Synthesis, structure and biological activity of diorganotin derivatives with pyridyl functionalized bis(pyrazol-1 -yl) methanes

Article abstract of DOI:10.1002/aoc.1664

Three pyridyl functionalized bis(pyrazol-1-yl) methanes, namely 2-[(4-pyridyl)methoxyphenyl] bis(pyrazol-1-yl)methane (L¹). 2-[(4-pyridyl)methoxyphenyl]bis(3,5-dimethylpyrazol-1-yl)methane (L²) and 2-[(3-pyridyl)methoxyphenyl]bis(pyrazol-1yl)methane (L³) have been synthesized by the reactions of (2-hydroxyphenyl)bis(pyrazol-1 -yl)methanes with chloromethylpyridine. Treatment of these three ligands with R ₂SnCl₂ (R = Et, n-Bu or Ph) yields a series of symmetric 2:1 adducts of (L)₂SnR₂Cl₂ (L = L¹, L² or L³), which have been confirmed by elemental analysis and NMR spectroscopy. The crystal structures of (L²) ₂Sn(nBu)₂Cl₂0.5C₆H₁₄ and (L³)₂SnEt₂Cl₂ determined by X-ray crystallography show that the functionalized bis(pyrazol-1-yl)methane acts as a monodentate ligand through the pyridyl nitrogen atom, and the pyrazolyl nitrogen atoms do not coordinate to the tin atom. The cytotoxic activity of these complexes for Hela cells in vitro was tested. Copyright

Full text of DOI:10.1002/aoc.1664

Full Paper
Received: 5 February 2010
Revised: 4 April 2010
Accepted: 4 April 2010
Published online in Wiley Online Library: 28 June 2010
(wileyonlinelibrary.com) DOI 10.1002/aoc.1664
Synthesis, structure and biological activity
of diorganotin derivatives with pyridyl
functionalized bis(pyrazol-1-yl)methanes
Fang-Lin Lia, Hai-Bin Songb, Bin Daia and Liang-Fu Tangb∗
Three pyridyl functionalized bis(pyrazol-1-yl)methanes, namely 2-[(4-pyridyl)methoxyphenyl] bis(pyrazol-1-yl)methane
(L1), 2-[(4-pyridyl)methoxyphenyl]bis(3,5-dimethylpyrazol-1-yl)methane (L2) and 2-[(3-pyridyl)methoxyphenyl]bis(pyrazol-1-
yl)methane (L3) have been synthesized by the reactions of (2-hydroxyphenyl)bis(pyrazol-1-yl)methanes with chloromethylpyri-
dine. Treatment of these three ligands with R2SnCl2 (R = Et, n-Bu or Ph) yields a series of symmetric 2 : 1 adducts of (L)2SnR2Cl2
(L = L1, L2 or L3), which have been confirmed by elemental analysis and NMR spectroscopy. The crystal structures of (L2)2Sn(n-
Bu)2Cl2·0.5C6H14 and (L3)2SnEt2Cl2 determined by X-ray crystallography show that the functionalized bis(pyrazol-1-yl)methane
acts as a monodentate ligand through the pyridyl nitrogen atom, and the pyrazolyl nitrogen atoms do not coordinate to the tin
c
atom. The cytotoxic activity of these complexes for Hela cells in vitro was tested. Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: bis(pyrazol-1-yl)methane; organotin; pyridyl; biological activity
Introduction
spectra were obtained with a Bruker 400 spectrometer using
CDCl3 as solvent unless otherwise noted, and the chemical
shifts were reported in ppm with respect to reference stan-
dards (internal SiMe4 for 1H NMR and 13C NMR spectra, external
SnMe4 for 119Sn NMR). Elemental analyses were carried out
on an Elementar Vairo EL analyzer. Melting points were mea-
sured with an X-4 digital micro melting-point apparatus and
are uncorrected. (2-Hydroxyphenyl)bis(pyrazol-1-yl)methane and
(2-hydroxyphenyl)bis(3,5-dimethylpyrazol-1-yl)methane[21] were
prepared by the published methods.
Organotin derivatives have been widely used in industrial and
agricultural fields as catalysts or biocides.[1] Among these organ-
otin derivatives, diorganotin derivatives containing a bidentate
nitrogen donor ligand [R2SnX2(N-N)] have attracted considerable
attention due to their potential biological applications. For ex-
ample, many such complexes have been synthesized and tested
for their antitumor activity.[2–10] Moreover, their antitumor ac-
tivity significantly depends on the Sn–N bond distance. For
active complexes, the average Sn–N bond distance is usually
longer than 2.39 Å.[6] As a flexible bidentate ligand, bis(pyrazol-
1-yl)methane has been found to act as a good donor to the
organotin acceptor.[11] The interactions between bis(pyrazol-1-
yl)methanes with monodentate and multidentate organotin Lewis
acids have also been extensively investigated.[12–18] In recent
years, the modification of bis(pyrazol-1-yl)methanes by organic
functional groups on the bridging carbon atom has drawn ex-
tensive attention owing to the versatile coordination chemistry
presented by these new heteroscorpionate ligands,[11,19,20] which
encourages us to investigate the interactions of these functional-
ized ligands with organotin acceptors. In the present work, three
pyridylfunctionalizedbis(pyrazol-1-yl)methanesweresynthesized
and their reactions with diorganotin dichloride were carried out.
