Activity of antifungal organobismuth(III) compounds derived from alkyl aryl Ketones against S. cerevisiae: Comparison with a heterocyclic bismuth scaffold consisting of a diphenyl sulfone

Article abstract of DOI:10.3390/molecules190811077

A series of hypervalent organobismuth(III) compounds derived from alkyl aryl ketones [XBi(5-R′C₆H₃-2-COR)(Ar)] was synthesized to investigate the effect of the compounds' structural features on their antifungal activity against the yeast Saccharomyces cerevisiae. In contrast to bismuth heterocycles [XBi(5-RC₆H₃-2-SO ₂C₆H₄-1′-)] derived from diphenyl sulfones, a systematic quantitative structure-activity relationship study was possible. The activity depended on the Ar group and increased for heavier X atoms, whereas lengthening the alkyl chain (R) or introducing a substituent (R′) reduced the activity. IBi(C₆H₄-2-COCH ₃)(4-FC₆H₄) was the most active. Its activity was superior to that of the related acyclic analogues ClBi[C₆H ₄-2-CH₂N(CH₃)₂](Ar) and ClBi(C ₆H₄-2-SO₂ tert-Bu)(Ar) and also comparable to that of heterocyclic ClBi(C₆H₄-2-SO₂C ₆H₄-1′-), which was the most active compound in our previous studies. Density function theory calculations suggested that hypervalent bismuthanes undergo nucleophilic addition with a biomolecule at the bismuth atom to give an intermediate ate complex. For higher antifungal activity, adjusting the lipophilicity-hydrophilicity balance, modeling the three-dimensional molecular structure around the bismuth atom, and stabilizing the ate complex appear to be more important than tuning the Lewis acidity at the bismuth atom.

Full text of DOI:10.3390/molecules190811077

Molecules 2014, 19, 11077-11095; doi:10.3390/molecules190811077
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Activity of Antifungal Organobismuth(III) Compounds Derived
from Alkyl Aryl Ketones against S. cerevisiae: Comparison with
a Heterocyclic Bismuth Scaffold Consisting of a Diphenyl Sulfone
Toshihiro Murafuji 1,*, Mai Tomura 1, Katsuya Ishiguro 2 and Isamu Miyakawa 2
1
Graduate School of Medicine, Yamaguchi University, Yamaguchi 753-8512, Japan
2
Graduate School of Science and Engineering, Yamaguchi University, Yamaguchi 753-8512, Japan
* Author to whom correspondence should be addressed; E-Mail: murafuji@yamaguchi-u.ac.jp;
Tel.: +81-83-933-5738; Fax: +81-83-933-5738.
Received: 27 May 2014; in revised form: 19 July 2014 / Accepted: 21 July 2014 /
Published: 29 July 2014
Abstract: A series of hypervalent organobismuth(III) compounds derived from alkyl aryl
ketones [XBi(5-R'C6H3-2-COR)(Ar)] was synthesized to investigate the effect of the
compounds’ structural features on their antifungal activity against the yeast Saccharomyces
cerevisiae. In contrast to bismuth heterocycles [XBi(5-RC6H3-2-SO2C6H4-1'-)] derived
from diphenyl sulfones, a systematic quantitative structure-activity relationship study was
possible. The activity depended on the Ar group and increased for heavier X atoms,
whereas lengthening the alkyl chain (R) or introducing a substituent (R') reduced the
activity. IBi(C6H4-2-COCH3)(4-FC6H4) was the most active. Its activity was superior to
that of the related acyclic analogues ClBi[C6H4-2-CH2N(CH3)2](Ar) and ClBi(C6H4-2-SO2
tert-Bu)(Ar) and also comparable to that of heterocyclic ClBi(C6H4-2-SO2C6H4-1'-),
which was the most active compound in our previous studies. Density function theory
calculations suggested that hypervalent bismuthanes undergo nucleophilic addition with a
biomolecule at the bismuth atom to give an intermediate ate complex. For higher antifungal
activity, adjusting the lipophilicity-hydrophilicity balance, modeling the three-dimensional
molecular structure around the bismuth atom, and stabilizing the ate complex appear to be
more important than tuning the Lewis acidity at the bismuth atom.
Keywords: bismuth; Lewis acidity; hypervalent; S. cerevisiae; antifungal activity; acetophenone

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1. Introduction
Biologically active bismuth compounds are the subject of considerable interest, although there have
been only a few biological studies of organobismuth compounds [1–6]. This is in contrast to their
growing use in synthetic reactions [7–9]. We recently reported the antifungal activity of hypervalent
organobismuth(III) and (V) compounds against the yeast Saccharomyces cerevisiae [10–12].
The Lewis acidity at the bismuth center was essential for the activity. Compounds A–D are
hypervalent organobismuth(III) derivatives, which are generally expressed by a “10-Bi-4” notation
based on the number of total electrons in the outermost shell and bonds to the relevant heteroatom
center [13,14] (Figure 1). Compounds A and B showed moderate activity but C1 was much more
active [10] (Table 1). The higher activity of C1 can be attributed to its structural characteristics as well
as the biopharmaceutical properties. Its lower ClogP value (1.18) indicates lower lipophilicity, the lack
of bulky alkyl substituents on the sulfonyl group reduces steric crowding around the tetracoordinate
bismuth atom, and weaker intramolecular coordination of the sulfonyl substituent arises from the
longer intramolecular Bi–O atomic distance [2.775(6) Å] [10] because of the rigid heterocyclic
structure and the highly coordinated geometry of the bismuth atom.
Figure 1. Molecular structure of hypervalent organobismuth compounds.
Table 1. Antifungal assay for bismuthanes.
Compound Inhibition Zone (mm) ClogP Compound Inhibition Zone (mm) ClogP
A1
A2
B1
B2
C1
C2
D1
D2
13
12
8
12
18
8
3.52
3.02
3.28
2.78
1.18
0.81
3.49
4.66
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
9a
9b
9c
8
2.54
3.12
2.63
2.77
3.34
4.12
2.54
3.12
2.63
2.77
3.34
4.12
3.62
4.55
3.34
4.18
4.71
3.96
12
16
17
15
0
17
12
9
15
17
19
14
0
10
7
10
9
4b
4c
4d
4e
5a
5b
5c
5d
5e
5f
0
0
0
0
8
13
15
16
14
0
5.81
4.82
5.10
6.24
2.54
3.12
2.63
2.77
3.34
4.12
11a
11b
11c
Nystatin
8
10
30

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In particular, the antifungal activity of monosubstituted C (R2 = H) decreases as ClogP increases,
which in turn depends on substituent R1 [11]. On the basis of this relationship, we synthesized C2,
which has hydrophilic substituents, but its activity was less than that of parent C1 [11]. Yet, compared
with C1, bismuth carboxylates D showed moderate to high activity despite their much higher
lipophilicity. To explain this, we proposed that in the yeast cell the bismuth-carboxylate or bismuth-
halogen bonds are cleaved into a cationic bismuth scaffold and a carboxylate or halide anion, and that
the bismuth scaffold plays an important role in the inhibition activity [12]. Stable cationic
organobismuth complexes have been isolated and characterized [15,16]. These findings indicate that
antifungal activity is not just affected by the hydrophilicity or lipophilicity.
To design bismuthanes that are more active than C1, it is important to understand how their
structural features affect their antifungal activity. Toward this end, we studied a series of
halobismuthanes (5–7, 9 and 11) derived from alkyl aryl ketone (Schemes 1–3). Unlike the diphenyl
sulfone structure of the heterocyclic bismuth scaffold C, the structures in this series could be
systematically modified by changing the alkyl and aryl groups of the ketone scaffold as well as the aryl
and halo groups attached to the bismuth atom. Furthermore, the various biological activities of
acetophenone derivatives were attractive from the viewpoint of bioavailability [17–19]. Through this
study, we aimed to better elucidate the effect of structural characteristics on the antifungal activity and
also to design a halobismuthane (7d) that was comparable to C1 in activity.
Scheme 1. Synthesis of silyl enol ethers.
Scheme 2. Synthesis of bismuthanes 4 and their transformation.

