Synthesis and some transformations of n,2,2-trimethyltetrahydro-2H-pyran-4- amine

Article abstract of DOI:10.1134/S1070428012010137

Reaction of 2,2-dimethyltetrahydro-2H-pyran-4-one with aqueous methanamine, followed by reduction of the Schiff base thus obtained with sodium tetrahydridoborate gave N,2,2-trimethyltetrahydro-2Hpyran-4-amine which was subjected to cyanoethylation with acrylonitrile. The resulting 3-(2,2-dimethyltetrahydro-2H-pyran-4-ylmethylamino)propanenitrile was reduced with lithium tetrahydridoaluminate to N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)- N-methylpropane-1,3-diamine, and some chemical transformations of the latter were studied. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S1070428012010137

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 1, pp. 89–93. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © N.S. Arutyunyan, R.L. Nazaryan, L.A. Akopyan, G.A. Panosyan, G.A. Gevorgyan, 2012, published in Zhurnal Organicheskoi
Khimii, 2012, Vol. 48, No. 1, pp. 94–98.
Synthesis and Some Transformations
of N,2,2-Trimethyltetrahydro-2H-pyran-4-amine
N. S. Arutyunyana, R. L. Nazaryana, L. A. Akopyana, G. A. Panosyanb, and G. A. Gevorgyana
a Mndzhoyan Institute of Fine Organic Chemistry, Scientific–Technological Center of Organic and Pharmaceutical
Chemistry, National Academy of Sciences of Armenia, pr. Azatutyan 26, Erevan, 0014 Armenia
e-mail: gyulgev@gmail.com
b Molecular Structure Research Center, National Academy of Sciences of Armenia, Erevan, Armenia
Received April 2, 2011
Abstract—Reaction of 2,2-dimethyltetrahydro-2H-pyran-4-one with aqueous methanamine, followed by
reduction of the Schiff base thus obtained with sodium tetrahydridoborate gave N,2,2-trimethyltetrahydro-2H-
pyran-4-amine which was subjected to cyanoethylation with acrylonitrile. The resulting 3-(2,2-dimethyltetra-
hydro-2H-pyran-4-ylmethylamino)propanenitrile was reduced with lithium tetrahydridoaluminate to N-(2,2-di-
methyltetrahydro-2H-pyran-4-yl)-N-methylpropane-1,3-diamine, and some chemical transformations of the
latter were studied.
DOI: 10.1134/S1070428012010137
We previously synthesized 4-amino-substituted
tetrahydropyrans which showed biological activity [1].
Some substituted diamines having a 3-aminopropyl-
amino group in position 4 of the tetrahydro-2H-pyran
ring may be valuable starting compounds for subse-
quent transformations.
Schiff base A generated from 2,2-dimethyltetra-
hydro-2H-pyran-4-one and 25% aqueous methylamine
was reduced with sodium tetrahydridoborate to
N,2,2-trimethyltetrahydro-2H-pyran-4-amine (I). Com-
pound I reacted with acrylonitrile to afford the corre-
sponding cyanoethylation product, 3-(2,2-dimethyl-
Scheme 1.
O
O
NMe
NHMe
Me
N
CH2=CHCN
EtOH
Me
Me
MeNH2
NaBH4, MeOH
CN
Me
Me
Me
Me
O
O
O
Me
Me
A
I
II
Me
N
Me
Me
Me
Me
Me
LiAlH4
ArCOR
NH2
N
N
Ar
O
O
R
III
B
Me
N
Me
N
COMe
N Ar
H
Me
Me
Me
NaBH4
MeCOCl
R = H
N
Ar
Me
O
R
O
IV–XII
XIII–XV
IV–X, R = H; XI, XII, R = Me; IV, XIV, Ar = 4-MeOC6H4; V, XII, XV, Ar = 4-ClC6H4; VI, Ar = 3,4-(MeO)2C6H3;
VII, Ar = 2-FC6H4; VIII, Ar = 1,3-benzodioxol-5-yl; IX, XIII, Ar = furan-2-yl; X, Ar = thiophen-2-yl; XI, Ar = Ph.
89

ARUTYUNYAN et al.
90
Scheme 2.
