New Synthesis of Diarylmethanes, Key Building Blocks for SGLT2 Inhibitors

Abstract

Synthesis of diarylmethanes, a key building block for SGLT2 inhibitors, has been developed through ketone synthesis by Friedel–Crafts acylation with TiCl₄, followed by reduction with TiCl₄/NaBH₄. The new protocol proceeded more cleanly than the previous methods employing AlCl₃ and BF₃·OEt₂/Et₃SiH to provide the diarylmethanes corresponding to canagliflozin, empagliflozin, and luseogliflozin in a highly expedient and affordable manner. In the case of a diarylmethane for the synthesis of dapagliflozin, the reduction step took place by an alternative method using InCl₃/Al/BF₃·OEt₂.

Introduction

Diarylmethanes 1 have received keen interest as a significant building block for drugs and natural products (Figure 1).¹ Intensive research has been directed toward an efficient synthesis of this class of compounds including Friedel–Crafts benzylation of benzyl alcohols^2a or benzyl halides^2b or benzyl acetates or benzyl ammonium salts;^2c Suzuki coupling of aryl boronic acids^2d or benzyl boronic acids;^2e Negishi coupling of benzyl zinc reagents;^2f Kumada coupling of benzyl Grignard reagents;^2g Stille coupling of benzyl tin reagents,^2h and coupling of aromatic carboxylic acids²ⁱ (Scheme 1). Among them, synthesis using aromatic carboxylic acids 2(2i) represents one of the major approaches to 1 because of commercial abundance of the carboxylic acids.³

Figure 1.

Diarylmethanes 1.

Scheme 1. Synthetic Approaches to Diarylmethanes 1.

In the meantime, as a part of our ongoing research program to develop an efficient and practical synthetic method for pharmaceuticals and their intermediates, we have undertaken the process development of SGLT2 inhibitors (sodium-glucose transporter 2 inhibitors) 3 due to their attractive medical efficacies such as a dual action for both diabetes and heart failure (Figure 2).⁴ The compounds contain a characteristic diarylmethane motif as a common structure in the molecules. Reported herein is a novel and efficient synthesis of diarylmethanes 1 in the SGLT2 inhibitors through Ti-based Friedel–Crafts acylation and reduction of the carbonyl group to methylene.

Figure 2.

SGLT2 inhibitors 3a–d and diarylmethane building blocks 1a–e.

Results and Discussion

For the synthesis of the diarylmethanes 1 leading to 3, a well-documented approach is the method involving synthesis of diarylketones 5 followed by reduction of the carbonyl group to methylene (Scheme 2). Although the method has been implemented on a large commercial scale to meet the growing demand of 1, they still have a drawback of employing expensive triethylsilane (reagent price: ca. US$153 per 1 mole of active hydride) as the reductant.²ⁱ To address this challenge, reported herein is an expedient synthesis of 1 by means of readily available TiCl₄-mediated Friedel–Crafts acylation and subsequent reduction of the resulting ketones with TiCl₄–NaBH₄ or InCl₃/BF₃·OEt₂/Al.

Scheme 2. Synthesis of Diarylmethanes 1 from Aromatic Carboxylic Acids 2.

In our initial study, synthesis of diarylketones 5 from aromatic carboxylic acids 2 has been examined through Friedel–Crafts acylation of acid chlorides in situ generated from 2 (Table 1).^2i,5 For a Lewis acid to effect the transformation, AlCl₃ is most widely employed for the aromatic substitution. Nonetheless, handling of the moisture-sensitive solid Lewis acid is problematic, especially on a large scale. Hence, as an alternative approach, the use of a readily available liquid TiCl₄ was tested. Thus, treatment of an acid chloride obtained from 5-iodo-2-methylbenzoic acid 2a with 2-(4-fluorophenyl)thiophene 4a in the presence of TiCl₄ was tested to provide the diarylketone 5a in 91% yield, which is comparable to the outcome with AlCl₃ (89%, Table 1, entries 1, 2). Although use of TiCl₄ for Friedel–Crafts acylation has been reported,⁶ it was only applied to simple substrates. Functionalized substrates such as the present case has never been employed especially for the synthesis of SGLT2 inhibitors.^4a Then, the method was applied to the synthesis of other diaryl ketones 5b–e including bromides for the synthesis of canagliflozin (3a), dapagliflozin (3b), empagliflozin (3c), and luseogliflozin (3d) (Table 1, entries 3–6) to give the corresponding diarylketones in moderate to high yields. The lower yield of empagliflozin intermediate 5d (39%) was owing to incomplete conversion with substrates remained intact. No formation of regioisomers was detected for all reactions. Remarkably, in contrast to AlCl₃, operation of TiCl₄ in DCM was quite easy in terms of avoiding exposure to moisture, and after addition of the TiCl₄ solution to the reaction mixture, a homogeneous solution was maintained throughout the reaction.

