Photocatalyzed Site-Selective C(sp3)–H Functionalization of

Nov 20, 2017 - Encouraged by our findings that no C–H functionalization took place α to carbonyl and cyano groups due to polar effects,(5-7) we bec...
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Photocatalyzed Site-Selective C(sp3)−H Functionalization of Alkylpyridines at Non-Benzylic Positions Takahide Fukuyama,† Tomohiro Nishikawa,† Keiichi Yamada,† Davide Ravelli,‡ Maurizio Fagnoni,‡ and Ilhyong Ryu*,†,§ †

Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka, 599-8531, Japan PhotoGreen Lab, Department of Chemistry, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy § Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan ‡

S Supporting Information *

ABST RA CT : Tetrabutylammonium decatungstate (TBADT)-photocatalyzed C−H functionalization of alkylpyridines was investigated. Unlike alkylbenzene counterparts, alkylation of α-C−H bonds did not proceed for the reaction of 2- and 4-alkylpyridines and reluctantly proceeded for 3alkylpyridines, which allow site-selective C(sp3)−H functionalization at nonbenzylic positions. The observed nonbenzylic site selectivities are rationalized by the polar inductive effects of pyridyl groups in the SH2 transition states. Consecutive γfunctionalization and α-bromofunctionalization were successfully carried out in selected cases. As the first model compound, we tested the reaction of 2propylpyridine (1a). When the reaction of 1a with dimethyl maleate (2a) was carried out in the presence of the TBADT catalyst under irradiation with a Xe lamp (300 W) for 24 h, βalkylated product 3a-β and γ-alkylated product 3a-γ were obtained in 69% total yield with a ratio of 86/14 (Scheme 2, eq 4). As expected, no formation of α-alkylated product was observed, which was confirmed by careful examination of the crude reaction mixture. In sharp contrast to this result, the C− H functionalization of propylbenzene (4) favored α-functionalization. In the reaction between propylbenzene (4) and fumaronitrile (2b), α-hydrogen abstraction took place with 76% selectivity (Scheme 2, eq 5). The failure of α-C−H functionalization for propylpyridine (1a) is ascribed to the unfavorable SH2 transition state by polar effects. This distinct result led us to assess the site selectivity of a variety of alkylpyridines, and the results are shown in Table 1. Similar to the case giving 3a, the reaction of 2-isobutylpyridine (1b) avoided α-C−H functionalization to give a mixture of βand γ-alkylated products in a 90/10 ratio (entry 2). When 2isopentylpyridine (1c) was used, alkylation took place at the γmethine C−H bond selectively to give 3c-γ as the sole product (entry 3). The reaction of 1c with electron-deficient alkenes 2c, 2d, 2e, and 2f gave the corresponding γ-alkylated products 3dγ, 3e-γ, 3f-γ, and 3g-γ with perfect site selectivity (entries 4−7). In the case of 3-propylpyridine (1d), β- and γ-alkylated products were obtained in a ratio of 50/14 (3h-β as the major

T

he site-selective functionalization of C(sp3)−H bonds remains a challenge in modern organic chemistry,1 and free radical-mediated approaches have attracted considerable attention.2 Tetrabutylammonium decatungstate (TBADT),3 when photoexcited, abstracts hydrogen from C(sp3)−H bonds reversibly to generate alkyl radicals and TBADT-H, and this unit sequence has been applied for many photocatalytic C−H functionalization reactions.3−8 We found that the SH2 transition states between C−H and decatungstate anion are highly influenced by radical polar and steric effects and reported distinct examples of site-selective functionalization of C(sp3)−H bonds of aliphatic ketones, esters, lactones, and nitriles.5−7 TBADT-catalyzed C−H functionalization of alkylbenzenes was previously reported,4e in which benzylic C(sp3)−H functionalization of toluene, xylenes, ethylbenzene, indane, cumene, and some other methyl-substituted aromatics proceeded preferentially (Scheme 1, eq 1).4e A recent example includes the TBADT-catalyzed benzylic fluorination of alkylbenzenes by Britton and co-workers (Scheme 1, eq 2).8 Encouraged by our findings that no C−H functionalization took place α to carbonyl and cyano groups due to polar effects,5−7 we became curious whether the introduction of a nitrogen atom into the aromatic ring would alter the site selectivity of C−H functionalization of the attached alkyl chain (Scheme 1, eq 3). In this letter we report that C(sp3)−H functionalization of alkylpyridines by TBADT photocatalysis proceeds with complete or a high degree of site selectivity to avoid functionalization of benzylic C−H bonds. These observations are rationalized by the polar effects in the SH2 transition states.9 © 2017 American Chemical Society

Received: October 26, 2017 Published: November 20, 2017 6436

DOI: 10.1021/acs.orglett.7b03339 Org. Lett. 2017, 19, 6436−6439

Letter

Organic Letters Scheme 1. Site Selectivity in TBADT-Photocatalyzed C−H Functionalization of Alkylbenzenes and Alkylpyridines

