Synthesis of 2,3-Difunctionalized Benzofuran Derivatives through

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Synthesis of 2,3-Difunctionalized Benzofuran Derivatives through Palladium-Catalyzed Double Isocyanide Insertion Reaction Weigao Hu, Meng Li, Guangbin Jiang, Wanqing Wu,* and Huanfeng Jiang* Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China S Supporting Information *

ABSTRACT: A novel palladium-catalyzed tandem cyclization of 1-(allyloxy)-2-ethynylbenzene derivatives with isocyanides in the presence of water has been developed. The key intermediates, benzofuran-3-α-carbonyl aldehydes, were obtained through a simple acid hydrolysis process and could serve as precursors for structurally diverse 2,3-difunctionalized benzofuran derivatives such as important 2-benzofurylquinoxalines, benzofuran-3-α-ketoesters and benzofuryl ynediones. This transformation features convenient operation, simple and commercially available starting materials, broad functional-group compatibility, and moderate to good reaction yields.

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Scheme 1. Palladium-Catalyzed Isocyanides Insertion Reaction

n the past decades, palladium-catalyzed cross-coupling reactions involving isocyanides have become powerful tools for the construction of valuable nitrogen-containing compounds,1 in which the reactivity of isocyanide as a carbon monoxide alternative has been demonstrated.2 In addition to most of the reported isocyanide single insertion reactions, multiple consecutive insertions such as with two or three molecules were also commonly described by Yamamoto,3 Whitby,4 our group,5 and others.6 Of note, all of these reactions involved the generation of aryl, vinyl, or alkyl imidoylpalladium species and were generally captured by intra- or intermolecular carbon, oxygen, nitrogen, and sulfur nucleophiles or other coupling partners (Scheme 1, eq 1).1b,c,7 In addition, this intermediate can also be captured by a hydride ion, and the only example comes from Ji and Zhu et al., who have developed a novel palladium-catalyzed formylation of aryl halides with isocyanide for synthesizing aromatic aldehydes by using Et3SiH as a reducing agent in 2014 (Scheme 1, eq 2).8 Despite the above achievements, the development of versatile methods to realize this type of reaction using stable and environmentally friendly reagents is still of great value. On the other hand, benzofurans constitute a valuable class of heterocyclic compounds for their natural occurrence and remarkable biological activities.9 As a consequence, significant effort has been put forth toward the construction of such a scaffold in organic synthesis. Undoubtedly, o-ethynylphenols are the most widely used precursors to construct this functionalized core through intra- or intermolecular annulations.10 It is noteworthy that this strategy applies equally to the 1-allyloxy-2-ethynylbenzene derivatives, which could undergo intramolecular cyclization to generate 2-substituted 3-allylben© XXXX American Chemical Society

zofurans under platinum11 or palladium12 catalysis. However, the intermolecular annulations of these derivatives for the synthesis of more complex functionalized benzofurans have not yet been discovered and, therefore, remain highly desirable. In a continuation of our interest in isocyanide chemistry5,13 and the synthesis of benzofurans,14 herein we disclose a novel palladium-catalyzed tandem intermolecular cyclization of 1(allyloxy)-2-ethynylbenzene derivatives with isocyanide in the presence of water (Scheme 1, eq 3), followed by acid hydrolysis to afford benzofuran-3-α-carbonyl aldehydes, which could be Received: April 22, 2018

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DOI: 10.1021/acs.orglett.8b01277 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

biheteroaryl molecules 4. For instance, the substituents with methyl, n-pentyl, and fluoro groups at the ortho, meta, and para positions of the phenyl ring all reacted smoothly to give the corresponding products in moderate to good yields (4b−i). On the whole, the substrates with ortho substituents on the benzene ring showed higher reactivity than others. Notably, the optimized conditions could be applied to thienyl- and alkylsubstituted alkynes, which could be transformed to the corresponding products in 76−86% yields (4j−l). Furthermore, the substrates 1m and 1n were also tolerated well in this catalytic system, and the target products 4m and 4n were obtained in 40% and 36% yields, respectively. To further evaluate the practicability of this approach, variations of the diamines were also briefly investigated. Gratifyingly, both the naphthalene-2,3-diamine and 4,5-dimethylbenzene-1,2-diamine underwent the reaction smoothly, giving the desired products 4o−q in satisfactory yields. A mixture of two isomers 4r with a 1:1 molar ratio was obtained for the reaction with 4methylbenzene-1,2-diamine. α-Ketoesters are important units in many biologically active molecules and are useful precursors in a variety of organic transformations.16 By taking advantage of the benzofuran-3-αcarbonyl aldehyde intermediates, we were delighted to find that the simple alkyl alcohols such as ethanol, benzyl alcohol, and phenylethanol were converted to the corresponding benzofuran-3-α-ketoesters 6a−c in good yields (Scheme 3).17

converted in situ into divergent 2,3-difunctionalized benzofuran derivatives. After extensive screening of different parameters, the best conditions for the synthesis of (1E,2E)-N1,N2-di-tert-butyl-1-(2phenylbenzofuran-3-yl)ethane-1,2-diimine (2a) are as follows: tert-butyl isocyanide (3 equiv), Pd(PPh3)4 (5 mol %), K2CO3 (1 equiv), and H2O (1.2 equiv) in DMA (2 mL) at 80 °C for 12 h (see the Supporting Information for details). On the other hand, the products 2 can be in situ hydrolyzed (2 M, 0.5 mL of HCl) to deliver benzofuran-3-α-carbonyl aldehydes, which were captured by aryl-1,2-diamine 3 and transformed into 2benzofurylquinoxalines 4 in high yields,15 because it is difficult to isolate them from PPh3. With the optimized reaction conditions in hand, we demonstrated the generality and scope of our method with a range of 1-(allyloxy)-2-ethynylbenzene derivatives and o-phenylenediamines, and representative results are summarized in Scheme 2. We were pleased to find that reactions employing 1 with differently substituted aryl groups attached on the triple bond all worked well to afford the desired Scheme 2. Scope of the 2-Benzofurylquinoxaline Synthesisa,b

