Schiff base Sn(IV) complexes as cytotoxic agents: Synthesis, structure, isosteric and bioisosteric replacement

Article abstract of DOI:10.1016/j.jorganchem.2017.08.017

The preparation and characterization of two series of organotin(IV) complexes are reported, each series differing in the nature of the substituent bonded to the tin atom (cyclohexyl or bis(trimethyl)silylmethyl). The isosteric and bioisosteric approach wa

Full text of DOI:10.1016/j.jorganchem.2017.08.017

Accepted Manuscript
Schiff base Sn(IV) complexes as cytotoxic agents: Synthesis, structure, isosteric and
bioisosteric replacement
José M. Galván-Hidalgo, Teresa Ramírez-Apan, Antonio Nieto-Camacho, Simón
Hernández-Ortega, Elizabeth Gómez
PII:
S0022-328X(17)30507-7
10.1016/j.jorganchem.2017.08.017
JOM 20070
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 2 August 2017
Revised Date: 0022-328X 0022-328X
Accepted Date: 25 August 2017
Please cite this article as: José.M. Galván-Hidalgo, T. Ramírez-Apan, A. Nieto-Camacho, Simó.
Hernández-Ortega, E. Gómez, Schiff base Sn(IV) complexes as cytotoxic agents: Synthesis, structure,
isosteric and bioisosteric replacement, Journal of Organometallic Chemistry (2017), doi: 10.1016/
j.jorganchem.2017.08.017.
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ACCEPTED MANUSCRIPT
.
HO
N
O
KOH
Toluene: Methanol
R
H2N
HO
H
(80:20)
H
OH
or
Cl
(Cy)2SnO
((CH3)3-Si- CH2-)2-SnO

ACCEPTED MANUSCRIPT
Schiff base Sn(IV) complexes as cytotoxic agents:
synthesis,
structure,
isosteric
and
bioisosteric
replacement
José M. Galván-Hidalgo, Teresa Ramírez-Apan, Antonio Nieto-Camacho, Simón
Hernández-Ortega and Elizabeth Gómez*
Instituto de Química, Universidad Nacional Autónoma de México (UNAM), Circuito
Exterior s/n, Ciudad Universitaria, 04510 Ciudad de México, México
*Corresponding author. Email: eligom@iquimica.unam.mx
ABSTRACT
The preparation and characterization of two series of organotin(IV) complexes are
reported, each series differing in the nature of the substituent bonded to the tin
atom (cyclohexyl or bis(trimethyl)silylmethyl). The isosteric and bioisosteric
approach was used as the strategy of molecular design. The ligand was 5-
hydroxymethyl-4-[(2-hydroxyphenyl)iminomethyl]-2-methylpyridin-3-ol substituted
at position 5 by methyl, halogeno (F, Cl), methoxy, nitro and tert-butylsilyl; the
synthesis of the organotin(IV) complexes was performed by a multi-component
strategy in reasonable to high yields depending on the nature of the ligand. All new
complexes were fully characterized by IR, MS, X-ray determinations and NMR (1H,
13C, 119Sn). Crystallographic data of complexes showed the geometries adopted
around the metal tin center varied between square pyramidal in 2c and a trigonal
bipyramidal in 3b-3d with the alkyl groups in the trigonal plane and the two oxygen
atoms in the equatorial plane. Additionally, the in vitro cytotoxicity tests of the
complexes towards six types of human cancerous cell lines U-251 (glioblastoma),
K-562 (chronic myelogenous leukemia), HCT-15 (human colorectal), MCF-7
(human breast), MB-231(human breast) and SKLU-1 (non-small cell lung) showed
the superior activity of the organotin complexes compared to the corresponding
cisplatin used as positive control. The complexes containing fluorine exhibited
excellent IC50 data indicating that both the bioisosteric replacement and the
cyclohexyl ring bonded to the tin atom increased the potency of the cytotoxic
activity towards the cancer cell lines tested.

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KEYWORDS
Cytotoxicity, Organotin (IV), Schiff base, NMR spectroscopy, X-ray crystallography
1 INTRODUCTION
Since the development of metal complexes with anticancer activity, medicinal
inorganic chemistry has encouraged investigators to search for new metal
complexes and organometallic compounds with growing importance in medicine,
particularly in oncology.[1-4] It is known that more than 99% of currently approved
clinical drugs are organic compounds. In contrast, the percentage of metal-
containing drugs (metallodrugs) is low.[5] Metal-based compounds offer versatility
and the possibility for designing therapeutic agents not seen in organic compounds
in terms of the ability to vary coordination number, geometry, and redox states.[4,
6, 7] Additionally, metals provide a positive effect in the pharmacological
properties, forming complexes with a variety of ligands. The metal is usually a key
feature in the mechanism action, however; a fragment of the complex, or the metal,
or the ligand may also be responsible for the biological activity.[8] Although
cisplatin has showed significant clinical benefit for the treatment of several types of
solid tumors, toxic side effects and tumor resistance leads to the occurrence of
secondary malignancies;[9] however, the discovery and use of cisplatin have
encouraged investigators to search for and develop novel non platinum-containing
metal species with superior anti-cancer activity and low side effects. Organotin
derivatives have attracted much attention due to their potential biological activities,
including antimicrobial, antituberculosis, cardiovascular, antiviral, anti-parasitic,
antihypertensive biocidal, antifungal, bactericidal, anti-inflammatory, antioxidant,
and cytotoxic properties.[10-14]
The biological activity of organotin(IV) complexes has been associated with the
molecular structure, coordination number and the nature of the organic groups
bonded to the tin atom.[10, 15, 16] In many cases, it is known that metal
complexes of ligands with biological activity are more active than the free
ligands.[17, 18]

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Schiff bases have often been used as chelating ligands in the field of coordination
chemistry, and their metal complexes have been of great interest. Their biological
activity is usually increased by complexation; consequently it is essential to
understand the properties of both ligands and metal for the synthesis of highly
active compounds.[19] The complexes of vitamin B6 have been studied with the
purpose of knowing about the electronic and structural properties that are
implicated in several important model reactions. The Schiff base complexes
derived from vitamin B6 (VB6) are important compounds due to their tumor-
targeting properties.[20] VB6 is known to be taken up by cells through a VB6
transporting membrane carrier (VTC)-mediated diffusion pathway. As cancer cells
have high demand for VB6, compounds having this moiety could achieve VTC-
mediated entry into the tumor cells in preference to normal ones.[21]
Schiff base ligands having a vitamin B6 moiety are selected for their tumor-
targeting properties. VB6 is known to be taken up in cells by facilitated diffusion
through VB6 transporting membrane carriers.[20, 22] Moreover, serine
hydroxymethyltransferase isoforms (SHMTs), are vitamin VB6-dependent
enzymes, and are implicated in DNA biosynthesis.[23] SHMTs have been
correlated with the increased demand for nucleotide biosynthesis in tumors and
their activity is known to be high in proliferative and tumor cells.[24] VB6 has an
enormous potential as a biologically active reagent; it is known that organotin
complexes incorporating pyridoxal moieties show biological activity. The organotin
derivatives from pyridoxine have shown activity against P388, L1210, P815
leukemias. We recently described a series of organotin(IV) complexes containing
pyridoxamine Schiff base skeletons. The complexes were tested across a panel of
human cell lines, namely, U-251 (glioblastoma), PC-3 (prostate), K-562 (chronic
myelogenous leukemia), HCT- 15 (human colorectal), MCF-7 (human breast),
SKLU-1 (non-small cell lung), and MDA-MB-231 (human breast), to establish their
activity. The bioisosteric replacement of a methyl group with iodine caused an
increase in cytotoxicity. [25] More recently a series of pentacoordinated diorganotin
complexes derived from pyridoxal hydrochloride and 4-ꢀor 5-R-substituted ortho-
aminophenols were described by our group. In this case the position of the

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substitution on the aromatic ring and the electronic character of the substituents
were associated with the cytotoxic activity.[26] The antimicrobial activity has also
been explored for pyridoxal organotin complexes containing methyl, butyl or phenyl
substituents bonded to the tin atom.[27-29] Although a wide range or organotin
complexes with a diversity of biological activities are known, the effect on the
biological response of sterically-hindered substituents such as cyclohexyl or
bis(trimethyl)silylmethyl bonded to the tin atom has scarcely been explored, despite
these moieties forming molecules with potent cytotoxic activity against human
tumor cell lines, which make them promising agents in cancer therapy.[30-35]
In the present paper, we report on the synthesis and characterization of diorganotin
complexes containing cyclohexyl and bis(trimethyl)silylmethyl moieties with various
aminophenols. The X-ray crystal structures of four complexes are described
herein. The in vitro anti-tumor activity of the complexes against human breast
adenocarcinoma (MCF-7, MB-231) U-251 (glioblastoma), K-562 (chronic
myelogenous leukemia), HCT-15 (human colorectal), and SKLU-1 (non-small cell
lung) tumor cell lines are also studied.
2. EXPERIMENTAL
2.1 Materials
All reagents and solvents were obtained from commercial suppliers and used
without further purification. The dicyclohexyl and bis[(trimethylsilyl)methyl] tin(IV)
oxides were obtained following the methodology described by Kong et al.[36]
2.2 Physical measurements
Meting points of the complexes were measured with a Fischer-Johns MEL-TEMP II
apparatus and are not corrected. Infrared (IR) spectra of ligands and complexes
were recorded with BRUKER TENSOR 27 spectrometer using KBr or CsI. Molar
conductivity measurements were recorded with a Metrohm 644 using anhydrous
methanol as solvent. The UV-vis absorption spectra were obtained with a
Shimadzu UV-160U spectometer in methanol at 2.4530 × 10-5 M for all complexes.

