Silyl modification of biologically active compounds. 10. Lipid type organosilicon derivatives of 8-hydroxyquinoline and n-(2-hydroxyethyl)-1,2,3,4- tetrahydro(sila, iso)quinolines

Article abstract of DOI:10.1007/s10593-005-0192-6

Organosilicon alkylation of the primary alcoholic groups of N-(2-hydroxyalkyl) derivatives of 1,2,3,4-tetrahydroquinoline, tetrahydroisoquinoline, and 4,4-dimethyltetrahydro-4-silaisoquinoline, and also the hydroxyl group of 8-hydroxyquinoline by trialkyl

Full text of DOI:10.1007/s10593-005-0192-6

Chemistry of Heterocyclic Compounds, Vol. 41, No. 5, 2005
SILYL MODIFICATION OF BIOLOGICALLY
ACTIVE COMPOUNDS. 10*. LIPID TYPE
ORGANOSILICON DERIVATIVES OF 8-HYDROXY-
QUINOLINE AND N-(2-HYDROXYETHYL)-
1,2,3,4-TETRAHYDRO(SILA, ISO)QUINOLINES
I. Segal, A. Zablotskaya, and E. Lukevics
Organosilicon alkylation of the primary alcoholic groups of N-(2-hydroxyalkyl) derivatives of
1,2,3,4-tetrahydroquinoline, tetrahydroisoquinoline, and 4,4-dimethyltetrahydro-4-silaisoquinoline, and
also the hydroxyl group of 8-hydroxyquinoline by trialkyl-chloroalkylsilanes under conditions of phase-
transfer catalysis has been investigated. The neurotropic properties and acute toxicity of the synthesized
compounds have been investigated.
Keywords: tetrahydroisoquinoline, tetrahydroquinoline, alkylation, phase-transfer catalysis,
psychotropic activity, silylation.
As a result of numerous investigations [1-10] it has been shown that silylation significantly increases the
lipophilicity of biologically active compounds and therefore assists their transport within the organism. This is
true not only in relation to reversibly silylated (hydrolytically unstable) compounds but also to compounds
containing a triorganosilyl(oxy) group stable to hydrolysis under physiological conditions.
According to literature data certain tetrahydro(iso)quinoline-containing ligands reveal affinity towards
serotonin (5-HT1A) [11, 12], dopamine [13], and N-methyl-D-aspartate (NMDA) [14] receptors, and certain
opiate alkaloids contain hydrogenated residues of quinoline and isoquinoline [15]. In addition it was noted that
on silylation of both aliphatic and heterocyclic amino alcohols, and also their salts, which are structural analogs
of the neuromediators choline and colamine (2-aminoethanol), psychotropic activity is increased [16, 17], and
the acute toxicity of the synthesized compounds is reduced [18].
With the aim of improving the pharmacological properties of biologically active molecules in vivo we
propose to extend this principle to organosilicon derivatives of N-heterocyclic amino alcohols, simultaneously
pursuing the aim of constructing lipid type bipolar compounds, consisting of derivatives of hydroxyquinoline or
tetrahydroquinoline, tetrahydroisoquinoline, and tetrahydrosilaisoquinoline as hydrophilic "heads", and
lipophilic trimethylsilylpropoxyethyl "tails".
We have developed a method of obtaining 8-(3-trimethylsilylpropoxy)quinoline 1 by the interaction of
8-hydroxyquinoline with (3-chloropropyl)trimethylsilane under phase-transfer catalysis conditions [19].
_______
* For Part 9 see [1].
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: aez@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 5, pp. 713-725, May, 2005. Original article submitted July 7, 2004.
0009-3122/05/4105-0613©2005 Springer Science+Business Media, Inc.
613

Organosilicon alkylation was carried out in the system benzene/KOH/KI/AliquatR 336 and according to
our experimental data proved to be more efficient than synthesis from the lithium salt of 8-hydroxyquinoline.
From the data of physicochemical investigations reaction proceeds with the formation of the O-alkyl derivative.
Scheme 1
Me3SiCH2Cl
N
C6H6/KOH/KI/AliquatR336
OCH2SiMe3
N
OH
Me3Si(CH2)3Cl
N
OCH2CH2CH2SiMe3
1
The developed method was used for the organosilicon alkylation of the primary alcoholic groups of
N-(2-hydroxyethyl) derivatives of 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline in the
synthesis of the corresponding N-trialkylsilylalkoxyethyl derivatives (4-7, 11-14). The interaction of compounds
1, 5, 11, and 15 with methyl iodide gave their iodomethylates 18-21 respectively.
The initial amino alcohols of 1,2,3,4-tetrahydroquinoline (2) and 1,2,3,4-tetrahydroisoquinoline (9) were
obtained by the hydroxyethylation of the appropriate heterocyclic base with ethylene iodohydrin [18] or ethylene
bromohydrin (Schemes 2 and 3).
