Advances in Vicinal Dicarbo-C–H-functionalization of Five-Membered Heteroarenes via Palladium/Norbornene Cooperative Catalysis

Abstract

Direct introduction of two carbon substituents to less functionalized aromatic cores has been an attractive objective for late-stage modification and streamlined synthesis of complex molecules. Using the palladium/norbornene (Pd/NBE) cooperative catalysis, while initial achievements on double C–H functionalization were made in the past, the scopes of reactions and substrates remain to be expanded. Here we report some new advances on the Pd/NBE-catalyzed dicarbofunctionalization of five-membered heteroarenes through sequential C–H activation. These efforts include the Pd/NBE-catalyzed C4-arylation/C5-alkenylation of diverse furans, the first C4-alkynylation of thiophenes/pyrroles, and the preliminary C4-methylation.

Graphical Abstract

Advances in the palladium/norbornene-catalyzed vicinal dicarbon-C–H-functionalization of furans, thiophenes and pyrroles are described, including the general furan-based reactions and the use of new electrophiles for C4 functionalization.

1. Introduction

Multisubstituted electron-rich five-numbered heteroarenes, such as pyrroles, furans and thiophenes, are frequently found in fd1small-molecule drugs and bioactive natural products (Fig. 1) [1–3]. Consequently, methods capable of rapid functionalizations of these heterocycles could be highly valuable for synthesis of pharmaceuticals. In particular, regioselective simultaneous introduction of two distinct vicinal carbon substituents onto these five-membered cores represents an attractive objective, which remains challenging to achieve to date. The current strategies primarily rely on stepwise operations, generally with pre-functionalized substrates (Scheme 1a) [4,5]. The established single-step double C−H activation strategies typically introduce two identical functional groups [6].

Fig. 1.

Examples of polysubstituted five-membered heteroarenes in natural products and drugs.

Scheme 1.

Vicinal di-carbo-functionalization of five-membered heteroarenes.

In recent years, palladium/norbornene (Pd/NBE) cooperative catalysis has gained prominence as a valuable approach for site-selective functionalization of arenes, heteroarenes, and alkenes [7–18]. This type of catalysis is centered on the unique reactivity of an aryl-norbornyl-palladacycle (ANP) intermediate generated from migratory insertion of NBE into an aryl-Pd species, followed by C–H palladation (Scheme 1b). Mechanistically, an electrophile first couples at the arene ortho position, the site bonded with Pd in ANP, and upon NBE extrusion, the adjacent ipso position can be functionalized through reacting with a nucleophile or an alkene. As a result, sequential difunctionalization of vicinal positions of arenes can be achieved. Currently, most of the Pd/NBE-catalyzed difunctionalization reactions employed mono-functionalized arenes as substrates, such as aryl halides or boronates. In 2019, we reported the first vicinal difunctionalization of thiophenes through Pd/NBE- catalyzed double C−H functionalization (Scheme 1b) [19], which capitalized on the Pd(II)-initiated C−H palladation [20–26]. More recently, this transformation was extended to pyrrole substrates, which was further strategically integrated into the total syntheses of leuconoxine-type alkaloids [27]. Despite these initial achievements, the corresponding transformation with furans remains challenging [19]. Additionally, the current reaction protocol is confined to the use of aryl iodide-based electrophiles, thereby restricted to arylation the C4 position of heteroarenes [28]. Herein, we describe our efforts on the development of a Pd/NBE-catalyzed C4-arylation/C5-alkenylation of diverse furans via double C−H activation, as well as preliminary findings on the use of new types of electrophiles for C4 functionalization.

To identify the optimal reaction conditions, 2-butylfuran (1a), methyl 2-iodobenzoate (2a) and methyl acrylate (3a) were selected as model substrates and reagents for the C4-arylation/C5-Heck reaction (Table 1). A careful screening of key reaction parameters was conducted, including palladium catalyst, NBE mediator, solvent, temperature, oxidant and reaction time. Guided by our previous work [19], the combination of Pd(OAc)₂ and AsPh₃, was initially employed, and the roles of benzoquinone (BQ) and AgOAc were evaluated (entries 1–3). Both these oxidants proved to be essential, as the omission of either component significantly diminished the product yield. We also evaluated O₂ as an alternative oxidant; however, it gave less than 5% yield (entries 3). A subsequent survey of different solvents (entries 4–7) identified ethyl acetate as the optimal medium. A variety of palladium precursors were also examined (entries 8–12), with Pd(acac)₂ affording the highest efficiency. The use of norbornenes N2 and N4 led to a marked improvement in yield (entries 13 and 15), whereas N3 was less effective than N1 (entry 14). A slight reduction in yield was observed upon lowering the reaction temperature to 60 ^oC (entry 16). Finally, extending the reaction time to 72 hours afforded the highest yield (72%), which was considered as the optimal condition (entry 17). Note that all the reactions were run in air using untreated solvents.

