Metal-Free C–O Bond Functionalization: Catalytic Intramolecular and

Letter Cite This: Org. Lett. 2018, 20, 3911−3914

pubs.acs.org/OrgLett

Metal-Free C−O Bond Functionalization: Catalytic Intramolecular and Intermolecular Benzylation of Arenes Luis Bering,†,‡ Kirujan Jeyakumar,‡ and Andrey P. Antonchick*,†,‡ †

Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany ‡ Faculty of Chemistry and Chemical Biology, TU Dortmund, Otto-Hahn-Straße 4a, 44227 Dortmund, Germany

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S Supporting Information *

ABSTRACT: A catalytic, metal-free intramolecular rearrangement of benzyl phenyl ethers using nitrosonium salt as a catalyst is described. The optimized reaction conditions enabled a catalytic and metal-free Friedel−Crafts alkylation reaction with benzylic alcohols, producing water as the stoichiometric byproduct. A comprehensive scope (>50 examples) for both approaches and application in drug synthesis were demonstrated. Mechanistic studies suggest a Lewis acid-based mechanism for the metal-free Friedel−Crafts reaction.

T

he electrophilic activation of hydroxyl groups, as well as the development of Friedel−Crafts reactions on nonactivated systems, have been identified as top priorities in green chemistry research.1 However, the direct employment of alcohols as electrophiles represents a significant challenge.2 C−O bonds are omnipresent in nature and the development of novel chemical methods for transformation of C−O bonds to C−C bonds is highly desired.3 Notably, nickel catalysis has emerged as a powerful tool for C−O bond activation.4 In contrast to organo halides, oxygen-containing compounds, such as alcohols, are inexpensive, readily available, and nontoxic.5 Diarylmethanes are important building blocks for pharmaceuticals, agrochemicals, and materials.6 Cross-coupling methods enable the regioselective synthesis, but it requires additional activating groups on both coupling partners.7 In 1952, Tarbell and Petropoulus reported the transformation of benzyl phenyl ethers using stoichiometric amounts of AlBr3 to a mixture of 2-benzylphenol and phenol (Figure 1A).8 Later, different methods for the synthesis of benzyl phenols have been described, but have proven to be limited to electron-rich substrates and elevated temperatures.9 Friedel−Craft reactions enable the efficient C−C bond formation via functionalization of Csp2−H bonds, but usually require metal-based Lewis acids, harsh reaction conditions, or lead to the undesired production of halohydric acid as a byproduct.10 Recently, different strategies for the metalfree synthesis of diarylmethanes have been reported (Figure 1B). Bode and co-workers demonstrated the arylation of benzyl hydroxamates mediated by an excess of BF3·OEt2.11 Later, the application of alkyl phosphates was reported.12 Paquin and coworkers developed the Friedel−Crafts alkylation with benzyl fluorides via the in situ generation of HF.13 Stephan’s group disclosed the activation of benzyl fluorides in the presence of electrophilic organofluorides and stoichiometric amounts of reductant.14 However, benzyl fluorides must be generated from the corresponding alcohols using stoichiometric amounts of fluorination reagent.15 Hall and co-workers explored © 2018 American Chemical Society

Figure 1. Synthesis of diarylmethanes.

the application of electron-deficient boronic acids16 and, later, Moran’s group demonstrated the super Brønsted acid-catalyzed dehydrative Friedel−Crafts reaction of deactivated benzylic alcohols.17 Nitrosonium salts were employed by us and others in oxidative coupling, π-bond activation, and oxygenation.18 Notably, nitrosonium salts are inexpensive, stable, and nontoxic.19 Reactive nitrogen−oxygen species are present in living cells and play an important role in oxidative-stress response and Received: May 11, 2018 Published: June 14, 2018 3911