Table 1. Synthesis of Diarylketones 5 from Aromatic Carboxylic Acids 2.

entry	compd	X	Y	R	Ar	Lewis acid (equiv)	temp. (°C)	time (h)	yield (%)a
1	5a	I	H	H	A	TiCl4 (1.5)	0–30	4	91
2	5a	I	H	H	A	AlCl3 (1.2)	5–25	2.5	89
3	5b	Br	H	H	A	TiCl4 (1.5)	0–30	4	88
4b	5c	Br	Cl	H	B	TiCl4 (1.5)	8–12	3.3	74
5	5d	Br	Cl	H	C	TiCl4 (1.5)	0–50	16	39
6c	5e	Br	H	OMe	B	TiCl4 (1.5)	5–25	2.3	80

^aIsolated yield.

^bThe acid chloride formation was conducted using oxalyl chloride (1.1 equiv) at 10–25 °C for 20 h.

^cThe acid chloride formation was conducted using oxalyl chloride (1.1 equiv) in CHCl₃ at 6–25 °C for 12 h.

Reduction of the diarylketones 5 to methylene derivatives 1 was our next subject for investigation. Combination of inexpensive reductants with various metal salts was tested using conversion of 5a to 1a as a typical example (Table 2). For a control experiment, a known procedure using Et₃SiH/BF₃·OEt₂ was tested to provide the desired product 1a in 41% yield (Table 2, entry 1).⁷ Expecting cost reduction, either use of trichlorosilane (TCS) or polymethylhydrosilane (PMHS) in the presence of BF₃·OEt₂ was tried (Table 2, entries 2 and 3). However, no desired product 1a was obtained with complete recovery of 5a. As alternative approaches, use of inexpensive NaBH₄ (reagent price: ca. US$7.7 per 1 mole of active hydride) in the presence of Brønsted acid (H₂SO₄) or Lewis acid (MgCl₂, CaCl₂, FeCl₃) was attempted (Table 2, entries 4–7). Contrary to our expectation, no reaction or formation of alcohol 6a resulted. Finally, the TiCl₄/NaBH₄ system was tested (Table 2, entry 8). To our delight, by the treatment, the desired product 1a was obtained in 64% yield. Finally, sequential reduction of 5a with NaBH₄ (1.5 equiv) at 70 °C for 2 h to alcohol 6 followed by reaction with TiCl₄ (1.5 equiv) at 50 °C for 5 h provided 1a in 85% yield (Table 2, entry 9). It should be noted that addition of TiCl₄ to the mixture resulted in no raise in temperature and heating up was needed to reach 50 °C. Hence, as far as for the scale of the reaction indicated, there is no concern about any significant exothermic reaction on adding TiCl₄.

Table 2. Reduction of Diaryl Ketone 5a to Diaryl Methane 1a.

entry	reductant (equiv)	additive (equiv)	solvent (V)	temp. (°C)	time (h)	yield (%)a
1	Et3SiH (4.0)	BF3·OEt2 (3.8)	DCM/CH3CN (10:10)	0–25	4	41
2	TCS (4.0)	BF3·OEt2 (3.8)	CH3CN (20)	50	5	NRb
3	PMHS (4.0)	BF3·OEt2 (3.8)	DME (20)	70	5	NRb
4	NaBH4 (1.2)	H2SO4 (0.6)	THF (10)	50	3	NRb
5	NaBH4 (1.0)	MgCl2 (0.5)	diglyme (10)	50	3	c
6	NaBH4 (1.0)	CaCl2 (0.5)	DME (10)	50	3	c
7	NaBH4 (1.0)	FeCl3 (1.0)	DME (10)	50	3	c
8	NaBH4 (1.0)	TiCl4d (1.0)	DME (20)	70	3	64
9e	NaBH4 (1.5)	TiCl4d (1.0)	DME (10)	70	2	85
				50	5

^aIsolated yield.

^bNo reaction.

^cThe product was an alcohol 6a as shown below:

^dAdded as a 25 wt % of DCM solution.

^eSequential treatment with NaBH₄ at 70 °C for 2 h and with TiCl₄ at 50 °C for 5 h.

