Silyl modification of biologically active compounds. 13. Synthesis, cytotoxicity and antibacterial action of N-methyl-N-(2-triorganylsiloxyethyl)-1, 2,3,4-tetrahydro(iso)quinolinium iodides

Article abstract of DOI:10.1002/aoc.2952

A series of N-methyl-N-(2-triorganylsiloxyethyl)-1,2,3,4-tetrahydro(iso) quinolinium iodides has been synthesized via dehydrocondensation reaction of N-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline, N-(2-hydroxyethyl)-1,2,3,4- tetrahydroquinoline and 4,4-dimethyl-N-(2-hydroxyethyl)-4-sila-1,2,3,4- tetrahydroisoquinoline with trialkyl(aryl)hydrosilanes and subsequent alkylation, and characterized by ¹H, ¹³C and ²⁹Si NMR and mass spectroscopy. The biological activity data exhibited a marked enhancement of inhibitory activity against tumour cell lines and almost all the test bacterial/fungal strains in comparison with their 2-hydroxyethyl precursors. Cytotoxicity in the microgram range against HT-1080 (human fibrosarcoma) and MG-22A (mouse hepatoma) cancer cell lines was observed for most of compounds. Copyright

Full text of DOI:10.1002/aoc.2952

Full Paper
Received: 13 July 2012
Revised: 10 November 2012
Accepted: 10 November 2012
Published online in Wiley Online Library: 19 December 2012
(wileyonlinelibrary.com) DOI 10.1002/aoc.2952
Silyl modification of biologically active
compounds. 13.† Synthesis, cytotoxicity and
antibacterial action of N-methyl-N-(2-
triorganylsiloxyethyl)-1,2,3,4-tetrahydro(iso)
quinolinium iodides
Alla Zablotskayaa*, Izolda Segala, Yuris Popelisa, Solveiga Grinbergaa,
Irina Shestakovaa, Vizma Nikolajevab and Daina Ezeb
A series of N-methyl-N-(2-triorganylsiloxyethyl)-1,2,3,4-tetrahydro(iso)quinolinium iodides has been synthesized via dehydro-
condensation reaction of N-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline, N-(2-hydroxyethyl)-1,2,3,4-tetrahydroquinoline
and 4,4-dimethyl-N-(2-hydroxyethyl)-4-sila-1,2,3,4-tetrahydroisoquinoline with trialkyl(aryl)hydrosilanes and subsequent
alkylation, and characterized by 1H, 13C and 29Si NMR and mass spectroscopy. The biological activity data exhibited a marked
enhancement of inhibitory activity against tumour cell lines and almost all the test bacterial/fungal strains in comparison with
their 2-hydroxyethyl precursors. Cytotoxicity in the microgram range against HT-1080 (human fibrosarcoma) and MG-22A
(mouse hepatoma) cancer cell lines was observed for most of compounds. Copyright © 2012 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: silicon; silylation; choline; drug research; tetrahydro(iso)quinoline; antitumour activity; antimicrobial activity
the tert-butyldimethylsilyl group in the enhancement of cytotoxic
Introduction
action.[16] 50-Triphenylsilyl modification of deoxyuridine acyclic
Functional groups containing silicon might provide lipophilicity
to a drug, allowing it to pass the cell membrane by passive
diffusion. This strategy has been successfully applied in the anti-
tumour drug analogues silatecans (silicon-containing camptothe-
cins)[1,2] and silaplatins (cisplatin analogues),[3] the HIV-1 reverse
transcriptase inhibitor TSAO-T[4] and the effective anabolic
’silabolin’.[5] Some silicon-containing drugs have entered phase I
or II human clinical trials.[6–10] Silylation of biologically active
compounds, possessing hydrophilic functional groups, is one of
the most effective methods for increasing lipophilicity, ensuring
drug permeability through lipophilic barriers inside living organ-
isms; silylation therefore can positively influence biological
activity appearance or enhancement.[11,12] Trialkylsilyl derivatives
of polyene macrolide antibiotic nystatin had a high level of anti-
fungal activity against a wide set of test strains and their acute
toxicity (LD50) was two to three times lower than that of the initial
antibiotic.[13] A 20-O-tert-butyldimethylsilyl group was found to be
necessary for optimal antiproliferative activity of N6,50-bis-urei-
doadenosine nucleosides.[14] Its 20,30-bis-O-tert-butyldimethylsilyl
derivative exhibited broad-spectrum antiproliferative activity
and was accepted as a new member of the N6,50-bis-ureidoade-
nosine class of anticancer nucleosides.[15] Cytotoxicity study of
(2R,3S)-disubstituted tetrahydropyranes bearing a tert-butyldi-
methylsilyl group at position 3 of the ring considerably induced
cytotoxicity against HL60 human leukaemia cells and MCF7
breast cancer cells in vitro and pointed to the relevant role of
analogues resulted in obtaining more potent inhibitors of
Plasmodium falciparum deoxyuridine 50-triphosphate nucleotido-
hydrolase, a target for the development of antimalarial drugs, in
comparison with their 50-trityloxy derivatives.[17] Within our
research activity, directed at the targeted modification of biolog-
ically active compounds aimed at the improvement of their
biological properties, including increased drug accumulation
and prolongation of drug retention inside cells, we have found
that 50-O-tert-butyldimethylsilyluridine, unlike uridine, exhibits
antitumour activity, suppressing the development of human lung
fibrosarcoma cells,[18] and N-(4-phenyl-2-thiazolyl)-2-(4-trimethyl-
siloxypiperidino)acetamide revealed the higher cytotoxic effect
on MG-22A cells in comparison with its unsilylated analogue.[19]
We have reported recently that silylation represents a plausible
strategy to modulate cytotoxic and antibacterial properties in
choline and colamine analogues. A first series of silylated choline
analogues was synthesized.[20] It was demonstrated that some
*
Correspondence to: Alla Zablotskaya, Latvian Institute of Organic Synthesis,
Aizkraukles 21, Riga, LV-1006, Latvia. E-mail: aez@osi.lv
†
Dedicated to the memory of Professor E. Lukevics.
a Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia
b Biological Faculty, University of Latvia, Riga LV-1586, Latvia
Appl. Organometal. Chem. 2013, 27, 114–124
Copyright © 2012 John Wiley & Sons, Ltd.

(2-Triorganylsiloxyethyl)-tetrahydro(iso)quinolines
silyl-modified aliphatic ethanolamines are low toxic compounds
and reveal biological activity, inhibiting tumour growth and
possessing antimicrobial properties, in comparison with their
unsilylated precursors. Rather small structural modifications
(for instance, silyl group nature) can significantly influence their
activity. Inspired by the results, and to make more general con-
clusions, we have synthesized a new series of silylated derivatives
of N-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline, which could
be considered heterocyclic choline analogues, possessing an
ambivalent nature, namely, lipophilic and hydrophilic fragment
combination in one molecule, and investigated their biological
properties against tumour HT-1080 and MG-22A and normal
NIH 3 T3 cell lines, and also against some Gram-positive – Bacillus
cereus MSCL 330 (BC) and Staphylococcus aureus MSCL 334 (SA) –
and Gram-negative microbial strains – Proteus mirabilis MSCL 590
(PM), Escherichia coli MSCL 332 (EC) and Pseudomonas aeruginosa
MSCL 331 (PA) – and fungi – Candida albicans MSCL 378 (CA) – in
comparison with their 2-hydroxyethyl precursors. Choline is
recognized as a metabolic marker of active tumour tissue due
to its ability to accumulate in cancer cells.[21] There are some
structural requirements of choline derivatives for ’conversion’ of
pneumococcal amidase, and this amino alcohol has been identi-
fied as an allosteric ligand necessary for recognition and degra-
dation of cell wall by the enzyme.[22]
On the other hand, quinoline derivatives, including tetrahydro
(iso)quinoline ones, are biologically active compounds posses-
sing a wide spectrum of biological activity. Structural fragments
of quinoline and its derivatives are included in the molecules of
antitumour drugs, for instance in amsacrine, bruneomicine and
vinblastine.[5,23,24] The tetrahydroisoquinoline ring system is an
important structural motif[25] that is commonly encountered in
naturally occurring alkaloids, with interesting biological activities.
Typical examples include saframycin-B,[26] narciclasine[27] and
ecteinascidin-743.[28] In this regard, tetrahydroisoquinoline has
become widely identified as a ’privileged’ structure, with repre-
sentation in several medicinal agents of diverse therapeutic action,
and are potential drug candidates.[29,30] Tetrahydroisoquinoline
derivatives possess antitumour properties.[31–33]
UV (254 nm). Column chromatography was performed using
Merck silica gel (0.040–0.063 nm). Solvents and reagents used in
this study were purchased from Fluka, Acros and Aldrich. Synthe-
ses involving air-sensitive compounds were carried out under dry
argon. All solvents used were freshly dried using standard techni-
ques and all glassware was oven dried.
Synthesis
N-(2-Hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline (1),[34] N-(2-
hydroxyethyl)-1,2,3,4-tetrahydroquinoline (2),[34], N-(2-hydroxyethyl)-
N-methyl-1,2,3,4-tetrahydroisoquinolinium iodide (3),[34]
N-(2-hydroxyethyl)-N-methyl-1,2,3,4-tetrahydroquinolinium iodide
(4),[34] bromomethyldimethyl(2-methylphenyl)silane (5),[34] (2-
bromomethylphenyl)bromomethyl-dimethylsilane (6),[34] 4,4-
dimethyl-N-(2-hydroxyethyl)-4-sila-1,2,3,4-tetrahydroisoquinoline
(7)[34] and 4,4-dimethyl-N-(2-hydroxyethyl)-N-methyl-4-sila-1,2,3,4-
tetrahydroisoquinolinium iodide (8)[34] were characterized by com-
paring their 1H NMR spectra with those reported in the literature.
An outline is given in Scheme 1.