DOI: 10.1021/acs.orglett.8b01495 Org. Lett. 2018, 20, 3911−3914

Letter

Organic Letters as cell-signaling molecules.20 At present, the application in C−O bond activation is limited to protecting group removal.21 Because of our ongoing interest in metal-free reaction methodologies,22 we aimed to target the catalytic functionalization of C−O bonds using nitrosonium salts. Herein, we report the metal-free intramolecular rearrangement of benzyl phenyl ethers using low loading of catalyst, which enabled a intermolecular and catalytic synthesis of various diarylmethanes from alcohols and arenes, producing water as the stoichiometric byproduct (Figure 1C). We began our investigation by selecting benzyl phenyl ether 1a as a model substrate to avoid the restriction to electron-rich starting materials. Multiparameter optimization for the rearrangement to benzyl phenol 2a was performed (see Tables S1− S5 in the Supporting Information). Under the optimized conditions, the rearranged product 2a was isolated in 84% yield, with an ortho:para selectivity of 6:1 and short reaction times while using only 0.5 mol % of nitrosonium tetrafluoroborate as catalyst in 2:1 dichloromethane/hexafluoro-isopropanol (Scheme 1). A notable feature of the developed reaction is

Scheme 2. Catalytic Rearrangement of Benzyl Ethers under Optimized Reaction Conditionsa

Scheme 1. Catalytic Rearrangement of Benzyl Ethers under Optimized Reaction Conditionsa

Reaction conditions: 1a (1 mmol, 1 equiv), NOBF4 (5 μmol, 0.5 mol %), 2:1 DCM/HFIP (10 mL, 0.1 M). Yield is given for the isolated product after column chromatography. o:p ratio according to GC-MSFID. Asterisk (*) denotes minor regioisomer. DCM = dichloromethane, HFIP = hexafluoroisopropanol. See the Supporting Information (SI) for details. a

a Reaction conditions: 1 (0.5 mmol, 1 equiv), NOBF4 (2.5 μmol, 0.5 mol %), 2:1 DCM/HFIP (5 mL, 0.1 M). Yields are given for isolated products after column chromatography. The abbreviation “rr” represents the regioisomer ratio, according to GC-MS-FID. Asterisk (*) denotes minor regioisomer.

deactivating groups were well-tolerated, yielding products 2u and 2v in high yields and selectivity. Finally, we also explored the rearrangement of allylic groups. Geranylated products 2x and 2y were isolated as single isomers, albeit in reduced yields. After studying the scope of the catalytic rearrangement of benzyl phenyl ethers, we aimed to develop an intermolecular variant based on the developed reaction conditions. To our delight, the direct employment of benzylic alcohols was found to be suitable for the intermolecular Friedel−Crafts reaction using a low loading of nitrosonium tetrafluoroborate (see Scheme 3). Synthesis of diarylmethane (5a) was achieved in good yield using benzene as a nucleophile and producing water as the stoichiometric byproduct. We began to explore the scope of the catalytic Friedel−Crafts reaction by testing secondary and tertiary benzylic alcohols. Products 5b−5d were isolated in high yields and with short reaction times. Electron-neutral and deactivated diarylmethanes were successfully synthesized in good yields, demonstrating no restriction to electron-rich starting materials (5e−5i). Even polyhalogenated arenes (5j) and benzylic alcohols (5k) yielded the desired products. The combination of two electron-rich coupling partners yielded products 5l−5o in high yield and selectivity. Notably, this intermolecular reaction leads to predominant formation of para-substituted products, while the earlier demonstrated intramolecular transformation gave ortho-substituted products. Furthermore, a set of diarylmethanes was successfully synthesized using polysubstituted arenes as a coupling partner (5p−5u). Arylation of dibenzylic alcohols was also demonstrated and yielded diarylated products with good yield (5v, 5w).