The reduction protocol was applied to the synthesis of diarylmethanes (1b (bromide), 1c, 1d, 1e) for canagliflozin (3a), empagliflozin (3c), and luseogliflozin (3d) to give the desired products in good yields (Table 3, entries 1, 3, and 4). In marked contrast, when reduction of diarylketone (5c) corresponding to dapagliflozin (3b) was examined, the reaction gave a dimer 7c (Table 3, entry 2).⁸

Table 3. Reduction of Diaryl Ketone 5b–e to Diarylmethane 1b–e with NaBH₄/TiCl₄.

entry	compd	X	Y	R	Ara	temp (°C)	time (h)	yield (%)c
1c	1b	Br	Me	H	A	65–70	3	86
						45–50	5
2d	1c	Br	Cl	H	B	50	0.2	96e
						50	2
3c	1d	Br	Cl	H	C	65–70	2	79
						45–50	6
4f	1e	Br	Me	OMe	B	70	2	79
						40	7

^aStructures of Ar groups:

^bIsolated yields.

^cSequential treatment with NaBH₄ at 65–70 °C and with TiCl₄ at 45–50 °C.

^dSequential treatment with NaBH₄ at 50 °C and with TiCl₄ at 50 °C.

^eThe product was not 1c but a dimer 7c as shown below:

^fSequential treatment with NaBH₄ at 70 °C and with TiCl₄ at 40 °C.

For reduction of 5c, another protocol using InCl₃/Al/BF₃·OEt₂⁹ was tested to furnish the desired diarylmethane 1c in 56% yield (Scheme 3).

Scheme 3. Reduction of Diarylketone 5c to Diarylmethane 1c with InCl₃/Al/BF₃·OEt₂.

A possible reaction mechanism for TiCl₄/NaBH₄ reduction of diarylketone 5 to diarylmethane 1 is shown in Scheme 4. To begin with, benzyl alcohol 6 is generated by treatment of 5 with NaBH₄.¹⁰ Then, benzylic carbocation 8 is formed from 6 by addition of TiCl₄. Subsequent single electron transfer (SET) produces benzylic radical 9, which produces diarylmethane 1 through another SET and protonation. Switch of the product from 1c to the dimer 7c was observed for the reaction starting from 5c. This might be accounted for by a subtle difference in stabilities of the benzylic radicals, but the detailed reasons behind this remain unclear.¹¹

Scheme 4. Possible Mechanism for TiCl₄/NaBH₄ Reduction of Diarylketones 5 to Diarylmethanes 1.

Conclusions

An alternative synthesis of diarylmethanes has been worked out by using TiCl₄-mediated Friedel–Crafts acylation and reduction of the resulting diarylketones either by TiCl₄/NaBH₄ or InCl₃/Al/BF₃·OEt₂ depending on the substrate employed. The entire procedure can be carried out using readily available and cheap reagents under mild reaction conditions. The scale-up studies such as precise evaluation of the quality of the products, safety assessment, telescoping of the reaction sequence, and removal of silica gel column chromatography purification are under current investigation, which will be reported elsewhere in due course.

Experimental Section

General

¹H, ¹³C, and ¹⁹F NMR spectra (JEOL JNM-LA 500 spectrometer, 500, 126, and 376 MHz, respectively) were recorded with tetramethylsilane used as an internal standard. Melting points were determined using a Büchi (Model M565) automated melting point system (temperature measurement accuracy is 0.1 °C). High-resolution mass spectrometry was performed by the Elemental Analysis Section of Osaka University. Thin-layer chromatography (TLC) was carried out on E. Merck 0.25 mm pre-coated glass-backed plates (60 F₂₅₄). Development was accomplished using 5% phosphomolybdic acid in ethanol with heating or visualized by UV light where feasible. Column chromatography was performed with SiO₂ (Silica Flash F60, 230–400 mesh). All solvents and reagents were used as received.

