An Intermolecular Azidoheteroarylation of Simple Alkenes via Free

Letter Cite This: Org. Lett. 2017, 19, 5649-5652

pubs.acs.org/OrgLett

An Intermolecular Azidoheteroarylation of Simple Alkenes via FreeRadical Multicomponent Cascade Reactions Zhi Liu† and Zhong-Quan Liu*,†,‡ †

State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China State Key Laboratory Cultivation Base for TCM Quality and Efficacy, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China

‡

S Supporting Information *

ABSTRACT: Based upon a radical polar effect, an intermolecular azidoheteroarylation of simple alkenes via a metal-free radical multicomponent cascade process was achieved. It allows a mild, rapid, and stepeconomic access to a broad range of azidoalkylated heteroaromatics. Given the diversity in transformations of organic azides and medicinally privileged scaffolds of heteroarenes, this strategy enables efficient synthesis and latestage derivatization of drugs and candidates.

M

Scheme 1. Design a Multicomponent Minisci Reaction through Radical Polar Reversal

ulticomponent cascade processes feature step-economy and simplicity of operation, which represent the most efficient and attractive synthetic organic transformations. Advances in ionic and/or organometallic multicomponent reactions have been made in recent decades.1 In contrast, freeradical mediated efficient multicomponent reactions remain to be explored.2 The critical challenge is often the several existing competing processes, and thus the production of more than one product. By tedious preparation of the carefully designed precursors, unimolecular radical cascade approaches to complex natural products were successfully achieved in the past century.3 However, they do not really solve the problems in intermolecular multicomponent radical tandem reactions using simple and commercially available starting materials. By summarizing a few of the effective cases reported by Mizuno,4 Ryu,5 and Renaud6 et al., Landais and a co-worker stated that the chemoselectivity in the interaction of each component is essential for well-controlled radical multicomponent reactions.2 Pioneering investigations by Waters7 and Walling8 revealed that the reactivity and selectivity in radical reactions depend heavily on radical polar effects,9 from which the polarity reversal catalysis is described.10 All these laws and concepts provide suggestions for designing ingenious radical multicomponent reactions. Minisci reactions are widely used in synthetic organic, medicinal, and biological chemistry.11,12 However, multicomponent Minisci reactions are very rarely investigated. One example is the AgNO3/K2S2O8 promoted radical tandem 2-alkylation of 4-cyanopyridine by acetone and 1-octene.13 Another is perfluoroalkylation of heterocycles by using perfluoroalkyl iodide with an alkene.14 Both examples were reported by Minisci and co-workers with a relatively limited substrate scope. Very recently, McCallum and Barriault reported an efficient cascade Minisci reaction via a photocatalysis process.11l Inspired by these pioneering studies, we proposed a possible general model for radical multicomponent Minisci reaction (Scheme 1). As demonstrated in Scheme 1, an electrophilic radical (REl) would © 2017 American Chemical Society

not react with an electron-deficient heteroarene but add to an electron-rich olefin. Subsequently a nucleophilic alkyl radical (RNu) would be generated by a radical polar reversal, which then could add to the heterocycle leading to the final product. The key factor to success may rely on utilizing radical polar effects to control the reactivity and selectivity.15 Generally, halogen atoms, alkoxyl, and N-centered radicals are considered as electrophilic radicals.15 Considering that organic azides are used as powerful and valuable building blocks in synthetic organic chemistry,16 we considered whether an azidyl radical could promote a multicomponent Minisci reaction, through which a series of functionalized heterocycles bearing an azide group could be synthesized efficiently. Recently, considerable advances in direct azidation have been made.17 Among them, strategies for difunctionalization of alkenes18 such as carboazidation19 and heteroazidation20 represent the most attractive access to organoazides. Most of the free radical processes utilized azides as C-centered radical traps to form the C−N3 bond. Herein, we wish to report a metal-free radical azidoheteroarylation of unactivated alkenes with TMSN3 and heteroarenes through a multicomponent cascade process. To the best of our knowledge, it is the first example for synthesis of organic azides via a multicomponent Minisci reaction. Initially, we started with optimizing an effective generation of azidyl radical to examine our hypothesis. Due to our continuous studies on single-electron redox-promoted radical trifluoromeReceived: September 8, 2017 Published: September 29, 2017 5649

