Synthesis and antifungal activities of pyridine bioisosteres of a bismuth heterocycle derived from diphenyl sulfone

Article abstract of DOI:10.3987/COM-18-13876

– Heterocyclic iodobismuthanes 7–9 [IBi(C₆H₄-2-SO₂C₅H₃N-1′-)] derived from phenyl pyridinyl sulfones were synthesized. Their antifungal activities against the yeast Saccharomyces cerevisiae were compared with those of halobismuthanes [XBi(RC₆H₃-2-SO₂C₆H₄-1′-)] (1: X=Cl; 2: X=I, R=H) derived from diphenyl sulfone derivatives to determine how the bioisosteric replacement of the benzene ring in 2 with the pyridine ring in 7–9 affects their activities. The antifungal activities of 7–9 were higher or comparable to those of 1 and 2. The DFT calculations suggested that the generation of the antifungal activity of the bismuthanes was well understood by the nucleophilic addition of methanethiolate anion as a model biomolecule at the bismuth atom to give an intermediate ate complex.

Full text of DOI:10.3987/COM-18-13876

HETEROCYCLES, Vol. 96, No. 6, 2018
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HETEROCYCLES, Vol. 96, No. 6, 2018, pp. 1037 - 1052. © 2018 The Japan Institute of Heterocyclic Chemistry
Received, 12th February, 2018, Accepted, 27th April, 2018, Published online, 16th May, 2018
DOI: 10.3987/COM-18-13876
SYNTHESIS AND ANTIFUNGAL ACTIVITIES OF PYRIDINE
BIOISOSTERES OF A BISMUTH HETEROCYCLE DERIVED FROM
DIPHENYL SULFONE
A. F. M. Hafizur Rahman,a Toshihiro Murafuji,a,b* Kazuki Yamashita,a
Masahiro Narita,b Isamu Miyakawa,b Yuji Mikata,c Katsuya Ishiguro,b and
Shin Kamijob
a
Graduate School of Medicine, Yamaguchi University, Yamaguchi 753-8512,
Japan. E-mail: murafuji@yamaguchi-u.ac.jp
b
Graduate School of Sciences and Technology for Innovation, Yamaguchi
University, Yamaguchi 753-8512, Japan.
c
Department of Chemistry, Biology, and Environmental Science, Faculty of
Science, Nara Women´s University, Nara 630-8506, Japan
Abstract – Heterocyclic iodobismuthanes 7–9 [IBi(C6H4-2-SO2C5H3N-1´-)]
derived from phenyl pyridinyl sulfones were synthesized. Their antifungal
activities against the yeast Saccharomyces cerevisiae were compared with those
of halobismuthanes [XBi(RC6H3-2-SO2C6H4-1´-)] (1: X=Cl; 2: X=I, R=H)
derived from diphenyl sulfone derivatives to determine how the bioisosteric
replacement of the benzene ring in 2 with the pyridine ring in 7–9 affects their
activities. The antifungal activities of 7–9 were higher or comparable to those of 1
and 2. The DFT calculations suggested that the generation of the antifungal
activity of the bismuthanes was well understood by the nucleophilic addition of
methanethiolate anion as a model biomolecule at the bismuth atom to give an
intermediate ate complex.
INTRODUCTION
Bismuth is a heavy metal that is less toxic to human in comparison to the metals surrounding it in the
periodic table.1–3 This factor makes it possible to use bismuth compounds as drugs in the treatment of
gastrointestinal disorders,1 a red light-excitable photosensitizer in cells,2 and biocompatible catalysts for
ring opening polymerization.3 Biologically active bismuth compounds have been the subject of
considerable interest due to their medicinal utility.4–13 We have reported the synthesis and antifungal

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HETEROCYCLES, Vol. 96, No. 6, 2018
activity against the yeast Saccharomyces cerevisiae of bismuth heterocycles 1–3 (Scheme 1 and Table
2).14–16
Cl
O2
S
O2
S
O2
S
O2
S
Me
Bi
Cl
1k
Bi
R
Bi
Cl
Bi
Cl
1j
Cl Cl
1l
1
R = H (a), F (b), Me (c),
Cl (d), OMe (e), CF3 (f),
NMe2 (g), t-Bu (h), Ph (i)
O2
S
O2
S
Bi
I
RO
Bi
Cl
OR
2
3
R = H (a), SiMe2Bu-t (b)
Scheme 1. Molecular structures of heterocyclic halobismuthanes 1–3
The Lewis acidity at the bismuth center was essential for generating the activity. Halobismuthanes 1a, 1b
and 2 showed high antifungal activities, and the activity of monosubstituted 1 decreased as the ClogP
value increased, depending on the substituent. Based on this relationship, to achieve higher activity we
synthesized 3a bearing hydrophilic substituents, but its activity was much lower than that of parent 1a.15
We attributed this to the considerable decrease in the lipophilicity of 3a. However, we have not tested this
hypothesis experimentally.
We envisaged that replacing one of the benzene rings in 1a or 2 with a pyridine ring should provide
important information about whether the decrease in antifungal activity is related to the hydrophilicity.
Pyridine is an isostere of benzene ring and is more hydrophilic than benzene.17–22 We designed several
bismuth heterocycles 4–9 derived from phenyl pyridinyl sulfone (Scheme 2).
O2
S
O2
S
O2
S
N
N
Tol: 4-MeC6H4
N
Bi
X
Bi
X
Bi
X
X = Tol (4), I (7)
X = Tol (5), I (8)
X = Tol (6), I (9)
Scheme 2. Molecular structures of bismuth heterocycles 4–9
This bioisosteric replacement is expected to make 7–9 much more hydrophilic than 2, although the
molecular shape is the same. In this paper, we report the synthesis and antifungal activities of 4–9. To the
best of our knowledge, organobismuth compounds in which the bismuth atom is directly attached to a

