Visible-Light-Induced ortho-Selective Migration on Pyridyl Ring: Trifluoromethylative Pyridylation of Unactivated Alkenes

Article abstract of DOI:10.1002/anie.201912746

The photocatalyzed ortho-selective migration on a pyridyl ring has been achieved for the site-selective trifluoromethylative pyridylation of unactivated alkenes. The overall process is initiated by the selective addition of a CF₃ radical to the alkene to provide a nucleophilic alkyl radical intermediate, which enables an intramolecular endo addition exclusively to the ortho-position of the pyridinium salt. Both secondary and tertiary alkyl radicals are well-suited for addition to the C2-position of pyridinium salts to ultimately provide synthetically valuable C2-fluoroalkyl functionalized pyridines. Moreover, the method was successfully applied to the reaction with P-centered radicals. The utility of this transformation was further demonstrated by the late-stage functionalization of complex bioactive molecules.

Full text of DOI:10.1002/anie.201912746

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Accepted Article
Title: Visible-Light-Induced Remote Pyridyl ortho-Migration for
Trifluoromethylative Pyridylation of Unactivated Alkenes
Authors: Jinwon Jeon, Yu-Tao He, Sanghoon Shin, and Sungwoo
Hong
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912746
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10.1002/anie.201912746
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Photochemistry
Visible-Light-Induced Remote Pyridyl ortho-Migration for
Trifluoromethylative Pyridylation of Unactivated Alkenes**
Jinwon Jeon, a,b,† Yu-Tao He, b,a,† Sanghoon Shin,a,b and Sungwoo Hong*,b,a
Abstract: The photocatalyzed remote pyridyl ortho-migration has
been achieved for the site-selective trifluoromethylative pyridylation
of unactivated alkenes. The overall process is initiated by the
selective addition of a CF3 radical to the alkene to provide a
nucleophilic alkyl radical intermediate, which enables an
intramolecular endo addition to the exclusively ortho-position of the
pyridinium salt. Both secondary and tertiary alkyl radicals are well-
suited for addition to the C2-position of pyridinium salts to ultimately
provide synthetically valuable C2-fluoroalkyl functionalized
pyridines. Moreover, the method could be successfully applied to the
reaction with P-centered radicals. The utility of this transformation
was further demonstrated by the late-stage functionalization of
complex bioactive molecules.
observed in the trapping of N-alkoxypyridinium salts with secondary
alkyl radicals while tertiary alkyl radicals provide para(C4)-selective
pyridyl products (Scheme 1b).
To overcome the regioselectivity issues, we envisioned the
possibility of a controlled remote pyridyl ortho-migration to afford
C2-substituted pyridyl derivatives. In our design, an electrophilic CF3
radical would chemoselectively react with the alkene over a
pyridinium salt to provide an alkyl radical intermediate.[10] This
process sets the stage for remote ortho-migration if the resulting
tethered nucleophilic alkyl radical would engage in an intramolecular
endo addition onto the C2-position of pyridinium.[11] Subsequent
cleavage of the N–O bond delivers C2-fluoroalkylated pyridine
derivatives, as outlined in Scheme 1c.[12]
P
yridine is a prevalent structural motif present in numerous natural
products, pharmaceuticals, and functional materials.[1] Accordingly,
considerable effort has been directed towards expedient access to an
array of diverse pyridine structures. Among them, the photocatalyzed
chemical modification of the pyridine core has attracted much
attention.[2] However, the pyridine scaffold contains multiple reactive
sites, and site-selective functionalization in radical additions remains
a long-standing challenge.[3] Recently, the remote radical (hetero)aryl
migration strategy has proven to be a powerful tactic for the efficient
construction of structurally complex target molecules by providing a
new synthetic toolbox to deal with the elusive radical
transformations.[4] For example, Zhu and coworkers highlighted the
power of distal heteroaryl ipso-migration, leading to various chemical
transformations with an excellent functional group tolerance (Scheme
1a).[5] Despite the significant advances reported in the field thus far,
the scope of this platform is mainly limited to ipso-substitution
reactions or migration (i.e., the radical Smiles-Truce
rearrangement).[6] A new successful strategy that enables the
incorporation of pyridyl groups via remote ortho-migration would
significantly broaden the potential of remote functionalizations by
overriding the commonly observed preference for the site selectivity.
