# One-Pot Synthesis of Hypervalent Diaryl(iodo)bismuthanes fromo-Carbonyl Iodoarenes by Zincation

Authors: Toshihiro Murafuji; A. F. M. Hafizur Rahman; Daiki Magarifuchi; Masahiro Narita; Isamu Miyakawa; Katsuya Ishiguro; Shin Kamijo
Journal: Heteroatom Chemistry
 (2019)

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## Abstract

Diaryl(iodo)bismuthanes possessing a hypervalent C=O•••Bi–I bond were conveniently synthesized in a one-pot reaction by using arylzinc reagents generated fromo-carbonyl iodobenzenes and zinc powder under ultrasonication. This method is superior to the conventional organolithium and Grignard methods because it has a wide functional group tolerance, requires no protecting group manipulations, and proceeds under mild reaction conditions that do not need low temperature control. Furthermore, no intermediate triarylbismuthane precursor for the hypervalent iodobismuthane is necessary.


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## Body

## 1. Introduction

Much effort has been devoted to the study of hypervalent bismuth(III) compounds [1–5]. Hypervalent bonds are formed efficiently via intramolecular coordination of a neutral donor to a bismuth(III) center [6–12]. We have used this method to synthesize various hypervalent organobismuth(III) compounds stabilized by intramolecular coordination and have characterized their molecular structures [13]. Furthermore, we have revealed that these compounds show antifungal activities against the yeastSaccharomyces cerevisiae [14, 15]. In particular, compounds1 and2, which possess diary sulfone and acetophenone molecular scaffold, respectively, exhibited high antifungal activities.These compounds are synthesized by directedortho-lithiation (Scheme 1). Directed lithiation is a very useful and reliable synthetic method for introducing a molecular scaffold bearing anortho-coordinative functional group, although the method can suffer from various practical difficulties. For example, the synthesis of1 and2 used triarylbismuthane as a precursor because theortho-functionalized aryllithiums were too reactive to give1 and2directly through their reactions with BiI3 and ArBiX2, respectively. Furthermore, the acetyl substituent of acetophenone is incompatible with BuLi, meaning that the synthesis of2 started from the protected silyl enol ether, and the harsh reaction conditions requiring excess BuLi caused the loss of Ar2BiCl or the decomposition of the product, lowering the reproducibility of the yield [13, 14]. To facilitate the search for active antifungal compounds, a general and convenient synthetic method that has wide functional group compatibility for introducing various molecular scaffolds to the bismuth(III) center is required.Scheme 1
Synthesis of1 and2 by directed lithiation.We have reported the synthesis under Grignard conditions ofp-substituted triarylbismuthanes3 and4, which have a formyl and ester substituent, respectively (Scheme 2) [16]. The imino and ester substituents were tolerated despite their polarized double bond, although3 required protection of the formyl substituent and4 needed low-temperature control. Based on these results, we investigated using a type of organometallic reagent that is less reactive than Grignard reagents. Such an organometallic reagent would be compatible with carbonyl functional group and thus a suitable synthetic tool for use in our desired general method.Scheme 2
Synthesis of3 and4.Several mild bismuth–carbon bond forming reactions have been reported, which include the treatment of aryl iodides with bismuth shot in the presence of Cu and CuI by ball milling [17], the arylation of bismuth(III) carboxylates by sodium tetraarylborate [18], and the reaction of BiCl3 with organozinc reagents [19]. To achieve wide functional group tolerance, we chose organozinc reagents because they are compatible with carbonyl functionalities such as ester, acetyl, and even formyl substituents, and the chemistry of these reagents is well established [20–22]. Herein, we report the synthesis of hypervalent iodobismuthanes2a and5a–10a, which contain a carbonyl group, by zincation of the corresponding iodoarenes (Scheme 3). The organozinc method was superior to our previously reported organolithium and Grignard methods owing to the high functional group tolerance, short synthesis, mild reaction conditions, and acceptable yields.Scheme 3
Hypervalent iodobismuthanes functionalized with a carbonyl group.


