Palladium-catalyzed 1,4-migration for the regioselective C–H bond functionalization at C2-position of 3-arylthiophenes

Abstract

The regioselective functionalization of the C–H bond at the C2-position of 3-substituted thiophenes is challenging, as both thienyl α-positions may be reactive, generally affording mixtures of C2-, C5- and C2,C5-(di)functionalized thiophenes. We established that using palladium 1,4-migration allows for the regioselective functionalization of only one of the two α-positions of 3-arylthiophenes. The oxidative addition of the 3-(2-bromoaryl)thiophenes to palladium followed by such palladium migration, regioselectively activates the thienyl C2-α-position. Next, C2-heteroarylated 3-arylthiophene derivatives can be obtained through palladium-catalyzed direct coupling with heteroarenes. The new C–C bond that this reaction generates comes from the functionalization of two C–H bonds. This thienyl heteroarylation method tolerates a variety of heteroarenes and several substituents on the 3-arylthiophene. In addition, an easily available air-stable catalyst and an inexpensive base were employed for this reaction.

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Introduction

Thiophene derivatives bearing a heteroaryl substituent at the C2 position and an aryl group at the C3 position exhibit properties that make them highly attractive for applications in pharmaceutical chemistry,^1–3 including as antitumor agents, as well as in organic electronics, such as solar cells.⁴ However, the preparation of such compounds remains a challenging process and necessitates a number of synthetic steps. They are currently generally prepared via palladium-catalyzed Suzuki and Stille cross-coupling reactions, typically from 3-aryl-2-halothiophenes.^5–11 Consequently, the identification of more straightforward methods for their preparation is a significant area of current research.

Catalytic reactions that functionalize specific C–H bonds of organic molecules often result in simple synthetic methods.^12–20 For instance, the Pd-catalyzed C–H bond activation/functionalization of heteroarenes, reported by Ohta et al. in 1990,^21,22 has become one of the most reliable and cost-effective methods for preparing heteroarylated arenes, including thiophenes.^23–26 However, in several cases, due to the similar reactivity of two C–H bonds on some substrates, such Pd-catalyzed C–H bond functionalization led to the formation of mixtures of products.²⁷ For example, the reaction of 3-phenylthiophene with 4-bromotoluene produced a mixture of C2-, C5-, and C2,C5-(di)arylated thiophenes in a 9 : 9 : 70 ratio, even when an equimolar amount of reactants was used (Scheme 1b).²⁸ Consequently, the regioselective C2-(hetero)arylation of such 3-arylthiophenes via a C–H bond functionalization remains challenging. This is why synthetic chemists currently rely on more traditional palladium-catalyzed reactions, such as the Suzuki coupling, to synthesize C2-(hetero)arylated 3-arylthiophene derivatives.^6–11

Scheme 1 Pd-catalyzed C2-(hetero)arylations of 3-arylthiophenes; direct arylation vs. classical cross-couplings.

We recently reported that, during the palladium-catalyzed heteroarylation of 2-(2-bromoaryl)thiophenes with heteroarenes, partial palladium 1,4-migration^29–33 occurred in some cases.³⁴ The predominant formation of 2-arylthiophenes heteroarylated at the β-position of thiophene, such as 2′-aryl-2,3′-bithiophenes, was the result of this Pd-migration, providing a simple method to functionalize such thienyl β-C–H bonds. To the best of our knowledge, there has been no report of the C–H bond activation of the thienyl α-position via such Pd 1,4-migration. Using Pd 1,4-migration with 3-(2-bromoaryl)thiophenes would enable the regioselective preparation of 2-heteroaryl-3-arylthiophenes in only two steps. This Pd 1,4-migration method is different from the more traditional Pd-catalyzed direct arylation in that it should only activate the thienyl C2-position, not its C5-position (see Scheme 1). Therefore, we investigated the outcome of the reaction of the palladium-catalyzed coupling of 3-(2-bromoaryl)thiophenes with heteroarenes. Herein, we report on (1) the regioselectivity of the Pd-catalyzed direct arylations of 3-(2-bromoaryl)thiophenes, (2) the scope of the reaction using various heteroarenes and 3-(2-bromoaryl)thiophene derivatives (Scheme 1, bottom).

Results and discussion

First, we synthesized a series of 3-(2-bromoaryl)thiophenes via palladium-catalyzed Suzuki (Scheme 2). The expected products 1a–1p were obtained in good yields.

Scheme 2 Preparation of the 3-(2-bromoaryl)thiophenes 1a–1p. ^a For procedure, see ref. 36.

Next, we determined the selectivity of the palladium-catalyzed coupling reaction between 3-(2-bromophenyl)thiophene 1a and 2-ethyl-4-methylthiazole (Table 1).^38–40 Based on our previously reported reaction conditions,³⁴ using a 5 mol% Pd(OAc)₂ catalyst and KOPiv as the base in DMA, the desired product 2b, arising from Pd-catalyzed 1,4-migration associated with direct arylation, was obtained in 78% selectivity (Table 1, entry 1). In contrast, product 2a, which arose from the non-migrated palladium intermediate, was obtained in 22% selectivity. The conversion of 1a was only 63% using this phosphine ligand-free Pd(OAc)₂ catalyst. Conversely, complete conversion of 1a was observed in the presence of the more stable PdCl(C₃H₅)(dppb)³⁷ catalyst (Table 1, entry 2). Furthermore, the ratio of products 2a and 2b increased to 5 : 95, and desired product 2b was isolated with a yield of 77%. Using acetate bases KOAc and NaOAc gave the product 2b with slightly lower selectivity and yield than when KOPiv base was employed (Table 1, entries 3 and 4). The Na₂CO₃ base also gave a good selectivity in the desired product 2b, but a very low conversion of 1a was observed (Table 1, entry 5). In contrast, the other carbonate bases, Cs₂CO₃ and K₂CO₃, led to poor selectivities in 2a and 2b products (Table 1, entries 6 and 7). With these two bases, the product 2a, resulting from the non-migrated palladium intermediate, was predominant with 60%–65% selectivity. The influence of a few solvents on the reaction outcome was also examined. Reactions performed in DMF and NMP gave the desired product 2b resulting from Pd 1,4-migration, albeit with slightly lower selectivity than in DMA (Table 1, entries 8 and 9). Conversely, the less polar solvents, xylene and diethyl carbonate (DEC) were ineffective (Table 1, entries 10 and 11). Finally, reducing the reaction temperature to 130 °C (from 150 °C) produced 2b in 70% yield due to a slightly lower selectivity of the reaction (Table 1, entry 12).

Table 1 Influence of the reaction conditions on the Pd-catalyzed coupling of 3-(2-bromophenyl)thiophene 1a with 2-ethyl-4-methylthiazole^a

Entry	Catalyst	Solvent	Base	Conv. (%)	Ratio 2a : 2b	Yield in 2b (%)
a [Pd] (0.05 equiv.), 2-ethyl-4-methylthiazole (2 equiv.), 3-(2-bromophenyl)thiophene 1a (1 equiv.), base (2 equiv.), 150 °C, 16 h, 2a : 2b ratios determined by ^1H NMR and GC/MS analysis of the crude mixtures, isolated yields.b 130 °C.
1	Pd(OAc)2	DMA	KOPiv	63	22 : 78	—
2	PdCl(C3H5)(dppb)	DMA	KOPiv	100	5 : 95	77
3	PdCl(C3H5)(dppb)	DMA	KOAc	99	6 : 94	75
4	PdCl(C3H5)(dppb)	DMA	CsOAc	100	11 : 89	71
5	PdCl(C3H5)(dppb)	DMA	Na2CO3	20	8 : 92	<5
6	PdCl(C3H5)(dppb)	DMA	K2CO3	100	60 : 40	—
7	PdCl(C3H5)(dppb)	DMA	Cs2CO3	100	65 : 35	41 of 2a
8	PdCl(C3H5)(dppb)	DMF	KOPiv	100	9 : 91	75
9	PdCl(C3H5)(dppb)	NMP	KOPiv	100	13 : 87	70
10	PdCl(C3H5)(dppb)	Xylene	KOPiv	100	Not determined	<10
11	PdCl(C3H5)(dppb)	DEC	KOPiv	100	Not determined	<10
12	PdCl(C3H5)(dppb)	DMA	KOPiv	100	11 : 89	70^b

