Photocycloaddition through Visible Light-Induced Energy Transfer

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Intramolecular Crossed [2+2] Photocycloaddition through Visible Light-Induced Energy Transfer Jiannan Zhao, Jonathan L. Brosmer, Qingxuan Tang, Zhongyue Yang, K. N. Houk, Paula L. Diaconescu, and Ohyun Kwon* Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095-1569, United States S Supporting Information *

Scheme 1. Regioselectivity in Intramolecular [2+2] Photocycloadditions

ABSTRACT: Herein, we present the intramolecular [2+2] cycloadditions of dienones promoted through sensitization, using a polypyridyl iridium(III) catalyst, to form bridged cyclobutanes. In contrast to previous examples of straight [2+2] cycloadditions, these efficient crossed additions were achieved under irradiation with visible light. The reactions delivered desired bridged benzobicycloheptanone products with excellent regioselectivity in high yields (up to 96%). This process is superior to previous syntheses of benzobicyclo[3.1.1]heptanones, which are readily converted to B-norbenzomorphan analogues of biological significance. Electrochemical, computational, and spectroscopic studies substantiated the mechanism of triplet energy transfer and explained the unusual regiocontrol.

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yclobutanes are prominent structural components in many bioactive natural products1 and are also valuable synthetic intermediates in the preparation of larger-ring systems.2 Photochemical [2+2] cycloaddition is the most frequently used reaction to access cyclobutane-containing structures.3−6 In addition to conventional UV light−promoted photochemical transformations,3 [2+2] cycloadditions through visible light photoredox catalysis are also efficient means for construction of four-membered carbocycles.4 The scope of these reactions is, however, limited to a pair of electron-deficient or -rich alkenes that are amenable to one-electron redox processes.5 There is also ongoing interest into the efficacious utilization of energy transfer pathways in visible light photocatalysis.6 The broad substrate scope, independent of the electronic nature, makes the energy transfer process more attractive than the single-electron transfer (SET) approach for performing [2+2] cycloadditions. In general, intramolecular [2+2] cyclizations give rise to either crossed or straight products, depending on the regioselectivity (Scheme 1).7 When the tether between the reacting olefinic units is only two atoms (n = 2), crossed adducts prevail to avoid the formation of strained four-membered rings. If the tether is longer (n = 3 or 4), a straight addition mode is preferred (Scheme 1a). Typically, these rules can be used to predict the regioselectivity, and exceptions are rareeven in examples of conventional [2+2] photocycloadditions promoted by UV light.8 Although visible light photocatalysis is enjoying increasing use in stereoselective [2+2] cycloadditions,6 the regioselectivity of the reactions has been limited previously to the head-to-head mode. Yoon had demonstrated that the © 2017 American Chemical Society

tethered bis(styrene) or bis(enone) 1 undergoes straight cycloaddition, producing the fused bicycloheptane 2 as the sole regioisomer, presumably facilitated by the rapid formation of five-membered rings and the stability of the radical intermediates generated through the SET4 or energy transfer6 process (Scheme 1b). In light of the versatility of energy transfer as a mode of photoactivation, however, the regioselectivity of the [2+2] photocycloadditions should be altered depending on the stability of the 1,4-diradical intermediates. We, therefore, reasoned that the benzoyl tethered substrate 3a should provide access to the thermodynamically preferred benzyl radical DR1, which, subsequently, would undergo ring closure to form the bridged bicyclo[3.3.1]heptanone 4a (Scheme 1c). Initially, the [2+2] cycloaddition was investigated using the ostyrenyl enone 3a as the model substrate in dichloromethane and irradiating with a 12 W white light emitting diode (LED).9,10 No reactions occurred in the presence of Ru(bpy)32+ (5a) and Ru(bpz)32+ (5b), which possess triplet energies of 46.5 and 48.4 kcal mol−1, respectively (Table 1, entries 1 and 2).11,12 Consequently, Ir[dF(CF3)ppy]2(dtbbpy)+ 6+ was strategically chosen as the triplet sensitizer because of its higher triplet energy (60.1 kcal mol−1) and long-lived triplet state (τ = 2300 ns).4b,13 To our delight, this iridium complex led to a clean intramolecular [2+2] cycloaddition, which generated the Received: May 22, 2017 Published: July 6, 2017 9807