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1H, 13C and 119Sn spectra were recorded with a Bruker Advance III spectrometer at
300.0, 75.4 and 111.8 MHz, in chloroform-d or DMSO-d6. COSY, HSQC and HMBC
experiments were used to completely assign the 1H and 13C signals. The FAB (fast
atom bombardment) mass spectra were recorded with a JEOL-JMS-X103
spectrometeter and for exact mass spectra, poly(ethylene glycol) 600 was used as
matrix. Single crystals of complexes 2d and 3b-3d suitable for X-ray diffraction
studies were grown from their solution in chloroform/heptane, choroform or
methanol. The crystals of each compound were mounted on a glass fiber at room
temperature for 3b-3d, and at 150 (2) K for 2d, and then placed in a Bruker Smart
Apex CCD diffractometer, equipped with a Mo radiation (λMo Kα = 0.71073 Å) and
graphite monochromator at 293 K; decay was negligible in all cases. Systematic
absences and intensity statistics were used in space group determination. The
structure was solved using the direct methods SHELXS-2014 program. Anisotropic
structure refinements were achieved using a full matrix, least-squares technique on
all non-hydrogen atoms. All hydrogen atoms were placed in idealized positions,
based on hybridization, with isotropic thermal parameters fixed at 1.2 times (for –
CH) and 1.5 times (for –CH3) the value of the attached atom. Structure solutions
and refinements were performed using SHELXL-2014 software.[37]
Crystallographic data of 2d, 3c, 3d and 3e have been deposited with the
Cambridge Crystallographic Data Centre CCDC 1554835-1554838 numbers.
2.3 General procedure for the synthesis of the Schiff bases 1b and 1e
To a solution of potassium hydroxide in 50 mL of toluene/methanol (60:40) mixture,
pyridoxal hydrochloride and the corresponding ortho-aminophenol-5-R-substituted
in a stoichiometric ratio were added. The reaction mixture was stirried over 4 days
at room temperature, and the solvent removed under reduced pressure to give light
brown and orange solids.
The synthesis of the Schiff bases 1a, 1c–d have been reported previously, using
sodium methanolate as base and methanol as solvent. [27, 38]

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5-Hydroxymethyl-4-[(2-hydroxy-5-fluorophenyl)iminomethyl]-2-methylpyridin-3-ol
(1b).
Compound 1b was prepared from 0.0450 g (0.8034 mmol) of potassium hydroxide,
0.1636 g of pyridoxal hydrochloride (0.8034 mmol) and 0.1021 g of 2-amino-4-
fluorophenol (0.8034 mmol), affording 0.1559 g (70%) of a light brown solid; m.p.
265–267ꢀoC (dec.); Molar conductance, ΛM (1 × 10-3 M, methanol): 5.0 ohm-1 cm2
mol-1 (non-electrolyte); UV-vis [methanol, λmax/nm (ε/ M-1cm-1)]: 205 (20383) π–π*
(aromatic), 285 (5340) π–π* (C=N), 385 (2935) n–π* (C=N); IR (KBr) cm-1: 3073
ν(OHAlcohol), 1597 ν(C=N), 1259 ν(C–OArom), 1146 ν(C–F), 1016 ν(C–OPrim); 1H NMR
(300.52 MHz, DMSO-d6) δ: 2.45 (3H, s, H-14), 4.80 (2H, s, H-15), 5.47 (1H, s, H-
16), 7.07 (2H, d, J = 5.71 Hz, H-9, H-7), 7.50 (1H, d, J = 9.52 Hz, H-10), 7.99 (1H,
s, H-3), 9.23 (1H, s, H-5), 10.13 (1H, s, H-13), 14.52 (1H, s, H-11); MS: (FAB+)
[m/z] (%): [M++1, 277] (7); HR-MS (FAB+) m/z: 277.0988 (Calc. for C14H14N2O3F),
observed: 277.0992.
5-Hydroxymethyl-4-[(2-hydroxy-5-methoxyphenyl)iminomethyl]-2-methylpyridin-3-ol
(1e).
This compound was synthesized from 0.0450 g (0.8034 mmol) of potassium
hydroxide, 0.1636 g pyridoxal hydrochloride (0.0450 mmol), 0.1118 g of 2-amino-4-
methoxyphenol (0.8034 mmol). Compound 1e was obtained as a dark orange solid
(0.1962 g, 85%); m.p. 223–225oC (dec.); Molar conductance, ΛM (1 × 10-3 M,
methanol): 75.0 ohm-1 cm2 mol-1 (non-electrolyte); UV-vis [methanol, λmax/nm (ε/ M-1
cm-1)]: 205 (21647), π–π* (aromatic), 276 (6400) π–π* (C=N), 394 (3342) n–π*
(C=N); IR (KBr) cm-1: 3063 ν(OHAlcohol), 1613 ν(C=N), 1194 ν(C–OArom), 1151 ν(C–
1
OCH3), 1016 ν(C–OPrim); H NMR (300.52 MHz, DMSO-d6)ꢀδ: 2.45 (3H, s, H-14),
3.76 (3H, s, H-17), 4.81 (2H, s, H-15), 5.61 (1H, s, H-16), 6.85 (1H, dd, Jꢀ=ꢀ1.53 Hz,
Jꢀ=ꢀ8.72 Hz, H-9), 6.98 (1H, d, Jꢀ=ꢀ8.72 Hz, H-10), 7.17 (1H, d, Jꢀ=ꢀ1.80 Hz, H-7),
7.95 (1H, s, H-3), 9.24 (1H, s, H-5), 9.77 (1H, s, H-13), 15.09 (1H, s, H-11); 13C
NMR (75.57 MHz, DMSO-d6)δ: 158.5 (C-5), 155.0 (C-13a), 153.2 (C-10a), 148.6
(C-4), 146.3 (C-8), 136.6 (C-3), 134.4 (C-4a), 133.8 (C-6a), 120.7 (C-1), 117.7 (C-

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10), 115.8 (C-9), 105.1 (C-7), 58.7 (C-17), 56.2 (C-15), 18.8 (C-14); MS: (FAB+)
[m/z] (%):ꢀ[M++1, 289] (12); HR-MS (FAB+) m/z: 289.1188 (Calc. for C15H17N2O4),
observed: 289.1191.
2.4 General procedure for the synthesis of the complexes
To a solution of potassium hydroxide in 50 mL of toluene/methanol (60:40) mixture,
pyridoxal hydrochloride, the corresponding ortho-aminophenol-5-R-substituted and
the corresponding diorganotin(IV) oxide in a stoichiometric ratio were added. The
reaction mixtured was refluxed for 8h for bis(trimethylsilyl)methyl tin(IV) oxide and
48 h for dicyclohexyltin(IV) oxide. It was then filtered to remove the potassium
chloride and the solvent removed under reduced pressure to afford the resultant
compound as a solid. All complexes had intense color and were soluble in most
common organic solvents. They were purified by crystallization from chlorform or
methanol solutions.
12,12-Dicyclohexyl-4-hydroxymethyl-1-methylbenzo[d]-pyrido[4,3-h]-11,13,2,6-
dioxazastannonine (2a).
Compound 2a was prepared from 0.0372 g of potassium hydroxide (0.6644 mmol),
0.1352 g pyridoxal hydrochloride (0.6644 mmol), 0.0725 g of 2-aminophenol
(0.6644 mmol) and 0.2 g of dicyclohexyl tin(IV) oxide (0.6644 mmol), affording
0.2596 g (72%) of a dark red solid; m.p. 168–170ꢀoC (dec.); Molar conductance, ΛM
(1 × 10-3 M, methanol): 6.5 ohm-1 cm2 mol-1 (non-electrolyte); UV-vis [methanol,
λmax/nm (ε/ M-1 cm-1)]: 207 (39625) π–π* (aromatic), 317 (6604) π–π* (C=N), 472
(10966) n–π* (C=N); IR (KBr) cm-1: 3153 ν(OHAlcohol), 1589 ν(C=N), 1180 ν(C–
OArom), 1021 ν(C–OPrim), 592 ν(Sn-C), 527 ν(Sn–O), 408 ν(Sn–N); 1H NMR (300.52
MHz, CDCl3) δ: 1.26–2.13 (22H, m, H-α, β, γ, δ), 2.41 (3H, s, H-14), 4.75 (2H, s, H-
15), 5.61 (1H, s, H-16), 6.67 (1H, t, Jꢀ=ꢀ7.51 Hz, H-9), 6.86 (1H, d, Jꢀ=ꢀ8.41 Hz, H-
10), 7.19 (1H, t, Jꢀ=ꢀ7.51 Hz, H-8), 7.39 (1H, d, Jꢀ=ꢀ8.71 Hz, H-7), 7.43 (1H, s, H-3),
3
13
9.46 (1H, s, J(1H-119/117Sn)ꢀ=ꢀ42 Hz, H-5); C NMR (75.57 MHz, CDCl3) δ: 162.2

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(C-13a), 160.5 (C-10a), 158.8 (C-5), 156.3 (C-4), 133.4 (C-3), 132.8 (C-4a), 132.2
(C-6a), 131.2 (C-8), 119.0 (C-10), 118.1 (C-1), 116.8 (C-9), 115.7 (C-7), 60.9 (C-
2
15), 40.5 (C-α), 30.04, 29.99 (C-β, J(119Sn-13C)ꢀ= 26 Hz), 28.61, 28.57 (C-γ,
3J(119Sn-13C)ꢀ= 86 Hz), 26.6 (C-δ), 19.4 (C-14); 119Sn NMR (112.07 MHz, CDCl3)ꢀδ:
-252; 119Sn NMR (112.07 MHz, DMSO-d6)ꢀδ: -268; MS: (FAB+) [m/z] (%): [M++1,
543] (100), [M+-2Cy, 377] (37), [M+-CH2OH, 346] (8); HR-MS (FAB+) m/z: 543.1670
(Calc. for C26H35N2O3Sn), observed: 543.1681.
12,12-Dicyclohexyl-8-fluoro-4-hydroxymethyl-1-methylbenzo[d]-pyrido[4,3-h]-
11,13,2,6-dioxazaestanonine (2b).
Compound 2b was synthesized from 0.0372 g of potassium hydroxide (0.6644
mmol), 0.1352 g of pyridoxal hydrochloride (0.6644 mmol), 0.0844 g of 2-amino-4-
fluorophenol (0.6644 mmol) and 0.2 g of dicyclohexyltin(IV) oxide (0.6644 mmol),
o
to give 0.2871 g (77%) of a dark red solid; m.p. 162–164 C (dec.); Molar
conductance, ΛM (1ꢀ×ꢀ10-3 M, methanol): 7.3 ohm-1 cm2 mol-1 (non-electrolyte); UV-
vis [methanol, λmax/nm (ε/ M-1 cm-1)]: 207 (43253) π–π* (aromatic), 287 (9335) π–π*
(C=N), 482 (12597) n–π* (C=N); IR (KBr) cm-1: 3158 ν(OHAlcohol), 1594 ν(C=N),
1253 ν(C-F), 1187 ν(C–OArom), 1023 ν(C–OPrim), 619 ν(Sn–C), 541 ν(Sn–O), 409
1
ν(Sn–N); H NMR (300.52 MHz, CDCl3) δ: 1.28–2.17 (22H, m, H-α, β, γ, δ), 2.46
(3H, s, H-14), 3.99 (1H, s, H-16), 4.80 (2H, s, H-15), 6.83 (1H, dd, Jꢀ=ꢀ5.40 Hz,
Jꢀ=ꢀ9.01 Hz, H-10), 6.96 (1H, td, Jꢀ=ꢀ2.40 Hz, Jꢀ=ꢀ8.56 Hz, H-7), 7.13 (1H, dd,
3
Jꢀ=ꢀ2.40 Hz, Jꢀ=ꢀ9.31 Hz, H-9), 7.54 (1H, s, H-3), 9.33 (1H, s, J(1H-119/117Sn)ꢀ=ꢀ40
Hz, H-5); 13C NMR (75.57 MHz, CDCl3) δ: 162.4 (C-13a), 159.3 (C-5), 156.4 (C-4),
1
156.9 (C-10a), 154.5 (d, J(13C-19F)ꢀ=ꢀ237 Hz, C-8), 133.6 (C-3), 132.8 (C-4a),
131.5 (d, 3J(13C-19F)ꢀ=ꢀ8.84 Hz, C-6a), 119.3 (d, 3J(13C-19F)ꢀ=ꢀ7.86 Hz, C-10), 118.3
(C-1), 118.2 (d, 2Jꢀ=ꢀ22.59 Hz, C-7), 102.3 (d, 2J(13C-19F)ꢀ=ꢀ24.93 Hz, C-9), 60.9 (C-
2
15), 40.7 (C-α), 30.00, 29.96 (C-β, J(119Sn-13C)ꢀ=ꢀ26 Hz), 28.59, 28.55 (C-γ,
3J(119Sn-13C)ꢀ=ꢀ81 Hz), 26.5 (C-δ), 19.4 (C-14); 119Sn NMR (112.07 MHz, CDCl3) δ:
-246; 119Sn NMR (112.07 MHz, DMSO-d6) δ: -268; MS: (FAB+) [m/z] (%): [M++1,
561] (100), [M+-2Cy, 395] (5); HR-MS (FAB+) m/z: 561.1575 (Calc. for
C26H34N2O3SnF), observed: 561.1576.

