Hindered aryl bromides for regioselective palladium-catalysed direct arylation at less favourable C5-carbon of 3-substituted thiophenes

Summary The use of the congested aryl bromide 2-bromo-1,3-dichlorobenzene as coupling partner allows to modify the regioselectivity of the arylation of 3-substituted thiophene derivatives in favour of carbon C5. The coupling of this aryl bromide with a variety of 3-substituted thiophenes gave in all cases the desired 5-arylation products in moderate to good yields using only 0.5 mol % of a phosphine-free and air-stable palladium catalyst. Then, from these 5-arylthiophenes, a second palladium-catalysed C–H bond functionalization at C2 of the thiophene ring allows the synthesis of 2,5-diarylthiophenes with two different aryl units.


Introduction
As thiophenes bearing aryl substituents are known to be present in several bioactive molecules and are used as precursors of materials, the regioselective introduction of aryls on thiophenes is an important research area in organic synthesis. The coupling of thiophene derivatives with aryl halides via a C-H bond activation/functionalisation [1][2][3][4][5][6][7][8][9][10][11][12] provides an environmentally attractive and cost-effective procedure for the preparation of a variety of arylated thiophenes. For such coupling reactions, the major byproduct is a base associated to HX, instead of metallic salts which are produced under the more classical Negishi, Suzuki or Stille cross-coupling reactions. Moreover, direct arylation avoids the preliminary preparation of organometallics reducing the number of steps to prepare these arylthiophenes.
Our goal was to promote arylation at carbon C5 of a range of 3-substituted thiophenes without the use of a blocking group at carbon C2. To our knowledge, ortho-substituents on aryl bromides have not been employed as directing groups for palladium-catalysed direct arylation of 3-substituted thiophenes. The use of congested aryl bromides for such couplings would certainly modify the regioselectivity in favour of arylation at the less hindered thiophene position. Herein, we wish to report on the influence of such ortho-substituents on aryl bromides on the regioselectivity of the palladium-catalysed direct arylations of 3-substituted thiophenes.

Results and Discussion
We first studied the palladium-catalysed direct arylation of 3-methylthiophene using tert-butyl 2-bromobenzoate as the coupling partner (Scheme 2). Based on previous results [19], DMA was initially chosen as the solvent and KOAc as the base. The reactions were performed at 150 °C under argon in the presence of 0.5 mol % Pd(OAc) 2 as the catalyst. However, under these conditions, a poor regioselectivity was observed as the desired C5-arylation product 1b was only obtained in 34% selectivity together with 66% of C2-arylation product 1a. Moreover, a moderate conversion of this aryl bromide was observed and purification by silica gel chromatography afforded a mixture of 1a and 1b. A slightly lower selectivity in favour of the formation of C5-arylation product 2b was observed using 2-bromonitrobenzene as the coupling partner, as a large amount of 2,5-diarylated product 2c was also produced with a 2a:2b:2c ratio of 34:21:45. However, a complete conversion of 2-bromonitrobenzene was observed. 2-Bromoaniline was found to be unreactive and was recovered. It should be noted that no amination reaction of 2-bromoaniline due to self-coupling was observed. From 2-(trifluoromethyl)bromobenzene, a very similar mixture of regioisomers than with 2-bromonitrobenzene was obtained, as 4a, 4b and 4c were formed in a 24:31:45 ratio. The use of 2-bromobenzaldehyde was not successful, as the desired product 5b was only obtained with 10% selectivity. From more hindered 2-bromobenzaldehyde diethyl acetal, the selectivity in favour of desired product 6b was slightly higher (34%), although still not synthetically useful. Next, we employed 2-chlorobromobenzene as the coupling partner. However, again the desired product 7b was only formed with 15% selectivity. It should be noted that with these aryl bromides, in all cases, mixtures of regioisomers a and b were obtained after column chromatography. On the other hand, the use of 2-bromo-1,3-dichlorobenzene allowed to obtain very selectively the desired 5-arylation product 8b. Only traces of the C2-arylated thiophene 8a and a low amount of 2,5-diarylated product 8c were detected by 1 H NMR and GC-MS analysis of the crude mixture. Moreover a high conversion of 86% of this aryl bromide was observed using only 0.5 mol % Pd(OAc) 2 as the catalyst.

Conclusion
In summary, we have demonstrated that the use of the congested coupling partner 2-bromo-1,3-dichlorobenzene allows to direct the arylation to the unfavourable C5 position of 3-substituted thiophenes. These less favoured regioisomers can be selectively obtained in moderate to good yields using a range of 3-substituted thiophenes, as chloro, ester, acetyl or ethyl acetate substituents are tolerated. Moreover, the sequential catalytic C5 and C2 arylations, allow the preparation of 2,5diarylthiophenes with two different aryl units in two steps. The major byproduct of these couplings is KBr/AcOH instead of metallic salts as with more classical coupling procedures. For these reasons, this process gives an economically viable access to C5-arylated 3-substituted heteroaromatics.

Experimental General
All reactions were perfomed in Schlenk tubes under argon. DMA analytical grade was not distilled before use. Commercial aryl bromide derivatives were used without purification. 1

General procedure for direct arylations
The aryl bromide (1 mmol), thiophene derivative (2 mmol), KOAc (2 mmol), Pd(OAc) 2 (0.005 mmol, 1.1 mg) and DMA (3 mL) were introduced in a Schlenk tube under argon equipped with a magnetic stirring bar. The Schlenk tube was placed in an oil bath pre-heated at 150 °C, and the reaction mixture was allowed to stir for 20 h. After cooling, the crude reaction mixture was analysed by gas chromatography and 1 H NMR to determine the conversion of the aryl bromide and the regioselectivity of the arylation. The solvent was removed by heating under vacuum, then the residue was charged onto a silica gel column.