In addition to the products of hydroxyethylation with ethylene iodohydrin N-(2-hydroxyethyl)-1,2,3,4-
tetrahydroquinoline and N-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline [18], we detected in the reaction
mixture the products of double O-alkylation 3 and 10 in 4 and 14% yield, respectively. These were isolated and
characterized by 1H NMR spectroscopy and chromato-mass spectrometry.
By replacing ethylene iodohydrin by ethylene bromohydrin in the hydroxyethylation reaction an
increase was noted in the yield of N-(2-hydroxyethyl)-1,2,3,4-tetrahydroquinoline and N-(2-hydroxyethyl)-
1,2,3,4-tetrahydroisoquinoline of more than twofold in comparison with the published data [18].
When obtaining compound 4 the phase-transfer organosilicon alkylation of N-(2-hydroxyethyl)-1,2,3,4-
tetrahydroquinoline with trimethyl(3-chloropropyl)silane was carried out in two systems: C6H6/KOH/KI/Aliquat
336R and C6H6/K2CO3/KI/18-crown-6 with variation of the reactant ratio and of the reaction time and
temperature. The system C6H6/KOH/KI/Aliquat 336R proved to be more efficient (Table 1).
TABLE 1. Synthesis of N-[2-(3-trimethylsilylpropoxy)ethyl]-1,2,3,4-
tetrahydroquinoline 4
Ratio [THQ] :
Reaction
[silane],
Catalyst
Temperature, °C
Yield, %
time, h
mole/mole
2:1
2:1
1:2
KOH/AliquatR 336
KOH/AliquatR 336
KOH/AliquatR 336
KOH/KI/AliquatR 336
K2CO3/KI/18-Crown-6
4
7
14
14
7
20
80
80
80
80
—
4
5
1:1.05
1:1
32
19
614

Scheme 2
N
HalCH2CH2OH
Hal = I, Br
CH2CH2OCH2CH2OH
3
N
H
N
2
C6H6/KOH/KI/AliquatR336
CH2CH2OH
R3SiCH2Cl
R1R2R3Si(CH2)3Cl
(
R = Me, Et)
+
N
N
N
CH2CH2O(CH2)3Si R1R2R3
CH2CH2OCH2SiR3
CH2CH2OMe
4–6
7
8
4 R1R2R3 = Me3; 5 R1R2 = Am2, R3 = Me; 6 R1R2 = Me2, R3 = Hp; 7 R = Me
It has revealed that interaction of N-(2-hydroxyethyl)-1,2,3,4-tetrahydroquinoline with
N-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline with chloromethyltrialkylsilanes under these conditions
(Schemes 2 and 3) resulted in the formation of desired N-[2-(trimethylsilylmethoxy)ethyl]-1,2,3,4-
tetrahydroquinoline (7) and N-2-(trimethylsilylmethoxy)ethyl]-1,2,3,4-tetrahydroisoquinoline (14) formed in
trace amounts of 4 and 0.4%, respectively.
The formation of the corresponding methyl ethers 8 and 15 (yields 42 and 48%) proceeds in significant
amounts in this reaction [20, 21]. The structure of the latter was confirmed by alternate syntheses: a) using
2-chloroethyl methyl ether as alkylating agent under conditions of phase-transfer catalysis in the system
toluene/K2CO3/KI/18-crown-6 [20], and b) by alkylation of N-(2-hydroxyethyl)tetrahydroisoquinoline sodium
salt with methyl iodide in situ. In the latter case, besides of the main product 15 (56% yield), compound 16,
1
containing C=O group was isolated (10% yield) from the reaction mixture and characterized by H NMR, IR,
and chromato-mass spectroscopy. The characteristic absorption band at 1745 cm-1 confirmed C=O group
presence in the molecule.
It could be speculated that compound 16 is formed by the interaction of unreacted N-(2-hydroxyethyl)-
1,2,3,4-tetrahydroisoquinoline sodium salt with ethyl acetate under the conditions of chromatography on silica
gel.
It could be noted that attempts to avoid the formation of the iodomethylate and to carry out methylation
of the primary alcoholic group of N-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline with methyl iodide under
phase-transfer catalysis conditions in the system benzene/KOH/AliquatR 336, lead, besides O- and
N-methylation, to opening of the hydrogenated ring of the tetrahydroisoquinoline system with the formation of
1
compound 17 in 32% yield, the structure of which was established by H NMR and chromato-mass
spectroscopy.
615

616

TABLE 2. 1H NMR Spectra of Compounds 1, 3-6, 8, 10-13, 15-21, 23
Com-
pound
Chemical shifts, δ, ppm. (J, Hz)
1
3
4
0.18 (9H, s, Si(CH3)3; 0.79 (2H, m, SiCH2); 2.07 (2H, m, CH2);
4.32 (2H, t, J = 7.5, OCH2); 7.09-9.09 (6H, m, arom.)