DOI: 10.1021/acs.orglett.7b02788 Org. Lett. 2017, 19, 5649−5652

Letter

Organic Letters

Scheme 2. Examination of the Heteroaromatic Substratesa

thylation reactions with I(V),21 we considered whether an azidyl radical would be formed similarly by one-electron oxidation of the azidyl anion. Previous investigations indicate that hypervalent iodine reagents could act as efficient single-electron oxidants.22 Hence, an array of hypervalent iodines were screened to stimulate the model reaction of 4-methylquinoline with sodium azide or allyltrimethylsilane (Table 1). No reaction occurred Table 1. Optimization of the Reaction Conditionsa

entry

oxidant (equiv)

azide

yield (%)b

1 2 3 4 5 6 7 8 9c

I2O5 (1) I2O5 (1) IBX (2) DMP (2) DIB (1) DIB (2) PIFA (2) DIB (2) DIB (2)

NaN3 TMSN3 TMSN3 TMSN3 TMSN3 TMSN3 TMSN3 NaN3 TMSN3

− − − − 18 62 40 59 82

a

Reaction conditions: 4-methylquinoline (1 equiv, 0.2 mmol), TFA (1.2 equiv, 0.24 mmol), allyltrimethylsilane (5 equiv, 1 mmol), azide (4 equiv, 0.8 mmol), AcOH (0.9 mL), DCM (0.4 mL), 0 °C, 1 h. b Isolated yields. c4- Methylquinoline (1.0 mmol), TFA (1.2 mmol), allyltrimethylsilane (5 mmol), azide (4 mmol), AcOH (4.7 mL), DCM (2.2 mL), 0 °C, 2.5 h.

a

Typical reaction conditions. bIsolated yields. cBis-alkylation product.

heterocycles containing more than one N-atom in the aromatic core such as pyrazine, quinoxaline, quinazoline, pyrimidine, pyrido[3,4-b]pyrazine, pyrido[2,3-b]pyrazine, phthalazine, and its derivatives were evaluated to be effective substrates (15−26). It is noteworthy that privileged scaffolds found in DNA bases and relevant drugs were amenable to this reaction (21 and 22). Sensitive formyl and amino groups to oxidative conditions could survive in this reaction (18 and 22), which might be due to the fast reaction rate and mild conditions. In order to further examine the substrate scope of this reaction, a variety of alkenes were studied (Scheme 3). Allylic silanes

when using iodine pentoxide and sodium azide (entry 1). When trimethylsilyl azide was utilized as an alternative azidyl source, a series of I(V) reagents failed to initiate the reaction (entries 2− 4). To our delight, 1 equiv of (diacetoxyiodo)benzene (DIB) gave the desired product in 18% yield (entry 5). Gratifyingly, the yield increased up to 62% with 2 equiv of DIB (entry 6). [Bis(trifluoroacetoxy)iodo]benzene (PIFA) did not improve but decreased the yield (entry 7). Further experimental results showed that DIB also enabled sodium azide to produce the corresponding product in good yield (entry 8). Finally, a scaledup experiment resulted in 82% yield of the product (entry 9), which indicated that this multicomponent azidoheteroarylation reaction could be potentially applied in the chemical industry. The addition of acids (TFA and HOAc) could improve the efficiency of the reaction by protonation of heterocycle and promoting dissolution of the reagents. With the optimized conditions in hand, we next evaluated the generality of this reaction. It can be seen from Scheme 2 that a wide range of heteroarenes were screened. First of all, a series of quinolines with diverse substituents such as alkyl, halogen, formyl, alkoxy, and ester gave the corresponding products in good to excellent yields (1−8). Surprisingly, C2 monoazidoalkylated quinoline was isolated as the dominant product with 3methoxyquinoline (6). It is mechanistically interesting that 4vinylquinoline resulted in a diazidated compound (9), which could be regarded as evidence for addition of an azidyl radical to alkene. In addition, an 83% yield of monoazidoalkylated product at the C1 position was obtained with methyl isoquinoline-3carboxylate (10). Next, substituted pyridines, phenanthridines, and benzo[h]quinolines were examined, and they are amenable to this system (11−14). 4-Substituted pyridines mainly afforded monoazidoalkylated compounds along with some minor diazidoalkylation products (11 and 12). Finally, a set of

Scheme 3. Examination of the Alkene Substratesa

a Typical reaction conditions. bIsolated yields. cA mixture of diastereomers were isolated, and NMR spectra showed the ratio of anti/syn > 20/1.