## 2. Materials and Methods

All of the reactions were carried out under argon unless otherwise noted.N,N-Dimethylformamide (DMF) was distilled from calcium hydride under reduced pressure. 1,4-Dioxane was distilled from calcium hydride. Diethyl ether was distilled from benzophenone ketyl before use. 1H 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: chloroform (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. Melting points were determined on a YANAGIMOTO melting point apparatus without correction. Elemental analysis was performed on a MICRO CORDER JM10 apparatus (J-SCIENCE LAB. Co.). HRMS were recorded on a Bruker Daltonics micrOTOF II (APCI) instrument. 2′-Iodoacetophenone and ethyl 2-iodobenzoate were commercially available. 2-Iodobenzaldehyde, 4-fluoro-2-iodobenzaldehyde, 2-iodo-5-methoxybenzaldehyde, 4′-fluoro-2′-iodoacetophenone, and 3-iodothiophene-2-carboxaldehyde were prepared in high yields by Finkelstein reaction of the corresponding bromoarenes in accordance with the literature [23].


### 2.1. Typical Procedure for the Finkelstein Reaction of Bromoarenes

To a round-bottomed flask (50 mL) equipped with a magnetic stir bar were added bromoarene (2.5 mmol), CuI (5 mol%), NaI (5 mmol), and 1,3-diaminopropane (10 mol%). After dry 1,4-dioxane (2.5 mL) was added to the flask, the mixture was refluxed for 24 h. The reaction was quenched with water (30 mL) at room temperature and the resulting mixture was extracted with ethyl acetate (3 × 30 mL). The organic layer was dried (Na2SO4) and concentrated to leave a residue, which was chromatographed on silica gel with hexane–ethyl acetate (5:1) to give the corresponding iodoarene, which was used in the next step without further purification.


### 2.2. 2-Iodobenzaldehyde

Yield 99% (574 mg, 2.48 mmol), Colorless solid, mp 39–41°C.1H NMR (400 MHz, CDCl3):δ 7.29 (1H, dt,J = 7.6 Hz, 1.6 Hz), 7.47 (1H, t,J = 7.6 Hz), 7.89 (1H, dd,J = 7.6 Hz, 1.6 Hz), 7.96 (1H, d,J = 8.0 Hz), 10.08 (1H, s).


### 2.3. 4-Fluoro-2-Iodobenzaldehyde

Yield 97% (606 mg, 2.43 mmol), Colorless solid, mp 49–51°C.1H NMR (400 MHz, CDCl3):δ 7.19 (1H, m), 7.68 (1H, m), 7.91 (1H, m), 9.99 (1H, d,J = 2.4 Hz).


### 2.4. 2-Iodo-5-Methoxybenzaldehyde

Yield 98% (642 mg, 2.45 mmol), Colorless solid, mp 113–116°C.1H NMR (400 MHz, CDCl3):δ 3.84 (3H, s), 6.92 (1H, dd,J = 8.4 Hz, 3.2 Hz), 7.43 (1H, d,J = 3.2 Hz), 7.80 (1H, d,J = 8.4 Hz), 10.02 (1H, s).


### 2.5. 4′-Fluoro-2′-Iodoacetophenone

Yield 98% (647 mg, 2.45 mmol), Colorless solid, mp 45–46°C.1H NMR (400 MHz, CDCl3):δ 2.59 (3H, s), 7.11 (1H, m), 7.52 (1H, m), 7.65 (1H, m).


### 2.6. 3-Iodothiophene-2-Carboxaldehyde

Yield 99% (589 mg, 2.48 mmol), Colorless solid, mp 82–85°C.1H NMR (400 MHz, CDCl3):δ 7.28 (1H, d,J = 4.8 Hz), 7.70 (1H, dd,J = 4.8 Hz, 1.2 Hz), 9.83 (1H, d,J = 1.2 Hz).


### 2.7. Typical Procedure for the Synthesis of Aryl(iodo)(4-methylphenyl)bismuthane

To a round-bottomed flask (50 mL) equipped with a magnetic stir bar were added bismuth(III) chloride (422 mg, 1.33 mmol) and tris(4-methylphenyl)bismuthane (323 mg, 0.67 mmol). After dry diethyl ether (6 mL) was added to the flask at room temperature, the mixture was stirred for 1 h. To another round-bottomed flask (50 mL) were added iodoarene (1 mmol), zinc powder (262 mg, 4 mmol), and dry DMF (5 mL). The flask was set in an ultrasonic water bath at room temperature (25°C) and the resulting mixture was sonicated for 1.5–4 h, during which time the water bath temperature rose to 48°C. The sonication was stopped and unreacted zinc powder precipitated. The resulting supernatant solution containing an arylzinc reagent was slowly transferred to the suspension of dichloro(4-methylphenyl)bismuthane (ca. 2 mmol) thus formed, and the resulting mixture was stirred for 3.5–8 h at room temperature. The reaction was quenched with a saturated aqueous solution of NaI (3 mL) and the resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined extracts were concentrated to leave an oily residue, which was chromatographed on silica gel with hexane–ethyl acetate (5:1) to afford the corresponding iodobismuthane.