1.91 (2H, m, 3-CH2); 2.44 (1H, br. s, OH); 2.72 (2H, t, J = 6, 4-CH2);
3.12-3.71 (10H, m, 2-CH2+NCH2+OCH2); 6.42-7.28 (4H, m, arom.)
0.02 (9H, c, Si(CH3)3; 0.49 (2H, m, SiCH2); 0.89 (2H, br. s, CH2); 1.93 (2H, m, 3-CH2);
2.73 (2H, t, J = 6, 4-CH2); 3.16-3.90 (8H, m, NCH2+OCH2+2-CH2);
6.35-7.14 (4H, m, arom.)
5
6
-0.04 (3H, s, SiCH3); 0.51 (6H, m, SiCH2); 0.90 (6H, t, J = 6.5, CH3);
1.31 (14H, br. s, CH2); 1.97 (2H, m, 3-CH2); 2.77 (2H, t, J = 6, 4-CH2);
3.27-3.66 (8H, m, NCH2+ OCH2+ 2-CH2); 6.44-7.17 (4H, br. s, arom.)
-0.02 (6H, s, Si(CH3)2); 0.51 (4H, m, SiCH2); 0.90 (3H, t, J = 6.5, CH3);
1.29 (10H, br. s, CH2); 1.98 (2H, m, 3-CH2); 2.78 (2H, t, J = 6, 4-CH2);
3.23-3.65 (8H, m, NCH2+OCH2+2-CH2); 6.40-7.20 (4H, br. s, arom.)
8
1.92 (2H, m, 3-CH2); 2.75 (2H, t, J = 6, 4-CH2);
3.23-3.66 (9H, m, OCH3+OCH2+2-CH2+ NCH2); 6.47-7.31 (4H, m, arom.)
10
11
2.58-3.01 (8H, m, 3,4-CH2+NCH2+OCH2); 3.35-4.01 (6H, m, OCH2 + 1-CH2);
6.88-7.13 (4H, m, arom.)
0.018 (9H, s, Si(CH3) 3); 0.52 (2H, m, SiCH2); 1.64 (2H, m, CH2);
2.80 (2H, t, J = 6, NCH2), 2.91 (4H, m, 3,4-CH2); 3.49 (2H, t, J = 7, OCH2);
3.69 (2H, t, J = 6, OCH2); 3.80 (2H, s, 1-CH2); 7.13 (4H, m, arom.)
12
13
-0.06 (3H, s, SiСН3); 0.49 (6H, m, SiCH2); 0.89 (6H, t, J = 6.5, CH3);
1.33 (12H, br. s, CH2); 1.60 (2H, m, CH2); 2.78 (2H, t, J = 6, NCH2);
2.90 (4H, m, 3,4-CH2); 3.56 (4H, m, OCH2); 3.73 (2H, br. s, 1-CH2); 7.09 (4H, m, arom.)
0.01 (6H, s, Si(CH3)2); 0.51 (4H, m, SiCH2); 0.91 (3H, t, J = 6.5, CH3); 1.27 (10H, br. s, CH2);
1.62 (2H, m, CH2); 2.78 (2H, t, J = 6, NCH2); 2.81 (2H, t, J = 6, 4-CH2);
2.92 (2H, t, J = 6, 3-CH2); 3.44 (2H, m, OCH2); 3.67 (2H, t, J = 6, OCH2);
3.73 (2H, br. s, 1-CH2); 7.10 (4H, m, arom.)
15
16
17
2.77 (2H, t, J = 6, NCH2); 2.83 (4H, m, 3,4-CH2); 3.37 (3H, s, OCH3);
3.47 (2H, t, J = 6, OCH2); 3.72 (2H, s, 1-CH2); 6.92-7.12 (4H, m, arom.)
2.06 (H, s, COCH3); 2.60-2.99 (6H, m, 3,4-CH2+NCH2); 3.68 (2H, s, 1-CH2);
4.17-4.36 (2H, t, J = 6, OCH2); 6.87-7.19 (4H, m, arom.)
2.24 (3H, s, NCH3); 2.62 (2H, t, J = 7, NCH2); 3.34 (3H, s, OCH3);
3.49 (3H, t, J =7, OCH2); 3.57 (2H, s, ArCH2N); 5.20 (1H, dd, J = 12, J = 2, cis=CH2),
5.60 (1H, dd, J = 18, J = 2, trans =CH2); 7.03-7.67 (5H, m, =CH + arom.)