5650

DOI: 10.1021/acs.orglett.7b02788 Org. Lett. 2017, 19, 5649−5652

Letter

Organic Letters afforded the corresponding products in high to excellent yields (27 and 28). Additionally, we found that an array of linear and cyclic unactivated alkenes are compatible with this radical multicomponent reaction (29−40). Diverse functional groups such as phenyl, carbonyl, hydroxyl, and its protecting groups are well tolerated. It is a remarkable fact that the regioselectivity in radical addition to an alkene is site-specific. Even in the case of polysubstituted olefins (33 and 38), no regioisomer is observed for all these reactions. It is very interesting that hexa-1,5-diene afforded product 36 with retention of a double bond, and no cyclized compound was observed. But in the case of 1-(4chloroquinolin-3-yl)pent-4-en-1-ol, product 41 was isolated in 51% yield, which should be formed via an intramolecular azidoheteroarylation cascade process. It is well-known that various N-heterocycles such as pyridine, quinoline, isoquinoline, pyrazine, quinoxaline, quinazoline, pyrimidine, etc., are core scaffolds for a large amount of drugs and bioactive natural products. Organic azides are widely used as powerful synthons in drug synthesis and material science.16 It can be seen from Schemes 2 and 3 that the present strategy allows a rapid and facile access to a wide range of alkylated Nheteroarenes with an appended azide. Thus, the products obtained by this method could allow diverse late-stage functionalization for library synthesis and drug discovery. Scheme 4 shows a series of transformations of the products.

Scheme 5. Radical Clock Experiments

for an intermolecular radical cascade process can also be found in Scheme 5b. Addition of the azidyl radical to diethyl 2,2diallylmalonate followed by a 6-endo-trig cyclization affords radical C, which then adds to protonated 4,7-dichloroquinoline. A radical cation D would be formed. Hydrogen-atom transfer (HAT) followed by deprotonation via workup gives the final product 50. In summary, through careful regulation and control of the radical polarity, a metal-free radical multicomponent cascade reaction of TMSN3 afforded unactivated alkenes with heterocycles achieved. It allows a mild, rapid, and step-economic access to a broad range of azidoalkylated heteroaromatics. Given the diversity in transformations of organic azides and medicinally privileged scaffolds of heteroarenes, this method enables facile synthesis and late-stage derivatization of pharmaceuticals and candidates, which would be expected to find wide applications in the medicinal chemistry community.

Scheme 4. Transformations of the Productsa

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02788. Experimental procedures, mechanistic studies, and characterization and spectral data (PDF) a

■

For the reaction conditions in details, see Supporting Information.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

For example, some triazoles can be conveniently obtained via click reaction and 1,3-dipolar cycloaddition (42 and 43). Amine 44 was produced in good yield through the Staudinger reaction of 1 with PPh3. Conversion of the dimethyl(phenyl)silyl group in 27 to a hydroxyl afforded alcohol 45. The Schmidt reaction of 45 with 4-fluorobenzaldehyde gave oxazoline 46. Intramolecular aza-Wittig reactions of 34 and 18 afforded ring closing piperidine 47 and 3,4-dihydropyrido[3,4-b]quinoxaline 48, respectively. In order to confirm the radical cascade mechanism for this reaction, two radical clock experiments were carried out (Scheme 5). As demonstrated in Scheme 5a, reaction of TMSN3 with DIB would generate intermediate PhI(N3)2,19d,22 which decomposes into PhI and the azidyl radical. The N3 radical would then add to the CC double bond of ethyl chrysanthemumate a less hindered position a via path I. But the release of steric compression via ring opening of cyclopropane provides the driving force to afford radical intermediate A by path II.9a Addition of radical A to the protonated N-heterocycle gives a radical cation B. Subsequently, hydrogen abstraction affords the desired product 49 in 45% yield with E/Z > 20/1. The evidence

ORCID

Zhong-Quan Liu: 0000-0001-6961-0585 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS In memory of Prof. You-Cheng Liu (University of Science and Technology of China). This project is supported by National Natural Science Foundation of China (Nos. 21672089, 21472080). We also thank Prof. R.-X. Tan (Nanjing University of Chinese Medicine) for helpful discussions.