These newly synthesized diorganotin derivatives of bis(pyrazol-1-
yl)methanes display significant antitumor activity in vitro against
Hela cells.
Synthesis of 2-[(4-Pyridyl)methoxyphenyl]bis(pyrazol-1-yl)
methane (L1)
KOH (4.03 g, 72 mmol) was added to a solution of (2-hydroxy-
phenyl)bis(pyrazol-1-yl)methane (7.21 g, 30 mmol) in 130 ml of
ethanol. The mixture was stirred for 30 min at room temperature,
and then 4-chloromethylpyridine hydrochloride (4.92 g, 30 mmol)
was added. After stirring for 30 min, the reaction mixture was
heated at reflux for 18 h. After cooling to room temperature, water
(50 ml) was added. The water solution was extracted with CH2Cl2
(3 × 60 ml). The organic layers were combined and dried over
anhydrous MgSO4. The solvent was removed in vacuo to give red
brown oil. This oil was recrystallized from anhydrous ether and
treated with activated charcoal to yield white crystals of L1. Yield:
∗
Correspondence to: Liang-Fu Tang, Department of Chemistry, State Key
Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China. E-mail: lftang@nankai.edu.cn
Experimental
Materials and Measurements
a
School of Chemistry and Chemical Engineering, Shihezi University, Shihezi
832003, Xinjiang, People’s Republic of China
Solvents were dried by standard methods and distilled prior
to use. The reactions involving organotin derivatives were car-
ried out under a water-free atmosphere. Multinuclear NMR
b
DepartmentofChemistry,StateKeyLaboratoryofElemento-OrganicChemistry,
Nankai University, Tianjin 300071, People’s Republic of China
c
Appl. Organometal. Chem. 2010, 24, 669–674
Copyright ꢀ 2010 John Wiley & Sons, Ltd.

F.-l. Li et al.
6.33 g (64%); m.p. 127–129 ◦C. 1H NMR: δ 5.06 (s, 2H, CH2), 6.33 (t,
J = 2.4 Hz, 2H, H4 of pyrazole), 6.83 (d, J = 7.7 Hz, 1H, C6H4), 6.90
(d, J = 8.3 Hz, 1H, C6H4), 7.00 (t, J = 7.6 Hz, 1H, C6H4), 7.34–7.36
(m, 1H, C6H4), 7.06, 7.40 (d, J = 5.2 Hz, d, J = 2.0 Hz, 2H, 2H,
H3 and H5 of pyrazole), 7.66 (d, J = 4.6 Hz, 2H, C5H4N), 8.66 (d,
J = 4.6 Hz, 2H, C5H4N), 8.08 (s, 1H, CH) ppm. 13C NMR: δ 68.1 (CH2),
73.5 (CH), 106.3 (C4 of pyrazole), 111.8, 121.1, 121.6, 124.7, 128.1,
129.4, 131.0, 140.7, 145.3, 150.0, 155.0 (C6H4, C5H4N as well as C3
and C5 of pyrazole) ppm. Anal. calcd for C19H17N5O.0.25Et2O: C,
68.65; H, 5.62; N, 20.02. Found: C, 68.79; H, 6.12; N, 20.40%.
and C5 of pyrazole) ppm. 119Sn NMR: δ −91.2, −138.7 ppm. Anal.
calcd for C42H44Cl2N10O2Sn: C, 55.40; H, 4.87; N, 15.38. Found: C,
55.41; H, 4.60; N, 15.00%.
Synthesis of (L1)2Sn(n-Bu)2Cl2 (2)
This complex was obtained similarly using (n-Bu)2SnCl2 instead of
Et2SnCl2 as described above for complex 1. After stirring for 10 h at
room temperature, the solution was concentrated to ca 5 ml, and
5 ml of he◦xane was added to give white solids of 2. Yield: 93%; m.p.
134–136 C. 1H NMR: δ 0.84 (t, J = 7.3 Hz, 3H, CH3), 1.28–1.34 (m,
2H, SnCH2CH2CH2), 1.64–1.67 (m, 2H, SnCH2CH2CH2), 1.81–1.85
(m, 2H, SnCH2CH2CH2), 5.14 (s, 2H, OCH2), 6.34 (s, br, 2H, H4 of
pyrazole), 6.83 (d, J = 7.6 Hz, 1H, C6H4), 6.93 (d, J = 8.3 Hz, 1H,
C6H4), 7.01 (t, J = 7.6 Hz, 1H, C6H4), 7.36–7.38 (m, 1H, C6H4), 7.23,
7.41 (d, J = 5.2 Hz, s, br, 2H, 2H, H3 and H5 of pyrazole), 7.66, 8.75
(s, br, d, J = 5.0 Hz, 2H, 2H, C5H4N), 8.10 (s, 1H, CH) ppm. 13C NMR:
δ 13.6 (CH3), 26.2, 27.6, 34.4 (SnCH2CH2CH2), 67.8 (OCH2), 73.5
(CH), 106.5 (C4 of pyrazole), 111.7, 121.8, 121.9, 124.7, 128.1, 129.4,
131.1, 140.8, 148.0, 148.4, 154.7 (C6H4, C5H4N as well as C3 and C5
of pyrazole) ppm. 119Sn NMR: δ −91.0, −138.1 ppm. Anal. calcd
for C46H52Cl2N10O2Sn.CH2Cl2: C, 53.68; H, 5.18; N, 13.32. Found: C,
54.04; H, 5.15; N, 13.05%.
