Anti-Markovnikov Hydroarylation of Unactivated Olefins via Pyridyl

May 4, 2017 - This process occurs with complete regiocontrol, where single-electron reduction of halogenated pyridines regiospecifically yields the co...
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Anti-Markovnikov Hydroarylation of Unactivated Olefins via Pyridyl Radical Intermediates Allyson J. Boyington, Martin-Louis Y. Riu, and Nathan T. Jui* Department of Chemistry, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, United States S Supporting Information *

ABSTRACT: The intermolecular alkylation of pyridine units with simple alkenes has been achieved via a photoredox radical mechanism. This process occurs with complete regiocontrol, where single-electron reduction of halogenated pyridines regiospecifically yields the corresponding radicals in a programmed fashion, and radical addition to alkene substrates occurs with exclusive antiMarkovnikov selectivity. This system is mild, tolerant of many functional groups, and effective for the preparation of a wide range of complex alkylpyridines.

H

eteroaromatic units are important structural features in bioactive small molecules, and pyridines are among the most highly represented heterocycles in pharmaceuticals.1 As a result, new methods for the construction of complex pyridines from abundant precursors is an important synthetic goal. Simple alkenes are ideal starting materials because they are highly abundant and stable. Hydroarylation, the addition of Ar−H across simple alkenes, is an attractive strategy for the construction of alkylarenes, and much progress has been made to enable this type of process.2−6 While simple olefin hydroarylation with pyridines remains challenging, Herzon and Shenvi described radical-based systems that efficiently accomplish selective formation of the branched alkylpyridine isomers (Markovnikov selectivity).7,8 To date, there are two distinct approaches to antiMarkovnikov hydroarylation with pyridines that both involve metal insertion into C−H bonds at elevated temperature. Lewis, Bergman, and Ellman described the ability of Rh(I) catalyst to accomplish the addition of 2-substituted pyridines to a range of alkenes, via N-heterocyclic carbene intermediates.9 Importantly, this approach delivers 2,6-disubstituted pyridines with complete regiocontrol (Figure 1). The groups of Nakao and Hiyama10 and Ong11 independently described a complementary strategy for selective functionalization of the pyridyl 4-position that operates through a bimetallic Lewis acid/Ni(0) cooperative catalytic system. An effective method for simple alkene hydropyridylation that allows for selective alkylation at any position on the pyridine ring (in a predictable and controllable manner) would be valuable, particularly if it operated at ambient temperature with high functional group tolerance. Here, we describe the realization of these objectives. Our system is founded on the understanding that highly reactive pyridyl radicals can be readily accessed via single electron reduction of pyridyl halides.12−14 We, and others, have demonstrated that photoredox catalysts15,16 are capable of © 2017 American Chemical Society

Figure 1. Strategies for anti-Markovnikov hydroarylation of simple alkenes with pyridines.

accomplishing (hetero)aryl radical formation through this manifold.17−21 Importantly, the resulting radicals can be utilized in a number of valuable synthetic processes. We recently demonstrated that nucleophilic pyridyl radical species effectively engage a wide range of electron-poor alkenes, in the presence of a stoichiometric reductant, to give conjugate addition products.21 We questioned whether simple alkenes could be employed as coupling partners for pyridyl radicals under a similar mechanistic model. More specifically, reductive radical formation followed by regioselective intermolecular addition to simple alkenes and radical termination via hydrogen-atom transfer (HAT) would deliver linear alkylpyridines, a pathway that Weaver has nicely demonstrated for 2-haloazoles and polyfluorinated arenes.18 Because substituted pyridines containing halogenation at any position (i.e., the 2-, 3-, 4-, 5-, or 6-position) are available and radical formation is regiospecific,13,14,22 the outlined approach could grant access to all of the possible regioisomeric hydroarylation products. Finally, pyridyl radicals can be formed by the action of reducing photoredox catalysts under very mild conditions, and they display orthogonal reactivity to many functional groups. Received: March 31, 2017 Published: May 4, 2017 6582

DOI: 10.1021/jacs.7b03262 J. Am. Chem. Soc. 2017, 139, 6582−6585

Communication

Journal of the American Chemical Society We began our study by evaluating the coupling of 1-octene (3 equiv) with 2-bromo-6-methylpyridine in the presence of a slight excess (1.3 equiv) of Hantzsch ester (HEH) and 1.0 mol % of the commercial photosensitizer Ir(ppy)2dtbbpy·PF6.23 After irradiation with a commercial blue LED for 16 h in a range of polar solvents, the desired radical hydroarylation product (1) was observed, albeit in low yield (Table 1, entries 1−5, 4−21% yield).

Table 2. Catalytic Olefin Hydroarylation: Halopyridine Scopea

Table 1. Optimization of Conditions for Simple Alkene Hydroarylationa

entry

solvent

1 2 3 4 5 6 7 8 9

25% H2O/DMSO DMSO DMF CH3CN CH3OH CF3CH2OH CF3CH2OH CF3CH2OH CF3CH2OH

additive

yield of 1b (%)

lutidine (1 equiv) AcOH (2 equiv) NH4Cl (2 equiv)

4 19 5 17 21 74 4 77 87

a

Conditions: 2-bromo-6-methylpyridine (0.25 mmol), 1-octene (0.75 mmol), Ir(ppy)2dtbbpy·PF6 (1.0 mol %), Hantzsch ester (0.325 mmol), 2,2,2-trifluoroethanol (2.5 mL), blue LED, 23 °C, 16 h. bYield determined by GC.