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Then, we investigated the influence of the substituents on the aryl group of the 3-(2-bromoaryl)thiophene in this reaction, using 2-ethyl-4-methylthiazole as the reaction partner (Scheme 3). Our study began with the examination of the influence of a set of 3-(2-bromoaryl)thiophene compounds with various substituents in the meta-position to the C–Br bond on the selectivity. The presence of a methyl substituent slightly increased the selectivity in the desired product 4b to 96%. Conversely, in the presence of fluorine and chlorine substituents, we obtained lower selectivities of 80% and 73%, respectively, for isomers 5b and 6b. These results suggest that the presence of an electron-withdrawing substituent on the aryl unit is less favourable to the palladium 1,4-migration. This trend was confirmed using a 3-arylthiophenes with CF₃ or OCF₃ substituents that were also in the meta-position relative to the C–Br bond, which gave isomers 7b and 8b with 79% and 76% selectivity, respectively. A nitrile substituent, which is strongly electron-withdrawing, on the aryl unit, was well tolerated, affording product 9b in 80% selectivity. Then, reactions involving 3-(2-bromoaryl)thiophene with substituents on the aryl in the para-position relative to the C–Br bond were performed. Methyl and fluoro substituents (Hammett σ_p constants of −0.17 and 0.06) furnished the target products 10b and 11b in 98% and 96% selectivities, respectively. A chloro para-substituent was also well tolerated and produced compound 12b in 93% selectivity. Therefore, the selectivity of this reaction appears to be influenced by the Hammett constants (σ_m or σ_p depending on the position of the aryl substituent relative to the C–Br bond), since low Hammett constants tend to favour Pd 1,4-migration in all cases (Scheme 4). However, kinetic studies would be required to gain more insight into the factors governing the Pd 1,4-migration process. In the presence of 3-(2-bromo-6-fluorophenyl)thiophene 1l, we also obtained a good selectivity of 87% in desired product 13b. It should be noted that reaction selectivity also depends on the heteroaryl coupling partner. For example, when we used 2-isobutylthiazole instead of 2-ethyl-4-methylthiazole, we observed a lower selectivity in the Pd-1,4-migration product, affording isomer 14b with only 77% selectivity.

Scheme 3 Pd-catalyzed direct C2-heteroarylations of the thienyl ring of a set of 3-(2-bromoaryl)thiophenes.

Scheme 4 Influence of the substituents on the aryl group of the 3-(2-bromoaryl)thiophenes: correlation of the a : b selectivity with meta Hammett constants.

The impact of the thienyl substituents of 3-(2-bromoaryl)thiophenes on the Pd 1,4-migration process was also examined (Scheme 5). The presence of a methyl substituent at the C5 position of the 3-arylthiophene had almost no effect on the selectivity or yield of the reaction. The desired products, 15b and 16b, were obtained with 94% and 75% selectivity, respectively, using 2-ethyl-4-methylthiazole and 2-isobutylthiazole. As expected, the reaction of a 5-hexyl-3-arylthiazole derivative with 2-ethyl-4-methylthiazole produced isomer 17b with a similar selectivity of 95%. A benzothiophene unit was also well tolerated. In the presence of 3-(2-bromophenyl)benzothiophene 1p, both 2-ethyl-4-methylthiazole and 2-isobutylthiazole gave the desired products 18b and 19b with very high selectivities of 99% and 98%, respectively. The presence of a formyl C2-substituent on the thienyl ring was also tolerated. Using 4-(2-bromophenyl)thiophene-2-carbaldehyde 1o and 2-ethyl-4-methylthiazole as the coupling partner, the target product 20b arising from Pd 1,4-migration was also obtained with a very high 99% selectivity and in 77% yield.

Scheme 5 Pd-catalyzed direct C5-heteroarylations of the thienyl ring of 4-(2-bromophenyl)thiophene derivatives.

Then, the heteroarylation of 3-(2-bromophenyl)thiophenes 1j–1m, using a variety of heteroarenes was explored (Scheme 6). Similar selectivity to that observed with 2-isobutylthiazole was achieved using 2-acetylthiazole, affording product 21b with 81% selectivity and 68% yield. Regioselectivities of 98% and 94% were obtained for isomers 22b and 23b, respectively, when 2-hexylthiophene was used with 1j and 1m as the reaction partners. With 2-chlorothiophene, the target product 24b was obtained with a lower selectivity of 68%. Notably, no cleavage of the thienyl C–Cl bond was observed in the course of this reaction, which allowed for subsequent transformations. The product 25b was obtained in 96% selectivity from 2-methyl-2-(thien-2-yl)-1,3-dioxolane and 4-(2-bromophenyl)-2-methylthiophene 1m. Using 2-butylfuran, products 26b and 27b were obtained with selectivities of 97%, but in quite low yield due to the formation of unidentified side products. Very high selectivity in isomer 29b was obtained when 1-methylpyrrole was used; however, unidentified side products were formed again. In the presence of 1l and 1m, imidazo[1,2-a]pyrazine afforded the target Pd 1,4-migration products 30b and 31b with 98% and 95% selectivity, respectively. Finally, a selectivity of 91% in product 32b was obtained using imidazo[1,2-a]pyrazine.

Scheme 6 Pd-catalyzed direct C2- or C5-heteroarylations of the thienyl ring of 3-(2-bromoaryl)thiophenes 1j–1m using a set of heteroarenes.

The synthesis of a 2,5-diheteroaryl-3-arylthiophene from the 5-(thien-2-yl)thiazole derivative 4b, prepared in Scheme 3, via Pd-catalyzed direct arylation, was also investigated (Scheme 7). We obtained the desired 2-heteroaryl-3,5-diarylthiophene derivative 33 in an 86% yield from 4b, 3-bromopyridine, 5 mol% PdCl(C₃H₅)(dppb) catalyst, and KOPiv base. This result demonstrates that our method allows for the introduction of two different heteroaryl substituents at positions C2 and C5 of the thienyl unit.

Scheme 7 Preparation of a tri(hetero)arylated thiophene derivative via successive Pd-catalyzed direct (hetero)arylations.

To further illustrate the advantage of our method for synthesizing 2-heteroaryl-3-arylthiophenes, we tried to synthesize one of them using palladium-catalyzed coupling of 3-phenylthiophene and a 2-bromothiophene (Scheme 8). We found that preparing 2-thienyl-substituted 3-phenylthiophene 34b from 3-phenylthiophene and 1-(5-bromothien-2-yl)ethan-1-one was very challenging. A low conversion of 3-phenylthiophene was observed in this reaction. Moreover, we obtained a mixture between the C2 and C5 arylated 3-phenylthiophene in a 47 : 53 ratio, affording the desired isomer 34b in only 8% isolated yield (Scheme 8, top). In addition, it should be noted that the formation of a large amount of the side product 1,1′-([2,2′-bithiophene]-5,5′-diyl)bis(ethan-1-one) was also observed. In contrast, our method produced 35b in 96% selectivity and 56% yield from 3-(2-bromophenyl)thiophene 1a and 2-methyl-2-(thien-2-yl)-1,3-dioxolane (Scheme 8, bottom). Product 35b could be easily deprotected under acidic conditions into product 34b in 86% yield.

Scheme 8 Use of 3-phenylthiophene vs. 3-(2-bromophenyl)thiophene 1a in Pd-catalyzed direct C2-heteroarylation.

Mechanism for the access to b products likely proceed via a Pd-1,4-migration^29–31 followed by a direct arylation^41–44 as described in the Scheme 9. The first step of the catalytic cycle certainly involves the oxidative addition of the 3-(2-bromoaryl)thiophene to palladium to give the intermediate A. Then, a Br/OPiv ligand exchange and a Pd-1,4-migration^29–31 occurs to give the intermediate B. From B, a concerted metallation deprotonation (CMD)^41–44 of the heteroarene coupling partner, gives the intermediate C. Finally, reductive elimination regenerates a Pd(0) species and produces the C2-heteroarylated 3-arylthiophene derivative b. In the absence of computational studies, we assume that the reaction is driven by the irreversible formation of the C–C bond.

Scheme 9 Proposed catalytic cycle for accessing b products.

Conclusions

In summary, Pd 1,4-migration associated with Pd-catalyzed direct arylation allowed for the synthesis of a variety of C2-heteroarylated 3-arylthiophenes in only two steps from commercially available compounds. This method enables the regioselective C2-heteroarylation of the thienyl ring, as the bromo substituent on the 3-arylthiophene behaves as a traceless directing group; whereas the thienyl C5-position remained untouched. This coupling reaction creates a C–C bond between two heteroarenes through the functionalization of two C–H bonds. This reaction is compatible with a variety of heteroarenes, as well as several substituents on the aryl unit of 3-(2-bromoaryl)thiophene. Furthermore, these reactions use an air-stable palladium catalyst associated with an inexpensive base. Therefore, this method is undoubtedly one of the most efficient synthetic pathways for producing C2-heteroarylated 3-arylthiophenes.

Experimental

General

[PdCl(C₃H₅)]₂ (98%) was purchased from Aldrich. DMA (99+%) extra pure was purchased from ACROS. Dppb (1,4-bis(diphenylphosphino)butane) (98%), KOPiv (95+%), thien-3-ylboronic acids, 1,2-dihalobenzenes and 3-phenylthiophene were purchased from Fluorochem. These compounds were not purified before use. All reagents were weighed and handled in air. All reactions were carried out under an inert atmosphere with standard Schlenk techniques. ¹H, ¹⁹F and ¹³C NMR spectra were recorded on a Bruker Avance III 400 MHz spectrometer. High-resolution mass spectra were measured on a Thermo Fisher Scientific Q-Exactive spectrometer. Melting points were determined with a Kofler hot bench system. 3-(2-Bromophenyl)thiophene³⁵ 1a and 4-(2-bromophenyl)-2-methylthiophene³⁶ 1m were prepared using reported procedures.

