Manganese-Catalyzed Ring Opening of Benzofurans and Its

Sep 29, 2017 - A new class of aromatic metamorphosis in which benzofurans are converted into diverse six-membered oxaheterocycles has been developed. ...
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Letter Cite This: Org. Lett. 2017, 19, 5557-5560

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Manganese-Catalyzed Ring Opening of Benzofurans and Its Application to Insertion of Heteroatoms into the C2−O Bond Shun Tsuchiya, Hayate Saito, Keisuke Nogi, and Hideki Yorimitsu* Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan S Supporting Information *

ABSTRACT: A new class of aromatic metamorphosis in which benzofurans are converted into diverse six-membered oxaheterocycles has been developed. This transformation is composed of two reactions in one pot: manganese-catalyzed arylative or alkylative ring-opening of benzofurans affording dianionic intermediates and subsequent trapping with multivalent heteroatom electrophiles. Various electrophiles containing silicon, boron, phosphorus, germanium, and titanium could be applied to this heteroatom insertion. should make a major impact in the field of synthetic organic chemistry. To further develop diversity-oriented aromatic metamorphosis, we focused on the formation of dianionic species from benzofurans via arylative or alkylative ring-opening. It was reported that treatment of 2-lithiobenzofuran with another organolithium reagent resulted in alkylative or arylative cleavage of the C2−O bond of the furan ring affording the corresponding dianionic species (Scheme 1B).3−5 We thus envisioned that the generation of dianionic intermediates (step a) followed by electrophilic trapping with multivalent electrophiles (step b) would furnish various six-membered oxaheterocycles. Here, we report a new class of aromatic metamorphosis of benzofurans composed of two sequential reactions: manganesecatalyzed arylative or alkylative ring-opening and subsequent heteroatom-introducing ring-closure. By means of this method, we have synthesized a series of six-membered oxaheterocycles such as oxasilin,6 oxaborin,7 oxaphosphin,8 oxagermin, and oxatitin from common benzofuran. First, we conducted phenylative ring-opening of benzofuran (1a) with an excess amount of phenyllithium as previously reported.3 However, the yield of the ring-opening product was not satisfactory. To our delight, addition of a catalytic amount of MnCl2 dramatically increased the yield of the product (Scheme 2). We suppose that triarylmanganate species would be formed from 2-lithiobenzofuran and phenyllithium and 1,2-

C

ompared to exocyclic functionalizations of aromatic rings, ring-opening transformations of arenes have rarely been achieved due to their aromatic stabilization. Recently, our group has been interested in “aromatic metamorphosis”, whereby an aromatic compound is converted into another cyclic skeleton through partial disassembly of the starting aromatic ring.1,2 For example, we have accomplished catalytic boron insertion into benzofurans with the aid of nickel−NHC catalysts (Scheme 1A, eq 1).1e Scheme 1. Boron Insertion into Benzofuran

Scheme 2. Phenylative Ring-Opening of Benzofuran

However, this transformation lacks in diversity, and an installable heteroatom is limited to only a boron atom. It is also difficult to synthesize 3-arylbenzoxaborin because of the sterically demanding 2-aryl group of benzofuran (Scheme 1A, eq 2). Therefore, a new methodology for the synthesis of a variety of heterocycles accompanying the insertion of alkyl or aryl groups starting from a common aromatic compound © 2017 American Chemical Society

Received: August 26, 2017 Published: September 29, 2017 5557

DOI: 10.1021/acs.orglett.7b02660 Org. Lett. 2017, 19, 5557−5560

Letter

Organic Letters migration of one of the phenyl groups from the manganese to the adjacent C2 carbon leads to the cleavage of the C2−O bond of benzofuran.3,4 The expected anionic species (Scheme 1B) was indeed generated through the ring-opening. Treatment of the reaction mixture with a mixture of AcOD and D2O afforded the corresponding deuterated 2-hydroxystilbene with 100% deuterium incorporation. MnCl2 was the optimal catalyst and other transition metal salts showed lower catalytic activities (Table S1). We then tried to construct benzoxasilin 2aa via electrophilic trapping of the dianionic species with dichlorodimethylsilane (Scheme 3). However, the phenylative ring-opening followed