Table 1:

Selected condition optimization^a

^aStandard conditions: 1a (0.25 mmol, 2.5 equiv), 2a (0.1 mmol, 1.0 equiv), 3a (0.18 mmol, 1.8 equiv), Pd(acac)₂ (10 mol %), AsPh₃ (25 mol%), NBE (150 mol%), AgOAc (3.0 equiv), BQ (1.0 equiv), HOAc (5.0 equiv), ethyl acetate (0.34 mL, 0.3 M), air, 65 °C, 48 hours. Yields were determined by ¹H NMR analysis using CH₂Br₂ as the internal standard.

^b72 hours.

^cthe yield under O₂.

^dIsolated yield.

With the reaction conditions optimized, the substrate scope was explored using a variety of substituted furans (Table 2). A range of substrates, including the parent furan (4b), mono- and di-substituted furans, underwent efficient difunctionalization, delivering the desired products in moderate to good yields. These examples demonstrated good functional group tolerance. For instance, substrates bearing potentially reactive groups such as aryl bromide (4c), protected primary alcohol (4d), and amine (4e) at the C2 position were well tolerated under the reaction conditions. Notably, a structurally more complex furan derived from estrone (4h) underwent smooth C4,C5-difunctionalization, giving the corresponding product in moderate yield. In addition, aryl iodides with diverse substituents (4i–4m) and a series of electron-deficient olefins (4n–4r) were compatible with this transformation. The regioselectivity of this difunctionalization reaction was confirmed by X-ray crystallographic analysis of the structure of compound 4g.

Table 2.

Substrates scope^a

^aThe reaction was run with 0.5 mmol 1, 0.2 mmol 2, 0.36 mmol 3, Pd(acac)₂ (0.02 mmol, 10 mol%), N4 (0.3 mmol, 1.5 equiv), AsPh₃ (0.05 mmol, 25 mol%), BQ (0.2 mmol, 1.0 equiv), AgOAc (0.6 mmol, 3.0 equiv), and HOAc (1.0 mmol, 5.0 equiv) in 0.67 mL ethyl acetate for 72 h. Isolated yield.

Beyond the C4-arylation with aryl iodides, other classes of electrophiles were also explored in this di-carbo-functionalization reaction. To our delight, the C4-alkynylation could be realized by using alkynylation bromide as the electrophile (Table 3). While the meta C−H alkynylation was reported by Yu in 2015 [29], alkyne electrophiles have not been used in the Pd/NBE-catalyzed difunctionalization reactions yet. Under a slightly modified reaction condition with N1 as the mediator, promising preliminary results were obtained on the C4-alkynylation with thiophene and pyrrole substrates (8a-8d). The regioselectivity of this method was unambiguously confirmed by X-ray structure of product 8d.

Table 3.

Preliminary C4-alkynylation of thiophenes and pyrroles.^a

^aThe reaction was run with 0.2 mmol 5 or 6, 0.4 mmol 7, 0.48 mmol 3a, Pd(OAc)₂ (0.02 mmol, 10 mol%), N1 (0.4 mmol, 2.0 equiv), AsPh₃ (0.05 mmol, 25 mol%), BQ (0.2 mmol, 1.0 equiv), AgOAc (0.6 mmol, 3.0 equiv), and HOAc (1.0 mmol, 5.0 equiv) in 1.0 mL ethyl acetate for 72 h.

On the other hand, initial success on employing methyl iodide as the electrophile was also achieved. When 2-chloro-1-methylpyrrole (5a) was subjected to the standard reaction condition with N1 as the mediator, the desired C4-methylated/C5-alkenylated pyrrole (10) was isolated in 43% yield (Eq. 1). Likewise, when 1-butylthiophene was subjected to the slightly modified reaction condition, the desired methylated thiophene (11) was isolated in 20% yield (Eq. 2). Considering the importance of methyl groups in drug design [30], further development of the method is expected to be useful in medicinal chemistry research. Given the relatively low efficiency of C4 alkynylation and methylation at this stage, the attempts with less reactive furan substrates was unfruitful yet.

(1)

(2)

Conclusion

In summary, we have extended the Pd/NBE-catalyzed vicinal dicarbo-C–H-functionalization of heteroarenes to the C4-arylation/C5-alkenylation of furans, as well as to the first C4-alkynylation and C4-methylation of thiophenes and pyrroles. These reactions can tolerate air, moisture, and many functional groups. Thus, this study should offer some notable advances in the field of Pd/NBE catalysis. Efforts on further improving the efficiency and generosity of this type of catalysis for practical synthetic applications are ongoing.

Supplementary Material

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