Visible-light-induced C(sp3)-H oxidative arylation with heteroarenes

Article abstract of DOI:10.1021/acs.orglett.9b00744

Considering the ubiquitous C(sp³)-H and the important value of alkylated heteroarenes, developing a universal method for C(sp³)-H arylation with heteroarenes is significant. Herein, we proposed a method where Selectfluor can promote

Full text of DOI:10.1021/acs.orglett.9b00744

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Induced C(sp3)−H Oxidative Arylation with
Heteroarenes
Xing-An Liang,† Linbin Niu,† Shengchun Wang, Jiamei Liu, and Aiwen Lei*
Institute for Advanced Studies (IAS), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072,
People’s Republic of China
S
* Supporting Information
ABSTRACT: Considering the ubiquitous C(sp3)−H and the
important value of alkylated heteroarenes, developing a
universal method for C(sp3)−H arylation with heteroarenes
is significant. Herein, we proposed a method where Selectfluor
can promote the oxidative C(sp3)−H arylation with
heteroarenes without external photocatalysis under visible-
light irradiation. By EPR study, the N−F activation of
Selectfluor by blue LED irradiation can generate the N radical cation, which is the key step for this conversion.
lkanes, ethers, and methylarenes are ubiquitous bulk
A
chemicals whose C(sp3)−H functionalization to value-
added compounds is significant. Over the past decades,
oxidation-induced C(sp3)−H functionalization served as a
general route to forge C−C and C−X (N, S, O, etc.).1
Oxidative cross-coupling between two C−H compounds is the
most step- and atom-economical method to construct a C−C
bond.2 Considering that alkylated heteroarenes are widespread
constituents of medicines and materials,3 numerous impressive
works for the synthesis of these valuable compound have been
reported.4 With the development of photocatalysis,5 C(sp3)−
H arylation with heteroarenes is usually achieved by the
combination of a photocatalyst and stoichiometric peroxides,6
which can effectively avoid high temperatures. Because
different types of C(sp3)−H may have different physical
properties,7 such as cyclohexane, tetrahydrofuran, and toluene,
their bond dissociation energies (BDEs) are different (Figure
1a). Therefore, a novel and universal method for these
C(sp3)−H arylations is highly desired.
Selectfluor is known as a powerful fluorination regent and
oxidant.8 A one-electron reduction event is considered the key
step for the N−F breakage of Selectfluor, delivering an N
radical cation and F anion. Direct photoinduced N−F
activation of Selectfluor to generate the N radical cation and
F radical is unknown (Figure 1b). Herein, we demonstrate a
visible-light-induced Selectfluor-mediated selective C(sp3)−H
arylation by using heteroaromatic compounds as the aryl
source (Figure 1c). The electron paramagnetic resonance
(EPR) experiments evidence that visible light can induce the
N−F activation of Selectfluor, which is the key step for this
transformation. A series of alkanes, ethers, and methylbenzenes
exhibit good reactivities and delivery of desired alkylated
heteroarenes.
Figure 1. Oxidative C(sp3)−H arylation with heteroarenes.
effective oxidant under blue LED irradiation, and trifluoro-
acetic acid (TFA) was served as a suitable acid (Table 1, entry
1). It was notable that blue-light irradiation was necessary
because no product was detected when the reaction mixture
was treated under green LED irradiation or darkness (entries 2
and 3), implying that the longer wavelength visible light could
not induce N−F activation and led to the failure of this
transformation. Even when the reaction system was heated to
80 °C under darkness, the reactivity was still poor (entry 4). In
contrast, N-fluorobenzenesulfonimide (NFSI), as the analogue
Initially, we chose isoquinoline 1a and cyclohexane 2a as the
model substrates to investigate these visible-light-induced
oxidative C(sp3)−H arylation conditions. An excellent yield
of 95% was observed when Selectfluor was employed as an
Received: February 27, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00744
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Investigation of the Reaction Conditions
Scheme 1. Substrate Scope for the Oxidative C(sp3)−H
a
Arylation with Heteroarenes
entry
variation from the standard conditions
yield (%)
1
2
3
4
5
6
7
none
95
nd
nd
trace
trace
37
green LEDs instead of blue LEDs
darkness
80 °C instead of blue LEDs
K2S2O8 instead of Selectfluor
NSFI instead of Selectfluor
CH3COOH instead of TFA
20
a
Conditions: 1a (0.3 mmol), 2a (1.5 mL), Selectfluor (0.6 mmol),
TFA (0.45 mmol) in 2.0 mL of CH3CN under a nitrogen atmosphere,
irradiated by 3 W blue LEDs, rt, 24 h; isolated yields.