The potential of N-alkoxypyridinium salts has been demonstrated
in synthesis as easily accessible, versatile, and bench-stable pyridine
Scheme 1. Design plan: site-selective alkene trifluoromethyl-pyridylation via
remote ortho-migration.
surrogates.[7-9]
For
example,
cobalt-mediated
alkene
functionalization[8] and a remote C(sp3)–H pyridylation strategy via
1,5-hydrogen atom transfer[9] were successfully achieved using N-
alkoxyheteroarenium salts to afford various alkylpyridine products.
Unfortunately, only modest regioselectivity (C2 vs. C4) has been
To explore such a strategy, we designed N-alkenyloxypyridinium
salts as starting substrates for the difunctionalization of alkenes with
concomitant pyridyl group migration. Despite this inspiration, the
crucial challenge in this proposed approach may lie in the competitive
fragmentation of the N-alkoxypyridinium salts by single-electron
transfer (SET), leading to the formation of alkoxy radicals and
pyridines.[13] Therefore, a successful photocatalytic system using this
approach requires the selective generation of radicals to promote the
remote pyridyl ortho-migration, while minimizing the competing
process of N–O bond cleavage to prevent undesired reactions,
exemplified by alkoxy radical cyclization.[14] Herein, we report the
successful realization of a trifluoromethylative pyridylation of
alkenes through an ortho-selective migration strategy. Notably, this
strategy enables not only secondary, but also tertiary alkyl radicals to
react with the C2-position of pyridinium salts, overriding the
[]
J. Jeon, Dr. Y.-T. He, S. Shin, Prof. Dr. S. Hong
aDepartment of Chemistry, Korea Advanced Institute of
Science and Technology (KAIST), Daejeon 34141 (Republic
of Korea)
bCenter for Catalytic Hydrocarbon Functionalizations, Institute
for Basic Science (IBS), Daejeon 34141 (Republic of Korea)
E-mail: hongorg@kaist.ac.kr
[] Supporting information for this article is available on the
WWW under http://www.angewandte.org.
†
these authors contributed equally
1
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10.1002/anie.201912746
Angewandte Chemie International Edition
commonly observed preference for the C4-addition. Moreover, the
utility of the current method was further expanded by successfully
applying to the reaction with P-centered radicals.
also successfully applied to this method. The reactions with C3-
substituted pyridinium salts proceeded to afford the desired products
as mixtures of C2- and C6-alkylated pyridines (3r-3u), and none of
the para(C4)-substituted product was detected. These results indicate
that the products were formed via intramolecular remote pyridyl
ortho-migration. The installation of ortho(C2)-substituted pyridyl
groups at the quaternary centers is quite challenging because tertiary
radicals generally tend to add preferentially at the C4-position of
pyridinium salts to provide C4-pyridylated products.[8,9] Impressively,
this strategy was not limited to secondary alkyl radical intermediates
but could also be successfully extended to tertiary radicals to forge
quaternary C-centers bearing ortho-substituted pyridyl groups with
excellent C2-selectivity (3w-3z). In addition, the scope could be
expanded to a secondary alkoxy structure, which afforded the
corresponding secondary alcohol product 3v. We subsequently
investigated the utility of our method by exploring other heteroarenes.
Substrates containing bipyridine (3i), isoquinoline (3p) and quinoline
(3q) were well tolerated and provided the corresponding products.
In line with our hypothesis, the feasibility of the proposed remote
pyridyl ortho-migration was investigated using an N-
alkoxypyridinium salt 1a as a model substrate under blue LED
irradiation. In the absence of the CF3 radical source, illuminating a
photocatalyst such as 3-phosphonated quinolinone Q1[15] or Eosin Y
(EY) enables the formation of the alkoxy radical that triggers a
competing intramolecular alkoxy radical cyclization with an alkene
and subsequent pyridylation, leading to the formation of pyridine-
tethered tetrahydrofuran (see the Scheme S7 for details).[14] We next
examined the use of Langlois reagent 2 as a CF3 radical source via a
reductive quenching photocatalytic cycle.[16] To our delight, the
desired product 3a was formed through trifluoromethylative ortho-
selective pyridyl migration when Q1 was used as a photocatalyst
(entry 1, 33% yield), highlighting that the proposed overall process
can be achieved effectively. The results revealed that the
dissociation of the N−O bond in the N-alkoxypyridinium salt 1a could
be minimized in the presence of NaSO2CF3 (see the Scheme S7 for
details). A variety of CF3 radical sources were screened to obtain the
maximum yield, and the yield of 3a was significantly lower using
other CF3 radical sources (see Table S1 for details). Among the
solvent screened, DMSO was most efficient for this reaction.
