Visible Light-Promoted Aliphatic C-H Arylation Using Selectfluor as a Hydrogen Atom Transfer Reagent

Article abstract of DOI:10.1021/acs.orglett.9b01635

A mild, practical method for direct arylation of unactivated C(sp³)-H bonds with heteroarenes has been achieved via photochemistry. Selectfluor is used as a hydrogen atom transfer reagent under visible light irradiation. A diverse range of chem

Full text of DOI:10.1021/acs.orglett.9b01635

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible Light-Promoted Aliphatic C−H Arylation Using Selectfluor as
a Hydrogen Atom Transfer Reagent
Hong Zhao and Jian Jin*
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai
200032, China
S
* Supporting Information
ABSTRACT: A mild, practical method for direct arylation of unactivated C(sp3)−H bonds with heteroarenes has been
achieved via photochemistry. Selectfluor is used as a hydrogen atom transfer reagent under visible light irradiation. A diverse
range of chemical feedstocks, such as alkanes, ketones, esters, and ethers, and complex molecules readily undergo intermolecular
C(sp3)−C(sp2) bond formation. Moreover, a broad array of heteroarenes, including pharmaceutically useful scaffolds, can be
alkylated effectively by the protocol presented here.
attention within modern drug discovery.8 Prefunctionalized
liphatic C−H bonds are the most abundant moiety but
Aare among the least reactive in organic chemistry. The reagents were typically employed as the alkyl radical
precursors.9−18 In a few cases, alkanes were coupled with
heteroarenes directly via a dual C−H functionalization way,
which represent a more ideal approach to molecule
construction.19 Herein, we describe a mild, practical method
for the aliphatic C−H arylation using Selectfluor as a HAT
reagent enabled by visible light.
direct functionalization of sp3 C−H bonds offers new strategies
for constructing organic molecules rapidly.1 Such reactions
could convert bulk chemical feedstocks such as light alkanes to
higher-value products and also could introduce more
functionality into natural products or pharmaceuticals at late
stages.2 The last two decades witnessed impressive progress in
the development of sp3 C−H functionalization techniques,
which could be categorized into three major types: hydrogen
atom transfer (HAT), transition metal-catalyzed C−H
activation, and carbene/nitrene insertion.3 Distinct from the
other two types, HAT possesses a radical mechanism. In this
pathway, a hydrogen atom is abstracted from the C−H bond
by a highly reactive radical species, such as a nitrogen, oxygen,
sulfur, or chlorine radical.4 The resulting alkyl radical could
then be trapped to form a new C−C or C−X bond (e.g., X = F,
N, or O). By accessing open-shell species, the unique HAT
strategy enables organic transformations that cannot be
accessed through polar pathways. The groups of Baran and
Lectka reported the first examples of Selectfluor as a hydrogen
atom transfer reagent.5 Intensive mechanistic experiments
suggested that the single-electron transfer (SET) event
between the Cu catalyst and Selectfluor furnished an N-radical
cation, which was responsible for the hydrogen atom transfer
from the alkane substrates.6
We proposed a radical chain mechanism for aliphatic C−H
arylation (Scheme 1). During the initial stage, Selectfluor 1 was
activated by visible light irradiation to provide N-radical cation
2. We anticipated that electrophilic N-radical cation 2 would
abstract a hydrogen atom from alkane 3 to provide ammonium
ion 4 and alkyl radical 5. Once generated, nucleophilic alkyl
radical 5 would be intercepted by protonated electron-deficient
heteroarene 6 at a rate approaching that of diffusion, although
in the presence of Selectfluor, to furnish aminyl radical cation
7. Deprotonation of the acidic α-C−H bond of 7 would form
α-amino radical 8. The following single-electron transfer from
intermediate 8 to Selectfluor would readily occur and, after
rearomatization, furnish the desired alkyl−aryl coupling
product 9 while regenerating N-radical cation 2.
We began our investigation into this aliphatic C−H arylation
by subjecting lepidine and cyclohexane to visible light
irradiation (Kessil 40 W 427 nm light-emitting diode) with
Selectfluor for 16 h (Table 1). To our delight, it afforded the
desired aryl−alkyl product 11 in 14% yield (entry 1).