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Scheme 3. Synthesis of bismuthanes 8 and 10 and their transformation.
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2. Results and Discussion
2.1. Synthesis
Silyl enol ethers 1–3 were prepared from the parent ketones [20,21] and used as starting materials
(Scheme 1). We have previously reported the synthesis of 4a–c and 4e, their corresponding bromides 6,
and 5b and 7b, but the yield of parent compound 4 is very low [22] because the lithiated silyl enol
ethers [23] and chlorobismuthanes are reactive. Hence, 4 and its homologues 8 and 10 were
synthesized by modifying our previous method (Schemes 2 and 3). The reactive lithiated silyl enol
ethers and chlorobismuthanes (Ar2BiCl) were replaced by the less reactive magnesiated derivatives
and iodobismuthanes (Ar2BiI), respectively. This made the synthesis of triarylbismuthanes 4, 8, and 10
more reliable. The triarylbismuthanes were converted into the corresponding halobismuthanes 5–7, 9,
and 11 by treatment with boron trifluoride diethyl ether complex and subsequent halogenation.
Because 4a, 4f, and 10 decomposed during purification by column chromatography, they were isolated
as the corresponding halobismuthanes. Compound 10c was isolated as bromobismuthane 11c because
the corresponding chlorobismuthane was unstable. In the 1H-NMR spectra of the halobismuthanes, the
ortho proton adjacent to the bismuth atom in the aryl ketone scaffold underwent anisotropic
deshielding because of its close proximity to the electronegative chlorine, bromine or iodine atom
attached to the bismuth center [24]. The ortho proton signal for 5b, 6b, and 7b appeared at δ 9.06, 9.21
and 9.42 ppm, respectively. Furthermore, compared with parent bismuthane 4b, the carbonyl carbon
13
signal in the C-NMR spectra of 5b, 6b, and 7b was shifted downfield by 6–8 ppm. The carbonyl
stretching vibration in the IR spectrum of the halobismuthanes also showed a shift to a lower
frequency by 40 cm−1. These observations indicate that the carbonyl oxygen atom was coordinated to
the bismuth atom to form a hypervalent C=O•••Bi–Cl, C=O•••Bi–Br, or C=O•••Bi–I bonds.
Hypervalent bond formation in 6b has been confirmed by X-ray crystallography [22].
Halobismuthanes 5–7, 9, and 11 were stable in water and DMSO, indicating that the hypervalent bond
formation suppresses hydrolysis and redistribution reactions of these compounds.

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2.2. Growth Inhibition Tests against S. cerevisiae
Initially, we tested the inhibition activity of 4–7 (Experimental Subsection 3.6, Table 1, and Figure 2).
Triarylbismuthanes 4b–e were inactive, but halobismuthanes 5–7 showed moderate to high antifungal
activity. This is consistent with our previous finding that the Lewis acidic bismuth center is the active
site [10–12]. Iodobismuthanes 7 showed higher activity than bromobismuthanes 6, which were slightly
more active than chlorobismuthanes 5. This suggests that the activity increases with decreasing the
electronegativity of the halo substituent. It should be noted that halobismuthanes 5d, 6d, and 7d
bearing a p-fluorophenyl group showed the highest activity among each compound’s halogen
homologues a–f. Although 5a, 6a, and 7a bearing a p-methoxyphenyl group were the most hydrophilic
among each compound’s homologues, they were not very active because their solubility was reduced
by the aryl group [25]. Halobismuthanes 5f, 6f, and 7f bearing a mesityl group were inactive. Next, we
determined the inhibition activity of 9a–c, which were prepared from p-substituted acetophenones. The
activity of 9a–c was reduced by the p-substituent. This trend is similar to that observed in the
quantitative structure-activity relationship study of C. In view of the higher activity of
halobismuthanes 5d, 6d, and 7d, an attempt to synthesize 9 bearing a p-fluoro substituent in the
acetophenone scaffold failed: It was difficult to control the lithiation of the corresponding silyl enol
ether because the electronegativity of the fluoro substituent increased the reactivity of the ether toward
the lithiation. We replaced the methyl substituent of the acetyl group in 5b with various alkyl
substituents to obtain 11a–c, but they were less active. Halobismuthane 7d showed the highest activity
of the compounds in this study, and its activity was also comparable to that of C1. Although the
activity of 7d was not as high as the standard antifungal drug, nystatin, this finding demonstrates the
high antifungal activity of organobismuth compounds. A certain organobismuth compound has been
reported to exhibit selective cytotoxicity to vascular endothelial cells, which may be applicable in
antivascular cancer therapy [26]. However, it remains to be determined whether 7d and its related
compounds exhibit specific cytotoxicity against fungi.
Figure 2. Plot of the antifungal assay for bismuthanes 5–7 and 9.
Clogp

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2.3. Structure-Activity Relationship
Based on this study, the structure-activity relationship of the hypervalent bismuthanes may be
summarized as follows. Firstly, steric crowding around the tetracoordinate bismuth atom substantially
lowers antifungal activity. The lack of activity of 5f, 6f, and 7f was attributed to the bulky mesityl
group, which possibly blocks the interaction of the bismuth atom with the biomolecules in the yeast.
The long chain or branched RCO group in 11a–c may also play a similar role, as suggested by A and B
bearing Me2N and tert-BuSO2 groups, respectively. Secondly, the hydrophilicity of the hypervalent
bismuthanes is not always proportional to their antifungal activity, as was observed in 5a, 6a and 7a,
and C2. In particular, 7d is less hydrophilic (ClogP = 2.77) than C1 (ClogP = 1.18) but comparably
more active. This suggests that the relationship in homologous series C between activity and ClogP
does not apply to 7d, which contains acetophenone, and is completely different from diphenyl sulfone
in terms of structure and properties. Thirdly, the heterocyclic structure in C1 is not essential for high
antifungal activity. Fourthly, introducing a fluoro substituent at an appropriate position in the
hypervalent bismuthanes enhances the antifungal activity. The enhancement of biological activity by
fluoro substituents is well known in drugs and pesticides [27–29]. Fifthly, the Lewis acidity at the
bismuth atom, although essential, does not correspond directly to the antifungal activity. Thus, 5a, 5f,
6b, and 7d showed a wide variation in activity depending on the aryl and halo groups (Table 1),
although the Lewis acidity of the bismuth atoms of these compounds were similar as assessed by the
13
carbonyl carbon signals (δ ppm) and the carbonyl stretching bands (ν cm−1) in the C-NMR and IR
spectra, respectively (5a, 209.2, 1620; 5f, 208.1, 1630; 6b, 208.7, 1625; and 7d, 207.7, 1630).
Therefore, we compared the Lewis acidity at the tetracoordinate bismuth atom between different
scaffolds by using the intramolecular Bi–O and Bi–N distances and examined their relationship to the
antifungal activity. The length of the metal-ligand bond has been used to quantify the Lewis acidity at
the metal center [30,31]. We have previously determined the Bi–O or Bi–N intramolecular distance in
6b [22], A1 [32], B1 [24], C1 [10], C2 [11], and D2 [12] by X-ray crystallography. We expected that
the metal-ligand interactions would decrease as the intramolecular distance is shortened because the
metal-ligand interactions would reduce the Lewis acidity at the metal center [33]. Hence, the Lewis
acidity in these compounds should be in the order C1 [2.775(6) Å] > D2 [2.754(2) Å] > C2 [2.634(7) Å]
> B1 [2.592(5) Å] > A1 [2.525(6) Å] > 6b [2.519(7) Å]. However, the antifungal activity decreased in
the order C1 > A1 > D2, 6b > B1, C2, which did not correspond to the order of the intramolecular
distance. Although hypervalent bond formation is known to enhance the Lewis acidity at the metal
center [34–38], the enhancement of the Lewis acidity at the bismuth atom in these bismuthanes, even if
it does occur, appears to be very slight because only one electron-accepting Bi–X bond is present.
2.4. Plausible Mechanism of Action for Hypervalent Bismuthanes
We have proposed that C and D undergo cleavage of the Bi–Cl or Bi–O bond in the yeast cell to
form a cationic bismuth scaffold, which plays an important role in the inhibition activity [12].
A plausible pathway for this reaction is shown as Path 1 in Scheme 4. Although we have not identified
the biomolecules to which these bismuthanes bind, we expect that the Lewis acidic bismuth atom
should have a high affinity for thiol groups [39]. Finally, we examined how the dissociation energy of