Scheme 3. Scope of the Benzofuran-3-α-ketoester Synthesisa,b

a Reaction conditions: (i) 1a (0.2 mmol), tert-butyl isocyanide (0.6 mmol), Pd(PPh3)4 (5 mol %), K2CO3 (0.2 mmol), H2O (1.2 equiv) in DMA (2.0 mL) at 80 °C for 12 h; (ii) heating in DMF/HCl (2 mL of DMF and 2 M, 0.5 mL HCl) at 80 °C for 1 h; (iii) I2 (1.0 equiv), ROH (1.2 equiv), K2CO3 (2.0 equiv) in toluene (2.0 mL) at rt for 1 h. b Yields of the isolated products are provided.

With the efficient synthesis of 2-benzofurylquinoxalines and benzofuran-3-α-ketoesters in hand, we next turned our attention to the construction of benzofuryl ynediones using the same strategy (Scheme 4).18 The results indicate that not only ethynylbenzene but also 2-ethynylthiophene and cyclopropyl acetylene were all compatible in this reaction to afford the desired products 8a−c. To gain more insight into the reaction mechanism, deuterium experiments were conducted in deuterated oxide (Scheme 5). The results indicate that there was no H/D exchange in the product 4a (Scheme 5, eq 1), and when the substrate 1d was conducted under the standard conditions, only 29% deuterium was detected in the final target product (Scheme 5, eq 2), which might be due to the significant H/D exchange during the hydrolytic process. On the other hand, other isocyanides such as 1,1,3,3-tetramethylbutyl isocyanide also could give the corresponding product in 62% GC yield.

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Reaction conditions: (i) 1a (0.2 mmol), tert-butyl isocyanide (0.6 mmol), Pd(PPh3)4 (5 mol %), K2CO3 (0.2 mmol), H2O (1.2 equiv) in DMA (2.0 mL) at 80 °C for 12 h; (ii) heating in DMF/HCl (2 mL of DMF and 2 M, 0.5 mL of HCl) at 80 °C for 1 h; (iii) ophenylenediamines (1.2 equiv) in 2.0 mL of DMF at 120 °C for 2 h. b Yields of the isolated products are provided. B

DOI: 10.1021/acs.orglett.8b01277 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 4. Scope of the Benzofuryl Ynedione Synthesisa,b

Scheme 6. Proposed Mechanism

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Reaction conditions: (i) 1a (0.2 mmol), tert-butyl isocyanide (0.6 mmol), Pd(PPh3)4 (5 mol %), K2CO3 (0.2 mmol), H2O (1.2 equiv) in DMA (2.0 mL) at 80 °C for 12 h; (ii) heating in DMF/HCl (2 mL of DMF and 2 M, 0.5 mL HCl) at 80 °C for 1 h; (iii) CuTC (10 mol %), terminal alkyne (5.0 equiv) in toluene (2.0 mL) at 90 °C for 4 h under O2. bYields of the isolated products are provided.

Scheme 5. Control Experiments furans such as 2-benzofurylquinoxalines, benzofuran-3-αketoesters, and benzofuryl ynediones from benzofuran-3-αcarbonyl aldehydes. This key intermediate was obtained through palladium-catalyzed cyclization of 1-allyloxy-2-ethynylbenzene derivatives with double isocyanides in the presence of water, followed by acid hydrolysis. The use of readily available starting materials, broad functional-group compatibility, and convenient operation make this approach particularly attractive. Further applications of this protocol on the synthesis of biologically active compounds are ongoing in our laboratory.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01277. Experimental procedures, condition screening table, characterization data, and NMR spectra for all products (PDF)

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However, the 1-isocyano-4-methoxybenzene and cyclohexyl isocyanide could not be tolerated in this transformation (Scheme 5, eq 3). We then subjected the allyl(2(phenylethynyl)phenyl)sulfane to the standard conditions. To our disappointment, no corresponding product was detected but the starting material (Scheme 5, eq 4). On the basis of the above results and previous reports, a plausible mechanism is illustrated in Scheme 6. The catalytic cycle is initiated by a Pd(0) oxidative addition into the allyl ether group, leading to the formation of an ion pair of a phenoxy anion and a π-allyl palladium(II) cation A, which coordinates with the triple bond of an o-ethynyl phenoxy anion to form B. Subsequently, intramolecular oxypalladation of the intermediate B affords the π-allyl palladium(II) benzofuran intermediate C, followed by isocyanide double insertion to form the corresponding imidoyl Pd(II) intermediate D. Intermediate D would be trapped by water to release the desired product 2 and the intermediate E, which finally undergoes reductive elimination to regenerate Pd(0) for the next catalytic cycle. In summary, we have developed a novel method for the construction of structurally diverse 2,3-difunctionalized benzo-

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Huanfeng Jiang: 0000-0002-4355-0294 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the National Key Research and Development Program of China (2016YFA0602900), the National Natural Science Foundation of China (21490572 and 21420102003), and the Pearl River S&T Nova Program of Guangzhou (201610010160).

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DOI: 10.1021/acs.orglett.8b01277 Org. Lett. XXXX, XXX, XXX−XXX