Reductive C–O, C–N, and C–S Cleavage by a Zirconium Catalyzed

Letter pubs.acs.org/OrgLett

Cite This: Org. Lett. XXXX, XXX, XXX−XXX

Reductive C−O, C−N, and C−S Cleavage by a Zirconium Catalyzed Hydrometalation/β-Elimination Approach Christof Matt, Frederic Kölblin, and Jan Streuff* Albert-Ludwigs-Universität Freiburg, Institut für Organische Chemie, Albertstr. 21, 79104 Freiburg, Germany

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S Supporting Information *

ABSTRACT: A zirconium catalyzed reductive cleavage of Csp3 and Csp2 carbon− heteroatom bonds is reported that makes use of a tethered alkene functionality as a traceless directing group. The reaction is successfully demonstrated on C−O, C−N, and C−S bonds and proposed to proceed via a hydrozirconation/β-heteroatom elimination sequence of an in situ formed zirconium hydride catalyst. The positional isomerization of the catalyst further enables the cleavage of homoallylic ethers and the removal of terminal allyl and propargyl groups.

T

reduced to an alkyl group, rendering the overall process a controlled reductive defunctionalization with an alkene as a traceless directing group. The capability of the zirconocene hydride catalyst, formed in situ from zirconocene dichloride and a hydride reductant, to undergo a positional isomerization (“Zr-walk”)10 enables the cleavage of allylic and homoallylic bonds. The individual steps of hydrozirconation, Zr-walk, and β-heteroatom elimination have previously been explored under stoichiometric conditions with Schwartz reagent [Cp2ZrHCl (1)],11,12 or Negishi reagent [Cp2Zr·(η2-1-butene) (2)].13,14 But only few catalytic reactions with 1 have been reported, comprising olefin hydroaluminations, radical cyclizations, and the cleavage of polybutadiene.15 This work now shows the combination of all three steps in a single catalytic sequence. The reaction was initially developed using readily available (Z)-1,4-diphenoxybut-2-ene (3a) as substrate, zirconocene dichloride (5 mol %) as catalyst precursor (Table 1), and 2methyl tetrahydrofuran (2-MeTHF) as solvent.16 Based on the earlier reports for the in situ generation of 1,17 aluminumbased reducing agents were tested for the generation of the active zirconium hydride catalyst and for achieving turnover. It was found that inexpensive LiAlH4 was a suitable terminal reductant and superior to other aluminum hydride reagents such as Red-Al, LiAlH(Ot-Bu)3, or DIBAL-H. Silane reducing agents gave no conversion. With LiAlH4, only trace amounts of cleavage products were observed at 23 °C, but raising the temperature to 70 °C gave 39% of the desired butyl phenyl ether 4a and 12% of alkenyl ether 5 after 20 h of reaction time (entry 1). Given that earlier attempts to achieve Cp2ZrCl2catalyzed hydroaluminations with an aluminum hydride reagent (DIBAL-H) had been unsuccessful, this was already an interesting result.15c It further showed that the β-oxygenelimination was faster than a direct transmetalation to aluminum, which otherwise would have produced 1,4-

he direct homogeneous-catalyzed scission of C−O, C−N, and C−S (herein: C−X) single bonds offers new strategies for organic synthesis and the conversion of renewable feedstocks into base chemicals.1−3 However, the catalytic cleavage of C−O and C−N bonds is particularly challenging if no activating groups are present.4,5 The activation of aliphatic C−X bonds (Scheme 1a) can be Scheme 1. Selected Concepts for the Catalytic Activation of Aliphatic Carbon−Heteroatom Bonds

facilitated by using strained substrates, a strategy that has been applied to numerous openings of small heterocycles by either oxidative addition or single-electron-transfer (SET).6 Other alternatives are given by the use of strong Brønsted and Lewis acid catalysts,7 or β-elimination reactions that are well-known to occur under palladium or rhodium catalysis. 8 In combination with a palladium-catalyzed C−H activation directed by an auxiliary group, such β-eliminations can be used to cleave remote C−X bonds, for example (Scheme 1b).9 We herein report a complementary approach to the cleavage of aliphatic and olefinic C−X bonds that is based on a catalytic hydrozirconation/β-heteroatom-elimination sequence (Scheme 1c). In the same process, the resulting olefin gets © XXXX American Chemical Society