HETEROCYCLES, Vol. 96, No. 6, 2018
1039
pyridine skeleton through a bismuth–carbon bond are rare and have been synthesized only recently.23,24 In
contrast, bismuth complexes with pyridine ligands bound through bismuth–nitrogen bonds have been
characterized.25–27
RESULTS AND DISCUSSION
Synthesis: Phenyl 2-pyridinyl sulfone 10 was prepared by heating 2-bromopyridine and sodium
benzenesulfinate in acetic acid.28 Phenyl 3-pyridinyl sulfone 1129 and phenyl 4-pyridinyl sulfone 1230
were prepared by heating the corresponding bromopyridine and thiophenol in DMF in the presence of
K2CO3 followed by the oxidation of the resulting phenyl pyridinyl sulfide.31
Our initial efforts were aimed at identifying conditions for the synthesis of 4 (Scheme 3). When 10 (1
mmol) was treated with LTMP (2.2 mmol) in THF at –40 °C for 20 min, an orange suspension was
obtained. Addition of TolBiCl2 (1 mmol) to the suspension at –70 °C, followed by workup and
subsequent purification of the reaction mixture by chromatography (silica gel) gave 4 (0.68 mmol) in
68% yield along with acyclic 13 (0.048 mmol) in 10% yield as a minor product. The formation of 13
indicates that the pyridine-ring-lithiated intermediate of 10 is stable. Based on this result, we decided to
lithiate 11 at a lower temperature because the lithiation of 3-substituted pyridines proceeds at the
4-position owing to the inherent higher acidity of the proton at this position.32–34 Furthermore, the
4-position of the pyridine ring is susceptible to the unfavorable nucleophilic reaction.35 When 11 was
treated with LTMP at –55 °C, the solution immediately turned dark red. The reaction with TolBiCl2 gave
5 in 40% yield. In this reaction, the bismuth analog, similar to 13 derived from the monolithiation of 11,
was not detected. Finally, we lithiated 12 under forcing conditions because the synthesis of 4 via the
lithiation of 10 at –40 °C gave 13 derived from the monolithiation of 10. Thus, 12 was lithiated with
LTMP at –15 °C, and an orange suspension was obtained that was treated with TolBiCl2 to give 6 in 58%
yield without a byproduct, but unreacted 12 was recovered (35%). The recovery of 12 suggests that the
pyridine ring proton adjacent to the sulfonyl group of 10 is susceptible to the lithiation compared to that
of 12. Iodination of 4–6 afforded the corresponding iodobismuthanes 7–9 in high yields together with
4-iodotoluene. This reaction may be rationalized as follows; the oxidative addition of iodine on the
bismuth atom gives a pentavalent intermediate, which undergoes the reductive elimination of
4-iodotoluene to form the iodobismuthane. The selective elimination of the tolyl group is understood by
the transannular interaction36,37 between the bismuth and sulfonyl oxygen atoms, which forms the
hypervalent O–Bi–I bond.38 It is known that the transannular interaction promotes the reductive
elimination on the pentavalent bismuth atom.39,40 Furthermore, arsenic halogenation of 9-arsafluorene has
shown that the reaction mechanism involves the oxidative addition and reductive elimination on the
arsenic atom.41