Markedly, trifluoroacetic acid (TFA) offered an increase in
In medicinal chemistry, the alkyl groups have magic effects
on drug metabolism and pharmacokinetic profiles.7 There is a
growing demand for the direct introduction of alkyl groups to
heteroarenes. The Minisci reaction, featuring a direct addition
of the alkyl radical to heteroarenes, has attracted a great deal of
Received: May 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01635
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Possible Mechanism for sp3 C−H Arylation
was well tolerated because the reaction could proceed robustly
without nitrogen purging (entry 12). The addition of free
radical scavengers could shut down the aliphatic C−H
arylation completely, which indicated a radical mechanism
(entry 13 and the Supporting Information).
With the optimal conditions in hand, we began to evaluate
the generality of this aliphatic C−H arylation transformation.
As shown in Scheme 2, a diverse range of heteroarenes were
alkylated with cyclohexane effectively under the identified
conditions A (with HCl in acetone) and B (with TFA in
acetonitrile). Quinolines with a variety of substituents (such as
methyl, methoxy, phenyl, and chloro groups) were function-
alized in good to excellent yields (11−17, 71−89% yields).
Isoquinolines were amenable to the protocol (18−23, 49−
83% yields), as well as phenanthridines, phthalazines, quinoxa-
lines, and quinazolines (24−30, 52−87% yields). Notably,
pyridine derivatives could be alkylated in good yields (31−36,
38−78% yields). Substituted pyrimidines provided the
alkylated products in useful yields, including those with free
amine substituents (37−42, 30−88% yields). Pyridazines and
pyrazines were competent substrates for the aliphatic C−H
arylation protocol (43−49, 51−85% yields). It is important to
note that a variety of five-membered heteroarenes performed
well in this reaction. (Benzo)thiazoles reacted at the C2
position regioselectively (50−52, 38−85% yields) as well as
benzoimidazoles (53−55, 26−50% yields). Imidazo[1,2-b]-
pyridazines underwent aryl−alkyl coupling smoothly (56 and
57, 80% and 78% yields, respectively). 1H-Pyrazolo[3,4-
b]pyridine was successfully used to deliver mono- and bis-
alkylated products in 77% total yield (58). Moreover, the
aliphatic C−H arylation could be applied to purine derivatives
(59−61, 23−78% yields). Finally, it turned out that this
photocatalyst-free protocol was compatible with the late stage
functionalization of agrochemical and pharmaceutical agents
(62 and 63, 87% and 51% yields, respectively).
Next, we explored the scope of the C−H arylation method
with regard to the aliphatic C−H component (Scheme 3).
Including but not limited to alkanes, a broad array of organic
frameworks with sp3 C−H bonds readily participated in the
C−H arylation reaction. While simple cycloalkanes afforded a
single arylation product for each case (64−67, 67−90%
yields), substituted cycloalkanes might be arylated at different
sites to afford regioisomers. More specifically, trans- and cis-
1,4-dimethylcyclohexanes could react at either secondary or
tertiary C−H bonds (68 and 69, 60% yield each). Not
surprisingly, quaternary products 68b and 69b turned out to
be the same compound because they had exactly the same alkyl
radical intermediate. It is noted that norbornane reacted at the
ethylene bridge only while the other strained C−H bonds were
left untouched (70, 87% yield). Acyclic alkanes were likewise
successful in the protocol with a greater-than-statistical
preference for position C2 due to the bond strength and
steric effect (71 and 72, 70% and 61% yields, respectively).
Imparted by the electrophilic nature of N-radical cation 2,
ketones and esters were functionalized distal to the electron-
withdrawing groups (73−77, 50−81% yields). Furthermore,
various cyclic ethers were regioselectively arylated in good to
high yields at the α-C−H position (78−83, 47−86% yields).20
As an exception, the arylation of bridged ether 1,4-
epoxycyclohexane occurred only on the ethylene bridge but
the bridgehead strained α-C−H bonds were left out (84, 90%
yield). Due to the electron-withdrawing effect, the α-oxy
position of propyl acetate was no longer the dominant site for
a
Table 1. Optimization of the sp3 C−H Arylation
entry
solvent
acid
wavelength
yield (%)
1
2
3
4
5
6
7
8
9
10
acetone
acetone
acetone
acetonitrile
acetonitrile
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
none
427 nm
427 nm
427 nm
427 nm
427 nm
440 nm
456 nm
467 nm
dark
dark, 50 °C
427 nm
427 nm
427 nm
14
33
91
92
84
70
27
39
0
1 equiv of TFA
1 equiv of HCl
2 equiv of TFA
2 equiv of HCl
1 equiv of HCl
1 equiv of HCl
1 equiv of HCl
1 equiv of HCl
1 equiv of HCl
1 equiv of HCl
1 equiv of HCl
1 equiv of HCl
0
b
11
78
90
0
c
12
d
13
a
Yields determined by 1H NMR using 1,3-benzodioxole as the
internal standard. One equivalent of Selectfluor used. Reaction
performed without N2 purging. One and one-half equivalents of
b
c
d
TEMPO added.