Preparation of the PdCl(C₃H₅)(dppb) catalyst³⁷

An oven-dried 40 mL Schlenk tube equipped with a magnetic stirring bar under argon atmosphere, was charged with [Pd(C₃H₅)Cl]₂ (182 mg, 0.5 mmol) and dppb (426 mg, 1 mmol). 10 mL of anhydrous dichloromethane were added, then, the solution was stirred at room temperature for twenty minutes. The solvent was removed in vacuum. The yellow powder was used without purification. ³¹P NMR (162 MHz, CDCl₃) δ 19.3 (s).

General procedure for the preparation of 3-(2-bromophenyl)thiophenes 1b–1l, 1o and 1p

As a typical experiment, a mixture of 1,2-dihalobenzene derivative (3 mmol), thien-3-ylboronic acid derivative (4.5 mmol), K₂CO₃ (0.828 g, 6 mmol), Pd(OAc)₂ (33.6 mg, 0.15 mmol) and dppf (166.2 mg, 0.30 mmol) in DMA (20 mL) was stirred at 150 °C for 16 h. After being allowed to cool to room temperature, the resulting mixture was extracted with Et₂O (3 × 10 mL). The combined organic phase was dried over MgSO₄, filtrated, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the 3-(2-bromoaryl)thiophenes.

3-(2-Bromo-4-methoxyphenyl)thiophene (1b). From thien-3-ylboronic acid (0.572 g, 4.5 mmol) and 2-bromo-1-iodo-4-methoxybenzene (0.939 g, 3 mmol), 1b was isolated in 82% (0.661 g) yield as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.40–7.36 (m, 2H), 7.34 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 3.3 Hz, 1H), 7.26 (d, J = 2.6 Hz, 1H), 6.93 (dd, J = 8.6, 2.6 Hz, 1H), 3.86 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 159.3, 140.9, 131.7, 130.0, 129.1, 124.7, 123.5, 122.9, 118.5, 113.6, 55.6.

HRMS calcd for [M + H]⁺ C₁₁H₁₀BrOS 268.9630, found: 268.9630.

3-(2-Bromo-4-methylphenyl)thiophene (1c). From thien-3-ylboronic acid (0.572 g, 4.5 mmol) and 2-bromo-1-iodo-4-methylbenzene (0.891 g, 3 mmol), 1c was isolated in 84% (0.638 g) yield as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.41 (dd, J = 3.1, 1.3 Hz, 1H), 7.38 (dd, J = 4.9, 3.0 Hz, 1H), 7.35–7.27 (m, 2H), 7.17 (d, J = 7.8 Hz, 1H), 2.39 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 141.1, 138.9, 134.6, 133.8, 131.0, 129.0, 128.2, 124.7, 123.7, 122.3, 20.7.

HRMS calcd for [M + H]⁺ C₁₁H₁₀BrS 252.9681, found: 252.9681.

3-(2-Bromo-4-fluorophenyl)thiophene (1d). From thien-3-ylboronic acid (0.572 g, 4.5 mmol) and 2-bromo-4-fluoro-1-iodobenzene (0.903 g, 3 mmol), 1d was isolated in 79% (0.609 g) yield as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.44 (dd, J = 8.3, 2.6 Hz, 1H), 7.42–7.38 (m, 3H), 7.28 (dd, J = 3.5, 3.0 Hz, 1H), 7.09 (ddd, J = 8.5, 7.9, 2.7 Hz, 1H).

¹⁹F NMR (376 MHz, CDCl₃) δ −113.2.

¹³C NMR (101 MHz, CDCl₃) δ 161.6 (d, J = 250.8 Hz), 140.1, 133.8 (d, J = 3.7 Hz), 132.1 (d, J = 8.4 Hz), 128.9, 125.0, 124.1, 122.7 (d, J = 9.6 Hz), 120.5 (d, J = 24.3 Hz), 114.6 (d, J = 21.0 Hz).

HRMS calcd for [M + H]⁺ C₁₀H₇BrFS 256.9430, found: 256.9429.

3-(2-Bromo-4-chlorophenyl)thiophene (1e). From thien-3-ylboronic acid (0.572 g, 4.5 mmol) and 2-bromo-4-chloro-1-iodobenzene (0.952 g, 3 mmol), 1e was isolated in 78% (0.641 g) yield as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.70 (t, J = 1.2 Hz, 1H), 7.42 (dd, J = 3.0, 1.4 Hz, 1H), 7.41–7.38 (m, 1H), 7.35–7.32 (m, 2H), 7.30–7.25 (m, 1H).

¹³C NMR (101 MHz, CDCl₃) δ 140.0, 136.1, 133.7, 132.9, 131.9, 128.7, 127.6, 125.1, 124.3, 122.9.

HRMS calcd for [M + H]⁺ C₁₀H₇BrClS 272.9135, found: 272.9135.

3-(2-Bromo-4-(trifluoromethyl)phenyl)thiophene (1f). From thien-3-ylboronic acid (0.572 g, 4.5 mmol) and 2-bromo-1-iodo-4-(trifluoromethyl)benzene (1.053 g, 3 mmol), 1f was isolated in 74% (0.681 g) yield as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.50 (dd, J = 3.0, 1.3 Hz, 1H), 7.44 (dd, J = 5.0, 3.0 Hz, 1H), 7.33 (dd, J = 5.0, 1.3 Hz, 1H).

¹⁹F NMR (376 MHz, CDCl₃) δ −62.6.

¹³C NMR (101 MHz, CDCl₃) δ 141.1, 139.8, 131.5, 130.8 (q, J = 33.2 Hz), 130.4 (q, J = 3.9 Hz), 128.5, 125.4, 124.9, 124.2 (q, J = 3.6 Hz), 122.7, 120.3 (d, J = 272.5 Hz).

HRMS calcd for [M]⁺ C₁₁H₆BrF₃S 305.9320, found: 305.9322.

3-(2-Bromo-4-(trifluoromethoxy)phenyl)thiophene (1g). From thien-3-ylboronic acid (0.572 g, 4.5 mmol) and 2-bromo-1-iodo-4-(trifluoromethoxy)benzene (1.101 g, 3 mmol), 1g was isolated in 84% (0.814 g) yield as a colourless oil.

¹H NMR (400 MHz, CDCl₃) (δ 7.62 s, 1H), 7.49–7.40 (m, 3H), 7.32 (dd, J = 5.0, 1.4 Hz, 1H), 7.27 (d, J = 7.4 Hz, 1H).

¹⁹F NMR (376 MHz, CDCl₃) δ −57.9.

¹³C NMR (101 MHz, CDCl₃) δ 148.3 (q, J = 2.0 Hz), 139.8, 136.5, 131.9, 128.7, 125.9, 125.2, 124.5, 122.9, 120.4 (d, J = 258.4 Hz), 119.9.

HRMS calcd for [M]⁺ C₁₁H₆BrF₃OS 321.9269, found: 321.9271.

3-Bromo-4-(thien-3-yl)benzonitrile (1h). From thien-3-ylboronic acid (0.572 g, 4.5 mmol) and 3-bromo-4-iodobenzonitrile (0.924 g, 3 mmol), 1h was isolated in 73% (0.576 g) yield as a white solid: mp 76–78 °C.

¹H NMR (400 MHz, CDCl₃) δ 7.94 (d, J = 1.7 Hz, 1H), 7.62 (dd, J = 8.0, 1.7 Hz, 1H), 7.53 (dd, J = 3.0, 1.4 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.42 (dd, J = 5.0, 3.0 Hz, 1H), 7.32 (dd, J = 5.0, 1.4 Hz, 1H).

¹³C NMR (101 MHz, CDCl₃) δ 142.2, 139.3, 136.7, 131.7, 130.9, 128.4, 125.8, 125.6, 122.8, 117.4, 112.4.

HRMS calcd for [M + H]⁺ C₁₁H₇BrNS 263.9477, found: 263.9477.

3-(2-Bromo-5-methylphenyl)thiophene (1i). From thien-3-ylboronic acid (0.572 g, 4.5 mmol) and 1-bromo-2-iodo-4-methylbenzene (0.891 g, 3 mmol), 1i was isolated in 76% (0.577 g) yield as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.57 (d, J = 8.1 Hz, 1H), 7.44 (dd, J = 3.0, 1.3 Hz, 1H), 7.40 (dd, J = 5.0, 3.0 Hz, 1H), 7.33 (dd, J = 5.0, 1.3 Hz, 1H), 7.26 (s, 1H), 7.04 (ddd, J = 8.1, 2.2, 0.8 Hz, 1H), 2.38 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 141.3, 137.3, 137.2, 133.1, 132.1, 129.6, 129.0, 124.7, 123.9, 119.2, 20.9.

HRMS calcd for [M + H]⁺ C₁₁H₁₀BrS 252.9681, found: 252.9681.