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HETEROCYCLES, Vol. 96, No. 6, 2018
O2
S
O2
S
O2
S
N
N
N
TolBiCl2
THF, –40 °C THF, –70 °C
I2
LTMP
Et2O, rt
Bi
Bi
10
Tol
I
7 (95%)
4 (68%)
O2
S
O2
S
O2
S
I2
TolBiCl2
THF, –55 °C THF, –70 °C
LTMP
N
N
N
Et2O, rt
Bi
Bi
I
11
Tol
5 (40%)
8 (90%)
O2
S
O2
S
O2
S
I2
TolBiCl2
LTMP
Et2O, rt
N
N
N
THF, –15 °C
THF, –70 °C
Bi
I
Bi
12
Tol
9 (90%)
6 (58%)
O2
S
O2
S
N
LTMP =
N
Li
2
Bi
Bi
N
Tol
Tol
5' (not formed)
13 (10%)
Scheme 3. Synthesis of bismuth heterocycles 4–9
1
NMR spectroscopic study: The H NMR spectra of compounds 4–6 in CDCl3 showed characteristic
proton signals due to the pyridine ring, which were used to assign these compounds. Compound 4
possesses only one proton adjacent to the nitrogen of the pyridine ring, whose signal appeared at the
highest chemical shift (δ 8.63 ppm) as a double doublet. However, compound 5 showed signals from the
two protons adjacent to the nitrogen, excluding the possibility of the formation of isomeric 5´. In 5, the
signal of the unique pyridine ring proton next to the sulfonyl substituent appeared at a high chemical shift
(δ 9.41 ppm) as a singlet owing to the effect of the adjacent nitrogen atom and the sulfonyl group.
Compound 6 also shows the signals due to the two protons adjacent to the nitrogen. The signal for the
pyridine ring proton neighboring the bismuth atom was characteristic of this compound and appeared as a
singlet at a lower chemical shift (δ 8.84 ppm) than the singlet proton signal (δ 9.41 ppm) for the pyridine
1
ring of 5. In the H NMR spectra of iodobismuthanes 7–9 in CDCl3, the protons adjacent to the bismuth

HETEROCYCLES, Vol. 96, No. 6, 2018
1041
atom in the benzene and pyridine rings underwent anisotropic deshielding because of their close
proximity to the iodine atom.9 Thus, the proton signal of the benzene ring for 7–9 appeared at about δ 9.2
ppm, 1.3 ppm higher than that of parent bismuthanes 4–6. However, the proton signal of the pyridine ring
for 7, 8 and 9 appeared at higher shifts of δ 9.55, 9.13 and 9.89 ppm, respectively, which are 1.0–1.3 ppm
higher than those of parent compounds 4–6. These observations indicate that the sulfonyl oxygen atom
was coordinated to the bismuth atom to form a hypervalent O–Bi–I bond. In the 13C NMR spectra of
iodobismuthanes 7, 8 and 9 in DMSO-d6, the signal for the ipso carbon attached to the bismuth in the
pyridine ring appeared at δ 170.8, 188.4 and 169.7 ppm, respectively, whereas the signal due to the
phenyl ipso carbon attached to the bismuth was always observed around δ 180 ppm.
X-Ray structure analysis of 9: We prepared single crystals of 9. The molecular structure of 9 is shown
in Figure 1, and the selected bond lengths, atomic distances and angles are shown in Table 1. This
molecule has a chiral bismuth center. Interestingly, we found that only one enantiomer is present in the
measured crystal.
Figure 1. Molecular structure of 9
The bismuth center adopts a distorted trigonal bipyramidal geometry, where the carbon atoms C(1) and
C(6) occupy the equatorial plane with a C(1)–Bi(1)–C(6) angle of 86.1(5)° (Table 1). The apical positions
of the distorted trigonal bipyramid are occupied by the sulfonyl oxygen and iodine atoms with an
O(1)•••Bi(1)–I(1) angle of 159.0(2)°. The lone pair of electrons is considered to occupy the remaining
equatorial position. The intramolecular Bi(1)•••O(1) distance 2.788(9) Å is longer than the sum of the