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12,12-Dicyclohexyl-8-chloro-4-hydroxymethyl-1-methylbenzo[d]-pyrido[4,3-h]-
11,13,2,6-dioxazastannonine (2c).
Compound 2c was obtained from 0.0372 g potassium hydroxide (0.6644 mmol),
0.1352 g of pyridoxal hydrochloride (0.6644 mmol), 0.0953 g of 2-amino-4-
chlorophenol (0.6644 mmol) and 0.2 g of dicyclohexyltin (IV) oxide (0.6644 mmol),
o
affording 0.3266 g (85%) of a dark brown solid; m.p. 175–177 C (dec.); Molar
conductance, ΛM (1 × 10-3 M, methanol): 3.9 ohm-1 cm2 mol-1 (non-electrolyte); UV-
vis [methanol, λmax/nm (ε/ M-1 cm-1)]: 207 (40155), π–π* (aromatic), 287 (8439), π–π*
(C=N), 479 (10885) n–π* (C=N); IR (KBr) cm-1: 3177 ν(OHAlcohol), 1588 ν(C=N),
1179 ν(C–OArom), 1070 ν(C–Cl), 1040 ν(C–OPrim), 536 ν(Sn–C), 517 ν(Sn–O), 406
1
ν(Sn–N); H NMR (300.52 MHz, CDCl3) δ: 1.26–2.15 (22H, m, H-α, β, γ, δ), 2.42
(3H, s, H-14), 4.77 (2H, s, H-15), 6.79 (1H, d, Jꢀ=ꢀ8.72 Hz, H-10), 7.14 (1H, d,
3
Jꢀ=ꢀ8.72 Hz, H-9), 7.34 (1H, s, H-7), 7.48 (1H, s, H-3), 9.35 (1H, s, J(1H-
13
119/117Sn)ꢀ=ꢀ40 Hz, H-5); C NMR (75.57 MHz, CDCl3) δ: 162.4 (C-13a), 159.6 (C-
5), 159.2 (C-10a), 156.4 (C-4), 133.9 (C-3), 132.9 (C-4a), 132.7 (C-6a), 130.9 (C-
9), 121.4 (C-8), 120.0 (C-10), 117.9 (C-1), 115.7 (C-7), 60.7 (C-15), 40.7 (C-α,
3
1J(119Sn-13C)ꢀ=ꢀ576 Hz), 30.00, 29.97 (C-β), 28.60, 28.57 (C-γ, J(119Sn-13C)ꢀ=ꢀ80
Hz), 26.5 (C-δ), 19.4 (C-14); 119Sn NMR (112.07 MHz, CDCl3) δ: -248; 119Sn NMR
(112.07 MHz, DMSO-d6) δ: -273; MS: (FAB+) [m/z] (%): [M++1, 577] (80), [M+-2Cy,
411] (22), [M+-CH2OH, 380] (12); HR-MS (FAB+) m/z: 577.1280 (Calc. for
C26H34N2O3SnCl), observed: 577.1276.
12,12-Dicyclohexyl-4-hydroxymethyl-1,8-dimethylbenzo[d]-pyrido[4,3-h]-11,13,2,6-
dioxazastannonine (2d).
Compound 2d was prepared from 0.0372 g of potassium hydroxide(0.6644 mmol),
0.1352 g of pyridoxal hydrochloride (0.6644 mmol), 0.0818 g of 2-amino-4-
methylphenol (0.6644 mmol) and 0.2 g of dicyclohexyltin (IV) oxide (0.6644 mmol),
o
to give 0.3132 g (85%) of a dark red solid; m.p. 200–202 C (dec.); Molar
conductance, ΛM (1ꢀ×ꢀ10-3 M, methanol): 5.7 ohm-1 cm2 mol-1 (non-electrolyte); UV-
vis [methanol, λmax/nm (ε/ M-1 cm-1)]: 207 (49776), 285 (8357) π–π* (aromatic), 320

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(8724) π–π* (C=N), 483 (13494) n–π* (C=N); IR (KBr) cm-1: 3197 ν(OHAlcohol), 1589
ν(C=N), 1182 ν(C–OArom), 1069 ν(C–OPrim), 540 ν(Sn–C), 518 ν(Sn–O), 477 ν(Sn–
1
N); H NMR (300.52 MHz, CDCl3) δ: 1.25–2.15 (22H, m, H-α, β, γ, δ), 2.30 (3H, s,
H-17), 2.43 (3H, s, H-14), 4.77 (2H, s, H-15), 5.30 (1H, s, H-16), 6.78 (1H, d,
J=8.41 Hz, H-10), 7.04 (1H, d, J=8.11 Hz, H-9), 7.17 (1H, s, H-7), 7.50 (1H, s, H-
3
3), 9.35 (1H, s, J(1H-119/117Sn)ꢀ=ꢀ42 Hz, H-5); 13C NMR (75.57 MHz, CDCl3) δ:
162.0 (C-13a), 158.4 (C-10a), 158.2 (C-5), 156.0 (C-4), 133.7 (C-3), 132.9 (C-4a),
132.3 (C-9), 131.7 (C-6a), 126.2 (C-8), 118.7 (C-10), 118.3 (C-1), 115.7 (C-7), 60.9
(C-15), 40.3 (C-α), 30.05, 30.00 (C-β), 28.61, 28.57 (C-γ), 26.6 (C-δ), 20.9 (C-17),
19.3 (C-14); 119Sn NMR (112.07 MHz, CDCl3)δ: -251; 119Sn NMR (112.07 MHz,
DMSO-d6)δ: -485; MS: (FAB+) [m/z] (%): [M++1, 557] (100), [M+-2Cy, 391] (36),
[M+-CH2OH, 360] (5); HR-MS (FAB+) [m/z] (%): 557.1826 (Calc. for
C27H37N2O3Sn), observed: 557.1840.
12,12-Dicyclohexyl-4-hydroxymethyl-8-methoxy-1-methylbenzo[d]-pyrido[4,3-h]-
11,13,2,6-dioxazastannonine (2e).
Compound 2e was obtained from 0.0372 g of potassium hydroxide(0.6644 mmol),
0.1352 g of pyridoxal (0.6644 mmol), 0.0924 g of 2-amino-4-methoxyphenol
(0.6644 mmol) and 0.2 g of dicyclohexyltin (IV) oxide (0.6644 mmol), affording
0.3211 g (93%) of a dark purple solid; m.p. 179–181ꢀoC (dec.); Molar conductance,
ΛM (1X10-3 M, methanol): 5.9 ohm-1 cm2 mol-1 (non-electrolyte); UV-vis [methanol,
λmax/nm (ε/ M-1 cm-1)]: 207 (31798) π–π* (aromatic), 293 (6645) π–π* (C=N), 498
(7419) n–π* (C=N); IR (KBr) cm-1: 3190 ν(OHAlcohol), 1595 ν(C=N), 1221 ν(C–OArom),
1
1149 ν(C–OCH3), 1026 ν(C–OPrim), 549 ν(Sn–C), 512 ν(Sn–O), 420 ν(Sn–N); H
NMR (300.52 MHz, CDCl3) δ: 1.26-2.12 (22H, m, H-α, β, γ, δ), 2.43 (3H, s, H-14),
3.79 (3H, s, H-17), 4.77 (2H, s, H-15), 6.82 (1H, d, J=8.72 Hz, H-10), 6.87 (1H, d,
Jꢀ=ꢀ2.40 Hz, H-7), 6.91 (1H, dd, Jꢀ=ꢀ2.40 Hz, Jꢀ=ꢀ8.72 Hz, H-9), 7.54 (1H, s, H-3),
3
13
9.31 (1H, s, J(1H-119/117Sn)ꢀ=ꢀ41 Hz, H-5); C NMR (75.57 MHz, CDCl3) δ: 162.2
(C-13a), 158.3 (C-5), 156.5 (C-4), 155.2 (C-10a), 151.1 (C-8), 134.0 (C-3), 132.3
(C-4a), 131.6 (C-6a), 119.3 (C-10), 118.2 (C-7), 118.0 (C-1), 100.7 (C-9), 61.1 (C-
15), 56.2 (C-17), 40.4 (C-α), 30.04, 29.99 (C-β, 2J(119Sn-13C)ꢀ=ꢀ27 Hz), 28.62, 28.57

