Bromide as the Directing Group for β-Arylation of Thiophenes

Abstract

Direct β-arylation of thiophene derivatives with bromide as directing group is disclosed. The reaction is conducted with PdCl₂/(p-tolyl)₃P as catalyst, silver carbonate as additive, and aryl iodide as coupling partner, affording brominated biaryl compounds as product. Control experiments indicated that the presence of bromide group enhances the reactivity of the C–H bond, enabling β-arylation. Furthermore, the C–Br bond can be easily converted into many useful functional groups through a wide range of methodologies. The mechanistic study suggests that silver salt plays a key role in the C–H bond-activation step.

Functionalized thiophenes are important heterocycles that are common motifs in a good range of biological molecules, and they are components in many organic functional materials.[2] Over the past decade, direct α-arylation of thiophene has been widely investigated due to the high reactivity of the C–H bond at the α-position.[3] On the other hand, explorations of direct β-arylation are less common due to low reactivity of the corresponding C–H bond. The primary strategy for direct β-arylation is via a Heck type mechanism with palladium complex as catalyst (Scheme [1]). For instance, Itami and co-workers reported a PdCl₂/P[OCH(CF₃)₂]₃ catalyzed β-selective arylation of thiophenes with iodoarenes as coupling partners.[4] Subsequent reports focusing on exploring other coupling partners including aryl boronic acids,[5] aryltrimethyl silanes,[6] aryl chlorides,[7] benzenesulfonyl chlorides[8] and diaryliodine salts[9] were reported that expanded the substrate scope and lowered the reaction temperature. Despite the great progress that has been made, moderate β-selectivity was still obtained in some cases, which limited further application of these methods in precise synthesis of thiophene-containing functional materials and drug precursors since it required much effort to remove α-arylated isomers for high-quality samples.

The use of directing groups for C–H bond activation has delivered both great efficiency and precise regioselectivity.[10] However, the removal of directing groups is a major issue that hinders its further application. In this context, the use of directing groups that can be easily converted into other useful functional groups, is a convenient strategy to solve this problem.[11] For instance, Ge and co-workers reported an aldehyde directed β-arylation reaction, which then gave mechanochromic materials via post-modification of the aldehyde groups (Scheme [1]).[12] However, high temperature (130 °C) was required to achieve reasonable yields, due to the reduced reactivity of the C–H bond at the β-position of the thiophene. To enhance C–H bond activity, a bromide group was installed at the α-position of thiophene as a directing group. After β-arylation, the C–Br bond can be easily converted into other useful functional groups via versatile transformations. However, due to the fragile nature of the C–Br bond in the presence of transition metals, the use of bromide as directing group for C–H bond activation was rarely reported. Recently, Hartwig, Larrosa, and Sanford separately discovered the unique role of silver salt in C–H bond activation and this has subsequently been applied for the direct functionalization of several arenes.[13] We then realized the silver salt catalyzed H/D exchange reaction of many aromatic compounds, which further established the unique effect of silver salt in C–H bond activation.[14] Herein, we report our findings on silver salt-mediated direct β-arylation of brominated thiophene derivatives.

We began our study by exploring direct β-arylation of 2-bromobezothiophene, with iodobenzene as coupling partner (Table [1]). We screened a range of catalysts, ligands, solvents, and additives in order to optimize the yields. The control experiments indicated that the palladium catalyst, phosphine ligands and silver salts were all essential for the reaction (entries 2, 5, and 11). The reaction was totally stopped without any one of them. Other palladium sources such as Pd₂(dba)₃ and Pd(OAc)₂ proved to be less effective than PdCl₂, resulting in lower yields (entries 3 and 4). The use of other phosphine ligands instead of (p-tolyl)₃P was also carried out (entries 6–10). We found several ligands had a positive effect on β-arylation, providing coupling products in moderate yields. On the other hand, Buchwald’s ligands showed nearly no reactivity. For the test of silver salts, the reaction with Ag₂O gave a reasonable yield, since it may generate Ag₂CO₃ in situ in the presence of K₂CO₃. However, the use of AgOAc or AgCl led to much lower yields (entries 12–14). These results indicated the choice of silver salts is very important for this β-arylation reaction. The subsequent mechanistic study suggested that silver-thiophene complex was generated from C–H bond activation and subsequently reacted with aryl palladium complex to form a key intermediate bi-aryl palladium(II) complex. Notably, the reaction can be performed in pure H₂O, albeit giving a lower yield of 53% (entry 15). On the other hand, the yield decreased to 59% without adding water (entry 16). Although the exact function of water is still unknown, the solubility in water is considered to play a role in this reaction.[15] We also performed the reaction at lower temperature, however, a dramatic decrease of yield was observed at 60 °C (entry 17). Therefore, the optimal conditions were established with PdCl₂/(p-tolyl)₃P as catalyst, Ag₂CO₃ as additive and the combination of water and toluene as solvent at 80 °C.