DOI: 10.1021/jacs.7b05277 J. Am. Chem. Soc. 2017, 139, 9807−9810

Communication

Journal of the American Chemical Society

Table 2. Scope of Photosensitized [2+2] Cycloadditionsa,b,c

Table 1. Optimization of the Photosensitized [2+2] Cycloaddition and Control Studiesa

entry

catalyst

solvent

conc. [M]

yieldb

1 2 3 4 5 6 7 8c

5a·Cl2·6H2O 5b·(PF6)2 6·PF6 6·PF6 6·PF6 6·PF6 none 6·PF6

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 THF MeCN CH2Cl2 CH2Cl2

0.1 0.1 0.1 0.02 0.02 0.02 0.02 0.02

0 0 78% 93% 48% 76% 0 0

a Reaction of photocatalyst (0.001 mmol) and 3a (0.1 mmol) was conducted under irradiation from a 12 W white LED light strip under N2 at 25 °C for 24 h. bDetermined from 1H NMR spectra, using 2,4dinitro-1-chlorobenzene as internal standard. cControl reaction conducted in the dark.

crossed product 4a as a single regioisomer (Table 1, entry 3).14 A lower concentration of the substrate 3a avoided polymerization and increased the product yield to 93% after an irradiation time of 24 h (Table 1, entry 4). Tests of alternative solvents (THF, CH3CN) delivered relatively unsatisfactory results (Table 1, entries 5 and 6). Control experiments confirmed that the cycloaddition did not occur in the absence of the photocatalyst or in the absence of light (Table 1, entries 7 and 8). To test the viability of this method, we turned our attention to using other styrenyl enones as substrates. Table 2 reveals that substrates presenting electron-withdrawing, -neutral, and -donating substituents on the aromatic ring all tolerated 1 mol % of the iridium complex 6·PF6, generating the benzobicycloheptanone derivatives 4b−f in high yields. Positioning a methoxy group at the para position of the styrene moiety, however, decreased the yields of 4g and 4h, presumably a result of polymerization of these more electron-rich olefins.15 Unfortunately, the 2-pyridyl enone substrate 4i was not a suitable reactant. Next, we investigated the substrate scope with respect to substituents on the carbon−carbon double bonds. Substrates bearing methyl or phenyl substituents at the αposition of the styrenic moiety successfully participated in the reaction, providing access to the cyclobutane structures 4j and 4k, bearing all-carbon quaternary centers with excellent regioselectivity. Substitution at the β-position of the styrenic unit was also tolerated, enabling the construction of nonsymmetric benzobicyclo[3.1.1]heptanones 4l−o. Reactions involving α-substituted enones gave the desired crossed products 4p−4s exclusively. For α-aryl enones, the reaction was insensitive to the electronic nature of the aryl rings (4q−s).

a

Reactions of 3 (0.1 mmol) in the presence of 1 mol % 6·PF6 under N2 with irradiation from a 12 W white LED light strip at a distance of 4 cm. bIsolated yields of cyclic products after 8−36 h. cDiastereoisomeric ratios determined from 1H NMR spectra of crude reaction mixtures.

To elaborate further the scope of this reaction, we tested the behavior of the naphthalene substrates 3t and 3u (Scheme 2). Surprisingly, the unusual bridged cyclobutanone products 4t and 4u were generated through rearrangement under the optimized conditions. Gratifyingly, crystals suitable for X-ray crystallographic analysis unambiguously revealed the bridged bicyclic structures of 4q and 4t.16 Scheme 2. Photocycloaddition of Naphthyl-Enones

9808

DOI: 10.1021/jacs.7b05277 J. Am. Chem. Soc. 2017, 139, 9807−9810

Communication

Journal of the American Chemical Society Manipulation of the cyclobutane-bridged tetralones 4 offers opportunities to generate other cyclobutane-containing structures (Scheme 3). For instance, treatment of the cycloadducts 4