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HETEROCYCLES, Vol. 96, No. 6, 2018
covalent radii (2.10 Å) but much shorter than that of the van der Waals radii (3.72 Å),42,43 in accord with
the formation of a hypervalent bond over the oxygen, bismuth and iodine atoms in 9. The intermolecular
atomic distances between the bismuth and nitrogen atoms and between the bismuth and iodine atoms are
both within the sum of the van der Waals radii (3.62 and 4.05Å, respectively),44 suggesting the existence
of a weak interaction.
Table 1. Selected bond lengths (Å), atomic distances (Å) and angles (°) for compound 9
Bond lengths
Torsion angles
I(1)–Bi(1)–C(1)–C(2)
Bi(1)–I(1)
Bi(1)–C(1)
Bi(1)–C(6)
S(1)–O(1)
S(1)–O(2)
2.8518(12)
2.293(14)
2.294(14)
1.485(16)
1.435(11)
–43.3(9)
–174.4(9)
3.7(15)
177.7(8)
43.9(10)
173.7(8)
133.2(10)
Bi(1)–C(1)–C(2)–N(1)
Bi(1)–C(1)–C(5)–S(1)
Bi(1)–C(1)–C(5)–C(4)
O(1)–S(1)–C(5)–C(1)
O(2)–S(1)–C(5)–C(1)
C(1)–Bi(1)–C(6)–C (7)
Bond angles
Atomic distances
C(1)–Bi(1)–C(6)
I(1)–Bi(1)–C(1)
I(1)–Bi(1)–C(6)
O(1)•••Bi(1)–I(1)
Bi(1)–C(1)–C(5)
C(5)–S(1)–C(11)
O(1)–S(1)–O(2)
86.1(5)
96.1(3)
92.8(3)
159.0(2)
118.2(10)
103.9(7)
119.2(6)
intramolecular
Bi(1)•••O(1)
2.788(9)
intermolecular
Bi(1)•••N(1)
Bi(1)•••I(1)
3.252(11)
3.877(1)
Qualitative antifungal assay: We tested the inhibition activity of iodobismuthanes 7–9 together with
triarylbismuthanes 4–6 and 13. Table 2 summarizes the inhibition activities of these compounds and our
previously reported compounds 1–3. Each compound was dissolved in DMSO at a concentration of 30
mM and 5 µL of each solution was directly spotted on the surface of the agar plate containing the yeast.
Iodobismuthanes 7–9 were stable in water and DMSO, indicating that the hypervalent bond formation
suppresses the hydrolysis and redistribution reactions of these compounds.
Triarylbismuthanes 4–6 and 13 were inactive, but iodobismuthanes 7–9 showed high antifungal activities.
This is consistent with our previous finding that the Lewis acidic bismuth center is the active site.9,14–16
The activity increased as the nitrogen atom moved further from the sulfonyl group and closer to the
bismuth atom. Thus, iodobismuthane 9 showed the highest activity of 7–9 and higher activity than 1a and
2. The effect of the position of the nitrogen atom on the activity may imply an efficient secondary
interaction of the nitrogen atom with biomolecules that bind to the active bismuth center. It has been
reported that replacing the phenyl ring of the core indole with a pyridine ring preserves or substantially
reduces the inhibitory activity, depending on the position of the nitrogen atom.19
Next, we investigated the effect of concentration of 9 on its antifungal activity. In response to decreasing

HETEROCYCLES, Vol. 96, No. 6, 2018
1043
the concentrations of 9 from 30 to 3.75 mM, the activity decreased (20, 15, 13, and 10 mm for 30, 15, 7.5,
and 3.75 mM, respectively). At the lowest concentration (3.75 mM), 9 still showed half of its original
activity. Although the activities of 7–9 were not as high as the standard antifungal drug, nystatin, this
finding demonstrates the high antifungal activity of organobismuth compounds.
Table 2. Antifungal assay for halobismuthanes and triarylbismuthanes
Inhibition
Zone (mm)
Inhibition
Zone (mm)
Compound
ClogP
Compound
ClogP
1a
1b
1c
1d
1e
1f
1g
1h
1i
18
17
14
13
11
11
7
0
0
8
10
13
1.18
1.45
1.68
2.02
1.52
2.28
1.77
3.00
3.06
1.68
2.02
2.02
2
3a
3b
4
5
6
13
7
8
9
17
8
0
0
0
0
0
16
19
20
30
1.18
0.81
6.13
3.10
3.10
3.10
6.29
0.29
0.29
0.29
–
1j
1k
1l
Nystatin
We have previously reported the antifungal activity of chlorobismuthanes 1 and related derivatives 3.15 A
clear structure–activity relationship was observed in 1a–l (r = –0.85, n = 12) between the size of the
inhibition zone and the value of ClogP, where the antifungal activity increased with decreasing
lipophilicity (Table 2). However, 3a (ClogP = 0.81), which was more hydrophilic, exhibited only low
activity compared to 1a. We attributed this to the considerable decrease in the lipophilicity of 3a because
the relationship appeared to be applied for the limited range of the ClogP values, depending on the
substituent on the benzene ring. In fact, chlorobismuthanes 1h, 1i and 3b, whose value of ClogP was
more lipophilic and over 3.00, did not show any antifungal activities despite the presence of the Lewis
acidic bismuth center. Hence, taking into account the fact that the activity of 3a was lower than that of 1a,
it was unexpected that more hydrophilic 7–9 (ClogP = 0.29) showed higher activities than 3a.
Furthermore, Figure 2 revealed that application of the data on 2 and 7–9 to the plot of 1 improved the
linearity of the correlation (r = –0.86, n = 16). Although the reason for the considerable deviation of 3a
from this plot is not clear, it may be attributed to the acidic phenolic hydroxy substituents which ionize or
aggregate through the intermolecular hydrogen bonding, preventing 3a from passing through the cell
membrane of the yeast.