3-(2-Bromo-5-fluorophenyl)thiophene (1j). From thien-3-ylboronic acid (0.572 g, 4.5 mmol) and 1-bromo-4-fluoro-2-iodobenzene (0.903 g, 3 mmol), 1j was isolated in 81% (0.624 g) yield as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.63 (dd, J = 8.8, 5.4 Hz, 1H), 7.47 (dd, J = 3.0, 1.4 Hz, 1H), 7.41 (dd, J = 5.0, 3.0 Hz, 1H), 7.31 (dd, J = 4.9, 1.3 Hz, 1H), 7.15 (dd, J = 9.3, 3.1 Hz, 1H), 6.94 (ddd, J = 8.8, 7.8, 3.1 Hz, 1H).

¹⁹F NMR (376 MHz, CDCl₃) δ −115.1.

¹³C NMR (101 MHz, CDCl₃) δ 161.8 (d, J = 247.3 Hz), 140.1 (d, J = 1.5 Hz), 139.2 (d, J = 8.1 Hz), 134.6 (d, J = 8.1 Hz), 128.6, 125.2, 124.6, 118.2 (d, J = 23.0 Hz), 116.7 (d, J = 3.2 Hz), 115.8 (d, J = 22.3 Hz).

HRMS calcd for [M]⁺ C₁₀H₆BrFS 255.9352, found: 255.9353.

3-(2-Bromo-5-chlorophenyl)thiophene (1k). From thien-3-ylboronic acid (0.572 g, 4.5 mmol) and 1-bromo-4-chloro-2-iodobenzene (0.952 g, 3 mmol), 1k was isolated in 80% (0.656 g) yield as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J = 8.5 Hz, 1H), 7.46 (dd, J = 3.0, 1.3 Hz, 1H), 7.43–7.37 (m, 2H), 7.30 (dd, J = 5.0, 1.3 Hz, 1H), 7.18 (dd, J = 8.5, 2.6 Hz, 1H).

¹³C NMR (101 MHz, CDCl₃) δ 139.9, 139.0, 134.4, 133.3, 131.1, 128.7, 128.6, 125.2, 124.6, 120.5.

HRMS calcd for [M + H]⁺ C₁₀H₇BrClS 272.9135, found: 272.9135.

3-(2-Bromo-6-fluorophenyl)thiophene (1l). From thien-3-ylboronic acid (0.572 g, 4.5 mmol) and 1-bromo-3-fluoro-2-iodobenzene (0.903 g, 3 mmol), 1l was isolated in 83% (0.640 g) yield as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J = 7.9 Hz, 1H), 7.48–7.42 (m, 2H), 7.27–7.11 (m, 3H).

¹⁹F NMR (376 MHz, CDCl₃) δ −109.0.

¹³C NMR (101 MHz, CDCl₃) δ 160.4 (d, J = 249.9 Hz), 133.4, 129.6 (d, J = 9.1 Hz), 129.2 (d, J = 1.5 Hz), 128.8 (d, J = 3.5 Hz), 126.3 (d, J = 18.1 Hz), 125.9 (d, J = 1.9 Hz), 124.8, 124.5 (d, J = 2.8 Hz), 114.9 (d, J = 23.5 Hz).

HRMS calcd for [M + H]⁺ C₁₀H₇BrFS 256.9430, found: 256.9429.

4-(2-Bromophenyl)-2-hexylthiophene (1n). Following the procedure of ref. 36, from 2-hexylthiophene (0.756 g, 4.5 mmol) and 2-bromobenzenesulfonyl chloride (0.765 g, 3 mmol), 1n was isolated in 71% (0.688 g) yield as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.66 (dd, J = 8.0, 1.3 Hz, 1H), 7.41 (dd, J = 7.7, 1.8 Hz, 1H), 7.34 (td, J = 7.5, 1.3 Hz, 1H), 7.19 (d, J = 1.5 Hz, 1H), 7.17 (td, J = 7.5, 1.7 Hz, 1H), 6.99 (s, 1H), 2.87 (t, J = 7.6 Hz, 2H), 1.75 (quint., J = 7.6 Hz, 2H), 1.50–1.21 (m, 6H), 0.95 (t, J = 7.6 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 145.2, 140.6, 138.0, 133.3, 131.2, 128.5, 127.3, 125.9, 122.5, 121.5, 31.6, 30.1, 28.8, 22.6, 14.1.

HRMS calcd for [M + H]⁺ C₁₆H₂₀BrS 323.0464, found: 323.0464.

4-(2-Bromophenyl)thiophene-2-carbaldehyde (1o). From (5-formylthien-3-yl)boronic acid (0.702 g, 4.5 mmol) and 1-bromo-2-iodobenzene (0.849 g, 3 mmol), 1o was isolated in 69% (0.552 g) yield as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 10.00 (d, J = 1.3 Hz, 1H), 7.97 (d, J = 1.5 Hz, 1H), 7.83 (t, J = 1.4 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.47–7.36 (m, 2H), 7.30–7.22 (m, 1H).

¹³C NMR (75 MHz, CDCl₃) δ 182.9, 143.4, 142.3, 137.5, 135.9, 133.5, 133.4, 131.0, 129.5, 127.7, 122.4.

HRMS calcd for [M + H]⁺ C₁₁H₈BrOS 266.9474, found: 266.9474.

3-(2-Bromophenyl)benzo[b]thiophene (1p)⁴⁵. From benzo[b]thien-3-ylboronic acid (0.801 g, 4.5 mmol) and 1-bromo-2-iodobenzene (0.849 g, 3 mmol), 1p was isolated in 85% (0.737 g) yield as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.68–7.59 (m, 1H), 7.55–7.42 (m, 5H), 7.36 (ddd, J = 8.0, 6.5, 2.6 Hz, 1H).

¹³C NMR (101 MHz, CDCl₃) δ 139.9, 138.5, 136.9, 136.7, 133.3, 132.1, 129.5, 127.4, 125.5, 124.6, 124.4, 124.2, 123.4, 122.9.

LRMS calcd for [M]⁺ C₁₄H₉BrS 290, found: 290.

General procedure for the preparation of products 2b–35b

As a typical experiment, the reaction of the 3-(2-bromoaryl)thiophene derivative 1a–1p (1 mmol), heteroarene (2 mmol) and KOPiv (0.280 g, 2 mmol) at 150 °C during 16 h in DMA (4 mL) in the presence of PdCl(C₃H₅)(dppb) (30.5 mg, 0.05 mmol) under argon affords the coupling product after evaporation of the solvent and purification by column chromatography on silica gel. The a : b ratios were determined by ¹H NMR and GC/MS analysis of the crude mixtures.

2-Ethyl-4-methyl-5-(3-phenylthien-2-yl)thiazole (2b). From 3-(2-bromophenyl)thiophene 1a (0.239 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), a mixture of 2a and 2b was obtained in 5 : 95 ratio and 2b was isolated in 77% (0.219 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J = 5.3 Hz, 1H), 7.37–7.25 (m, 5H), 7.23 (d, J = 5.3 Hz, 1H), 2.98 (q, J = 7.6 Hz, 2H), 2.08 (s, 3H), 1.38 (t, J = 7.6 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 172.1, 150.1, 141.4, 136.0, 129.5, 128.5, 128.4, 127.5, 127.1, 126.1, 122.7, 27.0, 15.7, 14.1.

HRMS calcd for [M + H]⁺ C₁₆H₁₆NS₂ 286.0719, found: 286.0717.

2-Ethyl-4-methyl-5-(2-(thien-3-yl)phenyl)thiazole (2a). From 3-(2-bromophenyl)thiophene 1a (0.239 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), using Cs₂CO₃ (0.652, 2 mmol) as the base, a mixture of 2a and 2b was obtained in 65 : 35 ratio and 2a was isolated in 41% (0.117 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J = 8.0 Hz, 1H), 7.47–7.34 (m, 3H), 7.21 (dd, J = 5.0, 3.0 Hz, 1H), 7.10 (dd, J = 2.9, 1.3 Hz, 1H), 6.86 (dd, J = 5.0, 1.3 Hz, 1H), 2.99 (q, J = 7.6 Hz, 2H), 2.02 (s, 3H), 1.38 (t, J = 7.6 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 171.2, 148.3, 141.3, 137.2, 132.1, 130.3, 129.9, 129.7, 128.6, 128.2, 127.2, 125.0, 123.0, 26.9, 15.3, 14.3.

HRMS calcd for [M + H]⁺ C₁₆H₁₆NS₂ 286.0719, found: 286.0719.

2-Ethyl-5-(3-(4-methoxyphenyl)thien-2-yl)-4-methylthiazole (3b). From 3-(2-bromo-4-methoxyphenyl)thiophene 1b (0.268 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), a mixture of 3a and 3b was obtained in 13 : 87 ratio and 3b was isolated in 61% (0.192 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.41 (d, J = 5.2 Hz, 1H), 7.23 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 5.3 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 2.98 (q, J = 7.6 Hz, 2H), 2.11 (s, 3H), 1.39 (t, J = 7.6 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 172.0, 158.7, 150.1, 141.0, 129.5, 129.4, 128.5, 126.5, 126.0, 122.9, 114.0, 55.2, 27.0, 15.7, 14.1.

HRMS calcd for [M + H]⁺ C₁₇H₁₈NOS₂ 316.0824, found: 316.0825.