Scheme 4. Mechanism of [2+2] Photocycloaddition of 3a

Scheme 3. Elaboration of Benzobicyclo[3.3.1]heptanones

with hydroxylamine hydrochloride and sodium acetate in methanol afforded the corresponding ketoximes 7 in excellent yields.17 Subsequent Beckmann rearrangements in the presence of thionyl chloride provided regioselective access to the lactams 8 via exclusive alkyl migration.18 Reduction and methylation of 8 gave the analogues of B-norbenzomorphan19 9 and 10, respectively, which are known to possess significant analgesic activity.20 Divergently, the bridged tricycle 8d was a pivotal intermediate in the synthesis of compound 11 reported by Genentech, who disclosed its inhibition of NF-κB inducing kinase (NIK) and therapeutic potential for inflammatory disease and cancer.14c,d Mechanistically, our crossed [2+2] cycloaddition proceeds via energy transfer from the triplet sensitizer 6+ to the o-styrenyl enone 3. In the cyclic voltammograms of 3a, oxidation and reduction features were observed with half-peak potentials of +1.81 V vs SCE and −1.56 V vs SCE, respectively.10 These electrochemical characteristics ruled out electron transfer pathways for 3a because the redox potentials of the photocatalyst 6+ indicate that either oxidation or reduction of 3a would be endergonic.21 We studied the energetics of 3a (singlet) and 3a* (triplet) computationally using the B3LYP/6311+G(2d,p) method with an implicit CH2Cl2 medium.22 The computed energy gap (58.5 kcal mol−1) was lower than the triplet energy of Ir*[dF(CF3)ppy]2(dtbbpy)+ (60.1 kcal mol−1),10 suggesting that energy transfer from the catalyst to the substrate was feasible. Stern−Volmer studies23 revealed that the quenching of 6*·PF6 was linear with respect to the concentration of 3a.10 The energy-transfer pathway was also supported by the observation that the reaction worked better in CH2Cl2 than in MeCN or THF. Charged radical ion intermediates, possibly generated through electron transfer, would have been strongly destabilized in nonpolar media. Scheme 4 outlines our proposed mechanism for the [2+2] photocycloaddition. Irradiation of the iridium complex with visible light produces the long-lived excited state *Ir(III). The exergonic energy transfer generates the triplet 3a*, which undergoes intramolecular cyclization to generate a series of 1,4diradical intermediates (DR1−DR4). Computations revealed that the benzyl radical DR1 is thermodynamically preferred and enables the second ring closure to the isolated bridged

cycloadduct 4a. In addition, the mechanism for the formation of 4t and 4u presumably involves crossed [2+2] cycloaddition of a ketene intermediate,24 which might arise from rearrangement of the diradical intermediate with involvement of the naphthyl moiety.10 In summary, the iridium photocatalyst 6·PF6 enables the synthesis of bridged benzobicyclo[3.1.1]heptanones through [2+2] photocycloadditions under irradiation with visible light. The excellent regioselectivity observed in this reaction is a considerable advance in the construction of bridged bicyclic structures; indeed, it is the first example of exclusive crossed [2+2] cycloaddition promoted by visible light. This approach provides ready access to bridged benzobicycloheptanone products that are easily elaborated to biologically active Bnorbenzomorphan analogues. This additive-free, atom-economical reaction can be performed using simple photochemical equipment under benign conditions. Detailed mechanistic studies have ruled out substrate activation by means of SET and, instead, have confirmed the role of photosensitization through energy transfer.

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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/jacs.7b05277. Experimental procedures and analytical data (PDF) Crystallographic data for 4q (CIF) Crystallographic data for 4t (CIF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

