A versatile synthesis of triarylantimony difluorides by fluorination of triarylstibanes with nitrosyl tetrafluoroborate and their antitumor activity

Article abstract of DOI:10.1016/j.jfluchem.2017.04.004

Triarylantimony difluorides were synthesized in moderate to excellent yields by oxidative fluorination of triarylstibanes with nitrosyl tetrafluoroborate (NOBF₄) under aerobic conditions. This reaction is the first example of fluorination of trivalent organoantimony compounds using NOBF₄ as a fluorinating agent. The triarylantimony difluorides exhibited good anti-proliferation activity against tumor cell lines. In particular, the IC₅₀ of p-Tol₃SbF₂ (2c) was the lowest in each cell lines.

Full text of DOI:10.1016/j.jfluchem.2017.04.004

Accepted Manuscript
Title: A versatile synthesis of triarylantimony difluorides by
fluorination of triarylstibanes with nitrosyl tetrafluoroborate
and their antitumor activity
Authors: Yuki Kitamura, Mio Matsumura, Yuki Murata,
Mizuki Yamada, Naoki Kakusawa, Motohiro Tanaka,
Hiroyuki Okabe, Hiroshi Naka, Tohru Obata, Shuji Yasuike
PII:
S0022-1139(17)30047-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2017.04.004
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8-4-2017
8-4-2017
Please cite this article as: Yuki Kitamura, Mio Matsumura, Yuki Murata, Mizuki
Yamada, Naoki Kakusawa, Motohiro Tanaka, Hiroyuki Okabe, Hiroshi Naka, Tohru
Obata, ShujiYasuike, Aversatilesynthesisoftriarylantimonydifluoridesbyfluorination
of triarylstibanes with nitrosyl tetrafluoroborate and their antitumor activity, Journal of
Fluorine Chemistryhttp://dx.doi.org/10.1016/j.jfluchem.2017.04.004
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Full Length Articles
A versatile synthesis of triarylantimony difluorides by fluorination of triarylstibanes with nitrosyl
tetrafluoroborate and their antitumor activity
Yuki Kitamura,a Mio Matsumura,a Yuki Murata,a Mizuki Yamada,a Naoki Kakusawa,b Motohiro
Tanaka,a Hiroyuki Okabe,c Hiroshi Naka,c,** Tohru Obata,a,*** Shuji Yasuikea,*
aSchool of Pharmaceutical Sciences, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku,
Nagoya 464-8650, Japan
bFaculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa-machi, Kanazawa
920-1181, Japan
cResearch Center for Materials Science and Graduate School of Science, Nagoya University,
Chikusa, Nagoya 464-8602, Japan
*Corresponding author.
**Corresponding author.
***Corresponding author.
E-mail address: s-yasuik@dpc.agu.ac.jp (S. Yasuike)
h_naka@nagoya-u.jp (H. Naka)
tobata@dpc.aichi-gakuin.ac.jp (T. Obata)
1

Graphical abstract
Highlights:
Triarylantimony difluorides were synthesized by oxidative fluorination of triarylstibanes with
NOBF4.
The antitumor activity of triarylantimony difluorides exhibited good anti-proliferation activity
against tumor cell lines.
p-Tol3SbF2 exhibited the best antitumor activity among the compounds in this series.
ABSTRACT
Triarylantimony difluorides were synthesized in moderate to excellent yields by oxidative
fluorination of triarylstibanes with nitrosyl tetrafluoroborate (NOBF4) under aerobic conditions. This
reaction is the first example of fluorination of trivalent organoantimony compounds using NOBF4 as
a fluorinating agent. The triarylantimony difluorides exhibited good anti-proliferation activity against
tumor cell lines. In particular, the IC50 of p-Tol3SbF2 (2c) was the lowest in each cell lines.
Keywords:
Triarylantimony difluoride
Nitrosyl tetrafluoroborate
2