■

REFERENCES

(1) For reviews on multicomponent cascade reactions, see: (a) Zhu, J.; Bienaymé, H. Multicomponent Reactions; Wiley-VCH: Weinheim, 2005. (b) Tietze, L. F.; Brasche, D. G.; Gericke, K. M. Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2007. (c) Pellissier, H. Chem. Rev. 2013, 113, 442. (d) Wille, U. Chem. Rev. 2013, 113, 813. (e) Liautard, V.; Landais, Y. Free-Radical Multicomponent Processes. In 5651

DOI: 10.1021/acs.orglett.7b02788 Org. Lett. 2017, 19, 5649−5652

Letter

Organic Letters

(c) Arthur, N. L.; Potzinger, P. Organometallics 2002, 21, 2874. (d) De Vleeschouwer, F.; Van Speybroeck, V.; Waroquier, M.; Geerlings, P.; De Proft, F. Org. Lett. 2007, 9, 2721. (16) For reviews on the chemistry of azides, see: (a) Azides and Nitrenes: Reactivity and Utility; Scriven, E. F. V., Ed.; Academic Press: New York, 1984. (b) Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188. (c) Minozzi, M.; Nanni, D.; Spagnolo, P. Chem. - Eur. J. 2009, 15, 7830. (d) Chiba, S. Synlett 2012, 2012, 21. (e) Wu, K.; Liang, Y.; Jiao, N. Molecules 2016, 21, 352. (17) For selected recent direct azidations, see: (a) Lubriks, D.; Sokolovs, I.; Suna, E. J. Am. Chem. Soc. 2012, 134, 15436. (b) Tang, C.; Jiao, N. J. Am. Chem. Soc. 2012, 134, 18924. (c) Deng, Q.; Bleith, T.; Wadepohl, H.; Gade, L. H. J. Am. Chem. Soc. 2013, 135, 5356. (d) Xie, F.; Qi, Z.; Li, X. Angew. Chem., Int. Ed. 2013, 52, 11862. (e) Vita, M. V.; Waser, J. Org. Lett. 2013, 15, 3246. (f) Liu, Z.; Liu, J.; Zhang, L.; Liao, P.; Song, J.; Bi, X. Angew. Chem., Int. Ed. 2014, 53, 5305. (g) Klahn, P.; Erhardt, H.; Kotthaus, A.; Kirsch, S. F. Angew. Chem., Int. Ed. 2014, 53, 7913. (h) Yin, H.; Wang, T.; Jiao, N. Org. Lett. 2014, 16, 2302. (i) Sharma, A.; Hartwig, J. F. Nature 2015, 517, 600. (j) Huang, X.; Bergsten, T. M.; Groves, J. T. J. Am. Chem. Soc. 2015, 137, 5300. (k) Vita, M. V.; Waser, J. Angew. Chem., Int. Ed. 2015, 54, 5290 and references therein. (l) Liu, C.; Wang, X.; Li, Z.; Cui, L.; Li, C. J. Am. Chem. Soc. 2015, 137, 9820. (m) Wang, Y.; Li, G.