ACCEPTED MANUSCRIPT
3
(C-γ, J(119Sn-13C)ꢀ=ꢀ80 Hz), 26.6 (C-δ), 19.6 (C-14); 119Sn NMR (112.07 MHz,
CDCl3) δ: -248; 119Sn NMR (112.07 MHz, DMSO-d6) δ: -475; MS: (FAB+) [m/z] (%):
[M++1, 573] (17), [M+-2Cy, 407] (9); HR-MS (FAB+) m/z: 573.1775 (Calc. for
C27H37N2O4Sn), observed: 573.1784.
12,12-Dicyclohexyl-4-hydroxymethyl-1-methyl-8-nitrobenzo[d]-pyrido[4,3-h]-
11,13,2,6-dioxazastannonine (2f).
Compound 2f was synthesized 0.0372 g (0.6644 mmol) of potassium hydroxide,
0.1352 g of pyridoxal (0.6644 mmol), 0.1024 g of 2-amino-4-nitrophenol (0.6644
mmol) and 0.2 g of dicyclohexyltin(IV) oxide (0.6644 mmol), to give 0.2894 g (74%)
of a light red solid; m.p. 240–242oC (dec.); Molar conductance, ΛM (1ꢀ×ꢀ10-3 M,
methanol): 4.1 ohm-1 cm2 mol-1 (non-electrolyte); UV-vis [methanol, λmax/nm (ε/ M-1
cm-1)]: 206 (26253) π–π* (aromatic), 340 (11415) π–π* (C=N), 434 (10395) n–π*
(C=N); IR (KBr) cm-1: 3093 ν(OHAlcohol), 1589 ν(C=N), 1305 ν(NO2), 1265 ν(C–
OArom), 1042 ν(C–OPrim), 542 ν(Sn–C), 504 ν(Sn–O), 415 ν(Sn–N); 1H NMR (300.52
MHz, CDCl3) δ: 1.26–2.25 (22H, m, H-α, β, γ, δ), 2.45 (3H, s, H-14), 4.88 (2H, s, H-
15), 6.85 (1H, d, Jꢀ=ꢀ9.32 Hz, H-10), 7.64 (1H, s, H-3), 8.12 (1H, dd, Jꢀ=ꢀ2.40 Hz,
3
Jꢀ=ꢀ9.02 Hz, H-9), 8.34 (1H, d, Jꢀ=ꢀ2.40 Hz, H-7), 9.56 (1H, s, J(1H-119/117Sn)ꢀ=ꢀ38
Hz, H-5); 13C NMR (75.57 MHz, CDCl3) δ: 166.8 (C-10a), 162.7 (C-13a), 162.1 (C-
5), 156.6 (C-4), 137.3 (C-8), 134.2 (C-3), 133.0 (C-4a), 131.8 (C-6a), 126.8 (C-9),
118.5 (C-10), 117.7 (C-1), 112.8 (C-7), 60.6 (C-15), 41.3 (C-α), 29.93, 29.91 (C-β),
3
28.57, 28.54 (C-γ, J(119Sn-13C)ꢀ=ꢀ84 Hz), 26.4 (C-δ), 19.4 (C-14); 119Sn NMR
(112.07 MHz, CDCl3) δ: -244; 119Sn NMR (112.07 MHz, DMSO-d6)δ: -290; MS:
(FAB+) [m/z] (%): [M++1, 588] (57), [M+-2Cy, 422] (12), [M+-CH2OH, 391] (7); HR-
MS (FAB+) m/z: 588.1520 (Calc. for C26H34N3O5Sn), observed: 588.1514.
12,12-Dicyclohexyl-8-t-butyl-4-hydroxymethyl-1-methylbenzo[d]-pyrido[4,3-h]-
11,13,2,6-dioxazastannonine (2g).
Compound 2g was prepared from 0.0372 g of potassium hydroxide (0.6644 mmol),
0.1352 g of pyridoxal hydrochloride (0.6644 mmol), 0.1097 g of 2-amino-4-tert-

ACCEPTED MANUSCRIPT
butylphenol (0.6644 mmol) and 0.2 g of dicyclohexyltin(IV) oxide (0.6644 mmol),
o
affording 0.3143 g (79%) of a light red solid; m.p. 75–77 C (dec.); Molar
conductance, ΛM (1ꢀ×ꢀ10-3 M, methanol): 57.0 ohm-1 cm2 mol-1 (non-electrolyte);
UV-vis [methanol, λmax/nm (ε/ M-1 cm-1)]: 207 (34244), 281 (5789) π–π* (aromatic),
318 (5422) π–π* (C=N), 481 (8316) n–π* (C=N); IR (KBr) cm-1: 3222 ν(OHAlcohol),
1595 ν(C=N), 1263 ν(C–OArom), 1024 ν(C–OPrim), 548 ν(Sn–C), 516 ν(Sn–O), 456
1
ν(Sn–N); H NMR (300.52 MHz, CDCl3) δ: 1.32 (9H, s, H-18), 1.54–2.12 (22H, m,
H-α, β, γ, δ), 2.43 (3H, s, H-14), 4.78 (2H, s, H-15), 6.82 (1H, d, Jꢀ=ꢀ8.41 Hz, H-10),
7.29 (1H, dd, Jꢀ=ꢀ1.80 Hz, Jꢀ=ꢀ8.71 Hz, H-9), 7.38 (1H, d, Jꢀ=ꢀ1.80 Hz, H-7), 7.46
3
(1H, s, H-3), 9.47 (1H, s, J(1H-119/117Sn)ꢀ=ꢀ43 Hz, H-5); 13C NMR (75.57 MHz,
CDCl3) δ: 162.1 (C-13a), 158.4 (C-10a), 158.0 (C-5), 155.7 (C-4), 139.8 (C-4a),
133.3 (C-3), 133.2 (C-8), 131.1 (C-6a), 128.9 (C-9), 118.6 (C-1), 118.5 (C-10),
111.9 (C-7), 60.9 (C-15), 40.4 (C-α), 34.3 (C-17), 31.5 (C-18), 30.05, 29.99 (C-β,
2J(119Sn-13C)ꢀ=ꢀ26 Hz), 28.63, 28.58 (C-γ), 26.6 (C-δ), 19.2 (C-14); 119Sn NMR
(112.07 MHz, CDCl3) δ: -251; 119Sn NMR (112.07 MHz, DMSO-d6) δ: -263; MS:
(FAB+) [m/z] (%): [M++1, 599] (36), [M+-2Cy, 433] (10); HR-MS (FAB+) m/z:
599.2296 (Calc. for C30H43N2O3Sn), observed: 599.2301.
12,12-Bis[(trimethylsilyl)methyl]-4-hydroxymethyl-1-methylbenzo[d]-pyrido[4,3-h]-
11,13,2,6-dioxazastannonine (3a).
Compound 3a was synthesized from 0.0362 g of potassium hydroxide (0.6469
mmol), 0.1317 g of pyridoxal hydrochloride (0.6469 mmol), 0.0706 g of 2-
aminophenol (0.6469 mmol) and 0.2 g of bis(trimethylsilyl)methyl tin(IV) oxide
o
(0.6469 mmol), affording 0.2605 g (73%) of a light red solid; m.p. 134–136 C
(dec.); Molar conductance, ΛM (1ꢀ×ꢀ10-3 M, methanol): 11.0 ohm-1 cm2 mol-1 (non-
electrolyte); UV-vis [methanol, λmax/nm (ε/ M-1 cm-1)]: 206 (21891) π–π* (aromatic),
324 (4117) π–π* (C=N), 469 (6971) n–π* (C=N); IR (KBr) cm-1: 3129 ν(OHAlcohol),
1590 ν(C=N), 1186 ν(C–OArom), 1020 ν(C–OPrim), 828 ν(Si–CH3), 532 ν(Sn–C), 515
1
ν(Sn–O), 407 ν(Sn–N); H NMR (300.52 MHz, CDCl3) δ: 0.00 (18H, s, CH2-
Si(CH)3), 0.45 (4H, s, CH2-Si(CH)3), 2.51 (3H, s, H-14), 4.86 (2H, s, H-15), 6.72
(1H, t, Jꢀ=ꢀ7.51 Hz, H-9), 6.81 (1H, d, Jꢀ=ꢀ7.81 Hz, H-10), 7.24 (1H, t, Jꢀ=ꢀ7.51 Hz, H-

ACCEPTED MANUSCRIPT
3
8), 7.46 (1H, d, Jꢀ=ꢀ8.11 Hz, H-7), 7.69 (1H, s, H-3), 9.39 (1H, s, J(1H-
13
119/117Sn)ꢀ=ꢀ41 Hz, H-5); C NMR (75.57 MHz, CDCl3) δ: 159.9 (C-13a), 158.2 (C-
10a), 157.2 (C-5), 154.8 (C-4), 132.1 (C-3), 131.8 (C-4a), 130.5 (C-8), 130.1 (C-
6a), 118.1 (C-10), 117.2 (C-1), 116.0 (C-9), 114.5 (C-7), 59.7 (C-15), 18.1 (C-14),
7.0 (CH2-Si(CH)3), 0.0 (CH2-Si(CH)3); 119Sn NMR (112.07 MHz, CDCl3) δ: -149;
119Sn NMR (112.07 MHz, DMSO-d6) δ: -161; MS: (FAB+) [m/z] (%): [M++1, 551]
(100), [M+-(CH2-Si(CH3)3)2, 377] (37), [M+-CH2OH, 346] (8); HR-MS (FAB+) m/z:
551.1208 (Calc. for C22H35N2O3Si2Sn), observed: 551.1198.
12,12-Bis[(trimethylsilyl)methyl]-8-fluoro-4-hydroxymethyl-1-methylbenzo[d]-
pyrido[4,3-h]-11,13,2,6-dioxazastannonine (3b).
Compound 3b was obtained from 0.0362 g of potassium hydroxide(0.6469 mmol),
0.1317 g of pyridoxal hydrochloride (0.6469 mmol), 0.0822 g of 2-amino-4-
fluorophenol (0.6469 mmol) and 0.2 g of bis(trimethylsilyl)methyl tin(IV) oxide
(0.6469 mmol), to give 0.2756 g (75%) of a dark red solid; m.p. 140–142ꢀoC (dec.);
Molar conductance, ΛM (1ꢀ×ꢀ10-3 M, methanol): 11.0 ohm-1 cm2 mol-1 (non-
electrolyte); UV-vis [methanol, λmax/nm (ε/ M-1 cm-1)]: 207 (41378) π–π* (aromatic),
284 (10273) π–π* (C=N), 482 (15124) n–π* (C=N); IR (CsI) cm-1: 3130 ν(OHAlcohol),
1597 ν(C=N), 1248 ν(C–F), 1188 ν(C–OArom), 1015 ν(C–OPrim), 832 ν(Si–CH3), 616
ν(Sn–C), 538 ν(Sn–O), 415 ν(Sn–N); 1H NMR (300.52 MHz, CDCl3) δ: 0.00 (18H, s,
CH2-Si(CH)3), 0.43 (4H, s, CH2-Si(CH)3), 2.42 (3H, s, H-14), 4.00 (1H, s, H-16),
4.80 (2H, s, H-15), 6.77 (1H, dd, Jꢀ=ꢀ4.81 Hz, Jꢀ=ꢀ8.41 Hz, H-10), 6.96 (1H, dd,
Jꢀ=ꢀ6.31 Hz, Jꢀ=ꢀ8.11 Hz, H-9), 7.16 (1H, d, Jꢀ=ꢀ6.61 Hz, H-7), 7.55 (1H, s, H-3),
3
13
9.33 (1H, s, J(1H-119/117Sn)ꢀ=ꢀ45 Hz, H-5); C NMR (75.57 MHz, CDCl3) δ: 160.1
(C-13a), 158.2 (C-5), 155.0 (C-10a), 154.5 (C-4), 153.4 (d, 1J(13C-19F)ꢀ=ꢀ236.84 Hz,
3
C-8), 132.3 (C-3), 131.9 (C-4a), 129.5 (d, J(13C-19F)ꢀ=ꢀ8.99 Hz, C-6a), 118.4 (d,
2
3J(13C-19F)ꢀ=ꢀ7.48 Hz, C-10), 117.4 (d, J(13C-19F)ꢀ=ꢀ23.12 Hz, C-9), 117.0 (C-1),
2
101.1 (d, J(13C-19F)ꢀ=ꢀ25.77 Hz, C-7), 59.6 (C-15), 18.2 (C-14), 7.2 (CH2-Si(CH)3),
0.0 (CH2-Si(CH)3); 119Sn NMR (112.07 MHz, CDCl3) δ: -142; 119Sn NMR (112.07
MHz, DMSO-d6) δ: -157; MS: (FAB+) [m/z] (%): [M++1, 569] (100), [M+-(CH2-