Fluorination
Antimony
Antitumor
1. Introduction
Organoantimony compounds have attracted much interest because of their use as important reagents
in organic synthesis and their potential biological activities [1–4]. Among these, triarylantimony
difluorides are used as precursors of pentavalent organoantimony compounds in main-group element
chemistry [5–7]. These triarylantimony difluorides have been typically synthesized by fluorination of
organoantimony compounds [5, 7–19]. Oxidative fluorination of triarylstibanes is a straightforward
strategy and has been widely conducted using fluorinating reagents such as HF/tBuOOH [15], IF5
[16], F2 [17], Et2NSF3 [7], methyl 3-azidotetrafluoropropionate (N3CF2CF2CO2Me) [18], and
triphenylbismuth difluoride (Ph3BiF2) [19]. However, most of these fluorinating reagents are difficult
to handle and can cause glass corrosion. In 2012 Fuchigami et al. reported a single example of
electrochemical fluorination of triphenylstibane (0.1 mmol scale) using KF as an inexpensive and
less glass-corrosive reagent in the presence of poly(ethylene glycol) [14]. However, substrate scope
and scalability of this reaction remains unclear. On the other hand, tetrafluoroborates (e.g.,
HBF4·OEt2, NOBF4, and Bu4NBF4) and boron trifluoride (e.g., BF3·OEt2) act as nucleophilic
fluorinating reagents that are easy to handle and do not cause glass corrosion [20]. For example, they
are used in the fluorination of aliphatic cyanoazides [21, 22], and -diazo--keto esters [23, 24] and
in the ring-opening fluorination of epoxides [25]. To the best of our knowledge, the synthesis of
triarylantimony difluorides by the reaction of triarylstibanes with tetrafluoroborate has not hitherto
been reported.
We have recently reported the synthesis and biological activity of organoantimony compounds
[26-30]. Among these, 1-[(2-di-p-tolylstibanophenyl)diazenyl]pyrrolidine [28] and
2-(di-p-tolylstibano)-N-p-tolylbenzamide [29] showed potent anti-proliferative activity against
3

human tumor cell lines such as NB4, HeLa, L1210, Mm1, and DLD-1. Moreover,
tris(pentafluorophenyl)stibane induced gene expression of metallothionein (MT)-1A and -2A, which
are the subisoforms of MT in bovine aortic endothelial cells [30]. This knowledge shows that
organoantimony compounds with fluorine atoms possibly show potent biological activity. As a
continuation of our previous studies, we now report a versatile synthesis of triarylantimony
difluorides by the fluorination of triarylstibanes with nitrosyl tetrafluoroborate (NOBF4) and their
antitumor activity.
2. Results and discussion
2.1. Synthesis of triarylantimony difluorides
We initially determined the optimum conditions for the fluorination of triphenylstibane (1a) with
fluorine reagents such as tetrafluoroborate and boron trifluoride. The results of the search for active
agents and the optimum amount of fluorine reagents for the reaction are summarized in Table 1. The
progress of the reaction was monitored by thin-layer chromatography (TLC), and the reaction time
was determined when 1a disappeared on TLC. First, we performed the reaction of 1a with a variety
of fluorine agents (2 eq) to compare their reactivity in CH2Cl2 at room temperature under aerobic
conditions (entries 1–11). Among these reagents, NOBF4, NO2BF4, and IPy2BF4 afforded the
expected triphenylantimony difluoride (2a) in good to high yields (entries 3–5). NOBF4 appeared to
be the best reagent for this reaction in terms of the yield (84%) of the fluorinated product (2a) and
reaction time (3 h) (entry 3). Next, the optimum amount of fluorine reagent was determined by the
reaction of 1a with NOBF4 (entries 3, 12–14). The best result was observed in the reaction of 1a with
NOBF4 in the ratio 1:2 (entry 3). It seems that one of the four fluorine atoms on the B atom in
NOBF4 was involved in the antimony–fluorine bond formation. Moreover, an excess amount of
NOBF4 seems to injure the product (entry 14). Screening of solvent showed that the reaction
proceeded effectively in CH2Cl2 (84%), toluene (71%), and CH3CN (59%). Other solvents such as
tetrahydrofuran and MeOH could not be used because of the poor solubility and low stability of
NOBF4. Consequently, the best result was obtained when 1a was treated with NOBF4 (2 eq) in
4