18
19
0.04 (9H, s, Si(CH3)3); 0.62 (2H, m, SiCH2); 1.93 (2H, m, CH2);
4.18 (2H, t, J = 7.5, OCH2); 5.07 (3H, s, N+Me); 7.49-10.11 (6H, m, arom.)
-0.07 (3H, s, SiCH3); 0.49 (6H, m, SiCH2); 0.91 (6H, t, J = 6.5, CH3);
1.33 (14H, br. s, CH2); 2.33 (2H, m, 3-CH2); 3.02 (2H, t, J = 6, 4-CH2);
3.29 (2H, m, NCH2); 3.51-4.04 (4H, m, OCH2); 4.00 (3H, s, N+Me); 4.60 (2H, m, 2-CH2);
7.27-8.31 (4H, m, arom.)
20
0.04 (9H, s, Si(CH3)3); 0.48 (2H, m, SiCH2); 1.51 (2H, m, CH2);
3.16-3.51 (4H, m, 3,4-CH2); 3.58 (3H, s, N+Me); 3.83-4.34 (6H, m, NCH2+OCH2);
4.97 (2H, s, 1-CH2); 7.00-7.50 (4H, m, arom.)
21
23
2.72-2.91 (6H, m, 3,4-CH2+NCH2); 3.22 (3H, s, OCH3); 3.54 (2H, t, J = 6, OCH2),
4.02 (3H, s, N+Me); 5.02 (2H, s, 1-CH2); 7.15-7.34 (4H, m, arom.)
0.01 (9H, s, Si(CH3)3); 0.21 (6H, s, Si(CH3)2); 0.42 (2H, t, J = 6.5, SiCH2);
1.29 (2H, br. s, CH2); 1.80 (2H, s, SiCH2N); 2.22 (2H, t, J = 6, NCH2);
2.44 (2H, m, OCH2); 3.49 (2H, s, 1-CH2); 3.90 (2H, m, OCH2);
6.99-7.51 (4H, br. s, arom.)
The developed method of silicoalkylation of a hydroxyl group under conditions of phase-transfer
catalysis was also used to obtain the 2-(trimethylsilylpropoxy)ethyl derivative of tetrahydroisoquinoline with a
silicon atom in the ring (23) from N-(2-hydroxyethyl)-4,4-dimethyl-1,2,3,4-tetrahydro-4-silaisoquinoline (22)
[22] and (3-chloropropyl)trimethylsilane.
617

Scheme 4
Me3Si(CH2)3Cl
C6H6/KOH/KI/AliquatR336
Si
Si
NCH2CH2OH
NCH2CH2O(CH2)3SiMe3
22
23
The neurotropic properties and the acute toxicity of the synthesized compounds have been investigated.
The action of substances on the CNS was assessed according to indicators of the rotating rod, tube, and traction
tests, characterizing the effect of compounds on the tone of the skeletal musculature and motor coordination, and
also according to tests of rectal temperature, analgesia, hypoxic hypoxia, Phenamine hyperactivity, hexenal and
ethanol narcosis, Corazole convulsions, electroshock, conditioned avoidance response and retrograde amnesia,
and the Porsolt test.
The results of the study of neurotropic properties and acute toxicity of the synthesized compounds are
given in Tables 3 and 4.
It follows from the data of Table 3 that the acute toxicity depends on the substituent in the
2-hydroxyethyl sidechain, and silicoalkylation contributes to a reduction of toxicity. In the series of
N-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinolines 11-15 the toxicity falls on going from compound 15
containing no organosilicon substituent to a compound with trimethylsilyl- (11), heptyldimethylsilyl- (13), and
diamylmethylsilylpropyl group (12) tenfold. Approximately the same rule became apparent on investigating
derivatives of 1,2,3,4-tetrahydroquinoline 4-8. The influence of the nature of the heterocycle may be noticed on
comparing derivatives of 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline. The toxicity of the first
was lower in some cases with analogous substituents at the nitrogen atom (see 6 and 13, 8 and 15). The
TABLE 3. Effect of Organosilicon Derivatives of 8-Hydroxyquinoline and
N-(2-Hydroxyethyl)tetrahydro(sila, iso)quinolines on the Tone of Skeletal
Musculature and Motor Coordination
ED50, mg/kg
Com-
pound
LD50,
mg/kg
Test
rotating
rod
rectal
tube
narcosis analgesia
traction
temperature
1
447
650
>500
>500
>500
258
>500
>500
355
346
355
355
355
410
112
10.3
51.5
8.1
410
>500
>500
>400
355
>500
>500
>500
>400
>500
>500
>500
>500
>250
>20
258
410
>500
>500
346
163
355
325
325
325
129
14.1
44.7
16.3
>50
325
4
5
>2500
2820
1030
650
>500
172
435
6
8
355
11
12
13
15
18
19
20
21
23
>500
325
>500
355
>500
>500
325
2820
2240
282
>500
205
447
>250
12.9
51.5
14.1
27.4
355
178
20.5
65
16.3
56.4
14.1
44.7
410
8.9
44.7
8.9
>50
70.8
65
815
>50
35.5
325
>50
>500
35.5
>500
618

619

introduction of a silicon atom into the tetrahydroisoquinoline ring (23) also assists a reduction in the acute
toxicity compared with the carbon analog 11. As a result of quaternization at nitrogen (18-21) the acute toxicity
of compounds 1, 5, 11, and 15 is increased.