### 2.8. (2-Acetylphenyl)iodo(4-methylphenyl)bismuthane2a

Yellow crystal, Yield 35% (191 mg, 0.35 mmol), mp 160–162°C.1H NMR (400 MHz, CDCl3):δ 2.25 (3H, s), 2.69 (3H, s), 7.25 (2H, d,J = 8.0 Hz), 7.71 (1H, dt,J = 7.6 Hz, 1.2 Hz), 7.88 (1H, dt,J = 7.6 Hz, 1.2 Hz), 8.07 (2H, d,J= 8.0 Hz), 8.22 (1H, dd,J = 7.6 Hz, 1.2 Hz), 9.41 (1H, dd,J = 7.2 Hz, 0.8 Hz). 13C NMR (100 MHz, CDCl3):δ 21.54, 27.08, 128.50, 132.36, 134.51, 138.01, 138.21, 138.98, 143.10, 145.55, 166.78, 172.09, 207.54. IR (KBr): ν 3738, 3037, 1622, 1552, 1276 and 761 cm−1. HRMS (APCI) calcd. for C15H13BiIO: [M–H]- 544.9832. found: 544.9821.


### 2.9. (2-Acetyl-5-fluorophenyl)iodo(4-methylphenyl)bismuthane5a

Yellow crystal, Yield 28% (158 mg, 0.28 mmol), mp 186–188°C.1H NMR (400 MHz, DMSO-d6):δ 2.19 (3H, s), 2.72 (3H, s), 7.29 (2H, d,J = 7.6 Hz), 7.54 (1H, dt,J = 8.4 Hz, 2.0 Hz), 8.11 (2H, d,J = 7.6 Hz), 8.55 (1H, dd,J = 8.4 Hz, 4.8 Hz), 8.89 (1H, br-s). 13C NMR (100 MHz, DMSO-d6):δ 21.13, 27.48, 115.62 (d,J = 22.6 Hz), 130.94 (br-d), 132.08(×2), 137.09, 138.45, 138.85 (d,J = 8.0 Hz), 140.51, 169.52, 172.12, 207.85. IR (KBr): ν 1620, 1575, 1558, 1358, 1299, 1262 and 1201 cm−1. HRMS (APCI) calcd. for C15H12BiFIO: [M–H]- 562.9730. found: 562.9726.


### 2.10. (2-Formylphenyl)iodo(4-methylphenyl)bismuthane6a

Yellow crystal, Yield 56% (298 mg, 0.56 mmol), mp 143–144°C.1H NMR (400 MHz, DMSO-d6):δ 2.21 (3H, s), 7.30 (2H, d,J = 7.6 Hz), 7.86 (1H, t,J = 7.2 Hz), 7.95 (1H, t,J= 7.2 Hz), 8.14 (2H, d,J =7.6 Hz), 8.44 (1H, d,J= 7.2 Hz), 9.02 (1H, d,J= 7.2 Hz), 10.75 (1H, s). 13C NMR (100 MHz, CDCl3):δ 21.55, 128.65, 132.47, 137.58, 138.23, 138.44, 139.63, 143.66, 146.16, 165.99, 170.92, 199.50. IR (KBr): ν 3058, 2857, 1633, 1572, 1553, 1296 and 1207 cm−1. HRMS (APCI) calcd. for C14H13BiIO: [M+H]+ 532.9808. found: 532.9810.