Synthesis of 2-[(4-Pyridyl)methoxyphenyl]bis(3,5-dimethyl
pyrazol-1-yl)methane (L2)
This ligand was obtained similarly using (2-hydroxyphenyl)
bis(3,5-dimethylpyrazol-1-yl)methane
instead
of
(2-
hydroxyphenyl)bis(pyrazol-1-yl)methane as described above
for L1. Yield: 57%; m.p. 150–152 ◦C. 1H NMR: δ 2.04, 2.18 (s, s,
6H, 6H, CH3), 4.96 (s, 2H, CH2), 5.84 (s, 2H, H4 of pyrazole), 6.69
(d, J = 7.6 Hz, 1H, C6H4), 6.82 (d, J = 8.2 Hz, 1H, C6H4), 6.92
(t, J = 7.6 Hz, 1H, C6H4), 7.26 (t, J = 7.7 Hz, 1H, C6H4), 7.03 (d,
J = 5.2 Hz, 2H, C5H4N), 8.51 (d, J = 5.2 Hz, 2H, C5H4N), 7.72 (s,
1H, CH) ppm. 13C NMR: δ 11.2, 13.4 (3 or 5-CH3), 68.0 (CH2), 70.6
(CH), 106.6 (C4 of pyrazole), 111.5, 121.2, 121.4, 125.4, 128.3, 130.0,
140.3, 145.7, 147.8, 149.8, 155.1 (C6H4, C5H4N as well as C3 and C5
of pyrazole) ppm. Anal. calcd for C23H25N5O: C, 71.29; H, 6.50; N,
18.07. Found: C, 70.96; H, 6.63; N, 18.34%.
Synthesis of (L1)2SnPh2Cl2 (3)
This complex was obtained similarly using Ph2SnCl2 instead of
Synthesis of 2-[(3-Pyridyl)methoxyphenyl]bis(pyrazol-1-yl)
methane (L3)
Et2SnCl2 as described above for complex 1. Yield: 95%; m.p.
◦
1
172–174 C. H NMR: δ 5.07 (s, 2H, CH2), 6.32 (t, J = 1.5 Hz, 2H,
H4 of pyrazole), 6.82 (d, J = 7.2 Hz, 1H, C6H4), 6.91 (d, J = 8.4 Hz,
1H, C6H4), 7.01 (t, J = 7.5 Hz, 1H, C6H4), 7.34–7.37 (m, 1H, C6H4),
7.39–7.50 (m, 5H, SnC6H5), 7.10, 7.64 (d, J = 5.4 Hz, s, br, 2H, 2H,
H3 and H5 of pyrazole), 7.72–7.75, 8.53 (m, d, J = 6.0 Hz, 2H, 2H,
C5H4N), 8.06 (s, 1H, CH) ppm. 13C NMR: δ 67.7 (CH2), 73.5 (CH),
106.5(C4 ofpyrazole), 111.7, 121.8, 121.9, 124.8, 127.9, 128.2, 128.4,
129.4, 129.6, 131.1, 135.6, 140.8, 148.7, 148.8, 154.7 (C6H4, C5H4N
as well as C3 and C5 of pyrazole) ppm. 119Sn NMR: δ −400.2 ppm.
Anal. calcd for C50H44Cl2N10O2Sn.0.25CH2Cl2: C, 58.72; H, 4.36; N,
13.63. Found: C, 58.87; H, 4.81; N, 13.38%.
This ligand was obtained similarly using 3-chloromethylpyridine
hydrochloride instead of 4-chloromethylpyridine hydrochloride
as described above for L1. Yield: 76%; m.p. 153–154 ◦C. 1H NMR:
δ 5.02 (s, 2H, CH2), 6.30 (t, J = 2.4 Hz, 2H, H4 of pyrazole), 6.81
(d, J = 7.2 Hz, 1H, C6H4), 6.95–6.99 (m, 2H, C6H4), 7.22–7.25 (m,
1H, C6H4), 7.35 (dd, J = 1.5 Hz, J = 7.8 Hz, 1H, C5H4N), 7.38, 7.62
(d, J = 2.3 Hz, d, J = 1.5 Hz, 2H, 2H, H3 and H5 of pyrazole),
7.39–7.41 (m, 1H, C5H4N), 8.42 (d, J = 1.6 Hz, 1H, C5H4N), 8.54 (dd,
J = 1.3 Hz, J = 4.8 Hz, 1H, C5H4N), 8.00 (s, 1H, CH) ppm. 13C NMR:
δ 67.5 (CH2), 73.5 (CH), 106.2 (C4 of pyrazole), 111.8, 121.5, 123.5,
124.8, 128.0, 129.4, 130.9, 131.8, 135.0, 140.7, 148.6, 149.5, 155.2
(C6H4, C5H4N as well as C3 and C5 of pyrazole) ppm. Anal. calcd for
C19H17N5O.0.25Et2O: C, 68.65; H, 5.62; N, 20.02. Found: C, 68.49; H,
5.20; N, 20.24%.
