Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Visible-Light-Mediated Synthesis of Ketones by the Oxidative Alkylation of Styrenes Adrian Tlahuext-Aca, R. Aleyda Garza-Sanchez, Michael Schaf̈ er, and Frank Glorius* Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany S Supporting Information *
ABSTRACT: The oxidative coupling of photogenerated alkyl radicals with readily available styrenes is disclosed. This visiblelight-mediated method allows rapid access to a wide range of α-alkyl-acetophenones in good yields and with high functional group tolerance. In addition, the developed protocol features room temperature conditions, low photocatalyst loadings, and the use of dimethyl sulfoxide as nontoxic and mild terminal oxidant.
K
under thermal- and light-mediated conditions.4−7 However, strategies for the use of C(sp3)-centered radicals have remained limited, and current methods suffer from elevated reaction temperatures and the use of strong oxidative conditions (Scheme 1b).8,9 Furthermore, due to the common use of peroxides as terminal oxidants as well as radical initiators, the scope of alkyl radicals has been limited to those that can be generated upon homolytic cleavage of a weak C−H bond at one of the coupling partners. This might limit the straightforward incorporation of relevant molecular scaffolds such as aliphatic heterocycles or tertiary carbon centers since they possess similarly weak C−H bonds that can be degraded during the course of the reaction. In light of the aforementioned limitations, herein we sought to demonstrate that C(sp3)-centered radicals generated by the direct photoinduced reduction of N-(acyloxy)phthalimides10 can be effectively engaged in the functionalization of styrenes leading to the formation of α-alkyl-acetophenones under mild lightmediated conditions where dimethyl sulfoxide (DMSO) acts as a nontoxic and mild oxidant (Scheme 1c).11,12 N-(Acyloxy)phthalimides have been widely used as electrophilic substrates to form alkyl radicals upon decarboxylation. Nevertheless, the large negative reduction potentials (Ered ≈ −1.3 V vs SCE in MeCN)10a generally hinder their use in direct photoinduced electron transfer (PET) chemistry since very few existing photocatalysts feature enough reductive power. Among them, however, the Ir(III)-catalyst fac-Ir(ppy)3 (ppy = 2phenylpyridine) should, in principle, be suitable to engage in direct PET with N-(acyloxy)phthalimides based on its estimated excited state oxidation potential (E1/2IV/*III = −1.73 V vs SCE in MeCN).12e On the basis of this, we began our optimization studies by irradiating an equimolar DMSO solution of 4-tertbutylstyrene (1a) and the N-(acyloxy)phthalimide (2a) with visible light from 5 W blue LEDs (λmax = 455 nm) in the presence of 0.1 mol % of fac-Ir(ppy)3. To our delight, the α-alkyl-
etones are among the most fundamental functionalities in synthetic organic chemistry since they are reactive centers for a wide range of functional group interconversions involving C−C and C−X bond forming reactions.1 Moreover, these carbonyl compounds are ubiquitous in important natural products and synthetic bioactive molecules.2 Owing to their relevance, the development of novel synthetic approaches toward ketones from simple and readily accessible building blocks has gained attention during recent years. In this regard, the oxidative coupling of olefins in the presence of reactive radical intermediates has emerged as a powerful transformation that enables the rapid installation of a carbonyl group and a C−R bond across an olefin (Scheme 1a).3 Using this elegant and stepeconomical strategy, a variety of transformations have been developed for the oxidative coupling of olefins with trifluoromethyl-, aryl-, sulfonyl-, and phosphinoyl-radical intermediates Scheme 1. Strategies of the Oxidative Coupling of Olefins with Radical Intermediates
Received: January 25, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00272 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Scheme 3. Scope of N-(Acyloxy)pthalimides Derived from Synthetic, Biomass, and Bioactive Carboxylic Acidsa
acetophenone 3aa was obtained in 55% GC-FID yield after 12 h of irradiation. Encouraged by this result, we conducted further optimization experiments where good yield of 3aa could be obtained with a slight excess of 2a (1.25 equiv) in combination with 0.2 mol % of fac-Ir(ppy)3 (Table 1, entry 3). Table 1. Optimization of the Oxidative Alkylation of 1aa
entry
photocatalyst (mol %)
2a (equiv)
yield (%)b
1 2 3
fac-Ir(ppy)3 (0.1) fac-Ir(ppy)3 (0.1) fac-Ir(ppy)3 (0.2)
1.0 1.25 1.25
55 62 78
a
General conditions: 1a (0.1 mmol), 2a, photocatalyst, and DMSO (1 mL) under argon. bYields determined by GC-FID using mesitylene as the internal standard.