Molecules 2014, 19
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the bismuth-halogen or bismuth-oxygen bond in Path 1 affects the antifungal activity. Using density
functional theory [40], we calculated the dissociation energy (enthalpies) of these bonds in A–D, 5–7,
and 9 (Table 2, Path 1).
Scheme 4. Plausible reaction pathway of the bismuthane.
Table 2. Dissociation and association energy.
Inhibition
Path 1
(kcal/mol)
12.82
13.12
19.33
19.66
25.22
24.75
36.93
35.49
16.93
17.37
17.75
18.07
18.36
18.15
Path 2
(kcal/mol)
–8.18
Inhibition
Path 1
(kcal/mol)
17.93
18.38
18.73
19.06
19.37
18.15
15.81
16.22
16.59
16.89
17.14
18.15
16.83
16.54
Path 2
(kcal/mol)
–12.29
–12.33
–12.65
–13.29
–13.38
-
Ar2BiX
Ar2BiX
Zone (mm)
Zone (mm)
A1
A2
B1
B2
C1
C2
D1
D2
5a
13
12
8
6a
6b
6c
6d
6e
6f
8
–8.46
12
16
17
15
0
–13.51
–13.85
–17.22
–17.15
–10.09
–10.97
–12.08
–12.00
–12.33
–13.02
–13.14
-
12
18
8
17
12
8
7a
7b
7c
7d
7e
7f
9
–15.18
–15.13
–15.43
–16.00
–16.26
-
15
17
19
14
0
5b
5c
13
15
16
14
0
5d
5e
9a
9c
10
10
–11.71
–11.32
5f
Contrary to our expectation, very active C1 and D1 had highly endothermic dissociation energy
(25.22 and 36.93 kcal/mol, respectively), indicating that generating the bismuth cation requires high
energy. Furthermore, the dissociation energy of moderately active A1 was quite low owing to the
stabilization of the bismuth cation by a strong coordination with the dimethylamino group. However,
the most active compound, 7d, was not as endothermic (16.89 kcal/mol), which is consistent with our
proposed mechanism. Comparing the dissociation energy of 7a, 7c, and 7d, and of 5a, 5c, and 5d,
revealed that the p-fluorophenyl group in 5d and 7d destabilizes the bismuth cation. No correlation
was observed between dissociation energy and antifungal activity (Figure 3). Hence, we concluded that
the bismuth cations are not generated from hypervalent bismuthanes in yeast cells. Alternatively, we
propose that an intermediate ate complex [Ar2BiXNu]− is formed by the bismuthanes undergoing
addition at the bismuth atom with biomolecules such as hydrolases (Scheme 4, Path 2). After the
release of X−, the resulting Ar2BiNu species is delivered to the organelle responsible for the antifungal
activity via a further biological process. We calculated the association energy (enthalpies) by using
methanethiolate anion as a model nucleophile (Nu−) (Table 2, Path 2). Among all the bismuthanes, C1

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and 7d had some of the most exothermic association reaction, indicating that this path is preferable.
Unlike Path 1, a weak but positive correlation between association energy and antifungal activity was
observed (Figure 4). It should be stressed that in 5f, 6f, and 7f, which contained a mesityl group, no
minimum energy path connects the reactants and the product. This is in good agreement with their lack
of activity. The activity of 7 was higher than that of 5 and 6, although the activity of C1 and its bromo
and iodo analogues did not depend on the halo group [10]. This may be because the intramolecular Bi–O
interaction of the carbonyl group is stronger than that of the sulfonyl group, which slightly enhances
the Lewis acidity [34–38] at the bismuth atom and promotes the nucleophilic addition of Nu−. Such
enhancement of the Lewis acidity has been observed in triorganotin halides bearing an intramolecular
coordination with a carbonyl group [41].
Figure 3. Plot of the dissociation energy against the antifungal activity.
Figure 4. Plot of the association energy against the antifungal activity.