Received: July 23, 2019

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DOI: 10.1021/acs.orglett.9b02572 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Selected Screening Experiments

Table 2. Application to the Reductive Removal of Ether Functions

entry

catalyst (mol %)

additive (equiv)

yield (4a)/%

1 2 3 4 5 6 7

Cp2ZrCl2 (5) Cp2ZrCl2 (5) Cp2ZrCl2 (5) Cp2ZrCl2 (5) Cp2ZrCl2 (1) none Cp2TiCl2 (5)

none TMSCl (2.0) NMP (1.5) NMP (0.5) NMP (0.5) NMP (0.5) NMP (0.5)

39a (5: 12) 35a (PhOH: 99) 85 93 90b 0 48c

a

NMR yield determined with 1,3-benzodioxole as internal standard. 72 h reaction time. cBenzene and other decomposition products were observed by GC analysis of the crude reaction mixture. b

diphenoxybutane as the product. In the following screening experiments, it was found that the addition of AlCl3 or TMSCl, both of which led to the in situ formation of AlH3, were unsuitable (entry 2). Premature C−O cleavage and other decomposition reactions took place, resulting in a quantitative formation of phenol, but only 35% of 4a. The addition of 1.5 equiv of N-methylpyrrolidine (NMP), on the other hand, gave 4a in 85% yield (entry 3). Although it was previously reported that NMP and LiAlH4 in ethereal solvents lead to the isolable, nonpyrophoric adduct LiAlH4·NMP, the role of NMP remained to be clarified.18,19 Nevertheless, this reagent combination improved the chemoselectivity while maintaining the required reactivity and a further optimization showed that 0.5 equiv of NMP was ideal, giving 93% of 4a (entry 4). Even with only 1 mol % of Cp2ZrCl2, the cleavage product was isolated in 90% yield after a reaction time of 72 h (entry 5). Importantly, 4a was not formed in the absence of the catalyst (entry 6). A reaction with Cp2TiCl2 led to significant amounts of benzene and other undesired products, diminishing the yield to 48% (entry 7).20,21 Using 3a, it was then demonstrated that the reaction could be scaled to 1.0 and 5.0 mmol with no decline in yield (93% and 91%, respectively, Table 2). Afterward, the reductive C−O cleavage was applied to a number of other bis-oxygenated internal alkenes. Bis-benzylether 3b was selectively monodeoxygentated in an almost quantitative yield (97%). Importantly, the bis-homoallylic ether 3c also underwent the reductive mono cleavage in 20% yield, which could be improved to 59% yield with 20 mol % of (Cp*)2ZrCl2 as catalyst and a 48 h reaction time. This was a unique example of a chain-walk of a zirconocene hydride under substoichiometric conditions. The reaction also worked smoothly with Econfigured alkenyl bis-para-methoxyphenyl ether 3d (78%). Cinnamyl ether 3e was a particularly difficult substrate, since βsubstituted styrenes favor a benzylic positioning of the zirconium.22 Still, the cleavage took place in 55% yield, giving a mixture of propylarene 4e and unsaturated products 6 and 7. Attempts to improve the ratio of saturated and unsaturated compounds by increasing the amount of LiAlH4/NMP or extending the reaction time were unsuccessful. An arylconjugated enol ether 3f could be deoxygenated as well, forming 2-ethylnaphthalene (4f) and traces of 2-vinylnaphthalene (8) in 55% combined yield.

a

Reaction on a 1.0 mmol scale. bReaction on a 5.0 mmol scale. c20 mol % (Cp*)2ZrCl2, 48 h. d1-Methoxy-4-propylbenzene (4e), 4-allyl1-methoxybenzene (6), and 4-methoxy-β-styrene (7) in a 1.6:2.0:1.0 ratio. e2-Ethylnaphthalene (4f) and 2-vinylnaphthalene (8) in a 20:1 ratio.