CH2Cl2 at room temperature. This reaction could also be scaled up to 10 mmol and the desired
product 2a was obtained in excellent yields of up to 88%, i. e., 3.44 g of the product could be
generated (entry 15).
Table 1
To demonstrate the efficiency and generality of the abovementioned protocol, the reactions of
various Ar3Sb (1b–m) and NOBF4 were investigated under the optimized conditions. The results are
shown in Table 2. The yields of Ar3SbF2 were sensitive to the electronic nature of the substituents on
the phenyl rings. The Ar3Sb with electron-withdrawing groups (1d–i) were fluorinated smoothly in
good to excellent yields, whereas those without an electron-attracting group (1b and 1c) gave 2b and
2c in moderate yields (entries 2–9). The reaction of 1b, which has a methoxy group on the phenyl
ring, with NOBF4 at room temperature gave the expected 2b in 25% yield and 4-nitrosoanisole as a
side product in 24% yield (entry 1). It was assumed that 4-nitrosoanisole was formed by the
nitroso-induced ipso-deantimonation of 1b with NOBF4. Therefore, the reaction of 1b and NOBF4
was performed at low temperature (–20 °C), and 2b was obtained in 45% yield without any side
product (entry 2). Comparison of methyl-substituted antimony substrates (1c, 1j, and 1k) showed
remarkable influence of the steric hindrance (entries 3, 10, and 11). The most bulky mesityl
derivative 1k was totally unreactive (entry 11). Fluorination of 1l and 1m with NOBF4 gave a
complex mixture (entries 12 and 13).
Table 2
At present, the mechanism of the fluorination of organoantimony compounds is unclear. We consider
a similar reaction mechanism proposed by Olah and Prakash et al. for the desulfurative fluorination
of sulfides and fluorination of arylacetylenes using NOBF4 [31, 32]. Fig. 1 shows a possible
mechanism for the synthesis of triarylantimony difluorides from Ar3Sb and NOBF4. The first step of
5

the reaction involves the generation of stibonium ion A from Ar3Sb (1a–j) with NO+. Intermediate B
–
is obtained through nucleophilic attack by F– from BF4 . The reaction of B with NO+ affords
stibonium ion D and H2N2O2 (E) via intermediate C. E decomposes to N2O and H2O [33].
Intermediate D is converted to triarylantimony difluorides (2a–j) by the nucleophilic attack of F–.
This mechanism is in line with the fact that the present fluorination protocol requires 2 equivalents of
NOBF4 (Table 1, entries 3, 12, and 13).
Fig. 1
2.2. Antitumor activity
The biological activity of the synthesized triarylantimony difluorides (2a-j) was evaluated in terms
of the antitumor effect in mouse and human cultured tumor cell lines. The tested compounds
presented good anti-proliferation activity against all the cell lines (Table 3). This series of
compounds exhibited antitumor activity against not only the mouse and human leukemia cell lines
but also human solid tumor cell lines such as colon and breast tumors. In particular, the IC50 of
p-Tol3SbF2 (2c) with the p-tolyl functional group was the lowest values (2.43–3.97 µM) in each cell
lines, indicating that this compound exhibited the best antitumor activity among those studied. In our
previous paper [29], we reported the anti-proliferative activity of cisplatin (CDDP, 1.0–6.2 µM
against 6 tumor cell lines), a famous platinum-based antitumor drug. Interestingly, the antitumor
activity of o-Tol3SbF2 (2j), a regioisomer of 2c, was significantly lower (IC50 = 5.13–15.2 µM). It
seems that the difference in the position of the methyl functional group caused a conformational
change and a consequent lack of interaction between the molecule and the unidentified biological
target. Furthermore, the electron-donating and electron-withdrawing substituents on the aromatic
ring were not affected significantly in this assay system. However, 2i having benzonitrile as an
aromatic side chain showed remarkably reduced sensitivity in all the tumor cell lines. Although the
mechanism of this organoantimony series for anti-proliferation in tumor cells is still unclear, these
compounds may become key molecules in the development of potent antitumor agents.
6