Table 1 Variation from Standard Conditions for β-Arylation^a

Entry	Variation from standard conditions	Conversion (%)b
1	None	80
2	no PdCl2	0
3	Pd(OAc)2 instead of PdCl2	40
4	Pd2(dba)3 instead of PdCl2	45
5	no (p-tolyl)3P	0
6	(o-tolyl)3P instead of (p-tolyl)3P	30
7	Cy3P instead of (p-tolyl)3P	10
8	dppe instead of (p-tolyl)3P	40
9	SPhos instead of (p-tolyl)3P	5
10	DavePhos instead of (p-tolyl)3P	5
11	No Ag2CO3	0
12	AgOAc instead of Ag2CO3	20
13	AgCl instead of Ag2CO3	5
14	Ag2O instead of Ag2CO3	73
15	no toluene	53
16	no H2O	59
17	60 °C instead of 80 °C	52

^a Standard conditions: 1a (2 mmol), 2a (1 mmol), PdCl₂ (0.1 mmol), (p-tolyl)₃P (0.2 mmol), Ag₂CO₃ (2 mmol), K₂CO₃ (1 mmol), H₂O/toluene (0.3 mL/0.3 mL), 80 °C.

^b Determined by GC-MS analysis.

With the optimized conditions in hand, the substrate scope for β-arylation was next explored as shown in Scheme [2]. We first examined the scope of aryl iodide. The reaction presented great tolerance to a variety of functional groups. Aryl iodides with either electron-withdrawing groups or electron-donating groups at para-position proved to be good substrates, providing coupling products 3a–i in good to excellent yields (63–88%). Aryl iodide with ortho-substitute was also tested, giving the product 3j without any decrease of yield. This result suggested that steric effects of the aryl iodide may have little influence on arylation. In addition, 4-iodopyridne is a good coupling partner, affording coupling product 3l with 78% yield. The reaction with 1,4-diiodobenzene as coupling partner was also conducted, affording diarylation product 3n in 69% yield. Debromination or self-coupling of 2-bromobenzo-thiophene was not observed in any case.

After testing the scope of the reaction with aryl iodides, we turned our attention to expand the scope of bromothiophene derivatives. As shown in Scheme [3], substituted 2-bromobenzothiophenes are good substrates under the optimal conditions, providing the coupling products 4a–e in 70 to 85% yields. The bromide group at the phenyl ring did not disturb the regioselectivity of the reaction, with the β-arylation compound 4e being observed as the only product. Furthermore, 2,5-dibromothiophene and 2-bromo-5-methylthiophene were also tested, affording single β-arylated thiophenes 4f and 4g, exclusively. The regioselectivity of product 4g was controlled by the bromide substituent (see competition experiment for details). When 3-bromobenzothiophene was employed, the α-arylation product 4h was also formed in high yield. Since thieno(3,2-b)thiophene (TT) is a common structure in functional materials as an electron donor, we then tested the possibility of direct β-arylation of 2,5-dibromothieno(3,2-b)thiophene. When the reaction was carried out with 0.2 equivalent of PdCl₂, the bis-β-arylation product 4i was isolated in 81% yield. Herein, our finding may provide a facile way to synthesize this kind of thiophene skeleton from commercially available starting materials in one step, which may increase the synthetic efficiency of thiophene-based functional materials.

Further transformation of the C–Br bond into other useful functional groups via versatile cross-coupling reactions is a great advantage of this direct β-arylation reaction. Therefore, we conducted the cross-coupling reaction between 3a and phenyl boronic acid, N-methylphenylamine as well as 1-ethynyl-4-methylbenzene, affording a range of benzothiophene derivatives (Scheme [4]).

As shown in Scheme [5], we then designed a series of experiments to investigate the nature of C–H bond activation. When the reaction was conducted without PdCl₂ as catalyst in D₂O, deuterated 2-bromo-benzothiophene was obtained with 99% deuterium incorporation. In addition, the reaction catalyzed by PdCl₂ without Ag₂CO₃ afforded only starting material. These results suggested that Ag₂CO₃ is likely responsible for the C–H bond-activation step. The one-pot competitive reaction between 2-bromobenzothiophene and 2-methylbenzothiophene showed a significant difference in reactivity, demonstrating the importance of the bromide group for β-arylation. On the basis of these results and on previous reports, we proposed the mechanistic pathway as follow. First, an aryl Pd(II) complex is formed by oxidative addition of Pd(0) to aryl iodide. Then, the palladium complex reacts with a silver complex, generated from C–H bond activation of brominated thiophene derivatives, to form a diaryl-palladium species. Finally, reductive elimination affords the coupling product and regenerates the Pd(0) catalyst.

In summary, we have developed a palladium-catalyzed β-arylation of thiophene derivatives, in which the silver salt was the key for achieving C–H bond activation. The reaction was conducted under relatively mild conditions, resulting in good tolerance to many functional groups. The presence of a bromide group not only assists C–H bond activation but also facilitates further transformation of the product into other functional molecules. The CMD mechanism is considered and supported with a series of control experiments. Since the bromide group was employed as a directing group, β-arylated thiophene was formed as the only product, without any α-arylated isomer. Our findings provide a convenient method for the preparation of pure thiophene-based functional materials and drug candidates. Further extension of the substrate scope of brominated arenes beyond thiophene is under investigation in our lab.

NMR spectra were recorded at 23 °C with a Varian VNMRS 400 MHz NMR spectrometer in CDCl₃ unless otherwise noted. Chemical shifts were determined relative to residual CHCl₃ (7.26 ppm) for proton, and to the CDCl₃ ‘triplet’ at 77.23 ppm for carbon. GC-MS experiments were carried out with an Agilent GC/MS instrument consisting of a 6890N series GC and a 5973 Mass Selective Detector System. All yields refer to isolated yields unless otherwise indicated. All the reagents and solvents were purchased from commercial sources and used as received. The HRMS data were obtained with a ThermoFisher LCQTM Deca XP plus ion trap LC/MS.