the predominant formation of ortho-substituted product, while intermolecular Friedel−Crafts alkylation of phenol usually gives para-isomers. With the optimized conditions in hand, we began to explore the scope of the catalytic rearrangement for various benzyl phenyl ethers (see Scheme 2). Using benzyl phenols substituted at the 4-position of phenols, the desired products were isolated in high yields with short reaction times and good to excellent regioselectivity (2b−2e). The presence of methoxy groups on 3or 4-position of the phenol part yielded the benzyl phenols in high yields, but as mixtures of regioisomers, which could be separated in a straightforward manner (2f, 2g). A set of polysubstituted phenols was employed, allowing the synthesis of complex products with high selectivity and yield (2h−2j). Substituted naphthols were successfully employed, yielding the products 2k and 2l in good yield and excellent regioselectivity. The rearrangement of ethers bearing substituents on the benzyl moiety was successfully demonstrated. Functional groups with electron-donating and electron-withdrawing effects were well tolerated, yielding the desired products in high yields with predominant formation of ortho-isomers (2m−2q). Substrates with highly electron-withdrawing groups did not yield the desired products. Furthermore, products 2r and 2s demonstrate the compatibility of secondary benzyl groups, even with a terminal double bond. Interestingly, the para regioisomer was isolated as a major product. Next, a set of polysubstituted starting materials were tested, bearing functional groups on the phenol and benzyl moiety (2t−2v). It is noteworthy that even 3912

DOI: 10.1021/acs.orglett.8b01495 Org. Lett. 2018, 20, 3911−3914

Letter

Organic Letters Scheme 3. Scope of the Catalytic Intermolecular Friedel− Crafts Alkylationa

Scheme 4. Metal-Free Drug Synthesis Using the Developed Reaction Conditions

synthesized using stoichiometric amounts of aluminum chloride.23 Next, we studied the mechanism for the intermolecular Friedel−Crafts alkylation reaction (see Table S7 in the Supporting Information). Oxidation of reactive nitrogen− oxygen species appeared to be unlikely, because of the inefficient performance of nitric acid. NOCl as catalyst yielded the desired product unaffectedly, which supports a Lewis acid-based mechanism. Notably, when hydrochloric acid or nitric acid were used respectively, only small amounts of product were isolated. The presence of the nitrosonium ion in solution appeared to be crucial for the reaction. Furthermore, the reaction was not affected by the radical trap BHT (Scheme S1 in the Supporting Information). The formation of a benzylic cation appeared to be reasonable, since racemization was observed upon functionalization of enantiopure starting material (see Scheme S2 in the Supporting Information). The proposed course of reaction is outlined in Figure 2. Nitrosonium

a

Reaction conditions: 3 (0.2 mmol, 1 equiv), 4 (2.5 equiv or 10 equiv) NOBF4 (10 μmol, 5 mol %), 1:1 DCE/HFIP (2 mL, 0.1 M). Yields are given for isolated products after column chromatography. The abbreviation “rr” represents the regioisomer ratio, according to 1 H NMR. Asterisk (*) denotes minor regioisomer. Abbreviations: Mes = mesityl; Naph = 1-naphthyl.

Figure 2. Proposed reaction mechanism for the intermolecular Friedel−Crafts alkylation reaction.

tetrafluoroborate activates the benzylic alcohol by generating intermediate A. The formation of intermediate B is followed by intermolecular SEAr with the arene nucleophile. The released NO+ species are scavenged by HBF4 to generate water and to maintain the catalytic cycle. We also compared the developed system for the Friedel−Crafts alkylation reaction with other acid catalysts, including triflic acid and HBF4. However, no acid was able to outperform nitrosonium tetrafluoroborate (see Table S6 in the Supporting Information). In summary, we have developed a catalytic and metal-free intramolecular rearrangement of benzyl phenyl ethers using low loading of nitrosonium tetrafluoroborate as a catalyst under mild conditions. A broad substrate scope was demonstrated revealing good functional group tolerance, predictable selectivity, and short reaction times. Furthermore, the developed reaction conditions were converted to the catalytic and metal-free Friedel−Crafts alkylation for the synthesis of various diaryl-