Typical Procedure for Synthesis of Diarylketone 5

(5-(4-Fluorophenyl)-thiophen)-2-yl-(5-iodo-2-methylphenyl)methanone (5a).⁷

To a suspension of 5-iodo-2-methylbenzoic acid 2a (5.00 g, 19.1 mmol) in CH₂Cl₂ (35 mL) was added DMF (0.0700 g, 0.950 mmol) followed by SOCl₂ (4.77 g, 40.1 mmol) at 20–30 °C. The mixture was stirred at 50 °C for 1 h under an argon atmosphere. Progress of the reaction was monitored through TLC by quenching with MeOH. The reaction mixture was evaporated, and the residue was dissolved in CH₂Cl₂ (35 mL). A solution of TiCl₄ (5.43 g, 28.6 mmol) in CH₂Cl₂ (17.5 mL) was added to the mixture at 0–10 °C, and the mixture was stirred at the same temperature for 30 min. Then, a solution of 2-(4-fluorophenyl)thiophene (4a)¹⁰ (3.40 g, 19.1 mmol) in CH₂Cl₂ (17.5 mL) was added to the above mixture at 0–10 °C and further stirred at 20–30 °C for 4 h. After quenching the reaction by addition of water (50 mL), the reaction mixture was extracted with CH₂Cl₂ (2 × 25 mL). Combined CH₂Cl₂ extracts were washed with water (2 × 25 mL) followed by sat. aq. NaHCO₃ (2 × 25 mL), dried over sodium sulfate, evaporated to give a crude 5a as a light brown solid (8.8 g). Trituration of the crude 5a in heptane (50 mL) provided pure 5a (7.30 g, 91%) as a light brown solid. MP: 138–142 °C; IR (NaCl) ν_max: 1638, 1612, 1530, 1441, 1294, 1235, 1160, 1059, 813 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ: 7.75 (d, J = 1.9 Hz, 1H), 7.70 (dd, J = 8.1, 1.9 Hz, 1H), 7.67–7.61 (m, 2H), 7.36 (d, J = 4.0 Hz, 1H), 7.25 (d, J = 3.9 Hz, 1H), 7.15–7.09 (m, 2H), 7.04 (d, J = 8.1 Hz, 1H), 2.32 (s, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ: 188.23, 163.30 (d, ¹J_C–F = 250.74 Hz), 153.27, 142.69, 140.32, 139.07, 136.81, 136.18, 135.98, 132.93, 129.43 (d, ⁴J_C–F = 3.7 Hz), 128.19 (d, ³J_C–F = 8.4 Hz), 124.09 (d, ⁵J_C–F = 1.6 Hz), 116.26 (d, ²J_C–F = 22.68 Hz), 89.62, 19.28; ¹⁹F{¹H} NMR (376 MHz, CDCl₃, 30 °C) δ: −111.16.

(5-(4-Fluorophenyl)-thiophen)-2-yl-(5-bromo-2-methylphenyl)methanone (5b).⁷

The compound was prepared according to the typical procedure for the synthesis of 5a using 5-bromo-2-methylbenzoic acid 2b (5.00 g, 23.3 mmol), SOCl₂ (5.80 g, 48.8 mmol), TiCl₄ (6.62 g, 34.9 mmol), and 2-(4-fluorophenyl)thiophene 4a (4.14 g, 23.2 mmol). Yield: 7.70 g (88%) as a pale-yellow solid. MP: 122–126 °C; IR (NaCl) ν_max: 1639, 1599, 1531, 1504, 1442, 1296, 1257, 1235, 1161, 1059 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ: 7.67–7.61 (m, 2H), 7.57 (d, J = 2.2 Hz, 1H), 7.50 (dd, J = 8.2, 2.1 Hz, 1H), 7.37 (d, J = 4.0 Hz, 1H), 7.25 (d, J = 4.0 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 7.15–7.09 (m, 2H), 2.33 (s, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ: 188.36, 163.30 (d, ¹J_C–F = 250.74 Hz), 153.29, 142.64 (d, ⁵J_C–F = 0.9 Hz), 139.97, 136.81, 135.35, 133.12, 132.71, 130.45, 129.41 (d, ⁴J_C–F = 3.7 Hz), 128.18 (d, ³J_C–F = 8.4 Hz), 124.08 (d, ⁵J_C–F = 1.6 Hz), 118.76, 116.25 (d, ²J_C–F = 22.68 Hz), 19.17; ¹⁹F{¹H} NMR (376 MHz, CDCl₃, 30 °C) δ: −111.15.