Following extensive optimization, we found that the reaction
occurred even more efficiently by using EY (Ered = 0.83 V vs.
SCE)[17] as a photocatalyst (entry 8, 70% yield). In addition, we
surveyed the counterions of the pyridinium salt and found that TsO−
provided optimal yields (see Table S1 for details). A series of control
experiments confirmed that the reaction did not proceed in the
absence of photocatalyst or visible light (entries 9 and 10).
Table 2. Exploration of substrate scope.[a,b]
Table 1. Optimization of the reaction conditions.[a]
Entry
1
Photocatalyst
Solvent
DCM
Yield (%)[b]
33%
Q1
2
Q1
Q1
MeCN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
59%
3
66%
4
fac-Ir(ppy)3
[IrdF(CF3)ppy2bpy]PF6
Ru(phen)3Cl2∙xH2O
Mes-Acr+
Eosin Y
60%
5
58%
6
59%
7
24%
8
70%
9[c]
10
11[d]
Eosin Y
0%
-
trace
trace
Eosin Y
[a] Reactions were performed with mixtures of 1a (0.2 mmol), 2 (0.4 mmol), and
PC (2.5 mol%) in solvent (2.0 mL), irradiating with a blue LED (440 nm, 8.5 W)
under N2 at rt for 12 h. [b] The yields determined by 19F crude NMR. [c] The
reaction was carried out in the dark. [d] TEMPO (2,2,6,6-tetramethylpiperidine-1-
oxyl, 2.0 equiv) was added.
Having identified the optimized reaction conditions, we
investigated the generality of this method as illustrated in Table 2. A
wide range of pyridinium substrates bearing various functional
groups such as methyl, ester, and substituted aryl groups (methoxy,
bromo, fluoro, and trifluoromethyl) at the C2-position are selectively
alkylated at the C2-position of pyridine scaffolds to afford the desired
products (3a-3h). Substrates with C4-substituents such as methyl (3j),
trifluoromethyl (3k), ketone (3l), phenyl (3m) and ester (3n) were
[a] Reactions were performed with 1 (0.2 mmol), 2 (0.4 mmol), and EY (2.5
mol%) in DMSO (2.0 mL), irradiating with a blue LED (440 nm, 8.5 W) under
N2 at rt for 12 h. [b] Isolated yields. [c] NaSO2CF3 (5 equiv) was used. [d] The
reaction was conducted for 6 h.
2
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10.1002/anie.201912746
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To further underline the broad applicability, we attempted late-
stage modifications of pharmaceutically relevant molecules. As
depicted in Scheme 2, structurally complex substrates derived from
pyridine-based drugs with various functional groups such as
vismodegib, roflumilast, pyriproxyfen, and menthol were subjected
to the optimized reaction conditions, and C2-fluoroalkyl
functionalized pyridines 3aa-3ad were formed with good functional
group tolerance. Therefore, this remote pyridyl ortho-migration
strategy represents an attractive synthetic tool for rapidly accessing a
wide range of valuable C2-fluoroalkyl functionalized pyridine motifs
with potential applications in the construction of compound libraries
and the late-stage functionalization of medicinally relevant
compounds.
Scheme 3. Control experiments.
To better understand the migration pathway, a series of substrates
containing different alkyl chain lengths were investigated (Table 3).
The desired products could be successfully obtained from the
substrates (n = 2, 3, 4), indicating that the ortho-migration favorably
proceeded via six-, seven-, and eight-endo addition to afford the
corresponding products 3ae, 3n, and 3af. It is noteworthy to
emphasize the breakthrough in long-distance radical migration,
especially via an eight-membered cyclic transition state. Moreover,
this method could be extended to the interesting examples of N-
amidopyridinium substrates bearing sulfonamide (3ag and 3ah) or
carboxamide chains (3ai and 3aj), effectively yielding the
corresponding products.
