Letter pubs.acs.org/OrgLett
Chemoselective Access to γ‑Ketoesters with Stereogenic Quaternary α‑Center or γ‑Keto Nitriles by Aerobic Reaction of α-Cyanoesters and Styrenes Song-Lin Zhang,* Xian-Jin Wang, and Ze-Long Yu Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi, Jiangsu 214122, China S Supporting Information *
ABSTRACT: Chemoselective access to either γ-ketoesters with a quaternary all-carbon α-stereogenic center or γ-keto nitriles is described by copper-catalyzed aerobic reaction of styrenes with α-cyanoesters. Formal oxo-enolation or oxocyanomethylation of styrenes is achieved via a sequence of addition of enolate (or cyanomethyl) radical to olefin and oxidation of the resulting radical adduct. This method starts from abundant and cheap feedstock under aerobic conditions, without any prefunctionalization or the production of stoichiometric metal salts waste, making it very attractive for practical use.
problems, and also environmental issues due to the production of large quantities of metal salts waste. In the past decades, oxidative C−H/C−H coupling reactions6 have attracted increasing attentions for economical and environmental considerations because abundant hydrocarbons, such as arenes and olefins, are directly used without prefunctionalization. It is therefore of great value to achieve oxidative 1,4-dicarbonyls synthesis from simple and abundant hydrocarbons and related compounds via double C−H activation. Herein we describe an aerobic reaction7 between styrenes and α-cyanoesters for the chemoselective synthesis of γ-ketoesters with an all-carbon quaternary α-stereogenic center by formally combining intermolecular oxidative enolate−olefin cross-coupling8 and Wacker-type oxidation of olefins9 (Scheme 1b). Interestingly, by slightly changing the solvent and reaction temperature, the reaction produces selectively γ-keto nitriles (Scheme 1b). Both products are versatile synthetic intermediates toward a range of biologically active compounds. Considering the direct use of abundant and cheap styrenes and α-cyanoesters as substrates and abundant O2 as the terminal oxidant, this method is an attractive straightforward and environmentally benign method. During this study, Lan et al. reported a closely related oxidative reaction of styrenes with alkyl nitriles to produce γ-keto nitriles.10 The reaction occurred under neat conditions promoted by DBU and excess TBHP, giving a range of γ-keto nitriles in good yields. However, this reaction is limited to alkyl nitriles, and α-cyanoesters are completely inactive under their conditions. More, large quantities (4 equiv) of TBHP are required as the terminal oxidant, which is less attractive than
1,4-Dicarbonyl compounds are versatile synthetic intermediates and biologically active compounds. Typically, they are prepared with the construction of C2−C3 bond by nucleophilic substitution reaction of a ketone (or a preformed enolate, or other activated enolate surrogates) with an α-halo carbonyl compound under basic conditions1,2 or aldol-type addition of an enolate to α-aldehyde carbonyls (Scheme 1a).3,4 Alternatively, they can also be prepared through C1−C2 connection, such as conjugate addition of an acyl to a Michael acceptor.5 In these reactions, prefunctionalization of either one or both reaction partners and the presence of stoichiometric amounts of base are generally required. This gives rise to step- and atom-economy Scheme 1. 1,4-Dicarbonyl Synthesis
Received: April 26, 2017 Published: May 31, 2017 © 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b01264 Org. Lett. 2017, 19, 3139−3142
Letter
Organic Letters
Scheme 2. Bis-α-Enolation of α-C−H Bonds of Cyanoestera,b
using O2. Therefore, our method is still of great synthetic interest using oxygen as the terminal oxidant and α-cyanoesters as the substrates, giving γ-keto esters with the construction of quaternary stereogenic α-center. This study was initially inspired by our recent study on developing cyanation reactions using α-cyanoesters as the nontoxic and readily available cyanating reagent via C−CN bond cleavage under aerobic conditions.11 Given the well-known Wacker-type reaction, we consider that reaction of olefins with αcyanoesters under aerobic conditions may achieve the oxycyanation of olefins to produce α-cyano ketones. As our test reaction, reaction of para-fluoride styrene (1a) and ethyl αcyanoacetate (2a) was studied in the presence of catalytic Cu2O/ PPh3 in DMSO under O2 atmosphere with catalytic AgF as cooxidant. To our surprise, the expected oxy-cyanation product was not observed, but a minor amount of another product was produced in about 10% yield. Further screening of other copper sources indicated that CuI performed better, improving the yield to 25% (Table 1, entries 1−4). This product was able to be fully characterized to be α-cyanoacetate bis-α-enolation product 3a with an all-carbon quaternary α-center. Table 1. Optimization Study for the Synthesis of γ-Ketoesters from α-Cyanoesters and Styrenea
a
entry
catalyst
ligand
solvent
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12
Cu2O Cu(OAc)2 CuBr CuI CuI CuI CuI CuI CuI CuI CuI CuI
PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 Xantphos bpy BINAP
DMSO DMSO DMSO DMSO NMP CH3CN DMA DMF DCE DCE DCE DCE
10 12 8 25 NR 25 35 37 66c 25c 28c 34c
Reaction conditions: 1 (0.5 mmol), 2a (2.0 mmol), CuI (0.1 mmol), PPh3 (0.1 mmol), AgF (0.2 mmol), and DCE (2 mL) stirred at 80 °C (oil bath) under O2 balloon. b Isolated yields after column chromatography.