2-Ethyl-4-methyl-5-(3-(p-tolyl)thien-2-yl)thiazole (4b). From 3-(2-bromo-4-methylphenyl)thiophene 1c (0.253 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), a mixture of 4a and 4b was obtained in 4 : 96 ratio and 4b was isolated in 76% (0.227 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.41 (d, J = 5.3 Hz, 1H), 7.27–7.16 (m, 3H), 7.12 (d, J = 8.4 Hz, 2H), 2.98 (q, J = 7.6 Hz, 2H), 2.36 (s, 3H), 2.09 (s, 3H), 1.39 (t, J = 7.6 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 172.0, 150.1, 141.4, 136.9, 133.0, 129.5, 129.2, 128.2, 127.0, 126.0, 122.8, 27.0, 21.2, 15.7, 14.1.

HRMS calcd for [M + H]⁺ C₁₇H₁₈NS₂ 300.0875, found: 300.0873.

2-Ethyl-5-(3-(4-fluorophenyl)thien-2-yl)-4-methylthiazole (5b). From 3-(2-bromo-4-fluorophenyl)thiophene 1d (0.257 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), a mixture of 5a and 5b was obtained in 20 : 80 ratio and 5b was isolated in 63% (0.191 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J = 5.3 Hz, 1H), 7.26 (dd, J = 8.7, 5.4 Hz, 1H), 7.19 (d, J = 5.3 Hz, 1H), 7.01 (t, J = 8.7 Hz, 2H), 2.98 (q, J = 7.6 Hz, 2H), 2.10 (s, 3H), 1.38 (t, J = 7.6 Hz, 3H).

¹⁹F NMR (376 MHz, CDCl₃) δ −114.8.

¹³C NMR (101 MHz, CDCl₃) δ 172.3, 162.0 (d, J = 246.9 Hz), 150.2, 140.3, 132.0 (d, J = 3.4 Hz), 130.0 (d, J = 8.1 Hz), 129.3, 127.5, 126.3, 122.4, 115.5 (d, J = 21.4 Hz), 27.0, 15.7, 14.1.

HRMS calcd for [M + H]⁺ C₁₆H₁₅FNS₂ 304.0625, found: 304.0624.

5-(3-(4-Chlorophenyl)thien-2-yl)-2-ethyl-4-methylthiazole (6b). From 3-(2-bromo-4-chlorophenyl)thiophene 1e (0.274 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), a mixture of 6a and 6b was obtained in 27 : 73 ratio and 6b was isolated in 57% (0.182 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J = 5.2 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 5.2 Hz, 1H), 2.99 (q, J = 7.6 Hz, 2H), 2.10 (s, 3H), 1.39 (t, J = 7.6 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 172.4, 150.3, 140.1, 134.4, 133.1, 129.7, 129.1, 128.8, 127.9, 126.5, 122.3, 27.0, 15.7, 14.0.

HRMS calcd for [M + H]⁺ C₁₆H₁₅ClNS₂ 320.0329, found: 320.0329.

2-Ethyl-4-methyl-5-(3-(4-(trifluoromethyl)phenyl)thien-2-yl)thiazole (7b). From 3-(2-bromo-4-(trifluoromethyl)phenyl)thiophene 1f (0.307 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), a mixture of 7a and 7b was obtained in 21 : 79 ratio and 7b was isolated in 60% (0.212 g) yield as a yellow solid: mp 116–118 °C.

¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 5.3 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 5.3 Hz, 1H), 3.00 (q, J = 7.6 Hz, 2H), 2.08 (s, 3H), 1.39 (t, J = 7.6 Hz, 3H).

¹⁹F NMR (376 MHz, CDCl₃) δ −62.6.

¹³C NMR (101 MHz, CDCl₃) δ 172.6, 150.4, 139.8, 139.5, 129.2 (q, J = 32.6 Hz), 129.1, 128.9, 128.6, 126.7, 125.5 (q, J = 3.9 Hz), 122.0, 121.2 (q, J = 272.0 Hz), 27.0, 15.7, 14.0.

HRMS calcd for [M + H]⁺ C₁₇H₁₅F₃NS₂ 354.0593, found: 354.0591.

2-Ethyl-4-methyl-5-(3-(4-(trifluoromethoxy)phenyl)thien-2-yl)thiazole (8b). From 3-(2-bromo-4-(trifluoromethoxy)phenyl)thiophene 1g (0.323 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), a mixture of 8a and 8b was obtained in 24 : 76 ratio and 8b was isolated in 57% (0.210 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 5.3 Hz, 1H), 7.17 (d, J = 8.3 Hz, 2H), 2.99 (q, J = 7.6 Hz, 2H), 2.09 (s, 3H), 1.39 (t, J = 7.6 Hz, 3H).

¹⁹F NMR (376 MHz, CDCl₃) δ −57.8.

¹³C NMR (101 MHz, CDCl₃) δ 172.4, 150.3, 148.3 (q, J = 1.8 Hz), 139.8, 134.6, 129.7, 129.2, 128.1, 126.5, 122.2, 120.9, 120.5 (q, J = 257.3 Hz), 27.0, 15.7, 14.0.

HRMS calcd for [M + H]⁺ C₁₇H₁₅F₃NOS 370.0542, found: 370.0542.

4-(2-(2-Ethyl-4-methylthiazol-5-yl)thien-3-yl)benzonitrile (9b). From 3-bromo-4-(thien-3-yl)benzonitrile 1h (0.264 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), a mixture of 9a and 9b was obtained in 20 : 80 ratio and 9b was isolated in 53% (0.164 g) yield as a white solid: mp 118–120 °C.

¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 5.3 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 5.3 Hz, 1H), 2.99 (q, J = 7.6 Hz, 2H), 2.09 (s, 3H), 1.39 (t, J = 7.6 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 172.8, 150.5, 140.5, 139.3, 132.4, 129.5, 128.9, 128.8, 127.0, 121.7, 118.8, 110.8, 27.0, 15.7, 14.0.

HRMS calcd for [M + H]⁺ C₁₇H₁₅N₂S₂ 311.0671, found: 311.0671.

2-Ethyl-4-methyl-5-(3-(m-tolyl)thien-2-yl)thiazole (10b). From 3-(2-bromo-5-methylphenyl)thiophene 1i (0.253 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), a mixture of 10a and 10b was obtained in 2 : 98 ratio and 10b was isolated in 78% (0.233 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.42 (d, J = 5.2 Hz, 1H), 7.21 (d, J = 5.3 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.13 (s, 1H), 7.11–7.02 (m, 2H), 2.98 (q, J = 7.6 Hz, 2H), 2.33 (s, 3H), 2.11 (s, 3H), 1.38 (t, J = 7.6 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 172.0, 150.1, 141.5, 138.0, 135.9, 129.5, 129.1, 128.4, 127.9, 127.3, 126.0, 125.5, 122.7, 27.0, 21.5, 15.8, 14.2.

HRMS calcd for [M + H]⁺ C₁₇H₁₈NS₂ 300.0875, found: 300.0873.

2-Ethyl-5-(3-(3-fluorophenyl)thien-2-yl)-4-methylthiazole (11b). From 3-(2-bromo-5-fluorophenyl)thiophene 1j (0.257 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), a mixture of 11a and 11b was obtained in 4 : 96 ratio and 11b was isolated in 80% (0.242 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J = 5.3 Hz, 1H), 7.31–7.24 (m, 1H), 7.20 (d, J = 5.3 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 7.04–6.93 (m, 2H), 2.99 (q, J = 7.5 Hz, 2H), 2.10 (s, 3H), 1.39 (t, J = 7.6 Hz, 3H).

¹⁹F NMR (376 MHz, CDCl₃) δ −112.9.

¹³C NMR (101 MHz, CDCl₃) δ 172.4, 162.8 (d, J = 245.8 Hz), 150.3, 140.0 (d, J = 2.3 Hz), 138.1 (d, J = 8.1 Hz), 130.0 (d, J = 8.5 Hz), 129.2, 128.3, 126.4, 124.1 (d, J = 3.0 Hz), 122.1, 115.3 (d, J = 22.2 Hz), 114.1 (d, J = 21.1 Hz), 27.0, 15.7, 14.1.

HRMS calcd for [M + H]⁺ C₁₆H₁₅FNS₂ 304.0625, found: 304.0625.

5-(3-(3-Chlorophenyl)thien-2-yl)-2-ethyl-4-methylthiazole (12b). From 3-(2-bromo-5-chlorophenyl)thiophene 1k (0.274 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), a mixture of 12a and 12b was obtained in 7 : 93 ratio and 12b was isolated in 74% (0.237 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J = 5.2 Hz, 1H), 7.31 (s, 1H), 7.30–7.22 (m, 2H), 7.20 (d, J = 5.3 Hz, 1H), 7.14 (dt, J = 6.7, 1.8 Hz, 1H), 2.99 (q, J = 7.6 Hz, 2H), 2.12 (s, 3H), 1.39 (t, J = 7.6 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 172.4, 150.4, 139.8, 137.7, 134.3, 129.7, 129.1, 128.4, 128.4, 127.3, 126.6, 126.5, 122.1, 27.0, 15.8, 14.1.