With the optimized reaction conditions in hand, we turned our attention to investigate the substrate scope of the oxidative alkylation with a diverse range of commercially available styrenes using 2a as the alkyl radical source (Scheme 2). Interestingly, a Scheme 2. Scope of Styrenesa
a
Reaction performed on a 0.40 mmol scale of 1a. bReaction performed on a 7 mmol scale of 1a.
a
ketone, fluorine, and Boc-protected piperidine units were efficiently engage in oxidative alkylation processes with 1a yielding ketones 3ab−3aj in good yields. Due to the fact that aliphatic acids are readily encountered functionalities in biomass and bioactive compounds, we investigated a selection of N-(acyloxy)phthalimides derived from such sources as radical precursors. As shown in Scheme 3, different α-alkyl-acetophenones (3ak−3ao) were prepared using radical sources derived from naturally occurring caproic and linoleic acids (both found in animal fats), Boc-protected γaminobutyric acid (a neurotransmitter), and deoxycholic acid (a synthetic bile acid). In addition, Gemfibrozil, which is a drug used to lower lipid levels, could be employed as a tertiary alkyl radical source to access 3ao in good yield. Finally, the scalability of our method was demonstrated by preparing ketone 3ak in good yield on a 7 mmol scale of 1a. To gain insight into the reaction mechanism for the developed oxidative alkylation protocol, several experiments were performed. Control experiments in the strict absence of either visible light irradiation or fac-Ir(ppy)3 showed no reactivity toward 3aa. Moreover, the presence of TEMPO as a radical scavenger completely inhibited the formation of 3aa. Altogether, these experiments support the visible-light-mediated nature as well as the intermediacy of radical species in our developed method. Next, a Stern−Volmer quenching study was conducted to monitor the kinetic behavior of the excited iridium-catalyst in the presence of the N-(acyloxy)phthalimide 2a. Interestingly, the photoexcited state of fac-Ir(ppy)3 was readily quenched by 2a in degassed DMSO at room temperature.13 From this analysis, a Stern−Volmer quenching constant of 3342 M−1 was obtained. These observations in combination with thermodynamic data
Reaction performed on a 0.40 mmol scale of 1a−1k.
variety of electron-donating and -withdrawing functional groups at the para-position of the arene moiety were well tolerated, giving access to the α-alkyl-acetophenones 3aa−3ha in good yields. Moreover, 3- and 2-substituted styrenes (1i and 1j) as well as the naphthalene derivative 1k could be reacted to give their corresponding ketones in moderate to good yield. N-(Acyloxy)phthalimides are attractive sources of C(sp3)centered radicals due to their low synthetic cost and straightforward synthesis from abundant aliphatic acid feedstocks. Thus, we prepared a variety of functionalized radical sources from commercially available carboxylic acids and tested them for our visible-light-mediated protocol. As shown in Scheme 3, a wide array of primary, secondary, and tertiary N(acyloxy)phthalimides bearing thioanisole, anisole, veratrol, B
DOI: 10.1021/acs.orglett.8b00272 Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters
■
(vide inf ra) suggest that electron transfer between *[facIr(ppy)3] and 2a is both exergonic and kinetically favorable. Finally, the quantum yield (Φ) of the reaction was estimated by chemical actinometry and a very low value was observed (Φ = 0.03) (see SI for details). Based on our assays as well as literature reports, a mechanistic proposal for the visible-light mediated oxidative alkylation of styrenes is depicted in Scheme 4. After photoexcitation with
Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Frank Glorius: 0000-0002-0648-956X Notes
The authors declare no competing financial interest.
■
Scheme 4. Mechanistic Proposal
ACKNOWLEDGMENTS Financial support by the NRW Graduate School of Chemistry (to A.T.A.) and the Deutsche Forschungsgemeinschaft (Leibniz Award) is gratefully acknowledged. We thank Dr. Sara Cembellin-Santos, Santanu Singa (WWU Mü nster), and Hyung Yoon (University of Toronto) for helpful discussions.