Depriming activity in the rotating rod, tube, and traction tests was expressed weakly for the synthesized
compounds, and as a rule was displayed at doses close to lethal. However salts 18-20 of silicoalkylated
derivatives of 8-hydroxyquinoline, 1,2,3,4-tetrahydroquinoline, and 1,2,3,4-tetrahydroisoquinoline possessed
clearly expressed depriming activity and analgesic action.
In difference to compound 8, containing no trialkylsilylalkyl substituent and reliably reducing the
lifespan of mice under conditions of hypoxia by 17%, all the investigated silicoalkylated derivatives displayed
antihypoxic properties and prolonged the life of mice under conditions of hypoxia by 15-46%. The most active
antihypoxic agents were salts 18-21.
Almost all of the synthesized compounds at a dose of 5 mg/kg are synergists of hexenal and ethanol,
reliably extending their narcotic action by 20-127% and by 40-150% respectively. The most reliable extension of
narcotic action (by 2.3 times for hexenal and 2.5 times for ethanol) on introducing an organosilicon substituent
was noted in the case of the iodomethylates of trimethylsilylpropyl derivatives of 8-hydroxyquinoline 18 and
1,2,3,4-tetrahydroisoquinoline 20 respectively. Tetrahydrosilaisoquinoline 23 is a stronger agonist of ethanol
compared with its carbon analog 11.
The only compound displaying a reliable reduction of the duration of narcosis (by 32%, ethanol) was
N-[-2-(3-trimethylsilylpropoxy)ethyl]-1,2,3,4-tetrahydroquinoline (4).
All the compounds studied possess antispasmodic action in corazole spasm (clonic and tonic) increasing
their threshold by 18-81% in the tonic and by 14-134% in the clonic phase. In the clonic phase of this test
compounds in which more bulky or long organosilicon substituents are present (5, 6, 13, and 15) are stronger
anticonvulsants. The greatest antispasmodic activity was possessed by the diaminomethyl- (5) and
heptyldimethylsilylpropyl- (6) derivatives of 1,2,3,4-tetrahydroquinoline. The investigated substances did not
display protective properties in maximal electroshock.
Almost all the investigated compounds act as amphetamine antagonists, reducing the locomotor activity
caused by administration of amphetamine by 24-69%. The greatest antagonistic effect on interacting with
amphetamine was observed for the trimethylsilylpropyl derivatives of 8-hydroxyquinoline 1 and
1,2,3,4-tetrahydroisoquinoline 11 and has a tendency to strengthen with additional alkylation of the nitrogen
(compounds 18 and 20). The only compound reliably strengthening the action of amphetamine (by 1.7 times,
66.4%) was compound 21, containing no organosilicon substituent.
Study of the effect of the investigated substances on memory processes showed that the greatest activity
was displayed by compounds 5, 18, and 20, which at a dose of 5 mg/kg completely (100%) prevented retrograde
amnesia.
Antistress activity in the Porsolt test is a reliable characteristic of the majority of the investigated
compounds (6, 8, 13, 18, 19, 23), with the exception of 1, 5, and 11. The introduction of a silicon atom into the
tetrahydroisoquinoline ring (compound 23) shows up positively on the display of sedative action compared with
its carbon analog 11.
As a result of the investigations carried out a dominant display is shown of a definite type of neurotropic
properties depending on the nature of the heterocyclic base, and also on the presence of a silicon atom in the
molecule. Tetrahydro-isoquinolines possess
a
tranquilizing/sedative action, tetrahydrosilaisoquinoline
derivatives an antihypnotic action (reduction in the duration of sleep caused by the action of ethanol).
Tetrahydroquinolines display an antispasmodic effect (pentylene-tetrazole-induced spasm test).
The data obtained show the expediency of a selected rational approach to the construction of new
neurotropic substances among silicon-containing heterocyclic derivatives.
620

EXPERIMENTAL
1
The H NMR spectra were taken on a Bruker WH 90/DS (90 MHz) spectrometer in CDCl3, internal
standard was TMS, 29Si NMR spectra were taken on a Mercury 200 Varian (40 MHz) spectrometer. Mass
spectra were recorded on a HP 6890 GC-MS instrument. GLC analysis was carried out on a Chrom-42
chromatograph with a flame-ionization detector and a glass column (1.2 m x 3 mm) with 5% OV-17 on
Chromosorb W-AW (60-80 mesh). Chromatographic separation of reaction products was carried out on an Acros
column (carrier was silica gel 0.060-0.200 mm, pore diameter 4 nm). Elemental analysis was carried out with the
aid of a Carlo Erba 1108 analyzer.