N-(2-Diethylmethylsiloxyethyl)-1,2,3,4-tetrahydroisoquinoline (9a)
Diethylmethylsilane (0.59 g, 5.77 mmol) was added to N-(2-hydro-
xyethyl)-1,2,3,4-tetrahydroisoquinoline (0.88 g, 4,97 mmol) and
the reaction mixture was heated at 70 ꢀC under stirring for 4 h
in the presence of a trace amount of metallic sodium. The course
of the reaction was followed using data provided by gas chroma-
tography–mass spectrometry (GC-MS). If necessary (presence of
unreacted alcohol detected by TLC), more hydrosilane was
added. Once the dehydrocondensation reaction had reached
completion, the reaction mixture was cooled to room tempera-
ture and the solid traces were filtered off. The resulting crude res-
idue was purified by column chromatography on silica gel eluted
with chloroform–methanol (4:1) to give the desired diethyl-
methylsilyl ether as a clear light-yellow liquid.
Yield 0.77 g (56%). LC-MS (m/z, %): 278 (M++1, 100), 277 (M+, 58),
262 (M+ ꢁ CH3, 9), 248 (M+ ꢁ C2H5, 12), 174 (32), 161 (M+ ꢁ OSi
(C2H5)2CH3 + 1, 52), 144 (26). GC-MS (m/z, %): 277 (M+, 2), 262
(M+ ꢁ CH3, 3), 248 (M+ ꢁ C2H5, 5), 146 (M+ ꢁ CH2CH2OSi(C2H5)
2CH3, 100), 132 (26). 1H NMR (CDCl3, d, ppm): 012 (3H, s, SiCH3),
0.66 (4H, m, SiCH2), 1.00 (6H, m, C&bond;CH3), 2.76 (2H, m, a-CH2N),
2.86 and 2.97 (total 4H, m and m, 3- and 4-CH2N), 3.75 (2H, m,
1-CH2N), 3.88 (2H, t, J = 6.6Hz, OCH2), 7.0–7.2 (4H, m, 5-, 6-, 7- and
8-H). 13C NMR (CDCl3, d, ppm): ꢁ5.01 (SiCH3), 6.16 (SiCH2), 6.70
(SiCCH3), 28.99 (4-CH2), 50.66 (3-CH2N), 55.74 (1-CH2N), 58.07
(OCH2), 59.17 (a-CH2N), 125.63 (7-C), 125.99 (8-C), 126.46 (6-C),
128.60 (5-C), 134.12 (9-C), 134.40 (10-C). 29Si NMR (CDCl3, d, ppm):
+19.90. Anal. calcd for C16H27NOSi: C, 69.26; H, 9.81; N, 5.05; found:
68.97; H, 9.73; N, 5.11.
Experimental
Chemicals and Instrumentation
1H, 13C and 29Si NMR spectra were obtained on Varian Mercury
200 and Varian Mercury 400 spectrometers with CDCl3 or
DMSO-d6 as solvent and CDCl3 (d = 7.25 ppm for CHCl3) as inter-
nal standard for compounds containing a silicon atom in the
molecule, and with hexamethyldisiloxane (d = 0.055 ppm) as
internal standard for the other compounds. Heteronuclear single-
quantum correlation and heteronuclear multiple-bond correla-
tion NMR 2-D correlation spectra were taken for compounds
1–4, 8, 9d, 12d, 12 g and 12 h for an unambiguous assignment
of 1H and 13C signals. Mass spectra under electron impact condi-
tions were recorded on an Agilent Technologies 5975C mass
spectrometer (GC 7890A, 70 eV) and on Waters 3100 mass spec-
trometer (LC Alliance Waters 2695). Elemental analyses (C, H, N)
were performed on a Carlo Erba 1108 elemental analyser.
Elemental analysis results agreed with calculated values. Melting
points were determined on a Boetius melting point apparatus
and were taken uncorrected. Analytical thin-layer chromatogra-
phy (TLC) was performed on 60 F254 (Merck) silica gel plates and
Machery-Nagel silica gel plastic plates, with visualization under
N-(2-Triethylsiloxyethyl)-1,2,3,4-tetrahydroisoquinoline (9b)
Compound 9b was obtained following the procedure described
for 9a, from 1.80 g (10.16 mmol) N-(2-hydroxyethyl)-1,2,3,4-tetra-
hydroisoquinoline (1) and 1.20 g (10.32 mmol) triethylsilane, as a
clear light-yellow liquid.
Yield 2.25 g (77%). LC-MS (m/z, %): 292 (M++1, 51), 291 (M+, 49);
290 (M+ ꢁ 1, 100), 262 (M+ ꢁ C2H5, 32), 176 (M+ ꢁ Si(C2H5)3, 5),
158 (88), 131 (50). GC-MS (m/z, %): 291 (M+, 1), 262 (M+ ꢁ C2H5, 3),
146 (M+ ꢁ CH2OSi(C2H5)3, 100), 132 (M+ ꢁ CH2CH2OSi(C2H5)3 ꢁ 1,
16). 1H NMR (CDCl3, d, ppm): 0.63 (6H, m, SiCH2), 0.97 (9H,
m, SiCCH3), 2.71 (2H, t, J = 6.5 Hz, a-CH2N), 2.81 and 2.89 (total 4H,
m and m, 3- and 4-CH2N), 3.69 and 3.71 (total 2H, d and d,
Appl. Organometal. Chem. 2013, 27, 114–124
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

A. Zablotskaya et al.
-
I
+
NH
N
N
X
OH
OH
OH
3
1
2
Et3N
CH3I
X = Br, I
-
I
+
N
N
N
OH
H
OH
4
O
NBr
O
Br
Mg/I2
Et2O
MgBr
Br
Si
Br
SiCl
(PhCOO)2, t°C
5
Si
Br
Si
NH2
Si
-
OH
CH3I
I
+
N
N
Br
OH
OH
8
7
6
Scheme 1. Synthesis of compounds 1–8.
J = 5.2Hz, 1-CH2N), 3.84 (2H, t, J = 6.5Hz, OCH2), 6.9–7.2 (4H, m, 5-,
6-, 7- and 8-H). 13C NMR (CDCl3, d, ppm): 4.41 (SiCH2), 6.75 (SiCCH3),
29.00 (4-CH2), 51.60 (3-CH2N), 56.65 (1-CH2N), 60.23 (OCH2), 61.22
(a-CH2N), 125.51 (7-C), 126.03 (8-C), 126.51 (6-C), 128.61 (5-C),
134.16 (9-C), 134.82 (10-C). 29Si NMR (CDCl3, d, ppm): +19.62. Anal.
calcd for: C17H29NOSi: C, 70.07; H, 10.03; N, 4.80; found: C, 69.78;
H, 10.04; N, 4.72.
d, ppm): 0.08 (3H, s, SiCH3), 0.55 (4H, m, SiCH2), 0.88 (6H, t,
J = 6.8 Hz, 2CH3), 1.26 (20H, m, 10CH2), 2.70 (2H, t, J = 6.4Hz,
a-CH2N), 2.80 and 2.88 (total 4H, m and m, 3- and 4-CH2), 3.71
(4H, m, 1-CH2N and OCH2), 7.1–7.20 (4H, m, 5-, 6-, 7- and 8-H).
13C NMR (CDCl3, d, ppm): ꢁ4.10 (SiCH3), 14.12 (CH3), 15.02 (SiCH2),
22.70, 23.19, 29.03, 29.05, 31.82 and 33.52 (CH2, 4-CH2), 50.68
(3-CH2N), 55.78 (1-CH2N), 58.08 (OCH2), 59.16 (a-CH2N), 125.52
(7-C), 126.05 (8-C), 126.54 (6-C), 128.61 (5-C), 134.18 (9-C),
134.46 (10-C). 29Si NMR (CDCl3, d, ppm): +18.20. Anal. calcd for:
N-(2-Di-n-butylethylsiloxyethyl)-1,2,3,4-tetrahidroisoquinoline (9c)
Compound 9c was obtained following the procedure described
for 9a, from 0.89 g (5.00 mmol) N-(2-hydroxyethyl)-1,2,3,4-tetrahy-
droisoquinoline (1) and 1.21 g (7.02 mmol) dibutylethylsilane, as a
clear light-yellow liquid.
C26H47NOSi: C, 74.75; H, 11.34; N, 3.35; found: C, 75.04; H, 11.40;
N, 3.29.
N-(2-n-Dimethyloctylsiloxyethyl)-1,2,3,4-tetrahydroisoquinoline (9e)
Yield 1.31 g (75%). LC-MS (m/z, %): 348 (M++1, 26), 347 (M+, 100),
160 (M+ ꢁ OSi(C4H9)2C2H5, 25). GC-MS (m/z, %): 347 (M+, 2), 318
(M+ ꢁ C2H5, 3), 290 (M+ ꢁ C4H9, 5), 146 (M+ ꢁ CH2OSi(C4H9)2C2H5,
100), 132 (M+ ꢁ CH2CH2OSi(C4H9)2C2H5 ꢁ 1, 27). 1H NMR (CDCl3,
d, ppm): 0.52–0.71 (6H, m, SiCH2), 0.93–1.10 (15H, m, SiCCH3,
SiCCH2CC and SiCCCCH3), 1.79 (4H, m, SiCCCH2C), 2.71 (2H, t,
J = 5.6Hz, a-CH2N), 2.80 and 2.91 (total 4H, m and m, 3- and
4-CH2), 3.69 (2H, s, 1-CH2N), 3.70 (2H, t, J = 5.6Hz, OCH2), 7.0–7.2
(4H, m, 5-, 6-, 7- and 8-H). 13C NMR (CDCl3, d, ppm): 4.09 (SiCH2)
and 8.36 (SiCCH3), 22.13, 25.33, 25.97, 26.42 (CCH2 CH2 CH3), 29.06
(4-CH2), 50.72 (3-CH2N), 55.79 (1-CH2N), 58.12 (OCH2), 59.27
(a-CH2N), 125.53 (7-C), 126.05 (8-C), 126.53 (6-C), 128.63 (5-C),
134.16 (9-C), 134.42 (10-C). 29Si NMR(CDCl3, d, ppm): +16.74. Anal.
calcd for: C21H37NOSi: C, 72.56; H, 10.73; N, 4.03; found: C, 72.80;
H, 10.65; N, 4.10.