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3. Experimental Section
3.1. General Information
All reactions were carried out under argon unless otherwise noted. Hexane, diethyl ether and
dichloromethane were distilled from calcium hydride before use. Melting points were determined on a
1
13
Yanagimoto melting point apparatus without correction. H- and C-NMR spectra were recorded in
CDCl3 or DMSO-d6 on a Bruker Avance 400S spectrometer with TMS as an internal standard. 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., Kyoto, Japan).
3.2. Synthesis of 4, 8 and 10
A typical example is exemplified by the synthesis of 4b: To a stirred solution of TMEDA (1.36 mL,
9 mmol) in hexane (5 mL) was added dropwise at ice bath temperature n-butyllithium (9 mmol) in
hexane followed by acetophenone trimethylsilyl enol ether 1 (576 mg, 3 mmol), and the mixture was
stirred for 24 h at room temperature. In a separate flask, a mixture of bismuth(III) chloride (315.5 mg,
1 mmol) and tris(4-methylphenyl)bismuthane (964 mg, 2 mmol) was stirred in ether (10 mL) at room
temperature for 1 h. To the suspension of chlorobis(4-methylphenyl)bismuthane (ca. 3 mmol) thus
formed was added sodium iodide (450 mg, 3 mmol) and a few drops of 15-crown-5 ether and the
resulting yellowish mixture was stirred for 3 h at room temperature. To a suspension of the lithium
compound previously prepared was added at room temperature magnesium dibromide diethyl etherate
(775 mg, 3 mmol) followed by, at −30 °C, a suspension of iodobis(4-methylphenyl)bismuthane
(ca. 9 mmol), and the resulting mixture was stirred for 1 h, during which time the temperature was
raised to ambient temperature. The reaction mixture was poured into brine (50 mL) and extracted with
ethyl acetate (50 mL × 3). The combined extracts were concentrated to leave an oily residue, which
was purified by chromatography (silica gel) using hexane-ethyl acetate (5:1) as the eluent to afford 4b
in 30% yield (459 mg, 0.9 mmol). Because 4a, 4f and 10 underwent decomposition when purified by
chromatography on silica gel, these compounds were converted into the corresponding
halobismuthanes 5a, 5f and 11, respectively, without isolation.
(2-Acetylphenyl)bis(4-methylphenyl)bismuthane (4b). Yield: 30%; mp 114–116 °C; 1H-NMR (400 MHz,
CDCl3): δ 2.30 (6H, s), 2.62 (3H, s), 7.17 (4H, d, J = 7.8 Hz), 7.41 (1H, dt, J = 1.4, 7.6 Hz), 7.47 (1H, dt,
J = 1.4, 7.6 Hz), 7.57 (4H, d, J = 7.8 Hz), 7.93 (1H, dd, J = 1.4, 7.6 Hz), 8.14 (1H, dd, J = 1.4, 7.6 Hz);
13C-NMR (100 MHz, CDCl3): δ 21.5, 27.2, 127.5, 131.2, 132.2, 135.0, 136.8, 137.7, 140.3, 141.5,
158.5, 159.8, 201.1. IR (KBr): ν = 1665, 1260, 790, 765, 600 and 480 cm−1. Anal. Calc. for
C22H21BiO: C, 51.77; H, 4.15. Found: C, 51.70; H, 4.00%.
1
(2-Acetylphenyl)diphenylbismuthane (4c). Yield: 16%; mp 96–98 °C; H-NMR (400 MHz, CDCl3): δ
2.63 (3H, s), 7.29 (2H, t, J = 7.6 Hz), 7.36 (4H, t, J = 7.6 Hz), 7.42 (1H, dt, J = 1.2, 7.6 Hz), 7.49 (1H,
dt, J = 1.4, 7.6 Hz), 7.69 (4H, d, J = 7.6 Hz), 7.91 (1H, dd, J = 1.2, 7.6 Hz), 8.16 (1H, dd, J = 1.2,
13
7.6 Hz). C-NMR (100 MHz, CDCl3): δ 27.2, 127.3, 127.6, 130.3, 132.3, 135.2, 137.7, 140.4, 141.5,

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201.2; ipso carbon signals were too weak to be observed. IR (KBr): ν = 1660, 1260, 1090, 1000, 800,
760, 725, 700 and 600 cm−1. Anal. Calc. for C20H17BiO: C, 49.80; H, 3.55. Found: C, 49.60; H, 3.50%.
1
(2-Acetylphenyl)bis(4-fluorophenyl)bismuthane (4d). Yield: 11%; mp 147–149 °C; H-NMR (400 MHz,
CDCl3): δ 2.64 (3H, s), 7.00–7.05 (4H, m), 7.46 (1H, dt, J = 1.6, 7.6 Hz), 7.52 (1H, dt, J = 1.6, 7.6 Hz),
7.58–7.62 (4H, m), 7.84 (1H, dd, J = 1.2, 7.2 Hz), 8.18 (1H, dd, J = 1.2, 7.6 Hz). 13C-NMR (100 MHz,
CDCl3): δ 27.2, 117.7 (d, JCF = 19 Hz), 127.9, 132.5, 135.3, 139.3 (d, JCF = 6.0 Hz), 140.1, 141.3,
156.8 (br), 160.3 (br), 162.5 (d, JCF = 245 Hz), 201.4. IR (KBr): ν = 1660, 1570, 1480, 1210, 1160, 820,
770, 600 and 500 cm−1. Anal. Calc. for C20H15BiF2O: C, 46.35; H, 2.92. Found: C, 46.37; H, 2.88%.
(2-Acetylphenyl)bis(4-chlorophenyl)bismuthane (4e). Yield: 23%; mp 129–131 °C; 1H-NMR (400 MHz,
CDCl3): δ 2.64 (3H, s), 7.30 (4H, d, J = 8.0 Hz), 7.46 (1H, dt, J = 1.2, 7.6 Hz), 7.52 (1H, dt, J = 1.2,
7.5 Hz), 7.57 (4H, d, J = 8.0 Hz), 7.84 (1H, dd, J = 1.2, 7.2 Hz), 8.19 (1H, dd, J = 1.2, 7.6 Hz).
13C-NMR (100 MHz, CDCl3): δ 27.2, 128.0, 130.6, 132.6, 133.7, 135.5, 139.0, 140.2, 141.3, 201.4;
ipso carbon signals were too weak to be observed. IR (KBr): ν = 1660, 1260, 1090, 1000, 800, 765 and
710 cm−1. Anal. Calc. for C20H15BiCl2O: C, 43.58; H, 2.74. Found: C, 43.40; H, 2.70%.
(2-Acetyl-4-methylphenyl)bis(4-methylphenyl)bismuthane (8a). Yield: 18%; mp 148–150 °C; 1H-NMR
(400 MHz, CDCl3): δ 2.22 (3H, s), 2.30 (6H, s), 2.59 (3H, s), 7.16 (4H, d, J = 7.6 Hz), 7.26 (1H, d,
13
J = 7.6 Hz), 7.57 (4H, d, J = 7.6 Hz), 7.74 (1H, d, J = 1.3 Hz), 8.03 (1H, d, J = 7.6 Hz). C-NMR
(100 MHz, CDCl3): δ 21.5, 21.6, 27.1, 128.2, 131.1, 132.2, 136.7, 137.7, 139.2, 141.03, 145.54,
158.48, 159.96, 200.6. IR (KBr): ν = 1660, 1580, 1290, 830, 790 and 480 cm−1. Anal. Calc. for
C23H23BiO: C, 52.68; H, 4.42. Found: C, 52.32; H, 4.38%.
(2-Acetyl-4-isopropylphenyl)bis(4-methylphenyl)bismuthane (8b). Yield: 22%; mp 145–147 °C;
1H-NMR (400 MHz, CDCl3): δ 1.07 (6H, d, J = 7.2 Hz), 2.30 (6H, s), 2.60 (3H, s), 2.77 (1H, sep,
J = 7.2 Hz), 7.16 (4H, d, J = 7.6 Hz), 7.30 (1H, dd, J = 1.6, 8.0 Hz), 7.58 (4H, d, J = 7.6 Hz), 7.78 (1H,
d, J = 1.6 Hz), 8.06 (1H, d, J = 7.6 Hz). 13C-NMR (100 MHz, CDCl3): δ 21.5, 23.4, 27.1, 34.0, 125.5,
131.0, 132.3, 136.7, 137.7, 139.5, 155.7, 158.6, 160.0, 200.5. IR (KBr): ν = 1650, 1580, 1350, 1190, 1050,
830, 790, 590 and 480 cm−1. Anal. Calc. for C25H27BiO: C, 54.35; H, 4.93. Found: C, 54.28; H, 4.84%.
(2-Acetyl-4-methoxyphenyl)bis(4-methylphenyl)bismuthane (8c). Yield: 8%; mp 135–137 °C; 1H-NMR
(400 MHz, CDCl3): δ 2.27 (3H, s), 2.32 (6H, s), 3.84 (3H, s), 7.02 (1H, d, J = 8.8 Hz), 7.20 (4H, d,
J = 7.6 Hz), 7.58 (4H, d, J = 7.6 Hz), 7.99 (1H, dd, J = 2.0, 8.4 Hz), 8.15 (1H, d, J = 2.0 Hz).
13C-NMR (100 MHz, CDCl3): δ 21.4, 26.2, 55.8, 109.4, 130.6, 131.2, 133.1, 137.3, 137.5, 139.7,
143.0, 151.1, 165.6, 197.2. IR (KBr): ν = 1670, 1580, 1240, 1010, 800, 580 and 480 cm−1. Anal. Calc.
for C23H23BiO2: C, 51.12; H, 4.29. Found: C, 50.88; H, 4.28%.
3.3. Synthesis of 5a, 5f and 11
A typical example is exemplified by the synthesis of 5a: An oily residue containing 4a obtained by
the concentration of the extracted organic layer was dissolved in dichloromethane (5 mL) and boron
trifluoride etherate (3 mmol) was added to the solution at 0 °C until 4a was completely consumed
(checked by TLC). The mixture was diluted by the addition of brine (5 mL) and the organic layer was