Next, the liberation of alcohols from vinyl, allyl, and prenyl ethers by the zirconium catalyzed C−O cleavage was explored (Table 3). The conditions of workup and purification were very carefully optimized to exclude any background cleavage due to hydrolysis: the reactions were quenched with acetone or ethyl acetate followed by an extraction with a Rochelle salt solution. Flash chromatography was carried out with triethyl amine as a solvent additive. Each substrate was independently tested and found to be stable under these conditions. The aryl vinyl ethers 9a−d and the cyclooctyl vinyl ether 9e were readily cleaved within only 4 h in 60−99% yield. Importantly, fluorinated and chlorinated aromatics (9c,d) were tolerated and only with longer reaction times dechlorination became observable. A double vinyl ether derived from hexane-1,6-diol (9f) and a cyclic enol ether (9g) were cleaved in 67% and 61% yield, respectively. Remarkably, the bis-vinylether 9f selectively gave the monodeprotected product 10f. The formation of a precipitate indicated that a low-soluble aluminum alkoxylate of 10f was produced, which then did not undergo the second devinylation. The reaction was further suitable for the cleavage of acetophenone-derived enol ethers as demonstrated on the reaction of 9h (66%). 2-Naphtyl allyl ether (9i), on the other hand, was a challenging substrate, since the intrinsic regioselectivity of the hydrozirconation favored a terminal positioning of the zirconium catalyst. The Zr-isomerization to B

DOI: 10.1021/acs.orglett.9b02572 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

A further extension of the method toward even more challenging C−O bond scissions and the cleavage of C−N and C−S bonds was investigated (Scheme 2). To our delight, a

Table 3. Application to the Devinylation, Deallylation, and Deprenylation of Ethers

Scheme 2. Cleavage of an Aromatic C−O Bond as well as Allylic, Vinylic, and Propargylic C−N and C−S Bonds

smooth cleavage of the aromatic C−O bond of benzofuran (13) took place under the standard conditions with 10 mol % catalyst, resulting in the formation of 2-ethylphenol (14) and 2-vinylphenol (15) in a 12:1 ratio and 60% combined yield. Within the topical area of homogeneous catalyzed benzofuran openings,23,24 this catalysis marked an unusual example of a reductive C2−O scission. Dihydropyrrole 16, which had previously been opened in a reaction with stoichiometric amounts of 1,11b also underwent a clean transformation into the saturated amine 17 as the major product and the unsaturated amine 18 as the minor product (5.4:1 ratio, 85% combined yield). The C−S cleavage was then first carried out on 2-naphthyl vinyl thioether 19, and an NMR analysis of the crude reaction mixture showed very good conversion to 2thionaphthol. Since an autoxidation of the thiol to disulfide 20 could not be completely suppressed, the crude mixture was treated with iodine to enforce the formation 20, which was afterward crystallized and quantified (71% yield). Finally, the depropargylation of thioether 21 was achieved in an analogous fashion and disulfide 20 was obtained in 84% yield. Again, this required a positional isomerization of the zirconium catalyst from the usually favored terminal to an internal position to trigger the β-S-elimination. Whether allene was formed in the depropargylation of 21 still remained to be investigated. For all of these transformations, it was confirmed that no background reaction took place. A simplified catalytic cycle is proposed for the example of the C−O cleavage reaction (Scheme 3). The reduction of Cp2ZrCl2 by LiAlH4/NMP leads to a zirconium hydride complex, which then undergoes a hydrozirconation of the alkene-containing substrate. Due to the reversibility of this step, a positional isomerization of the zirconium catalyst may occur. Once a vicinal position of zirconium and oxygen is reached, a β-oxygen elimination follows, releasing an olefin and a zirconium−alcoholate complex. The catalyst is regenerated by a hydride−OR′ (or −Y) exchange with the aluminum

a

3.0 equiv of LiAlH4, 1.0 equiv of NMP. bNaphthyl propyl ether (11, 47%) and 1-propyl-2-naphthol (12, 5%) were isolated as well. c10 mol % Cp2ZrCl2.

the adjacent carbon, triggering the β-elimination, would have to compete with a direct transmetalation to aluminum. Furthermore, a Claisen rearrangement could take place at the reaction temperature of 70 °C. Still, 2-naphthol was isolated in 31% yield. As expected, naphthyl propyl ether (11, 47%) and 1-propyl-2-naphthol (12, 5%) were received as byproducts. Finally, a sterically demanding prenyl ether (9j) underwent the C−O cleavage as well, giving arylethanol 10h in 39% yield, albeit at a catalyst loading of 10 mol %. C

DOI: 10.1021/acs.orglett.9b02572 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Notes

Scheme 3. Proposed Catalytic Cycle for the C−Heteroatom Cleavage

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The Deutsche Forschungsgemeinschaft (DFG) is acknowledged for financial support−project 408295365 (Heisenberg position to J.S.).