K. N. Houk: 0000-0002-8387-5261 Paula L. Diaconescu: 0000-0003-2732-4155 9809

DOI: 10.1021/jacs.7b05277 J. Am. Chem. Soc. 2017, 139, 9807−9810

Communication

Journal of the American Chemical Society

Bellus, D. Helv. Chim. Acta 1982, 65, 2405. (d) Matlin, A. R.; George, C. F.; Wolff, S.; Agosta, W. C. J. Am. Chem. Soc. 1986, 108, 3385. (e) Crimmins, M. T.; Hauser, E. B. Org. Lett. 2000, 2, 281. (f) Busqué, F.; March, P.; Figueredo, M.; Font, J.; Margaretha, P.; Raya, J. Synthesis 2001, 112, 1143. (g) Bach, T.; Kemmler, M.; Herdtweck, E. J. Org. Chem. 2003, 68, 1994. (h) Kohmoto, S.; Hisamatsu, S.; Mitsuhashi, H.; Takahashi, M.; Masu, H.; Azumaya, I.; Yamaguchi, K.; Kishikawa, K. Org. Biomol. Chem. 2010, 8, 2174. (i) Weixler, R.; Hehn, J. P.; Bach, T. J. Org. Chem. 2011, 76, 5924. (9) UV irradiation of 3a in the absence and presence of photosensitizers (xanthone, benzophenone and acetone) produced 4a in 10−46% yield. (10) For details, see the Supporting Information. (11) (a) Rillema, D. P.; Allen, G.; Meyer, T. J.; Conrad, D. Inorg. Chem. 1983, 22, 1617. (b) Haga, M.-A.; Dodsworth, E. S.; Eryavec, G.; Seymour, P.; Lever, A. B. P. Inorg. Chem. 1985, 24, 1901. (c) Teegardin, K.; Day, J. I.; Chan, J.; Weaver, J. Org. Process Res. Dev. 2016, 20, 1156. (d) In ref 6d, the Yoon group calculated values of ET for 5a (46.8 kcal mol−1) and 5b (47.4 kcal mol−1) based on the emission maxima reported in: Juris, A.; Balzani, V.; Barigelletti, F.; Campagna, S.; Belser, P.; von Zelewsky, A. Coord. Chem. Rev. 1988, 84, 85. (12) See ref 4b for the excited-state lifetimes of 5a (τ = 1100 ns) and 5b (τ = 740 ns). (13) (a) Lowry, M. S.; Hudson, W. R.; Pascal, R. A., Jr.; Bernhard, S. J. Am. Chem. Soc. 2004, 126, 14129. (b) Lowry, M. S.; Goldsmith, J. I.; Slinker, J. D.; Rohl, R.; Pascal, R. A., Jr.; Malliaras, G. G.; Bernhard, S. Chem. Mater. 2005, 17, 5712. (c) Singh, A.; Teegardin, K.; Kelly, M.; Prasad, K. S.; Krishnan, S.; Weaver, J. D. J. Organomet. Chem. 2015, 776, 51. (d) Ref 11c. (14) (a) Escale, R.; Girard, A. K. J. P.; Rossi, J. C.; Chapat, J. P.; Khayat, A. Org. Magn. Reson. 1981, 17, 217. (b) Liu, Q.; Meng, J.; Liu, Y.; Yang, C.; Xia, W. J. Org. Chem. 2014, 79, 8143. (c) Staben, S.; Castanedo, G. M.; Montalbetti, C.; Feng, J. Tricyclic Compounds and Methods of Use Therefor. U.S. Patent 9,034,866 B2, May 19, 2015. (d) Castanedo, G. M.; Blaquiere, N.; Beresini, M.; Bravo, B.; Brightbill, H.; Chen, J.; Cui, H.-F.; Eigenbrot, C.; Everett, C.; Feng, J.; et al. J. Med. Chem. 2017, 60, 627. (15) Gelation of 3g and 3h was observed upon standing at room temperature. (16) CCDC 1543972 (4q) and CCDC 1543973 (4t) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. (17) The ketoximes 7a and 7d were formed as 4:1 and 7:1 mixtures of isomers, respectively. Both pairs of isomers were successfully converted to the lactams 8a and 8d, respectively. (18) (a) Escale, R.; El Khayat, A.; Vidal, J.-P.; Girard, J.-P.; Rossi, J.-C. J. Heterocycl. Chem. 1984, 21, 1033. (b) Crosby, I. T.; Shin, J. K.; Capuano, B. Aust. J. Chem. 2010, 63, 211. (19) (a) Mokotoff, M.; Jacobson, A. E. J. Heterocycl. Chem. 1970, 7, 773. (b) Mazzocchi, P. H.; Stahly, B. C. J. Med. Chem. 1979, 22, 455. (20) For the analgesic activities of B-norbenzomorphan (ED50 = 20− 25 mg kg−1), 9 (ED50 = 47 mg kg−1), 10a (ED50 = 15 mg kg−1), and codeine (ED50 = 5 mg kg−1), see: Escale, R.; Vidal, J. P.; Rechencq, E.; Boucard, M.; Girard, J. P.; Rossi, J. C. Eur. J. Med. Chem. 1985, 20, 371. (21) For the redox potentials of Ir[dF(CF3)ppy]2(dtbbpy)+ 6+ [E1/2(IrIV/*IrIII) = −0.89 vs SCE; E1/2(*IrIII/IrII) = +1.21 vs SCE; E1/2(IrIV/IrIII) = +1.69; E1/2(IrIII/IrII) = −1.37 vs SCE], see refs 4b and 13. (22) Chang, X.-P.; Zheng, Y.; Cui, G.; Fang, W.-H.; Thiel, W. Phys. Chem. Chem. Phys. 2016, 18, 24713. (23) Lakowicz, J. R. Principles of Fluorescence Spectroscopy; 3rd ed.; Springer: New York, 2006. (24) Lachia, M.; Jung, P. M. J.; De Mesmaeker, A. Tetrahedron Lett. 2012, 53, 4514.

Ohyun Kwon: 0000-0002-5405-3971 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the NIH (GM071779 to O.K.) and the NSF (CHE1362999 to P.L.D.; CHE-1361104 to K.N.H.) for financial support. Calculations were performed on the Hoffman2 cluster at UCLA and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the NSF (OCI1053575). We also thank Prof. Ellen M. Sletten and Dr. Wei Cao for help with the Stern−Volmer studies and Prof. Hosea Nelson and Luke Boralsky for sharing their Rayoner RPR-200 UV reactor.

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DOI: 10.1021/jacs.7b05277 J. Am. Chem. Soc. 2017, 139, 9807−9810