PdCl₂-Catalyzed Coupling Reaction; Typical Procedure with 2-Bromothiophene and Iodobenzene

2-Bromothiophene (424 mg, 2 mmol) and iodobenzene (204 mg, 1 mmol) were added to a vigorously stirred solution of silver carbonate (540 mg, 2 mmol), palladium chloride (17.7 mg, 0.1 mmol), tri(p-tolyl)phosphine (60 mg, 0.2 mmol), and potassium carbonate (138 mg, 1 mmol) in H₂O (0.3 mL) and toluene (0.3 mL) under N₂. The reaction mixture was stirred at 80 °C in an oil bath for 12 hours, then the reaction was quenched with saturated NH₄Cl solution. The product was extracted with dichloromethane (3 × 20 mL) and the combined organic layer was washed with brine and dried over Na₂SO₄. After removal of solvents under vacuum, the crude product was purified by column chromatography (petroleum ether, 100%).

2-Bromo-3-phenylbenzothiophene (3a)

Purified by column chromatography (petroleum ether, 100%).

Yield: 232 mg (80%); yellow oil.

¹H NMR (DMSO-d ₆, 400 MHz): δ = 7.98 (d, J = 8.4 Hz, 1 H), 7.55–7.51 (m, 2 H), 7.4–7.42 (m, 4 H), 7.39–7.32 (m, 2 H).

¹³C NMR (DMSO-d ₆, 100 MHz): δ = 139.5, 138.5, 137.2, 133.6, 130.2, 129.4, 129.3, 129.3, 128.9, 125.9, 125.7, 122.9, 122.9, 113.4.

HRMS (EI): m/z [M]⁺ calcd for C₁₄H₉BrS⁺: 287.9608; found: 287.9597.

2-Bromo-3-(p-tolyl)benzothiophene (3b)

Purified by column chromatography (petroleum ether, 100%).

Yield: 190 mg (63%); yellow oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.78 (d, J = 7.6 Hz, 1 H), 7.60 (d, J = 7.2 Hz, 1 H), 7.43–7.31 (m, 6 H), 2.48 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 139.9, 138.9, 138.0, 137.2, 131.0, 129.9, 129.4, 124.8, 123.0, 121.7, 113.1, 21.5.

HRMS (EI): m/z [M]⁺ calcd for C₁₅H₁₁BrS⁺: 301.9765; found: 301.9751.

2-Bromo-3-(4-(tert-butyl)phenyl)benzothiophene (3c)

Purified by column chromatography (petroleum ether, 100%).

Yield: 294 mg (85%); yellow oil.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.96 (d, J = 8.0 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 2 H), 7.44 (d, J = 7.2 Hz, 1 H), 7.40–7.31 (m, 4 H), 1.31 (s, 9 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 151.2, 139.5, 138.6, 137.0, 130.7, 129.9, 126.1, 125.8, 125.7, 123.0, 122.8, 113.2, 35.0, 31.6.

HRMS (EI): m/z [M]⁺ calcd for C₁₈H₁₇BrS⁺: 344.0234; found: 344.0219.

2-Bromo-3-(4-methoxyphenyl)benzothiophene (3d)

Purified by column chromatography (petroleum ether/dichloromethane, 8:1).

Yield: 222 mg (70%); yellow solid; mp 101–103 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.96 (d, J = 8.0 Hz, 1 H), 7.50–7.34 (m, 7 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.6, 139.4, 138.7, 137.0, 131.5, 125.8, 125.6, 125.6, 123.0, 122.9, 114.7, 113.0, 55.7.

HRMS (EI): m/z [M]⁺ calcd for C₁₅H₁₁BrOS⁺: 317.9714; found: 317.9704.

2-Bromo-3-(4-(trifluoromethyl)phenyl)benzothiophene (3e)

Purified by column chromatography (petroleum ether/dichloromethane, 8:1).

Yield: 263 mg (74%); yellow oil.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.78 (d, J = 8.0 Hz, 2 H), 7.73–7.67 (m, 1 H), 7.62–7.49 (m, 2 H), 7.39–7.30 (m, 3 H).

¹⁹F NMR (376 MHz, CDCl₃): δ = –63.9 (s, 3 F).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 139.6, 138.1, 137.9 (q, J _F = 1.4 Hz), 135.8, 131.2, 129.4 (q, J _F = 31.8 Hz), 126.2 (q, J _F = 3.8 Hz), 126.1, 125.9, 124.7 (q, J _F = 270.9 Hz), 123.0, 122.7, 114.6.

HRMS (EI): m/z [M]⁺ calcd for C₁₅H₈BrF₃S⁺: 355.9482; found: 355.9472.

2-Bromo-3-(4-fluorophenyl)benzothiophene (3f)

Purified by column chromatography (petroleum ether, 100%).

Yield: 260 mg (85%); colorless oil.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.52 (d, J = 8.4 Hz, 1 H), 7.44 (d, J = 2.4 Hz, 1 H), 7.42–7.40 (m, 2 H), 7.35–7.31 (m, 3 H).

¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –114.2 (s, 1 F).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 162.5 (d, J _F = 244.4 Hz), 139.5, 138.4, 136.2, 132.4 (d, J _F = 8.5 Hz), 129.9 (d, J _F = 3.3 Hz), 125.9, 125.8, 122.9, 122.8, 116.4 (d, J _F = 21.5 Hz), 113.8 (d, J _F = 1.4 Hz).