ACCEPTED MANUSCRIPT
Si(CH3)3)2, 395] (5); HR-MS (FAB+) m/z: 569.1114 (Calc. for C22H34N2O3Si2SnF),
observed: 569.1115.
12,12-Bis[(trimethylsilyl)methyl]-8-chloro-4-hydroxymethyl-1-methylbenzo[d]-
pyrido[4,3-h]-11,13,2,6-dioxazastannonine (3c).
Compound 3c was prepared from 0.0362 g of potassium hydroxide (0.6469 mmol),
0.1317 g of pyridoxal hydrochloride (0.6469 mmol), 0.0928 g of 2-amino-4-
chlorophenol (0.6469 mmol) and 0.2 g of bis(trimethylsilyl)methyl tin(IV) oxide
(0.6469 mmol), affording 0.2866 g (76%) of a light red solid; m.p. 145–147ꢀoC
(dec.); Molar conductance, ΛM (1ꢀ×ꢀ10-3 M, methanol): 50.0 ohm-1 cm2 mol-1 (non-
electrolyte); UV-vis [methanol, λmax/nm (ε/ M-1 cm-1)]: 207 (30045) π–π* (aromatic),
283 (6807), 314 (5789) π–π* (C=N), 478 (9499) n–π*(C=N); IR (CsI) cm-1: 3150
ν(OHAlcohol), 1600 ν(C=N), 1251 ν(C–OArom), 1077 ν(C–OPrim), 1025 ν(C–Cl), 837
ν(Si–CH3), 678 ν(Sn–C), 541 ν(Sn–O), 413 ν(Sn–N); 1H NMR (300.52 MHz, CDCl3)
δ: 0.00 (18H, s, CH2-Si(CH)3), 0.44 (4H, s, CH2-Si(CH)3), 2.43 (3H, s, H-14), 4.81
(2H, s, H-15), 6.75 (1H, d, Jꢀ=ꢀ9.02 Hz, H-10), 7.16 (1H, d, Jꢀ=ꢀ8.72 Hz, H-9), 7.39
(1H, s, H-7), 7.58 (1H, s, H-3), 9.34 (1H, s, 3J(1H-119/117Sn)ꢀ=ꢀ46 Hz, H-5); 13C NMR
(75.57 MHz, CDCl3) δ: 160.1 (C-13a), 157.9 (C-5), 156.9 (C-10a), 153.9 (C-4),
133.2 (C-4a), 130.9 (C-3), 130.5 (C-9), 127.8 (C-6a), 120.7 (C-8), 119.1 (C-10),
117.9 (C-1), 114.7 (C-7), 59.0 (C-15), 17.4 (C-14), 7.3 (CH2-Si(CH)3), 0.0 (CH2-
Si(CH)3); 119Sn NMR (112.07 MHz, CDCl3) δ: -143, (1J(119Sn-13C)ꢀ=ꢀ503 Hz; 119Sn
NMR (112.07 MHz, DMSO-d6) δ: -159; MS: (FAB+) [m/z] (%): [M++1, 585] (100),
[M+- (CH2-Si(CH3)3)2, 411] (15), [M+-CH2OH, 380] (5); HR-MS (FAB+) m/z:
585.0819 (Calc. for C22H34N2O3Si2SnCl), observed: 585.0818.
12,12-Bis[(trimethylsilyl)methyl]-4-hydroxymethyl-1,8-dimethylbenzo[d]-pyrido[4,3-h]-
11,13,2,6-dioxazastannonine (3d).
Compound 3d was synthesized from 0.0362 g of potassium hydroxide (0.6469
mmol), 0.1317 g of pyridoxal hydrochloride (0.6469 mmol), 0.0796 g of 2-amino-4-
methylphenol (0.6469 mmol) and 0.2 g of bis(trimethylsilyl)methyl tin(IV) oxide
(0.6469 mmol), to give 0.2099 g (58%) of a dark red solid; m.p. 168–170ꢀoC (dec.);

ACCEPTED MANUSCRIPT
Molar conductance, ΛM (1ꢀ×ꢀ10-3 M, methanol): 4.3 ohm-1 cm2 mol-1 (non-
electrolyte); UV-vis [methanol, λmax/nm (ε/ M-1 cm-1)]: 207 (33143) π–π* (aromatic),
324 (5911) π–π* (C=N), 482 (10395) n–π* (C=N); IR (CsI) cm-1: 3128 ν(OHAlcohol),
1594 ν(C=N), 1250 ν(C–OArom), 1018 ν(C–OPrim), 830 ν(Si–CH3), 544 ν(Sn–C), 481
1
ν(Sn–O), 407 ν(Sn–N); H NMR (300.52 MHz, CDCl3) δ: 0.00 (18H, s, CH2-
Si(CH)3), 0.42 (4H, s, CH2-Si(CH)3), 2.31 (3H, s, H-17), 2.42 (3H, s, H-14), 4.80
(2H, s, H-15), 6.73 (1H, d, Jꢀ=ꢀ8.41 Hz, H-10), 7.05 (1H, d, Jꢀ=ꢀ8.41 Hz, H-9), 7.20
(1H, s, H-7), 7.54 (1H, s, H-3), 9.36 (1H, s, 3J(1H-119/117Sn)ꢀ=ꢀ48 Hz, H-5); 13C NMR
(75.57 MHz, CDCl3) δ: 159.7 (C-13a), 156.9 (C-5), 156.0 (C-10a), 155.2 (C-4),
132.9 (C-3), 131.4 (C-9), 131.3 (C-4a), 129.5 (C-6a), 125.2 (C-8), 117.7 (C-10),
116.9 (C-1), 114.3 (C-7), 59.8 (C-15), 19.7 (C-14), 18.4 (C-17), 6.9 (CH2-Si(CH)3),
0.0 (CH2-Si(CH)3); 119Sn NMR (112.07 MHz, CDCl3) δ: -149; 119Sn NMR (112.07
MHz, DMSO-d6) δ: -159; MS: (FAB+) [m/z] (%): [M++1, 565] (100), [M+-(CH2-
Si(CH3)3)2, 391] (10), [M+-CH2OH, 360] (5); HR-MS (FAB+) [m/z] (%): 565.1365
(Calc. for C23H37N2O3Si2Sn), observed: 565.1363.
12,12-Bis[(trimethylsilyl)methyl]-4-hydroxymethyl-8-methoxy-1-methylbenzo[d]-
pyrido[4,3-h]-11,13,2,6-dioxazastannonine (3e).
Compound 3e was obtained from 0.0362 g of potassium hydroxide (0.6469 mmol),
0.1317 g of pyridoxal hydrochloride (0.6469 mmol), 0.0900 g of 2-amino-4-
methoxyphenol (0.6469 mmol) and 0.2 g of bis (trimethylsilyl)methyl tin(IV) oxide
(0.6469 mmol), affording 0.3298 g (88%) of a dark purple solid; m.p. 120–121ꢀoC
(dec.); Molar conductance, ΛM (1ꢀ×ꢀ10-3 M, methanol): 4.1 ohm-1 cm2 mol-1 (non-
electrolyte); UV-vis [methanol, λmax/nm (ε/ M-1 cm-1)]: 206 (29759), 293 (5544) π–π*
(aromatic), 323 (4892) π–π* (C=N), 504 (7583) n–π* (C=N); IR (CsI) cm-1: 3165
ν(OHAlcohol), 1596 ν(C=N), 1250 ν(C–OArom), 1146 ν(C–OCH3), 1032 ν(C–OPrim), 828
ν(Si–CH3), 608 ν(Sn–C), 517 ν(Sn–O), 412 ν(Sn–N); 1H NMR (300.52 MHz, CDCl3)
δ: 0.00 (18H, s, CH2-Si(CH)3), 0.42 (4H, s, CH2-Si(CH)3), 2.42 (3H, s, H-14), 3.80
(3H, s, H-17), 4.80 (2H, s, H-15), 6.77 (1H, d, Jꢀ=ꢀ9.02 Hz, H-10), 6.89 (1H, dd,
Jꢀ=ꢀ2.40 Hz, Jꢀ=ꢀ9.01 Hz, H-9), 6.94 (1H, s, H-7), 7.58 (1H, s, H-3), 9.31 (1H, s,
3J(1H-119/117Sn)ꢀ=ꢀ47 Hz, H-5); 13C NMR (75.57 MHz, CDCl3) δ: 159.7 (C-13a),