(5-Bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone (5c).¹²

To a suspension of 5-bromo-2-chlorobenzoic acid (2c) (5.00 g, 21.2 mmol) in CHCl₃ (60 mL) was added DMF (0.0150 g, 0.200 mmol). Then, oxalyl chloride (2.96 g, 23.3 mmol) was added at 10 °C, and the mixture was stirred at 25 °C for 20 h. The mixture was evaporated, and the residue was dissolved in CH₂Cl₂ (20 mL). To the solution was added TiCl₄ (6.04 g, 31.8 mmol) in CH₂Cl₂ (20 mL) at 10 °C over 3 min, and the mixture was stirred at 10 °C for 15 min. To the solution was added phenetole 4b (2.59 g, 21.2 mmol) at 8–12 °C over 15 min, and the mixture was stirred at the same temperature for 3 h. To the mixture was added water (20 mL). The aqueous phase was extracted with CH₂Cl₂ (20 mL) and the combined organic phases were washed with water (20 mL), dried over MgSO₄, and evaporated to give crude 5c (7.1 g), which was subjected to recrystallization using hexane (30 mL) to obtain pure 5c as a colorless solid (5.30 g, 74%). MP: 68–70 °C; IR (NaCl) ν_max: 1736, 1659, 1595, 1244 cm^–1; ¹H NMR (500 MHz) δ: 7.75 (d, J = 8.7 Hz, 1H), 7.53–7.48 (m, 1H), 7.46 (dd, J = 2.2, 0.8 Hz, 1H), 7.30 (dd, J = 8.6, 0.7 Hz, 1H), 6.93–6.89 (m, 2H), 4.09 (q, J = 7.0 Hz, 1H), 1.42 (t, J = 7.0 Hz, 2H). ¹³C{¹H} NMR (125 MHz) δ: 192.13, 163.95, 140.78, 133.78, 132.67, 131.62, 131.53, 130.17, 128.65, 120.59, 114.56, 64.04, 14.74.

(S)-(5-Bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (5d).¹³

The compound was prepared according to the typical procedure for the synthesis of 5a using 5-bromo-2-methylbenzoic acid 2b (0.500 g, 2.12 mmol) in CH₂Cl₂ (3.5 mL), DMF (7.76 mg, 0.106 mmol), SOCl₂ (0.530 g, 4.46 mmol), TiCl₄ (0.60 g, 3.18 mmol), and (S)-3-phenoxytetrahydrofuran 4c (0.418 g, 2.55 mmol) under the conditions described in Table 1. The crude 5d was purified by silica gel column chromatography (hexane/ethyl acetate 9.5:0.5 to 6:4) to afford pure 5d (0.316 g, 39%) as a colorless sticky oil. IR (NaCl) ν_μmax: 3058, 2980, 2953, 2867, 1668, 1661, 1598, 1572, 1506, 1456, 1423, 1251, 1084, 845, 736 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ: 7.79–7.67 (m, 2H), 7.51 (dd, J = 8.5, 2.4 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 6.97–6.81 (m, 2H), 4.98 (ddt, J = 6.1, 4.1, 1.9 Hz, 1H), 4.04–3.92 (m, 3H), 3.88 (td, J = 8.4, 4.3 Hz, 1H), 2.31–2.19 (m, 1H), 2.17–2.09 (m, 1H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ: 191.85, 162.14, 140.42, 133.65, 132.48, 131.40, 131.35, 129.94, 128.79, 120.40, 115.10, 77.72, 72.83, 67.07, 32.86.

(5-Bromo-4-methoxy-2-methylphenyl)(4-ethoxyphenyl)methanone (5e).¹⁴

To a suspension of 5-bromo-4-methoxytoluic acid (3.00 g, 12.2 mmol) in CHCl₃ (36 mL) was added DMF (1 drop). To the mixture was added dropwise oxalyl chloride (1.71 g, 13.5 mmol) at 6 °C over 2 min. The mixture was stirred at the same temperature for 2 h and at 25 °C for 10 h. The mixture was evaporated, and the residue was dissolved in CH₂Cl₂ (12 mL). Then, TiCl₄ (3.50 g, 18.5 mmol) in CH₂Cl₂ (12 mL) was added at 10–12 °C over 5 min. The mixture was stirred at the same temperature for 15 min, and phenetole (1.50 g, 12.3 mmol) was added at 5–8 °C over 15 min. The mixture was stirred at the same temperature for 2 h and at 25 °C for 2 h. The mixture was poured into ice water (20 mL). The organic phase was separated and evaporated. To the residue was added hexane (30 mL) and the mixture was stirred at 5–10 °C for 1 h. The solid formed was filtered to give 5e as a white solid (3.40 g, 80%). MP: 83.0 °C. IR (KBr) ν_max: 2938, 1641, 1601, 1591, 1572 cm^–1; ¹H NMR (500 MHz, CDCl₃, 30 °C) δ: 7.75 (d, J = 9.0 Hz, 2H), 7.51 (s, 1H), 6.93 (d, J = 9.0, 2H), 6.79 (s, 1H), 4.11 (q, J = 7.0 Hz, 2H), 3.95 (s, 3H), 2.33 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H). ¹³C{¹H} NMR (126 MHz) δ: 195.69, 163.56, 157.33, 139.22, 134.22, 132.93, 130.88, 114.71, 114.65, 114.63, 108.19, 64.30, 56.79, 20.81, 15.15.