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reductant. The olefin product then gets further reduced under the reaction conditions, presumably via a catalyzed hydroalumination.15c Workup then provides the alkane and H−OR′ as the products of the reaction. The result is the defunctionalization of both groups, the alkene, and the C− OR′ function. Regarding the nature of the zirconium hydride intermediate, the remaining ligand Y could in principle be either a hydride, a chloride, or the alcoholate. Given that reductions with overstoichiometric amounts of aluminum hydride reagents usually lead to the corresponding dihydride complex, Cp2ZrH2, or zirconium hydride aluminum hydride adducts, such species could indeed be present after the reaction initiation.12,17a,25 However, a ligand scrambling at the zirconium center may take place in the course of the catalysis and detailed mechanistic studies will be required to further elucidate the exact nature of the intermediates. In conclusion, a catalytic hydrozirconation/β-elimination reaction for the reductive cleavage of C−heteroatom bonds has been developed. It has been applied to the scission of ethers, amines, and thioethers of alkenes and other unsaturated molecules. Furthermore, the selective monocleavage of bisethers and the positional isomerization of the catalyst have been demonstrated. Studies toward an improved catalyst chain walk and to investigate the reaction mechanism are ongoing and will be reported in due course. In the future, this hydrozirconation/β-elimination catalysis may find application in the activation of other nonactivated bonds.

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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.9b02572. Detailed experimental procedures, characterization data, and NMR spectra (PDF)

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*E-mail: jan.streuff@ocbc.uni-freiburg.de. ORCID