Synthesis of (L2)2SnEt2Cl2 (4)
To a solution of L2 (0.39 g, 1 mmol) in 40 ml of ether, the solution
of Et2SnCl2 (0.25 g, 1 mmol) in 15 ml of ether was added at room
temperature. The reaction mixture was continuously stirred for
10 h, during which a precipitate gradually formed. The precipitate
was filtered off, washed with ether (3 × 20 ml) and dried in vacuo
to give white solids of 4. Yield: 0.43 g (84%); m.p. 140–143 ◦C. 1H
NMR: δ 1.28 (t, J = 7.9 Hz, 3H, CH2CH3), 1.82 (q, J = 7.9 Hz, 2H,
SnCH2), 2.06, 2.20 (s, s, 6H, 6H, CH3), 4.95 (s, 2H, OCH2), 5.77 (s, 2H,
H4 of pyrazole), 6.57 (d, J = 7.6 Hz, 1H, C6H4), 6.75 (d, J = 8.0 Hz,
1H, C6H4), 6.87 (t, J = 7.2 Hz, 1H, C6H4), 7.22 (t, J = 7.6 Hz, 1H,
Synthesis of (L1)2SnEt2Cl2 (1)
To a solution of L1 (0.33 g, 1 mmol) in 40 ml of ether and 10 ml
of CH2Cl2, the solution of Et2SnCl2 (0.25 g, 1 mmol) in 15 ml of
ether was added at room temperature. The reaction mixture
was continuously stirred for 10 h, during which a precipitate
gradually formed. The precipitate was filtered off, washed with
ether (3 × 20 ml) and dried in vacuo to give white solids of 1.
Yield: 0.42 g (90%); m.p. 149–151 ◦C. 1H NMR: δ 1.28 (t, J = 7.9 Hz,
3H, CH3), 1.82 (q, J = 7.9 Hz, 2H, SnCH2), 5.11 (s, 2H, OCH2), 6.34
(s, br, 2H, H4 of pyrazole), 6.83 (d, J = 7.6 Hz, 1H, C6H4), 6.91 (d,
J = 8.3 Hz, 1H, C6H4), 7.01 (t, J = 7.6 Hz, 1H, C6H4), 7.36–7.38 (m,
1H, C6H4), 7.21, 7.41 (d, J = 5.6 Hz, d, J = 2.4 Hz, 2H, 2H, H3 and
H5 of pyrazole), 7.66, 8.79 (s, br, d, J = 5.3 Hz, 2H, 2H, C5H4N), 8.09
(s, 1H, CH) ppm. 13C NMR: δ 10.3 (CH3), 27.4 (SnCH2), 67.8 (OCH2),
73.5 (CH), 106.4 (C4 of pyrazole), 111.7, 121.9, 124.8, 128.1, 129.3,
129.4, 131.1, 140.8, 147.7, 148.8, 154.8 (C6H4, C5H4N as well as C3
C6H4), 7.06, 8.58(s, br, s, br, 2H, 2H, C5H4N), 7.62(s, 1H, CH)ppm. 13
C
NMR: δ 10.4 (CH2CH3), 18.7 (SnCH2), 11.3, 13.9 (3- or 5-CH3), 67.8
(OCH2), 70.7 (CH), 106.7 (C4 of pyrazole), 111.4, 121.7, 121.9, 125.4,
128.4, 130.1, 140.4, 147.8, 148.0, 148.9, 154.9 (C6H4, C5H4N as well
as C3 and C5 of pyrazole) ppm. 119Sn NMR: δ −91.2, −138.8 ppm.
Anal. calcd for C50H60Cl2N10O2Sn: C, 58.72; H, 5.91; N, 13.70. Found:
C, 58.40; H, 6.40; N, 13.46%.
c
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Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 669–674

Diorganotin derivatives with pyridyl functionalized bis(pyrazol-1-yl)methanes
Synthesis of (L2)2Sn(n-Bu)2Cl2 (5)
H5 of pyrazole), 8.01 (s, 1H, CH), 8.55, 8.64 (s, s, 1H, 1H, C5H4N)
ppm. 13C NMR: δ 13.6 (CH3), 26.3, 27.1, 29.0 (SnCH2CH2CH2), 67.4
(OCH2), 73.5 (CH), 106.3 (C4 or pyrazole), 111.8, 121.6, 124.0, 124.8,
128.1, 129.4, 131.0, 132.5, 135.8, 140.7, 147.9, 148.9, 155.1 (C6H4,
C5H4N as well as C3 and C5 of pyrazole) ppm. 119Sn NMR: δ −90.9,
−138.1 ppm. Anal. calcd for C46H52Cl2N10O2Sn.CH2Cl2: C, 53.68;
H, 5.18; N, 13.32. Found: C, 54.18; H, 5.53; N, 13.59%.
