Photocatalyzed Site-Selective C(sp3)-H Functionalization of Alkylpyridines at Non-Benzylic Positions

Article abstract of DOI:10.1021/acs.orglett.7b03339

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 3-alkylpyridines, 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 S_H2 transition states. Consecutive γ-functionalization and α-bromofunctionalization were successfully carried out in selected cases.

Full text of DOI:10.1021/acs.orglett.7b03339

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
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
ABSTRACT: Tetrabutylammonium decatungstate
(TBADT)-photocatalyzed C−H functionalization of alkylpyr-
idines 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 3-
alkylpyridines, which allow site-selective C(sp3)−H function-
alization at nonbenzylic positions. The observed nonbenzylic
site selectivities are rationalized by the polar inductive effects
of pyridyl groups in the SH2 transition states. Consecutive γ-
functionalization and α-bromofunctionalization were success-
fully carried out in selected cases.
he site-selective functionalization of C(sp3)−H bonds
As the first model compound, we tested the reaction of 2-
1
Tremains a challenge in modern organic chemistry, and propylpyridine (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, β-
alkylated 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-function-
alization. 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 β-
and γ-alkylated products in a 90/10 ratio (entry 2). When 2-
isopentylpyridine (1c) was used, alkylation took place at the γ-
methine 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 3d-
γ, 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
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 photo-
catalytic 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
Received: October 26, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03339
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Site Selectivity in TBADT-Photocatalyzed C−H
Functionalization of Alkylbenzenes and Alkylpyridines
Table 1. TBADT-Catalyzed C−H Functionalization of
a
Alkylpyridines 1 with 2
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,
b
Pyrex) for 24 h. Numbers with dashed arrow show the site selectivity
c
of the reaction. Overall yield of alkylated products isolated after flash
chromatography on SiO2; only the major (or exclusive) isomer has
been reported.
B
DOI: 10.1021/acs.orglett.7b03339
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
isomer, entry 8). In this case, hydrogen abstraction at the α-
position also took place to a small extent, and the resulting
benzyl radical reacted with another molecule of 3-propylpyr-
idine 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).
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
As mentioned above, C−H functionalization of propylben-
zene (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 α-
alkylation 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 2-
and 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
In summary, we have demonstrated that TBADT-photo-
catalyzed C−H functionalization of alkylpyridines exhibited
contrasting site selectivity with the corresponding alkylben-
zenes. 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
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03339.
Detailed experimental procedures and spectroscopic data
of all products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ryu@c.s.osakafu-u.ac.jp.
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 2-
isopentylpyridine. 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.
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.
C
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Letter
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