Afterward, we moved our attention to the coupling of complex starting materials embedding heterocycles. Functionalization of indoles was successfully achieved in good to excellent yield (5x− 5z). Impressively, synthesis of oxindole 5aa with a quaternary carbon proceeded with perfect yield and regioselectivity, using anisole and 3-hydroxy-2-oxindole derivative as coupling partners. Incorporation of heterocyclic moieties such as benzothiophene, chromone, and furan was achieved in good to excellent yield (5ab−5ad). In addition, we targeted the functionalization of natural products. Product 5ae was synthesized regioselectively in 92% yield by means of latestage functionalization of unprotected estrone. To further prove the utility of the developed reaction conditions, we targeted the metal-free synthesis of drugs (see Scheme 4). Phenprocoumon (5af) and Nafenopin (5ag) were synthesized in satisfying yields as single regioisomers. Notably, Nafeonpin is commonly 3913

DOI: 10.1021/acs.orglett.8b01495 Org. Lett. 2018, 20, 3911−3914

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Organic Letters

Higuchi, T.; Murakata, M.; Kobayashi, T.; Morikawa, K.; Shimma, N.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. Bioorg. Med. Chem. 2011, 19, 5334−5341. (d) Mondal, S.; Panda, G. RSC Adv. 2014, 4, 28317−28358. (7) (a) Endo, K.; Ishioka, T.; Ohkubo, T.; Shibata, T. J. Org. Chem. 2012, 77, 7223−7231. (b) Roscales, S.; Csaky, A. G. Chem. Soc. Rev. 2014, 43, 8215−8225. (c) Nambo, M.; Crudden, C. M. ACS Catal. 2015, 5, 4734−4742. (d) Lima, F.; Kabeshov, M. A.; Tran, D. N.; Battilocchio, C.; Sedelmeier, J.; Sedelmeier, G.; Schenkel, B.; Ley, S. V. Angew. Chem., Int. Ed. 2016, 55, 14085−14089. (e) He, Z.; Song, F.; Sun, H.; Huang, Y. J. Am. Chem. Soc. 2018, 140, 2693. (8) Tarbell, D. S.; Petropoulos, J. C. J. Am. Chem. Soc. 1952, 74, 244− 248. (9) (a) Bhure, M. H.; Rode, C. V.; Chikate, R. C.; Patwardhan, N.; Patil, S. Catal. Commun. 2007, 8, 139−144. (b) Zhou, L.; Wang, W.; Zuo, L.; Yao, S.; Wang, W.; Duan, W. Tetrahedron Lett. 2008, 49, 4876− 4878. (c) Luzzio, F. A.; Chen, J. J. Org. Chem. 2009, 74, 5629−5632. (d) Sagrera, G.; Seoane, G. Synthesis 2009, 24, 4190−4202. (e) Kraus, G. A.; Chaudhary, D. Tetrahedron Lett. 2012, 53, 7072−7074. (f) Veenboer, R. M. P.; Nolan, S. P. Green Chem. 2015, 17, 3819−3825. (10) (a) Friedel, C.; Crafts, J. M. J. Chem. Soc. 1877, 32, 725−791. (b) Mertins, K.; Iovel, I.; Kischel, J.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 238−242. (c) Rueping, M.; Nachtsheim, B. J. Beilstein J. Org. Chem. 2010, 6, 6−29. (11) Schäfer, G.; Bode, J. W. Angew. Chem., Int. Ed. 2011, 50, 10913− 10916. (12) Pallikonda, G.; Chakravarty, M. J. Org. Chem. 2016, 81, 2135− 2142. (13) Champagne, P. A.; Benhassine, Y.; Desroches, J.; Paquin, J.-F. Angew. Chem., Int. Ed. 2014, 53, 13835−13839. (14) Zhu, J.; Pérez, M.; Stephan, D. W. Angew. Chem., Int. Ed. 2016, 55, 8448−8451. (15) Desroches, J.; Champagne, P. A.; Benhassine, Y.; Paquin, J.