This complex was obtained similarly using (n-Bu)2SnCl2 instead
of Et2SnCl2 as described above for complex 4. Yield: 83%; m.p.
138–140 ◦C. 1H NMR: δ 0.84 (t, J = 7.6 Hz, 3H, CH3), 1.28–1.34 (m,
2H, SnCH2CH2CH2), 1.61–1.66 (m, 2H, SnCH2CH2CH2), 1.79–1.83
(m, 2H, SnCH2CH2CH2), 2.06, 2.19 (s, s, 6H, 6H, CH3), 5.04 (s, 2H,
OCH2), 5.86 (s, 2H, H4 of pyrazole), 6.66 (d, J = 7.6 Hz, 1H, C6H4),
6.84 (d, J = 8.4 Hz, 1H, C6H4), 6.94 (t, J = 7.2 Hz, 1H, C6H4), 7.30
(t, J = 7.6 Hz, 1H, C6H4), 7.19 (d, J = 5.6 Hz, 2H, C5H4N), 8.74 (d,
J = 5.6 Hz, 2H, C5H4N), 7.72 (s, 1H, CH) ppm. 13C NMR: δ 11.3, 13.8
(3 or 5-CH3), 13.6 (CH2CH3), 26.2, 27.6, 33.6 (SnCH2CH2CH2), 67.7
(OCH2), 70.6 (CH), 106.7 (C4 of pyrazole), 111.4, 121.6, 122.0, 125.4,
128.4, 130.1, 140.3, 147.9, 148.0, 148.6, 154.9 (C6H4, C5H4N as well
as C3 and C5 of pyrazole) ppm. 119Sn NMR: δ −91.0, −138.1 ppm.
Anal. calcd for C54H68Cl2N10O2Sn: C, 60.12; H, 6.35; N, 12.98. Found:
C, 60.24; H, 6.31; N, 12.75%.
Synthesis of (L3)2SnPh2Cl2 (9)
Thiscomplexwasobtainedsimilarlyusing L3 andPh2SnCl2 instead
of L1 and Et2SnCl2, respectively, as described above for complex
1. Yield: 90%; m.p. 181–183 ◦C. 1H NMR: δ 5.00 (s, 2H, CH2), 6.30 (t,
J = 1.6 Hz, 2H, H4 of pyrazole), 6.82 (d, J = 7.5 Hz, 1H, C6H4), 6.92
(d, J = 8.3 Hz, 1H, C6H4), 6.99 (t, J = 7.6 Hz, 1H, C6H4), 7.28–7.31
(m, 1H, C6H4), 7.35–7.43, 7.72–7.74 (m, m, 6H, 2H, H3 or H5 of
pyrazole, C6H5 and C5H4N), 7.48 (d, J = 7.8 Hz, 1H, C5H4N), 7.62 (s,
br, 2H, H3 or H5 of pyrazole), 7.98 (s, 1H, CH), 8.51 (s, 1H, C5H4N),
8.57 (d, J = 4.7 Hz, 1H, C5H4N) ppm. 13C NMR: δ 67.2 (CH2), 73.5
(CH), 106.3 (C4 of pyrazole), 111.8, 121.7, 124.2, 124.8, 128.1, 129.1,
129.5, 130.6, 131.0, 132.7, 135.3, 136.7, 140.7, 140.9, 147.7, 148.9,
155.0 (C6H4, C5H4N as well as C3 and C5 of pyrazole) ppm. 119Sn
NMR (DMSO-d6): δ −386.3 ppm. Anal. calcd for C50H44Cl2N10O2Sn:
C, 59.66; H, 4.41; N, 13.92. Found: C, 59.67; H, 4.49; N, 13.73%.
Synthesis of (L2)2SnPh2Cl2 (6)
Thiscomplexwasobtainedsimilarlyusing L2 andPh2SnCl2 instead
of L1 and Et2SnCl2, respectively, as described above for complex 1.
Yield: 94%; m.p. 155–157 ◦C. 1H NMR: δ 2.03, 2.12 (s, s, 6H, 6H, CH3),
5.02 (s, 2H, CH2), 5.81 (s, 2H, H4 of pyrazole), 6.65 (d, J = 7.6 Hz,
1H, C6H4), 6.83 (d, J = 8.0 Hz, 1H, C6H4), 6.94 (t, J = 7.6 Hz, 1H,
C6H4), 7.27 (t, J = 7.4 Hz, 1H, C6H4), 7.14 (d, J = 6.0 Hz, 2H, C5H4N),
8.54 (d, J = 6.0 Hz, 2H, C5H4N), 7.28–7.34 (m, 3H, C6H5), 7.83–7.86
(m, 2H, C6H5), 7.68 (s, 1H, CH) ppm. 13C NMR: δ 11.3, 13.8 (3
or 5-CH3), 67.6 (OCH2), 70.6 (CH), 106.7 (C4 of pyrazole), 111.5,
114.7, 121.8, 122.1, 125.4, 128.3, 128.4, 129.3, 130.2, 135.7, 140.3,
148.0, 148.2, 149.9, 154.7 (C6H4, C5H4N as well as C3 and C5 of
pyrazole) ppm. 119Sn NMR: δ −68.6, −476.7 ppm. Anal. calcd for
C58H60Cl2N10O2Sn.0.5CH2Cl2: C, 60.51; H, 5.29; N, 12.06. Found: C,
60.22; H, 5.01; N, 11.59%.