HRMS calcd for [M + H]⁺ C₁₆H₁₅ClNS₂ 320.0329, found: 320.0330.

2-Ethyl-5-(3-(2-fluorophenyl)thien-2-yl)-4-methylthiazole (13b). From 3-(2-bromo-6-fluorophenyl)thiophene 1l (0.257 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), a mixture of 13a and 13b was obtained in 13 : 87 ratio and 13b was isolated in 75% (0.227 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J = 5.3 Hz, 1H), 7.34–7.25 (m, 1H), 7.21 (dd, J = 5.3, 2.0 Hz, 1H), 7.16 (td, J = 7.5, 1.9 Hz, 1H), 7.13–7.03 (m, 2H), 2.96 (q, J = 7.6 Hz, 2H), 2.10 (s, 3H), 1.36 (t, J = 7.6 Hz, 3H).

¹⁹F NMR (376 MHz, CDCl₃) δ −114.7.

¹³C NMR (101 MHz, CDCl₃) δ 171.9, 159.8 (d, J = 248.1 Hz), 150.0, 135.1, 131.4 (d, J = 3.4 Hz), 130.1 (d, J = 2.7 Hz), 129.9, 129.3 (d, J = 8.2 Hz), 125.8, 124.1 (d, J = 3.7 Hz), 123.8 (d, J = 15.0 Hz), 122.3, 116.0 (d, J = 22.3 Hz), 27.0, 15.7, 14.0.

HRMS calcd for [M + H]⁺ C₁₆H₁₅FNS₂ 304.0625, found: 304.0625.

2-Isobutyl-5-(3-phenylthien-2-yl)thiazole (14b). From 3-(2-bromophenyl)thiophene 1a (0.239 g, 1 mmol) and 2-isobutylthiazole (0.282 g, 2 mmol), a mixture of 14a and 14b was obtained in 23 : 77 ratio and 14b was isolated in 62% (0.185 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.58 (s, 1H), 7.40–7.34 (m, 5H), 7.33 (d, J = 5.2 Hz, 1H), 7.12 (d, J = 5.3 Hz, 1H), 2.79 (d, J = 7.1 Hz, 2H), 2.15–1.93 (m, 1H), 0.98 (d, J = 6.6 Hz, 6H).

¹³C NMR (101 MHz, CDCl₃) δ 170.5, 140.7, 140.3, 135.8, 130.4, 130.1, 129.2, 128.5, 127.9, 127.7, 124.7, 42.3, 29.7, 22.2.

HRMS calcd for [M + H]⁺ C₁₇H₁₈NS₂ 300.0875, found: 300.0873.

2-Ethyl-4-methyl-5-(5-methyl-3-phenylthien-2-yl)thiazole (15b). From 4-(2-bromophenyl)-2-methylthiophene 1m (0.253 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), a mixture of 15a and 15b was obtained in 6 : 94 ratio and 15b was isolated in 78% (0.233 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.35–7.25 (m, 6H), 2.97 (q, J = 7.6 Hz, 2H), 2.54 (d, J = 1.1 Hz, 3H), 2.07 (s, 3H), 1.38 (t, J = 7.6 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 171.8, 149.8, 141.3, 140.5, 136.2, 128.4, 128.3, 127.7, 127.0, 124.8, 123.1, 27.0, 15.7, 15.3, 14.1.

HRMS calcd for [M + H]⁺ C₁₇H₁₈NS₂ 300.0875, found: 300.0875.

2-Isobutyl-5-(5-methyl-3-phenylthien-2-yl)thiazole (16b). From 4-(2-bromophenyl)-2-methylthiophene 1m (0.253 g, 1 mmol) and 2-isobutylthiazole (0.282 g, 2 mmol), a mixture of 16a and 16b was obtained in 25 : 75 ratio and 16b was isolated in 61% (0.191 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 7.37–7.28 (m, 5H), 6.79 (q, J = 1.1 Hz, 1H), 2.77 (d, J = 7.2 Hz, 2H), 2.52 (d, J = 1.1 Hz, 3H), 2.15–1.93 (m, 1H), 0.97 (d, J = 6.7 Hz, 6H).

¹³C NMR (101 MHz, CDCl₃) δ 170.0, 140.2, 139.2, 136.1, 130.4, 129.1, 128.8, 128.4, 127.5, 125.3, 42.3, 29.7, 22.2, 15.2.

HRMS calcd for [M + H]⁺ C₁₈H₂₀NS₂ 314.1032, found: 314.1031.

2-Ethyl-5-(5-hexyl-3-phenylthien-2-yl)-4-methylthiazole (17b). From 4-(2-bromophenyl)-2-hexylthiophene 1n (0.323 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), a mixture of 17a and 17b was obtained in 5 : 95 ratio and 17b was isolated in 76% (0.281 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.40–7.14 (m, 5H), 6.91 (s, 1H), 2.97 (q, J = 7.5 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H), 2.07 (s, 3H), 1.88–1.70 (m, 2H), 1.52–1.30 (m, 6H), 1.37 (t, J = 7.6 Hz, 3H), 0.93 (t, J = 7.6 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 171.7, 149.7, 146.6, 140.9, 136.3, 128.4, 128.3, 126.9, 126.5, 124.5, 123.3, 31.6, 31.4, 30.2, 28.9, 27.0, 22.6, 15.7, 14.1.

HRMS calcd for [M + H]⁺ C₂₂H₂₈NS₂ 370.1658, found: 370.1655.

2-Ethyl-4-methyl-5-(3-phenylbenzo[b]thien-2-yl)thiazole (18b). From 3-(2-bromophenyl)benzo[b]thiophene 1p (0.289 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), a mixture of 18a and 18b was obtained in 1 : 99 ratio and 18b was isolated in 80% (0.268 g) yield as a white solid: mp 112–114 °C.

¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, J = 7.0 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.46–7.32 (m, 7H), 2.96 (q, J = 7.6 Hz, 2H), 2.15 (s, 3H), 1.37 (t, J = 7.6 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 172.6, 150.5, 139.8, 139.6, 136.8, 134.8, 130.0, 129.2, 128.7, 127.6, 125.1, 124.7, 123.5, 122.7, 122.1, 27.0, 16.1, 14.1.

HRMS calcd for [M + H]⁺ C₂₀H₁₈NS₂ 336.0875, found: 336.0872.

2-Isobutyl-5-(3-phenylbenzo[b]thien-2-yl)thiazole (19b). From 3-(2-bromophenyl)benzo[b]thiophene 1p (0.289 g, 1 mmol) and 2-isobutylthiazole (0.282 g, 2 mmol), a mixture of 19a and 19b was obtained in 2 : 98 ratio and 19b was isolated in 78% (0.272 g) yield as a yellow solid: mp 67–69 °C.

¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J = 8.5 Hz, 1H), 7.70 (s, 1H), 7.57–7.47 (m, 3H), 7.47–7.27 (m, 5H), 2.77 (d, J = 7.2 Hz, 2H), 2.15–1.93 (m, 1H), 0.97 (d, J = 6.6 Hz, 6H).

¹³C NMR (75 MHz, CDCl₃) δ 170.9, 141.0, 140.9, 138.2, 134.8, 134.7, 130.5, 130.4, 129.5, 129.0, 128.4, 125.2, 124.7, 123.4, 121.9, 42.2, 29.7, 22.2.

HRMS calcd for [M + H]⁺ C₂₁H₂₀NS₂ 350.1032, found: 350.1028.

5-(2-Ethyl-4-methylthiazol-5-yl)-4-phenylthiophene-2-carbaldehyde (20b). From 4-(2-bromophenyl)thiophene-2-carbaldehyde 1o (0.267 g, 1 mmol) and 2-ethyl-4-methylthiazole (0.254 g, 2 mmol), a mixture of 20a and 20b was obtained in 1 : 99 ratio and 20b was isolated in 77% (0.241 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 9.96 (s, 1H), 7.85 (s, 1H), 7.40–7.33 (m, 3H), 7.32–7.26 (m, 2H), 2.98 (q, J = 7.6 Hz, 2H), 2.13 (s, 3H), 1.38 (t, J = 7.6 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 182.7, 173.2, 151.2, 142.8, 142.3, 137.9, 137.8, 134.7, 128.8, 128.4, 128.0, 121.6, 27.0, 16.1, 14.0.

HRMS calcd for [M + H]⁺ C₁₇H₁₆NOS₂ 314.0668, found: 314.0666.

1-(5-(5-Methyl-3-phenylthien-2-yl)thiazol-2-yl)ethan-1-one (21b). From 4-(2-bromophenyl)-2-methylthiophene 1m (0.253 g, 1 mmol) and 1-(thiazol-2-yl)ethan-1-one (0.254 g, 2 mmol), a mixture of 21a and 21b was obtained in 19 : 81 ratio and 21b was isolated in 68% (0.203 g) yield as a yellow solid: mp 116–118 °C.

