Heterogeneous Pd/C-catalyzed, ligand free Suzuki–Miyaura coupling reaction furnishes new p-terphenyl derivatives

Article abstract of DOI:10.1080/14786419.2020.1791112

A series of new para-terphenyls derivatives have been efficiently synthesized by a ligand-free heterogeneous Pd/C-catalyzed two-fold Suzuki–Miyaura coupling reaction. Methyl 5-bromo-2-iodobenzoate was selected to react with a variety of different aryl boronic acids (2a-i). Nine new p-terphenyl derivatives (3a–i) were prepared and the structures were confirmed by several analytical techniques including infrared, spectroscopy, ¹H and ¹³C NMR spectroscopy, mass spectrometry, and in the case of compound 3 b, by X-ray diffraction method. The new derivatives were obtained in very good yields (78–91percent). This synthetic facile route is envisioned to improve the preparation of p-terphenyl-based natural products.

Full text of DOI:10.1080/14786419.2020.1791112

Natural Product Research
Formerly Natural Product Letters
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Heterogeneous Pd/C-catalyzed, ligand free
Suzuki–Miyaura coupling reaction furnishes new p-
terphenyl derivatives
Satya Kumar Avula , Najeeb Ur Rehman , Muhammad U. Anwar , Ghanim
Aalthani , Rene Csuk & Ahmed Al-Harrasi
To cite this article: Satya Kumar Avula , Najeeb Ur Rehman , Muhammad U. Anwar , Ghanim
Aalthani , Rene Csuk & Ahmed Al-Harrasi (2020): Heterogeneous Pd/C-catalyzed, ligand free
Suzuki–Miyaura coupling reaction furnishes new p-terphenyl derivatives, Natural Product Research,
DOI: 10.1080/14786419.2020.1791112
To link to this article: https://doi.org/10.1080/14786419.2020.1791112
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2020.1791112
Heterogeneous Pd/C-catalyzed, ligand free
Suzuki–Miyaura coupling reaction furnishes
new p-terphenyl derivatives
Satya Kumar Avulaa, Najeeb Ur Rehmana, Muhammad U. Anwara,
Ghanim Aalthania, Rene Csukb and Ahmed Al-Harrasia
b
aNatural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman; Organic
Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
ABSTRACT
ARTICLE HISTORY
Received 30 March 2020
Accepted 26 June 2020
A series of new para-terphenyls derivatives have been efficiently
synthesized by a ligand-free heterogeneous Pd/C-catalyzed two-
fold Suzuki–Miyaura coupling reaction. Methyl 5-bromo-2-iodo-
benzoate was selected to react with a variety of different aryl bor-
onic acids (2a-i). Nine new p-terphenyl derivatives (3a–i) were
prepared and the structures were confirmed by several analytical
techniques including infrared, spectroscopy, 1H and 13C NMR
spectroscopy, mass spectrometry, and in the case of compound
3 b, by X-ray diffraction method. The new derivatives were
obtained in very good yields (78–91%). This synthetic facile route
is envisioned to improve the preparation of p-terphenyl-based
natural products.
KEYWORDS
Ligand-free catalysis; aryl
boronic acids;
Suzuki–Miyaura coupling
reaction; Pd/C;
heterogeneous catalysis
1. Introduction
Terphenyls are aromatic compounds comprising of central benzene ring substituted
with two phenyl rings and majority of them are isolated from microorganisms and
CONTACT Ahmed Al-Harrasi
aharrasi@unizwa.edu.om
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2020.1791112.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
S. K. AVULA ET AL.
Figure 1. Reported natural terphenyls.
mushrooms (Sawayama et al. 2006). Among natural terphenyls, p-terphenyl and m-ter-
phenyl analogs were reported in details, while o-terphenyls are unknown (Liu 2006).
The p-terphenyl skeleton has been described as a small molecule a-helix mimic of pro-
teins (Kazi et al. 2018). The natural and synthetic terphenyl analogs have demonstrated
interesting biological properties such as anti-thrombotic, neuro-protective, immuno-
suppressant, anti-coagulant, anti-microbial, and neuroprotective (Taylor and Felpin
2007; Kazi et al. 2018). The natural products with the p-terphenyl backbone viz., viali-
nin A and thelephantin O (Figure 1) possess significant cytotoxic effects towards
HepG2 and Caco2 cells and non-toxic to normal human cells (Kazi et al. 2018). The p-
terphenyl compound sarcodonin (Figure 1) has displayed remarkable cytotoxicity
ꢀ
towards MCF-7 and SF-268 cells (Calı et al. 2004).
The Suzuki-Miyaura (SM) cross-coupling (Miyaura et al. 1979) has witnessed excep-
tional attention in the past four decades by academia (Miyaura and Suzuki 1995) and
industry (Corbet and Mignani 2006). Initially, palladium complexes along with phos-
phine ligands were used, but later, highly effective ligands were discovered (Jansa
et al. 2017). There are some drawbacks for homogeneous catalysis, such as contamin-
ation of the product, sensitivity, cost and sometimes unavailability of the ligands
(Taylor and Felpin 2007). Heterogeneous catalysis using Pd/C, without any ligand con-
ditions, is an inexpensive and practical source of palladium, proved to be a perfect
alternative method (Yin and Liebscher 2007). The utilization of iterative double-Suzuki-
Miyaura coupling reactions (Sinclair and Sherburn 2005; Taylor and Felpin 2007;
Beaumard et al. 2009; Salomone et al. 2011; Al-Zoubi et al. 2015; Zhang et al. 2016;
Tsypysheva et al. 2019) for a “one pot” preparation of asymmetric p-terphenyl