ACCEPTED MANUSCRIPT
157.2 (C-5), 155.6 (C-10a), 152.8 (C-4), 150.0 (C-8), 133.3 (C-3), 130.9 (C-4a),
129.5 (C-6a), 118.3 (C-10), 117.3 (C-9), 116.6 (C-1), 99.3 (C-7), 59.9 (C-15), 54.9
(C-17), 18.7 (C-14), 6.9 (CH2-Si(CH)3), 0.0 (CH2-Si(CH)3); 119Sn NMR (112.07 MHz,
CDCl3) δ: -146; 119Sn NMR (112.07 MHz, DMSO-d6) δ: -157; MS: (FAB+) [m/z] (%):
[M++1, 581] (100), [M+-(CH2-Si(CH3)3)2, 407] (10); HR-MS (FAB+) m/z: 581.1314
(Calc. for C23H37N2O4Si2Sn), observed: 581.1306.
12,12-Bis[(trimethylsilyl)methyl]-4-hydroxymethyl-1-methyl-8-nitrobenzo[d]-
pyrido[4,3-h]-11,13,2,6-dioxazastannonine (3f).
Compound 3f was prepared from 0.0362 g of potassium hydroxide (0.6469 mmol),
0.1317 g of pyridoxal hydrochloride (0.6469 mmol), 0.0997 g of 2-amino-4-
nitrophenol (0.6469 mmol) and 0.2 g of bis (trimethylsilyl)methyl tin(IV) oxide
(0.6469 mmol), giving 0.2960 g (77%) of a dark yellow solid; m.p. 183–185ꢀoC
(dec.); Molar conductance, ΛM (1ꢀ×ꢀ10-3 M, methanol): 7.1 ohm-1 cm2 mol-1 (non-
electrolyte); UV-vis [methanol, λmax/nm (ε/ M-1 cm-1)]: 206 (28740) π–π* (aromatic),
348 (13983) π–π* (C=N), 463 (12108) n–π* (C=N); IR (CsI) cm-1: 3185 ν(OHAlcohol),
1603 ν(C=N), 1305 ν(NO2), 1243 ν(C–OArom), 1013 ν(C–OPrim), 830 ν(Si–CH3), 533
ν(Sn–C), 504 ν(Sn–O), 419 ν(Sn–N); 1H NMR (300.52 MHz, CDCl3) δ: 0.00 (18H, s,
CH2-Si(CH)3), 0.49 (4H, s, CH2-Si(CH)3), 2.45 (3H, s, H-14), 4.90 (2H, s, H-15),
6.81 (1H, d, Jꢀ=ꢀ8.41 Hz, H-10), 7.72 (1H, s, H-3), 8.13 (1H, d, Jꢀ=ꢀ8.41 Hz, H-9),
8.38 (1H, s, H-7), 9.54 (1H, s, 3J(1H-119/117Sn)ꢀ=ꢀ43 Hz, H-5); 13C NMR (75.57 MHz,
CDCl3) δ: 164.2 (C-10a), 160.8 (C-5), 160.5 (C-13a), 155.1 (C-4), 136.5 (C-8),
132.4 (C-4a), 132.3 (C-3), 129.7(C-6a), 126.0 (C-9), 117.6 (C-10), 117.1 (C-1),
111.7 (C-7), 59.4 (C-15), 18.0 (C-14), 7.4 (CH2-Si(CH)3), 0.0 (CH2-Si(CH)3); 119Sn
NMR (112.07 MHz, CDCl3) δ: -138; 119Sn NMR (112.07 MHz, DMSO-d6) δ: -163;
MS: (FAB+) [m/z] (%): [M++1, 596] (100), [M+-(CH2-Si(CH3)3)2, 422] (7); HR-MS
(FAB+) m/z: 596.1059 (Calc. for C22H34N3O5Si2Sn), observed: 596.1076.
12,12-Bis[(trimethylsilyl)methyl]-8-t-butyl-4-hydroxymethyl-1-methylbenzo[d]-
pyrido[4,3-h]-11,13,2,6-dioxazastannonine (3g).

ACCEPTED MANUSCRIPT
Compound 3g was synthetized from 0.0362 g of potassium hydroxide (0.6469
mmol), 0.1317 g pyridoxal hydrochloride (0.6469 mmol), 0.1068 g of 2-amino-4-
tert-butylphenol (0.6469 mmol) and 0.2 g of bis (trimethylsilyl)methyl tin(IV) oxide
(0.6469 mmol), affording 0.2784 g (71%) of a dark red solid; m.p. 103–105ꢀoC
(dec.); Molar conductance, ΛM (1ꢀ×ꢀ10-3 M, methanol): 3.7 ohm-1 cm2 mol-1 (non-
electrolyte); UV-vis [methanol, λmax/nm (ε/ M-1 cm-1)]: 207 (33020) π–π* (aromatic),
282 (8031) π–π* (C=N), 478 (4729) n–π* (C=N); IR (CsI) cm-1: 2952 ν(OHAlcohol),
1575 ν(C=N), 1247 ν(C–OArom), 1019 ν(C–OPrim), 831 ν(Si–CH3), 539 ν(Sn–C), 513
1
ν(Sn–O), 409 ν(Sn–N); H NMR (300.52 MHz, CDCl3) δ: 0.00 (18H, s, CH2-
Si(CH)3), 0.43 (4H, s, CH2-Si(CH)3), 1.31 (9H, s, H-18), 2.41 (3H, s, H-14), 4.81
(2H, s, H-15), 6.77 (1H, d, Jꢀ=ꢀ8.72 Hz, H-10), 7.28 (1H, d, Jꢀ=ꢀ9.61 Hz, H-9), 7.37
(1H, s, H-7), 7.58 (1H, s, H-3), 9.42 (1H, s, 3J(1H-119/117Sn)ꢀ=ꢀ48 Hz, H-5); 13C NMR
(75.57 MHz, CDCl3) δ: 159.6 (C-13a), 156.8 (C-5), 155.9 (C-10a), 155.2 (C-4),
138.9 (C-8), 132.9 (C-3), 131.2 (C-4a), 129.1 (C-6a), 127.9 (C-9), 117.4 (C-10),
116.9 (C-1), 110.5 (C-7), 59.9 (C-15), 33.1 (C-17), 30.3 (C-18), 18.5 (C-14), 6.8
(CH2-Si(CH)3), 0.0 (CH2-Si(CH)3); 119Sn NMR (112.07 MHz, CDCl3) δ: -149; 119Sn
NMR (112.07 MHz, DMSO-d6) δ: -158; MS: (FAB+) [m/z] (%): [M++1, 607] (30), [M+-
(CH2-Si(CH3)3)2, 432] (10), [M+-CH2OH, 401] (8); HR-MS (FAB+) m/z: 607.1834
(Calc. for C26H43N2O3Si2Sn), observed: 607.1846.
2.5 Cytotoxic Activity Assay
The cytotoxic activity was evaluated by sulforhodamine B assay,[39] using the
human cancerous cell lines: U-251 (glioblastoma), K-562 (chronic myelogenous
leukemia), HCT-15 (human colorectal), MCF-7 (human breast), MB-231(human
breast), SKLU-1 (non-small cell lung) and cisplatin as reference.

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3. Results and discussion
3.1 Synthesis
The synthetic route to the ligands and complexes is described in Scheme 1. The
Schiff-base ligands 1a–e were obtained by reaction of pyridoxal hydrochloride and
the corresponding 2-amino-5-R-phenol (R=H, F, Cl, CH3, OCH3) in the presence of
potassium hydroxide. The compounds 1a, 1c–d have been reported previously,
using sodium methanolate as base and methanol as solvent;[27, 38] however, the
methodology used by our group gives higher yields. The ligands were reacted with
dicyclohexyl and bis(trimethylsilyl)methyl tin(IV) oxides, under reflux, using a
toluene/methanol mixture as solvent. The expected complexes were isolated in
yields of 60–65%. Attempts to isolate ligands containing –NO2 and tert-bu
substituents failed, as the pure compounds could not be isolated. Keeping this in
mind and based on our previous results, we decided to use the multicomponent
strategy; in this case, the yields were improved with respect to the two-step
synthesis from the isolated ligands (71–93%). The obtained complexes were
solids, soluble in most organic solvents, with molar conductance values from 3.7 to
57.0 Λ (ohm-1 cm2 mol-1) indicating the non-electrolytic nature of these complexes
(The electronic data are given in S1Table 1 supporting material).

ACCEPTED MANUSCRIPT
HO
N
O
R
HO
H2N
HO
R
H
KOH
N
H
OH
Toluene: Methanol
N
Cl
HO
1a R=H
1b R=F
1c R=Cl
1d R=CH3
1e R= OCH3
OH
(80:20)
(R1)2SnO
KOH
Toluene: Methanol
(80:20)
Toluene: Methanol
(80:20)
(R1)2SnO
R
HO
N
N
R1
O
Sn
R1
O
a R= H
b R= F
c R= Cl
d R= CH3
e R= OCH3
f R= NO2
g R= tert-bu
2a-2g R1=Cy
3a-3g R1= -CH2-Si-(CH3)3
Scheme 1
3.2 Electronic Absorption Spectra
The electronic spectral data for ligands 1a–1e, show three main absorption bands:
the first one at 206–207 nm (εmax =ꢀ20628–23441 M-1 cm-1) is due to π–π* transition
of the aromatic ring; the second, at 76–287 nm (εmax =5177–6400) was assigned to
π–π* transition within the azomethine (C=N); and the band at 375–394 nm (εmax
2935–5422) to the n−π* transition (C=N). For the metal complexes 2a–2g and 3a–
3g the electronic spectra show the absorption bands similar to those of the ligands
for transition π–π* of the aromatic ring and (C=N); however, the band due to the
transition n−π* (C=N) 434–504 nm (4729–13494) is shifted lower on coordination,
because of the coordination of the nitrogen atom of the azomethine (Conductivity

ACCEPTED MANUSCRIPT
values are summarized in Table S1 supporting information). This shift can be
attributed to overlapping of the central-metal d-orbital with the p-orbital of the donor
atom.[25, 40-42] The complexes 2d, 2g, 3c and 3e also showed a band at 229–
293 nm (εmax = 4933–13333) associated with the charge transfer band, since it is
known that metalloids and metals form dπ–pπ bonds with ligands containing
nitrogen and oxygen as donor atoms. Additionally, the change of the substituent
cyclohexyl to bis(oftrimethylsilyl)methyl group results in a lower molar extinction
coefficient.
3.3 IR Spectra
The IR spectra of complexes 2a–g and 3a–g show vibrational bands in the range
of 3034 to 3335 cm-1 which are assigned to v(OH). The corresponding vibrational
bands v(O–H) of the free ligands appear at 2952–3222 cm-1, revealing the non-
participation of the hydroxyl group from the pyridoxal ring in the coordination with
the metal.
The vibration bands ν(C=N) for complexes 2a–g and 3a–g were observed in the
region of 1575–1603 cm-1; a comparative analysis of complexes 2a–e and 3a–e
with respect to the free ligands showed a shift of the stretching frequencies
∆ν(C=N) of 18 to 26 cm-1. Further evidence of the bonding is given by the
observation of new bands in the spectra of the metal complexes of medium or
weak intensity at the region 467–435 cm−1 due to ν(Sn—N) stretching vibrations
supporting the involvement of the nitrogen atom of the azomethine group via
coordination to the tin center. Two new bands at 532–619 and 481–541 cm-1 are
characteristic of Sn–C and Sn–O absorptions respectively, indicating the
deprotonation of the phenolic hydroxyl. All these values are consistent with those
detected in pyridoxamine and pyridoxal organotin compounds described
previously. [25, 26, 43] For complexes 3a–g an additional vibration band at 828–
837 cm-1 for ν(Si-CH3) was observed (Vibrational bands for all complexes are given
in Table S2 supporting information).

