), 1.66 1.91 m
7.35 7.39 m (3H) (CH2), 1.03 t (Me), JHH 15.2 Hz, R4 = H) 3.63
3
7.46 7.51 m (2H) 3.86 m
3
Ve
Vf
Vg
Vh
Vi
6.15a
6.03a
5.51a
6.14a
6.03a
6.00a
Ph
7.20 7.53 m (5H) (Hc), (R4 = Ph) 7.20 7.53 m
Ph
(R2 = H) 3.53 3.60 m, (R3 = Me) 1.09 d, JHH
7.23 7.49 m (5H) 6.54 Hz, 5.36 s (Hc), (R4 = Ph) 7.23 7.49 m
(R2 = R3 = H) 3.07 3.25 m, 5.17 d, JHH 10.2 Hz
AB 4.30, 4.16 9.92a
2JHH 16.72 Hz
3
3.74 s
9.69a
9.60a
t-Bu
1.23 s
t-Bu
1.25 s
t-Bu
1.28 s
H
3.33 s
(R2 = R3 = Me), 1.3 s, 3.48 s (R4 = H)
3
2.94 3.18 m
(R2 = R3 = H), 3.75 3.86 m, 5.10 d, JHH 9.0 Hz
(Hc), (R4 = Ph) 7.23 7.42 m
AB 3.79, 3.98 9.67a
2JHH 16.71 Hz
(R2 = H) 5.27 s, (R3 = Me) 1.03 d, JHH 6.0 Hz
3
(3H),3.40 3.52 m (Hc), R4 = Ph) 7.20 1.39 m
3
Vj
AB 3.91,4.07 9.82a
2JHH 16.71 Hz
(R2 = H) 5.30 s, (R3 = Me) 1.02 d, JHH 6.54 Hz,
3.40 3.52 m (Hc), (R4 = Ph) 7.23 7.42 m
a
b
c
Broad signal. Compound IVc does not correspond to the general formula and is a free base (see text). Single proton signal.
128.61 Hz) corresponds to the carbon atoms of two
chemically equivalent methyl groups. The C carbon
atom of the CH2N methylene group appears as a tri-
plet at C 32.73 ppm (1JCH 137.33 Hz) and the CH2OH
carbon atoms, as a triplet at
139.51 Hz). The C and C atoms of the triple bond
68.92 ppm (1JCH
C
resonate in their characteristic fields at
91.31 ppm, respectively.
82.54 and
C
Table 3. 13C NMR spectra of acetylenic aminoalcohol hydrochlorides Va Vj [R1
C
C
C H2 NH+2 C R2R3
C HR4OH]Cl , C, ppm
Comp.
no.
C
C
C
C
C
R1
R2
R3
R4
Va
Vb
87.83
87.83
81.77
81.75
91.31
82.89
81.93
37.16
37.42
32.77
32.23
35.26
49.00
53.44
54.58
60.84
58.65
57.19
63.06
68.92
65.84
60.15
Phc
Phc
Phc
Phc
Phc
H
H
H
H
H
Me, 22.01
H
IVca, b 82.54
Me, 24.37
Me, 21.38
H
Me, 24.37
Me, 21.38
H
Vcb
Vd
87.18
87.69
H
CH2Me,
CH2 21.06,
Me 10.73
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 5 2007

902
KARPOV et al.
Table 3. (Contd.)
Comp.
C
C
C
C
C
R1
R2
R3
R4
no.
Ve
Vf
Vg
87.93
87.80
96.15
81.72
81.96
71.76
37.48
35.26
31.74
53.65
58.75
60.63
69.01
69.93
65.49
Phc
Phc
Me3C,
H
H
H
Phc
Phc
H
Me, 10.17
Me, 21.41
Me, 21.41
C 27.93,
Me 31.21
Me3C,
C 27.99,
Me 31.24
Me3C,
C 28.04,
Me 31.24
H
Vh
Vi
97.39
97.26
80.29
70.67
70.78
75.96
36.89
34.75
34.44
53.20
58.14
58.44
68.80
69.80
69.85
H
H
H
Phc
Phc
Phc
Me,10.12
Vj b
Me, 9.96
H
a
b
13
c
Compound IVc does not correspond to the general formula and is a free base (see text). Proton-coupled C NMR spectra. The
chemical shifts of phenyl carbon signals fit tabulated values (
122 142 ppm).
C
1
As expected, the H NMR spectral patters of ace-
Va Vf, R1 = Ph) is replaced by tert-butyl (compounds
Vg Vi, R1 = t-Bu), the C signal is shifted downfield
by 10 ppm (96 97 ppm), and the C signal upfield by
10 ppm as well (70 71 ppm).
tylenic aminoalcohol IVc and its hydrochloride Vc
(Figs. 1 and 3, respectively) are essentially identical.
However, protonation causes downfield shifts of
almost all nonequivalent proton signals (Table 2).
As to the 13C NMR spectra, the protonation of the
nitrogen atom causes expected downfield shifts of the
C and C signals ( 5 ppm). At the same time, the
chemical shifts of methyl carbons and C and C are
scarcely affected, while the C signal is even shifted
upfield by about 8.5 ppm (Fig. 4).
The assignment of the chemical shifts of C and
C , presented in Table 3, was made in view of the fact
that the C signal in the all the studied cases is a tri-
2
plet with the JCH constant of 9 Hz, due to coupling
with two protons at C .
The resulting data show that neither the structure
of the starting 2-aminoethanol nor the nature of the
R1 radical at the triple bond (t-Bu, Ph) affect the
If the phenyl group at the triple bond (compounds
4
CH3
C C CH2NH C CH2OH
CH3
CH3
H
1
2
3
C C CH2N C CH2OH
CH3
2
HCl
CH3
1
NH+2
3
120
100
80
60
40
20
9
8
7
6
5
4
3
2
, ppm
, ppm
13
1
Fig. 2. C NMR spectrum of compound IVc.
Fig. 3. H NMR spectrum of compound Vc.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 5 2007