N-(2-Hydroxyethyl)-1,2,3,4-tetrahydroquinoline
tetrahydroisoquinoline (9) were synthesized by the procedure of [18].
N-(2-Hydroxyethyl)-4,4-dimethyl-1,2,3,4-tetrahydro-4-silaisoquinoline (22) was synthesized by the
procedure of [22].
Salts of Compounds 18-21 were obtained by the procedure described in [23].
Silicoalkylation of 8-Hydroxyquinoline, N-(2-Hydroxyethyl)-1,2,3,4-tetrahydroquinoline,
N-(2-Hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline, and N-(2-Hydroxyethyl)-4,4-dimethyl-1,2,3,4-
(2)
and
N-(2-Hydroxyethyl)-1,2,3,4-
tetrahydro-4-silaisoquinoline Under Conditions of Phase-transfer Catalysis (General Procedure).
A mixture of the heterocyclic 2-amino alcohol (1 equiv., 28 mmol), potassium hydroxide (5 equiv., 140 mmol),
potassium iodide (2 equiv., 56 mmol), trialkylchloroalkylsilane (1.05 equiv., 29 mmol), and AliquatR 336
(0.05 equiv., 1.4 mmol) in dry benzene (25 ml) was stirred at the boiling point of the solvent for 10-14 h. The
solid was then filtered off, and the solvent removed from the filtrate. The product was isolated by distillation in
vacuum or by separation on a chromatographic column.
8-(3-Trimethylsilylpropoxy)quinoline (1) was isolated in 19% yield, bp 175°C (14 mm Hg). Found, %:
C 68.72; H 9.22; N 5.23. C15H25NOSi. Calculated, %: C 68.38; H 9.56; N 5.32.
N-[2-(2-Hydroxyethoxy)ethyl]-1,2,3,4-tetrahydroquinoline (3) was isolated in 4% yield;
bp 167-168°C (2 mm Hg). Mass spectrum (EI, 70 eV), m/z (Irel): 221 (18) [M]+, 158 (4) [M-OCH2CH2OH]+, 146
(100) [M-CH2OCH2CH2OH]+. Found, %: C 70.97; H 8.94; N 6.44. C13H19NO. Calculated, %: C 70.56; H 8.65;
N 6.33.
N-[2-(3-Trimethylsilylpropoxy)ethyl]-1,2,3,4-tetrahydroquinoline (4) was isolated in 32% yield;
bp 164°C (3 mm Hg). Found, %: C 70.01; H 10.03; N 4.90. C17H29NOSi. Calculated, %: C 70.10; H 9.97;
N 4.81.
N-[2-(3-Diamylmethylsilylpropoxy)ethyl]-1,2,3,4-tetrahydroquinoline (5) was isolated in 43% yield;
bp 128 °C (3 mm Hg). Found, %: C 74.27; H 11.34; N 3.52. C25H45NOSi. Calculated, %: C 74.38; H 11.23;
N 3.47.
N-[2-(3-Heptyldimethylsilylpropoxy)ethyl]-1,2,3,4-tetrahydroquinoline (6) was isolated in 37%
yield; bp 178-180°C (3 mm Hg). Found, %: C 73.29; H 11.24; N 3.82. C23H41NOSi. Calculated, %: C 73.54;
H 11.00; N 3.73.
N-[2-(Trimethylsilylmethoxy)ethyl]-1,2,3,4-tetrahydroquinoline (7) was isolated in 4% yield by
chromatographic separation on a column. Eluent was CH2Cl2. The content of main substance was 86% according
to mass spectrometric data. Mass spectrum (EI, 70 eV), m/z (Irel, %): 263 (10) [M]+, 248 (1) [M-Me]+, 190 (1)
[M-SiMe3]+,
[M-ArCH2CH2CH2NCH2CH2OCH2]+.
N-(2-Methoxyethyl)-1,2,3,4-tetrahydroquinoline (8) was obtained by two procedures.
160
(4)
[M-OCH2SiMe3]+,
146
(100)
[M-CH2OCH2SiMe3]+,
73
(11)
A. (Using Me3SiCH2Cl). Isolated in 41% yield by chromatographic separation of the reaction products
on a column, eluent was ethyl acetate–hexane, 1:10.