O
Me
O
O
Me
N
O
N
N
H
Me
Me
N
O
O
O
O
O
OH
Me
Me
III
O
O
O
XVI
XVII
tetrahydro-2H-pyran-4-ylmethylamino)propanenitrile
(II). Reduction of II with lithium tetrahydridoalumi-
nate gave N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-
N-methylpropane-1,3-diamine (III). Diamine III was
brought into condensation with various aromatic alde-
hydes and ketones, and Schiff bases B thus formed
were reduced (without isolation) with sodium tetrahy-
dridoborate to the corresponding trimethylenediamines
IV–XII. Amides XIII–XV were synthesized by treat-
ment of amines IV, V, and IX, respectively, with
acetyl chloride (Scheme 1). The reaction of III with
phthalic anhydride led to the formation of 2-{3-[(2,2-
dimethyltetrahydro-2H-pyran-4-yl)methylamino]-
propyl}isoindole-1,3-dione (XVI), and 4-amino-N-[3-
(2,2-dimethyltetrahydro-2H-pyran-4-ylmethylamino)-
propyl]-4-oxobutanoic acid (XVII) was formed in the
reaction of III with succinic anhydride (Scheme 2).
with ice water so that the temperature did not exceed
20°C. The mixture was stirred for 1 h at room tempera-
ture and left overnight, the solvent was distilled off,
the residue was treated with a 20% solution of sodium
hydroxide, the product was extracted into diethyl ether,
and the extract was acidified with concentrated hydro-
chloric acid on cooling with ice water. The aqueous
phase was extracted with diethyl ether to remove
neutral impurities, neutralized with potassium carbo-
nate, and extracted with diethyl ether. The extract was
dried and evaporated, and the residue was distilled
under reduced pressure. Yield 39.5 g (73%), bp 84°C
1
(22 mm). IR spectrum: ν 3310 cm–1 (NH). H NMR
spectrum, δ, ppm: 1.20 br.s (1H, NH), 1.08 d.d (1H,
3-H, J = 12.7, 11.4 Hz), 1.17 s and 1.20 s (3H each,
2-CH3), 1.18 m (1H, 5-H), 1.72 d.d.d (1H, 5-H, J =
12.7, 4.0, 2.0 Hz), 1.80 m (1H, 3-H), 2.39 s (3H,
NCH3), 2.65 t.t (1H, 4-H, J = 11.8, 4.0 Hz), 3.59 d.t.d
(1H, 6-H, J = 12.5, 12.0, 2.3 Hz), 3.74 d.d.d (1H, 6-H,
J = 12.0, 5.1, 1.9 Hz). Found, %: C 67.15; H 12.00;
N 9.83. C8H17NO. Calculated, %: C 67.09; H 11.96;
N 9.78.
EXPERIMENTAL
The IR spectra were recorded on a Nicolet Avatar
1
330 FT-IR spectrometer. The H NMR spectra were
obtained on a Mercury VX-300 instrument at 300 MHz
from solutions in DMSO-d6, using tetramethylsilane as
internal reference. 2,2-Dimethyltetrahydro-2H-pyran-
4-one was synthesized according to the procedures
described in [2, 3].