of Selectfluor, provided a low yield of 37% under the standard
conditions (entry 5). We proposed that the N−F activation of
NFSI may be more difficult than that of Selectfluor because the
BDE of NFSI is higher than that of Selectfluor.9 Commonly
used chemical oxidant potassium superoxide (K2S2O8) was
unable to drive the conversion under blue LED irradiation
(entry 6). When TFA was placed into acetic acid
(CH3COOH), the yield dropped rapidly (entry 7), which
indicated that TFA can effectively achieve the protonation of
heteroarenes.
With the suitable conditions in hand, we hoped that various
C(sp3)−H with heteroarenes could be efficiently transformed
into the corresponding alkylated heteroarenes by use of our
method (Scheme 1). Other cycloparaffins like cycloheptane,
cyclooctane, and cyclopentane could also successfully deliver
oxidative C(sp3)−H arylation products in good yields (3b−d).
Notably, a single site-selectivity for the more contorted
C(sp3)−H of norbornane was observed under the standard
conditions (3e). Subsequently, we attempted to expand the
simple C(sp3)−H to ethers. Not only did the chain ethers such
as ethoxyethane, 1-butoxybutane, and tert-butyl methyl ether
show excellent reactivity (3f−h) but also cyclic ethers like
tetrahydrofuran, tetrahydro-2H-pyran, 1,4-dioxane proceeded
in high efficiency (3i−k). At the same time, a series of
methylarenes were examined. It was delightful that toluene was
smoothly compatible with this system, providing the desired
benzylic C(sp3)−H arylation product (3l). Furthermore, p-
xylene and mesitylene were competent substrates (3m and
3n). The functional group on the toluene moiety (Cl) was well
tolerated (3o), providing the potential chance for further
chemical transformation. To extend the synthetic utility of this
methodology, other electron-deficient heteroarenes as aryl
source were investigated with cyclohexane to synthesize those
valuable alkylated heteroarenes. The quinolines with different
substituents could be converted into the desired products in
good yields under the same conditions (3p−r). Moreover,
benzothiazole behaved a satisfactory reactivity for the oxidative
C(sp3)−H arylation (3s).
a
Conditions: 1 (0.3 mmol), 2 (1.5 mL), Selectfluor (0.6 mmol), TFA
(0.45 mmol) in 2.0 mL of CH3CN under a nitrogen atmosphere,
irradiated by 3 W blue LEDs, rt, 24 h; isolated yields.
Figure 2. Gram-scale synthesis experiment.
To get a deeper understanding about this protocol, an
intermolecular kinetic isotope effect experiment was carried
out. A kinetic isotope effect (KIE) value of 3.00 was observed,
revealing that the cleavage of C(sp3)−H might be the rate-
determining step (see the Supporting Information for details).
When 2,2,6,6-tetramethylpiperidinooxy (TEMPO) as a radical-
trapping reagent was subjected to the standard reaction
conditions, the oxidative C(sp3)−H arylation of alkane was
totally suppressed, which indicated a radical pathway might be
involved (see the Supporting Information for details).
Additionally, the gram-scale synthesis experiment was
carried out (see the Supporting Information for details). A
comparable yield 82% was obtained when the model reaction
was performed in 10 mmol scale, providing promising
application in preparative synthesis (Figure 2).
B
DOI: 10.1021/acs.orglett.9b00744
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To reveal the detail mechanism of the blue-light-induced
Selectfluor-promoted oxidative C(sp3)−H arylation, the
electron paramagnetic resonance (EPR) experiments were
designed to observe the behavior of Selectfluor under blue-
light irradiation and darkness (Figure 3). When Selectfluor in
Figure 3. EPR spectra of Selectfluor under blue LED irradiation and
darkness.
Figure 5. Proposed mechanism for the oxidative C(sp3)−H arylation
with heteroarenes.
acetonitrile was irradiated by blue LEDs, two kinds of radical
signals were detected by utilizing 5,5-dimethyl-1-pyrroline N-
oxide (DMPO) as a radical scavenger. One of the radicals was
confirmed as the radical adduct between two fluorine radicals
and DMPO, while the other one resulted from the oxidation of
DMPO, whose ratio is 3:8.10.10 In contrast, we did not detect
the radical adduct between two fluorine radicals and DMPO in
the dark.