Table 3
3. Conclusion
In conclusion, we have developed a novel fluorination of triarylstibanes by using nitrosyl
tetrafluoroborate as the fluorine source under aerobic conditions. Various triarylstibanes with
electron-donating and electron-withdrawing functional groups afforded the corresponding
triarylantimony difluorides in moderate to excellent yields. These compounds exhibited potent
antitumor activity against several cultured tumor cell lines. Particularly, the sensitivity of p-Tol3SbF2
(2c) was higher than that of the other triarylantimony difluorides in all the tested cell lines. These
findings indicate that the potential application of organoantimony compounds with fluorine atoms
may be extended to the development of a superior antitumor drug.
4. Experimental
4.1. General
Melting points were measured on a Yanagimoto micro melting point hot-stage apparatus (MP-S3)
and reported as uncorrected values. 1H NMR (TMS: δ: 0.00 ppm or CH2Cl2: 5.30 ppm as an internal
standard) and 13C NMR (CDCl3: δ: 77.00 ppm as an internal standard) spectra were recorded on
JEOL JNM-AL400 (400 MHz and 100 MHz respectively) spectrometers in CDCl3. 19F NMR
(α,α,α-trifluorotoluene: δ: –64.0 ppm as an internal standard) spectra were recorded on JEOL
ECA-600 spectrometers in CDCl3. Mass spectra were obtained on a JEOL JMP-DX300 instrument
(70 eV, 300 μA). IR spectra were recorded on a Shimadzu FTIR-8400S spectrophotometer and
reported in terms of frequency of absorption (cm–1). Only selected IR bands are absorbencies
reported. Chromatographic separations were carried out using Silica Gel 60N (Kanto Chemical Co.,
Inc.) under the solvent system stated. Thin-layer chromatography (TLC) was performed using Merck
Pre-coated TLC plates (silica gel 60 F254). Triphenylstibane (1a) was purchased from Sigma-Aldrich,
7

and other triarylstibanes of 1b, c, j [15], 1d, e, g, h [34], 1f [35], and 1i [36] were prepared according
to the reported procedures.
4.2. General procedure for triarylantimony difluorides
To a solution of triarylstibane (1a–j: 0.5 mmol) in dry CH2Cl2 (3.0 mL) was added NOBF4 (1.0
mmol) at –20 or 0 ºC. The reaction mixture was stirred at –20 ºC or room temperature for the
indicated time (2–5 h) until complete consumption of the starting material, as monitored by TLC.
After dilution with CH2Cl2 (20 mL) and water (20 mL), the organic layers were separated, and the
aqueous layer was extracted with CH2Cl2 (20 mL × 2). The combined organic layers were washed
with water and brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (2a, c–e, h, and 2j : n-hexane:Et2O =
5:1, 2b: CH2Cl2), affording triarylantimony difluorides (2a–e, h, and 2j). In the case of 2f, g, and 2i,
the crude product was purified by recrystallization.
4.2.1. Triphenylantimony difluoride (2a) [15]
Pale yellow plates (164 mg, 84%). mp 106–109 ºC (from n-hexane–CH2Cl2). 1H NMR (400 MHz,
CDCl3) : 7.52–7.53 (m, 9H, Ar-H), 8.14–8.19 (m, 6H, Ar-H); 13C NMR (100 MHz, CDCl3) :
129.5, 132.1, 134.1 (t, 2JC, F = 15.3 Hz), 135.3 (t, 3JC, F = 5.0 Hz); 19F NMR (565 MHz, CDCl3) : –
153.5 (s, 2F). LRMS (EI): m/z 390 (M+, 20%), 313 (95%), 154 (100%). HRMS: m/z [M]+ calcd for
C18H15F2Sb: 390.0180. Found: 390.0183.
4.2.2. Tris(4-methoxyphenyl)antimony difluoride (2b)
Brown oil (108 mg, 45%). 1H NMR (400 MHz, CDCl3) : 3.83 (s, 9H, Me), 7.04 (d, 6H, J = 8.8 Hz,
Ar-H), 8.04–8.07 (m, 6H, Ar-H); 13C NMR (100 MHz, CDCl3) : 55.3, 115.1, 124.7 (t, 2JC, F = 15.7
Hz), 136.6 (t, 3JC, F = 5.0 Hz), 162.7; 19F NMR (565 MHz, CDCl3): –151.1 (s, 2F); LRMS (EI): m/z
480 (M+, 45%), 373 (100%), 214 (90%); HRMS: m/z [M]+ calcd for C21H21F2O3Sb: 480.0494.
Found: 480.0497.
8