HRMS (EI): m/z [M]⁺ calcd for C₁₄H₈BrFS⁺: 305.9514; found: 305.9504.

2-Bromo-3-(4-bromophenyl)benzothiophene (3g)

Purified by column chromatography (petroleum ether, 100%).

Yield: 286 mg (78%); white solid; mp 125–127 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.78–7.76 (m, 1 H), 7.67–7.64 (m, 2 H), 7.52–7.50 (m, 1 H), 7.38–7.30 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 139.9, 138.4, 135.9, 132.8, 131.9, 131.7, 125.0, 125.0, 122.7, 122.4, 121.8, 113.7.

HRMS (EI): m/z [M]⁺ calcd for C₁₄H₈Br₂S⁺: 367.8693; found: 367.8678.

(4-(2-Bromobenzo[b]thiophen-3-yl)phenyl)(phenyl)methanone (3h)

Purified by column chromatography (petroleum ether/dichloromethane, 8:1).

Yield: 345 mg (88%); white solid; mp 136–138 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.98 (d, J = 8.4 Hz, 2 H), 7.91–7.89 (m, 2 H), 7.80–7.78 (m, 1 H), 7.64–7.52 (m, 6 H), 7.40–7.33 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 196.3, 139.9, 138.4, 138.2, 137.5, 137.1, 136.1, 132.6, 130.4, 130.2, 130.0, 128.4, 125.1, 122.7, 121.9, 114.1.

HRMS (EI): m/z [M]⁺ calcd for C₂₁H₁₃BrOS⁺: 391.9870; found: 391.9860.

5-(2-Bromobenzo[b]thiophen-3-yl)benzo[d][1,3]dioxole (3i)

Purified by column chromatography (petroleum ether/dichloromethane, 8:1).

Yield: 266 mg (80%); yellow oil.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.95 (d, J = 8.4 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.40–7.33 (m, 2 H), 7.06 (d, J = 8.0 Hz, 1 H), 6.99 (t, J = 1.6 Hz, 1 H), 6.88 (dd, J = 1.6 Hz, J = 8.0 Hz, 1 H), 6.09 (s, 2 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 148.0, 147.8, 139.4, 138.6, 136.9, 127.1, 125.8, 125.7, 124.0, 123.0, 122.8, 113.4, 110.5, 109.2, 101.9.

HRMS (EI): m/z [M]⁺ calcd for C₁₅H₉BrO₂S⁺: 331.9507; found: 331.9497.

2-Bromo-3-(o-tolyl)benzo[b]thiophene (3j)

Purified by column chromatography (petroleum ether, 100%).

Yield: 268 mg (88%); yellow oil.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.97 (d, J = 8.4 Hz, 1 H), 7.44–7.34 (m, 4 H), 7.32–7.20 (m, 3 H), 7.36 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 139.5, 138.6, 138.6, 137.3, 133.6, 130.6, 129.5, 129.2, 127.3, 125.8, 125.7, 123.0, 122.8, 21.5.

HRMS (EI): m/z [M]⁺ calcd for C₁₅H₁₁BrS⁺: 301.9765; found: 301.9751.

2-Bromo-3-(naphthalen-2-yl)benzo[b]thiophene (3k)

Purified by column chromatography (petroleum ether, 100%).

Yield: 284 mg (84%); white solid; mp 105–107 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.06–7.79 (m, 5 H), 7.57–7.35 (m, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 139.6, 138.7, 137.2, 133.4, 133.0, 131.2, 129.5, 128.8, 128.6, 128.2, 127.8, 127.2, 125.9, 125.8, 123.0, 122.9, 113.9.

HRMS (EI): m/z [M]⁺ calcd for C₁₈H₁₁BrS⁺: 337.9765; found: 337.9752.

4-(2-Bromobenzo[b]thiophen-3-yl)pyridine (3l)

Purified by column chromatography (petroleum ether/dichloromethane, 4:1).

Yield: 226 mg (78%); green solid; mp 85–87 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.78 (d, J = 8.4 Hz, 2 H), 7.80–7.78 (m, 1 H), 7.55–7.53 (m, 1 H), 7.45 (d, J = 6.0 Hz, 2 H), 7.41–7.32 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 150.3, 142.1, 140.0, 137.9, 134.6, 125.3, 125.3, 124.8, 122.3, 121.9, 114.7.

HRMS (EI): m/z [M]⁺ calcd for C₁₃H₈BrNS⁺: 288.9561; found: 288.9550.

2-Bromo-3-(9,9-dimethyl-9H-fluoren-2-yl)benzo[b]thiophene (3m)

Purified by column chromatography (petroleum ether, 100%).

Yield: 296 mg (74%); white solid; mp 142–144 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.66 (d, J = 8.0 Hz, 1 H), 7.53–7.47 (m, 2 H), 7.05 (s, 1 H), 6.98 (s, 2 H), 2.34–2.28 (s, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 153.9, 153.9, 139.9, 139.2, 138.9, 138.8, 137.6, 128.8, 127.1, 124.9, 124.9, 124.5, 122.7, 121.8, 120.3, 113.2, 47.1, 27.2.

HRMS (EI): m/z [M]⁺ calcd for C₂₃H₁₇BrS⁺: 404.0234; found: 404.0220.

1,4-Bis(2-bromobenzo[b]thiophen-3-yl)benzene (3n)

Purified by column chromatography (petroleum ether/dichloromethane, 8:1).