Finally, the intermolecular competition experiments were
designed to explore the preferred C(sp3)−H under this
oxidative C(sp3)−H arylation condition. As shown in Figure
4, the reaction rate of benzyl C(sp3)−H is much faster than
alkanes and ethers, while alkanes behaved a slower reactivity
than ethers.
nucleophilic radical and generate the radical adducts 8 (Figure
5c). Finally, further oxidation and deprotonation of this radical
adduct by another Selectfluor would then afford the C(sp3)−H
arylation product 3 (Figure 5d). Light on/off experiments
indicated that the radical-chain process might be impossible
(see the Supporting Information for details).
In conclusion, we have developed an intriguing and efficient
method for oxidative C(sp3)−H arylation with heteroarenes,
which was mediated by Selectfluor under blue LED irradiation.
The C(sp3)−H of simple alkanes, ethers, and methylarenes
under these special oxidative condition could be well tolerated.
The blue-light-induced N−F activation of Selectfluor evi-
denced by EPR study is key for this transformation. The
intermolecular competition experiments indicated that oxida-
tive methylarenes C(sp3)−H arylation are faster than ethers
and alkanes. The observed reactivity may have important
implications for chemical transformations.
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.9b00744.
Full experimental details and characterization data for all
products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: aiwenlei@whu.edu.cn.
ORCID
Figure 4. Intermolecular competition experiments.
Aiwen Lei: 0000-0001-8417-3061
Author Contributions
†X.-A.L. and L.N. contributed equally to this work.
Notes
On the basis of the above study, a plausible reaction
mechanism is shown in Figure 4. The N−F homolytic cleavage
of Selectfluor under blue LEDs irradiation can be achieved,
delivering the corresponding N radical cation 4 and F radical 5
(Figure 5a). The generated N radical cation is capable of
abstracting the sp3 C−H of cyclohexane to product the
corresponding alkyl radical 7 (Figure 5b). Then the electron-
deficient heteroarenes protonated by TFA can capture the
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science
Foundation of China (21520102003) and the Hubei Province
■
C
DOI: 10.1021/acs.orglett.9b00744
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
4057−4061. (g) Matsui, J. K.; Primer, D. N.; Molander, G. A. Chem.
Sci. 2017, 8, 3512−3522. (h) Nuhant, P.; Oderinde, M. S.; Genovino,
J.; Juneau, A.; Gagne, Y.; Allais, C.; Chinigo, G. M.; Choi, C.; Sach, N.
W.; Bernier, L.; Fobian, Y. M.; Bundesmann, M. W.; Khunte, B.;
Frenette, M.; Fadeyi, O. O. Angew. Chem., Int. Ed. 2017, 56, 15309−
15313. (i) Wu, X.; Zhang, H.; Tang, N.; Wu, Z.; Wang, D.; Ji, M.; Xu,
Y.; Wang, M.; Zhu, C. Nat. Commun. 2018, 9, 3343. (j) Zhang, L.;
Zhang, G.; Li, Y.; Wang, S.; Lei, A. Chem. Commun. 2018, 54, 5744−
5747.
(6) (a) Jin, J.; MacMillan, D. W. Angew. Chem., Int. Ed. 2015, 54,
1565−1569. (b) Quattrini, M. C.; Fujii, S.; Yamada, K.; Fukuyama,
T.; Ravelli, D.; Fagnoni, M.; Ryu, I. Chem. Commun. 2017, 53, 2335−
2338. (c) Deng, H. P.; Zhou, Q.; Wu, J. Angew. Chem., Int. Ed. 2018,
57, 12661−12665. (d) Rohe, S.; Morris, A. O.; McCallum, T.;
Barriault, L. Angew. Chem., Int. Ed. 2018, 57, 15664−15669.
(7) Xue, X. S.; Ji, P.; Zhou, B.; Cheng, J. P. Chem. Rev. 2017, 117,
8622−8648.
(8) (a) Pitts, C. R.; Bloom, M. S.; Bume, D. D.; Zhang, Q. A.;
Lectka, T. Chem. Sci. 2015, 6, 5225−5229. (b) Chen, H.; Liu, Z.; Lv,
Y.; Tan, X.; Shen, H.; Yu, H.-Z.; Li, C. Angew. Chem., Int. Ed. 2017,
56, 15411−15415. (c) Galloway, J. D.; Mai, D. N.; Baxter, R. D. Org.