Typical Procedure for Synthesis of Diarylmethane 1

2-(4-Fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene (1a).⁷

To a solution of (5-(4-fluorophenyl)-thiophen)-2-yl-(5-iodo-2-methylphenyl)methanone (5a) (100 mg, 0.240 mmol) in DME (1 mL) was added NaBH₄ (14.0 mg, 0.370 mmol) and the mixture was stirred at 70 °C for 2 h. Then, the mixture was cooled down to 25 °C, and TiCl₄ (67.0 mg, 0.350 mmol) in CH₂Cl₂ (0.2 mL) was added over 1 min, and the mixture was stirred at 50 °C for 5 h. The mixture was cooled down to 25 °C, water (5 mL) was added and the mixture was stirred for 30 min. The mixture was extracted with CHCl₃ (10 mL), and the organic phase was washed with water (2 × 5 mL) and evaporated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 20:1) to give 1a as a white solid (83.2 mg, 85%). MP: 106–110 °C; IR (NaCl) ν_max: 1509, 1480, 1440, 1232, 1159, 1098, 832, 800 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ: 7.57 (d, J = 1.5 Hz, 1H), 7.50 (dt, J = 8.1, 2.3 Hz, 3H), 7.09–7.01 (m, 3H), 6.93 (d, J = 8.0 Hz, 1H), 6.68 (d, J = 3.5 Hz, 1H), 4.06 (s, 2H), 2.28 (s, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ: 162.05 (d, ¹J_C–F = 246.96 Hz), 142.20 (d, ⁵J_C–F = 1.1 Hz), 141.73, 140.54, 138.01, 136.00, 135.90, 132.32, 130.64 (d, ⁴J_C–F = 3.5 Hz), 127.08 (d, ³J_C–F = 8.0 Hz), 126.15, 122.66 (d, ⁵J_C–F = 1.7 Hz), 115.69 (d, ²J_C–F = 21.42 Hz), 90.99, 33.63, 19.08; ¹⁹F{¹H} NMR (376 MHz, CDCl₃, 30 °C) δ: −116.3.

(5-(4-Fluorophenyl)thiophen-2-yl)(5-iodo-2-methylphenyl)methanol (6a).¹⁵

NaBH₄ (0.13 g, 3.56 mmol) was added to a solution of (5-(4-fluorophenyl)thiophen-2-yl)(5-iodo-2-methylphenyl)methanone 5a (1.00 g, 2.37 mmol) in DME (10 mL) at 20–30 °C. The mixture was heated to 65–70 °C for 3 h. After cooling the mixture to 20–30 °C, the reaction was quenched by addition of water (10 mL). The mixture was extracted with CH₂Cl₂ (2 × 10 mL). Combined CH₂Cl₂ extracts were washed with water (10 mL) and sat. aq. NaHCO₃ (10 mL), dried over sodium sulfate and evaporated to give crude compound 6. Trituration of the crude 6a with a mixture of heptane and Et₂O provided pure 6a (0.920 g, 92%) as a yellow solid. MP: 111–115 °C; IR (NaCl) ν_max: 1508, 1472, 1458, 1232, 1159, 1097, 833, 806 cm^–1; ¹H NMR (500 MHz, DMSO-d₆) δ: 7.87 (d, J = 1.9 Hz, 1H), 7.65–7.56 (m, 2H), 7.50 (dd, J = 7.9, 2.0 Hz, 1H), 7.23 (d, J = 3.7 Hz, 1H), 7.20–7.13 (m, 2H), 6.95–6.90 (m, 1H), 6.77 (dd, J = 3.7, 0.8 Hz, 1H), 6.29 (s, 1H), 5.97 (s, 1H), 2.17 (s, 3H); ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ: 161.74 (d, ¹J_C–F = 244.44 Hz), 148.14, 145.25, 141.63, 135.99, 134.65, 134.51, 132.76, 130.59 (d, ⁴J_C–F = 3.2 Hz), 127.34 (d, ³J_C–F = 8.1 Hz), 126.07, 123.27 (d, ⁵J_C–F = 0.8 Hz), 116.12 (d, ²J_C–F = 21.42 Hz), 91.63, 67.25, 18.60.