Yield: 345 mg (69%); white solid; mp 138–140 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.04 (d, J = 6.8 Hz, 2 H), 7.69 (s, 4 H), 7.61 (d, J = 8.0 Hz, 2 H), 7.48–7.41 (m, 2 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 139.8, 138.6, 136.9, 133.7, 130.6, 125.9, 125.8, 123.0, 122.8.

HRMS (EI): m/z [M]⁺ calcd for C₂₂H₁₂Br₂S₂ ⁺: 499.8727; found: 499.8713.

PdCl₂-Catalyzed Coupling Reaction; Typical Procedure with 4-Iodoanisole and 2-Bromo-5-methylbenzo[b]thiophene

2-Bromo-5-methylbenzo[b]thiophene (450 mg, 2 mmol) and 4-iodoanisole (234 mg, 1 mmol) were added to a vigorously stirred solution of silver carbonate (540 mg, 2 mmol), palladium chloride (17.7 mg, 0.1 mmol), tri(p-tolyl)phosphine (60 mg, 0.2 mmol), and potassium carbonate (138 mg, 1 mmol) in H₂O (0.3 mL) and toluene (0.3 mL) under N₂. The reaction mixture was stirred at 80 °C in an oil bath for 12 hours. The reaction was then quenched with saturated NH₄Cl solution. The product was extracted with dichloromethane (3 × 20 mL). The combined organic layer was washed with brine and dried over Na₂SO₄. After removal of solvents under vacuum, the crude product was purified by column chromatography (petroleum ether/dichloromethane, 8:1).

2-Bromo-3-(4-methoxyphenyl)-5-methylbenzo[b]thiophene (4a)

Purified by column chromatography (petroleum ether/dichloromethane, 8:1).

Yield: 231 mg (70%); white solid; mp 115–117 °C.

¹H NMR (CDCl₃, 400 MHz): δ = 7.71–7.63 (m, 4 H), 7.20 (d, J = 8.4 Hz, 1 H), 7.00 (d, J = 8.8 Hz, 2 H), 3.86 (s, 3 H), 2.51 (s, 3 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 150.0, 139.4, 138.3, 135.2, 134.6, 130.9, 130.9, 127.0, 125.6, 123.4, 121.8, 114.0, 103.9, 55.4, 21.6.

HRMS (EI): m/z [M]⁺ calcd for C₁₆H₁₃BrOS⁺: 331.9870; found: 331.9858.

2-Bromo-3,5-diphenylbenzothiophene (4b)

Purified by column chromatography (petroleum ether, 100%).

Yield: 309 mg (85%); white solid; mp 114–116 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.07 (d, J = 1.2 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.79–7.76 (m, 2 H), 7.72–7.69 (m, 2 H), 7.66–7.63 (m, 1 H), 7.52–7.37 (m, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 141.0, 139.7, 139.0, 138.9, 136.8, 133.1, 129.7, 129.0, 128.9, 128.7, 127.5, 127.5, 125.1, 122.6, 122.1, 105.2.

HRMS (EI): m/z [M]⁺ calcd for C₂₀H₁₃BrS⁺: 363.9921; found: 363.9907.

2-Bromo-5-methoxy-3-phenylbenzothiophene (4c)

Purified by column chromatography (petroleum ether/dichloromethane, 8:1).

Yield: 270 mg (85%); white solid; mp 118–120 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.92 (d, J = 8.8 Hz, 1 H), 7.77 (d, J = 7.2 Hz, 2 H), 7.70 (s, 1 H), 7.45 (t, J = 7.2 Hz, 2 H), 7.39 (d, J = 7.2 Hz, 1 H), 7.20 (d, J = 8.8 Hz, 1 H), 3.88 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 146.6, 141.6, 133.5, 131.7, 129.8, 129.6, 126.7, 123.1, 119.6, 111.9, 104.5, 57.0.

HRMS (EI): m/z [M]⁺ calcd for C₁₅H₁₁BrOS⁺: 317.9714; found: 317.9704.

2-Bromo-5-chloro-3-phenylbenzothiophene (4d)

Purified by column chromatography (petroleum ether, 100%).

Yield: 267 mg (72%); white solid; mp 104–106 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.09 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 2.0 Hz, 1 H), 7.71 –7.69 (m, 2 H), 7.55–7.46 (m, 4 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 140.9, 140.2, 136.1, 132.4, 131.5, 130.0, 129.7, 129.5, 125.6, 125.3, 122.7.

HRMS (EI): m/z [M]⁺ calcd for C₁₄H₈BrClS⁺: 321.9219; found: 321.9206.

2,5-Dibromo-3-phenylbenzo[b]thiophene (4e)

Purified by column chromatography (petroleum ether, 100%).

Yield: 305 mg (83%); white solid; mp 126–128 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.01 (d, J = 1.6 Hz, 1 H), 7.75–7.72 (m, 2 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.50–7.41 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 140.8, 140.2, 136.4, 132.6, 129.6, 129.2, 128.7, 128.6, 125.4, 123.6, 119.4.

HRMS (EI): m/z [M]⁺ calcd for C₁₄H₈Br₂S⁺: 367.8693; found: 367.8677.

2,5-Dibromo-3-(4-methoxyphenyl)thiophene (4f)

Purified by column chromatography (petroleum ether/dichloromethane, 8:1).

Yield: 268 mg (77%); yellow oil.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.47 (d, J = 8.0 Hz, 2 H), 7.33 (s, 1 H), 7.00 (d, J = 7.2 Hz, 2 H), 3.77 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 159.6, 142.1, 132.8, 130.2, 126.1, 114.5, 111.3, 106.8, 55.6.