3-(2,2-Dimethyltetrahydro-2H-pyran-4-yl-
methylamino)propanenitrile (II). A mixture of 30 g
(0.21 mol) of amine I, 22 g (0.41 mol) of freshly
distilled acrylonitrile, and 170 ml of 96% ethanol was
stirred and was then left to stand for three days at room
temperature. The solvent and excess acrylonitrile were
distilled off, and the residue was distilled under
reduced pressure. Yield 32.8 g (80%), bp 132–135°C
N,2,2-Trimethyltetrahydro-2H-pyran-4-amine
(I). A flask was charged with 64 g (0.5 mol) of 2,2-di-
methyltetrahydro-2H-pyran-4-one, 75 ml of 25% aque-
ous methanamine was added over a period of 10 min,
the flask was hermetically capped, and the mixture was
stirred (the reaction was accompanied by heat evolu-
tion) and left overnight. The solution was then saturat-
ed with sodium chloride and extracted with ether, the
extract was dried and evaporated, and the residue
[yield of crude Schiff base A 54 g (76%)] was sub-
jected to reduction. For this purpose, 0.38 mol of
Schiff base A was dissolved in 250 ml of anhydrous
methanol, and 14.4 g (0.8 mol) of sodium tetrahydrido-
borate was added in portions under stirring and cooling
1
(4 mm). IR spectrum: ν 2245 cm–1 (C≡N). H NMR
spectrum, δ, ppm: 1.16 s (6H, CH3), 1.24 t (1H, J =
12.2 Hz), 1.37 t.d (1H, CH2CH2CN, J = 12.2, 5.1 Hz),
1.60 m (2H, CH2CN), 2.26 s (3H, NCH3), 2.47 t (2H,
J = 6.8 Hz), 2.70 t (2H, 3-H, 5-H, J = 6.8 Hz), 2.73 t.t
(1H, CH, J = 12.2, 3.9 Hz), 3.52 t.d (1H, OCH2, J =
12.0, 2.4 Hz), 3.67 d.d.d (1H, OCH2, J = 12.0, 5.1,
1.9 Hz). Found, %: C 67.25; H 10.21; N 14.32.
C11H20N2O. Calculated, %: C 67.31; H 10.27; N 14.27.
N1-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-N1-
methylpropane-1,3-diamine (III). A solution of 21 g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 1 2012

SYNTHESIS AND SOME TRANSFORMATIONS OF N,2,2-TRIMETHYLTETRAHYDRO...
91
(0.1 mol) of nitrile II in 100 ml of anhydrous diethyl
ether was added dropwise under stirring and cooling to
a solution of 8 g (0.21 mol) of lithium tetrahydrido-
aluminate in 250 ml of anhydrous diethyl ether, main-
taining the temperature at 0±2°C. The mixture was
stirred for 1 h at that temperature and cooled to –10°C
with an ice–salt bath, 8 ml of water, 8 ml of a 15%
solution of sodium hydroxide and 24 ml of water were
added dropwise in succession, the inorganic material
was filtered off and washed with diethyl ether, the
filtrate was dried and evaporated, and the residue was
distilled under reduced pressure. Yield 18 g (84%),
bp 106°C (2 mm). IR spectrum, ν, cm–1: 3362, 3300
J = 12.1, 2.3 Hz), 3.62 s (2H, CH2C6H4), 3.66 d.d.d
(1H, 6-H, J = 11.8, 5.1, 1.9 Hz), 3.76 s (3H, OCH3),
6.77 m and 7.17 m (2H each, C6H4). Found, %:
C 71.40; H 10.16; N 8.54. C19H32N2O2. Calculated, %:
C 71.21; H 10.06; N 8.74.
N3-(4-Chlorobenzyl)-N1-(2,2-dimethyltetrahy-
dro-2H-pyran-4-yl)-N1-methylpropane-1,3-diamine
(V). Yield 76%, bp 200–203°C (4 mm). IR spectrum,
1
ν, cm–1: 1597, 1600 (C=Carom); 3290 (NH). H NMR
spectrum, δ, ppm: 1.14 s and 1.15 s (3H each, 2-CH3),
1.22 d.d (1H, 3-H, J = 12.7, 12.0 Hz), 1.33 q.d (1H,
5-H, J = 12.1, 5.1 Hz), 1.48–1.58 m (2H, 3-H, 5-H),
1.55 m (2H, NCH2CH2), 1.66 br (1H, NH), 2.16 s (3H,
NCH3), 2.42 t (2H, CH3NCH2, J = 6.9 Hz), 2.54 t (2H,
HNCH2, J = 6.7 Hz), 2.64 t.t (1H, 4-H, J = 12.0,
3.8 Hz), 3.50 t.d (1H, 6-H, J = 12.1, 2.4 Hz), 3.65 d.d.d
(1H, 6-H, J = 12.1, 5.1, 1.9 Hz), 3.68 s (2H, CH2C6H4),
7.22–7.29 m (4H, C6H4). Found, %: C 66.45; H 8.92;
N 8.53. C18H29ClN2O. Calculated, %: C 66.54; H 9.00;
N 8.62.
N3-(3,4-Dimethoxybenzyl)-N1-(2,2-dimethyltetra-
hydro-2H-pyran-4-yl)-N1-methylpropane-1,3-di-
amine (VI). Yield 68%, bp 210–215°C (1 mm). IR
spectrum, ν, cm–1: 1575, 1610 (C=Carom); 3302 (NH).