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extracted with ethyl acetate (20 mL × 3). The combined extracts were concentrated to leave an oily
residue, which was crystallized from MeOH to give 5a in 18% yield.
1
(2-Acetylphenyl)chloro(4-methoxylphenyl)bismuthane (5a). Yield: 18%; mp 156–158 °C; H-NMR
(400 MHz, CDCl3): δ 2.69 (3H, s), 3.73 (3H, s), 7.01 (2H, d, J = 8.8 Hz), 7.63 (1H, dt, J = 1.2, 8.8 Hz),
8.00 (1H, dt, J = 1.2, 8.8 Hz), 8.03 (2H, d, J = 8.8 Hz), 8.25 (1H, d, J = 8.0 Hz), 9.06 (1H, d, J = 6.8 Hz).
13C-NMR (100 MHz, CDCl3): δ 27.4, 55.0, 117.4, 128.3, 135.2, 138.0, 138.1, 138.3, 143.1, 159.5,
172.8, 185.3, 209.2. IR (KBr): ν = 1620, 1580, 1490, 1280, 1250, 810, 770 and 620 cm−1. Anal. Calc.
for C15H14BiClO: C, 39.62; H, 3.10. Found: C, 39.42; H, 2.94%.
1
(2-Acetylphenyl)chloro(2,4,6-trimethylphenyl)bismuthane (5f). Yield: 13%; mp 172–174 °C; H-NMR
(400 MHz, CDCl3): δ 2.18 (3H, s), 2.46 (6H, s), 2.63 (3H, s), 7.12 (2H, s) 7.61 (1H, dt, J = 1.2, 7.6 Hz),
7.95 (1H, dt, J = 1.2, 7.6 Hz), 8.22 (1H, dd, J = 0.8, 7.6 Hz), 9.23 (1H, d, J = 7.6 Hz). 13C-NMR (100 MHz,
CDCl3): δ 21.2, 26.1, 27.4, 128.1, 131.4, 134.9, 137.2, 138.6, 140.2, 144.1, 146.6, 182.4, 183.3, 208.1.
IR (KBr): ν = 1630, 1290, 760 and 610 cm−1. Anal. Calc. for C17H18BiClO: C, 42.30; H, 3.76. Found:
C, 42.10; H, 3.82%.
1
(2-Butyrylphenyl)chloro(4-methylphenyl)bismuthane (11a). Yield: 21%; mp 136–138 °C; H-NMR
(400 MHz, CDCl3): δ 0.94 (3H, t, J = 7.6 Hz), 1.75 (2H, m), 2.25 (3H, s), 3.02 (2H, m), 7.24 (2H, d,
J = 7.6 Hz), 7.69 (1H, t, J = 7.6 Hz), 7.86 (1H, t, J = 7.6 Hz), 8.07 (2H, d, J = 7.6 Hz), 8.24 (1H, d,
13
J = 7.6 Hz), 9.41 (1H, d, J = 7.6 Hz). C-NMR (100 MHz, CDCl3): δ 13.7, 17.9, 21.5, 41.2, 128.1,
132.4, 134.5, 136.4, 137.9, 138.0, 138.4, 143.0, 178.0, 185.5, 211.6. IR (KBr): ν = 1620, 1220, 800,
760 and 480 cm−1. Anal. Calc. for C17H18BiClO: C, 42.30; H, 3.76. Found: C, 41.89; H, 3.69%.
1
Chloro(2-valerylphenyl)(4-methylphenyl)bismuthane (11b). Yield: 21%; mp 133–135 °C; H-NMR
(400 MHz, CDCl3): δ 0.92 (3H, t, J = 7.6 Hz), 1.34 (2H, m), 1.70 (2H, m), 2.24 (3H, s), 3.05 (2H, m),
7.32 (2H, d, J = 7.6 Hz), 7.61 (1H, dt, J = 1.2, 7.6 Hz), 7.95 (1H, dt, J = 1.2, 7.6 Hz), 8.02 (2H, d, J =
7.6 Hz), 8.26 (1H, d, J = 7.6 Hz), 9.06 (1H, dd, J = 0.8, 7.6 Hz). 13C-NMR (100 MHz, CDCl3): δ 13.8,
21.5, 22.3, 26.5, 39.1, 128.1, 132.4, 134.6, 136.4, 137.9, 138.1, 138.4, 143.0, 178.0, 185.5, 211.8. IR
(KBr): ν = 1630, 1380, 1010, 800, 740 and 480 cm−1. Anal. Calc. for C18H20BiClO: C, 43.52; H, 4.06.
Found: C, 43.88; H, 4.24%.
1
Bromo(2-isobutyrylphenyl)(4-methylphenyl)bismuthane (11c). Yield: 25%; mp 146–148 °C; H-NMR
(400 MHz, DMSO-d6): δ 1.11 (6H, br-d, J = 4.1 Hz), 2.17 (3H, s), 3.89 (1H, sep, J = 6.8 Hz), 7.28
(2H, d, J = 7.6 Hz), 7.74 (1H, t, J = 7.6 Hz), 7.98 (2H, d, J = 7.6 Hz), 8.25 (1H, d, J = 7.6 Hz), 8.56
13
(1H, d, J = 7.6 Hz), 8.97 (1H, br-s). C-NMR (100 MHz, CDCl3): δ 19.1, 19.3, 21.5, 36.3, 128.2,
132.3, 134.3, 136.8, 137.9, 138.2, 140.9, 142.0, 174.4, 181.9, 215.1. IR (KBr): ν = 1620, 1260, 980,
770, 730 and 480 cm−1. Anal. Calc. for C17H18BiBrO: C, 38.73; H, 3.44. Found: C, 39.00; H, 3.63%.
3.4. Synthesis of 5b–e and 9
A typical example is exemplified by the synthesis of 5b: Compound 4b (510 mg, 1 mmol) was
dissolved in dichloromethane (5 mL) and boron trifluoride etherate (3 mmol) was added to the solution
at 0 °C until 4b was completely consumed (checked by TLC). The mixture was diluted by the addition