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HETEROCYCLES, Vol. 96, No. 6, 2018
25
20
15
10
5
1, 2, 7–9
3a
0
0
0.5
1
1.5
ClogP
2
2.5
3
3.5
Figure 2. Structure–activity relationship for halobismuthanes 1, 2, 3a and 7–9
DFT study: Recently, we have reported the antifungal activity of hypervalent organobismuth(III)
compounds derived from alkyl aryl ketones against S. cerevisiae.9 Bismuthane 14 showed the highest
activity comparable to 1a, but 15 bearing a bulky mesityl group was inactive (Scheme 4). Furthermore,
DFT calculations45 suggested that the generation of antifungal activity of the bismuthanes was well
understood by the nucleophilic addition of a biomolecule at the bismuth atom to give an intermediate ate
complex (Table 3).9 Although we have not identified the biomolecules to which these bismuthanes bind,
we expect that the Lewis acidic bismuth atom has a high affinity for thiol groups.1,46 There was a weak
but positive correlation between the antifungal activity and the association energy (enthalpy) in the ate
complex formation using methanethiolate anion as a model nucleophile.9 Thus, the reactions of 1a, 2 and
14 had high exothermic association energies while no minimum energy path connects the reactants and
the product in the reaction of 15 bearing a bulky mesityl group.
Scheme 4. Structures of iodobismuthanes 14 and 15
It should be noted that the association energy of 3a was almost the same as that of 1a. This indicates that
the hydroxy substituents little affect the ate complex formation of 3a. Despite this, the loss of the activity
in 3a may be attributed to the behavior of the phenolic hydroxy substituents mentioned above.

HETEROCYCLES, Vol. 96, No. 6, 2018
1045
Nu
+ Nu–
+ X–
Ar2Bi–Nu
Ar2Bi–X
Ar2Bi
X
Table 3. Association energy of halobismuthanes
Inhibition Association
Zone (mm) Energy (kcal/mol)
Compound
1a
2
3a
14
15
7
18
17
8
19
0
16
19
20
–17.22
–20.18
–17.15
–16.00
–
–20.87
–21.54
–21.95
8
9
We calculated the association energy of 7–9 by using methanethiolate anion as a model nucleophile
(Table 3 and Scheme 5). It is expected that the intramolecular bismuth–oxygen coordination is cleaved by
the ate complex formation to form a hypervalent S–Bi–I bond. Iodobismuthanes 7–9 had some of the
most exothermic association reactions. Interestingly, the association energy negatively increased in the
order 7 < 8 < 9, which is in good agreement with the order of the antifungal activity. Hence, this
association path is preferable to understand the mechanism of action of these iodobismuthanes.
Scheme 5. Plausible association pathway of iodobismuthanes 7–9 using methanethiolate anion
CONCLUSION
The bioisosteric replacement of the phenyl ring of the diphenyl sulfone scaffold by the pyridine ring
improved the antifungal activity of the hypervalent halobismuthanes. A clear structure–activity
relationship was observed in 1, 2 and 7–9 between the size of the inhibition zone and the value of ClogP.
Stabilizing the ate complex appears to be important. The present study provides insights that will aid the
design of antifungal hypervalent halobismuthanes by simply estimating the ClogP value and the
association energy. Further studies are now underway to find more active halobismuthanes.

