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

Hindered aryl bromides for regioselective palladiumcatalysed direct arylation at less favourable C5-carbon of 3-substituted thiophenes Rongwei Jin, Charles Beromeo Bheeter and Henri Doucet* Letter Address: Institut Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes "Organometalliques, Material and Catalysis", Campus de Beaulieu, 35042 Rennes, France. Fax: +33 (0)2-23-23-69-39; Tel: +33 (0)2-23-23-63-84 Email: Henri Doucet* - * Corresponding author Open Access Beilstein J. Org. Chem. 2014, 10, 1239–1245. doi:10.3762/bjoc.10.123 Received: 24 February 2014 Accepted: 24 April 2014 Published: 27 May 2014 Associate Editor: I. Marek © 2014 Jin et al; licensee Beilstein-Institut. License and terms: see end of document. Keywords: aryl bromides; atom economy; C–H bond activation; palladium; regioselectivity; thiophenes Abstract 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 phosphinefree 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 [1-12] 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. The regioselective arylation via a Pd-catalysed C–H bond activation at carbon C5 of 2-substituted thiophenes has been largely described in recent years [13-22]. On the other hand, the Pd-catalysed direct arylation of 3-substituted thiophenes has attracted much less attention (Scheme 1, top) [23-31]. With such thiophene derivatives, in most cases, either C2-arylated 1239 Beilstein J. Org. Chem. 2014, 10, 1239–1245. thiophenes or mixtures of C2- and C5-arylated products have been obtained. For example, Sharp et al. described conditions for the regioselective arylation at carbons C2 or C5 of methyl 3-thiophenecarboxylate [23]. The reaction performed with Pd(PPh 3 ) 4 as the catalyst in toluene led selectively to the 2-arylated thiophene; whereas, the use of Pd2(dba)3 in NMP afforded a mixture of 2- and 5-arylated thiophenes in a 15:51 ratio. Lemaire and co-workers have reported the C2-arylation of 3-formyl-, 3-cyano- and 3-nitrothiophenes with iodobenzenes [24,25]. Forgione, Bilodeau et al. reported that the reaction of 3-methylthiophene with bromobenzene using Pd[(P(t-Bu)3]2 as the catalyst affords a mixture of 2- and 5-phenylated thiophenes in a 3.3:1 ratio [26]. Fagnou and co-workers reported that the coupling of 3-n-hexylthiophene with 4-bromonitrobenzene also led to a mixture of C2- and C5-arylation products in a 1.3:1 ratio [27]. Then, they blocked one position on the thiophene ring using a chloro-substituent in order to selectively arylate positions C2 or C5. The direct arylation of 3-methoxythiophene, which was studied by Borghese and co-workers afforded regioselectively the C2-arylated thiophenes in moderate to high yields [28]. Finally, in the course of their studies on sp3 C–H bond activation, Baudoin and Pierre recently reported that in the presence of an extremely bulky substituent at C3 of a thiophene derivative, the C5-arylated compounds were selectively obtained in good yields [29]. In summary, due to the presence of two reactive C–H bonds in 3-substituted thiophenes (with position C2 generally slightly more reactive than position C5), the control of the regioselectivity of the palladium-catalysed direct arylation of such thiophene derivatives especially to provide 5-arylthiophenes remains a challenging reaction. 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 Scheme 1: Regioselectivity of coupling reactions of 3-substituted thiophenes with aryl halides. 1240 Beilstein J. Org. Chem. 2014, 10, 1239–1245. Scheme 2: Regioselectivity of the arylation of 2-methylthiophene with ortho-substituted aryl bromides. 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 di (...truncated)