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3.4 1H NMR spectra
The use of one and two-dimensional (COSY, HSQC and HMBC) NMR experiments
in CDCl3 allowed us to assign proton and carbon chemical shifts of the complexes
in solution. The chemical shifts were in accordance with the structures depicted in
Scheme 1, and the chemical shifts of complexes are summarized Table 1. A
common feature upon complexation to tin was the disappearance of the phenolic
hydroxyl protons at positions 11 and 13. The signal of the azomethine (CH=N)
around 9.35–9.56 ppm showed the expected satellite signals due to coupling to the
3
tin atom J(119/117Sn–1H) with values of 38 to 48 Hz, corroborating the formation of
the Sn–N coordination bond as a consequence of the complex formation.[44] All
complexes showed the expected single signal at 7.43 to 7.72 ppm for the H-3
proton of the pyridoxal ring, and the well-defined signals for the aromatic ring. The
protons of the methylene and hydroxyl of CH2OH, as well as the methyl group
attached to the pyridoxal ring, did not showed significant changes in the chemical
shift as a consequence of the complexation, as was observed previously for
pyridoxine, pyridoxamine and pyridoxal tin derivatives,[25, 26, 43] which suggest
that the hydroxyl groups do not participate in the coordination with the tin. For
complexes 2a–2g multiplet signals were observed in the aliphatic region in the
range 1.25–2.25 ppm for the cyclohexyl group, and for 3a–3g two singlet signals
were observed at 0.0–0.49 ppm for the moiety bis(trimethylsilyl)methyl bonded to
the tin atom.

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Table 1. 1H NMR (CDCl3, 300 MHz) data for complexes 2a-g.
Compound
2a
2b
2c
2d
2e
2f
2g
H-3
7.43 (s)
7.54 (s)
9.33 (40)
6.96 (td, J=2.4, 8.6 Hz)
7.48 (s)
9.35 (40)
7.34 (s)
7.50 (s)
9.35 (42)
7.17 (s)
7.54 (s)
9.31 (41)
6.87 (d, J=2.4 Hz)
7.64 (s)
9.56 (38)
8.34 (d, J=2.4 Hz)
7.46 (s)
9.47 (43)
7.38 (d, J=1.8 Hz)
H-5 ( 3J (1H119/117Sn)) 9.46 (42)
H-7
H-8
H-9
7.39 (d, J=8.7 Hz)
7.19 (t, J=7.5 Hz)
6.67 (t, J=7.5 Hz)
7.13 (dd, J=2.4, 9.3 Hz)
7.14 (d, J=8.7 Hz)
7.04 (d, J=8.1 Hz)
6.91 (dd, J=2.4, 8.7 Hz)
8.12 (dd, J=2.4, 9.02 Hz)
7.29 (dd, J=1.8, 8.7 Hz)
H-10
H-14
6.86(d, J=8.4 Hz)
2.41 (s)
6.83 (dd, J=5.4, 9.0 Hz)
2.46 (s)
6.79 (d, J=8.7 Hz)
2.42(s)
6.78 (d, J=8.4 Hz)
2.43 (s)
6.82 (d, J=8.7 Hz)
2.43 (s)
6.85 (d, J=9.3 Hz)
2.45 (s)
6.82 (d J=8.4 Hz)
2.43 (s)
4.75 (s)
4.80 (s)
4.77 (s)
4.77 (s)
4.77 (s)
4.88 (s)
4.78 (s)
H-16
5.61 (s)
3.99 (s)
3.75 (s)
H-17
5.61 (s)
3.99 (s)
3.75 (s)
H-18
2.30 (s)
3.79 (s)
1.26-2.13 (m)
1.28-2.17 (m)
1.26-2.15 (m)
1.25-2.15 (m)
1.26-2.12 (m)
1.26-2.25 (m)
1.54-2.12 (m)
H- Cy (α, β, γ, δ)
3a
3b
3c
3d
3e
3f
3g
H-3
7.69(s)
7.55 (s)
7.58 (s)
7.54 (s)
7.58 (s)
7.72 (s)
7.58 (s)
H-5 (3J (1H119/117Sn)) 9.39 (41)
9.33 (45)
7.16 (d,J=6.61 Hz)
9.34 (46)
7.39 (s)
9.36 (48)
7.20 (s)
9.31 (47)
6.94 (s)
9.54 (43)
8.38 (s)
9.42 (48)
7.37 (s)
H-7
7.46 (d, J=8.1 Hz)
7.24 (t. J=7.5 Hz)
6.72 (t, J=7.5 Hz)
6.81 (d, J=7.8 Hz)
2.51 (s)
H-9
6.96 (dd, J=6.3, 8.1 Hz)
6.77 (dd, J=4.8, 8.4 Hz )
2.42 (s)
4.80 (s)
4.00 (s)
7.16 (d, J=8.7 Hz)
6.75 (d, J=9.0 Hz)
2.43 (s)
7.05 (d, J=8.4 Hz)
6.73 (d, J=8.4 Hz)
2.42 (s)
6.89 (dd, J=2.4, 9.0 Hz)
6.77 (d J=9.0 Hz)
2.42 (s)
8.13 (d, J=8.4 Hz)
6.81 (d, J=8.4 Hz)
2.45 (s)
7.28 (d, J=9.6 Hz)
6.77 (d, J=8.7 Hz)
2.41 (s)
H-10
H-14
H-15
H-16
H-17
H-18
4.86 (s)
4.81 (s)
4.80 (s)
4.80 (s)
4.90 (s)
4.81 (s)
2.31 (s)
3.80(s)
1.31 (s)
Si(CH3)3
-CH2-Si(CH3)3
0.00 (s)
0.45 (s)
0.00 (s)
0.43 (s)
0.00 (s)
0.44 (s)
0.00 (s)
0.42 (s)
0.00 (s)
0.42 (s)
0.00 (s)
0.49 (s)
0.00 (s)
0.43 (s)
17
R
a R= H
b R= F
c R= Cl
HO
15
8
7
5
9
4
6a
α
2a-2g R1=
δ
3
N
d R= CH3
10a
10
R1
O
β
e R= OCH3
f R= NO2
g R= tert-bu
γ
N
Sn
O
1
R1
3a-3g R1= -CH2-Si(CH3)3
14

ACCEPTED MANUSCRIPT
3.5 13C NMR Spectra
The 13C NMR of organotin complexes showed signals in the aliphatic region from
26.4 to 41.3 for the cyclohexyl derivatives 2a–2g; for complexes 3a–g two signals
were detected: one at 0.0 ppm and the other at 6.8–7.3 ppm for the methylene and
methyl groups of the bis(trimethylsilyl)methyl fragment (13C NMR data for all
complexes are summarized in Table S3 supplementary material) . The azomethine
carbon C-5 appeared at 158.0–162.1 ppm; smaller up- and downfield effects were
observed for all the carbon atoms as a consequence of the coordination both of the
nitrogen atom from the azomethine, and of the phenolic groups to the tin atom. For
complexes 2a–b and 2g it was possible to observe the coupling constants
3
2J(119Sn–13C); 2a–c and 2e also showed the coupling constant J(119Sn–13C). For
the cyclohexyl groups attached to the tin, the obtained values are similar to those
described in the literature.[32-34] The C–Sn–C bond angle of 127.3º for 2c was
calculated using the value of the coupling constant J(119Sn–13C) = 576 Hz and the
Lockhart-Manders equation.[45] For complexes 3a–3g the satellite signals due to
13C–119Sn coupling in the 13C spectra were not observed.
3.6 119Sn NMR
Evidence of formation of the newly pentacoordinated heterocycle ring species was
provided by 119Sn NMR. It is well known that the chemical shifts of tin complexes
depend not only on the coordination number but are also sensitive to the type of
donor atoms bonded to the tin atom. So, the chemical shifts are an indicator of the
coordination number of organotin complexes. In this case, all complexes showed a
sharp singlet, revealing the formation of a single tin species. The 119Sn chemical
shifts for 2a–2g were found in the range of –244 to –252 ppm in a non-coordinated
solvent (CDCl3), suggesting that the tin atom is pentacoordinated. The complexes
2a–c and 2f–g exhibited chemical shifts in coordinated solvent DMSO-d6 at –263

ACCEPTED MANUSCRIPT
and –290 ppm, indicative of pentacoordinate tin species (Table 2) . In contrast, the
chemical shifts for complexes 2d–e bearing –CH3 and –OCH3 substituents on the
aromatic ring were found at –485 and –475 ppm which evidenced the formation of
hexacoordinated species, due to the coordination of DMSO to the metallic center.
For complexes 3a–g, chemical shifts in CDCl3 were found at –138 and –149 ppm;–
in this case non significative differences were observed when DMSO-d6 was used
as solvent the values were in the range of 157 to –163 ppm, indicating a
coordination number of five. The comparative analysis of the chemical shifts for
2a–2g and 3a–g derivatives evidenced that the cyclohexyl group is a better sigma
donor than its counterpart bis(trimethylsilyl)methyl, as has been described for
pyrazolone organotin derivatives.[46]
For complex 3c it was possible to observe the coupling constant J(119Sn–13C)ꢀ=
ꢀ503 Hz; using the Lockhard-Manders equation the C–Sn–C bond angle of 120.9º
was calculated.[45] Meanwhile, an angle of 125.0º was calculated using the
Holečeck equation (IV).[47] This value reveals a pentacoordinate geometry in
solution.
Table 2. 119Sn NMR data for complexes 2a-g and 3a-g
CDCl3 DMSO-d6
2a
2b
2c
2d
2e
2f
2g
3a
3b
3c
3d
3e
3f
-252
-246
-248
-251
-248
-244
-251
-149
-142
-143
-149
-146
-138
-149
-268
-268
-273
-485
-475
-290
-263
-161
-157
-159
-159
-157
-163
-158
3g