1H NMR spectrum, δ, ppm: 1.15 s (6H, 2-CH3),
1.22 d.d (1H, 3-H, J = 12.8, 12.0 Hz), 1.34 q.d (1H,
5-H, J = 12.0, 5.0 Hz), 1.49–1.59 m (2H, 3-H, 5-H),
1.54 br (1H, NH), 1.55 q (2H, NCH2CH2, J = 6.8 Hz),
2.16 s (3H, NCH3), 2.43 t (2H, NCH2, J = 6.8 Hz),
2.54 t (2H, NCH2, J = 6.8 Hz), 2.64 t.t (1H, 4-H, J =
12.0, 3.8 Hz), 3.50 t.d (1H, 6-H, J = 12.1, 2.4 Hz),
3.61 s (2H, CH2C6H3), 3.65 d.d.d (1H, 6-H, J = 12.1,
5.2, 2.0 Hz), 3.77 s and 3.80 s (3H each, OCH3), 6.74 d
(2H, 5′-H, 6′-H, J = 1.2 Hz), 6.85 t (1H, 2′-H, J =
1.2 Hz). Found, %: C 68.60; H 9.81; N 7.95.
C20H34N2O3. Calculated, %: C 68.54; H 9.78; N 7.99.
1
(NH2). H NMR spectrum, δ, ppm: 1.15 s (6H, CH3),
1.23 d.d (1H, 3-H, J = 12.8, 11.9 Hz), 1.35 q.d (1H,
5-H, J = 12.2 , 5.0 Hz), 1.50 q (2H, NCHCH2, J =
6.8 Hz), 1.51–1.57 m (2H, 3-H, 5-H), 2.16 s (3H,
NCH3), 2.41 t (2H, NCH2, J = 6.8 Hz ), 2.65 t.t (1H,
4-H, J = 11.9, 3.8 Hz), 2.65 br (2H, NH2), 2.98 m (2H,
NCH2), 3.51 t.d (1H, 6-H, J = 12.1, 2.4 Hz), 3.65 d.d.d
(1H, 6-H, J = 11.8, 7.0, 1.9 Hz). Found, %: C 66.02;
H 12.02; N 14.04. C11H24N2O. Calculated, %: C 65.95;
H 12.08; N 13.98.
Diamines IV–XII (general procedure). A mixture
of equimolar amounts of the corresponding aromatic
aldehyde (or ketone) and amine III in benzene (or
xylene in the reactions with aromatic ketones) was
heated for 4 h under reflux in a flask equipped with
a Dean–Stark trap until water no longer separated. The
solvent was removed, the residue was dissolved in
methanol (40 ml of methanol per 0.1 mol of Schiff
base), and an equimolar amount of sodium tetrahy-
dridoborate was added in portions under stirring and
cooling with ice water so that the temperature did not
exceed 20°C. The mixture was stirred for 1 h at room
temperature, the solvent was distilled off, the residue
was treated with a 20% solution of sodium hydroxide,
the product was extracted into diethyl ether, the extract
was dried and evaporated, and the residue was distilled
under reduced pressure.
N1-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-
N3-(2-fluorobenzyl)-N1-methylpropane-1,3-diamine
(VII). Yield 76%, bp 170–173°C (2 mm). IR spectrum,
1
ν, cm–1: 1585, 1643 (C=Carom); 3310 (NH). H NMR
N1-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-N3-
(4-methoxybenzyl)-N1-methylpropane-1,3-diamine
(IV). Yield 78%, bp 200–205°C (3 mm). IR spectrum,
spectrum, δ, ppm: 1.14 s (6H, CH3), 1.22 t (1H, CH2,
pyran, J = 12.3 Hz), 1.35 q.d (1H, CH2, pyran, J =
12.3, 5.1 Hz), 1.50 m and 1.53 m (1H each, CH2,
pyran), 1.56 m (2H, NCH2CH2), 1.58 br.s (1H, NH),
2.16 s (3H, NCH3), 2.43 t (2H, NCH2, J = 6.9 Hz),
2.56 t (2H, NCH2, J = 6.5 Hz), 2.63 t.t (1H, 4-H, J =
12.0, 3.8 Hz), 3.50 t.d (1H, 6-H, J = 12.0, 2.1 Hz),
3.65 d.d.d (1H, 6-H, J = 12.0, 5.1, 1.9 Hz), 3.73 s (2H,
CH2C6H4); 6.98 m, 7.07 m, 7.18 m, and 7.37 m
(1H each, C6H4). Found, %: C 70.15; H 9.44; N 9.03.