Scheme 4. Scope of Silicon Insertion

Scheme 3. Silicon Insertion into 1a

by an addition of 3 equiv of dichlorodimethylsilane furnished benzoxasilin 2aa only in 57% yield. We found that 1 equiv of TMEDA (N,N,N′,N′-tetramethylethylenediamine) significantly improved the efficiency of the electrophilic trapping, and 2aa was isolated in 81% yield. We assume that TMEDA mitigates the association of the dianionic intermediate and thus enhances the reactivity of the intermediate toward the electrophile.9 Next, we explored the scope of silicon insertion with an array of organolithium reagents (Scheme 4).10 Sterically demanding o-tolyl- and mesityllithium afforded the desired oxasilins 2ab and 2ac in 66% and 49% yields, respectively. However, a bulkier isopropyl group disturbed the first ring-opening step, and benzoxasilin 2ad was not obtained. p-Methoxyphenyl and 2-pyridyl moieties endured under the reaction conditions to afford 2ae and 2af. Unfortunately, electron-withdrawing fluorosubstituted aryllithium dramatically lowered the efficiency of the ring-opening process, resulting in the formation of 2ag in 13% yield. Naphthyl-substituted benzoxasilins 2ah and 2ai were obtained in satisfactory yields by means of 2 equiv of TMEDA. Instead of aryllithium reagents, methyl- and butyllithium could be also incorporated into this process to provide the corresponding benzoxasilins 2aj and 2ak, respectively. Silicon insertion into other benzofuran derivatives was then conducted. Electron-rich 5-methoxybenzofuran (1b) underwent the insertion to afford 2ba in moderate yield. Trifluoromethyl and dimethylamino moieties were also compatible with the silicon insertion to afford the corresponding benzoxasilins 2ca−ea. 3-Methylbenzofuran (1f) was reluctant to undergo the first ring-opening probably due to steric hindrance. A higher catalyst loading (20 mol % of MnCl2) overcame this barrier, and oxasilin 2fa was obtained in 55% yield. π-Extended naphthofurans 1g−i were uneventfully converted into the naphthoxasilins 2ga−ia. The present silicon insertion was applicable to gram scale synthesis of benzoxasilin; 1.8 g of benzoxasilin 2aa was obtained from 10 mmol of 1a without any trouble (Scheme 5). Owing to its versatility and scalability, this method would be more useful than the previous oxasilin syntheses which required extremely harsh conditions or complicated procedures.6 Next, we turned our attention to the insertion of other heteroatoms to prove diversity of our protocol (Scheme 6).

a NMR yield. b20 mol % of MnCl2. c−78 to −20 °C for ring-opening process. d2 equiv of TMEDA. eEt2O was used instead of THF.

Scheme 5. Gram-Scale Synthesis of 2aa

After phenylative ring-opening of 1a, addition of 6 equiv of B(OMe)3 provided 3-phenylbenzoxaborin 3aa in 58% yield. This result clearly demonstrates an advantage of the present system since 3-arylbenzoxaborins could not be synthesized by our previous boron insertion (Scheme 1A, eq 2).1e Treatment of the ring-opening dianionic species with dichlorophenylphosphine afforded the corresponding benzoxaphosphin. Because it was gradually oxidized during purification, the phosphorusinserted product was isolated as oxaphosphinoxide 4aa after oxidation with H2O2.11 By employing dimethylgermanium 5558

DOI: 10.1021/acs.orglett.7b02660 Org. Lett. 2017, 19, 5557−5560

Letter

Organic Letters Scheme 6. Diverse Heteroatom Insertion into 1a

a

6 equiv of B(OMe)3. bAfter acidic workup, H2O2 was added to the crude mixture.

dichloride or titanocene dichloride, the corresponding oxagermin 5aa or oxatitin 6aa was obtained. This is the first example of synthesis of oxagermin as well as oxatitin. These compounds are stable enough to be purified by silica gel chromatography under air.12 The UV/vis absorption and fluorescence spectra of 2aa, 4aa, and 5aa (Figure 1) show that the absorption and emission property of these oxaheterocycles could be changed depending on the installed heteroatoms.

Figure 2. Absorption (plain) and fluorescence (dashed) spectra of oxasilins 2aa, 2ga, 2ha, and 2ia in CH2Cl2 (excited at 350 nm for fluorescence measurement).

respectively, while benzoxasilin 2aa does at 389 nm. This heteroatom insertion could provide a diverse range of oxaheterocycles displaying different photophysical properties depending upon both the starting benzofuran motifs and the installed heteroatoms. In conclusion, we have developed diversity-oriented aromatic metamorphosis of benzofurans. The transformation is composed of two sequential reactions in one pot: manganesecatalyzed ring-opening arylation or alkylation with an organolithium reagent and subsequent electrophilic trapping of the resulting dianionic species with multivalent heteroatom electrophiles. This method is applicable to the synthesis of various heterocycles such as oxasilin, oxaborin, oxaphosphin, oxagermin, and oxatitin. This diversity-oriented aromatic metamorphosis would be a powerful tool to create heterocycles and provide a library of attractive heterocycles.13

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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.7b02660. Experimental details, optimization study, characterization data, and NMR spectra (PDF)

Figure 1. Absorption (plain) and fluorescence (dashed) spectra of 2aa, 4aa, and 5aa in CH2Cl2 (excited at 350 nm for fluorescence measurement).

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Figure 2 illustrates the effect of the extended π systems fused to the oxasilin skeleton on photophysical property. Compared with the absorption bands of benzoxasilin 2aa reaching 370 nm, π-extended naphthoxasilins 2ga, 2ha, and 2ia exhibited redshifted absorptions reaching 400 nm. This trend is also the case for their emission spectra: naphthoxasilins 2ga, 2ha, and 2ia show the emission maxima at 427, 433, and 448 nm,

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Hayate Saito: 0000-0002-4549-7917 5559

DOI: 10.1021/acs.orglett.7b02660 Org. Lett. 2017, 19, 5557−5560

Letter

Organic Letters

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Keisuke Nogi: 0000-0001-8478-1227 Hideki Yorimitsu: 0000-0002-0153-1888 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by JSPS KAKENHI Grant Nos. JP16H01019, JP16H04109,and JP16H06887, as well as JST ACT-C Grant Number JPMJCR12ZE, Japan. H.Y. thanks Japan Association for Chemical Innovation, Tokuyama Science Foundation, and The Naito Foundation for financial support.

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DOI: 10.1021/acs.orglett.7b02660 Org. Lett. 2017, 19, 5557−5560