¹H NMR (400 MHz, CDCl₃) δ 7.75 (s, 1H), 7.40 (m, 3H), 7.36–7.30 (m, 2H), 6.81 (q, J = 1.1 Hz, 1H), 2.65 (s, 3H), 2.55 (d, J = 1.1 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 191.6, 164.8, 142.3, 141.9, 141.3, 139.6, 135.6, 129.6, 129.0, 128.9, 128.2, 124.5, 25.7, 15.3.

HRMS calcd for [M + H]⁺ C₁₆H₁₄NOS₂ 300.0511, found: 300.0510.

3-(3-Fluorophenyl)-5′-hexyl-2,2′-bithiophene (22b). From 3-(2-bromo-5-fluorophenyl)thiophene 1j (0.257 g, 1 mmol) and 2-hexylthiophene (0.336 g, 2 mmol), a mixture of 22a and 22b was obtained in 2 : 98 ratio and 22b was isolated in 63% (0.217 g) yield as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.39–7.30 (m, 1H), 7.26 (d, J = 5.2 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 7.10 (ddd, J = 10.0, 2.6, 1.6 Hz, 1H), 7.07 (d, J = 5.2 Hz, 1H), 7.02 (tdd, J = 8.5, 2.6, 1.0 Hz, 1H), 6.80 (d, J = 3.5 Hz, 1H), 6.63 (d, J = 3.3 Hz, 1H), 2.75 (t, J = 7.6 Hz, 2H), 1.64 (quint., J = 7.4 Hz, 2H), 1.42–1.17 (m, 6H), 0.90 (t, J = 7.4 Hz, 3H).

¹⁹F NMR (376 MHz, CDCl₃) δ −113.4.

¹³C NMR (101 MHz, CDCl₃) δ 162.7 (d, J = 245.6 Hz), 147.1, 138.6 (d, J = 8.1 Hz), 137.0 (d, J = 2.2 Hz), 132.9, 132.6, 130.1, 129.7 (d, J = 8.4 Hz), 126.7, 125.0 (d, J = 3.0 Hz), 124.3, 123.9, 116.2 (d, J = 21.9 Hz), 114.1 (d, J = 21.0 Hz), 31.5, 31.5, 30.1, 28.7, 22.6, 14.0.

HRMS calcd for [M + H]⁺ C₂₀H₂₂FS₂ 345.1142, found: 345.1143.

5′-Hexyl-5-methyl-3-phenyl-2,2′-bithiophene (23b). From 4-(2-bromophenyl)-2-methylthiophene 1m (0.253 g, 1 mmol) and 2-hexylthiophene (0.336 g, 2 mmol), a mixture of 23a and 23b was obtained in 6 : 94 ratio and 23b was isolated in 61% (0.207 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.44–7.27 (m, 5H), 6.76 (d, J = 1.2 Hz, 1H), 6.73 (d, J = 3.6 Hz, 1H), 6.59 (d, J = 3.6 Hz, 1H), 2.72 (t, J = 7.6 Hz, 2H), 2.51 (d, J = 1.2 Hz, 3H), 1.64 (quint., J = 7.4 Hz, 2H), 1.41–1.30 (m, 6H), 0.90 (t, J = 7.4 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 146.1, 138.2, 137.9, 136.7, 133.6, 129.7, 129.2, 128.8, 128.2, 127.1, 125.8, 124.0, 31.5, 31.4, 30.1, 28.7, 22.6, 15.2, 14.0.

HRMS calcd for [M + H]⁺ C₂₁H₂₅S₂ 341.1392, found: 341.1389.

5′-Chloro-5-methyl-3-phenyl-2,2′-bithiophene (24b). From 4-(2-bromophenyl)-2-methylthiophene 1m (0.253 g, 1 mmol) and 2-chlorothiophene (0.237 g, 2 mmol), a mixture of 24a and 24b was obtained in 32 : 68 ratio and 24b was isolated in 50% (0.145 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.40–7.33 (m, 5H), 6.76 (q, J = 1.1 Hz, 1H), 6.74 (d, J = 3.9 Hz, 1H), 6.72 (d, J = 3.9 Hz, 1H), 2.51 (d, J = 1.1 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 139.3, 138.9, 136.1, 135.1, 129.4, 129.2, 128.9, 128.5, 128.2, 127.5, 126.1, 125.2, 15.2.

HRMS calcd for [M + H]⁺ C₁₆H₁₂ClS₂ 291.0064, found: 291.0064.

2-Methyl-2-(5′-methyl-3′-phenyl-[2,2′-bithiophen]-5-yl)-1,3-dioxolane (25b). From 4-(2-bromophenyl)-2-methylthiophene 1m (0.253 g, 1 mmol) and 2-methyl-2-(thien-2-yl)-1,3-dioxolane (0.340 g, 2 mmol), a mixture of 25a and 25b was obtained in 4 : 96 ratio and 25b was isolated in 53% (0.181 g) yield as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.43–7.30 (m, 5H), 6.84 (d, J = 3.6 Hz, 1H), 6.76 (q, J = 1.1 Hz, 1H), 6.73 (d, J = 3.7 Hz, 1H), 4.17–3.93 (m, 4H), 2.51 (d, J = 1.1 Hz, 3H), 1.75 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 146.8, 138.8, 138.4, 136.5, 136.0, 129.1, 129.0, 128.9, 128.3, 127.2, 125.7, 124.2, 107.1, 64.9, 27.3, 15.2.

HRMS calcd for [M + H]⁺ C₁₉H₁₉O₂S₂ 343.0821, found: 343.0822.

2-Butyl-5-(5-methyl-3-phenylthien-2-yl)furan (26b). From 4-(2-bromophenyl)-2-methylthiophene 1m (0.253 g, 1 mmol) and 2-butylfuran (0.248 g, 2 mmol), a mixture of 26a and 26b was obtained in 3 : 97 ratio and 26b was isolated in 50% (0.148 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.45–7.24 (m, 5H), 6.73 (q, J = 1.1 Hz, 1H), 5.96 (d, J = 3.2 Hz, 1H), 5.90 (d, J = 3.2 Hz, 1H), 2.60 (t, J = 7.5 Hz, 2H), 2.52 (d, J = 1.1 Hz, 3H), 1.65–1.52 (m, 2H), 1.44–1.27 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 155.6, 146.9, 137.8, 137.4, 137.1, 128.9, 128.7, 128.2, 127.1, 126.4, 107.2, 106.5, 30.2, 27.7, 22.2, 15.2, 13.8.

HRMS calcd for [M + H]⁺ C₁₉H₂₁OS 297.1308, found: 297.1306.

2-Butyl-5-(3-(3-chlorophenyl)thien-2-yl)furan (27b). From 3-(2-bromo-5-chlorophenyl)thiophene 1k (0.274 g, 1 mmol) and 2-butylfuran (0.248 g, 2 mmol), a mixture of 27a and 27b was obtained in 3 : 97 ratio and 27b was isolated in 36% (0.114 g) yield as a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.44 (s, 1H), 7.33–7.29 (m, 3H), 7.26 (d, J = 5.1 Hz, 1H), 7.03 (d, J = 5.2 Hz, 1H), 6.07 (d, J = 3.3 Hz, 1H), 5.95 (d, J = 3.3 Hz, 1H), 2.61 (t, J = 7.6 Hz, 2H), 1.67–1.51 (m, 2H), 1.46–1.30 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 156.4, 146.3, 138.7, 135.9, 134.1, 130.1, 129.6, 129.5, 129.1, 127.3, 127.2, 123.7, 108.2, 106.7, 30.2, 27.7, 22.2, 13.8.

HRMS calcd for [M + H]⁺ C₁₈H₁₈ClOS 317.0761, found: 317.0761.

Methyl 2-methyl-5-(5-methyl-3-phenylthien-2-yl)furan-3-carboxylate (28b). From 4-(2-bromophenyl)-2-methylthiophene 1m (0.253 g, 1 mmol) and methyl 2-methylfuran-3-carboxylate (0.280 g, 2 mmol), a mixture of 28a and 28b was obtained in 4 : 96 ratio and 28b was isolated in 66% (0.206 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.65–7.31 (m, 5H), 6.75 (q, J = 1.2 Hz, 1H), 6.29 (s, 1H), 3.79 (s, 3H), 2.56 (s, 3H), 2.53 (d, J = 1.1 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 164.3, 158.1, 146.7, 139.0, 139.0, 136.5, 128.9, 128.7, 128.4, 127.5, 124.6, 114.8, 106.9, 51.3, 15.2, 13.7.

HRMS calcd for [M + H]⁺ C₁₈H₁₇O₃S 313.0893, found: 313.0892.

1-Methyl-2-(5-methyl-3-phenylthien-2-yl)pyrrole (29b). From 4-(2-bromophenyl)-2-methylthiophene 1m (0.253 g, 1 mmol) and 1-methylpyrrole (0.243 g, 3 mmol), a mixture of 29a and 29b was obtained in 1 : 99 ratio and 29b was isolated in 55% (0.139 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 7.31–7.24 (m, 3H), 7.22 (d, J = 7.5 Hz, 2H), 6.97 (q, J = 1.2 Hz, 1H), 6.74–6.54 (m, 1H), 6.27 (dd, J = 3.6, 1.8 Hz, 1H), 6.19 (dd, J = 3.6, 2.7 Hz, 1H), 3.08 (s, 3H), 2.54 (d, J = 1.1 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 139.5, 139.4, 136.8, 128.5, 127.7, 127.1, 126.7, 126.6, 125.7, 122.9, 111.1, 107.8, 34.0, 15.3.