■
visible light, *fac-Ir(ppy)3 (E1/2IV/*III = −1.73 V vs SCE in MeCN)12e engages in single electron transfer (SET) with the N(acyloxy)phthalimide 2 (Ered ≈ −1.30 V vs SCE in MeCN)10a delivering the radical anion A. This open-shell species undergoes N−O bond cleavage followed by decarboxylation to deliver a reactive alkyl radical, which then adds to the styrene 1. Based on the measured oxidation potentials of structurally related secondary radicals (Eox = +0.37 V vs SCE in MeCN),14 we propose that B engages in SET with [fac-Ir(ppy)3]+ (E1/2IV/III = +0.77 V vs SCE in MeCN)12e to close the photocatalytic cycle while giving the carbocation C. Further oxidation of this intermediate by DMSO via a Kornblum-type mechanism affords the corresponding α-alkyl-acetophenone product 3.15 In conclusion, we have disclosed an operationally simple, mild, and efficient synthetic protocol to achieve the challenging conversion of a wide variety of styrenes as well as N(acyloxy)phthalimides into α-alkyl-acetophenones in good yields.16 Moreover, our developed protocol highlights the use of low photocatalyst loadings and dimethylsulfoxide as a mild and nontoxic oxidant. Overall, our method demonstrates the powerful application of visible-light photocatalysis for the conversion of simple organic substrates into carbonyl compounds.
■
REFERENCES
(1) (a) Smith, M. B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 2007. (b) Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000. (2) (a) Dörwald, F. Z. Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds; Wiley-VCH: Weinheim, 2012; pp 138−143. (b) Imamura, Y.; Narumi, R.; Shimada, H. J. Enzyme Inhib. Med. Chem. 2007, 22, 105−109. (c) Lee, K. Y.; Choi, J. H.; Kim, W.; Yan, X.-T.; Shin, H.; Jeon, J. H.; Sung, S. H. Planta Med. 2016, 82, 645−649. (3) Lan, X.-W.; Wang, N.-X.; Xing, Y. Eur. J. Org. Chem. 2017, 2017, 5821−5851. (4) (a) Zhang, C.-P.; Wang, Z.-L.; Chen, Q.-Y.; Zhang, C.-T.; Gu, Y.C.; Xiao, J.-C. Chem. Commun. 2011, 47, 6632−6634. (b) Deb, A.; Manna, S.; Modak, A.; Patra, T.; Maity, S.; Maiti, D. Angew. Chem., Int. Ed. 2013, 52, 9747−9750. (c) Tomita, R.; Yasu, Y.; Koike, T.; Akita, M. Angew. Chem., Int. Ed. 2014, 53, 7144−7148. (5) (a) Su, Y.; Sun, X.; Wu, G.; Jiao, N. Angew. Chem., Int. Ed. 2013, 52, 9808−9812. (b) Majhi, B.; Kundu, D.; Ranu, B. C. J. Org. Chem. 2015, 80, 7739−7745. (c) Ding, Y.; Zhang, W.; Li, H.; Meng, Y.; Zhang, T.; Chen, Q.-Y.; Zhu, C. Green Chem. 2017, 19, 2941−2944. (6) (a) Wei, W.; Ji, J.-X. Angew. Chem., Int. Ed. 2011, 50, 9097−9099. (b) Zhang, G.-Y.; Li, C.-K.; Li, D.-P.; Zeng, R.-S.; Shoberu, A.; Zou, J.-P. Tetrahedron 2016, 72, 2972−2978. (7) (a) Wei, W.; Liu, C.; Yang, D.; Wen, J.; You, J.; Suo, Y.; Wang, H. Chem. Commun. 2013, 49, 10239−10241. (b) Chawla, R.; Singh, A. K.; Yadav, L. D. S. Eur. J. Org. Chem. 2014, 2014, 2032−2036. (c) Liu, C.; Ding, L.; Guo, G.; Liu, W. Eur. J. Org. Chem. 2016, 2016, 910−912. (d) Yang, D.; Huang, B.; Wei, W.; Li, J.; Lin, G.; Liu, Y.; Ding, J.; Sun, P.; Wang, H. Green Chem. 2016, 18, 5630−5634. (8) (a) Cheng, K.; Huang, L.; Zhang, Y. Org. Lett. 2009, 11, 2908− 2911. (b) Yang, X.-H.; Wei, W.-T.; Li, H.-B.; Song, R.-J.; Li, J.-H. Chem. Commun. 