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EXPERIMENTAL
All reactions were carried out under argon unless otherwise noted. THF and Et2O were distilled from
benzophenone ketyl before use. Melting points were determined on a YANAGIMOTO melting point
1
apparatus without correction. H and 13C NMR spectra were recorded in CDCl3 or DMSO-d6 on a
BRUKER AVANCE 400S spectrometer. Chemical shifts were referenced to residual solvent peak:
CHCl3 (7.26 ppm, 77.0 ppm) and DMSO (2.50 ppm, 40.45 ppm). IR spectra were obtained as KBr
pellets on a Nicolet FT-IR Impact 410 spectrophotometer. Elemental analyses were performed on a
MICRO CORDER JM10 apparatus (J-SCIENCE LAB. Co.). HRMS were recorded on a Bruker Daltonics
1
micrOTOF II (APCI) instrument. Charts of H and 13C NMR spectra of reported compounds are
summarized in Supporting Information.
Synthesis of 4 and 13: A mixture of bismuth(III) chloride (211 mg, 0.67 mmol) and
tris(4-methylphenyl)bismuthane (162 mg, 0.33 mmol) was stirred in Et2O (8 mL) at room temperature for
1 h. To a stirred solution of 2,2,6,6-tetramethylpiperidine (0.37 mL, 2.2 mmol) in THF (10 mL) was
added dropwise at –78 °C butyllithium (2.2 mmol). After 50 min a solution of 10 (219 mg, 1 mmol) in
THF (3 mL) was added at –40 °C and the mixture was stirred for 20 min at this temperature. To this
solution was added at –70 °C the suspension of dichloro(4-methylphenyl)bismuthane (ca. 1 mmol) thus
formed, and the resulting mixture was stirred for 2 h, during which time the temperature was raised to
ambient. The reaction mixture was poured into brine (50 mL) and extracted with EtOAc (50 mL × 3). The
combined extracts were concentrated to leave an oily residue, which was purified by chromatography
(silica gel) using hexane–EtOAc (3:1) as the eluent to afford 4 and 13 in 68% yield (352 mg, 0.68 mmol)
and 10% yield (35 mg, 0.048 mmol), respectively.
1
4-Aza-10-(4-methylphenyl)phenothiabismine 5,5-dioxide (4): colorless solid; mp 232–234 °C; H
NMR (400 MHz, CDCl3): δ 2.35 (3H, s), 7.19 (1H, dd, J = 4.8, 7.4 Hz), 7.26 (2H, d, J = 7.6 Hz), 7.41
(1H, dt, J = 1.2, 7.2 Hz), 7.45 (1H, dt, J = 1.2, 7.2 Hz), 7.63 (2H, d, J = 7.6 Hz), 7.87 (1H, dd, J = 1.2, 7.6
13
Hz), 8.21 (1H, dd, J = 1.6, 7.2 Hz), 8.43 (1H, dd, J = 1.2, 7.6 Hz), 8.63 (1H, dd, J = 1.6, 4.4 Hz); C
NMR (100 MHz, CDCl3): δ 21.6, 127.3, 128.3, 129.0, 132.0, 133.8, 137.5, 138.6, 138.9, 141.9, 146.1,
149.0, 151.3 (br), 157.6, 159.2 (br), 163.1 (br). IR (KBr): ν = 1310, 1290, 1160, 1130, 1100, 1080, 1050,
1010, 790, 760, 590 and 570 cm–1. Anal. Calcd for C18H14BiNO2S: C, 41.79; H, 2.73; N, 2.71. Found: C,
41.97; H, 3.03; N, 2.66.
(4-Methylphenyl)bis(2-phenylsulfonylpyridin-3-yl)bismuthane (13): colorless solid; mp 229–231 °C;
1H NMR (400 MHz, CDCl3): δ 2.36 (3H, s), 7.26 (2H, d, J = 7.6 Hz), 7.28 (2H, dd, J = 4.8, 7.4 Hz), 7.43
(4H, t, J = 7.6 Hz), 7.56 (2H, t, J = 7.2 Hz), 7.60 (2H, d, J = 7.6 Hz), 7.86 (4H, d, J = 7.2 Hz), 8.20 (2H,
13
dd, J = 1.6, 7.6 Hz), 8.74 (2H, dd, J = 1.6, 4.4 Hz); C NMR (100 MHz, CDCl3): δ 21.6, 128.9, 129.0
(×2), 132.3, 133.6, 138.0, 138.1, 139.2, 149.3, 149.7, 157.2 (br), 162.6, 168.5 (br). IR (KBr): ν = 1450,