-F. Org. Biomol. Chem. 2015, 13, 2243−2246. (16) (a) Ricardo, C. L.; Mo, X.; McCubbin, J. A.; Hall, D. G. Chem. Eur. J. 2015, 21, 4218−4223. (b) Mo, X.; Yakiwchuk, J.; Dansereau, J.; McCubbin, J. A.; Hall, D. G. J. Am. Chem. Soc. 2015, 137, 9694−9703. (17) Vuković, V. D.; Richmond, E.; Wolf, E.; Moran, J. Angew. Chem., Int. Ed. 2017, 56, 3085−3089. (18) (a) Panek, J. S.; Beresis, R. T. J. Am. Chem. Soc. 1993, 115, 7898− 7899. (b) Olah, G. A.; Ramaiah, P. J. Org. Chem. 1993, 58, 4639−4641. (c) Wu, G. L.; Wu, L. M. Chin. Chem. Lett. 2008, 19, 55−58. (d) Khenkin, A. M.; Neumann, R. J. Am. Chem. Soc. 2008, 130, 11876− 11877. (e) Su, B.; Li, L.; Hu, Y.; Liu, Y.; Wang, Q. Adv. Synth. Catal. 2012, 354, 383−387. (f) Morse, P. D.; Jamison, T. F. Angew. Chem., Int. Ed. 2017, 56, 13999−14002. (g) Bering, L.; Paulussen, F. M.; Antonchick, A. P. Org. Lett. 2018, 20, 1978−1981. (h) Borodkin, G. I.; Shubin, V. G. Russ. Chem. Rev. 2017, 86, 18−46. (19) Olah, G. A.; Sury Prakash, G. K.; Wang, Q.; Li, X.-y. Nitrosonium Tetrafluoroborate. In Encyclopedia of Reagents for Organic Synthesis; John Wiley & Sons: Hoboken, NJ, 2001. (20) (a) Patel, R. P.; McAndrew, J.; Sellak, H.; White, C. R.; Jo, H.; Freeman, B. A.; Darley-Usmar, V. M. Biochim. Biophys. Acta, Bioenerg. 1999, 1411, 385−400. (b) Weidinger, A.; Kozlov, A. Biomolecules 2015, 5, 472. (21) (a) Ho, T.-L.; Olah, G. A. J. Org. Chem. 1977, 42, 3097−3098. (b) Bach, R. D.; Holubka, J. W.; Taaffee, T. A. J. Org. Chem. 1979, 44, 1739−1740. (c) Wang, J.; Wu, W.; Xu, Y.; Wu, L. Chin. Sci. Bull. 2010, 55, 2803−2806. (22) (a) Bering, L.; Antonchick, A. P. Org. Lett. 2015, 17, 3134−3137. (b) Bering, L.; Antonchick, A. P. Chem. Sci. 2017, 8, 452−457. (c) Bering, L.; Manna, S.; Antonchick, A. P. Chem. - Eur. J. 2017, 23, 10936−10946. (23) (a) Bencze, W. L.; Kisis, B.; Puckett, R. T.; Finch, N. Tetrahedron 1970, 26, 5407−5414. (b) Bencze, W. L. (Ciba-Geigy Corporation). U.S. Patent No. 3708589A, 1973.

methanes, using benzylic alcohols. A comprehensive scope was demonstrated, covering electron-deficient coupling partners up to complex products, including natural products and drugs. The synthesis of the target ortho- or para-isomers can be achieved by performing transformation in intramolecular or intermolecular fashion. The application of nitrosonium salts as efficient, inexpensive, and general catalysts represents an unprecedented and advanced entry into metal-free Friedel−Crafts chemistry.

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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.8b01495. General experimental procedures, detailed optimization studies, details on control experiments, mechanistic studies, and biological methods and characterization of starting materials and products (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Andrey P. Antonchick: 0000-0003-0435-9443 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.P.A. acknowledges the support of DFG (Heisenberg Scholarship No. AN 1064/4-1) and the Boehringer Ingelheim Foundation (Plus 3). L.B. is supported by the Verband der Chemischen Industrie e.V.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b01495 Org. Lett. 2018, 20, 3911−3914