-X.; Yang, G.; He, G.; Chen, G. Chem. Sci. 2016, 7, 2679. (n) Rabet, P. T.; Fumagalli, G.; Boyd, S.; Greaney, M. F. Org. Lett. 2016, 18, 1646. (18) For selected reviews on difunctionalization of olefins, see: (a) Minatti, A.; Muñiz, K. Chem. Soc. Rev. 2007, 36, 1142. (b) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111, 2981. (c) Merino, E.; Nevado, C. Chem. Soc. Rev. 2014, 43, 6598. (d) Yin, G.; Mu, X.; Liu, G. Acc. Chem. Res. 2016, 49, 2413. (19) For selected recent carboazidations of alkenes, see: (a) Weidner, K.; Giroult, A.; Panchaud, P.; Renaud, P. J. Am. Chem. Soc. 2010, 132, 17511. (b) Lapointe, G.; Schenk, K.; Renaud, P. Chem. - Eur. J. 2011, 17, 3207. (c) Matcha, K.; Narayan, R.; Antonchick, A. P. Angew. Chem., Int. Ed. 2013, 52, 7985. (d) Wang, F.; Qi, X.; Liang, Z.; Chen, P.; Liu, G. Angew. Chem., Int. Ed. 2014, 53, 1881. (e) Xu, L.; Mou, X.-Q.; Chen, Z.M.; Wang, S.-H. Chem. Commun. 2014, 50, 10676. (f) Wang, D.; Wang, F.; Chen, P.; Lin, Z.; Liu, G. Angew. Chem., Int. Ed. 2017, 56, 2054. (20) For selected heteroazidations, see: Diazidation: (a) Yuan, Y.-A.; Lu, D.-F.; Chen, Y.-R.; Xu, H. Angew. Chem., Int. Ed. 2016, 55, 534. Aminoazidation: (b) Sequeira, F. C.; Turnpenny, B. W.; Chemler, S. R. Angew. Chem., Int. Ed. 2010, 49, 6365. (c) Sequeira, F. C.; Chemler, S. R. Org. Lett. 2012, 14, 4482. (d) Zhang, B.; Studer, A. Org. Lett. 2014, 16, 1790. Oxyazidation: (e) Zhang, B.; Studer, A. Org. Lett. 2013, 15, 4548. (f) Zhu, L.; Yu, H.; Xu, Z.; Jiang, X.; Lin, L.; Wang, R. Org. Lett. 2014, 16, 1562. (g) Sun, X.; Li, X.; Song, S.; Zhu, Y.; Liang, Y.-F.; Jiao, N. J. Am. Chem. Soc. 2015, 137, 6059. (h) Fumagalli, G.; Rabet, P. T. G.; Boyd, S.; Greaney, M. F. Angew. Chem., Int. Ed. 2015, 54, 11481. Hydroazidation: (i) Waser, J.; Nambu, H.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 8294. (j) Kapat, A.; König, A.; Montermini, F.; Renaud, P. J. Am. Chem. Soc. 2011, 133, 13890. (k) Leggans, E. K.; Barker, T. J.; Duncan, K. K.; Boger, D. L. Org. Lett. 2012, 14, 1428. (l) Meyer, D.; Renaud, P. Angew. Chem., Int. Ed. 2017, 56, 10858. (21) (a) Hang, Z.; Li, Z.; Liu, Z.-Q. Org. Lett. 2014, 16, 3648. (b) Zhang, L.; Li, Z.; Liu, Z.-Q. Org. Lett. 2014, 16, 3688. (22) For selected reviews on chemistry of hypervalent iodines, see: (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299. (b) Dohi, T.; Ito, M.; Yamaoka, N.; Morimoto, K.; Fujioka, H.; Kita, Y. Tetrahedron 2009, 65, 10797. (c) Brand, J. P.; Gonzalez, D. F.; Nicolai, S.; Waser, J. Chem. Commun. 2011, 47, 102. (d) Narayan, R.; Manna, S.; Antonchick, A. P. Synlett 2015, 26, 1785. (e) Wang, X.; Studer, A. Acc. Chem. Res. 2017, 50, 1712.