Table 1. TBADT-Catalyzed C−H Functionalization of Alkylpyridines 1 with 2a

Scheme 2. Comparison of TBADT-Photocatalyzed Functionalizations of 2-Propylpyridine 1a and Propylbenzene 4

a

Reaction conditions: 1 (5 mmol), 2 (0.5 mmol), TBADT (4 mol %), MeCN (1 mL). Irradiation carried out by using a Xe lamp (300 W, Pyrex) for 24 h. bNumbers with dashed arrow show the site selectivity of the reaction. cOverall yield of alkylated products isolated after flash chromatography on SiO2; only the major (or exclusive) isomer has been reported. 6437

DOI: 10.1021/acs.orglett.7b03339 Org. Lett. 2017, 19, 6436−6439

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Organic Letters isomer, entry 8). In this case, hydrogen abstraction at the αposition also took place to a small extent, and the resulting benzyl radical reacted with another molecule of 3-propylpyridine via a Minisci-type reaction4g to give the dimer products (for details, see Supporting Information (SI)). In the reaction of 3-isobutylpyridine (1e) and 3-isopentylpyridine (1f), alkylation took place at the methine C−H bond selectively (entries 9 and 10). The reaction of 4-alkylpyridines 1g, 1h, and 1i gave similar site-selective results as those of 2-alkylpyridines (entries 11−13). As mentioned above, C−H functionalization of propylbenzene (4) mainly took place at the α-position. In the case of isobutylbenzene and isopentylbenzene, both α-hydrogen and methine C−H functionalization took place (for details, see SI). Unlike these alkylbenzenes, no α-alkylation took place for eight of the alkylpyridines examined, and only a small degree of αalkylation was observed for 3-propylpyridine 1d. The general avoidance of α-functionalization would be rationalized by the transition states influenced by unfavorable inductive polar effects originated from the pyridine ring. In the case of 1d, the formation of a small amount of α-products would be caused by the weaker inductive effect of the 3-pyridyl group compared with 2- and 4-pyridyl groups. As for the selectivity in the β-position, the weaker inductive effect ensured the exclusive alkylation of 3-isobutylpyridine (1e) in the methine C−H bond. On the other hand, incomplete methine C−H selectivity (ca. 90%) over methyl γ-C−H (ca. 10%) for 2and 4-isobutylpyridines 1b and 1h was due to the more pronounced inductive effect inherent to the position of nitrogen atom (Scheme 3, upper part).6,7 Noteworthy, there

of benzoyl peroxide (BPO), bromination took place at the benzylic position to give 6a in a 79% yield (Scheme 4, eq 6). Similarly, α-selective bromination of 3f-γ was successful to give 6b in a 60% yield (Scheme 4, eq 7). Scheme 4. Consecutive γ- and α-C−H Functionalization of 2-Isopentylpyridine 1c

In summary, we have demonstrated that TBADT-photocatalyzed C−H functionalization of alkylpyridines exhibited contrasting site selectivity with the corresponding alkylbenzenes. In general, C−H abstraction at the α-position was suppressed and, as a result, nonbenzylic C−H functionalization became possible as the preferred reaction course. Radical polar effects in the SH2 transition states can explain the unfavorable benzylic C−H functionalization. Application to consecutive functionalization at the γ- and α-positions was successful. We believe that polar-effects-driven design for site-selective C(sp3)−H functionalization could be extended to alkyl-tethered heteroaromatics, and research along this line is now ongoing in our laboratories.

Scheme 3. Proposed TSs for Benzylic C−H Cleavage in Alkylpyridines (unfavorable) by Decatungstate Anion and Acidity of the Benzylic Hydrogens Hα in Benzylpyridines and Diphenylmethane

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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/acs.orglett.7b03339. Detailed experimental procedures and spectroscopic data of all products (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Takahide Fukuyama: 0000-0002-3098-2987 Davide Ravelli: 0000-0003-2201-4828 Maurizio Fagnoni: 0000-0003-0247-7585 Notes

is a rough correlation between the capability of the excited TBADT to abstract benzylic hydrogens (Hα) with their acidity.10 The less acidic (or electrophilic) the H is, the more efficient the benzylic functionalization is (Scheme 3, lower part). We then examined consecutive C−H functionalization of 2isopentylpyridine. When the γ-C−H alkylation product 3c-γ was treated with N-bromosuccinimide (NBS) in the presence

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by Grants-in-Aid for Scientific Research (A) (26248031) from JSPS and Scientific Research on Innovative Areas 2707 Middle Molecular Strategy (15H05850) from MEXT. 6438

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Organic Letters

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REFERENCES

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DOI: 10.1021/acs.orglett.7b03339 Org. Lett. 2017, 19, 6436−6439