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of brine (5 mL) and the organic layer was extracted with ethyl acetate (20 mL × 3). The combined extracts
were concentrated to leave an oily residue, which was crystallized from MeOH to give 5b in 88% yield.
1
(2-Acetylphenyl)chloro(4-methylphenyl)bismuthane (5b). Yield: 88%; mp 164–166 °C; H-NMR
(400 MHz, CDCl3): δ 2.25 (3H, s), 2.69 (3H, s), 7.33 (2H, d, J = 7.6 Hz), 7.62 (1H, dt, J = 1.2, 7.6 Hz),
7.99 (1H, dt, J = 1.2, 7.6 Hz), 8.03 (2H, d, J = 7.6 Hz), 8.24 (1H, dd, J = 0.8, 7.6 Hz), 9.06 (1H, dd,
J = 0.8, 7.2 Hz). 13C-NMR (100 MHz, CDCl3): δ 21.5, 27.4, 128.2, 132.4, 135.2, 136.4, 138.1, 138.3,
143.1, 177.9, 185.2, 209.2; one ipso carbon signal was too weak to be observed. IR (KBr): ν = 1625,
1550, 1280, 800, 765, 620 and 480 cm−1. Anal. Calc. for C15H14BiClO: C, 39.62; H, 3.10. Found: C,
39.60; H, 3.10%.
1
(2-Acetylphenyl)chloro(phenyl)bismuthane (5c). Yield: 82%; mp 152–154 °C; H-NMR (400 MHz,
CDCl3): δ 2.69 (3H, s), 7.26 (1H, t, J = 7.8 Hz), 7.52 (2H, t, J = 8.0 Hz), 7.63 (1H, dt, J = 1.2, 7.6 Hz),
8.01 (1H, dt, J = 1.2, 7.6 Hz), 8.15 (2H, dd, J = 1.2, 8.0 Hz), 8.25 (1H, dd, J = 0.8, 7.2 Hz), 9.07 (1H,
13
dd, J = 0.4, 8.0 Hz). C-NMR (100 MHz, CDCl3): δ 27.4, 128.2, 128.3, 131.6, 135.2, 136.4, 136.2,
138.3, 143.2, 181.0, 185.3, 209.2. IR (KBr): ν = 1620, 1220, 800, 740 and 480 cm−1. Anal. Calc. for
C14H12BiClO: C, 38.16; H, 2.74. Found: C, 37.94; H, 2.80%.
1
(2-Acetylphenyl)chloro(4-fluorophenyl)bismuthane (5d). Yield: 79%; mp 130–132 °C; H-NMR
(400 MHz, CDCl3): δ 2.70 (3H, s), 7.11–7.15 (2H, m), 7.64 (1H, dt, J = 1.2, 7.6 Hz), 8.01 (1H, dt,
J = 1.2, 7.6 Hz), 8.07–8.12 (2H, m), 8.26 (1H, dd, J = 0.4, 7.6 Hz), 9.04 (1H, d, J = 7.2 Hz). 13C-NMR
(100 MHz, CDCl3): δ 27.4, 118.8 (d, JCF = 20 Hz), 128.5, 135.3, 138.2, 138.3, 138.5 (d, JCF = 7.0 Hz),
143.1, 162.5 (d, JCF = 246 Hz), 175.9, 185.1, 209.5. IR (KBr): ν = 1630, 1570, 1480, 1220, 1160, 830,
780, 610 and 500 cm−1. Anal. Calc. for C14H11BiClFO: C, 36.66; H, 2.42. Found: C, 36.73; H, 2.37%.
1
(2-Acetylphenyl)chloro(4-chlorophenyl)bismuthane (5e). Yield: 91%; mp 168–170 °C; H-NMR
(400 MHz, CDCl3): δ 2.70 (6H, s), 7.43 (2H, d, J = 8.0 Hz), 7.64 (1H, dt, J = 1.2, 7.6 Hz), 8.02 (1H, dt,
J = 1.2, 7.6 Hz), 8.08 (2H, d, J = 8.0 Hz), 8.26 (1H, dd, J = 0.8, 8.0 Hz), 9.05 (1H, dd, J = 0.8, 7.2 Hz).
13C-NMR (100 MHz, CDCl3): δ 27.4, 128.5, 131.7, 134.3, 135.4, 137.9, 138.2, 138.4, 143.1, 178.7,
185.5, 209.5. IR (KBr): ν = 1630, 1280, 1090, 1080, 810, 770 and 480 cm−1. Anal. Calc. for
C14H11BiCl2O: C, 35.39; H, 2.33. Found: C, 35.45; H, 2.45%.
(2-Acetyl-4-methylphenyl)chloro(4-methylphenyl)bismuthane (9a). Yield: 87%; mp 196–198 °C;
1H-NMR (400 MHz, CDCl3): δ 2.25 (3H, s), 2.52 (3H, s), 2.66 (3H s), 7.30 (2H, d, J = 7.6 Hz),
7.40 (1H, d, J = 7.6 Hz), 8.03 (2H, d, J = 7.6 Hz), 8.13 (1H, d, J = 7.6 Hz), 8.13 (1H, d, J = 7.6 Hz),
8.85 (1H, s). 13C-NMR (100 MHz, CDCl3): δ 21.5, 22.3, 27.3, 129.1, 132.4, 135.3, 136.4, 138.1, 139.0,
140.9, 149.8, 177.8, 185.6, 208.7. IR (KBr): ν = 1620, 1580, 1380, 800, 590 and 480 cm−1. Anal. Calc.
for C16H16BiClO: C, 41.00; H, 3.44. Found: C, 40.78; H, 3.42%.
(2-Acetyl-4-isopropylphenyl)chloro(4-methylphenyl)bismuthane (9b). Yield: 93%; mp 198–200 °C;
1H-NMR (400 MHz, CDCl3): δ 1.33 (6H, d, J = 7.2 Hz), 2.28 (3H, s), 2.65 (3H, s), 3.13 (1H, sep,
J = 7.2 Hz), 7.33 (2H, d, J = 7.6 Hz), 7.45 (1H, dd, J = 1.6, 8.0 Hz), 8.04 (2H, d, J = 7.6 Hz), 8.18 (1H,
13
d, J = 8.0 Hz), 8.92 (1H, d, J = 1.6 Hz). C-NMR (100 MHz, CDCl3): δ 21.5, 23.5, 23.7, 27.3, 34.9,