C18H29FN2O. Calculated, %: C 70.09; H 9.48; N 9. 08.
1
ν, cm–1: 1580, 1613 (C=Carom); 3291 (NH). H NMR
spectrum, δ, ppm: 1.15 s (6H, CH3), 1.23 d.d (1H, 3-H,
J = 12.7, 12.0 Hz), 1.34 q.d (1H, 3-H, J = 12.7,
12.0 Hz), 1.34 q.d (1H, 5-H, J = 12.1, 5.1 Hz), 1.49–
1.59 m (2H, 3-H, 5-H), 1.55 m (2H, NCH2CH2),
2.04 br.s (1H, NH), 2.16 s (3H, NCH3), 4.42 t (2H,
NCH2, J = 7.0 Hz), 2.54 t (2H, NCH2, J = 6.7 Hz),
2.64 t.t (1H, 4-H, J = 12.0, 3.8 Hz), 3.50 t.d (1H, 6-H,
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ARUTYUNYAN et al.
92
N3-(1,3-Benzodioxol-5-ylmethyl)-N1-(2,2-dimeth-
N1-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-
N1-methyl-N3-(1-phenylethyl)propane-1,3-diamine
(XI). Yield 70%, bp 193°C (3 mm). IR spectrum, ν,
yltetrahydro-2H-pyran-4-yl)-N1-methylpropane-
1,3-diamine (VIII). Yield 75%, bp 205°C (2 mm). IR
spectrum, ν, cm–1: 1609, 1640 (C=Carom); 3293 (NH).
1H NMR spectrum, δ, ppm: 1.14 s (6H, CH3), 1.22 t
(1H, CH2, pyran, J = 12.4 Hz), 1.35 t.d (1H, CH2,
pyran, J = 12.4, 5.1 Hz), 1.54 m (4H, CH2, pyran,
NCH2CH2), 1.55 br (1H, NH), 2.15 s (3H, NCH3),
2.42 t (2H, NCH2, J = 6.9 Hz), 2.52 t (2H, NCH2, J =
6.7 Hz), 2.64 t.t (1H, 4-H, J = 12.0, 3.8 Hz), 3.50 t.d
(1H, 6-H, J = 12.1, 2.3 Hz), 3.59 s (2H, 5′-CH2),
3.65 d.d.d (1H, 6-H, J = 11.7, 5.1, 1.7 Hz), 5.92 s (2H,
OCH2O), 6.65–6.71 m (2H, C6H3), 6.80 br (1H, C6H3).
Found, %: C 68.28; H 9.10; N 8.43. C19H30N2O3. Cal-
culated, %: C 68.23; H 9.04; N 8.38.
1
cm–1: 1600, 1660 (C=Carom); 3297 (NH). H NMR
spectrum, δ, ppm: 1.14 s (6H, CH3), 1.21 t (1H, J =
12.3 Hz), 1.34 d (1H, CH2, pyran, J = 12.3, 5.0 Hz),
1.27 d (3H, CH3CH, J = 6.6 Hz), 1.50 m (2H,
NCH2CH2), 1.48–1.57 m (2H, CH2, pyran), 1.53 br.s
(1H, NH), 2.13 s and 2.14 s (1.5H each, NCH3),
2.31–2.48 m (4H, NCH2), 2.62 t.t (1H, 4-H, J = 12.0,
3.7 Hz), 3.49 t.d (1H, 6-H, J = 12.0, 2.1 Hz), 3.65 m
(1H, 6-H), 3.65 q (1H, CHCH3, J = 6.6 Hz), 7.10–
7.26 m (5H, Ph). Found, %: C 74.90; H 10.65; N 9.14.
C19H32N2O. Calculated, %: C 74.95; H 10.59; N 9.20.
N3-[1-(4-Chlorophenyl)ethyl]-N1-(2,2-dimethyl-
tetrahydro-2H-pyran-4-yl)-N1-methylpropane-1,3-
diamine (XII). Yield 71%, bp 185–187°C (2 mm). IR
spectrum, ν, cm–1: 1594, 1651 (C=Carom); 3279 (NH).