4.2.3. Tris(4-tolyl)antimony difluoride (2c) [37]
Colorless prism (153 mg, 71%), mp 113–115 ºC (from n-hexane–CH2Cl2). 1H NMR (400 MHz,
CDCl3)  : 2.38 (s, 9H, Me), 7.33 (d, 6H, J = 7.8 Hz, Ar-H), 8.01 (d, 6H, J = 8.3 Hz, Ar-H); 13C
NMR (100 MHz, CDCl3) : 21.4, 130.2, 130.9 (t, 2JC, F = 15.2 Hz), 135.1 (t, 3JC, F = 5.0 Hz), 142.5;
19F NMR (565 MHz, CDCl3): –152.8 (s, 2F). LRMS (EI): m/z 432 (M+, 10%), 341 (100%), 182
(80%). HRMS: m/z [M]+ calcd for C21H21F2Sb: 432.0650. Found: 432.0652.
4.2.4. Tris(4-fluorophenyl)antimony difluoride (2d) [38]
Colorless plates (176 mg, 79%), mp 65–67 ºC (from n-hexane). 1H NMR (400 MHz, CDCl3) :
7.22–7.27 (m, 6H, Ar-H), 8.13–8.27 (m, 6H, Ar-H); 13C NMR (100 MHz, CDCl3) : 117.0 (d, 2JC, F
= 16.6 Hz), 128.6 (td, 2JC, F = 16.5, 3.3 Hz), 137.5 (dt, 3JC, F = 9.0, 5.0 Hz), 165.6 (d, 1JC, F = 253.2
Hz); 19F NMR (565 MHz, CDCl3) : –151.1 (s, 2F), –107.6 (s, 3F); LRMS (EI): m/z 444 (M+, 10%),
349 (100%), 190 (80%); HRMS: m/z [M]+ calcd for C18H12F2Sb: 443.9897. Found: 443.9894.
4.2.5. Tris(4-chlorophenyl)antimony difluoride (2e)
Pale yellow plates (210 mg, 85%), mp 114–116 ºC (from n-hexane–CH2Cl2). 1H NMR (400 MHz,
CDCl3): 7.52–7.54 (m, 6H, Ar-H), 8.06–8.08 (m, 6H, Ar-H); 13C NMR (100 MHz, CDCl3):
130.0, 131.5 (t, 2JC, F = 16.1 Hz), 136.5 (t, 3JC, F = 5.4 Hz), 139.4; 19F NMR (565 MHz, CDCl3): –
152.7 (s, 2F); LRMS (EI): m/z 494 (M+, 15%), 383 (100%), 222 (80%); HRMS: m/z [M]+ calcd for
C18H12Cl3F2Sb: 493.8981. Found: 493.8977.
4.2.6 Tris(4-bromophenyl)antimony difluoride (2f)
Pale yellow plates (270 mg, 86%), mp 111–113 ºC (from n-hexane–CH2Cl2). 1H NMR (400 MHz,
CDCl3): 7.68 (d, 6H, J = 7.8 Hz, Ar-H), 7.99 (d, 6H, J = 8.8 Hz, Ar-H); 13C NMR (100 MHz,
CDCl3) : 128.0, 132.0 (t, 2JC, F = 15.7 Hz), 132.8, 136.6 (t, 3JC, F = 4.1 Hz); 19F NMR (565 MHz,
CDCl3) : –153.1 (s, 2F). LRMS (FAB): m/z 625 (M+, 10%), 609 (100%), 297 (10%). HRMS: m/z
[M]+ calcd for C18H12Br3F2Sb: 625.7475. Found: 625.7478.
9