Synthesis of 2-(4-Fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene (1a) from (5-(4-Fluorophenyl)thiophen-2-yl)(5-iodo-2-methylphenyl)methanol (6a)

NaBH₄ (13.0 mg, 0.340 mmol) was added to a solution of (5-(4-fluorophenyl)thiophen-2-yl)(5-iodo-2-methylphenyl)methanol (6a) (50.0 mg, 0.120 mmol) in DME (1 mL) at 25 °C. Then, TiCl₄ (67.0 mg, 0.350 mmol) in CH₂Cl₂ (0.140 mL) was slowly added, and the mixture was stirred at 50 °C for 3 h. To the mixture was added water (5 mL), and the mixture was stirred at 25 °C for 30 min. The mixture was extracted with AcOEt (3 mL), dried over MgSO₄, and evaporated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 20:1) to give 1a as a white solid (37.5 mg, 78%). The analytical data were the same as those of 1a obtained from 5a.

2-(4-Fluorophenyl)-5-(5-bromo-2-methylbenzyl)thiophene (1b).⁷

The compound was prepared according to the typical procedure for the synthesis of 1a using (5-(4-fluorophenyl)-thiophen)-2-yl-(5-bromo-2-methylphenyl)methanone (5b) (1.00 g, 2.66 mmol), NaBH₄ (0.15 g, 4.00 mmol), and TiCl₄ (0.76 g, 4.00 mmol) under the conditions described in Table 3. Trituration of crude 1b in methanol provided pure 1b (0.83 g, 86%) as an off-white solid. MP: 102–106 °C; IR (NaCl) ν_max: 1592, 1548, 1509, 1483, 1471, 1231, 1097, 865, 829, 798 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ: 7.54–7.47 (m, 2H), 7.37 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 8.1, 2.0 Hz, 1H), 7.11–7.00 (m, 4H), 6.69 (d, J = 3.5 Hz, 1H), 4.09 (s, 2H), 2.29 (s, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ: 162.07 (d, ¹J_C–F = 246.96 Hz), 142.12 (d, ⁵J_C–F = 1.2 Hz), 141.78, 140.29, 135.25, 132.09, 132.00, 130.65 (d, ⁴J_C–F = 3.6 Hz), 129.84, 127.08 (d, ³J_C–F = 8.1 Hz), 126.22, 122.67 (d, ⁵J_C–F = 1.7 Hz), 119.61, 115.69 (d, ²J_C–F = 21.42 Hz), 33.76, 18.97; ¹⁹F{¹H} NMR (376 MHz, CDCl₃, 30 °C): −114.75.

(S)-3-(4-(5-Bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran (1d).¹³

The compound was prepared according to the typical procedure for the synthesis of 1a using (S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (5d) (0.100 g, 0.262 mmol), NaBH₄ (14.9 mg, 0.393 mmol), and TiCl₄ (75.0 mg, 0.393 mmol) under the conditions described in Table 3. Crude 1d was purified by silica gel column chromatography (hexane/ethyl acetate 9.5:0.5 to 6:4) to afford pure 1d (76.1 mg, 79%) as a white solid. MP: 48–52 °C; IR (NaCl) ν_max: 2980, 2867, 2355, 1610, 1582, 1507, 1464, 1436, 1352, 1240, 1131, 1116, 971, 812 cm^–1; ¹H NMR (500 MHz, CDCl₃) δ: 7.30–7.24 (m, 2H), 7.23–7.18 (m, 1H), 7.12–7.07 (m, 2H), 6.84–6.76 (m, 2H), 4.88 (d, J = 2.8 Hz, 1H), 4.02–3.95 (m, 5H), 3.92–3.86 (m, 1H), 2.22–2.10 (m, 2H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ (ppm): 155.90, 141.00, 133.34, 132.88, 130.70, 130.64, 130.40, 129.86, 120.30, 115.28, 77.08, 72.91, 66.99, 37.98, 32.83.

1-Bromo-5-(4-ethoxybenzyl)-2-methoxy-4-methylbenzene (1e).¹⁴

The compound was prepared according to the typical procedure for the synthesis of 1a using (5-bromo-4-methoxy-2-methylphenyl)(4-ethoxyphenyl)methanone (5e) (8.10 g, 23.2 mmol), NaBH₄ (1.30 g, 34.4 mmol), and TiCl₄ (6.58 g, 34.7 mmol) under the conditions described in Table 3. Crude 1e was purified by silica gel column chromatography (ethyl acetate). Product 1e obtained was dissolved at 50 °C in heptane (20 mL). The mixture was cooled down to 25 °C over 30 min and stirred at 5–10 °C for 2 h. The solid formed was filtered and washed with cooled heptane (5 mL) to give pure 1e as a white solid (6.10 g, 79%). MP: 65.0 °C; IR (KBr) ν_max: 2976, 1514, 1491, 1248, 1045 cm^–1; ¹H NMR (500 MHz, CDCl₃, 30 °C) δ: 7.24 (s, 1H), 6.98 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.6 Hz 2H), 6.69 (s, 1H), 3.98 (q, J = 7.0 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 2H), 2.18 (s, 3H), 1.38 (t, J = 7.0 Hz, 3H); ¹³C{¹H} NMR (126 MHz) δ: 57.41, 154.18, 137.20, 134.25, 133.27, 132.00, 129.61, 129.51, 114.56, 114.23, 63.49, 56.36, 37.65, 19.92, 15.02.