In these experiments, 2-picoline production (via hydrodehalogenation) was a significant deleterious pathway. However, the use of 2,2,2-trifluoroethanol as the solvent was uniquely promising, delivering the desired octylpyridine 1 in 74% yield (entry 6) without observable formation of picoline. We found that the reaction outcome was greatly impacted by the acidity/basicity of the reaction mixture. For example, the addition of lutidine (1.0 equiv) had a strong inhibitory effect on the reaction (entry 7, 4% yield), and the addition of 2 equiv of acetic acid or ammonium chloride allowed for complete conversion of the bromopyridine starting material (entries 8 and 9, 77% and 87% yield, respectively). Importantly, the desired linear coupled product was obtained with complete regiocontrol; the branched isomer was not detected by 1H NMR or GCMS. Having identified effective conditions for anti-Markovnikov hydroarylation of octene, we studied the scope of halogenated pyridines (pyridyl radical precursors). The results are illustrated in Table 2. There is no apparent requirement for specific substitution patterns (or lack thereof) in this system, and unsubstituted or alkyl-substituted pyridyl halides react to give mono-, di-, or trialkylpyridines 2−9 with good efficiency (66− 89% yield). In general, alkylation of the 2- and 4-positions is achieved through reductive radical formation from the corresponding bromopyridines, and alkylation of the 3-position is most efficient when the corresponding iodopyridines are employed. Electron-donating substituents are tolerated, including the phenol (10, 40% yield), carbamate (11, 52% yield), or amide (13, 53% yield) groups. While the yields of these products are lower, they exemplify the ability to functionalize compounds with acidic N−H or O−H bonds. In addition, the electron-poor 2-iodo-5-trifluoromethylpyridine couples to give the desired product 12 in 54% yield. Both 2,3- and 3,4-dibromopyridines

a

Conditions: halopyridine (1.0 mmol), 1-octene (3.0 mmol), Ir(ppy)2dtbbpy·PF6 (1.0 mol %), Hantzsch ester (1.3 mmol), 2,2,2trifluoroethanol (10.0 mL), blue LED, 23 °C, 16 h, isolated yields shown. bPyridine hydrochloride salt was used as starting material.

underwent selective activation of one of the C−Br bonds to ultimately give products 14 and 16 in 41% and 57% yield, respectively.24 This is noteworthy because it demonstrates both preferential radical formation at the most electrophilic 2- and 4positions (which parallels SNAr reactivity patterns25) and preservation of the second pyridyl bromide functional group for further synthetic elaboration. We investigated the scope of the olefin coupling partner using 3-iodopyridine as the radical precursor. As illustrated in Table 3, these trifluoroethanol-based photoredox conditions effectively couple a range of simple, unactivated alkenes. Allylic carbamate (17, 78% yield), alcohol (18−20, 76−83% yield), and ketone (21, 71% yield) derivatives are tolerated, as are the silane (22, 72% yield), primary alkyl chloride (23, 89% yield), and phosphonate (24, 61% yield) groups. Again, we observed exclusive formation of the linear (anti-Markovnikov) alkylpyridines in this system. In addition to monosubstituted alkenes, the disubstituted internal alkenes 2,5-dihydrofuran, norbornene, and cyclohexene smoothly react to afford the desired products 26− 28 in useful yields (42−82%). The 1,1-disubstituted alkenes methylenepiperidine and 2-methylheptene reacted with 36583

DOI: 10.1021/jacs.7b03262 J. Am. Chem. Soc. 2017, 139, 6582−6585

Communication

Journal of the American Chemical Society Table 3. Catalytic Olefin Hydroarylation: Scope of the Simple Alkenea

a

Conditions: 3-iodopyridine (1.0 mmol), alkene (3.0 mmol), Ir(ppy)2dtbbpy·PF6 (1.0 mol %), Hantzsch ester (1.3 mmol), NH4Cl (2.0 mmol), 2,2,2-trifluoroethanol (10.0 mL), blue LED, 23 °C, 16 h, isolated yields shown. bYield determined by NMR. cPyridine hydrochloride salt was used as starting material. d2:1 regioisomeric ratio (biaryl connectivity of the minor isomer is indicated by the asterisk). eConditions: bromopyridine (1.0 mmol), arene (5.0 mmol), Ir(ppy)2dtbbpy·PF6 (1.0 mol %), Hantzsch ester (1.3 mmol), TFA (2.0 mmol), 2,2,2-trifluoroethanol (10.0 mL), blue LED, 23 °C, 16 h.

