Article Cite This: J. Org. Chem. 2018, 83, 13088−13102
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Pd/PTABS: Low Temperature Etherification of Chloroheteroarenes Shatrughn Bhilare,† Siva Sankar Murthy Bandaru,‡ Jagrut Shah,† Nicolas Chrysochos,‡ Carola Schulzke,‡ Yogesh S. Sanghvi,§ and Anant R. Kapdi*,† †
Department of Chemistry, Institute of Chemical Technology, Nathalal Parekh Road, Matunga, Mumbai 400019, India Institut für Biochemie, Ernst-Moritz-Arndt Universität Greifswald, Felix-Hausdorff-Straße 4, D-17487 Greifswald, Germany § Rasayan Inc., 2802 Crystal Ridge Road, Encinitas, California 92024-6615, United States ‡
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ABSTRACT: A mild, general, and highly efficient catalytic etherification protocol for chloroheteroarenes was developed using the Pd/PTABS catalytic system. The protocol is selective for the etherification of chloroheteroarenes using a large variety of electron-rich and electron-deficient phenol bearing synthons which include inter alia biologically and commercially important estrone, estradiol, tyrosine, and several other molecules. The mildness of the new protocol is expected to be beneficial for the synthesis of complex drugs and drug intermediates offering late-stage modification of bioactive compounds.
1. INTRODUCTION Etherification of heteroarenes is an important synthetic methodology due to the frequent occurrence of diaryl ether linkages in naturally occurring bioactive molecules and pharmaceutical drugs such as Sorafenib,1 AMG 900,2 antitumor agent XK469,3 herbicides such as bispyribacsodium,4 and several others (Scheme 1A). The significance associated with this methodology has provided researchers with an increased impetus for the development of efficient metal-mediated routes for accessing these prized structural motifs. Copper-catalyzed Ullmann5 and Chan−Lam−Evanstype6 diaryl etherification protocols are well-known, though less attractive commercially due to the employment of stoichiometric amounts of copper as well as expensive boron reagents. Low to moderate yields associated with these transformations have further limited their utility and challenged researchers to develop more efficient protocols, e.g. palladium-catalyzed etherification. The coupling of aryl halides (I, Br, or Cl) with phenols has been explored extensively by researchers, including Buchwald,7 Olofsson,8 Hierso,9 and Beller.10 Several sterically hindered and electron-rich phosphines have been used as ligands in combination with common palladium precursors to facilitate etherification reactions.11 The possibility of using aryl silanes or stannanes as coupling partners has further fueled respective studies and improved their versatility. However, most of these protocols allow the formation of diaryl ethers (via coupling of Ar−X and phenols), while only a handful procedures are known which allow heteroaryl halides to be employed as coupling partners (Scheme 1B).7a,b,9 The importance of using the latter, though, is evident from their occurrence in a variety of naturally occurring bioactive molecules and pharmaceutical drugs. Recently, Yamaguchi and coworkers reported the © 2018 American Chemical Society
decarbonylative diaryl ether formation under Pd or Ni catalytic conditions.12 Besides providing the desired diaryl ethers, most of these protocols suffer from various process limitations such as high reaction temperature requirements, limited substrate scope, and employment of expensive ligands often accompanied by only moderate yields. Difficulties in overcoming such challenges have impeded wider application of these protocols. To address and overcome the above-described limitations, we provide herein a sustainable catalytic solution with a low temperature etherification protocol for chloroheteroarenes utilizing a simple phosphatriazene ligand (PTABS: phosphatriazene butane sulfonate). The method exhibits a large substrate scope (utility of the protocol demonstrated with >50 examples), providing the possibility of postsynthetic modifications of bioactive compounds and facilitates the synthesis of an antitumor agent, XK469 (Scheme 1C). The developed protocol is superior to the existing etherification procedures available in literature and makes use of a bench stable Pd catalyst system which is easy to synthesize.13 The inspiration for the current work came from our previous results in the employment of the PTA-based complexes14a−d and Pd/ PTABS catalytic system for the coupling of nucleosides under aqueous conditions and the room temperature amination of chloroheteroarenes.15