1H NMR spectrum, δ, ppm: 1.14 s and 1.14 s (3H each,
2-CH3), 1.21 d.d (1H, 3-H, J = 12.7, 12.0 Hz), 1.25 d
(3H, CH3CH, J = 6.5 Hz), 1.32 q.d (1H, 5-H, J = 12.1,
5.1 Hz), 1.45–1.57 m (4H, 3-H, 5-H, NCH2CH2),
1.60 br.s (1H, NH), 2.14 s (3H, NCH3), 2.28–2.46 m
(4H, CH2NCH2), 2.62 t.t (1H, 4-H, J = 12.0, 3.8 Hz),
3.49 t.d (1H, 6-H, J = 12.1, 2.4 Hz), 3.65 m (1H, 6-H),
3.65 q (1H, CHCH3, J = 6.5 Hz), 7.21–7.28 m
(4H, C6H4). Found, %: C 67.25; H 9.18; N 8.40.
C19H31ClN2O. Calculated, %: C 67.33; H 9.22; N 8.27.
N1-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-N3-
(furan-2-ylmethyl)-N1-methylpropane-1,3-diamine
(IX). Yield 73%, bp 155–160°C (1.5 mm). IR spec-
trum, ν, cm–1: 1600, 1650 (C=Carom); 3390 (NH).
1H NMR spectrum, δ, ppm: 1.14 s and 1.15 s (3H each,
CH3), 1.22 t (1H, 5-H, J = 12.4 Hz), 1.35 t.d (1H, 5-H,
J = 12.4, 5.00 Hz), 1.48–1.60 m (2H, 3-H), 1.53 m
(2H, NCH2CH2), 1.57 br (1H, NH), 2.15 s (3H,
NCH3), 2.41 t (2H, HNCH2, J = 6.9 Hz), 2.54 t (2H,
CH3NCH2, J = 6.6 Hz), 2.63 t.t (1H, 4-H, J = 11.9,
3.8 Hz), 3.50 t.d (1H, 6-H, J = 12.0, 2.4 Hz), 3.65 d.d.d
(1H, 6-H, J = 12.0, 5.1, 1.9 Hz), 3.65 s (2H, 2′-CH2),
6.10 d.d (1H, 3′-H, J = 3.2, 0.8 Hz), 6.26 d.d (1H,
4′-H, J = 3.2, 1.8 Hz), 7.32 d.d (1H, 5′-H, J = 1.8,
0.8 Hz). 13C NMR spectrum, δC, ppm: 21.7 (CH3), 27.2
(CH2), 28.0 (CH2), 31.5 (CH3), 36.7 (NCH3), 38.6
(CH2), 45.6 (CH2), 46.9 (CH2), 51.0 (CH2), 55.9
(NCH), 60.0 (CH2), 71.3 (C2), 105.7 (=CH), 109.5
(=CH), 140.5 (=CH), 154.2 (=C). Found, %: C 68.59;
H 10.10; N 10.04. C16H28N2O2. Calculated, %: C 68.53;
H 10.06; N 9.99.
N1-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-
N1-methyl-N3-(thiophen-2-ylmethyl)propane-1,3-di-
amine (X). Yield 74%, bp 168–170°C (2 mm). IR
spectrum, ν, cm–1: 1600, 1655 (C=Carom); 3290 (NH).
1H NMR spectrum, δ, ppm: 1.14 s (6H, 2-CH3), 1.22 t
(1H, J = 12.4 Hz), 1.34 d.t.d (1H, CH2, pyran, J = 12.4,
12.0, 5.1 Hz), 1.49–1.60 m (4H, NCH2CH2, CH2,
pyran), 1.73 br.s (1H, NH), 2.16 s (3H, NCH3), 2.43 t
(2H, CH3NCH2, J = 6.9 Hz), 2.60 t (2H, NHCH2, J =
6.6 Hz), 2.64 t.t (1H, 4-H, J = 12.0, 3.8 Hz), 3.50 t.d
(1H, 6-H, J = 12.0, 2.3 Hz), 3.65 d.d.d (1H, 6-H, J =
12.0, 5.1, 1.9 Hz), 3.88 s (2H, 2′-CH2), 6.84–6.88 m
(2H, 3′-H, 4′-H), 7.15 d.d (1H, 5′-H, J = 4.9, 1.4 Hz).