HETEROCYCLES, Vol. 96, No. 6, 2018
1047
1300, 1160, 1120, 1080, 770, 750, 740, 710, 690, 590 and 570 cm–1. Anal. Calcd for C29H23BiN2O4S2: C,
47.29; H, 3.15; N, 3.80. Found: C, 46.90; H, 3.47; N, 3.79.
3-Aza-10-(4-methylphenyl)phenothiabismine 5,5-dioxide (5): A mixture of bismuth(III) chloride (211
mg, 0.67 mmol) and tris(4-methylphenyl)bismuthane (162 mg, 0.33 mmol) was stirred in Et2O (8 mL) at
room temperature for 1 h. To a stirred solution of 2,2,6,6-tetramethylpiperidine (0.37 mL, 2.2 mmol) in
THF (10 mL) was added dropwise at –78 °C butyllithium (2.2 mmol). After 20 min a solution of 11 (219
mg, 1 mmol) in THF (3 mL) was added at –55 °C, and the temperature was lowered to –70 °C
immediately. To this solution was added at this temperature the suspension of
dichloro(4-methylphenyl)bismuthane (ca. 1 mmol) thus formed, and the resulting mixture was stirred for
2 h, during which time the temperature was raised to ambient. The reaction mixture was poured into brine
(50 mL) and extracted with EtOAc (50 mL × 3). The combined extracts were concentrated to leave an
oily residue, which was purified by chromatography (silica gel) using hexane–EtOAc (3:1) as the eluent
1
to afford 5 in 40% yield (207 mg, 0.4 mmol). Colorless solid; mp 224–226 °C; H NMR (400 MHz,
CDCl3): δ 2.35 (3H, s), 7.27 (2H, d, J = 7.2 Hz), 7.39 (1H, dt, J = 1.2, 7.2 Hz), 7.44 (1H, dt, J = 1.2, 7.2
Hz), 7.63 (2H, d, J = 7.2 Hz), 7.80 (1H, d, J = 4.4 Hz), 7.89 (1H, dd, J = 1.2, 7.2 Hz), 8.42 (1H, dd, J =
13
1.6, 7.6 Hz), 8.44 (1H, d, J = 4.4 Hz), 9.41 (1H, s); C NMR (100 MHz, CDCl3): δ 21.6, 127.4, 128.6,
132.1, 132.3, 133.9, 137.7, 138.6, 138.7, 139.1, 141.2, 146.3, 152.5, 158.9 (br), 162.4 (br), 168.7 (br). IR
(KBr): ν = 1550, 1440, 1390, 1300, 1150, 1100, 1080, 1060, 1010, 780, 760, 730, 600, 570, 520 and 460
cm–1. Anal. Calcd for C18H14BiNO2S: C, 41.79; H, 2.73; N, 2.71. Found: C, 41.93; H, 3.09; N, 2.70.
2-Aza-10-(4-methylphenyl)phenothiabismine 5,5-dioxide (6): A mixture of bismuth(III) chloride (211
mg, 0.67 mmol) and tris(4-methylphenyl)bismuthane (162 mg, 0.33 mmol) was stirred in Et2O (8 mL) at
room temperature for 1 h. To a stirred solution of 2,2,6,6-tetramethylpiperidine (0.37 mL, 2.2 mmol) in
THF (10 mL) was added dropwise at –78 °C butyllithium (2.2 mmol). After 50 min a solution of 12 (219
mg, 1 mmol) in THF (3 mL) was added at –15 °C, and the mixture was stirred for 10 min at this
temperature. To this solution was added at –70 °C the suspension of dichloro(4-methylphenyl)bismuthane
(ca. 1 mmol) thus formed, and the resulting mixture was stirred for 2 h, during which time the
temperature was raised to ambient. The reaction mixture was poured into brine (50 mL) and extracted
with EtOAc (50 mL × 3). The combined extracts were concentrated to leave an oily residue, which was
purified by chromatography (silica gel) using hexane–EtOAc (3:1) as the eluent to afford 6 in 58% yield
(301 mg, 0.58 mmol). Colorless solid; mp 100–102 °C; 1H NMR (400 MHz, CDCl3): δ 2.34 (3H, s), 7.26
(2H, d, J = 7.6 Hz), 7.39 (1H, dt, J = 1.2, 7.2 Hz), 7.44 (1H, dt, J = 1.2, 7.2 Hz), 7.65 (2H, d, J = 7.6 Hz),
7.90 (1H, dd, J = 0.8, 7.6 Hz), 8.17 (1H, d, J = 5.2 Hz), 8.41 (1H, dd, J = 0.8, 7.6 Hz), 8.69 (1H, d, J = 4.4
13
Hz), 8.84 (1H, s); C NMR (100 MHz, CDCl3): δ 21.6, 120.3, 127.8, 128.5, 132.0, 134.0, 137.9, 138.5,
139.0, 140.3, 150.2 (×2), 150.6 (br), 157.4, 158.8 (br), 160.8 (br). IR (KBr): ν = 1540, 1490, 1450, 1390,