### 2.11. (2-Formyl-5-fluorophenyl)iodo(4-methylphenyl)bismuthane7a

Yellow crystal, Yield 29% (195 mg, 0.29 mmol), mp 148–149°C.1H NMR (400 MHz, DMSO-d6):δ 2.21 (3H, s), 7.32 (2H, d,J = 7.6 Hz), 7.61 (1H, dt,J= 8.4 Hz, 2.4 Hz), 8.18 (2H, d,J = 7.6 Hz), 8.52 (1H, dd,J = 8.0 Hz, 5.2 Hz), 8.74 (1H, d,J = 6.4 Hz), 10.74 (1H, s). 13C NMR (100 MHz, DMSO-d6):δ 21.14, 115.75 (d,J = 22.7 Hz), 131.83 (br-s), 132.17(×2), 137.05, 139.01, 140.73 (d,J = 9.0 Hz), 140.88, 169.19, 171.80, 199.67. IR (KBr): ν 3061, 2875, 1638, 1582, 1561, 1259 and 1204 cm−1. HRMS (APCI) calcd. for C14H10BiFIO: [M–H]- 548.9566. found: 548.9570.


### 2.12. (2-Formyl-4-methoxyphenyl)iodo(4-methylphenyl)bismuthane8a

Yellow crystal, Yield 31% (175 mg, 0.31 mmol); mp 146–147°C;1H NMR (400 MHz, DMSO-d6):δ 2.22 (3H, s), 3.87 (3H, s), 7.31 (2H, d,J = 8.0 Hz), 7.48 (1H, dd,J= 7.6 Hz, 2.8 Hz), 7.99 (1H, d,J = 2.8 Hz), 8.13 (2H, d,J = 7.6 Hz), 8.78 (1H, d,J = 8.0 Hz), 10.66 (1H, s). 13C NMR (100 MHz, CDCl3):δ 21.57, 55.67, 122.95, 125.69, 132.38, 138.20, 138.31, 145.09, 147.94, 160.26, 161.34, 166.38, 199.13. IR (KBr): ν 3027, 2924, 2862, 1640, 1585, 1552, 1460, 1251 and 1044 cm–1. HRMS (APCI) calcd. for C15H13BiIO2: [M–H]- 560.9770. found: 560.9770.


### 2.13. (2-Formyl-3-thienyl)iodo(4-methylphenyl)bismuthane9a

Yellow crystal, Yield 53% (287 mg, 0.53 mmol), mp 132–133°C.1H NMR (400 MHz, CDCl3):δ 2.28 (3H, s), 7.31 (2H, d,J = 7.6 Hz), 8.04 (1H, d,J = 4.4 Hz), 8.09 (1H, d,J = 4.4 Hz), 8.14 (2H, d,J = 7.6 Hz), 10.12 (1H, s). 13C NMR (100 MHz, CDCl3):δ 21.58, 132.67, 138.50, 138.56, 142.08, 145.66, 148.47, 166.97, 174.32, 186.44. IR (KBr): ν 1586, 1483, 1450, 1397, 1337, 1195, 853 and 794 cm−1. HRMS (APCI) calcd. for C12H11BiIOS: [M+H]+ 538.9374. found: 538.9374.


### 2.14. (2-Ethoxycarbonylphenyl)iodo(4-methylphenyl)bismuthane10a

Yellow crystal, Yield 61% (351 mg, 0.61 mmol), mp 125–126°C.1H NMR (400 MHz, CDCl3):δ 1.40 (3H, t,J = 7.2 Hz), 2.26 (3H, s), 4.43 (2H, m), 7.26 (2H, d,J = 7.6 Hz), 7.36 (1H, dt,J = 7.6 Hz, 0.8 Hz), 7.84 (1H, dt,J = 7.6 Hz, 1.2 Hz), 8.09 (2H, d,J = 7.6 Hz), 8.22 (1H, dd,J = 7.6 Hz, 1.2 Hz), 9.43 (1H, d,J = 7.2 Hz). 13C NMR (100 MHz, CDCl3):δ 14.09, 21.54, 63.31, 128.29, 132.28, 132.77, 134.35, 137.96, 138.27, 138.70, 143.83, 166.84, 169.52, 175.85. IR (KBr): ν 2990, 1634, 1573, 1373, 1311, 1005, 785 and 733 cm−1. Anal. Calc. for C16H16BiIO2: C, 33.35; H, 2.80. Found: C, 33.32; H, 3.03.