HRMS calcd for [M + H]⁺ C₁₆H₁₆NS 254.0998, found: 254.0995.

3-(5-Methyl-3-phenylthien-2-yl)imidazo[1,2-a]pyridine (30b). From 4-(2-bromophenyl)-2-methylthiophene 1m (0.253 g, 1 mmol) and imidazo[1,2-a]pyridine (0.236 g, 2 mmol), a mixture of 30a and 30b was obtained in 2 : 98 ratio and 30b was isolated in 63% (0.183 g) yield as a white solid: mp 120–122 °C.

¹H NMR (400 MHz, CDCl₃) δ 7.73 (s, 1H), 7.63 (d, J = 9.1 Hz, 1H), 7.59 (dd, J = 6.9, 1.2 Hz, 1H), 7.21–7.15 (m, 5H), 7.12 (dd, J = 9.1, 6.9 Hz, 1H), 7.07 (q, J = 1.1 Hz, 1H), 6.55 (t, J = 6.8 Hz, 1H), 2.59 (d, J = 1.1 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 146.0, 141.5, 140.8, 135.9, 134.8, 128.7, 127.9, 127.3, 127.2, 124.5, 124.2, 121.1, 118.2, 117.7, 112.1, 15.4.

HRMS calcd for [M + H]⁺ C₁₈H₁₅N₂S 291.0550, found: 291.0548.

3-(3-(2-Fluorophenyl)thien-2-yl)imidazo[1,2-a]pyridine (31b). From 3-(2-bromo-6-fluorophenyl)thiophene 1l (0.257 g, 1 mmol) imidazo[1,2-a]pyrazine (0.238 g, 2 mmol), a mixture of 31a and 31b was obtained in 5 : 95 ratio and 31b was isolated in 66% (0.194 g) yield as a yellow solid: mp 167–169 °C.

¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J = 6.9 Hz, 1H), 7.68 (s, 1H), 7.61 (d, J = 9.1 Hz, 1H), 7.56 (d, J = 5.3 Hz, 1H), 7.38 (dd, J = 5.3, 2.3 Hz, 1H), 7.25–7.12 (m, 2H), 7.11–6.99 (m, 2H), 6.89 (td, J = 7.5, 1.2 Hz, 1H), 6.63 (td, J = 6.8, 1.2 Hz, 1H).

¹⁹F NMR (376 MHz, CDCl₃) δ −115.0.

¹³C NMR (101 MHz, CDCl₃) δ 159.4 (d, J = 248.0 Hz), 146.2, 135.0, 130.5 (d, J = 3.3 Hz), 130.3 (d, J = 3.1 Hz), 129.4 (d, J = 8.2 Hz), 126.6, 126.1, 124.6, 124.3 (d, J = 3.6 Hz), 123.8, 123.4 (d, J = 14.7 Hz), 117.8, 117.5, 116.0 (d, J = 22.2 Hz), 112.3.

HRMS calcd for [M + H]⁺ C₁₇H₁₂FN₂S 295.0700, found: 295.0699.

3-(5-Methyl-3-phenylthien-2-yl)imidazo[1,2-a]pyrazine (32b). From 4-(2-bromophenyl)-2-methylthiophene 1m (0.253 g, 1 mmol) and imidazo[1,2-a]pyrazine (0.238 g, 2 mmol), a mixture of 32a and 32b was obtained in 9 : 91 ratio and 32b was isolated in 71% (0.207 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 9.09 (d, J = 1.5 Hz, 1H), 7.86 (s, 1H), 7.63 (d, J = 4.7 Hz, 1H), 7.48 (dd, J = 4.7, 1.5 Hz, 1H), 7.24–7.19 (m, 3H), 7.18–7.12 (m, 2H), 7.08 (q, J = 1.2 Hz, 1H), 2.61 (d, J = 1.1 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 143.8, 142.4, 141.7, 141.1, 136.5, 135.6, 129.5, 129.0, 128.2, 127.7, 127.2, 120.0, 119.3, 117.0, 15.4.

HRMS calcd for [M + H]⁺ C₁₇H₁₄N₃S 292.0903, found: 292.0902.

2-Ethyl-4-methyl-5-(5-(pyridin-3-yl)-3-(p-tolyl)thien-2-yl)thiazole (33). From 2-ethyl-4-methyl-5-(3-(p-tolyl)thien-2-yl)thiazole 4b (0.299 g, 1 mmol) and 3-bromopyridine (0.316 g, 2 mmol), 33 was isolated in 86% (0.323 g) yield as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 8.93 (s, 1H), 8.57 (d, J = 3.4 Hz, 1H), 7.90 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 7.45 (s, 1H), 7.35 (dd, J = 7.2, 4.8 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 2.99 (q, J = 7.6 Hz, 2H), 2.37 (s, 3H), 2.14 (s, 3H), 1.39 (t, J = 7.6 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 172.3, 150.4, 148.9, 146.8, 142.5, 140.3, 137.3, 132.7, 132.7, 129.9, 129.4, 128.2, 127.7, 126.5, 123.7, 122.4, 27.0, 21.2, 15.9, 14.1.

HRMS calcd for [M + H]⁺ C₂₂H₂₁N₂S₂ 377.1141, found: 377.1138.

1-(3′-Phenyl-[2,2′-bithiophen]-5-yl)ethan-1-one (34b) and 1-(4′-phenyl-[2,2′-bithiophen]-5-yl)ethan-1-one (34c). From 3-phenylthiophene (0.160 g, 1 mmol) and 1-(5-bromothien-2-yl)ethan-1-one (0.410 g, 2 mmol), a mixture of 34b and 34c was obtained in 47 : 53 ratio. Product 34b was isolated in 8% (0.023 g) yield as a yellow solid: mp 127–129 °C, and product 34c was isolated in 9% (0.026 g) yield as a yellow solid: mp 121–123 °C.

34b. ¹H NMR (400 MHz, CDCl₃) δ 7.50 (d, J = 3.9 Hz, 1H), 7.43–7.32 (m, 6H), 7.11 (d, J = 5.1 Hz, 1H), 6.94 (d, J = 3.9 Hz, 1H), 2.51 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 190.3, 144.8, 143.4, 140.8, 135.8, 132.6, 131.1, 130.7, 129.2, 128.7, 127.9, 127.0, 125.6, 26.6.

HRMS calcd for [M + H]⁺ C₁₆H₁₃OS₂ 285.0402, found: 285.0403.

34c. ¹H NMR (400 MHz, CDCl₃) δ 7.66–7.58 (m, 4H), 7.49–7.41 (m, 3H), 7.39–7.32 (m, 1H), 7.24 (d, J = 4.0 Hz, 1H), 2.59 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 190.3, 145.6, 143.5, 142.7, 137.0, 135.1, 133.3, 129.0, 127.7, 126.4, 124.7, 124.3, 121.2, 26.6.

HRMS calcd for [M + H]⁺ C₁₆H₁₃OS₂ 285.0402, found: 285.0403.

2-Methyl-2-(3′-phenyl-[2,2′-bithiophen]-5-yl)-1,3-dioxolane (35b). From 3-(2-bromophenyl)thiophene 1a (0.239 g 1 mmol) and 2-methyl-2-(thien-2-yl)-1,3-dioxolane (0.340 g, 2 mmol), a mixture of 35a and 35b was obtained in 4 : 96 ratio and 35b was isolated in 56% (0.184 g) yield as a colourless oil.

¹H NMR (300 MHz, CDCl₃) δ 7.41–7.32 (m, 5H), 7.27 (d, J = 5.2 Hz, 1H), 7.09 (d, J = 5.2 Hz, 1H), 6.86 (d, J = 3.7 Hz, 1H), 6.80 (d, J = 3.7 Hz, 1H), 4.08–3.91 (m, 4H), 1.76 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 147.4, 139.0, 136.3, 135.6, 131.6, 130.6, 129.2, 128.4, 127.4, 126.2, 124.2, 124.1, 107.1, 64.9, 27.4.

HRMS calcd for [M + H]⁺ C₁₈H₁₇O₂S₂ 329.0665, found: 329.0665.

Deprotection of 35b into 34b: A 2 N aqueous HCl solution (1 mL) was added to a solution of 35b (0.164 g, 0.5 mmol) in THF (1 mL). The resulting mixture was stirred at 60 °C for 8 h. The mixture was extracted with Et₂O (3 × 10 mL). The combined organic phase was dried over MgSO₄, filtrated, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give product 34b in 86% (0.122 g).

Author contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data underlying this study are available in the published article and its supplementary information (SI). Supplementary information: copies of NMR spectra. See DOI: https://doi.org/10.1039/d6ob00099a.

Acknowledgements

We are grateful to the CSC for a grant to B. L. We thank CNRS and Rennes Metropole for providing financial support.

References

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