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3.7 Mass Spectra
The monomeric structure of all complexes was established by mass spectrometry,
which showed the molecular ions in all cases. Fragment ions [M+–R1] and [M+–
CH2OH] were also detected. The fragmentation pattern analysis showed the
characteristic natural isotopic profile, in which the 120Sn was the most abundant
isotope.
3.8 X-Ray Crystallography
Complexes 2d and 3b–3d were crystallized from a solution of chloroform (2d),
chloroform/heptane (3b, 3c), and methanol (3d). The crystals belonged to the
monoclinic crystal system. Selected crystallographic parameters are given in Table
3. An ORTEP view of the molecules is shown in Figure 1. Selected bond distances
and angles are given in Table 4. The structure showed a distorted
pentacoordinated geometry SnO2N(R1)2 with the ligand coordinating to the metal in
the equatorial mode, although the geometry is best described as intermediate
between trigonal bypyramidal (TB) and square pyramidal (SP). The pyridoxal Schiff
base coordinated through two phenolic oxygen atoms and a nitrogen atom. The
Sn(12)–O(11) and Sn(12)–O(13) bond distances were from 2.073(2) to 2.114(2)
and from 2.087(1) to 2.134(2) Å, respectively. In this case, the Sn–O bond length
for complexes bonded to bis(trimethylsilyl)methyl group (3b–3d) are shorter than in
the cyclohexyl derivative 2b. The Sn–N bond distances varied from 2.225(2) to
2.258(2) Å. The Sn(12)–N(6) of 2b is longer compared to the Sn(12)–N(6) in
complexes 3b–3d.
The C–Sn–C bond angles are in the range of 156.6(7)º to 115.2(9)º. The
characterization of the two possible limiting pentacoordinated geometries is well
established by the parameter τ, which adopts a value of zero for pure SP geometry
and τꢀ=ꢀ1 for TB geometry.[48] For the complexes, the τ parameter spanned a
relatively large range, with the lower value (τꢀ=ꢀ0.16) found for 2d and the largest
(τ=0.46) for 3d. Complexes 3b and 3c exhibited similar values (τꢀ=ꢀ0.38 and 0.39
respectively). This indicates that the use of dicyclohexyl tin oxide in preparing 2b

ACCEPTED MANUSCRIPT
results in a pentacoordinate complex with geometry close to SP, as has been
described for tin complexes
derivatives from
amino
acids and
naphthoylhydrazide.[32-35] In the crystalline system, the hydrogen bonds between
the hydroxyl from the pyridoxal ring and the nitrogen atom of the neighboring rings
stabilize a supramolecular dimer though a week intermolecular hydrogen bond
O(16)–H(16)... N(2); the donor acceptor distance is in the range 2.26(3) to 1.96(2)
Å (S1 Figure 1 Supporting Information).
2d
3b
3c
3d
Figure 1 Crystal structures of complexes 2d, 3b–3c, all hydrogen atoms were
omitted for clarity. Thermal ellipsoids at 30% level probability.

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Table 3. Crystal data and structure refinement for complexes 2d and 3b–d
.
2d
3b
3c
3d
Formula
C27H38N2O3Sn
557.28
C22H33N2O3Si2SnF
517.22
C22H33N2O3Si2SnCl
C23H36N2O3Si2Sn
563.41
Molecular Weight
Temperature (K)
Crystal size
Crystal system
Space group
a (Å)
583.82
298
150
296
296
0.26
ꢀ
×
ꢀ0.10
ꢀ×ꢀ0.09
0.22ꢀ×ꢀ0.14
ꢀ×ꢀ0.06
0.35ꢀ×ꢀ0.22
ꢀ×ꢀ0.14
0.22ꢀ×ꢀ0.21ꢀ×ꢀ0.12
Monoclinic
P-21/C
11.712(3)
21.931(6)
10.212(3)
90
104.29 (1)
90
2541.99(12)
4
Monoclinic
P-21/C
32.759(13)
8.069(3)
22.041(8)
90
114.30(1)
90
5310.3(3)
8
1.419
1.083
2320
Monoclinic
C2/c
33.172(10)
8.182(2)
22.022(7)
90
113.51(1)
90
5481.0(3)
8
1.415
1.141
2384
Monoclinic
C2/c
33.357(12)
8.658(3)
21.591(8)
90
113.74(1)
90
5707.7(4)
8
1.311
1.003
2320
b (Å)
c (Å)
α
β
γ
(o)
(o)
(o)
V (Å3)
Z
ρ
(g/cm3)
1.456
1.036
1152
Absorption coefficient (mm-1)
F (000)
θ
Range of collection data
2.26 to 25.38
29588
2.62 to 25.40
50955
1.93 to 25.40
30972
2.45 to 25.40
33050
Reflections collected
Independent reflections (Rint)
Max. and Min. Transmission
Data/restraints/parameters
Goodness-of-fit on F2
4649 (0.0782)
0.9321and 0.8382
4649/0/303
1.058
4887 (0.0368)
0.7452 and 0.6932
4887/72/310
1.060
5013 (0.0424)
0.8939 and 0.8009
5013/0/285
1.026
5245 (0.1119)
0.9068 and 0.8435
5245/73/316
1.084
Final R indices [I > 2
σ
(I)]
R1ꢀ= 0.0276
wR2ꢀ= 0.0665
R1ꢀ= 0.0325
wR2ꢀ= 0.0693
0.52 and –0.45
R1ꢀ= 0.0213
wR2ꢀ= 0.0494
R1ꢀ= 0.0263
wR2ꢀ= 0.0518
0.31 and –0.35
R1= 0.0236
wR2ꢀ= 0.0551
R1ꢀ= 0.0320
wR2ꢀ= 0.0582
0.42 and –0.39
R1ꢀ= 0.0316
wR2ꢀ= 0.0773
R1ꢀ= 0.0361
wR2ꢀ= 0.0811
0.68 and –0.38
R indices (all data)
∆ρmax /
∆ρmin (e Å-3)
Table 4. Selected bond lengths (Å) and bond angles for complexes 2c and 3b–d
.
2c
3b
3c
3d
Bond lengths
Sn(12)-N(6)
Sn(12)-C(18)
Sn(12)-C(24)
Sn(12)-O(11)
Sn(12)-O(13)
C(6a)-N(6)
2.258(2)
2.143(3)
2.150(2)
2.114(2)
2.134(2)
1.428(3)
1.303(3)
1.302(3)
Sn(12)-N(6)
Sn(12)-C(18)
Sn(12)-C(23)
Sn(12)-O(11)
Sn(12)-O(13)
C(6a)-N(6)
2.247(2) 2.243(2)
2.120(2) 2.122(2)
2.116(2) 2.117(2)
2.075(1) 2.075(2)
2.090(1) 2.087(1)
1.418(2) 1.417(2)
1.294(2) 1.299(3)
1.308(2) 1.311(2)
2.225(2)
2.123(3)
2.122(3)
2.073(2)
2.097(2)
1.424(3)
1.297(3)
1.301(3)
C(5)-N(6)
C(13a)-O(13)
C(5)-N(6)
C(13a)-O(13)
C(13a)-C(4a)
C(6a)-C(10a)
C(4a)-C(5)
1.403(3)
1.409(3)
1.439(3)
1.327(3)
C(13a)-C(4a)
C(6a)-C(10a)
C(4a)-C(5)
1.407(3) 1.403(3)
1.405(3) 1.403(3)
1.440(3) 1.439(3)
1.331(3) 1.311(2)
1.406(4)
1.404(4)
1.434(4)
1.328(3)
C(10a)-O(11)
C(10a)-O(11)
Bond angles
C(18)-Sn(12)-C(24)
O(11)-Sn(12)-C(18)
O(11)-Sn(12)-C(24)
O(13)-Sn(12)-C(18)
O(13)-Sn(12)-C(24)
O(11)-Sn(12)-O(13)
N(6)-Sn(12)-C(18)
N(6)-Sn(12)-C(24)
N(6)-Sn(12)-O(11)
N(6)-Sn(12)-O(13)
C(4a)-C(5)-N(6)
147.1(1)
94.8(9)
95.9(9)
91.7(9)
90.6(9)
156.6(7)
106.8(9)
105.9(8)
75.9(6)
C(18)-Sn(12)-C(23)
O(11)-Sn(12)-C(18)
O(11)-Sn(12)-C(23)
O(13)-Sn(12)-C(18)
O(13)-Sn(12)-C(23)
O(11)-Sn(12)-O(13)
N(6)-Sn(12)-C(18)
N(6)-Sn(12)-C(23)
N(6)-Sn(12)-O(11)
N(6)-Sn(12)-O(13)
C(4a)-C(5)-N(6)
124.9(8) 124.3(9)
127.4(1)
94.2(1)
99.6(1)
95.3(7)
101.5(8) 101.8(8)
86.9(7) 87.2(7)
94.8(4)
89.0(1)
97.9(1)
155.2(9)
127.3(9)
105.3(1)
76.7(8)
81.8(7)
127.7(2)
122.9(2)
120.6(2)
124.2(2)
103.5(7) 103.3(8)
147.7(6) 147.9(7)
136.5(7) 136.5(7)
98.6(7)
75.8(6)
80.6(5)
99.2(8)
75.7(6)
80.9(6)
80.7(7)
128.1(2)
123.1(2)
120.7(2)
123.8(2)
126.7(2) 126.8(2)
122.4(2) 122.5(2)
120.2(2) 119.9(2)
124.6(2) 124.6(2)
C(13a)-C(4a)-C(5)
C(10a)-C(6a)-O(11)
C(4a)-C(13a)-O(13)
C(13a)-C(4a)-C(5)
C(10a)-C(6a)-O(11)
C(4a)-C(13a)-O(13)

ACCEPTED MANUSCRIPT
3.9 Solubility and stability
The complexes were soluble in methanol, ethanol, dichloromethane, chloroform,
N,N-dimethylformamide and dimethyl sulfoxide. To examine the biological activity
of the complexes the stability of the complexes under physiological conditions a
solution DMSO–DPBS (1:1 v/v) was used, after 72 h the UV–vis spectra do not
show significant shift of the absorption bands or appearance of any new peaks.
The intensity of the bands also remained essentially similar, which exclude the
possibility of any degradation of the complexes in physiological conditions. In the
1H and 119Sn NMR after 72 h in DMSO no-decomposed products or changes in the
coordination number were observed.
3.10 Cytotoxicity and Structure activity relationship
The cytotoxicity of complexes 2a–2g and 3a–3g was examined in different cell
lines: U-251 (human glioblastoma), K-562 (human myelogenous leukemia), HCT-
15 (human colorectal adenocarcinoma), MCF-7 (human breast adenocarcinoma),
SKLU-1 (human lung adenocarcinoma) and MDA-MB-231 (human breast
adenocarcinoma). The ligands were not evaluated due to their instability in DMSO.
The IC50 values are listed in Table 5; cisplatin was used as positive control. The
cells were incubated for 48 h at different concentrations using the protein-binding
dye sulforhodamine B in a micro-culture assay to measure cell growth. The
complexes were remarkably more active than cisplatin. All tested complexes share
common structural characteristics; the main differences are the substitution of the
aromatic ring and the substituent attached to the tin atom (cyclohexyl or
bis(trimethylsilyl)methyl). In general, the bioisosteric replacement of hydrogen by
fluorine resulted in a greater cytotoxic effect. A closer inspection of the IC50 values
for the series 2a–2g showed that for U-251, K562, HCT-15 and SKLU-1 cell lines
the complex 2b (fluorine substituted) was the most cytotoxic, with IC50 values