## 2.1. Typical Procedure for the Finkelstein Reaction of Bromoarenes

To a round-bottomed flask (50 mL) equipped with a magnetic stir bar were added bromoarene (2.5 mmol), CuI (5 mol%), NaI (5 mmol), and 1,3-diaminopropane (10 mol%). After dry 1,4-dioxane (2.5 mL) was added to the flask, the mixture was refluxed for 24 h. The reaction was quenched with water (30 mL) at room temperature and the resulting mixture was extracted with ethyl acetate (3 × 30 mL). The organic layer was dried (Na2SO4) and concentrated to leave a residue, which was chromatographed on silica gel with hexane–ethyl acetate (5:1) to give the corresponding iodoarene, which was used in the next step without further purification.


## 2.2. 2-Iodobenzaldehyde

Yield 99% (574 mg, 2.48 mmol), Colorless solid, mp 39–41°C.1H NMR (400 MHz, CDCl3):δ 7.29 (1H, dt,J = 7.6 Hz, 1.6 Hz), 7.47 (1H, t,J = 7.6 Hz), 7.89 (1H, dd,J = 7.6 Hz, 1.6 Hz), 7.96 (1H, d,J = 8.0 Hz), 10.08 (1H, s).


## 2.3. 4-Fluoro-2-Iodobenzaldehyde

Yield 97% (606 mg, 2.43 mmol), Colorless solid, mp 49–51°C.1H NMR (400 MHz, CDCl3):δ 7.19 (1H, m), 7.68 (1H, m), 7.91 (1H, m), 9.99 (1H, d,J = 2.4 Hz).


## 2.4. 2-Iodo-5-Methoxybenzaldehyde

Yield 98% (642 mg, 2.45 mmol), Colorless solid, mp 113–116°C.1H NMR (400 MHz, CDCl3):δ 3.84 (3H, s), 6.92 (1H, dd,J = 8.4 Hz, 3.2 Hz), 7.43 (1H, d,J = 3.2 Hz), 7.80 (1H, d,J = 8.4 Hz), 10.02 (1H, s).


## 2.5. 4′-Fluoro-2′-Iodoacetophenone

Yield 98% (647 mg, 2.45 mmol), Colorless solid, mp 45–46°C.1H NMR (400 MHz, CDCl3):δ 2.59 (3H, s), 7.11 (1H, m), 7.52 (1H, m), 7.65 (1H, m).


## 2.6. 3-Iodothiophene-2-Carboxaldehyde

Yield 99% (589 mg, 2.48 mmol), Colorless solid, mp 82–85°C.1H NMR (400 MHz, CDCl3):δ 7.28 (1H, d,J = 4.8 Hz), 7.70 (1H, dd,J = 4.8 Hz, 1.2 Hz), 9.83 (1H, d,J = 1.2 Hz).


## 2.7. Typical Procedure for the Synthesis of Aryl(iodo)(4-methylphenyl)bismuthane

To a round-bottomed flask (50 mL) equipped with a magnetic stir bar were added bismuth(III) chloride (422 mg, 1.33 mmol) and tris(4-methylphenyl)bismuthane (323 mg, 0.67 mmol). After dry diethyl ether (6 mL) was added to the flask at room temperature, the mixture was stirred for 1 h. To another round-bottomed flask (50 mL) were added iodoarene (1 mmol), zinc powder (262 mg, 4 mmol), and dry DMF (5 mL). The flask was set in an ultrasonic water bath at room temperature (25°C) and the resulting mixture was sonicated for 1.5–4 h, during which time the water bath temperature rose to 48°C. The sonication was stopped and unreacted zinc powder precipitated. The resulting supernatant solution containing an arylzinc reagent was slowly transferred to the suspension of dichloro(4-methylphenyl)bismuthane (ca. 2 mmol) thus formed, and the resulting mixture was stirred for 3.5–8 h at room temperature. The reaction was quenched with a saturated aqueous solution of NaI (3 mL) and the resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined extracts were concentrated to leave an oily residue, which was chromatographed on silica gel with hexane–ethyl acetate (5:1) to afford the corresponding iodobismuthane.