621

B. (Using Et3SiCH2Cl). Isolated in 42% yield; bp 135-137°C (4 mm Hg). Content of main substance was
98.2% according to HPLC data (Symmetry C18, 4.6 × 150 mm, system: 70% acetonitrile + 30% [0.1% H3PO4 +
H2O], pH 2.5), UV detector (λ = 220 nm). Mass spectrum (EI, 70 eV), m/z (Irel, %): 191 (17) [M]+, 146 (100)
[M-CH2OCH3]+. Found, %: C 75.43; H 9.04; N 7.25. C12H17NO. Calculated, %: C 75.35; H 8.96; N 7.32.
N-[2-(2-Hydroxyethoxy)ethyl]-1,2,3,4-tetrahydroisoquinoline (10) was isolated in 14% yield;
bp 194-195°C (3 mm Hg). Found, %: C 70.64; H 8.44; N 6.27. C13H19NO. Calculated, %: C 70.56; H 8.65;
N 6.33.
N-[2-(3-Trimethylsilylpropoxy)ethyl]-1,2,3,4-tetrahydroisoquinoline (11) was isolated in 66% yield;
bp 179-181°C (4 mm Hg). 29Si NMR spectrum (CDCl3), δ, ppm: -0.70. Found, %: C 70.15; H 10.09; N 4.98.
C17H29NOSi. Calculated, %: C 70.10; H 9.97; N 4.81.
N-[2-(3-Diamylmethylsilylpropoxy)ethyl]-1,2,3,4-tetrahydroisoquinoline (12) was isolated in 58%
yield; bp 225-227°C (3 mm Hg). Found, %: C 74.92; H 11.66; N 3.79. C25H45NOSi. Calculated, %: C 74.38;
H 11.23; N 3.47.
N-[2-(3-Heptyldimethylsilylpropoxy)ethyl]-1,2,3,4-tetrahydroisoquinoline (13) was isolated in 72%
yield; bp 200-202°C (3 mm Hg). Found, %: C 73.67; H 10.56; N 3.96. C23H41NOSi. Calculated, %: C 73.54;
H 11.00; N 3.73.
N-[2-(3-Trimethylsilylmethoxy)ethyl]-1,2,3,4-tetrahydroisoquinoline (14) was detected in the
reaction in an analytical amount (0.4%). Mass spectrum (EI, 70 eV), m/z (Irel): 263 (1) [M]+, 248 (2) [M-Me]+,
160 (6) [M-OCH2SiMe3]+, 146 (100) [M-CH2OCH2SiMe3]+, 132 (10) [M-CH2CH2OCH2SiMe3]+, 73 (12)
[M-ArCH2CH2CH2NCH2CH2OCH2]+.
N-(2-Methoxyethyl)-1,2,3,4-tetrahydroisoquinoline (15) was isolated in 48% yield; bp 126-128°C
(3 mm Hg). Mass spectrum (EI, 70 eV), m/z (Irel, %): 191 (15) [M]+, 146 (100) [M-CH2OCH3]+. Found, %:
C 75.10; H 9.07; N 7.52. C12H17NO. Calculated, %: C 75.35; H 8.96; N 7.32.
N-(2-Acetoxyethyl)-1,2,3,4-tetrahydroisoquinoline (16). A mixture of N-(2-hydroxyethyl)-1,2,3,4-
tetrahydroisoquinoline (2.0 g, 11.3 mmol) and metallic sodium (0.14 g, 6.2 mmol) in dry benzene (4 ml) was
heated with stirring until complete disappearance of sodium. The mixture was diluted with benzene (10 ml),
cooled to +5°C, methyl iodide (0.81 g, 5.7 mmol) was added, and stirring continued at room temperature for 2 h.
The solid was then filtered off, the solvent was removed from the filtrate, and the residue was chromatographed
on silica gel, eluent was ethyl acetate. Two products were isolated, one of which (56% yield calculated on
1
methyl iodide), according to data of H NMR and chromato-mass spectrometry, was identical to compound 15.
Product 16 was isolated in 10% yield (calculated on the initial hydroxyethyltetrahydroisoquinoline). Mass
spectrum (EI, 70 eV), m/z (Irel, %): 218 (1) [M-H]+, 176 (1) [M-COCH3]+, 159 (10) [M-OCOCH3-H]+, 146 (100)
[M-CH2OCOCH3]+, 132 [M-CH2CH2OCOCH3]+. Found, %: C 71.55; H 7.81; N 6.08. C13H17NO2.