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HETEROCYCLES, Vol. 96, No. 6, 2018
1300, 1170, 1150, 1100, 1060, 1010, 790, 750, 730, 690, 590, 570 and 480 cm–1. Anal. Calcd for
C18H14BiNO2S: C, 41.79; H, 2.73; N, 2.71. Found: C, 41.81; H, 3.03; N, 2.67.
Synthesis of 7, 8 and 9: A typical example is exemplified by the synthesis of 7: To a suspension of 4
(104 mg, 0.2 mmol) in Et2O (5 mL) was added dropwise a solution of iodine (51 mg, 0.2 mmol) in the
same solvent (5 mL) at room temperature until 4 was completely consumed (checked by TLC). The
reaction mixture was concentrated to leave solids, which were crystallized from MeOH to give 7.
4-Aza-10-iodophenothiabismine 5,5-dioxide (7): pale yellow solid; yield 95%; mp > 307 °C; 1H NMR
(400 MHz, CDCl3): δ 7.45 (1H, dd, J = 4.8, 7.6 Hz), 7.54 (1H, t, J = 7.6 Hz), 7.69 (1H, t, J = 7.6 Hz),
8.36 (1H, d, J = 7.2 Hz), 8.74 (1H, d, J = 4.8 Hz), 9.21 (1H, d, J = 7.2 Hz), 9.55 (1H, d, J = 7.6 Hz); 13C
NMR (100 MHz, DMSO-d6): δ 128.9, 129.1, 130.3, 136.9, 141.9 (×2), 149.4, 150.3, 158.3, 170.8, 179.6.
IR (KBr): ν = 1550, 1300, 1150, 1130, 1100, 1070, 1010, 750, 740, 640, 590, 570, 510 and 460 cm–1.
HRMS (APCI): m/z [M+H]+ calcd for C11H8BiINO2S: 553.9119; found: 553.9110.
3-Aza-10-iodophenothiabismine 5,5-dioxide (8): pale yellow solid; yield 90%; mp 305–307 °C
(decomp.); 1H NMR (400 MHz, CDCl3): δ 7.55 (1H, t, J = 7.6 Hz), 7.67 (1H, t, J = 7.2 Hz), 8.38 (1H, d,
J = 7.6 Hz), 8.82 (1H, d, J = 4.4 Hz), 9.13 (1H, d, J = 4.8 Hz), 9.22 (1H, d, J = 7.2 Hz), 9.44 (1H, s); 13C
NMR (100 MHz, DMSO-d6): δ 127.6, 129.4, 136.2, 137.0, 139.2, 141.7, 142.1, 145.7, 155.3, 180.2 (br),
188.4 (br). IR (KBr): ν = 1560, 1290, 1150, 1130, 1100, 1080 and 1020 cm–1. HRMS (APCI): m/z
[M+H]+ calcd for C11H8BiINO2S: 553.9119; found: 553.9123.
2-Aza-10-iodophenothiabismine 5,5-dioxide (9): pale yellow solid; yield 90%; mp 232–234 °C
(decomp.); 1H NMR (400 MHz, CDCl3): δ 7.53 (1H, t, J = 7.2 Hz), 7.67 (1H, t, J = 7.2 Hz), 8.08 (1H, d,
J = 4.8 Hz), 8.35 (1H, d, J = 7.6 Hz), 8.84 (1H, d, J = 4.8 Hz), 9.25 (1H, d, J = 7.2 Hz), 9.89 (1H, s); 13C
NMR (100 MHz, DMSO-d6): δ 120.3, 128.0, 129.4, 137.1, 140.8, 142.3, 150.6, 150.7, 161.8, 169.7,
179.6. IR (KBr): ν = 1550, 1390, 1320, 1290, 1270, 1170, 1150, 1120, 1090, 840, 750, 590, 570, 520
and 470 cm–1. Anal. Calcd for C11H7BiINO2S: C, 23.89; H, 1.28; N, 2.53. Found: C, 23.89; H, 1.50; N,
2.47.
Qualitative antifungal assay: The yeast S. cerevisiae W303-1A (MATa ade2-1 can1-100 ura3-1
leu2-3,112 trp1-1 his3-11,15) was used for the qualitative antifungal assay. Yeast
extract-peptone-dextrose (YPD) plates contained 1% yeast extract, 2% peptone, 2% glucose and 1.2%
agar. The cells were inoculated at a concentration of 1.3×104 cells/mL in YPD agar medium at 48 °C and
YPD plates were immediately made in Petri dishes. Each compound was dissolved in dimethyl sulfoxide
(DMSO) at a concentration of 30 mM and 5 µL of each solution was directly spotted on the surface of the
plate. The plates were incubated for 24 h at 30 °C and antifungal activity was indicated by the presence of
clear inhibition zones around the spot. The control experiment showed that DMSO does not inhibit fungal

HETEROCYCLES, Vol. 96, No. 6, 2018
1049
growth at all. In order to know the error on the inhibition zone, we carried out the antifungal assay of
compounds many times and confirmed that the error was within ±1 mm.
Lipophilicity: The calculated logarithms of water-octanol partition coefficients (ClogP values) were
obtained from the ClogP tool in ChemDraw Ultra 11.0 (CambridgeSoft, Cambridge, MA, USA).
DFT calculation of the association energies: The geometries of the bismuth compounds and the
corresponding MeS–-adduct anions in Table 3 were fully optimized in water through density functional
theory (DFT) calculations within the polarizable continuum model (PCM) using the Gaussian 09 program
package.45 The hybrid B3LYP exchange-correlation functional and 6-31+G*/lanl2dz mixed basis set
(lanl2dz effective core potential for bismuth and iodine and 6-31+G* basis set for the remaining atoms)
were employed. All d functions in 6-31+G* are pure 5 D basis functions, which is the default form in the
Gaussian 09 GenECP calculations. The exothermicity for the nucleophilic addition of MeS– was
calculated from the energies in water of each substrate, in which only the most stable conformer with the
lowest energy was considered.
X-Ray crystallographic study: A colorless crystal of 9 was mounted on a glass fiber. All measurements
were made with a Rigaku Mercury 70 diffractometer using graphite monochromated Mo-Kα radiation.
The data were collected at a temperature of –119 ± 1 °C to a maximum 2θ value of 55.0°. The structure
was solved by direct methods47 and expanded using Fourier techniques. The non-hydrogen atoms were
refined anisotropically. All calculations were performed using the CrystalStructure48 crystallographic
software package except for refinement, which was performed using SHELXL Version 2016/6.49 Crystal
data, data collection summary and refinement parameters of 9 are given in Supporting Information.
Deposition number CCDC-1836491 for compound 9. Free copies of the data can be obtained via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, UK; Fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
ACKNOWLEDGEMENTS
We are grateful to the Center of Instrumental Analysis, Yamaguchi University and the Tokiwa
Instrumentation Analysis Center, Yamaguchi University.
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