## 2.8. (2-Acetylphenyl)iodo(4-methylphenyl)bismuthane2a

Yellow crystal, Yield 35% (191 mg, 0.35 mmol), mp 160–162°C.1H NMR (400 MHz, CDCl3):δ 2.25 (3H, s), 2.69 (3H, s), 7.25 (2H, d,J = 8.0 Hz), 7.71 (1H, dt,J = 7.6 Hz, 1.2 Hz), 7.88 (1H, dt,J = 7.6 Hz, 1.2 Hz), 8.07 (2H, d,J= 8.0 Hz), 8.22 (1H, dd,J = 7.6 Hz, 1.2 Hz), 9.41 (1H, dd,J = 7.2 Hz, 0.8 Hz). 13C NMR (100 MHz, CDCl3):δ 21.54, 27.08, 128.50, 132.36, 134.51, 138.01, 138.21, 138.98, 143.10, 145.55, 166.78, 172.09, 207.54. IR (KBr): ν 3738, 3037, 1622, 1552, 1276 and 761 cm−1. HRMS (APCI) calcd. for C15H13BiIO: [M–H]- 544.9832. found: 544.9821.


## 2.9. (2-Acetyl-5-fluorophenyl)iodo(4-methylphenyl)bismuthane5a

Yellow crystal, Yield 28% (158 mg, 0.28 mmol), mp 186–188°C.1H NMR (400 MHz, DMSO-d6):δ 2.19 (3H, s), 2.72 (3H, s), 7.29 (2H, d,J = 7.6 Hz), 7.54 (1H, dt,J = 8.4 Hz, 2.0 Hz), 8.11 (2H, d,J = 7.6 Hz), 8.55 (1H, dd,J = 8.4 Hz, 4.8 Hz), 8.89 (1H, br-s). 13C NMR (100 MHz, DMSO-d6):δ 21.13, 27.48, 115.62 (d,J = 22.6 Hz), 130.94 (br-d), 132.08(×2), 137.09, 138.45, 138.85 (d,J = 8.0 Hz), 140.51, 169.52, 172.12, 207.85. IR (KBr): ν 1620, 1575, 1558, 1358, 1299, 1262 and 1201 cm−1. HRMS (APCI) calcd. for C15H12BiFIO: [M–H]- 562.9730. found: 562.9726.


## 2.10. (2-Formylphenyl)iodo(4-methylphenyl)bismuthane6a

Yellow crystal, Yield 56% (298 mg, 0.56 mmol), mp 143–144°C.1H NMR (400 MHz, DMSO-d6):δ 2.21 (3H, s), 7.30 (2H, d,J = 7.6 Hz), 7.86 (1H, t,J = 7.2 Hz), 7.95 (1H, t,J= 7.2 Hz), 8.14 (2H, d,J =7.6 Hz), 8.44 (1H, d,J= 7.2 Hz), 9.02 (1H, d,J= 7.2 Hz), 10.75 (1H, s). 13C NMR (100 MHz, CDCl3):δ 21.55, 128.65, 132.47, 137.58, 138.23, 138.44, 139.63, 143.66, 146.16, 165.99, 170.92, 199.50. IR (KBr): ν 3058, 2857, 1633, 1572, 1553, 1296 and 1207 cm−1. HRMS (APCI) calcd. for C14H13BiIO: [M+H]+ 532.9808. found: 532.9810.


## 2.11. (2-Formyl-5-fluorophenyl)iodo(4-methylphenyl)bismuthane7a

Yellow crystal, Yield 29% (195 mg, 0.29 mmol), mp 148–149°C.1H NMR (400 MHz, DMSO-d6):δ 2.21 (3H, s), 7.32 (2H, d,J = 7.6 Hz), 7.61 (1H, dt,J= 8.4 Hz, 2.4 Hz), 8.18 (2H, d,J = 7.6 Hz), 8.52 (1H, dd,J = 8.0 Hz, 5.2 Hz), 8.74 (1H, d,J = 6.4 Hz), 10.74 (1H, s). 13C NMR (100 MHz, DMSO-d6):δ 21.14, 115.75 (d,J = 22.7 Hz), 131.83 (br-s), 132.17(×2), 137.05, 139.01, 140.73 (d,J = 9.0 Hz), 140.88, 169.19, 171.80, 199.67. IR (KBr): ν 3061, 2875, 1638, 1582, 1561, 1259 and 1204 cm−1. HRMS (APCI) calcd. for C14H10BiFIO: [M–H]- 548.9566. found: 548.9570.