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126.2, 132.4, 135.6, 136.4, 136.8, 138.1, 141.3, 159.9, 177.8, 185.7, 208.6. IR (KBr): ν = 1620, 1580,
1360, 1280, 1060, 830, 790 and 480 cm−1. Anal. Calc. for C18H20BiClO: C, 43.52; H, 4.06. Found: C,
43.48; H, 4.12%.
(2-Acetyl-4-methoxyphenyl)chloro(4-methylphenyl)bismuthane (9c). Yield: 82%; mp 178–180 °C;
1H-NMR (400 MHz, CDCl3): δ 2.25 (3H, s), 2.61 (3H, s), 4.01 (3H, s), 7.00 (1H, dd, J = 2.4, 8.8 Hz),
7.34 (2H, d, J = 7.6 Hz), 8.04 (2H, d, J = 7.6 Hz), 8.16 (1H, d, J = 8.8 Hz), 8.70 (1H, d, J = 2.4 Hz).
13C-NMR (100 MHz, CDCl3): δ 21.5, 27.1, 55.8, 115.2, 122.6, 132.5, 136.4 (2C), 137.5, 138.2, 168.8,
178.1, 189.3, 207.0. IR (KBr): ν = 1610, 1580, 1540, 1360, 1300, 1270, 1230, 1020, 820, 800, 600 and
480 cm−1. Anal. Calc. for C16H16BiClO2: C, 39.65; H, 3.33. Found: C, 39.57; H, 3.73%.
3.5. Synthesis of 6 and 7
A typical example is exemplified by the synthesis of 6b and 7b: Saturated aqueous NaBr (3 mL)
was added dropwise to a stirred solution of 5b (227 mg, 0.5 mmol) in dichloromethane (5 mL). After
15 min, the organic layer was extracted with ethyl acetate (10 mL × 3). The combined extracts were
concentrated to leave an oily residue, which was crystallized from MeOH to give 6b in 83% yield.
Saturated aqueous NaI (3 mL) was added dropwise to a stirred solution of 5b (227 mg, 0.5 mmol) in
dichloromethane (5 mL). After 15 min, the organic layer was extracted with ethyl acetate (10 mL × 3).
The combined extracts were concentrated to leave an oily residue, which was crystallized from MeOH
to give 7b in 89% yield.
1
(2-Acetylphenyl)bromo(4-methoxylphenyl)bismuthane (6a). Yield: 85%; mp 153–155 °C; H-NMR
(400 MHz, CDCl3): δ 2.69 (3H, s), 3.73 (3H, s), 6.98 (2H, d, J = 8.4 Hz), 7.66 (1H, dt, J = 1.2, 7.8 Hz),
7.97 (1H, dt, J = 1.2, 7.6 Hz), 8.02 (2H, d, J = 8.4 Hz), 8.25 (1H, d, J = 7.6 Hz), 9.21 (1H, d, J = 7.2 Hz).
13C-NMR (100 MHz, CDCl3): δ 27.4, 55.1, 117.5, 128.4, 135.1, 138.5, 138.7, 140.7, 143.1, 159.4,
169.0, 180.7, 208.7. IR (KBr): ν = 1625, 1550, 1300, 1280, 800, 765, 615 and 480 cm−1. Anal. Calc.
for C15H14BiBrO2: C, 34.97; H, 2.74. Found: C, 34.70; H, 2.70%.
1
(2-Acetylphenyl)bromo(4-methylphenyl)bismuthane (6b). Yield: 83%; mp 174–176 °C; H-NMR
(400 MHz, CDCl3): δ 2.05 (3H, s), 2.69 (3H, s), 7.31 (2H, d, J = 7.9 Hz), 7.65 (1H, t, J = 1.1, 7.5 Hz),
7.97 (1H, t, J = 1.1, 7.4 Hz), 8.05 (2H, d, J = 7.9 Hz), 8.24 (1H, d, J = 7.3 Hz), 9.21 (1H, d, J = 7.3 Hz).
13C-NMR (100 MHz, CDCl3): δ 21.5, 27.4, 128.3, 132.5, 135.1, 137.1, 138.2, 138.5, 140.7, 143.1,
174.2, 175.8, 208.7. IR (KBr): ν = 1625, 1550, 1300, 1280, 800, 770, 620 and 480 cm−1. Anal. Calc.
for C13H10BiClO2S: C, 36.09; H, 2.83. Found: C, 36.20; H, 2.80%.
1
(2-Acetylphenyl)bromo(phenyl)bismuthane (6c). Yield: 87%; mp 146–148 °C; H-NMR (400 MHz,
CDCl3): δ 2.70 (3H, s), 7.25 (1H, t, J = 7.3 Hz), 7.50 (2H, t, J = 7.3 Hz), 7.67 (1H, t, J = 7.3 Hz), 7.98
(1H, t, J = 7.3 Hz), 8.25 (1H, d, J = 7.3 Hz), 9.21 (1H, d, J = 7.3 Hz). 13C-NMR (100 MHz, CDCl3): δ
27.4, 128.2, 128.4, 131.7, 135.1, 137.1, 138.6, 140.7, 143.1, 177.3, 180.8, 208.8. IR (KBr): ν = 1620,
1280, 770 and 730 cm−1. Anal. Calc. for C14H12BiBrO: C, 34.66; H, 2.48. Found: C, 34.80; H, 2.40%.
1
(2-Acetylphenyl)bromo(4-fluorophenyl)bismuthane (6d). Yield: 83%; mp 132–134 °C; H-NMR
(400 MHz, CDCl3): δ 2.70, (3H, s), 7.09–7.13 (2H, m), 7.68 (1H, t, J = 7.2 Hz), 7.99 (1H, t, J = 7.6 Hz),

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13
8.10–8.13 (2H, m), 8.26 (1H, J = 7.6 Hz), 9.20 (1H, d, J = 7.2 Hz). C-NMR (100 MHz, CDCl3): δ
27.4, 118.9 (d, JCF = 21 Hz), 128.6, 135.1, 138.7, 139.2 (d, JCF = 7.0 Hz), 140.6, 143.1, 162.4 (d,
JCF = 246 Hz), 172.0, 180.5, 208.9. IR (KBr): ν = 1630, 1220, 1160, 810, 610 and 500 cm−1. Anal.
Calc. for C14H11BiBrFO: C, 33.42; H, 2.20. Found: C, 33.55; H, 2.24%.
1
(2-Acetylphenyl)bromo(4-chlorophenyl)bismuthane (6e). Yield: 86%; mp 157–159 °C; H-NMR
(400 MHz, CDCl3): δ 2.70 (3H, s), 7.41 (2H, d, J = 8.4 Hz), 7.68 (1H, t, J = 7.6 Hz), 7.99 (1H, t, J =
8.0 Hz), 8.10 (2H, d, J = 8.4 Hz), 8.25 (1H, d, J = 7.6 Hz), 9.20 (1H, d, J = 7.6 Hz). 13C-NMR (100 MHz,
CDCl3): δ 27.4, 128.6, 131.7, 134.3, 135.2, 138.6, 138.7, 140.6, 143.1, 174.9, 180.4, 209.0. IR (KBr):
ν = 1630, 1280, 1090, 1000, 800 and 770 cm−1. Anal. Calc. for C14H11BiBrClO: C, 32.36; H, 2.13.
Found: C, 32.70; H, 2.10%.
1
(2-Acetylphenyl)bromo(2,4,6-trimethylphenyl)bismuthane (6f). Yield: 86%; mp 181–183 °C; H-NMR
(400 MHz, CDCl3): δ 2.19 (3H, s), 2.45 (6H, s), 2.63 (3H, s), 7.12 (2H, s), 7.64 (1H, dt, J = 1.2, 7.6 Hz),
7.94 (1H, dt, J = 0.8, 7.2 Hz), 8.21 (1H, d, J = 7.2 Hz), 9.35 (1H, d, J = 7.6 Hz). 13C-NMR (100 MHz,
CDCl3): δ 21.2, 26.8, 27.3, 129.1, 131.2, 134.7, 137.6, 138.6, 142.2, 144.0, 146.6, 178.9, 179.3, 207.7.
IR (KBr): ν = 1630, 1280, 1260 and 760 cm−1. Anal. Calc. for C17H18BiBrO: C, 38.73; H, 3.44. Found:
C, 38.48; H, 3.55%.
1
(2-Acetylphenyl)iodo(4-methoxylphenyl)bismuthane (7a). Yield: 83%; mp 145–147 °C; H-NMR
(400 MHz, CDCl3): δ 2.69 (3H, s), 3.73 (3H, s), 6.93 (2H, d, J = 8.4 Hz), 7.71 (1H, t, J = 7.6 Hz), 7.87
(1H, t, J = 7.2 Hz), 8.07 (2H, d, J = 8.4 Hz), 8.23 (1H, d, J = 7.6 Hz), 9.42 (1H, d, J = 7.2 Hz). 13C-NMR
(100 MHz, CDCl3): δ 27.1, 55.0, 117.4, 128.5, 134.5, 139.0, 139.9, 143.1, 145.6, 159.4, 207.5; ipso
carbon signals were too weak to be observed. IR (KBr): ν = 1630, 1580, 1490, 1290, 1250, 1180, 810,
760 and 510 cm−1. Anal. Calc. for C14H13BiClNO2S: C, 32.05; H, 2.51. Found: C, 32.29; H, 2.60%.
(2-Acetylphenyl)iodo(4-methylphenyl)bismuthane (7b). Yield: 89%; mp 148–150 °C; 1H-NMR (400 MHz,
CDCl3): δ 2.26 (3H, s), 2.69 (3H, s), 7.25 (2H, d, J = 8.0 Hz), 7.71 (1H, dt, J = 1.2, 7.6 Hz), 7.86 (1H,
dt, J = 1.6, 7.9 Hz), 8.07 (2H, d, J = 8.0 Hz), 8.22 (1H, dd, J = 1.2, 8.0 Hz), 9.42 (1H, dd, J = 1.2, 7.2 Hz).
13C-NMR (100 MHz, CDCl3): δ 21.6, 27.1, 128.5, 132.4, 134.5, 138.0, 138.2, 139.0, 143.1, 145.6,
166.7, 172.1, 207.5. IR (KBr): ν = 1630, 1290, 800, 770 and 480 cm−1. Anal. Calc. for C15H14BiIO: C,
32.98; H, 2.59. Found: C, 33.00; H, 2.60%.
1
(2-Acetylphenyl)iodo(phenyl)bismuthane (7c). Yield: 88%; mp 111–113 °C; H-NMR (400 MHz,
CDCl3): δ 2.69 (3H, s), 7.25 (1H, dt, J = 0.8 Hz, 6.4 Hz), 7.37 (2H, dt, J = 1.6, 7.6 Hz), 7.89 (1H, dt,
J = 1.2, 7.6 Hz), 8.20 (2H, dd, J = 1.2, 7.6 Hz), 8.23 (1H, dd, J = 1.2, 8.0 Hz), 9.43 (1H, dd, J = 0.8,
13
7.6 Hz). C-NMR (100 MHz, CDCl3): δ 27.0, 128.0, 128.6, 131.5, 134.5, 138.2, 139.0, 143.1, 145.5,
169.8, 172.1, 207.6. IR (KBr): ν = 1630, 1430, 1280, 770, 730, 690, 610 and 460 cm−1. Anal. Calc. for
C14H12BiIO: C, 31.60; H, 2.27. Found: C, 31.78; H, 2.60%.
(2-Acetylphenyl)iodo(4-fluorophenyl)bismuthane (7d). Yield: 76%; mp 123–125 °C; 1H-NMR (400 MHz,
CDCl3): δ 2.70 (3H, s), 7.03–7.08 (2H, m), 7.73 (1H, dt, J = 0.8, 7.2 Hz), 7.90 (1H, dt, J = 0.8, 7.2 Hz),
13
8.11–8.16 (2H, m), 9.42 (1H, dd, J = 1.2, 7.6 Hz). C-NMR (100 MHz, CDCl3): δ 27.1, 118.8 (d,