Jan Streuff: 0000-0002-8320-4353 D

DOI: 10.1021/acs.orglett.9b02572 Org. Lett. XXXX, XXX, XXX−XXX

Letter

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8115−8116. (d) Kautzner, B.; Wailes, P. C.; Weigold, H. Hydrides of Bis(cyclopentadienyl)zirconium. J. Chem. Soc. D 1969, 1105. (13) Selected references: (a) Masarwa, A.; Didier, D.; Zabrodski, T.; Schinkel, M.; Ackermann, L.; Marek, I. Merging allylic carbon− hydrogen and selective carbon−carbon bond activation. Nature 2014, 505, 199−203. (b) Liard, A.; Marek, I. Stereoselective Preparation of E Vinyl Zirconium Derivatives from E or Z Enol Ethers. J. Org. Chem. 2000, 65, 7218−7220. (c) Negishi, E.-i.; Takahashi, T. Patterns of Stoichiometric and Catalytic Reactions of Organozirconium and Related Complexes of Synthetic Interest. Acc. Chem. Res. 1994, 27, 124−130. (d) Takahashi, T.; Suzuki, N.; Kageyama, M.; Kondakov, D. Y.; Hara, R. Allylzirconation of alkynes by the reactions of zirconocene-alkyne complexes with allylic ethers. Tetrahedron Lett. 1993, 34, 4811−4814. (e) Rousset, C. J.; Swanson, D. R.; Lamaty, F.; Negishi, E.-i. Zirconocene-promoted stereoselective bicyclization of 1,6- and 1,7-dienes to produce trans-zirconabicyclo[3.3.0]octanes and cis-zirconabicyclo[4.3.0]nonanes. Tetrahedron Lett. 1989, 30, 5105− 5108. (14) One should note that Zr-catalyzed carbomagnesation reactions with 2 involving a β-heteroatom elimination have been reported. Depending on the substrate, a β-heteroatom elimination from an organozirconium or an organomagnesium intermediate was proposed. See: (a) Didiuk, M. T.; Johannes, C. W.; Morken, J. P.; Hoveyda, A. H. Enantio-, Diastereo-, and Regioselective Zirconium-Catalyzed Carbomagnesiation of Cyclic Ethers with Higher Alkyls of Magnesium. Utility in Synthesis and Mechanistic Implications. J. Am. Chem. Soc. 1995, 117, 7097−7104. (b) Suzuki, N.; Kondakov, D. Y.; Takahashi, T. Zirconium-catalyzed highly regioselective carboncarbon bond formation reactions. J. Am. Chem. Soc. 1993, 115, 8485− 8486. (c) Morken, J. P.; Didiuk, M. T.; Hoveyda, A. H. Zirconiumcatalyzed asymmetric carbomagnesation. J. Am. Chem. Soc. 1993, 115, 6997−6998. (15) (a) Zheng, J.; Lin, Y.; Liu, F.; Tan, H.; Wang, Y.; Tang, T. Controlled Chain-Scission of Polybutadiene by the Schwartz Hydrozirconation. Chem. - Eur. J. 2013, 19, 541−548. (b) Fujita, K.; Nakamura, T.; Yorimitsu, H.; Oshima, K. Triethylborane-Induced Radical Reaction with Schwartz Reagent. J. Am. Chem. Soc. 2001, 123, 3137−3138. (c) Negishi, E.-i.; Yoshida, T. A novel zirconiumcatalyzed hydroalumination of olefins. Tetrahedron Lett. 1980, 21, 1501−1504. (16) 2-MeTHF was chosen to avoid undesired THF-opening. See: Bailey, W. J.; Marktscheffel, F. Cleavage of Tetrahydrofuran during Reductions with Lithium Aluminum Hydride. J. Org. Chem. 1960, 25, 1797−1800. (17) For precedence of the in situ generation of 1, see: (a) Zhao, Y.; Snieckus, V. A Practical in situ Generation of the Schwartz Reagent. Reduction of Tertiary Amides to Aldehydes and Hydrozirconation. Org. Lett. 2014, 16, 390−393. (b) Zhao, Y.; Snieckus, V. A. Schwartz reagents: methods of in situ generation and use. United States Patent, US 8,168,833 B2, 2012. (c) Huang, Z.; Negishi, E.-i. A Convenient and genuine Equivalent to HZrCp2Cl Generated in Situ from ZrCp2Cl2−DIBAL-H. Org. Lett. 2006, 8, 3675−3678. (18) (a) Fuller, J. C.; Stangeland, E. L.; Jackson, T. C.; Singaram, B. Lithium aluminum hydride-N-methylpyrrolidine complex. 1. Synthesis and Reactivity of Lithium Aluminum Hydride-N-Methylpyrrolidine Complex. An Air and Thermally Stable Reducing Agent Derived from Lithium Aluminum Hydride. Tetrahedron Lett. 1994, 35, 1515−1518. See also: (b) Marlett, E. M.; Park, W. S. Dimethylamine alane and N-Methylpyrrolidine-Alane. A Convenient Synthesis of Alane, a Useful Selective Reducing Agent in Organic Synthesis. J. Org. Chem. 1990, 55, 2968−2969. (c) Ehrlich, R.; Rice, G. The Chemistry of Alane. XII. The Lithium Tetrahydroalanate− Triethylamine Complex. Inorg. Chem. 1966, 5, 1284−1286. (19) Attempts to prepare and isolate LiAlH4·NMP according to the literature procedure (ref 18a) were unsuccessful. Instead, literatureknown AlH3·2NMP was observed by NMR together with a second aluminum species. See the Supporting Information for details. (20) A Cp2TiCl2/LiAlH4 catalyzed C−O cleavage of allylic ethers and other oxygenated molecules had been reported earlier, but it was E