Attempt to Obtain 1-Bromo-4-chloro-5-(4-ethoxybenzyl)benzene (1c) Using TiCl₄/NaBH₄

To a solution of (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone (5c) (1.00 g, 2.94 mmol) in DME (10 mL) was added NaBH₄ (0.220 g, 5.82 mmol), and the mixture was stirred at 50 °C for 10 min (foaming observed). Then, the mixture was cooled down to 25 °C, and TiCl₄ (1,12 g, 1.12 mmol) in CH₂Cl₂ (2 mL) was added over 1 min, and the mixture was stirred at 50 °C for 2 h. The mixture was cooled down to 25 °C, and water (30 mL) was added. The mixture was evaporated to remove organic solvent and extracted with AcOEt (2 × 15 mL). The combined organic phases were combined, washed with water (15 mL), dried over MgSO₄, and evaporated. The residue was purified by silica gel column chromatography (AcOEt) to give 1,2-bis(5-bromo-2-chlorophenyl)-1,2-bis(4-ethoxyphenyl)ethane (7c) (0.93 g, 97%) as an off-white semisolid. IR (NaCl) ν_max: 2925, 1612, 1582, 1511 cm^–1; ¹H NMR (500 MHz), δ: 7.55 (s, 2H), 7.13–7.02 (m, H), 6.67 (d, J = 7.9 Hz, 4H), 5.21 (s, 2H), 3.90 (q, J = 7.0 Hz, 4H), 1.34 (td, J = 6.9, 0.8 Hz, 6H). ¹³C{¹H} NMR (125 MHz) δ: 157.57, 142.67, 132.77, 132.29, 131.62, 131.02, 130.55, 129.63, 120.70, 114.37, 77.37, 77.12, 76.86, 63.31, 50.37, 14.91. HRMS: [M + H]⁺ calcd for C₃₀H₂₇Br₂Cl₂O₂ 649.9768, found 650.0461.

1-Bromo-4-chloro-5-(4-ethoxybenzyl)benzene (1c).¹⁶

In a 25 mL round-bottom flask were placed 2-propanol (1.50 mL) and (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone (5c) (250 mg, 0.740 mmol), and the mixture was warmed to 50 °C. To this was added BF₃·Et₂O (0.180 mL, 1.47 mmol) followed by finely shredded aluminum foil (Nippaku Foil, Mitsubishi Aluminium Corporation, 496 mg, 18.4 mmol). Then, to the mixture was added indium(III) chloride (0.800 mg, 0.04 mmol) dissolved in 2-propanol (50 μL) via a syringe slowly. After gently stirring overnight, the resulting mixture was diluted with MTBE (10 mL), filtered through a Celite pad and water (5 mL). Insoluble material was filtered off, and the filtrate was washed with a mixture of MTBE and 5 N HCl (10 mL). The organic layer was further washed with water. Then, the organic layer was concentrated using a rotary evaporator to obtain pale-yellow color crude 1c which was purified by silica gel column chromatography using ethyl acetate and hexane to obtain pure 1c (134 mg, 56%) as an off-white semisolid. IR (KBr) ν_max: 2480, 1609, 1508, 1244 cm^–1; ¹H NMR (500 MHz), δ: 7.55 (s, 1H), 7.13–7.02 (m, 4H), 6.67 (d, J = 7.9 Hz, 2H), 5.21 (s, 1H), 3.90 (q, J = 7.0 Hz, 2H), 1.34 (dt, J = 6.9, 0.8 Hz, 4H). ¹³C{¹H} NMR (125 MHz) δ: 157.73, 141.44, 133.63, 133.17, 130.95, 130.62, 130.46, 130.04, 120.55, 114.69, 77.38, 77.12, 76.87, 63.49, 38.30, 14.98.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.3c01972.

• ¹H and ¹³C NMR spectra of the products and HRMS data of compound 7c (PDF)

The authors declare no competing financial interest.