## 2.12. (2-Formyl-4-methoxyphenyl)iodo(4-methylphenyl)bismuthane8a

Yellow crystal, Yield 31% (175 mg, 0.31 mmol); mp 146–147°C;1H NMR (400 MHz, DMSO-d6):δ 2.22 (3H, s), 3.87 (3H, s), 7.31 (2H, d,J = 8.0 Hz), 7.48 (1H, dd,J= 7.6 Hz, 2.8 Hz), 7.99 (1H, d,J = 2.8 Hz), 8.13 (2H, d,J = 7.6 Hz), 8.78 (1H, d,J = 8.0 Hz), 10.66 (1H, s). 13C NMR (100 MHz, CDCl3):δ 21.57, 55.67, 122.95, 125.69, 132.38, 138.20, 138.31, 145.09, 147.94, 160.26, 161.34, 166.38, 199.13. IR (KBr): ν 3027, 2924, 2862, 1640, 1585, 1552, 1460, 1251 and 1044 cm–1. HRMS (APCI) calcd. for C15H13BiIO2: [M–H]- 560.9770. found: 560.9770.


## 2.13. (2-Formyl-3-thienyl)iodo(4-methylphenyl)bismuthane9a

Yellow crystal, Yield 53% (287 mg, 0.53 mmol), mp 132–133°C.1H NMR (400 MHz, CDCl3):δ 2.28 (3H, s), 7.31 (2H, d,J = 7.6 Hz), 8.04 (1H, d,J = 4.4 Hz), 8.09 (1H, d,J = 4.4 Hz), 8.14 (2H, d,J = 7.6 Hz), 10.12 (1H, s). 13C NMR (100 MHz, CDCl3):δ 21.58, 132.67, 138.50, 138.56, 142.08, 145.66, 148.47, 166.97, 174.32, 186.44. IR (KBr): ν 1586, 1483, 1450, 1397, 1337, 1195, 853 and 794 cm−1. HRMS (APCI) calcd. for C12H11BiIOS: [M+H]+ 538.9374. found: 538.9374.


## 2.14. (2-Ethoxycarbonylphenyl)iodo(4-methylphenyl)bismuthane10a

Yellow crystal, Yield 61% (351 mg, 0.61 mmol), mp 125–126°C.1H NMR (400 MHz, CDCl3):δ 1.40 (3H, t,J = 7.2 Hz), 2.26 (3H, s), 4.43 (2H, m), 7.26 (2H, d,J = 7.6 Hz), 7.36 (1H, dt,J = 7.6 Hz, 0.8 Hz), 7.84 (1H, dt,J = 7.6 Hz, 1.2 Hz), 8.09 (2H, d,J = 7.6 Hz), 8.22 (1H, dd,J = 7.6 Hz, 1.2 Hz), 9.43 (1H, d,J = 7.2 Hz). 13C NMR (100 MHz, CDCl3):δ 14.09, 21.54, 63.31, 128.29, 132.28, 132.77, 134.35, 137.96, 138.27, 138.70, 143.83, 166.84, 169.52, 175.85. IR (KBr): ν 2990, 1634, 1573, 1373, 1311, 1005, 785 and 733 cm−1. Anal. Calc. for C16H16BiIO2: C, 33.35; H, 2.80. Found: C, 33.32; H, 3.03.


