Synthesis of benzofurans via ruthenium-catalyzed redox-neutral C–H functionalization and reaction with alkynes under mild conditions

Abstract

Using an oxidizing directing group, a mild Ru^II-catalyzed direct coupling of N-phenoxypivalamide with internal alkynes was developed, generating the benzofurans in moderate to high yields.

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Benzofuran is a privileged structural framework widely existing in natural products, biologically active molecules and pharmaceuticals.¹ Accordingly, continued efforts have been devoted to the development of synthetic approaches for this motif.² Among these approaches, the transition-metal-catalyzed transformation has received considerable attention. In particular, the transition-metal-catalyzed C–H bond activation provides a powerful and straightforward synthetic method by obviating the need for prefunctionalized substrates.³ A representative example is the direct access to benzofurans by the oxidative annulation of phenols and unactivated internal alkynes (Scheme 1).^3f–h

Scheme 1 Synthesis of benzofurans by annulation of arenes with alkynes.

The transition-metal-catalyzed oxidative annulation of various aromatic substrates with alkynes represents a step-economical access to heterocycles.⁴ Despite the notable advances, the use of an external, mostly metallic oxidant for catalyst regeneration is inevitable and harsh conditions are generally required. To address these drawbacks, an attractive redox-neutral strategy employing an oxidizing directing group which acts as both a directing group and an internal oxidant has been applied in this field.⁵ Diverse oxidizing directing groups were designed to construct different heterocycles by Pd-, Rh- or Ru-catalyzed transformations.^6–8 In these reactions, the regeneration of the active catalyst was accompanied by the cleavage of the N–O or N–N bond.⁹ In our previous work,^10a,b we designed a novel oxidizing directing group for mild Rh-catalyzed C–H functionalizations of N-phenoxyacetamide¹⁰ with alkynes to furnish ortho-alkenyl phenols or benzofuran products selectively (Scheme 1). We envisioned that an analogous but more economic process may be achieved by the use of a less expensive catalyst, such as ruthenium.

Ruthenium(II) catalysts have recently attracted increasing interest in C–H functionalization due to their good stability, low cost and high efficiency.¹¹ Herein, we wish to describe the development of a mild Ru^II catalyzed C–H functionalization of N-phenoxypivalamide with internal alkynes for the synthesis of benzofurans without any external oxidant (Scheme 1).

In preliminary experiments, N-phenoxyacetamide (1.2 equiv.) was treated with [Ru(p-cymene)Cl₂]₂ (2.5 mol%), CsOAc (25 mol%) and ethyl 2-butynoate (2a, 1 equiv.) in DCM at room temperature. The benzofuran product 3aa was obtained in 46% yield (Table 1, entry 1). Further examination indicated that N-phenoxyacetamide was decomposed to phenol as a side product, which decreased the yield of 3aa. Other substrates with different substituents on the nitrogen atom were screened. Fortunately, N-phenoxypivalamide (1a) gave a nearly quantitative yield while other substrates were found to be less effective or ineffective (Table 1, entries 2 and 3).¹² K₂CO₃ appeared to be the ideal additive owing to the shorter reaction time (Table 1, entry 5). The addition of acetic acid (2 equiv.) inhibited the reaction (Table 1, entry 7). To our surprise, the transformation also proceeded well when DBU was used instead of metal carboxylate (Table 1, entry 6). Other solvents were not as good as DCM and no ortho-hydroxyphenyl substituted enamide was detected compared with Rh-catalyzed reactions in our previous work (Table 1, entries 8–11).^10a

Table 1 Optimization of the reaction conditions^a

Entry	R	Additive	Solvent	Yield^b (%)
a Reaction conditions: 1 (0.12 mmol), 2a (0.1 mmol), [Ru(p-cymene)Cl2]2 (2.5 mol%), and additives (25 mol%) in solvent (0.4 M) at room temperature for 12 h under air. Piv: pivaloyl. b ^1H NMR yield. c Reaction was run at room temperature for 24–48 h as monitored by TLC. d 2 equiv. of HOAc was added.
1^c	Ac	CsOAc	DCM	46
2^c	Piv	CsOAc	DCM	99
3^c	Ts	CsOAc	DCM	9
4	Piv	CsOAc	DCM	61
5	Piv	K2CO3	DCM	99
6	Piv	DBU	DCM	90
7^d	Piv	K2CO3	DCM	12
8	Piv	K2CO3	Dioxane	83
9	Piv	K2CO3	Toluene	90
10	Piv	K2CO3	CH3CN	76
11	Piv	K2CO3	MeOH	10

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With the optimized conditions in hand, various alkynes were reacted with 1a and the results are shown in Scheme 2. Several functional groups, such as ester (3aa, 3ab, 3an), ketone (3ac) and amide (3am), were well tolerated in this reaction to give good yields of the expected products with a high regioselectivity. Aryl–alkyl disubstituted alkynes seemed to be less effective unless an electron-withdrawing group was equipped (3ad–3af, 3al). Moreover, symmetrical diaryl acetylenes bearing various substituents were compatible with the reaction conditions furnishing the corresponding benzofurans in moderate to good yields (3ag–3aj). Unsymmetrical diaryl acetylene resulted in relatively poor regioselectivity (3ak and 3ak′). It is noteworthy that the ynamide 2o was also a good reactant for this transformation affording moderate yields of two isomers (3ao and 3ao′). Nevertheless, dialkyl alkynes and terminal alkynes gave poor results.