Calculated, %: C 71.23; H 7.76; N 6.39
[N-(2-Methoxyethyl)-N-methyl]-2-vinylbenzylamine (17). A mixture of N-(2-hydroxyethyl)-1,2,3,4-
tetrahydroisoquinoline (0.60 g, 3.4 mmol), potassium hydroxide (0.95 g, 17.0 mmol), methyl iodide (0.52 g,
3.7 mmol), and AliquatR 336 (0.07 g, 0.17 mmol) in benzene (1.5 ml) was heated with stirring for 3.5 h. The
solid was then filtered off, the solvent was removed from the filtrate, and the residue chromatographed on silica
gel using ethyl acetate–methylene chloride, 1:1, as eluent. The product was isolated in 32% yield (calculated on
methyl iodide). Mass spectrum (EI, 70 eV), m/z (Irel): 205 (1) [M]+, 174 (1) [M-OCH3]+, 160 (54)
[M-CH3OCH2]+, 147 (7) [M-OCH3-CH=CH2]+, 130 (2), 117 (100) [M-CH3NCH2CH2OCH3]+, 102 (4), 91 (26).
Found, %: C 75.57; H 9.44; N 6.72. C13H19NO. Calculated, %: C 76.06; H 9.33; N 6.82.
8-(3-Trimethylsilylpropoxy)quinoline Iodomethylate (18) was isolated in 47% yield; mp 105-107°C
(ethanol–diethyl ether). Found, %: C 47.56; H 6.02; N 3.45. C16H24INOSi. Calculated, %: C 47.88; H 5.98;
N 3.49.
N-[2-(3-Diamylmethylsilylpropoxy)ethyl]-1,2,3,4-tetrahydroquinoline Iodomethylate (19) was
isolated in 59% yield; mp 75-76°C (ethanol–diethyl ether). Found, %: C 56.92; H 8.65; N 2.71. C26H48INOSi.
Calculated, %: C 57.17; H 8.80; N 2.57.
622

N-[2-(3-Trimethylsilylpropoxy)ethyl]-1,2,3,4-tetrahydroisoquinoline Iodomethylate (20) was
isolated in 52% yield; mp 80-82°C (ethanol–diethyl ether). Found, %: C 49.83; H 7.45; N 3.27. C18H32INOSi.
Calculated, %: C 49.87; H 7.44; N 3.23.
N-(2-Methoxyethyl)-1,2,3,4-tetrahydroisoquinoline Iodomethylate (21) was isolated in 58% yield;
mp 135-137°C (ethanol–diethyl ether). Found, %: C 46.63; H 6.01; N 4.19. C13H20INO. Calculated, %: C 46.82;
H 6.00; N 4.20.
4,4-Dimethyl-N-[2-(3-trimethylsilylpropoxy)ethyl]-1,2,3,4-tetrahydro-4-silaisoquinoline (23) was
isolated in 21% yield; bp 100-101°C (4 mm Hg). Found, %: C 64.53; H 10.00; N 4.13. C18H33NOSi2.
Calculated, %: C 64.28; H 9.82; N 4.17.
BIOLOGICAL EXPERIMENTAL
Neurotropic activity was studied in BALB/c strain mice and in random-bred male rats. An oil solution of
the substance being investigated was administered intraperitoneally 30 min before carrying out the experiment.
Comparative assessment of the action of the substance being investigated at a dose of 5 mg/kg was carried out on
groups of 6 animals on the indicators of hypoxia, hexenal and ethanol narcosis, amphetamine hyperactivity,
corazole spasm, training, and the Porsolt test.
The action of a substance on the central nervous system was assessed 1) by its effect on motor
coordination and muscle tone (rotating rod, pipe, hanging on a beam); 2) on body temperature; 3) on analgesic
effect (hot plate test); 4) on antispasmodic activity (maximal electroshock test, alternating current 50 mA,
50 imp./sec at stimulation time 0.2 sec, and corazole spasms caused by an intravenous titration with 1% corazole
solution at 0.01 ml/sec); 5) on the duration of hexenal (0.4% hexenal solution at 70 mg/kg intravenously) and
ethanol narcosis (4 g/kg intraperitoneally); 6) by the duration of life under conditions of hypoxic hypoxia caused
by placing mice (singly) in a hermetically sealed chamber of volume 220 cm3 without absorption of carbon
dioxide gas; 7) by locomotor activity and body temperature on joint action with amphetamine
(0.4% amphetamine solution subcutaneously 10 mg/kg); 8) by the unavoidable stress situation (Porsolt test) and
the action on memory processes and retrograde amnesia.
The acute toxicity on intraperitoneal injection was also determined and the mean lethal dose
(LD50, mg/kg) established.
The experimental data were processed statistically. The express method [24] was used for calculating the
mean effective (ED50) and mean lethal (LD50) doses. For assessing the mean duration of narcotic action of
hexenal and alcohol, amphetamine hyperactivity, hypoxia, protective action on corazole spasm, the arithmetic
mean values and their standard errors (M±m) in comparison with the appropriate control data were calculated.
Assessment of the significance of the differences between the mean values was carried out on the basis of the
Student criterion. Differences were regarded as significant at a level of probability P ≤ 0.05.
The authors are grateful to Doctor of Medical Sciences S. K. Germane for carrying out the biological
experiment.
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