Multicomponent Reactions in Organic Synthesis; Zhu, J., Wang, Q., Wang, M.-X., Eds.; Wiley-VCH: Verlag GmbH & Co. KGaA, 2015; pp 401− 438. (2) For a review on radical multicomponent tandem reactions, see: Godineau, E.; Landais, Y. Chem. - Eur. J. 2009, 15, 3044. (3) For an exhaustive review on unimolecular free-radical cascade processes, see: McCarroll, A. J.; Walton, J. C. Angew. Chem., Int. Ed. 2001, 40, 2224. (4) (a) Mizuno, K.; Ikeda, M.; Toda, S.; Otsuji, Y. J. Am. Chem. Soc. 1988, 110, 1288. For reviews on radical carboallylation, see: (b) Porter, N. A.; Giese, B.; Curran, D. P. Acc. Chem. Res. 1991, 24, 296. (c) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163. (d) Sibi, M. P.; Manyem, S.; Zimmerman, J. Chem. Rev. 2003, 103, 3263. (5) For reviews on radical cascade carbonylation, see: (a) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. Rev. 1996, 96, 177. (b) Ryu, I.; Sonoda, N. Angew. Chem., Int. Ed. Engl. 1996, 35, 1050. (c) Ryu, I. Chem. Soc. Rev. 2001, 30, 16. (d) Tojino, M.; Ryu, I. Free-radical-mediated Multicomponent Coupling Reactions; In Multicomponent Reactions; Zhu, J., Bienaymé, H., Eds.; Wiley-VCH: Weinheim, 2005, pp 169−198. (6) For multicomponent cascade radical azidation, see: (a) Lapointe, G.; Kapat, A.; Weidner, K.; Renaud, P. Pure Appl. Chem. 2012, 84, 1633. (b) Ollivier, C.; Renaud, P. J. Am. Chem. Soc. 2001, 123, 4717. (c) Renaud, P.; Ollivier, C.; Panchaud, P. Angew. Chem., Int. Ed. 2002, 41, 3460. (d) Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett. 2002, 4, 4257. (e) Panchaud, P.; Renaud, P. Chimia 2004, 58, 232. (f) Chabaud, L.; Landais, Y.; Renaud, P.; Robert, F.; Castet, F.; Lucarini, M.; Schenk, K. Chem. - Eur. J. 2008, 14, 2744. (7) (a) Harris, E. F. P.; Waters, W. A. Nature 1952, 170, 212. (b) Barrett, K. E. J.; Waters, W. A. Discuss. Faraday Soc. 1953, 14, 221. (8) (a) Walling, C. Free Radicals in Solution; John Wiley & Sons: New York, 1957. (b) Walling, C. Pure Appl. Chem. 1967, 15, 69. (9) (a) Tedder, J. M. Angew. Chem., Int. Ed. Engl. 1982, 21, 401. (b) Giese, B. Angew. Chem., Int. Ed. Engl. 1985, 24, 553. (10) Roberts, B. P. Chem. Soc. Rev. 1999, 28, 25. (11) For selected reviews on Minisci reactions, see: (a) Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28, 489. (b) Duncton, M. A. J. MedChemComm 2011, 2, 1135. For selected recent examples, see: (c) Correia, C. A.; Yang, L.; Li, C.-J. Org. Lett. 2011, 13, 4581. (d) Antonchick, A. P.; Burgmann, L. Angew. Chem., Int. Ed. 2013, 52, 3267. (e) Matcha, K.; Antonchick, A. P. Angew. Chem., Int. Ed. 2013, 52, 2082. (f) Zhao, W.-M.; Chen, X.-L.; Yuan, J.-W.; Qu, L.-B.; Duan, L.-K.; Zhao, Y.-F. Chem. Commun. 2014, 50, 2018. (g) DiRocco, D. A.; Dykstra, K.; Krska, S.; Vachal, P.; Conway, D. V.; Tudge, M. Angew. Chem., Int. Ed. 2014, 53, 4802. (h) Neubert, T. D.; Schmidt, Y.; Conroy, E.; Stamos, D. Org. Lett. 2015, 17, 2362. (i) Jin, J.; MacMillan, D. W. C. Nature 2015, 525, 87. (j) Jin, J.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2015, 54, 1565. (k) Paul, S.; Guin, J. Chem. - Eur. J. 2015, 21, 17618. (l) McCallum, T.; Barriault, L. Chem. Sci. 2016, 7, 4754. (m) Li, G.-X.; Morales-Rivera, C. A.; Wang, Y.; Gao, F.; He, G.; Liu, P.; Chen, G. Chem. Sci. 2016, 7, 6407. (n) Lo, J. C.; Kim, D.; Pan, C.-M.; Edwards, J. T.; Yabe, Y.; Gui, J.; Qin, T.; Gutiérrez, S.; Giacoboni, J.; Smith, M. W.; Holland, P. L.; Baran, P. S. J. Am. Chem. Soc. 2017, 139, 2484. (o) Liu, S.; Liu, A.; Zhang, Y.; Wang, W. Chem. Sci. 2017, 8, 4044. (p) Cheng, W.M.; Shang, R.; Fu, Y. ACS Catal. 2017, 7, 907. (q) Matsui, J. K.; Primer, D. N.; Molander, G. A. Chem. Sci. 2017, 8, 3512. (12) For selected recent transition-metal-catalyzed alkylations of a heterocycle, see: (a) Xiao, B.; Liu, Z.-J.; Liu, L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 616. (b) Wu, X.; See, J. W. T.; Xu, K.; Hirao, H.; Roger, J.; Hierso, J.-C.; Zhou, J. Angew. Chem., Int. Ed. 2014, 53, 13573. (c) Schramm, Y.; Takeuchi, M.; Semba, K.; Nakao, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2015, 137, 12215. (d) Jo, W.; Kim, J.; Choi, S.; Cho, S. H. Angew. Chem., Int. Ed. 2016, 55, 9690. (e) Murakami, K.; Yamada, S.; Kaneda, T.; Itami, K. Chem. Rev. 2017, 117, 9302. (13) Minisci, F.; Citterio, A. Acc. Chem. Res. 1983, 16, 27−32. (14) Antonietti, F.; Mele, A.; Minisci, F.; Punta, C.; Recupero, F.; Fontana, F. J. Fluorine Chem. 2004, 125, 205−211. (15) For discussions on scale of electrophilicity and nucleophilicity for radicals, see: (a) Heberger, K.; Lopata, A. J. Org. Chem. 1998, 63, 8646. (b) Fischer, H.; Radom, L. Angew. Chem., Int. Ed. 2001, 40, 1340. 5652

DOI: 10.1021/acs.orglett.7b02788 Org. Lett. 2017, 19, 5649−5652