4.2.7. Tris(4-ethoxycarbonylphenyl)antimony difluoride (2g)
Colorless needles (258 mg, 85%), mp 121–123 ºC (from n-hexane–CH2Cl2). 1H NMR (400 MHz,
CDCl3) : 1.40 (t, 9H, J = 7.3 Hz, Me), 4.41 (q, 6H, J = 7.3 Hz, CH2), 8.20 (d, 6H, J = 8.3 Hz, Ar-H),
8.26 (d, 6H, J = 8.3 Hz, Ar-H); 13C NMR (100 MHz, CDCl3) : 14.2, 61.5, 130.3, 134.2, 135.3 (t,
3JC, F = 5.0 Hz), 138.4 (t, 2JC, F = 15.3 Hz), 165.6; 19F NMR (565 MHz, CDCl3) : –152.4 (s, 2F).
LRMS (FAB): m/z 606 (M+, 25%), 587 (100%), 253 (15%). HRMS: m/z [M]+ calcd for
C27H27F2O6Sb: 606.0814. Found: 606.0811; IR (KBr): 1724 cm–1.
4.2.8. Tris[4-(trifluoromethyl)phenyl]antimony difluoride (2h) [7]
Pale yellow plates (238 mg, 80%), mp 94–96 ºC (from n-hexane–CH2Cl2). 1H NMR (400 MHz,
CDCl3) : 7.82 (d, 6H, J = 7.8 Hz, Ar-H), 8.32 (d, 6H, J = 7.8 Hz, Ar-H); 13C NMR (100 MHz,
CDCl3): 123.4 (q, 1JC, F = 273.1 Hz), 126.4 (q, 3JC, F = 1.7 Hz), 134.7 (q, 2JC, F = 33.1 Hz), 135.9 (t,
3JC, F = 5.4 Hz), 137.3 (t, 2JC, F = 15.7 Hz); 19F NMR (565 MHz, CDCl3) : –153.4 (s, 2F), –64.6 (s,
9F); LRMS (FAB): m/z 594 (M+, 15%), 575 (100%), 271 (60%). HRMS: m/z [M]+ calcd for
C21H12F11Sb: 593.9802. Found: 593.9806.
4.2.9. Tris(4-cyanophenyl)antimony difluoride (2i)
Colorless prism (182 mg, 78%), mp 147–150 ºC (from n-hexane–CH2Cl2). 1H NMR (400 MHz,
CDCl3) : 7.85 (d, 6H, J = 7.8 Hz, Ar-H), 8.29 (d, 6H, J = 7.8 Hz, Ar-H); 13C NMR (100 MHz,
CDCl3) : 116.9, 117.4, 132.9, 136.1 (t, 3JC, F = 5.3 Hz), 138.0 (t, 2JC, F = 15.7 Hz); 19F NMR (565
MHz, CDCl3) : –154.5 (s, 2F); LRMS (EI): m/z 465 (M+, 5%), 363 (100%), 242 (35%). HRMS:
m/z [M]+ calcd for C21H12F2N3Sb: 465.0037. Found: 465.0034. IR (KBr): 2230 cm–1.
4.2.10. Tris(2-tolyl)antimony difluoride (2j) [8]
Pale yellow plates (130 mg, 60%). mp 197–199 ºC (from n-hexane–CH2Cl2). 1H NMR (400 MHz,
CDCl3) : 2.55 (s, 9H, Me), 7.31–7.37 (m, 6H, Ar-H), 7.45 (td, 3H, J = 7.6, 1.0 Hz, Ar-H), 7.73 (d,
10

3H, J = 7.3 Hz, Ar-H); 13C NMR (100 MHz, CDCl3) : 23.2 (t, 4JC, F = 2.5 Hz), 126.5, 131.6 (t, 3JC, F
= 9.9 Hz), 135.0, 136.8 (t, 2JC, F = 15.7 Hz), 142.9; 19F NMR (565 MHz, CDCl3) : –112.0 (s, 2F);
LRMS (EI): m/z 414 ([M-F]+, 70%), 412 (95%), 341 (100%). HRMS: m/z [M-F]+ calcd for
C21H21FSb: 414.0744. Found: 414.0740.
4.3. Antitumor activity
Mouse melanoma cells B16-F10, human promyelocytic leukemia cells HL-60, human fiblosarcoma
cells HT-1080, human breast adenocarcinoma cell line MCF-7 and human colorectal
adenocarcinoma cells DLD-1 were purchased from the American Type Culture Collection. The tested
all cell lines were maintained at 37 °C and 5% CO2 in RPMI-1640 medium supplemented with 10%
heat-inactivated fetal bovine serum (FBS) and 1% penicillin-streptomycin. The growth-inhibitory
effects of the compounds on tumor cells were examined using a colorimetric assay involving
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Briefly, 198-µL aliquots of an
exponentially growing cell suspension (10,000 cells/mL) were incubated with 2 µl of varying
concentrations of compounds dissolved by dimethyl sulfoxide (DMSO). After exposure to the
compounds for 72 h, 25 µl of MTT solution (3 mg/mL in PBS) was added to each well and the cell
cultures were incubated at 37 °C for 4 h. After removal of the medium, the formed formazan was
dissolved in 200 µl of DMSO. The absorbance of each well was measured at 570 nm with
MTP-800AFC immunoreader (CORONA Electric), and the inhibition ratio (IR) was calculated using
the following formula: IR (%) = (1 – T/C) × 100, where C is the mean of optical densities of the
control group and T of the treatment group. The IC50 value was defined as the concentration of the
compound needed to effect a 50% reduction in growth relative to the control. The IC50 value was
determined by a graphical correlation of the dose-response curve with at least three compound
concentration points.
11