Lett. 2017, 19, 5772−5775. (d) Ma, X.; Diane, M.; Ralph, G.; Chen,
C.; Biscoe, M. R. Angew. Chem., Int. Ed. 2017, 56, 12663−12667.
(e) Yuan, X.; Yao, J. F.; Tang, Z. Y. Org. Lett. 2017, 19, 1410−1413.
(f) Danahy, K. E.; Cooper, J. C.; Van Humbeck, J. F. Angew. Chem.,
Int. Ed. 2018, 57, 5134−5138. (g) Xie, L.-Y.; Qu, J.; Peng, S.; Liu, K.-
J.; Wang, Z.; Ding, M.-H.; Wang, Y.; Cao, Z.; He, W.-M. Green Chem.
2018, 20, 760−764. (h) Kee, C. W.; Chin, K. F.; Wong, M. W.; Tan,
C. H. Chem. Commun. 2014, 50, 8211−8214.
Natural Science Foundation of China (2017CFA010). The
Program of Introducing Talents of Discipline to Universities of
China (111 Program) is also appreciated.
REFERENCES
■
(1) (a) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.;
Baudoin, O. Chem. - Eur. J. 2010, 16, 2654−2672. (b) McMurray, L.;
O’Hara, F.; Gaunt, M. Chem. Soc. Rev. 2011, 40, 1885−1898.
(c) Newhouse, T.; Baran, P. S. Angew. Chem., Int. Ed. 2011, 50,
3362−3374. (d) Zhang, S. Y.; Zhang, F. M.; Tu, Y. Q. Chem. Soc. Rev.
2011, 40, 1937−1949. (e) Ramirez, T. A.; Zhao, B.; Shi, Y. Chem. Soc.
Rev. 2012, 41, 931−942. (f) Liu, C.; Liu, D.; Lei, A. Acc. Chem. Res.
2014, 47, 3459−3470. (g) Liu, C.; Yuan, J.; Gao, M.; Tang, S.; Li, W.;
Shi, R.; Lei, A. Chem. Rev. 2015, 115, 12138−12204. (h) Jie, X.;
Shang, Y.; Zhang, X.; Su, W. J. Am. Chem. Soc. 2016, 138, 5623−5633.
(i) Singh, K. S.; Sawant, S. G.; Dixneuf, P. H. ChemCatChem 2016, 8,
1046−1050. (j) Fu, N.; Sauer, G. S.; Lin, S. J. Am. Chem. Soc. 2017,
139, 15548−15553. (k) Li, Y.; Wang, C.; Zhu, F.; Wang, Z.; Dixneuf,
P. H.; Wu, X. F. ChemSusChem 2017, 10, 1341−1345. (l) Yi, H.;
Zhang, G.; Wang, H.; Huang, Z.; Wang, J.; Singh, A. K.; Lei, A. Chem.
Rev. 2017, 117, 9016−9085.
(2) (a) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J. Q. Angew. Chem.,
Int. Ed. 2009, 48, 5094−5115. (b) Cheng, K.; Huang, L.; Zhang, Y.
Org. Lett. 2009, 11, 2908−2911. (c) Li, B. J.; Shi, Z. J. Chem. Soc. Rev.
2012, 41, 5588−5598. (d) Park, S. J.; Price, J. R.; Todd, M. H. J. Org.
Chem. 2012, 77, 949−955. (e) Matcha, K.; Antonchick, A. P. Angew.
Chem., Int. Ed. 2013, 52, 2082−2086. (f) Rouquet, G.; Chatani, N.
Angew. Chem., Int. Ed. 2013, 52, 11726−11743. (g) Wei, W. T.; Zhou,
M. B.; Fan, J. H.; Liu, W.; Song, R. J.; Liu, Y.; Hu, M.; Xie, P.; Li, J. H.
Angew. Chem., Int. Ed. 2013, 52, 3638−3641. (h) Liu, D.; Liu, C.; Li,
H.; Lei, A. Chem. Commun. 2014, 50, 3623−3626.
(3) (a) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin.
Chem. Biol. 2010, 14, 347−361. (b) Duncton, M. A. J.
MedChemComm 2011, 2, 1135−1161. (c) Hu, Y. Q.; Gao, C.;
Zhang, S.; Xu, L.; Xu, Z.; Feng, L. S.; Wu, X.; Zhao, F. Eur. J. Med.