Crystal Structure Determinations
Colorless crystals of 5 and 7 suitable for X-ray analyses were
obtained by slow diffusion of hexane into their CH2Cl2 solutions
at room temperature. Crystals of 5 contained one-half of a
co-crystallized hexane molecule. Intensity data were collected
on a Rigaku Saturn CCD detector equipped with graphite-
monochromated Mo-Kα radiation (λ = 0.71073 Å) using the ω
scan mode at 113(2) K. Semi-empirical absorption corrections
were applied and all calculations were performed using the
Crystalclear program.[22] The structures were solved by direct
methods and difference Fourier map using SHELXS of the SHELXTL
package and refined with SHELXL[23] by full-matrix least-squares
on F2. The propyl group (C25–C27) in one of the butyl groups
in 5 was disordered and the site occupation factor of these
disordered atoms was adjusted (0.61 for C25–C27 atoms and 0.39
for C25ꢁ –C27ꢁ atoms, respectively) to give reasonable thermal
parameters. The highest residual peak of electron density was
away from the disordered C25 atom (0.65 Å) in 5 and the Sn1 atom
(1.46 Å) in 7, respectively. All non-hydrogen atoms were refined
anisotropically. A summary of the fundamental crystal data for 5
and 7 is listed in Table 1.
Synthesis of (L3)2SnEt2Cl2 (7)
This complex was obtained similarly using L3 instead of◦L1 as
described above for complex 1. Yield: 75%; m.p. 142–144 C. 1H
NMR: δ 1.29 (t, J = 7.8 Hz, 3H, CH2CH3), 1.81 (q, J = 7.8 Hz, 2H,
SnCH2), 5.08 (s, 2H, OCH2), 6.31 (s, br, 2H, H4 of pyrazole), 6.83
(d, J = 7.6 Hz, 1H, C6H4), 6.98–7.02 (m, 2H, C6H4), 7.37–7.41 (m,
4H, H3 or H5 of pyrazole, C6H4 and C5H4N), 7.54 (d, J = 7.8 Hz,
1H, C5H4N), 7.63 (s, br, 2H, H3 or H5 of pyrazole), 8.04 (s, 1H, CH),
8.71–8.76 (m, 2H, C5H4N) ppm. 13C NMR: δ 10.2 (CH2CH3), 26.3
(SnCH2), 67.2 (OCH2), 73.5 (CH), 106.3 (C4 of pyrazole), 111.9, 121.7,
124.4, 124.8, 128.1, 129.5, 131.0, 132.9, 136.6, 140.7, 147.3, 148.5,
155.0 (C6H4, C5H4N as well as C3 and C5 of pyrazole) ppm. 119Sn
NMR: δ −91.0, −138.8 ppm. Anal. calcd for C42H44Cl2N10O2Sn: C,
55.40; H, 4.87; N, 15.38. Found: C, 55.23; H, 4.51; N, 15.08%.
Cytostatic Activity Evaluation
The cytotoxic activity of ligands L1 –L3, complexes 1–9 and
their precursors for Hela cells in vitro was assayed by the MTT
method.[24] Hela cells were seeded into 96-well plates at a
concentration of about 4000 cells/well and were incubated in
5% CO2 atmosphere at 37 ◦C for 24 h. Then, these cells were
treated with different concentrations of each compound. Six-fold
wells per toxicant concentration were set. After further incubation
for 4 days, 100 µl of MTT (1.0 mg/ml) was added to each well. After
subsequent incubation for an additional 4 h, the culture medium
was removed, and 150 µl of DMSO was added to dissolve the
insoluble formazan precipitates. The plate was shaken on a plate
shaker to ensure complete dissolution. The optical density of each
Synthesis of (L3)2Sn(n-Bu)2Cl2 (8)
This complex was obtained similarly using L3 and (n-Bu)2SnCl2
instead of L1 and Et2SnCl2, respectively, as described above for
complex 1. After stirring for 10 h at room temperature, the solution
was concentrated to ca 5 ml, and 5 ml of hexane was added to give
white solids of 8. Yield: 82%; m.p. 104–106 ◦C. 1H NMR: δ 0.91 (t,
J = 7.3 Hz, 3H, CH3), 1.26–1.41 (m, 2H, SnCH2CH2CH2), 1.73–1.81
(m, 4H, SnCH2CH2CH2), 5.06 (s, 2H, OCH2), 6.31 (t, J = 2.0 Hz, 2H,
H4 of pyrazole), 6.82 (d, J = 7.6 Hz, 1H, C6H4), 6.97–7.00 (m, 2H,
C6H4), 7.31–7.39 (m, 4H, H3 or H5 of pyrazole, C6H4 and C5H4N),
7.48 (d, J = 7.8 Hz, 1H, C5H4N), 7.63 (d, J = 1.3 Hz, 2H, H3 or
c
Appl. Organometal. Chem. 2010, 24, 669–674
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

F.-l. Li et al.