2. RESULTS AND DISCUSSION First, the coupling of, 2-chloropyrazine (1a) with 4methoxyphenol (2a) was attempted using Pd/PTABS [Pd(OAc)2 1.0 mol %, PTABS 2.0 mol %] in DMF with Et3N Received: July 18, 2018 Published: October 8, 2018 13088
DOI: 10.1021/acs.joc.8b01840 J. Org. Chem. 2018, 83, 13088−13102
Article
The Journal of Organic Chemistry
(Table 1, entries 17−22). In all cases including the highly electron-rich phosphines and N-heterocyclic carbenes, only a minor amount of the desired product was observed, reaffirming the versatility and exceptional capability of the PTABS ligand system in catalyzing the transformation. The employment of the parent PTA as well as methyl substituted PTA (PTAMeI) failed to provide yields comparable to that of PTABS (Table 1, entries 22 and 23). A rationale for the enhanced activity of PTABS compared to other PTA analogues points toward the activating influence of the substitution on the nitrogen atom of the parent PTA as well as the chain length and anionic counterpart. Further studies are needed to ascertain the given assumption with DFT playing a crucial role in determining the exact influence of substituent’s and electronics on the donation capacity of phosphorus atom in different PTA ligands, which will be reported at a later stage as it falls outside the purview of this manuscript. With such a highly active catalytic system in hand, the substrate scope for the palladium-catalyzed diaryl ether synthesis was investigated (Scheme 2). It was decided to test the catalytic system for five different chloroheteroarenes: 2chloropyrazine, 2-chloro benzothiazole, 2-chloro benzoxazole, 2-chloroquinoxaline and 7-chloro-4-(pentyloxy)pteridin-2amine for ascertaining the extent of the utility. Initially, simple aromatic phenols such as 4-methoxyphenol, 4-tert-butylphenol, and a few others were employed as the nucleophilic coupling partners. As a general trend, it was observed that the employment of electronically activated phenols (OMe or tBu as electronreleasing substituents) provided good to excellent yields of the etherification product irrespective of the chloroheteroarene (Scheme 2). Even sterically demanding 2,4,6-trimethylphenol as substrate was well-tolerated without any loss in reactivity (Scheme 2, 3l). Electronically neutral phenol as well as several electronically deactivated phenols (3-NO2, 2-CHO, 4-F, 4CO2Me) were also well-tolerated, furnishing good to excellent yields of the etherified product. Pentafluoro phenol is an essential pharmacophore of high biological relevance16 and therefore a desirable coupling partner. The reactivity of this phenol as synthon, though, was found to be comparably lower due to the deactivating nature of the fluoro substituents (Scheme 2, 3r). The catalytic efficiency and the mild nature of Pd/PTABS were further demonstrated by performing a chemoselective17 etherification procedure using 1-bromo-2-naphthol as coupling partner (Scheme 2, 3u and 3v), which did not lead to bromine induced homocoupling. This selectivity for the activation of the C−Cl over the C−Br bond by the catalytic system provides a useful handle for further functionalization. The selectivity toward chloro functionality has been attributed to the possible coordination of the Pd/PTABS system to the nitrogen atom next to the chlorine atom, directing the activation of C−Cl bond, which is also more active due to the electronics on the heteroaromatic ring systems. It has also been observed that activation of C−Cl in the third position with regards to N atom does not occur. Some of the compounds synthesized were crystallized using suitable solvent to obtain single crystals, allowing their characterization via X-ray analysis (3j, 3k, 3l, 3n, and 3r). Given the success of the Pd/PTABS system with relatively simple phenols, we further explored the possibility of using benzylic alcohols as well as heteroaromatic phenols as coupling
Scheme 1. (A) Drugs Containing Ether Linkages, (B) Previous Reports, and (C) This Work: Etherification of Chloroheteroarenes
employed as the base at 60 °C, providing