Scheme 2 Scope of alkynes for the synthesis of the benzofurans. Reaction conditions: 1a (0.24 mmol), 2 (0.2 mmol), [Ru(p-cymene)Cl₂]₂ (2.5 mol%), and K₂CO₃ (25 mol%) in DCM (0.4 M) at room temperature under air; isolated yield was reported. ^a 5 mol% of the catalyst was used. ^b 10 mol% of catalyst was used. ^c NMR spectra indicated an inseparable mixture of isomers, the ratio was determined by ¹H NMR.

Various substituents on N-phenoxypivalamide were then examined and a significant electronic effect was observed (Scheme 3). With alkyl- or phenyl-substituted N-phenoxypivalamides, the reaction proceeded smoothly and provided the desired products in good to excellent yields (3aa–3fa). In addition, sterically hindered 3,5-dimethyl-substituted N-phenoxypivalamide was also tolerated (3ia). Unfortunately, low yields were obtained with 3-trifluoromethyl- and 3,5-difluoro-substituted N-phenoxypivalamides as the substrates (3ga, 3ha). Of note, when a meta-substituted N-phenoxypivalamide was employed, the areneruthenation mainly occurred at the less hindered site (3da).

Scheme 3 Reaction scope for substituted N-phenoxypivalamides. Reaction conditions: 1 (0.24 mmol), 2a (0.2 mmol), [Ru(p-cymene)Cl₂]₂(2.5 mol%), and K₂CO₃ (25 mol%) in DCM (0.4 M) at room temperature under air; isolated yield was reported. ^a NMR spectra indicated an inseparable mixture of isomers, the ratio was determined by ¹H NMR.

Experiments were then carried out to gain more insights into the reaction mechanism. As we mentioned before, phenol was detected as a side product in this reaction. When the reaction was run with stoichiometric amounts of [Ru(p-cymene)Cl₂]₂ under the standard conditions, 1a was decomposed to phenol and pivalamide quantitatively after 12 hours (eqn (1)). In another experiment, 1a was treated with [Ru(p-cymene)Cl₂]₂ under the standard conditions for 12 hours and subsequently 2a was added to the reaction mixture. No benzofuran was observed after several hours (eqn (2)), indicating that the catalytic cycle was not initiated by the cleavage of the O–N bond. In addition, N-methyl-substituted phenoxypivalamide cannot be converted to the desired product, implying that the N–H bond is crucial for this transformation (eqn (3)). Moreover, the regioselectivity of the electron-deficient alkynes (3aa–3af, 3am, 3an) probably excluded the possibility of direct nucleophilic addition of the amido group in 1a to alkynes. From these results, we believed that the catalytic cycle was initiated by the N-ruthenation in the presence of a base and subsequent C–H cleavage.¹³

Deuterium-labeling experiments were conducted in the presence of HOAc-d₄ or D₂O under the standard conditions. No deuterium incorporation was found at the ortho-positions of 1a in the absence of alkyne (eqn (4)). Similarly, when the reaction between 1a and 2a was performed in the presence of D₂O, 3aa was obtained smoothly and no deuterium incorporation was observed (eqn (5)). These results implied that the C–H activation might be irreversible under the reaction conditions.^8a,14 Furthermore, the KIE was determined to be

k_H/k_D ≈ 1.6 (eqn (6)), indicating that the C–H bond cleavage process is not involved in the rate determining step. Competition experiments between substituted diphenylacetylenes revealed that the more electron-deficient alkynes afford higher yields, which is consistent with the reported Ru-catalyzed annulation of arenes with alkynes (eqn (7)).^8a,15

Based on the results obtained above and the literature,^8a,b the mechanism hypotheses are proposed (Scheme 4). The radical mechanism might be excluded because the presence of TEMPO (1 equiv.) or catalytic amount of BHT did not affect the reaction under standard conditions. In addition, enamide 4 failed to afford the benzofuran product under the standard reaction conditions (eqn (8)) indicating that the benzofuran product was not derived from enamide.¹⁶ The reaction might be initiated with N-ruthenation in the presence of a base followed by an irreversible C–H cleavage by Ru^II to yield a five-membered ruthenacycle intermediate A. Subsequent alkyne insertion generates a seven-membered intermediate B, which upon protolysis would yield the intermediate C. Then, intramolecular substitution might occur to form the C–O bond and break the O–N bond simultaneously (path a). According to our previous work^10a and the literature,¹⁷ the non-oxidative cleavage of the O–N bond in phenoxyamide usually proceeded with the aid of acid. However, the addition of acetic acid inhibited the reaction (Table 1, entry 7), which makes the concerted non-oxidative process less reasonable. Alternatively, the intermediate C would lead reversibly to the intermediate D, in which oxygen and nitrogen atoms might both coordinate to ruthenium. The following intramolecular oxidative addition and reductive elimination involving Ru^IV intermediate F would provide the benzofuran product 3 and regenerate Ru(II).^11b,18 Further studies to understand the reaction pathway are ongoing in our laboratory.

Scheme 4 Mechanism hypotheses.

Finally, a relatively large-scale reaction was conducted. Under standard conditions, the desired benzofuran product could be produced conveniently on a gram scale without obvious decrease in yield (eqn (9)). Further hydrolysis of 3ab will result in 3-methylbenzofuran-2-carboxylic acid 5, which is a useful building block for complex heterocyclic compounds.¹⁹

In summary, we have developed a mild Ru-catalyzed C–H functionalization for the synthesis of benzofuran derivatives. Using –ONHPiv as a novel oxidizing directing group, no external oxidant is needed, and a clean and economic process was developed. More detailed investigations to understand the reaction mechanism and further studies to explore new transformation properties of the novel directing group are in progress.

Acknowledgements

We thank the National Basic Research Program of China (2015CB856600), the National Natural Science Foundation of China (21202184, 21232006), and the Chinese Academy of Sciences for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and compound characterisation. See DOI: 10.1039/c4qo00196f

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