Compound 9e was obtained following the procedure described
for 9a, from 0.88 g (4.95 mmol) N-(2-hydroxyethyl)-1,2,3,4-tetrahy-
droisoquinoline (1) and 1.28 g (7.43 mmol) dimethyloctylsilane, as
a clear yellow oil.
Yield 1.32g (77%). LC-MS (m/z, %): 348 (M++1, 100), 347 (M+, 62),
332 (M+ ꢁ CH3, 10). GC-MS (m/z, %): 332 (M+ ꢁ CH3, 5), 234
(M+ ꢁ C8H17, 12), 146 (M+ ꢁ CH2OSi(CH3)2C8H17, 100). 1H NMR
(CDCl3, d, ppm): 0.10 (6H, s, SiCH3), 0.60 (2H, m, SiCH2), 0.87
(3H, t, J = 6.8 Hz, CH3), 1.25 (12H, bs, &bond;CH2&bond;), 2.70
(2H, t, J = 6.6 Hz, a-CH2N), 2.80 and 2.89 (2H and 2H, t and t,
J = 5.9 Hz, 3- and 4-CH2), 3.69 (2H, s, 1-CH2N), 3.81 (2H, t,
J = 6.6 Hz, OCH2), 6.9–7.0 (1H, m, 8-H), 7.0–7.2 (3H, m, 5-,
6- and 7-H). 13C NMR (CDCl3, d, ppm): ꢁ2.13 (SiCH3), 14.07
(CH3), 16.31 (SiCH2), 22.72, 23.24, 23.33, 29.25, 29.32, 29.39,
32.0, 33.43 (CH2), 29.02 (4-CH2), 51.48 (3-CH2N), 56.61 (1-CH2N),
60.06 (OCH2), 60.92 (a-CH2N), 125.51 (7-C), 126.05 (8-C), 126.54
(6-C), 128.57 (5-C), 134.22 (9-C), 134.83 (10-C). 29Si NMR (CDCl3,
d, ppm): +18.32. Anal. calcd for C21H37NOSi: C, 72.56; H, 10.73; N,
4.03; found: C, 72.28 ; H, 10.63; N, 4.10.
N-(2-Di-n-heptylmethylsiloxyethyl)-1,2,3,4-tetrahydroisoquinoline (9d)
Compound 9d was obtained following the procedure described
for 9a, from 0.89 g (5.00 mmol) N-(2-hydroxyethyl)-1,2,3,4-tetrahy-
droisoquinoline (1) and 1.46 g (6.02 mmol) diheptylmethylsilane,
as clear yellow liquid.
N-(2-n-Decyldimethylsiloxyethyl)-1,2,3,4-tetrahidroisoquinoline (9f)
Yield 1.19 g (57%). LC-MS (m/z, %): 417 (M+, 71), 416 (M+ ꢁ 1,
100), 318 (M+ ꢁ C7H15, 15), 161 (M+ ꢁ OSi(C7H15)2CH3 + 1, 98), 160
(M+ ꢁ OSi(C7H15)2CH3, 57). GC-MS (m/z, %): 318 (M+ ꢁ C7H15, 9),
158 (M+ ꢁ OSi(C7H15)2CH3 ꢁ 2, 2), 146 (M+ ꢁ CH2OSi(C7H15)2CH3,
100), 132 (M+ ꢁ CH2CH2OSi(C7H15)2CH3 ꢁ 1, 27). 1H NMR (CDCl3,
Compound 9f was obtained as clear yellow oil following the
procedure described for 9a, from 5.05 g (28.5 mmol) N-(2-hydro-
xyethyl)-1,2,3,4-tetrahydroisoquinoline (1) and 6.28 g (31.2 mmol)
decyldimethylsilane, by heating the reagents at 80 ꢀC under stirring
for 15 h.
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Copyright © 2012 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2013, 27, 114–124

(2-Triorganylsiloxyethyl)-tetrahydro(iso)quinolines
Yield 8.04 g (75%). LC-MS (m/z, %): 376 (M++1, 100), 375 (M+,
52), 160 (M+ ꢁ OSi(CH3)2C10H21, 10). GC-MS (m/z, %): 375 (M+, 2),
360 (M+ ꢁ CH3, 4), 234 (M+ ꢁ CH3&bond;C10H21, 9), 146 (M+ ꢁ
hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline (1) and 1.0 g (5.0 mmol)
methyldiphenylsilane.
Yield 1.22 g (91%). LC-MS (m/z, %): 374 (M++1, 100), 296
(M+ ꢁ C6H5, 98). GC-MS (m/z, %): 372 (M+ ꢁ 1, 2), 295 (M+ ꢁ C6H5
1, 9), 146 (M+ ꢁ CH2OSi(C6H5)2CH3, 100). 1H NMR (CDCl3, d, ppm):
0.55 (3H, s, SiCH3), 2.64 (4H, m, 3- and 4-CH2), 2.74 (2H, t,
J = 6.0 Hz, a-CH2N), 3.52 (2H, s, 1-CH2N), 3.81 (2H, t, J = 6.0Hz,
OCH2), 6.84 (1H, m, 8-H), 6.98 (3H, m, 5-,6- and 7-H), 7.2–7.5 (10H,
m, C6H5-H). 13C NMR (CDCl3, d, ppm): ꢁ2.98 (SiCH3), 29.04 (4-CH2),
51.49 (3-CH2N), 56.41 (1-CH2N), 60.02 (OCH2), 61.68 (a-CH2N),
125.42 (7-C), 126.03 (8-C), 126.51 (6-C), 128.66 (5-C), 134.12 (9-C),
134.71 (10-C), 127.81, 129.77, 134.32, 137.51 (C6H5-C). 29Si NMR
(CDCl3, d, ppm): ꢁ2.39. Anal. calcd for C24H27NOSi: C, 77.16; H,
7.28; N, 3.75; found: C, 76.85; H, 7.20; N, 3.81.
1
CH2OSi(CH3)2C10H21, 100). H NMR (CDCl3, d, ppm): 0.10 (6H, s,
SiCH3), 0.59 (2H, m, SiCH2), 0.83 (3H, t, J = 6.8 Hz, CH3), 1.2–1.4
(16H, m, CH2), 2.71 (2H, t, J = 5.4 Hz, a-CH2N), 2.81 and 2.90
(2H and 2H, t, J = 5.8 Hz, 3- and 4-CH2), 3.70 (2H, s,1-CH2N), 3.71
(2H, t, J = 5.4 Hz, OCH2), 7.0–7.05 (1H, m, 8-H), 7.05–7.2 (3H, m,
5-, 6- and 7-H). 13C NMR (CDCl3, d, ppm): ꢁ2.10 (SiCH3), 14.09
(CH3), 16.31 (SiCH2), 22.66 23.16, 29.07, 29.34, 29.57, 29.64, 31.89
and 33.43 (CH2), 28.98 (4-CH2), 50.73 (3-CH2N), 55.71 (1-CH2N),
58.09 (OCH2), 59.32 (a-CH2N), 125.66 (7-C), 126.23 (8-C), 126.49
(6-C), 128.65 (5-C), 134.15 (9-C), 134.46 (10-C). 29Si NMR (CDCl3,
d, ppm): +18.36. Anal. calcd for C23H41NOSi: C, 73.54; H, 11.00;
N, 3.73; found: C, 73.28; H, 10.54; N, 3.78.
N-(2-n-Decyldimethylsiloxyethyl)-1,2,3,4-tetrahydroquinoline (10)
N-(2-n-Dimethylundecylsiloxyethyl)-1,2,3,4-tetrahidroisoquinoline (9 g)
Compound 10 was obtained as clear yellow oil following the pro-
cedure described for 9a, from 3.24 g (18.3 mmol) N-(2-hydro-
xyethyl)-1,2,3,4-tetrahydroquinoline (2) and 4.02 g (20.1 mmol)
decyldimethylsilane, by heating the reagents at 80 ꢀC under stirring
for 26 h.
Compound 9 g was obtained as a clear yellow oil following the
procedure described for 9a, from 0.76 g (3.54 mmol) N-(2-hydro-
xyethyl)-1,2,3,4-tetrahydroisoquinoline (1) and 0.91 g (4.25 mmol)
dimethylundecylsilane, by heating the reagents at 90 ꢀC under
stirring for 15 h.
Yield 1.66 g (24%). LC-MS (m/z, %): 376 (M++1, 50), 375 (M+, 100).
GC-MS (m/z %): 375 (M+, 11), 234 (M+ ꢁ C10H21, 3), 146 (M+ ꢁ CH2O-
SiMe2C10H21, 100). 1H NMR (CDCl3, d, ppm): 0.07 (6H, s, SiCH3), 0.57
(2H, m, SiCH2), 0.87 (3H, t, J = 6.8Hz, CH3), 1.25–1.30 (16H, m, CH2),
1.94 (2H, m, 3-CH2N), 2.77 (2H, m, 4-CH2), 3.32 (2H, m, 2-CH2N),
3.39 (2H, t, J = 6.8 Hz, a-CH2N), 3.73 (2H, t, J = 6.8 Hz, OCH2),. 6.58,
6.67, 6.93 and 7.02 (total 4H, m, dd, m and m, 5-, 6-,7- and 8-H).
13C NMR (CDCl3, d, ppm): ꢁ2.14 (SiCH3), 14.11 (CH3), 16.30 (SiCH2),
22.24 (3-CH2), 22.69, 23.18, 29.34, 29.35, 29.60, 29.67, 31.93 and
33.22 (CH2), 28.18 (4-CH2), 50.42 (2-CH2N), 53.63 (a-CH2N), 59.13
(OCH2), 110.40, 115.49, 127.06, 129.16 (5-, 6-, 7-, 8-C), 122.06 (9-C)
and 145.24 (10-C). 29Si (d, ppm): +18.62 Anal. calcd for C23H41NOSi:
C, 73.54; H, 11.00; N, 3.73; found: C, 73.28; H, 11.04; N, 3.68.