Table 1. Crystal data and refinement parameters for complexes 5
and 7
Complex
5.0.5C6H14
7
Formula
Formula weight
Crystal size (mm)
Crystal system
Space group
a (Å)
C57H75Cl2N10O2Sn
1121.86
C42H44Cl2N10O2Sn
910.46
0.16 × 0.12 × 0.08
0.20 × 0.18 × 0.12
Triclinic
Triclinic
¯
¯
P1
P1
8.5974(17)
12.429(3)
15.508(3)
111.25(3)
90.07(3)
96.95(3)
1531.3(6)
1
9.4329(19)
10.357(2)
11.570(2)
69.91(3)
79.90(3)
87.17(3)
1045.0(3)
1
b (Å)
c (Å)
α (deg)
β (deg)
γ (deg)
V (Å)3
Z
Dc (g cm−3
)
1.217
1.447
F(000)
µ (mm−1
587
466
Scheme 1. Functionalized bis(pyrazol-1-yl)methanes and their reactions
with R2SnCl2.
)
0.550
0.788
2θ range (deg)
3.5–50.0
5375 (0.058)
3.8–50.0
3671 (0.080)
No. of unique
phenyl)bis(pyrazol-1-yl)methanes with chloromethylpyridine un-
der basic conditions (Scheme 1). Treatment of these three ligands
with R2SnCl2 (R = Et, n-Bu or Ph) in a 1 : 1 ratio yields 2 : 1 adducts
(L)2SnR2Cl2 (1–9, L = L1, L2 or L3), which have been character-
reflections (Rint
)
No. of observed
reflections
[I > 2σ(I)]
4035
3007
No. of parameters
GOF
392
260
1
ized by NMR spectroscopy and elemental analyses. The H NMR
1.05
1.04
spectroscopic data support the suggested structures. Their 1H
NMR spectra exhibit the expected integration values and peak
multiplicities for the formulae of 2 : 1 adducts. The chemical shifts
of protons and carbons for the ligand moieties in complexes 1–9
are very close to those of the free ligands, suggesting that these
complexes are significantly dissociated even in non-coordinating
solvent. The 119Sn NMR spectra of these complexes also show the
partial loss of the hexacoordinated structures of the 2 : 1 adducts
in solution and concomitant formation of new organotin species,
such as pentacoordinated 1 : 1 adducts. Two 119Sn NMR signals,
correspondingtothevaluesofpenta-andhexacoordinatedorgan-
otin derivatives,[25,26] are observed in the ethyltin complexes 1, 4
and 7, the butyltin complexes 2, 5 and 8 as well as the phenyltin
complex 6. These dissociative behaviors have been extensively
observed in other diorganotin derivatives with nitrogen donor
ligands.[2–4,12,15]
Residuals R, Rw
0.075, 0.197
1.09, −0.93
0.059, 0.142
1.60, −1.42
Largest difference
peak and hole (e
Å−3
)
CCDC number
764853
764854
Table 2. The IC50 values of compounds for HeLa cells (10−6 mol/l)
Compound
IC50
2.9
Compound
IC50
1.8
Compound
IC50
13.1
1
2
5
3
4
4.9
4.0
7.2
6
2.4
7
17.9
8
9
L3
13.8
L1
>100
L2
>100
2.5
>100
4.8
Et2SnCl2
Etoposide
18.1 (n-Bu)2SnCl2
Ph2SnCl2
12.6
Crystal Structures of Complexes 5 and 7
To verify the coordination mode of these pyridyl functionalized
bis(pyrazol-1-yl)methanes, the molecular structures of complexes
5 and 7 were determined by X-ray crystallography, presented in
Figs 1 and 2, respectively. The fundamental frameworks in these
two complexes are similar to each other. L2 in complex 5 as well
as L3 in complex 7 acts as a monodentate ligand toward to the tin
atom only through the pyridyl nitrogen atom, possibly owing to
the stronger donating ability of the pyridyl ring than the pyrazolyl
ring.[27] The tin atoms in these two complexes lie on a centre of
inversion, and adopt a six-coordinate slightly distorted octahedral
geometry with two pyridyl nitrogen atoms, two chlorine atoms
and two alkyl carbon atoms in an all-trans configuration, similar to
those in diorganotin dichloride derivatives with monodentate
well was measured at a wavelength of 490 nm. The cytotoxicity
was determined by expressing the mean optical density for drug-
treated cells at each concentration as a percentage of that of
untreated cells. The activities of compounds were evaluated in
terms of their IC50 values obtained by linear regression analysis,
which are summarized in Table 2.
Results and Discussion
The Modification of Bis(Pyrazol-1-yl)Methanes and Their
Reactions
pyridyl nitrogen donor ligands, such as Et2SnCl2(C5H5N)2,[28]
The pyridyl functionalized bis(pyrazol-1-yl)methanes (L1 –L3)
can be easily obtained by the reactions of (2-hydroxy-
Ph2SnCl2(C5H5N)2
and Ph2SnCl2(Lꢁ)2 (Lꢁ = 3,5-dimethyl-4-(4ꢁ-
[29]
pyridyl)pyrazole).[12] The N–Sn–N, Cl–Sn–Cl and C–Sn–C angles
c
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Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 669–674

Diorganotin derivatives with pyridyl functionalized bis(pyrazol-1-yl)methanes
diorganotin chloride leads to a better activity in some complexes.