HRMS (EI): m/z [M]⁺ calcd for C₁₁H₈Br₂OS⁺: 347.8642; found: 347.8632.

2-Bromo-5-methyl-3-phenylthiophene (4g)

Purified by column chromatography (petroleum ether, 100%).

Yield: 196 mg (78%); yellow oil.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.53–7.50 (m, 2 H), 7.46–7.42 (m, 2 H), 7.38–7.34 (m, 1 H), 6.89 (d, J = 1.2 Hz, 1 H), 2.41 (s, 3 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 140.9, 140.7, 135.0, 128.7, 128.4, 127.7, 127.4, 104.5, 15.4.

HRMS (EI): m/z [M]⁺ calcd for C₁₁H₉BrS⁺: 251.9608; found: 251.9597.

3-Bromo-2-phenylbenzothiophene (4h)

Purified by column chromatography (petroleum ether, 100%).

Yield: 245 mg (85%); white solid; mp 62–63 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.89–7.87 (m, 1 H), 7.83–7.80 (m, 1 H), 7.78–7.75 (m, 2 H), 7.51–7.39 (m, 5 H).

¹³C NMR (100 MHz, CDCl₃): δ = 139.2, 138.3, 137.8, 133.1, 129.7, 128.9, 128.7, 125.5, 125.3, 123.7, 122.2, 105.0.

HRMS (EI): m/z [M]⁺ calcd for C₁₄H₉BrS⁺: 287.9608; found: 287.9596.

2,5-Dibromo-3,6-diphenylthieno[3,2-b]thiophene (4i)

Purified by column chromatography (petroleum ether/dichloromethane, 8:1).

Yield: 364 mg (81%); colorless oil.

¹H NMR (400 MHz, CDCl₃): δ = 7.68–7.66 (m, 4 H), 7.51 (t, J = 7.2 Hz, 4 H), 7.46–7.43 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 136.9, 133.9, 133.2, 128.9, 128.7, 128.5, 109.9.

HRMS (EI): m/z [M]⁺ calcd for C₁₈H₁₀Br₂S₂ ⁺: 449.8570; found: 449.8553.

Palladium-Catalyzed Suzuki Coupling Reaction; Typical Procedure

A 25 mL oven-dried Schlenk-tube was charged with Pd(PPh₃)₄ (116 mg, 10 mol%), phenylboronic acid (182 mg, 1.5 mmol), 2-bromo-3-phenylbenzothiophene (289 mg, 1 mmol) and potassium carbonate (552 mg, 4 mmol) in a mixture of toluene (2 mL) and H₂O (1 mL). The tube was evacuated and backfilled with argon (this procedure was repeated three times). The tube was then sealed and the mixture was allowed to stir at 80 °C for 12 hours. The reaction was monitored by TLC. Upon completion of the reaction, the mixture was cooled to room temperature and the product was extracted with dichloromethane (3 × 20 mL). The combined organic layer was washed with brine and dried over Na₂SO₄. After removal of solvents under vacuum, the crude product was purified by column chromatography. A white solid was isolated in 81% yield (232 mg).

2,3-Diphenylbenzothiophene (5a)

Purified by column chromatography (petroleum ether, 100%).

Yield: 232 mg (81%); white solid; mp 113–115 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.03 (d, J = 7.6 Hz, 1 H), 7.47–7.36 (m, 6 H), 7.30–7.28 (m, 7 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 140.9, 139.6, 138.9, 135.6, 134.3, 133.3, 130.5, 129.7, 128.7, 128.4, 127.8, 127.5, 124.6, 124.5, 123.4, 122.1.

HRMS (EI): m/z [M]⁺ calcd for C₂₀H₁₄S⁺: 286.0816; found: 286.0820.

Palladium-Catalyzed Buchwald–Hartwig Amination; Typical Procedure

A screw-cap vial equipped with a magnetic stir bar was charged with the 2-bromo-3-phenylbenzothiophene (289 mg, 1 mmol), N-methylaniline (129 mg, 1.2 mmol), Pd(OAc)₂ (3 mg, 0.01 mmol), RuPhos (9 mg, 0.02 mmol), and powdered NaO^tBu (115 mg, 1.2 mmol) in DMSO (2 mL). The vial was transferred to a preheated oil bath (100 °C). After 12 h, the reaction mixture was cooled and dissolved in CH₂Cl₂/H₂O mixture (1:1). The organic phase was separated and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography on a silica gel column. A white solid was obtained in 82% yield (258 mg).

N-Methyl-N,3-diphenylbenzo[b]thiophen-2-amine (5b)

Purified by column chromatography (petroleum ether/ethyl acetate, 4:1).

Yield: 258 mg (82%); white solid; mp 118–120 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.79–7.69 (m, 2 H), 7.45–7.32 (m, 7 H), 7.25–7.21 (m, 2 H), 6.91–6.89 (m, 2 H), 6.84 (t, J = 8.8 Hz, 1 H), 3.08 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 148.8, 147.5, 138.3, 137.1, 134.1, 131.7, 129.2, 128.9, 128.7, 127.6, 124.8, 124.4, 123.0, 122.9, 119.0, 114.5, 40.0.

HRMS (EI): m/z [M]⁺ calcd for C₂₁H₁₇NS⁺: 315.1082; found: 315.1092.

