Regiocontroled Pd-catalysed C5-arylation of 3-substituted thiophene derivatives using a bromo-substituent as blocking group

The use of a bromo-substituent as blocking group at the C2-position of 3-substituted thiophenes allows the regioselective introduction of aryl substituents at C5-position via Pd-catalysed direct arylation. With 1 mol % of a phosphine-free Pd catalyst, KOAc as the base and DMA as the solvent and various electron-deficient aryl bromides as aryl sources, C5-(hetero)arylated thiophenes were synthesized in moderate to high yields, without cleavage of the thienyl C–Br bond. Moreover, sequential direct thienyl C5-arylation followed by Pd-catalysed direct arylation or Suzuki coupling at the C2-position allows to prepare 2,5-di(hetero)arylated thiophenes bearing two different (hetero)aryl units in only two steps. This method provides a “green” access to arylated thiophene derivatives as it reduces the number of steps to prepare these compounds and also the formation of wastes.


Introduction
Thiophene derivatives bearing aryl substituents are important structures because of their biological and/or physical properties. Among them, 3-substituted 5-arylthiophenes are widely used as building blocks for the synthesis of semi-conductors [1][2][3].
Herein, we wish to report on green conditions in terms of number of steps, base nature, use of a phosphine-free catalyst at low loading and a quite "atom economic" aryl source promoting such a C5-arylation using C3-substituted 2-bromothiophenes. We report i) that only 1 mol % of air-stable Pd(OAc) 2 catalyst associated to KOAc promotes the regiospecific access to C5-arylated 2-bromothiophenes without cleavage of the thienyl Scheme 1: Blocking groups allowing regioselective C5-arylation of thiophenes.