Found, %: C 64.90; H 9.60; N 9.60. C16H28N2OS. Cal-
culated, %: C 64.82; H 9.52; N 9.45.
Amides XIII–XV (general procedure). A solution
of 0.01 mol of acetyl chloride in 20 ml of anhydrous
benzene was added dropwise to a mixture of 0.01 mol
of amine IV, V, or IX and 0.01 mol of triethylamine in
50 ml of anhydrous benzene. The mixture was heated
for 3 h under reflux, cooled, washed with water, and
dried, the solvent was distilled off, and the residue was
distilled under reduced pressure.
N-{3-[(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-
(methyl)amino]propyl}-N-(furan-2-ylmethyl)acet-
amide (XIII). Yield 66%, bp 185–190°C (2 mm). IR
1
spectrum, ν, cm–1: 1600, 1650 (C=O). H NMR spec-
trum (two stereoisomers at a ratio of 50:50), δ, ppm:
1.14 s and 1.15 s (3H each, CH3), 1.23 m and 1.36 m
(1H each, CH2, pyran), 1.45–1.65 m (4H, NCH2CH2
and CH2, pyran), 2.04 s and 2.10 s (1.5H each,
COCH3), 2.14 br and 2.15 br (1.5H each, NCH3),
2.35 m (2H, NCH2), 2.64 m (1H, 4-H), 3.21–3.31 m
(2H, NCH2), 3.50 m and 3.62–3.70 m (1H each, 6-H),
4.44 s and 4.46 s (1H each, 2′-CH2), 6.19 m and
6.23 m (0.5H each, 3′-H), 6.29 d.d and 6.32 d.d (0.5H
each, 4′-H, J = 3.1, 1.9 Hz), 7.36 d.d (0.5H, 5′-H, J =
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SYNTHESIS AND SOME TRANSFORMATIONS OF N,2,2-TRIMETHYLTETRAHYDRO...
93
1.9, 0.8 Hz), 7.42 d.d (0.5H, 5′-H, J = 1.9, 0.8 Hz).
Found, %: C 67.10; H 9.34; N 8.73. C18H30N2O3. Cal-
culated, %: C 67.05; H 9.38; N 8.69.
Stark trap until water no longer separated. The solvent
was removed, and the residue was distilled under
reduced pressure or recrystallized from ethanol).
N-{3-[(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-
(methyl)amino]propyl}-N-(4-methoxybenzyl)acet-
amide (XIV). Yield 70%, bp 235–240°C (3 mm). IR
spectrum, ν, cm–1: 1610, 1650 (C=Carom); 1690 (C=O).
1H NMR spectrum (two stereoisomers at a ratio of
57:43), δ, ppm: 1.12 s and 1.14 s (3H each, 2-CH3),
1.21 d.d (1H, 3-H, J = 12.7, 12.0 Hz), 1.32 q.d (1H,
5-H, J = 12.1, 5.0 Hz), 1.44–1.57 m (2H, 3-H, 5-H),
1.59 m (2H, NCH2CH2), 2.01 s (1.3H) and 2.06 s
(1.7H) (CH3CO), 2.11 s (1.3H) and 2.12 s (1.7H)
(NCH3), 2.32 t (1.1H, J = 6.5 Hz) and 2.33 t (0.9H, J =
6.9 Hz) (CH3NCH2), 2.62 t.t (0.6H) and 2.63 t.t (0.4H)
(4-H, J = 12.1, 3.8 Hz), 3.20 m (2H, NCH2CH2),
3.48 t.d (1H, 6-H, J = 12.0, 2.3 Hz), 3.64 m (1H, 6-H),
3.75 s (1.7H) and 3.76 s (1.3H) (OCH3), 4.41 s
(1.1H) and 4.43 s (0.9H) (CH2C6H4), 6.75–6.86 m and
7.04–7.14 m (2H each, C6H4). Found, %: C 69.50;
H 9.50; N 7.80. C21H34N2O3. Calculated, %: C 69.58;
H 9.45; N 7.73.
2-{3-[(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-
(methyl)amino]propyl}-2,3-dihydro-1H-isoindole-
1,3-dione (XVI). Yield 70%, bp 208–210°C (2 mm).