Yield 0.68 g (49%). LC-MS (m/z, %): 390 (M++1, 100). GC-MS
(m/z, %): 390 (M++1, 1), 147 (M+ ꢁ CH2OSi(CH3)2C11H23 + 1, 100). 1H
NMR (CDCl3, d, ppm): 0.07 (6H, s, SiCH3), 0.53 (2H, m, SiCH2), 0.88
(3H, t, J = 6.8Hz, CH3), 1.25 (18H, m, CH2), 2.71 (2H, t, J = 5.8Hz,
a-CH2N), 2.79 and 2.88 (2H and 2H, t and t, J = 5.9Hz, 3- and
4-CH2), 3.70 (4H, m, 1-CH2N + OCH2), 7.0–7.2 (4H, m, 5-, 6-, 7- and
8-H). 13C NMR (CDCl3, d, ppm): ꢁ2.21 (SiCH3), 14.03 (CH3), 17.72
(SiCH2), 22.63, 23.11, 29.28, 29.62, 29.74, 31.82 and 33.43 (CH2),
28.92 (4-CH2), 50.71 (3-CH2N), 55.70 (1-CH2N), 58.12 (OCH2), 59.34
(a-CH2N), 125.62 (7-C), 126.2 1(8-C), 126.39 (6-C), 128.63 (5-C),
134.02 (9-C), 134.31 (10-C). 29Si NMR (CDCl3, d, ppm): +18,23. Anal.
calcd for C24H43NOSi: C, 73.97; H, 11.12; N, 3.59; found: C, 74.21; H,
11.19; N, 3.52.
N-(2-n-Decyldimethylsiloxyethyl)-4,4-dimethyl-4-sila-1,2,3,4-tetrahidroiso-
quinoline (11)
N-(2-n-Hexadecyldimethylsiloxyethyl)-1,2,3,4-tetrahidroisoquinoline (9h)
Compound 9 h was obtained as a clear yellow oil following the
procedure described for 9a, from 0.80 g (4.50 mmol) N-(2-hydro-
xyethyl)-1,2,3,4-tetrahydroisoquinoline (1) and 2.56 g (9.0 mmol)
hexadecyldimethylsilane, by heating the reagents at 85 ꢀC under
stirring for 15 h.
Compound 11 was obtained as a clear yellow oil following the
procedure described for 9a, from 0.4 g (1.4 mmol) N-(2-hydro-
xyethyl)-4,4-dimethyl-4-sila-1,2,3,4-tetrahydroisoquinoline (7) and
0.31 g (1.54 mmol) of decyldimethylsilane.
Yield 0.13 g (22%). LC-MS (m/z, %): 420 (M++1, 100). GC-MS
Yield 0.78 g (38%). LC-MS (m/z, %): 460 (M++1, 100), 459 (M+, 5),
160 (M+ ꢁ OSi(CH3)2C16H33, 96). GC-MS (m/z, %): 459 (M+, 2), 444
(M+ ꢁ CH3, 3), 234 (M+ ꢁ C16H33, 9), 146 (M+ ꢁ CH2OSi(CH3)
1
(m/z, %): 389 (M+ ꢁ 2CH3, 33), 388 (M+ ꢁ 2CH3 ꢁ 1, 100). H NMR
(CDCl3, d, ppm): 0.09 (6H, s, SiCH3-acycl.), 0.27 (6H, s, SiCH3-cycl.),
0.57 (2H, m, SiCH2), 0.87 (3H, t, J = 6.8Hz, CH3), 1.25 (16H, m, CH2),
2.21 (2H, s, SiCH2N), 2.72 (2H, t, J = 5.2 Hz, a-CH2N), 3.65 (2H, m,
OCH2), 3.67 (2H, s, 1-CH2N), 7.0–7.5 (4H, m, 5-, 6-, 7- and 8-H). 13C
NMR (CDCl3, d, ppm): ꢁ2.12 (SiCH3), ꢁ2.01 (SiCH3-cycl.), 14.1
(CH3), 16.32 (SiCH2), 22.66, 23.18, 29.34, 29.37, 29.59, 29.66, 31.91
and 33.20 (CH2), 44.15 (SiCH2N), 58.1 (1-CH2N), 61.2 (OCH2), 63.5
(a-CH2N), 125.14, 126.61, 128.94, 133.61 (5-, 6-, 7- and 8-C), 134.35,
145.42 (9,10-C). 29Si NMR (CDCl3, d, ppm): ꢁ13.50, +18.06. Anal.
calcd for C24H45NOSi2: C, 68.67; H, 10.80; N, 3.33; found: C, 68.91;
H, 10.73; N, 3.25.
1
2C16H33, 100). H NMR (CDCl3, d, ppm): 0.10 (6H, s, SiCH3), 0.60
(2H, m, SiCH2), 0.87 (3H, t, J = 6.8 Hz, CH3), 1.24 (28H, m, CH2),
2.71 (2H, t, J = 6.0 Hz, a-CH2N), 2.80 and 2.87 (2H and 2H, m and
m, 3- and 4-CH2), 3.71 (2H, s, 1-CH2N), 3.81 (2H, t, J = 6.0 Hz,
OCH2), 7.00 (1H, m, 8-H), 7.10 (3H, m, 5-, 6- and 7-H). 13C NMR
(CDCl3, d, ppm): ꢁ4.42 (SiCH3), 14.13 (CH3), 16.41 SiCH2), 23.25,
24.42, 29.38, 29.61, 29.73, 31.94, 33.21 and 33.52 (CH2), 29.02
(4-CH2), 51.62 (3-CH2N), 56.81 (1-CH2N), 60.23 (OCH2), 60.92
(a-CH2N), 125.51 (7-C), 126.13 (8-C), 126.52 (6-C), 128.69 (5-C),
134.2 2 (9-C), 134.83 (10-C). 29Si NMR (CDCl3, d, ppm): +18.33.
Anal. calcd for C29H53NOSi: C, 75.75; H, 11.62; N, 3.05; found: C,
75.98; H, 11.69; N, 3.01.
N-(2-Diethylmethylsiloxyethyl)-N-methyl-1,2,3,4-tetrahydroisoquinolinium
iodide (12a)
A solution of diethylmethylsilyl ether 9a (0.84 g, 3.03 mmol) in
hexane (5 ml) was heated at 60 ꢀC for 5 h with methyl iodide
(2.22 g, 15.60 mmol). After cooling to room temperature the reac-
tion mixture was filtered, and the solid was washed with hexane
N-(2-Methyldiphenylsiloxyethyl)-1,2,3,4-tetrahydroisoquinoline (9i)
Compound 9i was obtained as a clear yellow oil following
the procedure described for 9a, from 0.63 g (3.8 mmol) N-(2-
Appl. Organometal. Chem. 2013, 27, 114–124
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

A. Zablotskaya et al.
and dried for 6 h in vacuo to give the desired methiodide as a
yellow powder.
(M+ ꢁ CH3I ꢁ CH3, 2), 318 (M+ ꢁ CH3I ꢁ C7H15, 5); 146 (M+ ꢁ CH3I ꢁ
CH2OSiCH3(C7H15)2, 100), 132 (M+ ꢁ CH3I ꢁ CH2CH2OSiCH3(C7H15)2,
26). 1H NMR (CDCl3, d, ppm): 0.08 (3H, s, SiCH3), 0.60 (4H, m, SiCH2),
0.86 (6H, t, J = 6.8Hz, 2CH3), 1.24 (20H, m, 10CH2), 3.25 (2H, m,
4-CH2), 3.56 (3H, s, N+CH3), 3.99–4.2 (6H, m, a-CH2N+, 3-CH2N+,
OCH2), 4.76 and 5.10 (total 2H, d and d, J = 15.0 Hz, 1-CH2N+);
Yield 0.41 g (33%), m.p. 138–139 ꢀC. LC-MS (m/z %): 293
(M+ ꢁ I + 1, 19), 292 (M+ ꢁ I, 100), 197 (2), 188 (9), 183 (5). 1H
NMR (CDCl3, d, ppm): 0.08 (3H, s, SiCH3), 0.59 (4H, q,
J = 7.9 Hz, SiCH2), 0.91 (6H, t, J = 7.9 Hz, SiC-CH3), 3.24 (2H, bt,
J = 6.1 Hz, 4-CH2, 3.54 (3H, s, N+CH3), 3.9–4.3 (6H, m, a-CH2N,+ 7.1–7.4 (4H, m, 5-, 6-, 7- and 8-H). 13C NMR (CDCl3, d, ppm):
3-CH2N+ and OCH2), 4.74 and 5.07 (total 2H, d and d,
J = 15.1 Hz, 1-CH2N+), 7.1–7.4 (4H, m, 5-, 6-, 7- and 8-H). 13C
NMR (CDCl3, d, ppm): ꢁ5.12 (SiCH3), 5.77 (SiCH2), 6.65 (SiC&–CH3),
23.86 (4-C), 49.06 (N+CH3), 57.23 (OCH2), 59.80 (3-CH2N+), 62.87
(1-CH2N+), 63.63 (a-CH2N+), 125.96, 127.34, 127.81, 128.54, 128.90
and 129.06 (5-,6-,7-,8-,9- and 10-C). 29Si NMR (CDCl3, d, ppm):
+24.23 (2JSiCH = 6.0 Hz). Anal. calcd for C17H30INOSi: C, 48.68; H,
7.21; N, 3.34; found: C, 48.42; H, 7.15; N 3.41.
ꢁ4.08 (SiCH3), 14.12 (CH3), 15.03 (SiCH2), 23.12, 28.89, 31.73 and
33.42 (CH2), 23.92 (4-CH2), 49.21 (N+CH3), 57.24 (OCH2), 59.78
(3-CH2N+), 62.73 (1-CH2N), 63.41 (a-CH2N+), 126,11, 127.32, 127.70,
128.6, 129.02 and 129.91 (5-, 6-, 7-, 8-, 9- and 10-C). 29Si NMR (CDCl3,
d, ppm): +22.35. Anal. calcd for C27H50INOSi: C, 57.94; H, 9.00; N,
2.50; .found: C, 57.68; H, 8.86; N 2.58.
N-(2-n-Dimethyloctylsiloxyethyl)-N-methyl-1,2,3,4-tetrahydroisoquinolinium
iodide (12e)
N-Methyl-N-(2-triethylsiloxyethyl)-1,2,3,4-tetrahydroisoquinolinium iodide
(12b)
Compound 12e was obtained following the procedure described
for 12b, from 0.96 g (2.76 mmol) of dimethyloctylsilyl ether 9e, as
a yellow powder.