2014, 50, 12867−12869. (c) Zhang, F.; Du, P.; Chen, J.; Wang, H.; Luo, Q.; Wan, X. Org. Lett. 2014, 16, 1932−1935. (d) Du, P.; Li, H.; Wang, Y.; Cheng, J.; Wan, X. Org. Lett. 2014, 16, 6350−6353. (e) Zhang, J.; Jiang, J.; Xu, D.; Luo, Q.; Wang, H.; Chen, J.; Li, H.; Wang, Y.; Wan, X. Angew. Chem., Int. Ed. 2015, 54, 1231−1235. (f) Jiang, J.; Liu, L.; Yang, L.; Shao, Y.; Cheng, J.; Bao, X.; Wan, X. Chem. Commun. 2015, 51, 14728−14731. (g) Cheng, J.-K.; Loh, T.-P. J. Am. Chem. Soc. 2015, 137, 42−45. (h) Lan, X.-W.; Wang, N.-X.; Zhang, W.; Wen, J.-L.; Bai, C.B.; Xing, Y.; Li, Y.-H. Org. Lett. 2015, 17, 4460−4463. (i) Lan, X.-W.; Wang, N.-X.; Bai, C.-B.; Lan, C.-L.; Zhang, T.; Chen, S.-L.; Xing, Y. Org. Lett. 2016, 18, 5986−5989. (j) Yi, N.; Zhang, H.; Xu, C.; Deng, W.; Wang, R.; Peng, D.; Zeng, Z.; Xiang, J. Org. Lett. 2016, 18, 1780−1783. (9) For a recent example using alkynes, see: Zhu, X.; Ye, C.; Li, Y.; Bao, H. Chem. - Eur. J. 2017, 23, 10254−10258. (10) (a) Okada, K.; Okamoto, K.; Oda, M. J. Am. Chem. Soc. 1988, 110, 8736−8738. (b) Okada, K.; Okamoto, K.; Morita, N.; Okubo, K.; Oda, M. J. Am. Chem. Soc. 1991, 113, 9401−9402. (c) Schnermann, M. J.;
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00272. Experimental procedures, mechanistic experiments, and spectroscopy data (PDF) C
DOI: 10.1021/acs.orglett.8b00272 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Overman, L. E. Angew. Chem., Int. Ed. 2012, 51, 9576−8580. (d) Pratsch, G.; Lackner, G. L.; Overman, L. E. J. Org. Chem. 2015, 80, 6025−6036. (e) Jamison, C. R.; Overman, L. E. Acc. Chem. Res. 2016, 49, 1578−1586. (f) Schwarz, J.; Kö nig, B. Green Chem. 2016, 18, 4743−4749. (g) Tlahuext-Aca, A.; Garza-Sanchez, R. A.; Glorius, F. Angew. Chem., Int. Ed. 2017, 56, 3708−3711. (h) Fawcett, A.; Pradeilles, J.; Wang, Y.; Mutsuga, T.; Myers, E. L.; Aggarwal, V. K. Science 2017, 357, 283−286. (i) Candish, L.; Teders, M.; Glorius, F. J. Am. Chem. Soc. 2017, 139, 7440−7443. (j) Zhao, W.; Wurz, R. P.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc. 2017, 139, 12153−12156. (11) (a) Wu, X.-F.; Natte, K. Adv. Synth. Catal. 2016, 358, 336−352. (b) Jones-Mensah, E.; Karki, M.; Magolan, J. Synthesis 2016, 48, 1421− 1436. (12) For selected reviews on visible light photoredox catalysis, see: (a) Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527−532. (b) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102−113. (c) Xuan, J.; Xiao, W.-J. Angew. Chem., Int. Ed. 2012, 51, 6828−6838. (d) Shi, L.; Xia, W. Chem. Soc. Rev. 2012, 41, 7687−7697. (e) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322−5363. (f) Schultz, D. M.; Yoon, T. P. Science 2014, 343, 1239176. (g) Hopkinson, M. N.; Sahoo, B.; Li, J.-L.; Glorius, F. Chem. Eur. J. 2014, 20, 3874−3886. (h) Xuan, J.; Zhang, Z.-G.; Xiao, W.-J. Angew. Chem., Int. Ed. 2015, 54, 15632−15641. (13) The presence of 4-tert-butylstyrene did not show any decrease of the emission intensity of *fac-Ir(ppy)3 under similar conditions (see SI for details). (14) Wayner, D. D. M.; McPhee, D. J.; Griller, D. J. Am. Chem. Soc. 1988, 110, 132−137. (15) Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W. J.; Larson, H. O.; Levand, O.; Weaver, W. M. J. Am. Chem. Soc. 1957, 79, 6562− 6562. (16) Recently, the synthesis of α-alkyl-acetophenones via photoredoxmediated decarboxylation processes was reported. However, this protocol requires silyl enol ethers as coupling partners, see: Kong, W.; Yu, C.; An, H.; Song, O. Org. Lett. 2018, 20, 349−352.
D
DOI: 10.1021/acs.orglett.8b00272 Org. Lett. XXXX, XXX, XXX−XXX