Acknowledgments
Partial financial support for this work was provided by a research grant from Institute of
Pharmaceutical Life Sciences, Aichi Gakuin University and Hokuriku University. We thank Takahiro
Isogawa (Nagoya U) for his technical assistance.
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14

Fig. 1. Possible Mechanism
Table 1
Reaction of triphenylstibane 1a with fluorine reagents.a
Yield (%)b
Entry Reagent (eq)
Time (h)
Recover
2a
y
1
2
3
4
5
6
7
8
HBF4·Et2O (2) 24
4
0
84
67
60
2
0
0
0
2
92
96
0
0
0
91
98
97
97
95
98
69
39
0
Bu4N·BF4 (2)
NOBF4 (2)
NO2BF4 (2)
IPy2BF4 (2)
Cp2FeBF4 (2)
NaBF4 (2)
NH4BF4 (2)
Et3OBF4 (2)
Et2OBF3 (2)
TBAF (2)
24
3
4
24
24
24
24
24
24
24
24
24
3
9
10
11
12
13
14
15c
0
NOBF4 (0.5)
NOBF4 (1.0)
NOBF4 (3)
NOBF4 (2)
22
49
50
88
4
0
a Conditions: 1a (0.5 mmol), CH2Cl2 (3 mL), rt, under air.
b Isolated yield.
c 1a (10 mmol), CH2Cl2 (60 mL).
15

Table 2
Synthesis of triarylantimony difluorides.a
Entry Substrate Ar
Time (h) Yield (%)b
1
1b
1b
1c
1d
1e
1f
3
5
3
2
3
3
2
2
3
4
2b: 25 (24)c
2b: 45
2c: 71
2d: 79
2e: 85
2f: 86
2d
3
4
5
6
7
1g
1h
1i
2g: 85
2h: 80
2i: 78
8
9
10
1j
2j: 60
11
1k
24
2k: 0
12
13
1l
24
24
2l: 0
1m
2m: 0
a Conditions: 1 (0.5 mmol), NOBF4 (1.0 mmol), CH2Cl2 (3 mL), rt, under air.
b Isolated yield.
c Yield of 4-nitrosoanisole in parentheses .
d –20°C.
Table 3
IC50a for compounds 2a–j in several tumor cell lines.
B16-F10
HL-60
HT-1080
DLD-1
MCF-7
2a
2b
2c
2d
2e
2f
7.17 ± 4.02
5.60 ± 4.21
2.43 ± 1.23
6.78 ± 3.71
3.85 ± 1.80
3.91 ± 2.11
8.20 ± 2.72
6.85 ± 1.01
3.63 ± 0.73
8.36 ± 2.76
7.20 ± 3.64
5.42 ± 1.13
13.2 ± 6.7
9.77 ± 5.00
3.97 ± 1.84
7.82 ± 3.67
8.76 ± 3.81
5.48 ± 1.40
8.09 ± 3.05
6.17 ± 1.26
3.26 ± 1.45
8.13 ± 4.24
8.30 ± 3.66
6.66 ± 3.09
14.2 ± 7.2
10.2 ± 0.9
3.78 ± 1.80
13.4 ± 1.0
7.16 ± 3.69
7.22 ± 2.48
16

2g
2h
2i
3.20 ± 1.31
4.43 ± 0.88
34.2 ± 12.3
5.13 ± 1.49
5.54 ± 1.84
3.68 ± 0.86
31.8 ± 7.1
7.39 ± 5.01
5.38 ± 1.28
40.1 ± 14.2
10.4 ± 1.2
5.04 ± 1.30
4.37 ± 1.34
43.8 ± 19.5
6.63 ± 2.12
5.69 ± 2.53
5.23 ± 2.34
30.3 ± 11.4
12.2 ± 0.3
2j
15.2 ± 11.1
a IC50 values (µM) were showed the mean ± SD.
17