A solution of triethylsilyl ether 9b (1.44 g, 8.13 mmol) and of methyl
iodide (5.75 g, 4.05 mmol) in ethyl ether (23 ml) was heated at 40ꢀC
for 3 h, the precipitate was filtered off, washed with 50 ml hexane
and dried for 6 h in vacuo to give the desired product as a light
yellow powder.
Yield 0.36 g (27%), m.p. 144–145 ꢀC. LC-MS (m/z, %): 363
(M+ ꢁ I + 1, 100); 346 (M+ ꢁ CH3I ꢁ 1, 5). GC-MS (m/z, %): 332
(M+ ꢁ CH3I ꢁ CH3, 5), 146 (M+ ꢁ CH3I ꢁ CH2OSi(CH3)2C8H17, 100).
1H NMR (CDCl3, d, ppm): 0.11 (6H, s, SiCH3), 0.58 (2H, m, SiCH2),
0.87 (3H, t, J = 7.0Hz, CH3), 1.2–1.3 (12H, m, CH2), 3.2 (2H, m,
4-CH2), 3.56 (3H, s, N+CH3), 3.9–4.2 (6H, m, a-CH2N+, 3-CH2N+,
OCH2), 4.77 and 5.07 (total 2H, d and d, J = 14.9 Hz, 1-CH2N+), 7.11
(1H, d, 8-H), 7.2–7.4 (3H, m, 5-, 6- and 7-H). 13C NMR (CDCl3,
d, ppm): ꢁ2.57 (SiCH3), 13.93 (CH3), 15.78 (SiCH2), 22.52, 22.96,
29.02, 29.16, 31.78 and 33.27 (CH2), 23.84 (4-CH2), 49.13 (N+CH3),
56.91 (OCH2), 59.59 (3-CH2N+), 62.54 (1-CH2N+), 63.42 (a-CH2N+),
126,03, 127.24, 127.58, 128.62, 128.77 and 128.85 (5-, 6-, 7-, 8-, 9-
and 10-C). 29Si NMR (CDCl3, d, ppm): +22.37. Anal. calcd for
C22H40INOSi: C, 53.98; H, 8.24; N, 2.8; found: C, 53.79; H, 8.15; N 2.93.
Yield 1.86 g (67%), m.p. 93–95 ꢀC. LC-MS (m/z, %): 307 (M+ ꢁ I +
1, 25), 306 (M+ ꢁ I, 100), 203 (M+ ꢁ CH3I ꢁ 3C2H5 ꢁ 1, 79), 179
(22), 147 (39). 1H NMR (CDCl3, d, ppm): 0.64 (6H, q, J = 7.8 Hz,
SiCH2), 0.94 (9H, t, J = 7.8 Hz, SiC&bond;CH3), 3.27 (2H, bt,
J = 5.8 Hz, 4-CH2), 3.58 (3H, s, N+CH3), 3.9–4.3 (6H, m, a-CH2N+,
3-CH2 and OCH2), 4.79 and 5.11 (total 2H, d and d, J = 15.8 Hz,
1-CH2N+), 7.15 (1H, m, 8-H), 7.2–7.4 (3H, m, 5-, 6- and 7-H). 13C
NMR (CDCl3, d, ppm): 3.95 (SiCH2), 6.62 (SiC-CH3), 23.80 (4-C),
49.07 (N+CH3), 57.3 (OCH2), 59.62 (3-C), 62.66 (1-CH2N+), 63.45
(a-CH2N+), 125.98, 127.22, 127.62, 128.56, 128.79 and 128.87
(5-,6-,7-,8-,9- and 10-C). 29Si NMR (CDCl3, d, ppm): +23.84. Anal.
calcd for C18H32INOSi: C, 49.88; H, 7.44; N, 3.23; found: C, 49.59;
H, 7.37; N 3.29.
N-(2-n-Decyldimethylsiloxyethyl)-N-methyl-1,2,3,4-tetrahydroisoquinolinium
iodide (12f)
Compound 12f was obtained following the procedure described
for 12b, from 0.23 g (0.80 mmol) decyldimethylsilyl ether 9f, as a
yellow oily precipitate.
N-(2-Di-n-butylethylsiloxyethyl)-N-methyl-1,2,3,4-tetrahydroisoquinolinium
iodide (12c)
Compound 12c was obtained following the procedure described
for 12b, from 0.90 g (2.58 mmol) dibutylethylsilyl ether 9c, as a
light-yellow oily powder.
Yield 0.28 g (68%), m.p. 142 ꢀC. LC-MS (m/z, %): 391 (M+ ꢁ I + 1, 15),
390 (M+ ꢁ I, 55), 389 (M+ ꢁ I ꢁ 1, 95), 376 (M+ ꢁ CH3I + 1, 100).
GC-MS (m/z, %): 391 (M+ ꢁ I + 1, 1), 234 (M+ ꢁ CH3I ꢁ C10H21, 4),
146 (M+ ꢁ CH3I ꢁ CH2OSi(CH3)2C10H21, 100). 1H NMR (CDCl3,
d, ppm): 0.11 (6H, s, SiCH3), 0.58 (2H, m, SiCH2), 0.85 (3H, t,
J = 6.8 Hz, CH3), 1.24 (16H, m, CH2), 3.26 (2H, m, 4-CH2), 3.54 (3H, s,
N+CH3), 4.0–4.2 (6H, m, a-CH2N+ 3-CH2N+, OCH2), 4.76 and 5.08
(total 2H, d and d, J = 15.3 Hz, 1-CH2N+), 7.11 (1H, d, 8-H), 7.1–7.4
(3H, m, 5-, 6- and 7-H). 13C NMR (CDCl3, d, ppm): ꢁ2.43 (SiCH3),
14.01 (CH3), 15.78 (SiCH2), 22.61, 23.02, 29.24, 29.38, 29.49, 31.85
and 33.22 (CH2), 23.82, (4-C), 49.21 (N+CH3), 57.03 (OCH2), 59.67
(3-C), 62.71 (1-CH2N+), 63.52 (a-CH2N+), 126.02 (9-C), 127.31 (8-C),
127.68 (5-C), 128.57 (6-C), 128.92 (7-C), 129.03 (10-C). 29Si NMR
(CDCl3, d, ppm): +22.50. Anal. calcd for C24H44INOSi: C, 55.69; H,
8.57; N, 2.71; found: C, 55.84; H, 8.66; N 2.55.
Yield 0.52g (41%), m.p. 124–126 ꢀC. LC-MS (m/z, %): 363 (M+ ꢁ I,
1
72), 362 (M+ ꢁ I ꢁ 1, 100). H NMR (CDCl3, d, ppm): 0.63 (6H, m,
SiCH2), 0.92 (13H, m, SiC&bond;CH3, SiCCH2CC and SiCCCCH3),
1.74 (4H, m, SiCCCH2C), 3.26 (2H, bt, J = 6.2Hz, 4-CH2), 3.55 (3H, s,
N+CH3), 4.00–4.15 (6H, m, a-CH2N+, 3-CH2N+, OCH2), 4.79 and 5.06
(total 2H, d and d, J = 15.1Hz, 1-CH2N+), 7.1–7.3 (4H, m, 5-, 6-,
7- and 8-H). 13C NMR (CDCl3, d, ppm): 6.04 (SiCH2) and 6.89 (SiCCH3),
23.65, 24.04 and 26.21 (CCH2 CH2 CH3 and 4-C), 48.94 (N+CH3), 57.14
(OCH2), 59.62 (3-C), 62.72 (1-CH2N+), 63.63 (a-CH2N+), 125.92,
127.21, 127.65, 128.52, 128.81 and 128.91 (5-,6-,7-,8-,9- and 10-C).
29Si NMR (CDCl3, d, ppm): +21.49. Anal. calcd for C22H40INOSi: C,
53.98; H, 8.24; N, 2.86; found: C, 53.70; H, 8.16; N 2.93.
N-(2-Di-n-heptylmethylsiloxyethyl)-N-methyl-1,2,3,4-tetrahydroisoquinolinium
iodide (12d)
N-(2-n-Dimethylundecylsiloxyethyl)-N-methyl-1,2,3,4-tetrahydroisoquino-
linium iodide (12g)
Compound 12d was obtained following the procedure described
for 12b, from 0.65 g (1.56 mmol) diheptylmethylsilyl ether 9d, as
a yellow oily product.
Compound 12 g was obtained following the procedure described
for 12b, from 0.11 g (0.28 mmol) dimethylundecylsilyl ether 9 g,
as a yellow oily precipitate.
Yield 0.52 g (44%), m.p. 104–106 ꢀC. LC-MS (m/z, %): 433 (M+ ꢁ I +
Yield 0.06 g (40%), m.p. 92–94 ꢀC. LC-MS (m/z, %): 405 (M+ ꢁ I + 1,
1, 40), 432 (M+ ꢁ I, 100). GC-MS (m/z, %): 417 (M+ ꢁ CH3I, 2), 402
11), 404 (M+ ꢁ I, 58), 390 (M+ ꢁ CH3I + 1, 100), 346 (2), 181 (2), 160
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Copyright © 2012 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2013, 27, 114–124

(2-Triorganylsiloxyethyl)-tetrahydro(iso)quinolines
(42). GC-MS (m/z, %): 530 (M+ ꢁ 1, 3), 374 (M+ ꢁ CH3I ꢁ CH3, 2), 146
(total 2H, m and m, 4-CH2), 3.84 (3H, s, N+CH3), 3.92 and 4.59 (total
2H, m and m, 2-CH2N+), 3.92 and 4.13 (total 2H, m and m, a-CH2N+),
4.33 and 4.42 (total 2H, m and m, OCH2), 7.3–7.5 (3H, m, 5-, 6- and
7-H), 7.91 (1H, d, J = 8.3, 8-H). 13C NMR (CDCl3, d, ppm): ꢁ2.42
(SiCH3), 14.10 (CH3), 15.82 (SiCH2), 17.63 (3-CH2), 22.67, 23.65,
28.69 , 29.28, 29.65, 31.85 and 33.30 (CH2), 25.82 (4-C), 56.28
(a-CH2N+), 57.25 (N+CH3), 62.35 (2-C), 65.87 (OCH2), 121.98,
128.65, 129.31, 131.39 (5-, 6-, 7-, 8-C), 130.80 (9-C) and 141.69
(10-C). 29Si NMR (CDCl3, d, ppm): +22.63. Anal. calcd for C24H44INOSi:
C, 55.69; H, 8.57; N, 2.71; found: C, 55.52; H, 8.51; N 2.75.