For example, the ethyl derivatives, especially complexes 1 and
4, exhibit relatively higher activity than their precursors. At the
same time, the butyl and phenyl derivatives 2 and 6 have a better
activity than their parent diorganotin chloride. Moreover, these
four complexes are even more active than etoposide. However,
the complexation of the 3-pyridyl ligand with diorganotin chloride
results in complexes with a lower activity compared with their
parent organotin compounds. The butyltin derivatives (complexes
2,5and8)aremoreactivethantheethyltinderivatives(complexes
1, 4 and 7). This behavior has been observed in other diorganotin
dihalide adducts containing N,Nꢁ-bidentate ligands.[3,4] The IC50
values of complexes 4 and 5 are larger than the corresponding
values of complexes 1 and 2, respectively, reflecting that the
methyl groups on the pyrazolyl rings decrease the cytotoxic
activities of complexes 4 and 5. Similar results have been observed
in other organotin derivatives with functionalized bis(pyrazol-1-
yl)methane.[30] However, the influence of substitutions on the
pyrazolyl rings on the activities of diphenyltin derivatives is
indistinctive. For example, complex 6 is the most active among
these three phenyl derivatives, according to its IC50 value. The
cytostatic activity discussed herein may be the result of the
cooperative effect of 2 : 1 adducts, 1 : 1 adducts and the ligands,
owing to the partial dissociation of complexes 1–9 in solution
shown by their NMR spectra.
Figure 1. The molecular structure of 5 with the thermal ellipsoids at
the 30% probability level. Hydrogen atoms and uncoordinated solvent
are omitted for clarity. Selected bond distances (Å) and angles (deg):
Sn1–N1, 2.387(3); Sn1–Cl1, 2.547(2); Sn1–C24, 2.101(5); N2–C13, 1.451(5);
N4–C13, 1.450(4) Å; and C24–Sn1–N1A, 86.4(2); N1A–Sn1–Cl1, 89.22(9);
C24–Sn1–N1, 93.6(2); N1–Sn1–Cl1, 90.78(9); N2–C13–N4, 111.8(3);
C6–O1–C7, 118.2(3)◦. Symmetry code: A = 1 − x, −y, −z.
In conclusion, three pyridyl functionalized bis(pyrazol-1-
yl)methanes (L) were synthesized by the reactions of (2-
hydroxyphenyl)bis(pyrazol-1-yl)methanes with chloromethylpyri-
dine. Treatment of these three ligands with R2SnCl2 (R = Et,
n-Bu or Ph) yielded 2 : 1 adducts (L)2SnR2Cl2, in which the pyridyl
functionalized bis(pyrazol-1-yl)methane acted as a monodentate
ligand through the pyridyl nitrogen atom, and the pyrazolyl nitro-
gen atoms did not coordinate to the tin atom. Some complexes
exhibited good cytotoxicities for Hela cells in vitro.
Figure 2. The molecular structure of 7 with the thermal ellipsoids at
the 30% probability level. Hydrogen atoms are omitted for clarity. Se-
lected bond distances (Å) and angles (deg): Sn1–N1, 2.399(4); Sn1–Cl1,
2.576(2); Sn1–C20, 2.145(5); N2–C13, 1.467(6); N4–C13, 1.444(6) Å; and
C20–Sn1–N1A, 92.1(2); N1–Sn1–Cl1, 90.0(1); N1–Sn1–Cl1A, 89.0(1);
N1–Sn1–C20, 87.9(2); N2–C13–N4, 108.6(4); C6–O1–C7, 117.8(3)◦. sym-
metry code: A = 1 − x, 1 − y, −z.
Supporting information
are each 180◦ owing to symmetry in these two complexes. The
Sn–N bond distance is 2.387(3) Å in complex 5 and 2.399(4)
Å in complex 7, respectively, longer than those reported in
Ph2SnCl2(C5H5N)2 [2.331(4) and 2.314(4) Å][29] and Ph2SnCl2(Lꢁ)2
(2.365(3) Å),[12] but shorter than those in Et2SnCl2(C5H5N)2
[2.410(3) and 2.411(3) Å][28] and the corresponding Sn–N(pyridyl)
bonddistancesindiorganotinderivativeswithchelatingbidentate
nitrogen donor ligands, such as in Me2SnCl2(PMP) [2.471(4) Å,
PMP = 2-(pyrazol-1-ylmethyl)pyridine].[2] The Sn–C [2.101(5) Å in
complex 5 and 2.145 (5) Å in complex 7] and Sn–Cl [2.547(2) Å
in complex 5 and 2.576 (2) Å in complex 7] bond distances are
also comparable to those in diorganotin dihalide derivatives with
monodentate nitrogen donor ligands.[15,28]
Supporting information may be found in the online version of this
article.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (nos 20721062 and 20672059). We thank
Professor Tian-Jun Liu (Institute of Biomedical Engineering,
Chinese Academy of Medical Sciences and Peking Union Medical
College) for friendly assistance in determining the cytotoxic
activities of compounds.
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