two equivalents of styrenes. Either para- or meta-substituent on the aromatic ring can be tolerated. A β-naphthyl olefin 1g was also a good substrate under the conditions, giving 3g in 65% isolated yield. Furthermore, α-cyanoesters with an additional α-substituent were also compatible with the optimized reaction conditions. Thus, mono-α-enolation of the tertiary α-C−H bond of cyanoesters by styrenes and naphthyl olefin can be achieved, giving rise to highly functionalized γ-ketoesters 4 with an allcarbon quaternary stereogenic α-center (Scheme 3). This stereogenic α-center distinguishes the two protons on β-C atom and also protons of methylene of ethoxy group, as reflected by two sets of separated resonances for both positions in 1H NMR spectroscopy (please refer to Supporting Information). This is in contrast to the situation in products 3 with a prochiral α-carbon where protons on both carbons are indistinguishable. Interestingly, when ortho-vinylpyridine (1j) was subjected to react with 2b under the reaction conditions, an unexpected product 7 was obtained in good isolated yield of 79% (eq 1). Compound 7 should be the product of formal hydroenolation of double bond of 1j.
a
Reaction conditions: 1a (0.5 mmol), 2a (2.0 mmol), copper catalyst (0.1 mmol), ligand (0.1 mmol), AgF (0.2 mmol), and solvent (2 mL) stirred at 120 °C (oil bath) under O2 balloon. bIsolated yield after column chromatography. cAt 80 °C.
It was later found that the solvent plays a crucial role for this reaction. After evaluating a series of common organic solvents including NMP, CH3CN, DMA, DMF, and 1,2-dicholoroethane (DCE) (entries 4−9), it was pleasing to see that the reaction gave a good yield of 66% in DCE at 80 °C (entry 9). Further attempts to improve the reaction yield were unsuccessful, including examining other ancillary ligands, such as Xantphos, bpy, and BINAP (entries 10−12), and additives other than AgF.12 Various styrenes were then studied under the optimized reaction conditions and γ-ketoesters with an all-carbon quaternary prochiral α-carbon were obtained in moderate to good yields (Scheme 2). The products come formally from consecutive double oxidative cross-coupling of α-cyanoester with 3140
DOI: 10.1021/acs.orglett.7b01264 Org. Lett. 2017, 19, 3139−3142
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Organic Letters Scheme 3. Mono-α-Enolation of Tertiary α-C−H of Cyanoestersa,b
Scheme 5. Control Reaction and Radical Trapping Experiments
a Reaction conditions: 1 (0.5 mmol), 2b (2.0 mmol), CuI (0.1 mmol), PPh3 (0.1 mmol), AgF (0.2 mmol), and DCE (2 mL) stirred at 80 °C (oil bath) under O2 balloon. b Isolated yields after column chromatography.
tetramethylpiperidinyloxy), a radical scavenger, was added to the reaction solution, the reaction yield of 3b decreased dramatically to only 18% (43% without TEMPO) (Scheme 5b). Similarly, in the presence of TEMPO, reaction of 1a with 2b gave trace amounts of the desired 4a (Scheme 2c). These results indicate that radical species should be involved during the reaction course. Furthermore, a 1:1 mixture of two TEMPO adducts (adduct1 and adduct2 in Scheme 5c) were generated from trapping experiment, indicating the involvement of radicals A and B (please refer to Figure 1) during the reaction course. The formation of 7 in eq 1 is also evidence suggesting the involvement of radical B.
In some of the reactions for the synthesis of γ-ketoesters, minor amounts of byproducts were observed and identified to be γ-keto nitriles 5 from oxo-cyanomethylation of olefins. This kind of product can be produced in higher yields in more polar DMSO at higher temperature of 120 °C. Scheme 4 shows several examples of such products from reactions between styrenes and α-cyanoester (2a). Scheme 4. Synthesis of γ-Keto Nitrilesa,b
a
Reaction conditions: 1 (0.5 mmol), 2a (2.0 mmol), CuI (0.1 mmol), PPh3 (0.1 mmol), AgF (0.2 mmol),and DMSO (2 mL) stirred at 120 °C (oil bath) under O2 balloon. bIsolated yields after column chromatography.
Figure 1. Plausible mechanism.