1
(M+ ꢁ CH3I ꢁ CH2OSi(CH3)2C11H23, 100). H NMR (CDCl3, d, ppm):
0.10 (6H, s, SiCH3), 0.57 (2H, m, SiCH2), 0.85 (3H, t, J = 6.8Hz, CH3),
1.23 (18H, m, CH2), 3.24 (2H, m, 4-CH2), 3.54 (3H, s, N+CH3), 4.0–4.2
(6H, m, a-CH2N+, 3-CH2N+, OCH2), 4.76 and 5.08 (total 2H, d and d,
J = 14.3 Hz, 1-CH2N+), 7.1–7.4 (4H, m, 5-, 6-, 7- and 8-H). 13C NMR
(CDCl3, d, ppm): ꢁ2.40 (SiCH3), 14.03 (CH3), 15.82 (SiCH2), 22.61,
23.1, 29.32, 29.48, 29.62, 31.81 and 33.34 (CH2), 23.82 (4-CH2),
49.12 (N+CH3), 57.03 (OCH2), 59.76 (3-CH2N+), 62.79 (1-CH2N+),
63.65 (a-CH2N+), 126.01 (9-C), 127.28 (8-C), 127.82 (5-C), 128.63
(6-C), 128.87 (7-C) and 129.02 (10-C). 29Si NMR (CDCl3, d, ppm):
+22.67 (2JSiCH = 6.8 Hz). Anal. calcd for C25H46INOSi: C, 56.48; H,
8.72; N, 2.64; found: C, 56.72; H, 8.83; N 2.57.
N-(2-n-Decyldimethylsiloxyethyl)-4,4-dimethyl-N-methyl-4-sila-1,2,3,4-
tetrahidroisoquinolinium iodide (14)
Compound 14 was obtained following the procedure described
for 12b, from 0.13 g (0.31 mmol) decyldimethylsilyl ether 11, as
a dark-yellow powder.
N-(2-n-Hexadecyldimethylsiloxyethyl)-N-methyl-1,2,3,4-tetrahydroisoqui-
nolinium iodide (12 h)
Yield 0.04 g (24%), m.p. 46 ꢀC. LC-MS (m/z, %): 434 (M+ ꢁ I, 100).
1H NMR (CDCl3, d, ppm): 0.10 (6H, s, SiCH3-acycl.), 0.47 (6H, m,
SiCH3-cycl.), 0.57 (2H, m, SiCH2), 0.86 (3H, t, J = 6.8 Hz, CH3), 1.24
(16H, m, CH2), 3.42 (3H, s, N+CH3), 3.52 and 3.68 (1H and 1H, d
and d, J = 14.8 Hz, SiCH2N+), 3.88 (2H, t, J = 4.7 Hz, a-CH2N+), 4.18
(2H, m, OCH2), 4.86 and 4.96 (1H and 1H, d and d, J = 14.5 Hz,
1-CH2N+), 7.4–7.8 (4H, bm, 5-, 6-, 7- and 8-H). 13C NMR (CDCl3,
d, ppm): ꢁ2.42 (SiCH3), ꢁ1.25 (SiCH3-cycl.), 14.00 (CH3), 15.82
(SiCH2), 22.55, 22.96, 23.82, 29.20, 29.45, 29.52, 31.78, and 33.23
(CH2), 53.22 (N+CH3), 55.45 (SiCH2N+), 55.72 (OCH2), 67.41
(ArCH2N+), 67.95 (a-CH2N+ ), 129.33, 129.77, 131.23, 131.28,
133.96, 135.17 (5-, 6-, 7-, 8-, 9- and 10-C). 29Si NMR (CDCl3, d, ppm):
ꢁ13.46, +22.23. Anal. calcd for C25H48INOSi2: C, 53.45; H, 8.61; N,
2.49; found: C, 53.20; H, 8.50; N 2.57.
Compound 12 h was obtained following the procedure described
for 12b, from 0.67 g (1.5 mmol) hexadecyldimethylsilyl ether 9 h,
as a yellow powder.
Yield 0.80 g (89%), m.p. 59 ꢀC. LC-MS (m/z, %): 475 (M+ ꢁ I + 1,
100), 474 (M+ ꢁ I, 67), 460 (M+ ꢁ CH3I + 1, 49). GC-MS (m/z, %):
460 (M+ ꢁ CH3I + 1, 3), 445 (M+ ꢁ CH3I ꢁ CH3 + 1, 4), 234 (M+ ꢁ CH3I
1
C16H33, 11), 146 (M+ ꢁ CH3I ꢁ CH2OSi(CH3)2C16H33, 100). H NMR
(CDCl3, d, ppm): 0.11 (6H, s, SiCH3), 0.58 (2H, m, SiCH2), 0.86 (3H, t,
J = 7.0Hz, CH3), 1.24 (28H, bs, CH2), 3.25 (2H, m, 4-CH2), 3.56 (3H, s,
N+CH3), 3.9–4.2 (6H, m, a-CH2N+, 3-CH2N+, OCH2), 4.78 and 5.07
(total 2H, d and d, J = 15.4 Hz, 1-CH2N+), 7.11 (1H, d, 8-H), 7.1–7.4
(3H, m, 5-, 6- and 7-H). 13C NMR (CDCl3, d, ppm): ꢁ2.4 (SiCH3),
14.01, 15.79, 22.57, 22.98, 23.83, 29.24, 29.48, 29.54, 29.6, 31.81,
33.26 (4-C, CH2, CH3, SiCH2), 49.10 (N+CH3), 57.00 (OCH2), 59.68
(3-C), 62.65 (1-CH2N+), 63.49 (a-CH2N+), 126.01 (9-C), 127.29 (8-C),
127.68 (5-C), 128.58 (6-C), 128.83 (7-C), 128.94 (10-C). 29Si NMR
(CDCl3, d, ppm): +22.49. Anal. calcd for C30H56INOSi: C, 59.88; H,
9.38; N, 2.33; found: C, 59.63; H, 9.32; N, 2.40.
Biological Tests
Cytotoxicity
N-Methyl-N-(2-methyldiphenylsiloxyethyl)-1,2,3,4-tetrahydroisoquinolinium
iodide (12i)
Monolayer tumour cell lines HT-1080 (human fibrosarcoma),
MG-22A (mouse hepatoma) and normal mouse fibroblasts
(NIH 3 T3) were cultivated for 72 h in Dulbecco’s modified Eagle’s
medium (DMEM) standard medium (Sigma) without an indicator
and antibiotics.[35]
Compound 12i was obtained following the procedure described
for 12b, from 1.22 g (3.3 mmol) methyldiphenylsilyl ether 9i, as a
white powder.
Yield 0.41 g (24%), m.p. 96 ꢀC. LC-MS (m/z, %): 388 (M+ ꢁ I, 100).
GC-MS (m/z, %): 516 (M++1, 1), 373 (M+ ꢁ CH3I, 4), 295 (M+ ꢁ CH3I
C6H5 ꢁ 1, 12), 146 (M+ ꢁ CH3I ꢁ CH2OSiCH3(C6H5)2, 100). 1H NMR
(CDCl3, d, ppm): 0.67 (3H, s, SiCH3), 3.17 (2H, m, 4-CH2), 3.50 (3H, s,
N+CH3), 4.0–4.2 (6H, m, a-CH2, 3-CH2, OCH2), 4.73 and 5.02 (total
2H, d and d, J = 14.9 Hz, 1-CH2N+), 6.9–7.2 (4H, m, 5-, 6-, 7- and
8-H), 7.3–7.5 (10H, m, C6H5-H). 13C NMR (CDCl3, d, ppm): ꢁ3.60
(SiCH3), 23.65 (4-CH2), 49.12 (N+CH3), 57.41 OCH2), 59.49
(3-CH2N+), 62.22 (1-CH2N+), 63.13 (a-CH2N+), 125.81, 127.09,
127.41, 128.42, 128.63 and 128.68 (5-, 6-, 7-, 8-, 9- and 10-C),
128.14, 130.42, 133.61, 133.65, 134.04 (C6H5&bond;C). 29Si NMR
(CDCl3, d, ppm): ꢁ0.36. Anal. calcd for C25H30INOSi: C, 58.25; H,
5.87; N, 2.72; found: C, 58.52; H, 5.78; N 2.64.
Tumour cell lines were taken from the European Collection of
Cell Culture (ECACC). After the ampoule was thawed not more than
four passages were performed. The control cells and cells with
tested substances in the range of 2–5 ꢂ 104 cells mlꢁ1 concentra-
tion (depending on line nature) were placed on separate 96-well
plates. The volume of each plate was 200 ml. Solutions containing
test compounds were diluted and added to wells to give final con-
centrations of 50, 25, 12.5 and 6.25 mg mlꢁ1. Control cells were trea-
ted in the same manner but in the absence of test compounds. The
plates were incubated for 72 h at 37ꢀC and 5% CO2. The number of
surviving cells was determined using tri(4-dimethylaminophenyl)
methyl chloride (crystal violet, CV) or 3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyl-2H-tetrazolium bromide (MTT) coloration, which was
assayed by multiscan spectrophotometer. The quantity of live cells
on the control plate was taken in calculations for 100%.[35,36]
The LC50 was calculated using the Graph Pad PrismW 3.0 program,
r < 0.05. Concentration of NO was determined according to the
procedure described in Fast et al.[36]
N-(2-n-Decyldimethylsiloxyethyl)-N-methyl-1,2,3,4-tetrahydroquinolinium
iodide (13)
Compound 13 was obtained following the procedure described for
12b, from 1.574 g (4.20 mmol) decyldimethylsilyl ether 10, as an oil.