Table 3. Exploration of the scope of alkyl chain
Scheme 2. Site-selective late-stage functionalization of complex molecules via
remote ortho-migration[a]
[a] Ru(phen)3Cl2∙xH2O (2.5 mol%) and NaSO2CF3 (5 equiv) were used. [b] Eosin
Y (2.5 mol%) and NaSO2CF3 (5 equiv) were used.
To gain insight into the reaction mechanism, we conducted a series
of control experiments (Scheme 3). First, the Stern-Volmer plots of
fluorescence data exhibit that the EY* excited state is quenched by
both the Langlois reagent and N-alkenyloxypyridinium. The
quenching was found to be linearly dependent on the concentration of
the Langlois reagent and pyridinium salt (see the Figure S3 and S4
for details). Kinetic isotope effect (KIE) experiments were carried out
with substrate d5-1a, in which the KH/KD ratio was found to be 1.1,
indicating that the deprotonation step is not significantly involved in
a rate-determining step. When a mixture of pyridinium salt 1a and 2-
phenylpyridine (or 2-phenylpyridine N-oxide) were subjected to the
standard reaction conditions, only C2-alkylated pyridine 3a was
observed, showing that alkylation occurred only at pyridinium salt
(Scheme 3b). To better understand remote ortho-migration pathway,
the 2,6-dimethyl substituted pyridinium salt 1ak was used as a
substrate. Notably, no desired product was detected (Scheme 3c),
which indicates that intramolecular radical addition to the C2 position
of the pyridinium salt is involved to provide the products.
Additionally, we noticed that the reaction of a substrate 1al gave a
mixture of products (C2/C4 = 1:1), implying that a long chain linker
is required to access to the C4 position of the pyridine core in an
intramolecular fashion (Scheme 3d).
[a] NaSO2CF3 (5 equiv) was used. [b] MsO- was used for 1 instead of TsO-
We next turned our attention to explore P-centered radicals, as
illustrated in Table 4. To our delight, phosphinoyl radicals
preferentially react with the alkene moiety of N-alkoxypyridinium
salts, enabling remote pyridyl ortho-migration to install pyridyl and
phosphorus groups. A series of pyridinium salts bearing various
functional groups, such as ester (5b), methyl (5c), 3-bromophenyl
(5d), and 4-trifluoromethylphenyl (5g), were successfully employed
3
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10.1002/anie.201912746
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to generate the corresponding products. In a similar fashion, the
reaction was further extended to tertiary radicals to construct
quaternary carbon center (5e-5g). The scope of the phosphine oxides
was next evaluated and worked well to furnish the corresponding
products 5h and 5i.
unprecedented remote pyridyl ortho-migration to afford synthetically
valuable C2-fluoroalkyl functionalized pyridines. This strategy
features a photoredox radical process involving a sequential
formation of a CF3 radical, the addition of the CF3 radical to the
alkene, and an intramolecular endo addition to the ortho-position of
the pyridinium salt. Notably, this method could be successfully
extended to tertiary radicals to forge quaternary C-centers bearing
ortho-substituted pyridyl groups with excellent C2-selectivity.
Moreover, the method could be successfully applied to the reaction
with P-centered radicals in these systems.
Table 4. Scope of remote ortho-migration using P-centered radicals[a,b]
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Acknowledgements
This research was supported financially by Institute for Basic Science
(IBS-R010-A2). We thank Dr. Dongwook Kim (IBS) for XRD analysis.
Conflict of interest
The authors declare no conflict of interest.
Keywords: remote ortho-migration • trifluoromethylation • pyridylation
• photocatalysis • N-alkoxypyridinium salt
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Figure 1. Plausible reaction mechanism
In
summary,
a
visible-light-induced
site-selective
trifluoromethylative pyridylation of alkenes has been achieved via
4
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5
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Photochemistry
Jinwon Jeon, Yu-Tao He, Sanghoon
Shin, and Sungwoo Hong __________
Page – Page
Visible-Light-Induced Remote Pyridyl
ortho-Migration for Trifluoromethylative
Pyridylation of Unactivated Alkenes
Remote migration: The photocatalyzed remote pyridyl ortho-migration has been achieved for
the site-selective trifluoromethylative pyridylation of unactivated alkenes under mild reaction
conditions. Notably, this method could be successfully extended to tertiary radicals to forge
quaternary C-centers bearing C2-substituted pyridyl groups, overriding the commonly observed
preference for the C4-addition.
6
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