Palladium-Catalyzed Sonogashira Reaction; Typical Procedure

In a 25 mL flask, a mixture of 4-ethynyltoluene (174 mg, 1.5 mmol), 2-bromo-3-phenyl-1-benzothiophene (289 mg, 1 mmol), PPh₃ (53 mg, 0.2 mmol), Pd(OAc)₂ (12 mg, 2 mmol%), and K₂CO₃ (207 mg, 1.5 mmol) in DMSO (5 mL) was heated at 80 °C. After 24 hours, the resulting mixture was poured into H₂O and extracted with EtOAc three times. Combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by flash chromatography on a silica gel column. A white solid was isolated in 80% yield (259 mg).

3-Phenyl-2-(p-tolylethynyl)benzothiophene (5c)

Purified by column chromatography (petroleum ether/ethyl acetate, 8:1).

Yield: 259 mg (80%); white solid; mp 122–123 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.99 (d, J = 7.2 Hz, 1 H), 7.69–7.64 (m, 3 H), 7.55 (t, J = 7.2 Hz, 2 H), 7.47–7.39 (m, 3 H), 7.28 (d, J = 8.4 Hz, 2 H), 7.16 (d, J = 7.6 Hz, 2 H), 2.23 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 141.0, 139.8, 139.3, 137.8, 134.0, 131.6, 130.0, 129.9, 129.2, 128.8, 126.7, 125.0, 123.7, 123.3, 119.0, 119.0, 96.8, 82.9, 21.7.

HRMS (EI): m/z [M]⁺ calcd for C₂₃H₁₆S⁺: 324.0973; found: 324.0976.

Reaction in D₂O without PdCl₂ as Catalyst

A 10 mL oven-dried Schlenk-tube was charged with 2-bromobenzothiophene (424 mg, 2 mmol), iodobenzene (204 mg, 1 mmol), silver carbonate (552 mg, 2 mmol), tri-p-tolylphosphine (60 mg, 0.20 mmol) and potassium carbonate (138 mg, 1 mmol). The tube was evacuated and backfilled with argon (this procedure was repeated three times). D₂O (0.3 mL) and toluene (0.3 mL) were added by syringe under a counter flow of argon at room temperature. The tube was then sealed and the mixture was allowed to stir at the appointed temperature (80 °C) for 12 hours. Upon completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate. The solution was directly analyzed by GC-MS, which showed no cross-coupling product formed. In contrast, the starting material, 1,4-dibromobenzene, was clearly deuterated, providing deuterated 2-bromobenzothiophene with deuterium incorporation of 99%.

Reaction in D₂O without Ag₂CO₃

A 10 mL oven-dried Schlenk-tube was charged with 2-bromobenzothiophene (424 mg, 2 mmol), iodobenzene (204 mg, 1 mmol), palladium chloride (18 mg, 0.1 mmol), tri-p-tolylphosphine (60 mg, 0.20 mmol) and potassium carbonate (138 mg, 1 mmol). The tube was evacuated and backfilled with argon (this procedure was repeated three times). D₂O (0.3 mL) and toluene (0.3 mL) were added by syringe under a counter flow of argon at room temperature. The tube was then sealed and the mixture was allowed to stir at the appointed temperature (80 °C) for 12 hours. Upon completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate. The solution was directly analyzed by GC-MS, which showed no cross-coupling product and no deuterated 2-bromobenzothiophene formed.

Reaction with both 2-Bromobenzothiophene and 2-Methylbenzothiophene

A 10 mL oven-dried Schlenk-tube was charged with 2-bromobenzothiophene (212 mg, 1 mmol), 2-methylbenzothiophene (148 mg, 1 mmol), iodobenzene (204 mg, 1 mmol), palladium chloride (18 mg, 0.1 mmol), tri-p-tolylphosphine (60 mg, 0.20 mmol), silver carbonate (552 mg, 2 mmol) and potassium carbonate (138 mg, 1 mmol). The tube was evacuated and backfilled with argon (this procedure was repeated three times). D₂O (0.3 mL) and toluene (0.3 mL) were added by syringe under a counter flow of argon at room temperature. The tube was then sealed and the mixture was allowed to stir at the appointed temperature (80 °C) for 12 hours. Upon completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate. The solution was directly analyzed by GC-MS, which showed cross-coupling product 3a was formed but no 3o was observed.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

Part of this work was conducted at Center for Nanophase Materials Sciences, which is a DOE Office of Science User Facility. Dr. Hong-Hai Zhang is currently supported by the Center for Structural Molecular Biology, sponsored by the office of Biological and Environmental Research. Dr. Kunlun Hong is supported by the Center for Nanophase Materials Sciences, which is a DOE Office of Science User Facility. This research was started by Hong-Hai Zhang as professor at Nanjing Tech University.