DOI: 10.1021/acs.orglett.9b02572 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters concluded to follow a conceptually different single-electron-transfer radical mechanism. See: Sato, F.; Tomuro, Y.; Ishikawa, H.; Oikawa, T.; Sato, M. Dealuminoxylation of Aluminum Allyl or Benzyl Alkoxides and Deoxygenation of Allyl Ethers by Lithium Aluminum Hydride in the Presence of Titanium Catalyst. Chem. Lett. 1980, 9, 103−106. (21) The active species formed from Cp2TiIVCl2 and LiAlH4 is Cp2TiIIICl and not Cp2TiIV(H)Cl. See: Gordon, J.; Hildebrandt, S.; Dewese, K. R.; Klare, S.; Gansäuer, A.; RajanBabu, T. V.; Nugent, W. A. Demystifying Cp2Ti(H)Cl and Its Enigmatic Role in the Reactions of Epoxides with Cp2TiCl. Organometallics 2018, 37, 4801−4809. (22) Gibson, T. Hydrozirconation of aromatic olefins. Organometallics 1987, 6, 918−922. (23) For examples, see: (a) Xu-Xu, Q.-F.; Liu, Q.-Q.; Zhang, X.; You, S.-L. Copper-Catalyzed Ring Opening of Benzofurans and an Enantioselective Hydroamination Cascade. Angew. Chem., Int. Ed. 2018, 57, 15204−15208. (b) Saito, H.; Nogi, K.; Yorimitsu, H. Copper-Catalyzed Ring-Opening Silylation of Benzofurans with Disilane. Angew. Chem., Int. Ed. 2018, 57, 11030−11034. (c) Tsuchiya, S.; Saito, H.; Nogi, K.; Yorimitsu, H. Manganese-Catalyzed Ring Opening of Benzofurans and Its Application to Insertion of Heteroatoms into the C2−O Bond. Org. Lett. 2017, 19, 5557− 5560. (d) Saito, H.; Otsuka, S.; Nogi, K.; Yorimitsu, H. NickelCatalyzed Boron Insertion into the C2−O Bond of Benzofurans. J. Am. Chem. Soc. 2016, 138, 15315−15318. (e) Iwasaki, T.; Akimoto, R.; Kuniyasu, H.; Kambe, N. Fe-Catalyzed Cross-Coupling Reaction of Vinylic Ethers with Aryl Grignard Reagents. Chem. - Asian J. 2016, 11, 2834−2837. (f) Guo, L.; Leiendecker, M.; Hsiao, C.-C.; Baumann, C.; Rueping, M. Nickel catalyzed dealkoxylative Csp2− Csp3 cross coupling reaction − stereospecific synthesis of allylsilanes from enol ethers. Chem. Commun. 2015, 51, 1937−1940. (g) Cornella, J.; Martin, R. Ni-Catalyzed Stereoselective Arylation of Inert C−O bonds at Low Temperatures. Org. Lett. 2013, 15, 6298−6301. (24) For benzofuran openings via β-elimination using stoichiometric reagents, see: (a) Xu, P.; Würthwein, E.-U.; Daniliuc, C. G.; Studer, A. Transition-Metal-Free Ring-Opening Silylation of Indoles and Benzofurans with (Diphenyl-tert-butylsilyl)lithium. Angew. Chem., Int. Ed. 2017, 56, 13872−13875. (b) Barluenga, J.; Á lvarez-Rodrigo, L.; Rodríguez, F.; Fañanás, F. J. Reaction of Alkene−Zirconocene Complexes and Cyclic Enol Ethers through New Reaction Pathways. Angew. Chem., Int. Ed. 2004, 43, 3932−3935. (c) Yus, M.; Foubelo, F.; Ferrández, J. V. Stereoselective Reductive Opening of 2,3-Benzofuran − A Two-Step Synthesis of 2H-Chromenes Including Deoxycordiachromene. Eur. J. Org. Chem. 2001, 2001, 2809−2813. (d) Nguyen, T.; Negishi, E.-i. Carbon-carbon bond formation by the reaction of organolithiums with α-lithiated cyclic enol ethers. Stereoselective synthesis of β-and γ-hydroxy di- and tri-substituted alkenes. Tetrahedron Lett. 1991, 32, 5903−5906. (25) (a) Khan, K.; Raston, C. L.; McGrady, J. E.; Skelton, B. W.; White, A. H. Hydride-Bridged Heterobimetallic Complexes of Zirconium and Aluminum. Organometallics 1997, 16, 3252−3254. (b) Wailes, P. C.; Weigold, H. Hydrido Complexes of Zirconium I. Preparation. J. Organomet. Chem. 1970, 24, 405−411.

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DOI: 10.1021/acs.orglett.9b02572 Org. Lett. XXXX, XXX, XXX−XXX