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JCF = 20 Hz), 128.7, 134.6, 139.1, 140.4 (d, JCF = 8.0 Hz), 143.0, 145.5, 162.4 (d, JCF = 246 Hz),
164.2, 171.7, 207.7. IR (KBr): ν = 1630, 1220, 1160, 810, 760, 610 and 500 cm−1. Anal. Calc. for
C14H11BiFIO: C, 30.57; H, 2.02. Found: C, 30.52; H, 1.99%.
(2-Acetylphenyl)iodo(4-chlorophenyl)bismuthane (7e). Yield: 79%; mp 153–155 °C; 1H-NMR (400 MHz,
CDCl3): δ 2.70 (3H, s), 7.43 (2H, dd, J = 1.6, 8.4 Hz), 7.73 (1H, dt, J = 1.2, 7.6 Hz), 7.90 (1H, dt,
J = 1.2, 7.2 Hz), 8.11 (2H, dd, J = 1.6, 8.4 Hz), 8.24 (1H, dd, J = 0.8, 7.6 Hz), 9.41 (1H, dd, J = 0.8,
13
7.2 Hz). C-NMR (100 MHz, CDCl3): δ 27.1, 128.8, 131.6, 134.2, 134.6, 139.2, 139.8, 143.1, 145.5,
207.7; ipso carbon signals were too weak to be observed. IR (KBr): ν = 1630, 1470, 1280, 1090, 1000,
760, 610 and 480 cm−1. Anal. Calc. for C14H11BiClIO: C, 29.68; H, 1.96. Found: C, 29.72; H, 2.03%.
1
(2-Acetylphenyl)iodo(2,4,6-trimethylphenyl)bismuthane (7f). Yield: 86%; mp 170–172 °C; H-NMR
(400 MHz, CDCl3): δ 2.20 (3H, s), 2.42 (6H, s), 2.63 (3H, s), 7.15 (2H, s), 7.67 (1H, dt, J = 0.8, 8.4 Hz),
7.84 (1H, dt, J = 1.2, 7.6 Hz), 8.19 (1H, d, J = 6.8 Hz), 9.52 (1H, d, J = 6.8 Hz). 13C-NMR (100 MHz,
CDCl3): δ 21.2, 27.1, 27.9, 128.3, 130.7, 134.2, 138.1, 138.6, 144.0, 146.4, 146.6, 170.6, 172.8, 206.7.
IR (KBr): ν = 1630, 1290, 1270, 850, 770 and 610 cm−1. Anal. Calc. for C17H18BiIO: C, 35.56; H,
3.16. Found: C, 35.56; H, 3.26%.
3.6. 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 48 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 did not inhibit fungal growth at all. In order to know the
error on the inhibition zone, we carried out the antifungal assay of compound C1 many times and
confirmed that the error was within ± 1 mm.
3.7. Lipophilicity
The calculated logarithms of water-octanol partition coefficients (ClogP values) were obtained from
the ClogP tool in Chem Draw Ultra 11.0 (Cambridge Soft, Cambridge, MA, USA).
3.8. DFT Calculation of the Dissociation and Association Energies
The geometries of the bismuth compounds, their dissociated cations and counter anions, and the
corresponding MeS−-adduct anions in Table 2 were fully optimized in water through density functional
theory (DFT) calculations within the polarizable continuum model (PCM) using the Gaussian 09
program package [40]. 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

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default form in the Gaussian 09 GenECP calculations. The endothermicity for the ionic dissociation
and the exothermicity for the nucleophilic addition of MeS− were calculated from the energies in water
of each substrate, in which only the most stable conformer with the lowest energy was considered.
4. Conclusions
In conclusion, the present study provides insights that will aid the design of fungicidal hypervalent
bismuthanes. For higher antifungal activity, adjusting the lipophilicity-hydrophilicity balance,
modeling the three-dimensional molecular structure around the bismuth atom, and stabilizing the
intermediate ate complex in Path 2 appeared to be more important than tuning the Lewis acidity at the
bismuth atom. Further studies are now underway to test this hypothesis.
Acknowledgments
We are grateful to the Center of Instrumental Analysis, Yamaguchi University and the Tokiwa
Instrumentation Analysis Center, Yamaguchi University.
Author Contributions
T.M. conceived the concept and design of this study and wrote the article. T.M. and M.T.
synthesized and characterized compounds. I.M. performed the antifungal assay. K.I. analyzed the
results and carried out the DFT calculation.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds A–D and 4–11 are available from the authors.
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