yield (entry 2, 33%), which was consistent with most Minisci-
type reactions by making the heteroarene substrates more
electron-deficient. Changing the acid to concentrated hydro-
chloric acid (HCl) dramatically improved the yield to 91%
(entry 3). An examination of common solvents showed that
the reaction could also be carried out efficiently in acetonitrile
with TFA as the superior acid additive (entries 4 and 5).
Visible light with longer wavelengths could promote this C−H
arylation, although in decreased yields (entries 6−8). Indeed,
light plays a critical role in the reaction. There was no desired
product in the absence of light, even upon heating to 50 °C
(entries 9 and 10). When the equivalent of Selectfluor was
reduced to 1, the C−H arylation protocol still could provide a
78% yield of the alkyl−aryl product (entry 11), while an only
minimal amount of fluorocyclohexane was detected by 19F
NMR. It is worth mentioning that a small amount of oxygen
B
DOI: 10.1021/acs.orglett.9b01635
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Organic Letters
Letter
a
Scheme 2. Scope of the Heteroarenes
a
Isolated yields. See the Supporting Information for experimental details.
the arylation, and other regioisomers were also obtained (85,
52% yield). Toward that end, Sclareolide, a sesquiterpene
lactone natural product, was subjected to the reaction
conditions for late stage functionalization (86, 56% yield),
C
DOI: 10.1021/acs.orglett.9b01635
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Scope of the Aliphatic C−H Components
a
Isolated yields. See the Supporting Information for experimental details.
showcasing the preparative potential of the arylation protocol
toward the rapid construction of molecular complexity.
In conclusion, we have developed a mild and operationally
simple method for the construction of C(sp3)−C(sp2) bonds
from alkanes and heteroarenes.21 Aliphatic C−H arylation
shows a broad scope with respect to both alkane and
heteroarene substrates. Remarkably, the results presented
above demonstrate that Selectfluor can be enabled by visible
light as a powerful hydrogen atom transfer reagent to convert
unactivated alkanes to high-value products in the context of
late stage functionalization of medicinal agents. As such, we
expect that the pharmaceutical sector will find this new
transformation to be of utility in medicinal chemistry studies.
D
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(5) (a) Michaudel, Q.; Thevenet, D.; Baran, P. S. Intermolecular
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01635.
■
S
(6) Pitts, C. R.; Bloom, S.; Woltornist, R.; Auvenshine, D. J.;
Ryzhkov, L. R.; Siegler, M. A.; Lectka, T. Direct, Catalytic
Monofluorination of sp3 C-H Bonds: A Radical-Based Mechanism
with Ionic Selectivity. J. Am. Chem. Soc. 2014, 136, 9780−9791.
General experimental procedures, characterization data,
spectra for all key compounds, and mechanistic studies
(PDF)
(7) (a) Barreiro, E. J.; Ku
Methylation Effect in Medicinal Chemistry. Chem. Rev. 2011, 111,
̈
mmerle, A. E.; Fraga, C. A. M. The
AUTHOR INFORMATION
■
̈
5215−5246. (b) Schonherr, H.; Cernak, T. Profound Methyl Effects
Corresponding Author
*E-mail: jjin@sioc.ac.cn.
ORCID
in Drug Discovery and a Call for New C-H Methylation Reactions.
Angew. Chem., Int. Ed. 2013, 52, 12256−12267.
(8) Duncton, M. A. J. Minisci Reactions: Versatile CH-
Functionalizations for Medicinal Chemists. MedChemComm 2011,
2, 1135−1161.
Hong Zhao: 0000-0002-5246-5817
Jian Jin: 0000-0001-9685-3355
Notes
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Org. Lett. 2016, 18, 3738−3741. (c) Cheng, W.-M.; Shang, R.; Fu, Y.
Photoredox/Brønsted Acid Co-Catalysis Enabling Decarboxylative
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the “Thousand Plan” Youth
program, the Chinese Academy of Sciences, the Shanghai
Institute of Organic Chemistry, and the CAS Key Laboratory
of Synthetic Chemistry of Natural Substances.
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F
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