Scheme 1. Competition Experiments: Solvent Dictates Reactivity Profile of Pyridyl Radicals

iodopyridine to give the corresponding 3-alkylated products 25 and 30 in 67% and 78% yield, respectively. As expected, alkylation of the 2- or 4-position of with 2-methylheptene was possible when the 2- or 4-bromopyridine substrates were employed (2-position, 29 (91% yield); 4-position, 31 (74% yield)). When allylbenzene was used as substrate, we observed efficient alkene hydroarylation (32, 76% yield), accompanied by 12% yield of the 3-arylpyridine products 32a (2:1 mixture of regioisomers). Simply substituting trifluoroacetic acid for

ammonium chloride under otherwise identical conditions allowed for the efficient coupling of pyridyl radical units with benzene derivatives (5 equiv).20,26−28 While we have not extensively evaluated the scope of this arylation process, a brief study indicated that a range of phenylpyridine derivatives would be accessible using this protocol (e.g., 33−35, 67−91% yield). In contrast to our previous report in this area, where pyridyl radical intermediates displayed nucleophilic reactivity (through effective coupling with Michael acceptors in aqueous DMSO),21 6584

DOI: 10.1021/jacs.7b03262 J. Am. Chem. Soc. 2017, 139, 6582−6585

Communication

Journal of the American Chemical Society

(14) Enemærke, R. J.; Christensen, T. B.; Jensen, H.; Daasbjerg, K. J. Chem. Soc. Perkin Trans. 2 2001, 9, 1620. (15) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322. (16) Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116, 10075. (17) Nguyen, J. D.; D’Amato, E. M.; Narayanam, J. M. R.; Stephenson, C. R. J. Nat. Chem. 2012, 4, 854. (18) (a) Arora, A.; Weaver, J. D. Acc. Chem. Res. 2016, 49, 2273. (b) Singh, A.; Kubik, J. J.; Weaver, J. D. Chem. Sci. 2015, 6, 7206. (c) Arora, A.; Weaver, J. D. Org. Lett. 2016, 18, 3996. (19) Discekici, E. H.; Treat, N. J.; Poelma, S. O.; Mattson, K. M.; Hudson, Z. M.; Luo, Y.; Hawker, C. J.; de Alaniz, J. R. Chem. Commun. 2015, 51, 11705. (20) Ghosh, I.; Marzo, L.; Das, A.; Shaikh, R.; Konig, B. Acc. Chem. Res. 2016, 49, 1566. (21) Aycock, R. A.; Wang, H.; Jui, N. T. Chem. Sci. 2017, 8, 3121. (22) Costentin, C.; Robert, M.; Savéant, J. J. Am. Chem. Soc. 2004, 126, 16051. (23) Lowry, M. S.; Hudson, W. R.; Pascal, R. A.; Bernhard, S. J. Am. Chem. Soc. 2004, 126, 14129. (24) In these cases, incomplete conversion of the dihalopyridine was observed and not double alkylation or product dehalogenation. (25) Bunnett, J. F.; Zahler, R. E. Chem. Rev. 1951, 49, 273. (26) Poelma, S. O.; Burnett, G. L.; Discekici, E. H.; Mattson, K. M.; Treat, N. J.; Luo, Y.; Hudson, Z. M.; Shankel, S. L.; Clark, P. G.; Kramer, J. W.; Hawker, C. J.; Read De Alaniz, J. J. Org. Chem. 2016, 81, 7155. (27) Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.; Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc. 2010, 132, 13194. (28) Senaweera, S.; Weaver, J. D. J. Am. Chem. Soc. 2016, 138, 2520. (29) For a discussion on radical nucleophilicity/electrophilicity, see: Giese, B. Angew. Chem., Int. Ed. Engl. 1983, 22, 753. (30) The same selectivity is observed in trifluoroethanol without added ammonium chloride, but conversion of starting material is lower.

pyridyl radicals that are generated in this system (slightly acidic trifluoroethanol as solvent) preferentially react with electron-rich alkenes. To clearly illustrate this differential behavior,29 we conducted the competition experiments that are shown in Scheme 1. Specifically, 2-bromo-6-methylpyridine was activated in the presence of both 1-octene and ethyl crotonate (2 equiv each). In aqueous DMSO without added acid, we observed exclusive formation of the radical conjugate addition product 36 (47% yield), and product 1 was not formed. The use of trifluoroethanol solvent with added ammonium chloride resulted in highly selective formation of the octene hydroarylation product 1 (68% yield), along with 2% yield of 36.30 In conclusion, we have developed a mild catalytic system that enables the general hydroarylation of simple alkenes with pyridine units. This method allows for the installation of alkyl substituents at any position of the pyridine rings and tolerates a wide range of functional groups. Key to this development was the finding that the use of trifluoroethanol as the solvent imparts electrophilic character on the pyridyl radical intermediates. Further mechanistic studies and the development of related processes are ongoing in our laboratory.

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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.7b03262. Experimental procedures and spectral data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Nathan T. Jui: 0000-0001-5315-0270 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This project was supported by funds from Emory University and Winship Cancer Institute. REFERENCES

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DOI: 10.1021/jacs.7b03262 J. Am. Chem. Soc. 2017, 139, 6582−6585