Palladium(0) catalyzed Suzuki cross-coupling reaction of 2,5-dibromo-3-methylthiophene: selectivity, characterization, DFT studies and their biological evaluations

Rizwan et al. Chemistry Central Journal (2018) 12:49 https://doi.org/10.1186/s13065-018-0404-7 Open Access RESEARCH ARTICLE Palladium(0) catalyzed Suzuki cross‑coupling reaction of 2,5‑dibromo‑3‑methylthiophene: selectivity, characterization, DFT studies and their biological evaluations Komal Rizwan1,2, Muhammad Zubair1*, Nasir Rasool1*, Tariq Mahmood3, Khurshid Ayub3, Noorjahan Banu Alitheen4*, Muhammad Nazirul Mubin Aziz4, Muhammad Nadeem Akhtar5, Faiz‑ul‑Hassan Nasim6, Snober Mona Bukhary6, Viqar Uddin Ahmad7 and Mubeen Rani7 Abstract Thiophene derivatives have shown versatile pharmacological activities. The Suzuki reaction proved a convenient method for C–C bond formations in organic molecules. In the present research work novel derivatives of 2,5-dibromo3-methylthiophene (3a–k and 3l–p) has been synthesized, via Suzuki coupling reaction in low to moderate yields. A wide range of functional groups were well tolerated in reaction. Density functional theory investigations on all synthesized derivatives (3a–3p) were performed in order to explore the structural properties. The pharmaceutical potential of synthesized compounds was investigated through various bioassays (antioxidant, antibacterial, antiu‑ rease activities). The compounds 3l, 3g, 3j, showed excellent antioxidant activity (86.0, 82.0, 81.3%), respectively by scavenging DPPH. Synthesized compounds showed promising antibacterial activity against tested strains. 3b, 3k, 3a, 3d and 3j showed potential antiurease activity with 67.7, 64.2, 58.8, 54.7 and 52.1% inhibition at 50 µg/ml. Results indicated that synthesized molecules could be a potential source of pharmaceutical agents. Keywords: Density functional theory, Thiophene, Antioxidant, Antibacterial, Palladium Background Thiophene is found in central core of various compounds and is well known for its intrinsic electronic properties [1, 2]. A number of thiophene based heterocycles have been reported for versatile pharmacological activities [3– 9]. Biaryl thiophenes are pharmacologically important agents and widely used as anti-inflammatory [10], chemotherapeutic [11], antimicrobial [12] and antioxidant *Correspondence: ; ; 1 Department of Chemistry, Government College University, Faisalabad 38000, Pakistan 4 Deparment of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Science, University Putra Malaysia, 43400 Serdang, Selangor Darul Ehsan, Malaysia Full list of author information is available at the end of the article agents [13]. Several reports about regioselective Suzuki coupling of dibromothiophene are available in literature [14, 15]. Palladium catalyzed coupling of 2,5-dibromothiophene has been reported and the yield of obtained product was low (29%) [16]. Synthesis of 2,5-diheteroarylated thiophenes from 2,5-dibromo thiophene derivatives has been reported in good yield [17]. Regioselective Suzuki coupling of 2,5-dibromo-3-hexylthiophene has been reported and preferably coupling occurred at C5 position [18]. The more electron deficient carbon moiety is preferably reactive towards attacking nucleophiles, whereas other reactive carbons do not show any response. Different heterocycles undergo electrophilic substitutions and this regioselectivity can be applied to these substrates [19]. In heterocycles substitution © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Rizwan et al. Chemistry Central Journal (2018) 12:49 reactions, heteroatom (O, S and N) electron lone pair is being donated to the ring. However, in halogenated thiophenes Suzuki reaction with high oxidative addition, the arylboronate anion preferably attacks the electron deficient carbon bonded with the halogen. And it was observed that transmetallation step is faster due to negatively charged boronate anion then the neutral boronic acids [20]. Extending the scope of Suzuki coupling reaction in regioselective domain a series of 2,5-dibromo3-methylthiophene derivatives has been synthesized specially with aim to explore their biological importance for the first time. Results and discussion Chemistry A series of thiophene derivatives (3a–k) and (3l–p) has been synthesized by reaction of 2,5-dibromo-3-methylthiophene with variety of arylboronic acids in low to moderate yields (27–63%) (Scheme 1, Table 1). Under the developed Suzuki reaction conditions, when 1.1 eq of arylboronic acid was used the bromo group at 5 position was selectively substituted and a variety of mono-substituted products was synthesized (3a–k) and double Suzuki cross coupling occurred by using 2.2 eq of arylboronic acids and diaryl derivatives of thiophene were synthesized (3l–p) (Table 1). To increase the substrate scope, the arylboronic acids with both electron donating and withdrawing groups were used. The reaction conditions were tolerant of both electron donating and electron withdrawing arylboronic acids. It was noted that some products were obtained in low yield as 3b, 3h, 3i, 3j, 3k, 3n, 3o which can be attributed to the presence of mixture of mono and di-arylated products in both Page 2 of 12 single and double Suzuki cross coupling reaction and it has been very difficult to separate this reaction mixture and low yields were obtained. This may be due to ineffective transmetallation and reductive elimination in overall reaction cycle [12]. Density functional theory (DFT) studies DFT investigations were computed by using GAUSSIAN 09 software, in order to explore the structural properties and reactivity’s of synthesized derivatives. First of all, compounds (3a–3p) were optimized by using B3LYP/631G(d,p) basis set along with the frequency analysis. After optimization the energy minimized structures were used further for frontier molecular orbitals and molecular electrostatic potential (MEP) analysis on the same basis set. Frontier molecular orbitals (FMOs) analysis Nowadays frontier molecular orbitals analysis is well known to explain the reactivity of compounds [21] by using different computational methods. The HOMO/ LUMO band gap has direct correlation with the reactivity, e.g. if the band is less the compound will be kinetically less stable (more reactive) and vice versa [22]. The FMOs analysis of all derivatives (3a–3p) was carried out by using B3LYP/6-31G(d,p) basis set. As observed from the HOMO/LUMO, the trend of dispersion of isodensity was almost similar in all compounds. Therefore, as a model here we have given the HOMO/LUMO surfaces of c (...truncated)