Results and Discussion
Based on some of our previous results on Pd-catalysed direct arylation, for this study, DMA and KOAc were selected as the solvent and base [35]. The reaction of 2 equiv of 2-bromothiophene with 1 equiv of 4-bromonitrobenzene using 1 mol % of phosphine-free Pd(OAc) 2 catalyst performed at 110 °C, only afforded the desired product 1 in a trace amount, but a complete conversion of 2-bromothiophene was observed, revealing the high reactivity of the thienyl C-Br bond under these conditions (Table 1, entry 1). Using a lower reaction temperature of 80 °C, and a reaction time of 15 h, the desired C5-arylated product 1 was formed in only 8% yield due again to the formation of several degradation products (Table 1, entry 2). Then, we examined the influence of the reaction time. After 2 or 4 h, higher yields of 1 (55% and 48%) were obtained, respectively; whereas, a very short reaction time of 0.5 h led to a lower yield of 27% due to the poor conversion of 4-bromonitrobenzene (Table 1, entries 3-6). The use of 0.5 mol % Pd(OAc) 2 catalyst at 80 °C during 2 h also afforded 1 in a lower yield of 35%. Again, a large amount of 4-bromonitrobenzene was recovered (Table 1, entry 7). When CsOAc, NaOAc or K 2 CO 3 were em-Scheme 2: Reactivity of 2-bromothiophene with aryl bromides. ployed as bases instead of KOAc, in the presence of 1 mol % Pd(OAc) 2 catalyst during 2 h, a partial conversion of 4-bromonitrobenzene was observed and 1 was isolated in 32-40% yield ( Table 1, entries 8-10). It should be noted that in the presence of cyclopentyl methyl ether or diethyl carbonate as solvents, no formation of 1 was observed, and 4-bromonitrobenzene was recovered unreacted (Table 1, entries 11 and 12). Then, we studied the scope of this reaction using a set of aryl bromides and 2-bromothiophene derivatives, employing the most effective reaction conditions for C5-arylation of 2-bromothiophene (  (Schemes 2-4). First, we investigated the reaction of 2-bromothiophene with 4-bromobenzonitrile, 4-bromobenzaldehyde and 4-bromo-2-(trifluoromethyl)nitrobenzene (Scheme 2). The expected coupling products 2-4 were obtained in moderate yields. On the other hand, with 4-bromoanisole as an electron-rich aryl bromide, the desired C5-arylated 2-bromothiophene could not be detected by GC-MS analysis of the crude mixture, and a large amount of unreacted 4-bromoanisole was recovered. Under these reaction conditions, the oxidative addition of 4-bromoanisole to palladium appears to be slower than the oxidative addition of 2-bromothiophene. Therefore, this procedure is limited to the use of electron-deficient aryl bromides. The reactivity of 2-bromofuran with 4-bromonitrobenzene was also investigated. Under the same reaction conditions, (1 mol % Pd(OAc) 2 , DMA, KOAc, 80 °C, 2 h) no formation of the desired 2-bromo-5-arylfuran derivative was observed.
The main interest to tolerate a C-Br bond at the C2-position on thiophene derivatives in the course of such couplings would be the regiospecific access to C5-arylated 3-substituted thiophenes, which cannot be obtained from 2-unsubstituted 3-substituted thiophenes such as 3-methylthiophene. Therefore, a set of aryl bromides was reacted with 2-bromo-3-methylthiophene, under these conditions (Scheme 3). Its reaction with aryl bromides para-substituted by nitro, cyano or formyl substituents gave the desired 5-arylated thiophenes 5-7 in 60-64% yields, without cleavage of the thienyl C-Br bond. Good yields of products 8 and 9 were also obtained from the meta-substituted aryl bromides, 3-bromobenzonitrile and 3-bromonitrobenzene. Again, a high yield of 85% of 10 was obtained with 4-bromo-2-(trifluoromethyl)nitrobenzene. Then, the reactivity of a set of ortho-substituted aryl bromides was examined. Bromobenzene containing nitro, nitrile or formyl ortho-substituents afforded the C5-arylated thiophenes 11-13 in 71-84% yields. Finally, 3-bromoquinoline and 3-bromopyrimidine were reacted with 2-bromo-3-methylthiophene affording 14 and 15 in 63% and 66% yields, respectively. The higher yields obtained for the arylation of 2-bromo-3-methylthiophene than with 2-bromo- thiophene are probably due to a slower oxidative addition of 2-bromo-3-methylthiophene to palladium which reduces the formation of side-products.
The reaction is not limited to the use of 2-bromo-3-methylthiophene. A 2-bromothiophene derivative bearing a CH 2 CO 2 Et substituent at C3 also provides regioselectively the desired C5-arylated thiophenes 16 and 17 in good yields; whereas, a lower yield of 18 was obtained for the coupling of 2-bromo-3chlorothiophene with 4-bromobenzonitrile (Scheme 4).
The synthesis of 3-substituted thiophenes derivatives containing two different aryl groups at C2 and C5 positions via Suzuki coupling in the second step was also attempted (Scheme 8). The reaction of 5 with phenylboronic acid in the presence of only 1 mol % Pd(OAc) 2 catalyst and K 2 CO 3 as base gave 3-methyl-5-(4-nitrophenyl)-2-phenylthiophene (27) in 60% yield. A higher yield of 80% in 28 was obtained for the coupling of 16 with phenylboronic acid. In order to further demonstrate that a bromo-substituent at C2-position of the thiophenes can be considered as a protecting group, we removed it via palladium-catalysed hydrogenolysis (Scheme 9). Treatment of 14 with 2 mol % Pd/C (10%) and trimethylamine in ethanol under hydrogen pressure, gave the desired debrominated product 29 in almost quantitative yield.

Conclusion
In summary, we report here that the use of a 2-bromo-substituent on thiophenes acts as a blocking group, allowing their regioselective Pd-catalysed C5-arylation even in the presence of aryl bromides as aryl sources. Only 1 mol % of phosphine-free air stable Pd(OAc) 2 catalyst in the presence of KOAc as base promotes the C5-arylation of 2-bromothiophenes containing various C3-substituents with electron-deficient (hetero)aryl bro- mides. The sequential direct C5-arylation of 2-bromothiophenes followed either by a Suzuki coupling or a second direct arylation was found to allow the preparation of 2,5di(hetero)arylated thiophenes bearing two different (hetero)aryl units. This method provides a convenient "greener" access to arylated thiophene derivatives as 1) it reduces the number of steps to prepare these compounds, 2) it employs the easily available Pd(OAc) 2 catalyst and aryl bromides as aryl sources, and the inexpensive base KOAc, 3) it reduces the formation of wastes.

Supporting Information
Supporting Information File 1 Procedures, 1 H and 13 C NMR data of all compounds.