NATURAL PRODUCT RESEARCH
3
a
Scheme 1. Synthesis of target terphenyl compounds (3a-i). Reaction conditions: (i) 1 (1.0 equiv),
2a-i (2.2 equiv), Pd/C (10 mol %), K2CO3 (6.0 equiv), CH3CN, 80 ꢁC, 8 h.
compounds is unknown. Recently, Kazi et al. (2018) reported a one pot ligand free
preparation of p-terphenyls using a homogeneous palladium, [Pd (OAc)2].
In the present study, for the first time, we have investigated the preparation of new
p-terphenyls using a Pd/C for heterogeneous catalysis. We used ethyl 5-bromo-
2-iodobenzoate as starting materials for the synthesis of new p-terphenyls. The
differences in the reactivity between the C-1 and C-4 positions (iodine and bromine)
of 5-bromo-2-iodobenzoate (ortho and meta to the CO2Me group respectively)
have been utilized to allow a successive introduction of two aryl groups in a highly
convergent and flexible manner.
2. Results and discussion
2.1. Synthesis of terphenyls (3a-i)
Initially, we explored the effect of the reaction temperature on the cross-coupling of
methyl 5-bromo-2-iodobenzoate (1) with a simple phenyl boronic acid (2a). We found
that, at room temperature, the product was not observed even stirring for 12 h (Table
S1, entry 10). The optimum reaction condition was acetonitrile, 6 eq. of K2CO3 and
10 mol% of Pd/C (Table S1, entry 9). When acetonitrile was replaced with DMF, the
yield dropped to 68%. Low yields were obtained (entry 3 and 7) when DMF and
DMSO were used as solvents
We investigated a diverse range of combinations including Pd/C/K2CO3/toluene
(Table S1, entry 1), Pd/C/Na2CO3/THF (Table S1, entry 2), Pd/C/Et3N/1,4-dioxane (Table
S1, entry 5), Pd/C/K2CO3/THF (Table S1, entry 4). The results proved to be unsatisfac-
tory (yields ꢀ 20%). On the other hand, the yields were improved using Pd/C/Na2CO3/
DMSO (yield: 36%; Table S1, entry 3), Pd/C/Et3N/CH3CN (yield: 36%; Table S1, entry 6),
Pd/C/Cs2CO3/CH3CN (yield: 51%; Table S1, entry 8), and Pd/C/KF/CH3CN (yield: 38%;
Table S1, entry 11). Furthermore, the 5 mol% Pd (OAc)2 resulted in lower yields (20%
(Table S1, entry 13). When Pd (OAc)2 was increased to 10 mol % in same reaction sys-
tem, an increase in yield (48%) was observed (Table S1, entry 14).
Very good yields were obtained using the optimised reaction conditions (78-91%)
(Scheme 1, Table S2). Both electron donating (-OMe, -Me) and electron withdrawing
(-NO2, -CF3, -F, -Cl) groups attached to the aromatic ring of boronic acid are compat-
ible with the reaction conditions. Interestingly, the electron donating groups in the
ortho (Table S2, entry 5) and the para (Table S2, entries 2 and 3) positions exhibited

4
S. K. AVULA ET AL.
better reactivity when compared to the electron-withdrawing groups (Table S2, entries
4, 6–9). The highest yield (91%) was obtained with an electron donating group viz.,
methyl at the para position (Table S2, entry 2).
The chemical structures of terphenyl compounds (3a-i, target compounds) were
confirmed by spectroscopic (1H NMR, 13C NMR, 19F NMR, IR and ESI-MS) analysis. The
single crystals of 3 b were grown from slow evaporation of CH2Cl2 solution. The struc-
ture of compound 3 b was confirmed by X-ray diffraction method (Figure S1).
3. Conclusion
A simple and highly efficient Suzuki–Miyaura double coupling reaction for the synthe-
sis of p-terphenyls has been developed, which involves the reactions of methyl 5-
bromo-2-iodobenzoate with a variety of aryl boronic acids at 80 ꢁC in the presence of
Pd/C catalyst. The present methodology employs a ligand free Pd/C heterogeneous
catalyst and an eco-friendly process for the Suzuki–Miyaura double coupling reaction.
The operational simplicity, a ligand free protocol and excellent yields are the notable
advantages of the present method. Applications of these useful coupling products are
under investigation in our laboratory.
Acknowledgements
The authors would like to thank the University of Nizwa for the generous support to this pro-
ject. We thank analytical and technical staffs of the University for Assistance.
Disclosure statement
No potential conflict of interest was reported by the author(s).
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