Yield 0.772 g (35%). LC-MS (m/z, %): 391 (M+ ꢁ I + 1, 17), 390
(M+ ꢁ I, 54), 389 (M+ ꢁ I, 100). 1H NMR (CDCl3, d, ppm): 0.11 (6H, s,
SiCH3), 0.58 (2H, m, SiCH2), 0.87 (3H, t, J = 6.8Hz, CH3), 1.24 (16H,
m, CH2), 2.25 and 2.39 (total 2H, m and m, 3-CH2N), 3.00 and 3.06
Antimicrobial activity
For the determination of antimicrobial activity, several reference
microbial strains, received from the Microbial Strain Collection
Appl. Organometal. Chem. 2013, 27, 114–124
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

A. Zablotskaya et al.
of Latvia (MSCL), Riga, Latvia, were used: Staphylococcus aureus
MSCL 334 (SA), Bacillus cereus MSCL 330 (BC), Proteus mirabilis
MSCL 590 (PM), Escherichia coli MSCL 332 (EC), Pseudomonas
aeruginosa MSCL 331 (PA) and Candida albicans MSCL 378 (CA).
All bacteria were cultivated on Plate Count Agar (Sanofi Diagnos-
tics Pasteur, France) at 37 ꢀC for 24 h. Candida albicans was
cultivated on DifcoTM Malt Extract Agar (Becton, Dickinson and
Co., UK) at 37 ꢀC for 48 h. Antimicrobial activity was determined
by agar well diffusion method.[37] The agar diffusion test was per-
formed on Mueller–Hinton (Carl Roth GmbH + Co. KG, Germany)
agar for bacteria and Malt Extract Agar for yeast. Suspensions of
18–24 h microbial cultures of turbidity A540 = 0.16 ꢃ 0.20 were
used and uniformly spread on Petri plates. Aliquots of 70 ml of
each test sample solution, corresponding solvent and reference
antimicrobial drugs solutions were added to 6.0mm diameter agar
wells. Gentamicin (KRKA, Slovenia) and fluconazole (Diflucan, Pfizer
Ltd, UK), 10 mg mlꢁ1 and 5 mgmlꢁ1, were used as reference
antibiotics. The antimicrobial activity was evaluated based on the
diameter of zone of inhibition. After incubation at 37ꢀC for 24 h
for bacteria and 48 h for yeast under aerobic conditions, the diam-
eter of the clear zone (no growth) around the well in the bacterial
lawn was measured. The inhibition zone diameter was measured
in millimetres (mm). The tests were performed in duplicate. The
results were expressed as the arithmetic average. The observed
zones of growth inhibition are presented in Table 4.
yield. It was revealed using GC-MS monitoring that under the same
reaction conditions the yield of the reaction products depends on
both the nature of hydrosilane and the nature of the heterocycle.
The influence of nature of the heterocyclic base on the reac-
tion result was more evident, provided the same triorganylsilane
was used and the same reaction conditions: N-(2-decyldimethysi-
loxyethyl)-1,2,3,4-tetrahydroisoquinoline (9f) was obtained with a
yield of 75% and the yield of N-(2-decyldimethysiloxyethyl)-
1,2,3,4-tetrahydroquinoline (10), in its turn, was significantly
lower: 24%. In the latter case the reaction proceeded more slowly
and it took a longer time in comparison with the N-(2-hydro-
xyethyl)-1,2,3,4-tetrahydroisoquinoline: 26 and 15 h, correspond-
ingly, to obtain the product with the highest yield. During
dehydrocondensation of 1 with different trialkylhidrosilanes, the
tendency of the reaction yield decrease has been observed with
carbon chain elongation of the alkyl substituent at the Si atom.
The yield of compounds 9a–f, possessing C2–C10 alkyl chain
length, ranged within 56–77%; for compounds 9 g (C11) and 9 h
(C16) it was lower – 49% and 38%, respectively – and the reaction
time for 9f and 9 h was longer.
The compounds synthesized were characterized by multinu-
clear NMR data. The values of 29Si NMR chemical shifts are pre-
sented in Tables 1 and 2. 29Si NMR resonance depends upon
the substituent at the silicon atom, and qualitatively similar
changes for 29Si chemical shifts of tetrahydroisoquinoline deriva-
tives 9a–h and their methiodides 12a–h during transition along
the sequence should be noted:
Results and Discussion
EtBu2< Hp2Me < OctMe2≤DcMe2≤ðC11H23ÞMe2≤ðC16H33ÞMe2
< Et3 < Et2Me
Chemistry
The synthesis of the compounds used in this study is outlined in
Schemes 1 and 2.
The low field shifting of 29Si NMR resonance from 16.74–19.90
to 21.49–24.23 ppm and the narrowing of its interval from 3.16 to
2.74 ppm have been noted for compounds containing positively
charged nitrogen (12a–h) in comparison with proper N-(2-
triorganylsiloxyethyl)-1,2,3,4-tetrahydroisoquinolines (9a–h). The
highest changes in d (29Si) values (4.75 ppm) under nitrogen qua-
ternization were observed for compound 12c with ethyldibutyl
substituent, revealing stronger N. . .Si interaction in the appropri-
ate silane.
N-Methyl-N-(2-triorganylsiloxyethyl)-1,2,3,4-tetrahydroisoquinoli-
nium iodides (12a–i) were envisioned as being prepared from the
common precursor alcohol 1[34] in moderate to good overall yields
(24–89%). N-(2-Decyldimethylsiloxyethyl)-N-methyl-1,2,3,4-tetrahy-
droquinolinium iodide (13) was prepared analogously from 2.
N-(2-Decyldimethylsiloxyethyl)-4,4-dimethyl-N-methyl-4-sila-1,2,3,4-
tetrahydroisoquinolinium iodide (14) was synthesized by a series of
sequenced reactions starting from 2-bromotoluene (Schemes 1
and 2). The reaction of dehydrocondensation,[38] a special feature
of hydrosilanes in their ability to undergo alcoholysis leading to
alkoxysilanes and gaseous hydrogen, was used in coupling the silyl
group to the organic substrates 1, 2 and 7.
Biological evaluation
In vitro antitumour and antimicrobial properties of the compounds
synthesized were investigated. A comparison of 8, 12a–i and 13
with 3 and 4 provided evidence that the latter compounds
The interaction of N-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquino-
line (1) with triorganylhydrosilanes R1R2R3SiH resulted in 38–91%
-
I
N+
N
N
OSiR1R2R3
OSiR1R2R3
OH
12a-i
1
2
9a-i
10
HSiR1R2R3
Na, t°C
CH3I
-
I
+
N
13
N
N
OSiR1R2R3
OSiR1R2R3
OH
Si
Si
Si
-
I
N+
N
N
OSiR1R2R3
OSiR1R2R3
OH
7
14
11
R1R2R3: Et2Me (9a, 12a); Et3 (9b, 12b); EtBu2 (9c, 12c); MeHp2 (9d, 12d); Me2Oct (9e, 12e); Me2Dc (9f, 10, 11, 12f, 13, 14);
Me2(C11H23) (9g, 12g); Me2(C16H33) (9h, 12h); MePh2 (9i, 12i)
Scheme 2. Synthesis of compounds 9–14.
wileyonlinelibrary.com/journal/aoc
Copyright © 2012 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2013, 27, 114–124

(2-Triorganylsiloxyethyl)-tetrahydro(iso)quinolines
Table 1. 29Si NMR resonance of, N-(2-triorganosiloxyethyl)-1,2,3,4-tetra-
hydroisoquinolines (9a–i), N-(2-decyldimethylsiloxyethyl)-1,2,3,4-tetra-
hydroquinoline (10) and N-(2-decyldimethylsiloxyethyl)-4,4-dimethyl-4-
sila-1,2,3,4-tetrahydroisoquinoline (11) R1R2R3SiOCH2CH2–HetN
Almost the same sequence has been determined concerning
MG-22A tumour cell lines:
Compound
R1
R2
R3
d
29Si (ppm)
Me2Dc < Et2Me < MePh2≤Me2ðC16H33Þ < Et3 < MeHp2
< Me2ðC11H23Þ< EtBu2
9a
9b
9c
9d
9e
9f
CH3
C2H5
C2H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
C2H5
C4H9
C7H15
CH3
C2H5
+19.90
+19.62
+16.74
+18.20
+18.32
+18.36
+18.24
+18.33
ꢁ2.39
C2H5
C4H9
C7H15
C8H17
C10H21
C11H23
C16H33
C6H5
The present investigation shows that compounds 12c and 12d
induced growth inhibition of HT-1080 and MG-22A cells, and
compound 12 g exhibits selective cytotoxic action against
MG-22A cells at a significant level. In general, N-methyl-N-(2-triorga-
nylsiloxyethyl)-1,2,3,4-tetrahydroisoquinolinium iodides screened
had high NO generation activity, being most active for 12d in both
the HT-1080 and MG-22A tests: 300% and 250% respectively
(Table 3). All the compounds synthesized possess low toxicity or
are non-toxic compounds (LD50 = 450–3200 mgkgꢁ1).
CH3
9 g
9 h
9i
CH3
CH3
C6H5
CH3
10
11
C10H21
C10H21
+18.62
ꢁ13.5, +18.06
CH3
The antibacterial and antifungal activity of compounds 12a–i, 13
and 14 have been investigated in dimethyl sulfoxide against two
Gram-positive – Bacillus cereus MSCL 330 (BC) and Staphylococcus
aureus MSCL 334 (SA) – and three Gram-negative microbial strains
– Proteus mirabilis MSCL 590 (PM), E. coli MSCL 332 (EC) and Pseudo-
monas aeruginosa MSCL 331 (PA) – and fungi – Candida albicans
MSCL 378 (CA) – in comparison with 2-hydroxyethyl precursors 3,
4 and 8, using the agar ditch diffusion method.[37] The results of
the study are presented in Table 4.