• References

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Corresponding Authors

Publication History

Received: 18 March 2022

Accepted after revision: 28 April 2022

Accepted Manuscript online:
28 April 2022

Article published online:
28 June 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 Current address: H. H. Zhang, Center for Nanophase Materials Sciences & Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA.
• 2a Gronowits S, Hornfeldt AB. Thiophenes . Elsevier; Oxford: 2004
  Search in Google Scholar
• 2b Takimiya K, Shinamura S, Osaka I, Miyazaki E. Adv. Mater. 2011; 23: 4347
  CrossrefPubMedSearch in Google Scholar
• 2c Nicolaou KC, Hale CR. H, Nilewski C, Ioannidou HA. Chem. Soc. Rev. 2012; 41: 5185
  CrossrefPubMedSearch in Google Scholar
• 2d Witter DJ, Belvedere S, Chen L, Secrist JP, Mosley RT, Miller TA. Bioorg. Med. Chem. Lett. 2007; 17: 4562
  CrossrefPubMedSearch in Google Scholar
• 3a He C, Fan S, Zhang X. J. Am. Chem. Soc. 2010; 132: 12850
  CrossrefPubMedSearch in Google Scholar
• 3b Gorelsky SI, Lapointe D, Fagnou K. J. Am. Chem. Soc. 2008; 130: 10848
  CrossrefPubMedSearch in Google Scholar
• 3c Kobayashi K, Sugie A, Takahashi M, Masui K, Mori A. Org. Lett. 2005; 7: 5083
  CrossrefPubMedSearch in Google Scholar
• 3d Schipper DJ, Fagnou K. Chem. Mater. 2011; 23: 1594
  CrossrefSearch in Google Scholar
• 4a Ueda K, Yanagisawa S, Yamaguchi J, Itami K. Angew. Chem. Int. Ed. 2010; 49: 8946
  CrossrefPubMedSearch in Google Scholar
• 4b Colletto C, Islam S, Julia-Hernandez F, Larrosa I. J. Am. Chem. Soc. 2016; 138: 1677
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• 5 Kirchberg S, Tani S, Ueda K, Yamaguchi J, Studer A, Itami K. Angew. Chem. Int. Ed. 2011; 50: 2387
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• 6 Funaki K, Sato T, Oi S. Org. Lett. 2012; 14: 6181
  CrossrefPubMedSearch in Google Scholar
• 7 Tang DT. D, Collins KD, Glorius F. J. Am. Chem. Soc. 2013; 135: 7450
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• 8a Yuan K, Doucet H. Chem. Sci. 2014; 5: 392
  CrossrefSearch in Google Scholar
• 8b Mao S, Shi X, Soule JF, Doucet H. Eur. J. Org. Chem. 2020; 91
  Crossref
• 9 Tang DT. D, Collins KD, Ernst JB, Glorius F. Angew. Chem. Int. Ed. 2014; 53: 1809
  CrossrefPubMedSearch in Google Scholar
• 10a Meng G, Lam NY. S, Lucas E, Saint-Denis TG, Verma P, Chekshin N, Yu JQ. J. Am. Chem. Soc. 2020; 142: 10571
  CrossrefPubMedSearch in Google Scholar
• 10b Gandeepan P, Muller T, Zell D, Cera G, Warratz S, Ackermann L. Chem. Rev. 2019; 119: 2192
  CrossrefPubMedSearch in Google Scholar
• 10c Sambiagio C, Schonbauer D, Blieck R, Dao-Huy T, Pototschnig G, Schaaf P, Wiesinger T, Zia MF, Wencel-Delord J, Besset T, Maes BU, Schnurch M. Chem. Soc. Rev. 2018; 47: 6603
  CrossrefPubMedSearch in Google Scholar
• 10d Wencel-Delord J, Droge T, Glorius F. Chem. Soc. Rev. 2011; 40: 4740
  CrossrefPubMedSearch in Google Scholar
• 11a Lapuh MI, Mazeh S, Besset T. ACS Catal. 2020; 21: 12898
  CrossrefSearch in Google Scholar
• 11b Chen XY, Sorensen EJ. J. Am. Chem. Soc. 2018; 140: 2789
  CrossrefPubMedSearch in Google Scholar
• 11c Huang Z, Lim HN, Mo F, Young MC, Dong G. Chem. Soc. Rev. 2015; 44: 7764
  CrossrefPubMedSearch in Google Scholar
• 12 Li B, Seth K, Niu B, Pan L, Yang H, Ge H. Angew. Chem. Int. Ed. 2018; 57: 3401
  CrossrefPubMedSearch in Google Scholar
• 13a Lotz MD, Camasso NM, Canty AJ, Sanford MS. Organometallics 2017; 36: 165
  Search in Google Scholar
• 13b Whitaker D, Bures J, Larrosa I. J. Am. Chem. Soc. 2016; 138: 8384
  CrossrefPubMedSearch in Google Scholar
• 13c Lee YS, Hartwig JF. J. Am. Chem. Soc. 2016; 138: 15278
  CrossrefPubMedSearch in Google Scholar
• 13d Liu KH, Hu GQ, Wang CX, Sheng FF, Bai JW, Gu JG, Zhang HH. Org. Lett. 2021; 23: 5626
  CrossrefPubMedSearch in Google Scholar
• 14a Li EC, Hu GQ, Zhu YX, Zhang HH, Shen K, Hang XC, Zhang C, Huang W. Org. Lett. 2019; 21: 6745
  Search in Google Scholar
• 14b Hu GQ, Li EC, Zhang HH, Huang W. Org. Biomol. Chem. 2020; 18: 6627
  CrossrefPubMedSearch in Google Scholar
• 14c Hu GQ, Bai JW, Li EC, Liu KH, Sheng FF, Zhang HH. Org. Lett. 2021; 23: 1554
  Search in Google Scholar
• 15a Li B, Dixneuf PH. Chem. Soc. Rev. 2013; 42: 5744
  CrossrefPubMedSearch in Google Scholar
• 15b Ohnmacht SA, Culshaw AJ, Greaney MF. Org. Lett. 2010; 12: 224
  CrossrefPubMedSearch in Google Scholar

• Supplementary Material