Based on the above information, a plausible mechanism is suggested for this chemoselective aerobic cross-coupling between styrenes and α-cyanoesters (Figure 1). Enolate radical species A should be initially formed from α-cyanoester and adds to olefins to get an enolate−olefin coupling radical B. Oxidation of radical B by O2 and dehydration would deliver the desired product 4. When α-H is present in intermediate C or 4 (i.e., R = H), C or 4 can further generate a new radical E that couples with a second styrene to give the bis-enolation product 3.
To shed light on the reaction mechanism, control experiment using acetophenone as substrate in place of styrene showed that no reaction occurred and that acetophenone was recovered under the optimized reaction conditions in Scheme 2 or 4 (Scheme 5a). This implies a late-stage oxidation of the alkene double bond for the synthesis of γ-ketoesters. In addition, radical trapping experiment indicates that when TEMPO (2,2,6,63141
DOI: 10.1021/acs.orglett.7b01264 Org. Lett. 2017, 19, 3139−3142
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Organic Letters
(6) For selected reviews on oxidative C−H/C−H cross-coupling, see: (a) Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170. (b) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J. Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (c) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (d) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (e) Yoo, W. J.; Li, C. J. Top. Curr. Chem. 2009, 292, 281. (7) For aerobic reactions reviews, see: (a) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400. (b) Piera, J.; Bäckvall, J.-E. Angew. Chem., Int. Ed. 2008, 47, 3506. (c) Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3381. (8) For intramolecular enolate−olefin coupling, see: (a) Rönn, M.; Andersson, P. G.; Bäckvall, J.-E. Tetrahedron Lett. 1997, 38, 3603. (b) Pei, T.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125, 648. (c) Liu, C.; Wang, X.; Pei, T.; Widenhoefer, R. A. Chem. - Eur. J. 2004, 10, 6343. (d) Yip, K.-T.; Li, J.-H.; Lee, O.-Y.; Yang, D. Org. Lett. 2005, 7, 5717. Intermolecular oxidative enolate−olefin cross-coupling reactions are rarely described, see: (e) Wang, X.; Widenhoefer, R. A. Chem. Commun. 2004, 660. (9) Wacker reaction: (a) Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.; Ruttinger, R.; Kojer, H. Angew. Chem. 1959, 71, 176. (b) Applied Homogeneous Catalysis with Organometallic Compounds, 2nd ed.; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: Weinheim, 2002; Vol. 1, pp 386−412. (10) Lan, X.-W.; Wang, N.-X.; Bai, C.-B.; Lan, C.-L.; Zhang, T.; Chen, S.-L.; Xing, Y. Org. Lett. 2016, 18, 5986. (11) Zhang, S.-L.; Huang, L. Org. Biomol. Chem. 2015, 13, 9963. (12) Other additives, e.g., peroxides, were also examined but gave lower yields than under the optimized conditions in entry 9 of Table 1. (13) For C−C activation reviews, see: (a) Jun, C.-H. Chem. Soc. Rev. 2004, 33, 610. (b) Chen, F.; Wang, T.; Jiao, N. Chem. Rev. 2014, 114, 8613. (c) Dong, G., Ed.; C−C Bond Activation. Topics in Current Chemistry, Vol. 346; Springer: Berlin, 2014. (d) Souillart, L.; Cramer, N. Chem. Rev. 2015, 115, 9410. (e) Marek, I.; Masarwa, A.; Delaye, P.-O.; Leibeling, M. Angew. Chem., Int. Ed. 2015, 54, 414. (14) For selected examples of C(carbonyl)−C activation, see: (a) Murakami, M.; Amii, H.; Ito, Y. Nature 1994, 370, 540. (b) Jun, C.-H.; Lee, H. J. Am. Chem. Soc. 1999, 121, 880. (c) Jun, C.-H. J. Am. Chem. Soc. 2001, 123, 751.
Alternatively, under more forcing conditions, C(carbonyl)−C cleavage13,14 may be enabled for α-cyanoester or radical intermediate A to generate cyanomethyl radical that couples with olefins followed by oxidation to give the γ-keto nitrile 5. In conclusion, an aerobic oxidative coupling between olefins and α-cyanoesters is described to produce 1,4-dicarbonyl compounds with the construction of C2−C3 bond. By slightly changing the solvent and temperature, the reaction produces selective γ-keto nitriles instead. A radical mechanism is suggested to involve a key step of addition of enolate radical to olefins, followed by aerobic oxidation. This method enables novel access to two important classes of biologically active compounds and synthetic intermediates from abundant and cheap starting materials in a straightforward and environmentally benign way.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01264. Experimental details, spectroscopic characterization data, and NMR spectra for all the products (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Song-Lin Zhang: 0000-0002-5337-8600 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This study was supported by the National Natural Science Foundation of China (Nos. 21472068 & 21202062). Financial support from MOE & SAFEA for the 111 Project (B13025), is gratefully acknowledged.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b01264 Org. Lett. 2017, 19, 3139−3142