## 3. Results and Discussion

Initially, we tried the one-pot synthesis of10a by the zincation of ethyl 2-iodobenzoate. The arylzinc was prepared by using the method reported by Takagi and coworkers [20], who treated iodoarenes containing an electron-withdrawing substituent, such as a methoxycarbonyl or an acetyl substituent, at the ortho position in the presence of zinc powder under ultrasonication at 30°C.When a mixture obtained by sonicating ethyl 2-iodobenzoate with zinc powder (1 equiv) at 25°C in DMF was allowed to react with TolBiCl2 (1 equiv),10a was obtained in only 4% yield (Table 1, Entry 1). The poor yield was attributed to the incomplete conversion of the starting iodoarene to the arylzinc. The yield of10a was increased by increasing the equivalents of zinc powder and TolBiCl2 (Entries 2 and 3). Furthermore, an increase in the temperature from 25 to 48°C during the sonication accelerated the zincation reaction (Entries 4–9). The reaction mixture turned dark yellow during the zincation, which was a good indicator for the completion of the reaction. The yield of10a was sensitive to the zinc powder loading and the best result was obtained when 4 equiv zinc powder and 2 equiv TolBiCl2 were used (Entry 7). Higher zinc powder or TolBiCl2 loadings decreased the yield of10a (Entries 8 and 9).Table 1
Optimization of the reaction conditions for the synthesis of10a.
Entry Zn TolBiCl2 Ultrasound Ultrasound Yield (%) (equiv) (equiv) Temp (°C) Time (h) 10a  1 1.0 1.0 25 6 4 2 1.5 1.0 25 6 9 3 2.0 1.5 25 5 14 4 2.5 1.5 25–48 3 18 5 3.0 2.0 25–48 4 28 6 3.5 2.0 25–48 4 41 7 4.0 2.0 25–48 4 61 8 4.5 2.0 25–48 5 60 9 4.0 3.0 25–48 5 55Encouraged by the success of the one-pot synthesis of10a, we performed the one-pot syntheses of2a and5a, which have an acetophenone scaffold, using the reaction conditions used in the synthesis of10a (Table 1, Entry 7). After the zincation reaction mixtures had turned dark yellow, the arylzinc was allowed to react with TolBiCl2, followed by quenching with a saturated aqueous solution of NaI to give2a and5a in 35% and 28% yields, respectively, despite the presence of acidic acetyl protons (Table 2, Entries 1 and 2). We have previously reported that the synthesis of5a from the corresponding silyl enol ether by conventional directed lithiation failed (Scheme 1) [14]. We explained the failure by the presence of the fluoro substituent, which can act as a directing group. The success in obtaining5a demonstrates the usefulness of the zincation method.Table 2
Synthesis of iodobismuthanes.
Entry ArI Ultrasound TolBiCl2 ArBi(Tol)I Yield (%) Time (h) Time (h)  1  2.0 3.5 2a 35  2  1.5 6.0 5a 28  3  3.5 8.0 6a 56  4  3.0 8.0 7a 29  5  3.5 8.0 8a 31  6  4.0 8.0 9a 53Furthermore, we used this method to synthesize6a–9a, which have a formyl substituent (Entries 3–6). We have previously reported the synthesis of6 by the directedortho-lithiation of lithium α-amino alkoxide (Scheme 4) [13]. This method required excess BuLi, which often caused the loss of Ar2BiCl or decomposition of the product by overreaction with unreacted BuLi. In addition, the lithium alkoxide moiety could form an undesired bismuth alkoxide by reacting with Ar2BiCl. Hence, the present zincation overcomes these drawbacks. In particular,7a, 8a, and9a were obtained in acceptable yields by the zincation; if conventional directed lithiation was used, the fluoro and methoxy substituents in7a and8a, respectively, would act as directing groups and the thienyl ring proton α to the sulfur atom in9a would undergo undesired lithiation.Scheme 4
Conventional synthesis of6 by directed lithiation.The molecular structure of2 (Ar = Tol, X = Br) has been characterized by X-ray structure analysis and 13C NMR and IR spectra, which reveals the formation of a hypervalent O–Bi–Br bond by the intramolecular coordination of the carbonyl group with the bismuth atom [13]. The hypervalent bond formation was also detected in the 1H NMR spectra. The 1H NMR spectrum of2a in CDCl3 shows anisotropic deshielding (δ 9.41 ppm) of theortho proton adjacent to the bismuth atom in the arylcarbonyl scaffold because of its close proximity to the electronegative iodine atom owing to the hypervalent O–Bi–I bond formation [14]. Compound10a showed a similar deshielding of theortho proton signal atδ 9.43 ppm in CDCl3, which is consistent with hypervalent bond formation. In contrast, no large deshielding of the aromatic proton was observed in the thienyl ring proton of9a. This may be attributed to the signal for the α-proton of the thienyl ring being shifted downfield because of the effect of the sulfur atom. As a result, the signal due to the β-proton is apparently not affected by anisotropic deshielding by the iodine atom.


## 4. Conclusions

Hypervalent iodobismuthanes bearing a carbonyl group were synthesized easily with a one-pot reaction using arylzinc reagents. The zinc reagents tolerated carbonyl group, acetyl protons, and ring protons adjacent to fluoro, methoxy, and sulfur functional groups. This indicates that the zincation reaction may be suitable for synthesizing a wide range of hypervalent antifungal bismuth(III) compounds with various molecular scaffolds.



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*Source: 2385064-2019-02-27.xml*