Chem. 2017, 139, 22−47.
(9) Rueda-Becerril, M.; Sazepin, C. C.; Leung, J. C.; Okbinoglu, T.;
Kennepohl, P.; Paquin, J. F.; Sammis, G. M. J. Am. Chem. Soc. 2012,
134, 4026−4029.
(10) (a) Buettner, G. R. Free Radical Biol. Med. 1987, 3, 259−303.
(b) Niu, L.; Liu, J.; Liang, X. A.; Wang, S.; Lei, A. Nat. Commun.
2019, 10, 467.
(4) (a) Deng, G.; Ueda, K.; Yanagisawa, S.; Itami, K.; Li, C. J. Chem.
- Eur. J. 2009, 15, 333−337. (b) He, T.; Yu, L.; Zhang, L.; Wang, L.;
Wang, M. Org. Lett. 2011, 13, 5016−5019. (c) Molander, G. A.;
Colombel, V.; Braz, V. A. Org. Lett. 2011, 13, 1852−1855.
(d) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder, E. D.; Dixon, D.
D.; Rodriguez, R. A.; Baxter, R. D.; Herle, B.; Sach, N.; Collins, M. R.;
Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95−99. (e) Antonchick, A.
P.; Burgmann, L. Angew. Chem., Int. Ed. 2013, 52, 3267−3271. (f) Xie,
Z.; Cai, Y.; Hu, H.; Lin, C.; Jiang, J.; Chen, Z.; Wang, L.; Pan, Y. Org.
Lett. 2013, 15, 4600−4603. (g) Wang, L.; Sha, W.; Dai, Q.; Feng, X.;
Wu, W.; Peng, H.; Chen, B.; Cheng, J. Org. Lett. 2014, 16, 2088−
2091. (h) Xia, R.; Xie, M. S.; Niu, H. Y.; Qu, G. R.; Guo, H. M. Org.
Lett. 2014, 16, 444−447. (i) Zhao, W. M.; Chen, X. L.; Yuan, J. W.;
Qu, L. B.; Duan, L. K.; Zhao, Y. F. Chem. Commun. 2014, 50, 2018−
2020. (j) Ambala, S.; Thatikonda, T.; Sharma, S.; Munagala, G.;
Yempalla, K. R.; Vishwakarma, R. A.; Singh, P. P. Org. Biomol. Chem.
2015, 13, 11341−11350. (k) Correa, A.; Fiser, B.; Gomez-Bengoa, E.
Chem. Commun. 2015, 51, 13365−13368. (l) Jin, J.; MacMillan, D. W.
Nature 2015, 525, 87−90. (m) Gutierrez-Bonet, A.; Remeur, C.;
Matsui, J. K.; Molander, G. A. J. Am. Chem. Soc. 2017, 139, 12251−
12258. (n) Li, Z.-l.; Jin, L.-k.; Cai, C. Org. Chem. Front. 2017, 4,
2039−2043. (o) Liu, W.; Yang, X.; Zhou, Z.-Z.; Li, C.-J. Chem. 2017,
2, 688−702. (p) McCallum, T.; Pitre, S. P.; Morin, M.; Scaiano, J. C.;
Barriault, L. Chem. Sci. 2017, 8, 7412−7418.
(5) (a) Xuan, J.; Xiao, W. J. Angew. Chem., Int. Ed. 2012, 51, 6828−
6838. (b) Dirocco, D. A.; Dykstra, K.; Krska, S.; Vachal, P.; Conway,
D. V.; Tudge, M. Angew. Chem., Int. Ed. 2014, 53, 4802−4806. (c) Jin,
J.; MacMillan, D. W. Nature 2015, 525, 87−90. (d) Li, G. X.;
Morales-Rivera, C. A.; Wang, Y.; Gao, F.; He, G.; Liu, P.; Chen, G.
Chem. Sci. 2016, 7, 6407−6412. (e) Cheng, W. M.; Shang, R.; Fu, M.
C.; Fu, Y. Chem. - Eur. J. 2017, 23, 2537−2541. (f) Garza-Sanchez, R.
A.; Tlahuext-Aca, A.; Tavakoli, G.; Glorius, F. ACS Catal. 2017, 7,
D
DOI: 10.1021/acs.orglett.9b00744
Org. Lett. XXXX, XXX, XXX−XXX