Table 2. 29Si NMR resonance of, N-methyl-N-(2-triorganosiloxyethyl)-
1,2,3,4-tetrahydroisoquinolinium (12a–i), N-(2-decyldimethylsiloxyethyl)-
N-methyl-1,2,3,4-tetrahydroquinolinium (13) and N-(2-decyldimethylsilox-
yethyl)-4,4-dimethyl-N-methyl-4-sila-1,2,3,4-tetrahydroisoquinolinium
iodides (14) [R1R2R3SiOCH2CH2–HetNMe]+I–
Compound
R1
R2
R3
d 29Si (ppm)
12a
12b
12c
12d
12e
12f
12 g
12 h
12i
CH3
C2H5
C2H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
C2H5
C4H9
C7H15
CH3
C2H5
+24.23
+23.84
+21.49
+22.35
+22.37
+22.50
+22.67
+22.49
–0.36
The results were compared with those of standard antibacterial
(gentamicin) and antifungal (fluconazole) drugs. N-(2-Hydroxyethyl)-
N-methyl-1,2,3,4-tetrahydroisoquinolinium iodide (3) showed low
activity against fungi and Gram-negative bacterial strains and was
inactive against the Gram-positive bacterial strains tested. Biological
activity data exhibited enhancement of inhibitory activity against
the tested pathogen microorganisms for N-methyl-N-(2-triorganyl-
siloxyethyl)-1,2,3,4-tetrahydro(iso,silaiso)quinolinium iodides 8,
12 and 14. In general, Gram-negative bacterial and fungal strains
were more resistant to the synthesized compounds than were
Gram positive strains. The most effective action of compounds
studied has been demonstrated against Gram-positive Bacillus ce-
reus MSCL 330 and Staphylococcus aureus MSCL 334 and Gram-neg-
ative Pseudomonas aeruginosa MSCL 331. Compound 12b was
found to be more active against Bacillus cereus MSCL 330 and
Staphylococcus aureus MSCL 334 than gentamicin. The highest
antifungal potency was revealed for N-(2-hydroxyethyl)-
N-methyl-1,2,3,4-tetrahydroquinolinium iodide (4). Selectivity of
antibacterial action was revealed concerning unsilylated 3, 4 and
8. Contrary to N-(2-hydroxyethyl)-N-methyl-1,2,3,4-tetrahydroiso-
quinolinium iodide (3), which is active only against Gram-negative
strains, compound 4 is mostly potent against Gram-positive anti-
bacterial strains. Compound 8, in turn, revealed a wide spectrum
of antibacterial activity. Among the heterocyclic choline derivatives
12f, 13 and 14 bearing the same substituents at the silicon atom
(dimethyldecylsilyl group) and their precursors 3, 4 and 8, silatetra-
hydroisoquinoline derivatives 14 and 8 possessed a wide spectrum
of biological activity and were the most potent compounds.
Contrary to tetrahydroisoquinoline derivatives 12f and 3, which
exhibited higher activity against Gram-negative antibacterial
strains, tetrahydroquinoline derivatives 13 and 4 were mostly
potent against Gram-positive strains. The degree of antibacterial
activity increased among the number of tetrahydroisoquinoline
derivatives with the silyl group nature in the following order
concerning Gram-positive strains:
C2H5
C4H9
C7H15
C8H17
C10H21
C11H23
C16H33
C6H5
CH3
CH3
CH3
C6H5
CH3
13
C10H21
C10H21
+22.63
–13.46, +22.23
14
CH3
possessed lower biological activity, practically did not reveal cyto-
toxic properties and in general were less active concerning the
microbial strains examined. The experimental evaluation of
cytotoxic properties is presented in Table 3.
In this study, two monolayer tumour cell lines – HT-1080
(human fibrosarcoma) and MG-22A (mouse hepatoma) – and
normal mouse fibroblasts (NIH 3 T3) have been employed to
evaluate the antiproliferative activity of the synthesized tetra-
hydro(iso)quinoline compounds in culture. N-(2-Hydroxyethyl)-
N-methyl-1,2,3,4-tetrahydroisoquinolinium iodide (3) and 4,4-
dimethyl-N-(2-hydroxyethyl)-N-methyl-4-sila-1,2,3,4-tetrahydroi-
soquinolinium iodides (8) did not exhibit cytotoxic action at
all. Thus this study clearly demonstrates that human fibrosar-
coma and mouse hepatoma cells are highly responsive to
some N-methyl-N-(2-triorganylsiloxyethyl)-1,2,3,4-tetrahydroi-
soquinolinium iodides. The following sequence of organosilicon
substituents in the cytotoxicity display concerning HT-1080 tumour
cell lines has been revealed:
Me2ðC11H23Þ< MePh2 < Me2ðC16H33Þ< Et3< MeHp2< EtBu2
Appl. Organometal. Chem. 2013, 27, 114–124
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

A. Zablotskaya et al.
Table 3. In vitro cell cytotoxicity and intracellular NO generation caused by N-methyl-N-(2-triorganylsiloxyethyl)-1,2,3,4-tetrahydroisoquinolinium
(12a-i), N-(2-hydroxyethyl)-N-methyl-1,2,3,4-tetrahydroisoquinolinium (3) and 4,4-dimethyl-N-(2-hydroxyethyl)-N-methyl-4-sila-1,2,3,4-tetrahydroiso-
quinolinium (8) iodides
Compound/test
HT-1080
MG-22A
NIH 3 T3
LC50 (mg mlꢁ1
)
NO (%)
CV
LC50 (mg mlꢁ1
)
NO (%)
CV
LC50
(mg mlꢁ1
NR
LD50
CV
MTT
CV
MTT
)
(mg kgꢁ1
)
3
**
**
8
**
**
2
5
100
73
6
**
100
10
1
4
9
1000
827
171
24
2202
2391
1214
539
12a
12b
12c
12d
12e
12f
12 g
12 h
12i
8
16
<1
3
200
150
300
2
150
150
250
3
<1
3
1
3
3
14
448
**
**
30
17
19
**
**
**
100
2
**
1340
**
3182
>2000
532
**
4
100
2
6
14
16
18
**
200
200
100
2
150
150
100
4
19
13
13
**
16
17
**
85
1083
722
41
452
1671
CV, crystal violet coloration; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide coloration; NR, neutral red coloration; NO,
nitrogen oxide concentration degree, determined according to the procedure.[36]
* LC50, concentration of compound providing 50% cell killing effect.
** No cytotoxic effect.
Table 4. In vitro antibacterial and antifungal activity data of N-methyl-N-(2-triorganylsiloxyethyl)- 1,2,3,4-tetrahydroisoquinolinium (12a–i), N-(2-n-
decyldimethylsiloxyethyl)-N-methyl-1,2,3,4-tetrahydroquinolinium (13) and N-(2-n-decyldimethylsiloxyethyl)-4,4-dimethyl-N-methyl-4-sila-1,2,3,4-
tetrahidroisoquinolinium (14) iodides given in concentrations of 5 mg mlꢁ1 (0.35 mg per disc) and 10 mg mlꢁ1 (0.7 mg per disc)
Compound
Diameter of zones showing complete inhibition of growth (mm)
BC EC PA PM
SA
CA
5
10
5
10
5
10
5
10
5
10
5
10
3
**
**
11
15
22
19
10
15
11
13
10
13
8
**
**
9
13
15
19
14
13
14
13
13
13
12
9
12
12
19
18
17
14
11
11
10
17
**
16
20
19
20
18
20
18
20
18
21
8
13
16
14
15
14
11
14
10
10
14
**
15
20
18
16
17
18
20
15
19
18
**
11
11
11
16
13
11
11
11
13
12
13
11
13
13
n
10
9
12a
22
25
19
9
26
30
20
8
16
23
19
9
12b
11
11
9
11
12
11
**
10
9
12c
12d
12e
16
11
**
18
11
12
**
15
10
**
12
9
12f
12 g
11
9
12 h
**
**
9
12i
13
8
15
11
13
14
21
27
14
10
13
15
19
22
8
11
18
11
13
14
n
4
8
13
12
18
19
25
n/n
12
17
17
19
n/n
8
10
10
12
23
**
**
**
**
8
10
11
21
n/n
10
10
40
n/n
14
12
42
9
**
14
**
**
Gentamicin
Fluconazole (2/0.2 mg mlꢁ1
20
n/n
21
)
10/**
n, non-determined.
** No inhibiting effect.
and in the following order concerning Gram-negative strains:
Me2ðC16H33Þ< MeHp2< Me2Dc < Me2ðC11H23Þ< MePh2
À
Á
À
Á
MePh2 < HO(SicyclMe2) < Me2Dc(SicyclMe2) < Me2(C16H33) ≤
Me2Dc ≤ MeHp2 < Me2(C11H23) < EtBu2 < Me2Oct < Et2Me < Et3
(E. coli MSCL 332)
< Me2Oct≤HO SicyclMe2 < Me2Dc SicyclMe2
< EtBu2< Et2Me < Et3
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Copyright © 2012 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2013, 27, 114–124

(2-Triorganylsiloxyethyl)-tetrahydro(iso)quinolines
Table 5. In vitro minimum inhibitory concentration (MIC) and minimum
bactericidal concentration (MBC) of compounds 13 and 14
hydroxyethyl)-1,2,3,4-tetrahydroisoquinolinium iodides with trior-
ganylsilyl group is essential for improvement of their biological
properties.
Compound
MIC (mg mlꢁ1
)
MBC (mg mlꢁ1
)
SA
BC
EC
PA
CA
SA
Supporting information
13
14
256 >256 >256 >256 >256
32 >256 >256 32
—
Supporting information may be found in the online version of
this article.
8
32
Acknowledgement
Me2Dc(SicyclMe2) < HO(SicyclMe2) < Me2(C16H33) ≤ Me2Dc <
MeHp2 < Et3 < Me2(C11H23) < Et2Me < Me2Oct < EtBu2 < MePh2
(Pseudomonas aeruginosa MSCL 331) and
Me2Dc(SicyclMe2) ≤ HO(SicyclMe2)Me2 < (C11H23) < EtBu2 <
MeHp2 < Me2Oct < MePh2 ≤ Et3 < Me2(C16H33) < Me2Dc < Et2Me
(Proteus mirabilis MSCL 590)
This work was supported by the Latvian Council of Sciences
(Pr. 09.1321).
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