IR spectrum, ν, cm–1: 1540, 1570 (C=Carom); 1620,
1
1670 (C=O). H NMR spectrum, δ, ppm: 1.13 s and
1.14 s (3H each, CH3), 1.21 t (1H, J = 12.4 Hz) and
1.33 d.t.d (1H, J = 12.4, 12.0, 5.0 Hz) (CH2, pyran),
1.50 m (2H, CH2, pyran), 1.75 m (2H, NCH2CH2),
2.16 s (3H, NCH3), 2.48 t (2H, CH3NCH2, J = 6.7 Hz),
2.69 t.t (1H, 4-H, J = 12.0, 3.8 Hz), 3.50 t.d (1H, 6-H,
J = 12.0, 2.4 Hz), 3.64 m (1H, 6-H), 3.65 m (2H,
NCH2), 7.74–7.84 m (4H, C6H4). Found, %: C 69.00;
H 8.00; N 8.54. C19H26N2O3. Calculated, %: C 69.06;
H 7.93; N 8.48.
4-{3-[(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-
(methyl)amino]propylamino}-4-oxobutanoic acid
(XVII). Yield 72%, mp 152°C. IR spectrum, ν, cm–1:
1
1660 (C=O, amide), 3232–3500 (OH). H NMR spec-
trum, δ, ppm: 1.15 s (6H, CH3), 1.24 t (1H, J =
12.4 Hz) and 1.35 d.t.d (1H, J = 12.4, 12.0, 5.1 Hz)
(CH2, pyran), 1.49–1.62 m (4H, NCH2CH2 and CH2,
pyran), 2.17 s (3H, NCH3), 2.29 m (2H, CH3NCH2),
2.38–2.45 m [4H, C(O)CH2CH2C(O)], 2.68 t.t (1H,
4-H, J = 12.0, 3.7 Hz), 3.07 t.d (2H, HNCH2, J = 6.8,
5.8 Hz), 3.51 t.d (1H, J = 12.0, 2.3 Hz) and 3.66 d.d.d
(1H, J = 12.0, 5.2, 1.9 Hz) (6-H), 4.95 br (1H, COOH),
7.51 t (1H, NH, J = 5.8 Hz). Found, %: C 60.00;
H 9.65; N 9.45. C15H28N2O4. Calculated, %: C 59.98;
H 9.40; N 9.33.
N-(4-Chlorobenzyl)-N-{3-[(2,2-dimethyltetra-
hydro-2H-pyran-4-yl)(methyl)amino]propyl}acet-
amide (XV). Yield 71%, bp 225–230°C (3 mm). IR
spectrum, ν, cm–1: 1690 (C=O); 1580, 1650 (C=Carom).
1H NMR spectrum (two stereoisomers at a ratio of
65:35), δ, ppm: 1.13 s and 1.15 s (3H each, CH3),
1.22 m (1H, 3-H), 1.33 m (1H, 5-H), 1.44–1.66 m (4H,
3-H, 5-H, NCH2CH2), 2.00 s (1H) and 2.09 s (2H)
(CH3CO), 2.12 s (1H) and 2.13 s (2H) (NCH3), 2.34 m
(2H, CH3NCH2), 2.63 m (1H, 4-H), 3.23 m (2H,
NCH2CH2), 3.49 t.d (1H, 6-H, J = 12.0, 2.3 Hz),
3.65 d.d.d (1H, 6-H, J = 12.0, 5.1, 1.9 Hz), 4.47 s
(1.3H) and 4.51 s (0.7H) (CH2C6H4), 7.16–7.34 m
(4H, C6H4). Found, %: C 65.53; H 8.60; N 7.70.
C20H31ClN2O2. Calculated, %: C 65.47; H 8.52;
N 7.63.
REFERENCES
1. Arutyunyan, N.S., Garibyan, K.M., Asatryan, T.O., Tosu-
nyan, A.O., and Akopyan, L.A., Arm. Khim. Zh., 1989,
vol. 42, p. 240.
Compounds XVI and XVII (general procedure).
A mixture of equimolar amounts of diamine III and
phthalic or succinic anhydride in benzene was heated
for 10 h under reflux in a flask equipped with a Dean–
2. Nazarov, I.N., Usp. Khim., 1949, vol. 18, p. 377.
3. Vartanyan, S.A., Zhamagortsyan, V.N., and Nora-
vyan, A.S., Izv. Akad. Nauk Arm. SSR, Khim. Nauki,
1963, vol. 16, p. 339.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 1 2012