SYNTHESIS OF 2-PROPARGYLAMINOETHANOLS
chemo- and regioselectivity of the hydrogenation re-
903
CH3
action, and the triple bond always remains intact. The
only compound that behaves unusually is azomethine
IVj which, due to the hydrolytic instability of the
Si Csp bond forms 2-propargylaminoethanol hydro-
chloride with a terminal acetylenic fragment (com-
pounds Vj).
C C CH2 NH+2HC CH2 OH
Cl
CH3
The data in Table 3 show that the yields of the
aminoalcohols within the series in question are in-
dependent on the nature of the amino group (which
can be primary, secondary, or tertiary), structure and
nature of radicals R2, R3, and R4 (methyl, ethyl,
phenyl), as well as radical R1 at the triple bond,
varying from 45 to 80%. The low yields of hydro-
chlorides Va, Vb, and Vj are probably due to their
better solubility in acetone.
130 120 110 100 90 80 70 60 50 40 30 20
, ppm
13
The sample of aminoalcohol hydrochloride Vc
prepared either by the reaction of amine IVc with HCl
in acetone or by the procedure excluding the amine
isolation step showed the same melting points and H
NMR spectra.
Fig. 4. C NMR spectrum of compound Vc.
emulsion that formed was left overnight. Crystals
formed and were filtered off and washed with water,
and the filtrate was extracted with two portions of
methylene chloride. The extract was evaporated, and
the residue was dissolved in 50 ml of ethanol and
combined with the crystals obtained before. The
resulting material was diluted with a little water and
cooled in a freezer. The crystalline residue was then
1
Hydrochlorides Va Vj are colorless crystals stable
in air and readily soluble in ethanol and water. The
yields, melting points, and elemental analyses of the
prepared compounds are listed in Table 3, and the
13C NMR spectral parameters, in Table 2.
filtered off and dried in air to obtain 1.12 g (55%) of
1
aminoalcohol IVc, mp 71 C, H NMR spectrum,
H
EXPERIMENTAL
(ppm): 1.02 s (6H), 1.60 s (1H), 3.20 d, 3JHH 5.09 Hz,
(2H), 3.49 s (2H), 5.53 t, 5.09 Hz, (1H), 7.28 7.36 m
The solvents and reagents were of analytical grade.
1
(5H). 13C NMR spectrum,
(ppm): 24.37 q JCH
1
The H and 13C NMR spectra were registered on a
C
1
1
128.61 Hz, 32.73 t, JCH 137.33 Hz; 68.92t, JCH
Varian XL-300 spectrometer at 300.013 and
75.45 MHz, respectively, in DMSO-d6 solutions.
2-Aminoethanol, 2-aminopropanol, 2-aminobutanol,
and 2-methyl-2-aminopropanol were purchased from
Acros and ( )-2-methyl-2-amino-1-phenylethanol,
from Fluka. The main substance content in all the
reagents was 98 mol % or higher. The starting al-
dehydes were synthesized by known procedures: 4,4-
dimethylpent-2-ynal [13], 3-methylsilylprop-2-ynal
[14], and 3-phenylprop-2-ynal [15].
3
139.51 Hz; 82.54 s; 91.31 t, JCH 8.72 Hz.
Aminoalcohols IVa, IVb, and IVd IVj (general
procedure). A solution of 2-aminoalcohol in 10 ml of
methanol was added dropwise at room temperature to
a stirred solution of 0.01 mol of freshly distilled prop-
3-ynal in 50 ml of methanol. The mixture was stirred
for 1 2 min and quickly heated to boil and cooled to
room temperature, after which a 1.2-fold molar excess
of NaBH4 was immediately added in small portions.
Therewith, the reaction mixture got warm and foamed
up. It was cooled and diluted with a 10-fold excess of
water. The resulting was extracted with methylene
chloride (3 50 ml). The extract was dried with cal-
cined magnesium sulfate and then evaporated at re-
duced pressure. The prepared aminoalcohols were oily
light yellow liquids.
2-Methyl-2-(3-phenylprop-2-ynylamino)propan-
1-ol (IVc). To a solution of 0.01 mol of freshly distil-
led 3-phenylprop-2-ynal in 50 ml of methanol, a solu-
tion of 0.01 mol of 2-methyl-2-aminopropanol in
10 ml of methanol was added dropwise at room
temperature with stirring. The mixture was stirred for
a few minutes and then quickly heated to boil and
cooled to room temperature. A 1.2-fold molar excess
of NaBH4 was then added to the solution in small
portions. The reaction mixture got warm and foamed
up. The mixture was cooled to room temperature and
diluted with a 10-fold excess of water, and the
Aminoalcohol hydrochlorides Va Vj (general
procedure). To a solution of crude aminoalcohol in
50 ml of acetone, concentrated hydrochloric acid was
added dropwise with stirring to a weakly acidic reac-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 5 2007

904
KARPOV et al.
tion of the medium (pH 5.5). The mixture was kept
in a freezer for 1 day. Crystals precipitated and were
filtered off and dried in air. The compounds obtained
are colorless crystals stable in air, readily soluble in
ethanol and water, and poorly soluble in benzene and
toluene. The yields, melting points, and elemental
analyses of the prepared compounds are listed in
Table 3.
6. Bottini, A.T. and Vasu, D., J. Org. Chem., 1962,
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